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APPROACH TO A PATIENT WITH SEVERE BONE PAIN
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APPROACH TO A PATIENT WITH
SEVERE BONE PAIN
Medical Research in Biblical Times

from the Viewpoint
of Contemporary Perspective
Liubov Ben-Nun
Liubov Ben-Nun
Professor Emeritus
Faculty of Health Sciences, Dept. of Family Medicine
Beer-Sheva, Israel
People have suffered from chronic pain, which can be associated

with various diseases, for thousands of years. Is chronic pain
described in the Bible? If so, who suffered from chronic pain? What is
the most likely cause of pain? What is the classification of pain? What
are the assessment tools? What are the psychosocial dimensions of
pain? Did any other comorbid disease afflict the sufferer? How is
chronic pain related to the family? What is the contemporary
epidemiology of chronic pain? What is mechanism of chronic pain?
What is the contemporary approach to non-malignant and malignant
chronic pain?
This research deals with verses relating to pain, evaluating the pain
in one biblical character from the viewpoint of contemporary
medicine. The research also evaluates the influence of pain on various
health and psychosocial dimensions in humans.
For the purpose of this research, the approaches to non-malignant
and malignant pain are described separately, although some strategies
for example, classification of pain, assessment tools, and management
overlap in non-malignant and malignant pain.
NOT FOR SALE

APPROACH TO A PATIENT WITH SEVERE
BONE PAIN

Liubov Ben-Nun
Professor Emertus
Faculty of Health Sciences, Dept. of Family Medicine,
Beer-Sheva, Israel
Published By B.N. Publications House, Israelin Israel

First 2013
Fax: +(972) 8 6883376 Mobile 050 5971592

E-Mail: L-bennun@smile.net.il
Graphics and Cover: Ilana Ben-Nun
All rights reserved
Distributed Worldwide
NOT FOR SALE 2013

`
Biblical Exegesis
It should be noted and stressed that this research is
in no way concerned with a discussion of any
interpretations of the Bible by the great commentators
such as Rambam, the sages of the Talmud and the
Mishnah, or interpretation based on knowledge of the
ancient world found in Julius Preuss’ book, Medicine
in the Talmud, as translated by Ferrer Rosner. The
research is based solely on the actual words on the
verses of the Bible.
CONTENTS
MY VIEW 1
PREFACE 2
FOREWORD 3
INTRODUCTION 6
THE MEDICAL RECORD OF KING DAVID 11
DEFINITION OF PAIN 19
CLASSIFICATION OF PAIN 20
NON-MALIGNANT PAIN 25
EPIDEMIOLOGY OF CHRONIC PAIN
MECHANISMS OF CHRONIC PAIN
CHARACTERISTICS OF NEUROPATHIC PAIN
ASSESSMENT TOOLS
CLINICAL APPLICABILTY
CATASTROPHIZING RESPONSE TO PAIN
GENDER DIFFERENCES IN THE PERCEPTION OF PAIN
SPECIAL CONSIDERATION IN THE ELDERLY
QUALITY OF LIFE
PSYCHOSOCIAL DIMENSIONS OF CHRONIC PAIN
RELIGION/SPIRITUALITY AND CHRONIC PAIN
PATIENT WITH CHRONIC PAIN AND THE FAMILY
PROGNOSTIC FACTORS
APPROACH TO A PATIENT WITH NON-MALIGNANT PAIN 127

NON-PHARMACOLOGICAL INTERVENTIONS
COPING STRATEGIES
PSYCHOLOGICAL INTERVENTIONS
SELF-MANAGEMENT INTERVENTIONS
COMPLIMENTARY AND ALTERNATIVE MEDICINE
MUSIC THERAPY
PHARMACOTHERAPY
OPIOID ANALGETICS
OPIOID ABUSE
ADJUVANT MEDICATIONS
CAPSAICIN
ANTIDEPRESSANTS
ANTIPSYCHOTICS
ANTIEPILEPTIC DRUGS
CANNABICOIDS
NEUROPATHIC PAIN
NEUROMODULATION THERAPY
NEUROSURGICAL TREATMENT
NON-ADHERENCE WITH MEDICATIONS
READINESS TO CHANGE
THE DISEASES OF THE BONES
OSTEOPOROSIS
RISK FACTORS FOR MALE OSTEOPOROSIS
TYPES
INVOLUTIONAL OSTEOPOROSIS
SECONDARY OSTEOPOROSIS
CLINICAL CHARACTERISTICS
DISEASES ASSOCIATED WITH SECONDARY
OSTEOPOROSIS
CUSHING SYNDROME
THYROID DISEASES
ACROMEGALY
HYPOGONADISM
HYPERPARATHYROIDISM
PAGET'S DISEASE
GASTROINTESTINAL DISEASES
LACTOSE INTOLERANCE
INFLAMMATORY BOWEL DISEASES
CELIAC DISEASE
WHIPPLE DISEASE
PRIMARY BILARY CIRRHOSIS
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
OSTEOARTHRITIS
RHEUMATOID ARTHRITIS
MALNUTRITION/UNDERNUTRITION
MEDICATIONS
IDIOPATHIC OSTEOPOROSIS
MALIGNANCY
349
EPIDEMIOLOGY
STAGING AND GRADING
ASSESSMENT OF CANCER PAIN
CANCER AND COMORBID CHRONIC DISEASES
CANCER-RELATED VISITS
HEMATOLOGICAL MALIGNANCIES 385

IMMUNOSECRETORY DISORDERS
MULTIPLE MYELOMA
MONOCLONAL GAMMOPATHY OF UNDETERMINED
SIGNIFICANCE
SMOLDERING MYELOMA
WALDENSTROM'S MACROGLOBULINEMIA
HEAVY CHAIN DISEASES
OSTEOMYELOFIBROSIS
SMALL LYMPHOCYTE CELL DISORDERS
CHRONIC LYMPHOCYTIC LEUKEMIA
SMALL LYMPHOCYTIC LYMPHOMA
LYMPHOPLASMACYTIC LYMPHOMA/
AMYLOIDOSIS
PLASMACYTOMA
RESPIRATORY SYSTEM MALIGNANCIES 447

LARYNGEAL CARCINOMA
TRACHEAL CANCER
BROCHOGENIC CARCINOMA
LUNG CANCER
GASTROINTESTINAL TRACT 473

ESOPHAGEAL CANCER
GASTRIC CARCINOMA
COLORECTAL CANCER
HEPATOCELLULAR CARCINOMA
PANCREAS CANCER
UROLOGICAL MALIGNANCIES 525

RENAL CELL CARCINOMA
UROTHELIAL CANCER
URINARY BLADDER CANCER
PROSTATE CANCER
HEMATURIA IN PRIMARY CARE
URINARY TRACT EVALUATION
BONE TUMORS 580

GIANT CELL TUMOR
OTHER BONE TUMORS
METASTATIC BONE DISEASE 606

CLASSIFICATION OF CANCER RELATED PAIN
CHARACTERISTICS OF BREAKTHROUGH PAIN
MECHANISMS OF METASTATIC BONE DISEASE
MECHANISM OF BONE CANCER PAIN
CLINICAL PRESENTATION
HAS THIS PATIENT CANCER?
CHARACTERISTICS OF CANCER PAIN
QUALITY OF LIFE
PSYCHOLOGICAL DISTRESS
CANCER AND FAMILY/INFORMAL CAREGIVERS
NEUROPATHIC PAIN 693

CHEMOTHERAPY INDUCED NEUROPATHY
PLATINUM AGENTS
CISPLATIN
CARBOPLATIN
OXALIPLATIN
MICROTUBULE-TARGETING AGENTS
VINCRISTINE
TAXANES
PACLITAXEL
EPOTHILONES
ERIBULIN
THALIDOMIDE
PROTEASOME INHIBITORS
BORTEZOMIB/CARFILZOMIB
SURAMIN
NEUROTOXICITY OF RADIATION THERAPY
APPROACH TO A PATIENT WITH CANCER PAIN 759
NON-PHARMACOLOGICAL THERAPY 761

PSYCHOSOCIAL INTERVENTION
HYPNOTHERAPY
COGNITIVE BEHAVIORAL THERAPY
EXERCISE INTERVENTION
DANCE/MOVEMENT THERAPY
MUSIC THERAPY
TRANSCUTANEOUS/PERCUTANEOUS ELECTRIC NERVE
STIMULATIONS
MASSAGE THERAPY
ACUPUNCTURE
PHARMACOLOGICAL THERAPY 800

ANALGETIC LADDER
NON-OPIOID ANALGETICS
NONSTEROIDAL ANTIINFLAMMATORY DRUGS/
ACETAMINOPHEN
OPIOID ANALGETIC AGENTS
TRAMADOL
CODEINE
HYDROCODONE
OXYCODONE
MORPHINE
FENTANYL
HYDROMORPHONE
BUPRENORPHINE
METHADONE
OTHER OPIOIDS
LEVORPHANOL
ADVERSE OPIOID EFFECTS
OPIOID EFFECTIVENESS FOR PAIN CONTROL
COMBINED PHARMACOTHERAPY
CONSENSUS STATEMENT
CANCER PAIN IN OPIOID ADDICTED PATIENTS
TREATMENT OF NEUROPATHIC PAIN
NMDA RECEPTOR ANTAGONISTS
KETAMINE
AMANTADINE/MEMANTINE
ANTIDEPRESSANTS
ANTIEPILEPTIC AGENTS
ANTIPSYCHOTICS
PSYCHOSTIMULANTS
BIPHOSPHONATES
CALCITONIN
CORTICOSTEROIDS
BACLOFEN
SOMATOSTATIN
ANTIHISTAMINE MEDICATIONS
SYSTEMIC LOCAL ANESTHETICS
CAPSAICIN
CLONIDINE
CANNABINOIDS
OTHER TREATMENT MODALITIES 930

RADIOTHERAPY
STRONTIUM-89 CHLORIDE
NERVE BLOCKS
INVASIVE STIMULATION THERAPIES
EPIDURAL ANALGESIA
INTRATHECAL NEUROLYTIC BLOCKS
INTRA-CEREBRO-VENTRICULAR MORPHINE
SURGERY FOR PATHOLOGICAL FRACTURE
NEUROSURGERY
DREZOTOMY
MANAGEMENT OF CANCER PAIN IN THE ELDERLY 983

UNNECESSARY SUFFERING 991
BARRIES TO CANCER PAIN MANAGEMENT 995
MULTIDISCIPLINARY APPROACH 1011
SUMMARY 1018
CONCLUDING REMARKS 1020
ABBREVIATIONS 1023
1
L. Ben-Nun Approach to a patient with pain
MY VIEW
MEDICINE IN THE BIBLE

AS A RESEARCH CHALLENGE
This is a voyage along the well-trodden routes of contemporary
medicine to the paths of the Bible, from the time of the first man to the
period of the People of Israel. It covers the connection between body
and soul, and the unbroken link between our earliest ancestors,
accompanied by spiritual yearning and ourselves. Through the verses
of the Bible flows a powerful stream of ideas for medical research
combined with study of our roots and the ancient texts.
It would not be too adventurous to state that if there is one book in
the world that all Jews are proud of, that is the Book of Books, the
greatest classic among all literary works, whose original language is
not Greek or Latin, but the Hebrew that I and other Israelis speak
every day, our mother tongue, the language of Eliezer Ben Yehuda.
The Bible exists as evidence in the Book of Books, open to all
humankind. For thousands of years it has been placed before us, still
as fresh as before, the history of peoples who have disappeared and of
the Jewish people, which has survived with its Holy Text that has
been translated into hundreds of languages and dialects, and remains
our eternal taboo.
Many people ask me about the connection between the Bible and
medical science. My reply is simple: the roots of science are buried
deep in the biblical period and I am just the archeologist and medical
researcher.
This scientific medical journey to the earliest roots of the nation in
the Bible has been and remains moving, exciting and enjoyable. It has
created a kind of meeting in my mind between the present and those
ancient times, through examining events frozen in time.
Sometimes it is important to stop, to look back a little. In real
time, it is hard to study every detail, because time is passing as they
appear. However, when we look back we can freeze the picture and
examine every detail, see many events that we missed during that
fraction of a second when they occurred.
The Book of Books, the Bible, is not just the identity card of the
Jewish, but an essential source for the whole world.
2
PREFACE
The purpose of this research is to analyze the medical situations
and conditions referred to in the Bible, as we are dealing with a
contemporary medical record.
These are scientific medical studies incorporating verses from the

Bible, without no interpretation or historical descriptions of places.
Fundamentally, this Research is constructed purely from an

examination of passages from the Bible, exactly as written.
The research is part of a long series of published studies on the

subject of biblical medicine from a modern medical perspective.
This is not a laboratory research. The Research is built entirely on

a secular foundation. With due to respects to people faith, this
Research takes a modern look at medical practices. Each to his own
beliefs.
3
FOREWORD
Pain means suffering. It has plagued humanity for as long as
humans have existed (1). Even in contemporary days, pain is an
enormous problem globally. Nevertheless, the problem of pain has
primarily been regarded as a medical problem and has been little
addressed by the field of public health. Despite the ubiquity of pain,
whether acute, chronic or intermittent, public health scholars and
practitioners have not addressed this issue as a public health problem.
The importance of viewing pain through a public health lens allows to
understand pain as a multifaceted, interdisciplinary problem for which
many of the causes are the social determinants of health. Addressing
pain as a global public health issue will aid in priority setting and
formulating public health policy to address this problem, which, like
most other chronic non-communicable diseases, is growing both in
absolute numbers and in its inequitable distribution across the globe.
The prevalence, incidence, and vast social and health consequences of
global pain requires that the public health community will give
attention to this issue. Doing so will mean that health care providers
and public health professionals will have a more comprehensive
understanding of pain and the appropriate public health and social
policy responses to this problem (2).
An estimated 10-55% of all adults suffer from chronic pain. This
pain that has detrimental effects on physical and mental health, daily
activities, family relationships, employment, and economic well-being
of the sufferers and family caregivers is a widespread public health
issue (3,4). Chronic pain is a multifactorial condition, caused by the
complex interplay of nociceptive, neuropathic or mixed pathogenic
mechanisms. Chronic pain is associated with specific and non-specific
medical conditions such as cancer, HIV/AIDS, RA, fibromyalgia,
osteoarthritis, LBP and spinal stenosis. Evaluation of chronic pain
requires a clear understanding of the nature of the pain and its
underlying pathophysiology. Adequate assessment of pain, using
validated tools, is an essential prerequisite of successful pain
management. Unidimensional scales are useful for the measurement
of pain intensity, while multidimensional scales measure both pain
intensity and the extent to which pain interferes with life activity and
emotional functioning. Patients should be reassessed and followed up
in order to monitor progress and measure improvements in pain (3).
There is growing recognition that persistent pain is a complex and
multidimensional experience stemming from the interrelationship
between biological, psychological, social and spiritual factors.
4
Chronic pain patients use a number of cognitive and behavioral

strategies to cope with the pain, including religious/spiritual forms,
such as prayer and seeking spiritual support to manage their pain (5).
A constructive approach to an ethics of pain medicine that is
animated by a core philosophy of medicine as specific and focal to the
uniqueness of pain, the pain patient, and the pain clinician is proposed.
This philosophy of pain medicine 1) defines the nature of pain, 2)
recognizes the variability and subjectivity of its expression in the pain
patient, 3) acknowledges and explicates the vulnerabilities rendered
by pain, 4) describes the inherent characteristics and asymmetries of
the patient-clinician relationship, and 5) defines the ends of pain care.
These ends entail the provision of "good" care links in the epistemic
domains of pain medicine to its anthropologic focus and ethically
sound conduct. An ethics of pain medicine should define the
profession and sustain the practice. Facts establish (the need for)
certain duties and rules of pain medicine. These emphasize the duty to
self and others, and an appreciation for relational asymmetries, and
dictates that those who enter the profession of pain medicine should
be generally aligned with this set of core practical and ethical
affirmations and duties. To maintain contemporary relevance, rules,
duties, and moral reasoning must adjust to changing conditions.
Applied ethics shape the practice within the infrastructure of core
rules and duties of the profession. An applied ethics of pain medicine
must be pragmatic, and therefore, cannot rely upon or be reduced to a
single principle or ethical system. A number of ethical systems (such
as the use of principles, utilitarianism, casuistry, and feminist/care
orientations) all have relative merit and potential limitations. The
obligation to recognize ethical issues and utilize knowledge to best
reflect appropriate moral values rest upon the clinician as a moral
agent, and therefore advocate the relevance and importance of an
agent-based virtue ethics, recognizing that virtue ethics cannot stand
alone, but must be employed within a larger system of ethical
intuition. Yet, if such a structure of normative and applied ethics is to
be realized, moral consideration must guide evaluation of the current
system of pain care, and provide direction for the development and
implementation of therapeutically and ethically integrative pain
medicine for the future (6).
Optimization of current pain management strategies is necessary in
order to reduce medication risks. Promoting patient and healthcare
provider education on pain and pain medications is an essential step in
reducing inadequate prescribing behaviors and AEs. In an effort to
raise awareness on medication safety, the FDA has launched the Safe
5
Use Initiative Program. This program seeks to identify areas with the
greatest amount of preventable harm and helps promote new methods
and practices to reduce medication risks. Since the establishment of
the program, FDA's Safe Use initiative staff convened a panel of key
opinion leaders throughout the medical community to address pain
management in older adults (≥ 65 years of age). The aim of the expert
panel is to focus on areas where significant risk occurs and where
potential interventions will be feasible, implementable and lead to
substantial impact. The panel suggests one focus can be the use of
NSAIDs for pain management in the elderly (7).
The prevalence of pain, as with many chronic diseases, is
increasing in the world. The high prevalence and negative
consequences of pain require that the public health community be
aware of this issue. Pain should be considered as a multifaceted,
interdisciplinary problem for which many of the causes are the social
determinants of health. It is necessary therefore to handle pain
appropriately in order to prevent unnecessary human suffering.
References
1. Cole BE. Pain Management: Classifying, Understanding, and Treating Pain.
University of Integrated Studies; Continuing Medical Education, American Academy
of Pain Management, Sonora, CA. Hospital Physician June 2002. Available 18 May
2013 at www.turner-white.com.
2. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public
Health. 2011 Oct 6;11:770.
3. Abu-Saad Huijer H. Chronic pain: a review. J Med Liban. 2010;58(1):21-7.
Erratum in: J Med Liban. 2010;58(2):110.
4. Vellucci R. Heterogeneity of chronic pain. Clin Drug Investig. 2012;32 Suppl
1:3-10.
5. Wachholtz AB, Pearce MJ, Koenig H. Exploring the relationship between
spirituality, coping, and pain. J Behav Med. 2007;30(4):311-8.
6. Giordano J, Schatman ME. A crisis in chronic pain care: an ethical analysis.
Part two: proposed structure and function of an ethics of pain medicine. Pain
Physician. 2008;11(5):589-95.
7. Taylor R Jr, Lemtouni S, Weiss K, Pergolizzi JV Jr. Pain management in the
elderly: an FDA safe use initiative expert panel's view on preventable harm associated
with NSAID therapy. Curr Gerontol Geriatr Res. 2012;2012:196159.
6
INTRODUCTION
High prevalence of chronic pain in the general population seems to
increase with age. The majority of cases with pain present with
musculoskeletal pain. The conditions associated with chronic
widespread pain are highly burdensome as their characteristic
symptoms include multifocal pain, fatigue, insomnia, memory
difficulties and a higher rate of concomitant mood disorders. After
many years of debate, it is still unclear whether chronic widespread
pain (central sensitization) is an entirely explainable neurotransmitter-
related process or is partially or totally due to individual cognitive
experiences and evaluations. The two models (neurochemical and
biopsychosocial) affect our ability to find therapeutic answers (1).
During the last 20 years, a great number of studies have
emphasized the potential role of psychological factors as relevant
predictors for the first onset of back pain as well as for the
development of chronic pain. The formulation of a biopsychosocial
perspective of the etiology and chronicity of back pain was a natural
consequence. Actual questions concern the relative impact of
psychological risk factors in the process of chronicity of back pain
compared to biomedical, social and occupational factors. Whereas
several review articles regarding the role of psychological risk factors
are available up to now, a review conducted by Steven Linton was the
first systematic analysis of well controlled prospective studies
published since 1967 (2). Using a grading system similar to that
recommended for guidelines the author defined a level A evidence
when at least 2 good-quality prospective studies supported the
prospective power of a variable. Level B evidence had support from 1
prospective study. Level C represented inconclusive data and level D
indicated that no studies met the criteria. Based on a literature search
of more than 900 studies, 37 good-quality prospective studies were
analyzed in detail. The results indicated level A evidence for the
following interrelations: [1] Psychosocial variables, especially chronic
distress in daily life, depression and work dissatisfaction were clearly
associated with the onset of back and neck pain [2]. Psychological
variables, especially chronic stress in daily life, work dissatisfaction,
depression, pain-related cognitions and coping behavior were linked
to the transition from acute to chronic pain and disability [3].
Psychological variables generally had more prospective power than
biomedical, social or objective occupational variables. Among the
pain-related cognitions, catastrophizing and fear-avoidance-beliefs
yielded the most empirical support. Among coping behavior passive
7
coping strategies such as avoiding behavior was most important. At

least level B evidence has been shown for the counterpart of an
extreme suppressive coping behavior. Patients who tended to suppress
or ignore pain in order to finish all activities they started, and who
were unable to integrate phases of passive relaxation into the daily
routine displayed a high risk of chronicity of pain 6 months after an
acute phase of pain. Prospective studies have shown the predictive
power of a maladaptive suppressive behavior pattern. Based on the
avoidance-endurance-model of pain chronification, both extreme and
one-sided passive pain coping as well as one-sided suppressive coping
modes were conceptualized as maladaptive due to the process of
chronicity. Extreme passive behavior will lead to immobility and
muscular atrophy. Neurophysiological processes of sensitization will
further lead to the development of chronic pain. On the other hand,
extreme suppressive behavior will lead to an overuse of muscles and
joints with a repetitive combination of muscular hyperactivity and
pain. These repetitive pain experiences will also elicit
neurophysiological processes of sensitization. [4] Psychosocial
variables displayed more predictive power than biomedical or
biomechanical factors. [5] Psychosocial factors may be used as
predictors of the risk for developing long-term pain and disability.
Mixed empirical evidence has been shown for the role of personality
factors (level C evidence) and no support has been found for the idea
of a "pain prone" personality disorder or for the role of sexual and
physical abuse. Twenty years of research, several qualitative reviews
and a recently published systematic review of 37 good-quality
prospective studies regarding the role of psychological, biomedical,
social and objective occupational factors in the process of chronicity
of back pain revealed that psychological factors are significantly
related to the onset of back pain as well as to the development of
chronic pain. The psychological factors displayed more predictive
power than biomedical or biomechanical variables. Therefore, for
clinical practice, these psychological risk factors have to be
considered as "yellow flags" if a back pain problem won't respond to
medical treatment for more than 4 weeks. As a further consequence,
special risk factor, based psychosocial interventions should be offered
in addition to the medical treatment to patients with high
psychological risk factors for the development of chronic pain. The
efficacy of such an interdisciplinary care in the very early phases of
back pain can prevent chronicity of pain and disability (3).
Thus, there is much evidence to suggest that psychological and
social issues are predictive of pain severity, emotional distress, work
8
disability, and response to medical treatments among persons with

chronic pain. Psychologists can play an important role in the
identification of psychological and social dysfunction and in matching
personal characteristics to effective interventions as part of a
multidisciplinary approach to pain management, leading to a greater
likelihood of treatment success. The assessment of different domains
using semi-structured clinical interviews and standardized self-report
measures permits identification of somatosensory, emotional,
cognitive, behavioral and social issues in order to facilitate treatment
planning. Measures to assess constructs related to pain, intervention
strategies for the behavioral treatment of chronic pain and related
psychiatric, and substance abuse issues are needed (4).
Pain relief is often the primordial treatment objective in pain
patients. However, an exclusive focus upon pain relief may have
costs. Evidence is accumulating that persistent attempts to gain control
over pain may, paradoxically, hinder successful adaptation to pain and
increase frustration and limitations due to pain. To better understand
these apparently paradoxical findings, a motivational perspective on
coping with pain can be adopted. Within this perspective, pain control
is recast as an attempt to protect and restore valued life goals
threatened by pain. This framework explains why some patients
engage excessively in pain control strategies despite the costs
associated with this, such as overuse of medication. A clinical
implication is that cautiousness is warranted in promoting strategies
exclusively aimed at pain relief. Beyond standard medical care,
interventions should be aimed at the improvement of functioning
despite pain. Patients for whom there is no definite or sound cure to
pain and who increasingly experience emotional and physical
problems due to pain might benefit from paramedical help by
psychologists and/or physiotherapists (5).
The concept of pain management as a human right recently gained
momentum with the 2004 European Federation of IASP Chapters,
IASP and WHO-sponsored "Global Day Against Pain," where it was
adopted as a central theme. The scope of the problem of unrelieved
pain included 3 areas - acute pain, chronic non-cancer pain, and
cancer pain and outlined the adverse physical and psychological
effects and social and economic costs of untreated pain. Reasons for
deficiencies in pain management include cultural, societal, religious,
and political attitudes, including acceptance of torture. The biomedical
model of disease, focused on pathophysiology rather than QOL,
reinforces entrenched attitudes that marginalize pain management as a
priority. Strategies currently applied for improvement include:
9
framing pain management as an ethical issue; promoting pain

management as a legal right; providing constitutional guarantees and
statutory regulations that span negligence law, criminal law, and elder
abuse; defining pain management as a fundamental human right;
categorizing failure to provide pain management as professional
misconduct; and issuing guidelines and standards of practice by
professional bodies. The role of the WHO is stressed with respect to
opioid availability for pain management. Because pain management is
the subject of many initiatives within the disciplines of medicine, and
ethics and law, we are at an "inflection point" in which unreasonable
failure to treat pain is viewed worldwide as poor medicine, unethical
practice, and an abrogation of a fundamental human right (6).
The Department of Health and Human Services and NIH have
requested that the Institute of Medicine convene the ad hoc committee
to address the current state of the science with respect to pain
research, care, and education and explore approaches to advance the
field. Specifically, the committee will review and quantify the public
health significance of pain, including the adequacy of assessment,
diagnosis, treatment, and management of acute and chronic pain in the
US. This effort will take a comprehensive view of chronic pain as a
biological, biobehavioral, and societal condition. Identify barriers to
appropriate pain care and strategies to reduce such barriers, including
exploring the importance of individualized approaches to diagnosis
and treatment of pain. Identify demographic groups and special
populations, including older adults, individuals with co-morbidities,
and cognitive impairment that may be disparately undertreated for
pain, and discuss related research needs, barriers particularly
associated with these demographic groups, and opportunities to reduce
such barriers. Identify and discuss what scientific tools and
technologies are available, what strategies can be employed to
enhance training of pain researchers, and what interdisciplinary
research approaches will be necessary in the short and long term to
advance basic, translational, and clinical pain research and improve
the assessment, diagnosis, treatment and management of pain. Discuss
opportunities for public–private partnerships in the support and
conduct pain research, care, and education (7).
People have suffered from chronic pain, which can be associated
with various diseases, for thousands of years. Is chronic pain
described in the Bible? If so, who suffered from chronic pain? What is
the most likely cause of pain? What is the classification of pain? What
are the assessment tools? What are the psychosocial dimensions of
pain? Did any other comorbid disease afflict the sufferer? How is
10
chronic pain related to the family? What is the contemporary

epidemiology? What is mechanism of chronic pain? What are
prognostic factures? What is the contemporary approach to non-
malignant and malignant chronic pain?
This research deals with verses relating to pain, evaluating the pain
suffered by one biblical character from a contemporary perspective.
The research also evaluates the influence of pain on various health and
psychosocial dimensions in humans.
For the purpose of this research, the approaches to non-malignant
and malignant pain are described separately, although some strategies
for example, classification of pain, assessment tools, and management
overlap in non-malignant and malignant pain.
References
1. Sarzi-Puttini P, Atzeni F, Mease PJ. Chronic widespread pain: from peripheral
to central evolution. Best Pract Res Clin Rheumatol. 2011; 25(2):133-9.
2. Steven JL. A Review of Psychological Risk Factors in Back and Neck Pain.
Literature Review. 2000;25(9):1148-56.
3. Hasenbring M, Hallner D, Klasen B. Psychological mechanisms in the
transition from acute to chronic pain: over- or underrated? Schmerz. 2001;15(6):442-
7.
4. Jamison RN, Edwards RR. Integrating pain management in clinical practice. J
Clin Psychol Med Settings. 2012;19(1):49-64.
5. Lauwerier E, Van Damme S, Goubert L, et al. To control or not? A
motivational perspective on coping with pain. Acta Neurol Belg. 2012;112(1):3-7.
6. Brennan F, Carr DB, Cousins M. Pain management: a fundamental human
right. Anesth Analg. 2007;105(1):205-21.
7. Relieving Pain in America: A Blueprint for Transforming Prevention, Care,
Education, and Research. Editors Institute of Medicine (US) Committee on
Advancing Pain Research, Care, and Education. Washington (DC): National
Academies Press (US). The National Academies Collection: Reports funded by
National Institutes of Health. 2011.
11
THE MEDICAL RECORD

OF KING DAVID
In the end of his life, King David the second and greatest of
Israel‘s Kings, who ruled the country 3535 years ago was an old man
"Now King David was old and stricken in years, Now the days of
David drew near that he should end his life.., And the days that David
reigned over Israel were forty years: seven years he reigned in
Hebron, and thirty three years he reigned in Jerusalem‖ (I Kings 1:1,
2:1,11).
In his old age, the King was afflicted by a visual disorder as
indicated by the subsequent passages ―My eye is consumed…‖ (Psalm
6:8; 31:10) and ―As for the light of my eyes, it is also gone from me‖
(38:11). Severe visual impairment is categorized as blindness or poor
vision (1,2). Since the King could not see even light, it follows that he
was blind.
What was the cause(s) of the blindness that afflicted the old King
David, a member of the highest socioeconomic stratum? Among the
numerous causes associated with the blindness, either age-related
neovascular macular degeneration, or mature cataract, or
asymptomatic open-angle glaucoma, or optic atrophy caused by the
end-stage open angle glaucoma are the most likely responsible for this
condition (3,4).
In addition, King David suffered from an eating disorder. A
passage in Psalm 102:4 ―..I (the King) forget to eat my bread‖ tells us
about lack of food intake. This condition indicates anorexia [from Gk,
a + orexis, no appetite]. Anorexia is defined as lack or loss of
appetite, resulting in the inability to eat (5). The word "cachexia"
comes from the Greek words "kakos" and "hexis", meaning bad
condition (6). Cachexia indicates general ill health and malnutrition,
marked by weakness and emaciation, usually associated with a severe
disease such as tuberculosis or cancer (5).
A subsequent passage ―My knees are weak through fasting; and my
flesh failed of fatness‖ (Psalm 109:24) shows that David‘s anorexia
led to fasting and consequently to unintentional weight loss. The
weight loss was so extreme that ―....my bones (the King‘s) cleave to
my skin‖ (Psalm 102:6). This condition is compatible with cachexia.
Among the numerous causes associated with weight loss, we can
consider malignancy, psychosocial problems such as depression,
loneliness, lack of close relationships and friends on whom he could
rely, loss of power and control over his people, feelings of neglect and
negative interpersonal relationships as playing a part (7).
12
King David also suffered from weakness. Passages ―My strength

fails…, My heart palpitates, my strength fails me‖ (Psalms 31:11;
38:11), ―My heart fails me‖ (Psalms 38:13) and ―My strength is dried
up like a potsherd‖ (Psalms 22:16) indicate generalized weakness.
Weakness is defined as a reduction in the strength of 1 or more
muscles (8). It may be generalized (total body weakness) or localized
to a specific area, side of the body, limb or muscle (8,9). According to
the contemporary definition, the passages mentioned above indicate a
generalized weakness. Among the numerous causes associated with
generalized weakness, cancer related fatigue, intractable bone pain,
malnutrition leading to cachexia, severe anemia of chronic diseases,
psychosocial problems associated with loneliness, social isolation,
neglect by others, and depression are the most likely (10).
In addition, the King suffered from a low body temperature ―Now
king David was old and stricken in years, and covered him with
clothes, but he gained no warmth‖ (I Kings 1:1). Thus, David‘s
servants summoned Abishag to warm the King ―...let her cherish him,
and let her lie in thy bosom, that my lord the king get heat‖ (1:2).
Although the King was covered with clothes, his body gained no
warmth. Accidental hypothermia is defined as an unintentional decline
in the core temperature below 35 degrees C. (11). Therefore, the
King‘s body temperature was lower than normally accepted, that is,
below 35 degrees C. It follows that the King was suffering from
hypothermia (12), most likely subclinical and mild. Among the
various diseases that lead to immobility and subsequent hypothermia
in this case are senile osteoporosis, hyperparathyroidism, dementia,
and malignant diseases. The presence of accidental hypothermia
associated with environmental factors is unlikely (13).
King David also suffered from some type of skin disease. The
passage in Psalm 38:6 ―My necrotic ulcers stink‖ tells us that the King
suffered from pressure ulcers.
Pressure sores are complex wounds with clinical appearances
ranging from mild redness of the skin to severe necrosis (14-17).
There are many terms used to describe pressure ulcers: pressure sores,
decubitus ulcers, bedsores, pressure necrosis, and ischemic ulcers
(18). A more general term such as decubitus ulcer may be a more
appropriate way to characterize wounds that emerge due to
compressive forces, shearing forces, and/or friction in patients
dependent on skilled care. For clinical practice, a 2-category
classification is proposed: superficial ulcers predominantly caused by
friction and deep ulcers predominantly caused by pressure (19).
13
Risk factors for pressure ulcers include weight, male gender, old
age, height, a low BMI, falls, use of repositioning sheet, hypertension,
humidity, friction/shearing, immobility, hemoglobin level, decreased
serum albumin level, incontinence, malnutrition, difficulty feeding
oneself, diabetes mellitus, circulatory troubles, neurologic deficiency
including stroke, limb paralysis, Parkinson's disease,
dementia/Alzheimer's disease, unconsciousness, hip fracture, surgery
including hip surgery, postsurgery, cataract, renal insufficiency,
peripheral vascular disease, congestive heart failure, COPD, deep
venous thrombosis, lower limb edema, malignancy, osteoporosis, RA,
and urinary tract infections (20-28).
In King David's case, the risk factors for pressure (decubitus)
ulcers include male gender, old age - a 70-year-old man, a disease that
affected his bones, dehydration, malnutrition and cachexia,
depression, and various social problems (29).
In addition, the medical record (that is the biblical text) tells us that
when the King reached old age, he suffered from sexual dysfunction:
―Now King David was old, advanced in years; and they covered him
with clothes, but he could not become warm‖ (Kings 1:1). David‘s
servants decided to summon ― a young virgin; and let her lie in thy
bosom, that my lord the king may become warm‖ (I Kings 1:2). They
―...found Avishag the Shunammite, and brought her to the king. And
the maiden was very fair, and she cherished the king, and ministered
to him: but the king knew her not‖ (I Kings 1:3-4). These words
indicate that the old King was unable to have sexual relations with this
young woman.
Male sexual dysfunction is a common entity in primary care
practice. Male sexual dysfunction includes hypoactive desire -
diminished or absent libido, premature ejaculatory dysfunction, and
difficulty in achieving orgasm, including anorgasmia, anatomical
abnormalities, e.g., Peyronie‘s disease, and erectile dysfunction (30).
Male erectile dysfunction, previously known as impotence, is
defined as the inability to achieve and maintain an erection sufficient
to permit satisfactory sexual intercourse and is one of the most
common and usually the most troubling forms of male sexual
dysfunction (31,32). The 3 most common types are erectile
dysfunction, premature ejaculation, and decreased libido (33).
We have here the case of an old man, from a high socioeconomic
stratum, who had loved many women during his long life, had wives,
concubines and many children, but in his old age was afflicted by
some type of sexual dysfunction (34,35).
14
Biological changes of aging can be included among the factors

relating to erectile dysfunction (36,37). Although this possibility may
exist, the presence of serious diseases and social problems rules out
advanced age as the cause of erectile dysfunction in King David.
Comorbidities such as heart disease, diabetes, dyslipidemia,
hypertension, depression, anxiety disorders, obsessive-compulsive
disorder, and psychotic disorders have been described as primary risk
factors for the development of erectile dysfunction (38-42).
A number of modifiable lifestyle factors, including physical
activity, smoking, alcohol consumption, diabetes control, and obesity,
have been associated with erectile dysfunction (38). Deep-seated
social factors or relationship conflicts are identified as causes of
erectile dysfunction (43-49). The numerous possible causes of King
David's sexual dysfunction include some serious disease, major
depression and various social problems such as loneliness, lack of
close relationships with friends on whom King could rely, feelings of
neglect, and loss of power and control over his people. Among various
types of sexual dysfunction, erectile dysfunction combined with low
or absent libido was most likely responsible (50,51).
King David suffered from a disease of the bones ―...my strength
failed..., and my bones are consumed‖ (Psalm 31:11) and ―My bones
wasted away through my anguished roaring all day long‖ (32:3). The
first sentence indicates that the King‘s bones were used up, his
strength decreased, and he had become very weak. In the second
sentence, the King‘s bones had reached a stage where they were
extremely thin and weak, causing him severe pain. What was the
cause of this severe pain?
King David was affected by some mental disorder. The well-
known criteria of DSM-IV are presented here as a means for
evaluating biblical verses relating to mental distress in King David.
Major depressive syndrome is characterized either by a severely
depressed mood [1] or by loss of interest or pleasure in nearly all
activities [2], with the change in previous level of functioning lasting
for at least 2 weeks. At least 4 additional symptoms are required for a
definite diagnosis of the disorder, including changes in appetite or
weight [3], insomnia or hypersomnia [4], psychomotor agitation or
retardation [5], fatigue or loss of energy [6], feelings of worthlessness
or excessive or inappropriate guilt [7], diminished ability to think or
concentrate or indecisiveness [8], and recurrent unfocused thoughts of
death or suicide, or suicide attempt (52,53).
15
The verses ―...a broken and depressed heart..‖.(Psalm 51:19) and

―I am feeble and depressed: I have groaned by reason of the suffering
of my heart‖ (38:9) indicate a depressed mood (criterion 1).
The verse ―My knees are weak through fasting; and my flesh failed
of fatness‖ (109:24) describes a significant loss of weight. This loss
may indicate criterion 3.
The verse ―..All the night make I my bed to swim; I water my couch
with my tears‖ (6:7) points to insomnia during which the King wept so
much that his bed was wet with tears (Criterion 4).
The passages ―Fearfulness and trembling are come upon me...‖
(55:6), ―My heart is shivering within me ..‖ (55:5) and ―..Like a deaf
man I would not hear and like a mute I would not speak..‖ (38:14)
indicate psychomotor agitation or retardation that are compatible with
criterion 5.
The verse ‖My strength failed because of mine iniquity...‖ (31:11)
indicates fatigue or loss of energy (criterion 6).
The subsequent verses ―But I am a worm, and no man; a disgrace
of men, and despised of the people‖ (22:7) and ―I am forgotten as a
dead man out of mine mind: I am like a lost tool‖ (31:13) express
feelings of worthlessness (criterion 7).
Fear of death and recurrent thoughts of death (criterion 9) are
found in numerous passages: ‖...has brought me into the dust of the
earth to death‖ (22:16), ―... the terrible fears of death had fallen upon
me‖ (55:5), ―The sorrows of death compassed me...‖ (18:5) and ―...The
mines of death preceded me..‖ (18: 6).
This study found 7 criteria for major depression in King David.
Third criterion can be related either to depression or to physical illness
such as bone diseases. Since this illness may have a link to
depression, this criterion is removed. Sixth criterion can also be
attributed to physical illness, for example anemia. If third and sixth
criteria are dropped, there are sufficient criteria (5) for a diagnosis of
major depression (51).
The mechanisms of the development of depression in King David‘s
case are demonstrated by the passages ―Be not far from me; for
trouble is near; for there is no help ― (Psalm 6:12), ―I am helpless‖
(25:16) and ―I am wretched..‖ (6:3). Here we learn about the King‘s
loneliness, need for close relationships and lack of friends on whom
he can rely. Additional passages: ―But I am a worm, and no man; a
disgrace of men, and despised of the people‖ (32:7) and ―I am
forgotten as a dead man out of mine mind. I am like a lost tool‖
(31:13) show a severe impairment of social functioning due to loss of
power and control over his people feelings of neglect and negative
16
interpersonal relationships. Persistent negative stress and negative

interpersonal experiences played a role in the development of his
major depression. Furthermore, the King was aware of his iniquity,
wickedness and sin ―...my strength failed because of mine iniquity‖
(31:11) and ―Save me from all my sins...‖ (39:9). All these causes
acted together in the development of the King‘s mental disorder.
Thus, the passages referring to King David indicate that he was
afflicted by major depression.
Although the King was afflicted by multiple diseases, this research
deals specifically with a disease that caused him severe bone pain.
How should we understand the verses associated with bone pain?
What is the definition of pain? What is its classification? Was the pain
acute? Or chronic? What was mechanism of this severe pain? What
was the disease that caused such severe intractable pain? Non-
malignant? Malignant? What were the psychosocial dimensions of the
pain? What was the relationship between the King's family and
friends to the King's illness? What contemporary tools can be used to
assess the pain? What is the contemporary epidemiology of chronic
pain? What are comorbid conditions? What is the QOL of patients
suffering from chronic pain? What is the contemporary approach to a
patient suffering from severe pain?
The main aim of this research is to study a patient with intractable
severe bone pain, evaluating various aspects of the pain from the
contemporary viewpoint.
References
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BMC Med. 2006 Mar 16;4:6.
2. Rosenberg EA, Sperazza LC. The visually impaired patient. Am Fam
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3. Ben-Nun L. The diseases of the eyes. In Ben-Nun L. ed. The Diseases that
Affected King David. Research in Biblical Times from the Viewpoint of
Contemporary Medicine. B.N. Publications. Israel. 2003, pp. 3-34.
4. Ben-Nun L. The diseases of the eyes. In Ben-Nun L. ed. The Family Life Cycle
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93-118.
5. Hamerman D. Molecular-based therapeutic approaches in treatment of
anorexia of aging and cancer cachexia. J Gerontol Med Sci. 2002;57A(8): M511-8.
6. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst. 1997;89:1763-73.
7. Ben-Noun L. The disease that caused weight loss in King David the Great. J
Gerontol A Biol Sci Med Sci. 2004;59A:M143-5.
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8. Aminof MJ. Weakness and paralysis. In: Fauci A, Kasper DL, Longo DL,
Braunwald E, et al. (eds). Principles of Harrison's Internal Medicine. 17th ed. New
York: McGraw-Hill. 2008, pp. 147-50.
9. Plum F. Disorders of motor function. Weakness, asthenia, and fatigue. In:
Benet JC, Plum F. (eds). Cecil Textbook of Medicine. Saunders. Philadelphia,
London. 1991, pp. 2027-8.
10. Ben-Nun L. The diseases that caused chronic weakness. In: Ben-Nun L ed.
The Family Life Cycle and the Medical Record of King David the Great. Research in
Biblical Times from the Viewpoint of Contemporary Medicine. B.N. Publications.
Israel. 2009, pp. 172-80.
11. Danzl D. Hypothermia. Semin Respir Crit Care Med. 2002;23(1):57-68.
12. Ben-Noun L. What the biblical King David affected by hypothermia? J
Gerontol A Med Sci. 2002;57(6):M364-7.
13. Ben-Nun L. Hypothermia. In Ben-Nun L. ed. The Family Life Cycle and the
Medical Record of King David the Great. Research in Biblical Times from the
Viewpoint of Contemporary Medicine. B.N. Publications. Israel. 2009, pp. 181-191.
14. Banks V. An educational initiative in pressure area management for nursing
staff. J Wound Care. 1997a;6;9:438441.
15. Banks V. Pressure sore education. J Wound Care. 1997b;10:506507.
16. Dealey C. The care of wounds. Blackwell Scientific Publications: London.
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17. Maklebust J, Sieggreen M. Pressure Ulcers. Guidelines for prevention and
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18. Clinical practice guidelines for the prediction and prevention of pressure
ulcers. Stedman‘s Medical Dictionary. 24th ed. Baltimore: Williams & Wilkins.
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19. Kottner J, Balzer K, Dassen T, Heinze S. Pressure ulcers: a critical review of
definitions and classifications. Ostomy Wound Manage. 2009;55(9):22-9.
20. Lee TT, Lin KC, Mills ME, Kuo YH. Factors related to the prevention and
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21. de Freitas MC, Medeiros AB, Guedes MV, et al. Pressure ulcers in the elderly:
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22. de Souza DM, Santos VL. Risk factors for pressure ulcer development in
institutionalized elderly. Rev Lat Am Enfermagem. 2007;15(5):958-64.
23. Sharp CA, McLaws ML. Estimating the risk of pressure ulcer development: is
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24. Brandeis GH, Ooi WL, Hossain M, et al. A longitudinal study of risk factors
associated with the formation of pressure ulcers in nursing homes. J Am Geriatr Soc.
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25. Ghoussoub K, Kareh I, Ferran F, et al. Prospective study about predictive
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26. Uzun O, Tan M. A prospective, descriptive pressure ulcer risk factor and
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27. Takahashi PY, Chandra A, Cha SS. Risk factors for pressure ulceration in an
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28. Margolis DJ, Knauss J, Bilker W, Baumgarten M. Medical conditions as risk
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29. Ben-Nun L. Pressure ulcers. In Ben-Nun ed. The Family Life Cycle and the
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32. Korenman SG. Advances in the understanding and management of erectile
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33. Diaz VA Jr, Close JD. Male sexual dysfunction. Prim Care. 2010;37(3):473-
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35. Ben-Noun L. Sexual dysfunction. In Ben-Noun L. ed. The Family Life Cycle
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36. Phanjoo AL. Sexual dysfunction in old age. Adv Psychiat Treat.2000;6:270-7.
37. Castro RP, Hernández PC, Casilda RR, et al. Epidemiology of erectile
dysfunction. Risk factors. Arch Esp Urol. 2010;63(8):637-9.
38. Glina S, Sharlip ID, Hellstrom WJ. Modifying Risk Factors to Prevent and
Treat Erectile Dysfunction. J Sex Med. 2012 Sep 12.
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among middle-aged and elderly men in Korea: Hallym aging study. Int J Impot Res.
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41. Perelman MA. Erectile dysfunction and depression: screening and treatment.
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47. Shabsigh R, Klein LT, Seidman S, et al. Increased incidence of depressive
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19
DEFINITION OF PAIN
According to the International Association for the Study of Pain,
pain is ―an unpleasant sensory and emotional experience associated
with actual and potential tissue damage, or described in terms of such
damage, or both‖ (1). This definition emphasizes the subjective and
psychological nature of pain and appropriately avoids making the
authenticity of pain contingent on an externally verifiable stimulus.
Price (2) similarly proposes that pain should be understood as a
somatic perception involving a bodily sensation with qualities similar
to those reported during tissue-damaging stimulation, an experienced
threat associated with this sensation, and a feeling of unpleasantness
or other negative emotions based on the experienced threat.
In its 2001 implementation of pain-related standards of care, the
Joint Commission on Accreditation of Healthcare Organizations
linked pain to physical and emotional responses. In justifying pain-
related accreditation standards, this Commission pointed out the
connection between unrelieved pain and negative physiologic and
psychological effects, generalizing these adverse outcomes from the
hospitalized patient to the majority of patients in nearly all health care
settings (e.g., hospitals, long-term care facilities, surgical centers,
mental health facilities, home health services, and health system
networks) (3).
References
1. Classification of chronic pain. Descriptions of chronic pain syndromes and
definitions of pain terms. Prepared by the International Association for the Study of
Pain, Subcommittee on Taxonomy. Pain Suppl 1986;3:S1-226.
2. Price DD. Psychological mechanisms of pain and analgesia. Seattle: IASP
Press. Progress in pain research and management. 1999, Vol. 15.
3. Pain management today. In: Pain Assessment and Management: an
Organizational Approach. Oakbrook Terrace (IL): Joint Commission on Accreditation
of Healthcare Organizations. 2000, pp. 1-6.
20
CLASSIFICATION OF PAIN
Pain is divided by its underlying etiology into non-cancer-related

pain (often called benign or non-malignant pain) and cancer-related
pain (often called malignant pain) (1-4). The classification of non-
malignant and malignant pain can overlap.
References
1. Foley KM. The treatment of cancer pain. N Engl J Med. 1985;313:84-95.
2. Crue BL. The neurophysiology and taxonomy of pain. In: Brena SF, Chapman
SL, eds. Management of Patients with Chronic Pain. New York: SP Medical &
Scientific Books. 1983.
3. Portenoy RK. Practical aspects of pain control in the patient with cancer. CA
Cancer J Clin. 1988;38:327–52
4. Cherubino P, Sarzi-Puttini P, Zuccaro SM, Labianca R. The management of
chronic pain in important patient subgroups. Clin Drug Investig. 2012;32 Suppl 1:35-
44 .
NON-CANCER PAIN
The common types of pain (1-4) include:
Nociceptive: Nociceptive pain results from activity in neural
pathways secondary to actual tissue damage or potentially tissue-
damaging stimuli. Nociceptive pain represents the normal response to
noxious insult or injury of tissues such as skin, muscles, visceral
organs, joints, tendons, or bones. Examples include Somatic pain:
musculoskeletal (joint pain, myofascial pain), cutaneous, often well
localized; Visceral: hollow organs and smooth muscle; this pain is
usually referred.
Neuropathic: neuropathic pain is chronic pain that is initiated by
nervous system lesions or dysfunction and can be maintained by a
number of different mechanisms. Neuropathic pain results from a
lesion to the peripheral or CNS. This type of pain is initiated or caused
by a primary lesion or disease in the somatosensory nervous system.
Sensory abnormalities range from deficits perceived as numbness to
hypersensitivity (hyperalgesia or allodynia) to paresthesias such as
tingling. Examples include DPN, postherpetic neuralgia, SCI pain,
phantom limb (post-amputation) pain, post-stroke central pain, and
cancer.
Inflammatory: this type of pain is a result of activation and
sensitization of the nociceptive pain pathway by a variety of mediators
21
released at a site of tissue inflammation. The mediators that have been

implicated as key players are proinflammatory cytokines such IL-1-
alpha, IL-1-beta, IL-6 and TNF-alpha, chemokines, reactive oxygen
species, vasoactive amines, lipids, ATP, acid, and other factors
released by infiltrating leukocytes, vascular endothelial cells, or tissue
resident mast cells. Examples include appendicitis, RA, IBD, and
herpes zoster.
Table 1 provides examples of each of these categories. These
subgroups focus on the site of nociception or potential tissue-
damaging event. Somatic pain is generally peripheral, visceral pain is
usually intra-abdominal, and neuropathic pain typically involves
afferent neural pathways. The pain that results from somatic processes
is well localized, constant, aching, or gnawing in character. By
contrast, visceral pain is poorly localized but is constant and aching in
character and is referred to cutaneous sites. Deafferentation pain is
characterized by tingling, sharp paroxysmal sensations or burning
dysesthesia and is traditionally managed with adjuvant medications,
including antidepressant and anticonvulsant drugs rather than the
opioid analgesic agents used for visceral and somatic pains (5).
Table 1. Types of Pain (6).

Somatic
Fracture
Incisional injury
Thermal injury
Traumatic injury
Visceral
Bowel obstruction
Constipation
Endometriosis
Metastatic organ involvement
Deafferentation
Alcoholic and nutritional neuropathy
Diabetic mononeuropathy and polyneuropathy
Pancoast‘s tumor (producing brachial plexopathy)
Postherpetic neuralgia
Pathological processes never occur in isolation and consequently more
than one mechanism may be present and more than one type of pain may be
detected in a single patient; for example, inflammatory mechanisms involved
in neuropathic pain (1).
22
PAIN INTENSITY
Pain intensity can be broadly categorized as mild, moderate and
severe (1). It is common to use a numeric scale to rate pain intensity
where 0 = no pain and 10 is the worst pain imaginable:
Mild: < 4/10
Moderate: 5/10 to 6/10
Severe: > 7/10.
ACUTE VERSUS CHRONIC PAIN

Acute pain is short-term pain of less than twelve-week duration
(7). Chronic persistent pain is defined as chronic, recurrent, or long-
lasting pain lasting for at least 6 months, from a non-life-threatening
cause; and/or which is not responsive to available treatment (8-10).
Acute-on-chronic pain: acute pain flare superimposes on underlying
chronic pain (1).
EPISODIC PAIN
An episodic pain is pain that varies with time (11).
CLASSIFICATION BY LOCATION
Chronic pain is classified as localized, regional or widespread (12).
ANATOMIC CLASSIFICATION
The anatomic pain classification system identifies sites of pain as
viewed from a regional perspective (e.g., LBP, headache, or pelvic
pain) (13).
Chronic non-cancer-related pain, the grist of most pain clinics,
involves several different pathophysiologic problems that usually
render the sufferer unable to enjoy life but do not directly threaten life.
This type of pain is most often described in relationship to an
anatomic site and typically engenders considerable anxiety.
Myofascial pain (e.g., pain arising from muscle and connective tissue)
accounts for a considerable amount of chronic non-cancer-related
pain; it requires specific active therapy (e.g., stretching, and trigger
point injections) and corrective actions for pain relief (14,15).
23
THE BODY SYSTEM CLASSIFICATION

The body system pain classification method focuses on classical
body systems (e.g., musculoskeletal, neurologic, and vascular).
Anatomic and body system classification systems address only a
single dimension (e.g. where or why does the patient hurt) and thus
may ultimately fail to adequately define the underlying
neurophysiology of the problem (13).
HYPERALGESIA
Hyperalgesia is increased responsiveness to noxious stimuli (16).
ALLODYNIA
Allodynia is painful responses to normally innocuous stimuli (17).
Assessment: the biblical verses "my bones are consumed‖ (Psalm

32:11) and ―My bones wasted away through my anguished roaring all
day long‖ (Psalm, 32:3) indicate severe, widespread and chronic
musculoskeletal pain.
Was somatic, visceral, or neuropathic pain responsible? Somatic
pain is generally peripheral, while visceral pain is usually intra-
abdominal, while neuropathic pain typically involves afferent neural
pathways. Therefore, it seems that the King suffered from nociceptive,
somatic pain. Was his pain non-malignant? Malignant?
References
1. Classification of Pain. University of Wisconsin. School of Medicine and Public
Health Projects. Accessed 12 May 2013 at hsl.wisc.edu/GME/ PainManagement/
session2.4.html.
2. Martin CM, Saleeby LG. All pain is not the same: an overview of neuropathic
pain in the elderly. Consult Pharm. 2007;22(4):283-94.
3. Francesca F, Bader P, Echtle D, Giunta F, Williams J; EAU. EAU guidelines
on pain management. Eur Urol. 2003;44(4):383-9.
4. Nicholson B. Differential diagnosis: nociceptive and neuropathic pain. Am J
Manag Care. 2006;12(9 Suppl):S256-62.
5. Foley KM. The treatment of cancer pain. N Engl J Med. 1985;313:84-95.
of Pain Management, Sonora, CA. Hospital Physician, June. 2002, pp 23-30.
Available 28 April 2013 at www.turner-white.com.
24
7. What is definition of acute pain. The British Pain Society. Accessed 28

October 2012. www.britishpainsociety.org.
8. West C, Usher K, Foster K. Family resilience: towards a new model of chronic
pain management. Collegian. 2011;18(1):3-10.
9. Johannes CB, Le TK, Zhou X, et al. The prevalence of chronic pain in United
States adults: results of an Internet-based survey. J Pain. 2010;11(11):1230-9.
10. Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being:
a World Health Organization Study in Primary Care. JAMA. 1998;280(2):147-51.
Erratum in: JAMA 1998;280(13):1142.
11. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in
cancer: a survey of hospice patients on admission. Palliat Med. 2001;15(1):9-18.
12. Sarzi-Puttini P, Atzeni F, Mease PJ. Chronic widespread pain: from peripheral
to central evolution. Best Pract Res Clin Rheumatol. 2011; 25(2):133-9.
13. Turk DC, Okifuji A. Pain terms and taxonomies of pain. In: Loeser JD, Butler
SH, Chapman CR, Turk DC, editors. Bonica‘s Management of Pain. 3rd ed.
Philadelphia: Lippincott Williams & Wilkins. 2001, pp.17–25.
14. Travell JG, Simons DG. Myofascial Pain & Dysfunction: the Trigger Point
Manual. Baltimore: Williams & Wilkins. 1983.
15. Simons DG, Travell JG. Simons LS. Travell & Simons‘ Myofascial Pain and
Dysfunction: the Trigger Point Manual. Vol 1, 2nd ed. Baltimore. Williams &
Wilkins. 1999.
44
17. Obata K, Noguchi K. Contribution of primary sensory neurons and spinal
glial cells to pathomechanisms of neuropathic pain. Brain Nerve. 2008; 60(5):483-92.
25
NON-MALIGNANT PAIN
EPIDEMIOLOGY OF CHRONIC PAIN

Epidemiological studies conducted in different parts of the world
reported prevalence rates of chronic pain ranging from 11% to 64%
(1), 12% to 80% (2), 20% (3), and from 25.0% to 50.0% (4). The
incidence of chronic pain is estimated at 20% to 25% worldwide (5).
The main aim of this study was to estimate the prevalence of
chronic pain worldwide paying particular attention to data from
countries with a HDI of less than 0.9. A literature search was
conducted for cross-sectional surveys of chronic pain (≥ 3 months) in
the adult general population using Medline, Embase, CINAHL,
SportDiscus, Sciencedirect, CAS ILLUMINA, Academic search
complete, PsycINFO and AMED. Forty-eight studies were identified
and 29 of these were excluded because they surveyed children, the
elderly or were longitudinal studies. Weighted mean ± SD prevalence
of chronic pain worldwide was 30.3% ± 11.7% (19 studies, 65
surveys, 34 countries, 182,019 respondents). There was no correlation
between HDI and prevalence. In countries with a HDI < 0.9 the
prevalence of chronic pain was 33.9% ± 14.5%, significantly higher
than prevalence in countries with a HDI of ≥ 0.9 (29.9% ± 12.7%),
although removal of a large study that may have included a sample of
individuals with comorbidities reduced the worldwide estimate to
28.0% ± 11.8% (47 surveys, 33 countries, 139,770 participants). The
estimate of countries with a HDI < 0.9 to 24.8% ± 8.9% (7 surveys, 7
countries, 6122 participants) became significantly lower than the
estimate of countries with a HDI ≥ 0.9 which was 28.1% ± 11.6%
(40 surveys, 21 countries, 133,648 participants). In conclusion, the
prevalence of chronic pain in the general population is high. However,
there was insufficient reliable data to estimate with any certainty the
prevalence of chronic pain in countries with an HDI < 0.9 with
variability in estimates between surveys being of concern (5).
The present study reports the prevalence by age and gender of
common chronic pain conditions (headache, back or neck pain,
arthritis or joint pain, and other chronic pain) in 10 developed and 7
developing countries and their association with the spectrum of both
depressive and anxiety disorders. It draws on data from 18 general
adult population surveys using a common survey questionnaire
(n=42,249). Results show that age-standardized prevalence of chronic
pain conditions in the previous 12 months was 37.3% in developed
26
countries and 41.1% in developing countries, with back pain and

headache being somewhat more common in developing than
developed countries. After controlling for comorbid chronic physical
diseases, several findings were consistent across developing and
developed countries. There was a higher prevalence of chronic pain
conditions among females and older persons; and chronic pain was
similarly associated with depression-anxiety spectrum disorders in
developed and developing countries. However, the large majority of
persons reporting chronic pain did not meet criteria for depression or
anxiety disorder. In conclusion, common pain conditions affect a large
percentage of persons in both developed and developing countries.
Chronic pain conditions are common in both developed and
developing countries. Overall, the prevalence of pain is greater among
females and among older persons. Although most persons reporting
pain do not meet criteria for a depressive or anxiety disorder,
depression/anxiety spectrum disorders are associated with pain in both
developed and developing countries (6).
A cross-sectional, Internet-based survey was conducted in a
nationally representative sample of US adults to estimate the point
prevalence of chronic pain and to describe sociodemographic
correlates and characteristics of chronic pain. The survey was
distributed to 35,718 members (aged 18 years and older) of a Web-
enabled panel that is representative of the US population, and 27,035
individuals responded. Crude and weighted prevalence estimates were
calculated and stratified by age, sex, and type of chronic pain. The
weighted point-prevalence of chronic pain was 30.7% (95% CI 29.8 -
31.7). Prevalence was higher for females (34.3%) than males (26.7%)
and increased with age. The weighted prevalence of primary chronic
LBP was 8.1% and primary osteoarthritis pain was 3.9%. Half of
respondents with chronic pain experienced daily pain, and average
(past 3 months) pain intensity was severe (≥ 7 on a scale ranging from
0 to 10) for 32%. Multiple logistic regression analysis identified low
household income and unemployment as significant socioeconomic
correlates of chronic pain. Chronic pain is prevalent among US adults
and is related to indicators of poorer socioeconomic status. The results
of this cross-sectional Internet-based survey suggest a considerable
burden of chronic pain in adults. Chronic pain, experienced by about a
third of the population, was correlated with indicators of poorer
socioeconomic status. Primary chronic pain was most commonly
attributed to LBP, followed by osteoarthritis pain (7).
A cross-sectional telephone survey was conducted in nationally
representative probability sample of non-Hispanic white subjects, non-
27
Hispanic African American subjects, and Hispanic subjects of any

race to explore relationships between chronic pain and race or
ethnicity. Approximately one third in each group reported "frequent or
persistent pain" for 3 months or longer during the past year, and
approximately one third of the 454 white subjects, 447 African
American subjects, and 434 Hispanic subjects in the final sample
experienced "disabling pain" (defined as both high severity and high
functional interference). White subjects had pain longer but with
lesser intensity than the other groups, and pain-related life interference
did not vary. Significantly, fewer Hispanic subjects (68%) than white
subjects (82%) or African American subjects (85%) had visited a
physician for pain, and African American subjects (81%) were more
likely than white subjects (75%) or Hispanic subjects (63%) to have
used prescription medications. Disabling pain was positively
associated with female sex (OR 1.45), income of $25,000 or less (OR
1.71), less than a high school education (OR 1.72), and divorce (OR
1.69) and was negatively associated with younger age (18-34 years,
OR 0.68), income between $25,000 and $74,999 (OR 0.64) or $75,000
or more (OR 0.37), being employed (OR 0.48), suburban residence
(OR 0.64), and having a college (OR 0.51) or graduate (OR 0.32)
degree. Multivariate logistic regression found that income of $25,000
or less (OR 2.54), less than a high school education (OR 1.59), and
being unemployed (OR 1.50) remained significant when other factors
were controlled. Neither race nor ethnicity predicted disabling pain,
but the minorities had more characteristics identified as predictors.
The data suggest that race and ethnicity contribute to clinical
diversity, but socioeconomic disadvantage is the more important
predictor of disabling pain. Race and ethnicity influence the
presentation and treatment of chronic pain. This study evaluated
community-dwelling white, African American, and Hispanic subjects
by using a sophisticated telephone survey methodology. In conclusion,
pain is highly prevalent across groups, and there are racial and ethnic
differences in pain experience and treatment preferences. Race and
ethnicity are not independently associated with severe pain, but both
minorities are more likely to possess the socioeconomic and
educational characteristics that are associated (8).
In a cross-sectional survey of Mississippi adults, telephone
interviews with a representative sample (random digit dialing) of 604
adults were conducted utilizing a computer-assisted telephone
interviewing system. The cooperation rate was 94.8% (5.2% refusal).
The Code of Standards and Ethics for Survey Research rate was
67.4% and the maximum sampling error was +/- 4.0% (95% CI). The
28
Mississippi survey data represent a subset of the data obtained in the

six-state Southern Pain Prevalence Study. The pain prevalence rate
was 37% of the overall Mississippi sample: 9% of the sample reported
severe pain on at least a monthly basis; 16% reported moderate pain;
and 12% reported mild pain. Among those reporting pain, a majority
(52%) experienced pain on a daily basis. The most commonly
reported origins of pain were back pain (49%), leg and knee pain
(41%), and shoulder and arm pain (20%). Respondents also reported
that both moderate and severe pain had substantial negative impacts
on multiple facets of everyday life, including interference with sleep
(84%), recreational/leisure activities (78%), ability to work (68%),
sexual relations (43%), and relationships with others (36%). Mental
health impacts for respondents with moderate to severe pain on at
least a monthly basis included increased feelings of anxiety (66%),
self-reported depression (63%), and loneliness (46%). When
responding to questions regarding beliefs and attitudes about pain and
pain management, the majority of respondents (62%) considered pain
to be a normal part of everyday life. Many respondents felt that
medicine should be saved until the pain becomes worse (55%), and a
substantial number of respondents felt that good patients do not
complain about pain to their doctors (22%). This study expands the
body of knowledge about the prevalence of pain in Mississippi,
suggesting that approximately one-third of the state's adults are
affected by pain on at least a monthly basis. Most of this pain is
moderate to severe and quite frequent - occurring daily for the
majority of pain sufferers. The study also illuminates social and
cultural dimensions of pain, revealing that a) the presence of pain
negatively affects almost every facet of life, from sleep and work to
relationships, leisure activities, and mental health, and b) respondents
attitudes and beliefs are often at variance with modern approaches to
pain management (9).
In Canada, the prevalence of chronic pain for men and women
between 1994 and 2008 ranged from 15.1% in 1996/97 to 18.9% in
1994/95. Chronic pain was most prevalent among women (range
16.5% to 21.5%), and in the oldest (≥ 65 years) age group (range
23.9% to 31.3%). Women aged ≥ 65 years consistently reported the
highest prevalence of chronic pain (range 26.0% to 34.2%). The
majority of adult Canadians who reported chronic pain also reported at
least a few activities prevented due to this pain (range 11.4% to 13.3%
of the overall population) (10).
Multiple databases (MEDLINE, EMBASE, Cochrane Library,
CRD Databases, and GIN) were systematically searched for primary
29
studies containing epidemiological data on chronic non-cancer pain in

Europe excluding studies that solely concerned migraines, headaches
and pain associated with specific disease conditions. Eighteen
research questions concerning aspects of chronic pain included
prevalence, incidence, pain treatments, control and compliance,
treatment satisfaction, and QOL and economic impacts. The search
yielded 16,619 references and 45 were relevant to Europe. Studies for
each question were selected that provided the most recent,
representative and valid data. There was a lack of studies concerning
chronic non-cancer pain in Europe as a whole. The 1-month
prevalence of moderate-to-severe non-cancer chronic pain was 19%.
Chronic pain significantly affected patient-perceived health status,
affected everyday activities including economic pursuits and personal
relationships, and was significantly associated with depressive
symptoms. The majority relied on drugs for pain control and NSAIDs
were the most frequent drug choice. Despite pain medications, a large
proportion had inadequate pain control. Chronic pain has a dramatic
impact on European society. Since chronic non-cancer pain is treated
differently from cancer-related pain, the lack of data in this area
clearly underlines the need for decision makers in healthcare to gather
further epidemiological data (11).
This large-scale computer-assisted telephone survey was
undertaken to explore the prevalence, severity, treatment and impact
of chronic pain in 15 European countries and Israel. Screening
interviews identified respondents aged 18 years with chronic pain for
in-depth interviews. Of 46,394 respondents, 19% were willing to
participate (refusal rate 46%) and had suffered pain for 6 months, had
experienced pain in the last month and several times during the last
week. Their pain intensity was 5 on a 10-point NPRS (1 = no pain, 10
= worst pain imaginable) during last episode of pain. In-depth
interviews with 4839 respondents with chronic pain (about 300 per
country) showed: 66% had moderate pain (NPRS = 5-7), 34% had
severe pain (NPRS = 8-10), 46% had constant pain, 54% had
intermittent pain; 59% had suffered with pain for 2 to 15 years, 21%
had been diagnosed with depression because of their pain, 61% were
less able or unable to work outside the home, 19% had lost their job
and 13% had changed jobs because of their pain; 60% visited their
doctor about their pain 2-9 times in the last 6 months. A pain
management specialist currently treated only 2%. One-third of the
chronic pain sufferers were currently not being treated. Two-thirds
used non-medication treatments, e.g., massage (30%), physical
therapy (21%), and acupuncture (13%). Almost half were taking non-
30
prescription analgesics; 'OTC', NSAIDs (55%), paracetamol (43%),

and weak opioids (13%). Two-thirds were taking prescription
medicines: NSAIDs (44%), weak opioids (23%), paracetamol (18%),
COX-2 inhibitors (1-36%), and strong opioids (5%). Inadequate
management of pain had 40%. Differences between countries were
observed, possibly reflecting differences in cultural background and
local traditions in managing chronic pain. This study indicates that
chronic pain of moderate to severe intensity occurs in 19% of adult
Europeans, seriously affecting the quality of their social and working
lives. Pain specialists managed very few and nearly half received
inadequate pain management. Although differences were observed
between the 16 countries, chronic pain remains a major health care
problem in Europe that needs to be taken more seriously (12).
The purpose of this study was to assess the burden of neuropathic
pain on HRQL, health status, employment status, absenteeism and
presenteeism, and direct medical costs in Western Europe. Data were
from the 2010 NHWS for 5 countries in Western Europe: the UK,
France, Spain, Germany, and Italy. Among subjects who reported
experiencing pain in the past month, those who attributed their pain to
neuropathic pain were compared with those who attributed their pain
to another chronic pain condition other than neuropathic pain (the
latter was the reference group). These 2 groups were compared on
demographic and both pain and non-pain related comorbidities.
Generalized linear models were used to estimate the independent
contribution of the presence of neuropathic pain on: (a) HRQL (using
the SF-12v2); (b) self-reported health status (the first item of the SF-
12v2); (c) employment status; (d) absenteeism and presenteeism
(using the WPAI questionnaire); and (e) direct medical costs
(estimated from self-reported healthcare resource use and unit costs
from the literature). Relative to the chronic pain reference group,
subjects with neuropathic pain reported a higher prevalence of severe
daily pain (38.12% vs. 12.67%, p < 0.05), lower labor force
participation (39.68% vs. 55.56%, p < 0.05), higher prevalence of
sleep difficulties (59.14% vs. 46.73%, p < 0.05), insomnia (45.61% vs.
29.78%, p < 0.05) anxiety (42.42% vs. 31.99%, p < 0.05), and
depression (35.25% vs. 24.03%, p < 0.05). Neuropathic pain subjects
reported higher rates of absenteeism (39.78% vs. 21.47%, p < 0.05)
and presenteeism (86.48% vs. 66.70%, p < 0.05). Direct medical costs
were approximately twice as high compared to non-neuropathic pain
controls. In addition, > 80% of neuropathic pain patients reported
having other pain conditions. Regression results amplified these
findings by indicating the independent contribution of confounding
31
factors on the presence of neuropathic pain. This study concludes that

the presence of neuropathic pain is associated with an increased
disease burden in the chronic pain population. This is in terms of
HRQOL, health status, employment, and direct medical costs (13).
A cross-sectional postal survey of all adults aged ≥ 50 years
registered with 3 general practices (n=11230) in North Staffordshire
using self-complete questionnaires was conducted. Respondents'
gender, age, employment status, socio-economic classification, and
general health status were gathered to characterize the population
under study. The location of any recent pain (past 4 weeks) was
recorded on a full-body manikin and pain interference was based on a
single question. Completed questionnaires were received from 7878
respondents (adjusted response of 71.3%). The four-week prevalence
of any pain was 72.4%; similar across 10-year age groups, and higher
in females than males. In those with pain, the median number of
painful areas (from 44) was 6, and 12.5% of the responding
population were classified as having widespread pain, both figures
similar across age groups. Most regional pains showed a decline in
prevalence in the older age groups, the exceptions being the lower
limb regions (hip, knee, and foot). Pain that interfered with daily
activities was reported by 3002 (38.1%) respondents overall. There
was a clear age-related rise in this prevalence with age up, including
the oldest group. Within each regional pain subgroup, the proportion
of people who also reported pain interference rose with age. This
study has provided evidence that increasing age in the elderly
population is not associated with any change in the overall prevalence
of pain, although, the pattern of pain prevalence in different body
regions does change with age. More importantly, the extent to which
pain interferes with everyday life increases incrementally with age up
to the oldest age group in the community-dwelling general population
(14).
The aim of this study was to present information on chronic, non-
malignant pain in Germany. In order to identify relevant studies on
chronic pain (> 3 months) 7 databases were searched in the timeframe
from 1995 to 2009. Representative, recent, comprehensive and valid
studies were selected. The prevalence of chronic pain in Germany is
estimated at 17% and varies according to the underlying cause of the
disease. Neck, shoulder and back pain are the most common forms.
Chronic pain has a direct impact on QOL, days off work and costs. A
variety of drugs and non-drug treatments are used. However,
treatment is often inadequate with 13-51% of the patients receiving
insufficient pain therapy. In conclusion, chronic pain is a common
32
problem which influences the QOL of patients resulting in high costs

for the health system. Treatment is often inadequate (15).
A random sample of 6419 participants from a population study (the
third HUNT study in Norway) was invited to report pain on the SF-8
VRS every 3 months over a 12-month period and to report pain lasting
more than 6 months at 12-month follow-up. Completed data were
obtained from 3364 participants. Pain reporting was highly stable
(intraclass correlation 0.66, 95% CI 0.65-0.67), and the prevalence of
chronic pain varied considerably according to level of severity and
persistence: 31% reported mild pain or more, whereas 2% reported
severe pain on 4 of 4 consecutive measurements. When defined as
moderate pain or more on at least 3 of 4 consecutive measurements,
the prevalence was 26%. Compared with the longitudinal
classification, a cross-sectional measure of moderate pain or more
during the last week on the SF-8 scale presented a sensitivity of 82%
and a specificity of 84%, and a sensitivity of 80% and a specificity of
90% when combined with a 6-month recall question. Thus, pain
reporting in the general population is stable and cross-sectional
measures may give valid prevalence estimates of chronic pain (16).
This study aimed to provide best-evidence epidemiological
information about chronic pain in the Netherlands. A systematic
search was performed which yielded 16,619 references, and 119
Dutch studies were relevant. At least 3 studies per question that
provided the most recent, representative and valid data were selected.
The prevalence of moderate to severe general chronic pain among
Dutch adults is estimated at 18%. This prevalence is 27% and 55% for
any cancer pain. Up to 74% of patients with general or non-cancer
chronic pain is treated or semitreated; this percentage is little higher
for patients with cancer pain. A substantial proportion of the patients
received drug treatment for their pain, mainly NSAIDs, but also non-
pharmacological interventions for pain were used. Up to 43% of the
chronic non-cancer pain patients reported not receiving treatment and
up to 79% of the patients believed their pain is inadequately treated.
All studies reported a detrimental effect of chronic pain on QOL,
activities of daily living and mental health. Chronic pain was also
associated with direct and indirect medical costs, and patients may
have decreased income and additional out-of pocket expenses. These
data show that chronic pain occurs frequently, has a negative impact
on the patient and society and treatment may not always be adequate.
Chronic pain is an important public health problem deserving more
attention of Dutch healthcare workers and policy makers (17).
33
In this descriptive, retrospective, cross-sectional study conducted

by analyzing medical records, the data were derived from the medical
records of 497 residents of chronic long-term stay and rehabilitation
nursing home units in 12 Dutch nursing homes. Four groups were
defined: actual (at some time in the previous year) neuropathic pain,
possible neuropathic pain, neuropathic pain in the past, and no signs
of neuropathic pain. The prevalence of actual neuropathic pain was
10.9% (95% CI 8.4-13.8%) and of possible neuropathic pain was
5.6% (95% CI 3.9-7.9%). The most common causes were CPSP and
phantom limb pain. In the subgroup with diabetes mellitus, 6.3% had
nonpainful diabetic polyneuropathy, 0.7% painful DPN, and 0.7%
had possible painful DPN. In the poststroke subsample, 4.7% were
identified as having CPSP, and 5.2% were identified as possibly
having CPSP. Within the actual neuropathic pain group, 68.5% of the
residents received antineuropathic drugs on the day the medical
records were examined, while 48.1% used anticonvulsants. In
conclusion, Dutch nursing home residents frequently experience
neuropathic pain; therefore, neuropathic pain should receive more
attention in frail elderly adults (18).
The main objective of this study was to investigate the prevalence
of current and chronic pain and their relationship to pain intensity,
sex, age, income, employment status, citizenship, marital status, urban
residence, occupational activity, and healthcare-seeking based on a
representative sample from a Swedish county. A cross-sectional
survey using a postal questionnaire was sent to a representative
sample (n=9952) of the target population (284,073 people, age 18-74
years) in a county (Ostergötland) in southern Sweden. A questionnaire
was mailed and followed by 2 postal reminders if necessary. The
participation rate was 76.7% (n=7637); nonparticipants were on
average younger, male, and earned less money. The overall point
prevalence of pain was 48.9%. The corresponding one-month period
prevalence was 63.0%, and pain on several occasions during the
previous 3 months was reported by 61.3% of participants. The
prevalence of chronic pain (pain > 3 months) was 53.7%. Female sex,
age, and sick leave/early retirement were generally of significant
importance in the regressions of pain. Sex factor was not in the
regressions of pain frequency and pain intensity. Chronic pain,
especially frequent and intensive, was associated with healthcare-
seeking and occupational activity. In conclusion, high prevalence of
current pain (48.9%) and chronic pain (53.7%) was in this
community-based study. Being female, older, and on sick leave or
early retirement were generally of significant importance in the
34
regressions of pain. Chronic pain showed associations with

healthcare-seeking and occupational activity, indicating considerable
socioeconomic costs (19).
In order to obtain epidemiological data on chronic pain in Denmark
and Sweden, a literature review of epidemiological data primarily on
chronic non-cancer pain was conducted, prioritizing studies of highest
quality, recency, and validity by conducting a systematic search for
relevant studies. The prevalence of moderate to severe non-cancer
pain was estimated at 16% in Denmark and 18% in Sweden. Chronic
pain affects negatively on perceived health status, QOL and is
associated with increased cost. Despite using pain medications, a large
proportion of chronic pain sufferers have inadequate pain control.
There was a lack of high-quality and low-bias studies with clear
inclusion criteria. This study concludes that in both Denmark and
Sweden, chronic pain is a common health problem, which is
potentially undertreated and warrants attention of health care workers,
policy makers and researchers (20).
The aim of the current study was to estimate the prevalence and
time trend of invalidating musculoskeletal pain in the Spanish
population and its association with socio-demographic factors,
lifestyle habits, self-reported health status, and comorbidity with other
diseases analyzing data from 1993-2006 SNHS. Individualized data
were taken from the surveys SNHS conducted in 1993 (n=20,707),
2001 (n=21,058), 2003 (n=21,650) and 2006 (n=29,478). Invalidating
musculoskeletal pain was defined as pain suffered from the preceding
2 weeks that decreased main working activity or free-time activity by
at least half a day. Socio-demographic characteristics, self-perceived
health status, lifestyle habits, and comorbid conditions using
multivariate logistic regression models were analyzed. Overall, the
prevalence of invalidating musculoskeletal pain in Spanish adults was
6.1% (95% CI 5.7 - 6.4) in 1993, 7.3% (95% CI 6.9 - 7.7) in 2001,
5.5% (95% CI 5.1 - 5.9) in 2003 and 6.4% (95% CI 6 - 6.8) in 2006.
The prevalence of invalidating musculoskeletal pain among women
was almost twice that of men in every year (p<0.05). The multivariate
analysis showed that occupational status (unemployed), sleep < 8
hours/day and having any accident in the preceding year were
significantly associated in both gender with a higher likelihood of
suffering from invalidating musculoskeletal pain among Spanish
adults. Within men, other predictors of invalidating musculoskeletal
pain were to be married and lower educational level, whereas in
women were age of 45-64 years old (OR 1.89, 95% CI 1.32 - 2.7),
obesity (OR 1.23, 95% CI 1.06 - 1.42), a sedentary lifestyle (OR 1.23,
35
95% CI 1.06 - 1.42), and presence of comorbid chronic diseases (OR

1.32, 95% CI 1.14 - 1.53). Worse self-reported health status was
related to a greater prevalence of invalidating musculoskeletal pain
(OR 6.88, 95% CI 5.62 - 8.40 for men, OR 7.24, 95% 6.11 - 8.57 for
women). The prevalence of invalidating musculoskeletal pain
increased from 1993 to 2001 for both men (OR 1.31, 95% CI 1.08 -
1.58) and women (OR 1.19, 95% CI 1.03 - 1.39) with insignificant
increase from the remaining surveys. These results suggest that
invalidating musculoskeletal pain deserves an increased awareness
among health professionals. Public Health Services should provide
more educational programs, which address postural hygiene, physical
exercise, and how to prevent obesity and sedentary lifestyle habits.
This population-based study indicates that invalidating
musculoskeletal pain that reduces main working activity is a public
health problem in Spain. The prevalence of invalidating
musculoskeletal pain is higher in women than in men and is associated
with lower income, poor sleeping, worse self-reported health status,
and other comorbid conditions. The prevalence of invalidating
musculoskeletal pain increased from 1993 to 2001, but remained
stable in the last years (2001 to 2006) (21).
Data were from the Internet-based, 2010 NHWS also conducted in
Spain. The sample was weighted by age and sex to correspond to the
2010 adult Spanish population. All respondents to the NHWS reported
on socio-demographic and economic characteristics, medication
adherence and major health conditions. They also reported on their
HRQL (the SF-12), their employment status and workplace
productivity experience (WPAI instrument) and their healthcare
resource utilization. Persons reporting experiencing pain gave details
on conditions causing pain, prescription and OTC medication
utilization, duration of utilization and satisfaction with medications.
An estimated 6.10 million (17.25%) of the adult population of Spain
reported experiencing pain in the last month. Of these, 11.7%
experienced severe pain, 64.2% moderate pain and 24.1% mild pain.
Daily pain was experienced by 6.95% of the population. The major
conditions causing pain were back pain (60.5%) followed by joint
pain (40.2%). Sleep difficulties (42.2%) and anxiety (40.6%) were
most commonly cited as comorbidities. Prescription medication
utilization was most important in the severe and moderate pain
categories, with 71.6% reporting they were satisfied with their
prescription pain medications. Adherence to pain medications was
high with an overall Morisky score of 0.99 (range 0-4). Pain had a
major negative effect on labor force participation for those reporting
36
moderate and severe pain with a participation rate of only 42.6% for
those with severe pain. Pain was associated with substantial HRQL
deficits as measured by the physical and mental score components of
the SF-12. In the case of SF-6D utilities, the utility score for the pain
population was markedly below that for the no-pain population (0.65
vs. 0.75, p < 0.05). The experience of pain also negatively affected
rates of absenteeism and presenteeism, as well as being associated
with greater healthcare resource utilization. For the 5 most populous
autonomous communities of Spain, estimated pain prevalence ranged
from 14.8% for Madrid to 18.8% for Comunidad Valenciana. This
study concludes that the experience of pain represents a substantial
burden on both individuals and the Spanish economy, and is
associated with a substantial reduction in both the PCS component of
the SF-12 and SF-6D absolute utilities - most notably in respect to
severe pain. The experience of pain is also associated, with not only
reduced labor force participation and increased absenteeism and
presenteeism, but with substantially higher patterns of healthcare
resource utilization (22).
A cross-sectional nationwide epidemiological study was performed
in a random sample of the Portuguese adult population aiming to
describe the prevalence and impact of chronic pain. The 5,094
participants were selected by random digit dialing, between January
2007 and March 2008, and estimates were adequately weighted for the
population. Prevalence of chronic pain was 36.7% (95% CI 35.3 -
38.2), based on the definition of the International Association for the
Study of Pain. Recurrent or continuous pain was present in 85% of
those with chronic pain, and moderate-to-severe intensity and
disability were present in 68% and 35%, respectively. Highest chronic
pain prevalence was observed among the elderly, retired, unemployed,
and less educated. Highest disability was found in relation with
family/home responsibilities, recreational activities, occupation/work,
and sleep/rest; 13% reported a diagnosis of depression and 49%
reported interference in their job. The main factors associated with
disability were sex, pain intensity, and depression or depressive
symptoms. Chronic pain is highly prevalent, causes high personal and
social burden, and affects particularly the most vulnerable subgroups.
Portugal, depending on chronic pain definition, could be placed in the
lower prevalence group in Europe. Improvement in pain intensity
management and special attention to affective components of chronic
pain are recommended. In conclusion, chronic pain is a significant
problem that is present in 37% of the Portuguese adult general
population, and is associated with high personal, family, and social
37
burden, and affects in particular the most vulnerable subgroups of the

population (23).
There are few studies estimating the prevalence of chronic pain in
countries from the Middle East. The Structured Telephone Interviews
Questionnaire on chronic pain was translated from English into Arabic
and assessed its reliability and linguistic validity before using it in a
telephone survey in Libya to gather preliminary prevalence data for
chronic pain. In a telephone survey participated 104 individuals. The
prevalence of chronic pain was 25.0% (95% CI 16.7 - 33.3%) and
50.0% (95% CI 30.8 - 69.2%) of the participants with chronic pain
scored ≥ 12 on the Arabic S-LANSS. Mean ± SD duration of pain was
2.8 ± 1.2 years, and pain was more frequent in women (p=0.02);
53.8% of participants had taken prescription medication for their pain,
and 76.9% had used nondrug methods of treatment including
traditional Libyan methods such as Kamara, a local herbal concoction.
While 80% believed that their doctor would rather treat their illness
than their pain, and 35% reported that their doctor did not think that
their pain was a problem. Some participants complained that the
questionnaire was too long with mean ± SD call duration of 20 ± 5.4
minutes. In conclusion, the Arabic Structured Telephone Interviews
Questionnaire on chronic pain was reliable and linguistically valid and
can be used in a large-scale telephone survey on the Libyan
population (24).
This was the population-based study in South America, and the
third in the world, to use the Douleur Neuropathique fourth
Questionnaire tool in epidemiologic studies. The main objectives of
this study were to estimate the prevalence and associated factors of
chronic pain with and without neuropathic characteristics in São Luís,
Brazil. The 1597 participants were served. The Douleur
Neuropathique fourth questionnaire was applied. The prevalence of
chronic pain was 42%, and 10% had chronic pain with neuropathic
characteristics. The results showed that female sex and age ≥ 30 years
were associated with an increased prevalence of chronic pain
(p<0.001) and education ≥ 12 years with a reduction in the prevalence
of chronic pain. The sensations listed in the questionnaire were more
common in people with chronic pain with neuropathy and most
frequent were pins and needles (87.9%). The cephalic region (36%)
and limbs (51%) were the locations most affected. Most respondents
felt pain between 4 months and 4 years (51.6%), with daily frequency
(45%). Pain intensity, the impediments caused by pain, and sadness
were more prevalent in people who had chronic pain with neuropathy
(p<0.001). Health status was regular for most, 50.9% did not know the
38
cause of their pain, 64.1% used drugs, and only 7% had consulted
with a pain specialist. Dissatisfaction with treatment was reported by
55%. These data indicate that chronic pain with and without
neuropathic characteristics is a public health problem in Brazil, with
high prevalence and great influence on people's daily lives (25).
The main aim of this study was to determine the prevalence of
chronic pain in the general population of Hong Kong, to evaluate the
relationship of chronic pain with sociodemographic and lifestyle
factors, and to describe the pain characteristics among chronic pain
sufferers. A total of 5.001 adults aged ≥ 18 years (response rate 58%)
drawn from the general population of Hong Kong completed the
Chronic Pain Grade questionnaire, providing information on chronic
pain and sociodemographic status using telephone interviews. Overall,
34.9% reported pain lasting more than 3 months (chronic pain),
having an average of 1.5 pain sites; 35.2% experienced multiple pain
sites, most commonly of the legs, back, and head with leg and back
rated as the most significant pain areas among those with multiple
pain problems. The chronic pain grade criteria classified as 21.5% in
those with chronic pain symptoms as Grade III or above. Fully
adjusted stepwise regression analyses identified being female, older
age, divorced/separated, having part-time employment, existing long-
term health problems, higher HADS Anxiety scores, poor QOL
(mental health component), and low self-perceived health to be
significantly associated with chronic pain. These data evidenced that
chronic pain is common in the general population of Hong Kong, and
the prevalence is highest among women and middle-aged adults (26).
This study estimated the co-occurrence of three conditions in terms
of prevalence and associated factors in the general adult population. In
a population-based, cross-sectional telephone survey, 5001 adults
aged ≥ 18 years drawn also from the Hong Kong general population
completed the Chronic Pain Grade questionnaire, the PSQI, the
Chronic Fatigue Scale, HADS, and socio-demographic questions. The
overall prevalence of reporting all three chronic conditions was 5.6%
(95% CI: 4.9-6.4) and increased with age, being higher in women, and
those in lower income and education level groups. Individuals with
multiple symptoms also reported poorer mental health, and self-
perceived health. Results of multi-ordinal regression analyses
identified female, divorced/separated, having part time employment,
retirees, unemployment, housewives, existing long-term health
problems, higher HADS scores, and low self-perceived health to be
significantly associated with reporting all three symptoms. This study
has shown that the co-occurrence of chronic pain, fatigue, and sleep
39
disturbances was common in the general adult population. Multiple

symptoms are comorbid of psychological distress (27).
A survey of Clalit Health Services members in Israel was
conducted, interviewing them by phone. A random sample of 4063
Clalit members, 25 years or older and Hebrew speakers, were
screened for chronic pain, defined as: any pain or discomfort that in
the last 6 months has persisted continuously or intermittently for more
than 3 months. Eight percent (n=325) refused to participate. Of the
3738 included in the study, 1722 (46%) reported chronic pain in at
least 1 site. Most were over 50-year-old patients (62%) (mean age 56
+/- 16, range 27-97 years). Women suffered significantly more than
men, as did those who were older, less educated and born in Israel and
Eastern Europe. Prevalent painful sites were the back (32%), limbs
(17%) and head (13%). More than a third reported severe pain and
impaired life activities. Only 4.8% of the patients suffering from
chronic pain were referred to pain specialists and 11% used
complementary medicine. A logistic regression model showed that
women and patients with a low education level were significant
variables predicting higher life impact index and higher pain severity.
In conclusion, a high prevalence of chronic pain was found in the
study population. Chronic pain caused severe disturbance to QOL. A
low rate of referral to pain specialists and complementary medicine
was observed (28).
Assessment: individuals suffer from chronic pain in all countries,

whether developed or developing, although different prevalence rates
are observed. Chronic pain is a common health problem, which is
potentially undertreated and warrants attention of health care workers,
policy makers and researchers.
Co-occurrence of chronic pain with fatigue, and sleep disturbances
is common in the general adult population. Chronic pain shows
associations with healthcare-seeking and occupational activity,
indicating considerable socioeconomic costs. Chronic pain occurs
frequently, having a negative effect on the patient and society.
References
1. Landmark T, Romundstad P, Dale O, et al. Estimating the prevalence of
chronic pain: validation of recall against longitudinal reporting (the HUNT pain
study). Pain. 2012;153(7):1368-73.
2. Abu-Saad Huijer H. Chronic pain: a review. J Med Liban. 2010;58(1):21-7.
Erratum in: J Med Liban. 2010;58(2):110.
3. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public
Health. 2011 Oct 6;11:770.
40
4. Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat

Med. 2010;16(11):1248-57.
5. Elzahaf RA, Tashani OA, Unsworth BA, Johnson MI. The prevalence of
chronic pain with an analysis of countries with a Human Development Index less than
0.9: a systematic review without meta-analysis. Curr Med Res Opin. 2012;
28(7):1221-9.
6. Tsang A, Von Korff M, Lee S, Alonso J, et al. Common chronic pain
conditions in developed and developing countries: gender and age differences and
comorbidity with depression-anxiety disorders. J Pain. 2008;9(10):883-91. Erratum
in: J Pain. 2009;10(5):553. Demytteneare, K [added].
7. Johannes CB, Le TK, Zhou X, et al. The prevalence of chronic pain in United
States adults: results of an Internet-based survey. J Pain. 2010; 11(11):1230-9.
8. Portenoy RK, Ugarte C, Fuller I, Haas G. Population-based survey of pain in
the United States: differences among white, African American, and Hispanic subjects.
J Pain. 2004;5(6):317-28.
9. Cosby AG, Hitt HC, Thornton-Neaves T, et al. Profiles of pain in Mississippi:
results from the Southern Pain Prevalence Study. J Miss State Med Assoc. 2005;
46(10):301-9.
10. Reitsma ML, Tranmer JE, Buchanan DM, Vandenkerkhof EG. The prevalence
of chronic pain and pain-related interference in the Canadian population from 1994 to
2008. Chronic Dis Inj Can. 2011;31(4):157-64.
11. Reid KJ, Harker J, Bala MM, et al. Epidemiology of chronic non-cancer pain
in Europe: narrative review of prevalence, pain treatments and pain impact. Curr Med
Res Opin. 2011;27(2):449-62.
12. Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe:
prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10(4):287-333.
13. Langley PC, Van Litsenburg C, Cappelleri JC, Carroll D. The burden
associated with neuropathic pain in Western Europe. J Med Econ. 2013; 16(1):85-
952012.
14. Thomas E, Peat G, Harris L, et al. The prevalence of pain and pain
interference in a general population of older adults: cross-sectional findings from the
North Staffordshire Osteoarthritis Project (NorStOP). Pain. 2004;110(1-2):361-8.
15. Wolff R, Clar C, Lerch C, Kleijnen J. Epidemiology of chronic non-malignant
pain in Germany. Schmerz. 2011;25(1):26-44.
16. Landmark T, Romundstad P, Dale O, et al. Estimating the prevalence of
chronic pain: validation of recall against longitudinal reporting (the HUNT pain
study). Pain. 2012;153(7):1368-73.
17. Bekkering GE, Bala MM, Reid K, et al. Epidemiology of chronic pain and its
treatment in The Netherlands. Neth J Med. 2011;69(3):141-53.
18. van Kollenburg EG, Lavrijsen JC, Verhagen SC, et al. Prevalence, causes, and
treatment of neuropathic pain in Dutch nursing home residents: a retrospective chart
review. J Am Geriatr Soc. 2012;60(8):1418-25.
19. Gerdle B, Björk J, Henriksson C, Bengtsson A. Prevalence of current and
chronic pain and their influences upon work and healthcare-seeking: a population
study. J Rheumatol. 2004;31(7):1399-406.
20. Harker J, Reid KJ, Bekkering GE, et al. Epidemiology of chronic pain in
denmark and sweden. Pain Res Treat. 2012;2012:371248.
21. Jiménez-Sánchez S, Jiménez-García R, Hernández-Barrera V, et al. Has the
prevalence of invalidating musculoskeletal pain changed over the last 15 years (1993-
2006)? A Spanish population-based survey. J Pain. 2010; 11(7):612-20.
22. Langley PC, Ruiz-Iban MA, Molina JT, et al. The prevalence, correlates and
treatment of pain in Spain. J Med Econ. 2011;14(3):367-80.
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23. Azevedo LF, Costa-Pereira A, Mendonça L, et al. Epidemiology of chronic

pain: a population-based nationwide study on its prevalence, characteristics and
associated disability in Portugal. J Pain. 2012;13(8):773-83.
24. Elzahaf RA, Tashani OA, Johnson MI. Prevalence of Chronic Pain Among
Libyan Adults in Derna City: A Pilot Study to Assess the Reliability, Linguistic
Validity, and Feasibility of Using an Arabic Version of the Structured Telephone
Interviews Questionnaire on Chronic Pain. Pain Pract. 2012 Sep 17.
25. de Moraes Vieira EB, Garcia JB, da Silva AA, et al. Prevalence,
characteristics, and factors associated with chronic pain with and without neuropathic
characteristics in São Luís, Brazil. J Pain Symptom Manage. 2012;44(2):239-51.
26. Wong WS, Fielding R. Prevalence and characteristics of chronic pain in the
general population of Hong Kong. J Pain. 2011;12(2):236-45.
27. Wong WS, Fielding R. The co-morbidity of chronic pain, insomnia, and
fatigue in the general adult population of Hong Kong: Prevalence and associated
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28. Neville A, Peleg R, Singer Y, et al. Chronic pain: a population-based study.
Isr Med Assoc J. 2008;10(10):676-80.
MECHANISMS OF CHRONIC PAIN

The mechanisms involved in the development of chronic pain are
varied and complex. Pain processes are plastic and unrelieved pain
may lead to changes in the neural structure involved in pain
generation. Nociceptive pain announces the presence of a potentially
damaging stimulus that occurs when noxious stimuli activate primary
afferent neurons. Neuropathic pain is initiated or caused by a primary
lesion or dysfunction in the nervous system resulting from trauma,
infection, ischemia, cancer or other causes such as chemotherapy. The
exact mechanisms involved in the pathophysiology of chronic pain are
not well understood, but rapid and long-term changes occur in parts of
the CNS that are involved in the transmission and modulation of pain
following injury. Peripheral and central sensitization of sensory nerve
fibers are the primary reasons for hypersensitivity to pain after injury,
and mainly occur in inflammatory and neuropathic pain. During these
processes, the sensation of pain is enhanced due to changes in the
environment, the nerve fibers and modifications of the functional
properties and the genetic program of primary and secondary afferent
neurons. NSAIDs and opioid analgesics are 2 of the most common
classes of drugs used for the treatment of pain. Response to drug
treatment shows significant interindividual variability and can lead to
side effects. The neurobiological mechanisms that cause pain may
account for the different types of pain observed. Identification of these
42
mechanisms may allow moving from an empirical therapeutic

approach that it is specifically targeted at the particular mechanisms of
the type of pain experienced by an individual patient (1).
Mechanisms underlying chronic pain differ from those underlying
acute pain. In chronic pain states, CNS factors appear to play
particularly prominent roles. In the absence of anatomical causes of
persistent pain, medical sub-specialities have historically applied
wide-ranging labels (e.g., fibromyalgia, IBS, interstitial cystitis, and
somatization) for what now is emerging as a single common set of
CNS processes. The hallmark of these 'centrally driven' pain
conditions is a diffuse hyperalgesic state identifiable using
experimental sensory testing, and corroborated by functional
neuroimaging. The characteristic symptoms of these central pain
conditions include multifocal pain, fatigue, insomnia, memory
difficulties and a higher rate of co-morbid mood disorders. In contrast
to acute and peripheral pain states that are responsive to NSAID and
opioids, central pain conditions respond best to CNS neuromodulating
agents, such as SNRI and anticonvulsants (2).
Pain mechanism
The purpose of this study was to evaluate the discriminative

validity of mechanisms-based classifications of pain by identifying
discriminatory clusters of clinical criteria predictive of "nociceptive,"
"peripheral neuropathic," and "central sensitization" pain in patients
with LBP (± leg) disorders. This study was a cross-sectional, between-
patients design using the extreme-groups method. Four hundred sixty-
four patients with LBP (± leg) were assessed using a standardized
assessment protocol. After each assessment, patients' pain was
assigned a mechanisms-based classification. Clinicians then
completed a clinical criteria checklist indicating the presence/absence
of various clinical criteria. Multivariate analyses using binary logistic
43
regression with Bayesian model averaging identified a discriminative

cluster of 7, 3, and 4 symptoms and signs predictive of a dominance of
"nociceptive," "peripheral neuropathic," and "central sensitization"
pain, respectively. Each cluster had high levels of classification
accuracy (sensitivity, specificity, positive/negative predictive values,
and positive/negative likelihood ratios). By identifying a
discriminatory cluster of symptoms and signs predictive of
"nociceptive," "peripheral neuropathic," and "central" pain, this study
provides some preliminary discriminative validity evidence for
mechanisms-based classifications of musculoskeletal pain.
Classification system validation requires the accumulation of validity
evidence before their use in clinical practice can be recommended (3).
Nociceptor inputs can trigger a prolonged but reversible increase in
the excitability and synaptic efficacy of neurons in central nociceptive
pathways, the phenomenon of central sensitization. Central
sensitization manifests as pain hypersensitivity, particularly dynamic
tactile allodynia, secondary punctate or pressure hyperalgesia, after
sensations, and enhanced temporal summation. It can be readily and
rapidly elicited in human volunteers by diverse experimental noxious
conditioning stimuli to skin, muscles or viscera, and in addition to
producing pain hypersensitivity, results in secondary changes in brain
activity that can be detected by electrophysiological or imaging
techniques. Changes in pain sensitivity have been interpreted as
revealing an important contribution of central sensitization to the pain
phenotype in patients with fibromyalgia, osteoarthritis,
musculoskeletal disorders with generalized pain hypersensitivity,
headache, temporomandibular joint disorders, dental pain, neuropathic
pain, visceral pain hypersensitivity disorders and post-surgical pain.
The comorbidity of those pain hypersensitivity syndromes that present
in the absence of inflammation or a neural lesion, their similar pattern
of clinical presentation and response to centrally acting analgesics
may reflect a commonality of central sensitization to their
pathophysiology. An important question that still needs to be
determined is whether there are individuals with a higher inherited
propensity for developing central sensitization than others, and if so,
whether this conveys an increased risk in both developing conditions
with pain hypersensitivity, and their chronification. Diagnostic criteria
to establish the presence of central sensitization in patients will greatly
assist the phenotyping of patients for choosing treatments that produce
analgesia by normalizing hyperexcitable central neural activity. We
have certainly come a long way since the first discovery of activity-
dependent synaptic plasticity in the spinal cord and the revelation that
44
it occurs and produces pain hypersensitivity in patients. Nevertheless,

discovering the genetic and environmental contributors to and
objective biomarkers of central sensitization will be highly beneficial,
as will additional treatment options to prevent or reduce this prevalent
and promiscuous form of pain plasticity (4).
Central sensitization represents an enhancement in the function of
neurons and circuits in nociceptive pathways caused by increases in
membrane excitability and synaptic efficacy as well as to reduced
inhibition and is a manifestation of the remarkable plasticity of the
somatosensory nervous system in response to activity, inflammation,
and neural injury. The net effect of central sensitization is to recruit
previously subthreshold synaptic inputs to nociceptive neurons,
generating an increased or augmented action potential output: a state
of facilitation, potentiation, augmentation, or amplification. Central
sensitization is responsible for many of the temporal, spatial, and
threshold changes in pain sensibility in acute and chronic clinical pain
settings and exemplifies the fundamental contribution of the CNS to
the generation of pain hypersensitivity. Because central sensitization
results from changes in the properties of neurons in the CNS, the pain
is no longer coupled, as acute nociceptive pain is, to the presence,
intensity, or duration of noxious peripheral stimuli. Instead, central
sensitization produces pain hypersensitivity by changing the sensory
response elicited by normal inputs, including those that usually evoke
innocuous sensations. There are the major triggers that initiate and
maintain central sensitization in healthy individuals in response to
nociceptor input in patients with inflammatory and neuropathic pain
as well as multiple mechanisms of synaptic plasticity caused by
changes in the density, nature, and properties of ionotropic and
metabotropic glutamate receptors (5).
Peripheral sensitization of the nociceptors by inflammatory mediators.

45
Few patients with chronic pain obtain complete relief from the
drugs that are currently available, and more than half report
inadequate relief. Underlying the challenge of developing better drugs
to manage chronic pain is incomplete understanding of the
heterogeneity of mechanisms that contribute to the transition from
acute tissue insult to chronic pain and to pain conditions for which the
underlying pathology is not apparent. An intact CNS is required for
the conscious perception of pain, and changes in the CNS are clearly
evident in chronic pain states. However, the blockage of nociceptive
input into the CNS can effectively relieve or markedly attenuate
discomfort and pain, revealing the importance of ongoing peripheral
input to the maintenance of chronic pain (6).
Numerous animal models of chronic pain following nerve injury
have been introduced. All these neuropathic pain models are generated
by partial nerve injury, where a few primary afferents are axotomized,
while the others are spared. Among these models, the L5 spinal nerve
ligation model is unique because in this model, the L4 DRG neurons
are clearly separated from the axotomized L5 DRG neurons. Previous
studies have focused considerable attention on the directly damaged
primary afferents and their influence on the activity of the dorsal horn
neurons. However, increasing evidence suggests that DRG neurons
with intact axons also exhibit alterad excitability and gene expression,
and these changes might play functional roles in the pathomechanisms
of neuropathic pain. For example, L5 spinal nerve ligation increases
the expression of SP, calcitonin gene-related peptide, brain-derived
neurotrophic factor, and the transient receptor potential ion channels
TRPV1 and TRPA1 in the uninjured L4 DRG neurons. Compelling
evidence suggests that the glial cells in the spinal cord may also play a
role in the pathogenesis of neuropathic pain. Recent studies have
shown that peripheral nerve injury results in the activation of mitogen-
activated protein kinases in spinal glial cells and mitogen-activated
protein kinase inhibitors diminish nerve injury-induced pain
hypersensitivity (7).
SP signaling facilitates nociceptive sensitization in various
inflammatory and chronic pain models and SP signaling might
contribute to the development of post-incisional hyperalgesia. These
studies used mice with a deletion of the pre-protachykinin A gene
(ppt-A(-/-)) which codes for SP to determine the role of SP signaling
in post-incisional pain and in the increased cytokine and nerve growth
factor expression observed in the incised skin. SP deficient ppt-A(-/-)
mice displayed reduced mechanical allodynia and heat hyperalgesia
compared to the wild-type mice at all post-incision time points,
46
despite similar baseline values (p<0.001). The NK-1 receptor

antagonist LY303870 attenuated mechanical allodynia produced by
incision in the wild micee (p<0.001). Incision also up-regulated IL-6,
TNF-alpha and keratinocyte levels but not IL-1beta after 2 hours in
the wild-type mice skin. However, ppt-A(-/-) mice had more skin
NGF levels 2 hours post-incision. SChind paw SP injection produced
acute and transient elevations of IL-1beta, IL-6, and keratinocyte but
modest elevations in TNF-alpha levels in the wild-type mice.
Systemic LY303870 reversed the SP-induced elevations of these
cytokines. Hind paw injection of IL-6 and nerve growth factor dose
dependently produced less mechanical allodynia in the ppt-A(-/-)
compared to wild mice. Additionally, SP produced mechanical
allodynia in a dose-dependent fashion in wild-type mice. Therefore,
SP supports nociceptive sensitization after hind paw incision and
potentially participates directly in modulating the intensity of
inflammatory response in peri-incisional tissue (8).
Nerve growth factor is the founding member of the neurotrophins
family of proteins. It was discovered more than half a century ago
through its ability to promote sensory and sympathetic neuronal
survival and axonal growth during the development of the peripheral
nervous system, and is the paradigmatic target-derived neurotrophic
factor on which the neurotrophic hypothesis is based. Since that time,
nerve growth factor has also been shown to play a key role in the
generation of acute and chronic pain and in hyperalgesia in diverse
pain states. Nerve growth factor is expressed at high levels in
damaged or inflamed tissues and facilitates pain transmission by
nociceptive neurons through a variety of mechanisms. Genetic
mutations in nerve growth factor or its tyrosine kinase receptor TrkA,
leads to a congenital insensitivity or a decreased ability of humans to
perceive pain. The HSANs encompass a spectrum of neuropathies that
affect one's ability to perceive sensation. HSAN type IV and HSAN
type V are caused by mutations in TrkA and nerve growth factor
respectively. Neuropathies and clinical presentations result from the
disruption of nerve growth factor signaling in HSAN type IV and
HSAN type V (9).
Assessment: mechanisms involved in the development of chronic

pain are varied and complex. Nociceptive pain announces the
presence of a potentially damaging stimulus that occurs when noxious
stimuli activate primary afferent neurons. Neuropathic pain is initiated
or caused by a primary lesion or dysfunction in the nervous system
resulting from trauma, infection, ischemia, cancer or other causes such
as chemotherapy. Pain processes are plastic and unrelieved pain may
47
lead to changes in the neural structure involved in pain generation. In

chronic pain, rapid and long-term changes occur in parts of the CNS
that are involved in the transmission and modulation of pain following
injury.
References
1. Fornasari D. Pain mechanisms in patients with chronic pain. Clin Drug
Investig. 2012;32 Suppl 1:45-52.
2. Phillips K, Clauw DJ. Central pain mechanisms in chronic pain states - maybe
it is all in their head. Best Pract Res Clin Rheumatol. 2011;25(2):141-54.
3. Smart KM, Blake C, Staines A, Doody C. The discriminative validity of
"nociceptive," "peripheral neuropathic," and "central sensitization" as mechanisms-
based classifications of musculoskeletal pain. Clin J Pain. 2011;27(8):655-63.
4. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of
pain. Pain. 201;152(3 Suppl):S2-15.
5. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain
hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895-926.
6. Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat
Med. 2010;16(11):1248-57.
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cells to pathomechanisms of neuropathic pain. Brain Nerve. 2008; 60(5):483-92.
8. Sahbaie P, Shi X, Guo TZ, et al. Role of substance P signaling in enhanced
nociceptive sensitization and local cytokine production after incision. Pain.
2009;145(3):341-9.
9. McKelvey L, Shorten GD, O'Keeffe GW. Nerve growth factor-mediated
regulation of pain signalling and proposed new intervention strategies in clinical pain
management. J Neurochem. 2013;124(3):276-89.
CHARACTERISTICS OF NEUROPATHIC PAIN

Neuropathic pain (associated with lesions or dysfunction of
nervous system) is a disease of global burden (1), relatively common,
occurring in about 1-1.5% of the population (2).
Pain, both acute and chronic, affects millions of people in the US.
Although estimates of DPN vary widely depending on the assessment
criteria employed, as many as 50% of people with diabetes have some
degree of DPN. Painful postherpetic neuralgia develops secondary to
herpes zoster infection, and there are 600,000 to 800,000 cases of
herpes zoster in the US each year, with 9-24% of patients progressing
to post-herpetic neuralgia (3).
Central neuropathic pain is found in SCI, MS, and some strokes.
Aside from diabetes and other metabolic conditions, the common
causes of painful peripheral neuropathies are herpes zoster infection,
HIV-related neuropathies, nutritional deficiencies, toxins, remote
48
manifestations of malignancies, immune mediated disorders and

physical trauma to a nerve trunk (4,5).
Symptoms of neuropathic pain include spontaneous and stimulus-
evoked painful sensations. Several maladaptive mechanisms
underlying these symptoms have been elucidated in recent years:
peripheral sensitization of nociception, abnormal excitability of
afferent neurons, central sensitization comprising pronociceptive
facilitation, disinhibition of nociception and central reorganization
processes, and sympathetically maintained pain (1).
Although neuropathic pain can be acute in nature, in most patients
the pain is persistent (or "refractory"). Patients with chronic
neuropathic pain are seen most often in clinical practice. It consists of
a number of different disease-specific indications, each of which can
have differing diagnostic definitions and cutoffs. Patients with
neuropathic pain experience a poor HRQL and consume a high level
of healthcare resources, and costs (6).
Peripheral neuropathies are a heterogeneous group of diseases
affecting peripheral nerves. The causes are multiple: hereditary,
metabolic, infectious, inflammatory, toxic, traumatic. The temporal
profile includes acute, subacute and chronic conditions. The majority
of peripheral neuropathies cause mainly muscle weakness and sensory
loss, positive sensory symptoms and sometimes pain. When pain is
present, however, it is usually extremely intense and among the most
disabling symptoms for the patients. In addition, the neurological
origin of the pain is often missed and patients receive inadequate or
delayed specific treatment. Independently of the disease causing the
peripheral nerve injury, pain originating from axonal pathology or
ganglionopathy privileges neuropathies affecting smaller fibres, a
clinical observation that points towards abnormal activity within
nociceptive afferents as a main generator of pain. Natural activation of
blood vessels or perineurial nociceptive network by pathology also
causes intense pain. Pain of this kind, i.e. nerve trunk pain, is among
the heralding symptoms of inflammatory or ischemic mononeuropathy
and for its intensity represents itself a medical emergency.
Neuropathic pain quality rekindles the psychophysical experience of
peripheral nerves intraneural microstimulation i.e. a combination of
large and small fibres sensation temporally distorted compared to
physiological perception evoked by natural stimuli. Pins and needles,
burning, cramping mixed with numbness, and tingling are the wording
most used by patients. Nociceptive pain instead is most often
described as aching, deep and dull. Good command of peripheral
nerve anatomy and pathophysiology allows timely recognition of the
49
different pain components and targeted treatment, selected according

to intensity, type and temporal profile of the pain (7).
There are specific cellular and molecular changes that affect
membrane excitability and induce new gene expression after nerve
injury, thereby allowing for enhanced responses to future stimulation.
The ectopic impulses of neuroma, changes of sodium and calcium
channels in injured nerves, sympathetic activation, and deficient
central inhibitory pathway contribute to the mechanisms of
neuropathic pain (8,9).
Neuropathic pain is caused by functional abnormalities of
structural lesions in the peripheral or CNS, and occurs without
peripheral nociceptor stimulation (8,9). Neuropathic pain is a chronic
pain syndrome caused by drug-, disease-, or injury-induced damage or
destruction of sensory neurons within the DRG of the peripheral
nervous system (10). Many common diseases, such as postherpetic
neuralgia, trigeminal neuralgia, DPN, SCI, cancer, stroke, and
degenerative neurological diseases may produce neuropathic pain
(8,9). Neuropathic pain, resulting from a lesion, damage, or
dysfunction of the somatosensory nervous system, can also arise
through several distinct etiologies ranging from toxicity, surgery,
radiation, trauma, and congenital disorders (11).
Neuropathic pain syndromes - pain after a lesion or disease of the
peripheral or CNS are clinically characterized by spontaneous and
evoked types of pain, which are underpinned by various distinct
pathophysiological mechanisms in the peripheral and central nervous
systems. In some patients, the nerve lesion triggers molecular changes
in nociceptive neurons, which become abnormally sensitive and
develop pathological spontaneous activity. Inflammatory reactions of
the damaged nerve trunk can induce ectopic nociceptor activity,
causing spontaneous pain. The hyperactivity in nociceptors induces
secondary changes in processing neurons in the spinal cord and brain,
so that input from mechanoreceptive A-fibers is perceived as pain.
Neuroplastic changes in the central pain modulatory systems can lead
to further hyperexcitability (12).
Studies in animal models describe a number of peripheral and
central pathophysiological processes after nerve injury that would be
the basis of underlying neuropathic pain mechanism. A change in
function, chemistry, and structures of neurons (neural plasticity)
underlie the production of the altered sensitivity characteristics of
neuropathic pain. Peripheral sensitization acts on the nociceptors, and
central sensitization takes place at various levels ranging from the
dorsal horn to the brain. In addition, abnormal interactions between
50
the sympathetic and sensory pathways contribute to mechanisms

mediating neuropathic pain (13).
A variety of distinct pathophysiological mechanisms in the
peripheral and CNS operate in concert: In some patients, the nerve
lesion triggers molecular changes in nociceptive neurons that become
abnormally sensitive and develop pathological spontaneous activity
(upregulation of sodium channels and receptors, e.g., vanilloid TRPV1
receptors, menthol-sensitive TRPM8 receptors, or alpha-receptors).
These phenomena may lead to spontaneous pain, shooting pain
sensations, as well as heat hyperalgesia, cold hyperalgesia, and
sympathetically maintained pain. Spontaneous activity in damaged
large nonnociceptive A-fibers may lead to paresthesias. All these
changes may also occur in uninjured neurons driven by substances
released by adjacent dying cells and should receive more attention in
the future. The hyperactivity in nociceptors in turn induces secondary
changes (hyperexcitability) in processing neurons in the spinal cord
and brain. This central sensitization causes input from
mechanoreceptive A-fibers to be perceived as pain (mechanical
allodynia). Neuroplastic changes in the central descending pain
modulatory systems (inhibitory or facilitatory) may lead to further
hyperexcitability (14).
The development of pain after peripheral nerve and tissue injury
involves not only neuronal pathways but also immune cells and glia.
Central sensitization is thought to be a mechanism for such persistent
pain, and ATP involves in the process. The contribution of glia to
neuronal excitation in the juvenile rat spinal dorsal horn, which is
subjected to neuropathic and inflammatory pain, was examined. In
rats subjected to neuropathic pain, immunoreactivity for the microglial
marker OX42 was markedly increased. By contrast, in rats subjected
to inflammatory pain, immunoreactivity for the astrocyte marker glial
fibrillary acidic protein was increased slightly. Optically recorded
neuronal excitation induced by single-pulse stimulation to the dorsal
root was augmented in rats subjected to neuropathic and inflammatory
pain compared to control rats. The bath application of a glial inhibitor
minocycline and a p38 mitogen-activated protein kinase inhibitor
SB203580 inhibited the neuronal excitation in rats subjected to
neuropathic pain. A specific P2X1,2,3,4 antagonist 2'-(or-3')-O-
(trinitrophenyl)adenosine 5'- tri-phosphate (TNP-ATP) largely
inhibited the neuronal excitation only in rats subjected to neuropathic
pain rats. By contrast, an astroglial toxin L-alpha-aminoadipate, a gap
junction blocker carbenoxolone and c-Jun N-terminal kinase inhibitor
SP600125 inhibited the neuronal excitation only in rats subjected to
51
inflammatory pain. A greater number of cells in spinal cord slices

from rats subjected to neuropathic pain showed Ca2+ signaling in
response to puff application of ATP. This Ca2+ signaling was
inhibited by minocycline and TNP-ATP. These results directly
support the notion that microglia is more involved in neuropathic pain
and astrocyte in inflammatory pain (15).
Neuropathic pain is induced by injury or disease of the nervous
system. Animal models of neuropathic pain mostly use injury to a
peripheral nerve, therefore, our focus is on results from nerve injury
models. To make sure that the nerve injury models are related to pain,
the behavior was assessed of animals following nerve injury, i.e.
partial/total nerve transection/ligation or chronic nerve constriction.
The following behaviors observed in such animals are considered to
indicate pain: (a) autotomy, i.e. self-attack, assessed by counting the
number of wounds implied, (b) hyperalgesia, i.e. strong withdrawal
responses to a moderate heat stimulus, (c) allodynia, i.e. withdrawal in
response to non-noxious tactile or cold stimuli. These behavioral
parameters have been exploited to study the pharmacology and
modulation of neuropathic pain. Nerve fibers develop abnormal
ectopic excitability at or near the site of nerve injury. The mechanisms
include unusual distributions of Na(+) channels, as well as abnormal
responses to endogenous pain producing substances and cytokines
such as TNF-alpha. Persistent abnormal excitability of sensory nerve
endings in a neuroma is considered a mechanism of stump pain after
amputation. Any local nerve injury tends to spread to distant parts of
the peripheral and CNS. This includes erratic mechano-sensitivity
along the injured nerve including the cell bodies in the DRG as well as
ongoing activity in the dorsal horn. The spread of pathophysiology
includes upregulation of nitric oxide synthase in axotomized neurons,
deafferentation hypersensitivity of spinal neurons following afferent
cell death, long-term potentiation of spinal synaptic transmission and
attenuation of central pain inhibitory mechanisms. In particular, the
efficacy of opioids at the spinal level is much decreased following
nerve injury. Repeated or prolonged noxious stimulation and the
persistent abnormal input following nerve injury activate a number of
intracellular second messenger systems, implying phosphorylation by
protein kinases, particularly protein kinase C. Intracellular signal
cascades result in immediate early gene induction which is considered
as the overture of a widespread change in protein synthesis, a general
basis for nervous system plasticity. Although these processes of
increasing nervous system excitability may be considered as a strategy
to compensate functional deficits following nerve injury, its by-
52
product is widespread nervous system sensitization resulting in pain

and hyperalgesia. Important sequelae of nerve injury and other
nervous system diseases such as virus attack is apoptosis of neurons in
the peripheral and CNS. Apoptosis seems to induce neuronal
sensitization and loss of inhibitory systems, and these irreversible
processes might be in common to nervous system damage by brain
trauma or ischemia as well as neuropathic pain. The cellular
pathobiology including apoptosis suggests future strategies against
neuropathic pain that emphasize preventive aspects (16).
Neuropathic pain
Neuropathic pain syndromes, i.e., pain after a lesion or disease of

the peripheral or CNS, are clinically characterized by spontaneous
pain (ongoing, or paroxysms) and evoked types of pain (hyperalgesia,
or allodynia) (14). Clinically, neuropathic pain is characterized by
spontaneous ongoing or shooting pain and evoked amplified pain
responses after noxious or non-noxious stimuli (9), the feeling of pins
and needles; burning, shooting, and/or stabbing pain with or without
throbbing; and numbness (10).
In a large, observational, cross-sectional survey, 602 patients with
neuropathic pain recruited from general practitioners in 6 European
countries were surveyed. Physicians recorded demographic and
treatment information, including prescription medications. Patients
completed BPI severity and interference questions, the EuroQOL
(EQ-5D), and questions about their productivity, non-prescription
treatments, and frequency of physician visits. The BPI Pain Severity
score (range: 0-10) is the mean of worst, least, average, and current
pain ratings, with scores of 4-6 and 7-10 considered moderate and
severe, respectively. Mean (SD) age was 62.9 (14.4) years (50%
female). Most patients reported moderate (54%) or severe (25%) pain.
Nearly all patients (93%) were prescribed medications for their
neuropathic pain: analgesics (71%); anti-epileptics (51%);
antidepressants (29%); sedatives/hypnotics (15%). Seventy-six
percent of patients visited their physician at least once in the past
53
month. Employment status was affected in 43% of patients; those

employed missed a mean (SD) of 5.5 (9.8) workdays during the past
month. Pain severity was associated significantly (p<0.001) with
poorer EQ-5D scores (mild=0.67, moderate=0.46, severe=0.16),
greater disruption of employment status (mild=24%, moderate=48%,
severe=54%), and more frequent physician visits (% with 1 or more
visits: mild=66%, moderate=79%, severe=83%). In conclusion,
patients with neuropathic pain visit their physician frequently and
report substantial pain that interferes with daily functioning despite
receiving treatment (17).
This study evaluated the burden of neuropathic pain in Indian
patients attending urban, private sector, specialty clinics. A cross-
sectional, observational study surveyed 467 patients with neuropathic
pain to assess the burden of pain (pain severity, patient-reported
treatment effectiveness, and impact of hypothetical pain relief on
overall health rating), burden because of QOL impairment (EQ health
state, pain interference with daily living, sleep and mood disturbances,
and medication-related AEs), and economic burden (treatment cost,
impact on employment and productivity). Physicians filled out a
clinical case report form to provide information on patient's
neuropathic pain disorder and treatment provided. The data were
analyzed to assess the overall burden of neuropathic pain. Painful
diabetic neuropathy was the most common cause of neuropathic pain
(72%). Majority (64%) of patients reported moderate to severe pain,
and about 50% reported moderate to severe pain-related interference
in activities of daily living. Substantial sleep impairment was reported
as compared with general population. About 50% of patients noted co-
morbid mood disorders, while 67% reported medication-related AE in
the preceding week. Of all patients, 57% noted an adverse impact on
their employment status, including 13% who retired early or were
unemployed. Among those currently working, 72% reported reduced
productivity, including 22% who described reduced productivity
"most" or "all" of the time. In conclusion, in Indian patients with
access to urban, private-sector, specialty clinics neuropathic pain
(particularly painful diabetic neuropathy) remains a significant
medical condition with substantial negative impact on their QOL (18).
The main objective of this study was to identify potential
predictors associated with the persistence of neuropathic pain. A 2-
round Delphi study was conducted among 17 experts in the field of
neuropathic pain at the University Medical Center and Pain
Management Research Center. Selection of the panel was based on the
citation index ranking for neuropathic pain-related research and/or
54
membership in the neuropathic pain special interest group of the

IASP, complemented with experts with demonstrated field
knowledge. Potential predictors were categorized according to the
International Classification of Functioning, Disability and Health
model. Participants were asked to identify important predictors,
suggest new predictors, and grade the importance on a 0-10 scale. For
the second round, predictors were considered important if the median
score was ≥ 7 and the IQR ≤ 3. In the first round, 20 predictors were
selected and 58 were added by the experts (patient characteristics [15],
environmental factors [25], functions & structure [4], and participation
& HRQL [14]). In the second round, 12 predictors were considered
important (patient characteristics [4; e.g., depression, pain
catastrophizing], environmental factors [surgery as treatment for
neuropathic pain], functions & structure [6; e.g., allodynia, duration of
the complaints], participation & trait anxiety/depression as a part of
HRQL). Presence of depression and pain catastrophizing were
considered the most important predictors for chronic neuropathic pain
(median ≥ 8; IQR ≤ 2). Overall, psychological factors and factors
related to sensory disturbances were considered important predictors
for persistence of neuropathic pain. Activity related factors and
previously received paramedical and alternative treatment were less
important. The list of possible predictors obtained by this study may
serve as a basis for development of a clinical prediction rule for
chronic neuropathic pain (19).
Neuropathic pain
Neuropathic pain often fails to respond to conventional pain

management procedures. Inflammatory mediators released from
damaged nerves and tissue are responsible for triggering ectopic
activity in primary afferents and that this, in turn, provokes increased
spinal cord activity and the development of 'central sensitization'.
Although evidence is mounting to support the role of IL-1β,
prostaglandins and other cytokines in the onset of neuropathic pain,
55
the clinical efficacy of drugs which antagonize or prevent the actions

of these mediators is yet to be determined. Basic science findings do,
however, support the use of pre-emptive analgesia during procedures,
which involve nerve manipulation and the use of anti-inflammatory
steroids as soon as possible following traumatic nerve injury (20).
The distinction between neuropathic and non-neuropathic pain
reflects partially distinct mechanisms and patterns of treatment
response. It was therefore hypothesized that patients with neuropathic
and non-neuropathic pain have different profiles of symptoms and
signs. To test this hypothesis, pain intensity, unpleasantness, quality,
and spatial characteristics 618 patients with 1 of 3 peripheral
neuropathic pain conditions (painful DPN, painful idiopathic sensory
polyneuropathy, or postherpetic neuralgia), osteoarthritis pain, or LBP
were examined. These assessments were conducted before treatment
had begun in clinical trials of lidocaine patch 5% administered alone
or with stable dosages of other analgesics. Patients with osteoarthritis
pain and LBP did not differ in their profile of pain quality and spatial
characteristics and were combined to form a group of patients with
non-neuropathic pain. In univariate analyses, patients with peripheral
neuropathic pain reported significantly more intense hot, cold,
sensitive, itchy, and surface pain and significantly less intense dull and
deep pain than patients with non-neuropathic pain. In a multivariate
analysis, the overall pattern of pain quality and spatial characteristics
differed significantly between patients with neuropathic and non-
neuropathic pain. Specific pain quality and spatial characteristics
improved the discrimination of patients with neuropathic and non-
neuropathic pain in a logistic regression model that adjusted for
demographic covariates and overall pain intensity and unpleasantness.
These results indicate that the distinction between neuropathic and
non-neuropathic pain is reflected in different profiles of pain quality
and spatial characteristics and suggest that the assessment of patterns
of pain symptoms might contribute to the identification of distinct
pathophysiologic mechanisms and the development of mechanism-
based treatment approaches (21).
Neuropathic pain syndromes are clinically characterized by
spontaneous pain and evoked pain (hyperalgesia or allodynia). The
optimal treatment approach for neuropathic pain is still under
development because of the complex pathological mechanisms
underlying this type of pain. The spinal cord is an important gateway
thorough which peripheral pain signals are transmitted to the brain,
and sensitization of the spinal neurons is one of the important
mechanisms underlying neuropathic pain. Central sensitization
56
represents enhancement of the function of neuronal circuits in

nociceptive pathways and is a manifestation of the remarkable
plasticity of the somatosensory nervous system after nerve injury. The
pathological features of central sensitization develop because of (1)
injury-induced abnormal inputs from primary afferents, (2) increase in
the excitability of dorsal horn neurons, and (3) activated glial cell-
derived signals (22).
Assessment: peripheral neuropathies are a heterogeneous group of

diseases affecting peripheral nerves. Postherpetic neuralgia, trigeminal
neuralgia, DPN, SCI, cancer, stroke, and degenerative neurological
diseases may produce neuropathic pain. Neuropathic pain, resulting
from a lesion, damage, or dysfunction of the somatosensory nervous
system, can also arise through several distinct etiologies ranging from
toxicity, surgery, radiation, metabolic, infectious, inflammatory,
trauma and congenital disorders.
Maladaptive mechanisms of neuropathic pain symptoms include
peripheral sensitization of nociception, abnormal excitability of
afferent neurons, central sensitization comprising pronociceptive
facilitation, disinhibition of nociception central reorganization
processes, and sympathetically maintained pain.
Neuropathic pain syndromes, i.e., pain after a lesion or disease of
the peripheral or CNS, are clinically characterized by spontaneous
pain (ongoing, or paroxysms) and evoked types of pain (hyperalgesia
or allodynia). Clinically, neuropathic pain is characterized by
spontaneous ongoing or shooting pain and evoked amplified pain
responses after noxious or non-noxious stimuli, the feeling of pins and
needles; burning, shooting, and/or stabbing pain with or without
throbbing; and numbness. Pins and needles, burning, cramping mixed
with numbness, and tingling are the wording most used by patients.
References
1. Nickel FT, Seifert F, Lanz S, Maihöfner C. Mechanisms of neuropathic pain.
Eur Neuropsychopharmacol. 2012;22(2):81-91.
2. Vranken JH. Mechanisms and treatment of neuropathic pain. Cent Nerv Syst
Agents Med Chem. 2009;9(1):71-8.
4. Portenoy RK. Painful polyneuropathy. Neurol Clin. 1989;7(2):265–88.
5. Vaillancourt PD, Langevin HM. Painful peripheral neuropathies. Med. Clin.
North Am. 1999;83(3):627-42,
6. Taylor RS. Epidemiology of refractory neuropathic pain. Pain Pract.
2006;6(1):22-6.
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7. Marchettini P, Lacerenza M, Mauri E, Marangoni C. Painful peripheral

neuropathies. Curr Neuropharmacol. 2006;4(3):175-81.
8. Ro LS, Chang KH. Neuropathic pain: mechanisms and treatments. Chang Gung
Med J. 2005;28(9):597-605.
9. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological
mechanisms, and treatment. Lancet Neurol. 2010;9(8):807-19.
10. Namaka M, Gramlich CR, Ruhlen D, et al. A treatment algorithm for
neuropathic pain. Clin Ther. 2004;26(7):951-79. Erratum in Clin Ther. 2004;
26(12):2163.
11. Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer-
related neuropathic pain: the intersection of cancer pain and neuropathic pain.
Oncologist. 2010;15 Suppl 2:3-8.
12. Baron R. Mechanisms of disease: neuropathic pain - a clinical perspective.
Nat Clin Pract Neurol. 2006;2(2):95-106.
14. Baron R. Neuropathic pain: a clinical perspective. Handb Exp Pharmacol.
2009;(194):3-30.
15. Ikeda H, Kiritoshi T, Murase K. Contribution of microglia and astrocytes to
the central sensitization, inflammatory and neuropathic pain in the juvenile rat. Mol
Pain. 2012 Jun 15;8:43.
16. Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol.
2001;429(1-3):23-37.
17. McDermott AM, Toelle TR, Rowbotham DJ, et al. The burden of neuropathic
pain: results from a cross-sectional survey. Eur J Pain. 2006; 10(2):127-35.
18. Agarwal CS, Anand M, Arjundas D, et al. IndINeP Study Group. Burden of
neuropathic pain in Indian patients attending urban, specialty clinics: results from a
cross sectional study. Pain Pract. 2008;8(5):362-78.
19. Boogaard S, Heymans MW, Patijn J, et al. Predictors for persistent
neuropathic pain - a Delphi survey. Pain Physician. 2011;14(6):559-68.
20. Stemkowski PL, Smith PA. Sensory neurons, ion channels, inflammation and
the onset of neuropathic pain. Can J Neurol Sci. 2012;39(4):416-35. Comment in:
Neuropathic pain: redundant pathways, inadequate therapy. [Can J Neurol Sci. 2012].
21. Dworkin RH, Jensen MP, Gammaitoni AR, et al. Symptom profiles differ in
patients with neuropathic versus non-neuropathic pain. J Pain. 2007;8(2):118-26.
Erratum in J Pain. 2007;8(6):531.
22. Yamanaka H, Noguchi K. Pathophysiology of neuropathic pain: molecular
mechanisms underlying central sensitization in the dorsal horn in neuropathic pain].
Brain Nerve. 2012;64(11):1255-65.
58
ASSESSMENT TOOLS
Pain scales are tools that can help to diagnose or measure pain's
intensity. The widely used scales are visual, verbal, and numerical or
some combination of all three forms (1).
Visual scales have pictures of human anatomy helping to explain
where your pain is located. The WBS features facial expressions to
show how the pain makes you feel. This scale is particularly useful for
children, who sometimes do not have the vocabulary to explain how
they feel. Verbal scales contain commonly used words such as "low,"
"mild" or "excruciating" helping to describe the intensity or severity
of patient's discomfort. Numerical scales help to quantify pain using
numbers, sometimes in combination with words [Figure 1, Figure 2]
(1).
Figure 1. Pain rating scales for classifying the intensity of pain
Visual analog scale is a simple assessment tool consisting of a 10 cm line

with 0 on one end, representing no pain, and 10 on the other, representing the
worst pain ever experienced, which a patient indicates so the clinician knows
the severity of his or her pain. Visual analog scale has been used in the social
and behavioral sciences to measure variety of phenomena.
59
Figure 2. Wong-Baker FACES Pain Rating Scale
The WBS, used in children to rate pain severity can be validated for
chronic pain.
The intensity of pain offers perhaps the least desirable system for
classifying pain, because intensity varies for most patients over time
and is uniquely subjective. A patient might rate the experience of pain
resulting from some pathologic condition as a 10, whereas another
patient with the same pathology might describe the intensity of pain
only as a 5, both using a 0 to 10 scale (with 0 signifying no pain at all
and 10 representing the worse pain imaginable). Whereas non–cancer-
related pain is often rated along a continuum (e.g., from mild to
moderate, and to severe), the words ―incapacitating,‖
―overwhelming,‖ and ―soul stealing‖ frequently become necessary
qualifiers for cancer pain (2).
The VAS is a tool widely used to measure pain, yet controversy
surrounds whether the VAS score is ratio or ordinal data. Fifty-two
postoperative patients were studied and their pain intensity using the
VAS was measured. Then patients were asked to consider different
amounts of pain (conceptually twice as much and then half as much)
and asked them to repeat their VAS rating after each consideration
(VAS2 and VAS3, respectively). Patients with unrelieved pain had
their pain treated with intravenous fentanyl and were then asked to
rate their pain intensity when they considered they had half as much
pain. The baseline VAS (VAS1) was compared with VAS2 and
VAS3. The mean (95% CI) for VAS2:1 was 2.12 (1.81-2.43) and for
VAS3:1 0.45 (0.38-0.52). It was concluded that the VAS is linear for
mild-to-moderate pain, and the VAS score can be treated as ratio data.
60
A change in the VAS score represents a relative change in the

magnitude of pain sensation. Use of the VAS in comparative analgesic
trials can quantify differences in potency and efficacy (3).
Multidisciplinary treatment programs for chronic pain typically
emphasize the importance of decreasing maladaptive and encouraging
adaptive coping responses. The CPCI, developed to assess coping
strategies targeted for change in multidisciplinary pain treatment, is a
64-item instrument that contains eight subscales: Guarding, Resting,
Asking for Assistance, Relaxation, Task Persistence,
Exercising/Stretching, Coping Self-Statements, and Seeking Social
Support. A previous validation study with 210 patients in a Canadian
academic hospital setting supported an eight-factor structure for the
CPCI. The current study was undertaken to validate the CPCI among
564 veterans with a more extended history of chronic pain. A
confirmatory factor analysis was used to examine the factor structure
of the 64-item CPCI. A series of hierarchical multiple regression
analyses were performed with depression, pain interference, general
activity level, disability, and pain severity as the criterion variables
and the eight CPCI factors as the predictor variables, controlling for
pain severity and demographic variables. The confirmatory factor
analysis results strongly supported an 8-factor model, and the
regression analyses supported the predictive validity of the CPCI
scales, as indicated by their association with measures of patient
adjustment to chronic pain. The 8-factor structure of the CPCI by
using a confirmatory factor analysis and a series of linear regressions
was validated. The results support the applicability and utility of the
chronic pain in a heterogeneous population of veterans with severe
chronic pain treated in a tertiary teaching hospital. The CPCI provides
an important clinical and research tool for the assessment of
behavioral pain coping strategies that might have an impact on patient
outcomes (4).
The PDQ is a psychometric evaluation study of a new measure of
functional status. The main objective of this study was to evaluate the
psychometric properties of the PDQ and compare its validity and
responsiveness to traditional measures of functional status, such as the
Oswestry, Million Visual Analogue Scale, and SF-36 instruments.
Measuring clinical outcomes is an essential element of any
musculoskeletal treatment. The PDQ was developed for this purpose.
It yields a total functional disability score ranging from 0 to 150. The
focus, much like other health inventories, is primarily on disability
and function. However, unlike most other measures, this instrument is
designed for the full array of chronic disabling musculoskeletal
61
disorders, rather than LBP alone. Further, psychosocial variables,

which recent studies have shown to play an integral role in the
development and maintenance of chronic pain disability, formed an
important core of the PDQ. Four groups were used in this
psychometric evaluation: an asymptomatic normative population
(n=50), musculoskeletal disorder population (n=52), a chronic
disabling musculoskeletal disorder population (n=230), and a
heterogeneous pain population (n=114). The normative population and
musculoskeletal disorder groups served as comparison samples for the
chronic disabling musculoskeletal disorder and heterogeneous pain
population groups. Analyses of PDQ reliability, validity, and
responsiveness were conducted. Test-retest reliability coefficients
(ranging from 0.94 to 0.98) and a Cronbach's alpha coefficient of 0.96
for the PDQ were found to be of excellent quality. The responsiveness
of the PDQ, as measured by Cohen's effect size statistic, ranged from
0.85 to 1.07, better than the Oswestry, MVAS, and SF-36. A high
level of face validity was observed for the PDQ, as the chronic
disabling musculoskeletal disorder population exhibited significantly
higher pretreatment PDQ scores than a group of patients suffering
from acute injuries. The construct-related validity of the PDQ was
excellent quality, as it correlated well to both the MVAS (0.65-0.81)
and Oswestry (0.55-0.80). The PDQ consistently demonstrated
stronger correlation coefficients to a wide variety of physical and
psychosocial measures of human function, such as the SF-36, Beck
Depression Inventory, Hamilton-D, State-Trait Anxiety Scale, and
Pain Intensity VAS, and either the Oswestry or MVAS. A factor
analysis of the PDQ revealed 2 factors: a Functional Status
Component and a Psychosocial Component. Analyses proved each of
these 2 components to be valid in assessing their theorized constructs.
The present study represents a comprehensive psychometric
evaluation of a new functional status measure for musculoskeletal
conditions in general, and a chronic disabling musculoskeletal
disorder population in particular. The psychometric properties of the
PDQ are excellent, demonstrating strong reliability, responsiveness,
and validity, relative to many other existing measures of functional
status. The many weaknesses cited for some of the existing measures
were taken into account in designing this instrument. Consequently,
the characteristics commonly noted as weaknesses for these other
measures (such as a restriction to only the LBP population, and
inconsistent responsiveness) can be cited as strengths of the PDQ (5).
Assessing chronic widespread pain and its impact on physical,
emotional and social function requires multidimensional qualitative
62
and HRQL instruments. The recommendations of the Initiative on

Methods, Measurement, and Pain Assessment in Clinical Trials
concerning outcome measurements for pain trials are useful for
making routine assessments, the most significant of which include
pain, fatigue, disturbed sleep, physical functioning, emotional
functioning, patient global ratings of satisfaction and HRQL.
However, despite the growing spread of instruments and theoretical
publications devoted to measuring the various aspects of chronic pain,
there is little widespread agreement, and no unified approach has yet
been devised. There is therefore still considerable scope for the
development of consensus around a core set of measures and response
criteria, as well as for the development and refinement of the related
instruments, standardized assessor training, the cross-cultural
adaptation of health status questionnaires, electronic data capture and
the introduction of valid, reliable and responsive standardized
quantitative measurements into routine clinical care. Clinicians need
to be aware of the psychometric properties of the instruments used,
including their levels of imprecision and minimum clinically
important differences (those indicating a meaningful change in clinical
status (6).
The purpose of this study was to determine the reliability and
validity of selected pain intensity scales such as the FPS, the VDS, the
NPRS, and the IPT to assess pain in cognitively impaired older adults.
A descriptive correlational design was used, and a convenience
sample of 66 volunteers age 60 and older residing in assisted living
facilities in the South was recruited for this study. The sample
included 22 (33%) men and 44 (67%) women, with a mean age of 76.
Of the sample, 98% (65) comprised Caucasian participants, with the
exception of 1 African-American man. High school and/or college
completed 70% (47). The mean MMSE score was 16, with a range of
1 to 29. Eighty-five percent scored 24 or lower, indicating some
degree of cognitive impairment. The remaining 15% were cognitively
intact. All but 1 participant could use each scale to rate their pain.
Concurrent validity of the VDS, NRS, and IPT was supported with
Spearman rank correlation coefficients ranging from 0.78 to 0.86 in
the cognitively impaired group. The FPS, however, demonstrated
weak correlations with other scales when used with the impaired
group, ranging from 0.48 to 0.53. In the cognitively intact group,
strong correlations ranging from 0.96 to 0.97 were among all of the
scales. Test-retest reliability at a 2-week interval was acceptable in the
cognitively intact group (Spearman rank correlations ranged from 0.67
to 0.85) and unacceptable for most scales in the cognitively impaired
63
group (correlations ranged from 0.26 to 0.67). When asked about scale
preference, both the cognitively impaired and the intact groups
preferred the IPT and the VDS. This study revealed that cognitive
impairment did not inhibit participants' ability to use a variety of pain
intensity scales, but the stability issue must be considered (7).
The FPS is effective with older adults in clinical assessment of
pain intensity. The 0-10 NPRS has universally adapted for assessment
of pain intensity. The commonly used versions of the FPS have 6, 7 or
9 faces. An 11 face modified version of the McGrath 9 face FPS was
compared with the 0-10 NPRS without the mathematical translation.
The psychometric properties of the proposed version were also
investigated in a sample of Korean older adults. This study employed
methodological research design. A sample of 31 older adults was
recruited through local senior citizen centers to examine the construct
validity and the test-retest reliability. For the concurrent validity
testing, a sample of 85 older adults with chronic pain was recruited
through a general hospital and an oriental medical hospital. The
construct validity was examined by determining if the subjects
perceive the FPS as representing pain and they agree on the rank of
each face. The concurrent validity was examined by using the NPRS
and the VAS. Subjects perceived the 11 FPS as a pain measure, and
the subjects' agreements in the rank ordering of the faces were almost
perfect (Kendall's W=0.93, p<0.001). Cohen's kappa of 0.61
(p<0.001) for test-retest reliability was acceptable in the cognitively
intact subjects. Concurrent validity measured by the correlation
between the FPS and the NPRS (r=0.73, p<0.001) and the VAS
(r=0.73, p<0.001) was supported. These results supported the
appropriateness of the 11 FPS for use with the older adults in clinical
practice to measure pain intensity. This study provided cross-cultural
evidence to evaluate usefulness of the FPS (8).
The goals of this study were to examine agreement and estimate
differences in sensitivity between pain assessment scales. Multiple
simultaneous pain assessments by patients in acute pain after oral
surgery were used to compare a 4-category VRS-4 and an NPRS-11
with a 100-mm VAS. The sensitivity of the scales (i.e., their ability
[power] to detect differences between treatments) was compared in a
simulation model by sampling from true pairs of observations using
varying treatment differences of predetermined size. There was
considerable variability in VAS scores within each VRS-4 or NRS-11
category both between patients and for repeated measures from the
same patient. Simulation experiments showed that the VAS was
systematically more powerful than the VRS-4 in all simulations
64
performed. The sensitivity of the VAS and NRS-11 was

approximately equal. In this acute pain model, the VRS-4 was less
sensitive than the VAS. The simulation results demonstrated similar
sensitivity of the NRS-11 and VAS when comparing acute
postoperative pain intensity. The choice between the VAS and NRS-
11 can thus be based on subjective preferences (9).
The main objective of this research was to determine the initial
psychometric properties of the Spanish Version of the FPS-R as a
measure of pain intensity for use with the elderly. To assess the
scaling properties, validity, and reliability of the FPS-R, a total sample
of 177 subjects aged ≥ 65 years participated in this study. Ranking
procedures, placement tasks, and test-retest methods were used. The
participants were asked to rate their pain intensity by using the FPS-R
and a pain thermometer and to inform about their affective state. They
were also asked to imagine themselves in 5 hypothetical painful
situations (Geriatric Painful Events Inventory) and rate the degree of
pain by using the FPS-R and the pain thermometer at 2 different times.
Rank ordering tasks for the individual faces showed excellent
agreement between the expected ranking and the 1 provided by the
participants (Kendall's W = 0.75, p<0.0001). The pain intensity ratings
reported with FPS-R and the pain thermometer were very similar, and
the relationship between the intensity of pain experienced and
participant's negative affective state was statistically significant
(r=0.32, p<0.01). Test-retest correlations on the Geriatric Painful
Events Inventory ranged from 0.44 to 0.7. All the participating
subjects were asked to choose the pain scale they preferred.
Regardless of their age and/or gender, the subjects preferred the FPS-
R to the pain thermometer. These results provide preliminary evidence
of its reliability and convergent and criterion-related validity as well
as its strong ordinal properties with a sample of elderly subjects. The
FPS-R scale could help clinicians to assess the intensity of pain in
cognitively intact elderly patients and might be helpful in making
decisions about treatment (10).
Pain intensity is frequently measured on an 11-point PI-NPRS,
where 0 = no pain and 10 = worst possible pain. However, it is
difficult to interpret the clinical importance of changes from baseline
on this scale (such as a 1- or 2-point change). A clinically important
difference on this scale by relating it to global assessments of change
in multiple studies of chronic pain was estimated. Data on 2724
subjects from 10 recently completed placebo-controlled clinical trials
of pregabalin in diabetic neuropathy, postherpetic neuralgia, chronic
LBP, fibromyalgia, and osteoarthritis were used. The studies had
65
similar designs and measurement instruments, including the PI-NPRS,

collected in a daily diary, and the standard seven-point patient global
impression of change, collected at the endpoint. The changes in the
PI-NPRS from baseline to the endpoint were compared to the patient
global impression of change for each subject. Categories of "much
improved" and "very much improved" were used as determinants of a
clinically important difference and the relationship to the PI-NPRS
was explored using graphs, box plots, and sensitivity/specificity
analyses. A consistent relationship between the change in PI-NPRS
and the global impression of change was demonstrated regardless of
study, disease type, age, sex, study result, or treatment group. On
average, a reduction of approximately 2 points or a reduction of
approximately 30% in the PI-NPRS represented a clinically important
difference. The relationship between percent change and the global
impression of change was consistent regardless of baseline pain, while
higher baseline scores required larger raw changes to represent a
clinically important difference. The application of these results to
future studies provides a standard definition of clinically important
improvement in clinical trials of chronic pain therapies (11).
The main objective of this study was to determine: (1) the
psychometric properties and utility of 5 types of commonly used PRSs
when used with younger and older adults, (2) factors related to failure
to successfully use a PRS, (3) PRS preference, and (4) factors
impacting scale preference. A quasi-experimental design was used to
gather data from a sample of 86 younger (age 25-55) and 89 older
(age 65-94) adult volunteer subjects. Responses of subjects to
experimentally induced thermal stimuli were measured with the
following pain intensity rating scales: VAS, 21-point NPRS, VDS, 11-
point VNRS, and FPS. All 5 pain scales were effective in
discriminating different levels of pain sensation; however the VDS
was most sensitive and reliable. Failure rates for pain scale completion
were minimal, except for the VAS. Although age did not affect failure
to properly use this PI-NPRS, but rather those conditions more
commonly associated with advanced age, including cognitive and
psychomotor impairment did. The scale most preferred to represent
pain intensity in both cohorts of subjects was the NPRS, followed by
the VDS. Scale preference was not related to cognitive status,
educational level, age, race, or sex. Although all 5 of the PI-NPRS
were psychometrically sound when used with either age group,
failures, internal consistency reliability, construct validity, scale
sensitivity, and preference suggest that the VDS is the scale of choice
66
for assessing pain intensity among older adults, including those with
mild to moderate cognitive impairment (12).
A diagnostic instrument is presented to assess chronic and acute
pain that allows multifaceted and standardized quantification of pain
experience. This tool - the Pain Experience Scale
("Schmerzempfindungsskala") - measures 2 dimensions of
subjectively felt pain, the affective characterization as well as modes
of sensory characterization of pain. Applications range from
degenerative or inflammatory joint and back pain to
headache/migraine, neuropathies and other pain-related diseases (age
16 to 80 years). Completion, evaluation, and interpretation are done
easily. Scale development had comprised 3 steps of research for
obtaining a model of invariant structure and homogenous factors.
Scale analyses demonstrated the instrument's reliability, and numerous
studies illustrated the validity of the scale. They showed that factorial,
convergent and discriminant validity can be regarded as given.
Moreover, the scale proved to be sensitive in experimental pain
studies. Additionally, specific patterns of scores could be observed
validly for 18 different groups of disease/pain. Special efforts were
invested to show its sensitivity to change in the course of pains. Here,
the Pain Experience Scale proved to be suitable in postoperative pain,
drug-based pain therapies, different psychological pain management
approaches, physiotherapeutic prevention, and a multimodal treatment
program of a specialized pain clinic. In German-speaking countries,
the Pain Experience Scale has been in use for several years as a well-
proven instrument in medical care, clinical research as well as field
evaluation (13).
This review aims to explore the research available relating to three
commonly used PRSs, the VAS, the VNRS and the NPRS. This
review can help clinicians to understand the main features of these
tools and thus use them effectively A MedLine review via PubMed
was carried out with no restriction of age of papers retrieved. Papers
were examined for methodological soundness before being included.
The search terms initially included PRSs, pain measurement, VAS,
VPRS, and NPRS. The reference lists of retrieved articles were used
to generate more papers and search terms. Only English Language
papers were examined. This study concludes that all three PRSs are
valid, reliable and appropriate for use in clinical practice, although the
VAS has more practical difficulties than the VNRS or the NPRS. For
general purposes, the NPRS has good sensitivity and generates data
that can be statistically analyzed for audit purposes. Patients who seek
a sensitive NPRS would probably choose this one. For simplicity,
67
patients prefer the VNRS, but it lacks sensitivity and the data it
produces can be misunderstood. In order to use PRSs well clinicians
need to appreciate the potential for error within the tools, and the
potential they have to provide the required information. Interpretation
of the data from a PRS is not as straightforward as it might first appear
(14).
The use of patient reported outcome measures within cost-
effectiveness analysis has become commonplace. However, specific
measures are required that produce values, referred to as 'utilities', that
are capable of generating quality adjusted life years. One such
measure - the EQ-5D - has come under criticism due to the inherent
limitations of its three-level response scales. In evaluations of chronic
pain, the NPRS which has eleven levels is routinely used which has a
greater measurement range, but which cannot be used in cost-
effectiveness analyses. This study derived utility values for a series of
EQ-5D health states that replace the pain dimensions with the NPRS,
thereby allowing a potentially greater range of pain intensities to be
captured and included in economic analyses. Interviews were
undertaken with 100 member of the general population. Health state
valuations were elicited using the time trade-off approach with a ten-
year time horizon. Additionally, respondents were asked where the
EQ-5D response scale descriptors of moderate and extreme pain lay
on the 11-point NPRS scale. Of all valuations, 625 were undertaken
across the study sample with the crude mean health state utilities
showing a negative non-linear relationship with respect to increasing
pain intensity. Relative to a NPRS of zero (NPRS0), the successive
pain levels (NPRS1-10) had mean decrements in utility of 0.034,
0.043, 0.061, 0.121, 0.144, 0.252, 0.404, 0.575, 0.771 and 0.793,
respectively. When respondents were asked to mark on the NPRS
scale the EQ-5D pain descriptors of moderate and extreme pain, the
median responses were '4' and '8', respectively. These results
demonstrate the potential floor effect of the EQ-5D with respect to
pain and provide estimates of health reduction associated with pain
intensity described by the NPRS. These estimates are in excess of the
decrements produced by an application of the EQ-5D scoring tariff for
both the US and the United Kingdom (15).
In this study, a new pain-relevant social support instrument, the
SPQ, is presented together with an evaluation of its psychometric
properties. A literature search was performed to establish different
aspects of social support. For each of the 6 aspects found, 1 item was
selected for inclusion in the new questionnaire. The draft version of
the questionnaire was field tested. Thereafter, the psychometric
68
properties of the SPQ were assessed in 250 patients with oro-facial

pain. Principal component analysis (n=250) showed that the SPQ had
a 1-factor structure. The test-retest reliability of the SPQ (in a
subsample of 54 patients) was fair-to-good (R=0·70, p<0·000).
Convergent validity, as compared with a non-specific social support
instrument, was good (n=140; R=0·54, p<0·000). The SPQ is a valid
and reliable instrument, which offers the possibility to explore the
patient's satisfaction with pain-related social support. With the SPQ, a
useful tool to assess the influence of social support in patients with
various types of pain is provided (16).
The aim of this publication is to introduce DoloTest(®) and to
document the validation of DoloTest(®). DoloTest(®) is a HRQL tool
for pain patients with low-time burden involving the patient in
interpretation of the test result by creating a graphic presentation of
the test result in a DoloTest(®) Profile and therefore, suitable use in
clinical setting. Validation was performed against SF-36, with 246
participants in 4 pain clinics. Face validity (domains) cognitive
interviewing (time and patient's perception), factor analysis (factors
and eigenvalues), construct validity (correlation coefficients),
Reliability included intern consistency (Cronbach's alpha), and test-
retest stability (correlation coefficients). Face validation: the eight
domains most important for assessment of the patients with persistent
pain were selected. The factor analysis shows equal relevance and
weighting of all domains. Construct validation against SF-36™ shows
positive correlation within each domain; correlation coefficients were
between 0.47 and 0.69. Reliability was tested with Cronbach's alpha
and test-retest. Cronbach's alpha values were 0.615 to 0.715.
Correlation coefficients for linear regressions of test and retest for the
DoloTest(®) and SF-36 were all positive. DOLOTEST(®) is a new
HRQL tool that can be used in pain patients (17).
Patients with chronic pain (n = 186) attended a 3-week,
multidisciplinary pain program, which was CBT based. Patients
completed a measure of pain intensity; the Chronic Pain Acceptance
Questionnaire; the catastrophizing subscale of the Pain Response Self-
Statements Scale; the Roland Morris Disability Questionnaire; the
Depression Anxiety and Stress Scale; and 2 measures of physical
functioning at pretreatment, post-treatment and 3-month follow-up.
Both acceptance and catastrophizing showed statistically significant
and clinically relevant changes from pre- to post-treatment. Changes
in both acceptance and catastrophizing showed a significant
correlation with changes in almost all of the outcome variables.
Regression analyses demonstrated that change in acceptance was a
69
significant predictor of changes in depression, disability, timed walk

and sit-to-stand performance, after controlling for changes in
catastrophizing and pain intensity. This study indicates that although
not specifically targeted in CBT treatment, acceptance of pain was an
important process variable that contributed to CBT treatment
outcomes after controlling for changes in pain intensity and
catastrophizing (18).
The current research addresses the need for formal evaluation of
the reliability and validity of the BPI for use in non-cancer pain
patients. Approximately 250 patients with arthritis or LBP self-
administered a number of generic and condition-specific health status
measures (including the BPI) in the clinic of their primary care
provider at 2 time points: the initial clinic visit and the first visit
following treatment. The reliability of BPI data collected from non-
cancer pain patients was comparable to that reported in the literature
for cancer patients and sufficient for group-level analyses (coefficient
alphas were greater than 0.70). The factor structure of the BPI was
replicated in this sample and the relationship of the BPI to generic
measures of pain was strong. The BPI exhibited similar relationships
to general and condition-specific measures of health as did a generic
pain scale (SF-36 Bodily Pain). Finally, the BPI discriminated among
levels of condition severity and was sensitive to change in condition
over time in arthritis and LBP patients. Results support the validity of
the BPI as a measure of pain in patients without cancer and, in
particular, as a measure of pain for arthritis and LBP patients (19).
The BPI SF is a validated, widely used, self-administered
questionnaire developed to assess the severity of pain and the impact
of pain on daily functions. A modified version was used daily in RCTs
of patients with arthritis undergoing treatment with cyclooxygenase-2
specific inhibitors and NSAID. Results indicate that the modified BPI
SF, much like the original scale, was internally reliable, consistent
over time, and had good construct, as well as convergent and
predictive validity in assessment of patients suffering from conditions
of chronic pain. Each scale and individual pain intensity item refers to
changes in osteoarthritis pain associated with medication use. The
modified BPI SF, like the parent scale, is a valid and reliable tool for
situations in which pain is assessed daily and minimizes the burden
placed on patients to record information necessary for scientific
investigations (20).
The main objective of this study was to examine the psychometric
properties of the Index de l'incapacité reliée à la douleur, a French-
Canadian version of the PDI. Chronic pain patients (n=176, 94
70
women and 82 men) completed the French-Canadian version of the

PDI (PDI-CF), as well as other pain-related measures. A subset of 52
patients (27 women, 25 men) also completed a lifting task designed to
assess physical tolerance and pain behavior. Confirmatory factor
analysis of the PDI-CF supported the 2-factor structure of the original
PDI. Reliability analyses revealed that the PDI-CF total score had a
high degree of internal consistency, comparable with the original PDI.
The PDI-CF total score was significantly correlated with self-reported
pain, pain catastrophizing, depressive symptoms, and fear of
movement or (re)injury, lift duration and pain behaviors. Thus, the
PDI-CF is a reliable and valid measure of self-reported disability that
is psychometrically similar to the original scale (21).
The WBS was validated in children presenting to the ED with pain
by identifying a corresponding mean value of the VAS for each face
of the WBS and determined the relationship between the WBS and
VAS. This was a prospective, observational study of children aged 8-
17 years with pain presenting to a suburban, academic pediatric ED.
Children rated their pain severity on a 6-item ordinal faces scale
(WBS) from none to worst and a 100-mm VAS from least to most. A
total of 120 patients were assessed: the median age was 13 years (IQR
= 10-15 years), 50% were female, 78% were white, and 6 patients
(5%) used a language other than English at home. The most
commonly specified locations of pain were extremity (37%), abdomen
(19%), and back/neck (11%). The mean VAS increased uniformly
across WBS categories in increments of about 17 mm. ANOVA
demonstrated significant differences in mean VAS across face groups.
Post hoc testing demonstrated that each mean VAS was significantly
different from every other mean VAS. Agreement between the WBS
and VAS was excellent (rho = 0.90, 95% CI 0.86-0.93). There was no
association between age, sex, or pain location with either pain score.
In conclusion, the VAS has an excellent correlation in older children
with acute pain in the ED and had a uniformly increasing relationship
with WBS. This finding has implications for research on pain
management using the WBS as an assessment tool (22).
Central sensitization has been proposed as a common
pathophysiological mechanism to explain related syndromes for which
no specific organic cause can be found. The term "central sensitivity
syndrome" has been proposed to describe these poorly understood
disorders related to central sensitization. The goal of this investigation
was to develop the Central Sensitization Inventory, which identifies
key symptoms associated with "central sensitivity syndromes" and
quantifies the degree of these symptoms. The utility of the Central
71
Sensitization Inventory in order to differentiate among different types

of chronic pain patients, who presumably have different levels of
central sensitization impairment, was then evaluated. Study 1
demonstrated strong psychometric properties (test-retest reliability =
0.817; Cronbach's alpha = 0.879) of the Central Sensitization
Inventory in a cohort of normative subjects. A factor analysis
(including both normative and chronic pain subjects) yielded 4 major
factors (all related to somatic and emotional symptoms), accounting
for 53.4% of the variance in the dataset. In Study 2, the Central
Sensitization Inventory was administered to 4 groups: fibromyalgia;
chronic widespread pain without fibromyalgia; work-related regional
chronic LBP; and normative control group. Analyses revealed that the
patients with fibromyalgia reported the highest Central Sensitization
Inventory scores and the normative population the lowest (p<0.05).
Analyses also demonstrated that the prevalence of previously
diagnosed "central sensitivity syndromes" and related disorders was
highest in the fibromyalgia group and lowest in the normative group
(p<0.001). Taken together, these 2 studies demonstrate the
psychometric strength, clinical utility, and the initial construct validity
of the Central Sensitization Inventory in evaluating central
sensitization-related clinical symptoms in chronic pain populations
(23).
A comprehensive systematic literature review was undertaken of
assessment instruments for persistent pain of noncancer origin, and
their developmental literature. Only assessment instruments which
were developed for patients with pain, or tested on them, were
included. A purpose-built 'Ready Reckoner' scored psychometric
properties and clinical utility. Potentially useful instruments were
identified (n=116), measuring severity, psychological, functional
and/or QOL constructs of persistent pain. Forty-five instruments were
short-listed, with convincing psychometric properties and clinical
utility. There were no standard tests for psychometric properties, and
considerable overlap of instrument purpose, item construct, wording,
and scoring. In conclusion, no one assessment instrument captured all
the constructs of persistent pain. While the compendium focuses
clinicians' choices, multiple instruments are required for
comprehensive assessment of adults with persistent pain (24).
The main objective of this study was to identify self-administered
pain-related self-efficacy measures used in people with chronic pain
and to evaluate the clinimetric evidence of the most commonly used
scales systematically. Two databases to identify self-efficacy
questionnaires were searched. Questionnaires that identified against
72
previously developed criteria for clinimetric assessment were

evaluated. Thirteen relevant measurements assessing self-efficacy
were identified, and 5 were clinimetrically assessed. These
questionnaires were the Arthritis Self-Efficacy Scale, the Chronic
Disease Self-Efficacy Scale, the Pain Self-Efficacy Questionnaire, the
Chronic Pain Self-Efficacy Scale, and the Self-Efficacy Scale. None
of the questionnaires showed satisfactory results for all properties. All
scales were easily scored and dimensionality was assessed in 2 of 6 of
the scales. Internal consistency was acceptable for all questionnaires.
There was positive evidence for construct validity in 4 of 6 of the
questionnaires. None of the studies used the most up-to-date method
of test-retest reliability or responsiveness. Information on
interpretability of the scores was minimal in all questionnaires.
Further research should focus on assessing responsiveness and
interpretability of these questionnaires. Researchers should select
questionnaires that are most appropriate for their study aims and
population and contribute to further validation of these scales (25).
A systematic review of the literature of the psychometric properties
of questionnaires that aimed to measure acceptance of chronic pain
was performed. Psychometric properties, including content construct
and criterion validity, internal consistency. agreement, reliability,
responsiveness, floor/ceiling effects and interpretability, were assessed
using a standardized protocol. All studies were assessed by 2
observers independent from each other. Twenty-three studies
including 4 questionnaires or subscales were identified. The
questionnaires/subscales included were the Chronic Pain Acceptance
Questionnaire, Illness Cognitions Questionnaire, Pain Solutions
Questionnaire and Acceptance of Illness Scale adapted to pain. When
applying the criteria of the protocol, results indicate that none of the
questionnaires are currently able to meet all 9 criteria for
psychometric quality. Individual questionnaires met between 0 and 3
of the criteria. If strict psychometric quality criteria are applied, none
of the questionnaires are currently able to meet all 9 criteria for
psychometric quality, but overlooking the cumulative results over all
the studies conducted, especially for the Chronic Pain Acceptance
Questionnaire, information on several important characteristics has
been reported and a fairly clear picture emerges about the
psychometric properties of this Questionnaire (26).
Assessment: a variety of pain-assessment scales are used in

different countries. In general, these scales are reliable and valid
instruments for assessing chronic pain. Among these scales, BPI is a
73
valid instrument for measuring pain in patients without cancer and, in

particular, as a measure of pain for arthritis and LBP patients.
Despite the growing spread of instruments and theoretical
publications devoted to measuring the various aspects of chronic pain,
little widespread agreement and no unified approach to measuring
pain intensity have yet been devised.
King David suffered from persistent severe bone pain. The biblical
words indicate extreme suffering by this ancient patient who was a
member of a high socioeconomic class. If evaluated by contemporary
assessment tools, each scale of pain would give a high score.
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12. Herr KA, Spratt K, Mobily PR, Richardson G. Pain intensity assessment in
older adults: use of experimental pain to compare psychometric properties and
usability of selected pain scales with younger adults. Clin J Pain. 2004;20(4):207-19.
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13. Geissner E. The Pain Perception Scale - a differentiated and change-sensitive

scale for assessing chronic and acute pain. Rehabilitation (Stuttg). 1995;34(4):XXXV-
XLIII.
14. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating
scales. J Clin Nurs. 2005;14(7):798-804.
15. Dixon S, Poole CD, Odeyemi I, et al. Deriving health state utilities for the
numerical pain rating scale. Health Qual Life Outcomes. 2011;9:96.
16. Van Der Lugt CM, Rollman A, Naeije M, et al. Social support in chronic pain:
development and preliminary psychometric assessment of a new instrument. J Oral
Rehabil. 2012;39(4):270-6.
17. Kristiansen K, Lyngholm-Kjaerby P, Moe C. Introduction and Validation of
DoloTest(®): a new health-related quality of life tool used in pain patients. Pain Pract.
2010;10(5):396-403.
18. Baranoff J, Hanrahan SJ, Kapur D, Connor JP. Acceptance as a process
variable in relation to catastrophizing in multidisciplinary pain treatment. Eur J Pain.
2013;17(1):101-10.
19. Keller S, Bann CM, Dodd SL, et al. Validity of the brief pain inventory for
use in documenting the outcomes of patients with noncancer pain. Clin J Pain.
2004;20(5):309-18.
20. Mendoza T, Mayne T, Rublee D, Cleeland C. Reliability and validity of a
modified Brief Pain Inventory short form in patients with osteoarthritis. Eur J Pain.
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Canadian version of the Pain Disability Index. Pain Res Manag. 2008;13(4):327-33.
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Pain Rating Scale in pediatric emergency department patients. Acad Emerg Med.
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23. Mayer TG, Neblett R, Cohen H, et al. The development and psychometric
validation of the central sensitization inventory. Pain Pract. 2012;12(4):276-85.
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efficacy. Clin J Pain. 2011;27(5):461-70.
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of Chronic Pain Acceptance Questionnaires: a systematic review. Eur J Pain.
2010;14(5):457-65.
CLINICAL APPLICABILTY
Post-operatively, elderly patients with impaired vision and
cognitive dysfunction may experience difficulties understanding
standard pain assessment tools such as the 10-cm VAS and the VRS.
There is a need to identify more feasible post-operative pain
assessments for elderly patients. With this goal in mind, the VAS and
VRS with 2 more expressive tools: the 50-cm RWS and the FPS were
compared. Cardiac surgery patients (73 +/- 5 years, mean +/- SD)
were allocated to an RWS (n=80) or an FPS (n=80) group. Pain was
75
assessed at rest and after movement during the first 4 days after
tracheal extubation. The RWS or FPS assessments were repeated after
10 min. All patients completed the VRS and VAS. The rates of
successful pain measurement on study day 1 were: VRS 86%, VAS
62%, RWS 78%, and FPS 60%. Pain measurements with the RWS
correlated with the VAS (r=0.758, p<0.001) and weaker with the VRS
(r=0.666, p<0.001) measurements. Pain measurements with the FPS
correlated with the VAS (r=0.873, p<0.001) and weaker with the VRS
(r=0.583, p<0.001) measurements. With all scales, success rates
improved during the study period. In conclusion, in elderly patients,
the VRS is the most feasible pain scale, followed by the RWS
immediately after cardiac surgery. The traditional 10-cm VAS is
unsuitable for pain measurement in this population (1).
The aims of this study were to describe the relationship between
the VAS and VRS; to compare characteristics of the noncompliant
groups in terms of age, gender, type of surgery and analgesics; to
explore the reasons for noncompletion of the VAS or VRS; and to
determine the noncompliance rates with each assessment scale. Worst
and average pain scores were obtained for the second postoperative
night for 417 patients. The VAS did not complete 59 (14.2%) patients.
By contrast, 2 patients did not complete the VRS (0.5%). The scores
generated from the VAS and VRS correlated well, although the range
of VAS scores corresponding to each VRS category was wide. The
VRS was more suitable for use in this clinical setting (2).
The present study was undertaken to determine if VAS could be
useful in the measurement of postoperative pain in usual medical
practice. The study comprised 212 patients with abdominal,
orthopedic or gynecological surgical procedures within the previous
24 hours. Patients evaluated their pain using a VRS of 5 points or a
VAS of 10 cm. The investigators also evaluated patient pain through a
VAS. A high correlation between VRS and VAS could be established
in all patients (p<0.001). The VAS of patients and researchers highly
correlated (p<0.001). When values of each group were compared by
pain intensity a total agreement of VAS scores at low pain level could
be established, but differences were at high pain intensity levels,
suggesting that physicians scored lower than patients did when pain
was severe to unbearable. In conclusion, VAS could be a reliable
method to assess pain in clinical setting (3).
The main purpose of this study was to evaluate the reliability and
validity of the FPS-R, the NPRS, and IPT for pain assessment in
Chinese elders who have had surgery. A descriptive correlational
design with repeated measures was used. A convenience sample of
76
180 Chinese elders (age range 65 to 95 years), undergoing scheduled

surgery at a university-affiliated hospital, was recruited. On the day
before surgery, recalled pain and anticipated postoperative pain
intensity were rated by patients with 3 scales presented in randomized
order, and then cognitive function was measured. On the first 3
postoperative days, participants completed the 3 scales in random
order to assess current, worst, and least pain on each day. On the 3rd
postoperative day, single retrospective ratings on worst, least, and
average pain over the 3 days for each scale were obtained and scale
preferences were investigated. The failure rates for all 3 scales were
extremely low. The interclass correlation coefficients across current,
worst, and least pain on each postoperative day were consistently high
(0.949 to 0.965), and all scales at each rating were strongly correlated
(r=0.833 to 0.962). Pain scores significantly decreased during the 3
postoperative days and all 3 scales were sensitive in evaluating
patient-controlled analgesia efficacy. The scale mostly preferred was
the IPT (54.7%), followed by the FPS-R (28.5%) and the NRS
(15.6%). Insignificant differences were noted in participant preference
by age and cognitive status, but preference for the IPT and the FPS-R
were significantly related to gender and education level. Although all
3 scales show good reliability, validity, and sensitivity for assessing
postoperative pain intensity in Chinese elders, the IPT appears to be a
better choice based on patient preference. The FPS-R, the NRS, and
the IPT can be used confidently to assess postoperative pain in
Chinese surgical elders (4).
Pain was evaluated for patients after open distal gastrectomy
(ODG, 52 cases), laparoscopically assisted distal gastrectomy (LADG,
112 cases), open total gastrectomy (OTG, 18 cases), and
laparoscopically assisted total gastrectomy (LATG, 33 cases). The
patients were administered continuous epidural anesthesia for 2 days
after the surgery. The WBS was used to evaluate the differences in
pain. Each patient was evaluated from postoperative day 1 to
postoperative day 7, and temporal changes in pain were studied
comparatively between ODG and LADG and between OTG and
LATG. Peak pain scores were recorded on postoperative day 3 for
both distal and total gastrectomy. The scores decreased over time after
postoperative day 3. There was insignificant difference in scores
between open and laparoscopic gastrectomy up to postoperative day 2,
but lower scores were shown on postoperative days 3, 4, and 5 for
LADG and on days 3 and 4 for LATG. In conclusion, the pain score
for laparoscopic gastrectomy was low. There was insignificant
difference in pain between procedures, and epidural anesthesia was
77
effective. Pain subsided earlier with laparoscopic than with open

gastrectomy. The same characteristics were observed with both
LADG and LATG (5).
The main aim of this study was to determine the agreement
between the VAS, the standardized color analog scale, the WBS and a
VNRS. Participants were children who were aged 8 to 18 years,
presented to a pediatric ED with abdominal pain suggestive of
appendicitis, and were recruited to participate in a RCT evaluating the
efficacy of morphine. Patients were initially asked to grade their pain
on a plasticized CAS, a paper VAS, a paper WBS, and then with a
VNRS. Thirty minutes after morphine or placebo administration, the
assessment was repeated. All scores were then converted to a value of
0 to 100. Agreements between scores were evaluated with the Bland-
Altman method, and the 95% lower and upper limits were reported. A
priori the maximum limit of agreement at +/-20 mm were defined. Of
87 children included in this study, 58 were with confirmed
appendicitis. The 95% limits of agreement for each pair of scales were
VAS/CAS -18.6, 14.4; VAS/WBS -20.1, 33.7; VAS/VNRS -30.2,
20.7; CAS/WBS -18.5, 36.3; CAS/VNRS -26.9, 22.1; and
WBS/VNRS -38.7, 15.7. This study suggests that only the VAS and
the CAS have acceptable agreement in children with moderate to
severe acute abdominal pain. In particular, the VNRS is not in
agreement with the other evaluated scales (6).
The main aim of this study was to evaluate the correlation between
the parents and the health care professionals regarding how
postoperative pain is estimated and to identify age and gender
differences regarding the pain after adenoidectomy. The study
included 100 children aged 3-10 years scheduled for adenoidectomy.
The nurse and the parent assessed the postoperative pain of the child
at different time intervals using a VAS. The child rated its pain by
using the WBS. The postoperative pain scores were higher at 10 min
after the operation than after 30 min. The parents scored the pain
higher than the nurse did, but there was still a strong correlation
between the observers' rating of the pain. The correlation between the
nurse's and the child's assessments was stronger than the correlation
between the parent's and the child's assessments. There was no gender
difference in how the pain was perceived by the child. The parents
tended to score the pain higher with older age of the child (7).
Neuropathic pain is the focus of current clinical research, clinical
identification, and treatment. It is unique from nociceptive pain and
requires evaluation of the relevance and utility of common pain
measures created for other painful conditions. This study evaluated the
78
psychometric properties of a modified BPI for patients with painful

DPN. Participants were patients with painful DPN (n=255) enrolled in
a DPN Burden of Illness Survey referred through 17 outpatient
settings (primary care physicians, endocrinologists, neurologists, and
anesthesiologists). Patients completed the BPI-DPN, and self-report
measures of HRQL, mood sleep, and healthcare utilization. Construct,
criterion and discriminant validity, and internal consistency reliability
were evaluated. Principal axis factoring with oblimin rotation revealed
2 interpretable factors (eigenvalues > 1.0), consistent with most
published BPI validation studies; a severity scale comprising the 4
BPI Severity items and an interference scale comprising the 7
Interference items, which satisfied criteria for interpretability and
model fit. Cronbach's alpha was high (0.94) for both scales. Mean pain
Severity was highly correlated with Bodily Pain from the Medical
Outcomes Study Short Form-12, version 2 (rs=0.63, p<0.001), the
Pain/Discomfort item in the Euro-QOL (rs=0.58, p<0.001), and a VRS
measure of pain severity (rs=0.74, p<0.001). Individual BPI-DPN
Interference domains were moderately correlated (rs's >0.5, p<0.001)
with analogous measures, and the Sleep Interference item had a high,
significant association with the 3 primary Medical Outcome Study-
Sleep scale subscales (rs's=0.66-71, p<0.001). Worst Pain and
Interference ratings were significantly associated with hospital
utilization and outpatient visits due to DPN. These results replicate, in
a pure peripheral neuropathic pain condition, the BPI psychometric
characteristics documented in populations with nociceptive or mixed
pain conditions. The BPI-DPN is a promising instrument in the
evaluation of painful DPN (8).
The BPI is a comprehensive instrument for pain assessment and
has been validated in several languages. The purpose of this study was
to determine the reliability and validity of the BPI for assessing pain
in patients undergoing abdominal surgery in Turkey. The sample
consisted of 178 patients who underwent abdominal surgery in general
surgery and in obstetrics and gynecology clinics of a university
hospital in Zmir, Turkey. A demographic questionnaire and the BPI
were used to collect data. The content validity was tested by
requesting opinions of experts. The structure validity of the scale was
evaluated with factor analyses and reliability of the scale with
Cronbach alpha and with item-to-total correlations. Two factors with
an eigenvalue greater than 1 were extracted, supporting the validity of
2-factor structure of the original BPI. Factor loads of these 2 factors
ranged from 0.55 to 0.91. The Cronbach alpha reliability coefficient
was 0.79 for the severity scale and 0.80 for the interference scale. The
79
item-to-total correlations of the scale ranged between 0.42 and 0.69.

Thus, the Turkish version of the BPI is a reliable and valid instrument
for assessing postsurgical pain severity and its interference (9).
The main objective of this study was to summarize and
systematically review FPSs most commonly used to obtain self-report
of pain intensity in children for evaluation of reliability and validity
and to compare the scales for preference and utility. Five major
electronic databases were systematically searched for studies that used
a faces scale for the self-report measurement of pain intensity in
children. Fourteen FPCs were identified, of which 4 have undergone
extensive psychometric testing: FPS (scored 0-6); FPS-R (0-10);
Oucher pain scale (0-10); and WBS (0-10). These 4 scales were
included in the review. Studies were classified by using psychometric
criteria, including construct validity, reliability, and responsiveness,
that were established a priori. From 276 articles retrieved, 182 were
screened for psychometric evaluation, and 127 were included. All 4
FPCs were found to be adequately supported by psychometric data.
When given a choice between faces scales, children preferred the
WBS. Confounding of pain intensity with affect caused by use of
smiling and crying anchor faces is a disadvantage of the WBS (10).
This study explored whether global unidimensional self-report pain
scales based on facial expression help children separately estimate the
sensory and affective magnitude of post-operative pain. Ninety
pediatric elective surgery patients (in 2 age groups: 5-9 and 10-15
years) used each of 4 scales to estimate pain intensity and pain affect
during the first 2 days after surgery. The 4 scales were: FPS, FAS, and
the CAS (1 for intensity and 1 for unpleasantness). As hypothesized,
ratings on the FPS correlated more highly with CAS ratings for
intensity than for unpleasantness, whereas ratings on the FAS
correlated more highly with those on the CAS for unpleasantness than
for intensity. Factor analysis indicated that although all measures
loaded on a single dimension of distress, there was an additional
weaker factor corresponding to a unique contribution of the FAS. No
systematic age effects were observed. It was concluded that the FPS
and the FAS may partly measure different aspects of the postoperative
pain experience in children, although shared instrument variance may
obscure true estimates of covariation in ratings of intensity and
affective magnitude. The clinical relevance of the present results
remains to be determined (11).
The PCS assists both treatment planning and outcome assessment.
Its use is limited in Portuguese-speaking countries because of the lack
of a validated translated version. The validation of the BP-PCS was
80
conducted and was explored its psychometric properties. This study

reports the internal consistency, factor structure, and its capability to
discriminate pain reported by patients with specific chronic pain
conditions. Of 384 patients, 317 women (82.6%) aged 18-79 years
with chronic nonmalignant pain, attending an outpatient
multidisciplinary pain center, participated in this cross-sectional study.
The instruments were the BP-PCS, pain intensity, pain interference in
functional capacity, and a sociodemographic questionnaire. One
subsample with chronic tensional headache according to the criteria of
the International Headache Society (n=19), and another with a
diagnosis of fibromyalgia according to the ACR criteria (n=50) were
selected to assess the discriminative properties of BP-PCS. Good
internal consistency (Cronbach's α values of 0.91 for the total BP-
PCS, and 0.93 [helplessness], 0.88 [magnification], and 0.86
[rumination] for the respective subdomains) was observed. The item-
total correlation coefficients ranged from 0.91 to 0.94. Confirmatory
factor analysis supported the 3 factors structure, with the comparative
fit index = 0.98, root mean square error of approximation = 0.09, and
formed fit index = 0.98. Significant correlations were found for pain
intensity, pain interference, and patient's mood (correlation
coefficients ranged from 0.48 to 0.66, p<0.01). Insignificant gender
difference was observed for BP-PCS scores. When comparing scores
of BP-PCS scale and subscales between the selected control group
(patients with pain scores on VAS equal or lower than 40 mm in the
most part of the day in the last 6 months) and patients with
fibromyalgia or chronic tensional headache, lower scores for the
former group were observed. These findings support the validity and
reliability of the BP-PCS. The scale showed satisfactory psychometric
properties. Confirmatory factor analysis provides support for the
three-factor structure reported in previous studies. This factor
structure presented good discriminative properties to identify
catastrophizers who present with mild chronic pain, fibromyalgia, and
chronic tensional headache. In conclusion, the BP-PCS is a valuable
tool for use in scientific studies and in the clinical setting in patients
with chronic pain in Brazilian Portuguese-speaking countries (12).
Difficulties in communication and lack of suitable pain scales may
lead to under treatment of pain in cognitively impaired patients. A
study was conducted in order to evaluate the usefulness of 4 simple
pain scales. Forty-one hospitalized elderly (76-95 years) patients who
suffered from pain with an acute component were studied. Cognitive
function was assessed with the MMSE and the degree of depression
was assessed on the GDS. Pain intensity was assessed at rest and after
81
a pain-provoking movement 3 times at 2-week intervals by repeating

the test at a 10-min interval at each test session. The pain scales were
the 50 cm RWS, the seven-point FPS, the 10 cm VAS and the five-
point VRS. In group MMSE ≥ 24, patients were able to use all 4
scales rather successfully. In the other groups (MMSE 17-23, 11-16
and ≤ 10), only the use of VRS was successful to a reasonable degree
(64-85% on average). GDS scores did not correlate with the pain
scores, with the exception of pain scores on FPS during movement
(p<0.01). The estimations of intensity and frequency of pain
performed by nurses failed to correlate with the patient's own pain
intensity estimations. In conclusion, scoring of pain with RWS, FPS
and VAS seems to be feasible in elderly patients with a normal
cognitive dysfunction. VRS appeared to be applicable in the elderly
with a clear cognitive dysfunction, i.e., with MMSE < 17 (13).
Assessment: various pain assessing instruments can be applied in

different medical situations including DPN, after surgery, and in
cognitively impaired patients.
References
1. Pesonen A, Suojaranta-Ylinen R, Tarkkila P, Rosenberg PH. Applicability of
tools to assess pain in elderly patients after cardiac surgery. Acta Anaesthesiol Scand.
2008;52(2):267-73.
2. Briggs M, Closs JS. A descriptive study of the use of visual analogue scales
and verbal rating scales for the assessment of postoperative pain in orthopedic
patients. J Pain Symptom Manage. 1999;18(6):438-46.
3. Baños JE, Bosch F, Cañellas M, et al. Acceptability of visual analogue scales in
the clinical setting: a comparison with verbal rating scales in postoperative pain.
Methods Find Exp Clin Pharmacol. 1989;11(2):123-7.
4. Li L, Herr K, Chen P. Postoperative pain assessment with three intensity scales
in Chinese elders. J Nurs Scholarsh. 2009;41(3):241-9.
5. Kawamura H, Homma S, Yokota R, et al. Assessment of pain by face scales
after gastrectomy: comparison of laparoscopically assisted gastrectomy and open
gastrectomy. Surg Endosc. 2009;23(5):991-5.
6. Bailey B, Bergeron S, Gravel J, Daoust R. Comparison of four pain scales in
children with acute abdominal pain in a pediatric emergency department. Ann Emerg
Med. 2007;50(4):379-83, 383.e1-2.
7. Knutsson J, Tibbelin A, Von Unge M. Postoperative pain after paediatric
adenoidectomy and differences between the pain scores made by the recovery room
staff, the parent and the child. Acta Otolaryngol. 2006; 126(10):1079-83.
8. Zelman DC, Gore M, Dukes E, et al. Validation of a modified version of the
brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom
Manage. 2005;29(4):401-10.
9. Dicle A, Karayurt O, Dirimese E. Validation of the Turkish version of the
Brief Pain Inventory in surgery patients. Pain Manag Nurs. 2009;10(2):107-113.e2.
10. Tomlinson D, von Baeyer CL, Stinson JN, Sung L. A systematic review of
faces scales for the self-report of pain intensity in children. Pediatrics.
2010;126(5):e1168-98.
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11. Perrott DA, Goodenough B, Champion GD. Children's ratings of the intensity
and unpleasantness of post-operative pain using facial expression scales. Eur J Pain.
2004;8(2):119-27.
12. Sehn F, Chachamovich E, Vidor LP, et al. Cross-Cultural Adaptation and
validation of the Brazilian Portuguese version of the pain catastrophizing scale. Pain
Med. 2012;13(11):1425-35.
13. Pesonen A, Kauppila T, Tarkkila P, et al. Evaluation of easily applicable pain
measurement tools for the assessment of pain in demented patients. Acta Anaesthesiol
Scand. 2009;53(5):657-64.
CATASTROPHIZING RESPONSE TO PAIN

Catastrophizing is a maladaptive response to pain and is one of the
factors that contribute to the chronicity of some pain syndromes (1) .
Pain catastrophizing is conceptualized as a negative cognitive-
affective response to anticipated or actual pain that has been
associated with a number of important pain-related outcomes (2).
The current study examined the associations between
catastrophizing and pain intensity, psychological adjustment,
functional ability, and community participation in youths with
physical disability and chronic pain. Participants consisted of 80
youths, aged 8-20 years, with cerebral palsy (n=34), neuromuscular
disease (n=22), and spina bifida (n=24). Measures from a cross-
sectional survey included demographic, pain, and disability
information, the PCS, the Child Health Questionnaire, and the
Functional Disability Inventory. Catastrophizing was significantly
associated with pain intensity and psychological adjustment; however,
catastrophizing demonstrated insignificant associations with
functional ability or community participation. These results indicate
significant associations between catastrophizing and both pain
intensity and psychological adjustment in youths with chronic pain
and disabilities (3).
The main objective of this study was to examine the influence of
sex and disability on catastrophizing, pain intensity, and pain
interference in individuals with a SCI or MS. A cross-sectional survey
design was employed. Community-dwelling adults (n=248) with a
physical disability (SCI=124; MS=124) and chronic pain completed
measures of demographic and clinical characteristics, pain intensity
and interference, psychological functioning and pain catastrophizing.
Men reported marginally greater catastrophizing (p<0.10) than women
across both disability groups; however, there was insignificant
difference in catastrophizing between disability groups.
Catastrophizing was the only significant predictor of pain intensity in
83
the multivariate regression analysis, with greater catastrophizing

associated with greater pain. Pain intensity and catastrophizing were
the only significant variables in the regression analyses predicting
pain interference and psychological functioning; as hypothesized,
greater pain intensity and catastrophizing were associated with more
pain interference and poorer psychological functioning. There was
also a trend (p<0.10) for females, relative to males, to have a stronger
association between catastrophizing and pain interference. These
findings are consistent with a biopsychosocial conceptualization of
pain and functioning in individuals with chronic pain secondary to a
physical disability. Assessment and treatment (when indicated) of
catastrophizing should be a regular part of the clinical management of
these patients (4).
The current study sought to examine how changes in pain-related
beliefs and coping responses are related to changes in pain
interference and psychological functioning in individuals with SCI
and pain. To measure longitudinal changes in these variables,
respondents completed a survey that included measures of pain
intensity, pain interference, and psychological functioning, as well as
specific psychosocial variables (pain-related beliefs, coping, and
social support) and then completed the same survey 6 months later;
analyses included only the individuals who reported pain at both times
(n=40). Demographic and injury-related variables were also assessed,
but none was to be significantly associated with changes in
functioning. Changes in catastrophizing and belief in one's ability to
control pain were each significantly associated with changes in the
outcome variables: greater pain interference and poorer psychological
functioning. Changes in specific coping strategies and social support
were not predictors of changes in pain, interference, or psychological
functioning. These findings support a biopsychosocial model of pain
in persons with SCI. Intervention studies targeting maladaptive pain-
related beliefs and catastrophizing may help to identify the causal
nature of these relationships and may improve multidisciplinary
treatment of pain in SCI (5).
The relationship between catastrophizing and distraction analgesia
was evaluated. Healthy participants completed 3 sessions in a
randomized order. In one session (Pain Alone), pain was induced by
topical application of a 10% capsaicin cream and simultaneous
administration of a tonic heat stimulus. In another session
(Pain+Distraction), identical Capsaicin+Heat application procedures
were followed, but subjects played video games that required a high
level of attention. During both sessions, verbal ratings of pain were
84
obtained and participants rated their degree of catastrophizing. During

the other session (Distraction Alone) subjects played the video games
in the absence of any pain stimulus. Pain was rated significantly lower
during the distraction session compared to the ―pain alone‖ session.
High catastrophizers rated pain significantly higher regardless of
whether the subjects were distracted. Catastrophizing did not
influence the overall degree of distraction analgesia; however, early in
the session high catastrophizers had little distraction analgesia, though
later in the session low and high catastrophizers rated pain similarly.
These findings suggest that both distraction and catastrophizing have
substantial effects on experimental pain in normal subjects and these
variables interact as a function of time (6).
The aim of the present study was to describe fear-avoidance
beliefs, catastrophizing, and emotional distress among
musculoskeletal pain patients in primary healthcare and to explore the
relationship of psychological risk profiles for pain, function, and sick
leave from baseline through 1-year and 3-year follow-ups. Ratings
from 110 musculoskeletal pain patients were collected and cluster
analysis was used to identify subgroups with similar patterns on fear-
avoidance beliefs, catastrophizing, and emotional distress. The
clusters were examined cross-sectionally and prospectively on sick
leave, function, and pain. Five distinct profiles were found: "low
scores cluster," "high score cluster," "fear-avoidance beliefs and
catastrophizing cluster," "distress only cluster," and "medium
catastrophizing cluster." The "low scores cluster" and "distress only
cluster" had the most favorable scores on outcome variables. The
analysis of common developmental pathways showed considerable
stability over time. Reorganization of clusters in a psychological "high
risk cluster" and a "low risk cluster" showed significant differences at
1-year and 3-year follow-ups in functional ability as well as in
decreased sick leave. There were insignificant differences between the
groups on average pain ratings at the 2 measure points. Distinct
profiles of catastrophizing, fear-avoidance beliefs, and emotional
distress were extracted and meaningfully related to future sick leave
and dysfunction outcomes. The structures of the profiles were
essentially stable and became more accentuated across a 3-year
period. The results underscore the need to address psychological
aspects as fear-avoidance beliefs, catastrophizing, and emotional
distress in the management of patients with musculoskeletal pain and
may open the path for a better-tailored treatment approach for this
patient group (7).
85
This study examines how cognitive representations of chronic pain

relate to interpersonal styles such as catastrophizing and the
behavioral process of acceptance of chronic pain, and how these
processes relate to emotional and physical functioning in chronic pain.
A cross-sectional design, employing validated questionnaires, was
used to measure pain, emotional and physical dysfunction, illness
representations, catastrophizing and acceptance in a heterogeneous
sample of 150 chronic pain sufferers. The psychological variables
significantly mediated the impact of pain severity on both emotional
and physical dysfunction. In addition, a distinct pattern of mediation
was observed. The relationship between pain and emotional
dysfunction was mediated by representations of pain as a highly
emotive experience and by catastrophizing; acceptance did not
mediate this relationship. By contrast, the relationship between pain
and physical dysfunction was mediated by acceptance and
representations of high consequences of chronic pain, but not by
catastrophizing. In conclusion, pain severity itself is a relatively poor
predictor of emotional and physical dysfunction in chronic pain states.
These relationships are significantly mediated by psychological
variables. Different approaches to chronic pain rehabilitation
emphasize different targets (changing illness representations and
reducing catastrophizing vs. acceptance and behavioral activation).
This cross-sectional study suggests that these processes may
differentially influence outcomes, but they are complex and
overlapping (8).
This study tests the idea that if depressed mood and catastrophizing
are separate entities then when one is absent the other should still
contribute to poor outcome, and, when both are present there should
be an additional AE. To this end, a prospective design, with a built-in
replication from 2 clinical samples of patients with sub-acute pain (1
from Sweden, n=373; 1 from Australasia, n=259), was employed.
Participants were classified as to having high/low scores on measures
of depression and catastrophizing. Subsequently, these classifications
were studied in relation to outcome variables cross-sectionally and at
follow-up. Results showed a small to moderate correlation between
catastrophizing and depression and there were individuals with 1, but
not the other problem. Having 1 or the other of the entities was
associated with current pain problems and outcome, while having both
increased the associations substantially. The replication showed very
similar results. In conclusion, pain catastrophizing and heightened
depressed mood have an additive and AE on the impact of pain,
relative to either alone (9).
86
Assessment: catastrophizing is a maladaptive response to pain and

is one of the factors that contribute to the chronicity of some pain
syndromes. Catastrophizing, a set of negative emotional and cognitive
processes, is associated with increased pain. Pain catastrophizing is a
negative cognitive-affective response to anticipated or actual pain and
is associated with a number of important pain-related outcomes.
In patients with physical disability, greater pain intensity and
catastrophizing are associated with more pain interference and poorer
psychological functioning. Changes in catastrophizing and belief in
one's ability to control pain are each significantly associated with
changes in the outcome variables. The relationship between pain and
physical dysfunction is mediated by acceptance and representations of
high consequences of chronic pain, but not by catastrophizing. Pain
catastrophizing and heightened depressed mood have additive and AE
on the impact of pain.
Can King David's behavior be regarded as catastrophizing?
Although the biblical verses studied in this research indicate a human
being who suffered from severe bone pain, it seems unlikely that the
King was afflicted by maladaptive response to pain expressed as
catastrophizing reaction.
References
1. Sehn F, Chachamovich E, Vidor LP, et al. Cross-cultural adaptation and
validation of the Brazilian Portuguese version of the pain catastrophizing scale. Pain
Med. 2012;13(11):1425-35.
2. Quartana PJ, Campbell CM, Edwards RR. Pain catastrophizing: a critical
review. Expert Rev Neurother. 2009;9(5):745-58.
3. Engel JM, Wilson S, Tran ST, et al. Pain catastrophizing in youths with
physical disabilities and chronic pain. J Pediatr Psychol. 2013;38(2):192-201.
4. Hirsh AT, Bockow TB, Jensen MP. Catastrophizing, pain, and pain
interference in individuals with disabilities. Am J Phys Med Rehabil. 2011;
90(9):713-22.
5. Hanley MA, Raichle K, Jensen M, Cardenas DD. Pain catastrophizing and
beliefs predict changes in pain interference and psychological functioning in persons
with spinal cord injury. J Pain. 2008;9(9):863-71.
6. Claudia M. Campbell, Witmer K, et al. Catastrophizing delays the analgesic
effect of distraction. Pain. 2010;149(2):202-7.
7. Westman AE, Boersma K, Leppert J, Linton SJ. Fear-avoidance beliefs,
catastrophizing, and distress: a longitudinal subgroup analysis on patients with
musculoskeletal pain. Clin J Pain. 2011;27(7):567-77.
8. Gillanders DT, Ferreira NB, Bose S, Esrich T. The relationship between
acceptance, catastrophizing and illness representations in chronic pain. Eur J Pain.
2013;17(6):893-902.
9. Linton SJ, Nicholas MK, MacDonald S, Boersma K, et al. The role of
depression and catastrophizing in musculoskeletal pain. Eur J Pain. 2011;15(4):416-
22.
87
GENDER DIFFERENCES IN THE PERCEPTION

OF PAIN
There are differences between males and females regarding the

perception, expression, and tolerance of pain that stems from a variety
of social and psychologic influences. Personal self-efficacy and
lifespan socialization are 2 such influences, and they provide new
dimensions to better understand the pain experience (1,2).
The differences about pain in men and women seem to be due to
the sex, the biological dimension of the person, and to the gender
related to the role given to a person in a given social and culture
environment. The pain prevalence is higher in women; its threshold
and tolerance are lower (2).
Females are at greater risk for developing several chronic pain
disorders, and women exhibit greater sensitivity to noxious stimuli in
the laboratory compared with men. Several mechanisms have been
proposed to account for these sex differences. Psychosocial factors
such as sex role beliefs, pain coping strategies, mood, and pain-related
expectancies may underlie these effects. Familial factors can alter pain
responses, and these intergenerational influences may differ as a
function of sex. Sex hormones affect pain responses, which may
mediate the sex differences. Although the magnitude of these effects
has not been well characterized, there are potentially important
practical implications of sex differences in pain responses (3).
For experimentally delivered somatic stimuli, females have lower
thresholds, greater ability to discriminate, higher pain ratings, and less
tolerance of noxious stimuli than males. These differences, however,
are small, and exist only for stimulations that are affected by many
situational variables such as presence of disease, experimental setting,
and even nutritive status. For endogenous pains, women report more
multiple pains in more body regions than men do. With no obvious
underlying rationale, some painful diseases are more prevalent among
females; others among males and, for many diseases, symptoms differ
between females and males. Sex differences in attitudes affect not
only reporting, coping, and responses to treatment, but also
measurement and treatment. So many variables are operative,
however, that the most striking feature of sex differences in reported
pain experience is the apparent overall lack of them. On the other
hand, deduction from known biological sex differences suggests that
these are powerful sex differences in the operation of pain
mechanisms. First, the vaginal canal provides an additional route in
women for internal trauma and invasion by pathological agents that
88
puts them at greater risk for developing hyperalgesia in multiple body

regions. Sex differences in temporal patterns are likely to give rise to
sex differences in how pain is "learned" and stimuli are interpreted, a
situation that can lead to a greater variability and wider range of pains
without obvious peripheral pathology among females. Sex differences
in the actions of sex hormones suggest pain-relevant differences in the
operation of many neuroactive agents, opiate and nonopiate systems,
nerve growth factor, and the sympathetic system. Thus, while
inductive analysis of existing data demonstrates more similarities than
differences in pain experience between females and males, deductive
analysis suggests important operational sex differences in its
production (4).
This systematic review summarizes the results of 10 years of
laboratory research on pain and sex/gender. An electronic search
strategy was designed by a medical librarian to access multiple
databases. Articles (n=172) published between 1998 and 2008 were
retrieved, analyzed, and synthesized. The second set of results
presented in this review (129 articles) examined various
biopsychosocial factors that may contribute to differences in pain
sensitivity between healthy women and men. The results revealed that
the involvement of hormonal and physiological factors is either
inconsistent or absent. Some studies suggest that temporal summation,
allodynia, and secondary hyperalgesia may be more pronounced in
women than in men. The evidence to support less efficient
endogenous pain inhibitory systems in women is mixed and does not
necessarily apply to all pain modalities. With regard to psychological
factors, depression may not mediate sex differences in pain
perception, while the role of anxiety is ambiguous. Cognitive and
social factors appear to partly explain some sex-related differences.
Finally, past individual history may be influential in female pain
responses. However, these conclusions must be treated with much
circumspection for various methodological reasons (5).
Two experiments assessed how interpersonal transactions influence
responses to cold pressor pain in women vs. men. In Experiment 1, 91
young adults (57 women, 34 men) were randomly assigned to either a
no transaction condition in which they coped alone with the cold
pressor test or a transaction opportunity condition in which they also
had the option of interacting with an empathetic, reflecting
experimenter. Compared to men, women had lower pain tolerance and
reported more pain and catastrophizing, although there were no gender
differences in support seeking or other ways of coping. Within the
transaction opportunity condition, women were no more likely than
89
men to initiate a transaction, but female speakers were more pain-

focused than male speakers, and speaking with the empathetic
interaction partner had generally negative effects on pain perception
and coping. In Experiment 2, 126 young adults (76 women, 50 men)
were randomly assigned to no transaction, transaction opportunity, or
experimenter-directed (1) Distraction, (2) Reinterpretation, or (3)
Encouragement conditions. Although men had similar levels of pain
tolerance across the 5 transaction conditions, women in no transaction
and transaction opportunity conditions exhibited reduced tolerance
compared with those in the distraction, reinterpretation, and
Encouragement conditions. Pain tolerance times among women in
distraction, Reinterpretation, and Encouragement conditions were
equal to or exceeded those of men in these conditions. Together, these
findings suggest the nature of interpersonal transactions exerts a
greater influence on women's responses to noxious stimulation than
those of men. Women exhibit reduced tolerance for experimentally
induced pain compared with men. The nature of interpersonal
transactions also affects women's responses to noxious stimulation,
more than those of men (6).
A current study sought to examine the extent to which gender-
specific expectations are associated with pain-related coping in more
detail by administering a standard pain coping measures on 3 separate
occasions, but with different instructions. The 122 participants (57
male, 65 female) were asked to complete the coping measure as
themselves, then again as they would expect the typical man and the
typical woman to complete it. There were insignificant differences
between men and women in their own self-reported usage of pain
coping strategies. However, there were differences in stereotypical
views of how men and women are thought to cope with pain. Sex
differences were in how participants viewed their own coping
behaviors in comparison to that of the typical man and typical woman.
These results confirm that alongside pain, men and women hold
different gender-specific expectations with respect to certain pain
coping strategies (7).
A review of the literature on gender and clinical pain reveals a
disproportionate representation of women receiving treatment for
many pain conditions and suggests that women report more severe
pain, more frequent pain, and pain of longer duration than men do.
Gender differences in pain perception have also been extensively
studied in the laboratory, and ratings of experimentally induced pain
show some sex disparity, with females generally reporting lower pain
thresholds and tolerance than males. However, there is little consensus
90
on whether these apparent differences reflect the way men and women
respond to pain, differing social rules for the expression of pain, or
biologic differences in the way noxious stimuli are processed. The
higher prevalence of chronic orofacial pain in women is a result of sex
differences in generic pain mechanisms and of as-yet unidentified
factors unique to the craniofacial system (8).
The main aim of this study was to determine the effect of sex on
pain perception, morphine consumption, and morphine analgesia after
surgery. A prospective cohort study included 423 women and 277
men who emerged from general anesthesia after surgical procedures
and who reported pain intensity of ≥ 5 on the 0-10 NPRS. 2.5 mg of
morphine was administered intravenously every 10 min until the pain
intensity was ≤ 4 of 10. Every 10 min, patients rated their pain on the
NPRS and indicated the degree of pain relief on a five-point Likert
scale. After adjustment for type of operation and age, women had
more intense pain and had larger morphine consumption than men.
The difference in NPRS pain intensity was 0.4 U (95% CI 0.1 - 0.6).
Women required 0.03 mg/kg more morphine than men did (95% CI
0.02 - 0.04 mg/kg). In conclusion, women have more intense pain and
require 30% more morphine to achieve a similar degree of analgesia
compared with men. Clinicians should anticipate the differences in
opioid requirement to avoid undertreatment of pain in women.
Women have more intense pain and required 30% more morphine to
achieve a similar degree of analgesia compared with men (9).
The purposes of this study were to determine gender differences in
pain threshold and tolerance among Chinese adults in Hong Kong and
to examine the role of anxiety in pain perception. One hundred
seventy-eight healthy, pain-free adults (89 men and 89 women) were
recruited from a local university by convenience sampling to
participate in the study. All participants completed the State and Trait
Anxiety Inventory and underwent a laboratory pain task to determine
their pain threshold and tolerance levels. Pain was assessed by using
the Pain Intensity VRS-Chinese version. Compared to men, women
had a lower threshold (p<0.001) and tolerance (p<0.001) for pressure
pain, and women reported more pain (p<0.01) at the pain tolerance
level. Higher trait anxiety scores were associated with higher pain
report in men only (p=0.04). This study indicated that gender
differences in pain perception exist among the Chinese population in
Hong Kong. A better understanding of the factors that contribute to
gender differences in pain perception could reduce gender bias in pain
management (10).
91
Assessment: there are sex-related differences in the experience of

both clinical and experimentally induced pain. Females have lower
thresholds, greater ability to discriminate, higher pain ratings, and less
tolerance of noxious stimuli than males.
Pain prevalence is higher and its threshold and tolerance are lower
in women compared to men. Women report more pain and
catastrophizing, although there are no gender differences in support
seeking or other ways of coping.
References
1. Miller C, Newton SE. Pain perception and expression: the influence of gender,
personal self-efficacy, and lifespan socialization. Pain Manag Nurs. 2006;7(4):148-52.
2. Jaunin-Stalder N, Mazzocato C. Are men and woman towards pain equal? Rev
Med Suisse. 2012;8(348):1470-3.
3. Fillingim RB. Sex, gender, and pain: women and men really are different. Curr
Rev Pain. 2000;4(1):24-30.
4. Berkley KJ. Sex differences in pain. Behav Brain Sci. 1997;20(3):371-80;
discussion 435-513.
5. Racine M, Tousignant-Laflamme Y, Kloda LA, et al. A systematic literature
review of 10 years of research on sex/gender and pain perception - part 2: do
biopsychosocial factors alter pain sensitivity differently in women and men? Pain.
2012;153(3):619-35.
6. Jackson T, Iezzi T, Chen H, et al. Gender, interpersonal transactions, and the
perception of pain: an experimental analysis. J Pain. 2005;6(4):228-36.
7. Keogh E, Denford S. Sex differences in perceptions of pain coping strategy
usage. Eur J Pain. 2009;13(6):629-34.
8. Dao TT, LeResche L. Gender differences in pain. J Orofac Pain. 2000;
14(3):169-84; discussion 184-95. Comment in: Sex, gender, and pain. [J Orofac Pain.
2000].
9. Cepeda MS, Carr DB. Women experience more pain and require more
morphine than men to achieve a similar degree of analgesia. Anesth Analg.
2003;97(5):1464-8.
10. Soetanto AL, Chung JW, Wong TK. Are there gender differences in pain
perception? J Neurosci Nurs. 2006;38(3):172-6.
SPECIAL CONSIDERATION IN THE ELDERLY
Over 50% of older adults experience chronic pain. Poorly managed

pain threatens independent functioning, limits social activities and
detrimentally affects emotional wellbeing. Yet, chronic pain is not
fully understood from older adults' perspectives; subsequently, pain
management in later life is not necessarily based on their priorities or
needs (1).
There are many myths and misconceptions about pain and its
management involving elderly patients. Many practitioners incorrectly
assume that pain is a natural outcome of growing old. Others believe
92
that pain perception or sensitivity decreases with age. The idea that
elderly persons not reporting pain do not have pain or that elderly
persons who are able to sleep do not have pain condemns many to
needless suffering. Compared to younger persons, elderly persons are
at greater risk for many painful conditions. Whereas the emotional
suffering related to pain may be less in older persons, there is no
evidence that the perception of pain diminishes with age. More
importantly, older persons commonly underreport pain and often
believe that it is unacceptable to show pain behavior. Opioid analgesic
agents may be used safely with older people, but starting dosages need
to be adjusted because of an increased sensitivity to them. Although
some older persons are cognitively impaired, they are still able to
perceive pain, so their reports of unrelieved pain must be taken
seriously (2). Pain assessment is often more complex with elderly
persons, especially when they are cognitively impaired, than with
younger patients. Nevertheless, self-reports about pain are still valid
and must be obtained, even from cognitively impaired patients.
Practitioners must consider the likelihood of some underreporting of
pain when working with cognitively impaired elderly patients; most of
these patients are still able to use PRSs, despite their cognitive
disabilities. When patients are extremely cognitively impaired,
behavioral indicators such as moaning, groaning, grimacing,
protecting involved areas, and assuming certain positions or postures
may prove as useful as formal PRSs for determining the presence or
absence of pain. Altered physiologic markers (e.g., tachycardia,
tachypnea, and hypertension) in a fearful, frightened, difficult to
console cognitively impaired patient should suggest the occurrence of
acute pain. Practitioners caring for elderly patients must remember
that chronic pain may not lead to the same physiologic changes and
behaviors, so they must be especially vigilant to detect pain (2).
Although pain is a common complaint in the elderly patient (3), it
is a significant, yet neglected problem, particularly in long-term care
settings. The effects of inadequate assessment and treatment of pain
among older people may lead to multiple problems. Problems arise
due to cognitive impairment of clients and inadequate assessment by
healthcare professionals. Analgesics are under-used and there is a
need for improved education of both healthcare professionals and
older people regarding attitudes to pain and ageing (4).
93
Overlap between frailty, co-morbidity and disability.
The main aim of this study was to explore sense of self, sense of
pain, daily living with pain, sense of others and ways of handling pain
in older people with persistent pain. Interviews with 90 older people
receiving home care from nursing auxiliaries in their own homes or in
sheltered accommodation were collected from January to June 2000.
A typology of older people in persistent pain was developed.
Respondents' experiences of themselves and their pain varied. Two
groups of older people, considered as 'competent and proud' and
'confident and serene', expressed satisfaction in spite of pain, while the
groups 'misunderstood and disappointed' and 'resigned and sad'
expressed dissatisfaction. The most common strategies used were
medications, rest, mobility, distracting activities and talking about
pain. Respondents chose strategies by balancing the advantages of the
activities against the disadvantages these brought for their daily living.
This study indicates that characteristics of the older people, such as
their way of experiencing themselves, how pain affects their daily life
and how they perceive effects and side effects of pain management
need to be identified when staff assess pain and plan pain
management. Caring for older people with pain could be improved by
listening and believing to their complaints, evaluating effects and side-
effects of medications and non-pharmacological pain management and
by emphasizing the importance of common everyday activities such as
mobility and distraction to relieve pain (5).
This cross-sectional conducted at the department of Medicine, San
Francisco, a nationally representative and the 2004 Health and
Retirement Study included 18,501 community-living persons aged 50
and older. Participants who reported that they were often troubled by
pain that was moderate or severe most of the time were defined as
having significant pain. For each of 4 functional domains, subjects
were classified according to their degree of functional limitation:
mobility (able to jog 1 mile, able to walk several blocks, able to walk
one block, unable to walk one block), stair climbing (able to climb
94
several flights, able to climb 1 flight, not able to climb a flight), upper
extremity tasks (able to do 3, 2, 1, or 0), and ADL function (able to do
without difficulty, had difficulty but able to do without help, or need
help). Of all participants, 24% had significant pain. Across all 4
domains, participants with pain had much higher rates of functional
limitations than subjects without pain. Participants with pain were
similar in terms of their degree of functional limitation to participants
2 to 3 decades older. For example, for mobility, of subjects aged 50 to
59 without pain, 37% were able to jog 1 mile, 91% were able to walk
several blocks, and 96% were able to walk 1 block without difficulty.
By contrast, of subjects aged 50 to 59 with pain, 9% were able to jog 1
mile, 50% were able to walk several blocks, and 69% were able to
walk 1 block without difficulty. Subjects aged 50 to 59 years with
pain were similar in terms of mobility limitations to subjects aged 80
to 89 years without pain, of whom 4% were able to jog 1 mile, 55%
were able to walk several blocks, and 72% were able to walk 1 block
without difficulty. After adjustment for demographic characteristics,
socioeconomic status, comorbid conditions, depression, obesity, and
health habits, across all 4 measures, participants with significant pain
were at much higher risk for having functional limitations
(AOR=2.85, 95% CI 2.20 - 3.69 for mobility; AOR=2.84, 95%
CI=2.48 - 3.26 for stair climbing; AOR=3.96, 95% CI=3.43 - 4.58 for
upper extremity tasks; and AOR=4.33, 95% CI 3.71 - 5.06 for ADL
function). In conclusion, subjects with pain develop the functional
limitations classically associated with aging at much earlier ages (6).
The main aim of this study was to assess the extent to which older
people experience pain, and to explore relationships between self-
reported pain and functional ability and depression. Secondary
analysis of baseline data from a RCT of health risk appraisal was
carried out. A total of 1090 community-dwelling non-disabled people
aged 65 years and over were included in the study from 3 group
practices in suburban London. Main outcome measures were pain in
the last 4 weeks and the impact of pain, measured using the 24-item
GPM; depression symptoms captured using the 5-item Mental Health
Inventory; social relationships measured using the 6-item Lubben
Social Network Scale; Basic and Instrumental Activities of Daily
Living and self-reported symptoms. Of women, 45% and 34% of men
reported pain in the previous 4 weeks. Pain experience appeared to be
less in the 'oldest old': 27.5% of those aged 85 years and over reported
pain compared with 38-53% of the 'younger old'. Those with arthritis
were 4 times more likely to report pain. Pain had a profound impact
on activities of daily living, but most of those reporting pain described
95
their health as good or excellent. Although there was a significant

association between the experience of pain and depressed mood, the
majority of those reporting pain did not have depressed mood. In
conclusion, a multidimensional approach to assessing pain is
appropriate. Primary care practitioners should also assess the impact
of pain on activities of daily living (7).
The goal of this study was to investigate the prevalence of pain
among a racially and gender-balanced sample of community-dwelling
older adults and evaluate sociodemographic factors associated with
the reporting of pain. Both nonprescription (OTC) and prescription
pain medications used by the participants and the sociodemographic
factors associated with having medication prescribed were evaluated.
This was a population-based, prospective, observational study.
Subjects were participants in the University of Alabama at
Birmingham Study of Aging, a stratified random sample of Medicare
beneficiaries who completed in-home interviews (1999-2001).
Assessments included sociodemographic factors and pain;
interviewers listed all prescription and OTC pain medications used.
Pain medications were coded as NSAIDs, opiates, and miscellaneous
pain medications. A composite ordinal measure reflecting pain
severity and frequency ranged from 0 = no pain to 4 = dreadful or
agonizing pain ≥ 4 times per week. There were 1000 participants in
the University of Alabama at Birmingham Study of Aging (mean [SD]
age, 75.3 [6.7] years; 50% black; 50% male; 51% rural residence). Of
the subjects, 74% reported pain; among these, 52% had daily pain,
with 26% reporting dreadful or agonizing pain. Logistic regression
controlling for other sociodemographic factors (age, gender, race,
education, income, and marital status) found that rural residence (OR
1.42, 95% CI 1.1 - 1.9, p=0.02) was significantly associated with the
reporting pain. Prescription pain medications were used by 35% of
persons with pain and by 17% without pain (p<0.001); OTC pain
medications were used by 52% of persons with pain and by 45% of
persons without pain (p=0.06). Of persons reporting pain, 28% were
taking neither prescription nor OTC pain medications; 16% took both
and 20% took only prescription pain medications. Logistic regression
found that factors associated with taking a prescription pain
medication were unmarried status (OR 1.56, 95% CI 1.1 - 2.2) and
pain frequency/severity (OR 1.39, 95% CI 1.3 - 1.6). Taking an OTC
pain medication was associated with lower odds of taking a
prescription pain medication (OR 0.50, 95% CI 0.4 - 0.7). Age,
gender, race, education, rural residence, transportation difficulty,
income, and being on Medicaid were not associated with prescription
96
pain medication use. In conclusion, prescription pain medication use

is associated with pain frequency/severity after adjusting for
sociodemographics and OTC pain medications in community-
dwelling older adults, suggesting that even with medications
individuals remain in pain (8).
The treatment of older adults with pain is complex and affected by
age-related changes in pharmacokinetics and pharmacodynamics.
Chronic pain encompasses a complex array of sensory-discriminatory,
motivational-affective, and cognitive-evaluative components. Because
of this complexity, both pharmacologic and nonpharmacologic
approaches should be considered to treat pain. Given the large number
of older persons with pain at the end of life and the few data about this
issue, the objective of this article is to review the treatment of pain in
this population. The Cochrane Library, MEDLINE and LILACS from
1990 to 2011 and the references in retrieved manuscripts were
searched. There are evidences of undertreatment among elderly
people. The association of non-pharmacologic resources with the
pharmacological treatment can help reduce the use of analgesics
minimizing the side effects of long term medication. Pharmacological
treatment is escalated in an orderly manner from non-opioid to weak
opioid to strong opioid. Adjuvant drugs like anticonvulsants and
antidepressants may be necessary. In conclusion, the sequential use of
analgesics drugs and opioids are considered effective and relatively
inexpensive for relieving pain, but no well-designed specific studies in
the elderly patient are available. There are no specific
recommendations about the long-term use of complementary and
alternative therapies and although their effectiveness remains
unproven, they should not be discouraged. Palliative sedation can be a
valid palliative care option to relieve suffering in the imminently
dying patient (9).
This paper reports a qualitative exploration of older adults'
accounts of living with chronic pain, focusing on how they describe
pain, with a view to informing approaches to its assessment.
Cognitively intact men and women aged > 65 years who lived in the
community opted into the study through responding to advertisements
in the media and via contacts with groups and organizations in North-
East Scotland. Interviews were transcribed and thematically analyzed
using a framework approach. Qualitative individual interviews and
one group interview were undertaken with 23 older adults. Following
analysis, the following main themes emerged: diversity in
conceptualizing pain using a simple numerical score; personalizing the
meaning of pain by way of stories, similes and metaphors; and,
97
contextualizing pain in relation to its impact on activities. In

conclusion, the importance of attending to individuals' stories as a
meaningful way of describing pain for older adults is highlighted,
suggesting that a narrative approach, as recommended and researched
in other areas of medicine, may usefully be applied in pain assessment
for older adults. Along with the judicious use of numerical tools, this
requires innovative methods to elicit verbal accounts, such as using
similes and metaphors to help older adults describe and discuss their
experience, and contextualizing the effects of pain on activities that
are important to them (1).
Assessment: pain is a common experience in later life. Compared

to younger persons, elderly persons are at greater risk for many
painful conditions. Older persons commonly underreport pain and
often believe that it is unacceptable to show pain behavior.
Altered physiologic markers (e.g., tachycardia, tachypnea, and
hypertension) in a fearful, frightened and difficult to console
cognitively impaired patient should suggest the occurrence of acute
pain.
Practitioners must consider the likelihood of some underreporting
of pain when working with cognitively impaired elderly patients; most
of these patients are still able to use PRSs, despite their cognitive
disabilities. When patients are extremely cognitively impaired,
behavioral indicators such as moaning, groaning, grimacing,
protecting involved areas and assuming certain positions or postures
prove as useful as formal PRSs for determining the presence or
absence of pain. Older patients with significant chronic pain are at
higher risk for having functional limitations.
Factors associated with taking a prescription pain medication are
unmarried status and pain frequency/severity. A multidimensional
approach to assessing pain is appropriate.
King David represented an elderly patient. Since he suffered from
intractable bone pain, he was at risk of higher rates of functional
limitation than subjects not suffering such pain.
References
1. Clarke A, Anthony G, Gray D, et al. "I feel so stupid because I can't give a
proper answer...". How older adults describe chronic pain: a qualitative study. BMC
Geriatr. 2012;12(1):78.
2. Pasero C, Reed BA, McCaffery M. Pain in the Elderly. In: McCaffery M,
Pasero CL, eds. Pain: Clinical Manual. 2nd ed. St. Louis: Mosby. 1999, pp. 674-710.
98
4. Cowan DT, Fitzpatrick JM, Roberts JD, et al. The assessment and management
of pain among older people in care homes: current status and future directions. Int J
Nurs Stud. 2003;40(3):291-8.
5. Blomqvist K, Edberg AK. Living with persistent pain: experiences of older
people receiving home care. J Adv Nurs. 2002;40(3):297-306.
6. Covinsky KE, Lindquist K, Dunlop DD, Yelin E. Pain, functional limitations,
and aging. J Am Geriatr Soc. 2009;57(9):1556-61. Comment in: Pain management to
promote independence in older adults. Podlasek S. J Am Geriatr Soc. 2010;
58(6):1195-6.
7. Carmaciu C, Iliffe S, Kharicha K, et al. Health risk appraisal in older people 3:
prevalence, impact, and context of pain and their implications for GPs. Br J Gen
Pract. 2007;57(541):630-5.
8. Sawyer P, Bodner EV, Ritchie CS, Allman RM. Pain and pain medication use
in community-dwelling older adults. Am J Geriatr Pharmacother. 2006;4(4):316-24.
9. Dalacorte RR, Rigo JC, Dalacorte A. Pain management in the elderly at the end
of life. N Am J Med Sci. 2011;3(8):348–54.
QUALITY OF LIFE
A heterogeneous group of 1208 chronic pain patients, who were
referred to the Maastricht University Hospital pain clinic, participated
in this cross-sectional study. At the initial assessment, all patients
completed a set of questionnaires on demographic variables, cause,
location, pain intensity (MPQ), pain coping and beliefs (PCCL), PCS
and eight dimensions of QOL (Rand-36). The sample of
heterogeneous pain patients reported low QOL on each domain and
significantly lower scores than have been found in previous studies
conducted in other Dutch chronic pain populations. Patients with LBP
and multiple pain localizations experienced most functional
limitations. Women reported more pain, more catastrophizing
thoughts about pain, more disability and lower vitality and general
health. When tested in a multiple regression analysis, pain
catastrophizing was the single most important predictor of QOL.
Social functioning, vitality, mental health and general health were
significantly associated with pain catastrophizing. These data indicate
that patients from a multi-disciplinary university pain clinic
experience low QOL, whereby LBP patients and patients with
multiple pain localizations have the lowest QOL. Pain catastrophizing
showed the strongest association with QOL, and was stronger than
pain intensity (1).
The present study profiles an Australian population in terms of
demographics, clinical characteristics and QOL, as measured by the
SF-36. Data were collected prospectively from consecutive patients
presenting to a multidisciplinary chronic pain chronic pain clinic at a
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major Sydney metropolitan teaching hospital. Cross-sectional analysis

of demographic and clinical characteristics and QOL were undertaken.
Descriptive analysis of demographics and clinical characteristics
suggest a patient population group reporting significant pain severity
and reduced QOL. The comparison of SF-36 domain scores between
clinic patients and Australian norm values indicates a greatly reduced
score on all SF-36 domains for clinic patients. Pain clinic patients
reported the most profound effect upon QOL in the role physical,
physical function and social function domains of the SF-36. Stepwise
multiple regressions indicated impaired coping ability and depressive
disability as the most significant correlates of low QOL. In
conclusion, patients who attend chronic pain clinics are likely to
report low QOL with an inability to cope (2).
The aims of this study were to describe and investigate pain from a
multidimensional point of view (duration, location, and psycho-social)
and HRQL of life as well as to compare sex and age groups in people
aged ≥ 80 years. In this cross-sectional study, 225 of 282 people
responded to a questionnaire consisting of 2 instruments and
background questions. The psychosocial dimension of pain was
measured using the MPI-Swedish language version (MPI-S) with 5
scales: Pain Severity, Interference, Life Control, Affective Distress
and Social Support. HRQL was measured using the Short Form
Health Survey-12 (SF-12). Median duration of pain was 9.0 years, and
the mean number of pain locations was 2.04. The MPI-S scale
Interference with a negative orientation had the highest mean score,
while the mean score for Social Support was the highest for the scales
with a positive orientation. The duration of pain was significantly
greater for women, and those aged 80-85 years had higher pain
severity than those aged > 86 years. Participants with a lower HRQL
experienced significantly more severe pain, were more troubled with
pain and had less control of their life. Older people with prolonged
pain suffered from a low HRQL. Pain interfered with their lives and
contributed to diminished control in their daily lives (3).
A number of different diseases or injuries can damage the central
or peripheral nervous system and produce neuropathic pain, which
seems to be more difficult to treat than many other types of chronic
pain. As a group, patients with neuropathic pain have greater medical
co-morbidity burden than age- and sex-adjusted controls, which
makes determining the humanistic and economic burden attributable
to neuropathic pain challenging. HRQL is substantially impaired
among patients with neuropathic pain. Patients describe pain-related
interference in multiple HRQL and functional domains, as well as
100
reduced ability to work and reduced mobility due to their pain. In

addition, the spouses of neuropathic pain patients experience adverse
social consequences related to neuropathic pain. In RCTs, several
medications improve various measures of HRQL. Changes in HRQL
appear to be linked to pain relief, but not to the development of AEs.
However, in cross-sectional studies, many patients continue to have
moderate or severe pain and markedly impaired HRQL, despite taking
medications prescribed for neuropathic pain. The quality of
neuropathic pain treatment appears to be poor, with few patients
receiving recommended medications in efficacious dosages. The
substantial costs to society of neuropathic pain derive from direct
medical costs, loss of the ability to work, loss of caregivers' ability to
work and possibly greater need for institutionalization or other living
assistance. No single study has measured all of these costs to society
for chronic neuropathic pain. The cost effectiveness of various
interventions for the treatment or prevention of different types of
neuropathic pain has been assessed in several different studies. The
most-studied diseases are post-herpetic neuralgia and painful DPN, for
which TCAs (both amitriptyline and desipramine) are either cost
effective or dominant relative to other strategies. Increasing the use of
cost-effective therapies such as TCA for post-herpetic neuralgia and
painful DPN may improve the HRQL of patients and decrease societal
costs (4).
Chronic pain, when not effectively treated and relieved, may have
a harmful effect on all aspects of HRQL. Pain beliefs are considered
an important mediating psychological factor in chronic pain. The
present study focused on HRQL as measured by the SF-36 and
addressed possible relationships between pain beliefs as measured by
the Pain Beliefs and Perceptions Inventory. The possible impact of
background variables such as age, gender, social support, pain
intensity, pain duration, and analgesics on HRQL were controlled for
the analyses. The study sample consisted of 81 people who were
recruited from a multidisciplinary pain management program. Data
were collected as the first part of a routine pretreatment evaluation.
The chronic pain patients reported lower scores on all dimensions of
HRQL compared to normal controls and other patient groups.
Insignificant association was between pain beliefs and the physical
health dimension of HRQL whereas gender, pain duration, and pain
intensity were significant predictors of that dimension. One of the
dimensions of pain beliefs (i.e., mystery) was predictive of the mental
health dimension of HRQL. Social support made an additional
contribution to the explained variance in mental health (5).
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Researchers have begun devising measures of the QOL the entire

last year of life of older community residents. Investigators in
Philadelphia surveyed 150 living elderly on features of their QOL, and
matched the responses with 200 retrospective estimates obtained from
relatives of decedents who had resided in the community much of the
year. Most indicators showed declines for the decreased over their
final year when compared with persons still alive; 82% of the
decedents, however, experienced a majority of "positive-quality"
months in their last year. Debates on the costs and ethical aspects of
treatment and care need to take account of "positive" and "negative"
aspects of QOL reflecting individuals' multifaceted existence (6).
A random sample of 200 deceased older community residents was
studied with a focus on the role of pain in the last year of life.
Interviews with a surviving close person elicited retrospective reports.
Pain increased over the final year; 1 month before death 66% felt pain
frequently or all of the time, substantially higher than a matched
comparison group of living persons (24%). For both groups across the
year, pain was associated with most measures of behavioral
competence, perceived QOL, and psychological well-being.
Hierarchical multiple regressions indicated that background and health
variables explained 28% to 32% of the variance of pain over the year.
Controlling for background variables and health, pain contributed
significantly to lowered happiness and to depression, but had no
independent impact on hope and interest in the world. After
controlling for physical health, the older old were judged to have less
pain than the younger old (7).
In this cross-sectional study, which is part of a larger study
evaluated the health and functional abilities of long-term social
assistance recipients in Norway. Of 405 long-term social assistance
recipients, 178 had chronic pain and were recruited from 14 of 433
municipalities. Long-term social assistance recipients with chronic
pain were older (p<0.001), married (p=0.002), feeling more lonely,
(p=0.048), and had more problems with alcohol (p=0.035). The final
regression model explained 41.2% (p<0.001) of the variance in
physical component summary scores and 32.2% (p<0.001) of the
variance in mental composite scores. Being in chronic pain (29.7%),
being older (4.7%), and never married (2%) predicted worse physical
component summary scores. Feeling lonely (11.9%), having problems
with illicit drug use (5.9%), and being in chronic pain (2.9%)
predicted worse mental component summary scores. In conclusion,
long-term social assistance recipients with chronic pain rated both the
physical and mental components of HRQL lower than long-term
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social assistance recipients without chronic pain. The mental

composite score in both groups was negatively affected (8).
The main objective of this study was to evaluate the HRQL in
Hong Kong Chinese patients with chronic non-cancer pain. In this
prospective cross-sectional survey conducted in regional public
hospitals, Hong Kong, patients attending outpatient pain management
clinics between 1 July 2002 and 28 February 2003 were approached to
complete a set of standardized questionnaires. Data from 166 patients
were analyzed. The median NPRS was 6 (IQR range, 2-10). Work-
related injury occurred in 34.3% of patients, while another 34% were
involved in pain-related litigation and 32% were receiving disability
or unemployment benefit. Of all patients, 64% were managed by 3 or
more disciplines, while 54.8% were also receiving CAM treatment,
mainly traditional Chinese medicine (49.7%). The HADS indicated
clinical anxiety or depression in 71.1% of patients. All SF-36 subscale
scores were lower than the local population norm. Unemployed
patients had higher depression scores (p=0.005), while students or
retirees had lower physical functioning scores (p=0.004). Patients who
were single had higher role emotion scores than those who were
married or separated/widowed (p=0.011). Logistic regression analysis
showed that younger age (OR=0.95), being married (6.62), work-
related injury (15.63) or higher general scores (1.03) were more likely
to be associated with litigation. Social welfare benefit was associated
with unemployment (3.39) and a lower level of physical functioning
(0.98). In conclusion, there was a high prevalence of clinical anxiety,
depression, and severe impairment in the HRQL in Hong Kong
Chinese patients with chronic non-cancer pain. Specific factors
affected the HRQL, likelihood of litigation, and social benefit (9).
Assessment: pain catastrophizing is the single important predictor

of QOL. Patients describe pain-related interference in multiple HRQL
and functional domains, as well as reduced ability to work and
reduced mobility due to their pain. The spouses of neuropathic pain
patients experience adverse social consequences related to neuropathic
pain. Participants with a lower HRQL experience more severe pain,
are more troubled with pain and have less control of their life. Older
people with prolonged pain suffer from a low HRQL. Pain interferes
with their lives and contributes to diminished control in their daily
lives. Chronic pain, when not effectively treated and relieved, has a
harmful effect on all aspects of HRQL.
Chronic neuropathic pain has a major effect on QOL. In order to
prevent neuropathic pain from becoming chronic and improve
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neuropathic pain care, it is important to identify predictors associated

with the persistence of neuropathic pain.
References
1. Lamé IE, Peters ML, Vlaeyen JW, et al. Quality of life in chronic pain is more
associated with beliefs about pain, than with pain intensity. Eur J Pain. 2005;9(1):15-
24.
2. Kerr S, Fairbrother G, Crawford M, et al. Patient characteristics and quality of
life among a sample of Australian chronic pain clinic attendees. Intern Med J.
2004;34(7):403-9.
3. Willman A, Petzäll K, Ostberg AL, Hall-Lord ML. The psycho-social
dimension of pain and health-related quality of life in the oldest old. Scand J Caring
Sci. 2012 Aug 3. [Epub ahead of print].
4. O'Connor AB. Neuropathic pain: quality-of-life impact, costs and cost
effectiveness of therapy. Pharmacoeconomics. 2009;27(2):95-112.
5. Dysvik E, Lindstrøm TC, Eikeland OJ, Natvig GK. Health-related quality of
life and pain beliefs among people suffering from chronic pain. Pain Manag Nurs.
2004;5(2):66-74.
6. Lawton MP, Moss M, Glicksman A. The quality of the last year of life of older
persons. Milbank Q. 1990;68(1):1-28.
7. Moss MS, Lawton MP, Glicksman A. The role of pain in the last year of life of
older persons. J Gerontol. 1991;46(2):P51-7.
8. Løyland B, Miaskowski C, Paul SM, et al. The relationship between chronic
pain and health-related quality of life in long-term social assistance recipients in
Norway. Qual Life Res. 2010;19(10):1457-65.
9. Lee S, Chen PP, Lee A, et al. A prospective evaluation of health-related quality
of life in Hong Kong Chinese patients with chronic non-cancer pain. Hong Kong Med
J. 2005;11(3):174-80. Erratum in: Hong Kong Med J. 2005;11(4):280.
PSYCHOSOCIAL DIMENSIONS OF CHRONIC

PAIN
Research on emotion and pain has burgeoned. The last decade‘s

literature focuses on links between emotional processes and persistent
pain. Neurobiological research documents the neural processes that
distinguish affective from sensory pain dimensions, link emotion and
pain, and generated CNS pain sensitization. Psychological research
demonstrates that greater pain is related to emotional stress and
limited emotional awareness, expression, and processing. Social
research shows the potential importance of emotional communication,
empathy, attachment, and rejection. Emotions are integral to the
conceptualization, assessment, and treatment of persistent pain.
Research should clarify when to eliminate or attenuate negative
emotions, and when to access, experience, and express them. Theory
104
and practice should integrate emotion into cognitive-behavioral

models of persistent pain (1).
One of the perplexing features of pain is the wide variety in
patients' responses to ostensibly the same extent of physical
pathology. One reason for this is that emotional states (feelings) and
thoughts (cognitions) mediate our pain perception. Maintenance of
pain and disability as well as response to treatment is related to a
number of factors such as self-efficacy beliefs and fear avoidance.
These pain-related beliefs are more important determinants of
disability and functioning in some disorders than pain intensity or
duration. A multi-dimensional assessment of patients with pain should
take into account factors such as specific feelings (emotions), thoughts
(cognitions), pain behaviors and pain-coping strategies. It is useful to
adopt a 'stepped care' approach to treatment. Most patients with IBS
will respond to reassurance, whereas those with more enduring and/or
difficult to manage symptoms may require treatments of a different
type and level of complexity, including antidepressants and CBT. It is
acceptable to adopt more than one treatment approach concurrently.
Antidepressant treatment is effective in concert with psychological
treatments that can improve QOL (2).
The comorbidity between chronic pain and depression is high: in
the general population setting, the OR for suffering from one of these
disorders when suffering from the other is around 2.5. For chronic
pain patients consulting in pain clinics, the comorbidity rate reaches
one third to half of the patients. For the IASP, pain includes an
emotional as well as a sensory dimension, both of them have to be
assessed systematically. Likewise, affective disorders must be
systematically evaluated in chronic pain patients. The reasons for such
comorbidity are complex and result from the conjunction of common
risk factors (environmental and genetic vulnerability factors) and of
bidirectional causality. The appraisal stress model offers an
opportunity to understand how chronic pain can cause depression (3).
Pain is conceptualized as a chronic stress. Its appraisal in terms of
loss, injustice, incomprehensibility or changes (primary appraisal),
and in terms of control (secondary evaluation) determine how the
subject will cope with pain. Several personality traits as optimism,
hardiness or internal locus of control play a protective role on these
evaluations, whereas others (neuroticism, negative affectivity or
external locus of control) are risk factors for depression. Low
perceived social support is related to depression. On the contrary, self-
efficiency is linked with low levels of depression. Self-management
therapies focus on increase of perceived control of pain by the patient
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in order to improve his/her motivation to change, and to let the patient

become active in the management of his/her pain. According to
Lazarus and Folkman (3), coping strategies are the constantly
changing cognitive and behavioral efforts to manage specific external
and/or internal demands that are appraised as taxing on or exceeding
the resources of the person. Pain patients can use a wide variety of
pain coping strategies: problem vs. emotion-focused strategies or
cognitive vs. behavioral strategies. Some of them are highly
dysfunctional, such as catastrophizing (cognitive strategy) or
avoidance (behavioral strategy). Their preferential use can lead to the
development of a depressive episode. The "fear-avoidance model"
explains pain chronicization by a vicious circle that begins with the
pain catastrophizing; this leads to fear of pain, which in turn leads to
avoidance and finally to pain and depression (4). This is why some
behavioral cognitive interventions focus on the reduction of
catastrophizing and avoidance. Some functional pain coping strategies
were identified: they are active strategies centered on problem
resolution such as distraction, reinterpretation or ignorance of pain
sensations, acceptance, and exercise and task persistence. New
therapeutic interventions focus on the development of better coping
strategies such as distraction, relaxation and acceptance (5).
The comorbidity of anxiety disorders with pain has received little
research attention even though studies show that these disorders are as
likely to co-occur with chronic pain conditions as depressive disorder.
Comorbid anxiety has implications for the impact and outcome of pain
conditions. Even though it may be intuitively plausible to suppose that
the anxiety occurs in the context of a preexisting pain condition, there
is evidence for a reverse causal link and shared risk factors, including
distal events occurring in childhood (6).
The main aim of this study was to investigate pain intensity,
posttraumatic stress, depression, anxiety, disability, and life
satisfaction in patients with injury-related chronic pain and to analyze
differences in these variables regarding gender. Questionnaires
addressing pain intensity (VAS), HADS, posttraumatic stress (impact
of event scale), disability (DRI), and life satisfaction [LiSat-11]) were
answered by 160 patients at the Pain Rehabilitation Clinic at Umeå
University Hospital (Sweden). High level of pain intensity was scored
on the VAS (mean value 64.5 ± 21.1 mm) together with high levels of
anxiety, depression, and posttraumatic stress. Activity limitations in
everyday life and decreased life satisfaction were reported, especially
on the items of physical health and psychological health. A
multivariate logistic regression model showed a statistically
106
significant association between low scores on the overall life

satisfaction on LiSat-11 and high scores on HADS-depression
(OD=1.141, 95% CI 1.014 - 1.285). Few gender differences were
found. These findings highlight the value of a broad screening in
patients with injury-related chronic pain with respect to the
relationship of life satisfaction with pain intensity, anxiety,
depression, posttraumatic stress, and disability. The findings support
the biopsychosocial approach to assess and treat these patients
optimally (7).
The main objective of this study was to systematically review the
associations between psychosocial factors and adjustment to chronic
pain in persons with physical disabilities. A key word literature search
was conducted using articles listed in PubMed, PsychInfo, and
CINAHL up to March 2010, and manual searches were made of all
retrieved articles to identify published articles that met the review
inclusion criteria. To be included in the review, articles needed to (1)
be written in English, (2) include adults with a physical disability who
report having pain, (3) include at least 1 measure of a psychosocial
predictor domain, (4) include at least 1 criterion measure of pain or
patient functioning, and (5) report the results of associations between
the psychosocial factors and criterion measures used in the study.
Twenty-nine studies met the inclusion criteria. The disability groups
studied included SCI, acquired amputation, chronic pain, MS, and
muscular dystrophy. Psychosocial factors were significantly
associated with pain and dysfunction in all disability groups. The
psychosocial factors most closely associated with pain and
dysfunction across the samples included (1) catastrophizing
cognitions; (2) task persistence, guarding, and resting coping
responses; and (3) perceived social support and solicitous responding
social factors. Pain-related beliefs were more strongly associated with
pain and dysfunction in the SCI, chronic pain, MS, and muscular
dystrophy groups than in the acquired amputation group. In
conclusion, these findings support the importance of psychosocial
factors as significant predictors of pain and functioning in persons
with physical disabilities (8).
Survey data were collected from representative samples of primary
care patients as part of the WHO Collaborative Study of Psychological
Problems in General Health Care conducted in 15 centers in Asia,
Africa, Europe, and the Americas. Consecutive primary care
attendees between the age of majority (mostly 18 years) and 65 years
were screened (n=25,916) and stratified random samples of patients
were interviewed (n=5,438). Persistent pain, defined as pain present
107
most of the time for a period of 6 months or more during the prior
year, and psychological illness were assessed by the CIDI. Disability
was assessed by the Groningen Social Disability Schedule and by
activity-limitation days in the prior month. Across all 15 centers, 22%
of primary care patients reported persistent pain, but there was wide
variation in prevalence rates across centers (range, 5.5-33.0%).
Relative to patients without persistent pain, pain sufferers were more
likely to have an anxiety or depressive disorder (AOR 4.14, 95% CI
3.52 - 4.86), to experience significant activity limitations (AOR 1.63,
95% CI 1.41 - 1.89), and to have unfavorable health perceptions
(AOR 1.26, 95% CI 1.07 - 1.49). The relationship between
psychological disorder and persistent pain was observed in every
center, while the relationship between disability and persistent pain
was inconsistent across centers. These data indicate that persistent
pain is a commonly reported health problem among primary care
patients and is consistently associated with psychological illness
across centers. Large variation in frequency and the inconsistent
relationship between persistent pain and disability across centers
suggests caution in drawing conclusions about the role of culture in
shaping responses to persistent pain when comparisons are based on
patient samples drawn from a limited number of health care settings in
each culture (9).
The aim of the current study was to replicate and extend previous
research on the relationship between pain-related beliefs, depression,
and disability by examining these relationships in a heterogeneous
sample of Iranian patients with chronic pain. A group of 430 patients
with chronic pain participated in the study and completed
questionnaires on demographic variables, pain intensity, pain self-
efficacy beliefs, physical disability, and depression. Patients with
higher education were less depressed and less physically disabled.
Younger patients were more physically disabled. Pain intensity and
pain self-efficacy beliefs were significantly related to physical
disability and depression. In hierarchical multiple regression analyses,
after controlling for patients' background variables and pain intensity,
pain self-efficacy beliefs accounted for significant variance in
depression and physical disability over and above the effect of
demographic variables and pain intensity. Patients with higher pain
self-efficacy compared to those with lower self-efficacy were less
depressed and less physically disabled. In conclusion, pain self-
efficacy was more strongly related to depression and physical
disability than pain intensity and demographic variables. The findings
of the present study suggest the importance of targeting pain self-
108
efficacy beliefs for modification in treatment of patients with chronic

pain (10).
The main objective of this study was to determine the nature of
depressive symptoms in a sample of patients with chronic pain and to
examine the relationship between depressive symptoms and physical
disability due to pain. A cross-sectional study included 812 patients
with complete datasets from 2419 patients with pain who were
referred to the Pain Management Research Institute at Royal North
Shore Hospital, Sydney, between January 2000 and December 2007.
Pain severity and distress, physical disability, depressive symptoms,
pain self-efficacy, catastrophising, fear of movement/(re)injury, use of
unhelpful self-management strategies, sense of control over life, and
perceived support from significant others were assessed by the West
Haven-Yale MPI, modified version of the Roland Morris Disability
Questionnaire, the depression subscale of the Depression Anxiety
Stress Scales, Pain Self-Efficacy Questionnaire, Pain-Related Self-
Statements Scale, Tampa Scale of Kinesiophobia, and Pain Self-
Management Checklist. After controlling for the effects of age, sex
and duration of pain, depressive symptoms correlated strongly with a
combination of catastrophising, sense of control over life, physical
disability, pain self-efficacy beliefs, higher use of unhelpful self-
management strategies and lower perceived social support. Depressive
symptoms were correlated with physical disability, but to a lesser
extent than other variables, including fear of re-injury, low self-
efficacy for activity and pain severity. The depressive symptoms that
were rated as most frequently experienced reflected sadness, lack of
initiative and lack of ability to experience pleasure. In conclusion, in
patients with chronic pain, depressive symptoms are correlated more
strongly with cognitive variables than pain severity and pain distress,
while physical disability is correlated more strongly with cognitive,
behavioral and pain variables than depressive symptoms. Depressive
symptoms are characterized predominantly by mood-related
symptoms, suggesting differences in the experience of depression in
patients with chronic pain compared with those presenting with
mental disorders (11).
This research investigated the impact of resilience and coping
strategies on the psychological functioning of 87 Australian adults
with chronic pain, using a self-report questionnaire. It included the
MPQ, the Connor-Davidson Resilience Scale, the Coping Strategies
Questionnaire, the SF-36, and the Depression, Anxiety and Stress
Scale. Using hierarchical regression, after the effects of pain severity,
catastrophizing, and ignoring the pain were controlled for, resilience
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was significantly associated with mental health-related QOL (β = 0.18,

p < 0.05), depression (β = -0.31, p < 0.01), and anxiety (β = -0.20,
p < 0.05). In the final model for depression, resilience had a stronger
association than pain severity. Resilience did not, however, influence
individual's perceptions of their physical HRQL (12).
The main purpose of this study was to identify subgroups of
patients with chronic pain based on the occurrence of depression,
anxiety, catastrophizing and the duration of pain and pain intensity. In
addition, the relationship between the subgroups with respect to
background variables, diagnosis, pain-related disability and perceived
QOL were investigated. This study used 433 patients with chronic
pain including 47 patients with SCI-related pain, 150 with chronic
whiplash associated disorders and 236 with fibromyalgia. Based on
depression, anxiety, catastrophizing, pain intensity and duration,
subgroups of patients with chronic pain who differed with respect to
perceived QOL, disability and diagnosis were identified. The
psychological factors, especially depression, significantly influenced
perceived QOL and disability. Pain intensity and duration played a
minor role with respect to QOL, although pain intensity was
associated to perceived disability. The results of this study highlight
the importance of not looking at patients with chronic pain as a
homogenous entity. A detailed assessment, including psychological
factors with emphasis on depressive symptoms, might be essential for
planning and carrying through treatment and rehabilitation (13).
This study aimed to: (1) determine prevalence of depression in
patients referred to specialist pain services using the SCID diagnostic
interview, (2) compare results on the BDI-II with the SCID to
determine the utility of the BDI-II as a screening tool in this
population. Thirty-six participants were recruited, mainly women,
with a mean age = 47.83 years (SD = 12.85 years), who were
heterogeneous with regard to their pain. All completed the BDI-II and
SCID. The SCID diagnosed 26 (72%) cases of depression. BDI-II
scores showed 31 (86%) that reported at least mild depression.
Agreement between BDI-II scores over threshold for mild depression
and SCID diagnosis were assessed by Cohen's kappa (= 0.6). ROC
analysis for BDI-II scores against SCID diagnosis gave a large area
under the curve (0.97, 95% CI 0.93 - 1.02), suggesting BDI-II is an
excellent screen for this population, although the curve was unusual in
that sensitivity was high even when the false positive rate was zero.
ROC analysis suggested 22 or above as an optimum cut-off score for
depression on the BDI-II-higher than for a general population sample.
The BDI overestimates incidence of depression in pain patients, but
110
this study confirmed through diagnostic interview the very high

incidence of depression in this population. It is therefore questionable
whether there is value in screening referrals for depression. When
using BDI-II for screening, audit or evaluation purposes with a pain
clinic population, a cut-off of 22 or above is suggested (14).
Because depression and painful symptoms commonly occur
together, a literature review to determine the prevalence of both
conditions and the effects of comorbidity on diagnosis, clinical
outcomes, and treatment were conducted. The prevalences of pain in
depressed cohorts and depression in pain cohorts are higher than these
conditions are individually examined. The presence of pain negatively
affects the recognition and treatment of depression. When pain is
moderate to severe, impairs function, and/or is refractory to treatment,
it is associated with more depressive symptoms and worse depression
outcomes (e.g., lower QOL, decreased work function, and increased
health care utilization). Similarly, depression in patients with pain is
associated with more pain complaints and greater impairment.
Depression and pain share biological pathways and neurotransmitters,
which has implications for the treatment of both concurrently. A
model that incorporates assessment and treatment of depression and
pain simultaneously is necessary for improved outcomes (15).
The prevalence of pain in depressed individuals and the prevalence
of depression in patients with pain are higher than when these
conditions are considered individually. When pain is severe, impairs
function, and/or is refractory to treatment, it is associated with more
depressive symptoms and worse depression outcomes. Similarly,
depression in patients with pain is associated with more complaints
and greater functional impairment. Whether alleviation of pain helps
depressive symptoms or, likewise, whether relief of depression
improves pain, are questions still incompletely clarified. However,
there is growing evidence that depression and pain share genetic
factors, biological pathways and neurotransmitters (16).
The objectives of this study were to explore which factors are
associated with depressed mood in older people experiencing pain,
and to test the hypothesis that older people experiencing pain are at
risk of depressed mood according to the severity or frequency of their
pain. In addition, whether other potentially modifiable factors might
increase the risk of depressed mood in these persons were explored.
The study is a secondary analysis of baseline data for 406 community-
dwelling non-disabled people aged ≥ 65 years registered with 3 group
practices in suburban London who had experienced pain in the past 4
weeks. Intensity and frequency of pain were measured using 24-item
111
GPM and the presence of depressive symptoms using the 5-item

Mental Health Inventory. Risk for social isolation was measured using
the 6-item Lubben Social Network scale and IADL were also
measured. Overall, 76 (19%) had depressed mood. Pain frequency and
severity were statistically insignificantly associated with depressed
mood. In multivariate analyses, significant predictors for the presence
of depressive symptoms were difficulties with basic ADL (OR 2.8,
95% CI 1.1 - 7.8), risk for social isolation (OR 4.1, 95% CI 1.8 - 9.3),
and basic education only (OR 2.2, 95% CI 1.1 - 4.4). These data
indicate that older people experiencing pain are likely to experience
depression. Among those experiencing pain, social network and
functional status seem to be more important predictors of depressive
symptoms than the severity of pain. Further studies should evaluate
whether improvement of social network and functional status might
reduce depressive symptoms in older patients (17).
Pain complaints commonly accompany MDD. The objective of
this study was to compare depressed outpatients with and those
without current pain complaints in terms of sociodemographic,
clinical and presenting symptom features. The baseline clinical and
sociodemographic data of a large representative outpatient sample
with non-psychotic MDD (n=3745) enrolled in the STAR*D
(Sequenced Treatment Alternatives to Relieve Depression) study were
collected. Baseline information on pain complaints was based on Item
No. 25 (somatic pain) of the 30-item Inventory of Depressive
Symptomatology-Clinician Rating (IDS-C(30)). After adjusting for
sex, depression severity (IDS-C(30) less Item No. 25), and general
medical comorbidities (as measured by the Cumulative Illness Rating
Scale total score), clinically meaningful differences were between
patients with and those without pain complaints. Younger, African
American, Hispanic, and less educated patients were more likely to
report pain complaints. Those with pain complaints were more likely
to report anxious features with irritable mood, sympathetic nervous
system arousal, and G-I problems as well as poorer QOL. Neither a
more chronic course of illness nor suicidal ideation was associated
with pain. In conclusion, pain complaints are common among
outpatients with MDD and are associated with certain symptom
features and poorer QOL. Depression accompanied by pain
complaints does not increase the clinical psychiatric burden or
chronicity of depression (18).
The present study examined the relationship between
psychological factors and pain in order to assess the contribution of
emotional disturbance to the perpetuation of pain. A group of 163
112
chronic pain sufferers in multiple settings was compared with 81

control subjects on measures of personal history antecedent to pain
onset, as well as on measures of current emotional disturbance. These
psychological variables were examined for their associations with
subjectively rated pain intensity. Overall, pain was related to more
current depression and less current life satisfaction, but was not
associated with most of the personal history variables examined.
These results suggests that emotional disturbance in pain patients is
more likely to be a consequence than a cause of chronic pain (19).
The main of this study was to determine the status for the
association of chronic pain and depression and to review the evidence
for whether depression is an antecedent or consequence of chronic
pain. A computer and manual literature review yielded 191 studies
that related to the pain-depression association. These reports were
reviewed and sorted into 7 categories relating to the topic of this
paper. Eighty-three studies were then selected according to inclusion
criteria and subjected to a structured review. Any medical treatment
setting including pain treatment as inclusion criteria for selection of
studies was included. Any patients with any type of chronic pain were
included. The reviewed studies were consistent in indicating that
there is a statistical relationship between chronic pain and depression.
Depression is more common in chronic pain patients than in healthy
controls due to the presence of chronic pain. At pain onset,
predisposition to depression (the scar hypothesis) may increase the
likelihood for the development of depression in some chronic pain
patients. Because of difficulties in measuring depression in the
presence of chronic pain, the reviewed studies should be interpreted
with caution (20).
The present study examined the prevalence and predictors of self-
perceived burden in a tertiary chronic pain sample. Participants were
consecutive patients (n=238) admitted to an outpatient,
interdisciplinary, chronic pain management program at a rehabilitation
hospital. At admission, participants completed a battery of
psychometric questionnaires assessing self-perceived burden, as well
as a number of clinically relevant constructs. Self-perceived burden
was a commonly reported experience among chronic pain patients,
with more than 70% of participants endorsing clinically elevated
levels. It was significantly correlated with pain intensity ratings,
functional limitations, depressive symptoms, attachment anxiety, pain
self-efficacy, and caregiver burden. Self-perceived burden was also
correlated with an item assessing suicidal ideation. In a hierarchical
regression model, depressive symptoms, pain self-efficacy, and adult
113
attachment significantly predicted self-perceived burden after

controlling for demographic and pain-related variables. In conclusion,
self-perceived burden is a clinically relevant and commonly reported
interpersonal experience in patients with longstanding pain (21).
The association between depressive symptoms and chronic pain
(arthritis, back or neck pain, headache, or other pain) in a community
population of Beijing, China was explored. In 2010, 2469 residents
aged 16 years and older were investigated. Data were collected from
face-to-face interviews using the CIDI-3rd version. The presence of
chronic pain condition and depressive symptoms were analyzed using
univariate and multivariate analysis methods. A 12-month prevalence
of MDD was at 3.28%. Nearly half (41.01%) of respondents with
depressive symptoms also had at least 1 chronic pain condition, and
64.2% of subjects with MDD experienced at least 1 chronic pain.
After adjusting for selected demographic variables, in multivariate
logistic regression analysis depressive symptom without MDD was
significantly associated with back-or neck pain (AOR=1.97, 95% CI
1.34 - 2.90), headache (AOR=3.17, 95% CI 1.81 - 5.58), and other
chronic pain (AOR=2.21, 95% CI 1.07 - 4.49). MDD was
significantly associated with arthritis (AOR=2.23), back or neck pain
(AOR=4.17), headache (AOR=3.16), and other chronic pain
(AOR=3.51). This study concludes that multiple types of chronic pain
are associated with depressive symptoms and MDD (22).
Assessment: psychosocial factors are significant predictors of pain

and functioning in persons with physical disabilities. Resilience has a
stronger association with depression than pain severity. Psychological
factors and factors related to sensory disturbances are predictors for
persistence of neuropathic pain.
Pain is related to emotional stress and limited emotional awareness,
expression, and processing, emotional communication, empathy,
attachment, and rejection. Emotional states (feelings) and thoughts
(cognitions) mediate our pain perception.
At pain onset, predisposition to depression may increase the
likelihood for the development of depression in some chronic pain
patients. Pain self-efficacy is more strongly related to depression and
physical disability than pain intensity and demographic variables.
Depression influences perceived QOL and disability.
When pain is severe, impairs function, and/or is refractory to
treatment, it is associated with more depressive symptoms and worse
depression outcomes. Similarly, depression in patients with pain is
associated with more complaints and greater functional impairment.
114
In later life, pain and depression are associated, having a negative

effect on physical performance both separately and in combination,
with depressive symptoms, pain self-efficacy, and adult attachment
predicting self-perceived burden of pain.
Disease, an adverse interruption of life, is the prevalent
interpretation of chronic pain conditions. Positive attitudes and higher
age are significant predictors of patients' life satisfaction. A major task
in patient care is to restore a sense of self-control over pain (and thus
congruence with the situation) and the conviction that one is not
necessarily disabled by disease.
Was persistent pain responsible for the development of MDD in
the King's case? The following verses indicate severe mental distress:
―...a broken and depressed heart (Psalm 51:19); I am feeble and
depressed: I have groaned by reason of the suffering of my heart
(38:9); All the night make I my bed to swim; I water my couch with
my tears (6:7); ...having agony in my heart daily (13:3); and "I am
forgotten as a dead man out of mine mind: and I am like a lost tool‖
(31:13). Social withdrawal is indicated by the passage ―But I am a
worm, and no man; a disgrace of men, and despised of the people‖
(22:7).
The mechanisms of the development of depression in King David‘s
case are demonstrated by the passages ―Be not far from me; for
trouble is near; for there is no help― (Psalm 6:12), ―I am helpless‖
(25:16) and ―I am wretched..‖ (6:3). Here we learn about the King‘s
loneliness, need for close relationships and lack of friends on whom
he can rely. Additional passages: ―But I am a worm, and no man; a
disgrace of men, and despised of the people‖ (32:7) and ―I am
(31:13) show loss of power and control over his people, feelings of
neglect and negative interpersonal relationships. Thus, persistent
negative stress and negative interpersonal experiences played a role in
the development of his MDD. Furthermore, the King was aware of
his iniquity, wickedness and sin ―...my strength failed because of mine
iniquity‖ (31:11) and ―Save me from all my sins...‖ (39:9). All these
causes acted together in the development of the King‘s mental
disorder.
Did MDD increase the King's bone pain and thus his unbearable
suffering?
115
References
1. Lumley MA, Cohen JL, Borszcz GS, et al. Pain and Emotion: A
Biopsychosocial Review of Recent Research. J Clin Psychol. 2011;67(9):942–968.
2. Bass C. The role of emotion in determining pain. Dig Dis. 2009;27 Suppl 1:16-
23.
3. Lazarus RS, Folkman S. Stress, Appraisal, and Coping Springer Publishing
Company. ISBN 0826141900. 1984.
4. Vlaeyen JWS, Linton SJ. Fear-avoidance and its consequences in chronic
musculoskeletal pain: a state of the art. Pain. 2000;85:317-32.
5. Radat F, Koleck M. Pain and depression: cognitive and behavioural mediators
of a frequent association. Encephale. 2011;37(3):172-9.
6. Gureje O. Comorbidity of pain and anxiety disorders. Curr Psychiatry Rep.
2008;10(4):318-22.
7. Stålnacke BM. Life satisfaction in patients with chronic pain - relation to pain
intensity, disability, and psychological factors. Neuropsychiatr Dis Treat.
2011;7:683-9.
8. Jensen MP, Moore MR, Bockow TB, et al. Psychosocial factors and adjustment
to chronic pain in persons with physical disabilities: a systematic review. Arch Phys
Med Rehabil. 2011;92(1):146-60.
9. Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being: a
World Health Organization Study in Primary Care. JAMA. 1998;280(2):147-51.
Erratum in: JAMA 1998;280(13):1142.
10. Asghari A, Julaeiha S, Godarsi M. Disability and depression in patients with
chronic pain: pain or pain-related beliefs? Arch Iran Med. 2008;11(3):263-9.
11. Nicholas MK, Coulston CM, Asghari A, Malhi GS. Depressive symptoms in
patients with chronic pain. Med J Aust. 2009;190(7 Suppl):S66-70.
12. Viggers LC, Caltabiano ML. Factors affecting the psychological functioning
of Australian adults with chronic pain. Nurs Health Sci. 2012;14(4):508-13.
13. Börsbo B, Peolsson M, Gerdle B. The complex interplay between pain
intensity, depression, anxiety and catastrophising with respect to quality of life and
disability. Disabil Rehabil. 2009;31(19):1605-13.
14. Poole H, White S, Blake C, et al. Depression in chronic pain patients:
prevalence and measurement. Pain Pract. 2009;9(3):173-80.
15. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain
comorbidity: a literature review. Arch Intern Med. 2003; 163(20):2433-45.
16. Gambassi G. Pain and depression: the egg and the chicken story revisited.
Arch Gerontol Geriatr. 2009;49 Suppl 1:103-12.
17. Iliffe S, Kharicha K, Carmaciu C, et al. The relationship between pain
intensity and severity and depression in older people: exploratory study. BMC Fam
Pract. 2009 Jul 28;10:54.
18. Husain MM, Rush AJ, Trivedi MH, et al. Pain in depression: STAR*D study
findings. J Psychosom Res. 2007;63(2):113-22.
19. Gamsa A. Is emotional disturbance a precipitator or a consequence of chronic
pain? Pain. 1990;42(2):183-95.
20. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated
depression: antecedent or consequence of chronic pain? A review. Clin J Pain.
1997;13(2):116-37.
21. Kowal J, Wilson KG, McWilliams LA, et al. Self-perceived burden in chronic
pain: relevance, prevalence, and predictors. Pain. 2012;153(8):1735-41.
22. Chen X, Cheng HG, Huang Y, et al. Depression symptoms and chronic pain
in the community population in Beijing, China. Psychiatry Res. 2012;200(2-3):313-7.
116
RELIGION/SPIRITUALITY AND CHRONIC PAIN

Chronic pain is a complex experience stemming from the
interrelationship among biological, psychological, social and spiritual
factors. Many chronic pain patients use religious/spiritual forms of
coping, such as prayer and spiritual support, to cope with their pain.
Religion/spirituality may affect the experience of pain and may help
or hinder the coping process (1).
Conditions with chronic, non-life-threatening pain and fatigue
remain a challenge to treat, and are associated with high health care
use. Understanding psychological and psychosocial contributing and
coping factors, and working with patients to modify them, is one goal
of management. An individual's spirituality and/or religion is one such
factor that can influence the experience of chronic pain or fatigue.
The Canadian Community Health Survey (2002) obtained data from
37,000 individuals 15 years of age or older. From these data, 4
conditions with chronic pain and fatigue were analyzed together -
fibromyalgia, back pain, migraine headaches and chronic fatigue
syndrome. Additional data from the survey were used to determine
how religion and spirituality affect psychological well-being, as well
as the use of various coping methods. Religious persons were less
likely to have chronic pain and fatigue, while those who were spiritual
but not affiliated with regular worship attendance were more likely to
have those conditions. Individuals with chronic pain and fatigue were
more likely to use prayer and seek spiritual support as a coping
method than the general population. Chronic pain and fatigue sufferers
who were both religious and spiritual were more likely to have better
psychological well-being and use positive coping strategies.
Consideration of an individual's spirituality and/or religion, and how it
is used in coping may be an additional component to the overall
management of chronic pain and fatigue (2).
Understanding the relationships between spirituality and health has
become increasingly important in health research. Very little of the
research thus far has focused on spirituality, religion, and pain even
though spiritual views have been intertwined with beliefs about pain
and suffering throughout history. Spiritual views can have a
substantial impact on patients' understanding of pain and decisions
about pain management. The analysis is concerned with how
spirituality and religion have been used to construct a meaning of pain
that shapes appraisal, coping, and pain management. The clinical
implications include respectful communication with patients about
spirituality and pain, inclusion of spirituality in education and support
117
programs, integration of spiritual preferences in pain management

where feasible and appropriate, consultation with pastoral care teams,
and reflection by nurses about spirituality in their own lives (3).
The influence of psychosocial factors on pain experience and
patient response has received increasing interest and recognition.
Patients with chronic pain from several sources (e.g., musculoskeletal,
cancer, or sickle cell) usually report that religiousness and spirituality
are important in their lives. Prayer is the most used complementary
therapy; religious coping is among the most common strategies used
to deal with pain. Religious variables are not usually associated with
pain measures, except in some studies indicating that petitionary
prayer is related to higher pain levels, possibly suggesting a turning to
religion due to increasing pain. The best available evidence supports a
positive association between religiousness and spirituality, with higher
well-being and positive effect and a negative association with
depressive and anxiety symptoms (4).
This study sought to better understand the relationship between
religion/spirituality and physical health and mental health in 122
patients with chronic musculoskeletal pain. The current study
conceptualized religion/spirituality as a multidimensional factor, and
measured it with a new measure of religion/spirituality for research on
health outcomes (Brief Multidimensional Measure of
Religion/Spirituality). In pain, patients' religious and spiritual beliefs
appear different than the general population (e.g. pain patients feel
less desire to reduce pain in the world and feel more abandoned by
God). Hierarchical multiple regression analyses revealed significant
associations between components of religion/spirituality and physical
and mental health. Private religious practice (e.g. prayer, meditation,
and consumption of religious media) was inversely related to physical
health outcomes, indicating that those who were experiencing worse
physical health were more likely to engage in private religious
activities, perhaps as a way to cope with their poor health.
Forgiveness, negative religious coping, daily spiritual experiences,
religious support, and self-rankings of religious/spiritual intensity
significantly predicted mental health status. Religion/spirituality was
unrelated to pain intensity and life interference due to pain. In
conclusion, there are relationships between religion/spirituality and
health in a chronic pain population, and religion/spirituality may have
both costs and benefits for the health of those with chronic pain (5).
The data were derived from the Israeli sample of the Survey of
Health, Ageing and Retirement in Europe (Share), a cross-national
survey program involving nearly a dozen nations. The Israeli sample
118
compromised 1287 Jewish responders aged ≥ 50 years. The results

indicate that recent synagogue attendance is a significant predictor of
better health for six of seven measures, even after adjusting for age
and several other covariates and mediators, including measures of
health-related behavior and social support. Prayer, by contrast, is
inversely associated with health according to five measures, perhaps
reflecting its use as a coping mechanism for individuals with health
problems. This study presents modest evidence of a salutary effect of
Jewish religiousness in this population of older adults. Religiousness,
in the form of synagogue participation, serves a protective function,
and prayer a coping function (6).
Assessment: chronic pain is a complex experience stemming from

the interrelationship among biological, psychological, social and
spiritual factors. Many chronic pain patients use religious/spiritual
forms of coping, such as prayer and spiritual support, to cope with
their pain. Religious persons are less likely to have chronic pain and
fatigue. Individuals with chronic pain and fatigue are more likely to
use prayer and seek spiritual support as a coping method than the
general population. Chronic pain and fatigue sufferers who are both
religious and spiritual are more likely to have better psychological
well-being and use positive coping strategies.
References
1. Wachholtz AB, Pearce MJ. Does spirituality as a coping mechanism help or
hinder coping with chronic pain? Curr Pain Headache Rep. 2009;13(2):127-32.
2. Baetz M, Bowen R. Chronic pain and fatigue: Associations with religion and
spirituality. Pain Res Manag. 2008;13(5):383-8.
3. Unruh AM. Spirituality, religion, and pain. Can J Nurs Res. 2007;39(2):66-86.
4. Moreira-Almeida A, Koenig HG. Religiousness and spirituality in fibromyalgia
and chronic pain patients. Curr Pain Headache Rep. 2008;12(5):327-32.
5. Rippentrop EA, Altmaier EM, Chen JJ, et al. The relationship between
religion/spirituality and physical health, mental health, and pain in a chronic pain
population. Pain. 2005;116(3):311-21.
6. Levin J. Religion and physical health among older Israeli Jews: findings from
the SHARE-Israel study. IMAJ. 2012:14:595-601.
PATIENT WITH CHRONIC PAIN AND THE

FAMILY
Chronic pain affects on not only the individual but also their
partner and/or other family members. Families of people with chronic
pain feel powerless, alienated, emotionally distressed, and isolated.
119
These effects have affected their relationship with the person with
chronic pain. An interpretive qualitative design using in-depth
interviews and thematic analysis was undertaken. Purposive sampling
and in-depth interviewing were undertaken to develop a rich
description of the experience. The impact of chronic pain on the
family was extensive, resulting in physical, social, and emotional
changes. Four themes were revealed: (1) Family loss, (2) Life
changes, (3) Emotional impact of pain, and (4) Future plans.
Understanding the effect of chronic pain on partners and families
opens opportunities for nurses and other health workers to develop
and implement strategies to better support partners/families. It is
important to reduce the negative effect of pain by including families in
assessment, education, referral and treatment processes, and by
offering support and education to partners/families (1).
The chronic pain experience is the product of a complex interaction
of many factors including biological, social, psychological,
environmental, and familial. The presence of chronic pain can affect
the family system with significant, negative consequences; the family
may also be responsible, in part, for maintaining and perpetuating pain
problems. The need to examine the family dimension of the chronic
pain experience and offer family/couple therapy is vital to
comprehensive pain management. Operant behavioral, cognitive-
behavioral, and structural family therapy approaches are advocated for
such families, along with a clear need for controlled evaluations of
these approaches (2).
This qualitative study was conducted to gain an understanding of
the experiences of persons with chronic pain and their relationships
with family members and the family as a whole. The framework of
systemic organization was used to define the areas of investigation
guiding the formulation of broad questions relative to family
functioning. Thirty persons with chronic pain (age 31-82 years, 73%
women, 83% married, 83% European-American, and 17% African-
American) participated in the study. A semi-structured interview was
conducted to elicit narrative descriptions of the participants'
perspective of the pain experience and family functioning. The data
were analyzed using a constant comparison method of analysis
described by Strauss. The dominant themes that emerged included: (1)
emotional distress, (2) distancing from family members, (3) inability
to share difficult feelings, (4) intense mutual involvement with family
members and identification with others' problems, (5) family isolation
from community, and (6) attempt at healing. A mid-range theory,
developed out of the data and explicated with the framework of
120
systemic organization, was one of balancing and counterbalancing

connectedness (spirituality) with personal autonomy or separateness
(control) in order to find congruence for the family and individuals
within. The pain sometimes acted as a mechanism regulating the
distance and closeness among family members. Based on this
information, better understanding among family members, and
encourage autonomy, assist individuals to express feelings and needs
more directly and facilitate members to respond to each other can be
facilitated (3).
The main aim of this study was to measure and explore the nature
of family resilience in the context of families with a member with
chronic pain in 2007 to 2010. Chronic pain affects the entire family.
An explanatory sequential mixed method study was conducted. In the
initial quantitative phase, assessment measures were administered
using the Connor-Davidson Resilience Scale, Family Impact of Pain
Scale, SF-36 and Medical Outcomes Study Social Support Survey.
Data were collected and analyzed from 31 family cases (n=67
participants). In the second, qualitative phase, follow-up semi-
structured interviews were undertaken with 10 families to help explain
the quantitative results. The effect of pain on the family was high
overall, but the perceived effect was greater for the person with pain.
Resilience scores were above the average for both the person with
pain and other family members. However, the person with pain scored
lower on the resilience scale than other members of the family. The
families scored high for social support overall, while the persons with
pain perceived that they had greater support than their family
members did. These findings indicate that identifying the strengths or
resilient properties inherent in families and using those strengths in the
planning and implementation of care, especially of chronic conditions
such as chronic pain, is pivotal to quality health outcomes. It is
important that nurses and healthcare professionals include family
members when planning and delivering care for persons with chronic
pain. Identification of strengths within families can help tailor nursing
interventions to meet family need (4).
The purpose of the study was to examine what kind of effect a
relative with chronic pain had on his or her partner and the other
members of the family. The methodology used was grounded theory.
The sample was a convenience group of 18 chronic pain sufferers,
their partners, and 1 adult child taken from 2 pain clinics. The subjects
were briefed in the purpose of the study, and how their confidentiality
would be protected. Informed consent was then obtained. Data were
collected through audiotaped interviews, which were conducted on an
121
individual basis in the subject's home environment. Analysis was

conducted through the constant comparative method. Findings
revealed that 2 main variables emerged, that of social relationships
and coping techniques. The aspects of social relationships affected
were the marital partnership, sexual activity, contact with friends and
relatives, and roles. This meant that chronic pain caused social
isolation, role tension, marital conflict, reduced sexual activity and
feelings of anger, anxiety, resentment and despondency in other
family members. The extent to which chronic pain negatively affected
the chronic pain sufferer's respective partner and other family
members was dependent to some extent on how effective the family
was in coping with a relative with chronic pain (5).
Families maintain the primary responsibility for the care of the
chronic pain sufferer. The family has etiological role in chronic pain,
ways influencing and maintaining pain, and affecting chronic pain on
the family unit. It is concluded that (a) there is a tendency for patients
to come from families, which include another member suffering from
pain or illness, (b) it is conceivable that spouses reinforce pain
behaviors in their partners, and (c) it is possible that the chronic pain
sufferer may significantly subscribe to poor marital relationships, poor
sexual adjustment and high levels of emotional distress (6).
Chronic illness in a family member can cause emotional distress
throughout the family, and may impair the family's ability to support
the patient. The familial impact of mental illness to other common
chronic conditions was compared. The impact of a person's chronic
illness on the psychological health of all persons in his or her family
and both individual and family-level risk factors associated with
psychological spillovers were indentified. This analysis was based on
data from the 1996 Medical Expenditure Panel Survey that, because of
its sample design, can be used to model both individual and family
health status. Psychological distress was measured using responses to
the general mental health question for each family member. The
chronic conditions considered included cancer, diabetes, stroke-related
disorders, arthritis, asthma, and mental illness (including dementia).
The relationships of interest using a semi-parametric method, the
discrete random effects probit model were estimated. Brain-related
conditions, including mental illness, impose the most significant risk
to the psychological well-being of family members. The effects of the
other chronic conditions studied, while not as significant, are notable
in that their negative effects on the psychological health of family
members are sometimes larger than their direct psychological effects
on the patient. Economic distress not only directly increases the
122
chance that an individual will experience emotional distress, but it

also reduces the family's ability as a whole to cope psychologically
with chronic illness. Because psychological distress is fairly
contagious in families confronted with chronic illness, effective
treatment strategies may need to be targeted to all members of the
primary patient's family. Providers should be particularly vigilant for
intra-family effects when their patients come from families that lack
the financial resources that might protect against the stress of caring
for a family member with a chronic illness. These results suggest that,
of the chronic conditions considered, priority for respite care and
supportive services should be given to families in which a member has
a brain-related disorder, particularly in families with limited financial
resources and inadequate insurance coverage (7).
Stress lowers resistance to disease and thus has a significant effect
on susceptibility to a variety of physical and psychological illnesses.
A correlation has been established between the degree of social stress
and an individual's use of medical services. However, the majority of
people do not respond to stress in these ways. Social supports (e.g. a
caring family) seem to be an important protective factor against the
effects of stress (8).
Assessment: experiences of persons with chronic pain and their

relationships with family members and the family as a whole include
emotional distress, distancing from family members, inability to share
difficult feelings, intense mutual involvement with family members
and identification with others' problems, family isolation from
community, and attempt at healing.
Families of people with chronic pain feel powerless, alienated,
emotionally distressed, and isolated. These dimensions affect their
relationship with the person with chronic pain. The effect of chronic
pain on the family is in physical, social, and emotional changes such
as family loss, life changes, emotional impact of pain, and future
plans.
The effect of pain on the family is high, but the perceived effect is
greater for the person with pain. Resilience scores are above the
average for both the person with pain and other family members.
However, the person with pain scores is lower on the resilience scale
than other members of the family.
Chronic pain causes social isolation, role tension, marital conflict,
reduced sexual activity and feelings of anger, anxiety, resentment and
despondency in other family members. Cancer, diabetes, stroke-
related disorders, arthritis, asthma, and mental illness (including
123
dementia) have negative effect on the psychological health of family

members and this effect is sometimes larger than their direct
psychological impacts on the patient.
Did the King's family help their husband and father to cope with
the severe bone pain? The King‘s family consisted of a husband,
seven wives - Ahinoam, Abigail, Maacah, Haggith, Abital, Ithream (II
Samuel 3:2-5) and Batsheba (II Samuel 11:27) and seven sons ―And
his firstborn was Amnon of Ahinoam the Jezreelitess; And his second
Chileab, of Abigail..., and the third, Absalom the son of Maacah the
daughter of Talmai king of Geshur; And the fourth Adonijah the son of
Haggith, and the fifth, Shephatiah, the son of Abital, and the sixth,
Ithream, by Eglah David’s wife ‖ (3:2-5), and Solomon of Batsheba
(12:24). After David left Hebron ―And David took him more
concubines and wives of Jerusalem.....And other children were born in
Jerusalem: Shammuah, Shobab, Nathan, Solomon, Ibhar, Elishua,
Nepheg, Japhia, Elishama, Eliada, and Eliphalet‖ (5:13-16). The
King‘s polygamous family included many wives, concubines and 17
children.
The passages ―Be not far from me; for trouble is near; for there is
no hepl‖ (Psalm 6:12), ―I am helpless‖ (25:16), ―I am wretched..‖
(6:3) and ―I am forgotten as a dead man out of mine mind. I am like
a lost tool‖ (31:13) indicate the King‘s loneliness, feelings of neglect
and negative interpersonal relationships, need for close relationships,
lack of friends, and lack of his family members on whom he can rely.
The King's family was not supportive in his struggle with his physical
illnesses and psychosocial situation.
References
1. West C, Usher K, Foster K, Stewart L. Chronic pain and the family: the experience
of the partners of people living with chronic pain. J Clin Nurs. 2012; 21(23-24):3352-60.
2. Lewandowski W, Morris R, Draucker CB, Risko J. Chronic pain and the family:
theory-driven treatment approaches. Issues Ment Health Nurs. 2007;28(9):1019-44.
3. Smith AA, Friedemann ML. Perceived family dynamics of persons with chronic
pain. J Adv Nurs. 1999;30(3):543-51.
4. West C, Buettner P, Stewart L, et al. Resilience in families with a member with
chronic pain: a mixed methods study. J Clin Nurs. J Clin Nurs. 2012;21(23-24):3532-45.
5. Snelling J. The effect of chronic pain on the family unit. J Adv Nurs.
1994;19(3):543-51.
6. Snelling J. The role of the family in relation to chronic pain: review of the literature.
J Adv Nurs. 1990;15(7):771-6.
7. Holmes AM, Deb P. The effect of chronic illness on the psychological health of
family members. J Ment Health Policy Econ. 2003;6(1):13-22.
8. Haggerty RJ. Life stress, illness and social supports. Dev Med Child Neurol.
1980;22(3):391-400.
124
PROGNOSTIC FACTORS
The CHANGE PAIN Advisory Board considered the evidence for
adopting a prognostic definition of chronic pain. The rationale
underlying this approach is to take psychological and behavioral
factors into account, as well as the multidimensional nature of pain.
Measures of pain intensity, interference with everyday activities, role
disability, depression, duration and number of pain sites are used to
calculate a risk score, which indicates the likelihood of a patient
having pain in the future. The consistency of a prognostic definition
with the concept of integrated patient care was also considered. When
this method was compared with the number of pain days experienced
over the previous 6 months in patients with back pain, headache or
orofacial pain, it was a better predictor of clinically significant pain 6
months later for all 3 pain conditions. Further evidence supporting this
approach is that several factors other than the duration of pain were
important prognostic indicators, including unemployment, functional
disability, anxiety and self-rated health. The use of a multifactorial
risk score may suggest specific measures to improve outcomes, such
as addressing emotional distress. These measures should be
undertaken as part of an integrated pain management strategy; chronic
pain is a biopsychosocial phenomenon and all aspects of the patient's
pain must be dealt with appropriately and simultaneously for
treatment to be effective. The implementation of a prognostic
definition and wider adoption of integrated care could bring
significant advantages. However, these measures require improved
training in pain management and structural revision of specialist
facilities, for which political support is essential (1).
This study compared duration-based and prospective approaches to
defining chronic pain in terms of their ability to predict future pain
course and outcomes for primary care patients with 3 common pain
conditions: back pain (n=971), headache (n=1078), or orofacial pain
(n=455). At baseline, their chronic pain was classified retrospectively
based on Pain Days in the prior 6 months and prospectively with a
prognostic Risk Score identifying patients with "possible" or
"probable" chronic pain. The 0-28 Risk Score was based on pain
intensity, pain-related activity limitations, depressive symptoms,
number of pain sites, and Pain Days. Pain and behavioral outcomes
were assessed at 6-month follow-up, and long-term opioid use was
assessed 2 to 5 years after baseline. Risk Score consistently predicted
clinically significant pain at 6 months better than did Pain Days alone
(area under the curve of 0.74-0.78 for Risk Score vs. 0.63-0.73 for
125
Pain Days). Risk Score was a stronger predictor of future SF-36

Physical Function, pain-related worry, unemployment, and long-term
opioid use than Pain Days alone. Thus, for these 3 common pain
conditions, a prognostic Risk Score had better predictive validity for
pain outcomes than did pain duration alone. However, chronic pain
appears to be a continuum rather than a distinct class, because long-
term pain outcomes are highly variable and inherently uncertain (2).
Chronic pain patients share many characteristics, but there is
important prognostic variability among them. By selecting for certain
characteristics, different recruitment methods and entry criteria for
clinical or research programs may influence the likelihood of success
regardless of treatment efficacy. This was demonstrated when subjects
(n=55) were recruited through lay publicity for a clinical trial of
therapy for chronic back pain. In comparison to routine pain clinic
patients (n=61), subjects in the clinical trial were better educated, were
more often employed, had more favorable personality profiles, and
were less likely to have had surgery or narcotic use (all, p<0.004).
Pain relief was significantly better for clinical trial subjects,
apparently due to baseline prognostic differences rather than uniquely
efficacious therapy. In conclusion, chronic pain patients vary in
prognostically important ways that recruitment methods and criteria
strongly influence (3).
This study aimed to investigate the outcome and outcome
predictors of multidisciplinary rehabilitation in terms of working
ability. Patients (n=143) with musculoskeletal pain (mean age=45.7,
SD=8.9) were included. Work status, pain, functional health status and
psychosocial factors were collected before treatment, after a 5-week
intensive training and a 52-week follow-up period. Demographics and
data on personal characteristics were also collected. Workability
increased from 57.4% to 80% during treatment period. Age,
sleeplessness, cognitive function, overall health, pain experience, and
anxiety were the strongest predictors of work ability. Pain severity and
depression were insignificant predictors of work ability. These data
suggest that emotional distress, cognitive function and overall health
are important priority areas in rehabilitation programs to improve
work ability (4).
A prospective study was conducted among 143 musculoskeletal
pain patients. Measures of pain, function, and functional health status
were obtained at baseline, after 5 weeks of intensive training, at the
end of the 57-week rehabilitation program, and at a 1-year follow-up,
using validated self-administrated measures. The participants studied
showed a significant increase in function during the 57 weeks of
126
rehabilitation period. There was also a significant increase in function

from the end of the rehabilitation period (57th week) to the one-year
follow-up measures. Pain intensity associated significantly with pain
experience over all measurement periods. High levels of pain intensity
(beta = .42**) and pain experience (beta = .37*), and poor
psychological capacity (beta = -.68*) at baseline, as well as poor
physiological capacity (beta = -.44**), high levels of anxiety (beta =
.48**) and depression (beta = .58***) at the end of the rehabilitation
program were the most important prognostic factors of variance in
functioning over the 4 measurement periods. In conclusion, physical
capacity, emotional distress and coping skills should be priority areas
in rehabilitation programs to improve functioning in daily life (5).
Assessment: measures of pain intensity, interference with

everyday activities, role disability, depression, duration and the
number of pain sites are used to calculate a risk score, which indicates
the likelihood of a patient having pain in the future. Several factors
other than the duration of pain are important prognostic indicators,
including unemployment, functional disability, anxiety and self-rated
health. Positive prognostic factors include higher education,
employment, favorable personality factors, and less likely to have
surgery or narcotic use. Chronic pain is a biopsychosocial
phenomenon and all aspects of the patient's pain must be dealt with
appropriately and simultaneously for treatment to be effective.
References
1. Pergolizzi J, Ahlbeck K, Aldington D, et al. The chronic pain conundrum:
should we CHANGE from relying on past history to assessing prognostic factors?
Curr Med Res Opin. 2012;28(2):249-56.
2. Von Korff M, Dunn KM. Chronic pain reconsidered. Pain. 2008;138(2):267-76.
3. Deyo RA, Bass JE, Walsh NE, et al. Prognostic variability among chronic pain
patients: implications for study design, interpretation, and reporting. Arch Phys Med
Rehabil. 1988;69(3Pt 1):174-8.
4. Lillefjell M, Krokstad S, Espnes GA. Factors predicting work ability following
multidisciplinary rehabilitation for chronic musculoskeletal pain. J Occup Rehabil.
2006;16(4):543-55.
5. Lillefjell M, Krokstad S, Espnes GA. Prediction of function in daily life
following multidisciplinary rehabilitation for individuals with chronic musculoskeletal
pain; a prospective study. BMC Musculoskelet Disord. 2007 Jul 10;8:65.
127
APPROACH TO A PATIENT
WITH NON-MALIGNANT PAIN
Pain is one of the most common reasons for seeking medical care.
Patients with severe chronic pain first come to their physician, family
physician or general practitioner, to receive appropriate treatment. The
primary care physician is the address for these patients. What should
be the approach to a patient, in ancient or modern times, suffering
from chronic non-malignant pain?
NON-PHARMACOLOGICAL INTERVENTIONS
COPING STRATEGIES
Perceptions of control over pain and specific pain coping strategies
are associated with a number of positive outcomes in patients with
chronic pain conditions. Transactional models of stress have
emphasized coping as a process that is both determined by, and
influences appraisals of control. Individuals (n=195, 65% females)
with chronic pain conditions admitted to an inpatient unit completed
the MPI, the Survey of Pain Attitudes and the Coping Strategies
Questionnaire. After controlling for pain severity and education,
coping self-statements and reinterpreting pain sensations predicted
greater perceptions of control over pain, whereas ignoring pain
sensations predicted lower perceptions of control over pain. The
coping strategies did not interact with pain severity in predicting
perceptions of control. Coping flexibility, or the number of pain
coping strategies reported at a high frequency also predicted
perceptions of control over pain and did not interact with pain
severity. Thus, regardless of pain severity, the use of specific
cognitive pain coping strategies may increase perceptions of control
over pain. Since the existing coping literature largely identifies
maladaptive pain coping strategies, it is especially critical to establish
which pain coping strategies are adaptive. Specific cognitive
strategies, particularly coping self-statements, are important
components for cognitive-behavioral interventions for chronic pain
management (1).
Adaptive coping strategies, referring to the concept of 'locus of
disease control', were of relevance for patients with chronic pain
128
conditions, and how they were interconnected with patients' LiSat and
interpretation of disease. In a multicenter cross-sectional anonymous
survey with the AKU (an acronym of the German translation of
"Adaptive Coping with Disease", life satisfaction, and appraisal
dimension) questionnaire, 579 patients (mean age 54 ± 14 years) with
various chronic pain conditions were enrolled. Disease as an adverse
interruption of life was the prevalent interpretation of chronic pain
conditions. Consequently, patients relied on external powerful sources
to control their disease (i.e., Trust in Medical Help; Search for
Information and Alternative Help), but also on internal powers and
virtues (i.e., Conscious Way of Living; Positive Attitudes). By
contrast, Trust in Divine Help as an external transcendent source and
Reappraisal: Illness as Chance as an internal (cognitive) strategy were
valued moderately. Regression analyses indicated that Positive
Attitudes and higher age were significant predictors of patients' LiSat,
but none of the other adaptive coping strategies. While the adaptive
coping strategies were not associated with negative interpretations of
disease, the cognitive reappraisal attitude was of significant relevance
for positive interpretations such as value and challenge. The
experience of illness may enhance intensity and depth of life, and thus
one may explain the association between internal adaptive coping
strategies (particularly Reappraisal) and positive interpretations of
disease. To restore a sense of self-control over pain (and thus
congruence with the situation), and the conviction that one is not
necessarily disabled by disease, is a major task in patient care. In the
context of health services research, apart from effective pain
management, a comprehensive approach is needed which enhances
the psycho-spiritual well-being of patients (2).
A 4-week Pain Coping Strategies program has been developed for
chronic pain patients who may still be undergoing medical
interventions but who would benefit from learning pain management
skills. The Pain Coping Strategies program combines all the
fundamental aspects of the traditional Pain Management Program
including exercise, relaxation, pacing, medication review, pain
pathways, posture and challenging negative thoughts. This study
compared 31 patients' mood, functional status and physical ability pre
and 6 weeks post the program using the HAD, Canadian Occupational
Performance Measure and a series of physical tests. A paired samples
t-test showed a significant improvement in levels of depression and
anxiety, functional status and physical ability. The results reveal that
an early intervention program may be effective for chronic pain
patients by promoting self-management and teaching positive coping
129
strategies. In conclusion, the current study has found promising results

for a brief early intervention for chronic pain, regardless of
completion of medical interventions (3).
The objective of this study was to describe the use and perceived
effectiveness of pain management strategies in a sample of older
adults and to explore the associations of these variables with
demographic and psychosocial characteristics. Adults ≥ 65 years old
and living in retirement facilities who reported persistent pain (n=235,
mean age 82 years, 84% female, 94% white) completed measures of
demographics, pain, depression, self-efficacy for managing pain, and a
Pain Management Strategies Survey. Participants identified current
and previous-year use of 42 pain management strategies and rated
helpfulness of each on a 5-point scale. Acetaminophen, regular
exercise, prayer, and heat and cold were the most frequently used pain
management strategies (61%, 58%, 53%, and 48%, respectively).
Strategies used by > 25% of the sample that were rated moderately or
more helpful (i.e., > 2 on a 0 to 4 scale) were prayer [mean (SD) = 2.9
(0.9)], opioids [2.6 (0.8)], regular exercise [2.5 (1.0)], heat/cold [2.5
(1.0)], NSAIDs [2.4 (1.0)], and acetaminophen [2.3 (1.0)]. Young-old
(65-74 years) study participants reported use of more strategies than
did old-old (> 85 years) participants (p=0.03). Perceived helpfulness
of strategy use was significantly associated with pain intensity (r=-.14,
p<0.0001), self-efficacy (r= .28, p<0.0001), and depression (r = -.20, p
=0.003). In conclusion, on average, older adults view the strategies
they use for persistent pain as only moderately helpful. The
associations between perceived helpfulness and self-efficacy and
depression suggest avenues of pain management that are focused less
on specific treatments and more on how persons with persistent pain
think about their pain (4).
In this cross-sectional study of older persons with chronic
nonmalignant pain, strategies perceived as effective in reducing pain
and to ascertain factors associated with their use were identified.
Participants included 272 community-dwelling persons aged 73 years
or older. Information regarding participants' sociodemographic,
clinical, psychological, and pain status was collected. Strategies
perceived as effective in reducing pain were identified using a
qualitative approach. Similar methods (e.g., "takes acetaminophen
when necessary" and "uses Tramadol daily") were grouped into
specific pain-reduction categories (e.g., analgesic medication use).
Participants had a mean (SD) age of 80.9 (5.1) years and were mostly
female (69%). Overall, 248 (91%) participants reported at least one
effective strategy for reducing pain; the mean number of strategies per
130
participant was 2.7 (range = 1-6). The 4 most prevalent pain-reduction

strategies were analgesic medication use (reported by 59% of
participants), activity restriction (38%), hot and/or cold modalities
(28%), and exercise (23%). Although most participants reported at
least one effective pain-reduction strategy, 60% rated their pain as
"quite a bit" or "extremely" bothersome. In logistic regression
analysis, no factor (including age and gender) was independently
associated with any of the prevalent pain-reduction strategies. In
conclusion, despite the fact that most participants perceived several
pain-reduction strategies as effective, 60% reported experiencing
substantial pain (5).
The main objective of this study was to determine outcomes for 2
rehabilitation strategies for patients with chronic pain: a 2-day
interdisciplinary team assessment followed by either: (i) a 4-week
outpatient multimodal rehabilitation program, or (ii) a subsequent
rehabilitation plan. After a 2-day interdisciplinary team assessment at
this pain rehabilitation clinic 296 consecutive patients were selected to
either multimodal rehabilitation (n=76) or rehabilitation plan (n=220).
They completed questionnaires regarding pain intensity (VAS),
disability (DRI), LiSat (LiSat-11), anxiety and depression (HADS) at
assessment and again at 1-year follow-up. Both groups showed
significant improvements at 1-year follow-up regarding pain intensity.
In addition, the multimodal rehabilitation group improved in the
disability items ("light work" and "heavy work"), depression and
LiSat ("leisure", "somatic health", and "psychological health"). In the
rehabilitation plan group "somatic health" improved, although not
statistically significant. This study indicates that multimodal
rehabilitation may have long-term positive effects on pain, disability,
depression and domains of life satisfaction. However, a minor
intervention, rehabilitation plan with follow-up in primary care, can
improve pain and "somatic health". Based on the biopsychosocial
approach, an interdisciplinary assessment of patients with chronic pain
seems to be of value for selecting patients to different rehabilitation
interventions (6).
Assessment: perceptions of control over pain and specific pain

coping strategies are associated with a number of positive outcomes in
patients with chronic pain conditions. The Pain Coping Strategies
program combines all the fundamental aspects of the traditional pain
management program including exercise, relaxation, pacing,
medication review, pain pathways, posture and challenging negative
thoughts. Acetaminophen, regular exercise/or activity restriction,
prayer, and heat and cold are the most frequently used pain
131
management strategies. Multimodal rehabilitation has long-term

positive effects on pain, disability, depression and domains of life
satisfaction.
References
1. Haythornthwaite JA, Menefee LA, Heinberg LJ, Clark MR. Pain coping
strategies predict perceived control over pain. Pain. 1998;77(1):33-9.
2. Büssing A, Ostermann T, Neugebauer EA, Heusser P. Adaptive coping
strategies in patients with chronic pain conditions and their interpretation of disease.
BMC Public Health. 2010 Aug 20;10:507.
3. Mead K, Theadom A, Byron K, Dupont S. Pilot study of a 4-week Pain Coping
Strategies (PCS) programme for the chronic pain patient. Disabil Rehabil.
2007;29(3):199-203.
4. Kemp CA, Ersek M, Turner JA. A descriptive study of older adults with
persistent pain: use and perceived effectiveness of pain management strategies
[ISRCTN11899548]. BMC Geriatr. 2005 Nov 8;5:12.
5. Barry LC, Gill TM, Kerns RD, Reid MC. Identification of pain-reduction
strategies used by community-dwelling older persons. J Gerontol A Biol Sci Med Sci.
2005;60(12):1569-75.
6. Merrick D, Sundelin G, Stålnacke BM. One-year follow-up of two different
rehabilitation strategies for patients with chronic pain. J Rehabil Med.
2012;44(8):764-73.
PSYCHOLOGICAL INTERVENTIONS
Chronic pain can be best understood from a biopsychosocial
perspective through which pain is viewed as a complex, multifaceted
experience emerging from the dynamic interplay of a patient's
physiological state, thoughts, emotions, behaviors, and sociocultural
influences. A biopsychosocial perspective focuses on viewing chronic
pain as an illness rather than disease, thus recognizing that it is a
subjective experience and that treatment approaches are aimed at the
management, rather than the cure, of chronic pain. Current
psychological approaches to the management of chronic pain include
interventions that aim to achieve increased self-management,
behavioral change, and cognitive change rather than directly eliminate
the locus of pain. Benefits of including psychological treatments in
multidisciplinary approaches to the management of chronic pain
include, but are not limited to, increased self-management of pain,
improved pain-coping resources, reduced pain-related disability, and
reduced emotional distress - improvements that are effected via a
variety of effective self-regulatory, behavioral, and cognitive
techniques. Through implementation of these changes, psychologists
can effectively help patients feel more in command of their pain
132
control and enable them to live as normal a life as possible despite

pain. Moreover, the skills learned through psychological interventions
empower and enable patients to become active participants in the
management of their illness and instill valuable skills that patients can
employ throughout their lives (1).
Chronic pain is a prevalent and costly problem that eludes adequate
treatment. Persistent pain affects all domains of people's lives and in
the absence of cure, success will greatly depend on adaptation to
symptoms and self-management. The psychological models have
been used to conceptualize chronic pain-psychodynamic, behavioral
(respondent and operant), and cognitive-behavioral issues. Treatments
based on these models include insight, external reinforcement,
motivational interviewing, relaxation, meditation, biofeedback, guided
imagery, and hypnosis. The cognitive-behavioral perspective has the
greatest amount of research supports the effectiveness of this approach
with chronic pain patients. The cognitive-behavioral perspectives are
differentiated and behavioral techniques suggest that the perspective
on the role of patients' beliefs, attitudes, and expectations in the
maintenance and exacerbation of symptoms are more important than
the specific techniques. The techniques are geared to fostering self-
control and self-management that will encourage a patient to replace
their feelings of passivity, dependence, and hopelessness with activity,
independence, and resourcefulness. In conclusion, psychosocial and
behavioral factors play a significant role in the experience,
maintenance, and exacerbation of pain. Self-management is an
important complement to biomedical approaches. CBT alone or within
the context of an interdisciplinary pain rehabilitation program has the
greatest empirical evidence for success. As none of the most
commonly prescribed treatment regimens are sufficient to eliminate
pain, a more realistic approach will likely combine pharmacological,
physical, and psychological components tailored to each patient's
needs (2).
As a biopsychosocial understanding of chronic pain has become
more sophisticated during recent decades, a variety of psychologically
based treatment approaches have been developed and empirically
validated for helping people better manage their pain. These
approaches to pain management have much to offer persons with
chronic pain in terms of enhancing QOL and pain-related coping, as
well as reducing disability and pain-related interference with
functioning. Although some treatments, like hypnotic analgesia, may
require referral to a specialized provider, several of the principles of
other psychologically based treatment approaches for pain
133
management (e.g., operant behavioral therapy, CBT, and motivational

interviewing) can easily be integrated into work with persons with
pain in a rehabilitation setting. Rehabilitation providers who are
interested in incorporating these treatment strategies into their clinical
work and who do not have prior exposure to these approaches are
encouraged to review the suggested references and to seek out related
training opportunities (3).
The aim of this study was to investigate the role of pain acceptance
as a process variable in CBT relative to 2 empirically supported
process variables, namely catastrophizing and pain intensity. Patients
with chronic pain (n = 186) attended a three-week, multidisciplinary
pain program, which was CBT based. Patients completed a measure of
pain intensity; the Chronic Pain Acceptance Questionnaire; the
catastrophizing subscale of the Pain Response Self-Statements Scale;
the Roland Morris Disability Questionnaire; the Depression Anxiety
and Stress Scale; and 2 measures of physical functioning at
pretreatment, post-treatment and three-month follow-up. Both
acceptance and catastrophizing showed statistically significant and
clinically relevant changes from pre- to post-treatment. Changes in
both acceptance and catastrophizing showed a significant correlation
with changes in almost all of the outcome variables. Regression
analyses demonstrated that change in acceptance was a significant
predictor of changes in depression, disability, timed walk and sit-to-
stand performance, after controlling for changes in catastrophizing
and pain intensity. Although not specifically targeted in CBT
treatment, acceptance of pain was an important process variable that
contributed to CBT treatment outcomes after controlling for changes
in pain intensity and catastrophizing (4).
The main aim of this study was to provide a review of the rationale
and evidence supporting 3 frequently used psychosocial interventions
for chronic pain: CBT, operant behavioral therapy and self-hypnosis
training. Recent work in these areas, with an emphasis on the 2006
publishing year was reviewed. Recent clinical trials and laboratory
work continue to support the use of CBT and operant behavioral
therapy as adjunctive treatments for chronic pain. Notable areas of
new research include a novel program of systematic exposure to pain-
related fear (such as fear of reinjury) and the adaptation of CBT for
special pain groups (e.g. juveniles and those with pain secondary to
physical disability). Regarding self-hypnosis training, recent work
suggests that hypnosis can provide temporary pain relief to the
majority of individuals with chronic pain and that a substantial
minority of these patients experience a clinically significant reduction
134
in baseline pain over time. In summary, CBT and operant behavioral

therapies focus on factors that exacerbate or maintain suffering in
chronic pain, and should be considered as part of a multidisciplinary
treatment paradigm. Self-hypnosis training may also be of benefit,
although it appears to be no more (or less) effective than other
relaxation strategies that include hypnotic elements (5).
The aim of this paper is to provide an overview of the theoretical
basis and application of psychological interventions used in the
management of chronic pain. A biopsychosocial model of chronic
pain is widely purported and pain management is often based upon
cognitive-behavioral principles as psychological factors meditating
pain and disability include emotional, cognitive and behavioral
components. Support for a biopsychosocial model of and for the
effectiveness and efficacy of psychological interventions for the
management of chronic pain conditions is supported (6).
A literature review was conducted in order to examine the outcome
of BT-CBT for chronic pain, to identify the predictors of treatment
outcome, and to investigate the change processes associated with these
treatments. Numerous controlled clinical trials of BT-CBT for chronic
pain, alone or more commonly in multidisciplinary treatment contexts,
suggest that these treatments are effective. However, further study is
needed to examine which outcome variables change, when, for whom,
and how. Published literature was gathered from Medline, PsychLit,
and searches of relevant journals. Overall, BT-CBT for chronic pain
reduces patients' pain, distress, and pain behavior, and improves their
daily functioning. Differences across studies in sample characteristics,
treatment features, and assessment methods seem to produce varied
treatment results. In addition, some patients benefit more than others
do. Highly distressed patients who see their pain as an uncontrollable
and highly negative life event derive less benefit than other patients
do. Decreased negative emotional responses to pain, decreased
perceptions of disability, and increased orientation toward self-
management during the course of treatment predict favorable
treatment outcome. In conclusion, current BT-CBT helps many
patients with chronic pain. Continuing clinical research should
improve the matching of treatments with patient characteristics and
refine the focus of treatments on behavior changes most associated
with positive outcome (7).
Pain is a serious health care problem and there is growing evidence
to support the use of hypnosis and CBT for pain management. Current
research emphasis the efficacy of hypnotherapy for pain management.
Evidence for cognitive hypnotherapy for the treatment of chronic pain
135
in cancer, osteoarthritis, sickle cell disease, temporomandibular

disorder, fibromyalgia, non-cardiac chest pain, and disability are
identified. The accumulating evidence supports of the efficacy and
effectiveness of cognitive hypnotherapy for pain management (8).
Chronic pain can be treated by combining hypnosis with brief
psychotherapy. Hypnosis alone, though useful for acute pain, is
seldom effective in relieving chronic pain because it does not address
the significant psychologic components in the patient's illness.
Treatment using self-hypnosis in conjunction with brief
psychotherapy, however, can enable the patient to recognize these
components, to change from a passive to an active role in achieving
relief, and to modify his attitude toward the pain. This procedure can
both reduce suffering and lead the patient to deemphasize pain in his
life (9).
Hypnosis has been demonstrated to reduce analogue pain, and
studies on the mechanisms of laboratory pain reduction have provided
useful applications to clinical populations. Studies showing CNS
activity during hypnotic procedures offer preliminary information
concerning possible physiological mechanisms of hypnotic analgesia.
RCTs with clinical populations indicate that hypnosis has a reliable
and significant impact on acute procedural pain and chronic pain
conditions (10).
Assessment: treatments based on behavioral (respondent and

operant), and cognitive-behavioral models, include insight, external
reinforcement, motivational interviewing, relaxation, meditation,
biofeedback, guided imagery, and hypnosis. Self-hypnosis training is
of benefit, although it is no more (or less) effective than other
relaxation strategies that include hypnotic elements. BT-CBT helps
many patients with chronic pain. Cognitive hypnotherapy is useful in
the treatment of chronic pain in cancer, osteoarthritis, sickle cell
disease, temporomandibular disorder, fibromyalgia, non-cardiac chest
pain, and disability. Hypnosis reduces pain, while chronic pain can be
treated by combining hypnosis with brief psychotherapy.
References
1. Roditi D, Robinson ME. The role of psychological interventions in the
management of patients with chronic pain. Psychol Res Behav Manag. 2011;4:41-9.
2. Turk DC, Swanson KS, Tunks ER. Psychological approaches in the treatment
of chronic pain patients - when pills, scalpels, and needles are not enough. Can J
Psychiatry. 2008;53(4):213-23.
3. Osborne TL, Raichle KA, Jensen MP. Psychologic interventions for chronic
pain. Phys Med Rehabil Clin N Am. 2006;17(2):415-33.
136
4. Baranoff J, Hanrahan SJ, Kapur D, Connor JP. Acceptance as a process

variable in relation to catastrophizing in multidisciplinary pain treatment. Eur J Pain.
2013;17(1):101-10.
5. Molton IR, Graham C, Stoelb BL, Jensen MP. Current psychological
approaches to the management of chronic pain. Curr Opin Anaesthesiol.
2007;20(5):485-9.
6. Adams N, Poole H, Richardson C. Psychological approaches to chronic pain
management: part 1. J Clin Nurs. 2006;15(3):290-300.
7. McCracken LM, Turk DC. Behavioral and cognitive-behavioral treatment for
chronic pain: outcome, predictors of outcome, and treatment process. Spine (Phila Pa
1976). 2002;27(22):2564-73.
8. Elkins G, Johnson A, Fisher W. Cognitive hypnotherapy for pain management.
Am J Clin Hypn. 2012;54(4):294-310.
9. Savitz SA. Hypnosis in the treatment of chronic pain. South Med J.
1983;76(3):319-21.
10. Patterson DR, Jensen MP. Hypnosis and clinical pain. Psychol Bull.
2003;129(4):495-521.
SELF-MANAGEMENT INTERVENTIONS
The main aim of this study was to review the evidence regarding
self-management interventions for pain due to musculoskeletal
disorders among older adults. The Medline and Cumulative Index to
Nursing and Allied Health Literature databases was searched to
identify relevant articles for review and analyzed English-language
articles that presented outcome data on pain, function, and/or other
relevant endpoints and evaluated programs/strategies that could be
feasibly implemented in the community. Abstracted information
included study sample characteristics, estimates of treatment effect,
and other relevant outcomes when present. Retained articles (n=27)
included those that evaluated programs sponsored by the Arthritis
Foundation and other programs/strategies including yoga, massage
therapy, Tai Chi, and music therapy. Positive outcomes were found in
96% of the studies. Proportionate change in pain scores ranged from
an increase of 18% to a reduction of 85% (median = 23% reduction),
whereas change in disability scores ranged from an increase of 2% to
a reduction of 70% (median = 19% reduction). Generalizability issues
identified included limited enrollment of ethnic minority elders, as
well as non-ethnic elders aged 80 and above. These results suggest
that a broad range of self-management programs may provide benefits
for older adults with chronic pain (1).
The main aim of this study was to evaluate the extent to which the
principles of chronic pain or illness self-management programs might
137
be adapted to focus on the workplace concerns of adults with

persistent or recurrent pain and lead to new workplace intervention
opportunities. Eight self-management programs were selected as
representative evidence-based programs and then compared to extract
common instructional elements. Elements were analyzed for potential
application to 4 workplace problem domains identified by workers
with pain: activity interference, negative self-perceptions,
interpersonal challenges, and the inflexibility of work. Of 24
instructional elements, 17 were shared by at least half of the self-
management programs. Instructional elements judged to be best suited
for dealing with workplace concerns included those focused on
reducing pain and discomfort, making informed decisions,
communicating effectively, and dealing with thoughts and feelings.
However, aspects of the workplace that may alter the feasibility or
effectiveness of self-management strategies include the level of
physical demands and limitations, job leeway, and the nature of
workplace roles and relationships. In conclusion, principles and
methods of self-management intervention programs are generally well
suited to address pain-related problems in the workplace, but tailoring
of messages may be necessary to incorporate the unique
organizational, physical, and social aspects of work into psycho-
educational programs (2).
The aim of this study was to compare 2 self-help-based
interventions; a coping-oriented approach, applied relaxation and an
acceptance-oriented approach, acceptance and commitment therapy,
for persons with chronic pain. In this RCT (n=90) study with a mixed
between-within participants design with repeated measures,
interventions in both conditions comprised an initial face-to-face
session, a seven-week manual-based self-help intervention including
weekly therapist telephone support and a concluding face-to-face
session. Outcome measures included LiSat, depression, anxiety,
acceptance of chronic pain, level of function, and pain intensity.
Effects were measured at preintervention and postintervention and at 6
and 12 months after the end of intervention. The results show that the
acceptance and commitment therapy condition increased their level of
acceptance significantly compared with the applied relaxation
condition. There was also a marginally significant interaction effect
regarding LiSat in which the acceptance and commitment therapy
condition had improved in comparison to the applied relaxation
condition. The acceptance and commitment therapy condition reported
a higher level of function and decreased pain intensity compared with
the applied relaxation condition. Both conditions improved
138
significantly regarding depression and anxiety. In conclusion, a

manual-based self-help intervention with weekly therapist support in
an acceptance and commitment therapy format adds value to the
treatment repertoire for persons suffering with chronic pain (3).
The main aim of this study was to carry out a systematic review of
program outcomes used in the evaluation of group-based self-
management interventions aimed at people with arthritis and other
chronic conditions. The systematic search was performed across
databases MEDLINE, EMBASE, CINAHL, and PsycINFO. Both
between-group and within-group effect sizes were calculated. Results
were interpreted as small (effect sizes ~ 0.2), medium (effect sizes ~
0.5), or large (effect sizes ~ 0.8) effects. The majority of 18 included
trials investigated the effectiveness of arthritis-specific interventions.
Across most outcomes, small effects on course participants were
shown. While effects on knowledge were large (between-group effect
sizes = 0.78), effects on clinical outcomes such as pain (effect sizes =
0.10) were negligible to small. This paper is consistent with other
reviews in this area, suggesting that people with arthritis receive only
marginal benefits from participating in chronic disease self-
management interventions. When looking at the types of outcomes
that trials are based on, however, alternative explanations for these
results seem probable. As evaluations heavily rely on patient self-
report, current approaches to program evaluation may not be sufficient
to assess the intended impact of self-management education (4).
Assessment: a broad range of self-management programs may

provide benefits for older adults with chronic pain. In the work place,
principles and methods of self-management intervention programs are
well suited to address pain-related problems. A manual-based self-
help intervention with weekly therapist support in an acceptance and
commitment therapy adds value for persons suffering with chronic
pain.
References
1. Reid MC, Papaleontiou M, Ong A, et al. Self-management strategies to reduce
pain and improve function among older adults in community settings: a review of the
evidence. Pain Med. 2008;9(4):409-24.
2. Shaw WS, Tveito TH, Geehern-Lavoie M, et al. Adapting principles of chronic
pain self-management to the workplace. Disabil Rehabil. 2012;34(8):694-703.
3. Thorsell J, Finnes A, Dahl J, et al. A comparative study of 2 manual-based self-
help interventions, acceptance and commitment therapy and applied relaxation, for
persons with chronic pain. Clin J Pain. 2011;27(8):716-23.
4. Nolte S, Osborne RH. A systematic review of outcomes of chronic disease self-
management interventions. Qual Life Res. 2012 Oct 31. [Epub ahead of print].
139
COMPLIMENTARY AND ALTERNATIVE

MEDICINE
The US National Centre for Complementary and Alternative
Medicine defined CAM as a 'group of diverse medical and healthcare
systems, practices and products that are not presently considered to be
part of conventional medicine' (1). Definition of CAM is adopted by
Cochrane Collaboration: 'CAM is a broad domain of healing resources
that encompasses all health systems, modalities, and practices and
their accompanying theories and beliefs, other than those intrinsic to
the politically dominant health system of a particular society or culture
in a given historical period. CAM includes all such practices and ideas
self-defined by their users as preventing or treating illness or
promoting health and well-being. Boundaries within CAM and
between the CAM domain and that of the dominant system are not
always sharp or fixed' (2).
Complementary medicine refers to a group of therapeutic and
diagnostic disciplines that exist largely outside the institutions where
conventional health care is taught and provided. Complementary
medicine is an increasing feature of healthcare practice, but
considerable confusion remains about what exactly it is and what
position the disciplines included under this term should hold in
relation to conventional medicine. In the 1970s and 1980s, these
disciplines were mainly provided as an alternative to conventional
health care and hence became known collectively as 'alternative
medicine.' The name 'complementary medicine' developed as the 2
systems began to be used alongside (to 'complement') each other. Over
the years, 'complementary' has changed from describing this relation
between unconventional healthcare disciplines and conventional care
to defining the group of disciplines itself. Some authorities use the
term ―unconventional medicine‖ synonymously. This changing and
overlapping terminology may explain some of the confusion that
surrounds the subject (2).
Which disciplines are complementary? The list is not exhaustive,
and new branches of established disciplines are continually being
developed. In addition, what is thought to be conventional varies
between countries and changes over time. The boundary between
complementary and conventional medicine is therefore blurred and
constantly shifting. For example, although osteopathy and chiropractic
are still generally considered complementary therapies in Britain, they
are included as part of standard care in guidelines from conventional
bodies such as the Royal College of General Practitioners (2).
140
Common complementary therapies include: Acupuncture,

Acupressure acupuncture, Alexander technique, Anthroposophic
medicine, Applied kinesiology, Aromatherapy, Ayurveda, Autogenic
training, Chiropractic, Environmental medicine, Healing,
Homoeopathy, Hypnosis, Massage, Meditation, Nutritional therapy,
Naturopathy, Osteopathy, Reiki, Reflexology, Relaxation and
visualization, Shiatsu, Therapeutic touch, Yoga, TENS, PENS,
Moxibustion, Low-level laser therapy, Prayer, Herbal medicine,
Vitamins, Glucosamine, Exercise, Meditation, Chiropractic medicine,
and Music therapy (2-7).
The use of CAM around the world has increased dramatically in
recent times and is still on the increase (8-10). The reported CAM
usage in western countries such as Australia, Canada, Denmark,
Norway, US and UK ranges from 9% to 69% (8,9,11-16). In the US,
approximately 20% of adults combined 2 CAM categories, with the
combination of mind-body therapies and biologically based therapies
estimated to be most common. Of adults, 5% uses therapies
representing 3 or more CAM categories. Combining therapies across
multiple CAM categories is more common among those aged 46-64
years, women, whites, and those with a college education (17).
The main objective of this study was to update previous systematic
reviews of 12-month prevalence of CAM use by general populations;
to explore trends in CAM use by national populations; to develop and
apply a brief tool for assessing methodological quality of published
CAM-use prevalence surveys. Nine databases were searched for
published studies from 1998 onwards. Studies prior to 1998 were
identified from 2 previous systematic reviews. A 6-item literature-
based tool was devised to assess robustness and interpretability of
CAM-use estimates. Fifty-one reports from 49 surveys conducted in
15 countries met the inclusion criteria. Thirty-two estimates of 12-
month prevalence of use of any CAM (range 9.8-76%) and 33
estimates of 12-month prevalence of visits to CAM practitioners
(range 1.8-48.7%). Quality of methodological reporting was variable;
30/51 survey reports (59%) met 4 or more of 6 quality criteria.
Estimates of 12-month prevalence of any CAM use (excluding prayer)
from surveys using consistent measurement methods showed
remarkable stability in Australia (49%, 52%, 52%; 1993, 2000, 2004)
and US (36%, 38%; 2002, 2007). In conclusion, there was evidence of
substantial CAM use in the 15 countries surveyed. Where national
trends were discernible because of consistent measurement, there was
no evidence to suggest a change in 12-month prevalence of CAM use
since the previous systematic reviews were published in 2000 (18).
141
The purpose of this study was to determine if there was a

difference between African American and Caucasian American rural
elders on use of CAM and self-reported satisfaction with CAM. The
design was a descriptive, comparative study of 183 elders who
reported the number of CAM used and satisfaction with CAM. A
convenience sample was recruited through community service
organizations in the state of Mississippi. The availability of elders
through the support groups, sampling bias, subject effect, and self-
report were limitations of the study. The commonest examples of
CAM used by rural elders were prayer, vitamins, exercise, meditation,
herbs, chiropractic medicine, glucosamine, and music therapy.
Significant findings on socioeconomic status and marital status were
calculated. Differences on ethnicity and demographic variables were
significant for age, education, and the use of glucosamine. In
conclusion, health care providers must be aware that elders are using
CAM and are satisfied with their use. Identifying different uses of
CAM by ethnicity is important for health care practitioners, affecting
how health care is provided (5).
In Taiwan, 60% of people use traditional Chinese medicine, a form
of CAM (19). In Japan, 76% of the general population is using some
form of CAM (20).
The main objective of this study was to determine whether chronic
conditions and patient factors, such as risk perception and decision-
making preferences, are associated with complementary medicine and
alternative practitioner use in a representative longitudinal population
cohort. Analysis involved data from Stage 2 of the North West
Adelaide Health Study of 3161 adults who attended a study clinic visit
in 2004–2006. The main outcome measures were the medications
brought by participants to the study clinic visit, chronic health
conditions, attitudes to risk, levels of satisfaction with conventional
medicine, and preferred decision-making style. At least one oral
complementary medicine was used by 27.9% of participants, and
7.3% were visiting alternative practitioners (naturopath, or osteopath).
Oral complementary medicine use was significantly associated with
arthritis, osteoporosis, and mental health conditions, but not with other
chronic conditions. Any pattern of complementary medicine use was
significantly associated with female gender, age at least 45 years,
patient-driven decision-making preferences (OR 1.38, 95% CI 1.08 –
1.77), and frequent general practitioner visits (> 5 per year, OR 3.62,
95% CI 2.13 – 6.17). Alternative practitioner visitors were younger,
with higher levels of education (diploma/trade, OR 1.88, 95% CI 1.28
– 2.76), bachelor‘s degree (OR 1.77, 95% CI 1.11 - 2.82), income > $
142
80,000 (OR 2.28, 95% CI 1.26 – 4.11), female gender (OR 3.15, 95%
CI 2.19 – 4.52), joint pain not diagnosed as arthritis (OR 1.68, 95% CI
1.17 – 2.41), moderate to severe depressive symptoms (OR 2.15, 95%
CI 1.04 – 4.46), risk-taking behavior (3.26, 1.80 - 5.92), or low-to-
moderate risk aversion (OR 2.08, 95% CI 1.26 – 4.11). In conclusion,
although there is widespread use of complementary medicines in the
Australian community, there are differing patterns of use between
those using oral complementary medicines and those using alternative
practitioners (21).
The use of CAM in the general Japanese population has been
previously reported to be as high as 76%. This study aims to
investigate the patterns of CAM use, perceived effectiveness and
disclosure of CAM use to orthodox medical practitioners amongst
patients attending typical primary and secondary care clinics in a busy
district general hospital in Tokyo, Japan. Data were collected during
March 2002 on patients attending general outpatient clinics held at
Shiseikai Daini Hospital by use of self-completed questionnaires
distributed to patients in the outpatient clinics waiting area. Of adults,
515 were approached to participate in this study and the overall
response rate was 96% (n=496). Of the patients, 50% were using or
have used at least 1 CAM therapy within the last 12 months. The 5
most commonly used therapies were massage (n=106, 43%), vitamins
(n=85, 35%), health foods including dietary supplements (n=56, 23%),
acupressure (n=51, 21%), and kampo (n=46, 19%). The majority of
CAM users (75%, n=145) found their CAM treatment to be effective
(95% CI 68–81%). Patients who were more likely to use CAM were
females (p=0.003) and those with a high number of medical
conditions (p<0.0001). Only a small proportion of patients reported
their CAM use to their physician (42%, n=74). There was insignificant
difference in CAM use for the different age groups (p=0.85),
education level (p=0.30) and financial status (p=0.82). In conclusion,
patterns of CAM usage in the sample surveyed were high (50%).
Despite this high prevalence rate and presumed acceptance of CAM in
Japan, the reporting of CAM use by patients to their physicians was
low (42%). It is therefore important that physicians are aware of the
possibility that their patients are using CAM and increase their
knowledge and understanding of these treatments (6).
The purpose of this study was to characterize patients visiting the
complementary medicine clinic for a pain complaint. This cross-
sectional study took place at Clalit Health Services complementary
clinic in Beer-Sheva, Israel. Patients visiting the complementary
clinic, aged ≥ 18 years, Hebrew speakers, with a main complaint of
143
pain were included. Patients were recruited consecutively on random

days of the month during a period of 6 months. Main outcome
measures were: pain levels, location of pain, and interference with
daily activities. Once informed consent was signed patients were
interviewed using a structured questionnaire by a qualified nurse. The
questionnaire included socio-demographic data, and the BPI. Of 385
patients seen at the complementary medicine clinic during the study
period, 201 (50.8%) met the inclusion criteria. Of them, 163 (81.1%)
agreed to participate in the study and were interviewed. Pain
complaints included: 69 patients (46.6%) with back pain, 65 (43.9%)
knee pain, and 28 (32.4%) other limbs pain. Of all patients, 82
(50.3%) treated their pain with complementary medicine as a
supplement for their conventional treatment, 55 (33.7%) felt
disappointed from the conventional medicine experience, 83 (50.9%)
claimed that complementary medicine can result in better physical
strength, or better mental state 51 (31.3%), and 37 patients (22.7%)
were hoping that complementary medicine will prevent invasive
procedures. In conclusion, given the high proportion of patients with
unsatisfactory pain relief using CAM, general practitioners should
gain knowledge about CAM and CAM providers should gain training
in pain topics to improve communication and counsel patients (22).
The purpose of this review was to determine how effective
acupuncture, TENS, acupuncture-like TENS, laser therapy, electrical
nerve stimulation, and neuroreflexotherapy are in the management of
chronic pain. The literature search identified 6 systematic reviews of
the literature and 4 RCTs to provide evidence for this review. The
systematic reviews included different methodologies and
heterogeneity of study groups, but studies were generally of poor
methodology. Although sham acupuncture may have analgesic effects,
it was used as a control in many studies. In general, the evidence was
contradictory or inadequate, reflecting poor study methodologies. No
positive conclusion could be reached for acupuncture, TENS,
acupuncture-like TENS, laser therapy, or neuroreflexotherapy. A
single RCT provided limited evidence (level 3) that electrical nerve
stimulation is effective for pain relief in myofascial pain syndrome for
up to 4 weeks, but further study in humans is needed. Future RCTs
and systematic reviews should include subgroup analyses of sham
acupuncture and inert placebos as controls (7).
144
Tens
The main objective of this study was to evaluate the effectiveness

of TENS in chronic pain. The Cochrane Library, EMBASE,
MEDLINE and CINAHL were searched. Reference lists from
retrieved reports and reviews were examined. Date of the most recent
search: April 2008. RCTs were eligible if they compared active TENS
vs. sham TENS controls; active TENS vs. 'no treatment' controls; or
active TENS vs. active TENS controls (e.g. High Frequency TENS vs.
Low Frequency TENS). Studies of chronic pain for 3 months or more,
which included subjective outcome measures for pain intensity or
relief, were eligible for evaluation. Abstracts, letters, or unpublished
studies, and studies of TENS in angina, headache, migraine,
dysmenorrheal and cancer-related pain were excluded. Of 124 studies
identified from the searches, 99 did not fulfill pre-defined entry
criteria. Twenty-five RCTs involving 1281 participants were
evaluated. Included studies varied in design, analgesic outcomes,
chronic pain conditions, TENS treatments and methodological quality.
The reporting of methods and results for analgesic outcomes were
inconsistent across studies and generally poor. Meta-analysis was not
possible. Overall in 13 of 22 inactive control studies, there was a
positive analgesic outcome in favor of active TENS treatments. For
multiple dose treatment comparison studies, 8 of 15 were considered
to be in favor of the active TENS treatments. Seven of the 9 active
controlled studies found no difference in analgesic efficacy between
High Frequency TENS and Low Frequency TENS (23).
Thirty patients with either tension headache, migraine, or
posttraumatic headache symptoms of at least 6 months' duration were
randomized to receive PENS (needles with electricity) or "needles
alone" according to a crossover study design. All treatments were
administered for 30 minutes, 3 times a week for 2 consecutive weeks
with 1 week off between the 2 different treatments. For the PENS
treatments, an alternating electrical stimulation frequency of 15 and 30
Hz was used. Pain, activity, and sleep scores were assessed using a
145
10-cm VAS, with 0 corresponding to the best and 10 to the worst,

during the 48-hour period prior to the beginning of the 2 treatments,
immediately before and after each treatment session, and 48 hours
after completing each treatment modality. Compared with the needles
alone, PENS therapy was significantly more effective in decreasing
the overall VAS pain scores for tension-type headache, migraine and
posttraumatic headache (58%, 59%, and 52% vs. 20%, 15%, and 20%,
respectively). Similarly, PENS therapy produced greater improvement
in the patients' physical activity (41% to 58% for PENS vs. 11% to
21% for needles only) and quality of sleep (41% to 48% for PENS vs.
12% to 20% for needles only). However, there were no differences in
the pattern of the response to PENS therapy among the 3 headache
groups. In conclusion, PENS appears to be a useful complementary
therapy to analgesic and antimigraine drugs for the short-term
management of headache. The analgesic response to PENS therapy
appears to be independent of the origin of the headache symptoms (4).
This sham-controlled study was designed to compare the effect of
3 different frequencies of electrical stimulation on the analgesic
response to PENS therapy. Sixty-eight consenting patients with LBP
secondary to degenerative lumbar disc disease were treated with
PENS therapy at 4 Hz, alternating 15 Hz and 30 Hz (15/30 Hz), and
100 Hz, as well as sham-PENS (0 Hz), according to a randomized,
cross-over study design. Each treatment was administered for a period
of 30 min 3e times per week for 3 weeks. The pre- and posttreatment
assessments included the health status survey short form and VAS for
pain, physical activity, and quality of sleep. The sham-PENS
treatments failed to produce changes in the degree of pain, physical
activity, sleep quality, or daily intake of oral analgesic medications.
By contrast, 4-Hz, 15/30-Hz, and 100-Hz stimulation all produced
significant decreases in the severity of pain, increases in physical
activity, improvements in the quality of sleep, and decreases oral
analgesic requirements (p<0.01). Of the 3 frequencies, 15/30 Hz was
the most effective in decreasing pain, increasing physical activity, and
improving the quality of sleep (p<0.05). Of the patients, 40% reported
that 15/30 Hz was the most desirable therapy, and it was more
effective in improving the patient's sense of well-being. In conclusion,
the frequency of electrical stimulation is an important determinant of
the analgesic response to PENS therapy. Alternating stimulation at 15-
Hz and 30-Hz frequencies was more effective than either 4 Hz or 100
Hz in improving outcome measures in patients with LBP. The
frequency of electrical stimulation seems to be an important
determinant of the analgesic efficacy of PENS. Mixed low- and high-
146
frequency stimulation was more effective than either low or high

frequencies alone in the treatment of patients with LBP (24).
The main objective of this study was to compare the effectiveness
of a novel non-pharmacologic pain therapy, PENS, with TENS and
flexion-extension exercise therapies in patients with long-term LBP. A
randomized, single-blinded, sham-controlled, crossover study from
March 1997 to December 1997 was conducted at an ambulatory pain
management center at a university medical center. Patients included
29 men and 31 women with LBP secondary to degenerative disk
disease. Interventions, including 4 therapeutic modalities (sham-
PENS, PENS, TENS, and exercise therapies), were each administered
for a period of 30 minutes 3 times a week for 3 weeks. Pretreatment
and posttreatment VAS scores for pain, physical activity, and quality
of sleep; daily analgesic medication usage; a global patient assessment
questionnaire; and SF-36 were studied. PENS was significantly more
effective in decreasing VAS pain scores after each treatment than
sham-PENS, TENS, and exercise therapies (after-treatment mean +/-
SD VAS for pain, 3.4 +/- 1.4 cm, 5.5 +/- 1.9 cm, 5.6 +/- 1.9 cm, and
6.4 +/- 1.9 cm, respectively). The average +/- SD daily oral intake of
non-opioid analgesics (2.6 +/- 1.4 pills per day) was decreased to 1.3
+/- 1.0 pills per day with PENS (p<0.008) compared with 2.5 +/- 1.1,
2.2 +/- 1.0, and 2.6 +/- 1.2 pills per day with sham-PENS, TENS, and
exercise, respectively. Compared with the other 3 modalities, 91% of
the patients reported that PENS was the most effective in decreasing
their LBP. The PENS therapy was also significantly more effective in
improving physical activity, quality of sleep, and sense of well-being
(p<0.05 for each). The SF-36 survey confirmed that PENS improved
posttreatment function more than sham-PENS, TENS, and exercise. In
this sham-controlled study, PENS was more effective than TENS or
exercise therapy in providing short-term pain relief and improved
physical function in patients with long-term LBP (25).
Although acupuncture is widely used for chronic pain, there
remains considerable controversy as to its value. The main aim was to
determine the effect size of acupuncture for 4 chronic pain conditions:
back and neck pain, osteoarthritis, chronic headache, and shoulder
pain. A systematic review was conducted to identify RCTs of
acupuncture for chronic pain in which allocation concealment was
determined unambiguously to be adequate. Individual patient data
meta-analyses were conducted using data from 29 of 31 eligible
RCTs, with 17,922 patients analyzed. In the primary analysis,
including all eligible RCTs, acupuncture was superior to both sham
and no-acupuncture control for each pain condition. After exclusion of
147
an outlying set of RCTs that strongly favored acupuncture, the effect

sizes were similar across pain conditions. Patients receiving
acupuncture had less pain, with scores 0.23 (95% CI 0.13 - 0.33), 0.16
(95% CI 0.07 - 0.25), and 0.15 (95% CI 0.07 - 0.24) SDs that were
lower than sham controls for back and neck pain, osteoarthritis, and
chronic headache, respectively; the effect sizes in comparison to no-
acupuncture controls were 0.55 (95% CI 0.51 - 0.58), 0.57 (95% CI
0.50 - 0.64), and 0.42 (95% CI 0.37 - 0.46) SDs. These results were
robust to a variety of sensitivity analyses, including those related to
publication bias. In conclusion, acupuncture is effective for the
treatment of chronic pain and is therefore a reasonable referral option.
Significant differences between true and sham acupuncture indicate
that acupuncture is more than a placebo. However, these differences
are relatively modest, suggesting that factors in addition to the specific
effects of needling are important contributors to the therapeutic effects
of acupuncture (26).
The current study (n = 69) examines the potential impact of
massage therapy in older adults (≥ 60 years) with persistent pain, by
comparing self-reported health outcome scores among those who have
and have not utilized massage therapy in the past year. The current
study was derived from a larger study that collected data as part of a
one-time, self-report, mail-in survey. Lexington, Kentucky area adults,
≥ 60 years who reported persistent pain were eligible to participate in
the study. The RAND 36-Item Health Survey was used to determine
participant HRQL. The current study demonstrated that for older
adults experiencing persistent pain, massage was associated with self-
report of less limitation due to physical or emotional issues, better
emotional health, more energy/less fatigue, better social functioning,
and better overall health. Age, education, cumulative morbidities,
number of areas in which participants reported experiencing persistent
pain, and number of CAM options in addition to massage therapy
utilized in the past year did not affect the association between receipt
of massage and better self-reports in those domains. In conclusion,
while many causes of pain for older adults elude cure, further study is
warranted that examines massage therapy as an intervention to
improve coping in older adults with persistent pain (27).
Assessment: CAM is as a 'group of diverse medical and healthcare

systems, practices and products that are not presently considered to be
part of conventional medicine'. The use of different types of CAM for
chronic pain around the world has increased dramatically in recent
years and is still on the increase. The majority of CAM users reported
that their CAM treatment is effective.
148
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23. Nnoaham KE, Kumbang J. Transcutaneous electrical nerve stimulation
(TENS) for chronic pain. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003222.
doi: 10.1002/14651858.CD003222.pub2.
24. Ghoname ES, Craig WF, White PF, et al. The effect of stimulus frequency on
the analgesic response to percutaneous electrical nerve stimulation in patients with
chronic low back pain. Anesth Analg. 1999;88(4):841-6.
25. Ghoname EA, Craig WF, White PF, et al. Percutaneous electrical nerve
stimulation for low back pain: a randomized crossover study. JAMA.
1999;281(9):818-23. Erratum in: JAMA 1999;281(19):1795.
26. Vickers AJ, Cronin AM, Maschino AC, et al.; for the Acupuncture Trialists'
Collaboration. Acupuncture for Chronic Pain: Individual Patient Data Meta-analysis.
Arch Intern Med. 2012 Sep 10:1-10.
27. Munk N, Kruger T, Zanjani F. Massage therapy usage and reported health in
older adults experiencing persistent pain. J Altern Complement Med. 2011;17(7):609-
16.
MUSIC THERAPY
The use of music as a therapeutic tool in health and medicine dates
back to ancient times. An evaluation of the passages referring to
ancient King Saul‘s health and disturbed behavior indicates that he
was afflicted by a mental disorder. Among many disorders which
could have affected the King, Manic Episode with Psychotic Phases,
Major Depression with Psychotic Features, Mixed Episode, Bipolar
Disorder I, Dysthymic Disorder later developed into Bipolar Disorder,
or Non-Specific Psychotic Disorder are the most likely. Among these
diagnoses, Bipolar Disorder I was found to be the most likely (1).
Here we are dealing with a psychiatric patient. The patient's
medical record (that is the biblical text) tell us that King Saul suffered
from mental distress ―...an evil spirit from the Lord troubled him‖ (I
Samuel 16:14). Fortunately, on hearing the music, the symptoms of
Saul‘s mental distress disappeared ―...David took a harp )‫ )כינור‬and
played with his hand: so Saul was refreshed, and was well, and the
evil spirit departed from him‖ (16:23).
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What does it mean "the evil spirit troubled him"? It can be assumed
that that these biblical words indicate an irritable mood, psychomotor
agitation or retardation, insomnia or hypersomnia, diminished ability
to think or concentrate, sadness, and low concentration. In any case,
regardless of King Saul's symptoms, the music therapy resulted in
significant improvement of his disturbed soul. The wonderful sounds
of the musical instrument calmed him, and he even felt well.
This is an example of a musical therapeutic intervention in an
ancient psychiatric patient (2). In contemporary times, music therapy
is used not only for psychiatric patients. There is a wide range of
diseases in which music therapy can reduce pain.
The understanding of music's role and function in therapy and
medicine is undergoing a rapid transformation, based on
neuroscientific research showing the reciprocal relationship between
studying the neurobiological foundations of music in the brain and
how musical behavior through learning and experience changes brain
and behavior function. Through this research, the theory and clinical
practice of music therapy is changing more and more from a social
science model, based on cultural roles and general well-being
concepts, to a neuroscience-guided model based on brain function and
music perception. This paradigm shift has the potential to move music
therapy from an adjunct modality to a central treatment modality in
rehabilitation and therapy (3).
Neuroscientific and clinical studies of music over the past 2
decades have substantially increased our understanding of its use as a
means of therapy. Neuroscientific studies have shown music to be an
agent capable of influencing complex neurobiological processes in the
brain and suggest that it can potentially play an important role in
treatment. Clinical studies provide some evidence that music therapy
can be used as an alternative therapy in treating depression, autism,
schizophrenia, and dementia, as well as problems of agitation, anxiety,
sleeplessness, and substance misuse, though whether it can actually
replace other modes of treatment remains undetermined (4).
The objective of this study was to assess the usefulness of music
intervention to the management of patients with chronic pain. A
controlled, single blind, randomized trial was used. Eighty-seven
patients presenting with lumbar pain, fibromyalgia, inflammatory
disease, or neurological disease were included in the study. During
their hospitalization, the intervention arm (n=44) received at least 2
daily sessions of music listening between D0 and D10, associated with
their standard treatment, and then pursued the music intervention at
home until D60 using a multimedia player in which the music
151
listening software program had been installed. The control arm

received standard treatment only (n=43). The endpoints measured at
D0, D10, D60, and D90 were: pain (VAS), anxiety-depression
(HADS) and the consumption of medication. At D60 in the music
intervention arm, this technique enabled a more significant reduction
(p<0.001) in pain (6.3 ± 1.7 at D0 vs. 3 ± 1.7 at D60) when compared
with the arm without music intervention (6.2 ± 1.5 at D0 vs. 4.6 ± 1.7
at D60). Music intervention contributed to significantly reducing both
anxiety/depression and the consumption of anxiolytic agents. These
results confirm the value of music intervention to the management of
chronic pain and anxiety/depression. This music intervention method
appears to be useful in managing chronic pain as it enables a
significant reduction in the consumption of medication (5).
The purpose of this study was to investigate the use of music as a
unitary-transformative means of altering the perception of chronic
pain among women with RA within the context of Newman's model
of health as expanding consciousness. In this repeated measures
investigation, 30 women diagnosed with RA for a minimum of 6
months, responded to the MPQ prior to listening to music of their
choice, during music, and 1 to 2 hours after completing the
intervention. The results of this study support the use of music as a
unitary-transformative intervention (6).
Musical interventions have been used in health care settings to
reduce patient pain, anxiety, and stress although the exact mechanism
of these therapies is not well understood. A systematic review of 42
RCTs of the effects of music interventions in perioperative settings
indicates that music intervention had positive effects on reducing
patients' anxiety and pain in approximately half of the reviewed
studies (7).
Osteoarthritis is the most common degenerative disease in humans.
It usually begins in middle age and is progressive. Chronic pain in
older people presents a significant obstacle in maintaining function
and independence. The purpose of this randomized clinical trial was to
examine the influence of music as a nursing intervention on
osteoarthritis pain in elders. Data were collected using the short form
of the MPQ with 66 elders suffering from chronic osteoarthritis pain.
Differences in perceptions of pain were measured over 14 days in an
experimental group who listened to music for 20 minutes daily and a
control group who sat quietly for 20 minutes daily. All participants
completed the Short Form MPQ (SF-MPQ) on day 1, 7, and 14 of the
study. Results of t-tests indicated that those who listened to music had
less pain on both the Pain Rating Index on day 1 (p=0.001), day 7
152
(p=0.001), and day 14 (p=0.001), and on the VAS on day 1 (p=0.001),

day 7 (p=0.001) and day 14 (p=0.001), when compared with those
who sat quietly and did not listen to music. A repeated measure
analysis of variance controlling for pretest measures demonstrated a
significant decrease in pain among experimental group participants
when compared with the control group on the pain descriptor section
of the SF-MPQ (p=0.001) and the visual analogue portion of the SF-
MPQ (p=0.001). In conclusion, listening to music was an effective
nursing intervention for the reduction of chronic osteoarthritis pain in
the community-dwelling elders (8).
This study investigates the effects of music listening on perception
and tolerance of experimentally induced cold pressor pain. Fifty-four
participants (34 females, 20 males) each underwent 3 cold pressor
trials while listening to (a) white noise, (b) specially designed
relaxation music, and (c) their own chosen music. Tolerance time,
pain intensity on VAS, and the pain rating index of the MPQ and
perceived control over the pain were measured in each condition.
While listening to their own preferred music, male and female
participants tolerated the painful stimulus significantly longer than
during both the relaxation music and control conditions. However,
only female participants rated the intensity of the pain as significantly
lower in the preferred music condition. Both male and female
participants reported feeling significantly more control when listening
to their preferred music. In conclusion, personal preference is an
influential factor when considering the efficacy of music listening for
pain relief (9).
The aim of the present study was to evaluate the effects of music
listening on BP, heart rate, and respiratory rate on operation day, and
on the first, second, and third postoperative days in abdominal surgery
patients. Abdominal surgery patients (n=169) were assigned every
second week to the music group (n=83) or to the control group (n=85)
for 25 months. In the music group, the respiratory rate was
significantly lower after intervention on both the first and second
postoperative days compared with the control group. A significant
reduction in systolic BP was demonstrated in the group that received
music compared with the control group on both the first and second
postoperative days. Evaluation of the long-term effects of music on
physiological factors showed that the respiratory rate in the music
group was significantly lower compared with the control group (10).
This paper reviews the use of music as an adjuvant to the control of
pain, especially in medical procedures. Surgery causes stress and
anxiety that exacerbates the experience of pain. Self-report of and
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physiological measures on post-surgical patients indicate that music

therapy or music stimulation reduces the perception of pain, both
alone and when part of a multimodal pain management program, and
can reduce the need for pharmaceutical interventions. However,
multimodal pain therapy, including non-pharmacological interventions
after surgery, is still rare in medical practice. Musical pieces chosen
by the patient are commonly, but not always, more effective than
pieces chosen by another person. Further research should focus both
on finding the specific indications and contra-indications of music
therapy and on the biological and neurological pathways responsible
for those findings (related evidence has implicated brain opioid and
oxytocin mechanisms in affective changes evoked by music). In turn,
these findings will allow medical investigators and practitioners to
design guidelines and reliable, standardized applications for this
promising method of pain management in modern medicine (11).
The main aim of this study was to describe the use of music as
intervention in painful conditions as experienced by people in five
Asian countries: China, Thailand, Philippines, South Korea and
Taiwan. Twelve studies, including theses and dissertations, published
and unpublished, were found; however, only nine met the inclusion
criteria. Data were categorized according to research design, sample
size, gender, age, duration of music, frequency of music intervention,
types of pain and instruments used to measure pain, conceptual or
theoretical frameworks and statistical significance of the study. Five
of the 9 studies declared significant decrease in pain, while 3 reported
mixed results. Fundamentally, the findings of the studies suggested
that with music, relief of pain was possible (12).
Assessment: music is useful in managing chronic pain and it

enables a significant reduction in the consumption of medication.
Musical interventions reduce patient pain, anxiety, and stress.
Listening to music is an effective nursing intervention for the
reduction of chronic osteoarthritis pain in the community-dwelling
elders. Personal preference is an influential factor when considering
the efficacy of music listening for pain relief.
References
1. Ben-Noun L. What was mental disease that afflicted King Saul? Clinical Case
Studies. 2003;2:4-7.
2. Ben-Nun L. Music Therapy in the Bible. In Ben-Nun L. ed. Research in
Biblical Times from the Viewpoint of Contemporary Medicine. Israel. B.N.
Publications. Israel. 2013, pp. 120-7.
3. Thaut MH. The future of music in therapy and medicine. Ann N Y Acad Sci.
2005;1060:303-8.
154
4. Lin ST, Yang P, Lai CY, et al. Mental health implications of music: insight
from neuroscientific and clinical studies. Harv Rev Psychiatry. 2011;19(1):34-46.
5. Guétin S, Giniès P, Siou DK, et al. The effects of music intervention in the
management of chronic pain: a single-blind, randomized, controlled trial. Clin J Pain.
2012;28(4):329-37.
6. Schorr JA. Music and pattern change in chronic pain. ANS Adv Nurs Sci.
1993;15(4):27-36.
7. Nilsson U. The anxiety- and pain-reducing effects of music interventions: a
systematic review. AORN J. 2008;87(4):780-807.
8. McCaffrey R, Freeman E. Effect of music on chronic osteoarthritis pain in
older people. J Adv Nurs. 2003;44(5):517-24.
9. Mitchell LA, MacDonald RA. An experimental investigation of the effects of
preferred and relaxing music listening on pain perception. J Music Ther.
2006;43(4):295-316.
10. Vaajoki A, Kankkunen P, Pietilä AM, et al. Music as a nursing intervention:
effects of music listening on blood pressure, heart rate, and respiratory rate in
abdominal surgery patients. Nurs Health Sci. 2011;13(4): 412-8.
11. Bernatzky G, Presch M, Anderson M, Panksepp J. Emotional foundations of
music as a non-pharmacological pain management tool in modern medicine. Neurosci
Biobehav Rev. 2011;35(9):1989-99.
10. Lim PH, Locsin R. Music as nursing intervention for pain in five Asian
countries. Int Nurs Rev. 2006;53(3):189-96.
PHARMACOTHERAPY
"Pain ladder" is a term coined by the WHO to describe its
guideline for the use of drugs in the management of pain. It was
originally applied to the management of cancer pain, but is now
widely used by medical professionals for the management of all types
of pain. The general principle is to start with first step drugs, and then
to climb the ladder if pain is still present. The medications range from
household, OTC drugs with minimal side effects at the lowest rung to
powerful opioids. The WHO guidelines (1,2) recommend prompt oral
administration of drugs when pain occurs, starting, if the patient is not
in severe pain, with non-opioid drugs such as paracetamol
(acetaminophen), dipyrone, NSAIDs or COX-2 inhibitors. Then, if
complete pain relief is not achieved or disease progression
necessitates more aggressive treatment, a mild opioid such as codeine
phosphate, dextropropoxyphene, dihydrocodeine, or tramadol are
added to the existing non-opioid regime. If this is or becomes
insufficient, a mild opioid is replaced by a stronger opioid, such as
morphine, diamorphine (heroin), fentanyl, buprenorphine,
oxymorphone, oxycodone, hydromorphone, while continuing the non-
opioid therapy, escalating opioid dose until the patient is pain free or
155
at the maximum possible relief without intolerable side effects. If the

initial presentation is severe pain, this stepping process should be
skipped and a strong opioid should be started immediately in
combination with a non-opioid analgesic (3).
Table. Commonly used analgesics and adjuvants (6).

Generic Names Suggested Starting Dosage* Dosing Interval
NSAIDs
Acetaminophen 650 mg PO** q** 4–6 h
Aspirin 650 mg PO q 4–6 h
Ibuprofen 400–600 mg PO q6h
Ketorolac 30 mg IV** q6h
Naproxen 250 mg PO q 12 h
Anticonvulsant agents
Carbamazepine 200 mg PO q 12 h
Clonazepam 0.5 mg PO q 8–12 h
Gabapentin 100 mg PO q8h
Phenytoin 300 mg PO at bedtime
Valproic acid 250 mg PO q 12 h
Antidepressant agents
Amitriptyline 10–25 mg PO at bedtime
Desipramine 10–25 mg PO in the morning
Imipramine 10–25 mg PO at bedtime
Nortriptyline 10–25 mg PO at bedtime
Paroxetine 20 mg PO in the morning
Local anesthetic (and
antiarrhythmic) agent
Mexiletine 150 mg PO q8h
Single-entity opioid
analgesic agents
Fentanyl 25 μg/h (patch) q3d
Hydrocodone 20 mg PO q4h
Hydromorphone 8 mg PO or 1.5–2 mg IV q4h
Meperidine 75 mg IV q3h
Morphine 10 mg IV or 30 mg PO q4h
Oxycodone 15–20 mg PO q4h
*There is considerable interpatient variability when making equianalgesic
conversions between agents in the same group. It is therefore advisable to convert
patients to only 50% to 75% of the equianalgesic dosages. Maximum daily doses must
be identified before starting treatment and should be adjusted downward for elderly,
fragile, or significantly ill patients, especially those with underlying hepatic or renal
dysfunction.
**PO = orally; q = every; IV = intravenously.
In spite of outstanding advances in pain management over the past

decades, chronic pain remains a significant problem. The usual
approach to treat mild to moderate pain is to start with a non-opioid
analgesic. If this is inadequate, and if there is an element of sleep
deprivation, then it is reasonable to add an antidepressant with
156
analgesic qualities. If there is a component of neuropathic pain or

fibromyalgia, then a trial with one of the gabapentinoids is
appropriate. If these steps are inadequate, then an opioid analgesic
may be added. For moderate to severe pain, one would initiate an
earlier trial of a long-term opioid (4).
NSAIDs are commonly taken orally, but they are also available in
topical preparations to be applied to or rubbed onto the skin of a
painful joint, typically one affected by arthritis, with the aim of
relieving pain locally. Topical NSAIDs are widely used in some parts
of the world for acute and chronic painful conditions, but have not
been universally accepted until recently (5).
The main objective of this study was to examine the use of topical
NSAIDs in chronic musculoskeletal pain, focusing on studies of high
methodological quality, and examining the measured effect of the
preparations according to study duration. The principal aim was to
estimate treatment efficacy in longer duration studies of at least 8
weeks. A series of electronic searches, together with bibliographic
searches, and searches of in-house databases were combined with
electronic searches of clinical trial registers and manufacturers of
topical NSAIDs, or companies known to be actively researching
topical NSAIDs. There had to be at least 10 participants in each
treatment arm, with application of treatment at least once daily.
Randomized, double blind studies with placebo or active comparators,
where at least 1 treatment was a topical NSAID product, in any topical
formulation (cream, gel, patch, or solution), in studies lasting at least 2
weeks were included. Two review authors independently assessed
study quality and validity, and extracted data. Numbers of participants
achieving each outcome were used to calculate RR and NNT or NNH
compared to placebo or other active treatment. Information was
available from 7688 participants in 34 studies from 32 publications;
23 studies compared a topical NSAID with placebo. Topical NSAIDs
were significantly more effective than placebo for reducing pain due
to chronic musculoskeletal conditions. The best data were for topical
diclofenac in osteoarthritis, where the NNT for at least 50% pain relief
over 8 to 12 weeks compared with placebo was 6.4 for the solution,
and 11 for the gel formulation. There were too few data of good
quality to calculate NNTs for other individual topical NSAIDs
compared with placebo. Direct comparison of topical NSAID with an
oral NSAID did not show any difference in efficacy. There was an
increase in local AEs (mostly mild skin reactions) with topical
NSAIDs compared with placebo or oral NSAIDs, but no increase in
serious AEs. G-I AEs with topical NSAID did not differ from placebo,
157
but were less frequent than with oral NSAID. In conclusion, topical
NSAIDs can provide good levels of pain relief; topical diclofenac
solution is equivalent to that of oral NSAIDs in knee and hand
osteoarthritis, but there is no evidence for other chronic painful
conditions. Formulation can influence efficacy. The incidence of local
AEs is increased with topical NSAIDs, but G-I AEs are reduced
compared with oral NSAIDs (5).
The comparative safety of non-selective NSAIDs, selective
cyclooxygenase 2 inhibitors (coxibs), and opioids were examined.
Medicare beneficiaries from Pennsylvania and New Jersey who
initiated therapy with non-selective NSAID, a coxib, or an opioid
from January 1, 1999, through December 31, 2005, were matched on
propensity scores. The risk of AEs related to analgesics using
incidence rates and adjusted HRs from Cox proportional hazards
regression were studied. The mean age of participants was 80.0 years,
and almost 85% were female. After propensity score matching, the 3
analgesic cohorts were well balanced on baseline covariates.
Compared with non-selective NSAIDs, coxibs (HR 1.28, 95% CI 1.01
- 1.62) and opioids (1.77, 1.39 - 2.24) exhibited elevated relative risk
for C-V events. G-I tract bleeding risk was reduced for coxib users
(HR 0.60, 95% CI 0.35 - 1.00) but was similar for opioid users. Use of
coxibs and nonselective NSAIDs resulted in a similar risk for fracture;
however, fracture risk was elevated with opioid use (HR 4.47, 95% CI
3.12 - 6.41). Use of opioids (HR 1.68, 95% CI 1.37 - 2.07) but not
coxibs was associated with an increased risk for safety events
requiring hospitalization compared with use of nonselective NSAIDs.
In addition, use of opioids (HR 1.87, 95 CI 1.39 - 2.53) but not coxibs
raised the risk of all-cause mortality compared with use of
nonselective NSAIDs. In conclusion, the comparative safety of
analgesics varies depending on the safety event studied. Opioid use
exhibits an increased relative risk of many safety events compared
with NSAIDs (7).
The UK's NICE recommends considering patient risk factors when
selecting a non-selective NSAID or COX-2 inhibitor, but GPs have
lacked practical guidance on assessing patient risk. A multi-
disciplinary group that included PCPs developed an evidence-based
consensus statement with an accompanying flowchart that aimed at
providing concise and specific guidance on NSAID use in
osteoarthritis treatment. In South Yorkshire, a round table meeting
was held that used a modified nominal group technique, aimed at
generating opinions and ideas from all stakeholders in the consensus
process. A draft developed from this meeting went through successive
158
revisions until a consensus was achieved. Four statements on the use

of non-selective NSAIDs and Coxibs (and an attached category of
evidence) were agreed: 1) non-selective NSAIDs are effective drugs
in relieving pain and immobility associated with osteoarthritis. Coxibs
are equally effective; 2) non-selective NSAIDs and Coxibs vary in
their potential G-I, liver, and cardio-renal toxicity. This risk varies
between individual treatments within both groups and is increased
with dose and duration of treatment; 3) Coxibs are associated with a
significantly lower G-I toxicity compared to non-selective NSAIDs.
Co-prescribing of aspirin reduces this advantage; 4) Proton pump
inhibitors should always be considered with non-selective NSAIDs
and with Coxibs in higher GI risk patients. In conclusion, individual
patient risk is an important factor in choice of treatment for patients
with osteoarthritis and the consensus statement developed offers
practical guidance for GPs and others in primary care. Where there are
clinical uncertainties, guidance developed and agreed by local
clinicians has a role to play in improving patient management (8).
Although paracetamol and NSAIDs play a continuing role in the
treatment of chronic rheumatic diseases, accumulating evidence of
potential toxicity with both traditional non-selective NSAIDs and
Coxibs has prompted a reassessment of their use. This has particular
resonance for the elderly, who are more likely to have significant pain
issues than younger patients and are at high risk of NSAID-related
AEs (9).
References
1. World Health Organization. Cancer pain relief. With a guide to opioid
availability (2 ed.). Geneva: WHO. 1996. ISBN 92-4-154482-1.
2. World Health Organization. Cancer pain relief and palliative care in children.
Geneva: WHO. 1998. ISBN 978-92-4-154512-9.
3. Schug SA & Auret K. Clinical pharmacology: Principles of analgesic drug
management. In: Sykes N, Bennett MI & Yuan C-S. Clinical Pain Management:
Cancer Pain. 2nd ed. London: Hodder Arnold.. ISBN 978-0-340-94007-5. 2008, pp.
104–22.
4. Park HJ, Moon DE. Pharmacologic management of chronic pain. Korean J
Pain. 2010;23(2):99-108.
5. Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal
pain in adults. Cochrane Database Syst Rev. 2012;9:CD007400.
7. Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of analgesics
in older adults with arthritis. Arch Intern Med. 2010;170(22): 1968-76. Erratum in:
Arch Intern Med. 2011;171(5):403.
159
8. Adebajo A. Non-steroidal anti-inflammatory drugs for the treatment of pain and

immobility-associated osteoarthritis: consensus guidance for primary care. BMC Fam
Pract. 2012 Mar 20;13:23.
chronic pain in important patient subgroups. Clin Drug Investig. 2012 Feb 22;32
Suppl 1:35-44
OPIOID ANALGETICS
Opioid analgesics have been used increasingly over the past 20
years for the management of chronic non-cancer pain in the US under
the assumption that they were safe and effective when used as
directed. The accuracy of that assumption has not been tested against
accumulated evidence. The safety of opioids used on a long-term basis
has not been tested in clinical trials. Epidemiologic evidence from
examinations of such use in the general population indicates that the
risk of overdose increases in a dose-response manner. Such evidence
also suggests increased risk of fractures and acute MI among elderly
users of opioids for chronic pain. Experimental evidence supports
short-term use of opioids, but trials of long-term use for chronic pain
have not been conducted. Epidemiologic evidence suggests that long-
term use does not result in improvement in function or QOL while
being associated with significant dropout rates and a high prevalence
of adverse drug effects. Substantial fractions of patients are not using
opioid analgesics as directed, while millions of US residents are using
them without a prescription for nonmedical reasons. A prudent
treatment approach consistent with the available evidence would be to
reserve chronic opioid therapy for serious pain-related problems for
which the effectiveness of opioids has been demonstrated and for
patients whose use as directed is assured through close monitoring and
for whom an explicit, informed calculation has been made that the
benefits of opioids outweigh the risks (1).
Opioids are broad spectrum analgesics that may be beneficial to
alleviate the intense perception of algesia in patients suffering with
pain. They have been one of the most controversial analgesics, in part
because of their potential for addiction. Opioids or any currently
available analgesic will not provide effective analgesia for every
patient with chronic neuropathic pain, but overall opioids are a second
or third line class of analgesics that may provide reasonable analgesia
to some patients with chronic neuropathic pain. Although opioids may
alleviate chronic neuropathic pain, overall, neuropathic pain tends to
160
be less opioid responsive than nociceptive pain. The mechanisms that

may contribute to neuropathic pain may simultaneously contribute to
diminishing the antinociceptive properties of opioids for neuropathic
pain. Some of these mechanisms also contribute to analgesic tolerance
and/or opioid-induced hyperalgesia. Hyperalgesia consequently to
nerve insult and opioid-induced analgesic tolerance may both involve
the NMDA receptor and share part of intracellular events producing a
state of neural hyperexcitation. Conversely, opioid therapy may
contribute to nociceptive processes that may be involved in
neuropathic pain such as opioid-induced cholecystokinin release.
Furthermore, within neuropathic pain, peripheral neuropathic pain
appears to be the most opioid responsive, followed by spinal
neuropathic pain while supraspinal neuropathic pain tends to be the
least responsive to opioids. Although, there is no robust evidence that
any specific opioid agent is better than any other opioid at effectively
treating neuropathic pain, it is conceivable that some opioids/opioid-
like analgesic agents may be particularly well suited to alleviate
neuropathic pain (2).
The present article contains 17 case reports of 11 chronic non-
cancer pain conditions (followed to 2011) selected to illustrate
specific issues from a survey of 84 patients with intractable chronic
non-cancer pain treated with opioids and followed every 3 months for
a median of 11 years. The previous published survey of this group
reported outcomes of pain severity, AEs, pain relief, satisfaction,
mood, problematic opioid use, tolerance, physical dependency,
functional status, HRQL, immune status and sexual function. The
outcome measures for that study included a NPRS, the HADS, the BPI
Inventory Interference Scale, the PDI and, for HRQL, the SF Health
Survey 12 version two. Most patients in the total sample reported 50%
or greater relief and a moderate improvement in disability. Scores for
functional status and HRQL were not severely affected. Problematic
use, tolerance and serious AEs, including constipation, were not major
issues. These selected patient reports were chosen not to illustrate
optimal results, but rather important aspects of the diagnoses, opioids
and doses, the paucity of intolerable AEs, particular issues (concurrent
addiction history, bipolar disorder and combination therapy), disease-
specific and other outcomes and duration of follow-up with complex
pain problems. Opioids were safe and useful in the long term for these
particular patients, as well as in the larger group from which they
originated. These 17 reports of patients with intractable chronic non-
cancer pain treated with opioids with some success over many years
puts a face on more of the participants in the larger survey of 84
161
subjects, suggesting that this approach is effective and safe for some
patients over many years (3).
A propensity-matched cohort analysis that used health care
utilization data collected from January 1, 1996, through December 31,
2005, was devised. Study participants were Medicare beneficiaries
from US who were new initiators of opioid therapy for non-malignant
pain, including codeine phosphate, hydrocodone bitartrate, oxycodone
hydrochloride, propoxyphene hydrochloride, and tramadol
hydrochloride; none had a cancer diagnosis, and none were using
hospice or nursing home care. Main outcome measures were incidence
rates and rate ratios with 95% CIs for C-V events, fractures, G-I
events, and several composite end points. Subjects (n=6275) were
matched in each of the 5 opioid groups. The groups were well
matched on baseline characteristics. The risk of C-V events was
similar across opioid groups 30 days after the start of opioid therapy,
but it was elevated for codeine (rate ratio 1.62, 95% CI 1.27 - 2.06)
after 180 days. Compared with hydrocodone, after 30 days of opioid
exposure the risk of fracture was significantly reduced for tramadol
(0.21, 95% CI 0.16 - 0.28) and propoxyphene (0.54, 0.44 - 0.66) users.
The risk of G-I safety events did not differ across opioid groups. All-
cause mortality was elevated after 30 days for oxycodone (2.43, 95%
CI 1.47 - 4.00) and codeine (2.05, 1.22 - 3.45) users compared with
hydrocodone users. In conclusion, the rates of safety events among
older adults using opioids for non-malignant pain vary significantly by
agent. Causal inference requires experimental designs, but these
results should prompt caution and further study (4).
The main objective of this study was to review, synthesize, and
summarize recent evidence on AEs of long-term opioid treatment for
non-cancer pain and present an organ system-based guide for primary
care physicians in initiating and monitoring patients receiving chronic
opioid therapy. A search for studies published in peer-reviewed
journals from 2005 to 2011 was conducted using MEDLINE, Agency
for Healthcare Research and Quality Clinical Guidelines and Evidence
Reports, and the Cochrane Database of Systematic Reviews. Related
citations and expert recommendations were included. Studies were
selected if the search terms opioid and the organ system of interest
were in the article's title, abstract, or text. Systems considered were
G-I, respiratory, C-V, CNS, musculoskeletal, endocrine, and immune.
Of 1,974 initially reviewed articles, 74 were selected for evidence
regarding effects of chronic opioid use on that organ system. Of these
articles, 43 were included based on direct relevance to opioid
prescriptions in the primary care setting. Through a variety of
162
mechanisms, opioids cause AEs in several organ systems. Evidence

shows that chronic opioid therapy is associated with constipation,
sleep-disordered breathing, fractures, hypothalamic-pituitary-adrenal
dysregulation, and overdose. However, significant gaps remain
regarding the spectrum of potentially opioid-related AEs. Opioid-
related AEs can cause significant declines in HRQL and increased
health care costs. In conclusion, the diverse AEs potentially caused by
chronic opioid therapy support recommendations for judicious and
selective opioid prescribing for chronic non-cancer pain by primary
care physicians (5).
The use of mild opioids, such as codeine and tramadol, and strong
opioids, such as morphine, hydromorphone and oxycodone, may be
appropriate where paracetamol and other non-opioid analgesics are
ineffective in chronic non-cancer pain. Cancer pain, either related to
the underlying disease or caused by cancer treatment, is also a
common cause of chronic pain in the elderly. An understanding of
individual needs is essential in providing adequate pain relief, which
is a central goal of care in all patients with chronic pain (6).
The main objective of this study was to evaluate whether opioid
use for non-cancer pain increases the risk of MI among adults. This
nested case-control study was conducted using UK General Practice
Research Database. Among 1.7 million opioid users during 1990-
2008, 11,693 incident MI cases aged 18-80 years were identified, and
randomly selected up to 4 controls matched by age, gender, index date
(date of onset symptoms or diagnosis of first-ever MI), and general
practice via risk-set sampling. Cases and controls were required to
have no cancer and no major risk factors for MI before the index date.
Compared with non-use, current use of opioids was associated with a
1.28-fold (95% CI 1.19 - 1.37) risk of MI. Cumulative use of opioids
with 11-50 (AOR 1.38, 95% CI 1.28 - 1.49) or > 50 (AOR 1.25, 95%
CI 1.11 - 1.40) prescriptions, was also marginally associated with
increased risk of MI. The risk was particularly increased in users of
morphine (AOR 1.71, 95% CI 1.09 - 2.68), meperidine (AOR 2.15,
95% CI 1.24 - 3.74), and polytherapy (OR 1.46, 95% CI 1.22 - 1.76).
In conclusion, current use of any opioids and cumulative use of 11 or
more prescriptions are associated with a small increased risk for MI
compared to non-use and the risk was greater in morphine, meperidine
and polytherapy users (7).
Tapentadol hydrochloride (Nucynta), an orally active, centrally
acting synthetic analgesic, exerts its analgesic effects via 2
mechanisms of action (mu-opioid receptor agonism and
norepinephrine reuptake inhibition) (8). This relatively new opioid is a
163
centrally acting oral analgesic approved by the US Food and Drug

Administration in November 2008 for the treatment of moderate to
severe acute pain (9).
Tapentadol is available as immediate-release 50-, 75-, and 100-mg
tablets. The purpose of this article is to review animal studies,
pharmacokinetic studies, drug-drug interaction studies, and Phase
II/III trials of tapentadol in various conditions producing moderate to
severe pain. Efficacy and tolerability data from these studies are
summarized. A search of MEDLINE and International Pharmaceutical
Abstracts was conducted from January 2005 through June 30, 2009.
Search terms included tapentadol, tapentadol hydrochloride, and (-)-
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydro-
chloride. Relevant information was extracted from the identified
articles, and the reference lists of these articles were reviewed for
additional pertinent publications. The manufacturer was contacted for
clinical trials, abstracts, and poster presentations that were not
identified by the literature search. ClinicalTrials.gov was searched to
identify recently completed studies. Tapentadol produces analgesia
through a dual mechanism of action: mu-opioid-receptor activation
and norepinephrine reuptake inhibition. Its efficacy has been reported
in a number of animal studies, as well as in Phase II/III clinical trials.
Primary pain disorders in which efficacy has been reported include
dental extraction pain, pain after bunionectomy surgery, osteoarthritis
pain of the knee and hip, and LBP. Major AEs reported in Phase II/III
trials primarily involved the G-I system (2-66% of subjects) and the
CNS (4-65% of subjects). The occurrence of G-I adverse effects
appeared to be less frequent in tapentadol recipients than in those
receiving oxycodone. In conclusion, tapentadol appears to be a well-
tolerated and effective analgesic for the treatment of moderate to
severe acute pain. Although not currently approved for the
management of chronic pain, tapentadol has been reported to be
effective in managing pain associated with osteoarthritis and LBP (9).
In the US, the IR formulation of the drug is approved for the relief
of moderate to severe acute pain in patients aged ≥ 18 years. In the
EU, the drug is currently in the marketing authorization process. In
clinical trials in patients with moderate to severe acute
(postorthopaedic surgical or musculoskeletal) pain, recommended
regimens of tapentadol IR (50-100 mg every 4-6 hours) provided an
analgesic effect that was superior to that of placebo, and non-inferior
or similar to that of oxycodone IR (10 or 15 mg every 4-6 hours).
Tapentadol IR therapy was generally well tolerated; it was associated
with significant reductions in the incidences of nausea, vomiting and
164
constipation compared with oxycodone IR therapy. Thus, tapentadol

IR is an effective treatment option for the management of moderate to
severe acute pain. However, further studies evaluating its clinical
utility in relation to that of tramadol and opioids other than oxycodone
are warranted. Because tapentadol IR offers the prospect of reduced
opioid-related G-I AEs while maintaining adequate analgesia, it is a
potentially valuable addition to the analgesic armamentarium (8).
Tramadol/paracetamol 37.5 mg/325 mg (Tramacet, Zaldiar,
Ixprim, Kolibri) is an orally administered fixed-dose combination of
the atypical opioid tramadol and paracetamol, which is indicated in
the EU for the symptomatic treatment of moderate to severe pain.
Fixed-dose tramadol/paracetamol is a rapidly-acting, longer-duration,
multimodal analgesic, which is effective and generally well tolerated
in patients with moderate to severe pain. In several well designed,
clinical studies, single- or multiple-dose tramadol/paracetamol was
effective in providing pain relief in adult patients with postoperative
pain after minor surgery, musculoskeletal pain (acute, subacute or
chronic), painful DPN, or migraine pain. It was also effective as an
add-on analgesic in patients who were experiencing moderate to
severe musculoskeletal pain (e.g. osteoarthritis or RA pain) despite
ongoing NSAID and/or disease-modifying antirheumatic drug
therapy. Moreover, in patients with postoperative pain, ankle sprain
pain or subacute LBP, the analgesic efficacy of tramadol/paracetamol
was better than that of paracetamol, generally similar to, or better than
that of tramadol and generally similar to that of ibuprofen or the fixed-
dose combinations - hydrocodone/paracetamol, codeine/paracetamol
and codeine/paracetamol/ibuprofen. In addition, the analgesic efficacy
of tramadol/paracetamol did not differ significantly from that of
gabapentin in patients with chronic pain associated with DPN.
Tramadol/paracetamol had no additional tolerability issues relative to
its components and, overall, the tolerability profile of
tramadol/paracetamol was generally similar to that of other active
comparators (fixed-dose combinations or single-agents); however,
incidences of some AEs were lower in tramadol/paracetamol than in
active comparator recipients. Although additional comparative and
long-term studies would help to definitively position
tramadol/paracetamol with respect to other analgesics, available
clinical data suggest that tramadol/paracetamol is a useful treatment
option for providing multimodal analgesia in patients with moderate
to severe pain (10).
165
References
1. Ballantyne JC. Safe and effective when used as directed: the case of chronic use
of opioid analgesics. J Med Toxicol. 2012;8(4):417-23.
2. Smith HS. Opioids and neuropathic pain. Pain Physician. 2012;15(3
Suppl):ES93-110.
3. Watson CP. Opioids in chronic noncancer pain: more faces from the crowd.
Pain Res Manag. 2012;17(4):263-75.
4. Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of opioids
for nonmalignant pain in older adults. Arch Intern Med. 2010;170(22):1979-86.
5. Baldini A, Von Korff M, Lin EH. A Review of Potential Adverse Effects of
Long-Term Opioid Therapy: A Practitioner's Guide. Prim Care Companion CNS
Disord. 2012;14(3). pii: PCC.11m01326.
44.
7. Li L, Setoguchi S, Cabral H, Jick S. Opioid use for non-cancer pain and risk of
myocardial infarction among adults. J Intern Med. 2013;273(5):511-26.
8. Wade WE, Spruill WJ. Tapentadol hydrochloride: a centrally acting oral
analgesic. Clin Ther. 2009;31(12):2804-18.
9. Frampton JE. Tapentadol immediate release: a review of its use in the treatment
of moderate to severe acute pain. Drugs. 2010;70(13):1719-43.
10. Dhillon S. Tramadol/paracetamol fixed-dose combination: a review of its use
in the management of moderate to severe pain. Clin Drug Investig. 2010;30(10):711-
38. Erratum in Clin Drug Investig. 2010;30(12):866.
OPIOID ABUSE
Opioid abuse has continued to increase at an alarming rate since
the 1990s. As documented by different medical specialties, medical
boards, advocacy groups, and the Drug Enforcement Administration
available evidence suggests a wide variance in chronic opioid therapy
of 90 days or longer in chronic non-cancer pain. The objectives of
opioid guidelines issued by the American Society of Interventional
Pain Physicians provide guidance for the use of opioids for the
treatment of chronic non-cancer pain, to produce consistency in the
application of an opioid philosophy among the many diverse groups
involved, to improve the treatment of chronic non-cancer pain, and to
reduce the incidence of abuse and drug diversion. The focus of these
guidelines is to curtail the abuse of opioids without jeopardizing non-
cancer pain management with opioids. 1] There is good evidence that
non-medical use of opioids is extensive; one-third of chronic pain
patients may not use prescribed opioids as prescribed or may abuse
them, and illicit drug use is significantly higher in these patients. 2]
There is good evidence that opioid prescriptions are increasing
166
rapidly, as the majority of prescriptions are from non-pain physicians,

many patients are on long-acting opioids, and many patients are
provided with combinations of long-acting and short-acting opioids.
3] There is good evidence that the increased supply of opioids, use of
high dose opioids, doctor shoppers, and patients with multiple
comorbid factors contribute to the majority of the fatalities. 4] There is
fair evidence that long-acting opioids and a combination of long-
acting and short-acting opioids contribute to increasing fatalities and
that even low-doses of 40 mg or 50 mg of daily morphine equivalent
doses may be responsible for ED admissions with overdoses and
deaths. 5] There is good evidence that approximately 60% of fatalities
originate from opioids prescribed within the guidelines, with
approximately 40% of fatalities occurring in 10% of drug abusers. 6)
The short-term effectiveness of opioids is fair, whereas the long-term
effectiveness of opioids is limited due to a lack of long-term (> 3
months) high quality studies, with fair evidence with insignificant
difference between long-acting and short-acting opioids. 7] Among
the individual drugs, most opioids have fair evidence for short-term
and limited evidence for long-term due to a lack of quality studies. 8]
The evidence for the effectiveness and safety of chronic opioid
therapy in the elderly for chronic non-cancer pain is fair for short-term
and limited for long-term due to lack of high quality studies; limited in
children and adolescents and patients with comorbid psychological
disorders due to lack of quality studies; and the evidence is poor in
pregnant women. 9] There is limited evidence for reliability and
accuracy of screening tests for opioid abuse due to lack of high quality
studies. 10] There is fair evidence to support the identification of
patients who are non-compliant or abusing prescription drugs or illicit
drugs through urine drug testing and prescription drug monitoring
programs, both of which can reduce prescription drug abuse or doctor
shopping (1).
Prescription opioid analgesic therapy can be effective in managing
chronic non-cancer pain in appropriately selected patients. However,
the risks and benefits of prescription opioids should be carefully
considered when treating this patient population. A dramatic increase
in opioid-related morbidity and mortality has been observed in the US
in the past decade. Therefore, health care providers must balance the
treatment of chronic pain with the need to minimize the risks of opioid
misuse, abuse, addiction, and diversion. Most patients with chronic
pain are managed at the primary care level. However, many of these
practitioners are not skilled in risk assessment, stratification, and
monitoring. Abuse-deterrent, extended-release opioid formulations to
167
reduce risk in patients and nonmedical users of opioids may

effectively reduce opioid misuse, abuse, and diversion without
denying adequate analgesia in appropriate patients (2).
Both chronic pain and prescription opioid abuse are prevalent and
continue to exact a heavy toll on patients, physicians, and society.
Individuals with chronic pain and co-occurring substance use
disorders and/or mental health disorders are at a higher risk for misuse
of prescribed opioids. Opioid abuse and misuse occurs for a variety of
reasons, including self-medication, use for reward, compulsive use
because of addiction, and diversion for profit. Treatment approaches
that balance treating chronic pain while minimizing risks for opioid
abuse, misuse, and diversion are much needed. The use of chronic
opioid therapy for chronic non-cancer pain has increased dramatically
in the past 2 decades in conjunction with a marked increase in the
abuse of prescribed opioids and accidental opioid overdoses.
Consequently, a validated screening instrument that provides an
effective and rational method of selecting patients for opioid therapy,
predicting risk, and identifying problems once they arise could be of
enormous benefit. Such an instrument could potentially curb the risk
of iatrogenic addiction. Although several screening instruments and
strategies have been introduced in the past decade, there is no single
test or instrument that can reliably and accurately predict patients who
are not suitable for opioid therapy or identify those who need
increased vigilance or monitoring during therapy. At present screening
for opioid abuse includes assessment of premorbid and comorbid
substance abuse; assessment of aberrant drug-related behaviors; risk
factor stratification; and utilization of opioid screening tools. Urine
drug testing, monitoring of prescribing practices, prescription
monitoring programs, opioid treatment agreements, and utilization of
universal precautions are essential. Presently, a combination of
strategies is recommended to stratify risk, identify and understand
aberrant drug related behaviors, and tailor treatments accordingly (3).
Chronic pain is pain that persists past the normal time of healing,
and is a common problem with a significant socioeconomic impact.
Pharmacological management for chronic non-cancer pain also
involves the prescription of opioids, with the aim of an improved
quality of life for the patient. New guidelines have been published to
aid prescribing clinicians improve opioid safety and patient care, and
include recommendations on when to refer patients to a pain
specialist. In recent years, there has been a rapid increase in opioid
prescription in the UK and US, prompting further concern regarding
opioid abuse and side effects. Opioid use may also result in physical
168
dependence and tolerance. Earlier recognition and diagnosis of

unwanted effects of long-term opioid use is needed, such as opioid
induced suppression of the hypothalamic-pituitary-gonadal axis, and
opioid induced immunosuppression. Patients may themselves
discontinue opioids, however, due to minor side effects. Recent
advances in opioid prescription include the increasing use of
transdermal preparations and extended release, oral, once daily
preparations. New formulations of existing drugs have been
developed, as well as a new chemical entity. Abuse deterrent
formulations and delivery systems may prevent the artificial
acceleration of drug delivery and reduce the potential for opioid
addiction. Overdose concerns and the potential for fatal overdose may
necessitate mandatory training for all clinicians who prescribe opioids.
Despite the widespread use of opioids in the management of chronic
non-cancer pain, significant research gaps remain. An improvement in
the evidence base for its prescription is required (4).
Health care professionals must balance aggressive treatment of
chronic pain with the need to minimize the risks of opioid abuse,
misuse, and diversion. A thorough, ongoing assessment can help
fashion a multimodal therapeutic plan, stratify patients by risk, and
identify those who may exhibit aberrant behaviors after receiving
opioid therapy. Appropriate safeguards (e.g., urine drug screens, pill
counts) may be used when necessary. Because not all aberrant
behaviors have the same origins or implications, physicians must
consider a differential diagnosis and tailor therapy accordingly.
Opioid formulations designed to deter and resist abuse are currently in
late-stage clinical development and address some but not all aspects of
inappropriate opioid use. By incorporating physical and
pharmacological barriers to obtaining the euphoric effects of opioids,
these novel formulations may minimize problematic opioid use. The
formulations use a variety of strategies, for example, combining
opioids with naltrexone or niacin or incorporating the opioid in a high-
viscosity matrix designed to resist physical and chemical extraction.
Non-opioid medications as well as cognitive, behavioral, and
interventional techniques should be considered for all patients with
chronic pain, particularly for those who are unable to safely take their
opioids in a structured fashion (5).
A secondary data analysis of regional VA longitudinal
administrative data (years 2000-2005) for chronic users of opioids for
chronic non-cancer pain (n=15,160) was conducted to investigate risk
factors for the development of clinically recognized (i.e., diagnosed)
opioid abuse or dependence among these individuals. Four broad
169
groups of possible risk factors were analyzed: (i) non-opioid substance

abuse disorders, (ii) painful physical health disorders, (iii) mental
health disorders, and (iv) socio-demographic factors. In adjusted
models, a diagnosis of non-opioid substance abuse was the strongest
predictor of opioid abuse/dependence (OR=2.34, p<0.001). Mental
health disorders were moderately strong predictors (OR=1.46,
p=0.005) of opioid abuse/dependence. However, the prevalence of
mental health disorders was much higher than the prevalence of non-
opioid substance abuse disorders (45.3% vs. 7.6%) among users of
opioids for CNCP, suggesting that mental health disorders account for
more of the population attributable risk for opioid abuse than does
non-opioid substance abuse. Males, younger adults, and individuals
with greater day's supply of prescription opioids dispensed in 2002
were more likely to develop opioid abuse/dependence. Clinicians need
to carefully screen for substance abuse and mental health disorders in
candidates for opioid therapy and facilitate appropriate treatment of
these disorders (6).
Assessment: opioid abuse has continued to increase at an alarming

rate since the 1990s. Screening for opioid abuse includes assessment
of premorbid and comorbid substance abuse, assessment of aberrant
drug-related behaviors, risk factor stratification, and utilization of
opioid screening tools. Urine drug testing, monitoring of prescribing
practices, prescription monitoring programs, opioid treatment
agreements, and utilization of universal precautions are essential.
Recent advances in opioid prescription include the increasing use
of transdermal preparations and extended release, oral, once daily
preparations. New formulations of existing drugs have been
developed, as well as a new chemical entity. Abuse deterrent
formulations and delivery systems may prevent the artificial
acceleration of drug delivery and reduce the potential for opioid
addiction.
The formulations use a variety of strategies, for example,
combining opioids with naltrexone or niacin or incorporating the
opioid in a high-viscosity matrix designed to resist physical and
chemical extraction. Non-opioid medications as well as cognitive,
behavioral and interventional techniques should be considered for all
patients with chronic pain, particularly for those who are unable to
safely take their opioids in a structured fashion.
A diagnosis of non-opioid substance abuse is the strongest
predictor of opioid abuse/dependence. Mental health disorders are
moderately strong predictors of opioid abuse/dependence.
170
References
1. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain
Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-
cancer pain: Part I - evidence assessment. Pain Physician. 2012;15(3 Suppl):S1-65.
2. Gudin JA. Clinical strategies for the primary health care professional to
minimize prescription opioid abuse. Postgrad Med. 2012;124(3):131-8.
3. Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain:
a review of opioid abuse predictors and strategies to curb opioid abuse. Pain
Physician. 2012;15(3 Suppl):ES67-92.
4. Snidvongs S, Mehta V. Recent advances in opioid prescription for chronic non-
cancer pain. Postgrad Med J. 2012;88(1036):66-72.
5. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and
solutions. Mayo Clin Proc. 2009;84(7):593-601.
6. Edlund MJ, Steffick D, Hudson T, et al. Risk factors for clinically recognized
opioid abuse and dependence among veterans using opioids for chronic non-cancer
pain. Pain. 2007;129(3):355-62.
CAPSAICIN
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a primary
pungent and irritating principle present in chilies and red peppers that
are widely used as spices. Because of its selective effects on the
functions of a defined subpopulation of sensory neurons, capsaicin is
currently used as a versatile tool for the study of pain mechanisms and
for pharmacotherapy to treat several pain disorders. Considering the
frequent consumption of capsaicin as a food additive and its current
medicinal use, correct assessment of hazardous effects of this
compound is important. Mutagenic and carcinogenic activities of
capsaicin and chili extracts have been studied, but results are
conflicting. Mammalian metabolism of capsaicin has been also
reported. Capsaicin appears to interact with xenobiotic metabolizing
enzymes, particularly microsomal cytochrome P450-dependent
monooxygenases which are involved in activation as well as
detoxification of various chemical carcinogens and mutagens. Hepatic
cytochrome P450 2E1 catalyzes the conversion of capsaicin to
reactive species such as the phenoxy radical intermediate capable of
covalently binding to the active site of the enzyme as well as tissue
macromolecules. While covalent modification of protein and nucleic
acids leads to toxicity including necrosis, mutagenesis, and
carcinogenesis, suicidal inhibition of microsomal cytochrome P450
may prohibit further activation of capsaicin and other toxic
171
xenobiotics. Results from recent studies indicate that capsaicin

possesses the chemoprotective activity against some chemical
carcinogens and mutagens (1).
Knee OA is prevalent and associated with both pain and functional
disability. Current treatments aim to alleviate mild to moderate
symptoms by various methods. Topical capsaicin (0.075% and 0.05%)
has been evaluated for the treatment of the painful joints. A burning
sensation was the most common side effect at these strengths. The
efficacy of 0.0125% capsaicin gel (Capsika gel) compared to a
placebo (the vehicle gel) in patients with symptomatic OA knee was
evaluated. This was a crossover; double blinded, RCT of 100 patients
with mild to moderate knee OA. All of the patients received either
capsaicin gel or placebo gel applied to the affected knee, 3 times daily
for 4 weeks with 1-week washout period after which the treatment
switched to either capsaicin gel or placebo gel for the next 4 weeks. A
blinded examiner used the VAS and WOMAC score to do weekly
assessments. Subjects averaged 61 years of age (range, 44 to 82).
During the enrollment phase, only female farmers presented. Mean
body weight and height was 62.97 +/- 10.25 kg and 1.54 +/- 0.053 m,
respectively. The respective baseline VAS and WOMAC score were
6.40 +/- 1.64 and 51.65 +/- 13.3. The severity of OA, according to the
KL criteria was: 83 patients with grade II and 16 with grade III. The
respective mean difference of VAS and total WOMAC score in the
capsaicin group vs. the placebo group was statistically significant
(p<0.05). The mean difference of the WOMAC pain, stiffness and
functional subscales in the capsaicin vs. the placebo group was
significant (p<0.05). The only AE reported was a burning sensation.
During the 4-week treatment with capsaicin, approximately 67% of
patients had a burning sensation but none withdrew for this reason. In
conclusion, 0.0125% capsaicin gel was an effective treatment in
mildly to moderately painful OA knees. The burning sensation
reported by patients in the capsaicin group was less disturbing than in
previous studies and none of the present patients withdrew for this
reason (2).
The neuropeptide SP has been implicated in the pathogenesis of
inflammation and pain in arthritis. In this double-blind randomized
study, 70 patients with OA and 31 with RA received capsaicin (a SP
depletor) or placebo for 4 weeks. The patients were instructed to apply
0.025% capsaicin cream or its vehicle (placebo) to painful knees 4
times daily. Pain relief was assessed using VAS for pain and relief, a
categorical pain scale, and physicians' global evaluations. Most of the
patients continued to receive concomitant arthritis medications.
172
Significantly the capsaicin-treated patients reported more relief of pain

than the placebo patients throughout the study; after 4 weeks of
capsaicin treatment, RA and OA patients demonstrated mean
reductions in pain of 57% and 33%, respectively. These reductions in
pain were statistically significant compared with those reported with
placebo (p=0.003 and p=0.033, respectively). According to the global
evaluations, 80% of the capsaicin-treated patients experienced a
reduction in pain after 2 weeks of treatment. Transient burning was
felt at the sites of drug application by 23 of the 52 capsaicin-treated
patients; 2 patients withdrew from treatment because of this side
effect. It is concluded that capsaicin cream is a safe and effective
treatment for arthritis (3).
Topical capsaicin 0.075% was evaluated for the treatment of the
painful joints of RA and OA in a 4-week double blind, placebo
controlled randomized trial. Of all patients, 21 had RA (n=7) and OA
(n=14) with painful involvement of the hands. Assessments of pain
(VAS), functional capacity, morning stiffness, grip strength, joint
swelling and tenderness (dolorimeter) were performed before
randomization. Treatment was applied to each painful hand joint 4
times daily with reassessment at 1, 2 and 4 weeks after entry.
Capsaicin reduced tenderness (p<0.02) and pain (p<0.02) associated
with OA, but not in RA as compared with placebo. A local burning
sensation was the only AE noted. These findings suggest that topical
capsaicin is a safe and potentially useful drug for the treatment of
painful OA of the hands (4).
The main objective of this study was to review the evidence from
controlled trials on the efficacy and tolerability of topically applied
low-concentration (< 1%) capsaicin in chronic neuropathic pain in
adults. Cochrane CENTRAL, MEDLINE, EMBASE and Oxford Pain
Relief Database were searched to July 2012. Selection criteria
included randomized, double-blind, placebo-controlled studies of at
least 6 weeks' duration, using low-concentration (< 1%) topical
capsaicin to treat neuropathic pain. Information was extracted on
numbers of participants with pain relief (clinical improvement) after at
least 6 weeks, and with local skin reactions, and used to calculate risk
ratio and NNT and NNH. Details of definition of pain relief and
specific AEs were sought. No additional studies were identified for
this update of low concentration capsaicin. Included studies were
published before 1996. Six studies (389 participants in total)
compared regular application of low dose (0.075%) capsaicin cream
with placebo cream. There was substantial heterogeneity in results,
probably due to the small number of studies each with small numbers
173
of participants, as well as the different pain conditions studied and

different definitions of "clinical success" reported. Only 2 studies
reported data for the preferred primary outcome of at least 50% pain
relief, and there were too few data for pooled analysis. Local skin
reactions were more common with capsaicin, usually tolerable, and
attenuated with time; the NNH for repeated low-dose application was
2.5 (95% CI 2.1 - 3.1). In conclusion, there were insufficient data to
draw any conclusions about the efficacy of low-concentration
capsaicin cream in the treatment of neuropathic pain. Low-
concentration topical capsaicin is without meaningful effect beyond
that found in placebo creams; given the potential for bias from small
study size, this makes it unlikely that low-concentration topical
capsaicin has any meaningful use in clinical practice. Local skin
irritation was often mild and transient but may lead to withdrawal, and
was common. Systemic AEs were rare (5).
References
1. Surh YJ, Lee SS. Capsaicin, a double-edged sword: toxicity, metabolism, and
chemopreventive potential. Life Sci. 1995;56(22):1845-55.
2. Kosuwon W, Sirichatiwapee W, Wisanuyotin T, et al. Efficacy of symptomatic
control of knee osteoarthritis with 0.0125% of capsaicin versus placebo. J Med Assoc
Thai. 2010;93(10):1188-95.
3. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical
capsaicin: a double-blind trial. Clin Ther. 1991;13(3):383-95.
4. McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of
painful osteoarthritis of the hands. J Rheumatol. 1992;19(4):604-7.
5. Derry S, Moore RA. Topical capsaicin (low concentration) for chronic
neuropathic pain in adults. Cochrane Database Syst Rev. 2012 Sep 12;9: CD010111.
ANTIDEPRESSANTS
Chronic pain represents one of the most important public health
problems and, in addition to classical analgesics, antidepressants are
an essential part of the therapeutic strategy. This article reviews
available evidence on the efficacy and safety of antidepressants in
major chronic pain conditions; namely, neuropathic pain, headaches,
LBP, fibromyalgia, IBS and cancer pain. Studies, reviews and meta-
analyses published from 1991 to March 2008 were retrieved through
MEDLINE, PsycINFO and the Cochrane database using numerous
key words for pain and antidepressants. Evidence supports the use of
TCAs in neuropathic pain, headaches, LBP, fibromyalgia and IBS.
The efficacy of the newer serotonin and norepinephrine reuptake
174
inhibitors is less supported by evidence, but can be recommended in

neuropathic pain, migraines and fibromyalgia. To date, evidence does
not support an analgesic effect of SSRI, but beneficial effects on well-
being were reported in several chronic pain conditions (1).
Persistent pain disorders are usually not adequately alleviated by
NSAIDs or other simple analgesics. Use of antidepressants as
adjuvant therapy for the control of persistent pain is currently being
practiced in disorders such as fibromyalgia, neuropathic pain,
rheumatoid conditions, LBP, and headache. Meta-analyses and
clinical studies of these agents were retrieved through the use of
MEDLINE, Google scholar, and Cochrane databases. Antidepressants
are effective in both neuropathic and non-neuropathic pain and have
diverse mechanisms independent of their antidepressant effects. TCAs
(amitryptiline, nortryptiline, and desipramine) are effective
compounds in the treatment of neuropathic pain, fibromyalgia, LBP,
and headaches. Studies are ongoing for the dual SNRI (duloxetine,
venlafaxine) in several persistent pain conditions and these may be
recommended in neuropathic pain, migraines, and fibromyalgia.
Evidence suggests that although the analgesic effects of SSRI
(fluoxetine, paroxetine, and citalopram) are limited and inconsistent,
yet they have a superior tolerability profile compared with TCAs (2).
Antidepressants are often applied in the treatment of chronic pain.
Analgesic action of TCAs has been extensively studied and proven.
TCAs are associated with a number of AEs which are inconvenient for
patients. The newer antidepressants have fewer side effects and
equivalent efficacy on mood disorders. This article reviews the
available publications (mainly placebo-controlled trials) concerning
the efficacy of these medications in the treatment of chronic pain. The
data regarding SSRI are conflicting. Trazodone (a serotonin-reuptake
inhibitor as well as a postsynaptic serotonin receptor antagonist) does
not appear to be effective for the treatment of chronic pain. No
placebo-controlled studies are available for noradrenergic and specific
serotoninergic antidepressant - mirtazapine and noradrenaline
reuptake inhibitor - reboxetine. Bupropion, a noradrenaline and
dopamine-reuptake inhibitor appears to be effective in the treatment of
neuropathic pain. Venlafaxine (SNRI) was shown to be effective in
the treatment of different kinds of pain. Duloxetine (SNRI) is effective
in relieving both the emotional and painful physical symptoms of
depression. Additional RCTs are necessary to fully evaluate the role
of new antidepressants in the treatment of chronic pain (3).
The main objective of this study was to review the use of
duloxetine, a new selective SNRI, and other antidepressants in the
175
treatment of patients with fibromyalgia. Two randomized, placebo-

controlled, double blind, parallel group, 12-week trials of duloxetine
in the treatment of fibromyalgia were reviewed. Other published,
randomized, placebo-controlled, double-blind trials, and meta-
analyses of antidepressant treatment of fibromyalgia were identified
by a PubMed search that was augmented by reference crosscheck.
Duloxetine is an effective and safe treatment for many of the
symptoms associated with fibromyalgia, particularly for women.
Other selective SNRIs also show promise in the treatment of
fibromyalgia. Until recently, TCAs that have serotonin and
norepinephrine reuptake inhibitory activity had been the most
commonly studied group of antidepressants, and they are effective in
treating pain and other symptoms associated with fibromyalgia,
although their use may be limited by safety and tolerability concerns.
There are few RCTs of SSRI in fibromyalgia, and the results have
been mixed. In conclusion, antidepressants play an important role in
the treatment of patients with fibromyalgia. Agents with dual effects
on serotonin and norepinephrine appear to have more consistent
benefits than selective serotonin antidepressants for the treatment of
persistent pain associated with fibromyalgia (4).
References
1. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic pain.
Drugs. 2008;68(18):2611-32.
2. Dharmshaktu P, Tayal V, Kalra BS. Efficacy of antidepressants as analgesics: a review. J
Clin Pharmacol. 2012;52(1):6-17.
3. Miller A, Rabe-Jabłońska J. The effectiveness of antidepressants in the treatment of
chronic non-cancer pain - a review. Psychiatr Pol. 2005;39(1): 21-32.
4. Arnold LM. Duloxetine and other antidepressants in the treatment of patients with
fibromyalgia. Pain Med. 2007;8 Suppl 2:S63-74.
ANTIPSYCHOTICS
The role of antipsychotics as adjuvant analgesics is a subject of
longstanding controversy. Neuroleptanalgesia (i.e. a state of
quiescence, altered awareness, and analgesia produced by a
combination of taking an opioid analgesic and an antipsychotic) is an
established term for the management of acute pain, negatively
influencing disease course and total mortality in unstable angina
patients. Nevertheless, antipsychotics are used to treat chronic pain
(e.g. chronic headache, fibromyalgia, and DPN). With atypical
antipsychotics, a new class of antipsychotics, fewer extrapyramidal
side effects and additional benefits are available. The main objective
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of this study was to assess analgesic efficacy and AEs of

antipsychotics in acute or chronic pain. Search strategy included
Cochrane Pain, Palliative & Supportive Care Register, CENTRAL,
MEDLINE, PsycINFO, and EMBASE searched in October 2007.
Selection criteria were RCTs of adults prescribed any dose of oral
antipsychotics for acute or chronic pain, describing subjective pain
assessment as either the primary or a secondary outcome, and were
included in this review. All trials were quality scored according to the
methods set out in section 6 of the Cochrane Handbook. A total of 770
participants were involved in the eleven included studies. Data from 5
included randomized double-blind studies showed beneficial effects of
antipsychotics in the treatment of acute and chronic pain. Quantitative
analysis of these studies showed a significant reduction of mean pain
intensity after administration of the antipsychotic compared to placebo
or another active compound: WMD -1.78 (95% CI -2.71 - -0.85) for
the continuous data and RR 0.43 (95% CI 0.25 - 0.73), NNT-to-
benefit 2.6 for the dichotomous data. Nevertheless, the test for
heterogeneity was significant for the continuous data (p=0.0007) and
the dichotomous data (p=0.04). The most frequently reported AEs
were extrapyramidal (i.e. involuntary movements, parkinsonism and
akathisia) and sedating effects. In conclusion, antipsychotics might be
used as an add-on therapy in the treatment of painful conditions.
Extrapyramidal and sedating side effects have to be considered before
using antipsychotics for treating painful conditions (1).
RCTs of adults prescribed any dose of oral antipsychotics for acute
or chronic pain, describing subjective pain assessment as either the
primary or a secondary outcome, were included in this review. Eleven
studies involved 770 participants. Data from 5 randomized, double-
blind studies showed beneficial effects of antipsychotics in the
treatment of acute and chronic pain. The most frequently reported AEs
were extrapyramidal (i.e., involuntary movements, parkinsonism, and
akathisia) and sedating effects. In conclusion, because of limitations in
the available evidence, further research is needed to understand
whether antipsychotics are effective for acute or chronic pain or
specific pain conditions (2).
References
1. Seidel S, Aigner M, Ossege M, et al. Antipsychotics for acute and chronic pain
in adults. Cochrane Database Syst Rev. 2008 Oct 8;(4): CD004844.
2. Seidel S, Aigner M, Ossege M, et al. Antipsychotics for acute and chronic pain
in adults. J Pain Symptom Manage. 2010;39(4):768-78.
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ANTIEPILEPTIC DRUGS
The main objective was to determine effectiveness and AEs of
anticonvulsant drugs in management of pain. Systematic review of
RCTs of anticonvulsants for acute, chronic, or cancer pain identified
by using Medline, by hand searching, by searching reference lists, and
by contacting investigators. Between 1966 and February 1994, 37
reports were found; 20 reports of 4 anticonvulsants, were eligible.
NNT were calculated for effectiveness, AEs, and drug related
withdrawal from study. The only placebo controlled study in acute
pain found no analgesic effect of sodium valproate. For treating
trigeminal neuralgia, carbamazepine had combined NNT of 2.6 for
effectiveness, 3.4 for AEs, and 24 for severe effects (withdrawal from
study). For treating DPN, anticonvulsants had a combined NNT of 2.5
for effectiveness, 3.1 for AEs, and 20 for severe effects. For migraine
prophylaxis, anticonvulsants had a combined NNT of 1.6 for
effectiveness, 2.4 for AEs, and 39 for severe effects. Phenytoin had no
effect on the IBS, and carbamazepine had little effect on pain after
stroke. Clonazepam was effective in one study for temporomandibular
joint dysfunction. No study compared one anticonvulsant with
another. In conclusion, anticonvulsants were effective for trigeminal
neuralgia and DPN and for migraine prophylaxis. Minor adverse
effects occurred as often as benefit (1).
AEDs have been used in pain management since the 1960s.
Pregabalin is a recently developed antiepileptic drug also used in
management of chronic neuropathic pain conditions. The main
objective of this study was to assess analgesic efficacy and associated
AEs of pregabalin in acute and chronic pain. MEDLINE, EMBASE,
and CENTRAL to May 2009 for RCTs were searched. Additional
studies were identified from the reference lists of retrieved papers and
on-line clinical trial databases. Randomized, double blind trials
reporting on the analgesic effect of pregabalin, with subjective pain
assessment by the patient as either the primary or a secondary
outcome. Two independent review authors extracted data and assessed
trial quality. NNT-to-benefit were calculated, where possible, from
dichotomous data for effectiveness, AEs and study withdrawals.
There was no clear evidence of beneficial effects of pregabalin in
established acute postoperative pain. No studies evaluated pregabalin
in chronic nociceptive pain, like arthritis. Pregabalin at doses of 300
mg, 450 mg, and 600 mg daily was effective in patients with
postherpetic neuralgia, DPN, central neuropathic pain, and
fibromyalgia (19 studies, 7003 participants). Pregabalin at 150 mg
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daily was generally ineffective. Efficacy was demonstrated for

dichotomous outcomes equating to moderate or substantial pain relief,
alongside lower rates for lack of efficacy discontinuations with
increasing dose. The best (lowest) NNT for each condition for at least
50% pain relief over baseline (substantial benefit) for 600 mg
pregabalin daily compared with placebo were 3.9 (95% CI 3.1 - 5.1)
for postherpetic neuralgia, 5.0 (95% CI 4.0 - 6.6) for DPN, 5.6 (95%
CI 3.5 - 14) for central neuropathic pain, and 11 (95% CI 7.1 - 21) for
fibromyalgia. With 600 mg pregabalin daily somnolence typically
occurred in 15% to 25% and dizziness occurred in 27% to 46% of
patients. Treatment was discontinued due to AEs in 18% to 28%. The
proportion of participants reporting at least 1 AE was not affected by
dose, nor was the number with a serious AE, which was not more than
with placebo. Higher rates of substantial benefit were found in
postherpetic neuralgia and DPN than in central neuropathic pain and
fibromyalgia. For moderate and substantial benefit on any outcome
NNT for the former were generally 6 and below for 300 mg and 600
mg daily; for fibromyalgia NNT were much higher, and generally 7
and above. In conclusion, pregabalin has proven efficacy in
neuropathic pain conditions and fibromyalgia. A minority of patients
will have substantial benefit with pregabalin, and more will have
moderate benefit. Many will have no or trivial benefit, or will
discontinue because of AEs. Individualization of treatment is needed
to maximize pain relief and minimize AEs. There is no evidence to
support the use of pregabalin in acute pain scenarios (2).
The main objective of this study was to evaluate the analgesic
effectiveness and AEs of anticonvulsant drugs for pain management in
clinical practice. Migraine and headache studies are excluded in this
revision. Randomized trials of anticonvulsants in acute, chronic or
cancer pain were identified by MEDLINE (1966-1999), EMBASE
(1994-1999), SIGLE (1980 to 1999) and the Cochrane Controlled
Trials Register (CENTRAL/CCTR) (The Cochrane Library Issue 3,
1999). In addition, 41 medical journals were hand searched.
Additional reports were identified from the reference list of the
retrieved papers, and by contacting investigators. Date of most recent
search: September 1999. Selection criteria included randomized trials
reporting the analgesic effects of anticonvulsant drugs in patients with
subjective pain assessment as either the primary or a secondary
outcome. Data were extracted by 2 independent review authors, and
trials were quality scored. Twenty-three trials of 6 anticonvulsants
were considered eligible (1074 patients). The only placebo-controlled
study in acute pain found no analgesic effect of sodium valproate.
179
Three placebo-controlled studies of carbamazepine in trigeminal

neuralgia had a combined NNT for effectiveness of 2.5 (95% CI 2.0 -
3.4). A single placebo-controlled trial of gabapentin in post-herpetic
neuralgia had an NNT of 3.2 (95% CI 2.4 - 5.0). For PDN, NNT for
effectiveness were as follows: (1 RCT for each drug) carbamazepine
2.3 (95% CI 1.6 - 3.8), gabapentin 3.8 (95% CI 2.4 - 8.7) and
phenytoin 2.1 (95% CI 1.5 - 3.6). NNHs were calculated where
possible by combining studies for each drug entity irrespective of the
condition treated. The results were, for minor harm, carbamazepine
3.7 (95% CI 2.4 - 7.8), gabapentin 2.5 (95% CI 2.0 - 3.2), and
phenytoin 3.2 (95% CI 2.1 - 6.3). NNH for major harm were
statistically insignificant for any drug compared with placebo.
Phenytoin had no effect in IBS, and carbamazepine little effect in
post-stroke pain. Clonazepam was effective in 1 study of
temporomandibular joint dysfunction. In conclusion, although
anticonvulsants are used widely in chronic pain surprisingly few trials
show analgesic effectiveness. Only 1 study identified considered
cancer pain. There is no evidence that anticonvulsants are effective for
acute pain. In chronic pain syndromes other than trigeminal neuralgia,
anticonvulsants should be withheld until other interventions have been
tried. While gabapentin is increasingly being used for neuropathic
pain, the evidence would suggest that it is not superior to
carbamazepine (3).
References
1. McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for management
of pain: a systematic review. BMJ. 1995 Oct 21;311(7012):1047-52.
2. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain
in adults. Cochrane Database Syst Rev. 2009 Jul 8;(3): CD007076.
3. Wiffen PJ, Collins S, McQuay HJ, et al. WITHDRAWN. Anticonvulsant drugs
for acute and chronic pain. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD00113 3.
CANNABICOIDS
Cannabis, also known as marijuana, is a plant from Central Asia
that is grown in many parts of the world today. In the US, it is a
controlled substance and has been classified as a Schedule I agent (a
drug with increased potential for abuse and no known medical use).
By Federal Law, possessing Cannabis is illegal in the US.
Cannabinoids are active chemicals in Cannabis that cause drug-like
effects throughout the body, including the CNS and the immune
system. They are also known as phytocannabinoids. The main active
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cannabinoid in Cannabis is delta-9-THC. Another active cannabinoid

is cannabidiol, which may relieve pain and lower inflammation
without causing the "high" of delta-9-THC. Cannabinoids may be
useful in treating the side effects of cancer and cancer treatment. Other
possible effects of cannabinoids include: anti-inflammatory activity,
blocking cell growth, preventing the growth of blood vessels that
supply tumors, and antiviral activity (1).
Hemp (Cannabis sativa L.) has been used since remotes ages as an
herbal remedy. Only recently, the medical community highlighted the
pharmacological scientific bases of its effects. The most important
active principle, delta-9-THC, was identified in the second half of the
last century, and subsequently 2 receptors were identified and cloned:
CB1 that is primarily present in the CNS, and CB2 is present on the
cells of the immune system. Endogenous ligands, called
endocannabinoids, were characterized. The anandamide was the first
one to be discovered. The effectiveness of the cannabinoids in the
treatment of nausea and vomit due to anti-neoplastic chemotherapy
and in the wasting-syndrome during AIDS is recognized. Moreover,
the cannabinoids are analgesic, and their activity is comparable to the
weak opioids. Furthermore, parallels exist between opioid and
cannabinoid receptors, and evidence is accumulating that the 2
systems sometimes may operate synergistically. The interest of the
pharmaceutical companies led to the production of various drugs,
whether synthetic or natural derived. The good ratio between the
polyunsatured fatty acids omega-3 and omega-6 of the oil of Cannabis
seeds led to reduction of the phlogosis and an improvement of the pain
symptoms in patients with chronic musculo-skeletal inflammation (2).
Cannabinoids are medically interesting, but the available data are
still weak scientifically and overwhelming anecdotally. In the
management of pain, cannabinoids have antinociceptive properties in
animal models of pain, with non-opiate mechanisms appearing to
predominate. A widely cited meta-analysis suggested that
cannabinoids offer moderate pain relief, similarly to codeine, and
limited by side effects (3).
A systematic review of RCTs examining cannabinoids in the
treatment of chronic non-cancer pain was conducted according to the
PRISMA statement update on the QUORUM guidelines for reporting
systematic reviews that evaluate health care interventions.
Cannabinoids studied included smoked cannabis, oromucosal extracts
of cannabis based medicine, nabilone, dronabinol and a novel THC
analogue. Chronic non-cancer pain conditions included neuropathic
pain, fibromyalgia, RA, and mixed chronic pain. Overall, the quality
181
of trials was excellent. Of the 18 trials, 15 that met the inclusion

criteria demonstrated a significant analgesic effect of cannabinoid as
compared with placebo and several reported significant improvements
in sleep. There were no serious AEs. AEs most commonly reported
were generally well tolerated, mild to moderate in severity and led to
withdrawal from the studies in only a few cases. Overall, there is
evidence that cannabinoids are safe and modestly effective in
neuropathic pain with preliminary evidence of efficacy in
fibromyalgia and RA (4).
Cannabis-based medications have been a topic of intense study
since the endogenous cannabinoid system was discovered 2 decades
ago. In 2011, for the first time, a cannabis extract was approved for
clinical use in Germany. Cannabis-based medications exert their
effects mainly through the activation of cannabinoid receptors (CB1
and CB2). More than 100 controlled clinical trials of cannabinoids or
whole-plant preparations for various indications have been conducted
since 1975. The findings of these trials have led to the approval of
cannabis-based medicines (dronabinol, nabilone, and a cannabis
extract [THC: CBD=1:1]) in several countries. In Germany, a
cannabis extract was approved in 2011 for the treatment of moderate
to severe refractory spasticity in MS. It is commonly used off label for
the treatment of anorexia, nausea, and neuropathic pain. Patients can
also apply for government permission to buy medicinal cannabis
flowers for self-treatment under medical supervision. The most
common side effects of cannabinoids are tiredness and dizziness (in
more than 10% of patients), psychological effects, and dry mouth.
Tolerance to these side effects nearly always develops within a short
time. Withdrawal symptoms are hardly ever a problem in the
therapeutic setting. In conclusion, cannabinoids are useful for the
treatment of various medical conditions (5).
The main objective of this study was to establish whether cannabis
is an effective and safe treatment option in the management of pain. In
this systematic review of RCTs, electronic databases - Medline,
Embase, Oxford Pain Database, and Cochrane Library; references
from identified papers; hand searches were studied. Trials of cannabis
given by any route of administration (experimental intervention) with
any analgesic or placebo (control intervention) in patients with acute,
chronic non-malignant, or cancer pain were included. Outcomes
examined were pain intensity scores, pain relief scores, and AEs. Data
included independent data extraction; discrepancies resolved by
consensus. Twenty RCTs were identified, 11 of which were excluded.
Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2
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to chronic non-malignant pain, and 2 to acute postoperative pain. No

RCTs evaluated cannabis; all tested active substances were
cannabinoids. Oral delta-9-THC 5-20 mg, an oral synthetic nitrogen
analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg
were about as effective as codeine 50-120 mg, and oral
benzopyranoperidine 2-4 mg was less effective than codeine 60-120
mg and no better than placebo. AEs, most often psychotropic, were
common. In conclusion, cannabinoids are no more effective than
codeine in controlling pain and have depressant effects on the CNS
that limit their use. Their widespread introduction into clinical practice
for pain management is therefore undesirable. In acute postoperative
pain, they should not be used (6).
Over a 6-week period in mid-2001, 209 chronic non-cancer pain
patients in Canada were recruited in an anonymous cross-sectional
survey. Seventy-two (35%) subjects reported ever having used
cannabis. Thirty-two (15%) subjects reported having used cannabis
for pain relief (pain users), and 20 (10%) subjects were currently using
cannabis for pain relief. Thirty-eight subjects denied using cannabis
for pain relief (recreational users). Compared to never users, pain
users were significantly younger (p=0.001) and were more likely to be
tobacco users (p=0.0001). The largest group of patients using cannabis
had pain caused by trauma and/or surgery (51%), and the site of pain
was predominantly neck/upper body and myofascial (68% and 65%,
respectively). The median duration of pain was similar in both pain
users and recreational users (8 vs. 7 years, p=0.7). There was a wide
range of amounts and frequency of cannabis use. Of the 32 subjects
who used cannabis for pain, 17 (53%) used 4 puffs or less at each
dosing interval, 8 (25%) smoked a whole cannabis cigarette (joint)
and 4 (12%) smoked more than 1 joint. Of these subjects, 7 (22%)
used cannabis more than once daily, 5 (16%) used it daily, 8 (25%)
used it weekly and 9 (28%) used it rarely. Pain, sleep and mood were
most frequently reported as improving with cannabis use, and 'high'
and dry mouth were the most commonly reported side effects. In
conclusion, cannabis use is prevalent among the chronic non-cancer
pain population, for a wide range of symptoms, with considerable
variability in the amounts used. Discussions between patients and
health care providers concerning cannabis use may facilitate education
and follow up, and would allow side effects and potential interactions
with other medications to be monitored (7).
183
References
1. Cannabis and Cannabinoids. National Cancer Institute at the National Institutes
of Health. Available 10 May 2013 at www.cancer.gov/ cancertopics/pdq/cam/
cannabis/.../page2.
2. Shaladi AM, Crestani F, Tartari S, Piva B. Cannabinoids in the control of pain.
Recenti Prog Med. 2008;99(12):616-24.
3. Mather L. Cannabinoid pharmacotherapy: past, present and future. Minerva
Anestesiol. 2005;71(7-8):405-12.
4. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer
pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011;72(5):735-
44.
5. Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and
cannabinoids. Dtsch Arztebl Int. 2012;109(29-30):495-501.
6. Campbell FA, Tramèr MR, Carroll D, et al. Are cannabinoids an effective and
safe treatment option in the management of pain? A qualitative systematic review.
BMJ. 2001;323(7303):13-6.
7. Ware MA, Doyle CR, Woods R, et al. Cannabis use for chronic non-cancer
pain: results of a prospective survey. Pain. 2003;102(1-2):211-6.
NEUROPATHIC PAIN
Neuropathic pain represents a major neurological problem and
treatment of patients with such pain has been largely neglected by
neurologists in the past. The medical management of neuropathic pain
consists of 5 main classes of oral medication (antidepressants with
reuptake blocking effect, anticonvulsants with sodium-blocking
action, anticonvulsants with calcium-modulating actions, tramadol,
and opioids) and several categories of topical medications for patients
with cutaneous allodynia and hyperalgesia (capsaicin and local
anesthetics). In many cases, an early combination of compounds
effecting different mechanisms is useful. At present, existing trials
only provide general pain relief values for specific causes, which in
part may explain the failure to obtain complete pain relief in
neuropathic pain conditions. In general, the treatment of neuropathic
pain is still unsatisfactorily. Therefore, a new hypothetical concept
was proposed in which pain is analyzed on the basis of underlying
mechanisms (1,2).
Neuropathic pain is due to lesion or dysfunction of the peripheral
or CNS. TCAs and anticonvulsants have long been the mainstay of
treatment of this type of pain. TCAs may relieve neuropathic pain by
their unique ability to inhibit presynaptic reuptake of the biogenic
amines serotonin and noradrenaline, but other mechanisms such as
NMDA receptor and ion channel blockade probably also play a role in
184
their pain-relieving effect. The effect of TCA in neuropathic pain in

man has been demonstrated in numerous RCTs, and a few trials have
shown that SNRI and SSRI antidepressants also relieve neuropathic
pain although with lower efficacy. TCAs will relieve 1 in every 2-3
patients with peripheral neuropathic pain, SNRI 1 in every 4-5 and
SSRI 1 in every 7 patients. Thus, based on efficacy measures such as
NNT, TCA tend to work better than the anticonvulsant gabapentin and
treatment options such as tramadol and oxycodone, whereas the SNRI
venlafaxine appears to be equally effective with these drugs and
SSRIs apparently have lower efficacy. Head-to-head comparisons
between antidepressants and the other analgesics are lacking.
Contraindications towards the use of TCA and low tolerability in
general of this drug class favor the use of the SNRI. A recent study on
bupropion, which is a noradrenaline and dopamine uptake inhibitor,
indicated a high efficacy of this drug in peripheral neuropathic pain. In
conclusion, antidepressants represent useful tools in neuropathic pain
treatment and must still be considered as first line treatments of
neuropathic pain. However, without head-to-head comparisons
between antidepressants and other analgesics, it is impossible to
provide real evidence-based treatment algorithms for neuropathic pain
(3).
The possible mechanisms involved in the antinociceptive effect of
venlafaxine, a selective SNRI, after a single administration and
chronic treatment were investigated in a DPN pain model.
Venlafaxine produced a significant antihyperalgesic effect after a
single and repeated administration. This effect was reversed by
pretreatment with yohimbine (a relatively selective α(2)-adrenergic
antagonist) and p-chloroamphetamine (a neurotoxin which destroys
serotonergic neurons). Conversely, naloxone (a nonselective opioid
antagonist) did not reverse the effect of venlafaxine in a DPN pain
model. In conclusion, both noradrenergic and serotonergic
mechanisms participate in the antinociceptive effect of venlafaxine in
the DPN pain model. However, the noradrenergic mechanism
probably plays a more important role (4).
Neuropathic pain is a debilitating chronic condition that remains
difficult to treat. Recently, a number of clinical studies have compared
the effectiveness of combination drug therapy with monotherapy for
neuropathic pain treatment. Despite a relatively small number of
clinical studies on this topic, several positive indications have
emerged. First, clinical studies using gabapentin (5 positive trials) and
pregabalin (5 positive trials and 1 negative trial) in combination with
an opioid, COX-2 inhibitor or antidepressant have shown positive
185
responses greater than the respective monotherapies for pain related to

DPN and postherpetic neuropathy. Second, high-concentration (8%)
topical capsaicin and a 5% lidocaine patch seem to be effective add-on
therapies (a modality of combination therapy) for various neuropathic
pain conditions. Third, combination therapy for cancer-related
neuropathic pain has yielded only limited success based on a number
of small-scale clinical studies (5).
Neuropathic pain is a complicated symptomatic disease as
migraine in recent years. Not because the pain character differed from
the nociceptive inflammatory symptoms but because of its complexity
of mechanisms. Though peripheral sensitization, ectopic discharge,
central sensitization, central re-organization and loss of inhibition play
part of roles in mechanisms, however, based on this mechanistic
treatment, the outcome still disappointed physicians and patients,
exampled as central post-stroke central pain. The pain reduction is far
less than the expectation from patients and physician's under-treatment
frequently occur due to the fear of AEs or off-label use of these anti-
neuropathic pain drugs. Therefore, a multidisciplinary procedure
including non-pharmacological management, rehabilitation program,
careful explanation, stepwise pain reduction, daily diary record, and
tailored individual planning for medications are helpful in treating this
kind of sufferers. Pharmacological treatment is the mainstream in
post-herpetic neuralgia, DPN pain, central post-stroke pain, trigeminal
neuralgia, complex regional pain syndrome, cancer pain, failed back
syndrome etc, while polypharmacy is still the major prescriptions
facing such kind of miserable patients. The TCAs, GABA, voltage-
dependent calcium channel blockers, SNRIs, opioid or morphine etc,
are still evidence-based medicines but with different outcome for
individuals. Acupuncture is effective in Taiwanese people with
perceived evidence or placebo (6).
Neuropathic pain is a persistent pain condition that develops
secondary to nerve injury. The 2 most common types of peripheral
neuropathic pain are post-herpetic neuralgia and painful DPN.
Amitriptyline, nortriptyline, desipramine and imipramine are TCAs
that are effective for the symptomatic relief of post-herpetic neuralgia
and painful DPN. SNRI such as venlafaxine and duloxetine are
promising for the treatment of painful diabetic neuropathy with fewer
AEs than TCA. SSRI in a number of studies have some efficacy in
relieving painful DPN, yet other studies of the SSRI have
demonstrated conflicting outcomes. Most of the older antiepileptic
studies were performed in patients with painful DPN; consequently,
little is known about the efficacy of these drugs in patients with post-
186
herpetic neuralgia. Carbamazepine, phenytoin and valproic acid are

effective in ameliorating painful DPN-related pain. Other AED,
including lamotrigine, oxcarbazepine and topiramate, have some
beneficial effects for the treatment of painful DPN, although they
were ineffective in some painful DPN studies. alpha2delta ligands
such as gabapentin and pregabalin are effective for the treatment of
post-herpetic neuralgia and painful DPN in a number of large placebo-
controlled trials. These drugs are useful not only in relieving pain but
also in improving QOL. Although the use of opioids for the treatment
of neuropathic pain is controversial, a number of studies support the
efficacy and safety of opioids in the treatment of neuropathic pain. Of
these, oxycodone and tramadol are superior to placebo for the
treatment of post-herpetic neuralgia and painful DPN. In a number of
small studies, extromethorphan is effective in patients with painful
DPN but not in patients with post-herpetic neuralgia. Topical agents
such as lidocaine 5% patches and topical capsaicin are useful in
ameliorating pain in patients with post-herpetic neuralgia but these
agents are unsatisfactory for use as a sole agent. Although a number of
drug treatments are available for the symptomatic relief of neuropathic
pain symptoms, these agents do not provide satisfactory relief in all
patients. For these patients, other treatment alternatives such as
combination drug therapy that produces pain relief via distinctly
different mechanisms may be successful (7). Treatments with
established efficacy in several neuropathic conditions include TCA,
gabapentin, pregabalin and strong opioids. Duloxetine and
venlafaxine, both antidepressants, and tramadol, an opioid agonist, are
effective in painful polyneuropathies, while lidocaine patches produce
analgesic effects, mainly in postherpetic neuralgia. Pregabalin,
gabapentin and duloxetine have positive effects that improve QOL,
and anxiety, depressive, and sleep disorders (8).
The development of newer classes of antidepressants and second-
generation AED has created unprecedented opportunities for the
treatment of chronic pain. These drugs modulate pain transmission by
interacting with specific neurotransmitters and ion channels. The
actions of antidepressants and AED differ in neuropathic and non-
neuropathic pain, and agents within each medication class have
varying degrees of efficacy. TCAs (e.g., amitriptyline, nortriptyline,
desipramine) and certain novel antidepressants (i.e., bupropion,
venlafaxine, and duloxetine) are effective in the treatment of
neuropathic pain. The analgesic effect of these drugs is independent of
their antidepressant effect and appears strongest in agents with mixed-
receptor or predominantly noradrenergic activity, rather than
187
serotoninergic activity. First-generation AED (i.e., carbamazepine,

and phenytoin) and second-generation AED (e.g., gabapentin, and
pregabalin) are effective in the treatment of neuropathic pain. The
efficacy of antidepressants and AED in the treatment of neuropathic
pain is comparable; tolerability also is comparable, but safety and side
effect profiles differ. TCAs are the most cost-effective agents, but
second-generation AED are associated with fewer safety concerns in
elderly patients. TCAs have documented (although limited) efficacy in
the treatment of fibromyalgia and chronic LBP. Recent evidence
suggests that duloxetine and pregabalin have modest efficacy in
patients with fibromyalgia (9).
New studies of the treatment of neuropathic pain have increased
the need for an updated review of randomized, double-blind, placebo-
controlled trials to support an evidence based algorithm to treat
neuropathic pain conditions. Available studies were identified using a
MEDLINE and EMBASE search. One hundred and 5 studies were
included. NNT and NNH were used to compare efficacy and safety of
the treatments in different neuropathic pain syndromes. The quality of
each trial was assessed. TCAs and the anticonvulsants gabapentin and
pregabalin were the most frequently studied drug classes. In peripheral
neuropathic pain, the lowest NNT was for TCAs, followed by opioids
and the anticonvulsants gabapentin and pregabalin. For central
neuropathic pain there is limited data (10).
Patients with chronic non-cancer pain, including neuropathic pain,
may have transitory exacerbations of pain (median duration, 60
minutes), termed BTP, that may reach peak intensity within minutes.
Typical short-acting oral opioids may not provide sufficiently rapid
relief (30- to 60-minute onset of analgesia). The FBT provides a rapid
onset of analgesia (10-15 minutes) by enhancing fentanyl absorption
across the buccal mucosa. This study evaluated the efficacy and
tolerability of FBT in opioid-tolerant patients with BTP associated
with chronic noncancer neuropathic pain. This was a multicenter,
randomized, double-blind, placebo-controlled study in men and
women aged 18 to 80 years who were opioid tolerant; had a ≥ 3-
month history of chronic persistent neuropathic pain associated with
DPN, postherpetic neuralgia, traumatic injury, or complex regional
pain syndrome; and reported having episodes of BTP. After an open-
label titration period to identify an effective FBT dose (the dose at
which the patient reported receiving adequate pain relief within 30
minutes after administration of a single tablet of that dose during at
least 2 of 3 BTP episodes), patients were randomly assigned to treat 9
consecutive episodes of BTP over the next 21 days with 1 of 3 double-
188
blind dose sequences of FBT and placebo tablets. Pain intensity (rated
on an 11-point pain scale, from 0 = no pain to 10 = worst pain) and
other outcomes were assessed before dosing and for 2 hours after
dosing. The primary efficacy measure was the sum of pain intensity
differences for the first 60 minutes (SPID(60)). Secondary efficacy
measures included the proportion of BTP episodes with ≥ 33% and ≥
50% improvement in pain intensity from baseline; pain intensity
differences at other time points (5, 10, 15, 30, 45, 60, 90, and 120
minutes after dosing); pain relief at the same time points (rated on a 5-
point Likert scale from 0 = none to 4 = complete); proportion of BTP
episodes with meaningful pain relief; time to meaningful pain relief;
and proportion of BTP episodes in which supplemental medication
was required after administration of study drug. AEs spontaneously
reported by the patient or elicited by the investigator were recorded
throughout the study. Of 102 patients in the open-label titration
period, in 80 were identified an effective dose of FBT and 79 entered
the double-blind phase. Of these 79 patients, 77 (97%) completed the
study and 75 (95%) were evaluable for efficacy. Of the 79 patients
who entered the double-blind phase, 63% were women and 92% were
white; their mean (SD) age was 48.3 (10.42) years, and their mean
weight was 96.8 (33.42) kg. Baseline demographic and pain
characteristics were similar between the overall population and the
double-blind population. SPID(60) was significantly greater for BTP
episodes treated with FBT compared with those in which placebo was
administered (mean [SE], 9.63 [0.75] vs. 5.73 [0.72], respectively;
p<0.001). Significant differences between FBT and placebo were seen
beginning at 10 minutes for pain differences (mean, 0.740 [0.149] vs.
0.427 [0.081]; p<0.047) and pain relief (mean, 0.561 [0.087] vs.
0.324 [0.056], p<0.001). A ≥ 33% improvement in pain intensity from
baseline was seen in a greater proportion of BTP episodes treated with
FBT compared with placebo from 10 minutes (9% vs. 3%, p=0.008)
through 2 hours (66% vs. 37%, p<0.001). Patients were almost 4 times
less likely to require supplemental opioids when BTP episodes were
treated with FBT compared with placebo (OR=0.28, 95% CI 0.18 -
0.42). AEs were reported by 64 (63%) of 102 patients. The most
commonly reported AEs were those typical of opioids (nausea [13%],
dizziness [13%], somnolence [10%], and vomiting [5%]) that occurred
more often during the dose-titration phase (55/102 [54%]) than during
the double-blind phase (22/79 [28%]). In conclusion, in opioid-
tolerant patients with chronic neuropathic pain who identified an
effective FBT dose, FBT had a rapid onset of action and was effective
and well tolerated in the treatment of BTP (11).
189
The main objective of this study was to determine the analgesic

effectiveness and safety of antidepressant drugs in neuropathic pain.
RCTs of antidepressants in neuropathic pain were identified in
MEDLINE (1966 to Oct 2005); EMBASE (1980 to Oct 2005); the
Cochrane Central Register of Controlled Trials (CENTRAL) in The
Cochrane Library, Issue 3, 2005; and the Cochrane Pain, Palliative
and Supportive Care Trials Register (May 2002). Additional reports
were identified from the reference list of the retrieved papers, and by
contacting investigators. Selection criteria were RCTs reporting the
analgesic effects of antidepressant drugs in adult patients, with
subjective assessment of pain of neuropathic origin. Studies that
included patients with chronic headache and migraine were excluded.
Two review authors agreed the included studies, extracted data, and
assessed methodological quality independently. Sixty-one trials of 20
antidepressants were considered eligible (3293 participants) for
inclusion. RR and NNT were calculated from dichotomous data for
effectiveness and AEs. This update includes 11 additional studies (778
participants). Sixty-one RCTs were included in total. TCAs are
effective and have NNT of 3.6 (95% CI 3 - 4.5), and RR 2.1 (95% CI
1.8 - 2.5) for the achievement of at least moderate pain relief. There is
limited evidence for the effectiveness of the newer SSRI but no
studies of SNRI were found. Venlafaxine (3 studies) has an NNT of
3.1 (95% CI 2.2 - 5.1), RR 2.2 (95% CI 1.5 - 3.1). There were
insufficient data to assess effectiveness for other antidepressants such
as St Johns Wort and L-tryptophan. For DPN the NNT for
effectiveness was 1.3 (95% CI 1.2 - 1.5), RR 12.4 (95% CI 5.2 - 29.2)
(5 studies); for postherpetic neuralgia 2.7 (95% CI 2 - 4.1), RR 2.2
(95% CI 1.6 - 3.1) (4 studies). There was evidence that TCAs are
ineffective in HIV-related neuropathies. The number NNH for major
AEs defined as an event leading to withdrawal from a study was 28
(95% CI 17.6 - 68.9) for amitriptyline and 16.2 (95% CI 8 - 436) for
venlafaxine. The NNH for minor AE was 6 (95% CI 4.2 - 10.7) for
amitriptyline and 9.6 (95% CI 3.5 - 13) for venlafaxine. There is still
limited evidence for the role of SSRI. Whether antidepressants prevent
the development of neuropathic pain (pre-emptive use) is still unclear.
Both TCA and venlafaxine have NNT of approximately 3. This means
that for approximately every 3 patients with neuropathic pain who are
treated with either of these antidepressants, 1 will get at least moderate
pain relief (12).
The steps of pharmacologic treatments for neuropathic pain include
(1) antidepressants (TAD, SSRI and SNRI), calcium channel alpha(2)-
delta ligands (gabapentin and pregabalin) and topical lidocaine, (2)
190
opioid analgesics and tramadol (for first-line use in selected clinical

circumstances), and (3) other antidepressant and antiepileptic
medications (topical capsaicin, mexiletine, and NMDA). It is essential
to have a thorough understanding about the different pain mechanisms
of chronic pain and evidence-based multi-mechanistic treatment and
to increase the individualization of treatment (13,14).
Recommendations for patients suffering from neuropathic pain are
proposed for first-line, second-line, and third-line pharmacological
treatments based on the level of evidence for the different treatment
strategies. Beside opioids, the available therapies shown to be
effective in managing neuropathic pain include anticonvulsants,
antidepressants, topical treatments (lidocaine patch, or capsaicin), and
ketamine. TCAs are often the first drugs selected to alleviate
neuropathic pain (first-line pharmacological treatment). Although they
are effective in reducing pain in several neuropathic pain disorders,
treatment may be compromised (and outweighed) by their side effects.
In patients with a history of C-V disorders, glaucoma, and urine
retention, pregabalin and gabapentine are emerging as first-line
treatment for neuropathic pain. In addition, these AEDs have a
favorable safety profile with minimal concerns regarding drug
interactions showing no interference with hepatic enzymes. Despite
the numerous treatment options available for relieving neuropathic
pain, the most appropriate treatment strategy is only able to reduce
pain in 70% of these patients. In the remaining patients, combination
therapies using 2 or more analgesics with different mechanisms of
action may also offer adequate pain relief. Although combination
treatment in clinical practice may result in greater pain relief, trials
regarding different combinations of analgesics are lacking (which
combination to use, occurrence of additive or supra-additive effects,
sequential or concurrent treatment, AE profiles of these analgesics,
alone and in combination) are lacking. Additionally, 10% of patients
still experience intractable pain and are refractory to all forms of
pharmacotherapy. If medical treatments fail, invasive therapies such
as intrathecal drug administration and neurosurgical interventions may
be considered (15,16).
This review evaluated the efficacy, tolerability and safety of
various drug combinations for the treatment of neuropathic pain.
RCTs of various drug combinations for neuropathic pain from
CENTRAL, MEDLINE, EMBASE and hand searches of other
reviews and trial registries were identified. Double-blind, randomized
studies comparing combinations of 2 or more drugs (systemic or
topical) to placebo and/or at least 1 other comparator for the treatment
191
of neuropathic pain were included. Data extracted from each study

included: proportion of participants a) reporting ≥ 30% pain reduction
from baseline, OR ≥ moderate pain relief, OR ≥ moderate global
improvement; b) dropping out of the trial due to treatment-emergent
AEs; c) reporting each specific AEs (e.g. sedation, or dizziness) of ≥
moderate severity. The primary comparison of interest was between
study drug(s) and 1 or both single-agent comparators. Studies were
combined if they evaluated the same drug class combination at
roughly similar doses and durations of treatment. Twenty-one eligible
studies were identified: 4 gapentin or pregabalin; 2 (77 participants)
evaluated an opioid with a TCA; 1 (56 participants) of gabapentin and
nortriptyline; 1 (120 participants) of gabapentin and alpha-lipoic acid,
3 (90 participants) of fluphenazine with a TAD; 3 (90 participants) of
an NMDA blocker with an agent from a different drug class; 5 (604
participants) of various topical medications; 1 (313 participants) of
tramadol with acetaminophen; and another 1 (44 participants) of a
cholecystokinin blocker (L-365,260) with morphine. The majority of
combinations evaluated to date involve drugs, each of which shares
some element of CNS depression (e.g. sedation, or cognitive
dysfunction). This aspect of side effect overlap between the combined
agents and reflected in similar or higher dropout rates for the
combination and may thus substantially limit the utility of such drug
combinations. Meta-analysis was possible for only 1 comparison of
only 1 combination, i.e. gabapentin + opioid vs. gabapentin alone.
This meta-analysis involving 386 participants from 2 studies
demonstrated modest, yet statistically significant, superiority of a
gabapentin + opioid combination over gabapentin alone. However,
this combination also produced significantly more frequent side
effect-related trial dropouts compared to gabapentin alone. In
conclusion, multiple, good-quality studies demonstrate superior
efficacy of 2-drug combinations. However, the number of available
studies for any 2 specific combination, as well as other study factors
(e.g. limited trial size and duration), preclude the recommendation of
any 1 specific drug combination for neuropathic pain. Demonstration
of combination benefits by several studies together with reports of
widespread clinical polypharmacy for neuropathic pain provide a
rationale for additional future rigorous evaluations (17,18).
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treatment: an evidence based proposal. Pain. 2005;118(3):289-305. Comment in: How
strong is the evidence for the efficacies of different drug treatments for neuropathic
pain? [Nat Clin Pract Neurol. 2006].
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of breakthrough pain in opioid-tolerant adult patients with chronic neuropathic pain: a
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for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012 Jul
11;7:CD008943.
NEUROMODULATION THERAPY
Chronic neuropathic pain is one of the most prevalent and
debilitating disorders. Conventional medical management, however,
remains frustrating for both patients and clinicians owing to poor
specificity of pharmacotherapy, delayed onset of analgesia and
extensive side effects. Neuromodulation presents as a promising
alternative, or at least an adjunct, as it is more specific in inducing
193
analgesia without associated risks of pharmacotherapy. Compared to

clinical SCS, investigational techniques of cerebral neuromodulation,
both invasive (DBS, motor cortical and epidural SCS, intrathecal
infusion, and radiosurgery) and noninvasive (repetitive transcranial
magnetic stimulation and transcranial direct current stimulation) are
be more advantageous (1,2).
Invasive neurostimulation therapies may be proposed to patients
with neuropathic pain refractory to conventional medical management
in order to improve pain relief, functional capacity, and QOL. In this
review, the respective mechanisms of action and efficacy of PNS,
nerve root stimulation, SCS, DBS, and MCS are discussed. PNS
appears to be useful in various refractory neuropathic pain indications
(as long as there is some preservation of sensation in the painful area),
such as intractable chronic headache, pelvic and perineal pain, and
LBP, but evidence for its efficacy is not strongly conclusive, and
large-scale RCSs are necessary to confirm the efficacy in the long
term. SCS has been validated for the treatment of selected types of
chronic pain syndromes, such as Failed Back Surgery Syndrome, and
Complex Regional Pain Syndrome type I. When neuropathic pain is
secondary to a brain lesion (especially following stroke) or a
trigeminal lesion, stimulation of brain structures is required. DBS,
which can be proposed with targets like the periventricular/
periaqueductal gray matter or the sensory thalamus, is increasingly
replaced by MCS, mainly because it is safer, more easily performed,
and probably more effective in a wider range of indications (including
central post-stroke pain). The respective places of DBS and MCS in
some selected indications, such as peripheral neuropathic pain and
phantom limb pain, have yet to be clearly delineated. Controlled trials,
with the stimulator switched ON or OFF in a double-blind procedure,
have demonstrated the efficacy of MCS in the treatment of peripheral
and central neuropathic pain, although these trials included a limited
number of patients and need to be confirmed by large, controlled,
multicenter studies. Despite technical progress in neurosurgical
navigation, guided by neuroimaging and intraoperative
electrophysiology to optimize electrode positioning, MCS results are
still variable, and validated criteria for selecting good candidates for
implantation are lacking, except clinical response to preoperative
repetitive transcranial magnetic stimulation, which showed
correlations with a good response to MCS-induced analgesia.
However, the evidence in favor of this technique is sufficient to
include it in the range of treatment options for refractory neuropathic
pain (3).
194
X-ray showing sacral nerve stimulator electrodes in position in the sacral

spine.
By adaptively targeting the multidimensional experience of pain,

subtended by integrative pain circuitry in the brain, including
somatosensory, thalamocortical, limbic, cognitive, and cerebral
methods modulate the sensory-discriminative, affective-emotional and
evaluative-cognitive spheres of the pain neuromatrix. Despite
promise, the current state of results alludes to the possibility that
cerebral neuromodulation has thus far not been effective in producing
analgesia as intended in patients with chronic pain disorders. These
techniques, thus, remain investigational and off-label. Issues are
implicated in inadequate efficacy, variability of responsiveness, and
poor retention of benefit, while recommending design and conceptual
refinements for future trials of cerebral neuromodulation in
management of chronic neuropathic pain (1).
Epidural SCS for pain control for the past 15 years was used. An
analysis of 235 patients has clarified the value of specific prognostic
parameters in the prediction of successful SCS. Patients were
followed up for periods ranging from 6 months to 15 years with a
mean follow-up of 66 months. The mean age of the 150 men and 85
women in the study was 51.4 years. Indications for SCS included
failed back syndrome (114 patients), peripheral vascular disease (39
patients), peripheral neuropathy (30 patients), MS (13 patients), reflex
sympathetic dystrophy (13 patients), and other etiologies of chronic
intractable pain (26 patients). Of 189 patients who received permanent
devices, 111 (59%) of patients continue to receive satisfactory pain
relief. Pain attributable to failed back syndrome, reflex sympathetic
dystrophy, peripheral vascular disease of lower limbs, MS, and
peripheral neuropathy responded favorably to SCS. By contrast,
paraplegic pain, cauda equina syndrome, stump pain, phantom limb
pain, and primary bone and joint disease pain did not respond as well.
Cases of cauda equina injury had promising initial pain relief, but
gradually declined after a few years. After long-term follow-up, 47 of
the 111 successfully implanted patients were gainfully employed
195
compared with 22 patients before implantation. The patients reported

improvements in daily living as well as a decrease in analgesic usage.
Multipolar stimulation systems were significantly more reliable
(p<0.001) than unipolar systems. Complications included hardware
malfunction, electrode displacement, infection, and tolerance. In
conclusion, aside from etiologies of pain syndromes as a prognostic
factor, other parameters of success were identified. In patients who
have undergone previous surgical procedures, the shorter the duration
of time to implantation, the greater the rate of success (p<0.001). The
diagnosis of failed back syndrome must be considered a confounding
factor in our analysis. Those patients whose pain did not follow a
surgical procedure had better responses to SCS than patients who had
multiple surgical procedures prior to their first implant. The advent of
multipolar systems has significantly improved clinical reliability over
unipolar systems. Age, sex, and laterality of pain did not prove to be
of significance (4).
This study aims to assess long-term follow-up of efficacy and QOL
for 34 geriatric patients (10 men, 24 women, mean age 72.3 ± 11.6
years) with IDDS, implanted between 1994 and 2002, for the
treatment of severe noncancerous chronic pain. Patients ≥ 64 years,
who had no pain relief after administration of a placebo injection
(subcutaneous saline), and who responded positively to an intrathecal
trial (morphine and bupivacaine at low doses) with pain relief greater
than 70% without intolerable AEs were included into this study.
Clinical assessment forms and questionnaires assessing pain intensity,
AEs events, complications, concomitant use of analgesics, and doses
of intrathecal drugs administered were filled out by patients prior to
and after IDDS implantation. Pain intensity was substantially reduced
(60%) at 3-month follow-up after commencing intrathecal therapy and
was consistently reduced at 48-month follow-up. The mean VAS
value decreased from 8.09 (± 1.25) before implantation to 1.68 (±
0.63) after implantation at 48-month follow-up. This benefit, at 48
months, was achieved using mean low doses of intrathecal morphine
and bupivacaine, 1.03 ± 0.61 mg and 1.15 ± 0.58 mg, respectively.
Only 2/34 patients (5.9%) had complications related to the
implantation procedure, itself. Side effects of therapy were reported
by 50% of the patients, the most frequent being constipation (34.4%),
drowsiness (21.9%), nausea (21.9%), and urinary retention (18.8%).
No side effects of therapy resulted in removal of the IDDS. The use of
through IDDS for the treatment of non-cancer and cancer-related pain
in geriatric patients is successful (5).
196
Neuromodulative treatment of chronic pain syndromes is a modern

mode of treatment of neuropathic and ischemic pain. Its effectiveness
is well documented in the literature. The objective of this work is to
present the results of treatment of chronic pain syndromes based on 8-
year experience in the Department of Neurosurgery, 10th Military
Clinical Hospital, Bydgoszcz, Poland. Since 2002, 9 operations of
MCS were conducted, 2 of DBS, 45 of SCS and 5 of sacral root
stimulation in the treatment of chronic pain. Good long-term results of
neuromodulation in the form of clinical improvement (> 50%) in 4 of
9 patients with MCS (44%) were obtained, in 13 diagnosed with failed
back surgery syndrome, 8 with other neuropathic pain, and 11 with
angina pectoris from a group of 45 were treated with SCS. Sacral root
stimulation has been successful in 3 of 5 patients with perianal pain.
The best treatment results in SCS, although statistically insignificant,
were observed in patients treated due to failed back surgery syndrome
(13 out of 15) and angina pectoris (11 out of 15) (p=0.12). In patients
with neuropathic pain, peripheral and central, improvement was
obtained in 8 out of 15 patients. In conclusion, a good indication for
SCS is failed back surgery syndrome and angina pectoris. MCS is
helpful in the treatment of chronic central neuropathic pain. Further
observations and a larger group of patients are necessary for a reliable
assessment of the effectiveness of neuromodulative treatment of
chronic pain (6).
Deep brain stimulation
The past decade (1999-2009) has witnessed a dramatic increase in

the use of electrical stimulation to treat chronic, intractable pain. The
implantation of electrodes in close proximity to peripheral nerves,
known as peripheral nerve stimulation, has been enthusiastically
adopted by neurosurgeons and interventional pain specialists. The
most common conditions treated with this technique are headache and
complex regional pain syndromes. The potential application of
197
peripheral neuromodulation to relatively common and frequently

disabling conditions such as migraine and LBP represents an exciting
phase in the evolution of contemporary pain surgery (7).
Electrical spinal neuromodulation in the form of SCS is currently
used for treating chronic painful conditions such as complex regional
pain syndrome, DPN, postherpetic neuralgia, peripheral ischemia,
LBP, and other conditions refractory to more conservative treatments.
To date, there are very few published reports documenting the use of
SCS in the treatment of head/neck and upper limb pain. This paper
reports a case series of 5 consecutive patients outlining the use of SCS
to treat upper extremity pain. All subjects had previously undergone
cervical fusion surgery to treat chronic neck and upper limb pain.
Patients were referred following failure of the surgery to manage their
painful conditions. Spinal cord stimulators were placed in the cervical
epidural space through a thoracic needle placement. Stimulation
parameters were adjusted to capture as much of the painful area(s) as
possible. In total, 4 out of 5 patients moved to implantation. In all
cases, patients reported significant (70-90%) reductions in pain,
including axial neck pain and upper extremity pain. Two patients with
associated headache and lower extremity pain obtained relief after
paresthesia-steering reportedly covered those areas. Moreover, 2
patients reported that cervical SCS significantly improved axial LBP.
Patients continue to report excellent pain relief up to 9 months
following implantation. This case series documents the successful
treatment of neck and upper extremity pain following unsuccessful
cervical spine fusion surgery (8).
During the past 15 years, 68 patients with chronic pain syndromes
underwent DBS. The objective of this study was to analyze the long-
term outcomes to clarify patient selection criteria for DBS. Patients
were referred from a multidisciplinary pain clinic after conservative
treatment failed. Electrodes for DBS were implanted within the
periventricular gray matter, specific sensory thalamic nuclei, or the
internal capsule. Each patient was followed on a 6-monthly follow-up
basis and evaluated with a modified VAS. Follow-up periods ranged
from 6 months to 15 years, with an average follow-up period of 78
months. The mean age of the 54 men and 14 women in the study was
51.3 years. Indications for DBS included 43 patients with failed back
syndrome, 6 with peripheral neuropathy or radiculopathy, 5 with
thalamic pain, 4 with trigeminal neuropathy, 3 with traumatic spinal
cord lesions, 2 with causalgic pain, 1 with phantom limb pain, and 1
with carcinoma pain. After initial screening, 53 of 68 patients (77%)
elected internalization of their devices; 42 of the 53 (79%) continue to
198
receive adequate relief of pain. Therefore, effective pain control was

achieved in 42 of 68 of our initially referred patients (62%). Patients
with failed back syndrome, trigeminal neuropathy, and peripheral
neuropathy fared well with DBS, whereas those with thalamic pain,
SCI, and postherpetic neuralgia did poorly. DBS in selected patients
provides long-term effective pain control with few side effects or
complications (9).
Intracranial neurostimulation for pain relief is most frequently
delivered by MCS, the sensory thalamus, or the periaqueductal and
periventricular gray matter. The stimulation of these sites through
MCS and DBS has proven effective for treating a number of
neuropathic and nociceptive pain states that are not responsive or
amenable to other therapies or types of neurostimulation. Prospective
randomized clinical trials to confirm the efficacy of these intracranial
therapies have not been published. Intracranial neurostimulation is
somewhat different than other forms of neurostimulation in that its
current primary application is for the treatment of medically
intractable movement disorders. However, the increasing use of
intracranial neurostimulation for the treatment of chronic pain,
especially for pain not responsive to other neuromodulation
techniques, reflects the efficacy and relative safety of these
intracranial procedures. First employed in 1954, intracranial
neurostimulation represents one of the earliest uses of
neurostimulation to treat chronic pain that is refractory to medical
therapy. Currently, 2 kinds of intracranial neurostimulation are
commonly used to control pain: MCS and DBS. MCS has shown
particular promise in the treatment of trigeminal neuropathic pain and
central pain syndromes such as thalamic pain syndrome. DBS may be
employed for a number of nociceptive and neuropathic pain states,
including cluster headaches, chronic LBP, failed back surgery
syndrome, peripheral neuropathic pain, facial deafferentation pain,
and pain that is secondary to brachial plexus avulsion. The unique lack
of stimulation-induced perceptual experience with MCS makes MCS
uniquely suited for blinded studies of its effectiveness (10).
The purpose of this study was to evaluate prospectively the effects
of SCS implantation, performed with the patient awake and providing
feedback, in patients with primary reports of intractable leg pain. The
surgical procedure was performed with the patient awake and
providing feedback to ensure optimal pain relief from the lead
placement. The study group comprised 40 patients, ranging in age
from 28 to 86 years. The average symptom duration was 65.4 months,
and the average number of prior lumbar spine surgeries was 2.3
199
(range, 1 to 8). The primary data collection periods were preoperative,

6 weeks after, and 12 and 24 months after surgery. Statistically
significant improvement in isometric lower extremity function was
demonstrated 6 weeks after the SCS implantation. In the more painful
leg, the performance increased from 457.5 ft-lb-sec to 629.8 ft-lb-sec
p<0.01). The performance remained significantly improved at the 12-
and 24-month follow-ups. Significant improvement was demonstrated
on the physical scale of the Sickness Impact Profile at 6 weeks. At 24
months, all 3 scales (physical, psychological, and other) as well as the
total score were significantly improved. Statistically significant
decreases in pain, assessed by changes in VAS, were noted in the legs,
when walking, and in overall lifestyle. The use of narcotic medication
decreased at all follow-up periods. At least 66% of the patients who
were taking narcotics before SCS were taking reduced amounts or no
narcotics 2 years later. At the time of the 24-month follow-up, at least
70% of patients reported that the procedure helped them, and would
recommend it to someone with similar symptoms. In conclusion, SCS
implantation can result in improved physical function and decreased
pain in patients who are carefully screened and in whom the
implantation is performed with the patient awake to help ensure
optimal pain-relieving lead placement (11).
References
1. Plow EB, Pascual-Leone A, Machado A. Brain stimulation in the treatment of
chronic neuropathic and non-cancerous pain. J Pain. 2012;13(5):411-24.
2. Pirotte B. Neurosurgical treatments for pain. Rev Med Brux. 2012; 33(4):359-
66.
3. Nizard J, Raoul S, Nguyen JP, Lefaucheur JP. Invasive stimulation therapies
for the treatment of refractory pain. Discov Med. 2012;14(77):237-46.
4. Kumar K, Toth C, Nath RK, Laing P. Epidural spinal cord stimulation for
treatment of chronic pain - some predictors of success. A 15-year experience. Surg
Neurol. 1998;50(2):110-20; discussion 120-1.
5. Raffaeli W, Righetti D, Caminiti A, et al. Implantable intrathecal pumps for the
treatment of noncancer chronic pain in elderly population: drug dose and clinical
efficacy. Neuromodulation. 2008;11(1):33-9.
6. Sokal P, Harat M, Paczkowski D, et al. Results of neuromodulation for the
management of chronic pain. Neurol Neurochir Pol. 2011;45(5):445-51.
7. Bittar RG, Teddy PJ. Peripheral neuromodulation for pain. J Clin Neurosci.
2009;16(10):1259-6.
8. Vallejo R, Kramer J, Benyamin R. Neuromodulation of the cervical spinal cord
in the treatment of chronic intractable neck and upper extremity pain: a case series
and review of the literature. Pain Physician. 2007;10(2):305-11.
9. Kumar K, Toth C, Nath RK. Deep brain stimulation for intractable pain: a 15-
year experience. Neurosurgery. 1997;40(4):736-46; discussion 746-7.
10. Levy R, Deer TR, Henderson J. Intracranial neurostimulation for pain control:
a review. Pain Physician. 2010;13(2):157-65.
200
11. Ohnmeiss DD, Rashbaum RF, Bogdanffy GM. Prospective outcome

evaluation of spinal cord stimulation in patients with intractable leg pain. Spine (Phila
Pa 1976). 1996;21(11):1344-50; discussion 1351.
NEUROSURGICAL TREATMENT
Pain represents the most frequent symptom faced by GPs and is
associated with 60% of neurological troubles. Pain consists of a
conscious, subjective, unpleasant and protective sensory experience
transmitted by thermoalgic pathways in the CNS (nociceptive pain).
Lesioning of peripheral or central sensory pathways can also generate
pain associated with hypoesthesia (phantom or neuropathic pain).
Since the 1920's, neurosurgeons have attempted to alleviate
nociceptive and neuropathic chronic pain by interrupting (irreversible
interruptive techniques) thermoalgic fibers (neurotomies, rhizotomies,
cordotomies, tractotomies, thalamotomies, and cingulotomies). Some
of them (neurotomies, and rhizotomies) are still used today when all
medications have failed. They can provide immediate and tremendous
pain relief like in trigeminal neuralgia. However, the technique, when
insufficiently selective, can generate a neuropathic pain and then a
short-lasting pain relief. Increasing knowledge on pathophysiological
mechanisms of pain allowed surgery to interfere with the functioning
of the sensory circuits without lessening and to modulate neuronal
activity in order to reduce pain (neuromodulation) (1).
Percutaneous thoracic cordotomy
The management of severe, medically intractable pain is a

significant challenge for neurosurgeons and pain management
physicians. An existing technique that can effectively alleviate
contralateral chronic pain is cordotomy, interruption of the lateral
spinothalamic tract of the spinal cord. Since 1912, cordotomy has
evolved from a relatively morbid open surgical procedure to a
percutaneous radiofrequency procedure with low morbidity. A case
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with a 41-year follow-up of percutaneous cordotomy for non-cancer

pain that resulted in over 35 years of complete analgesia is described.
This case shows that percutaneous cordotomy can provide long-
lasting, complete analgesia in some patients and merits continuation as
a part of the neurosurgical arsenal of pain therapies (2).
Neurosurgery can affect pain's pathways from the receptor up to
the "centers" of its reception and perception, either by destroying or
by stimulating them. Early in neurosurgery's development, and still
today, ablative procedures are able to suppress or alleviate pain.
However, in most cases, such ablations have only remained effective
for a few months or, at best, a few years. This is why, from the 1960s
on, a better understanding of the mechanism of pain inspired
development of electrical and chemical neuromodulation procedures
at every level of the nociceptive system (peripheral nerve, cord,
thalamic, periventricular/aqueductal gray, and cortical centers). The
encouraging outcomes are attracting increasing attention and interest
among clinicians. The indications for undertaking an ablative vs. a
neurostimulative procedure, as well as selection of the anatomical
target, depend largely on whether pain is nociceptive or neuropathic,
given that most of these indications overlap to some extent. In
addition, because the published outcomes are not based on universal
criteria, it is difficult for the attending physician to select the type of
procedure most suitable to the pain problem (3).
References
1. Pirotte B. Neurosurgical treatments for pain. Rev Med Brux. 2012;33(4):359-
66.
2. Collins KL, Taren JA, Patil PG. Four-decade maintenance of analgesia with
percutaneous cordotomy. Stereotact Funct Neurosurg. 2012;90(4):266-72.
3. Nicolaidis S. Neurosurgical treatments of intractable pain. Metabolism.
2010;59 Suppl 1:S27-31. l.2010.07.018.
To sum up: this is a contemporary approach to a patient with

chronic pain. As we see, different pharmacotherapeutic modalities can
be used for chronic pain management. When these modalities fail,
neuromodulation therapy can be considered.
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NON-ADHERENCE WITH MEDICATIONS

Chronic pain that has been recognized as a major worldwide health
care problem should be treated with the same priority as the disease
that caused it, and patients should receive adequate pain relief (1). In
chronic non-malignant pain, medication is often used as an important
cornerstone of the treatment. Medication non-adherence is a frequent
problem in chronic conditions. In patients with chronic non-malignant
pain, medication non-adherence ranges between 8-53%. Two types of
non-adherence can be identified: underuse and overuse of pain
medication (2).
With the growth in opioid therapy for the treatment of chronic
pain, health care providers have focused their attention on avoiding
overuse of opioid medications, specifically to avoid addiction,
dependency, and other misuse. Qualitative and quantitative reviews of
medication adherence, by contrast, focus primarily on why patients
underuse or do not take their medications as prescribed and find non-
adherence rates of approximately 25% (3).
To achieve good analgesia, patient adherence to a prescribed pain
treatment is of high importance. Patients with chronic pain often do
not use their medication as prescribed, but change the frequency of
intake. This can result in poor treatment outcomes and may necessitate
additional emergency treatment, which increases the overall costs.
Factors that influence adherence include knowledge of the disease,
realistic treatment expectations, perceived benefit from treatment, side
effects, depression, dosing frequency, and attitudes of relatives/others
toward opioids. Addressing these factors should ensure a good
treatment outcome. Good adherence to pain therapy is associated with
improved efficacy in pain relief and QOL. Opioids have become an
integral part of the treatment of moderate to severe chronic non-cancer
pain. They may cause unpleasant side effects such as nausea,
vomiting, and constipation. Patients should be informed adequately
about side effects, which should be treated pro-actively to foster
adherence to treatment. Signs of tolerance, hyperalgesia, and drug
abuse should be monitored as these may occur in some patients. An
individualized treatment algorithm with a clear treatment goal and
regular treatment reassessment is key for successful treatment. Long-
acting opioids offer sustained pain relief over 24 hours with
manageable side effects - they simplify treatment thereby supporting
treatment adherence (1).
The aim of this study was to determine the prevalence of
medication underuse and overuse non-adherence in a large sample of
203
chronic pain patients treated in a multidisciplinary pain center. An

extensive list of demographic, disease-related, treatment-related and
health behavior-related factors was included to compare these factors
between adherent, overusers, and underusers, respectively. Self-report
was used to measure medication adherence. Of the patients, 48% were
non-adherent, with 34% of them showing underuse and 14% overuse
of the prescribed medication. Multivariable analyses showed a
significant association between younger age and medication non-
adherence (both underuse and overuse). Underuse was significantly
associated with self-medication use. Overuse was associated with
current smoking, opioid prescription, and more medication intake
moments. In conclusion, medication non-adherence, especially
underuse of medication, occurs frequently among patients with
chronic non-malignant pain (4).
The main objective of this study was to examine determinants of
both medication underuse and overuse non-adherence in patients with
chronic non-malignant pain, with a focus on factors related to all 5
categories of determinants of medication non-adherence
simultaneously, as proposed by the WHO. In this multicenter cross-
sectional study, carried out in 3 multidisciplinary outpatient pain
centers in Flanders, Belgium, 265 patients with chronic non-malignant
pain were included. Medication non-adherence was assessed by a self-
report interview. Of the patients, 38% were fully adherent. Based on
multivariable analyses, underuse was significantly associated with
more prescribed analgesics (OR=2.303), self-medication (OR=4.679),
lower pain intensity (OR=0.821), active coping strategies (OR=1.132),
and lack of information (OR=0.268). Overuse of medication was
associated with more prescribed analgesics (OR=1.645) and current
smoking (OR=2.744). In conclusion, patients underusing or overusing
their medication do have a different risk profile. The set of
determinants of non-adherence, proposed by WHO, is suitable to
study determinants of underuse, but the framework is less suitable to
study determinants of medication overuse (2).
The objective of this study was to identify the degree to which
illness perceptions and medication beliefs explain variations in
reported adherence to medication prescribed for the treatment of non-
malignant chronic pain and to test the applicability of an extended
version of the self-regulatory model in the chronic pain population. A
cross-sectional design included 217 clinic patients completing
validated questionnaires assessing their illness perceptions,
medication beliefs and reported adherence to medication. Perceptions
of illness (pain) as chronic, uncontrollable and unremitting were
204
associated with greater adherence, fewer medication concerns and a

belief that treatment was necessary. Structural equation modeling
supports an extended self-regulatory model for chronic pain. It
suggests that patients holding perceptions of serious consequences of
pain and high emotion levels have more concerns about medication
and are less adherent. Perceptions of serious illness consequences are
associated with stronger beliefs about the necessity of medicines and
greater adherence. Beliefs about illness and medication are associated
with adherence to treatment in chronic pain and an extended self-
regulatory model can explain this (5).
The main objective of this study was to identify the prevalence of
underuse of opioid medications and the reasons and implications of
underuse. As part of a variety of structured assessments, subjects were
asked detailed questions about how they used their opioid medication
in their daily lives. Participants included 191 veterans who received an
opioid prescription for any pain problem within the 12 months before
the interview. A patient who underused his/her medication was
defined as one who took less than his/her prescribed dose of
medication and reported that pain impaired his/her ability to engage in
normal daily activities. Underuse of opioids (20%) was more
common than overuse (9%). Patients who underused their opioids
offered the same reasons for underuse that patients report for other
medications. However, while underusers reported more pain than
other opioid users they filled only slightly fewer opioid prescriptions.
Communication problems between patients and providers about
opioids were common. In conclusion, improved communication
between patients and providers and shared decision-making regarding
opioid prescriptions may improve pain management and minimize the
problems associated with over-prescription of opioids (i.e., diversion)
(3).
Non-adherence to opioid prescriptions can decrease the safety and
efficacy of opioid therapy. Identifying factors associated with over-
and underuse of opioids in patients presenting with pain may improve
prescribing and pain management. Patients presenting with pain often
also present with somatization, and somatization is associated with
both excessive use of and non-adherence to medications. This study
examines the relationship between somatization and non-adherence
(over- and underuse) to opioid prescriptions in the Veteran sample
(n=181). Veterans who received an opioid prescription at a Veterans
Affairs Palo Alto Health Care System in the prior year participated by
completing a 1.5 hour semistructured interview which included
assessments of depressive symptoms, somatization, medication side
205
effects, and opioid pain medication usage. The percentage of patients

non-adherent to opioid prescriptions increased as a function of
somatization: Compared to no somatization, all levels of somatization
were associated with higher rates of underuse, while severe
somatization was associated with increased rates of overuse. Increased
depression and medication side effects were associated with decreased
adherence to opioid prescriptions. However, somatization mediated
the relationship between depressive symptoms and opioid-use patterns
as well as medication side effects and opioid use patterns. These
findings suggest that pain management treatment plans can be
optimized by addressing patient distress about physical symptoms
when considering the use of prescription opioid medications (6).
Assessment: patients with chronic pain often do not use their

medication as prescribed, but change the frequency of intake. Factors
that influence adherence include knowledge of the disease, realistic
treatment expectations, perceived benefit from treatment, side effects,
depression, dosing frequency, younger age, and attitudes toward
opioids. Underuse is associated with more prescribed analgesics, self-
medication use, lower pain intensity, active coping strategies, lack of
information, perceptions of serious consequences of pain, high
emotion levels, having concerns about medication, and
communication problems between patients and providers about
opioids.
References
1. Graziottin A, Gardner-Nix J, Stumpf M, Berliner MN. Opioids: how to improve
compliance and adherence. Pain Pract. 2011;11(6):574-81.
2. Broekmans S, Dobbels F, Milisen K, et al. Determinants of medication
underuse and medication overuse in patients with chronic non-malignant pain: a
multicenter study. Int J Nurs Stud. 2010;47(11):1408-17.
3. Lewis ET, Combs A, Trafton JA. Reasons for under-use of prescribed opioid
medications by patients in pain. Pain Med. 2010;11(6):861-71.
4. Broekmans S, Dobbels F, Milisen K, et al. Pharmacologic pain treatment in a
multidisciplinary pain center: do patients adhere to the prescription of the physician?
Clin J Pain. 2010;26(2):81-6.
5. Nicklas LB, Dunbar M, Wild M. Adherence to pharmacological treatment of
non-malignant chronic pain: the role of illness perceptions and medication beliefs.
Psychol Health. 2010;25(5):601-15.
6. Trafton JA, Cucciare MA, Lewis E, Oser M. Somatization is associated with
non-adherence to opioid prescriptions. J Pain. 2011;12(5):573-80.
206
READINESS TO CHANGE
Readiness to change attitudes and behavior is an important
prerequisite for coping with chronic pain in respect to self-
management. Using the transtheoretical model, the stages are
described as precontemplation, contemplation, preparation, action and
maintenance. The process depends on the patient's decisional balance
as well as the subjective weighting of the advantages and
disadvantages of certain behavior patterns; the level of self-efficacy
also plays a role. To encourage the readiness to change and self-
motivation, a helpful concept should be used in medical and
psychological consultations that are motivational interviewing,
whereby together with the patient, the perceived advantages and
disadvantages of the necessary changes should be considered. More
weight to the advantages should be attempted in order to move the
decisional balance in the direction of behavioral change and
maintenance (1).
According to the transtheoretical model and criteria of treatment
outcome, patients' readiness to behavioral changes are positively
associated and have in part already been confirmed. For a stable effect
of therapeutic treatment, patients' readiness to change seems
indispensable for an independent and active pain management. In
addition to an enhanced QOL, increasing patients' motivation is a
declared objective of the treatment at Dresden's Comprehensive Pain
Center. In this study, it was examined how the readiness to change
develops in the course of and during the 2 years following the
multimodal treatment program. Associations between outcome criteria
of the treatment and patients' readiness to change were explored. The
database included 169 patients who took part in a 4-week
interdisciplinary, partially residential pain treatment. Beside the
Freiburg Pain Stages questionnaire ("Frieburger Fragebogen - Stadien
der Bewältigung chronischer Schmerzen", FF-STABS), a
comprehensive pain diagnostic inventory including the PDI, the SF-36
questionnaire, and the HADS was completed at 6 different time points
(beginning of treatment, end of treatment, booster session after 10
weeks, after 6, 12, and 24 months). Significant differences in the level
of readiness to change between the beginning of treatment and all
follow-up measures were observed. The average patients' readiness to
change was still higher after 2 years than at the first measurement.
However, a differentiated consideration revealed a small portion of
patients who showed no change or even a reduction of motivation.
The stages of readiness to change remained stable after an additional
207
week (booster session), irrespective of the direction of the previous

change. Regarding therapeutic outcome, significant short- and long-
term improvements were evident. For single outcome parameters,
positive associations with the stages of readiness to change were
found. The outpatient pain management program favorably affected
patients' motivation and general QOL. This effect was stable over a
long period (2).
Relative readiness to assume a self-management approach to
chronic pain can be conceptualized as a stage model. Although both
initial stage (precontemplation, action) and changes in attitudes
reflecting stage orientation predict treatment outcome, the joint
contributions of these factors need to be examined. Sixty-five chronic
pain patients, participating in a 4-week multidisciplinary pain
program, completed the PSOCQ, subscales of the MPI, and the Beck
Depression Inventory at pre-, mid- and post-treatment. Patients were
assigned to stage group (precontemplation or action) based on whether
their Precontemplation or Action subscale scores were highest.
Results showed that: (a) stage group interacted with pre- to mid-
treatment Precontemplation subscale changes to predict mid- to late-
treatment pain severity and interference changes such that
precontemplation attitude decreases were related to reduced pain and
interference only among patients who were already action stage at pre-
treatment; (b) stage group interacted with pre- to mid-treatment
Action subscale changes to predict mid- to late-treatment interference
and activity changes such that action attitude increases were related to
reduced interference and increased activity only among patients at the
action stage at pre-treatment; (c) pre- to mid-treatment decreases in
depression did not account for these effects. Results suggest that any
advantage enjoyed by patients with predominant action attitudes at
pre-treatment may be enhanced by consolidating a pain self-
management approach during treatment. By contrast, late-treatment
gains of patients initially taking a predominant precontemplation
stance were unaffected by their degree of early-treatment attitude
changes (3).
A patient's readiness to adopt a self-management approach to pain
has been hypothesized to increase during multidisciplinary pain
treatment and to impact pain coping responses. The PSOCQ was
designed to assess 4 components of readiness to self-manage pain:
pre-contemplation, contemplation, action, and maintenance. Three
hypotheses concerning this construct in 2 different samples of patients
with chronic pain were tested: (1) readiness to self-manage pain, as
assessed by the PSOCQ, would increase from pre-multidisciplinary
208
pain treatment to post-treatment and follow-up; (2) changes in

readiness to self-manage pain measured pre-treatment to post-
treatment and follow-up would be associated with changes in the use
of pain coping strategies; and (3) increases in readiness to self-manage
pain would be associated with improvement in multidisciplinary pain
treatment. In conclusion, the findings supported all 3 hypotheses.
Motivation in the self-management of pain is associated with
improvement in multidisciplinary pain treatment and pain coping (3).
Motivation in the concept of the transtheoretical model is the
readiness to change attitudes and behavior. According to this model,
patients with chronic pain pass through different stages of change
(precontemplation, preparation, action, and maintenance) before they
adopt a new behavior (e.g. relaxation exercise). This study analyses
the impact of readiness to change over the course of 3 months.
Different questionnaires [coping with pain, impairment of pain, self-
efficacy expectations and the German version of the PSOCQ, the FF-
STABS] were administered 2 times to 74 patients at a rehabilitation
clinic. The stages of preparation, action and maintenance show
statistically significant interrelations with coping with chronic pain
subscales, and precontemplation covaries significantly with
impairments of pain. The data suggest the relevance of the "readiness
to change" concept for the realization of appropriate coping with
chronic pain (4).
The main purpose of this study was to conduct a systematic review
to examine relationships among psychosocial factors and health
behavior change in cancer survivors. Electronic databases and
reference sections of relevant article and chapters located all studies
that met defined criteria (i.e., examined at least one psychosocial
variable and one health behavior change in a sample of cancer
survivors) were searched. Thirty studies met criteria. Social support,
locus of control, and distress were the focus of most of this literature.
Although findings are inconsistent, social support appears to be
helpful in making adaptive changes, particularly in exercise; internal
locus of control facilitates positive health behavior changes but may
depend on survivors' perceptions of links between behaviors and
cancer or recurrence, and cancer-related distress may facilitate
adaptive changes although more general distress may impede them.
Studies based on theoretical models of health behavior change have
demonstrated that stage of readiness to change, intentions, and self-
efficacy are powerful determinants of improvements in health
behaviors (5).
209
References
1. Rau J, Petermann F. Motivational readiness for chronic pain patients. Schmerz.
2008;22(2):209-17;
2. Küchler A, Sabatowski R, Kaiser U. Chronic pain patients' readiness to change
after multimodal treatment: short- and long-term effects. Schmerz. 2012;26(6):670-6.
3. Burns JW, Glenn B, Lofland K, et al. Stages of change in readiness to adopt a
self-management approach to chronic pain: the moderating role of early-treatment
stage progression in predicting outcome. Pain. 2005;115(3), 322-31.
3. Jensena MP, Nielsonc WR, Turnera JA, et al. Changes in readiness to self-
manage pain are associated with improvement in multidisciplinary pain treatment and
pain coping. Pain. 2004;111(1-2):84-95.
4. Rau J, Ehlebracht-König I, Petermann F. Impact of readiness to change of the
transtheoretical model (TTM) for the course of coping with chronic pain. Schmerz.
2007;21(6):522-8.
5. Park CL, Gaffey AE. Relationships between psychosocial factors and health
behavior change in cancer survivors: an integrative review. Ann Behav Med.
2007;34(2):115-34.
210
THE DISEASES OF THE BONES
Patients have suffered from pain in their bones, which may be

associated with various diseases, for thousands of years. Let us look at
the biblical verses: ―...my strength failed..., and my bones are
consumed‖ (Psalm 31:11) and ―My bones wasted away through my
anguished roaring all day long‖ (32:3). The first verse indicates that
the King‘s bones were used up, his strength decreased, and he had
become very weak. In the second verse, the King‘s bones have
reached a stage where they are extremely thin and weak, causing him
severe pain.
We see that King David suffered from some disease of the bones.
What are the characteristics of the disease of the bones? What is the
most likely diagnosis? What are the epidemiology, mechanism, and
approach to bone diseases?
If a patient with severe intractable bone pain comes to the family
physician or general practitioner clinic, what diagnostic evaluation
would his/her doctor carry out? In this specific ancient case, the
patient's medical record that is the biblical text gives us important
details (descriptions) which can lead to a diagnosis. Of course,
contemporary methods of investigation were unavailable in those
ancient times, for example CT, MRI, or histopathological
investigation. Nevertheless, a precise contemporary diagnosis can be
based on the descriptions given in this patient's medical record.
The topic is fascinating and is based on a logical and
comprehensive study of different diseases, non-malignant vs.
malignant, that can be related to the bone pain in this ancient patient.
This part of the research therefore deals specifically with the bone
diseases that could have been responsible for King David's severe
intractable chronic bone pain.
OSTEOPOROSIS
What does the phrase ―...my bones wasted away... ‖ mean? The
1990 Consensus Development Panel defined osteoporosis as a
―disease characterized by low bone mass and micro architectural
deterioration of bone tissue, leading to enhanced bone fragility and a
consequent increase in fracture risk‖ (1). In recent years, osteoporosis
is defined as a skeletal disorder characterized by compromised bone
211
strength predisposing to an increased risk of fracture. Bone strength

reflects integration of bone density and bone quality (2).
Osteoporosis is a severe public health problem. For example, there
are approximately 700.000 vertebral body compression fractures in
the US each year with approximately 70.000 of these resulting in
hospitalization, with an average hospital stay per patient of 8 days (3).
Osteoporosis is the most common skeletal disorder in the elderly,
characterized by impaired bone strength and increased risk of fracture.
Severe osteoporosis is currently defined by the threshold of bone
density value below the -2.5 SDs of T-score, determined by DXA, and
the presence of one or more fragility fractures. This definition does
not entirely reflect the spectrum of severity of the disease that
provides a variable increase in fracture risk. Italian physicians with
expertise in osteoporosis and metabolic bone diseases in a consensus
statement report the diagnostic criteria for severe osteoporosis in real-
life clinical setting. The group stated that a large number of fractures
occur in subjects with T-score above -2.5. In light of recent advances
on the structural basis of skeletal fragility, it became clear that bone
density represents only one of the contributors to bone strength and
number and severity of fragility fractures. The condition of 2 or more
fragility fractures should be considered as severe osteoporosis,
independently of bone density. The consensus statement proposes a
more specific definition of severe osteoporosis, which should consider
not only densitometric measurements, but also the number and
severity of fragility fractures. Patients' management and choice of
treatment should take into consideration the type and severity of
osteoporotic fractures, in addition to bone density (4).
Normal bone Osteoporotic bone
Taking into consideration a multifactorial nature of bone fragility

in osteoporosis, we do not diagnose "osteoporosis" but a total,
individual 10-year fracture risk (AR-10) based on independent and
212
self-sufficient risk factors. These are: advanced age, previous

osteoporotic fracture, parental history of proximal femur fracture, low
body weight or low BMI, low bone mass, weight loss, physical
inactivity, glycocorticosteroid treatment, androgen deprivation
therapy, RA, smoking, and overuse of alcohol (5,6).
Contemporary medicine measures reduced bone mass by various
techniques including conventional radiographs, CT, single or DXA,
radiographic measurements of cortical width (radiogrammetry),
resonance frequency of the ulna, total body neutron activation
analysis, and X-ray micro densitometry (7). DXA scans to measure
BMD at the spine and hip have an important role in the evaluation of
individuals at risk of osteoporosis, and in helping clinicians' advice
patients about the appropriate use of antifracture treatment. Compared
with alternative bone densitometry techniques, hip and spine DXA
examinations have a number of advantages that include a consensus
that BMD results can be interpreted using the WHO T-score definition
of osteoporosis, a proven ability to predict fracture risk, proven
effectiveness at targeting antifracture therapies, and the ability to
monitor response to treatment (8). At present, severe osteoporosis is
considered BMD below a T-score of -2.5 existing together with a
prevalent fragility fracture. This is a rough categorization of a wide
range of clinical conditions. In osteoporotic patients, 2 different
severities include prognostic severity, i.e., the risk of the occurrence of
other fragility fractures and clinical severity, i.e. the degree of pain
and disability experienced by the patient (9).
Graph of osteoporosis
Osteoporotic bone, structurally altered because of reduction of

BMD and quality deterioration, can easily head for fracture after
minimum mechanical stress. The most common sites of fracture, other
than spine and hip, are, in decreasing order: distal radius, forearm,
213
proximal humerus, other femoral sites, ribs, pelvis, tibia and fibula,
metatarsal bone and calcaneum. The role of diagnostic imaging is
essential in detecting fractures for their immediate and correct
assessment, which is necessary to the planning of treatment, whether
conservative or surgical. Imaging is also important in fracture
monitoring, evaluation of healing and relief of any complications.
Conventional radiology is the most widely used technique in the
diagnosis of fracture, although low sensitivity is mainly in
anatomically complex sites; the role of radiology is undisputed in
monitoring the healing bone callus formation. MDCT is of great help
in doubtful cases, especially in locations as "critical"; its diagnostic
accuracy is elevated with 3D and multi-planar reconstructions,
allowing the surgeon to implement an appropriate therapeutic strategy.
MR is the most sensitive technique in the relief of minimal structural
alteration of the cancellous bone, as it reveals both fracture line and
surrounding bone marrow edema. Its specificity is higher compared to
MDCT and conventional radiology in the differential diagnosis
between osteoporotic and malignant pathological fracture. Bone
scintigraphy is complementary to MRI in detecting occult fractures,
and is crucial in finding metastatic disease in other locations.
Ultrasonography is used in limited districts, and its role is confined to
the relief of cortical interruption in the fractured bone segment. In the
future, technological advances with three-dimensional techniques
(high resolution CT, and high resolution MRI) may improve in vivo
the diagnostic potential with an earlier detection of the ultrastructural
alterations that predispose to the risk of bone fracture (10).
In the diagnosis of femoral fractures, radiodiagnostic has a role in
the different phases of the natural history of these lesions: in diagnosis
and characterization of fractures, in follow up of the efficacy of
therapy, evolution of fractures and any complications, in studies of
risk factors of fractures. Diagnostic imaging employs method of
investigation as conventional radiology, still crucial in detection,
characterization and control of fracture, CT and MR, essential in
doubt of occult fracture and in differential diagnosis between the
possible causes of pathologic fracture. DXA is still the fundamental
methodic in diagnosis and assessment of osteoporosis, while
quantitative CT, peripheral quantitative CT and high resolution CT are
experimental techniques used to study in vivo bone microarchitecture
and its metabolic and pathological changes (11).
Insufficiency fractures are due to normal stress exerted on
weakened bone. Most commonly postmenopausal osteoporosis is the
cause for insufficiency fractures. Additional conditions affecting bone
214
turnover include osteomalacia, chronic renal failure, and high-dose

corticosteroid therapy. It is a challenge for the radiologist to detect and
diagnose insufficiency fractures as well as to differentiate them from
malignant fractures. Radiographs are the basic modality used for
screening of insufficiency fractures, yet depending on the location of
the fractures, sensitivity is limited. MRI is a very sensitive tool to
visualize bone marrow abnormalities associated with insufficiency
fractures and allows differentiation of benign vs. malignant fractures.
Thin section MDCT depicts subtle fracture lines allowing direct
visualization of cortical and trabecular bone. Dedicated Mikro-CTs
(Xtreme-CT) can detect subtle fractures reaching an in plane
resolution of 80 μm. Bone scintigraphy still plays a role in detecting
fractures, with good sensitivity but unsatisfactory specificity. PET-CT
with hybrid-scanners has been the upcoming modality for the
differentiation of benign from malignant fractures. Bone densitometry
and clinical fracture history may determine the future risk of possible
insufficiency fractures (12).
Assessment of the patient with osteoporosis includes history and
physical examination, laboratory testing, and imaging studies.
Information gathered during this assessment assists clinicians in
targeting strategies to prevent fractures. The medical history should
contain items such as personal and family history of fractures,
lifestyle, and intake of substances such as vitamin D, calcium,
corticosteroids and other medications. The physical examination can
reveal relevant information such as height loss and risk of falls. BMD,
most commonly determined by DXA, best predicts fracture risk in
patients without previous fracture. BMD testing is most efficient in
women > 65 years old but is also helpful for men and women with risk
factors. Serial BMD tests can identify individuals losing bone mass,
but clinicians should be aware of what constitutes a significant
change. Laboratory testing can detect other risk factors and can
provide clues to etiology. Selection of laboratory tests should be
individualized, as there is no consensus regarding which tests are
optimal. Biochemical markers of bone turnover have a potential role
in fracture risk assessment and in gauging response to therapy, but are
not widely used at present. Clinicians should be aware of problems
with vitamin D measurement, including seasonal variation, variability
among laboratories, and the desirable therapeutic range. Careful
assessment of the osteoporotic patient is essential in developing a
comprehensive plan that reduces fracture risk and improves QOL (13).
Because the King‘s bones were ―...wasted away...,‖ they became
weak, that is, the bone mass decreased. The decreased bone mass
215
indicates that the King was suffering from osteoporosis. Because there
is no word in the biblical text about any of the methods listed above,
one can suggest that no methods of evaluating osteoporosis were in
use at that time. Nevertheless, the biblical verses quoted above
indicate convincingly that the King suffered from osteoporosis.
References
1. Consensus Development Conference. Prophylaxis and treatment of
osteoporosis. Am J Med. 1991;90:107-11.
2. Kishimoto H. Change in the definition of osteoporosis especially on bone
quality. Clin Calcium. 2005;15:736-40.
3. Semionov K, Lieberman IH. Vertebral augmentation in osteoporosis and bone
metastasis. Curr Opin Support Palliat Care. 2007;1:323-7.
4. Nuti R, Brandi ML, Isaia G, et al. New perspectives on the definition and the
management of severe osteoporosis: the patient with two or more fragility fractures. J
Endocrinol Invest. 2009;32(9):783-8.
5. Czrewiński E, Badurski JE, Marcinowska-Suchowierska E, Osieleniec J.
Current understanding of osteoporosis according to the position of the World Health
Organization (WHO) and International Osteoporosis Foundation. Ortop Traumatol
Rehabil. 2007;9:337-56.
6. Liu H, Page NM, Goldzweig CL, et al. Screening for osteoporosis in men: a
systematic review for an American College of Physicians guideline. Ann Intern Med.
2008;148:685-701.
7. Rosenblum AL. Connective tissue disorder in diabetes. In: Alberti K.G.M.M,
Zimmet P, DeFronzo R.A, Keen H (eds). International Textbook of Diabetes. Vol.
2. 2nd ed. New York, NT: John Wiley & Sons. 1997, pp. 1517-29.
8. Blake GM, Fogelman I. The role of DXA bone density scans in the diagnosis
and treatment of osteoporosis. Postgrad Med. 2007;83:509-17.
9. Trevisan C. New proposals for the definition of severe osteoporosis. Aging Clin
Exp Res. 2007;19(4 Suppl):3-6.
10. D'Elia G, Roselli G, Cavalli L, et al. Severe osteoporosis: diagnosis of non-hip
non-vertebral (NHNV) fractures. Clin Cases Miner Bone Metab. 2010;7(2):85-90.
11. Caracchini G, Cavalli L. Severe osteoporosis: diagnosis of femoral fractures.
Clin Cases Miner Bone Metab. 2010;7(2):97-101.
12. Krestan CR, Nemec U, Nemec S. Imaging of insufficiency fractures. Semin
Musculoskelet Radiol. 2011;15(3):198-207.
13. Lata PF, Elliott ME. Patient assessment in the diagnosis, prevention, and
treatment of osteoporosis. Nutr Clin Pract. 2007;22(3):261-75.
216
RISK FACTORS FOR MALE OSTEOPOROSIS

Male osteoporosis is challenging to diagnose and to treat.
Underestimation of the risk of male osteoporosis, the combined
presence of several interwoven causative factors in many patients, and
uncertainty regarding the absorptiometry cutoffs associated with
fractures are major obstacles to the diagnosis of male osteoporosis and
to the identification of men at risk for fractures. The lifetime risk of
osteoporotic fracture is estimated at 15% among men older than 50
years. One-third of proximal femoral fractures occur in men, and the
associated mortality rate is 2- to 3-fold that in women. In men, nearly
half the cases of osteoporosis are related to disease, medications, or
risk factors. Although the criteria for diagnosing male osteoporosis are
not agreed on, the definitions developed by the WHO can be used
provided the reference population is composed of young males. An
absorptiometry T-score ≤ -2.5 is useful for diagnosing osteoporosis
but fails to adequately predict the fracture risk. The identification of
men at high risk for fractures requires a combined evaluation of BMD
data, clinical risk factors, and risk factors for falls (1).
Although osteoporosis is often regarded as a disease of women,
30% of osteoporotic fractures occur in men. Risk factors for
osteoporosis or fractures in men include previous fragility fractures,
maternal history of fragility fracture, hypogonadism, low body mass
or BMI, smoking, high alcohol consumption, low calcium intake,
corticoid therapy, low physical activity, and the presence of conditions
such as hyperthyroidism, hyperparathyroidism, hypercalcaemia,
hypercalciuria or chronic inflammatory diseases (2,3).
L1 osteoporotic fracture
217
The aim of this study was to estimate the magnitude of association

and quality of supporting evidence linking multiple risk factors with
low bone mass-related fractures in men. MEDLINE, EMBASE, Web
of Science, SCOPUS and Cochrane CENTRAL through February
2010 were searched. Further studies by reviewing reference lists from
selected studies and reviews were identified. Eligible studies had to
enroll men and quantitatively evaluate the association of risk factors
with low bone density-related fractures. Fifty-five studies provided
data sufficient for meta-analysis. The quality of these observational
studies was moderate with fair levels of multivariable adjustment and
adequate exposure and outcome ascertainment. Statistically significant
associations were established for age, low BMI, current smoking,
excessive alcohol use, chronic corticosteroid use, history of prior
fractures, history of falls, history of hypogonadism, history of stroke,
and history of diabetes. Statistical heterogeneity of the meta-analytic
estimates of all associations was significant except for chronic
corticosteroid use. None of these associations were of large magnitude
(i.e. AOR were generally < 2). Multiple risk factors for fractures in
men were identified, but their usefulness for stratifying and selecting
men for bone density testing remains uncertain (4).
Relevant literature was identified through a search of MEDLINE
(1966-June 2003) limited to English-language studies in men. The
search terms included fractures, bone density, or osteoporosis plus
either epidemiology, diagnosis, prevention, control, or therapy.
Additional search terms included specific subtopics (e.g.,
bisphosphonates, calcium, exercise, and PTH). Morbidity after
fragility fracture is at least as high in men as in women, and the rate of
fracture-related mortality 1 year hip fracture is approximately double
in men compared with women. The bioavailable fraction of
testosterone slowly declines into the ninth decade in men. There is
evidence that the effect of estrogen on bone is greater than that of
testosterone in men. Diagnosing osteoporosis in men is complicated
by a lack of consensus on how it should be defined (2).
Prevention is paramount and should begin in childhood. During
adulthood, calcium (1000-1500 mg/d), vitamin D (400-800 IU/d) and
adequate physical activity play crucial preventive roles (2).
Treatment of osteoporosis is recommended in men aged > 65 years
with low bone mass (T-score < -2.5), in men aged 50 to 65 years with
low bone mass and at least one risk factor for osteoporosis or fracture,
in men aged < 50 years with Z-score < -2 with at least one risk factor
for osteoporosis or fracture and in men with at least 2 fragility
fractures (3). The bisphosphonates are the first choice, whereas there
218
is less support for the use of calcitonin or androgen therapy. PTH is a

promising anabolic therapy. There is strong evidence for the use of
bisphosphonates for the treatment of glucocorticoid-induced
osteoporosis (2). For the King, risk factors for bone fragility were
advanced age, low bone mass, and low BMI. Low BMI indicates the
subsequent verses: ―My knees are weak through fasting; and my flesh
failed of fatness‖ (Psalm 109:24) and ―....my bones (the King‘s)
cleave to my skin‖ (102:6). It is understandable that prevention and
treatment of osteoporosis were not offered to the King.
References
1. Briot K, Cortet B, Trémollières F, et al.; Comité Scientifique du GRIO. Male
osteoporosis: diagnosis and fracture risk evaluation. Joint Bone Spine.
2009;76(2):129-33. Comment in: Osteoporosis in men: other secondary causes. [Joint
Bone Spine. 2009].
2. Olszynski WP, Shawn Davison K, Adachi JD, et al. Osteoporosis in men:
epidemiology, diagnosis, prevention, and treatment. Clin Ther. 2004; 26(1):15-28.
3. Blain H. Osteoporosis in men: epidemiology, physiopathology, diagnosis,
prevention and treatment. Rev Med Interne. 2004;25 Suppl 5: S552-9.
4. Drake MT, Murad MH, Mauck KF, et al. Clinical review. Risk factors for low
bone mass-related fractures in men: a systematic review and meta-analysis. J Clin
Endocrinol Metab. 2012;97(6):1861-70.
TYPES
Osteoporosis is a systemic skeletal disease associated with
increased fracture risk. According to the pathogenesis, there are
primary (70 - 80 %) and secondary osteoporosis (20 - 30 %) (1).
The term 'primary' osteoporosis refers to osteoporosis that results
from the involutional losses associated with aging and, in women,
additional losses related to natural menopause. Osteoporosis that is
caused or exacerbated by other disorders or medication exposures is
referred to as 'secondary' osteoporosis (2). In contrast to primary
osteoporosis, such "secondary" osteoporosis is more common in men
(3). Secondary osteoporosis comprises all entities in which
osteoporosis is predominantly and causally associated with certain
diseases or conditions (1).
What type of osteoporosis affected King David?
References
1. Leidig-Bruckner G, Raue F, Frank-Raue K. Secondary osteoporosis - relevant
clinical characteristics in diagnosis and therapy. Dtsch Med Wochenschr.
2012;137(7):326-32.
219
2. Retornaz F, Seux V, Soubeyrand J. Secondary osteoporosis and internal

medicine. Rev Med Interne. 2004;25 Suppl 5:S543-51.
3. Inoue D. Secondary osteoporosis. Nihon Rinsho. 2011;69(7):1295-9.
INVOLUTIONAL OSTEOPOROSIS
Involutional (primary) osteoporosis is one of the most prevalent
diseases all over the world (1). It is a unique disease of old people, and
is progressing from 5th decade of life. Risk factors for increasing
progress of the disease include estrogen (and androgen) deficiency,
low calcium diet, small physical activity, and low body weight. The
disease mainly affects women in whom normal loss of bone tissue
(average 0.3% of bone mass per year) increases with age up to 1-2%
in postmenopausal period and in every third woman, the loss may
reach several percent a year. These factors result in osteoporosis,
systemic disease of the skeleton, characterized by low bone mass,
damaged microarchitectonics and increased probability of
spontaneous fracture of bones (2).
In men aged 70 or older, involutional or age-dependent senile
osteoporosis is characterized by trabecular and cortical bone loss
leading to hip, vertebral, proximal humerus, proximal tibia, and pelvis
fractures (3).
Involutional osteoporosis
Involutional osteoporosis is divided into 2 types. Type-1

osteoporosis, known as postmenopausal osteoporosis, occurs in
women after menopause. Type-2 osteoporosis, known as senile
osteoporosis, occurs in men and women > 70 years of age. The
general symptoms are back pain in patients with Type-1 osteoporosis
and back pain with spinal deformity in Type-2. Vertebral fractures
occur in Type-1 and fractures of the femoral neck are common in
220
Type-2. Post-traumatic vertebral collapse following compression

fractures is one of the important and serious complications in
osteoporotic fractures. Other fractures such as femoral neck, wrist
(distal radius) and proximal humerus are common in this disease (4).
To screen a potential risk factor for femoral neck fracture, lumbar
vertebral fractures were characterized in 120 patients with femoral
neck fractures (19 men, 101 women; mean age, 78.7 years) by
investigating the frequency of patients with lumbar vertebral fracture,
the number of vertebral fractures per patient, and the severity of
deformity of the fractured vertebral bodies. The findings were
compared with data gathered from a population of age- and sex-
matched control patients (20 men, 89 women; mean age, 77.6 years)
who had no evidence of femoral neck fracture. The heights of the
anterior and posterior walls together with the mid part of the lumbar
vertebrae were measured on lateral radiographs to identify fractures.
The extent of height loss in the fractured vertebrae was calculated for
each group. The incidence of patients with vertebral compression
fractures was significantly higher in the femoral neck fracture group
than in the control group (65.0% vs. 41.1%). The difference in the
incidence of vertebral fractures in the 2 groups was greater in the less
aged (60-79-year-old) than in the more aged (> 80-year-old)
population. The mean number of lumbar vertebral fractures was
significantly greater in the femoral neck fracture group than in the
control group (1.59 +/- 1.39 vs. 0.75 +/- 1.19, p<0.001). The incidence
of more deformed vertebral fractures, which were defined as a
vertebral height loss of more than 50%, was significantly higher in the
group with femoral neck fracture than in the control group (23.0% vs.
7.3%). In conclusion, multiple and more severely deformed vertebral
fractures might represent a high risk for femoral neck fracture,
particularly in patients > 79 years of age. Care measures that
encompass fall prevention and protection of proximal femurs in
addition to drug therapy for osteoporosis should be recommended to
individuals in this category (5).
The BMD at the lumbar spine, proximal femur, and total skeleton
was evaluated in 38 men with primary osteoporosis and vertebral
fractures. BMD of the patients was significantly reduced over all
skeletal areas compared with controls. The Z-score of the lumbar
spine (-2.8 +/- 0.9) was less than that of the other areas (p<0.001)
except the legs (-2.5 +/- 1.1) showing that bone loss had a tendency to
be greater over the axial skeleton. Vertebral dimensions compared
with age-matched controls were as follows: projected L2-L4 area (cm
2): 45.7 +/- 5.6 vs. 53.7 +/- 3.6 (p<0.001); vertebral width (cm): 4.37
221
+/- 0.44 vs. 4.90 +/- 0.36 (p<0.001). Serum biochemical parameters
and testosterone levels were similar between osteoporotic and control
men. In conclusion, men with vertebral osteoporotic fractures have
reduced vertebral BMD and vertebral dimensions compared with age-
matched controls. The achievement of a reduced bone size at the end
of the growth period or a failure of periosteal increase during adult life
is likely to contribute to the pathogenesis of the vertebral fractures
observed in older men (6).
Was King David affected by involutional or primary osteoporosis?
It can be assumed that involutional osteoporosis may have affected
King David‘s bones. However, this does not entirely explain what
kind of disease ―...consumed...‖ his bones.
References
2. Skalska A, Kocemba J. Involutional osteoporosis - etiopathogenesis and
treatment. Folia Med Cracov. 1996;37(1-2):15-28.
3. Riggs BL, Melton LJ. Medical progress. Involutional osteoporosis. N Engl J
Med. 1986;314:1676-86.
4. Kaneda K, Kokaji M. Involutional osteoporosis. Nihon Rinsho.
1994;52(9):2378-81.
5. Kinoshita T, Ebara S, Kamimura M, et al. Nontraumatic lumbar vertebral
compression fracture as a risk factor for femoral neck fractures in involutional
osteoporotic patients. J Bone Miner Metab. 1999;17(3):201-5.
6. Vega E, Ghiringhelli G, Mautalen C, et al. Bone mineral density and bone size
in men with primary osteoporosis and vertebral fractures. Calcif Tissue Int.
1998;62(5):465-9.
SECONDARY OSTEOPOROSIS
In secondary osteoporosis, common causes include medications,
endocrine, G-I, hematologic diseases, genetic, rheumatic,
posttransplant, eating disorders, immobilization, renal diseases,
hypogonadism, and cancer. Glucocorticoid induced osteoporosis,
antihormonal therapy (aromatase inhibitor in women with breast
cancer, and androgen deprivation therapy in men with prostate cancer)
and vitamin D deficiency causing secondary hyperparathyroidism are
associated with the development of secondary osteoporosis (1-6).
History and basic laboratory testing are decisive to identify
possible causes for secondary osteoporosis and to initiate early
diagnostic procedures. Its clinical presentation is frequently
characterized by rapid development and multiple fractures. Therefore,
early diagnosis, prophylaxis and causal treatment is decisive. The risk
222
of severe osteoporosis can be reduced by early and causal treatment or

by risk stratified early bone specific medication if causal therapy is
impossible (1).
We see that various diseases can be associated with secondary
osteoporosis. It seems that the King was afflicted by secondary
osteoporosis, which "..consumed." his bones. What was the disease
that affected the King's bone?
References
1. Leidig-Bruckner G, Raue F, Frank-Raue K. Secondary osteoporosis - relevant
clinical characteristics in diagnosis and therapy. Dtsch Med Wochenschr.
2012;137(7):326-32.
2. Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc.
2002;77(5):453-68.
3. Retornaz F, Seux V, Soubeyrand J. Secondary osteoporosis and internal
medicine. Rev Med Interne. 2004;25 Suppl 5:S543-51.
4. Lafita J, Pineda J, Fuentas C, Martinez JP. Secondary Osteoporosis. An Sist
Sanit Navar. 2003;26 Suppl 3:63-62.
6. Ebeling PR. Osteoporosis in men. New insights into aetiology, pathogenesis,
prevention and management. Drugs Aging. 1998;13(6): 421-34.
CLINICAL CHARACTERISTICS
Osteoporosis in the absence of a fracture is an asymptomatic
condition. DEXA is obtained less often in men. Consequently,
fractures causing significant pain, disability, and functional
impairment may be the initial presentation in most men with
osteoporosis. In addition, men may present with a loss of height. The
most common fracture sites in men are the hip, vertebrae, forearm,
and humerus (1).
The aim of this study was to analyze the clinical characteristics and
etiological factors related to male osteoporosis in patients attending an
outpatient rheumatology department, Barcelona, Spain, during an 11-
year period (1995-2006), as well as to compare them with the
observed characteristics in a previous study performed 12 years ago.
Males (n=232) aged 21-88 years (mean 56.1 +/- 14) with osteoporosis
were included in the study. Previous skeletal fractures and family
history of osteoporosis were recorded. Bone mass assessment,
automated biochemical profile and hormonal measurements (including
PTH, 25-hydroxyvitamin D, cortisol, thyroid and sexual hormones)
were performed on most patients as well as 24 hours urinary calcium
223
and bone markers. In patients with idiopathic osteoporosis, 1-25-

hydroxy2 vitamin D was determined. In addition, x-rays of the spine
were obtained for all patients. Of all patients, 67% had previous
skeletal fractures and 51% had vertebral fractures; 57% of the patients
had idiopathic and 43% had secondary osteoporosis whereas in the
previous series only 22% of the patients had idiopathic disease. The
most frequent causes of secondary osteoporosis were corticosteroid
therapy, hypogonadism and alcoholism. Of the patients with
idiopathic osteoporosis, 38% had associated hypercalciuria. Patients
with secondary osteoporosis were older, shorter, had lower femoral
neck T-score and lower serum values of 25-hydroxyvitamin D and
testosterone, as well as higher gonadotropin and PTH values than the
patients with idiopathic osteoporosis, whereas patients with idiopathic
osteoporosis had higher urinary calcium and more frequent family
history of osteoporosis. Hypercalciuric patients were younger, had
lower lumbar BMD, higher urinary calcium and greater incidence of
lithiasis than normocalciuric patients with idiopathic osteoporosis.
Back pain, frequently associated with vertebral fractures, was the most
common cause of referral in all groups of patients. Idiopathic
osteoporosis was the most frequent cause of male osteoporosis.
Family history of osteoporosis and associated hypercalciuria were
frequent. In conclusion, the most frequent causes of secondary
osteoporosis in males included corticosteroid therapy, hypogonadism
and alcoholism. Although clinical characteristics of male osteoporosis
were similar to that previously reported, the percentage of patients
with idiopathic osteoporosis was higher than previously observed (2).
References
1. Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev.
2008;29(4):441–4.
2. Peris P, Martínez-Ferrer A, Monegal A, et al. Aetiology and clinical
characteristics of male osteoporosis. Have they changed in the last few years? Clin
Exp Rheumatol. 2008;26(4):582-8.
224
DISEASES ASSOCIATED WITH SECONDARY

OSTEOPOROSIS
CUSHING SYNDROME
Cushing syndrome is the result of extended exposure to excessive
glucocorticoids from endogenous or exogenous sources. Traditionally,
the most common cause of endogenous Cushing syndrome is a
pituitary adenoma (Cushing disease). Less common causes are
adrenocortical tumors and extrapituitary adrenocorticotropin-
producing neoplasias (1).
Endogenous Cushing's syndrome is a very rare entity, with an
incidence of 2-4 cases per million inhabitants per year (2), of which
benign adrenal adenomas account for 0.6/million (3). Cases caused by
ectopic ACTH secretion are under-diagnosed. Cushing's disease is the
most frequent cause of endogenous Cushing's syndrome, which is 5 or
6 times more frequent than adrenal Cushing's syndrome. Cushing's
disease is 3-8 times higher in women than in men. The frequency of
adrenal tumors is 3 times higher in women, while that of Cushing's
syndrome due to adrenal tumors is 3-5 times higher (2).
Cushing syndrome
Age at diagnosis of Cushing's syndrome varies according to the

etiology. Most cases of Cushing's disease are due to a pituitary
adenoma, although the tumor may not be visible on the available
imaging techniques. ACTH-independent Cushing's syndrome is found
in 20% of cases and is most frequently due to adenomas (10%) or
adrenal carcinomas. Bilateral micronodular hyperplasia and
macronodular hyperplasia are infrequent entities, representing less
than 10% of all cases of ACTH-independent Cushing's syndrome.
Both familial and sporadic forms exist: the familial form, or Carney
225
complex, and ACTH-independent bilateral macronodular hyperplasia,

in which the size of the adrenal glands is considerably enlarged (2).
The projected prevalence of Cushing's syndrome inclusive of
subclinical cases in the adult population ranges from 0.2-2% and it
may no longer be considered as an orphan disease (2-3
cases/million/year) (4). There is a high proportion of subclinical
Cushing's syndrome in certain risk populations such as patients with
type 2 diabetes or osteoporosis. Surgery remains first line treatment
for overt disease and initial cure or remission is obtained in 65-85% of
patients with Cushing's disease. Late recurrences, however, occur in
up to 20% and the risk does not seem to plateau even after 20 years of
follow-up. A 2- to 3-fold increase in mortality is observed in most
studies, and this excess mortality seems confined to patients in whom
initial cure was not obtained (3).
Cushing syndrome
Clinical signs of Cushing's syndrome derive from an exaggeration

of the physiological actions of cortisol inducing protein breakdown,
hyperglycemia, fat mobilization, dyslipidemia, hydrosaline retention,
immunosuppression and increased susceptibility to infection. Despite
its low specificity, symptoms such as unexplained development of
purple striae, facial plethora, central obesity, mood changes, fatigue,
weakness, myopathy, easy bruisability, red striae, arterial
hypertension, diabetes and hyperlipidemia are suggestive of the
diagnosis. From an epidemiological point of view, Cushing's
syndrome is to be suspected and consequently searched for among
patients with uncontrolled high BP or diabetes mellitus, metabolic
syndrome, polycystic ovarian syndrome, osteoporosis, depression or
226
adrenal incidentaloma. hypogonadism, and characteristic phenotypical

alterations (4-6). Cutaneous manifestations of hypercortisolism
include skin atrophy, excessive bruising, purple striations, poor wound
healing, facial plethora, vellous hypertrichosis and hirsutism (6). True
Cushing's syndrome has to be differentiated from pseudo syndromes.
Most sensitive physical signs for discriminating Cushing's syndrome
from pseudo-Cushing states are the presence of supraclavicular fat
pads, myopathy, thin skin and easy bruising (5).
The European Registry on Cushing's syndrome is designed to
collect prospective and follow-up data at EU level on Cushing's
syndrome. Baseline data on 481 Cushing's syndrome patients (390
females, 91 males; mean age [SD] 44 ± 14 years) were collected from
36 centers in 23 countries, including new patients from 2008 and
retrospective cases since 2000. Patients were divided into 4 major
etiologic groups: pituitary-dependent Cushing's syndrome (PIT-CS)
(66%), adrenal-dependent Cushing's syndrome (ADR-CS) (27%),
Cushing's syndrome from an ectopic source (ECT-CS) (5%) and
Cushing's syndrome from other etiologies (2%). Proportion of men in
the ECT-CS group was higher than in the other groups (p<0.05). The
ADR-CS group was older than the PIT-CS (p<0.05). Prevalence of
hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the
other groups (p<0.05 and p<0.01 respectively). PIT-CS had more skin
alterations, menstrual irregularities and hirsutism than ADR-CS
(p<0.01). Reduced libido was more prevalent in men than women
(p<0.01). Prevalence of spine osteoporosis was higher in men than
women (p<0.05), and males had more vertebral and rib fractures than
females (52% vs. 18% for vertebrae, p<0.001 and 34 vs. 23% for ribs,
p<0.05). ECT-CS consulted a diabetologist more frequently than
ADR-CS (p<0.05), while a gynecologist was consulted more often by
women with PIT-CS or ADR-CS than with ECT-CS (p<0.05).
Overall, weight gain was more common in women than men (p<0.01).
CushingQOL and EuroQOL VAS scores did not differ between the
groups. In conclusion, this project demonstrates a heterogeneous
clinical presentation of Cushing syndrome at a European level,
depending on gender and etiology (7).
Structural and functional impairment of the skeletal system
remains an important cause of morbidity and disability in patients with
Cushing's syndrome. Glucocorticoid excess inhibits bone formation
and calcium absorption from the gut, increases bone resorption, and
alters the secretion of gonadotropin and growth hormones, cytokines
and growth factors influencing bone. Both overt and subtle
endogenous hypercortisolism affect bone, leading to vertebral
227
fractures in up to 70% of patients. Fracture risk is related to age at

onset, duration and severity of the disease and individual susceptibility
to glucocorticoids that is genetically determined. BMD measurement
at the lumbar spine should be performed as a screening test in all
patients with Cushing's syndrome due to the preferential loss of
trabecular bone induced by glucocorticoids. The higher risk of
fractures at comparable BMD values with controls suggests that bone
quality features, not assessed by routine BMD approaches, are
important and should be addressed when indicated applying specific
radiological means. Successful treatment of glucocorticoid excess is
associated with improvement in bone mass, which although delayed
and often incomplete, reduces the risk of osteoporotic fractures.
Bisphosphonates can induce a more rapid improvement in BMD than
cortisol normalization alone and can be used in patients with increased
risks for further fractures and/or persistent hypercortisolemia to
prevent further bone loss. Anabolic agents have not yet been
systemically used. Avascular necrosis, mainly of the femoral neck,
and growth arrest in children are the most common skeletal disorders
unrelated to osteoporosis encountered in patients with endogenous
hypercortisolism (8).
Cushing's syndrome. A) Severe stage III dorsal vertebral fractures

(arrows), and moderate stage I-II dorsal fracture. (B) Fracture of the upper
sternal body.
Osteoporosis is the most common complication of Cushing's

syndrome. The prevalence and risk factors for osteoporosis in 42
female patients with Cushing's syndrome were examined.
Osteoporosis and atraumatic fractures were assessed by BMD of the
lumbar vertebral spine (L2-L4) using dual energy DXA and X-ray
examination. The prevalence of osteoporosis and fracture were 54.8%
and 21.4%, respectively. The prevalence of osteoporosis (69.6% vs.
37.8%) and atraumatic bone fracture (26.1% vs. 15.8%) were
significantly higher in patients with adrenal Cushing than in those
228
with pituitary Cushing. Anteroposterior and lateral BMD was

significantly higher in patients with pituitary origin than in those with
adrenal origin. Among several variables examined by multiple logistic
regression, the etiology of Cushing's syndrome (adrenal vs. pituitary
origin) was a significant factor affecting the prevalence of
osteoporosis. Neither age, BMI, duration of amenorrhea, nor extent of
hypercortisolism were significant factors in this analysis. Plasma
dehydroepiandrosterone sulfate and urinary 17-ketosteroids excretion
were significantly higher in pituitary Cushing than in adrenal Cushing.
In conclusion, the prevalence of osteoporosis in patients with
Cushing's syndrome is influenced by its etiology. A factor associated
with pituitary Cushing's syndrome, such as adrenal androgen, may
protect these patients from glucocorticoid-induced osteoporosis (9).
Overt endogenous glucocorticoid excess is a well-recognized cause
of bone loss and osteoporotic fractures. Cortisol excess inhibits bone
formation, increases bone resorption, impairs calcium absorption from
the gut, and affects the secretion of several hormones (in particular
gonadotropins and GH), cytokines, and growth factors, influencing
bone metabolism. The glucocorticoid excess mainly affects trabecular
bone, leading to vertebral fractures in up to 70% of patients.
Osteoporotic fractures may be the presenting symptom of an
otherwise silent glucocorticoid excess and can precede the diagnosis
of hypercortisolism by up to 2 years. The removal of glucocorticoid
excess leads to a recovery of bone mass which is, however, often
incomplete and delayed, although it reduces the risk of osteoporotic
fractures. Bisphosphonate therapy is useful in maintaining bone mass
in these patients. Subclinical hypercortisolism, a condition of impaired
hypothalamic- adrenal-axis homeostasis without the classical signs
and symptoms of glucocorticoid excess, is a recently defined entity,
which is associated to increased bone resorption, bone loss, and high
prevalence of vertebral fractures regardless of gonadal status.
However, data about the effect of this subtle glucocorticoid excess on
bone are still scarce and conflicting. It is not yet known whether
removing the cause of subclinical hypercortisolism leads to a recovery
of bone mass and reduces the risk of osteoporotic fractures. Recent
data suggest that subclinical hypercortisolism is a common and
underrated finding in patients with established osteoporosis. In
summary, it is crucial to evaluate the risk of osteoporosis and fractures
in patients with glucocorticoid excess; on the other hand, it seems
advisable to screen for glucocorticoid excess patients with
osteoporotic fractures without known secondary causes of
osteoporosis (10).
229
Spontaneous Cushing's syndrome is well known but unusual

clinical disorder. Many of the clinical features (central weight gain,
glucose intolerance, hypertension, muscle weakness) are seen in other
common conditions. Recognition of patients with multiple features,
features unusual for their age (i.e. early onset osteoporosis or
hypertension), patients with features more specific to Cushing's
syndrome (i.e. easy bruising, facial plethora, and violaceous striae),
and patients with incidental adrenal mass or polycystic ovary
syndrome should prompt an evaluation for cortisol excess (10).
Diagnostic tests used to screen for Cushing's syndrome include 24-
hour urine cortisol, the 1 mg dexamethasone suppression test, and late
night salivary cortisol. A normal screening test excludes the diagnosis
of Cushing's. Patients with an abnormal screening test should be
referred to an endocrinologist for complete evaluation of the pituitary-
adrenal axis (2,6,10.
Assessment: did Cushing‘s syndrome affect the King‘s bones? In

the absence of truncal obesity, hypertension, glucose intolerance,
hirsutism, plethoric face, purplish abdominal striae, edema, glucose
intolerance, and appropriate laboratory tests, this disease seems
unlikely.
References
1. Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an
endocrine disease. J Am Board Fam Med. 2012;25(2):199-208.
2. Lahera Vargas M, da Costa CV. Prevalence, etiology and clinical findings of
Cushing's syndrome. Endocrinol Nutr. 2009;56(1):32-9.
3. Steffensen C, Bak AM, Rubeck KZ, Jørgensen JO. Epidemiology of Cushing's
syndrome. Neuroendocrinology. 2010;92 Suppl 1:1-5.
4. Lila AR, Sarathi V, Jagtap VS, et al. Cushing's syndrome: Stepwise approach to
diagnosis. Indian J Endocrinol Metab. 2011;15 Suppl 4:S317-21.
5. Bruno OD, Juárez-Allen L, Rossi MA, Longobardi V. In what clinical settings
should Cushing's syndrome be suspected? Medicina (B Aires). 2009; 69(6):674-80.
6. Shibli-Rahhal A, Van Beek M, Schlechte JA. Cushing's syndrome. Clin
Dermatol. 2006;24(4):260-5.
7. Valassi E, Santos A, Yaneva M, et al.; ERCUSYN Study Group The European
Registry on Cushing's syndrome: 2-year experience. Baseline demographic and
clinical characteristics. Eur J Endocrinol. 2011;165(3):383-92.
8. Kaltsas G, Makras P. Skeletal diseases in Cushing's syndrome: osteoporosis
versus arthropathy. Neuroendocrinology. 2010;92 Suppl 1:60-4.
9. Ohmori N, Nomura K, Ohmori K, et al. Osteoporosis is more prevalent in
adrenal than in pituitary Cushing's syndrome. Endocr J. 2003;50(1):1-7.
10. Chiodini I, Torlontano M, Carnevale V, et al. Skeletal involvement in adult
patients with endogenous hypercortisolism. J Endocrinol Invest. 2008; 31(3):267-76.
10. Carroll TB, Findling JW. The diagnosis of Cushing's syndrome. Rev Endocr
Metab Disord. 2010;11(2):147-53.
230
THYROID DISEASES
HYPERTHYROIDISM
Graves' disease is an autoimmune disease where the thyroid is
overactive, producing an excessive amount of thyroid hormones, a
serious metabolic imbalance known as hyperthyroidism and
thyrotoxicosis. This is caused by thyroid autoantibodies that activate
the TSH-receptor, thereby stimulating thyroid hormone synthesis and
secretion, and thyroid growth (causing a diffusely enlarged goiter).
The resulting state of hyperthyroidism can cause a constellation of
neuropsychological and physical signs and symptoms (1).
Graves' disease is the most common cause of hyperthyroidism (60-
90% of all cases), and usually presents itself during midlife, but also
appears in children, adolescents, and the elderly (2). It has a powerful
hereditary component, affecting up to 2% of the female population,
and is between 5 and 10 times as common in females as in males (3).
Diagnosis is usually made based on symptoms, although thyroid
hormone tests may be useful (4). Graves‘ thyrotoxicosis frequently
builds over an extended period, sometimes years, before being
diagnosed (5). This is partially because symptoms can develop
insidiously, they go unnoticed; when they are reported, they are often
confused with other health problems. Thus, diagnosing thyroid disease
clinically can be challenging (6). Nevertheless, patients can
experience a wide range of symptoms and suffer major impairment in
most areas of HRQL (7).
All patients diagnosed with severe hyperthyroidism (free
thyroxine, FT4 > 100 pmol/l, NR: 11-23) seen in the endocrinology
clinic in the last 15 years were studied and compared with a sample of
patients with mild hyperthyroidism; (FT4, 23-50 pmol/l) and moderate
(FT4, 51-100 pmol/l) hyperthyroidism. A total of 107 patients with
overt hyperthyroidism (81 females, mean age +/- SD, 46.9 +/- 16.1
years) were evaluated. A historic group with severe hyperthyroidism
(n=21, 14 females, 40.9 +/- 17.2 years) was studied and, as a
comparator group, the data of 86 hyperthyroid patients (67 females,
48.4 +/- 15.5.6 years, NS) were comparable in age and gender. The
comparator group was classified to moderate hyperthyroidism (n=37,
26 females, 47.2 +/- 16.6 years) and mild hyperthyroidism (n=49, 41
females, 49.4 +/- 14.8 years). In comparison with mild
hyperthyroidism group, severe hyperthyroidism patients were
significantly (p<0.05) younger and showed a greater proportion of
231
first episode of thyroid hyperfunction (p<0.05). Graves' disease was

the main etiology in the 3 groups, but patients with severe
hyperthyroidism showed the highest titer of TSH-receptor antibodies
(p<0.001). Heart rate and size of goiter were higher in severe
hyperthyroidism group than in mild hyperthyroidism and moderate
hyperthyroidism groups (p<0.01). AF was more frequently reported in
severe hyperthyroidism group than in moderate and mild
hyperthyroidism groups (15.8% vs. 5.4% and 0%, respectively,
p<0.05). Younger age (OR 0.958, 95% CI 0.923 - 0.995, p=0.026),
presence of asthenia (OR 4.35, 1.48 - 12.78, p=0.008) and higher heart
rate (OR 1.03, 1.01 - 1.06, p=0.013) were independent clinical
variables associated with severe hyperthyroidism. Severe
hyperthyroidism patients showed similar biochemical parameters in
comparison with mild hyperthyroidism group, except for increased
serum AST (p<0.01) and calcium (p<0.05) levels, and decreased
serum cholesterol (p<0.05) and albumin (p<0.05) concentrations. Only
AST (OR 1.07, 1.02 - 1.11, p=0.005) was an independent biochemical
variable associated to severe hyperthyroidism. No differences in the
type of therapy, cure rate and time in achieving cure were found in
severe hyperthyroidism subjects in relation to patients with milder
forms of hyperthyroidism. FT4 was the only independent predictor of
cure (OR 0.98, 95% CI 0.97 - 0.99, p<0.05). In conclusion, Graves'
disease is the most common etiology in patients with severe
hyperthyroidism (8).
The most frequent clinical manifestations in 100 elderly
hyperthyroid patients entered in this study were weight loss (83%),
palpitations (85%), nodular goiter (71%), and tremor (74%).
Association of weight loss with anorexia and constipation was in 6%
of the patients. The apathetic form of thyrotoxicosis was present in 2%
of these patients. Thyrotoxic AF and thyrotoxic heart disease were in
42% and 51%, respectively (9).
The outpatient charts diagnosed as hyperthyroidism at Srinagarind
Hospital from June 1998-June 2004 were reviewed. The objective was
to compare the clinical features of hyperthyroidism in patients older
and younger than 60 years old. There were 922 cases enrolled, 84
cases (9.11%) were ≥ 60 years old. The female: male ratio was 3.4:1
and 4:1, with the mean ages 64.2 +/- 3.7 and 37.4 +/- 11.2 years in
the elder and younger group, respectively. The common presentations
were dyspnea (94.1%, 96.5%), weight loss (93.8%, 87.9%), and
palpitations (83.3%, 93.1%) in the elder and younger patients,
respectively. The significant clinical presentations in the elder group
were AF, weakness, anorexia, exophthalmos, goiter, heat intolerance
232
and hyperhidrosis. The classic presentations often lacked in the elder

group. Therefore, unexplained AF, weakness and anorexia indicate
hyperthyroidism even with paucity of typical clinical features (10).
In people older than 50 years of age in African countries, the
frequency of hyperthyroidism was 10%. Housewives were numerous,
with 20 cases observed in the 31 patients. The main group (13/31) was
of rural origin. Signs that predominantly led to consultation included
weight loss (23/31), cervical tumor (17/31), and palpitations (12/31).
Three major signs were associated with the thyrotoxic syndrome:
weight loss (29 cases), tachycardia (27/31), and the existence of
tremors in the extremities (22/31). Hormone assays showed that
thyroxine was about 265 +/- 74 nmol/L and triiodothyronine about 6
+/- 2 nmol/L at immunoradiometric assay; TSH was about 0.17 +/-
0.23 muIU/mL. Eye protrusion predominated in the nonthyrotoxic
syndrome, with 25 cases in the 31 patients. Etiologic forms of the
disease were composed of 25 Grave's disease, with 22 typical cases.
Etiologic factors were various, without any case of neoplasia. Cardiac
complications included 2 cases of AF. No iatrogenic form of the
disease was observed. Mean initial carbimazole dosage was about 34
+/- 8 mg/d. Of the 23 patients, 15 had a favorable outcome. (11).
References
1. Patterson NR, George J. Graves' Disease in our own words. Blue Note
Publications. 2002. ISBN 1-878398-20-2.
2. Graves‘ Disease & Thyroid Foundation. "About Graves‘ Disease". Available 20
April 2013 at http://www.gdatf.org/about/about-graves-disease.
3. Graves' Disease and the Manifestations of Thyrotoxicosis - Leslie l. De Groot,
Thyroid Disease Manager, Chapter 10. Available 15 April 2013 at
http://www.thyroidmanager. org/Chapter10/10-frame.htm.
4. Brent GA. Clinical practice. Graves' disease. N Engl J Med. 2008;358
(24):2594-605.
5. Elberling TV, Rasmussen AK, Feldt-Rasmussen U, et al. Impaired health-
related quality of life in Graves' disease. A prospective study. Eur. J. Endocrinol.
2004;151 (5): 549–55.
6. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid
disease prevalence study. Arch Intern Med. 2000;160(4):526–34.
7. Watt T, Groenvold M, Rasmussen AK, et al. Quality of life in patients with
benign thyroid disorders. A review. Eur J Endocrinol. 2006;154(4):501-10.
8. Iglesias P, Dévora O, García J, et al. Severe hyperthyroidism: aetiology, clinical
features and treatment outcome. Clin Endocrinol (Oxf). 2010;72(4):551-7.
9. Dumitriu L, Ursu H. Hyperthyroidism in the elderly. I. Clinical manifestations.
Endocrinologie. 1985;23(2):83-90.
10. Limpawattana P, Sawanyawisut K, Mahankanukrau A, Wongwipaporn C.
Clinical manifestations of primary hyperthyroidism in the elderly patients at the out-
patient clinic of Srinagarind Hospital. J Med Assoc Thai. 2006;89(2):178-81.
233
11. Sidibe EH, Fall L, Toure-Sow H, Sow AM. Hyperthyroidism in people over
50 years of age in Senegal. Study of 31 cases observed over a 14-year period. Rev
Med Interne. 1998;19(4):237-41.
HYPOTHYROIDISM
Hypothyroidism affects from 1.9-20% of women and 3-8% of men
(1,2). The occurrence varies with genetics with a high prevalence in
Caucasians (2). Hypothyroidism is common, potentially serious, often
clinically overlooked, readily diagnosed by laboratory testing, and
eminently treatable (3). Hypothyroidism is a clinical entity resulting
from deficiency of thyroid hormones or, more rarely, from their
impaired activity at tissue level (1). Worldwide, dietary iodine
deficiency remains an important cause (3).
Autoimmune thyroiditis is the predominant cause of primary
hypothyroidism (1,2). Hypothyroidism is congenital or acquired,
primary or secondary, chronic or transient (1). Causes of primary
hypothyroidism, chronic or transient, include congenital thyroid
disorders, previous thyroid surgery and irradiation, drugs such as
lithium carbonate and amiodarone, cytokines and lithium, and
pituitary and hypothalamic disorders (1-3). In secondary or central
hypothyroidim which is very rare, there is a lack of TSH or TSH
activity, due to a pituitary or hypothalamic causes. The clinical
features of hypothyroidism are dependent on the patient's age, the
presence of other disease, and the rate at which hypothyroidism
develops (1). Hypothyroidism can present with nonspecific
constitutional and neuropsychiatric complaints, or with
hypercholesterolaemia, hyponatraemia, hyperprolactinaemia, or
hyperhomocysteinaemia. Severe untreated hypothyroidism can lead to
heart failure, psychosis, and coma. Although these manifestations are
neither specific nor sensitive, the diagnosis is confirmed or excluded
by measurements of serum thyrotropin and free thyroxine, and thyroid
peroxidase antibodies (2,3).
As thyroid hormones are universal determinants of organ function,
there may be a multiplicity of symptoms. Particularly in the elderly,
the clinical features may be atypical, and the diagnosis easily missed
(1). First line tests for hypothyroidism are analyses of the
concentrations of free thyroxine and TSH in serum. In primary
hypothyroidism, the serum content of T4 is low and that of TSH high.
In central hypothyroidism, the serum content of T4 is low and that of
234
TSH generally low or normal, though slightly increased levels of

biologically inactive TSH may occur. When a diagnosis of chronic
hypothyroidism is confirmed, treatment with laevothyroxine is started,
the initial dose being adjusted to the age and general condition of the
patient, and the duration and severity of hypothyroidism. As a rule,
full thyroxine replacement therapy should bring the serum TSH level
into the normal range. In central hypothyroidism, laevothyroxine
treatment is similar, but pituitary function must be evaluated and, if
necessary, corticosteroid replacement instituted before laevothyroxine
treatment is started (1,4,5).
Thyroxine replacement therapy is highly effective and safe, but
suboptimal dosing is common in clinical practice. Patient
noncompliance, drug interactions, and pregnancy can lead to
inadequate treatment. Iatrogenic thyrotoxicosis can cause symptoms,
and, even when mild, provoke AF and osteoporosis (3).
Levothyroxine monotherapy remains the current standard for
management of primary, as well as central hypothyroidism. Treatment
can be started with the full calculated dose for most young patients.
However, treatment should be initiated at a low dose in elderly
patients, patients with coronary artery disease and patients with long-
standing severe hypothyroidism (5).
In primary hypothyroidism, treatment is monitored with serum
TSH, with a target of 0.5-2.0 mIU/L. In patients with central
hypothyroidism, treatment is tailored according to free or total T4
levels, which should be maintained in the upper half of the normal
range for age. In patients with persistently elevated TSH despite an
apparently adequate replacement dose of levothyroxine, poor
compliance, malabsorption and the presence of drug interactions
should be checked. Over-replacement is common in clinical practice
and is associated with increased risk of AF and osteoporosis, and
hence should be avoided (5).
Because of the long half-life of levothyroxine sodium, small
dosage adjustments may be performed by adding or withdrawing a
tablet once or twice weekly. Levothyroxine sodium is only partly
absorbed after oral ingestion, and food, minerals, drugs and tablet
composition influence absorption. A combination of levothyroxine
sodium and liothyronine may improve clinical results, but
comprehensive studies have not supported this hypothesis.
Accordingly, liothyronine replacement is not documented to be of
benefit. If liothyronine is added to replacement, the liothyronine dose
should be kept low, within the physiological range and, preferably be
administered twice daily. Thyroid hormone therapy has no beneficial
235
effect above placebo in elderly individuals with normal serum TSH

levels and T(4) levels. The major risk of levothyroxine sodium
therapy is over-replacement, with anxiety, muscle wasting,
osteoporosis and AF as AEs (5).
References
1. Hallengren B. Hypothyroidism - clinical findings, diagnosis, therapy. Thyroid
tests should be performed on broad indications. Lakartidningen. 1998;95(38):4091-6.
2. Laurberg P, Andersen S, Bülow Pedersen I, Carlé A. Hypothyroidism in the
elderly: pathophysiology, diagnosis and treatment. Drugs Aging. 2005;22(1):23-38.
3. Roberts CG, Ladenson PW. Hypothyroidism. Lancet. 2004;363(9411):793-
803. Comment in: Thyroxine adherence in primary hypothyroidism. [Lancet. 2004].
4. Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and
management. Med Clin North Am. 2012;96(2):203-21.
5. Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat
and how. Drugs. 2012;72(1):17-33.
SUBCLINICAL HYPERTHYROIDISM/
HYPOTHYROIDISM
Subclinical thyroid diseases - subclinical hyperthyroidism and
subclinical hypothyroidism - are common clinical entities that
encompass mild degrees of thyroid dysfunction. The clinical
significance of mild thyroid overactivity and underactivity is
uncertain, which has led to controversy over the appropriateness of
diagnostic testing and possible treatment (1).
Subclinical hyperthyroidism can be caused by increased
endogenous production of thyroid hormone (as in Graves's disease or
toxic nodular goiter), administration of thyroid hormone for treatment
of malignant thyroid disease, or unintentional excessive thyroid
hormone therapy. The rate of progression to overt hyperthyroidism is
higher in persons who have suppressed TSH levels compared with
those who have low but detectable levels. The effectiveness of
treatment in preventing these conditions is unknown. There is lesser-
quality evidence suggesting an association between subclinical
hyperthyroidism and other C-V effects, including increased heart rate
and left ventricular mass and increased bone turnover markers.
Possible associations between subclinical hyperthyroidism and QOL
parameters, cognition, and increased mortality rates are controversial.
Prospective RCTs are needed to address the effects of early treatment
236
on potential morbidities to help determine whether screening should

be recommended in the asymptomatic general population (2).
Individuals with subclinical hyperthyroidism demonstrate a 41%
increase in relative mortality from all causes versus euthyroid control
subjects. Absolute excess mortality depends on age, with an increase
beyond the age of 60, especially in aging men. For patients with
subclinical hyperthyroidism, the RR of all-cause mortality is increased
only in patients with comorbid conditions (3).
The term 'subclinical hypothyroidism' is used to define the grade of
primary hypothyroidism in which there is an elevated TSH
concentration in the presence of normal serum free thyroxine and
triiodothyronine concentrations (2,4,5). It is a common condition with
the prevalence in the general population estimated at 0.6-16% (2,4).
Whether or not subclinical hyperthyroidism should be treated
remains a matter of debate. Cross-sectional studies and longitudinal
population-based studies demonstrate an association between
subclinical hyperthyroidism and risk of AF, decreased BMD in
postmenopausal women, osteoporosis, C-V and global mortality, and
dementia. However, there are no RCTs answering the question
whether long term-health outcomes are improved by the treatment of
subclinical hyperthyroidism. Therefore, in the absence of evidence for
or against treatment of subclinical hyperthyroidism, it seems
appropriate to follow algorithms that consider the level of TSH and
the presence of risks factors (age > 65 years, osteoporosis, post
menopause and cardiac disease) (2-4,6-8).
In subclinical hypothyroidism, total cholesterol and LDL-C are
modestly elevated and levothyroxine may influence the lipid levels.
There is decreased cardiac contractility and increased peripheral
vascular resistance that improve with treatment (6,7). Depression,
panic disorders and alterations in cognitive testing are frequent in
subclinical hypothyroidism (6).
Subclinical hypothyroidism may progress to overt hypothyroidism
in approximately 2-5% cases annually. All patients with overt
hypothyroidism and subclinical hypothyroidism with TSH > 10
mIU/L should be treated. There is consensus on the need to treat
subclinical hypothyroidism of any magnitude in pregnant women and
women who are contemplating pregnancy to decrease the risk of
pregnancy complications and impaired cognitive development of the
offspring. (9). However, controversy remains regarding treatment of
non-pregnant adult patients with subclinical hypothyroidism and
serum TSH values ≤ 10 mIU/L. In this subgroup, treatment should be
considered in symptomatic patients, patients with infertility, and
237
patients with goiter or positive anti-thyroid peroxidase antibodies.

Limited evidence suggests that treatment of subclinical
hypothyroidism in patients with serum TSH of up to 10 mIU/L should
probably be avoided in those aged > 85 years. Other pituitary
hormones should be evaluated in patients with central
hypothyroidism, especially to assess the hypothalamic-pituitary-
adrenal axis, since hypocortisolism, if present, needs to be rectified
prior to initiating thyroid hormone replacement (9).
Patients with subclinical hypothyroidism should be informed about
the disease and offered the possibility of replacement. Only some
patients treated for subclinical hypothyroidism will feel better after
therapy. In elderly patients on replacement therapy, care should
include estimation of serum TSH level once or twice a year, with
small dosage adjustments of levothyroxine sodium to keep serum TSH
level within the normal range (10,11).
References
1. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;79
(9821):1142-54.
2. Donangelo I, Braunstein GD. Update on subclinical hyperthyroidism. Am Fam
Physician. 2011;83(8):933-8.
3. Haentjens P, Van Meerhaeghe A, Poppe K, Velkeniers B. Subclinical thyroid
dysfunction and mortality: an estimate of relative and absolute excess all-cause
mortality based on time-to-event data from cohort studies. Eur J Endocrinol.
2008;159:329-41.
4. Krysiak R, Marek B, Okopień B. Subclinical hyperthyroidism. Endokrynol
Pol. 2007;58(6):536-42.
5. Hallengren B. Hypothyroidism - clinical findings, diagnosis, therapy. Thyroid
tests should be performed on broad indications. Lakartidningen. 1998;95(38):4091-6.
6. Romaldini JH, Sgarbi JA, Farah SC. Subclinical thyroid disease: subclinical
hypothyroidism and hyperthyroidism. Arq Bras Endocrinol Metabol. 2004;48:147-58.
7. Sengupta N, Maji D. Subclinical thyrotoxicosis. J Indian Med Assoc.
2006;104:596, 598-600.
8. Corvilain B. Subclinical hyperthyroidism: from diagnosis to treatment. Rev
Med Brux. 2012;33(4):241-5.
9. Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat
and how. Drugs. 2012;72(1):17-33.
10. Laurberg P, Andersen S, Bülow Pedersen I, Carlé A. Hypothyroidism in the
elderly: pathophysiology, diagnosis and treatment. Drugs Aging. 2005;22(1):23-38.
11. Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and
management. Med Clin North Am. 2012;96(2):203-21.
238
THYROID HORMONE AND BONE

Thyroid hormones play the essential role in the regulation of
metabolism and bone remodeling in physiological conditions and in
the course of thyroid dysfunction. Introduction of densitometry to the
diagnostics of osteoporosis has made possible the evaluation of
influence of both hyperthyroidism and hypothyroidism and their
treatment on BMD. It became possible to estimate the influence of
treatment with exogenous thyroid hormones on the skeletal system (1).
The hypothalamic-pituitary-thyroid axis plays a key role in skeletal
development, and acquisition of peak bone mass and regulation of
adult bone turnover. Euthyroid status is essential for maintenance of
optimal bone mineralization and strength. In population studies,
hypothyroidism and hyperthyroidism have both been associated with
an increased risk of fracture. Recent studies in healthy euthyroid post-
menopausal women indicate that thyroid status in the upper normal
range is also associated with low BMD and an increased risk of non-
vertebral fracture. Studies in mutant mice have demonstrated that
thyroid hormone receptor α is the major mediator of T3 action in bone
and thyroid hormones exert anabolic actions during growth but have
catabolic effects on the adult skeleton. Nevertheless, TSH has a direct
negative regulator of bone turnover, although the relative importance
of T3 and TSH actions in the skeleton has yet to be clarified (2).
Thyroid hormones are essential for normal skeletal growth and the
maintenance of bone mass in adulthood, although their mechanism of
action in bone is poorly understood. Hypothyroidism causes impaired
bone formation and growth retardation whereas thyrotoxicosis results
in accelerated growth, advanced bone age and decreased bone mass.
Adults with thyrotoxicosis or a suppressed TSH from any cause have
an increased risk of osteoporotic fracture. Conventionally, bone loss in
thyrotoxicosis has been regarded as a direct consequence of thyroid
hormone excess acting locally on bone. TSH is a direct negative
regulator of bone turnover acting via the TSH receptor on both
osteoblasts and osteoclasts. Thus, TSH deficiency could be partly
responsible for the skeletal loss seen in thyrotoxicosis (3).
Thyroid hormones regulate skeletal development, and acquisition
of peak bone mass and adult bone maintenance. Abnormal thyroid
status during childhood disrupts bone maturation and linear growth,
while in adulthood it results in altered bone remodeling and an
increased risk of fracture. Euthyroid status is essential for normal bone
development and maintenance. Major thyroid hormone actions in
skeletal cells are mediated by thyroid hormone receptor alpha and
239
result in anabolic responses during growth and development but

catabolic effects in adulthood. These homeostatic responses to thyroid
hormone are locally regulated in individual skeletal cell types by the
relative activities of the type 2 and 3 iodothyronine deiodinases, which
control the supply of the active thyroid hormone 3,5,3'-L-
triiodothyronine to its receptor. Population studies indicate that both
thyroid hormone deficiency and excess are associated with an
increased risk of fracture. Understanding the cellular and molecular
basis of 3,5,3'-L-triiodothyronine action in skeletal cells will lead to
the identification of new targets to regulate bone turnover and
mineralization in the prevention and treatment of osteoporosis (4).
Euthyroid status is essential for normal skeletal development and
the maintenance of adult bone structure and strength. Established
thyrotoxicosis has long been recognized as a cause of high bone
turnover osteoporosis and fracture but subclinical hyperthyroidism
and long-term suppressive doses of thyroxine may result in decreased
BMD and an increased risk of fragility fracture, particularly in
postmenopausal women. Large population studies of euthyroid
individuals have demonstrated that a hypothalamic-pituitary-thyroid
axis points at the upper end of the normal reference range associated
with reduced BMD and increased fracture susceptibility. Despite these
findings, the cellular and molecular mechanisms of thyroid hormone
action in bone remain controversial and incompletely understood (5).
Thyrotoxicosis, a clinical syndrome characterized by
manifestations of excess thyroid hormone, is one of the commonly-
recognized conditions of the thyroid gland. Thyrotoxicosis causes
acceleration of bone remodeling and though it is one of the known risk
factors for osteoporosis. Thyroid hormones have effects on bone, both
in vitro and in vivo. Treatment of thyrotoxicosis leads to reversal of
bone loss and metabolic alterations, and decreases the fracture risk (6).
In hyperthyroidism, the bone loss is solely due to elevated thyroid
hormone level (7), occurring as a direct consequence of thyroid
hormone excess acting on bone (8), more on axial than appendicular
(9). Bone loss in thyrotoxicosis is independent on circulating TSH
levels, and mediated predominantly by thyroid hormone receptor
alpha, thus identifying thyroid hormone receptor as a novel drug target
in the prevention and treatment of osteoporosis (10).
Thyrotoxicosis is associated with high-turnover osteoporosis. The
bone loss, primarily due to accelerated resorption that is not
compensated by a coupled increase in bone formation, has been
attributed solely to elevated thyroid hormone levels. Evidence using
mice lacking the thyroid hormone receptors alpha and beta establishes
240
a role for thyroid hormones in regulating bone remodeling but does

not exclude an independent action of TSH, levels of which are low in
hyperthyroid states, even when thyroid hormones are normal, as after
thyroxine supplementation and in subclinical hyperthyroidism. TSH
directly suppresses bone remodeling and that TSH receptor null mice
have profound bone loss, suggesting that reduced TSH signaling
contributes to hyperthyroid osteoporosis. TSH and its receptor could
become valuable drug targets in treating bone loss (10).
Trabecular bone micro-architecture in adult TR mutant mice. (A)

Backscattered electron scanning electron microscopy (BSE-SEM) views
showing trabecular bone in thyrotoxic wild-type mice treated with daily
subcutaneous injections of T3 (30 ng T3/gram body weight) and congenitally
hypothyroid Pax8−/− mice. (B) Animals lacking either TRα or TRβ and (C)
mice harbouring a dominant-negative mutation of TRα (R384C). Scale bar,
200 μm.
The osteoporosis associated with human hyperthyroidism has

traditionally been attributed to elevated thyroid hormone levels. There
is evidence, however, that TSH, which is low in most hyperthyroid
states, directly affects the skeleton. Importantly, Tshr-knockout mice
are osteopenic. In order to determine whether low TSH levels
contribute to bone loss in hyperthyroidism, the skeletal phenotypes of
wild-type and Tshr-knockout mice that were rendered hyperthyroid
241
were compared. Hyperthyroid mice lacking TSHR had greater bone

loss and resorption than hyperthyroid wild-type mice, thereby
demonstrating that the absence of TSH signaling contributes to bone
loss. A TSH-like factor that may confer osteoprotection was
identified. These studies suggest that therapeutic suppression of TSH
to very low levels may contribute to bone loss in people (11).
The main aim of this study was to study fracture risk and risk
factors for fractures in patients with primary idiopathic
hypothyroidism (ICD 10: E03.9). In historical follow-up, a self-
administered questionnaire was issued to 628 patients with primary
idiopathic levothyroxine-substituted hypothyroidism. Of 412 (65.6%)
responders, 408 were analyzed. The 408 respondents were age- (+/- 5
years) and gender-matched with 408 normal controls randomly
selected from the background population who responded to the same
questionnaire. Overall fracture risk was increased in patients
compared to controls (RR 1.6, 95% CI 1.0 - 2.5). However, the
increase was temporary and limited to the period within the first 2
years after the diagnosis of hypothyroidism (RR 3.1, 95% CI 1.4 -
7.0). Before the diagnosis and > 2 years after the diagnosis, the
fracture risk in patients did not deviate from that of the controls. The
increase in fracture risk was only significant in the age group > 50
years (RR 1.8, 95% CI 1 - 3.2), and was limited to the forearms (RR
3.0, 95% CI 1.4 - 6.3 for the entire patient population). In conclusion,
there was a temporary increase in fracture risk within the first 2 years
after diagnosis of primary idiopathic hypothyroidism. The fracture
risk was mainly increased in the age group above 50 years, and the
increased risk was limited to the forearms (12).
A cross-sectional retrospective study of primary care patients was
conducted to estimate the prevalence of osteoporosis in patients being
treated with thyroid hormone. Experimental group included patients
diagnosed with subclinical hypothyroidism receiving thyroid hormone
replacement therapy. Control group included patients not receiving
replacement therapy. Once the sample was selected, its members were
summoned to complete a clinical questionnaire and undergo a bone
density scan with a validated measuring device. One hundred eighty
two patients (112 experimental and 70 control), diagnosed with
subclinical hypothyroidism were studied. The average age at diagnosis
was 42.5 and 41.2 years, respectively. 32.7% and 33.2% were
smokers. In the experimental group, the coexistence of 2 or more C-V
risk factors was detected in 5.7% of the patients. Mean TSH was 6.67
mU/L, mean free T(4) 1,04 ng/dl. Of the patients studied, 67% had
some level of bone loss: 87% osteopenia and 14% osteoporosis. Of
242
those suffering from bone loss, 56% were women. With regard to the
size of the thyroid hormone treatment, only 12% received 150 μg/day
thyroid hormone or more treatment, 61% had received treatment for 5
and 10 years and 19.5% for more than 10 years. In conclusion, there is
a high prevalence of bone loss in patients with subclinical
hypothyroidism treated with exogenous thyroxin (13).
Measurement of the serum TSH concentration with an assay of
adequate sensitivity is the cornerstone of thyroid function testing; for
untreated population at risk of primary thyroid dysfunction, a normal
TSH concentration rules out an abnormality with a high degree of
certainty (14). Osteoporosis is mainly associated with hyperthyroidism
either overt or subclinical. This diagnosis as a cause of osteoporosis
should be ruled out in all patients who have bone demineralization
(15). Since BMD is reduced in subclinical hyperthyroidism (16),
subclinical hyperthyroidism is a risk factor for osteoporosis (17).
Assessment: osteoporosis is associated with hyperthyroidism

either overt or subclinical and hypothyroidism. In subclinical
hypothyroidism, there is a high prevalence of bone loss in patients
treated with exogenous thyroxin. These diagnoses as a cause of
osteoporosis should be ruled out in all patients who have bone
demineralization.
Was King David afflicted by hyperthyroidism? In the absence of
nervousness, emotional lability, hyperhydrosis, heat intolerance, eye
symptoms (such as lid lag or exophtalmus), a wide pulse pressure,
sinus tachycardia, atrial arrhythmias (especially AF), systolic
murmurs, cardiac enlargement, heart failure, and data on TSH level in
serum, the diagnosis of hyperthyroidism seems unlikely.
Was King David affected by hypothyroidism? Hypothyroidism can
present with nonspecific constitutional and neuropsychiatric
complaints, or with hypercholesterolaemia, hyponatraemia,
hyperprolactinaemia, or hyperhomocysteinaemia. Severe untreated
hypothyroidism can lead to heart failure, psychosis, and coma. These
manifestations are neither specific nor sensitive, and the diagnosis is
confirmed or excluded by measurements of serum TSH and free
thyroxine.
The medical record of King David shows a variety of serious
diseases such as loss of vision, severe intractable bone pain, cachexia,
chronic weakness, mild hypothermia, pressure ulcers, erectile
dysfunction, and major depression (18). Although the diagnosis of
hypothyroidism requires a laboratory confirmation, the seriousness of
243
his medical condition does not entirely explain what kind of disease "
consumed.." his bones.
Was King David afflicted by subclinical hyperthyroidism?
Subclinical hypothyroidism? Subclinical hyperthyroidism and
subclinical hypothyroidism encompass mild degrees of thyroid
dysfunction with scare signs of thyroid dysfunction and laboratory
confirmation of these specific diagnoses. In these thyroid disorders
thyroid dysfunction is mild, so these disorders can be excluded in
King David's case.
References
1. Kosińska A, Syrenicz A, Kosiński B, et al. Osteoporosis in thyroid diseases.
Endokrynol Pol. 2005;56(2):185-93.
2. Gogakos AI, Duncan Bassett JH, Williams GR. Thyroid and bone. Arch
Biochem Biophys. 2010;503(1):129-36.
3. Galliford TM, Murphy E, Williams AJ, et al. Effects of thyroid status on bone
metabolism: a primary role for thyroid stimulating hormone or thyroid hormone?
Minerva Endocrinol. 2005;30(4):237-46.
4. Wojcicka A, Bassett JH, Williams GR. Mechanisms of action of thyroid
hormones in the skeleton. Biochim Biophys Acta. 2013;1830(7):3979-86.
5. Nicholls JJ, Brassill MJ, Williams GR, Bassett JH. The skeletal consequences
of thyrotoxicosis. J Endocrinol. 2012;213(3):209-21.
6. Reddy PA, Harinarayan CV, Sachan A, et al. Bone disease in thyrotoxicosis.
Indian J Med Res. 2012;135:277-86.
7. Sun L, Davies TF, Blair HC, et al. TSH and bone loss. An N Y Acad Sci.
2006;1068:309-18.
8 Seeman E, Wahner HW, Offord KP, et al. Differential effects of endocrine
dysfunction and the appendicular skeleton. J Clin Invest. 1982;69:1302.
9. Basset JP, O'Shea PJ, Sriskantharajah S, et al. Thyroid hormone excess rather
than thyrotropin deficiency induces osteoporosis in hyperthyroidism. Mol Edocrinol.
2007;21:1095-107.
10. Zaidi M, Davies TF, Zallone A, et al. Thyroid-stimulating hormone, thyroid
hormones, and bone loss. Curr Osteoporos Rep. 2009;7(2):47-52.
11. Baliram R, Sun L, Cao J, et al. Hyperthyroid-associated osteoporosis is
exacerbated by the loss of TSH signaling. J Clin Invest. 2012;122(10):3737-41.
12. Vestergaard P, Weeke J, Hoeck HC, et al. Fractures in patients with primary
idiopathic hypothyroidism. Thyroid. 2000;10(4):335-40. Comment in Worm-eaten
bones. [Thyroid. 2000].
13. Tárraga López PJ, López CF, de Mora FN, et al. Osteoporosis in patients with
subclinical hypothyroidism treated with thyroid hormone. Clin Cases Miner Bone
Metab. 2011;8(3):44-8.
14. Stockigt J. Assessment of thyroid function: towards an integrated laboratory –
clinical approach. Clin Biochem Rev. 2003;24:109-22.
15. Smith TJ. Connective tissue in thyrotoxicosis. In: Braverman LE, Utiger RD
(eds). Werner and Ingbar‘s The Thyroid. A Fundamental and Clinical Text. 6th ed.
Philadelphia: Lippincot. 1991, pp. 738-41.
16. Romaldini JH, Sgarbi JA, Farah SC. Subclinical thyroid disease: subclinical
hypothyroidism and hyperthyroidism. Arq Bras Endocrinol Metabol. 2004;48:147-58.
17. Zamrazil V. Subclinical thyroid diseases. Vnitr Lek. 2007;53(7-8):795-8.
244
18. Ben-Nun L. In Ben-Nun L. ed. The Family Life Cycle and the Medical Record
of King David the Great. Research in Biblical Times from the Viewpoint of
Contemporary Medicine. B.N. Publications. Israel. 2009.
ACROMEGALY
Acromegaly and gigantism are due to excess GH production,
usually because of a pituitary adenoma. In very rare cases, acromegaly
is due to ectopic secretion of growth-hormone-releasing hormone
responsible for pituitary hyperplasia (1).
The incidence of acromegaly is 5 cases per million and the
prevalence is 40-130 cases per million inhabitants per year (1,2).
Clinical manifestations in each patient depend on the levels of GH
and IGF-I, age, tumor size, and the delay in diagnosis. Acromegaly is
a disabling disease that is associated with increased morbidity and
reduced life expectancy. The diagnosis is based primarily on clinical
features and confirmed by measuring GH levels after oral glucose
loading and the estimation of IGF-I. The rate of mortality in patients
with acromegaly is correlated with the degree of control of GH.
Adequately treated, the relative mortality risk can be reduced towards
normal (2).
Acromegaly.
The disease has rheumatologic, C-V, respiratory and metabolic

consequences which determine its prognosis (1). The clinical features
include acral and soft tissue overgrowth such as broadened extremities
245
(hands and feet), widened, thickened, stubby fingers, and thickened

soft tissue; the facial aspect is characteristic and includes a widened
and thickened nose, prominent cheekbones, forehead bulges, thick lips
and marked facial lines. The forehead and overlying skin is thickened,
sometimes leading to frontal bossing. There is a tendency towards
mandibular overgrowth with prognathism, maxillary widening, tooth
separation and jaw malocclusion (1). Complications of acromegaly
include diabetes mellitus, hypertension, and heart and respiratory
failure (2).
The clinical diagnosis is confirmed biochemically by an increased
serum GH concentration following an oral glucose tolerance test and
by detection of increased levels of IGF-I. Assessment of tumor
volume and extension is based on imaging studies. Echocardiography
and sleep apnea testing are used to determine the clinical impact of
acromegaly (1).
The purpose of this article was to summarize the early
musculoskeletal complications of acromegaly. Some of the early signs
of acromegaly can be evaluated by the musculoskeletal radiologist. In
the early stage of disease, peripheral nerve enlargement associated
with carpal tunnel syndrome or cubital tunnel syndrome and
thickening of retinacula, such as A1 pulley in trigger finger, represent
the features that may be seen by radiologists and are worthy of an
endocrinological evaluation. Due to the insidious nature of the
disease, the diagnosis of acromegaly is significantly delayed. Few and
nonspecific symptoms characterize the initial phases of the disease,
and therefore, most patients will have generally consulted many
specialists (most frequently musculoskeletal radiologists) before an
adequate endocrinological assessment is performed. For this reason,
initial clinical signs are much more important than symptoms for an
early diagnosis of acromegaly. The first and most important
therapeutic approach to acromegaly is early diagnosis, whereas the
therapeutic goals are to eliminate morbidity and reduce mortality to
the expected age- and sex-adjusted rates and prevent the development
of systemic complications. Musculoskeletal radiologists should be
aware that these features might be early manifestations of acromegaly.
When both radiological and clinical abnormalities are present, an
endocrinological workup is useful to diagnose the disease in an early
phase (3).
246
In a lateral view of a pituitary adenoma, the expanded sella turcica

(between the orbit on the left and the radio-dense mastoid on the right) is
seen.
GH and IGF-1 stimulate proliferation, differentiation and

extracellular matrix production in osteoblastic cells. GH and IGF-1
stimulate recruitment and bone resorption activity in osteoclastic cells.
A chronic systemic GH and IGF-1 excess produces an increased bone
turn over in acromegalic patients. Osteoporosis, joint alterations and
bone deformities have a great clinical relevance in acromegalic
patients and favor mortality and morbidity. In the present study,
GH/IGF-1 activity on bone, BMD and risk of osteoporotic vertebral
fractures in relation to gender and gonadal status in acromegalic
patients were evaluated. Twenty acromegalic patients (12 females, 8
males) ranging 26-64 years were studied. Four patients were
hypogonadic (1 F, 3 M), 7 women were in post-menopause and 4
women eugonadic. The disease was active in 12 patients and inactive
in 8 patients. Serum and urinary 24/hours calcium and phosphate and
serum PTH, bone formation (P1NP) and resorption (beta-CTX)
markers were assayed. BMD was measured by using dual energy
DXA at the lumbar spine and femoral neck and bone quantitative
ultrasonography at phalanges. Osteoporotic vertebral fractures were
assessed by antero-posterior and lateral x-ray examinations of the
thoracic and lumbar spine. Serum IGF-1, calcium and phosphate and
24-hours urinary calcium were significantly higher in patients with
active disease in respect to patients with inactive disease. BMD was
reduced in more of 50% of patients, in each skeletal sites measured. Z-
score values were lower in males than in females. Vertebral fractures
prevalence was 39% (43% in women, 57% in men). Fractured and
non-fractured patients were insignificantly different for BMD, T-score
and Z-score. In conclusion, vertebral fractures are frequent in
acromegaly and, even mild and asymptomatic, play an important role
on QOL and survival, already decreased in acromegalic patients. DXA
and quantitative US methods are insufficient for identifying patients at
247
risk for fractures due to the many possible interferences (bone

deformities, osteoarthritis, joint rigidity and soft tissue thickening),
since BMD is just one determinant of bone fracture. In the screening
of acromegalic complications, it is necessary to perform a
radiographic study of the spine at the time of diagnosis and during
follow up (4).
A cross-sectional study was carried out at the Department of
Medical and Surgical Sciences, Montichiari, Italy. Patients included
40 males with acromegaly (25 patients with controlled disease and 15
patients with active disease) and 31 control males, with age and
gonadal status comparable to the patients. Although BMD was
insignificantly different between acromegalic patients and control
subjects, the prevalence of vertebral fractures was higher in
acromegalic patients as compared with the control subjects (57.5% vs.
22.6%, p=0.003). Fractured and non-fractured acromegalic patients
showed insignificant difference in age and BMD Z-score. Patients
with fractures showed significantly longer untreated hypogonadism as
compared to patients without fractures. The duration of active
acromegaly was the only risk factor that significantly correlated with
the occurrence of fractures. This study reported a high prevalence of
osteoporotic vertebral fractures in an unselected acromegalic male
population generally considered at low risk of osteoporosis suggesting
that complicated osteoporosis is an important comorbidity of
acromegaly (5).
The clinical features of 65 patients with acromegaly (31 males, 34
females; mean age 50 +/-2 years) who were admitted to Tokyo
Women's Medical University between 1990 and 1999 were analyzed
retrospectively from medical records. The retrospective analysis
revealed that the diagnosis of acromegaly was preceded by
approximately 8.1+/-1.1 years of signs and symptoms of the disease.
Of 65 patients, 46 (71%) had macroadenomas, 16 (25%)
microadenomas, and the remaining 3 had empty sella. The rate of
biochemical cure or remission was 81% for microadenoma (13/16),
64% for macroadenoma without extrasellar extension (9/14), and 13%
for macroadenoma with cavernous sinus extension (2/15). Eighteen
(28%) patients had IGT and 32 (49%) had diabetes mellitus. After
treatment for acromegaly, glucose metabolism was analyzed again in
38 patients, and it improved in 26 patients with IGT or diabetes
mellitus. Of 65 patients, 25 (38%) had hypertension. Of 26 patients
who underwent barium enema or colonoscopy, 10 had colonic polyps
and 4 had colon cancer. In conclusion, long-term excessive GH
secretion causes many complications. Therefore, awareness of the
248
early symptoms and signs of acromegaly and long-term careful

management of complications, along with therapy to reduce serum
GH/IGF-I levels are important for patients with acromegaly (6).
Acromegaly. Spade like hand with wide terminal tufts. Premature

osteoarthritis.
A case of a craniopharyngioma as a second primary tumor in a

patient with acromegaly due to a GH-secreting pituitary adenoma is
described. The patient was lost for follow-up for 18 years after trans-
sphenoidal pituitary surgery for a GH-secreting pituitary adenoma.
She presented with headaches and decreased visual acuity, and
showed unsuppressed GH in an oral glucose load test with high IGF-1
levels. Brain MRI showed a suprasellar cystic mass and the patient
underwent surgery for cyst drainage resulting in postoperative
improvement in her vision. Biopsy of the mass confirmed the
diagnosis of a craniopharyngioma (7).
Treatment is aimed at correcting (or preventing) tumor
compression by excising the disease-causing lesion, and at reducing
GH and IGF-I levels to normal values. Transsphenoidal surgery is
often the first-line treatment. When surgery fails to correct GH/IGF-I
hypersecretion, medical treatment with somatostatin analogs and/or
RT can be used. The GH antagonist (pegvisomant) is used in patients
who are resistant to somatostatin analogs. Adequate hormonal disease
control is achieved in most cases, allowing a life expectancy similar to
that of the general population. However, even if patients are cured or
well-controlled, sequelae (joint pain, deformities and altered QOL)
often remain (1).
249
Assessment: acromegaly and gigantism are due to excess GH

production, usually because of a pituitary adenoma. In rare cases,
acromegaly is due to ectopic secretion of growth-hormone-releasing
hormone responsible for pituitary hyperplasia.
The clinical features include acral and soft tissue overgrowth, IGT,
diabetes mellitus, hypertension, heart and respiratory failure,
osteoporosis, joint alterations and bone deformities, headaches and
decreased visual acuity.
Did the King suffer from acromegaly? Although King David
suffered from secondary osteoporosis, in the absence of acral and soft
tissue overgrowth such as broadened extremities (hands and feet),
widened, thickened, stubby fingers, thickened soft tissue, a widened
and thickened nose, prominent cheekbones, forehead bulges, thick lips
and marked facial lines, thickened forehead and overlying skin,
sometimes leading to frontal bossing, mandibular overgrowth with
prognathism, maxillary widening, tooth separation and jaw
malocclusion, diabetes mellitus, hypertension, and heart and
respiratory failure, peripheral nerve enlargement associated with
carpal tunnel syndrome or cubital tunnel syndrome, and thickening of
retinacula, such as A1 pulley in trigger finger, the diagnosis of
acromegaly unlikely. It would also be ironic if David who as a youth
had slain the pituitary giant, Goliath (9), was visited by the same
disorder in his old age.
References
1. Chanson P, Salenave S. Acromegaly. Orphanet J Rare Dis. 2008;3:17.
2. Lugo G, Pena L, Cordido F. Clinical manifestations and diagnosis of
acromegaly. Int J Endocrinol. 2012;2012:540398.
3. Tagliafico A, Resmini E, Ferone D, Martinoli C. Musculoskeletal
complications of acromegaly: what radiologists should know about early
manifestations. Radiol Med. 2011;116(5):781-92.
4. Padova G, Borzì G, Incorvaia L, et al. Prevalence of osteoporosis and vertebral
fractures in acromegalic patients. Clin Cases Miner Bone Metab. 2011;8(3):37-43.
5. Mazziotti G, Bianchi A, Bonadonna S, et al. Prevalence of vertebral fractures in
men with acromegaly. J Clin Endocrinol Metab. 2008; 93(12):4649-55.
6. Fukuda I, Hizuka N, Murakami Y, et al. Clinical features and therapeutic
outcomes of 65 patients with acromegaly at Tokyo Women's Medical University.
Intern Med. 2001;40(10):987-92.
7. El-Bilbeisi H, Ghannam M, Nimri CF, Ahmad AT. Craniopharyngioma in a
patient with acromegaly due to a pituitary macroadenoma. Ann Saudi Med.
2010;30(6):485-8.
8. Chanson P, Salenave S, Kamenicky P, et al. Pituitary tumours: acromegaly.
Best Pract Res Clin Endocrinol Metab. 2009;23(5):555-74.
9. Berginer VM. Neurological aspects of David-Goliath battle: restriction in the
giant's visual field. IMAJ. 2000;2:725-7.
250
HYPOGONADISM
Hypogonadism is a common condition which occurs frequently in
older men. It is characterized by low testosterone and is associated
with symptoms which are often nonspecific. A key symptom is low
libido, but it can be associated with erectile dysfunction, reduced
muscle mass and strength, increased body fat, reduced BMD,
decreased muscle mass, osteopenia or osteoporosis, reduced vitality,
fatigue, depressed mood, metabolic syndrome, hypertension, type 2
diabetes, and obesity. Hypogonadism is often under diagnosed (1-4).
Androgen deficiency in aging men is common, and the potential
sequelae are numerous. In addition to low libido, erectile dysfunction,
decreased bone density, depressed mood, and decline in cognition
studies suggest strong correlations between low testosterone, obesity,
and the metabolic syndrome. Because causation and its directionality
remain uncertain, the functional and C-V risks associated with
androgen deficiency have led to intense investigation of testosterone
replacement therapy in older men. Although promising, evidence for
definitive benefit or detriment of testosterone therapy is not
conclusive; treatment of late-onset hypogonadism is complicated (5).
Diagnosis of the condition requires the presence of hypogonadal
symptoms and low serum testosterone levels (4). Increased longevity
and population aging will increase the number of men with late-onset
hypogonadism, a common condition that is often underdiagnosed and
undertreated. The indication of testosterone replacement therapy
treatment requires the presence of low testosterone level and
symptoms and signs of hypogonadism (6).
A vertebral fracture occurred in a 51-year-old man with previously
undiagnosed osteoporosis. The underlying cause of the osteoporosis
was primary hypogonadism. Back pain was the presenting symptom in
primary hypogonadism. This case indicates that hypogonadism can be
associated with osteoporosis (7).
The majority of older men develop hypogonadism that can be
reversed by testosterone replacement (2,8-10). Testosterone
replacement therapy is warranted in the presence of both clinical
symptoms suggesting hormone deficiency and decreased hormone
levels. Hypogonadism is a common condition but often
underdiagnosed and undertreated (3).
There are a number of formulations available for testosterone
therapy including intramuscular injections, transdermal patches,
transdermal gels, buccal patches and subcutaneous pellets. These are
efficacious in establishing eugonadal testosterone levels in the blood
251
and relieving symptoms. Restoration of testosterone levels to the

normal range improves libido, sexual function, mood, reduces fat
body mass, increases lean body mass, improves BMD, and cognition
(3,6). Testosterone treatment is contraindicated in subjects with
prostate cancer or BPH and risks of treatment are perceived to be high
by many physicians. These risks, however, are often exaggerated and
should not outweigh the benefits of testosterone treatment (4,11)..
Hypogonadism is a risk factor for osteoporosis.
Perhaps the most controversial area is the issue of risk, especially

the possible stimulation of prostate cancer by testosterone, even
though there is no evidence to support this risk. Other possible risks
include worsening symptoms of BPH, liver toxicity, hyperviscosity,
erythrocytosis, worsening untreated sleep apnea, or severe heart
failure. Despite this controversy, testosterone supplementation in the
United States has increased substantially in the past several years. The
physician should discuss with the patient the potential benefits and
risks of testosterone replacement therapy (6).
Assessment: the verse "..And the maiden was very fair, and she
cherished the king, and ministered him; but the king knew her not.." (I
Kings 1:4) indicates that King David suffered from sexual
dysfunction. It is most likely that the King suffered from low or absent
libido relating to some organic disease and/or mental disorder (12).
Among various types of sexual dysfunction, erectile dysfunction
combined with low or absent libido was most likely responsible. The
numerous possible causes of King David's sexual dysfunction include
some serious disease, MDD and various social problems such as
loneliness, lack of close relationships with friends on whom King
could rely, feelings of neglect, and loss of power and control over his
people (13).
252
Did the King suffer from hypogonadism? Did King David suffer
from testosterone deficiency and because of that a decline in erectile
function? Since hypogonadism can be related to osteoporosis, it can
be assumed that this osteoporosis may have affected King David's
bones. Diagnosis of this condition requires the presence of
hypogonadal symptoms and low serum testosterone levels. However,
if the diagnosis of hypogonadism is accepted, it does not entirely
explain the disease that "..consumed.." his bones.
References
1. Lunenfeld B, Arver S, Moncada I, et al. How to help the aging male? Current
approaches to hypogonadism in primary care. Aging Male. 2012;15(4):187-97.
2. Surampudi PN, Wang C, Swerdloff R. Hypogonadism in the aging male
diagnosis, potential benefits, and risks of testosterone replacement therapy. Int J
Endocrinol. 2012;2012:625434.
3. Bassil N. Late-onset hypogonadism. Med Clin North Am.2011;95(3):507-23, x.
4. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the
primary care setting. Int J Clin Pract. 2010;64(6):682-96. Comment in: Listen:
testosterone is no longer a secret. [Int J Clin Pract. 2010].
5. Shelton JB, Rajfer J. Androgen deficiency in aging and metabolically
challenged men. Urol Clin North Am. 2012;39(1):63-75, 07.
6. Bassil N, Morley JE. Late-life onset hypogonadism: a review. Clin Geriatr
Med. 2010;26(2):197-222.
7. Bridges AB, Davies RR, Espley AJ. Male hypogonadism presenting as back
pain secondary to osteoporosis. Scott Med J. 1990;35(6):178-9.
8. Morley JE. Andropause: is it time for the geriatrician to treat it ? J Gerontol
Medical Sci. 2001;56A(5):M263-5.
9. Morley JE, Kaiser FE, Perry P, et al. Longitudinal changes in testosterone,
luteinizing hormone, and follicle-stimulating hormone in healthy older men.
Metabolism. 1997;46:410-3.
10. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on
serum total testosterone levels in healthy men. J Clin Endocrinol & Metab.
2001;86:724 -31.
11. Lunenfeld B, Arver S, Moncada I, et al. How to help the aging male? Current
approaches to hypogonadism in primary care. Aging Male. 2012; 15(4):187-97.
12. Ben-Noun L. Sexual dysfunction. In Ben-Noun L. ed. The Diseases of the
Kings of Israel. B.N. Publications. Israel. 2006, pp 80-87.
13. Ben-Noun L. Sexual dysfunction. In Ben-Nun L. ed. The Family Life Cycle
and the Medical Record of King David the Great. Research in Biblical Times from the
253
HYPERPARATHYROIDISM
Primary hyperparathyroidism is a generalized disorder of calcium,
phosphate, and bone metabolism that results from an increased
secretion of PTH (1).
The prevalence of primary hyperparathyroidism varies between 1
and 4/1.000 in the general population (2). Primary
hyperparathyroidism is diagnosed in approximately 100,000 patients
in the US each year, with a 2-3:1 female-to-male distribution. In most
cases, occurrence is sporadic rather than familial, and 80-85% of cases
of sporadic primary hyperparathyroidism are caused by a solitary
parathyroid adenoma, in 11-15% by glandular hyperplasia and in 1-
4% by parathyroid cancer (3,4).
The most frequent cause for primary hyperparathyroidism is
benign parathyroid adenoma, others have hyperplasia (5). In primary
hyperparathyroidism, the excessive concentration of PTH usually
leads to hypercalcemia and hypophosphatemia. Symptoms are usually
associated with the degree of hypercalcemia; however, the patient may
be asymptomatic. In advanced cases manifestations of hypercalcemia
include: CNS - lassitude, fatigability, poor memory, depression, and
obtundation; ophthalmic - band keratopathy; C-V – hypertension;
digestive - anorexia, vomiting, constipation, ulcers, and pancreatitis;
genitourinary - renal stones, decreased urine concentrating capacity,
and renal insufficiency; muscular – weakness; skeletal - osteoporosis,
fractures, bone pain, brown tumors, bone cysts, and joints -
pseudogout (1,3,6).
Hyperparathyroidism
Primary hyperparathyroidism is frequently an incidental finding in

asymptomatic patients. Often the diagnosis of primary
hyperparathyroidism is made by evaluation for osteoporosis, rarely in
254
the context of hypercalcemic crisis, myopathy, kidney stones,

nephrocalcinosis, and osteitis fibrosa (5).
The diagnosis is made by chance or during the workup of an
abnormal bone mass. Hypercalcemia and an elevated PTH
concentration, or at least a PTH level in the upper part of the normal
range, elevated ALP levels and decreased phosphorus levels generally
point to a diagnosis of hyperparathyroidism. Additional tests include
an evaluation of renal function, vitamin D measurement,
determination of 24-hours urinary calcium and bone densitometry
(2,3,5). Diagnostic imaging techniques such as ultrasonography, MRI
or CT have sensitivity about 52-75%. Highest sensitivity in
localization of ectopic parathyroid adenoma has sestamibi
scintigraphy with technetium-99. Skeleton x-rays show typical
changes in distal parts of bones and osteopenia (3).
Surgery is the definitive treatment for patients with symptomatic
primary hyperparathyroidism and asymptomatic patients who meet
one of the following criteria: serum calcium > 0.25 mmol/L (1.0
mg/dl) above the accepted normal reference range, renal failure (GFR
< 60 ml/min) and the presence of osteoporosis (T-score <-2.5 or
fracture) (2,5). Treatment of choice is surgical excision of adenoma.
Normalization of PTH and calcium levels after surgery and
improvement of renal, musculoskeletal and circulatory system
function can be achieved in 95%. Most common complications are
recurrent laryngeal nerve injury, hypoparathyroidism, bleeding or
stridor (3).
Distal clavicular resorption in a patient with primary

hyperparathyroidism.
An experienced surgeon should perform parathyroidectomy. As an

alternative in inoperable patients or preoperatively in severe
hypercalcaemia, cinacalcet successfully reduces calcium levels. In
asymptomatic patients not meeting the above mentioned criteria serum
calcium and creatinine levels should be measured once a year and
255
DXA every 2 years, since 30% of the patients with asymptomatic

primary hyperparathyroidism are progressive (5).
Surgical referral will take into account patient age and
comorbidities, as well as patient preferences. In the hands of an
experienced surgeon, the success rate of parathyroidectomy is 95-98%
and the rate of permanent complications is 1-3%. Parathyroid
scintigraphy is the best preoperative localization technique of the
adenoma. When surgery is contraindicated or refused by the patient,
bisphosphonates or cinacalcet can be indicated in cases of
osteoporosis or clinically significant hypercalcemia, respectively (2).
The NIH published guidelines in 2002, recommending
parathyroidectomy for all symptomatic patients and for asymptomatic
patients < 50 years or those who cannot participate in medical
surveillance. These criteria were questioned as being too limited,
because multiple studies have demonstrated symptomatic and
metabolic benefits of parathyroidectomy in "asymptomatic" patients.
Given the studies showing an improvement in QOL measures, future
risk for developing renal calculi, bone density, C-V health, and risk of
death, virtually all patients with primary hyperparathyroidism should
undergo surgical resection. An improvement in preoperative
localization studies as well as the development of a rapid
intraoperative PTH assay has changed the approach to parathyroid
surgery since the 1980s. Because most sporadic primary
hyperparathyroidism is caused by a single gland adenoma, a preferred
procedure has changed from a bilateral neck exploration to a focused
or unilateral approach, with similar rates of success in patients with a
solitary tumor identified preoperatively (4).
All patients (n=48), afflicted by primary hyperparathyroidism,
Sanata Crisitina, Madrid, had elevated PTH levels and 87% had
normal or moderately increased hypercalcaemia. The most common
clinical presentation was renal colic (34%), while 22.8% was
asymptomatic. Osteopenia was in 70.4% of patients and osteoporosis
in 81.3%. Fractures developed in 21.8% of the patients. Osteoporosis
was a common finding (7).
A 72-year-old woman with a delayed diagnosis of primary
hyperparathyroidism, produced by an intrathoracic adenoma with a
longstanding course, was presented with severe osteoporosis, multiple
fractures, bone deformities, and neurological impairments. Persisted
hypercalcaemia, high levels of ALP and PTH and a paratracheal mass
on a helicoids tomography of the thorax were found. After surgical
removal, the histopathological examination confirmed an ectopic
256
adenoma of the parathyroid gland and the patient achieved some

improvement in her clinical course (8).
A 64 year-old man was admitted to the hospital due to chronic
renal failure. An US and a CT of the kidneys showed bilateral, severe
nephrocalcinosis. He had hypercalcaemia, hyperparathyroidism, and a
bone disease caused by an adenoma in one of the parathyroid glands.
After removal of the adenoma, the plasma calcium level was in
control, but renal function deteriorated. The patient was treated with
dialysis and renal transplantation (9).
A 72-year-old patient presented to the ED with symptoms of
diffuse joint and muscular pain, fatigue and diminished memory.
Serum calcium and PTH levels were raised, consistent with primary
hyperparathyroidism. No abnormality was found on an
ultrasonography scan of the neck. However, a sestamibi scan
suggested a possible adenoma in the anterior mediastinum, which on
CT scan was 1.5 cm in size. A partial upper sternotomy was
performed in order to excise the adenoma and his symptoms
disappeared within several weeks. This case highlights the variable
and commonly nonspecific symptoms of primary hyperparathyroidism
and the less well-known fact that parathyroid adenoma may
occasionally be found intrathoracically (10).
A 50-year-old man presented at another hospital with non-specific
symptoms such as anorexia, nausea, vomiting, polyuria, dehydration,
abdominal pain, weight loss, fatigue, muscular weakness, irritability
and lethargy. Serum levels of calcium and PTH were markedly
increased to 23.6 mg/dL (reference values 8.6-10.2 mg/dL) and >
1900 ng/L (reference values 14-72 ng/L) respectively. After initial
treatment, the patient was transferred to the ICU of a tertiary care
university hospital for further stabilization and treatment because the
typical signs of hypercalcemia were not resolving. A parathyroid
adenoma was diagnosed and a few days later a parathyroidectomy was
performed. The postoperative course was uneventful. In conclusion,
acute primary hyperparathyroidism, also known as parathyroid storm
or parathyroid crisis, is a rare but potentially fatal endocrine
emergency if unrecognized and untreated. Appropriate diagnosis and
immediate adequate management of hypercalcemia are important in
reducing mortality. Nevertheless, mortality remains high, even with
surgical treatment, the cornerstone of the definitive therapy (11).
Assessment: primary hyperparathyroidism is a generalized

disorder of calcium, phosphate, and bone metabolism that results from
an increased secretion of PTH. In most cases, occurrence is sporadic
rather than familial; most cases of sporadic primary
257
hyperparathyroidism are caused by a solitary parathyroid adenoma,

following by glandular hyperplasia and parathyroid cancer.
Hypercalcemia and an elevated PTH concentration, or PTH level in
the upper part of the normal range, elevated ALP levels and decreased
phosphorus levels point to a diagnosis of hyperparathyroidism.
Additional tests include an evaluation of renal function, vitamin D
measurement, determination of 24-hours urinary calcium and bone
densitometry. Diagnostic imaging techniques include ultrasonography,
MRI, CT, sestamibi scintigraphy and skeleton x-rays for bone
osteoporosis. Treatment of choice is surgical excision of adenoma.
Did the King suffer from hyperparathyroidism? It can be assumed
that he may have suffered from this disease leading to osteoporosis,
subsequent fractures and severe bone pain. Did the King suffer from
asymptomatic renal stones, renal failure, or other asymptomatic
manifestations of this disease? There are insufficient data to answer
these questions. If this diagnosis is accepted, however, there is still no
explanation for the disease, which ―...consumed ...‖ the King‘s bones.
References
1. Moore TJ. Hypercalcemia. In: Branch WT (ed.). Office Practice of Medicine.
2nd ed. St. Louis, MO: W.B. Saunders. 1987; pp. 752-63.
2. Body JJ. Primary hyperparathyroidism: diagnosis and management. Rev Med
Brux. 2012;33(4):263-7.
3. Osmólski A, Osmólski R, Frenkiel Z, Adamiak G. Primary
hyperparathyroidism - case report and review of the literature. Otolaryngol Pol. 2006;
60(1):93-6.
4. Elaraj DM, Clark OH Current status and treatment of primary
hyperparathyroidism. Perm J. 2008;12(1):32-7.
5. Suter-Widmer I, Kraenzlin ME, Meier C. Primary hyperparathyroidism. Ther
Umsch. 2011;68(6):321-6.
6. Rude PK. Hyperparathyroidism. Otolaryngol Clin North Am. 1996;29:663-79.
7. Alcaraz MJ, Lorente R, Del Valle Y, et al. Primary hyperparathyroidism:
current role of bone densitometry. Radiologia. 2008;50:37-45.
8. Souza ER, Scrignoli JA, Bezerra FC, et al. Devastating skeletal effects of
delayed diagnosis of complicated primary hyperparathyroidism because of ectopic
adenoma. J Clin Rheumatol. 2008;14:281-4.
9. Grube M, Bech JN, Pedersen EB. Primary hyperparathyroidism as a cause of
chronic renal failure. Ugeskr Laeger. 2012;174(8):502-3.
10. Thórhallsdóttir H, Asgeirsson KS, Olafsdóttir A, Gudbjartsson T. Primary
hyperparathyroidism due to an intrathoracic parathyroid adenoma. A case report and
review of the literature. Laeknabladid. 2010;96(7-8):469-72.
11. Van den Hauwe K, Oeyen SG, Schrijvers BF, et al. A 50-year-old man with
severe hypercalcemia: a case report. Acta Clin Belg. 2009;64(5):442-6.
258
PAGET'S DISEASE
Paget‘s disease is a relatively common disorder, resulting from a
primary overactivity of osteoclasts, which leads to excessive
resorption of bone and the formation of disorganized, structurally
defective bone (1). This disease is the most common metabolic bone
disease following osteoporosis, affecting 2-4% of adults > 55 years of
age (2), and 2-7% of persons of age ≥ 55 years in North America and
western Europe (3).
Paget‘s disease results from bone remodeling and the formation of
bone that is structurally abnormal. Recent studies have confirmed that
both genetic and environmental factors are important in its etiology.
Epidemiological studies in Europe and North America have revealed
that Paget's disease shows an increasing frequency of occurrence with
age and is more prevalent among men than women. There is marked
geographic variation in the prevalence of Paget's disease throughout
western nations, with the highest rates during the 1970s in Britain.
Recent studies of the secular trends in Paget's disease suggest
declining rates in both prevalence and severity at diagnosis. The
overall age/sex standardized prevalence rate in Britain during the
period 1993-1995 was 2.5% among men and 1.6% among women ≥
55 years of age. Prevalence rates had fallen by approximately 50% in
several of the centers studied, suggesting an environmental
contribution to the etiology of this disorder. Similar findings have
been reported from other European countries and New Zealand.
Recent study of the incidence and clinical manifestations of Paget's
disease have emerged from large cohort studies in primary care record
linkage resources, such as the General Practice Research Database.
Over the period 1988-1999, the incidence rate of clinically diagnosed
Paget's disease of bone was 5 per 10,000 person-years among men and
3 per 10,000 person-years among women 75 years of age. The
disorder was associated with an increased risk of back pain (RR 2.1,
95% CI 1.9 - 2.3), osteoarthritis (RR 1.7, 95% CI 1.5 - 1.9), and
fracture (RR 1.2, 95% CI 1.0 - 1.5). Using life table methodology,
the estimated proportion of patients dying within 5 years of follow-up
was 32.7% among the cohort with Paget's disease of bone compared
with 28.0% among control patients (p<0.05) (4).
This study estimated changes in the age- and sex-specific
prevalence of Paget's disease in 6 European towns over a 20-year
period. Declines in prevalence were observed in this disorder,
occurring among both men and women. To estimate secular changes
in the age-and sex-specific prevalence of Paget's disease of bone in
259
Europe, a second radiographic survey was conducted using identical

sampling and methods in 6 European towns where a baseline study
was performed in 1978-1979. In addition to these towns, the survey
was carried out in 2 Hungarian centers not included in the initial
study. In each center, a sample of abdominal radiographs of people ≥
55 years of age was taken from stored films within the radiology
department of the principal general hospital. Radiographs showing the
entire pelvis, sacrum, femoral heads, and lumbar vertebrae were
studied for the period of 2000-2001. A trained observer and a
consultant radiologist evaluated the films. A total of 6935 radiographs
(3512 women and 3423 men) were assessed in the eight towns. The
overall age- and sex-standardized prevalence rate of Paget's disease
was 0.3% with a male/female ratio of 1.5. Prevalence increased with
age among men and women rising to 0.8% of men and 0.9% of
women ≥ 85 years of age. The differences in prevalence rate among
the European centers were relatively small, especially in women.
There was a decline in rates between 1978/79 and 2000/01. In
conclusion, these European data confirm the decrease in frequency of
Paget's disease (5).
A radiographic survey was conducted to determine the current
prevalence of Paget's disease in New Zealand (previously recognized
as a high prevalence area). Plain abdominal radiographs (n=3350)
taken in 2005-06 in subjects of European descent > 54 years old were
examined for Paget's disease. The results were compared with those of
a similar survey from 1996-98. The medical record of affected
subjects was examined to determine when the disease had been first
recognized and the plasma ALP at that time. Paget's disease was
detected in 87 radiographs (2.6%). In 55 cases (63%), it was already
known to have been present, for a mean 14 years beforehand. The
newly recognized or 'incident' cases were significantly older (mean
age 86 vs. 67 years, p<0.0001) and had milder disease (ALP 139 vs.
239 u/l, p<0.0001) than the known cases. Compared with the 1996-98
survey, the age distribution of affected patients shifted to the right,
with a significantly lower proportion in the youngest age group (55-69
years, p<0.004). These results confirm the secular trend of Paget's
disease presenting later in life and in milder form, suggesting that
there are important environmental determinants. The relatively few
'incident' cases are mostly in the elderly. Given the secular trend and
limitations to life expectancy, it is predicted that Paget's disease will
become increasingly rare (6).
The etiology of Paget's disease is only partly understood, but
includes both genetic and environmental factors and viral components
260
(2,3). Recently, mutations in the sequestosome 1/p62 gene have been

identified as a cause of familial Paget's disease and of some apparently
sporadic cases of the disease (7). Paget's disease is a common
condition characterized by increased and disorganised bone turnover
which can affect one or several bones throughout the skeleton. These
abnormalities disrupt normal bone architecture and lead to various
complications such as bone pain, osteoarthritis, pathological fracture,
bone deformity, deafness, and nerve compression syndromes. Genetic
factors play an important role in Paget's disease and mutations or
polymorphisms have been identified in 4 genes that cause classical
Paget's disease and related syndromes. These include TNFRSF11A,
which encodes RANK, TNFRSF11B which encodes OPG, valosin
containing protein which encodes p97, and SQSTM1 which encodes
p62. All of these genes play a role in the RANK-NFkappaB signaling
pathway and it is likely that the mutations predispose to PDB by
disrupting normal signaling, leading to osteoclast activation. Although
Paget's has traditionally be considered a disease of the osteoclast there
is evidence that stromal cell function and osteoblast function are also
abnormal, which might account for the fact that the disease is
associated with increased bone formation as well as resorption.
Environmental factors also contribute to Paget's disease. Most
research has focused on paramyxovirus infection as a possible
environmental trigger but evidence in favor of the involvement of
viruses in the disease remains conflicting. Other factors, which have
been implicated as possible disease triggers, include mechanical
loading, dietary calcium and environmental toxins (8).
This lateral skull x ray demonstrates changes of Paget‘s disease, with

areas of lysis, areas of sclerosis (‗cotton-wool spots‘) and calvarial
thickening.
The disease is often asymptomatic, but can cause bone pain,

deformity, fracture and other complications (2,7). Commonly affected
261
areas include the skull, spine, pelvis, femur, and tibia. The usual
presenting symptoms are deformity and pain, the latter probably
arising from periostal stretching, microfractures, degenerative joint
disease, or direct neural compression. The skull may become enlarged
and bowing of the femur and tibia are frequently seen. Increased
warmth and sweating of the skin overlying affected bones are
common. In addition, a high output cardiac failure may develop (1,3).
Other complications include bone pain, osteoarthritis, skeletal
deformity, hearing loss, and fractures (3).
Patients with typical radiological and clinical features of Paget's
disease referred to the Department of Endocrinology, Chile, during the
last decade were included in this review. Data were obtained from 15
patients with Paget's disease (10 males, 8 Chilean, 6 European and 1
Asian), 11 of them were diagnosed during the last 3 years. The mean
age at diagnosis was 68.7 +/- 11.1 years. No one had first-degree
relatives with Paget's disease. Bone pain was the main complaint in 13
patients and elevated total ALP in the other 2. The average duration of
the symptoms prior to diagnosis was 38.8 months. Eight patients had
monostotic lesions; the most commonly involved sites were the pelvis,
spine and femur. Radiological evaluation disclosed sclerotic changes
in all patients as well as bone deformity and osteoarthritis in 8
patients. Total ALP was elevated in 14 cases (mean 4 times over the
upper normal limit). In conclusion, when compared to series of the
Northern hemisphere, Paget's disease in Chile is characterized by an
older age at diagnosis, a higher frequency of symptomatic
presentation, advanced radiological involvement and greater
proportion of complications. Paget's disease should be suspected in
every patient, with bone pain or elevated ALP (9).
Paget's disease
262
A retrospective review evaluated the medical records of 51 patients

with Paget's disease at a tertiary referral centre in Southern India,
1995-2003. Symptoms included bone pain (65%), LBP (37%),
skeletal deformities (33%), pathological fractures (20%), neurogenic
claudication (4%), deafness and head enlargement (7%), and renal
stones (4%). Five patients (9.8%) were asymptomatic and were
incidentally diagnosed during evaluation of an elevated ALP. Two
patients had neurological symptoms (root pains in one and cauda
equina in the other) (10). Hypocalcemia was rare in Paget's disease,
usually occurring because of therapy with biphosphonates (11).
Paget's disease is treatable. Potent bisphosphonates such as
pamidronate, alendronate and risedronate relieve symptoms and may
reduce the risk of complications. The Pharmaceutical Benefits Scheme
subsidizes treatment for patients with symptomatic disease. A strong
case is made for treating asymptomatic patients with involvement of
long bones, vertebrae or base of skull, and for patients with significant
osteolytic lesions, and perhaps in younger patients (2,7).
Bisphosphonates restore normal bone turnover and relieve bone
pain, but oral formulations may be limited by complicated dosing
regimens and poor G-I absorption. The bisphosphonate, zoledronic
acid, administered as a single intravenous infusion, offers
antiresorptive efficacy and longer-lasting remission (3). The treatment
of choice is a single infusion of zoledronic acid; courses of oral
alendronate (3-6 months) or risedronate (2 months) are also effective
(2).
Typical bowing of the leg due to Paget‘s disease involving the right tibia.
Antiresorptive treatment with bisphosphonates is the standard

treatment, but there may be limitations to oral therapy; intravenous
pamidronate is efficacious and has long been available, but its use is
hindered by an impractical recommended dosing regimen of 30 mg
intravenously over 4 hours for 3 consecutive days. In 2 identical,
263
double-blind, 6-month trials, 96% of patients treated with a one-time

intravenous treatment of zoledronic acid 5 mg achieved therapeutic
response, compared with 74% treated with 60 days of daily oral
treatment with risedronate 30 mg (p<0.001) (3).
Assessment: Paget‘s disease of bone is a relatively common

disorder, resulting from a primary overactivity of osteoclasts, which
leads to excessive resorption of bone and the formation of
disorganized, structurally defective bone. Genetic and environmental
factors are important in its etiology. The disease is often
asymptomatic, but can cause bone pain, osteoarthritis, pathological
fracture, bone deformity, deafness, and nerve compression syndromes.
Commonly affected areas include skull, spine, pelvis, femur, and tibia.
The usual presenting symptoms are deformity and pain, the latter
arising from periostal stretching, microfractures, degenerative joint
disease, or direct neural compression.
Was Paget disease responsible for the King‘s bone pain? In the
absence of genetic and environmental risk factors, and characteristic
clinical features such as the deformity of bones, bowing of the femur
or tibia, enlargement of the skull, or warmth and sweating skin over
the affected bones, this diagnosis seems unlikely.
References
1. Brown EM. Osteoporosis and Paget‘s disease of bone. In: Branch WT (ed).
Office Practice of Medicine. 2nd ed. St Louis, MO: W.B. Saunders. 1987, pp. 952-
64.
2. Britton C, Walsh J. Paget disease of bone - an update. Aust Fam Physician.
2012;41(3):100-3.
3. Abelson A. A review of Paget's disease of bone with a focus on the efficacy
and safety of zoledronic acid 5 mg. Curr Med Res Opin. 2008; 24(3):695-705.
4. Cooper C, Harvey NC, Dennison EM, van Staa TP. Update on the
epidemiology of Paget's disease of bone. J Bone Miner Res. 2006;21 Suppl 2:P3-8.
5. Poór G, Donáth J, Fornet B, Cooper C. Epidemiology of Paget's disease in
Europe: the prevalence is decreasing. J Bone Miner Res. 2006; 21(10):1545-9.
6. Bastin S, Bird H, Gamble G, Cundy T. Paget's disease of bone - becoming a
rarity? Rheumatology (Oxford). 2009;48(10):1232-5.
7. Walsh JP. Paget's disease of bone. Med J Aust. 2004;181(5):262-5.
8. Ralston SH. Pathogenesis of Paget's disease of bone. Bone. 2008;43(5):819-25.
9. González G, Brusco F, Arteaga L, et al. Paget disease of bone in Chile: report
of 15 cases. Rev Med Chil. 2003;131(5):491-7.
10. Anjali Thomas N, Rajaratnam S, Shanthly N, et al. Paget's disease of bone:
experience from a centre in southern India. J Assoc Physicians India. 2006;54:525-9.
11. Kannan S, Mahadevan S, Sathya A, Sriram U. A tale of three disease of the
bone. Singapore Med J. 2008;49(10):e263-5.
264
GASTROINTESTINAL DISEASES
G-I disease is often overlooked or simply forgotten as a cause of
osteoporosis. Yet, the consequences of osteoporotic fractures can be
devastating. Although the bulk of the published experience regarding
osteoporosis is derived from the postmenopausal population, G-I
disorders are also implicated in osteoporosis. The unique aspects of
G-I diseases associated with osteoporosis include early onset of
disease (and, therefore, prolonged exposure to risk factors for
developing osteoporosis, particularly IBD and celiac disease),
malabsorption, and maldigestion of nutrients necessary for bone
health and maintenance (e.g., calcium, and vitamin D), as well as the
impact of glucocorticoids. These factors, when added to smoking, a
sedentary lifestyle, hypogonadism, and a family history of
osteoporosis, accumulate into an imposing package of predictors for
osteoporotic fracture (1).
Decreased BMD is a frequent finding in patients with
inflammatory bowel disease. Contributing factors include: 1)
malabsorption of vitamin D, calcium and possibly vitamin K and other
nutrients, 2) treatment with corticosteroids, 3) inflammatory cytokines
in inflammatory bowel disease, and 4) hypogonadism induced by the
inflammatory bowel disease. Among patients with CD, 32% to 38%
have osteopenia (Z-scores <-1), while among patients with UC
osteopenia have 23% to 25%. The mean deficit is 0.44+/-0.08 Z-
scores in the spine in CD and 0.34+/-0.08 in UC. A similar deficit is in
the hip in both conditions. From these deficits, an increase in overall
fracture risk of 1.1-1.3 should be expected. The observed excess
fracture risk is limited compared to the general population in both CD
(RR=1.2, 95% CI 0.9 - 1.6 for any fracture and 2.2, 95% CI 1.2 - 4.0
for spine fractures) and ulcerative colitis (RR=1.1, 95% CI 1 - 1.2 for
any fracture, and 1.5, 95% CI 0.9 - 2.5 for spine fractures). The
observed excess fracture risk is close to that expected from the
changes in BMD. Despite the limited excess of fracture risk, a
relatively large percentage of all fractures is attributable to
corticosteroid use (2).
References
1. Katz S, Weinerman S. Osteoporosis and gastrointestinal disease. Gastroenterol
Hepatol (N Y). 2010;6(8):506-17.
2. Vestergaard P. Prevalence and pathogenesis of osteoporosis in patients with
inflammatory bowel disease. Minerva Med. 2004;95(6):469-80.
265
LACTOSE INTOLERANCE
Lactose malabsorption and milk products intolerance symptoms
are the most common alimentary tract disorders. Lactose intolerance is
a result of lactase deficiency or lack of lactase and lactose
malabsorption (1). Persons with lactose intolerance are unable to
digest significant amounts of lactose because of a genetically
inadequate amount of the enzyme lactase (2). There are 3 types of
lactase deficiency: congenital, late-onset lactase deficiency and
secondary lactase deficiency. Lactose intolerance means the
appearance of clinical G-I symptoms after ingestion of lactose. The
clinical symptoms of lactose intolerance include nausea, vomiting,
abdominal distension, cramps, flatulence, flatus, diarrhea and
abdominal pain (1).
The ability of adult humans to digest the milk sugar lactose -
lactase persistence - is a dominant Mendelian trait that has been a
subject of extensive genetic, medical and evolutionary research.
Lactase persistence is common in people of European ancestry as well
as some African, Middle Eastern and Southern Asian groups, but is
rare or absent elsewhere in the world. The recent identification of
independent nucleotide changes that are strongly associated with
lactase persistence in different populations worldwide has led to the
possibility of genetic tests for the trait. However, it is highly unlikely
that all lactase persistence-associated variants are known. Using an
extensive database of lactase persistence phenotype frequencies,
together with information on how those data were collected and data
on the frequencies of lactase persistence variants, a global summary of
the extent to which current genetic knowledge can explain lactase
persistence phenotype frequency. Surface interpolation of Old World
lactase persistence genotype and phenotype frequency estimates
obtained from all available literature and perform a comparison
between predicted and observed trait frequencies in continuous space
were used. By accommodating additional data on sample numbers and
known false negative and false positive rates for the various lactase
persistence phenotype tests (blood glucose and breath hydrogen), a
Monte Carlo method to estimate the probability that known lactase
persistence-associated allele frequencies can explain observed trait
frequencies in different regions was applied. In conclusion, lactase
persistence genotype data is currently insufficient to explain lactase
persistence phenotype frequency in much of western and southern
Africa, southeastern Europe, the Middle East and parts of central and
southern Asia (3).
266
Milk avoidance is a significant risk factor for low bone density.

Individuals who avoid milk, due to intolerance or learned aversion,
consume significantly less calcium and have poorer bone health and
probable higher risk of osteoporosis (4). Thus, persons with a lifelong
low intake of dairy products because of lactase deficiency have an
increased incidence of osteoporosis (5).
A diagnosis of lactose intolerance can be made with a careful

history supported by dietary manipulation. If necessary, diagnosis can
be confirmed by using a breath hydrogen or lactose tolerance test (2),
and analysis of lactase activity in the small intestine mucosa. Dietary
treatment eliminates clinical symptoms (1,2).
The potential for lactose intolerance causes 25-50 million
Americans and an unknown number of people around the world to
avoid milk (4). Lactase deficiency is present in up to 15% of persons
of northern European descent, up to 80% of blacks and Latinos, and
up to 100% of American Indians and Asians. A sizable number of
adults believe they are lactose intolerant but do not actually have
impaired lactose digestion, and some persons with lactase deficiency
can tolerate moderate amounts of ingested lactose (2).
In 102 healthy adults born in western France, the prevalence of
lactase deficiency was 23.4% and symptoms of lactose intolerance
were in 24 (50%) subjects with lactase deficiency. The daily milk
consumption was insignificantly different in the 24 subjects with
lactase deficiency and in the 78 subjects without lactase deficiency
(281 +/- 197 vs. 303 +/- 217 ml/24 hours). The symptomatic group of
lactose malabsorbers (n=12) was characterized by a shorter lactose
mouth to caecum transit time (39 +/- 20 vs. 88 +/- 48 min, p<0.05),
and more marked hydrogen production (6.1 +/- 2.3 vs. 3.4 +/- 2.4
10(3) ppm.min, p<0.04). In the 10 subjects with lactase deficiency and
lactose intolerance, the hydrogen breath test was reproducible for
diagnosis of lactase deficiency, lactose intolerance and hydrogen
267
production. The quantity of lactose malabsorbed was 60%. This study

indicates that in France, symptoms of lactose intolerance are not
severe and do not affect the daily consumption of milk and dairy
products (6).
Data on the prevalence of the lactase deficiency among the nations
of the Finn-Ugric language group (Finns, Karelians, Vepses, Izhors,
and Estonians), Eastern Slavs (Russians, Ukrainians, and Belarusians)
living in the northwestern region of Russia are presented. The lactase
deficiency has been established: among Russians - 16%, Belarusians -
15%, Ukrainians -13%, Finns - 22%, Karelians - 20%, Vepses - 20%,
Izhors - 20%, and Estonians - 23%. Confirmations of the cultural and
historical hypothesis of the lactase deficiency prevalence have been
found. Under certain ecological conditions, the nature of human
nutrition during a continuous period of history can produce significant
genetic changes in the population (7).
Subjects for this study were Thai patients with functional
dyspepsia who had no history of milk allergy underwent
gastroduodenoscopy. Two mucosal biopsy specimens were taken from
beyond the distal end of the second part of the duodenum. The
specimens were graded: group I: finger shaped villi; group II: mixed
finger and leaf shaped villi; group III: clubbing or blunting shaped
villi. All subjects were tested for lactose malabsorption by breath
hydrogen analysis after consuming 50-gram lactose. Breath hydrogen
concentration was analyzed in samples collected intermittently by
end-expiratory technique. A rise in breath hydrogen concentration of
20 PPM over baseline was considered evidence of lactose
malabsorption. The 25 Thai subjects included 20 females (80.0%) and
5 males (20.0%) who ranged in age from 18 to 53 years (mean 31 +/-
8.29). Sixteen subjects belonged to the finger shaped villi group
(64.0%), 5 to the mixed finger and leaf shaped villi, group (20.0%)
and 4 to the clubbing or blunting shaped villi group (16.0%). Results
of breath hydrogen excretion test identified the prevalence of lactose
intolerance in 68% of the subjects: 15/16 (93.75%) of group I; 1/5
(20.0%) of group II and 1/4 (25%) of group III, respectively
(p<0.001). The symptom of diarrhea after lactose loading was
correlated in patients who had positive breath hydrogen analysis. In
conclusion, the lactose intolerance is not related to intestinal villi
morphology. Primary lactase deficiency is more common in Thai
people than secondary lactase deficiency (8).
Three men with osteoporotic fractures were found to have lactase
deficiency and low dietary calcium intakes, decreased urinary
calcium, and moderately increased serum osteocalcin and PTH levels.
268
Histomorphometric studies demonstrated increases in osteoid

parameters and resorption surfaces. In conclusion, a low calcium
intake due to aversion to dairy products caused by the lactase
deficiency may promote the development of osteoporosis (9).
Lactose intolerance is easily managed by: (1) regular consumption
of milk that adapts the colon bacteria and facilitates digestion of
lactose; (2) consumption of yogurts and cheeses and other dairy foods
low in lactose; consumption of dairy foods with meals to slow transit
and maximize digestion, and use of lactose-digestive aids. As dairying
spreads around the world to new markets and dairy foods become the
dominant source of calcium in these markets, the potential for lactose
intolerance will grow. Management of lactose intolerance globally
will require both education and product development (4).
Treatment consists of avoiding lactose-containing foods. Lactase
enzyme supplements may be helpful. The degree of lactose
malabsorption varies among patients with lactose intolerance, but
most of them can ingest up to 12 oz of milk daily and remain
asymptomatic. Lactose-intolerant patients must ensure adequate
calcium intake (2).
Assessment: lactose malabsorption and milk products intolerance

symptoms are the most common alimentary tract disorders. Lactose
intolerance is a result of lactase deficiency or lack of lactase and
lactose malabsorption. There are 3 types of lactase deficiency:
congenital, late-onset lactase deficiency and secondary lactase
deficiency. Lactose intolerance means the appearance of clinical G-I
symptoms after ingestion of lactose. The clinical symptoms of lactose
intolerance include nausea, vomiting, abdominal distension, cramps,
flatulence, flatus, diarrhea and abdominal pain. The diagnosis of
lactose intolerance is based on the breath hydrogen test and analysis of
lactase activity in the small intestine mucosa. Dietary treatment
eliminates clinical symptoms.
Was King David afflicted by lactase deficiency followed by
reduced milk consumption that led to osteoporosis? In the absence of
characteristic clinical symptoms such as abdominal pain, flatulence,
flatus and diarrhea after lactose ingestion, results of breath hydrogen
test and analysis of lactase activity in the small intestine mucosa, the
diagnosis of lactase deficiency seems unlikely.
References
1. Hutyra T, Iwańczak B. Lactose intolerance: pathophysiology, clinical
symptoms, diagnosis and treatment. Pol Merkur Lekarski. 2009;26(152):148-52.
269
2. Swagerty DL Jr, Walling AD, Klein RM. Lactose intolerance. Am Fam

Physician. 2002;65(9):1845-50. Erratum in: Am Fam Physician. 2003;67(6):1195.
3. Itan Y, Jones BL, Ingram CJ, et al. A worldwide correlation of lactase
persistence phenotype and genotypes. BMC Evol Biol. 2010 Feb 9;10:36.
4. Savaiano Savaiano D. Lactose intolerance: an unnecessary risk for low bone
density. Nestle Nutr Workshop Ser Pediatr Program. 2011;67:161-71.
5. Newcomer AD, Hodgson SF, McGill DB, Thomas PJ. Lactase deficiency:
prevalence in osteoporosis. Ann Intern Med. 1978; 89:218-232.
6. Cloarec D, Gouilloud S, Bornet F, et al. Lactase deficiency and lactose
intolerance-related symptoms in adult healthy subjects from western France.
Gastroenterol Clin Biol. 1991;15(8-9):588-93.
7. Valenkevich LN, Iakhontova OI. Prevalence of the lactase deficiency among
the population of the northwestern region of Russia Eksp Klin Gastroenterol.
2005;(1):97-100, 108.
8. Thong-Ngam D, Suwangool P, Prempracha J, et al. Lactose intolerance and
intestinal villi morphology in Thai people. J Med Assoc Thai. 2001;84(8):1090-6.
9. Laroche M, Bon E, Moulinier L, et al. Lactose intolerance and osteoporosis in
men. Rev Rhum Engl Ed. 1995;62(11):766-9.
INFLAMMATORY BOWEL DISEASES

Despite of scientific efforts during the last decades, etiology and
pathogenesis of the 2 major IBD, namely CD and UC, remain unclear.
It is accepted that the development of either disease is the result of an
exaggerated or insufficiently suppressed immune response to a
hitherto undefined luminal antigen, probably derived from the
microbial flora. This inflammatory process leads to the mucosal
damage and therefore a further disturbance of the epithelial barrier
function, resulting in an increased influx of bacteria into the intestinal
wall, even further accelerating the inflammatory process. However,
the immunological disturbances that have been investigated
extensively during the past years have to be considered on the genetic
background of the individual patient and the environmental factors the
patient is exposed to (1).
CD is a chronic inflammatory condition affecting the G-I at any
point from the mouth to the rectum. Patients may experience diarrhea,
abdominal pain, fever, weight loss, abdominal masses, and anemia.
Extraintestinal manifestations of CD include osteoporosis,
inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis,
and erythema nodosum. Acute phase reactants, such as CRP and ESR,
are often increased with inflammation and may correlate with disease
activity. Levels of vitamin B12, folate, albumin, prealbumin, and
vitamin D can help assess nutritional status. Colonoscopy with
270
ileoscopy, capsule endoscopy, CT enterography, and small bowel

follow-through are often used to diagnose CD. US, axial CT,
scintigraphy, and MRI can assess for extraintestinal manifestations or
complications (e.g., abscess, perforation) (2).
Crohn's disease
A systematic review was conducted to determine changes in the

worldwide incidence and prevalence of UC and CD in different
regions and with time. A systematic literature search of MEDLINE
(1950-2010; 8103 citations) and EMBASE (1980-2010; 4975
citations) were performed to identify studies that were population
based, including data that could be used to calculate incidence and
prevalence, and reported separate data on UC and/or CD in full
manuscripts (n=260). Data from 167 studies from Europe (1930-
2008), 52 studies from Asia and the Middle East (1950-2008), and 27
studies from North America (1920-2004) were evaluated. The highest
annual incidence of UC was 24.3 per 100,000 person-years in Europe,
6.3 per 100,000 person-years in Asia and the Middle East, and 19.2
per 100,000 person-years in North America. The highest annual
incidence of CD was 12.7 per 100,000 person-years in Europe, 5.0
person-years in Asia and the Middle East, and 20.2 per 100,000
person-years in North America. The highest reported prevalence
values for IBD were in Europe (UC, 505 per 100,000 persons; CD,
322 per 100,000 persons) and North America (UC, 249 per 100,000
persons; CD, 319 per 100,000 persons). In time-trend analyses, 75%
of CD studies and 60% of UC studies had an increasing incidence of
statistical significance (p<0.05). In conclusion, although there are few
epidemiologic data from developing countries, the incidence and
prevalence of IBD are increasing with time in different regions around
the world, indicating its emergence as a global disease (3).
271
Crohn's disease
The main objective of this study was to conduct a comprehensive

review and summary of the burden of IBD that encompasses the
epidemiology, direct medical costs, indirect costs and humanistic
impact of these diseases in Canada. A literature search focused on
Canadian data sources. Analyses were applied to the 2012 Canadian
population. There were approximately 233,000 Canadians living with
IBD in 2012 (129,000 individuals with CD and 104,000 with UC),
corresponding to a prevalence of 0.67%. Approximately 10,200
incident cases occur annually. IBD can be diagnosed at any age, with
typical onset occurring in the second or third decade of life. There are
approximately 5900 Canadian children < 18 years of age with IBD.
The economic costs of IBD are estimated to be $2.8 billion in 2012
(almost $12,000 per IBD patient). Direct medical costs exceed $1.2
billion per annum and are driven by cost of medications ($521
million), hospitalizations ($395 million) and physician visits ($132
million). Indirect costs (society and patient costs) of total $1.6 billion
are dominated by long-term work losses of $979 million. Compared
with the general population, the QOL patients experience is low
across all dimensions of health. In conclusion, the present review
documents a high burden of illness from IBD due to its high
prevalence in Canada combined with high per-patient costs. Canada
has the highest prevalence and incidence rates of IBD in the world.
Individuals with IBD face challenges in the current environment
including lack of awareness of IBD as a chronic disease, late or
inappropriate diagnosis, inequitable access to health care services and
expensive medications, diminished employment prospects and limited
community-based support (4).
IBD prevalence has increased and a North-South gradient has been
reported. The nationwide prevalence of IBD, UC and CD in 1993 and
prevalence of IBD in 2008 were estimated, and assessed the
geographical distribution of IBD in Finland. In addition, the vitamin D
272
levels in a study population from a large, nationally representative the

Health 2000 Survey were investigated. The register study for
prevalences included all patients who had special reimbursement of
medications for IBD in the years 1993 (n=10,958) and 2008 (31,703).
The study for D-vitamin measurement consisted of 6134 persons who
had participated in the Health 2000 Survey. The nationwide point
prevalence of IBD in 1993 was 216 per 100,000 inhabitants and 595
in 2008. In 1993, the prevalence of UC (177) was fourfold higher than
the prevalence of CD. The prevalence of IBD and UC in Finland
increased from South to North. For CD, no geographical variation
could be demonstrated. In the Health 2000 survey, vitamin D levels
were lower in Northern than in Southern Finland. In conclusion,
Finland belongs to high prevalence area of IBD and this prevalence
has increased nearly threefold during the past 15 years. A clear North-
South gradient has been shown for IBD and UC, but not for CD.
Slightly lower vitamin D levels in Northern Finland may be associated
with the observed higher prevalence of IBD there (5).
In London, Samuel Wilks, a physician at Guy's hospital, first
described UC in 1859. Recent data indicate that the prevalence in the
high incidence areas ranges from 80 to 120/100.000/year. Primarily
young adults are affected (20 to 40 years of age) but the disease may
present at all ages, from younger than 1 year of life to the 80s. Many
series show a secondary peak in incidence in the elderly (6).
UC is an idiopathic, chronic inflammatory disorder of the colonic
mucosa, which starts in the rectum and generally extends proximally
in a continuous manner through part of, or the entire, colon; however,
some patients with proctitis or left-sided colitis might have a cecal
patch of inflammation (6). UC usually manifests with bloody diarrhea,
is associated with a number of extra-intestinal manifestations, and
may be acutely complicated by toxic megacolon (7). Longstanding
disease may predispose to the development of CRC. Bloody diarrhea
is the characteristic symptom of the disease. The clinical course is
unpredictable, marked by alternating periods of exacerbation and
remission (7,8).
Typical macroscopic lesions are mucosal ulcerations, with immune
cell infiltration and cryptic abscesses at histology (7). The localization
of inflammation and disease activity represent crucial factors which
have to be considered (6).
273
Barium enema examination demonstrates loss of haustral folds in the

entire descending colon with small ulcerations suggested. The colon has a
"lead-pipe" appearance. The distribution and appearance are suggestive of
ulcerative colitis.
EXTRAINTESTINAL MANIFESTATIONS
Arthritis is the most common extraintestinal manifestation of IBD
and can have a significant impact on morbidity and QOL (9). Joint
involvement associated with IBD belongs to the concept of
spondyloarthritis and includes 2 types of arthritis: a peripheral arthritis
characterized by the presence of pauciarticular asymmetrical arthritis
affecting preferentially joints of lower extremities and an axial
arthropathy including inflammatory back pain, sacroiliitis and AS
(10). Arthritis associated with IBD belongs to the category of
spondyloarthropathies (11).
While there have been advances in identifying predisposing genetic
factors and in elucidating pathophysiology of IBD, the mechanisms
surrounding the development of arthritis in IBD remain unclear (9).
Inflammation of axial and/or peripheral joints is one of the most
frequent extra-intestinal manifestations complicating the clinical
course and therapeutic approach in IBD. The frequency of these
complications seems to be similar for both diseases, CD and UC. IBD-
associated arthropathy is considered a subtype of seronegative
spondyloarthropathy, with axial, peripheral, or a combination of both
joint manifestations. Peripheral arthritis is generally non-erosive and
the oligoarticular variant particularly may correlate with intestinal
disease activity (9). Axial arthritis may include inflammatory back
pain, sacroiliitis, or AS, and less likely to correlate with G-I
274
symptoms, whereas peripheral arthritis is noted in pauciarticular and

in polyarticular disease (9,11).
Asymptomatic radiological involvement of the sacroiliac joints is
reported in up to 50% of patients. Other musculoskeletal
manifestations such as buttock pain, dactylitis, calcaneal enthesitis,
and thoracic pain are frequently underdiagnosed and, consequently,
are not treated appropriately (11).
The prevalence and clinical spectrum of musculoskeletal
manifestations in an inception cohort of European IBD patients was
evaluated. From 1 October 1991 to 30 September 1993, 202 IBD
patients were diagnosed in 3 centers of 2 countries (Italy and The
Netherlands) by means of a population-based inception cohort study.
Of this group of patients, 160 (79%) were interviewed and examined
by a rheumatologist and a gastroenterologist in the period June-
September 1996. Antero-posterior radiograph of the pelvis had
139/160 patients, and in 140/160 HLA-B27 was determined. Of the
160 patients, 53 (33.1%) had experienced at least one musculoskeletal
manifestation, 29 (18.1%) satisfied the European Spondylarthropathy
Study Group criteria for spondylarthropathy and 5 (3.1%) satisfied the
modified New York criteria for AS. However, 23 (14.4%) patients
developed one or more spondylarthropathy-related manifestations
without fulfilling any of the classification criteria. In patients
satisfying European Spondylarthropathy Study Group criteria a
significantly higher frequency of women (p=0.03), ocular and liver
involvement (p=0.01, p=0.03, respectively), and use of
immunosuppressive drugs (p=0.02) were observed. In conclusion, this
study shows a high prevalence of musculoskeletal manifestations in an
inception cohort of IBD patients. The clinical spectrum is broader than
that defined by spondylarthropathy criteria (12).
Articular symptoms and signs were investigated by questionnaire
in a cohort of 651 patients, mean age 42+/-14 years, followed at 2
referral hospitals, Padua, Italy over a 12-month period. UC (n=142)
and CD (n=120) patients were referred articular pain during their IBD
history: in 46% this was associated with active IBD, in 56%
symptoms were intermittent and in 19% symptoms preceded IBD
diagnosis. Of all patients, 62 (28 UC, 34 CD) complaining of articular
symptoms at the time of the interview were investigated by the
rheumatologist: arthropathy was axial in 52%, oligoarticular in 16%
and polyarticular in 23%. Oligoarthritis commonly involved the lower
limbs and was more commonly associated with UC. The mean
number of small joints involved was significantly higher in CD than in
UC patients (9.9+/-8.2 vs. 5.6+/-4.3; p<0.01). Bone scintigraphy was
275
abnormal in 70% of patients. In conclusion, prevalence of self-

reported articular symptoms in IBD patients exceeds 40% with 9.5%
incidence during 1-year of follow up. Symptoms predict entheropatic
involvement of the locomotor system (13).
Patients with CD are at increased risk of developing disturbances
in bone and mineral metabolism because of several factors, including
the cytokine-mediated nature of the IBD, the intestinal malabsorption
resulting from disease activity or from extensive intestinal resection
and the use of glucocorticoids to control disease activity. Inability to
achieve peak bone mass when the disease starts in childhood,
malnutrition, immobilization, low BMI, smoking and hypogonadism
may play a contributing role in the pathogenesis of bone loss. The
relationship between long-term use of glucocorticoids for any disease
indication and increased risk for osteoporosis and fractures is well
established. However, the relationship between CD and UC and bone
loss remains controversial. Depending on the population studied, the
prevalence of osteoporosis has been variably reported to range from
12% to 42% in patients with IBD. In IBD, most studies demonstrate a
negative correlation between BMD and glucocorticoid use, but not all
authors agree on the relationship between long-term glucocorticoid
use and continuing bone loss. Whereas prospective studies do suggest
sustained bone loss at both trabecular and cortical sites in long-term
glucocorticoid users with IBD, a decrease in bone mass is also
observed in patients with active CD not using glucocorticoids, and
bone loss is not universally observed in patients with CD using orally
or rectally administered glucocorticoids. Data on vertebral fractures
are scarce and there is no agreement about the risk of non-vertebral
fractures in patients with CD, although it has been suggested that non-
vertebral fracture risk may be increased by up to 60% in patients with
IBD. A publication reports an increased risk of hip fractures in CD
related to current and cumulative corticosteroid use and use of opiates,
although these fractures could not be related to the severity of
osteoporosis. The issue of the magnitude of the problem of
osteoporosis has become particularly relevant in CD, since the ability
of therapeutic interventions to beneficially influence skeletal
morbidity has been established in patients with osteoporosis, whether
post-menopausal women, men or glucocorticoid users. The main
question that arises is whether all patients with CD should be treated
with bone protective agents assuming that they all have the potential
to develop osteoporosis or whether the use of these agents should be
restricted to patients clearly at risk of osteoporosis and fractures. All
patients with CD should be screened for osteoporosis by means of a
276
BMD measurement in addition to full correction of any potential

calcium and vitamin D deficiency to allow timely therapeutic
intervention of the patient at risk while sparing the vast majority
unnecessary medical treatment (14).
Decreased BMD is a frequent finding in patients with IBD. Factors
contributing to this are: 1) malabsorption of vitamin D, calcium and
possibly vitamin K and other nutrients, 2) treatment with
corticosteroids, 3) inflammatory cytokines in IBD, and 4)
hypogonadism induced by the IBD. Among patients with CD, 32-38%
and among patients with UC, 23-25% have osteopenia (Z-scores <-1).
The mean deficit was 0.44 +/- 0.08 Z-scores in the spine in CD and
0.34 +/- 0.08 in UC. A similar deficit was seen in the hip in both
conditions. From these deficits, an increase in overall fracture risk of
1.1-1.3 should be expected. The observed excess fracture risk was
limited compared to the general population in both CD (RR=1.2, 95%
CI 0.9 - 1.6 for any fracture and 2.2, 95% CI 1.2 - 4.0 for spine
fractures) and UC (RR=1.1, 95% CI 1 - 1.2 for any fracture, and 1.5,
95% CI 0.9 - 2.5 for spine fractures). The observed excess fracture
risk was close to that expected from the changes in BMD. Despite the
limited excess fracture risk, a relatively large percentage of all
fractures may be attributable to corticosteroid use among users of
corticosteroids (15).
The availability of osteodensitometry has contributed significantly
to increase the awareness of IBD-associated bone disease. Reported
osteoporosis prevalence in patients with IBD range between 2-30%.
The fractures risk varies between studies, influenced by demographic,
clinical and genetic factors. The main pathogenetic factors involved
are malabsorption, treatment with glucocorticoids, inflammation
(increased cytokine production) and hypogonadism. Screening should
be considered for all patients with small bowel CD and especially for
those with extensive disease, multiple resections, and malnutrition.
Supplementation with both calcium and vitamin D is frequently the
first step taken, but is insufficient to inhibit bone loss in many patients
requiring use of glucocorticoids. Among available therapies, only
biphosphonates are effective for treatment of glucocorticoid-induced
osteoporosis (16).
IBD is associated with an increased incidence of osteoporosis.
Osteoporosis with osteoporotic pain syndromes, fragility fractures and
osteonecrosis accounts for significant morbidity and affects negatively
on the QOL. There is a need to increase awareness for IBD associated
osteoporosis. However, the best ways in which to identify at-risk
patients, the epidemiology of fractures and an evidence-based rational
277
prevention strategy remain to be established. The overall prevalence

of IBD-associated osteoporosis is 15%, with higher rates seen in older
and underweight subjects. The incidence of fractures is about 1 per
100 patient years, with fracture rates dramatically increasing with age.
While old age is a significant risk factor, disease type (CD or UC) is
not related to osteoporosis risk. Corticosteroid use is a major variable
influencing IBD-associated bone loss; however, it is difficult to
separate the effects of corticosteroids from those of disease activity.
The recommendations in IBD are similar for postmenopausal
osteoporosis, with emphasis on lifestyle modification, vitamin D (400-
800 IE daily) and calcium (1000-1500 mg daily) supplementation and
hormone replacement therapy (oestrogens/selective oestrogen receptor
modulators in women, testosterone in hypogonadal men).
Bisphosphonates have been approved for patients with osteoporosis
(T-score < 2.5), osteoporotic fragility fractures and patients receiving
continuous steroid medication. Data on the recently Food and Drug
Administration-approved osteoanabolic substance PTH and on OPG
are promising in terms of both steroid-induced and inflammation-
mediated osteoporosis, the key elements of IBD-associated bone
disease (17).
Saudi patients with IBD, between 18 and 70 years of age, who had
BMD determined by DXA scanning at one of 3 hospitals in the
Kingdom of Saudi Arabia from 2001 to 2008 were retrospectively
reviewed. Case notes and BMDs results were carefully reviewed for
demographic and clinical data. Low bone mass, osteopenia, and
osteoporosis were defined according to the WHO guidelines. Ninety-
five patients were included; 46% had CD and 54% had UC. The
average age was 30.9 ± 11.6 years. Using T-scores, the frequency of
osteopenia was 44.2%, and the frequency of osteoporosis was 30.5%
at both lumbar spine and proximal femur. Only 25.3% of patients
exhibited a BMD within the normal range. These results revealed a
positive correlation between the Z-score in both the lumbar spine and
the proximal femur and BMI (p=0.042, p=0.018, respectively). On
regression analysis BMI, age, and calcium supplementation were the
most important independent predictors of BMD. In conclusion, Saudi
patients with IBD are at an increased risk of low BMD and the
frequency of decreased BMD with CD and UC were similar. BMI and
age were the most important independent predictors of low BMD (18).
Treatment of IBD arthritis includes a short-term use of NSAID
associated with optimized treatment of gut inflammation. Safety
concerns mean that long-term treatment with NSAID is best avoided if
possible. Salazopyrine can be recommended for treatment of
278
peripheral arthritis. Methotrexate and azathioprine are generally

ineffective. Finally, efficacy of anti-TNF therapy (infliximab and
adalimumab) is well established. However, use of etanercept is not
recommended because of the increased risk for intestinal disease
relapse. Pathogenesis of gut-joint iteropathy is not elucidated. Both
inflammations are tightly related as suggested by human evidence of
gut inflammation in patients with other forms of spondyloarthritis and
animal evidence of gut and joint inflammation in HLA-B27/human
beta(2)-microglobulin transgenic rat model and TNF(DeltaARE)
mice. Several clues for the linkage between gut and joint
inflammation have been put forward including an altered recognition
and handling of bacterial antigens, an aberrant trafficking of CD8+ T
cells with an impaired T-helper type 1 cytokine profile and expression
of aEb7 integrin, an altered trafficking of macrophages expressing
CD163 and evidence of an increased angiogenesis. A transcriptome
analysis of mucosal biopsies identified a set of 95 genes that are
differentially expressed in both CD and spondyloarthritis as compared
with healthy controls suggesting common pathways. TNF plays a key
role in the pathogenesis of various arthritic diseases and IBD.
Mesenchymal/myofibroblast-like cells may represent the local
primary targets of TNF in the induction of gut and joint pathology.
Selective expression of TNFRI on these cells seems to be sufficient to
orchestrate the complete development of spondyloarthritis related
pathologies at least in TNF(DeltaARE) mice. Finally, genetic
susceptibility is probably required to develop these pathologies.
Genotyping of AS patients provided evidence for an important overlap
between determinants of inherited predisposition to CD and AS. The
best documented common association is with an IL-23R
polymorphism, although the exact role remains unexplored. In
addition, evidence suggests that a number of recently identified CD-
susceptibility loci are associated with AS. Clinical, genetical,
immunological and therapeutic evidence support the tight junction
between gut and joint inflammation in 2 linked diseases, IBD and
spondilioarhtritis, belonging to the 'immune-mediated inflammatory
diseases' (9).
Treatment of IBD is not always sufficient for control of arthritis.
While treatment with biologic agents is promising, there remains a
great need for larger, randomized studies to address optimal therapy of
IBD associated arthropathy (9).
The rheumatological, ophthalmological and dermatological
complications are the most common ones among the extraintestinal
manifestations of IBD. The incidence of skin manifestations is
279
estimated at 15-20% in case of CD and 10% in case of UC. The so

called specific lesions (perianal fissures, or metastatic CD), which are
part of the skin symptoms associated with IBD, show intimate
connections with the bowel disease itself, as they histologically show
granulomatous inflammation with epitheloid cells, similarly to the
ones seen in the intestines. The reactive lesions (erythema nodosum,
and pyoderma gangraenosum) that form the second main group of
skin changes can be found in other systemic diseases, but they are
more frequently associated with IBD. Cutaneous manifestations occur
due to malabsorption or drug therapy. Finally, there are dermatoses
(epidermolysis bullosa acquisitia, and acne fulminans) which have a
still questionable connection with IBD (19).
The aim of this study was determine the prevalence of the major
extraintestinal manifestations of IBD and their differences between
CD and UC. This prospective study involved 566 patients - 295 CD
with median follow up 11.6 years, range 2-32 years, and 271 UC with
median follow up 10.4 years, range 2-36 years. Data related to the
clinical course, extraintestinal manifestations and laboratory tests were
obtained at diagnosis and during follow-up. Extraintestinal
manifestations related with IBD appeared at least once in 46.6% of the
patients. Joints manifestations were the most common extraintestinal
manifestations. The extraintestinal manifestations were equal frequent
in UC (51.5%) as in CD (42.2%). Hepatobiliary manifestations (OR
1.91, 95% CI 1.15 - 3.16, p=0.007), venous thromboembolism (OR
4.26, 95% CI 1.3 - 15.4, p=0.006), and arthralgias (OR 1.59, 95% CI
1.01 - 2.5, p=0.035) were more frequent in UC than CD. Erythema
nodosum (OR 2.35, 95% CI 1.13 - 5.0, p=0.013) and peripheral
arthritis (OR 1.95, 95% CI 1.02 - 3.74, p=0.029) were more frequent
in CD. The prevalences of ocular and the rest of joint manifestations
were not different according to UC or CD. In conclusion, prevalence
of extraintestinal manifestations in Spanish IBD patients is among the
highest ever reported. The distribution of the extraintestinal
manifestations observed is different between CD and UC. It is
necessary to know to allow to prompt diagnosis and prevent
undesirable complications (20).
Ocular manifestations occur in 4-12% of patients with IBD. Uveitis
and iritis are more frequently associated with UC while episcleritis is
more common in CD. Some ocular manifestations in IBD can be
secondary to treatment and/or effects of the intestinal disease itself.
The specific management of ocular manifestations in IBD requires the
use of topical steroids and FANS, cycloplegics, systemic steroids or
immunosuppressive drugs. When conventional therapies fail to control
280
the ocular manifestations in IBD, the new biologic drugs can be

considered as good alternative treatments. Early diagnosis and
effective treatment may avoid the onset of severe and sometimes
persisting complications. In some cases, a surgical approach is
required to treat eye complications, i.e. cataract, and to improve the
patient's QOL (21).
This was a prospective study of 60 patients diagnosed with IBD,
who underwent full ophthalmologic examination, including visual
acuity, slit lamp examination of the anterior segments, intraocular
pressure, and fundus examination were accompanied by color
photography. Thirty-seven (61,7%) patients were diagnosed with UC
and 23 (38,3%) with CD. Data from 276 control individuals were used
for the determination of the prevalence of dry eye. Ophthalmologic
manifestations were diagnosed in 26 (43%) patients (14 UC, 12 CD;
12 males and 14 females). Conjunctivitis was diagnosed in 1 patient
(CD), episcleritis in 2 patients (UC), and iridocyclitis in 3 (CD).
Fundus examination showed 1 patient (CD) with unilateral choroiditis,
1 (UC) with retinal vasculitis, and 1 (CD) with optic neuritis. Retinal
pigment epithelium disturbances were present in 3 patients (1 CD, and
2 UC) and 2 had serous retinal detachment. In total, 13/60 patients
(22%) had dry eye compared with the 11% prevalence in controls.
Eight patients developed glucocorticosteroid-induced cataracts, 2 of
them treated surgically. This study demonstrated the prevalence of
the spectrum of ophthalmologic manifestations in the IBD population,
including some rare and silent findings that merit consideration and
early intervention (22).
Cutaneous manifestations are well-recognized complications of CD
and UC. The incidence of these manifestations varies widely but, at
the time of diagnosis, the mean incidence is around 10%. During the
course of the disease, a great variety of skin lesions may develop,
many of which are secondary to granulomatous cutaneous disease,
reactive skin eruptions, nutritional deficiency and other associated
conditions. The disorders that are directly related to the inflammatory
process of CD include perianal and peristomal ulcers and fistulae,
metastatic CD and oral granulomatous lesions. Histologically, the
features are similar to those found in the inflamed bowel. These
lesions usually respond to treatment of the underlying intestinal
disease. The most common forms of reactive skin eruption are
erythema nodosum and pyoderma gangrenosum. Certain subsets of
patients are more susceptible to the development of erythema
nodosum; in a previous report from our group, erythema nodosum was
seen mainly in females, and in patients with colonic involvement
281
and/or arthritis. This manifestation tends to occur during the first 2

years of the clinical course of the disease and may recur in
approximately one-half of cases. Infliximab is highly effective in
healing refractory lesions of erythema nodosum and pyoderma
gangrenosum. Manifestations that are secondary to nutritional
deficiency or associated conditions include acrodermatitis
enteropathica, psoriasis and autoimmune disorders. For most of the
cutaneous manifestations, the primary therapeutic target remains the
bowel. Early aggressive therapy can minimize severe complications
and maintenance treatment may prevent some devastating
consequences (23).
In CD, mesalamine products are used for the medical management
of mild to moderate colonic disease. Antibiotics (e.g., metronidazole,
fluoroquinolones) are often used for treatment. Patients with moderate
to severe CD are treated with corticosteroids, azathioprine, 6-
mercaptopurine, or anti-TNF agents (e.g., infliximab, adalimumab).
Severe disease may require emergent hospitalization and a
multidisciplinary approach with a family physician, gastroenterologist,
and surgeon (2).
The therapeutic regimens in UC range from simple local therapy
with aminosalicylates to systemic immunosuppressive therapy, which
in extreme cases requires the administration of ciclosporin (6). Other
therapeutic options in UC include mesalazine, corticosteroids,
immunomodulators and biologic agents; however, if these treatments
fail, the only available therapeutic choice remaining is the surgical
removal of the colon (7). Since UC is associated with an increased
risk in developing colon carcinoma, medical therapy as well as
endoscopic surveillance are fundamental in the prevention of
carcinoma (6).
Assessment: the incidence and prevalence of IBD are increasing

with time in different regions around the world, indicating its
emergence as a global disease. Individuals with IBD face challenges
in the current environment including lack of awareness of IBD as a
chronic disease, late or inappropriate diagnosis, inequitable access to
health care services and expensive medications, diminished
employment prospects and limited community-based support.
CD is a chronic inflammatory condition affecting the G-I at any
point from the mouth to the rectum. Patients experience diarrhea,
abdominal pain, fever, weight loss, abdominal masses, and anemia.
UC is a chronic relapsing or chronic active disease which starts at
the rectum and presents with a continuous inflammation. Primarily
282
young adults are affected (20 to 40 years of age) but the disease may
present at all ages, from younger than 1 year of life to the 80s. Bloody
diarrhea is the characteristic symptom of the disease.
Arthritis is the most common extraintestinal manifestation of IBD
and can have a significant impact on morbidity and QOL. Clinical,
genetical, immunological and therapeutic evidence support the tight
junction between gut and joint inflammation in 2 linked diseases, IBD
and spondilioarhtritis, belonging to the 'immune-mediated
inflammatory diseases'. Joint involvement associated with IBD
belongs to the concept of spondyloarthritis and includes 2 types of
arthritis: a peripheral arthritis characterized by the presence of
pauciarticular asymmetrical arthritis affecting preferentially joints of
lower extremities and an axial arthropathy including inflammatory
back pain, sacroiliitis and AS. The so called specific lesions (perianal
fissures, or metastatic CD), which are part of the skin symptoms
associated with IBD, show a intimate connections with the bowel
disease itself, as they histologically show granulomatous inflammation
with epitheloid cells, similarly to the ones seen in the intestines. The
reactive lesions (erythema nodosum and pyoderma gangraenosum)
that form the second main group of skin changes can be found in other
systemic diseases, but they are more frequently associated with IBD.
Other extraintestinal manifestations include: hepatobiliary
manifestations, venous thromboembolism, conjunctivitis, episcleritis,
uveitis and iritis, iridocyclitis, choroiditis, retinal vasculitis, optic
neuritis, retinal pigment epithelium disturbances, serous retinal
detachment, and dry eye.
Decreased BMD is a frequent finding in patients with IBD.
Contributing factors are: 1) malabsorption of vitamin D, calcium and
possibly vitamin K and other nutrients, 2) treatment with
corticosteroids, 3) inflammatory cytokines in IBD, and 4)
hypogonadism induced by the IBD.
IBD is associated with an increased incidence of osteoporosis,
osteoporotic pain syndromes, fragility fractures and osteonecrosis,
accounting for significant morbidity affecting negatively the QOL.
In his old age, the King suffered from a skin disease. Was he
affected by pyoderma gangrenosa? Can pyoderma gangraenosum be
related to IBD?
As described previously, the passage in Psalm 38:6 ―My necrotic
ulcers stink‖ tells us that the King suffered from pressure ulcers (24).
Pyoderma gangrenosa is a different clinical entity and easily is
differentiated from pressure ulcers. Thus, the diagnosis of pyoderma
gangrenosa seems unlikely.
283
Were IBD responsible for the King's bone pain? Were different
arthropaties and/or arthritis responsible for King's bone pain? Were
osteoporosis or fractures related to osteoporosis in IBD responsible?
Although the King suffered from severe bone pain, in the absence of
characteristic G-I symptoms, the IBD diagnosis seems unlikely. If the
diagnosis of IBD is accepted, however, there is still no explanation for
the disease that "…consumed " the King's bones.
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CELIAC DISEASE
Celiac disease is common, occurring in about 1% of the population
worldwide. There are some countries with higher prevalence rates
such as Finland and others with lower rates, for example Germany.
The disease is found in most continents and appears to be increasing
(1). It occurs in 1 in 100-200 individuals, but still only 1 in 4 cases is
diagnosed (2). Most people with the disease are not currently
diagnosed though women are diagnosed more frequently than men (1).
The risk of celiac disease is increased in first-degree relatives, in
certain syndromes including Down syndrome and autoimmune
disorders (2).
The celiac disease is traditionally viewed as the children's disease
with a typical form accompanied mainly by intestinal symptoms and
malabsorption. The medical community still generally accepts this
opinion. Findings based on the area-wide screening show that the
prevalence has risen from the original 1:1000-1500 to 1:70-550. The
average prevalence in the western countries is nearly 1:100. The
prevalence of the celiac disease in the Czech Republic is estimated at
approximately 1:200-250. It means that the number of people in the
Czech Republic who are likely to be affected is about 40,000-50,000
people. Currently only 10-15% of the total number of the ill people
are diagnosed and monitored (3).
Celiac disease, an immune-mediated systemic condition, is elicited
by gluten and related prolamines in genetically predisposed
285
individuals and characterized by gluten-induced symptoms and signs,

specific antibodies, a specific HLA type and enteropathy. Small-bowel
biopsy is no longer deemed necessary in a subgroup of patients, i.e.
when all of the following are present: typical symptoms or signs, high
titers of anti-tTG antibody, EMA, and HLA-type DQ2 or DQ8. In all
other cases, small-bowel biopsy remains mandatory for a correct
diagnosis. Therapy consists of a strictly gluten-free diet. This should
result in complete disappearance of symptoms and of serological
markers. Adequate follow-up is considered essential. In conclusion,
although small-bowel biopsy may be omitted in a minority of patients,
small-bowel biopsy is essential for a correct diagnosis of celiac
disease in all other cases. Diagnostic work-up should be completed
before treatment with gluten-free diet is instituted (2).
Celiac disease
Celiac disease occurs in genetically susceptible individuals,

triggered by gluten and related prolamins. Well identified haplotypes
in the HLA class II region (either DQ2 [DQA*0501-DQB*0201] or
DQ8 [DQA*0301-DQB1*0302]) confer a large part of the genetic
susceptibility to celiac disease. Celiac disease originates due to a
combined action involving both adaptive and innate immunity. The
adaptive immune response to gluten has been well described, with the
identification of specific peptide sequences demonstrating HLA-DQ2
or -DQ8 restrictive binding motifs across various gluten proteins. As
for innate immunity, through specific natural killer receptors
expressed on their surface, intra-epithelial lymphocytes recognize
nonclassical major histocompatibility complex-I molecules such as
MICA, which are induced on the surface of enterocytes by stress and
inflammation, and this interaction leads to their activation to become
lymphokine-activated killing cells. Four possible presentations of
celiac disease are recognized: (i) typical, characterized mostly by G-I
286
signs and symptoms; (ii) atypical or extraintestinal, where G-I

signs/symptoms are minimal or absent and a number of other
manifestations are present; (iii) silent, where the small intestinal
mucosa is damaged and celiac disease autoimmunity can be detected
by serology, but there are no symptoms; and, finally, (iv) latent, where
individuals possess genetic compatibility with celiac disease and may
show positive autoimmune serology that have a normal mucosa
morphology and may or may not be symptomatic. The diagnosis of
celiac disease still rests on the demonstration of changes in the
histology of the small intestinal mucosa. The classic celiac lesion
occurs in the proximal small intestine with histological changes of
villous atrophy, crypt hyperplasia, and increased intraepithelial
lymphocytosis. Currently, serological screening tests are utilized
primarily to identify those individuals in need of a diagnostic
endoscopic biopsy. The serum levels of IgA, anti-tTG antibody, are
the first choice in screening for celiac disease, displaying the highest
levels of sensitivity (up to 98%) and specificity (around 96%). IgA
EMA, on the other hand, has close to 100% specificity and a
sensitivity of greater than 90%. The interplay between gliadin peptides
and anti-tTG antibody is responsible for the generation of novel
antigenic epitopes, the anti-tTG -generated deamidated gliadin
peptides. Such peptides represent much more celiac disease-specific
epitopes than native peptides, and deamidated gliadin antibodies have
shown promising results as serological markers for celiac disease.
Serology has also been employed in monitoring the response to a
gluten-free diet. Despite the gluten-free diet being so effective, there is
a growing demand for alternative treatment options. In the future, new
forms of treatment may include the use of gluten-degrading enzymes
to be ingested with meals, the development of alternative, gluten-free
grains by genetic modification, the use of substrates regulating
intestinal permeability to prevent gluten entry across the epithelium,
and, finally, the availability of different forms of immunotherapy (4).
Celiac disease, an autoimmune disorder, is caused by the continued
ingestion of gluten, a protein found in wheat, barley and rye, by
predisposed individuals. With the development of highly sensitive
serologic tests, this has become an increasingly recognized disease
with prevalence as high as 1% in certain patient populations, such as
Caucasian females. Almost all celiac patients carry the human
leukocyte antigen DQ2/DQ8 gene. Much has recently been discovered
about the role of the innate immune system in exposing genetically
vulnerable patients to the pathogenic gliadin fraction of gluten. The
"classical" presentation of chronic diarrhea and malabsorption is now
287
a rarity. Due to earlier detection and increased awareness, celiac

disease now presents with a myriad of "atypical" signs and symptoms
such as iron-deficiency anemia and osteoporosis. Associated
conditions include T-cell lymphoma, dermatitis herpetiformis,
autoimmune thyroiditis, and type 1 diabetes. Diagnosis requires
serologic confirmation with either EMA or anti-tTG antibodies as well
as histological confirmation from endoscopic small bowel biopsy. The
only effective treatment necessitates a lifelong, continual adherence to
a gluten-free diet (5).
A significant proportion of patients are diagnosed through
screening at-risk groups including relatives of patients and insulin-
dependent diabetics. Non-diarrheal presentations now are seen more
commonly than those with diarrhea. Patients with celiac disease have
a greater burden of disease than the general population because of
autoimmune diseases and malignancies. There is a need for screening
studies of patients with conditions associated with celiac disease to
determine whether the large numbers of people with undiagnosed
celiac disease currently are seeking health care (6).
The non-classic clinical presentation of celiac disease becomes
increasingly common in physician's daily practice, which requires an
awareness of its many clinical faces with atypical, silent, and latent
forms. Besides the common genetic background (HLA DQ2/DQ8) of
the disease, other non-HLA genes are now notably reported with a
probable association to atypical forms. The availability of high-
sensitive and specific serologic tests such as anti-tTG, EMA, and more
recent antideamidated, gliadin peptide antibodies permits to efficiently
uncover a large portion of the submerged celiac disease iceberg,
including individuals having conditions associated with a high risk of
developing celiac disease (type 1 diabetes, autoimmune diseases,
Down syndrome, family history of celiac disease, etc.), biologic
abnormalities (iron deficiency anemia, abnormal transaminase levels,
etc.), and extraintestinal symptoms (short stature, neuropsychiatric
disorders, alopecia, dental enamel hypoplasia, recurrent aphtous
stomatitis, etc.). Despite the therapeutic alternatives currently in
developing, the strict adherence to a gluten-free diet remains the only
effective and safe therapy for celiac disease (7).
Adult patients represent the main diagnostic problem because their
clinical pictures are individual and the main symptoms are atypical
(nonenteral). These are anemia (mainly sideropnic), early/premature
osteoporosis, herpetiformic (Duhring) dermatitis, polyneurititis,
ataxia, depression, behavioral disorders, menstrual cycle disorders and
infertility, IBS, osteoporosis, neurologic diseases, and malignancy
288
(3,6). Therefore, our attention is currently focused on the screening of

these groups of subjects. The purpose of this study was to check the
frequency of the celiac disease in patients with diagnosed osteoporosis
and osteopenia. The prevalence of the celiac disease in the group of
subjects was 1:50, which means that 2.2% of patients with
osteoporosis and osteopenia are affected by celiac sprue and therefore
screening examination of these patients with the subsequent causal
treatment (gluten-free diet) is recommended (3).
The mode of presentation of patients with celiac disease has
changed dramatically over the recent decades, with diarrheal or classic
presentations becoming less common. This trend is seen in children,
whose main presentations include recurrent abdominal pain, growth
issues, and screening groups at risk. Abdominal pain and growth
issues are major modes of presentation in children, while anemia,
osteoporosis, and recognition at endoscopy performed for GERD are
seen as modes of presentation in adults. Screening of at risk groups is
a major mode of presentation for both adults and children (8,9).
Numerous complications can occur in celiac disease such as
nutritional (growth failure in children, malnutrition, and vitamin
deficiencies), hematologic (anemia), bone disease (osteoporosis, and
fracture), gynecologic (hypo fertility), C-V (coronaropathy, and
venous thrombosis), neurological (peripheral neuropathy), and hepatic
(cytolysis, and cirrhosis). Celiac disease is associated with an
increased risk of autoimmune diseases (type 1 diabetes, and
thyroiditis), and cancer (upper G-I tract, HCC, or lymphoma). The
main digestive complications are microscopic colitis and refractory
sprue, which are resistant to gluten-free diet. It can be associated with
a monoclonal proliferation of intraepithelial lymphocytes (type 2
refractory sprue), which may be considered as a cryptic lymphoma
and can lead to invasive T lymphoma, which occurs in 1/1000 celiac
patients. Gluten-free diet protects from the occurrence of most
complications and corrects the over-mortality related to these
complications (10).
The relationship between bone derangements and celiac disease
was recognized almost 50 years ago, but many questions are still
open. Osteoporosis is a relatively frequent atypical presentation of
celiac disease, especially in adults, and undiagnosed celiac disease can
cause osteoporosis and related fractures. Chronic IBD, including
celiac disease D, can affect bone and mineral metabolism because of
alterations in both systemic and local regulatory factors. The
pathogenetic processes are still controversial, but 2 main mechanisms
289
seem to be involved: intestinal malabsorption and the presence of

chronic inflammation (11).
This was an observational, retrospective, cross-sectional review of
the medical notes of 32 adult patients attending the specialist celiac
clinic in a district general hospital. Anemia was the most common
mode of presentation accounting for 66% of patients. Less than half of
the patients had any of the classical symptoms of celiac disease and
25% had none of the classical symptoms at presentation. Anti-gliadin
antibodies, EMA and anti-tTG antibodies showed 75%, 68% and 90%
sensitivity respectively. In combination, serology results were 100%
sensitive as screening tests for adult celiac disease. Of all patients,
58% had either osteoporosis or osteopenia. There were no malignant
complications observed during the follow up of these patients. In
conclusion, most adults with celiac disease have a subclinical form of
the disease and iron deficiency anemia may be its sole presenting
symptom. Only a minority of adult celiac disease patients present with
classical malabsorption symptoms of diarrhea and weight loss.
Patients with atypical form of disease often present initially to hospital
specialists other than a gastroenterologist. An awareness of the broad
spectrum of presentations of adult celiac disease, among doctors both
in primary care and by the various hospital specialists in secondary
care, is necessary to avoid delays in diagnosis. It is important to
include serological screening tests for celiac disease in the evaluation
of adult patients with unexplained iron deficiency anemia or
unexplained G-I symptoms and in those who are considered to be at
increased risk for celiac disease (12).
The main objective of this study was to provide evidence of
underdiagnosis of celiac disease and to describe the main presenting
symptoms of celiac disease in primary care. Case finding was carried
out in a primary care setting by testing for celiac disease by using the
EMA test. Nine surgeries in and around a market town in central
England, serving a population of 70,000 were included. First 1000
patients were screened from October 1996 to October 1997. Outcome
was measured by determination of EMA titer of patients fulfilling the
study criteria, followed by small intestine biopsy of those with
positive results. The 30 patients (out of 1000 samples) with positive
results on the EMA test all had histological confirmation on small
intestine biopsy. The commonest mode of presentation (15/30) was
anemia of varying severity. Most patients (25/30) presented with non-
G-I symptoms. Specificity of the EMA test was 30/30. In conclusion,
under diagnosis and misdiagnosis of celiac disease are common in
general practice and often result in protracted and unnecessary
290
morbidity. Serological screening in primary care will uncover a large

proportion of patients with this condition and should be made widely
available and publicized. Celiac disease should be considered in
patients who have anemia or are tired all the time, especially when
there is a family history of the disease (13).
The main objective of this study was to compare celiac disease in
older and younger adults and to assess the effects of a gluten-free diet.
Retrospective retrieval of information prospectively entered into a
structured database. This study was carried out at celiac disease clinic,
Brescia, Italy. Two cohorts were identified (older, Group A, n=59, >
65 years; younger, Group B, n=1,166, 18-64 years), and Group B was
subgrouped (B1, n=600, 18-34 years; B2, n=440, 35-49 years; and B3,
n=26, 50-64 years). At presentation, weight loss (37% vs. 21%,
p=0.005) and dyspepsia (22% vs. 12%, p=0.04) were more frequent in
older than younger participants. Incidence at diagnosis of non-
Hodgkin's lymphoma was much higher in older (5%) than younger
participants (0.3%, p=0.003). Prevalence of osteoporosis was 67% in
older and 14% in younger male participants and 70% in older and 9%
in younger female participants (p<0.001). During treatment, adherence
to a gluten-free diet was 90%, normal villous structure was
reconstituted, anti-tTG antibodies were negative in 80% of older and
younger participants. Lumbar-sacral and femoral T scores increased
significantly during a gluten-free diet in pooled results of 48 older and
younger participants studied before and during gluten-free diet. In
conclusion, non-Hodgkin's lymphoma is already present at celiac
disease diagnosis in most cases in individuals aged 50 and older,
emphasizing the importance of early diagnosis. Older and younger
individuals are equally adherent and equally benefit from a gluten-free
diet, indicating that older age is not a barrier to dietary treatment (14).
A multidisciplinary team developed clinically relevant questions
for review. An electronic search of the literature was conducted using
the MEDLINE and EMBASE databases from 1996 to 2010. All
original studies, reviews and guidelines, both pediatric and adult, were
included. At diagnosis, approximately one-third of adult celiac disease
patients had osteoporosis, one-third osteopenia and one-third had
normal BMD. Children with celiac disease had low bone mass at
diagnosis. Adult and pediatric celiac disease patients were at increased
risk of fractures. For adults, serum calcium, albumin, 25-
hydroxyvitamin D3, PTH and 24 hours urine calcium testing should
be performed at diagnosis; patients with 'classic' celiac disease and
those at risk for osteoporosis should undergo a DXA scan. An
abnormal baseline DXA scan should be repeated one to 2 years after
291
initiation of a gluten-free diet. For children, BMD should be assessed

one year after diagnosis if gluten-free diet adherence is not strict. A
gluten-free diet is the most important treatment for bone loss.
Supplemental antiresorptives may be justified in those who remain at
high fracture risk (e.g., postmenopausal women, and older men) after
implementation of a gluten-free diet. In conclusion, current evidence
does not support the screening of all celiac disease patients for low
BMD at diagnosis. Follow-up BMD assessment should be performed
1 to 2 years after initiation of a gluten-free diet (15).
A 29-year-old man presented with back pain and had a non-
traumatic compression fracture of the lumbar and thoracic spine on
plain X-ray. DXA confirmed osteoporosis at the L3/L4 vertebral
bodies. PTH, calcium, and vitamin D levels were normal. He had no
G-I complaints, but serologic studies were positive to include an
elevated gliadin IgA Ab, gliadin IgG Ab, and an elevated tissue IgA
anti-tTG antibody. He was treated with a gluten-free diet, calcium,
and vitamin D supplementation as well as teriparatide. Follow up bone
density showed improvement and has no further fractures to date.
Primary care physicians, gastroenterologists and endocrinologists
must have a high index of clinical suspicion for celiac disease in any
patient who presents with low bone density regardless of the serum
25-hydroxyvitamin D levels or presence of G-I complaints (16).
In this cross-sectional study the data on the severity of celiac
disease and BMD were collected from 77 celiac patients (28 newly
diagnosed and 49 previously diagnosed celiac patients), and BMD
results were compared with those of 157 control subjects matched for
age, gender, and menopausal status. The celiac patients had
significantly lower BMD than the control subjects at the lumbar spine
(-6%) and femoral neck (-5%). The mean BMD did not differ
significantly among celiac patients classified by severity of disease.
Based on Z scores, 35% of the celiac patients and 17% of the control
subjects had low BMDs for age at the lumbar spine (p=0.005),
whereas 31% of celiac patients and 16% of control subjects had Z
scores of ≤ -1 at the femoral neck (p=0.01). Altogether, 26% of all
celiac patients, but only 5% of control subjects, were classified as
having osteoporosis (T score ≤ -2.5 SD) at the lumbar spine (p=0.03),
whereas osteoporosis was rare at the femoral neck in both groups (3%
vs. 1%, p=1.00). Prevalence of osteopenia and osteoporosis was
highest in newly diagnosed celiac patients and in patients with disease
not in remission. A low 25-hydroxyvitamin D concentration was a
typical biochemical abnormality in these patients (64% of men and
71% of women). The main associated variables of low BMD were age
292
(men), low serum vitamin D level, low body weight, and

postmenopausal status (women). In conclusion, celiac disease
constitutes a risk factor for osteoporosis. This finding applies
particularly to untreated and poorly treated patients (17).
Five patients were presented with severe metabolic bone disease as
the only manifestation of celiac disease. Records of 825 patients of
celiac disease diagnosed during 2002-2010 were retrospectively
analyzed for clinical features, risk factors, signs, biochemical, and
radiological parameters. Five patients (0.6%) with celiac disease had
monosymptomatic presentation with musculoskeletal symptoms and
signs in the form of bone pains, proximal myopathy, and fragility
fractures without any G-I manifestation. All the 5 patients had severe
metabolic bone disease in the form of osteopenia, osteoporosis, and
fragility fractures. Four of the 5 patients had additional risk factors
such as AED, chronic alcohol consumption, malnutrition, and
associated vitamin D deficiency which might have contributed to the
severity of metabolic bone disease. Severe metabolic disease as the
only presentation of celiac disease is rare. Patients show significant
improvement in clinical, biochemical, and radiological parameters
with gluten-free diet, calcium, and vitamin D supplementation. Celiac
disease should be looked for routinely in patients presenting with
unexplained metabolic bone disease (18).
Assessment: celiac disease is an autoimmune disorder caused by

the continued ingestion of gluten, a protein found in wheat, barley and
rye, by predisposed individuals. The disease is common, occurring in
about 1% of the population worldwide. There are some countries with
higher prevalence rates such as Finland and others with lower rates,
for example Germany. The disease is found in most continents and
appears to be increasing. The risk of celiac disease is increased in
first-degree relatives, Down syndrome and autoimmune disorders.
The "classical" presentation of chronic diarrhea and malabsorption
is now a rarity. Abdominal pain and growth issues are major modes of
presentation in children. In adults, celiac disease presents with a
myriad of "atypical" signs and symptoms such as iron-deficiency
anemia, osteoporosis, osteoporotic fracture, abnormal transaminase
levels, recognition at endoscopy performed for GERD, and
extraintestinal symptoms (short stature, neuropsychiatric disorders,
alopecia, dental enamel hypoplasia, recurrent aphtous stomatitis, etc.).
Associated conditions include autoimmune diseases (type 1
diabetes, and thyroiditis), dermatitis herpetiformis, Down syndrome,
and cancer (upper G-I tract, HCC, and lymphoma). Diagnosis requires
293
serologic confirmation with either EMA or anti-tTG antibodies, and

more recent antideamidated, gliadin peptide antibodies as well as
histological confirmation of endoscopic small bowel biopsy.
The only effective treatment necessitates a lifelong, continual
adherence to a gluten-free diet.
Was celiac disease responsible for King's severe bone pain? The
King's medical record, that is the biblical text, indicates that the King
suffered from anemia and intractable bone pain due to osteoporosis.
Were atypical manifestations of celiac disease such as iron deficiency
anemia and osteoporosis or osteoporotic bone fractures responsible?
The King's medical record did not indicate that he suffered from
diarrhea, or other extraintestinal symptoms, or some autoimmune
disease (19). Thus, the diagnosis of Celiac disease seems unlikely.
However, if the diagnosis of celiac disease is accepted, we have no
explanation for the disease which "...consumes.." the King's bones.
References
1. Reilly NR, Green PH. Epidemiology and clinical presentations of celiac
disease. Semin Immunopathol. 2012;34(4):473-8.
2. Kneepkens CM, von Blomberg BM. Clinical practice: coeliac disease. Eur J
Pediatr. 2012;171(7):1011-21.
3. Fojtík P, Novosad P, Kliment M, et al. Screening of celiac disease in patients
with osteoporosis and osteopenia. Vnitr Lek. 2011;57(12):1000-5.
4. Setty M, Hormaza L, Guandalini S. Celiac disease: risk assessment, diagnosis,
and monitoring. Mol Diagn Ther. 2008;12(5):289-98.
5. Scherer JR. Celiac disease. Drugs Today (Barc). 2008;44(1):75-88.
6. Green PH. The many faces of celiac disease: clinical presentation of celiac
disease in the adult population. Gastroenterology. 2005;128(4 Suppl 1):S74-8.
7. Admou B, Essaadouni L, Krati K, et al. Atypical celiac disease: from
recognizing to managing. Gastroenterol Res Pract. 2012;2012:637187.
8. Reilly NR, Green PH. Epidemiology and clinical presentations of celiac
disease. Semin Immunopathol. 2012;34(4):473-8.
9. Reilly NR, Fasano A, Green PH. Presentation of celiac disease. Gastrointest
Endosc Clin N Am. 2012;22(4):613-21.
10. Cosnes J, Nion-Larmurier I. Complications of celiac disease. Pathol Biol
(Paris). 2011 May 26.
11. Bianchi ML, Bardella MT. Bone in celiac disease. Osteoporos Int.
2008;19(12):1705-16.
12. Jones S, D'Souza C, Haboubi NY. Patterns of clinical presentation of adult
coeliac disease in a rural setting. Nutr J. 2006 Sep 14;5:24.
13. Hin H, Bird G, Fisher P, et al. Coeliac disease in primary care: case finding
study. BMJ. 1999 16;318(7177):164-7. Erratum in: BMJ 1999 7;318(7187):857.
Comment in: Anaemia in blood donors is not being properly investigated. [BMJ.
1999].
14. Casella S, Zanini B, Lanzarotto F, et al. Celiac disease in elderly adults:
clinical, serological, and histological characteristics and the effect of a gluten-free
diet. J Am Geriatr Soc. 2012;60(6):1064-9.
294
15. Fouda MA, Khan AA, Sultan MS, et al. Evaluation and management of
skeletal health in celiac disease: position statement. Can J Gastroenterol.
2012;26(11):819-29.
16. Mulder CJ, Cardile AP, Dickert J. Celiac disease presenting as severe
osteopenia. Hawaii Med J. 2011;70(11):242-4.
17. Kemppainen T, Kröger H, Janatuinen E, et al. Osteoporosis in adult patients
with celiac disease. Bone. 1999;24(3):249-55.
18. Rastogi A, Bhadada SK, Bhansali A, et al. Celiac disease: A missed cause of
metabolic bone disease. Indian J Endocrinol Metab. 2012;16(5):780-5.
19. Ben-Nun L. The diseases that caused chronic weakness. In Ben-Nun ed. The
Family Life Cycle and the Medical Record of King David the Great. Research in
Biblical Times from the Viewpoint of Contemporary Medicine. B. N. Publications.
Israel. 2009, pp. 172-180.
WHIPPLE DISEASE
Whipple's disease is a very rare systemic infection caused by the
bacterium Tropheryma whipplei that is characterized as an
actinomiceto por 16Sr RNA (1). The disease was initially described
in 1907 (2). Approximately one thousand infections caused by this
microorganism have been reported globally (3).
In the past decade, the responsible organism Tropheryma whipplei
has been cultivated, its genome sequenced and its antibiotic
susceptibility defined. Whipple's disease is a systemic infection that
may mimic a wide spectrum of clinical disorders and may have a fatal
outcome. If recognized, prolonged antibiotic therapy is a successful
form of treatment (2).
Whipple's disease usually affects middle-aged men and is
characterized by the presence of fever, diarrhea, weight loss,
malabsorption, abdominal pain and arthralgia (4). The disease usually
involves the small intestine with the presence of malabsorption; the
disease commonly affects other organs, especially the heart such as
culture-negative endocarditis, brain, eyes and joints (1,2). Arthritis or
arthralgia may appear as an isolated symptom and eventually through
the years with long-term, unexplained, seronegative oligoarthritis or
polyarthritis of large joints with a palindromic or relapsing course (4).
The characteristic histopathological features are in the small
intestine. These are variable villous atrophy and distension of the
normal villous architecture by an infiltrate of foamy macrophages
with a coarsely granular cytoplasm, which stain a brilliant magenta
with PAS. These pathognomonic PAS positive macrophages may be
present in the peripheral and mesenteric lymph nodes and various
295
other organs. The disease is fatal unless patients are treated with
antibiotics (2,5-9).
Whipple disease
In most patients, periodic acid-Schiff staining of proximal small

bowel biopsy specimens reveals inclusions within the macrophages,
corresponding to bacterial structures. However, patients may have no
G-I symptoms, negative jejunum biopsy results and even negative
PCR tests. Even in the absence of G-I symptoms, Whipple's disease
should be considered in case of negative blood culture endocarditis,
unexplained central neurological manifestations or unexplained
arthritis. Identification of the causative bacterium, Tropheryma
whipplei, has led to the development of PCR as a diagnostic tool,
particularly useful in patients in the early stages of the disease or with
atypical disease. The recent cultivation of Tropheryma whipplei and
the complete sequencing of its genome should improve our
understanding and treatment of the disease. The future development of
an assay for detection of specific antibodies in the serum and
generalization of the immunohistochemical detection of antigenic
bacterial structures may allow earlier diagnosis, thereby preventing
the development of the severe late systemic and sometimes fatal
outcome (4).
Two patients with Whipple's disease suffered from weight loss,
diarrhea, abdominal pain and distention, and were diagnosed with
microcytic anemia and significant hypoalbuminemia. In the third
patient, the manifestation was blood culture negative endocarditis
causing aortic insufficiency, AF and coronary embolization.
Antimicrobial drug therapy was effective for all 3 patients (3).
Spondylodiscitis is an extremely rare manifestation of the
infection. A 55-year-old man with persistent lumbago and signs of
systemic illness, but without any G-I symptoms or arthralgia is
presented. The signal response in the lumbar spine in MRI, both
296
native and after intravenous gadolinium administration was

compatible with spondylodiscitis at the L4/L5 level. Culture of a
specimen obtained by radiographically guided disc puncture and
repeated blood cultures remained sterile. Tropheryma whipplei was
detected by PCR amplification in material obtained from the disc
specimen, from a biopsy of the terminal ileum and from the stool. The
histology of duodenum, terminal ileum, colon and disc material was
normal and, in particular, showed no PAS-positive inclusions in
macrophages. Long-term antibiotic treatment with sulphamethoxazole
and trimethoprim was successful, with marked improvement of the
LBP and normalization of the systemic inflammatory signs. The
possibility of Whipple's disease must be suspected in the case of a
'culture-negative' spondylodiscitis even if no G-I symptoms and no
arthralgia are present (10).
A case of Whipple disease is reported. Bone biopsy demonstrated
that osteoporosis was the prominent histological feature in this patient.
Based on serial BMD measurements, antibiotic treatment was able to
reverse the initial reduced bone mass (11).
A patient with Whipple's disease was considered as cured after
treatment for 2 years, but relapse occurred in the neurological form.
Radiographic imaging showed destructive osteoarticular lesions, with
few or no symptoms, affecting the peripheral skeleton and the
sacroiliac joints (12).
A case of Whipple's disease in a 60-year-old man with severe
arthralgia and systemic disorders but without G-I manifestations is
reported. The patient had different clinical diagnoses over a period of
14 years. Tropheryma whipplei by real-time PCR was identified.
Molecular typing was performed by sequencing the 16S-23S rRNA
intergenic spacer region and domain III of the 23S rRNA gene (13).
Assessment: Whipple's disease is a rare systemic infection caused

by the bacterium Tropheryma whipplei. The disease usually affects
middle-aged men and is characterized by the presence of fever,
diarrhea, weight loss, malabsorption, abdominal pain and arthralgia.
Whipple's disease usually involves the small intestine with the
presence of malabsorption; the disease commonly affects other
organs, especially the heart causing culture-negative endocarditis,
brain, and eyes and joints. Arthritis or arthralgia may appear as an
isolated symptom and eventually through the years with long-term,
unexplained, seronegative oligoarthritis or polyarthritis of large joints
with a palindromic or relapsing course. Other manifestations include
spondylodiscitis, and osteoporosis.
297
Even in the absence of G-I symptoms, Whipple's disease should be

considered in case of negative blood culture endocarditis, unexplained
central neurological manifestations or unexplained arthritis. The
disease is fatal unless patients are treated with antibiotics.
The characteristic histopathological features in the small intestine
include variable villous atrophy and distension of the normal villous
architecture by an infiltrate of foamy macrophages with a coarsely
granular cytoplasm, which stain a brilliant magenta with PAS.
Was King David afflicted by Whipple's disease with the
involvement of his bones? In the absence of characteristic clinical
symptoms and characteristic histopathological findings of the small
intestine, this diagnosis seems unlikely.
References
1. Montes Montes J, Flores Guerrero R, Hernández Mendoza L, et al. First
centenary of Whipple's disease. Rev Alerg Mex. 2009;56(3):92-8.
2. Freeman HJ. Tropheryma whipplei infection. World J Gastroenterol.
2009;15(17):2078-80.
3. Nielsen C, Kerilahti M, Martelius T. Whipple's disease - a rare and severe
systemic infection. Duodecim. 2012;128(16):1699-704.
4. Puéchal X. Whipple's disease. Rev Med Interne. 2009;30(3):233-41.
5. Ghitoni G, Valentini G, Spada C, et al. Whipple's disease: progress in the
diagnosis and review of the literature. Minerva Med. 2002;93:447-51.
6. Ratnaike RN. Whipple's disease. Postgrad Med J. 2000;76(902):70-6.
7. Schijf LJ, Becx MC, de Bruin PC, van der Vegt SG. Whipple's disease: easily
diagnosed, if considered. Neth J Med. 2008;66:392-5.
8. Eriksen R, Westre B, Bergh K, Qvigstad G. Whipple's disease. Tidsskr Nor
Laegeforen. 2008;128:1406-9.
9. Dancygier H, Scharnke W. Whipple disease- a rare systemic disease. Praxis
(Bern 1994). 2002;91:1691-8.
10. Weber U, Morf MH, Gubler JG, et al. Spondylodiscitis as the first
manifestation of Whipple's disease - a removal worker with chronic low back pain.
Clin Rheumatol. 2003;22(6):443-6.
11. Carnevale V, Minisola S, Romagnoli E, et al. Case report: reversal of
decreased bone mass by antibiotic treatment in a patient with Whipple's disease. Am J
Med Sci. 1996;311(3):145-7.
12. Madoule P, Ciaudo-Lacroix C, Halimi P, Doyon D. Osteoarticular lesions in
Whipple's disease. Apropos of a destructive form and review of the literature J Radiol.
1985;66(5):345-50.
13. Mancini F, Sbaragli S, Colivicchi G, et al. Fourteen years of severe arthralgia
in a man without gastrointestinal symptoms: atypical Whipple's disease. J Clin
Microbiol. 2009;47(2):492-5.
298
PRIMARY BILARY CIRRHOSIS

PBC is an immune-mediated, a slowly progressive, cholestatic
chronic liver disease in which the epithelium of the intrahepatic biliary
tree is destroyed by a chronic inflammatory process (1,2). The origin
of this disease is unknown but has characteristics favoring an
autoimmune etiology (1). PBC primarily affects women (female
preponderance 9-10:1) with a prevalence of up to 1 in 1,000 women
over 40 years of age. Without treatment, most patients eventually
develop fibrosis and cirrhosis of the liver and may need liver
transplantation in the late stage of disease (1,2).
Typical symptoms are fatigue, pruritus, and abdominal pain, but
most patients are asymptomatic at first presentation (2,3). Jaundice
develops in the end stage disease. At presentation, about 40% of the
patients are asymptomatic, but 30-50% already have hepatomegaly,
and 15% present with splenomegaly. Even patients with fully
developed liver cirrhosis may be free of symptoms. Abnormal
physical signs and advanced histological stage are more frequent in
symptomatic than in asymptomatic patients. Fatigue, pruritus, and
Sjögren's syndrome are more common in women than men, but other
signs and symptoms do not differ in the 2 sexes. PBC is associated
with a large variety of other diseases, like arthropathy, CREST
syndrome, autoimmune thyroiditis, and so on, which in addition will
or will not produce symptoms. HCC carcinoma is a rare complication
in women, but more frequent in men (3).
The diagnosis is based on sustained elevation of serum markers of
cholestasis, i.e., ALP and GGT, and the presence of serum AMA
directed against the E2 subunit of the pyruvate dehydrogenase
complex (2). When AMA are not detected, then ANA (autoantibodies
against gp.210 and others) can be detected in 50% of AMA-negative
patients. AMA titers do not correlate with the course of the disease
nor histological progression. After liver transplantation, AMA recur in
nearly 100%. The liver enzyme pattern in PBC patients is cholestatic:
ALP and GGT increase to 10 or more times the upper limit of normal.
The amount of enzymes does not correlate with disease progression or
stage of the disease. The only prognostic factor in PBC is serum
bilirubin. AMA-negative patients account for about 10% to 15%.
Routine biochemical tests are not different from AMA-positive
patients, but usually higher ANA, smooth muscle actin (SMA), and
IgG concentrations are detected. The overlap-syndrome, autoimmune
hepatitis-PBC presents with the histological features of autoimmune
299
hepatitis and PBC, with AMA, ANA, or SMA. Imaging procedures

are not helpful for the diagnosis of PBC, except for liver histology (3).
Histologically, PBC is characterized by florid bile duct lesions with
damage to biliary epithelial cells, a dense portal inflammatory
infiltrate and progressive loss of small intrahepatic bile ducts.
Although the insight into pathogenetic aspects of PBC has grown
enormously during the recent decade and numerous genetic,
environmental, and infectious factors have been disclosed which may
contribute to the development of PBC, the precise pathogenesis
remains enigmatic (2).
Metabolic bone disease has been recognized as an important
complication of chronic liver disease particularly in cholestatic
disorders - PBC and primary sclerosing cholangitis and after liver
transplantation. It includes osteoporosis and more rarely osteomalacia,
which is more frequent in severe malabsorption and advanced liver
disease (4).
A 66-year-old woman with primary biliary cirrhosis. T1-weighted

gradient-echo 6-minute delayed phase gadolinium-enhanced MRI shows
numerous areas of low-signal-intensity rim surrounding high-signal-intensity
portal venous triad resulting in periportal halo sign (arrowheads). Large
hepatocellular carcinoma (arrows) associated with primary biliary cirrhosis
also is evident.
Osteoporosis is a common complication of chronic liver disease,

from cholestatic disorders to autoimmune, alcoholic, and posthepatitic
cirrhosis. Osteoporosis appears more striking in patients with PBC
because the disease usually affects elderly women, who are naturally
prone to osteoporosis (5).
The pathogenesis of this disorder is complex and is likely to be
multifactorial. Regardless of the etiology of osteoporosis in PBC
patients, they have an increased risk of spontaneous or low-trauma
fracturing leading to significant patient morbidity, deterioration of
QOL, and even patient mortality. The development of bone
300
densitometry has allowed assessment of bone mass and then

contributed in estimating the fracture risk. The gold standard of BMD
measurement is currently the DXA. Recommendations formulated by
the WHO have reported the diagnostic ranges of osteoporosis based
on the t-score: patient with osteoporosis has a t-score less than -2.5
SD, osteopenia has a t-score between -1.0 and -2.5 SD and a normal
individual has a t-score more than -1.0 SD. The risk of fracture shows
a correlation with BMD but no fracture threshold was determined and
the best site of characterizing the hip fracture risk is the measure of
the BMD of the proximal femur. The treatment of osteoporosis in
patients with PBC is largely based on trials of patients with
postmenopausal osteoporosis as there are a few and smaller studies of
osteoporotic patients with PBC. Bisphosphonates seem to be effective
in biliary disease and are more tolerated (4).
The main aims of this study were (1) to compare the prevalence of
osteoporosis (T-score < -2.5 SD) between PBC patients and a group of
age-and sex-matched controls consisting of healthy subjects from the
general population; and (2) to identify the main risk factors for the
development of bone loss. Thirty-three women with PBC (mean age,
47.3 +/- 10.4 years) and 66 healthy subjects were enrolled in the
study. BMD was assessed at the lumbar spine by DXA. Bone
metabolism was evaluated by measuring serum calcium corrected for
serum albumin, 25-hydroxyvitamin D, PTH, and osteocalcin.
Vertebral fractures were analyzed using vertebral fracture assessment.
The mean T-score was lower in the PBC group compared to healthy
controls, with a significant statistical difference (-2.39 +/- 0.93 and -
1.47 +/- 0.99 in lumbar spine and total hip, respectively, in the PBC
group vs. -0.99 +/- 0.51 and -0.56 +/- 1.14 in healthy controls
(p<0.001). The prevalence of osteoporosis was 51.5% in the PBC
group vs. 22.7% in healthy controls with a statistically significant
difference (p=0.004). BMD of the PBC group was correlated
positively with BMI and 25-hydroxyvitamin D, and negatively with
menopausal status, duration of disease and PTH levels. Vertebral
fractures were present in 9% of the patients. In conclusion,
osteoporosis is more prevalent in women with PBC than in the general
population. BMI, menopausal status, duration of the disease, and
vitamin D deficiency are the main risk factors for osteoporosis in this
liver disease (5).
A prospective study was performed on 58 cirrhotic patients (6 with
PBC, 14 with alcoholic cirrhosis, and 38 with posthepatitic cirrhosis),
who were referred for orthotopic liver transplantation. Patients,
excluding those with PBC, were classified in Child-Pugh groups
301
according to the severity of liver disease (class B [28 patients], class C

[24 patients]). Biochemical parameters of bone mineral metabolism
and standard liver function tests were measured in all patients.
Additionally, serum osteocalcin, urinary hydroxyproline/creatinine
ratio, serum intact PTH, serum 25-hydroxyvitamin D, serum 1,25-
dihydroxyvitamin D, follicle-stimulating hormone, and luteinizing
hormone levels were determined in patients and controls within the
same age range. Plasma testosterone, sex hormone-binding globulin
levels, and free testosterone index were obtained for all men included
in the study. Bone mass of the lumbar spine and femur were measured
by DXA, and were expressed as a SD of mean values (Z-score) from a
sex and age-matched control group. Spinal X-rays were obtained to
assess vertebral fractures. Osteoporosis was considered as a factor in
spinal BMD with a Z-score below 2 or at least one vertebral fracture.
Twenty-five patients (43%) had osteoporosis, with lower bone mass
measurements in the lumbar spine than in the femoral neck (p<0.005).
Alcoholic and Child-Pugh C patients showed the lowest femoral BMD
values. Cirrhotic patients showed lower osteocalcin levels than
controls (14.3 +/- 5.9 vs. 18.2 +/- 8.1 ng/ml; p<0.05) and increased
urinary hydroxyproline (125.1 +/- 51.5 vs. 107.9 +/- 26.6 nM/mg
creatinine; p<0.05). Serum 25-hydroxyvitamin D, 1,25-
dihydroxyvitamin D and PTH levels were significantly lower in
cirrhotic patients than in controls (10.3 +/- 9.1 vs. 23.1 +/- 26.6 ng/ml;
p=0.000), (12.9 +/- 9.1 vs. 48.3 +/- 11.5 pg/ml; p=0.000), (16.6 +/- 9.2
vs. 27.9 +/- 8.2 pg/ml; p=0.000), with no differences between Child-
Pugh groups. Alcoholic Child-Pugh C patients showed the lowest 25-
hydroxyvitamin D serum values (4.5 +/- 2.2 ng/ml; p<0.05). Male
patients had lower testosterone levels than controls (302.5 +/- 229.4
vs. 556.7 +/- 146.5 ng/dl; p=0.000), with increased sex hormone-
binding globulin values. Levels of testosterone and gonadotropin were
related to Child-Pugh classification. No correlation was found
between bone mass and hormonal values. In conclusion, a significant
decrease in bone mass, particularly in the lumbar spine, is seen in end-
stage cirrhotic patients. Reduced bone formation and significant
disorders of bone mineral metabolism, such as vitamin D deficiency,
reduced PTH levels, and hypogonadism are involved. Severity and
etiology of the liver disease are the main risk factors for developing
bone loss and mineral metabolism disorders in patients referred for
orthotopic liver transplantation (6).
In female patients with PBC (n=185; age, 55.7 +/- 0.7 years; range
28-79 years), age, duration of PBC, menopausal status, and
histological stage and severity of liver disease were assessed.
302
Vertebral and non-vertebral fractures were recorded in 170 and 172

patients, respectively. Osteoporosis and osteopenia were diagnosed
based on densitometry analysis. The prevalences of vertebral, non-
vertebral, and overall fractures were 11.2%, 12.2%, 20.8%,
respectively. Osteoporosis was significantly more frequent in patients
with PBC than in normal women. Osteoporosis was associated with
age, weight, height, histological stage, severity, and duration of liver
damage; fractures were associated with osteoporosis, menopause, age,
and height but not with severity of PBC. Osteoporosis was a risk
factor for vertebral fracture (OR 8.48, 95% CI 2.67 - 26.95). Lumbar
T score < -1.5 (OR 8.27, 95% CI 1.84 - 37.08) and femoral neck T
score < -1.5 (OR 6.83, 95% CI 1.48 - 31.63) were significant risk
factors for vertebral fractures. In conclusion, fractures, particularly
vertebral fractures, are associated with osteoporosis, osteopenia, and T
scores less than -1.5, whereas osteoporosis and osteopenia are
associated with the severity of liver damage. Patients with T scores
less than -1.5 might require additional monitoring and are considered
for therapy to prevent fractures (7).
MRI images of a patient with primary biliary cirrhosis.
The main objective of this study was to summarize the clinical

features, diagnosis and treatment of patients with PBC in China.
Systematic analysis of clinical characteristics was performed by
searching the Chinese literature. From 1955 to 2007, 2740 PBC
patients were reported in 103 papers (duplicated reports were deleted).
The detailed information of 985 patients from 16 papers were
collected. Female: male was 6.82:1. The age range was 42 to 56.2-
year-old. The time from onset to diagnosis was 12 to 98.4 months.
The most common symptoms were fatigue (72.40%), jaundice
(67.41%), anorexia (68.58%) and pruritus (45.60%); 20% patients
were asymptomatic at onset. The most frequent physical signs were
splenomegaly (57.53%), hepatomegaly (43.56%) and ascites
303
(18.45%). Serum ALP and GGT levels were markedly elevated in

most of these patients. The immunological marks of anti-
mitochondrial antibody AMA/AMA-M2 were positive in 89.0% and
83.0% patients, respectively. The most common comorbidities were
Sjögren syndrome (9.1%), RA (4.0%) and diabetes type 2 (2.5%). Of
the 507 patients treated with ursodeoxycholic acid, 345 patients got
complete or partial clinical biochemical response. The common
complications were G-I bleeding (41.7%) and liver failure (41.7%).
Liver transplantation was the only effective way for the treatment of
the end-stage liver disease. In conclusion, the clinical feature of PBC
in China was similar to the overseas literatures (8).
Ursodeoxycholic acid is currently the only FDA-approved medical
treatment for PBC. When administered at adequate doses of 13-15
mg/kg/day, up to 2 out of 3 patients with PBC may have a normal life
expectancy without additional therapeutic measures. The mode of
action of ursodeoxycholic acid is still under discussion, but
stimulation of impaired HCC and cholangiocellular secretion,
detoxification of bile, and antiapoptotic effects may represent key
mechanisms. One out of 3 patients does not adequately respond to
ursodeoxycholic acid therapy and may need additional medical
therapy and/or liver transplantation (2).
Assessment: PBC is an immune-mediated, a slowly progressive,

cholestatic, and chronic liver disease in which the epithelium of the
intrahepatic biliary tree is destroyed by a chronic inflammatory
process. PBC primarily affects women (female preponderance 9-
10:1). Without treatment, most patients eventually develop fibrosis
and cirrhosis of the liver and may need liver transplantation in the late
stage of disease.
Typical symptoms are fatigue, anorexia, pruritus, and abdominal
pain, but most patients are asymptomatic at first presentation. Other
manifestations include jaundice, splenomegaly, hepatomegaly and
ascites. PBC is associated with a large variety of other diseases,
including arthropathy, Sjögren's syndrome, CREST syndrome,
autoimmune thyroiditis, RA, and diabetes type 2. HCC carcinoma is a
rare complication.
Metabolic bone disease is an important complication of chronic
liver diseases such as cholestatic disorders – PBC, primary sclerosing
cholangitis and after liver transplantation. It includes osteoporosis and
more rarely osteomalacia, which is more frequent in severe
malabsorption and advanced liver disease. Osteoporosis appears in
patients with PBC because this disease usually affects elderly women,
who are naturally prone to osteoporosis. Vertebral fractures can occur.
304
The diagnosis is based on sustained elevation of serum markers of

cholestasis, i.e., ALP and GGT, and the presence of serum AMA
directed against the E2 subunit of the pyruvate dehydrogenase
complex. When AMA are not detected, then ANA (autoantibodies
against gp.210 and others) can be detected in 50% of AMA-negative
patients. Histologically, PBC is characterized by florid bile duct
lesions with damage to biliary epithelial cells, a dense portal
inflammatory infiltrate and progressive loss of small intrahepatic bile
ducts.
Was King David affected by PBC? Although primary biliary
cirrhosis can be associated with osteoporosis and bone fractures, in the
absence of typical clinical characteristics, appropriate laboratory
findings, and histological findings this diagnosis seems unlikely.
References
1. Kumagi T, Onji M. Presentation and diagnosis of primary biliary cirrhosis in
the 21st century. Clin Liver Dis. 2008;12(2):243-59; vii.
2. Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis. Semin
Immunopathol. 2009;31(3):283-307.
3. Leuschner U. Primary biliary cirrhosis - presentation and diagnosis. Clin Liver
Dis. 2003;7(4):741-58.
4. Wariaghli G, Allali F, El Maghraoui A, Hajjaj-Hassouni N. Osteoporosis in
patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol.
2010;22(12):1397-401.
5. Mounach A, Ouzzif Z, Wariaghli G, et al. Primary biliary cirrhosis and
osteoporosis: a case-control study. J Bone Miner Metab. 2008;26(4):379-84.
6. Monegal A, Navasa M, Guañabens N, et al. Osteoporosis and bone mineral
metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation.
Calcif Tissue Int. 1997;60(2):148-54.
7. Guañabens N, Cerdá D, Monegal A, et al. Low bone mass and severity of
cholestasis affect fracture risk in patients with primary biliary cirrhosis.
Gastroenterology. 2010;138(7):2348-56.
8. Gu EL, Yao GB. The clinical characteristics of primary biliary cirrhosis in
China: a systematic review. Zhonghua Gan Zang Bing Za Zhi. 2009;17(11):861-6.
305
CHRONIC OBSTRUCTIVE PULMONARY

DISEASE
COPD is a growing cause of morbidity and mortality worldwide
and accurate estimates of the prevalence of this disease are needed to
anticipate the future burden of COPD, target key risk factors, and plan
for providing COPD-related health services (1). COPD affects more
than 26 million adults in the US. Family physicians provide care for
most of these patients. Cigarette smoking is the leading risk factor for
COPD, although other risk factors, including occupational and
environmental exposures, account for up to 1 in 6 cases (2).
The main aim of this study was to measure the prevalence of
COPD and its risk factors and investigate variation across countries by
age, sex, and smoking status. Participants from 12 sites (n=9425)
completed postbronchodilator spirometry testing plus questionnaires
about respiratory symptoms, health status, and exposure to COPD risk
factors. COPD prevalence estimates based on the GOLD staging
criteria were adjusted for the target population. Logistic regression
was used to estimate AORs for COPD associated with 10-year age
increments and 10-pack-year (defined as the number of cigarettes
smoked per day divided by 20 and multiplied by the number of years
that the participant smoked) increments. The prevalence of stage II or
higher COPD was 10.1% (SE 4.8) overall, 11.8% (7.9) for men, and
8.5% (5.8) for women. The AORs for 10-year age increments were
much the same across sites and for women and men. The overall
pooled estimate was 1.94 (95% CI 1.80 – 2.10) per 10-year increment.
Site-specific pack-year AORs varied significantly in women (pooled
AOR=1.28, 95% CI 1.15 – 1.42, p=0.012), but not in men (1.16, 1.12
- 1.21, p=0.743). This worldwide study showed higher levels and
more advanced staging of spirometrically confirmed COPD than have
typically been reported. However, although age and smoking are
strong contributors to COPD, they do not fully explain variations in
disease prevalence - other factors seem to be important. Although
smoking cessation is becoming an increasingly urgent objective for an
ageing worldwide population, a better understanding of other factors
that contribute to COPD is crucial to assist local public-health officials
in developing the best possible primary and secondary prevention
policies for their regions (1).
Patients presenting with chronic cough, increased sputum
production, or progressive dyspnea should be evaluated for COPD.
Asthma is the disease most often confused with COPD. The diagnosis
of COPD is based on clinical suspicion and spirometry confirmation.
306
A FEV in one second/forced vital capacity ratio that is less than 70%
and is incompletely reversible with the administration of an inhaled
bronchodilator suggests COPD (2,3). Disease severity is classified by
symptomatology and spirometry. Joint guidelines from the American
Thoracic Society and the European Respiratory Society recommend a
single quantitative test for alpha1-antitrypsin deficiency in patients
diagnosed with COPD who remain symptomatic despite
bronchodilator therapy. Other advanced testing is usually not
necessary (2).
COPD is a preventable and treatable disease with some significant
extrapulmonary effects that may contribute to the severity in
individual patients. Its pulmonary component is characterized by
airflow limitation that is not fully reversible, is usually progressive
and associated with an abnormal inflammatory response of the lung to
noxious particles or gases. Although COPD is a nonspecific term
referring to a set of conditions that develops progressively because of
a number of different disease processes, it most commonly refers to
patients with chronic bronchitis and emphysema and to a subset of
patients with asthma. COPD is not asthma but can coexist with
asthma, the other major airways obstructive disease caused by airway
inflammation. Inflammation underlying in asthma has characteristic
features, distinct of that from COPD. Longitudinal studies revealed
the heterogeneous character of COPD. The pathological hallmarks of
COPD are inflammation of the small airways (bronchiolitis) and
destruction of lung parenchyma (emphysema) (4).
Chronic obstructive pulmonary disease
COPD is characterized by the gradual progression of irreversible

airflow obstruction and increased inflammation in the airways and
lung parenchyma that is generally distinguishable from the
inflammation caused by asthma. Most COPDs are associated with
smoking, but occupational exposure to irritants and air pollution also
are important risk factors. Patients with COPD typically present with
307
coughing, sputum production, and dyspnea on exertion (3,5).

However, none of these findings alone is diagnostic (3).
Based on airflow limitation as measured by spirometry, COPD can
be classified as mild, moderate, severe and very severe. COPD can
coexist with asthma, although the inflammation characteristic of
COPD is distinct from that of asthma (5). Severity is further stratified
based on FEV in one second and symptoms. Chest radiography may
rule out alternative diagnoses and comorbid conditions. Selected
patients should be tested for alpha1-antitrypsin deficiency. Arterial
blood gas testing is recommended for patients presenting with signs of
severe disease, right-sided heart failure, or significant hypoxemia.
COPD is a systemic disorder with weight loss and dysfunction of
respiratory and skeletal muscles (3,5).
COPD risk factors were investigated in an international cohort of
young adults using different spirometric definitions of the disease.
Subjects without asthma (n=4636) were studied and who had
prebronchodilator FEV(1)/FVC measured in the European
Community Respiratory Health Survey both in 1991 to 1993 (when
they were 20-44 years old) and in 1999 to 2002. COPD was defined
according to the GOLD fixed cut-off criterion (FEV(1)/FVC < 0.70),
and 2 criteria based on the Quanjer and LuftiBus reference equations
(FEV(1)/FVC less than lower limit of normal). COPD incidence
ranged from 1.85 (lower limit of normal [Quanjer]) to 2.88 (GOLD)
cases/1,000/yr. Although about half of the cases had smoked less than
20 pack-years, smoking was the main risk factor for COPD, and it
accounted for 29-39% of the new cases during the follow-up. Airway
hyperresponsiveness was the second strongest risk factor (15-17% of
new cases). Other determinants were respiratory infections in
childhood and a family history of asthma, whereas the role of sex, age,
and underweight largely depended on the definition of COPD used. In
conclusion, COPD may start early in life. Smoking prevention should
be given the highest priority to reduce COPD occurrence. Airway
hyperresponsiveness, a family history of asthma, and respiratory
infections in childhood are other important determinants of COPD (6).
The main objective of this study was to measure the prevalence of
COPD and its risk factors, investigate variation in prevalence across
countries and develop standardized methods that can be used in
industrialized and developing countries. Non-institutionalized adults
aged ≥ 40 years were recruited using population-based sampling
plans. Each site targeted a minimum of 600 participants (300 women,
300 men), who filled out questionnaires and performed spirometry
before and after administration of 200 mug salbutamol using
308
standardized methods. Data from 12 sites (n=8775) showed that the

estimated population prevalence of COPD (GOLD Stage II and
higher) was 10.1 +/- SE = 4.8% overall (11.8 +/- 7.9% for men and
8.5 +/- 5.8% for women). Prevalence increased with age and pack-
years of smoking, but other less understood risk factors, such as
biomass heating and cooking exposures, occupational exposures and
tuberculosis contribute to the location-specific variations in disease
prevalence that BOLD is finding. BOLD has estimated the social and
economic burden of COPD in 12 countries to date. BOLD and the
Proyecto Latinoamericano de Investigación en Obstrucción Pulmonar
(the PLATINO study) are developing a growing database of COPD
prevalence. In conclusion, cigarette smoking and age are the most
important COPD risk factors, but other risk factors should also be
explored (7).
There is growing interest in preventable, non-smoking causes of
COPD, among which are chronic exposures to respiratory irritants in
the workplace. Sources of data were reviews of occupational COPD in
specific occupations and industries and in general populations,
supplemented with other or more recently published material. There is
good evidence for an increased risk of COPD from certain specific
exposures (coal mine dust, silica, welding fume, textile dust,
agricultural dust, and cadmium fume). Less clear is the causal role of
non-specific dusts or fumes/gases in general populations where the
available literature is notably uncritical (8).
The aim of this study was to analyze the impact of occupational
exposures on respiratory symptoms, lung function, and employment
status in a series of COPD patients. A cross-sectional study of 185
male COPD patients was conducted. Patients underwent baseline
spirometry and answered a questionnaire that included information on
respiratory symptoms, hospitalizations for COPD, smoking habits,
current employment status, and lifetime occupational history.
Exposure to biological dust, mineral dust, and gases and fumes was
assessed using an ad hoc job exposure matrix. Having worked in a job
with high exposure to mineral dust or to any dusts, gas, or fumes was
associated with an FEV(1) of < 30% predicted (mineral dust: RR ratio
11, 95% CI 1.4 - 95; dusts, gas, or fumes: RR ratio 6.9, 95% CI 1.1 -
45). High exposure to biological dust was associated with chronic
sputum production (OR 4.3, 95% CI 1.6 - 12), dyspnea (OR 2.7, 95%
CI 1.1 - 6.7), and work inactivity (OR 2.4, 95% CI 1.4 - 4.2). High
exposure to dusts, gas, or fumes was associated with sputum
production (OR 2.8, 95% CI 1.2 - 6.7) and dyspnea (OR 1.2, 95% CI
1.1 - 1.4). In conclusion, occupational exposures are independently
309
associated with the severity of airflow limitation, respiratory

symptoms, and work inactivity in patients with COPD (9).
The association between occupational exposures and incidence of
COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart
Diseases in Adults (SAPALDIA) was evaluated. Prebronchodilator
ratio of FEV in 1 second over forced vital capacity (FEV(1)/FVC) was
measured in 4,267 nonasthmatic SAPALDIA participants aged 18-62
years at baseline in 1991 and at follow-up in 2001-2003. COPD was
defined by the GOLD criterion (FEV(1)/FVC < 0.70) and Quanjer
reference equation (FEV(1)/FVC < lower limit of normal, and
categorized by severity (≥ 80% and < 80% predicted FEV(1) for stage
I and stage II+, respectively). Using a job-exposure matrix, self-
reported occupations at baseline were assigned exposures to biological
dusts, mineral dusts, gases/fumes, and VGDF (high, low, or
unexposed as reference). Statistically significant (p<0.05) incident rate
ratios of stage II+ GOLD and LLN-COPD, indicating risks between
two- and fivefold, were observed for all occupational exposures at
high levels. Occupational exposure-associated risk of stage II+ COPD
was observed mainly in males and ages ≥ 40 years, and remained
elevated when restricted to nonsmokers. In conclusion, in a Swiss
working adult population, occupational exposures to biological dusts,
mineral dusts, gases/fumes, and VGDF are associated with COPD
incidence of at least moderate severity (10).
Data from the FLOW study of 1202 subjects with COPD (of which
742 had disease classified as stage II or above by GOLD criteria) and
302 referent subjects matched by age, sex and race recruited from a
large managed care organization were analyzed. Occupational
exposures were assessed using 2 methods: self-reported exposure to
VGDF on the longest held job and a job exposure matrix for
probability of exposure based on occupation. The OR and adjusted
population attributable fraction associated with occupational exposure
were calculated. VGDF exposure was associated with an increased
risk of COPD (OR 2.11, 95% CI 1.59 - 2.82) and a population
attributable fraction of 31% (95% CI 22 - 39%). The risk associated
with high probability of workplace exposure by job exposure matrix
was similar (OR 2.27, 95% CI 1.46 - 3.52), although the PAF was
lower (13%, 95% CI 8 - 18%). These estimates were not substantively
different when the analysis was limited to COPD GOLD stage II or
above. Joint exposure to both smoking and occupational factors
markedly increased the risk of COPD (OR 14.1, 95% CI 9.33 - 21.2).
In conclusion, workplace exposures are strongly associated with an
increased risk of COPD. On a population level, prevention of both
310
smoking and occupational exposure, and especially both together, is

needed to prevent the global burden of disease (11).
Household air pollution from biomass fuels, coal, and kerosene
burned in open fires, primitive stoves, and lamps causes at least 2
million deaths per year. Many of these deaths occur in children 5
years of age with pneumonia and in women with COPD, lung cancer,
and C-V disease. Household air pollution is inextricably linked to
poverty, with activities to obtain fuel consuming a large proportion of
the time and financial resources of poor households. Thus, fewer
resources used in this way means less are available for basic needs
like food, education, and health care. The burden of work and the
exposure to smoke, particularly during cooking, are predominantly
borne by women and children. Although historically household air
pollution has not received sufficient attention from the scientific,
medical, public health, development, and policy-making communities,
the tide has clearly changed with the broad-based support and launch
of the Global Alliance for Clean Cookstoves in 2010 (12).
It is estimated that up to half of the world's population burns
biomass fuel (wood, crop residues, animal dung and coal) for indoor
uses such as cooking, lighting and heating. As a result, a large
proportion of women and children are exposed to high levels of
household air pollution. The short and long-term effects of these
exposures on the respiratory health of this population are not clearly
understood. On May 9-11, 2011 NIH held an international workshop
on the "Health Burden of Indoor Air Pollution on Women and
Children," in Arlington, VA. To gather information on the knowledge
base on this topic and identify research gaps, ahead of the meeting a
literature search was conducted using PubMed to identify publications
that related to household air pollution, asthma, and COPD. Abstracts
were analyzed and those considered by the respiratory sub study group
at the meeting to be most relevant to the field are reported. Many of
the studies published were symptom-based studies (as opposed to
objective measures of lung function or clinical examination etc.) and
measurement of household air pollution was not done. Many found
some association between indoor exposures to biomass smoke as
assessed by stove type (e.g., open fire vs. liquid propane gas) and
respiratory symptoms such as wheeze and cough. Among the studies
that examined objective measures (e.g. spirometry) as a health
outcome, the data supporting an association between biomass smoke
exposure and COPD in adult women were robust, but the findings for
asthma were mixed. If an association was observed between the
exposures and lung function, most data demonstrate mild to moderate
311
reductions in lung function, and the pathophysiological mechanisms

need to be investigated (13).
Patients with COPD are at increased risk of osteoporosis because
of their age, limited physical activity, low BMI, smoking,
hypogonadism, malnutrition, and use of corticosteroids. Systemic
inflammation represents an additional pathomechanism contributing to
the development of osteoporosis in COPD patients. Males in their mid
to late 60s with a smoking history of greater than 60 pack-years have a
prevalence rate of vertebral fractures similar to, and possibly greater
than, postmenopausal women ≥ 65 years old: in patients with severe
COPD, up to 50-70% have osteoporosis or osteopenia, and up to 24-
30% have compression vertebral fractures. Correlates of osteoporosis
in COPD are mainly measures of body composition, disease severity
and the use of corticosteroids, although causality has not been proven.
Systemic corticosteroids remain the most common cause of drug-
related osteoporosis, and a meta-analysis concluded that the use of
more than 6.25 mg prednisone daily led to decreased BMD and
increased fracture risk. By contrast, the effects of the long-term use of
inhaled corticosteroids on BMD remain debatable. Effects of
treatment of osteoporosis have not been investigated in samples
consisting of COPD patients only but the recommendations follow for
the diagnosis and treatment of osteoporosis. Early recognition of
BMD loss is essential, and assumes close interdisciplinary cooperation
between respirologists and rheumatologists. In the future, novel
therapeutical strategies such as monoclonal antibodies against
osteoclasts activators may prove their beneficial effects in the
treatment of COPD-related osteoporosis (14).
The aim of this study was to determine the prevalence and
correlates of osteoporosis in COPD patients based on DXA, spinal X-
rays, and combinations thereof. DXA and spinal X-rays were obtained
and pulmonary function tests, body composition, 6-minute walking
distance, medical history, and medication use were assessed in 255
clinically stable COPD outpatients in a large teaching hospital in the
Netherlands. Half of all patients had radiologic evidence of
osteoporosis. Combining the results of DXA with spinal X-rays
augmented the proportion of COPD patients with osteoporosis
compared with both methods separately. The prevalence of
osteoporosis was insignificantly different after stratification for
GOLD stage. Most patients with osteoporosis did not receive
pharmacologic treatment. Age, BMI, and PTH level were significant
independent correlates for osteoporosis. Chest physicians should be
aware of the high prevalence of osteoporosis in patients with COPD,
312
even in the presence of a low GOLD score, as well as in elder COPD

patients with a low BMI and/or an increased PTH level (15).
Osteoporosis in COPD
The main aims of the current study were to determine the

percentage of newly diagnosed osteoporotic patients after a follow up
of 3 years and to identify baseline risk factors for the progression of
osteoporosis in COPD. Clinically stable COPD outpatients were
included. Lung function parameters, body composition measures, 6
minute walk distance; DXA-scan and X-spine were assessed at
baseline and repeated after 3 years. Prevalence of osteoporosis in
COPD patients increased from 47% to 61% in 3 years mostly due to
an increase of vertebral fractures. Lower baseline T-score at the
trochanter independently increased the risk for the development of
osteoporosis. Additionally, baseline vitamin D deficiency increased
this risk 7.5-fold. In conclusion, the prevalence of osteoporosis
increased over a 3-year period in patients with COPD. Baseline risk
factors for the development of osteoporosis are osteopenia at the
trochanter and vitamin D deficiency (16).
BMD alone does not reliably predict osteoporotic fractures. The
FRAX was developed to estimate the risk of fracture in the general
population. This study was designed to identify predictors of
osteoporosis and vertebral fractures in patients presenting with COPD.
Eighty-five patients (mean age = 75 years, 92% men) with moderate
to very severe COPD were studied. Osteoporosis and vertebral
fractures were diagnosed with DXA scan and vertebral X-rays,
respectively. Patient characteristics, including age, gender, BMI, and
results of pulmonary function tests, chest CT scan, blood and urinary
biomarkers of bone turnover were recorded, and a FRAX score was
calculated by a computer-based algorithm. Osteoporosis, defined as a
T score < -2.5, found in 20 patients (24%), was associated with female
gender, BMI, dyspnea scale, long-term oxygen therapy, vital capacity,
313
emphysema score on CT, and measurements of serum and urinary

biomarkers of bone turnover. Vertebral fractures, diagnosed in 29
patients (35%), were correlated with age, long-term oxygen therapy,
vital capacity, and FEV in 1 second, treatment with oral corticosteroid
or warfarin, and weakly associated with the presence of osteoporosis.
There was no correlation between FRAX score and prevalence of
vertebral fractures, suggesting that neither BMD alone nor FRAX
score would predict the presence of vertebral fractures in COPD
patients (17).
The aim of this study was to compare COPD GOLD II patients
(that is, patients with moderate COPD, stage II, according to the
GOLD classification) with osteoporosis (cases) to COPD GOLD II
patients without osteoporosis (controls) to identify risk factors for
osteoporosis. The diagnosis of osteoporosis was based on BMD and
vertebral fractures. Cases (n=49) were matched for gender, age and
FEV in the first second to controls (n=49). Pulmonary function, body
composition, vitamin D, emphysema score (by high-resolution CT),
medical history and medication use in all patients were assessed.
Variables that were significantly different between the cases and
controls were included in a logistic regression analysis. COPD
patients with osteoporosis had a significantly lower BMI and higher
residual volume as the percentage of total lung capacity compared to
COPD patients without osteoporosis. Decreasing BMI and increasing
residual volume as the percentage of total lung capacity increased the
OR for osteoporosis. Overweight and obese BMI values were
protective for osteoporosis. Screening for osteoporosis should be
performed even in moderate COPD patients, especially in those with a
low BMI and/or a high residual volume as the percentage of total lung
capacity (18).
Assessment: the pathological hallmarks of COPD are

inflammation of the small airways (bronchiolitis) and destruction of
lung parenchyma (emphysema). Risk factors for COPD include
smoking, coal mine dust, silica, VGDF, biomass fuel such as wood,
crop residues, animal dung and coal for indoor uses such as cooking,
lighting and heating, coal and kerosene burned in open fires, primitive
stoves, and lamps. Other risk factors include airway
hyperresponsiveness, a family history of asthma, and respiratory
infections in childhood. Patients with COPD typically present with
coughing, sputum production, and dyspnea on exertion. COPD is a
systemic disorder with weight loss and dysfunction of respiratory and
skeletal muscles.
314
Patients with COPD are at increased risk of osteoporosis because

of their age, limited physical activity, low BMI, smoking,
hypogonadism, malnutrition, and use of corticosteroids.
Was King David affected by COPD? Although COPD is associated
with osteoporosis, in the absence of a family history of asthma,
respiratory infections in childhood, specific exposures such as
smoking, occupational and household air pollution, as well as airway
hyperresponsiveness, a history of chronic cough, increased sputum
production (sometimes with wheezing) over many years, and
progressive dyspnea the diagnosis of COPD seems unlikely.
References
1. Buist A S, McBurnie MA, Vollmer WM, et al., on behalf of the BOLD
Collaborative Research Group. International variation in the prevalence of COPD
(The BOLD Study): a population-based prevalence study. The Lancet. 2007;370
(9589),741-50.
2. Stephens MB, Yew KS. Diagnosis of chronic obstructive pulmonary disease.
Am Fam Physician. 2008;78(1):87-92. Comment in: Understanding rating systems
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3. Murărescu ED, Mitrofan EC, Mihailovici MS. Chronic obstructive pulmonary
disease in a new concept. Rom J Morphol Embryol. 2007;48(3): 207-14.
4. Dewar M, Curry RW Jr. Chronic obstructive pulmonary disease: diagnostic
considerations. Am Fam Physician. 2006;73(4):669-76. Comment in: Using COPD
guidelines to improve patient care. [Am Fam Physician. 2006].
5. Romagnoli M, Fabbri LM. Chronic obstructive pulmonary disease: definition
and classification of severity. Ann Ist Super Sanita. 2003;39(4): 461-6.
6. de Marco R, Accordini S, Marcon A, et al.; European Community Respiratory
Health Survey (ECRHS). Risk factors for chronic obstructive pulmonary disease in a
European cohort of young adults. Am J Respir Crit Care Med. 2011;183(7):891-7
7. Buist AS, Vollmer WM, McBurnie MA. Worldwide burden of COPD in high-
and low-income countries. Part I. The burden of obstructive lung disease (BOLD)
initiative. Int J Tuberc Lung Dis. 2008;12(7):703-8.
8. Cullinan P. Occupation and chronic obstructive pulmonary disease (COPD). Br
Med Bull. 2012;104:143-61.
9. Rodríguez E, Ferrer J, Martí S, et al. Impact of occupational exposure on
severity of COPD. Chest. 2008;134(6):1237-43.
10. Mehta AJ, Miedinger D, Keidel D, et al.; SAPALDIA Team. Occupational
exposure to dusts, gases, and fumes and incidence of chronic obstructive pulmonary
disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in
Adults. Am J Respir Crit Care Med. 2012; 185(12):1292-300. Comment in:
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11. Blanc PD, Iribarren C, Trupin L, et al. Occupational exposures and the risk of
COPD: dusty trades revisited. Thorax. 2009;64(1):6-12.
12. Mortimer K, Gordon SB, Jindal SK, et al. Household air pollution is a major
avoidable risk factor for cardiorespiratory disease. Chest. 2012;142(5):1308-15.
13. Diette GB, Accinelli RA, Balmes JR, et al. Obstructive Lung disease and
exposure to burning biomass fuel in the indoor environment. Glob Heart.
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14. Pobeha P, Lazúrová I, Tkácová R. Osteoporosis in chronic obstructive

pulmonary disease. Vnitr Lek. 2010;56(11):1142-9.
15. Graat-Verboom L, van den Borne BE, Smeenk FW, et al. Osteoporosis in
COPD outpatients based on bone mineral density and vertebral fractures. J Bone
Miner Res. 2011;26(3):561-8.
16. Graat-Verboom L, Smeenk FW, van den Borne BE, et al. Progression of
osteoporosis in patients with COPD: a 3-year follow up study. Respir Med.
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17. Ogura-Tomomatsu H, Asano K, Tomomatsu K, et al. Predictors of
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18. Graat-Verboom L, Smeenk FW, van den Borne BE, et al. Risk factors for
osteoporosis in Caucasian patients with moderate chronic obstructive pulmonary
disease: a case control study. Bone. 2012;50(6):1234-9.
OSTEOARTHRITIS
OA, the most common form of arthritis, is a major contributor to
functional impairment, reduced independence, and the most frequent
cause of disability in older adults (1-3). Worldwide, OA is estimated
to be the fourth leading cause of disability. Most of this disability
burden is attributable to the involvement of the hips or the knees (4).
The prevalence of arthritis is high, with OA being one of the most
frequent disorders in the population (5). Symptomatic knee OA occurs
in 10% men and 13% in women aged ≥ 60 years (6). Everybody > 60
years of age has pathological features of OA in at least one joint (3).
OA is a complex process affecting many different joint areas in the
body. From a pathophysiological point of view, some features are
crucial for the diagnosis, such as cartilage fibrillation and thinning,
subchondral sclerosis and the presence of osteophytes. From a clinical
perspective, OA is the most prevalent rheumatic joint disorder,
causing pain and stiffness of the joints and, for the individual,
impaired function and health status (7).
OA has a multifactorial etiology, and can be considered the
product of an interplay between systemic and local factors (1,6). Old
age, female gender, overweight and obesity, knee injury, repetitive use
of joints, bone density, muscle weakness, and joint laxity play roles in
the development of joint OA, particularly in the weight-bearing joints.
Modifying these factors may reduce the risk of OA and prevent
subsequent pain and disability (6).
Loss of articular cartilage is a crucial event in OA. Concomitant
features are osseous deformation and sclerosing, shrinkage of the
capsule, atrophy of muscles, and variable degrees of synovitis. The
316
cardinal symptom of OA is pain. Later, deformation and malalignment

with deprived function of the joint are seen. The clinical and
radiological features make up the diagnosis (3).
Osteoarthritis
OA is a social disease characterized by pain, inflammation and

stiffness due to an involvement of articular cartilage, soft tissues and
bone. It is the most common rheumatic disease, every age can be
affected but prevalence increases dramatically with age with a greater
incidence in subjects between 40 and 50 years of age. Hip OA has an
important correlation with weight, genetic factors, sex, previous
traumas, occupational factors and age. People > 35 years have a
prevalence of hip OA of 10.8% and 35.4% in people > 85 years. Knee
OA correlates with weight, life style and physical activity (8).
Obesity and joint injury appear to be the strongest risk factors for
knee OA that are both modifiable and have the potential for
substantial impact on a population level. The course of functional
decline in persons with symptomatic OA on a population level is
generally one of stable to slowly deteriorating function, but on an
individual level, many patients maintain function or improve during
the first 3 years of follow-up. Obesity stands out as one of few
modifiable risk factors of OA that also is a potentially modifiable
predictor of functional decline. Physical activity has a substantial
protective impact on future OA-related disability (9).
OA of the hip and knee are 2 of the most important causes of pain
and physical disability in community-dwelling adults Differences in
the prevalence of OA are attributable to both genetic and life-style
factors. Disease definition may be based upon clinical or radiographic
criteria, although case definition should rely on radiographic features
for epidemiological studies. Symptomatic hand OA is a common
disease that impairs hand function among the elderly, this impairment
being largely mediated by pain (1).
317
Primary osteoarthritis of the knee. Note the osteophytes, narrowing of the

joint space (arrow), and increased subchondral bone density (arrow).
In the US, OA is the most common joint disorder. Twenty seven

million adults, more than 10% of the US adult population, had clinical
OA in 2005, and in 2009 OA was the fourth most common cause of
hospitalization. OA is the leading indication for joint replacement
surgery; 905,000 knee and hip replacements were performed in 2009
at a cost of $42.3 billion (2).
Obesity is a strong risk factor for OA of the knee and hip (2). The
number of people affected by symptomatic OA is likely to increase
due to the aging of the population and the obesity epidemic (6). In
England and Wales, between 1.3 and 1.75 million people have OA
and a further 0.25-0.5 million have RA, while in France some 6
million new diagnoses of OA are made each year. This prevalence is
expected to increase in the coming years, as arthritis more often
affects the elderly, a proportion of the population that is increasing.
The economic burden of such musculoskeletal diseases is high,
accounting for up to 1-2.5% of the gross national product of western
nations. This burden comprises both the direct costs of medical
interventions and indirect costs, such as premature mortality and
chronic and short-term disability. The impact of arthritis on QOL is of
particular importance. Musculoskeletal disorders are associated with
some of the poorest QOL issues, particularly in terms of bodily pain
(mean score from the Medical Outcome study 36-item SF Health
Survey of 52.1) and physical functioning (49.9), where QOL is lower
than that for G-I conditions (bodily pain 52.9, physical functioning
55.4), chronic respiratory diseases (72.7, 65.4) and C-V conditions
(64.7, 59.3) (5).
A case-control study was nested in a one-year prevalence survey of
consultations in 60 general practices in England and Wales. Cases
were 11,375 subjects aged 50 and over who had consulted with OA
during the study year. Controls were 11,780 subjects matched for age
318
and sex who had consulted during the study year, but not for OA.
Morbidity outcomes were based on a standard clinical classification
system. After adjusting for age, sex, and social class, cases were
significantly more likely to have high levels of comorbidity than
controls (2.35; 2.16 to 2.55). Significant OA comorbid associations
with other musculoskeletal conditions included arthropathies (OR
2.26, 99% CI 1.50 - 3.41), upper limb sprain (2.04, 1.38 - 3.00),
synovial and tendon disorders (2.03, 1.54 - 2.68), and other joint
disorders (2.00, 1.71 - 2.32). OA non-musculoskeletal associations
were with obesity (2.25, 1.73 - 2.92), gastritis (1.98, 1.46 - 2.68),
phlebitis (1.80, 1.28 - 2.52), diaphragmatic hernia (1.80, 1.29 - 2.51),
ischemic heart disease (1.73, 1.13 - 2.66) and intestinal diverticula
(1.63, 1.20 - 2.23). In conclusion, comorbidity for OA is extensive,
with musculoskeletal as well as non-musculoskeletal conditions. Age,
sex, and social class do not explain this comorbidity but propensity to
consult may be a part explanation (10).
In Norway, in 2004, postal questionnaires were sent to all people in
a local community born in 1928-30, 1938-40, 1948-50, 1958-60,
1968-70, and 1978-80, and 3266 (56.7%) responded. The prevalence
of hip, knee, and/or hand OA was obtained by the item "Have you
ever been diagnosed with osteoarthritis in hip/knee/hand by a medical
doctor or by x-ray?" The overall prevalence of OA was 12.8% (95%
CI 11.7 - 14.0), being significantly higher among women (14.7%,
95% CI 13.1 - 16.4) than men (10.5%, 95% CI 9.0 - 12.1). The
prevalence for hip OA was 5.5% (95% CI 4.7 - 6.3), knee OA 7.1%
(95% CI 6.3 - 8.0), and for hand OA 4.3% (95% CI 3.6 - 5.0). OA was
significantly (all p<0.001) associated with higher age, less than 12
years of education, being out of work, pain duration > 1 year, pain in
several body sites, sick leave for more than 8 weeks, emotional
distress, poor sleeping quality, fatigue, and frequent use of healthcare
providers in primary health care. A significant dose-response
relationship between increasing BMI and OA was found (p=0.001).
In conclusion, the overall prevalence of OA was 12.8% and higher
found among women and older people, people with < 12 years of
education, those out of work, and those overweight. OA was
associated with pain, disability, and poor health status, and frequent
use of healthcare providers (11).
An Italian study demonstrated that the prevalence of knee OA is
highest in subjects ≥ 65 years and 44% in people < 80 years of age. A
study was conducted in the South of Italy called the OstheoArtrithis
Southern Italy Study that involved 456 doctors and 1782 patients in 3
different regions. The mean age of these patients was 66.3 years. Knee
319
OA is the most common subset of OA that requires the highest

number of examinations and causes the greatest disability. The most
common used drugs are Fans and Coxibs. Condroprotectors are not
used much, probably because they are not considered to be effective
(12).
The main objective of this study was to assess the clinical
characteristics and determinants of pain observed by GPs in Italian
patients with OA of the hand, hip, and knee. The 2764 GPs
participating in the study were asked to enroll 10 consecutive patients
with OA diagnosed according to the ACR clinical criteria A
questionnaire evaluating demographic data, the clinical characteristics
of OA, and previous diagnostic and therapeutic interventions was
administered by the GPs. Of 25,589 evaluable patients enrolled during
a mean period of 2.8 weeks by the GPs, 17,567 were women (69%)
and 7878 men (31%). The most painful OA joints were the knee in
12,827 patients (54%), the hip in 5645 patients (24%), and the hand in
5467 patients (23%) - percentages calculated on the 23,939 patients
for whom this information was available. The weekly incidence of
referrals to GPs for OA was higher for women and for knee OA. The
median age of the patients was 70 years (range 50 to 104 years) and
disease duration was 8.3 +/- 7.10 years. The most frequent
comorbidities were hypertension (53%), obesity (22%), osteoporosis
(21%), type 2 diabetes mellitus (15%), and COPD (13%). The median
pain VAS score was higher for women than for men, for hip OA, and
for generalized OA than for knee and hand OA (p<0.0001). Intense
pain, defined as VAS readings of > 60 mm, was increased in women
only in the knee (OR 1.24, 95% CI 1.15 - 1.34) and in generalized OA
(OR 1.17, 95% CI 1.03 - 1.33). It was significantly increased in
patients > 70 years (OR 1.46, 95% CI 1.39 - 1.54), in those with a low
educational level (OR 1.44, 95% CI 1.36 - 1.5), a BMI of ≥ 30 (OR
1.52, 95% CI 1.42 - 1.61), a disease duration of more than 7 years
(OR=1.60, 95% CI 1.52 - 1.68), comorbidities (OR=1.61, 95% CI 1.5
-1.73), and generalized OA (OR 2.05, 95% CI 1.91 - 2.19). Manual
occupations were associated with highly intense pain only in men. The
results of this study underscore the major impact of OA on care in
general practice, the high frequency of OA-associated comorbidities,
and the role of different risk factors in OA pain (13).
This cross-sectional population based study was conducted on the
total adult population of 7 communities (8547 subjects) and on 2100
out of 5686 randomly selected subjects in an additional 2 communities
in the general adult population in Greece. Sixteen rheumatologists
visited the target population at their homes; an interview based on a
320
standardized questionnaire was conducted and clinical evaluation and

laboratory investigations were done, when necessary. The ACR
classification criteria were used for diagnosing symptomatic OA. Of
the final target population, of 10,647 subjects, 8740 (82.1%)
participated in the study. The age and sex adjusted prevalence of
symptomatic knee, hand, and hip OA was 6.0% (95% CI 5.6 - 6.4),
2% (1.8 - 2.2), and 0.9% (0.7 - 1.1), respectively. Symptomatic knee,
hand, and hip OA prevalence was significantly higher among women
than men and increased significantly with age. Symptomatic knee OA
was significantly more common in the rural compared to urban and
suburban populations. Logistic regression analysis showed a
significant association between female sex and age ≥ 50 years with all
sites of OA, obesity with knee and hip OA, and of a low level of
education with knee OA. In conclusion, symptomatic knee, hand, and
hip OA is common in the general adult population in Greece, showing
a female preponderance and a prevalence increasing with age. Female
sex and age are risk factors for all sites of OA, obesity for knee and
hip OA, and a low level of education for knee OA (14).
Hip osteoarthritis
Charts with diagnosis of OA from 2 arthritis clinics (Philippine

General Hospital and a private clinic) from January 2008 to May
2011, were reviewed for demographics, clinical presentation, risk
factors and management. Primary OA had 859 patients. Female: male
ratio was 3:1. Mean age at diagnosis was 63 years, onset at 59 years.
Men consulted 10 months later. Mean BMI was 27.1 kg/m(2). Women
were overweight, men, obese. Co-morbid conditions included
hypertension (53%), dyslipidemia (16%) and diabetes (13%). Women
(94.7%) developed symptoms 12 years after menopause. One-third of
patients were of low socioeconomic status. Chief complaint was pain
in 92.8%. Joint findings included crepitus (70.8%) and Heberden's
nodes (13.0%) for knees and hands, respectively. Commonly involved
joints were knees (62.5%), knees and hands (14.3%), and generalized
321
joint involvement (13.5%). The hip was involved in 2.9% of cases.

Radiographs showed K-L score of 2 in 56.6%. Less than 25%
received physical therapy. Most prescribed drugs were glucosamine
sulfate (45.5%), paracetamol (42.8%) and coxibs (40.6%). Less than
8% received intra-articular treatment, or were referred for surgery. In
conclusion, clinical characteristics show more women than men, with
knees as the most common and hips as the least involved joints.
Medical management was based on a local practice guideline (15).
Arthritis affects around 3 million people in Australia, representing
about 15% of the population. Osteoarthritis is the leading cause of
pain and disability among the elderly. Osteoarthritis is the third
leading cause of life-years lost due to disability. Obesity and joint
injury are important potentially modifiable risk factors for the
development of osteoarthritis. Obesity is also an important predictor
of progression of osteoarthritis. Currently, about 19,000 hip and 20000
knee replacements are performed for osteoarthritis in Australia each
year. Prevalence of osteoarthritis and the need for total joint
replacement surgery are likely to increase because of a combination of
increasing risk factors (age, obesity, and injury), increasing
expectations for improved QOL, and improved surgical and anesthetic
techniques making surgery possible for more people. Primary and
secondary prevention programs aimed at reducing obesity, preventing
injury and improving rehabilitation and physical activity are urgently
required (16).
OA is associated with ageing with the Asian region ageing rapidly,
with heavy physical occupational activity, a required livelihood for
many people living in rural communities in developing countries.
Unfortunately, joint replacement surgery, an effective intervention for
people with severe OA involving the hips or knees, is inaccessible to
most people in these regions. On the other hand, obesity, another
major risk factor, is less prevalent, although it is on the increase (17).
The main objective of this study was to investigate the prevalence
of radiographic knee OA and knee pain in the Japanese elderly using a
large-scale population of a nationwide cohort study, Research on
Osteoarthritis Against Disability. From the baseline survey of this
study, 2,282 participants ≥ 60 years (817 men and 1,465 women)
living in urban, mountainous and seacoast communities were
analyzed. The radiographic severity at both knees was determined by
the KL grading system. KL≥2 and KL≥3 knee OA were examined
separately to assess osteophytosis and joint space narrowing. The
prevalence of KL≥2 OA (47.0% and 70.2% in men and women,
respectively) was much higher than that of previous studies in
322
Caucasians, while that of KL≥3 OA was not different in men. Age,

BMI, female sex and rural residency were risk factors for radiographic
knee OA, knee pain and their combination. The prevalence of knee
pain was age-dependent in women, but not in men. Knee pain was
more strongly associated with KL≥3 OA than with KL=2, and the
association was higher in men than in women. Female sex was a
strong risk factor even in the subgroup without radiographic knee OA
(KL=0/1). The present cross-sectional study revealed a high
prevalence of radiographic knee OA in the Japanese elderly. Knee
pain was strongly associated with joint space narrowing especially in
men, while women tended to have knee pain even without
radiographic OA (18).
Index patients (n=232) with symptomatic large joint and/or hand
OA, and 257 of their first-degree relatives were included. Heberden's
nodes were graded 0-II; Bouchard's nodes were scored as
present/absent. Joint space narrowing and osteophyte were each
scored 0-3 using the Osteoarthritis Research Society International
atlas. The AOR of Heberden's nodes for underlying joint space
narrowing in the same digit was 1.72 (95% CI 1.47 - 2.02), whereas
for osteophyte it was higher at 5.15 (95% CI 4.37 - 6.08). A similar
trend was seen with Bouchard's nodes and underlying OA, with
osteophyte having a higher OR (OR 2.98, 95% CI 2.55 - 3.47) than
joint space narrowing (OR 1.62, 95% CI 1.37 - 1.91). In conclusion,
there is a positive relationship between Heberden's nodes/ Bouchard's
nodes and underlying radiographic changes of OA, especially
osteophyte. Nodes do appear to link pathologically to OA in
interphalangeal joints (19).
The main objective of this study was to identify estimates of the
prevalence of radiographic knee OA in adults with knee pain and of
knee pain in adults with radiographic knee OA, and determine if the
definitions of x ray osteoarthritis and symptoms, and variation in
demographic factors influence these estimates. A systematic literature
search identifying population studies combined x rays, diagnosis,
clinical signs and symptoms in knee OA. Estimates of the prevalence
of radiographic OA in people with knee pain were determined and
vice versa. In addition, the effects of influencing factors were
scrutinized. The proportion of those with knee pain found to have
radiographic osteoarthritis ranged from 15-76%, and in those with
radiographic knee OA the proportion with pain ranged from 15-81%.
Considerable variation occurred with x ray view, pain definition, OA
grading and demographic factors. Knee pain is an imprecise marker of
radiographic knee OA but this depends on the extent of radiographic
323
views used. Radiographic knee OA is likewise an imprecise guide to

the likelihood that knee pain or disability will be present. Both
associations are affected by the definition of pain used and the nature
of the study group. The results of knee x rays should not be used in
isolation when assessing individual patients with knee pain (20).
References
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cause of hospitalization in U.S. adults. Orthop Nurs. 2012;31(2):85-91.
3. Veje K, Hyllested JL, Østergaard K. Osteoarthritis. Pathogenesis, clinical
features and treatment. Ugeskr Laeger. 2002;164(24):3173-9.
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Asia. Int J Rheum Dis. 2011;14(2):113-21.
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7. Petersson IF, Jacobsson LT. Osteoarthritis of the peripheral joints. Best Pract
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Italy Study). Epidemiology and risk factors in osteoarthritis: literature review data
from "OASIS" study. Reumatismo. 2004;56(3):169-84.
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associated comorbidities. PM R. 2012;4(5 Suppl):S10-9.
10. Kadam UT, Jordan K, Croft PR. Clinical comorbidity in patients with
osteoarthritis: a case-control study of general practice consulters in England and
Wales. Ann Rheum Dis. 2004;63(4):408-14.
11. Grotle M, Hagen KB, Natvig B, et al. Prevalence and burden of osteoarthritis:
results from a population survey in Norway. J Rheumatol. 2008;35(4):677-84.
12. De Filippis L, Gulli S, Caliri A, et al.; Gruppo OASIS (Osteoarthritis South
Italy Study). Epidemiology and risk factors in osteoarthritis: literature review data
from "OASIS" study. Reumatismo. 2004;56(3):169-84.
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2005;35(1 Suppl 1):17-23.
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Group. Prevalence of symptomatic knee, hand, and hip osteoarthritis in Greece. The
ESORDIG study. J Rheumatol. 2006;33(12):2507-13.
15. Racaza GZ, Salido EO, Penserga EG. Clinical profile of Filipino patients with
osteoarthritis seen at two arthritis clinics. Int J Rheum Dis. 2012;15(4):399-406.
16. March LM, Bagga H. Epidemiology of osteoarthritis in Australia. Med J Aust.
2004;180(5 Suppl):S6-10.
17. Fransen M, Bridgett L, March L, et al. The epidemiology of osteoarthritis in
Asia. Int J Rheum Dis. 2011;14(2):113-21.
18. Muraki S, Oka H, Akune T, et al. Prevalence of radiographic knee
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based cohorts: the ROAD study. Osteoarthritis Cartilage. 2009;17(9):1137-43.
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19. Thaper A, Zhang W, Wright G, Doherty M. Relationship between Heberden's

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Disord. 2008 Sep 2;9:116.
OSTEOPOROSIS AND OSTEOARTHRITIS

The etiology of osteoporosis and OA is multifactorial: both
constitutional and environmental factors, ranging from genetic
susceptibility, endocrine and metabolic status to mechanical and
traumatic injury, are thought to be involved. When interpreting
research data, one must bear in mind that pathophysiologic factors,
especially in disorders associated with aging, must be regarded as
either primary or secondary. Therefore, findings in end-stage
pathology are not necessarily the evidence or explanation of the
primary cause or event in the diseased tissue. Both aspects of research
are important for potentially curative or preventive measures. These
considerations, in the case of this topic - the inverse relationship of
osteoporosis and OA - are of particular importance. Although the
inverse relationship between 2 frequent diseases associated with
aging, OA and osteoporosis, has been observed and studied for more
than 30 years, the topic remains controversial for some and
stimulating for many. The anthropometric differences of patients
suffering from OA compared with osteoporosis are well established.
OA cases have stronger body build and are more obese. There is
overwhelming evidence that OA cases have increased BMD or bone
mineral content at all sites. This increased BMD is related to high
peak bone mass, as shown in mother-daughter and twin studies. With
aging, the bone loss in OA is lower, except when measured near an
affected joint (hand, hip, and knee). The lower degree of bone loss
with aging is explained by lower bone turnover as measured by bone
resorption-formation parameters. OA cases not only have higher
apparent and real bone density, but also wider geometrical measures
of the skeleton, diameters of long bones and trabeculae, both
contributing positively to better strength and fewer fragility fractures.
Not only is bone quantity in OA different but also bone quality,
compared with controls and osteoporosis cases, with increased content
of growth factors such as IGF and TGF beta, factors required for bone
repair. In vitro studies of osteoblasts recruited from OA bone have
different differentiation patterns and phenotypes. These general bone
325
characteristics of OA bone may explain the inverse relationship OA-

osteoporosis and why OA cases have fewer fragility fractures. The
role of bone, in particular subchondral bone, in the pathophysiology,
initiation and progression of OA is not fully elucidated and is still
controversial. In 1970, it was hypothesized that an increased number
of microfractures lead to an increase in subchondral bone stiffness,
which impairs its ability to act as a shock absorber, so that cartilage
suffers more. Although subchondral bone is slightly hypomineralized
because of local increased turnover, the increase in trabecular number
and volume compensates for this, resulting in a stiffer structure. There
is also some experimental evidence that osteoblasts themselves release
factors such as metalloproteinases directly or indirectly from the
matrix, which predispose cartilage to deterioration. Instead, the
osteoblast regenerative capacity of bone in osteoporosis is
compromised compared with OA, as suggested by early cell adhesion
differences. The proposition that drugs which suppress bone turnover
in osteoporosis, such as bisphosphonates, are be beneficial for OA is
speculative. Although bone turnover in the subchondral region of
established OA is increased, the general bone turnover is reduced.
Further reduction of bone turnover, however, may lead to
overmineralized (aged) osteons and loss of bone quality, resulting in
increased fragility (1).
Pro-inflammatory cytokines possess osteoclastogenic or anti-
osteoclastogenic activities. They influence osteoclasts directly or via
the RANK, RANKL and OPG system. Recent evidence suggests that
inflammation may play a role in osteoporosis and OA. The aim of this
study was to determine whether there is a difference between both
groups: first, in the expression of the osteoclastogenic and anti-
osteoclastogenic cytokines, second, in correlation of these cytokines
with BMD and levels of bone turnover markers and third, in
correlation between the expression of these cytokines and osteoclast
specific genes and RANK/RANKL/OPG genes. Human bone samples
from 54 age and sex matched patients with osteoporosis or OA were
collected during hip arthroplasty surgery. The expression of 25 genes
encoding pro-inflammatory cytokines, their receptors, osteoclast
specific genes and RANK/RANKL/OPG genes was measured using
quantitative real-time PCR. Total hip, femoral neck and lumbar spine
BMD and bone turnover markers in blood samples were measured.
The comparison between osteoporosis and OA was assessed. The
results demonstrated a higher expression of IL-6 and IL-1α in
osteoporosis, and IFN-γ in OA (p<0.0005). Negative correlations of
total hip BMD with TNF-α in OA and with RANKL/RANK in
326
osteoporosis were found (p<0.05). Significant correlations with bone

turnover markers were for IL-1α and IFN-γ in OP (rho = 0.608 and -
0.634) and for TNF-α, IL-6 and transforming growth factor-β1 (TGF-
β1) in OA (rho = 0.591, -0.521 and 0.636). Results showed
osteoporosis specific negative correlations (IFN-γ with ITGB3, IFN-
β1 with CTSK, tartrate resistant acid phosphatase (TRAP), CALCR,
RANK, RANKL, IL-1α with CTSK, OPG, IL-17A with CALCR) and
positive (TGF-β1 with CTSK, TRAP, RANK), and OA specific
negative (IL-1α with osteoclast associated immunoglobulin-like
receptor (OSCAR), TNF-α with RANK, RANKL, OPG) and positive
(IL-6 with RANK, RANKL, OPG) correlations. The relationship
between osteoclastogenic and anti-osteoclastogenic pro-inflammatory
cytokines differs in human osteoporosis and OA bone and could
present an important factor for characteristics of osteoporosis and OA
bone phenotypes (2).
Data from the Baltimore Longitudinal Study of Aging were
examined in this longitudinal cohort study to determine (1) whether
persons with radiographic features of OA of the hands and knees had
different rates of bone loss than subjects with normal knee
radiographs, and (2) whether persons with normal knee radiographs
who had higher adjusted levels of BMD were at greater risk of
developing radiographic features of knee OA. Subjects included 298
Caucasian men and 139 Caucasian women aged ≥ 20 years who had
radiographs of the hands and knees read for features of OA and 2 or
more measurements of BMD at the forearm at least 4 years apart; 179
Caucasian men and 110 Caucasian women aged ≥ 20 years who had
longitudinal knee radiographs on average 10 years apart, a subgroup
of whom had baseline measurement of lumbar spine and/or femoral
neck BMD. Women with radiographic OA of the hand had a
significantly greater adjusted rate of bone loss at the radius than
women with normal hand radiographs; no such differences were noted
in men for hand OA. There were insignificant differences in adjusted
rate of bone loss at the radius in men or women by presence of
radiographic knee OA. Higher BMD at the lumbar spine but not at the
femoral neck was associated with an increased risk of developing
incident radiographic knee OA after adjustment for age, gender, and
BMI. These data demonstrate that persons with radiographic OA lose
bone at different rates than those with normal radiographs and that this
relationship varies between the site of OA and the site of measurement
of BMD. They further support a role for higher bone mass in the
development of radiographic knee OA (3).
327
Several epidemiological studies have shown a lower incidence and

prevalence of hip fractures in people with OA and vice versa which
has led to numerous studies examining the association between OA
and osteoporosis more generally. There is an inverse relationship
between these 2 diseases. The evidence for an association with
osteoporosis is stronger for large joint OA than hand OA or primary
generalized OA. A number of possible mechanisms for this
association include genetic factors, common risk factors, role of
subchondral bone in cartilage damage and growth factors. Despite the
inverse relationship seen in some studies, there is currently no
evidence that treatment of one disease can have a detrimental effect on
the other (4).
The main objective of this cross-sectional observational study was
to determine the prevalence of osteoporosis among patients with OA
awaiting total knee arthroplasty or total hip arthroplasty aged between
65 and 80 years at tertiary referral centre in Newcastle upon Tyne,
UK. Lumbar spine, bilateral femoral and forearm BMD measurements
were obtained using DXA. The cohort consisted of 199 patients with a
mean age of 72 years (SD 4), and 113 (57%) were women. The
overall rate of osteoporosis at any site was 23% (46/199) and a further
43% (85/199) of patients would have been classified as osteopenic
according to WHO criteria. Osteoporosis was more commonly
detected in the forearm (14%) than the lumbar spine (8.5%) and
proximal femur of the index side (8.2%). In summary, a significant
proportion of patients with end-stage OA have osteoporosis but this
diagnosis may be missed unless BMD measurements are performed at
sites distant from joints affected by OA (5).
The BMD of the lumbar spine and the proximal femur of 119 OA
patients (83 postmenopausal female patients aged 50-83 years and 35
male patients aged 36-86 years) who subsequently required hip or
knee replacements, but were otherwise healthy, were measured by
DXA, Hologic QDR-2000. Biochemical markers of bone turn over,
i.e., CICP, ICTP, DPD, PTH, estrogen, testosterone, bAP, hydroxy
vitamin D and the normal blood count were measured. There was a
high occurrence of a low BMD among the patients. Of women, 28.9%
were affected by osteoporosis and 52.9% by osteopenia. Of the male
patients, 20% had osteoporosis and 38.8% osteopenia. This is
astonishing high. Age was a significant factor in the degree of BMD.
An association between disuse osteoporosis and degree of BMD in the
OA affected joint could not be proven. The use of the biochemical
markers for an earlier diagnosis or to assess bone metabolism in
osteoporosis and OA was not possible. The hypotheses that OA
328
prevents osteoporosis cannot be supported. The occurrence of

osteoporosis in this study reflects the incidence of osteoporosis in the
average female and the high incidence in the male population;
however, it does not mean that the 2 conditions are mutually
exclusive. The biochemical markers of bone turnover could not
deliver additional information with respect to bone metabolism and an
earlier diagnosis of osteoporosis (6).
Assessment: OA, the most common form of arthritis, is a major

contributor to functional impairment, reduced independence, and the
most frequent cause of disability in older adults. The prevalence of
arthritis in the world is high, with OA being one of the most frequent
disorders in the population.
Commonly involved joints are knees, hands, or generalized joint
involvement take place. Old age, female gender, overweight and
obesity, knee injury, repetitive use of joints, bone density, muscle
weakness, and joint laxity play roles in the development of joint OA,
particularly in the weight-bearing joints.
Clinical symptom of OA include pain, inflammation, stiffness,
cartilage thinning, subchondral sclerosis, the presence of osteophytes,
loss of articular cartilage, osseous deformation, shrinkage of the
capsule, atrophy of muscles, and variable degrees of synovitis,
crepitus, Heberden's nodes, Bouchard's nodes, deformation and
malalignment with deprived function of the joint.
There is an inverse relationship between OA and osteoporosis.
Although the inverse relationship between these frequent diseases is
associated with aging, the topic remains controversial for some and
stimulating for many.
Was King David affected by generalized OA? Let us look again at
the medical record that is the biblical text. The verses ―...my strength
failed..., and my bones are consumed‖ (Psalm 31:11) and ―My bones
wasted away through my anguished roaring all day long‖ (32:3)
indicate the diseases of the bones. Since the disease in generalized OA
mainly affect joints, the diagnosis of OA seems unlikely. Thus, there
is no place to suspect the coexistence of osteoporosis and OA.
References
1. Dequeker J, Aerssens J, Luyten FP. Osteoarthritis and osteoporosis: clinical and
research evidence of inverse relationship. Aging Clin Exp Res. 2003;15(5):426-39.
2. Zupan J, Komadina R, Marc J. The relationship between osteoclastogenic and
anti-osteoclastogenic pro-inflammatory cytokines differs in human osteoporotic and
osteoarthritic bone tissues. J Biomed Sci. 2012 Mar 1;19:28.
329
3. Hochberg MC, Lethbridge-Cejku M, Tobin JD. Bone mineral density and

osteoarthritis: data from the Baltimore Longitudinal Study of Aging. Osteoarthritis
Cartilage. 2004;12 Suppl A:S45-8.
4. Sambrook P, Naganathan V. What is the relationship between osteoarthritis and
osteoporosis? Baillieres Clin Rheumatol. 1997;11(4):695-710.
5. Lingard EA, Mitchell SY, Francis RM, et al. The prevalence of osteoporosis in
patients with severe hip and knee osteoarthritis awaiting joint arthroplasty. Age
Ageing. 2010;39(2):234-9.
6. Drees P, Decking J, Ghezel-Ahmadi V, et al. The common occurrence of
osteoarthritis and osteoporosis and the value of markers of bone turnover. Z
Rheumatol. 2005;64(7):488-98.
RHEUMATOID ARTHRITIS
RA is a chronic inflammatory disease characterized by progressive
damage of synovial-lined joints and variable extra-articular
manifestations. Tendon and bursal involvement are frequent and often
clinically dominant in early disease. RA can affect any joint, but it is
usually found in metacarpophalangeal, proximal interphalangeal and
metatarsophalangeal joints, as well as in the wrists and knee. Articular
and periarticular manifestations include joint swelling and tenderness
to palpation, and morning stiffness and severe motion impairment in
the involved joints. The clinical presentation of RA varies, but an
insidious onset of pain with symmetric swelling of small joints is the
most frequent finding. RA onset is acute or subacute in about 25% of
patients, but its patterns of presentation also include palindromic
onset, monoarticular presentation (both slow and acute forms), extra-
articular synovitis (tenosynovitis, and bursitis), polymyalgic-like
onset, and general symptoms (malaise, fatigue, weight loss, and
fever). The palindromic onset is characterized by recurrent episodes of
oligoarthritis with no residual radiologic damage, while the
polymyalgic-like onset may be clinically indistinguishable from
polymyalgia rheumatica in elderly subjects. RA is characteristically a
symmetric erosive disease. Although any joint, including the
cricoarytenoid joint, can be affected, the distal interphalangeal, the
sacroiliac, and the lumbar spine joints are rarely involved. The clinical
features of synovitis are particularly apparent in the morning. Morning
stiffness in and around the joints, lasting at least 1 hour before
maximal improvement is a typical sign of RA. It is a subjective sign
and the patient needs to be carefully informed as to the difference
between pain and stiffness. Morning stiffness duration is related to
disease activity. Hand involvement is the typical early manifestation
330
of RA. Synovitis involving the metacarpophalangeal, proximal

interphalangeal and wrist joints causes a characteristic tender swelling
on palpation with early severe motion impairment and no radiologic
evidence of bone damage. Fatigue, fever, weight loss, and malaise are
frequent clinical signs, which can be associated with variable
manifestations of extra-articular involvement such as rheumatoid
nodules, vasculitis, hematologic abnormalities, Felty's syndrome, and
visceral involvement. Although there is no laboratory test to exclude
or prove the diagnosis of RA, several laboratory abnormalities can be
detected. Abnormal values of the tests for evaluation of systemic
inflammation are the most typical humoral features of RA. These
include ESR, acute phase proteins and plasma viscosity. ESR and
CRP provide the best information about the acute phase response. The
CRP is strictly correlated with clinical assessment and radiographic
changes. Plain film radiography is the standard investigation to assess
the extent of anatomic changes in RA patients. The radiographic
features of the hand joints in early disease are characterized by soft
tissue swelling and mild juxtaarticular osteoporosis. In the past 10
years, US has gained acceptance for studying joint, tendon and bursal
involvement in RA. The follow-up of these patients show synovial
thickening even within finger joints. Other imaging techniques, such
as MR, CT and scintigraphy may provide useful information about
both the features and the extent for anatomic damage in selected RA
patients. The natural history of the disease is poorly defined; its
clinical course is fluctuating and the prognosis unpredictable (1).
Rheumatoid arthritis
Pain is the predominant problem for people with RA. Pain in RA is

distressing and adversely affects disability and psychosocial
outcomes. RA pain is due to joint inflammation and augmented by
central sensitization and structural joint damage. Noninflammatory
331
pain mechanisms may confound the assessment of disease activity in

RA and treatment should aim to both suppress inflammatory disease
and relieve pain symptoms. Effective treatment stratification requires
a full assessment of pain mechanisms by clinical history and
examination, as well as objective assessment of synovitis and joint
damage. Biologic therapies and joint replacement surgery have major
impacts on RA pain, but may only be available for those with most
severe or advanced disease. Holistic approaches to pain management
are indicated, including pharmacologic analgesia where RCTs offer
evidence of efficacy (2).
Rheumatoid arthritis
Bone is a target for many inflammatory rheumatic diseases, such as

RA and AS. The generalized effect of inflammation on bone results in
a decreased quality of bone and is associated with an increased risk of
fractures and deformities, both in RA and AS. RA is characterized by
periarticular osteopenia, systemic osteoporosis and bone erosions.
Periarticular osteopenia and bone erosions are mainly correlated with
disease activity. Unlike postmenopausal osteoporosis, osteoporosis in
RA is characterized by marked loss of bone in the hip and the radius,
while the axial bone is relatively preserved. Several cross-sectional
studies documented a lower BMD in patients with RA, with a two-
fold increase in osteoporosis compared to age- and sex-matched
controls and relates to an increased fracture risk. Several factors
contribute to the increased risk: older age, little exercise, long-term
use of corticosteroids, and high disability index (3).
332
Osteoporosis in rheumatoid arthritis
RA, a bone-destructive disease, is a serious risk factor for the

development of osteoporosis, which is defined by a loss in bone
quality and an increased fracture risk. The proinflammatory cytokines
TNFα, IL-6 and IL-17, in particular, contribute to local and systemic
bone loss in RA. While effectively reducing inflammation,
glucocorticoids add to the fracture risk. Therefore, an adequate supply
of calcium and vitamin D is essential. For many patients with RA,
bone density measurements are recommended (4).
In RA, periarticular bone loss, bone erosions, and systemic
osteoporosis with an increased risk of fractures are observed.
Determinants of fractures are underlying conditions (RA has a female
preponderance and an increased prevalence with age), severity of the
disease, and use of glucocorticoids. However, bone loss can occur
even in glucocorticoid-naive patients. Prospective data show that the
optimal control of inflammation in RA is associated with decrease in
structural damage and bone loss. RA illustrates the role of
inflammation on bone resorption (5).
This study's objective was to investigate whether DXR-BMD loss
early in the course of the disease predicts the development of joint
damage in RA patients followed for up to 20 years. A total of 183
patients (115 women and 68 men) with early RA (mean disease
duration, 11 months) included from 1985 to 1989 were followed
prospectively (the Lund early RA cohort). Clinical and functional
measures were assessed yearly. Joint damage was evaluated according
to the Larsen score on radiographs of the hands and feet obtained in
years 0 to 5 and years 10, 15 and 20. These radiographs were
digitized, and BMD of the second to fourth metacarpal bones was
evaluated by DXR. Early DXR-BMD change rate (that is, bone loss)
per year calculated from the first 2 radiographs obtained on average 9
months apart (SD ± 4.8) were available for 135 patients. Mean values
of the right and left hand were used. Mean early DXR-BMD loss
during the first year was -0.023 g/cm2 (SD ± 0.025). Patients with
333
marked bone loss, that is, early DXR-BMD loss above the median for
the group, had significantly worse progression of joint damage at all
examinations during the 20-year period. In conclusion, early DXR-
BMD progression rate predicts the development of joint damage
evaluated according to Larsen score at year 1 and for up to 20 years in
RA patients (6).
Assessment: RA is a chronic inflammatory disease characterized

by damage of synovial-lined joints and variable extra-articular
manifestations. RA can affect any joint, but it is usually found in
metacarpophalangeal, proximal interphalangeal and
metatarsophalangeal joints, as well as in the wrists and knee. Articular
and periarticular manifestations include joint swelling and tenderness
to palpation, and morning stiffness and severe motion impairment in
the involved joints. Fatigue, fever, weight loss, and malaise are
frequent clinical signs associated with variable manifestations of
extra-articular involvement such as rheumatoid nodules, vasculitis,
hematologic abnormalities, Felty's syndrome, visceral involvement,
periarticular osteopenia, bone erosions, and systemic osteoporosis.
The clinical presentation of RA varies, but an insidious onset of
pain with symmetric swelling of small joints is the most frequent
finding. RA onset is acute or subacute in about 25% of patients, but its
patterns of presentation include palindromic onset, monoarticular
presentation (both slow and acute forms), extra-articular synovitis
(tenosynovitis, and bursitis), polymyalgic-like onset and general
symptoms (malaise, fatigue, weight loss, and fever). Tendon and
bursal involvement are frequent and often clinically dominant in early
disease. Pain that is the predominant problem for people with RA is
distressing adversely affecting disability and psychosocial outcomes.
Abnormal values of the tests include ESR, acute phase proteins and
plasma viscosity with ESR and CRP providing the best information
about the acute phase response. The CRP is correlated with clinical
assessment and radiographic changes. Plain film radiography is the
standard investigation to assess the extent of anatomic changes in RA
patients. In early disease, soft tissue swelling and mild juxtaarticular
osteoporosis characterize the radiographic features of the hand joints.
Was RA responsible for severe bone pain King David suffered
from? Were periarticular osteopenia, systemic osteoporosis or bone
erosion responsible for the bone pain? Although osteoporosis and
subsequent pain can be related to RA, in the absence of joint
involvement accompanied by constitutional symptoms this diagnosis
seems unlikely.
334
The King suffered from severe bone pain ―My bones wasted away
through my anguished roaring all day long‖ (32:3). RA affects mainly
joints, not bones. If the diagnosis of RA is accepted, however, there is
still no explanation for the disease which "..consumed.." the King's
bones.
References
1. Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of
rheumatoid arthritis. Eur J Radiol. 1998;27 Suppl 1:S18-24.
2. Walsh DA, McWilliams DF. Pain in Rheumatoid Arthritis. Curr Pain
Headache Rep. 2012;16(6):509-17.
3. Vosse D, de Vlam K. Osteoporosis in rheumatoid arthritis and ankylosing
spondylitis. Clin Exp Rheumatol. 2009;27(4 Suppl 55):S62-7.
4. Rauner M, Hofbauer LC, Aringer M. Local and systemic bone effects of
rheumatoid arthritis. Z Rheumatol. 2012;71(10):869-73.
5. Roux C. Osteoporosis in inflammatory joint diseases. Osteoporos Int.
2011;22(2):421-33.
6. Kapetanovic MC, Lindqvist E, Algulin J, et al. Early changes in bone mineral
density measured by digital X-ray radiogrammetry predict up to 20 years radiological
outcome in rheumatoid arthritis. Arthritis Res Ther. 2011;13(1):R31.
MALNUTRITION/UNDERNUTRITION
The prevalence of malnutrition, particularly under nutrition,
increases with age (1). Undernutrition is a global problem among
older people and is considered as inadequate nutritional status,
characterized by insufficient food intake and weight loss (2).
Deficiencies in micronutrients such as calcium and vitamin D can
accelerate age-dependent bone loss (3), while vitamin K can
accelerate bone fracture. A deficiency in macronutrient (protein)
leads to lower femoral neck mineral density (1). Several factors can
cause weight loss and lead to a state of malnutrition in elderly persons.
Most of them act by reducing spontaneous food intake, although
malabsorption and increased metabolism are implicated in some
situations (4). Reduction in food intake occurs physiologically with
aging (5), and this can be aggravated by various physical and mental
disorders, poor appetite due to consumption of drugs, loss of taste and
smell, inadequate access to foods due to poverty or to impairment of
cognitive or physical functions, and chronic alcohol abuse (4,6).
Osteoporosis affects 50% of women aged > 80 years. Prevalence of
energizing and protein malnutrition is high as for institutional elderly
people as for community dwelling elderly people. Malnutrition,
335
physical inactivity and many etiological factors lead to tissular losses

especially on protein compartment, named sarcopenia. Among the
common etiological factors, some cytokines have an effect on
proteolysis and bone restructuring, interfering with osteoclast
metabolism. Inflammation or stress, mechanisms which product
cytokines, are responsible for unfavorable bone restructuring and for a
loss of protein mass, deteriorating the muscular functional prognostic.
Articles on Medline(®) between 1980 and 2010 about relations
between protein compartment, malnutrition and bone density were
searched. Several studies in literature suggest that increase in protein
intake in daily caloric needs could have a positive effect on BMD and
functional performances (in primary prevention as in secondary
prevention). Therefore, primary and secondary preventive measures
must comprise an increase protein intake and a sufficient physical
activity (7).
A hidden clue to diagnose nutritional deficiencies
The literature on the MNA to Spring 2006, MEDLINE, Web of

Science and Scopus, J Nutr Health Aging, Clin Nutr, Eur J Clin Nutr
and free online available publications was reviewed. The MNA was
validated against 2 principal criteria, clinical status and
comprehensive nutrition assessment using principal component and
discriminant analysis. The MNA-SF was developed and validated to
allow a 2-step screening process. The MNA and MNA-SF are
sensitive, specific, and accurate in identifying nutrition risk. The
prevalence of malnutrition in community-dwelling elderly (21 studies,
n=14149 elderly) was 2 +/- 0.1% (mean +/- SE, range 0-8%) and risk
of malnutrition was 24 +/- 0.4% (range 8-76%). A similar pattern was
seen in out-patient and home care elderly (25 studies, n=3119 elderly)
with prevalence of undernutrition 9 +/- 0.5% (mean +/- SE, range 0-
30%) and risk of malnutrition 45 +/- 0.9% (range 8-65%). A high
336
prevalence of undernutrition has been reported in hospitalized and

institutionalized elderly patients: prevalence of malnutrition was 23
+/- 0.5% (mean +/- SE, range 1- 74%) in hospitals (35 studies,
n=8596) and 21 +/- 0.5% (mean +/- SE, range 5-71%) in institutions
(32 studies, n=6821 elderly). An even higher prevalence of risk for
malnutrition was observed in the same populations, with 46 +/- 0.5%
(range 8-63%) and 51 +/- 0.6% (range 27-70%), respectively. In
cognitively impaired elderly subjects (10 studies, n=2051 elderly
subjects), prevalence of malnutrition was 15 +/- 0.8% (mean +/- SE,
range 0-62%), and 44 +/- 1.1% (range 19-87%) of risk for
malnutrition. In hospital settings, a low MNA score was associated
with an increase in mortality, prolonged length of stay and greater
likelihood of discharge to nursing homes. Malnutrition was associated
with functional and cognitive impairment and difficulties eating. The
MNA(R) detected risk of malnutrition before severe change in weight
or serum proteins occurs. In conclusion, timely intervention can stop
weight loss in elderly at risk of malnutrition or undernourished and is
associated with improvements in MNA scores. The MNA is a
screening and assessment tool with a reliable scale and clearly defined
thresholds, usable by health care professionals (8).
The main objective of this study was to describe the nutritional
status of older persons living at home, to investigate factors of
importance for nutritional status, and to describe possible relationships
between nutritional status and HRQL. In this longitudinal study, data
from older persons born between 1916 and 1925 were collected at 3
occasions separated by 4-year intervals in the participants' own homes.
A randomized selection from the Swedish Twin Register included 258
persons, all still living at home. Nutritional status was assessed using
the MNA, cognitive function using the MMSE and HRQL using the
Nottingham Health Profile. Questions covering physical,
psychological and social factors that may have an impact on
nutritional status were posed. Approximately 17% of participants
were assessed as being at risk for malnutrition or as being
malnourished. Cognitive impairment, reduced perceived health, recent
hospital stay and receiving meals-on-wheels were factors associated
risk for malnutrition. Being at risk for malnutrition is common in older
persons living at home and many factors related to frailty increase in
later life (9).
The main aim of this study was to describe the prevalence of being
at risk of undernutrition among a group of older home-dwelling
individuals, and to relate the results to reported self-care ability, sense
of coherence, perceived health and other health-related issues. A
337
cross-sectional design was applied. A questionnaire with instruments

for nutritional screening, self-care ability, and sense of coherence, and
health-related questions was sent to a randomized sample of 450
persons (aged > 65 years) in southern Norway. Of 158 (35.1%)
participants, 19% were at medium risk of undernutrition and 1.3% at
high risk. The nutritional at-risk group had lower self-care ability and
weaker sense of coherence. Living alone, receiving help regularly to
manage daily life, not being active and perceived helplessness
emerged as predictors for being at risk for undernutrition (2).
The aim of this study was to evaluate prevalence of malnutrition
and to determine factors independently associated with malnutrition.
A cross-sectional, multi-centre study was conducted in 23 nursing
homes in Flanders, Belgium. The nutritional status was assessed using
the MNA. The study included 1188 elderly residents; 38.7% were at
risk for malnutrition and 19.4% were malnourished. The presence of a
wound/pressure ulcer, a recent hospitalization (< 3 months ago), being
involved in a tailored nutritional intervention, and suffering from a
lower cognitive state were significantly associated with malnutrition.
Receiving additional meals provided by family members was
negatively associated with malnutrition. In conclusion, malnutrition is
a prevalent problem in nursing homes in Flanders (10).
In this study, nutritional status, bone mineral mass and its
association with body composition were investigated in underweight
and normal weight elderly subjects. The hypothesis that malnutrition
in elderly is associated with a higher risk of osteoporosis was tested.
The participants were 111 elderly subjects divided into 2 groups
according to BMI: 51 patients were underweight (BMI < 22 kg/m2)
while in 60 subjects BMI ranged from 22 to 30 kg/m2. In all patients,
anthropometric parameters and blood indices of malnutrition and of
bone turnover were measured. Fat-free soft mass, fat mass, bone
mineral content and BMD 'total body' and at the hip were obtained by
DXA. Dietary intake was evaluated with the diet history method,
while resting energy expenditure was measured by indirect
calorimetry. Underweight subjects had other signs of malnutrition,
such as low visceral proteins, sarcopenia, and an inadequate energy
intake. They showed a significant reduction of bone mineral content
and BMD compared with normal subjects. In men with BMI < 22
kg/m2, T-score was below -2.5 (-3 at femoral neck and -2.7 at total
hip) while men in the control group had normal bone mineral
parameters. T-score at different sites was lower in underweight
women than in underweight men, always showing values under -3.5,
with clear osteoporosis and a high fracture risk. In healthy women, the
338
T-score values indicated the presence of mild osteoporosis. In

underweight subjects, low levels of albumin (< 35 g/l) were associated
with higher femoral bone loss. Using a partial correlation model, bone
mineral content, adjusted for age, bone area, knee height and albumin
showed a significant association with fat mass in women (r=0.48,
p<0.01) and with fat-free soft mass in men (r=0.48, p<0.05). Albumin,
when adjusted for other variables, was significantly correlated
(r=0.52, p<0.05) with femoral neck bone mineral content only in
women. In conclusion, the underweight state in the elderly is
associated with malnutrition and osteoporosis; other factors occurring
in malnutrition, besides body composition changes, such as protein
deficiency, could be involved in the association between underweight
and osteoporosis. Bone mineral status seems to be related to fat-free
soft mass tissue in men while in women it is much more closely
associated with total body fat (11).
The aims of this study were to investigate the relationship between
sarcopenia, dietary intake, nutritional indices and hip BMD in the
elderly, and to estimate the risk of low BMD due to specific
independent predictor thresholds. BMI, serum albumin, energy and
protein intake were studied in 352 elderly outpatients (216 women
aged 73.5+/-5.3 years and 136 men aged 73.9+/-5.6 years). BMD at
different hip sites and appendicular skeletal muscle mass were
assessed by DXA. The prevalence of osteoporosis was 13% in men
and 45% in women, while the prevalence of sarcopenia (50%) and
hypoalbuminemia (5%) were similar in both genders. BMI, albumin
and appendicular skeletal muscle mass were associated with BMD in
both genders: so was protein intake, but only in men. By multiple
regression analysis, the variables that retained their independent
explanatory role on total hip BMD were BMI and protein intake in
men, and BMI and albumin in women. By logistic regression analysis,
men risked having a low BMD with a BMI < 22 (OR=12) and a
protein intake < 65.7 g/day (OR=3.7). Women carried some risk in the
BMI 25-30 class (OR=5), and a much greater risk in the BMI < 22
class (OR=26). Albumin < 40 g/l emerged as an independent risk
factor (OR=2.6). BMI in both genders, albumin in women and protein
intake in men have an independent effect on BMD. BMI values < 22
are normal for younger adults but carry a higher risk of osteoporosis in
the elderly, particularly in women. Age-related sarcopenia does not
seem to be involved in bone mass loss (12).
This study was carried out at the Soroka University Medical Center
in the south of Israel. From September 2003 through December 2004,
all patients ≥ 65 years of age admitted to any of the internal medicine
339
departments, were screened within 72 hours of admission to determine

nutritional status using the short version of the MNA-SF. Patients at
nutritional risk were entered the study and were divided into
malnourished or 'at risk' based on the full version of the MNA. Elderly
patients (n=259, 43.6% men), participated in the study; 18.5% were
identified as malnourished and 81.5% were at risk for malnutrition.
The malnourished group was less educated, had a higher depression
score and lower cognitive and physical functioning. Higher prevalence
of chewing problems, nausea, and vomiting was detected among
malnourished patients. There was no difference between the groups in
health status indicators except for subjective health evaluation which
was poorer among the malnourished group. Lower dietary score
indicating lower intake of vegetables fruits and fluid, poor appetite
and difficulties in eating distinguished between malnourished and at-
risk populations with the highest sensitivity and specificity as
compared with the anthropometric, global, and self-assessment of
nutritional status parts of the MNA. In a multivariate analysis, lower
cognitive function, education < 12 years and chewing problems were
risk factors for malnutrition. This study indicates that low food
consumption as well as poor appetite and chewing problems are
associated with the development of malnutrition (13).
Assessment: undernutrition is a global problem among older

people with the prevalence of malnutrition, particularly
undernutrition, increasing with age. Undernutrition can be considered
as inadequate nutritional status, characterized by insufficient food
intake and weight loss.
Deficiencies in calcium and vitamin D can accelerate age-
dependent bone loss and vitamin K deficiency can accelerate bone
fracture, while macronutrient (protein) deficiency leads to lower
femoral neck mineral density. Reduction in food intake occurs
physiologically with aging, aggravated by various physical and mental
disorders, poor appetite due to consumption of drugs, loss of taste and
smell, inadequate access to foods due to poverty, impairment of
cognitive or physical functions, chronic alcohol abuse, reduced
perceived health, recent hospital stay, receiving meals-on-wheels,
living alone, receiving help regularly to manage daily life, not being
active, perceived helplessness, the presence of a wound/pressure ulcer,
a recent hospitalization (< 3 months ago), poor appetite and chewing
problems.
Did the King suffer from malnutrition or under nutrition? A
passage in Psalm 102:4 ―..I (the King) forget to eat my bread‖ tells us
340
about lack of food intake. The condition is compatible with anorexia

defined as lack or loss of appetite, resulting in the inability to eat (14).
A subsequent passage ―My knees are weak through fasting; and my
flesh failed of fatness‖ (Psalm 109:24) shows that David‘s anorexia
led to fasting and consequently to unintentional weight loss. The
weight loss was so extreme that ―....my bones (the King‘s) cleave to
my skin‖ (Psalm 102:6). The condition is compatible with cachexia.
The word "cachexia" comes from the Greek words "kakos" and
"hexis", meaning bad condition (15). Cachexia indicates general ill
health and malnutrition, marked by weakness and emaciation (14).
Other risk factors for malnutrition in King David include:
perceived helplessness ―Be not far from me; for trouble is near; for
there is no help ― (Psalm 6:12), ―I am helpless‖ (25:16) and ―I am
(31:13) and pressure ulcers ―My necrotic ulcers stink‖ (Psalm 38:6).
We see that that the intake of food was reduced in King David.
Although malnutrition or under nutrition are associated with
osteoporosis and subsequent bone fractures, this does not entirely
explain what kind of the disease "..consumed.." the King's bones (16).
References
1. Bonjour J-P, Schurch M-A, Rizzoli R. Nutritional aspects of hip fractures.
Bone. 1996;18:139S-44S.
2. Tomstad ST, Söderhamn U, Espnes GA, Söderhamn O. Living alone, receiving
help, helplessness, and inactivity are strongly related to risk of undernutrition among
older home-dwelling people. .Int J Gen Med. 2012;5: 231-40.
3. Riggs BL, Melton LJ. Medical progress. Involutional osteoporosis. N Engl J
Med. 1986;314:1676-86.
4. Lipschitz DA. Nutritional assessment in interventions in the elderly. In:
Buerhardt P, Heaney RP (eds.). Nutritional Aspects of Osteoporosis 94. Challenges
of Modern Medicine. Vol. Rome: Ares-Seromo Symposia Publications. 1995, pp.
177-91.
5. MacIntosh C, Morley JE, Chapman IM. The anorexia of aging. Nutrition.
2000;16:983-95.
6. Munro HN, Suter PM, Russell RM. Nutritional requirements of the elderly.
Ann Rev Nut. 1987;7:23-49.
7. Riaudel T, Guillot P, De Decker L, et al. Nutrition and osteoporosis in elderly.
Geriatr Psychol Neuropsychiatr Vieil. 2011;9(4):399-408.
8. Guigoz Y. The Mini Nutritional Assessment (MNA) review of the literature -
What does it tell us? J Nutr Health Aging. 2006;10(6):466-85; discussion 485-7.
9. Johansson L, Sidenvall B, Malmberg B, Christensson L Who will become
malnourished? A prospective study of factors associated with malnutrition in older
persons living at home. J Nutr Health Aging. 2009; 13(10):855-61.
10. Verbrugghe M, Beeckman D, Van Hecke A, et al. Malnutrition and associated
factors in nursing home residents: A cross-sectional, multi-centre study. Clin Nutr.
2012 Oct 3. pii: S0261-5614(12)00212-9.
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11. Coin A, Sergi G, Benincà P, et al. Bone mineral density and body composition
in underweight and normal elderly subjects. Osteoporos Int. 2000;11(12):1043-50.
12. Coin A, Perissinotto E, Enzi G, et al. Predictors of low bone mineral density in
the elderly: the role of dietary intake, nutritional status and sarcopenia. Eur J Clin
Nutr. 2008;62(6):802-9.
13. Feldblum I, German L, Castel H, et al. Characteristics of undernourished older
medical patients and the identification of predictors for undernutrition status. Nutr J.
2007 Nov 2;6:37.
14. Hamerman D. Molecular-based therapeutic approaches in treatment of
anorexia of aging and cancer cachexia. J Gerontol Med Sci. 2002;57A(8):M511-8.
15. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst. 1997;89:1763-73.
MEDICATIONS
Drug-induced osteoporosis is common and has a significant impact
on the prognosis of patients suffering from chronic debilitating
diseases. Glucocorticoid-induced osteoporosis is the leading cause of
medication-induced osteoporosis (1-4). The incidence of new fractures
after one year of glucocorticoid therapy can be high as 17%, and
observational studies suggest that fractures, which are often
asymptomatic, occur in 30-50% of chronic glucocorticoid-treated
patients (5).
Steroid induced osteoporosis in a 29-year-old patient with longstanding

severe inflammatory bowel disease.
Osteoporosis with fractures is observed in women treated with

aromatase inhibitors for breast cancer, in men receiving anti-androgen
therapy for prostate cancer, in postmenopausal women treated with
high doses of thyroxine, and in men and women treated with
342
thiazolinediones for type 2 diabetes mellitus. Bone loss with fractures

also occurs in patients treated with drugs targeting the immune
system, such as calcineurin inhibitors, antiretroviral drugs,
anticonvulsants, loop diuretics, heparin, oral anticoagulants, and
proton pump inhibitors (6).
Other medications include AEDs (4,7,8), thyroid hormone which is
used to suppress TSH because of thyroid cancer, goiters, or nodules
(9), neuroleptics (10), gonadotropin-releasing hormone agonists, and
SSRI (4). The risk for skeletal fractures in patients with epilepsy is 2
to 6 times greater than in the general population. Fractures may be
caused by seizures themselves or by falls, with or without seizures.
Side effects of AEDs, such as ataxia, and coexisting neurological
deficits contribute to the risk for falls. The effects of older AEDs on
BMD probably increase the risk for fractures associated with seizures
and falls. Preventive measures include optimal control of seizures and
supplementation with calcium and vitamin D (11).
Anti-epileptic drugs are a risk factor for osteoporosis.
Assessment: drug-induced osteoporosis is common and has a

significant effect on the prognosis of patients suffering from chronic
debilitating diseases. Was some drug related to osteoporosis
responsible for the King's severe bone pain? In the absence of
appropriate anamnesis, it seems unlikely that the King took any of the
above-mentioned medications.
References
1. De Nijs RN. Glucocorticoid-induced osteoporosis: a review on
pathophysiology and treatemtn options. Minerva Med. 2008;99:23-43.
2. Devogelaer JP, Goemaere S, Boonen S, et al. Evidence-based guidelines for
the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus
document of the Belgian Bone Club. Osteoporos Int. 2006;17:8-19.
3. Briot K. Drug-induced osteoporosis. Rev Prat. 2012;62(2):187-92.
4. Briot K, Roux C. Drug-induced osteoporosis: beyond glucocorticoids. Curr
Rheumatol Rep. 2008;10(2):102-9.
343
5. Civitelli R, Ziambaras K. Epidemiology of glucocorticoid-induced

osteoporosis. J Endocrinol Invest. 2008;31(7 Supp):2-6.
6. Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms
and clinical implications. Am J Med. 2010;123(10):877-84.
7. Ensrud KE, Walczak TS, Blackwell TL, et al. Antiepileptic drug use and rates
of hip bone loss in older men: a prospective study. Neurology. 2008;71:723-30.
8. Pack AM, Walczak TS. Bone health in women with epilepsy: clinical features
and potential mechanisms. Int Rev Neurobiol. 2008;83:305-28.
9. Greenspan SL, Greespan FS. The effect of thyroid hormone on skeletal
integrity. Ann Intern Med. 1999;130:750-8.
10. Vestergaard P. Skeletal effects of central nervous system, active drugs:
anxiolytics, sedative, antidepressants, lithium and neuroleptics. Curr Drug Saf.
2008;3:185-9.
11. Mattson RH, Gidal BE. Fractures, epilepsy, and antiepileptic drugs. Epilepsy
Behav. 2004;5 Suppl 2:S36-40.
IDIOPATHIC OSTEOPOROSIS
Idiopathic osteoporosis refers to the development of osteopenia and
fractures with minimal or no trauma in otherwise young, healthy
individuals who are not postmenopausal or have other, identifiable
secondary causes of osteoporosis. It is a relatively rare disorder, with
an incidence of 0.4 cases per 100,000 person-years. It appears to affect
both sexes equally and results primarily in the development of
trabecular bone fractures such as vertebral compression fractures and
Colles' fractures, although hip fractures are also seen. The disease may
be temporally related to pregnancy and/or lactation in some patients,
although it is unclear whether pregnancy plays a pathophysiological
role or, more likely, simply leads to the clinical presentation of the
disease in individuals who are already affected. Various
pathophysiological abnormalities have been described in these
patients, including hypercalciuria, abnormalities in vitamin D
metabolism, and in the production of IGF I and IL1. Findings on bone
biopsy have been variable, with some patients having evidence of a
defect in osteoblast function, whereas others having evidence for
increased bone resorption. No specific therapy has been proven to be
effective in these patients. However, an individualized approach based
on an assessment of bone turnover may be reasonable and may
decrease the bone loss and subsequent fracture risk (1).
TGF-beta1 is a growth factor in human bone, which is produced by
osteoblasts, has various effects on osteoclasts and osteoblasts. The aim
of this study was to determine serum TGF-beta1 levels in male
344
patients with idiopathic osteoporosis. Twenty-five males with

idiopathic osteoporosis and 25 age-matched controls were studied.
Osteoporosis was defined by a T score of < -2.5 in the lumbar spine or
at the femoral neck. Levels of TGF-beta1, estradiol, total and
bioactive testosterone were measured. Various markers of bone
remodeling were also measured. TGF-beta1 was significantly lower in
osteoporotic patients than in controls (3.706 ng/dl, 25 - 75 percentiles:
2.81 - 5.33 vs. 8.659 ng/dl, 25 - 75 percentiles: 4.837 - 11.835;
p=0.000). Moreover, TGF-beta1 levels were positively correlated with
BMD at the femoral neck (r=0.439, p=0.028), and at the lumbar spine
(r=0.41, p=0.042). No correlation was found between serum estradiol,
testosterone and TGF-beta1 levels. The results of this study indicate
that serum TGF-beta1 levels are depressed in osteoporotic men and
are positively correlated with hip and spine BMD. TGF-beta1 may
play a role in the pathogenesis of IMO (2).
Idiopathic male osteoporosis
The main objective of this study was to determine biochemical,

radiological and micro-architectural bone factors related to fragility
fractures in IMO patients. IMO is a rare disorder characterized by low
areal BMD (Z-score < -2) occurring in men after excluding secondary
345
causes of low BMD. A case-control study in 31 males with IMO with

fragility fracture that had occurred after the age of 40 years and 37
males with IMO without fracture was conducted. IMO group to 40
age-matched disease-free men was compared. Low areal BMD and
bone micro-architectural indices at distal radius and tibia sites with a
high resolution peripheral quantitative CT using standard and
extended cortical analysis were measured. Urine and blood samples
were collected in order to determine the levels of bone-turnover
markers and the potential determinant of bone fragility. Compared to
their controls, IMO patients showed marked disturbance of their
micro-architectural parameters at tibia and radius affecting both
trabecular and cortical parameters. IMO with fracture subjects were
significantly older than subjects without fracture (58 ± 8 vs. 53 ± 9
yrs, p=0.01). BMD Z-score at the total-hip was significantly lower in
IMO subjects with fracture than without fracture (-1.3 ± 0.5 vs. -0.9 ±
0.8g/cm(2), p=0.01). After adjustment, trabecular micro-architectural
parameters, biochemical markers and hormonal parameters were
similar in the 2 groups. At distal tibia, cortical v-BMD was
significantly lower in IMO with fracture patients than without fracture
(799 ± 73 vs. 858 ± 60mg/cm(3), p=0.03), while cortical thickness
was not different. These results show that patients with IMO display a
marked disturbance of trabecular and cortical bone micro-architecture,
and that age and low cortical density are determinants of the fracture
occurrence (3).
In men, vertebral fractures are poorly associated with bone density,
and both cortical and trabecular micro-architectural changes could
contribute to bone fragility. A cross sectional study using iliac crest
biopsies to investigate the trabecular and cortical bone structure in
men with or without vertebral fractures was conducted. Bone biopsies
(n=93) were from IMO (defined as a T-score < -2.5), between 40 and
70 years of age. Patients were divided into 2 groups based on the
presence (n=46) or absence (n=47) of prevalent vertebral fracture.
Micro-architectural indices in trabecular and cortical bone by
histomorphometry at the iliac crest were measured. Patients with
vertebral fracture had lower trabecular bone volume (BV/TV: 12.4 +/-
3.8 vs. 14.7 +/- 3.1 % (m+/-SD)), p<0.01), higher trabecular
separation (Tb.Sp: 871 +/- 279 vs. 719 +/- 151 microm, p<0.01), and
higher marrow star volume (V*(m.space): 1.617 +/- 1.257 vs. 0.945
+/- 0.466 mm(3), p<0.01). Cortical thickness (Ct.Th) was the same in
patients with or without vertebral fracture, whereas cortical porosity
(Ct.Po) was higher in patients with vertebral fracture (6.5 +/- 2.6 vs.
5.0 +/- 2.0 %, p<0.01), because their Haversian canals had higher
346
mean areas (8291 +/- 4135 vs. 5438 +/- 2809 microm(2), p<0.001).
There was no correlation between any trabecular and cortical micro-
architectural parameters. Using a logistic regression model, the
vertebral fracture as a function of the V*(m.space) and Ct.Po, adjusted
for age was evaluated. The OR of having a vertebral fracture was 3.89
(95% CI 1.19 - 12.7, p=0.02) for the third tertile of V*(m.space)
(adjusted on age and Ct.Po), and 4.07 (95% CI 1.25 - 13.3, p=0.02) for
the third tertile of Ct.Po (adjusted on age and V*(m.space)). These
data show that both trabecular and cortical bone microarchitecture
contribute independently to vertebral fractures in IMO. In contrast to
data reported in women, in men it is cortical porosity, and not cortical
width, that is associated with vertebral fractures. Thus, the cortical
deficit is different in men and in women with fragility fractures (4).
Idiopathic osteoporosis of the talus.
In the present study fasting amino acid profiles in plasma and

erythrocytes were determined in 22 IMO patients and in 20 age-
matched healthy men and associated with BMD, bone
histomorphometry and hormones. The osteoporotic patients had
normal plasma essential amino acids but increased non-essential
amino acids (p=0.001), particularly glutamine and glycine. The ratio
essential/non-essential amino acids, an index of protein nutritional
status, was decreased in the 22 IMO patients (0.59 (0.04) μmol/l,
mean (SD)), compared to controls (0.66 (0.05), p=0.001). In the 22
IMO patients, the ratio essential/non-essential plasma amino acids
(r=0.60, p=0.003) was positively correlated with lumbar spine BMD.
The erythrocyte amino acids represent a large proportion of the free
amino acids in blood. A novel finding was the lower levels of
erythrocyte tryptophan in IMO (12 (2) μmol/l) compared to controls
(16 (3), p=0.001) and decreased erythrocyte/plasma ratio (0.28 (0.07)
vs. 0.33, (0.06), p<0.01), suggesting an altered amino acid transport of
tryptophan between plasma and erythrocytes. In the combined group
of IMO and control men (n=42), BMD was positively correlated with
erythrocyte tryptophan in both the lumbar spine (r=0.45, p=0.003) and
347
femoral neck (r=0.56, p<0.001). The bone histomorphometric

variables wall thickness, trabecular thickness and mineral apposition
rate were all positively associated with erythrocyte tryptophan levels
in the IMO patients. In the combined group of IMO and controls, a
multiple regression analysis showed that erythrocyte tryptophan could
explain 22% of the variation of lumbar spine and 30% of the variation
in femoral neck BMD. In conclusion, men with IMO have changes in
free amino acid profiles which indicate their altered utilization. The
correlations between tryptophan and BMD and bone
histomorphometry suggest a link between tryptophan and osteoblast
function which is important for bone health (5).
Assessment: idiopathic osteoporosis refers to the development of

osteopenia and fractures with minimal or no trauma in otherwise
young, healthy individuals who are not postmenopausal or have other,
identifiable secondary causes of osteoporosis. It is a relatively rare
disorder, with an incidence of 0.4 cases per 100,000 person-years.
Idiopathic osteoporosis affects both sexes equally resulting primarily
in the development of trabecular bone fractures such as vertebral
compression fractures, Colles' and hip fractures.
TGF-beta1 may play a role in the pathogenesis of IMO. Men with
IMO have changes in free amino acid profiles, which indicate their
altered utilization, marked disturbance of trabecular and cortical bone
micro-architecture, while age and low cortical density are
determinants of the fracture occurrence. Both trabecular and cortical
bone microarchitecture contribute independently to vertebral fractures
in men with idiopathic osteoporosis.
Did IMO affect the old King David? It can be assumed that IMO
may have affected King David‘s bones. However, this does not
entirely explain what kind of disease ―...consumed...‖ his bones.‖
References
1. Heshmati HM, Khosla S. Idiopathic osteoporosis: a heterogeneous entity. Ann
Med Interne (Paris). 1998;149(2):77-81.
2. Akinci B, Bayraktar F, Saklamaz A, et al. Low transforming growth factor-
beta1 serum levels in idiopathic male osteoporosis. J Endocrinol Invest.
2007;30(5):350-5.
3. Ostertag A, Collet C, Chappard C, et al. A case-control study of fractures in
men with idiopathic osteoporosis: Fractures are associated with older age and low
cortical bone density. Bone. 2012 23;52(1):48-55.
4. Ostertag A, Cohen-Solal M, Audran M, et al. Vertebral fractures are associated
with increased cortical porosity in iliac crest bone biopsy of men with idiopathic
osteoporosis. Bone. 2009;44(3):413-7.
5. Pernow Y, Thorén M, Sääf M, et al. Associations between amino acids and
bone mineral density in men with idiopathic osteoporosis. Bone. 2010;47(5):959-65
348
To sum up: this part of research examines the diseases that may
have affected King David including Cushing syndrome, thyroid
diseases (hyperthyroidism, hypothyroidism, subclinical
hyperthyroidism, and subclinical hypothyroidism), acromegaly,
hypogonadism, hyperparathyroidism, Paget's diseases, G-I tract
diseases such as lactose intolerance, IBD, celiac disease, Whipple
disease, and PBC, as well as COPD, osteoarthritis, RA, malnutrition,
medications, and IMO. An extensive investigation indicates that none
of these diseases entirely explains what kind of disease "consumed.."
his bones.
Was the King afflicted by some malignant disease?
349
MALIGNANCY
Cancer is one of the leading causes of morbidity, disability and
mortality worldwide (1). It is predicted that by 2020, the number of
new cases of cancer in the world will increase to more than 15 million,
with deaths increasing to 12 million. Much of the burden of cancer
incidence, morbidity, and mortality will occur in the developing
world. This forms part of a larger epidemiological transition in which
the burden of chronic, non-communicable disease, once limited to
industrialized nations, is now increasing in less developed countries.
In addition to the accumulating risks associated with diet, tobacco,
alcohol, lack of exercise, and industrial exposures, cancers some of
which are attributable to infectious diseases already burden the
developing world. These disparities in cancer risk combined with poor
access to epidemiological data, research, treatment, and cancer control
and prevention result in significantly poorer survival rates in
developing countries for a range of specific malignancies. The recent
trends in the epidemiology and survival of patients with cancers in the
developing and developed world, and potential causes and policy
responses to the disproportionate and growing cancer burden in less
developed countries may include raising awareness as well as
education and training to foster better informed decision-making,
together with improved cancer surveillance, early detection and
emphasis on prevention. Improved health care financing and
international initiatives and/or partnerships could also provide
additional impetus in targeting resources where needed urgently (1).
DALY were calculated to estimate the global burden of cancer in
2008. Population-based data were used, mostly from cancer registries,
for incidence, mortality, life expectancy, disease duration, and age at
onset and death, alongside proportions of patients who were treated
and living with sequelae or regarded as cured, to calculate years of life
lost and years lived with disability. Years of life lost and years lived
with disability were used to derive disability-adjusted life-years for 27
sites of cancers in 184 countries in 12 world regions. Estimates were
grouped into 4 categories based on a country's HDI. Worldwide, an
estimated 169.3 million years of healthy life were lost because of
cancer in 2008. Colorectal, lung, breast, and prostate cancers were the
main contributors to total disability-adjusted life-years in most world
regions and caused 18-50% of the total cancer burden. An additional
burden of 25% from infection-related cancers (liver, stomach, and
cervical) was estimated in sub-Saharan Africa, and 27% in eastern
Asia. Substantial global differences in the cancer profile of DALY as
350
noted by country and region; however, years of life lost were the most
important component of DALY in all countries and for all cancers,
and contributed to more than 90% of the total burden. Nonetheless,
low-resource settings had consistently higher years of life lost as a
proportion of total DALY than did high-resource settings. In
conclusion, age-adjusted disability-adjusted life-years lost from cancer
are substantial, irrespective of world region. The consistently larger
proportions of years of life lost in low HDI than in high HDI countries
indicate substantial inequalities in prognosis after diagnosis, related to
degree of human development. Therefore, radical improvement in
cancer care is needed in low-resource countries (2).
The control of the burden of cancer would be achievable by
promoting health-maintaining lifestyle behavioral practices in
conjunction with facilitated access to affordable and effective periodic
screening and early detection examinations combined with
comprehensive treatment services. In a global population exceeding 6
billion in the year 2002, there were approximately 10.9 million new
cancer cases, 6.7 million cancer deaths, and 22.4 million persons
surviving from cancer diagnosed in the previous 5 years. In 2020, the
world's population is projected to increase to 7.5 billion and will
experience 15 million new cancer cases and 12 million cancer deaths.
This perspective on advances, challenges, and future directions in
cancer epidemiology and prevention reviews the conceptual
foundation for multistep carcinogenesis, causal mechanisms
associated with chronic inflammation and the microenvironment of
the cancer cell, obesity, energy expenditure, and insulin resistance.
Strategic priorities in global cancer control initiatives should embrace
these fundamental concepts by targeting tobacco and alcohol
consumption, the increasing prevalence of obesity and metabolic
sequelae and persistent microbial infections (3).
Since the invention of a machine that could rapidly manufacture
cigarettes in the 1880s, tobacco smoking has progressively been the
major causative agent for the lung cancer epidemic. Until tobacco
inhalation is ceased, globally, there will continue to be readily
preventable lung cancers. Due to cigarettes and other products the
tobacco industry develops or modifies for inhalation are continually
changing, the types of lung cancer could continue to change. There are
other causes of lung cancer in people who never smoke, which include
environmental and occupational. Enough is now known to implement
strong policies that could eliminate most lung cancers (4).
351
References
1. Kanavos P. The rising burden of cancer in the developing world. Ann Oncol.
2006;17 Suppl 8:viii15-viii23.
2. Soerjomataram I, Lortet-Tieulent J, Parkin DM, et al. Global burden of cancer
in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions.
Lancet. 2012 Oct 15. pii: S0140-6736(12)60919-2.
3. Schottenfeld D, Beebe-Dimmer J. Alleviating the burden of cancer: a
perspective on advances, challenges, and future directions. Cancer Epidemiol
Biomarkers Prev. 2006;15(11):2049-55.
4. Dresler C. The changing epidemic of lung cancer and occupational and
environmental risk factors. Thorac Surg Clin. 2013;23(2):113-22
EPIDEMIOLOGY
The proportion of elderly persons (≥ 65 years) has increased in
most countries during the last few decades, and will increase further in
the coming years. Annual age-standardized cancer incidence rates per
100,000 elderly persons (1988 to 1992) were calculated based on data
from cancer registries in 51 countries in 5 continents kept by the
International Agency for Research on Cancer and International
Association of Cancer Registries. The proportions of all cancers
among elderly men and women were 61% and 56% respectively. All
cancers combined (except non-melanoma skin cancer) were, based on
the standardized rates, almost 7-fold more frequent among elderly
men (2158 per 100,000 person-years), and around 4-fold more
frequent among elderly women (1192 per 100,000 person-years) than
among younger persons (30 to 64 years old). However, large
variations exist between different cancer sites. Contrary to the pattern
in younger age groups, in which annual cancer rates are almost
equally distributed among the 2 genders, elderly men have an almost
double cancer incidence rate compared with elderly women. For all
major specific cancer sites except testicular cancer, the incidence rate
is significantly higher among the elderly than among any groups of
younger and middle-aged persons. Among elderly men, cancer of the
prostate (451 per 100,000), the lung (449 per 100,000) and the colon
(176 per 100,000) make up around half of all diagnosed cancers.
Prostate cancer is around 22 times more frequent among elderly men
than among younger men. The corresponding most frequent cancers
among elderly women, making up 48% of all malignant cancers, are
breast (248 per 100,000), colon (133 per 100,000), lung (118 per
100,000), and stomach cancer (75 per 100,000). For most cancers,
marked geographical variations in incidence rates are among the
352
elderly, reflecting socioeconomic differences, particularly between the

developing and the developed countries. In contrast with other major
causes of death among the elderly, cancer incidence and mortality
have not in general declined, indicating that primary prevention
(especially cessation of tobacco smoking) remains a most valuable
approach to decrease mortality; for most of the major cancers
(prostate, colon, and breast) the causes remain almost unknown. Since
the mortality rates for female cancer in general are declining, and the
incidence is increasing more steeply than the mortality among the
men, the number of living elderly ever diagnosed with a cancer will
further increase during the next years (1).
Every year in Europe and in US, more than 60% of new cases of
cancer are diagnosed in the patients of > 65 years with a mortality of >
70% (2). Prevalence of MBD in the US population was estimated
from a commercially insured cohort (ages 18-64 years, MarketScan
database) and from a fee-for-service Medicare cohort (ages ≥ 65 years,
Medicare 5% database) with coverage on December 31, 2008,
representing approximately two-thirds of the US population in each
age group. Claims-based evidence of MBD from January 1, 2004 were
searched, using a combination of relevant diagnosis and treatment
codes. The number of cases in the US adult population was
extrapolated from age- and sex-specific prevalence estimated in these
cohorts. Results are presented for all cancers combined and separately
for primary breast, prostate, and lung cancer. In the commercially
insured cohort (mean age = 42.3 years, SD=13.1), 9505 patients
(0.052%) with MBD were identified. Breast cancer was the most
common primary tumor type (n=4041). In the Medicare cohort (mean
age = 75.6 years, SD = 7.8), 6427 (0.495%) patients with MBD were
identified. Breast (n=1798) and prostate (n=1862) cancers were the
most common primary tumor types; 279,679 (95% CI 274,579 -
284,780) US adults alive on December 31, 2008, had evidence of
MBD in the previous 5 years. Breast, prostate, and lung cancers
accounted for 68% of these cases. These findings suggest that
approximately 280,000 US adults were living with MBD on
December 31, 2008 (3).
The present study was designed to estimate the number of and
describe the pattern of disease among cancer survivors living with a
history of multiple malignant tumors in the US. Incidence and follow-
up data from the Surveillance, Epidemiology, and End Results
program (1975-2001) were used to calculate the number of survivors
with more than one malignant primary at January 1, 2002. US
prevalence counts were calculated by multiplying the age, sex, and
353
race-specific prevalence proportions from the Surveillance,

Epidemiology, and End Results program by the corresponding US
populations. In the US, 756,467 people have been affected by cancer
more than once between 1975 and 2001, representing almost 8% of
the current cancer survivor population. Women whose first primary in
that period was breast cancer represent 25% of survivors with multiple
cancers, followed by men and women (15%) whose first primary was
CRC and men (13%) whose first primary was prostate cancer. With
individuals diagnosed with cancer living longer and the aging of the
US population, the number who will develop multiple malignancies is
expected to increase. Consequently, there is a growing need to
promote effective cancer screening along with healthy life-styles
among these at-risk populations if we are to ensure optimal physical
and psychosocial well-being of these long-term cancer survivors and
their families (4).
Metastatic bone disease
In Canada, more than 140,000 new cases of cancer are diagnosed

annually, nearly half of which metastasize to bone (5).
Cancer incidence and mortality estimates for 1995 are presented
for the 38 countries in the 4 United Nations-defined areas of Europe,
using WHO mortality data and published estimates of incidence from
national cancer registries. Additional estimation was required where
national incidence data was unavailable, and the method involved
incorporating the high quality incidence and mortality data available
from the expanding number of population-based cancer registries in
Europe. There were an estimated 2.6 million new cases of cancer in
Europe in 1995, representing over one-quarter of the world burden of
cancer. The corresponding number of deaths from cancer was
approximately 1.6 million. After adjusting for differing population age
structures, overall incidence rates in men were highest in the Western
European countries (420.9 per 100,000), with only Austria having a
rate under 400. Eastern European men had the second highest rates of
354
cancer (414.2), with extremely high rates in Hungary (566.6) and in

the Czech Republic (480.5). The lowest male all-cancer rate by area
was in the Northern European countries, with low rates in Sweden
(356.6) and the UK (377.8). In contrast to men, the highest rates in
women were in Northern Europe (315.9) and were particularly high in
Denmark (396.2) and the other Nordic countries excepting Finland.
The rates of cancer in Eastern European women were lower than in
the other 3 areas, although as with men, female rates were very high in
Hungary (357.2) and in the Czech Republic (333.6). There was greater
disparity in the mortality rates within Europe - generally, rates were
highest in Eastern European countries, notably in Hungary, reflecting
a combination of poorer cancer survival rates and a higher incidence
of the more lethal neoplasms, notably cancer of the lung. Lung cancer,
with an estimated 377,000 cases, was the most common cancer in
Europe in 1995. Rates were particularly high in much of Eastern
Europe reflecting current and past tobacco smoking habits of many of
its inhabitants. Together with CRCs (334,000), and female breast
(321,000), the 3 cancers represented approximately 40% of new cases
in Europe. In men, the most common primary sites were lung (22% of
all cancer cases), CRC (12%) and prostate (11%), and in females,
breast (26%), CRC (14%) and stomach (7%). The most common
cause of death was lung cancer (330,000) - about one-fifth of the total
number of cancer deaths in Europe in 1995. Deaths from CRCs
(189,000) ranked second, followed by deaths from stomach cancer
(152,000) that due to poorer survival ranked higher than breast cancer
(124,000). Lung cancer was the most common cause of death from
cancer in men (29%). Breast cancer was the leading cause of death in
females (17%) (6).
Secular and cohort trends in mortality from cancer in Scotland
during 1953-93, and incidence during 1960-90 were analyzed using
individual records from the national mortality and registration files.
For cancer sites, the secular analyses of mortality were extended back
to 1911 by use of published data. Mortality from cancer at older ages
in Scotland has increased over the last 40 years. In each sex, the
effects of smoking have dominated this trend: all-cancer rates and
rates of lung cancer, now the most common fatal cancer in men and in
women in Scotland, reached a peak in the cohort of men born at the
turn of the century and the cohort of women born in the 1920s. For
much of the period, the Scottish all-age rates of lung cancer were the
highest reported in the world; they are now decreasing on a secular
basis in men, but are still increasing in women. There have also been
large increases at older ages in the incidence and mortality rates for
355
cancer of the prostate in recent years. Bladder cancer, nervous system

cancer, non-Hodgkin's lymphoma, MM and leukemia; for each there
is likely to be a considerable artefactual element to the increase, with
differing degrees of possibility that there may in addition be an
element of real increase. Substantial decreases in mortality at all ages
have occurred for stomach and CRC and substantial increases at all
ages for pleural cancer and melanoma. Rates of mortality from breast
cancer, the most common cancer in women in Scotland, have
generally increased over the past 80 years; a temporary cessation in
this upward trend occurred in the years during and after the Second
World War, and recently rates have turned downward, probably at
least in part because of better treatment. Mortality from ovarian
cancer, the second most common reproductive-related female tumor in
Scotland, has also increased at older ages. At younger ages, mortality
from cancer in Scotland has decreased, especially in men, whereas
incidence has not. This divergence, which has been a consequence of
better treatment, has occurred especially for cancers of the testis and
ovary, Hodgkin's disease and leukemia. There have been increases at
young adult ages, however, in both mortality from and incidence of
oral and pharyngeal, esophageal and laryngeal cancers in men, and
melanoma and non-Hodgkin's lymphoma in each sex. Cervical cancer
rates at young ages also increased, but this trend has reversed for
incidence in the most recent birth cohorts. Incidence rates have also
increased for testicular cancer in young adults and leukemia in
children. With the possible exceptions of non-Hodgkin's lymphoma
and childhood leukemia, the increasing rates are likely largely to
reflect real rises in incidence, and they highlight the need for
investigation of the causes of these cancers, and, when causes are
known, for preventive action (7).
Increasing incidences of CUP have been observed in Sweden
previously. Site-specific data are available based on the ninth
international classification of diseases. CUP patients were identified
between 1987 and 2008 from the Swedish Family-Cancer Database.
Malignant neoplasms of ill-defined sites were diagnosed in 4042
patients, 1976 developed metastasis in lymph nodes, 9615 had
metastasis in specified organs and in 8052 patients, the malignant
neoplasm was diagnosed without further specification. Age-
standardized incidence rates for 23,685 patients were analyzed using a
direct method of standardization. Overall, the incidence of CUP
decreased from 6.98 to 6.00 per 100,000 from 1987 to 2008. The
number of patients diagnosed with metastasis in specified organs
decreased, whereas the number of patients diagnosed with CUP
356
without further specification increased from 2.65 to 3.02 per 100,000.

With improvements in diagnostic methods and imaging techniques for
identification of cancer, the incidences of CUP have been decreasing
because primary tumors can be specified more often. CT is typically
sensitive in detecting lung, kidney, and CRCs, which are known to
have a genetic link with CUP. PSA testing is used to detect prostate
cancer, for which bone is a common metastatic site. Liver metastases
are common if the primary tumor is located in the colorectum (8).
This paper presents the statistical analysis of current and past
trends of cancer mortality rates in Germany in terms of annual percent
change, overall and for the major sites, and contrasts them with trends
in incidence of the Cancer Registry of the Saarland, the only registry
in this country with long-term completeness. It addresses the issue of a
crossover of cancer mortality and mortality from C-V diseases in the
near future. Analyses are based on the mortality data of the official
mortality statistics as published by the Federal Statistical Office and
reported annually to the WHO, and the regularly reported incidence
data of the Cancer Registry of the Saarland. The report shows a
downward trend of mortality rates for all cancers combined based on
declining rates for many individual sites with only few exceptions
affecting mainly females (e.g. lung cancer). Recently, the long-term
increase of cancer incidence also flattened out with rather
heterogeneous underlying site-specific trends increasing for some sites
(e.g. cancers of the intestine, breast, prostate, or some lymphoma) and
decreasing for others (e.g. cancers of the stomach, gall bladder in
females, larynx, and lung in males). A crossover of cancer mortality
and mortality from C-V diseases might occur-if at all-after 2,020 in
males and 2,030 in females. In conclusion, depending on cancer site,
primary prevention (e.g. lung cancer among males), early detection
(cervical cancer), and treatment (e.g. breast and testicular cancer, and
lymphoma) contributed to the current decline of mortality rates.
Absence of a turnaround (e.g. lung cancer among females), slower
decline than in other countries (e.g. cervical cancer), or later
turnaround (e.g. breast cancer) may be related to failures in promoting
prevention (lung cancer among females), early detection programs
(cervical cancer), or delays in the translation of modern treatment into
routine health care (breast cancer) and indicate major challenges for
current and future health policy (9).
The objective of this study was to provide updated estimates of
national trends in cancer incidence and mortality for France for 1980-
2005. Twenty-five cancer sites were analyzed. Incidence data over the
1975-2003 period were collected from 17 registries working at the
357
department level, covering 16% of the French population. Mortality

data for 1975-2004 were provided by the Inserm. National incidence
estimates were based on the use of mortality as a correlate of
incidence, mortality being available at both department and national
levels. The number of new cancer cases in 2005 was approximately
320,000. This corresponded to an 89% increase since 1980.
Demographic changes were responsible for almost half of that
increase. The remainder was explained by increases in prostate cancer
incidence in men and breast cancer incidence in women. The relative
increase in the world age-standardized incidence rate was 39%. The
number of deaths from cancer increased from 130,000 to 146,000.
This 13% increase was much lower than anticipated based on
demographic changes (37%). The relative decrease in the age-
standardized mortality rate was 22%. This decrease was steeper over
the 2000-2005 period in both men and women. Alcohol-related cancer
incidence and mortality continued to decrease in men. The increasing
trend of lung cancer incidence and mortality among women
continued; this cancer was the second cause of cancer death among
women. Breast cancer incidence increased regularly, whereas
mortality has decreased slowly since the end of the 1990s. This study
confirmed the divergence of cancer incidence and mortality trends in
France over the 1980-2005 period. This divergence can be explained
by the combined effects of a decrease in the incidence of the most
aggressive cancers and an increase in the incidence of less aggressive
cancers, partly due to changes in medical practices leading to earlier
diagnoses (10).
The purpose of this work was to present detailed and updated
prevalence estimates in Italy over the period 1970-2010 by cancer site
(all cancers combined, stomach, colon and rectum, lung, breast and
prostate) and gender. To estimate prevalence trends, survival was
assumed to improve in the future with the same rate observed in the
period 1978-1994. A double scenario for survival, increasing or
stationary, was considered to decompose the prevalence growth from
1995 to 2005 by its determinants: demographic changes, incidence
and survival dynamics. The prevalence estimates were decomposed by
disease duration (2, 5 and 10 years) and by age (0-44, 45-59, 60-74
and 75-99 years). The highest dynamics was observed for prostate
cancer, with a three-fold increase just in the 1995-2005 period (from
212 to 623 per 100,000), whereas in absolute terms breast cancer
presented the highest levels (1700 per 100,000 in 2010). The overall
number of cancer prevalent cases was expected to rise by about 48%
in the decennium 1995-2005 (from 1,152,000 to 1,709,000), and this
358
growth was mainly attributable to incidence dynamics (+21%), then to

survival improvements (+14%) and population aging (13%). In 2005,
the 2-year prevalent cases were estimated to be 20% of all cancer
survivors, 21% between 2 and 5 years from the diagnosis, 23%
between 5 and 10 years, with 36% surviving for more than 10 years.
Prevalence proportion was very high in the elderly (12.6% for 75-84
years and 8% for 60-74 years) (11).
Mortality counts, provided by the Italian National Institute of
Statistics, were grouped according to data availability: in quinquennia
from 1970-74 through 1995-99, and in 2000-03 and 2006-08 groups.
Age-standardized rates (world population) were computed by calendar
periods while APCs were computed for elderly and middle aged (35-
64 years) people for the period 1995-2008. The number of cancer
deaths in elderly nearly doubled between 1970-74 (31,400 deaths/year
in men, and 24,000 in women) and 2006-08 (63,000 deaths/year in
men, and 42,000 in women). Overall cancer mortality rates peaked
during the quinquennia 1985-89 and 1990-94 (about 1,500/100,000 in
men and 680 in women) and declined thereafter. Throughout 1995-
2008, cancer mortality rates decreased by -1.6%/year in men and -
0.9%/year in women. These decreases were mainly driven by cancers
of the stomach, bladder, prostate, and lung (APC = -3.3%, -2.7%, -
2.5%, -2.2%, respectively) in men, and by cancers of the stomach,
bladder, and breast (APC = -3.5%, -1.9%, -1.1%, respectively) in
women. Conversely, increases in mortality rates between 1995 and
2008 were recorded for lung cancer (APC = +0.6%) in women,
cutaneous melanoma (APC = +1.7%) in men, and pancreatic cancer
(APC = +0.6% in men and +0.9% in women). In conclusion, overall
favorable trends in cancer mortality were observed among Italian
elderly between 1995 and 2008. Early diagnosis, improved efficacy of
anti-cancer treatments and management of comorbidities are the most
likely explanations of these positive observations. However, enduring
preventive interventions against the most common risk factor (e.g.
cigarette smoking), early diagnosis, and access to care should be
reconsidered and extended to match the reductions of cancer mortality
recorded in the elderly with those in the middle aged (12).
The objective of this study was to characterize the hospital burden
of disease associated with MBD and SREs following breast, lung and
prostate cancer in Spain. Patients admitted into a participating
hospital, between 1 January 2003 and 31 December 2003, with one of
the required cancers were identified and selected for inclusion into the
study. The index admission to hospital, incidence of patients admitted
and hospital length of stay were analyzed. There were 28,162 patients
359
identified with breast, lung and prostate cancer. The 3-year incidence
rates of hospital admission due to MBD were 95 per 1000 for breast
cancer, 156 per 1000 for lung cancer and 163 per 1000 for prostate
cancer. For patients admitted following an SRE, the incidence rates
were 211 per 1000 for breast cancer, 260 per 1000 for lung cancer and
150 per 1000 for prostate cancer. This study has shown that cancer
patients consume progressively more hospital resources as MBD and
subsequent SREs develop (13).
Estimates of national cancer incidence in Portugal in 1996-1998,

predictions for the year 2000, and interpretation of the recent cancer
mortality trends in light of observations from epidemiological research
and risk factor patterns were presented. In Portugal, national mortality
data from vital statistics are available from 1960, while cancer
registration has been mandatory since 1988, when 3 regional cancer
registries covering the mainland of the Portuguese Republic were set
up. Up until now, however, none of these registries has been able to
produce data with an acceptable completeness of registration hence
this study. Mortality data from Portugal for 1996-1998 and incidence
data for 1990-1995 from Vila Nova de Gaia (the most complete of the
Portuguese cancer registries), 14 Italian registries and 9 Spanish
registries were assembled to produce the best possible estimates of
numbers of incident cases for each age group and gender. New cancer
cases (n=19,880) were estimated among men in the year 2000, and
nearly 17,000 new cancer cases in women. The most common cancer
among Portuguese men in 2000 was CRC (3173 new cases), followed
by cancers of the prostate (2973), lung (2611), stomach (2206) and
urinary bladder (1360). In women, breast cancer was the most
common (4358) followed by CRC (2541), stomach (1494), and corpus
uteri (1083) cancers. The overall age-standardized cancer mortality
rate for men in Portugal increased steeply (1.4% annually) during
1988-1998, with prostate cancer (3.6% annually), CRC (3.3%) and
lung (2.4%) mostly contributing. Among women, the overall cancer
mortality rate was stable (a non-significant decrease of approximately
360
0.2% per year). These results, particularly in males, demonstrate the

need for a comprehensive national program against cancer. Since the
increasing epidemic of lung cancer (in men), as well as other tobacco-
related cancers, are observed in Portugal, the important component of
such program should be a nationwide tobacco control program.
Improving accessibility to highly effective diagnostic and treatment
procedures for cancer in general and CRC and prostatic cancer in
particular should be a priority in the fight against cancer (14).
In this study, incidence rates of the histopathologically confirmed
malignancies in the in the Republic of Suriname from 1980 through
2000 were investigated. Numbers of diagnoses, as well as patient
information, were acquired from the Pathology Laboratory. The
General Bureau of Statistics of Suriname provided relevant
demographic information. For each year, crude incidence and sex-
specific rates were calculated for: cancer overall; the most frequent
cancer sites; age strata 0-19, 20-49, and 50+ years; as well as for the
presumably largest, second largest, and third largest ethnic group, viz.
the Hindustani, Creole, and Javanese. From these data, average rates
were calculated, which were expressed as mean +/- SD per 100,000
populations per year, or per 100,000 males or females per year.
Average yearly crude and sex-specific incidence rates for cancer
overall were 70 +/- 12: 59 +/- 9 for men and 83 +/- 12 for women. The
leading cancer sites were cervix uteri (sex-specific rate of 22.1 +/- 5.1)
as well as G-I tract, breast, hematological system, prostate, head and
neck, lung, and liver (sex-specific rates ranging from 2 to 17). The
relatively high rate of cervical cancer was for an important part
responsible for the 1.4-fold female over male overall cancer excess.
Incidence rates of most cancers increased from age group 20-49 years
on, being highest after age 50+ years, but hematological malignancies
occurred in all age groups with rates of 1-3 new cases per 100,000
males or females per year. Cancer was 2-6 times more common in
Creole than in Hindustani and Javanese. However, cervical cancer was
as often in Hindustani as in Creole. Most cases of primary liver cancer
involved, besides Creole of both genders, Javanese males. Thyroid
cancer occurred more frequently in Hindustani women. The data from
the study suggest that the incidence profile of cancer in Suriname may
resemble that of most developing countries. It was relatively low for
cancer overall as well as for most individual sites, but relatively high
for cervical cancer (15).
The oncological hospital in Arkhangelsk, in co-operation with
Tromsø (Norway) University, has established a population based
cancer registry for Arkhangelskaja Oblast. Arkhangelskaja Oblast is
361
an administrative unit with 1.3 million inhabitants in northwestern

Russia. The aim of this investigation was to assess the content and
quality of the Arkhangelskaja Oblast cancer registry and to present the
site-specific cancer-incidence rates in Arkhangelskaja Oblast in the
period 1993-2001. All new cancer cases in the period 1993-2001,
were included in the study (ICD-10: C00-C95, except for C77-78).
The annual gender and age-group-specific population figures were
obtained from the Arkhangelskaja Oblast statistics office. Of 34,697
cases of primary cancers, the age-adjusted (world standard) incidence
rate for all sites combined was 164/100,000 for women and
281/100,000 for men. The highest incidence was for cancer of the
trachea, bronchus and lung (16.3% of all cases), whereof 88.6 % of
the cases were among men. Among women, cancer of the breast
constituted 15.9% of all cases. The age-adjusted incidences of the
most frequent cancer sites among men were: lung (77.4/100,000),
stomach (45.9), rectum (13.4), esophagus (13.0), colon (12.2), bladder
(11.6), and prostate cancer (11.1). Among women they were: breast
(28.5), stomach (19.7), colon (12.2), and ovary cancer (9.0). In
conclusion, these findings confirm and strengthen the indication that
the incidences of stomach, larynx, liver, pancreas, prostate, colon,
bladder and melanoma cancer are quite different in male populations
in Russia compared to many other European countries. Among
women, most major cancer types, except stomach, appear to be
relatively low in Russian populations (16).
A register-based analysis of the overall and main site-specific
cancer incidence in NAO in the period 1993-2006 was carried out.
NAO, a part of Arkhangelskaja Oblast in north-west Russia, has a
population of 42,000 inhabitants. All new cases recorded in the study
period among official residents of NAO were included in the study,
except for secondary malignant neoplasm, cases revealed by autopsy
and cancers diagnosed within 6 months of a previous cancer
diagnosis. The census and annual sex and age-group-specific
population figures for NAO were obtained from the regional statistics
office. The average crude cancer incidence per year was 204/100,000
among men and 194/100,000 among women. Adjusted for age, the
incidence was 322/100,000 and 182/100,000, respectively. The most
frequent primary site of cancer was trachea, bronchus and lung, which
constituted 17.3% of all cases (of which 87% were among men),
followed by stomach cancer (12.5%). Breast cancer constituted 17.5%
of all cases among women. These results are consistent with reports of
a low cancer risk among women compared with men in Russia and
compared with women in Western countries (17).
362
The main objective of this study was to investigate the incidence of

SREs in urological cancer patients with bone metastases in Japan.
Patients (n=511) with urological cancer and documented bone
metastases treated from January 2003 to April 2008 in ten Japanese
institutions were included in a retrospective analysis. Type and
incidence of SREs (fracture, RT, spinal cord compression, surgery,
hypercalcemia, and bone pain) were determined from patient medical
records. The overall incidence of SREs, including 'pain', was 61%.
The most common event was RT for bone metastases, with an
incidence of 31%. The overall incidence of events seemed to be
similar among Japanese and Western patients with prostate cancer and
RCC when comparing data with previously published reports.
Nevertheless, a much lower incidence of fracture (19.1%) was
observed in Japanese RCC patients. In conclusion, the overall
incidence of SREs in Japanese urological cancer patients with bone
metastasis was similar to that in Western patients, but the incidence of
fracture was lower in Japanese RCC patients (18).
Assessment: people are suffering from different types of cancer in

different countries, whether developed or developing, although
different prevalence rates are observed.
References
1. Hansen J. Common cancers in the elderly. Drugs Aging. 1998;13(6):467-78.
2. Chouahnia K, Luu M, Baba-Hamed N, Des Guetz G. Bone metastases pain in
the elderly. Rev Med Suisse. 2009;5(204):1126, 1128, 1130 passim.
3. Li S, Peng Y, Weinhandl ED, et al. Estimated number of prevalent cases of
metastatic bone disease in the US adult population. Clin Epidemiol. 2012;4:87-93.
4. Mariotto AB, Rowland JH, Lynn A.G. Ries LAG, et al. Multiple Cancer
Prevalence: A Growing Challenge in Long-term Survivorship. Cancer Epidemiol
Biomarkers Prev 2007;16(3):566–71.
5. Kelly M, Lee M, Clarkson P, O'Brien PJ. Metastatic disease of the long bones:
a review of the health care burden in a major trauma centre. Can J Surg.
2012;55(2):95-8.
6. Bray F, Sankila R, Ferlay J, Parkin DM. Estimates of cancer incidence and
mortality in Europe in 1995. Eur J Cancer. 2002;38(1):99-166.
7. Swerdlow AJ, dos Santos Silva I, Reid A, et al. Trends in cancer incidence and
mortality in Scotland: description and possible explanations. Br J Cancer. 1998;77
Suppl 3:1-54.
8. Bevier M, Sundquist J, Hemminki K. Incidence of cancer of unknown primary
in Sweden: analysis by location of metastasis. Eur J Cancer Prev. 2012;21(6):596-
601.
9. Becker N, Altenburg HP, Stegmaier C, Ziegler H. Report on trends of incidence
(1970-2002) of and mortality (1952-2002) from cancer in Germany. J Cancer Res
Clin Oncol. 2007;133(1):23-35.
363
10. Belot A, Grosclaude P, Bossard N, et al. Cancer incidence and mortality in

France over the period 1980-2005. Rev Epidemiol Sante Publique. 2008;56(3):159-
75.
11. De Angelis R, Grande E, Inghelmann R, et al. Cancer prevalence estimates in
Italy from 1970 to 2010. Tumori. 2007;93(4):392-7.
12. Bidoli E, Fratino L, Bruzzone S, et al. Time trends of cancer mortality among
elderly in Italy, 1970-2008: an observational study. BMC Cancer. 2012 Oct 2;12:443.
13. Pockett RD, Castellano D, McEwan P, et al. The hospital burden of disease
associated with bone metastases and skeletal-related events in patients with breast
cancer, lung cancer, or prostate cancer in Spain. Eur J Cancer Care (Engl).
2010;19(6):755-60.
14. Pinheiro PS, Tyczyński JE, Bray F, et al. Cancer incidence and mortality in
Portugal. Eur J Cancer. 2003;39(17):2507-20.
15. Mans DR, Mohamedradja RN, Hoeblal AR, et al. Cancer incidence in
Suriname from 1980 through 2000 a descriptive study. Tumori. 2003;89(4):368-76.
16. Vaktskjold A, Lebedintseva JA, Korotov DS, et al. Cancer incidence in
Arkhangelskaja Oblast in northwestern Russia. The Arkhangelsk Cancer Registry.
BMC Cancer. 2005 Jul 19;5:82.
17. Vaktskjold A, Ungurjanu TN, Klestsjinov NM. Cancer incidence in the
Nenetskij Avtonomnyj Okrug, Arctic Russia. Int J Circumpolar Health.
2008;67(5):433-44.
18. Yokomizo A, Koga H, Shinohara N, et al. Skeletal-related events in urological
cancer patients with bone metastasis: a multicenter study in Japan. Int J Urol.
2010;17(4):332-6.
STAGING AND GRADING

Staging systems for cancer have evolved over time. They continue
to change as scientists learn more about cancer. Some staging systems
cover many types of cancer; others focus on a particular type. The
common elements considered in most staging systems are as follows:
Site of the primary tumor, Tumor size, Number of tumors, Lymph
node involvement (cancer spread into lymph nodes), Cell type and
tumor grade (how closely the cancer cells resemble normal tissue
cells), and the presence or absence of Metastasis (1).
THE TNM SYSTEM

The TNM system is one of the most widely used staging systems.
This system has been accepted by the International Union Against
Cancer and the American Joint Committee on Cancer. Most medical
facilities use the TNM system as their main method for cancer
364
reporting. The TNM system is based on the extent of the tumor (T),
the extent of spread to the lymph nodes (N), and the presence of
distant metastasis (M). A number is added to each letter to indicate the
size or extent of the primary tumor and the extent of cancer spread
(2,3).
PRIMARY TUMOR (T)

TX - Primary tumor cannot be evaluated.
T0 - No evidence of primary tumor.
Tis - Carcinoma in situ. Abnormal cells are present but have not
spread to neighboring tissue; and are not cancer. Carcinoma in situ
may become cancer and is sometimes called preinvasive cancer.
T1, T2, T3, T4 - Size and/or extent of the primary tumor (2).
REGIONAL LYMPH NODES (N)

NX - Regional lymph nodes cannot be evaluated.
N0 - No regional lymph node involvement.
N1, N2, N3 - Involvement of regional lymph nodes (number of
lymph nodes and/or extent of spread) (2).
DISTAL METASTASIS (M)

MX - Distant metastasis cannot be evaluated.
M0 - No distant metastasis.
M1 - Distant metastasis is present (2).
For example, breast cancer classified as T3 N2 M0 refers to a large

tumor that has spread outside the breast to nearby lymph nodes but not
to other parts of the body. Prostate cancer T2 N0 M0 means that the
tumor is located only in the prostate and has not spread to the lymph
nodes or any other part of the body.
For many cancers, TNM combinations correspond to 1 of 5 stages.
Criteria for stages differ for different types of cancer. For example,
bladder cancer T3 N0 M0 is stage III, whereas colon cancer T3 N0
M0 is stage II (2).
365
DEFINITION OF STAGING
Stage 0. Carcinoma in situ.
Stage I, Stage II, and Stage III. Higher numbers indicate more
extensive disease: larger tumor size and/or spread of the cancer
beyond the organ in which it first developed to nearby lymph nodes
and/or organs adjacent to the location of the primary tumor.
Stage IV. The cancer has spread to another organ(s) (2).
SUMMARY STAGING
Many cancer registries, such as NCI‘s Surveillance, and SEER use
summary staging. This system is used for all types of cancer. It groups
cancer cases into 5 main categories (2):
In situ: Abnormal cells are present only in the layer of cells in
which they developed.
Localized: Cancer is limited to the organ in which it began, without
evidence of spread.
Regional: Cancer has spread beyond the primary site to nearby
lymph nodes or organs and tissues.
Distant: Cancer has spread from the primary site to distant organs
or distant lymph nodes.
Unknown: There is insufficient information to determine the stage.
GRADING
Grading refers to the appearance of the cancer cells under the
microscope and gives an idea of how the cancer may behave. Low-
grade means that the cancer cells look like normal cells. High-grade
means the cells look abnormal. A low-grade tumor will usually grow
more slowly and less likely spread than a high-grade tumor (1).
References
1. Tracheal cancer - Cancer Information. Available 15 May 2013 at Macmillan
Cancer Supportwww.macmillan.org.uk › Cancer information › Cancer types.
2. Cancer staging. National Cancer Institute. Available 20 April 2013 at
www.cancer.gov/cancertopics/factsheet/detection/staging.
3. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th ed.
New York, NY: Springer, 2002.
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ASSESSMENT OF CANCER PAIN

Although tools for the assessment of non-cancer and cancer pain
sometimes overlap, for the purpose of this research the tools are
described separately for non-cancer and cancer patients.
Pain is a subjective perception that is influenced by psychosocial
and behavioral factors and physical pathology. In cancer, the source of
the pain may be the disease itself, the treatment, or co-occurring pain
syndromes. Often, cancer is a progressive disease, and pain may be
marked by exacerbations, additional treatment, and remissions. Thus,
pain assessment must become part of routine care. Ratings of pain
should be performed on a regular basis, just as vital signs are taken on
a regular basis. Unlike the other vital signs, however, pain can only be
assessed by the patients' verbal and nonverbal behavior. Therefore, it
is necessary to actively involve the patient in the assessment process.
In deciding what to assess about the pain and how, the clinician needs
to balance the purposes of the evaluation with the patient's capacity.
During initial assessment, it may be possible to include a more
comprehensive evaluation of the patient and his or her pain. Relatively
brief measures may be used on a routine ongoing basis. When a new
type of pain or exacerbation of pain is identified, additional attention
beyond pain severity and location may be appropriate. For the very ill
patient, it may be possible only to ask a few questions and to observe
his or her behavior. In some circumstances, such as when patients are
unwilling or unable to report on their pain, it is useful to gather
information from caretakers. At a minimum, the severity, location,
and pattern of pain and patients' functional activity and mood should
be assessed. Timely, appropriate, and thorough assessment and
treatment of cancer patients experiencing pain should reduce their
suffering and improve the QOL (1).
The Pain Research Group of the WHO Collaborating Centre for
Symptom Evaluation in Cancer Care has developed the BPI, a pain
assessment tool for use with cancer patients. The BPI measures both
the intensity of pain (sensory dimension) and interference of pain in
the patient's life (reactive dimension). It also queries the patient about
pain relief, pain quality, and patient perception of the cause of pain.
The BPI is a powerful tool and, having demonstrated both reliability
and validity across cultures and languages, is being adopted in many
countries for clinical pain assessment, epidemiological studies, and in
studies of the effectiveness of pain treatment (2).
The BPI demonstrated good construct and concurrent validity. It
was translated and validated into many languages – Brazilian,
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Chinese, Greek, Hindi, Italian, Japanese, Korean, Malay, Norwegian,

Polish, Russian, Spanish, Taiwanese and Thai. The BPI was validated
in patient populations such as bone metastases, breast cancer and
postoperative cancer patients. The BPI can be used both as a
quantitative and as a qualitative measure for statistical analysis. The
BPI is a powerful tool and, having both reliability and validity across
cultures and languages, and is adopted in many countries for clinical
pain assessment, epidemiological studies, and in studies on the
effectiveness of pain treatment (3).
The objectives of this study were 1) to validate the psychometric
properties of the BPI and its Pain and Interference subscales in
patients with clinically significant metastatic bone pain requiring
palliative RT and 2) to examine differences in BPI subscales among
predefined subgroups of bone metastases patients. A total of 258
patients were evaluated and treated through a rapid access RT clinic
between July 2002, and November 2006. High internal consistency of
the BPI subscales of Pain, Activity interference, and Affect
interference was demonstrated by Cronbach's alpha between 0.81 and
0.89. Removing sleep interference improved model fit in confirmatory
factor analysis. The BPI revealed an alarming pattern in patients with
lower body metastases, who reported substantial interference of
activity even though pain levels were mild or moderate. Such patients
may require prompt clinical attention to meet their needs. Finally, the
allocation of interference from sleep within the BPI framework, in this
population of pain patients, requires further study (4).
One hundred eleven patients with advanced cancer and pain newly
referred to a palliative care center completed the BPI weekly for up to
4 weeks. The aims were (a) to review the numbers and causes of pain,
(b) to consider the usefulness of the BPI in the evaluation of pain in
cancer patients, and (c) to determine the impact of treatment. A total
of 370 pains were recorded initially, a median of 3 per patient; 85%
had more than 1 pain and more than 40% had 4 or more pains. Causes
of pain were cancer (46%), debility (29%), treatment (5%), concurrent
disorder (8%), and no stated cause (12%). The top 10 individual
causes accounted for 73% of the pains. Seventy-six (68%) of the
patients completed 2 BRIs, but only 46 (41%) completed 5. After 4
weeks, the median number of pains had fallen to 1.5; 78% still had
more than 1 pain, but only 20% had 4 or more pains. Intensity of pain
also declined, particularly in the first 2 weeks. With their last BPI,
23% had become completely pain free and a further 27% achieved
acceptable relief (worst pain scores 1-4), compared with none and
24% initially. Of those who completed all 5 BPIs, the final respective
368
figures were 22% and 29%. By contrast, 23% of patients still had
unacceptable severe pain noted on their last BPI (worst pain scores 8-
10), compared with 36% initially. Of those who completed 5 BPIs, the
final figure was 20%. Highly significant correlations were observed
between all 7 interference factors and present, worst, and average pain
intensities. After 4 weeks, the pattern was more variable, particularly
in relation to present pain, suggesting that interference factors may
have a limited utility as a measure of satisfactory pain management.
Many patients did not answer all the questions in the BPI. It was
concluded that the BPI is not brief enough for routine clinical use, and
that the short form of the BPI (BPI-SF) is too short. A pain diary card
will be developed comprising mainly pain scores, a pain relief score
and a satisfaction with pain management score (5).
The purpose of this study was to develop a CPI that measures
cancer patients' beliefs and concerns about pain. Subjects were
recruited from inpatient and outpatient oncology services of an NCI-
designated comprehensive cancer center. Participants completed the
50 potential CPI items and these standard measures-Orientation-
Memory-Concentration Test, Survey of Pain Attitudes, BPI, Pain
Disability Index, and Center for Epidemiological Studies-Depression
Scale. The magnitude and significance of associations between the
CPI and the other measures were examined. Of 366 patients who were
eligible and agreed to participate in the study, 262 completed the
questionnaires. Principal components analyses were used to select
items most appropriate for retention in the preliminary version of the
CPI and to describe its factor structure. Based on the content of items
that loaded on each factor, the 5 factors were labeled as
Catastrophizing, Interference with Functioning, Stoicism, Social
Aspects, and Concerns about Pain Medication. Correlations between
the CPI and other measures supported construct validity of the 5 CPI
factors. The results supported the validity of the CPI as a measure of 5
constructs relevant to the experience of pain in the cancer setting. The
results also underscored the presence of unique features of cancer-
related pain that clearly differ from commonly recognized dimensions
of chronic, non-cancer-related pain (6).
The aim of this study was to evaluate the effectiveness of bedside
self-assessment of pain intensity for inpatients with cancer pain using
a self-reporting pain board. Fifty consecutive inpatients admitted to
the Oncology Department of Chungbuk National University Hospital
were included in this observational prospective study from February
2011 to December 2011. The medical staff performed pain
assessments by asking patients questions and using VRS over 3
369
consecutive days. Then, for 3 additional days, patients used a self-

reporting pain board attached to the bed, which had movable
indicators representing 0-10 on a NPRS and the frequency of BTP.
Patient reliability over the medical staff's pain assessment increased
from 74% to 96% after applying the self-reporting pain board
(p=0.004). The gap (mean ± SD) between the NPRS reported by
patients and the NPRS recorded on the medical records decreased
from 3.16±2.08 to 1.00±1.02 (p<0.001), and the level of patient
satisfaction with pain management increased from 54% to 82%
(p=0.002). This study suggests that the self-reporting bedside pain
assessment tool provides a reliable and effective means of assessing
pain in oncology inpatients (7).
The aim of this exploratory study was to characterize CIBP using
self-rating scales. A cross-sectional survey of patients with CIBP was
carried out in a regional oncology centre. Patients described their pain
over the preceding 24 hours using the MPQ, BPI, and a BTP
questionnaire. Fifty-five patients were recruited. Annoying, gnawing,
aching, and nagging were the most commonly used words to describe
CIBP. From the BPI, median average pain was 4/10 and worst pain
was 7/10 on a 0-10 NPRS. The worst pain score correlated more
strongly with BPI interference score (p=0.001). Forty-one patients had
BTP pain. Patients with BTP pain had higher total BPI interference
scores than those with no breakthrough pain; median (IQR); 35.0 (2.5-
44.7) vs. 18.5 (5.5-26.7), p<0.01. Of the patients, 20/41 (48%) had
BTP of rapid onset (less than 5 min) and short duration (less than 15
min). These data indicate that in CIBP, worst pain most accurately
reflects the characteristics of pain flares and functional impairment.
BTP is often unpredictable, sudden onset and short duration (8).
Methods are presented to separate 16 frequently occurring cancer
symptoms measured on 10-point symptom severity rating scales into
mild, moderate, and severe categories that are clinically interpretable
and significant for use in oncology practice settings. At their initial
intervention contact, 588 solid tumor cancer patients undergoing
chemotherapy reported severity on a standard 11-point rating scale for
16 symptoms. All reporting a 1 or higher were asked to rate on an 11-
point scale how much the symptom interfered with enjoyment of life,
relationship with others, general daily activities, and emotions. Factor
analysis revealed that these items tapped into the same dimension, and
the items were summed to form an interference scale. Cut-points for
mild, moderate, and severe categories of symptom severity were
defined by comparing the differences in interference scores
corresponding to each successive increase in severity for each
370
symptom. Pain, fatigue, weakness, cough, difficulty remembering, and

depression had lower cut-points for each category compared to other
symptoms. Cut-points for each symptom were not related to site or
stage of cancer, age, or gender but were associated with a global
depression measure. Cut-points were related to limitations in physical
function, suggesting differences in the quality of patients' lives. The
resulting cut-points summarize severity ratings into clinically
significant and useful categories that clinicians can use to assess
symptoms in their practices (9).
As a way of delineating different levels of cancer pain severity, the
relationship between NPRS and ratings of pain's interference with such
functions as activity, mood, and sleep were explored. Interference
measures were used as critical variable to grade pain severity. Pain
severity could be classified into groupings roughly comparable to
mild, moderate, and severe. Mild, moderate, and severe pain would
differentially impair cancer patients' function. Boundaries among
these categories of pain severity in terms of their interference with
function were identified. The extent to which cancer patients from
different language and cultural groups differ in their self-reported
interference as a function of pain severity level was examined.
Optimal cutpoints that form 3 distinct levels of pain severity can be
defined on a 0-10-point numerical scale. Based on the degree of
interference with cancer patients' function, ratings of 1-4 correspond
to mild pain, 5-6 to moderate pain, and 7-10 to severe pain. This
analysis illustrates that the pain severity-interference relationship is
non-linear. The cut points were the same for each of the national
samples in this analysis, although there were slight differences in the
specific interference items affected by pain. These cut points might be
useful in clinical evaluation, epidemiology, and clinical trials (10).
Grouping patients' rating of pain intensity from 0 to 10 into
categories of mild, moderate, and severe pain is useful for informing
treatment decisions, interpreting study outcomes, as well as aiding
policy or clinical practice guidelines development. In 1995, Serlin and
colleagues (10) developed a technique to establish the cut points for
mild, moderate, and severe pain by grading pain intensity with
functional interference. Since then, a number of studies attempted to
confirm these findings in similar or different populations but had
different results. Such inconsistencies in the literature prompt for more
research to establish the definition of mild, moderate and severe pain.
Thus, the purpose of the current study was to identify optimal cut
points of the three chronic pain severity categories for worst, average,
and current pain. The study population (n=199) was patients with
371
symptomatic bone metastases referred to a palliative RT clinic. Using

the BPI, patients reported their worst, average, and current pain
intensity, as well as the degree of functional interference due to pain.
Results confirmed a non-linear relationship between cancer pain
severity and functional interference. The optimal cut points for worst
and average pain was cut points 4, 6 (mild = 1-4, moderate = 5-6, and
severe = 7-10), confirming Serlin and colleagues' findings. These
findings are pivotal in further understanding the meaning of pain
intensity levels and the assessment of pain in patients with metastatic
cancer (11).
The aim of this systematic review was to explore the evidence on
cut points by using 0-10 NRSs for the symptoms of the ESAS.
Relevant literature was searched in PubMed, CINAHL(®), EMBASE,
and PsycINFO(®). A cut point as the lower bound of the scores
representing moderate or severe burden was defined. Eighteen articles
were eligible for this review. Cut points were determined using the
interference with daily life, another symptom-related method, or a
verbal scale. For pain, cut point 5 and, to a lesser extent, cut point 7
were the optimal cut points for moderate pain and severe pain,
respectively. For moderate tiredness, the best cut point seemed to be
cut point 4. For severe tiredness, both cut points 7 and 8 were
suggested frequently. A lack of evidence exists for nausea, depression,
anxiety, drowsiness, appetite, well-being, and shortness of breath. Few
studies suggested a cut point below 4. For many symptoms, there is no
clear evidence as to what the optimal cut points are. In daily clinical
practice, a symptom score ≥ 4 is recommended as a trigger for a more
comprehensive symptom assessment. Until there is more evidence on
the optimal cut points, we should hold back using certain cut point in
quality indicators and be cautious about strongly recommending a
certain cut point in guidelines (12).
All patients referred to the Rapid Response Radiotherapy Program
for palliative RT of symptomatic bone metastases were considered for
the study. Patients rated the intensity and functional interference of
their pain at the irradiated sites according to the BPI before and 2
months after palliative RT. Worst, average and current pain scores
were correlated with functional interference scores using Spearman
rank coefficients. Responders and non-responders to palliative RT
were defined for each pain intensity scale according to the end points
specified by the International Bone Metastases Consensus Working
Party. Between May 2003 and June 2005, 199 patients were enrolled
in the study (102 men and 97 women). Ninety-five patients returned
complete questionnaires at 2 months of follow-up. All pain intensity
372
and interference scores for evaluable patients were significantly lower

at 2 months (p<0.0021). Response rates differed depending on the
definition of pain intensity. An overall response rate was observed in
66%, 58% and 54% of patients for worst, average and current pain,
respectively. Worst pain showed the best correlation with functional
interference. Responders reported significantly larger decreases in
functional interference scores at follow-up in general activity, normal
work, enjoyment of life and average functional interference. In
conclusion, worst pain intensity had higher correlations with all
functional interference scores except relationships with others. An 11-
point scale measuring worst pain to evaluate response rates in future
RT trials is recommended. The mean difference from baseline to
follow-up in functional interference scores was significantly larger in
patients who responded to RT treatment (13).
Symptom clusters are a dynamic construct. They consist of at least
2 or 3 interrelated symptoms that may be a significant predictor of
patient morbidity. From February to September 2007, this study
accrued 52 patients with bone metastases (29, 56% men, 23, 44%
women; median age - 68.5 years (range 39-87 years) who were
referred for palliative RT. Prostate (31%), breast (29%), and lung
(19%) were the most common primary cancer sites. Treatment arms
ranged from single to multiple fractions, with most patients receiving
a single 8-Gy fraction (77%) or 20 Gy in 5 fractions (21%). The most
prevalent sites for RT were spine (42%), hips (17%), and pelvis
(14%). Worst pain at the site of RT and functional interference scores
were assessed using the BPI, a multidimensional pain instrument that
uses 11-point NRSs. Patients provided their symptom severity scores
on the BPI at baseline and at 4, 8, and 12 weeks post RT. At all time
points, a principal component analysis with varimax rotation was
performed on 8 items (worst pain and 7 functional interference items)
to determine relationships between symptoms before and after
palliative RT for bone pain. Two symptom clusters were identified.
Cluster 1 included worst pain and interference with general activity,
normal work, and walking ability; cluster 2 consisted of interference
with mood, sleep, enjoyment of life, and relations with others. This
statistical analysis produced varied results for the 2 clusters found in a
previous investigation. The differences may be an indicator for the
instability of symptom clusters or a result of the fewer number of
patients accrued in the present validation study. The symptom
clusters in these 2 studies were not identical for patients receiving
palliative RT for symptomatic bone metastases. Another symptom
clusters validation study should be conducted with a larger sample
373
before a conclusion is drawn about the existence of an unstable

phenomenon in symptom cluster research (14).
Patients experiencing lower body pain resulting from bone
metastases have greater levels of functional interference than those
with upper body pain. The purpose of this study was to assess the
levels of interference caused by pain after treatment with conventional
RT using the BPI and to validate this tool for telephone use. After RT,
159, 129, and 106 patients completed the BPI over the telephone at
months one, 2, and 3, respectively. Cronbach's alpha, confirmatory
factor analysis, and discriminant validity tests were performed to
assess the validity of the BPI. One-way ANOVA was used to compare
BPI scores. There was insignificant difference in functional
interference among patients after treatment. Internal consistency of the
BPI was high. Functional interference may be inherently higher in
patients with pain in the lower body. Telephone use of the BPI is
reliable and recommended in this population (15).
Assessment: ratings of pain should be performed on a regular

basis, just as vital signs are taken on a regular basis. The severity,
location, and pattern of pain and patients' functional activity and mood
should be assessed.
There are different pain assessment tools for evaluation pain in
cancer patients. One of the practical assessment tools is BPI. BPI
measures both the intensity of pain (sensory dimension) and
interference of pain in the patient's life (reactive dimension). It is
translated and validated into many languages and was validated in
patient populations such as bone metastases, breast cancer and
postoperative cancer patients. The BPI, a powerful tool, has both
reliability and validity across cultures and languages, and is adopted in
many countries for clinical pain assessment, epidemiological studies,
and in studies on the effectiveness of pain treatment.
References
1. Turk DC, Monarch ES, Williams AD. Cancer patients in pain: considerations
for assessing the whole person. Hematol Oncol Clin North Am. 2002;16(3):511-25.
2. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain
Inventory. Ann Acad Med Singapore. 1994;23(2):129-38.
3. Kumar SP. Utilization of Brief Pain Inventory as an Assessment Tool for Pain
in Patients with Cancer: A Focused Review. Indian J Palliat Care. 2011;17(2):108–15.
4. Wu JS, Beaton D, Smith PM, Hagen NA. Patterns of pain and interference in
patients with painful bone metastases: a brief pain inventory validation study. J Pain
Symptom Manage. 2010;39(2):230-40.
5. Twycross R, Harcourt J, Bergl S. A survey of pain in patients with advanced
cancer. J Pain Symptom Manage. 1996;12(5):273-82.
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6. Deshields TL, Tait RC, Manwaring J, et al. The Cancer Pain Inventory:
preliminary development and validation. Psychooncology. 2010;19(7):684-92.
7. Kim EB, Han HS, Chung JH, et al. The Effectiveness of a Self-Reporting
Bedside Pain Assessment Tool for Oncology Inpatients. J Palliat Med. J Palliat Med.
2012;15(11):1222-33.
8. Laird BJ, Walley J, Murray GD, et al. Characterization of cancer-induced bone
pain: an exploratory study. Support Care Cancer. 2011;19(9):1393-401.
9. Given B, Given CW, Sikorskii A, et al. Establishing mild, moderate, and severe
scores for cancer-related symptoms: how consistent and clinically meaningful are
interference-based severity cut-points? J Pain Symptom Manage. 2008;35(2):126-35.
10. Serlin RC, Mendoza TR, Nakamura Y, et al. When is cancer pain mild,
moderate or severe? Grading pain severity by its interference with function. Pain.
1995;61(2):277-84.
11. Li KK, Harris K, Hadi S, Chow E. What should be the optimal cut points for
mild, moderate, and severe pain? J Palliat Med. 2007;10(6):1338-46.
12. Oldenmenger WH, de Raaf PJ, de Klerk C, van der Rijt CC. Cut Points on 0-
10 Numeric Rating Scales for Symptoms Included in the Edmonton Symptom
Assessment Scale in Cancer Patients: A Systematic Review. J Pain Symptom Manage.
2012 Sep 24. pii: S0885-3924(12)00340-5.
13. Harris K, Li K, Flynn C, Chow E. Worst, average or current pain in the Brief
Pain Inventory: which should be used to calculate the response to palliative
radiotherapy in patients with bone metastases? Clin Oncol (R Coll Radiol).
2007;19(7):523-7.
14. Hadi S, Zhang L, Hird A, et al. Validation of symptom clusters in patients
with metastatic bone pain. Curr Oncol. 2008;15(5):211-8.
15. Zeng L, Sahgal A, Zhang L, et al. Patterns of pain and functional
improvement in patients with bone metastases after conventional external beam
radiotherapy and a telephone validation study. Pain Res Treat. 2011;2011:601720.
CANCER AND COMORBID CHRONIC

DISEASES
Comorbidity is associated with higher mortality, increased
disability, a decline in functional status, a lower QOL, and increased
utilization of health care (1). Newly diagnosed older cancer patients
who have lived into the later years of life are likely to have concurrent
ailments, such as diabetes, COPD, heart disease, arthritis, and/or
hypertension. These are some of the more common health problems
associated with advancing age that may affect treatment choice,
patient prognosis, and survival (2-4). Four out of 5 older individuals ≥
65 years have one or more chronic condition (5). In addition to the
concurrent presence of chronic conditions, older individuals may have
such geriatric syndromes as frailty, urinary incontinence, malnutrition,
depression, and balance disorders. Although investigators have begun
375
to address the coexistence of comorbidity and cancer in the elderly,

research is in the preliminary phases of conceptual and measurement
development (6-12). Limitations in functional status, such as self-
reliance in eating, washing, toileting, dressing, mobility, and
transportation that are associated with the aging continuum in later
years of the life span introduce an additional order of comorbidity
assessment complexity as do other age-related declines in physical
and physiologic functioning, cognitive impairment, and other
incapacities. Levels of severity of comorbidity quite likely include
additive and multiplicative relationships (13).
An observational prospective cohort study using comorbidity data
collected by trained hospital-based cancer registrars was carried out.
Comorbidity was obtained through medical record review using the
Adult Comorbidity Evaluation 27, a validated chart-based comorbidity
instrument. A total of 17,712 patients received care between January
1, 1995, and January 31, 2001 for the primary diagnosis of new cancer
of the prostate, lung (nonsmall cell), breast, G-I system,
gynecological, urinary system, or head and neck at the Department of
Otolaryngology-Head and Neck Surgery, Washington. In this study
were included 19,268 patients; median duration of follow-up was 31
months. Of these patients, 1556 (8.0%) were excluded due to missing
or unknown data. Severity of comorbidity strongly influenced survival
in a dose-dependent fashion and the impact of comorbidity was
independent of cancer stage. Compared with patients without
comorbidity, the adjusted HR associated with mild comorbidity was
1.21 (95% CI 1.13 - 1.30), moderate comorbidity was 1.86 (95% CI
1.73 - 2.00), and severe comorbidity was 2.56 (95% CI 2.35 - 2.81).
Adjusted Kaplan-Meier survival curves revealed that at any point in
time the patients with more severe levels of comorbidity had worse
survival (p<0.001). Model discrimination ranged from 0.71 for head
and neck to 0.86 for prostate cancers. In conclusion, comorbidity is an
important independent prognostic factor for patients with cancer (14).
A case comparison study of 15,626 population-based incident
cases of cancer was conducted between 1984-1992 in 3 metropolitan
Detroit counties (a NCI Surveillance, Epidemiology, and End Results
program). Chronic disease status and demographics were collected by
self-report; cancer diagnoses and staging were obtained by medical
record review. Comorbidity was present in 68.7% of cancer patients,
and 32.6% of these individuals had ≥ 2 comorbid conditions.
Frequency was increased in the elderly, African-American patients
(particularly African-American women), smokers, and those with
lower socioeconomic status. Rates appeared to vary by specific tumor
376
site. In conclusion, comorbid chronic diseases are common in persons

with cancer. The prevalence of comorbidities has important clinical,
health service, and research implications. The disease specific model
of oncology may limit appropriate care for these patients, while
enhanced integration of primary care into the ongoing management of
cancer may offer better outcomes (15).
Comorbid conditions of cancer patients, treated at 4 university
hospitals, each representing a different geographic location in Turkey
were examined. A total of 769 consecutive cancer patients presenting
to outpatient clinics were recruited between November 2007 and May
2008. The patients filled in a questionnaire on comorbidities. Based on
the questionnaire, Charlson Comorbidity Index was calculated. The
patients median age was 55 years (range 21-87) and 456 (59.3%) were
female. Breast (36.5%), CRC (21.4%) and lung cancers (13.9%) were
the most frequent malignancies. Of the patients, 59.3% had at least
one comorbid disease and 46.3% used at least one medication daily.
The most frequent comorbidities were hypertension (25.3%), diabetes
mellitus (13.1%) and peptic ulcer (7.7%). Increasing age positively
correlated with the extent of comorbidities (p<0.001), the number of
medications (p<0.001), and the Charlson Comorbidity Index
(p<0.001). In conclusion, comorbid illnesses are not rare and many
patients are treated for conditions unrelated to cancer, which
potentially may affect various stages of their clinical management
(16).
The prognostic role of increasing age and comorbid conditions in
patients diagnosed with stage I-III CRC, stage I-II NSCLC or stage I-
III breast cancer between 1995 and 2004 in the southern part of the
Netherlands was summarized. Almost all patients with stage I-III
colon or rectal cancer underwent surgery regardless of age or
comorbidity. By contrast, the resection rate among elderly patients
with stage I-II NSCLC was lower than among younger patients and
was significantly lower when COPD, C-V diseases or diabetes were
present. Among patients with stage I-III breast cancer, and those aged
≥ 80 years underwent less surgery, and the resection rate appeared to
be lower when C-V diseases or diabetes were present. Among patients
with resected CRC, postoperative morbidity and mortality were higher
among those undergoing emergency surgery, and among those with
reduced pulmonary function, C-V disease or neurological
comorbidity. Among those with resected NSCLC, postoperative
morbidity and mortality were related to reduced pulmonary function
or C-V disease. Since surgery for breast cancer is low risk, elective
surgery, morbidity and mortality were not higher for elderly or those
377
with comorbidity. Among patients with CRC or breast cancer,

comorbidity in general, C-V diseases, COPD, diabetes (only colon and
breast cancer) and venous thromboembolism had a negative effect on
overall survival, while the effect of comorbidity on survival of stage I-
II NSCLC was less clear. Elderly and those with comorbidity
(especially C-V diseases and COPD) among CRC cancer and NSCLC
patients had more postoperative morbidity and mortality (17).
The aim of the study was to identify chronic comorbidities and
cancer types in palliative home care patients and to compare their
incidence with the general Polish population. The data was obtained
for 543 patients who received palliative home care between 2005-
2009. The occurrence of the most common chronic conditions such as
arterial hypertension, ischemic heart disease, diabetes, COPDs and
CNS diseases were analyzed together with the cancer types. The study
group included 259 women (47.7%) and 284 men (52.3%) aged 25-91
years old. The most common primary neoplasm locations for men
were lung (28.2% vs. 21.4% in general population) and CRC (18.7%
vs. 11.4% in general population), and for women breast (19.7% vs.
22.8% in general population) and CRC (17.4% vs. 9.2% in general
population). The incidence of ischemic heart disease, diabetes, and
COPD was significantly different in comparison to the general
populations (47.0% vs. 11.3%, 20.3% vs. 6.8%, 16.6% vs. 27.5%,
respectively). The mean number of concomitant diseases was 1.6 for
women and 1.8 for men vs. 1.7 and 1.2, respectively. In conclusion,
the majority of the patients had concomitant disease, with C-V
diseases being most common. The most common primary diagnoses in
palliative home care patients were lung cancer and CRC, which
corresponded to the cancer prevalence in the general population (18).
Assessment: multimorbidity is a common problem in aged

populations with a wide range of individual and societal
consequences. There is an inverse relationship between
multimorbidity and disability, QOL, functional status and survival.
Comorbid chronic diseases are common in persons with cancer.
Older cancer patients who have lived into the later years of life are
likely to have concurrent ailments, such as diabetes, COPD, C-V
diseases, arthritis, peptic ulcer, and hypertension. In addition, older
individuals have such geriatric syndromes as frailty, urinary
incontinence, malnutrition, depression, and balance disorders.
As previously described (19) King David suffered from many
diseases. Was the King's multimorbidity related to higher mortality,
increased disability, a decline in functional status and a lower QOL?
378
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2. Day JC. Population Projections of the United States by Age, Sex, Race, and
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overview. Cancer. 1997;80:1273-83.
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risk for early mortality in male and female colon cancer patients: A population based
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10. Fried LP, Bandeen-Roche K, Kasper JD, et al. Associaton of comorbidity with
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for the prognostic classification of cancer. Cancer. 1996;77:834-42.
12. Newschaffer CJ, Penberthy L, Desch CD, et al. The effect of age and
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13. Yancik R, Ganz PA, Varricchio CG, Conley B. Perspectives on comorbidity
and cancer in older patients: approaches to expand the knowledge base. JCO.
2001;19(4):1147-51.
14. Piccirillo JF, Tierney RM, Costas I, et al. Prognostic importance of
comorbidity in a hospital-based cancer registry. JAMA.2004;291(20):2441-7.
15. Ogle KS, Swanson GM, Woods N, Azzouz F. Cancer and comorbidity:
redefining chronic diseases. Cancer. 2000;88(3):653-63.
16. Abali H, Ata A, Ozdogan M, et al. Frequency of comorbid illnesses in cancer
patients in Turkey. J BUON. 2011;16(3):557-60.
17. Janssen-Heijnen ML, Maas HA, Houterman S, et al. Comorbidity in older
surgical cancer patients: influence on patient care and outcome. Eur J Cancer.
2007;43(15):2179-93.
18. Ciałkowska-Rysz A, Kowalczyk M, Gottwald L, Kaźmierczak-Łukaszewicz
S. The comparison of common cancer types and the coincidence of concomitant
chronic diseases between palliative home care patients in Lodz Voivodeship and the
general Polish population. Arch Med Sci. 2012;8(3):496-503.
19. Ben-Noun L. King David the Great. In Ben-Noun L. ed. The Diseases of the
Kings of Israel. B.N. Publications. Israel. 2006, pp. 29-99.
379
CANCER-RELATED VISITS
Because of the growing cancer incidence and the increasing trend
towards chemotherapy treatment, a higher number of cancer
outpatients ask for unplanned visits. This study aimed to describe the
nature and magnitude of this phenomenon and to identify risk factors
for repeated unplanned presentations and hospital admission.
Unplanned consultations (2,811) of 1,431 cancer patients who
accessed a clinic at the Department of Oncology, University Hospital
'S. Maria della Misericordia', Italy over a 2-year period were
reviewed. Demographics, clinical variables and reason(s) for
presentation were recorded. Recurrent event survival analysis was
used to evaluate the relation of potential predictors to the 2 outcome
events repeated presentations and hospitalization. Of 1,431 patients,
625 (43%) received chemotherapy during the 90 days before the
unplanned visit. Pain (27.7%), fatigue (17.6%), dyspnea (13.8%),
fever (11.5%), and G-I problems (31%) were reported frequently. The
time interval since the last chemotherapy was significantly related to
the rate of repeated presentation. After an unplanned presentation, 208
(7%) patients were hospitalized. Number of symptoms and selected
toxicities, along with distance from the hospital, were predictors for
hospitalization. In conclusion, the management of unscheduled
presentations of cancer outpatients is becoming crucial to avoid
inappropriate selection for hospital admission and interferences with
the ordinary work plan, improving quality of oncology services (1).
After approval by the institutional review board, 2008, The North
Carolina Disease Event Tracking and Epidemiologic Collection Tool
ED visit data were acquired and cancer-related visits were identified.
Of 4,190,911 ED visits in 2008, there were 37,760 ED visits by
27,644 patients with cancer. Among patients, 77.2% had only one ED
visit in 2008, the mean age was 64 years, and there were slightly more
men than women. Among visits, the payer was Medicare for 52.4%
and Medicaid for 12.1%. More than half the visits by patients with
cancer occurred on weekends or evenings, and 44.9% occurred during
normal hours. The top 3 chief complaints were related to pain,
respiratory distress, and G-I issues. Lung, breast, prostate, and CRCs
were identified in 26.9%, 6.3%, 6%, and 7.7% of visits, respectively,
with diagnosis. Of all visits, 63.2% resulted in hospital admittance.
When controlling for sex, age, time of day, day of week, insurance,
and diagnosis position, patients with lung cancer were more likely to
be admitted than patients with other types of cancer. In conclusion,
this is the study to provide a population-based snapshot of ED visits
380
by patients with cancer in North Carolina. Efforts that target clinical

problems and specific populations may improve delivery of quality
cancer care and avoid ED visits (2).
Cancer patients visiting the emergency center are seldom assessed
or treated for severe fatigue, a common symptom in sick patients due
to acute medical conditions arising from cancer and cancer treatment.
A profile of cancer-related fatigue within the emergency center setting
is provided. Using a single-item screening tool derived from the BFI,
928 patients (636 with solid tumors, and 292 with hematological
malignancies) triaged in the emergency center of a tertiary cancer
center rated their fatigue at its worst in the last 24 hours. Patient
demographic and clinical factors were retrospectively reviewed from
medical records. The chief complaints of patients seeking emergency
care included fever, pain, G-I symptoms, dyspnea, fatigue, and
bleeding. More than half (54%) reported severe fatigue 7 or higher on
a 0-10 scale) upon EC admission. Moderate to severe pain was highly
associated with fatigue severity. Patients with severe fatigue were
more likely to be unstable and unable to go home after emergency
center care. In multivariate logistic regression analysis for severe
fatigue, the significant risk factors for patients with solid tumors
included dizziness (OR=3.59), severe pain (OR=1.98), poor
performance status (OR=1.81), and being female (OR=1.56). Dyspnea
was significantly associated with severe fatigue in patients with
hematological malignancies (OR=4.74). Although fatigue was not the
major reason for an ER visit, single-item fatigue-severity screening
demonstrated highly prevalent severe fatigue in sicker emergency
center cancer patients and in those patients who also suffered from
other symptoms (3).
Dyspnea is the fourth most common symptom of patients who
present to the ED at The University of Texas M. D. Anderson Cancer
Center and in some patients with advanced cancer represent a clinical
marker for the terminal phase of their disease. This retrospective study
describes the clinical characteristics of these patients, the resource
utilization associated with the management of dyspnea, and the
survival of patients with this symptom. Of 1068 patients, 102
presenting with dyspnea for a retrospective analysis were randomly
selected. The median age of the patients was 58 years (range, 23-90
years) and 53% were female. Underlying malignancies were breast
cancer (30%), lung cancer (37%), and other cancers (34%).
Approximately 94% of the patients had received prior cancer
treatment and the majority (69%) had uncontrolled, progressive
disease. The most common treatments administered in the ED were
381
oxygen (31%), beta-2 agonists (14%), antibiotics (12%), and narcotics

(11%). Approximately 60% of patients were admitted to the hospital
from the ED for further treatment of dyspnea and the underlying
malignancy, and the median length of stay was 9 days. The median
overall survival after the ED visit for dyspnea was 12 weeks. Specific
diagnoses were associated with different median survival rates: lung
cancer patients: 4 weeks; breast cancer patients: 22 weeks (p=0.0073,
vs. lung cancer); and other cancer diagnoses: 27 weeks (p=0.0027, vs.
lung cancer). In conclusion, lung cancer patients presenting to the ED
with dyspnea have much shorter survival than patients with other
malignancies. For some patients, the presence of dyspnea requiring
emergency treatment may indicate a phase in their illness in which
resources should be shifted from acute intervention with
hospitalization to palliative and supportive care measures (4).
A retrospective cohort study was conducted to determine whether
evidence of cancer progression is an independent predictor of short-
term mortality in acutely symptomatic cancer patients. The records of
396 patients who visited Anderson cancer emergency center, Houston,
in January 2000 were reviewed for clinical characteristics, including
symptoms, type and extent of cancer, and whether the patient's cancer
was stable or progressing (uncontrolled) at the time of the emergency
center visit. Cox regression analysis was used to assess survival at 90
and 180 days, after controlling for patient characteristics. Patients who
died within 14, 90, or 180 days were more likely to have disease
progression than those who did not. Dyspnea on emergency center
presentation and disease progression were independent predictors of
death within 90 or 180 days, after controlling for patient age,
symptoms, signs, and the presence of metastases. The ORs for death
within 90 and 180 days were 3.97 and 4.34, respectively (95% CIs
1.44-10.94 and 1.87-10.09). In conclusion, cancer disease progression
is a clinical measure of increased risk of short-term mortality in
acutely symptomatic cancer patients. Symptomatic cancer patients
presenting to a cancer center emergency room were more likely to die
within 14, 90, or 180 days if they had evidence of recent progression
of their cancer. Among patients with disease progression, 47% died
within 90 days and 61% within 180 days (5).
Since 2007 in Ontario, Canada, the ESAS has been routinely used
for cancer outpatients. The purpose of this study is to determine the
relationship between individual patient symptoms and symptom
severity, with the likelihood of an ED visit. The cohort included all
cancer patients in Ontario who completed an ESAS between January
2007 and March 2009. Using multiple linked provincial health
382
databases, the adjusted association between symptom scores and the

likelihood of an ED visit within 7 days of assessment was examined.
The cohort included 45,118 patients whose first assessment
contributed to the study, of whom 3.8% made a subsequent ED visit.
A severe well-being score was associated with the highest odds of a
subsequent ED visit (AOR 1.9, 95% CI 1.5 - 2.4). Nausea, drowsiness,
and dyspnea with moderate or severe scores were associated with ED
visits (AOR 1.2 - 1.5), whereas pain, tiredness, poor appetite, and
well-being had a significant association for mild scores (AOR 1.2, 1.3,
1.2, and 1.3, respectively), moderate scores (AOR 1.3, 1.5, 1.5, and
1.7, respectively), and severe scores (AOR 1.4, 1.7, 1.7, and 1.9,
respectively). Anxiety and depression were not associated with ED
visits. In conclusion, worsening symptoms contribute to emergency
visits in cancer patients. Specific symptoms such as pain are obvious
management targets, but constitutional symptoms were associated
with even higher odds of ED usage and therefore warrant detailed
assessment to optimize both patient outcomes and resource use (6).
This study measures the proportion of cancer patients in Ontario,
Canada, ICU admissions, ER visits, or chemotherapy in the last 2
weeks of life. The Ontario Cancer Registry was used to identify a
cohort of cancer patients who died in 2001. These cases were then
linked to administrative sources of data to measure each indicator, and
to describe the associated clinical and health service factors. In the
cohort, 27% had at least 1 ER visit and 5% had an ICU visit in the last
2 weeks of life. Of those who received chemotherapy in the last 6
months, 16% received chemotherapy in the last 2 weeks of life.
Receiving a home care visit in the last 6 months of life, or a physician
house call or a palliative care assessment in the last 2 weeks of life
was associated with decreased odds of each of the indicators. In
conclusion, a significant proportion of Ontario cancer patients have
indicators of poor quality end-of-life care (7).
For patients dying of cancer, a visit to the ED can be disruptive,
distressing and exhausting. Such visits made near the end of life are
considered an indicator of poor-quality cancer care. Between 2002 and
2005 in Ontario, 91,561 patients died of cancer. Of these, 76,759
patients made 194,017 visits to the ED during the final 6 months of
life. Further, 31,076 patients made 36,600 visits to the ED during the
final 2 weeks of life. In both periods, the most common reasons were
abdominal pain, lung cancer, dyspnea, pneumonia, malaise, fatigue,
and pleural effusion. This study indicates that many visits made to the
ED by patients with cancer near the end of life may be avoidable. An
understanding of the reasons for such visits could be useful in the
383
development of dedicated interventions for preventing or avoiding

their occurrence (8).
This descriptive, retrospective study sought to identify the nature
and magnitude of chemotherapy outpatients' unplanned presentations
and admissions to the ED and/or cancer centre at a large metropolitan
tertiary hospital, and to explore the antecedents to those presentations.
Retrospective data were collected for outpatients who made an
unplanned presentation to a large metropolitan hospital in Sydney,
Australia between October 1, 2006 and September 30, 2007. Detailed
information was collected for those who had received cytotoxic
chemotherapy at the hospital's cancer centre within the 6 months prior
to the unplanned presentation to hospital. Demographic and
explanatory variables were identified, including: reasons for
presentation, cancer diagnosis, chemotherapy regimens, and position
in the chemotherapy trajectory. The Cancer Institute New South
Wales figures indicate that each year approximately 518 outpatients
are treated with chemotherapy at the participating cancer centre.
During the study period, 316 cancer outpatients made 469 unplanned
presentations to either the Cancer Centre or the hospital ED. Of those
outpatients presented, 233 (73.7%) had received chemotherapy in the
previous 6 months and made 363 presentations. Of these
presentations, 253 (69.7%) occurred within 4 weeks of receiving
chemotherapy. The majority of presentations by those who had
received chemotherapy in the previous 6 months resulted in hospital
admission (87.6%) for a median length of stay of 5 days. The most
frequent presentation symptoms were nausea and/or vomiting
(45.2%), pain (27%), fever, and/or febrile neutropenia (23.4%),
dyspnea (19.3%), dehydration (12.1%), anemia (8.8%), fatigue
(8.8%), diarrhea (8.8%), and anxiety and/or depression (5.5%). In
conclusion, chemotherapy outpatients have significant unmet needs
following treatment, indicating an urgent need for improved
continuity of care and better integration of primary and tertiary health
care services (9).
Assessment: because of the growing cancer incidence and the

increasing trend towards chemotherapy treatment, a higher number of
cancer outpatients ask for unplanned visits. Reasons for emergent
visits included pain, fatigue, dyspnea, fever, G-I problems, nausea,
drowsiness, and dyspnea. Chemotherapy treatment was associated
with visits for nausea and/or vomiting, pain, fever and/or febrile
neutropenia, dyspnea, dehydration, anemia, fatigue, diarrhea, and
anxiety and/or depression. Dyspnea on emergency center presentation
384
and disease progression were independent predictors of death within

90 or 180 days.
References
1. Aprile G, Pisa FE, Follador A, et al. Unplanned presentations of cancer
outpatients: a retrospective cohort study. Support Care Cancer. 2013;21(2):397-404.
2. Mayer DK, Travers D, Wyss A, et al. Why do patients with cancer visit
emergency departments? Results of a 2008 population study in North Carolina. J Clin
Oncol. 2011;29(19):2683-8.
3. Escalante CP, Manzullo EF, Lam TP, et al. Fatigue and its risk factors in cancer
patients who seek emergency care. J Pain Symptom Manage. 2008;36(4):358-66.
4. Escalante CP, Martin CG, Elting LS, et al. Dyspnea in cancer patients.
Etiology, resource utilization, and survival-implications in a managed care world.
Cancer. 1996;78(6):1314-9.
5. Geraci JM, Tsang W, Valdres RV, Escalante CP. Progressive disease in
patients with cancer presenting to an emergency room with acute symptoms predicts
short-term mortality. Support Care Cancer. 2006;14(10):1038-45.
6. Barbera L, Atzema C, Sutradhar R, et al. Do Patient-Reported Symptoms
Predict Emergency Department Visits in Cancer Patients? A Population-Based
Analysis. Ann Emerg Med. 2013 Jan 3. pii: S0196-0644(12)01617-4.
7. Barbera L, Paszat L, Chartier C. Indicators of poor quality end-of-life cancer
care in Ontario. J Palliat Care. 2006;22(1):12-7.
8. Barbera L, Taylor C, Dudgeon D. Why do patients with cancer visit the
emergency department near the end of life? CMAJ. 2010;182(6):563-8.
9. McKenzie H, Hayes L, White K, et al. Chemotherapy outpatients' unplanned
presentations to hospital: a retrospective study. Support Care Cancer. 2011;19(7):963-
9.
385
HEMATOLOGICAL MALIGNANCIES
IMMUNOSECRETORY DISORDERS
The immunosecretory disorders are a diverse group of diseases
associated with proliferation of an abnormal clone of Ig synthesizing
terminally differentiated B cells. These disorders include MM and its
variants, plasmacytoma, WM, MGUS, and monoclonal Ig deposition
diseases, the latter includes amyloidosis and non-amyloidotic types.
The disorders are histologically composed of plasma cells, or
plasmacytoid cells, which produce Ig that is synthesized, is usually
secreted and can be deposited in some diseases. The Ig can be
complete or can be composed of either heavy or light chains and is
termed M-(monoclonal) protein (1).
Reference
1. Shaheen SP, Talwalker SS, Medeiros LJ. Multiple myeloma and
immunosecretory disorders: an update. Adv Anat Pathol. 2008;15:196-210.
MULTIPLE MYELOMA
MM is the second most common hematologic malignancy, with
approximately 16.000 new cases per year, and accounts for 11.000
deaths in the USA. It is the most common cancer to metastasize to the
bone, with up to 90% of patients developing bone lesions (1).
MM is a tumor of terminally differentiated plasma cells that home
to and expands in the bone marrow (1). It is a hemato-oncologic
disease in the elderly population, with a peak incidence in the eight
decade, and represents a malignant bone marrow neoplasia in which a
monoclonal strain of atypical plasma cells proliferates and may result
in bone destruction. Skeletal metastases represent the most common
malignant bone tumor and are the third most common location for
distant metastases (2,3).
MM accounts for ∼10% of all hematologic malignancies (4), and
is characterized by the accumulation more than 10% of monoclonal
plasma cells in the bone marrow and the production of large amounts
of a monoclonal immunoglobulin or paraprotein (5,6). The diagnosis
requires 10% or more clonal plasma cells on bone marrow
386
examination or a biopsy proven plasmacytoma plus evidence of end-

organ damage related to the underlying plasma-cell disorder (4,7).
Patients with 17p deletion, t(14;16), t(14;20), or high-risk gene
expression profiling signature have high-risk for myeloma. Patients
with t(4;14) translocation, karyotypic deletion 13, or hypodiploidy
have intermediate-risk disease. All others are considered to have
standard-risk for myeloma (4).
Chromosomal aberrations in MM are important prognostic
determinants that influence the clinical decision-making in newly-
diagnosed MM. Patients are considered high-risk if any of the
following features are detected: hypodiploidy, deletion 13 by
cytogenetics, t(4;14), t(14;16), t(14;20) and/or 17 p deletion. In the
absence of these features patients are considered standard risk (8).
Skeletal-related complications affect nearly all patients with MM
and have a major impact on both patient morbidity and mortality (7).
In MM, enhanced bone loss is commonly associated with a diffuse
osteopenia, or osteoporosis, focal lytic lesions, pathological fractures,
cord compression, severe bone pain, malaise, hypercalcaemia, anemia,
and renal insufficiency (2,7,9-12).
A patient exhibits marked diffuse osteopenia, endplate fractures and

pathologic compression fractures due to widespread multiple myeloma.
Diagnosis of MM should be based on the following tests:

*Detection and evaluation of the monoclonal (M-) component.
*Serum and urine protein electrophoresis (concentrate of 24-hours
urine); quantification of IgG, IgA and IgM immunoglobulins.
*Characterization of the heavy and light chain by immunofixation.
Serum free light chain measurement for identifying and monitoring
non-secretory MM; evaluation of bone marrow plasma cell
387
infiltration; bone marrow aspiration and biopsy to detect quantitative

and/or qualitative abnormalities of bone marrow plasma cells.
*Evaluation of lytic bone lesions. Comprehensive skeletal imaging,
using first plain radiographs and then more advanced modalities if
necessary, is critical both at the time of diagnosis and throughout the
course of therapy to assess the skeletal impact of the disease (7).
*Assessment is required to differentiate symptomatic and
asymptomatic MM: hemoglobin (and full blood cell count), serum
creatinine and calcium levels (2,13).
Comprehensive skeletal imaging, using first plain radiographs and
then more advanced modalities if necessary, is critical both at the time
of diagnosis and throughout the course of therapy to assess the
skeletal impact of the disease (7).
A skull x-ray shows typical findings of multiple myeloma.
Typical symptoms are bone pain, malaise, anemia, renal

insufficiency, and hypercalcemia. Incidental discovery on
comprehensive laboratory panels is common. The disease is diagnosed
with serum or urine protein electrophoresis or immunofixation and
bone marrow aspirate analysis. Skeletal radiographs are important in
staging MM and revealing lytic lesions, vertebral compression
fractures, and osteoporosis. MRI, PET or CT are emerging as useful
tools in the evaluation of patients with myeloma; MRI is preferred for
evaluating acute spinal compression. Nuclear bone scans and DXA
have no role in the diagnosis and staging of MM. The differential
diagnosis of monoclonal gammopathies includes MGUS, smoldering
(asymptomatic) and symptomatic MM, amyloidosis, B-cell non-
Hodgkin lymphoma, WM, rare plasma cell leukemia, and HCD.
Patients with MGUC or smoldering MM should be followed closely,
but not treated (2).
Patients with MM commonly develop focal osteolytic bone
disease, as well as generalized osteoporosis. The mechanisms
388
underlying the development of osteoporosis in patients with myeloma

are poorly understood. Although disruption of the RANKL/OPG
pathway underlies formation of focal osteolytic lesions, its role in the
development of osteoporosis in MM remains unclear. Increased
soluble RANKL in serum from patients with myeloma raises the
possibility that this molecule plays a key role. The aim of the present
study was to establish whether sRANKL produced by myeloma cells
contributes directly to osteoporosis. C57BL/KaLwRij mice were
injected with either 5T2MM or 5T33MM murine myeloma cells.
5T2MM-bearing mice developed osteolytic bone lesions (p<0.05)
with increased osteoclast surface (p<0.01) and reduced trabecular
bone volume (p<0.05). Bone volume was also reduced at sites where
5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice
soluble mRANKL was increased (p<0.05), whereas OPG was not
altered. By contrast, 5T33MM-bearing mice had no changes in
osteoclast surface or trabecular bone volume and did not develop
osteolytic lesions. Soluble mRANKL was undetectable in serum from
5T33MM-bearing mice. In separate experiments, RPMI-8226 human
myeloma cells were transduced with a human RANKL/eGFP
construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not
RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption
(p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with
RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in
tumor development in all mice. RPMI-8226/hRANKL/eGFP-bearing
mice exhibited increased serum soluble hRANKL (p<0.05) and a
three-fold increase in osteoclast number (p<0.05) compared to RPMI-
8226/eGFP-bearing mice. This was associated with reduced trabecular
bone volume (27%, p<0.05), decreased trabecular number (29%,
p<0.05) and increased trabecular thickness (8%, p<0.05). These
findings demonstrate that soluble RANKL produced by myeloma cells
causes generalized bone loss, suggesting that targeting RANKL may
prevent osteoporosis in patients with myeloma (15).
Osteolytic bone disease is the most debilitating manifestation of
MM (16). The disease of the spine is a growing problem, affecting
70% of patients with metastatic disease or MM. Tumor-induced
osteolysis may lead to pain, dysfunction, and ultimately vertebral
collapse. If left untreated, vertebral body compression fractures take
place with progressive kyphosis over multiple levels, cord
compression, and intractable pain (17).
Although bone pain related to multiple lytic lesions is the most
common clinical presentation, up to 30% of patients are diagnosed
incidentally while being evaluated for unrelated problems, and one
389
third of patients are diagnosed after a pathological fracture, commonly

in axial skeleton (6).
The clinical presentation of MM is varied and depends on the sites
and extent of involvement. Most importantly for chiropractors, the
leading clinical symptoms of MM are related to bone neoplasm and
may mimic pain of musculoskeletal origin. The following is the case
of a 56-year-old male chiropractic patient presenting with a 6-month
history of sacroiliac joint pain previously diagnosed and managed
unsuccessfully as a hematoma by multiple providers. Physical
examination, imaging, and laboratory investigations confirmed a
diagnosis of MM (18).
Symptomatic MM is treated with chemotherapy followed by
autologous stem cell transplantation, if possible. Melphalan,
prednisolone, dexamethasone, vincristine, doxorubicin, bortezomib,
and thalidomide and its analogue lenalidomide have been used
successfully. It is important that family physicians recognize and
appropriately treat MM complications. Bone pain is treated with
opiates, bisphosphonates, RT, vertebroplasty, or kyphoplasty;
nephrotoxic NSAIDs should be avoided. Hypercalcemia is treated with
isotonic saline infusions, steroids, furosemide, or bisphosphonates.
Because of susceptibility to infections, patients require broad-
spectrum antibiotics for febrile illness and immunization against
influenza, pneumococcus, and Haemophilus influenzae B. Five-year
survival rates approach 33%, and the median survival rate is 33
months (2).
The widespread use of intravenous bisphosphonate therapy has
significantly improved the QOL of myeloma patients by limiting the
amount of osteolytic destruction that occurs. Bisphosphonate
treatment, however, does not lead to repair of bone damage that has
already occurred. The recent identification of multiple molecular
targets with key roles in the osteolytic process has illuminated our
understanding of myeloma bone disease, and may transform our future
approaches to providing MM patients with optimal skeletal care (7).
Standard-risk patients are treated with nonalkylator-based therapy
such as lenalidomide plus low-dose dexamethasone (Rd) followed by
ASCT. An alternative strategy is to continue initial therapy after stem-
cell collection, reserving ASCT for first relapse. Intermediate-risk and
high-risk patients are treated with a bortezomib-based induction
followed by ASCT and then bortezomib-based maintenance. Patients
not eligible for ASCT can be treated with Rd for standard risk disease
or with a bortezomib-based regimen if intermediate-risk or high-risk
features are present. To reduce toxicity, when using bortezomib, the
390
once-weekly subcutaneous dose is preferred; similarly, when using

dexamethasone, the low-dose approach (40 mg once a week) is
preferred, unless there is a need for rapid disease control. Patients with
indolent relapse can be treated first with 2-drug or 3-drug
combinations. Patients with more aggressive relapse often require
therapy with a combination of multiple active agents. The most
promising new agents in development are pomalidomide and
carfilizomib (4).
Outside of trials, risk-adapted therapy in the transplant-eligible
high-risk patients advocates use of bortezomib-based induction
therapy followed by ASCT and bortezomib-based maintenance
therapy. High-risk, transplant-ineligible patients should also utilize
bortezomib as initial therapy since it is known to overcome the poor
prognosis associated with some high-risk features. The goal of therapy
in high-risk patients is to attain and maintain a state of complete
remission as much as possible. By contrast, the standard-risk,
transplant-eligible patients may be treated with either lenalidomide-
dexamethasone or bortezomib-based therapy followed by ASCT. In
such patients, ASCT can be deferred until first relapse if the patients
are tolerating initial therapy well. Lenalidomide maintenance therapy
in the post-transplant setting in standard-risk patients is controversial
and not recommended routinely. For transplant-ineligible standard-
risk patients, multiple options exist, although in the absence direct
comparisons, lenalidomide plus low-dose dexamethasone over
melphalan-based combinations are preferred (8).
Assessment: was the King afflicted by MM? MM is a hemato-

oncological disease of the elderly population, with a peak incidence in
the eight decade, and represents a malignant bone marrow neoplasia.
MM accounts for ∼10% of all hematologic malignancies, and is
characterized by the accumulation more than 10% of monoclonal
plasma cells in the bone marrow and the production of large amounts
of a monoclonal immunoglobulin or paraprotein. The diagnosis
requires 10% or more clonal plasma cells on bone marrow
examination or a biopsy proven plasmacytoma plus evidence of end-
organ damage related to the underlying plasma-cell disorder.
Typical symptoms are bone pain, malaise, anemia, renal
insufficiency, and hypercalcemia. Incidental discovery on
comprehensive laboratory panels is common. Skeletal-related
complications affect nearly all patients with MM and have a major
impact on both patient morbidity and mortality. Osteolytic bone
disease is the most debilitating manifestation of MM. Enhanced bone
391
loss is associated with a diffuse osteopenia, or osteoporosis, focal lytic

lesions, pathological fractures, severe bone pain, malaise,
hypercalcaemia, anemia, and renal insufficiency.
The disease of the spine is a growing problem, affecting 70% of
patients with metastatic disease or MM. Tumor-induced osteolysis
may lead to pain, dysfunction, and ultimately vertebral collapse. If left
untreated, vertebral body compression fractures take place with
progressive kyphosis over multiple levels, cord compression, and
intractable pain.
The disease is diagnosed with serum or urine protein
electrophoresis or immunofixation and bone marrow aspirate analysis.
Skeletal radiographs are important in MM staging, revealing lytic
lesions, vertebral compression fractures, and osteoporosis. The
diagnosis of MM or other immunosecretory disorders requires an
extensive evaluation including laboratory, radiological, and bone
marrow examination.
This is a contemporary approach to establishing appropriate
diagnosis of the disease (MM) that afflicted the patient. We can
assume that such evaluation was not performed in the King's case.
Was MM responsible for severe bone pain in King David's case?
We have 3 parameters: the King was an elderly person, he suffered
from severe intractable bone pains, and he was afflicted by anemia
(19,20). Bone pain related to multiple lytic lesions is the most
common presentation of MM. Although in King David's case no
contemporary diagnostic evaluation was performed, the biblical words
"My bones wasted away through my anguished roaring all day long‖
(Psalm 32:3) and ―...my strength failed..., and my bones are
consumed‖ (Psalm 31:11) may indicate MM.
References
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Pract Res Clin Haematol. 2007;20:613-24.
2. Nau KC, Lewis WD. Multiple myeloma: diagnosis and treatment. Am Fam
Physician. 2008;78:853-9.
3. Baur-Melnyk A, Reiser M. Oncohaematologic disorders affecting the skeleton
in the elderly. Radiol Clin North Am. 2008;46(4):785-98, vii.
4. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification,
and management. Am J Hematol. 2012;87(1):78-88. Erratum in: Am J Hematol.
2012;87(4):452.
5. Caers J, Vande broek I, De Raeve H, et al. Multiple myeloma – an update on
diagnosis and treatment. Eur J Haematol. 2008;81:329-43.
6. George ED, Sadovsky R. Multiple myeloma: recognition and management. Am
Fam Physician. 1999;59:1885-94.
7. Drake MT. Bone disease in multiple myeloma. Oncology (Williston Park).
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8. Kapoor P, Rajkumar SV. Update on risk stratification and treatment of newly

diagnosed multiple myeloma. Int J Hematol. 2011;94(4):310-20.
9. Yeh HS, Berenson JR. Myeloma bone disease and treatment options. Eur J
Cancer. 2006;42:1554-63.
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Cancer Biol Ther. 2006;5:1082-5.
11. Itse M, Takagi T. Bone lesions in multiple myeloma. Nuppon Rinsho.
2007;65:2224-8.
12. Huff CA, Matsui W. Multiple myeloma cancer stem cells. J Clin Oncol.
2008;26:2895-900.
13. Harousseau JL, Dreyling M. Multiple myeloma: ESMO clinical
recommendations for diagnosis, treatment and follow-up. Ann Oncology. 2008;19
(Supplement 2):ii55-57.
14. Hansmann HJ, Wunsch C, Schneider B, et al. Radiologic diagnosis of bone
metastases. Orthopade. 1998;27:224-30.
15. Buckle CH, De Leenheer E, Lawson MA, et al. Soluble rank ligand produced
by myeloma cells causes generalised bone loss in multiple myeloma. PLoS One.
2012;7(8):e41127.
16. Epstein J, Walker R. Myeloma and bone disease:"the dangerous tango". Clin
Adv Hematol Oncol. 2006;4:300-6.
17. Siemionov K, Lieberman IH. Vertebral augmentation in osteoporosis and
bone metastasis. Curr Opin Support Palliat Care. 2007;1:323-7.
18. Southerst D, Dufton J, Stern P. Multiple Myeloma presenting as sacroiliac
joint pain: a case report. J Can Chiropr Assoc. 2012 ;56(2):94-101.
19. Ben-Nun L. The diseases of the bones. In Ben-Nun L. ed. The Family Life
Cycle and the Medical record of King David the Great. B.N. Publications. Israel.
2009, pp. 119-158.
20. Ben-Nun L. The diseases that caused chronic weakness. In: Ben-Nun L. ed.
Israel. 2009, pp. 172-80.
MONOCLONAL GAMMOPATHY
OF UNDETERMINED SIGNIFICANCE
MGUS is a premalignant plasma-cell proliferative disorder
characterized by the presence of a monoclonal immunoglobulin and
associated with a life-long average 1% annual risk of developing
lymphoproliferative malignancies. The prevalence of MGUS is 3% for
persons > 50 years of age and 5% in those > 70 years of age. The risk
of progression to MM or a related disorder is 1% per year (1,2).
During long-term follow-up, approximately one fourth of patients
develop MM, amyloidosis, macroglobulinemia, or a similar malignant
lymphoproliferative disorder (1).
393
Currently, there are no methods for classification patients due to

the risk of progression to MM, and there is no therapy to prevent the
progression, so the standard treatment for patients with MGUS is
observation. The increased risk of developing MGUS among first-
degree relatives of MGUS patients is observed, however, due to the
low absolute risk for MGUS and the lack of available intervention and
early disease therapies, familial screening for MGUS is not
recommended (2).
MGUS is characterized by the serum M-protein less than 3 g/dl;
fewer than 10% plasma cells in the bone marrow; no, or only small
amounts of M protein in the urine; lack of organ damage including
hypercalcaemia, renal impairment, anemia and bone lesions; and,
most importantly stability of the M-protein and failure of development
of other abnormalities (1-3). The size and type of M protein, the
number of bone marrow plasma cells, and the results of the free light
chain ratio are independent risk factors for progression. Patients may
be tested for a monoclonal gammopathy by serum protein
electrophoresis, immunofixation, and the free light chain assay (1).
MGUS is a common, age-related medical condition characterized
by an accumulation of bone marrow plasma cells derived from a
single abnormal clone. Patients are diagnosed with MGUS if they
fulfill the following 3 criteria: 1. A monoclonal paraprotein band less
than 30 g/L (< 3g/dL); 2. Plasma cells less than 10% on bone marrow
examination; 3. No evidence of bone lesions, anemia, hypercalcemia,
or renal insufficiency related to the paraprotein, and 4. No evidence of
another B-cell proliferative disorder (4).
Schematic representation of a protein electrophoresis gel. A small spike

would be present in the gamma (γ) band of monoclonal gammopathy of
undetermined significance.
A monoclonal spike on serum protein electrophoresis is a frequent

finding in the general population and pathognomonic of a plasma cell
dyscrasia. In otherwise healthy individuals, it is diagnostic of 2
394
asymptomatic, premalignant conditions called MGUS and smoldering

MM, which carry a lifelong risk of progression to MM or related
malignancy (5).
Differential diagnosis: several other illnesses can present with a
monoclonal gammopathy and the monoclonal protein may be the first
discovery before a formal diagnosis is made: MM, AIDS, CLL, non-
Hodgkin lymphoma, particularly splenic marginal zone lymphoma (6)
and lymphoplasmocytic lymphoma, hepatitis C, connective tissue
disease such as lupus (7), immunosuppression following organ
transplantation, WM, and Guillain-Barre syndrome (8).
The finding of MGUS is frequent during an evaluation for
osteoporosis or a fracture. In most cases, the diagnosis is MGUS,
whose prevalence increases with age. Although the effect of MGUS
on BMD, bone remodeling, and the fracture risk remains unclear, this
asymptomatic hematological disorder may constitute a risk factor for
osteoporosis. Each year, 1% of patients with MGUS progress to MM,
a disease whose pathophysiology and association with bone loss and
pathological fractures are increasingly understood. Osteoporotic
fractures, although probably common in MM, are less likely to be
recognized (9).
During 1990 at the Mayo Clinic, 787 patients were found to have
monoclonal gammopathy. IgG accounted for 61% of the cases,
followed by IgM (18%), IgA (11%), Bence Jones proteinemia (6%),
biclonal gammopathy (3.5%), and IgD (0,5%). MGUS accounted for
approximately two thirds of patients. This denotes the presence of
monoclonal protein in persons without evidence of MM,
macroglobulinemia, amyloidosis, or other related diseases. During the
long-term follow-up of patients with MGUS, one fourth developed
MM or related disorders. The interval from recognition of the
monoclonal gammopathy to the development of MM ranged from 2 to
29 years (median, 10 years). WM developed in 7 patients four to 20
years (median, 8.5 years) after recognition of the monoclonal protein.
Systemic amyloidosis was found in 8 patients 6 to 19 years (median, 9
years) after the diagnosis of a serum monoclonal protein. Five patients
developed a malignant lymphoproliferative process 6 to 22 years
(median, 10.5 years) after the recognition of a monoclonal protein.
Minimal criteria for the diagnosis of MM included the presence of at
least 10% abnormal plasma cells in the bone marrow or histological
proof of a plasmacytoma, the usual clinical features of MM, and at
least of the following abnormalities: monoclonal serum protein
(usually greater than 3 g/dL), monoclonal protein in the urine, or
osteolytic lesions. No single technique differentiated benign from
395
malignant plasma cell proliferation. In conclusion, the most

dependable means is serial measurement of the monoclonal protein in
the serum and urine and periodic reevaluation of pertinent clinical and
laboratory features to determine whether MM, systemic amyloidosis,
macroglobulinemia, or other lymphoplasma cell proliferative disease
have developed (10).
Assessment: MGUS is a premalignant plasma-cell proliferative

disorder characterized by the presence of a monoclonal
immunoglobulin and associated with a life-long average 1% annual
risk of developing lymphoproliferative malignancies. The prevalence
of MGUS is 3% for persons > 50 years of age and 5% in those > 70
years of age. The risk of progression to MM or a related disorder is
1% per year.
MGUS is characterized by the serum M-protein less than 3 g/dl;
fewer than 10% plasma cells in the bone marrow; no, or only small
amounts of M protein in the urine; absence of bone lesions, anemia,
hypercalcaemia, and renal insufficiency; and, most importantly
stability of the M-protein and failure to develop other abnormalities.
Was King David afflicted by MGUS that later developed into MM
or other related disorders? In the absence of the bone lesions in
MGUS, it seems unlikely that the King was afflicted by MGUS.
References
1. Kyle RA, Rajkumar SV. Monocolonal gammopathy of undetermined
significance and smouldering multiple myeloma: emphasis on risk factors for
progression. Br J Haematol. 2007;139:730-43.
2. Stelmach-Gołdyś A, Czarkowska-Paczek B. Monoclonal gammopathy of
undetermined significance - potential risk factor of multiple myeloma. Przegl Lek.
2012;69(5):194-6.
3. Kyle RA. Monoclonal gammopathy of undetermined significance and solitary
plasmocytoma. Implications for progression to overt multiple myeloma. Hematol
Oncol Clin North Am. 1997;11:71-87.
4. International Myeloma Working Group. Criteria for the classification of
monoclonal gammopathies, multiple myeloma and related disorders: a report of the
International Myeloma Working Group. Br J Haematol. 2003;121(5):749-57.
5. Bianchi G, Ghobrial IM. Does my patient with a serum monoclonal spike have
multiple myeloma? Hematol Oncol Clin North Am. 2012;26(2):383-93, ix.
6. Murakami H, Irisawa H, Saitoh T, et al. Immunological abnormalities in
splenic marginal zone cell lymphoma. Am. J. Hematol. 1997;56(3):173-8.
7. Larking-Pettigrew M, Ranich T, Kelly R.. Rapid onset monoclonal
gammopathy in cutaneous lupus erythematosus: interference with complement C3 and
C4 measurement. Immunol. Invest. 1999;28(4):269-76.
8. Czaplinski A, Steck A. Immune mediated neuropathies - an update on
therapeutic strategies. J. Neurol. 2004;251(2):127-37.
396
9. Bouvard B, Royer M, Chappard D, et al. Monoclonal gammopathy of

undetermined significance, multiple myeloma, and osteoporosis. Joint Bone Spine.
2010;77(2):120-4.
10. Kyle RA. Diagnostic criteria of multiple myeloma. Hematol Onco Clin North
Am. 1992;6:347-58.
SMOLDERING MYELOMA
Smoldering (asymptomatic) MM is a more advanced premalignant
phase than MGUS and is characterized by more than 3 g/dL of serum
M protein, more than 10% clonal plasma cells in the bone marrow, or
both, with no evidence of end-organ damage including
hypercalcaemia, renal insufficiency, anemia, and bone lesions (1,2).
MGUS and smoldering MM are both caused by a proliferation of

monoclonal plasma cells leading to a detectable serum monoclonal
protein and/or excess of plasma cells in the bone marrow. Prerequisite
for the diagnosis is that plasma cell disease does not cause clinical
symptoms. Cytogenetic aberrations are detectable in the majority of
patient in the clonally expanded plasma cells. MGUS consistently
proceeds symptomatic MM. The lifetime risk of progression into
symptomatic MM lies between 15-59% for patients with MGUS or
smoldering MM. Prognostic parameters for development of
symptomatic MM from MGUS or smoldering MM are concentration
of monoclonal protein, bone marrow plasmacytosis, a non-IgG
subtype and an abnormal free-light chain ratio. Detection of more than
1 focal lesion in whole body MRI, 95% or more of bone marrow
plasma cells displaying an aberrant phenotype in flow cytometry and
an evolving clinical course in 2 consecutive follow-up visits are
397
additional prognostic parameters for smoldering MM. Currently there

is no accepted secondary prevention strategy available for smoldering
MM and MGUS progression (3).
A computerized database was searched and the medical records of
all patients at Mayo Clinic who fulfilled the criteria of the
International Myeloma Working Group for the diagnosis of
smoldering MM between 1970 and 1995 were reviewed. Bone
marrow aspirate and biopsy specimens were studied, and patients were
followed throughout the course of disease. During the 26-year period,
276 patients fulfilled the criteria for smoldering MM. During 2131
cumulative person-years of follow-up, symptomatic MM or
amyloidosis developed in 163 persons (59%). The overall risk of
progression was 10% per year for the first 5 years, approximately 3%
per year for the next 5 years, and 1% per year for the last 10 years; the
cumulative probability of progression was 73% at 15 years. At
diagnosis, significant risk factors for progression included the serum
level and type of monoclonal protein, the presence of urinary light
chain, the extent and pattern of bone marrow involvement, and the
reduction in uninvolved immunoglobulins. The proportion of plasma
cells in the bone marrow and the serum monoclonal protein level were
combined to create a risk-stratification model with 3 distinct
prognostic groups. In conclusion, the risk of progression from
smoldering MM to symptomatic disease is related to the proportion of
bone marrow plasma cells and the serum monoclonal protein level at
diagnosis (4).
Smoldering myeloma patients with a high percentage of plasma cells in

the blood are likely to progress to active myeloma within two years of
diagnosis compared to patients with a lower percentage of plasma cells.
In 144 patients with smoldering MM, the risk of progression

predicted by bone marrow plasma cell involvement in the bone
marrow biopsy vs. bone marrow aspirates was compared. From
398
January 1980 to July 2010, 397 patients with smoldering MM were

observed in 12 centers of the Multiple Myeloma GIMEMA (Gruppo
Italiano Malattie EMatologiche dell'Adulto) Latium Working Group.
At progression to symptomatic MM, the severity of clinical
presentation was graded according to the need of intensive supportive
care. After a median follow-up of 135 months, the cumulative
incidence of progression rates to symptomatic MM were 45%, 55%,
and 75% at 10, 15, and 20 years, respectively. Hemoglobin ≤ 12.5
g/dL, monoclonal component ≥ 2.5 g/dL, and bone marrow plasma
cells ≥ 60% were the only parameters negatively affecting the
cumulative incidence of progression. In particular, 10 of 397 (2.5%)
patients with bone marrow plasma cell ≥ 60% had a 5.6-fold increased
risk of fast progression (within 2 years), which occurred with severe
clinical manifestations in 62% of cases. Bone marrow biopsy was
more sensitive for the detection of bone marrow plasma cell
involvement, even though bone marrow aspirates were a more reliable
indicator of a rapid progression to symptomatic MM. In conclusion,
the highest risk of rapid evolution to symptomatic MM and the
severity of clinical manifestation at the progression suggest that
smoldering MM patients with a bone marrow plasma cells ≥ 60%
should be treated soon after diagnosis (5).
Assessment: smoldering (asymptomatic) MM is a more advanced

premalignant phase than MGUS and is characterized by more than 3
g/dL of serum M protein, more than 10% clonal plasma cells in the
bone marrow, or both, with no evidence of end organ damage
including hypercalcaemia, renal insufficiency, anemia, and bone
lesions. Smoldering MM is a plasma-cell proliferative disorder
associated with a high risk of progression to symptomatic MM or
amyloidosis. The risk of progression from smoldering MM to
symptomatic disease is related to the proportion of bone marrow
plasma cells and the serum monoclonal protein level at diagnosis.
Did King David suffer from smouldering MM? Although the King
suffered from severe bone pain and anemia (6,7), these manifestations
are not characteristic of smouldering MM. For this reason, it seems
unlikely that this disease afflicted the King.
References
1. Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined
significance and smoldering multiple myeloma. Curr Hematol Malig Rep.
2010;5(2):62-9.
2. Kyle RA, Rajkumar SV. Monocolonal gammopathy of undetermined
significance and smouldering multiple myeloma: emphasis on risk factors for
progression. Br J Haematol. 2007;139:730-43.
399
3. Hillengass J, Moehler T, Hundemer M. Monoclonal gammopathy and

smoldering multiple myeloma: diagnosis, staging, prognosis, management. Recent
Results Cancer Res. 2011;183:113-31.
4. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of
smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-90.
5. Rago A, Grammatico S, Za T, et al.; on behalf of the Multiple Myeloma
GIMEMA-Latium Region Working Group. Prognostic factors associated with
progression of smoldering multiple myeloma to symptomatic form. Cancer.
2012;118(22):5544-5549.
6. Ben-Nun L. The diseases that caused chronic weakness. In: Ben-Nun L. ed. The
Israel. 2009, pp. 172-80.
7. Ben-Noun L. What was the disease of the bones that affected King David ? J
Gerontol Med Sci. 2002;57:152-154.
WM is an uncommon disease with overall incidence of
approximately 3 per million persons per year, accounting for
approximately 1-2% of all hematologic cancers. It has only one-sixth
the estimated prevalence of plasma cell myeloma (1).
In Waldenström's macroglobulinemia, lymphocytes cells go bad.
Over time, WM has evolved conceptually from a clinical syndrome

to a distinct clinicopathological entity. Progress is being made in
standardization of the disease definition and treatment response
criteria, although nosologic controversies persist. According to the
Second International Workshop on WM, the disease is defined as a B-
cell neoplasm characterized by a lymphoplasmacytic infiltrate in the
bone marrow, with an associated Ig M paraprotein. Disease symptoms
are often divided into those related to tumor infiltration and those
related to the rheological effects of the monoclonal IgM. As with other
400
low-grade lymphomas, asymptomatic patients are observed only, with

treatment reserved for symptomatic patients (2).
In WM, a B-cell neoplasm, characterized by lymphoplasmacytic
infiltration of the bone marrow and a monoclonal IgM protein, the
symptoms are attributable to the extent of tumor infiltration and to
elevated IgM levels. The prognostic factors predictive of survival
include the patient's age, beta(2)-microglobulin level, monoclonal
protein level, hemoglobin concentration, and platelet count (1,3-6).
WM remains incurable with a median of 8-year of overall survival for
patients with symptomatic WM (6).
A 75-year-old woman with Waldenstrom macroglobulinemia. In MR of

the lumbosacral spine, diffuse pattern of marrow infiltration and enlarged
retroperitoneal lymph nodes (arrows) are seen.
The clinical features include normochromic normocytic anemia,

thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and signs
of hyperviscosity (3,7). Aside from uncommon idiopathic IgM peaks,
most patients have evidence of an underlying lymphoma, which is
characterized by bone marrow infiltration, enlargement of lymph
nodes and/or spleen, CLL, or a combination of these features (8).
Some patients may present with constitutional symptoms only or may
be asymptomatic (1).
A patient was presented with main complaints of fatigability and
dyspnea and was misdiagnosed as plasma cell leukemia on peripheral
blood film and bone marrow morphology, but turned out to be a case
of WM on cytoflorometry. The patient was referred for chemotherapy
but expired on 10th day of admission. The suspected cause of death
was cardiorespiratory failure (1).
Pulmonary involvement in WM occurs in 3-5% of cases, but lung
involvement without bone marrow infiltration is extremely rare. Two
patients presented with bilateral consolidations on chest X-ray and
non-specific symptoms and were treated for a long period for
pulmonary infections until the diagnosis was made by open lung
biopsy. Both patients presented high monoclonal IgM in the serum
401
and one had blood lymphoplasmacytosis. Trephine bone biopsy and

bone marrow smears were normal and there was no other site of
involvement (9).
Bone scan. Waldenström's macroglobulinemia.
A 54-year-old female with WM presented with a bilateral ocular

involvement. Ophthalmic involvement in WM is very rare. There are a
few reports in the literature in which a primary diagnosis was made on
the basis of ocular involvement. Diagnosis of malignancy in this case
was established based on the presence of small lymphocytes in fine-
needle aspiration cytology from the orbital mass and typical bone
marrow aspiration immunophenotype for WM (10).
WM rarely exhibits specific cutaneous findings. A patient of WM
developed cutaneous lesions while his systemic disease seemed to be
under control with chlorambucil therapy. The skin lesions of WM do
not respond well to systemic therapy. This case was successfully
treated with RT (11).
A case of a 58-year-old man presented macules, papules, and an
erythema of the trunk with the "deck-chair" sign revealing the relapse
of WM. Histologic and immunohistochemical examinations
confirmed that cutaneous lesions were related to specific infiltration
with neoplastic cells. Remission of both skin lesions and
immunological abnormalities was obtained with oral
cyclophosphamide (12).
Two patients who presented with UC are described. Both had
evidence of IgG monoclonal gammopathy and Bence-Jones
proteinuria. This association has been reported previously only in the
402
presence of myelomatous infiltration of the G-I or in amyloidosis, and

hence these cases reported appear to be unique (13).
Fluorescein angiography of the right eye demonstrates an extended area

of capillary non-perfusion distal to the microaneurismal lesions. A 39-year-
old male is presented with a recent diagnosis of asymptomatic Waldenström's
macroglobulinemia confirmed with bone marrow biopsy (IgM 2.3 g/L, total
protein 10.4 gr/dl).
Treatment is postponed for asymptomatic patients while

progressive anemia is the most common indication for initiation of
treatment. The main therapeutic options include alkylating agents,
nucleoside analogues, and rituximab, either alone or in combination
(3,6) as well as autologous peripheral blood stem cell transplant in
eligible patients (2,6). Studies involving new combination
chemotherapy are ongoing and preliminary results are encouraging.
However, there are several limitations to these approaches. The
complete response rate is low and the treatment free survival is short
in many patients, no specific agent or regimen is superior to another,
and no treatment is specifically approved for WM. Efforts have led to
the development of proteasome inhibitors as bortezomib, several
Akt/mTor inhibitors, such as perifosine, Rad001, atacicept,
oblimersen sodium, and tositumomab (6).
Assessment: WM is a B-cell neoplasm characterized by infiltration

of the bone marrow by a lymphoplasmacytic infiltrate and an IgM
monoclonal gammopathy. The symptoms of WM are attributable to
the extent of tumor infiltration and elevated IgM levels. The clinical
features include normochromic, normocytic anemia,
thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and signs
of hyperviscosity. Patients may present with constitutional symptoms
only or be asymptomatic.
Most patients have evidence of an underlying lymphoma, which is
characterized by bone marrow infiltration, enlargement of lymph
nodes and/or spleen, CLL, or a combination of these features.
403
Was King David afflicted by WM? The King suffered from severe
bone pain and anemia of chronic diseases (14). Although anemia is
characteristic in WM, the bone pain is not characteristic manifestation
of WM. Thus, it seems unlikely that the King was afflicted by WM.
References
1. Sethi B, Butola KS, Kumar Y. A Diagnostic Dilemma: Waldenström's
Macroglobulinemia/Plasma Cell Leukemia. Case Report Pathol. 2012;2012:271407.
2. Fonseca R, Hayman S. Waldenström macroglobulinaemia. Br J Haematol.
2007;138(6):700-20.
3. Vijay A, Gertz MA. Waldenström macroglobulinemia. Blood. 2007;
109(12):5096-103.
4. Pangalis GA, Kyrtsonis MC, Kontopidou FN, et al. Differential diagnosis of
Waldenstrom's macroglobulinemia and other B-cell disorders. Clin Lymphoma. 2005;
5:235-40.
5. Leleu X, Roccaro AM, Moreau AS, et al. Waldenstrom macroglobulinemia.
Cancer Lett. 2008;270:95-107.
6. Poulain S, Wemeau M, Balkaran S, et al. Waldenström's macroglobulinemia.
Rev Med Interne. 2010;31(5):385-94.
7. Gertz MA. Waldenström macroglobulinemia. Hematology. 2012;17 Suppl
1:S112-6.
8. Alexanian R. Plasma cell neoplasms and related disorders. In: Petersdorf RG,
Adams RD, Braunwald E, et al. (eds). Harrison's Principles of Internal Medicine. 10
ed. McGrawn-Hill, New York, St Louis. 1983, pp. 362-371.
9. Kyrtsonis MC, Angelopoulou MK, Kontopidou FN, et al. Primary lung
involvement in Waldenström's macroglobulinaemia: report of two cases and review of
the literature. Acta Haematol. 2001;105(2):92-6.
10. Verdú J, Andrés R, Sánchez-Majano JL, Fernández JA. Bilateral ocular
involvement as a presentation of Waldenström's macroglobulinemia. Med Oncol.
2011;28(4):1624-5.
11. Orengo IF, Kettler AH, Bruce S, et al. Cutaneous Waldenström's
macroglobulinemia. A report of a case successfully treated with radiotherapy. Cancer.
1987;60(6):1341-5.
12. Autier J, Buffet M, Pinquier L, et al. Cutaneous Waldenstrom's
macroglobulinemia with "deck-chair" sign treated with cyclophosphamide. J Am
Acad Dermatol. 2005;52(2 Suppl 1):45-7.
13. Haeney MR, Ross IN, Thompson RA, Asquith P. IgG myeloma presenting as
ulcerative colitis. J Clin Pathol. 1977;30(9):862–7.
14. Ben-Nun L. The disease that caused chronic weakness. In: Ben-Nun L. ed.
Israel. 2009, pp. 172-80.
404
HEAVY CHAIN DISEASES

HCDs are immunoproliferative disorders characterized by the
production of monoclonal immunoglobulin molecules composed of
deleted heavy chains devoid of light chains by the malignant B-cells
(1-3). The diagnosis is established by immunoelectrophoresis or
immunofixation (3).
Since the first report of gamma-HCD in 1964, alpha-HCD and mu-
HCD have also been described (1). There are 3 types of HCDs defined
by the class of Ig heavy chain produced: IgA (alpha-HCD), IgG
(gamma-HCD), and IgM (mu-HCG). Alpha-HCD is the most common
and occurs most commonly as intestinal malabsorption in a young
adult from a country bordering the Mediterranean Sea (2,3). In its
usual digestive form, the clinicopathologic pattern is typical. The main
clinical features are chronic diarrhea and severe malabsorption
syndrome (3).
The complete map of the Ig heavy chain.
The clinicopathologic features of gamma HCD are heterogeneous

often somewhat similar to macroglobulinemia. Some patients show no
evidence of underlying malignant lymphoproliferation. Gamma HCD
most often presents as a lymphoproliferative disorder, characterized
by lymphadenopathies, splenomegaly, constitutional symptoms, and
the absence of bone lesions (4,5).
Of 23 patients with gamma-HCD (8 patients previously reported,
15 new patients), 15 were women and 8 men; the median age at
diagnosis was 68 years (range, 42-87 years). Sixteen patients had an
associated lymphoplasma cell proliferative disorder, 3 a
lymphoplasma cell proliferative disorder and an autoimmune disorder,
another 3 an autoimmune disorder only, and 1 had no underlying
disease. The lymphoplasma cell proliferative disorder was
disseminated in 10 patients and localized in 6. Patients with localized
405
lymphoplasma cell proliferative disorder included 3 with

plasmacytoma (1 tongue, 1 submandibular area, and 1 thyroid), 2 with
lymphoplasma cell proliferative disorder involving the bone marrow
only, and 1 with amyloid of the skin. At the time of diagnosis,
lymphadenopathy was present in 8 patients, splenomegaly in 7, and
hepatomegaly in 1. A monoclonal spike on serum protein
electrophoresis was documented in 19 patients. Gamma-heavy chain
was documented by immunofixation in the serum of all patients; 2 had
an additional immunoglobulin M-lambda. Gamma-heavy chain was
present in the urine in 19 of 22 patients. Sixteen patients were treated
for lymphoplasma cell proliferative disorder or autoimmune disorder
(14 with chemotherapy, 1 splenectomy, and 1 thyroidectomy followed
by RT). For 5 patients, treatment was not necessary; 2 patients were
too sick for treatment. Of the 16 patients treated, 6 had a complete
clinical response (in 2, gamma-heavy chain disappeared; in 2, gamma-
heavy chain persisted; and for 2, no serologic follow-up was
available); in 10 patients, clinical disease persisted (in 3, gamma-
heavy chain disappeared; in 6, it persisted; and for 1, no serologic
follow-up was available). Of 7 patients not treated, 2 died within 5
months; 1 died after 15 months; 2 had no clinical disease at latest
follow-up, although gamma-heavy chain persisted; and 2 had no
change in clinical and serologic status. The median duration of follow-
up was 33 months (range, 1-261 months). Median survival was 7.4
years (6).
A 79-year-old woman was presented with proteinuria and

microscopic hematuria whose renal biopsy showed nodular
glomerulosclerosis with deposition of gamma3 heavy chains and
complement in the glomeruli and tubular basement membranes with
no associated light chain deposition. The patient did not have MM.
This case is unique in that in all previously reported cases of heavy
chain deposition disease the gamma chain subtype has been either
gamma1 or gamma4 (7).
406
A case of gamma HCD was presented with several unique features:

extensive osteolytic lesions simulating advanced MM, skin
involvement, > 40 years, and the appearance of a series of
pathological cells with indented or lobulated nuclei. The most
remarkable feature was extensive bone destruction. Except for the
presence of this bone disease, the clinical and pathological features of
the patient resembled those of gamma HCD rather than those of MM.
Three previously reported cases of gamma HCD were associated with
skeletal involvement and compared with the present case (8).
alpha-HCD primarily involves the secretory IgA system and
mainly the digestive tract. Its clinical pattern is strikingly uniform.
alpha-HCD is the most common of the HCDs, while mu-HCD is
relatively rare. The demonstration of Bence Jones proteins in the urine
in association with lymphoproliferative disorders and vacuolated
plasma cells in the bone marrow deserves further investigation for mu-
HCD. In addition, 2 disease entities related to molecular abnormalities
of heavy chains have been reported; heavy-chain-associated
amyloidosis and heavy chain deposition disease (1).
IPSID is a variant of the B-cell lymphoma of MALT, which
involves mainly the proximal small intestine resulting in
malabsorption, diarrhea, and abdominal pain. Geographically, IPSID
is most prevalent in the Middle East and Africa. IPSID lymphomas
reveal excessive plasma cell differentiation and produce truncated
alpha heavy chain proteins lacking the light chains as well as the first
constant domain. The corresponding mRNA lacks the variable heavy
chain (V(H)) and the constant heavy chain 1 (C(H)1) sequences and
contains deletions as well as insertions of unknown origin. The
encoding gene sequence reveals a deletion of V region and parts of
C(H)1 domain. Cytogenetic studies demonstrate clonal
rearrangements involving predominantly the heavy and light chain
genes, including t(9;14) translocation involving the PAX5 gene.
Early-stage IPSID responds to antibiotics (30-70% complete
remission). Most untreated IPSID patients progress to
lymphoplasmacytic and immunoblastic lymphoma invading the
intestinal wall and mesenteric lymph nodes, and may metastasize to a
distant organ. IPSID lymphoma shares clinical, morphologic, and
molecular features with MALT lymphoma, lymphoplasmacytic
lymphoma, and plasma cell neoplasms (9).
IPSID, or alpha chain disease, is a rare disease. In the recent WHO
classification of hematopoietic and lymphoid tissue, IPSID is
considered as a variant of extranodal mucosa-associated lymphoid
tissue (MALT) lymphoma. C. jejuni is a specific pathogen related to
407
IPSID. Diagnosis is based on histology and immunochemistry (±

fluorescent in situ hybridization), with presence of many variable
levels of abnormal immunoglobulin in the serum, identified to be
truncated alpha-heavy chains (10).
IPSID, IgA type lymphoma.
IPSID (alpha chain disease) is a form of lymphoma that arises in

small intestinal MALT and is associated with the expression of a
monotypic truncated immunoglobulin alpha heavy chain without an
associated light chain. Early-stage disease responds to antibiotics,
suggesting a bacterial origin. PCR, DNA sequencing, fluorescence in
situ hybridization, and immunohistochemical studies on intestinal-
biopsy specimens from a series of patients with IPSID were
performed. Analysis of frozen intestinal tissue obtained from an index
patient with IPSID who had a dramatic response to antibiotics
revealed the presence of C. jejuni. A follow-up retrospective analysis
of archival intestinal-biopsy specimens disclosed C. jejuni species in 4
of 6 additional patients with IPSID. These results indicate that C.
jejuni and IPSID are associated and C. jejuni should be added to the
growing list of human pathogens responsible for immunoproliferative
states (11).
G-I lymphoma, uncommon in the West, is far more prevalent in
developing countries where it falls into 2 groups: 'Western'-type
lymphomas, similarly to those seen in developed countries, and the so-
called Mediterranean-type lymphoma. Mediterranean lymphoma
408
represents, in the majority if not in all cases, the late stage of alpha
HCD. This disease is characterized by abnormal secretion of an
immunoglobulin fragment; alpha-HCD and Mediterranean lymphoma
that constitute 2 ends of a spectrum of pathology now classified as
IPSID. IPSID is associated predominantly with poor socioeconomic
conditions; patients present with progressive malabsorption in the
second and third decades of life. Diagnosis is established by small
bowel biopsy, with or without high serum levels of the alpha heavy
chain protein (12).
alpha-heavy chain disease. IPSID.
Early-stage alpha-heavy chain disease is treated by antibiotics

(tetracyclines). Chemotherapy is recommended for patients with
advanced disease at presentation or refractory to antibiotics. The
chemotherapy used is the CHOP (cyclophosphamide, vincristine,
doxorubicin, and prednisone) regimen (10). In addition, treatment
consists of an initial staging laparotomy, with debulking of
lymphomatous deposits if appropriate, followed by chemotherapy or
RT. Overall prognosis is poor but the recent use of doxorubicin-based
chemotherapy offers some hope for the future (12).
Twenty-three patients with gamma-HCD (8 patients previously
reported, 15 new patients) were described. There were 15 women and
8 men; the median age at diagnosis was 68 years (range, 42-87 years).
Sixteen patients had an associated lymphoplasma cell proliferative
disorder, 3 a lymphoplasma cell proliferative disorder and an
autoimmune disorder, another 3 an autoimmune disorder only, and 1
had no underlying disease. The lymphoplasma cell proliferative
disorder was disseminated in 10 patients and localized in 6. Patients
with localized lymphoplasma cell proliferative disorder included 3
with plasmacytoma (1 tongue, 1 submandibular area, and 1 thyroid), 2
with lymphoplasma cell proliferative disorder involving the bone
409
marrow only and 1 with amyloid of the skin. At the time of diagnosis,
lymphadenopathy was present in 8 patients, splenomegaly in 7, and
hepatomegaly in 1. A monoclonal spike on serum protein
electrophoresis was documented in 19 patients. Gamma-heavy chain
was documented by immunofixation in the serum of all patients; 2 had
an additional immunoglobulin M-lambda. Gamma-heavy chain was
present in the urine in 19 of 22 patients. Sixteen patients were treated
for lymphoplasma cell proliferative disorder or autoimmune disorder
(14 with chemotherapy, 1 received splenectomy, and 1 thyroidectomy
followed by RT). For 5 patients, treatment was not necessary; 2
patients were too sick for treatment. Of the 16 patients treated, 6 had
a complete clinical response (in 2, gamma-heavy chain disappeared; in
2, gamma-heavy chain persisted; and for 2, no serologic follow-up
was available); in 10 patients, clinical disease persisted (in 3, gamma-
heavy chain disappeared; in 6, it persisted; and for 1, no serologic
follow-up was available). Of 7 patients not treated, 2 died within 5
months; 1 died after 15 months; 2 had no clinical disease at latest
follow-up, although gamma-heavy chain persisted; and 2 had no
change in clinical and serologic status. The median duration of follow-
up was 33 months (range, 1-261 months). Median survival was 7.4
years (6).
mu-HCD is a rare monoclonal lymphoid disorder characterized by
the failure to assemble a complete IgM immunoglobulin (13). mu-
HCD often presents as CLL with hepatosplenomegaly and vacuolated
plasma cells on bone marrow smears (2), and thrombocytopenia (14).
Renal failure is a rare disease in mu-HCD (15). The prognosis for
patients with mu-HCD is poor (14).
A patient with mu-HCD and associated with systemic amyloidosis
is reported. The diagnosis of mu-HCD was based on findings of mu-
heavy chain fragments in the serum, Bence Jones proteinuria and
vacuolated plasma cells in the bone marrow. This is the case in which
systemic amyloidosis led to the patient's death (16).
A case of mu-HCD was presented as a benign monoclonal
gammopathy. The literature on the 27 reported mu-HCD cases was
reviewed. The ages of the patients ranged from 15 to 80 years
(median, 57.5 years). Twenty-two of 27 patients had an associated
lymphoplasma cell proliferative disorder. A monoclonal spike on
routine serum protein electrophoresis was in 8 of 19 patients. Fourteen
of 22 patients had Bence Jones proteinuria, but mu-HCD protein was
reported in the urine of 2 patients. The survival ranged from less than
1 month to 11 years (median, 24 months) (13).
410
Assessment: HCDs are immunoproliferative disorders

characterized by the production of monoclonal immunoglobulin
molecules composed of deleted heavy chains devoid of light chains by
the malignant B-cells. The diagnosis is established by
immunoelectrophoresis or immunofixation.
There are 3 types of HCD defined by the class of Ig heavy chain
produced: IgA (alpha-HCD), IgG (gamma-HCD), and IgM (mu-
HCG). Alpha-HCD is the most common and occurs most commonly
as intestinal malabsorption in young adults from a country bordering
the Mediterranean Sea. The main clinical features are chronic diarrhea
and severe malabsorption syndrome. Gamma HCD most often
presents as a lymphoproliferative disorder, characterized by
lymphadenopathies, splenomegaly, constitutional symptoms, and
generally the absence of bone lesions. mu-HCD is a rare monoclonal
lymphoid disorder characterized by the failure to assemble a complete
IgM immunoglobulin. Although rare, gamma HCD disease is related
to extensive osteolytic lesions simulating advanced MM.
mu-HCD often presents as CLL with hepatosplenomegaly,
vacuolated plasma cells on bone marrow smears and
thrombocytopenia. Most untreated IPSID patients progress to
lymphoplasmacytic and immunoblastic lymphoma invading the
intestinal wall and mesenteric lymph nodes may metastasize to a
distant organ.
Did some type of HCD afflict the King? Since bone pain is not
characteristic symptom of alpha-HCD and mu-HCG, it seems unlikely
that these types affected the King.
Did gamma HCD disease afflict the King? Since this type of HCD
can be associated with rare extensive osteolytic bone lesions, the
biblical verses ―...my strength failed..., and my bones are consumed‖
(Psalm 31:11) and ―My bones wasted away through my anguished
roaring all day long‖ (32:3) may indicate gamma HCD.
References
1. Nomura S, Kanoh T. Heavy chain disease. Nihon Rinsho. 1995;53(3):730-5.
2. Witzig TE, Wahner-Roedler D. Heavy chain disease. Curr Treat Options Oncol.
2002;3:247-54.
3. Seligman M. Heavy chain diseases. Rev Prat. 1993;43:317-20.
4. Fermand JP, Brouet JC, Danon F, Seligmann M. Gamma heavy chain
"disease": heterogeneity of the clinicopathologic features. Report of 16 cases and
review of the literature. Medicine (Baltimore). 1989;68:321-35.
5. Leglise MC, Briere J, Abgrall JF, Hurez D. Non-secretory myeloma of heavy
mu-chain type. Nouv Rev Fr Hematol. 1983;25:103-6.
6. Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA. Gamma-heavy chain
disease: review of 23 cases. Medicine (Baltimore). 2003;82(4):236-50.
411
7. Herzenberg AM, Lien J, Magil AB. Monoclonal heavy chain (immunoglobulin

G3) deposition disease: report of a case. Am J Kidney Dis. 1996;28(1):128-31.
8. Kanoh T, Nakasato H. Osteolytic gamma heavy chain disease. Eur J Haematol.
1987;39(1):60-5.
9. Al-Saleem T, Al-Mondhiry H. Immunoproliferative small intestinal disease
(IPSID): a model for mature B-cell neoplasms. Blood. 2005;105(6):2274-80.
10. Mrabti H, Raiss G, Raissouni S, et al. Intestinal non-Hodgkin lymphoma:
"immunoproliferative small intestinal disease". Presse Med. 2011;40(11):995-1000.
11. Lecuit M, Abachin E, Martin A, et al. Immunoproliferative small intestinal
disease associated with Campylobacter jejuni. N Engl J Med. 2004;350(3):239-48.
12. Martin IG, Aldoori MI. Immunoproliferative small intestinal disease:
Mediterranean lymphoma and alpha heavy chain disease. Br J Surg. 1994;81(1):20-4.
13. Wahner-Roedler DL, Kyle RA. Mu-heavy chain disease: presentation as a
benign monoclonal gammopathy. Am J Hematol. 1992;40:56-60.
14. Yanai M, Marda A, Watanabe N, et al. Successful treatment of mu-heavy
chain disease with fludarabine monophosphate: a case report. Int J Hematol.
2004;79Z:L174-7.
15. Preud'home JL, Bauwens M, Dumont G, et al. Cast nephropathy in mu chain
disease. Clin Nephrol. 1997;48:118-21.
16. Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease associated
with systemic amyloidosis. Hematology. 2004;9(2):135-7.
OSTEOMYELOFIBROSIS
Osteomylofibrosis and sclerosis are chronic myeloproliferative
diseases of the elderly, in which fibrosis and sclerosis finally lead to
bone marrow obliteration (2), with a peak incidence in the sixth and
seventh decade of life (1). Bone marrow fibrosis, anemia,
splenomegaly and a leuko-erythrobastic blood picture generally
characterize idiopathic myelofibrosis. Apart from minor hemorrhage
and peripheral thrombosis, patients with early stage of idiopathic
myelofibrosis present with non-specific symptoms including varying
degrees of leukocytosis (51%), anemia (38%), a platelet count
exceeding 600 x 10(9)/l (86%), splenomegaly (15%), increase in
leukocyte ALP (24%) and LDH (20%) (3).
Bone marrow biopsy shows marked osteomyelosclerosis.

412
A retrospective clinicopathologic study was performed on 250

consecutively recruited patients (115 males and 135 females) with an
established diagnosis of idiopathic (primary) osteomyelofibrosis. In
contrast to previous studies, the current study cohort encompassed the
full spectrum of initial to advanced stages of the disease process
according to laboratory data and particularly histology. Because of the
relatively high patient's age on admission (median, 66.5 years),
relative survival rates with corresponding life expectancies and
disease specific life loss were calculated. Analysis of the life
expectancy and the proportion of deaths attributable to idiopathic
osteomyelofibrosis showed a global reduction in life expectancy of
31%. Further calculation disclosed a consistently greater impact of
disease in older patients. Age, hemoglobin level on admission, and
leukocyte and thrombocyte counts remained the most relevant
parameters for prognosis in multivariate consideration (classification
and regression tree analysis) and facilitated a clear-cut separation into
3 risk groups. The life expectancy of low risk patients was
approximately 10 times higher than that of high-risk patients (22.07
years vs. 2.25 years). These results are in keeping with the
assumption that features signaling bone marrow insufficiency are
associated with a worsening survival. Generalization, indicated by
myeloid metaplasia, can occur at every stage, even in so-called
hypercellular phases of idiopathic osteomyelofibrosis. Conversely,
myelofibrosis alone is not necessarily predictive of poor survival (4).
A retrospective clinico-pathological study was performed on 208
consecutively recruited patients (94 males, 114 females, median age
67 years) with idiopathic (primary) osteomyelofibrosis. According to
bone marrow histology (cellularity) as well as extent (semiquantitative
grading) and quality (reticulin/collagen) of myelofibrosis, stages of
the disease process were determined. At closure of this study
(observation time 65 months), 133 patients were dead and 75 alive
with median survival 56 months. The wide spectrum of clinical signs
and symptoms and laboratory data on admission was reflected by a
corresponding variety of histological features. Significant differences
of hematological values could be calculated between patients with or
without early reticulin fibrosis (fiber scores 0 and 1) and advanced
fibro-osteosclerotic stages (fiber scores 2 and 3). Evolution of disease
features was elicited by longitudinal follow-up studies and sequential
bone marrow biopsies. Morphometric assessment of fiber density in
patients without preceding chemotherapy revealed an unpredictable
and varying progression of myelofibrosis associated with alterations
of certain laboratory parameters (hemoglobin level, spleen size, and
413
thrombocytosis). Differentiation from essential (primary)

thrombocythemia was required in 25 patients who fulfilled the
postulated diagnostic criteria. In fact, this group was consistent with
hypercellular, early stages of idiopathic osteomyelofibrosis without
relevant reticulin fibrosis and an excessively raised platelet count (≥
1000 x 10(9)/1). Discrimination was only feasible by regarding
histology carefully, particularly abnormalities of megakaryopoiesis
and follow-up data. Parameters of predictive value indicating a
significant loss in life expectancy in comparison with a sex- and age-
adjusted normal population included: age (≥ 60 years), hemoglobin
levels (≤ 10 g/dl), thrombocyte count (≤ 600 x 10(9)/1) and the
presence of myeloblasts and promyelocytes. In the so-called early
stages of idiopathic osteomyelofibrosis without relevant
myelofibrosis, findings indicative for extramedullary hemopoiesis or
generalization of the disease process exerted an unfavorable influence
on survival (5).
A clinicopathological study was performed on 90 patients (39
males, 51 females, aged 68 years) with primary (idiopathic)
osteomyelosclerosis in order to correlate laboratory and
histomorphological parameters with each other and to calculate factors
of prognostic impact on survival. In addition to multiple interactions
between various laboratory features, there was a significant
correlation between degree of medullary fibrosis and osteosclerotic
changes with sizes of spleen and liver, level of LDH and duration of
relevant prediagnostic symptoms. In trephine biopsies of the bone
marrow, reduction of hematopoietic tissue was assessed by evaluating
the amount of fat cells plus the degree of osteosclerotic lesions. This
histological parameter revealed insignificant relationships with
hepatosplenomegaly, duration of relevant symptoms or length of
disease, but was correlated with the clinical findings of bone marrow
failure. On univariate analysis, several clinical (age > 45 years,
presence of relevant prediagnostic symptoms, hemoglobin level < 9
g/dl, counts of myelo- and normoblasts, thrombocyte count < 100 and
> 700 x 10(9)/l, spleen size and LDH level) and histological features
(reduction of hematopoiesis, counts for megakaryocytes and lymphoid
nodules) exerted a predictive value on prognosis. However, on
multivariate regression analysis only age remained significant. This
result apparently reflects the numerous interactions between the
various clinical as well as histological variables tested (6).
Assessment: osteomylofibrosis and sclerosis are chronic

myeloproliferative diseases of the elderly, with a peak incidence in the
sixth and seventh decade of life, in which fibrosis and sclerosis finally
414
lead to bone marrow obliteration. Bone marrow fibrosis, anemia,

splenomegaly and a leuko-erythrobastic blood picture generally
characterize idiopathic myelofibrosis. Apart from minor hemorrhage
and peripheral thrombosis, patients with early stage of idiopathic
myelofibrosis present with non-specific symptoms including varying
degrees of leukocytosis, anemia, and a platelet count exceeding 600 x
10(9)/l, splenomegaly, increase in leukocyte ALP and LDH levels.
Did osteomylofibrosis affect the old King? Although this disease is
prevalent in the elderly, the disease is mainly manifests with non-
specific symptoms. Since the King suffered from severe bone pains,
the diagnosis of osteomyelofibrosis seems unlikely.
References
1. Baur-Melnyk A, Reiser M. Oncohaematologic disorders affecting the skeleton
in the elderly. Radiol Clin North Am. 2008;46(4):785-98, vii.
2. Böhner H, Rötzscher VM, Tirier C, et al. Splenectomy in osteomyelofibrosis.
Indications and outcome. Chirurg. 1996;67: 1016-9.
3. Thiele J. Kvasnicka HM, Zankovich R, Diehl V. Early-stage idiopathic
(primary) myelofibrosis- current issues of diagnostic features. Leuk Lymphoma.
2002;43:1035-41.
4. Kvasnicka HM, Thiele J, Werden C, et al. Prognostic factors in idiopathic
(primary) osteomyelofibrosis. Cancer. 1997;80(4):708-19.
5. Thiele J, Kvasnicka HM, Werden C, et al. Idiopathic primary osteo-
myelofibrosis: a clinico-pathological study on 208 patients with special emphasis on
evolution of disease features, differentiation from essential thrombocythemia and
variables of prognostic impact. Leuk Lymphoma. 1996;22(3-4):303-17.
6. Thiele J, Steinberg T, Zankovich R, Fischer R. Primary myelofibrosis-
osteomyelosclerosis (agnogenic myeloid metaplasia): correlation of clinical findings
with bone marrow histopathology and prognosis. Anticancer Res. 1989;9(2):429-35.
SMALL LYMPHOCYTE CELL DISORDERS

Small lymphocyte cell disorders include B-cell CLL, SLL, and
LPL/WM (1).
Reference
1. Pangalis GA, Angelipoulou MK, Vassilakopoulos TP, et al. B-chronic
lymphocytic leukemia, small lymphocytic lymphoma, and lymphoplasmacytic
lymphoma, including Waldenström's macroglobulinemia: a clinical, morphologic, and
biologic spectrum of similar disorders. Semin Hematol. 1999;36:104-14.
415
CHRONIC LYMPHOCYTIC LEUKEMIA

B-cell CLL is a highly common form of leukemia characterized by
the accumulation of long-lived, functionally inactive and mature
appearing neoplastic B-lymphocytes. In addition, immune
disturbances such as hypogammaglobulinemia and autoimmune
phenomena (particularly, autoimmune hemolytic anemia) are
frequently found in CLL patients. The etiology of CLL is unknown. In
contrast with other leukemias, there is no relationship between CLL
and exposure to radiation or other cytotoxic agents. A genetic basis is
highly likely since there are differences in the incidence of CLL in
different countries (e.g., CLL accounts for 30-40% of all the
leukemias in Western countries as compared to 5-10% in Asian
countries) and the risk of contracting CLL is higher among persons
with first-degree relatives with the disease. Because the incidence of
CLL increases with age and the longer life expectancy of the general
population, the age of patients at diagnosis is increasing. The median
age at diagnosis is about 70 years, with only one-third of the patients
being < 60 years of age. In the majority of the series, males
predominate over females in a proportion of 1.5/1. The prognosis of
patients with CLL is variable. However, clinical stages and other
prognostic factors allow the individual risk of each patient to be
assessed very accurately, which is useful for making treatment
decisions (1).
B cell chronic CLL
B cell CLL patients always have blood and bone marrow

involvement by a CD5+ B lymphocyte. They frequently present with
lymphadenopathy and/or hepatosplenomegaly, although in a
considerable number of patients, no abnormal physical findings are
found. They are prone to develop hypogammaglobulinemia,
416
autoimmune hemolysis, or autoimmune thrombocytopenia. The

typical immunophenotype of the malignant cell is CD5+, surface
immunoglobulin (slg)+ (weak), CD23+, CD79b-, and FMC7-.
Trisomy 12 and 13q deletions are frequent chromosomal
abnormalities. The bcl-2 protein is usually overexpressed. SLL
patients present with lymphadenopathy, usually generalized.
Lymphocytosis is by definition absent and bone marrow involvement,
usually nodular, is found in 25-50% of patients. The lymph node
lymphocytes are CD5+ and have a similar immunophenotype with
CLL, but frequently express the LFA-1 adhesion molecule. Patients
are at low risk to develop hypogammaglobulinemia, autoimmune
hemolysis, or autoimmune thrombocytopenia. LPL/WM patients may
present either with an accidental discovery of IgM gammopathy,
symptoms related to paraproteinemia, or lymphadenopathy and/or
splenomegaly. The bone marrow is frequently involved and a
leukemic picture may be found. A monoclonal gammopathy of IgM
class is by definition present in WM and is frequently accompanied by
hypogammaglobulinemia. Immunophenotypic studies usually reveal a
CD5-, slg+ (moderate), cytoplasmic immunoglobulin (clg)+, FMC7+,
and CD38+ cell. A significant proportion of cases carry the
translocation t(9;14)(p13;q32) involving the PAX-5 gene. All these
disorders may potentially undergo transformation to large-cell
lymphoma or Richter's syndrome. Prognostic factors have been
extensively studied in B-chronic CLL, but more studies are needed for
small lymphocytic lymphoma and LPL/MW. These entities should be
differentiated from other B-chronic small lymphocyte cell disorders,
particularly when the latter are leukemic (1,2).
The cellular origin of CLL is still debated, although this
information is critical to understanding its pathogenesis.
Transcriptome analyses of CLL and the main normal B cell subsets
from human blood and spleen revealed that immunoglobulin variable
region (IgV) gene unmutated CLL derives from unmutated mature
CD5(+) B cells and mutated CLL derives from a distinct, previously
unrecognized CD5(+)CD27(+) post-germinal center B cell subset.
Stereotyped V gene rearrangements are enriched among CD5(+) B
cells, providing independent evidence for a CD5(+) B cell derivation
of CLL. Notably, these CD5(+) B cell populations include oligoclonal
expansions already found in young healthy adults, putatively
representing an early phase in CLL development before the CLL
precursor lesion monoclonal B cell lymphocytosis. Deregulated
proteins, including EBF1 and KLF transcription factors, that were not
417
detected in previous comparisons of CLL and conventional B cells

were identified (3).
Though B cell CLL is a heterogeneous disease, only recently has
the familial component of CLL been more thoroughly investigated.
This entity is in approximately 5-10% of all patients with CLL and
can be associated with earlier age of diagnosis, higher female
prevalence, and increased incidence of other lymphoproliferative
disorders, such as non-Hodgkin lymphoma and the more recently
described monoclonal B-cell lymphocytosis CLL in family members.
The prognostic parameters and clinical course of familial CLL is not
clearly distinguishable from that of sporadic disease. In addition, it is
not clear that the treatment responses for progressive disease has any
discernible difference in familial vs. sporadic CLL. The genetic
etiology of CLL is unknown, and early work on familial CLL has not
yet uncovered any obvious gene or group of genes that can be clearly
related to the pathophysiology of CLL. However, the detailed genetic
study of familial CLL is likely to be critical in uncovering relevant
genes. At present, it is best to indicate to concerned CLL patients that
their relatives are at relatively low risk of developing CLL or other
lymphoproliferative disorders (4).
In an ongoing study, families with 2 or more living cases of B cell
CLL in first-degree relatives have been recruited through physician
and self-referral. Since 1967, 28 kindred with 73 cases of B cell CLL
have been enrolled within the NCI Familial B cell CLL Registry.
medical, clinical, and demographic information have been obtained
from private physicians, patient interview, hospital records, and death
certificates. SEER Registry data were used to compare characteristics
of sporadic B cell CLL to familial B cell CLL. The mean age at
diagnosis was approximately 10 years younger among familial cases
(57.9 +/- 12.1) than that observed in sporadic cases (70.1 +/- 11.9). A
higher percentage of second primary tumors among familial CLL
cases compared to reports in sporadic was also observed (16% vs.
8.8%). However, the transformation rate to non-Hodgkin's lymphoma
does not appear to be different from that reported for sporadic cases.
In conclusion, some differences between familial and sporadic cases
were observed; whether any of these characteristics affect survival
time or severity of disease is unknown (5).
The t(14;18)(q32;q21) is a cytogenetic hallmark of follicular
lymphoma and also occurs in approximately 20% of diffuse large B-
cell lymphomas of follicle center cell origin. Relatively few cases of
CLL/SLL with t(14;18) have been reported previously. The
clinicopathologic, cytogenetic, and molecular genetic features of 12
418
patients with CLL associated with t(14;18) are reported. There were 9
men and 3 women, with a median age of 51 years at diagnosis. To
date, 11 patients have required chemotherapy, 6 before coming to the
institution. At last follow-up, 5 patients have died of disease.
Karyotypic analysis showed that 10 cases had t(14;18) in the stemline
and 2 cases in the sideline; t(14;18) was the sole abnormality in the
stemline in 2 cases. In 11 cases, other abnormalities were identified in
the stemline or sidelines, most commonly trisomy 12 in 6 cases.
Trisomy 12 was associated with atypical morphology and
immunophenotype. Of 8 cases tested, 7 showed somatically mutated
immunoglobulin heavy chain variable region genes. In conclusion, the
t(14;18) in CLL is associated with relatively young age at diagnosis,
mutated immunoglobulin heavy chain variable region genes, and a
clinical course that usually requires chemotherapy. The cytogenetic
findings, in particular, t(14;18) in the stemline in 10 cases and as the
sole karyotypic abnormality in 2 cases, suggest that t(14;18) is an
early pathogenetic event in this small subset of CLL cases (6).
The clinico-hematological profile and treatment outcome of
patients with CLL were assessed using retrospective case record
analysis over 11 years. There were 95 (75 males: 20 females) patients
with a median age of 61 years. Thirty patients were aged ≤ 55 years
(young CLL patients) and 65 were ≥ 55 years of age (elder CLL
patients). Of all patients, 60% had non-specific complaints, such as
weakness, cough and indigestion, 26 (27%) had pallor and 24 (25%)
had fever as initial presenting manifestation. Bleeding manifestations
were seen in 7 patients. Seven patients were diagnosed incidentally.
Lymphadenopathy, splenomegaly and hepatomegaly were seen in 52
(55%), 63 (66%) and 60 (63%) patients, respectively. The median
white blood cell count and absolute lymphocyte counts were 70,600
and 51,490/mul, respectively. Three patients had autoimmune
hemolytic anemia. Twenty-five patients (26%) had anemia with
hemoglobin < 11 g/dl and thrombocytopenia with platelet count 100 x
10(3)/mm(3) was in 17 (18%). Interstitial nodular, mixed and diffuse
bone marrow involvement was in 10.2, 67.3, 6.1 and 16.3% cases,
respectively. Eighteen (60%) young patients and 35 (54%) older
patients required treatment with chlorambucil. The mean time from
initial diagnosis to treatment was 4.6 +/- 10.7 months. None of these
patients attained complete response. Six patients obtained partial
response. Median duration of chlorambucil was 7 months (1-86
months). Forty-six patients had stable disease. Three patients died.
Median survival of study group was 4 years (8 months-13 years). In
419
older patients, CLL lasted 4 years (8 months-11 years) and in young

patients, survival duration was 5.5 years (1-13 years) (7).
The objective of this study was to retrospectively analyze the
clinical presentations and outcome of a large cohort of Thai CLL
patients diagnosed at a single institution in Bangkok, Thailand, from
1963-1998. One hundred and eighty-four patients were included in the
study. The most frequent age group was 60-80 years old with the male
to female ratio of 2:1. Only 12% of patients were younger than the age
of 50. Clinical findings at presentation included splenomegaly (64%),
lymphadenopathy (60%), anemia (54%), hepatomegaly (49%), fatigue
(39%), weight loss (33%), fever (21%), thrombocytopenia (18%), and
anorexia (8%). Only 8% of Thai CLL patients were asymptomatic at
presentation. The majority of patients were categorized as stages III
and IV with the median survival of 20 months and 8 months,
respectively. Infection was the most common cause of death,
particularly in the elderly patients who had comorbid illnesses.
Twenty-two percent of the patients had associated autoimmune
disorders. The unfavorable prognostic factors observed were older age
(> 70 years), weight loss and hepatosplenomegaly. In conclusion, the
age and gender of Thai CLL patients were similar to those of the
Western countries but Thai patients came to medical attention at a
later and more advanced stage (8).
Assessment: B-cell CLL is a highly common form of leukemia

characterized by the accumulation of long-lived, functionally inactive,
and mature appearing neoplastic B-lymphocytes. In addition, immune
disturbances such as hypogammaglobulinemia and autoimmune
phenomena (particularly, autoimmune hemolytic anemia) are
frequently found in CLL patients. B-cell CLL patients always have
blood and bone marrow involvement by a CD5+ B lymphocyte.
Clinical symptoms include fatigue, weight loss, fever, anorexia,
splenomegaly, lymphadenopathy, anemia, hepatomegaly,
thrombocytopenia, and anorexia. In a considerable number of patients,
no abnormal physical findings are found. They are prone to develop
hypogammaglobulinemia, autoimmune hemolysis, or autoimmune
thrombocytopenia.
Was the King afflicted by B cell CLL? Although the King suffered
from weakness, weight loss, anorexia (9,10) and severe bone pain,
bone pain is not characteristic manifestation of CLL. Thus, the
diagnosis of B-cell CLL seems unlikely.
420
References
1. Montserrat E, Bosch F, Rozman C. B-cell chronic lymphocytic leukemia:
recent progress in biology, diagnosis, and therapy. Ann Oncol. 1997;8 Suppl 1:93-
101.
3. Seifert M, Sellmann L, Bloehdorn J, et al. Cellular origin and pathophysiology
of chronic lymphocytic leukemia. J Exp Med. 2012; 209(12):2183-98.
4. Slager SL, Kay NE. Familial chronic lymphocytic leukemia: what does it mean
to me? Clin Lymphoma Myeloma. 2009;9 Suppl 3:S194-7.
5. Ishibe N, Sgambati MT, Fontaine L, et al. Clinical characteristics of familial B-
CLL in the National Cancer Institute Familial Registry. Leuk Lymphoma. 2001;42(1-
2):99-108.
6. Tang G, Banks HE, Sargent RL, et al. Chronic lymphocytic leukemia with
t(14;18)(q32;q21). Hum Pathol. 2012 Oct 16. pii: S0046-8177(12) 00245-6.
7. Agrawal N, Naithani R, Mahapatra M, et al. Chronic lymphocytic leukemia in
India - a clinico-hematological profile. Hematology. 2007;12(3):229-33.
8. Sriphatphiriyakun T, Auewarakul CU. Clinical presentation and outcome of
Thai patients with chronic lymphocytic leukemia: retrospective analysis of 184 cases.
Asian Pac J Allergy Immunol. 2005;23(4):197-203.
9. Ben-Nun L. The diseases that caused chronic weakness. In: Ben-Nun L. ed. The
Israel. 2009, pp. 172-80.
SMALL LYMPHOCYTIC LYMPHOMA

SLL patients present with lymphadenopathy, usually generalized.
Lymphocytosis is by definition absent and bone marrow involvement,
usually nodular, is found in 25-50% of patients (1).
The first sign is often a painless swelling in the neck, armpit or
groin, caused by enlarged lymph nodes. Sometimes more than one
group of nodes is affected. Other symptoms include loss of appetite
and tiredness (fatigue). Some people have night sweats, unexplained
high temperatures (fever) and weight loss. These are known as B
symptoms of SLL (2).
The aim of this study was to define clinical factors that predict for
survival in "B-cell small lymphocytic lymphoma". The term "B-cell
small lymphocytic lymphoma" is generally reserved for patients with
lymph node masses that show the histology and immunophenotype of
421
B-cell CLL but who are not leukemic. Thirty-nine patients with B-cell
SLL with less than 5,000 mature-appearing lymphocytes/microL in
the peripheral blood were studied. The median follow-up of survivors
was 6.6 years (range, 1.6-12.3 years). The estimated 5-year overall
survival and failure-free survival were 66% and 23%, respectively. In
the univariate analysis, significant adverse predictors for overall
survival were age ≥ 60 years, B symptoms (fever, night sweats, and
weight loss), elevated serum LDH, low hemoglobin (< 11 g/dL), and
high IPIS. In multivariate analysis, the IPIS was the only significant
predictor of overall survival. Anemia and B symptoms were
additionally predictive of poor overall survival in patients with low
IPIS (3).
A 61-year-old man with small lymphocytic lymphoma.
A 61-year-old man with a history of CREST syndrome (calcinosis

cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly,
and telangiectasia) was presented for evaluation of thrombocytopenia.
He had evident systemic adenopathy and lymph node biopsy showed
SLL with bone marrow involvement. The patient achieved a complete
remission with FCR (fludarabine/cyclophosphamide/rituximab)
chemotherapy. This is a case of a SLL in association with limited
cutaneous systemic sclerosis with classic features of the CREST
syndrome (4).
Two cases of primary prostatic SLL/CLL, and in one case a
combination with prostate carcinoma are reported. Lymphocytic
infiltration of the prostate associated with obstructive symptoms is
rare but can already occur in very early disease. Microscopically, SLL
/CLL infiltration can be distinguished from chronic prostatitis by its
pattern of infiltration and by immunohistochemistry. As the incidence
of both SLL/CLL and prostatic carcinoma increases with age,
composite tumors might occur more often in the future (5).
Assessment: SLL patients present with lymphadenopathy, usually

generalized. The first sign is often a painless swelling in the neck,
422
armpit or groin, caused by enlarged lymph nodes. Sometimes more

than one group of nodes is affected. Other symptoms may include loss
of appetite and tiredness (fatigue). Some people have night sweats,
unexplained high temperatures (fever) and weight loss.
Was the King afflicted by SLL? In the absence of severe bone
pains from which suffered the King, the diagnosis of SLL seems
unlikely.
References
1. Ghia P, Ferreri AM, Galigaris-Cappio F. Chronic lymphocytic leukemia. Crit
Rev Oncol Hematol. 2007;64:234-46.
2. Small lymphocytic lymphoma. Macmillan Cancer Support. Available 20 May
2013 at .macmillan.org.uk/.../Lymphomanon.../ Smalllymphoc.
3. Nola M, Pavletic SZ, Weisenburger DD, et al. Prognostic factors influencing
survival in patients with B-cell small lymphocytic lymphoma. Am J Hematol.
2004;77(1):31-5.
4. William BM, Harbert T, Ganti AK, Bierman PJ. Small lymphocytic lymphoma
in a patient with CREST syndrome. Hematol Oncol Stem Cell Ther. 2011;4(3):132-5.
5. Fehr M, Templeton A, Cogliatti S, et al. Primary manifestation of small
lymphocytic lymphoma in the prostate. Onkologie. 2009;32(10):586-8.
LYMPHOPLASMACYTIC LYMPHOMA/
WALDENSTROM'S MACROGLOBULNEMIA
LPL/WM patients present either with an accidental discovery of
IgM gammopathy, and symptoms related to paraproteinemia, or
lymphadenopathy, and/or splenomegaly. The bone marrow is
frequently involved and a leukemic picture may be found (1). Some
patients have an indolent leukemia, with long survival while others
experience an aggressive disease, with early and frequent need of
treatment (2).
The presence of IgM paraproteinemia in low-grade lymphomas is
usually considered a clinical syndrome known as WM. In the WHO
classification, WM is associated to LPL; it is a clinicopathologic
entity characterized by a monoclonal expansion of predominantly
small B-lymphocytes with variable plasmacytoid differentiation. LPL
constitutes less than 5% of all non-Hodgkin B-cell lymphoma and it is
associated with HCV infection in 26% of cases. Cells of LPL/WM are
B cells positive for monocytic Ig light chains, IgM, pan-B-cell
markers, and negative for CD3 and CD103. The t(9;14)(p13;q32) is
present in 50% of LPL and determines PAX-5 over-expression. 6q21
deletion is observed in 42% of cases. LPL occurs in older adults.
423
Clinical presentation usually consists of disseminated disease, but

extranodal involvement and leukemic phase are rare. Most WM
patients have symptoms attributable to tumor infiltration and/or
monoclonal protein. In fact, a monoclonal serum paraprotein of IgM
type and hyperviscosity symptoms may occur in more than 20% of
cases (WM). Hyperviscosity syndrome is usually manifested by
bleeding, blurring or loss of vision, dizziness, headache, and
neurologic symptoms. Malignant infiltration of the CNS (Bing-Neel
syndrome) is uncommon. LPL/WM is an indolent malignancy that is
not usually curable with conventional treatments. The median survival
of patients with LPL or WM is 50-60 months, and transformation to
large cell lymphoma may occur. Stage definition is irrelevant in WM
considering that initiation of therapy is decided on the bases of
prognostic factors and the development of disease-related symptoms
and signs. The main adverse prognostic factors are older age, B
symptoms, anemia, low albumin serum levels, raised SGOT, and high
beta 2-microglobulin values. Several therapeutic alternatives for
newly diagnosed or relapsed LPL/WM are available; however, the
best location for every strategy is a matter of investigation (3).
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia in the

brain.
The concept of WM has evolved from the original description of a

clinical syndrome to its more recent designation as a distinct
clinicopathologic entity, that is, LPL/WM, in the WHO classification
and by the participants of consensus meetings on WM. The diagnosis
of LPL/WM, however, remains a challenge in daily practice.
Distinguishing LPL/WM from other B-cell lymphomas, especially
marginal zone B-cell lymphomas, which share overlapping
morphologic features, is difficult. The traditional practice of
separating LPL/WM from other lymphomas by an arbitrary level of
serum IgM is no longer considered valid. The characteristic
424
immunophenotype described for LPL/WM by the WHO classification,

that is, CD5(-)CD10(-)CD23-, is observed in 60-80% of neoplasms,
but variations from this pattern of antigen expression are common,
with CD23 being detected in up to 40% of cases. Lack of a distinct
molecular genetic hallmark complicates the distinction of LPL/WM
from other B-cell lymphomas. Although the t(9;14) is stated to be
present in 50% of cases in the WHO classification, translocations
involving the Ig heavy chain including the t(9;14) are actually rare in
LPL/WM. Deletion of 6q21-q23, a nonspecific finding, is the most
common aberration reported in 40-70% of patients. At the molecular
level, the neoplastic clone in most cases has undergone Ig variable
gene mutation, but not isotype switching, and the clone retains the
capability of plasmacytic differentiation. Currently, the diagnosis of
LPL/WM can only be established by incorporating clinical and
pathologic findings and excluding alternative diagnoses. In some
cases, distinguishing LPL/WM from marginal zone B-cell lymphomas
seems arbitrary using currently recommended criteria (4).
The immunophenotypic profile of 75 cases of LPL/WM was
analyzed by flow cytometry. All patients had monoclonal IgM
(median, 2,100 mg/dL [21 g/L]) in serum and were considered
clinically to have WM. The neoplastic cells, in all cases, expressed
monoclonal immunoglobulin light chain (k, 55; l, 20) and CD19, and
every case assessed was positive for CD20 (n=68) and CD52 (n=60).
The results for other antigens assessed in decreasing frequency of
positivity were as follows: surface IgM (26/28 [93%]), CD79b (11/13
[85%]), CD11c (13/16 [81%]), CD25 (5/7 [71%]), CD23 (17/28
[61%]), CD38 (24/50 [48%]), FMC7 (11/29 [38%]), CD22 (4/12
[33%]), CD5 (3/65 [5%]), and CD10 (1/38 [3%]). These results show
that the immunophenotype of LPL/WM is variable and overlaps with
other B-cell lymphoproliferative disorders. CD23, usually of dim
intensity, and CD11c are expressed commonly in LPL/WM. Rare
CD5+ and CD10+ cases of LPL/WM also exist (5).
In order to investigate the clinical manifestations, diagnosis,
therapy and prognosis of LPL/WM, 16 patients with LPL/WM were
analyzed retrospectively. The results showed that the average age of
16 patients with LPL/WM was 65.1 years old, the most common
syndromes were anemia and hyperviscosity syndrome, bone marrows
were composed of small lymphocyte, admixed with variable numbers
of plasma cells and plasmacytoid lymphocytes. Lymph node biopsy
revealed that most cells expressed B-cell-associated antigen. Among
the 16 cases, complete remission was 25%, overall response rate was
81.3%, and overall survival time was 6 to 108 months. Three patients
425
died and survival rate was 81.3%. In conclusion, the clinical course of
LPL/WM is typically indolent. These patients can acquire remission in
clinic, but cannot be cured, some of them can transform into patients
with more malignant lymphoma (6).
Assessment: LPL/WM patients may present either with an

accidental discovery of IgM gammopathy, symptoms related to
paraproteinemia, or lymphadenopathy and/or splenomegaly. Some
patients have an indolent leukemia, with long survival while others
experience an aggressive disease, with early and frequent need of
treatment. Clinical symptoms include anemia and hyperviscosity
syndrome with bone marrows are composing of small lymphocyte,
admixed with variable numbers of plasma cells and plasmacytoid
lymphocytes. Lymph node biopsy revealed that most cells expressed
B-cell-associated antigen.
Was the King afflicted by LPL/WM? In the absence of severe bone
pains from which suffered the King and the results of blood and bone
marrow examinations, the diagnosis of LPL/WM seems unlikely.
References
2. Ghia P, Ferreri AM, Galigaris-Cappio F. Chronic lymphocytic leukemia. Crit
Rev Oncol Hematol. 2007;64:234-46.
3. Vitolo U, Ferreri AJ, Montoto S. Lymphoplasmacytic lymphoma-
Waldenstrom's macroglobulinemia. Crit Rev Oncol Hematol. 2008;67(2):172-85.
4. Lin P, Medeiros LJ. Lymphoplasmacytic lymphoma/waldenstrom
macroglobulinemia: an evolving concept. Adv Anat Pathol. 2005;12(5):246-55.
5. Konoplev S, Medeiros LJ, Bueso-Ramos CE, et al. Immunophenotypic profile
of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Am J Clin
Pathol. 2005;124(3):414-20.
6. Wang JJ, Jing HM, Shen HW, et al. Clinical features of 16 cases of
lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Zhongguo Shi Yan
Xue Ye Xue Za Zhi. 2010;18(6):1494-8.
AMYLOIDOSIS
Amyloidoses are disorders of diverse etiology in which deposits of
abnormally folded proteins share distinctive staining properties and
426
fibrillar ultrastructural appearance. Amyloidosis ultimately leads to

destruction of tissues and progressive disease (1).
In amyloidosis, a protein misfolding disorder, in which soluble
proteins aggregate as insoluble amyloid fibrils causing functional and
structural organ damage. To date, at least 24 different proteins have
been recognized as causative agents of amyloid diseases, localized or
systemic. The 2 most common forms of systemic amyloidosis are
light-chain amyloidosis and reactive amyloidosis due to chronic
inflammatory diseases. Beta(2)-microglobulin amyloidosis is a
common complication associated with long-term hemodialysis.
Hereditary systemic amyloidoses are a group of autosomal dominant
disorders caused by mutations in the genes of several plasma proteins.
Heterogeneity in clinical presentation, pattern of amyloid-related
organ toxicity and rate of disease progression is observed among
systemic amyloidoses. In particular, beta(2)-microglobulin presents
unique clinical features compared to the other systemic forms. The
phenotypic features of hereditary systemic amyloidoses may instead
overlap those of the 2 more common forms of acquired amyloidoses
mentioned above and therefore a correct diagnosis cannot rely only on
clinical grounds. Unequivocal identification of the deposited protein is
essential in order to avoid misdiagnosis and inappropriate treatment.
Amyloid deposits can be reabsorbed and organ dysfunction reversed if
the concentration of the amyloidogenic protein is reduced or zeroed.
At present, the most effective approach to treatment of the systemic
amyloidoses involves shutting down, or substantially reducing the
synthesis of the amyloid precursor, or, as in the case of beta(2)-
microglobulin, promoting its clearance (2).
The aggregation of normally soluble proteins into insoluble
unbranching fibrils is the basic underlying pathology in amyloidosis.
The process of amyloid formation generates toxic insoluble (in saline)
protein aggregates that are deposited in tissues in the form of β-
pleated sheets of fibrillary material. The amyloidoses are considered
to be part of the so-called protein storage diseases (protein
thesauroses). In addition, due to the unusual protein folding associated
with amyloid, this group of diseases has been referred to as
conformational and protein folding disorders. For many years,
amyloidosis was considered an extremely rare, somewhat mysterious
disease. However, in recent years its pathogenesis, particularly that of
renal amyloidosis, has been carefully dissected in the research
laboratory using in vitro and, to a lesser extent, in vivo models. These
have provided a molecular understanding of sequential events that
take place in the renal mesangium leading to the formation of amyloid
427
fibrils and eventual extrusion into the mesangial matrix, which itself
becomes seriously damaged and, in due time, replaced by the fibrillary
material. Amyloid, once considered an 'inert' substance, has been
proven involved in crucial biological processes that result in the
destruction and eventual replacement of normal renal constituents.
Although there are more than 2 dozen recognized amyloid precursor
proteins (and new ones being added to the list) that can be involved in
the genesis of amyloid fibrils, the pathophysiologic mechanisms that
occur in the renal mesangium are likely to be very similar, if not the
same, regardless of the type of amyloidosis. Likewise, the same is true
of amyloid formation in the renal vasculature. Mesangial cells are
essentially smooth muscle cells and the events that take place in the
mesangium and vasculature (where smooth muscle cells and/or
pericytes are present) in the entire body responsible for the formation
of amyloid are the same. In the renal interstitium, fibroblasts likely
participate in the formation of amyloid, following a similar sequence
of events as smooth muscle cells. Although much of the information
gathered has been from in vitro systems, and in vivo model of renal
amyloidosis has recently been designed to study renal
amyloidogenesis. Crucial steps in the cascade of events that result in
the formation of amyloid fibrils have been elucidated in the
laboratory. The information that has been gathered regarding the
pathogenesis of amyloidosis has been translated to the clinical arena
where implementation of new therapeutic approaches is beginning to
occur (3).
Amyloidoses, a heterogeneous group of diseases, characterized by
extracellular fibrillar protein deposits in the organs and tissues. These
proteins are not biochemically related to each other, but share certain
common characteristics, including apple green birefringence with
polarized light after staining with Congo red, and beta-pleated sheet
configuration through x-ray diffraction. Amyloid deposits may occur
in many organs (systemic amyloidoses) or may affect a single tissue
(localized or organ-specific amyloidoses). Clinical symptoms, which
are determined by the amyloid protein involved. Cutaneous and
mucous membrane manifestations are often the first sign of the
disease and are useful for early diagnosis, thus avoiding more
aggressive procedures (4).
The fibrils of primary amyloidosis consist of kappa or lambda
monoclonal light chains (5). Amyloid deposits have particular
ultrastructural appearance with 7 to 10 nm-diameter fibrils. Amyloid
is defined by its tinctorial affinity, which includes Congo red
positivity, which must polarize and produce apple-green
428
birefringence. Immunohistochemical characterization allows to know

the origin of amyloidosis (characterization, which must be performed
on frozen tissue). This restatement is proposed to renal pathologists in
indicating the traps of studying amyloidosis, the tissues performing for
the diagnosis, the specific staining and the immunohistochemical
characterization (6).
The main objective of this study was to summarize current

recommendations for the diagnosis of amyloidosis. Presentation given
at the 4th Annual Renal Pathology Society Satellite meeting in
Istanbul was based on discussions and recommendations formulated
during an interactive diagnostic session held at the XIth International
Symposium on Amyloidosis in Woods Hole, Massachusetts. Congo
red stain is currently the gold standard for amyloid detection and the
goal is to detect amyloid early. Diagnosis of the amyloid type must be
based on the identification of amyloid protein within the deposits and
not solely by reliance on clinical or DNA studies. However, the latter
are recommended for confirmation of the amyloid type based on
evaluation of the protein in deposits. Immunohistochemistry must be
performed and interpreted with caution and inconclusive results must
be evaluated further using the more sophisticated methods available in
referral centers (1).
Signs and symptoms of amyloidosis depend on which organs are
affected. When signs and symptoms are evident, they include:
swelling of ankles and legs, weakness, weight loss, dyspnea,
numbness or tingling in hands or feet, diarrhea or constipation,
fatigue, macroglossia, thickening or easy bruising of skin, purpura
around the eyes, arrhythmia, dysphagia, and protein in the urine. An
429
M-protein is found in the serum or urine in 90%. The presence of

nephritic syndrome, renal insufficiency, congestive heart failure,
orthostatic hypotension, or sensorimotor peripheral neuropathy, and
an M-protein in the serum or urine suggest the possibility of primary
amyloidosis. The diagnosis depends upon the demonstration of
amyloid in tissues (5,7).
Renal amyloidosis
Descriptive case series involved ten patients with biopsy proven

amyloidosis involving the orbit, conjunctiva and eyelids. All patients
had some form of eyelid abnormality or malposition. Presenting
complaints included ptosis, epiphora and ocular discomfort. Other
clinical findings included conjunctival lesions and proptosis. The
majority of patients had localized amyloidosis and one patient had
systemic disease. Conservative management included lubrication and
the use of bandage contact lenses. Surgical management included
debulking, ptosis or other lid surgery. In conclusion, amyloidosis can
present to an oculoplastic clinic in a wide variety of ways. Definitive
diagnosis is based on the histopathological findings. Management is
often challenging. Multi-disciplinary team involvement is critical in
view of its systemic associations (8).
Conjunctival amyloidosis is an uncommon condition that
occasionally is associated with systemic involvement. The clinical
presentations of conjunctival amyloidosis are diverse. Six patients
with conjunctival amyloidosis were referred with the suspicion of
another conjunctival lesion. The conjunctival lesion was
circumscribed in two patients and diffuse in four patients. The lesion
color was yellow in 1 patient and yellow-pink in 5 patients. The
associated features were intrinsic vascularization (6 patients),
recurrent subconjunctival hemorrhage (4 patients) and blepharoptosis
that involved the palpebral conjunctiva (2 patients). Systemic
evaluation revealed primary systemic amyloidosis in 1 patient and no
430
related systemic abnormalities in 5 patients. Management consisted of

complete excisional biopsy for the 2 circumscribed lesions and
incisional biopsy for the 4 diffuse lesions. Two patients with diffuse
involvement showed progressive involvement of the conjunctiva over
3 years following incisional biopsy and the other 4 patients remained
stable. There was no systemic involvement in 5 patients. In
conclusion, conjunctival amyloidosis generally manifests as a
yellowish-pink, hemorrhagic mass deep to the epithelium. Most
patients show no evidence of systemic amyloidosis (9).
Primary systemic amyloidosis
Macular amyloidosis is a form of cutaneous amyloidosis

characterized by dusky-brown lesions usually located on the upper
back between the shoulder blades. A case of a 45-year-old female was
presenting with hyperpigmented macules and lace-like, non-pruritic
erythema in the sacral and cervical region as well as on both arms and
legs. Histology revealed amyloid deposits in the papillary dermis
which exhibited apple-green birefringence after Congo red staining.
There were no systemic findings. This is a case of macular
amyloidosis with an unusual presentation (10).
Nodular cutaneous amyloidosis is the rarest form of primary
cutaneous amyloidosis. Lesions typically present as a crusted nodule
on the face, extremities, or acral sites. The amyloid fibrils are
immunoglobulin-derived and either kappa or lambda light chains.
Systemic involvement is dependent on plasma cell amyloid protein
deposition. Lesions may otherwise be classified as a local plasma cell
clone or cutaneous plasmacytoma. There is < 10% risk of systemic
progression. Workup should include at least a full history and physical
examination; serum protein electrophoresis and urine protein
electrophoresis; and gingival, rectal, or abdominal fat pad biopsies to
rule out the presence of extracutaneous amyloid deposition.
431
Management of nodular cutaneous amyloidosis is challenging, as

there is no consistently effective treatment and local recurrence is
common (11).
A 57-year-old male was presented with a 2-year history of malaise,
dyspnea and myalgias. On physical examination, ungueal dystrophy,
orange pigmentation of eyelids with periocular petechiae and mild
macroglossia were observed. Incisional biopsies of the eyelids, cheeks
and hands were obtained. The pathological study demonstrated
amyloid deposits. Since protein electrophoresis was normal, the
diagnosis of AA amyloidosis was postulated (12).
The records of patients with pathologically proven isolated
pulmonary amyloidosis treated at the Department of Respiratory
Disease, Shanghai hospital, China from 1990 to 2011 were reviewed.
There were 9 males and 4 females with a mean age of 54.7 years
(range, 45-72 years) and the mean course of disease was 46.5 months
(range, 5 months-15 years). The most common symptoms were cough
(10/13), expectoration (8/13), hemophtysis (4/13), chest tightness
(12/13), dyspnea (10/13), chest pain (3/13), fever (5/13), and body
weight loss (2/13). Radiological findings included tracheal stenosis
(2/13), bronchial stenosis with atelectasis (5/13), pulmonary nodules
(3/13), lung consolidation (1/13), and lymph node enlargement with
pleural effusion (2/13). Treatments included endotracheal stenting,
endoscopic resection of tracheal and bronchial lesions, lung resection,
and drug therapy with glucocorticoids, antineoplastic agents, or
antibiotics. Four patients died of the disease within 1 year of
diagnosis, 2 died of pneumonia at 3-4 years after original treatment,
and the remaining patients are alive with follow-up ranging from 3 to
15 years. In conclusion, isolated pulmonary amyloidosis is a rare
disease with a relatively high mortality and its various manifestations
make diagnosis challenging. Surgical resection of lesions and
chemotherapy tend to be effective treatments (13).
Heart involvement by amyloid deposition remains the most
challenging of all organ systems that may become involved, in what is
generally a systemic disease. The correct diagnosis of amyloid type is
critical to selection of the appropriate and wide range of therapies. The
treatment of amyloid heart disease comprises 2 strategies:
conventional management of a restrictive cardiomyopathy, and varied
therapies aimed at the underlying amyloidogenic process. In light
chain amyloidosis, many of the most efficacious therapies involve
chemotherapeutic agents with their own inherent toxicities to the heart
and bone marrow. In the case of the hereditary amyloidosis, major
surgery in the form of liver transplantation is usually required.
432
Consideration should be given to screening family members for a

potentially hereditary disease. Several types of amyloidosis may
require 1 or more, of heart, liver and/or kidney transplantation,
sometimes in addition to high-dose chemotherapy (14).
The kidney is one of the most frequent sites of amyloid deposition
in light chain amyloidosis, AA, and several of the hereditary
amyloidoses. Amyloid fibril formation begins with the misfolding of
an amyloidogenic precursor protein. The misfolded variants self-
aggregate in a highly ordered manner, generating protofilaments that
interact to form fibrils. The fibrils have a characteristic appearance by
electron microscopy and generate birefringence under polarized light
when stained with Congo red dye. Advances in elucidating the
mechanisms of amyloid fibril formation, tissue deposition, and tissue
injury have led to new and more aggressive treatment approaches for
these disorders (15).
Amyloid deposition in kidneys
A case of a 75-year-old woman was presented with progressive

kidney failure. Kidney biopsy performed to determine the cause of
kidney failure showed amyloidosis of undetermined type. Laser
microdissection of the Congo Red-positive glomeruli followed by
mass spectrometry studies showed a large number of spectra matching
apolipoprotein E, serum amyloid P component, and gelsolin,
consistent with a diagnosis of gelsolin-associated renal amyloidosis.
Sequencing of the gelsolin gene revealed a previously undescribed
sequence variant, a guanine to adenine substitution at nucleotide 580
of the coding sequence, corresponding to a predicted glycine to
arginine mutation at amino acid 194. Gelsolin amyloidosis typically
involves the nerves and skin, with only rare reported involvement of
the kidney. An atypical finding on electron microscopy was that of a
swirling pattern of the amyloid fibrils. The novel gelsolin variant may
be responsible for the unusual clinical and pathologic presentation.
433
The report also highlights the usefulness of laser microdissection and

mass spectrometry in the typing of difficult cases of amyloidosis (16).
In recent years, management of amyloidosis has shifted from a
purely supportive approach to quite diverse, radical and aggressive
treatments. The central issue is the understanding that treatment of
systemic amyloidoses depends on the molecular type of the amyloid
protein. In the US and the Western world, light chain-amyloidosis is
the most prevalent type of systemic amyloidosis, but hereditary
amyloidoses are being diagnosed with increasing frequency; genetics
also plays a role in a subset of familial reactive amyloidoses. The
biggest challenge is in the diagnosis of light chain-type with
confidence and in differentiation of light chain and hereditary
amyloidoses. While careful clinico-pathologic correlation is
recommended for all patients with amyloidosis, it is, in itself, not a
substitute for amyloid typing. The diagnosis of the amyloid type
ultimately depends on the examination of the amyloid protein within
the deposits. The role of immunohistochemistry - the current standard
of care in amyloid typing - is evolving with emergence of alternative
biochemical methods. Amyloid, being essentially a protein disorder,
presents an attractive venue for the application of proteomics
methodologies, despite their inherent complexities (17).
Assessment: amyloidoses are disorders of diverse etiology in

which deposits of abnormally folded proteins share distinctive staining
properties and fibrillar ultrastructural appearance. Amyloidosis
ultimately leads to destruction of tissues and progressive disease. The
aggregation of normally soluble proteins into insoluble unbranching
fibrils is the basic underlying pathology in amyloidosis.
The 2 most common forms of systemic amyloidosis are light-chain
amyloidosis and reactive amyloidosis due to chronic inflammatory
diseases. Beta(2)-microglobulin amyloidosis is a common
complication associated with long-term hemodialysis. Hereditary
systemic amyloidoses are a group of autosomal dominant disorders
caused by mutations in the genes of several plasma proteins. Signs and
symptoms of amyloidosis depend on which organs are affected.
Did primary amyloidosis afflict the King? Let us look at the
biblical verses: ―..my bones are consumed‖ (Psalm 31:11) and ―My
bones wasted away through my anguished roaring all day long‖
(32:3). In amyloidosis, severe bone pain is not characteristic
presentation of the disease. Thus, it seems unlikely that amyloidosis
was responsible for King David's severe bone pain.
434
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2012;7(4):243-9.
14. Dubrey SW. Amyloid heart disease: a brief review of treatment options.
Postgrad Med J. 2012;88(1046):700-5.
15. Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol.
2006;17(12):3458-71.
16. Sethi S, Theis JD, Quint P, et al. Renal amyloidosis associated with a novel
sequence variant of gelsolin. Am J Kidney Dis. 2013;61(1):161-6.
17. Picken MM. New insights into systemic amyloidosis: the importance of
diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007;16(3):196-203.
PLASMACYTOMA
Plasmacytoma is a rare disease, which afflicts 2 to 3 people per
every 100,000 of the general population. Solitary plasmacytoma,
which accounts for 5% of the plasma cell neoplasm, affects more the
axial skeleton (25-60%) that has the red marrow and usually the
thoracic vertebrae (1).
435
Plasmacytoma results from clonal proliferation of plasma cells that

are identical to plasma cells of myeloma on both the cytologic and
immunophenotypic levels. Plasmacytoma can be subclassified as
osseous disease or extraosseous tumor (1-8).
The clinical presentation of these diseases represent different
groups of patients in terms of location, tumor progression, and overall
survival rate (8); however, they share many of the biologic features of
other plasma cell disorders Skeletal plasmacytoma is characterized
clinically by a radiolytic lesion involving any part of the skeleton, a
clonal plasma cell infiltrate and an absence of disseminated bone
marrow involvement (1,10).
Plasmacytoma consists of 2 cohorts of patients with different
overall survival; patients that do not progress to systemic disease and
patients who develop myeloma. Age > 60 years is associated with
disease progression. Identifying patients with systemic disease early
will permit aggressive and novel treatment strategies to be
implemented (11).
A 38-year-old man with solitary plasmacytoma of L5. Relatively T2-

weighted gradient recalled echo (400/21, TR/TE, flip angle 20°) sagittal MR
image of the lumbar spine shows a bright signal of mass in L5 and extension
of tumor into the spinal canal (arrows) with impingement of the thecal sac.
Solitary plasmacytoma is characterized by a mass of neoplastic

monoclonal plasma cells in either bone or soft tissue without evidence
of systemic disease attributing to myeloma. Biopsy confirmation of a
monoclonal plasma cell infiltration from a single site is required for
diagnosis. The common presentation of solitary plasmacytoma of
bone is in the axial skeleton, whereas the extramedullary
plasmacytoma is usually seen in the head and neck. The ratio of
solitary plasmacytoma seen at males to females is 2: 1 and the median
age of patients is 55 years. The incidence rate of solitary
plasmacytoma in black race is approximately 30% higher than in the
436
white race. Incidence rate increases exponentially by advancing age.

Solitary plasmacytoma of bone has a significant higher risk for
progression to myeloma, and the choice of treatment is RT that is
applied with curative intent at min. 4000 cGy. By only RT application,
long-term disease-free survival is possible for approximately 30% of
patients with solitary plasmacytoma of bone and 65% of patients with
the extramedullary plasmacytoma (12).
Data of 20 patients with solitary plasmacytoma of the cervical
spine were identified and patients were treated between January 1995
and December 2006 at the Spine Center, Changzheng Hospital,
Shanghai, China. There were 13 men and 7 women ranging in age
from 32 to 76 years with a mean of 56 years. Among them, 1 patient
underwent RT alone, and the other 19 patients received surgery with
adjuvant RT. According to the Weinstein-Boriani-Biagini staging
system, the surgical procedures consisted of subtotal resection and
gross-total resection. All cases were managed using an anterior
approach or a combined anterior and posterior approach in 1 stage.
Reconstruction of the cervical spine was achieved through an anterior
cervical titanium plate and titanium mesh cage filled with autoiliac
graft or bone cement, or anterior and posterior combined instrumented
fusion. All surgery patients received RT as adjunctive therapy
postoperatively. Follow-up of the 20 patients ranged from 25 to 132
months with a mean of 61 months. Neck pains improved significantly,
and motor or sensory deficits disappeared or improved in varying
degrees after surgery. Neurologic function level of the patients
improved by I to III grades based on the Frankel grading system 3
months after surgery. All the internal fixations fused well, stability of
the cervical vertebrae was secure, and no spinal instability was
observed. The bone graft fusion rate reached 100%. During the
follow-up period, 4 surgery cases progressed to MM, in which 2
elderly patients died of respiratory and circulatory failure at 90 and 43
months, respectively. The other 15 patients achieved disease-free
survival after surgery with adjunctive RT. Insignificant abnormality
was detected on M protein, bone marrow aspiration, and emission CT
or PET/CT examinations. In conclusion, plasmacytoma of the cervical
spine is relatively rare, and no typical early symptoms are present.
Gross total tumor resection or total spondylectomy by piecemeal
manner with adjuvant RT can reduce local recurrences and lower the
possibility of progressing to MM. Patients with progression to MM
should be treated with individualized chemotherapy, but the prognosis
is poor (13).
437
A 45-year-old man presented with gradually progressive legs to

arms numbness preceded by upper respiratory tract infection and
followed by rapid flaccid quadriparesis over 1 week. Because of the
above symptoms, he was initially thought to have Guillain-Barré
syndrome, but this diagnosis was ruled out by an emergent normal
NCS and needle EMG. Cervical MRI revealed an enhancing epidural
mass at the C4-C7 level on T1-weighted images and increased signal
on T2, causing spinal cord compression. Complete surgical evacuation
was performed. Subsequent histology revealed plasmacytoma
associated with anaplastic MM, and the patient was referred to the
hematology department for further treatment. Follow-up at 9 and 13
months after surgery revealed complete remission of the primary
disease (MM). The patient was neurologically improved and
ambulatory with unilateral support. In conclusion, the reported case
describes epidural extramedullary plasmacytoma isolated in the
cervical spine. Emergent neuroimaging and surgery can dramatically
affect prognosis of this rare spinal neoplasm (14).
A case of solitary plasmacytoma of the sternum by MR imaging of
the cervical spine was incidentally detected. At detection, the patient
had no symptoms, the lesion was localized in the bone marrow of the
sternum, and there were no findings of bone destruction. The lesion
showed high contrast on diffusion-weighted images, gradually
enlarged over 3 years, and was confirmed as a solitary plasmacytoma
at open biopsy 3 years after detection. Radiologists should pay
attention to incidental findings in the upper part of the sternum at MR
imaging examination of the cervical spine (15).
A 35-year-old man presented with insidious onset of severe sacral
pain. Plain radiography, CT, and MRI revealed a large, locally
invasive mass within the sacrum. Skeletal scintigraphy showed
marked hyperemia and minimal peripheral osteoblastic activity of the
sacral mass. An F-18 FDG PET study was performed for further
assessment and clinical staging. The mass demonstrated high glucose
avidity consistent with a high-grade tumor. Histological examination
confirmed the lesion to be a plasmacytoma. This case is interesting in
view of the large dimension, sacral involvement, the young age of the
patient, and the appearance of this lesion across multiple imaging
modalities (16).
A case of multiple plasmacytomas of the bone (IgM-lambda type)
in a 70-year-old female is reported. This patient had 5 foci of bony
destruction for a three-year follow-up period after surgery of solitary
plasmacytoma of the rib (17).
438
A case of multiple plasmacytoma in a woman is described, with a

several-year radicular syndrome and recently, with numerous
pathologic fractures and tumor formation on the head and sternum.
Bone pains, pathologic fractures and tumors – osseous manifestations
characterized this disease (18).
A 54-year-old man was presented with a chest pain on the right
side. After being treated for the muscle pain, his symptoms of pain
were changed into weakness and allesthesia. In the MRI, a mass lesion
in the T5 vertebra was found, but there were insignificant laboratory
findings, in blood and urine samples. Finally, he got an operation due
to the aggravation of the weakness. The result of biopsy indicated a
solitary plasmacytoma. After 5 months later, the weakness and
allesthesia had disappeared (19).
Plasmacytomas with associated compression fracture of C7. Sagittal T1-

weighted (left; 600/15) and STIR (right; 2,000/150/20) MR images of
cervical spine show focal lesion (arrows) involving C7 vertebral body, with
associated fracture. There is protrusion of the plasmacytoma into adjacent
spinal canal.
A 53-year-old woman was admitted to the hospital complaining of

sudden severe paraplegia and back pain. Emergency MRI revealed a
tumor of the thoracic vertebra Th10. Pressure fracture of the Th10 was
also recognized. The tumor was not osteolytic and invasion was
recognized around the Th10. The tumor directly compressed the spinal
cord. An excision of the tumor was performed under the clinical
diagnosis of metastatic carcinoma. Pathologically, the tumor consisted
of plasmacytoid atypical cells with hyperchromatic nuclei.
Histochemically, the tumor cells showed pyroninophilia.
Immunohistochemically, the tumor cells were positive for λ-light
chain, but negative for cytokeratin, epithelial mermbrane antigen,
vimentin, CD45, CD20, CD45RO, κ-light chain, α-heavy chain, λ-
heavy chain, μ-heavy chain, δ-heavy chain, ε-heavy chain, IgA, IgG,
IgM, synaptophysin, chromogranin, S100 protein, desmin, α-smooth
439
muscle antigen, myoglobin, and p53 protein. The Ki-67 labeling was
73%. The tumor was diagnosed as solitary plasmacytoma with λ-light
chain disease. After the diagnosis, whole body CT and MRI revealed
no other tumors. Blood and serum test revealed insignificant changes;
no M-protein was recognized. However, voided urine test revealed λ-
light chain protein. The patient underwent fixation operation of TH10,
and received RT (50 Gray) and chemotherapy. No recurrence or
transformation into myeloma occurred at the present time 25 months
after the first manifestation. The present study indicated that
pathological examination is an only clue to the diagnosis of solitary
plasmacytoma of the vertebra bone (20).
The bodies of the vertebrae are common locations for plasma cell
diseases such as MM and solitary plasmacytoma. Secondary invasion
of the epidural space is infrequent but can cause neurological
symptoms. Spinal cord compression due to pure intradural plasma cell
infiltration is very rare. The authors report a 25-year-old woman who
developed a progressive difficulty in walking due to a solitary spinal
dural plasmacytoma. This is the example in the English language
literature of a purely intradural spinal plasmacytoma in a patient
without other myelomatous lesions. An entirely intradural solitary
plasmacytoma has a relatively better prognosis (21).
Plasmacytoma often forms an intramedullary mass in the vertebrae
with absorption of trabecula and cortex of the bone. However,
occasionally, it forms a mass in the extramedullary space of the
vertebrae. A rare case of plasmacytoma that formed a mass in the
thoracic epidural space without evidence of involvement of the
adjacent vertebra is reported. An 80-year-old man was presented with
chief complaints of gait disturbance and hypoesthesia below the
umbilical level. Difficulty of walking developed approximately 4
months prior to admission with gradual aggravation and hypesthesia
added thereafter. Neurological examinations at admission showed
paraparesis with positive Babinski's and Chaddock's reflexes,
hypesthesia and disturbances of vibration and position senses below
the 9th thoracic nerve level. Myelography and CT scan using
metrizamide indicated a presence of epidural mass at the 8th to 9th
thoracic vertebrae. There was no abnormal bony change in the spine
on plain X-ray and CT scan. On May 30, 1985, total removal of
epidural tumor was performed by removing the laminae from the 7th
to 10th vertebrae. Histological examinations including immunological
staining showed a plasmacytoma which produced monoclonal
immunoglobulin of IgG-lambda type. RT was not carried out. The
serum protein fraction, immunoglobulin, immunoelectrophoresis,
440
Bence-Jones protein and CSF immunoglobulin examined after

operation, supported a histological diagnosis of plasmacytoma. Slight
proliferation of plasma cells was noted in the bone marrow and
peripheral blood (22).
The clinical, radiologic and pathologic features, as well as
treatment and follow-up data, of 13 solitary plasmacytoma of spine
cases were retrieved and analyzed at the Department of Pathology,
Changhai Hospital. Immunohistochemical study using EnVision
method for LCA, CD19, CD20, CD79a, CD3, CD7, PC, MUM1,
CD138, IgG, IgM, kappa, lambda and Ki-67 was carried out. All the
tumors were primarily located in the vertebrae (including 9 cases in
thoracic vertebrae and 4 cases in lumbar vertebrae). The male: female
ratio was 3.3:1. The age of the patients ranged from 42 to 69 years
(mean age = 56 years). The commonest symptom was pain in the
surrounding regions. The degree of neurologic disturbance mostly
depended on the extent of vertebral destruction and structural
instability of the spine. Radiologic examination showed mainly
osteolytic lesions in vertebrae. MRI demonstrated the presence of
heterogeneous intensity inside the involved vertebrae (low in T1
weighted and high in T2 weighted images). Histological examination
showed diffuse infiltration by malignant cells. In well-differentiated
plasmacytomas, the tumor cells resembled normal plasma cells. In
poorly differentiated examples, the cellular morphology mimicked
that of the centroblasts. The interstitial stroma was scanty and
contained plenty of vessels, sometimes with formation of blood lakes.
Amyloid deposition was present in some of the cases.
Immunohistochemical study showed that the tumor cells were positive
for CD79a and negative for CD20. Light chain restriction was
detected in all the 13 cases studied. Plasma cell marker PC was
expressed in all cases, while IgG was positive in 5 cases, IgM in 1
case, MUM1 in 10 cases and CD138 in 8 cases. Ki-67 index varied
from 10% to 50%. All cases were operated, with adjuvant
chemotherapy and RT given. In conclusion, correlation of clinical,
radiologic and pathologic features is important in diagnosis of solitary
plasmacytoma of spine. The possibility of MM needs to be excluded.
Early detection by radiologic examination, local surgical resection,
post-operative chemoradiotherapy and long-term follow-up are
prudent for successful management of this condition (23).
Intracranial plasmacytomas are a rare abnormality in a
neurosurgeon's practice. The plasmacytomas may originate from the
skull bones or soft tissue intracranial structures; they may be solitary
or occur as a manifestation of MM, this type being typical of most
441
intracranial plasmacytomas. The final diagnosis of plasmacytoma is

based on a morphological study (24-27).
Solitary plasmacytoma in the spine.
A 49-year-old-man suffered from amnesia, irritability and a

rubbery swelling which was gradually increased approximately to 4-5
cm in diameter at the frontal vertex over a year. His neurological
examination was normal. The skull direct X-ray revealed patchy
destruction of the left frontal bone 10 cm in diameter. CT with bone
windows showed relatively preserved but severely thinned inner table
and irregularly destructed outer table. MR scan showed a
hypervascular, mainly solid mass measuring 9 x 5.5 x 8.5 centimeters.
Radical surgery consisting of total tumor extirpation was undertaken.
Histopathological examination confirmed a plasmacytic proliferation.
The postoperative period was uneventful and the patient was
discharged on the 6th day postoperatively. Bone marrow sampling
was scheduled to rule out MM, but the patient committed suicide a
week later for unknown reasons. Although the prognosis of a
plasmacytoma is relatively good, patients with ventral frontal cortex
tumor may have significantly worse mood pre- or postoperatively.
Clinicians should therefore be careful in the follow-up period (28).
Two cases of solitary plasmacytoma of the skull, a very unusual
presentation and location of this tumor, are reported. There was no
difference in prognosis between the tumor originating from the skull
(osseous form) and from the dura mater (non-osseous form),
differently from the other parts of the body. The risk of secondary
MM was low but the mean follow-up is too short for any conclusion
on this point (29).
442
Plasmacytoma of the skull Plasmacytoma of humerus
A case of solitary plasmacytoma of the skull is presented. The

tumor was radically removed. There was no systemic involvement and
the patient was not submitted to RT. Lytic lesions in the skull were
observed (30).
Solitary plasmacytoma of bone is a rare type of plasma cell tumor.
A case of a solitary extramedullary plasmacytoma of the frontal bone
was presented as an asymptomatic forehead lump with clinically
benign characteristics. This case highlights the need for a high index
of suspicion when dealing with enlarging subcutaneous lumps of the
forehead and scalp. The significance of this lies in the appropriate
sequencing of investigations and the implementation of the necessary
treatment regimen (31).
A 66 year-old woman was diagnosed as a cranial base solitary
plasmacytoma and was treated with RT and chemotherapy with
complete remission. After receiving that treatment, she presented with
tetraparesis and a cranio-cervical instability was diagnosed. She was
operated on, under cranial traction, of posterior occipito-cervical
instrumentation with C1 to C2 transarticular Magerl screws. The right
vertebral artery was injured during surgery without additional
neurological deficit. Two years after the operation she remains
independent for daily activities. In conclusion, transarticular screws at
the C1 to C2 level of the cervical spine may provide rigid fixation in
posterior cranio-cervical instrumentation for osteolytic lesions, but
there is a risk of injury to the vertebral artery, especially when some
variations in the surgical anatomy exist (32).
Solitary plasmacytomas of the paranasal sinuses are uncommon
neoplasms of B lymphocyte origin. They comprise one per cent of all
head and neck tumors of the upper respiratory tract, and can be
solitary plasmacytoma of the bone, an extramedullary plasmacytoma
or a local manifestation of MM. Conversion to MM happens more
443
frequently in solitary plasmacytomas of the bone. RT is the common

modality of treatment with, or without, adjuvant chemotherapy.
Extramedullary plasmacytoma carries a better prognosis than a
solitary plasmacytoma of the bone. Four cases of solitary
plasmacytoma of the bone and an extramedullary plasmacytoma of the
paranasal sinuses and soft palate are reported (33).
The solitary plasmacytoma of the maxilla is a rare condition that
focuses solely on myelomatous tissue and is not disseminated to other
parts of the skeleton. Some lesions appear to be benign and do not
recur after complete removal, while others are locally invasive. The
dense plasma cell infiltration that commonly is associated with
inflammatory lesions within the oral tissues makes diagnosing
plasmacytoma at this site problematic. A case of solitary
plasmacytoma in the maxilla is presented. Radiographic examination
revealed an osteolytic lesion over the right maxillary bone, invading
the maxillary sinus. A CT scan showed that the tumor mass occupied
the right maxillary sinus and the lateral wall of the nasal cavity. The
tumor cells were composed of densely packed, round, polygonal cell
structures that were scattered in relatively sparse stoma. The
neoplastic cells had a large, single eccentric nucleus, resembling
typical plasma cells (34).
Extramedullary plasmacytomas are localized plasma cell
neoplasms that occur within the soft tissues; by definition they cannot
occur within bone. They account for 1-2% of all plasma cell growths
and have a great predilection for the upper respiratory tract, without
specific manifestations. Males are more frequently affected during the
fifth and sixth decades of life. At initial presentation, MM should be
excluded. A 63-year-old man with an extramedullary plasmacytoma
arising in the right maxillary sinus was referred for surgical excision
and postoperative RT (35).
The included articles are published in English from 1948 to March
2011 and describe the population affected by solitary plasmacytoma
of the jaw with site, clinical and radiographic features, special
findings, initial diagnosis, treatment, and follow-up. Fifty cases of
solitary plasmacytomas of the jaw were identified. It typically presents
as a single osteolytic lesion with no plasmacytosis involvement of
bone marrow. Long bones and vertebrae are the most common sites of
solitary plasmacytomas. Rarely, it involves the jaw occurring in only
4% of cases, mainly in the bone marrow-rich areas, angulus and
ramus. Solitary plasmacytoma of the jaw has a worse prognosis than
MM, and in half of the cases, it evolves to MM. In conclusion,
because solitary plasmacytoma of bones is an uncommon tumor that
444
rarely involves the jaws, early diagnosis and appropriate management

are essential to avoid progression to MM (36).
A 43-year-old man was hospitalized because of paraplegia due to
spinal cord compression by the solitary plasmacytoma arising in the
cervical spine, producing an IgG-lambda paraprotein. RT and standard
chemotherapy followed the tumor excision. Two years later, new
lesions on the thoracic spine, the left clavicle, and the occipital bone
developed with Bence Jones proteinuria (lambda), but without IgG-
lambda paraproteinemia. Ga-67 scanning was performed to detect
extramedullary tumors. The marked accumulation of the radionuclide
revealed intraabdominal tumors. A CT scan of the abdomen revealed a
large soft-tissue mass (73 x 50 mm) emanating from the right kidney
and several enlarged lymph nodes. Ultrasonography of the right
kidney revealed a solid mass with hydronephrotic change.
Radioisotope-renogram showed delayed excretion from the right
kidney. Clusters of myeloma cells were repeatedly observed in the
urinary sediment. A diagnosis of plasmacytoma of the kidney was
made. Treatment with RT alone was sufficient (37).
Assessment: plasmacytoma results from clonal proliferation of

plasma cells that are identical to plasma cells of myeloma on both the
cytological and immunophenotypical levels. Plasmacytoma is
subclassified as osseous disease or extraosseous tumor. The clinical
presentation of these diseases represents different groups of patients in
terms of location, tumor progression, and overall survival rate;
however, they share many of the biologic features of other plasma cell
disorders. Skeletal plasmacytoma is characterized clinically by a
radiolytic lesion involving any part of the skeleton, a clonal plasma
cell infiltrate and an absence of disseminated bone marrow
involvement. Plasmacytoma consists of 2 cohorts of patients with
different overall survival; patients who do not progress to systemic
disease and patients who develop myeloma.
Was the King afflicted by plasmacytoma, solitary or multiple?
Since the King suffered from severe bone pains, the diagnosis of a
solitary plasmacytoma seems unlikely. In the case of multiple
plasmacytomas, numerous pathological fractures may indicate this
disease. Literature reports plasmacytoma arising in the cervical spine,
and lesions in the thoracic spine, left clavicle, and occipital bone with
tumor originating in the kidney. However, although this diagnosis
cannot be absolutely ignored, the formation of tumors on the head and
sternum, and the presence of tumors in the bones combined with the
tumor in the kidney make the diagnosis of multiple plasmacytomas
unlikely in the King's case.
445
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To sum up: the King's medical record, that is the biblical text,
documents the patient's complaints: ―...my strength failed..., and my
bones are consumed‖ (Psalm 31:11) and ―My bones wasted away
through my anguished roaring all day long‖ (32:3). The anamnestic
findings indicate a very serious and lethal disease that caused the King
severe intractable bone pain and great suffering. Among the
hematological diseases examined, the most likely are either MM or
gamma HCD.
447
RESPIRATORY SYSTEM
MALIGNANCIES
LARYNGEAL CARCINOMA
Laryngeal cancer is one of the most frequent types of head and
neck cancer. The incidence is decreasing for men but still increasing
for women (1,2). This cancer is a serious disease associated with high
mortality. Survival rates for these tumors vary and depend on the
presence of early symptoms, anatomic accessibility and lymphatic
supply. Despite advances in therapy and novel surgical and non-
surgical approaches, early diagnosis remains the best predictor of
survival. Screening of asymptomatic individuals would detect tumors
at an early stage to patients' benefit. The progress in the elucidation of
the molecular genetic changes in these tumors should soon bring novel
diagnostic procedures into the clinical practice. TNM staging, biopsy
and histopathological grading remain the gold standard for diagnosis
of laryngeal carcinoma. A great number of novel endoscopic methods
are only supplementary tools to microlaryngoscopy. Some of the most
significant biological markers might be integrated with the evaluation
of behavioral factors, clinical and histopathological examinations for a
new clinicomolecular approach to laryngeal cancer (3).
Retrospective cohort analysis was carried out in the US population
using the Surveillance, Epidemiology, and End Results database of the
NCI. The data were used to design 5 cohorts of patients with laryngeal
cancer: 1977-1978, 1983-1984, 1989-1990, 1995-1996, and 2001-
2002. Among patients with supraglottic cancer, 5-year relative
survival rates for distant disease worsened over time while rates for
local and regional disease did not change (p=0.01 and p>0.05,
respectively). For localized glottic cancer, survival remained stable
from 1977-1978 to 2001-2002. However, patients with regional and
distant glottic cancer demonstrated a significant decrease in survival
in the past 3 decades (p<0.001). This trend was independent of
treatment strategy. The proportion of well-differentiated tumors in
patients with regional laryngeal cancer decreased over time (p<0.001
for supraglottic and p=0.007 for glottis cancer). A decreasing 5-year
survival trend was among patients with glottic cancer who had
regional disease and in all patients with distant disease.
Histopathological trends not previously reported in those with
laryngeal cancer seem to parallel those seen in other tobacco-related
cancers (4).
448
According to a large population-based case-control study in

Southern Europe, over 90% of the present incidence of laryngeal
cancer could be prevented by avoiding smoking and alcohol
consumption. Most of the risk is attributable to tobacco, but reducing
alcohol alone could still prevent a quarter of the cases. Tobacco
smoking, on the other hand, explains 80-90% of lung cancer incidence
in Italy. Other factors include occupational exposures, which,
according to several studies, may account for one third of the cases in
the highly industrialized areas of Northern Italy; environmental
pollution; passive smoking; radon; and dietary factors. Factors
associated with diet rich in fruit and vegetables are protective for both
larynx and lung cancer. Cigarette smoking, however, remains by far
the most important cause of respiratory cancer, and geographical and
temporal trends in incidence can easily be interpreted in terms of
market trends, both in Italy and worldwide. According to several
population surveys in Italy, the prevalence of smokers in successive
male cohort generations reached a maximum (almost 80%) in the
1920-1930 birth cohorts and decreased to about 60% among males
born in the forties and fifties. In the same period, the mean number of
cigarettes per day for smokers increased, and the age of starting
smoking decreased; however, the market changed from unfiltered
black tobacco to filtered low-tar cigarettes. This market trend is
consistent with the observation of decreasing incidence and mortality
of both larynx and lung cancer in young male cohorts and the
persistent increase of both cancers in older males. For women, the
prevalence of smokers increased from less than 10% in the 1920's
birth cohorts to over 30% among women born in the late forties. This
reflects a steady increase of respiratory cancers mortality which,
however, is still lower than the mortality for males (5).
The incidence of laryngeal carcinoma in Germany is about 5-
7/100,000 persons/year for men and 0.6-0.8/100,000 persons/year for
women. Due to the increased life expectancy, the average age of
patients diagnosed with laryngeal cancer is increasing. Nevertheless,
449
adequately prepared older patients treated by standard protocols can

have the same survival and complication rates as younger patients.
Tobacco and alcohol are still the primary risk factors responsible for
disease in at least 80% of the patients. Despite the many new
diagnostic tools, still more than half of the patients are diagnosed at an
advanced tumor stage. Survival rates have not improved significantly
in the last 10 years in Germany, and the average 5-year overall
survival rate is about 60%. However, a decrease in the survival rate, as
observed in the USA, cannot be confirmed for Germany (1).
The city of São Paulo exhibits one of the highest incidences of
laryngeal cancer in world and Brazil presents remarkable occurrence
compared with other Latin American countries. Around 8,000 new
cases and 3,000 deaths by laryngeal cancer occur annually in the
Brazilian population. In the city of São Paulo, incidence rates for
laryngeal cancer among males have been decreasing since the late
1980s while among females the rates have shown a stable trend. This
phenomenon is probably the expression of changes in gender behavior
related to tobacco smoking. Several risk factors are involved in the
genesis of laryngeal cancer. The most important are tobacco smoking
and alcohol intake, but occupational hazards have also been associated
with the disease, such as asbestos, strong inorganic acids, cement dust
and free crystalline silica. Additionally, salted meat and total fat intake
have been linked to elevated risk of laryngeal cancer. Conversely,
several studies have confirmed that fruits, raw leaf vegetables and
legumes protect against this cancer. Some researchers have postulated
a possible association between laryngeal squamous cell carcinoma and
HPV, but this is not universally accepted. GERD is weakly, but
consistently correlated with laryngeal cancer. Familial cancer clusters,
particularly of head and neck tumors, seem to increase the risk of
laryngeal cancer. Some genetic polymorphisms, such as of genes that
code for xenobiotic-metabolizing enzymes, elevated risk for laryngeal
cancer according to recent studies (6).
Subglottic malignancies are rare. They constitute about 1% of
laryngeal cancer. Most of these malignancies are squamous cell
carcinoma. The incidence of primary subglottic carcinoma is low. The
origin of most cancers in this area is the glottic cancer that extends
into the subglottic region. The tumor tends to spread through
lymphatic channels to the paraglottic and preglottic (delphian) nodes
and secondary to the jugular chain. The delayed diagnosis is due to the
lack of symptoms in the early stage of the disease and the hidden
location of the tumor. The presenting symptoms are usually dyspnea
and stridor. Direct laryngoscopy is essential for early detection of the
450
tumor and the use of CT and MRI is advocated. Therapy is usually

radical. Total laryngectomy and RT have both been advocated (7).
In this cross-sectional study, patients referred to 2 tertiary referral
hospitals with a diagnosis of laryngeal cancer, Iran, during a ten-year
period from 1997 to 2007 were enrolled. Laryngeal cancer was
diagnosed in 453 patients and confirmed histologically. The average
patient age was 59.92 years. Men outnumbered women (9.5:1); 400
patients (88.5%) were tobacco smokers. The primary location of the
tumor was supraglottic in 221 (49%) cases, followed by glottic in 163
(36.2%), transglottic (the tumor involved all regions of the larynx and
the origin was unspecified) in 60 (13.3%), and subglottic in 7 (1.6%).
In conclusion, the supraglottic tumor was dominant and the ratio of
supraglottic to glottic tumors was 1.36 (8).
Of 289 patients diagnosed with laryngeal cancer at

Songklanagarind Hospital, Thailand, over the past 10 years, 106 were
with supraglottic cancer, 180 with glottic cancer and 3 with subglottic
cancer The majority of the patients was male, active smokers, alcohol
consumers and had a histology showing squamous cell carcinoma.
Most cases of supraglottic cancer were in advanced stage (84.4%),
whereas most patients with glottic cancer were diagnosed at early
stage (61.3%). Hoarseness was the most common presenting
symptom. Regarding the complete response rate, glottic cancer was
superior to supraglottic cancer. For glottic cancer treatments, surgery
alone or primary RT showed good 5-year overall survival rates with
no difference in modality results (87.5% vs. 83.2%). In supraglottic
cancer treatments and contrary to glottic cancer surgery with
postoperative RT improved the 5-year overall survival rate in
comparison with primary RT alone (52.2% vs. 39.2%). Primary RT
or surgery alone is suitable treatments for early stage laryngeal cancer
especially in glottic cancer whereas surgery with postoperative RT
should be the treatment for advanced stage laryngeal cancer (9).
451
Records of patients managed for laryngeal carcinoma at the

Department of Surgery, Ile-Ife, Nigeria, from January 1994 to
December 2004 were reviewed. Only 13 cases with tissue diagnosis
were included in this review. The patients had a mean age of 69.9
years (range 38-88 years) and a male: female ratio of 12:1.
Histopathology was squamous cell carcinoma in all. Symptoms
included hoarseness in voice and breathlessness in all, cough in 7
(53.8%), weight loss in 7 (53.8%), and otalgia in 6 (46.2%). Two
patients indulged in alcohol and 2 were also regular cigarette smokers.
All the patients presented with stage IV disease and in respiratory
distress necessitating emergency tracheostomy. Seven (53.8%)
patients had total laryngectomy plus postoperative RT while 2
(15.4%) had pharyngolaryngectomy, thyroidectomy, radical neck
dissection plus postoperative RT and thyroxine supplement. Surgical
complications included pharyngocutaneous fistula in 2 (15.4%)
patients, pharyngeal stenosis, stomal stenosis, and hypocalcemia with
hypothyroidism in one patient, each. The fistulae were managed
conservatively and prognosis was good despite late presentation. In
conclusion, laryngeal carcinoma mainly occurs in males. Presentation
is late with hoarseness and breathlessness. Soft-tissue neck x-ray is a
useful diagnostic tool. Scarce RT centers, ignorance, local taboo,
poverty, and poor recognition by primary healthcare providers have a
negative impact on its management. Laryngeal carcinoma should be
excluded when managing elderly patients for bronchial asthma (10).
Larynx cancer
A rare case of distant metastasis to spinal column - lumbar vertebra

(L5) - from laryngeal cancer was reported. In 10% of cases,
metastases to vertebral column are first symptom of a neoplastic
disease and 65% of patients with advanced cancer present with bone
metastases. MBD is one of the most frequent causes of pain in cancer
patients and represents one of the first signs of widespread neoplastic
452
disease. Nevertheless, metastases to lumbar vertebral column from

laryngeal cancer are very rare. In presented case, MRI and CT were
performed to confirm metastasis. Laryngological examination
revealed tumor of a right part of larynx - squamous cell carcinoma
(G2) in histopathological examination. The patient was qualified to
palliative RT and still is under laryngological observation (11).
Cases of laryngeal cancer (n=227) hospitalized in Cancer Center,
Guangzhou, China, from 1990 to 1995 were reviewed. Eighteen cases
with distal metastases were investigated to confirm the distant
metastatic rate, target organ, time interval, and prognosis. The overall
incidence of distal metastases in laryngeal cancer was 6.5% (18/277).
The target site of distal metastases was mainly in lung 83.3% (15/18),
liver 16.7% (3/18); 3 cases with distal metastases in lung also showed
bone metastases in vertebra one, lib 1 and 1 in multi-sites. Two
patients were diagnosed with distal metastases when admitted, and the
rest with time interval between 1-103 months (median 7 months). The
3-year and 5-year cumulative survival in laryngeal cancer with distal
metastases was 23.8% and 11.9%, respectively. The time interval
between the presentation of distal metastases and death was 2.77
months (median 4.6 months). The worst prognosis was liver
metastasis with 4.6 months survival. Kaplan-Meier analysis in 277
laryngeal cancers showed that pathology, pathological differentiation
of squamous cell carcinoma, N stage, and clinical stage were
significant indicators for distal metastases from laryngeal cancer. Cox
model analysis showed that only N stage was the significant
prognostic factor for distal metastases in laryngeal cancer (p=0.005).
In conclusion, laryngeal mainly metastasizes to lung and the prognosis
is usually poor. Non-squamous cell carcinoma, low pathological
differentiation, cervical metastasis and advanced cancer are the
possible indicators for distal metastases, but only N stage significantly
predicts distal metastases from laryngeal cancer (12).
Following a review of the world literature dealing with the
incidence of remote metastases in tumors in the Ear Nose and Throat
field in general and of the larynx and hypopharynx in particular, this
study covered 927 patients suffering from cancer of the larynx and
hypopharynx. Of 786 patients followed over a minimum of 4 years, 52
cases (6.7%) of metastases were recorded. They occur more
frequently when the primary tumor was hypopharyngeal, low
differentiated type, or a cervical ganglionic extension took place (13).
453
Assessment: laryngeal cancer is the second most common

respiratory cancer after lung cancer and is a serious disease associated
with high mortality, occurring mainly in males. Risk factors include
active and passive smoking, alcohol consumption, occupational
exposures, environmental pollution, radon, dietary factors, HPV,
GERD, and genetic factors.
The supraglottic tumor is dominant and the ratio of supraglottic to
glottic tumors is 1.36. The target site of distal metastases is mainly in
lung, liver, bone, or lung combined with bone. The characteristic
clinical signs of laryngeal carcinoma are hoarseness, dyspnea and
stridor.
Was King David afflicted by laryngeal carcinoma? Although
laryngeal cancer can metastasize to the bone, in the absence of
dyspnea, stridor, and hoarseness the diagnosis of laryngeal cancer
seems unlikely.
References
1. Pantel M, Guntinas-Lichius O. Laryngeal carcinoma: epidemiology, risk
factors and survival. HNO. 2012;60(1):32-40.
2. Cattaruzza MS, Maisonneuve P, Boyle P. Epidemiology of laryngeal cancer.
Eur J Cancer B Oral Oncol. 1996;32B(5):293-305.
3. Jovanović MB. Diagnosis of laryngeal carcinoma. Med Pregl. 2008; 61(11-
12):591-5.
4. Cosetti M, Yu GP, Schantz SP. Five-year survival rates and time trends of
laryngeal cancer in the US population. Arch Otolaryngol Head Neck Surg.
2008;134(4):370-9.
5. Berrino F, Crosignani P. Epidemiology of malignant tumors of the larynx and
lung. Ann Ist Super Sanita. 1992;28(1):107-20.
6. Wünsch Filho V. The epidemiology of laryngeal cancer in Brazil. Sao Paulo
Med J. 2004;122(5):188-94.
7. Popovtzer A, Mharshak G, Feinmesser R. Subglottic carcinoma. Harefuah.
2002;141(10):914-8, 929.
8. Saedi B, Razmpa E, Sadeghi M, et al. The epidemiology of laryngeal cancer in
a country on the esophageal cancer belt. Indian J Otolaryngol Head Neck Surg.
2009;61(3):213–7.
9. Dechaphunkul T. Epidemiology, risk factors, and overall survival rate of
laryngeal cancer in Songklanagarind Hospital. J Med Assoc Thai. 2011;94(3):355-60.
10. Amusa YB, Badmus A, Olabanji JK, Oyebamiji EO. Laryngeal carcinoma:
experience in Ile-Ife, Nigeria. Niger J Clin Pract. 2011;14(1):74-8.
11. Izabela O, Marek Ł, Tomasz D, Wioletta P. The rare case of metastasis to
lumbar part of spinal column from laryngeal cancer. Otolaryngol Pol. 2008;62(6):787-
90.
12. Liu WW, Zeng ZY, Guo ZM, et al. Distant metastases and their significant
indicators in laryngeal cancer. Zhonghua Er Bi Yan Hou Ke Za Zhi.2003;38(3):221-4.
13. Traserra J, Arias C, Comas J, et al. Distant metastases originating from tumors
of the larynx and hypopharynx. Rev Laryngol Otol Rhinol (Bord). 1989;110(3):267-
71.
454
TRACHEAL CANCER
Primary tumors of the trachea account for less than 0.1% of all
tumors. They are malignant in more than 90% of cases with squamous
cell carcinoma and adenoid cystic carcinoma accounting for 2/3 of all
tracheal tumors. Since they are often misdiagnosed as asthma or
chronic lung disease, diagnosis can be delayed for years (1-3).
For most people the cause is unknown. However, smoking is
linked with squamous cell cancer of the trachea. This type of tracheal
cancer is more common in men > 60. There is not any evidence
linking adenoid cystic carcinoma of the trachea to smoking. Like
many cancers, the cause is unknown. It affects men and women
equally and is more common between the ages of 40 and 60 years (4).
Tumors of the trachea are rare and create signs and symptoms that
mimic common upper airway diseases. A tracheal mass is not usually
considered in the clinical differential diagnosis of an affected patient
and is often overlooked on chest radiographs. The most common
symptoms are a dry cough, breathlessness, hoarse voice, difficulty in
swallowing, fevers, chills, recurrent chest infections, hemophtysis, and
wheezing. Tracheal cancer is rare and is difficult to diagnose (4,5).
Benign tumors are usually misdiagnosed as asthma or COPD and
can delay diagnosis for months or years. Because of their rapid growth
and onset of hemophtysis, malignant tumors are often diagnosed
earlier than benign tumors and patients thus often present with locally
advanced disease (2).
Primary tumors of the trachea are rare and most of the symptoms
relate to obstruction of the air passage leading to inspiratory and
expiratory stridor. Unfortunately, the inclusion of malignant tracheal
neoplasms in the differential diagnosis of onset of wheeze in adults is
even more rare than the tumors themselves (6). Malignant tracheal
tumors, the most frequently diagnosed types of such tumors are
squamous cell and adenoid cystic carcinomas usually manifest with
the obstructive symptom of wheezing; thus, they are often
misdiagnosed as asthma (7).
A case with a tracheal adenoid cystic carcinoma symptoms
suggested bronchial asthma. Delay by the physician in diagnosing
tracheal tumors is the principal problem, and adult patients who
experience onset of stridor and dyspnea that do not respond to
accepted medical treatment deserve systematic radiographic and
endoscopic evaluation of the entire air passage (6).
Inappropriate treatment is an equally frustrating issue. Modern
techniques for tracheal surgery - laryngotracheal, tracheal, or carinal
455
resection combined with RT can be offered curatively with low

perioperative risks. Nevertheless, the low numbers of patients
undergoing resection and the associated poor survival in
epidemiological studies over the past 2 decades have shown that
surgery is rarely considered outside referral centers, with RT or
another form of local treatment (e.g., endotracheal stents,
debridement, and brachytherapy) generally preferred. The liberal use
of these other techniques should be avoided because surgery has the
potential to cure all patients with benign and low-grade tumors and
most patients with malignant primary tracheal tumors, and other
techniques are usually palliative at best (2).
A retrospective analysis of the clinical data of 8 patients with
primary tracheal tumors admitted to the Department of Pulmonary
Medicine, SHAW Hospital, Hangzhou, China, during the period of
May 1994 to May 2006 was performed, with detailed description of
the clinical manifestations, chest radiography, fiberoptic
bronchoscopy, lung function measurements, treatment and prognosis
for 4 cases. Seven patients presented with irritable cough and
progressive inspiratory dyspnea mostly misdiagnosed as asthma or
chronic bronchitis. Examination by fiberoptic bronchoscopy
confirmed the diagnosis of tracheal tumor in all the cases. One case
with benign neurinoma and 2 cases with adenoid cystic carcinomas
had a long-term postoperative remission. Two cases of squamous cell
carcinoma with severe tracheal stenosis got rapid symptom remission
after intervention of tracheal stent by fiberoptic bronchoscopy and
argon plasma coagulation. One patient with adenoid cystic carcinoma
refused any treatment. One patient with squamous cell carcinoma lost
follow-up after surgery. One patient with adenocarcinoma died of
progressive deterioration after 2-month chemotherapy. In conclusion,
primary tracheal tumors occur infrequently and early clinical
symptoms are unspecific. Early diagnosis can be made by chest CT
and fiberoptic bronchoscopy. Benign tracheal tumors can be resected,
and for some low-grade malignant tumors surgical resection and
postoperative RT can improve long term survival. Intervention with
fiberoptic bronchoscopy to unresectable diseases can lead to symptom
remission and thus improve patients' QOL (8).
Pre- and intraoperative evaluations are mandatory, along with strict
attention to technical details and postoperative care. Both squamous
and adenoidcystic cancers should be treated with postoperative
irradiation. Successfully removed benign tumors do not require
additional therapy and are usually cured by resection and
reconstruction (3).
456
Cancer near the distal end of the trachea. The left tracheal wall is pushed
by tumor outside of the airway (compare to the more rounded right tracheal
wall). The tumor sub-totally occludes the distal trachea without much room
left for airflow. The patient‘s initial symptom was coughing blood and chest
pain. Treatment was radiation therapy and chemotherapy.
Malignant neoplasms occurring from the trachea are extremely

rare. These tumors are often misdiagnosed and treated as bronchial
asthma or COPD. It is important to probe the cause-effect relationship
between the medical presentations and the clinical diagnosis. In this
report, 2 cases of tracheal malignancy suffering from dyspnea due to
obstruction of the proximal trachea are described (9).
In cases of recent asthma in which clinical control with the usual
treatment (corticosteroids and bronchodilator) is unsatisfactory, it is
important to consider other diagnoses, such as congestive heart
failure, GERD or other forms of airway obstruction. The case of a
female patient with mucoepidermoid carcinoma of the trachea
mimicking asthma is reported. The patient presented cough and
wheezing, as well as abnormal spirometry results with an obstructive
pattern that was responsive to bronchodilators. One year later, the
patient presented clinical and spirometric worsening. The chest X-ray
revealed no abnormalities. A CT scan showed a vegetative lesion
obstructing the tracheal lumen and located 1 cm from the carina.
Fiberoptic bronchoscopy showed a finding similar to a bronchial
carcinoid tumor. The anatomopathological diagnosis made after
surgical resection was low-grade mucoepidermoid carcinoma, without
lymph node involvement. Although the flow-volume curve was not
suggestive of upper airway obstruction, the spirometry performed
after the surgery showed a significant reduction in the degree of
obstruction and greater reversibility after bronchodilator use. There
was no evidence of recurrence of the disease or of the symptoms after
a two-year follow-up period (10).
The clinical and pathologic features of 22 cases of papillary
carcinoma of the thyroid that invaded the trachea and was treated by
457
thyroidectomy and airway resection with or without reconstructive

surgery over an interval of 16 years are described. The manner of
invasion of papillary carcinoma of the thyroid was by blunt dissection
along blood vessels and collagen fibers oriented perpendicularly to the
tracheal lumen between cartilaginous rings. Although lymph node
metastases were in 14 patients (64%), lymphangitic tumor in the
tracheal mucosa was in 3 patients (14%). A staging system for
papillary carcinoma of the thyroid based on the extent of invasion of
the trachea was proposed. Of the 11 patients with stage I, II, or III
disease, none of 6 (0%) followed for 5 years died of thyroid cancer; 1
patient in this group died later of thyroid cancer. Of the 11 patients
with stage IV disease, 5/7 (71%) followed for 5 years died of thyroid
cancer; 1 additional patient in this group died later of thyroid cancer
(11).
Tracheal stricture after invasion of adjacent thyroid cancer.
An 18-year-old male was presented with hemophtysis, cough,

dyspnea and stridor. A wide-based polypoid tumor that was localized
at the right wall of the distal trachea was observed over 3 cm from the
carina by flexible bronchoscope. CT showed an intraluminal soft
tissue density mass in the trachea. Thorough right thoracotomy, a
tracheal resection that contained 3 rings of the trachea with malignant
lesion was performed. Pathologic examination reported a tracheal
mucoepidermoid carcinoma. The patient is alive without recurrence 3
years after surgery (12).
Rigid bronchoscopy is the best procedure for determining a
definitive diagnosis (7). Treatment will depend on a number of
factors, including patient's general health, the position and size of the
cancer and whether it metastasizes in the body. The main treatments
for cancer of the trachea are surgery and RT. They can be given alone
or in combination (4).
Once the diagnosis has been established, surgical resection is the
only curative treatment. Modern techniques for tracheal surgery such
as laryngotracheal, tracheal or carinal resection and different tracheal
458
mobilization maneuvers such as laryngeal and hilar release allow for

resection of more than 50% of the trachea and anastomosis without
excessive tension. Results in patients with complete tumor resection
are good with 5-year and 10-year survival between 39-79% and
between 18-51%, respectively. However, careful patient evaluation,
preservation of tracheal blood supply and accepting the limits of
resectability are mandatory to avoid major complications that
accompany tracheal resections in more than 20% of cases depending
on the type of resection (1).
Airway interventions at the time of diagnosis should be selected
carefully to avoid a compromise of curative treatment. Precise
judgment is required to determine resectability. The proximity of
intrathoracic organs creates anatomical limits to en bloc resection and
necessitates adjuvant RT in malignant tumors. Early referral for
consideration of surgical resection might offer the best opportunity for
improving the overall prognosis of tracheal tumors (13).
If the lesion is too extensive, RT, bronchoscopic "coring out" the
tumor, laser treatment, or internal stenting may provide palliation.
Surgical resection necessitates experience with complex airway
procedures and can be done with minimal morbidity. The long-term
prognosis depends on the histological type and the size of the tumor;
excellent results can be achieved with early diagnosis and appropriate
surgical treatment (7).
A case of primary adenoid cystic carcinoma of the trachea which
was ever misdiagnosed as asthma and hysteria is reported. In this case,
the pulmonary function test was normal, and firstly no obvious
abnormalities were found by laryngoscopy, bronchoscopy and CT
scan of chest. Later a sagittal and coronal reconstruction CT scan of
trachea showed a mass situated in the subglottic trachea. A
laryngoscopy was again performed after a tracheal incision and
showed a small mass in the posterior wall of the subglottic trachea,
and tumor ablation was performed (14).
Between 1987 and 1996, 14 patients were treated by resection and
reconstruction of the trachea and bifurcation for primary tracheal
tumors at the Department of Surgery, Benjamin Franklin Medical
Center, Berlin. The most common histological finding was adenoid
cystic carcinoma (n=7), followed by a squamous cell carcinoma (n=2),
a mucoepidermoid carcinoma (n=2), a carcinoid tumor (n=1), and 2
benign tumors (xanthogranuloma, and pleomorphic adenoma).
Various reconstruction techniques were used and one prosthesis was
implanted. Eight patients required preoperative Nd-YAG laser
recanalisation. Six were treated by postoperative external beam RT,
459
and in 3 cases combined with endoluminal brachytherapy. Two major

postoperative wound-healing impairment at the anastomosis occurred.
Four minor wound-healing disorders were successfully treated by
interventional endoscopy. Two patients died postoperatively with
mediastinitis respectively with bilateral pneumonia. A local recurrence
was observed in 2 cases. At the follow-up in January 1998, 9 patients
were still alive. Five long-term survivors (> 6 years) with an adenoid
cystic carcinoma or mucoepidermoid carcinoma were observed. In
conclusion, extensive segmental resection of the trachea is the
treatment of choice for primary malignant and occasionally for benign
tracheal tumors. Interventional endoscopy is a part of modern tracheal
surgery (15).
Since 1962, 110 primary tracheal tumors have been seen including
43 squamous cell carcinomas, 38 adenoid cystic, and 29 varied. Sixty-
nine patients underwent resection of their primary tumors; an
additional 33 patients with secondary tumors involving the trachea
also underwent resection. Of these 102 patients, 73 underwent primary
reanastomosis. In 17, laryngotracheal resection was required; staged
resections were done for the rest. Survival data indicate that benign
tumors are cured by resection with reconstruction and patients with
squamous cell carcinoma, adenoid cystic carcinoma, and other types
of malignant lesions obtained either long-term palliation or cure if
surgical resection was possible. In patients with selected types of
secondary tumors, resection and reconstruction provide prolonged
palliation (16).
Other treatment options include chemotherapy usually given to
relieve symptoms, surgery, RT, brachytherapy used to open up the
airway and relieve symptoms, laser treatment, cryotherapy, diathermy,
photodynamic therapy and airway stents (4,15).
Assessment: tracheal cancer is rare and can be difficult to

diagnose. These cancers are malignant in more than 90% of cases with
squamous cell carcinoma and adenoid cystic carcinoma accounting for
2/3 of all tracheal tumors. Since they are often misdiagnosed as
asthma or chronic lung disease, diagnosis can be delayed for years.
Smoking is linked with squamous cell cancer of the trachea.
Clinical symptoms of tracheal cancer include dry cough, dyspnea,
hoarseness, difficulty in swallowing, fevers, chills, recurrent
respiratory tract infections, hemophtysis, wheezing, and inspiratory
and expiratory stridor.
460
Was King David afflicted by tracheal cancer? In the absence of

risk factors for this diseases and characteristic clinical symptoms, the
diagnosis of tracheal cancer seems unlikely.
References
1. Hoerbelt R, Padberg W. Primary tracheal tumors of the neck and mediastinum :
resection and reconstruction procedures. Chirurg. 2011;82(2):125-33.
2. Macchiarini P. Primary tracheal tumours. Lancet Oncol. 2006;7(1):83-91.
3. Mathisen DJ. Tracheal tumors. Chest Surg Clin N Am. 1996;6(4):875-98.
4. Tracheal cancer - Cancer Information - Macmillan Cancer. Available 28 May
2013 at Supportwww.macmillan.org.uk › Cancer information › Cancer types.
5. McCarthy MJ, Rosado-de-Christenson ML. Tumors of the trachea. J Thorac
Imaging. 1995;10(3):180-98.
6. Sander KM, Kristensen S, Pedersen U. Malignant tracheal tumor - differential
diagnosis in bronchial asthma. Tidsskr Nor Laegeforen. 1991;111(29):3510-1.
7. Allen MS. Malignant tracheal tumors. Mayo Clin Proc. 1993;68(7):680-4.
8. Wen SL, Zhou X, Hu HH, Peng ZZ. Clinical characteristics of 8 cases of
primary tracheal tumors. Zhonghua Jie He He Hu Xi Za Zhi. 2009;32(9):660-3.
9. Yasumatsu R, Fukushima J, Nakashima T, Kadota H, et al. Surgical
management of malignant tumors of the trachea: report of two cases and review of
literature. Case Rep Oncol. 2012;5(2):302-7.
10. Mussi RK, Toro IF, Pereira MC. Mucoepidermoid carcinoma of the trachea
mimicking asthma. J Bras Pneumol. 2009;35(3):280-4.
11. Shin D-H, Mark EJ, Suen HC, Grillo HC. Pathologic staging of papillary
carcinoma of the thyroid with airway invasion based on the anatomic manner of
extension to the trachea: A clinicopathologic study based on 22 patients who
underwent thyroidectomy and airway resection. Human Pathology.1993;24(8):866-70.
12. Oz N, Sarper A, Karaveli S, et al. A rare tracheal malignant tumor:
mucoepidermoid carcinoma (a case report). Tuberk Toraks. 2004;52(1):83-5.
13. Gaissert HA. Primary tracheal tumors. Chest Surg Clin N Am. 2003;
13(2):247-56.
14. Li W, Hua W, Yan FG, et al. Adenoid cystic carcinoma of trachea: a case
report and review of literature. Chin Med J (Engl). 2012;125(12):2238-9.
15. Schneider P, Schirren J, Muley T, Vogt-Moykopf I. Primary tracheal tumors:
experience with 14 resected patients. Eur J Cardiothorac Surg. 2001;20(1):12-8.
16. Grillo HC. Management of tracheal tumors. Am J Surg. 1982;143(6):697-700.
BRONCHOGENIC CARCINOMA
Bronchogenic carcinoma is the most common cancer in the world
(1). In the US, bronchogenic carcinoma is the leading cause of death
from cancer in men and women. Although the cause of this
malignancy is probably multifactorial, approximately 85% of lung
cancer deaths are attributable to cigarette smoking. Patients present
with symptoms of airway obstruction caused by central tumors,
symptoms related to direct tumor invasion of surrounding structures,
461
or symptoms produced by distant metastases. There are 4 major cell

types: adenocarcinoma, squamous cell carcinoma, undifferentiated
large cell carcinoma, and small cell carcinoma. Adenocarcinoma and
undifferentiated large cell carcinoma are generally peripheral lesions
manifesting as solitary nodules or masses, whereas squamous cell
carcinoma and small cell carcinoma are typically central and may
manifest as hilar masses, atelectasis, or pneumonia. The prognosis for
patients with bronchogenic carcinoma is poor, with an overall 5-year
survival of 10-15%. In general, patients with squamous cell carcinoma
have the best prognosis, those with adenocarcinoma and
undifferentiated large cell carcinoma have an intermediate prognosis,
and those with small cell carcinoma have the worst prognosis (2).
A 71–year-old patient with a right upper lobe bronchogenic carcinoma.
The clinical presentation, smoking habits, radiographic findings,

treatment and survival of 21 patients with bronchioloalveolar
carcinoma treated at Clinic for Pulmonary Oncology, Vojvodina,
Serbia, from 2000-2004 were studied. Registered were 16 (76.2%)
male and 5 (23.8%) female patients, most of them in the 6th and 7th
decade of life. Among younger patients, females prevailed. Most
common symptoms were dyspnea 15 (71.4%), cough 14 (66.6%) and
bronchial hypersecretion 9 (42.8%). There were 5 (23.8%) smokers, 6
(28.6%) ex-smokers, and 10 (47.6%) nonsmokers. Main radiographic
findings were lung consolidation (nine, 42.8%), diffuse interstitial
infiltrates (6, 28.6%), solitary (4, 19.0%), and multiple pulmonary
lesions (2, 9.5%). Surgery was performed in 8 (38.0%) patients and 5
of them received adjuvant radio- and chemotherapy, while 9 (42.8%)
received chemotherapy alone and 4 (19.0%) received symptomatic
treatment. The median survival was 25 months and 1-year survival
70%, regardless of stage. In the group of patients treated surgically 1-
and 2-year survival rate was 100% and the median survival 33
months. In non-operated patients, the median survival was 18 months
and 1- and 2-year survival was 55% and 25%, respectively. In
462
conclusion, bronchioloalveolar carcinoma is a special clinical and

pathological form of adenocarcinoma of the lung. Surgical treatment
is the best option for selected bronchioloalveolar carcinoma patients.
Survival is associated with the treatment modality (3).
Of 279 diagnosed cases with primary bronchogenic carcinoma,
86% were males with an average age of 57 years, while smoking was
the risk factor in 81.6%. Of female patients, 47% were smokers with a
significant overlap in use of smoking objects. Of all patients, 24
(8.8%) were < 40 years of age at the time of diagnosis. Average
duration of illness was 4.5 months. Weight loss (77%) and fever
(34%) were the commonest general symptoms. Other chest symptoms
include cough (68%), dyspnea (59%), chest pain (22%), hemophtysis
(20%), and dysphagia (6%). Fiberoptic bronchoscopy (75%) and FNA
cytology (74.8%) were the most efficient diagnostic procedures.
Histologically, squamous cell carcinoma, adenocarcinoma, large cell
carcinoma and small cell carcinoma were in 42%, 20%, 18% and 14%
cases, respectively. Of patients, 6% showed malignant cells only and
were marked as unclassified. Radiologically, obstructive pneumonitis
was the commonest presentation (59.5%) followed by mass lesion
(31.8%) and rib destruction (5.1%) (4).
Bronchogenic carcinoma
This was a retrospective study conducted in 174

histopathologically proven cases of bronchogenic carcinoma that were
referred from different parts of the country to a private hospital in
Kathmandu over a period of 4 years. The mean age of the patients
developing bronchogenic carcinoma was 64 years. Squamous cell
carcinoma was the commonest histological subtype followed by small
cell carcinoma. Adenocarcinoma was more common in females.
Clinical history was available in 133 cases. Among them, almost all
patients had a history of smoking, the average number of pack years
463
being 39.99. Most of the patients consulted doctor for chief complaint
of cough and dyspnea, the average duration of symptoms being 117.53
days. The lung cancer must be ruled out in all patients who have
persistent signs and symptoms of pulmonary disease with a history of
smoking (1).
Four hundred consecutive patients with histopathologically proven
bronchogenic carcinoma, hospitalized between 1985 and 1999 at a
large teaching and tertiary care referral hospital at King George's
Medical University in Lucknow, India, were analyzed. The average
age of the bronchogenic carcinoma patients was 57 years; 9.8% of
patients were < 40 years of age; the ratio of male: female patients was
4.3:1.0; 71% were smokers. The most common histological type was
squamous-cell carcinoma (46.5%), followed by adenocarcinoma
(18.5%) and small-cell carcinoma (18.2%). The majority of patients
(74.2%) were diagnosed in the late stages of the disease (IIIb and IV).
In conclusion, smoking is an important contributory factor in the
development of bronchogenic carcinoma in India, while
approximately 25% of patients with bronchogenic carcinoma are non-
smokers (5).
A retrospective clinical study was carried out on 227
pathologically proven cases of bronchogenic carcinoma from eastern
Taiwan, between October 1986 and March 1990. The ratio of males to
females was low (2.15:1). The most common cell type was
adenocarcinoma (39.2%), followed by squamous cell carcinoma
(36.1%). Adenocarcinoma contributed to 51.4% of the bronchogenic
carcinoma in women and 33.5% in men. History of cigarette smoking
was strongly associated with squamous cell carcinoma and small cell
carcinoma. The most common symptom was cough (69%). The
majority of small cell carcinoma and squamous cell carcinoma was the
central type in location while most adenocarcinoma was the peripheral
type. Bronchoscopic examination was the most valuable method for
confirming the diagnosis of bronchogenic carcinoma. Most patients
presented late and only 19 cases (8.4%) underwent surgery.
Aborigines have a lower risk of developing bronchogenic carcinoma.
The clinical manifestations of bronchogenic carcinoma in eastern
Taiwan are similar to those found in Taiwan as a whole (6).
Distal metastases of bronchial cancers are classically situated
below the knee or elbow. The distal bone metastases are often solitary.
Bronchial cancers represent the most frequent cause of distal
metastases (20% of all cases). They are responsible for 50% of distal
metastases of the upper limb and more often occurs as a squamous
cancer. Their localization sometimes reveals a bronchial cancer, and
464
so allow curative surgery. The metastases of soft tissue are

exceptional. Clinically, it is a painful swelling preserving the under
lying bone. In bronchial metastasis cancer, an average survival is 3-6
months (7).
Retrospective and follow-up analyses were conducted for 62 cases
of bronchoscopically confirmed endotracheal/endobronchial
metastases. Clinical staging, location in the tracheobronchial tree, the
number of lesions, treatment and prognosis were analyzed. The most
common neoplasms associated with endotracheal/endobronchial
metastases were breast cancer (17.7%), coronal cancer (17.7%), and
esophageal carcinoma (14.5%). Most endotracheal/endobronchial
metastases patients presented with cough, hemophtysis, dyspnea, chest
pain and fever. Abnormal changes on chest X-ray were in 87.1%
cases, and CT changes were in all patients. A total of 76 intraluminal
lesions were recorded, of which 19 in the trachea and 57 in the
bronchus, including 31 in the right bronchus and 26 in the left
bronchus. Type I endotracheal/endobronchial metastases accounted
for 28.9%; Type II, 23.7%; Type III, 14.5%, and Type IV, 32.9%. The
median survival time was 9.8 months. There was significant
difference in survival time between Type IV
endotracheal/endobronchial metastases and the other 3 types (p<0.05).
In conclusion, endotracheal/endobronchial metastases may occur in
the trachea or in the bronchus. Flexible bronchoscopy is a valuable
tool for the diagnosis of endotracheal/endobronchial metastases.
Although there are cases of long survival, the prognosis of
endotracheal/endobronchial metastases is generally poor (8).
The records of 9678 patients who had undergone bronchoscopic
procedures were reviewed. Forty patients were diagnosed as having
endobronchial metastasis. The most common site of primary tumors
was the head and neck (10 nasopharyngeal carcinomas, 2 buccal
cancers, 2 glossal cancers, and 2 laryngeal cancers). Clinical
manifestations included cough (50%), hemophtysis (20%), dyspnea
(15%), and absence of respiratory symptoms (15%). The most
common findings in chest roentgenograms were single masses (40%).
The median length of survival for all patients was 12 months (range, 6
to 18 months). The median length of survival in patients whose ages
were > 70 years was 1 month and in patients < 70 years old it was 12
months (range, 7 to 19 months) (p=0.002). In patients whose
endobronchial metastasis extended to the main bronchus, the median
length of survival was 1 month (range, 1 to 3 months) and in those
whose endobronchial metastasis did not extend to main bronchus was
12 months (range, 11-21 months) (p=0.0004). In patients whose
465
primary tumors were due to head and neck cancer other than
nasopharyngeal carcinoma, the survival time was 1 month (range, 1-
11 months), and in others 12 months (range, seven 7-19 months)
(p=0.0008). In conclusion, 3 factors contributed to a poor prognosis,
including the patient's age > 70 years, head and neck cancer other than
nasopharyngeal carcinomas, and extension of the endobronchial
metastatic lesion to the main bronchus (9).
Endobronchial metastasis from nonpulmonary tumors is
uncommon. A 9-year retrospective study at the University Hospital
Vall d'Hebron (Barcelona, Spain) identified 32 patients with
endobronchial metastasis. All but 4 cases were diagnosed by
fiberoptic bronchoscopy with bronchial biopsy. Primary tumors
included the following types: breast cancer (20), CRC (3), melanoma
(2), gastric cancer (1), neuroblastoma of the olfactory nerve (1),
abdominal leiomyosarcoma (1), hypernephroma (1), endometrial
carcinoma (1), papillary thyroid cancer (1), and HCC (1). Median age
at diagnosis of endobronchial metastasis was 58.7 years and median
interval from the diagnosis of the primary tumor to the diagnosis of
endobronchial metastasis was 50.4 months. Seventeen patients (53%)
had evidence of other metastatic sites at endobronchial relapse. The
more common clinical manifestations included cough (37.5%),
hemophtysis (28%), dyspnea (18.7%), and recurrent pulmonary
infections (6.2%). Eight patients (25%) had no symptoms. There was
a predilection for metastatic involvement of the right and left upper
lobe bronchus. Treatment was instituted in 20 patients, and their
median survival was 11 months, in comparison with 3 months in 12
patients who received only palliative therapy because of advanced
disseminated disease. In conclusion, breast cancer is the most
common tumor causing endobronchial metastasis. The prognosis of
patients with endobronchial metastasis depends on the type of the
primary tumor and the presence of other metastatic sites. Treatment
must be individualized (10).
Secondary hypertrophic osteoarthropathy, known as Marie-
Bamberger syndrome, is a rare neoplastic syndrome featuring
clubbing of the tips of the digits, periosteal proliferation and synovial
effusion of adjacent joints. A patient without any other known medical
condition developed persistent arthralgia and mobility restriction after
bruising the left knee. As the initial X-ray examination of the knee
showed a distinct periosteal proliferation of the left femoral bone,
extended diagnostics were initiated during which a bronchial
carcinoma was identified. After surgical removal of the primary
tumor, the symptoms of irritation in the knee joint subsided (11).
466
Hypertrophic osteoarthropathy caused by bronchogenic carcinoma.
The morphologic appearance of osseous metastasis may rarely

suggest a specific site of origin. A subperiosteal location has recently
been reported to be typical for metastatic lung carcinoma. In 3 cases,
such metastasis destroyed the cortex so that it appears saucer shaped.
The primary tumor was a bronchogenic carcinoma in every case. In
conclusion, in the cancer-age group cortical metastasis is a highly
characteristic feature of lung carcinoma (12).
Orbital metastasis in systemic cancer is known to occur and occurs
in up to 7% of all systemic cancers. Orbital features typically present
after the diagnosis of the primary tumor. In about 20% of cases, there
is no known primary cancer at the time of presentation with orbital
metastatic disease. A case of a 60-year-old male smoker, with
proptosis due to metastasis in greater wing of left sphenoid bone
secondary to bronchogenic carcinoma was the initial symptom (13).
A patient with initial complaints of leg pain and difficulty walking
had a large right tibial metastatic tumor and poorly differentiated
adenocarcinoma of the lung. Findings from total-body bone
scintigraphy include a large area of increased uptake in the proximal
half of the right tibia with a photon-deficient area medially, and focal
areas of uptake in a right rib, in the femoral neck and the left ileum.
An irregular area of increased uptake in the left lung mass was shown
by thoracic bone SPECT. This is an unusual case of a tibial metastasis
as the first clinical presentation of bronchogenic adenocarcinoma (14).
Common symptoms of the musculoskeletal system may occur as a
rare presentation of an underlying malignancy. A case of
bronchogenic adenocarcinoma was presented as bilateral knee pain
with arthritis due to bilateral metastases to the patellae (15).
Assessment: bronchogenic carcinoma is common cancer in the

world. The clinical manifestations include cough, bronchial
hypersecretion, hemophtysis, dyspnea, recurrent pulmonary
467
infections, weight loss, fever, chest pain, and dysphagia; or patients

are asymptomatic.
Endobronchial metastases from nonpulmonary tumors include
breast cancer, CRC, melanoma, gastric cancer, neuroblastoma of the
olfactory nerve, abdominal leiomyosarcoma, hypernephroma,
endometrial carcinoma, papillary thyroid cancer, and HCC. Bronchial
cancers represent the most frequent cause of distal metastases. They
are responsible for 50% of distal metastases to the upper limb.
Radiographic findings of bronchogenic carcinoma include lung
consolidation, obstructive pneumonitis, and mass lesion, diffuse
interstitial infiltrates, solitary, or multiple pulmonary lesions, and rib
destruction. Fiberoptic bronchoscopy and FNA cytology are the most
efficient diagnostic procedures. Histological diagnosis includes
squamous cell carcinoma, adenocarcinoma, large cell carcinoma or
small cell carcinoma
Was bronchogenic carcinoma responsible for the bone metastasis
in the King's case? The medical record of King David mentions one
symptom - weight loss (16). In the absence of risk factors for
bronchial carcinoma and characteristic clinical symptoms associated
with this type of tumor, including radiological evaluation,
brochoscopy and histopathological studies, this diagnosis seems
unlikely.
References
1. Shrestha HG, Chokhani R, Dhakhwa R. Clinicopathologic profile of
bronchogenic carcinoma. JNMA J Nepal Med Assoc. 2010;49(178):100-3.
2. Rosado-de-Christenson ML, Templeton PA, Moran CA. Bronchogenic
carcinoma: radiologic-pathologic correlation. Radiographics. 1994;14(2):429-46; quiz
447-8.
3. Stanic J, Zaric B, Andjelkovic A, et al. Clinical presentation, treatment options
and outcome in patients with bronchioloalveolar carcinoma. J BUON. 2007;
12(2):233-8.
4. Gupta RC, Purohit SD, Sharma MP, Bhardwaj S. Primary bronchogenic
carcinoma: clinical profile of 279 cases from mid-west Rajasthan. Indian J Chest Dis
Allied Sci. 1998;40(2):109-16.
5. Prasad R, James P, Kesarwani V, et al. Clinicopathological study of
bronchogenic carcinoma. Respirology. 2004;9(4):557-60.
6. Lee JJ, Lin RL, Chen CH, Chen RC. Clinical manifestations of bronchogenic
carcinoma. J Formos Med Assoc. 1992;91(2):146-51.
7. Letanche G, Dumontet C, Euvrard P, et al. Distal metastases of bronchial
cancers. Bone and soft tissue metastases. Bull Cancer. 1990;77(10): 1025-30.
8. Bai C, Huang Y, Li Q, et al. Clinical features of endotracheal/ endobronchial
metastases: analysis of 62 cases. Zhonghua Nei Ke Za Zhi. 2007;46(10):806-9.
9. Wang YH, Wong SL, Lai YF, et al. Endobronchial metastatic disease.
Changgeng Yi Xue Za Zhi. 1999;22(2):240-5.
10. Salud A, Porcel JM, Rovirosa A, Bellmunt J. Endobronchial metastatic
disease: analysis of 32 cases. J Surg Oncol. 199;62(4):249-52.
468
11. Baranowski A, Hansen M. Bronchial carcinoma and knee pain: Secondary

hypertophic osteoarthropathy. Unfallchirurg. 2012 Oct 4.
12. Guilbeau JC, David M, Grenier P, et al. Bone metastases of bronchial
carcinomas. 3 cases of subperiosteal cortical osteolysis. J Radiol. 1986;67(2):79-82.
13. Gupta PK, Mital M, Dwivedi A, Gupta K. Metastasis of greater wing of
sphenoid bone in bronchogenic carcinoma: a unusual case report. J Cancer Res Ther.
2011;7(2):195-7.
14. Shih WJ, Magoun S, Lahar B, et al. An unusual case of a tibial metastasis as
the clinical presentation of bronchogenic adenocarcinoma. J Nucl Med Technol.
1998;26(2):91-3.
15. Pauzner R, Istomin V, Segal-Lieberman G, et al. Bilateral patellar metastases
as the clinical presentation of bronchogenic adenocarcinoma. J Rheumatol.
1996;23(5):939-41.
LUNG CANCER
In the US, the 20th century witnessed the emergence of a lung
cancer epidemic that peaked and began to decline by the century's end,
a decline that continues today. However, lung cancer continues to be
an unabating pandemic. Cigarette smoking is identified as the single
most predominant cause of the lung cancer epidemic, but other causes
include gender, race, and pre-existing lung disease (1), workplace
agents (e.g., asbestos, arsenic, chromium, nickel, and radon) and other
environmental factors (passive smoking, indoor radon, and air
pollution) (2). However, not all people with these risk factors develop
lung cancer, and some without any known risk factor do, indicating
the importance of genetic influences (1).
Contemporary epidemiologic research on lung cancer focuses on a
new set of issues, primarily related to susceptibility to the well-
identified causal factors, particularly smoking, and on the
consequences of changes in tobacco products for risks to smokers.
Diet and the possibility of reducing risk through chemoprevention
remain a focus of research emphasis through experimental and
observational approaches. Questions have been raised about possible
differences in susceptibility to lung cancer by sex and race. Population
patterns in smoking prevalence will continue to be the most powerful
predictor of the future occurrence of lung cancer. Evaluation of recent
US patterns in smoking prevalence indicates that for the next
approximately 10 to 15 years, lung cancer rates will decrease, but will
then level off starting in approximately 2030. Unless further
reductions in the prevalence of cigarette smoking are achieved over
469
the next decade, lung cancer will remain as an all too common, but
avoidable disease (2). Future advances in understanding and treating
lung cancer will be based on genetic analysis. The most effective
preventive measure is to never start or to stop cigarette smoking (1).
Lung cancer
The skeleton is one of the most common sites of metastasis in

patients with lung cancer. The incidence of bone metastases in lung
cancer patients is approximately 30-40%, while the median survival
time of patients with such metastases is 6-7 months. MBD leads to
various complications or SREs, including pain, pathologic fracture,
vertebral deformity and collapse, spinal cord compression, and
hypercalcemia of malignancy. These events often lead to rapid
deterioration in QOL (3).
A population based case-control study was undertaken in all 21
general practices in Exeter, Devon, UK (population 128,700). Primary
lung cancers (n=247) were studied in subjects aged > 40 years
diagnosed between 1998 and 2002 and 1235 controls matched by age,
sex and general practice. The entire primary care record for 2 years
before diagnosis was coded using the International Classification of
Primary Care-2 was studied. Seven symptoms (hemophtysis, loss of
weight, loss of appetite, dyspnea, thoracic pain, fatigue and cough),
one physical sign (finger clubbing), and 2 abnormal investigation
results (thrombocytosis and abnormal spirometry) were associated
with lung cancer in multivariable analyses, as was cigarette smoking.
After excluding variables reported in the final 180 days before
diagnosis, hemophtysis, dyspnea and abnormal spirometry remained
independently associated with cancer (4).
A total of 114 patients were studied at the University Hospital in
Saudi Arabia with lung cancer. Mean age ± SD was (59.8 ± 10.8)
years, 71.1% were smokers, 95.1% were male, 90.1% smoked > 20
pack/year (96.2%) for 20 years or more. Cough (76.3%) and clubbing
470
(40.4%) were the most common symptom and physical abnormality

respectively. The right lung (64.9%) was more commonly affected
than the left (37.7%). Metastases were present in 49.1% at
presentation. The right and left upper bronchi (24% vs. 16%) were the
mostly affected. Hypercalcemia was more common in squamous cell,
while hyponatremia was more common in adenocarcinoma and small
cell. Squamous cell carcinoma was the most common cell type
(51.8%) and significantly associated with smoking (p≤0.001). In
conclusion, squamous cell carcinoma was the most common cell type,
significantly associated with smoking. The incidence of metastasis
was high at presentation. The right lung and right upper bronchus
were often affected. Hypercalcemia and hyponatremia were the most
common biochemical abnormalities (5).
The distribution of metastatic tumors of 935 lung cancers with
blood borne metastases has been analyzed. The frequency of affected
organs decreased in the following sequence: liver, bone, adrenal,
brain, lung, kidney, thyroid gland, pancreas, spleen and heart. In cases
with only one metastatic affected organ, the frequency of brain and
lung metastases is greater than the frequency of liver, bone and
adrenal metastases. Especially in cases with 2 different affected
organs the pair combination of liver and bone metastases as well as of
brain and adrenal metastases is evident, however, combined brain and
bone metastases and brain and liver metastases rarely occur. The
distinct pattern of metastatic distribution in the body supports the
evidence of the "soil" hypothesis. Seldom affected organs rarely show
a strong metastatic involvement and go hand in hand with many other
affected organs. In autopsies, the duration of cancer disease is much
longer in cases without metastasis or small metastatic involvement
than in cases with many affected organs. Therefore, the generalization
of metastatic spread mainly depends on the malignancy of tumors and
to a less extent on the duration of cancer disease (6).
The cases of patients diagnosed with lung cancer at Pulmonary
Department, Barcelona, from January 1998 through December 2002,
were studied retrospectively and compared with data published for the
period from 1978 through March 1981. Of 678 patients (89% men,
mean age 67 years) studied, 56% of the men and 38% of the women
were smokers (p<0.001). The most common histological types were
squamous cell carcinoma (33%) and adenocarcinoma (30%):
squamous carcinoma in men (36%) and adenocarcinoma in women
(56%). Metastasis was present in 42% of the patients with non-small
cell lung cancer and in 55% of those with small cell lung cancer. In
patients with a history of neoplastic disease, laryngeal tumors were
471
most common in patients with squamous carcinoma whereas bladder

tumors were the most frequent in patients with adenocarcinoma. The
ratio of men to women was lower in the recent series than in the
historical one. The percentage of squamous carcinoma was lower and
that of adenocarcinoma higher (p<0.001). The percentage of patients
diagnosed with regional involvement was greater in the recent series
(p<0.001). In conclusion, squamous cell carcinoma continues to be the
most frequent histological type. Male sex and smoking are associated
with squamous carcinoma and female sex is associated with
adenocarcinoma. Epidemiological and histological patterns have
changed, possibly in relation to changes in smoking habits (7).
In Turkey, of 945 patients with non-small cell lung cancer, 377
(39.9%) had metastases. Of the 224 patients with the stage I and II of
the disease, 73 had 73 metastases, including bone metastases, with
10.9% of silent metastases (8).
Small cell lung cancer
The charts of 259 patients with NSCLC, who consulted the

Department of Medical Oncology at Kinki University School of
Medicine between February 2002 and January 2005, were
restropectively investigated. Their TNM stage, presence of skeletal
metastases (on bone scintigraphy, MRI, and plain X-ray films), and
outcome parameters such as SREs, analgesic use, and survival were
assessed. Seventy patients (30.4%) had skeletal metastases during
their clinical course and 35/70 patients (50%) had SREs. Among 135
stage IV patients, 56 (41%) had skeletal metastases, and 25/56 patients
(45%) had SRE. The most common SREs were hypercalcemia (20%),
and the need for RT (34.3%). Patients with SREs tended to have
worse survival, while insignificant difference of survival observed
between patients with and without skeletal metastases. It is important
to prevent SREs during the treatment of NSCLC, so further studies
evaluating bisphosphonates in combination with chemotherapy are
warranted (9).
472
Assessment: risk factors for lung cancer include cigarette smoking,

workplace agents (asbestos, arsenic, chromium, nickel, and radon) and
other environmental factors (passive smoking, indoor radon and air
pollution), pre-existing lung disease, and genetic factors. The
distribution of lung metastatic tumors includes liver, bone, adrenal,
brain, lung, kidney, thyroid gland, pancreas, spleen and heart.
Symptoms of lung cancer include hemophtysis, loss of weight, loss
of appetite, dyspnea, thoracic pain, fatigue and cough, finger clubbing,
thrombocytosis and abnormal spirometry.
Did lung cancer with metastases to the bones affect the King?
Although the King lost his weight (10), in the absence of risk factors
for lung cancer and characteristic clinical symptoms, the diagnosis of
lung cancer seems unlikely.
References
1. de Groot P, Munden RF. Lung cancer epidemiology, risk factors, and
prevention. Radiol Clin North Am. 2012;50(5):863-76.
2. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the
future. J Clin Oncol. 2005;23(14):3175-85.
3. Tsuya A, Fukuoka M. Bone metastases in lung cancer. Clin Calcium.
2008;18(4):455-9.
4. Hamilton W, Peters T, Round A, Sharp D. What are the clinical features of lung
cancer before the diagnosis is made? A population based case-control study. Thorax.
2005;60(12):1059-1065.
5. Alamoudi OS. Lung cancer at a University Hospital in Saudi Arabia: a four-
year prospective study of clinical, pathological, radiological, bronchoscopic, and
biochemical parameters. Ann Thorac Med. 2010;5(1):30-6.
6. Barz H, Barz D, Klemm P. Distribution of lung cancer metastases. I.
Combination and frequency of organ metastases. Arch Geschwulstforsch. 1982;
52(7):551-60.
7. Santos-Martínez MJ, Curull V, Blanco ML, et al. Lung cancer at a university
hospital: epidemiological and histological characteristics of a recent and a historical
series. Arch Bronconeumol. 2005;41(6):307-12.
8. Metintas M, Ak G, Akcayi IA, et al. Detecting extrathoracic metastases in
patients with non-small cell lung cancer: is routine scanning necessary? Lung Cancer.
2007;58:59-67.
9. Tsuya A, Kurata T, Tamura K, Fukuoka M. Skeletal metastases in non-small
cell lung cancer: a retrospective study. Lung Cancer. 2007;57(2):229-32.
473
GASTROINTESTINAL TRACT
ESOPHAGEAL CANCER
Esophageal cancer is highly aggressive and is a common cancer
both worldwide and in the US (1), and is the sixth most common
cause of cancer death in the world (2). In the past 2 decades, the
incidence and mortality of esophageal cancer in the US have both
increased, where the incidence and mortality of other cancers have
decreased. Although esophageal squamous cell carcinoma and
esophageal adenocarcinoma differ in their histology and
epidemiologic distribution, some of their risk factors (e.g. dietary
deficiencies and tobacco) and underlying mechanisms of
carcinogenesis are the same. Intensive research into risk factors
combined with the ability to identify precursor lesions (e.g. squamous
dysplasia in esophageal squamous cell carcinoma and Barrett's
esophagus in esophageal adenocarcinoma) has paved the way for
studies of chemoprevention for esophageal cancer (1).
This study aimed to compare incidence rates of esophageal
adenocarcinoma and squamous cell carcinoma by race, to evaluate the
impact of race, age, gender, and histology on presenting stage, and to
describe tobacco use history in esophageal adenocarcinoma as
documented in a cancer registry. Invasive esophageal cancer cases
reported to Ohio's Cancer Registry 1998-2002 were identified.
Incident staged esophageal adenocarcinoma and squamous cell
carcinoma cases were analyzed for factors associated with metastatic
disease. Of 930 squamous cell carcinoma and 1801 esophageal
adenocarcinoma cases identified, African-Americans had higher
squamous cell carcinoma incidence than whites (5.0 vs. 1.3 cases/
100,000/year). However, whites had higher esophageal
adenocarcinoma incidence (3.3 vs. 0.8 cases/100,000/year); 77% of
esophageal adenocarcinoma cases with available tobacco history were
reported in tobacco users. In univariate analyses, race, age, gender,
and histology differed significantly by stage. Of patients aged ≥ 65
years, 31% presented with distant stage vs. 26% of those < 65
(p<0.001). Of African-Americans, 32% had distant stage vs. 34% of
whites (p=0.048). In logistic regression modeling, male gender (OR
1.76, CI 1.15 - 2.67) and age < 75 years (OR 1.95, CI 1.21 - 3.15), but
not race, predicted distant stage squamous cell carcinoma. Distant
stage esophageal adenocarcinoma was associated with age < 56 (OR
1.82, CI 1.39 - 2.38) but insignificantly associated with African-
474
American race (p=0.062) for the sample size available. In conclusion,

whites have higher esophageal adenocarcinoma and African-
Americans have higher squamous cell carcinoma rates. African-
Americans are less likely than whites to present metastatic squamous
cell carcinoma (3).
The main aim of this study was to study the autopsy findings of
171 patients with primary esophageal cancer and compare these
results with those of other investigators. The ratio of men: women was
5.84:1. The average age of the women was 72.9 years while of the
men 61.6 years. Squamous cell carcinomas were in 91.8% of the
cases, adenocarcinomas in 6.4% of the cases, and sarcomas in 1.8% of
the cases. In the cases of squamous cell carcinoma, there was an
ulcerating and infiltrating growth, primarily. In the cases of
adenocarcinoma, there was a polypoid exophytic growth and an
ulcerating growth. Most of the tumors were localized in the medial
third of the esophagus (50.9%), followed by the distal third of the
esophagus (39.7%), and, lastly, the proximal third of the esophagus
(9.4%). Of all tumors, 42.7% had an extension of more than 5 cm in
the longitudinal axis at autopsy. The trachea was the organ most
commonly infiltrated (21%). No metastases occurred in 28.6% of the
cases. Lymph node metastases existed in 67.3% and visceral
metastases were present in 29.8% of the cases (4).
Risk factors for esophageal cancer include age - most patients are >
60 years, the median age in US patients is 67 years (5), sex - the
disease is more common in men, heredity - it is more likely in people
who have close relatives with cancer, tobacco smoking and heavy
alcohol use increase the risk, and together appear to increase the risk
more than either individually; tobacco and/or alcohol account for
approximately 90% of all esophageal squamous cell carcinomas;
tobacco smoking is linked to esophageal adenocarcinoma; no
scientific evidence has been found between alcohol and esophageal
475
adenocarcinoma (6), GERD and its resultant Barrett's esophagus

increase esophageal cancer risk due to the chronic irritation of the
mucosal lining with adenocarcinoma more common in this condition
(7); a consequence of GERD is increased exposure of the esophagus
to bile acids; bile acids have been implicated as causal agents in
esophageal adenocarcinoma (8); HPV (9); corrosive injury to the
esophagus by swallowing strong alkalines (lye) or acids, particular
dietary substances, such as nitrosamines; a medical history of other
head and neck cancers increases the chance of developing a second
cancer in the head and neck area, including esophageal cancer;
Plummer-Vinson syndrome (anemia and esophageal webbing);
Tylosis and Howel–Evans syndrome (hereditary thickening of the skin
of the palms and soles); RT for other conditions in the mediastinum
(5); celiac disease predisposes towards squamous cell carcinoma (10);
obesity increases the risk of adenocarcinoma fourfold (11), it is
suspected that increased risk of reflux may be behind this association
(7,12); thermal injury as a result of drinking hot beverages (13,14);
alcohol consumption in individuals predisposed to alcohol flush
reaction (15); and achalasia (16). The role of C. pylori in progression
to esophageal adenocarcinoma is still uncertain, but, on the basis of
population data, it may carry a protective effect (17,18). It is
postulated, however, that C. pylori induces chronic gastritis, which is
a risk factor for reflux, which in turn is a risk factor for esophageal
adenocarcinoma (19).
Both cigarette smoking and alcohol drinking are well-established
risk factors for esophageal squamous cell carcinoma, and the
relationship of dose to cancer risk has already been described.
Furthermore, the synergistic effect of these 2 factors has been
reported. A case-control study revealed the OR of esophageal
squamous cell carcinoma 50.1 for those who were both heavy smokers
and heavy drinkers in comparison to people who neither drank nor
smoked. In patients with esophageal squamous cell carcinoma, head
and neck cancers as well as dysplastic lesions are frequently observed.
Heavy smoking and heavy drinking are closely related to such
multicentre carcinogenesis events in the upper aerodigestive tract,
including the esophagus and head and neck region. Polymorphisms in
acetaldehyde dehydrogenase 2 are reported to be a key event in
deciding individual susceptibility to upper aerodigestive tract cancer.
Patients with inactive acetaldehyde dehydrogenase, in whom facial
flushing is usually observed after the drinking of alcohol, are at high
risk for esophageal squamous cell carcinoma as well as multiple upper
aerodigestive tract cancers. For the early detection of the disease,
476
effective follow up using endoscopy with Lugol staining or narrow

band imaging endoscopy is strongly recommended for high-risk
populations, such as smokers, heavy drinkers, people with experience
of flushing after the drinking of alcohol, and patients with upper
aerodigestive tract cancer (20).
The aim of this study was to examine at what stage known risk
factors exert their influence toward the progression to cancer. Of 113
consecutive outpatients without GERD, 188 with GERD, 162 with
Barrett's esophagus, and 100 with esophageal adenocarcinoma or
high-grade dysplasia were involved in the study. All patients
underwent a standard upper endoscopy and completed a standardized
questionnaire about their social history, symptoms, dietary habits, and
prescribed medications. Overall, male gender, smoking, increased
BMI, low fruit and vegetable intake, duration of reflux symptoms, and
presence of a hiatal hernia were risk factors for cancer/high-grade
dysplasia. However, different combinations of risk factors were
associated with different disease stages. Hiatal hernia was the only
risk factor strongly associated with the development of GERD. For
GERD patients, male gender, age, an increased BMI, duration of
reflux symptoms, and presence of a hiatal hernia were all associated
with the development of Barrett's esophagus. Finally, the development
of cancer high-grade dysplasia among patients with Barrett's
esophagus was associated with male gender, smoking, decreased fruit
and vegetable intake, and a long segment of Barrett's esophagus, but
not with age, BMI, or a hiatal hernia. In conclusion, while some risk
factors act predominantly on the initial development of reflux disease,
others appear to be primarily responsible for the development of more
advanced disease stages (21).
Dysphagia and odynophagia are the most common symptoms of
esophageal cancer. Dysphagia is the first symptom in most patients.
Odynophagia may also be present. Fluids and soft foods are usually
tolerated, while hard or bulky substances (such as bread or meat)
cause much more difficulty. Substantial weight loss is characteristic
because of reduced appetite, poor nutrition and the active cancer. Pain
behind the sternum or in the epigastrium, often of a burning,
heartburn-like nature, may be severe, present almost daily, and is
worsened by swallowing any form of food. Another sign is an
unusually husky, raspy, or hoarse-sounding cough, a result of the
tumor affecting the recurrent laryngeal nerve, fatigue, and frequent
choking while eating (5,22). Early esophageal cancer typically causes
no signs or symptoms (22).
477
The presence of the tumor may disrupt normal peristalsis (the

organized swallowing reflex), leading to nausea and vomiting,
regurgitation of food, coughing and an increased risk of aspiration
pneumonia. The tumor surface may be fragile and bleed, causing
hematemesis. Compression of local structures occurs in advanced
disease, leading to such problems as upper airway obstruction and
superior vena cava syndrome. Fistulas may develop between the
esophagus and the trachea, increasing the pneumonia risk; this
condition is usually heralded by cough, fever or aspiration (5).
Cases of esophageal cancer with intramural metastasis to the
stomach and esophageal cancer with metastasis to an intramural
lymph node of the stomach are reported. The former patient was a 52-
year-old male. Squamous cell carcinoma of the lower esophagus with
an intramural metastasis located at the gastric cardia and a small
leiomyoma at the fornix were resected. The latter patient was a 70-
year-old female. Squamous cell carcinoma of the lower esophagus and
an intramural lymph node metastasis located at the anterior wall of the
gastric cardia were resected. The patient died nevertheless of multiple
liver metastases. These gastric involvements were detectable by
endoscopy before surgery. The clinicopathological features of these
esophageal cancers were characterized; the sites were the lower part of
the esophagus, and extreme lymphatic and vascular invasions were
shown histologically. The gastric tumors were located in the upper
third of the stomach, and the findings revealed submucosal tumors. It
is therefore important to discriminate other gastric tumors, and to
resect them simultaneously with esophageal cancer when a gastric
tube has been used for reconstruction after esophagectomy (23).
This report presents a case of esophageal squamous cell cancer
with osteoplastic bone metastasis. A 58-year-old male patient
underwent multimodality treatment for esophageal cancer. Sclerotic
changes resembling bone metastasis from prostate cancer were
detected in the 4th thoracic and the 5th lumber vertebral body soon
after the adjuvant chemoradiotherapy. Systemic examinations
revealed no primary cancer as a cause of osteoplastic bone metastasis
and no esophageal cancer recurrence. A needle biopsy revealed
metastases of esophageal squamous cell cancer with osteoplastic
changes. Multiple sclerotic changes were detected in the systemic
bones at that time, and new carcinomatous bilateral pleural effusion
developed. The drastic systemic progression of the cancer caused the
rapid deterioration of the patient's general condition (24).
The case of a patient diagnosed with esophagus adenocarcinoma
presented metastasis in upper-left maxillary bone (25).
478
The present case illustrates a patient with established esophageal

adenocarcinoma that metastasized to involve the halux. In the present
case, evaluation of various abnormalities such as chronic paronychia
could mask additional underlying conditions related to the patient's
primary cancer (26).
In a rare case of metastatic esophageal adenocarcinoma to the wrist
developed years after diagnosis and treatment of the primary lesion.
Awareness of the potential for developing these lesions should be
raised, particularly in the absence of systemic symptoms (27).
Assessment: esophageal cancer is highly aggressive and is a

prevalent common cancer worldwide. Histologically there are
squamous cell carcinomas, adenocarcinomas, and sarcomas. Although
esophageal squamous cell carcinoma and esophageal adenocarcinoma
differ in their histology and epidemiologic distribution, some of their
risk factors (e.g. dietary deficiencies and tobacco) and underlying
mechanisms of carcinogenesis are the same. Esophageal cancer can
metastasize to the bone.
Symptoms include dysphagia and odynophagia, weight loss, pain
behind the sternum or in the epigastrium, often of a burning,
heartburn-like nature, cough, a result of the tumor affecting the
recurrent laryngeal nerve, nausea and vomiting, regurgitation of food,
an increased risk of aspiration pneumonia, and hematemesis.
Did esophageal cancer afflict King David? Did esophageal cancer
metastasize to the bone? Although the King lost his weight (28), in the
absence of risk factors associated with esophageal cancer and
characteristic clinical symptoms, this diagnosis seems unlikely.
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GASTRIC CARCINOMA
Gastric carcinoma is the third most common G-I malignancy after
colon and pancreatic carcinoma. The incidence of bone metastases of
gastric cancer is 13.4% among autopsies (1).
Carcinoma of the stomach is still the second most common cause
of cancer death worldwide, although the incidence and mortality have
fallen dramatically over the last 50 years in many regions. The
incidence of gastric cancer varies in different parts of the world and
among various ethnic groups. Despite advances in diagnosis and
treatment, the 5-year survival rate of stomach cancer is only 20%.
Stomach cancer can be classified into intestinal and diffuse types
based on epidemiological and clinicopathological features. The
etiology of gastric cancer is multifactorial and includes both dietary
and nondietary factors (2). Substantial evidence strongly suggests that
the risk may increase with smoking and a high intake of salted foods,
and decrease with a higher intake of fruits and vegetables.
Accumulating evidence has implicated the role of H. pylori infection
in the pathogenesis of gastric cancer (2,3). The development of gastric
cancer is a complex, multistep process involving multiple genetic and
epigenetic alterations of oncogenes, tumor suppressor genes, DNA
repair genes, cell cycle regulators, and signaling molecules. A
plausible program for gastric cancer prevention involves intake of a
balanced diet containing fruits and vegetables, improved sanitation
and hygiene, screening and treatment of H. pylori infection, and
follow-up of precancerous lesions. The fact that diet plays an
important role in the etiology of gastric cancer offers scope for
nutritional chemoprevention (2).
There are geographic and ethnic differences in gastric cancer
incidence around the world, as well as trends in each population over
time. Incidence patterns observed in immigrant group changed in
relation to the countries they lived in. All these factors indicate a close
association of gastric cancer with modifiable factors (3).
The data that alcohol is an important factor increasing the risk to
develop G-I cancer are consolidating. Acetaldehyde is the first
metabolite of ethanol metabolism and has direct carcinogenic and
481
mutagenic effects by modifying DNA via generation of DNA adducts.

Oxidative stress has a prominent role in triggering chronic
inflammation and carcinogenesis through formation of reactive
oxygen species. Functional genetic variants of alcohol-metabolizing
enzymes proved to be associated with increased risk for esophageal
and gastric cancer. The highest risk increase for malignancy was
observed in the upper aerodigestive tract (oral cavity, pharynx, and
larynx) and esophagus (squamous cell carcinoma), weaker
correlations were established regarding gastric, pancreatic, and
colorectal neoplasias. In summary, alcohol overconsumption is a
serious avoidable risk factor for the development of G-I tract cancer,
both alone but even more in combination with other risk factors such
as tobacco and obesity (4).
Gastric cancer is one of the leading types of cancer worldwide,
particularly in East Asian populations. H. pylori infection has been
established as a major risk factor for gastric cancer. Although more
than 50% of the world population is infected with this bacterium, less
than 2% develop gastric cancer. Therefore, further risk factors (such
as host genetic polymorphisms and lifestyle, as well as environmental
and epigenetic factors) also play a role in its occurrence. The
correlation between H. pylori infection and gastric cancer represents a
typical model of a multi‑step process, characterized by some pre-
neoplastic lesions with a high risk of progression (atrophic gastritis,
intestinal metaplasia and dysplasia). In addition, H. pylori also plays
an oncogenic role in the development of MALT lymphoma that
accounts for approximately 3% of all gastric tumors. Hyperplastic
polyps often arise in patients with atrophic gastric mucosa and H.
pylori‑associated gastritis (25% of cases); however, their malignant
trasformation is rare (< 3% of cases). A number of trials have
demonstrated the possibility of cancer prevention through H. pylori
screening and eradication, particularly in high‑risk populations,
whereas it may not be cost‑effective in areas of low risk (5).
A retrospective analysis of 468 patients with gastric
adenocarcinoma operated in the 3rd Surgical Clinic, Cluj Napoca,
Romania, 1998-2003 was carried out. The median age was 62 years.
Patients in pTNM 0 stage were significantly younger than the rest of
patients, with an average of 7.5 years. The male: female ratio was
1.7:1, this ratio was significantly higher in cases with proximal gastric
cancers. There was insignificant correlation between the onset of
symptoms and surgery, and pTNM stage. The most frequent signs and
symptoms were epigastric pain, weight loss, indigestion, fatigue,
pallor and loss of appetite, each of them were in more than 40% of
482
patients. Multivariate analysis showed that weight loss (p=0.006) was

independently correlated with advanced pTNM stages. The number of
signs and symptoms was significantly correlated with advanced
pTNM stages (p=0.00003). This group of patients has characteristics
encountered in populations with higher incidence of gastric
adenocarcinoma, men more frequently affected, distal localization and
intestinal histological type encountered more frequently (6).
In a case series study, carried out at a single unit of the Department
of General Surgery, Dow University of Health Sciences and Civil
Hospital, Karachi, from April 2006 to April 2010 patients were
included with gastric cancer confirmed on histopathology. Patients
diagnosed with acid peptic disease and benign gastric ulcer were
excluded. Total number of patients was 15, 9 males (60%) and 6
females (40%), male: female ratio was 1.5:1. Mean age was 48.6, ±
4.47 years, ranging from 26-65 years. Common presenting complains
were vague upper abdominal pain, mass, ascites, peritonitis and
hematemesis. On endoscopy, tumor was found at the cardiac end in 5
patients (33%), at pylorus and antrum in 6 patients (40%), linitis
plastica in 2 patients (13.3%), and body and pylorus were involved in
1 patient (6.7%) each. Ten patients (66.6%) presented at stage IV and
3 patients (20%) in stage III. Surgical resection was possible in 5
patients (33.3%). Total gastrectomy was performed in 1 patient
(6.7%), while subtotal gastrectomy in 4 patients (26.7%). Palliative
gastrojejunostomy was performed in 4 (26.7%) and feeding
gastrostomy and endoscopic stenting in 2 patients (13.3%), each.
Chemotherapy was given to 8 patients (53.3%) while RT to 2 patients
(13.3%). Histopathological diagnosis was diffuse infiltrating
adenocarcinoma in 10 (66.6%), infiltrating intestinal type in 3 (20%)
and gastric lymphoma in 2 (13.3%) patients. Mortality was 13.3%. In
conclusion, majority of the patients with gastric carcinoma were
young males, presenting with advanced stage disease. Only 33%
tumors were resectable while 53.3% tumors were managed by
palliative treatment. Overall mortality was 13.3% (7).
In a retrospective study conducted at Ofir Loiola Hospital, Brazil,
records of 302 patients with gastric cancer undergoing surgery
between 2006 and 2008 were analyzed. Data regarding patient profile,
early symptoms, alterations upon physical examination, type of
surgery, and macroscopic and histological findings were obtained
from the records. Most patients (63.9%) were men, 48% were older
than 60 years, 50.9% were from the metropolitan region of Belém,
68.2% presented epigastric pain as an early symptom, and abdominal
tenderness upon palpation was in 63.7%. The antrum was the most
483
affected anatomical site (62.1%), followed by the gastric body

(26.9%). Borrmann III (ulcerated-infiltrative) was the predominant
endoscopic type. Adenocarcinoma accounted for 95.4% of all cases,
including the intestinal type in 56.6% and the diffuse type in 41.3%.
Most patients had stage IIIB and IV and total gastrectomy was the
most frequent type of surgery (37.4%). In conclusion, gastric
adenocarcinoma mainly affected men over the age of 60 who were
from the metropolitan region of Belém. Most adenocarcinomas were
in an advanced stage at the time of diagnosis, a fact requiring more
aggressive surgical resection in these cases (8).
The main cause of death in patients with gastric cancer is disease
dissemination. It is not clear why gastric cancer metastasizes to
different organs. Early detection and destruction of circulating
malignant cells before developing metastases may markedly improve
survival of these patients. Krukenberg tumors (metastases of non-
gynecological origin in the ovaries) usually are circular cell
carcinomas of gastric cancer. Bone metastases of gastric cancer are
rare, but if they are diagnosed, patients survive only 2-5 months on the
average. Disseminated bone marrow metastases from gastric cancer
do not always show the sudden course of the disease, but
hematological complications are signs of poor prognosis.
Hematological paraneoplastic disorders can be miscellaneous: they
usually manifest as anemia of various origin, leukocytosis in half of
the patients, leukemoid reactions in one-third of the patients, and
hemolysis and thrombocytopenia in half of the patients (often with
DIC). Currently, chemotherapy is the most effective treatment for
outspread gastric cancer (9).
The subjects were 19 patients diagnosed with stomach cancer and
bone metastasis at Hanyang University Medical Center, Korea, from
June 1992 to August 2010. The survival rate according to many
clinicopathologic factors was retrospectively analyzed. Eleven
patients out of 18 patients (61%) who received an operation were in
stage IV and the most common bone metastasis location was the
spine. Bone scintigraphy was mostly used for diagnosing bone
metastasis and PET-CT and MRI were used singly or together. The
serum ALP at the time of diagnosis had increased in 12 cases and
there were clinical symptoms (bone pain) in 16 cases. Treatment was
given to 14 cases and it was mostly RT. There were 2 cases with bone
metastasis at the time of diagnosing stomach cancer. The interval after
operation to the time of diagnosing bone metastasis for the 18 cases
who received a stomach cancer operation was on average 14.9 ± 17.3
months and the period until death after the diagnosis of bone
484
metastasis was on average 3.8 ± 2.6 months. In univariate survival rate

analysis, the group that was treated for bone metastasis had a
significantly better survival period when the bone metastasis was
singular rather than multiple, as compared to the non-treatment group,
yet both factors were not independent prognosis factors in multivariate
survival analysis. Making the diagnosis at the early stage and suitable
treatments are expected to enhance the survival rate and improve the
QOL even for the patients with bone metastasis (10).
The case files of the patients that were managed at the University
of Benin Teaching Hospital for gastric tumors over a 5-year period
(January 2004 to December 2006) were analyzed for symptoms and
signs of disease, findings at operation, treatment offered, and outcome
of treatment. The male: female ratio was 2.3:1, with the youngest
patient being 38 years while the oldest patient was 76 years old. Upper
abdominal pain and a palpable mass in abdomen were the commonest
symptoms and signs, respectively. Alcohol ingestion was the
commonest identifiable risk factor. Only 30.4% of the patients
presented within a year of the onset of symptoms. The gastric antrum
was affected in over 78% of the cases, and adenocarcinoma was found
in about 90% of the patients. Partial gastrectomy with
gastrojejunostomy was the commonest procedure carried out. The
mortality rate was 39.1%, and 66.7% of the patients died within a year
from time of diagnosis. Most of gastric carcinoma cases were
presented late with associated significant mortality (11).
Gastric carcinoma
Of 58 patients with bone metastasis from gastric cancer, 33

patients were operated cases and 25 were autopsies. The incidence of
bone metastasis of gastric cancer was 13.4% (33/246) among
autopsies and among operated cases 1.5% (33/2242). Bone metastasis
had a tendency to occur in invasive cancer such as Borrmann types III
or IV. Histological examination revealed that 86% (50/58) of bone
metastasis was poorly differentiated adenocarcinoma and the stroma
485
was scirrhous type in almost all cases. Serum ALP level in patients
with bone metastasis of recurrent gastric cancer was related to the
condition of bone metastasis. The prognosis of patients with bone
metastasis was poor and the mean survival time was about 5 months
after the appearance of symptoms. In these cases, total body
hyperthermia was used. This method was effective for bone
metastasis, shown in bone scintigram and changes in serum ALP
values (12).
Thirty-eight patients with bone metastasis from a primary gastric
cancer were selected and placed into 2 groups, consisting of 15 with
diffuse bone metastasis with DIC and/or MAHA and 23 patients who
had bone metastasis without hematological disorders. The
clinicopathological features and prognosis between the 2 groups were
compared. The clinicopathological features in patients with diffuse
bone metastasis accompanied by hematologic disorders were
significantly related to undifferentiated adenocarcinoma, a relatively
younger age, elevated levels of serum ALP-bone isoenzyme and LDH,
and a lower frequency of extraosseous metastasis. The median
survival time after manifestation was 2 and 1 month for the patients
with or without hematologic disorders, respectively. The prognosis
was significantly worse in cases of DIC with the median survival
being only 1 month. Since, prognosis of diffuse bone metastasis from
gastric cancer is significantly poor, close attention should be directed
to the specific clinicopathologic features related to diffuse bone
metastasis plus hematologic disorders. Regarding high-risk patients, a
regular follow-up of the serum chemistry levels and a bone scan will
aid the early detection of the disease (13).
A 63-year-old man was operated a year and a half before for a
poorly differentiated gastric carcinoma affecting the fundus. This
patient developed bilateral metastasis to the femoral head as the sole
manifestation of recurrence. He was treated with RT to control pain
with a poor response and both femoral heads had to be eventually
resected. Metastases to the bone as the sole manifestation of
recurrence of a gastric carcinoma are extremely rare. This case
demonstrates the rare occurrence of osseous metastasis from gastric
carcinoma (14).
In 1998, a female patient was admitted due to multiple thrombosis,
thrombocytopenia and fever. The initial diagnostic procedures
revealed peri-aortic lymphomas and a tumor bulk (7 x 8 cm) in the
upper abdomen. Gastroscopy revealed a 2 cm ulcer at the backside of
the gastric corpus. Histologically, a signet-ring cell carcinoma was
diagnosed. Final diagnosis stated a multilocular metastasising gastric
486
cancer with infiltration of bone, peritoneum and dura and signet-cell

infiltration of the bone marrow. Hematologic investigation revealed a
MAHA associated with DIC. Parallel to initial symptomatic therapy of
coagulopathy, systemic cytostatic therapy with CDDP and VP-16 was
initiated. In addition, RT of the brain was performed. After
histological confirmation of the diagnosis, weekly therapy with 5-FU
(2600 mg/m2) and folic acid (500 mg/m2) according to the Ardalan
protocol was given. After first signs of moderate response, OXL (60
mg/m2, day 1) was added. Although the chemotherapy dose had to be
reduced due to prolonged neutropenia, the disturbances of
homeostasis resolved completely resulting in reduced substitution
rates with fresh frozen plasma and platelets. Unfortunately, the patient
died at home due to pulmonary embolism. In conclusion, MAHA and
DIC as initial paraneoplastic symptoms of a solid tumor present a rare
clinical situation. Tumor-associated hematological alteration requires
immediate substitution of fresh frozen plasma and platelets. However,
it should be followed by specific therapy of malignancy, since tumor-
induced metabolites (e.g. mucin) maintain the alteration of
homeostasis (15).
A 46-year-old female woman patient presented with a thoracic
vertebral wedge fracture and widespread vertebral metastatic deposits
with marrow infiltration. An acute bleeding into the extradural space
causing spinal cord compression complicated the infiltration and
suppression of marrow function. Gastric cancer, although less
common than breast, kidney, thyroid, prostate and bronchial cancers,
was a cause of metastases to the bones. It highlights the complications
of bone metastases, marrow suppression, leukoerythroblastic anemia,
spinal canal hematoma and cord compression (16).
Twenty-seven patients who were diagnosed with gastric cancer on
endoscopy at Kosin University Gospel Hospital between 2001-2010
and did not receive any treatment at diagnosis. Nine of the patients
were women with the median age 73 years (range 38-95). Initial
endoscopic findings revealed 11 cases of protruded type, 16 cases of
flat and depressed type. Histopathological analysis indicated that there
were 14 cases of well and moderately differentiated adenocarcinoma,
6 cases of poorly differentiated adenocarcinoma and signet ring cell
carcinoma. Twelve patients underwent follow-up endoscopy and 3 of
them developed advanced gastric cancer within a mean of 9.6 months
(range, 5-12 months). Overall, median survival time was 40 months
and the 5-year survival rate was 45%. In conclusion, although there
were some differences in early gastric cancer progression, patients
who did not receive any treatment progressed eventually (17).
487
The surgical outcome of most early gastric cancer is usually

satisfactory. Some cases show bone metastasis even though the depth
of cancer invasion is confined to the mucosa. The most frequent site
for recurrence of early gastric cancer is the liver. Risk factors for bone
metastasis from early gastric cancer include depressed-type signet-
ring cell carcinoma, poorly differentiated carcinoma, and/or the likely
involvement of lymph node metastasis, even though the cancer is
confined to the gastric mucosa. The mechanism of bone metastasis
from early gastric cancer is via lymphatic channels and systemic
circulation. Post-operative follow-up of cases should consider the
development of bone metastasis from early gastric cancer. The use of
elevated ALP levels for the detection of bone metastasis and bone
scintigraphy in positive cases are recommended (18).
A 40-year-old female complained of epigastralgia. She underwent
endoscopy, which showed irregular shaped ulceration with fold
convergence; the biopsy specimen revealed poorly differentiated
adenocarcinoma. She underwent subtotal gastrectomy and lymph node
dissection. Histological findings revealed the signet-ring-cell cancer
confined to the mucosa and no lymph node metastasis. The serum
CEA was elevated 2 years and 11 months after operation. Bone
scintigraphy demonstrated multiple accumulation and bone biopsy of
the sacrum revealed the metastatic gastric cancer. She underwent
chemotherapy and RT, however, later complained of nausea, vomiting
and diminished visual acuity. Brain CT revealed multiple brain
metastases. She died 3 years and 6 months after her operation. Signet-
ring-cell carcinoma and poorly differentiated carcinoma have a
possibility of bone metastasis even though the early gastric cancer is
confined to the mucosa (19).
Three cases of bone metastases were described in patients with
advanced G-I stromal tumors: 2 women (82 and 54 years of age) and 1
man (62 years of age). Bones metastases involved the spine, pelvis
and ribs in 1 patient, multiple vertebral bodies and pelvis in 1, and the
spine and iliac wings in the third case. The lesions presented a lytic
pattern in all cases. Two patients presented with multiple bone
metastases at the time of initial diagnosis and 1 patient after 7 years
during the follow-up period (20).
Assessment: carcinoma of stomach is still the second most

common cause of cancer death worldwide, although the incidence and
mortality have fallen dramatically over the last 50 years in many
regions. There are geographic and ethnic differences in gastric cancer
incidence around the world, as well as trends in each population over
488
time. The development of gastric cancer is a complex, multistep

process involving multiple genetic and epigenetic alterations of
oncogenes, tumor suppressor genes, DNA repair genes, cell cycle
regulators, and signaling molecules. Risk factors for gastric cancer
include smoking, alcohol ingestion, a high intake of salted foods, and
decrease in a higher intake of fruits and vegetables. Accumulating
evidence has implicated the role of H. pylori infection in the
pathogenesis of gastric cancer.
The antrum is the most affected anatomical site, followed by the
gastric body. Histopathological diagnosis is diffuse infiltrating
adenocarcinoma, infiltrating intestinal type, and gastric lymphoma.
Gastric cancer, although far less common than breast, kidney,
thyroid, prostate and bronchial cancers, is a cause of metastases to the
bones. The clinicopathological features in patients with diffuse bone
metastasis accompanied by hematologic disorders are related to
undifferentiated adenocarcinoma, a relatively younger age, elevated
levels of serum ALP-bone isoenzyme and LDH, and a lower
frequency of extraosseous metastasis. The most frequent signs and
symptoms are epigastric pain, weight loss, indigestion, fatigue, pallor
and loss of appetite, abdominal mass, ascites, peritonitis,
hematemesis, and abdominal tenderness upon palpation.
Disseminated bone marrow metastases from gastric cancer do not
always show the sudden course of the disease, but hematological
complications are signs of poor prognosis. Hematological
paraneoplastic disorders manifest as anemia, leukocytosis, leukemoid
reactions, hemolysis, and thrombocytopenia (often with DIC). The use
of elevated ALP levels for the detection of bone metastasis and bone
scintigraphy in positive cases is recommended.
Did the King suffer from gastric carcinoma with metastases to the
bones? Although King David suffered from loss of appetite, weight
loss, anemia and severe bone pain (21,22), in the absence of epigastric
pain, a palpable mass, ascites, gastroscopic evaluation and
histopathological findings the diagnosis of gastric cancer seems
unlikely.
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Disseminated ovarian, bone, and bone marrow metastases from gastric cancer.
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Gastric Cancer. 2011;11(1):38-45.
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challenge in a poor economy. J Gastrointest Cancer. 2010;41(2):101-6.
12. Nishidoi H, Koga S. Clinicopathological study of gastric cancer with bone
metastasis. Gan To Kagaku Ryoho. 1987;14(5 Pt 2):1717-22.
13. Etoh T, Baba H, Taketomi A, et al. Diffuse bone metastasis with hematologic
disorders from gastric cancer: clinicopathological features and prognosis. Oncol Rep.
1999;6(3):601-5.
14. Fernández-Aceñero MJ, Aramendi Sánchez T. Bilateral metastasis to the
femoral head as the only manifestation of recurrence of gastric adenocarcinoma: a
case report. World J Surg Oncol. 2003;1(1):18.
15. Dempke W, von Poblozki A, Kellner O, et al. Hemorrhagic diathesis as initial
symptom of stomach carcinoma. Wien Klin Wochenschr. 2000;112(24):1053-8.
16. Metintas M, Ak G, Akcayi IA, et al. Detecting extrathoracic metastases in
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18. Kobayashi M, Okabayashi T, Sano T, Araki K. Metastatic bone cancer as a
recurrence of early gastric cancer - characteristics and possible mechanisms. World J
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19. Kobayashi M, Araki K, Matsuura K, et al. Early gastric cancer giving rise to
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20. Di Scioscio V, Greco L, Pallotti MK, et al. Three cases of bone metastases in
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21. Ben-Nun L. The disease that caused weight loss. "My knees are weak through
fasting, my flesh failed of fatness,.. my bones cleave to my skin". In Ben-Nun L. ed.
Israel. 2009, pp. 159-171.
490
COLORECTAL CANCER
Patients have suffered from CRC for thousands of years. Verses
relating to the disease that afflicted King Jehoram, who ruled in
Jerusalem 843-851 BCE, were closely studied (1). The verses ―...the
Lord smote him in his bowels with an incurable disease….. in the
process of time, after the end of two years, his bowels fell out by
reason of his sickness : so he died of sore diseases...‖ (II Chronicles
21:18,19) indicate that the King suffered from some kind of disease
which affected his bowels. Among the various diseases which can be
associated with prolapse of the bowel, CRC carcinoma is the most
acceptable. It seems that the CRC carcinoma was poorly
differentiated, invaded perirectal adipose tissue, blood vessels, and/or
lymphatic vessels, and/or perineural areas, was lymph node positive
and reached the fourth stage with the spread of metastases to the distal
organs. Viewed by a modern physician, the story of King Jehoram
unfolds as possibly the earliest description of a patient afflicted by
CRC carcinoma (1-2).
Even today, despite the availability of an efficient screening
protocol review, colon cancer is a leading health problem of the world
population (3). It is a leading cause of cancer mortality in the
industrialized world, second to lung cancer: each year there is nearly
one million new cases of CRC diagnosed worldwide and half a
million deaths (4).
In the UK, CRC is the second most common cause of death from
cancer. Common alarming symptoms include rectal bleeding, change
in bowel habit and iron deficiency anemia. Abdominal mass, weight
loss, nausea and vomiting, anorexia and abdominal swelling are less
common presenting symptoms. Patients meeting the NICE criteria for
urgent referral should be referred via the two-week wait pathway to
the local colorectal department for prompt assessment to exclude
CRC. CRC has a male predominance and is strongly associated with
age; 80% of new cases occur in patients aged > 60 years. Obesity and
limited exercise are strong risk factors. Diets low in fruit and
vegetables and fiber and high in red meat have been associated with
an increased risk. Patients with one first-degree relative < 45 years or
2 first-degree relatives of any age have an approximate lifetime risk of
developing CRC at 16-25% in men and 10-15% in women. Having
one first-degree relative who developed the disease > 65 years barely
increases lifetime risk. Patients with UC and CD also have an
increased lifetime risk of CRC. In the NHS Bowel Cancer Screening
Program, patients are screened with a fecal occult blood test, which
491
they complete at home and return by post. Patients with positive tests
are offered further investigation, typically colonoscopy. The
sensitivity of colonoscopy for detecting abnormalities is > 90% and
hence it is the gold standard test for evaluating the large bowel. Once
a diagnosis of CRC has been confirmed, the extent of disease is
evaluated by a CT scan of the chest, abdomen and pelvis (5).
Amongst the most important currently available markers for CRC
that provide prognostic or predictive information are serum markers
CEA and CA 19-9, markers expressed by tumor tissues, such as
thymidylate synthase, and also the expression/loss of expression of
certain oncogenes and tumor suppressor genes such as K-ras and p53.
The prognostic value includes genomic instability, angiogenesis and
proliferative indices, such as the apoptotic index. The advent of new
therapies created the pathway for a personalized approach to the
patient. This will take into consideration the complex of genetic
mechanisms involved in tumorigenesis, besides the classical clinical
and pathological staging. The growing number of therapeutic agents
and known molecular targets in oncology lead to a compulsory study
of the clinical use of biomarkers with improving response and
survival, as well as in reducing toxicity and establishing economic
stability (4).
The purpose of this study was to examine the influence of race,
gender, and age on CRC cases and to determine the implications of
these factors on screening strategies at the Department of General
Surgery, North Carolina. Tumors were defined as early (Stage I/II) or
late (Stage III/IV) and proximal or distal (relationship to splenic
flexure). Effect of age was examined by stratifying patients into 3
groups (< 50 years, 50-70 years, > 70 years). Two periods (1/87-12/96
and 1/97-12/00) were compared. Between January 1987 and
December 2000, 1355 patients (male: female, 699:656; mean, 65.9
years) entered into the tumor registry (998 whites, 357 African
Americans). The African American population had a significantly
higher proportion of females (p=0.0001) and patients < 50 years
(p=0.01). The incidence of carcinoma in situ was significantly higher
in African Americans (p=0.01). African Americans were more likely
to present with late disease (p=0.05), proximal cancers (p=0.05), and
well-differentiated tumors (p=0.04). In the entire cohort, proximal
lesions were significantly larger (p=0.002), poorly differentiated
(p=0.002), occurred more often in females (p=0.03), patients aged >
70 years (p=0.04), and patients with family history of colon cancer
compared to distal lesions. Proximal migration of tumors occurred in
the latter part (1997-2000 compared to 1987-1996) of the study
492
(p=0.002). Patients aged < 50 years had a higher incidence of late

stage (p=0.03) and poorly differentiated tumors (p=0.009). The
probability for a proximal tumor in an African American female aged
> 70 years was 61.9% and in a white male aged > 50 years was 35.1%.
Significant differences existed in the stage and location of tumors
according to patient's age, race, and gender. African-American
patients were more likely to present with late-stage tumors, and more
aggressive patient education and screening programs should be
implemented. For all groups, a proximal migration of colorectal
tumors was identified. This factor should eliminate use of
sigmoidoscopy as a screening tool. Complete colonoscopy, instead,
should be the procedure of choice to identify colonic neoplasia (6).
Patients with metastatic CRC were identified from 1993 to 2002 at
the Fox Chase Cancer Center, Philadelphia. The records of 1020
patients were reviewed. Incidence of bone and brain metastases were
10.4% (95% CI 8.6 - 12.4) and 3% (95% CI 2.2 - 4.5), respectively.
Patients with primary rectal vs. primary colon cancer were more likely
to develop bone metastases (16% vs. 8.6%, p=0.01). Patients with
lung metastases were more likely to have bone metastases (16.1% vs.
6.4%, p<0.001) or brain metastases (6.2% vs. 1.2%, p<0.0001) than
those without it (7).
Colon cancer cells
MEDLINE, Embase, Cochrane Library, and CINAHL were

searched to February 2010 for diagnostic studies of symptomatic adult
patients in primary care. Studies of asymptomatic patients, screening,
referred populations, or patients with CRC recurrences or with fewer
than 100 participants were excluded. The target condition was CRC.
Data were extracted to estimate the diagnostic performance of each
symptom or pair of symptoms. Data were pooled in a meta-analysis.
The quality of studies was assessed with the QUADAS tool. Twenty-
493
three studies were included. Positive predictive values for rectal

bleeding from 13 papers ranged from 2.2% to 16%, with a pooled
estimate of 8.1% (95% CI 6.0 - 11%) in those aged ≥ 50 years. Pooled
positive predictive values estimates for other symptoms were:
abdominal pain (3 studies) 3.3% (95% CI 0.7 - 16%), and anemia (4
studies) 9.7% (95% CI 3.5 - 27%). For rectal bleeding accompanied
by weight loss or change in bowel habit, pooled positive likelihood
ratios were 1.9 (95% CI 1.3 - 2.8) and 1.8 (95% CI 1.3 - 2.5)
respectively, suggesting higher risk when both symptoms were
present. Conversely, the pooled positive likelihood ratio was one or
less for abdominal pain, diarrhea, or constipation accompanying rectal
bleeding. In conclusion, investigation of rectal bleeding or anemia in
primary care patients is warranted, irrespective of whether other
symptoms are present. The risks from other single symptoms are
lower, though multiple symptoms also warrant investigation (8).
This report is a 25-year retrospective review that covers patients
with skeletal metastases secondary to CRC registered at the Cancer
Foundation from 1970 to 1995. The latter is the sole registration
agency of all cancers in the one million-population base of the
province of Saskatchewan (Canada). Of 5352 cases of primary CRC,
seen between 1970 and 1995, 355 had skeletal metastases. The
incidence of osseous metastases was 6.6%. Among the latter, 60 cases
(16.9%) had skeletal metastases only, whereas 295 cases (83.1 %) had
skeletal metastases in combination with lung, liver or brain
metastases. This is in keeping with the fact that solitary skeletal
metastases from a primary colonic carcinoma are a rare event, with an
incidence of 1.1%. The disease-free interval from the time of
diagnosis of the cancer to the onset of skeletal metastases ranged from
10 days to 5,309 days. Of the cases with skeletal metastases, 38% only
were alive at the end of 5 years in comparison with 16% of the cases
with skeletal and other metastases. However, there was insignificant
difference in the 10-year survival curves from the onset of osseous
metastases in the 2 groups. A bone scan or plain radiography or both
diagnosed the majority. Most received a multimodal treatment
consisting of RT in conjunction with palliative surgery or
chemotherapy or both. In conclusion, skeletal metastasis is a rare
event in primary CRC. Among these cases, there is an emerging trend
of a different clinical-biological behavior pattern between patients
who develop solitary skeletal metastases vs. patients with skeletal and
other organ metastases (9).
Over a 10-year period (1995-2005), 113 patients were diagnosed
with CRC at King Khalid University Hospital in Riyadh, Saudi
494
Arabia. The average age at diagnosis was 55 years (SD=15), 58% of

the patients were males and 42% were females. Of the patients, 37%
were ≤ 50 years of age. The most common clinical presentation was
abdominal pain (68%) followed by rectal bleeding (62%) and weight
loss (55%), while 45% of patients presented with complete large
bowel obstruction. Left-sided lesions and rectal cancer constituted
76% and 48% of all CRC tumors, respectively. Of lesions, 38% were
stage C and above. In conclusion, Saudi patients were more likely to
present with CRC at a more advanced stage of the disease and at
younger ages compared to Western populations (10).
Data from 419 patients from a population that received no
screening between April 1995 and March 2001, and were operated in
the Cancer Institute and Imam Khomieni Hospital, Iran with a
diagnosis of CRC and were used to describe distribution of the CRC
by age, gender, tumor subsite, pathology and stage at diagnosis.
There were 403 (96.2%) cases of adenocarcinoma. Males and females
constituted 52.4% and 47.6% of cases, respectively. The mean age
was 52.3 years. Patients were divided into 2 age groups (≤ 40 years,
and > 40 years); 16.4% of patients had tumors in the proximal colon
and 83.6% in distal parts. Most patients were Stage II and III (48.1%
and 33.4%, respectively). Tumor subsite distribution was almost the
same between the 2 age groups (aged ≤ 40 years: proximal 18.5%, and
distal 81.5%; older > 40 years: proximal 15.7%, and distal 84.3%).
Most patients in the younger age group were Stage III (45%) and in
the older age group were Stage II (53.2%, p<0.001). Tumor
differentiation proportions in patients aged ≤ 40 years were: good
24.4%, moderate 53.6%, and poor 22%; while in patient aged > 40
years were: good 41.5%, moderate 52.6%, and poor 5.9% (p<0.001).
There were no differences in stage and tumor differentiation between
2 genders, but most of the patients with tumors in proximal colon
were males (62.5%, p=0.1). In conclusion, most of the CRC were in
distal parts, so most of these carcinomas can be detected by
proctosigmoidoscopy. Because younger patients had more advanced
disease, the importance of screening and "clinical suspicion" in the
young is important (11).
In a retrospective study of 947 consecutive Japanese patients aged
≥ 65 with 1,039 lesions were examined. Pathologic findings in the
very old group (> 85 years, n=140) were compared with those in the
younger groups; young-old group (65-74 years, n=352) and middle-
old group (75-84 years, n=455). Although male: female ratio
significantly decreased with advancing age, reaching 1:1.8 in the very
old group, the relative odds of CRC in men were higher than that in
495
women in all age groups. In the very old group, cancer of the proximal
colon (proximal to the splenic flexure) accounted for 52% in women
and 37% in men, being significantly higher than those in the younger
groups. Proximal colonic cancers increased with advancing age in
both genders. Higher proportions of poorly differentiated
adenocarcinoma, mucinous carcinoma, cancer > 5 cm in size, and
protruding type cancer were present in the very old group, although
these kinds of tumors typically occur in the proximal colon. The
incidence of multiple cancers in the large intestine was not different
among any age group (average, 8.6%). Even in the very old, CRC
showed marked proximal excess, being explained by effect of both
age and gender. The proximal shift may influence the proportion of
histological type and size of the tumor (12).
The cancer registry records at the Cancer Institute Hospital, Tokyo,
Japan were analyzed from 1986 to 1995. For CRC, another database
of patients between 1946 and 1991 was analyzed, with special
reference to synchronous and metachronous cancers. Of 24,498
registered cases, there were 1281 (5.2%) multiple cancers, of which
464 (1.9%) were in the same organs and 817 (3.3%) were in other
organs. Gastric or CRC frequently developed as the second cancer
regardless of the site of the index cancer. Although the majority of the
second cancers developed within 3 years after the index cancer, some
developed within 5 years or more after the index cancer. In CRC, the
cases with metachronous cancer were similar to those with hereditary
nonpolyposis colon cancer. The frequent combination of an advanced
index cancer and an advanced second cancer and relatively poor
survival after the second cancers in the metachronous cases may
reflect delayed diagnosis of the second CRC. In conclusion, careful
attention should be paid to the second cancer in treating cancer
patients (13).
Among 1669 patients who underwent surgery for primary CRC
cancer from January 1997 to June 2005, 26 patients (1.6%) with
multiple primary CRC were identified at the Department of Surgery,
Busan, Korea. For the purposes of this study, the colon and rectum
were classified into 3 segments. The right-side colon included the
appendix, cecum, ascending colon, hepatic flexure, and transverse
colon, and the left-side colon included the splenic flexure, descending
colon, and sigmoid colon. Of the 26 patients with multiple primary
CRC, 19 patients were male and 7 patients were female, with a mean
age of 61.5 years. Synchronous CRC cancers had 19 patients and 7
patients had metachronous CRC cancers. In the metachronous cases,
the mean diagnostic interval was 36.8 months. The site of the first
496
lesion in metachronous CRC cancers was the right colon in five cases
(71.4%), the left colon in 2 cases (28.6%), and the site of the second
lesion was the rectum in 6 cases (55.5%), the right colon in 3 cases
(33.3%), and the left colon in 1 case. The TNM stage of the second
lesions in the metachronous CRC cancers was stage II in 4 cases
(57.1%), stage III in 1 case (14.3%), and stage IV in 1 case (14.3%).
For the synchronous CRC cancers, the operation methods were single-
segment resection combined with endoscopic mucosal resection in 5
cases (26.3%), single-segment resection alone in 6 cases, two-segment
resection in 6 cases, and total colectomy in 2 cases. In conclusion, in
metachronous CRC cancers, the secondary lesions were later-stage
cancer (14).
CRC patients (n=1,031) who underwent surgical treatment at the
Department of Surgery of Kaohsiung Hospital, Taiwan, between
January 1998 and December 2004 were studied. Among these
patients, CRC was accompanied by cancer of other organs in 17
patients (1.65%), either synchronously or metachronously. Of the 17
patients in whom CRC was accompanied by primary cancer of other
organs, there were 4 synchronous and 13 metachronous multiple
cancer patients. This patient group comprised 6 men and 11 women
with ages ranging from 47 to 88 years (median age, 66 years). The
most common location of CRC was the sigmoid colon. In patients, 6
gastric cancers (35.2%) and 6 breast cancers (35.2%) were associated
with primary CRC. The remaining 6 second primary cancers were
related to 1 cancer, each: lung, thyroid, cervical, ovarian, skin, and
urinary bladder. Of the 13 metachronous multiple cancer patients, 8
patients developed subsequent CRC after primary cancers of other
organs, whereas 2 patients developed a subsequent second primary
cancer after CRC. The intervals between the developments of
metachronous multiple cancers ranged from 2 to 19 years. In this
retrospective analysis, breast and gastric cancer patients were at
increased risk of developing subsequent secondary CRC. Cancer
patients with hematochezia or G-I symptoms/signs should be
evaluated for the possibility of second primary CRC during their
regular follow-up (15).
A clinic-endoscopic study on 365 patients, aged 26-95 years, with
colonoscopic diagnosis of CRC was conducted at the
Gastroenterological Department, Lima, Peru. Of all patients, 61.9%
were men and 38.1% women; in 92.6% the disease occurred being >
40-year-old; 13.4% had CRC, uterus and breast cancer, and other
cancers; 14.0% had colorectal adenoma, cholecystectomy, and other
benign condition. Abdominal pain, change in intestinal habits, and
497
bleeding were the moist frequent symptoms, with differences

depending of the tumors localization in the colon or rectum. Of
patients, 62.6% had anemia under 10 g% of hemoglobin, in 85.2% the
fecal occult blood test was positive. On 199 patients, the simple
barium enema diagnosed the tumor in 66.3% only; but in the same
group, colonoscopy diagnosed the cancer in 96.5% at first
examination. In all patients, colonoscopy was excellent for diagnosis
of the principal lesion, and for the identification of synchronous
neoplasia. On 365 patients, colonoscopy diagnosed the cancer in
98.1% at first examination. The localization of tumors was: 57.6% in
left colon (49.5% in rectum and sigmoid colon); 34.2% in the right
colon; and 8.2% in transverse. Pathology showed that adenocarcinoma
was the most frequent tumor 95.2% following 1.1% mucoid
carcinoma, 1,1% epidermoid carcinoma and 2.7% lymphoma. In
32.1% of cases, there were synchronous lesions, 3.0% had other
cancer, 54 patients had 112 polyps: 62.5% adenomatous polyp, 6.3%
adenoma with non invasive or invasive adenocarcinoma, and 31.3%
hyperplastic polyp (16).
CRC patients (n=3870) pathologically confirmed at the Nanfang
Hospital and Huizhou Municipal Central Hospital of Guangdong
province, China were studied. The hospitalization number of CRC in
the 2000-2004 was 102%, higher than that of the 1985-1989 period
with an annual increase of 5.1%. The median age of incidence in
2000-2004 was 58.6 years, 8.4 years higher than that in 1985-1989.
The male: female ratio of the 3870 patients was 1.42:1. The male:
female ratio in 2000-2004 was 1.35:1, lower than that in 1985-1989
(1.50:1). The proportion of rectal cancer in 2000-2004 was 49.7%,
significantly lower than that in 1985-1989 (64.8%), while the
proportion of right hemi-colon cancer in 2000-2004 was 28.7%,
significantly higher than that in 1985-1989 (18.0%). The proportion of
moderately and well differentiated cancer in 2000-2004 was 80.6%,
higher than that in 1985-1989 (70.1%), and the proportion of poorly
differentiated cancer in 2000-2004 was 19.4%, lower than that in
1985-1989 (29.9%). The proportion of colorectal cancer at Dukes A
stage in 2000-2004 was 9.8%, higher than that in 1985-1989 (3.2%).
In conclusion, in the past 20 years, the incidence of CRC has
increased in Guangdong province with a n increase of median age of
incidence. The male to female ratio has decreased, and the incidence
of right hemi-colon cancer, the rates of higher differentiated cancer
and Dukes A stage cancer have increased (17).
498
In barium enema, the area in the circle shows an advanced cancer of

colon that has produced an apple core lesion. The name apple core comes
from the x-ray appearance of circumferentially eaten apple.
A total of 3607 patients with pathologically confirmed CRC who

were hospitalized in Tumor Hospital of Harbin Medical University,
Heilongjiang province, China, between 1981-2005, were divided into
5-year groups. The annual hospitalization number of CRC patients in
1985-2005 was increased by 8.5%. The median age increased by 7
years. There was insignificant change in the male: female ratio. The
proportion of rectal cancer decreased by 13.6%, while the proportions
of both right and left hemi-colon cancers increased by 6.8%; the
proportion of CRC at Dukes' A increased by 3.8%, while the
proportion of CRC at Dukes' D decreased by 8.1%. In conclusion, in
the past 25 years, the incidence of CRC has increased in Heilongjiang
province with an increase in median age; the male: female ratio has
insignificant change. The incidence of rectal cancer and proportion of
Dukes' A cancer have increased (18).
A total of 343 patients (older than 60 years) with rectal cancer were
treated surgically during a period of 10 years at the Department of
Gastroenterology, Tianjin Cancer Hospital, also China. R0, R1, and
R2 operations were carried out in 261 patients (76.09%), 29 patients
(8.45%), and 53 patients (15.45%), respectively. Low anterior
resection was performed in 116 patients; 169 patients underwent
Miles operation, and 58 patients underwent the other operations. The
operation mortality was 0.87%, while 149 patients died of occurrence
or metastases of the tumor within 108 months postoperatively. Liver,
lung, and bone metastases occurred in 17, 18, and 1 patients,
respectively. The mean survival time for all patients was 72.12 +/-
2.60 months and the overall 3-, 5-, and 10-year survival rates were
69.6%, 55.7%, and 34.2%, respectively. Univariate analysis showed
that the predictors of survival were type of operations, radical
resection, histological type, diameter of the tumors, depth of tumor
499
invasion, lymphatic invasion, distance metastases, and liver and lung

metastases. Multivariate analysis showed that only radical resection,
lymphatic invasion, liver and lung metastases were independent
factors. In conclusion, the follow prognostic factors influence the
survival of rectal cancer in the elderly: type of operations, nature of
operation, histological type, diameter of the tumors, depth of tumor
invasion, lymphatic invasion, distance metastases, and liver and lung
metastases (19).
The frequency of CRC metastases is fairly low (1.3% of all cases
of bony metastases) as tumors of the large intestine do not tend to
migrate to the bones. At the time of diagnosis, about 25% of cases
with CRC have distant metastases. Distant metastases are most
frequently metastases to the liver, lungs, brain, but rare to the bones
(3). However, sometimes bony metastases are the presenting symptom
but, usually the metastases occur within 5 years of the diagnosis of the
primary tumor (20).
The clinical picture shows no special characteristics.
Radiologically, these bony metastases may be either single or
multiple. Their distribution recalls that of other metastases in the
bones with a few differences, however. The frequency of pelvic
involvement, distal localizations (hands or feet) is not exceptional
(20). An early diagnosis of secondary deposits in the bones of the
hand can be very difficult. The symptoms are subclinical or similar to
other bone diseases (3).
The histological appearances of the bony lesions depend on
differentiation of the tumor and the characteristics of the neighboring
bony abnormalities which include both osteolysis and osteogenesis.
The mixed appearances are, however, not rare, and usually give a
pseudo-sarcomatous appearance, with invasion of the soft parts and
very marked periosteal reaction. Sometimes, bony condensation is
noted (20).
Symptoms usually appear in the advanced disease, and treatment is
palliative (21). The treatment (RT, chemotherapy, and surgery) is
determined according to the general condition of the patient and the
localization of the lesion. RT can reduce tumor mass and reduce pain
especially among patients with multiple lesions or inoperable ones (3).
The treatment of CRC with bony metastases is disappointing as the
disease is always fatal within a relatively short period, usually less
than one year after the diagnosis of the bone involvement (20).
A 73-year-old man was referred for evaluation of a mass of 2
months' duration in the right parotid gland. He gave a history of
watery bowel movements of unknown duration. Physical examination
500
revealed a 7- x 6 cm hard mass, which seemed to be fixed to the right

mandible. A CT scan revealed a destructive process involving the
ramus and condyle of the right mandible that invaded the
pterygopalatine fossa, pterygoid muscles, and middle cranial fossa.
CT scans of the abdomen and pelvis revealed a 5 cm mass in the
sigmoid colon with metastases to the liver. A biopsy of the mass in the
mandible was performed, and metastatic adenocarcinoma of colonic
origin was diagnosed. Colonoscopy and biopsy of the colonic mass
substantiated that the sigmoid colon was the primary site of the
cancer. Because the patient had disseminated disease, he declined
treatment, and he died shortly thereafter. Although rare, metastatic
adenocarcinoma from the colon to the mandible and parotid area
should be included in the differential diagnosis of masses in this area.
Metastasis from adenocarcinoma of the colon is quite rare and
represents incurable disseminated disease (21).
Metastases to the mandible are very rare and account for only 1%
of all oral tumors. The most common primary in such cases is the
breast. Only 20 cases of metastases to the mandible are from tumors
of the large bowel. A case of a 59-year-old woman with metastatic
disease of the mandible in whom the primary tumor was an
adenocarcinoma of the sigmoid. Metastases to the oral cavity and
mandible should be included in the differential diagnosis of gingival
or mandibular lesions in a patient with a previous or current
malignancy (22).
A 56-year-old man was referred with lower rectal cancer showing
anal canal invasion and liver metastasis. He underwent an
abdominoperineal resection and a partial hepatectomy. Adjuvant
therapy with tegafur-uracil and leucovorin was administered
postoperatively. Lung metastasis was detected 2 years later and was
resected. Right mandibular metastasis was diagnosed 2 months after
the resection of the lung metastasis. A partial mandibular resection
was performed after chemoradiotherapy, followed by reconstruction
with a titanium frame and oral cavity reconstruction with a greater
pectoral musculocutaneous flap. The pathological diagnosis was
metastatic rectal cancer, and the therapeutic effect chemoradiotherapy
was Grade II. He is presently alive without any evidence of cancer,
and has maintained a good QOL 3 years after the mandibular resection
and more than 5 years after his first operation. Mandibular metastasis
from rectal cancer is very rare and the prognosis is poor according to
the literature, so this case is considered to be very unusual (23).
Metastatic malignancies of the hand are rare and usually develop
from lung, breast, or kidney tumors. Metastases from tumors and
501
sarcomas of the G-I system are even more uncommon. A case of

differentiated adenocarcinoma of the colon in a 76-year-old man who
presented with distal phalangeal metastasis and osteolysis in the form
of a painful swelling at the tip of the right little finger of 6 months
duration is reported. CT of the abdomen and colonoscopy revealed a
mass in the transverse colon. Diagnosis was confirmed by biopsy.
Treatment was given with palliative local RT and systemic
chemotherapy. After 4 weeks of chemotherapy, the patient
discontinued treatment and eventually succumbed to the disease (24).
A 65-year-old female patient with a recent diagnosis of
adenocarcinoma of the sigmoid colon and massive hematochezia in
the context of a general bleeding disorder is reported. Disseminated
malignant disease with hepatic metastases as well as bone marrow
involvement was demonstrated. Moreover, circulating tumor cells
were demonstrated by flow cytometry. The patient had right lower
quadrant abdominal pain due to a spontaneous psoas intramuscular
hematoma. At the time of admission to the hospital, the patient
displayed MAHA and secondary hyperfibrinolysis with a pronounced
bleeding tendency. There was an acute renal failure which improved
with fluid resuscitation. With immediate chemotherapy consisting of
5-fluorouracil, folinic acid and OXL (FOLFOX regimen) and
cetuximab initiated with the second course, plasmatic coagulation was
stabilized. Treatment with tranexamic acid, fibrinogen, fresh frozen
plasma as well as red blood cell and platelet infusions was stopped.
Continuation of chemotherapy was possible on an outpatient basis and
the further course was associated with a good QOL until her end. The
patient died at home 7 months after initial diagnosis of her colon
cancer due to progressive disease with CNS metastases. DIC with
microangiopathic hemolysis and secondary hyperfibrinolysis is a rare
albeit possible event in disseminated CRC, especially when the bone
marrow is involved. Treatment of the underlying cause is the most
important therapeutic measure (25).
Over 37,000 new colorectal cancers are diagnosed in the UK each
year. Most present symptomatically to primary care. The main aim of
this study was to conduct a systematic review of the diagnostic value
of symptoms associated with CRC. In this systematic review, Embase,
Cochrane Library, and CINAHL were searched to February 2010 for
diagnostic studies of symptomatic adult patients in primary care.
Studies of asymptomatic patients, screening, referred populations, or
patients with CRC recurrences, or with fewer than 100 participants
were excluded. The target condition was CRC. Data were extracted to
estimate the diagnostic performance of each symptom or pair of
502
symptoms. Data were pooled in a meta-analysis. The quality of studies

was assessed with the QUADAS tool. Twenty-three studies were
included. Positive predictive values for rectal bleeding from 13 papers
ranged from 2.2% to 16%, with a pooled estimate of 8.1% (95% CI
6.0% - 11%) in those aged ≥ 50 years. Pooled positive predictive
value estimates for other symptoms were: abdominal pain (3 studies)
3.3% (95% CI 0.7% - 16%); and anemia (4 studies) 9.7% (95% CI
3.5% - 27%). For rectal bleeding accompanied by weight loss or
change in bowel habit, pooled positive likelihood ratios were 1.9 (95%
CI 1.3 - 2.8) and 1.8 (95% CI 1.3 - 2.5) respectively, suggesting
higher risk when both symptoms were present. Conversely, the pooled
positive likelihood ratio was one or less for abdominal pain, diarrhea,
or constipation accompanying rectal bleeding. These findings suggest
that investigation of rectal bleeding or anaemia in primary care
patients is warranted, irrespective of whether other symptoms are
present. The risks from other single symptoms are lower, though
multiple symptoms warrant investigation (26).
Assessment: patients have suffered from CRC for thousands of

years. Even today, CRC remains an important public health problem
and is a leading cause of cancer mortality in the industrialized world,
second to lung cancer. Each year there are nearly one million new
cases of CRC diagnosed worldwide with half a million deaths.
CRC has a male predominance and is strongly associated with age;
obesity, limited exercise, CD and UC are strong risk factors. Diets low
in fruit, vegetables, fiber and high in red meat are associated with an
increased risk. Patients with one first-degree relative < 45 years or 2
first-degree relatives of any age have an approximate lifetime risk of
developing CRC of 16-25% in men and 10-15% in women.
Higher proportions of poorly differentiated adenocarcinoma,
mucinous carcinoma, cancer > 5 cm in size, and protruding type
cancer are present in the very old group, although these kinds of
tumors typically occur in the proximal colon. Proximal lesions are
larger, poorly differentiated, occur more often in females, patients
aged > 70 years, and patients with family history of colon cancer
compared to distal lesions. The incidence of multiple cancers in the
large intestine is not different among any age group (average, 8.6%).
Even in the very old, CRC showed marked proximal excess, being
explained by effect of both age and gender. There is a trend with the
decrease percentage in rectal cancer and the gradual increasing in right
hemi colon cancer with increased patients' age.
503
Distant metastases are most frequently metastases to the liver,

lungs, brain, but they are rare in the bones. Patients with primary
rectal vs. primary colon cancer were more likely to develop bone
metastases. Sometimes bony metastases are the presenting symptom
but usually the metastases occur within 5 years of the diagnosis of the
primary tumor.
Common symptoms include rectal bleeding, change in bowel habit
and iron deficiency anemia. Abdominal mass, weight loss, nausea and
vomiting, anorexia and abdominal swelling, bowel obstruction, and
positive fecal occult blood test are less common presenting symptoms.
Did the King suffer from CRC? Were intractable, severe bone
pains related to CRC with metastases to the bones? The medical
record did not document any risk factor related to CRC. Among
specific symptoms that can be related to CRC, the King's medical
record gives descriptions of anemia, weight loss and anorexia (27,28).
Although CRC can metastasize to the bones, in the absence of
abdominal pain, changes in bowel habit, abdominal mass, rectal
bleeding, diarrhea, or constipation, occult stool examination,
colonoscopic evaluation and histopathological findings the diagnosis
of CRC seems unlikely.
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3. Vasić L. Osteolysis of hand bones due to metastatic deposits from colon cancer
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505
HEPATOCELLULAR CARCINOMA
HCC is the most frequent malignant tumor of the liver (1) and is
the sixth most common cancer worldwide with a wide geographic
distribution (2). HCC is the third most common cause of cancer-
related deaths worldwide, with about 600,000 patients dying from the
disease annually (3). In 70-90% of patients, HCC develops on the
background of chronic liver cirrhosis or inflammation. Risk factors
and etiologies vary among geographical regions. In regions with a
high incidence, the majority of cases are related to HBV and HCV
hepatitis. In developed countries, in addition to virus-related HCC,
high consumption of alcohol as well as non-alcoholic fatty liver
disease often in the context of metabolic syndromes are the prevalent
causes (3).
The most common risk factors for HCC are chronic hepatitis B and
HCV infections, alcohol use, smoking, and aflatoxin exposure (2,4).
Emerging risk factors such as obesity might play an important role in
the future because of the increasing prevalence of this condition (2).
Pain is a common feature of most human cancers, including HCC.
Unresectable HCC patients with pain at presentation has a worse
prognosis and adverse tumor characteristics (5). Early recognition
remains an obstacle and lack of it results in poor outcomes for HCC,
the most prevalent primary liver cancer, and cholangiocarcinoma (2).
The diagnosis of HCC depends on the measurement of serum AFP
levels and imaging techniques while liver biopsy is recommended in
uncertain cases (1).
A database of 778 biopsy-proven, unresectable and
untransplantable HCC in older patients were followed from diagnosis
till death. In the older age patients, 2 survival sub-groups were
identified, with 45-80 days in the first and 330-1,250 days survival in
the second group. The longer surviving group had the lowest serum
bilirubin and AFP levels and the lowest tumor mass. The trends for
both AFP and bilirubin were similar, suggesting that they were not
independent variables. This was supported by the similar correlation
of typical AFP with GGT, ALP and SGOT levels. In conclusion, a
large HCC cohort showed significant age clustering characteristics for
survival, especially in older patients. AFP, bilirubin and age were
inter-related factors for HCC severity and survival (6).
506
60-year-old woman with hepatocellular carcinoma and liver cirrhosis.

Subcostal sonogram of liver reveals 3.5-cm-diameter hepatocellular
carcinoma in segment V.
Forty-seven patients (males=43, females=4) with HCC diagnosis

based on history, clinical examination, and imaging (ultrasonography,
CT/MRI), AFP and by ultrasonography/CT guided FNA, were
included. Patients were screened for HBV, HCV and history of
alcohol. Tumor size was assessed on imaging and upper G-I
endoscopy for the presence of varices. The mean age was 53.4 +/-
14.6 years. Clinical presentation included anorexia in 32 (68%),
abdominal pain in 28 (60%), loss of weight in 23 (49%), fever in 12
(26%), and jaundice in 6 (13%) patients. Twenty-nine (62%) had
underlying cirrhosis, diagnosed by ultrasonography or CT; 17% had
normal AFP (< 10 ng/ml) and the remaining 83% had raised AFP (<
10 ng/ml=7, 10-400 ng/ml=27, > 400 ng/ml=8). Thirteen patients
(28%) consumed alcohol in cirrhogenic doses and 10 (21%) were
smokers; 54% were positive for HBsAg and 47% of these were also
positive for HBeAg; 27% were positive for anti-HCV. In 33 patients,
tumor size varied from < 3 cm in eight (18%), 3-5 cm in 12 (27%) and
> 5 cm in 25 (56%) patients. Twenty-three patients were lost to
follow-up, 4 died and 6 did not agree for any treatment. Only 5
patients could be subjected to hepatic resection. Remaining 9 patients
had a large tumor size and were put on tamoxifen. In conclusion, more
than half of the HCC cases have underlying cirrhosis. Hepatitis B
virus infection is commonly associated. Most of patients have a large
tumor (> 5 cm) at presentation (4).
A retrospective analysis of 235 patients with HCC divided patients
into 2 groups by age at diagnosis: ≤ 75 years (n=186) and > 75 years
(n=49). There were no differences between groups for sex, presence of
cirrhosis, etiology, Child-Pugh score, BCL Cancer stage, presence of
ascites or portal thrombosis, or bilirubin, AST, ALT, GGT, LDH or
hematocrit values. Patients of advanced age were more frequently
diagnosed in the presence of clinical manifestations, had multifocal,
507
non-localized disease and AFP > 400 ng/mL (all p<0.05). This group
received exclusively symptomatic treatment in 78% of cases
(compared to 33% in younger patients), and only 3 of them underwent
surgical resection (p<0.0001). Age > 75 years was a predictive factor
for not receiving locoregional therapy (p<0.0001). Survival in the
elderly group (9.8 +/- 1 months) differed substantially from that of
younger patients (25.6 +/- 2 months) (p<0.00001). In the multivariate
analysis, advanced age continued to be a prognostic factor of poor
survival (p=0.025), but lost significance when the analysis was
stratified by treatment subgroups (p=0.344). In conclusion, the lower
survival in elderly patients with HCC, beyond differences in tumor
extension or liver failure, seems conditioned by the use of suboptimal
treatment in this population (7).
In this a cross-sectional study, patients with HCC evaluated at the
Medical Out-patient Department or admitted to the Medical wards of
the Nnamdi Azikiwe Hospital, Nnewi, were recruited. The study
lasted from June 2007 to May 2008. Subjects were clinically
evaluated and blood samples collected for HBsAg, anti-HCV and
HBeAg assays. The prevalence of HCC was 2.4%. Of the 60 patients
studied, 38 were males and 22 were females with male: female ratio of
2:1. Their ages ranged from 19-86 years with a mean age of 50.62 +/-
17.54. The mean duration of symptoms before presentation was 16
weeks and the mean duration from onset of symptoms to death was 20
weeks. Common presenting symptoms were painful right
hypochondrial mass, abdominal swelling, weight loss, early satiety
and fatigue, coagulopathy, ascites and hepatic encephalopathy.
Multiple lesions affecting both lobes of the liver were in 48 patients
on ultrasonography, 36.6% were positive for HBsAg of which 41%
were HBeAg positive. HCV antibodies were present in 8.3% of the
patients. Well-differentiated HCC of the pseudo-glandular variety was
the most common histological type. In conclusion, though well
differentiated, HCC presents late with clinical features of advanced
disease leading to death within 6 months. It is more often associated
with chronic HBV than HCV infection (8).
The clinical records of 482 patients who had been diagnosed as
having HCC during the period from January 1995 to March 2001 were
retrospectively reviewed. Sixty five patients with extrahepatic
metastases had more advanced intrahepatic tumors at the first
diagnosis of HCC: 73.8% of the patients with extrahepatic metastases
had tumors of intrahepatic tumor stage T3 or T4 according to the
TNM classification, while only 28.5% of the patients without
extrahepatic metastases had tumors of T3 or T4 (p<0.001). Vessel
508
invasion was detected at the first diagnosis of HCC more frequently in

the patients with extrahepatic metastasis (p<0.001). The frequent
metastatic sites were lung (53.8%), bone (38.5%), and lymph node
(33.8%). Other metastatic sites were the adrenal gland, peritoneum,
skin, brain and muscle. The median survival time and 1-year survival
rate were 7 months (range: 1-59 months) and 24.9%, respectively.
Patients with Child-Pugh grade B and C (p=0.0018) and patients with
positive serum AFP (p=0.011) had significantly poor prognosis. In
conclusion, the possibility of extrahepatic metastases and the clinical
features of extrahepatic metastases should be considered when
examining patients with HCC, particularly those with advanced
intrahepatic tumors to enable precise evaluation of the spread of HCC
and determination of the appropriate treatment (9).
Contrast-enhanced CT image through the abdomen prior to ethanol

ablation. The hepatocellular carcinoma is identified as an avidly enhancing
rounded mass within the liver (arrow).
After the diagnosis of HCC, 995 consecutive HCC patients were

followed up at the Department of Medicine and Molecular Science,
Hiroshima at regular intervals and 151 (15.2%) patients had
extrahepatic metastases at the initial diagnosis of primary HCC or
developed such tumors during the follow-up period. The most
frequent site of extrahepatic metastases was the lungs (47%), followed
by lymph nodes (45%), bones (37%), and adrenal glands (12%). The
cumulative survival rates after the initial diagnosis of extrahepatic
metastases at 6, 12, 24, and 36 months were 44.1%, 21.7%, 14.2%,
7.1%, respectively. The median survival time was 4.9 months (range,
0-37 months). Fourteen patients (11%) died of extrahepatic HCC,
while others died of primary HCC or liver failure. In conclusion, the
prognosis of HCC patients with extrahepatic metastases is poor. Many
patients would die of intrahepatic HCC and few of extrahepatic
metastases. Although most of HCC patients with extrahepatic
509
metastases should undergo treatment for the primary HCC mainly,

treatment of extrahepatic metastases in selected HCC patients who
have good hepatic reserve, intrahepatic tumor stage (T0-T2) and are
free of portal venous invasion may improve survival (10).
In total, 342 patients who had HCC with extrahepatic metastasis
were enrolled. The metastases were diagnosed at initial presentation
with HCC in 28 patients and during follow-up in the remaining
patients. The most frequent site of extrahepatic metastasis was the
lung followed by lymph nodes, bone, and adrenal glands. These
metastases were related directly to death in 23 patients (7.6%). The
median survival after diagnosis of extrahepatic metastasis was 8.1
months (range 0.03-108.7 months). In univariate analysis of the
training set (n=171), performance status, Child-Pugh classification,
the number and size of intrahepatic lesions, macroscopic vascular
invasion, symptomatic extrahepatic metastases, AFP levels, and
complete responses to treatment were associated significantly with
prognosis. Based on multivariate analysis, a scoring system was
developed to predict prognosis that assessed uncontrollable
intrahepatic lesions, extent of vascular invasion, and performance
status. This scoring system was validated in the testing set (n=171)
and produced a concordance index of 0.73. In conclusion, the
controllability of intrahepatic lesions and performance status were
identified as important prognostic factors in patients with advanced
HCC who had extrahepatic metastasis (11).
CT findings in 403 consecutive patients with HCC since 1992 were
reviewed retrospectively. Patients with extrahepatic metastatic HCC
(n=148) were identified, and the locations, sizes, and attenuation and
enhancement characteristics of the lesions were recorded. A majority
(128/148, 86%) of patients with extrahepatic HCC foci had either
intrahepatic stage IVA tumor (112, 76% patients) or an intrahepatic
stage III tumor (16, 11% patients) at the occurrence of metastases. The
most frequent site of the first detectable metastasis was the lung (58,
39% patients). Tabulation of all extrahepatic metastatic sites showed
the most common to be the lung in 81 (55%) patients, the abdominal
lymph nodes in 60 (41%) patients, and the bone in 41 (28%) patients.
In conclusion, the lung, abdominal lymph nodes, and bone are the
most common sites of extrahepatic metastatic HCC. Most extrahepatic
HCC occurs in patients with advanced intrahepatic tumor stage (stage
IVA). Incidental extrahepatic lesions at CT in patients with stage I or
II intrahepatic HCC are unlikely to represent metastatic HCC (12).
Twenty two patients were studied to determine the characteristics
of bone metastases of HCC. The diagnosis was established either
510
based on concomitant occurrence of malignant bone lesions and HCC

in the absence of other detectable malignant disease (n=15) or by
histological evidence of bone metastasis from an HCC (n=7). There
were 21 males and 1 female. Mean age was 62.5 years. Most patients
(88.2%) had chronic alcohol abuse. The bone metastases occurred as
the first manifestation of the liver cancer in half the cases (11/22).
Time interval between onset of bone symptoms and admission was
less than one month in 6 of 11 patients; mean interval was 7.4 weeks.
Hepatomegaly was in 9 of 11 patients. Pain was the main symptom of
bone disease (18/22). Palpable bone masses were in 6 of 22 patients.
Purely osteolytic lesions were seen on roentgenograms in every case;
rupture of the cortex and spread to adjacent soft tissues were common
findings. The radionuclide bone scan was normal in 4 of 12 patients.
An advanced primary hepatic tumor was in 84.2% of cases.
Histological examination of bone specimens established the diagnosis
of metastasis from a HCC in 7/9 patients (77.8%). Severe bleeding
occurred during 1/9 biopsy procedures. Patients were given
symptomatic treatment. Systemic chemotherapy was used in 5
patients, unsuccessfully. Median survival was 3 months (13).
A total of 673 patients with HCC during the period 1978-1997
were studied. Bone metastasis was screened by bone scintigraphy,
and bone lesions were confirmed by plain radiography, CT and/or
MRI. The serum levels of the C-terminal telopeptide of type 1
collagen, which represent osteoclastic bone resorption, were
measured. The incidence of bone metastasis during the decade 1988-
1997 was significantly higher than that during the period 1978-1987.
The median survival time of patients with HCC during 1988-1997 was
significantly longer than that during 1978-1987. Portal thrombus was
in about half of the patients with bone metastases. The most common
site of bone metastases was the vertebra followed by the pelvis, rib,
and skull. All bone lesions depicted by plain radiograph, CT and/or
MRI imaging were of the osteolytic type, and the serum levels of C-
terminal telopeptide of type 1 collagen were significantly elevated in
the patients with bone metastases. In conclusion, the increased
incidence of bone metastasis in HCC in the decade 1988-1997 is
attributed to the prolonged survival rate of HCC patients due to recent
progress in both the diagnosis and treatment of the disease.
Dissemination of HCC cells to the vertebra through the portal vein-
vertebral vein plexuses due to the presence of portal thrombus and/or
portal hypertension may be related to a higher incidence of bone
metastasis in HCC (14).
511
Fifty-three patients (84 lesions) with bone metastasis from a

primary HCC completed palliative RT. All patients underwent one of
following imaging studies prior to the initiation of RT: a bone scan,
CT or MRI. The median radiation dose was 30 Gy (7 approximately
40 Gy). Soft tissue formation at the site of bony disease was identified
from either a CT/MRI scan (41 lesions) or from a symptomatic
palpable mass (5 lesions). The adjustment of the radiation field size
based on a bone scan was necessary for 31 of 41 soft tissue-forming
lesions (75.6%), after a review of the CT/MRI scan. The median
survival from the initial indication of a hepatoma diagnosis was 8
months (2 to 71 months), with a 2-year survival rate of 38.6%. The
median survival from the detection of a bone metastasis was 5 months
(1 to 38 months) and the 1-year overall survival rate was 8.7%. In
conclusion, bone metastasis from a primary HCC is accompanied by
soft tissue formation. From this finding, an adjustment of the radiation
field size based on imaging studies is required. It is advisable to obtain
a CT or MRI scan of suspected bone metastasis for better tumor
volume coverage prior to the initiation of RT (15).
Spinal cord compression secondary to bone metastases from HCC
is unusual cause of metastatic HCC (16).
A 46-year-old male was diagnosed as HCC and was operated on by
trans-arterial embolization and lobectomy in 2004. He complained of
a painless mass over the left frontal region for 2 months. Radiograph
of the skull revealed an osteolytic mass about 4-5 cm in size over the
left frontal region. A cranial CT demonstrated a destructive lesion
with soft tissue mass over the left frontal region. A left frontal
craniotomy was performed and tumor was totally removed. The
histological diagnosis was cranial metastasis from HCC. Postoperative
recovery was uneventful without any neurological deficits. Because of
improved and advancing treatment for HCC, survival time for HCC
has been lengthened and distant metastases have increased. Skull
metastases from HCC should be considered as a differential diagnosis
in patients with scalp subcutaneous mass and osteolytic defect on X-
ray skull films (17).
A seventy-year-old man presented with bone pains. Investigation
revealed a metastatic bone lesion in the humerus. The primary was
found in the liver. The patient achieved good palliation with
chemotherapy and RT and survived for one year (18).
A 65-year-old man was presented with bone pain and anemia.
Skull X-ray revealed multiple osteolytic lesions. The patient was
evaluated for MM but detailed workup revealed the diagnosis of
primary HCC with osteolytic bone metastases (19).
512
A case of a 45-year old man with unusual metastases of HCC to

skull, sternum and ribs is reported (20).
Two cases of patients with bone metastases of HCC at presentation
are reported. Patient No. 1 with liver cirrhosis and HCC was admitted
with a bone metastasis in the rib. The patient was treated with hepatic
arterial chemotherapy and rib resection. Patient No. 2 had an
asymptomatic liver mass of uncertain histology for a year when he
presented with back pain. Because of signs of spinal compression,
laminectomy was performed, and the diagnosis of metastatic HCC
was established. The presence of bone metastases in HCC at
presentation is extremely rare. More frequently, bone lesions are
observed after successful treatment of the primary liver tumor. Both
surgery and RT are used as palliative treatment in bone metastases of
HCC. The treatment of HCC presenting with bone metastasis by bone
resection and intraarterial chemotherapy seems to be of limited effect
on patient survival because of dissemination of micrometastases in
other organs and the frequent presence of other comorbid conditions.
However, effective palliation using this multimodality approach is
feasible. HCC should be considered in the differential diagnosis of
bone metastases (21).
Assessment: HCC, the most frequent malignant tumor of the liver,

is the sixth most common cancer worldwide with a wide geographic
distribution, and is the third most common cause of cancer-related
deaths worldwide. The most common risk factors associated with
HCC are chronic hepatitis B and HCV infections, alcohol use,
smoking, non-alcoholic fatty liver, liver cirrhosis, and aflatoxin
exposure.
Clinical presentation includes anorexia, early satiety, abdominal
pain, loss of weight, abdominal swelling, fever, fatigue, jaundice,
hepatomegaly, ascites, coagulopathy, hepatic encephalopathy, raised
AFP, positive for HBsAg, positive for HBeAg, and positive for anti-
HCV.
The metastatic sites are lung, bone, lymph node, adrenal gland,
peritoneum, skin, brain and muscle, nasal septum, nasal cavity, heart,
skin, sigmoid colon, stomach, and epidural space. Bone metastasis
from a primary HCC can be accompanied by soft tissue formation.
The diagnosis of HCC is based on the serum AFP levels, imaging
techniques, and liver biopsy.
The longer survival is related to low serum bilirubin, AFP levels
and the lowest tumor mass. The prognosis of HCC patients with
extrahepatic metastases is poor.
513
Did the King suffer from HCC that spread to the bones? The
medical record of King David showed no data on the risk factors
associated with HCC. Among clinical signs anorexia, fatigue, and
weight loss can be identified (22). Thus, although HCC can
metastasize to the bones causing osteolytic lesions, in the absence of
abdominal pain, fever, jaundice, coagulopathy, underlying cirrhosis,
ascites, hepatic encephalopathy and appropriate investigation –
laboratory, ultrasonography, and/or CT of the abdomen and
histopathological findings, the diagnosis of HCC seems unlikely.
References
1. Kalinski T, Roessner A. Hepatocellular carcinoma: pathology and liver biopsy.
Dig Dis. 2009;27(2):102-8.
2. Ananthakrishnan A, Gogineni V, Saeian K. Epidemiology of primary and
secondary liver cancers. Semin Intervent Radiol. 2006;23(1):47-63.
3. Schütte K, Bornschein J, Malfertheiner P. Hepatocellular carcinoma--
epidemiological trends and risk factors. Dig Dis. 2009;27(2):80-92.
4. Saini N, Bhagat A, Sharma S, et al. Evaluation of clinical and biochemical
parameters in hepatocellular carcinoma: experience from an Indian center. Clin Chim
Acta. 2006;371(1-2):183-6.
5. Carr BI, Pujol L. Pain at presentation and survival in hepatocellular carcinoma.
J Pain. 2010;11(10):988-93.
6. Carr BI, Pancoska P, Branch RA. HCC in older patients. Dig Dis Sci.
2010;55(12):3584-90.
7. Fernández-Ruiz M, Guerra-Vales JM, Llenas-García J, Colina-Ruizdelgado F.
Hepatocellular carcinoma in the elderly: clinical characteristics, survival analysis, and
prognostic indicators in a cohort of Spanish patients older than 75 years. Rev Esp
Enferm Dig. 2008;100(10):625-31.
8. Okonkwo UC, Nwosu MN, Ukah C, et al. The clinical and pathological
features of hepatocellular carcinoma in Nnewi, Nigeria. Niger J Med. 2011;
20(3):366-71.
9. Natsuizaka M, Omura T, Akaike T, et al. Clinical features of hepatocellular
carcinoma with extrahepatic metastases. J Gastroenterol Hepatol.2005;20(11):1781-7.
10. Uka K, Aikata H, Takaki S, et al. Clinical features and prognosis of patients
with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol.
2007;13(3):414-20.
11. Uchino K, Tateishi R, Shiina S, et al. Hepatocellular carcinoma with
extrahepatic metastasis: clinical features and prognostic factors. Cancer. 2011;117
(19):4475-83.
12. Katyal S, Oliver JH 3rd, Peterson MS, et al. Extrahepatic metastases of
hepatocellular carcinoma. Radiology. 2000;216(3):698-703.
13. Maillefert JF, Tebib J, Aho S, et al. Bone metastasis of hepatocellular
carcinoma. Apropos of 22 cases. Rev Rhum Ed Fr. 1993;60(12):907-12.
14. Fukutomi M, Yokota M, Chuman H, et al. Increased incidence of bone
metastases in hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2001;
13(9):1083-8.
15. Kim S, Chun M, Wang H, et al. Bone metastasis from primary hepatocellular
carcinoma: characteristics of soft tissue formation. Cancer Res Treat.
2007;39(3):104-8.
514
16. Doval DC, Bhatia A, Vaid AK, et al. Spinal cord compression secondary to
bone metastases from hepatocellular carcinoma. World J Gastroenterol.
2006;12:5247-52.
17. Hsieh CT, Sun JM, Tsai WC, et al. Skull metastasis from hepatocellular
carcinoma. Acta Neurochir (Wien). 2007;149(2):185-90.
18. Doval DC, Rao CR, Acharya R, et al. Hepatocellular carcinoma metastatic to
bones (Case report with review of literature). Indian J Cancer. 1995;32(1):31-5.
19. Dovai DC, Bhatia K, Vaid AK, et al. Bone metastases from primary
hepatocellular carcinoma simulating multiple myeloma. Hepatobilliary Pancrear Dis
Int. 2005;4:308-10.
20. Shakya VC, Agrawal CS, Pandey SR, et al.Multiple skeletal metastases as
unusual manifestations of hepatocellular carcinoma in a noncirrhotic liver. Nepal Med
Coll J. 2010;12(3):198-200.
21. Melichar B, Voboril Z, Toupková M, Dvorák J. Hepatocellular carcinoma
presenting with bone metastasis. J Exp Clin Cancer Res. 2002; 21(3):433-6.
Israel. 2009, pp. 159-71.
PANCREAS CANCER
Pancreatic ductal adenocarcinoma is the fifth leading cause of
death among all malignancies, leading to approximately 40,000 deaths
each year in Europe (1). Ductal adenocarcinoma of the pancreas has
an incidence of approximately 10 per 100,000 populations per year.
This number pertains to Europe, North America and parts of South
America (Argentina) (2).
Adenocarcinoma of the pancreas (pancreatic cancer) is the most
frequent tumor entity in the pancreas (3). Although only 32,000 new
cases of adenocarcinoma of the pancreas occur in the US each year, it
is the fourth leading cause of cancer deaths in this country (2). The
overall five-year survival rate is 4%, and localized, resectable disease
has only a 17% survival rate (2,4).
Men are more often afflicted than women (male: female ratio is
about 1.5:1, though reports vary). There has been a very small but
steady increase in the incidence over the last 50 years. Unfortunately,
numbers for incidence and mortality are still practically identical for
this cancer. The peak of incidence is between 60 and 80 years of age.
In absolute numbers, there are 8,000 cases diagnosed annually in
Germany, and 33,000 in the US. Pancreatic cancer at < 40 years of age
is extremely rare (2 cases per million per year), but among 80-year-
515
olds, the incidence is about 200 new cases per 100,000 population per
year. In men, carcinoma of the pancreas is the fourth most common
cause of cancer death after lung, prostate and colorectal cancer. In
women, it is the fifth most common cause of cancer death (2).
Risk factors for pancreatic cancer include high-fat diet, smoking,
chronic pancreatitis, primary sclerosing cholangitis, hereditary
pancreatitis, family history of pancreatic cancer, diabetes mellitus, and
obesity. In chronic pancreatitis, the risk for pancreatic cancer is
increased 20-fold; in hereditary pancreatitis, it is 60-fold higher than
in the general population. In kindred with 2 first-degree relatives with
pancreatic cancer, the risk for pancreatic cancer for other members of
that kindred is 7-fold higher (2-7).
In the UK, adenocarcinoma of the pancreas is one of the top ten
leading causes of cancer deaths and around 8,000 people are
diagnosed with the disease each year. The incidence is similar in men
and women and rises with age. Rates increase significantly in people
aged ≥ 45 years and around three-quarters of patients diagnosed with
pancreatic cancer are the age > 65 years. Overall, the long-term
prognosis of the disease is poor with a one-year survival rate of
approximately 10-20% (5). In Germany, there are 8,000 cases of
pancreas carcinoma diagnosed annually (3). In Japan, cases of
pancreatic cancer have increased in number, and the number of deaths
from that disease has reached 20,000 in recent years. Only a few
patients with pancreatic cancer are cured (6).
The presenting symptoms are largely dependent on tumor location.
Approximately half of patients are diagnosed with a tumor within the
head of the pancreas and many of these will present with jaundice.
There are also a number of familial cancer syndromes which, although
rare, carry a significantly higher risk (5).
Pancreas anatomy
516
Typical symptoms of pancreatic cancer are jaundice, epigastric or

back pain, abdominal pain and weight loss (2,5,7). Most patients
present with obstructive jaundice caused by compression of the bile
duct in the head of the pancreas (2). Jaundice is the dominant
symptom in patients with biliary obstruction from carcinomas of the
pancreatic head area (8). The many symptoms usually associated with
prolonged biliary stasis (malnutrition, coagulopathy, pruritus
hepatocellular failure, renal dysfunction, and angiocolitis) are
commonly resolved or relieved by biliary drainage (8). More than
one-half of cases have distant metastasis at diagnosis (2).
Serum pancreatic enzyme and tumor markers in terms of CA 19-9
and CEA are measured first. Ultrasonography should be performed as
soon as possible. Not only tumors but also slightly dilated main
pancreatic ducts and/or small simple cysts that may represent indirect
changes due to pancreatic cancer can be detected with
ultrasonography. Enhanced CT, magnetic resonance
cholangiopancreatography and endoscopic ultrasonography are useful.
ERCP yields more detailed images of branch ducts, and the cytology
of pancreatic juice can be determined following examination.
Unfortunately, PET is unreliable method for the diagnosis of small
tumors in the pancreas. Finally, TNM staging of pancreatic cancer is
performed based on the results of these imaging examinations (2,5,6).
Pancreas cancer cell
Diagnosis of pancreatic cancer is made late, and prognosis remains

extremely poor. This study was carried out to investigate whether
symptoms exist before pain or jaundice that could suggest pancreatic
cancer and favor earlier diagnosis. The study involved 305 patients
with confirmed pancreatic cancer and 305 controls. All subjects were
interviewed personally at least twice about their clinical history;
pancreatic cancer patients were asked about any disturbances before
517
abdominal pain or jaundice. Of the 305 pancreatic cancer patients, 151

(49.5%) had some prior disturbances, 108 (35.4%) 6 months or less
before pain or jaundice and 43 (14.1%) more than 6 months before.
Among the latter, 14 (4.6% of all patients) had had anorexia and/or
early satiety and/or asthenia (7-20 months before pain or jaundice), 11
(3.6%) had disgust for coffee, and/or smoking, and/or wine (7-20
months before), 14 (4.6%) had diabetes (7-24 months before), and 4
(1.3%) had acute pancreatitis (8-26 months before). Among the
controls, the only reports of these symptoms were 2 (0.7%) cases of
asthenia (4 and 6 years earlier), 22 (7.2%) cases of diabetes, of which
only 2 (0.7%) were diagnosed 7-24 months before the interview, and 1
(0.33%) case of acute pancreatitis (10 years earlier). Apart from acute
pancreatitis, all the other differences between patients and controls
were statistically significant. In approximately 15% of patients,
disturbances existed more than 6 months before pain or jaundice,
which, although not specific, could raise suspicion of the possibility of
pancreatic cancer. These disturbances could represent the one current
opportunity for an earlier diagnosis in a significant minority of
pancreatic cancer patients (9).
CT of abdomen
Cancer of the pancreas is a typical and frequent disease of the

elderly. The prognosis is bad and one-year life expectancy is about
11%. One of the reasons is that early symptoms are missing. Specific
symptoms like pain, weight loss or jaundice occur lately. Diagnostic
evaluation includes CT, MRCP, ultrasonography, ERCP and PET in
addition to the specific tumor markers CA 19-9 and CEA (10).
Stage of primary malignancies, interval between diagnosis of
primary tumors and detection of pancreatic metastases, treatment for
metastases to the pancreas, survival rate and prognostic factors in 31
patients with pancreatic metastases were studied. The mean age at the
time of primary cancer diagnosis was 52.4 ± 13.2 years. Primary
518
cancers were RCC (n=16), non-small cell lung cancer (n=6), small cell
lung cancer (n=3), CRC (n=2), osteosarcoma (n=1), gastric carcinoma
(n=1), malignant melanoma (n=1), and thymic carcinoma (n=1).
Pancreatic metastases were synchronous in 6 cases and metachronous
in 25 cases, with median interval time of 40.8 months (range 3-186)
between the diagnosis of primary tumor and detection of pancreatic
metastases. The median survival after the detection of the metastases
was 16 months. In multivariate analysis, non-RCC as primary
malignancy and positive symptom related to pancreatic metastases
were associated with poor prognosis (HR 8.33, 95% CI 2.1-33,
p=0.003, and HR 4.02, 95% CI, 1.27-12.7, p=0.018). In conclusion,
metastatic tumors to the pancreas have to be kept in mind when a
patient with pancreatic mass has a history of other malignancy, even if
treated several years before. In the absence of widely metastatic
disease, aggressive diagnostic and therapeutic approach may offer the
chance of long-term survival in selected patients (11).
The records of patients with pancreatic metastasis managed in the
Paris area were reviewed between 1990 and 2000. The series analyzed
included 22 patients, 10 men and 12 women, mean age 61 years
(range: 35-76). The primary tumors were RCC (n=10), CRC (n=4),
lung cancer (n=4), breast cancer (n=2), cutaneous melanoma (n=1)
and ileal carcinoid (n=1). The mean interval between primary
treatment and presentation was 73.5 months (range: 2-151). Diagnosis
was established because of clinical symptoms (n=15) or during
surveillance (n=7). CT (n=19) and EUS (n=18) mainly showed
solitary and hypodense/or hypoechoic masses. Histological diagnosis
was obtained before surgery by EUS-guided FNA (n=6),
ultrasonography-guided biopsy (n=3) or duodenoscopy (n=3). Among
10 patients with primary RCC, 7 were treated by surgery. Median
global survival was 33 months. Median survival was 61 months in the
event of surgical treatment and 20 months in the other patients (NS).
Mean survival depended on the type of primary tumor, 61 months for
RCC and 33 for CRC (p=0.06). In conclusion, most pancreatic
metastases develop from RCC and can occur several years after
nephrectomy. Histological diagnosis is often obtained before surgery.
Surgical resection can allow long-term survival (12).
Symptom-producing bone metastases are relatively uncommon; the
vast majority is osteolytic in nature with only a few isolated case
reports of purely blastic deposits. Of 12 patients with symptom-
producing bone deposits secondary to adenocarcinoma of the
pancreas, 5 (41.6%) were purely blastic in nature. The pancreas is a
potential source of purely blastic bone metastases and should be
519
considered as a possible primary site in patients who present initially

with osteoblastic bone deposits of unknown origin (13).
A patient was presented with large bowel obstruction due to
splenic flexure mass, which proved to be due to pancreatic mucinous
adenocarcinoma. Pancreatic adenocarcinoma can rarely have the same
presentation as colon cancer, and should therefore be considered in the
differential diagnosis of large bowel obstruction (14).
An abdominal CT scan shows a small, vaguely seen 2-cm pancreatic

adenocarcinoma (mass) causing obstruction of both the common bile duct
(cbd) and pancreatic duct (pd).
A 72-year-old man was admitted to the hospital after detection of a

tumor in the pancreatic tail by CT imaging. Several images revealed
that he suffered from cancer of the tail of the pancreas with multiple
liver and bone metastases. Endoscopic ultrasonography-guided FNA
detected adenocarcinoma cells from the tumor of the pancreatic tail.
Bone marrow aspiration confirmed adenocarcinoma cells in the bone
marrow. Gemcitabine weekly 1,000 mg/m2 was started. Laboratory
data revealed thrombocytopenia that developed into DIC after the first
the administration of gemcitabine. In spite of the DIC state with
thrombocytopenia, anticancer treatment using combination
gemcitabine and S-1 was provided. He recovered from his DIC state,
and the primary tumor was shrunk with a decrease of tumor markers
after 2 courses of combination chemotherapy (15).
Pancreatic cancer may cause osteolytic metastases, but the
osteoblastic ones are extremely rare. It usually presents with
symptoms related to the invasion of the structures in the abdomen. A
case of pancreas body cancer was presented with severe back pain due
to an osteoblastic lesion to L3 vertebra. Biopsy of the vertebra led to
the diagnosis. Radiographs, CT, MR, scintigraphy images as well as
pathology slices confirmed the diagnosis. The present case raises the
issue that pancreatic cancer, as a cause of an osteolytic bone lesion,
should not be overlooked in an unknown primary investigation (16).
520
Skeletal metastases represent an underappreciated site of

metastasis in patients with pancreatic cancer. Previous reports have
estimated the prevalence to range from 5-20%. With the use of
gemcitabine and novel targeted agents such as erlotinib, there has
been a modest increase in survival in patients with advanced
pancreatic cancer. As such, it is anticipated that previously uncommon
occurrences such as skeletal metastases will become more frequent. A
retrospective chart review was conducted at 2 academic institutions to
identify pancreatic cancer patients with skeletal metastases over a
two-year period. Seven patients were identified from a database of
323 patients (2.2%). All patients had advanced disease and had
received prior systemic therapy (range 1-4 lines, median 2 lines).
Approximately half (57.1%) of the patients were symptomatic from
their skeletal metastases. The most common sites of skeletal
metastases were vertebrae (100%), hips (57.1%), and ribs (57.1%).
Both blastic and lytic lesions were noted, with a predominance of
blastic lesions (71.4%). A majority of patients (71.4%) received
bisphosphonates as part of their care. In conclusion, skeletal
metastases are an uncommon but clinically important occurrence in
patients with pancreatic cancer. Clinicians caring for patients with
pancreatic cancer should be alert regarding skeletal metastases, due to
the morbidity it can cause for these patients (e.g., back pain, fractures,
etc.) (17).
An unusual case of purely osteoblastic metastasis in the spine from
adenocarcinoma of the pancreas was reported. Severe LBP with
osteoblastic lesions in a lumbar X-ray study were the initial
manifestations. A percutaneous transpedicular vertebral bodies biopsy
was performed and showed a metastatic adenocarcinoma. This clinical
presentation is unusual and the diagnosis of pancreatic carcinoma
should be considered when radiographs or bone scans show
osteoblastic bone lesions (18).
The prognosis of pancreatic carcinoma depends mainly on radical
surgery and the presence of negative resection margins, as well as on
the biological tumor stage, which also influences the treatment
strategy (7).
Prognosis of pancreatic cancer is one of the worst among other
cancers; however, the incidence of the bone metastases has been
increased in recent years. Among 13 patients diagnosed with
pancreatic cancer at National Kyushu Cancer Center, Japan,
pancreatic cancer was located at pancreatic body to tail in 10 cases,
and at pancreatic head in 3 cases. Liver metastases were noted in 7 of
13 patients with bone metastases. Radiographical imaging of bone
521
lesions revealed osteolytic bone destruction, and serum levels of bone

resorption marker, 1CTP, were elevated (19).
After diagnostic is completed, curative resection is possible in only
a low percentage of all cases. Old age is not contraindication for
surgery; prognosis and the risk of surgery do not differ from other age
groups. In most case, palliative therapy is the only possible option
because of an advanced tumor stage. Sufficient pain therapy,
endoscopic stenting in case of obstructive jaundice or
gastroenterostomy in case of duodenal are useful interventions (10).
Treatment of pancreatic cancer is undertaken with 2 aims. Radical
surgery is indicated for patients with early stage of disease, mainly in
stage I and partially II. In all other cases, the aim of treatment is the
palliation of different very distressing symptoms related to this
neoplasm (7).
Stage, grade and resection margin status are currently accepted as
the most accurate pathologic variables predicting survival. All
classification systems fail prognostically to distinguish between
different stages. Even in patients with seemingly early tumors (T1,
N0), the likelihood of relapse is high. This reflects the shortcomings
of the pathologic staging to sufficiently discriminate patients with a
high risk to develop tumor recurrence from those that carry a lower
risk. On the other hand, none of the currently used systems includes or
takes into consideration the role of disseminated tumor cells neither in
the lymph nodes nor in the bone marrow. Occult residual tumor
disease is suggested when either bone marrow or lymph nodes, from
which tumor relapse may originate, are affected by micrometastatic
lesions undetectable by conventional histopathology. For detection,
antibodies against tumor-associated targets can be used to detect
individual epithelial tumor cells both in lymph nodes and in bone
marrow. The clinical significance of these immunohistochemical
analyses is still controversial. Various monoclonal antibodies are still
in use for micrometastatic detection, thus contributing to the
incongruity of data and validity of results. These assays have been
rarely used in patients with pancreatic carcinoma. In conclusion, the
presence or absence of lymph-node metastases can predict the
likelihood of survival for most, if not all, patients with pancreatic
ductal adenocancer and the likelihood that metastases will develop at
distant sites (1).
While the results of surgical therapy of pancreatic cancer were
disappointing in the past due to high perioperative mortality rates,
resection of pancreatic cancer nowadays represents the standard
treatment for non-metastatic cancer with a mortality rate below 5%.
522
This decrease in perioperative mortality of the Whipple operation is

inversely correlated to the caseload of the hospital and the responsible
surgeon, and is mainly related to improvements in the intensive care
management, the surgical technique and patient selection. In
particular, the perioperative use of octreotide resulted in a significant
decrease in the rate of pancreatic fistula. Furthermore, modern staging
examinations such as diagnostic laparoscopy, PET, or endoscopic
ultrasonography resulted in improved patient selection. In addition,
the long-term results of the surgical treatment of pancreatic cancer has
been improved by adjuvant and neoadjuvant chemotherapy in the past
10 years. Similar progress has been made in the palliative treatment of
metastatic or locally advanced cancer. Nowadays, endoscopic
procedures can replace surgical palliation of obstructive jaundice in
most cases and sometimes even gastric outlet obstruction. Moreover,
systemic chemotherapy using gemcitabine-based protocols has
resulted in a significant prolongation of survival. An interdisciplinary
management of this disease can achieve further progress in the
treatment of pancreatic cancer (1).
The majority of tumors are not surgically resectable because of
metastasis and invasion of the major vessels posterior to the pancreas.
Resectable tumors are treated with the Whipple procedure or the
pylorus-preserving Whipple procedure. Adjuvant fluorouracil-based
chemotherapy may prolong survival. For nonresectable tumors,
chemotherapy with gemcitabine prolongs survival. RT combined with
chemotherapy has slowed progression in locally advanced cancers.
Throughout the illness and during end-of-life care, patients need
comprehensive symptom control (2).
Palliation is frequently the only feasible treatment in these patients
due to the biological aggressiveness of these tumors characterized by
the early infiltration of adjacent tissues. Endoscopic and percutaneous
procedures of biliary recanalization, effective as those of surgical
palliation, are more comfortable to the patients and burdened with a
lower morbidity and mortality. In selected patients, palliation of
jaundice can be combined with intraluminal RT or pancreatic drainage
the latter aimed at the relief of the "obstructive" pain present in some
patients with carcinoma of the area of the head of the pancreas (8).
Assessment: adenocarcinoma of the pancreas is the most frequent

tumor entity in the pancreas. The peak of incidence is between 60- and
80 years of age. Men are more often afflicted than women (male:
female ratio is about 1.5:1). Risk factors for pancreatic cancer include
523
high-fat diet, smoking, chronic pancreatitis, hereditary pancreatitis,

primary sclerosing cholangitis, diabetes mellitus, and obesity.
Typical symptoms of pancreatic cancer are abdominal, and/or back
pain, weight loss, and jaundice. Symptoms that usually associated
with prolonged biliary stasis (malnutrition, coagulopathy, pruritus
hepatocellular failure, renal dysfunction, and angiocolitis) are
commonly resolved or relieved by biliary drainage. Skeletal
metastases represent an underappreciated site of metastasis in patients
with pancreatic cancer. The most common sites of skeletal metastases
are vertebrae, hips, and ribs. Both blastic and lytic lesions are noted.
Serum pancreatic enzyme and tumor markers include CA 19-9 and
CEA measurements. CT, ultrasonography, MRI, and ERCP can
provide additional information.
Did the King suffer from pancreatic carcinoma with metastases to
the bones? Although the King suffered from anorexia, early satiety,
weight loss, and bone pain (20,21), in the absence of risk factors for
pancreatic carcinoma, as well as abdominal and/or back pain,
jaundice, pruritus, hepatocellular failure, ascites, and appropriate
laboratory tests, radiological investigations and histopathological data,
this diagnosis seems unlikely.
References
1. Bogoevski D, Strate T, Yekebas EF, Izbicki JR. Pancreatic cancer: a
generalized disease - prognostic impact of cancer cell dissemination. Langenbecks
Arch Surg. 2008;393(6):911-7.
2. Krejs GJ. Pancreatic cancer: epidemiology and risk factors. Dig Dis.
2010;28(2):355-8.
3. Heinrich S, Schäfer M, Bauerfeind P, et al. Current diagnosis and treatment of
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Gakkai Zasshi. 2006;107(4):164-7.
7. de Braud F, Cascinu S, Gatta G. Cancer of pancreas. Crit Rev Oncol Hematol.
2004;50(2):147-55.
8. Costamagna G, Cotroneo AR, Mutignani M, et al. Carcinoma of the pancreatic
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9. Gullo L, Tomassetti P, Migliori M, et al. Do early symptoms of pancreatic
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524
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study of 22 patients. Gastroenterol Clin Biol. 2004;28(10 Pt 1): 872-6.
13. Joffe N, Antonioli DA. Osteoblastic bone metastases secondary to
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15. Nakamura K, Takamori H, Nakahara O, et al. A case of cancer of the
pancreatic tail with disseminated carcinomatosis of the bone marrow. Gan To Kagaku
Ryoho. 2012;39(8):1275-7.
16. Pneumaticos SG, Savidou C, Korres DS, Chatziioannou SN. Pancreatic
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fasting, my flesh failed of fatness,.. my bones cleave to my skin". In Ben-Nun L ed.
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525
UROLOGICAL MALIGNANCIES
RENAL CELL CARCINOMA

RCC represents 2-3% of all cancers and more than 50% of these
are detected incidentally (1,2). In Europe, renal cancer (that is
neoplasia of the kidney, renal pelvis or ureter) ranks as the seventh
most common malignancy in men amongst whom there are 29.000
new cases each year (3.5%) of all cancers (3).
Smoking, obesity, and end-stage renal disease are important risk
factors. Localized RCC may be cured with surgical excision.
However, over one-third of patients eventually develop metastatic
disease (4).
Metastases to bone occur in 35-40% of patients, second in
prevalence of metastases only to the lungs. These metastases are
highly destructive, while hypervascular tumors are difficult to manage
(2). Skeletal involvement is commonly an aggressive, lytic process
that causes substantial morbidity through skeletal complications and
occurrence of SREs (5).
A review of 23 cases with RCC was undertaken. The sex
distribution was 3.6 males to 1 female, with the male preponderance
higher than in most reported series. The RCC was most common in
the 6th and 7th decades of life. Hematuria was the commonest
presenting symptom (52.2%); however, all the features of the classical
triad of hematuria, loin pain and swelling were not present in any of
the patients; 26% of patients presented with non-urological symptoms.
At the time of diagnosis, 4 patients (17.3%) had evidence of
metastasis, while another 4 developed metastases after nephrectomy.
All 23 patients, including those with metastasis, were treated by
nephrectomy (6).
RCC may remain clinically occult for most of its course. The
classic presentation of pain, hematuria and flank mass occurs in only
9% of patients and is often indicative of advanced disease.
Approximately 30% of patients with RRC present with metastatic
disease, 25% with locally advanced RCC and 45% with localized
disease. Metastases are typically found in the lung, soft tissue, bone,
liver, cutaneous sites, and CNS (3).
This longitudinal retrospective study included 42 patients with
clinical and histological diagnosis of RCC, evaluated at Manuel
Fajardo University Hospital, Cuba, between July 2002 and September
2007. There was a predominance of men over women; the age of
526
greater incidence was between the fifth and seventh decades. The
tumors were classified as: asymptomatic 27%; symptomatic 67%,
with flank pain 31%; with hematuria 24%, tumor 10%, the classic
triad of hematuria, flank pain and mass 2.3% and with paraneoplastic
syndrome 24%. The patients with non-metastatic disease 57%, and
43% presented metastases. 5-year survival for patients with RCC by
TNM stage was T1 - 100%, T2 - 97%, T3 - 36%, T4 - 0%. The
survival of localized and metastatic RCC was 95%, and 22% of cases,
respectively, and in all stages 64%. In conclusion, the asymptomatic
RCCs were smaller; pain, hematuria, and mass were the most common
manifestations in symptomatic RCC. The prognosis is dismal in
patients with RCC showing paraneoplastic syndromes (7).
This study population included 803 patients with advanced or
metastatic RCC treated in a tertiary centre, Section of Oncology and
Clinical Research, Leeds, UK, serving a regional population of 2.6
million between 1998 and 2007. Of the study population, 254 (32%)
patients presented with (n=131) or later developed (n=123) bone
metastases and 83% of these (n=210) developed metastases elsewhere.
The mean number of SREs experienced by the bone metastatic
patients over the course of their disease was 2.4 and 37 patients
experienced no SREs. A high proportion of patients (80%) received
RT for bone pain and there was a high incidence of spinal cord/nerve
root compression, which was experienced by 28% patients. Although
bisphosphonate use increased following the availability of zoledronic
acid in 2004, approximately 50% patients with bone metastases did
not receive bisphosphonate treatment. The skeletal morbidity rate
(number of SREs per patient years at risk) was 1.0 and 1.4 for patients
who received or did not receive bisphosphonates, respectively. The
median survival following diagnosis of RCC was similar in patients
who developed bone metastases (20.4 months) and those who did not
(20.9 months). Median survival from diagnosis of metastases was 13.3
months for those who never developed bone metastases, 10.6 months
for those who presented with them, 19.6 months for those who
developed them later and 22.6 months for patients who had only bone
metastases (5).
Twenty-nine cases of bone metastases from RCC were examined.
Eight had metastatic bone pain as the initial symptom and were
diagnosed with the primary lesion in a kidney. In 8 cases, bone
metastases appeared after treatment of the primary site. Seven had
only bone metastases and another 22 cases had multiple metastases in
organs such as the lung and lymph node when the bone metastasis was
found. Curable surgical treatment was performed in only 2 cases. The
527
survival curves of these patients were: 1 year - 41%, 2 years - 30%

and 3 years - 15%. Bone scan used for detection of bone metastases of
carcinoma frequently ends with false positive results. CT scan and
angiography are available for differential diagnosis of bone
metastasis. Six cases (9 lesions) of bone metastases from RCC (3
pelvic bones, 2 lumbar bones, 2 femurs and 2 humerus) were
examined. All lesions were hypervascular by angiography and were
easily diagnosed as bone metastases. For early detection of bone
metastases from RCC, angiography is useful because hypervascularity
and tumor stain are easily detected even in such small lesions as 2 cm.
Angiography was useful for chemoembolization (8).
Renal adenocarcinoma findings from 307 autopsied cases with
metastasis to 1 and 2 organs were investigated concerning the mode of
metastasis. The lung was the most frequent site of metastasis to one
organ, although the frequency was rather low (30%), followed by
bones (over-all), lymph nodes (over-all) and brain, and involving
frequently the thoracic spine and retroperitoneal lymph nodes. In
patients with metastases to 2 organs, a significant correlation was
found between the pulmonary-tracheal lymph nodes and those to the
lungs. Potential indications for treatment of metastatic lesions were 1)
lymphadenectomy and/or RT for the retroperitoneal and para-aortic
lymph nodes and 2) resection of metastatic lesions in the lungs
combined with lymphadenectomy and/or RT for the pulmonary-
tracheal lymph nodes. In conclusion, in patients without lung
metastasis lymphadenectomy and/or RT for the pulmonary-tracheal
lymph nodes is not always necessary (9).
A 71-year-old man underwent a radical nephrectomy for right RCC
in April 2005. Pathological findings revealed clear cell carcinoma,
G3＞G2, pT3a. Three years later, he underwent a craniotomy for
tumor resection of solitary brain metastasis. In October 2008, he came
to the hospital because of urinary retention. BPH was diagnosed by
ultrasonography and digital rectal examination. Serum PSA level was
2.55 ng/dl. While he was treated with oral α 1-blocker initially, a
urethral catheter was inserted in December 2009. Because of frequent
obstruction of the catheter by hematuria, transureathral prostatectomy
was performed. Pathological findings revealed prostatic metastasis
from RCC (10).
The patient was a 74-year-old man. CT detected a right renal tumor
with paraaortic lymph node swelling. Radical nephrectomy and left
lymphadenectomy were performed in September 2008. Interferon-
alpha (6 million international units 3 times per week) was
administered as adjuvant therapy. Due to the development of side
528
effects, including fatigue, the patient's immunotherapy was

discontinued after 6 months. Radiofrequency ablation for pulmonary
metastasis was performed 9 months after surgery. A nodular
pedunculated tumor was detected on the posterior wall of the urinary
bladder by CT, and transurethral resection was performed 18 months
after nephrectomy/lymphadenectomy. Since the pathological
diagnosis of the bladder tumor was clear cell carcinoma, the tumor
originated from the RCC (11).
CT. Renal carcinoma MRI. Renal carcinoma
A 73-year-old man presented with gross hematuria.

Ultrasonography and CT showed small bladder tumors and a left renal
mass protruding to renal pelvis. Transurethral resection of bladder
tumor and ureteroscopic tumor biopsy were performed, and
pathological examinations revealed transitional cell carcinoma in the
bladder and RCC in the kidney. He underwent left radical
nephrectomy. A 4-month postoperative cystoscopy revealed a solitary
non-papillary tumor in the bladder. Transurethral resection was
performed and pathological diagnosis was metastasis from RCC. At
that time, multiple metastases to ureteral stump and lung were found.
He had undergone palliative treatment because of his poor general
condition until he died 26 months postoperatively. In conclusion, care
should be taken for management of ureteral stump when diagnostic
ureteroscopy was performed for RCC invading the renal pelvis (12).
A patient was disease free for 33 years from initial nephrectomy
for treatment of primary RCC to discovery of metastatic disease to the
pelvis. Search for an unknown primary was performed, consisting of a
complete blood count, chemistry, ALP, calcium, serum and urine
protein electrophoresis, immunoglobulin levels, PSA, liver function
tests, bone scan, and chest, abdomen and pelvis CT scans. This
workup was negative for any other primary source of malignancy, and
the patient's remaining kidney was found to be free from any tumor
burden. The patient successfully underwent excisional biopsy of the
529
lesion, which proved to be vascular in nature, consistent with the final

pathology of RCC. The longest amount of time from completion of
treatment for the primary RCC to discover the first metastatic disease
has previously been reported at 22.3 years. Mean interval between
primary treatment and discovery of metastases has been defined as 3.0
+/- 5.4 years. This article highlights the need for advanced medical
workup as well as maintaining a high clinical suspicion in patients
with remote histories of primary malignancies who present with bony
lesions (2).
The case of a 56-year-old male patient with asynchronous isolated
metastases to the ureteral stump and bladder from RCC is presented.
Ureteral metastasis was discovered 2 years after nephrectomy.
Cystoscopy and MRI were performed. An excision of the ureteral
stump with a cuff of bladder was carried out. No other metastasis was
observed. Six months later a transurethral resection was performed on
account of metastasis of the right wall of the bladder. Pathological
examination demonstrated a RCC metastasis. After 6 months, a new
vesical metastasis from RCC was found. The small nodule of the
lower part of the right wall of the bladder was removed (13).
A rare case of ureteral stump metastasis 3 months after
nephrectomy for a RCC is presented. A 62-year-old female had
undergone right radical nephrectomy 3 months earlier because of
RCC, and she came back due to gross hematuria. Cystoscopy revealed
a papillary mass with a vascular pedicle protruding from the right
ureteral orifice. Transurethral resection of the bladder tumor over right
ureteral orifice was performed and the pathologic result showed clear
cell adenocarcinoma, which argued in favor of a metastatic lesion
from the previous RCC. Ureterectomy and a bladder cuff excision
were adopted for this patient, but no residual tumor was found over
the remaining ureter. Nevertheless, the patient died of cancer 36
months after the event of ureteral stump metastasis (14).
A 48-year-old woman was referred to the hospital with a bladder
mass which was detected by a GP. Ultrasonography showed a small
bladder tumor and right renal mass. Cystoscopy revealed a solitary,
non-papillary tumor at the right side of the retro-trigone. CT revealed
a large tumor at the right kidney. Transurethral resection of the
bladder tumor was performed. The histopathological diagnosis was
clear cell carcinoma. There was no other distant metastasis.
Sequentially, radical nephrectomy was performed.
Histopathologically, the right renal tumor showed clear cell
carcinoma. This was a case of a solitary metastatic bladder tumor from
RCC (15).
530
Small renal masses are defined as renal masses less than 4 cm in

diameter. They comprise a heterogeneous group of lesions; 20% are
benign and only 20-25% prove to be potentially aggressive kidney
cancers at the time of diagnosis. Work-up involves a full history,
looking for evidence of paraneoplastic syndromes and examination,
which is usually normal. Recommended blood tests include basic
biochemistry, hematology, and imaging. A four phase contrasted CT
scan of the kidneys allows a detailed examination of each aspect of the
functional anatomy of the kidney, which can help approximate risk of
malignancy and direct management. Not all patients with small renal
masses require a biopsy. However, biopsy is required in patients who
opt for active surveillance or ablative therapy. Management options
include surveillance, surgery and ablative techniques (1).
Of 42 cases of bone metastasis from RCC, 30 had bone metastases
at the time of RCC diagnosis. Bone metastasis appeared after
treatment of the primary site in 12 cases. Fifteen cases had only bone
metastasis and another 27 had metastasis in multiple organs. The total
cause-specific survival curve of these patients was 10% at 5 years. All
patients with bone metastases died of cancer within 5 years after the
bone metastases had developed. There was insignificant difference in
the survival rate between patients with bone metastases and patients
with lung metastases. The prognostic value of laboratory studies in
bone metastases of RCC was investigated. However, insignificant
markers were detected for bone metastases. Patients were treated with
decompressed laminectomy (2), wide resection (3) and excision of the
metastatic lesions (3). The QOL was improved in all the patients
although they died of cancer (16).
In Nagasaki, bone scan was performed at presentation in 205
patients with confirmed RCC. Overall, bone metastasis was present in
34 (17%) of the patients (17).
Data on 94 RCC cases with bone metastasis treated at 3 tertiary
referral centers in Tokyo were collected. There were 64 males with a
median age of 63.9 years. Histological diagnosis showed clear cell
RCC in 63 patients, nonclear cell RCC in 7 and unclassified cancer in
6. Sarcomatoid differentiation was in 17 cases. Metastasis was
detected synchronously in 37 patients or metachronously at a median
interval of 33.1 months. Multivariate analysis identified sarcomatoid
differentiation (p=0.001), vertebral bone involvement (p=0.003), and
extraosseous metastasis (p=0.021), ALP increased to 1.5 times the
upper limit of normal (p=0.0003) and CRP increased to greater than
0.3 mg/dl (p=0.018) as significant risk factors. Cases were classified
into 3 groups based on the number of risk factors, including low risk -
531
28 with 0 or 1 risk factor, intermediate risk - 26 with 2 risk factors and

high risk - 40 with 3 to 5 risk factors. This grouping clearly separated
survival among these groups (each, p<0.001). The risk classification
incorporating 5 risk factors enables accurate prediction of survival,
which can be helpful to make clinical decisions in cases of RCC with
bone metastasis (18).
Acute flank pain is a common ED presenting symptom, and
bedside ultrasonography is being used increasingly in its evaluation.
Emergency renal ultrasonography concentrates on the focused
presence or absence of hydronephrosis as is often seen in patients with
acute flank pain secondary to renal colic. Three cases in which other
abnormal sonographic signs indicate RCC. Baseline knowledge of
sonographic characteristics of tumors will benefit the occasional
emergency patient who has unsuspected RCC (19).
The subjects of this study were 38 patients with bone metastasis
out of 124 cases of primary RCC. Histopathological investigations of
primary lesions indicate a tendency for bone metastasis in alveolar-
type, solid (sarcomatoid)-type and mixed-type tumors classified on the
basis of histological structure, for granular cell subtype classified by
cell type, and for grades III and IV classified by nuclear grading.
Although RT and tumor artery infusion therapy were performed for
metastatic bone lesions, insignificant improvements were found (20).
Skeletal metastases in 19 patients with bone lesions who received
either moderate- or high-dose IL-2 therapy were evaluated. Skeletal
metastases resulted in significant morbidity by causing pain (75%)
and other complications requiring surgical and/or RT intervention
(94%) before beginning IL-2 therapy. In most patients, the response of
bone lesions to IL-2 was similar to that in their other systemic sites.
Treatment with IL-2 had insignificant effect on the requirement for
pain medication for bone pain. However, it may have prevented
skeletal complications requiring surgery or RT. None of the patients
had hypercalcaemia; there was insignificant association between bone
metastases and elevated ALP levels. In conclusion, skeletal metastases
are a significant contributor to morbidity among patients with RCC.
Bone lesions respond similarly to IL-2 therapy as other systemic sites.
Bisphosphonates appear promising for these predominantly osteolytic
lesions (21).
While chemotherapy and RT are relatively ineffective for RCC,
immunotherapy modestly extends survival and may lead to tumor
regression in a small minority of patients. Recently, research into the
pathology of genetic syndromes associated with RCC has led to
remarkable advances in our understanding of the pathogenesis of
532
sporadic RCC. Rational therapeutic agents developed from this

understanding have established new treatment paradigms for this
disease (22).
Assessment: RCC represents 2-3% of all cancers and more than

50% of these are detected incidentally. RCC is most common in the
6th and 7th decades of life. Risk factors include smoking, obesity, and
end-stage renal disease.
Clinical symptoms include hematuria, loin pain, or swelling
although RCC may remain clinically occult for most of its course, and
even in the advanced stages of the disease the classical presentation of
pain, hematuria and flank mass occur in only 9% of patients.
Histological diagnosis shows clear cell RCC, nonclear cell RCC,
and unclassified cancer.
Approximately 30% of patients with RRC at diagnosis present with
metastatic disease, 25% with locally advanced RCC and 45% with
localized disease. Metastases are typically found in the lung, soft
tissue, bone, liver, lymph nodes, cutaneous sites, and CNS. RCC can
also metastasize to prostate, urinary bladder, uretheral stump, and
ureteral stump + bladder. Skeletal metastases occur in around one
third of patients with advanced or metastatic RCC. Skeletal
involvement is commonly an aggressive, lytic process, which causes
substantial morbidity through skeletal complications and occurrence
of SREs. Metastases to bone are highly destructive, with
hypervascular tumors difficult to manage.
Was RCC responsible for the bone metastases in the King David?
We see that RCC is a malignant disease, which spreads to the bones.
Since RCC may manifest itself even without overt clinical symptoms,
severe intractable bone pains in the King's case may indicate RCC
with metastases to the bones.
References
1. Roy. Rao K, Royce PL. Incidentally detected small renal masses -
investigation and management. Aust Fam Physician. 2011;40(10):776-82.
2. Parada Parada SA, Franklin JM, Uribe PS, Manoso MW. Renal cell carcinoma
metastases to bone after a 33-year remission. Orthopedics. 2009;32(6):446.
3. Corgna E, Betti M, Gatta G, et al. Renal cancer. Crit Rev Oncol Hematol.
2007;64:247-62.
4. Nelson EC, Evans CP, Lara PN Jr. Renal cell carcinoma: current status and
emerging therapies. Cancer Treat Rev. 2007;33(3):299-313.
5. Woodward E, Jagdev S, Mcarland L, et al. Skeletal complications and survival
in renal cancer patients with bone metastases. Bone. 2011;48(1):160-6.
6. Tung KH, Foo KT, Rauff A, et al. Renal cell carcinoma - a local experience.
Ann Acad Med Singapore. 1981;10(2):190-3.
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7. Ares Valdés Y. Correlation between symptoms and survival in patients with

renal cell carcinoma. Arch Esp Urol. 2009;62(3):201-6.
8. Hoshi S, Orikasa S, Yoshikawa K, et al. Evaluation of bone metastases from
renal cell carcinoma. Nihon Hinyokika Gakkai Zasshi. 1991;82(4):649-54.
9. Saitoh H, Hida M, Nakamura K, et al. Metastatic processes and a potential
indication of treatment for metastatic lesions of renal adenocarcinoma. J Urol.
1982;128(5):916-8.
10. Kim H, Usui Y, Soeda S, et al. Prostatic metastasis of renal cell carcinoma.
Hinyokika Kiyo. 2011;57(12):705-8.
11. Miki M, Soga N, Masui S, et al. A case of bladder metastasis of renal cell
carcinoma: a case report and literature review. Hinyokika Kiyo. 2012;58(5):231-5.
12. Kamota S, Harabayashi T, Suzuki S, et al. Ureteral and bladder metastases of
renal cell carcinoma following synchronous renal cell carcinoma and bladder cancer;
a case report. Nihon Hinyokika Gakkai Zasshi. 2003;94(7):705-8.
13. Vecchioli Scaldazza C, Morosetti C, Diamanti L, Magagnini M. Metastases of
the ureteral stump and bladder from renal cell carcinoma: report of a case. Minerva
Urol Nefrol. 1998;50(3):191-4.
14. Chiu KY, Ho HC, Chen JT, et al. Renal cell carcinoma metastasized to the
ureteral stump. Zhonghua Yi Xue Za Zhi (Taipei). 2001;64(1):64-8.
15. Nakanishi Y, Arisawa C, Ando M. Solitary metastasis to the urinary bladder
from renal cell carcinoma: a case report. Hinyokika Kiyo. 2006;52(12):937-9.
16. Tsuda S, Koga S, Nishikido M, et al. Evaluation of bone metastases from
renal cell carcinoma. Hinyokika Kiyo. 2001;47(3):155-8.
17. Koga S, Tsuda S, Nishikido M, et al. The diagnosis of bone scan in patients
with renal cell carcinoma. J Urol. 2001;166:2126-8.
18. Kume H, Kakutani S, Yamada Y, et al. Prognostic factors for renal cell
carcinoma with bone metastasis: who are the long-term survivors? J Urol.
2011;185(5):1611-4.
19. Mandavia DP, Pregerson B, Henderson SO. Ultrasonography of flank pain in
the emergency department: renal cell carcinoma as a diagnostic concern. J Emerg
Med. 2000;18(1):83-6.
20. Matsumoto K. Bone metastasis from renal cell carcinoma. Gan To Kagaku
Ryoho. 1987;14(5 Pt 2):1710-6.
21. Adiga GU, Dutcher JP, Larkin M, Garl S, Koo J. Characterization of bone
metastases in patients with renal cell cancer. BJU Int. 2004;93(9):1237-40.
UROTHELIAL CANCER
Urothelial carcinoma is less common than that of the renal pelvis,
accounting for about 25% of all upper urinary tract tumors (1). UTUC
is relatively rare and potentially lethal disease occurring in 5% of all
urothelial tumors (1-3). The 5-year cancer-specific survival in the US
is roughly 75% with grade and stage being the most powerful
predictors of survival (3).
Accurate risk stratification remains a challenge owing to the
difficulty of clinical staging. Identification of risk factors may lead to
534
individualized treatment and patient counseling and holds the potential

to improve outcome (1).
The main objective of this study was to evaluate epidemiological
and survival patterns of UTUC over the past 30 years through a
review of a large, population-based database. Data from the SEER
database from 1973 to 2005 were reviewed in 10-year increments to
evaluate disease trends. In total, 13,800 SEER-registered cases of
UTUC were included. The overall incidence of UTUC increased from
1.88 to 2.06 cases per 100,000 person-years during the period studied,
with an associated increase in ureteral disease (0.69 to 0.91) and a
decrease in renal pelvic cancers (1.19 to 1.15). The proportion of in
situ tumors increased from 7.2% to 31.0% (p<0.001), whereas local
tumors declined from 50.4% to 23.6% (p<0.001). There was no
change in the proportion of patients presenting with distant disease. In
multivariate analysis, increasing patient age (p<0.001), male gender
(p<0.001), black non-Hispanic race (p<0.001), bilateral UTUC
(p=0.001) and regional/distant disease (p<0.001) were associated with
poorer survival outcomes. In conclusion, the incidence of UTUC has
slowly risen over the past 30 years. Increased use of bladder cancer
surveillance regimens and improved abdominal cross-sectional
imaging may contribute to the observed stage migration towards more
in situ lesions. Although pathological disease characteristics affect
cancer outcomes, certain sociodemographic factors also appear to
portend worse prognosis (4).
Inter-individual variation in the metabolism of xenobiotics, caused
by factors such as cigarette smoking or inorganic arsenic exposure, is
hypothesized to be a susceptibility factor for urothelial carcinoma.
Therefore, this study aimed to evaluate the role of gene-environment
interaction in the carcinogenesis of urothelial carcinoma. A hospital-
based case-control study was conducted. Urinary arsenic profiles were
measured using high-performance liquid chromatography-hydride
generator-atomic absorption spectrometry. Genotyping was performed
using a PCR-restriction fragment length polymorphism technique.
Information about cigarette smoking exposure was acquired from a
lifestyle questionnaire. Urothelial carcinoma patients had higher
urinary levels of total arsenic, higher percentages of inorganic arsenic
and monomethylarsonic acid and lower percentages of dimethylarsinic
acid compared to controls. Subjects carrying the glutathione S-
transferase mu 1 (GSTM1) null genotype had significantly increased
urothelial carcinoma risk. However, no association was observed
between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and
GSTT1 and urothelial carcinoma risk after adjustment for age and sex.
535
Significant gene-environment interactions among urinary arsenic

profile, cigarette smoking, and GSTM1 wild/null polymorphism and
urothelial carcinoma risk were observed after adjustment for potential
risk factors. Overall, gene-environment interactions simultaneously
played an important role in urothelial carcinoma carcinogenesis (5).
UTUC are rare but usually invasive at diagnosis. Upper urinary
tract has the same embryological origin with bladder and BLCA-4 (a
specific nuclear matrix protein found in bladder cancer) is a highly
sensitive and specific marker for bladder cancer. Urines from 30
UTUC patients, 10 ureteral polyp patients, 20 infected patients with
incarcerated ureteral stones, and 30 normal controls were included.
BLCA-4 antibody was produced and applied in an indirect ELISA
assay. Urinary BLCA-4 is significantly higher in UTUC group than
«Polyp» group (p=0.0017), «Infection» group (p<0.0001), or
«Normal» group (p<0.0001). The «Polyp» group is also higher than
«Infection» group (p=0.015), or «Normal» group (p=0.0009). ROC
curve revealed at cut-off of 5.5×10(-4)A, sensitivity was 93.3% and
specificity was 100%. When grouped as ureteral mass vs. normal,
same cut-off value yielded 93.3% sensitivity and 83.3% specificity. At
2.4×10(-4)A, sensitivity was 56.7% and specificity was 97.2%. In
conclusion, urinary BLCA-4 is highly specific in UTUCs detection.
For incidentally identified ureteral mass, BLCA-4 can be considered
an auxiliary indicator besides biopsy (6).
A clinical and histopathologic study of 33 patients diagnosed with
a malignant neoplasm in the renal pelvis or ureter in the period of
1994 to 2004 at the Division of Urology and Department of
Pathology, Sao Paulo, Brazil was conducted. Among the patients with
UTUC, 70% were males and 30% females, with mean age of 65 +/- 16
years (ranging from 31 to 91 years). Nineteen patients presented renal
pelvis tumor (58%), 9 ureteral tumor (27%), and 5 synchronic pelvic
and ureteral tumors (15%). Renal pelvis tumors represented 2.8% of
all the urothelial neoplasms, and 11.4% of all renal neoplasms treated
at the same period. Ureteral tumors represented 1.6% of all the
urothelial malignancies surgically managed in these 11 years. Tobacco
smoking was the most common risk factor, while analgesic abuse was
not reported. Most carcinomas were high-grade and muscle-invasive.
Mean time to diagnosis was 7 months, with hematuria as the most
common symptom. In conclusion, a high association was found
between and bladder urothelial carcinoma. UTUCs were mostly seen
in men in their seventies and related to a high overall and cancer-
related mortality rates. The overall disease-specific survival was 40%,
much lower than found in most of the reported series (7).
536
The main objective of this study was to compare the predictive

value for 5-year survival of demographic characteristics, pathological
grade and stage between UTUC of the RPUC and UUC in a
Taiwanese population. In this study, (1986-98) 141 patients with
UTUC, including 71 with RPUC and 70 with UUC (median age 59
years, median follow-up 54 months, SD 2.5) were analyzed. A
significant percentage of patients had tumor on the right side and a
high proportion of those with UUC were women. Gross hematuria and
hypertension were the most common symptoms of RPUC. The
sensitivity of IVP in diagnosing RPUC and UUC was 49% (34/69)
and 36% (25/70), respectively. However, in patients assessed by
retrograde pyelography the diagnostic sensitivity was 85% (60/71) for
RPUC and 89% (55/62) for UUC. The incidence of tumor recurrence
after nephroureterectomy with bladder cuff excision was significantly
higher in those with UUC (13%) than RPUC (3.6%). Distant
metastasis was detected in 37/141 (26%) patients, the most common
sites were bone (46%), lung (22%), liver (14%) and colon (8%).
Univariate logistic regression analysis showed significant differences
in the prognosis for high-grade and high-stage tumors. The prognosis
was particularly poor in patients aged > 60 years. In the multivariate
logistic regression analysis, tumor stage and grade were the best
outcome predictors for RPUC, but stage and age were the best
outcome predictors for UUC. In conclusion, UUC is more common in
women and has a more aggressive clinical outcome than RPUC after
nephroureterectomy with bladder cuff incision. Tumor stage and grade
are the best predictors of survival in patients with RPUC. In patients
with UUC, the prognosis is poor in older patients and those with
advanced stages of cancer (8).
During the last ten years, 16 patients have been treated for UTUC,
10 carcinomas of the renal pelvis and 6 carcinomas of the ureter at the
urological Department, Porsgrunn, Norway. Mean age at the time of
diagnosis was 64.3 years. The most common symptoms were
hematuria, flank pain and loss of weight. The diagnosis was
established by IVP and retrograde ureteropyelography. Ureteral
carcinomas were operated with local resection of the ureter, while
carcinomas of the renal pelvis were treated with a
nephroureterectomy. Most tumors were highly malignant. Four tumors
were non-invasive and, in retrospect, could have been treated with a
local resection only. Only 35% of patients with urothelial carcinoma
in the upper urinary tract are alive 5 years after diagnosis (9).
537
Transitional cell carcinoma of the ureter.
The aim of this study was to evaluate the clinical behavior,

survival, recurrence and prognostic information of primary UUC from
11 years of experience at the Taipei Veterans General Hospital.
Patients (n=111) with UUC had been treated in the hospital between
January 1993 and December 2003. Tumor staging was according to
the 2002 the American Joint Committee on Cancer TNM
classification and stage groupings. Patients with stage Oa and stage
Ois were categorized as stage Oa/is, and patients with pathologic T
stage pTa and pTis were categorized as pTa/is for statistical analysis.
There were 69 males and 42 females, with a mean age of 70.5 +/- 9.4
years at diagnosis. Of the 111 patients, 5 presented with stage Oa/is,
38 with stage I, 23 with stage II, 21 with stage III, and 24 with stage
IV. Nephroureterectomy with bladder cuff excision was performed in
78 patients, 12 patients received segmental resection of the ureter, 4
received ureteroscopic laser coagulation, and 17 underwent
chemotherapy or RT or both. Tumors were located on the left side in
53 patients, on the right in 53, and bilaterally in 5. The most frequent
initial presenting symptom was gross hematuria (65%). The mean
postoperative follow-up period was 49.3 months. Disease recurrence
in the nephroureterectomy group occurred in 36 patients (46.2%), with
17 (21.8%) at the urinary bladder, 2 (2.6%) at the retroperitoneum, 1
(1.3%) at the contralateral ureter, 6 (7.7%) with distant metastases to
the lung, bone, distant lymph nodes or liver, and 10 (12.8%) at
multiple sites. The 5-year cancer-specific survival rate was 100% for
pTa/is, 95.2% for pT1, 69.4% for pT2, and 43.8% for pT3. All 3 pT4
cases died of cancer in a median of 12 months. Significant prognostic
factors for cancer-specific survival by univariate analysis were pT
(p=0.00001), stage (p=0.00001), type of treatment (p=0.00001) and
grade (p=0.0001). On multivariate analysis, only stage (p=0.0001) and
grade (p=0.014) were significant for cancer-specific and overall
survival. Stage (p=0.0001), pT (p=0.0001) and grade (p=0.026) were
significant prognostic factors of recurrence in multivariate analysis. In
538
conclusion, patients with pTa/is and pT1 tumors treated with radical
surgery have excellent prognoses. Tumor stage and grade are the only
significant prognostic factors for both cancer-specific and overall
survival (2).
Eighty-two patients with renal pelvic and ureteral tumors were
admitted to Kyoto Second Red Cross Hospital and Shakai-Hoken
Kyoto Hospital between January 1981 and December 1991. Sixty-two
were males and 24 were females, and they were between 47 and 93
years old (average 68.2 years). The tumor occurred on the right side in
34 patients, on the left side in 51 patients and on both sides in 1
patient. There were 43 renal pelvic tumors, 37 ureteral tumors, and 6
renal pelvic with ureteral tumors. The most frequent symptom was
macrohematuria, which was in 54 patients (62.8%). Urinary cytology
was performed in 76 patients and a positive result was obtained in 44
patients (57.9%). Surgical treatment was performed on 71 patients.
The most frequently adopted method was total nephroureterectomy
with partial cystectomy which was performed on 51 patients (71.8%).
Of the 73 specimens diagnosed histopathologically, 71 specimens
were transitional cell carcinoma, 1 was a squamous cell carcinoma
and 1 was a mixed type of transitional cell carcinoma and
adenocarcinoma. Six specimens were G1, 28 G2, 38 G3 and 1 GX.
Eight specimens were pTa, 17 pT1, 21 pT2, 18 pT3, 8 pT4 and 1 pTX.
The overall survival rate (by Kaplan-Meier's method) at 3 and 5 years
was 47.0% and 39.5%, respectively. The patients with high-grade
tumors and those who had ureter preservation, the survival rate was
lower than in the other patients (10).
Obstructing transitional cell carcinoma of the ureter.
Metachronous presentation of metastatic RCC to the ureter is

extremely rare. A solitary metachronous metastatic RCC in the
contralateral ureter 14 months after right radical nephrectomy for
Fuhrman grade II pT3a clear cell disease after the patient re-presented
539
with gross hematuria is reported. The proximal left ureteral lesion was
excised followed by ileal-ureteral interposition. Pathologic
examination confirmed metastatic RCC. To date, only 51 cases of
metastatic RCC to the ureter have been reported, with only 6
occurring metachronously in the contralateral ureter. The presence of
focal extramedullary hematopoiesis occurring within this metastatic
lesion is reported (11).
A rare case of ureteral stump metastasis 3 months after
nephrectomy for a RCC is presented. A 62-year-old female had
undergone right radical nephrectomy three months earlier because of
RCC in the hospital, and she came back due to gross hematuria.
Cystoscopy revealed a papillary mass with a vascular pedicle
protruding from the right ureteral orifice. Transurethral resection of
the bladder tumor over right ureteral orifice was performed and the
pathologic result showed clear cell adenocarcinoma, which argued in
favor of a metastatic lesion from the previous RCC. Ureterectomy and
a bladder cuff excision were adopted for this patient, but no residual
tumor was found over the remaining ureter. Nevertheless, the patient
died of cancer 36 months after ureteral stump metastasis (12).
A case of ureteral metastasis from RCC is reported. A 71-year-old
man who had received radical nephrectomy for left RCC, G1 and
about 2 years earlier presented with asymptomatic macrohematuria.
He had received interferon therapy and surgical treatments for bone
metastasis 2 times after the operation. Cystoscopic examination
revealed bleeding from the left residual ureter but CT scan showed no
abnormal findings. Left ureterectomy and partial cystectomy was
performed and a small finger tip-sized tumor was found at 13.5 cm
above the ureteral orifice. Pathological examination showed metastatic
RCC, G1 > G2. Histologically and clinically, this tumor seemed to
have metastasized by a hematological pathway (13).
A 75-year-old woman was admitted because of asymptomatic
gross hematuria. Right radical nephrectomy for RCC had been
performed 2 years and 9 months prior to admission. Cystoscopy
revealed efflux of blood from right ureteral orifice. Right retrograde
ureterogram revealed a filling defect at the upper end of the stump,
where a soft tissue mass was observed by CT scan. She underwent
right ureteral stump excision with a bladder-cuff. Pathological study
was consistent with metastatic RCC (14).
540
Transitional cell carcinoma of the ureter.
A 74-year-old male patient with a significant history of a high-

grade urothelial carcinoma was presented with progressive back pain
and concomitant weakness, grade III-IV/V proximally and 0-I/V
distally, and distal hyperesthesia and hyperalgesia, particularly of the
left lower limb. MRI revealed a contrast-enhancing intramedullary
lesion at Th11/Th12. Laminectomies of Th11/Th12 and lesion
resection were performed. Postoperative histopathological
examinations confirmed the metastatic nature of the lesion.
Subsequently the patient developed multiple brain metastases. RT was
refused by the patient. In conclusion, intramedullary spinal cord
metastases are devastating complications of systemic cancer. Early
and thorough diagnosis, as well as carefully considered and prompt
therapy, is important for minimizing the patient's functional deficit,
thus improving QOL (15).
A new case of acrometastasis to the hand, from an urothelial
carcinoma of the bladder, in a 46-year-old woman, with a history of
left lower lobectomy for bronchial carcinoma is reported. Physical
examination revealed a tumor of the dorsal hand, inflammatory and
painful. The radiograph showed ill-defined osteolysis of the base of
the fourth metacarpal. Two immunohistochemical studies were needed
to confirm the origin of the bladder metastasis (16).
Radical nephroureterectomy is currently standard treatment for
high-grade and muscle invasive UTUC. Several clinical and
pathological factors (e.g. stage, grade, age, hydronephrosis,
lymphovascular invasion, tumor necrosis and architecture, and delay
between diagnosis and surgery) were associated with outcome.
Urinary cytology and fluorescence in-situ hybridization are the most
commonly used urinary markers. The incorporation of such
prognosticators into multivariable prediction models may help to
guide decision-making with regard to type of treatment, performance
541
of lymphadenectomy and consideration of neoadjuvant or adjuvant

systemic therapy (1).
Nephroureterectomy with excision of the ipsilateral ureteral orifice
and bladder cuff en bloc remains the gold standard treatment of the
UTUC, while endoscopic and laparoscopic approaches are rapidly
evolving as reasonable alternatives of care depending on grade and
stage of disease. Several controversies remain in their management,
including a selection of endoscopic vs. laparoscopic approaches,
management strategies on the distal ureter, the role of
lymphadenectomy, and the value of chemotherapy in upper tract
disease (3).
Assessment: UTUC is relatively rare, potentially lethal disease

occurring in 5% of all urothelial tumors. UUC is even less common
than that of the renal pelvis, accounting for about 25% of all upper
urinary tract tumors. Significant gene-environment interactions among
urinary arsenic profile, cigarette smoking, and GSTM1 wild/null
polymorphism and urothelial carcinoma risk are observed after
adjustment for potential risk factors.
Clinical symptoms include hematuria, hypertension, flank pain and
loss of weight. Literature reports a case of intramedullary spinal cord
metastasis and multiple brain metastases from urothelial carcinoma,
and acrometastasis to the hand from a urothelial carcinoma of the
bladder.
Was King David afflicted by this type of malignant disease?
Although the King lost his weight (18), in the absence of specific risk
factors and characteristic clinical symptoms, the diagnosis of UUC
seems unlikely.
References
1. Chen WJ, Kuo JY, Chen KK, et al. Primary urothelial carcinoma of the ureter:
11-year experience in Taipei Veterans General Hospital. J Chin Med Assoc. 2005;
68(11):522-30.
2. Rink M, Adam M, Hansen J, et al. Upper tract urothelial carcinoma. An update
on clinical and pathological prognostic factors. Urologe A. 2012;51(9):1228-39.
3. Koukourakis G, Zacharias G, Koukourakis M, et al. Comprehensive
management of upper tract urothelial carcinoma. Adv Urol. 2009:656521. doi:
10.1155/2009/656521. Epub December 10.
4. Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of
patients with carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU
Int. 2011;107(7):1059-64.
5. Chung CJ, Huang CY, Pu YS, et al. The effect of cigarette smoke and arsenic
exposure on urothelial carcinoma risk is modified by glutathione S-transferase M1
gene null genotype. Toxicol Appl Pharmacol. 2012 Nov 15. pii: S0041-008X(12)
00478-4.
542
6. Feng CC, Wu Z, Jiang HW, et al. Urinary BLCA-4 level is useful to detect
upper urinary tract urothelial cell carcinoma. Actas Urol Esp. 2012;36(10):597-602.
7. Korkes F, Silveira TS, Castro MG, et al. Carcinoma of the renal pelvis and
ureter. Int Braz J Urol. 2006;32(6):648-53; discussion 653-5.
8. Tan LB, Chang LL, Cheng KI, et al. Transitional cell carcinomas of the renal
pelvis and the ureter: comparative demographic characteristics, pathological grade
and stage and 5-year survival in a Taiwanese population. BJU Int. 2009;103(3):312-6.
9. Markset AC, Johansen TE. Urothelial carcinoma of the upper urinary tract. 10
years' material from a central hospital. Tidsskr Nor Laegeforen. 1990;110(5):591-4.
10. Ebisui K, Nakagawa S, Takada H, et al. Clinical evaluation on renal pelvic
and ureteral tumors]. Hinyokika Kiyo. 1994;40(3):201-8.
11. Zorn KC, Orvieto MA, Mikhail AA, et al. Solitary ureteral metastases of renal
cell carcinoma. Urology. 2006;68(2):428.e5-7.
12. Chiu KY, Ho HC, Chen JT, et al. Renal cell carcinoma metastasized to the
ureteral stump. Zhonghua Yi Xue Za Zhi (Taipei). 2001;64(1):64-8.
13. Shimura H, Miura T, Kondoh I. Ureteral stump metastasis from renal cell
carcinoma: a case report]. Hinyokika Kiyo. 1993;39(3):257-60.
14. Iimori H, Nishimoto K, Ikemoto S, Hayahara N. A case report of ureteral
stump metastasis from renal-cell carcinoma. Hinyokika Kiyo. 1994;40(3):237-40.
15. Abdulazim A, Backhaus M, Stienen MN, et al. Intramedullary spinal cord
metastasis and multiple brain metastases from urothelial carcinoma. J Clin Neurosci.
2011;18(10):1405-7.
16. Taleb C, Pelissier P, Choughri H. Bladder urothelial carcinoma with
acrometastasis: a case report and review of the literature.Chir Main.2011;30(2):136-9.
URINARY BLADDER CANCER

Bladder cancer is a chronic condition and is estimated to be the
ninth most common type of cancer worldwide (386,000 cases in 2008)
and the thirteenth most frequent cause of cancer mortality (150,000
deaths) (1,2). No screening is available, so diagnosis depends on
investigations of symptoms (2).
The main purpose of this study was to examine trends in bladder
cancer incidence, mortality and survival in England and Wales during
a 30-year period. Age standardized incidence and mortality rates for
bladder cancer, cohort incidence ratios, and 1 and 5-year relative
survival from bladder cancer was calculated, and current trends were
assessed. The total number of cases of bladder cancer increased by
57% from around 7,200 to almost 11,400 between 1971 and 1998.
Direct age standardized incidence increased by 16% in males and 37%
in females. Direct age standardized mortality decreased by 26% in
males and showed little change in females during the same period.
Five-year relative survival improved by around 15% points in the
543
1970s and early 1980s. However, there was less improvement in

survival thereafter in 5-year relative survival for patients diagnosed in
1993 to 1995 and was 67% in men and 58% in women. In conclusion,
with an almost 60% increased incidence during the last 3 decades,
bladder cancer incidence remains much higher in men but has
increased more rapidly in women. There have been steady decreases
in mortality rates, more marked in men than in women. Unusually,
women have a significantly lower survival rate than men. Reasons for
these patterns and trends are unclear. The trends in bladder cancer
incidence by birth cohort suggest that the relationship with smoking
may not be strong and other factors may be involved (3).
Smoking, mainly cigarette smoking, is a well-known risk factor for
various diseases, including bladder cancer. Another factor strongly
associated with bladder cancer is exposure to arsenic in drinking water
at concentrations higher than 300 µg/l. The most notable risk factor
for development of bladder cancer is occupational exposure to
aromatic amines (2-naphthylamine, 4-aminobiphenyl and benzidine)
and 4,4'-methylenebis(2-chloroaniline), which can be found in the
products of the chemical, dye and rubber industries as well as in hair
dyes, paints, fungicides, cigarette smoke, plastics, metals and motor
vehicle exhaust. There are data suggesting an effect from other types
of smoking besides cigarettes (cigar, pipe, Egyptian water pipe,
smokeless tobacco and environmental tobacco smoking), and other
sources of arsenic exposure such as air, food, occupational hazards,
and tobacco. Hairdressers and barbers with occupational exposure to
hair dyes experience enhanced risk of bladder cancer. There is an
elevated bladder cancer risk for people who used permanent hair dyes
at least once a month, for one year or longer. In conclusion, smoking,
in particular from cigarettes, exposure to arsenic in drinking water,
and occupational exposure to aromatic amines and 4,4'-
methylenebis(2-chloroaniline) are risk factors for various diseases
including bladder cancer. Although the number of chemicals related to
occupational exposure is still growing, it is worth noting that it may
take several years or decades between exposure and the subsequent
cancer (4).
A case-control study was carried out, using electronic medical
records from UK primary care. Participants were 4915 patients aged
≥ 40 years, diagnosed with bladder cancer during January 2000 to
December 2009, and 21,718 age, sex, and practice-matched controls
selected from the General Practice Research Database, UK. Cases
consulted their GP more frequently than controls before diagnosis:
median 15 consultations (IQR 9-22) vs. 8 (4-15), p<0.001. Seven
544
features were independently associated with bladder cancer: visible

hematuria OR 34 (95% CI 29 - 41), dysuria 4.1 (95% CI 3.4 -5.0),
UTI 2.2 (95% CI 2.0 - 2.5), raised white blood cell count 2.1 (95% CI
1.6 - 2.8), abdominal pain 2.0 (95% CI 1.6 - 2.4), constipation 1.5
(95% CI 1.2 - 1.9), raised inflammatory markers 1.5 (95% CI 1.2 -
1.9), and raised creatinine 1.3 (95% CI 1.2 - 1.4). The positive
predictive value for visible hematuria in patients aged ≥ 60 years was
2.6% (95% CI 2.2 - 3.2). In conclusion, visible hematuria is the
commonest and most powerful predictor of bladder cancer in primary
care, and warrants investigation (1).
Irritative urinary symptoms and micro-hematuria are the common

findings in bladder cancer patients. Nine hundred and eighty-eight
patients were studied during the period of 2005-2007. Voiding
symptoms were evaluated with international prostate symptoms score,
and urine samples were collected for microscopy and cytological
examination. Cystoscopy was performed in patients with microscopic
hematuria, suspicious/malignant cells in urine or at the time of
transurethral resection of prostate. Subjects, who had no indication
and did not receive cystoscopy, were followed up in clinic for
progress of symptoms, including gross hematuria and occurrence of
bladder cancer. Fifty-two (5.26%) urine samples were documented as
atypical, and 936 (94.7%) were negative. There was no suspicious or
malignant cytology result in this series. Micro-hematuria was noticed
in 6 patients (0.61%). The mean follow-up time was 29.1 ± 12.5
months. One (0.10%) patient had bladder cancer 44 months after the
first visit in the cohort, who had micro-hematuria, atypical urine
cytology, but normal cystoscopy before diagnosis. In conclusion, the
prevalence rate of bladder cancer in male patients with lower urinary
tract symptoms is low. Microscopy and cytological examination are
not useful to detect bladder cancer. Due to the economic concerns and
545
burden of unnecessary investigations, the routine use of these tests is

in doubt (5).
Ultrasonography. Large bladder carcinoma.
Two hundred and twenty-one patients with invasive bladder cancer

had routine bone scintigraphy performed as part of tumor staging. The
incidence of detectable metastases was 12%. Skeletal scintigraphy at
diagnosis has a sensitivity of only 38%. The predictive value of a
negative examination was 92%. These results suggest that skeletal
scintigraphy is not indicated as a routine staging procedure in
carcinoma of the bladder (6).
Bladder cancer is a heterogeneous and frequently multifocal
disease with a variable clinical course. The management of bladder
cancer is therefore challenging and complicated. CT and MR imaging
have replaced the traditional excretory urography and are emerging as
the imaging modalities of choice for work-up of patients who have
bladder cancer. Imaging provides essential diagnostic information for
detection, staging, and post-treatment follow-up of bladder cancer (7).
From a clinic population of 392 patients with muscle-invasive
(pT2-4) bladder cancer treated at the Department of Imaging, Dana-
Farber Cancer Institute, from 2004 through 2009, consecutively
registered patients with pathologically proven metastatic disease were
studied. The study group consisted of 150 patients (men=116, 77%)
(women=34, 23%), median age, 64 years. The transitional cell
carcinoma group consisted of 94 (63%) patients and the atypical
histological features group of 56 (37%) patients. The most common
metastatic sites were lymph nodes (104 patients, 69%), bone (71,
47%), lung (55, 37%), liver (39, 26%), and peritoneum (24, 16%).
Patients with tumors of a more advanced T category had shorter
metastasis-free intervals (p=0.001). There was insignificant difference
in the metastatic patterns of tumors in the different T categories.
Patients with atypical histological features had a shorter median
546
metastasis-free interval (3 months, range 0-29 months) than patients

with transitional cell carcinoma (12 months, range 0-192 months)
(p=0.0001). Patients with atypical histological features had a
significantly higher incidence of peritoneal metastasis (p<0.0002). In
conclusion, lymph nodes, bones, lung, liver, and peritoneum are the
most common sites of metastasis from bladder cancer. Tumors in a
more advanced T category and those with atypical histological
features metastasize earlier. Tumors with atypical histological features
have a higher frequency of peritoneal metastasis (8).
A 76-year-old man after radical cystectomy for bladder carcinoma.

Patient has high-grade papillary transitional cell carcinoma of left collecting
system and invasion into renal parenchyma (stage T3). Although maximum-
intensity-projection image shows distortion of collecting system from upper
pole tumor (arrow), full extent of tumor is not determined and renal
parenchymal invasion cannot be identified.
Oral cavity metastases mostly originate from the breasts, lungs, or

kidneys. Transitional cell carcinoma, the most frequent malignant
tumor of the urinary bladder, rarely metastasizes to the jaws. A case of
mandibular metastasis of urinary bladder transitional cell carcinoma
with extension to the gingiva is presented in a 64-year-old white man.
The patient was referred for a periodontal infection of the upper right
first molar. The clinical examination also showed a gingival swelling
located in the lower left premolar region with a hypoasthesia of the
left side of the lower lip. The gingival mass was biopsied, and the
microscopy showed a mandibular metastatic transitional cell
carcinoma of the urinary bladder extending to the gingiva.
Periodontists should be aware that, although gingival metastases are
rare, when they occur they might mimic other local benign
pathological conditions (9).
Transitional cell carcinoma is the most common carcinoma of the
bladder (> 90% of cases). A case of a 60 year-old man was presented
547
with multiple bony metastases of transitional cell carcinoma affecting

the humerus, femur, spine, iliac wing, and ribs. The metastases were
discovered within a year after first presentation of hematuria with a
subsequent biopsy diagnosis of transitional cell carcinoma of bladder,
Grade III of III with no definite muscle invasion. Metastasis of
transitional cell carcinoma of bladder to bone is an uncommon
occurrence when compared with breast and prostate carcinoma. This
is due to intrinsic properties of tumor cells and/or mechanisms of
metastases. Recent studies confirm that bone is the preferred site of
metastasis (35%) of transitional cell carcinoma outside of the pelvis,
with the spine being the most common site (40% of bony metastases).
Histological grading, emphasizing the presence of invasion, is
generally accepted as being very important prognostically. Diagnostic
screening tests of hematuria should include urothelial biomarkers such
as profile tumor-associated antigen M344 and DD23 (10).
Assessment: bladder cancer accounts for over 150,000 deaths

worldwide. No screening is available, so diagnosis depends on
investigations of symptoms. Risk factors include smoking, in
particular from cigarettes, exposure to arsenic in drinking water, and
occupational exposure to aromatic amines and 4,4'-methylenebis(2-
chloroaniline.
Symptoms associated with bladder cancer include irritative urinary
symptoms, micro-hematuria, visible hematuria, dysuria, UTI, raised
white blood cell count, abdominal pain, constipation, and raised
inflammatory markers and creatinine level.
Microscopy and cytological examination are not useful to detect
bladder cancer. CT and MRI have replaced the traditional excretory
urography and are emerging as the imaging modalities of choice for
work-up of patients who have bladder cancer.
Lymph nodes, bones, lung, liver, and peritoneum are the most
common sites of metastasis from bladder cancer. Tumors in a more
advanced T category and those with atypical histological features
metastasize earlier. Tumors with atypical histological features have a
higher frequency of peritoneal metastasis.
Was King David afflicted by bladder carcinoma? Although bladder
carcinoma can metastasize to the bones, in the absence of risk factors
for bladder carcinoma, characteristic clinical symptoms, results of CT,
and MRI and appropriate histopathological findings, the diagnosis of
bladder carcinoma seems unlikely.
548
References
1. Parkin DM. The global burden of urinary bladder cancer. Scand J Urol
Nephrol Suppl. 2008;218:12-20.
2. Shephard EA, Stapley S, Neal RD, et al. Clinical features of bladder cancer in
primary care. Br J Gen Pract. 2012;62(602):e598-604.
3. Hayne D, Arya M, Quinn MJ, et al. Current trends in bladder cancer in England
and Wales. J Urol. 2004;172(3):1051-5.
4. Letańiová S, Medveďová A, Ńovčíková A, et al. Bladder cancer, a review of
the environmental risk factors. Environ Health. 2012;11(Suppl 1): S11.
5. Chan ES, Ng CF, Hou SM, Yip SK. Using urine microscopy and cytology for
early detection of bladder cancer in male patients with lower urinary tract symptoms.
Int Urol Nephrol. 2011;43(2):289-94.
6. Davey P, Merrick MV, Duncan W, Redpath AT. Bladder cancer: the value of
routine bone scintigraphy. Clin Radiol. 1985;36(1):77-9.
7. Zhang J, Gerst S, Lefkowitz RA, Bach A. Imaging of bladder cancer. Radiol
Clin North Am. 2007;45(1):183-205.
8. Shinagare AB, Ramaiya NH, Jagannathan JP, et al. Metastatic pattern of
bladder cancer: correlation with the characteristics of the primary tumor. AJR Am J
Roentgenol. 2011;196(1):117-22.
9. de Courten A, Irle C, Samson J, Lombardi T. Metastatic transitional cell
carcinoma of the urinary bladder presenting as a mandibular gingival swelling. J
Periodontol. 2001;72(5):688-90.
10. Punyavoravut V, Nelson SD. Diffuse bony metastasis from transitional cell
carcinoma of urinary bladder: a case report and review of literature. J Med Assoc
Thai. 1999;82(8):839-43.
PROSTATE CARCINOMA
Prostate cancer continues to be a significant public health issue
worldwide, particularly in countries where men have life expectancies
long enough to clinically manifest the disease. In many countries, it
remains one of the leading causes of cancer-related morbidity and
mortality. Although significant progress has been made over the past
few decades, many elements regarding the diagnosis and management
of patients with prostate cancer remain enigmatic (1).
Prostate cancer incidence rates and trends using the 2001-2007
National Program of Cancer Registries and Surveillance,
Epidemiology, and End Results Program data (representing over 93%
of US population) were described. Because of coding changes in
cancer grade, analysis was restricted to 2004-2007. The overall
prostate cancer incidence rate was stable from 2001 to 2007; however,
rates significantly increased among men aged 40-49 years (APC =
3.0) and decreased among men aged 70-79 years (APC = 2.3), and ≥
80 years (APC = -4.4). About 42% of localized prostate cancers
diagnosed from 2004 to 2007 were poorly differentiated. The
549
incidence of poorly differentiated cancer significantly increased

among localized (APC = 8.0) and regional stage (APC = 6.1) prostate
cancers during 2004-2007. In conclusion, the recent trend in prostate
cancer incidence was stable but varied dramatically by age. Given the
large proportion of poorly differentiated disease among localized
prostate cancers and its increasing trend in more recent years,
continued monitoring of prostate cancer incidence and trends by
demographic and tumor characteristics is warranted (2).
The main aim of this study was to study trends over time in
prostate-cancer mortality and incidence in the US and UK in 1975-
2004, and compare these patterns with trends in screening and
treatment. Joinpoint regression analysis of cancer-mortality statistics
from Cancer Research UK (London, UK) and from the US NCI SEER
program from 1975 to 2004 was used to estimate the annual
percentage change in prostate-cancer mortality in both countries and
the points in time when trends changed. The ratio of US to UK age-
adjusted prostate-cancer incidence was also assessed. Age-specific
and age-adjusted prostate-cancer mortality peaked in the early 1990s
at almost identical rates in both countries, but age-adjusted mortality
in the US subsequently declined after 1994 by -4.17% (95% CI -4.34 -
-3.99) each year, four-times the rate of decline in the UK after 1992
(95% CI -1.14%, -1.44 - -0.84). The mortality decline in the US was
greatest and most sustained in patients aged ≥ 75 years (95% CI -
5.32%, -8.23 - -2.32), whereas death rates had plateaued in this age
group in the UK by 2000. The mean ratio of US to UK age-adjusted
prostate-cancer incidence rates in 1975-2003 was 2.5, with a
pronounced peak around the time that PSA testing was introduced in
the US. NNT to prevent one death from prostate cancer were 33 000
in the 55-64-year age group. The striking decline in prostate-cancer
mortality in the US compared with the UK in 1994-2004 coincided
with much higher uptake of PSA screening in the US. Explanations
for the different trends in mortality include the possibility of an early
effect of initial screening rounds on men with more aggressive
asymptomatic disease in the US, different approaches to treatment in
the 2 countries, and bias related to the misattribution of cause of death.
Speculation over the role of screening will continue until evidence
from RCTs is published (3).
Prostate cancer is the most common non-skin cancer among men in
most western populations, and it is the second leading cause of cancer
death among US men. Despite its high morbidity, the etiology of
prostate cancer remains largely unknown. Advancing age, race, and a
family history of prostate cancer are the only established risk factors.
550
Many putative risk factors, including androgens, diet, physical

activity, sexual factors, inflammation, and obesity, have been
implicated, but their roles in prostate cancer etiology remain unclear.
As much as 42% of the risk of prostate cancer may be accounted for
by genetic influences, including individual and combined effects of
rare, highly penetrant genes, more common weakly penetrant genes,
and genes acting in concert with each other. Numerous genetic
variants in the androgen biosynthesis/metabolism, carcinogen
metabolism, DNA repair, and chronic inflammation pathways have
been explored but the results are largely inconclusive. The
pathogenesis of prostate cancer likely involves interplay between
environmental and genetic factors. To unravel these complex
relationships, large well-designed interdisciplinary epidemiologic
studies are needed. With newly available molecular tools, a new
generation of large-scale multidisciplinary population-based studies is
beginning to investigate gene-gene and gene-environment
interactions. Results of these studies may lead to better detection,
treatment, and, ultimately, prevention of prostate cancer (4).
Prostate cancer is the most common malignancy of male genital
organs. The etiology of the disease is complex and remains mainly
unclear. The only established risk factors are advancing age, ethnicity
and genetics, including changing in expression of ELAC2, RNASEL,
MSR1 and HOXB13 genes as well as low number of CAG repeats in
the androgen receptor gene. There are number of coexisting
environmental risk factors, such as eating habits mostly diet reach in
animal fats. An early sexual initiation and sexually transmitted
infections, both viral (HSV-2, HPV-18 and -16, and CMV) and
bacterial (Neisseria gonorrhea, Treponema pallidum, and Chlamydia
trachomatis) are also included. The etiology of prostate cancer also
involves the influence of hormones - androgens and estrogens, as well
as chronic inflammation of the prostate. In contrast to the incidence
rate, which varies significantly depending on the geographic region,
the incidence of the malignancy at autopsy is similar (5).
The aim of this study was to identify and quantify the features of
prostate cancer before diagnosis, both individually and in
combination. In this population-based case-control study, all 21
general practices in Exeter, Devon, UK were involved. All 217
prostate cancer patients diagnosed between 1998 and 2002 and 1080
male controls matched by age and general practice were studied. The
full medical record for 2 years before diagnosis was coded, using the
International Classification of Primary Care. Eight features were
associated with prostate cancer before diagnosis. Their positive
551
predictive values against a background risk of 0.35% were: urinary

retention 3.1% (95% CI 1.5 - 6.0); impotence 3.0% (95% CI 1.7 -
4.9); frequency 2.2% (95% CI 1.3 - 3.5); hesitancy 3.0% (95% CI 1.5
- 5.5); nocturia 2.2% (95% CI 1.2 - 3.6); hematuria 1.0% (95% CI
0.57 - 1.8); weight loss 0.75% (95% CI 0.38 - 1.4); abnormal rectal
examination, deemed benign 2.8% (95% CI 1.6 - 4.6); abnormal rectal
examination, deemed malignant 12% (95% CI 5.0 - 37): all p<0.001,
except for hesitancy p=0.032, nocturia p=0.004, and hematuria
p=0.009. Loss of weight, impotence, frequency, and abnormal rectal
examination remained associated with cancer after excluding the final
180 days from analysis. In conclusion, most men with prostate cancer
present with symptoms. The predictive values for these symptoms will
help guide GPs and patients about the value of further investigation
(6).
The British Association of Urological Surgeons Cancer Registry
2000 and 2001 data were used to identify the clinical features and
outcome of 33 patients with metastatic prostate carcinoma who
presented with serum PSA levels < 10 ng/mL. Seventeen patients
(51%) presented with urinary symptoms and/or pelvic pain, 6% with
cachexia and 21% with bone pain. Characteristic bone metastases
were in 81% of patients, similarly to the men with high serum PSA
levels (7).
A case-control study was nested within the UK population-based
ProtecT (Prostate testing for cancer and Treatment) study. Men aged
50-69 years were invited for PSA testing and those with a PSA level
of ≥ 3.0 ng/mL were invited for biopsy. Whether lower urinary tract
symptoms were associated with a PSA level of ≥ 3.0 ng/mL and
prostate cancer using logistic regression models adjusted for age,
family history of prostate cancer and PSA level as appropriate were
determined. All men (n= 65,871) had a PSA test: 7251 had a PSA
level of ≥ 3.0 ng/mL including 2467 subsequently diagnosed with
prostate cancer (2119 localized, and 348 advanced). Lower urinary
tract symptoms were positively associated with a PSA level of ≥ 3.0
ng/mL: ORs were 1.18 (95% CI 1.01 - 1.38), 1.69 (95% CI 1.32 -
2.16), and 1.60 (95% CI 1.33 - 1.93) for daytime urination frequency
(hourly vs. less frequent), urgency and hesitancy (most/all the time vs.
never), respectively. Lower urinary tract symptoms among men with a
PSA level of ≥ 3 ng/mL were negatively associated with prostate
cancer: ORs were 0.44 (95% CI 0.22 - 0.83), 0.74 (95% CI 0.63 -
0.87), and 0.83 (95% CI 0.73 - 0.94) for nocturia (4+ vs. 0), leakage
and hesitancy (occasionally/sometimes vs. never), respectively. Lower
urinary tract symptoms improved the prediction of a PSA level of ≥
552
3.0 ng/mL (under the ROC curve 0.635 vs. 0.606, p<0.001) and
prostate cancer (under the ROC curve 0.661 vs. 0.638; p<0.001). In
conclusion, a history of lower urinary tract symptoms before PSA
testing marginally improves the prediction of an individual's risk for
prostate cancer; men with a PSA level of ≥ 3 ng/mL and lower urinary
tract symptoms were more likely to be diagnosed as benign disease
than prostate cancer (8).
Metastatic frequency to various organ sites in 137 autopsy cases
with histologically confirmed prostatic adenocarcinoma was examined
retrospectively. Bone and lymph node metastases were observed in
81% and 82.5% of the cases, respectively. Lung and liver metastases
were noted in 46.7% and 30.7% of the cases respectively. Statistical
analysis of the inter-relation among metastases to the bones, lymph
nodes, lungs and liver revealed that 83.2% of cases with lymph node
metastasis also had bone metastasis. Of 64 cases, 60 with lung
metastasis presented with bone metastasis. There was a significant
correlation of metastases between bones and lymph nodes, bones and
lungs, and lymph nodes and lungs. Although approximately 88% of
cases with liver metastasis also had bone metastasis, this relationship
was statistically insignificant. There was a statistically significant
relationship between lung metastasis and specific sites of bone
metastases, i.e. vertebrae, ribs, and sternum. The metastatic
combination between lung and bone was significantly related to cases
with or without lymph node metastasis. These observations suggest
that the Batson's vertebral system might play an important role in the
metastatic spread of prostatic adenocarcinoma either to the bones or to
lungs (9).
Urological complications, essentially bladder outflow obstruction
and hydronephrosis, are caused by the local extension and lymphatic
spread of prostate cancer. Although bladder outflow obstruction is a
common finding at diagnosis, results from clinical studies have
revealed that it is not a prognostic factor for response to androgen
blockade. Hydronephrosis has an independent prognostic value for
progression after hormonal treatment and correlates with time to death
from prostate cancer. Persistent or newly developed hydronephrosis
during treatment predicts a shorter time to progression. The incidence
of bladder outflow obstruction is significant in advanced prostatic
cancer and is a source of morbidity, which affects the patient's QOL.
Decompression of ureteric obstruction in hormone-refractory cancer
decreases the length of hospital stay, thereby improving QOL.
Hydronephrosis, but not bladder outflow obstruction, can be
553
considered as independent prognostic variable for the response to

androgen blockade (10).
A prospective and consecutive series of 279 men with metastatic
cancer of the prostate was analyzed. Significant variations were
observed in their metastatic load (p=0.0035) and in case-specific
survival (p=0.0038). Bladder outflow obstruction, bone pain and
anemia not only dictated treatment selection but each of these
symptoms has considerable prognostic significance in patients with
metastatic cancer of the prostate (11).
Sixty-seven cases of stage D prostatic carcinoma were analyzed
according to age, chief complaints, histopathological types, metastatic
sites, serum acid and ALP levels. In spite of metastasis, which were in
62 cases (92.5%) to the bone, 17 cases (25.4%) to lymph nodes, and in
3 cases (4.5%) to the lung, the most common chief complaints were
symptoms related to the primary lesion, such as dysuria and urinary
frequency. There was insignificant correlation between the incidence
of bone metastasis and histopathological type. However, higher
incidence of lymph node metastasis was observed in the histological
types of moderate and poorly differentiated adenocarcinoma than well
differentiated type. When cases were divided into 2 groups by age,
significant differences were observed between younger (≤ 64 years
old) and older (≥ 65 years old) groups in the following points: 1)
Histopathologically, well differentiated type was not recognized in the
younger group, while 3 histological types of well, moderate and
poorly differentiated adenocarcinoma, were equally distributed among
the older one. 2) Although there was insignificant difference in the
incidence or the numbers of metastatic sites to bone between the 2
groups, the younger patients had less symptoms related to bone
metastasis. The prominent symptoms in the younger group were
complaints about voiding (12).
This study aims to establish the clinical profile of Stage D
carcinoma of the prostate in the local population in Singapore. Of 47
patients with Stage D disease treated at the Department of Urology,
Singapore General Hospital in 1981-90, 47.7% was in the age-group
66-75 years and the most common presenting symptom was bone pain
(36.2%). Both acid phosphatase and ALP were poor diagnostic
markers of the extent of the disease. Acid phosphatase was not
elevated in 25.0% and ALP not elevated in 39.1% of the patients. Of
these patients, 40 had orchidectomy and of these, 10 were treated with
oral stilbesterol. Five-year survival for the orchidectomy group was
22.7% and 23.0% for the orchidectomy-plus-stilbesterol group. Eight
patients died within the first year of diagnosis but those who survived
554
remained symptom-free within this first year. The proportion of those

who remained symptom-free was 25.0% (13).
A 56-year-old man was admitted to the hospital complaining of

dyspnea, general fatigue and lumbago. Several examinations revealed
severe pancytopenia with DIC, multiple lymph node metastases, and
extremely high serum PSA level. Hormonal therapy under a diagnosis
of advanced prostate cancer was started. Bone marrow biopsy,
performed for the assessment of pancytopenia, revealed that there
were no hematopoietic cells but only diffuse infiltration of prostate
cancer cells. His bone scintigraphy showed a super scan image.
Therefore, the diagnosis was prostate cancer with disseminated
carcinomatosis to bone marrow. Although the response to hormonal
therapy had been initially good, the time to PSA nadir was 9 weeks
and he died 34 weeks after the start of the treatment (14).
Fifty-one patients with stage D carcinoma of the prostate,
previously treated for their primary tumor by surgery or RT combined
with hormonal manipulation and for metastases by hormones and
chemotherapy, were included in the study. The metastatic
dissemination, characterized primarily by the appearance of bone
metastases, could follow 2 distinct patterns: The first, is characterized
by sequential appearance of osteoblastic metastases, followed by the
development of osteolytic bone lesions, and the second pattern is
characterized by the simultaneous appearance of osteoblastic and
osteolytic bone lesions. In cases with solely osteoblastic bone
555
metastases, the lesions are hormone sensitive and long-lasting

remissions could be obtained. The development of osteolytic bone
lesions is usually accompanied by the recurrence of the primary tumor
and appearance of metastases in other sites, such as the lymph nodes
and lungs. Bone metastases became resistant to hormonal
manipulation and with chemotherapy short remissions were obtained.
The course of the terminal period is faster, with shorter survival times.
The determination of serum acid and ALP levels seems to reflect the
course of the disease during the initial period of the disease only, i.e.
when bone metastases are sensitive to hormonal treatment (15).
Prostatic cancer in 1885 autopsy cases was classified according to
the number of organs involved in metastasis, and a comparison was
made concerning the frequency of metastasis to the various organs.
The frequencies of metastasis to the lungs and para-aortic lymph
nodes were low in cases with single-organ involvement (4.6% and
2.3%, respectively), but increased rectilinearly in accordance with the
number of organs involved and became high in cases with metastasis
to 3 or more organs (49.1% and 21.8% in total, respectively). On the
other hand, the frequencies of local extension to the bladder and
invasion of the pelvic lymph nodes were high even in cases with
single-organ involvement (34.5% and 9.2%, respectively) and were
insignificantly changed regardless of the number of organs involved.
Insignificant correlation was between pelvic and para-aortic lymph
node involvement. In cases with single-organ involvement, metastasis
to the lumbar spine occurred frequently, but those to the ribs, sternum,
and ilium occurred less frequently. There may be multiple metastases
in cases with metastases to the para-aortic lymph nodes, sternum, and
ilium. The number of metastatically involved organs is useful in
analyzing the mode of metastasis (16).
Patients with bone metastases from prostate cancer (n=115)
between 1997 and 2009 were studied. The follow-up rate was 100%,
the follow-up cases during 1, 3 and 5 years were 103, 79 and 55,
respectively. The 1-, 3- and 5-year survival rates were 89.1%, 60.9%
and 49.8%, respectively, with a median survival time of 48.5 months.
In univariate analysis, age, Gleason score, clinical stage, the number
of bone lesions, ALP level, invasion of neighboring organs and non-
regional lymph node metastases were correlated with prognosis. By
multivariate analysis using Cox regression, ALP level, Gleason score
and non-regional lymph node metastases were independent prognostic
factors. These prognostic factors will help us to determine the
appropriate dose and fraction of RT for these patients (17).
556
Men with prostate cancer are at high risk of developing bone

metastases that can lead to clinically significant skeletal morbidity.
Recently, a randomized, placebo-controlled, phase III trial in 422 men
with hormone-refractory prostate cancer and bone metastases
demonstrated that zoledronic acid (4 mg every 3 weeks) significantly
reduced the incidence and onset of skeletal complications and
provided significant long-term reductions in bone pain compared with
placebo. Patients received zoledronic acid for a 15-month core phase,
with the option to continue therapy for 9 more months on the
extension phase. To evaluate the continuing benefit of long-term
zoledronic acid therapy, retrospective exploratory analyses were
conducted based on the incidence of SREs (pathologic bone fracture,
spinal cord compression, surgery or radiation therapy to bone, or
change in antineoplastic therapy for bone pain) occurring only during
the extension phase of this trial. QOL parameters included assessment
with the BPI. Similar to results reported for the 15-month core phase
and the entire 24-month study, the 9-month extension phase
demonstrated that zoledronic acid significantly reduced the percentage
of patients with SRE (p=0.02), prolonged the median time to the first
SRE (p=0.04), reduced the annual incidence of SRE by 52% (p=0.02),
and reduced the risk of SREs by 53% (p=0.02) compared with
placebo. Zoledronic acid was safe and well tolerated. Therefore,
zoledronic acid provides long-term continuing clinical benefit for men
with prostate cancer and bone metastases and represents a new
therapeutic option for this population (18).
A cohort study of 23,087 incident patients with prostate cancer
with a median 2.2-year follow up, identified through the Danish
National Patient Registry from 1999 to 2007, was performed. Of the
569 (almost 3%) patients presented with bone metastasis at prostate
cancer diagnosis, 248 (43.6%) experienced a SRE during follow up.
Of the 22,404 men (97% overall) without bone metastasis at
diagnosis, 2,578 (11.5%) were diagnosed with bone metastasis and
1,329 (5.9%) also experienced a SRE during follow up. One and 5-
year survival was 87% and 56% in patients with prostate cancer
without bone metastasis, 47% and 3% in those with bone metastasis,
and 40% and less than 1% in those with bone metastasis and SREs,
respectively. The adjusted 1-year mortality rate ratio was 4.7 (95% CI
4.3 - 5.2) in patients with bone metastasis and no SREs, and 6.6 (95%
CI 5.9 - 7.5) in patients with bone metastasis and SREs. In conclusion,
bone metastasis and SREs predict poor prognosis in men with prostate
cancer (19).
557
Transverse T2-weighted MR image (5,000/96 [effective]) obtained in a

49-year-old man with a PSA level of 4.5 ng/mL and positive finding after
transrectal biopsy, which indicated a Gleason Grade VI tumor at the right
apex. Image shows a tumor focus (arrow) at the right apex.
A patient with a solitary tibial metastasis of a prostatic carcinoma

is reported. Metastases to the peripheral skeleton are relatively rare
with a frequency of only 1-2% and are found in cases of general
spread of the disease. Complaints due to peripheral solitary metastases
often cause misinterpretations. Bone scintigraphy is the primary
method in the diagnosis of skeletal metastases, and is sometimes
supported by specific radiographs. MRI yields excellent images of the
extension of the tumor. It is therefore of high diagnostic value in the
preoperative definition of the metastatic spread in bone and
neighboring soft tissue structures (20).
Bone scans with 99mTc-methylene diphosphonate were performed
in 144 patients with pathologically proven prostate cancer, and
distribution regularity of metastatic bony lesions was analyzed
retrospectively. Of 2000 lesions, bone metastases were detected in 102
patients, 28.9% of which were distributed in the ribs, 14.8% in
thoracic vertebrae, 13.8% in the ilium, and 8.0% in the lumbar
vertebrae. The distribution of metastatic bony lesions was correlated
with the total number of lesions. The proportion of metastatic lesions
of vertebrae and pelvis was up to 84.5% (49/58) in fewer bone
metastases. The proportion gradually decreased with an increase in the
total number of lesions, but the proportion of the bony lesions, except
for the vertebrae and pelvis, gradually increased with an increase in
the total number of lesions. Of metastatic bony lesions, 98%
(903/912), except for the vertebrae and pelvis, coexisted with
metastasis of vertebrae or pelvis, whereas only 1.0% (9/912) of those
were detected in no metastasis of the vertebrae and pelvis; their
difference was significant (p=0.000). About 98.8% (571/578) of
metastatic costal lesions coexisted with vertebrae metastasis, but only
1.2% (7/578) of these were detected in no metastasis of vertebrae;
558
their difference was significant (p=0.000). The difference between left

body and right body was insignificant (p=0.249). In conclusion,
metastatic bony lesions of prostate cancer are located mainly in the
vertebrae and pelvis in the early stage. The distribution of metastatic
bony lesions is not only characterized by spreading to left body and
right body randomly, but also presents the tendency of developing
with orderliness to a certain extent in the whole body (21).
The clinical data of 91 patients with bone metastases, Warsaw,
Poland, were reviewed. The RCC and prostatic carcinoma were
diagnosed respectively in 53% and 47% of the patients; 21% of the
patients presented a bone pain (22).
A 67-year-old man had a renal mass on CT scan incidentally. He
had had total androgen blockage (bicalutamide + leuprolerin) and
chemotherapy (docetaxel hydrate) for treatment of prostate cancer
discovered 33 months ago. Based on the clinical features and
radiologic results, the patient had a second malignant tumor, and left
nephrectomy was performed. The pathological finding of this case
was renal metastasis from prostatic adenocarcinoma. He died 18
months postnephrectomy (23).
Metastases of RCC to the prostate gland are very rare. A case of a
metastasic RCC to the prostate occurred 10 years after nephrectomy.
Treatment with sunitinib was initiated and a notable response
achieved (24).
A delayed (9 years) metachronous solitary metastasis presentation
of RCC to the prostate is reported. Including this patient, 5 cases of
metastatic RCC to the prostate have been reported. Four patients
presented with hematuria and 2 with bladder outlet obstruction; 1 had
an incidental finding after prostate biopsy. Radical prostatectomy
could be considered for patients with the prostate as the only site of
disease (25).
An 86-year-old man was admitted to the hospital with a complaint
of gross hematuria. Urological examination revealed right
hydronephrosis and poorly differentiated adenocarcinoma of the
prostate with bone metastases. Abdominal CT scan and retrograde
pyelography showed thickening of the ureteral wall with irregular
stenosis in the right upper ureter. Right nephroureterectomy
demonstrated diffuse lymphatic infiltration of PSA-positive cancer
cells in the submucosa and muscle layer of the ureter as well as renal
pelvis. This is the case of metastatic ureteral tumor from prostate
cancer (26).
A 71-year-old man underwent a radical nephrectomy for right RCC
in April 2005. Pathological findings revealed clear cell carcinoma,
559
G3＞G2, pT3a. Three years later, he underwent a craniotomy for

tumor resection of solitary brain metastasis. In October 2008, he came
to the hospital because of urinary retention. BPH was diagnosed by
ultrasonography and digital rectal examination. Serum PSA level was
2.55 ng/dl. While he was treated with oral α 1-blocker initially, a
urethral catheter was inserted in December 2009. Because of frequent
obstruction of the catheter by hematuria, transureathral prostectomy
was performed. Pathological findings revealed prostatic metastasis of
RCC. Metastasis of RCC to the prostate is rare (27).
When RCC that has metastasized to the prostate is identified, it has
been associated with widespread MBD and short-term survival. A
case of metachronous RCC was found only in the prostate with the
longest reported interval of 9 years between radical nephrectomy and
clinically apparent disease (28).
Assessment: prostate cancer remains one of the leading causes of

cancer-related morbidity and mortality in the world. The majority of
patients are in the age group 66-75 years. Metastatic prostate cancer
metastasizes to bone, lymph node, lung and liver.
Risk factors include advancing age, race, and a family history of
prostate cancer. Many putative risk factors, including androgens, diet,
physical activity, sexual factors, inflammation, and obesity are
implicated, but their roles in prostate cancer etiology remain unclear.
Symptoms include dysuria, urinary frequency, and/or pelvic pain,
cachexia, and bone pain. Urological complications, including
essentially bladder outflow obstruction and hydronephrosis, are
caused by the local extension and lymphatic spread of prostate cancer.
Bladder outflow obstruction, bone pain and anemia not only dictate
treatment selection each of these symptoms but also have prognostic
significance in patients with metastatic cancer of the prostate. The
metastatic dissemination, characterized primarily by the appearance of
bone metastases, could follow 2 distinct patterns: The first is
characterized by sequential appearance of osteoblastic metastases,
followed by the development of osteolytic bone lesions, and the
second pattern is characterized by the simultaneous appearance of
osteoblastic and osteolytic bone lesions.
Was prostate carcinoma responsible for the bone metastases in the
King? The medical record of the King, that is the biblical text, did not
mention any urinary complaints. However, only 51% of patients
afflicted with prostate carcinoma may suffer from urinary symptoms
and/or pelvic pain. Thus, the absence of urinary complains cannot
point to the absence of the disease, in this case the prostate cancer.
560
For this reason, the diagnosis of prostate cancer is still possible for
King David.
Was King David afflicted by a combined RCC and prostate
cancer? Renal metastases from prostate cancer show the possibility of
tumor metastasis. RCC and prostatic carcinoma can occur in patients
presenting with bone pain.
We see that a combined diagnosis of RCC and prostate cancer is
possible in King David's case.
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26. Maeda N, Yoshida T. Metastatic tumor of renal pelvis and ureter from
prostatic cancer: a case report. Hinyokika Kiyo. 1999;45(4):273-5.
27. Kim H, Usui Y, Soeda S, et al. Prostatic metastasis of renal cell carcinoma.
Hinyokika Kiyo. 2011;57(12):705-8.
28. Greene GF, Gokden N, Hutchins LF, Williams RC. Metastatic renal cell
carcinoma to prostate. Urology. 2005;65(6):1227.
HEMATURIA IN PRIMARY CARE

Hematuria, including asymptomatic microscopic and gross
hematuria, is a common finding in primary care practice (1,2). The
prevalence of asymptomatic microscopic hematuria in adults ranges
from 0.19-21% (3). The range is wide because of differing definitions
of clinically significant microscopic hematuria and varying ages of the
study populations. Urine normally contains a few red blood cells, and
microscopic hematuria generally is defined as one to 10 red blood
cells per high-power field of urine sediment (4). The AUA defines
clinically significant microscopic hematuria as 3 or more red blood
cells per high-power field on microscopic evaluation of urinary
sediment from 2 of 3 properly collected urinalysis specimens (3,5).
Each laboratory, however, establishes its own thresholds based on the
method of detection used and in reference to healthy persons as
controls. Urine dipstick evaluation may be misleading because it lacks
the ability to distinguish red blood cells from myoglobin or
hemoglobin. Therefore, a positive finding of microscopic hematuria
562
on urinary dipstick testing requires follow-up examination by

microscopic technique to confirm the presence of red blood cells ׁ(6).
Microscopic hematuria, unlike gross hematuria, is often an
incidental finding but may be associated with urologic malignancy in
up to 10% of adults (7,8). Despite this risk, 39-90% of persons with
microscopic hematuria on screening urinalysis receive no follow-up
testing (9). Microscopic hematuria presents a challenging clinical
scenario for family physicians. Obtaining a thorough history and
physical examination and assessing each patient's risk factors for
urothelial cancer can assist physicians in choosing how to proceed
with radiographic evaluation of the upper urinary tract, urine cytology,
or cystoscopy (6).
Although screening asymptomatic patients is not generally
recommended (3), microscopic hematuria is still diagnosed
incidentally by urine dipstick studies. Many available urine dipstick
tests are so sensitive that they can detect as few as 1 or 2 red blood
cells per high-power field (4). However, these tests cannot distinguish
among myoglobin, hemoglobin, and red blood cells. Urine dipstick
testing is 91-100% sensitive and 65-99% specific for detection of red
blood cells, hemoglobin, and myoglobin (10-13). A positive finding
on urine dipstick testing should be evaluated further by microscopic
analysis to confirm the finding of red blood cells.
During the evaluation of patients with suspected UTI, the urine
dipstick may reveal blood as well as the leukocyte esterase, nitrites,
and bacteria consistent with the patient's symptoms. In such cases,
treatment with antibiotics should lead to resolution of microscopic
hematuria as demonstrated by follow-up urine studies 6 weeks after
therapy. When microscopic hematuria resolves in this scenario, no
further evaluation is necessary (3).
Hematuria is identified by taking a patient history and by
performing a routine urine dipstick test. If a patient has a history of
gross hematuria and/or a positive urine dipstick test, he or she should
then have a microscopic urinalysis. The primary care physician can
order ancillary tests such as laboratory tests to assess renal function
and imaging tests such as ultrasonography, CT urography, or MR
urography. The patient may be referred to a nephrologist or urologist
for further assessment if required. Cystoscopy should be considered.
Even if the patient has a negative work up, guidelines recommend that
primary care physicians follow the patient semi-annually for 3 years
(1).
Etiologies of microscopic hematuria range from incidental causes
to life-threatening urinary tract neoplasm (6). Causes of microscopic
563
hematuria are presented in the TABLE 1. Drug induced microscopic

hematuria is presented in the TABLE 2.
TABLE 1. Causes of microscopic hematuria*#

Glomerular causes Metabolic
Alport's syndrome Hypercalciuria
Fabry's disease Hyperuricosuria
Goodpasture's syndrome Vascular disease
Hemolytic uremia Arteriovenous malformation
Henoch-Schönlein purpura Malignant hypertension
Immunoglobulin A nephropathy Renal artery embolism/
Lupus nephritis thrombosis
Membranoproliferative glomerulonephritis Renal venous thrombosis
Mesangial proliferative glomerulonephritis Sickle cell disease
Other postinfectious glomerulonephritis Extrarenal
Endocarditis Calculi
Viral Coagulopathy related
Poststreptococcal glomerulonephritis Malignancy
Thin basement membrane nephropathy Renal cell carcinoma
(benign familial hematuria) Transitional cell carcinoma of
Loin pain - hematuria syndrome ureter, bladder
Non-glomerular causes Systemic disease
Renal (tubulointerstitial) Sarcoidosis
Acute tubular necrosis Lymphoma
Congenital abnormalities Sjögren's syndrome
Hereditary nephritis Wegener's granulomatosis
Medullary cystic disease Medication induced
Polycystic kidney disease Other causes
Other congenital abnormalities Endometriosis
Inflammation Factitious
Pyelonephritis Foreign bodies
Interstitial nephritis Posterior ureteral valves
Prostatitis Solitary renal cyst
Epididymitis Strictures
Urethritis Trauma
Cystitis Catheterization
Radiation induced Exercise hematuria
Infectious diseases Menstrual contamination,
Schistosomiasis Sexual intercourse
Syphilis
Toxoplasmosis
Cytomegalovirus
Epstein-Barr virus
*Ref (1,2,4,5,14-16). #TABLE 1 is with mild changes.
564
TABLE 2. Medications that can cause hematuria (6,14-16).

Aminoglycosides Diuretics
Amitriptyline Heparin
Analgesics NSAIDs
Anticonvulsants Oral contraceptives
Aspirin Penicillins (extended spectrum)
Busulfan (Busulfex) Quinine (QM-260)
Chlorpromazine (Thorazine Vincristine (Oncovin)
Cyclophosphamide (Cytoxan) Warfarin/Coumadin
Painless gross hematuria is the most important clinical sign with a

high predictive value, especially in older men. The value of
microscopic hematuria is unclear and most patients with microscopic
hematuria do not have a malignancy. Yet despite this, current
guidelines still advise additional tests for all types of hematuria (17).
The lack of evidence-based imaging guidelines of microscopic
hematuria can complicate the family physician's decision about the
best way to proceed. Patients with proteinuria, red cell casts, and
elevated serum creatinine levels should be referred promptly to a
nephrology subspecialist. Microscopic hematuria with signs of UTI
should resolve with appropriate treatment for the underlying infection.
Patients with asymptomatic microscopic hematuria or with hematuria
persisting after treatment of UTI need to be evaluated (6).
There is little controversy regarding whether gross or visible
hematuria requires complete upper and lower urinary tract evaluation.
With regard to microscopic hematuria, investigators have disagreed on
precisely which patients require a complete work-up. Most agree that
older patients (> 40 years), patients with a history of cigarette use, and
those with occupational exposure or history of chronic phenacetin use
should undergo upper tract imaging, cystourethroscopy, and cytologic
examination of the urine in addition to a thorough history and physical
examination. A multidisciplinary group of oncologists, radiologists,
urologists and internists has published its recommendations as part of
the AUA best practice policy. The formal guidelines, which were
distributed, re-reviewed, and modified following a nationwide survey
of clinicians, recommend complete urologic evaluation for all patients
with microscopic hematuria who are > 40 years of age, and younger
patients with a history suspicious for urologic disease. This identifies
those at highest risk for malignancy while minimizing the number of
evaluations in patients unlikely harboring significant disease (18).
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Assessment: hematuria, including asymptomatic microscopic and

gross hematuria, is a common finding in primary care practice. The
prevalence of asymptomatic microscopic hematuria in adults ranges
between 0.19-21%. The AUA defines clinically significant
microscopic hematuria as 3 or more red blood cells per high-power
field on microscopic evaluation of urinary sediment from 2 of 3
properly collected urinalysis specimens.
Etiologies of microscopic hematuria range from incidental causes
to life-threatening urinary tract neoplasm. Microscopic hematuria with
signs of UTI should resolve with appropriate treatment of the
underlying infection. Patients with asymptomatic microscopic
hematuria or with hematuria persisting after treatment of UTI need to
be evaluated. Complete urologic evaluation for all patients with
microscopic hematuria who are > 40 years of age, and younger
patients with a history suspicious for urologic disease is
recommended.
References
1. Sing RI, Singal RK. What is significant hematuria for the primary care
physician? Can J Urol. 2012;19(5 Suppl 1):36-41.
2. Patel JV, Chambers CV, Gomella LG. Hematuria: etiology and evaluation for
the primary care physician. Can J Urol. 2008;15 Suppl 1:54-61; discussion 62.
3. Grossfeld GD, Wolf Jr, Litwan MS, et al. Asymptomatic microscopic
hematuria in adults: summary of the AUA best practice policy recommendations. Am
Fam Physician. 2001;63:1145–54.
4. Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J
Med. 2003;348:2330–8.
5. Sokolosky MC. Hematuria. Emerg Med Clin North Am. 2001;19:621-32.
6. McDonald MM, Swagerty D, Wetzel L. Assessment of microscopic hematuria
in adults. Am Fam Physician. 2006;73(10):1748-54.
7. Sultana SR, Goodman CM, Byrne DJ, Baxby K. Microscopic haematuria:
urological investigation using a standard protocol. Br J Urol. 1996;78:691–8.
8. Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1,930
patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;
163:524–7.
9. Sutton JM. Evaluation of hematuria in adults. JAMA. 1990;263:2475-80.
10. Woolhandler S, Pels RJ, Bor DH, et al. Dipstick urinalysis screening of
asymptomatic adults for urinary tract disorders I. Hematuria and proteinuria. JAMA.
1989;262:1214-9.
11. Arm JP, Peile EB, Rainford DJ, et al. Significance of dipstick haematuria. 1.
Correlation with microscopy of the urine. Br J Urol. 1986; 58:211-7.
12. Vallancien G, Cadranel J, Jardin A. What should be done in the presence of
isolated microscopic hematuria in man in the work environment? Presse Med.
1985;14:1279–81.
13. Mariani AJ, Luangphinith S, Loo S, et al. Dipstick chemical urinalysis: an
accurate cost-effective screening test. J Urol. 1984;132:64-6.
14. Mazhari R, Kimmel PL. Hematuria: an algorithmic approach to finding the
cause. Cleve Clin J Med. 2002;69:870, 872-4,876.
566
15. Harper M, Arya M, Hamid R, Patel HR. Haematuria: a streamlined

approach to management. Hosp Med. 2001;62:696–8.
16. Feld LG, Waz WR, Perez LM, Joseph DB. Hematuria. An integrated
medical and surgical approach. Pediatr Clin North Am. 1997;44:1191-210.
17. Blanker MH. Diagnosis of urothelial carcinoma by the general practitioner -
significance of haematuria. Ned Tijdschr Geneeskd. 2009;153: A1198.
18. Yun EJ, Meng MV, Carroll PR. Evaluation of the patient with hematuria. Med
Clin North Am. 2004;88(2):329-43.
URINARY TRACT EVALUATION

IVU, ultrasonography, and CT are used to evaluate the upper
urinary tract of persons with microscopic hematuria. Although many
studies have been conducted comparing these 3 radiographic methods,
no clear evidence-based imaging guidelines are available (1).
INTRAVENOUS UROGRAPHY
Traditionally, IVU has been the initial radiographic approach for
the evaluation of the upper urinary tract in patients with microscopic
hematuria (2,3). It defines the anatomy of the urologic tract from the
kidney to the bladder, and its advantages include relatively low cost
and ready availability. One concern regarding IVU as the sole
radiographic evaluation of microscopic hematuria is its limited
sensitivity for detecting small renal masses (4). IVU identified 85% of
lesions greater than 3 cm in diameter but only 21-52% of smaller
lesions (5). IVU is superior to CT in detecting transitional cell
carcinoma involving the kidney or ureter but has limited application in
the evaluation of the bladder and urethra. Patients undergoing IVU are
exposed to contrast media that is potentially nephrotoxic, especially in
patients with renal insufficiency. The cost savings of IVU may be
offset by the frequent need for follow-up study with ultrasonography
or CT for indeterminate findings or to better characterize a renal
lesion as cystic or solid (2).
567
Intravenous urogram of transitional cell carcinoma in a 60-year-patient.
RENAL ULTRASONOGRAPHY
Ultrasonography is the least expensive and safest choice for
evaluating microscopic hematuria because it does not expose the
patient to intravenous radiographic contrast medium. It is an
appropriate choice for the evaluation of hematuria during pregnancy.
Although ultrasonography is limited in its ability to detect solid
tumors that are less than 3 cm in diameter (4), masses 3 cm or greater
in diameter, cysts, and hydronephrosis are detected with a high degree
of sensitivity (3).
Ultrasound of renal cell carcinoma in a 51-year-old man.
Ultrasonography has been found to be more sensitive than IVU in

detecting RCC but less so in detecting urothelial transitional cell
carcinoma (1,3). The sensitivity of ultrasonography for detecting renal
calculi is at 64-96%, significantly lower than with noncontrast CT (3).
568
COMPUTED TOMOGRAPHY
Microscopic hematuria associated with renal colic is best evaluated
with CT in light of its high sensitivity for identifying renal calculi
(5,6). Unenhanced helical CT is more accurate for evaluating patients
with renal colic compared with ultrasonography, IVU, or plain
radiography and has replaced these imaging techniques as the test of
choice in many institutions. When compared with IVU, unenhanced
helical CT has the advantage of higher accuracy, decreased radiation
dose, faster examination time, and improved sizing and localization of
stones (6).
Contrast-enhanced CT has favorable sensitivity over IVU or
ultrasonography for identifying small renal parenchymal masses.
Contrast-enhanced CT also enables detection of aneurysms in vessels
that run along the ureter, a potentially life threatening, albeit
uncommon condition. Renal and perirenal abscesses are best
evaluated by contrast-enhanced CT. After a renal mass has been
identified by IVU or ultrasonography, CT likely would be indicated as
follow-up evaluation to better characterize the mass as a simple cyst,
complex cyst, or solid mass, or to stage for surgical planning. This
alone warrant initial evaluation by CT despite its higher cost (1,5).
Axial contrast-enhanced CT scan shows 1.5 cm RCC in lower pole of

right kidney. Intraprocedural axial contrast-enhanced CT scan shows
electrode within mass in lower pole of right kidney, with adjacent small (< 2
cm) perinephric hemorrhage (arrow). This finding is frequently seen and is
typically self-limited, resolving at follow-up imaging.
569
ASESSMENT OF LOWER URINARY TRACT

Identifying an abnormality in the upper urinary tract does not
preclude evaluation of the lower urinary tract because a comorbid
lesion may exist. The etiology of asymptomatic microscopic
hematuria remains unclear in 70% of patients after imaging of the
upper urinary tract and assessment of urine for signs of glomerular
disease. Urine cytology studies and cystoscopy are used routinely to
evaluate the lower urinary tract (7).
URINE CYTOLOGY
The AUA recommends that patients with microscopic hematuria
have radiographic assessment of the upper urinary tract followed by
urine cytology studies (1). Voided urine cytology studies are less
sensitive (66% and 79% in 2 studies) than cystoscopy for the
evaluation of bladder cancer. The sensitivity can be optimized by
following urine collection protocols in which urine is collected from
the first void of the morning on 3 consecutive days. Urine cytology
does, however, have high specificity (95% and 100% in 2 studies) (7).
The sensitivity of urine cytology is highest for detection of high-grade
lesions in the bladder and carcinoma in situ (9). The primary
advantage of urine cytology vs. cystoscopy is that because it is
noninvasive, it does not cause the patient any discomfort. Urine
cytology is limited in its ability to detect low-grade lesions in the
bladder as well as RCC (8).
Because upper and lower urinary tract pathologies often coexist,
patients should be evaluated using cytology plus IVU,
ultrasonography, or CT. When urine cytology results are abnormal,
cystoscopy should be performed to complete the investigation (9).
Patients who have no identifiable cause after an extensive workup
should be monitored for early detection of malignancy or occult renal
disease (10).
The objective of this study was to determine the value of routine
urine cytology in the initial evaluation of patients presenting to a one-
stop hematuria clinic. A total of 1000 consecutive patients who
attended the hematuria clinic between June 2003 and November 2004
were studied prospectively. A standard protocol was used to
investigate these patients. This included urine cytology, upper tract
imaging and flexible cystoscopy. Overall, 986 samples of urine were
570
sent for cytology. In 126 patients, the report was abnormal; of these,
71 patients were found to have bladder transitional cell carcinoma by
flexible cystoscopy and a further 3 had upper tract transitional cell
carcinoma diagnosed radiologically. The remaining 52 patients with
abnormal cytology had not cancer on further investigations. The total
cost for urine cytology and additional investigations was pound
50,535. In this study of the initial evaluation of patients with
hematuria, urothelial malignancy was not diagnosed based on urine
cytology alone. Therefore, urine cytology should not be used routinely
in the initial diagnostic work-up for hematuria (11).
CYSTOSCOPY
The AUA recommends that all patients > 40 years and those who
are younger but have risk factors for bladder cancer obtain cystoscopy
to complete the evaluation of microscopic hematuria (1). Abnormal
urine cytology findings would necessitate cystoscopy, which has 87%
sensitivity for bladder cancer (7). Cystoscopy is the only reliable
method of detecting transitional cell carcinoma of the bladder and the
urethra (12). The primary disadvantages of cystoscopy are patient
discomfort with this invasive procedure and its limited ability to detect
carcinoma in situ of the bladder (8).
A 54-year-old woman was presented with gross hematuria. In cystoscopy,

polypoid lesion (arrows) was found.
FOLLOW-UP
There has been some debate about the recommended follow-up for
patients with idiopathic microscopic hematuria. An acceptable
approach would include repeated urinalysis with urine cytology every
6 months and repeated cystoscopy every year. This is especially
571
important for persons > 40 years and younger persons who have risk
factors for urothelial cancer (i.e., smoking history, occupational
exposure to benzenes or aromatic amines - leather dye, rubber, and
tire industries, or history of urologic neoplasm) (13).
COMPARISON OF DIFFERENT DIAGNOSTIC

MODALITIES
The main objective of this study was to evaluate a new diagnostic
algorithm for microscopic hematuria in which IVU is performed as a
secondary radiographic study when microhematuria has persisted for 3
months after the initial workup with negative renal ultrasonography
and cystoscopy. Consecutive patients (n=372) who presented with
microhematuria and negative urine cultures and cytological findings
underwent renal ultrasonography scanning and cystoscopy as their
initial evaluation and re-evaluation 3 months after the initial workup.
Patients with persistent microhematuria with no apparent etiology
were then evaluated with IVU. The initial evaluation was negative in
212 of 372 patients. Of these patients, 81 had persistence of their
microhematuria at the 3-month follow-up without a definitive
diagnosis. Seventy-five of these patients underwent IVU.
Abnormalities were found in 11 of the 75 patients. Six patients had
renal stones, 2 had ureteral stones, 2 had ureteral tumors, and 1 had a
tumor of the renal pelvis. Of the 131 patients, 40 with resolution of
their microhematuria underwent IVU at their request. All those studies
were normal. In conclusion, the combination of cystoscopy and renal
ultrasonography along with urinalysis, urine culture, and cytology is a
good initial evaluation in patients with microhematuria. Patients with
persistent microhematuria after 3 months without definite etiology of
the bleeding may still benefit from IVU (3).
The main aim of this study was to derive and validate an algorithm
to estimate the absolute risk of renal tract cancer in patients with and
without symptoms in primary care. In a cohort study using data from
375 UK QResearch® general practices for development and 189 for
validation, included patients aged 30-84 years free at baseline of a
diagnosis of renal tract cancer (bladder, kidney, ureter, or urethra) and
without hematuria, abdominal pain, appetite loss, or weight loss in
previous 12 months. The primary outcome was incident diagnosis of
renal tract cancer recorded in the next 2 years. Risk factors examined
were age, BMI, smoking, alcohol, deprivation, treated hypertension,
572
renal stones, structural kidney problems, diabetes, previous diagnosis

of cancer apart from renal tract cancer, hematuria, abdominal pain,
appetite loss, weight loss, diarrhea, constipation, tiredness, and
anemia. There were 2878 incident cases of renal tract cancer from 4.1
million person-years in the derivation cohort. Independent predictors
in both males and females were age, smoking status, hematuria,
abdominal pain, weight loss, and anemia. A history of prior cancer
other than renal tract cancer, and appetite loss were predictors for
females only. The 10% of patients with the highest predicted risks
contained 87% of all renal tract cancers diagnosed over the next 2
years. In conclusion, the algorithm has good discrimination and
calibration and could potentially be used to identify those at highest
risk of renal tract cancer to facilitate more timely referral and
investigation (14).
The main objective of this study was determine whether patients
found to have hematuria by their primary care physicians are
evaluated according to best practice policy. The University of Texas
at Southwestern Medical Center maintains institutional outpatient
electronic medical records that are used by all providers in all
specialties. An Institutional Review Board approved observational
study of patients found to have more than 5 red blood cells/high power
field between March 2009 and February 2010. The majority was
female (82%), and Caucasian (39%), with microscopic hematuria
(85%) of 449 patients. Almost 58% of patients were initially
symptomatic with urinary symptoms or pain. Evaluation for the source
of hematuria was limited and included imaging (35.6%), cystoscopy
(9%), and cytology (7.3%). Only 36% of men and 8% of women were
referred to an urologist. No abnormality was found in 32% and 51%
of patients with gross hematuria and microscopic hematuria,
respectively (p=0.004). There were 4 bladder tumors and 1 renal mass.
Male gender, ethnicity and gross (vs. microscopic) hematuria were
associated with higher rate of urological referral. Advanced age,
smoking, provider practice type, and the presence of urinary
symptoms were not associated with an increase rate of urological
referral. No additional cancers were diagnosed with 29-month follow-
up. In conclusion, while urinalysis remains a common diagnostic tool,
most cases of both microscopic and gross hematuria are not fully
evaluated according to guidelines. Use of cystoscopy, cytology, and
upper tract imaging is limited (15).
The aim of the present study was to evaluate the diagnostic
accuracy of CT urography in patients with visible hematuria aged > 40
years and to determine if CT urography has a role for diagnosing
573
bladder cancer. The optimum diagnostic strategy for investigating

patients with visible hematuria aged > 40 years with infection
excluded is a combined strategy using CT urography and flexible
cystoscopy. Patients positive for bladder cancer on CT urography
should be referred directly for rigid cystoscopy and so avoid flexible
cystoscopy. The number of flexible cystoscopies required therefore
may be reduced by 17%. The diagnostic accuracy of voided urine
cytology is too low to justify its continuing use in a hematuria clinic
using CT urography and flexible cystoscopy (16).
In 2001, the AUA Best Practice Policy Panel recommended CT or
IVU over ultrasonography as the initial imaging modality in patients
with asymptomatic microhematuria. This study compared the results
of IVU and ultrasonography in patients > 40 years of age who were
referred to a single urology department for evaluation of microscopic
hematuria between 1994 and 2000. There were 290 patients who
agreed to participate by undergoing ultrasonography in addition to
IVU; 247 completed both tests. There were 81 men and 166 women
with a mean age of 56.4 years (range 40-86 years). Thirty patients
(12%) were smokers. A renal lesion or mass suggestive of tumor was
found in 8 patients (3.2%); 3 patients had this finding on the IVU
examination and 5 on ultrasonography. None of the patients had such
a lesion/mass on both examinations. Two patients with suspected
lesions were found to have RCC. Both of the patients with RCC had a
suspected lesion on the ultrasonography but not on the
contemporaneous IVU. In conclusion, IVU may miss lesions/masses
that lead to a diagnosis of upper-tract neoplasia (17).
The main aim of this study was to assess the value of a single-
phase DECT urography protocol with synchronous nephrographic-
excretory phase enhancement and to calculate the potential dose
reduction by omitting the unenhanced scan. Eighty-four patients
referred for hematuria underwent CT urography using a protocol that
included single-energy unenhanced and dual-energy contrast-
enhanced with synchronous nephrographic-excretory phase scans.
DECT-based images (virtual unenhanced, weighted average, and
colour-coded iodine overlay) were reconstructed. Opacification degree
by contrast media of the upper urinary tract, and image quality of
virtual unenhanced images were independently evaluated using a 4-
point scale. The diagnostic accuracy in detecting urothelial tumors on
DECT-based images was determined. The dose of a theoretical dual-
phase single-energy protocol was obtained by multiplying the
effective dose of the unenhanced single-energy acquisition by 2.
Radiation dose saving by omitting the unenhanced scan was
574
calculated. The degree of opacification was scored as optimal or good

in 86.9% of cases (k = 0.72); virtual unenhanced image quality was
excellent or good in 83.3% of cases (k = 0.82). Sensitivity, specificity,
positive predictive value, and negative predictive value for urothelial
tumors detection were 85.7, 98.6, 92.3, and 97.1%. Omission of the
unenhanced scan led to a mean dose reduction of 42.7 ± 5%. In
conclusion, single-phase DECT urography with synchronous
nephrographic-excretory phase enhancement represents an accurate
"all-in-one'' approach with a radiation dose saving up to 45%
compared with a standard dual-phase protocol (18).
A retrospective review was performed of the radiological,
urological and pathological records of 468 patients without a history
of urinary neoplasms who presented with hematuria. All patients
underwent MDCT urography and completed urological evaluation,
including cystoscopy. Laboratory urinalysis and cytology were done
in 350 and 318 of the 468 patients, respectively. Fifty urinary
neoplasms were diagnosed in 468 patients. MDCT urography detected
32 of 50 neoplasms for a sensitivity of 64%, specificity of 98%,
positive predictive value of 76% and negative predictive value of
96%. There were 10 false positive and 18 false negative MDCT
urography studies. Multivariate logistic regression showed that
abnormal MDCT urography findings, i.e. neoplasm (p<0.0001), and
suspicious or positive urine cytology (p=0.0009) were significant.
Patients with an abnormal MDCT urography diagnosis and suspicious
or positive urine cytology had 44 and 47 times greater odds,
respectively, of having urinary neoplasms compared to the odds in
those with normal examinations. In conclusion, MDCT urography is
relatively sensitive and highly specific for detecting urinary
neoplasms. It may serve as the primary imaging modality to evaluate
patients with hematuria. MDCT urography does not eliminate the role
of cystoscopy in the evaluation of hematuria (19).
The objective of this study was to investigate the diagnostic
accuracy of MDCT urography for the detection of bladder tumors.
The medical records of 143 patients were scanned by use of 64-
channel MDCT urography and underwent cystoscopy due to painless
hematuria or a clinical suspicion of bladder tumor. The accuracy of
MDCT urography for the detection of bladder tumors by comparing
the results obtained by MDCT urography with those obtained by
cystoscopy was examined. The associations between tumor
characteristics, frequency of transurethral resection, and bladder
volume and detectability of bladder tumors on MDCT urography were
analyzed. Of 143 patients, 50 patients had a history of urothelial
575
carcinomas. In these patients, the sensitivity and specificity of MDCT

urography were 60.0% and 80.0%, respectively. In 93 patients without
previous urothelial carcinomas, the sensitivity and specificity of
MDCT urography were 86.7% and 96.8%, respectively. Falsely
diagnosed cases had a smaller distended bladder volume (p=0.014)
and a smaller tumor size (p=0.022) than did true diagnosed cases. The
false-negative rate increased when the bladder tumor was located at
the bladder neck. In the univariate analysis, the tumor location, size,
frequency of transurethral resection, bladder volume, and initial
hematuria were associated with detectability by MDCT urography
(p<0.05). In conclusion, to improve the accuracy of MDCT urography
for diagnosing bladder tumors, bladder filling is recommended. Thus,
cystoscopy should be considered as a standard diagnostic tool for
bladder tumors even in patients with normal MDCT urography results,
especially in the evaluation of recurrent, bladder neck-located, small,
or sessile bladder tumors (20).
The main aim of this study was to evaluate the diagnostic
performance of MRU vs. RPU in the detection of upper urinary tract
neoplasms. This retrospective study included 35 patients with
suspected upper urinary tract malignancy who underwent MRU and
RPU within 6-months during February 2002 to January 2007. For
each patient, the urinary tract was sub-divided into 4 regions for
analysis: left kidney/renal pelvis, left ureter, right kidney/renal pelvis,
and right ureter. Of 113 regions analyzed on MRU and 90 regions on
RPU, 19 neoplasms were identified. Sensitivity, specificity, positive
predictive value, and negative predictive value for the detection of
urinary tract neoplasms were 63%, 91%, 60%, and 92% for MRU,
respectively, and 53%, 97%, 83%, and 88% for RPU, respectively.
These differences were statistically insignificant (p>0.05). In
conclusion, the high negative predictive value of MRU in the present
series supports its use as a non-invasive screening examination for
excluding the presence of upper urinary tract malignancy (21).
A 74-year-old-man with urothelial carcinoma of the left ureter.

576
The purpose of this study was to prospectively compare IVP and

combined unenhanced and excretory phase MDCT with respect to
image quality, diagnostic certainty and diagnostic concordance with
the final clinical diagnosis in patients with painless microhematuria.
Unenhanced MDCT, IVP and excretory phase MDCT were performed
in 59 consecutive patients (21 women, 38 men, mean age 56 +/- 19
years, range 23 - 83 years) with painless microhematuria of unknown
origin during a single examination with a single contrast media
application (100 ml, non-ionic iodinated contrast media). Images were
assessed by 2 experienced urogenital radiologists in consensus for
image quality, diagnostic certainty of stone detection, obstruction,
parenchymal lesions and morphological distinctive features. Imaging
diagnoses of MDCT and IVP were compared with the final clinical
diagnoses. In case of failure to detect a relevant pathology, the final
clinical diagnosis was established after a mean follow-up period of 18
+/- 6 months (10 months to 2 years). MDCT scan performed better
than IVP in terms of image quality for all regarded variables. Image
quality of MDCT was rated in all parameters as very good or good;
the image quality of IVP differed in a wide range. MDCT and IVP
reached a sensitivity of 100% and 50% for stone detection (n=14,
p=0.008), respectively. Two bladder stones were not detected by IVU
but correctly seen with MDCT. MDCT and IVP were unsatisfactory
for detecting transitional cell carcinomas (n=4, 2 of 4 detected with
MDCT, 0 of 4 detected with IVU). One false positive transitional cell
carcinoma was detected with IVP, none with MDCT. Additional
relevant pathological changes (one teratoma, one abdominal aortic
aneurysm and one abscess) were detected using MDCT but missed
with IVP. In 38/59 (64%) patients, imaging and clinical follow-up
over up to 24 months did not reveal any pathology to explain the
microhematuria. The costs of the IVP (283 Euro) were lower
compared with non-enhanced MDCT (380 Euro) or combined non-
enhanced and contrast-enhanced MDCT (560 Euro). The radiation
exposure was 23 - 27 mSv for MDCT and 2.3 mSv for IVP. In
conclusion, MDCT is better regarding image quality, subjective
diagnostic certainty and diagnostic results with respect to stone
detection. Since urolithiasis is a frequent cause of painless
microhematuria MDCT is recommended as the initial imaging
modality rather than IVU (22).
577
REFERRAL PATTERN
Hematuria is one of the most common findings on urinalysis in
patients encountered by primary care physicians. In many instances, it
can be the first presentation of a serious urological problem.
Questionnaires were mailed to all registered primary care physicians
across Quebec. Questions covered each physician's personal approach
to men and postmenopausal women with painless gross hematuria or
with asymptomatic microscopic hematuria, as well as screening
techniques, general knowledge concerning urine collection and
sampling, and referral patterns. Of the surveys mailed, 599 were
returned. Annual routine screening urinalysis on all adult male and
female patients was performed by 47% of respondents, regardless of
age or risk factors. Of all the respondents, 95% stated microscopic
hematuria was associated with bladder cancer. However, in an older
male with painless gross hematuria, only 64% of respondents
recommended further evaluation by urology. In a postmenopausal
woman with 2 consecutive events of significant microscopic
hematuria, only 48.6% recommended referral to urology. Findings
were not associated with the gender of the respondent, experience or
geographic location of practice (urban vs. rural). There seems to be
reluctance amongst primary care physicians to refer patients with
gross or significant microscopic hematuria to urology for further
investigation. A higher level of suspicion and further education should
be implemented to detect serious conditions and to offer earlier
intervention when possible (23).
Assessment: patients with microscopic hematuria should be

evaluated using cytology plus ultrasonography, IVU, or CT. When
urine cytology results are abnormal, cystoscopy should be performed
to complete the investigation.
Patients > 40 years and who are younger but have risk factors for
bladder cancer should obtain cystoscopy to complete the evaluation of
microscopic hematuria. The combination of cystoscopy and renal
ultrasonography along with urinalysis, urine culture, and cytology is a
good initial evaluation in patients with microhematuria.
IVU may miss lesions/masses that lead to a diagnosis of upper-
tract neoplasia. Cystoscopy should be considered as a standard
diagnostic tool for bladder tumors even in patients with normal
MDCT urography results, especially in the evaluation of recurrent,
bladder neck-located, small, or sessile bladder tumors. MDCT
urography is sensitive and highly specific for detecting urinary
578
neoplasms. It may serve as the primary imaging modality to evaluate

patients with hematuria. MDCT urography does not eliminate the role
of cystoscopy in the evaluation of hematuria. Since urolithiasis is a
frequent cause of painless microhematuria, MDCT is recommended as
the initial imaging modality rather than IVU. The high negative
predictive value of MRU supports its use as a non-invasive screening
examination for excluding the presence of upper urinary tract
malignancy.
Single-phase DECT urography with synchronous nephrographic-
excretory phase enhancement represents an accurate "all-in-one''
approach with a radiation dose saving up to 45% compared with a
standard dual-phase protocol.
This is a contemporary approach to a patient with hematuria.
Ancient and contemporary patients deserve appropriate evaluation of
hematuria.
References
1. Grossfeld GD, Wolf JS Jr, Litwan MS, et al. Asymptomatic microscopic
hematuria in adults: summary of the AUA best practice policy recommendations. Am
Fam Physician. 2001;63:1145–54.
2. Mazhari R, Kimmel PL. Hematuria: an algorithmic approach to finding the
cause. Cleve Clin J Med. 2002;69:870,872-4,876.
3. Jaffe JS, Ginsberg PC, Gill R, Harkaway RC. A new diagnostic algorithm
for the evaluation of microscopic hematuria. Urology. 2001;57:889-94.
4. Jamis-Dow CA, Choyke PL, Jennings SB, et al. Small (< or = 3-cm) renal
masses: detection with CT versus US and pathologic correlation. Radiology.
1996;198:785–8.
5. Gray Sears CL, Ward JF, Sears ST, et al. Prospective comparison of
computerized tomography and excretory urography in the initial evaluation of
asymptomatic microhematuria. J Urol. 2002;168:2457-60.
6. Luchs JS, Katz DS, Lane MJ, et al. Utility of hematuria testing in patients
with suspected renal colic: correlation with unenhanced helical CT results. Urology.
2002;59:839-42.
7. Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J
Med. 2003;348:2330–8.
8. Koss LG, Deitch D, Ramanathan R, Sherman AB. Diagnostic value of
cytology of voided urine. Acta Cytol. 1985;29:810-6.
9. McDonald MM, Swagerty D, Wetzel L. Assessment of microscopic hematuria
in adults. Am Fam Physician. 2006;73(10):1748-54.
10. Patel JV, Chambers CV, Gomella LG. Hematuria: etiology and evaluation for
the primary care physician. Can J Urol. 2008;15 Suppl 1:54-61; discussion 62.
11. Viswanath S, Zelhof B, Ho E, et al. Is routine urine cytology useful in the
haematuria clinic? Ann R Coll Surg Engl. 2008;90(2):153-5.
12. Harper M, Arya M, Hamid R, Patel HR. Haematuria: a streamlined
approach to management. Hosp Med. 2001;62:696-8.
13. Sutton JM. Evaluation of hematuria in adults. JAMA. 1990;263:2475-80.
579
14. Hippisley-Cox J, Coupland C. Identifying patients with suspected renal tract

cancer in primary care: derivation and validation of an algorithm. Br J Gen Pract.
2012;62(597):e251-60.
15. Buteau A, Seideman CA, Svatek RS, et al. What is evaluation of hematuria by
primary care physicians: Use of electronic medical records to assess practice patterns
with intermediate follow-up. Urol Oncol. 2012 Nov 12. pii: S1078-1439(12)00243-8.
16. Blick CG, Nazir SA, Mallett S, et al. Evaluation of diagnostic strategies for
bladder cancer using computed tomography (CT) urography, flexible cystoscopy and
voided urine cytology: results for 778 patients from a hospital haematuria clinic. BJU
Int. 2012;110(1):84-94.
17. Dikranian AH, Petitti DB, Shapiro CE, Kosco AF. Iv urography in evaluation
of asymptomatic microscopic hematuria. J Endourol. 2005;19(5):595-7.
18. Ascenti G, Mileto A, Gaeta M, et al. Single-phase dual-energy CT urography
in the evaluation of haematuria. Clin Radiol. Clin Radiol. 2013;68(2):e87-94.
19. Sudakoff GS, Dunn DP, Guralnick ML, et al. Multidetector computerized
tomography urography as the primary imaging modality for detecting urinary tract
neoplasms in patients with asymptomatic hematuria. J Urol. 2008;179(3):862-7;
discussion 867.
20. Hwang EC, Kim JS, Kim SO, et al. Accuracy and factors affecting the
outcome of multi-detector computerized tomography urography for bladder tumors in
the clinical setting. Korean J Urol. 2011;52(1):13-8.
21. Leea KS, Zeikusa E, DeWolfb W.C. et al. MR urography versus retrograde
pyelography/ureteroscopy for the exclusion of upper urinary tract malignancy.
Clinical Radiology. 2010;65(3);185–92.
22. Michael M, John H, Wildermuth S, et al. Diagnostic assessment of painless
microhematuria: prospective study comparing image quality, accessibility and
diagnostic certainty of multidetector-row CT and iv pyelography within a single
examination. Rofo. 2005;177(10):1436-46. Erratum in Rofo. 2005;177(11):1589.
23. Yafi FA, Aprikian AG, Tanguay S, Kassouf W. Patients with microscopic and
gross hematuria: practice and referral patterns among primary care physicians in a
universal health care system. Can Urol Assoc J. 2011;5(2):97-101.
580
BONE TUMORS
Among human neoplasms, primary malignant bone tumors are
rare. They present an incidence rate of roughly 10 cases per 1 million
inhabitants per year. During childhood (< 15 years), the percentage of
malignant bone tumors amounts to 6% of all infantile malignancies.
Only leukemia and lymphoma show a higher incidence in
adolescence. Of all primary malignant bone tumors, 60% affect
patients < 45 years and the peak incidence of all bone tumors occurs
between 15 and 19 years. The most common primary malignant bone
tumors are osteosarcoma (35%), chondrosarcoma (25%), and Ewing's
sarcoma (16%). Less frequently (≤ 5%) occurring tumors are
chordoma, malignant fibrous histiocytoma of bone, and fibrosarcoma
of bone. Vascular primary malignant tumors of bone and
adamantinoma are rare. Staging of the lesion is essential for systemic
therapeutic decision-making and includes complete imaging and
histopathological confirmation of the suspected entity. In most cases,
this is established by open- or image-guided biopsy. Based on this
information, an interdisciplinary tumor board will determine the
individual therapeutic approach. Endoprosthetic or biological
reconstruction following wide tumor resection is the most common
surgical therapy for primary malignant bone tumors (1).
Malignant bone tumors represent a small percentage of cancers

nationwide and are much less common than malignant soft-tissue
tumors. The rarity of the condition makes it imperative that orthopedic
surgeons in nononcologic practices be able to recognize the symptoms
that suggest a possible bony malignancy to avoid inappropriate or
delayed treatment. The most common primary malignant bone tumors,
osteosarcoma and Ewing's sarcoma, occur in childhood.
Chondrosarcoma occurs more frequently in older adults. Rare tumors
such as chordoma and adamantinoma have anatomic predilections for
581
the sacrum and tibia, respectively. The primary symptom of a patient

with a malignant bone tumor is pain, which often occurs at rest or at
night. There are also characteristic findings on physical examination
such as swelling or decreased joint range of motion. Patients with a
likely malignancy require thorough staging to determine the extent of
disease and a well-planned biopsy for accurate diagnosis. The biopsy
can be an image-guided needle biopsy or an open incisional biopsy.
Knowledge of specific tumor characteristics and treatment options for
osteosarcoma, Ewing's sarcoma, chondrosarcoma, malignant fibrous
histiocytoma, chordoma, and adamantinoma is important. Patients
with osteosarcoma and resectable Ewing's sarcoma are treated with
chemotherapy followed by surgical resection. Secondary sarcomas can
occur in previously benign bone lesions and require aggressive
treatment. Specific techniques are available for the resection of
malignant bone tumors from the upper extremities, lower extremities,
pelvis, and spine. Reconstruction options include the use of allografts,
megaprostheses, and vascularized autografts. There has been a trend
toward more prosthetic reconstructions because of early complications
with allografts. The care of patients with primary malignant bone
tumors requires a multidisciplinary approach to treatment. The
orthopedic oncologist is a vital member of a team composed of
musculoskeletal radiologists and pathologists, radiation oncologists,
medical and pediatric oncologists, and microvascular surgeons (2).
References
1. von Eisenhart-Rothe R, Toepfer A, Salzmann M,et al. Primary malignant bone
tumors. Orthopade. 2011;40(12):1121-42.
2. Weber K, Damron TA, Frassica FJ, Sim FH. Malignant bone tumors. Instr
Course Lect. 2008;57:673-88.
GIANT CELL TUMOR

GCT is a locally highly aggressive tumor of bone comprising 5-
10% to ~20% of all benign bone tumors (1,2). The incidence rates are
higher in Asia; in China it constitutes also about 20% of all primary
bone tumors (3). It is slightly more common in females, has a
predilection for the epiphyseal/metaphyseal region of long bones
(4,5), and generally occurs in the third to fourth decade (6). Although
classified as a benign tumor, GCT of the bone has been observed to
metastasize to the lungs in up to 5% of cases, and in rare instances (1-
582
3%) can transform to the malignant sarcoma phenotype with equal

disease outcome (4,7,8).
Using data from the NCI's Surveillance, Epidemiology and End
Results program, the overall incidence and determinants of survival
among patients diagnosed with malignant GCT of bone from 1975-
2004 were estimated. Based on analyses of 117 malignant GCT cases,
the estimated annual incidence in the US was 1.6 per 10,000,000
persons per year. Incidence was highest among adults aged 20 to 44
years (2.4 per 10,000,000 per year) and most patients were diagnosed
with localized (31.6%) or regional (29.9%) disease compared to
distant disease (16.2%). Approximately 85% of patients survived at
least 5 years, with survival poorest among older patients and those
with evidence of distant metastases at time of diagnosis. This tumor is
rare while age and stage at diagnosis are strongly associated with
long-term survival (9).
Giant-cell lesions of bone-neoplastic and reactive growths form a
group of clinicopathological entities that differ in their behavior and
may present substantial problems in differential diagnosis. The
presence of multinucleated giant cells of the osteoclast type, reactive
osteoplasia and the formation of secondary aneurysmal cysts in many
unrelated lesions of bone further complicates their classification (10).
GCT of bone is a locally osteolytic tumor with variable
aggressiveness. In rare cases, pulmonary metastasis can be observed.
The lesion most frequently occurs in the epiphysis of long tubular
bones of the knee region, predominantly affecting young adults after
closure of the growth plate. The characteristic histological appearance
of GCT displays a high number of osteoclast-like multinucleated giant
cells, which resulted in the classification "osteoclastoma" or "giant
cell tumor". Apart from the multinucleated giant cells, there are 2
mononuclear cell types in GCT. The first one has a round morphology
and resembles monocytes. The second cell type is the spindle-shaped,
fibroblast-like stromal cell. Cell culture experiments with GCT cells
revealed the stromal cell to be the proliferating component of the
GCT. The other 2 cell types, the monocyte and the multinucleated
giant cell, were lost after a few cell culture passages. Latest results
from GCT reveal that the stromal cells secrete a variety of cytokines
and differentiation factors, including MCP1, ODF, and M-CSF. These
molecules are monocyte chemoattractants and are essential for
osteoclast differentiation, suggesting that the stromal cell stimulates
blood monocyte immigration into tumor tissue and enhances their
fusion into osteoclast-like, multinucleated giant cells. The
multinucleated giant cell itself resembles a normal osteoclast that is
583
able to resorb bone leading to extended osteolysis. This new model of

GCT genesis supports the hypothesis that the stromal cell is the
neoplastic component whilst the monocytes and the multinucleated
giant cells are just reactive components of this tumor. Taking this into
consideration, the nomenclature of the "giant cell tumor" needs to be
reconsidered (11).
Giant cell tumors
Comprehending the pathogenesis of GCT of bone is of critical

importance for developing novel targeted treatments for this locally
aggressive primary bone tumor. GCT is characterized by the presence
of large multinucleated osteoclast-like giant cells distributed amongst
mononuclear spindle-like stromal cells and other monocytes. The
giant cells are principally responsible for the extensive bone
resorption by the tumor. However, the spindle-like stromal cells
chiefly direct the pathology of the tumor by recruiting monocytes and
promoting their fusion into giant cells. The stromal cells also enhance
the resorptive ability of the giant cells. RANKL and proteases,
including numerous matrix metalloproteinases, are involved in the
development of GCT. The mesenchymal lineage of the stromal cells
and the origin of the hematopoietic monocytes are also important.
Several aspects of GCT require further understanding, including the
etiology of the tumor, the mechanisms of metastases, and the
development of an appropriate animal model (12).
Clinicopathologic correlation of all findings, including the
radiologic features and laboratory tests, is of paramount importance in
reaching a correct diagnosis in this group of histologically overlapping
entities. Malignant features can be identified in the primary and
secondary conventional malignant GCTs and in some types of
osteosarcoma with a giant cell component (10).
Patients with GCT of bone typically present with mechanical
difficulty and pain due to bone destruction and are at an increased risk
584
for fracture (9). The sacrum is the third most common site of GCT
involvement. Patients with sacral GCTs present with localized LBP
that may radiate to one or both lower limbs. Vague abdominal
complaints and bowel and bladder symptoms may also be present.
Neuroimaging workup should include advanced modalities, preferably
MRI, prior to obtaining a biopsy specimen. GCT has a 1-5% rate of
metastasizing to the lung and may convert to a fulminate malignant
variant, which has a very poor prognosis. The standard treatment for
GCT is curettage combined with adjuvant bone grafting or cement-
augmented stabilization. In appropriately selected cases, sacral
resection is a valuable procedure to effect local tumor control and
overall survival. Embolization may also prove palliative and/or
curative in cases in which the tumor is unresectable or refractory to
treatment (1).
X-ray of a typical giant cell tumor in the end of the radius bone.
Cases from the Rizzoli Institute (Bologna, Italy) of primary GCT

and secondary GCT malignancy in GCTs were reviewed. Primary
GCT is a high-grade sarcoma that arises side by side with benign
GCTs. Secondary GCT is a high-grade sarcoma that occurs at the sites
of previously treated GCTs of bone. Five primary GCTs and 12
secondary GCTs; half of the secondary GCTs that were postradiation
sarcomas are reported. Patient age ranged from 20 to 68 years
(median, 62 years) for primary GCT and from 30 to 77 years (median,
40 years) for secondary GCT. The average latent period between
diagnosis of GCT and diagnosis of secondary GCT was 9 years
(range, 3-15 years) for patients with postradiation secondary GCT and
19 years (range, 7-28 years) for patients with secondary GCT resulting
from spontaneous transformation. The histological classification of
high-grade sarcomas in the primary GCT group was osteosarcoma in 4
cases and malignant fibrous histiocytoma in 1 case. In the secondary
585
GCT group, the histological classification was osteosarcoma in 9

cases, fibrosarcoma in 2 cases, and malignant fibrous histiocytoma in
1 case. The outcomes associated with all malignancies in GCTs were
poor, with the worst outcome associated with postradiation secondary
GCT. In conclusion, malignancies in GCTs of bone always are high-
grade sarcomas with a poor prognosis. These lesions must be
distinguished from benign GCTs of bone. Secondary GCT usually is
easy to diagnose upon malignant clinicoradiographic presentation. By
contrast, primary GCT often mimics GCTs both clinically and
radiographically. Upon histological examination, primary GCT shows
areas of conventional GCT, which can lead to difficulties in making
the correct diagnosis (13).
Malignant GCTs of bone are rare, and the diagnosis can be difficult
due to the occurrence of a variety of malignant tumors containing
giant cells. Five cases were primary malignant GCT of bone, and 12
cases were GCTs of bone initially diagnosed as benign but malignant
in a recurrent lesion (secondary malignant GCT of bone). The patients
included 6 women and 11 men (age ranged from 17 to 52 years; mean,
30.5 years). The tumor arose in the femur (6 cases), the tibia (7 cases),
the humerus (3 cases), and the fibula (1 case). Microscopically,
primary malignant GCT of bone showed both conventional GCT and
malignant sarcoma features. Secondary malignant GCT was initially
diagnosed as conventional GCT of bone, while the recurrent lesion
showing malignant features. Histologically, the malignant components
included osteosarcoma (11 cases), undifferentiated high-grade
pleomorphic sarcoma (2 cases), and fibrosarcoma (4 cases).
Secondary malignant GCT cases showed strong expression of p53.
Follow-up information revealed that 4 patients died of lung metastasis,
2 patients are alive with lung metastases, and 11 patients are alive
without tumor. Malignant GCTs of bone should be considered as a
high-grade sarcoma. It must be distinguished from GCT of bone and
other malignant tumors containing giant cells. p53 might play a role in
the malignant transformation of GCT of bone (14).
Over 20 years, 470 cases of GCT of bone were diagnosed at a
tertiary cancer hospital, India. Tumors measured 6 to 20 cm and, in
402 cases, showed "usual" histology comprising uniformly scattered
multinucleate giant cells amidst mononuclear stromal cells, together
imparting a syncitium-like appearance. The presence of osteoid,
hemorrhage, and aneurismal bone cyst-like areas; spindle cells in
sheets (devoid of giant cells); or storiform pattern and intravascular
osteoclasts were less common (15).
586
GCTs of bone are common, aggressive, or low-grade malignant

tumors that occur infrequently in the spine above the sacrum, and their
presence in the cervical vertebrae is even more exceptional. Though
surgical resection of GCT arising in the cervical spine is commonly
regarded as a recommended treatment method, it is still a challenge to
achieve satisfactory results, especially for the late or recurrent cases,
and there are few large series of cases reported with long-term follow-
up of this tumor that are found in special segments in the literature.
Clinical and follow-up data of 22 patients of GCT arising in cervical
spine, who received surgical treatment from January 1990-December
2003, were collected at the Spine Center, Changzheng Hospital,
China. The choice of surgical intervention was based on the
Weinstein-Boriani-Biagini grading system. Two meanly different
protocols of surgical treatment were applied: 8 patients underwent
subtotal resection (1 of them died shortly after surgery), while 13
cases received total spondylectomy. One special lesion located in the
posterior element of C7 received "en bloc" resection. Postoperative
RT was given to 18 cases as an adjunctive therapy method. One
patient with C1-C2 GCT (vertebral body and posterior element
involvement) who received subtotal resection of the tumor showed
aggravation of neurologic deficit and died shortly after the surgery.
Twenty-one cases remained for mid and long-term follow-up with an
average of 67.8 months that ranged from 36 to 124 months. The
symptom of radicular pain almost disappeared, and patients suffering
from spinal cord compression recovered well with at least 1 or 2 levels
based on Frankel grading system when re-evaluated at 3 months after
operation. The rate of fusion for the bone graft was 100%. All the
internal fixations were well fused and no spine instability could be
seen. Local recurrence was detected in 5 of 7 cases (71.4%) who
underwent subtotal resection, but in only 1 of the 13 cases (7.7%) of
total spondylectomy. Four cases died within follow-up and these
patients were recurrent cases. One patient developed pulmonary
metastases. In conclusion, GCT of the cervical spine onsets between
20-40 years of age. As a kind of benign but local aggressive or low
potential malignancy tumor, an aggressive attitude to excise the tumor
as much as possible with reserving the neural function as a
precondition should be taken. Unlike in the thoracic and lumbar spine,
a strictly "en bloc" resection is often not a feasible option because of
the involvement of critical neurovascular structures. Total
spondylectomy (even intralesional) with RT as an adjunctive
treatment has significantly lowered the local recurrence rate of the
GCT in the special segments (16).
587
In this report, 23 cases of GCT in the spine and sacrum are

reported. Ten lesions occurred in the sacrum with an average age of
31 years (range 13-49) and 13 occurred in the mobile spine with an
average age of 39.1 years (range 13-64). Most patients presented with
pain or neurologic deficit at the site of tumor involvement, and
symptoms were usually present for many months prior to diagnosis.
Six of the sacral GCT patients were treated with pre-operative arterial
embolization and intralesional surgical resection, and 2 developed a
recurrence. Two of the sacral GCT patients had an en bloc resection
and neither developed a recurrence. One sacral GCT patient was
treated with serial arterial embolization with good disease control.
One sacral GCT patient did not receive any treatment. Eleven spinal
GCT patients were treated with en bloc surgical resection and 2
developed a recurrence, the other 2 spinal GCT patients were treated
with intralesional surgical resection and both developed a recurrence.
In conclusion, GCTs of the spine and sacrum should be managed with
en bloc resections whenever possible as this provides the greatest
chance for cure. When the risk of post-operative neurologic deficit
after en bloc excision is high, conservative therapy involving arterial
embolization and intralesional resection offers the best results (17).
Assessment: malignant GCT of bone is a rare tumor with

debilitating consequences. This tumor is a locally osteolytic tumor
with variable aggressiveness. In rare cases, pulmonary metastasis can
be observed. The lesion most frequently occurs in the epiphysis of
long tubular bones of the knee region, predominantly affecting young
adults after closure of the growth plate. The giant cells principally are
responsible for the extensive bone resorption. The outcome associated
with all malignancies in GCTs is poor. Malignancies in GCTs of bone
are high-grade sarcomas with a poor prognosis.
Did the King suffer from a GCT of bone? Since the King suffered
from widespread pain in his bones, the diagnosis of GCT seems
unlikely.
References
1. Randall RL. Giant cell tumor of the sacrum. Neurosurg Focus. 2003;
15(2):E13.
2. Gamberi G, Serra M, Ragazzini P, et al. Identification of markers of possible
prognostic value in 57 giant-cell tumors of bone. Oncol Rep 2003;10(2):351–6.
3. Thomas DM, Skubitz T. Giant-cell tumour of bone. Current Opinion in
Oncology. 2009;21:338-344.
4. Werner, M. Giant cell tumour of bone: morphological, biological and
histogenetical aspects. Springer-Verlag. 2006;30:484-9.
588
5. Dickson B C, Li S-Q, Wunder JS, et al. Giant-cell tumor of bone express p63.
Modern Pathology. 2008;21:369-75.
6. Mendenhall W M, Zlotecki RA, Scarborough MT, et al. Giant Cell Tumor of
Bone. American Journal of Clinical Oncology. 2006;29(1):96-9.
7. Thomas DM, Skubitz T. Giant-cell tumour of bone. Current Opinion in
Oncology. 2009;21:338-44.
8. Dickson BC, Li S-Q, Wunder JS, et al. Giant-cell tumor of bone express p63.
Modern Pathology. 2008;21:369-75
9. Beebe-Dimmer JL, Cetin K, Fryzek JP, et al. The epidemiology of malignant
giant cell tumors of bone: an analysis of data from the Surveillance, Epidemiology
and End Results Program (1975-2004). Rare Tumors. 2009;1(2):e52.
10. Povýńil C. Giant-cell lesions of bone and their differential diagnosis. Cesk
Patol. 2012;48(3):141-5.
11. Wülling M, Engels C, Jesse N, et al. The nature of giant cell tumor of bone. J
Cancer Res Clin Oncol. 2001;127(8):467-74.
12. Cowan RW, Singh G. Giant cell tumor of bone: A basic science perspective.
Bone. 2012;52(1):238-46.
13. Bertoni F, Bacchini P, Staals EL. Malignancy in giant cell tumor of bone.
Cancer. 2003;97(10):2520-9.
14. Gong L, Liu W, Sun X, et al. Histological and clinical characteristics of
malignant giant cell tumor of bone. Virchows Arch. 2012;460(3):327-34.
15. Gupta R, Seethalakshmi V, Jambhekar NA, et al. Clinicopathologic profile of
470 giant cell tumors of bone from a cancer hospital in western India. Ann Diag
Pathol. 2008;12:239-48.
16. Junming M, Cheng Y, Dong C, et al. Giant cell tumor of the cervical spine: a
series of 22 cases and outcomes. Spine (Phila Pa 1976). 2008;33(3): 280-8.
17. Martin C, McCarthy EF. Giant cell tumor of the sacrum and spine: series of 23
cases and a review of the literature. Iowa Orthop J. 2010;30:69-75.
OTHER BONE TUMORS

BONE TUMORS AT THE CRANIO-CERVICAL
JUNCTION
Bone tumors located at the cranio-cervical junction are rare.
Tumoral involvement of the neighbouring structures including bone,
nerves and vertebral artery and the dynamic aspects of the bone
structures raise technical difficulties in the surgical approach. The
surgical management includes tumor resection and stabilization of the
cranio-cervical junction. Forty-one patients presenting a bone tumor
(26 benign and 15 malignant tumors), excluding chordomas, located at
the cranio-cervical junction (including lower third of the clivus, C1
and C2) were observed over 20 years from 1981 to 2001 at the
Department of Neurosurgery, Paris. Imaging work-up included CT
589
scanner with bone windows sequences and reconstruction in the

coronal and sagittal plane; since 1984 most of the patients (n=35)
underwent a MRI and angioMR scanning. Vertebral angiography was
rarely performed (n=9) and mostly when the diagnosis was doubtful.
In some cases the diagnosis was clear but in others, imaging studies
showed destructive lesions suggesting a malignancy, which sometimes
required a biopsy (n=4). The surgical resection was performed through
a lateral approach. Complete resection was achieved in 38 cases while
in 3 cases a small remnant was left behind. A complementary
stabilization procedure was necessary in 18 cases using either bone
grafting during the same procedure and through the same approach
(n=5) or a craniocervical plating and bone grafting (n=13). No
recurrence in the group of benign tumors was seen during an average
follow-up of 6 years (from 2 to 11 years). The pre-operative
symptoms of pain and neck stiffness improved or disappeared in most
patients. Three patients with lower cranial nerves (n=2) or sphincter
disturbances (n=1) remained unchanged. One patient with tetraplegia
eventually died. In conclusion, various types of bone tumors are found
at the cranio-cervical junction. Confusion between benign and
malignant tumor or pseudo tumors must be avoided, sometimes
requiring a biopsy. Surgery, using a lateral approach, usually permits
the surgeon to achieve a complete resection with preserving the
stability of the cranio-cervical junction whenever intact and a
stabilization procedure (2).
Preoperative sagittal (A,B) and axial (C,D) T2-weighted MR images

show an extensive lesion located ventrolaterally at the upper cervical spine
with spinal cord compression and involvement of the left vertebral artery.
590
PRIMARY TUMORS OF THE CERVICAL SPINE
Primary tumors of the cervical spine are rare. In this retrospective

study, 66 surgeries were performed on 35 patients, ranging in age
from 7 to 70 years for primary tumors of the cervical spine at the
Department of Neurosurgery, Izmir, Turkey. Preoperative and
postoperative degree of pain and neurological status were quantified.
Radiological investigations were used to detect recurrence and
evaluate the stability and fusion. Data were collected on patient
characteristics, therapy, and results. Follow-up ranged from 6 months
to 15 years (mean 59.9 months). Posterior (26), anterolateral (24),
retropharyngeal (9), combined (4), lateral (2), and transmandibular
approaches (1) were used. Chordomas (n=8) and 17 different types of
tumors were encountered. One patient died 3 weeks postoperatively
and 5 died of their disease at follow-up. Twenty patients had no
evidence of disease, and 7 patients had recurrent tumors. According to
the Weinstein-Boriani-Biagini classification, tumor extension into
both anterior and posterior columns of a vertebra was correlated with
a poor outcome. Incomplete resections resulted in tumor recurrence
which warranted subsequent surgeries (up to 9), especially in
chordoma cases. Complete tumor resection is the oncologically best
surgical strategy and should be attempted whenever possible.
However, this may not be feasible in every case because of the
complexity of the cervical spine. In these cases, acceptable mortality-
morbidity rates and symptom-free years could be achieved by subtotal
resections, even for malignant tumors (1).
Chordoma of the cervical spine in a 50-year-old woman with neurologic

symptoms.
591
TUMORS OF SHOULDER GIRDLE

The purpose of this review is to demonstrate typical X-ray, CT and
MR morphology of primary bone tumors and "tumor-like lesions" of
the shoulder in correlation with histopathology. Of 711 primary bone
tumors of the shoulder and proximal humerus studied at the
Department of Radiology Münster, 602 were localized in the humerus,
90 in the scapula and 19 in the clavicula. The most frequent benign
tumors were osteochondromas (n=143), simple bone cysts (n=115),
enchondromas (n=75) and aneurysmal bone cysts (n=50). Fibrous
dysplasia (n=25), chondroblastoma (n=15), osteoid osteoma (n=13),
GCTs (n=12) and non ossifying fibroma (n=11) were less frequent.
The most frequent malignant bone tumors were osteosarcoma (n=72),
chondrosarcoma (n=52) and Ewing's sarcoma (n=46). Focal
plasmacytoma (n=20) and lymphoma (n=10) were less frequent. The
average age of the patients was 31.5 years. Some of these tumors were
typically located in the shoulder, i.e. simple bone cysts and
chondroblastoma. In conclusion, the shoulder was a rather infrequent
site of primary bone tumors, but since most of these tumors were
benign, the radiologist should be aware of the differential diagnosis to
guide therapy (3).
The shoulder radiograph demonstrates a large osteolytic lesion in the head

of the patient‘s humerus involving the epiphysis and metaphysis. Thinning of
medial cortex with a small amount of external new bone growth or
calcification is seen. The differential diagnosis would include giant cell
tumor, bone cyst and epiphyseal chondroblastoma.
This was a retrospective review of 194 consecutive neoplasms of

the shoulder girdle seen by the senior author from 1996 through 2000
at the Manhattan Orthopaedic & Sports Medicine Group, Mount Sinai
Medical Center, New York. Benign tumors (n=139) were more
common than malignant tumors (n=55). The presence of pain and the
presence of mass were not risk factors for malignancy (p=0.41 and
592
p=0.16, respectively). Malignant tumors occurred in an older

population (p<0.0007). Tenderness and tumor location in the scapula
were also found to be risk factors for malignancy (p=0.0002 and
p=0.0001, respectively). In conclusion, older age, tenderness on
palpation, and a lesion in the scapula were associated with malignancy
in the shoulder girdle (4).
CHONDROSARCOMA
Chondrosarcoma is the third most common primary malignant
bone tumor after osteosarcoma and chondrosarcoma. Clear cell
chondrosarcoma is a rare subtype variant of chondrosarcoma, most
commonly encountered in the proximal part of the femur or humerus.
Vertebral involvement is exceedingly rare and shows a predilection
for the thoracic spine. The case of a woman with clear cell
chondrosarcoma of the thoracic spine, which has been surgically
excised is reported. Although it has a reasonably benign biological
behavior, clear cell chondrosarcoma needs to be treated as a
malignancy. The best treatment for spinal chondrosarcoma is surgery.
It should be promptly and adequately resected. Gross-total resection
should be the ultimate surgical goal. RT should also be considered,
especially in the case of subtotal resection or inoperable lesions. In
conclusion, it is important to keep in mind this entity in the
differential diagnosis of spinal tumors in order to optimize treatment
planning. With adequate treatment, local recurrence rates as low as
20% can be achieved (5).
A retrospective review was carried out of 72 patients with
histopathologically confirmed clear cell chondrosarcoma at the
Department of Radiology, Mayo Clinic, Rochester, US. Imaging
studies were available for 34 patients: conventional radiographs
(n=28), CT scans (n=14), and MR images (n=15). Of the 34 patients
with imaging studies, 30 were males and 4 were females (mean age
38.6 years, range 11-74 years). Twenty-two lesions were in long
bones (15, proximal femur; 1, distal femur; 1, proximal tibia; 5,
proximal humerus) and 11 in flat bones (5, vertebra; 4, rib; 1, scapula;
1, innominate). One lesion occurred in the tarsal navicular bone.
Typically, long bone lesions were located in the epimetaphysis (19/22)
and were lucent with a well-defined sclerotic margin and no cortical
destruction or periosteal new bone formation. Pathologic fractures
593
were present in six long bone lesions (4, humerus; 2, femur). Lesions
in the proximal humerus were more likely to have indistinct margins
(4/5) and extend into the diaphysis. Flat bone lesions were typically
lytic and expansive and occasionally demonstrated areas of cortical
disruption. Typically, matrix mineralization, when present, was
amorphous. MR imaging, when available, was superior to
conventional radiographs for demonstrating the intramedullary extent
of a lesion as well as soft tissue extension. CT images better
delineated the presence of cortical destruction and the character of
matrix mineralization patterns. Clear cell chondrosarcoma lesions
were low signal intensity on T1-weighted images and moderately or
significantly bright on T2-weighted images. Areas of lesion
heterogeneity on T1- and T2-weighted images and on post-gadolinium
T1-weighted images corresponded pathologically to areas of
mineralization, intralesional hemorrhage, and cystic changes.
Adjacent bone marrow edema was typically absent (12/15) or only
minimally observed in a few cases (3/15). In conclusion, clear cell
chondrosarcoma typically presents radiographically as a geographic
lytic lesion located in the epimetaphyseal region of long bones. Most
common lesions are found in the proximal femur, followed by the
proximal humerus. Lesions within the proximal humerus may exhibit
more aggressive features. Lesions in the axial skeleton are typically
expansible and destructive, often with soft tissue extension and lack of
mineralization. MR imaging may show the presence or absence of
bone marrow edema (6).
Conventional intramedullary chondrosarcoma of the humerus in a 21-

year-old man with shoulder pain.
Chondrosarcoma is a rare malignant tumor of bone. This family of

tumors can be primary malignant tumors or a secondary malignant
transformation of an underlying benign cartilage tumor. Pain is often
the initial presenting complaint when chondrosarcoma involves the
spine. In the mobile spine, chondrosarcoma commonly presents within
594
the vertebral body and shows a predilection for the thoracic spine. Due
to the resistance of chondrosarcoma to both RT and chemotherapy,
treatment is focused on surgery. With en bloc excision of
chondrosarcoma of the mobile spine and sacrum patients can have
local recurrence rates as low as 20% (7).
A 52-year-old man presented to another institution with a
pathologic L1 compression fracture. Intraoperatively, this fracture was
discovered to be secondary to a chondrosarcoma involving T12, L1,
and L2. He was then referred to the Department of Neurosurgery,
Johns Hopkins Medical Institutions, Baltimore, for further evaluation
and treatment. A 2-stage operation was performed with successful en
bloc resection of residual chondrosarcoma with negative margins. The
first stage using a posterior approach resulted in placement of pedicle
screws from T9 to L4, laminectomies from T12 to L2, and placement
of Tomita saws between the thecal sac and the vertebral body at both
the T11-12 and L2-3 disc levels. The second stage of the procedure
involved a transthoracic, and retroperitoneal approach to the
thoracolumbar spine. Osteotomies between T11-12 and L2-3 were
completed, and the vertebral bodies of T12, L1, and L2 were delivered
as an en bloc specimen. The final pathology of the specimen was
clear-cell chondrosarcoma with negative margins. This is a rare
occurrence of clear-cell chondrosarcoma in the osseous spine.
Aggressive surgical intervention with the goal of en bloc resection of
tumor is recommended to promote tumor-free survival (8).
OSTEOSARCOMAS
Primary malignant bone tumors, osteosarcomas, and Ewing's
sarcomas are rare diseases which occur mainly in adolescents and
young adults. With the current therapies, some patients remain very
difficult to treat, such as tumor with poor histological response to
preoperative CT (or large initial tumour volume for Ewing's sarcomas
not operated), and patients with multiple metastases at or those who
relapsed. In order to develop new therapies against these rare tumors,
we need to unveil the key driving factors and molecular abnormalities
behind the malignant characteristics and to broaden our understanding
of the phenomena sustaining the metastatic phenotype and treatment
resistance in these tumors (9).
595
Osteosarcoma
An 11-year-old girl presented with progressively increasing

swelling in scalp of 8-month duration with no neurological deficit.
Local examination showed a hard swelling that seemed to be arising
from frontal bone. General and systemic examination was normal.
MRI revealed a well-defined lytic lesion in left frontoparietal bone
with a subgaleal component. The patient was operated upon and
excision of tumor with reconstruction of skull was done.
Histopathological examination showed a monomorphic small round
cell tumor of bone infiltrating into the subcutaneous tissue.
Immunohistochemical stain showed diffuse immunopositivity for
MIC-2 in tumor cells, thus final diagnosis of Ewing's sarcoma was
made. The patient was followed up for 3 months and remained
asymptomatic (10).
The main objective of this study was to determine whether Ewing's
sarcoma of the bone and primary cutaneous Ewing's sarcoma are
different in terms of epidemiology and prognosis. A systematic
review of the literature was carried out using the keywords 'cutaneous
Ewing's sarcoma', 'primary Ewing's sarcoma of skin' and 'primary
neuroectodermal tumor and skin' in the Medline database. Series of 5
or more cases were included. Six series met the inclusion criteria,
making 61 patients. Median age at diagnosis was 17 years and 33%
were male. The median size of the tumor was 2.3 cm. The treatment
consisted of surgery in all cases, adjuvant multiagent chemotherapy in
69% of cases, adjuvant chemoradiotherapy in 38% of cases and
adjuvant RT without adjuvant chemotherapy in 3% of cases. Of 6
patients who developed metastases, 4 died. The overall survival was
93% and the 10-year probability of survival was estimated at 91%
(95% CI 83-100). Primary cutaneous Ewing sarcoma has a female
predominance, occurs at a later age, but, more importantly, has a
better outcome. Multimodal therapy for Ewing's sarcoma is associated
with immediate and long-term morbidity and mortality (11).
596
Ewing's sarcoma
Patients < 40 years of age with Ewing's sarcoma or peripheral

primitive neuroectodermal tumor reported to the US Surveillance,
Epidemiology, and End Results Program database from 1973 to 2007
were evaluated based on skeletal (n=1519) vs. extraskeletal (n=683)
site of origin. Patients with extraskeletal Ewing's sarcoma had a higher
mean age (19.5 vs. 16.3 years, p<0.001) and were less likely to be
male (53.4% vs. 63.3%, p<0.001) or white (84.8% vs. 92.5%,
p<0.001) compared with patients with skeletal tumors. Extraskeletal
tumors were more likely to arise in axial locations (72.9% vs. 54.2%,
p=0.001) but were less likely to arise specifically in the pelvis (19.8%
vs. 26.6%, p<0.001). Metastatic status or tumor size did not differ by
group. Five-year overall survival was superior for localized
extraskeletal Ewing's sarcoma compared with localized skeletal
tumors (69.7% vs. 62.6%, p=0.02). The HR for death in patients with
localized skeletal tumors compared with localized extraskeletal Ewing
sarcoma was 2.36 (95% CI 1.61-3.44) beyond 24 months from initial
diagnosis. Thus, patient characteristics and outcomes differ among
patients with extraskeletal Ewing's sarcoma compared with patients
with skeletal Ewing sarcoma (12).
The aim of this study was to evaluate prognostic factors, survival
rate and the efficacy of the treatment modalities used in patients with
extraskeletal Ewing's sarcoma. Data of patients with extraskeletal
Ewing's sarcoma followed up at the Department of Medical Oncology,
Istanbul, Turkey between 1997 and 2010 were retrospectively
analyzed. The median age of 27 patients was 24 years (range 16-54
years). The median follow-up was 31.8 months (range 6-144 months).
Tumor size was between 1.5 and 14 cm (median 8 cm). Of all patients,
85% had localized disease at presentation and 15% metastatic disease.
Local therapy was surgery alone in 16% of patients, surgery combined
with RT in 42% and RT alone in 27%. All patients were treated with
vincristine, doxorubicin, cyclophosphamide and actinomycin-D,
alternating with ifosfamide and etoposide every 3 weeks. In patients
597
with localized disease at presentation, the 5-year event-free survival

and overall survival were 59.7% and 64.5%, respectively. At
univariate analysis, patients with tumor size ≥ 8 cm, high serum LDH,
metastasis at presentation, poor histological response to chemotherapy
and positive surgical margin had significantly worse event-free
survival. The significant predictors of worse overall survival at
univariate analysis were tumor size ≥ 8 cm, high LDH, metastasis at
presentation, poor histological response to chemotherapy, RT only as
local treatment and positive surgical margin. In conclusion, prognostic
factors were similar to primary osseous Ewing's sarcomas. Adequate
surgical resection, aggressive chemotherapy (vincristine, doxorubicin,
cyclophosphamide, actinomycin-D alternating with ifosfamide and
etoposide) and RT if indicated are the recommended therapy for
patients with extraskeletal Ewing's sarcoma (13).
Of extraskeletal Ewing's sarcoma patients > 15 years, referred to
the Department of Medical Oncology, King Faisal Hospital and
Research Center, Riyadh, between January 1995 and December 2004,
57 patients were identified. Their median age at diagnosis was 20
years (range 15-57). The median size of the primary tumor was 11 cm
(range 4-30 cm). Eighteen patients (31%) had metastatic disease at
initial presentation. Wide surgical resection with negative margins
was achieved in 23 cases (40%). Chemotherapy consisting of
vincristine, adriamycin, ifosfamide, actinomycin D was given for 50
patients (88%), while RT for 37 patients (65%). Forty-one patients
(72%) achieved complete remission and 16 (28%) progressed despite
of therapy. Twenty-one patients (51%) relapsed. Local recurrence was
encountered in 15 patients (36%). At a median follow-up of 46
months (range 6-143 months), the 5-year event-free survival and
overall survival rates were 35% and 47%, respectively. Metastases at
presentation, tumor size and surgical resection margin associated
significantly with overall survival and event-free survival. In
conclusion, extraskeletal Ewing's sarcoma is an aggressive type of
tumor with a high incidence of local recurrence and distant metastasis.
This series showed that the outcome of adult extraskeletal Ewing's
sarcoma is different than skeletal Ewing's sarcoma in terms of
response to multi-modality treatment and the prognostic factors
influencing treatment outcome. Adequate surgical resection,
aggressive chemotherapy and adjuvant local RT, when indicated,
constitute the optimal treatment to achieve the best results in this rare
type of disease (14).
Clinical data of 18 patients with extraskeletal Ewing's sarcoma
treated at Cancer Center of Sun Yat-sen University, China, between
598
1995 and 2007, were analyzed. Of the 18 patients, 13 were male and
8 were female, aged from 8 months to 60 years. Twelve (66.7%)
patients were between 5-25 years of age. Eight (44.4%) patients had
tumors originated from low extremities. Sixteen patients had masses at
their first visit. Sixteen patients were treated by the combined
modality therapy, and 2 patients were treated by the single modality
therapy. The 1-, 3- and 5-year actuarial survival rates were 82.4%,
64.2% and 32.1%, respectively. The presence of metastatic disease at
the time of diagnosis and the mode of treatment were prognostic
factors. In conclusion, extraskeletal Ewing's sarcoma is common in
adolescent. It often manifests as a localized mass. The combined
modality therapy is recommended for this disease. The presence of
metastatic disease at the time of diagnosis and the mode of treatment
are prognostic factors (15).
MALIGNANT FIBROUS HISTIOCYTOMA

AND FIBROSARCOMA
Malignant fibrous histiocytoma and fibrosarcoma of bone are rare
malignant tumours and contentious entities. Sixty-seven cases labeled
as bone malignant fibrous histiocytoma (57) and bone fibrosarcoma
(10) were retrieved from 5 bone tumor referral centers and reviewed
to determine whether recent advances allowed for reclassification and
identification of histological subgroups with distinct clinical behavior.
A panel of immunostains was applied: smooth muscle actin, desmin,
h-caldesmon, cytokeratin AE1-AE3, CD31, CD34, CD68, CD163,
CD45, S100 and epithelial membrane antigen. Additional
fluorescence in situ hybridisation and immunohistochemistry were
performed whenever appropriate. All cases were reviewed by 6 bone
and soft tissue pathologists and a consensus was reached. Follow-up
for 43 patients (median 42 months, range 6-223 months) was
available. Initial histological diagnosis was reformulated in 18 cases
(26.8%). Seven cases were reclassified as leiomyosarcoma, 6 as
osteosarcoma, 3 as myxofibrosarcoma and 1 as embryonal
rhabdomyosarcoma and interdigitating dendritic cell sarcoma. One
case showed a peculiar biphasic phenotype with epithelioid nests and
myofibroblastic spindle cells. Among the remaining 48 cases, who
met the WHO criteria for bone fibrosarcoma and bone malignant
fibrous histiocytoma, 5 subgroups were identified. Seven cases were
reclassified as undifferentiated pleomorphic sarcoma and 11 as
599
undifferentiated pleomorphic sarcoma with incomplete myogenic

differentiation due to positivity for at least one myogenic marker. Six
were reclassified as spindle cell sarcoma not otherwise specified.
Among the remaining 24 cases, a further 2 recurrent morphologic
patterns were observed: 8 cases demonstrated a myoepithelioma-like
phenotype and 16 cases a myofibroblastic phenotype. One of the
myoepithelioma-like cases harboured a Ewing sarcoma breakpoint
region 1 - nuclear factor of activated T-cells C2 fusion. It appears that
bone malignant fibrous histiocytoma and bone fibrosarcoma represent
at best exclusion diagnoses (16).
Malignant fibrous histiocytoma is a pleomorphic high grade tumor
composed of fibroblasts, myofibroblasts, and histiocytes. Malignant
fibrous histiocytoma is the most frequent soft tissue tumor in adults.
This tumor is found in the lower extremity. Other less common sites
include the retroperitoneum, and the head and neck. The highest
incidence is during the fifth decade of life and there is a male to
female ratio of 1.5 to 1. Clinically, malignant fibrous histiocytoma
presents with local pain and swelling. There is often a history of a
rapidly enlarging mass. Radiologically, malignant fibrous
histiocytoma is an aggressive, permeating lesion which often lacks
distinct features found in other high grade primary bone malignancies.
It usually presents with a soft tissue mass with or without cortical
erosion (17).
A patient developed a malignant fibrous histiocytoma at the site of
a benign GCT, which had been treated by curettage 38 years
previously. This female patient was initially treated for a benign GCT
of the proximal tibia when she was 33 years old; she underwent
curettage and Kiel bone grafting. She had not received RT. She
underwent a second operation due to recurrence of a tumor twenty-
eight years later. No specific histological diagnosis was possible:
histology suggested a benign tumor, however compatible with a low-
grade malignant potential but not associated with GCT. The patient
underwent a third operation, with extensive curettage and total knee
arthroplasty 38 years after the initial surgery, because of progressive
knee pain. Postoperative histopathology study showed high-grade
malignant fibrous histiocytoma. Finally, she underwent above-knee
amputation because of uncontrollable progression of the tumor. The
use of xenogenic bone graft, bone cement and associated bone
necrosis potentially contributed to the development of a malignant
tumor adjacent to the primary GCT (18).
600
Malignant fibrous histiocytoma
A case of late development of a high-grade malignant fibrous

histiocytoma at the site of a previously surgically treated GCT is
reported. The patient initially was treated for a benign GCT of the
lateral condyle of the distal femur by curettage, implant of auto and
allograft bone, but no radiation. Eighteen years later, he noted
progressively increasing pain and disability. Radiographs showed
some change, but MRI disclosed a tumor arising at the site and
extending outside the bone. After chemotherapy, the tumor was
resected and histologically showed no evidence of a recurrent GCT,
only a high-grade malignant fibrous histiocytoma (19).
ADAMANTINOMA
Adamantinoma is a primary low-grade, malignant bone tumor that
is predominantly located in the mid-portion of the tibia. The etiology
of the tumor is still a matter of debate. The initial symptoms of
adamantinoma are often indolent and nonspecific and depend on
location and extent of the disease. Histologically, classic
adamantinoma is a biphasic tumor characterized by epithelial and
osteofibrous components that may be intermingled with each other in
various proportions and differentiating patterns. To assure the
histological diagnosis, pathologists should employ
immunohistochemistry for demonstrating the sometimes sparse
epithelial cell nests when the radiological features are suggestive of
adamantinoma (20).
Adamantinoma is a rare tumor, which most often affects the tibia
and produces lytic and sometimes destructive lesions, which can cause
fractures. The lesions occur principally in adults and are more
common in males. A small percentage of the patients develop
601
metastases, sometimes quite late in the course. Forty-two patients with

adamantinomas were evaluated by imaging studies and histology. The
majority of the patients was treated by resection of the lesion and
insertion of an intercalary allograft. Only 3 of the patients died of
disease with the time until death ranging from 10 to 17 years.
Recurrence occurred in 3 patients and the allograft success rate in
terms of function was 71% at a mean time of 10 years (21).
Adamantinoma
The clinical and histological data of 23 cases of adamantinomas of

the long bone collected by the Working Group on Bone Tumors at the
DKFZ/FRG are reported including immunohistochemical
observations in 21 of the cases. Females and males between 5-67
years (mean 25.4 years) were affected equally (11/12). All
adamantinomas were positive for cytokeratins often in coexpression
with vimentin, at least focally. Although exhibiting varying
histological patterns, no correlation between histology and clinical
course was seen. However, sex and mode of initial therapy seem to
influence an unfavorable clinical outcome. Three deceased patients
were males receiving marginal or delayed surgery. This underlines the
low-grade malignant character of adamantinoma. To assure the
histological diagnosis pathologists should employ
immunohistochemistry to demonstrate the sometimes sparse epithelial
cell nests when radiology is suggestive for adamantinoma. Correct
diagnosis should lead to resection with wide surgical margins (22).
The aim of this study was to evaluate the clinicopathological
features and prognostic significances of 11 histologically proven
adamantinoma cases based on an average 12.7-year long follow-up.
The male: female ratio was 8:3, aged between 4 and 80 years (mean
29.3 years). The initial diagnosis at referral was other than
adamantinoma in 6 patients (fibrous dysplasia, carcinoma metastasis,
osteofibrous dysplasia, bone cyst, and non-ossifying fibroma),
referring to the differential diagnostic problems. All tumors were
602
localized to the mid part of tibia. By histological evaluation, basaloid

pattern on a background of fibrotic stroma dominated in 6 patients,
while spindle and squamous features were less frequently seen. All
adamantinoma were positive for cytokeratins often in coexpression
with vimentin. No correlation was experienced between histology and
clinical outcome. Intralesional curettage (2 patients) was followed by
recurrence of the tumor. Wide resection was performed in 8 patients
with reconstruction using intercalary fibula autografts in 7 patients.
Reconstruction-related complications occurred in two third of the
cases, all of them could however be controlled by repeated surgery.
Six recurrences occurred in 4 patients, 2 of these recurrences occurred
16 and 20 years after initial surgery. One patient died 9 years after
recognition of the tumor of pulmonary metastases. Adamantinoma of
the long bones is a low-grade malignant tumor, which clinical
outcome is difficult to predict based on histology or surgical stage of
the tumor. Wide surgical margin, e.g. resection the tumor reduces the
rate of recurrence. This study underlines that recurrences do occur
even decades after recognition the tumor, therefore, a life-long follow-
up of the patient is necessary (23).
Adamantinoma
The records of 32 patients who had had an adamantinoma of the

long bones were examined to investigate the relationship between the
clinical presentation, the histological subtype, the method of
treatment, and the clinical result. All histological patterns of
differentiation characteristic of adamantinoma were observed,
including the basaloid, spindle-cell, tubular, squamous, and
osteofibrous dysplasia-like subtypes. Follow-up data were available
603
for 28 (88%) of the 32 patients. These patients were followed for a

mean duration of 122 months (range, 11 months to 29 years and 2
months). Nine patients (32%), all of whom had been managed with an
intralesional or marginal procedure, had a local recurrence of the
tumor after a mean disease developed in 3/9 patients. In 5 patients,
metastasis developed without having been preceded by a local
recurrence. Thus, the over-all rate of metastasis was 29% (8 patients).
The mean duration of survival for the patients who had metastasis was
12 years and 8 months. Intralesional or marginal excision was the
most significant risk factor for a local recurrence or metastasis
(p<0.001). Two patients who had had a presumed osteofibrous
dysplasia-like adamantinoma, which contained few isolated keratin-
positive epithelial cells within the stroma at the time of presentation,
had a full-blown adamantinoma at the time of the local recurrence.
Although the clinical course may be the result of a sampling error, it
poses questions as to the regressive nature of osteofibrous dysplasia-
like adamantinoma. In conclusion, an osteofibrous dysplasia-like
adamantinoma may be a precursor lesion of the classic type of
adamantinoma (24).
Assessment: this section deals with different bone tumors, apart

from GBT. Pain in the case of these bone tumors, is generally located
in the affected bone. Since the King suffered from generalized bone
pain ―My bones wasted away through my anguished roaring all day
long‖ (Psalm 32:3), the diagnosis of various bone tumors, as presented
above, seems unlikely in this case.
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10. Gupta A, Bansal S, Chaturvedi S. Primary Ewing's Sarcoma of Frontoparietal
Bone with Major Soft Tissue Extension: An Unusual Presentation and Review of the
Literature. Case Report Pathol. 2012;2012:713836.
11. Delaplace M, Lhommet C, de Pinieux G, et al. Primary cutaneous Ewing
sarcoma: a systematic review focused on treatment and outcome. Br J Dermatol.
2012;166(4):721-6.
12. Applebaum MA, Worch J, Matthay KK, et al. Clinical features and outcomes
in patients with extraskeletal Ewing sarcoma. Cancer. 2011; 117(13):3027-32.
13. Tural D, Molinas Mandel N, Dervisoglu S, et al. Extraskeletal Ewing's
sarcoma family of tumors in adults: prognostic factors and clinical outcome. Jpn J
Clin Oncol. 2012;42(5):420-6.
14. El Weshi A, Allam A, Ajarim D, et al. Extraskeletal Ewing's sarcoma family
of tumours in adults: analysis of 57 patients from a single institution. Clin Oncol (R
Coll Radiol). 2010;22(5):374-81.
15. Xie CF, Liu MZ, Xi M. Extraskeletal Ewing's sarcoma: a report of 18 cases
and literature review. Chin J Cancer. 2010;29(4):420-4.
16. Romeo S, Bovée JV, Kroon HM, et al. Malignant fibrous histiocytoma and
fibrosarcoma of bone: a re-assessment in the light of currently employed
morphological, immunohistochemical and molecular approaches. Virchows Arch.
2012;461(5):561-70.
17. Malignant fibrous histiocytoma. BONE TUMOR.ORG. Available 23 April
2013 at www.bonetumor.org/.../malignant-fibrous-histiocytoma.
18. Muramatsu K, Ihara K, Miyoshi T, et al. Late development of malignant
fibrous histiocytoma at the site of a giant cell tumour 38 years after initial surgery.
Acta Orthop Belg. 2012;78(2):279-84.
19. Ortiz-Cruz EJ, Quinn RH, Fanburg JC, et al. Late development of a malignant
fibrous histiocytoma at the site of a giant cell tumor. Clin Orthop Relat Res. 1995;
(318):199-204.
20. Jain D, Jain VK, Vasishta RK, et al. Adamantinoma: a clinicopathological
review and update. Diagn Pathol. 2008 Feb 15;3:8.
21. Roque P, Mankin HJ, Rosenberg A. Adamantinoma: an unusual bone tumour.
Chir Organi Mov. 2008 Dec;92(3):149-54.
22. Jundt G, Remberger K, Roessner A, et al. Adamantinoma of long bones. A
histopathological and immunohistochemical study of 23 cases. Pathol Res Pract.
1995;191(2):112-20.
23. Szendroi M, Antal I, Arató G. Adamantinoma of long bones: a long-term
follow-up study of 11 cases. Pathol Oncol Res. 2009;15(2):209-16.
24. Hazelbag HM, Taminiau AH, Fleuren GJ, Hogendoorn PC. Adamantinoma of
the long bones. A clinicopathological study of thirty-two patients with emphasis on
histological subtype, precursor lesion, and biological behavior. J Bone Joint Surg Am.
1994;76(10):1482-99.
605
To sum up: among the many malignant diseases examined in this

research that could have been associated with osteoporosis, MM,
gamma HCD, RCC, prostate cancer, or RCC combined with prostate
cancer are the most likely diagnoses.
Due to the lack of space, it was impossible to present all neoplastic
diseases associated with pain in the bones. Nevertheless, the main
types of diseases which may have afflicted the King are presented in
this research.
Contemporary diagnosis requires an extensive evaluation including
an appropriate anamnesis, physical examination, laboratory
evaluation, extensive radiological, isotopic and other procedures, for
example gastroscopy, or colonoscopy, in addition to histopathological
evaluation. Although these investigations were not performed on
King David, the most likely diagnosis is based on the description
given in the medical record that is the biblical text.
606
METASTATIC BONE DISEASE

Bone is a common site of metastatic cancer with skeletal
metastases representing the most common malignant bone tumor
(1,2). They occur mainly in adults and even more frequently in the
elderly (3). Tumor infiltration of bones is the most common cause of
cancer pain, and is the most often secondary to the primary disease in
the prostate, breast, thyroid, lung or kidney (4-9).
The skeleton is the most common organ for metastasis from solid
tumors. Bone metastases pose significant diagnostic and clinical
challenges and represent an important cause of cancer-related
morbidity. Without appropriate bone-directed therapy, many patients
will be at high risk for potentially debilitating SRE, such as pain, bone
fractures, neurologic deficits and hypercalcemia, severely affecting
the patient's QOL. Because of their high incidence, bone metastases
impose significant demands on health care resources. The optimal
management of skeletal metastases depends on the underlying biology
of the disease, the extent of bone involvement, the presence and
severity of symptoms, the availability of effective systemic therapies
and life expectancy of the patient (10).
MBD constitutes a major clinical problem. Skeletal complications
are common and lead to significant morbidity; patients live with MBD
for several years, increasing the prevalence of this problem. Effective
management aims to reduce the incidence of complications and
relieve symptoms, such as severe bone pain, which adversely affects
patient mobility and QOL (11).
Up to 90% of patients with metastatic or advanced stage cancer,
will experience significant cancer-related pain. Approximately half or
more of patients diagnosed with cancer may experience bone pain.
Tumor metastases to the skeleton affect roughly 400,000 US citizens
annually. Carcinoma from breast, lung, and prostate cancers account
for about 80% of secondary MBD. Bone metastases may cause
devastating clinical complications associated with dramatic reductions
in QOL, mobility, and independence as well as excruciating refractory
pain. Associated complications from osseous metastases present a
substantial economic burden. Currently, there is still a significantly
high number of patients suffering with unrelieved pain from osseous
metastases (12).
Due to the increase of mean life span and to other factors, the
incidence of tumors is growing. Nevertheless, survival chances of
patients suffering from tumors are improving due to advance in
diagnostics and to the application of complex therapy. These trends
607
have substantially increased the number of recognized and

manageable bone metastases. Life expectations of a tumor-patient are
determined by the metastases therefore, the question of diagnostics
and management of bone metastases is worth of special attention. In
one-third of patients who have suffered fracture due to bone
metastases and are treated surgically, the primary tumor is unknown at
the time of the fracture. Based on the histological pattern, the
detection of the parent-organ, particularly in adenocarcinoma, is
impossible. Independently from the radiological appearance of the
metastasis, simultaneous osteogenesis and osteolysis are histologically
observed (13).
Although the mechanisms underlying the development of bone
metastases are not completely understood, there appears to be
important bi-directional interactions between the tumor and the bone
microenvironment. A greater understanding of the pathophysiology of
painful osseous metastases may lead to better and more selective
targeted analgesic therapy. Potential future therapeutic approaches to
painful osseous metastases may revolutionize approaches to analgesia
for this condition, leading to optimal outcomes with maximal pain
relief and minimal AEs (12).
Malignant bone disease is a potentially devastating condition that
is prevalent in patients with advanced cancers. Most patients with
bone metastases experience at least 1 SRE, which may reduce survival
and add considerably to healthcare costs. Bone pain, the most
common source of severe pain in these patients, can often be managed
with analgesics or RT. However, treatment may be difficult because of
associated side effects. Bisphosphonates palliate bone pain and can
treat the underlying cause of the symptoms: malignant osteolysis.
Preventing or delaying the onset of SRE is crucial because patients
with an SRE have an increased risk of additional SRE, thereby
reducing QOL. MBD is a tremendous burden on patients and society.
Supportive therapy with zoledronic acid for patients with bone
metastases delay the onset and reduce the incidence of SRE, thus
preserving patients' QOL and functional independence (14).
Clinical charts of 100 cancer patients (70 women and 30 men were
studied; mean age 63 years, range 55-87). The primary lesions
responsible for bone metastases were located in the breast (51 cases),
colon (30 cases), lung (7 cases), stomach (4 cases), skin (4 cases),
kidney (2 men), pleura (1 woman), and liver (1 men). The most
frequent radiographic pattern was lytic type (52%), followed by
osteosclerotic, mixed, lytic vs. mixed and osteosclerotic vs. lytic
patterns. Skeletal metastases were the most common malignant bone
608
tumors: among these metastases, the spine and the pelvis were the
most frequent. Pain was the main symptom, even though many bone
metastases were asymptomatic. Pathological fractures were the most
severe consequences. Bone scintigraphy remains the technique of
choice in asymptomatic patients in whom skeletal metastases are
suspected. However, this technique though very sensitive is poorly
specific, and thus a negative bone scan finding is double-checked with
another physical examination: if the findings remain negative, the
diagnostic workup is over. On the contrary, in patients with a positive
bone scan or with local symptoms and pain, RT and CT are used for
screening of metastatic lesions: results may be negative (for low
sensitivity of conventional radiology) or questionable (in which case
bone biopsy is necessary), or symptoms are due to the different causes
than metastatic lesions (i.e., osteoarthritis). Before bone biopsy, MRI
must be performed because it is the only technique that allows
distinguishing between bone marrow components (15).
Bone scanning allows the detection of bony metastatic disease.
Patients (n=420) with cancer of breast, prostate, lung and colon

were investigated with 99mTc Methylene-diphosphonate whole body
scintigraphy. The presence of pathologic radiotracer uptake was
qualitatively and quantitatively analyzed in order to establish the
metastases distribution. Over 2455 whole body scintigraphies were
performed at Nuclear Medicine Service, Romania. The mean number
of the metastatic skeletal regions was significantly greater in breast
and prostate cancers in comparison with lung and colon cancers
(p<0.0001). The higher metastases site frequency was in the spine
than in the pelvis, the ribs and the sternum. The skull metastases
localization was more frequent in breast cancer in comparison with
other cancers (7.7% vs. 4% other cancer types). The pelvis was more
involved in the metastatic prostate neoplasm. The mean anatomic sites
number per patient was 5.7 in breast cancer, 4.8 in prostate cancer, 3.3
609
in colon and 3.0 in lung cancers. In conclusion, even some

particularities were evident between the metastases distribution in
these 4 cancer types, the data are insufficient for the existence of a
characteristic pattern related to the primary cancer origin. Metastases
localization can be related to the metastatic mechanism (16).
The 141 cases of metastatic carcinoma in bone encountered at the
People's Hospital Peking University, 1998–2004, were retrospectively
reviewed. Skeletal metastases occurred more commonly in males
(male: female ratio = 1.7:1). The age of patients ranged from 23 to 86
years (mean age = 56.5). The presenting symptoms included pain and
dysfunction of the affected bones. The locations of skeletal
metastases were as follows: spine (58), pelvic bone (46), long bone
(34), and others (3). Twenty-three cases suffered from multiple bone
lesions. The primary sites were identified in 130 cases (92.2%),
which included lung (37), female genital system and breast (25),
kidney (18), G-I system (17), liver (12), thyroid (11), prostate (7),
bladder (2), and skin (1). In conclusion, skeletal metastases occurred
more often in elderly males. Axial bones (spine and pelvis) were
usually affected (17).
The purpose of this study was to assess the usefulness of laboratory
analysis, chest, abdominal and pelvic CT and CT-guided biopsy in
patients with spinal metastases of unknown origin. A retrospective
review of the clinical histories of 27 patients with spinal metastases of
unknown origin was carried out. Of 43 patients with spinal metastases
of unknown origin, treated between 2002 and 2007, 27 underwent 3
tests (laboratory analysis including M protein and tumor markers,
chest, abdominal and pelvic CT and CT-guided biopsy) and were
included in this study. The final diagnosis was obtained in 26 patients.
Myeloma was the most common malignancy followed by lung
carcinoma. M protein was positive in 7 patients with myeloma and
negative in patients with other malignancies. The level of tumor
markers was elevated in 16 of 17 patients with a solid tumor and in 3
with lymphoma. Of 27 patients, CA 15-3 was elevated in 4 patients,
CA 19-9 in 5, CA 125 in 2, CEA in 6, skin squamous cell carcinoma
in 2, neuron-specific enolase in 7, AFP in 1, PIVKA-II in 1, time-
resolved phosphorescence anisotropy in 6, The Inhibitor of Apoptosis
Prot in 3 of 12 patients, thyroglobulin in 2 of 27 patients, sIL-2R in 3
of 24 patients, and PSA in 5 of 17 male patients. Myeloma, lymphoma
and prostate carcinoma had a marker with high sensitivity and
specificity (M protein, sIL-2R and PSA). Eleven primary tumor sites
(40.7%) were detected (6 lung, 1 prostate, 1 kidney, 1 thyroid, 1 liver,
and 1 pancreas) by chest, abdominal and CT scanning. Biopsy led to
610
determination of the final diagnosis in 12 (44.4%) of 27 patients (5

myelomas, 3 lymphomas, 2 prostate carcinomas, 1 RCC, and 1 thyroid
carcinoma). In the remaining 15 patients, biopsy did not lead to
determination of the final diagnosis, because the histological diagnosis
was an adenocarcinoma or an undifferentiated carcinoma, the tissue
sample was not diagnostic. In conclusion, a laboratory analysis,
limited to specific tumor markers such as PSA and protein
electrophoresis, is useful in a final diagnosis. Chest, abdominal and
pelvic CT are useful for a final diagnosis in solid tumors, but not for
hematologic tumors. A CT-guided biopsy has a low determination rate
in the final diagnosis in comparison to a laboratory analysis and CT
scanning for solid tumors, and it is not essential for the diagnosis of
hematologic tumors (18).
Painful large metastatic deposit of the iliac bone with osteolysis.
A single-center retrospective study was conducted in a cohort of

patients admitted between October 1990 and January 2000, Brest,
France, for evaluation of 1 or more bone metastases with unknown
primary. The 152 patients (104 men and 48 women) had a mean age
of 63.5 +/- 12.5 years. The primary was located in the lung in 37
patients, prostate in 26, and breast or female genital tract in 24,
urinary system in 11, G-I tract in 11, head and neck in 6, and other
organs in 4. In 33 patients, no primary was identified. The
extraskeletal metastases were located chiefly in the liver (20.4%), lung
(17.1%), pleura (13.2%), and brain (7.2%). Bone biopsies were
performed in 107 patients: 84 had a single bone biopsy, 16 had 2 bone
biopsies, and 7 had 3 bone biopsies. The first bone biopsy was taken
from the iliac bone in 48 patients, spine in 32, sacrum in 10, rib in 3,
and other sites in 7. The histological biopsy findings indicated
adenocarcinoma in 58 cases, epidermoid carcinoma in 28 cases,
undifferentiated carcinoma in 2 cases, and other histological patterns
in 9 cases. In 80 patients, another metastatic site was easier to access
than the bone metastasis. Tumor marker assays were of limited value
611
for determining the site of the primary, with the exception of PSA. In
conclusion, bone biopsies usually indicate the site of the primary or at
least the histological type. Tumor markers are often positive but are of
limited usefulness for identifying the primary (19).
Data from RCT of zoledronic acid were retrospectively analyzed to
assess the effect of pathologic fractures on survival in patients with
malignant bone disease. A Cox regression model was used to estimate
the effect of fractures (time-dependent variable) on survival in patients
with stage III MM or bone metastases from solid tumors enrolled in 3
large trials. Patients were randomized to receive zoledronic acid,
pamidronate, or placebo every 3-4 weeks for up to 24 months
(prostate cancer, breast cancer, and MM) or up to 21 months (lung and
other solid tumors). Of 3049 patients, 513 with MM, 1130 with breast,
640 with prostate, 766 with lung cancer or other solid tumors were
included in this analysis. Patients with MM had the highest fracture
incidence (43%), followed by breast (35%), prostate (19%), and lung
cancer (17%). In all tumor types except lung, pathologic fracture was
associated with a significant increase in risk of death, and breast
cancer patients had the greatest increased risk. After adjustment for
baseline characteristics, including performance status and prior
skeletal complications, breast cancer patients who developed a
pathologic fracture had a significant 32% increased risk for death than
patients without a fracture (HR=1.32, p<0.01); patients with MM or
prostate cancer had > 20% increased risk of death. In conclusion,
fractures are associated with increased risk of death in patients with
malignant bone disease. Therefore, preventing fractures is an
important goal of therapy (20).
Typical scintigraphic pattern of bone metastases.

612
According to Scutellari et al. (3), the most common metastases in

men are from prostate cancer (60%) while in women from breast
cancer (70%). Other tumors responsible for bone metastases are lung,
kidney, thyroid, G-I tract, bladder, and skin. The spine and pelvis are
the most common metastatic sites, due to the presence of red
(hematopoietic active) bone marrow in a high amount. Generally, the
radiographic pattern is lytic type; other aspects are osteosclerotic,
mixed, lytic vs. mixed and osteosclerotic vs. lytic patterns. The main
symptom is pain, although many bone metastases are asymptomatic.
The most severe consequences are pathological fractures and cord
compression. Clinical evaluation of patients with skeletal metastases
needs multimodal diagnostic imaging, able to detect lesions, to assess
their extension and location, and eventually to perform the biopsy (for
histo-morphological diagnosis). These techniques give different
performances in terms of sensitivity and specificity; but none of the
modalities alone seems to be adequate to yield a reliable diagnostic
outcome. Therefore, multidisciplinary cooperation is required to
optimize the screening, and clinical management and follow-up of the
patients (3).
There were 124,655-fracture cases and 373,962 ages and gender
matched controls. An increased risk of fractures, primarily within the
first year after diagnosis occurred in patients with primary bone
cancer, MM, metastases to the bones, metastases to other organs than
bone, lung cancer, and cancer of the liver, gall bladder and pancreas.
For patients with prostate cancer an increased risk of fractures
occurred with time. Other cancer types were not associated with an
increased risk of fractures. A high-risk group regarding fractures
included cancers primarily affecting the bone (primary bone cancer,
MM, metastases to the bone, metastases to other organs than bone,
lung cancer, and cancer of the liver, gall bladder, and pancreas, and
prostate cancer). The main increase in risk of fractures in this group
occurred within the first year following diagnosis. A low risk group
for fractures included all other cancer types (e.g. cancer of the breast,
colon, and skin) (21).
Tumor registry data were collected between 1994-1996 on 11
primary tumor sites and 15 metastatic sites from 4399 patients. Three
primary tumors had single, dominant metastatic sites: ovary to
abdominal cavity (91%), prostate to bone (90%), and pancreas to liver
(85%). The liver was the dominant metastatic site for G-I primary
tumors (71% of patients), whereas bone and lung metastases were
noted most frequently in non-GI primary tumors, 43% and 29%,
respectively. In a study of combinations of liver, abdominal cavity,
613
and bone metastases, 86% of prostate primary tumors had only bone
metastases, and 74% of pancreas primary tumors had only liver
metastases (22).
Bone metastases
The records of 429 patients seen at the Alexis-Vautrin Centre,

France, in 1979 and 1980 with bony metastases were retrospectively
reviewed to assess their natural history and survival. Breast was the
location of primary lesion in 140 patients (32.6%), lung in 95 patients
(22.1%) and prostate in 33 patients (7.7%). The primary tumor was of
unknown origin in 42 cases (10.9%). The median survival from time
of diagnosis was 5 months. Two and 5-year survival rates were 17.5%
and 5.1% respectively. According to the nature of the primary tumor,
2 and 5-year survival periods for bony metastases were 36.4% and
7.9% in breast cancer, 33.3% and 15.2% in prostatic cancer, 4.3% and
2.1% in metastases of unknown origin, 2.1% and 0% in pulmonary
carcinoma. Multivariate analysis revealed four factors to be of
prognostic significance for survival: the nature of the primary tumor,
the absence of local relapse, the disease-free interval, and the absence
of metastases in other sites. Patients with hormone-sensitive lesions or
slowly growing tumors had a better prognosis (23).
Assessment: skeletal metastases represent the most common

malignant bone tumor. They occur mainly in adults and even more
frequently in the elderly.
The most common metastases in men are from prostate cancer.
Other tumors responsible for bone metastases are lung, kidney,
thyroid, G-I tract, bladder, and skin. The spine and pelvis are common
metastatic sites due to the presence of red (hematopoietic active) bone
marrow in a high amount. The most severe consequences are
pathological fractures and cord compression. Patients with MM had
614
the highest fracture incidence, followed by breast, prostate and lung

cancer.
Tumor infiltration of bones is the most common cause of cancer
pain, and is most often secondary to the primary disease in the
prostate, breast, thyroid, lung or kidney. The radiographic pattern is
lytic type, osteosclerotic, mixed, lytic vs. mixed and osteosclerotic vs.
lytic patterns. Independently from the radiological appearance of the
metastasis, simultaneous osteogenesis and osteolysis are histologically
observed.
The main symptom is pain, although many bone metastases are
asymptomatic. In one-third of patients who suffer fracture due to bone
metastases and were treated surgically, the primary tumor is unknown
at the time of the fracture.
A laboratory analysis is limited to specific tumor markers such as
PSA and protein electrophoresis and is useful in a final diagnosis.
Tumor markers are often positive but are of limited usefulness for
identifying the primary.
Chest, abdominal and pelvic CT are useful for a final diagnosis in
solid tumors, but not for hematologic tumors. A CT-guided biopsy has
a low determination rate in the final diagnosis in comparison with a
laboratory analysis and CT scanning for solid tumors and it is not
essential for the diagnosis of hematologic tumors. Bone biopsies
usually indicate the site of the primary or at least the histological type.
The King suffered from severe intractable bone pains, which point
towards MBD. As previously noted, it seems very likely that some
neoplastic disease that metastasized to the bones such as MM, gamma
HCD, RCC, prostate cancer, or RCC combined with prostate cancer
afflicted the King. Where were the metastases located? What was the
radiographic pattern of the lesions? Osteolytic? Osteosclerotic? Did
pathological fractures occur? Did cord compression take place?
In this research, an evaluation of MBD was based mainly on the
description given in the King's medical record that is the biblical text.
Although different cancers can metastasize to various organs, this
study mainly concentrated on cancers that metastasize to the bones.
In the present, such an old patient should undergo a full
radiological as well as histopathological investigation. The right
diagnosis is essential for providing appropriate treatment. Both
ancient and modern patients deserve appropriate investigation and
treatment of their diseases.
615
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616
CLASSIFICATION OF CANCER RELATED

PAIN
There are three types of pain, based on where in the body the pain
is felt: somatic, visceral, and neuropathic (1). The classification of
non-malignant and malignant pain can overlap, see Vol. 1, p. 20.
SOMATIC PAIN
Somatic pain is caused by the activation of pain receptors in either
the cutaneous (body surface) or deep tissues (musculoskeletal tissues).
When it occurs in the musculoskeletal tissues, it is called deep somatic
pain. Common causes of somatic cancer pain include metastasis in the
bone (an example of deep somatic pain) and postsurgical pain from a
surgical incision (an example of surface pain). Deep somatic pain is
usually described as dull or aching but localized. Surface somatic pain
is usually sharper and may have a burning or pricking quality (2).
VISCERAL PAIN
"Viscera" refers to the internal areas of the body that are enclosed
within a cavity. Visceral pain is caused by activation of pain receptors
resulting from infiltration, compression, extension, or stretching of the
thoracic (chest), abdominal, or pelvic viscera. Common causes of
visceral pain include pancreatic cancer and metastases in the
abdomen. Visceral pain is not well localized and is usually described
as pressure-like and deep squeezing (2).
NEUROPATHIC PAIN
Neuropathic pain is caused by injury to the nervous system either
because of a tumor compressing nerves or the spinal cord or cancer
actually infiltrating the nerves or spinal cord. It also results from
chemical damage to the nervous system that is caused by cancer
treatment (chemotherapy, RT, and surgery). This type of pain is
617
severe and is usually described as burning or tingling. Tumors that lie

close to neural structures cause the most severe pain that cancer
patients feel (2).
Somatic, visceral, and neuropathic pain can be felt at the same time
or singly and at different times. Most cancer patients experience both
somatic and visceral pain. About 15–20% of all cancer patients report
neuropathic pain. The different types of pain respond differently to the
various pain management therapies. Somatic and visceral pain are
both easier to manage than neuropathic pain (2).
PAIN CLASSIFICATION ACCORDING TO

DURATION
ACUTE PAIN
Acute pain is short lasting and usually manifests in ways that can
be easily described and observed. It may, for example, cause sweating
or increased heart rate. Pain can last for several days, increasing in
intensity over time (subacute pain), or it can occur intermittently
(episodic or intermittent pain) (2).
CHRONIC PAIN
Chronic pain is defined as pain lasting for more than 3 months.
Effectively treating chronic pain poses a great challenge for
physicians. This kind of pain usually affects a person's life in many
ways. It can change someone's personality, ability to function and
QOL (2).
If the acute cancer pain does not subside with initial therapy,
patients experience pain of more constant nature, the characteristics of
which vary with the cause and the involved sites (2). Chronic pain
related to cancer is considered as tumor-induced pain, chemotherapy-
induced pain, and RT-induced pain (3).
618
PERSISTENT PAIN
Persistent pain is continuous and may last all day (2).
INTERMITTENT PAIN
Something that is intermittent happens occasionally rather than
continuously (4), or comes and goes at intervals that are not
continuous (5).
The characteristics of intermittent cancer pain are reported and a
new clinically based classification is proposed. Consecutive patients
with cancer (n=100) referred to the palliative medicine service
reported 158 different pain sites. Pain temporal pattern observed was:
60% of patients had continuous plus intermittent pain, 29%
intermittent pain alone, and 11% continuous pain alone. The etiology
of intermittent pain was somatic (58%), visceral (24%), neuropathic
(7%), and mixed (11%). Median duration of intermittent pain was 4
months with a median daily frequency of 4 episodes. Intermittent pain
should be classified into intermittent pain alone or non-BTP. Both
BTP and non-BTP should be each subclassified into 4 categories: (1)
incident, (2) non-incident, and (3) mixed. In addition, a fourth
category exclusive to BTP should be end-of-dose failure. Incident
pains made up (n=42, 47%) nearly half of all intermittent pain.
According to this classification, incident pain was part of BTP in 41%
(n=25) and non-BTP in 58% (n=17). Incident non-BTP received less
treatment than incident BTP, and was less controlled. In conclusion,
(1) intermittent pain is a major problem in patients with cancer, (2)
non-BTP is a common and underrecognized form of cancer pain, (3)
non-BTP is less defined and controlled than BTP, (4) incident non-
BTP accounts for 40% of all incident cancer pain, and (5) variable
intermittent pain definitions and classifications make comparisons
between studies difficult (6).
BREAKTHROUGH PAIN
BTP is defined as transitory, severe flares of pain that occur on a
background of otherwise controlled and persistent pain (7). In the
cancer population, the term BTP typically refers to a transitory flare of
pain in the setting of chronic pain managed with opioid drugs (8).
619
BTP or transient worsening of pain in patients with an ongoing

steady pain is a feature in cancer pain patients. This type of pain is
also seen in non-malignant pain conditions with involvement of
nerves, muscles, bones or viscera (9). BTP is a brief flare-up of severe
pain that can occur even while the patient is regularly taking pain
medication. It usually comes on quickly and may last from a few
minutes to an hour. Many patients can experience a number of
episodes of BTP each day (2).
BTP cancer pain can result from the cancer or cancer treatment, or
it may occur during a certain activity (e.g., walking, dressing, and
coughing). It also can occur unexpectedly, without a preceding
incident or clear cause. BTP pain usually is treated with strong, short-
acting pain medications (2). With the progression of tumor-induced
bone destruction, BTP which is an intermittent occurrence of severe
pain, manifests itself either spontaneously or following weight bearing
or strenuous movement of the affected bone (10).
COMBINED PAIN
Cancer pain is often experienced as several combined different
types of pain, with combined somatic and neuropathic types the most
frequently occurring (2).
CLASSIFICATION ACCORDING TO THE

TYPE OF PATIENTS
Cancer patients with pain are classified into 5 groups: (1) patients
with acute cancer-related pain, (2) patients with chronic cancer-related
pain caused by either progression of disease or therapy, (3) patients
with preexisting chronic non–cancer-related pain as well as cancer-
related pain, (4) patients with a history of chemical dependency and
cancer-related pain, (5) and actively dying patients who must be
provided comfort measures (11). This system of classifying pain
allows for a rich psychosocial approach and prospective planning for
the comprehensive needs of the patient, rather than focusing too
narrowly on a single dimension of the pain (12).
620
CLASSIFICATION ACCORDING TO PAIN

MECHANISM
There are 5 mechanisms that operate in patients with cancer pain:
central sensitization, peripheral sensitization, sympathetically
maintained pain, nociceptive and cognitive-affective. This
classification is based upon mechanisms addresses the underlying
pathophysiology and provides with an understanding behind patient's
symptoms and treatment responses. Effective palliative physical
therapy care, using a mechanism-based classification model, should be
tailored to suit each patient's findings, using a biopsychosocial model
of pain (13).
References
1. Levy MH, Chwistek M, Mehta RS. Management of chronic pain in cancer
survivors. Cancer J. 2008;14(6):401-9.
2. Types of Pain - Cancer Pain. Available 23 May 2013 at
HealthCommunities.comwww. healthcommunities.com/cancer-pain/types.
3. Slavik E, Ivanović S, Grujicić D. Cancer pain (classification and pain
syndromes). Acta Chir Iugosl. 2004;51(4):9-14.
4. Collins Cobuild. Essential English Dictionary. Collins Publishers. The
University of Bimingham. Collins. London and Glasgow. 1988.
5. The Penguin. English Dictionary. 2nd edition. Consultant ed. Robert Allen.
Penguin Books. England, New York. 2003.
6. Lasheen W, Walsh D, Sarhill N, Davis M. Intermittent cancer pain: clinical
importance and an updated cancer pain classification. Am J Hosp Palliat Care.
2010;27(3):182-6.
7. Messina J, Darwish M, Fine PG. Fentanyl buccal tablet. Drugs Today (Barc).
2008;44(1):41-54.
8. Portenoy, RK, Hagen NA. Breakthrough pain: definition, prevalence and
characteristics. Pain. 1990;41(3):273–81.
9. Svendsen KB, Andersen S, Arnason S, et al. Breakthrough pain in malignant
and non-malignant diseases: a review of prevalence, characteristics and mechanisms.
Eur J Pain. 2005;9:195–206.
10. Luger NM, Mach DB, Sevcik MA, Mantyh PW. Bone cancer pain: from
model to mechanism to therapy. J Pain and Symptom Manag. 2005;29 (5 suppl):S32-
46.
11. Portenoy RK. Practical aspects of pain control in the patient with cancer. CA
Cancer J Clin. 1988;38:327–52.
12. Foley KM. The treatment of cancer pain. N Engl J Med. 1985;313: 84-95.
13. Kumar SP. Cancer Pain: A critical review of mechanism-based classification
and physical therapy management in palliative care. Indian J Palliat Care.
2011;17(2):116-26.
621
CHARACTERISTICS OF BREAKTHROUGH
PAIN
The present study is a systematic review of published literature on
cancer BTP to answer the following questions: which terms and
definitions have been used; are there validated assessment tools;
which domains of BTP do the tools delineate, and which items do they
contain; how have assessment tools been applied within clinical
studies; and are there validated classification systems for BTP. A
systematic search of the peer-reviewed literature was performed using
5 major databases. Of 375 titles and abstracts initially identified, 51
articles were examined in detail. Analysis of these publications
indicates a range of overlapping but distinct definitions have been
used to characterize BTP; 42 of the included papers presented one or
more ways of classifying BTP; and while 10 tools to assess patients‘
experience of BTP were identified, only 2 have been partially
validated. There is no widely accepted definition, classification system
or well-validated assessment tool for cancer-related BTP, but there is
strong concurrence on most of its key attributes (1).
This study involved 320 cancer patients from 4 Northern European
countries. Patients with BTP were questioned about the characteristics
of their pain, the current management of their pain, and the
acceptability/utility of alternative routes of administration. The
median number of episodes was 3/day; 44% of patients reported
incident-type pain, 39% spontaneous-type pain, and 17% a
combination of these pains. The median duration was 60 min, and the
median time to peak intensity was 15 min. Three percent of patients
reported "mild" pain, 37% "moderate" pain, and 60% "severe" pain;
90% of patients stated that the pain interfered with their daily
activities. All patients were using opioids as rescue medication
(mainly oral morphine/oxycodone), whilst 28% of patients were using
non-opioids, and 50% patients were using non-pharmacological
interventions. Only 55% of patients took rescue medication every time
they experienced BTP pain. Of all patients, 65% considered using an
oral transmucosal product; patients from Denmark were less likely to
answer positively, and a positive response was associated with
previous use of the route for BTP. Of all patients, 73% reported
regular oral problems. Of all patients, 42% considered using an
intranasal product, while 26% stating they would not use such a
preparation; patients from Denmark and Sweden were less likely to
answer positively, and a positive response was associated with male
gender, and previous use of the route. Of all patients, 44% reported
622
regular nasal problems; 60% considered using a subcutaneous

product, and 44% considered using an intrapulmonary product (2).
A retrospective survey of the prevalence of BTP in consecutive
patients in 4 Italian pain clinics, subsequent to application of an Italian
law mandating detailed clinical records on pain characteristics,
treatment, and results was conducted. Mean pain intensity was
assessed with a NPRS from 0 to 10. Records of 1,401 patients (58%
women, 33.1% patients with cancer) were analyzed. Transient
episodes of severe pain or BTP were referred by 790 patients (56.4%),
including 58.2% of the men (342/588) and 55.1% of the women
(448/813). Among the 464 patients with cancer, 70.3% reported daily
exacerbation of pain. The mean BTP intensity was 8.31 ± 1.58 and
31.1% of patients reported experiencing 3 episodes per day. Despite
some limitations of the study, transient episodes of severe pain or BTP
are significantly present both in cancer and other diseases, and many
patients are not yet receiving appropriate opioid therapy (3).
Operational definitions for BTP and its major characteristics were
developed, and applied in a prospective survey of patients with cancer
pain. Data were collected during a 3-month period from consecutive
patients who reported moderate pain or less for more than 12 hours
daily and stable opioid dosing for a minimum of 2 consecutive days.
Of 63 patients surveyed, 41 (64%) reported BTP, transient flares of
severe or excruciating pain. Fifty-one different pains were described
(median 4 pains/day, range 1-3600). Pain characteristics extremely
varied. Twenty-two (43%) pains were paroxysmal in onset; the
remainders were more gradual. The duration varied from seconds to
hours (median/range, 30 min/1–240 min), and 21 (41%) were both
paroxysmal and brief (lancinating pain). Fifteen (29%) of the pains
were related to the fixed opioid dose, occurring solely at the end of the
dosing interval. Twenty-eight (55%) of the pains were precipitated; of
these, 22 were caused by an action of the patient (incident pain), and 6
were associated with a non-volitional precipitant, such as flatulence.
The pathophysiology of the pain was somatic in 17 (33%), visceral in
10 (20%), neuropathic in 14 (27%), and mixed in 10 (20%). Pain was
related to the tumor in 42 (82%), the effects of therapy in 7 (14%), and
neither in 2 (4%). Diverse interventions were employed to manage
these pains, with variable efficacy. These data clarify the spectrum of
BTP and indicate their importance in cancer pain management (4).
BTP in cancer patients can place physical, psychological and
economic burdens on patients and their productive life. By preventing
instead of treating BTP after it occurs, the efficacy of analgesic
treatment in cancer patients could be maximized. Circadian variations
623
in the occurrence of BTP events in cancer patients were investigated.

The circadian variation of BTP was assessed in 2 different series
(group 1, n=47; group 2, n=76) of advanced cancer patients suffering
from severe chronic pain and undergoing analgesic treatment with
major opioids. BTP episodes showed a circadian pattern, with an
acrophase occurring at 10:00 a.m. (p<0.001) in all patients. When the
2 series of patients were considered separately, an acrophase was
similarly observed, with 60% of BTP episodes recorded between
10:00 a.m. and 6:00 p.m. The circadian rhythm of BTP was
maintained after stratifying the patients according to whether they had
bone metastases or visceral metastases. BTP episodes negatively
correlated with QOL. In conclusion, BTP onset follows a circadian
rhythm, with an acrophase occurring in the late morning (5).
References
1. Haugena DF, Hjermstada MH, Hagend N, et al. On behalf of the European
Palliative Care Research Collaborative (EPCRC). Assessment and classification of
cancer breakthrough pain: A systematic literature review. Pain. 2010;149, 476–82.
2. Davies A, Zeppetella G, Andersen S, et al. Multi-centre European study of
breakthrough cancer pain: pain characteristics and patient perceptions of current and
potential management strategies. Eur J Pain. 2011; 15(7):756-63.
3. Gatti A, Mediati RD, Reale C, et al. Breakthrough pain in patients referred to
pain clinics: the Italian pain network retrospective study. Adv Ther. 2012;29(5):464-
72.
4. Portenoy, RK, Hagen NA. Breakthrough pain: definition, prevalence and
characteristics. Pain. 1990;41(3):273–81.
5. Saini A, Tucci M, Tampellini M, et al. Circadian variation of breakthrough pain
in cancer patients. Eur J Pain. 2013;17(2):264-70.
MECHANISMS OF METASTATIC BONE

DISEASE
Advanced cancers are prone to metastasize. Visceral metastases are
more likely to be fatal, while patients with only metastases to bone
can survive up to 10 years or more. However, effective treatments for
bone metastases are not yet available and bisphosphonates improve
the QOL with no life-prolonging benefits. Bone metastases are
classified as osteolytic, osteosclerotic or mixed lesions according to
the bone cell types more prominently involved. Either conditions
induce high morbidity and dramatically increase the risk of
pathological fractures. Several molecular mechanisms bring about
624
cancer cells to metastasize to bone, and osteotropic cancer cells

acquire bone cell-like properties which improve homing, adhesion,
proliferation and survival in the bone microenvironment. The
acquisition of a bone cell pseudo-phenotype, denominated
osteomimicry, is likely to rely on expression of osteoblastic and
osteoclastic genes, thus requiring a multigenic program. Several
microenvironmental factors improve the ability of cancer cells to
develop at skeletal sites, and a reciprocal deleterious stimulation
generates a vicious cycle between the tumor cells and the cells
residing in the bone environment. The effect of the stem cell niche in
the development of bone metastases and in the phenomenon of tumor
dormancy, that allows tumor cells to remain quiescent for decades
before establishing overt lesions, is at present only speculative.
However, the osteoblast niche, known to maintain the haematopoietic
stem cell population in a quiescent status, is likely to be involved in
the development of bone metastases and this promising research field
is rapidly expanding (1).
Both breast and prostate carcinomas have a propensity to
metastasize to bone. In general, metastatic breast cancers result in
osteolytic lesions. On the other hand, prostate cancer metastases are
osteoblastic and result in osteosclerosis. Thus, bone formation and
bone resorption are at the crux of the cancer metastasis problem. For
example, in the prostate, there is a vicious cycle of metastasis to bone.
Metastases to bone cause excruciating bone pain, pathological
fractures, and eventually death, and therefore is a serious challenge to
both bone biologists and cancer cell biologists. The stromal-epithelial
interactions in breast and prostate are critical in initiation of
carcinogenesis and the progression of the metastatic cascade to bone.
Over a hundred years ago, Stephen Paget enunciated the seed and soil
hypothesis in which seeds of metastatic cancer cells of breast
preferentially settle in the soil of bone matrix. Thus, the
prostate/breast cancer bone interface and continuum has continuously
presented challenges and opportunities (2).
The 'seed and soil' hypothesis for metastasis sets forth the concept
that a conducive microenvironment, or niche, is required for
disseminating tumor cells to engraft distant sites. This opinion
presents emerging data that support this concept and outlines the
potential mechanism and temporal sequence by which changes occur
in tissues distant from the primary tumor. To enable improvements in
the prognosis of advanced malignancy, early interventions that target
both the disseminating seed and the metastatic soil are likely to be
required (3).
625
Metastatic bone disease.
Bone pain is the most common complications in bone metastases,

causing increased morbidity and undermining QOL in patients.
Algesic factors produced by tumor tissues and nerve injury are
involved in pain progression. Acidic microenvironment created in
bone metastasis is relevant to pain signal through the activation of
acid-sensing nociceptor in sensory neurons. These elucidations might
lead to the development of therapeutic approaches for cancer pain (4).
Certain solid tumors metastasize to bone and cause osteolysis and
abnormal new bone formation. The respective phenotypes of
dysregulated bone destruction and bone formation represent two ends
of a spectrum, and most patients will have evidence of both. The
mechanisms responsible for tumor growth in bone are complex and
involve tumor stimulation of the osteoclast and the osteoblast as well
as the response of the bone microenvironment. Factors that increase
bone resorption, independent of tumor, such as sex steroid deficiency,
may contribute to this vicious cycle of tumor growth in bone (5).
Biologic mechanisms resulting in metastases of tumor cells to bone
include the RANKL pathway, osteoclast activation via cytokines
(produced by tumor cell and cells in the bone microenvironment),
interactions with transient and stromal cells in the bone
microenvironment, and molecules such as PTH-rP and endothelin-1.
These molecules offer important opportunities for targeted
interventions to decrease bone metastases-associated morbidity.
Relationships among cancer cells, bone-derived cells, and cytokines
provide opportunities for the development of new interventions.
Therapy targeting osteoclast/osteoblast interactions has proven benefit
for patients with bone metastases (6).
626
Interaction between bone and cancer cells in bone metastases.
Bone, as well as the lung and liver, is among the sites of

predilection for cancer metastasis. The bone stores large amounts of
growth factors such as IGFs and TGF-b, and provides fertile soil for
metastatic cancer cells by continuously releasing these bone-stored
growth factors, which are a consequence of osteoclastic bone
resorption. Metastatic cancer cells in turn produce osteoclast-
stimulating cytokines such as PTH-rP, prostaglandin E2, and various
ILs. These cancer-produced osteoclast-stimulating cytokines bind to
their cognitive receptors and promote the expression of ligands for the
RANKL in osteoblasts. RANKL then binds to its receptor RANK,
expressed in pre-osteoclasts, stimulates mature osteoclast formation,
and subsequently, osteoclastic bone resorption. This vicious cycle
between metastatic cancer cells and osteoclasts is critical to the
development and progression of bone metastases. It is likely that
metastatic cancer cells are influenced by bone environments (or niche)
and acquire additional capacities such as an epithelial-mesenchymal
transition, allowing them to be resistant to chemotherapy or apoptosis,
to survive in a dormant state, or to aggressively spread to distant
organs including lung and liver. Thus, the bone can serve as transit
port. Disrupting this cycle by inhibiting osteoclastic bone resorption,
antagonizing bone-derived growth factors, and neutralizing RANKL
or PTH-rP, should be a promising therapeutic intervention for bone
metastases. Bisphosphonates are specific inhibitors of osteoclasts, and
significantly reduce SREs associated with bone metastasis.
Denosumab is a neutralizing monoclonal antibody to RANKL that
inhibits SRE more effectively than bisphosphonates (7).
Bone pain is one of the most common complications in cancer
patients with bone metastases. Although the mechanism of cancer-
associated bone pain is poorly understood, clinical observations that
inhibitors of osteoclasts such as bisphosphonates efficiently reduce
bone pain suggest a potential role of osteoclasts, which play a central
627
role in the development and progression of bone metastasis.

Osteoclasts dissolve bone minerals by releasing protons through the
a3 isoform of the vacuolar-H(+)-ATPase, creating acidic
microenvironments. In addition, cancer cells, inflammatory cells and
immune cells that reside in bone metastases also produce acidic
conditions by releasing protons. Acidic conditions due to proton
release cause pain. The sensory nociceptive neurons innervate bone
and these neurons express acid-sensing nociceptors such as the acid-
sensing ion channels and transient receptor potential channel-vanilloid
subfamily members. Acid signals received by these nociceptors
subsequently activate intracellular signaling pathways and
transcription factors in sensory neurons. The understanding of the
nociceptive events following proton release and subsequent creation
of acidic microenvironments leads us to design novel molecular-based
approaches for reducing bone pain associated with cancer and
inflammation (8).
Previous findings that inhibitors of osteoclastic bone resorption
such as bisphosphonates reduce bone pain suggest a critical role of
osteoclasts. Osteoclasts destroy bone by secreting protons, thereby
making adjacent microenvironment acidic. Because acidosis is a well-
known cause of pain, it is plausible that an osteoclasts-created acidic
microenvironment may cause bone pain associated with cancer
colonization in bone. To test this notion, an animal model in which
inoculation of MRMT-1 rat breast cancer cells into the tibiae in
female rats induced hyperalgesia was studied. Radiographic and
histological analyses demonstrated that MRMT-1 cells caused
aggressive bone destruction with an increased number of osteoclasts.
Behavioral analyses showed that rats exhibited hyperalgesia in the
tumor-inoculated legs. The bisphosphonate zoledronic acid
significantly reduced the hyperalgesia. In addition,
immunohistochemical examinations revealed that c-Fos expression in
the ipsilateral spinal cord neurons was increased. zoledronic acid
decreased these c-Fos-positive neurons. To investigate the role of
acidosis, mRNA expression of acid-sensing receptors including acid-
sensing channels (ASICs) and transient receptor potential channel-
vanilloid subfamily member 1 (TRPV1) in the DRGs was determined.
The expression of ASIC1a and ASIC1b was increased in the
ipsilateral DRGs, whereas the ASIC3 and TRPV1 expression was not
changed. Of note, zoledronic acid reduced the expression of ASIC1a
and ASIC1b. In conclusion, an acidic microenvironment created by
osteoclasts, at least in part, contributes to the induction of hyperalgesia
through upregulating ASICs expression (9).
628
Solid cancers metastasize to bone by a multistep process that

involves interactions between tumor cells and normal host cells. Some
tumors, most notably breast and prostate carcinomas, grow avidly in
bone because the bone microenvironment provides a favorable soil. In
the case of breast carcinoma, the final step in bone metastasis (namely
bone destruction) is mediated by osteoclasts that are stimulated by
local production of the tumor peptide PTH-rP, whereas prostate
carcinomas stimulate osteoblasts to make new bone. Production of
PTH-rP by breast carcinoma cells in bone is enhanced by growth
factors produced due to normal bone remodeling, particularly
activated TGF-beta. Thus, a vicious cycle exists in bone between
production by the tumor cells of mediators such as PTH-rP and
subsequent production by bone of growth factors such as TGF-beta,
which enhance PTH-rP production. The metastatic process can be
interrupted either by neutralization of PTH-rP or by rendering the
tumor cells unresponsive to TGF-beta, both of which can be
accomplished experimentally. Drugs such as the new-generation
bisphosphonates can inhibit osteoclasts; because of this inhibition,
there is a marked reduction in the skeletal events associated with
metastatic cancer to bone, such as pain, fracture, and hypercalcemia.
There is also a reduction of tumor burden in bone. In experimental
situations, this affects not only morbidity but also survival. The
precise mechanism by which bisphosphonates inhibit osteoclasts is
still unclear and may represent a combination of inhibition of
osteoclast formation as well as increased apoptosis in mature
osteoclasts. However, studies with potent bisphosphonates such as
ibandronate, pamidronate, and risedronate have documented that
reduction of bone turnover and osteoclast activity leads to beneficial
effects not only on skeletal complications associated with metastatic
cancer, but also on tumor burden in bone (10).
Three breast cancer lines that cause osteoblastic metastases in
female nude mice were identified providing evidence that tumor-
produced endothelin-1 mediates the osteoblastic response. Tumor
conditioned media, as well as exogenous endothelin-1, stimulated
osteoblast proliferation and new bone formation in cultures of mouse
calvariae. These effects were blocked by antagonists of the endothelin
A, but not endothelin B, receptors. Mice inoculated with the ZR-75-1
breast cancer line and treated with a selective endothelin A receptor
antagonist (ABT-627) had significantly fewer osteoblastic bone
metastases and less tumor burden compared with untreated mice. By
contrast, there was no effect of ABT-627 on osteolytic bone
metastases caused by endothelin-1-negative breast cancer, MDA-MB-
629
231. ABT-627 had no effect on growth in vitro or at the orthotopic site

of ZR-75-1 or MDA-MB-231 cells. Collectively, the data suggested
that tumor-produced endothelin-1 mediates osteoblastic bone
metastases by stimulating osteoblast proliferation and new bone
formation. Thus, endothelin A receptor blockade may be useful (11).
Acquisition of an invasive phenotype of cancer cells in primary
tumors is an absolute requirement for bone metastasis. The majority of
bone metastases are derived from epithelial cancers, particularly those
of the breast and prostate. Transformed epithelial cells can activate
embryonic programs of epithelial plasticity and switch from a sessile,
epithelial phenotype to a motile, mesenchymal phenotype also
referred to as epithelial-to-mesenchymal transition. Induction of
epithelial-to-mesenchymal transition can, therefore, lead to invasion
of surrounding stroma, intravasation, dissemination and colonization
of distant sites. In bone/bone marrow, disseminated tumor cells can
partially regain their original epithelial characteristics via a
mesenchymal-to-epithelial transition as glandular structures in bone
metastasis are frequently observed. To date, the importance of
epithelial plasticity in cancer cells disseminated to the bone/bone
marrow microenvironment has remained largely elusive. A number of
growth factors that play a prominent role in epithelial-to-mesenchymal
transition induction in the primary tumor have been identified as
important stimulators of skeletal metastasis formation. Epithelial-to-
mesenchymal transition may render cancer cells with properties of
stem cells, which in turn can lead to escape from immune
surveillance, increased resistance to apoptosis, diminished senescence
and, last-but-not least, therapy resistance (12).
Cancer stem cells, which are subset of tumor cells resistant to

radiation and chemotherapy, are associated with malignant
characteristics of tumor and possess both self-renewal ability and
pluripotency for tumor formation. In the process of generating non-
cancer stem cells from cancer stem cells, gene mutations and
630
epigenetic changes are induced in those cells, resulting in composition

of tumor tissue with heterogeneous cell population. Cancer stem cells
have been recognized as the source of metastatic foci. Epithelial-
mesenchymal transition is a change in cellular phenotype
characterized by the loss of cell-to-cell adhesions and the gain of
migratory behaviors, which has been shown to be a critical factor for
initiating cancer invasion and metastasis. However, some recent
studies suggest that epithelial-mesenchymal transition is not essential
requirement for tumor invasion and metastasis (13).
In patients with advanced disease, several cancer types frequently
metastasize to the skeleton, where they cause bone destruction.
Osteolytic metastases are incurable and cause pain, hypercalcemia,
fracture, and nerve compression syndromes. It was proposed over a
century ago that certain cancers, such as that of the breast,
preferentially metastasize to the favorable microenvironment provided
by bone. Bone matrix is a rich store of immobilized growth factors
that are released during bone resorption. Histological analysis of
osteolytic bone metastases indicates that the bone destruction is
mediated by the osteoclast rather than directly by the tumor cells.
These observations suggest a vicious cycle driving the formation of
osteolytic metastases: tumor cells secrete factors stimulating
osteoclasts through adjacent bone marrow stromal cells; osteoclastic
resorption in turn releases growth factors from the bone matrix;
finally, locally released growth factors activate the tumor cells. This
vicious cycle model has now been confirmed at the molecular level. In
particular, TGF3beta is abundant in bone matrix and released as a
consequence of osteoclastic bone resorption. Bone-derived TGFbeta
plays an integral role in promoting the development and progression
of osteolytic bone metastases by inducing tumor production of PTHrP,
a known stimulator of osteoclastic bone resorption. In breast cancer
cells TGFbeta appears to stimulate PTHrP secretion by a
posttranscriptional mechanism through both Smad and p38 mitogen
activated protein kinase signaling pathways. Osteolytic metastases can
be suppressed in vivo by inhibition of bone resorption, blockade of
TGFbeta signaling in tumor cells, and by neutralization of PTH-rP.
Other factors released from bone matrix may also act on tumor cells in
bone, which in turn may produce other factors that stimulate bone
resorption, following the vicious cycle paradigm established for
TGFbeta and PTH-rP. An understanding at the molecular level of the
mechanisms of osteolytic metastasis will result in more effective
therapies for this devastating complication of cancer (14).
631
Numerous growth factors present in the bone matrix are released

during bone remodeling, potentially providing a fertile environment
for the growth of tumor cells. Factors such as PTH-related protein and
IL-6 stimulate osteoclast-mediated bone resorption, thus enhancing
the release of bone-derived growth factors. Prostate cancer cells
secrete factors, including protease-activated receptor 1, that are
involved in the multistep process of tumor cell detachment and
migration to bone and factors that stimulate osteoblast-mediated bone
formation, such as transforming growth factor-beta and bone
morphogenetic proteins. Prostate cancer cells produce endothelin-1, a
peptide under intense investigation that stimulates the proliferation of
osteoblasts and plays a role in the development of osteoblastic bone
lesions. These tumor-derived factors cause dysregulation of normal
bone remodeling. Interactions between prostate tumor cells and the
bone typically result in the formation of osteoblastic lesions
characterized by increased osteolysis and uncoupled new bone
formation. Preclinical evidence suggests that zoledronic acid has
antitumor activity in animal models of prostate cancer. In conclusion,
bone metastasis is a complex process involving multiple molecular
interactions between tumor cells and the bone microenvironment
resulting in disruption of bone remodeling. In patients with prostate
cancer, bone lesions are primarily osteoblastic, but are also associated
with increased osteolytic activity, resulting in marked increases in
bone turnover and clinically significant morbidity (15).
Assessment: there are different mechanisms involved in the MBD.

Bone metastasis is a complex process involving multiple molecular
interactions between tumor cells and the bone microenvironment
resulting in disruption of bone remodeling. Several
microenvironmental factors improve the ability of cancer cells to
develop at skeletal sites, and a reciprocal deleterious stimulation
generates a vicious cycle between the tumor cells and the cells
residing in the bone environment. The 'seed and soil' hypothesis for
metastasis sets forth the concept that a conducive microenvironment,
or niche, is required for disseminating tumor cells to engraft distant
sites. Metastatic cancer cells are influenced by bone environments (or
niche) and acquire additional capacities such as an epithelial-
mesenchymal transition, allowing them to be resistant to
chemotherapy or apoptosis, to survive in a dormant state, or to
aggressively spread to distant organs including lung and liver.
Inhibitors of osteoclasts such as bisphosphonates efficiently reduce
bone pain suggest a potential role of osteoclasts, which play a central
632
role in the development and progression of bone metastasis. Biologic

mechanisms resulting in metastases of tumor cells to bone include the
RANKL pathway, osteoclast activation via cytokines (produced by
tumor cell and cells in the bone microenvironment), interactions with
transient and stromal cells in the bone microenvironment, and
molecules such as PTH-rP and endothelin-1.
An understanding at these mechanisms will result in more effective
therapies for this devastating complication of cancer.
References
1. Clezardin P, Teti A. Bone metastasis: pathogenesis and therapeutic
implications. Clin Exp Metastasis. 2007;24(8):599-608.
2. Reddi AH, Roodman D, Freeman C, Mohla S. Mechanisms of tumor metastasis
to the bone: challenges and opportunities. J Bone Miner Res. 2003;18(2):190-4.
3. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev
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633
MECHANISM OF BONE CANCER PAIN

A metastasis is a consequence of a cascade of events including a
progressive growth at the primary site, vascularization phase,
invasion, detachment, embolization, survival in the circulation, arrest
at the site of a metastasis, extravasion, evasion of host defense and
progressive growth. Once cancer cells establish in the bone, the
normal process of bone turnover is disturbed. The different
mechanisms responsible for osteoclast activation correspond to typical
radiologic features showing lytic, sclerotic or mixed metastases,
according to the primary tumor. The release of chemical mediators,
the increased pressure within the bone, microfractures, the stretching
of periosteum, reactive muscle spasm, nerve root infiltration and
compression of nerves by the collapse of vertebrae are the possible
mechanisms of malignant bone pain. Pain is often disproportionate to
the size or degree of bone involvement. A comprehensive assessment
including a trusting relationship with the patient, taking a careful
history of the pain complaint, the characteristics of the pain, the
evaluation of the psychological status of the patient, neurological
examination, the reviewing of diagnostic studies and laboratory
findings, and individualization of the therapeutic approach should
precede any treatment (1).
Once tumors metastasize to bone, they are a major cause of
morbidity and mortality as the tumor induces significant skeletal
remodeling, fractures, pain, and anemia. Several recently introduced
models of bone cancer pain, which closely mirror the human
condition, are providing insight into the mechanisms that drive bone
cancer pain and guide the development of mechanism-based therapies
to treat the cancer pain. Several of these mechanism-based therapies
have now entered human clinical trials. If successful, these therapies
have the potential to significantly enlarge the repertoire of modalities
that can be used to treat bone cancer pain and improve the QOL,
functional status, and survival of patients with bone cancer (2).

634
The development of optimal analgesics for cancer pain has been

hampered by the lack of understanding of basic mechanisms that
contribute to cancer pain, which is due in part to the lack of
appropriate animal models. Recently, preclinical models of bone
cancer pain have been developed. These models have begun to
provide insight into the mechanisms by which tumors cause pain and
how cancer pain-related sensory information is processed. Once the
mechanism by which cancer induces pain is elucidated, this would
lead to the identification of molecular targets and the development of
mechanism based therapies, which improve the QOL of all those who
suffer from cancer pain (3).
The mechanism by which tumors produce pain include obstruction
of lymphatic and vascular channels, distension of a hollow viscous,
edema and tissue inflammation or necrosis. Injury to tissues results in
the local release of numerous chemicals that mediate transmission of
pain stimulus. Cancer pain syndromes result from 1 or more of 3
fundamental causes; direct tumor involvement of tissues, cancer-
directed therapy, and mechanisms unrelated to cancer or its treatment.
Cancer pain characteristics provide some of the data essential for
syndrome identification. These characteristics include intensity,
quality, distribution and temporal relationships (4). Pain in cancer
survivors is caused by residual tissue damage from the cancer and/or
the cancer therapy (5).
Ongoing and BTP is a primary concern for the cancer patient.
Although the etiology of cancer pain remains unclear, animal models
of cancer pain have allowed investigators to unravel some of the
cancer-induced neuropathologic processes that occur in the region of
tumor growth and in the dorsal horn of the spinal cord. Within the
cancer microenvironment, cancer and immune cells produce and
secrete mediators that activate and sensitize primary afferent
nociceptors. Pursuant to these peripheral changes, nociceptive
secondary neurons in spinal cord exhibit increased spontaneous
activity and enhanced responsiveness to 3 modes of noxious
stimulation: heat, cold, and mechanical stimuli (6).
Malignant bone disease creates a chronic pain state through
sensitization and synaptic plasticity within the spinal cord that
amplifies nociceptive signals and their transmission to the brain (7).
MBD is one of the most frequent causes of pain in cancer patients and
represents one of the first signs of widespread neoplastic disease. The
pain may originate directly from bone destruction, compression of
nerve roots and spinal cord, or from muscle spasms in the area of the
lesions (8,9).
635
Mechanisms of malignant bone pain include the release of

chemical mediators, the increased pressure within the bone,
microfractures, the stretching and irritation of periosteum, medullar
pressure, nerve root infiltration and compression of nerves by the
collapse of vertebrae, or toxicity relating to chemotherapy used to
treat cancer (1,9-12).
The mechanism of metastatic bone pain is mainly somatic

(nociceptive), even though, in some cases, neuropathic and visceral
stimulations may overlap (4). Pain mechanisms in cancer patients
include inflammation due to infection, such as local sepsis or the pain
of herpes zoster, and pain due to the obstruction or occlusion of a
hollow organ, such as that caused by large bowel in cancer of colon.
Pain also is commonly due to destruction of tissue, such as is often
seen with bony metastases. Pain may be produced by the growth of
tumor in a closed area richly supplied with pain receptors
(nociceptors). Examples are tumors growing within the capsule of an
organ such as the pancreas. Chest pain occurs after tumor of the lung
or the mediastinum due to invasion of the pleura. Certain tumors
produce characteristic types of pain. For example, back pain is seen
with MM, while and severe shoulder and arm pain is seen with
Pancoast tumors (12). New insights into the mechanisms that induce
cancer pain are coming from animal models. Chemicals derived from
tumor cells, inflammatory cells, and cells derived from bone are
involved simultaneously in driving this frequently difficult-to-control
pain state. Understanding the mechanisms involved in the
pathophysiology of bone cancer pain will improve both our ability to
provide mechanism-based therapies and improve the QOL of cancer
patients (13).
636
Sensitization of primary afferent fibers may occur via multiple

mechanisms. These include release of pro-nociceptive compounds from
tumor cells and/or inflammatory cells or their byproducts, release of factors
from resorbing bone, and the interactions of protons released by activated
osteoclast with receptors expressed on primary afferent fibers. Cellular and
molecular targeting of pain mechanisms may help elucidate the role of
cellular elements in the generation of the bone cancer state.
Mouse and rat models using the intramedullary injection and

containment of tumor cells into the femur were developed. These
tumor cells induced bone remodeling as well as ongoing and
movement evoked pain behaviors similar to that found in patients with
bone cancer pain. There is a significant reorganization of the spinal
cord that received sensory input from the cancerous bone and this
reorganization generated a neurochemical signature of bone cancer
pain that is both dramatic and significantly different from that
observed in mouse and rat models of chronic neuropathic or
inflammatory pain. These models have provided insight into the
mechanisms that drive cancer pain and have begun to allow the
development of mechanism-based therapies. Together these advances
should reduce tumor-induced pain and suffering and significantly
improve the QOL of cancer patients (14).
To begin to define the mechanisms that give rise to bone cancer
pain, a mouse model using the intramedullary injection and
containment of osteolytic sarcoma cells into the mouse femur was
developed. These tumor cells induced bone destruction as well as
ongoing and movement evoked pain behaviors similar to that found in
patients with bone cancer pain. There was significant neurochemical
reorganization of sensory neurons that innervate the tumor bearing
bone as well as in the spinal cord segments that received sensory input
from the cancerous bone. This reorganization generated a
neurochemical signature of bone cancer pain that was different from
that observed in mouse models of chronic neuropathic or
inflammatory pain. There is an inflammatory, neuropathic and
tumorigenic component of bone cancer pain (15).
637
The main aim of this study was to define the mechanisms that give
rise to advanced bone cancer pain. Osteolytic 2472 sarcoma cells or
media were injected into the intramedullary space of the femur of
C3H/HeJ mice, and the injection hole was sealed using dental
amalgam, confining the tumor cells to the bone. Twelve days after
injection of 2472 tumor cells, animals showed advanced tumor-
induced bone destruction of the injected femur, bone cancer pain, and
a stereotypic set of neurochemical changes in the spinal cord dorsal
horn that receives sensory inputs from the affected femur.
Administration of OPG, a naturally secreted decoy receptor that
inhibits osteoclast maturation and activity and induces osteoclast
apoptosis, or vehicle that was begun at 12 days, when significant bone
destruction had already occurred, and administration was continued
daily until day 21. Ongoing pain behaviors, movement-evoked pain
behaviors, and bone destruction were assessed on days 10, 12, 14, 17,
and 21. The neurochemistry of the spinal cord was evaluated at days
12 and 21. Results indicated that OPG treatment halted further bone
destruction, reduced ongoing and movement-evoked pain, and
reversed several aspects of the neurochemical reorganization of the
spinal cord. Thus, even in advanced stages of bone cancer, ongoing
osteoclast activity appears to be involved in the generation and
maintenance of ongoing and movement-evoked pain. Blockade of
ongoing osteoclast activity appears to have the potential to reduce
bone cancer pain in patients with advanced tumor-induced bone
destruction (16).
Several tumor types including sarcomas and breast, prostate, and
lung carcinomas grow in or preferentially metastasize to the skeleton
where they proliferate, and induce significant bone remodeling, bone
destruction, and cancer pain. Many of these tumors express the
isoenzyme COX-2, which is involved in the synthesis of
prostaglandins. To begin to define the role COX-2 plays in driving
bone cancer pain, we used an in vivo model where murine osteolytic
2472 sarcoma cells were injected and confined to the intramedullary
space of the femur in male C3HHeJ mice. After tumor implantation,
mice develop ongoing and movement-evoked bone cancer pain-
related behaviors, extensive tumor-induced bone resorption,
infiltration of the marrow space by tumor cells, and stereotypic
neurochemical alterations in the spinal cord reflective of a persistent
pain state. Thus, after injection of tumor cells, bone destruction is first
evident at day 6, and pain-related behaviors are maximal at day 14. A
selective COX-2 inhibitor was administered either acutely (NS398;
100 mg/kg, intraperitoneally) on day 14 or chronically in chow (MF.
638
tricyclic; 0.015%, orally) from day 6 to day 14 after tumor

implantation. Acute administration of a selective COX-2 inhibitor
attenuated both ongoing and movement-evoked bone cancer pain,
whereas chronic inhibition of COX-2 significantly reduced ongoing
and movement-evoked pain behaviors, and reduced tumor burden,
osteoclastogenesis, and bone destruction by > 50%. These results
suggest that chronic administration of a COX-2 inhibitor blocks
prostaglandin synthesis at multiple sites, and may have significant
clinical utility in the management of bone cancer and bone cancer pain
(17).
Transduction of pain signals. Nociceptive substances released from

cancer cells, inflammatory cells and bone-resorbing osteoclasts or following
tissue injury are sensed by nociceptors of sensory neurons and are converted
into electrochemical signals. These signals are subsequently transmitted to
the spinal cord (secondary afferent neuron) via the dorsal root ganglia
(primary afferent neuron) and finally reach the brain.
Three novel cancer models in mice that together recapitulate the

anatomical, temporal, and functional characteristics of acute and
chronic head and neck cancer pain in humans were developed. Using
pharmacologic and genetic approaches in these novel cancer models,
the interaction between PAR2 and serine proteases to be of central
importance were identified. Serine proteases such as trypsin induce
acute cancer pain in a PAR2-dependent manner. Chronic cancer pain
is associated with elevated serine proteases in the cancer
microenvironment and PAR2 upregulation in peripheral nerves. Serine
protease inhibition greatly reduces the severity of persistent cancer
pain in wild-type mice, but most strikingly, the development of
chronic cancer pain is prevented in PAR2-deficient mice. These
results demonstrate a direct role for PAR2 in acute cancer pain and
suggest that PAR2 upregulation may favor the development and
maintenance of chronic cancer pain. Targeting the PAR2-serine
protease interaction is a promising approach to the treatment of acute
cancer pain and prevention of chronic cancer pain (18).
639
Tumors including sarcomas and breast, prostate, and lung

carcinomas frequently grow in or metastasize to the skeleton where
they can induce significant bone remodeling and cancer pain. To
define products that are released from tumors that are involved in the
generation and maintenance of bone cancer pain, it was focused on
endothelin-1 and endothelin receptors as several tumors including
human prostate and breast have been shown to express high levels of
endothelins and the application of endothelins to peripheral nerves can
induce pain. In a murine osteolytic 2472 sarcoma model of bone
cancer pain, the 2472 sarcoma cells express high levels of endothelin-
1, but express low or undetectable levels of endothelin A (ETAR) or B
(ETBR) receptors whereas a subpopulation of sensory neurons express
the ETAR and non-myelinating Schwann cells express the ETBR.
Acute (10 mg/kg, intraperitoneally) or chronic (10 mg/kg/day, orally)
administration of the ETAR selective antagonist ABT-627
significantly attenuated ongoing and movement-evoked bone cancer
pain and chronic administration of ABT-627 reduced several
neurochemical indices of peripheral and central sensitization without
influencing tumor growth or bone destruction. By contrast, acute
treatment (30 mg/kg, intraperitoneally) with the ETBR selective
antagonist, A-192621 increased several measures of ongoing and
movement evoked pain. As tumor expression and release of
endothelin-1 is regulated by the local environment, location specific
expression and release of endothelin-1 by tumor cells may provide
insight into the mechanisms that underlie the heterogeneity of bone
cancer pain that is frequently observed in humans with multiple
skeletal metastases (19).
Metastasis of prostate cancer to bone is a common complication of
progressive prostate cancer. Skeletal metastases are often associated
with severe pain and thus demand therapeutic interventions. Although
often characterized as osteoblastic, prostate cancer skeletal metastases
usually have an underlying osteoclastic component. Advances in
osteoclast biology and pathophysiology have led toward defining
putative therapeutic targets to attack tumor-induced osteolysis. Several
factors are important in tumor-induced promotion of osteoclast
activity. One key factor is the RANKL, which is required to induce
osteoclastogenesis. RANKL is produced by prostate cancer bone
metastases, enabling these metastases to induce osteolysis through
osteoclast activation. Another factor, OPG, is a soluble decoy receptor
for RANKL and inhibits RANKL-induced osteoclastogenesis. OPG in
murine models inhibits tumor-induced osteolysis. In addition to
RANKL, PTH-related protein and IL-6 are produced by prostate
640
cancer cells and can promote osteoclastogenesis. Finally, matrix

metalloproteinases are secreted by prostate cancer cells and promote
osteolysis primarily through degradation of the non-mineralized bone
matrix. Matrix metalloproteinase inhibitors diminish tumor
establishment in bone in murine models. Thus, many factors derived
from prostate cancer metastases can promote osteolysis, and these
factors may serve as therapeutic targets. The importance of osteoclasts
in the establishment and progression of skeletal metastases has led to
clinical evaluation of therapeutic agents to target them for slowing
metastatic progression. Bisphosphonates are a class of compounds that
decrease osteoclast life span by promoting their apoptosis. The
bisphosphonate pamidronate relieves bone pain associated with breast
cancer metastases and has a promising outlook for prostate cancer
metastases. Another bisphosphonate, zoledronic acid, appears to
directly target prostate cancer cells in addition to diminishing
osteoclast activity at the metastatic site (20).
Bone cancer pain is common among cancer patients and can have a
devastating effect on their QOL. A chief problem in designing new
therapies for bone cancer pain is that it is unclear what mechanisms
drive this distinct pain condition. OPG, a secreted 'decoy' receptor that
inhibits osteoclast activity, also blocks behaviors indicative of pain in
mice with bone cancer. A substantial part of the actions of OPG seems
to result from inhibition of tumor-induced bone destruction that in turn
inhibits the neurochemical changes in the spinal cord that are involved
in the generation and maintenance of cancer pain. These results
demonstrate that excessive tumor-induced bone destruction is
involved in the generation of bone cancer pain and that OPG may
provide an effective treatment for this common human condition (21).
Prostate cancer forms osteoblastic skeletal metastases with an
underlying osteoclastic component. In the present study, prostate
cancer cells directly induced osteoclastogenesis from osteoclast
precursors in the absence of underlying stroma in vitro. Prostate
cancer cells produced a soluble form of RANKL, which accounted for
the prostate cancer-mediated osteoclastogenesis. To evaluate for the
importance of osteoclastogenesis on prostate cancer tumor
development in vivo, prostate cancer cells were injected both
intratibially and subcutaneously in the same mice, followed by
administration of the decoy receptor for RANKL, OPG. OPG
completely prevented the establishment of mixed
osteolytic/osteoblastic tibial tumors, as were observed in vehicle-
treated animals, but it had no effect on subcutaneously tumor growth.
Consistent with the role of osteoclasts in tumor development,
641
osteoclast numbers were elevated at the bone/tumor interface in the

vehicle-treated mice compared with the normal values in the OPG-
treated mice. Furthermore, OPG had no effect on prostate cancer cell
viability, proliferation, or basal apoptotic rate in vitro. These results
emphasize the important role that osteoclast activity plays in the
establishment of prostate cancer skeletal metastases, including those
with an osteoblastic component (22).
In this study, excitatory synaptic responses evoked in substantia
gelatinosa (lamina II) neurons in spinal cord slices of adult mice
bearing bone cancer, using whole-cell voltage-clamp recording
techniques were examined. Mice at 14 to 21 days after sarcoma
implantation into the femur exhibited hyperalgesia to mechanical
stimuli applied to the skin of the ipsilateral hind paw, as well as
showing spontaneous and movement evoked pain-related behaviors.
substantia gelatinosa neurons exhibited spontaneous excitatory
postsynaptic currents. The amplitudes of spontaneous excitatory
postsynaptic currents were significantly larger in cancer bearing than
control mice without any changes in passive membrane properties of
substantia gelatinosa neurons. In the presence of tetrodotoxin, the
amplitude of miniature spontaneous excitatory postsynaptic currents
in substantia gelatinosa neurons was increased in cancer-bearing mice
and this was observed for cells sampled across a wide range of lumbar
segmental levels. Alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor- and NMDA receptor-mediated
spontaneous excitatory postsynaptic currents evoked by focal
stimulation were also enhanced in cancer-bearing mice. Dorsal root
stimulation elicited mono- and/or polysynaptic spontaneous excitatory
postsynaptic currents that were caused by the activation of A delta
and/or C afferent fibers in substantia gelatinosa neurons from both
groups of animals. The number of cells receiving monosynaptic inputs
from Adelta and C fibers was not different between the 2 groups.
However, the amplitude of the monosynaptic C fiber-evoked
excitatory postsynaptic currents and the number of substantia
gelatinosa neurons receiving polysynaptic inputs from Adelta and C
fibers were increased in cancer-bearing mice. These results show that
spinal synaptic transmission mediated through Adelta and C fibers is
enhanced in the substantia gelatinosa across a wide area of lumbar
levels following sarcoma implantation in the femur. This widespread
spinal sensitization may be one of the underlying mechanisms for the
development of chronic bone cancer pain (23).
Whilst not strictly a neuropathic injury, CIBP is a unique state with
features of neuropathy and inflammation. Osteoclasts damage
642
peripheral nerves (peptidergic C fibres and sympathetic nervous

system) within trabeculated bone leading to deafferentation. In
addition, glia cell activation and neuronal hyperexcitability within the
dorsal horn, are all similar to a neuropathy. Gabapentin and
carbamazepine (both anti-convulsants that modulate neuropathy) are
effective at attenuating dorsal horn neuronal excitability and
normalizing pain-like behaviors in a rat model of CIBP. However,
alterations in neuroreceptors in the dorsal horn do not mimic
neuropathy, rather only dynorphin is upregulated, glia cells are active
and hypertrophic and c-fos expression is increased post-noxious
behavioural stimulus. CIBP perhaps illustrates best the complexity of
cancer pains. Rarely are they purely neuropathic, inflammatory,
ischemic or visceral but rather a combination. Management is
multimodal with RT, analgesics (opioids, and NSAIDs),
bisphosphonates, radioisotopes and tumouricidal therapies. The
difficulty with opioids relates to efficacy on spontaneous pain at rest
and movement-related pain. Potential adjuvants to standard analgesic
therapies for CIBP are being explored in clinical trials and include
inhibitors of glutamate release (24).
Tumor cells produce factors that increase the formation of osteoclasts.
Ongoing and BTP is a primary concern for the cancer patient.

Although the etiology of cancer pain remains unclear, animal models
of cancer pain have allowed investigators to unravel some of the
cancer-induced neuropathologic processes that occur in the region of
tumor growth and in the dorsal horn of the spinal cord. Within the
cancer microenvironment, cancer and immune cells produce and
secrete mediators that activate and sensitize primary afferent
nociceptors. Pursuant to these peripheral changes, nociceptive
secondary neurons in spinal cord exhibit increased spontaneous
activity and enhanced responsiveness to 3 modes of noxious
stimulation: heat, cold, and mechanical stimuli. As our understanding
643
of the peripheral and central cancer pain mechanisms improves,

targeted analgesics for the cancer patient will likely follow (6).
BTP or transient worsening of pain in patients with an ongoing
steady pain is a well-known feature in cancer pain patients, but it is
also seen in non-malignant pain conditions with involvement of
nerves, muscles, bones or viscera. Continuous and intermittent pain
seems to be a general feature of these different pain conditions, and
this raises the possibility of one or several common mechanisms
underlying BTP in malignant and non-malignant disorders. Although
the mechanisms of spontaneous ongoing pain and intermittent flares
of pain (BTP) is difficult to separate, peripheral and/or central
sensitization (hyperexcitability) may play a major role in many causes
of BTP. Mechanical stimuli (e.g. micro-fractures) changes in chemical
environments and release of tumor growth factors may initiate
sensitization both peripherally and centrally. Sensitization can be the
common denominator of BTP in malignant and non-malignant pain
(25).
Assessment: MBD is one of the most frequent causes of pain in

cancer patients and represents one of the first signs of widespread
neoplastic disease. Pain may originate directly from bone destruction,
compression of nerve roots and spinal cord, or from muscle spasms in
the area of the lesions. The release of chemical mediators, the
increased pressure within the bone, microfractures, the stretching of
periosteum, reactive muscle spasm, nerve root infiltration and
compression of nerves by the collapse of vertebrae are the possible
mechanisms of malignant bone pain. The mechanism by which tumors
produce pain include obstruction of lymphatic and vascular channels,
distension of a hollow viscous, edema and tissue inflammation or
necrosis. Pain mechanisms in cancer patients include inflammation
due to infection, such as local sepsis or the pain of herpes zoster, and
pain due to the obstruction or occlusion of a hollow organ, such as that
caused by large bowel in cancer of colon.
Injury to tissues results in the local release of numerous chemicals
that mediate transmission of pain stimulus. Within the cancer
microenvironment, cancer and immune cells produce and secrete
mediators that activate and sensitize primary afferent nociceptors.
Pain also is commonly due to destruction of tissue, such as in bony
metastases. Pain may be produced by the growth of tumor in a closed
area richly supplied with pain receptors (nociceptors). Cancer pain
syndromes result from 1 or more of 3 fundamental causes; direct
tumor involvement of tissues, cancer-directed therapy, and
mechanisms unrelated to cancer or its treatment.
644
Malignant bone disease creates a chronic pain state through

sensitization and synaptic plasticity within the spinal cord that
amplifies nociceptive signals and their transmission to the brain.
Even in advanced stages of bone cancer, ongoing osteoclast
activity appears to be involved in the generation and maintenance of
ongoing and movement-evoked pain. Many factors derived from
prostate cancer metastases can promote osteolysis and these factors
may serve as therapeutic targets. Excessive tumor-induced bone
destruction is involved in the generation of bone cancer pain and that
OPG may provide an effective treatment for this common human
condition.
What was the mechanism of severe intractable bone pain that King
David suffered from?
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CLINICAL PRESENTATION
Metastatic bone lesions can cause serious skeletal complications,
including hypercalcemia of malignancy, severe bone pain requiring
palliative RT, spinal cord or nerve root compression, pathologic
fractures, and bone surgery all of which can significantly compromise
QOL, functional status of the patient and negatively affect survival (1-
13).
Of great clinical importance is the observation that MBD may

remain confined to the skeleton. In patients with MBD, the decline in
QOL and eventual death is due almost entirely to skeletal
646
complications and their subsequent treatment. Bone pain is the most

common complication of MBD, resulting from structural damage,
periosteal irritation, and nerve entrapment. Pain caused by bone
metastasis may also be related to the rate of bone resorption.
Hypercalcemia occurs in 5-10% of all patients with advanced cancer
but is most common in patients with breast carcinoma, MM, and
squamous carcinomas of the lung and other primary sites. Pathologic
fractures are a relatively late complication of bone involvement. The
clinical courses of breast and prostate carcinoma are relatively long,
with a median survival of 2-3 years. For patients with breast
carcinoma, good prognostic factors for survival after the development
of bone metastases are good histologic grade, positive estrogen
receptor status, bone disease at initial presentation, a long disease free
interval, and increasing age. Patients with disease that remains
confined to the skeleton have a better prognosis than those with
subsequent visceral involvement. For patients with prostate
carcinoma, adverse prognostic features include poor performance
status, involvement of the appendicular skeleton and visceral
involvement, whereas for patients with MM, the levels of serum
beta2-microglobulin and LDH and the immunologic phenotype are the
most important factors (12).
A pathological fracture of the humeral diaphysis in lung metastasis.
The skeleton is the most common organ to be affected by

metastatic cancer and the site of disease that produces the greatest
morbidity. Randomized trials in advanced cancer indicate that one of
major skeletal events (pain that requires RT, hypercalcemia,
pathologic fracture, and spinal cord or nerve root compression) occurs
on average every 3 to 6 months. MBD may remain confined to the
skeleton with the decline in QOL and eventual death almost entirely
due to skeletal complications and their treatment. The prognosis of
MBD depends on the primary site, with breast and prostate cancers
associated with a survival measured in years compared with lung
647
cancer, where the average survival is only a matter of months. The

presence of extra osseous disease and the extent and tempo of the
bone disease are powerful predictors of outcome. The latter is best
estimated by measurement of bone-specific markers, and studies have
shown a strong correlation between the rate of bone resorption and
clinical outcome, both in terms of skeletal morbidity and progression
of the underlying disease or death (1).
Metastatic bone cancer is usually diagnosed by graphical
examinations. On plain x-ray film, it demonstrates osteolytic change
with bone destruction in most cases, and sclerotic change without
bone destruction is observed in some cases. In the spine metastases, it
is important to differentiate compression fracture of the osteoporosis
from the pathological destruction of the metastatic cancer. Although
on plain x-ray film, the differentiation of these 2 conditions is
difficult, MRI is useful to differentiate between them (14).
Biochemical bone markers, such as bone isoenzyme, form of ALP,
have been used to assess the bone formation phase of bone turnover in
health and disease. Bone markers can be valuable clinical tools for the
management of patients with metastatic bone disease. Serum levels of
bone ALP, along with serum levels of beta-CrossLap, were measured
in a large group (n=200) of patients with newly diagnosed or
progressive cancer of the prostate, breast, colon, liver and pancreas.
Tumor markers such as CEA, PSA, CA 19-9, AFP, CA 15-3 and bone
marker levels were correlated with the presence or absence of bone
scan documented metastases. Markers of biochemical bone
remodeling can be used in assessing and managing patients with
malignancies that metastasize to the bone (15).
Clinical data of 390 patients with pathologically confirmed
metastatic bone tumors, treated from 1980 to 2003 at The First
Affiliated Hospital of Sun Yat-sen University, Guangzhou, China,
were reviewed respectively to summarize the clinical features,
including disease history, predilection sites, clinical manifestation, and
imaging presentations. Of the 390 patients, the ratio of men to women
was 2.12:1; the median age was 55.7 years, and 81.5% of the patients
were over 41 years old. The primary tumors were lung cancer
(21.8%), prostate cancer (13.1%), breast cancer (7.4%), liver cancer
(6.4%), G-I cancer (5.7%), and unknown cancers (24.6%). The
common metastatic sites were spine (47.7%), pelvis (18.2%), femur
(15.4%), and rib (12.6%). Multiple metastases occurred in 20.5% of
the patients. The main symptoms were skeletal pain (53.3%),
pathologic fractures (10.3%), dysfunction (4.9%), and paraplegia
(2.1%). Primary tumor detected before metastasis accounted for
648
29.7% of the patients with a median metastatic time of 319 days, and
the metastatic intervals were uncertain in 70.3% of the patients.
Osteolytic types accounted for 80.7% of the cases in radiographic
patterns, followed by osteosclerotic (10.5%) and mixed types. In
conclusion, metastatic bone tumors most frequently occur in patients >
41 years, and commonly originate from lung, prostate, breast, and
liver. Vertebrae, pelvis, femur, and rib are the most common sites of
metastases. The clinical manifestation is extensive and nonspecific.
Most lesions present osteolytic patterns. Metastases with unknown
origin accounted for 24%. In spite of complexity, the clinical features
should be mastered for early diagnosis and treatment (16).
Pathological fracture
The clinical data and survival time of 355 patients with bone
metastasis of malignant tumors were retrospectively analyzed. The
bone metastasis occurred more frequently in men (male: female ratio
1.45:1). The most common primary tumors were lung cancer in men
and breast cancer in women. The thoracic vertebrae, ribs, lumbar
vertebrae and pelvic were frequently involved metastatic sites and the
multiple bone metastasis was common (83.4%). The main symptom
was pain (75.2%). Local masses, dysfunctions, pathologic fracture and
paraplegia occurred in a few patients while many patients were
asymptomatic (22.0%). The most frequent radiographic manifestation
was the osteolytic bone destruction (82.2%). Integrated treatments
were taken, including chemotherapy, hormonal therapy, biological
therapy, RT, surgery, bisphosphonate analgetics, etc. The clinical
benefit rate in pain relief was 98.5% and the effective rate was 72.2%
in radiographic imaging. The median survival time was 13.9 months.
Among them, it was 34.9 months in prostate cancer and 4.6 months in
HCC. The survival time was longer in bone metastasis without other
organ metastasis. There was insignificant difference between the
single and multiple bone metastases regarding the survival time. In
649
conclusion, it is important to master the clinical features of bone

metastasis of malignant tumors for early diagnosis and treatment, and
to improve the QOL and prolong the survival time (17).
T1 metastatic epidural spinal cord compression.
Based on the analysis of 156 hospitalized patients, the most

important traits differentiating metastasis of various organs to the
bones have been presented. The bones are most frequently invaded by
kidney cancer, somewhat less frequently by breast cancer and the
bronchus cancer and more rarely by cancer of other organs. The types
of metastasis expansion in the bones were determined radiologically:
the most frequent - osteolytic, less frequent - mixed, and the
osteoplastic type (prostate cancer, gall-bladder cancer, and pancreas
cancer). Metastasis is situated most often in the spine and the femur.
The tactics of diagnosis of metastasis include anamnesis, clinical and
radiological examination, specific examinations, for instance
arteriography of the kidneys at suspicion of kidney cancer. In spite of
complex diagnostics, the source of metastasis was not found in over a
dozen of patients (18).
Bone metastases presenting with pain and body-ache may be the
first presentation of carcinoma in about a fourth of patients with
cancer. Radiologically majority of the metastases are osteolytic and
multiple. Sometimes these may be confused with infective or
inflammatory conditions, particularly in young individuals, and
degenerative conditions of the spine and hip in elderly, which may
delay the diagnosis and treatment leading to poor outcomes. A 30-
year-old non-smoking male teetotaler presented with intermittent,
high-grade nocturnal fever with night sweats of one year. He also had
LBP over his right hip. He was febrile, pale and his long bones, ribs
and pelvis were tender. He had a 3 x 4 cm tender and hard swelling
over the upper part of his sternum. Another firm, non-tender swelling
650
about 4 x 5 cm was seen in the right iliac region. Radiographs of the

skull, spine and pelvis revealed multiple variable sized lytic lesions. A
metastatic malignancy or disseminated tuberculosis was considered.
His anti-tubercular therapy was intensified. Fine needle aspiration
from sternal lesion showed inflammatory cells. A bone marrow biopsy
showed infiltration by tumor cells suggestive of metastatic
adenocarcinoma. Patient's condition continued to deteriorate and he
died within a fortnight of his hospitalization. In conclusion, although
masquerading as tuberculosis lytic lesions might be an evidence of
malignant metastatic. Although, treatment is ineffective in this stage
palliative efforts to improve QOL should be made (19).
Cancer patients often experience multiple symptoms, and those

symptoms can independently predict changes in patient function,
treatment failures, and post-therapeutic outcomes. Symptom clusters
are defined as 2 or more concurrent symptoms that are related and
may or may not have a common cause. The purpose of the present
study was to review in cancer patients common symptom clusters and
their predictors. Using MEDLINE, EMBASE, Cochrane Central, and
CINAHL, a literature search on symptom clusters in cancer patients
was conducted. Studies that investigated predetermined clusters were
not included. Seven individual studies and one group of 5 studies
validating the MDASI were identified. These studies had been
published between 1997 and 2006. Two of the 7 individual studies and
the group of 5 studies that had validated the MDASI included patients
with any cancer type; 3 studies included breast cancer patients only;
and 2 studies included lung cancer patients only. A G-I cluster
consisting of nausea and vomiting was the single cluster common to 2
of the studies. The severity of this cluster increased when patients
were treated with chemotherapy. No common clusters were found in
651
the lung and breast cancer patient populations. However, breast cancer
patients experienced more symptom cluster involvement while
undergoing chemotherapy. Research on symptom clusters is still in an
early stage. Multiple symptoms clearly affect prognosis, QOL, and
functional status. The study of symptom clusters is important for its
implications regarding patient management, and a consensus on
appropriate research methodology is vital (20).
Cancer patients often experience multiple symptoms, many of
which have been reported to correlate with each other. The goals of
this study were to understand which cancer-related symptoms cluster
together and to test the conceptual meanings of the revealed symptom
clusters. Patients with various cancer diagnoses (n=151) were
recruited from a medical center in northern Taiwan. The 13-item
MDASI was used to assess patients' symptom severity. Selected
symptoms were factored using principal-axis factoring with oblique
rotation. The known-group technique was used to validate the
conceptual meanings of revealed factors. Patients' symptom severity
ratings fit a 3-factor solution that explained 55% of the variance.
These 3 factors (symptom clusters) were named sickness symptom
cluster, G-I symptom cluster, and emotional symptom cluster. Patients
with pain and with advanced diseases had significantly higher mean
scores in the sickness symptom cluster than patients without pain and
with earlier-stage diseases. The patients' functional status was
negatively correlated with mean scores in the sickness symptom
cluster. Patients under chemotherapy demonstrated significantly
higher mean scores in the G-I symptom cluster than patients under
other treatments. Patients with anxiety or depression also had
significantly higher mean scores in the emotional symptom cluster
than patients without anxiety or depression. In conclusion, this study
identified 3 underlying symptom clusters and verified their conceptual
meaning in cancer patients. Knowing these symptom clusters may
help healthcare professionals understand plausible mechanisms for the
aggregation of symptoms (21).
The primary objective of this study was to explore how patients'
worst pain clustered together with functional interference items.
Secondary objectives were to determine whether symptom clusters
change with palliative RT and to compare the difference between
responders and nonresponders to radiation. Worst pain at the site of
treatment and functional interference scores were assessed using the
BPI. Patients provided their scores at baseline, 4, 8 and 12 weeks post-
RT. A principal component analysis was performed on the 8 items
(worst pain and 7 functional interference items) at all time points to
652
determine interrelationships between symptoms. Principal components

with an eigenvalue higher than 0.90 and explaining more than 10% of
the variance were selected. From May 2003 to January 2007, 348
patients with bone metastases that were referred for palliative RT were
accrued into the study. There were 206 males (59%) and 142 females
(41%), with a median age of 68 years (range, 30-91). Lung (26%),
breast (25%) and prostate (24%) were the most common primary
cancer sites. Treatment ranged from single to multiple fractions, with
the majority of patients receiving a single 8 Gy (58%) and 20 Gy/5
(35%). The most prevalent sites of RT were spine (31%), pelvis
(16%), and hips (15%). Two symptom clusters were identified.
Cluster 1 included walking ability, general activity, normal work,
enjoyment of life and worst pain. Cluster 2 included relations with
others, mood and sleep. The 2 clusters at baseline accounted for 67%
of the total variance with a Cronbach alpha of 0.87 and 0.70,
respectively. In responders to RT, the 2 symptom clusters
disintegrated at 4, 8, and 12 weeks post-RT. All symptom severity
items improved over time (p<0.0001). In nonresponders, 2 clusters
had disappeared at week 4, reemerged at week 8, and disintegrated at
week 12. In conclusion, symptom clustering has proved to be
therapeutically important because treatment of one symptom may
affect others within the same cluster. The significant correlations
between worst pain and the functional interference items reaffirm the
importance of pain reduction as a treatment goal for palliative RT. By
treating a patient's symptom of worst pain, it would subsequently ease
their response burden on their daily functional activities by decreasing
symptom severity, increasing function, and improving overall QOL
(22).
Assessment: bone metastases presenting with pain and body-ache

may be the first presentation of carcinoma in about a fourth of patients
with cancer. Bone metastases occur in most tumor types but are most
prevalent in cancers of the breast, prostate, and lung, thyroid, and
kidney. These bone lesions can cause serious skeletal complications,
including hypercalcemia of malignancy, severe bone pain requiring
palliative RT, pathologic fractures, dysfunctions, pathologic fracture,
paraplegia, spinal cord or nerve root compression, paraplegia, bone
surgery, local masses, all of which can significantly compromise
QOL, functional status of the patient, and negatively affect survival.
Some patients are asymptomatic.
The types of metastasis expansion in the bones are determined
radiologically: the most frequent - osteolytic, osteoplastic type
653
(prostate cancer, gall-bladder cancer, and pancreas cancer), and less

frequent - mixed. Tumor markers such as CEA, PSA, CA 19-9, AFP,
CA 15-3 and bone marker levels are correlated with the presence or
absence of bone scan documented metastases.
Bone pain is the most common complication of MBD, resulting
from structural damage, periosteal irritation, nerve entrapment, or the
rate of bone resorption.
References
morbidity. Clin Cancer Res. 2006;12(20 Pt 2):6243–9.
2. Selvaggi G, Scagliotti GV. Management of bone metastases in cancer: a
review. Crit Rev Oncol Hematol. 2005;56(3):365–378.
3. Jimenez-Andrade JM, Mantyh PW. Bone cancer pain. Pain Clinical Updates.
2009;17(2):1-6.
5. Fitch M, Maxwell C, Ryan C, et al. Bone metastases from advanced cancers:
clinical implications and treatment options. Clin J Oncol Nurs. 2009; 13(6):701-10.
patients with bone metastases. Nat Clin Pract Oncol.2009;6(3):163-74.
7. Lipton A. Management of bone metastases in breast cancer. Curr Treat Options
Oncol. 2005;6(2):161–71.
8. Clemons MJ, Dranitsaris G, Ooi WS, et al. Phase II trial evaluating the
palliative benefit of second-line zoledronic acid in breast cancer patients with either a
skeletal-related event or progressive bone metastases despite first-line bisphosphonate
therapy. J Clin Oncol. 2006;24(30):4895-900.
9. Wardley A, Davidson N, Barrett-Lee P, et al. Zoledronic acid significantly
improves pain scores and quality of life in breast cancer patients with bone
metastases: a randomised, crossover study of community vs hospital bisphosphonate
administration. Br J Cancer. 2005;92(10):1869–76.
10. Weinfurt KP, Li Y, Castel LD, et al. The impact of skeletal-related events on
health-related quality of life of patients with metastatic prostate cancer [abstract
662P]. Ann Oncol. 2002;13(Suppl 5):180.
11. Weinfurt KP, Castel LD, Li Y, et al. Health-related quality of life among
patients with breast cancer receiving zoledronic acid or pamidronate disodium for
metastatic bone lesions. Med Care. 2004;42(2):164-75.
12. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(8
Suppl):1588-94.
13. Theriault RL, Theriault RL. Biology of bone metastases. Cancer Control.
2012;19(2):92-101.
14. Tateishi A. Diagnosis and treatment of metastatic bone cancer. Gan To
Kagaku Ryoho. 1996;23(10):1262-8.
15. Oremek GM, Weiss A, Sapoutzis N, Sauer-Eppel H. Diagnostic value of bone
and tumour markers in patients with malignant diseases. Anticancer Res.
2003;23:987-90.
16. Xu DL, Zhang XT, Wang GH, et al. Clinical features of pathologically
confirmed metastatic bone tumors - a report of 390 cases. Ai Zheng.
2005;24(11):1404-7.
654
17. Liu NN, Shen DL, Chen XQ, He YL. Clinical analysis of 355 patients with
bone metastasis of malignant tumors. Zhonghua Zhong Liu Za Zhi. 2010;32(3):203-7.
18. Warda E, Mazurkiewicz T, Gronowska S. Characteristics and diagnosis of
neoplastic metastasis to bones. Chir Narzadow Ruchu Ortop Pol. 1990; 55(3):231-6.
19. Vijay H, Navil VK, Vaibhav J, et al. Body aches, tender bones and rapid loss
of weight: a case report. Cases J. 2009;2(1):37.
20. Fan G, Filipczak L, Chow E. Symptom clusters in cancer patients: a review of
the literature. Curr Oncol. 2007;14(5):173-9.
21. Chen ML, Tseng HC. Symptom clusters in cancer patients. Support Care
Cancer. 2006;14(8):825-30.
22. Hadi S, Fan G, Hird AE, et al. Symptom clusters in patients with cancer with
metastatic bone pain. J Palliat Med. 2008;11(4):591-600.
HAS THIS PATIENT CANCER?

Weight loss occurs commonly in elderly individuals, and is
associated with functional decline and mortality. A 10% loss of body
weight over 10 years is consistently associated with increased
mortality and functional decline. A 4% body weight loss over 1 year
should trigger a search for causes, which commonly include
depression, cancers, benign G-I conditions, and medication toxicity.
To evaluate weight loss, physicians should distinguish between 4
problems: anorexia, dysphagia, weight loss despite normal intake, or
socioeconomic problems. In most cases, the cause of weight loss is
identified by a thorough history, a targeted physical examination, and
a simple laboratory evaluation. Assessment should include evaluation
of functional and nutritional status. Management should include
correction of potential causes and nutritional supplementation (1).
Data from 328 patients were evaluated in a predictive model for
cancer for isolated involuntary weight loss from January 1991 to
December 1997 at the Department of Internal Medicine, Santander,
Spain. There were 236 in-patients (72%) and 92 out-patients (28%).
Malignancies were the most frequent cause of isolated involuntary
weight loss (35%), followed by psychiatric disorders (24%). Age,
white blood count, and serum albumin, ALP, and LDH levels were
selected as the best predictors. The regression model discriminated
between patients with or without a malignant neoplasm (area under
the ROC curve 0.90, 95% CI 0.88-0.92). Model sensitivity was 69%,
specificity 93% and positive likelihood ratio 9.9 (using a cut-off point
of 0.5 (2).
Of 306 patients referred to an urban tertiary care teaching hospital
for isolated involuntary weight loss, 276 were followed for at least 1
year or until a final diagnosis was reached. Of the 276 patients, 104
655
(38%) had cancer, mainly of the digestive system (54%, n=56). The
first diagnostic clue usually came from routine blood tests (complete
blood count, ESR, and a biochemical profile), which led to a more
targeted diagnostic procedure, such as abdominal ultrasonography,
CT, and G-I endoscopy. Only 2 patients with cancer had normal
results in all of these tests. Nine of the patients with cancer were not
detected during the initial evaluation. Median survival was 2 months
among patients with cancer, and only 9 survived longer than 1 year. A
clinical approach, including routine laboratory tests (complete blood
count, ESR, serum albumin, aminotransferases, GGT, ALP, and LDH
levels) and abdominal ultrasonography seems to be appropriate for
detecting the majority of cases of cancer among patients with isolated
involuntary weight loss (3).
In a prospective observational study, 101 consecutive patients were
presented to a general internal medicine department of a university
hospital with an unexplained unintentional weight loss of at least 5%
within 6-12 months. Laboratory tests of interest included CRP,
albumin, hemoglobin, and liver function tests. Weight loss of the 101
patients [age (mean, IQR range): 64 (51-71) years, 46% male]
averaged 10 (7-15) kg. Organic causes were found in 57 patients
(56%), including malignancy in 22 (22%). In 44 patients without
obvious organic cause for the weight loss (44%), a psychiatric
disorder was implicated in 16 (16%) and no cause was established in
28 (28%), despite vigorous effort and follow-up of at least 6 months.
Baseline evaluation was entirely normal in none of the 22 patients
(0%) with malignancy, in 2/35 (5.7%) with non-malignant organic
disease, and in 23/44 (52%) without physical diagnosis. Additional
testing, often extensive, after a normal baseline evaluation led to one
additional physical diagnosis (lactose intolerance). In conclusion, in
patients presenting with substantial unintentional weight loss, major
organic and especially malignant diseases seem highly unlikely when
a baseline evaluation is completely normal. A watchful waiting
approach may be preferable to undirected and invasive testing (4).
In this prospective study, 158 patients (89 female, 56%; 69 male,
44%) were referred by GPs for unexplained weight loss or for other
reasons. In the latter case, weight loss was established after admission
to hospital. Follow-up lasted for up to 3 years. The cause of weight
loss was established in 132 (84%) patients and remained unclear in 26
(16%). Reasons were non-malignant (60% of patients) and malignant
(24%) diseases. Psychological disorders represented 11% of the non-
malignant group. G-I tract disease caused weight loss in 50 (30%)
patients. Of malignant disorders, 53% (20 of 38 patients) were G-I.
656
Amongst the non-malignant group, 39% (30 of 77 patients) had

somatic disorders. The prognosis for unknown causes of weight loss
was the same as for non-malignant causes. In conclusion, contrary to
common belief, weight loss is not usually due to a malignant disease.
G-I tract disorder accounts for weight loss in every third patient. If
minimal diagnostic procedures cannot establish a diagnosis, then
endoscopic investigation of the upper and lower G-I tract and function
tests should be performed to exclude malabsorption (5).
"Does this patient have cancer?" is a question frequently asked
when confronted by patients with involuntary weight loss. A
retrospective study of 7850 patients admitted to the Department of
Internal Medicine, Bucharest, Romania, from January to September
2003 was performed. Especially selected were 431 patients with
weight loss. Age, ESR, hemoglobin and the discharge diagnosis were
recorded. Of the patients with involuntary weight, 24% of patients had
cancer. Age, ESR, and anemia were not of value in the diagnosis of
cancer (areas under the curve were 0.684, 0.690, and 0.766,
respectively). When diagnostic tests for age, a high ESR, and anemia
were used serially, the positive predictive value for a malignancy was
64% (CI 27 - 90%); when the tests were utilized in parallel, the
negative predictive value was 91% (CI 85 - 100%). In conclusion, any
patient admitted to the Department of Internal Medicine for
involuntary weight loss had a 24% probability of having a
malignancy. In conclusion, neither age, nor ESR, nor anemia, used
separately as a multilevel, diagnostic test or combined serially or in
parallel, can exclude or rule in the diagnosis of cancer. However, they
can increase (from 24% to 64%) or decrease (from 24% to 9%) the
probability of cancer (6).
A total of 253 consecutive patients with involuntary weight loss
were admitted to a secondary care university hospital. Routine
hematological and inflammatory parameters (hemoglobin level, mean
corpuscular volume, red blood cell distribution width, serum iron
level, ESR, CRP level, and ferritin level) were recorded for all
patients. The investigative workup was not standardized, but the
patients were followed up for 6 months to avoid misclassification
concerning the final diagnosis. All parameters, excepting mean
cellular volume, were statistically associated with cancer. The areas
under the curve were 0.708 (95% CI 0.627 - 0.790) for CRP, 0.690
(95% CI 0.620 - 0.760) for ESR, 0.651 (95% CI, 0.566 - 0.735) for
serum iron level, 0.607 (95% CI 0.526 - 0.687) for hemoglobin level,
0.598 (95% CI 0.518 - 0.679) for ferritin level, 0.594 (95% CI 0.517 -
0.671) for RDW, and 0.561 (95% CI 0.474 - 0.649) for mean cellular
657
volume. In the multivariable analysis, only ESR remained associated

with cancer. In conclusion, in patients with involuntary weight loss,
the hematological and inflammation parameters were statistically
different in patients with cancer and in those without cancer.
However, in clinical practice, they were modest diagnostic tests for
cancer (7).
Patients with osteoporosis were identified from the Swedish
Hospital Discharge Register and then linked to the Cancer Registry.
Follow-up of patients was carried out from the date of first
hospitalization, that is in or after 1969 to 2008. Standardized incidence
ratios were calculated for cancers in these patients and these ratios
were compared with those for individuals without osteoporosis. Of
26,833 patients hospitalized for osteoporosis during 1969-2008, 3941
developed subsequent cancer, giving an overall standardized incidence
ratio of 1.25; for cancer diagnosed after 1 year of follow-up the
standardized incidence ratios was 1.06. A significant increase in risk
was noted for cancers of the upper G-I, skin (squamous cell
carcinoma), lung, and for myeloma. The risk decreased for breast,
endometrial, and ovarian cancers among female patients. Patients with
multiple hospitalizations showed higher risks for myeloma and skin
cancer and lower risk for breast and endometrial cancers. In total, a
25% increase in cancer risk was noted among osteoporosis patients,
but the increase was confined mainly to the first year after
hospitalization. However, the increased risk of certain types of cancers
calls for clinical attention (8).
Assessment: reasons for unintentional weight loss are non-malignant

and malignant. Malignancies are the most frequent cause of isolated
involuntary weight loss, followed by psychiatric disorders. G-I tract
disorders account for weight loss in every third patient.
A clinical approach, including routine laboratory tests (complete
blood count, ESR, serum albumin, aminotransferases, GGT, ALP and
LDH levels) and abdominal ultrasonography is appropriate for
detecting the majority of cases of cancer among patients with isolated
involuntary weight loss.
As described previously, King David suffered for weight loss (9).
In addition, King David suffered from MDD (10). Persistent negative
stress and negative interpersonal experiences played a role in the
development of his MDD (11).
Among the numerous causes associated with weight loss,
malignancy, psychosocial problems such as depression, loneliness,
lack of close relationships and friends on whom he could rely, loss of
658
power and control over his people, feelings of neglect and negative
interpersonal relationships were most likely responsible (12).
We have 2 parameters: weight loss and MDD. Co-existence of
these 2 diagnoses indicates the diagnosis of malignant disease in the
King (13). If the King had been admitted to the Department of Internal
Medicine, he had a 24% probability of having a malignancy (6).
However if we look at the other considerations, then a significant loss
of weight combined with anemia increases the probability of having
cancer to 44% (14). This research reinforces the conclusion of the
previous research that some type of cancer afflicted King David
(9,13), adding that there is a high probability that he was afflicted by a
neoplastic disease.
References
1. Gazewood JD, Mehr DR. Diagnosis and management of weight loss in
the elderly. J Fam Pract. 1998;47(1):19-25.
2. Hernández JL, Matorras P, Riancho JA, González-Macías J.
Involuntary weight loss without specific symptoms: a clinical prediction
score for malignant neoplasm. QJM. 2003;96(9):649-55.
3. Hernández JL, Riancho JA, Matorras P, González-Macías J. Clinical
evaluation for cancer in patients with involuntary weight loss without specific
symptoms. Am J Med. 2003;114(8):631-7.
4. Metalidis C, Knockaert DC, Bobbaers H, Vanderschueren S.
Involuntary weight loss. Does a negative baseline evaluation provide
adequate reassurance? Eur J Intern Med. 2008;19(5):345-9.
5. Lankisch P, Gerzmann M, Gerzmann JF, Lehnick D. Unintentional
weight loss: diagnosis and prognosis. The first prospective follow-up study
from a secondary referral centre. J Intern Med. 2001;249(1):41-6.
6. Baicus C, Ionescu R, Tanasescu C. Does this patient have cancer? The
assessment of age, anemia, and erythrocyte sedimentation rate in cancer as a
cause of weight loss. A retrospective study based on a secondary care
university hospital in Romania. Eur J Intern Med. 2006;17(1):28-31.
7. Baicus C, Caraiola S, Rimbas M, et al.; for Grupul de Studiu al
Scaderii Ponderale Involuntare. Utility of routine hematological and
inflammation parameters for the diagnosis of cancer in involuntary weight
loss. J Investig Med. 2011;59(6):951-5.
8. Ji J, Sundquist K, Sundquist J. Cancer risk after hospitalization for
osteoporosis in Sweden. Eur J Cancer Prev. 2012;21(4):395-9.
9. Ben-Nun L. The disease that caused weight loss. "My knees are weak
through fasting.. my flesh failed of fatness.. my bones cleave to my skin.."
(Psalm, Bible). In Ben-Nun L. ed. The Family Life Cycle and the Medical
Record of King David the Great. Research in Biblical Times from the
Viewpoint of Contemporary Medicine. B.N. Publications. Israel. 2009, pp.
159-71.
659
10. Ben-Noun L. Mental disorder that afflicted King David the Great.
Hist Psychiatry. 2004;15(4):467-76.
11. Ben-Noun L. King David the Great. In Ben Noun L ed. The Diseases
of the Kings of Israel. B.N. Publications. Israel. 2006, pp. 29-99.
12. The Diseases That Affected King David. Ben-noun ed. The diseases
and psychosocial problems. (In Hebrew). B.N. Publications. Israel. 2003.
13. Ben Nun L. What was the disease of the bones that affected King
David? J Gerontol Med Sci. 2002;57:M152-4.
14. Băicuş C, Tănăsecu C, Ionescu R. Has this patient a cancer? The
assessment of weight loss, anemia and erythrocyte sedimentation rate as
diagnostic tests in cancer. A retrospective study in a secondary university
hospital in Romania. Rom J Intern Med. 1999;37:261-7.
CHARACTERISTICS OF CANCER PAIN

Pain, is a major symptom which often accompanies cancer (1) and
is a major health care problem for these patients (2-4). It is always
painful and intolerable, notably when pain is linked to bone
metastases in elderly patients often multipathological. In 1/3 of cases,
pain is present at the time of diagnosis of cancer and in 2/3 of cases at
the advanced diseases. The bone metastases occupy the third place
after the pulmonary and liver metastases (1).
The prevalence of chronic cancer pain varies with diagnosis and
disease severity, ranging from 14-100% (5-10), and 64-85% in
patients with advanced stage of the disease or metastatic cancer (11).
CIBP association with increased morbidity combined with limitations
of currently available therapies makes it a clinical challenge (4).
Bone cancer pain is common in patients with advanced breast,
prostate, and lung cancer as these tumors have a remarkable affinity to
metastasize to long bones, spinal vertebrae, and/or pelvis (12-17).
Bone metastases represent a devastating clinical problem in the most
frequent malignancies, especially in MM, tumors of the breast,
kidney, prostate, and lungs. The consequences include pain, which is
refractory to conventional analgesics, while osteolysis often leads to
bone-marrow compression, pathological fractures, and metabolic
disorders (1,18).
Cancer pain most commonly occurs in patients with locally
advanced or metastatic disease. Certain characteristics of cancer-
related pain, including its multifocal nature, severity, heterogeneity,
progressive nature, and other special challenges, distinguish it from
most other types of chronic pain. Bone metastases are the most
660
common cause of pain in patients with malignant disease, in part due

to the high frequency of axial (vertebrae, rib, and pelvis) and
appendicular (femoral and humeral) fractures. Relief begins with a
thorough understanding of the extent of the disease and the risks of
associated complications, such as spinal cord compression.
Pharmacologic approaches to pain treatment include acetaminophen,
anti-inflammatory agents, opiates, and bisphosphonates. As new
investigational treatments continue to develop, clinicians must
continue to rely on skilled assessment techniques and an
understanding of the many causes of cancer-related pain to effectively
diagnose and treat pain caused by bone metastasis (19).
A cross-sectional survey of patients with CIBP was carried out in a
regional oncology centre. Patients described their pain over the
preceding 24 hours using the MPQ, BPI, and a BTP questionnaire.
Fifty-five patients were recruited. Annoying, gnawing, aching, and
nagging were the most commonly used words to describe CIBP. From
the BPI, median average pain was 4/10 and worst pain was 7/10 on a
0-10 NPRS. The worst pain score correlated more strongly with BPI
interference score (p=0.001). Forty-one patients had BTP. Patients
with BTP had higher total BPI interference scores than those with no
BTP; median (IQR); 35.0 (2.5-44.7) vs. 18.5 (5.5-26.7), p<0.01. Of
the patients, 20/41 (48%) had BTP pain of rapid onset (< 5 min) and
short duration (< 15 min). In conclusion, in CIBP, worst pain most
accurately reflects the characteristics of pain flares and functional
impairment. BTP is often unpredictable, sudden onset and short
duration (4).
Based on recent estimates, approximately 320500 people were
diagnosed with cancer in the UK in 2009 (Cancer Research UK,
2012). Cancer is a major public health problem and is becoming even
more significant as the population grows, ages, and increasingly
embraces cancer-causing habits such as smoking, poor diet, and
physical inactivity. Patients with cancer may experience acute and
chronic pain because of their disease or as an outcome of its treatment.
Extensive research findings indicate that cancer pain is a problem for
many patients and that it is often undertreated (18,20).
A systematic review of the literature was conducted. An instrument
especially designed for judging prevalence studies on their
methodological quality was used. Methodologically acceptable
articles were used in the meta-analyses. In the meta-analysis 52
studies were used. Pooled prevalence rates of pain were calculated for
4 subgroups: (i) studies including patients after curative treatment,
33% (95% CI 21 - 46%); (ii) studies including patients under
661
anticancer treatment: 59% (95% CI 44% - 73%); (iii) studies including

patients characterized as advanced/metastatic/terminal disease, 64%
(95% CI 58 - 69%) and (iiii) studies including patients at all disease
stages, 53% (95% CI 43 - 63%). Of the patients with pain, more than
one-third graded their pain as moderate or severe. Pooled prevalence
of pain was > 50% in all cancer types with the highest prevalence in
head/neck cancer patients 70% (95% CI 51 - 88%). Thus, despite the
clear WHO recommendations, cancer pain still is a major problem (9).
Symptom control is the goal of palliative irradiation.
Approximately 1 month is required before symptomatic relief is
accomplished with RT. However, many patients with cancer-related
pain do not receive adequate analgesics, and opioids are often not
prescribed until patients fail to respond to palliative irradiation. The
presenting symptoms of 108 patients who were referred to a
multidisciplinary clinic for bone metastases were evaluated with the
Wisconsin BPI. This validated instrument evaluates the severity of
pain using a 0-10 scale; 10 represent the worst pain imaginable. The
population comprised 65 men (60%) and 43 women whose ages
ranged from 33 years to 81 years; median age was 55 years, and 69%
of patients were < 65 years of age. Despite the presence of metastatic
disease, 21% of patients were working full-time outside the home, and
6% were employed part-time outside the home; 13% were
homemakers. Only 17 patients (16%) were unemployed. The time
since diagnosis ranged from 2 weeks to 23 years; the median time
since diagnosis was 22 months, and 30% of patients had been
diagnosed with the past 6 months. Pain was a presenting symptom in
74% (n=80) of patients at diagnosis. At its worst, the pain was rated as
severe (levels 7-10) by 78% and intolerable (level 10) in 22% of the
patients in the 24 hours prior to the clinic appointment. On average,
the pain was rated moderate to severe (levels 4-10) in 79% and severe
in 23% of patients. Only 45% of patients experienced good relief from
the prescribed analgesics, and 23% of patients indicated that the
prescribed analgesics were ineffective. This survey demonstrates that
bone metastases incur significant pain that is often undertreated with
analgesics before antineoplastic therapy is administered (21).
The high incidence of bone metastasis secondary to carcinomas
and its serious functional repercussion are motives for constant study
and advance in the methods of evaluation, diagnosis and treatment.
Pain is the most frequently shown symptom, although at times the
start is a pathological fracture. The classic tests of detection and
evaluation of the spread of the metastatic disease, simple radiology
and gammagraphy, are today complemented by others such as CT and
662
MR, improving the information on the characteristics of the lesion

both inside and outside the bone. On the other hand, PET is showing a
far higher sensitivity than gammagraphy and will probably be the test
of the future for the early detection of metastasis and of silent primary
tumors. The possibilities of treatment of bone metastasis are based on
the use of bone regenerators, RT and surgery. The former 2 are
indicated in lesions already detected in radiography, whether
symptomatic or not, if there is no foreseeable risk of fracture. Surgery
is indicated in situations of poor or null response to those treatments,
when the risk of fracture is high or a pathological fracture has been
produced. Before any therapeutic planning, a detailed evaluation of
the patient must be carried out, both at a local level (size, site, and
extension of the metastasis) and general (type of primary tumor, phase
of treatment and response, and estimated survival) (22).
Assessment: pain is a major health care problem for patients with

cancer and 64-85% of patients with advanced stage disease or
metastatic cancer will experience pain. CIBP association with
increased morbidity combined with limitations of currently available
therapies makes it a clinical challenge. Bone metastases incur
significant pain that is often undertreated with analgesics before
antineoplastic therapy is administered.
Pain is always painful and intolerable, notably when pain is linked
to bone metastases. Bone cancer pain is common in patients with
advanced breast, prostate, and lung cancer as these tumors have a
remarkable affinity to metastasize to long bones, spinal vertebrae,
and/or pelvis. Annoying, gnawing, aching, and nagging are the most
commonly used words to describe CIBP.
The classic tests of detection and evaluation of the spread of the
metastatic disease, simple radiology and gammagraphy, are
complemented by CT and MR, improving the information on the
characteristics of the lesion both inside and outside the bone. On the
other hand, PET is showing a far higher sensitivity than gammagraphy
and will probably be the test of the future for the early detection of
metastasis and of silent primary tumors.
References
2. Lin C, Ward SE. Patient-related barriers to cancer pain management in Taiwan.
Cancer Nurs 1995;18:16–22.
3. Delaney A, Fleetwood-Walker SM, et al. Translational medicine: cancer pain
mechanisms and management. Br J Anaesth. 2008;101(1):87-94.
663
4. Laird BJ, Walley J, Murray GD, et al. Characterization of cancer-induced bone

pain: an exploratory study. Support Care Cancer. 2011;19(9): 1393-401.
5. Faris M, Al Bahrani B, Emam Khalifa A, et al. Evaluation of the prevalence,
pattern and management of cancer pain in Oncology Department, The Royal Hospital,
Oman. Gulf J Oncol. 2007;1:23–8.
6. Mercadante S, Roila F, Berretto O, et al. Prevalence and treatment of cancer
pain in Italian oncological wards centres: A cross-sectional survey. Support Care
Cancer. 2008;16:1203-11.
7. Liu Z, Lian Z, Zhou W, et al. National survey on prevalence of cancer pain.
Chin Med Sci J. 2001;16:175-8.
8. Beck SL, Falkson G. Prevalence and management of cancer pain in South
Africa. Pain. 2001;94:75-84.
9. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al.
Prevalence of pain in patients with cancer: A systematic review of the past 40 years.
Ann Oncol. 2007;18:1437-49.
10. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of cancer
pain. Cancer Invest. 2005;23:182-190.
11. Breitbart W, Rosenfeld BD, Passik SD et al. The undertreatment of pain in
ambulatory AIDS patients. Pain 1996;65:243–9.
morbidity. Clin Cancer Res. 2006;12(20 Pt 2):6243s–9s.
13. Luger NM, Honore P, Sabino MA, et al. OPG diminishes advanced bone
cancer pain. Cancer Res. 2001;61(10):4038–47.
14. Luger NM, Mach DB, Sevcik MA, Mantyh PW. Bone cancer pain: from
model to mechanism to therapy. J Pain and Symptom Manage. 2005;29(5 suppl):S32–
46.
1997;69(1–2):1–18.
16. Mantyh PW. A mechanism-based understanding of bone cancer pain. Novartis
Found Symp. 2004;261:194-214; discussion 214-9, 256-61.
17. Jimenez-Andrade JM, Mantyh PW. Bone cancer pain. Pain Clin Updates.
2009;17(2):1–6.
18. Breuer B, Fleishman SB, Cruciani RA, Portenoy RK. Medical Oncologists'
Attitudes and Practice in Cancer Pain Management: A National Survey. JCO.
2011;29(36):4769-75.
19. Slatkin N. Cancer-related pain and its pharmacologic management in the
patient with bone metastasis. J Support Oncol. 2006;4(2 Suppl 1):15-21.
20. Clancy J. Cancer-related neuropathic pain: pharmalogical options. Br J Nurs.
2012;21(17):S31.
21. Janjan NA, Payne R, Gillis T, et al. Presenting symptoms in patients referred
to a multidisciplinary clinic for bone metastases. J Pain Symptom Manage.
1998;16(3):171-8.
22. Garbayo AJ, Villafranca E, De Blas A, et al. Metastatic bone disease.
Diagnosis and treatment. An Sist Sanit Navar. 2004;27 Suppl 3:137-53.
664
QUALITY OF LIFE
The presence of bone metastases predicts pain and is the most
common cause of cancer-related pain. Although bone metastases do
not involve vital organs, they may determine deleterious effects on
patients with prolonged survival (1-4). CIBP is a major clinical
problem of patients with bony metastases having pain, and is often
associated with anxiety and depression, reduced performance status,
and a poor QOL (5).
Cancer pain significantly affects the diagnosis, QOL and survival
(6). Pain is a serious complication of cancer and can have a
devastating effect on the QOL in advanced cancer patients (4,7). In
the elderly, bone metastases are at the origin of the loss of autonomy,
with consequent impairment of QOL (8). Similarly, bone fractures,
hypercalcaemia, neurological deficits, reduced mobility, and
treatment-related events reduce QOL (1,2).
Recent improvements in the primary treatment of cancer have
increased the life span of cancer patients, but not necessarily their
QOL (3). Advances in medical knowledge and treatment have resulted
in improved 5-year survival rates for some forms of cancer. However,
pain syndromes resulting from chemotherapy, RT, surgery or
interventional procedures continue to have a significant effect on
cancer survivors' QOL (9).
The pain and suffering cancer patients experience may be the result
of the tumor itself, or the treatments required to arrest tumor growth
and progression. In contrast to the rapid, highly mechanistic, tailored
medicine approach used to target and treat the primary tumor burden,
the evolution of pain and other supportive treatment approaches for
cancer patients have been slow to non-existent. A movement is
emerging to use more rational mechanistic approaches to the treatment
of pain created by cancer and chemotherapeutics. Delivering
improved broader spectrum supportive care medicines to cancer
patients will fill a significant unmet need and enable these patients to
live productive, fulfilling lives that preserve their overall QOL (3).
As advances in cancer detection and treatment have increased the
life expectancy of cancer patients, more attention to improving patient
QOL is needed. The WHO has proposed a structured approach to drug
selection for cancer pain, known as the "WHO analgesic ladder". This
approach is capable of providing adequate relief to 70-90% of
patients. However, the remaining 10-30% of patients is difficult to
treat (4). Palliation of pain, prevention of skeletal complications, and
665
maintenance of QOL are the primary objectives in managing patients

with MBD (10).
This paper reports a comparative study of the symptom experience,
physical and psychological health, perceived control of the effects of
cancer and QOL of terminally ill cancer patients receiving inpatient
and home-based palliative care, and the factors that predict QOL.
QOL is a major goal in the care of patients with terminal cancer. In
addition to symptom management, psychological care and provision
of support, cared at home is considered an important determinant of
patient well-being. A more comprehensive understanding of the
impact of cancer on patients and their families will inform the delivery
of palliative care services. Fifty-eight patients with terminal cancer
(32 inpatients, 26 home-based) were recruited from major palliative
care centers in Australia in 1999. A structured questionnaire designed
to obtain sociodemographic information, medical details and standard
measures of symptoms, physical and psychological health, personal
control and QOL was administered by personal interview. The 2
groups were similar on most demographic measures, although more
home-care patients were married, of Australian descent and had
private health insurance cover. The most prevalent symptoms reported
were weakness, fatigue, sleeping during the day and pain. Patients
receiving home-based services had statistically significantly less
symptom severity and distress, lower depression scores, and better
physical health and QOL than those receiving inpatient care. Home-
care patients also reported more control over the effects of their
illness, medical care and treatment received, and the course of the
disease. Multiple regression analyses showed that better global
physical health, greater control over the effects of cancer and lower
depression scores were statistically significant predictors of higher
QOL. In conclusion, the main issues are the early detection and
management of both physical and psychological symptoms,
particularly fatigue, pain, anxiety and depression, and the need to use
strategies that will empower patients to have a greater sense of control
over their illness and treatment (11).
The main objective of this study was to identify the association
between QOL and pain intensity, and the magnitude of change of pain
scores that have a clinically significant impact on patients' QOL. In
this multi-center, prospective cohort study, patients suffering from
cancer pain were recruited from 7 university hospitals and 3 tertiary
care centers in Thailand. The FACT-G and the BPI were used to
assess QOL and cancer pain severity, respectively, at study entry and
at 2-week follow-up. Of 520 patients recruited with a mean age of 52
666
years, 76% reported 2 sites of pain with 80% being treated at either
step 2 or 3 (WHO guidelines of pain management). After 2 weeks, the
average level of maximum pain was reduced from 6.6 to 4.8 (MD = -
1.8, p<0.001) and the QOL was improved from 58.6 to 61.0 (MD =
2.4, p<0.001). There was a high correlation between the average
change of pain intensity and QOL scores (rs = -0.42, p<0.001). The
results show that changes of pain scores of at least 3 points (3 out of
10) were required for a minimal important difference of FACT-G
scores, indicating a significant change on patients' QOL. Pain
deterioration had slightly more impact on QOL than pain
improvement. A 3-point pain deterioration impaired QOL 10.3 points
while 3-point reduction increased QOL only 7.6 points. The present
findings suggest the importance of pain management. The change of
pain scores of at least 3 points (out of 10 points) had statistical and
clinical significance to patients' QOL (12).
As the proportion of older adults in the population continues to
grow, the number of patients with cancer is expected to increase
proportionally. The purpose of this study was to examine differences
in reported pain, fatigue, sleep problems and QOL between middle-
aged and elderly hospitalized patients with cancer. Hospitalized
cancer patients included 53 middle-aged (between 18 and 50 years)
and 47 elderly (> 60 years). Pain (VAS, VRS), fatigue (BFI), sleep
problems, QOL (Short Form 36=SF36), and EORTC QLQ-C30 data
were gathered using standardized measures. In the elderly group,
insignificant difference was detected in VAS, VRS, fatigue, fatigue
type, sleep problems and QOL scores (p>0.05). When the 2 age
groups were compared, BFI scores were significantly higher among
the elderly patients (p<0.05). A significant relationship was observed
in both age groups between the scores of pain, fatigue and sleep
problems, and QOL (p<0.05). Elderly hospitalized cancer patients did
not demonstrate a distinctive difference in terms of pain, sleep and
QOL compared to the younger group. The relationship between pain,
fatigue, sleep and QOL should be definitely kept in mind in clinical
practice (13).
The purpose of this study is to compare self-reported QOL scores
in old and young patients with metastatic cancer using the EORTC
QLQ-C15-PAL questionnaire. Patients receiving palliative RT for
bone metastases and brain metastases completed the questionnaire
prior to treatment. Using multiple linear regression analysis, a
parametric test, the QLQ-C15-PAL scores were compared using 65
and 70 years as cutoff ages. A total of 340 patients were referred for
palliative RT for bone metastases (n=190) or brain metastases
667
(n=150). Physical functioning and appetite were worse in the older

group using either 65 or 70 years as the cutoff age. Age-related
differences in the QLQ-C15-PAL scores varied as a function of age
cutoff used and location of metastatic site irradiated (14).
The main aim of this study was to investigate whether fatigue is a
major contributor to overall QOL in preterminal cancer patients.
Ninety-eight preterminal cancer patients, mainly lung (44%) and G-I
cancer (25%), with an estimated life expectancy of 1-6 months were
included. QOL domains as well as overall QOL were measured using
the EORTC QLQ-C30 questionnaire. Fatigue showed the strongest
correlation with overall QOL (r=-0.63, p<0.001), followed in
decreasing order by role functioning (r=0.53), physical functioning
(r=0.47), social functioning (r=0.44), nausea (r=-0.37), cognitive
functioning (r=0.33), appetite loss (r=-0.31), dyspnea (r=-0.26) and
emotional functioning (r=0.24). Multivariate analysis confirmed that
the fatigue scale paid by far the highest individual contribution to
overall QOL (standardized regression coefficient (SRC): -0.41,
p=0.002), followed by social functioning (SRC: 0.18, p=0.05). None
of the other domains or symptom scales contributed independently to
overall QOL. These results demonstrate that, in preterminal cancer
patients, fatigue is a major contributor of overall QOL, corroborating
reports in cancer patients in earlier disease stages (15).
The aims of this replication study were to determine if subgroups
of oncology outpatients receiving active treatment could be identified
based on their experience with the symptoms of fatigue, sleep
disturbance, depression, and pain; whether patients in these subgroups
differed on selected demographic, disease, and treatment
characteristics; and if patients in these subgroups differed on
functional status and QOL. A convenience sample of 228 oncology
outpatients was recruited from 7 outpatient settings in Israel. Patients
completed a demographic questionnaire, a Karnofsky Performance
Status score, the Multidimensional Quality of Life Scale-Cancer, the
Lee Fatigue Scale, the General Sleep Disturbance Scale, the Center for
Epidemiological Studies-Depression Scale, and a NRS of worst pain
intensity. Cluster analysis was used to identify the patient subgroups
based on their symptom experience. Four relatively distinct patient
subgroups were identified based on their experiences with the above
symptoms i.e., low levels of all 4 symptoms (32.9%), low levels of
pain and high levels of fatigue (18.0%), high levels of pain and
moderate levels of fatigue (42.5%), and high levels of all 4 symptoms
(6.6%). No differences were found among the 4 subgroups on any
demographic, disease, or treatment characteristics. The subgroup of
668
patients with high levels of all 4 symptoms reported the worst

functional status and poorest QOL. In conclusion, differences in the
symptom experience of oncological outpatients suggest that patients
may harbor different phenotypic characteristics (e.g., environmental or
physiologic) or genetic determinants for experiencing symptoms that
are independent of demographic, disease and treatment characteristics
(16).
In a prospective study, 84 consecutive patients with cancer-related
pain were interviewed and they completed a comprehensive self-
questionnaire concerning their pain and its influence on physical,
emotional, cognitive and social qualities of life. VAS (10 cm lines)
was used. The mean intensity of pain was 3.9 (range 1-9). Sixty-one
(73%) patients experienced 2 or more different types of pain. Anxiety
and depressive feelings correlated with the intensity of pain (p=0.003
and p=0.0004). The parameters were significantly higher in patients
who had no pain-free or almost pain-free periods (p=0.02 and
p=0.002). Pain had a negative influence on ADL functions and on
concentration in 76% and 56% of the patients, respectively. Social
activities such as visits and conversations decreased significantly with
increasing pain (p=0.0001). In conclusion, unrelieved pain not only
causes physical suffering, but also influences different aspects of
QOL. As effective pain control is achievable in most cases with
already existing analgesics and complementary methods, more efforts
should be focused on pain relief (17).
The main objective of this study was to investigate whether and
how perceived social support is associated with depression and QOL
among patients with various cancer diagnoses. Data were collected
from 1930 cancer patients treated at the NCC and 9 regional cancer
centers across Korea. The Duke-UNC functional social support scale
was used to measure the perceived social support, and the Patient
Health Questionnaire, the 9-item depression module (PHQ-9), and the
EORTC QLQ-C30 were used to measure the cancer patients'
depression levels and QOL, respectively. Subjects with low perceived
social support reported significantly higher levels of depression, lower
scores on all functional scales, higher scores on all 3 symptoms scales,
lower global health/QOL scale scores, and higher scores on most
single items than subjects with high-perceived social support. There
was no interaction between potential stressors and perceived social
support, supporting the main effect model as the mechanism that the
perceived social support reduce the adverse psychological outcomes.
In conclusion, perceived social support was associated with mental
health and QOL in cancer patients, through direct effect rather than
669
stress-buffering effect. Interventions to enhance perceived social

support might be helpful for improving mental health and QOL in
cancer patients (18).
Treatments for painful osseous metastases may not only diminish
pain, but may also improve QOL and independence/mobility, reduce
skeletal morbidity, potential pathologic fractures, spinal cord
compression, and other "SREs" (19).
Neuropathic pain causes greater pain intensity and worse QOL
than nociceptive pain. It was hypothesized that patients with
neuropathic cancer pain had more intense pain, experienced greater
suffering and were treated with more analgesics than those with
nociceptive cancer pain, and a neuropathic pain-screening tool,
painDETECT, would perform as well in those with cancer pain as is
reported in those with non-cancer pain. The data were obtained from
an international cross-sectional observational study. In 17 centers
within eight countries, 1051 inpatients and outpatients with incurable
cancer completed a computerized assessment on symptoms, function
and QOL. Medical data were recorded by physicians. Pain type was a
clinical diagnosis recorded on the ESAS. Of the patients, 670 had pain:
534 nociceptive pain, 113 neuropathic pain and 23 were unclassified.
Patients with neuropathic cancer pain were significantly more likely
received oncological treatment, strong opioids and adjuvant analgesia
and have a reduced performance status. These patients reported worse
physical, cognitive and social function. Sensitivity and specificity of
pain DETECT for identifying neuropathic cancer pain was less
accurate than in non-cancer populations. In conclusion, neuropathic
cancer pain is associated with a negative impact on daily living and
greater analgesic requirements than nociceptive cancer pain (20).
The purpose of this study was to explore differences in the
experience of cancer patients who describe their pain using
neuropathic descriptors compared to those who do not. A secondary
analysis of data from 234 outpatients from a large the NCI designated
cancer center in west, central Florida, was conducted to identify
differences in pain, pain interference, symptoms, HRQL, and
depression between the two groups. Patients with numbness, tingling,
or electric-like sensations reported higher levels of current pain
(p=0.001), pain at its worst (p=0.001), pain on average (p=0.019),
pain at its least (p=0.008), and pain interference (p<0.001). They
reported problems with dizziness/lightheadedness significantly more
often (p=0.004) and more severe problems with concentration
(p=0.047), poorer physical (p=0.019), and mental health (p=0.024)
although no differences in depressive symptoms were found. The
670
results of this study indicate that cancer patients with numbness,

tingling, or electric-like sensations have significantly higher levels of
pain and pain interference, and lower HRQL than do patients without
these symptoms (21).
This study examined which domains/symptoms from the EORTC
QLQ-C15-PAL, an abbreviated version of the health-related EORTC
QLQ-C30 questionnaire designed for palliative cancer patients, were
predictive of overall QOL in advanced cancer patients. Patients with
advanced cancer from 6 countries completed the QLQ-C15-PAL at
consultation and at one follow-up point. Univariate and multivariate
regression analyses were conducted to determine the predictive value
of the EORTC QLQ-C15-PAL functional/symptom scores for global
QOL (question 15). At baseline, 349 patients completed the EORTC
QLQ-C15-PAL. In the total patient sample, worse emotional
functioning, pain, and appetite loss were the most significant
predictive factors for worse QOL. In the subgroup of patients with
bone metastases (n = 240), the domains mentioned above were also the
most significant predictors, whereas in patients with brain metastases
(n = 109), worse physical and emotional functioning most significantly
predicted worse QOL. One-month follow-up in 267 patients revealed
that the significant predictors changed somewhat over time. For
example, in the total patient sample, physical functioning, fatigue, and
appetite loss were significant predictors at the follow-up point. A sub-
analysis of predictive factors affecting QOL by primary cancer (lung,
breast, and prostate) was also conducted for the total patient sample.
In conclusion, deterioration of certain EORTC QLQ-C15-PAL
functional/symptom scores significantly contributes to worse overall
QOL. Special attention should be directed to managing factors most
influential on overall QOL to ensure optimal management of
advanced cancer patients (22).
Assessment: pain is a serious complication of cancer and can have

a devastating effect on the QOL in advanced cancer patients. Cancer
pain significantly affects the diagnosis, QOL and survival. In the
elderly, bone metastases are at the origin of the loss of autonomy, with
for consequent impairment of QOL.
Better global physical health, greater control over the effects of
cancer and lower depression scores are predictors of higher QOL. The
change of pain scores of at least 3 points (out of 10 points) has
statistical and clinical significance to patients' QOL. Pain deterioration
has slightly more impact on QOL than pain improvement.
671
Subjects with low perceived social support reported significantly

higher levels of depression, lower scores on all functional scales,
higher scores on 3 symptom scales, lower global health/QOL scale
scores, and higher scores on most single items than subjects with high
perceived social support.
What was QOL in King David's case? As described previously,
King David suffered from weakness ―My strength is dried up like a
potsherd‖ (Psalms 22:16), ‖My strength failed because of mine
iniquity...‖ (31:11) and ―My knees are weak through fasting; and my
flesh failed of fatness‖ (Psalm 109:24); general discomfort ―I am
feeble and depressed: I have groaned by reason of the suffering of my
heart‖ (38:9), ―..Like a deaf man I would not hear and like a mute I
would not speak..‖ (38:14), ―Be not far from me; for trouble is near;
for there is no help ― (Psalm 6:12) and ―I am helpless‖ (25:16); loss of
appetite ―..I (the King) forget to eat my bread‖ (Psalm 102:4); severe
bone pain ―My bones wasted away through my anguished roaring all
day long‖ (32:3); and insomnia ―..All the night make I my bed to
swim; I water my couch with my tears‖ (6:7). All these verses indicate
poor QOL in this ancient patient (23-25).
References
1. Mercandane S. Malignant bone pain: pathophysiology and treatment. Pain.
1997;69:1-18.
2. Ford JA, Mowatt G, Jones R. Assessing pharmacological interventions for
bone metastases: the need for more patient-centered outcomes. Expert Rev Clin
Pharmacol. 2012;5(3):271-9.
3. Knopp Knopp KL, Nisenbaum ES, Arneric SP. Evolving cancer pain
treatments: rational approaches to improve the quality of life for cancer patients. Curr
Pharm Biotechnol. 2011;12(10):1627-43.
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9. Chapman S. Chronic pain syndromes in cancer survivors. Nurs Stand.
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11. Peters L, Sellick K. Quality of life of cancer patients receiving inpatient and
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worse quality of life scores? Support Care Cancer. 2012;20(9):2121-7.
15. Beijer S, Kempen GI, Pijls-Johannesma MC, et al. Determinants of overall
quality of life in preterminal cancer patients. Int J Cancer. 2008; 123(1):232-5.
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The Family Life Cycle and the Medical Record of King David the Great. B.N.
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through fasting. .my flesh failed of fatness. . my bones cleave to my skin" (Psalm,
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Israel. 2006, pp. 47-54.
PSYCHOSOCIAL DISTRESS
Psychological distress is common among patients with cancer;
however, it often goes unrecognized (1). The NCCN defines distress
as a multifactorial, unpleasant emotional experience of a
psychological (cognitive, and emotional), social, and/or spiritual
nature that may interfere with the ability to cope effectively with
cancer, its physical symptoms, and its treatment (2). Despite the fact
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that approximately 60% of cancer diagnoses and 70% of cancer

mortality occur in patients age ≥ 65 years (3), few studies have
specifically focused on the prevalence or causes of distress in older
adults with this disease.
Psychosocial factors including stress, chronic depression and lack
of social support are risk factors for cancer progression (4). In modern
lifestyle societies, chronic stress has been associated with the
pathogenesis of many diseases, including cancer. Chronic stress
results in the activation of specific signaling pathways in cancer cells
and the tumor microenvironment, leading to tumor growth and
progression (5).
Longitudinal associations between stress and cancer using meta-

analytic methods were evaluated. The results of 165 studies indicate
that stress-related psychosocial factors are associated with higher
cancer incidence in initially healthy populations (p=0.005); in
addition, poorer survival in patients with diagnosed cancer was noted
in 330 studies (p<0.001), and higher cancer mortality was seen in 53
studies (p<0.001). Subgroup meta-analyses demonstrate that stressful
life experiences are related to poorer cancer survival and higher
mortality but not to an increased incidence. Stress-prone personality or
unfavorable coping styles and negative emotional responses or poor
QOL were related to higher cancer incidence, poorer cancer survival
and higher cancer mortality. Site-specific analyses indicate that
psychosocial factors are associated with a higher incidence of lung
cancer and poorer survival in patients with breast, lung, head and
neck, hepatobiliary, and lymphoid or hematopoietic cancers. These
analyses suggest that stress-related psychosocial factors have an AE
on cancer incidence and survival, although there is evidence of
publication bias and results should be interpreted with caution (4).
There are several potential reasons why older adults with cancer
are at risk for psychological distress. First, they are more likely to
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require assistance with their daily functions than older adults without
cancer (6). Furthermore, this increased need for assistance persists in
cancer survivors (7). Second, changes in the social support structure
that often accompany aging, such as the death of a spouse or friends or
the loss of a job, can lead to social isolation in older adults, isolation
that can be exacerbated by a serious illness. Third, treatment-related
short- and long-term toxicity is common in older adults because of
age-related declines in physiologic function (8). Fourth, comorbid
medical conditions increase with age may have an impact on tolerance
to cancer therapy, or may be acquired as AEs to therapy (9-11). All
these factors can contribute to psychological distress in older adults
with cancer.
A substantial percentage of cancer patients suffer from
psychosocial distress to severe mental disorders and psychosocial
crisis during the course of the illness and cancer treatment. However,
only a small percentage of patients with severe psychosocial distress
and mental disorders in the present oncological practice is accurately
identified, diagnosed, and appropriately treated. Therefore, sufficient
knowledge about psychosocial distress and mental disorders as well as
screening procedures is urgent concerns to improve psychosocial care
for cancer patients (10).
Whereas evidence for the role of psychosocial factors in cancer
initiation is limited and some-what contradictory (11-14), support is
stronger for links between psychological factors such as stress,
depression and social isolation and disease progression (15,16).
Chronicity of negative effect, as manifested by depressed mood or
hopelessness, appears to have stronger relationships with outcomes
than do stressful events, suggesting that sustained activation of
negative affective pathways may provide the strongest links to cancer
progression (17-20). Moderators of stress, such as social support, have
been studied with respect to cancer outcomes. Social support refers to
an individual‘s perceived satisfaction with social relationships and
plays a major role in buffering psychological and biological stress
responses (21). Several studies have linked high levels of social
support to improved clinical outcomes in cancer patients. For
example, in breast cancer patients, social support has been related to
longer survival in several large-scale studies (22-24), although
negative findings were noted in some studies (25-27).
Appropriate management of cancer pain is essential and requires a
multidisciplinary approach that includes a major role for a
psychologist and/or psychiatrist. An increased incidence of psychiatric
disturbance, in particular, anxiety and depression, is found in patients
675
with pain. Psychiatric symptoms in patients with cancer pain must be

initially viewed because of uncontrolled pain. Personality factors may
be quite distorted by the presence of pain, and its relief often results in
the disappearance of a perceived psychiatric disorder. Reassessment
after pain control is imperative. Optimal treatment of cancer pain
includes pharmacologic, psychologic, behavioral, anesthetic,
stimulatory, and rehabilitative approaches, often in combination. CBT,
such as relaxation, imagery, hypnosis, distraction, and biofeedback,
are effective as part of a comprehensive multimodal approach and
must never be used as a substitute for appropriate analgesic
management of cancer pain. Psychotropic drugs, particularly the
TCAs, are useful as adjuvant analgesic agents in the pharmacologic
management of cancer pain (28).
The NCCN recommends that all patients with cancer should be
evaluated regularly for psychosocial distress as a part of routine care.
The NCCN guidelines for distress management recommend using the
Distress Thermometer as a screening tool. This is a single-item, zero-
to 10-point scale with a threshold score of 4 indicating significant
distress that warrants further evaluation. The Distress Thermometer is
a quick and valid alternative to other psychometric instruments for use
in busy outpatient cancer clinics. However, once a distressed older
adult is identified, there is little research to guide oncologists in
determining which of the risk factors is most likely to cause distress.
An understanding of the predictors of distress would help streamline
the evaluation and guide interventions for decreasing the level of
distress (2).
The main purpose of this study was to determine the predictors of
distress in older patients with cancer. Patients aged ≥ 65 years with a
solid tumor or lymphoma completed a questionnaire that addressed
these geriatric assessment domains: functional status, comorbidity,
psychological state, nutritional status, and social support. Patients self-
rated their level of distress on a scale of zero to 10 using the Distress
Thermometer. The relationship between distress and geriatric
assessment scores was examined. The geriatric assessment
questionnaire was completed by 245 patients (mean age, 76 years; SD
7 years; range, 65 to 95 years) with cancer (36% stage IV; 71%
female). Of these, 87% also completed the Distress Thermometer,
with 41% (n=87) reporting a distress score of ≥ 4 on a scale of zero to
10 (mean score 3; SD 3; range zero to 10). Bivariate analyses
demonstrated an association between higher distress (≥ 4) and poorer
physical function, increased comorbid medical conditions, poor
eyesight, inability to complete the questionnaire alone, and requiring
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more time to complete the questionnaire. In a multivariate regression

model based on the significant bivariate findings, poorer physical
function such as increased need for assistance with instrumental
activities of daily living (p=0.015) and lower physical function score
on the Medical Outcomes Survey (p=0.018) correlated significantly
with a higher distress score. In conclusion, significant distress was
identified in 41% of older patients with cancer. Poorer physical
function was the best predictor of distress (29).
The results and conclusions of an observational prospective cohort
design study using self-administered questionnaires determined
correlation between psychosocial factors and cancer outcome among
80 consecutive newly diagnosed treatment naïve cancer subjects who
were referred to the Oncology Clinic, Hospital Universiti Kebangsaan,
Malaysia. Subjects were recruited over a period of 43 weeks from
October 2000 until July 2001. Follow-up assessments were carried out
at 6-months and 12 to 26 months later. Depression (p=0.001), stage 4
cancer disease (p=0.016), neurological (p=0.032), G-I tract (p=0.04),
head and neck (p=0.011), gynecological (p=0.005) and bone and soft
tissue (p=0.030) malignancies were independent and statistically
significant prognostic factor of survival. Depressed patients had
almost four-fold greater risk of dying than non-depressed patients and
patients with stage 4 cancer illness have a 5-fold greater risk of dying
than patients with stage 1 disease. Based on tumor types, subjects with
neurological, gynecological, head and neck, bone and soft tissue and
G-I tract malignancies had approximately 36, 25, 22, 16 and 7 fold
greater risk of dying respectively when compared to subjects with
genitourinary cancers. This study further affirms the need for health
care providers to be aware of the psychological aspects of the cancer
patient and provide appropriate therapy to ensure that this group of
individuals would have enhanced survival rates (30).
Pain and depression are two of the most prevalent and treatable
cancer-related symptoms, each present in at least 20-30% of oncology
patients. The main objective of this study was to determine the
associations of pain and depression with HRQL, disability, and health
care use in cancer patients. The Indiana Cancer Pain and Depression
study is a randomized clinical trial comparing telecare management
vs. usual care for patients with cancer-related pain and/or clinically
significant depression. Baseline data on patients enrolled from 16
urban or rural community-based oncology practices were analyzed to
test the associations of pain and depression with HRQL, disability,
and health care use. Of the 405 participants, 32% had depression only,
24% pain only, and 44% both depression and pain. The average
677
Hopkins Symptom Checklist 20-item depression score in the 309

depressed participants was 1.64 (on 0-4 scale), and the average BPI
severity score in the 274 participants with pain was 5.2 (on 0-10
scale), representing at least moderate levels of symptom severity.
Symptom-specific disability was high, with participants reporting an
average of 16.8 of the past 28 days (i.e., 60% of their days in the past
4 weeks) in which they were either confined to bed (5.6 days) or had
to reduce their usual activities by 50% (11.2 days) because of pain or
depression. Moreover, 176 (43%) participants reported being unable
to work because of health-related reasons. Depression and pain had
both individual and additive adverse associations with QOL. Most
patients were currently not receiving care from a mental health or pain
specialist. In conclusion, depression and pain are prevalent and
disabling across a wide range of types and phases of cancer,
commonly co-occur, and have additive AEs. Enhanced detection and
management of this disabling symptom dyad is warranted (31).
Type D personality is a general propensity to psychological
distress that is related to poor C-V outcomes. Individuals diagnosed
with endometrial cancer, or CRC between 1998 and 2007, or with
lymphoma or MM between 1999 and 2008 registered in the
Eindhoven Cancer Registry, received the Self-Administered
Comorbidity Questionnaire, questions on health care utilization and
the Type D personality scale; 69% (n=3080) responded. Survivors
(19%) with a type D personality reported significantly more often
osteoarthritis, back pain, and depression. They felt bothering by high
blood pressure, osteoarthritis, heart disease, depression, diabetes, and
lung disease during daily activities. Type D survivors more often
visited their GP than non-type D survivors (p<0.001), also in relation
to cancer (0 visits: 54% vs. 60%; 1-5: 28% vs. 22%; >5: 9% vs. 5%;
p<0.001), as well as their specialist (0 visits: 6% vs. 7%; 1-5 visits:
59% vs. 64%; >5 visits: 30% vs. 23%; p<0.01). In conclusion, type D
personality is a vulnerability factor that may help to identify
subgroups of cancer survivors who are at an increased risk for
comorbidity burden and increased health care utilization (32).
The emotional and social consequences of pain were studied in 93
consecutive in-patients, 44 males and 49 females, suffering from
cancer-related pain. The methods used were VAS, standardized
interviews and comprehensive self-questionnaires. Forty-seven
patients (51%) experienced certain or pronounced anxiety (4-6 or 7-9
on a 9-grade scale) because of their pain and 66 patients (71%)
expressed depressive pain-associated symptoms, which had a high
correlation with the intensity of their pain. Physical activities such as
678
movements, dressing/undressing, washing, cooking were hampered in

about 2/3 of the patients, and mental activities such as reading were
significantly disturbed in 48% of the cases. For every social activity
listed in the questionnaires (hobbies, seeing friends, etc) most patients
reported a decreased activity because of pain and in most cases, the
decrease correlated significantly with the intensity of the pain. The
family roles had changed since the patient could not participate in a
usual manner. The study underlines the profound consequences of
pain: physical suffering, emotional distress, social handicap and
altered family roles. Thus, pain control should be a high-priority
matter in palliative care (33).
Palliative care for cancer patients receiving chemotherapy in the
outpatient setting is important. The aims of this study were 1) to
identify symptom prevalence and intensity in cancer patients receiving
chemotherapy and 2) to describe longitudinal follow-up data obtained
from repeated assessment using the distress thermometer.
Questionnaires were distributed to consecutive cancer outpatients
newly starting chemotherapy at the first appointment and at every
hospital visit. The questionnaire included the severity of 11 symptoms
(MDASI, Japanese version), the distress thermometer, and the need
for help in 4 psychosocial areas (decision-making, economic
problems, nutrition, and daily activities). In total, 4000 questionnaires
were returned by 462 patients. The frequently identified problems
were oral problems (21%), insomnia (19%), psychological distress
(defined as a distress thermometer score of 6 or more, 15%), help with
information and decision-making (14%), severe fatigue (8.2%), and
severe appetite loss (6.3%). Cluster analysis identified 4 symptom
clusters: 1) fatigue and somnolence; 2) pain, dyspnea, and numbness;
3) nausea, appetite loss, and constipation; and 4) psychological
distress. Of 165 patients with a distress thermometer score 6 or more,
115 patients (70%) demonstrated a distress thermometer score below
6 at a median of 17 days follow-up. In the remaining 50 patients who
had a distress thermometer score of 6 or more at follow-up, 34
patients (68%) had 1 or more physical symptoms rated at 7 or more on
an 11-point NRS. Compared with patients with a distress thermometer
score below 6 at follow-up, patients with a distress thermometer score
of 6 or more at follow-up had higher levels of all physical symptoms.
Frequent symptoms experienced by cancer outpatients receiving
chemotherapy are categorized as: 1) psychosocial issues (insomnia,
psychological distress, and decision-making support); 2) nutrition -
G-I issues (oral problems, appetite loss, and nausea); 3) fatigue; and 4)
679
pain, dyspnea, and numbness. Developing a systematic intervention

program targeting these 4 areas is urgently required (34).
In this study, an attempt was made to explore the presence of
common concerns in a group of advanced cancer patients. Patients'
disclosure of concerns was assessed in 50 consecutive patients having
advanced cancer using a shortened version of a concerns checklist.
Commonly reported concerns were cancer pain (68%), physical health
(60%), finances (54%), and the future (52%). Other concerns were
about low mood and sadness (32%), anxiety (24%), being slowed
down (40%), and not being able to work (and earn) (40%). Cancer
patients with additional psychiatric diagnoses significantly more often
reported concern for physical health, sadness, anxiety, future, work or
occupation and being slowed down, rather than for cancer pain,
interpersonal relationships, marital relationship, socialization or body
image. The emotional distress due to the concerns needs to be
alleviated, in order to improve the QOL and help the patient cope with
pain and other distressing symptoms (35).
Assessment: psychosocial risk factors for cancer progression

include stress, chronic depression and lack of social support. Chronic
stress results in the activation of specific signaling pathways in cancer
cells and the tumor microenvironment, leading to tumor growth and
progression. Stress-related psychosocial factors are associated with
higher cancer incidence in initially healthy populations. Stress-prone
personality or unfavorable coping styles and negative emotional
responses or poor QOL are related to higher cancer incidence, poorer
cancer survival and higher cancer mortality.
A substantial percentage of cancer patients suffer from
psychosocial distress to severe mental disorders and psychosocial
crisis during the course of the illness and cancer treatment. However,
only a small percentage of patients with severe psychosocial distress
and mental disorders in the present oncological practice is accurately
identified, diagnosed, and appropriately treated. Depression, stage IV
cancer disease, neurological, G-I tract, head and neck, gynecological,
and bone and soft tissue malignancies are significant prognostic
factors of survival.
Advanced cancer patients report concerns about cancer pain,
physical health, finances, and the future, low mood, sadness, anxiety,
being slowed down, and not being able to work.
Did King David suffer from psychological distress? The following
verses ―...a broken and depressed heart..‖ (Psalm 51:19) and ―I am
feeble and depressed: I have groaned by reason of the suffering of my
heart‖ (38:9) indicate a depressed mood, while ―Fearfulness and
680
trembling are come upon me...‖ (55:6), ―My heart is shivering within
me ..‖ (55:5) and ―..Like a deaf man I would not hear and like a mute I
would not speak..‖ (38:14) indicate chronic stress.
The subsequent passages ―But I am a worm, and no man; a
disgrace of men, and despised of the people‖ (22:7), I am forgotten as
a dead man out of mine mind: I am like a lost tool (31:13), I am
helpless‖ (25:16) and ―Be not far from me; for trouble is near; for
there is no help ― (Psalm 6:12) express lack of social support.
As we see, King David suffered from chronic stress, chronic
depression and lack of social support (36-39). Were psychological
factors related to survival in King David?
Let us look again at the biblical verses: The passages ―....My soul
in distress...‖ (Psalm 31:8), ―...having agony in my heart daily‖
(13:3), ―My soul is alarmed..‖ (6:4), ―...Heal my soul; because I
sinned..‖ (41:5), and ―The troubles of my heart are widened;. bring
thou me out of my distress‖ (25:17) indicate that the King can be
defined as type D personality. Was type D personality affected the
King's psychological distress?
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CANCER AND FAMILY/INFORMAL CAREGIVERS
Involvement of family caregivers is essential for optimal treatment

of cancer patients in ensuring treatment compliance, continuity of care
and social support, particularly at the end of life. The diagnosis of
cancer presents a major crisis not only to the patient but also to the
patient's primary caregiver. Caregivers often assume this role under
sudden and extreme circumstances, with minimal preparation and
uneven guidance and support from the healthcare system. The primary
setting for the delivery of care to patients with cancer has shifted from
the hospital to the home as a result of increased use of outpatient
services for cancer treatment, shortened hospital visits, longer
survival, and the trend for caregivers to accommodate patients' desire
to be cared for at home for as long as possible. Caring for a family
member with cancer poses significant challenges, with considerable
psychological and physical consequences for the caregiver. Family
caregiving has gained attention in the past decade with growing
realization that support for family caregivers benefits the caregiver,
the patient, and the healthcare team. An understanding of the
multifaceted role of caregivers in cancer care, the impact of this role
on the caregiver's QOL, an understanding of the caregiver's burden
and unmet needs, adaptation requirements of caregivers along the
disease trajectory, and interventions for providing support to
nonmedical persons caring for patients with cancer are needed (1).
683
Family caregivers face multiple demands as they care for their

loved ones with cancer, and these demands have increased
dramatically in recent years. Patients with cancer receive toxic
treatments in outpatient settings and return home to the care of their
family members. Some patients receive in-home infusions, which
were unheard of a few years ago. Family caregivers provide tasks that
were previously provided by nurses; however, caregivers lack the
educational preparation that nurses receive (2).
The main objective of this study was to describe the needs of
family members of older persons undergoing cancer treatment and to
examine the interventions designed to alleviate caregiver distress.
Data sources included Research studies and published articles.
Interventions to reduce distress for caregivers of older persons with
cancer have the potential to lower patients' hospital re-admissions and
interruptions in cancer treatment and to improve patients' and
caregivers emotional health. Oncology practitioners must consider the
needs of family caregivers when planning and implementing
interventions to improve or maintain caregiver health (3).
The main aim of this study was to discuss the impact of cancer on
families of patients with cancer. Data sources included National
reports on care giving and research articles related to cancer and
families. Family caregivers are the bedrock of chronic care in the US.
They provide an enormous amount of unpaid care that is often
invisible. Cancer can affect the emotional, social, physical, and
spiritual well-being of family members. In conclusion, family
intervention research can have a positive effect on patient and family
caregiver outcomes (4).
The main objective of this study was to systematically review
literature regarding the QOL of family caregivers of patients with
cancer and evaluate the instruments measuring family caregivers'
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QOL. Data sources included PubMed, CINAHL, PsycINFO, ISI Web

of Science, EBSCO electronic databases, and published literature.
Overall, the QOL of family caregivers of patients with cancer varied.
Influences related to family caregivers' QOL were identified. Global
and generic measures have been used because of the lack of specific
instruments. Comparisons are complicated because several measures
were used at different times along the illness trajectory with caregivers
caring for people with various types and stages of cancer. A more
explicit definition of QOL for family caregivers of patients with
cancer and specific instruments suitable for different cultures are
needed to enhance knowledge. Maintaining the QOL of caregivers is
important in their ability to provide the care required to keep family
members with cancer in the community (5).
Family caregivers need adequate support from healthcare

professionals to complete the demands associated with care giving
with minimal impact on their own health and well-being. An optimal
balance of provision of care between family and support services has
not been achieved; therefore, this literature review investigates how
family caregivers endure and cope with the challenges of caring for an
adult relative with cancer. The characteristics of caregivers and their
functioning, the external and internal supports that help them cope, the
ongoing challenges as they journey along the care giving trajectory,
the personal costs of care giving, and how caregivers cope with
supporting their family members through to the end of their journeys
should be considered. The literature provides an abundance of
research on the numerous challenges encountered by families living
with cancer patients; however, little research has been conducted on
the coping strategies used by family caregivers at specific stages along
the illness trajectory that either optimize or hinder personal recovery.
Even less information is available on interventions nurses can
introduce to ease the caregiving burden. Improving nurses'
685
understanding of the stressors and unmet needs associated with care

giving is fundamental to the development of effective family-focused
clinical interventions (6).
Receiving a cancer diagnosis affects family members as well as the
person diagnosed. Family members often provide support for the sick
person in daily life out of duty and love, and may not always think of
their own vulnerability to illness. To individualize support for them,
family members who are most at risk for becoming ill must be
identified. The aim of this study was to investigate HRQL in family
members of patients with advanced lung or G-I cancer 3 to 15 months
after diagnosis. Data on mental and physical dimensions of HRQOL
were collected from family members of these patients in this
prospective quantitative study. Five assessments using the SF-36 and
EQ-5D were conducted during a 1-year period starting 3 months after
diagnosis. Thirty-six family members completed the study, i.e.
participated in all 5 data collections. Insignificant changes in physical
or mental HRQOL within the study group appeared over the 1-year
follow-up. Compared with norm-based scores, family members had
significantly poorer mental HRQOL scores throughout the year as
measured by the SF-36. Family members also scored statistically
significantly worse on the EQ-5D VAS in 5 assessments compared to
the norm-based score. Findings showed that older family members
and partners were at higher risk for decreased physical HRQOL
throughout the 1-year period, and younger family members were at
higher risk for poorer mental HRQOL. It is known that ill health is
associated with poor HRQOL. By identifying family members with
poor HRQOL, those at risk of ill health can be identified and
supported (7).
Family care giving is common and important in Taiwanese culture.
However, the combination of anticipated loss, prolonged
psychological distress, and the physical demands of care giving can
seriously compromise the QOL of a family caregiver. The purposes of
this study were to: (1) identify the trajectory of the QOL of family
caregivers of terminally ill cancer patients in Taiwan; and (2)
investigate the determinants of the QOL of family caregivers, in a
large sample and with longer follow-ups, until the patient dies. A
prospective, longitudinal study was conducted among 167 family
caregivers. Trajectory and determinants of family caregiver's QOL
were identified by a generalized estimation equation. Care giving for a
terminally ill cancer patient extracts a toll from a family caregiver's
QOL and causes it to deteriorate significantly over time. The results
indicated that the deterioration of a family caregiver's QOL reflects
686
the patient's increasing distress from symptoms, the gradual loss of

confidence in care giving and an increased subjective care giving
burden on the family caregiver as the patient's death approaches, and a
weaker psychological resource (i.e., sense of coherence) of the family
caregiver. In conclusion, Taiwanese family caregiver's QOL
deteriorated significantly as the patient's death approached. The
available psychological resource of a family caregiver and the
'appraisals of care giving' are more salient in determining a family
caregiver's QOL than the patient's/family caregiver's characteristics
and the care giving demands (8).
Literature on the QOL of family caregivers at the acute and

middle- to long-term cancer survivorship phases as well as the
bereavement phase were reviewed. By using several databases, the
authors searched the literature published in English from 1996 through
July 2007. Keywords searched included cancer, carcinoma, family,
family member, caregivers, and quality of life. Several criteria were
used to guide the literature review: Articles had to be published in
refereed journals and had to use rigorous methods, sample, and
validated measures. The findings suggested that the QOL of family
caregivers of individuals with cancer varies along the illness
trajectory. These highlights were important of assessing the ongoing
adjustment of the caregivers over time. However, there were few
theory-driven studies, and significant gaps remain in the current
understanding of the effects of family care giving beyond the time of
diagnosis and treatment. In conclusion, accumulating evidence has
supported the concept that cancer affects not only the
patients/survivors but also their family members. However,
theoretically and methodologically rigorous research on various
aspects of the family's QOL, including not only the psychological but
also the physical, spiritual, and behavioral adjustment to cancer in the
687
family, remains sparse. Family-based interventions across the

trajectory of the illness also are needed (9).
The purpose of this study was to identify the experiences of
families caring for patients with terminal cancer. The question was,
"What is the care giving experience of a family who has a member
with terminal cancer?" Grounded Theory was applied and in-depth
interviews were done with 11 family members at the Center for Lung
Cancer, National Cancer Center, Goyang, Korea. Interviews were
recorded with the interviewees' consent and were transcribed and
analyzed. Participants' relationships to patients were 6 spouses, 4
daughters, and 1 mother. The ages of the participants were between 32
and 62, with an average of 47.5 years. This study showed "enduring
with bonds" as the main category and the main factor affecting this
category was the "patients' diagnosis of terminal cancer." The care
giving experience was divided into 4 stages: shock, confusion,
struggle, and acceptance. Mediating factors were relationship with the
patient, intimacy with the patient, social support, communication, and
trust. Conclusively, participants underwent internal maturity, and
changes occurred in family, social and personal life. The families took
care of the patients with responsibility and love. These results should
help with the understanding of a family with a member with terminal
cancer and should be used to develop nursing, mediating, and
consulting programs for these caregivers (10).
Informal caregivers are relatives, friends, and partners who have a
significant relationship with and provide assistance (i.e., physical,
emotional) to a patient with a life-threatening, incurable illness. The
multidimensional burden that results from providing care to a patient
with cancer is well documented, and as a result, a growing number of
psychosocial interventions have been developed specifically to
address this burden. The purpose of the present study was to
characterize the state of the science of psychosocial interventions for
informal cancer caregivers. A comprehensive systematic review of
interventions for cancer caregivers was conducted via an electronic
literature search of publications between 1980 and January 13, 2011.
A final sample of 49 interventions was reviewed in detail. The
interventions, which varied in terms of modality and patient
population, fell into the following eight categories: psycho education,
problem-solving/skills building interventions, supportive therapy,
family/couples therapy, CBT, interpersonal therapy, CAM
interventions, and existential therapy. There are benefits and
disadvantages of each of the categories. Beyond specific techniques,
integrative structured, goal-oriented, and time-limited interventions
688
are the most feasible and offer the greatest benefits for informal
caregivers of cancer patients (11).
The main aim of this study was to assess the needs of informal
caregivers of terminally ill cancer patients. Fifty-four informal
caregivers of patients registered in palliative care service were
interviewed 3-6 months after the death of the patient with the help of a
semistructured questionnaire covering the physical, medical,
psychological, social, and information domains. Most of the
caregivers were middle aged and had no prior experience of care
giving. The caregivers were satisfied by the information and medical
support provided to them by their treatment team. Most had an
"emergency plan". Caregivers had unmet needs including homecare,
psychological support, and financial help. In conclusion, informal
caregivers provide most of the nursing and psychological support to
the patient. However, palliative care services need to recognize that
the caregiver too may need psychological and technical support (12).
Patients in the terminal phase of a disease may have complex
needs. It is often family and friends who play a central role in
providing support, despite health professional input and regardless of
whether the patient is at home or elsewhere. Such informal caring may
involve considerable physical, psychological, and economic stresses.
A range of supportive programs for caregivers is being developed
including psychological support and practical assistance. The main
objective of this study was to assess the effects of supportive
interventions that aim to improve the psychological and physical
health of informal caregivers of patients in the terminal phase of their
illness. The Cochrane Central Register of Controlled Trials
(CENTRAL, The Cochrane Library, Issue 2 2010); MEDLINE (1950
to May 2010); EMBASE (1980 to May 2010); PsycINFO (1872 to
May 2010); CINAHL (1937 to May 2010); National Health Service
Research Register (2000 to November 2008) and Dissertation
Abstracts (1716 to May 2010) were searched. The reference lists of
relevant studies; contacted experts; and hand searched journals, RCTs
of interventions to support adults who were caring for a friend or
relative with a disease in the terminal phase were searched.
Interventions could include practical and emotional support and/or the
facilitation of coping skills. Interventions could support caregivers
indirectly via patient care. Two authors independently screened
citations against the selection criteria. Data were extracted by one
author and checked by another. This included extraction of any AEs.
Eleven RCTs were included involving 1836 caregiver participants.
Nine interventions were delivered directly to the caregiver. Of these, 7
689
provided support in the caring role; another involved a family life

review, and 1 grief therapy. None provided practical support. The
other 2 interventions aimed to support caregivers indirectly via patient
care. Overall, the risk of bias is unclear, as all trials under-reported
methods. There is low quality evidence that interventions directly
supporting the caregiver significantly reduce psychological distress in
the short term (8 trials: SMD -0.15, 95% CI -0.28 - -0.02). There is
also low quality evidence that these interventions in the short term
may marginally improve coping skills and QOL, but results were
statistically insignificant (7 trials, SMD -0.05, 95% CI -0.24 - 0.14, 6
trials: SMD 0.08, 95% CI -0.11 - 0.26, respectively). One study
assessed physical outcomes, specifically sleep improvement, and
found no difference (median effect 0.00). In one study, a subgroup of
intervention participants had higher levels of family conflict. Evidence
was less clear on the indirect interventions. While both trials in this
category found that supporting the patient might reduce psychological
distress, 4 assessments were statistically insignificant. There were no
evaluations of coping with the caring role, QOL, service use or
adverse outcomes. In 1 trial, there was no difference between trial
arms in the proportion of caregivers reporting good physical health. In
conclusion, there is evidence that supportive interventions may help
reduce caregivers' psychological distress. These findings suggest that
practitioners should enquire about the concerns of caregivers and
should consider that they may benefit from additional support (13).
The main objective of this study was to describe some informal
roles consistently enacted by family members involved in the process
of end-of-life decision making in ICUs. In this ethnographic study,
data were collected via participant observation with field notes and
semistructured interviews on 4 ICUs in an academic health center in
the mid-Atlantic US from 2001 to 2004. The units studied were a
medical, a surgical, a burn and trauma, and a C-V ICU. Participants
included health care clinicians, patients, and family members.
Informal roles for family members consistently observed were
primary caregiver, primary decision maker, family spokesperson, out-
of-towner, patient's wishes expert, protector, vulnerable member, and
health care expert. The identified informal roles were part of families'
decision-making processes, and each role was part of a potentially
complicated family dynamic for end-of-life decision making within
the family system and between the family and health care domains. In
conclusion, these informal roles reflect the diverse responses to
demands for family decision making in what is usually a novel and
stressful situation. Identification and description of these informal
690
roles of family members can help clinicians recognize and understand

the functions of these roles in families' decision making at the end of
life and guide development of strategies to support and facilitate
increased effectiveness of family discussions and decision-making
processes (14).
Assessment: cancer affects not only the patients/survivors but also

their family members. Involvement of family caregivers is essential
for optimal treatment of cancer patients in ensuring treatment
compliance, continuity of care, and social support, particularly at the
end of life. Family caregivers face multiple demands as they care for
their loved ones with cancer, and these demands have increased
dramatically in recent years.
Interventions to reduce distress for caregivers of older persons with
cancer have the potential to lower patients' hospital re-admissions and
interruptions in cancer treatment and to improve patients' and
caregivers emotional health.
In the US, family caregivers are the bedrock of chronic care. They
provide an enormous amount of unpaid care that is often invisible.
Cancer can affect the emotional, social, physical, and spiritual well-
being of family members. Maintaining the QOL of caregivers is
important in their ability to provide the care required to keep family
members with cancer in the community.
The care giving experience can be divided into 4 stages: shock,
confusion, struggle, and acceptance. Mediating factors include
relationship with the patient, intimacy with the patient, social support,
communication, and trust. Participants underwent internal maturity,
and changes occurred in family, social and personal life. Families can
take care of the patients with responsibility and love.
Informal caregivers are relatives, friends, and partners who have a
significant relationship with and provide assistance (i.e., physical,
emotional) to a patient with a life-threatening, and incurable illness.
Informal caregivers provide most of the nursing and psychological
support to the patient. The interventions, which varied in terms of
modality and patient population, fell into the following eight
categories: psycho education, problem-solving/skills building
interventions, supportive therapy, family/couples therapy, CBT,
interpersonal therapy, CAM interventions, and existential therapy.
Supportive interventions may help reduce caregivers' psychological
distress.
Was the family involved in the King's David care? What was the
relationship with the father, the wives? Was psychological support
provided for this elderly patient? What was the pattern of
691
communication between the King and his family? Did mutual trust
exist between the patient – the King, and his family members?
The King‘s extended family consisted of a husband, seven wives -
Ahinoam, Abigail, Maacah, Haggith, Abital, Ithream (II Samuel 3:2-
5), and Batsheba (II Samuel 11:27) and seven sons ―And his firstborn
was Amnon of Ahinoam the Jezreelitess; And his second Chileab, of
Abigail..., and the third, Absalom the son of Maacah the daughter of
Talmai king of Geshur; And the fourth Adonijah the son of Haggith,
and the fifth, Shephatiah, the son of Abital, and the sixth, Ithream, by
Eglah David’s wife ‖ (3:2-5), and Solomon of Batsheba (12:24).
The following verses indicate that in the end of his life King David
was a lonely man ―I am forgotten as a dead man out of mine mind. I
am like a lost tool‖ (31:13); negative interpersonal relationships
demonstrate ―But I am a worm, and no man; a disgrace of men, and
despised of the people‖ (32:7); lack of close, warm relations, and lack
of friends on whom the King can rely show ―Be not far from me; for
trouble is near; for there is no help ― (Psalm 6:12) and ―I am helpless‖
(25:16) (15-17). The King's medical record shows that his family did
not support him. In modern times, supportive intervention may help to
reduce psychological distress of the whole family, including the
patient.
References
1. Glajchen M. The emerging role and needs of family caregivers in cancer care. J
Support Oncol. 2004;2(2):145-55.
2. Northouse LL. Helping patients and their family caregivers cope with cancer.
Oncol Nurs Forum. 2012;39(5):500-6.
3. Given B, Sherwood PR. Family care for the older person with cancer. Semin
Oncol Nurs. 2006;22(1):43-50.
4. Northouse L. Helping families of patients with cancer. Oncol Nurs Forum.
2005;32(4):743-50.
5. Kitrungroter L, Cohen MZ. Quality of life of family caregivers of patients with
cancer: a literature review. Oncol Nurs Forum. 2006;33(3):625-32.
6. Northfield S, Nebauer M. The caregiving journey for family members of
relatives with cancer: how do they cope? Clin J Oncol Nurs. 2010;14(5):567-77.
7. Sjolander C, Rolander B, Järhult J, et al. Health-related quality of life in family
members of patients with an advanced cancer diagnosis: A one-year prospective
study. Health Qual Life Outcomes. 2012 Jul 30;10:89.
8. Tang ST, Li CY, Chen CC. Trajectory and determinants of the quality of life of
family caregivers of terminally ill cancer patients in Taiwan. Qual Life Res.
2008;17(3):387-95
9. Kim Y, Given BA. Cancer. Quality of life of family caregivers of cancer
survivors: across the trajectory of the illness. Cancer. 2008;112(11 Suppl):2556-68.
10. Choi ES, Kim KS. Experiences of family caregivers of patients with terminal
cancer. J Korean Acad Nurs. 2012;42(2):280-90.
11. Applebaum AJ, Breitbart W. Care for the cancer caregiver: A systematic
review. Palliat Support Care. 2012 Oct 10:1-22.
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12. Joad AS, Mayamol T, Chaturvedi M. What does the informal caregiver of a
terminally ill cancer patient need? A study from a cancer centre. Indian J Palliat Care.
2011;17(3):191-6.
13. Candy B, Jones L, Drake R, et al. Interventions for supporting informal
caregivers of patients in the terminal phase of a disease. Cochrane Database Syst Rev.
2011 Jun 15;(6):CD007617. pub2. Comment in: Review: supportive interventions
may improve short-term psychological distress in informal caregivers of patients at
the end of life. [Evid Based Ment Health. 2012].
14. Quinn JR, Schmitt M, Baggs JG, et al. Family members' informal roles in end-
of-life decision making in adult intensive care units. Am J Crit Care. 2012;21(1):43-
51.
Psychiatry. 2004;15(4):467-76.
16. Ben-Nun L. Mental Disorder. In Ben-Nun L. ed. The Family Life Cycle and
the Medical Record of King David the Great. B.N. Publications. Israel. 2009, pp.
220-46.
17. Ben-Noun L. Mental disorder. In Ben-Noun L. ed. The Diseases of the Kings
of Israel. Research in Biblical Times from the Viewpoint of Contemporary Medicine.
B.N. Publications. Israel. 2006, pp. 88-98.
693
NEUROPATHIC PAIN
Neuropathic pain is widely recognized as a common consequence
of cancer that may also result from administration of several common
oncology drugs (1). It not only affects QOL, but it also affects patient
outcomes because of resulting treatment delays, dose reductions, and
discontinuations. Neuropathic pain is present in at least 25-40% (2)
and even in more than 50% of patients with cancer pain (3), and is
more difficult to control than other types of cancer related pain (3).
The cost of the neuropathic pain in the US alone is approximately $2.3
billion (1).
Although neuropathic pain can be acute in nature, in most patients
the pain is persistent (or "refractory"). Patients with chronic
neuropathic pain are seen most often in clinical practice. It consists of
a number of different disease-specific indications, each of which can
have differing diagnostic definitions and cutoffs. Consequently, it is
difficult to estimate precisely the prevalence and incidence of
neuropathic pain. The burden of neuropathic pain on patients and
healthcare systems appears to be potentially large, with an estimated
prevalence of 1.5%. Patients with neuropathic pain experience a poor
HRQL and consume a high level of healthcare resources and costs.
The future prioritization by healthcare policy makers for neuropathic
pain treatment funding requires further data to clarify its
epidemiology, the burden on the health of patients, and the demand on
healthcare budgets (4).
During the past decade, preclinical and clinical data has begun to
provide insight into the mechanisms that drive and mask cancer pain
and the mechanisms by which anti-neoplastic agents induce peripheral
neuropathy. Developing a mechanism-based understanding and
mechanism-based therapies to treat cancer-associated pain and
sensory neuropathy, and incorporating these into mainstream cancer
research and therapy will be crucial to improving the QOL and
survival of patients with cancer (5).
Neuropathic pain resulting from a lesion, damage, or dysfunction
of the somatosensory nervous system can arise through several
distinct etiologies ranging from toxicity, surgery, radiation, trauma,
and congenital disorders. Neuropathic pain is widely recognized as a
common consequence of cancer and results from administration of
several common oncology drugs. Despite its widely recognized
importance, there is a paucity of reliable information available
regarding the incidence, prevalence of patient-and physician-reported
severity, and time course of cancer-related neuropathic pain. To
694
address this severe knowledge gap, we need new, high quality,

population-based studies of individual cancer pain syndromes and
conditions. However, in order to gather this information, we also need
substantial improvements in the specific classification of cancer-
related neuropathic syndromes and better validated diagnostic tools
that can help to elucidate the incidence, prevalence, severity, and
potential economic impact of cancer-associated neuropathies (1).
Nerve damage or neuropathy occurs when the outer sheathing or the

myelin (protective covering) of nerve cells degenerate. Without this
protection, the electrical signals are not transferred properly. As the nerve
damage gets worse, either the nerves lose their ability to transmit information
(numbness), or they start sending false signals (pain and tingling).
Adult and teenage patients (age > 12 years), with active cancer
reported pain, in which a clinical assessment of their pain had been
made. Twenty-two eligible studies reported on 13,683 patients.
Clinical assessment methods varied and only 14 studies reported
confirmatory testing for either sensory abnormality or diagnostic
lesion to corroborate a diagnosis of neuropathic pain. The prevalence
of patients with neuropathic pain varied from a conservative estimate
of 19% (95% CI 9.4 - 28.4%) to a liberal estimate of 39.1% (95% CI
28.9 - 49.5%) when patients with mixed pain were included. The
prevalence of pain with a neuropathic mechanism ranged from a
conservative estimate of 18.7% (95% CI 15.3 - 22.1%) to a liberal
estimate of 21.4% (95% CI 15.2 - 27.6%) of all recorded cancer pains.
The proportion of pain caused by cancer treatment was higher in
neuropathic pain compared with all types of cancer pain (6).
Symptoms of peripheral neuropathy depend on the type of nerve(s)
affected and where the nerve is located in the body. If nerves to the
skin are affected, a patient may suffer from numbness and tingling
(pins and needle feeling), a feeling of wearing an invisible glove or
sock, extreme sensitivity to touch, burning feeling in toes or fingers,
695
inability to feel hot or cold, or the ability to feel hot/cold is lessened. If

nerves to the internal organs are affected, symptoms may include
dizziness, constipation, bladder difficulties, or sexual problems. If
nerves to the muscles are affected, symptoms may include muscle
weakness (trouble turning a knob), muscle cramping, muscle spasms,
and problems with balance (7).
A retrospective analysis of 213 cancer patients with neuropathic
pain treated by a pain service following the WHO guidelines for relief
of cancer pain was performed. Of these, 79% presented with nerve
compression pain, 16% with nerve injury pain, and 5% with
sympathetically-maintained pain. Whereas nerve compression and
nerve injury pain were caused most frequently by cancer growth,
sympathetically maintained pain was caused most frequently by
cancer treatment. There were insignificant differences in the use of
analgesics, the mean pain intensity, or the efficacy of analgesic
treatment among the 3 groups. Nerve injury pain and sympathetically
maintained pain were treated more frequently with adjuvant
analgesics, especially antidepressants and AEDs (8).
A prospective cross-sectional survey of consecutive patients with
symptomatic bone metastases was conducted between December 2006
and March 2008 at a comprehensive cancer center at Tom Baker
Cancer Centre, Alberta, Canada. Patients completed the BPI, the S-
LANSS, and the EORTC QLQ-C30. Of 98 patients, 17% (95% CI 10
- 24%) had positive S-LANSS scores suggesting pain with
neuropathic features. Mean worst pain and mean interference scores
were 7.2 (SD 2.0) and 5.8 (SD 2.5), respectively. EORTC QLQ-C30
global QOL, function, and symptom scores were 42 (SD 24), 52 (SD
20), and 46 (SD 17), respectively. Patients with neuropathic features
had a higher BPI worst pain score than patients without neuropathic
features (8.3 vs. 7.0, respectively, p=0.016). Corticosteroid use, oral
morphine equivalent dosing, and site of bone pain were not associated
with neuropathic features. In conclusion, some patients with bone
metastases manifest bone pain with distinguishable neuropathic
features, and these patients reported greater pain intensity (9).
Metastatic plexopathy is often a disabling accompaniment of
advanced systemic cancer, and may involve any of the peripheral
nerve plexuses. Brachial plexopathy most commonly occurs in
carcinoma of the breast and lung, while lumbosacral plexopathy is
most common with colorectal and gynecologic tumors, sarcomas, and
lymphomas. Neoplastic plexopathy is often characterized initially by
severe, unrelenting pain followed by development of weakness and
focal sensory disturbances. In previously treated patients, the main
696
differential diagnostic consideration is radiation-induced plexopathy,

which can be difficult to distinguish from tumor plexopathy.
Diagnosis is made following an analysis of the clinical, neuroimaging,
and electrophysiologic features. Treatment of metastatic plexopathy
has included surgical resection of tumor in selected cases, RT to the
plexus, systemic chemotherapy, interventional pain management
procedures, and symptomatic treatment. These measures offer
temporary (months) relief or improvement. Physicians treating these
patients should focus on effective management of pain and prevention
of complications of immobility produced by the neuromuscular
dysfunction (10).
References
1. Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer-related
neuropathic pain: the intersection of cancer pain and neuropathic pain. Oncologist.
2010;15 Suppl 2:3-8.
2. Tofthagen CS, McMillan SC. Pain, neuropathic symptoms, and physical and
mental well-being in persons with cancer. Cancer Nurs. 2010;33(6):436-44.
4. Taylor RS. Epidemiology of refractory neuropathic pain. Pain Pract.
2006;6(1):22-6.
6. Bennett MI, Rayment C, Hjermstad M, et al. Prevalence and aetiology of
neuropathic pain in cancer patients: a systematic review. Pain. 2012; 153(2):359-65.
7. Peripheral neuropathy in persons with cancer. University of Iowa Hospitals and
Clinics. Available 22 May 2013 at www.uihealthcare. org/2column.aspx?id=22776.
8. Stute P, Soukup J, Menzel M, et al. Analysis and treatment of different types of
neuropathic cancer pain. J Pain Symptom Manage. 2003;26(6):1123-31.
9. Kerba M, Wu JS, Duan Q, et al. Neuropathic pain features in patients with bone
metastases referred for palliative radiotherapy. J Clin Oncol. 2010; 28(33):4892-7.
10. Jaeckle KA. Neurologic manifestations of neoplastic and radiation-induced
plexopathies. Semin Neurol. 2010;30(3):254-62.
CHEMOTHERAPY INDUCED NEUROPATHY

The peripheral nervous system can be vulnerable to the toxic action
of several drugs since it is not protected as effectively as the CNS
from noxious exogenous agents. Drug-induced neurotoxicity can
affect the nerve fibers or the neuronal bodies (generally the DRG of
the primary sensory neurons). Among the neurotoxic drugs,
antineoplastic agents represent a major clinical problem, given their
widespread use and the potential severity of their toxicity. In fact, the
697
peripheral neurotoxicity of antineoplastic agents frequently represents

one of their dose-limiting side effects. Moreover, even when
antineoplastic agents' peripheral neurotoxicity is not dose limiting, its
onset may severely affect the QOL of cancer patients and cause
chronic discomfort (1).
Neurotoxic side effects of chemotherapy occur frequently and are
often a reason to limit the dose of chemotherapy. Since bone marrow
toxicity, as the major limiting factor in most chemotherapeutic
regimens, can be overcome with growth factors or bone marrow
transplantation, the use of higher doses of chemotherapy is possible,
which increases the risk of neurotoxicity. Chemotherapy may cause
both peripheral neurotoxicity, consisting mainly of a peripheral
neuropathy, and central neurotoxicity, ranging from minor cognitive
deficits to encephalopathy with dementia or even coma. These drugs
are widely used for various malignancies such as ovarian, breast and
hematological cancers. CIPN is related to cumulative dose or dose-
intensities. Patients who already have neuropathic symptoms due to
diabetes mellitus, hereditary neuropathies or earlier treatment with
neurotoxic chemotherapy are more vulnerable for the development of
CIPN. Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide
are known for their central neurotoxic side effects. Central
neurotoxicity ranges from acute toxicity, such as aseptic meningitis, to
delayed toxicities comprising cognitive deficits, hemiparesis, aphasia
and progressive dementia. Risk factors include high doses, frequent
administration and RT preceding methotrexate chemotherapy, which
is more neurotoxic than methotrexate as single modality (2).
Chemotherapy-induced peripheral neuropathy.
Central and peripheral nervous system toxicity, frequent

complications of most chemotherapy regimens, lead to reduction of
dosages or cessation of the responsible drugs. However, sometimes
the afflicted toxicity may not be reversible, especially if it is not
recognized early, further compromising the QOL of the cancer
698
patients. The most common chemotherapeutic agents that might cause

CNS toxicity manifested as encephalopathy of various severities
include methotrexate, vincristine, ifosfamide, cyclosporine,
fludarabine, cytarabine, 5-fluorouracil, cisplatin and the interferons
(alpha > beta) (3).
CIPN ranks among the most common non-hematological AEs of a
number of effective chemotherapeutic agents (4). CIPN results from
therapy with the platinum derivates (OXL, cisplatin, and carboplatin),
proteasome inhibitors (bortezomib, and carfilzomib), microtubule
targeting agents (vincristine, taxanes - epothilones, paclitaxel,
docetaxel, and eribulin), thalidomide, and suramine (1-9).
CIPN may result from a variety of mechanisms and are related to
causal factors, such as single dose per course, cumulative dose and
risk factors including treatment schedule, prior or concomitant
administration of other neurotoxic agents, age and pre-existing
peripheral neuropathy of other causes. The symptoms usually begin
during chemotherapy and they may even worse after cessation of
treatment. In most of the cases, patients experience positive (pain, and
paresthesias) or negative (numbness) sensory symptoms in distal
extremities in a stocking-and-glove distribution with less prominent
motor and autonomic involvement. To date, several neuroprotective
agents including thiols, neurotrophic factors, AED and antioxidants
have been tested in preclinical models and clinical open label or RCTs
for their ability to prevent or treat symptoms of CIPN (4).
Although several compounds have been proposed as
neuroprotective agents, only few have been shown to be active against
the chemotherapy induced neurotoxicity (3).
CIPN is an increasingly frequent problem. Contrary to hematologic
AEs, which can be treated with hematopoietic growth factors, neither
prophylaxis nor specific treatment is available, and only symptomatic
treatment can be offered. Neurotoxic drugs are becoming a major
dose-limiting factor. The epidemiology is still unclear. Several drug-
dependent pathogenetic mechanisms exist. CIPN is predominately
sensory, length-dependent neuropathies that develop after a typical
cumulative dose. Usually, the appearance of CIPN is dose dependent,
although in at least 2 drugs (OXL and taxanes), immediate toxic
effects occur. The role of synergistic neurotoxicity caused by
previously given chemotherapies and concomitant chemotherapies and
the role pre-existent neuropathy on the development of a CIPN is not
clear. As the number of long-term cancer survivors increases and a
new focus on long-term effects of chemotherapy-induced neuropathies
699
emerge, concepts of rehabilitation need to be implemented to improve

the patients' functions and QOL (7,10).
The induction of peripheral neuropathy is a common factor in
limiting therapy with chemotherapeutic drugs. Depending on the
substance used, a pure sensory and painful neuropathy (with cisplatin,
OXL, or carboplatin) or a mixed sensorimotor neuropathy with or
without involvement of the autonomic nervous system (with
vincristine, taxol, or suramin) can ensue. Neurotoxicity depends on the
total cumulative dose and the type of drug used. In individual cases,
neuropathy can evolve even after a single drug application. A general
predisposition for developing a chemotherapy-induced neuropathy has
been observed in nerves previously damaged by diabetes mellitus,
alcohol or inherited neuropathy. The recovery from symptoms is often
incomplete and a long period of regeneration is required to restore
function (11).
Between January 2002 and June 2004, 448 patients who were
treated with vinca alkaloids, taxanes or platinum derivatives, using a
simple questionnaire of neuropathic symptoms, were screened. The
response rate was 75%. Neuropathic symptoms were reported by 258
respondents (76%), of whom 152 patients were eligible for the final
analyses. The severity of neuropathy was scored using the NCI
Common Toxicity Criteria. At the screening visit, 90 patients (59%)
reported neuropathic symptoms. Tingling (71%), numbness (58%),
impaired sensory function (46%), and pain in hands and feet (40%)
were the most common symptoms. The median intensity of
neuropathic symptoms was 28/100 on the VAS. Grade I sensory
neuropathy was in 19 out of 90 patients (21%), Grade II in 38 (42%)
and Grade III in 33 (37%) patients. Grade I motor neuropathy was in
28 (31%), Grade II in 14 (16%), and Grade III in one patient (1%).
Grade IV sensory or motor neuropathy was not recorded. In the whole
cohort of 152 patients, fatigue (66%), mucositis (61%) and
neuropathic symptoms (59%) were the most commonly reported
symptoms. Every third patient (37%) with neuropathic symptoms
ranked them as the most troublesome symptom. In conclusion,
neuropathy is a common and troublesome AE of chemotherapy, even
though the intensity of the symptoms is mild. Thus, the intensity and
inconvenience does not correlate to each other (12).
References
1. Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced
peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol. 2012;82(1):51-
77.
700
2. Verstappen CC, Heimans JJ, Hoekman K, Postma TJ. Neurotoxic

complications of chemotherapy in patients with cancer: clinical signs and optimal
management. Drugs. 2003;63(15):1549-63.
3. Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of
common chemotherapeutic agents. Cancer Chemother Pharmacol. 2009; 63(5):761-7.
4. Argyriou AA, Zolota V, Kyriakopoulou O, Kalofonos HP. Toxic peripheral
neuropathy associated with commonly used chemotherapeutic agents. J BUON.
2010;15(3):435-46.
5. Amptoulach S, Tsavaris N. Neurotoxicity caused by the treatment with
platinum analogues. Chemother Res Pract. 2011;2011:843019.
6. Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the
proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events.
Clin Cancer Res. 2011;17(9):2734-43.
7. Grisold W, Cavaletti G, Windebank AJ. Peripheral neuropathies from
chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro
Oncol. 2012 Sep;14 Suppl 4:iv45-iv54.
8. Argyriou AA, Marmiroli P, Cavaletti G, Kalofonos HP. Epothilone-induced
peripheral neuropathy: a review of current knowledge. J Pain Symptom Manage.
2011;42(6):931-40.
9. O'Sullivan Coyne G, Walsh J, Kelly CM. Effectiveness and safety of eribulin
mesylate: a new therapeutic option in the treatment of metastatic breast cancer. Expert
Opin Drug Saf. 2012;11(4):643-50.
10. Zheng H, Xiao WH, Bennett GJ. Mitotoxicity and bortezomib-induced
chronic painful peripheral neuropathy. Exp Neurol. 2012 c;238(2): 225-34.
11. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J
Neurol. 2002;249(1):9-17.
12. Kautio AL, Haanpää M, Kautiainen H, et al. Burden of chemotherapy-induced
neuropathy--a cross-sectional study. Support Care Cancer. 2011;19(12):1991-6.
PLATINUM AGENTS
Platinum drugs are among the most important cytotoxic drugs
available to oncologists. Although they share some structural
similarities, there are marked differences in their therapeutic use,
pharmacokinetics, and AE profiles (1–3). Cisplatin is the first agent of
platinum drugs, which was approved in 1978 for the treatment of
testicular and ovarian cancer (4). In view of its considerable toxicity
profile, many attempts have been made to develop analogues with less
toxicity, increased efficacy, or both. Carboplatin is a second-
generation platinum drug with equivalent activity, in some cancer
types, to cisplatin. Carboplatin is often administered in combination
with a taxane as a first-line treatment for ovarian cancer (5,6). Lung
cancer is also treated with carboplatin in combination with
vinorelbine, gemcitabine, or paclitaxel (7). Oxaliplatin, a third-
701
generation platinum drug, is the standard of treatment, together with

5-fluorouracil/leucovorin (5 FU/LV), for locally advanced and
metastatic CRC (8).
Platinum agents (cisplatin, carboplatin, and OXL) are a class of
chemotherapy agents that have a broad spectrum of activity against
several solid tumors. Toxicity to the peripheral nervous system is the
major dose-limiting toxicity of at least some of the platinum drugs of
clinical interest. Among the platinum compounds in clinical use,
cisplatin is the most neurotoxic, inducing mainly sensory neuropathy
of the upper and lower extremities. Carboplatin is generally
considered less neurotoxic than cisplatin, but it is associated with a
higher risk of neurological dysfunction if administered at high dose or
in combination with agents considered to be neurotoxic. The incidence
of OXL-induced neuropathy is related to various risk factors such as
treatment schedule, cumulative dose, and time of infusion (9).
References
1. Calvert AH, Harland SJ, Newell D R, et al. Early clinical studies with cis-
diammine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol.
1982;9(3):140–7.
2. Go RS, Adjei AA. Review of the comparative pharmacology and clinical
activity of cisplatin and carboplatin. J Clin Oncol. 1999;17(1):409-22.
3. Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: a new cisplatin
analog. Drug Intell Clin Pharm. 1988;22(11):843–49.
4. Higby DJ, Wallace Jr. HJ, Albert DJ, Holland JF. Diaminodichloroplatinum: a
phase I study showing responses in testicular and other tumors. Cancer.
1974;33(5):1219–25.
5. Neijt JP, Engelholm SA, Tuxen MK, et al. Exploratory phase III study of
paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.
J Clin Oncol. 2000;18(17):3084–92.
6. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based
chemotherapy versus conventional platinum-based chemotherapy in women with
relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet.
2003;361(9375):2099–106.
7. de Cos Escuín JS, Delgado IU, Rodríguez JC, et al. Stage IIIA and IIIB non-
small cell lung cancer: results of chemotherapy combined with radiation therapy and
analysis of prognostic factors. Arch Bronconeumol. 2007;43(7):358–65.
8. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of
fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with
previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23–30.
702
CISPLATIN
Peripheral neurotoxicity is the most important dose-limiting
problem associated with cisplatin (1). A number of pathophysiological
mechanisms have been proposed to explain this phenomenon with
some data suggesting that cisplatin kills malignant cells and peripheral
neurons by means of a similar mechanism of apoptosis (2). Peripheral
neurotoxicity develops in approximately 50% of patients receiving
cisplatin (3), but the onset of toxicity is delayed until a cumulative
dose higher than 300 mg/m2 has been given (4,5). Signs and
symptoms of peripheral neurotoxicity involve the upper and lower
extremities and include loss of vibration sense, loss of position sense,
tingling paraesthesia, weakness, tremor, and loss of taste (6-8).
Seizures and leukoencephalopathy have also been described (9,10).
After discontinuation of treatment, the neurological dysfunction may
gradually improve, but it may persist for a period, or it can be
permanent (3,11).
Cisplatin is ototoxic. Tinnitus and hearing loss have been observed
in up to 31% of patients treated with initial intravenous cisplatin dose
of 50 mg/m2 (12,13). Transient hearing loss and mild audiometric
abnormalities were observed in 30% of patients receiving 150 mg/m2
of cisplatin (14,15). The mechanisms of cisplatin-induced damage to
the outer hairy cells of the cochlea probably include the formation of
reactive oxygen radicals and depletion of glutathione (16). Other risk
factors include simultaneous use of other potentially ototoxic agents
(e.g., aminoglycosides), previous cranial irradiation, preexisting renal
dysfunction, or inner ear damage (13,15,17,18).
Cisplatin, a widely used chemotherapeutic agent, induces a sensory
neuropathy with selective loss of vibration sense and proprioception.
Neurotrophin-3, a member of the nerve growth factor family of
neurotrophic factors, restored to normal levels the reduced H-reflex-
related sensory nerve conduction velocity induced by cisplatin in rats.
Neurotrophin-3 treatment corrected an abnormal cytoplasmic
distribution of neurofilament protein in large sensory neurons in DRG
and the reduction in the numbers of myelinated fibers in sural nerves
caused by cisplatin. The neurotrophin-3 dependent reversal of
cisplatin neurotoxicity thus suggests the possible use of neurotrophin-
3 in the treatment of peripheral sensory neuropathy (19).
The pathogenesis of cisplatin neuropathy remains obscure. Yet the
fact that cisplatin affects mainly the sensory peripheral nerve fibers
points towards an involvement of the DRG. In a rat model of cisplatin
neuropathy, following a cumulative dose of approximately 12 mg/kg
703
cisplatin the sensory nerve conduction velocity began to slow as

compared to age-matched controls. Peptides derived from ACTH and
melanocyte-stimulating hormone are known to exert neurotrophic
effects. In vivo they facilitate postlesion repair mechanisms in the
peripheral nervous system by enhancing the early sprouting response
of the damaged nerve. Surprisingly, chronic treatment with a synthetic
ACTH4-9 analog not only prevented cisplatin neurotoxicity following
a low or high dose regimen, but also counteracted already existing
cisplatin-induced neurotoxicity. Stimulated by these findings a
randomized, double blind, placebo-controlled study was performed to
assess the efficacy of the peptide in the prevention of cisplatin
neuropathy in women suffering from ovarian cancer. The threshold of
vibration perception was used as the principal measure of
neurotoxicity. Following 6 cycles of chemotherapy, the vibration
perception had increased more than 8-fold in women receiving
placebo as co-medication. Whereas the vibration perception in women
receiving 1 mg/m2 body surface ACTH4-9 analog before and after
each cisplatin cycle only increased less than 2-fold. No side effects of
the peptide treatment were observed and the clinical response to the
chemotherapy was similar in all treatment groups. Collectively these
preclinical and clinical data suggest that treatment based on non-
endocrine fragments of ACTH/MSH may be a therapeutic option in
the treatment of cisplatin neuropathy (20).
Cisplatin is a widely used antitumor agent, the dose-limiting
toxicity of which is predominantly large-fiber sensory neuropathy.
Prevention of such a neuropathy would extend the usefulness of this
agent, allowing higher doses and longer periods of treatment.
Cisplatin neuropathy was established in mice measured by using
behavioral, biochemical, and electrophysiological techniques, and
subcutaneous administration of human recombinant nerve growth
factor prevented or delayed the neuropathy. Cisplatin administration
reduced sensory ganglion levels of the peptide transmitter, calcitonin
gene-related peptide, slowed nerve conduction in the tail and impaired
proprioception as measured by the ability to balance on a rotating
dowel. Nerve growth factor coadministration appeared to prevent all
these abnormalities (21).
References
1. Ozols R F, Young RC. High-dose cisplatin therapy in ovarian cancer. Semin
Oncol. 1985;12(4):21–30.
2. Gill JS, Windebank A J. Cisplatin-induced apoptosis in rat dorsal root ganglion
neurons is associated with attempted entry into the cell cycle. J Clin Invest.
1998;101(12):2842–50.
704
3. van der Hoop RG, van der Burg MEL, ten Bokkel Huinink WW, et al.
Incidence of neuropathy in 395 patients with ovarian cancer treated with or without
cisplatin. Cancer, 1990;66(8):1697–702.
4. Cersosimo RJ. Cisplatin neurotoxicity. Cancer Treat Rev. 1989;16(4):195–211.
5. Gregg RW, Molepo JM, Monpetit VJA, et al. Cisplatin neurotoxicity: the
relationship between dosage, time, and platinum concentration in neurologic tissues,
and morphologic evidence of toxicity., J Clin Oncol. 1992;10(5):795–803.
6. Thompson SW, Davis LE, Kornfeld M., et al. Cisplatin neuropathy. Clinical,
electrophysiologic, morphologic, and toxicologic studies. Cancer. 1984;54(7):1269–
75.
7. Roelofs. RI, Hrushesky W, Rogin J, Rosenberg L. Peripheral sensory
neuropathy and cisplatin chemotherapy. Neurology. 1984;34(7):934–38.
8. Von Hoff DD, Schilsky R, Reichert CM., et al. Toxic effects of cis-
dichlorodiammineplatinum(II) in man. Cancer Treatment Rep. 1979;63(9-10):1527–
31.
9. Bruck W, Heise E, Friede RL. Leukoencephalopathy after cisplatin therapy.
Clin Neuropathol. 1989;8(6):263–65.
10. Cattaneo MT, Filipazzi V, Piazza E, et al. Transient blindness and seizure
associated with cisplatin therapy. J Cancer Res Clin Oncol. 1988;114(5):528–30.
11. von Schlippe M, Fowler CJ, Harland S J. Cisplatin neurotoxicity in the
treatment of metastatic germ cell tumour: time course and prognosis. Br J Cancer.
2001;85(6):823–6.
12. Hartmann JT, Lipp H P. Toxicity of platinum compounds. Expert Opin
Pharmacother. 2003;4(6):889–901.
13. Laurell G, Beskow C, Frankendal B, Borg E. Cisplatin administration to
gynecologic cancer patients: long term effects on hearing. Cancer. 1996;78(8):1798-
804.
14. Glover D, Glick JH, Weiler C, et al. Phase I trials of WR-2721 and cis-
platinum. Int J Radiat Oncol Biol Phys. 1984;10:1781–4.
15. Hallmark RJ, Snyder JM, Jusenius K, Tamimi HK. Factors influencing
ototoxicity in ovarian cancer patients treated with cis-platinum based chemotherapy.
Eur J Gynaecol Oncol. 1992;13(1):35–44.
16. Peters U, Preisler-Adams S, Hebeisen A et al. Glutathione S-transferase
genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin.
Anti-Cancer Drugs. 2000;11(8): 639–43.
17. Moroso MJ, Blair L. A review of cis-platinum ototoxicity. J Otolaryngol.
1983;12(6):365–9.
18. Chapman P. Rapid onset hearing loss after cisplatinum therapy: case reports
and literature review. J Laryngol Oto.1982;96(2):159-62.
19. Gao WQ, Dybdal N, Shinsky N, et al. Neurotrophin-3 reverses experimental
cisplatin-induced peripheral sensory neuropathy. Ann Neurol. 1995;38(1):30-7.
20. Gispen WH, Hamers FP, Vecht CJ, et al. ACTH/MSH like peptides in the
treatment of cisplatin neuropathy. J Steroid Biochem Mol Biol. 1992; 43(1-3):179-83.
21. Apfel SC, Arezzo JC, Lipson L, Kessler JA. Nerve growth factor prevents
experimental cisplatin neuropathy. Ann Neurol. 1992;31(1):76-80.
705
CARBOPLATIN
Carboplatin is less neurotoxic than cisplatin (1). Neurological
dysfunction is a side effect in the carboplatin-based regimen but
appears later on and mostly after the administration of carboplatin at
high-dose levels or in combination with other cytotoxic agents known
to be neurotoxic (e.g., taxanes) (2-4). Only 4-6% of patients who
receive carboplatin may develop peripheral neuropathy (5). Pretreated
patients with other neurotoxic agents (e.g., cisplatin, and etoposide)
and those who are > 65 years have a higher risk (6,7).
References
1. McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug
Safety. 1995;13(4):228-44.
2. Neijt JP, S. Engelholm A, Tuxen MK, et al. Exploratory phase III study of
paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.
J Clin Oncol. 2000;18(17):3084-92.
3. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based
chemotherapy versus conventional platinum-based chemotherapy in women with
relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361(9375):
2099-106.
4. Canetta R, Rozencweig M, Carter SK. Carboplatin: the clinical spectrum to
date. Cancer Treat Rev. 1985;12(suppl):125-36.
5. McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity
pharmacogenetics. Mol Cancer Ther. 2009;8(1):10-16,
6. Heinzlef O, Lotz JP, Roullet E. Severe neuropathy after high dose carboplatin
in three patients receiving multidrug chemotherapy. J Neurol Neurosurg Psychiatry.
1998;64(5):667-9.
7. Cvitkovic E. Cumulative toxicities from cisplatin therapy and current
cytoprotective measures. Cancer Treat Rev.1998;24(4):265–81.
OXALIPLATIN
Oxaliplatin is like cisplatin in its potential to produce significant
neurological dysfunction. Peripheral neuropathy is the most common
dose-limiting toxicity of oxaliplatin, and it is one of the major causes
of discontinuation of therapy. Sensory peripheral neuropathy caused
by administration of oxaliplatin is distinguished in 2 forms: (1) an
acute peripheral sensory neuropathy that may appear during the
administration of the drug or after the first few drug infusions and (2)
a chronic dose-limiting cumulative peripheral sensory neuropathy.
The mechanisms underlying these 2 forms of oxaliplatin-induced
peripheral neuropathy have not been clearly defined. Acute neurotoxic
effects may result from the impairment of voltage-gated sodium
706
channels occurring approximately in 85-95% of all patients exposed to

oxaliplatin. Symptoms consist mainly of paresthesias and dysesthesias
in the extremities and the perioral region and are exacerbated by cold
exposure (1,2).
One other rare manifestation of acute oxaliplatin-induced
neurotoxicity is laryngopharyngeal dysesthesia, a transient sensation
of difficulty in breathing without evidence of respiratory distress (3,4).
This transient syndrome affects approximately 1-2% of patients and
recovers between cycles (5). The risk of acute neuropathy appears to
be lower if oxaliplatin is administrated in a dose of 85 mg/m2 every 2
weeks rather than 130 mg/m2 every 3 weeks (2,4).
The most accepted mechanism of the chronic form oxaliplatin-
induced neurotoxicity is decreased cellular metabolism and
axonplasmatic transport resulting from the accumulation of oxaliplatin
in the DRG cells. As a result, oxaliplatin produces symmetrical,
axonal, and sensory distal neuropathy (6). Neurological symptoms in
this form of sensory neurotoxicity are dominated by pronounced
paresthesias and dysesthesias of the extremities and dysfunction of
fine sensory-motor coordination which may result in impairment of
daily life (3,7). Other rare atypical neurosensory symptoms associated
with higher cumulative dose of oxaliplatin (higher than 1000 mg) are
those of spinal cord compression (Lhermitte sign) and urinary
retention (8). The incidence of chronic oxaliplatin-induced peripheral
neuropathy is related to various risk factors such as cumulative dose,
treatment schedule, and time of perfusion (9). The peripheral sensory
neuropathy induced by oxaliplatin tends to improve after treatment is
stopped. Symptoms are partly reversible in approximately 80% of
patients and resolve completely in about 40% of patients 6–8 months
after the discontinuation of oxaliplatin treatment (6,10).
Ototoxicity due to administration of oxaliplatin is very uncommon
(11,12).
The aims of this current explorative study were to assess persistent
neuropathy in 45 patients up to 6 years after treatment with cisplatin
or OXL and to determine the most adequate method to evaluate
neuropathy. Furthermore, the effect of possible determinants on
persistent neuropathy was investigated. The assessment of neuropathy
was performed using a questionnaire, by neurological tests, and by
vibration threshold measurements. Because vibration threshold
determination gives the most objective information, vibration
threshold measurements were used for further analyses. Neuropathy
of the hands was related to follow-up time, with an observed recovery
half-life of 6.8 (+/- 3.1) years. Insignificant reversibility of neuropathy
707
of the feet within the observation period was demonstrated. For

cisplatin, the severity of neuropathy was related to the cumulative
dose and sodium thiosulfate use. OXL induced neuropathy did not
appear to be related to the dose within the studied dose range.
Relationship with platinum levels, renal function, glutathione
transferase genotypes, diabetes mellitus, alcohol use, or co-medication
could not be demonstrated (13).
The main objective of this study was to review the incidence,
mechanism, signs, symptoms, and management of OXL-induced
neurotoxicity. English-language publications from the MEDLINE
database (1995-August 2004), published articles, and meeting
abstracts were reviewed. Neurotoxicity is a common AE of OXL that
usually presents as peripheral neuropathy. There are 2 forms of
oxaliplatin-induced neurotoxicity: acute and chronic. The acute form
occurs in > 90% of patients and may begin during the infusion or
within hours of completion, is usually self-limited, and may be
exacerbated by exposure to cold. Chronic neuropathy is cumulative
and is most commonly seen in patients who have received total doses
≥ 540 mg/m2. Although it is a sensory neuropathy, the intensity can
increase to the point that it impairs physical functions, such as holding
objects and writing (14).
The acute OXL-induced peripheral neuropathy is linked to the
rapid chelation of calcium by OXL-induced oxalate and OXL is
capable of altering the voltage-gated sodium channels through a
pathway involving calcium ions. On the other hand, decreased cellular
metabolism and axoplasmatic transport resulting from the
accumulation of OXL in the DRG cells is the most widely accepted
mechanism of chronic OXL-induced peripheral neuropathy. As a
result, OXL-induced peripheral neuropathy produces a symmetric,
axonal, sensory distal primary neuronopathy without motor
involvement. The incidence of OXL-induced peripheral neuropathy is
usually related to various risk factors, including treatment schedule,
dosage, cumulative dose and time of infusion. The assessment of
OXL-induced peripheral neuropathy is primarily based on neurologic
clinical examination and quantitative methods, such as nerve
conduction study. To date, several neuroprotective agents including
thiols, neurotrophic factors, anticonvulsants and antioxidants have
been tested for their ability to prevent OXL-induced peripheral
neuropathy. However, the clinical data are still controversial (6).
Sixteen patients treated with OXL for cancer were characterized
with neurological assessment and a standardized and validated set for
quantitative sensory testing. Patients were allocated to 2 groups
708
depending on the presence or absence of pain symptoms of acute

neuropathy. Comparison with normative data revealed a characteristic
somatosensory profile of cold and mechanical hyperalgesia in patients
with pain symptoms. Group-to-group analysis revealed additional heat
hyperalgesia and warm hypoesthesia. Pain symptoms of acute OXL-
induced neuropathy are related to signs of sensitization within the
peripheral (cold and heat hyperalgesia) and central nervous
nociceptive system (mechanical hyperalgesia). This strengthens the
rationale for treatment with anticonvulsants and antidepressants and
fosters research on ion channel and receptor related mechanisms (15).
References
1. Adelsberger H, Quasthoff S, Grosskreutz J, et al. The chemotherapeutic
oxaliplatin alters voltage-gated Na+ channel kinetics on rat sensory neurons. Eur J
Pharmacol. 2000;406(1):25–32.
2. Gamelin E, Gamelin L, Bossi L, Quasthoff S. Clinical aspects and molecular
basis of oxaliplatin neurotoxicity: current management and development of preventive
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3. Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin
Pharmacother. 2003;4(6):889–901.
4. Cassidy J, Misset JL. Oxaliplatin-related side effects: characteristics and
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oxaliplatin-based chemotherapy for colorectal cancer patients. Oncology.
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induced peripheral nerve damage. Cancer Treat Rev. 2008;34(4):368-77.
7. Cavaletti G, Zanna C. Current status and future prospects for the treatment of
chemotherapy-induced peripheral neurotoxicity. Eur J Cancer. 2002;38(14):1832-7.
8. Taieb S, Trillet-Lenoir V, Rambaud L, et al. Lhermitte sign and urinary
retention: atypical presentation of oxaliplatin neurotoxicity in four patients. Cancer.
2002;94(9):2434–40.
9. Grothey A. Clinical management of oxaliplatin-associated neurotoxicity. Clin
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profile of oxaliplatin. Semin Oncol.1998;25(2):13-22.
11. Hellberg V, Wallin I, Eriksson S, et al. Cisplatin and oxaliplatin toxicity:
importance of cochlear kinetics as a determinant for ototoxicity. J Natl Cancer Inst.
2009;101(1):37-47.
12. Malhotra NK, Aslam R, Lipman SP, Bilski VJ. Acute ototoxicity from a
single infusion of oxaliplatin. Ear, Nose, Throat J. 2010;89(6):258-61.
13. Brouwers EE, Huitema AD, Boogerd W, et al. Persistent neuropathy after
treatment with cisplatin and oxaliplatin. Acta Oncol. 2009;48(6):832-41.
14. Cersosimo RJ. Oxaliplatin-associated neuropathy: a review. Ann
Pharmacother. 2005;39(1):128-35.
15. Binder A, Stengel M, Maag R, et al. Pain in oxaliplatin-induced neuropathy -
sensitisation in the peripheral and central nociceptive system. Eur J Cancer.
2007;43(18):2658-63.
709
PREVENTION AND TREATMENT OF

PLATINUM-INDUCED NEUROTOXICITY
Many studies have examined the efficacy of a number of potential
neuroprotective agents administered together with platinum
analogues. The use of these agents generally aims to reduce the
incidence and severity of the neurotoxicity without impairing the
antitumor efficacy of the platinum drugs. To date, several
neuroprotective agents including thiol compounds, vitamin E, various
anticonvulsants, calcium-magnesium infusions and other
nonpharmacological strategies have been tested for their ability to
preent platinum-induced neurotoxicity with controversial results.
Further studies on the prevention and treatment of neurotoxicity of
platinum analogues are warranted (1).
THIOL COMPOUNDS
Three thiol compounds have been studied as neuroprotective
agents in patients receiving cisplatin: amifostine, glutathione, and the
melanocortin Org 2766. Among these agents, glutathione seems to
have some neuroprotective effects in platinum-induced neurotoxicity.
Glutathione has been studied as a chemoprotective agent in patients
receiving chemotherapy with cisplatin in small randomized trials.
Published data are conflicting as some of the studies have shown that
glutathione may provide neuroprotection in patients treated with
cisplatin without altering its antineoplastic effect (2,3,4), while others
found no reduction in toxicity (5,6). Cascinu et al. (7) were the first to
study the potentially protective effect of glutathione on oxaliplatin
neurotoxicity in a randomized, placebo-controlled clinical trial. This
study showed that glutathione could exert a beneficial effect on
oxaliplatin-induced neurotoxicity without interferences with
oxaliplatin antitumor activity. Other studies, however, have shown no
benefit from the use of glutathione for preventing the oxaliplatin-
induced peripheral neuropathy (8). In addition, the fact that elevated
intracellular levels of glutathione have been correlated with increased
resistance to platinum agents raises some concerns over the use of
glutathione as a neuroprotective agent (8-10). More trials are needed
to confirm the safety and usefulness of glutathione as a protective
agent against platinum-induced neurotoxicity.
With respect to cisplatin-induced ototoxicity, there is some
evidence that amifostine may be useful as a protective agent (11,12).
710
ORAL GLUTAMINE
Relevant literature was accessed through PubMed (1990-May
2008), using the search terms glutamine, chemotherapy, peripheral
neuropathy, neurotoxicity, safety, paclitaxel, platinum compounds,
and vinca alkaloids. References in the identified articles were also
reviewed for pertinent information. Studies evaluating the role of oral
glutamine for prevention and treatment of CIPN were included.
Studies regarding the role of glutamine in the reduction of other
radiation- and chemotherapy-related toxicities, such as mucositis,
cardiotoxicity, diarrhea, and cachexia, were excluded. There is no
standard therapy for the treatment of this dose-limiting reaction.
Glutamine is a nonessential amino acid that is thought to have a
neuroprotective role, possibly due to the upregulation of nerve growth
factor. Two studies revealed that oral glutamine was effective in
reducing peripheral neuropathy associated with high-dose paclitaxel,
as evidenced by a reduction in numbness, dysesthesias, and motor
weakness, as well as a smaller loss of vibratory sensation. Another
study found that glutamine effectively reduced peripheral neuropathy
in patients with CRC being treated with OXL, thereby decreasing the
need for an OXL dose reduction. However, data are limited by small
sample sizes in these studies and the lack of placebo-controlled,
randomized clinical trials. In conclusion, larger, well-designed,
placebo-controlled trials assessing both safety and efficacy of oral
glutamine are warranted before this agent can be definitively
recommended for the prevention of CIPN in patients treated with
high-dose paclitaxel or OXL (12).
VITAMIN E
The neuroprotective role of vitamin E against cisplatin
neurotoxicity has recently been evaluated in a randomized, placebo-
controlled trial (13). This was a phase III study in which 108 patients,
treated with cisplatin, were randomized to receive vitamin E (alpha-
tocopherol 400 mg/day) or placebo. Class II evidence that vitamin E
supplementation significantly reduces the RR of developing signs or
symptoms of neurotoxicity (RR = 0.14) (95% CI = 0.02 - 1.00) was
provided (13).
711
CALCIUM AND MAGNESIUM INFUSIONS

Peripheral neuropathy is seen in the majority of patients who
receive OXL. The acute form is usually transient and self-limited;
however, the chronic form can be dose-limiting. Preventive measures
include administration of calcium and magnesium solutions,
gabapentin, carbamazepine, amifostine, and glutathione. Treatment
measures include calcium and magnesium solutions, gabapentin, and
alpha-lipoic acid. Calcium and magnesium solutions are an effective
and convenient means of treating and reducing the severity of
neuropathic symptoms (14).
Calcium/magnesium infusions have been used to decrease the
incidence of oxaliplatin-induced neuropathy without any influence on
antitumor activity (15-17). However, the CONCEPT study reported
that treatment with calcium/magnesium decreased antitumor effect in
patients with metastatic CRC treated with oxaliplatin, and thus, they
are not advisable in combination with the FOLFOX regimen (18).
The purpose of this meta-analysis was to determine the efficacy of
calcium and magnesium infusions in OXL-induced neurotoxicity.
Two independent authors conducted database searches of the literature
to find clinical-controlled trials analyzing calcium and magnesium
infusions in OXL-induced neurotoxicity. The keywords used to search
were OXL, neurotoxicity, Calcium, Magnesium, neuropathy, and
peripheral. Clinical studies that included at least 1 primary or
secondary event were eligible for the analysis, where primary events
were incidences of acute and cumulative neurotoxicity, and secondary
events were the total doses and cycles of oxaliplatin, response rate,
overall survival, and progression-free survival. ORs and WMDs were
analyzed using models of fixed and random effects. This meta-
analysis comprised 4 prospective RCTs and 3 retrospective clinical
trials involving 1170 CRC patients, of which 802 received
calcium/magnesium infusions (calcium/magnesium group) and 368
did not (control group). According to the NCI-Common Terminology
Criteria for Adverse Events, the incidence of grade III acute
neurotoxicity in those who received calcium/magnesium was
significantly lower than that of the control group (OR = 0.26, 95% CI
0.11 - 0.62, p=0.0002). The total rate of cumulative neurotoxicity, and
that of grade III in particular, was significantly lower in the
calcium/magnesium group than in the control group (OR = 0.42, 95%
CI 0.26 - 0.65, p=0.0001; OR=0.60, 95% CI 0.39 - 0.92, p=0.02,
respectively). The differences in total doses and cycles of OXL were
significant between the calcium/magnesium and control group (WMD
712
= 246.7 mg/m(2), 95% CI 3.01 - 490.5, p=0.05; WMD = 1.55, 95% CI

0.46 - 2.63, p=0.005, respectively). Insignificant differences were
found in median progression-free survival (WMD = 0.71 month, 95%
CI -0.59 - 2.01, p=0.29), median overall survival (WMD= 0.10 month,
95% CI -0.41 - 0.61, p=0.70) or response rates (OR = 0.82, 95% CI
0.61 - 1.10, p=0.18). In conclusion, calcium/magnesium infusions tend
to decrease the incidence of oxaliplatin-induced acute and cumulative
neurotoxicity and thus enhance patients' tolerance to oxaliplatin,
without significantly altering the efficacy of chemotherapy (19).
ANTICONVULSANTS
Gabapentin is an AED which has been used in the management of
neuropathic pain. Some studies attempted to assess the impact of
gabapentin on OXL-induced neurotoxicity, but they could not support
a role for gabapentin in reducing the severity of OXL-induced
neurotoxicity (20-22).
Pregalin is also an anticonvulsant drug used for neuropathic pain.
A case of successful treatment of hyperexcitability syndrome with
pregalin after oxaliplatin and gemcitabine therapy for pancreatic
cancer has been described (23). In a recent study, Saif et al. treated 23
patients with G-I tumors and grade II and III oxaliplatin-induced
neurotoxicity with pregabalin at a dose of 150 mg orally three times a
day and found that pregabalin reduced the severity of oxaliplatin-
induced neuropathy (24).
OTHER STRATEGIES
Non-pharmacological approaches to prevent oxaliplatin-induced
neurotoxicity include the ―stop and go‖ concept. This strategy is based
on the observation of reversibility of neurotoxic symptoms after
discontinuation of oxaliplatin.
In metastatic CRC, a combination of leucovorin and fluorouracil
with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The
cumulative neurotoxicity of oxaliplatin often requires therapy to be
stopped in patients who are still responding. This study evaluates a
new strategy of intermittent oxaliplatin treatment that is based on
FOLFOX7, a simplified leucovorin and fluorouracil regimen with
high-dose oxaliplatin. Previously untreated patients were randomly
assigned to either FOLFOX4 administered every 2 weeks until
713
progression (arm A) or FOLFOX7 for 6 cycles, maintenance without

oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). Of
620 patients enrolled, 95 were elderly or poor prognosis patients.
Median progression-free survival and survival times were 9.0 and 19.3
months, respectively, in patients allocated to arm A compared with 8.7
and 21.2 months, respectively, in patients allocated to arm B (p=
insignificant). Response rates were 58.5% with arm A and 59.2% with
arm B. NCI Common Toxicity Criteria grade III or IV toxicity was
observed in 54.4% of the patients in arm A vs. 48.7% of patients in
arm B. From cycle 7, fewer patients experienced grade III or IV
toxicity in arm B. Grade III sensory neuropathy was observed in
17.9% of the patients in arm A vs. 13.3% of patients in arm B
(p=0.12). In arm B, oxaliplatin was reintroduced in only 40.1% of the
patients but achieved responses or stabilizations in 69.4% of these
patients. In conclusion, oxaliplatin can be safely stopped after 6 cycles
in a FOLFOX regimen (25).
In this approach, patients receive treatment with OXL plus 5
leucovorin/fluorouracil until either the beginning of the development
of peripheral neurotoxicity or a predetermined ―time to best response‖.
Next, maintain angiotensin converting enzyme inhibitors therapy with
5 leucovorin/fluorouracil continued without OXL so that any
neurologic damage is given time to recede. Subsequently, OXL is
reintroduced to maximize the potential effect of the combination
regime (25).
Another strategy involves longer duration of oxaliplatin
administration which is supposed to result in decreased neurotoxicity
(26).
Assessment: platinum compounds are active in the treatment of

solid tumors, but peripheral neuropathy is the major non-
hematological dose-limiting AE especially for cisplatin and
oxaliplatin. Despite efforts to find specific agents that will prevent or
minimize neurotoxicity caused by platinum drugs, there is no effective
strategy for the management of the neurotoxicity induced by these
agents. Unfortunately, none of the symptomatic treatments discussed
above have proven useful. Therefore, new drugs or strategies for the
prevention and amelioration of platinum-induced neurotoxicity must
be found.
References
714
2. Cavaletti G, C. Zanna C. Current status and future prospects for the treatment
of chemotherapy-induced peripheral neurotoxicity. Eur J Cancer. 2002;38(14):1832–
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3. Kemp G., Rose P, Lurain J. et al. Amifostine pretreatment for protection
against cyclophosphamide-induced and cisplatin-induced toxicities: results of a
randomized control trial in patients with advanced ovarian cancer. J Clin
Oncol.1996;14(7):2101–12.
4. Screnci D, McKeage MJ. Platinum neurotoxicity: clinical profiles,
experimental models and neuroprotective approaches. J Inorg Biochem. 1999;77(1-
2):105–10.
5. Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced
glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a
randomized double-blind placebo- controlled trial. J Clin Oncol. 1995;13(1):26–32.
6. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and
improves quality of life of women diagnosed with ovarian cancer treated with
cisplatin: results of a double-blind, randomised trial. Ann Oncol. 1997;8:569–3.
7. Cascinu S, Catalano V, Cordella L et al. Neuroprotective effect of reduced
glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a
randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002;20(16):3478–
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8. Dong M, Xing PY, Liu P, et al. Assessment of the protective effect of calcium-
magnesium infusion and glutathione on oxaliplatin-induced neurotocixity. Chinese J
Oncol. 2010;32:208–11.
9. Arrick BA, Nathan CF. Glutathione metabolism as a determinant of therapeutic
efficacy: a review. Cancer Res. 1984;44(10):4224–32.
10. Bates SE, Regis JI., Robey RW et al. Chemoresistance in the clinic: overview.
Bull Cancer. 1994;81(suppl 2):55–61.
11. Foster-Nora JA, Siden R. Amifostine for protection from antineoplastic drug
toxicity. Am J Health Syst Pharm. 1997;54(7):787–800.
12. Amara S. Oral glutamine for the prevention of chemotherapy-induced
peripheral neuropathy. Ann Pharmacother. 2008;42(10):1481-5.
13. Pace A, D. Giannarelli, E. Galiè et al. Vitamin E neuroprotection for cisplatin
neuropathy: a randomized, placebo-controlled trial. Neurology. 2010;74(9):762–6.
14. Cersosimo RJ. Oxaliplatin-associated neuropathy: a review. Ann
Pharmacother. 2005;39(1):128-35.
15. Saif MW. Oral calcium ameliorating oxaliplatin-induced peripheral
neuropathy. J Appl Res. 2004;4(4):576–82.
16. Ishibashi K, Okada N, Miyazaki T, et al. Effect of calcium and magnesium on
neurotoxicity and blood platinum concentrations in patients receiving mFOLFOX6
therapy: a prospective randomized study. Int J Clin Oncol. 2010;15(1):82–7.
17. Gamelin L, Boisdron-Celle M, Delva R. et al. Prevention of oxaliplatin-related
neurotoxicity by calcium and magnesium infusions: a retrospective study of 161
patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for
advanced colorectal cancer. Clin Cancer Resvol. 2004;10(12):4055–61.
18. Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to
reduce oxaliplatin-related neurotoxicity. J Clin Oncol. 2007; 25(25): 4028-9.
19. Wen F, Zhou Y, Wang W, et al. Ca/Mg infusions for the prevention of
oxaliplatin-related neurotoxicity in patients with colorectal cancer: a meta-analysis.
Ann Oncol. 2013;24(1):171-8.
20. Mitchell PL, Goldstein D, Michael M et al. Addition of gabapentin to a
modified FOLFOX regimen does not reduce oxaliplatin-induced neurotoxicity. Clin
Colorectal Cancer. 2006;6(2):146-51.
715
21. Rao RD, Michalak J C, Sloan JA et al. Efficacy of gabapentin in the

management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized,
double-blind, placebo-controlled, crossover trial (N00C3). Cancer. 2007;110(9):2110-
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22. Tsavaris N, Kopterides P, C. Kosmas C et al. Gabapentin monotherapy for
the treatment of chemotherapy-induced neuropathic pain: a pilot study. Pain Med.
2008;9(8):1209–16.
23. Saif MW, Hashmi S. Successful amelioration of oxaliplatin-induced
hyperexcitability syndrome with the antiepileptic pregabalin in a patient with
pancreatic cancer. Cancer Chemother Pharmacol. 2008; 61(3):349-54.
24. Saif MW, Syrigos K, Kaley K, Isufi I. Role of pregabalin in treatment of
oxaliplatin-induced sensory neuropathy. Anticancer Res. 2010;30(7):2927-33.
25. Tournigand C, A. Cervantes, A. Figer et al. OPTIMOX1: a randomized study
of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced
colorectal cancer - a GERCOR study. J Clin Oncol 2006; 24(3):394-400.
26. Petrioli R, Pascucci A, Francini E et al. Neurotoxicity of FOLFOX-4 as
adjuvant treatment for patients with colon and gastric cancer: a randomized study of
two different schedules of oxaliplatin. Cancer Chemother Pharmacol. 2008;61(1):
105–11.
MICROTUBULE-TARGETING AGENTS
VINCRISTINE
Vincristine (brand name, Oncovin), formally known as
leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from
the Catharanthus roseus (Madagascar periwinkle), formerly Vinca
rosea and hence its name. It is a mitotic inhibitor, and is used in cancer
chemotherapy. Vincristine is created by the coupling of indole
alkaloids vindoline and catharanthine in the vinca plant (1).
Tubulin is a structural protein that polymerizes to microtubules.
The cell cytoskeleton and mitotic spindle, among other things, are
made of microtubules. Vincristine binds to tubulin dimers, inhibiting
assembly of microtubule structures. Disruption of the microtubules
arrests mitosis in metaphase. Therefore, the vinca alkaloids affect all
rapidly dividing cell types including cancer cells, but also those of
intestinal epithelium and bone marrow. The main side effects of
vincristine are peripheral neuropathy, hyponatremia, constipation, and
hair loss (2).
Peripheral neuropathy can be severe, and hence a reason to avoid,
reduce, or stop the use of vincristine. One of the first symptoms of
peripheral neuropathy is foot drop: a person with a family history of
716
foot drop and/or Charcot-Marie-Tooth disease may benefit from

genetic testing for Charcot-Marie-Tooth before taking vincristine (3).
Vincristine causes an axonal sensorimotor neuropathy often early
during treatment, heralded by paresthesias and followed by severe
motor weakness if treatment is continued (1). Pain is not a prominent
feature. Autonomic neuropathy is often prominent (ileus, and
orthostatic hypotension). Even in cases with a more severe
neuropathy, in time, recovery may be good. The cause is probably a
vincristine-induced interference with microtubuli, affecting axonal
transport. Neurotoxicity is the dose-limiting toxicity of vincristine, in
related to dose per cycle. Other Vinca alkaloids are far less neurotoxic
(4).
The natural course of vincristine-induced peripheral neuropathy in
patients with lymphoma (n=114) receiving vincristine in 2 different
dose intensities is described. Neuropathic changes were observed in
both dose intensity groups, but the higher dose intensity group
reported significantly more symptoms during therapy, whereas
neurologic signs were significantly more prominent after a cumulative
dose of 12 mg vincristine. Furthermore, off-therapy worsening of
symptoms (24%) and signs (30%) occurred unexpectedly (5).
In a retrospective case series study conducted at Hurlingham
Oncology Clinic, Nairobi, 38 patients were treated for various
neoplasms with vincristine containing chemotherapeutic regimens.
The frequency and degree of neurotoxicity when vincristine was given
at the standard dose of 1.4 mg/m2 were studied. Five patients (13.2%)
developed peripheral neuropathy, 1 having had it even before
vincristine was started. Therefore only 4 (10.5%) had it attributed to
vincristine. Four of the patients who developed neuropathy (80%)
were HIV-positive. Neuropathy grade II (severe) occurred in only 2
patients leading to discontinuation of the drug. All the neurotoxicity
resolved after discontinuation of vincristine. Vincristine induced
neuropathy occurred but was rarely severe at a dose of 1.4 mg/m2. It
was more frequent in HIV infected individuals, but controlled studies
with bigger sample sizes are required to determine whether this may
warrant routine capping of the dose at a maximum of 2 mg (6).
Vincristine-induced vocal cord paralysis is a rare but serious
complication. Two patients with acute lymphoblastic leukemia
developed progressive stridor during induction chemotherapy. There
were no clinical features of peripheral or autonomic neuropathy.
Flexible laryngoscopy confirmed the diagnosis of bilateral vocal cord
palsy; the nerve conduction test revealed axonal motor neuropathy
involving the median and common peroneal nerves in both patients.
717
The first patient required prolonged ventilatory support necessitating

unilateral cordectomy before extubation, whereas the second required
supplemental oxygen therapy. There was resolution of stridor in the
first patient after cordectomy and gradual clinical improvement in the
second. These cases illustrate that a high index of suspicion of
vincristine-induced vocal cord palsy with prompt otolaryngology
consultation for laryngoscopy in the diagnostic evaluation of a patient
who has received vincristine (7).
A child with acute lymphoblastic leukemia developed vincristine-
induced bilateral vocal cord paralysis. Vocal cord paralysis resolved
spontaneously upon withdrawal of the vincristine. Vinca-alkaloid-
induced vocal cord paralysis is a potentially dangerous but reversible
condition (8).
Eighteen patients of lymphoma, treated with vincristine were
assessed clinically and electrophysiologically before and for 3 months
after therapy. The earliest evidence of neuropathy was impaired ankle
jerk (around 2 weeks) and the earliest symptom was paresthesia (by 4-
5 weeks). At the end of the study, all the patients had absent ankle
jerks and 75% had sensory symptoms and/or signs, the most frequent
being impaired vibration sensation (62.5%). Motor abnormalities were
much less common (18.7%) and constipation (62.5%) was the only
autonomic manifestation. Concentric needle EMG showed evidence of
denervation (46.7%), especially in the small muscles of hand.
Conduction studies showed prolonged mean distal latencies, decreased
mean amplitudes of compound muscle action potentials, with almost
unchanged conduction velocities. However, no conduction block was
noted and F-wave studies were normal. During early weeks, in spite of
impaired absent ankle jerks, H reflex was elicitable in the majority.
However, later 56.2% had absent H reflex. In conclusion, vincristine
produces a distal symmetrical sensorimotor neuropathy,
predominantly involving the large diameter fibers in the early stages.
Electrophysiological studies characterize it as a distal axonopathy.
However it is dependent on the dose of vincristine and the duration of
therapy: though in the usual doses it does produce neuropathy, it is
rarely disabling in the early months (9).
Ten out of 20 children, treated with usual doses of vincristine for
various types of childhood cancers, developed neurotoxicity during
treatment. Peripheral neurotoxicity (mixed motor-sensory 4/10, pure
motor 3/10, pure sensory 3/10) was seen in the form of weakness of
lower limbs, areflexia, neuropathic pain, or sensory loss. Autonomic
neuropathy presented as constipation and urinary retention in 2
children, while 2 children developed encephalopathy in form of
718
seizures, confusion, aphasia, and transient blindness. In children with

severe neuropathy, vincristine administration was withheld/dose
reduced until clinical improvement started, which took about 2-3
weeks time. Nerve conduction velocity showed motor-sensory axonal
polyneuropathy. Electrophysiological abnormalities were found to
persist even 6 months after clinical recovery in children with
neurotoxicity. A relatively higher incidence of vincristine-induced
neuropathy was found in Indian children, which was probably due to
coexistence of severe malnutrition (10).
References
1. Evans WC. Trease and Evans Pharmacognosy, 16th ed. Elsevier: New York,
2009.
2. Kokate CK, Gokhale SB, Purohit AP. A Textbook of Pharmacognosy, 29th ed.
Nirali Prakashan: Pune. 2009.
3. Graf WD, Chance PF, Lensch MW. et al. Severe Vincristine Neuropathy in
Charcot-Marie-Tooth Disease Type 1A. Cancer. 1996;77(7):1356–62.
4. Martin J. van den Bent. Prevention of Chemotherapy-Induced Neuropathy:
Leukemia Inhibitory Factor. Clin Cancer Res. 2005:11:1691.
5. Verstappen CC, Koeppen S, Heimans JJ, et al. Dose-related vincristine-induced
peripheral neuropathy with unexpected off-therapy worsening. Neurology.
2005;64(6):1076-7.
6. Othieno-Abinya NA, Nyabola LO. Experience with vincristine - associated
neurotoxicity. East Afr Med J. 2001;78(7):376-8.
7. Latiff ZA, Kamal NA, Jahendran J, et al. Vincristine-induced vocal cord palsy:
case report and review of the literature. J Pediatr Hematol Oncol. 2010;32(5):407-10.
8. Naithani R, Dolai TK, Kumar R. Bilateral vocal cord paralysis following
treatment with vincristine. Indian Pediatr. 2009;46(1):68-9.
9. Pal PK. Clinical and electrophysiological studies in vincristine induced
neuropathy. Electromyogr Clin Neurophysiol. 1999;39(6):323-30.
10. Gomber S, Dewan P, Chhonker D. Vincristine induced neurotoxicity in
cancer patients. Indian J Pediatr. 2010;77(1):97-100.
TREATMENT
Vincristine is a commonly used antineoplastic drug and frequently
causes neurotoxicity. In a 4-year-old boy with acute lymphoblastic
leukemia, vincristine-induced peripheral and cranial neuropathy
developed during remission induction therapy. The patient seemed to
benefit from pyridoxine and pyridostigmine therapy and this therapy
is recommended in patients with severe vincristine-induced
neuropathy (1).
Four children with vincristine-induced neuropathy are reported. All
cases were followed with the diagnosis of acute lymphoblastic
leukemia. Two were boys aged two and 13 years. EMG examination
719
consisted of sensoriomotor polyneuropathy with axonal involvement

in 3 patients. In another patient, it consisted of motor axonal
polyneuropathy. In all patients, pyridoxine and pyridostigmine were
used in the treatment of vincristine-induced neuropathy. They
recovered completely with these drugs combination. Recovering
period of symptoms was between 1 and 2 weeks (2).
Some steroids are synthesized within the central and peripheral
nervous system, mostly by glial cells. These are known as
neurosteroids. In the brain, neurosteroids have been shown to act
directly on membrane receptors for neurotransmitters. For example,
progesterone inhibits the neuronal nicotinic acetylcholine receptor,
whereas its 3alpha,5alpha-reduced metabolite 3alpha,5alpha-
tetrahydroprogesterone (allopregnanolone) activates the A gamma-
aminobutyric acid receptor complex. Besides these effects,
neurosteroids regulate important glial functions, such as the synthesis
of myelin proteins. In cultures of glial cells prepared from neonatal rat
brain, progesterone increases the number of oligodendrocytes
expressing the myelin basic protein and the 2',3'-cyclic nucleotide-3'-
phophodiesterase. An important role for neurosteroids in myelin repair
has been demonstrated in the rodent sciatic nerve, where progesterone
and its direct precursor pregnenolone are synthesized by Schwann
cells. After cryolesion of the male mouse sciatic nerve, blocking the
local synthesis or action of progesterone impairs remyelination of the
regenerating axons, whereas administration of progesterone to the
lesion site promotes the formation of new myelin sheaths (3).
Painful neuropathy is major side-effect limiting cancer
chemotherapy. Therefore, novel strategies are required to suppress the
neuropathic effects of anticancer drugs without altering their
chemotherapeutic effectiveness. By combining biochemical,
neuroanatomical/neurochemical, electrophysiological and behavioral
methods, progesterone-derived neurosteroids including 5alpha-
dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone
suppressed neuropathic symptoms evoked in naive rats by vincristine.
Neurosteroids counteracted vincristine-induced alterations in
peripheral nerves including 2',3'-cyclic nucleotide 3'-
phosphodiesterase, neurofilament-200 kDa and intraepidermal nerve
fiber repression, nerve conduction velocity, and pain transmission
abnormalities (allodynia/hyperalgesia). In skin-tumor rats generated
with carcinosarcoma-cells, vincristine, which suppressed the skin
tumor and restored normal blood concentration of vascular endothelial
growth factor, reproduced neuropathic side effects. Administered
alone, neurosteroids did not affect the tumor and vascular endothelial
720
growth factor level. Combined with vincristine, neurosteroids

preserved vincristine anti-tumor action but counteracted vincristine-
induced neural side effects. Together, these results provide valuable
insight into the cellular and functional mechanisms underlying
anticancer drug-induced neuropathy and suggest a neurosteroid-based
strategy to eradicate painful neuropathy (4).
Neuropathic pain is difficult to treat. Classic analgesics (i.e., opioid
receptor agonists) usually possess low activity. Therefore, other agents
such as antidepressants, anticonvulsants, and corticosteroids are used.
NMDA antagonists increase analgesic activity of opioids.
Unfortunately, clinical use of NMDA antagonists is limited because of
the relatively frequent occurrence of AEs e.g., memory impairment,
psychomimetic effects, ataxia and motor in-coordination. Magnesium
ions (Mg(2+)) are NMDA receptor blockers in physiological
conditions. Therefore, in this study the effect of opioid receptor
agonists and the influence of Mg(2+) on the action of opioid agonists
in vincristine-induced hyperalgesia were examined. Opioid agonists
such as morphine (5 mg/kg, intraperitoneally), and fentanyl (0.0625
mg/kg, intraperitoneally), as well as the partial agonist buprenorphine
(0.075 mg/kg, intraperitoneally) administered alone on 5 consecutive
days did not modify the hyperalgesia in vincristine rats. By contrast,
pretreatment with a low dose of magnesium sulfate (30 mg/kg, ip)
resulted in a progressive increase of the analgesic action of all 3
investigated opioids. After discontinuation of drug administration, the
effect persisted for several days (5).
References
1. Ozyurek H, Turker H, Akbalik M, et al. Pyridoxine and pyridostigmine
treatment in vincristine-induced neuropathy. Pediatr Hematol Oncol. 2007;24(6):447-
52.
2. Akbayram S, Akgun C, Doğan M, et al. Use of pyridoxine and pyridostigmine
in children with vincristine-induced neuropathy. Indian J Pediatr. 2010;77(6):681-3.
3. Baulieu EE, Schumacher M. Neurosteroids, with special reference to the effect
of progesterone on myelination in peripheral nerves. Mult Scler. 1997;3(2):105-12.
4. Meyer L, Patte-Mensah C, Taleb O, Mensah-Nyagan AG. Cellular and
functional evidence for a protective action of neurosteroids against vincristine
chemotherapy-induced painful neuropathy. Cell Mol Life Sci. 2010;67(17):3017-34.
5. Bujalska M, Makulska-Nowak H, Gumułka SW. Magnesium ions and opioid
agonists in vincristine-induced neuropathy. Pharmacol Rep. 2009; 61(6):1096-104.
721
TAXANES
Taxanes are diterpenes produced by the plants of the genus Taxus
(yews), and are widely used as chemotherapy agents. Taxane agents
include paclitaxel (Taxol) and docetaxel (Taxotere). Taxanes present
difficulties in formulation as medicines because they are poorly
soluble in water. The principal mechanism of action of the taxane
class of drugs is the disruption of microtubule function. Microtubules
are essential to cell division, and taxanes stabilize GDP-bound tubulin
in the microtubule, thereby inhibiting the process of cell division - a
"frozen mitosis". Thus, in essence, taxanes are mitotic inhibitors. In
contrast to the taxanes, the vinca alkaloids destroy mitotic spindles.
Both taxanes and vinca alkaloids are, therefore, named spindle
poisons or mitosis poisons, but they act in different ways. Taxanes are
also thought to be radiosensitizing (1).
Evidence from animal models of chemotherapy-induced painful
peripheral neuropathy produced by the taxane agent, paclitaxel, and
the platinum-complex agent, OXL, indicate that they produce
neuropathy via a common mechanism - a toxic effect on the
mitochondria in primary afferent sensory neurons (2).
References
1. Hagiwara H, Sunada Y. Mechanism of taxane neurotoxicity. Breast Cancer.
2004;11:82–5.
2. Zheng H, Xiao WH, Bennett GJ. Mitotoxicity and bortezomib-induced chronic
painful peripheral neuropathy. Exp Neurol. 2012 c;238(2):225-34.
PACLITAXEL
Paclitaxel is an antineoplastic agent derived from the bark of the
western yew, Taxus brevifolia, with a broad spectrum of activity.
Because paclitaxel promotes microtubule assembly, neurotoxicity is
one of its side effects. Clinical use of paclitaxel has led to peripheral
neuropathy has been demonstrated to be dependent upon the dose
administered, the duration of the infusion, and the schedule of
administration. Vehicles in the drug formulation, for example
Cremophor in Taxol, have been investigated for their potential to
induce peripheral neuropathy. A variety of neuroprotective agents has
been tested in animal and clinical studies to prevent paclitaxel
neurotoxicity. Recently, novel paclitaxel formulations have been
developed to minimize toxicities (1).
722
Paclitaxel, a new anticancer agent, with a novel mechanism of

action, promotes polymerisation of tubulin dimers to form
microtubules and stabilises microtubules by preventing
depolymerisation. In noncomparative trials, continuous infusion of
paclitaxel 110 to 300 mg/m2 over 3 to 96 hours every 3 to 4 weeks
produced a complete or partial response in 16 to 48% of patients with
ovarian cancer and 25-61.5% of patients with metastatic breast cancer,
many of whom were refractory to treatment with cisplatin or
doxorubicin, respectively. Of patients with ovarian cancer, 23-100%
achieved complete or partial responses with paclitaxel in combination
with cisplatin, carboplatin, cyclophosphamide, altretamine and/or
doxorubicin. Similarly, response rates of 30-100% were observed with
paclitaxel plus doxorubicin, cisplatin, mitoxantrone and/or
cyclophosphamide in patients with metastatic breast cancer.
Comparative trials in patients with advanced ovarian cancer showed
paclitaxel therapy to produce greater response rates than treatment
with parenteral hydroxyurea (71% vs. 0%) or cyclophosphamide
(when both agents were combined with cisplatin) (79% vs. 63%).
Paclitaxel was also more effective than mitomycin in 50 patients with
previously untreated breast cancer (partial response in 20% vs. 4% of
patients). Paclitaxel therapy also produced promising results in
patients with advanced squamous cell carcinoma of the head and neck,
malignant melanoma, advanced NSCLC, SCLC, germ cell cancer,
urothelial cancer, esophageal cancer, non-Hodgkin's lymphoma or
MM, and was successfully combined with cisplatin, carboplatin and/or
etoposide in patients with NSCLC, SCLC or advanced squamous cell
carcinoma of the head and neck. Hypersensitivity reactions were
initially a concern with administration of paclitaxel, although current
dosage regimens have reduced the incidence of these events to less
than 5%. The major dose-limiting AEs of paclitaxel are leucopenia
(neutropenia) and peripheral neuropathy. Other hematological toxicity
was generally mild. Cardiac toxicity was reported in small numbers of
patients and most patients developed total alopecia. Several aspects of
paclitaxel use remain to be clarified, including the optimal treatment
schedule and infusion time, confirmation of the tolerability profile and
efficacy of combination regimens in an expanded range of
malignancies. Long-term follow-up of paclitaxel recipients will also
allow the effects of the drug on patient survival to be determined.
Nevertheless, paclitaxel is a promising addition to the current
therapies available, with significant activity reported in patients with
advanced ovarian or breast cancer or other types of tumors (2).
723
Taxane-related neuropathy remains a challenging clinical problem

causing treatment delays and worsening QOL. Taxane-based cytotoxic
chemotherapeutic agents are among the most potent agents for the
treatment of a variety of types of cancers including breast, lung, and
ovarian cancers (3,4). Taxanes are standard components of many
therapeutic regimens in both early stage and metastatic breast cancer.
These medications, by inhibiting microtubules, are known to cause
neurotoxicity which can decrease the QOL in many patients and may
necessitate discontinuation of chemotherapy (5-9).
Twenty-seven patients were treated with single-agent paclitaxel at
3 dose levels. Paclitaxel was administered by 3-hour intravenous
infusion every 3 weeks in all patients, and if possible, all were
evaluated neurologically before paclitaxel, after every other cycle and
after discontinuation of therapy. Six, 14 and 7 patients were treated
with 135 mg/m2, 175 mg/m2 and 250-300 mg/m2, respectively.
Neuropathic symptoms occurred in 50%, 79% and 100%, neuropathic
signs in 83%, 86% and 100%, and dose-limiting neurotoxicity in 0%,
21% and 71% of patients, respectively. Neurotoxicity progressed with
higher cumulative dose and was more pronounced with higher dose
per course. Paclitaxel-induced neuropathy was predominantly sensory
in character, though minor motor signs were present. Follow-up data
of 12 patients after discontinuation of paclitaxel therapy showed that
paclitaxel-induced neuropathy is at least partially reversible. In
conclusion, paclitaxel-induced neuropathy is a dose-dependent
phenomenon, occurring with higher cumulative dose and higher dose
per cycle. Using 3-weekly 3-hour infusions of paclitaxel, dose-
limiting neurotoxicity can be expected in patients treated with 250
mg/m2 or more each cycle (10).
References
1. Scripture CD, Figg WD, Sparreboom A. Peripheral neuropathy induced by
paclitaxel: recent insights and future perspectives. Curr Neuropharmacol. 2006;4(2):
165-72.
2. Spencer CM, Faulds D Paclitaxel. A review of its pharmacodynamic and
pharmacokinetic properties and therapeutic potential in the treatment of cancer.
Drugs.1994;48(5):794-847
3. Hagiwara H, Sunada Y. Mechanism of taxane neurotoxicity. Breast Cancer.
2004;11:82–5.
4. Guastalla JP, Dieras V. The taxanes: toxicity and quality of life consideration
in advanced ovarian cancer. Br J Cancer. 2003;89:S16–22.
5. Rowinski E, Donehower R. Paclitaxel (Taxol) N Engl J Med. 1995;332:1004-
14.
6. Postma T, Vermorket J, Liefting A, et al. Paclitaxel-induced neuropathy. Ann
Oncol. 1995;6:489–94.
7. Mielke S, Sparreboom A, Mross K. Peripheral neuropathy: a persisting
challenge in paclitaxel-based regimes. European Journal of Cancer. 2006;42:24–30.
724
8. Jones S, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel

compared with paclitaxel in metastatic breast cancer. Journal Clin Oncol.
2005;23:5542–51.
9. Gradishar W, Sergei T, Davidson N, et al. Superior efficacy of albuminbound
paclitaxel, ABI-007 compared with polyethylated castor-oil based paclitaxel in
women with metastatic breast cancer: results from a phase III trial. Journal Clin
Oncol. 2005;23:1–10.
10. Postma TJ, Vermorken JB, Liefting AJ, et al. Paclitaxel-induced neuropathy.
Ann Oncol. 1995;6(5):489-94.
TREATMENT
The effect of the COX-2 inhibitor etodolac on the mechanical
allodynia induced by paclitaxel was investigated in mice and
compared with the effects of the nonselective COX inhibitors
indomethacin and diclofenac, the selective COX-2 inhibitor celecoxib,
the calcium channel α(2)δ subunit inhibitor pregabalin, the sodium
channel blocker mexiletine, and the serotonin-norepinephrine reuptake
inhibitor duloxetine. The decrease in the paw-withdrawal threshold
induced by paclitaxel was reversed by oral administration of etodolac
at 10 mg/kg but was not affected by indomethacin, diclofenac, or
celecoxib. The antiallodynic effect of etodolac gradually increased
during repeated administration, and after 2 weeks, the paw-withdrawal
threshold at the preadministration point was significantly increased.
Pregabalin, duloxetine, and mexiletine showed an antiallodynic effect
in this model. Whereas pregabalin had a preadministration effect
similar to that of etodolac during repeated administration, mexiletine
or duloxetine had no such effect. There was almost no difference in
the distribution of etodolac and diclofenac in nervous tissue,
indicating that COX inhibition is unlikely to be involved in the
antiallodynic effect of etodolac. Etodolac did not show a
neuroprotective effect against morphological transformations such as
the axonal degeneration induced by paclitaxel. Instead, etodolac
probably acts at the level of functional changes accompanying
paclitaxel treatment, such as alterations in the activation state of
components of the pain transmission pathway. These findings suggest
that etodolac attenuates paclitaxel-induced peripheral neuropathy by a
COX-independent pathway and it might be useful for the treatment of
paclitaxel-induced peripheral neuropathy (1).
Although paclitaxel is a commonly used anticancer drug,
peripheral neuropathy may develop as a side effect. Worsening of the
symptoms with time may cause patients who receive paclitaxel to give
up their chemotherapy. Duloxetine, a serotonin- and norepinephrine-
725
reuptake inhibitor, has been used to treat peripheral neuropathic pain.

A 68-year-old man with gastric cancer underwent gastrectomy and
then received 8 cycles of chemotherapy involving weekly
administrations of paclitaxel. Under this paclitaxel treatment, he
complained of severe peripheral neuropathy, leading to a diminished
QOL. Following treatment with a combination of duloxetine and
pregabalin, a remission of his symptoms was achieved. Duloxetine
plus pregabalin therapy may be useful for the peripheral neuropathy
induced by paclitaxel (2).
A 51-year-old male left renal pelvic cancer patient with paclitaxel-
induced peripheral neuropathy was successfully treated with
pregabalin. From June 2010, a gemcitabine/paclitaxel regimen was
used as third-line treatment. In order to relieve the paclitaxel-induced
peripheral neuropathy, pregabalin (75mg/day, at night) was
administered from day 6 of the 16th course. Pregabalin was increased
to 150mg/day from day 12 of the course. Sensory neurotoxicity after
the administration of pregabalin was decreased from CTCAE (version
4.0) grade III to I at day 19 of the course. Therefore, there is a
possibility that the paclitaxel-induced peripheral neuropathy may be
improved by pregabalin administration (3).
Pregabalin is one of the first-line treatments for painful DPN in
many countries, and pregabalin is administered to relieve the
neurotoxicity associated with AEs of vincristine in a diffuse large B-
cell lymphoma patient treated with the R-CHOP (rituximab,
cyclophosphamide, doxorubicin, vincristine and prednisone) regimen.
A 49-year-old man with kidney diffuse large B-cell lymphoma had
surgery performed. Afterward, the R-CHOP regimen was introduced.
In order to relieve the neurotoxicity of vincristine, pregabalin was
used from day 8 in the second course. The severity of sensory
neurotoxicity after the administration of pregabalin was improved
from CTCAE (version 4.0) grade III to grade I. Therefore, there is a
possibility that vincristine-induced neurotoxicity was relieved by
pregabalin (4).
A 75-year-old female gastric cancer patient with paclitaxel-induced
peripheral neuropathy was successfully treated by the H2-blocker,
lafutidine. From December 2007, she underwent second-line
chemotherapy using paclitaxel (80 mg/m/2 day 1, 7, 14/28 days) for
peritoneal dissemination which had been refractory to first-line
chemotherapy using S-1 (80 mg/m/2, day 1-28/42 days). After 2
courses, CT showed a complete response of the peritoneal
dissemination. However, at the same time peripheral neuropathy
appeared, which was aggravated to grade III at the 6th course.
726
Beginning with the 7th course, lafutidine (10 mg/day) for peripheral
neuropathy was administered, which recovered to grade I after 14
days of lafutidine administration. Lafutidine was administered until
July 2008, when peripheral neuropathy kept grade I without lafutidine.
After 9 courses, paclitaxel therapy failed because of general fatigue
(5).
This study identified 2 compounds, lithium and ibudilast,
administered as a single prophylactic injection prior to paclitaxel
treatment, to prevent the development of CIPN in mice at the sensory-
motor and cellular level. The prevention of neuropathy was not
observed in paclitaxel-treated mice that were only prophylactically
treated with a vehicle injection. The coadministration of lithium with
paclitaxel allows for administration of higher doses of paclitaxel
(survival increases by 60%), protects against paclitaxel-induced
cardiac abnormalities, and, notably, does not interfere with the
antitumor effects of paclitaxel. Lithium and ibudilast inhibit
development of peripheral neuropathy by disrupting the interaction
between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the
inositol 1,4,5-trisphosphate receptor to prevent treatment-induced
decreases in intracellular calcium signaling. This study shows that
lithium and ibudilast are candidate therapeutics for the prevention of
paclitaxel-induced neuropathy and could enable patients to tolerate
more aggressive treatment regimens (6).
A RCT was performed to assess the efficacy and safety of vitamin
E supplementation for prophylaxis against paclitaxel-induced
peripheral neuropathy. Thirty-two patients undergoing 6 courses of
paclitaxel-based chemotherapy were randomly assigned to receive
either chemotherapy with vitamin E (300 mg twice a day, Group I) or
chemotherapy without vitamin E supplementation (Group II). A
detailed neurological examination and electrophysiological study was
performed during and 3 months after chemotherapy. The severity of
paclitaxel-induced peripheral neuropathy was summarized by means
of a modified Peripheral Neuropathy score. The incidence of
neurotoxicity differed significantly between groups, occurring in 3/16
(18.7%) patients assigned to the vitamin E supplementation group and
in 10/16 (62.5%) controls (p=0.03). The RR of developing paclitaxel-
induced peripheral neuropathy was significantly higher in controls
than in vitamin E group patients (RR=0.3, 95% CI 0.1-0.9). Mean
peripheral neuropathy scores were 2.25 +/- 5.1 (range 0-15) for
patients in Group 1 and 11 +/- 11.63 (range 0-32) for those in Group 2
(p=0.01). Vitamin E supplementation was well tolerated and showed
an excellent safety profile. This study shows that vitamin E effectively
727
and safely protects patients with cancer from the occurrence of

paclitaxel-induced peripheral nerve damage (7).
Melatonin has neuroprotective effects in animal studies and has
been suggested to decrease adverse reactions of chemotherapy
including neuropathy. This pilot trial aimed at assessing whether
melatonin, given during taxane chemotherapy for breast cancer, will
decrease the incidence and/or severity of neuropathy. Twenty-two
consecutive patients beginning chemotherapy for breast cancer with
paclitaxel, or docetaxel were enrolled. Patients received melatonin 21
mg daily at bedtime. Incidence and severity of neuropathy were
assessed using neurological examinations, toxicity assessment per
NCI-CTC 3.0 scale and FACT-Taxane QOL questionnaire.
Neuropathy was seen in 45% (n=10) of patients, 23% (n=6) grade I
and 22% (n=5) grade II neuropathy. No grade III neuropathies were
reported. The majority (55%) of all patients reported no neuropathy.
Compliance with melatonin (> 60% of dose) was seen in most patients
(86%) No patient reported daytime sedation. The median FACT-
Taxane QOL end of study score was 137, with only a 0.5 median
decline from baseline. In conclusion, patients receiving melatonin
during taxane chemotherapy had a reduced incidence of neuropathy.
Melatonin may be useful in the prevention or reduction of taxane-
induced neuropathy and in maintaining QOL (8).
In this non-randomized study, neurologic signs and symptoms, and
changes in nerve-conduction studies in 46 consecutive patients given
high-dose paclitaxel either with (n=17) or without (n=29) glutamine
were evaluated. Neurological assessments and electrodiagnostic
studies were carried out at baseline and at least 2 weeks (median 32
days) after treatment. Patients who received glutamine developed
significantly less weakness (p=0.02), less loss of vibratory sensation
(p=0.04) and less toe numbness (p=0.004) than controls. The percent
change in the compound motor action potential and sensory nerve
action potential amplitudes after paclitaxel treatment was lower in the
glutamine group, but this finding was statistically insignificant in
these small groups. In conclusion, serial neurologic assessment of
patient symptoms and signs seemed to be a better indicator of a
possible glutamine effect than sensory- or motor-nerve-conduction
studies (9).
References
1. Ito S, Tajima K, Nogawa M, et al. Etodolac, a cyclooxygenase-2 inhibitor,
attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical
allodynia. J Pharmacol Exp Ther. 2012;342(1):53-60.
728
2. Takenaka M, Iida H, Matsumoto S, et al. Successful Treatment by Adding

Duloxetine to Pregabalin for Peripheral Neuropathy Induced by Paclitaxel. Am J
Hosp Palliat Care. 2012 Oct 11. [Epub ahead of print].
3. Nakashima T, Kiba T, Ogawa Y, et al. A case of paclitaxel-induced peripheral
neuropathy successfully treated with pregabalin. Gan To Kagaku Ryoho.
2012;39(9):1443-5.
4. Nakashima T, Kiba T, Ogawa Y, et al. A case of neurotoxicity reduced with
pregabalin in R-CHOP chemotherapy for diffuse large B-cell lymphoma. Gan To
Kagaku Ryoho. 2012;39(5):809-12.
5. Matsumura T, Imamura H, Kishimoto T, et al. A case of paclitaxel-induced
peripheral neuropathy successfully treated by H2-blocker, lafutidine. Gan To Kagaku
Ryoho. 2009;36(9):1565-8.
6. Mo M, Erdelyi I, Szigeti-Buck K, et al. Prevention of paclitaxel-induced
peripheral neuropathy by lithium pretreatment. FASEB J. 2012; 26(11):4696-709.
7. Argyriou AA, Chroni E, Koutras A, et al. Preventing paclitaxel-induced
peripheral neuropathy: a phase II trial of vitamin E supplementation. J Pain Symptom
Manage. 2006;32(3):237-44.
8. Nahleh Z, Pruemer J, Lafollette J, Sweany S. Melatonin, a promising role in
taxane-related neuropathy. Clin Med Insights Oncol. 2010;4:35-41.
9. Stubblefield MD, Vahdat LT, Balmaceda CM. Glutamine as a neuroprotective
agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and
electrophysiologic study. Clin Oncol (R Coll Radiol). 2005;17(4):271-6.
EPOTHILONES
Tubulin polymerization into microtubules is a dynamic process,
with the equilibrium between growth and shrinkage being essential for
many cellular processes. The antineoplastic agent taxol hyperstabilizes
polymerized microtubules, leading to mitotic arrest and cytotoxicity in
proliferating cells. Using a sensitive filtration-calorimetric assay to
detect microtubule nucleating activity, epotheliones A and B as
compounds that possess all the biological effects of taxol both in vitro
and in cultured cells were identified. The epothilones are equipotent
and exhibit kinetics similar to taxol in inducing tubulin polymerization
into microtubules in vitro (filtration, light scattering, sedimentation,
and electron microscopy) and in producing enhanced microtubule
stability and bundling in cultured cells. Furthermore, these 16-
membered macrolides are competitive inhibitors of [3H] taxol
binding, exhibiting a 50% inhibitory concentration almost identical to
that of taxol in displacement competition assays. Epothilones also
cause cell cycle arrest at the G2-M transition leading to cytotoxicity,
similarly to taxol. In contrast to taxol, epothilones retain a much
greater toxicity against P-glycoprotein-expressing multiple drug
resistant cells. Epothilones, therefore, represent a novel structural
class of compounds, the first to be described since the original
729
discovery of taxol, which not only mimic the biological effects of

taxol but also appear to bind to the same microtubule-binding site as
taxol (1).
MTAs, which include vinca alkaloids, taxanes, and the recently
introduced epothilone and ixabepilone, are widely used
chemotherapeutic agents for treatment of patients with cancer. MTAs
interfere with the normal structure and function of microtubules,
leading to cell-cycle arrest and tumor cell death. Microtubule function
is critical to normal neuronal function, thus MTA therapy is
commonly associated with some form of neuropathy. There is poor
agreement between tools for clinical assessment of MTA-associated
peripheral neuropathy, and standardization of grading scales is needed
to reduce variability. For a majority of patients, MTA-associated
neuropathy is mild to moderate in intensity and reversible, but it can
be severe and resolve incompletely. The incidence and severity of
MTA-associated neuropathy is drug, dose, and schedule dependent.
The first-generation vinca alkaloids (e.g., vincristine) are associated
with severe mixed sensory and motor neuropathy, whereas the newer
vinca alkaloids (e.g., vinorelbine, and vinflunine) induce a milder
sensory neuropathy. Taxane-associated sensory neuropathy occurs
more often with standard (polyoxyethylated castor oil-based) and
albumin-bound paclitaxel than with docetaxel. The incidence and
presentation of peripheral neuropathy with ixabepilone, alone or in
combination with capecitabine, are similar to that with taxanes.
Management of neuropathy may involve reducing or delaying the
MTA dose, or in severe persistent or disabling cases discontinuing
treatment. Reversal of neuropathy after dosage intervention appears to
be more rapid with ixabepilone than with other MTAs (2).
MTAs, including taxanes and epothilones, are effective
chemotherapeutic agents for the treatment of many cancers.
Neuropathy is a major AEs of MTA-based chemotherapy, with severe
peripheral neuropathy (grade III or IV) occurring in as many as 30%
of patients treated with a MTA. MTAs-induced neuropathy usually
resolves gradually after cessation of the treatment. The most reliable
method to accurately assess MTAs-induced neuropathy is by clinical
evaluation, although additional techniques are being developed and
evaluated. Among MTAs-induced neuropathy, the most extensively
studied is that induced by taxanes; such a neuropathy usually presents
as sensory neuropathy and is more common with paclitaxel than
docetaxel. The incidence of MTAs-induced neuropathy seems to
depend on the MTA dose per treatment cycle, the schedule of
treatment, and the duration of the infusion. Although there have been
730
several small clinical trials with neuroprotective agents, early

recognition and supportive care are the best approaches for prevention
and management of MTAs-induced neuropathy (3).
Dose-limiting neuropathy is a major AE associated with most of
the microtubule-stabilizing agent-based chemotherapy regimens.
Ixabepilone, a semisynthetic analogue of the natural epothilone B, has
activity against a wide range of tumor types. Peripheral neuropathy,
associated with ixabepilone treatment, is usually mild to moderate,
predominantly sensory and cumulative. Preclinical studies
demonstrate that ixabepilone and taxanes produce a similar
neurotoxicity profile. Databases of phase II/III clinical trials involving
patients receiving ixabepilone as a monotherapy or in combination
with capecitabine for incidences of neuropathy were searched.
Potential risk factors for grade III/IV peripheral neuropathy were
identified by a Cox regression analysis on a dataset of 1,540 patients
with different tumor types across multiple studies. Rates for incidence
of ixabepilone-induced severe peripheral neuropathy (CTCAE grade
III/IV) ranged from 1% in early untreated breast cancer up to 24% in
heavily pretreated metastatic breast cancer; IV peripheral neuropathy
was rare (≤ 1%). Common symptoms included numbness,
paresthesias, and sometimes dysesthesias. Cox regression analysis
identified only preexisting neuropathy as a risk factor for increased
ixabepilone-associated peripheral neuropathy (4).
Some patients who receive an agent that targets microtubules (e.g.,
taxanes, vinca alkaloids, and epothilones) are at risk for encountering
peripheral neuropathy. Some patients are at higher risk than others
based on their chemotherapeutic regimen, pretreatment history, and
comorbidities. When interacting with at-risk patients, nurses should be
alerted for primarily sensory neuropathy that presents as loss of
sensation, numbness, or tingling, beginning at the distal ends of the
extremities and moving proximally with a stocking or glove
distribution. Clinical assessments for neuropathy generally employ
grading scales, questionnaires, quantitative sensory testing, and
psychometric assessments; each has benefits and limitations. Patients
who experience moderate or severe neuropathy may require a dose
reduction or delay until symptoms resolve; these patients may need a
lower dose for the next treatment cycle. No known agents have proven
to prevent or treat severe neuropathy more effectively than regular
neurologic examinations, early intervention, and patient education (5).
Epothilones, belonging to the family of MTAs, prolong remissions
and improved survival in various types of refractory, treatment-
resistant cancer. Ixabepilone (BMS-247550) is the main representative
731
of these compounds. Peripheral neuropathy is a significant toxicity of

epothilones, eventually resulting in dose modification and changes in
the treatment plan. References were identified by searches of PubMed
from 2000 until December 2010 with terms epothilone-induced
peripheral neuropathy. The mechanism underlying epothilone-induced
peripheral neuropathy remains unclear. Damage to the ganglion soma
cells and peripheral axons through disruption of microtubules of the
mitotic spindle and by interference with the axonal transport in the
affected neurons may significantly contribute to the pathogenesis of
epothilone-induced peripheral neuropathy. As a result, epothilones
primarily produce an axonal, dose-dependent, sensory distal
peripheral neuropathy, which is reversible in most cases on
discontinuation of treatment. The incidence of epothilone-induced
peripheral neuropathy is related to risk factors, including cumulative
dose and probably pre-existing neuropathy. To date, apart from the
use of dose reduction and schedule change algorithm, there is no
effective treatment for epothilone-induced peripheral neuropathy (5).
The management of peripheral neuropathy has been primarily
through dose adjustments (dose delays and/or dose reduction).
Patients had resolution of their neuropathy within a median time of 5
to 6 weeks. Peripheral neuropathy is a dose-limiting toxicity
associated with ixabepilone treatment, is reversible in most patients,
and can be managed with dose reduction and delays (6).
References
1. Bollag DM, McQueney PA, Zhu J, et al. Epothilones, a new class of
microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res.
1995;55;2325
2. Carlson K, Ocean AJ. Peripheral neuropathy with microtubule-targeting agents:
occurrence and management approach. Clin Breast Cancer. 2011;11(2):73-81.
3. Lee JJ, Swain SM. Peripheral neuropathy induced by microtubule-stabilizing
agents. J Clin Oncol. 2006;24(10):1633-42.
4. Vahdat LT, Thomas ES, Roché HH, et al. Ixabepilone-associated peripheral
neuropathy: data from across the phase II and III clinical trials. Support Care Cancer.
2012;20(11):2661-8.
5. Argyriou AA, Marmiroli P, Cavaletti G, Kalofonos HP. Epothilone-induced
peripheral neuropathy: a review of current knowledge. J Pain Symptom Manage.
2011;42(6):931-40.
6. Donovan D. Management of peripheral neuropathy caused by microtubule
inhibitors. Clin J Oncol Nurs. 2009;13(6):686-94.
732
ERIBULIN
Chemotherapy-induced neurotoxicity is a significant problem
associated with successful treatment of many cancers. Tubulin is a
well-established target of antineoplastic therapy; however, tubulin-
targeting agents, such as paclitaxel and the newer epothilones, induce
significant neurotoxicity. Eribulin mesylate, a novel microtubule-
targeting analogue of the marine natural product halichondrin B, has
shown antineoplastic activity, with relatively low incidence and
severity of neuropathy, in metastatic breast cancer patients. The
mechanism of CIPN is not well understood. One of the main
underlying reasons is incomplete characterization of pathology of
peripheral nerves from treated subjects, either from patients or
preclinically from animals (1).
Structurally, eribulin is a fully synthetic macrocyclic ketone
analogue of the marine sponge natural product halichondrin B (2,3),
the latter being a potent naturally-occurring mitotic inhibitor with a
unique mechanism of action found in the Halichondria genus of
sponges (4,5). Eribulin is a mechanistically-unique inhibitor of
microtubule dynamics (6,7), binding predominantly to a small number
of high affinity sites at the plus ends of existing microtubules (8).
Eribulin exerts its anticancer effects by triggering apoptosis of cancer
cells following prolonged and irreversible mitotic blockade (9,10).
There is no standard treatment for women with metastatic breast
cancer in whom multiple lines of chemotherapy, including
anthracycline- and taxane-based regimens, have failed. Eribulin is
now authorized for this indication in the European Union. Like
taxanes, eribulin inhibits microtubule function. Initial evaluation is
mainly based on a randomized controlled, but unblinded trial
comparing eribulin with various standard regimens chosen by the
investigators. The median overall survival time was 2.7 months longer
with eribulin (13.2 vs. 10.5 months, a statistically significant
difference), while the time to cancer progression did not differ. The
AE profile of eribulin in this trial was similar to that of taxanes;
neutropenia and peripheral neuropathy were the most frequent AEs.
Several other AEs, including asthenia, loss of appetite and pain, affect
quality of survival. In practice, the benefits of eribulin are uncertain
and are currently outweighed by AEs. It is better to avoid eribulin and
to focus on symptomatic treatment (11).
The main objective of this study was to review the chemistry,
pharmacology, pharmacokinetics, safety, and efficacy of eribulin
(Halaven). A literature search (up to December 2011) using the terms
733
eribulin, Halaven, ER-086526, and E7389 was performed with

PubMed, Google Scholar, selected Ovid bibliography searches, and
the abstract search tool from the American Society of Clinical
Oncology Annual Meetings and the San Antonio Breast Cancer
Symposia. Additional references from the bibliographies of these
articles were also assessed. English-language preclinical and clinical
studies on the chemistry, pharmacology, pharmacokinetics, safety, and
efficacy of eribulin were reviewed. Eribulin is a novel microtubule
inhibitor with a unique mechanism of action, which involves
interaction with a distinct binding site on β-tubulin leading to G(2)/M
phase cell-cycle arrest and apoptosis. Eribulin has been approved by
the Food and Drug Administration for the treatment of metastatic
breast cancer in patients who have been previously treated with an
anthracycline and a taxane. In a pivotal Phase 3 study, conducted in
patients with metastatic breast cancer, eribulin 1.4 mg/m(2),
administered over 2-5 minutes as an intravenous infusion on days 1
and 8 of 21-day cycles, was associated with a significantly increased
median overall survival of 13.1 months compared to the median
overall survival of 10.6 months in the therapy of physician's choice.
Eribulin has also shown activity in Phase 2 studies in other types of
cancers, such as non-small cell lung cancer, prostate cancer, urothelial
cancer, soft tissue sarcomas, and platinum-susceptible ovarian,
fallopian tube, or peritoneal cancers. The most severe (grade III/IV)
AEs associated with eribulin include neutropenia, leukopenia, and
peripheral neuropathy. Common toxicities include fatigue,
neutropenia, alopecia, anemia, and peripheral neuropathy. In
conclusion, eribulin is a promising new cytotoxic chemotherapy agent
due to its ability to treat cancers that are refractory or resistant to other
drugs as well as its manageable toxicity profile (12).
Eribulin (eribulin mesylate) is a non-taxane microtubule dynamics
inhibitor with tubulin-based antimitotic activity and chemotherapeutic
effects. Eribulin is used in the treatment of patients with locally
advanced or metastatic breast cancer who have previously been
treated with at least 2 chemotherapeutic regimens, including an
anthracycline and a taxane. In vitro studies, eribulin displayed
antiproliferative activity against human breast cancer cell lines.
Regression and elimination of breast tumours were observed in human
tumour xenograft models. In the randomized, open-label,
multinational, phase III EMBRACE trial in patients with locally
recurrent or metastatic breast cancer, median overall survival was
significantly longer in patients who received intravenous eribulin
(n=508) [13.1 months] compared with that in patients who received a
734
treatment of physician's choice (n=254) [10.6 months, HR 0.81, 95%

CI 0.66 - 0.99, p=0.041]. Prior to enrolment, study participants had
received between 2 and 5 chemotherapeutic regimens, including an
anthracycline and a taxane. Consistent with the findings of earlier
phase I and II trials, eribulin had a manageable tolerability profile in
the EMBRACE trial. Peripheral neuropathy (incidence 5%) was the
most common AE resulting in the discontinuation of eribulin
treatment. The most common grade III/IV AEs in the eribulin group
were neutropenia, leukopenia, asthenia or fatigue (13).
A recent Phase III RCT compared eribulin mesylate with
physician's treatment of choice in heavily pretreated patients with
metastatic breast cancer, and a survival advantage was observed.
Eribulin is a non-taxane microtubule dynamics inhibitor, approved by
the US FDA in November 2010 for use in patients who previously
received at least 2 prior lines of chemotherapy for metastatic breast
cancer. Phase II and a recent Phase III trial indicated that eribulin is
well tolerated with a predictable safety profile. The most frequent AEs
in patients receiving eribulin were asthenia/fatigue, neutropenia,
alopecia, peripheral neuropathy, and nausea. It represents a new
treatment option in the setting of anthracycline and taxane-refractory
metastatic breast cancer (14).
The current study was conducted to directly compare, in mice, the
neuropathy-inducing propensity of 3 drugs: paclitaxel, ixabepilone,
and eribulin mesylate. Effects of each drug on caudal and digital nerve
conduction velocity, nerve amplitude, and sciatic nerve and DRG
morphology at 0.25 × MTD, 0.5 × MTD, 0.75 × MTD, and MTD were
compared. Paclitaxel and ixabepilone, at their respective MTDs,
produced significant deficits in caudal nerve conduction velocity,
caudal amplitude and digital nerve amplitudes, as well as moderate to
severe degenerative pathologic changes in DRG and sciatic nerve. By
contrast, eribulin mesylate produced insignificant deleterious effects
on any nerve conduction parameter measured and caused milder, less
frequent effects on morphology. These findings indicate that eribulin
mesylate induces less neuropathy in mice than paclitaxel or
ixabepilone at equivalent MTD-based doses (1).
References
1. Wozniak KM, Nomoto K, Lapidus RG, et al. Comparison of neuropathy-
inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res.
2011;71(11):3952-62.
2. Towle MJ, Salvato KA, Budrow J, et al. In vitro and in vivo anticancer
activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res.
2001; 61(3):1013–21.
735
3. Yu MJ, Kishi Y, Littlefield BA. Discovery of E7389, a fully synthetic

macrocyclic ketone analogue of halichondrin B. In Newman DJ, Kingston DGI,
Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor &
Francis. 2005;ISBN 0-8493-1863-7.
4. Hirata Y, Uemura D. Halichondrins - antitumor polyether macrolides from a
marine sponge. Pure Appl. Chem. 1986;58(5):701–10.
5. Bai RL, Paull KD, Herald CL, et al. Halichondrin B and homohalichondrin B,
marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-
based mechanism of action by analysis of differential cytotoxicity data. J. Biol. Chem.
1991;266 (24):15882–9.
6. Okouneva T, Azarenko O, Wilson L, et al. Inhibition of centromere dynamics
by Eribulin (E7389) during mitotic mMetaphase. Mol. Cancer Ther. 2008;7(7):2003–
11.
7. Smith JA, Wilson L, Azarenko O, et al. Eribulin binds at microtubule ends to a
single site on tubulin to suppress dynamic instability. Biochemistry. 2010;49(6):1331–
7.
8. Kuznetsov G, Towle MJ, Cheng H, et al. Induction of morphological and
biochemical apoptosis following prolonged mitotic blockage by halichondrin B
macrocyclic ketone analog E7389. Cancer Res. 2004;64(16):5760-6.
9. Towle MJ, Salvato KA, Wels BF, et al. Eribulin induces irreversible mitotic
blockade: implications of cell-based pharmacodynamics for in vivo efficacy under
intermittent dosing conditions. Cancer Res. 2011;71(2):496-505.
10. Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of
action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol.
Cancer Ther. 2005;4(7):1086-95.
11. No authors listed. Eribulin: Heavily pretreated breast cancer: uncertain
advantages, excessive adverse effects. Prescrire Int. 2012;21(124):37-8.
12. Preston JN, Trivedi MV. Eribulin: a novel cytotoxic chemotherapy agent. Ann
Pharmacother. 2012;46(6):802-11.
13. Perry CM. Eribulin. Drugs. 2011;71(10):1321-31.
14. O'Sullivan Coyne G, Walsh J, Kelly CM. Effectiveness and safety of eribulin
mesylate: a new therapeutic option in the treatment of metastatic breast cancer. Expert
Opin Drug Saf. 2012;11(4):643-50.
THALIDOMIDE
German pharmaceutical company Grünenthal in Stolberg near
Aachen has developed thalidomide. Heinrich Mückter, a former Nazi
Party member and army physician, had headed Grünenthal's research
department since the foundation of the company and was responsible
for inventing thalidomide. During World War II, he had been
responsible at the German Supreme High Command institute for virus
and typhus research in Kraków to produce Rudolf Weigl's vaccine
against epidemic typhus (1).
Thalidomide, launched by Grünenthal on 1 October 1957 (2), was
found to act as an effective tranquilizer and painkiller, and was
736
proclaimed a "wonder drug" for insomnia, coughs, colds, and

headaches. It was an effective antiemetic that had an inhibitory effect
on morning sickness, so thousands of pregnant women took the drug
to relieve their symptoms. At the time of the drug's development,
scientists did not believe that any drug taken by a pregnant woman
could pass the placental barrier and harm the developing fetus (3).
Thalidomide is a drug that, since its development, has made history
in the world of medicine - having been withdrawn and now has
returned with a boom as an anticancer and immunomodulatory drug.
However, its mode of action in various diseases (i.e. different types of
hematologic malignancies, and solid tumors) as well as in various
infections (i.e. pneumonia, tuberculosis, HIV infection etc.) and
related inflammatory conditions is not well understood. As the
immune system plays an important role in the pathogenesis of both
infection-related as well as noninfectious (i.e. cancer) inflammatory
diseases, much research has been done in the past few years to
discover and design better immunomodulatory agents. Such
immunomodulatory agents should be able to target the immune
system in such a way that host suffers minimum damage and normal
function of the immune system remains intact (4).
Thalidomide has immunomodulatory and anti-angiogenic
properties which may underlie its activity in cancer. After its success
in myeloma, it has been investigated in other plasma cell dyscrasias,
myelodysplastic syndromes, gliomas, Kaposi‘s sarcoma, RCC,
advanced breast cancer, and colon cancer. Thalidomide causes
responses in 30–50% of myeloma patients as a single agent, and acts
synergistically with corticosteroids and chemotherapy. Thalidomide
results in the reduction or elimination of transfusion-dependence in
some patients with myelodysplastic syndrome. Responses have been
seen in one-third of patients with Kaposi‘s sarcoma, in a small
proportion of patients with RCC and high-grade glioma, and in some
patients with colon cancer in combination with irinotecan. The drug is
being investigated currently in a number of clinical trials for cancer.
Drowsiness, constipation, and fatigue are common side effects,
whereas peripheral neuropathy and skin rash are seen in one-third. A
minority of patients experience bradycardia. Thrombotic phenomena
are especially common when thalidomide is combined with
chemotherapy. AEs severe enough to necessitate cessation of therapy
are in around 20% of patients. A therapeutic trial of thalidomide is
essential in all patients with relapsed or refractory myeloma (5).
This is the 50(th) anniversary of the discovery that the drug
thalidomide causes birth defects and should therefore be considered as
737
a teratogen. However, despite the existence of several other drugs that

are also human teratogens, thalidomide continues to cause concern
among health professionals as well as the general population. This
drug severely alters the embryo development, the critical period of
gestation and the identification of the real effect of thalidomide. The
proportions of the different types of malformations groups from the
series of patients considered to be affected by thalidomide from the
literature were compared with the proportions of the same
malformations groups in non-exposed infants from the ECEMC. The
aim of the analysis was to calculate the relative frequencies of 13
groups of malformations observed in series of patients exposed to
thalidomide, by comparison with the same groups of defects in 1,491
patients with limb malformations from the ECEMC consecutive
newborn infants non-exposed to thalidomide. The results showed that
the groups with the most classical limb malformations attributed to
thalidomide (phocomelia, and thumb absence/hypoplasia) had a
significantly very higher frequency in exposed cases than in the non-
exposed cases. However, cases presenting with only lower limb
malformations were 3 times less frequent in thalidomide cases than in
those of ECEMC. Other groups presented the same frequency as those
observed in the ECEMC's cases. The results of the 2 last groups
suggest that they were not due to the effect of thalidomide. This drug
caused not all malformations observed in infants prenatally exposed to
thalidomide. The paradox that the «feared» thalidomide drug caused a
great human drama affecting about 10,000 infants and has led to a
formidable contribution to the scientific knowledge, and large range of
therapeutic applications (6).
The main aim of this study was to perform the clinical and
electrophysiological assessment of peripheral sensory nerves in
patients with MM treated with thalidomide. Neurological examination
together with allocation to different groups was performed. Standard
sensory conduction velocity was measured in ulnar and sural nerves.
Quantitative Sensory Testing was used to determine thermal detection
thresholds. Of 27 MM patients and 30 controls examined, all patients
informed about subjective positive sensory symptoms and sensory
deficit of symmetrical, and distal pattern. Electroneurography revealed
axonal and demyelinating abnormalities with dominance of axonal
injury. Warm and heat-pain detection thresholds were elevated, while
threshold for skin cooling was decreased in palm and foot in MM
patients in comparison with controls. There were no differences in the
thresholds for cold-pain detection between examined groups.
Thalidomide-induced sensory neuropathy can appear shortly after the
738
introduction of treatment. Patients with longer duration of treatment or

with higher cumulative dose present higher degree of neuropathy.
Sensory deficit in thalidomide' neuropathy is associated with
dysfunction in A delta and C caliber primary afferent fibers (7).
Diverse mechanisms may be involved in thalidomide-induced
peripheral neuropathy: reduction in nerve blood supply due to the anti-
angiogeneic properties of thalidomide, direct toxic effects of
thalidomide on neurons of the posterior root ganglia or dysregulation
of neurotrophin activity through effects of thalidomide on NFκ-B. In
fact, alteration in the usual process of Wallerian degeneration due to a
reduction in TNF-α, and secondary inhibition of NFκ-B has already
been described. Studies based on sural nerve biopsies have shown
signs of Wallerian degeneration and a selective loss of large diameter
fibers without demyelinization (8). Genetic variations in genes
involved in drugs‘ neurotoxicity are likely to impact on whether an
individual patient will develop this AE. The most significant single
nucleotide polymorphisms associated with thalidomide-induced
peripheral neuropathy were seen in the ADME genes group (drug
Absorption, Distribution, Metabolism and Excretion), ABC,
cytochromes and solute carrier families‘ genes. Significant
associations were also seen in genes involved in neurological system
processes and CNS development (ERBB2, NQO1, MY03A, PPARD,
dopamine beta-hydroxylase, Nerve Growth Factor Receptor,
glutathione S-transferase pi 1, TCF8 and ICF1R) (9).
The neurological complications usually occur after prolonged
exposure: 70% of the patients treated for 12 months will develop
peripheral neuropathy. The clinical manifestations include bilateral
and symmetrical sensory disorders, rarely motor disorders or
dysautonomia. Patients can experience stinging sensations or
numbness (distal paresthesia and hyperesthesia) that initially affect the
toes, sometimes the fingers, and may extend proximally. Trembling is
very common but rarely interferes with daily activities in the initial
stage. Later, the deep vibratory sensitivity and proprioception may be
affected, leading to progressive ataxia, difficulty in walking and
trembling when posture is maintained. From the electrophysiological
standpoint, thalidomide is most frequently reported to cause a length-
dependent axonal neuropathy (10). Symptoms are rather sensory and
affect small and large diameter fibers. Motor impairment is rare but
possible in the most severe cases. However, in motor NES, changes
commonly and frequently developed concurrently with sensory
changes, suggesting that thalidomide frequently causes a sensorimotor
axonal neuropathy by contrast to bortezomib, which causes a
739
predominantly sensory neuropathy. The cardinal sign on NES is a

50% decrease in the sensory nerve action potential amplitude, with
relative conservation of nerve conduction velocities (11).
Whether thalidomide induces a sensory ganglionopathy or a
length-dependent axonal neuropathy is disputed. The effect of age,
gender disease duration, and total cumulative dose on the clinical and
electrophysiologic parameters was examined. Fifteen patients who had
previously received 100 mg/day of thalidomide for the treatment of
MM were evaluated retrospectively. Clinical findings and nerve
conductions studies were evaluated using a modified total neuropathy
scoring system. Sensory symptoms (p=0.033, r=0.552) and objective
sensory findings (p=0.002, r=0.730) worsened with higher
thalidomide doses. There was no effect of age, gender and disease
duration, neither on clinical symptoms and objective findings, nor on
electrophysiologic data. Twelve patients (80%) developed the
electrophysiological findings of neuropathy. Six (40%) had pure
sensory and 4 (26.6%) had sensori-motor peripheral neuropathy, while
4 (26.6%) had carpal tunnel syndrome. Sural sensory nerve action
potential amplitudes were more prominently reduced compared to
sural sensory nerve action potentials obtained from the upper
extremities. Sural sensory nerve action potential amplitude showed a
tendency toward reduction with the total cumulative dose, although it
was statistically insignificant (respectively, p=0.187). Significantly
reduced ulnar peroneal and tibial compound muscle action potential
amplitudes, and slow motor nerve conduction velocities of the ulnar
and peroneal nerves were in the study group compared to reference
norms (p<0.05). In conclusion, thalidomide produces a dose
dependent peripheral neuropathy, mainly localized to the peripheral
nerves in a length dependent manner. The patient must be monitored
closely to prevent irreversible consequences (12).
Thalidomide-induced neuropathy using electrodiagnostic studies
was evaluated prospectively. Sixty-seven men with metastatic
androgen-independent prostate cancer in an open-label trial of oral
thalidomide underwent neurologic examinations and NCS prior to and
at 3-month intervals during treatment. These examinations included
recording of SNAPs from median, radial, ulnar, and sural nerves.
SNAP amplitudes for each nerve were expressed as the percentage of
its baseline, and the mean of the 4 was termed the SNAP index. A
40% decline in the SNAP index was considered clinically significant.
Thalidomide was discontinued in 55 patients for lack of therapeutic
response. Of 67 patients initially enrolled, 24 remained on thalidomide
for 3 months, 8 remained at 6 months, and 3 remained at 9 months.
740
Six patients developed neuropathy. Clinical symptoms and a decline

in the SNAP index occurred concurrently. Older age and cumulative
dose were possible contributing factors. Neuropathy may thus be a
common complication of thalidomide in older patients. The SNAP
index can be used to monitor peripheral neuropathy, but not for early
detection (13).
References
1. Klee E: Das Personenlexikon zum Dritten Reich. Wer war was vor und nach
1945. Fischer Taschenbuch Verlag, Frankfurt am Main ISBN 978-3-596-16048-8.
2005, p. 418.
2. Vijay MV; Kulkarni U, Parmar UI. Thalidomide. Bombay Hospital J.
2008;50(3):442-76.
3. Heaton, C. A. The Chemical Industry. Springer. 1994, p. 40. ISBN 0-7514-
0018-1.
4. Kumar V, Chhibber S. Thalidomide: an old drug with new action. J Chemother.
201;23(6):326-34.
5. Singhal S, Mehta J. Thalidomide in cancer. Biomedicine & Pharmacotherapy.
2002;56:4-12.
6. Martínez-Frías ML. The thalidomide experience: review of its effects 50 years
later. Med Clin (Barc). 2012;139(1):25-32.
7. Bilińska M, Usnarska-Zubkiewicz L, Szymczyk M, et al. Thalidomide-induced
sensory neuropaty in patients with multiple myeloma. Pol Merkur Lekarski.
2011;31(182):86-91.
8. Mileshkin L, Prince HM. The troublesome toxicity of peripheral neuropathy
with thalidomide. Leuk Lymphoma. 2006;47(11):2276-9.
9. Johnson DC. Genetic Variation in ADME Genes is associated with thalidomide
related peripheral neuropathy in multiple myeloma patients. Blood ASH Annual
Meeting. Abstract. 2008;112(11):1675.
10. Giannini F, Volpi N, Rossi S, et al. Thalidomide-induced neuropathy: a
ganglionopathy? Neurology. 2003;60(5):877–8.
11. Mileshkin L, Stark R, Day B, et al. Development of neuropathy in patients
with myeloma treated with thalidomide: patterns of occurrence and the role of
electrophysiologic monitoring. J Clin Oncol.2006;24(27):4507-14.
12. Kocer B, Sucak G, Kuruoglu R, et al. Clinical and electrophysiological
evaluation of patients with thalidomide-induced neuropathy. Acta Neurol Belg.
2009;109(2):120-6.
13. Molloy FM, Floeter MK, Syed NA, et al. Thalidomide neuropathy in patients
treated for metastatic prostate cancer. Muscle Nerve. 2001;24(8): 1050-7.
TREATMENT
Before the sensory peripheral neuropathy becomes painful,
complicated by motor deficiency and interfering with daily activities,
it is necessary to reduce or discontinue thalidomide (1). In contrast to
BIPN, if thalidomide is not interrupted quickly, peripheral neuropathy
741
symptoms can often aggravate and become irreversible. Since the

occurrence of thalidomide induced peripheral neuropathy is not
predictable and a preventive treatment still does not exist, it is
important to minimize other potential risk factors for peripheral
neuropathy such as vitamin B12 deficiency. Vitamin B12 deficiency
occurs in 13.6% of patients with plasma cell dyscrasia (2). Diabetes
must be considered since it predisposes to peripheral neuropathy and
thalidomide has been involved in the aggravation of the glycemic
balance (3). The symptomatic treatment of this peripheral neuropathy
does not differ from that of BIPN.
References
1. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple
myeloma: 10 years later. Blood. 2008;111(8):3968-77.
2. Baz R, Alemany C, Green R, Hussein MA. Prevalence of vitamin B12
deficiency in patients with plasma cell dyscrasias: a retrospective review. Cancer.
2004;101(4):790-5.
3. Pathak RD, Jayaraj K, Blonde L. Thalidomide-associated hyperglycemia and
diabetes: case report and review of literature. Diabetes care. 2003;26(4):1322-3.
PROTEASOME INHIBITORS
BORTEZOMID/CARFILZOMIB
Bortezomib (INN, originally codenamed PS-341; marketed as
Velcade by Millennium Pharmaceuticals) is the first therapeutic
proteasome inhibitor to be tested in humans. It is approved in the US
for treating relapsed MM (1) and mantle cell lymphoma. In MM,
complete clinical responses have been obtained in patients with
otherwise refractory or rapidly advancing disease (1).
BIPN occurred in 37-44% of clinical trial patients with MM, with
the cumulative treatment dose as its single most significant predictor.
Lower rates of BIPN are observed during treatment of solid tumors
compared with rates of hematologic cancers (2).
BIPN can be worse in patients with pre-existing neuropathy. In
addition, myelosuppression causing neutropenia and
thrombocytopenia can also occur and be dose limiting. However,
these side effects are usually mild relative to bone marrow
transplantation and other treatment options for patients with advanced
742
disease. Bortezomib is associated with a high rate of shingles (3),

although prophylactic acyclovir can reduce the risk of this (4).
A model of painful BIPN in the rat was developed and
mitochondrial function (respiration and ATP production) was assessed
in sciatic nerve samples harvested at 2 time points: day 7, which is 3
days after treatment and before pain appears, and day 35, which is 1
month post-treatment and the time of peak pain severity. Significant
deficits in Complex I-mediated and Complex II-mediated respiration
were found, and in ATP production at both time points. Prophylactic
treatment with acetyl-l-carnitine, which has been shown to prevent
paclitaxel- and OXL-induced mitochondrial dysfunction and pain,
completely blocked bortezomib's effects on mitochondria and pain.
These results suggest that mitotoxicity may be the core pathology for
all CIPN and drugs that protect mitochondrial function may be useful
chemotherapy adjuncts (5).
Bortezomib (Velcade), a dipeptide boronate 20S proteasome
inhibitor and an approved treatment option for MM, is associated with
a treatment-emergent, painful peripheral neuropathy in more than 30%
of patients. Carfilzomib, a tetrapeptide epoxyketone proteasome
inhibitor, currently in clinical investigation in MM, is associated with
low rates of peripheral neuropathy. Neurodegenerative effects of
proteasome inhibitors were assessed in an in vitro model utilizing a
differentiated neuronal cell line. Secondary targets of both inhibitors
were identified by a multifaceted approach involving candidate
screening, profiling with an activity-based probe, and database
mining. Secondary target activity was measured in rats and patients
receiving both inhibitors. Despite equivalent levels of proteasome
inhibition, only bortezomib reduced neurite length, suggesting a
nonproteasomal mechanism. In cell lysates, bortezomib, but not
carfilzomib, significantly inhibited the serine proteases cathepsin G
(CatG), cathepsin A, chymase, dipeptidyl peptidase II, and HtrA2/Omi
at potencies near or equivalent to that for the proteasome. Inhibition of
CatG was detected in splenocytes of rats receiving bortezomib and in
peripheral blood mononuclear cells derived from bortezomib-treated
patients. Levels of HtrA2/Omi, which is known to be involved in
neuronal survival, were upregulated in neuronal cells exposed to both
proteasome inhibitors but was inhibited only by bortezomib exposure.
These data show that bortezomib-induced neurodegeneration in vitro
occurs via a proteasome-independent mechanism and that bortezomib
inhibits several nonproteasomal targets in vitro and in vivo, which
may play a role in its clinical adverse drug reaction profile (6).
743
Peripheral neuropathy is a significant toxicity of bortezomib,

requiring dose modification and potential changes in the treatment
plan when it occurs. Metabolic changes resulting from the
accumulation of bortezomib in the DRG cells, mitochondrial-mediated
disregulation of calcium (++) homeostasis, and disregulation of
neurotrophins contribute to the pathogenesis of BIPN. BIPN may
have a proteasome inhibitor class effect, producing primarily a small
fiber and painful, axonal, sensory distal neuropathy. Incidence of
BIPN is mainly related to various risk factors, including cumulative
dose and evidence of preexisting neuropathy. Assessment of BIPN is
based primarily on neurologic clinical examination and
neurophysiologic methods (7).
Although BIPN is usually easy to diagnose from a clinical point of
view, its pathophysiology remains unclear. BIPN seems to have a
proteasome-inhibitor class effect. In the rat, bortezomib induced a
significant and dose-dependent reduction in the sensory nerve fibers‘
conduction velocities, with recovery taking several weeks (8). Sciatic
nerve examination and morphometric determinations demonstrated
mild to moderate pathological changes, involving predominantly the
Schwann cells and myelin, although axonal degeneration was also
observed. Bortezomib-induced changes were also observed in DRG
neurons and they were represented by satellite cell intracytoplasmatic
vacuolization due to mitochondrial and endoplasmic reticulum
damage, closely resembling the changes observed in sciatic nerve
Schwann cells. In another study, the primary target for proteasome
inhibitor-induced peripheral neuropathy was the DRG neuronal cell
bodies. After proteasome inhibition in vivo, chromatolysis of DRG
neurons was observed, followed by cytoplasmic accumulation of
eosinophilic material. Evidence of neurofilaments and juxtanuclear
electron-dense cytoplasmic deposits was also noted within the DRG
neurons. These lesions were likely related to blood and cellular
proteasome inhibition levels (9). At the molecular level, mitochondrial
and endoplasmic reticulum damage seems to play a key role in BIPN,
since bortezomib is able to activate the mitochondrial-based apoptotic
pathway (10). Co-treatment with a panel of calcium++ modulating
agents identified the mitochondrial uniporter as a critical determinant
in bortezomib cytotoxicity, suggesting that mitochondrial mediated
dysregulation of calcium++ homeostasis is a critical regulator of
bortezomib cytotoxicity (11). Proteasome inhibitors increase tubulin
polymerization and stabilization in tissue culture cells. This
microtubule stabilization represents a possible mechanism
contributing to BIPN and cellular toxicity following proteasome
744
inhibition with bortezomib (12). It is recognized that BIPN may be

triggered by some autoimmune or inflammatory factors (13,14).
The clinical profile of BIPN is quite characteristic. Although some
rare cases of sudden polyradiculoneuritis may occur, BIPN typically
occurs within the first treatment cycles with bortezomib, reaches a
plateau around cycle 5, and does not appear to increase thereafter (13,
15). It is more a sensory rather than a motor peripheral neuropathy
(pain, paresthesia, burning sensation, dysesthesia, numbness, and
sensory loss) affecting the feet more than the hands (8). Patients may
present a suppression/reduction in their deep tendon reflexes in
proportion to sensory loss and changes in proprioception and vibratory
sensitivity (15). A significantly elevated touch detection threshold and
slotted pegboard time, impaired sharpness detection, and elevated
thresholds for the detection of skin warming and heat pain are
described. Patients also had increased reports of cold pain, indicating
that BIPN is associated with deficits in all fiber types in sensory
nerves (16). Pain, positive sensory symptoms in a stocking-and-glove
distribution, and proprioception changes usually do not subside
between courses of therapy and may severely affect normal daily
living activities (7). From the electrophysiological standpoint, NCS
predominantly reveals low amplitude of sensory action potentials, in
keeping with a length-dependant, sensory, axonal polyneuropathy,
with predominant small-fiber involvement (17).
Motor impairment is rare, even if the pain and stinging of the
extremities result in a reduction in activity complicating the diagnosis
of pure muscular weakness. However, grade I to III motor neuropathy,
consisting of mild to severe distal weakness in the lower limbs, may
occur in approximately 10% of patients with cases of life-threatening
grade IV motor neurotoxicity (18,19).
In terms of dysautonomic neurotoxicity, orthostatic hypotension
has been reported in about 10% of the patients. The pooled data from
228 patients treated in phase II trials (20,21) revealed
orthostatic/postural hypotension in 27 (12%) patients (4% grade III,
no grade IV). This complication is often dose-dependent and can be
difficult to recognize and manage.
In the present study, of 58 relapsed/refractory MM patients, 35
MM patients were previously treated with Bortezomib and 24 MM
patients were evaluated by a neurologist periodically during BTZ
treatment in order to prevent high-grade BIPN. Seven (29%) patients
in the monitored group and 19 (56%) in the historical cohort
developed BIPN (p=0.044). In the univariate analysis, factors related
to BIPN in the whole series were age, number of vincristine and
745
bortezomib cycles, LDH and neurological monitoring. In multivariate

analysis, absence of neurological monitoring (HR 4.94, 95% CI 1.31-
18.68, p=0.019) and prior treatment with vincristine (HR 1.34, 95%
CI 1.04-1.74, p=0.026) were associated with greater risk of BIPN.
Baseline total neuropathy score-clinical version was a good predictor
of BIPN, with higher risk for patients with the score > 2 (p=0.038).
Neurological monitoring is useful for diminishing BIPN (22).
Carfilzomib is a second-generation proteasome inhibitor with well-
documented clinical activity as a single agent in patients with
relapsed/refractory MM. Carfilzomib can partially overcome
resistance in bortezomib-refractory patients and has significant
efficacy in bortezomib-naïve patients. Responses generally occur
rapidly and are durable in the majority of cases. Carfilzomib can be
safely administered in patients with renal failure and adverse
cytogenetics do not seem to interfere with its activity. Carfilzomib has
the advantage of a favorable safety profile, especially a low incidence
of peripheral neuropathy, which is often the dose-limiting factor in
thalidomide and bortezomib-based regimens. The most frequently
observed high-grade adverse event is cytopenia. However, long-term
tolerability is good with no cumulative toxicity (23).
References
1. Takimoto CH, Calvo E. Principles of Oncologic Pharmacotherapy. In Pazdur R,
Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A
Multidisciplinary Approach. UBM Company. 2008, 11 ed.
2. Cavaletti G, Jakubowiak AJ. Peripheral neuropathy during bortezomib
treatment of multiple myeloma: a review of recent studies. Leuk Lymphoma.
2010;51(7):1178-87.
3. Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-
341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients
with multiple myeloma. Br J Haematol 2005;129(6):755–62.
4. Pour L, Adam Z, Buresova L, et al. Varicella-zoster virus prophylaxis with
low-dose acyclovir in patients with multiple myeloma treated with bortezomib.
Clinical Lymphoma & Myeloma. 2009;9(2):151–3
5. Zheng H, Xiao WH, Bennett GJ. Exp Mitotoxicity and bortezomib-induced
chronic painful peripheral neuropathy. Neurol. 2012 c;238(2):225-34.
6. Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the
proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events.
Clin Cancer Res. 2011;17(9):2734-43.
7. Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral
neuropathy in multiple myeloma: a comprehensive review of the literature. Blood.
2008;112(5):1593-9.
8. Cavaletti G, Gilardini A, Canta A, et al. Bortezomib-induced peripheral
neurotoxicity: a neurophysiological and pathological study in the rat. Exp Neurol.
2007;204(1):317-25.
746
9. Silverman LCL, Kadambi VJ, Decoster R, et al. Model for proteasome

inhibition associated peripheral neuropathy. Toxicologic Pathology [Abstract].
2006;34(989).
10. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and
apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib
and histone deacetylase inhibitors. Clin Cancer Res. 2004; 10(11):3839–52.
11. Landowski TH, Megli CJ, Nullmeyer KD, et al. Mitochondrial-mediated
disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib)
cytotoxicity in myeloma cell lines. Cancer Res. 2005;65(9): 3828-36.
12. Poruchynsky MS, Sackett DL, Robey RW, et al. Proteasome inhibitors
increase tubulin polymerization and stabilization in tissue culture cells: a possible
mechanism contributing to peripheral neuropathy and cellular toxicity following
proteasome inhibition. Cell cycle (Georgetown, Tex). 2008;7(7):940–9.
13. Chaudhry V, Cornblath DR, Polydefkis M, et al. Characteristics of
bortezomib- and thalidomide-induced peripheral neuropathy. J Peripher Nerv Syst.
2008;13(4):275-82.
14. Ravaglia S, Corso A, Piccolo G, et al. Immune-mediated neuropathies in
myeloma patients treated with bortezomib. Clin Neurophysiol.2008;119 (11):2507-12.
15. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics,
and reversibility of peripheral neuropathy during treatment of advanced multiple
myeloma with bortezomib. J Clin Oncol. 2006;24(19): 3113-20.
16. Cata JP, Weng HR, Burton AW, et al. Quantitative sensory findings in
patients with bortezomib-induced pain. J Pain.2007;8(4):296-306.
17. Meisler AI. Bortezomib in multiple myeloma. N Engl J Med. 2003;349(13):
1287–8, author reply.
18. El-Cheikh J, Stoppa AM, Bouabdallah R, et al. Features and risk factors of
peripheral neuropathy during treatment with bortezomib for advanced multiple
myeloma. Clinical Lymphoma & Myeloma. 2008;8(3): 146-52.
19. Gupta S, Pagliuca A, Devereux S, et al. Life-threatening motor neurotoxicity
in association with bortezomib. Haematologica. 2006;91(7):1001.
20. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib
in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609-17.
21. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of
bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004; 127(2):165–72.
22. Velasco R, Petit J, Clapés V, et al. Neurological monitoring reduces the
incidence of bortezomib-induced peripheral neuropathy in multiple myeloma patients.
J Peripher Nerv Syst. 2010;15(1):17-25.
23. Fostier K, De Becker A, Schots R. Carfilzomib: a novel treatment in relapsed
and refractory multiple myeloma.Onco Targets Ther.2012;5:237-44.
TREATMENT
Since BIPN is dose-dependent and often reversible, the use of an
algorithm of modifications for the treatment regimen is required.
BIPN can improve, stabilize or completely resolve in most patients
upon discontinuation or reduction of bortezomib doses after a median
interval of three months (1). However, one should bear in mind that
the median duration of improvement is longer with grade III-IV
747
impairments than with grade I-II impairments. Dose reduction

algorithm, longer intervals between cycles, but also a weekly instead
of a twice-weekly administration schedule, are effective strategies to
prevent aggravation of symptoms. The occurrence of peripheral
neuropathy with pain requires a dose reduction under the classical
dose of 1.3 mg/m2. The beneficial impact of a weekly administration
schedule of bortezomib in terms of BIPN could be shown in the
Spanish multicenter study comparing melphalan and prednisone with
bortezomib vs. VTP (bortezomib-thalidomide-prednisone) (2).
To date, apart from the use of dose reduction and schedule change
algorithm, there is no effective treatment with neuroprotective agents
for BIPD. Analgesics, TCAs, anticonvulsants, and vitamin
supplements have been used as symptomatic treatment against BIPN
with some success (3).
The treatment of BIPN is usually symptomatic. Treatment with
analgesics or anti-depressants may be beneficial (such as
amitriptylline, serotonin uptake inhibitors, duloxetine or AEDs, such
as gabapentine). The use of topical skin agents may be useful in
certain patients (capsaicin cream). Certain authors have used low
doses of vitamin supplements (B6, C, and L-carnitine). However, one
should be cautious since high doses of pyridoxine may induce lesions
of the sensory neurons (especially in case of renal insufficiency or
low-protein diet) (4,5). The use of high doses of vitamin C is also not
recommended since it may interfere with the metabolism of
bortezomib and reduce its efficacy (6,7). Colvin et al. described a case
of a rapid reversal of BIPN by using the topical transient receptor
potential melastatin (TRPM8) receptor activator, menthol (8). In case
of BIPN, first pregabalin 150–600 mg/day should be used for at least
3 months. Gabapentin (300–2,400 mg/day) is another alternative and
the highest tolerated doses should be aimed. In case of failure,
duloxetine (30–60 mg/day) is a valid second-line choice. The use of
tramadol to fight against chronic pain was suggested (9). The patient
is advised to: (i) wear loose-fitting shoes, roomy cotton socks, and
padded slippers; (ii) keep feet uncovered in bed since bedding that
presses down on the toes can add to the problem; (iii) walk to help
blood circulate in the feet, though too much walking or standing can
make the problem worse; and (iv) soak feet in icy water (or the coldest
water available) and massage the feet for temporary pain relief (10).
When considering dysautonomic side effects, especially if
myeloma is complicated by Al amyloidosis, bortezomib should be
used cautiously in patients with a history of syncope, receiving
medications known to be associated with hypotension or who are
748
dehydrated. Management of orthostatic/postural hypotension includes

adjustment of antihypertensive medications, hydration, increased salt
intake, or the administration of corticosteroids with mineralocorticoid
effects. Patients should rise slowly, keep physically active, and drive
vehicles or operate machinery with caution. They should report any
episodes of hypotension or symptoms of light-headedness, dizziness,
or fainting. This symptom may be reduced by concomitant hydration
(500 mL normal saline) with each dose of bortezomib (11).
It is likely that with: (i) a systematic neurological examination at
the beginning of bortezomib treatment (particularly in those patients
who received prior neurotoxic agents such as vincristine, cisplatine or
thalidomide); (ii) compliance with the rules of treatment schedule
modifications for patients presenting de novo peripheral neuropathy or
aggravation of a pre-existing peripheral neuropathy; and (iii) a switch
towards a weekly administration schedule (especially in case of
combinations such as bortezomib, thalidomide and dexamethasone),
the incidence and management of BIPN will be less problematic (10).
Several areas of research are reviewed that may improve the
management of BIPN, including co-therapies with the novel heat
shock protein inhibitor tanespimycin, which appears to reduce the
incidence of BIPN, and recent studies with second-generation
proteasome inhibitors such as carfilzomib and NPI-0052. Adherence
to the NCI dose-modification algorithm is the most effective method
for mitigating BIPN. Reversal of BIPN after treatment cessation
occurs in most cases, but recovery in some patients takes as long as
1.7 years, and some individuals fail to return to baseline neurologic
function. BIPN can cause a significant reduction in QOL, primarily
due to severe treatment-emergent pain (12).
References
1. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics,
and reversibility of peripheral neuropathy during treatment of advanced multiple
myeloma with bortezomib. J Clin Oncol. 2006;24(19):3113–20.
2. Mateos MV. Bortezomib (Velcade)-Melphalan-Prednisone (VMP) Versus
Velcade- Thalidomide-Prednisone (VTP) in Elderly Untreated Multiple Myeloma
Patients: Which Is the Best Partner for Velcade: An Alkylating or An
Immunomodulator Agent. Blood ASH Annual Meeting. Blood. 2008;112(11).
3. Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral
neuropathy in multiple myeloma: a comprehensive review of the literature. Blood.
2008;112(5):1593-9.
4. Levine S, Saltzman A Pyridoxine (vitamin B6) toxicity: enhancement by
uremia in rats. Food Chem Toxicol. 2002;40(10):1449–51.
5. Levine S, Saltzman A. Pyridoxine (vitamin B6) neurotoxicity: enhancement by
protein-deficient diet. J Appl Toxicol. 2004;24(6):497–500.
749
6. Catley L, Anderson KC. Velcade and vitamin C: too much of a good thing?
Clin Cancer Res. 2006;12(1):3–4.
7. Zou W, Yue P, Lin N, et al. Vitamin C inactivates the proteasome inhibitor PS-
341 in human cancer cells. Clin Cancer Res. 2006;12(1):273–80.
8. Colvin LA, Johnson PR, Mitchell R, et al. From bench to bedside: a case of
rapid reversal of bortezomib-induced neuropathic pain by the TRPM8 activator,
Menthol. J Clin Oncol 2008;26(27):4519–20.
9. Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain and
allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain.
1999;83(1):85-90.
10. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new
treatments for multiple myeloma: background and practical recommendations.
Haematologica. 2010;95(2):311-9.
11. San Miguel J, Blade J, Boccadoro M, et al. et al. A practical update on the use
of bortezomib in the management of multiple myeloma. Oncologist. 2006;11(1):51–
61.
12. Cavaletti G, Jakubowiak AJ. Peripheral neuropathy during bortezomib
treatment of multiple myeloma: a review of recent studies. Leuk Lymphoma.
2010;51(7):1178-87.
SURAMIN
Suramin is a polysulfonated polyaromatic symmetrical urea. It is
currently used to treat African river blindness and African sleeping
sickness. Suramin has also been extensively trialed recently to treat a
number of other diseases, including many cancers (1).
Suramin is being used either alone, or in combination with other
chemotherapeutic agents, in the treatment of hormone-refractory or
metastatic prostate cancer. Use of this potentially valuable
chemotherapy is limited by a dose-dependent polyneuropathy. It has
been difficult in human studies to characterize peripheral suramin
toxicity separately from cancer-related neuropathy. To characterize
suramin-induced neuropathy in a rat model, adult rats were given
either a single dose of 500 mg/kg (high dose) or 50 mg/kg (low dose)
weekly suramin for 2 months. Electrophysiology and peroneal/sural
nerve morphometry were performed. In high dose animals, neuropathy
developed within 2 weeks, most severe in the digital sensory
responses (p<0.05) and tail and hind limb compound muscle action
potential (p<0.001). Histologically, there was evidence of axonal
degeneration and axon atrophy. With low dose suramin, the digital
sensory responses (p<0.05) and tail distal sensory and motor responses
(p<0.01) were most severely affected at 2 months. Axonal
degeneration was seen in teased fibers from most animals. With
transmission electron microscopy, there were abundant characteristic
750
lysosomal inclusion bodies in DRG and Schwann cells.

Electrophysiological and histological evidence of peripheral
demyelination was rare, being observed in only one animal. Suramin
induced a length, dose and time-dependent axonal sensorimotor
polyneuropathy associated with axonal degeneration, atrophy, and
accumulation of glycolipid lysosomal inclusions (2).
Suramin is an investigational drug that has shown therapeutic
activity in hormone-refractory metastatic prostate cancer in Phase I/II
trials. Dose-limiting neurotoxicity remains the most serious
complication of suramin treatment. Twenty-two patients who received
suramin in a Phase-I trial underwent baseline and serial follow-up
neurological evaluations consisting of history, examination, nerve
conduction studies and quantitative sensory testing. Suramin was
administered intravenously in escalating dosages by using a 5-day
schedule (repeated monthly), with the dose, determined by a
population pharmacokinetic model, to accomplish 30-min post-
infusion concentrations of 300 micrograms ml-1 (cohort I), 350
micrograms m-1 (cohort II) and 400 micrograms ml-1 (cohort III).
Twelve patients developed a mild, axonal, length-dependent, sensory-
motor poly-neuropathy. Three other patients developed a subacutely
progressive, functionally disabling, demyelinating neuropathy; sural
nerve biopsy in 2 patients showed lymphocytic inflammation. These 3
patients improved after drug discontinuation and plasmapheresis.
Although there was no apparent correlation between the cumulative
dose and the severity of the neuropathy, no patient from cohort I, but
88% of patients from cohorts II and III, developed neuropathy. In
conclusion, when suramin is used at peak concentrations of ≥ 350
micrograms ml-1 its administration is associated with 2 patterns of
neuropathy, a distal axonal neuropathy and an inflammatory
demyelinating neuropathy are partially reversible (3).
The development of a severe polyneuropathy in 4 of 38 patients
who were receiving parenteral suramin therapy for the treatment of
various underlying malignancies is reported. In 2 of these patients, the
neuropathy progressed to generalized flaccid paralysis with bulbar and
respiratory involvement, requiring endotracheal intubation and ICU
monitoring. EMG and NCSs showed evidence of conduction block,
suggestive of a demyelinating polyneuropathy. After several weeks,
both patients improved clinically. The other 2 patients developed a
reversible neuropathy with flaccid paresis of the limbs but without
bulbar or respiratory compromise. No immediate response to
plasmapheresis was noted. All 4 patients demonstrated an elevated
CSF protein in the acute phase of their neuropathy, which declined or
751
returned to normal during recovery. The development of

polyneuropathy correlated with the maximum plasma suramin level,
with an estimated 40% risk of developing neurotoxicity in those
patients whose maximum level was 350 micrograms/ml or greater. No
correlation could be made with the total dose of suramin administered
or with the duration of therapy. Two of these 4 patients manifested
tumor shrinkage while receiving suramin therapy. In conclusion,
suramin, a promising antineoplastic agent, is capable of inducing a
severe sensorimotor polyneuropathy which appears to be related to the
plasma concentration of suramin. Serial measurements of the plasma
concentration during suramin therapy are recommended (4).
A Phase I study of suramin included serial neurologic and
electrophysiologic examinations as part of the safety evaluation. Of all
patients, 6/41 (15%) developed suramin-induced demyelinating
neuropathy which resembled Guillain-Barre syndrome clinically.
There was 1 asymptomatic patient with electrophysiologic
abnormalities suggestive of a demyelinating neuropathy. In addition, 1
patient with mild axonal neuropathy at baseline had deterioration of
his symptoms during suramin treatment. Four asymptomatic patients
developed electrophysiologic findings suggestive of a mild axonal
neuropathy. In conclusion, (1) serial electrophysiologic monitoring is
helpful for early detection of suramin-induced neuropathy; and (2)
fixed dosing schedule of suramin without adaptive control does not
lead to an increased incidence of demyelinating neuropathy when
compared to adaptively controlled dosing schedules (5).
References
1. McGeary RP, Bennett AJ, Tran QB, et al. Suramin: clinical uses and structure-
activity relationships. Mini Rev Med Chem. 2008;8(13):1384-94.
2. Russell JW, Gill JS, Sorenson EJ, et al. Suramin-induced neuropathy in an
animal model. J Neurol Sci. 2001;192(1-2):71-80.
3. Chaudhry V, Eisenberger MA, Sinibaldi VJ, et al. A prospective study of
suramin-induced peripheral neuropathy. Brain. 1996;119 ( Pt 6):2039-52.
4. La Rocca RV, Meer J, Gilliatt RW, et al. Suramin-induced polyneuropathy.
Neurology. 1990;40(6):954-60.
5. Soliven B, Dhand UK, Kobayashi K, et al. Evaluation of neuropathy in
patients on suramin treatment. Muscle Nerve. 1997;20(1):83-91.
To sum up: chemotherapy may cause both peripheral

neurotoxicity, consisting mainly of a peripheral neuropathy, and
central neurotoxicity, ranging from minor cognitive deficits to
encephalopathy with dementia or even coma. Involvement of the
peripheral nervous system manifested as distal peripheral neuropathy
752
results after therapy with the platinum derivates (OXL, cisplatin, and
carboplatin), proteasome inhibitors (bortezomib, and carfilzomib),
microtubule targeting agents (vincristine, taxanes - epothilones,
paclitaxel, docetaxel, and eribulin), thalidomide, and suramine.
A pure sensory and painful neuropathy (cisplatin, OXL, or
carboplatin) or a mixed sensorimotor neuropathy with or without
involvement of the autonomic nervous system (vincristine, taxol, or
suramin) depend on the substance used. Neurotoxicity depends on the
total cumulative dose and the type of drug used.
Neuropathic symptoms include tingling, numbness, impaired
sensory function and pain in hands and feet.
Peripheral neurotoxicity may severely affect the QOL of cancer
patients and cause chronic discomfort.
NEUROTOXICITY OF RADIATION THERAPY

The success of radiation oncology has led to longer patient
survival. This provides a greater opportunity for radiation injuries of
the peripheral nerves to develop. However, peripheral neuropathy in
cancer patients may result from either tumor recurrence or due to RT.
Distinguishing between radiation injury and cancer disease recurrence
as a cause of nerve dysfunction may be difficult (1).
RIPN is a chronic handicap and frightening because progressive
and usually irreversible, usually appearing several years after RT. Its
occurrence is rare but increasing with improved long-term cancer
survival. The pathophysiological mechanisms are not yet fully
understood. Nerve compression by indirect extensive radiation-
induced fibrosis plays a central role, in addition to direct injury to
nerves through axonal damage and demyelination and injury to blood
vessels by ischemia following capillary network failure. There is great
clinical heterogeneity in neurological presentation since various
anatomic sites are irradiated. The well-known frequent form is
radiation-induced brachial plexopathy following breast cancer
irradiation, while tumor recurrence is easier to discount today with the
help of MRI and PET. Radiation-induced brachial plexopathy
incidence is in accordance with the irradiation technique, and ranges
from 66% RIBP with 60Gy in 5Gy fractions in the 1960s to less than
1% with 50Gy in 2Gy fractions today. Whereas a link with previous
RT is forgotten or difficult to establish, this has recently been
facilitated by a posteriori conformal RT with 3D-dosimetric
753
reconstitution: lumbosacral radiculo-plexopathy following testicular

seminoma or Hodgkin's disease misdiagnosed as amyotrophic lateral
sclerosis. Promising treatments via the antioxidant pathway for
radiation-induced fibrosis suggest a way to improve the everyday
QOL of these long-term cancer survivors (2).
Direct or incidental exposure of the nervous system to therapeutic
irradiation carries the risk of symptomatic neurologic injury. CNS
toxicity from radiation includes focal cerebral necrosis,
neurocognitive deficits, and less commonly cerebrovascular disease,
myelopathy, or the occurrence of a radiation-induced neoplasm.
Brachial or lumbosacral plexopathy are the most common syndromes
of radiation toxicity affecting the peripheral nervous system (3).
Radiation injury to peripheral nerve is a dose-limiting toxicity in
the clinical application of IORT, particularly for pelvic and
retroperitoneal tumors. IORT RIPN in humans receiving doses of 20–
25 Gy is manifested as a mixed motor-sensory deficit beginning 6–9
months following treatment. In an experimental study of IORT RIPN
of the lumbro-sacral plexus, an approximate inverse linear relationship
was reported between the intraoperative dose (20–75 Gy range) and
the time to onset of hind limb paresis (1–12 months following IORT).
The principal histological lesion in irradiated nerve was loss of large
nerve fibers and perineural fibrosis without significant vascular injury.
Similar histological changes in irradiated nerves were found in
humans. To assess peripheral nerve injury to lower doses of IORT in
this same large animal model, groups of 4 adult American Foxhounds
(weight 20–25 kg) received doses of 10, 15, or 20 Gy to the right
lumbro-sacral plexus and sciatic nerve using 9 MeV electrons. The
left lumbro-sacral plexus and sciatic nerve were excluded from the
intraoperative field to allow each animal to serve as its own control.
Following treatment, a complete neurological examinations, EMG,
and NCSs were performed monthly for 1 year. Monthly neurological
exams were performed in years 2 and 3 whereas EMG and NCSs were
performed every 3 months during this follow-up period. With follow-
up of > 42 months, no dog receiving 10 or 15 Gy IORT showed any
clinical or laboratory evidence of peripheral nerve injury. However,
all 4 dogs receiving 20 Gy developed right hind limb paresis at 8, 9, 9,
and 12 months following IORT. These experimental data suggest that
intraoperative doses of < 20 Gy may not result in clinically significant
peripheral nerve injury with follow-up of 3.5 years. Longer (5 years)
follow up with planned sacrifice of the remaining dogs is scheduled to
assess any late peripheral nerve damage (4).
754
Radiation-induced pain syndromes such as myelopathy, which is

characterized by damage to nerve tracts along the spinal cord and
tissue necrosis or damage, while less common with advances in RT,
are not well described. Refinements in technical applications of X-
rays, CT scans, MRI, PET scans, and electronic portal imaging are
among the improvements in the ability to localize tumors and spare
normal tissue from the effects of radiation exposure (5). Combined
treatment modalities (RT with chemotherapy) minimize the need for
aggressive RT (6). The diagnosis of RT-induced pain syndromes,
specifically myelopathy and other tissue damage, can often be
obscured by the recurrence of tumor in the irradiated area, which can
also cause pain and neurologic impairment (7).
Radiation-induced neuropathies are characterized by their
heterogeneity in both symptoms and disease course. Signs and
symptoms depend on the affected structures of the peripheral nerve
system (nerve roots, nerve plexus or nerve trunks). Early-onset
complications are often transient and late complications are usually
progressive and associated with a poor prognosis. The most frequent
and well known is delayed radiation-induced brachial plexopathy,
which may follow breast cancer irradiation. Radiation-induced
lumbosacral radiculoplexopathy is characterized by pure or
predominant lower motor neuron signs. They can be misdiagnosed,
confused with amyotrophic lateral sclerosis or with leptomeningeal
metastases since nodular MRI enhancement of the nerve roots of the
cauda equina and increased CSF protein content can be observed. In
the absence of specific markers of the link with RT, the diagnosis of
post-radiation neuropathy may be difficult. Recently, a posteriori
conformal RT with 3D dosimetric reconstitution has been developed
to link a precise anatomical site to unexpected excess irradiation. The
importance of early diagnosis of RIPN is underscored by the
emergence of new disease-modifying treatments. Although the
pathophysiology is not fully understood, it is possible to target
radiation-induced fibrosis and associated factors such as ischemia,
oxidative stress and inflammation. A phase III trial evaluating the
association of pentoxifylline, tocopherol and clodronate
(PENTOCLO, NCT01291433) in RIPN is recruiting (8).
Limited information is available about nerve damage with early
use of RT; however, one study of 71 cancer survivors treated between
1963 and 1965 found that 92% experienced paralysis of the affected
arm up to 34 years after radiation (9). By tracking the time course for
late effects, these investigators documented 86% patients with fibrosis
and 14% who had already developed brachial plexus neuropathy at 2
755
years after treatment. Nineteen percent experienced grade III to IV

pain (on a scale of 0, no pain, to 4, very severe pain) an average of 3.1
years following therapy. A case report described a patient with severe
cervical neuropathy 3 decades after being treated for Hodgkin
lymphoma (10).
A 60-year-old female was presented with right upper limb weakness 18

months after radiation therapy for breast cancer. Coronal fat-suppressed T2W
image (A) shows radiation plexopathy appearing as an abnormal thickening,
and increased signal in the right brachial plexus (arrow). Sagittal T1W image
(B) shows radiation-induced fat marrow replacement in the cervical vertebrae
(arrows).
Between April 1981 and July 1984, 51 patients received IORT as a

component of therapy for the management of primary or recurrent
pelvic malignancies which were initially unresectable for cure. For
these patients, curative surgical alternatives did not exist, or would
have involved extensive procedures such as pelvic exenteration, distal
sacrectomy, hemipelvectomy, or hemicorporectomy. The primary
disease was colorectal in 38 patients. Treatment consisted of external
beam radiation (range 3000 to 6890 cGy, median 5040 cGy), surgical
debulking when feasible, and an intraoperative electron beam boost to
the gross or microscopic residual disease (dose range 1000 to 2500
cGy, median 1750 cGy) utilizing 9-18 MeV electrons. The most
common IORT associated toxicities were peripheral neuropathy and
ureteral obstruction. None was life threatening or fatal in severity. Of
the 50 patients evaluable for neurotoxicity analysis, 16 (32%)
developed peripheral neuropathy consisting of pain in 16 patients,
numbness and tingling in 11, and weakness in 8. The pain, numbness
and tingling resolved in about 40% of patients, while weakness
resolved in only 1 of 8. Sixteen ureters were initially unobstructed by
tumor at the time of IORT. Of these, 10 (63%) subsequently showed
evidence of obstruction and hydronephrosis. The development of
neurotoxicity was more common at IORT doses of 1500 cGy or more
756
vs. 1000 cGy. Ureteral obstruction with hydronephrosis occurred more

frequently at IORT doses of 1250 cGy or more compared to 1000
cGy. There was no relationship between the likelihood of developing
complications and the total external beam dose. The observed
dependence of human nerve toxicity primarily on the IORT dose is
consistent with data generated from animal experiments (11).
The physiopathology of peripheral nerve injury after RT remains
unclear. Vascular alterations play an important role. Direct damage to
axon or Schwann cell and nervous compression in areas of radiation
fibrosis could also be involved. Clinically, brachial plexopathy is a
well-recognized complication but all the structures of the peripheral
nervous system can be involved: cranial nerves, roots, plexus and
nerve trunks. A syndrome of early and reversible plexopathy differs
from the classical progressive form with pejorative outcome.
Radiation-induced peripheral nerve tumors are infrequent (12).
Radiation-induced brachial plexopathy, especially the chronic and
progressive form, has become an increasingly rare entity in patients
receiving RT to the chest wall and axilla. However, for the patients
affected by this pathologic process, the chronic pain, decline in
function, and absence of a satisfactory treatment are a continuing
challenge to the reconstructive peripheral nerve surgeon (13).
Radiation myelopathy is a relatively rare disorder characterized by
white matter lesions of the spinal cord resulting from irradiation. It is
divided into 2 forms by the latent periods: transient radiation
myelopathy and delayed radiation myelopathy. The delayed radiation
myelopathy develops usually non-transverse myelopathy symptoms
such as dissociated sensory disturbance, unilateral leg weakness, and
gait disturbance with asymmetric steps. Spinal MRI shows initially
cord swelling and long T1/T2 intramedullary lesion with
enhancement, then exhibits cord atrophy. Histopathological findings
of delayed radiation myelopathy are white matter necrosis,
demyelination, venous wall thickening and hyalinization. Glial theory
and vascular hypothesis have been proposed to explain its
pathophysiology. Several therapies such as adrenocorticosteroid,
anticoagulation and hyperbaric oxygen have been tried to this disease
with variable benefits. Radiation plexopathy is classified into 2 major
types by the location: radiation-induced brachial plexopathy and
radiation-induced lumbosacral plexopathy. The brachial plexopathy
initially emerges as arm and shoulder pain, whereas lumbosacral
plexopathy as leg weakness. Myokymia and fasciculations are
observed in both types. Electrophysiological study reveals findings of
peripheral neuropathy. It is often difficult to distinguish the radiation
757
plexopathy from cancer invasion to the plexus, and MRI is useful to

differentiate between these diseases. Pathological findings are small
vessel obstruction, thick fibrosis, axonal degeneration and
demyelination. In its assumed pathomechanism, radiation-induced
fibrous tissue compresses the nerve root as well as microvascular
obstruction of the nerve. Adrenocorticosteroid and anticoagulation are
considered as the strategy for symptomatic relief (14).
Assessment: RIPN is a chronic handicap and frightening

conditions because it is progressive and usually irreversible, appearing
several years after RT. Peripheral neuropathy in cancer patients may
result from either tumor recurrence or due to RT. Distinguishing
between radiation injury and cancer disease recurrence as a cause of
nerve dysfunction may be difficult.
RIPNs are characterized by their heterogeneity in both symptoms
and disease course. Signs and symptoms depend on the affected
structures of the peripheral nerve system (nerve roots, nerve plexus or
nerve trunks). Early-onset complications are often transient and late
complications are usually progressive and associated with a poor
prognosis. The most frequent is delayed radiation-induced brachial
plexopathy, which may follow breast cancer irradiation. Radiation-
induced lumbosacral radiculoplexopathy is characterized by pure or
predominant lower motor neuron signs. Direct damage to axon or
Schwann cell and nervous compression in areas of radiation fibrosis
could also be involved.
CNS toxicity from radiation includes focal cerebral necrosis,
neurocognitive deficits, and less commonly cerebrovascular disease,
myelopathy, or the occurrence of a radiation-induced neoplasm.
Radiation myelopathy is a relatively rare disorder characterized by
white matter lesions of the spinal cord resulting from irradiation. It is
divided into 2 forms by the latent periods: transient radiation
myelopathy and delayed radiation myelopathy. In the delayed
radiation myelopathy, non-transverse myelopathy symptoms such as
dissociated sensory disturbance, unilateral leg weakness, and gait
disturbance with asymmetric steps develop.
References
1. Ljiljana V. Radiation-induced peripheral neuropathies: Etiopathogenesis, risk
factors, differential diagnostics, symptoms and treatment. Arch Oncol. 2007;15(3-4),
81-4.
2. Delanian S, Lefaix JL, Pradat PF. Radiation-induced neuropathy in cancer
survivors. Radiother Oncol. 2012;105(3):273-82.
3. Dropcho EJ. Neurotoxicity of radiation therapy. Neurol Clin. 2010; 28(1):217-
34.
758
4. Kinsella TJ, Deluca AM, Barnes M, et al. Threshold dose for peripheral
neuropathy following intraoperative radiotherapy (IORT) in a large animal model. Int
J Radiat Oncol Biol Phys. 1991;20(4):697-701.
5. Bucci MK, Bevan A, Roach M 3rd. Advances in radiation therapy:
conventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J Clin 2005;55(2):117-
34.
6. Gordils-Perez J, Rawlins-Duell R, Kelvin JF. Advances in radiation treatment
of patients with breast cancer. Clin J Oncol Nurs.2003;7(6):629-36.
7. Azinovic I, Calvo FA, Puebla F, et al. Long-term normal tissue effects of
intraopera-tive electron radiation therapy (IOERT): late sequelae, tumor recurrence,
and second malignancies. Int J Radiat Oncol Biol Phys 2001;49(2):597-604.
8. Pradat PF, Maisonobe T, Psimaras D, et al. Radiation-induced neuropathies:
Collateral damage of improved cancer prognosis. Rev Neurol (Paris).
2012;168(12):939-50.
9. Johansson S, Svensson H, Denekamp J. Timescale of evolution of late radiation
injury after postoperative radiotherapy of breast cancer patients. Int J Radiat Oncol
Biol Phys. 2000;48(3):745-50.
10. McFarlane VJ, Clein GP, Cole J, et al. Cervical neuropathy following mantle
radiotherapy. Clin Oncol (R Coll Radiol) 2002; 14(6):468-71.
11. Shaw EG, Gunderson LL, Martin JK, et al. Peripheral nerve and ureteral
tolerance to intraoperative radiation therapy: clinical and dose-response analysis.
Radiother Oncol. 1990;18(3):247-55.
12. Pradat PF, Poisson M, Delattre JY. Radiation-induced neuropathies.
Experimental and clinical data. Rev Neurol (Paris). 1994;150(10):664-77.
13. Schierle C, Winograd JM. Radiation-induced brachial plexopathy: review.
Complication without a cure. J Reconstr Microsurg. 2004;20(2):149-52.
14. Shimazaki H, Nakano I. Radiation myelopathy and plexopathy. Brain Nerve.
2008;60(2):115-21.
759
APPROACH TO A PATIENT WITH

CANCER PAIN
Approximately 60% of cancer patients experience pain and 25-
30% have severe pain (1). Pain affects up to 50% of patients
undergoing active cancer treatment and up to 90% of those with
advanced disease. Although adequate relief can be achieved in the
majority of cancer patients, pain is often treated inadequately in
traditional settings and sometimes even under the management of
more specialized units. The evaluation and diagnosis of pain
syndromes and the principles of management is in keeping with
increasing recognition by bodies such as the WHO and other
governmental agencies that have recognized the importance of pain
management as part of routine cancer care. Conducting a
comprehensive assessment, competently providing analgesic drugs
and communicating with the patient and family allow effective
management of pain in the cancer patient (2).
For many cancer survivors, disease-related long-term morbidities
and the application of advanced cancer treatments have resulted in the
development of a chronic pain state. Poorly treated acute pain can lead
to protracted pain conditions; acute pain should be recognized and
treated promptly, both for short- and long-term gain. In the short term,
better acute pain treatment can improve functionality and
psychological well-being, whereas in the long term, it could prevent
future chronic pain (3).
Pain management in end-of-life care presents a unique set of
opportunities for patients and physicians. Physicians will encounter
patients at the end of life regardless of type of specialty practice.
Symptom relief is the concern of all physicians. Knowledge of "total
pain" concepts along with basic end-of-life pain management offers
much to patients and their families. Osteopathic principles and
treatment philosophy complement quality pain management in end-of-
life care. Physicians providing supportive care can assist patients and
their families with comfort at the end of life. Good pain management
at the end of life enhances the patient-physician relationship (4).
This prospective, cross-sectional study aimed to assess cancer pain
and its management in an inpatient setting at a comprehensive cancer
centre in Denmark. Inpatients with cancer (n=188) were invited to
participate (May/June 2011). Demographics, diagnoses, WHO
performance status, HRQL, pain and data regarding analgesic
treatment were registered. Of all patients, 134 (71.3%) agreed to
participate in the study. Most frequent diagnoses were leukemia
760
(27.6%) and lung cancer (14.2%). A high prevalence of pain was

observed, 65.7%. Moderate to severe pain when it was at its worst
reported 32%, 96% noted no or mild pain when it was at its least.
Nearly 22% reported moderate to severe pain when the pain was
categorized as average. BTP episodes were reported by 30.5%.
Adjuvant medication was sparsely used and not always correctly
indicated. Out of 88 patients with pain, 62.5% were left untreated
according to the Electronic Medication System. HRQL was associated
with lower pain intensity. The use of opioids with or without
adjuvants was associated with higher pain intensity and higher number
of BTP episodes (5).
References
1. Davis MP, Lasheen W, Gamier P. Practical guide to opioids and their
complications in managing cancer pain. What oncologists need to know. Oncology
(Williston Park). 2007;21(10):1229-38; discussion 1238-46, 1249.
2. Bhagat K, Chinyanga HM. Trends in cancer pain management. Cent Afr J Med.
2000;46(2):46-54.
3. Burton AW, Fine PG, Passik SD. Transformation of acute cancer pain to
chronic cancer pain syndromes. J Support Oncol. 2012;10(3):89-95.
4. Leleszi JP, Lewandowski JG. Pain management in end-of-life care. J Am
Osteopath Assoc. 2005;105(3 Suppl 1):S6-11.
5. Kurita GP, Tange UB, Farholt H, et al. Pain characteristics and management of
inpatients admitted to a comprehensive cancer centre: a cross-sectional study. Acta
Anaesthesiol Scand. 2013;57(4):518-25.
761
NON-PHARMACOLOGICAL THERAPY
PSYCHOSOCIAL INTERVENTION
The diagnosis and treatment of cancer are highly stressful
experiences that can profoundly affect emotional and physical well-
being. Hundreds of longitudinal investigations that identify risk and
protective factors for psychological and physical adjustment in adults
living with cancer and numerous randomized controlled psychosocial
intervention trials constitute the relevant knowledge base on factors
that promote QOL and health in this group. A critical step for the
development of maximally effective interventions is to attend the
mechanisms by which interventions achieve their effects. From the
existing conceptual and empirical literature regarding examination of
mediating processes review of 16 RCTs, including evaluations of
mediators, were carried out. The current conceptual and empirical
literature on evaluating mediators of interventions provides robust
rationales and procedures for testing mediators of psychosocial
interventions for adults diagnosed with cancer. Promising classes of
mediators include alterations in cognitions (i.e., expectancies, illness
representations), self-efficacy for using coping strategies and other
skills targeted by the intervention, psychological and physical
symptoms related to cancer (e.g., mood disturbance, pain), and
psychosocial resources (e.g., self-esteem). Focused attention to
mechanisms underlying the efficacy of interventions can help
integrate theory, research, and practice to promote the well-being and
health of individuals with cancer (1).
Pain is one of the most common, burdensome, and feared
symptoms experienced by patients with cancer. American Pain
Society standards for pain management in cancer recommend both
pharmacologic and psychosocial approaches. To obtain a current,
stable, and comprehensive estimate of the effect of psychosocial
interventions on pain, an important clinical topic, a meta-analysis of
RCSs among adult patients with cancer published between 1966 and
2010 was conducted. Three pairs of raters independently reviewed
1,681 abstracts, with a systematic process for reconciling
disagreement, yielding 42 papers, of which 37 had sufficient data for
meta-analysis. Studies were assessed for quality using a modified
seven-item PEDro coding scheme. Pain severity and interference were
primary outcome measures. Study participants (n=4,199) were
primarily women (66%) and white (72%). The weighted averaged
762
effect size across studies for pain severity (38 comparisons) was 0.34
(95% CI 0.23 - 0.46, p<0.001), and the effect size for pain interference
(4 comparisons) was 0.40 (95% CI 0.21 - 0.60, p<0.001). Studies that
monitored whether treatment was delivered as intended had larger
effects than those that did not (p=0.04). In conclusion, psychosocial
interventions had medium-size effects on both pain severity and
interference. These robust findings support the systematic
implementation of quality-controlled psychosocial interventions as
part of a multimodal approach to the management of pain in patients
with cancer (2).
The purpose of this qualitative inquiry was to broaden the context
for understanding perceived control as a concept related to the cancer
pain response in the homecare setting. Ten patient/caregiver dyads
participated in semistructured interviews focused on questions
pertaining to the patients' perceived control over their own pain as
well as the caregivers' control over the patients' pain. Line-by-line
analysis was used to code, categorize, and analyze the data. Six
themes emerged among patients: feeling robbed of the simplest of
tasks and pleasures, the pain is hungry, feeling desperate, the pain is
winning, fatigue/sleep disturbances, and perceived control is soothing.
For the caregivers, 4 main themes emerged: monitoring the suffering,
feeling like an outsider, inability to control the interventions, and
importance of resources. Overall, patients and their caregivers were
eager to discuss how their perceived lack of control over pain affected
their daily lives. The results suggest that perceived control over pain is
an important aspect of the pain response in the homecare setting (3).
Pain is an important problem for patients with cancer and is
particularly important for elderly patients with cancer and their family
caregivers. Increasingly, cancer is managed on an outpatient basis
with pain management responsibility assumed by the family at home.
This study evaluated a structured pain education program that
included 3 components: basic pain management principles and
assessment, pharmacologic interventions, and nondrug treatments.
The pain education intervention was implemented across 3 home
visits with 2 points of follow-up evaluation. Outcomes of the 66
elderly patients with cancer completing the educational program
included measures of QOL, patient knowledge and attitudes regarding
pain, and use of a self-care log to document drug and nondrug
interventions and their effectiveness. Repeated measurement analysis
was used to evaluate the outcomes of the three-part education
intervention. Results indicate an improvement in knowledge and
attitudes regarding pain as well as the use of drug and nondrug
763
interventions. Outcomes of the QOL instrument suggest significant

effect of pain on all aspects of QOL, including physical well being,
psychological well being, social concerns, and spiritual well being.
The pain education intervention provided important support to elderly
patients with cancer and family members at home. Structured pain
education based on an evolving science of pain relief should become a
part of the standard health care for pain management. Improved pain
management includes QOL for the elderly patient with cancer as well
as for family caregivers (4).
A pilot trial was carried out to determine if a focused narrative
interview could alleviate the components of suffering and anxiety and
depression in advanced cancer patients. Patients were invited to
participate in a focused narrative interview and reflect on their
perspectives on their sense of "meaning", regarding suffering and their
psychological, physical, social and spiritual well-being - the emphasis
was on allowing the patient to tell their story. Patients were
encouraged to share what resources they themselves had utilized in
addition to what professional care they may have received to maintain
a sense of well being. Patients with advanced metastatic disease were
recruited from hospices in the North West of England - the only
exclusion criteria were not being able to understand written and
spoken English and a non-cancer diagnosis. At recruitment patients
were asked to complete a NRS for suffering; the Brief Edinburgh
Depression Scale, ESAS, and FACIT Spiritual well being
questionnaire. Demographic information was collected and patients
were randomized to either the intervention arm of the trial or the usual
care arm of the study. Patients in both groups were invited to complete
each measure at 2, 4 and 8 weeks. One hundred people were recruited
into the study - 49 were randomized to intervention group and 51 to
control group. The median age of patients was 66 years age range (31-
89 years) and 68% of patients were female. At baseline, the
electrocorticographic performance of 75% of patients recruited was 1
or 2. The median survival of all patients in the study was 169.5 days
(range 10 days to still alive at end of study). There was insignificant
difference at any time point in scores on suffering measure between
intervention group and control group. At each time point the
intervention demonstrated mean improvement in scores for depression
and anxiety on ESAS - the greatest changes for both depression and
anxiety were seen at 4 weeks. In conclusion, this trial of a focused
narrative intervention demonstrated an improvement in mean changes
in scores for depression and anxiety at 2, 4 and 8 weeks (5).
764
This review aimed to quantify the benefit of patient-based

educational interventions in the management of cancer pain. A
systematic review and meta-analysis of experimentally randomized
and non-randomized controlled clinical trials were identified from 6
databases from inception to November 2007. Two reviewers
independently selected trials comparing intervention (formal
instruction on cancer pain and analgesia on an individual basis using
any medium) to usual care or other control in adults with cancer pain.
Methodological quality was assessed, and data extraction undertaken
by one reviewer with a second reviewer checking for accuracy. Main
outcome measures were effects on knowledge and attitudes towards
cancer pain and analgesia, and pain intensity. Twenty-one trials (19
randomized) totaling 3501 patients met inclusion criteria, and 15 were
included in the meta-analysis. Compared to usual care or control,
educational interventions improved knowledge and attitudes by half a
point on 0-5 PRS (WMD 0.52, 95% CI 0.04 - 1.0), reduced average
pain intensity by over one point on 0-10 PRS (WMD -1.1, -1.8 - -
0.41) and reduced worst pain intensity by just under one point (WMD
-0.78, -1.21 - -0.35). Equivocal evidence for the effect of education
on self-efficacy was found, but insignificant benefit on medication
adherence or on reducing interference with daily activities. Patient-
based educational interventions can result in modest but significant
benefits in the management of cancer pain, and are probably
underused alongside more traditional analgesic approaches (6).
Within the last 2 decades, psychosocial group interventions have
been developed to help cancer patients cope better with the
psychosocial sequelae of cancer diagnosis and treatment. Support
groups include a variety of different approaches some of which focus
on behavioral aspects and symptoms (e.g. pain, fatigue) and some on
the expression of emotions. Most of these support programs are
structured and short-term and include elements such as delivery of
information, emotional and social support, stress management
strategies based on the cognitive behavioral approach and the teaching
of relaxation techniques. Beyond individual therapy, group therapies
can address cancer-related issues to enable patients to gain emotional
support from other patients with similar experiences and to use these
experiences to buffer the fear of dying and the unknown future. One
of the overall therapeutic targets is the promotion of the patient's
individual resources. Therefore, such groups are helpful not only for
the patients, but also for their spouses and other family members, in
relieving the cancer-related distress. In Germany, support groups are
established in rehabilitation clinics as well as outpatient programs and
765
play an important role in palliative and supportive care of cancer

patients. Against the background of changes in the patients' role, the
increasing availability of information technology (e.g. the internet)
and patient advocacy in cancer treatment, support groups may be
understood as a mean of empowerment of the patient. The need for
group interventions such as outpatient programs for cancer patients is
claimed not only by the health professionals but also by the patients
themselves. There is some research emphasizing that avoidance of
feelings, denial of concerns, feelings of helplessness and social
isolation are correlated with poorer health outcome and poorer QOL.
Many empirical studies have provided evidence-based knowledge that
structured group interventions for cancer patients improve
psychological wellbeing, reduce anxiety and depression, and improve
QOL, coping and mental adjustment. Positive effects on survival have
even been reported, but these effects have not yet been proven (7).
This study explored psychosocial and supportive care resource
utilization in a large cancer population at a Canadian tertiary cancer
centre over a 12-month period in a usual care setting. Patients who
were new to the Tom Baker Cancer Centre completed the Distress
Thermometer, the Pain and Fatigue Thermometers, the Psychological
Screen for Cancer (Part C) that measures anxiety and depression, self-
report questions on resources accessed and a demographic form at
baseline, 3, 6 and 12 months. No feedback or specific triage to
services was provided in order to observe usual care practices. A total
of 714 patients provided baseline data with 505 retained at 12 months.
Twenty-four percent indicated they accessed at least one service (e.g.
individual counseling, nutritionist or resource social worker) over the
12 months. Patients who were older, less educated and with lower
income were less likely to access services. People who reported higher
symptom burden were more likely to access services at each time
point. In conclusion, overall levels of access of psychosocial services
were relatively low in this population and varied by socio-
demographic variables and symptom burden. Routine monitoring of
psychosocial, practical and physical concerns is a potential strategy
for targeting individuals who may require additional information or
support in accessing available services to manage their concerns (8).
Cancer patients experience enormous psychological stress in
addition to their physical suffering. Neither disease nor symptom
specific approaches in the conventional Western medical model or
single-modal psychological intervention focusing on stress and
anxiety are sufficient to relieve patients of their pain and trauma
resulting from cancer. Through years of working with Chinese cancer
766
patients and witnessing their growth and resilience, an Eastern Body-

Mind-Spirit Group Intervention model was developed, having a strong
emphasis on turning crisis into opportunities, and growth through
pain. The model blends different intervention approaches, techniques,
and outcome measures from both the East and the West (9).
Pain is one of the most common, burdensome, and feared
symptoms experienced by patients with cancer. American Pain
Society standards for pain management in cancer recommend both
pharmacologic and psychosocial approaches. To obtain a current,
stable, and comprehensive estimate of the effect of psychosocial
interventions on pain-an important clinical topic a meta-analysis of
RCTs among adult patients with cancer published between 1966 and
2010 was conducted. Three pairs of raters independently reviewed
1,681 abstracts, with a systematic process for reconciling
disagreement, yielding 42 papers, of which 37 had sufficient data for
meta-analysis. Studies were assessed for quality using a modified
seven-item PEDro coding scheme. Pain severity and interference were
primary outcome measures. Study participants (n=4,199) were
primarily women (66%) and white (72%). The weighted averaged
effect size across studies for pain severity (38 comparisons) was 0.34
(95% CI 0.23 - 0.4, p <0.001), and the effect size for pain interference
(4 comparisons) was 0.40 (95% CI 0.21 - 0.60, p<0.001). Studies that
monitored whether treatment was delivered as intended had larger
effects than those that did not (p=0.04). In conclusion, psychosocial
interventions had medium-size effects on both pain severity and
interference. These robust findings support the systematic
implementation of quality-controlled psychosocial interventions as
part of a multimodal approach to the management of pain in patients
with cancer (10).
Assessment: mediators of psychosocial interventions for adults

diagnosed with cancer include alterations in cognitions (i.e.,
expectancies, and illness representations), self-efficacy for using
coping strategies and other skills targeted by the intervention,
psychological and physical symptoms related to cancer (mood
disturbance and pain), and psychosocial resources (self-esteem).
Commonly reported concerns of cancer patients include cancer
pain, physical health, finances, the future, low mood and sadness,
anxiety, being slowed down, and not being able to work (and earn).
Pain education intervention provides important support to elderly
patients with cancer and family members. Perceived control over pain
is an important aspect of the pain response in the homecare setting.
767
CBT is related to short-term effects on depression and anxiety and

both short and long-term effects on QOL. Various CBT approaches
can assist cancer survivors in reducing emotional distress and
improving QOL.
References
1. Stanton AL, Luecken LJ, Mackinnon DP, Thompson EH. Mechanisms in
psychosocial interventions for adults living with cancer: opportunity for integration of
theory, research, and practice. J Consult Clin Psychol. 2013;81(2):318-35.
2. Sheinfeld Gorin S, Krebs P, Badr H, et al. Meta-analysis of psychosocial
interventions to reduce pain in patients with cancer. J Clin Oncol. 2012;30(5):539-47.
3. Vallerand AH, Saunders MM, Anthony M. Perceptions of control over pain by
patients with cancer and their caregivers. Pain Manag Nurs. 2007;8(2):55-63.
4. Ferrell BR, Ferrell BA, Ahn C, Tran K. Pain management for elderly patients
with cancer at home. Cancer. 1994;74(7 Suppl):2139-46.
5. Lloyd-Williams M, Cobb M, O'Connor C, et al. A pilot randomised controlled
trial to reduce suffering and emotional distress in patients with advanced cancer. J
Affect Disord. 2012 Dec 6. pii: S0165-0327(12)00766-5.
6. Bennett MI, Bagnall AM, José Closs S. How effective are patient-based
educational interventions in the management of cancer pain? Systematic review and
meta-analysis. Pain. 2009;143(3):192-9.
7. Weis J. Support groups for cancer patients. Support Care Cancer.
2003;11(12):763-8.
8. Waller A, Williams A, Groff SL, e al. Screening for distress, the sixth vital
sign: examining self-referral in people with cancer over a one-year period.
Psychooncology. 2011 Dec 2. doi: 10.1002/pon.2102.
9. Chan CL, Ho RT, Fu W, Chow AY. Turning curses into blessings: an Eastern
approach to psychosocial oncology. J Psychosoc Oncol. 2006;24(4):15-32.
10. Sheinfeld Gorin S, Krebs P, Badr H, et al. Meta-analysis of psychosocial
interventions to reduce pain in patients with cancer. J Clin Oncol. 2012;30(5):539-47.
HYPNOTHERAPY
In the treatment of cancer, particularly when pain is a serious
symptom, psychological support of a patient is important and can, in
fact, facilitate ongoing oncologic treatment. Hypnosis represents a
psychological technique of great potency for reducing pain, increasing
patients' life-enhancing attitudes, and helping patients deal with death
and separation. Ultimately, the value of hypnosis lies in enabling an
individual to potentiate inner capacities for creating psychological
quiescence and physical comfort. For a suffering cancer patient, relief
that comes from within can provide a much-needed experience of
personal efficacy and strength (1).
Hypnosis is extremely valuable in the treatment of cancer patients.
Specific applications include: establishing rapport between the patient
768
and members of the medical health team; control of pain with self-
regulation of pain perception through the use of glove anesthesia, time
distortion, amnesia, transference of pain to a different body part, or
dissociation of the painful part from the rest of the body; controlling
symptoms, such as, nausea, anticipatory emesis, learned food
aversions, etc.; psychotherapy for anxiety, depression, guilt, anger,
hostility, frustration, isolation, and a diminished sense of self-esteem;
visualization for health improvement; and, dealing with death anxiety
and other related issues. Hypnosis has unique advantages for patients
including improvement of self-esteem, involvement in self-care,
return of locus of control, lack of unpleasant side effects, and
continued efficacy despite continued use (2).
Fear of death, pain, or the recurrence of the illness of tumor
patients can narrow their attention to a point where a spontaneous
altered state of consciousness occurs. In these cases, hypnosis either in
formal psychotherapy or embedded into the everyday communication
with the physician can effectively complement other already known
medical and psychological techniques. New studies meeting the most
rigorous methodological standards, new reviews and the
characteristics of hypnosis shown by neuroimaging techniques support
the acceptance of this method. Hypnosis is used and studied with adult
and child tumor patients alike mostly in the areas of anxiety, pain,
nausea, vomiting, QOL, mood amelioration, immune system and hot
flushes. Most of the assays describe hypnosis as an empirically
validated treatment technique that in most cases surpass attention
diversion, coping trainings, cognitive behavior and relaxation
techniques and other regular treatments (3).
The literature supports the benefits of hypnosis for improving QOL
during the course of cancer and its treatment. However, more work
needs to be done to explore the use of hypnosis in survivorship, to
understand the mediators and moderators of hypnosis interventions,
and to develop effective dissemination strategies (4).
Evidence suggests that hypnosis is an effective intervention for
reducing distress, pain and other side effects associated with cancer
and its treatment. This study (n=115) investigated overall intentions to
use hypnosis to control side effects of cancer and its treatment, as well
as demographic predictors of such intentions among healthy
volunteers. Results suggest that the vast majority of participants (89%)
would be willing to use hypnosis to control side effects associated
with cancer treatment. Mean intention levels did not differ by gender,
ethnicity, education or age. In the public, there is a willingness to
consider the use of hypnosis, and willingness is not determined by
769
demographic factors. This broad acceptance of hypnosis argues for

more widespread dissemination (5).
Many patients with cancer often seek some means of connecting
their mental activity with the unwelcome events occurring in their
bodies, via techniques such as imagery and hypnosis. Hypnosis is an
effective method for controlling cancer pain. The techniques most
often employed involve physical relaxation coupled with imagery that
provides a substitute focus of attention for the painful sensation. Other
related imagery techniques, such as guided imagery, involve attention
to internally generated mental images without the formal use of
hypnosis. The most well known of these techniques involves the use
of "positive mental images" of a strong army of white blood cells
killing cancer cells. Despite claims to the contrary, no reliable
evidence has shown that this technique affects disease progression or
survival. Studies evaluating more broadly defined forms psychosocial
support have come to conflicting conclusions about whether or not
these interventions affect survival of cancer patients. However, 10-
year follow-up of a randomized trial involving 86 women with cancer
showed that a year of weekly "supportive/expressive" group therapy
significantly increased survival duration and time from recurrence to
death. This intervention encourages patients to express and deal with
strong emotions and focuses on clarifying doctor-patient
communication. Numerous other studies suggest that suppression of
negative effect, excessive conformity, severe stress, and lack of social
support predict a poorer medical outcome from cancer (6).
This qualitative exploratory study aimed to examine the
contribution of hypnosis to the care of advanced cancer patients.
Results demonstrate that hypnosis is an effective and efficient means
of developing the resources of people suffering from serious illness.
After an average of 4 hypnotherapy sessions, patients reported they
were able to locate previously unexploited resources within
themselves and were able to become autonomous in the use of self-
hypnosis. The major benefit reported concerned a reduction in
anxiety. For patients experiencing anxiety about death, hypnosis
allowed them, within a therapeutic environment perceived as safe, to
explore different facets of their fears and to develop adaptive
strategies. Aside from slight fatigue experienced during the sessions,
no adverse side effects were noted. This study exploring the effects of
hypnosis allowed to identify important benefits for patients suffering
from advanced cancer (7).
The aim of this review was to find the evidence for or against the
use of hypnotherapy in the treatment of symptoms in terminally ill
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adult cancer patients. The title and abstract were evaluated following a
search through Index Medicus/MEDLINE, EMBASE, CINHAHL,
CancerLit, AHMED, Psychinfo, CISCOM, Cochrane and DARE.
Search terms included hypnotherapy, cancer, terminal care and
palliative care. Inclusion criteria included systematic reviews, RCTs,
observational and prospective studies, retrospective surveys, case
studies and reports. A total of 27 papers were evaluated. These papers
comprised a RCT, an observational study, a retrospective
questionnaire and 24 case studies. Hypnotherapy was used to treat a
variety of symptoms, including pain, anxiety and depression (8).
Assessment: hypnosis is extremely valuable in the treatment of

cancer patients, representing a psychological technique of great
potency for reducing pain, increasing patients' life-enhancing
attitudes, and helping patients deal with death and separation.
Hypnotherapy can be used to treat a variety of symptoms,
including pain, anxiety and depression, guilt, anger, hostility,
frustration, isolation, and a diminished sense of self-esteem,
controlling nausea, anticipatory emesis, learned food aversions, and
dealing with death anxiety.
References
1. Barber J, Gitelson J. Cancer pain: psychological management using hypnosis.
CA Cancer J Clin. 1980;30(3):130-6.
2. Levitan AA. The use of hypnosis with cancer patients. Psychiatr Med.
1992;10(1):119-31.
3. Jakubovits E. Possibilities of hypnosis and hypnosuggestive methods in
oncology. Magy Onkol. 2011;55(1):22-31.
4. Montgomery GH, Schnur JB, Kravits K. Hypnosis for cancer care: over 200
years young. CA Cancer J Clin. 2013;63(1):31-44.
5. Sohl SJ, Stossel L, Schnur JB, et al. Intentions to use hypnosis to control the
side effects of cancer and its treatment. Am J Clin Hypn. 2010; 53(2):93-100.
6. Spiegel D, Moore R. Imagery and hypnosis in the treatment of cancer patients.
Oncology (Williston Park).1997;11(8):1179-89; discussion 1189-95.
7. Teike Luethi F, Currat T, et al. Hypnosis as a resource in palliative care. A
qualitative study of the contribution of hypnosis to the care of oncology patients. Rech
Soins Infirm. 2012;110:78-89.
8. Rajasekaran M, Edmonds PM, Higginson IL. Systematic review of
hypnotherapy for treating symptoms in terminally ill adult cancer patients. Palliat
Med. 2005;19(5):418-26.
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COGNITIVE BEHAVIORAL THERAPY

Meta analyses of RCTs of CBT and patient education were
conducted. MEDLINE, PSYCHINFO and the Cochrane Database
were searched from 1993-2004. The effects of individual vs. group
interventions and short (< 8 months) vs. long (> 8 months) term
follow up are also reported. Fifteen studies met quality criteria. Of
1,492 adult cancer survivors with an age range of 18-84 years, 790
were randomly assigned to intervention groups and 702 to control
groups. CBT varied in duration from 4 weekly one-hour sessions to 55
weekly two-hour sessions. Patient education ranged from a single 20-
minute session to 6 weekly one-hour sessions. Follow up ranged from
1 week to 14 months. CBT was effective for depression (ES = 1.2,
95% CI 0.22 - 2.19), anxiety (ES = 1.99, 95% CI 0.69 - 3.31), and
QOL (ES = 0.91, 95% CI 0.38 - 1.44). QOL was improved at both
short (ES = 1.45, 95% CI = 0.43 - 2.47) and long term (ES = 0.26,
95% CI 0.06 - 0.46) follow up. Patient education was not related to
improved outcomes. In conclusion, CBT is related to short-term
effects on depression and anxiety and both short and long-term effects
on QOL. Individual interventions were more effective than group.
Various CBT approaches provided in an individual format can assist
cancer survivors in reducing emotional distress and improving QOL
(1).
This study compared oral mucositis pain levels in 4 groups of
cancer patients receiving bone marrow transplants: (1) treatment as
usual control, (2) therapist support, (3) relaxation and imagery
training, and (4) training in a package of cognitive-behavioral coping
skills which included relaxation and imagery. A total of 94 patients
completed the study which involved 2 training sessions prior to
treatment and twice a week 'booster' sessions during the first 5 weeks
of treatment. Results confirmed the hypothesis that patients who
received either relaxation and imagery alone or patients who received
the package of cognitive-behavioral coping skills would report less
pain than patients in the other 2 groups. The hypothesis that the
cognitive-behavioral skills package would have an additive effect
beyond relaxation and imagery alone was not confirmed. Average
VAS report of pain within the therapist support group was
insignificantly lower than the control group (p=0.103) nor
significantly higher than the training groups. Patient reports of relative
helpfulness of the interventions for managing pain and nausea
matched the results of VAS reports. In conclusion, relaxation and
imagery training reduces cancer treatment-related pain; adding
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cognitive-behavioral skills to the relaxation with imagery does not, on

average, further improve pain relief (2).
The main purpose of this study was to evaluate the feasibility of a
patient-controlled CBT for pain, fatigue, and sleep disturbance during
treatment for advanced cancer and to assess initial efficacy of the
intervention. This study was conducted at outpatient oncology clinics
at a comprehensive cancer center in the Midwestern US. In a one
group pre- and post-test design, 30 adults with advanced (recurrent or
metastatic) CRC, lung, prostate or gynecologic cancer receiving
chemotherapy or RT were included. Participants completed baseline
measures (e.g., demographics, and symptom inventory) and received
education and training to use a media player (MP3) loaded with 12
cognitive-behavioral strategies (e.g., relaxation exercises, guided
imagery, and nature sound recordings). Participants used the strategies
as needed for symptom management for 2 weeks, keeping a log of
symptom ratings with each use. Following the 2-week intervention,
participants completed a second symptom inventory and an evaluation
of the intervention. Thirty of 43 eligible patients (73%) agreed to
participate; of them, 27 (90%) completed the study. Most reported that
they enjoyed the intervention, had learned useful skills, and perceived
improvement in their symptoms. Symptom scores at 2 weeks differed
insignificantly from baseline; however, significant reductions in pain,
fatigue, and sleep disturbance severity were in ratings made
immediately before and after use of a CBT. In conclusion, the patient-
controlled CBT could reduce day-to-day severity of co-occurring pain,
fatigue, and sleep disturbance (3).
Pain, fatigue, and sleep disturbance commonly co-occur in patients
receiving treatment for advanced cancer. A RCT was conducted to
assess initial efficacy of a patient-controlled CBT for the pain, fatigue,
and sleep disturbance symptom cluster. Eighty-six patients with
advanced lung, prostate, colorectal, or gynecologic cancers receiving
treatment at a comprehensive cancer center were stratified by
recruitment clinics (chemotherapy and RT) and randomized to
intervention or control groups. Forty-three patients were assigned to
receive training in and use of up to 12 relaxation, imagery, or
distraction exercises delivered via a media player (MP3) player for 2
weeks during cancer treatment. Forty-three patients were assigned to a
waitlist control condition for the same two-week period. Outcomes
included symptom cluster severity and overall symptom interference
with daily life measured at baseline (Time 1) and 2 weeks later (Time
2). Eight participants dropped out; 78 completed the study and were
analyzed (36 intervention and 42 control subjects). Participants used
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the CBT an average of 13.65 times (SD=6.98). Controlling for

baseline symptom cluster severity and other relevant covariates, the
symptom cluster severity at Time 2 was lower in the intervention
group (M(Adj)=2.99, SE=0.29) than in the waitlist group
(M(Adj)=3.87, SE=0.36), F(1, 65)=3.57, p=0.032. Symptom
interference with daily life did not differ between groups. Significant
AEs were not noted with the CBT. These findings suggest that the
CBT may be an efficacious approach to treating the pain, fatigue, and
sleep disturbance symptom cluster (4).
References
1. Osborn RL, Demoncada AC, Feuerstein M. Psychosocial interventions for
depression, anxiety, and quality of life in cancer survivors: meta-analyses. Int J
Psychiatry Med. 2006;36(1):13-34.
2. Syrjala KL, Donaldson GW, Davis MW, et al. Relaxation and imagery and
cognitive-behavioral training reduce pain during cancer treatment: a controlled
clinical trial. Pain. 1995;63(2):189-98.
3. Kwekkeboom KL, Abbott-Anderson K, Wanta B. Feasibility of a patient-
controlled cognitive-behavioral intervention for pain, fatigue, and sleep disturbance in
cancer. Oncol Nurs Forum. 2010;37(3):E151-9.
4. Kwekkeboom KL, Abbott-Anderson K, Cherwin C, et al. Pilot randomized
controlled trial of a patient-controlled cognitive-behavioral intervention for the pain,
fatigue, and sleep disturbance symptom cluster in cancer. J Pain Symptom Manage.
2012;44(6):810-22.
EXERCISE INTERVENTION
The importance of physical activity for chronic disease prevention
and management has become generally well accepted. The number of
research interventions and publications examining the benefits of
physical activity for patients with cancer has been rising steadily.
However, much of that research has focused on the impact of physical
activity either prior to or early in the cancer diagnosis, treatment, and
survivorship process. Research focusing on the effects of physical
activity, specifically for patients with advanced-stage cancer and
poorer prognostic outcomes, has been addressed only recently. The
purpose of this article is to examine the state of the science for
physical activity in the advanced-stage disease subset of the cancer
population. Exercise in a variety of intensities and forms, including
yoga, walking, biking, and swimming, has many health benefits for
people, including those diagnosed with cancer. For people with cancer
(including advanced-stage cancer), exercise can decrease anxiety,
stress, and depression while improving levels of pain, fatigue,
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dyspnea, constipation, and insomnia. People diagnosed with cancer

should discuss with their oncologist safe, easy ways they can
incorporate exercise into their daily lives (1).
The main objectives of this study were to evaluate the effectiveness
of exercise on overall HRQL and HRQL domains among adult post-
treatment cancer survivors. The Cochrane Central Register of
Controlled Trials (CENTRAL), PubMed, MEDLINE, EMBASE,
CINAHL, PsycINFO, PEDro, LILACS, SIGLE, SportDiscus,
OTSeeker, and Sociological Abstracts from inception to October 2011
with no language or date restrictions were searched. In addition,
citations through Web of Science and Scopus, PubMed's related article
feature, and several websites were searched. Reference lists of
included trials and other reviews in the field were reviewed. All RCTs
and controlled clinical trials comparing exercise interventions with
usual care or other no exercise intervention to assess overall HRQL or
at least one HRQL domain in adults were included. Included trials
tested exercise interventions that were initiated after completion of
active cancer treatment. Trials including people who were terminally
ill, or receiving hospice care, or both, and where the majority of trial
participants were undergoing active treatment for either the primary or
recurrent cancer were excluded. Where the majority of trial
participants were undergoing active treatment for either the primary or
the recurrent cancer were excluded. Five paired review authors
independently extracted information on characteristics of included
trials, data on effects of the intervention and assessed risk of bias
based on predefined criteria. Where possible, meta-analyses results
were performed for HRQL and HRQL domains for the reported
difference between baseline values and follow-up values using SMD
and a random-effects model by length of follow-up. Forty trials with
3694 participants randomized to an exercise (n=1927) or comparison
(n=1764) group. Cancer diagnoses in study participants included
CRC, breast, head and neck, lymphoma, and other. Thirty trials were
conducted among participants who had completed active treatment for
their primary or recurrent cancer and 10 trials included participants
both during and post cancer treatment. Mode of the exercise
intervention included strength training, resistance training, walking,
cycling, yoga, Qigong, or Tai Chi. Results indicated that exercise
compared with control has a positive impact on HRQL and certain
HRQL domains. Exercise improved: global HRQL at 12 weeks' (SMD
0.48, 95% CI 0.16 - 0.81) and 6 months' (0.46, 95% CI 0.09 - 0.84)
follow-up, breast cancer concerns between 12 weeks' and 6 months'
follow-up (SMD 0.99, 95% CI 0.41 - 1.57), body image/self-esteem
775
when assessed using the Rosenberg Self-Esteem scale at 12 weeks

(MD 4.50, 95% CI 3.40 - 5.60) and between 12 weeks' and 6 months'
(MD 2.70, 95% CI 0.73 - 4.67) follow-up, emotional well-being at 12
weeks' follow-up (SMD 0.33, 95% CI 0.05 - 0.61), sexuality at 6
months' follow-up (SMD 0.40, 95% CI 0.11 - 0.68), sleep disturbance
when comparing follow-up values by comparison group at 12 weeks'
follow-up (SMD -0.46, 95% CI -0.72 - -0.20), and social functioning
at 12 weeks' (SMD 0.45, 95% CI 0.02 - 0.87) and 6 months' (SMD
0.49, 95% CI 0.11 - 0.87) follow-up. Exercise interventions resulted in
decreased anxiety at 12 weeks' follow-up (SMD -0.26, 95% CI -0.07 -
-0.44), fatigue at 12 weeks' (SMD -0.82, 95% CI -1.50 - -0.14) and
between 12 weeks' and 6 months' (SMD -0.42, 95% CI -0.02 - -0.83)
follow-up, and pain at 12 weeks' follow-up (SMD -0.29, 95% CI -
0.55 - -0.04) when comparing follow-up values by comparison group.
Positive trends and impact of exercise intervention existed for
depression and body image (when analyzing combined instruments);
however, because few studies measured these outcomes the robustness
of findings is uncertain. No conclusions can be drawn regarding the
effects of exercise interventions on HRQL domains of cognitive
function, physical functioning, general health perspective, role
function, and spirituality. Exercise may have beneficial effects on
HRQL and certain HRQL domains including cancer-specific concerns
(e.g. breast cancer), body image/self-esteem, emotional well-being,
sexuality, sleep disturbance, social functioning, anxiety, fatigue, and
pain at varying follow-up periods (2).
To assess whether a supervised exercise program would benefit
cancer survivors' perceived psychological well-being over the course
of a 6-month program, 8 female and 2 male cancer survivors, aged 45
to 69 years (M=56.2, SD=8.1) were recruited into the program from a
presentation given to a breast-cancer support group and by word of
mouth. Activity sessions were twice per week and typically involved
treadmill and bicycle ergometer time, plus 8 to 10 weight-training
stations. A QOL measure was taken at baseline, 3, and 6 months.
Analyses showed a significant increase in QOL from baseline to 3
months and from baseline to 6 months. Being physically active in a
supervised exercise program provided increased perceived benefits in
QOL for these cancer survivors over 6 months (3).
The purpose of this pilot study was to assess the effects of a
physical exercise program on physical performance and QOL in a
population with incurable cancer and a short life expectancy. Thirty-
four patients participated in a 50-minute group exercise program twice
a week for 6 weeks. Physical performance was measured by 3 tests:
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"6-minute walk test," "timed repeated sit to stand," and "functional

reach." Fatigue was measured by the Fatigue Questionnaire. QOL was
assessed by the European Organization for Research and Treatment of
Cancer Core QOL. The outcome variables were assessed before and
after the intervention. The walk length increased and the "timed
repeated sit to stand" was reduced (p<0.05). Emotional functioning
improved and physical fatigue was reduced (p<0.05). Physical
exercise seems to be a feasible way to improve well-being among
patients with incurable cancer (4).
This review takes into account experimental and clinical evidence
to provide an overview of the rationale for the use of exercise in
cancer cachexia, its clinical application, and future developments.
Studies targeting cachectic patients have demonstrated that even in
advanced disease peripheral muscle has the capacity to respond to
exercise training. Effects of exercise include enhancing muscle protein
synthesis, attenuating the catabolic effects of cachexia, and
modulating levels of inflammation. Nonetheless, there are challenges
in applying therapeutic exercise, particularly once cachexia is
established, not all patients are able or willing to undertake programs
currently being offered. Strategies to make exercise a more accessible
therapy are required and could include offering it earlier in the course
of the disease, at lower intensities, and in various forms, including
novel approaches. In conclusion, the use of therapeutic exercise has a
rationale, even in patients with advanced disease and cachexia has the
potential to help maintain or slow the loss of physical function (5).
Physical exercise can improve cancer patients' functioning and
reduce their symptom levels. A RCT was launched to test the
hypothesis that physical exercise reduces fatigue and improves
physical performance in cancer patients with advanced and incurable
disease. Cancer patients (n=231) with a life expectancy ≤ 2 years were
randomized to a physical exercise group (n=121) or a control usual
care group (n=110). The physical exercise group exercised under
supervision 60 minutes twice a week for 8 weeks. The primary
outcome was physical fatigue measured by the Fatigue Questionnaire.
Physical performance was a secondary outcome measured by the
shuttle walk test and handgrip strength test. Of the physical exercise
group, 36% were lost to follow-up compared with 23% of the control
usual care group, primarily because of disease progression. Seventy-
eight physical exercise group and 85 control usual care group patients
completed the intervention. Analyses showed insignificant effects
between groups in physical fatigue. However, clinically and
statistically significant between-group effects were found for the
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Shuttle Walk Test and handgrip strength test. In conclusion, fatigue

was not reduced but physical performance (shuttle walk test and
handgrip strength test) was significantly improved after 8 weeks of
physical exercise. Physical exercise might therefore be a suitable
approach for maintaining physical capacity in cancer patients with
incurable and advanced disease (6).
The main objective of this study was to assess the effect of a
multimodal group exercise intervention, as an adjunct to conventional
care, on fatigue, physical capacity, general wellbeing, physical
activity, and QOL in patients with cancer who were undergoing
adjuvant chemotherapy or treatment for advanced disease. In this
RCT, carried out in 2 university hospitals in Copenhagen, Denmark,
of 269 patients with cancer, 73 men, 196 women, mean age 47 years
(range 20-65) representing 21 diagnoses, 235 patients completed
follow-up. Main exclusion criteria were brain or bone metastases.
Supervised exercise comprised high intensity C-V and resistance
training, relaxation and body awareness training, massage, 9 hours
weekly for 6 weeks in addition to conventional care compared with
conventional care. Main outcome measures included EORTC QLQ-
C30, Medical Outcomes Study Short Form (MOS SF-36), Leisure
Time Physical Activity Questionnaire, muscular strength (one
repetition maximum), and maximum oxygen consumption
(Vo(2)max). Adjusted for baseline score, disease, and demographic
covariates, the intervention group showed an estimated improvement
at 6 weeks for the primary outcome, fatigue, of -6.6 points (95% CI -
12.3 - -0.9, p=0.02; effect size=0.33, 0.04-0.61). Significant effects
were seen on vitality (effect size 0.55, 95% CI 0.27 - -0.82), physical
functioning (95% CI 0.37, 0.09 - 0.65), role physical (95% CI 0.37,
0.10 - 0.64), role emotional (95% CI 0.32, 0.05 - 0.59), and mental
health (95% CI 0.28, 0.02 - -0.56) scores. Improvement was noted in
physical capacity: estimated MD between groups for maximum
oxygen consumption was 0.16 l/min (95% CI 0.1 - 0.2, p<0.0001) and
for muscular strength (leg press) 29.7 kg (95% CI 23.4 - 34.9,
p<0.0001). Insignificant effect was seen on global health status/QOL.
In conclusion, a supervised multimodal exercise intervention
including high and low intensity components is feasible and can safely
be used in patients with various cancers who are receiving adjuvant
chemotherapy or treatment for advanced disease. In conclusion, the
intervention reduces fatigue and improves vitality, aerobic capacity,
muscular strength, physical and functional activity, and emotional
wellbeing, but not QOL (7).
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The purpose of this study was to compare the effects of supervised-

exercise intervention with those of usual care on cardiorespiratory
fitness, muscle strength, fatigue, emotional distress, sleep quality, and
QOL in patients with CRC undergoing chemotherapy. Patients with
stage II or III CRC admitted for adjuvant chemotherapy were
allocated to either a supervised-exercise group that received a
combined aerobic and resistance exercise program or a "usual care"
control group for 12 weeks. The outcomes, QOL, muscle strength,
cardiorespiratory fitness, emotional distress, physical activity, fatigue,
and sleep quality were assessed at baseline and after intervention.
Significant interactions between intervention and time were observed
for the role functioning and pain subscales of QOL and physical
activity level. The time main effects were significant for the secondary
outcomes: handgrip strength, cardiorespiratory fitness, physical
activity level, and physical functioning, role functioning, social
functioning, fatigue, and pain subscales of QOL. In conclusion,
compared with usual care, the supervised exercise demonstrated larger
effects than usual care on physical activity level and role functioning
and pain subscales of QOL. Supervised-exercise program is suggested
to be incorporated as part of supportive care to promote the
cardiorespiratory fitness, muscle strength, physical activity level, and
QOL of patients with CRC undergoing chemotherapy (8).
Assessment: exercise for people with cancer (including advanced-

stage cancer) can decrease anxiety, stress, and depression, and
improves levels of pain, fatigue, dyspnea, constipation, and insomnia.
Exercise may have beneficial effects on HRQL domains including
cancer-specific concerns (e.g. breast cancer), body image/self-esteem,
emotional well-being, sexuality, sleep disturbance, social functioning,
fatigue, and pain at varying follow-up periods. Being physically active
in a supervised exercise program provides increased perceived
benefits in QOL for cancer survivors over 6 months. Therapeutic
exercise even in patients with advanced disease and cachexia has the
potential to help maintain or slow the loss of physical function.
References
1. Albrecht TA, Taylor AG. Physical activity in patients with advanced-stage
cancer: a systematic review of the literature. Clin J Oncol Nurs. 2012;16(3):293-300.
2. Mishra SI, Scherer RW, Geigle PM. Exercise interventions on health-related
quality of life for cancer survivors. Cochrane Database Syst Rev. 2012 Aug
15;8:CD007566.
3. Wiggins MS, Simonavice EM. Quality of life benefits in cancer survivorship
with supervised exercise. Psychol Rep. 2009;104(2):421-4.
779
4. Oldervoll LM, Loge JH, Paltiel H, et al. The effect of a physical exercise
program in palliative care: A phase II study. J Pain Symptom Manage.
2006;31(5):421-30.
5. Maddocks M, Murton AJ, Wilcock A. Therapeutic exercise in cancer cachexia.
Crit Rev Oncog. 2012;17(3):285-92.
6. Oldervoll LM, Loge JH, Lydersen S, et al. Physical exercise for cancer patients
with advanced disease: a randomized controlled trial. Oncologist. 2011;16(11):1649-
57.
7. Adamsen L, Quist M, Andersen C, et al. Effect of a multimodal high intensity
exercise intervention in cancer patients undergoing chemotherapy: randomised
controlled trial. BMJ. 2009 Oct 13;339:b3410.
8. Lin KY, Shun SC, Lai YH, et al. Comparison of the Effects of a Supervised
Exercise Program and Usual Care in Patients With Colorectal Cancer Undergoing
Chemotherapy. Cancer Nurs. 2013 Jan 25. [Epub ahead of print].
DANCE/MOVEMENT THERAPY
Dance involves the culturally mediated body, emotion, and mind.
So do illness and pain. Dance may promote wellness by strengthening
the immune system through muscular action and physiological
processes. Dance conditions an individual to moderate, eliminate, or
avoid tension, chronic fatigue, and other disabling conditions that
result from the effects of stress. Dance may help the healing process
as a person gains a sense of control through [1] possession by the
spiritual in dance, [2] mastery of movement, [3] escape or diversion
from stress and pain through a change in emotion, states of
consciousness, and/or physical capability, and [4] confronting
stressors to work through ways of handling their effects (1).
Even though the field of medicine has developed tremendously, the
wide variety of cancer is still among chronic and life threatening
disease today. Therefore, the specialists constantly research and try
every possible way to find cure or preventive ways to stop its further
development. For this reason, studies concerning the chronic disease
such as cancer have been spread to many different fields. In this
regard, many other alternative ways besides medicine, are used in
prevention of cancer. Nutritional therapy, herbal therapy, sportive
activities, art therapy, music therapy, dance therapy, imagery, yoga
and acupuncture can be given as examples. Among these,
dance/movement therapy which deals with individuals physical,
emotional, cognitive as well as social integration is widely used as a
popular form of physical activity. The physical benefits of dance
therapy as exercise are well documented. Physical activity is known to
increase special neurotransmitter substances in the brain (endorphins),
780
which create a state of well-being. Total body movement such as

dance enhances the functions of other body systems, such as
circulatory, respiratory, skeletal, and muscular systems. Regarding its
unique connection to the field of medicine, many researchers have
been undertaken on the effects of dance/movement therapy in special
settings with physical problems such as amputations, traumatic brain
injury, and stroke, chronic illnesses such as anorexia, bulimia, cancer,
Alzheimer's disease, cystic fibrosis, heart disease, diabetes, asthma,
AIDS, and arthritis. Today dance/movement therapy is a well
recognized form of complementary therapy used in hospitals as well
as at the comprehensive clinical cancer centers (2).
Current cancer care increasingly incorporates psychosocial
interventions. Cancer patients use dance/movement therapy to learn to
accept and reconnect with their bodies, build new self-confidence,
enhance self-expression, address feelings of isolation, depression,
anger and fear and to strengthen personal resources. The main
objective of this study was to compare the effects of dance/movement
therapy and standard care with standard care alone or standard care
and other interventions in patients with cancer. Search strategy
included the Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library 2011, Issue 2), MEDLINE,
EMBASE, CINAHL, PsycINFO, LILACS, Science Citation Index,
CancerLit, International Bibliography of Theatre and Dance, Proquest
Digital Dissertations, ClinicalTrials.gov, Current Controlled Trials
and the National Research Register (all to March 2011), hand
searched dance/movement therapy and related topics journals,
reviewed reference lists and contacted experts. There was no language
restriction. All randomized and quasi-randomized controlled trials of
dance/movement therapy interventions for improving psychological
and physical outcomes in patients with cancer were included. Two
review authors independently extracted the data and assessed the
methodological quality. Two studies with 68 participants were
included. No evidence was found for an effect of dance/movement
therapy on body image in women with breast cancer. The data of one
study with moderate risk of bias suggested that dance/movement
therapy had a large beneficial effect on participants' QOL. The second
trial reported a large beneficial effect on fatigue. However, this trial
was at high risk of bias. The individual studies did not find support for
an effect of dance/movement therapy on mood, distress, and mental
health. It is unclear whether this was due to ineffectiveness of the
treatment or limited power of the trials. Finally, the results of one
study did not find evidence for an effect of dance/movement therapy
781
on shoulder range of motion or arm circumference in women who

underwent a lumpectomy or breast surgery. However, this was likely
due to large within-group variability for shoulder range of motion and
a limited number of participants with lymphedema. Support was not
found for an effect of dance/movement therapy on body image. The
findings of one study suggest that dance/movement therapy may have
a beneficial effect on QOL. However, the limited number of studies
prevents us from drawing conclusions concerning the effects of
dance/movement therapy on psychological and physical outcomes in
cancer patients (3).
Older breast cancer survivors are at risk for late and long-term
treatment effects on QOL, including lower physical functioning and
fear of recurrence. Two promising approaches to address this include
dance/movement therapy and mindfulness. The purpose of this 2-
group randomized controlled pilot feasibility study was to test short-
term effects of a 12-week Mindful Movement Program intervention
combining mindfulness with self-directed movement on QOL and
mindfulness in female breast cancer survivors 50 years or older and at
12 months or more following treatment. Consented participants were
randomized to an experimental group (12 weekly Mindful Movement
Program sessions) or a control group (no sessions). All completed
questionnaires 3 times. The experimental group participants kept
home practice diaries. Analysis was conducted after intervention for
immediate effects on outcome variables and 6 weeks later for
maintenance of effects. Participants (n=49) ranged in age from 50 to
90 years (average, 65.6 years) and were at 9.8 years since diagnosis
(range, 1-32 years), and the majority were white, unpartnered, and
retired. After intervention, experimental group participants showed
improved QOL via decreased fear of recurrence and increased
mindfulness attitude. At 6 weeks, initial effects were retained. In
conclusion, the Mindful Movement Program appears to benefit older
breast cancer survivors by reducing fear of recurrence and improving
mindfulness attitude. The combination of self-directed movement and
mindfulness, as tested here, may be a valuable tool for promoting
health and well-being in older long-term survivors of breast cancer
(4).
Assessment: dance may promote wellness by strengthening the

immune system through muscular action and physiological processes.
Dance in an individual moderates, eliminates, or avoids tension,
chronic fatigue, and other disabling conditions that result from the
effects of stress. Dance/movement therapy which deals with
782
individuals physical, emotional, cognitive as well as social integration

is widely used as a popular form of physical activity. Today
dance/movement therapy is a well recognized form of complementary
therapy for cancer patients. The individual studies did not find support
for an effect of dance/movement therapy on mood, distress, and
mental health. The limited number of studies prevents from drawing
conclusions concerning the effects of dance/movement therapy on
psychological and physical outcomes in cancer patients.
References
1. Hanna JL. The power of dance: health and healing. J Altern Complement Med.
1995;1(4):323-31.
2. Aktas G, Ogce F. Dance as a therapy for cancer prevention. Asian Pac J Cancer
Prev. 2005;6(3):408-11.
3. Bradt J, Goodill SW, Dileo C. Dance/movement therapy for improving
psychological and physical outcomes in cancer patients. Cochrane Database Syst Rev.
2011 Oct 5;(10):CD007103.
4. Crane-Okada R, Kiger H, Sugerman F, et al. Mindful movement program for
older breast cancer survivors: a pilot study. Cancer Nurs. 2012;35(4):E1-13.
MUSIC THERAPY
Pain associated with advanced cancer is multifaceted and complex,
and is influenced by physiological, psychological, social, and spiritual
phenomena. Suffering may be identified in patients when pain is
associated with impending loss, increased dependency, and an altered
understanding of one's existential purpose. Comprehensive pain
management aims to address problematic symptoms in order to
improve comfort, peace of mind, and QOL. Music therapy is a
treatment modality of great diversity that can offer a range of benefits
to patients with advanced cancer pain and symptoms of suffering.
Music therapists perform comprehensive assessments that include
reviews of social, cultural, and medical history; current medical status;
and the ways in which emotions are affecting the pain. A variety of
music therapy techniques may be used, including vocal techniques,
listening, and instrumental techniques. These techniques provide
opportunities for exploration of the feelings and issues compounding
the pain experience. Case examples are presented to demonstrate the
"lifting", "transporting", and "bringing of peace" qualities of music
that offer patients moments of release, reflection, and renewal (1).
An analysis of the music therapy literature yields numerous reports
to support the role of music in the alleviation of pain in palliative care.
783
Four theoretical perspectives that support why many patients report

reduced pain sensation after music therapy include: the psychological
relationship between music and pain; the psychophysiological theory;
spinal mechanisms involved in pain modulation; and the role of
endorphins. Considerations significant to the use of music in pain
relief include how music, used inappropriately, can aggravate pain
sensation. Case studies, which include the use of creative music
therapy techniques, point to the efficacy of music therapy in
alleviating the pain experiences of both palliative care patients and
their significant others (2).
Development of a holistic approach and awareness in the medical
and allied professions has led to a renewal of interest in the inclusion
of music and other expressive media in contemporary concepts of
palliative care, which are consistent with problem areas, clinical
manifestations and the needs of patients. Music offers a direct and
uncomplicated medium of intimacy, living in a man who listens to
her, has a place where words lose their power. Music is like our
existence, constantly polarizing and emotionally stimulating, as it
touches the medium of the earliest layers of our becoming. The use of
music in palliative care has proved very effective for a variety of
effects that music creates in patients. These effects are achieved with
various musical techniques, such as musical improvisation,
songwriting, receiving creative techniques, guided by imagination and
music. The techniques allow the diversity of objectives in treating
patients such as reducing anxiety and stress, relaxation, pain control,
reducing confusion spiritual, emotional expression, experience, self-
awareness, encourage creative expression, causing mood swings -
emotional, cognitive and behavioral, inducing the patient's
imagination, enabling patient's chronological classification of life
experiences, and the elaboration of unresolved pain, sorrow or errors.
Adequate selection and use of musical techniques in palliative care in
the service can achieve the best possible QOL for patients at the end
of life (3).
In modern Western medicine, music therapy has been available
since the 1950s and is now often incorporated into conventional
medicine care. Music therapy is a common modality that is used in
hospital settings as part of complementary and integrative medicine
programs. It is also a key therapeutic tool used within most integrative
medicine programs at large cancer centers in the US. When used in
conjunction with conventional cancer treatments, music therapy helps
patients promote a better QOL; better communicate their fear,
784
sadness, or other feelings; and better manage stress, while alleviating

physical pain and discomfort (4).
Music therapy is the supervised and therapeutic use of music by a
credentialed therapist to promote positive clinical outcomes. It can be
a valuable form of complementary medicine in the oncology setting to
decrease patient stress and anxiety, relieve pain and nausea, provide
distraction, alleviate depression, and promote the expression of
feelings. The music therapist assesses the patient and consults other
members of the multidisciplinary team to create a therapeutic
treatment plan. Music therapists design music sessions based on
patients' needs and their intended therapeutic goals. Patients can
participate actively or passively in individual or group sessions. Only
a credentialed music therapist can provide safe and beneficial music
therapy interventions (5).
The main purpose of this study was to a systematic review and
meta-analysis to examine the effect of music interventions on
psychological and physical outcome measures in cancer patients. Six
English-language databases and 3 major Chinese-language databases
in March 2011 were searched. Nine databases were reviewed from
1966 or the start of the database to March 2011. All RCTs comparing
music intervention with standard care, other interventions, or placebo
for psychological and physical outcomes in cancer were included.
Study quality was evaluated by the Grading of Recommendations
Assessment, Development, and Evaluation Working Group. A meta-
analysis of music interventions for psychological and physical
outcomes in cancer was performed. Of 322 total studies, 32
randomized trials (3181 participants) met the inclusion criteria. Seven
high-quality studies indicated that music had positive effects on
coping anxiety assessed by the Self-Rating Anxiety Scale. Two
moderate-quality studies suggested music reduced anxiety assessed by
the Hamilton Anxiety Scale. Eight moderate-quality studies revealed
music lowered anxiety assessed by the STAI-S. Seven moderate-
quality studies demonstrated that music improved depression. Seven
moderate-quality studies observed that music had positive effects on
pain management. Two moderate-quality studies suggested music
worsened fatigue. Four moderate-quality studies indicated that music
lowered heart rate. Three low-quality studies suggested that music
could reduce respiratory rate. Two moderate-quality studies indicated
that music improved QOL. These findings indicate that music
intervention is accepted by patients and associated with improved
psychological outcomes. The effects of music on vital signs especially
BP are small (6).
785
The purpose of this review was to explore the theoretical

underpinnings for the selection of the music stimuli used to influence
targeted outcomes. It was hypothesized that disparate findings were
due in part to the atheoretical nature of music selection and the
resulting diversity in music stimuli between and within studies. A
systematic research synthesis including a comprehensive database and
reference list search resulted in 22 studies. Included studies were
compiled into 2 tables cataloging intervention theory, intervention
content, and outcomes. A majority of studies did not provide a
rationale or intervention theory for the delivery of music or choice of
outcomes. Recorded music was the most common delivery method,
but the specific music was rarely included within the report. Only 2
studies that included a theoretical framework reported null results on
at least some of the outcomes. Null results are partially explained by
an incomplete or mismatch in intervention theory and music selection
and delivery. While the inclusion of an intervention theory does not
guarantee positive results, including a theoretical rationale for the use
of music, particular therapeutic processes or mechanisms and the
specifics of how music is selected and delivered increases scientific
rigor and the probability of clinical translation (7).
This review article is a systematic assessment of the published
literature related to music and cancer pain management. A
comprehensive systematic evaluation of the data based literature was
undertaken and analyzed using matrix analysis. As an adjunctive form
of pain management, music therapy has been shown to address some
of these hardships by providing patients with an alternative effective
means by which to reduce their subjective experiences of pain. Studies
investigating the efficacy of music therapy during invasive cancer
procedures and chemotherapy demonstrated the role that attention
states play in distracting patients from and therefore minimizing their
experience of the pain associated with such treatments. Other studies
examining diverse outpatient populations revealed similar findings,
illustrating well the cognitive-affective dimensions of pain perception.
Although these findings fail to address the ambiguity surrounding
music therapy's role in cancer pain management, music therapy has
nonetheless been shown to reduce anxiety and, in so doing, indirectly
lessen the intensity of pain while improving patient QOL (8).
The main aim of this study was to explore the role of music
therapy within multidisciplinary palliative care teams, and guide the
future development of the discipline. In-depth qualitative interviews
with 20 multidisciplinary colleagues of music therapists, based in 5
UK hospices were conducted. Most interviewees valued music
786
therapy; however, there exists some lack of understanding of the role

of the music therapist, particularly amongst nurses. Emotional,
physical, social, environmental, creative and spiritual benefits of
music therapy have some benefits perceived as synergistic, arising
from collaborations with other disciplines. Interviewees found that
experiencing or witnessing music therapy is effective in developing an
understanding of the discipline. In conclusion, music therapy is an
appropriate therapeutic intervention for meeting the holistic needs of
palliative care service users. More understanding and integration of
music therapy could be encouraged with collaborative work,
educational workshops, and the utilization of environmentally focused
techniques (9).
The purpose of this study was to evaluate the effects of music
therapy on QOL, length of life in care, physical status, and
relationship of death occurrence to the final music therapy
interventions of hospice patients diagnosed with terminal cancer.
Subjects were adults who were living in their homes, receiving
hospice care, and were diagnosed with terminal cancer. Eighty
subjects who participated in the study were randomly assigned to 1 of
2 groups: experimental (routine hospice services and clinical music
therapy) and control (routine hospice services only). QOL was
measured by the Hospice Quality of Life Index-Revised, a self-report
measure given every visit. Functional status of the subjects was
assessed by the hospice nurse during every visit using the Palliative
Performance Scale. All subjects received at least 2 visits and QOL and
physical status assessments. Repeated measures ANOVA revealed a
significant difference between groups on self-report QOL scores for
visits 1 and 2. QOL was higher for those subjects receiving music
therapy, and their QOL increased over time as they received more
music therapy sessions. Subjects in the control group, however,
experienced a lower QOL than those in the experimental group, and
without music, their QOL decreased over time. There were
insignificant differences in results by age or gender of subjects in
either condition. There were insignificant differences between groups
on physical functioning, length of life, or time of death in relation to
the last scheduled visit by the music therapist or counselor. This study
provides an overview of hospice/palliative care, explains the role of
music therapy in providing care, and establishes clinical guidelines
grounded in research for the use of music therapy in improving the
QOL among the terminally ill (10).
In this RCT carried out at 2 large medical centers in Kaoshiung
City, in southern Taiwan, 126 hospitalized persons with cancer pain
787
were randomly assigned to an experimental (n=62) or a control group

(n=64), with computerized minimization, stratifying on gender, pain,
and hospital unit. Music choices included folk songs, Buddhist hymns
(Taiwanese music), plus harp, and piano (American). The
experimental group listened to music for 30 min, while the control
group rested in bed. Sensation and distress of pain were rated on
100mm VAS before and after the 30-min test. Using MANCOVA,
there was significantly less posttest pain in the music vs. the control
group, p<0.001. Effect sizes were large, Cohen's d=0.64, sensation,
d=0.70, distress, indicating that music was very helpful for pain.
Thirty minutes of music provided 50% relief in 42% of the music
group compared to 8% of the controls. The NNT to find 1 with 50%
sensation relief was 3 patients. More patients chose Taiwanese music
(71%) than American music (29%), but both were liked and effective.
In conclusion, offering a choice of familiar, culturally appropriate
music is a key element of the intervention to cancer pain. Soft music is
safe, effective, and liked by participants. It provides greater relief of
cancer pain than analgesics alone (11).
The main aim of this study was to compare the effects of music
therapy or music medicine interventions and standard care with
standard care alone, or standard care and other interventions in
patients with cancer. The Cochrane Central Register of Controlled
Trials (CENTRAL) (The Cochrane Library 2010, Issue 10),
MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, Science
Citation Index, CancerLit, www.musictherapyworld.net, CAIRSS,
Proquest Digital Dissertations, ClinicalTrials.gov, Current Controlled
Trials, and the National Research Register were searched. All
databases were searched from their start date to September 2010.
Hand searched music therapy journals and reference lists and experts
were contacted. There was no language restriction. All RCTs and
quasi-randomized trials of music interventions for improving
psychological and physical outcomes in patients with cancer were
included. Participants undergoing biopsy and aspiration for diagnostic
purposes were excluded. Two review authors independently extracted
the data and assessed the risk of bias. Where possible, results were
presented in meta analyses using MDs and SMDs. Thirty trials with
1891 participants were included. Music therapy interventions, offered
by trained music therapists, as well as listening to pre-recorded music,
offered by medical staff were included. The results suggest that music
interventions may have a beneficial effect on anxiety in people with
cancer, with a reported average anxiety reduction of 11.20 units (95%
CI -19.59 - -2.82, p=0.009) on the STAI-S scale and -0.61
788
standardized units (95% CI -0.97 - -0.26, p=0.0007) on other anxiety

scales. Results also suggested a positive impact on mood (SMD =
0.42, 95% CI 0.03 - 0.81, p=0.03), but no support was found for
depression. Music interventions may lead to small reductions in heart
rate, respiratory rate, and BP. A moderate pain-reducing effect was
found (SMD = -0.59, 95% CI -0.92 - -0.27, p=0.0003), but no strong
evidence was found for enhancement of fatigue or physical status. The
pooled estimate of 2 trials suggested a beneficial effect of music
therapy on patients' QOL (SMD = 1.02, 95% CI 0.58 - 1.47,
p=0.00001). No conclusions could be drawn regarding the effect of
music interventions on distress, body image, oxygen saturation level,
immunologic functioning, spirituality, and communication outcomes.
Seventeen trials used listening to pre-recorded music and 13 trials
used music therapy interventions that actively engaged the patients.
This systematic review indicates that music interventions may have
beneficial effects on anxiety, pain, mood, and QOL in people with
cancer. Music may have a small effect on heart rate, respiratory rate,
and BP. Most trials were at high risk of bias and, therefore, these
results need to be interpreted with caution (12).
The purpose of this experimental crossover study was to evaluate
to what extent the therapeutic use of music would decrease pain in
patients with cancer who were receiving scheduled analgesics.
Baseline data were collected for 3 days. Subjects then were assigned
randomly to listen to their preference of 7 types of relaxing music or a
control (a 60-cycle hum) twice daily for 3 days. Then they crossed
over into the alternate group for the next 3 days. Finally, each subject
returned to a follow-up baseline period. Pain, the dependent variable,
and mood, which was proposed as an intervening variable, were
measured by VASs. The convenience sample included 15 outpatients
with cancer, 12 females and 3 males, ages 20 through 87 years.
Results of the MPQ, administered upon entry into the study, indicated
that the study sample was comparable to other samples of patients
with cancer who were in pain. There was an inconsistent relation
between pain and mood. The effect of the music on pain varied by
individual; 75% had at least some response and 47% had a moderate
or great response. Multivariate Analysis of Variance (MANOVA)
indicated a statistically significant decrease in pain from using either
the music or sound, but there was no effect on mood. Although the
mean percentage of change in pain for music was twice that for sound,
the results did not differ statistically. The findings support the use of
music as an independent nursing intervention to relieve pain (13).
789
Assessment: in modern Western medicine, music therapy has been

available since the 1950s and is incorporated into conventional
medicine care. Music therapy is a treatment modality of great
diversity that can offer a range of benefits to patients with advanced
cancer pain and symptoms of suffering. Effects that music creates in
patients are achieved with various musical techniques, such as musical
improvisation, songwriting, receiving creative techniques, guided by
imagination and music. These techniques allow the diversity of
objectives in treating patients such as reducing anxiety and stress,
relaxation, pain control, reducing confusion spiritual, emotional
expression, experience, self-awareness, encourage creative expression,
causing mood swings - emotional, cognitive and behavioral, inducing
the patient's imagination, enabling patient's chronological
classification of life experiences, and the elaboration of unresolved
pain, sorrow or errors. When used in conjunction with conventional
cancer treatments, music therapy helps patients promote a better QOL;
better communicate their fear, sadness, or other feelings; and better
manage stress, and pain while alleviating physical pain and
discomfort.
References
1. Magill L. The use of music therapy to address the suffering in advanced cancer
pain. J Palliat Care. 2001;17(3):167-72.
2. O'Callaghan CC. Pain, music creativity and music therapy in palliative care.
Am J Hosp Palliat Care. 1996;13(2):43-9.
3. Skrbina D, Simunović D, Santek V, Njegovan-Zvonarević T. Use of music in
palliative care. Acta Med Croatica. 2011;65(5):415-23.
4. Richardson MM, Babiak-Vazquez AE, Frenkel MA. Music therapy in a
comprehensive cancer center. J Soc Integr Oncol. 2008;6(2):76-81.
5. Mahon EM, Mahon SM. Music therapy: a valuable adjunct in the oncology
setting. Clin J Oncol Nurs. 2011;15(4):353-6.
6. Zhang JM, Wang P, Yao JX, et al. Music interventions for psychological and
physical outcomes in cancer: a systematic review and meta-analysis. Support Care
Cancer. 2012;20(12):3043-53.
7. Burns DS. Theoretical rationale for music selection in oncology intervention
research: an integrative review. J Music Ther. 2012;49(1):7-22.
8. Igawa-Silva W, Wu S, Harrigan R. Music and cancer pain management. Hawaii
Med J. 2007;66(11):292-5.
9. O'Kelly J, Koffman J. Multidisciplinary perspectives of music therapy in adult
palliative care. Palliat Med. 2007;21(3):235-41.
10. Hilliard RE. The effects of music therapy on the quality and length of life of people
diagnosed with terminal cancer. J Music Ther. 2003;40(2):113-37.
11. Huang ST, Good M, Zauszniewski JA. The effectiveness of music in relieving pain in
cancer patients: a randomized controlled trial. Int J Nurs Stud. 2010;47(11):1354-62.
12. Bradt J, Dileo C, Grocke D, Magill L. Music interventions for improving psychological
and physical outcomes in cancer patients. Cochrane Database Syst Rev. 2011 Aug
10;(8):CD006911.
13. Beck SL. The therapeutic use of music for cancer-related pain. Oncol Nurs Forum.
1991;18(8):1327-37.
790
TRANSCUTANEOUS/PERCUTANEOUS
ELECTRIC NERVE STIMULATIONS
TENS is a method of pain relief in which a special device transmits
low-voltage electrical impulses through electrodes on the skin to an
area of the body that is in pain (1). The aim of this systematic review
was to determine the effectiveness of TENS for cancer-related pain in
adults. The initial review searched The Cochrane Library, MEDLINE,
EMBASE, CINAHL, PsychINFO, AMED and PEDRO databases in
April 2008. An updated search of CENTRAL, MEDLINE, EMBASE,
CINAHL and PEDRO databases in November 2011 was performed.
Only RCTS investigating the use of TENS for the management of
cancer-related pain in adults were included. The search strategy
identified a further 2 studies for possible inclusion. One of the review
authors screened each abstract using a study eligibility tool. Where
eligibility could not be determined, a second author assessed the full
paper. One author used a standardized data extraction sheet to collect
information on the studies and independently assess the quality of the
studies using the validated 5-point Oxford Quality Scale. The small
sample sizes and differences in patient study populations of the 3
included studies (2 from the original review and a third in this update)
prevented meta-analysis. For the original review, the search strategy
identified 37 possible published studies; these were divided between 2
pairs of review authors who decided on study selection; all 4-review
authors discussed and agreed final scores. Only 1 additional RCT met
the eligibility criteria (24 participants) for this updated review.
Although this was a feasibility study, not designed to investigate
intervention effect, it suggested that TENS may improve bone pain on
movement in a cancer population. The initial review identified 2
RCTs (64 participants) therefore, this review included 3 RCTs (88
participants). In one RCT, there were insignificant differences
between TENS and placebo in women with chronic pain secondary to
breast cancer treatment. In the other RCT, there were insignificant
differences between acupuncture-type TENS and sham in palliative
care patients; this study was underpowered. In conclusion, despite the
1 additional RCT, the results of this updated systematic review remain
inconclusive due to a lack of suitable RCTs. Large multi-centre RCTs
are required to assess the value of TENS in the management of
cancer-related pain in adults (2).
This multicenter study assessed the feasibility of conducting a
phase III trial of TENS in patients with cancer bone pain recruited
from palliative care services. Eligible patients received active and
791
placebo TENS for 1 hour at site of pain in a randomized crossover

design; median interval between applications 3 days. Responses
assessed at 30 and 60 minutes included numerical and verbal ratings
of pain at rest and on movement, and pain relief. Recruitment,
tolerability, AEs, and effectiveness of blinding were also evaluated.
Of 24 randomized patients, 19 completed both applications. The
intervention was well tolerated. Five patients withdrew: 3 due to
deteriorating performance status, and 2 due to increased pain (1 each
following active and placebo TENS). CI estimation around the
differences in outcomes between active and placebo TENS suggests
that TENS has the potential to decrease pain on movement more than
pain on rest. Nine patients did not consider that a placebo was used;
the remaining 10 correctly identified placebo TENS. Feasibility
studies are important in palliative care prior to undertaking clinical
trials. These findings suggest that further work is required on
recruitment strategies and refining the control arm before evaluating
TENS in cancer bone pain. Cancer bone pain is common and severe,
and partly mediated by hyperexcitability. Animal studies suggest that
TENS can reduce hyperalgesia (3).
The main objective of this study was to evaluate the use of a non-
pharmacologic analgesic therapy known as PENS in the management
of opioid-resistant cancer pain. PENS therapy was administered to 3
cancer patients on 3 or more occasion using acupuncture like needle
probes that were stimulated for 30 minutes at frequencies of 4-100 Hz.
Two of the 3 patients achieved good to excellent pain relief that lasted
24-72 hours after each treatment session. In conclusion, PENS
therapy is a useful supplement to opioid analgesics for the
management of pain secondary to bony metastasis in terminal cancer
patients (4).
Assessment: the effectiveness of TENS for cancer-related pain in

adults is questionable. PENS therapy is a useful supplement to opioid
analgesics for the management of pain secondary to bony metastasis
in terminal cancer patients.
References
1. Transcutaneous Electrical Nerve Stimulation. Available 28 May 2013 at
American Cancer Society. www.cancer.org › ... › Manual Healing and Physical
Touch.
2. Hurlow A, Bennett MI, Robb KA, et al. Transcutaneous electric nerve
stimulation (TENS) for cancer pain in adults. Cochrane Database Syst Rev. 2012 Mar
14;3:CD006276.
3. Bennett MI, Johnson MI, Brown SR, et al. Feasibility study of Transcutaneous
Electrical Nerve Stimulation (TENS) for cancer bone pain. J Pain. 2010;11(4):351-9.
792
4. Ahmed HE, Craig WF, White PF, Huber P. Percutaneous electrical nerve
stimulation (PENS): a complementary therapy for the management of pain secondary
to bony metastasis. Clin J Pain. 1998;14(4):320-3.
MASSAGE THERAPY
The care of patients with cancer not only involves dealing with its
symptoms but also with complicated information and uncertainty;
isolation; and fear of disease progression, disease recurrence, and
death. Patients whose treatments require them to go without human
contact can find a lack of touch to be an especially distressing factor.
Massage therapy is often used to address these patients' need for
human contact, and findings support the positive value of massage in
cancer care. Several reviews of the scientific literature have attributed
numerous positive effects to massage, including improvements in the
quality of patients' relaxation, sleep, and immune system responses
and in the relief of their fatigue, pain, anxiety, and nausea. Based on
these reviews, some large cancer centers in the US have started to
integrate massage therapy into conventional settings. The importance
of touch, review findings regarding massage for cancer patients, the
massage therapy program in one of these centers and future challenges
and implications for the effective integration of massage therapy in
large and small cancer centers are recognized (1).
Massage therapy
Patients with metastatic cancers, such as bone metastases, are more
likely to report pain, compared to patients without metastatic cancer
(50-74% and 15%, respectively). Their cancer pain results in
substantial morbidity and disrupted QOL in 34-45% of cancer
patients. The purpose of this RCT was to compare the efficacy of
massage therapy to a social attention control condition on pain
intensity, mood status, muscle relaxation, and sleep quality in a
793
sample of Taiwanese cancer patients (n=72) with bone metastases. In

this investigation, massage therapy was beneficial within- or between-
subjects effects on pain, mood, muscle relaxation, and sleep quality.
Results from repeated-measures analysis of covariance demonstrated
that massage resulted in a linear trend of improvements in mood and
relaxation over time. The reduction in pain with massage was both
statistically and clinically significant, and the massage-related effects
on relaxation were sustained for at least 16-18 hours post intervention.
Massage-related effects on sleep were associated with within-subjects
effects. Overall, results from this study support employing massage
therapy as an adjuvant to other therapies in improving bone pain
management (2).
This paper is a report of a review to assess evidence of the
effectiveness of massage for patients with cancer, in terms of reducing
physical or psychological symptoms, improving QOL, or producing
unwanted side effects. Patients with cancer may use complementary
therapies, including massage and aromatherapy massage. However,
their use and provision by state-financed healthcare services is
controversial. A systematic review was carried out, using the
Cochrane principles. No meta-analysis was appropriate. An initial
comprehensive search of electronic databases search was carried out
in 2003 and updated in 2006. Eligible trials were RCTs, controlled
before-and-after (pre-post) studies and interrupted time-series studies.
Participants were adults with a diagnosis of cancer and receiving care
in any healthcare setting. Interventions were limited to massage and/or
aromatherapy massage carried out by a qualified therapist. Outcome
measures to be included were patient-reported levels of physical and
psychological indices of symptom distress and QOL (measured using
validated assessment tools). In the review, 1325 papers were
considered. Ten trials met the inclusion criteria and their results
suggest that massage might reduce anxiety in patients with cancer in
the short term and may have a beneficial effect on physical symptoms
of cancer, such as pain and nausea. In conclusion, further well-
designed large trials with longer follow-up periods are needed to be
able to draw firm conclusions about the efficacy and effectiveness of
massage for cancer patients (3).
The results of several studies on the use of massage therapies for
cancer patients have been published in the peer-reviewed literature
over the past 20 years. The current article provides a summary and
critique of published studies in which patient-reported symptom
ratings were assessed in relation to massage. Twenty-two studies are
discussed. Most studies were on Swedish massage, followed by
794
aromatherapy massage, foot reflexology, and acupressure. Symptoms

assessed as outcomes included pain, fatigue, anxiety, nausea, and
depression. Study designs included uncontrolled observational studies,
crossover designs, and quasiexperimental and RCTs. Several studies
included methodologic limitations such as small sample sizes, lack of
blinded assessment, lack of accounting for subject attrition in
statistical analyses, and other limitations. The results of the studies are
mixed and vary as a function of several study characteristics. The
most consistent symptom was anxiety reduction (4).
Evaluating the effectiveness of nursing interventions in decreasing
pain is a top priority for clinical research. Unfortunately, most of the
research on cancer pain relief has been limited to treatment studies
involving the administration of analgesics. Research is needed to
determine which non-analgesic methods of pain control are effective
and under what conditions. Consequently, an experimental study was
designed to test the effectiveness of massage as an intervention for
cancer pain. Twenty-eight patients were randomly assigned to a
massage or control group. The patients in the massage group were
given a 10-minute massage to the back; the patients in the control
group were visited for 10 minutes. For males, there was a significant
decrease in pain level immediately after the massage. For females,
there was insignificant decrease in pain level immediately after the
massage. There were insignificant differences between pain 1 hour
and 2 hours after the massage in comparison with the initial pain for
males or females. Massage was an effective short-term nursing
intervention for pain in males in this sample (5).
The main aim of this study was to describe application of manual
therapy (techniques of effleurage and petrissage) to the extremities in
a patient with grade II CIPN subsequent to prior treatment with
docetaxel and cisplatin for stage III esophageal adenocarcinoma.
Superficial cutaneous temperature was monitored using infrared
thermistry as proxy for microvascular blood flow. By the end of the
course of manual therapy without any change in medications, CIPN
symptoms were greatly reduced to grade I, with corresponding
improvement in QOL. Improvements in superficial temperature were
observed in fingers and toes. In conclusion, manual therapy was
associated with almost complete resolution of the tingling and
numbness and pain of CIPN in this patient. Concurrently increased
superficial temperature suggests improvements in CIPN symptoms
may have involved changes in blood circulation. In conclusion,
manual therapy is useful for amelioration of CIPN (6).
795
The study objectives were to determine the feasibility and effects

of providing therapeutic massage at home for patients with metastatic
cancer. This was a RCS. Patients were enrolled at Oncology Clinics at
a large urban academic medical center; massage therapy was provided
in patients' homes. Subjects were patients with metastatic cancer.
There were 3 interventions: massage therapy, no-touch intervention,
and usual care. Primary outcomes were pain, anxiety, and alertness;
secondary outcomes were QOL and sleep. In this study, it was
possible to provide interventions for all patients at home by
professional massage therapists. The mean number of massage
therapy sessions per patient was 2.8. A significant improvement was
found in the QOL of the patients who received massage therapy after
1-week follow-up, which was not observed in either the No Touch
control or the Usual Care control groups, but the difference was not
sustained at 1 month. There were trends toward improvement in pain
and sleep of the patients after therapeutic massage but not in patients
in the control groups. There were no serious AEs related to the
interventions. The study results showed that it is feasible to provide
therapeutic massage at home for patients with advanced cancer, and to
randomize patients to a no-touch intervention. Providing therapeutic
massage improves the QOL at the end of life for patients and may be
associated with further beneficial effects, such as improvement in pain
and sleep quality (7).
Assessment: patients whose treatments require without human

contact can find a lack of touch to be an especially distressing factor.
Massage therapy is often used to address these patients' need for
human contact, and findings support the positive value of massage in
cancer care.
Massage can improve mood and relaxation, reduce anxiety in
patients with cancer and may have a beneficial effect on physical
symptoms of cancer, such as pain and nausea. Massage therapy as an
adjuvant to other therapies can improve bone pain management.
Manual therapy is associated with almost complete resolution of the
tingling and numbness and pain of CIPN.
References
1. Russell NC, Sumler SS, Beinhorn CM, Frenkel MA. Role of massage therapy
in cancer care. J Altern Complement Med. 2008;14(2):209-14.
2. Jane SW, Chen SL, Wilkie DJ, et al. Effects of massage on pain, mood status,
relaxation, and sleep in Taiwanese patients with metastatic bone pain: a randomized
clinical trial. Pain. 2011;152(10):2432-42.
3. Wilkinson S, Barnes K, Storey L. Massage for symptom relief in patients with
cancer: systematic review. J Adv Nurs. 2008;63(5):430-9.
796
4. Myers CD, Walton T, Bratsman L, et al. Massage modalities and symptoms

reported by cancer patients: narrative review. J Soc Integr Oncol. 2008;6(1):19-28.
5. Weinrich SP, Weinrich MC. The effect of massage on pain in cancer patients.
Appl Nurs Re. 1990;3(4):140–5.
6. Cunningham JE, Kelechi T, Sterba K, et al. Case report of a patient with
chemotherapy-induced peripheral neuropathy treated with manual therapy (massage).
Support Care Cancer. 2011;19(9):1473-6.
7. Toth M, Marcantonio ER, Davis RB, et al. Massage Therapy for Patients with
Metastatic Cancer: A Pilot Randomized Controlled Trial. J Altern Complement Med.
2013 Jan 31. [Epub ahead of print].
ACUPUNCTURE
Acupuncture has become a popular complementary treatment in
oncology, particularly as patients seek non-pharmacological
alternatives to provide symptom control. A considerable body of
evidence suggests that acupuncture modulates neurological processes
to bring about its effects. The literature was searched to identify,
where possible, RCTs involving acupuncture and various common
cancer symptoms. A potential role for acupuncture was in the
following cancer symptoms: pain, nausea and vomiting, xerostomia,
hot flushes, fatigue, anxiety, depression and insomnia. Acupuncture is
safe with minimal side effects, and is clinically effective for the
management of these symptoms. In the interim, health professionals
should be open to explore the use of acupuncture with their cancer
patients (1).
Acupuncture has been evaluated in clinical studies for its effect in
reducing some of the common symptoms experienced by cancer
patients. There is good evidence supporting acupuncture's effects in
the reduction of cancer-related pain and chemotherapy-induced acute
nausea and vomiting. Acupuncture may help reduce post-
chemotherapy fatigue and xerostomia caused by radiation.
Acupuncture has a good safety record when performed by qualified
practitioners, and is useful complementary therapy in cancer care. Its
integration into regular oncology practice can improve the supportive
care for cancer patients (2).
Between August 1999 and May 2000, 123 patients with varying
symptoms received acupuncture at Radiation and Medical Oncology
Clinics and Breast Health Center, Naval Medical Center, California.
These patients had 823 visits during this time. A practice outcome
analysis was performed on patients receiving therapy between 1
January 2000 and 30 April 2000. The 89 patients treated during this
797
interval had 444 total visits. In June and July 2000, a questionnaire
was administered by phone to 79 of these patients (89%). Standard
allopathic care continued while patients were receiving acupuncture.
Major reasons for referral included pain (53%), xerostomia (32%), hot
flashes (6%), and nausea/loss of appetite (6%). Patients had a mean of
5 acupuncture visits (range 1-9). Most patients (60%) showed at least
30% improvement in their symptoms. About one-third of patients had
no change in severity of symptoms. There were no untoward effects
reported related to the acupuncture. Irrespective of response to
therapy, 86% of respondents considered it 'very important' to continue
to provide acupuncture services. In conclusion, acupuncture may
contribute to control of symptoms for cancer patients (3).
Acupuncture for pain treatment
The main objective of this study was to discuss the use of

acupuncture for CIBP by reviewing the physiological rationale for
using acupuncture to treat CIBP and the risks and benefits of using
acupuncture in clinical practice. Evidence was identified by searching
seven major databases: Cochrane Central Register of Controlled Trials
(CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, AMED
and SPORTDiscus. Available physiological evidence supports
potentially efficacious effects of acupuncture for reduction of CIBP.
Clinical literature suggests that acupuncture may be effective as an
adjunctive treatment for CIBP and that risks are manageable. In
conclusion, acupuncture has the potential to provide sustained
background analgesia and/or rapid onset analgesia for BTP if the
appropriate points and techniques are used (4).
This paper describes the population given acupuncture treatment
and the effects of the intervention on symptom management. In this
study, 183 patients from the Department of Internal Medicine, Sao
Paulo, Brazil, were enrolled. Baseline and final symptom intensity
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was recorded using a VAS ranging from 0 to 10 cm, with a higher

score meaning higher symptom intensity. Fifty-four (29.50%) were
receiving active treatment with chemotherapy and/or RT, 29 (15.85%)
were receiving hormone therapy and 100 (54.65%) were considered to
be in remission. The main symptoms were: oncological pain in 44
(24.0%), chemotoxicity in 34 (18.6%), lumbar pain in 53 (29.0%) and
chronic postoperative pain in 54 (28.4%). The mean (SD) initial
symptom score was 7.04 (1.8), which was reduced to 2.56 (2.75) after
treatment (p<0.001), an improvement of 63.6% in control of the
symptoms. The effect was similar in different indications for
acupuncture treatment. In conclusion, use of acupuncture may have
improved symptom control in cancer patients (5).
For the prospective survey, a questionnaire was distributed for self-
administration by Singapore patients while waiting for consultation at
the NCC outpatient departments. Literature searches on advances in
pain management were conducted, reviewed and discussed. In the last
decade, there have been advances in pain pharmacology ranging from
wider therapeutic options and management approaches to novel
delivery techniques. Acupuncture and massage therapy became
increasingly popular among cancer patients. Some clinical trials of
acupuncture show benefits in palliation of cancer pain. From the
prospective survey, 41.2% of the responders reported pain in the past
week, and only 70.8% talked to their doctors about their pain. One
third of the patients received analgesics. Of these, 86.5% said that they
were taking the prescribed medications, however, 37.4% admitted to
having difficulties taking them. Non-drug methods were used by
25.4% of the patients. Medicated oil, cream or gel was used by 49.3%;
only 2.6% reported use of Chinese herbs. In conclusion, pain is a
significant symptom in outpatients attending a cancer centre, affecting
41.2% of the patients. Although majority of patients who suffered
from pain reported this to doctors, much more medical effort is needed
to help patients to relieve their pain and proper complementary
therapy could be considered (6).
A pilot study was conducted to evaluate the therapeutic effect of
acupuncture on CIPN as measured by changes in NCSs in 6 patients
treated with acupuncture for 10 weeks in addition to best medical care
and 5 control patients who received the best medical care but no
specific treatment for CIPN. In 5 of the 6 patients treated with
acupuncture, NCSs improved after treatment. In the control group, 3
of 5 patients did not show any difference in NCSs, 1 patient improved
and 1 showed impaired NCSs. In conclusion, acupuncture has a
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positive effect on CIPN. The encouraging results of this pilot study

justify a RCT of acupuncture in CIPN based on NCSs (7).
Assessment: acupuncture has become a popular complementary

treatment in oncology. A potential role for acupuncture is in the
following cancer symptoms: pain, nausea and vomiting, xerostomia,
hot flushes, fatigue, anxiety, depression and insomnia.
Acupuncture can be effective as an adjunctive treatment for CIBP,
and has the potential to provide sustained background analgesia and/or
rapid onset analgesia for BTP if the appropriate points and techniques
are used.
References
1. O'Regan D, Filshie J. Acupuncture and cancer. Auton Neurosci. 2010;157(1-
2):96-100.
2. Deng G, Vickers A, Simon Yeung K, Cassileth BR. Acupuncture: integration
into cancer care. J Soc Integr Oncol. 2006;4(2):86-92.
3. Johnstone PA, Polston GR, Niemtzow RC, Martin PJ. Integration of
acupuncture into the oncology clinic. Palliat Med. 2002;16(3):235-9.
4. Paley CA, Johnson MI, Bennett MI. Should physiotherapists use acupuncture
for treating patients with cancer-induced bone pain? A discussion paper.
Physiotherapy. 2011;97(3):256-63.
5. D'Alessandro E, de Brito C, Cecatto R, et al. Evaluation of acupuncture for
cancer symptoms in a cancer institute in Brazil. Acupunct Med. 2013;31(1):23-6.
6. Saw CL, Chew L, Goh C. Recent non-interventional advances in cancer pain
among singapore patients. Ann Acad Med Singapore. 2012;41(9):407-16.
7. Schroeder S, Meyer-Hamme G, Epplée S. Acupuncture for chemotherapy-
induced peripheral neuropathy (CIPN): a pilot study using neurography. Acupunct
Med. 2012;30(1):4-7.
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PHARMACOLOGICAL THERAPY
Pain is the most feared symptom for patients with advanced cancer.
Although effective pain relief is critical to preserving QOL for these
patients, the incidence of uncontrolled pain is high. A variety of
physiological mechanisms contributes to cancer pain, and
psychological, social and spiritual factors all contribute to the overall
pain experience. Therefore, the rationale for treatment must be
appropriate. Regular assessment of both pain and treatment is
indicated, as is the management of adverse reactions of treatment (1).
In the past, much distinction was made between the treatment of
acute and chronic pain, especially between the treatment of cancer-
related and non–cancer-related pain. Today, these distinctions are less
clear, and more commonality exists between the various types of pain
and the pharmacologic agents used to treat them (2).
From the origins of formalized guidelines by the WHO to recent
developments in implantable therapies, great strides have been made
to meet the needs of cancer patients. Relatively recent animal models
of malignant bone disease have allowed a better understanding of the
intimate mechanisms involved in the genesis of pain, resulting in a
mechanistic approach to its treatment. Analgesic strategies can be
developed with specific targets in mind to complement the classic,
opioid-centered WHO analgesic ladder obtaining improved outcomes
and QOL. Unfortunately, high-quality evidence is difficult to produce
in pain medicine, and these concepts are evolving slowly. Treatment
options are expanding for the challenging clinical problem of painful
MBD. Efforts are concentrated on developing alternative non-opioid
approaches that appear to increase the success rate and improve
patients' QOL (3).
Current treatment for metastatic bone pain is mainly palliative.
Recent insights into the molecular mechanisms involved in bone
metastases have led to the identification of promising therapeutic
targets. Biphosphonates are the gold standard of bone-targeted therapy
in bone metastases, for their anti-resorptive and analgesic effects. New
drugs aim at breaking the 'vicious cycle' of MBD, due to the
bidirectional interaction between cancer cells and bone
microenvironment. OPG, RANK/RANKL interaction, cathepsin K,
the Wnt/beta-catenin pathway and sclerostin are emerging targets for
modulation of cancer-induced bone desorption. Other promising
targets are those expressed in cancer cells that metastasize to bone,
including Src (a tyrosine kinase involved in the regulation of a range
of cellular processes including proliferation, adhesion, motility and
801
survival), nerve growth factor, endothelin A, transforming growth

factor-beta and chemokine C-X-C motif receptor 4 (CXCR4).
Interesting therapeutic options include targets on nociceptors that
innervate the bone, such as TPRV1, Trk and cannabinoid receptors.
Emerging therapies promise, in the next 10 years, a significant
expansion in the array of therapeutic options for bone metastases.
Most of these drugs are still in an early phase of development. Further
clinical trials are needed to support the evidence of their efficacy and
tolerability profile (4).
References
1. Regaard A.T. The principles of pain management in advanced cancer. Br J
Community Nurs. 2000;5(8):382-6, 388.
3. Buga S, Sarria JE. The management of pain in metastatic bone disease. Cancer
Control. 2012;19(2):154-66.
4. Coluzzi F, Mandatori I, Mattia C. Emerging therapies in metastatic bone pain.
Expert Opin Emerg Drugs. 2011;16(3):441-58.
ANALGETIC LADDER
The WHO has adopted an "analgesic ladder" (Figure 1) and
Guideless for using it for relief of cancer pain. The method for cancer
pain relief consists of guidelines for a 3-step treatment, from non-
opioids to weak and then strong opioids, according to need. Adjuvant
drugs can be added to each step (1).
WHO guidelines recommend prompt oral administration of drugs
when pain occurs, starting, if the patient is not in severe pain, with
non-opioid drugs such as paracetamol (acetaminophen), dipyrone,
NSAIDs or COX-2 inhibitors (1-3). Then, if complete pain relief is
not achieved or disease progression necessitates more aggressive
treatment, a mild opioid such as codeine phosphate,
dextropropoxyphene, dihydrocodeine or Tramadol are added to the
existing non-opioid regime (2,3). If this becomes insufficient, a mild
opioid is replaced by a stronger opioid, such as morphine,
diamorphine (heroin), fentanyl, buprenorphine, oxymorphone,
oxycodone, or hydromorphone, while continuing the non-opioid
therapy, escalating opioid dose until the patient is pain free or at the
maximum possible relief without intolerable side effects. If the initial
802
presentation is severe pain, this stepping process should be skipped

and a strong opioid should be started immediately in combination with
a non-opioid analgesic (4).
Pain is one of the most frequent and most distressing symptoms in
the course of cancer. The management of pain in cancer patients is
based on the concept of the WHO analgesic ladder that was updated
with the EAPC recommendations. Cancer pain may be relieved with
opioids administered alone or in combination with adjuvant analgesics
(5). Through an adequate use of the analgesic ladder, pain can be
relieved in the great majority of cancer patients (1).
Figure 1. Analgetic ladder

High potency opioid
+Nonopioid
±adjuvant
Moderate potency opioids Morphine
+Nonopioid Hydromorphone
±adjuvants Methadone
Fentanyl
Oxycodone*
Nonopioid Codeine Step 3

±adjuvant Hydrocodone Severe pain
Oxycodone*
Tramadol
Aspirin, NSAID Step 2

Acetaminophen Moderate pain
Step 1
Mild Pain
Analgetic Ladder. *Oxycodone (5-10 mg) in combination with aspirin,

acetaminophen or NSAID is a step 2 agent; alone it is a step 3 agent. Adapted
from the World Health Organization, Cancer Pain Relief: With a Guide to
Opioid Availability, 2nd ed. Geneva: World Health Organization. 1996.
A WHO method has been developed providing that drugs are

administered immediately if there is pain, to be given 'by the clock'
rather than 'on demand' and to be increased from non-opioids (aspirin
or paracetamol) to weak opioids (codeine) and then to strong opioids
(morphine) until the patient is free from pain - hence the concept of a
3-step ladder for cancer pain relief. Field tests have shown that the
803
right drug in the right dose at the right time relieves 80-90% of pain.
Thus, a scientifically valid, relatively inexpensive method suitable for
reaching patients at community level does exist (6).
However, in developed countries, in which all step-3 drugs are
available, the routine use of the step-2 medications can be associated
with significant disadvantages. The above-mentioned evidence
suggests that the transition from step-1 to step-2 drugs does not
necessarily result in improved analgesia. This apparently ineffective
transition may cause a delay in achieving optimal pain control,
especially in patients with rapidly progressive pain or in those who
need rapid titration of analgesic therapy (7).
The fear of administering strong opioids may instead cause
physicians to increase the dosages of step-1 and step-2 medications, or
even combinations of step-2 medications, to levels that are associated
with a higher risk of AEs, compared with those expected of the use of
strong opioids (8).
This report presents the two-year experience of the WHO
Collaborating Centre at the NCI of Milan in the use of analgesic
ladder method. A retrospective study shows that a correct use of the
analgesic ladder can reduce pain to a third of its initial intensity. The
use of non-opioids had an average duration of 19.2 days; in 52% of
the cases, treatment was discontinued due to inefficacy and in 42%
due to side effects. Weak opioids were administered on an average for
28.0 days. A shift to strong opioids was made in 92% of the cases due
to inefficacy and in 8% because of side effects. Treatment with strong
opioids lasted for an average of 46.6 days and can be considered the
mainstay of cancer pain therapy. Performance status was not altered
considerably during the study and hours of sleep were doubled. The
analgesic ladder proved efficacious in 71% of the cases. Neurolytic
procedures had to be used in 29%. In conclusion, analgesics, as
proposed by WHO is the most suitable treatment arm in controlling
pain in palliative treatment for advanced cancer patients. Lack of
availability or underuse of opioids constitute the real obstacle to the
application of this method (9).
This paper reports on the experience gained using WHO
Guidelines for cancer pain relief over a 10-year period in an
anesthesiology-based pain service associated with a palliative care
program. The course of treatment of 2118 patients was assessed
prospectively over a period of 140,478 treatment days. Non-opioid
analgesics (WHO step I) were used on 11%, weak opioids (WHO step
II) on 31% and strong opioids (WHO step III) on 49% of treatment
days. Administration was via the enteral route on 82% and
804
parenterally on 9% of treatment days. On the remaining days, either

spinally applied opioids (2%) or other treatments (6%) were utilized.
Fifty-six percent of the patients were treated with morphine. Morphine
dose escalation was observed in about one-half of the patients being
cared for until death, whereas the other half had stable or decreasing
doses over the course of treatment. Co-analgesics were administered
on 37% of days, most often antidepressants (15%), anticonvulsants
(13%) and corticosteroids (13%). Adjuvants to treat symptoms other
than pain were prescribed on 79% of days, most commonly laxatives
(42%), histamine-2-receptor antagonists (39%) and antiemetics (35%).
In addition, palliative antineoplastic treatment was performed in 42%,
nerve blocks in 8%, physiotherapy in 5%, psychotherapy in 3% and
TENS in 3% of patients. A highly significant pain reduction was
achieved within the 1st week of treatment (p<0.001). Over the whole
treatment period, good pain relief was reported in 76%, satisfactory
efficacy in 12% and inadequate efficacy in 12% of patients. In the
final days of life, 84% rated their pain as moderate or less, while 10%
were unable to give a rating. Analgesics remained constantly effective
in all 3 steps of the WHO ladder. Other clinical symptoms were
significantly reduced at 1 week after initial assessment, with the
exception of neuropsychiatric symptoms. During the course of
treatment, the latter were the major symptoms on 23% of days,
followed by nausea (23%), constipation (23%), and anorexia (20%).
These results emphasize once again the marked efficacy and low rate
of complications associated with oral and parenteral analgesic therapy
as the mainstay of pain treatment in the palliative care of patients with
advanced cancer. Wide dissemination of WHO guidelines among
doctors and healthcare workers is thus necessary to effect a clear
improvement in the treatment of the many patients suffering from
cancer pain in the clinical and home setting (10).
The efficacy of the WHO guidelines for cancer pain relief was
examined in 401 dying patients. At the time of death, only 3% of the
patients experienced severe or very severe pain; whereas 52% had no
pain at all, 24% experienced only mild or moderate pain, and 20%
were unable to rate their pain intensity. Analgesic drugs were the
mainstay of therapy during the last 24 hours of life, being
administered by mouth in 47% and parenterally in 44% of the patients.
Only 9% of the patients required no systemic analgesics. Nonopioid
analgesics alone were effective in 5% and a combination of
nonopioids and "weak" opioids were effective in 16% of the patients.
In the remaining 70% of the patients, "strong" opioids alone or in
combination with nonopioid analgesics were necessary to achieve
805
adequate pain reduction. Additional adjuvant drugs to treat special

types of pain or other symptoms were prescribed in 90% of the
patients. Non-pharmacological measures, such as RT, nerve blocks or
neurosurgery played only a minor role at this stage of the disease.
Thus, cancer pain can be treated satisfactorily until death (11).
In this study, the results of pain treatment practices according to
the WHO analgesic ladder treatment and other treatment modalities in
cancer patients who were admitted to an anesthesiology-based pain
service were evaluated. Patient characteristics, distribution of the
patients according to the primary pathologic sites, initial and last
distribution of the patients according to analgesic ladder treatment,
other invasive or non-invasive treatment modalities, side effects, and
other data related with the patients were examined. Of 475 patients,
416 (87.5%) were treated using the WHO analgesic ladder treatment,
while 57 patients (12%) were treated by invasive techniques. The
number of successfully treated patients in step I, II and III were 49
(11.77%), 307 (73.79%) and 60 (14.42) respectively; 181 of 416
(43.50%) patients used anticonvulsants or neuroleptics, and 341 of
416 (81.97%) patients used antidepressants. In 31 of 416 patients
(7.5%), non-invasive or invasive treatment modalities had become
necessary to augment the WHO analgesic ladder treatment. Over the
entire treatment period, side effects were reported in 17.1% of the
patients. The follow-up time for the patients was 42 +/- 109.7 days,
the mean interview number was 5.6 +/- 7.6, the longest follow-up time
was 1380 days, and the maximum number of the interviews made by
the same patient was 68. In conclusion, using the WHO analgesic
ladder treatment and administering appropriate analgesics and
adjuvants in appropriate oral doses determined for appropriate
subjects could successfully treat a great number of these patients (12).
The aims of the present study were to verify whether an innovative
therapeutic strategy for the treatment of mild-moderate chronic cancer
pain, passing directly from step I to step III of the WHO analgesic
ladder, is more effective than the traditional 3-step strategy and to
evaluate the tolerability and therapeutic index in both strategies.
Patients aged ≥ 18 years with multiple viscera or bone metastases or
with locally advanced disease were randomized. Pain intensity was
assessed using a 0-10 NRS based on 4 questions selected from the
validated Italian version of the BPI. Treatment-specific variables and
other symptoms were recorded at baseline up to a maximum follow-up
of 90 days per patient. Fifty-four patients were randomized onto the
study, and pain intensity was assessed over a period of 2,649 days.
The innovative treatment presented a statistically significant
806
advantage over the traditional strategy in terms of the percentage of

days with worst pain ≥ 5 (22.8% vs. 28.6%, p <0.001) and ≥ 7 (8.6%
vs. 11.2%, p=0.023). Grades III and IV anorexia and constipation
were more frequently reported in the innovative strategy arm,
although prophylactic laxative therapy was used less in this setting.
These data would seem to suggest that a direct move to the 3 step of
the WHO analgesic ladder is feasible and could reduce pain scores but
requires careful management of side effects (13).
Assessment: according to the WHO "analgesic ladder", cancer

pain relief consists of guidelines for a 3-step treatment, from non-
opioids to weak and then strong opioids, according to need. Adjuvant
drugs can be added to each step. WHO guidelines recommend prompt
oral administration of drugs when pain occurs, starting, if the patient
is not in severe pain, with non-opioid drugs. If complete pain relief is
not achieved or disease progression necessitates more aggressive
treatment, a mild opioid should be added to the existing non-opioid
regime. If this becomes insufficient, a mild opioid is replaced by a
stronger opioid, while continuing the non-opioid therapy, escalating
opioid dose until the patient is pain free or at the maximum possible
relief without intolerable side effects. If the initial presentation is
severe pain, this stepping process should be skipped and a strong
opioid should be started immediately in combination with a non-
opioid analgesic.
A direct move to the third step of the WHO analgesic ladder is
feasible and could reduce pain scores but requires careful management
of side effects.
References
1. Ventafridda V, Saita L, Ripamonti C, De Conno F. WHO guidelines for the use
of analgesics in cancer pain. Int J Tissue React. 1985;7(1):93-6.
2. WHO Guidelines. World Health Organization. Cancer pain relief. Geneva:
WHO. 1986.
3. World Health Organization. Cancer pain relief. Second ed. Geneva, WHO.
1996.
4. Schug SA & Auret K. Clinical Pharmacology: Principles of Analgesic Drug
Management. In: Sykes N, Bennett MI & Yuan C-S. Clinical Pain Management:
Cancer Pain. 2nd ed. London: Hodder Arnold. 2008, pp. 104–22.
5. Leppert W, Buss T. The role of corticosteroids in the treatment of pain in
cancer patients. Curr Pain Headache Rep. 2012;16(4):307-13.
6. Stjernswärd J. WHO cancer pain relief programme. World Health Organization,
Geneva, Switzerland. Cancer Surveys.1988,7(1):195-208.
7. Eisenberd E, Shifrin A. Reassessing the need for step 2 of the WHO analgesic
ladder. Paineurope. 2011;1:4-5.
8. Eisenberg E, Mariangeli F, Birkhan J, et al. Time to modify the WHO
Analgetic Ladder? Pain: Clinical Updates. 2005;13(5):1-4.
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9. Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the

WHO method for cancer pain relief. Cancer. 1987;59:850-6.
10. Zech DF, Grond S, Lynch J, et al. Validation of World Health Organization
Guidelines for cancer pain relief: a 10-year prospective study. Pain. 1995;63(1):65-
76.
11. Grond S, Zech D, Schug SA, et al. Validation of World Health Organization
guidelines for cancer pain relief during the last days and hours of life. J Pain
Symptom Manage. 1991;6(7):411-22.
12. Orhan ME, Bilgin F, Ergin A, et al. Pain treatment practice according to the
WHO analgesic ladder in cancer patients: eight years experience of a single center.
Agri. 2008;20(4):37-43.
13. Maltoni M, Scarpi E, Modonesi C, et al. A validation study of the WHO
analgesic ladder: a two-step vs three-step strategy. Support Care Cancer.
2005;13(11):888-94.
NON-OPIOID ANALGETICS
For relieving any underlying inflammatory process, anti-
inflammatory agents are likely to be useful, whether they are non-
steroidal or steroidal in their composition. The use of these
medications helps control the toxic chemical events leading to the
sensitization of the peripheral nervous system and the further
experience of pain in response to injury. Which anti-inflammatory
drug is used is less important than is the fact that some agent is
administered for relief of pain. Although the toxicity profiles for
NSAIDs vary, the ability of these agents to relieve inflammation and
pain is clear. When inflammation plays a role in the development and
experience of pain, then relieving the inflammation will likely
improve the pain (1).
Reference
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NONSTEROIDAL ANTIINFLAMMATORY
DRUGS/ACETAMINOPHEN
Acetaminophen (paracetamol) is recommended as a first step
analgesic for mild to moderate pain. Although its mechanism of action
is not fully understood, it is thought to inhibit central prostaglandin
synthesis in the CNS, which explains its analgesic and antipyretic
activity without any effects on inflammation. Acetaminophen is not
generally used alone for cancer pain, but rather in combination with
opioids (i.e., hydrocodone, codeine, etc). Although acetaminophen is
effective and well tolerated by most of the patients, its use is limited
by a maximum daily dose of 4000 mg (2000 mg/day in patients with
hepatic dysfunction) due to potential hepatic toxicity. On the other
hand, the G-I toxicities with chronic NSAIDs use are not seen with
acetaminophen. Acetaminophen is excreted by kidneys and dosing
must be adjusted in patients with significant renal insufficiency (1).
Aspirin's origins lie with willow bark, but they may be unaware of
its role in the development of the pharmaceutical industry. Evolving
from salacin (the active ingredient in many plant remedies) to salicylic
acid (an analgesic in its own right) to the more effective, less toxic
acetylsalicylic acid, this pain reliever cornered the nonsteroidal anti-
inflammatory market for more than 70 years. It helped the dye
industry branch into pharmaceuticals, and is used in multiple
indications (2). For several millennia, the willow tree and salicin have
been associated with salicylic acid, the key precursor molecule that
has contributed to the discovery of acetylsalicylic acid, traded as
aspirin. These molecules have been shown to possess phyto- and
chemotherapeutic activities as analgesic drugs. In recent decades,
aspirin has become the focus of extensive investigation into
antiproliferative and anticancer activities (3).
Aspirin has been used to control pain and inflammation for over a
century. Epidemiological studies first associated a decreased incidence
of CRC with the long-term use of aspirin in the early 1980s. Near the
same time, the first reports show regression of colorectal adenomas in
response to the NSAID sulindac. In subsequent years, the use of other
NSAIDs, which inhibit COX enzymes, was linked to reduced cancer
risk in multiple tissues including those of the breast, prostate, and
lung. Together these studies resulted in the identification of a new
cancer preventive and/or therapeutic target-COX enzymes, especially
COX-2. Meanwhile, the overexpression of COX-2, and less
consistently, the upstream and downstream enzymes of the
prostaglandin synthesis pathway, was demonstrated in multiple cancer
809
types and some pre-neoplastic lesions. Direct interactions of

prostaglandins with their receptors through autocrine or paracrine
pathways to enhance cellular survival or stimulate angiogenesis have
been proposed as the molecular mechanisms underlying the pro-
carcinogenic functions of COX-2. The rapid development of safe and
effective inhibitors targeting individual COX enzymes not only
dramatically improved our understanding of the function of COX-2,
but also resulted in discovery of COX independent functions of
NSAIDs, providing important hints for future drug design (4).
Aspirin, a NSAID, can be used for mild to moderate pain control.
Unlike acetaminophen, aspirin serves not only as an analgesic and
antipyretic but also as an anti-inflammatory agent, which can be an
important addition to the therapeutic effect in patients who have
severe inflammatory pain. It is a safe over-the-counter drug widely
used for noncancerous acute pain control and for management and
prophylaxis of MI due to its well-established anti-platelet action.
However, it has to be used very cautiously in cancer patients, as in
high doses required for adequate pain control (650–1000 mg orally
every 4-5 hours) aspirin can cause a number of unwanted side effects,
such as tinnitus, vertigo, hyperventilation, as well as increased risk of
peptic ulcer disease and G-I bleedings. If overdosed, aspirin can cause
C-V instability, exacerbate underlying renal insufficiency, and even
lead to coma with renal failure, metabolic acidosis, and respiratory
arrest (1).
Non-opioid analgesics (NSAIDs, acetaminophen) are the most
basic drugs used from the first to third steps according to the WHO
analgesic ladder. Even after the initiation of the use of opioids,
improvement in pain is observed by the continuation of non-opioid
analgesics. NSAIDs have anti-inflammatory effects and are
particularly effective against somatic pain represented by that due to
bone metastasis. On the other hand, NSAIDs should be prescribed
with adequate attention being paid to side effects (G-I disorders and
nephropathy) due to long-term administration. Acetaminophen with
few side effects is useful for long-term administration, and its use is
recommended (5).
The role of NSAIDs in cancer pain has been well established in the
treatment of mild pain alone or in association with opioids for the
treatment of moderate to severe pain. Acutely, NSAIDs may be more
than mild analgesics, and may provide additional analgesia when
combined with opioids. However, NSAIDs have ceiling effects and
there is no therapeutic gain from increasing dosages beyond those
recommended. As there is no clearly superior NSAID, the choice
810
should be based on experience and the toxicity profile that probably

relates to the COX-1:COX-2 ratio. Among the older drugs, ibuprofen
seems to have these properties. NSAIDs have an opioid-sparing effect.
Although the value of a simple narcotic-sparing effect can be
questioned in cancer pain treatment, the use of NSAIDs can be useful
when the increase in opioid dosage determine the occurrence of opioid
toxicity. Like opioids, NSAIDs should not be considered analgesics
for a specific type or cause of pain. There is a lack of evidence for any
difference between different routes of NSAIDs administration. The
long-term toxicity of NSAIDs in cancer pain is poorly defined due to a
lack of studies. A variety of strategies has been used in an attempt to
reduce the risks associated with NSAID therapy. Concomitant
administration of misoprostol is recommended in patients at increased
risk for upper G-I complications (6).
NSAIDs play a central role for patients with cancer pain as well as
for those with acute pain. Pain management using non-opioid
analgesics need to avoid potential side effects, and the analgesic
action of NSAIDs, COX inhibitors, would synergistically potentiate
opioids' effects via the activation of the periaquaductal grey of the
midbrain. The analgesic action of opioids would also be potentiated
by the activation of alpha 2-adrenoceptors of the spinal cord. Thus, the
use of non-opioid analgesics for cancer patients taking opioid needs
meticulous care. Undertreatment of pain is a persistent clinical
problem for patients with cancer. Although changing medical practice
is difficult and improving pain management with the rational use of
combination of drugs may especially difficult, supplementation of
non-opioid analgesics for opioid treatment would provide a better
QOL of cancer patients (7).
NSAIDs are primarily used for the treatment of acute or chronic
conditions with pain and inflammation. Evidence from a wide range
of sources suggested that chronic administration of NSAIDs reduced
the risk of cancer incidences. Both the epidemiological and animal
studies showed an inverse association between the incidence of
various cancers and the use of aspirin or other NSAIDs. The
chemopreventive and therapeutic interventions of NSAIDs in cancer
are obvious; however, the instigation of drug and treatment period
depends on the study objective. Typically, prevention involves
initiating the medication before the appearance of clinical symptoms
and lasts long-term, while treatment could be short-term and
contingent to the response of patient to the medication. Recent studies
provided substantial evidence on the anti-cancer activity of tolfenamic
811
acid, a NSAID for the potential applications in pancreatic, esophageal

and lung cancers (8).
NSAIDs are potent analgesics, antipyretics, and anti-inflammatory
agents, which makes them useful for cancer related pain of
musculoskeletal origin. They work through nonspecific inhibition of
COX, an enzyme that mediates prostaglandin synthesis from
arachidonic acid. Because of nonspecific inhibition of both
isoenzymes of COX-1 and COX-2, all nonselective NSAIDs have
significant AEs on gastric mucosa and renal parenchyma, and some
inhibit platelet function. With chronic use, they can cause serious
gastric ulcerations and bleeding, which is a result of the inhibition of
COX-1 isoenzyme. Therefore, NSAIDs may not be an optimal choice
in patients who are experiencing nausea and vomiting associated with
receiving chemotherapy or who have a history of G-I bleeding. Care
must be taken in patients who have renal insufficiency related to
advanced age or disease progression because of the potential to
exacerbate these conditions due to modulation of prostaglandin
activity on renal blood flow (9).
The NSAIDs have maximum daily doses that limit their utility in
moderate to severe cancer pain management. All of the NSAIDs are
available orally, while ketorolac is available in parenteral form for
pain control. Indomethacin, like aspirin, is available in suppository
forms for rectal administration (1). The use of NSAIDs is limited to
the alleviation of mild to moderate pain and have been recently
reported to delay bone healing following fracture (10).
NSAIDs are widely applied to treat cancer pain and are frequently
combined with opioids in combination preparations for this purpose.
The Cochrane Central Register of Controlled Trials (Issue 2, 2002),
MEDLINE (January 1966 to March 2003), EMBASE (January 1980
to December 2001), LILACS (January 1984 to December 2001) and
reference list of articles were searched. RCTs and controlled clinical
trials that compared NSAID vs. placebo, NSAID vs. NSAID, NSAID
vs. NSAID plus opioid, opioid vs. opioid plus NSAID, or NSAID vs.
opioid were included. Forty-two trials involving 3084 patients were
included. Seven of 8 papers that compared NSAID with placebo
demonstrated superior efficacy of NSAID with no difference in side
effects. Thirteen papers compared 1 NSAID with another; 4 reported
increased efficacy of 1 NSAID over another. Four different studies
found that 1 NSAID had fewer side effects than 1 or more others did.
Twenty-three studies compared NSAIDs and opioids in combination
or alone with NSAID/opioid combinations. Thirteen out of 14 studies
found no difference, or low clinical difference, when combining a
812
NSAID plus an opioid vs. either drug alone. Comparisons between

various NSAID/opioid combinations were inconclusive. Nine studies
assessed the association between dose and efficacy and safety. Four
papers demonstrated increased efficacy with increased dose, but no
dose-dependent increase in side effects within the dose ranges studied.
Study duration ranged from single dose studies performed over 6
hours to crossover studies lasting 6 weeks; however, the majority of
studies were of less than 7 days duration. Based upon limited data,
NSAIDs appear to be more effective than placebo for cancer pain;
clear evidence to support superior safety or efficacy of one NSAID
over another is lacking; and trials of combinations of an NSAID with
an opioid have disclosed either no difference (4 out of 14 papers), a
statistically insignificant trend towards superiority (1 out of 14
papers), or at most a slight but statistically significant advantage (9 out
of 14 papers), compared with either single entity. The short duration
of studies undermines generalization of their findings on efficacy and
safety of NSAIDs for cancer pain (11).
The effectiveness of diclofenac 50 mg thrice a day as additive
treatment to parenteral patient-controlled administration therapy with
morphine in cancer pain has been investigated in a double-blind study.
In the 15 patients who completed the study, morphine intravenously
was titrated to optimal pain relief over 5 days. The mean total
morphine consumption was significantly reduced during diclofenac
administration (82.8 mg morphine per day) compared to placebo (95.0
mg morphine per day). The reduction in mean morphine consumption
during active treatment with diclofenac was independent of the initial
dose of self-titrated morphine. Pain, self-assessed according to VAS,
tended to be lower during the diclofenac period, although the
difference did not reach statistical significance. No AEs were recorded
among the 15 patients who completed the study. The present findings
show that a NSAID agent, such as diclofenac, has a morphine-sparing
effect in morphine-treated patients with cancer pain (12).
The main objective of this study was to compare the analgesic
efficacy and safety of 2 single doses of ketorolac with diclofenac in
acute cancer pain. In this double-blind, randomized, clinical study
conducted at Hospital-based clinical research center, 180 patients
suffering acute, moderate, or severe cancer pain were studied.
Interventions included a single intramuscular injection of ketorolac 10
or 30 mg or diclofenac 75 mg. Pain intensity was assessed 30 minutes
and 1, 2, 3, 4, 5, and 6 hours after injection or until rescue drug
administration. In approximately 70% of patients, all treatments
provided prompt sustained pain relief throughout the 6-hour
813
observation period. There were statistically insignificant differences in

any of the analyzed efficacy measures among the 3 groups. In
conclusion, intramuscular ketorolac 10 mg is adequate to relieve
cancer pain, and is equivalent to ketorolac 30 mg and to diclofenac 75
mg (13).
Sixty-four patients with advanced cancer pain were treated with
either nimesulide or diclofenac as initial analgesia. Patients were
randomly allocated to 1 of 4 treatment groups: oral nimesulide 300
mg/day, oral diclofenac 150 mg/day, rectal nimesulide 400 mg/day,
and rectal diclofenac 200 mg/day. After 1 week of treatment, both
drugs provided an adequate degree of pain relief and allowed an
increase in sleep duration. There were insignificant differences in
efficacy between the drugs or routes of administration. Fewer side
effects were observed with nimesulide, giving this agent a better
therapeutic index than the reference compound (14).
In a single blind random study, simultaneously carried out by 5
Pain Therapy and Palliative Care Centers, the analgesic power and
side-effects of sodium naproxen (CAS 26159-34-2) and sodium
diclofenac (CAS 15307-86-5) by mouth were compared in a group of
100 advanced cancer patients. The patients complained of somatic
and/or visceral pain and were treated with NSAIDs as required. The
dose administered amounted to 550 mg every 12 hours for sodium
naproxen and to 100 mg every 12 hours for sodium diclofenac. The
study stressed the similar analgesic effect of the 2 drugs - pain
intensity and duration decreased by half in the first week of treatment
and a comparatively low morbidity rate was observed (15).
Celecoxib (Celebrex) was developed as a selective COX-2
inhibitor for the treatment of chronic pain. However, this compound
harbors additional pharmacologic activities that are entirely
independent of its COX-2-inhibitory activity. The recently emerged
direct non-COX-2 targets of celecoxib and their proposed role in
mediating this drug's antitumor effects can be demonstrated (16).
COX-2 inhibitors (rofecoxib, celecoxib, and valdecoxib) have less
potential for G-I and hematological side effects seen with the
traditional NSAIDs, a factor that makes them more attractive for
cancer pain management. These drugs specifically inhibit the COX-2
isoenzyme, which is considered the inducible isoenzyme during
painful stimuli. This selectivity spares the inhibition of COX-1, which
is constitutive in the G-I tract and required for normal G-I function. In
addition, an antitumoral effect with these agents is due to inhibition of
cytokine production seen in many solid tumors (17). This class of
drugs is an attractive option in those patients with cancer involving
814
inflammation and those who are at high risk for G-I bleeding or
platelet dysfunction. COX-2 inhibitors may also be considered as one
of the most effective agents for patients with bone metastasis as
prostaglandins appear to play an important role in pathogenesis of
bone pain (18). In addition, smaller doses of opioids can be used with
COX-2 inhibitors thereby minimizing potential risk for opioid side
effects. Because of their relatively short half-lives, they are also
capable of treating BTP (1).
However, like NSAIDs, COX-2 inhibitors should be used with
caution with patients at risk for renal failure (19). The overall safety of
COX-2 inhibitors, particularly rofecoxib, has recently come into
question due to increased risk of acute MI and sudden cardiac death
among high-dose chronic users of this drug (20, 21), which led to
voluntarily withdrawal of rofecoxib (Vioxx®) from the US market in
2004 (22). On the other hand, the majority of patients with
disseminated MBD will accept the risk of having a heart attack while
on COX-2 inhibitors as opposed to living with unbearable pain or
experiencing severe side effects from high-dose opioid therapy.
Therefore, COX-2 inhibitors may still serve as a good option for relief
of musculoskeletal pain in patients with terminal cancer. No parenteral
forms of COX-2 inhibitors are commercially available at present in
the US (1).
More than half of all chronic cancer pain arises from metastases to
bone, and bone cancer pain is one of the most difficult of all persistent
pain states to fully control. Several tumor types including sarcomas
and breast, prostate, and lung carcinomas grow in or preferentially
metastasize to the skeleton where they proliferate, and induce
significant bone remodeling, bone destruction, and cancer pain. Many
of these tumors express the isoenzyme COX-2, which is involved in
the synthesis of prostaglandins. To begin to define the role COX-2
plays in driving bone cancer pain, in vivo model was used where
murine osteolytic 2472 sarcoma cells were injected and confined to
the intramedullary space of the femur in male C3HHeJ mice. After
tumor implantation, mice develop ongoing and movement-evoked
bone cancer pain-related behaviors, extensive tumor-induced bone
resorption, infiltration of the marrow space by tumor cells, and
stereotypic neurochemical alterations in the spinal cord reflective of a
persistent pain state. Thus, after injection of tumor cells, bone
destruction is first evident at day 6, and pain-related behaviors are
maximal at day 14. A selective COX-2 inhibitor was administered
either acutely (NS398; 100 mg/kg, intraperitoneal) on day 14 or
chronically in chow (MF. tricyclic; 0.015%, orally) from day 6 to day
815
14 after tumor implantation. Acute administration of a selective COX-

2 inhibitor attenuated both ongoing and movement-evoked bone
cancer pain, whereas chronic inhibition of COX-2 significantly
reduced ongoing and movement-evoked pain behaviors, and reduced
tumor burden, osteoclastogenesis, and bone destruction by > 50%.
Thus, chronic administration of a COX-2 inhibitor blocks
prostaglandin synthesis at multiple sites, and may have significant
clinical utility in the management of bone cancer and bone cancer pain
(23).
The aim of this study was to verify the effects of NSAIDs on
morphine escalation in advanced cancer patients with pain followed-
up at home and to assess the pharmacoeconomic implications. A
prospective RCT was carried out in 156 consecutive advanced cancer
patients with pain followed-up at home in the period December 1999-
December 2000. In this group of patients, 47 were selected with pain
progression after 1 week of opioid stabilization. Patients were
randomly assigned to 1 of 2 groups: group 'O' patients were treated
with continuing opioid escalation according to their clinical needs;
group 'OK' received ketorolac 60 mg/daily PO in 3 doses and then
continued opioid escalation according to their clinical situation.
Performance status, doses of morphine before and after starting
treatment, mean weekly pain intensity (assessed by means of a PRS
from 0 to 10), mean weekly symptoms intensity, AEs and pain
mechanisms were recorded. Moreover, drug costs per day in both
groups were calculated. Patients who received ketorolac in addition to
morphine showed a better analgesia after a week in comparison to the
group treated with morphine only (p=0.005). Thereafter, morphine
escalation was slower and the maximum morphine dose was lower in
the group treated with ketorolac. The incidence and the severity of
gastric discomfort were more evident in patients treated with
ketorolac, while constipation was significantly increased in patients
who received morphine only. The use of NSAIDs reduces the need for
an opioid dose escalation or allows the use of lower doses. Their use is
associated with a more intense gastric discomfort, but results in less
opioid-related constipation. The eventual additive cost for NSAIDs
therapy is negligible, especially in patients taking high doses of
morphine (24).
The study aim was to investigate potential analgesic benefits of 4
grams of paracetamol daily for palliative cancer patients requiring
high-dose opioids. Thirty-one patients, using at least 200 mg of oral
morphine equivalent daily, were recruited to a prospective, double-
blinded, randomized, crossover trial. Patients received usual
816
medications plus 4 grams of paracetamol or placebo for 5 days each in

random order. Primary outcome, effect on pain, was assessed using
daily diaries, including a NRS from zero (no pain) to 10 (unbearable)
and recording numbers of breakthrough analgesics. Secondary
outcomes - nausea, vomiting, cognitive impairment, constipation, and
overall well-being were assessed using the NRS. Data from the last 4
days of each treatment were analyzed. Patients also indicated in which
part of the study their pain was better controlled. Twenty-two patients,
requiring a median dose of 255 mg of oral morphine equivalent daily,
completed the trial. For none of the variables was there a statistically
significant difference when assessed with placebo compared with
paracetamol. No change approached clinically significant levels, with
a MD in rated pain of 0.16, and MD of 0.42 for a number of
breakthrough medications. Fifteen patients were undecided whether
paracetamol improved pain. In conclusion, these data do not support
the common practice of adding regular paracetamol daily as an
adjunct to high-dose opioids for pain control in cancer patients
receiving palliative care (25).
Assessment: non-opioid analgesics are the most basic drugs used

from the first to third steps according to the WHO analgesic ladder.
NSAIDs play a central role for patients with cancer pain as well as for
those with acute pain. NSAIDs are potent analgesics, antipyretics, and
anti-inflammatory agents, which makes them useful for cancer related
pain of musculoskeletal origin.
NSAIDs have anti-inflammatory effects and are particularly
effective against somatic pain due to bone metastasis. On the other
hand, NSAIDs should be prescribed with adequate attention being
paid to side effects (G-I disorders and nephropathy) due to long-term
administration.
For relieving any underlying inflammatory process, anti-
inflammatory agents are likely to be useful, whether they are non-
steroidal or steroidal in their composition. The use of these
medications helps control the toxic chemical events leading to the
sensitization of the peripheral nervous system and the further
experience of pain in response to injury. Which anti-inflammatory
drug is used is less important than some agent is administered for
relief of pain. Although the toxicity profiles for NSAIDs vary, there is
the ability of these agents to relieve inflammation and pain. When
inflammation plays a role in the development and experience of pain,
relieving the inflammation is likely.
COX-2 inhibitors (rofecoxib, celecoxib, and valdecoxib) have less
potential for G-I and hematological side effects seen with the
817
traditional NSAIDs, a factor that makes them more attractive for

cancer pain management. These drugs specifically inhibit the COX-2
isoenzyme, which is considered the inducible isoenzyme during
painful stimuli.
NSAIDs are effective for cancer pain, clear evidence to support
superior safety or efficacy of one NSAID over another is lacking; and
in trials of combinations of an NSAID with an opioid have disclosed
either no difference, a statistically insignificant trend towards
superiority, or a slight but statistically significant advantage. There is
a lack of evidence for any difference between different routes of
NSAIDs administration.
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OPIOD ANALGESIC AGENTS

Opioids are the mainstay of treatment for moderate to severe
cancer pain. In recent years, there have been many advances in the use
of opioids for cancer pain. Availability and consumption of opioids
have increased and opioids other than morphine (including
methadone, fentanyl, and oxycodone) have become more widely used.
Inter-individual variation in response to opioids has been identified as
a significant challenge in the management of cancer pain. Many
studies have been published demonstrating the benefits of opioid
switching as a clinical maneuver to improve tolerability. Constipation
has been recognized as a significant burden in cancer patients on
opioids. Peripherally restricted opioid antagonists have been
developed for the prevention and management of opioid induced
constipation. The phenomenon of BTP has been characterized and
novel modes of opioid administration (transmucosal, intranasal, or
819
sublingual) have been explored to facilitate improved management of

BTP of cancer. Advances have also been made in the realm of
molecular biology. Pharmacogenetic studies have explored
associations between clinical response to opioids and genetic variation
at a DNA level. To date these studies have been small but future
research may facilitate prospective prediction of response to
individual drugs (1).
Opioids work by binding to μ-opioid receptors within the CNS,
which are responsible for opioid-mediated analgesia, respiratory
depression, sedation, physiological dependence, and tolerance (2).
Analgesic effect of opioids is largely dependent on μ-receptor
saturation and is thus influenced by the type and severity of the pain,
prior exposure to opioids, and individual distribution of receptors (3).
There is no maximum dose for these agents; they are only limited by
the development of side effects that are patient specific in their onset
and severity. Common opioid side effects include nausea,
constipation, sedation, and confusion, and they can be managed
without compromising pain control by adjusting the daily dose of the
drug or in persistent cases by instituting additional medications, such
as metoclopramide for nausea, laxatives for constipation, or
methylphenidate for sedation (4).
The opioids are typically the most common drug class used in the
treatment of cancer pain (2). Appropriate and successful management
of pain with opioid analgesics is based on tailoring pharmacologic
treatment to the individual and identifying the minimal effective dose
at which pain is controlled with minimal AEs. Morphine and
morphine-like-agonists exhibit similar pharmacodynamic profiles, but
substantially different receptor affinities and pharmacokinetic
properties, which dictate the dosage, route and regimen required to
achieve analgesic effect. Opioids exhibit differences in drug
elimination resulting in marked variations in the plasma half-life
value. Although fentanyl is more potent than morphine, with a shorter
duration of action than parenteral morphine, its oral bioavailability is
poor and it is administered transdermally. Morphine, with a short half-
life and a time to steady-state plasma concentrations of 10-12 hours is
better suited than TDF for initial opioid therapy and for the treatment
of unstable pain, which requires a fluctuating opioid dose.
International guidelines recommend normal-release morphine for
initial optimization of individual dose because its pharmacokinetics
allow 'real-time' dose regimen changes and rapid identification of the
dose required for pain control. Once an effective normal-release
morphine dosage is achieved, other administration routes,
820
formulations and opioids can be considered as required. Despite

guidelines advocating that TDF should only be used in patients who
are tolerant to strong opioid therapy, in Italy and other European
countries, CR or transdermal opioids are often used when starting
opioid therapy. Opioids are associated with a wide range of adverse
reactions, but these can be minimized with careful drug titration and
maintenance. A major challenge with pain control is polypharmacy
and the risk of pharmacokinetic or pharmacodynamic drug-drug
interactions. Prevention and management of interactions rely on
careful and timely adjustment of drug regimens involved, according to
the severity of the effect. Dose titration is the key to successful
therapy initiation with strong opioids in patients with moderate-to-
severe pain. It is the only way to establish the optimal and minimal
effective dose and provides the best protection against AEs.
Committed physicians should adhere to guidelines on the appropriate
use of opioids in all patients, particularly those with a high risk of
adverse reactions (5).
Prolonged use of opioids may lead to development of tolerance
(the need to increase opioid dose with time to maintain equipotent
analgesic effects) and opioid-induced abnormal hypersensitivity to
pain (so-called pro-nociceptive sensitization). Experimental studies
suggest that both phenomena could be related to NMDA receptor
mediated changes in CNS (6-8). Opioid desensitization and
hypersensitization of NMDA receptors from prolonged opioid therapy
may both contribute to an apparent decrease in analgesic efficacy,
regardless of the progression of the pain. Thus, in some instances,
treating increasing pain with increasing doses of same opioid may be
futile (9). Although this has not been shown conclusively in the
clinical setting, NMDA receptor antagonists (ketamine,
dextromethorphan, memantine, and amantadine) and low-dose opioid
antagonists (naloxone, or naltrexone) might partially reverse opioid
tolerance. In addition, because the cross-tolerance to opioids is
incomplete, opioid rotation (switching from one opioid to another) can
be also used to overcome the unwanted AEs of opioid receptor
desensitization (4,10,11).
Exogenous opioids may also affect hormonal and immune systems
with prolonged use, leading to reduced fertility, libido, and drive,
along with moderate immunosuppression (9,12). However, in cases of
chronic cancer pain these AEs of opioid therapy, along with fear of
physical dependence and addiction, are not very important and should
not prevent the physician from providing adequate pain control to the
patient (4).
821
A wide variety of opioids are currently available in the market, and

are roughly categorized into CR (or sustained), such as MS Contin®,
Avinza®, Kadian®, Oxycontin®, Duragesic®, and IR formulations,
such as MSIR, Oxycodone, Hydromorphone, Actiq®, etc. (4).
Chronic use of opiates results in several unwanted side effects
including analgesic tolerance, somnolence, constipation, respiratory
depression and paradoxical states of hyperalgesia (13). However,
murine bone cancer models treated with sustained morphine not only
intensifies pain after a week of treatment but also accelerates bone
destruction when compared to vehicle treated animals (14).
Opioid analgesic agents also can be used in the setting of acute
pain; their benefits generally outweigh their few significant risks (e.g.,
sedation, constipation, nausea, vomiting, itching, and respiratory
depression). Providing opioid analgesic agents have become the
standard of care for postoperative pain management. The optimal
analgesic dose varies widely among patients, especially among age
groups. There is enormous variability in the dose of opioids required
to provide pain relief, even among opioid-naive patients with identical
surgical lesions. This great variability underscores the need to write
analgesic orders that include provisions for supplementary doses and
to use intravenous boluses and infusions to provide rapid relief of
severe pain. An oral route of administration is generally preferred for
most patients with pain, whether acute or chronic. However, when
patients cannot tolerate orally administered analgesics or when the
onset of pain is so rapid that it must be treated rapidly, alternative
routes (e.g., rectal, buccal, sublingual, intravenous, subcutaneous,
transdermal, nasal-spray, intraspinal and epidural) should be
considered. The potential of the sublingual route has been successfully
exploited by fentanyl and buprenorphine products but is not as well
established for morphine. Moreover, the latter drug has relatively poor
buccal absorption; lipophilic medications are better absorbed buccally.
Today, there is considerable interest in semisynthetic opioid agents,
which avoid the known toxicity associated with meperidine and
morphine. Higher doses of meperidine have caused confusion,
delirium, hallucinations, and seizures because of the accumulation of
the metabolite normeperidine, and patients with compromised renal
function are particularly at risk for having CNS toxicity.
Administration of naloxone does not reverse and may even exacerbate
this hyperexcitability. For these reasons, meperidine should not be
used for acute pain in patients who have renal or CNS disease and
should not be given to those without such diseases for more than 48
822
hours or at doses greater than 600 mg/24 hours; the drug should not be
prescribed for chronic pain (15-17).
In all recommended guidelines put forth for the treatment of cancer
pain, opioids continue to be an important part of a physician's
armamentarium. Though opioids are used regularly for cancer pain,
there is a paucity of literature proving efficacy for long-term use.
Cancer is no longer considered a "terminal disease"; 50-65% of
patients survive for at least 2 years, and there are about 12 million
cancer survivors in the US. There is a concern about side effects,
tolerance, abuse and addiction with long-term opioid use and a need to
evaluate the effectiveness of opioids for cancer pain (18).
The main aim of this study was to evaluate the performance and
quality of cancer pain management in hospital settings.
Anaesthesiologists specialized in pain and palliative medicine studied
pain management in departments of oncology and surgery. Study days
were randomly chosen and patients treated with oral opioids were
included. Information regarding pain etiology and mechanisms, pain
medications and opioid side effects were registered from the medical
records and by examining patients. Pain intensity was assessed using
the BPI. In total, 59 cancer patients were included. In 49 (83%)
patients, pain etiology was assessed by the physicians of the
departments of oncology and surgery. In only 19 (32%) patients, they
assessed pain mechanisms. The median oral morphine dose was 120
mg/day (range 10-720 mg/day). Of patients, 78% received opioids at
adequate regular intervals according to the duration of action. In 88%
of patients, supplemental short-acting oral opioids were given on
demand and the median supplemental oral dose was 16.5% of the
daily dose. Seven patients with neuropathic pain received adjuvant
drugs, whereas 6 patients with non-neuropathic pain received adjuvant
drugs. Regarding opioid side effects, only constipation and nausea
were treated in the majority of the patients. Average pain intensity in
the last 24 hours for the total number of patients (n=59) ≤ 5 cm was
88.1% (CI 77.1 - 95.1) In conclusion, cancer pain was prevalent in
opioid-treated patients in hospital settings: however, focusing on
average pain intensity, the outcome seems favorable compared with
other countries. Pain mechanisms were seldom examined and adjuvant
drugs were not specifically used for neuropathic pain. Opioid dosing
intervals and supplemental opioid doses were most often adequate.
However, opioid side effects were highly prevalent and most side
effects were left untreated (19).
823
Assessment: opioids are the mainstay of treatment for moderate to

severe cancer pain. Appropriate and successful management of pain
with opioid analgesics is based on tailoring pharmacologic treatment
to the individual and identifying the minimal effective dose at which
pain is controlled with minimal AEs. In the treatment of cancer pain,
opioids continue to be an important part of a physician's
armamentarium. A wide variety of opioids are currently available in
the market, and are roughly categorized into CR (or sustained), and IR
formulations.
Chronic use of opiates results in several unwanted side effects
including analgesic tolerance, nausea, vomiting, itching, sedation,
somnolence, constipation, respiratory depression and paradoxical
states of hyperalgesia. These adverse reactions can be minimized with
careful drug titration and maintenance.
An oral route of administration is generally preferred for most
patients with pain, whether acute or chronic. However, when patients
cannot tolerate orally administered analgesics or when the onset of
pain is so rapid that it must be treated rapidly, alternative routes (e.g.,
rectal, buccal, sublingual, intravenous, subcutaneous, transdermal,
intraspinal, and epidural) should be considered.
References
1. Droney J, Riley J. Recent advances in the use of opioids for cancer pain. J Pain
Res. 2009;2:135-55.
2. Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbrid E, editors.
Goodman and Gilman‘s the Pharmacological Basis of Therapeutics. 10. New York:
McGraw-Hill Professional. 2001, pp. 569–619.
3. Friedman LL, Rodgers PE. Pain management in palliative care. Clin Fam Pract.
2004;6:371.
4. Nersesyan H, Slavin KV. Current approach to cancer pain management:
2007;3(3):381-400.
5. Geppetti P, Benemei S. Pain treatment with opioids: achieving the minimal
effective and the minimal interacting dose. Clin Drug Investig. 2009;29 Suppl 1:3-16.
6. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the
NMDA receptor antagonist MK-801. Science. 1991;251:85–7.
7. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and opiate tolerance:
a current view of their possible interactions. Pain. 1995;62:259-74.
8. Alvarez V, Arttamangkul S, Williams JT. A RAVE about opioid withdrawal.
Neuron. 2001;32:761-63.
9. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med.
2003;349:1943–53.
10. Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects.
Cancer. 1999a;86:1856–66.
11. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain
management. The Oncologist. 2004;9:571-91.
824
12. Finch PM, Roberts LJ, Price L, et al. Hypogonadism in patients treated with
intrathecal morphine. Clin J Pain. 2000;16:251-54.
13. Vanderah TW, Luis R, Gardell LR, et al. Dynorphin promotes abnormal pain
and spinal opioid antinociceptive tolerance. J Neuroscience. 2000;20(18):7074–9.
14. King T, Vardanyan A, Majuta L, et al. Morphine treatment accelerates
sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of
bone cancer. Pain. 2007;132(1–2):154–68.
15. Max MB, Payne R, Edwards WT, et al. Principles of analgesic use in the
treatment of acute pain and cancer pain. 4th ed. Glenview (IL): American Pain
Society. 1999.
16. Kornick CA, Santiago-Palma J, Moryl N, et al. Benefit-risk assessment of
transdermal fentanyl for the treatment of chronic pain. Drug Safety. 2003;26:951-73.
17. Lyseng-Williamson KA. Fentanyl pectin nasal spray: in breakthrough pain in
opioid-tolerant adults with cancer. CNS Drugs. 2011;25(6):511-22.
18. Koyyalagunta D, Bruera E, Solanki DR, et al. A systematic review of
randomized trials on the effectiveness of opioids for cancer pain. Pain Physician.
2012;15(3 Suppl):ES39-58.
19. Lundorff L, Peuckmann V, Sjøgren P. Pain management of opioid-treated
cancer patients in hospital settings in Denmark. Acta Anaesthesiol Scand.
2008;52(1):137-42.
TRAMADOL
Weak opioids have been used as analgesics in cancer patients with
moderate to severe chronic pain (1). One of the most useful weak
opioids is tramadol (Adolonta, Contramal, Nobligan, Top-Algic,
Tramal, Tramal Long, Tramal Retard, Tramundin, Trodon, Ultram,
Zydol). Its unique mechanism of action, analgesic efficacy and profile
of adverse reactions have been the reason of performing many
experimental and clinical studies (2)
Tramadol is a centrally acting nonopiate analgesic with low
affinity for μ-opioid receptors, and is effective in the treatment of
moderate to severe pain. Tramadol inhibits reuptake of serotonin and
norepinephrine, which synergistically enhances its weak opioid
mechanism of action (3,4). This may explain the reduced incidences
of abuse, respiratory depression and other AEs of traditional opioids
in patients on long-term tramadol therapy (5). Tramadol can be
beneficial in patients who fail non-opioid therapy and wish to delay
taking opioids avoiding the common side effects of constipation,
somnolence, and fatigue. It is effective in such nonmalignant opioid-
resistant chronic pain states as fibromyalgia and DPN (6,7), and has
marginal to moderate success in the treatment of chronic cancer pain
(8). Unlike the NSAIDs, tramadol has no anti-inflammatory activity,
is extensively metabolized in the liver and is available in tablet form
only (9).
825
The main aim of this study was to analyze the evidence supporting
the widespread use of modified analgesic ladders or oral tramadol as
alternatives to codeine/paracetamol for mild to moderate cancer pain.
A systematic review of the literature was independently performed by
2 authors. The level of evidence and risk/benefit ratio were assessed in
all the selected trials. A comprehensive analysis of the level of
evidence, risk/benefit ratio and strength of the recommendations was
carried out. The analysis was performed using the GRADE system.
Eighteen papers were included into the analysis. The level of evidence
was low or very low for all the trials, and as a result, the risk/benefit
ratio was uncertain. Likewise, the strength of the final
recommendations was considered weak negative for either the use of
modified analgesic ladders (bypassing the second step of the WHO
analgesic ladder) or the use of oral tramadol as an alternative to
codeine/paracetamol in the second step of the WHO analgesic ladder.
Data supporting the role of modified two-step analgesic ladders or oral
tramadol as an alternative to codeine/paracetamol are insufficient to
recommend their routine use in cancer patients with mild to moderate
cancer pain (10).
References
1. Shiratsuchi T, Ogawa S. Weak opioids. Nihon Rinsho. 2001;59(9):1795-9.
2. Leppert W, Łuczak J. The role of tramadol in cancer pain treatment - a review.
Support Care Cancer. 2005;13(1):5-17.
3. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components
independently contribute to the mechanism of action of tramadol, an ‗atypical‘ opioid
analgesic. J Pharmacol Exp Ther. 1992;260:275-85.
4. Desmeules JA, Piguet V, Collart L, et al. Contribution of monoaminergic
modulation to the analgesic effect of tramadol. Br J Clin Pharmacol. 1996;41:7-12.
5. Raffa RB. Pharmacology of oral combination analgesics: rational therapy for
pain. J Clin Pharm Ther. 2001;26:257-64.
6. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of
tramadol for the treatment of the pain of diabetic neuropathy. Neurology.
1998;50:1842–46.
7. Russell IJ, Kamin M, Bennett RM, et al. Efficacy of tramadol in treatment of
pain in fbromyalgia. J Clin Rheumatol. 2000;6:250-57.
8. Grond S, Zech D, Lehmann K, et al. Transdermal fentanyl in the long-term
treatment of cancer pain: a prospective study of 50 patients with advanced cancer of
the gastrointestinal tract or the head and neck region. Pain. 1997;69:191–98.
2007; 3(3):381–400.
10. Tassinari D, Drudi F, Rosati M, et al. The second step of the analgesic ladder
and oral tramadol in the treatment of mild to moderate cancer pain: a systematic
review. Palliat Med. 2011;25(5):410-23.
826
CODEINE
Codeine is one of the weak opioids which is assigned as a
representative analgesic of the 2nd ladder-drugs for the treatment of
cancer pain by WHO cancer pain relief program (1). Codeine mediates
its analgesic effect through the active metabolite morphine, a reaction
which is catalyzed by the cytochrome P450-isoenzyme CYP2D6.
Approximately 7-10% of the population does not express functional
CYP2D6; for them codeine have no analgesic effect. They may,
however, experience side effects from codeine. Used alone, codeine is
an inefficient analgesic (2).
Codeine is designated as one of the essential medicines of
palliative care for symptoms such as pain and diarrhea. Essential
drugs for palliative care are drugs that are effective for the treatment
of common symptoms in palliative medicine, easily available, and are
affordable. Codeine is recommended for the management of mild to
moderate pain and is available as a combination product or as a stand-
alone opioid. It is a prodrug and exhibits an affinity to micro-opioid
receptors 200 times lower than morphine. Codeine is metabolized in
the liver to inactive metabolites, which account for 90% of the
transformed product, and morphine, which accounts for 10% of the
transformed product and provides the main analgesic effect. The
production of morphine is dependent on cytochrome oxidase 2D6
enzyme activity, which may not be fully active in some populations
(3). Analgesic effect of codeine is recognized when it is administered
with 20 mg orally or more. Clinical ceiling effect of codeine is seemed
to be 200-300 mg/day, although it is described as 600 mg/day. Side
effects of codeine are same as those of morphine; therefore, drugs for
the side effects should be given to the patients simultaneously when
codeine is administered (1).
The purpose of this study was to evaluate the clinical efficacy and
safety of CR codeine given every 12 hours in patients with cancer
pain. Thirty-five patients with chronic cancer pain were randomized in
a double-blind crossover study to CR codeine or placebo, for 7 days
each. Pain intensity was assessed at 08.00 hour and 20.00 hour using a
VAS and a 5-point categorical scale, and the use of "rescue"
acetaminophen-plus-codeine (300 mg/30 mg every 4 hours as needed)
was recorded. Thirty patients completed the study (17 male, 13
female; mean age, 64.4 +/- 9.8 years) with a mean daily CR codeine
dose of 277 +/- 77 mg (range, 200-400 mg). CR codeine treatment
resulted in significantly lower overall VAS pain intensity scores (22
+/- 18 mm vs. 36 +/- 20 mm, p=0.0001), categorical pain intensity
827
scores (1.2 +/- 0.8 vs. 1.8 +/- 0.8, p=0.0001), and pain scores when
assessed by day of treatment and by time of day. Daily "rescue"
analgesic consumption was significantly lower on CR codeine,
compared to placebo treatment (2.2 +/- 2.3 vs. 4.6 +/- 2.8 tablets per
day, p=0.0001). Both patients and investigators preferred CR codeine
to placebo (80% vs. 3%, p=0.0014 and 73% vs. 7%, p=0.0160,
respectively). These data indicate that CR codeine, given every 12
hours results in significant reductions in pain intensity and the use of
"rescue" acetaminophen-plus-codeine in patients with cancer pain. CR
provides the benefits of a flexible single entity codeine formulation
and the convenience of 12-hours duration of action, which allows
patients uninterrupted sleep and improved compliance (4).
Terminal lung cancer patient with severe back pain and dyspnea
refused the use of morphine, and succeeded in home palliative care
with the use of an original prescription (CA), the main ingredient of
which was codeine phosphate (5).
Meta-analyses have shown little therapeutic advantage by adding
codeine to paracetamol. Codeine is an opiate with uncertain and
unpredictable effects. The therapeutic benefit from the codeine
component in combination with paracetamol is small, even in single
dose evaluations. In chronic use, the therapeutic efficacy is most likely
outweighed by side effects, including development of tolerance and
abuse (2).
References
1. Shiratsuchi T, Ogawa S. Weak opioids. Nihon Rinsho. 2001;59(9):1795-9.
2. Helland A, Spigset O, Slørdal L. Problem forte - is paracetamol-codeine
combination rational? Tidsskr Nor Laegeforen. 2004;124(16):2084-7.
3. Prommer E. Role of codeine in palliative care. J Opioid Manag. 2011;7(5):
401-6.
4. Dhaliwal HS, Sloan P, Arkinstall WW, et al. Randomized evaluation of
controlled-release codeine and placebo in chronic cancer pain. J Pain Symptom
Manage. 1995;10(8):612-23.
5. Ishiguro T, Kato H, Takahashi M, et al. Home drug therapy for a patient who
rejected use of morphine - management of dyspnea and pain by codeine phosphate.
Gan To Kagaku Ryoho. 2000;27 Suppl 3:697-9.
HYDROCODONE
Hydrocodone is an epoxy-methoxy-methylmorphinan
semisynthetic opioid (6-deoxy-3-O-methyl-6-oxomorphine hydrogen
tartrate hemipentahydrate), which is structurally related to codeine,
and is classified as a step 2 opioid on the WHO stepladder for pain.
828
Hydrocodone is typically found in fixed dose combination with

acetaminophen and is often used for pain management. Hydrocodone
is a heavily prescribed drug and it is important to understand the
evidence base that is guiding this use (1).
For patients with mild to moderate cancer pain opioid analgesic
therapy may start with the trial of codeine or hydrocodone. Codeine is
a weak opium alkaloid with a potency 1/10 of morphine.
Hydrocodone is a more potent hydrogenated ketone derivative of
codeine, which is typically available only as a combination product
with acetaminophen (Vicodin, Norco) or ibuprofen (Reprexain,
Vicoprofen). Although both these drugs are very well suited for the
treatment of different mild to moderate pain syndromes, they have
almost no role in the treatment of severe chronic cancer pain (2).
With the objective of comparing incidence of AEs of the opioids
codeine, hydrocodone, and tramadol in the relief of cancer pain, in a
RCT patients with cancer were randomly assigned according to a
computer-generated schedule to receive 1 of the 3 opioids. Of 177
patients, 62 patients received hydrocodone, 59 patients received
codeine, and 56 patients received tramadol. The pain originated most
frequently from the stomach, breast, or prostate gland and was
classified as somatic (33%), visceral (52%), mixed (6%), or
neuropathic (9%). At the first visit, 60% of the patients described their
pain intensity as moderate (4-6/10), with the remaining 40% of the
patients describing their pain as severe (7-10/10). The symptoms most
associated with pain were weakness, insomnia, and anorexia. In 77%
of the total number of cases, the patient was aware of his/her diagnosis
prior to admittance to the palliative care unit. Of the total number of
cases, 57% fell in the age range of 60-89 years and 50% of the
participants were female. Insignificant statistical difference was found
in the analgesic efficacy of the 3 opioids (p=0.69). Use of tramadol
produced higher rates of AEs than codeine and hydrocodone:
vomiting, dizziness, loss of appetite, and weakness (p<0.05) (3).
Hydrocodone, a semisynthetic opioid, has been used for decades as
a short-acting analgesic combined with acetaminophen (or less
commonly ibuprofen). Several long-acting, non-acetaminophen-
containing hydrocodone formulations are undergoing trials in the US
under the auspices of the US FDA, and may be available shortly.
There are some of the advantages (including drug familiarity and lack
of acetaminophen toxicity) and potential disadvantages (including
altered use patterns and high morphine equivalent dosing) of such a
medication formulation (3).
829
References
1. Prommer E. Hydrocodone: does it have a role in palliative care? J Opioid
Management. 2010;6(4):295-9.
2. Fukshansky M, Are M, Burton AW. The role of opioids in cancer pain
management. Pain Practice. 2005;5:43–54.
3. Rodriguez RF, Bravo LE, Castro F, et al. Incidence of weak opioids adverse
events in the management of cancer pain: a double-blind comparative trial. J Palliat
Med. 2007;10(1):56-60.
3. Krashin D, Murinova N, Trescot AM. Extended-release hydrocodone - gift or
curse? J Pain Res. 2013;6:53-7.
OXYCODONE
The traditional ―gold standard‖ of pure single-entity opioid agents
used for the management of chronic pain has generally been
morphine. However, the accumulation of the morphine metabolites
morphine-3-glucuronide and morphine-6-glucuronide can cause
significant problems with long-term and high-dose oral morphine
therapy (1). As an alternative to morphine is oxycodone, with or
without acetaminophen or aspirin, is an excellent orally administered
analgesic agent. Physicians must always carefully consider the risks
associated with using fixed-combination products containing a
specific amount of acetaminophen (or ibuprofen) and a fixed amount
of analgesic agents (i.e., hydrocodone or oxycodone) over time, in
light of potential hepatic and renal toxicity (2).
Use of CR single-entity oxycodone only, either initially or after
converting from another combination opioid-containing product,
allows for the continued use of the same opioid analgesic agent, from
mild, through moderate, to severe pain (2).
Oxycodone is a synthetic opioid that is metabolized hepatically to
the active oxymorphone (3). The compound oxycodone injection, but
not pure oxycodone, has been available since the 1920's in Japan. The
compound, containing oxycodone and hydrocotarnine, can be
subcutaneously administered. Hydrocotarnine is a non-narcotic opium
alkaloid. Nowadays, along with the increase in the prescription
frequency of oral oxycodone, the compound oxycodone injection is
regarded as an important alternative in palliative care. This study
examines the safety and efficacy of the continuous oxycodone
subcutaneous administration. Ninety-seven patients were naively
administered the compound for cancer pain control and the mean
administered period was 18. 0 +/- 15.5 days. Of all cases, 61.9% were
switched from oral oxycodone. The efficacy in cancer pain control
830
was evaluated for the first 2 weeks using a NPRS (0, no pain, and 10,
imaginary worst). They had statically pain control improvement from
6.8 +/- 2.8 on administration to 2.4 +/- 2.5 1 week later, 1.7 +/- 1.9 2
weeks later, and 2.3 +/-2.6 on the last observation day of the study
(p<0.001). One week later on administration, insignificant AEs were
in the serology, conscious level, and subjective symptoms of nausea
and vomiting. AEs difficult to manage were experienced in 7 (2%),
including delirium, constipation, nausea and vomiting, vertigo, and
local skin toxicity on the injected site. All episodes were experienced
within 16 days of compound administration, which had been followed
by switching to fentanyl or subcutaneous morphine injection. The
conversion ratio from compound oxycodone injection to oral
oxycodone was 1.43 without adjustment required (n=35). This
compound can be regarded as a pure oxycodone injection using
continuous subcutaneous administration. The continuous
subcutaneous administration of the compound oxycodone injection
should be effective and safe in clinical use for cancer pain control (4).
The main objective of this study was to evaluate the
pharmacodynamic effects (subjective and physiologic) of a new
formulation of IR oxycodone HCl (IRO-A; Oxecta™) tablets
compared with IR oxycodone HCl (IRO; Roxicodone®) tablets when
crushed and administered intranasally to nondependent recreational
opioid users. Single-center, single-dose, randomized, double-blind,
active-controlled 2-way crossover study was carried out at inpatient
Clinical Pharmacology Unit, Toronto, Canada. Participants included
nondependent, recreational opioid users aged 18-55 years. Subjects
able to discriminate intranasally administered crushed IRO from
placebo were randomized to receive 15 mg crushed IRO-A and
crushed IRO in crossover fashion in treatment phase. Primary
subjective endpoints were maximum effect (E(max)) for Drug Liking
and effect at 8 hours (E(8h)) postdose for Take Drug Again and
Overall Drug Liking. All were assessed using bipolar 0-100 VAS (50
points = neutral). Secondary pharmacodynamic endpoints included
other VAS endpoints, pupillometry, and subject-rated scales for nasal
effects. Forty subjects were randomized to treatment; 39 were
evaluable, while 1 subject was excluded of postdose vomiting.
Subjects were mostly male (80%) and White (75%). Least squares
mean Drug Liking VAS E(max) (70.8 vs. 93.5), Overall Drug Liking
E(8h) (47.8 vs. 87.4), and Take Drug Again E(8h) (45.9 vs. 91.3) were
significantly lower for crushed IRO-A vs. IRO (all p<0.0001). A
significant sequence effect was found, but lower liking of IRO-A was
observed for both treatment sequence groups. Pupillary responses
831
between treatments were similar overall, but differences were noted

for some endpoints/time points. AEs common to opioids were
observed with both treatments. Subjects experienced more nasal-
related symptoms with IRO-A. In conclusion, crushed IRO-A tablets
demonstrated lower scores on "drug liking," "overall drug liking," and
"take drug again" than crushed IRO when administered intranasally to
nondependent recreational opioid users (5).
The main objective of this study was to determine the efficacy and
adverse reactions of OxyContin®* (Oxycontin=Oxycodone HCL)
administered by rectal route in advanced cancer patients. The VAS
was applied to score pain intensity, separated into 5 degrees. NCI-
Common Toxicity Criteria were adopted to record the side effects.
VASs scores were 10 before treatment, and decreased to 5-6 after
OxyContin application by the rectal route. The main side effects were
constipation, flatulence and fatigue, with no elevation of
transaminases and creatinine. These data indicate that OxyContin
administered by rectal route is safe for advanced cancer patients with
satisfactory pain control effects, thus deserving further clinical
observation (6).
One study compared CR oxycodone and morphine tablets in 45
cancer patients, and although both drugs have provided similar
analgesic effects, there were differences in pain relief in those patients
who had underlying renal or hepatic dysfunction with better pain
control in patients receiving oxycodone (3). This may be due to the
accumulation of active metabolites or differences in the phenotype for
CYP2D6 that metabolizes oxycodone. This study stresses the
importance of pharmacogenomics in guiding and individualizing pain
therapy in the future. In most markets, oxycodone is significantly
more expensive than morphine and is thus less attractive as a first-line
analgesic (7). CR oxycodone (Oxycontin®), based on special drug
delivery system known as AcroContin system, uses a dual-control
matrix with 2 hydrophobic polymers, which are not influenced by pH
and therefore are independent of acidity. Oxycontin® is effective in
moderate to severe cancer pain and allows for convenience of every
12 hours administration (8).
The aims of this study were (1) to prospectively evaluate the
clinical benefits of switching from morphine to an alternative opioid,
using oxycodone as first-line alternative opioid, in patients with
cancer, (2) to evaluate the consistency of the clinical decision for the
need to switch by comparing 2 hospital sites, and (3) to evaluate
whether there were objective predictors that would help identify
morphine non-responders who require switching to an alternative
832
opioid and from this to construct a clinical model to predict the need
to switch. Of 186 palliative care patients prospectively recruited from
2 hospital sites, responders were patients treated with morphine for
more than 4 weeks with good analgesia and minimal side effects.
Non-responders (switchers) were patients who had either uncontrolled
pain or unacceptable side effects on morphine and therefore required
an alternative opioid. The differentiation between responders and
switchers was made clinically and later confirmed by objective
parameters. In this prospective study, 74% (138/186) had a good
response to morphine (responders). One patient was lost to follow up.
Twenty-five percent (47/186) did not respond to morphine. These
non-responders were switched to alternative opioids (switchers). Of
186 patients, 37 achieved a successful outcome when switched to
oxycodone and an additional 4 were well controlled when switched to
more than 1 alternative opioid. Overall, successful pain control with
minimal side effects was achieved in 96% (179/186) of patients. There
were insignificant differences in the need to switch between the 2
hospital sites. In conclusion, clinical identification and management of
patients who require opioid switching is reproducible in different
clinical settings that can significantly improve pain control (9).
The efficacy of opioid rotation from oral morphine to oral
oxycodone in cancer patients who had difficulty in continuing oral
morphine treatment because of inadequate analgesia and/or intolerable
side effects was investigated. Twenty-seven patients were enrolled
and 25 were evaluated. The rate of patients, who achieved adequate
pain control, which provided an indication of treatment success, was
evaluated as primary endpoint. The acceptability and
pharmacokinetics of oxycodone were evaluated in addition to the
assessment of analgesic efficacy and safety during the study period. In
spite of intense pain, the morphine daily dose could not be increased
in most patients before the study because of intolerable side effects.
However, switching to oral oxycodone allowed approximately 1.7-
fold increase as morphine equivalent dose. Consequently, 84.0%
(21/25) of patients achieved adequate pain control. By the end of the
study, all patients except one had tolerated the morphine-induced
intolerable side effects (i.e. nausea, vomiting, constipation, and
drowsiness). Common side effects (> 10%) that occurred during the
study were known for strong opioid analgesics, and most were mild to
moderate in severity. A significant negative correlation between
creatinine clearance value and the trough concentrations of the
morphine metabolites was observed. On the other hand, insignificant
correlation was found between creatinine clearance value and the
833
pharmacokinetic parameters of oxycodone or its metabolites. In

conclusion, for patients who had difficulty in continuing oral
morphine treatment, regardless of renal function, opioid rotation to
oral oxycodone may be an effective approach to alleviate intolerable
side effects and pain (10).
The intravenous or subcutaneous route is a useful option for
administering opioids when cancer patients with moderate to severe
pain are unable to take oral medication. An injectable form of
oxycodone is now available, and 3 patients with cancer-related pain
were treated successfully with continuous intravenous or
subcutaneous oxycodone. The first case showed transient switching
from oral oxycodone to the parenteral form during the active treatment
phase, resulting in satisfactory pain management. The second case
suggested that oxycodone may have a more favorable analgesic
profile in severe neuropathic cancer pain compared with fentanyl.
Finally, the third case demonstrated that oxycodone injection is
relatively safe for renal-impaired patients (11).
Patients with bone metastasis-related pain at NRS ≥ 4 were
enrolled in this randomized placebo-controlled trial. They had also
received morphine or TDF patches for at least 1 week. During the 3-
day efficacy phase, patients received placebo or 1-3 tablets of
oxycodone/paracetamol (5/325 mg), 4 times daily for 3 days. All
patients kept a daily pain diary. The primary endpoint was the PID.
Secondary endpoints were cases of BTP and rescue morphine
consumption. Additional analyses included the SF-6D QOL scale and
a general impression of patient satisfaction with treatment at the end
of the phase. Of the 246 patients in the intent-to-treat set, 89.4%
completed the 3-day efficacy phase. PIDs were 0.9 and 0.3 in the
oxycodone/paracetamol and placebo groups respectively, on day 1
(p<0.001), and 1.5 and 0.3 respectively on day 3 (p<0.001). Thirty-
eight patients in the treatment group, and 58 in the placebo group,
suffered BTP on day three (p<0.001). The SF-6D score decreased to
21.2 ± 2.5 in the oxycodone/paracetamol group at the end of the phase
(p=0·001). In the oxycodone/paracetamol group, 67% rated general
impression as good, very good, or excellent. This study indicates that
patients with bone-cancer pain, already on opioids, obtain clinically
important, additional pain-control, with regular
oxycodone/paracetamol dosing (12).
834
References
1. Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG,
Limbird LE, Molinoff PB, et al, eds. Goodman and Gilman‘s the Pharmacological
Basis of Therapeutics. 9th ed. New York: McGraw-Hill, Health Professions Division.
1996, pp. 521–55.
2. Beckwith SK, Cole BE. Hospice, cancer pain management and symptom
control. In: Weiner RS, ed. Pain Management: a Practical Guide for Clinicians. Boca
Raton (FL): St. Lucie Press. 1998, pp. 705-20.
3. Heiskanen TE, Ruismaki PM, Seppala TA, et al. Morphine or oxycodone in
cancer pain? Acta Oncologica. 2000;39:941-47.
4. Yoshimoto T, Hisada A, Hasegawa T, et al.; Symptom Control Research Group
SCORE-G. Efficacy and safety of continuous subcutaneous injection of the
compound oxycodone in cancer pain management: the first 4-year audit. Gan To
Kagaku Ryoho. 2009;36(10):1683-9.
5. Schoedel KA, Rolleri RL, Faulknor JY, et al. Assessing subjective and
physiologic effects following intranasal administration of a new formulation of
immediate release oxycodone HCl (Oxecta™) tablets in nondependent recreational
opioid users. J Opioid Manag. 2012;8(5):315-27.
6. Li CG, Huang XE, Li Y, Lu YY. Clinical observations on safety and efficacy of
OxyContin® administered by rectal route in treating cancer related pain. Asian Pac J
Cancer Prev. 2011;12(10):2477-8.
2004;6:371.
9. Riley J, Ross JR, Rutter D, et al. No pain relief from morphine? Individual
variation in sensitivity to morphine and the need to switch to an alternative opioid in
cancer patients. Support Care Cancer. 2006;14(1):56-64.
10. Narabayashi M, Saijo Y, Takenoshita S, et al. Opioid rotation from oral
morphine to oral oxycodone in cancer patients with intolerable adverse effects: an
open-label trial. Jpn J Clin Oncol. 2008;38(4):296-304.
11. Shinozaki K, Nitta T, Yamauchi M, Doi M. Three cases of cancer-related pain
for which oxycodone injection was efficacious. Gan To Kagaku Ryoho.
2013;40(1):119-23.
12. Sima L, Fang WX, Wu XM, Li F. Efficacy of oxycodone/paracetamol for
patients with bone-cancer pain: a multicenter, randomized, double-blinded, placebo-
controlled trial. J Clin Pharm Ther. 2012;37(1):27-31.
MORPHINE
Morphine is the standard opiate and the drug of first choice in the
treatment of moderate to severe cancer pain (1-3). It should be titrated
to maximum tolerability before moving on to another opiate such as
fentanyl, hydromorphone, or oxycodone. Morphine, first identified
nearly 200 years ago, is available in a variety of formulations (i.e.,
parenteral, oral, and rectal) and the oral form is available in a range of
preparations, from IR to SR, allowing it to be precisely titrated to the
835
patient‘s response. The oral formulation is recommended initially due

to its ease of administration and convenience of use. A typical
regimen consists of a SR preparation given every 8–12 hours with
breakthrough doses of IR form given every 3-4 hours in between if
needed. The cumulative as-needed doses should not exceed the total
dose given as a sustained preparation for that interval. Thus, a patient
requiring morphine 120 mg SR every 12 hours should receive
morphine 30 mg IR every 3 hours for BTP. Regimens will require
frequent adjustments allowing 3-4 days for the patient to respond
before initiating a change unless toxicity is apparent (4).
One of the important aspects to consider for adequate opioid
treatment is that patients may have varying responses to an individual
opioid based on various pharmacodynamic and pharmacokinetic
interactions. For example, morphine is hepatically glucuronidated to 2
metabolites: morphine-3-glucuronide and morphine-6-glucuronide.
Morphine-3-glucuronide has no analgesic properties but may be
involved in certain side effects such as myoclonus. Morphine-6-
glucuronide is a more potent analgesic than the parent compound and
passes much more readily into the CNS. Morphine and its metabolites
are excreted by the kidneys and toxicity can be seen in patients with
underlying renal insufficiency or failure. In cirrhosis, the
bioavailability of morphine is increased due to the lack of first pass
metabolism; however, the production of the more potent morphine-6-
glucuronide metabolite may decrease resulting in a less than optimal
analgesic effect. Older individuals, who make the vast majority of
terminal cancer patients, may have an increased sensitivity to opioids,
due to decreased hepatic metabolism and decreased renal excretion, as
well as a reduced number of opioid receptors due to brain atrophy (5).
Therefore, it is vital to incorporate interpatient differences into the
dosing scheme in order to arrive at a tolerable but effective regimen.
One double blind, multi-centered crossover study compared the
efficacy, safety, and pharmacokinetics of a novel once-daily morphine
formulation and a 12-hour SR morphine formulation in the treatment
of chronic cancer pain. Insignificant difference between treatments for
evaluations of overall pain intensity, analgesic efficacy, or AEs was
found. However, the once-daily formulation showed less fluctuation
in plasma morphine concentration to compare with SR form, and
most patients chose once-daily morphine dosing for continuing pain
management, as it was providing more stable pain control over the
day (6).
The most common AEs of morphine include sedation and some
degree of cognitive impairment, which usually improves with time in
836
patients taking stable and moderate doses of opioid. Nausea and

vomiting are frequently seen upon initiation of therapy and after large
dose increases, but usually subside with time. Constipation is seen
with chronic therapy; patients do not develop tolerance to it and
typically require preemptive treatment with laxatives (7,8).
The data were retrieved from PubMed between 2001 to 2006 years
(keywords used alone or in combination were: opioids, cancer, pain,
pain killers, rotation, intraspinal, ketamine, side effects), the
"Standard, Options and Recommendations on cancer nociceptive pain
treatments for adult patients" published by the French Union of
Comprehensive Cancer Centers (FNCLCC; Fédération nationale des
centres de lutte contre le cancer) and the EAPC recommendations on
morphine and alternative opioids in cancer pain. Data also include an
analysis of studies before 2001, which gave information about the
pharmacokinetic data of transdermal and transmucosal fentanyl.
Studies written in English or French related to the medical treatments
(commercialized in France) for nociceptive cancer pain for adult
patients were analyzed. Analyzed articles were clinical or
experimental studies or metaanalyses. Studies on neuropathic cancer
pain, editorials and letters to the editor were discarded. Nociceptive
cancer pain is characterized by its frequent instability. More than 50%
of patients have paroxysmal painful accesses, either spontaneous or
induced by care or mobilizations. Morphine is the main treatment but
the prescription of CR morphine must be associated with the
prescription of IR morphine to treat the paroxysmal painful accesses
or to transmucosal fentanyl which has a faster onset of action than IR
morphine. Morphine treatment can be introduced either by MIR or by
CR morphine. The introduction of MIR is recommended for old or
fragile patients, patients with malnutrition, or patients with hepatic or
renal failure. For patients suffering unbearable side effects under
morphine or morphine resistant pain, opioid rotation or intravenous
morphine or fentanyl are recommended. Spinal opioids administration
(by epidural or intrathecal routes) is most often indicated in patients
with very severe and resistant pain in terminal disease. In the
postoperative period, previous pain treatment must be maintained or
increased. Pain related to care procedures must be prevented with
various and associated treatments: for example, mixed topics
lidocaïne-prilocaine for venous or arterial punctures; infiltration of
local anesthetics and inhalation of an oxygen - nitrous oxide mixture
for medullary biopsies. In conclusion, oral IR or CR morphine is the
most common and effective pain treatment for most patients with
nociceptive cancer pain but rotation with other opioids or alternative
837
routes of administration must be discussed quickly if pain persists or if

AEs occur (9).
This is an updated version of a previous Cochrane review first
published in Issue 4, 2003 of The Cochrane Library. Morphine has
been used for many years to relieve pain. Oral morphine in either IR
or modified release form remains the analgesic of choice for moderate
or severe cancer pain. The main objective of this study was to
determine the efficacy of oral morphine in relieving cancer pain and to
assess the incidence and severity of AEs. The following databases
were searched: Cochrane Pain, Palliative and Supportive Care Group
Trials Register (December 2006); Cochrane Central Register of
Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4);
MEDLINE (1966 to December 2006); and EMBASE (1974 to
December 2006). Published RCTs reporting on the analgesic effect of
oral morphine in adults and children with cancer pain were included.
Any comparator trials were considered. Trials with fewer than 10
participants were excluded. There were insufficient comparable data
for meta-analysis to be undertaken or to produce NNT for the
analgesic effect. In this update, 9 new studies with 688 participants
were added. Fifty-four studies (3749 participants) met the inclusion
criteria. Fifteen studies compared Mm/r preparations with MIR.
Twelve studies compared Mm/r in different strengths, 5 of these
included 24-hour modified release products. Thirteen studies
compared Mm/r with other opioids. Six studies compared MIR with
other opioids. Two studies compared oral Mm/r with rectal Mm/r.
Two studies compared MIR with MIR by a different route of
administration. One study was found comparing each of the following:
Mm/r tablet with Mm/r suspension; Mm/r with non-opioids; MIR with
non-opioids; and oral morphine with epidural morphine. Morphine
was an effective analgesic. Pain relief did not differ between Mm/r
and MIR. Modified release versions of morphine were effective for 12
or 24-hour dosing depending on the formulation. Daily doses in
studies ranged from 25 mg to 2000 mg with an average of between
100 mg and 250 mg. Dose titration were undertaken with both IR and
modified release products. AEs were common but only 4% of patients
discontinued treatment because of intolerable AEs. In conclusion, the
randomized trial literature for morphine is small given the importance
of this medicine. Most trials recruited fewer than 100 participants and
did not provide appropriate data for meta-analysis. Trial design was
frequently based on titration of morphine or comparator to achieve
adequate analgesia, then crossing participants over in crossover design
studies. It was not clear if these trials are sufficiently powered to
838
detect any clinical differences between formulations or comparator

drugs. Studies added to the review reinforce the view that it is possible
to use modified release morphine to titrate to analgesic effect. There is
qualitative evidence for effectiveness of oral morphine which
compares well to other available opioids. There is limited evidence to
suggest that transmucosal fentanyl provides more rapid pain relief for
BTP compared to morphine (10).
The effects of active morphine metabolites can be induced or
inhibited by a variety of medications. The AEDs carbamazepine,
phenobarbital and phenytoin, as well as the antibiotic rifampin can
accelerate clearance of morphine. Phenothiazines, TCAs, and
cimetidine will interfere with morphine metabolism and may potentate
its effect if administered simultaneously. Co-administration of
morphine and benzodiazepines may produce strong synergistic action
resulting in sedation, hypotension, and sometimes delirium (11).
References
1. Schug SA, Zech D, Dorr U. Cancer pain management according to WHO
analgesic guidelines. J Pain Symptom Manage. 1990;5:27–32.
2. Wilson PR, Caplan RA, Connis RT, et al. Practice guidelines for chronic pain
management: a report by the American Society of Anesthesiologists Task Force on
Pain Management, Chronic Pain Section. Anesthesiology. 1997;86:995-1004.
3. Benedetti C, Brock C, Cleeland C, et al. NCCN practice guidelines for cancer
pain. Oncology. 2000;14:135-50.
2007;3(3):381-400.
5. Balducci L. Management of cancer pain in geriatric patients. J Support Oncol.
2003;1:175-91.
6. Hagen NA, Thirlwell M, Eisenhoffer J, et al. Efficacy, safety, and steady-state
pharmacokinetics of once-a-day controlled-release morphine (MS Contin XL) in
cancer pain. J Pain Symptom Manage. 2005;29:80-90.
7. Bruera E, Macmillan K, Hanson J, et al. The cognitive effects of the
administration of narcotic analgesics in patients with cancer pain. Pain. 1989; 9:13-16.
8. Chapman SL, Byas-Smith MG, Reed BA. Effects of intermediate- and long-
term use of opioids on cognition in patients with chronic pain. Clin J Pain.
2002;18(Suppl 4):S83-90.
9. Binhas M, Krakowski I, Marty J. Nociceptive cancer pain in adult patients:
statement about guidelines related to the use of antinociceptive medicine. Ann Fr
Anesth Reanim. 2007;26(6):502-15.
10. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database
Syst Rev. 2007 Oct 17;(4):CD003868.
11. Donnely S, Davis MP, Walsh D, et al. Morphine in cancer pain management:
a practical guide. Support Care Cancer. 2002;10:13-35.
839
FENTANYL
In the last two decades, opioid analgesics have assumed an
important place in general anesthetic practice in the US. Part of the
reason for this has been the introduction of the potent new agonists
fentanyl, sufentanil, and alfentanil. Because of problems with
morphine-oxygen anesthesia (incomplete amnesia, occasional
histamine-related reaction, marked increases in intra- and
postoperative respiratory depression), a suitable alternative was sought
but not found among existing opioids. A breakthrough came in 1960,
when fentanyl was synthesized, laying the foundation for a better
understanding of the structure-activity relationships of narcotic
analgesics and stimulating interest in developing compounds with
even greater potency and safety margins. Investigators interested in
opioid anesthesia began to study fentanyl in animals and then in
humans. Fentanyl (50-100 micrograms/kg) with oxygen (100%) was
evaluated as an anesthetic in patients undergoing mitral valve and
coronary artery surgery. Changes in C-V dynamics with induction
doses ranging from 8 to 30 micrograms/kg consisted of small
decreases in heart rate and arterial BP. All other C-V variables
studied, including cardiac output, remained unchanged, even with
additional doses up to 100 micrograms/kg. It was determined that
fentanyl had use as a narcotic anesthetic, despite its potential for C-V
depression and stimulation, respiratory depression, and muscle
rigidity. Since the introduction of fentanyl, 2 other potent synthetic
opioids have been introduced into clinical practice - sufentanil and
alfentanil (1).
When medications cannot be administered orally because of
swallowing difficulties, intolerance of previous analgesic agents, or
unacceptable AEs, consideration may be given to the use of TDF as an
alternative to starting parenteral or rectal opioids, as long as pain is
stabilized and dose titration is not needed (2). Although fentanyl is
readily absorbed through the skin, there are a few caveats to recall
when selecting this ―pain patch.‖ Notably, the transdermal delivery
system only works when the patch is firmly attached to the patient. No
special skin preparation other than clipping the hair and placing the
patch over a nondependent, fleshy area is required; ―defatting‖ the
skin with any solvents to improve the adhesiveness of the patch
should be avoided, because such a step can decrease the effectiveness
of the patch. If the patient is extremely cachectic, absorption may
become erratic. Temperature and reservoir concentration drive the
fentanyl into the body; when the temperature is not normal, delivery is
840
altered. During episodes of fever (e.g., temperatures of 38.9°C-40°C

[102°F–104°F]), during exertion in sunny and warm environments,
and during exposure to external heat-producing sources (e.g., heating
pads, heated water beds, electric blankets, and car seats in the
summer), the dose delivered may exceed the dose printed on the patch
and lead to dangerous increases in fentanyl levels (3).
The release of fentanyl from the transdermal system is
characterized by 2 distinct phases following initial application: during
the first phase, a rapid loading dose is absorbed from the contact
adhesive, which is followed by a plateau phase when fentanyl is
released from the patch reservoir at a constant rate (4). Although it
may take 12–24 hours for the initial onset of action to occur,
transdermal route eliminates G-I absorption and subsequently first-
pass metabolism of fentanyl, which makes possible to use lower doses
of medication and reduce incident of AEs. Fentanyl usually is not
recommended for children under 12 years, due to unknown safety
profile at this age, and is not suitable for patients with severe cachexia
due to limited subcutaneous fat stores. One of the main drawbacks of
TDF is that its elimination half-life is up to 18 hours after patch
removal, thus patients who experience side effects, especially
respiratory depression, will need to be monitored and supported for a
full day following discontinuation (5-7).
Fentanyl is a quick acting lipophilic opiate available in parenteral,
transmucosal, and transdermal formulations. Intravenous fentanyl is
70 to 100 times more potent than intravenous morphine (8) and has
very rapid onset of action – 5 minutes to peak analgesia, vs. at least 15
minutes for intravenous morphine (9). Fentanyl is most widely used in
palliative medicine in the form of a transdermal patch (Duragesic®),
which is especially useful in those patients who do not have enteral
access for analgesia or for whom nausea and vomiting limit the
ingestion of the required dose of opioid (10-13).
FBT (FENTORA((R)), Cephalon, Inc.) employs OraVescent((R))
drug delivery technology, which enhances the rate and extent of
fentanyl absorption. OraVescent technology enhances the oral
dissolution and buccal absorption of fentanyl, which facilitates rapid
uptake of fentanyl into the bloodstream, reducing G-I absorption and
minimizing extensive first-pass metabolism. The resulting
pharmacokinetic profile of FBT is characterized by greater
bioavailability and a higher early systemic exposure compared with
the earlier oral transmucosal fentanyl citrate formulation. In clinical
studies of opioid-tolerant patients with cancer-related and non-cancer-
related BTP, FBT has provided consistent and clinically relevant
841
improvements in pain intensity and pain relief relative to placebo,

with a safety and tolerability profile that is generally typical of that
observed with other potent opioids. The pharmacokinetic properties of
FBT allow for meaningful clinical efficacy, with an onset of action
that closely matches the onset of BTP (14).
The FBT is a new formulation of fentanyl that uses an effervescent
drug delivery system to enhance penetration across the buccal mucosa
for the treatment of BTP in opioid-tolerant patients with cancer.
Fentanyl is rapidly absorbed from FBT across the buccal mucosa and
into the bloodstream. Fentanyl is more rapidly absorbed and
bioavailability is higher from FBT than from the oral transmucosal
fentanyl citrate formulation. In a well designed phase III trial in
opioid-tolerant patients with cancer, a single dose of FBT 100-800
micrograms provided clinically significant improvements in pain
intensity from 15 to 60 minutes after the dose. Single FBT doses of
100-800 micrograms were generally well tolerated; the majority of
AEs were mild to moderate in nature and typical of those associated
with opioids (15).
This study evaluated FBT for BTP in opioid-tolerant patients with
chronic cancer pain. The study had a randomized, double-blind,
placebo-controlled design and was conducted at 30 outpatient
treatment centers in the US. Following open-label titration, patients
were randomly assigned to 1 of 18 double-blind dose sequences (7
FBT tablets, 3 placebo) to treat 10 BTP episodes. Pain intensity was
measured on an 11-point scale (0 = no pain, 10 = worst pain). The
primary efficacy measure was the sum of pain intensity differences for
the first 60 minutes; secondary efficacy measures included pain
intensity differences and pain relief measured from 5 minutes through
2 hours. Of 129 patients enrolled, 87 entered the double-blind phase.
PIDs for the first 60 minutes significantly favored FBT vs. placebo
(mean +/- SE, 9.7 +/- 0.63 vs. 4.9 +/- 0.50; p<0.0001). Secondary
measures also favored FBT: PIDs and pain relief showed significant
differences vs. placebo at 10 minutes (0.9 vs. 0.5, 0.815 vs. 0.606,
respectively, p<0.0001) and all subsequent time points (p<0.0001).
AEs were typical of opioids (e.g., nausea, dizziness, and fatigue). In
conclusion, in opioid-tolerant patients with chronic cancer pain and
BTP, FBT was efficacious, well-tolerated, demonstrated rapid onset of
analgesia (within 10 minutes), and had a sustained effect (16).
TDF is effective and well tolerated for the treatment of chronic
pain caused by malignancy and non-malignant conditions when
administered according to the manufacturer's recommendations.
Compared with oral opioids, the advantages of TDF include a lower
842
incidence and impact of AEs (constipation, nausea and vomiting, and

daytime drowsiness), a higher degree of patient satisfaction, improved
QOL, improved convenience and compliance resulting from
administration every 72 hours, and decreased use of rescue
medication. TDF is a useful analgesic for cancer patients who are
unable to swallow or have G-I. TDF forms a depot within the upper
skin layers before entering the microcirculation. Therapeutic blood
levels are attained 12-16 hours after patch application and decrease
slowly with a half-life of 16-22 hours following removal. Patients
with chronic pain should be titrated to adequate relief with short-
acting oral or parenteral opioids prior to the initiation of TDF in order
to prevent exacerbations of pain or opioid-related AEs. TDF can then
be initiated based on the 24-hours opioid requirement once adequate
analgesia has been achieved. The prolonged elimination of TDF can
become problematic if patients develop opioid-related AEs, especially
hypoventilation. AEs do not improve immediately after patch removal
and may take many hours to resolve. Patients who experience opioid-
related toxicity associated with respiratory depression should be
treated immediately with an opioid antagonist such as naloxone and
closely monitored for at least 24 hours. Because of the short half-life
of naloxone, sequential doses or a continuous infusion of the opioid
antagonist may be necessary. TDF should be administered cautiously
to patients with pre-existing conditions such as emphysema that may
predispose them to the development of hypoventilation. TDF is
indicated only for patients who require continuous opioid
administration for the treatment of chronic pain that cannot be
managed with other medications. It is contraindicated in the
management of acute and postoperative pain, as pain may decrease
more rapidly in these circumstances than fentanyl blood levels can be
adjusted, leading to the development of life-threatening
hypoventilation. Cognitive and physical impairments such as
confusion and abnormal co-ordination can occur with TDF. Therefore,
patients should be instructed to refrain from driving or operating
machinery immediately following the initiation of TDF, or after any
dosage increase. Patients may resume such activities once the absence
of these potential AEs is documented (13).
Cancer patients requiring strong analgesia were recruited into an
open-label, multicentre study, conducted in 8 countries. Patients
received TDF treatment for 28 days. Pain severity, overall satisfaction
with pain control, convenience of use of patches and treatment
preferences were recorded daily. Of the 292 participants, 135 had
previously received a strong opioid, 84 had previously received a
843
weak opioid and 73 had received no regular opioids. Thirty-eight

patients did not complete the study, mainly due to AEs. For all groups
the proportion of patients with 'good to excellent' pain control
increased after TDF treatment. TDF was well tolerated, with the most
common treatment-related AEs being nausea, vomiting and
constipation. The percentage of strong-opioid-tolerant patients with
constipation decreased following TDF treatment and increased
slightly in the strong-opioid-naïve groups. Most patients rated the
convenience of the patches as 'good to excellent', and most preferred
TDF to their previous therapy. In conclusion, TDF is an effective and
well-tolerated treatment for cancer-related pain for patients regardless
of whether they have previously received opioids. Previous guidelines
have often advocated initial dose finding with short-acting opioids but
this study demonstrates that such a complex titration and conversion
schedule may not be necessary, and treatment can be initiated directly
with long-acting formulations such as TDF when previous analgesic
therapy fails to provide adequate relief (17).
This study was carried out to assess the efficacy, safety and
pharmacokinetic profiles of a 12.5 micrograms/hour TDF (matrix)
administered with the objective of replacing morphine, oral
oxycodone or fentanyl injection formulations. The study also
evaluated how the pharmacokinetic profiles of higher dose fentanyl
patches (25, 37.5 and 50 micrograms/hour) changed following dose
adjustments to optimize management of cancer pain. This open-label,
multicentre study involved 87 patients of both sexes (≥ 20 years) with
a confirmed diagnosis of cancer. Patients were receiving any one of
the following at the time of enrollment for the management of their
cancer pain: (a) morphine < 45 mg/day orally, < 30 mg/day as
suppositories, or < 15 mg/day by injection; (b) oral oxycodone < 30
mg/day; or (c) fentanyl injectable preparations < 0.3 mg/day. The
patients were administered a 3-day course of TDF matrix patch
application 3 times. The initial dose was 12.5 micrograms/hour, which
could be increased when a new patch was applied if the physician
deemed this to be appropriate based on pain intensity ratings and use
of rescue medications. Efficacy outcomes included patients' global
assessment scores (primary efficacy endpoint) measured on a 5-step
scale and dichotomous scores for physicians' global assessment. The
occurrence of AEs and changes in laboratory tests were evaluated as
safety variables. Serum fentanyl levels were measured immediately
after removal of the old patch on days 4, 7 and 10 to obtain data on
trough serum concentrations. The percentage of patients in category 3
or higher (very satisfied, satisfied, or neither satisfied nor dissatisfied)
844
for the patient's global assessment score was 89.4% (76/85), indicating
high patient satisfaction and attainment of sufficient pain control after
patients switched from their previously used opioid analgesics.
Similar findings were obtained on physicians' global assessment
scores. A total of 316 AEs occurred in 78/86 (90.7%) patients who
were administered at least 1 patch. These included nausea (31,
36.0%), somnolence (26, 30.2%), vomiting (22, 25.6%), diarrhea (17,
19.8%), constipation (14, 16.3%), pyrexia (11, 12.8%) and insomnia
(9, 10.5%). The mean (+/- SD) serum fentanyl concentration
determined on day 4 was 169.9 +/- 103.4 pg/mL (n=83). The same
TDF dose resulted in similar serum fentanyl levels, while increased
doses produced higher serum fentanyl concentrations. In conclusion,
the TDF matrix patch formulation demonstrated sufficient cancer pain
control for patients switching from morphine or oral oxycodone
preparations. The patch tested was well tolerated and its use did not
result in any increased incidence of adverse drug reactions over those
commonly found with opioid analgesics (18).
The prevalence of BTP has been well described in patients with
chronic cancer pain (19,20), and intravenous fentanyl can be
successfully used for BTP in the hospital or hospice care. However,
for outpatient management more convenient choice for cancer BTP
will be a rapid-onset opioid Actiq®— the oral transmucosal fentanyl
citrate lozenge that patients can dissolve in the buccal space for IR,
usually within 5-10 minutes (21). One study compared its use with
oral IR morphine and found oral transmucosal fentanyl citrate to be
superior for fast pain control (22). Other study demonstrated that oral
transmucosal fentanyl citrate is an effective alternative to intravenous
opioids in rapidly titrating analgesia in selected opioid-tolerant cancer
patients who are in pain crisis (23).
Fentanyl Pectin Nasal Spray (PecFent) uses an innovative delivery
system and is now approved in the EU (24). This nasal spray
(PecFent®) uses a novel pectin-based delivery system that turns from
an aqueous solution into a gel when applied to mucosal surfaces.
Fentanyl is absorbed in a controlled manner from the pectin gel
formed in the nasal cavity, and has a rapid onset of pain relief and
duration of action that matches the time course of a typical episode of
BTP in cancer. Relative to administration as oral transmucosal
fentanyl, fentanyl administered as fentanyl pectin nasal spray is more
rapidly absorbed, reaches higher maximum plasma concentrations and
has greater bioavailability. In the treatment of BTP in cancer in 2
randomized, double-blind, crossover trials in opioid-tolerant adults,
fentanyl pectin nasal spray (100-800 μg titrated doses) was
845
significantly more effective than placebo in reducing pain intensity

and provided a significantly faster onset of pain relief than oral
immediate-release morphine. During long-term treatment of BTP in
cancer episodes, fentanyl pectin nasal spray consistently provided
effective pain relief in an open-label, 16-week trial. Most patients
were satisfied or very satisfied with the ease of use and convenience
of the nasal spray. Fentanyl pectin nasal spray 100-800 μg was
generally well tolerated and was not associated with nasal tolerability
problems (25).
Adult cancer patients receiving stable background opioid treatment
and experiencing BTP episodes were recruited from 44 study centers
in seven European countries (Austria, France, Germany, Italy, Poland,
Spain and the United Kingdom); of the 196 patients enrolled, 139
were randomized to receive intranasal fentanyl spray followed by oral
transmucosal fentanyl citrate, or vice versa. Patients were titrated to an
effective dose of 1 agent (50, 100 or 200 micrograms intranasal
fentanyl spray; 200, 400, 600, 800, 1200 or 1600 micrograms oral
transmucosal fentanyl citrate) to treat 6 BTP episodes, then titration
and treatment were repeated with the other agent. The primary
outcome was patient-recorded time to onset of 'meaningful' pain relief.
Secondary outcomes included PID at 10 and 30 minutes (PID(10),
PID(30)), SPID at 15 and 60 minutes (SPID(0-15), SPID(0-60)), ease
of administration, treatment preference and relationship between
background opioid dose and effective intranasal fentanyl sprays dose.
Additional outcome measures included proportions of episodes with ≥
33% and ≥ 50% pain intensity reduction, and PID at additional time
points. Among the intention-to-treat population (n=139), median time
to onset of 'meaningful' pain relief was 11 minutes with intranasal
fentanyl spray vs. 16 minutes with oral transmucosal fentanyl citrate;
65.7% of patients attained faster time to 'meaningful' pain-relief onset
with intranasal fentanyl spray (p<0.001). PID was statistically
significantly greater for intranasal fentanyl sprays than oral
transmucosal fentanyl citrate from 5 minutes post-dosing.
Significantly more intranasal fentanyl spray-treated BTP episodes
achieved clinically important pain relief (≥ 33% and ≥ 50% pain
intensity reduction) up to 30 minutes post-dosing. The proportions of
episodes treated with intranasal fentanyl sprays and oral transmucosal
fentanyl citrate achieving a pain intensity reduction of ≥ 33% at 5
minutes were 25.3% vs. 6.8% (p<0.001), and at 10 minutes were
51.0% vs. 23.6% (p<0.001), respectively; the proportions of episodes
treated with intranasal fentanyl spray and oral transmucosal fentanyl
citrate achieving a ≥ 50% pain intensity reduction at 5 minutes were
846
12.8% vs. 2.1% (p<0.001), and at 10 minutes were 36.9% vs. 9.7%
(p<0.001), respectively. Higher SPID(0-15) and SPID(0-60) scores
were achieved with intranasal fentanyl spray (p<0.001). More patients
preferred intranasal fentanyl spray than oral transmucosal fentanyl
citrate (p<0.001) and more patients found it very easy/easy to use.
Both treatments were well tolerated. In the safety population (n=139),
56.8% (n=79) of patients experienced ≥ 1 AE during the trial. The
only AE that occurred in ≥ 5% of patients in either treatment group
was nausea. Among those patients who experienced serious AEs
(13.7%, n=19), none were considered to be related to either study
medication. There was a weak correlation between effective intranasal
fentanyl spray doses and background opioid doses. In conclusion, in
this open-label, randomized, crossover trial significantly more patients
attained faster 'meaningful' pain relief with intranasal fentanyl spray
than oral transmucosal fentanyl citrate, and more patients preferred
intranasal fentanyl spray to oral transmucosal fentanyl citrate (26).
References
1. Stanley TH. The history and development of the fentanyl series. J Pain
Symptom Manage. 1992;7(3 Suppl):S3-7.
2. Hardy JR, Rees EA. A survey of transdermal fentanyl use in a major cancer
center. J Pain Symptom Manage 1998; 15:213–4.
3. Newshan G. Heat related toxicity with the Fentanyl transdermal patch. J Pain
Symptoms manage. 1998;16:277-8.
4. Varvel JR, Shafer SL, Hwang SS, et al. Absorption characteristics of
transdermally administered fentanyl. Anesthesiology. 1989;70:928–34.
5. Korte W, Stoutz N, Morant R. Day-to-day titration to initiate transdermal
fentanyl in cancer patients: short- and long-term experience in a prospective study of
39 patients. J Pain Symptom Manage. 1996;11:139–46.
6. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral
morphine in cancer pain: preference, efficacy, and quality of life. J Pain Symptom
Manage. 1997;13:254–61
7. Donner B, Zenz M, Strumpf M, et al. Long-term treatment of cancer pain with
transdermal fentanyl. J Pain Symptom Manage. 1998;15:168-75.
8. Pereira J, Lawlor P, Vigano A, et al. Equianalgesic dose ratios for opioids: a
critical review and proposals for long-term dosing. J Pain Symptom Manage.
2001;22:672–87.
9. Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbrid E, editors.
Goodman and Gilman‘s the Pharmacological Basis of Therapeutics. 10. New York:
McGraw-Hill Professional. 2001, pp. 569-619.
10. Grond S, Zech D, Lehmann K, et al. Transdermal fentanyl in the long-term
treatment of cancer pain: a prospective study of 50 patients with advanced cancer of
the gastrointestinal tract or the head and neck region. Pain. 1997;69:191–98.
11. Payne R, Mathias SD, Pasta DJ, et al. Quality of life and cancer pain:
satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin
Oncol. 1998;16:1588–93.
12. Radbruch L, Sabatowski R, Petzke F, et al. Transdermal fentanyl for the
management of cancer pain: a survey of 1005 patients. Palliat Med. 2001;15:309–21.
847
13. Kornick CA, Santiago-Palma J, Moryl N, et al. Benefit-risk assessment of

transdermal fentanyl for the treatment of chronic pain. Drug Safety. 2003;26:951–73.
14. Darwish M, Hamed E, Messina J. Fentanyl buccal tablet for the treatment of
breakthrough pain: pharmacokinetics of buccal mucosa delivery and clinical efficacy.
Perspect Medicin Chem. 2010;4:11-21.
15. Blick SK, Wagstaff AJ. Fentanyl buccal tablet: in breakthrough pain in
opioid-tolerant patients with cancer. Drugs. 2006;66(18):2387-93; discussion 2394-5.
16. Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of
breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. J
Support Oncol. 2007;5(7):327-34.
17. Tawfik MO, Bryuzgin V, Kourteva G; FEN-INT-20 Study Group Use of
transdermal fentanyl without prior opioid stabilization in patients with cancer pain.
Curr Med Res Opin. 2004;20(3):259-67.
18. Miyazaki T, Hanaoka K, Namiki A, et al. Efficacy, safety and
pharmacokinetic study of a novel fentanyl-containing matrix transdermal patch
system in Japanese patients with cancer pain. Clin Drug Investig. 2008; 28(5):313-25.
19. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and
characteristics. Pain. 1990;41:273-82.
20. Fine PG, Busch MA. Characterization of breakthrough pain by hospice
patients and their caregivers. J Pain Symptom Manage. 1998;16:179-83.
21. Farrar JT, Cleary J, Rauck R, et al. Oral transmucosal fentanyl citrate:
randomized, double blind placebo controlled trial for treatment of breakthrough pain
in cancer patients. Anesth Analg. 1998;89:732–38.
22. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a
randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine
sulfate immediate release (MSIR) Pain. 2001;91:123–30.
23. Burton AW, Driver LC, Mendoza TR, et al. Oral transmucosal fentanyl
citrate in the outpatient management of severe cancer pain crises. Clin J Pain.
2004a;20:195–97.
24. Mystakidou K, Panagiotou I, Gouliamos A. Fentanyl nasal spray for the
treatment of cancer pain. Expert Opin Pharmacother.2011;12(10):1653-9.
25. Lyseng-Williamson KA. Fentanyl pectin nasal spray: in breakthrough pain in
opioid-tolerant adults with cancer. CNS Drugs. 2011;25(6):511-22.
26. Mercadante S, Radbruch L, Davies A, et al. A comparison of intranasal
fentanyl spray with oral transmucosal fentanyl citrate for the treatment of
breakthrough cancer pain: an open-label, randomised, crossover trial. Curr Med Res
Opin. 2009;25(11):2805-15.
HYDROMORPHONE
Hydromorphone (Dilaudid®) is a water-soluble opioid that is
several times more potent than morphine allowing smaller doses to be
used. It is available in parenteral, rectal, subcutaneous, and oral
formulations. However, hydromorphone can be also administered via
epidural and intrathecal routes (1). Hydromorphone should be
considered particularly for patients on morphine who have side effects
of increased confusion or myoclonus (2). Although intravenous
848
hydromorphone is 6 to 7 times more potent than intravenous morphine

(3), it could be 20 times more potent than oral morphine.
Hydromorphone relieves continuous dull pain more effectively than
sharp intermittent pain, while when mixed with epinephrine it
provides superior pain relief (1).
A meta-analysis of the clinical effects of morphine and
hydromorphone to compare their benefit in analgesia was conducted.
Embase and Medline were searched with an end-date of June 2009 for
RCTs or observational studies that addressed comparative analgesic
and side effects or particular side effects. Two researchers
independently identified included studies and extracted the data.
Estimates of opioid effects were combined by using a random-effects
model. Meta-analysis of 8 studies suggested that hydromorphone (494
patients) provides slightly better (p=0.012) clinical analgesia than
morphine (510 patients). The effect-size was small (Cohen's d=0.266)
and disappeared when 1 study was removed, although the advantage
of hydromorphone was more evident in studies of better quality
(Jadad's rating). Side effects were similar, for example, nausea
(p=0.383, 9 studies, 456 patients receiving hydromorphone and 460
morphine); vomiting (p=0.306, six studies, 246 patients receiving
hydromorphone and 239 morphine); or itching (p=0.249, 8 studies,
405 patients receiving hydromorphone, 410 morphine). This suggests
some advantage of hydromorphone over morphine for analgesia.
Additional potential clinical pharmacological advantages with regard
to side effects, such as safety in renal failure or during acute analgesia
titration, are based on limited evidence and require substantiation by
further studies (4).
This open-label, multicenter study assessed the efficacy and
tolerability of conversion to once-daily OROS hydromorphone from
previous opioid agonist therapy in patients with chronic cancer pain.
Patients were stabilized on their previous therapy before conversion at
a 5:1 ratio of morphine sulfate to hydromorphone hydrochloride. The
OROS hydromorphone dose was titrated over 3-21 days to achieve
effective analgesia and was maintained for up to 14 days. Efficacy
was assessed using the BPI. Dose stabilization was achieved in 119 of
the 127 (94%) patients who received the study medication; in 77%,
stabilization was achieved with no titration steps. Mean BPI pain
intensity ratings and BPI pain interference scores decreased
significantly after OROS hydromorphone treatment compared with
pretreatment values. Mean pain-relief level remained stable after
conversion and throughout treatment with OROS hydromorphone.
849
AEs were as expected for cancer patients receiving opioid agonists.

There were no clinically significant changes in vital signs (5).
References
2004;6:371.
3. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical
applications in cancer patients. Support Care Cancer. 2001;9:84–96.
4. Felden L, Walter C, Harder S, et al. Comparative clinical effects of
hydromorphone and morphine: a meta-analysis. Br J Anaesth. 2011;107(3):319-28.
5. Wallace M, Rauck RL, Moulin D, et al. Conversion from standard opioid
therapy to once-daily oral extended-release hydromorphone in patients with chronic
cancer pain. J Int Med Res. 2008;36(2):343-52.
BUPRENORPHINE
Buprenorphine is a broad spectrum, highly lipophilic, and long-
acting partial mu opioid receptor agonist that is noncross tolerant to
other opioids. Buprenorphine can be given by several routes.
Metabolism is through CYP3A4 and CYP2C8 and by conjugases.
Constipation and sexual dysfunction appear to be less with
buprenorphine than with other opioids. The recent development of a
polymer matrix patch delivery system for buprenorphine prevents
"dose dumping" and facilitates pain management in those unable to
take oral analgesics. Sublingual buprenorphine has been combined
with naloxone to prevent illicit conversion to parenteral
administration. Buprenorphine has been used extensively to control
cancer pain. In certain clinical situations, buprenorphine may have
particular advantages over other opioids (1).
Buprenorphine is an opioid that has a complex and unique
pharmacology which provides some advantages over other potent mu
agonists. There are 12 reasons for considering buprenorphine as a
frontline analgesic for moderate to severe pain: (1) buprenorphine is
effective in cancer pain; (2) buprenorphine is effective in treating
neuropathic pain; (3) buprenorphine treats a broader array of pain
phenotypes than do certain potent mu agonists, is associated with less
analgesic tolerance, and can be combined with other mu agonists; (4)
buprenorphine produces less constipation than do certain other potent
mu agonists, and does not adversely affect the sphincter of Oddi; (5)
buprenorphine has a ceiling effect on respiratory depression but not
analgesia; (6) buprenorphine causes less cognitive impairment than do
850
certain other opioids; (7) buprenorphine is not immunosuppressive

like morphine and fentanyl; (8) buprenorphine does not adversely
affect the hypothalamic-pituitary-adrenal axis or cause hypogonadism;
(9) buprenorphine does not significantly prolong the QTc interval, and
is associated with less sudden death than is methadone; (10)
buprenorphine is a safe and effective analgesic for the elderly; (11)
buprenorphine is one of the safest opioids to use in patients in renal
failure and those on dialysis; and (12) withdrawal symptoms are
milder and drug dependence is less with buprenorphine. In light of
evidence for efficacy, safety, versatility, and cost, buprenorphine
should be considered as a first-line analgesic (2).
Another centrally acting synthetic opioid, transdermal
buprenorphine, is now being widely prescribed in Europe and
Australia for cancer pain management (3,4). Transdermal
buprenorphine is contained in a matrix patch as opposed to traditional
reservoir patch technology used for TDF, which makes it more robust
in handling. In a matrix system, the substance is an integral part of the
polymer structure of the patch. Thus, while damaging a reservoir
patch might result in ‗dose dumping‘ and potentially overdosing the
patient, damaging a matrix patch will not interfere with the controlled
release of the medication (5).
In 2001, a transdermal matrix patch formulation of buprenorphine
was approved for the treatment of moderate to severe cancer pain and
severe pain that is unresponsive to nonopioid analgesics. The primary
recommendation contained in the prescribing information was that
transdermal patches be worn for a 3-day period before application of a
new patch. This single-center, randomized, open-label, crossover
Phase III study compared the efficacy and tolerability of the
buprenorphine transdermal patch applied for different durations, with
patch changes every 3 days vs. every 4 days (12 days each), in
patients with chronic moderate or severe pain of malignant or
nonmalignant origin. Study participants were aged > 18 years, had
already responded to at least 4 weeks of transdermal buprenorphine,
and had achieved steady-state conditions for at least 2 weeks before
enrollment. The primary end point was patients' rating of the quality
of treatment (analgesic efficacy and tolerability, rated on a 5-point
scale: very good, good, satisfactory, poor, and inadequate) at the
completion of each treatment regimen. Also recorded were physicians'
ratings of the quality of treatment; pain intensity, rated on an 11-point
NRS (from 0 = no pain to 10 = worst pain imaginable) and on the
MPQ (maximum pain = 3.0); health status, assessed using the SF-36,
expressed as a percentage of the best health condition (100%); and
851
pain relief (5-point scale: complete, good, satisfactory, slight, and

none). Local skin tolerability was evaluated for objective and
subjective dermatologic symptoms at the patch application sites.
Patients recorded daily pain intensities at specified times of day and
night, pain relief (5-point VRS), and sleep duration (≤ 2 hours, > 2-3
hours, > 3 - < 6 hours, or ≥ 6 hours) in a diary. The safety profile was
evaluated based on standard monitoring of AEs, vital signs, and
routine laboratory tests. Forty-nine white patients (25 women, 24
men) were enrolled; their mean (SD) age was 61.6 (11.5) years, and
their mean weight was 74.7 (16.7) kg. The most common source of
pain was musculoskeletal disorders (40 patients), followed by nervous
system disorders (10), neoplasms (9), injuries (5), and other causes
(6). Forty-one patients completed the study; 2 patients discontinued
because of AES, 1 because of lack of efficacy, and 5 for nonmedical
reasons. Thirty-three patients provided data per protocol. Patients in
the per-protocol population received a mean (SD) transdermal
buprenorphine dose of 49.9 (38.9) micrograms/hour. The proportion
of patients in the per-protocol population rating the quality of
treatment as adequate (combined ratings of very good, good, and
satisfactory) was 93.9% (31/33) for both regimens. The physicians'
ratings indicated adequate quality of treatment in 93.8% (30/32) of
patients applying 4 patches for 3 days each and 97.0% (32/33) of
patients applying 3 patches for 4 days each. Mean (SD) pain intensity
scores on the NRS were similar after completion of the 3- and 4-day
regimens (3.73 [1.88] and 3.88 [1.75] points, respectively), as were
MPQ scores (0.79 [0.67] and 0.79 [0.78]). The mean (SD) proportion
of days with at least satisfactory pain relief was 83.9% (26.1%) and
85.6% (24.4%) for the 3- and 4-day regimens; the corresponding
proportions of nights with at least satisfactory pain relief were 85.2%
(26.6%) and 88.1% (21.4%). Continuously assessed pain intensities at
specified times of day and night (NPRS) differ insignificantly between
regimens. Mean SF-36 health status scores differ insignificantly
between regimens (total score: 37.7% [17.0%] and 37.7% [17.3%]).
Mean rates of nights with good sleep quality were 28.5% (39.9%) for
the 3-day regimen and 36.0% (42.6%) for the 4-day regimen. Local
skin tolerability was comparable for the 3- and 4-day regimens, with
objective findings (mainly erythema) at the patch-application sites in
17 of 32 and 11 of 33 patients, respectively, and subjective symptoms
(mainly itching) in 16 of 32 and 13 of 33 patients. The most common
AEs in the safety population were nausea, dizziness/giddiness, and
malaise/fatigue (3/49 [6.1%] each). In conclusion, analgesic efficacy,
patients' satisfaction with the quality of treatment, and skin tolerability
852
differ insignificantly between 3 and 4 days of patch application in

these patients with chronic pain who had been previously stabilized on
transdermal buprenorphine (6).
The main objective of this study was to determine the effectiveness
of converting patients from traditional full agonist opioid medication
to sublingual buprenorphine, as well as to identify patient groups that
are most likely to benefit from this therapy. Patients, who underwent
conversion or had developed tolerance with diminished analgesia or
were experiencing side effects on their opioid medications, were
included. An observational report of outcomes assessment was
carried out at an interventional pain management practice setting in
the US. Retrospective data from clinical records was compiled on 104
de-identified chronic pain patients whose personal information had
been redacted (60 men and 44 women, aged 21-78) and who had
previously been treated with opioid-agonist drugs; they were
converted to buprenorphine sublingual in tablet form during the study.
Chronic pain was defined as persistent pain for at least 6 months. Data
collected from patient profiles included age, sex, diagnosis,
medication history, pre-induction opioid intake, reason for
detoxification, pre-induction Clinical Opiate Withdrawal Score, and if
applicable, cause of sublingual buprenorphine cessation. Pain levels
and QOL scores were recorded before and after conversion to
sublingual buprenorphine. After initiation of buprenorphine sublingual
therapy for more than 2 months, the mean pain scores on a scale from
0-10 decreased by 2.3 points (p<0.001). Patient QOL scale was
insignificantly affected by buprenorphine sublingual therapy (p=0.14).
The success rate was highest for patients using morphine, oxycodone,
and fentanyl before buprenorphine sublingual induction. These patient
groups had a 3.7-point decrease in pain for those taking morphine, a
2.5-point decrease in pain for those taking oxycodone, and a 2.2-point
decrease for those taking fentanyl. The smallest pain reduction was in
the patient group using oxymorphone before conversion with a 1.1-
point decrease in pain. Patients taking between 100-199 mg morphine
equivalents per day experienced the greatest reduction (2.7 points) in
pain scores. Patients taking between 200-299 mg morphine equivalent
before buprenorphine sublingual induction exhibited a decrease of
over 2 points on average. Patients taking > 400 mg morphine
equivalent reported the smallest reduction in pain scores, on average a
1.1-point decrease. In conclusion, patients continuing sublingual
buprenorphine therapy for more than 60 days reported significant
decreases in pain (2.3 points). Patients on doses of opioid medication
between 100-199 mg morphine equivalents seemed to fare better with
853
conversion to sublingual buprenorphine than patients on the highest

doses (> 400 mg morphine equivalents). The opioid drug used by the
patient before sublingual buprenorphine induction appears to have
some effect on sublingual buprenorphine conversion success. Patients
previously taking morphine, oxycodone, and fentanyl had the greatest
decrease in pain after conversion to sublingual buprenorphine (7).
The main objective of this study was to review the current
evidence on buprenorphine-naloxone for the treatment of opioid-
related disorders, with a focus on primary care settings. MEDLINE
and the Cochrane Database of Systematic Reviews were searched.
Evidence was mainly level I. Buprenorphine is a partial μ-opioid
agonist and κ-opioid antagonist with a long half-life and less abuse
potential than methadone. For detoxification, buprenorphine is at least
equivalent to methadone and is superior to clonidine. For maintenance
treatment, buprenorphine is clearly superior to placebo. Methadone
has a slight advantage in terms of retention in treatment, but initial use
of buprenorphine-naloxone is an efficacious stepped approach. Use of
buprenorphine in the primary care setting is feasible, safe, and
effective. In conclusion, buprenorphine is a safe and effective agent
for detoxification from opioids. It can be used as a first-line agent in
maintenance programs, owing to its lower abuse potential relative to
other opioids. Its effectiveness in primary care settings makes it a
useful therapeutic tool for family physicians (8).
References
1. Davis MP. Buprenorphine in cancer pain. Support Care Cancer. 2005;
13(11):878-87.
2. Davis MP. Twelve reasons for considering buprenorphine as a frontline
analgesic in the management of pain. J Support Oncol. 2012;10(6):209-19.
3. Budd K. Buprenorphine and the transdermal system: the ideal match in pain
management. Int J Clin Pract Suppl. 2003;133:9–14.
4. Skaer TL. Practice guidelines for transdermal opioids in malignant pain. Drugs.
2004;64:2629–38.
5. Evans HC, Easthope SE. Transdermal buprenorphine. Drugs. 2003; 63:1999–
2010.
6. Likar R, Lorenz V, Korak-Leiter M, et al. Transdermal buprenorphine patches
applied in a 4-day regimen versus a 3-day regimen: a single-site, Phase III,
randomized, open-label, crossover comparison. Clin Ther. 2007;29(8):1591-606.
7. Daitch J, Frey ME, Silver D, et al. Conversion of chronic pain patients from
full-opioid agonists to sublingual buprenorphine. Pain Physician. 2012;15(3
Suppl):ES59-66.
8. Ducharme S, Fraser R, Gill K. Update on the clinical use of buprenorphine: in
opioid-related disorders. Can Fam Physician. 2012;58(1): 37-41.
854
METHADONE
Methadone is an inexpensive synthetic opioid agonist that has a
long half-life, no active metabolites, and little tendency to induce
tolerance in patients. It has unique properties that make it useful in
treating pain which is poorly controlled by other opioids. In addition
to binding to the opioid μ-receptor, methadone produces analgesic
effects through its antagonism at the NMDA receptor site and by
increasing the availability of neurotransmitters serotonin and
norepinephrine within the CNS (1). Methadone works particularly
well in opioid rotation and may be an effective alternative for cancer
patients, although its equianalgesic dosing to morphine has not been
firmly established and can vary widely depending on the cumulative
dose of morphine (2-4). It occurs more frequently in patients
previously exposed to high doses of opioids than in patients receiving
low dose. Methadone is available for oral, sublingual, rectal,
intravenous, and subcutaneous administration, and has relatively low
risk for opioid-associated AEs (5).
The occurrence of undesirable side effects due to opioids (delirium,
confusion, myoclonus, nausea, and emesis) is one of the major
complications in the management of pain, especially in chronic cancer
pain states. Methadone, as an alternative to morphine, has been
proposed in the control of opioid-induced toxicity. Methadone is a
synthetic opioid, with mu and delta receptor activity, associated with
the capacity to inhibit NMDA. Questions have arisen concerning its
equianalgesic ratio since its rediscovery over the past few years are
related to its receptor interactions. Opioid rotation is a new tool in the
management of cancer pain, deserving more attention (6).
The purpose of this study was to determine the outcome of
methadone initiation or rotation for cancer pain treatment in outpatient
settings. Chart review was done of 189 consecutive patients who
underwent methadone initiation or rotation at the authors' palliative
care outpatient center. Data were collected regarding demographic and
clinical characteristics, symptoms, and opioid side effects at baseline
and for 2 follow-up visits (F1, F2). Failure was defined as methadone
discontinuation by the palliative care physician or patient's
hospitalization for uncontrolled pain or methadone-related side effects
at F1. One hundred (53%) initiations and 89 (47%) rotations were
conducted. Success rates for methadone initiation and rotation were 82
of 89 (92%) and 85 of 100 (84%), respectively. Mean (SD) age was
60 (11) years. One hundred (53%) patients were women, 138 (73%)
were white, and 182 (96%) had solid cancers. The main reason for
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rotation was pain (65 of 89 patients, 47%). Median (IQR) pain scores
(ESAS/0-10) were 6 (5-8), 4 (3-6), and 3 (2-5) at baseline, F1, and F2,
respectively (p<0.0001). Median (IQR) daily methadone dose for
initiation and rotation was 10 (5-15) mg and 15 (10-30) mg at F1
(p<0.0001) and 10 (8-15) mg and 18 (10-30) mg at F2 (p<p.0001),
respectively. Constipation and nausea improved (p<0.005) after
initiation/rotation to methadone. Frequency of sedation,
hallucinations, myoclonus, and delirium did not increase after
initiation/rotation to methadone. In conclusion, outpatient methadone
initiation and rotation for cancer pain treatment were safe, with high
success rates and low side effect profiles (7).
Pain management is a central issue in the care of cancer patients in
hospice services. Morphine is at present the first line opioid
recommended. However, when morphine is used in large doses,
especially in renal patients, an active metabolite of morphine,
morphine-6-glucoronide, may cause delirium and myoclonus and
sometimes antagonize the analgesic effect of morphine. Both fentanyl
and methadone have some potential advantages over morphine since
they are longer acting and have no active metabolites. However, large
doses of fentanyl or long-acting morphine are expensive while
methadone has an extremely low cost. Retroactive comparative
observations in 50 cancer patients are presented. Methadone was as
effective as morphine, TDF and common combinations of other
opioids in controlling the types of cancer pain was presented by
patients in a hospice in the Northwestern Region of Puerto Rico. The
use of methadone on elderly patients with cancer pain as first line
therapy is growing in European and North-American hospices.
Hospitals should add methadone to their therapeutic armamentarium
and physicians should develop skills to use this long acting opioid (8).
The aim of this study was to retrospectively review the chart of
cancer patients switched to methadone for unfavorable response to the
previous opioid. Retrospective reviewed consecutive medical records
of patients undergoing opioid switching to methadone were evaluated.
Patients who were switched from different opioids to methadone,
because of poor pain relief in the presence of AEs limiting further
dose increases despite symptomatic treatment, were selected. After the
initial oral dose, the subsequent doses were flexible and were changed
timely to fit the patients' needs in an attempt to find the best balance
between pain and opioid-related symptoms. Of 345 patients who
underwent switching to methadone, 27 patients were not considered
feasible for analysis. Only 1 patient required the use of naloxone for
the occurrence of bradypnea. A total of 77.4% substitutions for
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methadone were considered successful. The median time to achieve

daily dose stabilization in patients successfully switched was 3 days.
Fifty-one substitutions failed. For all previous opioids, insignificant
differences between initial conversion ratios and ratios achieved after
stabilization were found (p=0.42). Insignificant correlation between
the previous opioid dose and the final conversion ratio was found
(p=0.19). In conclusion, switching to methadone from different
opioids, using an initial fixed ratio followed by a flexible dosing,
according to the clinical need, is highly effective and safe when
performed in an acute pain relief and palliative care unit (9).
A prospective study was carried out on a cohort of consecutive
sample of patients receiving oxycodone, who were switched to
methadone for different reasons mainly because of an inconvenient
balance between analgesia and AEs. An initial conversion ratio
between oxycodone and methadone was 3.3:1. Intensity of pain and
symptoms associated with opioid therapy were recorded, and a
distress score was also calculated as a sum of symptom intensity. A
successful switching was considered when the intensity of pain and/or
a distress score or the principal symptom requiring switching
decreased at least of 33% of the value recorded before switching.
Nineteen out of 542 patients admitted to the unit in 1 year underwent a
switching from oxycodone to methadone. Almost all substitutions
were successful. The prevalent indication for opioid switching was
uncontrolled pain and AEs (12 patients). Insignificant changes
between the initial conversion ratio and final conversion ratio between
the 2 opioids were found. In conclusion, switching from oxycodone to
methadone is a reliable method to improve the opioid response in
advanced cancer patients. A ratio of 3.3 appears to be reliable, even at
high doses (10).
Retrospectively reviewed consecutive medical records of patients
undergoing an opioid rotation from methadone to an alternative opioid
were evaluated. For inclusion, patients were required to have received
methadone for at least 3 days and have reached stable dose of the
alternative opioid(s) during the 7 days following. Stable dose was
defined as a 30% or less change in opioid dose from one day to the
next. Records of 39 patients met inclusion criteria. Excluded from
analysis were 5 patients who were restarted on methadone within 7
days, 2 with irregular opioid use resulting in negligible regular opioid
doses post-switch, and 3 due to concerns about reliability of multiple
routes used for fentanyl. Data from 29 patients, 10 female, mean age
48 +/- 14.4 years, were evaluable. The mean dose ratio for oral
methadone to oral morphine equivalent daily dose (MEDD) was 1:4.7
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(95% CI 3.0 - 6.5, n=16), and for intravenous methadone to oral

morphine equivalent daily dose was 1:13.5 (95% CI, 6.6 - 20.5, n=13),
p=0.06. Methadone dose was significantly correlated to stable
morphine equivalent daily dose after switching opioids for both
methadone intravenous and oral (Spearman = 0.86, p=0.0001 and
Spearman = 0.72, p=0.0024), respectively. Mean day of achieving
stable dose was day 2.5 +/- 0.2 for intravenous methadone and day 2.6
+/- 0.3 for oral methadone. In conclusion, these dose ratios are new
findings that may assist in switching patients more safely to
alternative opioids when side effects or pain problems occur when
patients are receiving methadone. An important difference in
analgesic potency appears to exist between intravenous and oral
methadone (11).
The purpose of this study was to compare the effectiveness and
side effects of methadone and morphine as first-line treatment with
opioids for cancer pain. Patients in international palliative care clinics
with pain requiring initiation of strong opioids were randomly
assigned to receive methadone (7.5 mg orally every 12 hours and 5
mg every 4 hours as needed) or morphine (15 mg SR every 12 hours
and 5 mg every 4 hours as needed). The study duration was 4 weeks.
A total of 103 patients were randomly assigned to treatment (49 in the
methadone group and 54 in the morphine group). The groups had
similar baseline scores for pain, sedation, nausea, confusion, and
constipation. Patients receiving methadone had more opioid-related
dropouts (11 of 49, 22%) than those receiving morphine (3 of 54, 6%,
p=0.019). The opioid escalation index at days 14 and 28 was similar
between the 2 groups. More than three fourths of patients in each
group reported a 20% or more reduction in pain intensity by day 8.
The proportion of patients with a 20% or more improvement in pain at
4 weeks in the methadone group was 0.5 (95% CI 0.3 - 0.6) and was
similar in the morphine group (0.6, 95% CI 0.4 - 0.7). The rates of
patient-reported global benefit were nearly identical to the pain
response rates and did not differ between the treatment groups. In
conclusion, methadone did not produce superior analgesic efficiency
or overall tolerability at 4 weeks compared with morphine as a first-
line strong opioid for the treatment of cancer pain (12).
References
1. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of
pharmacokinetics, pharmacodynamics, drug interactions and protocols of
administration. Support Care Cancer. 2001;9:73–83.
2. Lawlor PG, Turner KS, Hanson J, et al. Dose ratio between morphine and
methadone in patients with cancer pain: a retrospective study. Cancer. 1998;82:1167–
73.
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3. Ripamonti C, Groff L, Brunelli C, et al. Switching from morphine to oral

methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol.
1998;16:3216–21.
4. Berland D. Pain management in patients with advanced cancer. Ann Intern
Med. 2000;132:593.
6. Mancini I, Lossignol DA, Body JJ. Opioid switch to oral methadone in cancer
pain. Curr Opin Oncol. 2000;12(4):308-13.
7. Parsons HA, de la Cruz M, El Osta B, et al. Methadone initiation and rotation
in the outpatient setting for patients with cancer pain. Cancer. 2010;116(2):520-8.
8. Shelton BW, Deynes-Romero J, Tofani-Montalvo M, et a. Methadone: an
effective alternative to morphine for pain relief in cancer patients. Bol Asoc Med P R.
2008;100(3):7-10.
9. Mercadante S. Switching methadone: a 10-year experience of 345 patients in an
acute palliative care unit. Pain Med. 2012;13(3):399-404.
10. Mercadante S, Ferrera P, Villari P, et al. Switching from oxycodone to
methadone in advanced cancer patients. Support Care Cancer. 2012;20(1):191-4.
11. Walker PW, Palla S, Pei BL, et al. Switching from methadone to a different
opioid: what is the equianalgesic dose ratio? J Palliat Med. 2008;11(8):1103-8.
12. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-
line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol.
2004;22(1):185-92.
OTHER OPIOIDS
There are many other opioids available on the market today.
However, they are not usually recommended for routine use in cancer
pain management. These include diamorphine (commonly known as
heroin), meperidine, propoxyphene, and mixed agonist-antagonist
agents (ie, butorphanol, pentazocine, and nalbuphine). Heroin is not
used in the US in medical practice and considered as one of the most
dangerous street drugs; however, it is still widely used in UK for
chronic malignant and nonmalignant pain control. Meperidine is
metabolized to a neurotoxic metabolite normeperidine which can
induce seizures if accumulated. The effect of propoxyphene can be
considered more euphoric than analgesic. The mixed agents have a
ceiling effect as well as the potential in reversing analgesic effects of
any pre-existing opioid the patient is already taking and, therefore,
they are not considered efficacious (1).
A study was designed to determine the relative analgesic potency
of intramuscular heroin and morphine and to compare mood and side
effects in 166 cancer patients with postoperative pain. Heroin was
about twice as potent as morphine (95% CI 1.6-2.6 times) in graded-
dose, twin-crossover assays. Heroin provided an analgesic peak effect
859
earlier than morphine (1.2 plus or minus 0.08 and 1.5 plus or minus
0.10 hours, respectively [mean plus or minus S.E.M.]). Doses with
equal analgesic effects provided comparable improvements in various
elements of mood, particularly feelings of peacefulness. Peak mood
improvement occurred earlier after heroin than after morphine (1.2
plus or minus 0.10 and 1.8 plus or minus 0.13 hours, respectively).
Both analgesia and mood improvement were less sustained after
heroin at doses providing equal peak analgesic effects. The drugs
shared the most common side effects, with no marked differences in
their occurrence; sleepiness was the most frequent side effect after
both drugs (46%, each). Heroin has no apparent unique advantages or
disadvantages for the pain relief in patients with cancer (2).
The results of a propoxyphene study, which prompted the Darvocet
and Darvon recall, indicated that the drug significantly changes the
electrical activity of the heart. These changes can be seen on
electrocardiograms and may increase the risk of abnormal heart
rhythms, which have been linked to serious AEs, including death.
Other cardiac side effects include bradycardia, decreased ability of the
heart to contract properly, and interruption of the heart‘s transmission
of electrical impulses. According to available data, even small
changes in a patient, such as dehydration, a change in medication, or
changes in kidney function can affect the risk of adverse
propoxyphene side effects. Even when taken in appropriate dosages,
propoxyphene can cause significant changes to the electrical activity
of the heart. After reviewing this information, the FDA decided that
the drug‘s effectiveness in treating pain no longer outweighed its
risks. Following the release of clinical data linking the drug to heart
rhythm abnormalities, the FDA has requested a recall of
propoxyphene, a prescription pain medication. Xanodyne, the
pharmaceutical company which manufactured propoxyphene under
the brand name Darvon and Darvocet, had agreed to withdraw the
medication (3).
The analgesic meperidine has been reported to produce signs of
CNS excitation in human beings. To determine the relationship
between signs and symptoms of CNS excitation and plasma levels of
meperidine and normeperidine, 67 patients receiving meperidine for
the relief of postoperative or chronic pain were studied. In 48 patients,
excitatory effects ranging from mild nervousness to tremors, twitches,
multifocal myoclonus, and seizures were directly correlated with
accumulation of normeperidine in plasma. Evidence of compromised
renal function occurred in only 14 of the 48 symptomatic patients,
suggesting that renal dysfunction may contribute to but is not the sole
860
factor in the accumulation of normeperidine or its relation to adverse

neurological signs. In a second study, mood alterations in 47 patients
receiving meperidine and in 29 receiving other narcotic analgesics for
postoperative pain were surveyed. The repeated administration of
meperidine was associated with adverse alterations in various
elements of mood (e.g., apprehension, sadness, and restlessness) (4).
References
2007;3(3):381-400.
2. Kaiko RF, Wallenstein SL, Rogers AG, et al. Analgesic and mood effects of
heroin and morphine in cancer patients with postoperative pain. N Engl J Med.
1981;304(25):1501-5.
3. Darvocet and Darvon Recall. Prescription Pain Medication. Available 22 May
2013 at forthepeople.com › ... › Consumer Alerts.
4. Kaiko R F, Foley KM, Grabinski PY, et al. Central nervous system excitatory
effects of meperidine in cancer patients. Ann Neurol. 1983; 13(2):180-5.
LEVORPHANOL
Levorphanol (levo-3-hydroxy-N-methylmorphinan) is a strong
opioid that is the only available opioid agonist of the morphinan
series. Levorphanol was originally synthesized as a pharmacological
alternative to morphine more than 40 years ago. It is considered a
step-3 opioid by the WHO and has a greater potency than morphine.
Analgesia produced by levorphanol is mediated via its interactions
with mu, delta, and kappa opioid receptors. Levorphanol is also an
NMDA receptor antagonist. There is evidence that levorphanol may
inhibit uptake of norepinephrine and serotonin. Similarly to morphine,
levorphanol undergoes glucuronidation in the liver, and the
glucuronidated products are excreted in the kidney. Levorphanol can
be given orally, intravenously, and subcutaneously. The long half-life
of the drug increases the potential for drug accumulation. Levorphanol
has clinical efficacy in neuropathic pain (1).
Levorphanol, a potent opioid with simultaneous action at NMDA
receptor site, can be considered for treatment of cancer-associated
pain in some patients. Its main compound dextromethorphan is
beneficial for adequate analgesia after bone-malignancy resection,
especially when used for epidural infusion. However, earlier reports
have provided controversial data and showed low efficacy of
861
dextromethorphan in controlling cancer-associated pain compared

with more traditional opioids, such as morphine (2).
Plasma concentrations of the narcotic analgesic, levorphanol, have
been determined following intravenous, intramuscular and oral
administration of therapeutic doses of the drug to patients with pain.
In 2 patients who received single intravenous doses of levorphanol,
the plasma concentration-time profile in each subject was best
described by a triexponential decline of the concentrations with
terminal half-lives (t 1/2) of about 11 hours. Following intramuscular
and oral administrations, peak plasma concentrations of intact drug
were generally reached after about 0.5 and 1 hour, respectively.
Conjugated (beta-glucuronidase labile) levorphanol appeared rapidly
in plasma following all routes of administration and quickly reached
concentrations, which were 5 to 10 fold higher than the intact drug.
Effective analgesic steady-state concentrations of levorphanol in
patients receiving a wide range of chronic oral and intramuscular
dosages of the drug ranged from about 10 to 100 ng/ml and these
concentrations showed no apparent correlation with either the dose or
the subjective analgesic response achieved. The latter observations are
probably a reflection of extensive and variable inter-subject "first-
pass" metabolism of the drug combined with different degrees of
pharmacologic tolerance at the receptor level. However, in the non-
tolerant patient it appears that a plasma concentration of about 10
ng/ml is associated with a positive analgesic effect. It seems that
analgesia is often maintained within a narrow plasma concentration
range for each subject and relatively small decreases in plasma
concentration in some patients may be associated with either mild or
severe pain. Plasma protein binding at steady state in 10 patients
averaged 40 +/- 2.6%. Concentrations of the drug in the CSF of 2
patients studied were 60-70% of the corresponding plasma levels of
the drug (4).
Case series of patients were treated with levorphanol when pain did
not respond adequately to other opioids, including methadone. During
a 5-year period in a single palliative medicine practice, 20 of 244
patients with chronic non-malignant pain in a palliative care clinic and
11 of 1508 terminally ill patients enrolled in hospice care whose
severe chronic pain was not relieved by treatment with other opioids
were treated with oral levorphanol. Of those 31 patients, 16 (52%)
reported excellent relief of pain while 7 (22%) reported fair relief for a
total response rate of 74%. These results suggest that levorphanol has
a role in the treatment of pain syndromes that are refractory to other
opioids. The pattern of relief seen in this case series is similar to that
862
reported for methadone. Could it be that levorphanol may have a role

like methadone for pain that is poorly controlled with other pure
agonist opioids? (5).
References
1. Prommer E. Levorphanol: the forgotten opioid. Support Care Cancer. 2007;
15(3):259-64.
2. Weinbroum AA, Bender B, Nirkin A, et al. Dextromethorphan-associated
epidural patient-controlled analgesia provides better pain - and analgesics-sparing
effects than dextromethorphan-associated iv patient-controlled analgesia after bone-
malignancy resection: a randomized, placebo-controlled, double-blinded study.
Anesth Analg. 2004;98:714-22.
3. Mercandante S, Casuccio A, Genovese G. Ineffectiveness of dextromethorphan
in cancer pain. J Pain Symptom Manage. 1998;16:317–22.
4. Dixon R, Crews T, Inturrisi C, Foley K. Levorphanol: pharmacokinetics and
steady-state plasma concentrations in patients with pain. Res Commun Chem Pathol
Pharmacol. 1983;41(1):3-17.
5. McNulty JP. Can levorphanol be used like methadone for intractable refractory
pain? J Palliat Med. 2007;10(2):293-6.
ADVERSE OPIOID EFFECTS

Opioids, defined as drugs that stimulate opioid receptors, are
primarily used in the treatment of moderate to severe pain. They
induce CNS AEs which are divided into 3 groups. The first group
includes effects that lower the level of consciousness - sedation,
drowsiness and sleep disturbance. The second group affects the
thinking process and the ability to react - cognitive impairment,
psychomotor impairment, delirium, hallucinations, dreams and
nightmares. The third group is of the direct toxic effects of opioids on
neurons and includes myoclonus, hyperalgesia and tolerance (1).
This is a systematic review examining the management of opioid-
induced central side effects. It has been conducted as part of a larger
European Palliative Care Research collaborative review into the use
and role of opioids in cancer pain. The review process identified 26
studies that met the inclusion criteria. The overall quality of the data
was low and the few recommendations that can be made are weak and
require confirmatory studies. The main central side effects examined
were sedation, cognitive failure, sleep disturbance and myoclonus.
Overall, there is limited evidence for the use of methylphenidate in
counteracting opioid-induced sedation and cognitive disturbance. No
clear recommendations can be made concerning other individual drugs
863
for the management of any of the central side effects examined. Given
the lack of available data from this review there need to be further
prospective controlled trials to confirm or refute these findings (2).
Successful opioid therapy often depends on achieving a balance
between analgesic effectiveness and side effects. The risk of opioid-
induced cognitive impairment often hinders clinicians and patients
from initiating or optimizing opioid therapy. Despite subjective
experiences of mental dullness and sedation, objective tests of
cognitive functioning do not always demonstrate marked changes
following opioid administration. The purpose of this article is to
review the empiric literature on opioids and cognitive functioning,
including the relationships among pain, cognition, delirium, and
opioids. In general, research reflects minimal to insignificant
impairments in cognitive functioning. If impairment does occur, it is
most often associated with parenteral opioids administered to opioid-
naive individuals. Some evidence suggests that opioids may actually
enhance cognitive function and decrease delirium in some patient
populations (3).
Opioid use in patients with renal impairment can lead to increased
AEs. Opioids differ in their effect in renal impairment in both efficacy
and tolerability. This systematic literature review forms the basis of
guidelines for opioid use in renal impairment and cancer pain as part
of the European Palliative Care Research Collaborative opioid
guidelines project. The objective of this study was to identify and
assess the quality of evidence for the safe and effective use of opioids
for the relief of cancer pain in patients with renal impairment and to
produce guidelines. The Cochrane Database of Systematic Reviews,
Cochrane Central Register of Controlled Trials, MedLine, EMBASE
and CINAHL were systematically searched in addition to hand
searching of relevant journals. Studies were included if they reported a
clinical outcome relevant to the use of selected opioids in cancer-
related pain and renal impairment. The selected opioids were
morphine, diamorphine, codeine, dextropropoxyphene,
dihydrocodeine, oxycodone, hydromorphone, buprenorphine,
tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and
methadone. No direct comparator was required for inclusion. Studies
assessing the long-term efficacy of opioids during dialysis were
excluded. This is a narrative systematic review and no meta-analysis
was performed. The GRADE approach was used to assess the quality
of the studies and to formulate guidelines. Fifteen original articles
were identified. Eight prospective and 7 retrospective clinical studies
were identified but no RCTs. Results were not found for diamorphine,
864
codeine, dihydrocodeine, buprenorphine, tramadol,

dextropropoxyphene, methadone or remifentanil. All of the studies
identified have a significant risk of bias inherent in the study
methodology and there is additional significant risk of publication
bias. Overall evidence is of very low quality. The direct clinical
evidence in cancer-related pain and renal impairment is insufficient to
allow formulation of guidelines but is suggestive of significant
differences in risk between opioids. Fentanyl, alfentanil and
methadone are identified, with caveats, as the least likely to cause
harm when used appropriately. Morphine may be associated with
toxicity in patients with renal impairment. Unwanted side effects with
morphine may be dealt with by either increasing the dosing interval or
reducing the 24-hour dose or by switching to an alternative opioid (4).
The aim of this study was to evaluate the effectiveness of
prophylactic treatment with laxatives and antiemetics on the incidence
of G-I adverse reactions such as constipation, nausea and vomiting in
cancer patients who received oral opioid analgesics for the first time.
A multi-institutional retrospective study was carried out, in which 619
eligible hospitalized patients receiving oral opioid analgesics for
cancer pain were enrolled from 35 medical institutions. The primary
endpoint was the incidence of opioid-induced side effects in patients
receiving prophylactic medication. ORs of the incidence of adverse
reactions in the absence or presence of premedication obtained from
several institutions were subjected to a meta-analysis. Among 619
patients, the incidence of constipation was significantly lower in
patients receiving laxatives, including magnesium oxide, as
premedication than in those without them (34% vs. 55%, OR =0.432,
95% CI 0.300 - 0.622, p<0.001). However, the incidence of nausea or
vomiting was similar regardless of prophylactic medication with
dopamine D2 blockers. The results of the meta-analysis revealed that
prophylactic laxatives significantly reduced the incidence of
constipation (overall OR 0.469, 95% CI 0.231 - 0.955, p=0.037),
whereas dopamine D2 blockers were ineffective in preventing opioid-
induced nausea or vomiting. In conclusion, premedication with
laxatives for prevention of opioid-induced constipation is effective.
However, premedication with dopamine D2 blockers is insufficient to
prevent nausea or vomiting (5).
Constipation and the laxatives polyethylene glycol, sodium
picosulphate and lactulose were investigated in outpatients with
cancer on opioid therapy. Randomly selected patients were enrolled in
a prospective, controlled, open-label trial. Endpoints were number of
patients taking laxatives > 28 days, number of patients with sfi72,
865
dosage, NRS for constipation, and EORTC QLQ questionnaire scores.

The 348 patients had comparable demographic and medical data. In
this ambulatory population, mobility scores remained unaffected.
Constipation incidence was 5.7%, with sfi72 42, mean NRS 2.3557
and mean QOL 2.1. A total of 53.2% discontinued their laxative
medication. Laxative use correlated with higher opioid usage
(morphine-equivalent mg/day: no laxative 98.2, sodium picosulphate
128.2, polyethylene glycol 139.9, lactulose 154.5). Polyethylene
glycol was the most frequently prescribed laxative (polyethylene
glycol 27.3%, sodium picosulphate 10.3%, lactulose 9.2%).
Polyethylene glycol (sfi72 12.6%, NRS 2.2, QOL 2.1) and sodium
picosulphate (sfi72 11.1%, NRS 2.7, QOL 2.2) were more effective
than lactulose (sfi72 15.5%, NRS 3.8, QOL 2.5). In spite of opioid
therapy, the incidence of constipation was low in these ambulatory
cancer pain patients at an early disease stage. For prevention of
constipation, polyethylene glycol or sodium picosulphate is
recommended instead of lactulose (6).
Morphine, oxycodone, and fentanyl are major opioids available as
CR morphine, CR oxycodone, and TDF, respectively, in Japan. A
retrospective chart review was conducted to examine (1) nausea and
somnolence on commencement of CR morphine, CR oxycodone, and
TDF for cancer pain treatment, (2) the antiemetic effectiveness of
prochlorperazine to prevent opioid-induced nausea, and (3) the side
effect of prochlorperazine on somnolence in patients with cancer pain.
Patients with cancer (n=413) were prescribed with CR morphine
(n=66), CR oxycodone (n=196), and TDF (n=151). The incidence of
nausea on commencement of the TDF group (6.8%) was significantly
lower than that of both the CR morphine group (22.6%) and the CR
oxycodone group (35.4%, p<0.001). There was insignificant
difference in the incidence of nausea on commencement of all groups
combined with prochlorperazine at dosage of 15 mg/d. The incidence
of somnolence on commencement of the TDF group (9.0%) was
significantly lower than that of both the CR morphine group (31.3%)
and the CR oxycodone group (41.5%, p<0.001). The incidence of
somnolence on commencement of the CR oxycodone group combined
with prochlorperazine was significantly higher than that of the CR
oxycodone combined without prochlorperazine (p<0.05). In
conclusion, the incidence of nausea and somnolence on
commencement of TDF are significantly lower than that of both CR
morphine and CR oxycodone for cancer pain treatment.
Prochlorperazine at a dosage of 15 mg/d may not be effective in
866
preventing opioid-induced nausea and may cause somnolence in

patients with cancer pain (7).
Constipation is reported in 52% of people with advanced
malignancy. This figure rises to 87% in people who are terminally ill
and taking opioids. Constipation may be the most common AE of
opioids. There is no reason to believe that people with chronic non-
malignant disease who take opioids will be less troubled by this AE. A
systematic review aimed to answer the following clinical questions:
What are the effects of oral laxatives, rectally applied medications,
and opioid antagonists for constipation in people prescribed opioids?
Medline, Embase, The Cochrane Library, and other important
databases up to August 2009 were searched. Harms alerts from
relevant organizations such as the US FDA and the UK Medicines and
Healthcare products Regulatory Agency were included. Twenty-three
systematic reviews, RCTs, or observational studies that met inclusion
criteria were included. The interventions included arachis oil enemas,
bisacodyl, co-danthrusate/co-danthramer, docusate, glycerol
suppositories, ispaghula husk, lactulose, liquid paraffin, macrogols
plus electrolyte solutions, magnesium salts, methylcellulose, opioid
antagonists, phosphate enemas, senna, sodium citrate micro-enema,
and sodium picosulfate (8).
Opioids are the drugs of choice for treating moderate-to-severe
pain, especially for patients in the end stage of cancer or other
advanced illnesses, and also in critical care or for the treatment of
chronic pain. Side effects such as nausea, pruritus, dizziness and
constipation have to be controlled in order to use these drugs to their
full potential. Opioid-induced bowel syndrome and constipation
caused by activation of μ-receptors in the gut can have such
distressing effects that some patients prefer to forego adequate pain
control. Methylnaltrexone is a μ-opioid receptor antagonist that,
unlike naltrexone or naloxone, does not pass the blood-brain barrier,
and therefore does not impair the centrally mediated analgesic effect
of opioids. It is licensed for the treatment of opioid-induced
constipation in palliative care in more than 50 countries (9).
Whilst prophylaxis remains the first-line management option,
methylnaltrexone is a recommended treatment option for opioid-
related constipation if administration of laxatives is ineffective. Due to
its inability to cross the blood-brain barrier, methylnaltrexone exerts a
peripheral inhibition of opioid-related effects without influencing the
opioid-induced central effects; as a result, the analgesic effect of
opioids is unaffected. Moreover, multiple clinical trials, albeit not
always conducted specifically in cancer patients, have demonstrated
867
that up to 4 months' treatment with either intramuscular or

subcutaneous methylnaltrexone provides effective relief from opioid-
related constipation and is well tolerated. Preliminary evidence
indicates that the addition of methylnaltrexone to standard care for
opioid-related constipation may also be advantageous from a
pharmacoeconomic perspective. In addition, preliminary data suggest
that methylnaltrexone could be associated with some further clinical
benefits other than the treatment of opioid-related constipation, such
as the improvement of gastric emptying, the relief of nausea/vomiting,
and the reduction of the risk of regurgitation and pulmonary
aspiration. This narrative review examines the most recent evidence
and evaluates the current role of methylnaltrexone in the management
of opioid-related constipation, and its potential efficacy in cancer
patients (10).
The medical records of people prescribed methylnaltrexone over a
four-month period were reviewed to examine characteristics of people
in order to examine whether the reason for constipation was charted,
whether other factors that could contribute to constipation were
considered and the effectiveness of methylnaltrexone. Over the study
period, 10 people received methylnaltrexone, only 4 of whom had a
bowel action less than 24 hours, after administration with 3 not having
any bowel actions reported 6 days after administration. Whilst all
were receiving opioids, the opioids doses were in the moderate range
(61-200 mg morphine equivalent). However, all had other factors that
could contribute to constipation including impaired functional status
and medications with anti-cholinergic effects (mean anti-cholinergic
load 4.5). In conclusion, methylnaltrexone is targeted treatment for the
management of opioid-induced constipation. However, there is a
percentage of people who fail to respond (11).
Assessment: opioid induced AEs can be divided into 3 groups.

The first group includes effects that lower the level of consciousness -
sedation, drowsiness and sleep disturbance. The second group affects
the thinking process and the ability to react - cognitive impairment,
psychomotor impairment, delirium, hallucinations, dreams and
nightmares. The third group is the direct toxic effects of opioids on
neurons and includes myoclonus (perhaps), hyperalgesia and
tolerance.
The direct clinical evidence in cancer-related pain and renal
impairment is insufficient to allow formulation of guidelines but is
suggestive of significant differences in risk between opioids. Fentanyl,
alfentanil and methadone are identified, with caveats, as the least
868
likely to cause harm when used appropriately. Morphine may be

associated with toxicity in patients with renal impairment.
Side effects such as nausea, pruritus, dizziness and constipation
have to be controlled in order to use these drugs to their full potential.
Opioid-induced bowel syndrome and constipation caused by
activation of μ-receptors in the gut can have such distressing effects
that some patients prefer to forego adequate pain control.
Premedication with laxatives for prevention of opioid-induced
constipation is effective. Methylnaltrexone is a μ-opioid receptor
antagonist that, unlike naltrexone or naloxone, does not pass the
blood-brain barrier, and therefore does not impair the centrally
mediated analgesic effect of opioids. It is licensed for the treatment of
opioid-induced constipation in palliative care in more than 50
countries.
References
1. Vella-Brincat J, Macleod AD. Adverse effects of opioids on the central nervous
systems of palliative care patients. J Pain Palliat Care Pharmacother. 2007;21(1):15-
25.
2. Stone P, Minton O. European Palliative Care Research collaborative pain
guidelines. Central side-effects management: what is the evidence to support best
practice in the management of sedation, cognitive impairment and myoclonus? Palliat
Med. 2011;25(5):431-41.
3. Ersek M, Cherrier MM, Overman SS, Irving GA. The cognitive effects of
opioids. Pain Manag Nurs. 2004;5(2):75-93.
4. King S, Forbes K, Hanks GW, et al. A systematic review of the use of opioid
medication for those with moderate to severe cancer pain and renal impairment: a
European Prim Care Companion CNS Disord. 2012;14(3). pii: PCC.11m01326.
5. Ishihara M, Ikesue H, Matsunaga H, et al.; Japanese Study Group for the Relief
of Opioid-induced Gastrointestinal Dysfunction. A multi-institutional study analyzing
effect of prophylactic medication for prevention of opioid-induced gastrointestinal
dysfunction. Clin J Pain. 2012;28(5):373-81.
6. Wirz S, Nadstawek J, Elsen C, et al. Laxative management in ambulatory
cancer patients on opioid therapy: a prospective, open-label investigation of
polyethylene glycol, sodium picosulphate and lactulose. Eur J Cancer Care (Engl).
2012;21(1):131-40.
7. Okamoto Y, Tsuneto S, Tsugane M, et al. A retrospective chart review of
opioid-induced nausea and somnolence on commencement for cancer pain treatment.
J Opioid Manag. 2010;6(6):431-4.
8. Ahmedzai SH, Boland J. Constipation in people prescribed opioids. Clin Evid
(Online). 2010 Apr 6;2010. pii: 2407.
9. Bader S, Dürk T, Becker G. Methylnaltrexone for the treatment of opioid-
induced constipation. Expert Rev Gastroenterol Hepatol. 2013;7(1):13-26.
10. Gatti A, Sabato AF. Management of opioid-induced constipation in cancer
patients: focus on methylnaltrexone. Clin Drug Investig. 2012;32(5):293-301.
11. Clark K, Byfieldt N, Dawe M, Currow DC. Treating constipation in palliative
care: the impact of other factors aside from opioids. Am J Hosp Palliat Care. 2012;
29(2):122-5.
869
OPIOID EFFECTIVENESS FOR PAIN

CONTROL
This analysis, carried out in the context of a wider observational
prospective study, tried to explore whether 4 WHO /step-III opioids
(morphine, oxycodone, fentanyl, and buprenorphine) had different
effectiveness when using several different outcomes and endpoints. In
a cross-sectional and longitudinal study carried out at oncologic,
palliative, and pain centers in Italy, 258 cancer patients were
monitored over a 3-week follow-up program. Mean values of PID led
to differences among opioids ranging from 10-30%. Full-responders
(PID ≥ 30%) were more frequent in buprenorphine-fentanyl-
oxycodone groups than in morphine; nonresponders (PID ≤ 0%) were
variable. The percentage of switches resulted 3 times more frequent
when using morphine than buprenorphine (24.4% vs. 8.6%). An
increase of dose ≥ 5% a day was observed in 33.3% of fentanyl
patients vs. 15% of buprenorphine. As a whole, opioids show some
different behaviors based on the considered endpoints. The small
sample size and the nature itself of the study do not allow a definitive
evaluation of the effectiveness of the drugs, and underline a degree of
variability among opioids and address toward a correct planning of a
comparative RCT. For this reason, a confirmative effectiveness of
RCT is required (1).
The objective of this systematic review was to look at the
effectiveness of opioids for cancer pain. In a systematic review of
randomized trials of opioids for cancer pain, a comprehensive review
of the current literature for RCTs of opioids for cancer pain was done.
The literature search was done using PubMed, EMBASE, Cochrane
library, clinical trials, national clearinghouse, Web of Science,
previous narrative systematic reviews, and cross references. The
studies were assessed using the modified Cochrane and Jadad criteria.
Analysis of evidence was done utilizing the modified quality of
evidence developed by US Preventive Services Task Force. Pain relief
was the primary outcome measure. Secondary outcome measures were
QOL and side effects including tolerance and addiction. The level of
evidence for pain relief based on these criteria was fair for TDF and
poor for morphine, tramadol, oxycodone, methadone, and codeine. In
conclusion, this systematic review of RCTs of opioids for cancer pain
showed fair evidence for the efficacy of TDF and poor evidence for
morphine, tramadol, oxycodone, methadone, and codeine (2).
The 2008 World Cancer Declaration included a target to make
effective pain control more accessible. Several key documents
870
highlight the importance of effective pain control, including

‗Improving supportive and palliative care for adults with cancer‘
(NICE cancer service guidance 2004), ‗Control of pain in adults with
cancer‘ (Scottish Intercollegiate Guidelines Network guideline 106),
‗A strategic direction for palliative care services in Wales‘ (Welsh
Assembly Government 2005) and ‗End of life care strategy‘
(Department of Health 2008). Strong opioids, especially morphine, are
the principal treatments for pain related to advanced and progressive
disease, and their use has increased significantly in the primary care
setting. However, the pharmacokinetics of the various opioids are very
different and there are marked differences in bioavailability,
metabolism and response among patients. A suitable opioid must be
selected for each patient and, because drug doses cannot be estimated
or calculated in advance, the dose must be individually titrated.
Effective and safe titration of opioids has a major impact on patient
comfort. The WHO has produced a pain ladder for the relief of cancer
pain; strong opioids are represented on the third level of the 3-step
ladder. The guideline will address first-line treatment with strong
opioids for patients who have been assessed as requiring pain relief at
the third level of the WHO pain ladder. It will not cover second-line
treatment with strong opioids where a change in strong opioid
treatment is required because of inadequate pain control or significant
toxicity. A number of strong opioids are licensed in the UK. However,
for pain relief in palliative care a relatively small number are
commonly used. This guideline has therefore looked at the following
drugs: buprenorphine, diamorphine, fentanyl, morphine and
oxycodone. Misinterpretations and misunderstanding have surrounded
the use of strong opioids for decades, and these are only slowly being
resolved. Until recently, prescribing advice has been varied and
sometimes conflicting. These factors, along with the wide range of
formulations and preparations, have resulted in errors causing
underdosing and avoidable pain, or overdosing and distressing AEs.
Despite repeated warnings from regulatory agencies, these problems
have led on occasion to patient deaths, and resulted in doctors facing
the General Medical Council or court proceedings. Additional
guidance, including advice on reducing dosing errors with opioid
medicines, patient safety incidents arising from medication errors
involving opioids and safer use of injectable medicines is available
from the National Patient Safety Agency (3).
The purpose of this randomized study was to prospectively
compare the efficacy and tolerability of strong opioids as first-line
agents with the recommendations of the WHO in terminal cancer
871
patients. One hundred patients with mild-moderate pain were

randomized to treatment according to WHO guidelines or to treatment
with strong opioids. Evaluated outcomes included pain intensity, need
for change in therapy, QOL, Karnofsky Performance Status, general
condition of the patient, and AEs. No differences between-treatment
were observed for changes in QOL or performance status, but patients
started on strong opioids had significantly better pain relief than
patients treated according to WHO guidelines (p=0.041). Additionally,
patients started on strong opioids required significantly fewer changes
in therapy, had greater reduction in pain when a change was initiated,
and reported greater satisfaction with treatment than the comparator
group (p=0.041). Strong opioids were safe and well-tolerated, with no
development of tolerance or serious AEs. These data suggest the
utility of strong opioids for first-line treatment of pain in patients with
terminal cancer (4).
The prevalence of cancer-related pain and residual pain in cancer
survivors is high. Opioids serve as the gold standard for treating
moderate to severe cancer pain. The evaluation of the effectiveness of
opioids in chronic non-cancer pain has shown a lack of effectiveness,
or rather weak evidence for some of the drugs. By contrast, in cancer
pain, opioids are expected to be very effective. Due to the nature of
the disease, there is evidence of a paucity of randomized trials
investigating opioid effectiveness in cancer pain on a long-term basis.
The comprehensive literature search was conducted for the period
1996 through June 2010. Databases for the search included PubMed,
EMBASE, Cochrane Reviews, and clinicaltrails.gov, along with
reviews and cross references. Methodological quality assessment of
the observational studies managing chronic cancer pain with opioids
was conducted utilizing the Agency for Healthcare Research and
Quality criteria for observational studies. Analysis of evidence
included 5 levels of evidence developed by the US Preventive
Services Task Force ranging from Level I to III with 3 subcategories
in Level II. Grading recommendations were based on Guyatt et all's
recommendations with 6 levels: 3 in the strong category and 3 in the
weak category. This evaluation is of 18 manuscripts considered for
inclusion; 7 manuscripts met the inclusion criteria based on the
Agency for Healthcare Research and Quality quality assessment.
Level of evidence for opioid therapy in cancer pain was Level II-3,
and recommendations were 1C/strong recommendation based on
observational studies, which could change based on future evidence.
This systematic review of observational studies indicates Level II-3
evidence for effectiveness of opioids in cancer pain therapy, with
872
1C/strong recommendation based on observational studies, which

could change based on future evidence (5).
Assessment: strong opioids, especially morphine, are the principal

treatments for pain related to advanced and progressive disease, and
their use has increased significantly in the primary care setting.
However, the pharmacokinetics of the various opioids are very
different and there are marked differences in bioavailability,
metabolism and response among patients. A suitable opioid must be
selected for each patient and, because drug doses cannot be estimated
or calculated in advance, the dose must be individually titrated.
Effective and safe titration of opioids has a major impact on patient
comfort.
Misinterpretations and misunderstanding have surrounded the use
of strong opioids for decades. Until recently, prescribing advice has
been varied and sometimes conflicting. These factors, along with the
wide range of formulations and preparations, have resulted in errors
causing underdosing and avoidable pain, or overdosing and distressing
AEs.
One systematic review of RCTs of opioids for cancer pain showed
fair evidence for the efficacy of TDF and poor evidence for morphine,
tramadol, oxycodone, methadone, and codeine.
Another systematic review of observational studies indicates Level
II-3 evidence for effectiveness of opioids in cancer pain therapy, with
1C/strong recommendation based on observational studies.
Patients started on strong opioids had significantly better pain
relief than patients treated according to WHO guidelines. Strong
opioids are safe and well-tolerated, with no development of tolerance
or serious AEs. These data suggest the utility of strong opioids for
first-line treatment of pain in patients with terminal cancer.
References
1. Corli O, Montanari M, Deandrea S, et al. An exploratory analysis on the
effectiveness of four strong opioids in patients with cancer pain. Pain Med. 2012;
13(7):897-907.
2. Koyyalagunta D, Bruera E, Solanki DR, et al. A systematic review of
randomized trials on the effectiveness of opioids for cancer pain. Pain Physician.
2012;15(3 Suppl):ES39-58.
3. Editors National Collaborating Centre for Cancer (UK). Opioids in Palliative
Care: Safe and Effective Prescribing of Strong Opioids for Pain in Palliative Care of
Adults. National Collaborating Centre for Cancer (UK). 2012 May.
4. Marinangeli F, Ciccozzi A, Leonardis M, et al. Use of strong opioids in
advanced cancer pain: a randomized trial. J Pain Symptom Manage. 2004;27(5):409-
16. Comment in: Use of strong opioids in advanced cancer pain. [J Pain Symptom
Manage. 2005].
873
5. Colson J, Koyyalagunta D, Falco FJ, Manchikanti L. A systematic review of

observational studies on the effectiveness of opioid therapy for cancer pain. Pain
Physician. 2011;14(2):E85-102.
COMBINED PHARMACOTHERAPY
The combination of 2 analgesic agents offers several advantages in
the treatment of chronic pain. Paracetamol (acetaminophen) has
central analgesic activity without a NSAID-like or opioid-like effect.
Oxycodone is a semisynthetic opioid agonist. The oral fixed-dose
combination of oxycodone and paracetamol IR formulation has a
synergistic mechanism of action that is useful for moderate-to-severe
pain and for nonresponders to NSAIDs or paracetamol alone. This
fixed-dose combination offers several advantages: lower individual
drug doses can be used because of their synergistic mechanisms of
action, its opioid-sparing effect and it has a good efficacy and
tolerability profile. Efficacy and safety of this fixed-dose combination
were assessed in a wide range of clinical settings: in patients with
osteoarthritis or chronic musculoskeletal pain, including when
complicated by a neuropathic component; for chronic pain in elderly
patients; cancer-related pain; postoperative pain; and for neuropathic
pain, in the latter case usually given in combination with a NSAID or
other drugs. The large variety of indications for which this fixed-dose
combination is useful can be attributed to the pharmacological
synergy between oxycodone and paracetamol and because lower
individual drug dosages can be used, this should be a first-line agent
for the treatment of chronic moderate-to-severe pain (1).
Many fixed-combination opioid/acetaminophen medications
contain 500 mg of acetaminophen per tablet, so patients taking 2
tablets every 4 hours are actually ingesting 6 grams of acetaminophen
daily (2).
This was a double-blind placebo-controlled randomized crossover
study. Thirty-four ambulatory cancer patients experiencing cancer-
related pain for which oral morphine was to be started at the dose of
10 mg orally every 4 hours were randomized to take either dipyrone
500 mg orally every 6 hours or placebo. After 48 hours, patients
would be switched from dipyrone to placebo and vice versa. Pain was
the primary outcome and was measured using a VAS before starting
medications, at 48 and 96 hours. Sixteen patients were randomized to
start with placebo (group 1) and 18 with dipyrone (group 2). Pain
874
scores for groups 1 and 2 were at baseline: 7.31 +/- 0.29 vs. 6.88 +/-
0.28 (p = 0.3), at 48 hours: 7.06 +/- 0.32 vs. 5.5 +/- 0.31 (p=0.001),
and at 96 hours: 3.18 +/- 0.39 vs. 1.94 +/- 0.37 (p=0.03). Both groups
had significant improvements in pain scores after introducing
dipyrone (p<0.001, for both). Main toxicities were nausea, vomiting,
epigastric pain, and myalgias. Twenty-eight patients chose dipyrone, 4
placebo, and 2 were indifferent. In conclusion, dipyrone adds
significantly to the analgesic effect of morphine and, when given at
the time of starting morphine, results in better pain scores even after
dipyrone is discontinued (3).
The main aim of this study was to perform a systematic literature
review of the evidence of the efficacy and toxicity of NSAIDs or
paracetamol added to WHO Step III opioid treatment for cancer pain.
A systematic literature review of MedLine, EMBASE and Cochrane
Central register of controlled trials database was carried out using both
text words and MeSH/EMTREE terms. Seven eligible papers were
retrieved from the new search and 5 from the Cochrane review. Five
of 7 studies showed an additive effect of NSAIDs when combined
with opioids either by improving analgesia (3 studies) or by reducing
the opioid dose (2 studies). Paracetamol was only marginally effective
in 1 of 5 trials. The study designs were not adequate to assess
differences in side effects between the opioids alone and opioids in
combination with NSAIDs or paracetamol. The evidence from the
available clinical trials is of limited amount and quality, but it weakly
supports the proposal that the addition of NSAIDs to WHO Step III
opioids can improve analgesia or reduce opioid dose requirement.
There is insufficient evidence to support the use of paracetamol in
combination with Step III opioids. Data on the toxicity of NSAIDs in
this indication are insufficient owing to the small number of patients
and the short duration of treatment reported in the studies (4).
A prospective double-blind randomized trial was conducted on 184
cancer patients with moderate to severe chronic pain to evaluate the
analgesic efficacy and tolerability of diclofenac alone (50 mg four
times a day) or in combination with a weak opioid (codeine 40 mg
four times a day), or with an anti-depressant (imipramine, 10 or 25 mg
thrice a day). All demographic and clinical characteristics including
cancer type, presence of bone metastases, baseline pain severity,
neuropathic and nociceptive pain, and depressive state, were well
balanced between the 3 treatment groups. The main analysis of the
study was on the VAS scores at visit 2 (day 4). The mean VAS values
for both associations imipramine plus diclofenac and codeine plus
diclofenac were similar to the association placebo plus diclofenac.
875
Patients on imipramine plus diclofenac and on placebo plus diclofenac

were withdrawn mainly for inadequate efficacy, while patients on
codeine plus diclofenac discontinued equally for inadequate efficacy
or AEs. In conclusion, in a short-term evaluation the addition of a
TCA or a weak opioid to diclofenac did not provide further analgesia
with respect to diclofenac administration alone (5).
Opioids are often used in conjunction with NSAIDs in the
treatment of moderate to severe pain. In this study, interactions
between these 2 classes of drugs were examined. NSAIDs are inactive
in the radiant heat tail-flick test, an assay of moderate to severe pain in
which opioids are effective. In this assay, ibuprofen potentiated the
analgesic actions of hydrocodone and oxycodone, shifting their
ED(50) values by 2.5-fold and 4.6-fold despite its inactivity when
given alone. These opioid/NSAID interactions were dependent upon
both the opioid and the NSAID. Neither aspirin nor ketorolac
influenced hydrocodone actions in this model and ibuprofen did not
potentiate fentanyl or morphine analgesia. Together, these studies
demonstrate potent interactions between selected combinations of
opioids and NSAIDS and may help explain the clinical utility of
combinations. However, the findings also illustrate differences
between the drugs within each class (6).
The main purpose of this study was to assess the safety and
efficacy of NSAIDs, alone or combined with opioids, for the treatment
of cancer pain. Forty-two trials involving 3,084 patients met inclusion
criteria: eight compared NSAIDs with placebo; 13 compared one
NSAID with another; 23 compared NSAIDs with opioid, NSAID or
opioid vs. NSAID plus opioid combinations, or NSAID plus opioid
combinations vs. NSAID plus opioid combinations; and 9 studies
assessed the effect of increasing NSAID dose. Sixteen studies lasted 1
week or longer and 11 evaluated a single dose. Seven of 8 trials
demonstrated superior efficacy of single doses of NSAID compared
with placebo. Only 4 of 13 studies reported increased efficacy of 1
NSAID compared with another; 4 other studies found that one NSAID
had fewer side effects than one or more others did. Thirteen of 14
studies found no difference, or minimal clinical difference, when
comparing an NSAID plus opioid combination vs. either drug alone.
Comparisons between various NSAID plus opioid combinations were
inconclusive. Four studies demonstrated increased efficacy with
increased NSAID dose, without dose-dependent increases in side
effects. In conclusion, heterogeneity of study methods and outcomes
precluded meta-analyses. Short duration of studies undermines
generalization of findings on efficacy and safety. On the basis of
876
limited data, NSAIDs appear to be more effective than placebo for

cancer pain; clear evidence to support superior safety or efficacy of
one NSAID compared with another is lacking; and trials of
combinations of an NSAID with an opioid have disclosed either
insignificant difference, or at most a slight but statistically significant
advantage, compared with either single entity (7).
Through the last 2 decades, the routine of always combining a
strong opioid with paracetamol has been widely spread in Sweden.
Thirty-four incurable cancer patients with well controlled pain, treated
by specialized palliative home care teams, with ongoing medication
with the strong opioid paracetamol combination was recruited to this
prospective clinical study. The effect of completely stopping
paracetamol medication was evaluated 4 days later at follow-up. At
follow-up nine patients (26%) felt more pain compared to when they
entered the study, 2 patients (6%) felt less pain and 23 (68%) felt no
difference. When asked about their preference about future
paracetamol treatment 18 patients (53%) wanted to stop taking it, 6
patients (18%) wanted to continue with regular paracetamol
medication as before, and 10 patients (29%) wanted to take
paracetamol as needed. No clinical predictors of paracetamol response
could be identified. The results of this study indicate that a critical
evaluation, in every patient, of the subjective additive analgesic effect
of paracetamol in concurrent strong opioid therapy is advisable while
stopping paracetamol medication not necessarily implies increased
pain. Rather in some patients, the cessation of paracetamol medication
is experienced as a relief as pain control is maintained with a lesser
tablet burden (8).
The main aim of this study was to determine whether adding
regular acetaminophen (paracetamol) could improve pain and well-
being in people with advanced cancer and pain despite strong opioids.
Participants took acetaminophen for 48 hours and placebo for 48
hours. The order (acetaminophen or placebo first) was randomly
allocated. Pain was the primary outcome. Preferences, number of
opioid breakthrough doses, overall well-being, nausea and vomiting,
drowsiness, constipation, and cold sweats were secondary outcomes.
Patients rated themselves daily with VAS and a VNRS for pain, all
scaled from 0 to 10. Thirty patients completed the trial. The oral
opioid was morphine in 23 patients and hydromorphone in 7 patients.
The median daily opioid dose in oral morphine equivalents was 200
mg (range, 20 to 2,100 mg). NSAIDs, corticosteroids, or both were
used by 16 patients. Pain and overall well-being were better for
patients receiving acetaminophen than for those receiving placebo.
877
The MD was 0.4 (95% CI 0.1 - 0.8, p=0.03) in VNRS for pain, 0.6
(95% CI -0.1 - 1.3, p=0.09) in VAS for pain, and 0.7 (95% CI, 0.0 -
1.4, p=0.05) in VAS for overall well-being. More patients preferred
the period they took acetaminophen (n=14) than the period they took
placebo (n=8), but many had no preference (n=8). There were no
differences in the other outcomes. In conclusion, acetaminophen
improved pain and well-being without major side effects in patients
with cancer and persistent pain despite a strong opioid regimen. Its
addition is worth considering in all such patients (9).
The use of combinations of opioids is a common clinical practice;
however, this is not advocated by the WHO analgesic ladder. As
opioid combination therapy becomes used increasingly, a review of
the evidence on this practice was conducted. The main aim of this
systematic review was to carry out a systematic review of the use of
strong opioids in combination in cancer pain. The following databases
were searched electronically: Embase (1980-2010 week 2), Medline
(1950-2010 week 1) and the Cochrane Database of Systematic
Reviews (fourth quarter 2009). Only strong opioids as defined by the
WHO ladder and full opioid agonists were examined. Only studies
conducted in human, adult patients with chronic cancer pain were
eligible. Studies must have contained data on efficacy and/or side
effects in the key point. Appraisal was conducted using predetermined
criteria set by the EAPC guideline development group. All potential
papers were reviewed independently by both authors. In total, 596
articles were retrieved resulting in only 2 eligible studies, which were
rated as grade C and grade D evidence. These examined morphine in
combination with oxycodone or fentanyl/methadone. In conclusion,
only a weak recommendation can be used to support combination
opioid therapy. This recommendation is also based on the caveat that
the desirable effects of combination opioid therapy is outweighed by
any disadvantages that this would confer. Prospective randomized
trials are needed to clarify the benefits and safety of combination
opioid therapy (10).
The purpose of this study was to compare the analgesic efficacy
and tolerability of opioids hydrocodone and tramadol in the relief of
cancer pain. One hundred and eighteen patients with chronic cancer
pain participated in a double blind, RCT. Sixty-two patients received
hydrocodone and 56 patients received tramadol.
Hydrocodone/acetaminophen was effective in relieving pain in 56.5%
of the patients at the starting dose of 25 mg/2500 mg/d. An additional
14.5% of the patients responded to a double dose, and the remaining
29% of patients did not experience any pain relief from hydrocodone
878
administration. One dose of tramadol at 200 mg/d produced pain relief

in 62% of the patients and alleviated pain in another 11% of patients
at a dose of 400 mg/d, and remaining 27% of patients did not
experience pain relief from tramadol. Insignificant statistical
difference in the analgesic efficacy of tramadol clorhydrate and
hydrocodone/acetaminophen was found. The groups differed
significantly in the incidence of side effects like nausea (p=0.03, RR
1.69, 95% CI 1.03 - 2.77), vomiting (p=0.02, RR 2.21, 95% CI 1.14 -
4.32), dizziness (p=0.03, RR 2.12, 95% CI 1.17 - 3.86), loss of
appetite (p=0.02, RR 3.27, 95% CI 1.12 - 9.55), and weakness
(p=0.019, RR 7.75, 95% CI 0.98 - 61.05). In conclusion, there was no
superior analgesic efficacy with the administration of
hydrocodone/acetaminophen when compared to patients receiving
tramadol in the relief of cancer pain. Tramadol produced more mild
side effects than hydrocodone (11).
Assessment: there are different combinations of analgesic drugs

that can be used for patients with cancer pain. Some combinations are
effective, but some not. Acetaminophen improves pain and well-being
without major side effects in patients with cancer and persistent pain
despite a strong opioid regimen. Some studies demonstrate potent
interactions between selected combinations of opioids and NSAIDS
and may help explain the clinical utility of combinations. Trials of
combinations of an NSAID with an opioid have disclosed either
insignificant difference, or at most a slight but statistically significant
advantage, compared with either single entity.
There is insufficient evidence to support the use of paracetamol in
combination with Step III opioids. While the addition of a TCA or a
weak opioid to diclofenac did not provide further analgesia with
respect to diclofenac administration alone.
There is no superior analgesic efficacy with the administration of
hydrocodone/acetaminophen when compared to patients receiving
tramadol in the relief of cancer pain. Tramadol produces more mild
side effects than hydrocodone
Only a weak recommendation can be used to support combination
of opioid therapy.
References
1. Gatti A, Sabato E, Di Paolo AR, et al. Oxycodone/paracetamol: a low-dose
synergic combination useful in different types of pain. Clin Drug Investig. 2010;30
Suppl 2:3-14.
2. Beckwith SK, Cole BE. Hospice, cancer pain management and symptom
control. In: Weiner RS, editor. Pain management: a practical guide for clinicians.
Boca Raton (FL): St. Lucie Press; 1998:705–20.
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3. Duarte Souza JF, Lajolo PP, Pinczowski H, del Giglio A. Adjunct dipyrone in
association with oral morphine for cancer-related pain: the sooner the better. Support
Care Cancer. 2007;15(11):1319-23.
4. Nabal M, Librada S, Redondo MJ, et al. The role of paracetamol and
nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the
control of pain in advanced cancer. A systematic review of the literature. Palliat Med.
2012;26(4):305-12.
5. Minotti V, De Angelis V, Righetti E, et al. Double-blind evaluation of short-
term analgesic efficacy of orally administered diclofenac, diclofenac plus codeine,
and diclofenac plus imipramine in chronic cancer pain. Pain. 1998;74(2-3):133-7.
6. Zelcer S, Kolesnikov Y, Kovalyshyn I, et al. Selective potentiation of opioid
analgesia by nonsteroidal anti-inflammatory drugs. Brain Res. 2005;1040(1-2):151-6.
7. McNicol E, Strassels S, Goudas L, et al. Nonsteroidal anti-inflammatory drugs,
alone or combined with opioids, for cancer pain: a systematic review. J Clin Oncol.
2004;22(10):1975-92. Comment in: Looking for the role of NSAIDs in cancer pain. [J
Clin Oncol. 2005].
8. Axelsson B, Stellborn P, Ström G. Analgesic effect of paracetamol on cancer
related pain in concurrent strong opioid therapy. A prospective clinical study. Acta
Oncol. 2008;47(5):891-5.
9. Stockler M, Vardy J, Pillai A, Warr D. Acetaminophen (paracetamol) improves
pain and well-being in people with advanced cancer already receiving a strong opioid
regimen: a randomized, double-blind, placebo-controlled cross-over trial. J Clin
Oncol. 2004;22(16):3389-94.
10. Fallon MT, Laird BJ. A systematic review of combination step III opioid
therapy in cancer pain: an EPCRC opioid guideline project. Palliat Med.
2011;25(5):597-603.
11. Rodriguez RF, Castillo JM, Castillo MP, et al. Hydrocodone/acetaminophen
and tramadol chlorhydrate combination tablets for the management of chronic cancer
pain: a double-blind comparative trial. Clin J Pain. 2008;24(1):1-4. Erratum in: Clin J
Pain. 2008;24(7):649.
CONSENSUS STATEMENT
Summary of Consensus statement of an International Expert Panel
with focus on the 6 clinically most often used WHO Step III opioids
(buprenorphine, fentanyl, hydromorphone, methadone, morphine, and
oxycodone) 1. The use of opioids in cancer pain: The criteria for
selecting analgesics for pain treatment in the elderly include, but are
not limited to, overall efficacy, overall side-effect profile, onset of
action, drug interactions, abuse potential, and practical issues, such as
cost and availability of the drug, as well as the severity and type of
pain (nociceptive, acute/chronic, etc.). At any given time, the order of
choice in the decision-making process can change. This consensus is
based on evidence-based literature (extended data are not included and
chronic, extended-release opioids are not covered). The transdermal
880
formulation of buprenorphine is available in most European countries,

particularly those with high opioid usage, with the exception of
France; however, the availability of the sublingual formulation of
buprenorphine in Europe is limited, as it is marketed in only a few
countries, including Germany and Belgium. The opioid patch is
experimental at present in US and the sublingual formulation has
dispensing restrictions, therefore, its use is limited. It is evident that
the population pyramid is upturned. Globally, there is going to be an
older population that needs to be cared for in the future. This older
population has expectations in life, in that a retiree is no longer an
individual who decreases their lifestyle activities. The "baby-
boomers" in their 60s and 70s are "baby zoomers"; they want to have
a functional active lifestyle. They are willing to make trade-offs
regarding treatment choices and understand that they may experience
pain, providing that can have increased QOL and functionality.
Therefore, comorbidities, including cancer and noncancerous pain,
osteoarthritis, RA, and postherpetic neuralgia, and patient functional
status need to be taken carefully into account when addressing pain in
the elderly. WHO step III opioids are the mainstay of pain treatment
for cancer patients with morphine the most commonly used for
decades. All opioids are considered effective in cancer pain
management (although parts of cancer pain are not or only partially
opioid sensitive), but no well-designed specific studies in the elderly
cancer patient are available. Of the 2 opioids that are available in
transdermal formulation - fentanyl and buprenorphine-fentanyl is the
most investigated, but based on the published data both seem to be
effective, with low toxicity and good tolerability profiles, especially at
low doses. 2. The use of opioids in non-cancer-related pain: Evidence
is growing that opioids are efficacious in non-cancer pain (treatment
data mostly level Ib or IIb), but need individual dose titration and
consideration of the respective tolerability profiles. No specific studies
in the elderly have been performed, but it can be concluded that
opioids have shown efficacy in non-cancer pain, which is often due to
diseases typical for an elderly population. When it is not clear which
drugs and which regimes are superior in terms of maintaining
analgesic efficacy, the appropriate drug should be chosen based on
safety and tolerability considerations. Evidence-based medicine,
which has been incorporated into best clinical practice guidelines,
should serve as a foundation for the decision-making processes in
patient care; however, in practice, the art of medicine is realized when
we individualize care to the patient. This strikes a balance between the
evidence-based medicine and anecdotal experience. Factual
881
recommendations and expert opinion both have a value when applying

guidelines in clinical practice. 3. The use of opioids in neuropathic
pain: The role of opioids in neuropathic pain has been under debate in
the past but is nowadays more and more accepted; however, higher
opioid doses are often needed for neuropathic pain than for
nociceptive pain. Most of the treatment data are level II or III, and
suggest that incorporation of opioids earlier on might be beneficial.
Buprenorphine shows a distinct benefit in improving neuropathic pain
symptoms, which is considered a result of its specific pharmacological
profile. 4. The use of opioids in elderly patients with impaired hepatic
and renal function: Functional impairment of excretory organs is
common in the elderly, especially with respect to renal function. For
all opioids except buprenorphine, half-life of the active drug and
metabolites is increased in the elderly and in patients with renal
dysfunction. It is, therefore, recommended that - except for
buprenorphine - doses be reduced, a longer time interval be used
between doses, and creatinine clearance be monitored. Thus,
buprenorphine appears to be the top-line choice for opioid treatment in
the elderly. 5. Opioids and respiratory depression: Respiratory
depression is a significant threat for opioid-treated patients with
underlying pulmonary condition or receiving concomitant CNS drugs
associated with hypoventilation. Not all opioids show equal effects on
respiratory depression: buprenorphine is the only opioid
demonstrating a ceiling for respiratory depression when used without
other CNS depressants. The different features of opioids regarding
respiratory effects should be considered when treating patients at risk
for respiratory problems, therefore careful dosing must be maintained.
6. Opioids and immunosuppression: Age is related to a gradual
decline in the immune system: immunosenescence, which is
associated with increased morbidity and mortality from infectious
diseases, autoimmune diseases, and cancer, and decreased efficacy of
immunotherapy, such as vaccination. The clinical relevance of the
immunosuppressant effects of opioids in the elderly is not fully
understood, and pain itself may also cause immunosuppression.
Providing adequate analgesia can be achieved without significant
AEs, opioids with minimal immunosuppressive characteristics should
be used in the elderly. The immunosuppressive effects of most opioids
are poorly described and this is one of the problems in assessing true
effect of the opioid spectrum, but there is some indication that higher
doses of opioids correlate with increased immunosuppressant effects.
Taking into consideration all the very limited available evidence from
preclinical and clinical work, buprenorphine can be recommended,
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while morphine and fentanyl cannot. 7. Safety and tolerability profile

of opioids: The AE profile varies greatly between opioids. As the
consequences of AEs in the elderly can be serious, agents should be
used that have a good tolerability profile (especially regarding CNS
and G-I effects) and are as safe as possible in overdose especially
regarding effects on respiration. Slow dose titration helps to reduce
the incidence of typical initial AEs such as nausea and vomiting.
Sustained release preparations, including transdermal formulations,
increase patient compliance (1).
Reference
1. Pergolizzi J, Böger RH, Budd K, et al. Opioids and the management of chronic
severe pain in the elderly: consensus statement of an International Expert Panel with
focus on the six clinically most often used World Health Organization Step III opioids
(buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain
Pract. 2008;8(4):287-313.
CANCER PAIN IN OPIOID ADDICTED

PATIENTS
Opioid-addicted individuals represent a challenging and
heterogeneous population to treat. Addiction is linked to
psychopathology and antisocial behaviors (e.g., lying) which often
complicate evaluation. Chronic exposure to opioids may lead to
physiologic dependence and its correlates, tolerance and hyperalgesia.
Given the variability and subjectivity of the cancer pain experience,
there are no objective measures, which capture the adequacy of pain
control. Thus, when faced with complaints of uncontrolled pain,
clinicians must consider a differential diagnosis of tolerance, disease
progression, addiction, pseudoaddiction, chemical coping, or even
criminal behavior (1).
The problem of therapeutic opioid misuse largely affects patients
who need opioids to treat chronic pain conditions. Opioid misuse is
rarely an overt clinical problem during end of life or acute pain
treatment. Misuse attaches a stigma to opioid use, and makes many
patients and prescribers reluctant to use these uniquely effective drugs,
even when misuse is unlikely. Cancer was once an explosive, typically
terminal disease and became the prototype for end-of-life opioid pain
treatment. However, cancer is no longer such an explosive disease,
and many cancer sufferers can now expect to have a prolonged, even
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normal lifespan. They may need pain treatment, but this treatment
should not be modeled on palliative care paradigms (2).
Opioids are extremely effective in managing cancer pain, and are
utilized for longer periods in cancer patients as the treatment for
malignancies has become more successful. The goals in cancer pain
treatment includes maintaining function in patients with cancer pain
(especially in earlier stage disease), and palliation in advanced
disease. The perception of the lay public and inexperienced clinicians
that addiction is inevitable often leads to an inappropriate fear to
utilize opioids to appropriately manage pain; resulting in persistent
under-treatment of cancer pain internationally. There is much
confusion about the phenomenon of physical dependence and how this
can be differentiated from the maladaptive behaviors that constitute a
diagnosis of substance abuse. The burden of cancer and associated
cancer pain is projected to continue to rise, and is often at an advanced
stage at diagnosis in less developed countries. To be able to provide
quality care for this patient population availability of opioids and
skilled clinicians in pain management is paramount. In the majority of
cases, the main concern is to abate concerns about risks of opioid
addiction and to allow adequate pain relief. To understand the
infrequent phenomenon of substance abuse in the setting of cancer
pain management clear definitions are needed. It is important to
separate the issues of substance abuse at the patient level and
diversion of prescribed opioids. There are principles of managing
cancer pain in the rare clinical scenario when the risk of substance
abuse is high, which can still allow safe management of cancer pain
with opioids (3).
In the oncology community, opioids have become the cornerstone
of cancer pain management. This has led to a rapid increase in opioid
prescribing in an effort to address the growing public health problem
of chronic pain. A new paradigm in noncancer pain management has
emerged, that of risk assessment and stratification in opioid therapy.
Techniques foreign to cancer pain management have become
commonplace in the noncancer pain setting, such as the use of
monitoring compliance via urine drug screens. Amidst these strides in
opioid use for pain management, cancer has been changing. The
survival rate has increased, and a group of these patients with chronic
pain was treated with opioid therapy. With opioid exposure being
longer and against the backdrop of prescription drug abuse, the
question is how much of the adaptation of the risk management
paradigm in chronic pain management is to be imported to cancer pain
management? (4).
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Two patients with an active or recent history of opioid abuse had

painful complications of cancer that required narcotic analgesic
therapy. Initial pain management was difficult due to issues of
distinguishing tolerance from disease progression, concurrent
methadone maintenance, and drug-seeking behavioral patterns. Pain
control was achieved with psychological support, medication
contracts, and attention to proper dosing of opioids (5).
Methadone is commonly used in the treatment of heroin addiction.
Patients with a history of opioid misuse or on methadone maintenance
therapy with cancer often have difficult to manage pain. Twelve
patients who were on methadone maintenance therapy were referred
to the palliative care service with cancer pain. All had difficult to
control pain, and a third required 5 or more analgesic agents. Two
patients had documented ''drug-seeking'' behavior. Methadone was
used subcutaneously as an analgesic agent in 1 patient. Patients on
methadone maintenance therapy have difficult to manage pain, while
the optimal management of their pain is difficult (6).
Two patients with an active or recent history of opioid abuse had
painful complications of cancer that required narcotic analgesic
therapy. Initial pain management was difficult due to issues of
distinguishing tolerance from disease progression, concurrent
methadone maintenance, and drug-seeking behavioral patterns. Pain
control was achieved with psychological support, medication
contracts, and attention to proper dosing of opioids (7).
Assessment: addiction is linked to psychopathology and antisocial

behaviors (e.g., lying) which often complicate evaluation. Chronic
exposure to opioids may lead to physiologic dependence and its
correlates, tolerance and hyperalgesia.
There are no objective measures, which capture the adequacy of
pain control. Thus, when faced with complaints of uncontrolled pain,
clinicians must consider a differential diagnosis of tolerance, disease
progression, addiction, pseudoaddiction, chemical coping, or even
criminal behavior.
The problem of therapeutic opioid misuse largely affects patients
who need opioids to treat chronic pain conditions. Opioid misuse is
rarely an overt clinical problem during end of life or acute pain
treatment. There is much confusion about the phenomenon of physical
dependence and how this can be differentiated from the maladaptive
behaviors that constitute a diagnosis of substance abuse.
Patients with an active or recent history of opioid abuse may have
painful complications of cancer that require narcotic analgesic
therapy. Pain management is difficult due to issues of distinguishing
885
tolerance from disease progression, concurrent methadone

maintenance, and drug-seeking behavioral patterns. Pain control can
be achieved with psychological support, medication contracts, and
attention to proper dosing of opioids.
References
1. Modesto-Lowe V, Girard L, Chaplin M. Cancer pain in the opioid-addicted
patient: can we treat it right? J Opioid Manag. 2012;8(3):167-75.
2. Ballantyne JC. Opioid misuse in oncology pain patients. Curr Pain Headache
Rep. 2007;11(4):276-82.
3. Meera A. Pain and opioid dependence: Is it a matter of concern. Indian J Palliat
Care. 2011;17(Suppl):S36-8.
4. Starr TD, Rogak LJ, Passik SD. Substance abuse in cancer pain. Curr Pain
Headache Rep. 2010;14(4):268-75.
5. Hoffman M, Provatas A, Lyver A, Kanner R. Pain management in the opioid-
addicted patient with cancer. Cancer. 1991;68(5):1121-2.
6. Rowley D, McLean S, O'Gorman A, et al. Review of cancer pain management
in patients receiving maintenance methadone therapy. Am J Hosp Palliat Care.
2011;28(3):183-7.
7. Hoffman M, Provatas A, Lyver A, Kanner R. Pain management in the opioid-
addicted patient with cancer. Cancer. 1991;68(5):1121-2.
TREATMENT OF NEUROPATHIC PAIN

Neuropathic pain is defined as pain related to abnormal
somatosensory processing in either the peripheral or CNS. This
pathophysiologic label is typically applied when the painful symptom
is associated with an overt injury to neural structures, is part of a
recognized syndrome, or has a dysesthetic quality (usually burning,
shooting, or electrical). Most neural injury does not lead to clinically
important neuropathic pain, but sometimes even a small degree of
tissue injury can precipitate severe pain. In the cancer population,
neuropathic pain is often related to compression, direct neoplastic
invasion of the peripheral nerves or spinal cord, or to a neuropathy
caused by chemotherapy. To manage neuropathic pain in this
population, non-opioid adjuvant drugs that are neuroactive or
neuromodulatory are often needed to complement opioid therapy. The
primary adjuvant analgesics are anticonvulsant and antidepressant
medications, but a wide variety of other drugs are also used. To
optimize analgesic therapy in patients with neuropathic pain, both
opioid and adjuvant analgesics must be used effectively (1).
886
Neuropathic cancer pain, commonly encountered in clinical

practice, may be cancer-related, namely resulting from nervous system
tumor invasion, surgical nerve damage during tumor removal,
radiation-induced nerve damage and chemotherapy-related
neuropathy, or may be of benign origin, unrelated to cancer. A
neuropathic component is evident in about 1/3 of cancer pain cases.
Although from a pathophysiological perspective neuropathic cancer
pain may differ from chronic neuropathic pain, such as non-
cancerous-related pain, clinical practice, while limited publications
have shown that these 2 pain entities may share some treatment
modalities. For example, co-analgesics have been well integrated into
cancer pain-management strategies and are often used as First-Line
options for the treatment of neuropathic cancer pain. These drugs,
including antidepressants and anticonvulsants, are recommended by
evidence-based guidelines, whereas, others such as lidocaine patch
5%, are supported by randomized, controlled, clinical data and are
included in guidelines for restricted conditions treatment. The vast
majority of these drugs have already been proven useful in the
management of benign neuropathic pain syndromes. Treatment
decisions for patients with neuropathic pain can be difficult. The
intrinsic difficulties in performing RCTs in cancer pain have
traditionally justified the acceptance of drugs already known to be
effective in benign neuropathic pain for the management of malignant
neuropathic pain, despite the lack of relevant high quality data.
Interest in neuropathic cancer pain mechanisms and pharmacotherapy
has increased, resulting in significant mechanism-based treatment
advances for the future (2).
This study aimed to compare the effectiveness and safety of
gabapentin combined with an opioid vs. opioid monotherapy for the
management of neuropathic cancer pain. Of 75 cancer patients who
were receiving opioid therapy and reported sufficient pain relief of
nociceptive, but not neuropathic, pain, 63 patients completed the
study. Patients were randomized to one of the following treatment
protocols: 1) gabapentin adjuvant to ongoing opioid treatment titrated
according to pain response while opioid dose was kept constant (group
GO), and 2) continuation of opioid monotherapy according to the
WHO treatment ladder approach (group OO). Changes in pain
intensity, allodynia, and analgesic drug consumption were evaluated at
Day 4 and Day 13. Side effects were also recorded. Both treatments
resulted in a significant reduction of pain intensity at Day 4 and Day
13 compared to baseline. However, mean pain intensity for burning
and shooting pain was significantly higher in the OO group compared
887
to the GO group at both the fourth (p=0.0001) and 13th (p=0.0001)

days of the study. An earlier significant decrease (at Day 4, p=0.002)
was observed for allodynia in the GO group compared to the OO
group. The rate of side effects in the GO group was significantly
lower than that in the OO group (p=0.015). These data suggest that
gabapentin added to an opioid provides better relief of neuropathic
pain in cancer patients than opioid monotherapy; this combination of
gabapentin and an opioid may represent a potential first-line regimen
for the management of pain in these patients (3).
The 818 neuropathic cancer pain patients were enrolled in the
study and pain was managed according to WHO analgesic ladder and
followed up to 6 months. Main adjuvant drugs used were
amitryptaline (29.9%), gabapentin (29.9%) and gabapentine with
dexamethasone in (19.9%) and dexamethasone alone in (20.2%)
patients. Opioids prescribed were mainly tramadol, codeine sulphate
and morphine while 52% of patients received morphine as rescue
analgesic. At the end of 6 months, 53.2% patients had no pain and
41.9% of patients had mild pain as compared to 0% and 10.2%
patients respectively at the first visit; and 4.9% of patients had
moderate pain even after the treatment. In conclusion, neuropathic
cancer pain can be relieved by multimodal treatment following WHO
guidelines as majority of cancer patients suffered multiple types of
pain (4).
The aim of this work was to systematically analyze all the
evidences of literature about the treatment options against neuropathic
pain in oncology, focusing our attention upon the efficacy and the
safety of the different therapeutic options assessed as NNT and NNH.
A critical analysis of literature was finally performed using the
GRADE system. On the basis of this review and the NNT and NNH
ratio, gabapentin, pregabalin and strong opiates seem to be the most
effective and well tolerated options against neuropathic pain in
oncology, while carbamazepine, amitryptiline, tramadol and NSAIDs
do not seem to be valid options in front line approach against
oncologic neuropathic pain, either for a minor efficacy or for an
unfavorable safety profile (5).
Gabapentin was initially developed as an AED but was later
discovered to be an effective treatment of neuropathic pain.
Gabapentin has been successfully used for the treatment of multiple
neuropathic pain syndromes such as DPN and postherpetic neuralgia.
However, limited data exist about its efficacy for other pain
syndromes. The objective of the current review is to describe, from
the literature, the role of gabapentin for the treatment of cancer-related
888
pain syndromes. Studies were identified by searching the PubMed

electronic databases. Additional review articles and article reference
lists were used to identify other studies. Recent studies showed
effectiveness of gabapentin in improving the pain control in patients
with neuropathic cancer pain, already treated with opiates. Moreover,
gabapentin appeared promising in reducing the need for high total
doses of opioids and avoiding unplanned treatment interruptions for
patients with head and neck malignancies treated with RT or
concurrent chemoradiotherapy. The combination of gabapentin and
morphine affected better pain relief at lower doses of each drug when
compared with gabapentin or morphine alone in patients with DPN or
postherpetic neuralgia. The combination of both drugs was associated
with a beneficial effect on pain-related interference with daily activity,
mood, sleep and QOL. In conclusion, given the significant benefits of
gabapentin and the combination of gabapentin with opioids for the
treatment of neuropathic pain, randomized clinical trials are needed to
establish the role of these analgesic regimens for the treatment of
neuropathic cancer pain (6).
Neuropathic pain mechanisms are present in up to 40% of patients
with cancer pain. In these situations, additional or adjuvant analgesic
drugs (such as antidepressants or AED) are often required to optimize
pain control alongside standard opioid therapy. This systematic review
aimed to determine the effectiveness of antidepressants and AED
when added to opioids, compared to opioids alone, for the
management of pain caused directly by cancer. Prospective clinical
studies, published in English that used a before-after design or
randomized or non-randomized group comparisons were identified.
Data were extracted on pain intensity, pain relief and AEs. Eight
studies were eligible (5 RCTs) that recruited 465 patients in total, of
whom 370 (79.5%) completed the study period. A narrative analysis
was performed because clinical and methodological heterogeneity
prevented meta-analysis. Included studies suggested that adjuvants
improve pain control within 4-8 days when added to opioids for
cancer pain; the strongest evidence supports gabapentin. However, a
reduction in pain intensity of greater than 1 point on a 0-10 NRS is
unlikely, but an increase in AEs is likely. For all adjuvants, the effect
size was much less than that seen in patients with non-cancer
neuropathic pain (7).
Using a large US health insurance claims database, all persons
aged ≥ 18 years with ≥ 2 medical encounters with diagnoses of cancer
and ≥ 2 medical encounters with diagnoses of painful neuropathies in
calendar year 2000 were identified; persons with seizure disorders or
889
depression were excluded. The use of AED, TCAs and other pain-
related pharmacotherapy among these selected persons, as proxies by
pharmacy dispenses was examined. Of 956 persons who met all entry
criteria, 17% received AEDs in calendar year 2000 and 14% received
TCAs. Gabapentin was the most widely used AED (92% of all AED
patients); amitriptyline was the most widely used TCA (79% of all
TCA patients). Patients who received AEDs and/or TCAs were similar
in age, gender and the presence of metastases to those who had not
received these medications; they were more likely to have received
other pain-related therapies, however, including short-acting opioids
(73% vs. 53%, p<0.01) and long-acting opioids (23% vs. 8%, p<0.01).
Use of AEDs and TCAs appears to be relatively low among cancer
patients with painful neuropathies (8).
This study aims to evaluate the utility of a new technology,
lidocaine 5% patch, for providing analgesia without other sensory
deficit in cancer patients with focal neuropathic pain related or not
with cancer. During the period February 2011 to July 2011, 83
patients were seen for the first time in the department and lidocaine
5% patch were prescribed to 15 of those patients (18.07%).
Information recorded in relation to the lidocaine 5% patch included
the following: (a) nature of neuropathic pain, (b) medications tested,
(c) drug combinations, (d) lidocaine 5% patch therapy duration, (e)
efficacy, and (f) undesirable effects. Six patients had neuropathic pain
related to their cancer and 8 chronic neuropathic pain unrelated to
their cancer diagnosis, but all referred to the Radiotherapy and
Oncology Department for RT. The analgesic effect of the lidocaine
5% patch was potent in 8 cases and partial in 4 cases. This represents
79.99% efficacy in selected patients. There were no serious AEs
reported in any of the patients. In conclusion, there are patients with
neuropathic pain within a cancer setting who are suitable for treatment
and successfully managed with topical lidocaine 5% patch, alone or in
combination with other drugs (9).
The purpose of this study was to investigate the effect of
duloxetine in cancer patients suffering from neuropathic pain. The
subjects of the study were 15 cancer patients with neuropathic pain
who visited the Kinki University Faculty of Medicine Hospital, Japan,
and met the International Association for the Study of Pain diagnostic
criteria for neuropathic pain. Duloxetine was administered to patients
in whom pregabalin could not be administered. The influence of
duloxetine was investigated retrospectively with the use of a NRS.
Pain was reduced in 7 out of the 15 patients. Sleepiness and the light-
headed feeling were improved in 4 patients, in whom, however, the
890
pain was not reduced. Thus, duloxetine was effective in 11 patients.

The maintenance dose of duloxetine was 20-40 mg/day. Duloxetine
administration may be effective for neuropathic pain in cancer patients
who cannot tolerate pregabalin administration (10).
The case of a 68-year-old male patient with metastatic rectal cancer
is presented. A pelvic recurrence resulted in neuropathic pain,
radiating down his left leg. The pain was resistant to standard
treatments. However, after nearly 3 years of debilitating pain, the
patient experienced dramatic relief just hours after an infusion of the
antiepidermal growth factor receptor antibody cetuximab. The
analgesic effect lasted for 10-12 days and was repeated roughly every
12 days for 3 and half years. To test for placebo effect, the patient
received (unknown to him) 20% of his usual cetuximab dose and
experienced no pain relief. The dramatic analgesic effect was
documented in clinical notes, medication lists and in NRSs even his
cancer was in radiological progression. Mitogen-activated protein
kinase (MAPK)-signaling was an important driver of neuropathic pain
and therefore, the authors hypothesize a direct inhibition of MAPK-
signalling by cetuximab in neuronal or glial cells (11).
The aim of this study was to identify published data for 3
pharmacological treatments: pregabalin, lidocaine plaster, and
duloxetine, which are typically used at 2(nd) line or later in UK
patients with neuropathic pain. A systematic review of the literature
databases including MEDLINE, EMBASE and CCTR was carried out
and supplemented with extensive conference and grey literature
searching. Studies of any design (except single patient case studies)
that enrolled adult patients with refractory neuropathic pain were
included in the review and qualitatively assessed. Seventeen studies
were included in the review: 9 of pregabalin, 7 of the lidocaine plaster,
and 1 of duloxetine. Pain scores were most commonly assessed in
studies including pregabalin; trials of pregabalin and the lidocaine
plaster reported the proportion of responders. Significant
improvements in the total, sensory and affective scores of the Short-
form MPQ, and in function interference, sleep interference and pain
associated distress were associated with pregabalin treatment; limited
or no QOL data were available for the other 2 interventions. In
conclusion, little evidence is available relevant to the treatment of
refractory neuropathic pain despite the clinical need. There is a
notable lack of high-quality comparative studies. It is evident that
there is a need for future, high quality trials, particularly "gold-
standard" RCTs in this refractory patient population (12).
891
A retrospective investigation on patients hospitalized in the

department with cancer-related neuropathic pain under pregabalin
treatment was carried out. Patients were divided into 2 groups: A
group (≤ 300 mg pregabalin daily) and B group (> 300 mg pregabalin
daily). The 2 groups were compared in terms of a suite of factors (e.
g., age starting and maintenance dose of pregabaline, AEs). Patient's
age was significantly lower in the B group (> 300 mg pregabalin
daily). Of the total number of patients involved in the study, 67%
experienced mild and moderate somnolence. In conclusion, the
younger cancer patients may need lager doses of pregabalin to relieve
cancer-related neuropathic pain. The mild and moderate somnolence
occurs frequently when pregabalin is administered with opioid
analgesics for the treatment of cancer-related neuropathic pain (13).
Neuropathic cancer pain, commonly encountered in clinical
practice, is cancer-related, namely resulting from nervous system
tumor invasion, surgical nerve damage during tumor removal,
radiation-induced nerve damage and chemotherapy-related
neuropathy, or is of benign origin, unrelated to cancer. A neuropathic
component is evident in about 1/3 of cancer pain cases. Although from
a pathophysiological perspective neuropathic cancer pain may differ
from chronic neuropathic pain, such as non-cancer-related pain,
clinical practice, and limited publications have shown that these 2 pain
entities may share some treatment modalities. For example, co-
analgesics have been well integrated into cancer pain-management
strategies and are often used as First-Line options for the treatment of
neuropathic cancer pain. These drugs, including antidepressants and
anticonvulsants, are recommended by evidence-based guidelines,
whereas, others such as lidocaine patch 5%, are supported by
randomized, controlled, clinical data and are included in guidelines for
restricted conditions treatment. The vast majority of these drugs have
already been proven useful in the management of benign neuropathic
pain syndromes. Treatment decisions for patients with neuropathic
pain can be difficult. The intrinsic difficulties in performing RCTs in
cancer pain have traditionally justified the acceptance of drugs already
known to be effective in benign neuropathic pain for the management
of malignant neuropathic pain, despite the lack of relevant high
quality data. Interest in neuropathic cancer pain mechanisms and
pharmacotherapy has increased, resulting in significant mechanism-
based treatment advances for the future (14).
The aim of the study was to evaluate comparative clinical efficacy
of pregabaline with amitriptyline and gabapentin in neuropathic
cancer pain. A total of 120 patients with cancer having severe
892
neuropathic cancer pain were enrolled in the study after approval of

Institutional Ethics Committee and divided in to 4 groups:
amitriptyline group, gabapentin group, pregabalin group, and placebo
group. Oral morphine was used for rescue analgesic for continued
pain. Pain score (VAS) and secondary outcome measures such as
intensity of lancinating, dysesthesia, and burning on NRS, Global
satisfaction score, ECOG, and AEs were assessed. At the end of study
there was significant decrease in pain score in group pregabalin as
compared to the other groups; group amitriptyline (p=0.003), group
gabapentin (p=0.042), and group placebo (p=0.024). Percentage of
patients with lancinating pain and dysesthesia were significantly less
in group pregabalin as compared to groups gabapentin and placebo.
All the patients in placebo group needed rescue morphine. After 4
visits, maximum improvement in ECOG scoring and Global
satisfaction score scoring was observed in group pregabalin patients.
These results suggest that all antineuropathic drugs are effective in
relieving cancer-related neuropathic pain. There was statistically and
clinically significant morphine sparing effect of pregabaline in
relieving neuropathic cancer pain and neuropathic symptoms as
compared to other antineuropathic drugs (15).
The clinical usefulness of gabapentin in combination with opioids
for Japanese patients with neuropathic cancer pain was assessed in an
open-label, single-center, prospective study. Gabapentin was initiated
in addition to the drugs currently being administered. The dose of
gabapentin was titrated from 200 mg to a maximum dose of 2400 mg
per day over 15 days, based on discussion with each patient. The
primary endpoint variable was the NRS of 0-10 measured using the
brief pain inventory. From February 2007 to December 2007,
gabapentin was administered to 24 patients that were already
receiving an opioid without sufficient analgesia. Administration of
gabapentin statistically reduced the worst-NRS, the least-NRS, and the
average-NRS (7.3 > 5.8, 3.6 > 3.0, 5.8 > 4.5, respectively). Four
patients (16.7%) were withdrawn from the study because of AEs
(headache, myoclonus, heartburn, and bronchial asthma). In
conclusion, although gabapentin might be regarded as a promising
new adjuvant analgesic for neuropathic cancer pain, the decrease in
pain score was of minimal clinical benefit (16).
Assessment: neuropathic pain in patients with cancer is often

related to compression, direct neoplastic invasion of the peripheral
nerves or spinal cord, or to a neuropathy caused by chemotherapy. To
manage neuropathic pain in this population, non-opioid adjuvant
893
drugs that are neuroactive or neuromodulatory are often needed to

complement opioid therapy.
Neuropathic cancer pain can be relieved by multimodal treatment
following WHO guidelines as majority of cancer patients suffered
multiple types of pain. To optimize analgesic therapy in patients with
neuropathic pain, both opioid and adjuvant analgesics must be used
effectively.
The primary adjuvant analgesics are anticonvulsant and
antidepressant medications, but a wide variety of other drugs are also
used. Gabapentin, pregabalin and strong opiates are the most effective
and well tolerated options against neuropathic pain in oncology, while
carbamazepine, amitryptiline, tramadol and NSAIDs do not seem to
be valid options in front line approach against oncologic neuropathic
pain, either for a minor efficacy or for an unfavorable safety profile.
Gabapentin added to an opioid provides better relief of neuropathic
pain in cancer patients than opioid monotherapy, this combination of
gabapentin and an opioid may represent a potential first-line regimen
for the management of pain.
The younger cancer patients may need lager doses of pregabalin to
relieve cancer-related neuropathic pain. The mild and moderate
somnolence occurs frequently when pregabalin is administered with
opioid analgesics for the treatment of cancer-related neuropathic pain.
Duloxetine administration may be effective for neuropathic pain in
cancer patients who cannot tolerate pregabalin administration.
There are patients with neuropathic pain within a cancer setting
who are suitable for treatment with topical lidocaine 5% patch, alone
or in combination with other drugs.
An infusion of the antiepidermal growth factor receptor antibody
cetuximab for neuropathic cancer pain is also available.
References
1. Farrar JT, Portenoy RK. Neuropathic cancer pain: the role of adjuvant
analgesics. Oncology (Williston Park). 2001;15(11):1435-42, 1445; discussion 1445,
1450-3.
2. Vadalouca A, Raptis E, Moka E, et al. Pharmacological treatment of
neuropathic cancer pain: a comprehensive review of the current literature. Pain Pract.
2012;12(3):219-51.
3. Keskinbora K, Pekel AF, Aydinli I. Gabapentin and an opioid combination
versus opioid alone for the management of neuropathic cancer pain: a randomized
open trial. J Pain Symptom Manage. 2007;34(2):183-9.
4. Mishra S, Bhatnagar S, Gupta D, et al. Management of neuropathic cancer pain
following WHO analgesic ladder: a prospective study. Am J Hosp Palliat Care.
2008;25(6):447-51.
5. Tassinari D, Drudi F, Carloni F, et al. Neuropathic pain in oncology. Novel
evidence for clinical practice. Recenti Prog Med. 2011;102(5):220-7.
894
6. Bar Ad V. Gabapentin for the treatment of cancer-related pain syndromes. Rev

Recent Clin Trials. 2010;5(3):174-8.
7. Bennett MI. Effectiveness of antiepileptic or antidepressant drugs when added
to opioids for cancer pain: systematic review. Palliat Med. 2011;25(5):553-9.
8. Berger A, Dukes E, Mercadante S, Oster G. Use of antiepileptics and tricyclic
antidepressants in cancer patients with neuropathic pain. Eur J Cancer Care (Engl).
2006;15(2):138-45.
9. López Ramírez E. Treatment of acute and chronic focal neuropathic pain in
cancer patients with lidocaine 5 % patches. A radiation and oncology department
experience. Support Care Cancer. 2013;21(5):1329-34.
10. Matsuoka H, Makimura C, Koyama A, et al. Pilot study of duloxetine for
cancer patients with neuropathic pain non-responsive to pregabalin. Anticancer Res.
2012;32(5):1805-9.
11. Kersten C, Cameron MG. Cetuximab alleviates neuropathic pain despite
tumour progression. BMJ Case Rep. 2012 Jun 14;2012. pii: bcr1220115374.
11. Plested M, Budhia S, Gabriel Z. Pregabalin, the lidocaine plaster and
duloxetine in patients with refractory neuropathic pain: a systematic review. BMC
Neurol. 2010 Nov 19;10:116.
13. Baba M, Gomyo I. Retrospective evaluation of pregabalin for cancer-related
neuropathic pain. Masui. 2012;61(2):147-54.
14. Vadalouca A, Raptis E, Moka E, Zis P, et al. Pharmacological treatment of
neuropathic cancer pain: a comprehensive review of the current literature. Pain Pract.
2012;12(3):219-51.
15. Mishra S, Bhatnagar S, Goyal GN, et al. A comparative efficacy of
amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: a prospective
randomized double-blind placebo-controlled study. Am J Hosp Palliat Care. 2012;
29(3):177-82.
16. Takahashi H, Shimoyama N. A prospective open-label trial of gabapentin as
an adjuvant analgesic with opioids for Japanese patients with neuropathic cancer pain.
Int J Clin Oncol. 2010;15(1):46-51.
The term ―adjuvant analgesic‖ describes any drug with a primary

indication other than pain, but with analgesic properties in some
painful conditions. They can be added to the regimen at any time
depending on the quality of the pain. In some cases, the type of pain
suggests the value of one category of adjuvant analgesic over another;
in others, the existence of another symptom concurrent with pain
favors the use of a specific drug (1).
The group includes numerous drugs in diverse classes. Although
the widespread use of these drugs as first-line agents in chronic
nonmalignant pain syndromes suggests that the term "adjuvant" is a
misnomer, they usually are combined with a less-than-satisfactory
895
opioid regimen when administered for cancer pain. Some adjuvant

analgesics are useful in several painful conditions and are described as
multipurpose adjuvant analgesics (antidepressants, corticosteroids,
alpha(2)-adrenergic agonists, and neuroleptics), whereas others are
specific for neuropathic pain (anticonvulsants, local anesthetics, and
NMDA receptor antagonists), bone pain (calcitonin, bisphosphonates,
and radiopharmaceuticals), musculoskeletal pain (muscle relaxants),
or pain from bowel obstruction (octreotide, and anticholinergics) (2).
Several major groups of adjuvant analgesics (i.e., antidepressants,
AEDs, muscle relaxants, corticosteroids, etc) are used o intensify the
effect of opioids and NSAIDs on long-term pain control. For example,
pain that is neuropathic in nature is typically not amenable to standard
opiate therapy, and the addition of TCA or/and AED can offer a very
effective treatment strategy in such patients (3).
Although cancer pain usually can be relieved in more than 70% of
patients using a simple opioid-based regimen, there will be always
patients who experience little or no pain relief despite substantial
analgesic doses of opiates or who develop intolerable AEs.
Unsatisfactory analgesic response are due to a variety of factors:
differences in patient metabolism, multiple pain mechanisms, disease
progression, and sensitivity to side effects. Some non-analgesic
medications are helpful in amplifying the effect of many analgesic
drugs, particularly in patients with neuropathic pain. In such cases, a
variety of strategies can be implemented to improve the pain control
and balance between analgesia and side effects (4). Among these
strategies is the use of adjuvant analgesics, although very few of these
drugs have been actually studied in cancer populations (5).
References
1. Lussier D, Pappagallo M. 10 most commonly asked questions about the use of
opioids for chronic pain. The Neurologist. 2004;10:221-24.
management. Oncologist. 2004;9(5):571-91.
3. Collins SL, Moore RA, McQuay HJ, et al. Antidepressants and anticonvulsants
for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J
Pain Symptom Manage. 2000;20:449-58.
4. Vielhaber A, Portenoy RK. Advances in cancer pain management. Hematol
Oncol Clin North Am. 2002;16:527-41.
2007;3(3):381-400.
896
NMDA RECEPTOR ANTAGONISTS
KETAMINE
Ketamine is a widely used drug for its anesthetic and analgesic
properties; it is also considered as a drug of abuse, as many cases of
ketamine illegal consumption were reported. Ketamine is N-
demethylated by liver microsomal cytochrome P450 into norketamine.
The identification of the enzymes responsible for ketamine
metabolism is of great importance in clinical practice. In the present
study, the metabolism of ketamine in human liver microsomes at
clinically relevant concentrations was investigated. Liver to plasma
concentration ratio of ketamine was taken into consideration. Pooled
human liver microsomes and human lymphoblast-expressed P450
isoforms were used. N-demethylation of ketamine was correlated with
nifedipine oxidase activity (CYP3A4-specific marker reaction), and it
was also correlated with S-mephenytoin N-demethylase activity
(CYP2B6-specific marker reaction). Orphenadrine, a specific inhibitor
to CYP2B6, and ketoconazole, a specific inhibitor to CYP3A4,
inhibited the N-demethylation of ketamine in human liver
microsomes. In human lymphoblast-expressed P450, the activities of
CYP2B6 were higher than those of CYP3A4 and CYP2C9 at 3
concentrations of ketamine, 0.005, 0.05, and 0.5 mM. When these
results were extrapolated using the average relative content of P450
isoforms in human liver, CYP3A4 was the major enzyme involved in
ketamine N-demethylation. CYP3A4 is the principal enzyme
responsible for ketamine N-demethylation in human liver microsomes
while CYP2B6 and CYP2C9 have a minor contribution to ketamine
N-demethylation at therapeutic concentrations of the drug (1).
There are 2 optical isomers of the 2-(2-chlorophenyl)-2-
(methylamino)-cyclohexanone ketamine: S(+) ketamine and R(-)
ketamine. Effects of this drug are mediated by NMDA, opioid,
muscarinic and different voltage-gated receptors. Clinically, the
anesthetic potency of the S(+)-isomer is approximately 3 to 4 times
that of the R(-)-isomer, which is attributable to the higher affinity of
the S(+)-isomer to the phencyclidine binding sites on the NMDA
receptors. Ketamine is water- and lipid-soluble, allowing it to be
administered conveniently via various routes and providing extensive
distribution in the body. Ketamine metabolism is mediated by hepatic
microsomal enzymes. It causes bronchodilation and stimulation of the
sympathetic nervous system and C-V system. In clinics, ketamine and
particularly S(+)-ketamine are used for premedication, sedation, and
897
induction and maintenance of general anesthesia, which is than termed

"dissociative anaesthesia". Ketamine and its S(+)-isomer are ideal
anesthetic agents for trauma victims, patients with hypovolemic and
septic shock and patients with pulmonary diseases. Even
subanaesthetic doses of this drug have analgesic effects, so ketamine
is also recommended for post-operative analgesia and sedation. The
combination of ketamine with midazolam or propofol can be
extremely useful and safe for sedation and pain relief in intensive care
patients, especially during sepsis and C-V instability. In the treatment
of chronic pain, ketamine is effective as a potent analgesic or
substitute together with other potent analgesics, whereby it can be
added by different methods. There are some important patient side
effects, however, that limit its use, whereby psycho-mimetic side
effects are most common (2).
Although it is sometimes forgotten, ketamine is still considered a
viable drug. Water soluble, stable and non-irritant when administered
intravenously, ketamine has rapid onset after intravenous injection and
provides acceptable anesthesia when administered in continuous
infusion. There properties make ketamine useful for total intravenous
anesthesia. Both propofol and midazolam are effective in reducing
ketamine's adverse side effects. Administered in children by oral,
nasal, rectal and intramuscular routes, ketamine allows for gentle
anesthetic induction. It can also serve as an adjuvant in regional
anesthesia to supplement analgesia. In adults, ketamine is most often
used for major surgery, particularly in the elderly or in high-risk
patients who are in shock, severely dehydrated or hemodynamically
unstable, or in obstetric patients with hypovolemia or hemorrhage. It
is probably the anesthetic of choice for patients with hyperreactive
airways. Ketamine's strong analgesic effect at subanesthetic doses
allows it to be used as an analgesic during postoperative intensive care
or as an analgesic-plus-sedative for patients receiving mechanical
ventilation. Interest in using ketamine at low doses for cancer and
non-cancer patients with chronic pain has grown recently (3).
Ketamine has potent analgesic properties at low dosages.
Bioavailability is high when it is given parenterally, but low after oral
or rectal administration. Active metabolites should account for part of
the analgesic effect of ketamine during long-term oral administration.
NMDA receptor inhibition by ketamine may reflect a wind-down
phenomenon, and should alleviate NMDA-related neuropathic pain,
reversing the rightward shift of the opioid-response curve. A
synergistic effect between ketamine and opioids has been observed in
898
cancer pain patients who have lost an analgesic response to high doses
of morphine (4).
Ketamine blocking the NMDA receptors has some success in
treating neuropathic pain, especially in a situation where large doses
of opioids have contributed to the development of severe hyperalgesia
(5,6). Ketamine can be given by multiple routes: intravenous,
intramuscular, subcutaneous, oral, rectal, nasal, transdermal, epidural,
or even intrathecal, although the optimal route of administration
remains unclear due to a lack of good clinical trials and limited
experimental studies. Ketamine has been used in a variety of
neuropathic pain syndromes that are refractory to high-dose opioids,
such as central pain, ischemic pain, and pain associated with
posttraumatic nerve or SCI, as well as in fibromyalgia, refractory
facial pain, and post-herpetic neuralgia (6). In addition, apart from a
few cases of complete resolution, ketamine generally did not provide a
long-term solution in clinical trials for chronic pain, and the
magnitude of reported benefit was often only a little more than a
placebo effect. However, there is very limited data on ketamine trials
in cancer pain management (5). Nevertheless, ketamine may be used
in refractory cancer pain management as an adjunctive modality for its
opioid-sparing benefits, allowing smaller doses of morphine to be
given. Limiting its use are also the side effects that include sedation,
delirium, and hallucinations at higher doses (7).
A systematic review of randomized, double-blind clinical trials of
ketamine added to opioid analgesia was performed. Thirty-seven trials
with 51 treatment arms and 2385 patients were included. Studies were
divided into 5 subgroups: intravenous ketamine as single dose (n=11),
continuous infusion (n=11), patient-controlled analgesia (n=6),
epidural ketamine with opioids (n=8), and studies in children (n=4).
Outcome measures included pain scores, time to first request for
analgesia, supplemental analgesics, and AEs. As compared to
morphine alone, intravenous patient-controlled analgesia with
ketamine and morphine did not improve analgesia. Intravenous
infusion of ketamine decreased intravenous and epidural opioid
requirements in 6 of 11 studies. A single bolus dose of ketamine
decreased opioid requirements in 7 of 11 studies. Five of 8 trials with
epidural ketamine showed beneficial effects. AEs were not increased
with small dose ketamine. In conclusion, small dose ketamine is a safe
and useful adjuvant to standard practice opioid-analgesia (8).
Patients taking high-dose opioids chronically for tumor-related or
neuropathic pain may develop pain that is refractory to opioids. One
option for control of such pain is the use of the NMDA receptor
899
antagonist ketamine. A case of opioid-refractory pain responded to a

low-dose intravenous infusion of ketamine in the inpatient setting. The
patient was then successfully transitioned to oral memantine for long-
term outpatient management, in a novel use of this oral NMDA
receptor antagonist (9).
References
1. Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9
isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab
Dispos. 2002;30(7):853-8.
2. Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;182:313-33.
3. Reboso Morales JA, González Miranda F. Ketamine. Rev Esp Anestesiol
Reanim. 1999;46(3):111-22.
4. Mercadante S. Ketamine in cancer pain: an update. Palliat Med. 1996;
10(3):225-30.
5. Kannan TR, Saxena A, Bhatnagar S, et al. Oral ketamine as an adjuvant to oral
morphine for neuropathic pain in cancer patients. J Pain Symptom Manage.
2002;23:60-5.
6. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-
based review. Anesth Analg. 2003;97:1730-39.
7. Mercadante S, Arcuri E, Tirelli W, et al. Analgesic effects of iv ketamine in
cancer patients on morphine therapy: a randomized controlled, double-blind,
crossover, double-dose study. J Pain Symptom Manage. 2000;20:246-52.
8. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant
analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg.
2004;99(2):482-95.
9. Grande LA, O'Donnell BR, Fitzgibbon DR, Terman GW. Ultra-low dose
ketamine and memantine treatment for pain in an opioid-tolerant oncology patient.
Anesth Analg. 2008;107(4):1380-3.
AMANTADINE/MEMANTINE
The present trial was designed to test the efficacy of acute
administration of the NMDA receptor antagonist amantadine in
relieving surgical neuropathic pain in patients with cancer. The study
sample consisted of 15 cancer patients with the diagnosis of surgical
neuropathic pain. Two 500 ml infusions of either 200 mg amantadine
or placebo were administered over a 3 hours period, in a randomized
order, 1 week apart from each other. Spontaneous and evoked pain
were measured for 48 hours before treatment, during treatment, and
for 48 hours following treatment. An average pain reduction of 85%
was recorded at the end of amantadine infusion vs. 45% following
placebo administration. The difference in pain relief between the 2
treatments was statistically significant (p=0.009). Mean pain intensity
900
remained significantly lower during the 48 hours following

amantadine treatment as compared with the 48 hours prior to
treatment (31% reduction, p=0.006), whereas no such effect was
found with the placebo (6% reduction, p=0.40). Amantadine, but not
the placebo, also reduced 'wind up' like pain (caused by repeated
pinpricking) in 4 patients. In conclusion, amantadine infusion is a safe
and effective acute treatment for surgical neuropathic pain in cancer
patients (1).
Patients taking high-dose opioids chronically for tumor-related or
neuropathic pain may develop pain that is refractory to opioids. One
option for control of such pain is the use of the NMDA receptor
antagonist ketamine. A case of opioid-refractory pain that responded
to a low-dose intravenous infusion of ketamine in the inpatient setting
is described. The patient was then successfully transitioned to oral
memantine for long-term outpatient management, in a novel use of
this oral NMDA receptor antagonist (2).
References
1. Pud D, Eisenberg E, Spitzer A, et al. The NMDA receptor antagonist
amantadine reduces surgical neuropathic pain in cancer patients: a double blind,
randomized, placebo controlled trial. Pain. 1998;75(2-3):349-54.
2. Grande LA, O'Donnell BR, Fitzgibbon DR, Terman GW. Ultra-low dose
ketamine and memantine treatment for pain in an opioid-tolerant oncology patient.
Anesth Analg. 2008;107(4):1380-3.
ANTIDEPRESSANTS
Antidepressants in oncology offer a wide range of applications in
everyday supportive care while at the same time, they are often not
well known by oncologists. Several recent studies suggest that
depressive disorders have a negative impact on the overall survival in
oncology. The care of the depressed patient in oncology would
therefore request early detection prior to adapted drug treatment and
psychotherapy interventions. This requires better knowledge of
antidepressants whose effectiveness has been demonstrated in severe
major depression. The use of antidepressants should also be part of the
therapeutic armaments in the treatment of pain and hot flushes.
However, their effectiveness in improving minor depressive disorders
and cancer-related fatigue has not been proved yet (1).
Depressive disorders and pain syndromes are common in the
experience of cancer patients and may be experienced simultaneously.
There is an intuitive association between cancer pain and cancer
901
depression, both of which are multidimensional entities. Research has

suggested, but not conclusively proven a cause-effect relationship.
Suicidal ideation is a common concern in cancer patients with severe
depression or pain. Antidepressant therapy is a mainstay of
management of depression. Some antidepressants have use in the
management of cancer pain may influence choice of drug selection in
depressed patients. Antidepressant side effects and the patient's drug
history are relevant variables. Because antidepressants that are
effective as coanalgesics may not be tolerated at doses effective for
depression, the clinician must be familiar with newer classes of
antidepressants and psychostimulants. Combination drug therapy may
be required. Psychotherapy also is common to the treatment of cancer
pain and depression. With or without the intervention of pain and
mental health specialists, ongoing supportive therapy from the
primary clinician is essential (2).
The role of TCAs in the treatment of cancer pain is of growing
interest. Various studies, all but one of them open, have suggested that
TCAs are effective and safe in the treatment of pain caused by
different types of cancer. The mechanisms of action by which TCAs
decrease the pain perception are not fully clear. However, there are 2
main hypotheses. The first suggests that the drugs act primarily on the
emotional component of pain, thus breaking the vicious circle of the
perception of pain; the second suggests that the TCAs themselves
have a specific analgesic action linked to a direct activity on the
structures of the CNS. Further clinical studies, and in particular
double-blind studies, are clearly necessary to provide more convincing
and definitive results (3).
TCAs such as amitriptyline, imipramine, doxepin, and
clomipramine are attractive adjuvant agents in cancer patients due to
their positive effects on mood and sleep. The analgesic properties of
TCAs have been extensively studied in a variety of chronic
nonmalignant pain conditions (4,5). Although only few clinical trials
have specifically evaluated these drugs for cancer pain (6,7), the
experience supports their analgesic effects. Early use of
antidepressants is also justified when pain is accompanied by
depression, which is common in patients with advanced cancer.
However, the use of TCAs, especially in medically ill or elderly
patients is limited due to frequent side effects similar to those seen
with opiates, which include drowsiness, constipation, urinary
retention, and dry mouth, as well as such serious AEs as orthostatic
hypotension, liver function impairment and cardiotoxicity (8,9). TCAs
902
are contraindicated in patients with a known history of glaucoma and

should be avoided in patients who are suicidal.
Nontricyclic compounds, such as SSRI and SNRI, are generally
safer, have fewer side effects than TCAs and, therefore, are
considered for patients who have relative contraindications to
tricyclics or have experienced severe AEs during the treatment (10).
However, there are only limited data supporting the analgesic efficacy
in nonmalignant pain management of few SSRI, i.e., paroxetine (11),
citalopram (12), and SNRI, i.e., venlafaxine (13), and duoxetine (14),
and no studies have been reported on cancer pain (15).
Norepinephrine reuptake is necessary for an antidepressant to be
effective on neuropathic pain, therefore, TCAs and SNRI may have
better results on alleviating neuropathic pain than SSRI (16).
The secondary amines, desipramine and nortriptyline, are less
anticholinergic, usually better tolerated than the tertiary amines, and
are more desirable in the elderly (17-19). Another nontricyclic
antidepressant, trazadone, has been shown to have same effectiveness
in cancer-related neuropathic pain as amitriptyline (20).
References
1. Barrière J, Cherikh F, Pringuey D, et al. Antidepressants in oncology: issues
and clinical perspectives. Bull Cancer. 2008;95(11):1103-11.
2. Valentine AD. Cancer pain and depression: management of the dual-diagnosed
patient. Curr Pain Headache Rep. 2003;7(4):262-9.
3. Magni G, Conlon P, Arsie D. Tricyclic antidepressants in the treatment of
cancer pain: a review. Pharmacopsychiatry. 1987;20(4):160-4.
4. Onghena P, van Houdenhove B. Antidepressant-induced analgesia in chronic
non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain.
1992;49:205–19.
5. Watson CP. The treatment of neuropathic pain: antidepressants and opioids.
Clin J Pain. 2000;16(Suppl 2):49–55.
6. Walsh TD. Controlled study of imipramine and morphine in chronic pain due to
advanced cancer. Proc Am Soc Clin Oncol. 1986;5:237.
7. Magni G, Arsie D, De Leo D. Antidepressants in the treatment of cancer pain: a
survey in Italy. Pain. 1987;29:347-53.
8. Glassman AH, Bigger JT. C-V effects of therapeutic doses of tricyclic
antidepressants. A review. Arch Gen Psychiatr. 1981;38:815-20.
9. Pharo GH, Zhou L. Pharmacologic management of cancer pain. JAOA.
2005;105:S21–28.
10. Masand PS, Gupta S. Selective serotonin-reuptake inhibitors: an update.
Harvard Rev Psychiatry. 1999;52:547–52.
11. Sindrup SH, Gram LF, Brosen K, et al. The selective serotonin reuptake
inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms.
Pain. 1990;42:135–44.
12. Sindrup SH, Bjerre U, Dejgaard A, et al. The selective serotonin reuptake
inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol
Ther. 1992;52:547–52.
903
13. Sindrup SH, Bach FW, Madsen C, et al. Venlafaxine versus imipramine in
painful polyneuropathy: a randomized, controlled trial. Neurology. 2003;60:1284–89.
14. Arnold L, Lu Y, Crofford L, et al. A double-blind, multicenter trial comparing
duloxetine with placebo in the treatment of fibromyalgia patients with or without
major depressive disorder. Arthritis Rheum. 2004;50:2974-84.
15. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database
Syst Rev. 2005;3:CD005454.
16. Lynch M. Antidepressants as analgesics: a review of randomized controlled
trials. J Psychiatry Neurosci. 2001;26:30-6.
17. Lussier D, Pappagallo M. 10 most commonly asked questions about the use of
opioids for chronic pain. The Neurologist. 2004;10:221-24.
18. Maizels M, McCarberg B. Antidepressants and antiepileptic drugs for chronic
non-cancer pain. Am Fam Physician. 2005;71:483-90.
19. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain:
pharmacotherapeutic opportunities to enhance compliance, quality of life, and
analgesia. Am J Ther. 2001;8:181-86.
20. Carr DB, Goudas LC, Balk EM, et al. Evidence report on the treatment of pain
in cancer patients. J Nat Cancer Inst Monogri. 2004;32:23–31.
ANTIEPILEPTIC AGENTS
Certain types of pain associated with cancer are difficult to treat
with standard therapies, often resulting in intractable pain and
suffering for the patient. The use of an opioid as analgesic
monotherapy can lead to poorly controlled pain as well as multiple
side effects. Non-opioid adjunctive analgesics, such as antidepressants
and AEDs, can improve pain control and side effect prevalence (1).
AEDs are particularly useful as adjuvant therapy in the long-term
management of neuropathic pain (1-6). Of the all AED, gabapentin
(Neurontin) is probably the most widely prescribed medication for the
treatment of cancer-related neuropathic pain (7,8), although its
specific mechanism of action has not been fully elucidated.
Nonetheless, due to its proven analgesic effects, good tolerability, and
a rarity of drug-drug interactions, gabapentin is recommended as a
first-line agent for the treatment of neuropathic pain of diverse
etiologies, especially in the medically ill population (9,10). It should
be initiated at a daily dose of 100–300 mg and can be increased every
3 days. The usual maximum dose is 3600 mg daily, but can be higher
if needed, and an adequate trial should include 1-2 weeks at the
maximum-tolerable dose. Gabapentin is usually well tolerated, and the
most common side effects are somnolence, dizziness, and
unsteadiness, which are typically not severe if carefully titrated (11).
904
Gabapentin is a new AED with an original spectrum of activity. Its

mechanism of action has not yet been fully elucidated but appears not
to involve binding to GABA receptors despite being a structural
analogue of GABA and is distinct from TCAs. It modulates high
threshold calcium currents in brain neurons. As some other
anticonvulsants, gabapentin has been recently proposed for the
treatment of non-cancer neuropathic pain like DPN and post herpetic
neuralgia (double blind studies with placebo). Twenty cancer patients
with advanced disease suffering from neuropathic pain were
prospectively followed. All were already treated for their pain
syndrome. Gabapentin was started with 300 mg and was given orally
in order to reach a dose of 900 mg on day 3. All coanalgesics were
stopped before entering the study. The only relevant side effect due to
gabapentin was somnolence. Gabapentin treatment was associated
with a decrease of opioids doses in 9 patients and a decrease of VAS
for pain intensity in all cases. The need of rescue doses decreased in
all cases but 2. Gabapentin appears to be one of the most effective
drugs for the treatment of neuropathic pain. It is well tolerated and its
effectiveness appears shortly after its administration. A synergistic
action with opioids is suggested. Despite the small number of patients,
this study suggests that gabapentin could be a treatment of neuropathic
pain in cancer (12).
Several other AEDs, such as carbamazepine (3), phenytoin (13),
lamotrigine (14,15), pregabalin (16,17), and levetiracetam (18) are
efficacious in alleviating different neuropathic pain syndromes,
including cancer-related pain (13). In general, the last 3 drugs are well
tolerated and lack significant drug-drug interaction, which makes
them superior to carbamazepine or phenytoin for the long-term
management of neuropathic pain. The most frequent serious AEs of
long-term therapy with carbamazepine, phenytoin, and lamotrigine are
bone marrow suppression and liver toxicity, whereas levetiracetam
only rarely causes pancytopenia, while pregabalin has almost no
serious AEs, except mild thrombocytopenia and some congestive
heart failure exacerbation (19).
Levetiracetam is an AED with unique mechanisms of action that
may have analgesic properties in various pain syndromes. Seven
patients with neoplasms involving neural structures (4 invading the
brachial plexus and 3 the lumbosacral plexus) had severe pain of 8 to
9 out of 10 on a VAS, despite the use of parenteral opioids and
various adjunctive therapies. These patients were treated with oral
levetiracetam titrated over days to 20 weeks, depending on the
location of pain, drug response, and tolerance to tapering of opioid
905
analgesics. Opioid and adjunctive analgesic use and VAS scores were
recorded periodically. The maximum levetiracetam dose ranged from
500 mg to 1500 mg BID. All patients experienced pain control
improvement after the addition of levetiracetam, with VAS scores
decreasing from 8-9 out of 10 to 0-3 out of 10 within 2 to 14 days of
therapy initiation. Overall opioid use decreased by at least an
estimated 70%, without drug related AEs. In this small series of
patients, levetiracetam effectively and safely improved pain relief in
patients with neoplastic plexopathies previously resistant to standard
analgesic approaches (1).
References
1. Dunteman ED. Levetiracetam as an adjunctive analgesic in neoplastic
plexopathies: case series and commentary. J Pain Palliat Care Pharmacother.
2005;19(1):35-43.
2. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of
postherpetic neuralgia: a randomized controlled trial. J Am Med Assoc.
1998;280:1837–42.
3. Backonja MM. Anticonvulsants (antineuropathics) for neuropathic pain
syndromes. Clin J Pain. 2000;16(Suppl 6):67-72.
4. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for
neuropathic pain syndromes: mechanism of action and place in therapy. Drugs.
2000;60:1029-52.
5. Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomized, double
blind, placebo-controlled study. Pain. 2001;94:215-24.
6. Jensen TS. Anticonvulsants in neuropathic pain: rationale and clinical evidence.
Eur J Pain. 2002;6A:61-8.
7. Caraceni A, Zecca E, Martini C, et al. Gabapentin as an adjuvant to opioid
analgesia for neuropathic cancer pain. J Pain Symptom Manage. 1999;17:441-45.
8. Oneschuk D, al-Shahri MZ. The pattern of gabapentin use in a tertiary
palliative care unit. J Palliat Care. 2003;195:185-87.
9. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic
pain: diagnosis mechanisms and treatment recommendations. Arch Neurol.
2003a;60:1524-34.
10. Caraceni A, Zecca E, Bonezzi C, et al. Gabapentin for neuropathic cancer
pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J
Clin Oncol. 2004;22:2909–17.
11. Lussier D, Pappagallo M. 10 most commonly asked questions about the use
of opioids for chronic pain. The Neurologist. 2004;10:221-24.
12. Lossignol DA, Plehiers B, Body JJ. Gabapentin (Neurontin) and cancer pain: a
pilot study. Rev Med Brux. 2004;25(5):429-35.
13. Yajnik S, Singh GP, Singh G, et al. Phenytoin as a coanalgesic in cancer pain.
J Pain Symptom Manage. 1992;7:209-30.
14. Zakrzewska JM, Chaudhry Z, Nurmikko TJ, et al. Lamotrigine (lamictal) in
refractory trigeminal neuralgia: results from a double-blind placebo controlled
crossover trial. Pain. 1997;73(2):223-30.
15. Vestergaard K, Andersen G, Gottrup H, et al. Lamotrigine for central
poststroke pain: a randomized controlled trial. Neurology. 2001;56:184-90.
906
16. Dworkin RH, Corbin AE, Young JP, et al. Pregabalin for the treatment of
postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology.
2003b;60:1274-83.
17. Baba M, Gomyo I. Retrospective evaluation of pregabalin for cancer-related
neuropathic pain. Masui. 2012;61(2):147-54.
18. Price MJ. Levetiracetam in the treatment of neuropathic pain: three case
studies. Clin J Pain. 2004;20:33-36.
2007;3(3):381-400.
ANTIPSYCHOTICS
The use of adjuvant medications to treat opiate side effects can also
allow an increase in the analgesic dose. The second-generation
(atypical neuroleptic) agent olanzapine (Zyprexa) was reported to
decrease pain intensity and opioid consumption, and improve
cognitive function and anxiety in a case series of cancer patients.
Other mechanisms may include independent or adjuvant analgesic
effects of olanzapine. In conclusion, olanzapine may be useful in the
treatment of patients with uncontrolled cancer pain associated with
cognitive impairment or anxiety (1).
Use of epidural haloperidol to enhance epidural morphine
analgesia in 3 individuals is reported. Pharmacodynamic interactions
of haloperidol explains its analgesic efficacy (2).
Terminally ill cancer patients commonly suffer from several
symptoms at the same time, such as pain, nausea, anxiety, cognitive
failure, bowel obstruction, and fatigue. To obtain optimal symptom
control, the simultaneous administration of more than one drug by
continuous infusion is often required. Tramadol is considered an
effective step II agent of the WHO analgesic ladder for the control of
chronic pain conditions, including neuropathic pain, and exhibits a
good safety profile. Haloperidol is efficient in controlling agitation
with or without pain, nausea and/or vomiting of central origin,
intestinal obstruction, and delirium. Although the combination of
tramadol and haloperidol in the same solution for continuous infusion
may be desirable, the physicochemical stability of this combination
has not yet been documented. Drug admixtures composed of tramadol
hydrochloride and haloperidol lactate can be stored in polypropylene
syringes at 4 degrees C and 25 degrees C, and assayed at 0, 5, 7, and
15 days after preparation (3).
907
Reference
1. Khojainova N, Santiago-Palma J, Kornick CA, et al. Olanzapine in the
management of cancer pain. J Pain Symptom Manage. 2002;23:346-50.
2. Colclough G, McLarney JT, Sloan PA, et al. Epidural haloperidol enhances
epidural morphine analgesia: three case reports. J Opioid Manag. 2008;4(3):163-6.
3. Negro S, Martín A, Azuara ML, et al. Stability of tramadol and haloperidol for
continuous SCinfusion at home. J Pain Symptom Manage. 2005;30(2):192-9.
PSYCHOSTIMULANTS
Stimulants such as methylphenidate or caffeine can increase
alertness in patients who are experiencing somnolence on a dose of
morphine that provides sufficient pain control (1). In cancer patients,
methylphenidate not only can reduce opioid-induced somnolence, but
can also significantly improve cognition, treat depression, and
alleviate fatigue. Liberal use of laxatives to treat constipation can also
allow an opioid dose to be escalated (2).
Methylphenidate, a psychostimulant, is most commonly used in the
treatment of attention deficit hyperactivity disorder. This review was
based on the basis of a computerized literature search of Medline. All
English language publications from 1966 to present using the
following key words: methylphenidate, palliative care, and cancer
were considered. Relevant for this review, 49 articles were identified.
In conclusion, methylphenidate can be used to ameliorate opioid-
induced somnolence, to augment the analgesic effects of opioids, to
treat depression, and to improve cognitive function in patients with
cancer. The medical literature supports the palliative use of
methylphenidate in the care of patients with cancer (2).
In this open, uncontrolled trial, 15 patients with severe incident
cancer pain receiving regular opiates were administered 10 mg oral
methylphenidate at 08.00 hour and 15 mg at 12.00 hour in order to
antagonize opiate-induced sedation. The daily dose of opiate was
increased by 30% 24 hours after starting methylphenidate, followed
by a 10% increase twice a day until maximal tolerated dose. In 14
evaluable patients, pain (VAS 0-100 mm), sedation (VAS), and mean
equivalent daily dose of morphine were 55 +/- 17, 65 +/- 18 and 248
+/- 150 48 hours before methylphenidate vs. 38 +/- 12 (p<0.01), 42 +/-
12 (p<0.01), and 405 +/- 130 (p<0.01) 48 hours after methylphenidate
administration, respectively. After 48 hours of treatment, 12 of 14
patients felt better on methylphenidate, 2 of 12 patients felt no
difference, and no patients felt worse (p<0.05). In conclusion, the
908
addition of methylphenidate allowed for an increase in the mean

equivalent daily dose of morphine and increased pain control (3).
Thirty-two patients with chronic pain due to advanced cancer were
treated with methylphenidate (10 mg with breakfast and 5 mg with
lunch) for 3 days, vs. placebo, in a randomized, double-blind, cross-
over study designed to evaluate the capacity of methylphenidate to
potentiate the analgesic effect of narcotics and/or to decrease sedation
induced by narcotics. In 28 evaluable patients, the intensity of pain
(VAS 0-100) and intake of extra doses of analgesics (number of
doses/day) were 43 +/- 27 and 2.2 +/- 2.4 during methylphenidate, vs.
55 +/- 24 (p<0.02) and 2.9 +/- 2.9 (p<0.002) during placebo,
respectively. Activity and drowsiness (VAS 0-100) were 57 +/- 25 and
58 +/- 24 after methylphenidate, respectively, vs. 41 +/- 26 (p< 0.05)
and 45 +/- 27 (p< 0.02) after placebo. Upon completion of the study,
the investigator and the patient chose methylphenidate blindly as a
more useful drug in 23 cases (83%) and 20 cases (70%), respectively
(p<0.02). No cases of severe toxicity were observed. In conclusion,
methylphenidate can increase the analgesic effect and decrease
sedation of narcotics in this population (4).
Recent research has shown that the psychostimulant drug
dextroamphetamine can increase the analgesia produced by opioids.
Despite the strong, positive results in human clinical subjects and in
animals, this combination is rarely used in clinical practice. The
purpose of this paper is to investigate whether the psychostimulant
drug methylphenidate can potentiate morphine analgesia in the rat
formalin test, and to compare its effectiveness to that of
dextroamphetamine. The formalin test was used because its long-
lasting pain of moderate intensity resembles human clinical pain. Two
different drug administration times were used to observe whether the
early phase of the formalin response would be differentially affected
by the drugs. At Drug Administration Time 1, rats received morphine
30 min prior to the formalin injection (-30 min) and methylphenidate
or dextroamphetamine 20 min prior to the formalin injection (-20
min). At Drug Administration Time 2, rats received morphine 10 min
prior to the formalin injection (-10 min) and methylphenidate or
dextroamphetamine immediately prior to the formalin injection (0
min). All drugs were given subcutaneously. In conclusion, low doses
of methylphenidate or dextroamphetamine potentiate the analgesic
effects of morphine. The clinical value of these drug combinations
merits further investigation in animals and in humans (5).
909
References
1. Dalal S, Melzack R. Potentiation of opioid analgesia by psychostimulant drugs:
a review. J Pain Symptom Manage. 1998;16:245-53.
2. Rozans M, Dreisbach A, Lertora JJ, et al. Palliative uses of methylphenidate in
patients with cancer: a review. J Clin Oncol. 2002; 20:335–39.
3. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate
in patients with incident cancer pain receiving regular opiates. A preliminary report.
Pain. 1992;50(1):75-7.
4. Bruera E, Chadwick S, Brenneis C, et al. Methylphenidate associated with
narcotics for the treatment of cancer pain. Cancer Treat Rep. 1987; 71(1):67-70.
5. Dalal S, Melzack R. Psychostimulant drugs potentiate morphine analgesia in
the formalin test. J Pain Symptom Manage. 1998;16(4):230-9.
BIPHOSPHONATES
The inhibition of bone resorption and hypercalcaemia can be
reduced by the use of bisphosphonates (1). Patients who develop bone
metastases from advanced cancers commonly receive bisphosphonates
to not only delay the onset of SREs and reduce their frequency but
also provide clinically meaningful palliative effects for bone pain (2).
This class of drugs potentiates the effects of analgesics in improving
metastatic bone pain (1).
Bisphosphonates bind to the surface of the bone, impair osteoclast-
mediated bone resorption, and reduce the tumor-associated osteolysis
that is initiated by the development of skeletal metastases. In addition
to preventing SREs, bisphosphonates can palliate bone pain caused by
a variety of solid tumors. Among bisphosphonates for the prevention
of SREs and the palliation of bone pain, nitrogen-containing
bisphosphonates are the most effective, and zoledronic acid has
demonstrated the broadest clinical utility (3).
Patients who have pain associated with bone metastases may
especially benefit from the use of bisphosphonate compounds, such as
pamidronate or zolendronate. These agents decrease the effect of bone
osteoclast resorption and are typically given intravenously every 4
weeks (4-6).
The main aim of this study was to evaluate whether
bisphosphonate therapy was differentially beneficial depending on
initiation before or after the onset of bone pain. Exploratory analyses
were performed in patients with bone metastases from breast cancer or
lung cancer/other solid tumors enrolled in 2 randomized trials
comparing monthly zoledronic acid vs. pamidronate (breast cancer) or
placebo (lung cancer/other solid tumors). Analyses included
910
proportion of patients with one or more SRE(s), time to first SRE, and
skeletal morbidity rate in patients with and without baseline pain.
Approximately 80% of patients reported baseline pain. Similar to
overall trial results, zoledronic acid reduced the skeletal morbidity rate
in all groups. Although some subsets lacked statistical power, benefits
were generally greater in patients without baseline pain. For example,
in breast cancer, zoledronic acid increased the 25th quartile of time to
first SRE vs. pamidronate by 522 days in patients with no baseline
pain (median not reached for either group), but by only 10 days in
patients with baseline pain. Similar trends were observed in lung
cancer. In conclusion, benefits from zoledronic acid appeared to be
greater if introduced before bone pain onset. Early diagnosis and
treatment of bone metastases may delay onset of SREs (7).
Bisphosphonates form part of standard therapy for hypercalcemia
and the prevention of skeletal events in some cancers. However, the
role of bisphosphonates in pain relief for bony metastases remains
uncertain. The main objective of this study was to determine the
effectiveness of bisphosphonates for the relief of pain from bone
metastases. MEDLINE (1966-1999), EMBASE (1980-1999),
CancerLit (1966-1999), the Cochrane library (Issue 1, 2000) and the
Oxford Pain Database were searched using the strategy devised by the
Cochrane Pain, Palliative and Supportive Care Group with additional
terms 'diphosphonate', 'bisphosphonate', 'multiple myeloma' and 'bone
neoplasms'. (Last search: January 2000). Randomized trials of
bisphosphonates compared with open, blinded, or different
doses/types of bisphosphonates in cancer patients were included
where pain and/or analgesic consumption were outcome measures.
Studies where pain was reported only by observers were excluded.
Article eligibility, quality assessment and data extraction were
undertaken by both reviewers. The proportions of patients with pain
relief at 4, 8 and 12 weeks were assessed. The proportion of patients
with analgesic reduction, the mean pain score, mean analgesic
consumption, adverse drug reactions, and QOL data were compared as
secondary outcomes. Thirty RCTs (21 blinded, 4 open and 5 active
control) with 3682 subjects were included. For each outcome, there
were few studies with available data. For the proportion of patients
with pain relief (8 studies) pooled data showed benefits for the
treatment group, with an NNT at 4 weeks of 11 (95% CI 6 - 36) and at
12 weeks of 7 (95% CI 5 - 12). In terms of adverse drug reactions, the
NNH was 16 (95% CI 12 - 27) for discontinuation of therapy. Nausea
and vomiting were reported in 24 studies with a insignificant trend for
greater risk in the treatment group. One study showed a small
911
improvement in QOL for the treatment group at 4 weeks. In

conclusion, there is evidence to support the effectiveness of
bisphosphonates in providing some pain relief for bone metastases.
There is insufficient evidence to recommend bisphosphonates for
immediate effect; as first line therapy; to define the most effective
bisphosphonates or their relative effectiveness for different primary
neoplasms. Bisphosphonates should be considered where analgesics
and/or RT are inadequate for the management of painful bone
metastases (8).
Bisphosphonates prevent SREs in advanced breast cancer, prostate
cancer, and MM. This systematic review assessed the efficacy of
bisphosphonates in preventing SREs, controlling pain, and overall
survival in patients with bone metastases from lung cancer.
MEDLINE, EMBASE, Web of Science, and the Cochrane Library
databases through November 10, 2011 were searched for controlled
trials that included lung cancer patients with bone metastases treated
with bisphosphonates. Two reviewers independently extracted data on
pain control, survival, and SREs and evaluated the quality of each
study. Twelve trials met inclusion criteria and included 1,767 patients.
Studies were placebo-controlled, or had compared bisphosphonates
with other modalities (chemotherapy, RT, or radioisotope therapy), or
had used different bisphosphonates as active controls. RCTs did not
report adequate descriptions of randomization procedures, allocation
concealment, and blinding, resulting in low-quality scores. Patients
treated with zoledronic acid + chemotherapy had fewer SREs than
those receiving chemotherapy alone (RR 0.81, 95% CI 0.67 - 0.97).
Pain control improved when a bisphosphonate was added to another
treatment modality (chemotherapy or RT; RR 1.18, 95 % CI 1.0 - 1.4).
Bisphosphonate therapy improved survival compared to controls, but
the difference failed to reach statistical significance (mean of 72 days,
95% CI -8.9 - 152.9). In conclusion, treatment with bisphosphonates
reduced SREs, improved pain control, and showed a trend to increased
survival. Bisphosphonates should be used in the treatment of patients
with lung cancer and bone metastases (9).
Bisphosphonates are specific inhibitors of osteoclastic activity and
used in the treatment of patients with MM. Use of bisphosphonates in
patients with MM reduces pathological vertebral fractures, SREs and
pain. Assuming a baseline risk of 20-50% for vertebral fracture
without treatment, between 8 and 20 MM patients should be treated to
prevent vertebral fracture(s) in one patient. Assuming a baseline risk
of 31-76% for pain amelioration without treatment, between 5 and 13
MM patients should be treated to reduce pain in one patient. With a
912
baseline risk of 35-86% for SREs without treatment, between 6 and 15

MM patients should be treated to prevent SRE(s) in one patient.
Overall, there were insignificant AEs associated with the
administration of bisphosphonates identified in the included RCTs. No
evidence of superiority of any specific aminobisphosphonate
(zoledronate, pamidronate or ibandronate) or
nonaminobisphosphonate (etidronate or clodronate) for any outcome
was found. However, zoledronate appears to be superior to placebo
and etidronate improves overall survival (10).
References
1997;69(1-2):1-18.
2. Fitch M, Maxwell C, Ryan C, et al. Bone metastases from advanced cancers:
clinical implications and treatment options. Clin J Oncol Nurs. 2009; 13(6):701-10.
patients with bone metastases. Nat Clin Pract Oncol. 2009;6(3):163-74.
4. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in
the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions
of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J.
2001;7:377–87.
5. Serafini AN. Therapy of metastatic bone pain. J Nucl Med. 2001;42: 895-906.
6. Gordon DH. Efficacy and safety of iv bisphosphonates for patients with breast
cancer metastatic to bone: a review of randomized, double-blinded, phase III trials.
Clin Breast Cancer. 2005;6:125-31.
7. Costa L, Lipton A, Hadji P, et al. Treatment of bone metastases before the onset
of pain. Int J Clin Oncol. 2012 May 11. [Epub ahead of print].
8. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone
metastases. Cochrane Database Syst Rev. 2002;(2):CD002068.
9. Lopez-Olivo MA, Shah NA, Pratt G, et al. Bisphosphonates in the treatment of
patients with lung cancer and metastatic bone disease: a systematic review and meta-
analysis. Support Care Cancer. 2012; 20(11):2985-98.
10. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple
myeloma: a network meta-analysis. Cochrane Database Syst Rev. 2012 May
16;5:CD003188.
CALCITONIN
Hormone calcitonin has shown some beneficial effect in alleviating
the pain associated with bone metastases (1,2). The most essential role
of Miacalcic (Calcitonin Sandoz), a 32-amino-acids peptide, is the
preservation of osseal integrity. Based on this physiological fact, this
hormone may have a bone-regenerating effect in bone metastasis
formation and sometimes in other malignancies. Though no
considerable calcium incorporation could be revealed in 58 patient
913
treated with Miacalcic, a marked relief of pain was observed in 65.5%

of the patients. The pain-killing character of Miacalcic cannot be
explained, but the following assumptions are made: (1) it partially
inhibits the synthesis of algogenous peptides; (2) with its possibly
cytostatic effect it inhibits the cell proliferation in loco and normalizes
the internal pressure of the destroyed region, and (3) by conversion
into beta-endorphin it exerts its effect centrally. Compared to the pain-
killing effect, the simultaneous improvement of the QOL seems to be
even more essential. A hormone physiologically presents, when
applied in a high dose, has an analgesic effect, i.e. by utilizing the
endogenous substance of the organism, and relief of pain can be
achieved. Miacalcic is the only analgesic agent capable of ensuring
relief of pain with a simultaneous improvement of the QOL. The
application of Miacalcic in patients suffering from malignant tumors
is highly recommended (3).
The main objective of this study was to assess the effectiveness of
calcitonin in controlling metastatic bone pain and reducing bone
complications (hypercalcemia, fractures, and nervous compression) in
patients with bone metastases. Electronic searches were performed in
MEDLINE (1966-2001), EMBASE (1974-2001), the Cochrane
Central Register of Controlled Trials (Issue 2, 2001), specialized
registers of the Cochrane Cancer Network and of the Cochrane Pain,
Palliative and Supportive Care Group. Registers of clinical trials in
progress were also searched. Studies were included if they were
randomized, double-blind clinical trials of patients with metastatic
bone pain, treated with calcitonin, where the major outcome measure
was pain, assessed at 4 weeks or longer. Only 2 studies (90 patients)
were eligible for inclusion in the review and therefore meta-analysis
of the data was not possible. Intention-to-treat analysis was performed
by imputing all missing values as adverse outcomes. Of the 2 small
studies were included in the review, 1 study showed insignificant
effect of calcitonin in the number of patients with total pain reduction
(RR 2.50, 95% CI 0.55 - 11.41). The second study provided no
evidence that calcitonin reduced analgesia consumption (RR 1.05,
95% CI 0.90 - 1.21) in patients with painful bone metastases. There
was no evidence that calcitonin was effective in controlling
complications due to bone metastases, improved QOL, or patients'
survival. Although statistically insignificant, a greater number of AEs
were observed in the groups given calcitonin in the 2 included studies
(RR 3.35, 95% CI 0.72 - 15.66). In conclusion, the limited evidence
currently available for systematic review does not support the use of
calcitonin to control pain from bone metastases. Until new studies
914
provide additional information on this treatment, other therapeutic

approaches should be considered (4).
The main objective of this prospective, nonrandomized study was
to evaluate the efficacy of salmon calcitonin in controlling pain
secondary to bone metastases. A study population consisted of 45
cancer patients with bone metastases (26 men) with a mean age of 64
years (range, 48-70) who had completed chemotherapy, hormonal
therapy and RT at least 30 days prior to enrollment in the study, and
had intractable pain despite the use of common analgesics
(acetaminophen, NSAIDs, opioids) and bisphosphonates. The study
medication was a 300-IU dose of salmon calcitonin administered
intravenously daily for 5 consecutive days and repeated every 2 weeks
until no response was noticeable. The analgesic efficacy of salmon
calcitonin was evaluated by means of Huskisson's VAS and Keele's
pain scale; the daily consumption of analgesic drugs and performance
status were also monitored. None of the patients managed to
discontinue the use of other analgesics, but 5 patients (11% of the total
number) had an analgesic response that lasted 4 weeks and less than
5% of the patients continued to respond for 6 weeks. Insignificant side
effects were observed. These data show that intravenous calcitonin
administered in a relatively high dose has a very limited therapeutic
potential as an adjuvant analgesic for a short period in selected cancer
patients with bone metastases (5).
The analgesic effect of salmon calcitonin was evaluated in an open
study of 34 patients with bone metastases of a lung cancer. Two
different administration protocols were used: 18 subjects received
salmon calcitonin 400 IU/day for 3 consecutive days, while the
remaining 16 were given salmon calcitonin 200 IU/day for 6
consecutive days. In both protocols, salmon calcitonin was diluted in
saline and infused intravenously in one hour. Bone, visceral and
neuritic pain were evaluated by means of Huskisson's VAS and
Keele's pain scale. The analgesic efficacy of salmon calcitonin was
also evaluated based on daily consumption of analgesic drugs. Salmon
calcitonin proved extreme efficacy in the treatment of intractable pain
from advanced malignancy. A higher and earlier analgesic activity
was observed with salmon calcitonin at the 400 IU daily dosage (6).
References
1. Roth A, Kolaric K. Analgesic activity of calcitonin in patients with painful
osteolytic metastases of breast cancer: results of a controlled randomized study.
Oncology. 1986;43:283-87.
2. Szanto J, Ady N, Jozsef S. Pain killing with calcitonin nasal spray in patients
with malignant tumors. Oncology. 1992;49:180-2.
915
3. Szántó J, József S, Radó J, et al. Pain killing with calcitonin in patients with
malignant tumours. Oncology. 1986;43(2):69-72.
4. Martinez MJ, Roqué M, Alonso-Coello P, et al. Calcitonin for metastatic bone
pain. Cochrane Database Syst Rev. 2003;(3):CD003223. Update in: Cochrane
Database Syst Rev. 2006;(3):CD003223.
5. Tsavaris N, Kopterides P, Kosmas C, et al. Analgesic activity of high-dose iv
calcitonin in cancer patients with bone metastases. Oncol Rep. 2006; 16(4):871-5.
6. Schiraldi GF, Soresi E, Locicero S, et al. Salmon calcitonin in cancer pain:
comparison between two different treatment schedules. Int J Clin Pharmacol Ther
Toxicol. 1987;25(4):229-32.
CORTICOSTEROIDS
Corticosteroids belong to another major group of medications
widely used as an adjuvant therapy for cancer-related pain syndromes,
which include bone pain, neuropathic pain from infiltration or
metastatic compression of neural structures, superior vena cava
obstruction, headache due to increased intracranial pressure,
arthralgias, and pain due to obstruction of hollow viscus or distention
of an organ capsule (1-5).
Corticosteroids inhibit prostaglandin production, reduce
inflammation, decrease capillary permeability, and have membrane
stabilization effects, which reduces neuronal excitability (6).
Corticosteroids can also improve appetite, nausea, malaise, and
overall QOL (7,8). However, corticosteroids when used for a long
time can produce significant AEs, such as immunosuppression,
hypertension, hyperglycemia, gastric ulcers, and psychosis; although
in cancer patients, the benefit from corticosteroid administration can
often outweigh the potential risk for AEs, particularly in cases of CNS
involvement (9).
The main objective of this study was to assess the evidence for the
use of corticosteroids in cancer pain management. A systematic
literature search was performed. The articles were evaluated according
to the Grading of Recommendations Assessment, Development and
Evaluations system by 2 independent reviewers. The search provided
514 references, 4 of which were included. Another 2 trials were
identified from reference lists. Two of these 6 studies were excluded
from the qualitative review. One crossover study showed a significant
reduction in pain intensity of 13 (VAS 0-100) accompanied by
significant lower analgesic consumption in favor of the steroid group.
In another study, the addition of steroids did not have any effect on
pain. In 2 studies, outcomes of pain intensity or analgesic
916
consumption were not adequately reported. However, one of these

studies showed significant pain reduction, whereas the other found no
effect. Corticosteroids given in medium doses were well tolerated in
studies for up to 7 days. However, the studies indicated that
corticosteroids may have serious toxicity and even higher mortality
when administered in high doses over 8 weeks. In conclusion,
corticosteroids may have a moderate analgesic effect in cancer
patients. The paucity of relevant studies was striking; consequently,
the evidence was graded as "very low" (10).
This RCT evaluated the role of corticosteroids as adjuvants to
opioid therapy in 76 advanced cancer patients with pain requiring
strong opioids. Patients were divided in 2 groups. Group O received
conventional opioid treatment. Group OS received dexamethasone (8
mg orally) along with conventional treatment. Pain and symptom
intensity, sense of well-being, and opioid escalation index and distress
score were recorded at weekly intervals until death. No differences in
pain intensity, opioid consumption, and opioid escalation index were
found in 66 patients who survived 33 to 37 days. Corticosteroids did
not provide significant additional analgesia to opioids, but persistently
decreased opioid-related G-I symptoms for the patients with limited
survival and improved the sense of well-being for some weeks.
Corticosteroid-related toxicity was minimal (11).
In cancer pain, corticosteroids are commonly used adjuvant
analgesics and play an important role in neuropathic and bone pain
treatment. However, in spite of the common use of corticosteroids,
there is limited scientific evidence demonstrating their efficacy in
cancer patients with pain. The use of corticosteroids in spinal cord
compression, superior vena cava obstruction, raised intracranial
pressure and bowel obstruction is better established than in other
nonspecific indications (4).
Despite the fact that there are only a few controlled trials
demonstrating the benefits associated with the use of corticosteroids in
specific situations, these agents are administered frequently to patients
with advanced cancer. Corticosteroids may be used alone or as
adjuvants in combination with other palliative or antineoplastic
treatments. For example, corticosteroids may help prevent nausea,
vomiting, and hypersensitivity reactions to treatment with
chemotherapy or RT. They are also commonly used as appetite
stimulants in patients with advanced cancer. In the adjuvant setting,
corticosteroids help to alleviate pain in advanced cancer patients,
including specific situations such as back pain related to epidural
compression (12).
917
Mr. C. is a married, 80-year-old man with a straight posture and a

sharp wit. Ten years ago, he was diagnosed with a pancreatic
carcinoid tumour and underwent a Whipple procedure. Since then, his
symptoms have been well controlled with intermittent chemotherapy
despite his known liver and multiple spinal metastases. One year ago,
Mr. C. developed bony pain from his cervical spine disease and was
started on hydromorphone. Despite escalating doses, he presented
with increasing pain. The pain was moderate in severity and described
as aching and constant in his neck, with intermittent, sharp, shooting
pain through his left upper back and shoulder. Adding a corticosteroid
as an adjuvant analgesic to Mr. C.'s hydromorphone regimen should
be considered (13).
References
1. Greenberg HS, Kim JH, Posner JB. Epidural spinal cord compression from
metastatic tumor: results with a new treatment protocol. Ann Neurology. 1980;8:361-
66.
2. Ettinger AB, Portenoy RK. The use of corticosteroids in the treatment of
symptoms associated with cancer. J Pain Symptom Manage. 1988;3:99-103.
3. Watanabe S, Bruera E. Corticosteroids as adjuvant analgesics. J Pain Symptom
Manage. 1994;9:442-45.
management. The Oncologist. 2004;9:571-91.
5. Leppert W, Buss T. The role of corticosteroids in the treatment of pain in
cancer patients. Curr Pain Headache Rep. 2012;16(4):307-13.
6. Pharo GH, Zhou L. Pharmacologic Management of Cancer Pain. JAOA.
2005;105:S21–28.
7. Farr WC. The use of corticosteroids for symptom management in terminally ill
patients. Am J Hosp Care. 1990;7:41-6.
8. Mercadante S, Fulfaro F, Casuccio A. The use of corticosteroids in home
palliative care. Support Care Cancer. 2001;9:386-89.
2007;3(3):381-400.
10. Paulsen O, Aass N, Kaasa S, Dale O. Do Corticosteroids Provide Analgesic
Effects in Cancer Patients? A Systematic Literature Review. J Pain Symptom
Manage. 2012 Nov 10. pii: S0885-3924(12)00441-1.
11. Mercadante SL, Berchovich M, Casuccio A, et al. A prospective randomized
study of corticosteroids as adjuvant drugs to opioids in advanced cancer patients. Am
J Hosp Palliat Care. 2007;24(1):13-9.
12. Wooldridge JE, Anderson CM, Perry MC. Corticosteroids in advanced cancer.
Oncology (Williston Park). 2001;15(2):225-34; discussion 234-6.
13. Vyvey M. Steroids as pain relief adjuvants. Can Fam Physician.
2010;56(12):1295-7, e415.
918
BACLOFEN
Baclofen is a g-aminobutyric acid receptor agonist commonly used
for managing many types of neuropathic pain. This retrospective study
evaluated the efficacy of baclofen in patients with cancer pain. The
medical records of all patients given baclofen orally as an analgesic
for cancer at 5 institutions were reviewed. Twenty-five patients
received 10 to 40 mg of baclofen for cancer pain relief. Twenty
patients had neuropathic pain such as paroxysmal or lancing, sharp, or
like an electric shock. Baclofen was effective in 21 of 25 patients and
significantly reduced NPRS (pain score 0-10, p<0.0001). Nine
patients reported mild AEs: none of these patients had to discontinue
baclofen due to AES. In conclusion, baclofen may be a useful
adjuvant analgesic in the treatment of cancer pain (1).
In this case, a dual approach to the palliation of difficult muscle
spasms using intrathecal baclofen via a fully implanted system,
together with the homeopathic approach to symptom control is
described. The homeopathy is seen to complement rather than to
replace conventional prescribing and using both approaches together
avoided the necessity for increasing drug doses and to have minimized
side effects. As well as encouraging us to take on experience from
other disciplines, palliative care could be a forum for evaluating the
effectiveness of the homeopathic approach in symptom control in
carefully designed studies (2).
References
1. Yomiya K, Matsuo N, Tomiyasu S, et al. Baclofen as an adjuvant analgesic for
cancer pain. Am J Hosp Palliat Care. 2009;26(2):112-8.
2. Thompson E, Hicks F. Intrathecal baclofen and homeopathy for the treatment
of painful muscle spasms associated with malignant spinal cord compression. Palliat
Med. 1998;12(2):119-21.
SOMATOSTATIN
There have been many reports of the growth-inhibitory activity of
somatostatin on normal and transformed cells in vitro. Many processes
involved in malignant tumor growth depend on autocrine growth
mechanisms, and somatostatin receptors are present on many human
cancers. It is possible that mutations in somatostatin receptors result in
a loss of check on proliferation in cancer cells. Somatostatin analogs
may have a number of roles in clinical oncology. Use of radiolabeled
919
tracers enables imaging of tumors bearing somatostatin receptors;

newer agents may enable PET analyses or be used to deliver lethal
radiation doses to cells bearing a unique subset of somatostatin
receptors. Although the ability of somatostatin and its analogs to
inhibit cellular proliferation has been shown in vitro, it has yet to be
demonstrated in humans with cancer. Clinical improvements seen
with somatostatin or its analogs in cancer patients may be related to
indirect effects, such as pain relief, reduction of G-I side effects of
chemotherapeutic agents, effects on local production of growth
factors, and inhibition of tumoral angiogenesis. Thus, with regard to
their potential therapeutic role, somatostatin analogs are likely to be
used only in conjunction with other approaches, such as RT,
immunotherapy, chemotherapy, and growth factor modulation (1).
In this study, the efficacy of somatostatin in cancer pain
management and its potential neurotoxicity were determined. Eight
patients with intractable cancer pain were studied. Pain intensity was
assessed by patients on IV-Grade scale (severe, moderate, mild, none).
Additional analgesic drug requirements before and concomitant with
somatostatin treatment were used to evaluate the pain relief and
assessed on IV-Grade scale (poor, fair, good, or excellent). Spinal
cords of 5 patients were autopsied. The mean duration of somatostatin
treatment was 11.3 days. The mean daily dose was 1,252 micrograms
(range 250-3,000 micrograms). In 6 patients, the pain relief was rated
"excellent" or "good" and in 2 patients it was assessed "poor" or "fair".
None of the patients demonstrated any evidence of neurologic deficit
related to the somatostatin treatment. At autopsy, 2 patients exhibited
a moderate demyelination of some spinal dorsal roots and 1 patient
had a slight demyelination of the dorsal columns. In conclusion,
somatostatin administered intrathecally and epidurally was an
effective analgesic in patients with terminal cancer. Because the
described neuropathologic changes could also be cancer-related or
result from chemotherapy or RT, further judicious use of somatostatin
is justified in this category of patients if their pain remains unrelieved
despite large doses of opioid analgesics (2).
Intrathecal morphine has been shown to be reliable in producing
analgesia in patients with intractable cancer pain. Intrathecal
somatostatin is as effective in the treatment of cancer pain as
intrathecal morphine. This report presents 2 cases in whom analgesia
could be maintained for 60 and 25 days, respectively, under
continuous intrathecal infusion of somatostatin by means of infusion
devices (3).
920
References
1. Robbins RJ. Somatostatin and cancer. Metabolism. 1996;45(8 Suppl 1):98-100.
2. Mollenholt P, Rawal N, Gordh T Jr, Olsson Y. Intrathecal and epidural
somatostatin for patients with cancer. Analgesic effects and postmortem
neuropathologic investigations of spinal cord and nerve roots. Anesthesiology.
1994;81(3):534-42.
3. Meynadier J, Chrubasik J, Dubar M, Wünsch E. Intrathecal somatostatin in
terminally ill patients. A report of two cases. Pain. 1985;23(1):9-12.
ANTIHISTAMINE MEDICATIONS
Histamine activates pain-transmitting nerve fibres, releases pain-
related neuropeptides, and is painful when injected into the skin.
Histamine agonists mimic these effects, suggesting that histamine
plays a role in mediating the signal transduction of tissue damage or
other painful stimulus. Certain 'antihistamines' (histamine H1 receptor
antagonists) and other antihistaminics are 'analgesic' in preclinical or
clinical models. Potential sites of action of these agents include the
brain and spinal cord and a specific histamine receptor subtype might
be involved (3 subtypes have been identified). However, it is possible
that other mechanisms account for the analgesic effect (1).
Clinical and animal data suggest that antihistamines may have
efficacy in the management of pain. While many mechanisms of
action have been proposed for the analgesic action of antihistamines,
the exact mechanism is unknown. Controlled clinical trials in different
pain models have demonstrated that antihistamines have direct and
adjuvant analgesic activity. Three patients with advanced cancer pain
refractory to adjuvants and oral, intravenous, and epidural opioids
achieved sustained pain relief after the repeated administration of
diphenhydramine. Diphenhydramine may be useful in the treatment of
neuropathic and nociceptive pain that has failed to respond to
treatment with opioids and adjuvant analgesics. A starting dose of 25
mg of oral or parenteral diphenhydramine every 6 to 8 hours, with
titration to effect has been suggested (2).
References
1. Raffa RB. Antihistamines as analgesics. J Clin Pharm Ther. 2001;26(2):81-5.
2. Santiago-Palma J, Fischberg D, Kornick C, et al. Diphenhydramine as an
analgesic adjuvant in refractory cancer pain. J Pain Symptom Manage.
2001;22(2):699-703.
921
SYSTEMIC LOCAL ANESTHETICS

Lidocaine, mexiletine, tocainide and flecainide are local
anesthetics which give an analgesic effect when administered orally or
parenterally. Early reports described the use of intravenous lidocaine
or procaine to relieve cancer and postoperative pain (1-3). Interest
reappeared decades later when patient series and clinical trials
reported that parenteral lidocaine and its oral analogs tocainide,
mexiletine, and flecainide relieved neuropathic pain (4-6).
The main objective of this study was evaluate pain relief and AE
rates between systemic local anesthetic-type drugs and other control
interventions. MEDLINE (1966 through 15 May 2004), EMBASE
(January 1980 to December 2002), Cancer Lit (through 15 December
2002), Cochrane Central Register of Controlled Trials (2nd Quarter,
2004), System for Information on Grey Literature in Europe (SIGLE),
and LILACS were searched from January 1966 through March 2001.
In addition, hand searched conference proceedings, textbooks, original
articles, reviews, and double blinded trials, with a parallel or crossover
design were included. The control intervention was a placebo or an
analgesic drug for neuropathic pain from any cause. Thirty-two
controlled clinical trials met the selection criteria; 2 were duplicate
articles. The treatment drugs were intravenous lidocaine (16 trials),
mexiletine (12 trials), lidocaine plus mexiletine sequentially (1 trial),
and tocainide (1 trial). Lidocaine and mexiletine were superior to
placebo (WMD = -11, 95% CI -15 - -7, p<0.00001), and limited data
showed no difference in efficacy (WMD = -0.6, 95% CI -7 - 6), or
AEs vs. carbamazepine, amantadine, gabapentin or morphine. In these
trials, systemic local anesthetics were safe, with no deaths or life-
threatening toxicities. In conclusion, lidocaine and oral analogs are
safe drugs in controlled clinical trials for neuropathic pain, were better
than placebo, and were as effective as other analgesics (7).
Systemic administration of lidocaine has been widely reported to
provide effective analgesia in both cancer and non-malignant pain.
The use of intravenous lidocaine in the management of cancer-related
neuropathic pain and its pivotal role in restoring function and
facilitating end-of-life care at home is reported (8).
Twenty-one courses of either mexiletine or flecainide were
administered to patients with an Eastern Cooperative Oncology Group
performance status of 3 or better, who were suffering from cancer pain
inadequately controlled with opioid analgesics. In 17 cases, there was
no suggestion of benefit. Two cases had relatively clear-cut analgesic
benefit, and 2 others had some suggestion of mild-to-moderate
922
analgesic relief. Flecainide was relatively well tolerated, but

mexiletine caused nausea and/or vomiting in 5 of 8 patients. This trial
suggests that systemically administered local anesthetics can relieve
pain in a minority of patients with cancer pain (9).
References
1. Keats AS, D'Alessandro GL, Beecher HR. Controlled study of pain relief by iv
procaine. J Am Med Assoc. 1951;147(18):1761-3.
2. De Clive-Lowe SG, Desmond J, North J. Iv lignocaine anaesthesia.
Anaesthesia. 1958;13(2):138-46.
3. Bartlett EE, Hutserani O. Xylocaine for the relief of postoperative pain. Anesth
Analg. 1961;40:296-304.
4. Boas RA, Covino BG, Shahnarian A. Analgesic responses to i.v. lignocaine Br
J Anaesth. 1982;54(5):501-5.
5. Dunlop R, Davies RJ, Hockley J, Turner P. Analgesic effects of oral flecainide.
Lancet. 1988;1(8582):420-1.
6. Awerbuch GI, Sandyk R. Mexiletine for thalamic pain syndrome. Int J
Neurosci. 1990;55(2-4):129-33.
7. Challapalli V, Tremont-Lukats IW, McNicol ED, et al. Systemic administration
of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev.
2005 Oct 19;(4):CD003345.
8. Buchanan DD, J MacIvor F. A role for intravenous lidocaine in severe cancer-
related neuropathic pain at the end-of-life. Support Care Cancer. 2010;18(7):899-901.
9. Chong SF, Bretscher ME, Mailliard JA, et al. Pilot study evaluating local
anesthetics administered systemically for treatment of pain in patients with advanced
cancer. J Pain Symptom Manage. 1997;13(2):112-7.
CAPSAICIN
Our current understanding of the molecular basis for pain relief by
capsaicin and other TRPV1 agonists is explained. Search of
MEDLINE and other databases was conducted. The capsaicin receptor
TRPV1 is a polymodal nociceptor exhibiting a dynamic threshold of
activation that could be lowered under inflammatory conditions.
Consistent with this model, TRPV1 knock-out mice are devoid of
post-inflammatory thermal hyperalgesia. TRPV1 desensitization of
primary sensory neurons is a powerful approach to relieve symptoms
of nociceptive behavior in animal models of chronic pain. However,
over-the-counter capsaicin creams have shown moderate to poor
analgesic efficacy. This is in part related to low dose, poor skin
absorption, and compliance factors. Recently developed site-specific
capsaicin therapy with high-dose patches and injectable preparations
seem to be safe and reportedly provide long-lasting analgesia with
923
rapid onset. In conclusion, TRPV1 agonists and antagonists are not

mutually exclusive but rather complimentary pharmacologic
approaches for pain relief and a "revival" for capsaicin and other
TRPV1 agonists in the clinical management of pain associated with
inflammation, metabolic imbalances (e.g., diabetes), infections (HIV),
and cancer, despite the current focus of the pharmaceutical industry on
TRPV1 antagonists is predicted (1).
Cancer colonization of bone leads to the activation of osteoclasts,
thereby producing local tissue acidosis and bone resorption. This
process may contribute to the generation of both ongoing and
movement-evoked pain, resulting from the activation of sensory
neurons that detect noxious stimuli (nociceptors). The capsaicin
receptor TRPV1 is a cation channel expressed by nociceptors that
detects multiple pain-producing stimuli, including noxious heat and
extracellular protons, raising the possibility that it is an important
mediator of bone cancer pain via its capacity to detect osteoclast- and
tumor-mediated tissue acidosis. TRPV1 is present on sensory neuron
fibers that innervate the mouse femur and that, in an in vivo model of
bone cancer pain, acute or chronic administration of a TRPV1
antagonist or disruption of the TRPV1 gene results in a significant
attenuation of both ongoing and movement-evoked nocifensive
behaviors. Administration of the antagonist had similar efficacy in
reducing early, moderate, and severe pain-related responses,
suggesting that TRPV1 may be a novel target for pharmacological
treatment of chronic pain states associated with bone cancer
metastasis (2).
A minority of cancer survivors develops long-term postsurgical
neuropathic pain. Ninety-nine assessable patients with postsurgical
neuropathic pain were entered onto this study. After stratification,
patients were to receive 8 weeks of a 0.075% capsaicin cream
followed by 8 weeks of an identical-appearing placebo cream, or vice
versa. A capsaicin/placebo cream was to be applied to the painful site
4 times daily. During the first 8-week study period, the capsaicin-
cream arm was associated with substantially more skin burning, skin
redness, and coughing (p<0.0001 for each). Nonetheless, treatment
was stopped for patient refusal or toxicity just as often while patients
were receiving the placebo as compared with the capsaicin. The
capsaicin cream arm had substantially more pain relief (p=0.01) after
the first 8 weeks, with an average pain reduction of 53% vs. 17%. On
completion of the 16-week study period, patients were asked which
treatment period was most beneficial. Of the responding patients, 60%
chose the capsaicin arm, 18% chose the placebo arm, and 22% chose
924
neither (p=0.001). In conclusion, a topical capsaicin cream decreases

postsurgical neuropathic pain in cancer patients and, despite some
toxicities, is preferred by patients over a placebo by a three-to-one
margin among those expressing a preference (3).
Capsaicin, (trans-8-methyl-N-vanillyl-6-nonenamide), is the
principal pungent component in hot peppers, including red chili
peppers, jalapeños, and habaneros. Consumed worldwide, capsaicin
has a long and convoluted history of controversy about whether its
consumption or topical application is entirely safe. Conflicting
epidemiologic data and basic research study results suggest that
capsaicin can act as a carcinogen or as a cancer preventive agent.
Capsaicin is unique among naturally occurring irritant compounds
because the initial neuronal excitation evoked is followed by a long-
lasting refractory period, during which the previously excited neurons
are no longer responsive to a broad range of stimuli. This process is
referred to as desensitization and has been exploited for its therapeutic
potential. Capsaicin-containing creams have been in clinical use for
many years to relieve a variety of painful conditions. However, their
effectiveness in pain relief is also highly debated and some adverse
side effects have been reported. Chronic, long-term topical application
of capsaicin increased skin carcinogenesis in mice treated with a
tumor promoter. These results might imply that caution should be
exercised when using capsaicin-containing topical applications in the
presence of a tumor promoter, such as, for example, sunlight (4).
References
1. Knotkova H, Pappagallo M, Szallasi A. Capsaicin (TRPV1 Agonist) therapy
for pain relief: farewell or revival? Clin J Pain. 2008;24(2):142-54.
2. Ghilardi JR, Röhrich H, Lindsay TH, et al. Selective blockade of the capsaicin
receptor TRPV1 attenuates bone cancer pain. J Neurosci. 2005; 25(12):3126-31.
3. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of
capsaicin cream in the management of surgical neuropathic pain in cancer patients. J
Clin Oncol. 1997;15(8):2974-80.
4. Bode AM, Dong Z. The two faces of capsaicin. Cancer Res. 2011;71(8):2809-
14.
925
CLONIDINE
Clonidine is an alpha2-adrenergic agonist with analgetic properties.
Due to its side effects, the drug is administered via the epidural or
spinal route. A literature search yielded 9 controlled studies on
clonidine as a supplemental drug in the epidural or spinal treatment of
cancer pain. These studies were systematically reviewed to evaluate
the evidence of efficacy in patients with cancer pain. Despite weak
evidence, clonidine is a useful adjunct in epidural or spinal morphine
therapy for cancer pain (1).
Clonidine is approved in the US for epidural administration in the
treatment of intractable neuropathic cancer pain, is also administered
intrathecally for this indication and both epidurally and intrathecally
in the treatment of acute, postoperative pain. The purpose of the
current study was to estimate the relative potency of clonidine by
epidural and intrathecal routes in the treatment of capsaicin-induced
hyperalgesia and allodynia as a model of central hypersensitivity and
of noxious heat as a model of acute pain. Twenty-four healthy
volunteers were randomized to receive either intrathecal clonidine (75,
150, or 300 micrograms) or epidural clonidine (150, 300, or 600
micrograms) and rated pain from a Peltier-controlled thermode at a
lumbar, thoracic, and cervical dermatomal site before and after drug
administration. In addition, they rated pain from intradermal capsaicin
injections at a lumbar dermatome before and 60 min after clonidine
injection and described areas of hyperalgesia and allodynia to
mechanical stimuli. Clonidine's effect differed with route of
administration and modality of sensory testing. For acute thermal
pain, intrathecal clonidine produced a dose-dependent analgesia with a
lumbar>thoracic>cervical gradient, whereas only one dose of epidural
clonidine reduced thermal pain and this was at the thoracic testing site.
By contrast, the potency of clonidine to reduce capsaicin-induced
allodynia was similar between the 2 routes of injection, and for
hyperalgesia, clonidine was only slightly more potent after intrathecal
than epidural injection. These data suggest that there is a > 6-fold
potency ratio of intrathecal: epidural administration of clonidine for
acute pain, but a < 2-fold potency ratio for these routes for mechanical
hypersensitivity (2).
Although the vast majority of patients with cancer pain receive
effective analgesia from standard therapy, a few patients, particularly
those with neuropathic pain, continue to experience severe pain
despite large doses of systemic or intraspinal opioids. Animal studies
suggest intraspinal alpha 2-adrenergic agonists may be effective in
926
such cases. Eighty-five patients with severe cancer pain despite large
doses of opioids or with therapy-limiting side effects from opioids
were randomized to receive, in a double-blind manner, 30
micrograms/hour epidural clonidine or placebo for 14 days, together
with rescue epidural morphine. Pain was assessed by VAS, MPQ, and
daily epidural morphine use. Success was defined as a decrease in
either morphine use of VAS pain, with the alternative variable either
decreasing or remaining constant. BP, heart rate, and degree of nausea
and sedation were monitored. Successful analgesia was more common
with epidural clonidine (45%) than with placebo (21%). This was
particularly prominent in those with neuropathic pain (56% vs. 5%).
Pain scores were lower at the end of the treatment period in patients
with neuropathic pain treated with clonidine rather than placebo,
whereas morphine use was unaffected. Clonidine, but not placebo,
decreased BP and heart rate. Hypotension was considered a serious
complication in 2 patients receiving clonidine and in 1 patient
receiving placebo. This study confirms the findings from previous
animal studies which showed the effective, potent analgesic properties
of intraspinal alpha 2-adrenergic agonists and suggests that epidural
clonidine may provide effective relief for intractable cancer pain,
particular of the neuropathic type (3).
References
1. Nielsen JB, Sjøgren P. Clonidine in the treatment of cancer pain. Ugeskr
Laeger. 2008 3;170(45):3650-3.
2. Eisenach JC, Hood DD, Curry R. Relative potency of epidural to intrathecal
clonidine differs between acute thermal pain and capsaicin-induced allodynia. Pain.
2000;84(1):57-64.
3. Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for
intractable cancer pain. The Epidural Clonidine Study Group. Pain. 1995;61(3):391-9.
CANNABINOIDS
Cannabis sativa L. is possibly one of the oldest plants cultivated by
man, but has remained a source of controversy throughout its history.
Whether pariah or panacea, this most versatile botanical has provided
a mirror to medicine and has pointed the way in the last 2 decades
toward a host of medical challenges from analgesia to weight loss
through the discovery of its myriad biochemical attributes and the
endocannabinoid system wherein many of its components operate.
Cannabis usage in Ancient Egypt serves as an archetype, while
927
examining first mentions from various Old World cultures and their
pertinence for contemporary scientific investigation. Cannabis
historians of the past have provided promising clues to potential
treatments for a wide array of currently puzzling medical syndromes
including chronic pain, spasticity, cancer, seizure disorders, nausea,
anorexia, and infectious diseases that remain challenges for 21st
century medicine. Information gleaned from the history of cannabis
administration in its various forms may provide useful points of
departure for research into novel delivery techniques and
standardization of cannabis-based medicines that will allow their
prescription for treatment of these intractable medical conditions (1).
Historically cannabinoids have been used for both therapy and
recreation, yet the elucidation of the endocannabinoid system and their
chemistry has been relatively recent. Meta-analysis was based on
historical studies related to the utility of cannabinoids in pain due to
modest analgesia and problematic central side effects. However, there
has been resurgence in clinical trials of cannabis extracts and
analogues. New data have contributed to the understanding of how
cannabinoids work and proposed how to obtain analgesia unfettered
by AEs. Recent clinical trials have demonstrated the current role of
cannabinoids may be to attain small but significant benefit in
refractory chronic and cancer pain. In conclusion, cannabinoids may
be a useful addition to current analgesic treatments. The evidence
supports a possible role for cannabinoids in refractory cancer pain.
However, to realize the full potential of cannabinoids suggested by
preclinical data, it is likely that peripheral CB1 or CB2 receptors or
modulation of endocannabinoids will have to be targeted to achieve
analgesia without dose limiting side effects (2).
Cannabinoid CB2 agonists have been shown to alleviate behavioral
signs of inflammatory and neuropathic pain in animal models.
AM1241, a CB2 agonist, does not demonstrate CNS side-effects seen
with CB1 agonists such as hypothermia and catalepsy. Metastatic
bone cancer causes severe pain in patients and is treated with
analgesics such as opiates. Sustained opiates can produce paradoxical
hyperalgesic actions and enhance bone destruction in a murine model
of bone cancer. Bn contrast, CB2 selective agonists reduce bone loss
associated with a model of osteoporosis. A CB2 agonist administered
over a 7-day period inhibits bone cancer-induced pain as well as
attenuates cancer-induced bone degradation. A murine bone cancer
model was used in which osteolytic sarcoma cells were injected into
the intramedullary space of the distal end of the femur. Behavioral and
radiographic image analysis was performed at days 7, 10 and 14 after
928
injection of tumor cells into the femur. Osteolytic sarcoma within the
femur produced spontaneous and touch evoked behavioral signs of
pain within the tumor-bearing limb. The systemic administration of
AM1241 acutely or for 7 days significantly attenuated spontaneous
and evoked pain in the inoculated limb. Sustained AM1241
significantly reduced bone loss and decreased the incidence of cancer-
induced bone fractures. These findings suggest a novel therapy CIBP,
bone loss and bone fracture while lacking many unwanted side effects
seen with current treatments for bone cancer pain (3).
Interest in the use of cannabinoids in a clinical setting is gradually
increasing, particularly in patients where more conventional
treatments have failed. They offer perceived benefits in a wide range
of conditions, but the major interest at present is on their place in pain
management and in the palliation of symptoms secondary to terminal
cancer and neurological disease. The potential benefits include
symptomatic relief for patients suffering from intractable neuropathic
pain, anorexia, anxiety and muscle spasm. There is clear consensus
that cannibinoids should not be used as a first-line monotherapy, but
should be considered as valuable adjuvants to more commonly
indicated therapeutic options in the management of palliative care
patients. Scientific evidence documenting the benefits of the
canibinoids nabilone and sativex is accumulating, but needs to be
evaluated carefully in the light of the paucity of available data. Both
drugs are usually used under the guidance of specialist units. Nabilone
and Sativex are now controlled drugs, and are frequently used outside
of their licensed indication (control of chemotherapy-induced nausea
and vomiting) and hence particular care needs to be taken in
evaluating the rational for their use. Sativex has been recently licensed
for use in the management of patients with MS (4).
Controversy is associated with the issue of cannabis and
cannabinoids in clinical care in the US. Recent research has
demonstrated the underlying mechanisms of cannabinoid analgesia via
endocannabinoids, an endogenous system of retrograde
neuromodulatory messengers that work in tandem with endogenous
opioids. Additional receptor and non-receptor mechanisms of
cannabinoid drugs have pertinent activity, including anti-
carcinogenesis and neuroprotection that may be of key importance in
aging and terminal patient populations. The results of clinical trials
with synthetic and plant-based cannabinoids suggest that the role of
formulation and delivery system is critical in optimizing the risk-
benefit profile of cannabinoid products. Synergy between opioids and
cannabinoids may produce opioid-sparing effects, as well as extend
929
the duration of analgesia and reduce opioid tolerance and dependence.

The mechanism of action of cannabinoids, their marketed agents and
those in clinical trials, the role in treatment of chronic pain, cancer,
neurodegenerative diseases, and HIV/AIDS are important issues. The
ability of cannabinoid medicines to treat pain, associated sleep
disorders, appetite loss, muscle spasm and a wide variety of other
symptoms suggests that such agents may in the future play an
important role in palliative care (5).
References
1. Russo EB. History of cannabis and its preparations in saga, science, and
sobriquet. Chem Biodivers. 2007;4(8):1614-48.
2. Farquhar-Smith WP. Do cannabinoids have a role in cancer pain management?
Curr Opin Support Palliat Care. 2009;3(1):7-13.
3. Lozano A, Wright C, Vardanyan A, et al. A cannabinoid 2 receptor agonist
attenuates bone cancer-induced pain and bone loss. Life Sci. 2010;86(17-18):646–53.
4. Peat S. Using cannabinoids in pain and palliative care. Int J Palliat Nurs.
2010;16(10):481-5.
5. McCarberg BH. Cannabinoids: their role in pain and palliation. J Pain Palliat
Care Pharmacother. 2007;21(3):19-28.
To sum up: this is a pharmacological approach including non-

opioid, opioid and adjuvant medications for a patient who is suffering
from cancer pain. New, more potent and less toxic drugs are
developed and ineffective or toxic drugs are removed. Ancient and
modern patients deserve appropriate treatment in order to cope with
unbearable pain and to prevent unnecessary suffering.
930
OTHER TREATMENT MODALITIES
RADIOTHERAPY
Opioid analgesia does make a useful contribution to the
management of CIBP, especially in terms of suppressing tonic
background pain. However, CIBP remains a clinical challenge
because the spontaneous and movement-related components are more
difficult to treat with opioids and commonly used analgesic drugs,
without unacceptable side effects. Of all patients, 50% are expected to
gain adequate analgesia from palliative RT within 4-6 weeks of
treatment. Recently developed laboratory models of CIBP, which
show congruency with the clinical syndrome, are contributing to an
improved understanding of the neurobiology of CIBP. This chronic
pain syndrome appears to be unique and distinct from other chronic
pain states, such as inflammatory or neuropathic pain. This has clear
implications for treatment and development of future therapies. A
translational medicine approach, using a highly iterative process
between the clinic and the laboratory, may allow improved
understanding of the underlying mechanisms of CIBP to be rapidly
translated into real clinical benefits in terms of improved pain
management (1).
In MBD, RT is the cornerstone of the treatment. Low doses given
in a single session are safe and effective, and reduce distress and
inconvenience associated with repeated session. Radioisotopes are
more imprecise in delivering specific doses of radiation, but have less
toxicity and easy administration as well as effectiveness in subclinical
sites of metastases, although storage, dispensing and administration
should be under strict control (2).
Patients with bone metastases referred to a palliative RT clinic
were asked to rate their symptom distress using the ESAS. Analgesic
consumption during the previous 24 hours was captured at initial
consultation. To determine interrelationships between symptoms, a
principal component analysis with "varimax rotation" was performed
on the 9 ESAS symptoms. This study defined a "symptom cluster" as
2 or more symptoms that occur together, are stable, and are relatively
independent of other clusters. Patients were followed 1, 2, 4, 8, and 12
weeks post-radiation treatment by telephone. Patients (n=518) with
bone metastases provided complete baseline data using the ESAS. The
4 most prevalent symptoms were poor sense of well-being (93.5%),
fatigue (92.3%), pain (84.1%), and drowsiness (81.8%). Three clusters
931
were identified and accounted for 66% of the total variance at

baseline. The clusters changed post-radiation in both responders and
non-responders and pain clustered with different symptoms (or
remained a separate symptom in responders). In non-responders, 3
symptom clusters were consistently present, except in week 8. In
conclusion, RT influenced the structure of symptom clusters in both
responders and non-responders. Pain clustered out in responders of
radiation to pain. Pain clustered with fatigue, drowsiness, and poor
sense of well-being at baseline (3).
The primary objective was to explore how patients' worst pain
clustered together with functional interference items. Secondary
objectives were to determine whether symptom clusters change with
palliative RT and to compare the difference between responders and
nonresponders to radiation. Worst pain at the site of treatment and
functional interference scores were assessed using the BPI. Patients
provided their scores at baseline, 4, 8, and 12 weeks post-RT. A
principal component analysis was performed on the 8 items (worst
pain and 7 functional interference items) at all time points to
determine interrelationships between symptoms. Principal components
with an eigenvalue higher than 0.90 and explaining more than 10% of
the variance were selected. From May 2003 to January 2007, 348
patients with bone metastases that were referred for palliative RT were
accrued into the study. There were 206 males (59%) and 142 females
(41%), with a median age of 68 years (range, 30-91). Lung (26%),
breast (25%) and prostate (24%) were the most common primary
cancer sites. Treatment ranged from single to multiple fractions, with
the majority of patients receiving a single 8 Gy (58%) and 20 Gy/5
(35%). The most prevalent sites of palliative RD were spine (31%),
pelvis (16%), and hips (15%). Two symptom clusters were identified.
Cluster 1 included walking ability, general activity, normal work,
enjoyment of life and worst pain. Cluster 2 included relations with
others, mood and sleep. In responders to RT, the 2 symptom clusters
disintegrated at 4, 8, and 12 weeks post-RT. All symptom severity
items improved over time (p<0.0001). In non-responders, 2 clusters
had disappeared at week 4, reemerged at week 8, and disintegrated at
week 12. In conclusion, symptom clustering has proved to be
therapeutically important because treatment of one symptom may
affect others within the same cluster. The significant correlations
between worst pain and the functional interference items reaffirm the
importance of pain reduction as a treatment goal for palliative RT. By
treating a patient's symptom of worst pain, it would subsequently ease
their response burden on their daily functional activities by decreasing
932
symptom severity, increasing function, and improving overall QOL

(4).
The main purpose of this study was to explore the relationships
(clusters) among the functional interference items in the BPI in
patients with bone metastases. Patients with 9714 bone metastases
were enrolled in the Radiation Therapy Oncology Group (RTOG)
study. Patients were assessed at baseline and 4, 8, and 12 weeks after
randomization for the palliative RT with the BPI, which consists of
seven functional items: general activity, mood, walking ability,
normal work, relations with others, sleep, and enjoyment of life.
Principal component analysis with varimax rotation was used to
determine the clusters between the functional items at baseline and the
follow-up. There were 448 male and 461 female patients, with a
median age of 67 years. There were 2 functional interference clusters
at baseline, which accounted for 71% of the total variance. The first
cluster (physical interference) included normal work and walking
ability, which accounted for 58% of the total variance. The second
cluster (psychosocial interference) included relations with others and
sleep, which accounted for 13% of the total variance. The functional
clusters changed at week 12 in responders but persisted through week
12 in non-responders. In conclusion, palliative RT is effective in
reducing bone pain. Functional interference component clusters exist
in patients treated for bone metastases. These clusters changed over
time in this study, possibly attributable to treatment (5).
RT is the gold standard treatment for CIBP, but only 50% of
patients achieve adequate pain relief within 6 weeks. The aim of this
preliminary study was to explore the effect of RT on sensory changes
in CIBP with a view to predicting response. After ethics committee
approval, patients with CIBP were assessed prior to and 4-6 weeks
after palliative RT. This included completion of the BPI and bedside
Quantitative Sensory Testing measuring evoked sensations to
quantified stimuli on the skin over the area of CIBP and a control site.
Twenty-three patients were assessed pre and post RT. Thirteen (57%)
had an analgesic response (defined as ≥ 30% reduction in total BPI).
Those patients who had normalization of abnormal warm sensation
("warm responders", n = 6) were different in that they had higher
baseline functional BPI pain scores (median score (IQR) in warm
responders = 43 (31.75-58) compared to 31 (12-39.5) in the remaining
patients, p = 0.039), larger reductions in pain scores (median
difference of 33.5 in total BPI, p = 0.027) and increased likelihood of
resolution of sensitivity to pinprick. This clinical study demonstrates
alterations in sensory responses in CIBP. Alterations in specific
933
sensory characteristics seem to be associated with an increased

likelihood of successful analgesia from palliative RT. This supports
the use of Quantitative Sensory Testing in further biomarker studies to
predict response to therapy and aid clinical decision-making (6).
The members of 3 global radiation oncology professional
organizations - ASTRO, CARO, and New Zealand College of
Radiologists completed an Internet-based survey. The respondents
described what RT dose fractionation they would recommend for 5
hypothetical cases describing patients with single or multiple painful
MBD from breast, lung, or prostate cancer. Radiation oncologists
rated the importance of patient, tumor, institution, and treatment
factors, and descriptive statistics were compiled. Of 962 respondents,
three-quarters ASTRO members described 101 different dose
schedules in common use (range, 3 Gy/1 fraction to 60 Gy/20
fractions). The median dose overall was 30 Gy/10 fractions. Single-
fraction RT schedules were used the least often by ASTRO members
practicing in the US and most often by CARO members. Case,
membership affiliation, country of training, location of practice, and
practice type were independently predictive of the use of single-
fraction RT. The principal factors considered when prescribing were
prognosis, risk of spinal cord compression, and performance status. In
conclusion, despite abundant evidence, most radiation oncologists
continue to prescribe multifraction schedules for patients who fit the
eligibility criteria of previous RCTs. These results have confirmed a
delay in the incorporation of evidence into practice for palliative RT
for painful bone metastases (7).
The main purpose of this study was to compare pain relief among
various dose-fractionation schedules of localized RT in the treatment
of painful bone metastases. A systematic search for randomized trials
of localized RT on bone metastases using different dose fractionations
was performed using Medline (1966 to February 2001) and other
sources. The studies were divided into 3 groups: comparisons of doses
given as a single fraction, single vs. multiple fractions, and
comparisons of doses given as multiple fractions. The complete and
overall pain responses for studies comparing single vs. multiple
fractions were pooled. Exploratory analyses of the dose-response
relationship, using the biologic effective dose (alpha/beta = 10), were
performed using results from all 3 groups of trials. Two trials
comparing single vs. single, 8 trials comparing single vs. multiple, and
6 trials comparing multiple vs. multiple fractions were included. The
complete and overall response rates from studies comparing single-
fraction RT (median 8 Gy, range 8-10 Gy) vs. multifraction RT
934
(median 20 Gy in 5 fractions, range 20 Gy in 5 fractions to 30 Gy in

10 fractions) were homogeneous and allowed pooling of data. Of 3260
randomized patients in 7 studies, 539/1613 (33.4%) and 523/1618
(32.3%) patients achieved a complete response after single and
multifraction RT, respectively, giving a risk ratio of 1.03 (95% CI
0.94 - 1.14, p=0.5). The overall response rate was in favor of single-
fraction RT (1011/1629, 62.1%) compared with multifraction
(958/1631, 58.7%); risk ratio 1.05 (95% CI 1.00 - 1.11, p=0.04),
reaching statistical significance. However, when the analysis was
restricted to evaluated patients alone, the overall response rates were
similar for single-fraction and multifraction RT, at 1011 (72.7%) of
1391 and 958 (72.5%) of 1321, respectively (risk ratio 1.00, p=0.9).
Exploratory analyses by biologic effective dose did not reveal any
dose-response relationship among the fractionation schedules used
(single 8 Gy to 40 Gy in 15 fractions). Of the other results and
observations reported in the trials, only the re-irradiation rates were
consistently different between the treatment arms (more frequent re-
irradiation in lower dose arms among trials reporting re-irradiation
rates). Meta-analysis of reported randomized trials shows insignificant
difference in complete and overall pain relief between single and
multifraction palliative RT for bone metastases. No dose-response
relationship could be detected by including data from the multifraction
vs. multifraction trials (8).
The main objective of this study was to undertake a systematic
review and meta-analysis of single fraction RT vs. multifraction RT
for metastatic bone pain relief and prevention of bone complications.
Trials were identified through MEDLINE, EMBASE, Cancerlit,
reference lists of relevant articles and conference proceedings.
Selection criteria included randomized studies comparing single
fraction RT with multifraction RT on metastatic bone pain. The
analyses were performed using intention-to-treat principle. Eleven
trials that involved 3435 patients were identified. Of 3435 patients, 52
patients were randomized more than once for different painful bone
metastasis sites. Altogether, 3487 painful sites were randomized. The
trials included patients with painful bone metastases of any primary
sites, but were mainly prostate, breast and lung. The overall pain
response rates for single fraction RT and multifraction RT were 60%
(1059/1779) and 59% (1038/1769) respectively, giving an OR of 1.03
(95% CI 0.89 - 1.19) indicating no difference between the 2 RT
schedules. There was no difference in complete pain response rates for
single fraction RT (34%, 497/1441) and multifraction RT (32%,
463/1435) with an OR of 1.11 (95% CI 0.94 - 1.30). Patients treated
935
by single-fraction RT had a higher re-treatment rate with 21.5%

(267/1240) requiring re-treatment compared to 7.4% (91/1236) of
patients in the multifraction RT arm (OR 3.44, 95% CI 2.67 - 4.43).
The pathological fracture rate was also higher in single fraction RT
arm patients. Of patients treated by single fraction RT, 3% (37/1240)
developed pathological fracture compared to 1.6% (20/1236) for those
treated by multifraction RT (OR 1.82, 95% CI 1.06 - 3.11). The spinal
cord compression rates were similar for both arms (OR 1.41, 95% CI
0.72 - 2.75). In conclusion, single fraction RT was as effective as
multifraction RT in relieving metastatic bone pain. However, the re-
treatment rate and pathological fracture rates were higher after single
fraction RT. Studies with QOL and health economic end points are
warranted to find out the optimal treatment option (9).
Radiotherapy for cancer
Analyzing referrals from an inpatient palliative care unit to the

radiation oncology service may help in planning palliative care
services and educational programs. The main aim of this study was to
determine the pattern and rate of referrals from a palliative care unit to
the radiation oncology service at a tertiary oncology facility in Saudi
Arabia. Referrals from the palliative care unit to the radiation
oncology service were prospectively identified over the period
beginning November 27, 2007 and ending March 9, 2011. The
appropriateness of referrals was determined by 2 radiation
oncologists. Of the 635 cancer admissions to the palliative care unit,
25 (3.9%) referrals to radiation oncology were made, and 32 sites
were irradiated. All patients had a poor performance status (ECOG ≥
3). The most common areas irradiated were vertebrae (40.6%), pelvis
(18.7%) and other bony structures (28.1%). Pain control was the most
frequent reason for referral (87.5%). Only one referral was regarded
by the radiation oncology service as inappropriate, indicating that 96%
of the referrals were appropriate. The mean time lapse between
936
referral and starting radiation was 4 ± 3.6 days. Of the patients, 75%
died in the palliative care unit within a median of 30 days post RT. In
conclusion, the small minority of patients in the palliative care unit
referred for RT were deemed appropriate referrals by the radiation
oncologists despite their poor performance status and limited time
remaining. When planning a palliative care unit with similar
admission criteria, the availability of a RT facility in close proximity
may not be a priority (10).
The main purpose of this study was to determine the current
patterns of practice in Japan and to investigate factors that may make
clinicians reluctant to use single-fraction RT. Members of the
Japanese Radiation Oncology Study Group completed an Internet-
based survey and described the RT dose fractionation they would
recommend for 4 hypothetical cases describing patients with painful
MBD. Case 1 described a patient with an uncomplicated painful MBD
in a non-weight-bearing site from non-small-cell lung cancer. Case 2
investigated whether management for a case of uncomplicated spinal
MBD would be different from that in Case 1. Case 3 was identical
with Case 2 except for the presence of neuropathic pain. Case 4
investigated the prescription for an uncomplicated painful MBD
secondary to oligometastatic breast cancer. Radiation oncologists who
recommended multifraction RT for Case 2 were asked to explain why
they considered multifraction RT superior to single-fraction RT. Fifty
two radiation oncologists from 50 institutions (36% of the Japanese
Radiation Oncology Study Group institutions) responded. In all 4
cases, the most commonly prescribed regimen was 30 Gy in 10
fractions. Single-fraction RT was recommended by 13% of
respondents for Case 1, 6% for Case 2, 0% for Case 3, and 2% for
Case 4. For Case 4, 29% of respondents prescribed a high-dose
multifraction RT regimen (e.g., 50 Gy in 25 fractions). The following
factors were most often cited as reasons for preferring multifraction
RT: "time until first increase in pain" (85%), "incidence of spinal cord
compression" (50%), and "incidence of pathologic fractures" (29%).
In conclusion, Japanese radiation oncologists prefer a schedule of 30
Gy in 10 fractions and are less likely to recommend single-fraction
RT. Most Japanese radiation oncologists regard multifraction RT as
superior to single-fraction RT, based primarily on the time until first
increase in pain (11).
937
References
mechanisms and management. Br J Anaesth. 2008;101(1):87-94.
1997;69(1-2):1-18.
3. Chow E, Fan G, Hadi S, Filipczak L. Symptom clusters in cancer patients with
bone metastases. Support Care Cancer. 2007;15(9):1035-43.
4. Hadi S, Fan G, Hird AE, et al. Symptom clusters in patients with cancer with
metastatic bone pain. J Palliat Med. 2008;11(4):591-600.
5. Chow E, James J, Barsevick A, et al. Functional interference clusters in cancer
patients with bone metastases: a secondary analysis of RTOG 9714. Int J Radiat
Oncol Biol Phys. 2010;76(5):1507-11.
6. Scott AC, McConnell S, Laird B, et al. Quantitative Sensory Testing to assess
the sensory characteristics of cancer-induced bone pain after radiotherapy and
potential clinical biomarkers of response. Eur J Pain. 2012;16(1):123-33.
7. Fairchild A, Barnes E, Ghosh S, et al. International patterns of practice in
palliative radiotherapy for painful bone metastases: evidence-based practice? Int J
Radiat Oncol Biol Phys. 2009;75(5):1501-10.
8. Wu JS, Wong R, Johnston M, et al. Cancer Care Ontario Practice Guidelines
Initiative Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy
trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys.
2003;55(3):594-605.
9. Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain:
single fraction versus multifraction radiotherapy - a systematic review of the
randomised trials. Cochrane Database Syst Rev. 2004;(2):CD004721.
10. Al-Shahri MZ, Al-Omair A, Al-Shabanah M, El-Sebaei M. Utilization of
Radiotherapy Services by a Palliative Care Unit: Pattern and Implication. J Support
Oncol. 2012 Oct 15. pii: S1544-6794(12)00144-9.
11. Nakamura N, Shikama N, Wada H, et al.; Japanese Radiation Oncology Study
Group Working Subgroup of Palliative Radiotherapy. Patterns of practice in palliative
radiotherapy for painful bone metastases: a survey in Japan. Int J Radiat Oncol Biol
Phys. 2012;83(1):e117-20.
STRONTIUM-89 CHLORIDE
More than two-thirds of the patients with osseous metastases
experience debilitating bone pain, requiring some form of pain relief.
Analgesics are limited in their efficacy. Palliative application of hemi-
body external beam RT in the treatment of multiple osseous
metastases is limited due to toxicity associated with large treatment
ports. Intravenous injections of bone seeking radioisotopes are
effective in the palliation of pain with fewer side effects (1).
St-89 (Metastron) is an FDA-approved treatment for palliation of
cancer pain (2). Forty-one patients with multiple osseous metastases
due to prostate and breast cancer were treated with Sr89 at the
department of radiation oncology, in a university hospital. A
938
retrospective analysis of these patients indicated that all subjects had

severe pain that diminished their QOL. Most of these patients had
multiple co-morbid factors. Many were on opioids leading to AEs
such as nausea, constipation, and drowsiness that required additional
medication. Objective findings and evaluation of the responses were
not always available for all patients. Following treatment with Sr89,
over two-thirds of the patients responded favorably and required lower
doses of opioids (1).
Blood count changes and pain relief in 28 patients with widespread
painful bony metastasis were treated with Sr89 (Metastron) at the
University of Minnesota Hospital and Clinics. Eighteen patients had
prostate cancer (all hormone-refractory cancer), 7 patients had breast
cancer, and 3 patients had lung cancer, all previously treated with
either radiation, chemotherapy, or a combination of the 2. Serial blood
counts were performed weekly up to 8 weeks and at 12 weeks after
administering Metastron. Pain scale and blood values were monitored
simultaneously. The mean baselines of hemoglobin (Hgb), white
blood count (WBC), and platelets (Platelets) were 11.4, 5900, and
258,000, respectively. The mean dose of Metastron was 3 mCi (range
2.2-4.4). The median time (range) to nadir was about 6 weeks. The
percentage reductions relative to baseline were 32% (range 0-72%) for
WBC; 14% (range 0-50%) for Hgb; 15% (range 0-47%) for the red
blood cell (RBC) count; and 40% (range 0-85%) for platelets. The
median time of survival was 23 weeks (range 2-66 weeks). At 12
weeks, 29% of patients had moderate to dramatic improvement of
pain, 32% had some relief of pain, and 50% had no improvement in
pain. Of the treated patients, 32% required additional palliative
external beam radiation to their bony lesions. In conclusion, Metastron
for palliation for bony metastases should be used with caution because
of moderate to severe bone marrow toxicity, especially in platelets (2).
The main objective of this study was to present the current state of
systemic radiopharmaceutical therapy for the palliation of pain in
individuals with metastatic cancer and to evaluate the palliative effect
and degree of hemotoxicity of Sr89 in patients with painful
osteoblastic metastases primarily from prostate and breast cancer. A
MEDLINE search through December 1994 was performed to identify
English-language studies that met the following criteria. All eligible
studies reported treatment of patients with painful osteoblastic bony
metastases primarily from prostate or breast cancer treated with
intravenous Sr89 chloride. For study eligibility, evaluation of clinical
response as assessed by the Karnofsky index, need for pain
medication, or changes in mobility or sleep patterns was required.
939
Hemotoxicity data were a requirement. A minimum of 10 prostate

cancer cases was necessary for study inclusion. Only those studies
assessing clinical response following one injection of 89Sr were
included. Doses of 89Sr ranged from 0.6 MBq/kg (16 microCi/kg) to
400 MBq (10.8 mCi) per patient. Evaluation of patients for at least 3
months following 89Sr treatment was required. In addition, 2 studies
examining issues of cost with regard to Sr89 treatment were
identified. Baseline pain assessment and periodic pain estimates as
measured by the Karnofsky index, medication diaries, changes in
mobility, sleep patterns, and/or ability to work were the basis for
assessment of response. Baseline and periodic complete blood cell
counts were the basis for hemotoxicity evaluation. Some improvement
occurred in as many as approximately 80% of patients. Several studies
demonstrated complete relief of pain in at least 10% of patients. The
nadir of platelet and white blood cell counts appears at approximately
4 to 8 weeks following injection, with a partial return to baseline by
12 weeks. As many as 10 injections spaced 3 months apart have been
given to some patients with repeated palliative effect and without
serious hemotoxicity. Reinjection may be limited by a platelet count
below 60 x 10(9)/L, a white blood cell count below 2.4 x 10(9)/L, or
the absence of osteoblastic skeletal metastasis as seen on bone scan.
Studies examining treatment costs suggest that 89Sr may decrease
costs associated with palliation of pain due to metastatic disease. In
conclusion, as many as 80% of selected patients with painful
osteoblastic bony metastases from prostate or breast cancer may
experience some pain relief following 89Sr administration. In
addition, as many as 10% or more may become pain free. Duration of
clinical response may average 3 to 6 months in some cases.
Hemotoxicity is mild. A decrease in treatment costs with
administration of Sr89 to patients with painful osteoblastic bony
metastases from prostate cancer may occur (3).
This study was designed to compare the effectiveness of Sr89
injections by 50 Mbk fractions with standard 150 Mbk injection in
patients with bone metastases. Of 50 patients with bone metastases, 25
received Sr89 by fractional and 25 (control group) single injection.
The pain intensity, white blood cells and thrombocytes concentration
values were evaluated in both groups before and after treatment. The
study proved the possibility of using systemic Sr89 fractional RT in
patients with bone metastases and concurrent stage 2-3
myelosupression. The method of fractial Sr89 injection is effective in
symptomatic treatment of patients with bone metastases (4).
940
Sr89 for the palliative treatment of metastatic bone pain was used.
Seventy-six patients (50 males with prostate carcinoma and 26
females with breast cancer) were treated with 148 MBq of Sr89.
Sixteen patients were retreated, receiving 2 or 3 doses; the total
number of injected doses was consequently 95. The Karnofsky
performance status was assessed and pain and analgesia were scored
on scales of 9 and 5 points, respectively. The efficacy of Strontium-89
chloride was evaluated at 3 months of treatment. Three levels of
response were considered: good - when there was an increase in the
Karnofsky status and a decrease in the pain score (equal to or higher
than 4) or analgesic score (equal to or higher than 1); partial - when
there was an increase in the Karnofsky status and a decrease in the
pain score (2 or 3 points) without significant changes in the analgesic
score; no response - if no variation or deterioration in these parameters
was observed. In prostate cancer patients, the response was good in
64% of cases and partial in 25%, and there was no response in the
remaining 11%. In breast cancer patients, the response was good in
62% of cases and partial in 31%, and there was no response in the
remaining 8%. Duration of the response ranged from 3 to 12 months
(mean 6 months). In the patients who were retreated the effectiveness
was as good as after the first dose of 89Sr. A decrease in the initial
leukocyte and platelet counts was observed after the first month of
treatment, with a gradual partial to complete recovery within 6
months. In conclusion, 89Sr is an effective agent in palliative therapy
for metastatic bone pain in patients with prostate or breast carcinoma.
If required, retreatment can be administered safely and with the same
efficacy as is achieved by the first dose (5).
Radioactive Sr89 was administered for pain relief in 6 patients with
bone metastases (4 prostate cancer and 2 breast cancer patients). Of 6
patients, 2 showed apparent relief of bone pain and improvement of
QOL, and 3 showed slight relief of the pain with or without
improvement of QOL; that is, 83% was effective. Side effects were
seen in two patients; transient deterioration of bone pain in 1 patient
and bone marrow suppression in the other patient. The patient who
showed bone marrow suppression had rather more lesions of bone
metastasis (diffuse metastasis) and least urinary excretion of the
radioactivity. Urinary excretion for 2 days varied 5-40% of the
administered dose and was less in the patients with more metastatic
lesions (6).
Sr89 is a relatively new bone-seeking radiopharmaceutical that has
FDA-approved labeling for use in relieving pain associated with
skeletal metastases. An analogue of calcium, Sr89 is rapidly cleared
941
from the blood after intravenous injection. The agent selectively

irradiates metastatic sites while generally sparing normal soft-bone
tissue. In clinical studies, a majority of patients with prostate or breast
cancer obtained substantial relief from bone pain after receiving Sr89
alone or in combination with external-beam irradiation. AEs effects
tend to be mild, but patients should be monitored for possible
hematologic toxicity. Patients should discontinue any calcium-
containing products before receiving the agent. The typical dose is 4
mCi (148 MBq) administered by slow intravenous push over 1 to 2
minutes; doses can be repeated at 3-month intervals. Pain relief
usually begins in 10-20 days and lasts up to 6 months. Radiation
safety measures are necessary in handling Sr89 and the wastes of
patients. Sr89 is costly, but preliminary analysis indicates that it may
reduce management expenditures overall (7).
Sr89 has been available at Division of Radiotherapy and
Radiology, Sakai Municipal Hospital, Japan for painful osseous
metastases since October 2008. Of the 17 patients (22 treatments) seen
until September 2010, response to initial treatment of 13 patients was
analyzed. These included cancers of the lung (5 patients, 6
treatments), breast (4 patients), thyroid (2 patients, (5 treatments),
liver, 1, and prostate, 1. Other treatments patients received within 1
month of Sr-89 injection were: chemotherapy, 5 patients;
radiotherapy, 3 patients; and bisphosphonate, 9 patients. The treatment
effects were assessed 1 month after injection, and for 11 of the 13
patients, pain-relief was obtained in a mild and gradual manner.
Transient flare was frequently observed, some of which made
assessment of pain-relief in 6 patients difficult. The bone marrow
function before treatment was well above the 'Optimal Treatment
Manual Japan ' criteria. After treatment, bone marrow functions kept
above the value of grade II (CTCAE), and even in 5 patients with
recent or concomitant chemotherapy, it remained above grade III of
the CTCAE criteria. In conclusion, the indication and inclusion
criteria for Sr89 treatment should be patients with an earlier bone
metastasis burden that is currently manifested, without too much
attention to bone marrow function criteria (8).
References
1. Ashayeri E, Omogbehin A, Sridhar R, Shankar RA. Strontium 89 in the
treatment of pain due to diffuse osseous metastases: a university hospital experience. J
Natl Med Assoc. 2002;94(8):706-11.
2. Lee CK, Aeppli DM, Unger J, et al. Strontium-89 chloride (Metastron) for
palliative treatment of bony metastases. The University of Minnesota experience. Am
J Clin Oncol. 1996;19(2):102-7.
942
3. Robinson RG, Preston DF, Schiefelbein M, Baxter KG. Strontium 89 therapy

for the palliation of pain due to osseous metastases. JAMA. 1995; 274(5):420-4.
4. Fomin DK, Smirnov IuN, Tararukhina OB, Nazarov AA. Strontium chloride
(89Sr-chloride) fractional injection method for bone metastases treatment. Vopr
Onkol. 2012;58(1):116-8.
5. Pons F, Herranz R, Garcia A, et al. Strontium-89 for palliation of pain from
bone metastases in patients with prostate and breast cancer. Eur J Nucl Med. 1997
Oct;24(10):1210-4.
6. Koizumi K, Arbab AS, Toyama K, et al. 89Sr Therapy for pain relief in patients
with bone metastases. Kaku Igaku. 1996;33(11):1243-8.
7. Nightengale B, Brune M, Blizzard SP, et al. Strontium chloride Sr 89 for
treating pain from metastatic bone disease. Am J Health Syst Pharm. 1995 Oct
15;52(20):2189-95.
8. Ikeda H, Ichida W, Nakaseko Y, et al. Initial report of strontium-89 chloride
treatment for painful osseous metastases at Sakai Municipal Hospital. Gan To Kagaku
Ryoho. 2012;39(1):63-8.
NERVE BLOCKS
Methods of pain management include: 1) neurolytic blockade:
stellate ganglion block, celiac plexus block, lumbar sympathetic
block, epidural phenol, and subarachnoid neurolysis; and 2) non-
pharmacologic methods: radiofrequency thermocoagulation lumbar
sympathectomy, TENS, and dorsal column stimulation. Every
possible combination of therapeutic modalities for cancer pain should
be utilized. With so many safe procedures available, the primary
physician should be encouraged to refer patients early in their disease
process. Neurolytic procedures should be performed prior to initiation
of high dose narcotic therapy, radiation, chemotherapy, and surgery
when possible (1). Neurolytic blocks are a mainstay in the
armamentarium of cancer pain management, more in intractable pain
from advanced cancer. There is no clear consensus on patient
selection, technique, or timing of these blocks (2).
In addition to systemic pharmacological therapy for pain
management, neurolytic blocks are also effective in controlling cancer
pain in selected patients. Several studies have documented the efficacy
of neurolytic blocks in reducing pain intensity and opioid
consumption, although good prospective RCTs are scarce. The narrow
risk-benefit ratio associated with neurolysis techniques requires
knowledge of the complications associated with the different
neurolytic blocks in order to minimize undesirable effects.
Interventional techniques continue to play an important role in the
management of cancer pain. The quality of the neurolytic blocks
943
improves when they are performed image-guided in collaboration with

an interventional radiologist. These blocks should never be considered
an isolated treatment, but as a component of a comprehensive
therapeutic strategy (3).
Chronic abdominal pain associated with pancreatic and other types
of intra-abdominal cancer can be successfully treated by celiac plexus
block (injection of a neurolytic agent near the celiac plexus). Analysis
of the available data regarding the efficacy and safety of this
procedure to control cancer pain has shown that celiac block provided
long-lasting benefit for 70-90% of patients with different types of
abdominal cancer with mean pain scores decreasing by 40% in
average (4,5). Orthostatic hypotension, local pain, and diarrhea were
some of common side effects of this procedure, but were
conservatively managed with prompt resolution of the symptoms.
Only a few patients had been reported to develop severe neurological
complications, such as lower extremity weakness and paresthesia,
from the procedure (4). In cases of visceral and pelvic pain associated
with extensive gynecologic, CRC, or genitourinary cancer, neurolytic
block of the hypogastric plexus can be used (6,7). Although the
reported results of this procedure in general are less convincing than
for celiac plexus block (probably due the character of the cancer and
possible more extensive involvement of bone structures in this group
of patients), in cases of medically intractable pelvic pain, hypogastric
block may be still beneficial to consider, all the more that no serious
complications were reported in literature related to this procedure (8).
Neurolytic celiac plexus block: needle position in the anterior posterior view.
The needles enter at level L2 and are directed obliquely upwards to L1.
In addition, local nerve blocks or neurolysis with phenol or alcohol

can be used for treating localized pain (9). Local anesthetic
bupivacaine produces its analgesic effect by blocking voltage-
944
sensitive sodium channels and thus, preventing the generation and

conduction of nerve impulses. Bupivacaine can be helpful adjunct to
morphine, particularly in the treatment of neuropathic pain (10,11).
However, its dosing is limited by potential neurotoxicity, which can
result in numbness, motor weakness, and bowel or bladder
dysfunction at higher doses. Motor block may occur at doses as low as
10 mg per day, but slower dose titration can generally overcome this
AE (8).
The use of neurolytic blockade is a staple in the management of
cancer pain. However, the data on neurolysis for chronic pain are
plagued by inconsistencies in patient selection, diagnostic criteria,
technical standards, and outcome measures. No one neurolytic agent
or technique has been proven superior to another. Current evidence
suggests that patients with pain of malignant origin may benefit from
a variety of neurolytic techniques, as the benefit of documented short-
term pain relief may outweigh risk at the end of life. In the absence of
compelling data suggesting low-risk long-term efficacy, neurolysis for
chronic benign pain should be cautiously considered, in most cases,
only after failure of aggressive multidisciplinary management (12).
Patients with pain caused by cancer frequently experience visceral
pain. In addition to oral pharmacologic therapy to manage pain,
neurolytic blocks of the sympathetic axis are also effective in
controlling visceral cancer pain. Four types of neurolytic blocks
(interpleural phenol, celiac plexus, superior hypogastric plexus, and
ganglion impar) are used in the treatment of visceral cancer pain.
Several studies have documented the efficacy of neurolytic blocks in
reducing pain intensity and opioid consumption. However, the narrow
risk-benefit ratio associated with neurolysis techniques requires
knowledge of the implications associated with the different neurolytic
blocks to minimize undesirable effects. In conclusion, neurolysis of
the sympathetic axis has been shown to be an effective and safe
approach to treat visceral pain in cancer patients and should be
incorporated in the armamentarium of the pain specialist as a useful
adjunct to oral pharmacologic therapy (13).
Patients with advanced G-I and pelvic malignancies commonly
present with pain of varying severity. In a majority of these patients,
pain can be managed using an integrated systemic pharmacological
approach with oral morphine being the cornerstone of treatment.
However, with escalating doses, intolerable side effects of oral
morphine may lead to patient dissatisfaction. When oral
pharmacotherapy fails to adequately address the issue of pain or leads
to insufferable side effects, neurolytic blocks of the sympathetic axis
945
are usually used for pain alleviation. As these blocks may reduce oral
analgesic requirement, a reevaluation of their timing is merited. This
article presents hospital-based in-patient palliative care unit
experience with early ultrasonography-guided neurolysis of celiac
plexus, superior hypogastric plexus and ganglion impar. Of the 44
patients studied, 20 underwent celiac plexus neurolysis, 18 superior
hypogastric plexus neurolysis, and 6 ganglion impar neurolysis. Their
pain was being managed with oral morphine before neurolysis, but
only 11.4% patients required oral morphine for satisfactory pain
control, 2 months after neurolysis. The mean VAS score before block
placement was 5.64 ± 0.69 and fell to 2.25 ± 1.33 at 2 months post
neurolysis (p<0.001). In conclusion, bedside ultrasonography-guided
sympathetic axis neurolysis may be employed early in patients with
incurable abdominal or pelvic cancer (14).
Pancreatic carcinoma, an important leading cause of cancer death,
has increased steadily in incidence and still has a poor prognosis. Pain
is one of the most frequent symptoms, affecting more than 75% of
patients. It is often present in the early stages of disease and is severe
and difficult to treat. Abdominal viscera, including pancreas, liver,
gallbladder, adrenal, kidney, and the G-I tract from the level of the
gastroesophageal junction to the splenic flexure of the colon are
innervated, at least in part, via the celiac plexus. Thus, painful tumors
in these viscera may have pain relieved through the use of a neurolytic
celiac plexus block. Neurolytic celiac plexus block represents the
optimal treatment, especially for pancreatic cancer pain (15).
Abdominal pain in patients with pancreatic cancer is a common
symptom that is often difficult to manage. Opioids are frequently used
in an attempt to mitigate pain; however, side effects may develop.
Celiac plexus neurolysis affords effective pain control in patients with
pancreatic cancer and is not associated with opioid side effects.
Endoscopic ultrasonography-guided celiac plexus neurolysis has
demonstrated safety and efficacy due to real-time imaging and
anterior access to the celiac plexus from the posterior gastric wall,
thereby avoiding complications related to the puncture of spinal
nerves, arteries and the diaphragm, and is practiced widely.
Furthermore, 2 new techniques of endoscopic ultrasonography-guided
neurolysis for abdominal pain management in pancreatic cancer
patients have recently been developed. The first technique is
endoscopic ultrasonography-guided celiac ganglia neurolysis in which
endoscopic ultrasonography facilitates celiac ganglia neurolysis by
enabling direct injection into the individual celiac ganglion, and the
946
second technique is endoscopic ultrasonography-guided broad plexus

neurolysis which extends over the superior mesenteric artery (16).
References
1. Arter OE, Racz GB. Pain management of the oncologic patient. Semin
Surg Oncol. 1990;6(3):162-72.
2. Koyyalagunta D, Burton AB. The role of chemical neurolysis in cancer
pain. Curr Pain Headache Rep. 2010;14(4):261-7.
3. Kongsgaard UE, Bjørgo S, Hauser M. Neurolytic blocks for cancer pain -
still a useful therapeutic strategy. Tidsskr Nor Laegeforen. 2004;124(4):481-3.
4. Eisenberg E, Carr DB, Chalmers TC. Neurolytic celiac plexus block for
treatment of cancer pain: a meta-analysis. Anesth Analg. 1995;80:290–95.
5. Bahn BM, Erdek MA. Celiac plexus block and neurolysis for pancreatic
cancer. Curr Pain Headache Rep. 2013;17(2):310.
6. de Leon-Casasola OA, Kent E, Lema MJ. Neurolytic superior hypogastric
plexus block for chronic pelvic pain associated with cancer pain. Pain.
1993;54:145–51.
7. Plancarte R, de Leon-Casasola OA, El-Helay M, et al. Neurolytic superior
hypogastric plexus block for chronic pelvic pain associated with cancer. Reg
Anesth. 1997;22:562–68.
Availability and implications of different treatment options. Ther Clin Risk
Manag. 2007;3(3):381–400.
9. Miguel R. Interventional treatment of cancer pain: the fourth step in the
World Health Organization analgesic ladder? Cancer Control. 2000;7:149-56.
10. Mercadante S. Neuraxial techniques for cancer pain: an opinion about
unresolved therapeutic dilemmas. Reg Anesth Pain Med. 1999b;24:74–83.
11. Kedlaya D, Reynolds L, Waldman S. Epidural and intrathecal analgesia
for cancer pain. Best Pract Res Clin Anaesthesiol. 2002;16:651–65.
12. Jackson TP, Gaeta R. Neurolytic blocks revisited. Curr Pain Headache
Rep. 2008;12(1):7-13.
13. de Leon-Casasola OA. Critical evaluation of chemical neurolysis of the
sympathetic axis for cancer pain. Cancer Control. 2000;7(2):142-8.
14. Bhatnagar S, Khanna S, Roshni S, et al. Early ultrasound-guided
neurolysis for pain management in gastrointestinal and pelvic malignancies: an
observational study in a tertiary care center of urban India. Pain Pract.
2012;12(1):23-32.
15. Polati E, Luzzani A, Schweiger V, et al. The role of neurolytic celiac
plexus block in the treatment of pancreatic cancer pain. Transplant Proc.
2008;40(4):1200-4.
16. Sakamoto H, Kitano M, Komaki T, et al. Endoscopic ultrasound-guided
neurolysis in pancreatic cancer. Pancreatology. 2011;11 Suppl 2:52-8.
947
INVASIVE STIMULATION THERAPIES
SCS has been used in the treatment of chronic pain for more than
40 years. The most common indication for SCS in the US is failed
back surgery syndrome. The first 2 spinal cord stimulators ever
implanted were in patients suffering from bronchogenic carcinoma
and pelvic cancer, respectively. While cancer accounts for millions of
deaths each year in the US, pain is often the first sign of malignancy.
An increasing number of people suffer from cancer-related pain each
year and many receive suboptimal relief. Given the demonstrated
value of SCS in the treatment of neuropathic pain, SCS should be
considered "earlier" as an adjunct to the treatment of cancer-related
pain. In addition, with the improving survival rates associated with
advances in cancer treatment, SCS may help reduce the risk of
development of chronic neuropathic pain in survivors (1).
Of chronic cancer pain patients, 15-40% has a neuropathic
component, and this type of pain often responds poorly to opioids. In
an attempt to provide increased pain relief for patients with intractable
cancer pain, unconventional agents and interventional management
approaches have received considerable attention. SCS has been used
with increased frequency for the treatment of intractable cancer pain.
The patients with a history of cancer-related chest wall pain
underwent an uneventful SCS trial with percutaneous placement of 2
temporary 8-electrode leads (Medtronic Inc, Minneapolis, Minnesota)
placed at the level of T3-T4-T5. After experiencing excellent pain
relief over the next 2 days, the patients were implanted with
permanent leads and rechargeable generator 2 to 2 ½ weeks later and
reported sustained pain relief at 12-month follow-up visit. In
conclusion, SCS provides an effective, alternative treatment option for
selected patients with cancer-related chest wall pain who have failed
conservative treatment. SCS may provide pain relief with advantages
over conservative treatments and more invasive techniques (2).
Nearly 6,750,000 people suffer moderate to severe cancer-related
pain each year. Unfortunately, 10-15% of these patients fail to achieve
acceptable pain relief with conventional management. SCS has been
used with increased frequency for successful treatment of intractable
cancer pain. Two cases of intractable, refractory-to-conventional
treatment cancer pain were successfully treated with SCS. Case 1
reports a 51-year-old male with burning pain at the left groin site of
inguinal metastases, post-surgical and intraoperative RT for treatment
of squamous cell carcinoma of the anus. Case 2 reports a 43-year-old
woman with intractable, burning, throbbing, and shooting pain, post-
948
debulking followed by radiation of a metastatic colon carcinoma. In

both cases, SCS implantation provided 90-100% pain relief, improved
functioning and sleep, and discontinuation of pain medications,
sustained through 12 months (3).
Two patients with chemotherapy-induced painful neuropathy that
had been poorly controlled with medications but was successfully
treated with SCS. A trial period of SCS provided effective pain relief
in both patients who subsequently underwent permanent stimulator
implantation. Psychophysical tests were performed before and after
the implantation of trial and permanent stimulators. SCS improved
pain scores and facilitated a reduction of medications. Both patients
reported improved gait and one of them reported an increase in leg
flexibility. Psychophysical tests demonstrated an improvement in
touch and sharpness detection thresholds. In summary, SCS offers a
therapeutic option for patients with CIPN who have poor pain relief
with standard medical treatment (4).
Spinal cord stimulation
A 76-year-old man was referred to the pain clinic for the treatment
of bilateral lower extremity pain due to metastasis of RCC to the
sacrum. The pain could not be controlled with narcotics,
antidepressant or the epidural block. The characteristics of pain were
like those of benign disease, being spontaneous, not exacerbated by
body movement, and having a dysesthetic nature with chill sensations.
Therefore, SCS was performed, relieving the pain until death, 6
months after its induction. This case shows the usefulness of SCS for
neuropathic cancer pain that shows signs similar to those of benign
disease (5).
Surgery is the mainstay of therapy for resectable-type tumors
associated with non-small-cell lung cancer. Today, thoracotomy and
video-assisted thoracotomy are surgical options. The prevalence of
chronic pain with neuropathic symptoms is relatively high after
thoracotomy. The aim of this article is to report on the use of SCS in a
single case of neuralgia after thoracotomy with lobectomy to treat
949
NSCLC. At 24 months after implantation of the SCS system, the

patient reported > 75% pain relief, an overall improvement in QOL
described as less pain with breathing, and improved functional ability
pertaining to arm movements-and improved sleep patterns. This
detailed case presentation provides a qualitatively weighted
investigation into SCS for postthoracotomy neuralgia against the
backdrop of oncologic care. Further investigations relying on
quantitative assessment tools are necessary to further explore this
form of therapy in this patient population. In the single case reported
here, the use of SCS suppressed intractable pain targeted at the T6 and
T7 dermatomes of the chest wall in the manifestation of
postthoracotomy neuralgia (6).
At least one third of patients with cancer have pain at the time of
their diagnosis. In an attempt to provide increased pain relief for
patients with intractable cancer pain, unconventional agents and
interventional procedures including SCS have received considerable
attention. Patients with cancer-related LBP underwent an uneventful
SCS trial with percutaneous placement of 2 temporary 8-electrode
leads placed at the level of T8-T9-T10. After experiencing excellent
pain relief during the 2-day trial, patients were subsequently implanted
with permanent leads and generator with sustained pain relief at 12
months postoperation. SCS provides an effective, alternative treatment
option for select patients with cancer-related pain who have failed
conservative treatment (7).
Seventeen patients with intractable pain due to progressive
malignancies were treated by electrical stimulation of the brain after
more conventional pain therapies applied in Los Angeles Cancer Pain
Clinic had failed. Electrodes were stereotactically implanted under
local anesthesia in the periaqueductal grey or periventricular grey in
11 patients. In 6 patients, electrodes were placed in both
periaqueductal grey- periventricular grey targets and in the sensory
thalamic nuclei. Thirteen of the 17 patients achieved virtually total
pain relief and 2 others achieved partial pain relief. At the hospital
discharge only 4 of 17 patients required narcotic analgesics for pain
relief. Follow-up periods ranged from 1 to 21 months and 6 patients
remain alive, 14 patients eventually required narcotics for pain relief,
usually in the terminal few weeks of their lives. Pain relief was
achieved in spite of the fact that all patients were tolerant to large
doses of systematically or intraspinally administered narcotics at the
time of electrode placement. No complications related to brain
stimulation were identified. In conclusion, brain stimulation is a safe
950
and effective method for treatment of intractable pain due to

malignancy in certain patients (8).
Deep Brain Stimulation
The objective of this study was to analyze the long-term outcomes

and to clarify patient selection criteria for DBS. During the past 15
years, 68 patients were followed with chronic pain syndromes who
underwent DBS. Patients were referred from a multidisciplinary pain
clinic after conservative treatment failed. Electrodes for DBS were
implanted within the periventricular gray matter, specific sensory
thalamic nuclei, or the internal capsule. Each patient was followed on
a 6-monthly follow-up basis and evaluated with a modified VAS.
Follow-up periods ranged from 6 months to 15 years, with an average
follow-up period of 78 months. The mean age of the 54 men and 14
women in the study was 51.3 years. Indications for DBS included 43
patients with failed back syndrome, 6 with peripheral neuropathy or
radiculopathy, 5 with thalamic pain, 4 with trigeminal neuropathy, 3
with traumatic spinal cord lesions, 2 with causalgic pain, 1 with
phantom limb pain, and 1 with carcinoma pain. After initial screening,
53 of 68 patients (77%) elected internalization of their devices; 42 of
the 53 (79%) continue to receive adequate relief of pain. Therefore,
effective pain control was achieved in 42 of 68 of referred patients
(62%). Patients with failed back syndrome, trigeminal neuropathy,
and peripheral neuropathy fared well with DBS, whereas those with
thalamic pain, SCI, and postherpetic neuralgia did poorly. In
conclusion, DBS in selected patients provides long-term effective pain
control with few side effects or complications (9).
DBS with chronically implanted electrodes has provided
satisfactory control of pain in patients with intractable chronic pain
syndromes, which have been refractory to medication and other
conventional modalities of management. In this series, 48 patients
were followed for periods ranging from 6 months to 10 years. Long-
term pain control was achieved in 30 patients (63%). Both the
951
periventricular gray and specific sensory thalamic nuclei have been

used as targets. The results indicate that there is an initial 2-year fall-
off of pain control caused by idiopathic tolerance, with stable results
thereafter, regardless of site of the implant. This is suggestive of some
biochemical modification of tissues around the electrode. Patients
with failed-back syndrome secondary to multiple disc operations fared
well; those with pain secondary to progressive neurological disorders
or cancer had only short-term pain relief, and those with thalamic
pain, cauda equina injury, or phantom limb pain usually had a poor
result. DBS, in selected patients, appears to provide long-term pain
control safely with few side effects or complications (10).
References
1. Flagg A 2nd, McGreevy K, Williams K. Spinal cord stimulation in the
treatment of cancer-related pain: "back to the origins". Curr Pain Headache Rep.
2012;16(4):343-9.
2. Yakovlev AE, Resch BE, Karasev SA. Treatment of cancer-related chest wall
pain using spinal cord stimulation. Am J Hosp Palliat Care. 2010; 27(8):552-6.
3. Yakovlev AE, Ellias Y. Spinal cord stimulation as a treatment option for
intractable neuropathic cancer pain. Clin Med Res. 2008;6(3-4):103-6.
4. Cata JP, Cordella JV, Burton AW, et al. Spinal cord stimulation relieves
chemotherapy-induced pain: a clinical case report. J Pain Symptom Manage.
2004;27(1):72-8.
5. Tsubota S, Higaki N, Nagaro T. A case of neuropathic cancer pain in the lower
extremities successfully treated with spinal cord stimulation. Masui.
2009;58(11):1460-1.
6. Wininger KL, Bester ML, Deshpande KK. Spinal cord stimulation to treat
postthoracotomy neuralgia: non-small-cell lung cancer: a case report. Pain Manag
Nurs. 2012;13(1):52-9.
7. Yakovlev AE, Resch BE. Spinal cord stimulation for cancer-related low back
pain. Am J Hosp Palliat Care. 2012;29(2):93-7.
8. Young RF, Brechner T. Electrical stimulation of the brain for relief of
intractable pain due to cancer. Cancer. 1986;57(6):1266-72.
9. Kumar K, Toth C, Nath RK. Deep Brain Stimulation for Intractable Pain: A 15-
Year Experience. Neurosurgery. 1997;40:736-47.
10. Kumar K, Wyant GM, Nath R. Deep brain stimulation for control of
intractable pain in humans, present and future: a ten-year follow-up. Neurosurgery.
1990;26(5):774-81; discussion 781-2.
952
EPIDURAL ANALGESIA
The charts of patients who received epidural analgesia for over 5
years for the control of terminal cancer pain were reviewed
retrospectively. Ninety-six patients received 127 epidural catheters.
The mean duration for epidural catheterization was 31.5 ± 55.6 (5-
509) days. The dose of epidural morphine increased by 3.5% per day.
The efficacy of epidural analgesia at 2 weeks follow up revealed
improved pain control (n=56), as the morphine equivalent drug dose
dropped from 213.4 mg/day to 94.1 mg/day (p<0.05) at 2 weeks
follow up. Accordingly, after 2 weeks institution of epidural analgesia,
there was a significant reduction in the proportion of patients with
severe pain, from 78.1% to 19.6% (p<0.05). In conclusion, epidural
analgesia was an effective pain control method in patients with
terminal cancer pain, however, a systematized algorithm for the
control of cancer-related pain in needed (1).
Epidural opiates were administered to 139 patients with pain due to
malignant diseases via a chronic indwelling catheter inserted
percutaneously. So far, 9,716 days of treatment can be evaluated. In
87% of the patients whose pain previously could not be controlled
with conventional analgesic approaches, epidural opiates resulted in
remarkable pain relief. With a mean daily dose of 15.6 mg morphine
(range 2-290 mg) or 0.86 mg buprenorphine (range 0.15-7.2 mg) half
of the patients could be treated as outpatients. The mean duration of
therapy was 72 days (range 1-700 days), 26 catheters being in place
for more than 100 days and 1 catheter being in place for 510 days.
Severe side effects (meningitis) were observed in both patients being
free of symptoms after catheter removal and antibiotic therapy.
Epidural opiates proved to be a valuable method of pain control in
terminal illness. The method should be reserved for those patients, for
whom oral opiates fail to produce effective pain relief (2).
A patient receives an epidural, which is a shot of painkiller injected into

the body's spinal fluid.
953
In a population of 1205 cancer patients, the aggressive use of

systemic opiates limited the trial of epidural analgesia to 16 cases.
Successful analgesia was achieved with epidural morphine alone in 6
of these 16 cases following systemic opiate failure. The addition of
bupivacaine produced analgesia in all of the 10 remaining cases and
was successful chronically in 6 cases. Complications occurred in 11 of
the 16 cases of epidural analgesia and included dislodged or broken
catheters, pain on injection, hyperesthesia from epidural morphine and
bleeding or infection related to the epidural catheter. Epidural
morphine is indicated in selected cancer pain patients and, although
bupivacaine extends the efficacy of epidural analgesia, these methods
are accompanied by problems and limitations (3).
The long-term analgesic effects and the complications of epidural
narcotic analgesia were investigated in 40 cancer patients in whom
systemic narcotic therapy failed to relieve pain or caused unacceptable
side effects. In 32 patients, an externally fixated polyamide epidural
catheter was used ("external group"), and in 8 patients, a polyurethane
epidural catheter was tunneled and connected to a subcutaneous
access port ("internal group"). The average duration of catheter
treatment was 80.9 days (range 9-533 days). Twenty-five patients
were treated as outpatients, and 15 remained hospitalized. Initially, all
patients had significant or complete pain relief from 10 mg
morphine/day, but the daily epidural morphine requirement showed a
threefold increase during the first 3 weeks. During epidural narcotic
analgesia, other methods of pain relief (RT, chemotherapy, surgery,
epidural administration of local anesthetics and nerve blocks) were
necessary in 14 patients. Pharmacological side effects were of minor
importance, with transient pruritus being the main subjective
complaint. In the "external" group, 31 catheter replacements were
necessary, mostly due to backflow of injected morphine outside the
catheter. In 2 patients of the internal group, neurological
complications occurred, but these disappeared spontaneously after
removal of the system. They were presumably due to epidural fibrosis
with compression of the spinal cord (4).
The main objective of this study was to examine analgesia and AEs
of combination epidural pain therapy consisting of administration of
morphine with either low dose of ketamine, neostigmine, or
midazolam in terminal cancer pain patients. A randomized double-
blind study was carried out at teaching hospital, involving 48 terminal
cancer patients suffering from chronic pain. Patients were randomized
to one of 4 groups (n=12). The concept of VAS, which consisted of a
10-cm line with 0 equaling "no pain at all" and 10 equaling "the worst
954
possible pain" was introduced. All patients were taking oral

amitriptyline 50 mg at bedtime. Pain was initially treated with
epidural morphine 2 mg twice daily (12-hour intervals) to maintain the
VAS below 4/10. Afterwards, VAS scores ≥ 4/10 at any time were
treated by adding the epidural study drug (2 ml), which was
administered each morning, just after the 2-mg epidural morphine
administration. The control group received 2 mg of epidural morphine
(2 ml). The ketamine group received 0.2 mg/kg epidural ketamine (2
ml). The neostigmine group received 100 micrograms epidural
neostigmine (2 ml). The midazolam group received 500 micrograms
epidural midazolam (2 ml). Patients received the study drugs on a
daily basis. Only the patients in the ketamine group demonstrated
lower VAS scores compared to the midazolam group (p=0.018). Time
since the epidural study drug administration until patient complaint of
pain VAS ≥ 4/10 was higher for both the ketamine group and
neostigmine group compared to the control group (ketamine group >
control group, p=0.049; neostigmine group > control group,
p=0.0163). Only the ketamine group used less epidural morphine
compared to the control group during the period of study (25 days)
(p=0.003). In conclusion, the association of either low-dose epidural
ketamine or neostigmine (but not midazolam) to epidural morphine
increased the duration of analgesia in the population studied (20 days)
compared to the control group and midazolam group (8 to 10 days)
when administered in the early stages of terminal cancer pain therapy,
without increasing the incidence of AEs (5).
When an effective pain relief cannot be achieved by systemic
administration of analgesics, which provide adequate pain relief for up
to 70-90% of patients, alternative remedies should be offered. A
patient with colon cancer was controlled effectively for pain using an
epidural catheter with subcutaneous reservoir (epidural subcutaneous
catheter implantation). Four other patients with an epidural catheter
with subcutaneous reservoir during 2007 to 2008 showed significant
improvement in their pain level calculating by NRS. The epidural
catheter with subcutaneous reservoir should be needed not only to
manage dosages of epidural morphine accurately but also to prevent
the incidence of catheter obstruction by general practitioners in home
care service. This solution is necessary to establish the common strict
guidelines between hospital doctors and general practitioners (6).
This study was designed to evaluate the role of epidural
methadone-lidocaine in cancer pain combined or not to epidural
dexamethasone. All 72 cancer patients, 32- to 67-year-old were
randomized to 6 groups (n=12) and prospectively studied to examine
955
analgesia and AEs for 3 weeks. Patients received single-dose protocol

epidural test drugs: Control group (CG) received epidural 40-mg
lidocaine diluted to 10-ml volume with saline. Dexamethasone group
(DG) 40-mg lidocaine plus 10-mg dexamethasone. The 2.5MetG 2.5-
mg epidural methadone with 40-mg lidocaine; the 5MetG, 5-mg
epidural methadone plus 40-mg lidocaine, the 7.5MetG, 7.5-mg
epidural methadone plus 40-mg lidocaine and finally the 7.5Met-
DexG, 7.5-mg methadone with 40-mg lidocaine and 10-mg
dexamethasone. Groups CG, DG and 2.5MetG were similar regarding
analgesia and side effects. Patients from 5MetG and 7.5MetG took 3 ±
1 and 5 ± 1 days, respectively, to restart oral morphine. Patients from
7.5MetDG took 14 ± 2 to restart oral morphine (p<0.001). Daily
somnolence and appetite improved in the 7.5MetDG during 2-week
evaluation (p<0.005). Fatigue improved for both DG and 7.5MetDG
during 2-week evaluation (p<0.005). By the third week of evaluation,
all patients were similar. In conclusion, epidural methadone plus
lidocaine resulted in dose-dependent analgesia, further improved by
epidural dexamethasone, which also improved fatigue (7).
References
1. Jeon YS, Lee JA, Choi JW, et al. Efficacy of epidural analgesia in patients with
cancer pain: a retrospective observational study. Yonsei Med J. 2012;53(3):649-53.
2. Zenz M, Piepenbrock S, Tryba M. Epidural opiates: long-term experiences in
cancer pain. Klin Wochenschr. 1985;63(5):225-9.
3. Hogan Q, Haddox JD, Abram S, et al. Epidural opiates and local anesthetics for
the management of cancer pain. Pain. 1991;46(3):271-9.
4. Driessen JJ, de Mulder PH, Claessen JJ, et al. Epidural administration of
morphine for control of cancer pain: long-term efficacy and complications. Clin J
Pain. 1989;5(3):217-22.
5. Lauretti GR, Gomes JM, Reis MP, Pereira NL. Low doses of epidural ketamine
or neostigmine, but not midazolam, improve morphine analgesia in epidural terminal
cancer pain therapy. J Clin Anesth. 1999;11(8):663-8.
6. Mezawa H, Inoue D, Nagasaki E, et al. Usefulness of epidural catheter with
distal SCreservoir for cancer pain control in home care services. Gan To Kagaku
Ryoho. 2008;35 Suppl 1:22-4.
7. Lauretti GR, Rizzo CC, Mattos AL, Rodrigues SW. Epidural methadone results
in dose-dependent analgesia in cancer pain, further enhanced by epidural
dexamethasone. Br J Cancer. 2013;108(2):259-64.
956
INTRATHECAL NEUROLYTIC BLOCKS

Intrathecal neurolytic blocks for the treatment of chronic pain were
first described by Dogliotti in 1931. Since then, many authors have
described the intrathecal injection of various neurolytic substances for
the treatment of oncologic pain. In recent years, alcohol and phenol
have been the substances most commonly used for this purpose. Four
cases of cancer patients whose intractable pain was treated by using
intrathecal neurolysis (1).
Intrathecal analgesia is an interventional form of pain relief with
definite advantages and multiple complications. Administration of
intrathecal analgesia needs a good resource setting and expertise.
Early complications of intrathecal analgesia can be very distressing
and managing these complications will need a high degree of
knowledge, technical expertise and level of experience. Pain control
alone cannot be the marker of quality in palliative care. A holistic
approach may need to be employed that is more person and family
oriented (2).
The use of intrathecal analgesics is an important treatment
consideration for many patients with chronic cancer pain. The various
opioid and nonopioid analgesics have been used in this setting,
including morphine, hydromorphone, fentanyl, meperidine,
methadone, sufentanil, local anesthetics, clonidine, ketamine,
baclofen, midazolam, betamethasone, and octreotide, bupivacaine,
clonidine, baclofen, and ziconotide (3,4).
Chemical neuromodulation has become widely accepted in the
treatment of cancer pain. Intrathecal opioids (such as morphine and
hydromorphone) given alone or in combination with adjuvant
medications (alpha-adrenergic agonists, e.g., clonidine, or local
anesthetics, e.g., bupivacaine) are commonly used for medically
intractable cancer pain (5,6). Although these agents may be delivered
via variety of catheters and ports, most accepted practice consists of
the implantation of a self-contained pump that delivers medication at a
specific rate into the subarachnoid space via a dedicated intrathecal
catheter (7). Intrathecal administration of opioids is an option for
those patients whose effective systemic dose cannot be tolerated due
to presence of unacceptable side effects or whose pain is refractory to
conventional therapy. Intrathecal infusion bypasses the blood-brain
barrier and results in much higher CSF concentrations with less
medication. Compared with the epidural route, intrathecal infusion is
associated with higher rates of satisfactory pain relief and lower rates
of treatment failure and technical complications (8).
957
Between 10-20% of cancer pain patients fail to obtain adequate

pain relief despite comprehensive medical management. The totally
implantable programmable IDDS is an attractive option for managing
refractory cancer pain. In suitable patients, IDDS can provide reliable
long-term analgesia without any permanent nerve or plexus
destruction. IDDS can also allow patient care on an outpatient basis.
This retrospective study, describes experience of managing totally
implantable programmable IDDS in 6 refractory cancer pain patients
including patient selection, intraspinal morphine trial, surgical
techniques, complications, and drug adjustment in Taiwan. Pain
scores and functional status were compared before and after IDDS.
By delivering liberal dose of intrathecal morphine, patients' pain
scores decreased from 10 to 3.5. Due to much better pain control and
improved QOL, Eastern Cooperative Oncology Group performance
status also improved in 4/6 patients. During the mean 5 ± 4.1 months
of follow-up, 2 patients experienced pocket seroma, and resolved
spontaneously after short-term abdominal binder compression.
Otherwise, no serious complication was noted. In conclusion,
intrathecal morphine delivery by using totally implantable
programmable IDDS is an effective method to relieve refractory
cancer pain (9).
Morphine has been extensively studied intrathecally for patients
with cancer and was more effective in relieving nociceptive pain
versus neuropathic pain (10). One multicenter, randomized clinical
trial demonstrated that patients with refractory cancer pain are more
effectively treated with addition of implantable IDDS to a
comprehensive medical management (5). In this study, the patients
who received intrathecal morphine infusion had significantly better
pain relief at 4 weeks than patients treated by conventional
medications alone. In addition, the toxicity scores representing the
cumulative analysis of combined side effects from the treatment were
reduced by 50% in intrathecal pump group. Patients with implanted
IDDS had significant reduction of fatigue and depressed
consciousness, as well as improved rate of survival at 6 months (5).
Several other clinical studies (retrospective, as well as prospective,
randomized multicenter trials) have shown that addition of intrathecal
opioid administration through programmable IDDS can significantly
increase pain control, reduce toxicities, and improve overall survival
and QOL in cancer patients with refractory pain (6,11,12).
An intrathecal pump can be implanted into the subcutaneous fat of
the abdomen to provide a continuous infusion of medications. The
older pumps had preset infusion rates (continuous flow pumps);
958
therefore, each dose adjustment had to be done by changing the

concentration of the drug inside the pump. More commonly used
programmable pumps contain an electronic module that allows
adjustment of the drug infusion rate using telemetry programming. All
pumps have to be refilled at regular time intervals, but patients usually
tolerate these refills quite well as they are done every 1 to 3 months in
office or clinic settings by simple insertion of the needle into the
center of the reservoir through the skin. The most common side effects
of intrathecal opioid therapy are nausea and vomiting, and the most
frequent complications include infection or hematoma at the surgical
site (13).
Hydromorphone is one of the first alternatives to consider for
intrathecal administration when morphine therapy becomes not
suitable for any reason. Fentanyl has been also tried intrathecally,
however, due to low solubility in CSF it does not dissipate far from
the site of injection, therefore is not widely used for cancer pain
treatment (14).
Clonidine and bupivacaine are the most commonly used nonopioid
medications for intrathecal administration in cancer patients. They are
both used in combination with morphine to amplify its analgesic
effect. Clonidine produces analgesia by its action on alpha-2 receptors
on presynaptic primary afferents and postsynaptic dorsal horn neurons
of the spinal cord, which causes a decrease in the release of C-fiber
neurotransmitters (e.g., SP) and inhibition of preganglionic
sympathetic transmission (15). Clonidine can produce marked
bradycardia, orthostatic hypotension, and sedation at higher doses and
should be used cautiously.
GABAB agonist baclofen can be used in cancer patients with
associated sever spasticity and/or dystonia (16). When administered
intrathecally, baclofen inhibits both monosynaptic and postsynaptic
reflexes at the spinal level and produces muscle relaxation. In
addition, doses ranging 3–20 μg/hr have been shown to be effective in
a variety of neuropathic pain syndromes through unclear yet
mechanism (17). Sedation, hypotonia with weakness, and urinary
retention are some of the side effects of intrathecal baclofen therapy.
Abrupt discontinuation of intrathecal baclofen, regardless of the cause,
can be life-threatening, and may result in high fever, altered mental
status, exaggerated rebound spasticity, and even rhabdomyolysis,
multiple organ-system failure and death (18-20).
A 60-year-old man had recurrent sigmoid cancer and metastases to
the lumbar (L4-5) and sacral bones. He complained of refractory pain
in the lower back and lower extremities despite high-dose opioid
959
treatment based on the WHO ladder. On admission to the hospital, he

received continuous intravenous infusion of morphine (7,000 mg/day)
with ketamine (300 mg/day) and lidocaine (700 mg/day). Intravenous
midazolam was required to treat extreme anxiety. Because of
inadequate pain relief and severe drowsiness, intrathecal phenol-
glycerol neurolytic block was performed twice at the L2/3
intervertebral space. His analgesia was greatly improved and high-
dose intravenous opioid was retitrated and ceased. He remained
comfortable and lucid at home for 2 months, until 2 days before his
death at hospital. Intrathecal neurolytic block may be appropriate for
some patients suffering from refractory pain that is resistant to
conventional opioid analgesic treatment (21).
Indications for the use of spinal opioids in advanced cancer pain
include patients treated by systemic opioids with effective pain relief
but with unacceptable side effects, or unsuccessful treatment with
sequential strong opioid drug trials despite escalating doses.
Therefore, the previous aggressive treatment with systemic opioids
would leave as failures patients with difficult pain syndromes
unresponsive to opioids. The choice of external or totally implanted
delivery systems is based on different clinical considerations. The use
of externalized tunneled intrathecal catheters has not been associated
with higher rates of complications and is easier to place and use at
home in debilitated patients late in the course of their disease. The
intrathecal administration has a lower incidence of catheter occlusion,
lower malfunctioning rate, lower dose requirement, and more effective
pain control. Due to the lower daily doses and volumes, intrathecal
treatment proved to be more suitable for treatment at home by a
continuous infusion than the epidural treatment. Advantages of
infusion techniques are more evident when using local anesthetics,
since intermittent administration of bupivacaine often results in motor
paralysis and hemodynamic instability. Morphine is the opioid of
choice. An epidural dose of 10% of the systemic dose is often used.
However, intrathecal administration of opioids and bupivacaine may
substantially improve pain relief in patients unresponsive to high
epidural doses of these drugs, Bupivacaine-induced AEs, including
sensory deficits, motor complaints, signs of autonomic dysfunction or
neurotoxicity have been reported to not occur with bupivacaine doses
less than 30-60 mg/day. Adjuvant drugs may further improve
analgesia. Different ranges of technical complication rates have been
reported, most of them being associated with epidural catheters.
Subcutaneous tunneling and fixation of the catheter, bacterial filters,
minimum changes of tubings, careful exit site care weekly, site
960
protection and monitoring of signs of infection, and training for family

under supervision, are recommended (22).
The control of severe cancer pain may be problematic despite
advances in pain management. Patients with severe intractable pain
and/or intractable side effects may require aggressive interventional
pain management strategies including the administration of
medications by the continuous intrathecal route and/or neurosurgical
procedures. Various medications, including opioids, local anesthetics,
and alpha-2 agonists may be used intrathecally for the control of
cancer pain. Failure of the intrathecal route may require the additional
use of neurosurgical procedures such as cordotomy for pain control. A
case of severe cancer pain refractory to conventional intrathecal
medications and cordotomy that was successfully managed by the
addition of meperidine to the intrathecal regimen is described (23).
Several years ago, Elan Pharmaceuticals introduced a new
analgesic drug, ziconotide, which has been recently approved by FDA
for intrathecal treatment of persistent neuropathic pain in the US.
Ziconotide binds to specific N-type voltage-sensitive calcium
channels found in neural tissue and acts by blocking neurotransmitter
release from primary nociceptive afferents terminating in the
superficial layers of the dorsal horn of the spinal cord (24,25). This
mechanism of action distinguishes ziconotide from all other
analgesics, including opioids. In fact, ziconotide is potently
antinociceptive in animal models in which morphine exhibits poor
anti-nociceptive activity (26). The results from few multicenter
randomized, double-blind, placebo-controlled trials showed that
intrathecal ziconotide provided clinically and statistically significant
analgesia in patients with severe pain from cancer or AIDS (27,28).
However, although the safety of ziconotide administered as a
continuous intrathecal infusion has been evaluated in over 1000
patients participating in acute and chronic pain clinical trials, lack of
long-term prospective studies and high incidence of dose-dependent
AEs during the initial titration stage of continuous intrathecal infusion
of ziconotide currently limit its use as a drug of first choice even in
patients with advanced cancer who fail the traditional methods of pain
control (29-31).
Benefits of intrathecal pumps are obvious: due to drug delivery
route, equianalgesic effect may be reached at doses about 100 times
lower than with systemic administration, which significantly decreases
the dose-related side effects of opioid medications; the patient does
not have to think about constant need to have the oral medication
available (with associated reduction of risks related to abuse and
961
mishandling of opioids); continuous drug delivery eliminates

fluctuations in the drug level that are inevitable with bolus oral or
parenteral dosing (32). Chemical neuromodulation is both adjustable
and reversible, so the side effects of the treatment may be minimized
by either changing the rate of infusion or drug composition, or by
stopping the therapy altogether without any lasting consequences. The
treatment is also testable; the patient and the caregiver may estimate
the degree of pain relief from the results of a pre-surgical medication
trial (12). At the same time, implantable devices are associated with
higher upfront costs related to the procedure and the device itself,
potential risk for infection and hardware malfunction, need for general
anesthesia for system implantation, and similar procedural
contraindications (coagulopathy, active systemic infection, etc.) as
with any other surgical intervention (12).
Besides AEs that are related directly to intrathecal administration
of medications, there are not many serious complications reported for
IDDS implantation itself. Some of the common complications are
infection, including few reports of associated meningitis, granuloma
formation at the tip of the subarachnoid catheter, bleeding or
hematoma at the site of the surgery, and malfunctioning of the device.
All hardware-related complications are fully reversible without
serious consequences and usually easily treated by either surgical
revision of the IDDS or complete removal of the device. Another
consideration that may affect the decision to proceed with permanent
implantation of IDDS could be the cost of the hardware and related
expenses, which may be noteworthy. However, several studies
showed overall cost-saving benefit of this modality vs., for example,
externalized epidural catheter in the treatment of intractable cancer
pain when patients have estimated life expectancy of at least 3 to 4
months (33-35). Therefore, hard-to-control cancer pain in patients
with more than 3 months survival is a well-founded indication for
intrathecal drug delivery pump implantation when all conventional
medical treatment regimens fail (12).
The aim of this study was to evaluate the clinical response to a
combination of intrathecal morphine and levobupivacaine in advanced
cancer patients who were highly opioid-tolerant, being previously
treated with multiple opioid trials unsuccessfully. Initial intrathecal
morphine dose was calculated from the previous opioid consumption
using a morphine oral-intrathecal ratio of 100:1. Then, doses of both
drugs were modified during the treatment according to the clinical
needs and balanced with AEs. Fifty-five patients were assessed during
admission, before starting the intrathecal treatment, during the titration
962
phase, and followed up to death, by frequent phone contacts or visits,

as available. Pain and symptom intensities were recorded before
starting the intrathecal treatment (T0), at time of hospital discharge (T
dis), and then at 1 month (T1), 3 months (T3), 6 months (T6)
intervals, and the last observation, at least 1 week before death (T
death). Fifty-five patients were selected for starting an intrathecal
treatment. Thirty-two patients were males. The mean age was 60 years
(95% CI 57-63), and 65.4% of patients were under 65 years. The most
frequent indication was the presence of AEs and poor pain control.
Complete data with adequate follow-up until death were available in
45 patients. Statistical decreases in the intensity of drowsiness and
confusion were until 1 month after starting intrathecal therapy.
Statistical differences were in daily intrathecal morphine doses, with a
3-fold increase at time of hospital discharge. Subsequently, further
increases in doses were insignificant. Conversely, systemic opioids,
expressed as oral morphine equivalents, significantly decreased at all
the intervals examined until death. Early complications included mild
bleeding in 2 patients, without consequences, headache in 4 patients,
bladder catheterization in 6 patients, reoperation for bleeding or
changes of catheter position in 4 patients, unrelated death in 1 patient,
and stroke in another 1. Late complications included local infection in
2 patients, and discontinuation of intrathecal therapy due to spinal
compression. In patients who had received multiple trial of opioids
and routes of administration, the intrathecal treatment started with an
oral-intrathecal morphine conversion ratio of 100:1, and local
anesthetics at the most convenient clinical doses provided a long-term
improvement of analgesia, with a decrease in AEs and opioid
consumption until death (36).
The present study is a qualitative exploration of the impact of
intrathecal pump implantation on cancer patients, and the impact of
the intervention on the staff caring for those patients. Palliative care
unit patients who received an implanted intrathecal pump or dome
catheter for intractable cancer pain participated in multiple
semistructured interviews. Doctors and nurses caring for each patient
were also interviewed. Interviews were recorded and analyzed for
themes. The study terminated when saturation was reached. Six
patients participated, with up to 3 interviews each. Twenty-four staff
interviews took place. Patients' hopes and expectations were not
always fully met, but the infusions had a profound positive effect on
QOL. Patients expressed anxiety about dependence on the device, and
on a few highly skilled individuals. Staff interviews revealed a
significant impact on the 'culture' of the palliative care unit. Clear
963
communication of the rationale for infusion was important, as was

regular education about infusion management. In conclusion, IDDSs
are a necessary part of a tertiary level cancer pain management service
for the unfortunate minority with intractable pain. Practical
recommendations for care are made for palliative care programs
contemplating offering intrathecal infusions (37).
Intrathecal drug delivery catheter.
In most patients, cancer pain is effectively treated with

conservative medical management consisting of oral and/or
transdermal analgesics. Cancer patients tend to fail conservative
medical management near the end of their life expectancy, thus
requiring alternative routes of analgesia such as intravenous, epidural,
or intrathecal. The intrathecal route provides the most effective
analgesia due to the close proximity of the opioid receptors in the
spinal cord. Though there are many techniques that exist for
intrathecal drug delivery, complications can limit effectiveness such
as infection, bleeding, CSF leaks, post-dural puncture headaches,
pump and/or catheter malfunctions, or limitations of technical
expertise. Therefore, an important goal in palliative cancer pain
therapy is to use equipment that is going to have the fewest number of
complications and will be the most familiar to the health care
providers. The combination of the Medtronic Indura 1P catheter,
which has the least catheter-related complications, can be used with
any external drug infusion pump is described. These are regular
infusion pumps that the health care workers are familiar with, so they
can provide excellent and efficient service to the patient. In an
operating room, the intrathecal catheter is placed using sterile
technique under fluoroscopic guidance. The epidural space is
identified with loss of resistance technique. Then the introducer needle
(supplied in the Indura 1P catheter kit) is advanced until free-flowing
964
CSF is obtained. The spinal catheter is advanced into the intrathecal

space through the introducer needle to lumbar 2-3 level. The catheter
is tunneled subcutaneously 10 cm lateral to the catheter exit site. A
syringe-filling device is inserted into the catheter opening and is
secured with silk suture. A luer lock syringe is attached to the syringe
filling device and CSF is aspirated. The syringe-filling device is
capped and later attached to an external drug infusion pump. It is the
successful use of the Medtronic Indura 1P, one piece intrathecal
catheter, connected with the external drug pump for a 3 week period
in a patient with metastatic cervical cancer. In conclusion, this
technique is simple to perform by pain specialists. The catheter
modification allows the use of the Medtronic intrathecal catheter with
standard external drug infusion pumps. This facilitates the patient's
care in the hospice setting (38).
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1995;35:707–34.
25. McGivern JG, McDonough SI. Voltage-gated calcium channels as targets for
the treatment of chronic pain. Curr Drug Targets CNS Neurol Disord. 2004;3:457-78.
26. Miljanich GP. Ziconotide: neuronal calcium channel blocker for treating
severe chronic pain. Curr Med Chem. 2004;11:3029-40.
27. Mathur V. Ziconotide: a new pharmacological class of drug for the
management of pain. Semin Anesth Periop Med Pain. 2000;19:67–75.
28. Staats PS, Yearwood T, Charapata S, et al. Intrathecal ziconotide in the
treatment of refractory pain in patients with cancer or AIDS. JAMA. 2004;291:63–70.
29. Webster L, Henderson R, Katz N, et al. Characterization of confusion, an
adverse event associated with intrathecal ziconotide infusion in chronic pain patients.
Pain Med. 2001;2:253-54.
30. Wermeling D, Drass M, Ellis D, et al. Pharmacokinetics and
pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin
Pharmacol. 2003;43:624-36.
31. Doggrell SA. Intrathecal ziconotide for refractory pain. Expert Opin Investig
Drugs. 2004;13:875-7.
32. Slavin KV, Solko AM. Intrathecal narcotics: spinal and intraventricular. In:
Schulder, editor. Handbook of stereotactic and functional neurosurgery. New York:
Marcel Dekker; 2003, pp. 443-57.
33. Bedder MD, Burchiel K, Larson A. Cost analysis of two implantable narcotic
delivery systems. J Pain Symptom Manage. 1991;6:368-73.
966
34. Erdine S, Talu GK. Cost effectiveness of implantable devices versus tunneled catheters.
Curr Rev Pain. 1998;2:157–62.
35. Miguel R. Interventional treatment of cancer pain: the fourth step in the World Health
Organization analgesic ladder? Cancer Control. 2000;7:149-56.
36. Mercadante S, Intravaia G, Villari P, et al. Intrathecal treatment in cancer patients
unresponsive to multiple trials of systemic opioids. Clin J Pain. 2007;23(9):793-8.
37. Hawley P, Beddard-Huber E, Grose C, et al. Intrathecal infusions for intractable cancer
pain: a qualitative study of the impact on a case series of patients and caregivers. Pain Res
Manag. 2009;14(5):371-9.
38. Wilkes D, Cook M, Solanki D. Intrathecal catheter-syringe adaptor for short-term
intrathecal analgesia with an externalized pump: a case report. Pain Physician. 2010;13(2):151-6.
INTRA-CEREBRO-VENTRICULAR MORPHINE
ADMINISTRATION
The durable effectiveness of intrathecal morphine administration is

well established for the management of intractable cancer pain, after
failure of systemic opioids, secondary to the persistence of non-
reversible undesirable side effects. Many patients are referred to late
in the disease course. This conservative method to control pain of
malignant origin must not be reserved for last resort treatment for
terminal patients. Intra-cerebro-ventricular morphine administration is
a very effective and generally safe method for controlling intractable
cancer pain. Because of the chronic implantation of an intra-
ventricular catheter, this method is somewhat invasive. Its indications
remain a simple and effective alternative when the topography of
nociceptive pain is diffuse or cephalic. In clinical practice, intrathecal
and/or intra-cerebro-ventricular administration of opioids is limited by
cost, the need for specialized maintenance and mechanical
malfunctions of IDDS, or by the risk of bacterial contamination and
ambulatory constraints when repeated daily injections via an
intrathecal access port are used. To answer these limitations, cell
therapy using intrathecal chromaffin cell allograft is a promising
approach for the management of cancer pain refractory to traditional
drug therapy and pain lesion surgery. The basic rationale and
preclinical studies on experimental pain models have enabled starting
prospective clinical trials. Prior to transplantation, handling and
preparation of the chromaffin tissue is critical for allograft viability.
The initial results of clinical trials with human chromaffin cell grafts
from intractable cancer pain have reported long-lasting pain relief, in
correlation with met-enkephalin release into the CSF. The limitations
of this innovative cell therapy and especially the lack of human
967
adrenal gland availability point to the need for new sources of cells.
Perspectives include xenogenic or engineered cell lines (1).
Intracerebroventricular morphine analgesic for the treatment of
cancer pain was administered, using implanted access ports, in 82
patients. All of the patients who were selected for treatment were no
longer responsive and had developed drug side effects to oral or
parenteral opiates in varying doses (60-400 mg/d). The mean follow-
up was 66 days (range, 12-443 days) for this series of patients. The
effective control of pain was achieved in nearly all of the patients,
with only 2 failures. During the treatment, the daily morphine doses
were moderately increased. The initial doses of morphine were a mean
of 0.30 mg (range, 0.10-2 mg), and the final doses were a mean of 2.5
mg (range, 0.10-60 mg). The results show that the ratio of the terminal
dose to the initial dose increased more rapidly for patients who had a
follow-up of over 60 days. However, the increase seems to have been
because of the progress of the disease rather than because of drug
tolerance (2).
The study evaluated the effect of intraventricular morphine
administration on chronic pain associated with malignant diseases in 5
subjects. To facilitate repeated application of the analgesic a reservoir
was fixed subcutaneously on the calvaria with the catheter tip place in
the lateral ventricle. The described approach made it possible to
reduce substantially the dosage and to protract the action of morphine,
as compared with intramuscular administration. No serious
complications developed when the described mode of application was
used. Because of the technically unpretentious procedure, the simple
administration into the reservoir and the significant analgesic effect
this method can be used in patients with malignant pain even in
advanced stages of the disease (3).
The main objective of this study was to quantitate the relief of
intractable cancer pain by the use of intraventricular morphine
administration. Intraventricular morphine administration was
performed through an Ommaya reservoir. An initial dose of 0.25 mg
of morphine sulfate per 24 hours was administered to all of the
patients. This dose was progressively increased in 0.25-mg increments
until optimal analgesia was attained. Sixty men and 30 women with a
median age of 58 years (range, 23-80 years) entered the study. The
median duration of pain was 6 months (range, 0.5-120 months). A
daily morphine dose of up to 1 mg was adequate to achieve an
analgesic effect in 77% of the patients. Only 9 patients (10%)
achieved < 50% pain relief. Using a multiple regression analysis, only
the morphine dosage was an independent prognostic factor. The most
968
frequent side effect (22%) was nausea/vomiting. There were 2 patients

with opioid intolerance, 2 with intracerebral hematomas, while 3
reservoirs failed. In conclusion, intraventricular morphine
administration is a useful method for palliation of intractable cancer
pain (4).
The treatment of intractable pain, especially in cancer patients,
often sets problems to patient and therapist. While epidural and
intrathecal spinal administration of opiates is a routine treatment in
pain with a sub-diaphragmatic topography, it is almost ineffective in
cervicocephalic or thoracic cancer. An alternative is the administration
of morphine into the lateral or third ventricle by a catheter-reservoir
system. Twenty patients, mostly suffering from cancer (18 cases) were
treated. It was an effective, non-destructive method with minimal side
effects in the treatment of nociceptive pain. Analgesia takes effect
within a few minutes and the necessary doses were low. These results
indicate good to excellent results in 95% of patients with somatogenic
pain. However, no or only minimal effect is achieved in the treatment
of neurogenic pain by intracerebroventricular morphine therapy (5).
The continuous intraventricular administration of small daily doses
of morphine by means of an implantable pump is an effective method
of obtaining considerable pain reduction for patients suffering from
otherwise intractable carcinoma pain. This method is an excellent
alternative to the epidural and intrathecal application. Particularly in
cases with obstruction of the spinal canal or in cases suffering from
intractable pain in the face, neck or upper thoracic area. During the
period of treatment, none of the patients involved in the study
developed tolerance to morphine or specific opiate side effects. The
programmable pump allows precise dosage, which is adjusted to the
requirements of the individual patient. The high cost of a pump is a
justifiable investment in patients in good general condition with a life
expectancy longer than 3 months. In most cases, the patient may be
cared for at home, making further hospitalization unnecessary (6).
Intractable pain in 4 patients enduring disseminated cancer was
treated by intraventricular morphine. For all these patients, previous
efficiency of opiates therapy had been assessed by a positive trial of
epidural injections of morphine. The latter method had to be stopped
and a switch to intraventricular morphine was motivated in 3 cases by
a local non-tolerance to the subarachnoid catheter. In 1 case, an
intraventricular system was inserted at the first onset. In all cases, the
intraventricular system consisted of a Holter type device, using a
reservoir subcutaneously implanted in the frontal scalp and connected
at right angle with a catheter inserted in the lateral ventricle. Trial
969
times were respectively of 8 days, 1 month, 2 months and 7 months,

with a self-administration system in 1 case. In comparison with the
epidural and lumbar intrathecal, administration of morphine, the
quality of analgesia can be obtained, with the absence of respiratory
depression, and the comfort and minimal daily quantities of morphine
injected (inferior to one mg daily in 3 cases) (7).
Refractory cancer pain may be effectively controlled by titrating
intracerebroventricular preservative-free opioid. In this case report, a
continuous infusion of intracerebroventricular morphine permitted a
patient with lung cancer and painful spinal metastases to be
discharged to home hospice with family. The approach exploits the
high potency of morphine injected into CSF. Sterile, injectable,
preservative-free morphine is directly infused into CSF through a
subcutaneous Ommaya reservoir placed under the scalp by a
neurosurgeon, with an attached catheter passed through a burr hole in
the skull with its tip in a cerebral ventricle. Although investigators
have described home care of patients receiving intraspinal analgesics,
no report describes the process of transitioning the patient receiving
continuous intracerebroventricular morphine infusion to the home
setting (8).
Ommaya reservoir
When pain is refractory to systemic opioid and non-opioid

analgesic therapy and palliative chemoradiation or ablative or
stimulant neurosurgical procedures are not possible, palliative
treatment becomes limited, particularly if the patient wishes to be at
home at the end of life. Intracerebroventricular infusion of morphine
in the home setting might be presented as an option. Information was
gathered from various bibliographic sources, including PubMed and
others, and summarized and evaluated to assess the efficacy and safety
of intracerebroventricular opioids for pain relief. Results from
intracerebroventricular infusion of morphine into terminally ill
patients refractory to other pain treatments have been reported since
970
the early 1980s. Good efficacy has been achieved for the vast majority
of patients, without serious development of analgesic tolerance. There
have also been a low incidence of AEs, such as constipation and
respiratory depression, and a significant retention of alertness
associated with this route of administration. Intracerebroventricular
infusion of opioid analgesics is a safe and effective therapy for the
palliative treatment of refractory pain (9).
References
1. Lazorthes Y, Sallerin B, Verdie JC, et al. Management of intractable cancer
pain: from intrathecal morphine to cell allograft. Neurochirurgie. 2000;46(5):454-65.
2. Lazorthes YR, Sallerin BA, Verdié JC. Intracerebroventricular administration
of morphine for control of irreducible cancer pain. Neurosurgery. 1995;37(3):422-8;
discussion 428-9.
3. Opavský J, Houdek M. Administration of morphine into the cerebral ventricles
in chronic intractable pain. Cesk Neurol Neurochir. 1990;53(4):264-8.
4. Karavelis A, Foroglou G, Selviaridis P, Fountzilas G. Intraventricular
administration of morphine for control of intractable cancer pain in 90 patients.
Neurosurgery. 1996;39(1):57-61; discussion 61-2.
5. Seiwald M, Alesch F, Kofler A. Intraventricular morphine administration as a
treatment possibility for patients with intractable pain. Wien Klin Wochenschr.
1996;108(1):5-8.
6. Weigl K, Mundinger F, Chrubasik J. Continuous intraventricular morphine- or
peptide-infusion for intractable cancer pain. Acta Neurochir Suppl (Wien).
1987;39:163-5.
7. Roquefeuil B, Blanchet P, Batier C, Benezech J. Intraventricular morphine
analgesia. Apropos of 4 cases, 1 with self-administration. Ann Fr Anesth Reanim.
1982;1(6):649-54.
8. Adolph MD, Stretanski MF, McGregor JM, et al. Intracerebroventricular
morphine for refractory cancer pain: transitioning to the home setting. Am J Hosp
Palliat Care. 2010;27(5):326-32.
9. Raffa RB, Pergolizzi JV Jr. Intracerebroventricular opioids for intractable pain.
Br J Clin Pharmacol. 2012;74(1):34-41.
SURGERY FOR PATHOLOGICAL FRACTURE
Surgery is rarely used for the treatment of cancer pain these days,
particularly since longer-acting opioids, such as SR oxycodone or
morphine, and TDF patches became available. Prior to considering
surgical intervention, one should try a variety of less invasive
techniques, such as nerve blocks, radiofrequency ablations or
neurolytic destructions, as well as many other procedures available
nowadays from the wide pain management arsenal (1).
971
The most important factor to consider in deciding between

treatment options in the management of MBD is the level of the
patient's dysfunction and pain. Severe dysfunction or pain demands a
treatment that predictably leads to a quick resumption of the painless
activities of daily living. A treatment that predictably will restore
function in months may seem reasonable in patients with a normal
remaining life span, but is untenable if those months represent a high
percentage of remaining life span, as they do in metastatic disease
afflicted patients. The treating physician needs also to understand the
basis for the patient's dysfunction. A destroyed joint will not return to
painless function even if the metastasis responsible is eliminated. A
bone that has lost its structural integrity, even though not grossly
fractured, will not support weight bearing for months even if the
metastasis is eliminated. Control of the metastatic tumor does not
always equate with return to function. Treatment options in the
management of MBD are not mutually exclusive. In many patients,
treatment options are combined. Surgical stabilization may best return
the patient's function while he is being treated postoperatively with RT
or chemotherapy for good neoplasm control. Neoplasm control should
not be such an overriding concern that function is not addressed.
Function can almost always be returned to the patient, but neoplasm
"cure" is rarely achieved in this group of patients. It is a reasonable
goal to avoid allowing bone metastasis to progress to pathological
fracture. Routine periodic examinations and bone scans should
commonly alert the treating physician to the presence of MBD well
before fracture occurs. Pathological fracture narrows the range of
treatment options, and mitigates against full functional restoration,
demands a rehabilitation hiatus, and acutely frightens the patient who
does not have time to participate fully in treatment decisions. An
impending pathological fracture can be treated with surgery, RT,
chemotherapy, or hormonal manipulation. The options are operative
or non-operative. Lesions that predictably will fracture short term,
involve joints, or will cause catastrophic consequences if fracture
should be strongly considered for surgical stabilization. Other factors
to consider are the location of the metastasis, the primary tumor, and
the expected response to non-operative therapy. The patient becomes a
surgical candidate for the above reasons and not because of any
estimated life span (2).
The improved prognosis of cancer patients has led to an increased
incidence of both bone metastases and (impending) pathological
fractures. A solitary bone lesion seen on radiography should never be
assumed a metastasis. Preoperative biopsy is necessary in patients
972
with a known malignancy and a solitary lytic bone lesion as well as in

patients in whom the primary tumor is unknown, in order to prevent
an incorrect operation (also known as 'whoops surgery') (3).
Prophylactic fixation surgery can lead to improved survival and
QOL of patients with bone metastases. Surgical treatment should be
undertaken when fracture occurs. Careful selection of patients for
surgical spinal decompression is required. The potential benefits of
surgical interventions have to be tempered with patient survival (4).
Pathological fracture from adrenal carcinoma.
If the patient has an (impending) pathological fracture, normal

bone healing is not to be expected, not even after stable fixation.
Surgical fixation of an impending pathologic fracture is recommended
when radiography indicates that a length of more than 3 cm of the
cortex of a long bone has been destroyed. If surgical treatment is
necessary, it should support the whole long bone in order to enable
full weight bearing. When the diagnosis of a bone lesion is uncertain,
referral to an experienced treatment centre is recommended (3).
Coincident with improved overall cancer palliation during the past
2 decades has been an increasing incidence of clinically apparent bone
metastases, and from these metastases subsequent pathologic fractures
of the long bones, spine, and pelvis. Current techniques for surgical
management of these fractures are extremely effective in alleviating
pain and allowing patients to resume an ambulatory status, often
without the need of external support. This, in turn, has significantly
improved the QOL of the remaining months or years of these
individuals. In fact, the long-term survival of patients after their first
long bone pathologic fracture from malignancy has more than tripled
for the most common cancers (breast carcinoma, prostate carcinoma,
lymphomas, and myelomas) during the past 25 years. Surgical
techniques for stabilizing pathologic or impending fractures must be
individualized for the area of involvement, the particular qualities of
the bone involved, and the potential for involvement of adjacent soft
973
tissue structures. Long bone fractures most commonly occur in the

femur and humerus and are typically internally fixed by
intramedullary devices that control impaction, distraction, and
torquing stresses by the use of proximal and distal interlocking
fixation. Such fixation must be able to withstand weight-bearing
stresses on lower extremity long bones. Upper extremity pathologic
fractures are often subjected to distractive forces inherent in lifting
and pulling, but they are also subjected to heavy compressive forces,
particularly in patients who require crutches or other devices to assist
them in walking. Fixation of upper or lower extremity long bone
fractures ordinarily may be accomplished with minimal blood loss or
morbidity. By contrast, fractures or impending fractures involving the
acetabulum necessitate extensive joint reconstruction, with inherent
increased potential for morbidity and complications. For this reason,
the anticipated prognosis for survival and mobility should be greater
preoperatively for patients with acetabular fractures than for patients
with fractures of either upper or lower extremity long bones (5).
Most spinal metastases can be managed conservatively. Those
requiring surgical intervention present with progressive neurologic
compromise, which requires decompression, or spinal instability,
which requires stabilization (5). For example, kyphoplasty used for
painful vertebral compression fractures in patients with disseminated
metastatic cancer (6). Constructs for internal stabilization of the spine
must not be adversely affected by local postoperative irradiation. Of
patients, 86% experience good or excellent relief of pain after internal
fixation of pathologic malignant long bone fractures, 84% of patients
with acetabular fractures experience good or excellent relief of pain
after joint reconstruction, 82% of patients with neurologic
compromise secondary to vertebral malignancy improve at least 1
functional grade after decompression and stabilization, 88%
experience good or excellent relief of spinal pain with restoration of
walking ability, and 32% survive for more than 2 years after spinal
decompression and stabilization. Patients with pathologic fractures
from metastatic carcinoma of the breast had a mean survival of 24.6
months after surgical management of their fractures. There is a
similarly improvement in the survival statistics for patients with other
primary tumor types. Most malignant pathologic fractures of the
pelvis, long bones, or spine are amenable to effective stabilization.
Various techniques allow resumption of weight-bearing ambulation in
all but a few patients, good or excellent relief of pain in the vast
majority, and an enhanced anticipation of survival and improvement
in QOL (5).
974
In this retrospective study carried out in South Municipal Hospital

and the Daniël den Hoed Cancer Centre, The Netherlands, 199
consecutive patients treated surgically between 1978 to 1990 for 233
fractures (161 actual and 72 impending) caused by metastatic lesions
of the femur, humerus and tibia were studied. Interventions included
local resection of the tumor was followed by endoprostheses (n=52)
and by internal plate osteosynthesis (n=167); 14 fractures were treated
with intramedullary nails. Bone cement was added in 211 cases
(91%). Pain relief was achieved in about 90%. 145 (76%) who were
treated for fractures of the lower extremity were able to walk again.
There were 13 local complications: 26 (11%) implanted devices failed
(cumulative probability 40%, after 60 months). In 11 cases, the
fixation failed after 7 weeks. The failure rate was 16% in the
subtrochanteric region treated with an angled blade (probability 70%
after 4 years). The patients' survival rate was 55% after 6 months and
20% at 2 years. In conclusion, despite the poor life expectancy
hemiarthroplasty or osteosynthesis with bone cement for treatment of
pathological (impending) fractures is a safe way to restore limb
function and to improve QOL (7).
Two years after a nephrectomy, a patient sustained a pathologic fracture.
The study was based on patients treated for skeletal metastases,

myeloma or lymphoma between 1986 and 1998 at the Oncology
Service, Department of Orthopedics, Karolinska Hospital and on
patients diagnosed with symptomatic skeletal metastases 1989-1994 in
the Stockholm Region. Breast cancer patients (n=641) were diagnosed
with symptomatic skeletal metastases. Based upon 1100 new primary
breast cancer cases yearly, the overall risk of developing symptomatic
skeletal metastases was 10-15%. One out of 5 patients with skeletal
metastases required surgical treatment for skeletal complications. The
975
survival rate after surgical treatment for skeletal complications was

0.3 at 1 year and 0.008 at 3 years. Multivariate analysis based on 619
patients showed that complete pathologic fracture and soft tissue
metastases were negative prognostic variables for 1-year survival after
operation. Solitary skeletal metastasis, breast, prostate, kidney cancer,
myeloma, and lymphoma were positive variables. FNAB was assessed
in 110 patients for diagnostic accuracy and to which extent
information about primary site of the metastatic carcinoma could be
gained. There were 80 patients with metastatic carcinoma, 14 with
lymphoma, and 16 with myeloma. FNAB offered correct diagnosis in
9 of 10 patients and also provided guidance in the search for the
primary lesions. Hence, 27 of 30 myeloma or lymphomas were
diagnosed by FNAB and in half of the patients with metastatic
carcinoma, the site of the primary tumor could be ascertained. For
patients with a suspected skeletal metastasis the search for the primary
tumor may preferably start with FNAB. Risk factors for failure after
operation for pathologic fractures were identified in 192 patients
treated for 228 metastatic lesions of the long bones. Of 228
procedures, 26 (11%) led to failures necessitating reoperation. Long
survival after surgery was the most important risk factor for failure of
the reconstruction. RCC was the primary tumor associated with the
highest rate of reoperations. There was a tendency for a high
reoperation rate in hospitals with few treated patients. In conclusion,
to decrease the risk of reoperation, it is important to identify patients
with a long expected survival. Patients with a good prognosis should
be considered for wide resection and reconstruction as applied in
primary malignant bone tumors (8).
Neoplasms of limbs appear as primary of changes or as bone
metastases. In 1989-2002 due to neoplasms of limbs, 795 patients
were hospitalized, of whom 278 suffered from malignant metastases
to bones. In this group, 242 patients were identified with lesions
localized within the femoral (169), humeral (55), and tibial (18)
bones. In 75% of patients, pathological fractures were diagnosed, in
the remaining ones the metastasis was manifested in the form of
osteolytic lesion. In most cases, early surgical treatment was
performed to eliminate pain complaints, improve patient's physical
mobility through restoration of limb functions and to enable nursing
care to be performed in palliative management. The choice of
treatment method depended on: location of metastasis, degree of bone
tissue destruction, type of primary tumor, progression of malignant
process and technical resources. Within the long bones, intramedullary
nails (189) of different generations were implanted. In the proximal
976
part of femoral bone, various types of endoprostheses (65) were used,

enabling oncological radicalism and early rehabilitation of the
patients. Resection of bones with neoplasm-induced lesions, filling the
lesion with bony cement and stabilization with blocking nails
permitted early rehabilitation of patients. The most common
malignancies inducing metastases were breast, kidney, lung cancers
and myeloma. Patients with these neoplasms constituted nearly 74%
of all hospitalized subjects. In conclusion, necessity of systemic
management and importance of early surgical treatment of metastases
in specialized centers were underlined (9).
The experience in a major Canadian orthopedic trauma centre
treating long bone metastases is reviewed. The primary aim was to
quantify the caseload, and the secondary aim was to report on the
methods of fixation. A retrospective review of all patients treated for
pathologic lesions or fracture secondary to metastatic disease over a
20-year period from July 1987 to March 2007 was conducted. The
mean number of cases treated annually was 13. Most patients came
from the local oncology centre. The median length of stay in hospital
was 11 days. In-hospital mortality was 14%. The fatal pulmonary
embolus rate was 5% for femoral lesions. The revision rate for the
operative intervention was 3%. The caseload was much lower than
anticipated, likely owing to under-referring from oncology services.
The high mortality rate may reflect delay in seeking orthopedic
opinion, but overall the fixation methods appeared durable (10).
References
2007;3(3):381–400.
2. Colyer RA. Surgical stabilization of pathological neoplastic fractures. Curr
Probl Cancer. 1986;10(3):117-68.
3. van de Sande MA, Bramer JA, Jutte PC, et al. Diagnosis and treatment of bone
metastasis. Ned Tijdschr Geneeskd. 2010;154:A2125.
1997;69(1-2):1-18.
5. Harrington KD. Orthopedic surgical management of skeletal complications of
malignancy. Cancer. 1997;80(8 Suppl):1614-27.
6. Fourney DR, Schomer DF, Nader R, et al. Percutaneous vertebroplasty and
kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg.
2003;98(Suppl 1):21–30.
7. Dijstra S, Wiggers T, van Geel BN, Boxma H. Impending and actual
pathological fractures in patients with bone metastases of the long bones. A
retrospective study of 233 surgically treated fractures. Eur J Surg. 1994;160(10):535-
42.
8. Wedin R. Surgical treatment for pathologic fracture. Acta Orthop Scand Suppl.
2001;72(302):2p., 1-29.
977
9. Karwicki L, Kmieciak M, Kopka M. Surgical treatment of metastasic tumors to

long bones in the material of the Unit. Ortop Traumatol Rehabil. 2003;5(3):358-63.
10. Kelly M, Lee M, Clarkson P, O'Brien PJ. Metastatic disease of the long bones:
a review of the health care burden in a major trauma centre. Can J Surg.
2012r;55(2):95-8.
NEUROSURGERY
The management of cancer pain represents a difficult diagnostic
and therapeutic problem for the clinician. In a multidisciplinary
approach to the management of cancer pain, neurosurgical methods
are an essential part of the therapy. Frequently, patients with advanced
cancer suffer from an increasing pain, requesting ever-higher dosage
of narcotics, and finally seeming to respond only to high dosage of
intravenous narcotics. Gradually, the opioids produce less satisfactory
analgetic effects and more serious side manifestations. These patients
can be considered for surgical management of pain. Historically,
surgery for cancer pain began with destructive procedures
(neurectomy, rhizotomy, and sympathectomy), often referred to as
ablative. In past 2 decades, with the help of the current knowledge of
cancer pain mechanisms and some of the technological developments,
such as microsurgical and stereotactic techniques, CT and MRI, the
majority of ablative procedures have been replaced by new methods.
Among them, a few are selectively and minimally ablative
(microsurgical spinothalamic cordotomy, DREZ operation, and
limited midline myelotomy) and the others ones are
neuroaugumentative operations (DBS, SCS, and drug-delivery
systems) (1).
In the century of science and technology, the average life span has
increased, bringing with it an increase in the incidence of degenerative
and cancer disease. Intractable pain is usually the main symptom of
cancer. With the advancement in technology, there is a large group of
patients with intractable pain problems who can benefit from special
help, medical or surgical. Destructive pain procedures are necessary to
control the cancer pain and are based on the lesioning of the pain
conducting pathways. Percutaneous cordotomy, trigeminal tractotomy
and extralemniscal myelotomy are special methods based on lesioning
of the pain conducting pathways. The procedure consists of obtaining
direct morphological appearance of the upper spinal cord and
surrounding structures by CT. The next step is functional evaluation
of the target and its environment by impedance measurement and
stimulation. The final step is terminated with controlled lesioning
978
obtained by a radiofrequency system (generator, needles, and

electrode system). In the last 2 decades, CT-guided destructive
procedures were used as minimally invasive procedures as follows:
percutaneous cordotomy, trigeminal tractotomy-nucleotomy, and
extralemniscal myelotomy. Most of these patients had cancer pain.
Minimally invasive CT-guided destructive pain procedures are still
safe and effective operations for relieving intractable cancer pain in
selected cases (2).
Percutaneous lower cervical cordotomy.
When it comes to the choice of pain-relieving surgical procedures,

these are usually divided into 2 broad categories: neurodestruction and
neuromodulation. Neurodestructive procedures involve interruption of
pain pathways, which can be performed anywhere starting at the level
of the nerve, nerve root, ganglion, spinal cord, thalamus, or the brain
stem depending on the nature and extent of the pain (3,4). One of the
most commonly used procedures in the past was spinal cordotomy that
targets the spinothalamic tract on the cervical or upper thoracic level
and results in eliminating pain sensation from the opposite side of the
body (5). Although safe and effective if done on one side only, it may
be associated with a very high rate of complications if performed
bilaterally. Midline myelotomy is reserved for patients with severe
bilateral or visceral pain (6); it interrupts a nonspecific pain-
transmitting pathway located in the vicinity of the central canal of the
spinal cord. Thalamotomy is usually aimed at either nuclei involved in
somatosensory perception or more anteriorly located centers that relay
affective aspects of pain (7). Cingulotomy targets the part of the
limbic system that appears to modulate painful sensations and certain
psychological aspects of pain experience; it is usually reserved for
patients with intractable cancer pain after failure of antineoplastic and
palliative pharmacological treatments and when more conservative
analgesic procedures are not applicable (8).
Neurosurgical procedures to treat pain are mainly destructive and
involve the spinal cord and occasionally the brain. Targets include the
979
spinothalamic tract, the trigeminal tract nucleus, and the midline

ascending visceral pain pathway, the brainstem spinal lemniscus, the
thalamus, and the cingulate gyrus. Since the introduction of intrathecal
opioids, the need for neurosurgical destructive procedures has been in
decline. In recent years, cordotomy, trigeminal tractotomy, and DREZ
operations are the neurosurgical procedures most often utilized to treat
cancer pain. The addition of CT guidance to spinal cord pain pathway
ablation was a major addition and refinement to the procedure. The
latest techniques include CT-guided cordotomy, CT-guided trigeminal
tractotomy, and DREZ operations utilized to treat cancer pain (9).
CT-guided stereotactic percutaneous destructive procedures, i.e.
percutaneous cordotomy, trigeminal tractotomy, and extralemniscal
myelotomy, have been routinely used for the treatment of localized
intractable pain in malignancy since 1987. In 67 cases if local pain
due to malignancy, CT guided percutaneous cordotomy was
performed and in 97% complete pain control was achieved. In 45 of
these cases, a "selective cordotomy" was performed meaning that
analgesia was produced only in the painful region of the body. CT
guided trigeminal tractotomy was applied to 19 cases in 5 pain had
been caused by malignancy. Twelve cases, suffering from visceral
pain due to malignancy, were treated by CT-guided extralemniscal
myelotomy and in 10 cases pain relief was achieved (10).
References
1. Slavik E, Ivanović S. Cancer pain (neurosurgical management). Acta Chir
Iugosl. 2004;51(4):15-23.
2. Kanpolat Y. Percutaneous destructive pain procedures on the upper spinal cord
and brain stem in cancer pain: CT-guided techniques, indications and results. Adv
Tech Stand Neurosurg. 2007;32:147-73.
3. Fenstermaker RA. Neurosurgical invasive techniques for cancer pain: a pain
specialist‘s view. Curr Pain Headache Rep. 1999;6:190–97.
4. Lordon SP. Interventional approach to cancer pain. Curr Pain Headache Rep.
2002;6:202-6.
5. Jones B, Finlay I, Ray A, Simpson B. Is there still a role for open cordotomy in
cancer pain management? J Pain Symptom Manage. 2003;25(2):179-84.
6. Nauta HJ, Soukup VM, Fabian RH, et al. Punctate midline myelotomy for the
relief of visceral cancer pain. J Neurosurg. 2000;92(2 Suppl):125-30.
7. Whittle IR, Jenkinson JL. CT-guided stereotactic antero-medial pulvinotomy
and centromedian-parafascicular thalamotomy for intractable malignant pain. Br J
Neurosurg. 1995;9:195-200.
8. Wong DL, Baker CM. Pain in children: comparison of assessment scales.
Pediatr Nurs. 1988;14:9-17.
9. Raslan AM, Burchiel KJ. Neurosurgical advances in cancer pain management.
Curr Pain Headache Rep. 2010;14(6):477-82.
10. Kanpolat Y, Caglar S, Akyar S, Temiz C. CT-guided pain procedures for
intractable pain in malignancy. Acta Neurochir Suppl. 1995;64:88-91.
980
DREZOTOMY
Cancer-related pain is a common problem that may be intractable
by medical and neuromodulatory treatment. The DREZ is a
hyperactive focus in neuropathic pain syndromes, and DREZotomy
has been used in selective cases of neuropathic cancer pain. The aim
of this study was to describe the technique of spinal DREZotomy in
the treatment of cancer pain and review the relevant published
literature. A PubMed database search for 'DREZ', 'dorsal root entry
zone' and 'cancer', and a search of the references of these manuscripts,
was undertaken. Fourteen papers were identified and reviewed that
described 123 patients with cancer pain or radiation-induced pain who
have been treated with DREZotomy. Though heterogeneous, these
studies reported an overall favorable outcome in carefully selected
patients with topographically limited pain syndromes. In conclusion,
for patients with well-localized neuropathic cancer pain intractable to
medical and first-line surgical management, DREZotomy is a viable
treatment option. Further prospective studies are needed to evaluate
the outcomes of this procedure (1).
DREZotomy
DREZ operations came into medical practice after the

demonstration of increased electrical activity in the dorsal horn of the
spinal cord and brainstem in patients with deafferentation of the CNS
after injury to these areas. The aim of the study was to describe the
technique and the effectiveness of spinal DREZ and nucleus caudalis
DREZ operations, which may be the treatments of choice in unique
chronic pain conditions that do not respond to medical therapy or any
other surgical methods. Fifty-five patients (44 spinal, and 11 nucleus
caudalis DREZ) underwent 59 (48 spinal, 11 nucleus caudalis DREZ)
operations. There were 44 men and 11 women with a mean age of
981
46.4 years (range, 24-74 years). The mean follow-up period was 72
months (range, 6 months-20 years). Follow-up assessments were
performed with clinical examination on the first day and in the 6 and
12 months postoperatively. Patients' pain scores and Karnofsky
Performance Scale scores were evaluated pre- and postoperatively.
The initial success rates for spinal and nucleus caudalis DREZotomy
procedures were 77% and 72.5%, respectively. In the spinal
DREZotomy group, mortality occurred in one patient (2.2%). There
were 2 cases of transient muscle weakness (4.4%) and 2 of CSF
fistulae (4.4%). In the nucleus caudalis DREZotomy group, mortality
occurred in one patient (9%). There were 2 cases of transient ataxia
(18%) and 2 of transient hemiparesis (18%). In conclusion, spinal and
trigeminal nucleus caudalis DREZ operations are effective in the
treatment of intractable pain syndromes, especially in traumatic
brachial plexus avulsions, segmental pain after spinal cord injury,
postherpetic neuralgia, topographically limited cancer pain, and
atypical facial pain (2).
The DREZ thermocoagulation for intractable pain after brachial
plexus avulsion was performed in 21 patients. Good results in pain
relief (relief of more than 75% of preoperative pain) were achieved in
62% of patients, whereby fair results (relief of 25-75% of preoperative
pain) in 38% of patients. There was no patient with poor result (relief
of less than 25% of preoperative pain). Complication rate was 14%.
The patient population was subdivided into 2 groups (Group 1 and
Group 2). Direct spinal cord bipolar stimulation and registration with
the goal to localize DREZ was performed in the Group 2 consisting of
12 patients (n=12). The point on the spinal cord surface where no
response after stimulus of low intensity was obtained was the site (the
posterolateral sulcus) identified as the most suitable point for the
placement of radiofrequency thermocoagulation electrode. Comparing
with the Group 1 consisting of 9 patients (n=9), where the localization
of DREZ by evoked potentials was not performed, significantly better
effect of pain relief was recorded (p<0.05, OR 10). There was
statistically insignificant difference in complication rate in Group 1
and Group 2. Described electrophysiological technique is very helpful
in identifying of DREZ and, in combination with microsurgical
technique, can create DREZ thermocoagulation more effective (3).
During a 3-year period, 25 nucleus caudalis DREZ operations were
performed for severe, facial pain. Primary diagnosis included
refractory trigeminal neuralgia, atypical headaches or facial pain,
posttraumatic closed head injuries, postsurgical anesthesia dolorosa,
MS, brainstem infarction, postherpetic neuralgia and cancer-related
982
pain. At the time of discharge, good to excellent pain relief was

present in 24/25 patients and fair relief in 1. At 1 month, 19/25 (76%)
patients had good to excellent results and at 3 months following
surgery, 17/25 (68%) continued to have good to excellent pain relief.
One year following surgery, 18 patients could be evaluated, 12/18
(67%) still considered their relief as good to excellent, 2 fair and 4
poor. Transient postoperative ataxia was present in 15/25 patients
(60%), but was resolved at 1 month. In 3/18 (17%) patients, a degree
of ataxia was still present at 1 year although in none was it disabling.
Two patients had transient diplopia, and 3 had increased corneal
anesthesia with 1 later developing a keratitis. No surgical or
postsurgical mortality was noted. This procedure has proven to be a
satisfactory treatment for many patients with debilitating facial pain
syndromes with acceptable morbidity (4).
References
1. Gadgil N, Viswanathan A DREZotomy in the treatment of cancer pain: a
review. Stereotact Funct Neurosurg. 2012;90(6):356-60.
2. Kanpolat Y, Tuna H, Bozkurt M, Elhan AH. Spinal and nucleus caudalis dorsal
root entry zone operations for chronic pain. Neurosurgery. 2008;62(3 Suppl 1):235-
42; discussion 242-4.
3. Tomás R, Haninec P. Dorsal root entry zone (DREZ) localization using direct
spinal cord stimulation can improve results of the DREZ thermocoagulation
procedure for intractable pain relief. Pain. 2005;116(1-2):159-63.
4. Bullard DE, Nashold BS Jr. The caudalis DREZ for facial pain. Stereotact
Funct Neurosurg. 1997;68(1-4 Pt 1):168-74.
983
MANAGEMENT OF CANCER PAIN IN

THE ELDERLY
Cancer is a disease of aging. With the aging of the population and
the improved survival of cancer patients, rehabilitation of older cancer
survival is an increasingly common problem. Age, constructed as a
progressive reduction in functional reserve of multiple organ systems,
lead to decreased life expectancy and reduced stress tolerance.
Physiologic age may be different from chronologic age and is best
assessed with a CGA. The goals of cancer treatment in the older aged
person include prolongation of active life expectancy that is
prevention of functional dependence. Cancer is a condition in which
rehabilitation of older individuals is needed. Cancer and cancer
treatment may accelerate physiologic aging. Rehabilitation is
especially necessary in the case of curable malignancies or
malignancies for which a prolonged survival is likely. Rehabilitation
is needed in older cancer survivors. Long-term complications of
cancer treatment that may compromise life expectancy and functional
independence include fatigue, cognitive decline and peripheral
neuropathy. In conclusion, the number of older cancer survivors is
expected to increase with the aging of the population. Prevention and
management of fatigue, cognitive decline and peripheral neuropathy
appear as the most important issue to prolong the active life
expectancies of these individuals (1).
Cancer in the older person is an increasingly common problem,
due to the progressive prolongation of the life expectancy of the
Western population. A CGA is commonly used to predict life
expectancy and functional reserve and to unearth conditions that may
jeopardize cancer prevention and treatment. In the interest of cost and
time, shortened forms of CGA are being explored. Chemoprevention
of cancer is a promising form of prevention that at present has no
conclusive clinical indications. Early diagnosis of breast and colon
cancer through screening of asymptomatic patients at risk is
beneficial for individuals with a life expectancy of 5 years or longer.
Early detection of lung cancer in ex-smokers is undergoing clinical
trials, as this disease is becoming more and more common. Age
should not prevent appropriate treatment of cancer in older
individuals, especially in those with adequate life expectancy and
functional reserve. The NCCN has issued a series of guidelines to
minimize the toxicity and promote the effectiveness of cancer in older
patients. Important interventions include prevention of neutropenic
infections with filgrastim and peg-filgrastim, prevention of anemia
984
with epoietin or darbepoietin, and prevention and early management

of mucositis (2).
The prevalence of cancer rises with advancing age, and pain is a
common complaint of those with cancer. The elderly, especially those
> 85, are at risk for undertreatment of pain. Despite multiple barriers,
assessment difficulties, and an increased risk of side effects with
opioids, cancer pain can be effectively managed in this population.
The QOL of elderly patients with cancer depends on good symptom
management, the appropriate use of analgesics, and prevention of
opioid-related side effects (3).
Existing studies indicate a high prevalence rate and poor
management of cancer pain in the elderly. Pain is often considered an
expected concomitant of aging, and older patients are considered more
sensitive to opioids. Despite the well known pharmacokinetic changes
in the elderly, the complex network of factors involved in the opioid
response make the evaluation of a single element, such as age, more
difficult. Notwithstanding such difficulties, appropriate analgesic
treatment is able to control cancer pain in the elderly in most cases.
Skills necessary to optimize pain control in older cancer patients
include the ability to objectively assess functional age (not necessarily
related to chronological age since the rate of decline is variable),
understand the impact of coexisting conditions, carefully manage the
numbers and types of drugs taken at the same time and adequately
communicate with patients and relatives. The most common treatment
of cancer pain consists of the use of regularly given oral analgesics.
The elderly are at increased risk of developing toxicity from NSAIDs,
and the overall safety of these drugs in frail elderly patients should be
considered. When older patients have clear contraindications to
NSAIDs, manifest signs of toxicity from these agents, or find that pain
is no longer controlled with this class of drugs, opioids should be
started. A variety of opioids is available, and they differ widely with
respect to analgesic potency and AEs among the elderly. Although the
aged population requires lower doses of opioids, only careful titration
based on individual response can ensure the appropriate response to
clinical demand. Elderly patients are potentially more likely to be
affected by opioid toxicity because of the physiological changes
associated with aging. Nevertheless, appropriate dosage and
administration may limit these risks. Cancer patients with pain who do
not respond to increasing doses of opioids because they develop AEs
before achieving acceptable analgesia may be switched to alternative
opioids. Despite the favorable effects reported with opioid switching,
monitoring is crucial, particularly in the elderly or patients who are
985
switched from high doses of opioids. Adjuvant analgesics, including

antidepressants, AEDs, corticosteroids and bisphosphonates may help
in the treatment of certain types of chronic pain. With an appropriate
and careful approach, it should be possible to reduce or eliminate
unrelieved cancer pain in most elderly patients and, consequently, to
enhance their QOL. Older patients with cancer should be continuously
assessed for cancer pain, both before and after analgesic treatment (4).
The main aim of this study was to assess which of the frailty
screening methods available show the best sensitivity and specificity
for predicting the presence of impairments on CGA in elderly patients
with cancer. A systematic search of Medline and Embase, and a hand-
search of conference abstracts for studies on the association between
frailty screening outcome and results of CGA in elderly patients with
cancer was performed. This search identified 4440 reports, of which
22 publications from 14 studies, were included in this Review. Seven
different frailty-screening methods were assessed. The median
sensitivity and specificity of each screening method for predicting
frailty on CGA were as follows: Vulnerable Elders Survey-13 (VES-
13), 68% and 78%; Geriatric 8 (G8), 87% and 61%; Triage Risk
Screening Tool (TRST 1+; patient considered frail if one or more
impairments present), 92% and 47%, Groningen Frailty Index, 57%
and 86%, Fried frailty criteria 31% and 91%, Barber 59% and 79%,
and abbreviated CGA 51% and 97%. However, even in case of the
highest sensitivity, the negative predictive value was only roughly
60%. G8 and TRST 1+ had the highest sensitivity for frailty, but both
had poor specificity and negative predictive value. These findings
suggest that, for now, it might be beneficial for all elderly patients
with cancer to receive a CGA, since available frailty screening
methods have insufficient discriminative power to select patients for
further assessment (5).
Management of elderly and frail patients with cancer is complex
and requires a multidisciplinary approach. This article reviews and
discusses the current literature that evaluates the relevance of CGA
and other evaluation tools in the detection of this vulnerable patient
population. A literature search of articles in English, Spanish and
Portuguese was conducted in PubMed through September 2011.
Recent guidelines advocate a careful patient selection through a CGA.
For vulnerable (pre-frail) and frail elderly cancer patients, there is no
consensus in relation to selection and type of treatments. CGA has
been advocated as the gold standard for evaluation of elderly patients,
but thorough evaluation of vulnerable and frail patients has not been
undertaken. A tool to evaluate vulnerable elderly patients to predict
986
treatment outcomes is also needed. The adoption of the CGA in

oncology practice has been slow because of the difficulties with
practicality and objectivity. A shorter reliable tool for rapid and
complete assessment is needed. Inclusion of frail elderly patients in
treatment trials is recommended. New treatment approaches for frail
elderly cancer patients need to be further investigated. Some studies
that used serum markers of frailty found that even in the absence of
clinical signs, some elderly patients might be already vulnerable. A
potential cancer frailty index also needs further investigation (6).
More than half of new cancers are diagnosed in elderly patients,
but data from RCTs do not represent the elderly population. CGA can
contribute valuable information to oncologists for risk stratification of
elderly cancer patients. Functional impairments, frailty markers,
cognitive impairments, and physical disabilities increase the risk for
adverse outcomes during cancer treatment. Evidence is accumulating
that selected elderly cancer patients benefit from CGA and geriatric
interventions. However, perceived barriers to CGA include time,
familiarity, cost, and lack of a well-defined procedure to interpret and
apply the information. A model for rapid selection of elderly who
would benefit from CGA using screening tools is the Vulnerable
Elders-13 Survey. Important geriatric functional risk factors should
include mobility limitation, frailty, and dementia, and demonstrate
how brief screening tests can make use of data realistically available
to clinical oncologists to determine a stage of aging (7).
Pain in older cancer patients is a common event, and many times, it
is undertreated. Barriers to cancer pain management in the elderly
include concerns about the use of medications, the atypical
manifestations of pain in the elderly, and side effects related to opioid
and other analgesic drugs. The care of older cancer patients
experiencing pain involves a comprehensive assessment, which
includes evaluation for conditions that may exacerbate or be
exacerbated by pain, affecting its expression, such as emotional and
spiritual distress, disability, and comorbid conditions. It is important
to use appropriate tools to evaluate pain and other symptoms that can
be related to it. Pain in older cancer patients should be managed in an
interdisciplinary environment using pharmacologic and no
pharmacologic interventions (8).
Existing studies indicate a high prevalence rate and poor
management of cancer pain in the elderly. Pain is often considered an
expected concomitant of aging, and older patients are considered more
sensitive to opioids. Despite the well known pharmacokinetic changes
in the elderly, the complex network of factors involved in the opioid
987
response make the evaluation of a single element, such as age, more

difficult. Notwithstanding such difficulties, appropriate analgesic
treatment is able to control cancer pain in the elderly in most cases.
Skills necessary to optimize pain control in older cancer patients
include the ability to objectively assess functional age (not necessarily
related to chronological age since the rate of decline is variable),
understand the impact of coexisting conditions, carefully manage the
numbers and types of drugs taken at the same time and adequately
communicate with patients and relatives. The most common treatment
of cancer pain consists of the use of regularly given oral analgesics.
The elderly are at increased risk of developing toxicity from NSAIDs,
and the overall safety of these drugs in frail elderly patients should be
considered. When older patients have clear contraindications to
NSAIDs, manifest signs of toxicity from these agents, or find that pain
is no longer controlled with this class of drugs, opioids should be
started. A variety of opioids is available, and they differ widely with
respect to analgesic potency and AEs among the elderly. Although the
aged population requires lower doses of opioids, only careful titration
based on individual response can ensure the appropriate response to
clinical demand. Elderly patients are potentially more likely to be
affected by opioid toxicity because of the physiological changes
associated with aging. Nevertheless, appropriate dosage and
administration may limit these risks. Cancer patients with pain who do
not respond to increasing doses of opioids because they develop AEs
before achieving acceptable analgesia may be switched to alternative
opioids. Despite the favorable effects reported with opioid switching,
monitoring is crucial, particularly in the elderly or patients who are
switched from high doses of opioids. Adjuvant analgesics, including
antidepressants, AED, corticosteroids and bisphosphonates may help
in the treatment of chronic pain. With appropriate and careful
approach, it should be possible to reduce or eliminate unrelieved
cancer pain in most elderly patients and, consequently, to enhance
their QOL. Older patients with cancer should be continuously assessed
for cancer pain, both before and after analgesic treatment (9).
Patients who are ≥ 65 years of age are the fastest growing segment
of the US population. These patients with already existing physiologic
decline and comorbidities, when diagnosed with cancer, provide
considerable challenges in management issues. Along with therapy for
the tumor, the practicing oncologist must keep in mind the various
symptoms, like fatigue, pain, and depression that may occur due to the
tumor itself or due to therapy. The prevalence of fatigue is greater
than 50-70% in advanced cancer. The tools to measure fatigue are all
988
subjective in nature and no one tool has been tested in the elderly
cancer patient. Treatment of fatigue in the elderly may involve
education, antidepressants, treatment of anemia, exercise, and use of
psychostimulants. Pain is present is 80% of elderly patients with
advanced cancer. Pain should be assessed in a systematic way and the
VAS is the tool most preferred by the elderly. Several guidelines for
management of pain exist and options include acetaminophen,
NSAIDs, opioids, adjuvant analgesics, and education of patients and
caregivers. Depression is also a prevalent symptom arising from a
variety of causes. There are many validated tools to measure
depression in the elderly as the GDS. Treatment includes use of
education, SSRI, psychotherapy, and electroconvulsive therapy. There
exists interplay of many of these symptoms and they can occur
simultaneously in the elderly cancer patient (10).
Populations around the world are aging, and the associated increase
in cancer incidence has led to the recognition of the importance of
geriatric oncology. Chronological age is a poor determinant of
pharmacological response to cancer chemotherapy agents. Age-
associated changes in physiology and organ function have a
significant impact on the clinical pharmacology of cancer
chemotherapy agents used in cancer treatment. Altered response to
medicines in older people is a consequence of changes in body
composition, organ function, concomitant pathophysiology, multiple
medications, genetic determinants of drug response, and patient's
clinical status. These issues highlight the need to individualize the
management of cancer in the older people with consideration of age-
related changes in the clinical pharmacology of cancer drugs,
analgesics, and adjunctive therapies (11).
The main objective of this study was to determine whether pain
medication use and inpatient consultations and services were
associated with significantly better pain control. Secondary data
analysis included a randomized two-by-two factorial trial.
Hospitalized, frail individuals aged ≥ 65 years were randomized to
receive care in a geriatric inpatient unit, a geriatric outpatient clinic,
both, or neither. This study was conducted at 11 Veterans Affairs
Medical Centers. Of 89 individuals with a diagnosis of cancer,
excluding nonmelanoma skin cancer, 44 received GEMU care and 55
usual care. Pain medications were measured at baseline and discharge;
consultations and other services were quantified for the entire
admission. Participants receiving GEMU care had a significantly
higher number of consultations than those in usual care. Participants
in GEMU care received psychiatry, endocrinology, and psychology
989
consultations 12.7% (p=0.004), 9.1% (p=0.04), and 21.8% (p=0.05)

times more, respectively, and occupational and physical therapy
27.3% (p=0.004) and 18.2% (p=0.04) more, respectively. There were
insignificant differences in pain medication use between intervention
and usual care. In conclusion, significantly greater use of psychology,
psychiatry, physical and occupational therapy in the GEMU
participants have improved the effectiveness of pain management
(12).
Assessment: the number of older cancer survivors is expected to

increase with the aging of the population. With the aging of the
population and the improved survival of cancer patients, rehabilitation
of older cancer survival is an increasingly common problem. Age
should not prevent appropriate treatment of cancer in older
individuals, especially in those with adequate life expectancy and
functional reserve.
Pain is present is 80% of elderly patients with advanced cancer.
Pain should be assessed in a systematic way and the VAS is the tool
most preferred by the elderly. The elderly, especially those > 85, are at
risk for under treatment of pain.
The most common treatment of cancer pain consists of the use of
regularly given oral analgesics. The elderly are at increased risk of
developing toxicity from NSAIDs, and the overall safety of these
drugs in frail elderly patients should be considered. When older
patients have clear contraindications to NSAIDs, manifest signs of
toxicity from these agents, or pain is no longer controlled with this
class of drugs, opioids should be started. A variety of opioids is
available, and they differ widely with respect to analgesic potency and
AEs among the elderly. Although the aged population requires lower
doses of opioids, only careful titration based on individual response
can ensure the appropriate response to clinical demand. Adjuvant
analgesics, including antidepressants, AEDs, corticosteroids and
bisphosphonates may help in the treatment of certain types of chronic
pain. Prevention and management of fatigue, cognitive decline and
peripheral neuropathy appear as the most important issue to prolong
the active life expectancies of these individuals.
Treatment of fatigue in the elderly may involve education,
antidepressants, treatment of anemia, exercise, and use of
psychostimulants. Depression is also a prevalent symptom arising
from a variety of causes. Treatment includes use of education, SSRI,
psychotherapy, and electroconvulsive therapy. There exists interplay
of many of these symptoms and they can occur simultaneously in the
elderly cancer patient.
990
Barriers to cancer pain management in the elderly include concerns

about the use of medications, the atypical manifestations of pain in the
elderly, and side effects related to opioid and other analgesic drugs.
References
1. Balducci L, Fossa SD. Rehabilitation of older cancer patients. Acta Oncol.
2013;52(2):233-8.
2. Carreca I, Balducci L, Extermann M. Cancer in the older person. Cancer Treat
Rev. 2005;31(5):380-402.
3.Maxwell T. Cancer pain management in the elderly. Geriatr Nurs.
2000;21(3):158-63.
4. Mercadante S, Arcuri E. Pharmacological management of cancer pain in the
elderly. Drugs Aging. 2007;24(9):761-76.
5. Hamaker ME, Jonker JM, de Rooij SE, Vos AG, et al. Frailty screening
methods for predicting outcome of a comprehensive geriatric assessment in elderly
patients with cancer: a systematic review. Lancet Oncol. 2012;13(10):e437-44.
6. Ruiz M, Reske T, Cefalu C, Estrada J. Management of elderly and frail elderly
cancer patients: the importance of comprehensive geriatrics assessment and the need
for guidelines. Am J Med Sci. 2012 Nov 17. [Epub ahead of print].
7. Rodin MB, Mohile SG. A practical approach to geriatric assessment in
oncology. J Clin Oncol. 2007;25(14):1936-44.
8. Delgado-Guay MO, Bruera E. Management of pain in the older person with
cancer. Part 2: treatment options. Oncology (Williston Park). 2008;22(2):148-52;
discussion 152, 155, 160 passim.
9. Camaioni D, Evangelista M, Mascaro A, Bosco M, et al. Pain therapy in elderly
cancer patients. Rays. 1997;22(1 Suppl):47-52.
10. Rao A, Cohen HJ. Symptom management in the elderly cancer patient:
fatigue, pain, and depression. J Natl Cancer Inst Monogr. 2004;(32):150-7.
11. He X, Clarke SJ, McLachlan AJ. Clinical pharmacology of chemotherapy
agents in older people with cancer. Curr Gerontol Geriatr Res. 2011;2011:628670.
12. Nipp R, Sloane R, Rao AV, et al. Role of pain medications, consultants, and
other services in improved pain control of elderly adults with cancer in geriatric
evaluation and management units. J Am Geriatr Soc. 2012;60(10):1912-7.
991
UNNECESSARY SUFFERING
Pain at the end-of-life is usually treatable, but most dying patients
are undertreated and die in unnecessary pain. The most important
factor is for physicians to make pain control a matter of paramount
importance in the care of dying patients (1).
After the first 5 years of life, cancer is one of the 3 most common
causes of death. Most investigations of cancer pain have shown that
50-70% of patients suffer needlessly. Pain may be due to the tumor or
a co-existent benign pain syndrome (2).
Although methods for controlling most cases of severe cancer pain
exist, probably about 50% of patients still suffer from unnecessary,
poorly controlled pain. Cancer pain has a substantial negative effect
on mood, resulting in anxiety, depressive feelings and even suicidal
thoughts and cognitive functions are disturbed. As cancer pain often
originates from skeletal metastases, movements and ADL functions
are restricted. Cancer pain is associated by the public with progressive
disease and dying and is therefore a trigger of existential fears, for
both patients and the public. Pain treatment and education are
therefore high-priority matters with effects far beyond the physical
suffering (3).
Pain management is correspondingly diverse, including primary
and secondary analgesics, physical and psychologic nondrug methods,
and modification of daily activities. Careful evaluation of the
neuropathologic mechanisms underlying the patient's pain is the first
step, followed by an explanation to the patient. Palliative RT is
generally the preferred treatment, in addition to drug therapy with a
combination of a NSAID and an opioid used in accordance with the
WHO Method for Relief of Cancer Pain. Alternative strategies are
needed for neuropathic and functional muscle pains that are opioid
resistant. Pain management is only one part of palliative care that
addresses psychological, social, and spiritual aspects of suffering (4).
Management of cancer pain is still a significant problem in
healthcare today despite the fact that such discomfort can be
controlled in approximately 90% of patients. Emotional, psychosocial,
and spiritual suffering associated with this disease complicates the
problem. Guidelines issued by the Agency for Healthcare Research
and Quality address management of cancer pain. Pain intensity scales,
complementary and alternative methods, and the role of an
interdisciplinary care team, as well as a need to provide spiritual
support to both patient and family, are included in this discussion. A
992
case vignette describes management of cancer pain in a typical patient

admitted to hospice (5).
Despite improvements in cancer therapies, cancer is the leading
cause of death worldwide. Many patients experience severe,
unnecessary symptoms during treatment at the end of life. Often,
patients receive 'aggressive' care at the end of life that is discordant
with their preferences. Palliative care is an approach that focuses on
communication and QOL, including treatment of physical,
psychosocial, and spiritual suffering. This approach is appropriate for
patients with life-limiting cancer, throughout the course of their
disease. A growing body of evidence supports the integration of
palliative care into routine cancer care, owing to the benefits in
symptom control, QOL, patient satisfaction, and resource utilization.
Palliative care can be delivered in inpatient, outpatient, and home-
based settings. The specialty and associated infrastructure is
expanding rapidly with support from the international medical
community. Through collaboration between oncologists and palliative
care teams, there is hope of improving the quality of care for patients
with both curable and life-limiting cancers (6).
Palliative medicine includes clinical palliative care, education, and
research that focus on the QOL of patients with advanced disease and
their families. The domain of palliative medicine is the relief of
suffering: physical, psychological, social, and spiritual. Palliative
medicine and care for patients at the end of life and their families
include the following key components: compassionate
communication; exploration of patient and family values and goals of
care; expert attention to relief suffering; management of pain,
depression, delirium, and other symptoms; awareness of the
manifestations of grief; and sensitivity to the concerns of bereaved
survivors (7).
The quality of cancer pain treatment in Norwegian hospitals was
evaluated. A one-day prevalence study targeting hospitalized cancer
patients above 18 years of age was performed. A questionnaire based
on the BPI was used, and additional information regarding sex, age,
diagnosis, BTP, and treatment was included. Of the included patients,
52% stated having cancer related pain (n=453), and mean pain during
the previous 24 hours for these patients was NPRS 3.99 (NPRS 1-10).
Presence of metastasis, occurrence of BTP, and abnormal skin
sensibility in the area of pain were associated with higher pain scores.
Of all patients, 42% used opioids. However, these patients still had
higher pain scores, more episodes of BTP, and more influence of the
pain on daily life functions than average. Of patients with severe pain
993
(NPRS ≥ 5), 30% did not use opioids, and some of these patients did
not receive any analgesics at all. In conclusion, although most cancer
patients receive an acceptable pain treatment in Norwegian hospitals,
there are patients who are not adequately managed. Lack of basic
knowledge and individual systematic symptom assessment are reasons
for the underuse of analgesics and the resulting unnecessary suffering
among the cancer patients (8).
Forty-four GPs recruited end-of-life cancer patients with an
estimated life expectancy of half a year or shorter. The inclusion
period was 3 years, and follow-up lasted one additional year.
Unbearable aspects in 5 domains and overall unbearable suffering
were quantitatively assessed (5-point scale) through patient interviews
every 2 months with a comprehensive instrument. Scores of 5
(serious) or 5 (hardly can be worse) were defined unbearable. The last
interviews before death were analyzed. Sources providing strength to
bear suffering were identified through additional open-ended
questions. Of 148 patients, 76 (51%) requested to participate
consented; the attrition rate was 8%, while 8% were alive at the end of
follow-up. Of 64 patients followed up until death, interviews were
complete in 60 patients. Overall, unbearable suffering occurred in
28%. A mean of 18 unbearable aspects was present in patients with
serious (score 4) overall unbearable suffering. The most frequent
unbearable aspects were weakness, general discomfort, tiredness,
pain, loss of appetite and not sleeping well (25-57%). The other half
of the unbearable aspects involved the domains of function,
personhood, environment, and nature and prognosis of disease. The
most frequent unbearable aspects were impaired activities, feeling
dependent, help needed with housekeeping, not being able to do
important things, trouble accepting the situation, being bedridden and
loss of control (27-55%). The combination of love and support was
the most frequent source (67%) providing strength to bear suffering.
In conclusion, overall unbearable suffering occurred in 1 in every 4
end-of-life cancer patients. Half of the unbearable aspects involved
medical symptoms, the other half concerned psychological, social and
existential dimensions. Physicians need to comprehensively assess
suffering and provide psychosocial interventions alongside physical
symptom management (9).
Assessment: although methods for controlling most cases of severe

cancer pain exist, about 50% of patients still suffer from unnecessary,
poorly controlled pain. Unbearable suffering occurs in 1 in every 4
end-of-life cancer patients.
994
Many patients experience severe, unnecessary symptoms during

treatment at the end of life. Often, patients receive 'aggressive' care at
the end of life that is discordant with their preferences.
Although most cancer patients receive an acceptable pain treatment
in, there are patients who are not adequately managed. Lack of basic
knowledge and individual systematic symptom assessment may be
reasons for the underuse of analgesics and the resulting unnecessary
suffering among the cancer patients.
The most frequent unbearable aspects are weakness, general
discomfort, tiredness, pain, loss of appetite and not sleeping well. The
other of the unbearable aspects involve the domains of function,
personhood, environment, and nature and prognosis of disease. The
most frequent unbearable aspects are impaired activities, feeling
dependent, help needed with housekeeping, not being able to do
important things, trouble accepting the situation, being bedridden and
loss of control.
Palliative medicine includes clinical palliative care, education, and
research that focus on the QOL of patients with advanced disease and
their families. The domain of palliative medicine is the relief of
suffering: physical, psychological, social, and spiritual.
References
1. Anderson CM. Pain relief at the end-of-life: a clinical guide. Mo Med.
2002;99(10):556-9.
2. Arter OE, Racz GB. Pain management of the oncologic patient. Semin Surg
Oncol. 1990;6(3):162-72.
3. Strang P. Cancer pain - a provoker of emotional, social and existential distress.
Acta Oncol. 1998;37(7-8):641-4.
4. Twycross RG. Management of pain in skeletal metastases. Clin Orthop Relat
Res. 1995;(312):187-96.
5. Bitros BS. Advocating for management of cancer pain. J Am Osteopath Assoc.
2007;107(12 Suppl 7):ES4-8.
6. Rocque GB, Cleary JF. Palliative care reduces morbidity and mortality in
cancer. Nat Rev Clin Oncol. Nat Rev Clin Oncol. 2013;10(2):80-9.
7. Abrahm JL. Update in palliative medicine and end-of-life care. Annu Rev Med.
2003;54:53-72.
8. Holtan A, Aass N, Nordøy T, Haugen DF, et al. Prevalence of pain in
hospitalised cancer patients in Norway: a national survey. Palliat Med. 2007;21(1):7-
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9. Ruijs CD, Kerkhof AJ, van der Wal G, et al. The broad spectrum of unbearable
suffering in end-of-life cancer studied in Dutch primary care. BMC Palliat Care. 2012
Aug 1;11:12.
995
BARRIES TO CANCER PAIN MANAGEMENT

Pain remains one of the top 5 reasons for consultations in general
practice, presenting either alone or as comorbidity. WHO analgesic
ladder proposed in 1986 has been the cornerstone of pain
management, but is often inadequate in daily practice, especially when
dealing with the diverse nature and etiology of various pain
conditions. There is a need for a better concept which is universally
applicable that acknowledges the value of, and need for, other
domains of treatment for pain. This article reviews the original ideas
of the WHO analgesic ladder and proposes its extension to a platform
model in the context of pain management. Pain affects both the
physical and psychological wellbeing of patients and should not be
treated with pharmacotherapy alone. The model of WHO analgesic
ladder provides guidelines for choosing the analgesic agents, but has
its limitations. Incorporating the latest paradigm of neuromatrix
theory, both acute and chronic pain should be best managed with a
broader perspective incorporating multimodal non-pharmacological
and supportive treatments, illustrated by the concept of interacting
domains on a broad platform. Different levels of pain severity and
chronicity necessitate different analgesic platforms of management,
and the clinician should move up or down the appropriate platform to
explore the various treatment options as per the status and needs of the
patient (1).
Pain is a major health care problem for patients with cancer:
despite the existence of guidelines for cancer pain management,
undertreatment is a widespread problem. PMIs evaluate the
congruence between the patient's reported level of pain and the
intensity/strength of the analgesic therapy. Negative scores indicate
inadequate prescriptions. A Medline search was carried out using
terms for 'pain management', 'index' or 'measure' selected studies
which measured undertreatment in cancer settings. Among the 44
studies identified, 26 studies used the PMI as proposed by Cleeland.
The range of negative PMI varied from 8-82% with a weighted mean
value of 43%. In multivariate analyses, factors associated with
negative PMI were date of publication before 2001, provenance from
Europe or Asia and countries with a gross national income per capita
< $40,000 per year and a care setting not specific for cancer. Age was
insignificant predictor for undertreatment. In conclusion, nearly 1 of 2
patients with cancer pain is undertreated. The percentage is high, but
consists of a large variability of undertreatment across studies and
settings (2).
996
A multicenter, open-label, prospective, non-randomized study was

launched in Italy in 2006 to evaluate the epidemiology, patterns and
quality of pain care of cancer patients. To assess the adequacy of
analgesic care, a standardized measure, the PMI was used, that
compares the most potent analgesic prescribed for a patient with the
reported level of the worst pain of that patient together with a selected
list of clinical indicators. A total of 110 centers recruited 1801 valid
cases; 61% of cases received a WHO-level III opioid; 25.3% were
classified as potentially undertreated, with wide variation (9.8-55.3%)
according to the variables describing patients, centers and pattern of
care. After adjustment with a multivariable logistic regression model,
type of recruiting centre, receiving adjuvant therapy or not and type of
patient recruited (new or already on follow-up) had a significant
association with undertreatment. Non-compliance with the predefined
set of clinical indicators was generally high, ranging from 41-76%.
Despite intrinsic limitations of the PMI that may be considered as an
indicator of the poor quality of cancer pain care, the recourse to WHO
third-level drugs still seems delayed in a substantial percentage of
patients. This delay is probably related to several factors affecting
practice in participating centers and suggests that the quality of cancer
pain management in Italy deserves specific attention and interventions
aimed at improving patients' outcomes (3).
Barriers to Effective Pain Management include problems related to
health care professionals: inadequate knowledge of pain management;
poor assessment of pain (4-6); concern about regulation of controlled
substances; fear of patient addiction (5); concern about side effects of
analgesics (4), concern about patients becoming tolerant to analgesics;
problems related to patients: reluctance to report pain; concern about
distracting physicians from treatment of underlying disease; fear that
pain means disease is worse; concern about not being a ―good‖
patient; reluctance to take pain medications; fear of addiction or of
being thought of as an addict. This fear may be more pronounced in
minority patients (7); worries about unmanageable side effects (such
as constipation, nausea, or clouding of thought); concern about
becoming tolerant to pain medications; poor adherence to the
prescribed analgesic regimen (8); financial barriers (5); problems
related to the health care system: low priority given to cancer pain
treatment (4); inadequate reimbursement for pain assessment and
treatment; the most appropriate treatment may not be reimbursed or
may be too costly for patients and families (5); restrictive regulation
of controlled substances; problems of availability of treatment or
access to it; opioids unavailable in the patient‘s pharmacy;
997
unaffordable medication; patient reluctance to report pain and adhere

to treatment recommendations, insufficient physicians' knowledge
about cancer pain management, inadequate patterns of pain
assessment, and inadequate opioid prescription (9).
Pain is among the most common reasons patients seek medical
attention, and the care of patients with pain is a significant problem in
the US. Acute pain (mild-to-moderate intensity) represents one of the
most frequent complaints encountered by primary care physicians and
accounts for nearly half of patient visits. However, the overall quality
of pain management remains unacceptable for millions of US patients
with acute or chronic pain, and under recognition and under treatment
of pain are of particular concern in primary care. Primary care
physicians face dual challenges from the emerging epidemics of
undertreated pain and prescription opioid abuse. Negative impacts of
untreated pain on patient activities of daily living and public health
expenditures, combined with the success of opioid analgesics in
treating pain provide a strong rationale for primary care physicians to
learn best practices for pain management. These clinicians must
address the challenge of maintaining therapeutic access for patients
with a legitimate medical need for opioids, while simultaneously
minimizing the risk of abuse and addiction. Safe and effective pain
management requires clinical skill and knowledge of the principles of
opioid treatment as well as the effective assessment of risks associated
with opioid abuse, addiction, and diversion. Easily implementable
patient selection and screening, with selective use of safeguards, can
mitigate potential risks of opioids in the busy primary practice setting.
Primary care physicians can become advocates for proper pain
management and ensure that all patients with pain are treated
appropriately (10).
A stress-coping model of relationships between patients' beliefs
about pain, coping (analgesic use), pain severity, analgesic side
effects, and 3 QOL outcomes was tested. Participants were 182 men
and women with cancer who completed valid and reliable self-report
measures of relevant variables. Antecedent variables (age and
education) showed expected relationships with beliefs. As predicted,
beliefs were significantly related to analgesic use. Analgesic use was
inversely related to pain severity, but was not related to side-effect
severity. Analgesic use was inversely related to impairments in QOL
before controlling for pain and side-effect severity, but not after these
2 variables were controlled. Both analgesic side-effects and pain
severity were related to impaired QOL outcomes, including difficulty
998
performing life activities, depressed mood, and poor perceived health

status (11).
Morphinofobia among the general population and among health
care professionals is not without danger for the patients: it may lead to
the inappropriate management of debilitating pain. The aim of this
study was to explore among general population and health care
professionals the representation and attitudes concerning the use of
morphine in health care. A cross-sectional study was done among 412
general population (physicians and nurses) of the 4 hospitals and 10
community health centers of Beira Interior (Portugal) and among 193
persons of the general population randomly selected in public places.
Opinions were collected through a translated self-administered
questionnaire. A significant difference of opinion exists among
general population and health care professionals about the use of
morphine. The word morphine first suggests drug to general
population (36.2%) and analgesia to health care professionals
(32.9%). The reasons for not using morphine most frequently cited
are: for general population morphine use means advanced disease
(56%), risk of addiction (50%), legal requirements (49,7%); for health
care professionals it means legal risks (56,3%) and adverse side
effects of morphine such as somnolence - sedation (30,5%). The
socio-demographic situation was correlated with the opinions about
the use of morphine. In conclusion, false beliefs about the use of
morphine exist. There seems to be a need for developing information
campaigns on pain management and the use of morphine targeting.
Better training and more information of health care professionals
might be needed (12).
Chronic pain is a frequent complication of cancer and its
treatments and is often under reported, under diagnosed, and under
treated (13). An anonymous survey was mailed to a geographically
representative sample of medical oncologists randomly selected from
the American Medical Association's Physician Master File. From
2,000 oncologists, 354 responded to the original questionnaire and
256 responded to one of 2 subsequent shortened versions (overall
response rate, 32%). Responders were demographically similar to all
US medical oncologists. Using NRSs of 0 to 10, oncologists rated
their specialty highly for the ability to manage cancer pain (median 7,
IQR 6 to 8) but rated their peers as more conservative prescribers than
themselves (median 3, IQR 2 to 5). The quality of pain management
training during medical school and residency was rated as 3 (IQR 1 to
5) and 5 (IQR 3 to 7), respectively. Barriers to pain management were:
poor assessment (median 6, IQR 4 to 7), patient reluctance to take
999
opioids (median 6, IQR 5 to 7), report pain (median 6, IQR 4 to 7),

physician reluctance to prescribe opioids (median 5, IQR 3 to 7), and
perceived excessive regulation (median 4, IQR 2 to 7). In response to
2 vignettes describing challenging clinical scenarios, 60% and 87%,
respectively, endorsed treatment decisions that would be considered
unacceptable by pain specialists. Frequent referrals to pain or
palliative care specialists were reported by only 14% and 16%,
respectively. In conclusion, for more than 20 years, a focus on cancer
pain has not adequately addressed the perception of treatment barriers
or limitations in pain-related knowledge and practice within the
oncology community (14).
Two representative samples of primary care physicians (n=600)
and medical oncologists (n=300) in France were surveyed about their
attitudes toward and knowledge about cancer pain management. The
survey was conducted by telephone with a questionnaire based on a
model developed by the University of Wisconsin-Madison Pain
Research Group. It was designed to assess physicians' estimates of the
prevalence of pain among patients with cancer, their practice in
prescribing analgesics, their training in cancer pain management, and
the quality of care received by cancer patients in their own practice.
Barriers to adequate cancer pain management are prevalent and
consistently more common among primary care physicians than
among medical oncologists. Although 85% of primary care physicians
and 93% of medical oncologists express satisfaction with their own
ability to manage cancer pain, 76% of primary care physicians and
50% of medical oncologists report being reluctant to prescribe
morphine for cancer pain. Both groups cite fear of side effects as their
main reason to hesitate to prescribe morphine. Concerns about the risk
of tolerance (OR, 1.15-2.52), perceptions that other effective drugs are
available (OR, 1.11-2.41), morphine has a poor image in public
opinion (OR, 0.96-2.07), and the constraints of prescription forms
(OR, 1.12-2.26) contribute significantly to physicians' infrequent
prescription of morphine, as are being female (OR, 1.01-2.03) and
being an older oncologist (OR, 1.09-2.51). This study indicates that
among French physicians attitudinal barriers and knowledge deficits
can impede cancer pain management, as well as identifies barriers to
the proper prescription of morphine for cancer pain control, and
reveals discrepancies in physicians' attitudes and knowledge about
pain control (15).
The purpose of this review was to summarize the main findings of
empirical research on barriers of cancer pain management in patients
with malignant diseases in the literature. The most significant patient-
1000
related barriers were patient reluctance to report pain and adhere to

treatment recommendations. The most prominent physician-related
barriers were insufficient physicians' knowledge about cancer pain
management, inadequate patterns of pain assessment, and inadequate
opioid prescription. The methodologies used to conduct the majority
of the studies on physician-related barriers were weak. Nevertheless,
physician knowledge of pain management guidelines, the quality of
pain assessment and opioid prescription were better in a few Western
countries. Institutional and health care system-related barriers were
relevant only in countries with restrictive opioid prescription
regulations (9).
The main objective of this study was to describe the experience of
cancer and cancer pain in a sample of southwestern American Indians.
Ethnographic interviews were conducted with 13 patients and 11
health care providers, caregivers, and community members; 2
questionnaires were used to collect demographic and pain data.
Barriers to pain control among American Indians included difficulties
describing pain, a belief that cancer pain is inevitable and untreatable,
and an aversion to taking opioid pain medication. Prescriber
inexperience also was cited as a barrier to pain management.
American Indians described a strong desire to protect their privacy
regarding their illness, and many felt that expressing pain was a sign
of weakness. The inability to participate in spiritual and cultural
activities caused distress, and some discontinued treatment or missed
chemotherapy appointments to engage in these activities. Results
revealed new knowledge about the cancer pain experience in
American Indians. The observation of the close relationship between
treatment compliance and the patient's ability to participate in
ceremonial and spiritual activities provides new insight into the
problem of incomplete cancer treatment in this population. The
finding that American Indians patients have a multidimensional
conceptualization of pain will assist clinicians with obtaining more
detailed and informative pain assessments (16).
Although chronic pain affects around 20% of adults in Europe and
the US, there is substantial evidence that it is inadequately treated. In
June 2009, an international group of pain specialists met in Brussels to
identify the reasons for this and to achieve consensus on strategies for
improving pain management. Literature on chronic pain management
was reviewed, and information presented to and discussed by a panel
of experts. Those involved in pain management did not universally
accept guidelines, and pain treatment seems to be driven mainly by
tradition and personal experience. Other factors include poor
1001
communication between patients and physicians, the side effects of

analgesic drugs, and limited individualization of therapy. Difficulty in
maintaining the balance between adequate pain relief and acceptable
tolerability, particularly with strong opioids, can lead to the
establishment of a 'vicious circle' that alternates between lack of
efficacy and unpleasant side effects, prompting discontinuation of
treatment. The medical community's understanding of the
physiological differences between nociceptive pain and neuropathic
pain, which is often more severe and difficult to treat, could be
improved. Increasing physicians' knowledge of the pharmacological
options available to manage these different pain mechanisms offers
the promise of better treatment decisions and more widespread
adoption of a multi-mechanistic approach; this could involve loosely
combining 2 substances from different drug classes, or administering
an analgesic with 2 different mechanisms of action. In some
circumstances, a single compound capable of addressing both
nociceptive and neuropathic pain is desirable. To improve patient
outcomes, a thorough understanding of pain mechanisms, sensitization
and multi-mechanistic management is required. Universal, user-
friendly educational tools are therefore required to familiarize
physicians with these topics, and to improve communication between
physicians and their pain patients, so that realistic expectations of
treatment can be established (17).
Underdiagnosis of pain is a serious problem in cancer care.
Accurate pain assessment by physicians may form the basis of
effective care. The aim of this study is to examine the association
between late referral to a PCT after admission and the underdiagnosis
of pain by primary physicians. This retrospective study was performed
in the Tokyo University teaching hospital for a period of 20 months.
Triads composed of 213 adult cancer inpatients who had coexisting
moderate or severe pain at the initial PCT consultation, 77 primary
physicians, and 4 palliative care physicians were investigated. The
outcome of the present study was the underdiagnosis of pain by
primary physicians with routinely self-completed standard format
checklists. The checklists included coexisting pain documented
independently by primary and palliative care physicians at the time of
the initial PCT consultation. Underdiagnosis of pain was defined as
existing pain diagnosed by the palliative care physicians only. Late
referral to PCTs after admission was defined as a referral to the PCT
at ≥ 20 days after admission. Because the 2 groups displayed
significantly different regarding the distributions of the duration from
admission to referral to PCTs, 20 days as the cut-off point for "late
1002
referral" were used. Accurate pain assessment was observed in 192

triads, whereas 21 triads displayed underdiagnosis of pain by primary
physicians. Underdiagnosis of pain by primary physicians was
associated with a longer duration between admission and initial PCT
consultation compared with accurate pain assessment (25 days vs.
4 days, p < 0.0001). After adjusting for potential confounding factors,
underdiagnosis of pain by the primary physicians was significantly
associated with late (20 or more days) referral to a PCT (AOR 2.91,
95% CI 1.27 - 6.71). Other factors significantly associated with
underdiagnosis of pain were coexisting delirium and case management
by physicians with < 6 years of clinical experience. In conclusion,
underdiagnosis of pain by primary physicians was associated with late
referral to PCTs. Shortening the duration from admission to referral to
PCTs, and increasing physicians' awareness of palliative care may
improve pain management for cancer patients (18).
The purpose of this article is to describe pain-related issues of
cancer survivors using case presentations of selected patients enrolled
in a randomized trial to eliminate barriers to pain management. Case
presentations were selected from a NCI-funded study that utilizes
patient and professional educational content derived from the clinical
guidelines of the NCCN. Case presentation criteria included a pain
rating of ≥ 6 and diagnosis of Stage I, II, or III of the following
cancers: breast, colon, lung, or prostate cancer. Cases are presented
based on the study's framework of patient, professional, and system-
related barriers to optimal pain relief. Across all 3 case presentations,
barriers such as fear of side effects from pain medications, fear of
addiction, lack of professional knowledge of the basic principles of
pain management, and lack of timely access to pain medications due
to reimbursement issues are prevalent in cancer survivorship. In
conclusion, chronic pain syndromes related to cancer treatments are
common in cancer survivors. Patient, professional, and system-related
barriers that are seen during active treatment continue to hinder
optimal pain relief during survivorship. Healthcare providers must
acknowledge the impact of chronic, persistent pain on the quality of
cancer survivorship. Clinical as well as scientific efforts to increase
knowledge in chronic pain management will improve the symptom
management of cancer survivors (19).
There are many potential barriers to adequate cancer pain
management, including lack of physician education and prescription
monitoring programs. The authors surveyed physicians about their
specific knowledge of pain management and the effects of the
regulation of opioids on their prescribing practices. A questionnaire
1003
was mailed out to British Columbia physicians who were likely to

encounter cancer patients. The survey asked for physicians' opinions
about College of Physicians and Surgeons of British Columbia
regulation and other issues related to their prescribing practices, and
assessed basic knowledge of cancer pain management. There was a
69% return rate with 4618 evaluable responses. There was a
significant difference among medical disciplines, years in practice,
number of chronic pain patients seen and size of community of
practice. The highest knowledge scores were achieved by oncologists
and the lowest scores were from surgeons. Those who practiced in
smaller communities had a higher average knowledge score. Those
who felt their knowledge about cancer pain was inadequate scored
lower than those who felt their knowledge was adequate. The
questions most frequently answered incorrectly (or by "don't know")
were those about equianalgesic dosing (68%) and adequate
breakthrough dosing (45%), revealing knowledge deficiencies that
would significantly impair a physician's ability to manage cancer pain.
In conclusion, the details of opioid prescribing are crucial areas to
target education for cancer pain management. The surveyed
physicians accepted the need for regulation of opioid prescribing with
very few being fearful of scrutiny from the College of Physicians and
Surgeons of British Columbia. However, the inconvenience of the
triplicate prescription pad was more of a barrier to prescribing and is
concern of 20% of respondents, particularly surgeons and medical
specialists (20).
Pain is still one of the most frequently occurring symptoms at the
end of life, although it can be treated satisfactorily in most cases if the
physician has adequate knowledge. In the Netherlands, almost 60% of
the patients with non-acute illnesses die at home where end of life care
is coordinated by the GP; about 30% die in hospitals (cared for by
clinical specialists), and about 10% in nursing homes (cared for by
elderly care physicians). The research question of this study is: what is
the level of knowledge of Dutch physicians concerning pain
management and the use of opioids at the end of life? A written
questionnaire was sent to a random sample of physicians of specialties
most often involved in end of life care in the Netherlands. Of all
physicians, 406 completed the questionnaire, response rate 41%.
Almost all physicians were aware of the most basal knowledge about
opioids, e.g. that it is important for treatment purposes to distinguish
nociceptive from neuropathic pain (97%). Approximately half of the
physicians (46%) did not know that decreased renal function raises
plasma concentration of morphine(-metabolites) and 34% of the
1004
clinical specialists erroneously thought opioids are the favored drug

for palliative sedation. Although 91% knew that opioids titrated
against pain do not shorten life, 10% sometimes or often gave higher
dosages than needed with the explicit aim to hasten death. About half
felt sometimes or often pressured by relatives to hasten death by
increasing opioid dosage. The majority (83%) of physicians was
interested in additional education about subjects related to the end of
life, while the most popular subject was opioid rotation (46%). In
conclusion, although the basic knowledge of physicians was adequate,
there seemed to be a lack of knowledge in several areas, which can be
a barrier for good pain management at the end of life. Three areas
emerge, in which an improvement can improve the quality of pain
management at the end of life for many patients in the Netherlands: 1)
palliative sedation; 2) expected effect of opioids on survival; and 3)
opioid rotation (21).
To be able to distinguish end-stage palliative sedation from
euthanasia without having to refer to intentions that are difficult to
verify, physicians must be able to manage palliative sedation
appropriately (i.e., see that death is not hastened as a result of
disproportionate medication). In the present study, whether or not this
requirement is met in the Netherlands was assessed. A retrospective
questionnaire to 1,464 medical specialists, GPs, and nursing home
physicians in the Netherland was sent. Two sets of 20 and 22 semi-
structured in-depth interviews with general practitioners, internists,
lung specialists, and nursing home physicians were held. Although
most guidelines discourage the administration of opioids alone for
purposes of palliative sedation, opioids alone were administered for
22% of all the patients reported upon. Those physicians who were
more experienced, GPs, and physicians who had consulted a palliative
care expert administered only opioids significantly less often than the
other physicians did. The interviewees reported difficulties in
assessing the appropriateness of medication, feeling uncertain about
the pharmacokinetics of drugs used in moribund patients. Given that
no more than 2% of the respondents perceived palliative sedation to
be used as a form of euthanasia and that the use of opioids alone was
not associated with shorter survival rates, the inappropriate use of
opioids can only be attributed to a lack of knowledge or skill and/or a
tradition of alleviating refractory dyspnea with the use of opioids and
not as an intentional means of hastening death (22).
This study compares the distance and mode of transportation to RT
and chemotherapy and perceptions of transportation as a barrier to
care among white, black, and Hispanic cancer patients receiving
1005
treatment from a consortium of cancer treatment facilities in Texas. A

mail questionnaire was developed to assess the perceived barriers to
cancer treatment for patients who had been diagnosed clinically with
breast, colon, cervical, prostate cancer, or lymphoma between 1989
and 1993. Of 910 surveys mailed to prospective participants, 593 were
returned, yielding a 65.2% response rate. By race, the respondents
included whites (42%), blacks (40%), Hispanics (15%), and Asian-
Pacific Islanders (3%). Two respondents were 17 years of age; the
remaining respondents were ≥ 18 years. This study shows that some
patients may forgo needed treatment because of problems with
transportation. This was perceived as an issue more for minority
patients than for white patients. Black and Hispanic patients
consistently reported that barriers such as distance, access to an
automobile, and availability of someone to drive them to the treatment
center were potential major problems. The distance to the facilities
was farther for whites than for blacks and Hispanics. Patients
generally had to travel farther for chemotherapy than for RT. Patients,
particularly minorities, may opt to forgo needed care in the absence of
available and affordable means of transportation to treatment
facilities. The need for healthcare providers to be aware of the
transportation problems that patients with cancer experience in
obtaining treatment. Healthcare providers must work with patients,
their families, and volunteer agencies in the community to facilitate
transportation to cancer treatment services (23).
Undertreatment of cancer pain remains a major health-care
problem. Focus groups of hospice and home-health nurses and
patients to elucidate factors contributing to inadequate pain
management and to generate solutions for closing the gap between the
current reality and optimal pain management were utilized. Focus
groups were conducted among hospice and home-health-care nurses
(2 groups; n=22) and patients 6 groups; n=54) using a standardized
question guide. Themes discovered among patients and nurses were
analyzed for similarities and differences. Of 22 participants in the 2
home-health and hospice nurses focus groups, all were white women,
the average age was 43 (range 29-64) years, and the average number
of years in nursing was 21 (range 8-47) years. Of 54 participants in the
six-cancer patient focus groups, 80% were women, the average age
was 54 (range 25-76) years, and 76% were white. Fifty-four percent of
patients reported a history of pain associated with their cancer, and
almost 30% had pain that they rated as 8 or higher on the pain scale.
Barriers to adequate pain management fell into 4 categories: fears;
attitudes, beliefs, and values; patient and provider behaviors; and
1006
structural barriers. Patients and nurses reported similar barriers to pain

management; however, patients identified more barriers related to
provider behavior and structure of the health care system (24).
Despite advances in early detection and effective treatment, cancer
remains one of the most feared diseases. Among the most common
side effects of cancer and treatments for cancer are pain, depression,
and fatigue. Although research is producing increasingly hopeful
insights into the causes and cures for cancer, efforts to manage the
side effects of the disease and its treatments have not kept pace. The
challenge that faces us is how to increase awareness of the importance
of recognizing and actively addressing cancer-related distress. The
NIH convened a State-of-the-Science Conference on Symptom
Management in Cancer: Pain, Depression, and Fatigue to examine the
current state of knowledge regarding the management of pain,
depression, and fatigue in individuals with cancer and to identify
directions for future research. Specifically, the conference examined
how to identify individuals who are at risk for cancer-related pain,
depression, and/or fatigue; what treatments work best to address these
symptoms when they occur; and what is the best way to deliver
interventions across the continuum of care. A non-advocate, non-
Federal, 14-member panel of experts representing the fields of
oncology, radiology, psychology, nursing, public health, social work,
and epidemiology prepared the statement. In addition, 24 experts in
medical oncology, geriatrics, pharmacology, psychology, and
neurology presented data to the panel and to the conference audience
during the first 1.5 days of the conference. The panel then prepared its
statement, addressing the 5 predetermined questions and drawing on
submitted literature, the speakers' presentations, and discussions held
at the conference. The statement was presented to the conference
audience, followed by a press conference to allow the panel to respond
to questions from the media. After its release at the conference, the
draft statement was made available on the Internet. The panel's final
statement is available at http://consensus.nih.gov. In conclusion, the
panel concluded that the available evidence supports a variety of
interventions for treating cancer patients' pain, depression, and fatigue.
Clinicians should routinely use brief assessment tools to ask patients
about pain, depression, and fatigue and to initiate evidence-based
treatments. Assessment should include discussion about common
symptoms experienced by cancer patients, and these discussions
should continue over the duration of the illness. Impediments to
effective symptom management in cancer patients can arise from
different sources and interactions among providers, patients and their
1007
families, and the health care system. Numerous factors could interfere
with adequate symptom management. Among these factors are
incomplete effectiveness of some treatments, a lack of sufficient
knowledge regarding effective treatment strategies, patient reluctance
to report symptoms to caregivers, a belief that such symptoms are
simply a part of the cancer experience that must be tolerated, and
inadequate coverage and reimbursement for some treatments (25).
In the Caribbean, pain is widely perceived as an unavoidable part
of life, and where unnecessary suffering results from untreated and
under treated pain. Barriers to pain relief in the Caribbean include
patient and family attitudes, inadequate knowledge among health
professionals and unduly restrictive regulations on the medical use of
opioids. Similar barriers exist all over the world. Medical, nursing and
public health professionals, and educators should be urged to examine
attitudes towards pain and pain relief and to work towards making
effective pain relief and palliation more accessible. It is recommended
that i) health professionals and officials be better educated about pain,
palliation and opioids, ii) regulatory restrictions be updated in light of
clinical and scientific evidence, iii) opioid procurement policies be
adjusted to facilitate increased medical use, iv) medical charts and
records be modified to routinely elicit and document patients levels of
pain, and v) educational campaigns be developed to inform the public
that moderate and severe pain can be safely relieved at the end of life
and other stages of life. The professional, respectful, and beneficent
response to patients in pain is to provide rapid and aggressive pain
relief or to urgently consult a pain or palliative specialist. When a
health system hinders such efforts, the ethical response is to identify,
facilitate and advocate for overcoming barriers to improvement (26).
Sixty cancer patients in each province, Beijing, China, were
randomly selected to participate in this survey. Of randomly selected
patients, 61.6% (958/1555) had different types of cancer related pain.
Majority of pain (85.1%) was caused by advanced cancer. The major
reasons (64.4%) for poor management or impedimental factors of pain
care were due to patient including over-concern on opioid analgesic
addiction, reluctance to report pain or refused to use opioid analgesic
until at times when pain is intolerable; 26.8% belonged to physician's
reasons including fear to cause addiction on opioid and lack of
knowledge about cancer pain management; 16.2% were due to lack of
different kinds of opioid analgesic for use and 16.1% belonged to drug
regulation. These results showed that majority of patients (61.6%)
had different types of cancer related pain. In most of patients, cancer
pain was relieved when patients were treated. The major reason for
1008
undertreatment or impeded factors for effective relief of cancer pain

were fear of opioid addiction by both medical professionals and
patients (27).
Factors associated with patient's high barrier score to manage
cancer-associated pain were studied. Patients (n=201) completed the
Korean Barriers Questionnaire II, the BPI-Korean, the European
Organization for Research and Treatment of Cancer Quality of Life
Questionnaire Core 30, and the Korean Beck Depression Inventory.
The PMI was also assessed. The patients were from 9 oncology clinics
in university hospitals and a veterans' hospital in South Korea. The
median pain score (0-10 scale) was 4, with a median percentage of
pain improvement during the last 24 hours of 70 %. Of 150 patients,
75% who received strong opioids, 177 (88%) achieved adequate
analgesia (positive The PMI). Mean scores ± SD for the Barriers
Questionnaire II ranged from 1.5 ± 1 to 2.8 ± 1.1, with the harmful
effects subscale the highest. In the multiple regression model,
depression was significantly associated with total barrier score to pain
management (p<0.0001). Pain reduction was significantly associated
with the fatalism subscale. In conclusion, depression was associated
with high barrier score in patients with cancer pain. Management of
cancer pain should include screening for depression, and management
of depression could reduce patient-reported barriers of pain
management (28).
Assessment: chronic pain is a frequent complication of cancer and

its treatments and is often underreported, underdiagnosed, and under-
treated. Undertreatment is a widespread problem and nearly half of
patients with cancer pain are undertreated.
Barriers to effective pain management include: inadequate
knowledge of pain management, poor assessment of pain, concern
about regulation of controlled substances, concern about patients
becoming tolerant to analgesics, patients' reluctance to report pain;
concern about distracting physicians from treatment of underlying
disease, fear that pain means disease is worse, concern about not being
a ―good‖ patient, reluctance to take pain medications, fear of addiction
or of being thought of as an addict, worries about side effects (such as
constipation, nausea, or clouding of thought), concern about becoming
tolerant to pain medications, poor adherence to the prescribed
analgesic regimen, financial barriers, low priority given to cancer pain
treatment, inadequate reimbursement for pain assessment and
treatment, the most appropriate treatment is too costly for patients and
families, restrictive regulation of controlled substances, problems of
1009
availability of treatment or access to it, distance, access to an

automobile, and availability of someone to drive patients to the
treatment center, opioids unavailable in the patient‘s pharmacy,
unaffordable medication, insufficient physicians' knowledge about
cancer pain management, and inadequate opioid prescription, lack of
professional knowledge of the basic principles of pain management,
incomplete effectiveness of some treatments, a lack of sufficient
knowledge regarding effective treatment strategies, a belief that
symptoms are simply a part of the cancer experience that must be
tolerated, depression, patient's and family attitudes, poor
communication between patients and physicians, and limited
individualization of therapy.
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1. Leung L. From ladder to platform: a new concept for pain management. J Prim
Health Care. 2012;4(3):254-8.
2. Deandrea S, Montanari M, Moja L, Apolone G. Prevalence of undertreatment
in cancer pain. A review of published literature. Ann Oncol. 2008;19(12):1985-91.
3. Apolone G, Corli O, Caraceni A, et al.; Cancer Pain Outcome Research Study
Group (CPOR SG) Investigators. Pattern and quality of care of cancer pain
management. Results from the Cancer Pain Outcome Research Study Group. Br J
Cancer. 2009;100(10):1566-74.
4. Breivik H, Cherny N, Collett B, et al. Cancer-related pain: a pan-European
survey of prevalence, treatment, and patient attitudes. Ann Oncol. 2009;20(8):1420-
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5. Sun V, Borneman T, Piper B, et al. Barriers to pain assessment and
management in cancer survivorship. J Cancer Surviv. 2008;2(1):65-71.
6. Bruera E, Willey JS, Ewert-Flannagan PA, et al. Pain intensity assessment by
bedside nurses and palliative care consultants: a retrospective study. Support Care
Cancer. 2005;13(4):228-31.
7. Anderson KO, Richman SP, Hurley J, et al. Cancer pain management among
underserved minority outpatients: perceived needs and barriers to optimal control.
Cancer. 2002;94(8):2295-304.
8. Miaskowski C, Dodd MJ, West C, et al. Lack of adherence with the analgesic
regimen: a significant barrier to effective cancer pain management. J Clin Oncol.
2001;19(23):4275-9.
9. Jacobsen R, Liubarskiene Z, Møldrup C, et al. Barriers to cancer pain
management: a review of empirical research. Medicina (Kaunas). 2009;45(6):427-33.
10. McCarberg BH. Pain management in primary care: strategies to mitigate
opioid misuse, abuse, and diversion. Postgrad Med. 2011;123(2):119-30.
11. Ward SE, Carlson-Dakes K, Hughes SH. The impact on quality of life of
patient-related barriers to pain management. Res Nurs Health. 1998;21(5):405-13.
12. Verloo H, Mpinga EK, Ferreira M, et al. Morphinofobia: the situation among
the general population and health care professionals in North-Eastern Portugal. BMC
Palliat Care. 2010 Jun 22;9:15.
1010
14. Breuer B, Fleishman SB, Cruciani RA, Portenoy RK. Medical oncologists'
attitudes and practice in cancer pain management: a national survey. J Clin Oncol.
2011;29(36):4769-75.
15. Larue F, Colleau SM, Fontaine A, Brasseur L. Oncologists and primary care
physicians' attitudes toward pain control and morphine prescribing in France. Cancer.
1995;76(11):2375-82.
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of chronic pain - the need for CHANGE. Curr Med Res Opin. 2010;26(5):1231-45.
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and late referral to a palliative care team. BMC Palliat Care. 2012 Jun 7;11:7.
19. Sun V, Borneman T, Piper B, Barriers to pain assessment and management in
cancer survivorship. J Cancer Surviv. 2008;2(1):65-71.
20. Gallagher R, Hawley P, Yeomans W. A survey of cancer pain management
knowledge and attitudes of British Columbian physicians. Pain Res Manag.
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1011
MULTIDISCIPLINARY APPROACH
MBD is a common cause of pain in cancer patients (1). The
mainstay of pain management entails an interdisciplinary cooperation;
it requires a full knowledge of the methods of evaluation and
treatment of this condition (2). A multidisciplinary approach to
treatment is necessary because simplified analgesic regimens may fail
in the face of complex pain generators, especially those involved in
the genesis of neuropathic pain (1).
Chronic pain is a frequent complication of cancer and its
treatments and is often underreported, underdiagnosed, and
undertreated. Pain in cancer survivors is caused by residual tissue
damage from the cancer and/or the cancer therapy. This pain can be
divided into 3 pathophysiologic categories: somatic, visceral, and
neuropathic. The most common treatment-induced chronic pain
syndromes are neuropathies secondary to surgery, RT, and
chemotherapy. Comfort and function are optimized in cancer
survivors by a multidisciplinary approach using an individually
tailored combination of opioids, coanalgesics, physical therapy,
interventional procedures, psychosocial interventions, and
complementary and alternative modalities. Management of chronic
pain must be integrated into comprehensive cancer care so that cancer
patients can fully enjoy their survival (4).
The number of people requiring palliative care is growing.
Palliative care does not intend to either accelerate or postpone death, it
emphasizes the life and looks at dying as a normal process. It is an
active form of care for patients with advanced, progressive illness,
with the aim of suppressing pain and other symptoms in addition to
providing psychological, social and spiritual support ensuring the best
possible QOL for patients and their families. Therefore, it is required a
coordinated and interdisciplinary contribution team. The variety of
professions in a team, and determine the needs of patients should be
ready to provide physical, psychological, social and spiritual support
using methods that result from an interdisciplinary, and collaborative
team approach (4).
Comfort and function are optimized in cancer survivors by a
multidisciplinary approach using an individually tailored combination
of opioids, coanalgesics, physical therapy, interventional procedures,
psychosocial interventions, and complementary and alternative
modalities. Management of chronic pain must be integrated into
comprehensive cancer care so that cancer patients can fully enjoy their
survival (5).
1012
Current approach to pain control should be individualized for every

patient and will require knowledge of the cancer type, the drugs
available on the market, the patients‘ metabolism, drug tolerances, and
even their genetic morphology. Periodical re-evaluation of patient‘s
medication regimen is essential to tune their analgesia and to
minimize the exposure to potentially dangerous AEs. The approach
must be interdisciplinary in nature: a surgeon, oncologist, pain
specialist, pharmacist, psychologist, or physical therapist cannot treat
the cancer pain alone; only by working together can these specialists
give the cancer patient relief from the most fearsome symptom of their
disease - their persistent pain (6).
With recent advances in the management of cancer, the clinical
course of patients with MBD is more likely to be prolonged and
accompanied by morbidity, including severe pain, hypercalcemia,
pathologic fracture, and spinal cord and/or nerve root compression.
The early identification of patients at higher risk for developing bone
metastases enables practitioners to be proactive in their diagnosis and
treatment. A multidisciplinary approach that integrates the diagnosis
and treatment of the cancer, symptom management, and rehabilitation
ensures optimal care. Bisphosphonates can reduce the number of
skeletal-related complications, delay the onset of progressive disease
in bone, and relieve metastatic bone pain caused by a variety of solid
tumors with a resulting enhanced QOL. The complexity of the clinical
problem and the need to involve an array of health-care providers
present a logistical and clinical challenge. A strong argument is made
for a thematically integrated bone metastases program as part of the
primary care of patients with cancer (7).
A systematic review and synthesis of qualitative studies was
carried out. Medline, PsycINFO, Embase, AMED, CINAHL, and
Sociological Abstracts were searched from May 20 to 26, 2011. To be
included, the articles had to be published in a peer-reviewed journal
since 2000; written in English; and report original qualitative studies
on the perspectives of patients, their significant others, or health care
providers. Thematic synthesis followed a three-stage approach using
Evidence for Policy and Practice Information and Co-coordinating
Centre-Reviewer 4 software: 1) free line-by-line coding of "Results,"
2) organization into "descriptive" themes, and 3) development of
"analytical" themes informative to our objective. At Stage 3, a
conceptual framework was selected from the peer-reviewed literature
according to prima facie "fit" for descriptive themes. Of 659 articles
screened, 70 met the criteria, reporting 65 studies with 48 patient, 19
caregiver, and 21 health care provider samples. In conclusion, these
1013
findings highlight the need to integrate patient/family education within

improved communication, individualize care, use more non-
pharmacological strategies, empower patients/families to self-manage
pain, and reorganize multidisciplinary roles around patient-centered
care and outcomes (8).
The objective in this study was to review the experience of a one-
stop multidisciplinary bone metastases clinic that offers a coordinated
multidisciplinary approach to the care of cancer patients with bone
metastases in a tertiary cancer centre. Patients with symptomatic bone
metastases were referred to bone metastases clinic and assessed by a
team of specialists in various disciplines – interventional radiology,
orthopedic surgery, palliative medicine, and radiation oncology. At
initial consultation, patient demographics, reasons for referral, and
case disposition were recorded. From January 1999 to February 2005,
272 patients with bone metastases were referred to the bone
metastases clinic. The median age was 65 years (range 28–95) and
median Karnofsky Performance Scale score at consultation was 60
(range 30-90). The majority of patients came from home (74%), while
others came from a nursing home or the hospital (9%). Almost a third
(28%) of patients had 2 or more reasons of referral, yielding a total of
354 reasons. The most common reason for referral was bone pain
(42%), bone metastases (21%), high risk for pathological fracture
(12%), and pathological fracture (10%). Of the 272 patients who
received consultation, 40% received palliative RT, 19% interventional
surgery, 7% were referred to other support services such as palliative
care, physiotherapy, and 7% had further investigation or imaging. In
conclusion, a multidisciplinary clinic is useful for co-coordinating the
management of multidisciplinary bone metastases clinic in
symptomatic patients (9).
Even with specialist-level palliative care, cancer pain can be
difficult to treat especially when the pain is complicated by profound
suffering. It is paramount to consider not only the patients'
biochemical factors but also their psychosocial and
spiritual/existential influences. A multidimensional approach with
knowledge of the risk factors for poor pain control is important to
prevent, detect, and manage risk factors for intractable pain, including
psychosocial distress, addictive behavior, and delirium in patients with
terminal cancer (10).
In January 2005, an Osteo-Oncology Center, Meldola, Italy, was
opened to provide multidisciplinary care (19 specialists involved) for
patients with bone metastases, to train physicians, and to conduct
research in the field. In its first 3 years of activity, 601
1014
multidisciplinary team consultations were made and 425 patients were

seen. The most frequent primary tumor site was the lung in males and
the breast in females. Upon presentation at the Center, 79% of patients
reported experiencing a level of pain (median pain intensity, 3.69) that
interfered with normal daily activities. An anonymous questionnaire
was also completed on the quality of the service provided: 75% of
patients were very satisfied, 23% were satisfied, 1% responded "I
don't know", and only 1% expressed dissatisfaction. In conclusion,
these results confirm the usefulness of a multidisciplinary center for
the management of patients with bone metastases, especially in terms
of decreasing psychophysical suffering (11).
Patients with bone metastases may experience pain, fatigue, and
decreased mobility. Multiple medications for analgesia are often
required, each with attendant side effects. Although palliative-intent
RT is effective in decreasing pain, additional supportive care
interventions may be overlooked. The objective was to describe the
feasibility of multidisciplinary assessment of patients with
symptomatic bone metastases attending a dedicated outpatient
palliative RT clinic. Consecutive patients referred for RT for painful
bone metastases were screened for symptoms and needs relevant to
their medications, nutritional intake, activities of daily living, and
psychosocial and spiritual concerns from January 1 to December 31,
2007. Consultations by appropriate team members and resulting
recommendations were collected prospectively. Patients who received
RT were contacted by telephone 4 weeks later to assess symptom
outcomes. A total of 106 clinic visits by 82 individual patients
occurred. As determined by screening form responses, the clinical
Pharmacist, Occupational Therapist, Registered Dietician and Social
Worker were consulted to provide assessments and recommendations
within the time constraints presented by 1-day palliative RT delivery.
In addition to pain relief, significant improvements in tiredness,
depression, anxiety, drowsiness and overall well-being were reported
at 4 weeks. In conclusion, systematic screening of this population
revealed previously unmet needs, addressed in the form of custom
verbal and written recommendations. Multidisciplinary assessment is
associated with a high number of recommendations and decreased
symptom distress. These findings lend strong support to the routine
assessment by multiple supportive care professionals for patients with
advanced cancer considered for palliative RT (12).
Thus, treatment for bone cancer involves multidisciplinary
modalities including psychosocial, hypnotherapy, CBT, music,
exercise, dance and movement, TENS, PENS, massage, acupuncture,
1015
non-opioid analgetics as well as opioid analgetics. Different modes of

administration (e.g. oral, rectal. transdermal/subcutaneous, or
sublingual routes) can be used (13). Additional options include
adjuvant medications such as NMDA receptor antagonists, as well as
antidepressants, AEDs, atypical neuroleptic, psychostimulants,
biphosphonates, calcitonin, corticosteroids, baclofen, somatostatin,
antihistamin medications, systemic local anesthetics, capsaicin,
clonidine, and cannabinoids. In addition, RT including Sr89, SCS,
DBS, nerve blocks, intrathecal neurolytic blocks, intra-cerebro-
ventricular/ventricular morphine injection, epidural analgesia, surgery
for pathological fracture, neurosurgery, and drezotomy are available
(2,13-17).
Man is mortal, which means that the earthly body final perishes.
Disease and death will always be an inevitable and integral part of
human experience. The way in which we try to identify and respond to
the unique and individual needs of the dying is an indication of our
maturity as a society (6).
Because of the negative consequences on both patients and their
families, and wide variety of pain management techniques available
nowadays, patients with cancer should be comforted with maximally
achievable pain control and not live in fear of inadequately treated
pain. As the survival of patients with cancer becomes longer, reliable
pain relief is now a high-priority issue that warrants both scientific
research and industrial development of new devices and
pharmaceutical agents that would make this pain relief complete, safe,
and lasting (7).
Cancer pain management is a crucial aspect of patients' QOL.
During the course of the disease, patients with cancer may develop
difficult pain management problems that do not respond to
interventions that use the basic principles of pain management.
Ongoing assessment, multiple approaches, and excellent
communication among all care management team members are
critical. Pain management goals must be continually evaluated,
reestablished if necessary, and negotiated by patients and the team.
Difficult pain management cases demand the involvement of all team
members, especially patients, to assist in determining acceptable
approaches. Nurses must recognize the challenge, advocate for better
management, and provide ongoing assessment. Through nurse
leadership, suffering is minimized and QOL is improved for this
patient population (18).
1016
Assessment: the mainstay of pain management entails an

interdisciplinary cooperation; it requires a full knowledge of the
methods of evaluation and treatment of this condition. A
multidisciplinary approach to treatment is necessary because
simplified analgesic regimens may fail in the face of complex pain
generators, especially those involved in the genesis of neuropathic
pain. It is required a coordinated and interdisciplinary contribution
team. The variety of professions in a team, to determine the needs of
patients should be ready to provide physical, psychological, social and
spiritual support using methods that result from an interdisciplinary,
and collaborative team approach.
The approach must be interdisciplinary in nature: a surgeon,
oncologist, pain specialist, pharmacist, psychologist, or physical
therapist cannot treat the cancer pain alone. Only by working together
can these specialists give the cancer patient relief from the most
fearsome symptom of their disease - their persistent pain.
A multidisciplinary clinic is useful for co-coordinating the
management of multidisciplinary bone metastases clinic in
symptomatic patients.
References
1. Buga S, Sarria JE. The management of pain in metastatic bone disease. Cancer
Control. 2012;19(2):154-66.
2. Francesca F, Bader P, Echtle D, et al.; EAU. EAU guidelines on pain
management. Eur Urol. 2003;44(4):383-9.
4. Skrbina D, Simunović D, Santek V, Njegovan-Zvonarević T. Use of music in
palliative care. Acta Med Croatica. 2011;65(5):415-23.
2007;3(3):381–400.
7. Blum RH, Novetsky D, Shasha D, Fleishman S. The multidisciplinary approach
to bone metastases. Oncology (Williston Park). 2003;17(6):845-57; discussion 862-3,
867.
8. Luckett T, Davidson PM, Green A, et al. Assessment and management of adult
cancer pain: a systematic review and synthesis of recent qualitative studies aimed at
developing insights for managing barriers and optimizing facilitators within a
comprehensive framework of patient care. J Pain Symptom Manage. 2012 Nov 15.
pii: S0885-3924(12)00470-8.
9. Li KK, Sinclair E, Pope J, et al. On behalf of the Bone, and Metastases Team.
A multidisciplinary bone metastases clinic at Toronto Sunnybrook regional cancer
centre - a review of the experience from 1999 to 2005. J Pain Res. 2008;1:43-8.
10. Mori M, Elsayem A, Reddy SK, et al. Unrelieved pain and suffering in
patients with advanced cancer. Am J Hosp Palliat Care. 2012;29(3):236-40.
1017
11. Ibrahim T, Flamini E, Fabbri L, et al. Multidisciplinary approach to the

treatment of bone metastases: Osteo-Oncology Center, a new organizational model.
Tumori. 2009;95(3):291-7.
12. Pituskin E, Fairchild A, Dutka J, et al. Multidisciplinary team contributions
within a dedicated outpatient palliative radiotherapy clinic: a prospective descriptive
study. Int J Radiat Oncol Biol Phys. 2010;78(2):527-32.
13. Regaard A. The principles of pain management in advanced cancer. Br J
Community Nurs. 2000;5(8):382-6, 388.
patients with bone metastases. Nat Clin Pract Oncol.2009;6(3):163-74.
15. Mercadante S, Fulfaro F. Management of painful bone metastases. Current
Opinion in Oncology. 2000;19(4):308-14.
16. Smith HS. Painful osseous metastases. Pain Physician. 2011; 14(4): E373-403.
17. Ripamonti C, Fulfaro F. Malignant bone pain: pathophysiology and
treatments. Curr Rev Pain. 2000;4(3):187-96.
18. Griffie J, Coyne P, Coyle N. Difficult cases in pain management: use of
methadone in a multifactorial approach. Clin J Oncol Nurs. 2006;10(1):45-9.
1018
SUMMARY
The medical record of King David indicates that he suffered from
the following diseases:
BLINDNESS OR POOR VISION

The blindness or poor vision was due either to age-related
neovascular macular degeneration, or mature cataract, or
asymptomatic open-angle glaucoma, or optic atrophy caused by the
end-stage open angle glaucoma.
WEIGHT LOSS
Weight loss was due to malignancy, and psychosocial problems
such as depression, loneliness, lack of close relationships and friends
on whom he could rely, loss of power and control over his people,
feelings of neglect and negative interpersonal relationships as playing
a part.
GENERALIZED WEAKNESS
Generalized weakness due to cancer related fatigue, intractable
bone pain, malnutrition leading to cachexia, severe anemia of chronic
diseases, psychosocial problems associated with loneliness, social
isolation, neglect by others, and depression.
HYPOTHERMIA
The King suffered from subclinical mild hypothermia. Among the
various diseases that lead to immobility and subsequent hypothermia,
the most likely are senile osteoporosis, hyperparathyroidism,
dementia, and malignant diseases. Among these diseases, malignancy
is the most acceptable. The presence of accidental hypothermia
associated with environmental factors is unlikely.
1019
SEVERE BONE PAIN

Severe, intractable bone pain most probably were due to MM,
HCD, RCC, prostate cancer, or RCC combined with prostate cancer.
PRESSURE ULCERS
In King's case, risk factors for this skin disease include male
gender, old age - a 70-year-old man, osteoporosis, dehydration,
malnutrition, cachexia, depression, and various social problems.
ERECTILE DYSFUNCTION
Erectile dysfunction and reduced or absent libido in King David
were due to a combination of causes, but the most likely is a
malignant disease together with major depression and various deep-
seated social problems
MAJOR DEPRESSION
The mechanisms of the development of depression include King's
loneliness, need for close relationships , lack of friends on whom he
can rely, loss of power and control over his people, feelings of neglect
and negative interpersonal relationships, and persistent negative stress.
1020
CONCLUDING REMARKS
This report analyzes the most likely disease that affected King
David. The sentences ―...my strength failed..., and my bones are
consumed..,‖ (Psalm 31:1) and ―My bones wasted away through my
anguished roaring all day long‖ (Psalm 32:3) indicate that King
David suffered from severe intractable bone pain. Thus, we are
dealing with an ancient patient from the highest socioeconomic
stratum who suffered from severe intractable bone pain.
The first part of this research deals with a patient who may have
suffered from non-malignant chronic pain. It evaluates non-malignant
pain definition, classification, epidemiology, mechanism, assessment
tools, clinical applicability, catastrophizing response to pain, gender
differences in the perception of pain, special consideration of pain in
the elderly, QOL, the psychosocial factors of chronic pain, the
relationship between chronic pain and the family, religion and
spirituality, prognostic factors, pain reduction strategies, adherence to
medications, readiness to change, and approaches to patients.
The second part of this research examines the disease that may
have afflicted the King's bones. Because the King‘s bones were
―...wasted away...‖ (Psalms 32:3) they became very weak, that is, the
bone mass decreased. The decreased bone mass indicates that the
King was suffering from osteoporosis.
There are 2 types of osteoporosis: primary or involutional and
secondary osteoporosis. The term 'primary' osteoporosis refers to
osteoporosis that results from the involutional losses associated with
aging. Osteoporosis that is caused or exacerbated by other disorders or
medication exposures is referred to as 'secondary' osteoporosis.
Was King David affected by involutional or primary osteoporosis?
Clinical characteristics of involutional osteoporosis studied do not
entirely explain what kind of disease ―...consumed...‖ (Psalms 31:11)
his bones.
The diseases studied in this research that were associated with
secondary osteoporosis include Cushing syndrome, thyroid diseases,
acromegaly, hypogonadism, hyperparathyroidism, Paget's disease, G-I
diseases such as lactose intolerance, IBD, Celiac disease, Whipple
disease, primary biliary cirrhosis, as well as COPD, osteoarthritis, RA,
malnutrition, medications, and IMO.
Among all the diseases studied, none explains what kind of disease
―...consumed...‖ his bones.
Did some malignant disease affect the King? This research deals
with malignant diseases that may have afflicted the King's bones,
1021
evaluating their epidemiology, mechanisms of MBD, comorbidity of

cancer, and assessment of cancer pain. Hematological malignancies
studied include MM, MGUS, smoldering myeloma, WM, HCD,
osteomyelofibrosis, small lymphocyte cell disorders – CLL,
lymphoplasmacytic lymphoma/WM, amyloidosis, and plasmacytoma.
Other malignancies include pulmonary carcinoma, bronchogenic
carcinoma, laryngeal carcinoma, esophageal carcinoma, gastric
carcinoma, CRC, HCC, pancreas carcinoma, urothelial carcinoma,
RCC, prostate carcinoma, urinary bladder carcinoma, and different
bone tumors.
Of all neoplastic diseases, MM, HCD, or RCC, prostate cancer, or
RCC combined with prostate cancer are the most likely diagnoses.
The third part of this research evaluates MBD, describing its
clinical presentation, cancer related pain, mechanism, classification,
characteristics of cancer, BTP, neuropathic pain, QOL of patients with
MBD, psychological distress, and family/informal caregiver
involvement in the care of patients with cancer.
If a patient with severe bone pain comes to a family physician
clinic, what would the approach be to such a patient? The first step is
a good anamnesis, following by physical examination, laboratory
examinations, including malignancy marker tests, radiological,
ultrasonography, isotopic, CT, MRI, and various additional studies
for example, colonoscopy or gastroscopy, and histopathological
examinations.
In this ancient patient, anamnesis is based on the description given
in his medical record that is the biblical text. Although the modern
approach requires performing various examinations, as described
above, it is understandable that such tests were not performed in the
King's case. Nevertheless, logical evaluation led to the most likely
diagnosis of the disease from which the King suffer.
When a diagnosis is reached, a contemporary patient receives the
appropriate medical treatment for his neoplastic disease. Approaches
used with patients with severe bone pain due to metastatic disease
include multidisciplinary non-pharmacological or pharmacological
interventions. A physician should make maximal efforts to alleviate a
patient's severe intractable bone pain.
We see a patient who suffered unnecessarily from severe bone pain
due most probably to neoplastic disease. The medical record, that is
the biblical text provides us with no information as to whether the
King received any treatment for his condition. Thus, most probably he
received no medication at all for his pain. If King David had received
1022
appropriate therapy for his severe bone pain, he would have suffered
significantly less, if at all.
In spite of his great suffering, pain-killing medications were not
used in the King's case. By comparison, contemporary patients who
suffer from severe bone pains would receive some medication and
therefore their QOL is much better than patients in ancient times, as in
this example of King David.
In each primary care practice, the family physician or general
practitioner should recognize the main principles of managing patients
with severe malignant bone pain. Both ancient and contemporary
patients deserve appropriate therapy for pain related to MBD.
1023
ABBREVIATIONS
ACR American College of Rheumatology

ADL Activity of daily living
AE Adverse effect/event
AED Antiepileptic drug
AF Atrial fibrillation
AFP Alpha-fetoprotein
AIDS Acquired immunodefiency syndrome
ALP Alkaline phosphatase
ALT Alanine aminotransferase
AMA Antimitochondrial antibodies
AMD Acute musculoskeletal disorder
ANA Antinuclear antibodies
Anti-tTG Anti transglutaminase
AOR Adjusted odds ratio
APC Annual percent change
AS Ankylosing spondylitis
ASCT Autologous stem cell transplantation
AST Aspartate aminotransferase
ASTRO American Society for Radiology Oncology
ATP Adenosine triphosphate
AUA American Urological Association
BDI Beck Depression Inventory
BFI Brief Fatigue Inventory
BIPN Bortezomib-induced peripheral neuropathy
BMD Bone mineral density
BMI Body mass index
BOLD The burden of obstructive lung disease
BP Blood pressure
BPH Benign prostate hypertrophy
BPI Brief Pain Inventory
BP-PCS Brazilian Portuguese Pain Catastrophizing Scale
BT-CBT Behavioral and cognitive-behavioral treatment
BTP Breakthrough pain
C. Campylobacter
CAM Complementary and alternative medicine
CARO Canadian Association of Radiation Oncology
CAS Colored Analogue Scale
CBT Cognitive behavioral therapy
CD Crohn's disease
CDMD Chronic disabling musculoskeletal disorders
CEA Carcinoembryonic antigen
CGA Comprehensive geriatric assessment
CI Confidence interval
CIDI Composite International Diagnostic Interview
CIBP Cancer-induced bone pain
1024
CIPN Chemotherapy-induced peripheral neurotoxicity

CMV Cytomegalo virus
CLL Chronic lymphocytic leukemia
CNS Central nervous system
COPD Chronic obstructive pulmonary disease
COX Cyclooxygenase
Coxib Selective cyclooxygenase 2 inhibitor
CPCI Chronic Pain Coping Inventory
CPI Cancer Pain Inventory
CPSP Central poststroke pain
CR Controlled release
CRC Colorectal cancer
CRP C-reactive protein
CSF Cerebrospinal fluid
CT Computed tomography
CTCAE Common Terminology Criteria for Adverse Events
CUP Cancer of unknown primary
C-V Cardiovascular
DALY Disability adjusted life years
DBS Deep brain stimulation
DECT Dual-energy computed tomography
delta-9-THC Delta-9-tetrahydrocannabinol
DIC Disseminated intravascular coagulation
DPN Diabetic peripheral neuropathy
DREZ Dorsal root entry zone
DRG Dorsal root ganglion
DRI Disability Rating Index
DXA Dual energy x-ray absorptiometry
DXR Digital X-ray radiogrammetry
EAPC European Association for Palliative Care
ECOG Eastern Co-operative Oncology Group scoring
ED Emergency department
EMA Endomysial antibody
ECEMC Spanish Collaborative Study of Congenital
Malformation
EMG Electromyography
EORTC QLQ European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire
EQ Euro quality of life
ER Emergency room
ERCP Endoscopic retrograde cholangiopancreatography
ESR Erythrocyte sedimentation rate
ESAS Edmonton Symptom Assessment Scale
EU European Union
EUS Endoscopic ultrasound
FACIT Functional Assessment of Chronic Illness Therapy-
Ascites Index
1025
FACT Functional assessment of cancer therapy

FAS Facial Affective Scale
FDA Food and Drug Administration
FEV Forced expiratory volume
FNA Fine-needle aspiration
FNAB Fine-needle aspiration biopsy
FPS The Faces Pain Scale
FPS-R FPS-Revised
FRAX Fracture Risk Assessment Tool
GABA Gamma-aminobutyric acid
GCT Giant cell tumor
GDS Geriatric depression scale
GEMU Geriatric evaluation and management unit
GERD Gastroesophageal reflux disease
GGT Gamma glutamyl transpeptidase
GH Growth hormone
G-I Gastrointestinal tract
GIC Global impression of change
GOLD Global Initiative for Chronic Obstructive Lung
Disease
GP General practitioner
GPM Geriatric pain measure
GRADE Grading of Recommendations Assessment,
Development and Evaluation
HADS Hospital Anxiety and Depression Scale
HCD Heavy chain disease
HCC Hepatocellular carcinoma
HCV Hepatitis C virus
HDI Human Development Index
HIV Human immune deficiency virus
HLA Human leukocyte antigen
H. Helicobacter
HPV Human papillomavirus
HR Hazard ratio
HRQL Health-related quality of life
HSAN Hereditary sensory autonomic neuropathy
HSV Herpes simplex virus
IADL Instrumental activities of daily living
IASP International Association for the Study of Pain
IBD Inflammatory bowel diseases
IBS Irritable bowel syndrome
ICD International Classification of Diseases
ICU Intensive care unit
IDDS Intrathecal drug delivery system
Ig Immunoglobulin
IGT Impaired glucose tolerance
1026
IGF Insulin-like growth factor

IgM Immunoglobulin M
IGT Impaired glucose tolerance
IFN Interferon
IL Interleukin
IMO Idiopathic male osteoporosis
IORT Intraoperative radiation therapy
IPIS International prognostic index score
IPSID Immunoproliferative small intestinal disease
IPT Iowa Pain Thermometer
IR Immediate-release
IVP Intravenous pyelography
IQR Interquartile range
IVU Intravenous urography
KL Kellgren/Lawrence
LBP Low back pain
LDH Lactate dehydrogenase
LiSat Life satisfaction
LPL Lymphoplasmacytic lymphoma
MAHA Microangiopathic hemolytic anemia
MALT Mucosa-associated lymphoid tissue
MBD Metastatic bone disease
MCS Motor cortex stimulation
MD Mean difference
MDASI M. D. Anderson Symptom Inventory
MDCT Multidetector Computerized Tomography
MDD Major depressive disorder
MGUS Monoclonal gammopathy of undetermined
significance
MI Myocardial infarction
MIO Male idiopathic osteoporosis
MIR Immediate release morphine
MM Multiple myeloma
Mm/r Oral modified release morphine
MMSE Mini-Mental State Examination
MNA Mini Nutritional Assessment
MNA-SF MNA short form
MPI Multidimensional Pain Inventory
MPQ McGill pain questionnaire
MR Magnetic resonance
MRI Magnetic resonance imaging
MRU Magnetic resonance urography
MS Multiple sclerosis
MTA Microtubule-targeting agent
MTD Maximum tolerated dose
NAO Nenetskij Avtonomnyj Okrug
1027
NCC National Cancer Centre
NCCN National Comprehensive Cancer Network

NCI National Cancer Institute
NCI-CTC National Cancer Institute Common Toxicity
Criteria
NCS Nerve conduction study
NES Nerve electrophysiological study
NICE National Institute for Health and Clinical
Excellence criteria
NIH National Institutes of Health
NHS National Health Service
NHWS National Health and Wellness Survey
NMDA N-methyl-D-aspartate
NNH Numbers needed to harm
NNT Numbers needed to treat
NPRS Numerical pain rating scale
NRS Numerical rating scale
NSAIDs Non-steroidal anti-inflammatory drugs
NSCLC Non-small cell lung cancer
OA Osteoarthritis
OPG Osteoprotegerin
OR Odds ratio
OTC Over the counter
OXL Oxaliplatin
PAR2 Protease-activated receptor 2
PBC Primary biliary cirrhosis
PCCL Pain coping and cognition list
PCPs Primary care professionals
PCR Polymerase chain reaction
PCS Pain Catastrophizing Scale
PCT Palliative Care Team
PDI Pain Disability Index
PDQ Pain Disability Questionnaire
PEDro Physiotherapy Evidence Database
PENS Percutaneous electrical nerve stimulation
PET Position-emission tomography
PID Pain intensity difference
PI-NPRS Pain intensity numerical pain rating scales
PMI Pain Management Index
PNS Peripheral nerve stimulation
PRS Pain rating scale
PSA Prostate specific antigen
PSOCQ Pain Stages of Change Questionnaire
PSQI Pittsburgh Sleep Quality Index
PTH Parathyroid hormone
PTH-rP Parathyroid hormone-related protein
1028
RA Rheumatoid arthritis
RANK Receptor activator of nuclear factor κB
RANKL Receptor activator of nuclear factor-κB ligand

RCC Renal cell carcinoma
RCT Randomized controlled trial
RIPN Radiation-induced peripheral neuropathy
RPU Retrograde pyelography and/or ureteroscopy
RPUC Renal pelvis urothelial carcinoma
RR Relative risk
RT Radiotherapy
RWS Red Wedge Scale
QLQ-C15-PAL Quality of Life Questionnaire Core 15 Palliative
QOL Quality of life
QUADAS Quality Assessment of Diagnostic Accuracy
Studies
SCI Spinal cord injury
SCID Structured Clinical Interview
SCLC Small cell lung cancer
SCS Spinal cord stimulation
SD Standard deviation
SE Standardized effect size
SEER Surveillance, Epidemiology and End Result
Program
SGOT Glutamic-oxaloacetic transaminase
SF Short form
SF-6D Short Form 6 Dimensions
SF-36 Short Form 36 Quality of Life Questionnaire
Sfi72 A stool-free interval > 72 hours
S-LANSS Self-Reported Leeds Assessment of Neuropathic
Symptoms and Signs
SLL Small lymphocytic lymphoma
SMD Standardized mean difference
SNAP Sensory nerve action potential
SNHS Spanish National Health Surveys
SNRI Serotonin-norepinephrine reuptake inhibitor
SNS Sacral nerve stimulation
SP Substance P
SPID Sum of Pain Intensity Difference
SPQ Social support and pain questionnaire
SR Sustained-release
SRE Skeletal-related event
Sr89 Strontium chloride 89
SSRI Selective serotonin-reuptake inhibitor
STAI-S Spielberger State Anxiety Inventory
TCA Tricyclic antidepressant
TDF Transdermal fentanyl
1029
TENS Transcutaneous electric nerve stimulation

TGF Transforming growth factor
THC Novel Δ(9)-tetrahydrocannabinol
TNF Tumor necrotic factor

TRPV1 Transient receptor potential vanilloid subfamily,
member 1
TRPV1 Transient receptor potential vanilloid subfamily,
member 1
TSH Thyroid-stimulating hormone
UC Ulcerative colitis
UTI Urinary tract infection
UTUC Upper-tract urothelial carcinoma
UUC Ureter urothelial carcinoma
VAS Visual analog scale
VDS Verbal Descriptor Scale
VGDF Vapors, gases, dusts, and fumes
VNRS Verbal numeric rating scale
VRS Verbal rating scale
WBS Wong-Baker FACES Pain Rating Scale
WHO World Health Organization
WM Waldenström's macroglobulinemia
WMD Weighted mean difference
WOMAC Western Ontario and McMaster Universities
WPAI Work Productivity and Activity Impairment
questionnaire
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APPROACH TO A PATIENT WITH SEVERE BONE PAIN

Book · September 2013

Liubov Ben-Noun (Nun)

Unique Medical Research in Biblical Times View project

The user has requested enhancement of the downloaded file.

Medical Research in Biblical Times

People have suffered from chronic pain, which can be associated

NOT FOR SALE

Ben-Gurion University of the Negev

Published By B.N. Publications House, Israelin Israel

Fax: +(972) 8 6883376 Mobile 050 5971592

Graphics and Cover: Ilana Ben-Nun

All rights reserved

NOT FOR SALE 2013

APPROACH TO A PATIENT WITH NON-MALIGNANT PAIN 127

HEMATOLOGICAL MALIGNANCIES 385

RESPIRATORY SYSTEM MALIGNANCIES 447

GASTROINTESTINAL TRACT 473

UROLOGICAL MALIGNANCIES 525

BONE TUMORS 580

METASTATIC BONE DISEASE 606

NEUROPATHIC PAIN 693

APPROACH TO A PATIENT WITH CANCER PAIN 759

NON-PHARMACOLOGICAL THERAPY 761

PHARMACOLOGICAL THERAPY 800

OTHER TREATMENT MODALITIES 930

MANAGEMENT OF CANCER PAIN IN THE ELDERLY 983

MEDICINE IN THE BIBLE

These are scientific medical studies incorporating verses from the

Fundamentally, this Research is constructed purely from an

The research is part of a long series of published studies on the

This is not a laboratory research. The Research is built entirely on

Chronic pain patients use a number of cognitive and behavioral

coping strategies such as avoiding behavior was most important. At

disability, and response to medical treatments among persons with

framing pain management as an ethical issue; promoting pain

chronic pain related to the family? What is the contemporary

THE MEDICAL RECORD

King David also suffered from weakness. Passages ―My strength

Biological changes of aging can be included among the factors

The verses ―...a broken and depressed heart..‖.(Psalm 51:19) and

interpersonal relationships. Persistent negative stress and negative

Pain is divided by its underlying etiology into non-cancer-related

released at a site of tissue inflammation. The mediators that have been

Table 1. Types of Pain (6).

ACUTE VERSUS CHRONIC PAIN

THE BODY SYSTEM CLASSIFICATION

Assessment: the biblical verses "my bones are consumed‖ (Psalm

7. What is definition of acute pain. The British Pain Society. Accessed 28

EPIDEMIOLOGY OF CHRONIC PAIN

countries and 41.1% in developing countries, with back pain and

Hispanic African American subjects, and Hispanic subjects of any

Mississippi survey data represent a subset of the data obtained in the

studies containing epidemiological data on chronic non-cancer pain in

prescription analgesics; 'OTC', NSAIDs (55%), paracetamol (43%),

factors on the presence of neuropathic pain. This study concludes that

problem which influences the QOL of patients resulting in high costs

In this descriptive, retrospective, cross-sectional study conducted

regressions of pain. Chronic pain showed associations with

95% CI 1.06 - 1.42), and presence of comorbid chronic diseases (OR

burden, and affects in particular the most vulnerable subgroups of the

disturbances was common in the general adult population. Multiple

Assessment: individuals suffer from chronic pain in all countries,