Management of Pain in the Cancer Patient

Ashburn Michael A. MD; Lipman, Arthur G. PharmD

Anesthesia & AnalgesiaAnesthesia & Analgesia. 76:p 402–416, February

1993.

Author Information

Acute Pain Service, Department of Anesthesiology, and College of

Pharmacy, Pain Management Center, University of Utah Health Sciences
Center, Salt Lake City, Utah

Accepted for publication September 17, 1992.

Address correspondence and reprint requests to Michael A. Ashburn, MD,

Department of Anesthesiology, University of Utah Health Sciences Center,
50 North Medical Drive, Salt Lake City, UT 84132.

Up to 40% of patients with cancer suffer from pain (1), and up to 80% of
patients with cancer with advanced disease experience moderate to severe
pain (2,3). As many as 25 million people throughout the world die each year
without adequate pain control (4). In patients with progressive cancer, pain
is not a helpful aspect of the disease process. It does not provide useful
diagnostic clues; it leads to suffering and markedly diminishes the patient's
quality of life (5).

Information, attitudes, and expectations about pain and pain management

have changed dramatically in the past 30 yr among health professionals,
patients, and the general public. The acute pain model of pain as an
indicator of disease or injury is now recognized as inadequate in defining
and treating pain in the patient with cancer. In 1979, the International
Association for the Study of Pain published the following definition:

Pain is an unpleasant sensory and emotional experience associated with

actual or potential tissue damage or described in terms of such damage.
Pain is always subjective. Each individual learns the application of the word
through experiences related to injury in early life. It is unquestionably a
sensation in a part or parts of the body but it is always unpleasant and
therefore an emotional experience (6).

Both the physical and emotional components of pain should be addressed

for management of this symptom in patients with cancer.

In 1986 the National Institutes of Health conducted a consensus

development conference which resulted in a report entitled, “The Integrated
Approach to the Management of Pain” (7). This report differentiated among
acute pain, chronic pain of malignant origin, and chronic pain of
nonmalignant origin. These three types of pain differ neurologically,
psychologically, in associated problems, in prognosis, in social effects, and
in biological value (Table 1). Therefore, different therapeutic approaches
are indicated.

Categories of Pain

With increasing understanding of the pain experience, more attention is

being paid to its management. (8). A $15 million judgment recently was
awarded to the family of a man who suffered from severe pain. At the time
of his death, the staff of a skilled nursing facility refused to administer to
the patient the opioid analgesics that had been ordered to relieve his cancer
pain. The court stated that the patient had a right to appropriate pain
treatment (9).

Cancer patients may experience acute pain associated with pathological

fractures, tumor invasion, surgery, radiation, and chemotherapy. Guidelines
for the management of acute pain in adults and children have been
published recently (10,11). Many cancer patients have histories of chronic,
nonmalignant pain which co-exists with their neoplastic disease. Others
may develop deafferentation pain, ischemic pain, or other problems
commonly considered nonmalignant pain due to the progress of their
disease or its treatment. Management of these types of pain recently has
been described elsewhere (12-14).

Anesthesiologists commonly become involved in cancer pain management

through patient referral. Some anesthesiologists [play] a well-defined role,
providing diagnostic or therapeutic nerve block therapy as suggested by
referring physicians. This is important, but it is only one aspect of patient
evaluation and care that anesthesiologists can offer, often through
interdisciplinary pain management centers (15,16). This manuscript
describes evaluation and management strategies for patients with cancer
referred for pain.

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The Pain Experience

The pain experience is multidimensional (17). It includes the physiological

component (nociception); the sensory component (i.e., the individual's
perception of nociception, such as pain location, intensity, and quality); the
affective component (i.e., mood and anxiety response); the cognitive
component (i.e., how the pain affects patients' thought processes and how
the patients view themselves); and the behavioral component (i.e., pain
behaviors such as analgesic intake or activity level) (18).

Patients with cancer who suffer from pain frequently exhibit signs of
depression and increased anxiety (19). They also exhibit higher depression
and anxiety scores than matched cancer patients not experiencing pain (18).
Suicidal ideation may be present in 7-20% of patients suffering from cancer
pain (20-22). Because signs and symptoms of depression frequently go
unrecognized by primary care physicians (23,24), assessment and
appropriate treatment of affective and anxiety disorders must be included in
any cancer pain management plan. The evaluation and treatment of
psychiatric complications in the patient with cancer recently has been
reviewed elsewhere (22).

The behavioral component plays an important role in the cancer pain

experience. Many physicians assume that analgesic intake reflects the
intensity of noxious stimuli. In fact, there is no correlation between pain
intensity and analgesic intake in patients with advanced disease (25). Nor is
there a demonstrable pharmacokinetic-pharmacodynamic relationship for
the dosing of methadone to patients with cancer pain (26). Analgesic intake
is impacted by physiological, affective, and cognitive components of the
pain experience (18).

Pain may be affected by other behavioral factors (27). For example, the
reaction of significant others to the patient's pain may result in secondary
gain exacerbating pain behavior. Ahles et al reported that more than three-
fourths of cancer patients experiencing pain believed significant others
knew when they were experiencing pain (18). In response, those significant
others offered expressions of concern or aid, and often assumed some of the
patients' responsibilities.

Health care providers may play a role in the development or maintenance of

the pain experience by impacting the affective component of pain. Many
patients view pain as an indication of a worsening of their physical status
(28). Although this impression may be justified, other factors can affect the
pain experience as well. In a survey of 667 cancer patients, among those
evaluated for moderate to severe pain, the cancer was the on use of the pain
only half of the time (29). Unfortunately, many physicians do not give
cancer patients adequate information concerning the source or meaning of
their pain (18). The patients, lack of understanding and possible
misinterpretation of pain may increase depression and anxiety, as well as
interfere with activities of daily living and the patients' enjoyment of life
(29). Poor physician communication skills have been identified as a major
stumbling block in the development of a good physician/ patient
relationship, and can affect patient care adversely (30-32). Effective
communication and empathy is especially important when caring for cancer
patients suffering from pain (33).

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Patient Assessment

The goal of patient assessment is to identify possible sources of pain and

guide the implementation of a treatment plan to decrease the pain
experience. In patients with advanced cancer, effecting a cure (i.e.,
eradicating the cancer) may not be an achievable goal. However, one must
continue to look at pain as a symptom, not a diagnosis (34).

The assessment of pain in cancer patients can be difficult (35). In one study
of cancer pain, nearly twothirds of patients referred for pain consultation
had a previously undiagnosed etiology for their pain (16). The most
frequent source of pain was metastatic neoplasm, but many other causes of
pain were identified. Care should be taken to identify patients who may
benefit from chemotherapy or radiation therapy for palliation and pain
control (36). Examples of causes of pain which are indicators for very
different approaches than simple opioid analgesics are illustrated in Table 2.
Several different assessment methods have been suggested, based on the
etiology, the temporal aspect, or the pathophysiology of the pain.

Drugs Which May Be Useful in Pain of Different Etiologies

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Pain Assessment

Etiology of Pain Foley has described pain in the cancer patient based on the
etiology of the pain (1). These syndromes are divided into three major
categories: pain associated with direct tumor involvement, pain associated
with cancer therapy, and pain not associated with cancer or cancer therapy
(Table 3). In a major cancer center, 78% of the pain problems seen in the
inpatient population (1) and 62% of the pain problems seen in the outpatient
population (34) were due to direct tumor involvement. Of the inpatients,
50% experienced pain due to metastatic bone disease, 25% experienced
pain due to nerve compression or infiltration, and 3% experienced pain due
to hollow viscus involvement.

Specific Pain Syndromes in Patients with Cancer*

Pain syndromes associated with cancer surgery, chemotherapy, or radiation

therapy accounted for 19% of the inpatient pain problems (1) and 25% of
the outpatient pain problems (34). These included phantom limb syndrome,
postthoracotomy syndrome, and pain due to the adverse side effects of
chemotherapy or radiation therapy.

Three percent of inpatient pain problems (1) and 10% of outpatient pain
problems (34) were the result of neither the cancer or cancer therapy.
Causes for such pain included osteoporosis and diabetic neuropathy.
Another study of 100 cancer pain patients (37) reported that more than 20%
of pain experienced by cancer patients was unrelated to the disease or its
treatment. That study led to the recognition of a fourth category: pain
related to chronic disease or debility (Table 4).

Source of Cancer Pain in Adults

Bone pain is the leading specific cause of pain. Up to 85% of patients with
bony tumors or metastases experience severe pain at some time in the
course of their disease. Conversely, less than 10% of patients with
lymphomas or certain leukemias experience severe pain.

Data on the epidemiology of cancer pain in children are limited. Initial

reports document that fewer children with cancer suffer from pain when
compared to their adult counterparts (38). The prevalence and nature of
pain in children and young adults with cancer were studied at the National
Cancer Institute for 6 months (39,40). Forty-eight percent of the inpatients
and 26% of the outpatients reported pain. As opposed to adults, the
predominate cause of pain was related to cancer therapy rather than to
tumors (Table 5). This may be due to the lower incidence of solid tumors in
children. Therapy-related pain accounted for 78% of the pain in inpatients
and 80% in outpatients. Tumor pain accounted for only 30% of the pain in
inpatients and less than 20% in outpatients. Pain not related to the tumor or
cancer therapy accounted for none of the pain in inpatients and only 6% in
outpatients.
Etiology of Cancer Pain in Children*

When considering only those children experiencing pain associated with

active malignancy, 46% had pain due to the tumor alone, 14% had pain due
to both tumor and therapy, and 40% had pain caused by the cancer therapy
(Table 6). As in adults, a majority of tumor-related pain is bone pain.

Etiology of Cancer Pain in Children with Active Malignancy*

Temporal Aspect Cancer pain has also been described according to its
temporal aspect as either acute, chronic, or incidental (41). Acute pain is
characterized by a well-defined temporal onset of limited duration. Chronic
pain is described as pain lasting for more than 3 mo. Incident pain is pain
which occurs on movement, usually due to mechanical changes as a result
of the underlying cancer. An additional term, “breakthrough pain” is also
useful in the description of the cancer pain experience. Breakthrough pain
has been defined as a transitory flare of pain in the setting of chronic pain
managed with opioid drugs (42).

Pathophysiology In the evaluation of cancer pain, pain pathophysiology has

been described as organic or psychologic (Table 7) (43-45). While
recognizing that the psychologic aspects of pain can contribute greatly to
the pain experience, the authors recommended that the organic cause of the
pain experience should be identified in order to guide pain management.

Pathophysiologic Classification of Cancer Pain

Organic pain may be subdivided into nociceptive or neuropathic pain.

Nociceptive pain includes somatic and visceral pain (42), and refers to pain
due to the peripheral stimulation of nociceptors in somatic or visceral
structures. Somatic pain is related to tumor involvement of somatic
structures such as bone or muscle, and is commonly described as “aching,”
“stabbing,” or “throbbing.” Visceral pain is related to a lesion in a hollow or
solid viscus and is described as “diffuse,” “gnawing,” or “crampy” if a
hollow viscus is involved. It is more commonly described as “aching” or
“sharp” if a solid viscus is involved. Nociceptive pain is usually responsive
to nonopioid and/or opioid analgesics (46-48).

Neuropathic pain involves peripheral or central afferent neural pathways

and commonly is described as unfamiliar burning or lancinating pain. The
terms “neuropathic,” “neurogenic,” and “deafferentation” have been used
synonymously to describe non-nociceptive pain associated with evidence of
peripheral nerve involvement by the tumor (35). These pain descriptors
have been effective in identifying which patients may be more responsive to
certain treatment modalities (48,49). In particular, patients suffering from
neuropathic pain frequently respond poorly to opioid analgesics (49-52).

In summary, the evaluation of the patient with cancer pain should be guided
toward identifying the source(s) of the pain. In adults, the most frequent
source of pain is metastatic disease, particularly bone pain. However, other
sources of pain, some of which are not directly the result of cancer, are
frequently present. Diagnosis and treatment of behavioral components of
the pain experience should be part of the care of the patient with cancer
pain. As time progresses, patients often experience changes in their pain,
requiring reevaluation and changes in intervention (34,37).

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Pain Management

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Basic Principles

The guiding principle of pain management is to individualize the approach

to the patient's needs (41). Although drug therapy is the mainstay of cancer
pain management, individual assessment must be performed to identify pain
which may be treated better using other modalities. In choosing among
treatment options, usually the simplest, least invasive therapy should be
attempted first. Examples of various nonpharmacologic approaches to
cancer pain management are listed in Table 8.
Examples of Nonpharmacologic Approaches to Cancer

Drug therapy is the cornerstone of cancer pain management due to its

efficacy, rapid onset of action, and relatively low cost. Opioid analgesics are
the major drugs used in advanced cancer pain. However, the dose ranges
and routes commonly used to treat acute pain are often inappropriate and
inadequate for the management of cancer pain.

Opioids can be differentiated according to the categories of receptors which

they preferentially occupy and activate. These receptors, and the effects of
their being activated, are illustrated in Table 9 and the relative affinities of
commonly used opioids for the receptors are illustrated in Table 10.
Effects of Activation of Opioid Receptors

Relative Affinities of Selected Opioids for Differentiated Opioid Receptors

κ-agonist and partial μ-agonists play a limited role in the management of

cancer pain. The agonist-antagonist (pentazocine, nalbuphine, butorphanol)
and partial agonist (buprenorphine) opioids have a ceiling effect above
which additional analgesia does not occur but where there are additional
side effects. Therefore, the maximum doses listed in the labeling for these
drugs should not be exceeded (53).
Much of the pharmacology of opioids learned from animal models and
acute pain studies is not applicable to the use of these drugs in managing
chronic cancer pain. Animal models do not describe the cognitive
components of pain that are important in man. Moreover, the effects of
opioids vary with acute and chronic use. Several myths about the use of
morphine and other opioid analgesics are still taught in some health
professional curricula and postgraduate training programs (54).

Generally, severe cancer pain is an indication for a drug which is primarily

a μ-receptor agonist. Low doses provide good analgesia for moderate pain
and higher doses can be administered for more severe pain. Up to fiftyfold
interpatient variances have been reported for the oral doses of morphine that
are safe and effective (55). Morphine is the most commonly used drug
because of its availability in a wide range of dosage forms, its relatively low
cost, and its well-characterized kinetics. However, patients may have a
variable response to different opioids, and selection of an alternative opioid
may be indicated (56).

Large doses of potent opioids can be administered orally. Oral doses often
provide more consistent serum levels than subcutaneous or intramuscular
doses. A large majority of cancer patients can be treated using only the oral
route; however, up to 60% of patients will require additional or alternative
routes of drug delivery during the last 4 wk of life (21,57). In those cases,
intravenous, subcutaneous, epidural, intrathecal, rectal, or other noninvasive
(transmucosal or transdermal) routes should be considered.

There is no maximum safe dose of morphine and most other μ-agonist

opioids. Serum concentrations do not provide a useful indicator of efficacy
for most opioids. Only titration of these opioids to response will
consistently and reliably allow a clinician to determine the optimal dose for
a specific patient. Median oral morphine doses that have provided pain
relief for advanced cancer patients have commonly been in the range of 10-
20 mg every 4 h (58,59). Using this as a starting point, a clinician may
increase the dose aggressively, e.g., 25-50% each dosing interval until pain
relief is obtained, or until unacceptable side effects occur (60).
Tolerance to opioids does occur, but it need not be a clinical problem. Most
of the effects of opioid tolerance occur in the first weeks of therapy.
Titration to response obviates clinical implications of tolerance. With
continued opioid dosing as in cancer pain, patients' dose requirements
commonly remain stable over weeks to months (61). Often, in advanced
cancer, opioid dose requirements decrease over time with resolution of
tumor size, decreased anxiety, destruction of nerve endings in painful
organs or tissues secondary to disease or treatment, or are the result of other
comorbidity factors. Therefore, increased dose requirements are often
indicative of progressive disease, not tolerance (62).

Unnecessary fear of addiction is a major reason that opioids are under-used.

Opioids certainly may cause addiction among recreational drug users and
drug abusers. Addiction is rare, however, when opioids are used correctly
(63). An analysis of 11,882 patients who received opioids for medical
indications and who were monitored for addiction revealed only four cases
in patients who did not have a previous history of substance abuse (64).

Commonly, one type of pain will mask another. When the initial pain is
treated, another pain may appear. Most cancer patients have pain of more
than one etiology. A study of advanced cancer patients revealed that more
than three-fourths of these patients have pain of more than one cause and
more than one-third will experience pain of four or more different etiologies
(37). Each pain must be treated separately as it occurs, and the fact that
multiple pains are common should be explained carefully to the patient.
Continual reassessment of the patient is required to identify the
effectiveness of pain management, to identify and treat adverse side effects,
and because the pain experience itself often changes over time. The
clinician must also ensure that the expertise necessary to provide the
treatment modality is available.

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Analgesic Therapy

Drug therapy which follows the World Health Organization (WHO) cancer
pain relief guidelines (65) or treatment as described by the American Pain
Society (66) is the mainstay of cancer pain management. Drug therapy is
widely available, and is frequently successful if used correctly. Analgesic
therapy according to the WHO guidelines was successful in 71% of patients
suffering from cancer pain during therapy (67) and in at least 76% of
patients suffering from cancer pain at the end of their lives (57). In this
study, only 3% of the patients reported severe or very severe pain following
maximal drug therapy near the time of their death. Parenteral administration
of opioid analgesics is necessary in some patients. Intramuscular
administration is often uncomfortable, inconvenient, and may lead to
inadequate pain control. Intravenous infusion is useful (68,69), especially
when a patient-controlled analgesia (PCA) device is employed (70-72).
Subcutaneous administration can provide good analgesia and is achievable
when small, continuous infusion pumps are used (73-75).

The WHO has described a simple and effective three-step ladder for relief
of cancer pain (Figure 1). The first step is for mild to moderate pain, which
is treated with nonopioid analgesics. These drugs, which include
nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Table
11), are excellent for treating mild to moderate pain, especially when they
are administered on a time-contingent dosing schedule. In addition to
analgesic effects, NSAIDs also have antipyretic and anti-inflammatory
effects. Acetaminophen, while having analgesic and antipyretic effects,
lacks useful peripheral anti-inflammatory activity.
WHO Analgesic Ladder. Reproduced with permission from the World Health Organization (65).

Analgesics Commonly Used for the Management of Mild to Moderate Cancer Pain
The use of NSAIDs is sometimes associated with numerous side effects,
most notably gastric ulceration and renal damage (76,77). Hepatic, central
nervous system (CNS), and pulmonary side effects rarely occur (78).
NSAIDs may interact with other drugs, such as diuretics, β-blockers, and
some other antihypertensive medications. Careful patient monitoring is
indicated when these drugs are given on a long-term basis (79). These
analgesics also have a ceiling, above which increased doses have no
increased analgesic effect. Patients should be well hydrated. Patients with
true or relative hypovolemia (e.g., those receiving diuretics, congestive
heart failure) are at increased risk for adverse events. Aspirin is normally
avoided in cancer patients with advanced disease because its acetyl moiety
irreversibly impairs platelet adhesiveness. Other NSAIDs, including the
non-acetylated salicylates, cause this effect reversibly and, therefore, are
preferred in many cancer patients.

NSAIDs are especially effective for the management of bone pain and,
therefore, play a major role in the management of cancer pain. The most
common cause of pain in adults and children with active cancer is invasion
of bone by tumor (80) which appears to cause pain by direct involvement of
the bone and activation of local nociceptors and/or by compression of
adjacent nerves, tissues, or vascular structures (80,81).

The second step of the WHO three-step ladder is for moderate to severe
pain and requires the addition of codeine or an analogue of this drug. These
opioids can also be used as alternatives to NSAIDs for the management of
mild to moderate pain if NSAIDs are not tolerated or are contraindicated.
Codeine, oxycodone, and hydrocodone are the most frequently used opioids
in this group. These drugs often are given together with to a nonopioid
analgesic, because the combination results in potentiation due to the fact
that opioids act centrally and NSAIDs act primarily in the periphery (82).

Codeine, oxycodone, and hydrocodone are commercially available and are

used most commonly in fixed-dose combinations with acetaminophen or
aspirin. These combinations limit the effective doses of codeine or
oxycodone that can be used because of the toxic effects of high doses of the
nonopioid. A preferred method is to administer the selected nonopioid on a
time-contingent basis and to titrate the opioid dosage while administering it
separately. There appears to be a diminishing return when oral codeine
doses are increased more than 65 or 100 mg. Once those dose levels are
reached, additional increments provide less incremental analgesia but full
additional incremental side effects.

The third step of the WHO ladder is for the management of severe pain.
Codeine or a congener is replaced with a more effective opioid, usually
morphine. Morphine (83), hydromorphone, and methadone (84) are
frequently used potent opioids. The dosage of the opioid is individualized
for each patient (83) and often requires adjustment over time. Occasionally,
the cancer patient may require massive doses of opioids for adequate pain
management (21,85,86). While the analgesic potency varies among opioids
(Table 12), effective analgesia can be obtained with most of the drugs in
this class. The selection of an opioid for a particular patient is often made
on the basis of the possible adverse side effects with a particular drug in that
patient, drug cost and availability, and the prescribing physician's
experience.

Comparative Pharmacokinetic Dosing Data for Opioid Analgesics

Morphine has a linear dose-response curve with a broad therapeutic range.

Therefore, low-dose morphine may be appropriate when the pain is not
advanced, and high-dose morphine may be used as the pain progresses (62).
Because tolerance is not a clinical issue, morphine (or another potent
opioid) should be started as soon as it is indicated.
The patient should be monitored for the development of unique side effects
occasionally seen in patients receiving long-term high-dose opioids, such as
noncardiac pulmonary edema (87), unexpected drug accumulation, and
unexpected accumulation of drug metabolites (88,89).

Opioids depress respiration and must be used with caution in patients with
impaired respiratory capability. However, pain also suppresses breathing in
many patients, especially those with chest disease or injury. Too often,
opioids are wrongly withheld or incorrectly dosed in patients with impaired
respiratory capability. A study of patients with lung cancer who received
aggressive opioid analgesia for pain relief revealed that the drugs did not
adversely affect respiratory function as determined by analysis of arterial
blood gases (90).

Meperidine is an effective oral and parenteral μ-agonist for the treatment of

acute pain. However, it should be avoided in the management of cancer
pain. Meperidine has a short duration of action (2.5-3.5 h) which requires
frequent dosing. In addition, the meperidine toxicity of metabolism can lead
to the accumulation of nor-meperidine (6-desmethylmeperidine). This
metabolite can accumulate due to its long half-life (24-36 h), especially in
elderly patients and patients with impaired renal function. It is a cerebral
irritant which can cause effects ranging from mood irritability to grand mal
seizures (91).

Fentanyl has been incorporated into a transdermal delivery system and has
been released for use in the management of chronic pain requiring opioid
administration (TTS-fentanyl) (92,93). TTS-fentanyl is designed to deliver
fentanyl at a constant rate of 25, 50, 75, or 100 μg/h. Plasma concentrations
of fentanyl increase slowly with the TTS-fentanyl system and peak only
after about 15 h. The fentanyl levels remain level, then decrease slowly
after removal of the patch, with an apparent half-life of 21 h (Figure 2) (94).
This system may be useful in selected cancer pain patients in whom the oral
tract is no longer available for opioid delivery, or who experience adverse
side effects to oral morphine or methadone. This dosage form should not be
used to titrate patients' doses due to the long time needed to achieve steady
state serum levels. Fentanyl is much more expensive than oral morphine or
methadone and should be used only when more conventional alternatives
have failed. Other noninvasive drug delivery systems, such as iontophoresis
of morphine (95) and oral transmucosal fentanyl citrate (OTFC) (96-98),
are being investigated. They may have a role in the management of cancer
pain, but are not currently available for clinical use.

Mean serum concentrations of fentanyl in patients who received fentanyl transdermally, preceded by a 300-μg loading dose at time zero (error bar ± SD). Reproduced with
permission from Holley and van Steenis (94).

Adjuvant Drugs Adjuvant drugs are suggested for consideration at each step
of the WHO three-step analgesic ladder. Adjuvant drugs are those drugs
which enhance the effects of analgesics, have independent analgesic activity
in certain pain syndromes, or lessen other symptoms which exacerbate pain.
Adjuvants include the tricyclic antidepressants, anticonvulsants, and
steroids.

Tricyclic antidepressants are recommended by WHO for patients who

remain depressed despite improved pain control, as well as for those
patients suffering from deafferentation pain. However, these agents are also
effective in patients without depression (99). They have been used in
patients with cancer pain for many indications, appear to have direct
analgesic effects, and may potentiate opioid analgesia (100). The
mechanism of action is unclear, but it may be through the blocking of re-
uptake of serotonin and norepinephrine at the CNS synapse. These drugs
usually are not useful as analgesics alone in treating chronic, malignant
pain.
Tricyclic antidepressants have been used for many chronic pain syndromes
(55,101), including migraine headache (102), diabetic neuropathy
(99,103,104), postherpetic neuralgia (105,106), myofascial pain (107), and
potentiation of opioid analgesia in cancer pain. Amitriptyline has been well
documented for its effectiveness in the management of chronic pain. Other
tricyclic antidepressants, including imipramine and desipramine, have also
been useful and are particularly helpful for the management of continuous
dysesthesia and lancinating neuropathic pain (108).

The analgesic effect of tricyclic antidepressants often occurs at doses less

than (1/3 to 1/2) than that used for the management of major depression.
Oral doses of 50-125 mg/day amitriptyline started at 25 mg at bedtime and
titrated upward in 25-mg increments about every 3 days until desired or
bothersome effects occur are common. Sleep may improve within a few
days of starting the tricyclic agent, and some analgesic effects of these
drugs may be seen within a week of beginning drug therapy. However, it
may take up to 3 wk to see the full analgesic effect. Side effects include
anticholinergic effects (dry mouth, urinary retention, delirium), sedation,
and orthostatic hypotension. The side effect of sedation may be helpful in
many patients with cancer pain, and the medication can be administered at
bedtime to facilitate sleep.

Anticonvulsant drugs also are used in the management of chronic,

neuropathic pain (109,110). Carbamazepine suppresses spontaneous
neuronal firing and may be effective for the management of acute neuralgic
pain, particularly for pain originating from the cranial and cervical area.
Carbamazepine is helpful in the management of neuralgic cancer pain.
Carbamazepine may be helpful in the management of acute, lancinating
neuralgic pain due to surgical trauma or nerve destruction by tumor. It may
also be useful in treating trigeminal neuralgia, postherpetic neuralgia, and
diabetic neuropathy.

The usual dose of carbamazepine is 400-800 mg/ day. Commonly, an initial

dose 100 mg is administered at bedtime, and doses are increased gradually
until symptoms improve. Carbamazepine is associated with many side
effects and may not be tolerated. Neutropenia is a serious side effect;
patients' neutrophil counts must be monitored. Carbamazepine may be
contraindicated in cancer patients with bone marrow suppression. While the
data are limited, phenytoin (111) and valproic acid have been used as
adjuvant drugs for the management of cancer pain.

Steroids have several benefits to the cancer patient. They can lower pain
perception, have a sparing effect on opioid dose, improve mood, increase
appetite, and lead to weight gain. In the patient with advanced disease,
steroids can improve quality of life (112). In addition, steroids are part of
the routine management of patients suffering from spinal cord compromise
secondary to tumor because steroids reduce edema in the tumor and nervous
tissue (81). Steroids alone are effective in the management of bone pain
caused by metastatic breast and prostate cancer. Many of these effects are
seen at relatively low doses, e.g., 5-10 mg of prednisone each morning.
Relatively low mineralocorticoid drugs, such as prednisone or
dexamethasone, should be used to lessen the risk of exacerbating edema
and water-electrolyte disturbances associated with the underlying disease.
Long-term use of steroids can lead to weight gain, Cushing's syndrome,
proximal myopathy, and rarely psychosis. In addition, NSAIDs should be
used with extreme caution or not at all in patients receiving steroids, as the
combination increases the risk of gastric ulceration and gastrointestinal
bleeding.

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Spinal Opioid Administration

Spinal opioids cause analgesia by binding to and activating (agonizing)

opioid receptors located at the dorsal horn of the spinal cord (113,114).
Morphine, administered either intrathecally or epidurally, has been used for
the management of acute and chronic pain (115). However, this method of
drug delivery has not had widespread use due to technical difficulties in
long-term spinal opioid administration and a poor understanding of which
patients may benefit from this method of analgesia.

Until recently, the duration of spinal opioid administration has been limited
(116). Catheters designed for short-term use frequently dislodge, occlude,
or break if left in place for more than several days. The development of new
catheter materials and placement techniques has allowed delivery of spinal
opioids for weeks to months (117-119). This can be accomplished by the
placement of long-term, subcutaneously tunneled, exteriorized catheters, or
by the use of implantable drug delivery systems. The implantable systems
can be either intrathecal (120-122) or epidural (48) and feature either a drug
reservoir (123) or an implanted infusion device (117). More recent models
of the implanted infusion devices allow for external reprogramming.

The choice of drug delivery system is made on the basis of physician

expertise, system cost (124), and patient criteria (125). There appears to be
no difference between the efficacy of bolus and continuous infusion of
spinal opioids for the management of cancer pain (126). The choice of the
method of drug delivery can be made based on patient preference, cost, and
the availability of nursing support when required.

Complications often occur with all the long-term spinal opioid delivery
systems, which may limit their usefulness (127). These include superficial
and deep infection, catheter malfunction, and pain on injection (128,129).
There is an infection rate of 5% with a longterm externalized, tunneled
catheter (128) which can become occluded or dislodged and require
replacement. In addition, up to 12% of patients develop pain on injection,
possibly due to formation of a fibrous sheath around the catheter tip (130).
Similar complications can occur with implanted devices. The use of a Port-
A-Cath implanted epidural access system caused 6.7% of the patients to
experience a superficial or deep infection, and 16% of the catheters
migrated, leaked, or became occluded (Table 13).
System-related Complications

Neurogenic pain often is opioid resistant (48,52), whereas somatic and

visceral pain usually is responsive to opioids (49,131). Careful selection of
patients, including identifying those at increased risk for device placement,
is required. In our practice, patients are considered for spinal opioid
administration only when systemic opioid administration with analgesic
adjunct administration has failed, either as a result of the onset of
intolerable adverse (systemic) side effects, or because adequate analgesia
has not been provided. These patients then receive a trial of spinal opioid
administration for several days, usually as inpatients, using a short-term
epidural catheter. If this trial is successful, a long-term spinal opioid
administration system is placed. Patients who have a long-term spinal
opioid delivery system in place require extensive, long-term physician
follow-up (132).

Spinal administration of opioids is successful in most patients requiring

spinal analgesia. However, a subset of patients with cancer pain may require
additional analgesia not achievable with opioids alone. In those patients, the
addition of a low-concentration local anesthetic (usually bupivacaine) may
be beneficial, particularly if a component of the pain experience is
neurogenic pain. The addition of a local anesthetic to spinal opiates act in a
synergistic manner as far as analgesia is concerned (133-136). Intrathecal
and epidural infusions of bupivacaine and morphine have been used for
extended periods with good success and with no apparent neuropathologic
complications (137,138). The expected additional side effects (postural
hypotension, partial motor blockade, sensory blockade) occur, but are
usually well accepted by the patient.

Back to Top

Neurolytic Procedures

Neurolytic procedures for the management of cancer pain have been

attempted for years (139). Destructive nerve blocks have limited usefulness.
In general, the destruction of the sensory component cannot be
accomplished without the destruction of sympathetic and motor function as
well. However, in selected patients, nerve blocks may be very helpful (140).

As with other pain management modalities, patient selection is important.

Important aspects of determining the suitability of a destructive nerve block
are the location and quality of the pain, the effectiveness of less destructive
pain treatment modalities, the patient's life expectancy, the inherent risks
associated with the block, and the availability of trained health care
providers to perform the procedure. In general, constant pain is usually
more amenable to destructive nerve blocks than intermittent pain. To relieve
intermittent pain, the nerve block must often produce complete denervation
of all sensation modalities, which will have a profound effect on motor
function.

Neurolytic celiac plexus block has been used to treat pain originating from
the abdominal viscera (141,142). Blockade of the celiac plexus is often
effective in the management of pancreatic cancer pain, as well as for other
cancer pain originating in this area of the body (143-145). The block can be
completed using alcohol or phenol, and may be successful 80% of the time.
Analgesia usually lasts for more than a month and may last 6 months or
longer. The block is associated with many complications, but these are
infrequent or easily managed. Although there are several reports advocating
celiac plexus block, others have criticized these studies and question its role
(146).

Peripheral nerve blocks, which usually involve the destruction of mixed

nerves, will cause motor deficits and are of limited value. An exception is
the blockade of cranial nerves or pain originating from metastases involving
the intercostal nerves. Intrathecal neurolytic blocks have produced pain
relief lasting for months.

Intrathecal neurolytic blocks can be performed with alcohol (147) or phenol

(148,149). The patient usually can be positioned so that the posterior roots
of the spinal cord can be isolated. This leads to permanent anesthesia in the
corresponding derrnatomes. However, the anterior roots also can be
affected, causing the destruction of all types of fibers and leading to motor
dysfunction as well as a potential loss of bladder and rectal sphincter
function. Pain relief can be achieved in patients experiencing pain in the
lower chest, abdomen, inguinal, or lumbar regions. Pain in the upper
extremities or the upper chest frequently does not respond to intrathecal
neurolytic block.

Epidural neurolytic nerve blocks have been used for the management of
thoracic and cervical cancer pain (150). While the technique is fairly
simple, it can cause a large sensory deficit. In addition, motor block and
loss of bladder and rectal sphincter function can occur. Although motor
function usually resolves over time, it can be long lasting.

Neurosurgical procedures for the management of cancer pain (Table 8) are

reserved for those patients unresponsive to other less invasive procedures
(151,152). Previously, these techniques have led to limited analgesia with
significant adverse side effects (153,154). Surgical procedures for pain
relief can be divided into two main categories: neuroablative procedures
and neurostimulatory procedures. Neuroablative procedures attempt to
interrupt pain transmission along the neuropathway Neurostimulatory
procedures are operations during which electrodes are placed for the
electrical stimulation of portions of the central nervous system.

Cordotomy involves the interruption of the spinothalamic tract in the spinal

cord. It can be completed as an open cordotomy (155) or as a percutaneous
cordotomy (156). Cordotomy can be used for the treatment of unilateral
pain involving the lower extremity, thorax, or upper extremity (157,158).
Bilateral percutaneous high cervical cordotomy has been used for bilateral
or midline pain (159). Somatic and viseral pain is well controlled in 70-90%
of patients. Cordotomy is less effective in the treatment of neurogenic pain.
It is reserved for patients with limited life expectancy, because up to 50% of
patients may have resumption of pain within 12 mo. Complications are
more common following open cordotomy, and include bladder and bowel
dysfunction, ipsilateral paresis and ataxia, dysesthesia and sexual
dysfunction. Percutaneous cordotomy is associated with a 6% perioperative
mortality (158).

Dorsal rhizotomy involves the interruption of the sensory nerve root. It can
be completed as an open surgical procedure or by the use of a neurolytic
agent (160,161). Dorsal rhizotomy is used when pain is localized to a
specific dermatomal level, and may be useful in the treatment of pain
involving the chest wall (162). Some authors have advocated dorsal
rhizotomy for perineal pain (160,163). Unfortunately, it has limited
usefulness in the treatment of pain involving the upper extremity.
Rhizotomy of the trigeminal nerve, glossopharyngeal nerve, and vagus
nerve also have been attempted for treatment of pain involving the head and
neck with variable results (164). Other neurosurgical procedures, such as
radiofrequency cingulotomy, have been described recently for the treatment
of intractable cancer pain (119,165). As with cordotomy, the experience
with the use of rhizotomy and cingulotomy is limited and not widely
available.

Neurostimulatory procedures, such as dorsal column stimulators or deep

brain stimulation, have been used on a very limited basis for treating pain in
the cancer patient (166-168). The role of these techniques in this patient
population has not been defined.

Back to Top

Summary

The pain experience of the cancer patient is the result of many factors,
including nociceptive sources, specific pain syndromes, and behavioral
contributions. Careful evaluation of the patient is necessary to identify the
contributors to the patient's pain experience and to select treatment
modalities which address the underlying causes. For patients who are
experiencing poorly controlled pain as a result of cancer, therapy often
includes multiple management strategies involving more than one
discipline. Therefore, an interdisciplinary approach may be more useful for
pain management (15). Disciplines and specialties involved in such care
commonly include anesthesiologists, oncologists, psychiatrists,
psychologists, physical therapists, pharmacists, nurses, and social workers.

The locus of control often influences how patients respond to their

physicians' advice. Patients with a strong internal locus of control usually
want to participate actively in treatment decisions. Such patients often
resent having decisions made about their treatment without their
participation. A lack of sense of control can exacerbate such patients' pain
and limit compliance with recommended treatments.

Drug therapy is the mainstay of cancer pain management. The therapy

should be individualized to the patient, and medications should be selected
for specific indications. The WHO three-step analgesic ladder should be
used as a guide in selecting analgesics. Drugs should be administered by
mouth unless it is impossible to do so, and drug costs should be considered
when selecting analgesic medications. Doses should be titrated to response.
Adjuvant drug therapy should be considered early and implemented when
indicated. Practitioners should be familiar with the medications prescribed
and be alert for the appearance of adverse side effects. Patients should be
monitored and reassessed continuously. A thorough diagnostic work-up
should be completed for new symptoms when indicated. For patients with
specific pain syndromes, or for whom drug therapy has not been successful,
local anesthetic and neurolytic block therapy and more invasive drug
delivery systems (e.g., epidural catheters) should be considered.

Although cure may not be attainable in many cancer patients, the

obligations of health professionals to these patients are no less than to
patients for whom a cure is achievable. Effective pain management has a
profound impact on the quality of life, and may give the patient the
opportunity to face death with dignity and reduced suffering.

Back to Top

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