CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

5th Edition — 2007/2008 Editor-in-Chief

David J. Straus, M.D.
Professor of Clinical Medicine, Weill Medical College of Cornell University Attending Physician, Memorial Sloan-Kettering Cancer Center

Supportive and Palliative Care
Russell K. Portenoy, MD

Contents

1. Introduction 2 Issues in Supportive Care 3. Assessment and Management of Cancer Pain 4. Assessment and Management of Other Common Symptoms 5. Conclusion 6. References

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1. Introduction
Oncologists have long recognized the obligation to provide comprehensive care to patients with cancer. Providing “whole person” or patient-centered care is an ongoing process that parallels intensive efforts to cure or control the neoplasm itself. The terms supportive care and palliative care typically refer to the therapeutic strategies applied to this end. Although confusion about the nature of supportive and palliative care continues in oncology, the need to address quality-of-life concerns is the unifying thread. While antineoplastic therapies are being implemented, quality-of-life concerns include the immediate effects of antineoplastic therapies, such as nausea and fatigue, and the psychosocial implications of a life-threatening diagnosis. If a cure is achieved, concerns may involve late effects of treatment and complex issues of survivorship. When cancer becomes a chronic illness, the rigors of therapy often are accompanied by numerous symptoms, progressive physical impairments, psychosocial disturbances, and spiritual distress. These concerns may evolve over a period that continues for months or years. When the disease is far advanced, quality-of-life concerns may become inextricably linked with profound end-of-life issues. Symptom control, support for the family, psychological and spiritual distress, and the specific fears related to abandonment and fear of dying may be some of the specific concerns that arise. time, it is best to define supportive care as those interventions that are intended to manage the adverse effects of antineoplastic therapy. From this perspective, supportive care includes the use of blood products, growth factors, antibiotics, symptom management approaches, and interventions that address the psychosocial consequences of therapy.

The World Health Organization has defined palliative care in broad terms that connect to quality of life.3 “Palliative care is the active total care of patients whose disease is not responsive to curative treatment. Control of pain, of other symptoms, and of psychological, social and spiritual problems is paramount. The goal of palliative care is the achievement of the best possible quality of life for patients and their families.” Palliative care is an interdisciplinary therapeutic approach that focuses on the comprehensive management of the physical, psychological, social, and spiritual needs of patients with progressive, incurable illnesses and their families.4 The model applies throughout the course of the illness, and includes an array of interventions that are intended to maintain the quality of life, or attenuate the suffering of the patient and family. As death approaches, palliative care must intensify and ensure that comfort is a priority, practical needs are addressed, psychosocial and spiritual distress is managed, values and decisions are respected, and opportunities are available for growth and resolution. Palliative care is both an approach to patient care that should be routinely integrated with life-prolonging therapies and a growing practice specialty for highly trained physicians, nurses, social workers, chaplains, and others. Palliative medicine is the medical specialty dedicated to excellence in palliative care.

Although oncologists understand the importance of the broad issues subsumed under supportive care and palliative care, there are problems in providing even the most basic aspect: good symptom control. This chapter focuses on symptom control as one of the prerequisites for a satisfactory quality of life, and an element of care that should be an expected part of good oncology practice. This focus is not to imply that other, very challenging concerns, such as communication issues, psychosocial and spiritual distress, and bioethical considerations, are less important. These latter concerns and additional detail about symptom management are discussed in recent texts.1,2
Definitions: Supportive Care and Palliative Care

Although some consider the terms supportive care and palliative care to be synonymous, this has led to confusion and may ultimately impede the development of palliative care as a medical specialty. At this
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Palliative medicine is a recognized medical subspecialty in some countries, and has gained the stature of academic posts in the United Kingdom, Canada, and elsewhere. In 2006, the American Board of Medical Specialties (ABMS) is expected to formally accept Hospice and Palliative Medicine as a new subspecialty. Remarkably, numerous Boards have agreed to cosponsor this subspecialty. These include the American Board of Internal Medicine, American Board of Family Medicine, American Board of Anesthesiology, American Board of Neurology and

Psychiatry, American Board of Pediatrics, American Board of Surgery, and American Board of Physical Medicine and Rehabiliation. Other Boards are considering sponsorship as well. The acceptance of Hospice and Palliative Medicine by more Boards than any subspecialty in history reflects the broadening acceptance of specialist-level palliative care as within the purview of multiple disciplines. Each of these disciplines will be challenged to develop and maintain standards of specialist-level professional practice in palliative medicine. A major step in ensuring these standards of professional practice is the requirement for Fellowship training. In 2006, the Accreditation Council of Graduate Medical Education (ACGME) accepted Hospice and Palliative Medicine for accreditation of training programs. From the practice perspective, this means that federal funds will begin to flow to postgraduate training programs in this discipline. It also means that participation in an accredited Fellowship will be required for Board certification after a “grandfathering” period passes.

benefit (later expanded to Medicaid). Hospice is a capitated entitlement program that should be made available to all eligible patients. It was established to provide home-based, comprehensive care targeting symptom palliation, quality of life and end-of-life care for patients with all types of terminal illnesses and their families. There are only two eligibility requirements for hospice: patient election of the benefit and certification by a physician that patients have a terminal illness with a life expectancy less than 6 months (should the illness run its usual course). At the present time, there are more than 4000 hospices in the United States, which deliver care to more than 1 million patients annually, more than 90% of whom are at home. By regulation, hospice offers a group of services at no cost to the patient. The fundamental goal is to provide specialist-level palliative care to patients who are approaching the end of life, to help patients and families live with advanced illness and face impending death with a system to address potential sources of suffering. To accomplish these goals, hospices are required to provide home-based interventions by an interdisciplinary team (nurse, social worker, chaplain, and limited aides, and often volunteers, a music therapist or others), access to a hospice physician (with level of involvement varying by case), drugs related to the terminal diagnosis, test and other treatments related to the terminal diagnosis, durable medical equipment, and bereavement services after a death. The services provided by hospice programs in the United States are underused. Referral is typically late (average length of stay in hospice is less than 2 months and median length of stay is less than three weeks) and many eligible patients are never referred. Limited access is presumably related to multiple factors, including both patient and clinician reluctance to directly address end-of-life issues, clinician lack of knowledge about the details of the hospice benefit, and limitations in the care that can be provided by most smaller hospices. Efforts are underway to address these issues and improve access to hospice programs. A small number of hospices is championing a model known as “open access,” which essentially states that eligibility for the Benefit should be determined solely by the regulations. In this model, any appropriate treatment, including those that are disease-modifying such as chemotherapy and radiaSUPPORTIVE AND PALLIATIVE CARE

Acceptance of Hospice and Palliative Medicine by the ABMS and the ACGME will mainstream specialistlevel palliative care in U.S medical practice. Specialists in this discipline are expected to staff institutionbased palliative care services and hospice programs. These physicians will assist in the parallel process by which generalist-level palliative care becomes incorporated into all appropriate venues, including oncology practice. Encouragement for this change will occur through the work of the National Quality Forum, which in 2006 endorsed a “National Framework and Preferred Practices for Palliative and Hospice Care,” and potentially through other organizations focused on quality medical care. The recent publication of a consensus document known as the Consensus Project for Best Practices in Palliative Care, which has been endorsed by numerous organizations, also will provide an ongoing foundation for positive change in this area of medicine.4a

The goals of palliative care initially found expression in the hospice movement. Although hospice may be viewed as a philosophy of care identical to palliative care, it is better understood in the United States as a health care system that was created by the federal government in the early 1980s through the Medicare

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tion therapy, is allowed and will be covered by the hospice as long as it does not alter the estimation of prognosis sufficiently to reverse eligibility. Oncologists should understand the nature of hospice eligibility and explore the extent to which local hospices are adopting an open access approach. This will hopefully expand the opportunity for hospice benefits to larger numbers of patients and families. To meet the broader need for palliative care in the United States, palliative care programs are rapidly developing in hospitals and some nursing homes. Like hospices, these programs attempt to provide specialist-level interdisciplinary care to patients with advanced disease. Some are limited to an interdisciplinary consultation service, whereas others have more comprehensive services that may include an inpatient unit. Some focus on expertise in symptom control, whereas others are developing primarily to address practical and ethical issues related to the care of the imminently dying. Many of these hospitalbased programs are attempting to meaningfully link to home care programs, including hospice, and thereby meet the need for expertise in palliative care through the course of the illness. Guidelines for individuals or institutions interested in developing palliative care services have been developed and disseminated by the Center to Advance Palliative Care.4b

Oncologists should understand the available resources for specialized palliative care services. With knowledge of the range of programs and services offered, patients with complex palliative care needs can be appropriately referred. In the absence of a comprehensive program that provides specialist-level care appropriate to the needs of the patient and family, the oncologist should attempt to fashion the clinical liaisons that could address the most pressing needs. This may involve referral to a pain management program or the institutional bioethics committee, or to individuals who may be appropriate to address psychosocial issues or spiritual distress.

As an approach to the care of patients with lifethreatening illnesses, palliative care should be routinely integrated into oncology practice. All oncologists should develop skills in symptom control, communication about end-of-life issues, assessment and management of psychosocial concerns, identification of spiritual distress, and the like. At the same time, however, optimal palliative care may require interventions that are best provided by a specialist. Palliative care specialists work in teams, either through hospice or palliative care programs, and usually are needed when the disease is advanced, life expectancy is short, and problems become complex and more urgent. In practice, these problems most often relate to uncontrolled symptoms, conflicted or unclear goals of care, distress related to the process of dying, and increasing family burden.

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2. Issues in Supportive Care
Supportive care refers to a group of interventions that lessen the adverse effects of antineoplastic therapies or, more globally, attempt to maintain or improve the quality of life of patients undergoing aggressive disease-oriented treatments.2 This includes the use of blood products, growth factors, antibiotics, symptom management approaches, and interventions that address the psychosocial consequences of therapy. anticipatory. Most antiemetic research has focused on the management of acute emesis.5,6 The pathophysiology of this syndrome presumably involves direct activation of the chemoreceptor trigger zone of the brainstem which, in turn, activates the socalled vomiting center situated nearby. This region of the brain has a complex neurochemistry and interacts with the gastrointestinal tract, the vestibulolabyrinthine system, and higher cortical centers.7
Influences on Emetogenicity

Although symptom distress is common among patients undergoing active therapy, the specific problems have evolved during the past two decades. Chemotherapyassociated nausea and vomiting was widely considered to be the major concern until advances in pharmacotherapy effectively resolved this problem for most patients. At the present time, there is increasing appreciation for the problem of therapy-associated fatigue.

Chemotherapy-Associated Nausea and Vomiting

Five categories of emesis associated with chemotherapy have been described (Table 1), the most important of which are acute, delayed and
Table 1 Chemotherapy-Associated Emesis Syndromes

Many factors influence the likelihood of acute nausea and vomiting after treatment. Chemotherapeutic agents vary greatly in this potential. A classification system for the potential to cause acute emesis has been proposed in an effort to develop costeffective decision models for the selection of antiemetic therapy.8 The system groups chemotherapeutic drugs into 5 levels: level 1, <10% of patients develop acute emesis; level 2, 10% to 30% develop emesis; level 3, 30% to 60% develop emesis; level 4, 60% to 90% develop emesis; and level 5, >90% develop emesis (Table 2).

Emesis Syndrome

Characteristics

Acute Delayed emesis

Occurs within 24 hours of treatment, and usually within 1-2 hours Begins >24 hours after treatment; More common with cisplatin or cyclophosphamide therapy; more common if acute emesis occurred; usually less intense but longer duration than acute emesis Conditioned response in which emesis occurs before a subsequent course of therapy; more likely to develop if acute nausea is poorly controlled Episode of emesis that occurs on the day of treatment and “breaks through” treatment with appropriate antiemetics Emesis that develops despite optimal treatment during prior cycles of chemotherapy

Anticipatory emesis

Breakthrough emesis

Refractory emesis

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Table 2 Emetogenic Potential of Chemotherapeutic Drugs

Level

Examples

1 (<10%)

Bleomycin, busulfan, chlorambucil, fludarabine, hydroxyurea, methotrexate (<50 mg/m2), vinblastine, vincristine, vinorelbine Etoposide, 5-fluorouracil, methotrexate (>50-250 mg/m2) gemcitabine, mitomycin, paclitaxel Cyclophosphamide (<750 mg/m2 or oral), ifosphamide, doxorubicin (20-60 g/m2), methotrexate (>250-1000 mg/m2), mitoxantrone (<15 mg/m2) Carboplatin, carmustine (<250 mg/m2), cisplatin (<50 mg/m2), cyclophosphamide (>750-1500 mg/m2), procarbazine, doxorubicin (>60 mg/m2), methotrexate (>1000 mg/m2) Carmustine (>250 mg/m2), cisplatin (>50 mg/m2), dacarbazine, cyclophosphamide (>1500 mg/m2)

2 (10%-30%)

3 (30%-60%)

4 (60%-90%)

5 (>90%)

As indicated in Table 2, both drug and dose are important determinants of emesis. Patient-related influences have also been identified, however, and are important in predicting the likelihood of nausea in an individual case. Poor control of symptoms during a prior course of chemotherapy increases the likelihood of acute emesis and also predisposes to the development of anticipatory nausea and vomiting, and refractory emesis. Other factors that increase the likelihood of emesis include younger age and female sex. Heavy alcohol consumption appears to reduce the likelihood of emesis.
Management of Acute Emesis

During the past 20 years, a very large number of clinical trials have established the efficacy of specific drug classes for the management of acute chemotherapy-associated emesis. This has allowed the development of rational guidelines for the selection of combination therapy based on the emetogenicity of the chemotherapeutic regimen and other factors.5,6,8,9

Antiemetic research began with studies of the substituted benzamide, metoclopramide10, which in high doses blocks both dopamine and 5-HT3 receptors. Subsequent studies have established that drugs that block either of these receptors can be effective, and the 5-HT3 antagonists have become the mainstay approach in the management of acute emesis.11 Other studies support the utility of corticosteroids12 despite an unclear antiemetic mechanism of action, and cannabinoids, including the commercially available dronabinol (delta-9-tetrahydrocannabinol).13 Benzodiazepines have modest antiemetic efficacy but have been used to relieve anxiety and provide amnesis.14 Most recently, studies have established the benefit of an antagonist at the neurokinin 1 (NK1) receptor, aprepitant, and a new 5HT3 antagonist with a longer half-life and higher binding affinity than the first-generation drugs, palonosetron, for both acute and delayed emesis.6,15,15a Drugs in all these classes are now used commonly (Table 3).

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Table 3 Drugs Used to Treat Chemotherapy-Associated Nausea and Vomiting

Class

Mechanism

Drugs

5-HT3 antagonists

5-HT3 blockade

Ondansetron Granisetron Dolasetron Metoclopramide

Substituted Benzamide Corticosteroids Butyrophenones Phenothiazines Cannabinoids

5-HT3 blockade Dopamine blocker Unknown Dopamine blocker Dopamine blocker Cannabinoid receptor blocker Benzodiazepine receptor blocker NK-1 receptor blocker

Dexamethasone Haloperidol Prochlorperazine Dronabinol

Benzodiazepines

Lorazepam

Neurokinin antagonists

Aprepitant

Recommendations for anti-emetic therapy match the drug regimen to the likelihood of nausea and vomiting.5 Unless the patient has other significant risk factors for emesis (the most important being poorly controlled symptoms during a prior course of therapy), the administration of chemotherapy with low emetogenic potential can be managed initially with dexamethasone (usual dose 20 mg IV 30 minutes before treatment) plus antiemetics as needed (eg, metoclopramide 10 mg orally, ondansetron 8 mg orally, or prochlorperazine 20 mg rectally). Although progress has been made in identifying an oral antiemetic regimen for a highly emetogenic chemotherapy,16 most patients are managed using an intravenous combination regimen, which is administered shortly before treatment. This regimen includes dexamethasone (usual dose 20 mg IV), a 5-HT3 receptor antagonist (eg, ondansetron 8-32 mg or granisetron 10 mcg/kg), and lorazepam (usual dose

1-3 mg).17,17a The use of palonosetron or the addition of aprepitant, the specific NK-1 receptor antagonist, may substantially reduce the risk of delayed emesis5,6,15,15a,18 and should be considered if the risk or consequences of delayed emesis appears high. These antiemetic regimens are highly effective and can be expected to provide complete or nearly complete control to most patients. All patients may benefit from education and, if available, specific cognitive techniques can be added and further improve outcomes.19
Treatment-Related Fatigue

Fatigue is a nearly universal symptom in patients undergoing primary antineoplastic therapy or treatment with biologic response modifiers, and is extremely common in populations with persistent or advanced disease.20,21 A population-based survey of
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419 randomly selected cancer patients observed that 78% experienced fatigue, which was defined as debilitating tiredness or loss of energy at least once each week; most of these patients reported that fatigue had either significantly (31%) or somewhat (39%) affected their daily routine.20 The fatigue associated with cancer or its treatment (also known as asthenia) must be differentiated from the “normal” fatigue experienced by the general population. Fatigue is inherently subjective and may be described in terms of a variety of characteristics (eg, severity, distress, temporal features) and specific impairments (eg, lack of energy, weakness, somnolence, difficulty concentrating). A definition proposed for the International Classification of Diseases 10th Revision-Clinical Modification (ICD-10-CM) stresses the multidimensional nature of the phenomenon (Table 4).22
Table 4 Proposed Criteria for Cancer-Related Fatigue

Oncologists are now recognizing that the assessment and management of pathologic fatigue is extraordinarily important in maintaining a good quality of life. A supplement to the journal Cancer,23 and subsequent reviews,23a-23e have highlighted recent understanding of the pathophysiology, evaluation and management of this problem. Fatigue may be associated with any of a large number of potential etiologies (Table 5). When due primarily to a treatment, there is generally a clear temporal relationship between the condition and the intervention. In patients receiving chemotherapy, for example, fatigue often peaks within a few days and declines until the next treatment cycle. During a course of fractionated radiotherapy, fatigue is often cumulative and may peak after a period of weeks. Although treatment-related fatigue usually declines over time, a prolonged fatigue syndrome

Symptoms present every day or nearly every day during the same 2-week period in the past month Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level, plus 5 or more of the following additional symptoms: • • • • • • • • • • Complaints of generalized weakness or limb heaviness Diminished concentration or attention Decreased motivation or interest in engaging in usual activities Insomnia or hypersomnia Experience of sleep as unrefreshing or nonrestorative Perceived need to struggle to overcome inactivity Marked emotional reactivity to feeling fatigued (eg, sadness, frustration, or irritability) Difficulty completing daily tasks attributed to feeling fatigued Perceived problems with short-term memory Postexertional malaise lasting several hours

Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer-related therapy The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium.

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Table 5 Potential Etiologies of Cancer-Related Fatigue
Directly related to the disease Related to antineoplastic therapy

ies). Other proposed mechanisms link fatigue to the pathophysiology of sleep disorders and major depression. There is no clear evidence in support of any of these mechanisms, and further research is needed. Given the high prevalence of fatigue, clinicians should integrate fatigue assessment into routine care. Patients should be asked if fatigue is a problem, and if the response is affirmative, information should be sought on its severity and impact. Consistent use of a simple unidimensional severity scale, such as a verbal rating scale (none, mild, moderate, severe) or a numeric scale (eg, a 0-10 scale where 0 equals no fatigue and 10 equals the worst fatigue imaginable) can provide useful information that can be documented in the medical record. The impact of fatigue can be assessed by a question about the degree to which it interferes with the ability to function. More sophisticated scales for unidimensional or multidimensional fatigue assessment exist24 and are usually used for research purposes.
Fatigue Assessment

Radiotherapy Chemotherapy Immunotherapy Surgery
Related to metabolic or other disorders

Anemia Electrolyte disturbances Malnutrition Infection Cardiopulmonary disorders Renal disorders Hepatic disorders Neuromuscular disorders
Related to the use of centrally acting drugs Related to mood disorder

Depression Anxiety
Related to sleep disorder Related to other symptoms

Pain
Related to immobility and deconditioning

If the cause of fatigue is not obvious, additional information may be needed to define a specific etiology which, in turn, may suggest therapeutic strategies. Patients may describe fatigue in terms of decreased vitality or lack of energy, muscular weakness, dysphoric mood, somnolence, impaired cognitive functioning, or some combination of these disturbances. Although the variability suggests the existence of fatigue subtypes, this has not been empirically confirmed.
Management of Cancer-Related Fatigue

after completion of therapy occurs, and may in fact be common. The epidemiology of this phenomenon has not been adequately studied.23c The pathophysiology of cancer-related fatigue presumably varies with the etiology. Proposed mechanisms include abnormalities in energy metabolism related to increased requirements (eg, due to tumor growth, infection, fever, or surgery); decreased availability of metabolic substrate (eg, due to anemia, hypoxemia, or poor nutrition); or the abnormal production of substances that impair metabolism or normal functioning of muscles (eg, cytokines or antibod-

Education of the patient regarding the nature of fatigue, options for therapy, and anticipated outcomes is an essential aspect of the therapy. Unfortunately, results of a recent survey indicate that fatigue is seldom discussed by patients and their oncologists.20

In some cases, evaluation of the cancer patient with fatigue reveals one or more potentially treatable etiologies (Table 5). The interventions to address these conditions are diverse, and the decision to pursue one or another must be based on a case-by-case analysis of the feasibility, risks and benefits, goals of care, and other factors. Some of these interventions may be relaSUPPORTIVE AND PALLIATIVE CARE

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Some of the etiologies that may be associated with cancer-related fatigue are extremely prevalent. Depression may occur in as many as 25% of cancer patients but is often underdiagnosed.25 Atrial with an antidepressant usually is warranted in a patient with fatigue associated with any significant degree of depressed mood, particularly if concurrent anxiety or pain exists. Anemia is extremely prevalent among populations undergoing primary antineoplastic therapy and also is likely to be a major factor in the development of cancer-related fatigue. Studies have suggested an association between mild-to-moderate anemia (hemoglogbin between 10 gm/dL and 12 gm/dL) and both fatigue and quality-of-life impairment. Among the 413 patients in 3 randomized, placebo-controlled trials of epoetin alfa, the recombinant form of human erythropoietin, patients who received the drug experienced a significant increase in hematocrit, a reduced need for transfusion, and a significant improvement in overall quality of life26; those whose hematocrit increased by at least 6% also experienced significant improvement in energy level and daily activities. In very large prospective, nonrandomized, community-based trials of epoetin alfa, a rise in hemoglobin was significantly correlated with improvements in energy level, activity level, functional status, and overall quality of life, independent of antitumor response.27,28 A recent randomized trial in patients with prostate cancer demonstrated a doserelated improvement in hemoglobin, fatigue and quality of life in this population.29

tively simple (eg, eliminating nonessential centrally acting drugs or using a hypnotic to improve sleep); indicated for physiologic reasons (eg, correction of metabolic disturbances); or likely to independently benefit quality of life (treatment of depression or pain).

In addition to the treatment of potential etiologies, a variety of symptomatic therapies can be considered. There is evidence to support the use of several pharmacotherapies and exercise.23b,23d,23e,24 Among the pharmacologic approaches, the psychostimulants usually are tried first. Although there are no controlled studies of these drugs for cancer-related fatigue, experience with methylphenidate, dextroamphetamine, amphetamine, and modafinil has been favorable. A phase II trial of methylphenidate was positive.30 Both methylphenidate and dextroamphetamine have been evaluated for the treatment of opioid-related somnolence and cognitive impairment,30a and for depression in the elderly and medically ill;31-33 these data suggest positive effects on cognitive functioning and mood, and provide additional support for their use in the management of fatigue. Clinical response to one of the psychostimulant drugs does not necessarily predict response to the others, and sequential trials may be needed to identify the most beneficial therapy. Experience is greatest with methylphenidate and this drug usually is tried first. The starting dose is 5-10 mg in the morning and again at midday. Doses are gradually increased as needed; occasional patients require more than 100 mg/d. Experience with modafinil, which has less sympathomimetic activity than other psychostimulants, also has been favorable; the starting dose in the medically ill is 100-200 mg in the morning. A new stimulant drug, atomoxetine, has a pharmacology that may indicate its utility for fatigue, but experience is lacking and it has not yet been studied. All psychostimulants can cause anorexia, insomnia, tremulousness, anxiety, delirium, and tachycardia. To ensure safety, doses should be escalated slowly and carefully to minimize potential adverse effects. Extensive anecdotal observations and very limited data from controlled trials34,35 also support the use of low-dose corticosteroids, typically dexamethasone and prednisone, in fatigued patients with advanced disease and multiple symptoms. This approach is seldom considered for patients with limited disease whose fatigue appears mostly related to cancer therapy.

On the basis of these data, patients with significant fatigue and even moderate anemia should be considered for a trial of either epoetin alfa or darbepoetin alfa. The usual starting dose of epoetin alfa is 40,000 IU weekly, which is increased to 60,000 IU weekly after 1 month if the increase in hemoglobin level is <1.0 g/dL. Darbepoetin alfa is usually given at an initial dose of 100 mcg weekly, which is increased if the response is inadequate. Doses can be reduced and maintain benefit in some patients.

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Occasionally, other drugs have been tried when fatigue has been severe and refractory to conventional treatment. There has been some favorable anecdotal experience with the antidepressant bupropion.36 One of the selective serotonin-reuptake inhibitors (SSRIs, eg, sertraline or paroxetine), or a secondary amine tricyclic antidepressant (eg, nortriptyline or desipramine) occasionally is offered in refractory cases, notwithstanding a controlled trial that found no benefit on fatigue among patients treated with paroxetine during chemotherapy.36 Amantadine has been used to treat fatigue in patients with multiple sclerosis, but it has not been studied in other patient populations. This drug is usually well tolerated, however, and an empiric trial may be warranted in selected patients with severe refractory cancerrelated fatigue. Limited data suggest that treatment with the micronutrient L-carnitine may be useful in those patients with carnitine deficiency.36b Some patients benefit from nonpharmacologic symptomatic therapies for fatigue.23b.23d.23e,24 Education about fatigue can be very helpful, and reassurance about the transitory nature of most treatment-related fatigue can sometimes obviate the need for other interventions. The use of a patient diary may help the clinician and patient discern a pattern to the fatigue or identify specific activities that are associated with increased levels. This information may be useful in developing a management plan that modifies specific activities and incorporates appropriate periods of rest.

ated with anxiety or cognitive changes. Referral to a psychologist for counseling and training in stress management techniques or cognitive therapies may be warranted in some patients.

Exercise may be beneficial in relieving fatigue.37 This may be counterintuitive to patients, and considerable education may be needed to foster cooperation with an exercise program. The exercise program should be initiated gradually and include a light-to-moderate workout several days a week. Although the relationship between fatigue and nutrition is ill-defined, the association with weight loss is clear. During aggressive antineoplastic therapy, weight, hydration status, and electrolyte balance should be monitored and maintained to the extent possible. Referral to a dietitian for nutritional guidance, suggestions for nutritional supplements, and in selected cases, administration of an appetite stimulant (eg, megestrol, oxandrolone, or dronabinol) should be considered.

In a similar manner, some patients benefit from interventions to improve sleep. Instructions should be individualized and attempt to address factors that could be contributing to non-restorative sleep. For example, some patients benefit from establishment of a specific sleeping time and waking time, or routine procedures before sleep. Patients also should be instructed to avoid stimulants and central nervous system depressants before sleep. Regular exercise performed at least six hours before bedtime may improve sleep, whereas napping in the late afternoon or evening may worsen it. Stress reduction techniques or cognitive therapies, such as relaxation therapy, hypnosis, guided imagery, or distraction, appear to help some patients, particularly when the symptom is associ-

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3. Assessment and Management of Cancer Pain
Chronic pain is experienced by 30%-60% of patients who are undergoing active treatment for a solid tumor.38,39 The prevalence rate in children with cancer is lower because of the higher proportion of hematologic malignancy; those with solid tumors, however, often have the same kinds of chronic pain as their adult counterparts.40 Surveys of adult cancer patients with advanced disease, which are often performed in a hospice or palliative care setting, indicate that the prevalence of pain is generally higher, ranging from 50%-90%.41 Unrelieved pain is associated with both psychological distress and functional impairment. Numerous factors may mediate or influence impairment, including the intensity of the pain. Large surveys suggest that pain rated from 1 to 4 on a 10-point scale has a generally mild impact on functioning, pain rated 5 and 6 has a moderate impact, and pain rated 7 or greater has a severe impact.42 ing recognition that the current situation needs improvement. Recently, institutional efforts to manage pain were added to the practice standards reviewed by the Joint Commission for the Accreditation of Health Care Organizations. Oncologists must ensure that their medical information concerning pain control is current and that patients receive appropriate education.
Pain Assessment

Undertreatment of cancer pain continues to be a major public health concern. Data from numerous sources suggest that rates of undertreatment may be as high as 40%.39 Undertreatment of ambulatory cancer patients has been associated with minority status, female sex, and history of substance abuse39 and undertreatment of institutionalized elderly patients with cancer has been linked to age greater than 85, minority race, impaired cognition, and the requirement for multiple medications.43 The undertreatment of cancer pain can be attributed to the combined effects of deficiencies in clinician practice, patient underreporting and therapeutic nonadherence, noncompliance, and system-wide impediments to optimal analgesic therapy.45 There is growEDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

Many factors have been associated with an increased prevalence or severity of cancer pain. In a very large survey of institutionalized elderly patients with cancer (N = 13,625), the prevalence of pain was 27.4%, and pain was independently associated with age, gender, race, marital status, physical functioning, depression, and cognitive status.43 A survey of almost 300 newly diagnosed patients in Taiwan observed that ethnic minority status, lower insurance coverage, good prior pain tolerance, poor performance status, and metastatic disease all significantly related to the presence of pain.44

The management of pain in all populations with serious medical illnesses depends on a comprehensive assessment that characterizes symptoms in terms of phenomenology, syndrome, and pathogenesis; evaluates the relationship between the pain and the disease; and clarifies other quality-of-life concerns. The initial steps in the comprehensive assessment involve a detailed description of the pain phenomenology, syndrome identification, and the elaboration of hypotheses about etiology and pathophysiology. This information is acquired through the history, physical examination, and review of laboratory and imaging studies (Table 6). Pain is inherently subjective, and patient self-reporting is the gold standard for assessment. Ideally, the description of the pain should characterize its temporal relations, severity, topography, quality, and factors that exacerbate or relieve it (Table 6). Each of these characteristics may provide information relevant to diagnosis or management. For example, the temporal characteristics of the pain and fluctuations in severity often suggest the utility of an approach that provides a long-acting analgesic on a continuous basis and a short-acting analgesic on an “as needed” basis for breakthrough pain. Half to twothirds of those with chronic pain experience these breakthrough pains, whose presence correlates with a more problematic pain syndrome.46 The process of measuring pain intensity over time, and documenting these measurements, may have a strong positive influence on the outcome of pain therapy. Pain can be measured validly and reliably using simple scales or more sophisticated multidimensional instruments. The most common approaches in the clinic are a verbal rating scale (none, mild, moderate, severe, excruciating) and/or an 11-point numeric scale (where 0 is no pain and 10 is the worst pain

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imaginable). A visual analog scale (VAS) that uses a 10 cm line anchored at one end by the words “no pain” or “least possible pain” and at the other end by “worst possible pain” is another simple and valid approach to pain measurement. The specific scale used to measure pain intensity is less important than ensuring its use over time. The words used by patients to describe the quality of their pains are widely considered to be clues to its underlying mechanisms. Pain that is familiar to patients, usually aching or throbbing, and related to injured somatic tissues is known as nociceptive somatic pain and is presumed to be sustained by ongoing activation of pain-sensitive primary afferent nerves that invest tissues such as bone, muscle, and joints. Nociceptive visceral pain is related to injured viscera and has qualities that vary with the structures involved. Obstruction of hollow viscus is associated with cramping or gnawing pain, whereas damage to other visceral tissues, such as mesentery, is associated with pain that is described as aching, stabbing, or throbbing.
Table 6 Assessment of Cancer Pain Characteristics

Pains that are unfamiliar and often described as burning or electric-like are known as dysesthesia. Neuropathic pain, which is defined as pain that is believed to be related to injury or dysfunction of the nervous system, often is dysesthetic in quality and suggests that the pain is sustained by aberrant processing in the peripheral or central nervous system. Depending on the source and nature of the injury, neuropathic pains also can be described in terms that mirror nociceptive pains.

The characteristics of the pain elicited through a detailed history, combined with information from the physical examination and review of laboratory and imaging studies, usually provide sufficient foundation for a more sophisticated understanding of the pain. With this assessment, the clinician should be able to identify the pain syndrome, clarify its etiology or etiologies, and infer a pathophysiology. This set of constructs, in turn, guides clinical decisions about additional evaluation, prognostication, and therapy.

Characteristic

Descriptors

Temporal Onset and duration Course and variation Intensity

Acute, recurrent, or chronic; when present, continuous or intermittent Degree of fluctuation (ie, occurrence of breakthrough pain) severity on average, at its worst, at its least, right now Focal or multifocal Focal or referred Superficial or deep Varied descriptors (eg, aching, throbbing, stabbing, or burning) Familiar or unfamiliar Volitional (incident pain) or nonvolitional

Topography

Quality

Exacerbating/ Relieving factors

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Table 7 Acute Cancer Pain Syndromes

Examples Caused by procedures

Lumbar puncture headache; bone marrow biopsy; paracentesis; thoracentesis; pleurodesis, tumor embolization Postoperative pain radiation therapy (eg, mucositis, enteritis) Chemotherapy (eg, mucositis, infusional pain; pain associated with intrathecal or intraperitoneal administration) Hormonal therapy (eg, LHRF-flare in prostate cancer) Immunotherapy (eg, arthralagias/myalgias from interferon) Pathologic fractures; acute obstruction of bowel or other hollow viscus Headache from intracranial hypertension Acute pain associated with infection

Caused by therapy

Caused by the neoplasm

Caused by other pathology

Cancer Pain Syndromes

Numerous pain syndromes have been described in the cancer population. The acute pain syndromes have not been systematically characterized (Table 7). Most are caused by therapeutic or diagnostic interventions. Chronic pain syndromes have been extensively described.47,48 As many as three-quarters of these cancer pain syndromes result from a direct effect of the neoplasm; a smaller but important proportion result from therapies administered to manage the disease, and a still smaller group represents disorders unrelated to the disease or its treatment. Chronic cancer pain syndromes can be classified in many ways. A useful classification is based on infrared pathophysiology, which broadly distinguishes nociceptive from neuropathic syndromes.

uncommon marrow expansion syndrome can be seen without abnormalities on either plain radiography or bone scintigraphy.

The spine is the most common site of bone metastasis. Focal pain may occur at any site along the vertebral column, and several specific syndromes, which are characterized by pain referral patterns or associated features, have been described. Tumor invasion of the C1 or C2 vertebra can cause progressive neck pain, which radiates over the posterior aspect of the vertex and is exacerbated by flexion of the neck. Metastasis to the C7 or T1 vertebral bodies may cause focal pain or pain that refers inferiorly to the interscapular region, and a lesion of the T12 or L1 vertebral bodies can refer pain to the ipsilateral sacroiliac joint or iliac crest. Imaging can be directed to the wrong location without recognition of these pain referral patterns. Base of skull syndromes may be caused by metastasis or local extension of tumors in the head and neck. These syndromes cause face or head pain and cranial nerve palsies.49 Chronic somatic pain syndromes also may be caused by antineoplastic therapies. For example, radiation to bone and systemic corticosteroid therapy can cause

The most common pain syndromes are nociceptive and related to metastatic injury to bone (Table 8). Only a small proportion of bone metastases become painful, and the factors that result in pain are unknown. Multifocal bone pain usually is caused by widespread metastases. Rarely, a similar syndrome is produced by multiple sites of marrow expansion. This
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Table 8 Chronic Nociceptive Cancer Pain Syndromes

Somatic Pain

focal painful osteonecrosis. Examples of radiationinduced syndromes include osteoradionecrosis of the mandible after radiation for head and neck cancer, and osteoradionecrosis of the pelvis after radiation for pelvic malignancies. Radiation can also cause progressive changes in soft tissues and joints, which can result in a chronic pain syndrome.

Metastatic bone pain syndromes Multifocal or generalized pain (focal metastases or marrow expansion) Base of skull metastasis Vertebral syndromes Long bone or pelvic metastases Tumor invasion of joint Tumor invasion of soft tissue Hypertrophic osteoarthropathy Radiation-induced or steroid-induced painful osteonecrosis Painful lymphedema Painful gynecomastia

Interruption of lymphatic channels by surgical manipulation or radiation can result in chronic lymphedema. Some patients experience an associated chronic pain syndrome that probably relates to stretching of soft tissues and chronic overload of structures supporting the limb. Obstruction, infiltration, and compression of visceral structures produce an extremely diverse group of pain syndromes (Table 8). Patients with liver metastases may experience progressive pain related to stretching of the capsule or injury to the diaphragm or biliary tree. Capsular injury produces pain that is usually experienced focally in the right upper quadrant of the abdomen and sometimes extends to the flank or right paraspinal region. The pain may be associated with tenderness to palpation and cutaneous hyperesthesia in the right upper quadrant. Diaphragmatic irritation may refer pain to the shoulder, and involvement of structures inferior to the liver can refer pain to the ipsilateral scapula. These sites of referred pain occasionally predominate. Any lesion in the rostral retroperitoneum can produce pain that mimics the pain of pancreatic cancer. Pain may be diffuse in the abdomen or more focal in the epigastrium or right or left upper quadrants, or present in some combination. Back pain in the region of the T10-L2 vertebral bodies is common and may be the sole site of pain.

Visceral Pain

Hepatic distention syndrome Rostral retroperitoneal syndrome Chronic intestinal obstruction and peritoneal carcinomatosis Malignant pelvic and perineal pain Chronic ureteral obstruction Chronic abdominal pain caused by intraperitoneal chemotherapy or radiation therapy Radiation-induced chronic pelvic pain

Chronic partial bowel obstruction is a common complication of many tumors, particularly ovarian and colorectal. Patients may experience frequent cramps or aching pains that may be worsened by eating, activity, and constipation. Patients who develop ascites may also report pain that appears to originate from stretching of the abdominal wall. Chronic visceral pain also can occur as a result of antineoplastic therapies. For example, patients occasionally develop chronic abdominal pain after intraperiSUPPORTIVE AND PALLIATIVE CARE

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toneal chemotherapy or pelvic or abdominal radiation therapy. These syndromes presumably represent persistent injury to intra-abdominal or pelvic tissues and chronic partial obstruction related to scar formation.

Table 9 Chronic Neuropathic Cancer Pain Syndromes

Although cancer-related neuropathic pains can respond well to conventional analgesic approaches.50 they are often more challenging to treat. Cancerrelated neuropathic pain syndromes (Table 9) usually are caused by tumor infiltration or compression of peripheral nerves or nerve roots. They may also result from the remote effects of malignancy on peripheral nerves. The resultant pain syndromes are highly variable. Some patients experience deep aching pains occurring anywhere in the dermatomal region innervated by the damaged neural structure, and others experience abnormal sensations, including spontaneous or evoked paresthesias or dysesthesias. Patients may or may not develop motor, sensory, or autonomic dysfunction in the distribution of the involved nerve. Painful mononeuropathies can occur after injury to any nerve that carries afferent fibers and may result in chronic neuropathic pain. Just as tumors at the base of the skull cause painful cranial mononeuropathies, a lesion in a rib or paraspinal gutter can produce intercostal nerve injury and retroperitoneal masses, or a lesion in the pelvic sidewall can cause similar pains that affect the lower trunk or legs.

Tumor-Related Neuropathic Pain Syndromes

Painful peripheral mononeuropathies Painful polyneuropathies Painful plexopathy Radiculopathy Epidural spinal cord compression
Treatment-Related Neuropathic Pain Syndromes

Postsurgical neuropathic pain syndromes Postmastectomy syndrome Postthoracotomy syndrome Postradical neck dissection syndrome Postnephrectomy syndrome Stump pain and phantom pain
Postradiotherapy Pain Syndromes

Irritation of the intrathoracic vagus nerve by a neoplasm in the lung can produce a referred facial pain syndrome.51 The pain in this rare condition may be centered on the eye, cheek, or ear. This syndrome leads patients with unexplained facial pain to undergo imaging of the chest.

Radiation fibrosis of cervical, brachial, or lumbosacral plexus Radiation-induced neoplasm Radiation myelopathy
Postchemotherapy Pain Syndromes

Painful polyneuropathies

A painful polyneuropathy may have an etiology unrelated to the cancer, such as multiple vitamin deficiencies, metabolic derangements, or neurotoxic drugs, or may more uncommonly be paraneoplastic. The painful paraneoplastic polyneuropathies include a dorsal root ganglionopathy and a painful sensorimotor neuropathy.52 Tumor infiltration of the cervical, brachial, or lumbosacral plexus causes pain in the neck, arm and leg, respectively. Symptoms and signs mimic multiple peripheral nerve or nerve root involvement. Painful radiculopathy is usually caused by a metastatic tumor
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arising from the vertebral body. Other possible causes include leptomeningeal metastases, primary epidural metastases, and primary tumors that arise from the root. Like other neuropathic syndromes, painful radiculopathy is highly variable. The pain may be intermittent or constant, aching or dysesthetic, and experienced either throughout the dermatome or at any site in it. In addition to radiculopathy, vertebral metastases can cause epidural spinal cord or cauda equina compression.53 This is a potentially devastating complication,

which can usually be prevented if effective treatment, typically radiation therapy, is administered before neurologic damage occurs.

Early treatment is the key to good outcome in the management of epidural spinal cord or cauda equina compression. The oncologist must exercise a high level of vigilance in the population with known metastatic disease and select patients for definitive imaging of the epidural space before they develop neurologic compromise. Back or neck pain is almost always the first indication of epidural disease. For this reason, all patients with back and neck pain deserve a meticulous evaluation to identify high-risk patients who should undergo definitive imaging, usually by MRI.

usually branches off the T2 root, has been implicated. This syndrome is not associated with tumor recurrence, and a positive statement to this effect can be highly reassuring to the patient.

Guidelines for the management of patients with cancer-related back pain generally recommend that definitive imaging of the epidural space be pursued when pain is associated with symptoms or signs of radiculopathy or myelopathy (including just radicular pain); pain has certain ominous characteristics; or pain is associated with a highly suspicious lesion on plain radiography or CT.53 The characteristics of the pain that should raise suspicion of coexisting epidural disease include: 1) pain that gradually increases over time; 2) a “crescendo” pattern of pain (rapid escalation); 3) pain that flares with Valsalva maneuvers (cough, sneeze, or strain); 4) Lhermitte’s sign (flash of pain down back and perhaps into limbs); and 5) an illdefined, often-ascending pain in the legs. The most suspicious finding on plain radiography is a greater than 50% collapse of the vertebral body, and the most worrisome finding on CT is erosion of the bony cortex adjacent to the spinal canal.

The term postthoracotomy pain is used by some clinicians to describe any persistent pain that occurs after thoracotomy, including those caused both by the surgery and by persistent or recurrent disease. Others limit the term to the specific syndrome that results from injury to intercostal nerves at the time of surgery. This confusion should not obscure the clinically important observation that persistent or recurrent pain after thoracotomy usually is related to the neoplasm and not the surgery. In this regard, postthoracotomy pain contrasts with postmastectomy pain. Other postsurgical neuropathic pain syndromes have been described. These include a postradical neck dissection syndrome, a postnephrectomy syndrome, and both stump pain and phantom pain. Neuropathic pain syndromes related to radiation therapy are similarly diverse and include mononeuropathies and plexopathies (Table 9). Symptoms associated with radiation-induced nerve injury usually appear months to years after treatment.54 Pain is generally less prominent than nerve injury related to neoplasm.

Cancer-related neuropathic pain syndromes also can be caused by an invasive diagnostic or therapeutic procedure, or by antineoplastic therapy. A surgical incision anywhere in the body injures small afferents and produces a neuropathic pain syndrome in some patients. The postmastectomy syndrome, which is characterized by a tight, burning sensation in the medial aspect of the upper arm, the axilla, and the upper aspect of the anterior chest wall, is caused by injury to one or more cutaneous nerves in the chest. The intercostobrachial nerve, a cutaneous nerve that

Painful polyneuropathies can complicate numerous chemotherapies, including vincristine, which usually causes a painful sensorimotor neuropathy, and both cisplatin and paclitaxel, which usually produce sensory neuropathies. Although most patients report gradual improvement after therapy is discontinued, some develop a persistent painful polyneuropathy. Off-therapy deterioration after cisplatin neuropathy can continue for months, after which improvement usually occurs.

Headache is difficult to classify and may relate to many pathologic processes in patients with cancer. Neoplasms produce headache by injuring pain-sensitive intracranial structures, either directly or indirectly through increased intracranial pressure. The headache associated with this increased pressure may be diffuse, hemicranial, or occipital, and is typically worse on awakening and improves throughout the day. It usually begins insidiously, is seldom severe, and progresses over time. A history of progressive headache should lead to appropriate imaging.
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Interventions targeted to the etiology of the pain can have analgesic consequences and should be considered in every case. An extensive literature on the potential analgesic consequences of radiotherapy55 is being complemented by a small number of studies that have documented the potential utility of chemotherapy for pain control.56,57 To realize the potential benefits of primary therapy, the pain assessment must include a competent examination and appropriate imaging studies, which together clarify the extent of disease and the etiology of the pain. Once the underlying problem is characterized, decision-making is further influenced by numerous other factors, such as the availability, safety and efficacy of treatment; the potential of treatment to prolong life or reduce the likelihood of further complications; and the overriding goals of care.
Pain Management: Opioid Pharmacotherapy

Pain Management: Primary Therapies

Opioid Selection

An “analgesic ladder” approach to the selection of analgesic drugs for cancer pain has been popularized by the World Health Organization and is now widely accepted as a broad guideline and educational tool.58 According to this approach, analgesic selection should be guided by the usual severity of pain: Patients with mild to moderate pain usually are first treated with acetaminophen or a nonsteroidal antiinflammatory drug (NSAID). This is combined with one or more adjuvant drugs if a specific indication for one exists. These adjuvants include drugs selected to treat a side effect of the analgesic (eg, laxatives) and drugs with analgesic effects (the socalled adjuvant analgesics).

Opioid analgesics can be classified as pure agonists or agonist-antagonists, based on their interactions with opioid receptors. The agonist-antagonist drugs can be further divided into a mixed agonist-antagonist subclass (including butorphanol, nalbuphine, pentazocine, and dezocine) and a partial agonist subclass (including buprenorphine). Drugs in the agonistantagonist subclass have a ceiling effect for analgesia and reverse the effects of pure agonists in patients who are physically dependent; some produce psychotomimetic side effects more readily than do the pure agonist opioids. For these reasons, they are not favored for the treatment of cancer pain. For the management of chronic pain, the pure mu agonist drugs are preferred (Table 10).

Opioid therapy can provide adequate pain relief to more than three-quarters of patients with cancer pain.58-60 This success rate justifies the widely held view that long-term opioid therapy is the first-line approach for moderate or severe cancer pain.58,59,61,62

Patients with moderate to severe pain (including those with insufficient relief after a trial of acetaminophen or an NSAID), are treated with an opioid conventionally used for moderate pain. This opioid usually is combined with acetaminophen or an NSAID, and may be coadministered with an adjuvant drug, if indicated. The most common approach in the United States involves the administration of a combination product containing an opioid plus either acetaminophen or aspirin. The dose of this drug is increased as needed until the maximum safe dose of the aspirin or acetaminophen is reached. For acetaminophen, this maximal safe dose is usually considered to be 4 g/d, and lower (eg, 2-3 g/d) in patients with known hepatopathy or heavy alcohol use. Patients with severe pain (including those who fail to achieve adequate relief after appropriate administration of drugs on the second rung of the analgesic ladder) receive an opioid conventionally selected for severe pain. This treatment may also be combined with acetaminophen or an NSAID, or an adjuvant drug as indicated.

The analgesic ladder approach to drug selection must be individualized. Some patients with generally moderate pain should be considered for treatment with a long-acting opioid typically used for the third rung of the ladder, particularly if the convenience of the formulation or the likelihood of progressive pain provides a justification for this strategy.

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Table 10 Opioid Analgesics

Morphine-like Agonists

Equianalgesic Dosesa

Half-life (h)

Duration (h)

Toxicity

Comments

Morphine

10 IM/IV/SQ 20-60 POb

2-3 2-3

3-4 3-6

Constipation, nausea, Standard for sedation most common; comparison for opioids; respiratory depression multiple routes rare in cancer patients available MS Contin® (generic available) Once-a-day dosing morphine recently approved in the U.S. Typical opioid effects Avinza®; Kadian®

Controlledrelease morphine Sustainedrelease morphine

20-30 POb

2-3

8-12

20-30 POb

2-3

12-24

Hydromorphone

1.5 IM/IV/SQ 7.5 PO

2-3 2-3

3-4 3-6

Potency and high solubility may be beneficial for patients requiring high opioid doses and for subcutaneous administration. Available as a single entity or combined with aspirin or acetaminophen

Oxycodone

20-30 PO

2-3

3-6

Typical opioid effects

Controlledrelease oxycodone Oxymorphone

20-30 PO

N/A

8-12

Typical opioid effects Typical opioid effects

1 IM/IV/SQ 10 PR 50 PO 15 PO

— —

3-6 3-6

Controlledrelease oxymorphone Meperidine

N/A

12

Typical opioid effects Typical opioid effects Not preferred because of toxic metabolite, normeperidine With long half-life, accumulation possible after beginning or increasing dose
(continued)

75 IM 300 PO

2-3 2-3

3-4 3-6

Levorphanol

2 IM/IV/SQ 4 PO

12-15 12-15

3-6 3-6

Typical opioid effects

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Table 10 (continued)

Opioid Analgesics

Morphine-like Agonists

Equianalgesic Dosesa

Half-life (h)

Duration (h)

Toxicity

Comments

Methadone

Variable

12-150

3-6

Typical opioid effects

Highly variable half-life and potential for accumulation require greater vigilance for development of opioid toxicity; can prolong the QTc interval. Only available combined with acetaminophen, aspirin, or ibuprofen Can be administered as a continuous IV or SQ infusion

Hydrocodone

30 PO

2-4

3-6

Typical opioid effects

Fentanyl

50 - 100 mcg IV/SQ

7-12

1-2

Typical opioid effects

Fentanyl transdermal system

N/A

48-72 per patch

Typical opioid effects

Refer to package insert for oral and parenteral medication equianalgesic dosing guidelines. Not usually recommended for opioid naïve patients in currently available doses. Not recommended for acute pain. Not recommended for opioid-naïve patients. Recommended starting dose for breakthrough pain, 200-400 mcg, even with high-baseline opioid doses

Oral transmucosal fentanyl citrate

7-12

1-2

Typical opioid effects

a Dose that provides analgesia equivalent to 10 mg IM morphine. These ratios are useful guides when switching drugs or routes of administration. In clinical practice, the potency of the IM route is considered to be identical to the IV and subcutaneous routes. b Extensive survey data suggest that the relative potency of IM:PO morphine, which has been shown to be 1:6 in an acute dosing study, is 1:2-3 with chronic dosing. c When switching from one opioid to another, incomplete cross-tolerance requires a reduction in the dose of the new drug by 25-50% to prevent excessive opioid effects. Provision of “rescue” medication during the conversion period (a few days) prevents breakthrough pain that might result from relative underdosing. When switching to methadone from another drug, the reduction in the equianalgesic dose should be greater, usually 75-90%.
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The unique analgesic, tramadol, also can be used to manage cancer pain at the second rung of the analgesic ladder.63 The analgesic mechanism of this drug involves a mixture of mu-agonism and interaction with analgesic monoaminergic pathways in the central nervous system.

In the United States, the opioids conventionally used for moderate pain include codeine, hydrocodone, dihydrocodeine, and oxycodone (when administered as a single entity, this drug also is commonly used for severe pain). Meperidine also is used occasionally but is not preferred for chronic pain management because of the potential for adverse effects related to accumulation of an active metabolite, normeperidine. These adverse effects include dysphoria, tremulousness, hyperreflexia, and seizures.

The opioids conventionally used in the United States for severe pain include morphine, hydromorphone, fentanyl, oxycodone (used as a single entity), levorphanol, and methadone. Oxymorphone is available as a suppository and an injectable formulation, and will soon be available in both a modified-release long-acting oral formulation and an oral short-acting formulation. All these drugs should be viewed as alternatives in practice. Although morphine has been considered to be the usual first-line drug for severe pain, there is now a large clinical experience that establishes very substantial individual variation in the response to different opioids. For every patient, therefore, the overall balance between analgesia and side effects, and the pattern of side effects, can vary dramatically from opioid to opioid. This phenomenon justifies sequential trials of different opioid drugs, a technique known as opioid rotation, to identify the opioid that yields the most favorable balance between analgesia and side effects.64 The role of morphine in the management of chronic pain also has evolved with recognition of its active metabolites.65 Morphine 6-glucuronide, an active metabolite that may contribute to the analgesia and side effects observed during morphine therapy, can accumulate in patients with renal insufficiency, and has been associated with toxicity in some renally impaired patients. Morphine 3-glucuronide also may cause toxicity, possibly including myoclonus and worsening pain. Patients who develop morphine toxicity, particularly in the setting of renal insufficiency, should be offered a trial of an alternative opioid in the

The use of methadone for the treatment of pain is increasing as evidence mounts that this drug has a unique pharmacology, which in some cases leads to a much greater potency than anticipated.67,68 Based on this growing experience, a trial of methadone should especially be considered for patients whose opioid requirements are increasing and side effects, such as sedation, confusion, or myoclonus, are compromising therapy. Methadone may also be useful if the cost of therapy is an important consideration. It is substantially less expensive than other opioids typically used for chronic therapy.

Methadone has a uniquely long and highly variable half-life, and irrespective of the patient population, presents additional issues in drug selection. Because its half-life can vary from 12 hours to more than 150 hours66, the time to approach steady state after treatment begins or is changed can be as brief as several days or as long as 2 weeks. If the dose is rapidly increased to an effective level, the plasma concentration can continue to rise toward steady-state levels, and late toxicity can occur. For this reason, physicians should carefully monitor patients for a prolonged period after methadone dosing is initiated or increased.

hope that lesser metabolite accumulation may contribute to a better response. Based on the relative lack of active metabolites, fentanyl and methadone have been recommended in patients with renal insufficiency;65a this recommendation must be tempered, however, by the challenges inherent in the use of long half-life drugs in patients with poor renal function.

Given the long and variable half-life, and a potency that can be far greater than indicated on standard relative potency tables, the safe use of methadone requires more careful dosing and monitoring at the start of therapy than is typical for other drugs. Clinicians who offer this therapy must be aware of the need for caution.

Some early data also indicate that methadone can prolong the QTc interval.68a,68b Although the risk of cardiac toxicity appears very low and there is no consensus concerning ECG monitoring, it is reasonable to obtain a baseline ECG in patients with heart disease or concurrent treatment with cardioactive drugs, who may be predisposed to a prolonged QT interval, and in those whose methadone dose reaches relatively high levels (eg, above 200 mg per day).
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Clinicians who prescribe methadone as an analgesic also must be clear about the differences between this use and its administration for opioid addiction. In the United States, any clinician may prescribe methadone for pain, but a special license is required to use the drug in maintenance therapy for addiction. In contrast to the once-daily administration that is adequate for treating addiction, the use of methadone as an analgesic requires multiple daily doses in most patients.
Route of Opioid Administration

For chronic therapy, the oral route for opioid delivery is usually attempted first and the transdermal route for fentanyl is a widely accepted alternative.69,70 The availability of oral controlled release oral formulations allows convenient dosing, either once daily or twice daily. Some patients require doses three times per day to optimize therapy, but this, too, is usually accommodated well. The transdermal route offers a 48- to 72hour dosing interval, and is very useful for patients who are unable to swallow or absorb an orally administered opioid, and those who perceive non-oral administration as a convenience. It allows a trial of fentanyl during opioid rotation and appears to improve adherence to therapy in some cases. The observation in open-label studies that transdermal fentanyl produces less constipation than oral morphine70 suggests that severe constipation may be another indication for a trial. The use of the transdermal system is limited by the difficulties involved in delivering high doses and the need for an alternative route to provide supplemental doses for breakthrough pain. It also is not preferred when rapid dose titration is needed for severe pain. Because drug delivery is influenced by temperature, frequent fever spikes could lead to unstable absorption from the transdermal system and may also complicate the use of this approach.

A variety of techniques for intraspinal opioid delivery have been adapted to long-term treatment, and properly selected patients can benefit greatly.71 The clearest indication is intolerable somnolence or confusion in a patient who is not experiencing adequate analgesia during systemic opioid treatment of a pain syndrome located below the level of mid-chest. Continuous epidural infusion can be accomplished through either a percutaneous or implanted epidural catheter. These approaches are generally preferred if life expectancy is measured in a few months. Intrathecal infusion using a totally implanted pump should be considered for patients with longer life expectancies. The use of intraspinal infusion in the management of cancer pain is likely to increase with further evidence of favorable outcomes in the oncology population. A recent controlled trial comparing neuraxial infusion and comprehensive medical management demonstrated that the spinal opioid treatment improved pain, side effects, quality of life and even survival.71a

pain breakthrough at the end of the dosing interval), and can be implemented in the home with relative ease. Any opioid available in an injectable formulation can be used for continuous infusion. Longterm intravenous administration is possible if the patient has an indwelling venous access device. If subcutaneous infusion is chosen, a 25-gauge butterfly needle is conventionally used. The needle, which can be placed at any convenient site, usually is changed weekly.

Patients who are unable to swallow or absorb opioid drugs and who do not experience intolerable side effects from systemic administration also are candidates for other approaches to long-term parenteral dosing. Repetitive injections are painful and should be avoided. Continuous infusion techniques are generally preferred because they reduce the need for nursing support, eliminate the potential for bolus effects (side effects at peak concentration or
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The potential for intraspinal infusion has increased further with the use of drug combinations. The longterm administration of opioid, local anesthetic, and clonidine is widely available. Ziconotide, a unique calcium-channel blocker, is now available in the United States and has been shown to be effective for cancer pain in controlled trials.71b As new drugs are tested for intraspinal therapy, the indications for the approach are likely to increase.

An oral transmucosal formulation of fentanyl (oral transmucosal fentanyl citrate or OTFC) has been approved for the treatment of cancer-related breakthrough pain. This formulation incorporates fentanyl into a candy matrix that is sucked, allowing partial absorption through the buccal mucosa. The formulation is effective and well tolerated, and

appears to have an onset of effect faster than oral doses.72,72a The safety and efficacy of OTFC has spurred the development of other formulations that speed drug delivery in an effort to better address the problem of cancer-related breakthrough pain. An effervescent buccal tablet of fentanyl will soon be available72b and alternative sublingual, transbuccal, intranasal and intrapulmonary delivery systems are undergoing investigation.

opioid should be reduced relatively more when the patient is medically frail or the patient is taking relatively high doses; it should be reduced relatively less if the ongoing pain is severe.

The rectal route occasionally is used for prolonged therapy, particularly at the end of life. Rectal administration of a controlled-release oral morphine preparation and specially compounded methadone suppositories have been effective.

Dosing Guidelines

For the patient with limited prior opioid exposure (eg, the use of an acetaminophen-oxycodone combination product several doses per day), the starting dose of an opioid conventionally used for severe pain is usually equivalent to morphine sulfate 5-10 mg intramuscularly every 4 hours. When a patient is switched to a new opioid, the initial dose is calculated from a table of equianalgesic doses (Table 10). This calculation is revised based on the specific drug, the medical status of the patient, and the degree of pain at the time of the switch.73 Because of interindividual variability and the possibility of incomplete cross-tolerance, the dose of the new drug should routinely be reduced by 30%-50%. The usual two exceptions to this are methadone, which may have a potency greater than anticipated and should be reduced by 75%-90%, and transdermal fentanyl, which typically is administered at the calculated equianalgesic dose based on the conversions in the package insert. The dose of the new

Fixed schedule dosing is preferred for continuous or frequently recurring pain. An as-needed “rescue dose” usually is combined with the fixed regimen to treat breakthrough pains. As-needed dosing alone should be considered at the start of therapy in relatively opioid-naive patients (this is particularly appropriate with methadone because of the risk of late toxicity from drug accumulation); in patients with rapidly changing pain (eg, after radiotherapy to a painful bony lesion); and in patients with intermittent pain separated by pain-free intervals.

There are few studies of rescue dosing, and the selection of a drug, dose, and dosing interval is usually based on clinical experience. Except during therapy with methadone or transdermal fentanyl, the rescue drug is usually the same drug as that administered on a fixed-schedule basis (eg, short-acting oxycodone is offered as needed for breakthrough pain when modified-release oxycodone is the baseline opioid). There is no evidence, however, that results are better with this approach than when a different short-acting drug is used to supplement the baseline opioid. When methadone or transdermal fentanyl is used, an alternative short-acting opioid, such as morphine, is typically coadministered (OTFC, which can be selected with any baseline opioid, can be selected for use with transdermal fentanyl if there is a specific desire to limit opioid exposure to fentanyl). With the exception of OTFC, the size of the rescue dose is usually 5% to 15% of the total daily dose, and the dosing interval in the ambulatory population is usually 1 to 2 hours as needed. Controlled studies of OTFC did not confirm that the dose administered on a scheduled basis predicts the effective size of the rescue72 and guidelines for the use of this new formulation include a low starting dose in all cases (200 mcg or, perhaps, 400 mcg), followed by dose titration. The success of opioid therapy ultimately depends on individualization of the dose through titration. The goal of titration is to identify a dose associated with a favorable balance between analgesia and side effects.

The opioid dose should be increased when pain is inadequately controlled and there are no treatmentlimiting side effects, The size of the increase usually is selected as either the total quantity of rescue drug consumed during the previous day, or 30%-50% of the current total daily dose. The increment can be larger (75%-100% of the total daily dose) if pain is severe, or smaller if the patient is already experiencing opioid toxicity or is predisposed to adverse effects because of advanced age or coexisting major organ dysfunction. Caution is also reasonable if the patient has a limited prior opioid exposure.
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There is no ceiling dose during this process of dose finding. The absolute dose is immaterial as long as side effects do not supervene. Occasional patients require opioid doses equivalent to many grams of morphine per day.

In most cases, titration identifies a dose that yields a favorable balance between analgesia and side effects, and the opioid requirement remains stable for a prolonged period. In the absence of progressive disease, patients may find the same dose effective for many months or years. This phenomenon belies the inevitability of tolerance as a problem in the longterm administration of opioid drugs.74 Moreover, when pain does increase again, this declining efficacy of the opioid regimen often can be attributed to one or more overt processes that could potentially increase pain even if tolerance were not occurring (Table 11). Progression of the disease is usually identified as the most likely etiology. Thus, although analgesic tolerance to opioid drugs can occur and limit therapy, it seldom appears to be the sole driving force for declining effects. When pain increases during long-term therapy, the devel-

opment of tolerance should not be assumed. Rather, recurrent pain should signal the need to re-evaluate the nature of the pain. Dose titration should start again and should continue until the favorable balance between analgesia and side effects is regained or the therapy is determined to be ineffective because of treatment-limiting toxicity.

Some patients will not attain a favorable balance between analgesia and side effects during dose titration. Guidelines for the management of such patients, which are based entirely on clinical experience, encompass 4 main strategies (Table 12). There are numerous options, which range from more sophisticated side effect management to invasive analgesic therapies. Therapeutic decision-making must be based on a careful reassessment of the patient. The goals of care must be considered in balancing the risks and benefits of any intervention.
Pain Management: NSAIDs and Adjuvant Analgesics

Table 11 Reasons for Increasing Pain During Opioid Therapy

The term non-opioid analgesic is conventionally applied to acetaminophen and all the nonsteroidal anti-inflammatory drugs (NSAIDs). The term adjuvant analgesic refers to any drug that has a primary indication other than pain but is known to be analgesic in specific circumstances. Both categories of analgesics are fundamental to the analgesic ladder approach to cancer pain management.
Nonopioid Analgesics

Increasing nociception Tumor growth Inflammation Development of neuropathic mechanisms Nerve injury related to tumor Nerve injury related to therapy Psychological or psychiatric processes Increasing anxiety or depression Delirium Conditioned pain behavior or decline in drug effect Tolerance

Although acetaminophen and the many NSAIDs constitute a diverse group of drugs (Table 13), all inhibit the enzyme cyclo-oxygenase and reduce the synthesis of prostaglandins. Cyclo-oxygenase has at least several isoforms. Two that are best characterized are cyclo-oxygenase-1 (COX-1), which is constitutive in most tissues and involved in the normal functioning of stomach, kidney and other organs, and cyclo-oxygenase-2 (COX-2), which is constitutive in some tissues (eg, kidney and brain) and inducible as a component of the inflammatory cascade in other tissues.75 All NSAIDs presumably produce analgesic effects through inhibition of both peripheral and central COX. Inflammation is not required for analgesia, but clinical observation suggests that inflammatory pain

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Table 12 Therapeutic Options When an Opioid Regimen Fails

Approach

Options

Try to open the therapeutic window Try to find an opioid with a more favorable balance between analgesia and side effects Use a pharmacologic approach to reduce the systemic opioid requirement Use a nonpharmacologic approach to reduce the systemic opioid requirement

More aggressive side effect management

Opioid rotation

Coadminister an NSAID or an adjuvant analgesic Consider intraspinal opioid therapy

Anesthetic approaches, eg, nerve blocks Surgical approaches, eg, cordotomy Physiatric approaches, eg, an orthotic Psychological approaches, eg, biofeedback Alternative medicine approaches, eg, acupuncture

is more likely to respond than pain of other types, such as neuropathic pain. Metastatic bone pain appears to be relatively responsive to these drugs. NSAIDs vary in the degree to which they each inhibit COX-1 and COX-2. Relatively selective COX-2 inhibitors, including celecoxib, rofecoxib and valdecoxib, have been developed in an effort to reduce gastrointestinal toxicity, including ulcer formation.76,77 This reduced risk is favorable, and, on theoretical grounds, supported the preferential use of these NSAIDs in medically frail populations, such as those with cancer pain.

after publication of several studies documented a risk of adverse cardiovascular outcomes greater than comparator drugs, and the U.S. Food and Drug Administration decided to withdraw valdecoxib from the market based on this risk and an unrelated risk of cutaneous hypersensitivity reactions. Additional studies, including secondary analyses of a series of trials and epidemiologic surveys, have altered this view, however, and suggest that the potential for prothrombotic effects is linked to inhibition of COX-2, whether or not the drug is a selective COX-2 inhibitor or a nonselective COX-1 and COX-2 inhibitor. The risk, therefore, attends the use of any NSAID, not only the selective COX-2 inhibitors. Moreover, risk appears to vary with the specific drug, the dose and the duration of treatment. Following a review of the available evidence on safety, the U.S. Food and Drug Administration required a boxed warning on all NSAIDs that highlights the potential for both serious cardiovascular and gastrointestinal toxicity.
SUPPORTIVE AND PALLIATIVE CARE

The role of the selective COX-2 drugs, and of the NSAIDs overall, is undergoing re-examination, however, as a result of recent safety concerns related to cardiovascular toxicity.78 Early publications suggested that this risk, which takes the form of an increased incidence of myocardial infarction, transient ischemic attacks and stroke, and peripheral vascular disease, was specifically associated with the selective COX-2 drugs. Rofecoxib was withdrawn by the manufacturer

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Table 13 Nonsteroidal Anti-Inflammatory Drugs

Chemical Class

Generic Name

Recommended Starting Dose (mg/d)*

Recommended Maximum Dose (mg/d)

Comment

P-aminophenol derivative

Acetaminophen**

2,600

4,000

Overdosage produces hepatotoxicity. Not anti-inflammatory. Lack of GI and platelet toxicity

Nonselective COX-1 and COX-2 Inhibitors

Salicylates

Aspirin**

2,600

6,000

Standard for comparison. May not be tolerated as well as some of the newer NSAIDs**** Less than aspirin**** Less GI toxicity than other NSAIDs. No effect on platelet aggregation****

Diflunisal** Choline magnesium trisalicylate**

1,000 x 1 1,500 x 1 then 1000

1,500 4,000

Salsalate

1,500 x 1 then 1000 1,600 500 550 800 100 100 600

4,000

Propionic acids

Ibuprofen** Naproxen** Naproxen sodium** Fenoprofen Ketoprofen Flurbiprofen** Oxaprozin

4,200 1,500 1,375 3,200 300 300 1,800

Available over the counter**** Available over the counter and available as a suspension**** **** **** Available over the counter**** *** Once-daily dosing may be useful**** Available in sustained-release and rectal formulations. Higher incidence of side effects than propionic acids**** **** **** **** Parenteral formulation available. Long-term use not recommended**** Long-term use not recommended**** ****
(continued )

Acetic acids

Indomethacin

75

200

Tolmetin Sulindac Diclofenac Ketorolac (IM)

600 300 75 30 (loading)

2,000 400 200 60

Ketorolac (PO) Etodolac

40 600

40 1,200

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Table 13 (continued) Nonsteroidal Anti-Inflammatory Drugs

Chemical Class

Generic Name

Recommended Starting Dose (mg/d)*

Recommended Maximum Dose (mg/d)

Comment

Oxicams

Piroxicam

20

40

Administration of 40 mg for >3 weeks is associated with a high incidence of peptic ulcer, particularly in the elderly**** Highly COX-2 selective at lower doses Relatively low risk of GI toxicity; once-daily dosing Not recommended for use longer than 1 week, and therefore not indicated for cancer pain**** **** More toxic than other NSAIDs Not preferred for cancer pain therapy

Meloxicam

7.5

15

Naphthylalkanones Fenamates

Nabumetone

1,000

1,000-2,000

Mefenamic acid**

500 x 1

1,000

Meclofenamic acid Pyrazoles Phenylbutazone

150 300

400 400

Selective COX-2 Inhibitors

Celecoxib

200

400

Significantly less risk of gastrointestinal toxicity Lesser risk of renal toxicity not established

* Starting dose should be one-half to two-thirds recommended dose in the elderly, those on multiple drugs, and those with renal insufficiency. Doses must be individualized. Studies of NSAIDs in the cancer population are meager; dosing guidelines are thus empiric. ** Pain is approved indication in the United States. *** Half-life of aspirin increases with dose. **** At high doses, stool guaiac, liver function tests, BUN, creatinine and urinalysis should be checked periodically.

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The NSAIDs as a class have other potentially important toxicities, including congestive heart failure and renal disease. Given the risk of both acute and chronic renal disease, all NSAIDs must be used cautiously in patients who have clinically evident renal dysfunction or who are likely to have subclinical disease as a result of advanced age, prior nephrotoxic therapy (such as platinum-based chemotherapy), or the underlying disease. All of these concerns suggest the need to evaluate each patient carefully in terms of risk. Short-term use of a NSAID has low risk, irrespective of drug, but long-term therapy requires an ongoing risk-to-benefit assessment that includes the potential for gastrointestinal, cardiovascular and renal events.

The risk of NSAID-induced ulcer disease also can be reduced by coadministration of other drugs. Several studies have confirmed the efficacy of proton pump inhibitors, such as omeprazole; misoprostol, a prostaglandin analog; and possibly higher doses of H2 blockers (eg, famotidine 40 mg/d).80-83 Other interventions used to treat ulcer or gastritis, such as antacids and sucralfate, have not been shown to reduce the risk of NSAID-induced ulceration. Given the strong evidence of efficacy and a favorable side effect profile, most clinicians opt for coadministration of a proton pump inhibitor as the means to reduce risk of ulcer formation. The use of a selective COX-2 inhibitor may also be justified by the presence of a bleeding diathesis. These drugs have no effect on platelet function.

There have been very few clinical trials of the NSAIDs in the cancer population and no trials of the selective COX-2 inhibitors. Nonetheless, a NSAID usually is considered a first-line therapy for patients with generally mild cancer pain. Coadministration of one of these drugs also should be considered for patients who are receiving an opioid regimen for moderate or severe pain, particularly for the treatment of bone pain. Drug-specific toxicity profiles should be considered in selecting a drug. In terms of gastrointestinal toxicity, a relatively better risk profile has been demonstrated for the selective COX-2 inhibitors (a designation now limited to celecoxib in the United States) and suggested for a number of traditional NSAIDs, including ibuprofen, diclofenac, nabumetone, choline magnesium trisalicylate, and others. The need to consider a favorable gastrointestinal risk profile when selecting a NSAID is particularly important in those patients with risk factors for these events. Nausea and abdominal pain are poor predictors of serious gastrointestinal toxicity and as many as two-thirds of NSAID users experience no symptoms before bleeding or perforation. The factors associated with an increased risk of ulceration include advanced age, the use of higher NSAID doses, concomitant administration of a corticosteroid, and a history of either ulcer disease or previous gastrointestinal complications from NSAIDs.78,79 Heavy alcohol or cigarette consumption may also increase the risk of adverse events. A role for infection by the bacterium Helicobacter pylori in NSAID-related gastropathy has not been proven.
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In medically ill populations, titration of the NSAID dose is prudent to reduce the risks of therapy. This approach, which involves gradual dose escalation from a relatively low starting dose, is most appropriate for patients with relatively mild pain and those with an increased risk of NSAID toxicity, such as the elderly. If dose titration is used, the likelihood of benefit from a dose change can usually be judged within 1 to 2 weeks. Dose escalation can continue until analgesia is adequate, the ceiling dose is reached, side effects occur, or the dose approaches a conventionally accepted maximum.
Adjuvant Analgesics

In the cancer population, the corticosteroids have been shown to improve pain, appetite, nausea, malaise, and overall quality of life.85,86 Among the accepted pain-related indications are refractory neuropathic pain, bone pain, pain associated with capsular expansion or duct obstruction, pain from bowel

The adjuvant analgesics encompass numerous drugs in diverse drug classes (Table 14).84 All are commercially available for indications other than pain but are analgesic in selected circumstances. In the population with cancer pain, these drugs usually are administered after opioid therapy has been optimized. Very few of the adjuvant analgesics have been studied in the medically ill, and the information used to develop dosing guidelines for cancer pain is usually extrapolated from other patient populations.

Table 14 Adjuvant Analgesics

Class

Examples

Antidepressants Tricyclic antidepressants Tertiary amine Secondary amine SSRIs SSNRIs Others Anticonvulsants Amitriptyline, imipramine Desipramine, nortriptyline Fluoxetine, paroxetine, citalopram Venlafaxine, duloxetine Trazodone, maprotiline, nefazadone, mirtazepine Gabapentin, pregabalin, carbamazepine, phenytoin valproate, clonazepam, topiramate, lamotrigine Mexiletine, tocainide Clonidine, tizanidine Dextromethorphan, ketamine, amantadine Dexamethasone, prednisone Capsaicin, local anesthetics, NSAIDs Baclofen, calcitonin

Oral local anesthetics Alpha-2 adrenergic agonists NMDA receptor antagonists Corticosteroids Topical agents Miscellaneous drugs for neuropathic pain Drugs for bone pain Drugs for bowel obstruction

Bisphosphonates, calcitonin,strontium-89, samarium-153 Scopolamine, glycopyrrolate, octreotide

obstruction, pain caused by lymphedema, and headache caused by increased intracranial pressure. Current data are inadequate to evaluate drug-selective differences, dose-response relationships, predictors of efficacy, or the durability of favorable effects. Because the risk of adverse effects associated with corticosteroids increases with both the dose and duration of use, long-term therapy usually involves the administration of relatively low doses to patients with advanced disease, whose overriding need for symptom control justifies the risk. Typically, prednisone,

5-10 mg, or dexamethasone, 1-2 mg, is administered once or twice daily. Therapy is continued as long as potential benefits appear to outweigh adverse effects. Dose escalation for worsening symptoms is appropriate if benefits decline with progressive disease, particularly at the end of life. Another approach to corticosteroid therapy is considered for selected patients with severe pain. The usual scenario is the occurrence of rapidly worsening pain related to a nerve injury, bony lesion, or duct obstruction that has failed to respond promptly to an opioid.
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This high-dose regimen may begin with dexamethasone 24-100 mg intravenously, followed by 6-24 mg daily in 4 divided doses. This dose is gradually tapered over weeks as an alternative analgesic approach is implemented, such as radiation therapy or neural blockade.
Adjuvant Analgesics Used for Neuropathic Pain

lamotrigine and topiramate. Other drugs, such as clonazepam, oxcarbazepine, tiagabine, zonisamide and levetiracetam, also are sometimes tried empirically in practice.

At the present time, gabapentin is the most common adjuvant analgesic used for neuropathic pain. This drug is an anticonvulsant with proven efficacy in different neuropathic pain syndromes.87,88 It has an acceptable adverse effect profile, is not metabolized in the liver, and has no known drug-drug interactions. Treatment usually starts with 100-300 mg/d, and dose titration usually continues until benefit occurs, side effects supervene, or the total daily dose is at least 3,600 mg. Some patients respond to 600 mg/d in divided doses, whereas others do not reach a maximal response until the dose is increased to 6,000 mg/d. Gabapentin’s analgesic effects are mediated through modulation of the alpha-2-delta protein of the voltage-gated calcium channel in the central nervous system. Pregabalin has the same mechanism and has been demonstrated to be safe and effective in varied neuropathic pains.88a,88b Unlike gabapentin, pregabalin has stable pharmacokinetics through the clinically-relevant dose range and studies suggest that dose titration to the usual effective dose of 300 mg to 600 mg per day in two divided doses can be accomplished within one week. Clinical observations suggest that some patients who did not respond to gabapentin report more satisfactory effects from pregabalin. Many other anticonvulsant drugs have been evaluated as treatments for neuropathic pains.89 There is limited evidence in support of several older anticonvulsant drugs, including carbamazepine, phenytoin, and divalproex, and several newer drugs, including
EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

Many adjuvant analgesics are primarily used in medically ill populations for the treatment of neuropathic pain that fails to respond adequately to an opioid. These drugs include anticonvulsants, antidepressants, local anesthetics, and others.

The existing evidence suggests that the antidepressant drugs are nonspecific analgesics90 and that the tricyclic drugs are somewhat more efficacious for neuropathic pain than gabapentin or pregabalin.88a An antidepressant should be considered as the first adjuvant analgesic selected for neuropathic pain if depression is a significant comorbidity; if not, one of these drugs is usually tried if gabapentin or pregabalin do not yield adequate results.

All anticonvulsants are administered using the dosing schedules typically employed for seizures. Plasma concentrations of carbamazepine, phenytoin, and divalproex can be monitored to ensure that maximum anticonvulsant doses have been reached if pain relief does not occur with routine dose escalation.

The tricyclic antidepressants (TCAs) have been most extensively studied, and there is strong evidence that both the tertiary amine TCAs (eg, amitriptyline, doxepin, and imipramine), and the secondary amine TCAs (eg, desipramine and nortriptyline) can be effective analgesics. There is good evidence that a serotonin and norepinephrine reuptake inhibitor (SSNRI), duloxetine, is analgesic and this drug has been approved in the United States for neuropathic pain associated with diabetes.90a Limited evidence favors analgesic effects for venlafaxine, another SSNRI; several of the serotonin-selective reuptake inhibitors, including paroxetine, citalopram and trazodone; and several other types of antidepressants, including bupropion and maprotiline.84 Amitriptyline is the best studied TCA and, on this basis, may be preferred when pain is the target symptom. Patients who cannot tolerate amitriptyline, or are predisposed to its sedative, anticholinergic, or hypotensive effects, should be considered for a trial with a secondary amine TCA such as desipramine. Given the relatively better side effect profile, however, a trial of duloxetine may be preferred initially and should be strongly considered if a patient has poorly tolerated a TCA or is likely to do so.

390

Systemic administration of local anesthetic drugs also may provide analgesia for patients with neuropathic pains.91,92 The availability of oral local anesthetic drugs offers an acceptable approach for longterm therapy. There is limited experience in the use of these drugs as analgesics in the medically ill, however, and they should be considered second-line therapy for this indication. In the United States, mexiletine has been the preferred oral local anesthetic for the treatment of pain. Treatment usually begins with a low dose (150 mg/d), which is followed by gradual dose escalation. Brief intravenous local anesthetic infusions also are analgesic.93,93a Treatment usually involves the infusion over 30 minutes of a dose that ranges from 1 mg/kg to 4 mg/kg. Given the existence of a dose response, a prudent approach may be to start with a low-dose infusion and follow it, if unsuccessful, with infusions at incrementally higher doses. There is no evidence that a brief local anesthetic infusion is more effective than oral therapy, but the ability to give a larger dose more quickly may have clinical advantages. In the cancer population, this approach usually has been tried when neuropathic pain is severe and progressive.

Antidepressants do not exert their therapeutic effects rapidly. Dose titration from a low starting dose is necessary with the TCAs, and sometimes even the newer drugs, and analgesic effects may not occur for a week or more after an effective dose is reached. To enhance adherence to the therapy, patients should be educated about these pharmacodynamics. The failure of one antidepressant drug does not presage the failure of others, and some patients should be considered for additional trials of drugs in this class.

Antagonists at the N-methyl-d-aspartate (NMDA) receptor also are undergoing investigation as potential analgesics. Four such drugs—memantine, dextromethorphan, amantadine and ketamine—are commercially available in the United States. There is substantial evidence that ketamine is analgesic,96a,97 but this drug has a difficult side effect profile, which includes nightmares and delirium, and its long-term use is likely to be limited. The use of ketamine infusion has been favored by some in the setting of severe, refractory pain in far advanced disease.97a Evidence that the available oral NMDA receptor antagonists are analgesic is limited.98-100 Memantine is marketed for Alzheimer’s disease and is generally well-tolerated. Relatively high doses (eg, 30 mg per day or more) anecdotally have proved occasionally helpful in challenging neuropathic pain states. Dextromethorphan may be tried as a commercially available antitussive, starting at 120 to 240 mg/d in 3 to 4 divided doses; doses higher than 1 g have been administered safely, at least for the short term, and it is likely that the analgesic dose will be at least 350 mg/d. Experience with amantadine as an analgesic is very limited. The GABA agonist baclofen has been shown to be effective in the treatment of trigeminal neuralgia101 and may be useful for neuropathic pain in the medically ill. The therapeutic dose appears to vary widely, ranging from 30 mg to more than 200 mg per day.

Several other drug classes may be useful in managing neuropathic pain. The alpha-2-adrenergic agonists, which in the United States include clonidine and tizanidine, have established analgesic efficacy in a variety of pain syndromes.94-96 and may be considered nonspecific analgesics. Like the antidepressants, they usually are considered as adjuvant analgesics for neuropathic pain in populations with cancer. Epidurally administered clonidine has proven efficacy in cancer pain and was shown to be relatively more effective for neuropathic pain.96

Cannabinoid receptors have been identified in both the peripheral and the central nervous system, and there is now abundant data indicating that exogenous cannabinoid compounds have potential analgesic effects.101a Tetrahydrocannabinol (THC) is now available and several other compounds are in development. Given the potential for adverse cognitive and mood effects, and the still limited clinical experience, a trial of THC is usually considered in the setting of refractory neuropathic pain, after a number of other adjuvant analgesic trials have been unsuccessful. The advent of new compounds may change this approach in the future. Benzodiazepines also may have salutary effects in patients with chronic cancer pain, and it may be impossible to determine the degree to which psychotropic or primary analgesic actions contribute to this outcome. As noted previously, clonazepam often is tried for neuropathic pain despite limited
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evidence of efficacy, and a survey of patients with mixed types of cancer-related neuropathic pains suggested that alprazolam also may have analgesic effects.102 Patients with cancer pain also commonly experience anxiety and muscle spasms, phenomena that may exacerbate the intensity of pain, and respond well to other benzodiazepines, such as diazepam.

pains presumed to have a strong peripheral input. An adequate trial is generally believed to require 4 applications daily for 1 month.
Adjuvant Analgesics for Bone Pain

Topical local anesthetics can be administered by patch or cream. A lidocaine-impregnated patch (Lidoderm®) has been approved for use in patients with postherpetic neuralgia.104 This formulation appears to be well accepted by patients and should be considered for any patient who is a candidate for topical local anesthetic therapy. A 1:1 mixture of lidocaine and prilocaine known as EMLA (eutectic mixture of local anesthetics) can produce dense cutaneous anesthesia if applied thickly under an occlusive dressing. Cutaneous anesthesia may not be necessary to yield analgesic effects in patients with neuropathic pains, however, and patients can use alternative methods of application, as well as pure lidocaine creams (eg, lidocaine 5%), which are far less costly than EMLA.

Topical analgesic therapies may particularly benefit medically ill patients with chronic pain by providing pain relief that complements a systemic analgesic regimen without the risk of additional side effects. Topical therapies include local anesthetics, NSAIDs, capsaicin, and numerous other compounds.103

There is substantial evidence that topical NSAIDs can be effective for soft tissue pain and perhaps joint pain.105 A trial of a compounded formulation containing diclofenac, ketoprofen, or another NSAID may be considered, particularly when pain has a superficial element of inflammation.

Based on the abundance of supporting evidence, the benefit to nonpainful skeletal comorbidities (such as fracture rate), and convenience, the bisphosphonates are generally preferred as the first-line approach. There is strong evidence that certain bisphosphonates, including pamidronate and clodronate, can be analgesic.107,108 Pamidronate, zolendronate and ibandronate are available in the United States and any of these drugs may be considered for its analgesic effects. Studies with pamidronate suggest that several doses may be needed to judge efficacy. The oral bisphosphonates alendronate and risedronate have not been studied for malignant bone pain. They are highly potent, however, and a trial may be warranted because of their simpler modes of administration. Recent evidence that treatment with the intravenous bisphosphonates may lead to osteonecrosis of the jaw has altered the risk:benefit analysis applied to the use of these drugs.112a The cause of this lesion is not known, and although the risk appears to be very small, the complication can be serious in terms of pain and functional consequences. Most cases have been associated with intravenous therapy over a period of years, and a link with prior dental extraction or other procedures is likely, but not absolute. The potential for this adverse effect must be considered in positioning intravenous bisphosphonate therapy for analgesic purposes in the population with metastatic bone pain.

Radiation therapy is usually considered when bone pain is focal and poorly controlled with an opioid or is associated with impending fracture. Multifocal bone pain that has been refractory to opioid therapy may benefit from coadministration of an NSAID or corticosteroid. Adjuvant analgesics that may be useful for this indication include bisphosphonate compounds,107,108 calcitonin,109,110 and bone-seeking radionuclides.55,111,112 There have been no comparative trials of these adjuvant analgesics for bone pain, and the selection of one over another is usually based on convenience, patient preference, and several clinical indicators.

Patients with neuropathic pain caused by peripheral nerve injury also can be considered for a trial of topical capsaicin, a peptide that depletes peptides in small primary afferent neurons, including those that mediate nociceptive transmission. Although anecdotal experience with this compound has been mixed, there is evidence of efficacy from controlled trials.106 A therapeutic trial of the high-concentration formulation (0.075%) is reasonable in patients with neuropathic
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Although a recent systematic review identified little evidence that calcitonin is effective for metastatic bone pain,112b some reports have been positive109,110 and anecdotal experience suggests that some patients may benefit. Interestingly, this drug also may be useful for some types of neuropathic pain.113,114 Given its relative safety, a trial may be justified in patients with difficult bone pain or neuropathic pain syndromes.

Octreotide inhibits the secretion of gastric, pancreatic, and intestinal secretions, and reduces gastrointestinal motility. Like the anticholinergic drugs, the use of this compound in the symptomatic treatment of bowel obstruction is supported by favorable anecdotal experience.117
Pain Management: Nonpharmacologic Approaches

The bone-seeking radiopharmaceuticals, such as strontium-89 and samarium-153, should be considered for patients with refractory multifocal pain caused by osteoblastic lesions or lesions with an osteoblastic component.111,112 Samarium-153 allows imaging with bone scintigraphy during treatment for bone pain. Patients who receive these drugs should have life expectancies greater than 3 months, adequate bone marrow reserve, and no further planned therapy with myelosuppressive chemotherapy. Patients with a platelet count below 60,000 or a white blood cell count below 2,400 generally should not be treated. The onset of effect is often slow (2 weeks or longer), and peak effects may not be attained for more than a month. Some patients experience a flare of pain before analgesic effects occur. Patients with malignant bowel obstruction who are not candidates for surgical decompression require intensive palliative interventions to reduce pain and other obstructive symptoms, including distention, nausea, and vomiting.115,116 Surveys of patients with far advanced disease suggest that the use of opioids, a corticosteroid, anticholinergic drugs, and the somatostatin analog octreotide can provide good symptom control for most patients and, for many, obviate the need for tube drainage.
Adjuvant Analgesics for Bowel Obstruction

A small proportion of cancer patients will be unable to attain adequate analgesia from optimally administered pharmacotherapy. A large number of non-pharmacologic approaches may be considered when this occurs (Table 15). These approaches are reviewed elsewhere1,2,59,118-120 and may be broadly categorized. Interventional techniques include injection therapies, neural blockade, and implant therapies (spinal cord stimulation or neuraxial infusion). Another group of invasive approaches—neurosurgical therapies—involve surgical interruption of afferent neural pathways. With the advent of nondestructive procedures, such as neuraxial analgesia, these procedures now are rarely performed. Psychological therapies range from education, mind-body therapies such as imagery, and numerous psychotherapeutic approaches. Rehabilitative treatments include therapeutic exercise, occupational therapy, and the use of modalities such as heat, cold, ultrasound, and topical stimulation. Finally, complementary modalities include a very broad array of treatments, some of which (acupuncture, therapeutic massage, a number of movement therapies, some nutritional interventions) are mainstream.

A variety of anticholinergic drugs are used for this indication. Scopolamine is available in a transdermal system and is often tried first. Hyoscyamine is available in a sublingual formation, and glycopyrrolate has lesser penetration through the blood-brain barrier and, therefore, may be less likely to produce central nervous system toxicity.

Although some of these modalities, such as trigger point injections, are within the purview of oncologists, most require appropriate referral to either a specialist who can perform a specific technique or a pain specialist, who may be able to provide a broader evaluation and help select the best course among many options. To recommend wisely and assist inpatient and family education, the oncologist should have a working knowledge of the indications, risks and potential benefits of all these approaches.

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Table 15 Nonpharmacologic Interventions for Cancer Pain

Approach

Type

Type/Examples

Interventional

Injections Neural blockade Implant therapies Spinal cord stimulation Neuraxial infusion Cordotomy Transcutaneous electrical nerve Physical/occupational therapy Modalities Psychoeducational Cognitive techniques Psychotherapy Therapeutic massage Acupuncture

Surgical Neurostimulatory Physiatric

Psychologicical

Complementary

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4. Assessment and Management of Other Common Symptoms
Numerous other symptoms must be addressed in providing palliative care to patients with cancer. The management of constipation and dyspnea exemplify the medical sophistication necessary to optimize the management of these problems.
Constipation

in diet is impeded by anorexia or some other intercurrent medical problem. If uncomfortable flatulence or obstructive symptoms such as cramping or painful distention occur with increased fiber intake, the amount should be adjusted.

Constipation is a symptom characterized by diminished frequency of defecation associated with difficulty or discomfort. It may contribute to abdominal pain, distention, nausea, and worsening anorexia. In the cancer population, the etiology and pathophysiology is presumably multifactorial. Contributing factors may include structural extraluminal or intraluminal pathology, drugs (such as the opioids), physiologic disturbances (such as hypercalcemia), and neurologic disorders. A more detailed evaluation of potential etiologies may be appropriate when constipation develops or progresses without a clear precipitant, or when it is more severe than expected. In such cases, the history should explore a broad range of possible causes, and the examination must include a digital rectal examination. The need for imaging studies may be limited to a plain abdominal radiograph or may include a barium enema, an upper gastrointestinal series, or computed tomography of the abdomen and pelvis. Occasionally, the evaluation requires colonoscopy. Although prophylactic laxative therapy is often considered appropriate when constipation is likely to occur, most notably when opioid therapy is initiated, the need for prophylaxis should be determined on a case-by-case basis. If multiple potential etiologies exist (eg, opioid therapy in the setting of debilitation, poor diet, and the use of other constipating drugs), prophylactic laxative therapy usually is warranted.

Routine laxative therapy should not be initiated in patients with severe constipation until serious problems, such as bowel obstruction, have been excluded and the clinician is reasonably certain that impaction has not occurred. Low impaction can be assessed by examination of the rectum; suspicion of a high impaction requires abdominal imaging for evaluation. The management of impaction may require physical disimpaction; repeated enemas; and a combination of rectal and oral laxatives, including a lubricant, softening agent, osmotic laxative, or contact laxative. There are many laxative therapies, but few have been subjected to controlled comparative trials in medically ill populations. Oral laxatives can be: 1) bulkforming agents; 2) osmotic agents (including the socalled saline cathartics, specifically magnesium and sodium salts, and poorly absorbed sugars, specifically lactulose and sorbitol); 3) lubricants; 4) surfactants (specifically docusate); 5) contact cathartics (including the anthraquinones senna and cascara, and the diphenylmethanes phenolphthalein and bisacodyl); 6) prokinetic drugs (specifically cisapride and metoclopramide); 7) agents for colonic lavage; and 8) opioid antagonist therapy. Various strategies may be considered in combining one or more of these approaches with other interventions (Table 16). In the absence of data from clinical trials, treatment selection is based on conventional practices and good clinical judgment. Patients should be well informed about the varying options for therapy, and patient preferences should influence recommendations.

There are many therapeutic strategies for managing constipation.121-123 The assessment may yield information about a potential etiology that can be reversed. Simple approaches, including enhanced fluid and fiber intake, usually should be encouraged. The consumption of increased fiber can be accomplished by adding fruits or high-fiber cereals, or a fiber supplement, to the diet. A fiber intake of at least 10 g/d is an appropriate goal. Additional fiber should be avoided if the patient is extremely debilitated, if partial bowel obstruction is suspected, or if a change

In most cases, routine management begins with either an osmotic laxative or a contact laxative such as senna. Alternative approaches, such as daily lactulose or sorbitol, a prokinetic drug, or an approach involving intestinal lavage, usually are reserved for patients who do not tolerate or benefit from the more widely

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Table 16 Management of Constipation

General Approaches

Increase fluid intake Increase dietary fiber Consider bulk laxative (unless debilitated or bowel obstruction is suspected) Ensure that impaction has not occurred Intermittent use (every 2 to 3 days) of osmotic laxative, such as magnesium hydroxide, magnesium citrate, or sodium phosphate Daily softening agent (docusate sodium) alone Intermittent use (every 2 to 3 days) of a contact cathartic, such as senna, bisacodyl, or phenolphthalein Daily contact cathartic (with or without concurrent softening agent) Daily lactulose or sorbitol Rectal approaches, including contact cathartic or enemas in refractory cases Intermittent or daily use of colonic lavage with polyethylene glycol Daily treatment with a prokinetic drug, such as cisapride or metoclopramide Daily treatment with oral naloxone

Specific Approaches*

Alternative Approaches

* Should be discussed with patient; select one or more than one Adjust dose and dosing schedule of selected therapy to optimize effects Switch or combine conventional approaches if initial therapy inadequate

Patients with refractory opioid-induced constipation now may benefit from oral naloxone therapy.124 The latter approach is feasible because naloxone has a very low oral bioavailability and oral administration and therefore may reverse opioid bowel effects without producing systemic withdrawal. Treatment usually involves a starting dose of 1 mg orally twice daily, which is gradually increased until bowel function improves or side effects (typically just abdominal cramping but occasionally also symptoms of systemic opioid withdrawal) supervene. The use of other opioid antagonists, quaternary compounds that do not cross the blood-brain barrier, in the treatment of opioid-induced bowel dysfunction is under active investigation. Studies of oral alvimopan124a and intravenous methylnaltrexone124b demonstrate efficacy in reversing opioid-related bowel dysfunction and suggest that opioid antagonist
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used interventions. Daily lavage therapy has recently been simplified by the availability of a powdered polyethylene glycol (Miralax®).

therapy may provide a safe and effective alternative for larger numbers of patients with refractory constipation or other significant adverse opioid-induced gastrointestinal effects. Alvimopan is likely to appear on the United States market first, initially indicated for the treatment of postoperative ileus. Further studies will be needed to clarify the positioning of these new therapies among the many currently used to manage opioid-related constipation.
Dyspnea

Dyspnea is an extremely distressing symptom and is highly prevalent in populations with advanced cancer, particularly those with lung cancer. Significant dyspnea is associated with a relatively short life expectancy, and the management of this symptom is often a critical part of comprehensive palliative care at the end of life.

The pathophysiology of dyspnea is complex, and a careful assessment is needed to clarify the existence of potentially treatable etiologies or mechanisms (such

as pleural effusion or bronchospasm) that might be targeted for specific interventions.125 To clarify the range of contributing factors, the clinical evaluation may be complemented by diagnostic tests that range in complexity from bedside pulmonary function tests and plain radiography to axial imaging of the chest, pleurocentesis, and cardiac evaluation. In the setting of advanced disease, the decision to pursue any of these diagnostic tests must consider the goals of care and patient wishes. Given the association between dyspnea and anxiety, reassurance, counseling and education of the patient and family are fundamental to the overall therapeutic approach. Primary therapy directed against the most important etiologies may be feasible and should be considered in every case. The dramatic symptomatic improvement experienced by the patient with superior vena cava syndrome after treatment with radiation therapy exemplifies the potential benefits of this approach.

Although data are very limited in the cancer population, there is an abundant experience with the use of systemic opioid therapy for the treatment of dyspnea. This experience is favorable and suggests that these drugs are both potentially effective and, when titrated correctly, acceptably safe.126,129 Morphine is used most commonly, but there is no evidence that its efficacy is better than that of other pure mu agonists. In the opioid-naive patient, the starting dose usually is equivalent to morphine 5-10 mg orally every 4 hours. For those receiving chronic opioid therapy, the treatment of superimposed dyspnea requires a trial of a dose increase (usually 25%50%). Once a daily dose is established using a short-acting drug, a switch to a controlled release drug may follow. Rescue doses to treat acute episodes of dyspnea also should be considered. As an alternative to systemic opioid therapy, some clinicians have used inhaled nebulized morphine to treat cancer-related dyspnea. There is no evidence from clinical trials that this approach is effective or should be favored over the more routine approach.

If bronchospasm appears to contribute to the dyspnea, bronchodilator therapy is appropriate. Methylxanthines have been used less often than adrenergic agonists in recent years because of concerns about toxicity, but there is evidence that these drugs improve respiratory muscle contractility127 and a trial occasionally is considered in patients with severe dyspnea. Symptomatic drug therapy for dyspnea is limited to a small group of agents. Oxygen can help, particularly in hypoxemic patients.128 A trial usually is warranted even if hypoxemia cannot be demonstrated.

Symptomatic therapies may be pharmacologic or nonpharmacologic.126 The nonpharmacologic approaches range widely in complexity and cost, and have not been specifically studied in the cancer population. Their use is empirical and suggested by the clinical setting, medical condition of the patient, and resources of the patient and family. In addition to reassurance, more-sophisticated cognitive therapies can be used to reduce anxiety and enhance coping and function. If warranted, a more comprehensive program of pulmonary rehabilitation combining education, cognitive approaches, nutritional support, and chest physical therapy may be considered. Occasionally, assistive devices, such as a unit that provides continuous positive airway pressure, are tried.

Other drugs can also help in symptom control. Although evidence of efficacy for dyspnea is lacking for benzodiazepines, these drugs may reduce anxiety and have been useful anecdotally. Neuroleptics are sometimes tried instead, or in addition to the latter agents. Similarly, there is no evidence that corticosteroids directly reduce dyspnea, but they can be very useful when bronchospasm, bronchial or superior vena cava obstruction, or lymphangitic spread of neoplasm is involved in the pathophysiology of the symptom. Dexamethasone or another drug in this class is often administered empirically, particularly in the setting of advanced disease. As noted, theophylline is sometimes offered in refractory cases, even in the absence of bronchospasm.

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5. Conclusion
Most oncologists provide long-term, primary care to patients with cancer. This role necessitates an ongoing integration of interventions generally described by the terms “supportive care” and “palliative care” with aggressive management of the disease and its comorbidities. These interventions assist the patient and family in their effort to maintain a good quality of life throughout the course of the illness and, if necessary, prepare well for the end of life. Symptom distress is a major concern at all times, and expertise in the assessment and management of common symptoms is an essential element in oncology practice. Although optimal palliative care is more than symptom control alone, expert symptom management is a key role for the oncologist, who must develop communication skills that include the ability to reliably assess inherently subjective phenomena and practical skills in the pharmacotherapy of diverse symptoms. Continuing education to acquire and maintain the competencies needed to provide optimal supportive care and palliative care deserves high priority in oncology practice.

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