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

SUPPORTIVE AND PALLIATIVE CARE 361

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 support-
ive care and palliative care typically refer to the thera-
peutic 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 diag-
nosis. 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 distur-
bances, 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 con-
cerns may become inextricably linked with profound
end-of-life issues. Symptom control, support for the
family, psychological and spiritual distress, and the spe-
cific fears related to abandonment and fear of dying may
be some of the specific concerns that arise.
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 pre-
requisites for a satisfactory quality of life, and an ele-
ment 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 communica-
tion 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 develop-
ment of palliative care as a medical specialty. At this
362 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
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, symp-
tom 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 psycholog-
ical, 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 man-
agement of the physical, psychological, social, and
spiritual needs of patients with progressive, incur-
able 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 pri-
ority, practical needs are addressed, psychosocial
and spiritual distress is managed, values and deci-
sions 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 spe-
cialty dedicated to excellence in palliative care.
Palliative medicine is a recognized medical subspe-
cialty 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 subspe-
cialty. 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, Ameri-
can Board of Surgery, and American Board of Phys-
ical 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 broaden-
ing 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 profes-
sional practice is the requirement for Fellowship
training. In 2006, the Accreditation Council of Grad-
uate Medical Education (ACGME) accepted Hos-
pice 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 Fel-
lowship will be required for Board certification after
a “grandfathering” period passes.
Acceptance of Hospice and Palliative Medicine by the
ABMS and the ACGME will mainstream specialist-
level palliative care in U.S medical practice. Special-
ists in this discipline are expected to staff institution-
based palliative care services and hospice programs.
These physicians will assist in the parallel process by
which generalist-level palliative care becomes incor-
porated into all appropriate venues, including oncol-
ogy practice. Encouragement for this change will
occur through the work of the National Quality
Forum, which in 2006 endorsed a “National Frame-
work and Preferred Practices for Palliative and Hos-
pice Care,” and potentially through other organiza-
tions focused on quality medical care. The recent pub-
lication of a consensus document known as the Con-
sensus 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
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 ben-
efit 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 fami-
lies 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 thera-
pist 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 fac-
tors, 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 champi-
oning a model known as “open access,” which essen-
tially 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 radia-
SUPPORTIVE AND PALLIATIVE CARE 363
tion therapy, is allowed and will be covered by the Oncologists should understand the available
hospice as long as it does not alter the estimation of resources for specialized palliative care services.
prognosis sufficiently to reverse eligibility. Oncolo- With knowledge of the range of programs and ser-
gists should understand the nature of hospice eligibil- vices offered, patients with complex palliative care
ity and explore the extent to which local hospices are needs can be appropriately referred. In the absence
adopting an open access approach. This will hopefully of a comprehensive program that provides special-
expand the opportunity for hospice benefits to larger ist-level care appropriate to the needs of the patient
numbers of patients and families. and family, the oncologist should attempt to fashion
the clinical liaisons that could address the most
To meet the broader need for palliative care in the pressing needs. This may involve referral to a pain
United States, palliative care programs are rapidly management program or the institutional bioethics
developing in hospitals and some nursing homes. committee, or to individuals who may be appropriate
Like hospices, these programs attempt to provide to address psychosocial issues or spiritual distress.
specialist-level interdisciplinary care to patients with
advanced disease. Some are limited to an interdisci-
plinary 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 hospital-
based 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 indi-
viduals or institutions interested in developing pallia-
tive care services have been developed and dissemi-
nated by the Center to Advance Palliative Care.4b

As an approach to the care of patients with life-

threatening illnesses, palliative care should be rou-
tinely integrated into oncology practice. All oncolo-
gists should develop skills in symptom control, com-
munication about end-of-life issues, assessment and
management of psychosocial concerns, identifica-
tion 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.

364 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

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 dis-
ease-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.
Although symptom distress is common among patients
undergoing active therapy, the specific problems have
evolved during the past two decades. Chemotherapy-
anticipatory. Most antiemetic research has focused
on the management of acute emesis.5,6 The patho-
physiology of this syndrome presumably involves
direct activation of the chemoreceptor trigger zone
of the brainstem which, in turn, activates the so-
called vomiting center situated nearby. This region
of the brain has a complex neurochemistry and inter-
acts with the gastrointestinal tract, the vestibulo-
labyrinthine system, and higher cortical centers.7
Influences on Emetogenicity

associated nausea and vomiting was widely considered
to be the major concern until advances in pharma-
cotherapy effectively resolved this problem for most
patients. At the present time, there is increasing appre-
ciation for the problem of therapy-associated fatigue.
Chemotherapy-Associated Nausea
Many factors influence the likelihood of acute nau-
sea and vomiting after treatment. Chemotherapeu-
tic agents vary greatly in this potential. A classifi-
cation system for the potential to cause acute eme-
sis has been proposed in an effort to develop cost-
effective decision models for the selection of
antiemetic therapy.8 The system groups chemother-
apeutic drugs into 5 levels: level 1, <10% of

patients develop acute emesis; level 2, 10% to 30%

and Vomiting

Five categories of emesis associated with develop emesis; level 3, 30% to 60% develop eme-
chemotherapy have been described (Table 1), the sis; level 4, 60% to 90% develop emesis; and level
most important of which are acute, delayed and 5, >90% develop emesis (Table 2).

Table 1

Chemotherapy-Associated Emesis Syndromes

Emesis Syndrome Characteristics

Acute Occurs within 24 hours of treatment, and usually within 1-2 hours

Delayed emesis 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

Anticipatory emesis Conditioned response in which emesis occurs before a subsequent

course of therapy; more likely to develop if acute nausea is poorly
controlled

Breakthrough emesis Episode of emesis that occurs on the day of treatment and “breaks
through” treatment with appropriate antiemetics

Refractory emesis Emesis that develops despite optimal treatment during prior cycles
of chemotherapy

SUPPORTIVE AND PALLIATIVE CARE 365

Table 2

Emetogenic Potential of Chemotherapeutic Drugs

Level Examples

1 (<10%) Bleomycin, busulfan, chlorambucil, fludarabine, hydroxyurea,

methotrexate (<50 mg/m2), vinblastine, vincristine, vinorelbine

2 (10%-30%) Etoposide, 5-fluorouracil, methotrexate (>50-250 mg/m2) gemcitabine,

mitomycin, paclitaxel

3 (30%-60%) Cyclophosphamide (<750 mg/m2 or oral), ifosphamide,

doxorubicin (20-60 g/m2), methotrexate (>250-1000 mg/m2),
mitoxantrone (<15 mg/m2)

4 (60%-90%) Carboplatin, carmustine (<250 mg/m2), cisplatin (<50 mg/m2),

cyclophosphamide (>750-1500 mg/m2), procarbazine,
doxorubicin (>60 mg/m2), methotrexate (>1000 mg/m2)

5 (>90%) Carmustine (>250 mg/m2), cisplatin (>50 mg/m2), dacarbazine,

cyclophosphamide (>1500 mg/m2)

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 dur-
ing a prior course of chemotherapy increases the
likelihood of acute emesis and also predisposes to
the development of anticipatory nausea and vomit-
ing, 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
Antiemetic research began with studies of the sub-
stituted benzamide, metoclopramide10, which in
high doses blocks both dopamine and 5-HT3 recep-
tors. Subsequent studies have established that drugs
that block either of these receptors can be effective,
and the 5-HT3 antagonists have become the main-
stay 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-tetrahydrocannabi-
nol).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 neu-

During the past 20 years, a very large number of clin-
ical trials have established the efficacy of specific
drug classes for the management of acute chemother-
apy-associated emesis. This has allowed the devel-
opment of rational guidelines for the selection of
combination therapy based on the emetogenicity of
the chemotherapeutic regimen and other factors.5,6,8,9
rokinin 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 eme-
sis.6,15,15a Drugs in all these classes are now used
commonly (Table 3).

366 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

Table 3

Drugs Used to Treat Chemotherapy-Associated Nausea and Vomiting

Class Mechanism Drugs

5-HT3 antagonists 5-HT3 blockade Ondansetron

Granisetron
Dolasetron

Substituted 5-HT3 blockade Metoclopramide

Benzamide Dopamine blocker

Corticosteroids Unknown Dexamethasone

Butyrophenones Dopamine blocker Haloperidol

Phenothiazines Dopamine blocker Prochlorperazine

Cannabinoids Cannabinoid receptor Dronabinol

blocker

Benzodiazepines Benzodiazepine receptor Lorazepam

blocker

Neurokinin antagonists NK-1 receptor blocker Aprepitant

Recommendations for anti-emetic therapy match the
drug regimen to the likelihood of nausea and vomit-
ing.5 Unless the patient has other significant risk fac-
tors for emesis (the most important being poorly con-
trolled symptoms during a prior course of therapy),
the administration of chemotherapy with low emeto-
genic potential can be managed initially with dexam-
ethasone (usual dose 20 mg IV 30 minutes before
treatment) plus antiemetics as needed (eg, metoclo-
pramide 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
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 eme-
sis5,6,15,15a,18 and should be considered if the risk or con-
sequences of delayed emesis appears high.
These antiemetic regimens are highly effective and
can be expected to provide complete or nearly com-
plete control to most patients. All patients may ben-
efit from education and, if available, specific cogni-
tive techniques can be added and further improve
outcomes.19
Treatment-Related Fatigue

intravenous combination regimen, which is adminis-
tered 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
Fatigue is a nearly universal symptom in patients
undergoing primary antineoplastic therapy or treat-
ment with biologic response modifiers, and is
extremely common in populations with persistent or
advanced disease.20,21 A population-based survey of

SUPPORTIVE AND PALLIATIVE CARE 367

419 randomly selected cancer patients observed that
78% experienced fatigue, which was defined as debili-
tating 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 pop-
ulation. 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, somno-
lence, difficulty concentrating). A definition pro-
posed for the International Classification of Diseases
10th Revision-Clinical Modification (ICD-10-CM)
stresses the multidimensional nature of the phe-
nomenon (Table 4).22
Oncologists are now recognizing that the assess-
ment and management of pathologic fatigue is
extraordinarily important in maintaining a good
quality of life. A supplement to the journal Can-
cer,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 num-
ber of potential etiologies (Table 5). When due pri-
marily to a treatment, there is generally a clear tem-
poral 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

Table 4

Proposed Criteria for Cancer-Related Fatigue

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.

368 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

 ies). Other proposed mechanisms link fatigue to the
pathophysiology of sleep disorders and major depres-
Table 5

sion. There is no clear evidence in support of any of

these mechanisms, and further research is needed.
Potential Etiologies of
Cancer-Related Fatigue

Directly related to the disease Fatigue Assessment

Given the high prevalence of fatigue, clinicians

should integrate fatigue assessment into routine care.
Related to antineoplastic therapy

Patients should be asked if fatigue is a problem, and if

Radiotherapy

the response is affirmative, information should be

Chemotherapy

sought on its severity and impact. Consistent use of a

Immunotherapy

simple unidimensional severity scale, such as a verbal

Surgery

rating scale (none, mild, moderate, severe) or a

numeric scale (eg, a 0-10 scale where 0 equals no
Related to metabolic or other disorders

fatigue and 10 equals the worst fatigue imaginable)

Anemia

can provide useful information that can be docu-

Electrolyte disturbances

mented in the medical record. The impact of fatigue

Malnutrition

can be assessed by a question about the degree to

Infection

which it interferes with the ability to function. More

Cardiopulmonary disorders

sophisticated scales for unidimensional or multidi-

Renal disorders

mensional fatigue assessment exist24 and are usually

Hepatic disorders

used for research purposes.

Neuromuscular disorders

If the cause of fatigue is not obvious, additional

Related to the use of centrally acting drugs

information may be needed to define a specific eti-

ology which, in turn, may suggest therapeutic
Related to mood disorder

strategies. Patients may describe fatigue in terms of

Depression

decreased vitality or lack of energy, muscular weak-

Anxiety

ness, dysphoric mood, somnolence, impaired cog-

nitive functioning, or some combination of these
Related to sleep disorder

disturbances. Although the variability suggests the

existence of fatigue subtypes, this has not been
Related to other symptoms

empirically confirmed.
Pain

Related to immobility and deconditioning

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 pre-
sumably varies with the etiology. Proposed mecha-
nisms include abnormalities in energy metabolism
related to increased requirements (eg, due to tumor
growth, infection, fever, or surgery); decreased avail-
ability of metabolic substrate (eg, due to anemia,
hypoxemia, or poor nutrition); or the abnormal pro-
duction of substances that impair metabolism or nor-
mal 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 sel-
dom discussed by patients and their oncologists.20
In some cases, evaluation of the cancer patient with
fatigue reveals one or more potentially treatable etiolo-
gies (Table 5). The interventions to address these con-
ditions 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 rela-

SUPPORTIVE AND PALLIATIVE CARE 369

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).
Some of the etiologies that may be associated with can-
cer-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, partic-
ularly 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 expe-
rienced 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, func-
tional status, and overall quality of life, independent
of antitumor response.27,28 A recent randomized trial
in patients with prostate cancer demonstrated a dose-
related improvement in hemoglobin, fatigue and
quality of life in this population.29
On the basis of these data, patients with significant
fatigue and even moderate anemia should be consid-
ered 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 ini-
tial dose of 100 mcg weekly, which is increased if the
response is inadequate. Doses can be reduced and
maintain benefit in some patients.
370 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
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 phar-
macotherapies and exercise.23b,23d,23e,24 Among the phar-
macologic 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 somno-
lence 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 sympath-
omimetic 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 lack-
ing 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 dexametha-
sone 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.
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 tri-
cyclic 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, how-
ever, and an empiric trial may be warranted in
selected patients with severe refractory cancer-
related 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 symp-
tomatic 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.
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 nutri-
tion 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 guid-
ance, suggestions for nutritional supplements, and in
selected cases, administration of an appetite stimu-
lant (eg, megestrol, oxandrolone, or dronabinol)
should be considered.

The use of a patient diary may help the clinician and

patient discern a pattern to the fatigue or identify spe-
cific activities that are associated with increased lev-
els. This information may be useful in developing a
management plan that modifies specific activities and
incorporates appropriate periods of rest.

In a similar manner, some patients benefit from inter-

ventions 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-

SUPPORTIVE AND PALLIATIVE CARE 371

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 can-
cer 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 per-
formed in a hospice or palliative care setting, indi-
cate 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
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 pres-
ence of pain.44
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 prac-
tice, patient underreporting and therapeutic nonadher-
ence, noncompliance, and system-wide impedi-
ments to optimal analgesic therapy.45 There is grow-
372 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
ing recognition that the current situation needs
improvement. Recently, institutional efforts to man-
age pain were added to the practice standards
reviewed by the Joint Commission for the Accredi-
tation of Health Care Organizations. Oncologists
must ensure that their medical information concern-
ing pain control is current and that patients receive
appropriate education.
Pain Assessment
The management of pain in all populations with
serious medical illnesses depends on a comprehen-
sive assessment that characterizes symptoms in
terms of phenomenology, syndrome, and pathogen-
esis; evaluates the relationship between the pain and
the disease; and clarifies other quality-of-life con-
cerns. The initial steps in the comprehensive assess-
ment involve a detailed description of the pain phe-
nomenology, syndrome identification, and the elab-
oration of hypotheses about etiology and pathophys-
iology. This information is acquired through the his-
tory, physical examination, and review of laboratory
and imaging studies (Table 6).
Pain is inherently subjective, and patient self-report-
ing is the gold standard for assessment. Ideally, the
description of the pain should characterize its tem-
poral relations, severity, topography, quality, and
factors that exacerbate or relieve it (Table 6). Each
of these characteristics may provide information rel-
evant 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 continu-
ous basis and a short-acting analgesic on an “as
needed” basis for breakthrough pain. Half to two-
thirds 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 ther-
apy. 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
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 associ-
ated with pain that is described as aching, stabbing,
or throbbing.
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 pro-
cessing 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 eti-
ologies, and infer a pathophysiology. This set of con-
structs, in turn, guides clinical decisions about addi-
tional evaluation, prognostication, and therapy.

Table 6

Assessment of Cancer Pain Characteristics

Characteristic Descriptors

Temporal Acute, recurrent, or chronic;

Onset and duration when present, continuous or
Course and variation intermittent

Intensity Degree of fluctuation (ie, occurrence of breakthrough pain) severity on

average, at its worst, at its least, right now

Topography Focal or multifocal

Focal or referred
Superficial or deep

Quality Varied descriptors (eg, aching, throbbing, stabbing, or burning)

Familiar or unfamiliar

Exacerbating/ Volitional (incident pain)

Relieving factors or nonvolitional

SUPPORTIVE AND PALLIATIVE CARE 373

Table 7

Acute Cancer Pain Syndromes

Examples

Caused by procedures Lumbar puncture headache; bone marrow biopsy; paracentesis;

thoracentesis; pleurodesis, tumor embolization

Caused by therapy 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)

Caused by the neoplasm Pathologic fractures; acute obstruction of bowel or other hollow viscus
Headache from intracranial hypertension

Caused by other pathology Acute pain associated with infection

uncommon marrow expansion syndrome can be seen

without abnormalities on either plain radiography or
Cancer Pain Syndromes

Numerous pain syndromes have been described in the bone scintigraphy.

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 can-
cer 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 unre-
lated 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 distin-
guishes nociceptive from neuropathic syndromes.
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
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

374 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

 focal painful osteonecrosis. Examples of radiation-
induced syndromes include osteoradionecrosis of the
Table 8

mandible after radiation for head and neck cancer, and

osteoradionecrosis of the pelvis after radiation for
Chronic Nociceptive Cancer

pelvic malignancies. Radiation can also cause pro-

Pain Syndromes

gressive changes in soft tissues and joints, which can

Somatic Pain result in a chronic pain syndrome.

Interruption of lymphatic channels by surgical manip-

ulation or radiation can result in chronic lymphedema.
Metastatic bone pain syndromes

Some patients experience an associated chronic pain

Multifocal or generalized pain

syndrome that probably relates to stretching of soft

(focal metastases or marrow expansion)

tissues and chronic overload of structures supporting

Base of skull metastasis

the limb.
Vertebral syndromes
Long bone or pelvic metastases

Obstruction, infiltration, and compression of visceral

structures produce an extremely diverse group of pain
Tumor invasion of joint

syndromes (Table 8). Patients with liver metastases

may experience progressive pain related to stretching
Tumor invasion of soft tissue

of the capsule or injury to the diaphragm or biliary

tree. Capsular injury produces pain that is usually
Hypertrophic osteoarthropathy

experienced focally in the right upper quadrant of the

abdomen and sometimes extends to the flank or right
Radiation-induced or steroid-induced painful

paraspinal region. The pain may be associated with

osteonecrosis

tenderness to palpation and cutaneous hyperesthesia

in the right upper quadrant. Diaphragmatic irritation
Painful lymphedema

may refer pain to the shoulder, and involvement of

structures inferior to the liver can refer pain to the ipsi-
Painful gynecomastia

lateral scapula. These sites of referred pain occasion-

ally predominate.

Any lesion in the rostral retroperitoneum can produce

Visceral Pain

pain that mimics the pain of pancreatic cancer. Pain

may be diffuse in the abdomen or more focal in the
Hepatic distention syndrome

epigastrium or right or left upper quadrants, or present

in some combination. Back pain in the region of the
Rostral retroperitoneal syndrome

T10-L2 vertebral bodies is common and may be the

sole site of pain.
Chronic intestinal obstruction and peritoneal
carcinomatosis

Chronic partial bowel obstruction is a common com-

plication of many tumors, particularly ovarian and
Malignant pelvic and perineal pain

colorectal. Patients may experience frequent cramps

or aching pains that may be worsened by eating, activ-
Chronic ureteral obstruction

ity, and constipation. Patients who develop ascites

may also report pain that appears to originate from
Chronic abdominal pain caused by intraperitoneal

stretching of the abdominal wall.

chemotherapy or radiation therapy

Chronic visceral pain also can occur as a result of anti-

Radiation-induced chronic pelvic pain

neoplastic therapies. For example, patients occasion-

ally develop chronic abdominal pain after intraperi-

SUPPORTIVE AND PALLIATIVE CARE 375

toneal chemotherapy or pelvic or abdominal radiation
therapy. These syndromes presumably represent per-
Table 9

sistent injury to intra-abdominal or pelvic tissues and

chronic partial obstruction related to scar formation.
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. Cancer-
Tumor-Related Neuropathic Pain Syndromes

related neuropathic pain syndromes (Table 9) usually

are caused by tumor infiltration or compression of
Painful peripheral mononeuropathies

peripheral nerves or nerve roots. They may also result

Painful polyneuropathies

from the remote effects of malignancy on peripheral

Painful plexopathy

nerves. The resultant pain syndromes are highly vari-

Radiculopathy

able. Some patients experience deep aching pains

Epidural spinal cord compression

occurring anywhere in the dermatomal region inner-

vated by the damaged neural structure, and others
Treatment-Related Neuropathic Pain

experience abnormal sensations, including sponta-

Syndromes

neous or evoked paresthesias or dysesthesias. Patients

may or may not develop motor, sensory, or autonomic
dysfunction in the distribution of the involved nerve.
Postsurgical neuropathic pain syndromes
Postmastectomy syndrome

Painful mononeuropathies can occur after injury to

Postthoracotomy syndrome

any nerve that carries afferent fibers and may result

Postradical neck dissection syndrome

in chronic neuropathic pain. Just as tumors at the

Postnephrectomy syndrome

base of the skull cause painful cranial mononeu-

Stump pain and phantom pain

ropathies, a lesion in a rib or paraspinal gutter can

produce intercostal nerve injury and retroperitoneal
Postradiotherapy Pain Syndromes

masses, or a lesion in the pelvic sidewall can cause

similar pains that affect the lower trunk or legs.
Radiation fibrosis of cervical, brachial, or
lumbosacral plexus

Irritation of the intrathoracic vagus nerve by a neo-

Radiation-induced neoplasm

plasm in the lung can produce a referred facial pain

Radiation myelopathy

syndrome.51 The pain in this rare condition may be

centered on the eye, cheek, or ear. This syndrome
Postchemotherapy Pain Syndromes

leads patients with unexplained facial pain to

undergo imaging of the chest.
Painful polyneuropathies

A painful polyneuropathy may have an etiology unre-

lated to the cancer, such as multiple vitamin deficien-
cies, metabolic derangements, or neurotoxic drugs,
or may more uncommonly be paraneoplastic. The
painful paraneoplastic polyneuropathies include a
dorsal root ganglionopathy and a painful sensorimo-
tor neuropathy.52
Tumor infiltration of the cervical, brachial, or lum-
bosacral 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
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 compres-
sion.53 This is a potentially devastating complication,

376 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

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.
Guidelines for the management of patients with can-
cer-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 escala-
tion); 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 ill-
defined, 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.
Cancer-related neuropathic pain syndromes also
can be caused by an invasive diagnostic or therapeu-
tic procedure, or by antineoplastic therapy. A surgi-
cal incision anywhere in the body injures small
afferents and produces a neuropathic pain syndrome
in some patients.
The postmastectomy syndrome, which is character-
ized 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
usually branches off the T2 root, has been impli-
cated. This syndrome is not associated with tumor
recurrence, and a positive statement to this effect can
be highly reassuring to the patient.
The term postthoracotomy pain is used by some clini-
cians 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 dis-
section 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 plex-
opathies (Table 9). Symptoms associated with radia-
tion-induced nerve injury usually appear months to
years after treatment.54 Pain is generally less promi-
nent than nerve injury related to neoplasm.
Painful polyneuropathies can complicate numerous
chemotherapies, including vincristine, which usu-
ally 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-sensi-
tive intracranial structures, either directly or indirectly
through increased intracranial pressure. The headache
associated with this increased pressure may be dif-
fuse, hemicranial, or occipital, and is typically worse
on awakening and improves throughout the day. It
usually begins insidiously, is seldom severe, and pro-
gresses over time. A history of progressive headache
should lead to appropriate imaging.
SUPPORTIVE AND PALLIATIVE CARE 377
Pain Management: Primary Therapies
Interventions targeted to the etiology of the pain can
have analgesic consequences and should be consid-
ered 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 chemother-
apy for pain control.56,57 To realize the potential bene-
fits 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 underly-
ing problem is characterized, decision-making is fur-
ther 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
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
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 sub-
class (including butorphanol, nalbuphine, penta-
zocine, and dezocine) and a partial agonist subclass
(including buprenorphine). Drugs in the agonist-
antagonist subclass have a ceiling effect for analgesia
and reverse the effects of pure agonists in patients who
are physically dependent; some produce psy-
chotomimetic 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 man-
agement of chronic pain, the pure mu agonist drugs
are preferred (Table 10).
378 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
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 anti-
inflammatory 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, lax-
atives) and drugs with analgesic effects (the so-
called adjuvant analgesics).
Patients with moderate to severe pain (including those
with insufficient relief after a trial of acetaminophen
or an NSAID), are treated with an opioid convention-
ally used for moderate pain. This opioid usually is
combined with acetaminophen or an NSAID, and
may be coadministered with an adjuvant drug, if indi-
cated. 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 con-
sidered 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 administra-
tion of drugs on the second rung of the analgesic lad-
der) 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 mod-
erate 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 for-
mulation or the likelihood of progressive pain pro-
vides a justification for this strategy.
Table 10

Opioid Analgesics

Equi-
Morphine-like analgesic Half-life Duration
Agonists Dosesa (h) (h) Toxicity Comments

Morphine 10 IM/IV/SQ 2-3 3-4 Constipation, nausea, Standard for

sedation most common; comparison for opioids;
20-60 POb 2-3 3-6 respiratory depression multiple routes
rare in cancer patients available

Controlled- 20-30 POb 2-3 8-12 MS Contin® (generic

release morphine available)

Sustained- 20-30 POb 2-3 12-24 Once-a-day dosing Avinza®; Kadian®

release morphine morphine recently
approved in the U.S.

Hydromorphone 1.5 IM/IV/SQ 2-3 3-4 Typical opioid Potency and high
7.5 PO 2-3 3-6 effects solubility may be
beneficial for patients
requiring high opioid
doses and for subcuta-
neous administration.

Oxycodone 20-30 PO 2-3 3-6 Typical opioid Available as a single

effects entity or combined with
aspirin or
acetaminophen

Controlled- 20-30 PO N/A 8-12 Typical opioid

release oxycodone effects

Oxymorphone 1 IM/IV/SQ — 3-6 Typical opioid

10 PR — 3-6 effects
50 PO

Controlled- 15 PO N/A 12 Typical opioid

release oxymorphone effects

Meperidine 75 IM 2-3 3-4 Typical opioid Not preferred

300 PO 2-3 3-6 effects because of toxic
metabolite,
normeperidine

Levorphanol 2 IM/IV/SQ 12-15 3-6 Typical opioid With long half-life,

4 PO 12-15 3-6 effects accumulation possible
after beginning or
increasing dose

(continued)

SUPPORTIVE AND PALLIATIVE CARE 379

Table 10 (continued)

Opioid Analgesics

Equi-
Morphine-like analgesic Half-life Duration
Agonists Dosesa (h) (h) Toxicity Comments

Methadone Variable 12-150 3-6 Typical opioid Highly variable half-life

effects and potential for
accumulation require
greater vigilance for
development of opioid
toxicity; can prolong
the QTc interval.

Hydrocodone 30 PO 2-4 3-6 Typical opioid Only available com-

effects bined with
acetaminophen,
aspirin, or ibuprofen

Fentanyl 50 - 100 mcg 7-12 1-2 Typical opioid Can be administered

IV/SQ effects as a continuous IV or SQ
infusion

Fentanyl — N/A 48-72 Typical opioid Refer to package

transdermal per effects insert for oral and
system patch parenteral medication
equianalgesic dosing
guidelines. Not usually
recommended for opioid
naïve patients in
currently available
doses. Not
recommended for
acute pain.

Oral transmucosal — 7-12 1-2 Typical opioid effects Not recommended for
fentanyl citrate opioid-naïve patients.
Recommended starting
dose for breakthrough
pain, 200-400 mcg, even
with high-baseline
opioid doses

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 subcu-
taneous 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%.

380 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

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, normeperi-
dine. These adverse effects include dysphoria,
tremulousness, hyperreflexia, and seizures.
The unique analgesic, tramadol, also can be used to
manage cancer pain at the second rung of the anal-
gesic ladder.63 The analgesic mechanism of this drug
involves a mixture of mu-agonism and interaction
with analgesic monoaminergic pathways in the cen-
tral nervous system.
The opioids conventionally used in the United States
for severe pain include morphine, hydromorphone,
fentanyl, oxycodone (used as a single entity), levor-
phanol, and methadone. Oxymorphone is available as
a suppository and an injectable formulation, and will
soon be available in both a modified-release long-act-
ing oral formulation and an oral short-acting formula-
tion. 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 sub-
stantial individual variation in the response to different
opioids. For every patient, therefore, the overall bal-
ance between analgesia and side effects, and the pat-
tern 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 toxi-
city, particularly in the setting of renal insufficiency,
should be offered a trial of an alternative opioid in the
hope that lesser metabolite accumulation may con-
tribute to a better response. Based on the relative lack
of active metabolites, fentanyl and methadone have
been recommended in patients with renal insuffi-
ciency;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.
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 treat-
ment 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 concentra-
tion 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.
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 substan-
tially less expensive than other opioids typically used
for chronic therapy.
Given the long and variable half-life, and a potency
that can be far greater than indicated on standard rela-
tive potency tables, the safe use of methadone requires
more careful dosing and monitoring at the start of ther-
apy 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 pro-
long 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 con-
current 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).
SUPPORTIVE AND PALLIATIVE CARE 381
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 anal-
gesic 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 avail-
ability 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 accommo-
dated well. The transdermal route offers a 48- to 72-
hour dosing interval, and is very useful for patients
who are unable to swallow or absorb an orally admin-
istered 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 mor-
phine70 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 absorp-
tion from the transdermal system and may also com-
plicate the use of this approach.
Patients who are unable to swallow or absorb opi-
oid drugs and who do not experience intolerable
side effects from systemic administration also are
candidates for other approaches to long-term par-
enteral 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
382 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
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 formula-
tion can be used for continuous infusion. Long-
term intravenous administration is possible if the
patient has an indwelling venous access device. If
subcutaneous infusion is chosen, a 25-gauge butter-
fly needle is conventionally used. The needle,
which can be placed at any convenient site, usually
is changed weekly.
A variety of techniques for intraspinal opioid delivery
have been adapted to long-term treatment, and prop-
erly 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 demon-
strated that the spinal opioid treatment improved pain,
side effects, quality of life and even survival.71a
The potential for intraspinal infusion has increased
further with the use of drug combinations. The long-
term 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 break-
through pain. This formulation incorporates fen-
tanyl 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.
The rectal route occasionally is used for prolonged
therapy, particularly at the end of life. Rectal adminis-
tration of a controlled-release oral morphine prepara-
tion and specially compounded methadone supposito-
ries have been effective.
Dosing Guidelines
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 rela-
tively opioid-naive patients (this is particularly appro-
priate with methadone because of the risk of late toxi-
city from drug accumulation); in patients with rapidly
changing pain (eg, after radiotherapy to a painful bony
lesion); and in patients with intermittent pain sepa-
rated by pain-free intervals.
For the patient with limited prior opioid exposure
(eg, the use of an acetaminophen-oxycodone com-
bination 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 calcu-
lated from a table of equianalgesic doses (Table
10). This calculation is revised based on the spe-
cific 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 cal-
culated equianalgesic dose based on the conver-
sions in the package insert. The dose of the new
opioid should be reduced relatively more when the
patient is medically frail or the patient is taking rel-
atively high doses; it should be reduced relatively
less if the ongoing pain is severe.
There are few studies of rescue dosing, and the selec-
tion 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 modi-
fied-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 alterna-
tive short-acting opioid, such as morphine, is typically
coadministered (OTFC, which can be selected with
any baseline opioid, can be selected for use with trans-
dermal fentanyl if there is a specific desire to limit opi-
oid 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 res-
cue72 and guidelines for the use of this new formula-
tion 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 treatment-
limiting side effects, The size of the increase usually is
selected as either the total quantity of rescue drug con-
sumed 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.
SUPPORTIVE AND PALLIATIVE CARE 383
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 long-
term administration of opioid drugs.74 Moreover,
when pain does increase again, this declining effi-
cacy 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-
Table 11
Reasons for Increasing Pain During
Opioid Therapy
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
384 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
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 bal-
ance 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 titra-
tion. 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 sophisti-
cated 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
The term non-opioid analgesic is conventionally
applied to acetaminophen and all the nonsteroidal
anti-inflammatory drugs (NSAIDs). The term adju-
vant 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 anal-
gesics are fundamental to the analgesic ladder
approach to cancer pain management.
Nonopioid Analgesics
Although acetaminophen and the many NSAIDs con-
stitute a diverse group of drugs (Table 13), all inhibit
the enzyme cyclo-oxygenase and reduce the synthesis
of prostaglandins. Cyclo-oxygenase has at least sev-
eral 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-oxyge-
nase-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
Table 12
Therapeutic Options When an Opioid Regimen Fails
Approach
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
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 valde-
coxib, have been developed in an effort to reduce gas-
trointestinal toxicity, including ulcer formation.76,77 This
reduced risk is favorable, and, on theoretical grounds,
supported the preferential use of these NSAIDs in med-
ically frail populations, such as those with cancer pain.
The role of the selective COX-2 drugs, and of the
NSAIDs overall, is undergoing re-examination, how-
ever, 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
Options
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
after publication of several studies documented a risk
of adverse cardiovascular outcomes greater than com-
parator drugs, and the U.S. Food and Drug Adminis-
tration decided to withdraw valdecoxib from the mar-
ket based on this risk and an unrelated risk of cuta-
neous 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 inhi-
bition of COX-2, whether or not the drug is a selec-
tive 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 high-
lights the potential for both serious cardiovascular
and gastrointestinal toxicity.
SUPPORTIVE AND PALLIATIVE CARE 385
Table 13

Nonsteroidal Anti-Inflammatory Drugs

Recommended Recommended
Starting Maximum
Chemical Class Generic Name Dose (mg/d)* Dose (mg/d) Comment

P-aminophenol Acetaminophen** 2,600 4,000 Overdosage produces

derivative hepatotoxicity. Not anti-inflam-
matory. 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****
Diflunisal** 1,000 x 1 1,500 Less than aspirin****

Choline magnesium 1,500 x 1 4,000 Less GI toxicity than other

trisalicylate** then 1000 NSAIDs. No effect on platelet
aggregation****

Salsalate 1,500 x 1 4,000

then 1000

Propionic acids Ibuprofen** 1,600 4,200 Available over the counter****

Naproxen** 500 1,500 Available over the counter and
available as a suspension****
Naproxen sodium** 550 1,375 ****
Fenoprofen 800 3,200 ****
Ketoprofen 100 300 Available over the counter****
Flurbiprofen** 100 300 ***
Oxaprozin 600 1,800 Once-daily dosing may
be useful****

Acetic acids Indomethacin 75 200 Available in sustained-release

and rectal formulations. Higher
incidence of side effects than
propionic acids****
Tolmetin 600 2,000 ****
Sulindac 300 400 ****
Diclofenac 75 200 ****
Ketorolac (IM) 30 (loading) 60 Parenteral formulation
available. Long-term use
not recommended****
Ketorolac (PO) 40 40 Long-term use not
recommended****
Etodolac 600 1,200 ****

(continued )

386 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

Table 13 (continued)

Nonsteroidal Anti-Inflammatory Drugs

Recommended Recommended
Starting Maximum
Chemical Class Generic Name Dose (mg/d)* 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****

Meloxicam 7.5 15 Highly COX-2 selective at

lower doses

Naphthyl- Nabumetone 1,000 1,000-2,000 Relatively low risk of GI

alkanones toxicity; once-daily dosing

Fenamates Mefenamic acid** 500 x 1 1,000 Not recommended for use

longer than 1 week, and
therefore not indicated for
cancer pain****

Meclofenamic acid 150 400 ****

Pyrazoles Phenylbutazone 300 400 More toxic than other NSAIDs

Not preferred for cancer pain
therapy

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.

SUPPORTIVE AND PALLIATIVE CARE 387

The NSAIDs as a class have other potentially impor-
tant toxicities, including congestive heart failure and
renal disease. Given the risk of both acute and
chronic renal disease, all NSAIDs must be used cau-
tiously in patients who have clinically evident renal
dysfunction or who are likely to have subclinical dis-
ease 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 gastroin-
testinal, cardiovascular and renal events.
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 mod-
erate or severe pain, particularly for the treatment of
bone pain. Drug-specific toxicity profiles should be
considered in selecting a drug. In terms of gastroin-
testinal 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, nabume-
tone, 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 predic-
tors of serious gastrointestinal toxicity and as many
as two-thirds of NSAID users experience no symp-
toms 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 corticos-
teroid, and a history of either ulcer disease or previ-
ous gastrointestinal complications from NSAIDs.78,79
Heavy alcohol or cigarette consumption may also
increase the risk of adverse events. A role for infec-
tion by the bacterium Helicobacter pylori in
NSAID-related gastropathy has not been proven.
388 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
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 coadministra-
tion 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.
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 appropri-
ate 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 bene-
fit from a dose change can usually be judged within 1
to 2 weeks. Dose escalation can continue until analge-
sia is adequate, the ceiling dose is reached, side effects
occur, or the dose approaches a conventionally
accepted maximum.
Adjuvant Analgesics
The adjuvant analgesics encompass numerous drugs
in diverse drug classes (Table 14).84 All are commer-
cially available for indications other than pain but
are analgesic in selected circumstances. In the popu-
lation with cancer pain, these drugs usually are
administered after opioid therapy has been opti-
mized. 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.
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 neu-
ropathic pain, bone pain, pain associated with capsu-
lar expansion or duct obstruction, pain from bowel
Table 14

Adjuvant Analgesics

Class Examples

Antidepressants
Tricyclic antidepressants
Tertiary amine Amitriptyline, imipramine
Secondary amine Desipramine, nortriptyline
SSRIs Fluoxetine, paroxetine, citalopram
SSNRIs Venlafaxine, duloxetine
Others Trazodone, maprotiline, nefazadone, mirtazepine

Anticonvulsants Gabapentin, pregabalin, carbamazepine, phenytoin valproate,

clonazepam, topiramate, lamotrigine

Oral local anesthetics Mexiletine, tocainide

Alpha-2 adrenergic agonists Clonidine, tizanidine

NMDA receptor antagonists Dextromethorphan, ketamine, amantadine

Corticosteroids Dexamethasone, prednisone

Topical agents Capsaicin, local anesthetics, NSAIDs

Miscellaneous drugs Baclofen, calcitonin

for neuropathic pain

Drugs for bone pain Bisphosphonates, calcitonin,strontium-89, samarium-153

Drugs for bowel Scopolamine, glycopyrrolate, octreotide

obstruction

obstruction, pain caused by lymphedema, and
headache caused by increased intracranial pressure.
Current data are inadequate to evaluate drug-selec-
tive differences, dose-response relationships, predic-
tors of efficacy, or the durability of favorable effects.
Because the risk of adverse effects associated with
corticosteroids increases with both the dose and dura-
tion of use, long-term therapy usually involves the
administration of relatively low doses to patients with
advanced disease, whose overriding need for symp-
tom 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 appropri-
ate if benefits decline with progressive disease, partic-
ularly at the end of life.
Another approach to corticosteroid therapy is consid-
ered 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 obstruc-
tion that has failed to respond promptly to an opioid.

SUPPORTIVE AND PALLIATIVE CARE 389

This high-dose regimen may begin with dexametha-
sone 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
Many adjuvant analgesics are primarily used in medi-
cally 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.
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 interac-
tions. 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 mecha-
nism 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 stud-
ies 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. Clini-
cal observations suggest that some patients who did
not respond to gabapentin report more satisfactory
effects from pregabalin.
Many other anticonvulsant drugs have been evalu-
ated as treatments for neuropathic pains.89 There is
limited evidence in support of several older anticon-
vulsant drugs, including carbamazepine, phenytoin,
and divalproex, and several newer drugs, including
390 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
lamotrigine and topiramate. Other drugs, such as
clonazepam, oxcarbazepine, tiagabine, zonisamide
and levetiracetam, also are sometimes tried empiri-
cally in practice.
All anticonvulsants are administered using the dos-
ing schedules typically employed for seizures.
Plasma concentrations of carbamazepine, pheny-
toin, 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 existing evidence suggests that the antidepres-
sant drugs are nonspecific analgesics90 and that the tri-
cyclic drugs are somewhat more efficacious for neu-
ropathic pain than gabapentin or pregabalin.88a An
antidepressant should be considered as the first adju-
vant analgesic selected for neuropathic pain if depres-
sion is a significant comorbidity; if not, one of these
drugs is usually tried if gabapentin or pregabalin do
not yield adequate results.
The tricyclic antidepressants (TCAs) have been
most extensively studied, and there is strong evi-
dence that both the tertiary amine TCAs (eg,
amitriptyline, doxepin, and imipramine), and the
secondary amine TCAs (eg, desipramine and nor-
triptyline) can be effective analgesics. There is
good evidence that a serotonin and norepinephrine
reuptake inhibitor (SSNRI), duloxetine, is anal-
gesic and this drug has been approved in the United
States for neuropathic pain associated with dia-
betes.90a Limited evidence favors analgesic effects
for venlafaxine, another SSNRI; several of the sero-
tonin-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 symp-
tom. 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, how-
ever, 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.
Antidepressants do not exert their therapeutic effects
rapidly. Dose titration from a low starting dose is nec-
essary 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.
Systemic administration of local anesthetic drugs
also may provide analgesia for patients with neuro-
pathic pains.91,92 The availability of oral local anes-
thetic drugs offers an acceptable approach for long-
term 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 anes-
thetic for the treatment of pain. Treatment usually
begins with a low dose (150 mg/d), which is fol-
lowed by gradual dose escalation.
Brief intravenous local anesthetic infusions also are
analgesic.93,93a Treatment usually involves the infu-
sion 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.
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 neu-
ropathic 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
Antagonists at the N-methyl-d-aspartate (NMDA)
receptor also are undergoing investigation as potential
analgesics. Four such drugs—memantine, dex-
tromethorphan, amantadine and ketamine—are com-
mercially available in the United States. There is sub-
stantial 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 infu-
sion 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 chal-
lenging 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 anal-
gesic 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 medi-
cally ill. The therapeutic dose appears to vary widely,
ranging from 30 mg to more than 200 mg per day.
Cannabinoid receptors have been identified in both
the peripheral and the central nervous system, and
there is now abundant data indicating that exoge-
nous cannabinoid compounds have potential anal-
gesic effects.101a Tetrahydrocannabinol (THC) is
now available and several other compounds are in
development. Given the potential for adverse cogni-
tive 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 psy-
chotropic or primary analgesic actions contribute
to this outcome. As noted previously, clonazepam
often is tried for neuropathic pain despite limited
SUPPORTIVE AND PALLIATIVE CARE 391
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, phenom-
ena that may exacerbate the intensity of pain, and
respond well to other benzodiazepines, such as
diazepam.
Topical analgesic therapies may particularly benefit
medically ill patients with chronic pain by providing
pain relief that complements a systemic analgesic reg-
imen without the risk of additional side effects. Topi-
cal therapies include local anesthetics, NSAIDs, cap-
saicin, and numerous other compounds.103
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 topi-
cal local anesthetic therapy.
A 1:1 mixture of lidocaine and prilocaine known as
EMLA (eutectic mixture of local anesthetics) can pro-
duce 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.
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 contain-
ing diclofenac, ketoprofen, or another NSAID may be
considered, particularly when pain has a superficial
element of inflammation.
Patients with neuropathic pain caused by peripheral
nerve injury also can be considered for a trial of topi-
cal capsaicin, a peptide that depletes peptides in small
primary afferent neurons, including those that mediate
nociceptive transmission. Although anecdotal experi-
ence with this compound has been mixed, there is evi-
dence of efficacy from controlled trials.106 A therapeu-
tic trial of the high-concentration formulation
(0.075%) is reasonable in patients with neuropathic
392 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
pains presumed to have a strong peripheral input. An
adequate trial is generally believed to require 4 appli-
cations daily for 1 month.
Adjuvant Analgesics for 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 use-
ful for this indication include bisphosphonate com-
pounds,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.
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 bisphospho-
nates, including pamidronate and clodronate, can be
analgesic.107,108 Pamidronate, zolendronate and iban-
dronate 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 bis-
phosphonates 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 extrac-
tion or other procedures is likely, but not absolute.
The potential for this adverse effect must be consid-
ered in positioning intravenous bisphosphonate ther-
apy for analgesic purposes in the population with
metastatic bone pain.
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.
The bone-seeking radiopharmaceuticals, such as
strontium-89 and samarium-153, should be consid-
ered 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, ade-
quate 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.
Adjuvant Analgesics for Bowel Obstruction
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 somato-
statin analog octreotide can provide good symptom
control for most patients and, for many, obviate the
need for tube drainage.
A variety of anticholinergic drugs are used for this
indication. Scopolamine is available in a transdermal
system and is often tried first. Hyoscyamine is avail-
able in a sublingual formation, and glycopyrrolate has
lesser penetration through the blood-brain barrier and,
therefore, may be less likely to produce central ner-
vous system toxicity.
Octreotide inhibits the secretion of gastric, pancre-
atic, and intestinal secretions, and reduces gastroin-
testinal 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
A small proportion of cancer patients will be unable
to attain adequate analgesia from optimally adminis-
tered pharmacotherapy. A large number of non-phar-
macologic 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 thera-
pies, neural blockade, and implant therapies (spinal
cord stimulation or neuraxial infusion). Another
group of invasive approaches—neurosurgical thera-
pies—involve surgical interruption of afferent neu-
ral pathways. With the advent of nondestructive pro-
cedures, such as neuraxial analgesia, these proce-
dures now are rarely performed. Psychological ther-
apies range from education, mind-body therapies
such as imagery, and numerous psychotherapeutic
approaches. Rehabilitative treatments include thera-
peutic 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 interven-
tions) are mainstream.
Although some of these modalities, such as trigger
point injections, are within the purview of oncolo-
gists, 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 in-
patient and family education, the oncologist should
have a working knowledge of the indications, risks
and potential benefits of all these approaches.
SUPPORTIVE AND PALLIATIVE CARE 393
Table 15

Nonpharmacologic Interventions for Cancer Pain

Approach Type Type/Examples

Interventional Injections
Neural blockade
Implant therapies
Spinal cord stimulation
Neuraxial infusion

Surgical Cordotomy

Neurostimulatory Transcutaneous electrical nerve

Physiatric Physical/occupational therapy

Modalities

Psychologicical Psychoeducational
Cognitive techniques
Psychotherapy

Complementary Therapeutic massage

Acupuncture

394 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

4. Assessment and Management
of Other Common Symptoms
Numerous other symptoms must be addressed in pro-
viding 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
Constipation is a symptom characterized by dimin-
ished frequency of defecation associated with diffi-
culty or discomfort. It may contribute to abdominal
pain, distention, nausea, and worsening anorexia. In
the cancer population, the etiology and pathophysi-
ology is presumably multifactorial. Contributing
factors may include structural extraluminal or intra-
luminal pathology, drugs (such as the opioids),
physiologic disturbances (such as hypercalcemia),
and neurologic disorders. A more detailed evalua-
tion 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 tomogra-
phy of the abdomen and pelvis. Occasionally, the
evaluation requires colonoscopy.
Although prophylactic laxative therapy is often con-
sidered 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.
There are many therapeutic strategies for managing
constipation.121-123 The assessment may yield infor-
mation 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 accom-
plished 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 diet is impeded by anorexia or some other inter-
current medical problem. If uncomfortable flatu-
lence or obstructive symptoms such as cramping or
painful distention occur with increased fiber intake,
the amount should be adjusted.
Routine laxative therapy should not be initiated in
patients with severe constipation until serious prob-
lems, 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 medi-
cally ill populations. Oral laxatives can be: 1) bulk-
forming agents; 2) osmotic agents (including the so-
called saline cathartics, specifically magnesium and
sodium salts, and poorly absorbed sugars, specifically
lactulose and sorbitol); 3) lubricants; 4) surfactants
(specifically docusate); 5) contact cathartics (includ-
ing the anthraquinones senna and cascara, and the
diphenylmethanes phenolphthalein and bisacodyl);
6) prokinetic drugs (specifically cisapride and meto-
clopramide); 7) agents for colonic lavage; and 8) opi-
oid antagonist therapy.
Various strategies may be considered in combining
one or more of these approaches with other inter-
ventions (Table 16). In the absence of data from
clinical trials, treatment selection is based on con-
ventional practices and good clinical judgment.
Patients should be well informed about the varying
options for therapy, and patient preferences should
influence recommendations.
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 involv-
ing intestinal lavage, usually are reserved for patients
who do not tolerate or benefit from the more widely
SUPPORTIVE AND PALLIATIVE CARE 395
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

Specific Approaches*
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

Alternative Approaches 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

* 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

used interventions. Daily lavage therapy has recently
been simplified by the availability of a powdered
polyethylene glycol (Miralax®).
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
therapy may provide a safe and effective alternative
for larger numbers of patients with refractory consti-
pation 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

improves or side effects (typically just abdominal
cramping but occasionally also symptoms of systemic
opioid withdrawal) supervene.
The use of other opioid antagonists, quaternary com-
pounds that do not cross the blood-brain barrier, in the
treatment of opioid-induced bowel dysfunction is
under active investigation. Studies of oral alvi-
mopan124a and intravenous methylnaltrexone124b
demonstrate efficacy in reversing opioid-related
bowel dysfunction and suggest that opioid antagonist
Dyspnea is an extremely distressing symptom and is
highly prevalent in populations with advanced can-
cer, 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

396 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY

as pleural effusion or bronchospasm) that might be tar-
geted for specific interventions.125 To clarify the range
of contributing factors, the clinical evaluation may be
complemented by diagnostic tests that range in com-
plexity from bedside pulmonary function tests and
plain radiography to axial imaging of the chest, pleu-
rocentesis, 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 therapeu-
tic 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.
Symptomatic therapies may be pharmacologic or non-
pharmacologic.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 pul-
monary rehabilitation combining education, cognitive
approaches, nutritional support, and chest physical
therapy may be considered. Occasionally, assistive
devices, such as a unit that provides continuous posi-
tive airway pressure, are tried.
If bronchospasm appears to contribute to the dyspnea,
bronchodilator therapy is appropriate. Methylxan-
thines have been used less often than adrenergic ago-
nists in recent years because of concerns about toxic-
ity, but there is evidence that these drugs improve res-
piratory 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.
Although data are very limited in the cancer popu-
lation, there is an abundant experience with the use
of systemic opioid therapy for the treatment of dys-
pnea. 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 ago-
nists. 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.
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 corticos-
teroids directly reduce dyspnea, but they can be very
useful when bronchospasm, bronchial or superior
vena cava obstruction, or lymphangitic spread of neo-
plasm 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, theo-
phylline is sometimes offered in refractory cases,
even in the absence of bronchospasm.
SUPPORTIVE AND PALLIATIVE CARE 397
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 comor-
bidities. 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 assess-
ment and management of common symptoms is an
essential element in oncology practice. Although opti-
mal 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 inher-
ently 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 pallia-
tive care deserves high priority in oncology practice.
398 EDUCATIONAL REVIEW MANUAL IN MEDICAL ONCOLOGY
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