Beruflich Dokumente
Kultur Dokumente
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
5. Conclusion
6. References
Oncologists have long recognized the obligation to time, it is best to define supportive care as those
provide comprehensive care to patients with cancer. interventions that are intended to manage the
Providing “whole person” or patient-centered care is adverse effects of antineoplastic therapy. From this
an ongoing process that parallels intensive efforts to perspective, supportive care includes the use of
cure or control the neoplasm itself. The terms support- blood products, growth factors, antibiotics, symp-
ive care and palliative care typically refer to the thera- tom management approaches, and interventions that
peutic strategies applied to this end. address the psychosocial consequences of therapy.
Although confusion about the nature of supportive and The World Health Organization has defined palliative
palliative care continues in oncology, the need to care in broad terms that connect to quality of life.3
address quality-of-life concerns is the unifying thread. “Palliative care is the active total care of patients
While antineoplastic therapies are being implemented, whose disease is not responsive to curative treatment.
quality-of-life concerns include the immediate effects of Control of pain, of other symptoms, and of psycholog-
antineoplastic therapies, such as nausea and fatigue, and ical, social and spiritual problems is paramount. The
the psychosocial implications of a life-threatening diag- goal of palliative care is the achievement of the best
nosis. If a cure is achieved, concerns may involve late possible quality of life for patients and their families.”
effects of treatment and complex issues of survivorship.
When cancer becomes a chronic illness, the rigors of Palliative care is an interdisciplinary therapeutic
therapy often are accompanied by numerous symptoms, approach that focuses on the comprehensive man-
progressive physical impairments, psychosocial distur- agement of the physical, psychological, social, and
bances, and spiritual distress. These concerns may spiritual needs of patients with progressive, incur-
evolve over a period that continues for months or years. able illnesses and their families.4 The model applies
When the disease is far advanced, quality-of-life con- throughout the course of the illness, and includes an
cerns may become inextricably linked with profound array of interventions that are intended to maintain
end-of-life issues. Symptom control, support for the the quality of life, or attenuate the suffering of the
family, psychological and spiritual distress, and the spe- patient and family. As death approaches, palliative
cific fears related to abandonment and fear of dying may care must intensify and ensure that comfort is a pri-
be some of the specific concerns that arise. ority, practical needs are addressed, psychosocial
and spiritual distress is managed, values and deci-
Although oncologists understand the importance of sions are respected, and opportunities are available
the broad issues subsumed under supportive care and for growth and resolution.
palliative care, there are problems in providing even
the most basic aspect: good symptom control. This Palliative care is both an approach to patient care that
chapter focuses on symptom control as one of the pre- should be routinely integrated with life-prolonging
requisites for a satisfactory quality of life, and an ele- therapies and a growing practice specialty for highly
ment of care that should be an expected part of good trained physicians, nurses, social workers, chaplains,
oncology practice. This focus is not to imply that and others. Palliative medicine is the medical spe-
other, very challenging concerns, such as communica- cialty dedicated to excellence in palliative care.
tion issues, psychosocial and spiritual distress, and
bioethical considerations, are less important. These Palliative medicine is a recognized medical subspe-
latter concerns and additional detail about symptom cialty in some countries, and has gained the stature of
management are discussed in recent texts.1,2 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-
Definitions:
Although some consider the terms supportive care to cosponsor this subspecialty. These include the
and palliative care to be synonymous, this has led to American Board of Internal Medicine, American
confusion and may ultimately impede the develop- Board of Family Medicine, American Board of
ment of palliative care as a medical specialty. At this Anesthesiology, American Board of Neurology and
Supportive care refers to a group of interventions that anticipatory. Most antiemetic research has focused
lessen the adverse effects of antineoplastic therapies on the management of acute emesis.5,6 The patho-
or, more globally, attempt to maintain or improve the physiology of this syndrome presumably involves
quality of life of patients undergoing aggressive dis- direct activation of the chemoreceptor trigger zone
ease-oriented treatments.2 This includes the use of of the brainstem which, in turn, activates the so-
blood products, growth factors, antibiotics, symptom called vomiting center situated nearby. This region
management approaches, and interventions that of the brain has a complex neurochemistry and inter-
address the psychosocial consequences of therapy. acts with the gastrointestinal tract, the vestibulo-
labyrinthine system, and higher cortical centers.7
Although symptom distress is common among patients
undergoing active therapy, the specific problems have
evolved during the past two decades. Chemotherapy-
Influences on Emetogenicity
associated nausea and vomiting was widely considered Many factors influence the likelihood of acute nau-
to be the major concern until advances in pharma- sea and vomiting after treatment. Chemotherapeu-
cotherapy effectively resolved this problem for most tic agents vary greatly in this potential. A classifi-
patients. At the present time, there is increasing appre- cation system for the potential to cause acute eme-
ciation for the problem of therapy-associated fatigue. 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
Chemotherapy-Associated Nausea
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
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
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
Level Examples
As indicated in Table 2, both drug and dose are Antiemetic research began with studies of the sub-
important determinants of emesis. Patient-related stituted benzamide, metoclopramide10, which in
influences have also been identified, however, and high doses blocks both dopamine and 5-HT3 recep-
are important in predicting the likelihood of nausea tors. Subsequent studies have established that drugs
in an individual case. Poor control of symptoms dur- that block either of these receptors can be effective,
ing a prior course of chemotherapy increases the and the 5-HT3 antagonists have become the main-
likelihood of acute emesis and also predisposes to stay approach in the management of acute emesis.11
the development of anticipatory nausea and vomit- Other studies support the utility of corticosteroids12
ing, and refractory emesis. Other factors that despite an unclear antiemetic mechanism of action,
increase the likelihood of emesis include younger and cannabinoids, including the commercially
age and female sex. Heavy alcohol consumption available dronabinol (delta-9-tetrahydrocannabi-
appears to reduce the likelihood of emesis. 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-
Management of Acute Emesis
During the past 20 years, a very large number of clin- rokinin 1 (NK1) receptor, aprepitant, and a new
ical trials have established the efficacy of specific 5HT3 antagonist with a longer half-life and higher
drug classes for the management of acute chemother- binding affinity than the first-generation drugs,
apy-associated emesis. This has allowed the devel- palonosetron, for both acute and delayed eme-
opment of rational guidelines for the selection of sis.6,15,15a Drugs in all these classes are now used
combination therapy based on the emetogenicity of commonly (Table 3).
the chemotherapeutic regimen and other factors.5,6,8,9
Recommendations for anti-emetic therapy match the 1-3 mg).17,17a The use of palonosetron or the addition of
drug regimen to the likelihood of nausea and vomit- aprepitant, the specific NK-1 receptor antagonist,
ing.5 Unless the patient has other significant risk fac- may substantially reduce the risk of delayed eme-
tors for emesis (the most important being poorly con- sis5,6,15,15a,18 and should be considered if the risk or con-
trolled symptoms during a prior course of therapy), sequences of delayed emesis appears high.
the administration of chemotherapy with low emeto-
genic potential can be managed initially with dexam- These antiemetic regimens are highly effective and
ethasone (usual dose 20 mg IV 30 minutes before can be expected to provide complete or nearly com-
treatment) plus antiemetics as needed (eg, metoclo- plete control to most patients. All patients may ben-
pramide 10 mg orally, ondansetron 8 mg orally, or efit from education and, if available, specific cogni-
prochlorperazine 20 mg rectally). tive techniques can be added and further improve
outcomes.19
Although progress has been made in identifying an
oral antiemetic regimen for a highly emetogenic
chemotherapy,16 most patients are managed using an
Treatment-Related Fatigue
intravenous combination regimen, which is adminis- Fatigue is a nearly universal symptom in patients
tered shortly before treatment. This regimen includes undergoing primary antineoplastic therapy or treat-
dexamethasone (usual dose 20 mg IV), a 5-HT3 ment with biologic response modifiers, and is
receptor antagonist (eg, ondansetron 8-32 mg or extremely common in populations with persistent or
granisetron 10 mcg/kg), and lorazepam (usual dose advanced disease.20,21 A population-based survey of
Table 4
Symptoms present every day or nearly every day during the same 2-week period in the past month
empirically confirmed.
Pain
after completion of therapy occurs, and may in fact Education of the patient regarding the nature of
be common. The epidemiology of this phenomenon fatigue, options for therapy, and anticipated outcomes
has not been adequately studied.23c is an essential aspect of the therapy. Unfortunately,
results of a recent survey indicate that fatigue is sel-
The pathophysiology of cancer-related fatigue pre- dom discussed by patients and their oncologists.20
sumably varies with the etiology. Proposed mecha-
nisms include abnormalities in energy metabolism In some cases, evaluation of the cancer patient with
related to increased requirements (eg, due to tumor fatigue reveals one or more potentially treatable etiolo-
growth, infection, fever, or surgery); decreased avail- gies (Table 5). The interventions to address these con-
ability of metabolic substrate (eg, due to anemia, ditions are diverse, and the decision to pursue one or
hypoxemia, or poor nutrition); or the abnormal pro- another must be based on a case-by-case analysis of
duction of substances that impair metabolism or nor- the feasibility, risks and benefits, goals of care, and
mal functioning of muscles (eg, cytokines or antibod- other factors. Some of these interventions may be rela-
On the basis of these data, patients with significant Extensive anecdotal observations and very limited
fatigue and even moderate anemia should be consid- data from controlled trials34,35 also support the use
ered for a trial of either epoetin alfa or darbepoetin of low-dose corticosteroids, typically dexametha-
alfa. The usual starting dose of epoetin alfa is 40,000 sone and prednisone, in fatigued patients with
IU weekly, which is increased to 60,000 IU weekly advanced disease and multiple symptoms. This
after 1 month if the increase in hemoglobin level is approach is seldom considered for patients with
<1.0 g/dL. Darbepoetin alfa is usually given at an ini- limited disease whose fatigue appears mostly
tial dose of 100 mcg weekly, which is increased if the related to cancer therapy.
response is inadequate. Doses can be reduced and
maintain benefit in some patients.
Chronic pain is experienced by 30%-60% of patients ing recognition that the current situation needs
who are undergoing active treatment for a solid improvement. Recently, institutional efforts to man-
tumor.38,39 The prevalence rate in children with can- age pain were added to the practice standards
cer is lower because of the higher proportion of reviewed by the Joint Commission for the Accredi-
hematologic malignancy; those with solid tumors, tation of Health Care Organizations. Oncologists
however, often have the same kinds of chronic pain must ensure that their medical information concern-
as their adult counterparts.40 Surveys of adult cancer ing pain control is current and that patients receive
patients with advanced disease, which are often per- appropriate education.
formed in a hospice or palliative care setting, indi-
cate that the prevalence of pain is generally higher,
ranging from 50%-90%.41
Pain Assessment
Table 6
Characteristic Descriptors
Examples
Caused by the neoplasm Pathologic fractures; acute obstruction of bowel or other hollow viscus
Headache from intracranial hypertension
the limb.
Vertebral syndromes
Long bone or pelvic metastases
Guidelines for the management of patients with can- Other postsurgical neuropathic pain syndromes have
cer-related back pain generally recommend that been described. These include a postradical neck dis-
definitive imaging of the epidural space be pursued section syndrome, a postnephrectomy syndrome, and
when pain is associated with symptoms or signs of both stump pain and phantom pain. Neuropathic pain
radiculopathy or myelopathy (including just radicular syndromes related to radiation therapy are similarly
pain); pain has certain ominous characteristics; or diverse and include mononeuropathies and plex-
pain is associated with a highly suspicious lesion on opathies (Table 9). Symptoms associated with radia-
plain radiography or CT.53 The characteristics of the tion-induced nerve injury usually appear months to
pain that should raise suspicion of coexisting epidural years after treatment.54 Pain is generally less promi-
disease include: 1) pain that gradually increases over nent than nerve injury related to neoplasm.
time; 2) a “crescendo” pattern of pain (rapid escala-
tion); 3) pain that flares with Valsalva maneuvers Painful polyneuropathies can complicate numerous
(cough, sneeze, or strain); 4) Lhermitte’s sign (flash of chemotherapies, including vincristine, which usu-
pain down back and perhaps into limbs); and 5) an ill- ally causes a painful sensorimotor neuropathy, and
defined, often-ascending pain in the legs. The most both cisplatin and paclitaxel, which usually produce
suspicious finding on plain radiography is a greater sensory neuropathies. Although most patients report
than 50% collapse of the vertebral body, and the most gradual improvement after therapy is discontinued,
worrisome finding on CT is erosion of the bony cortex some develop a persistent painful polyneuropathy.
adjacent to the spinal canal. Off-therapy deterioration after cisplatin neuropathy
can continue for months, after which improvement
Cancer-related neuropathic pain syndromes also usually occurs.
can be caused by an invasive diagnostic or therapeu-
tic procedure, or by antineoplastic therapy. A surgi- Headache is difficult to classify and may relate to
cal incision anywhere in the body injures small many pathologic processes in patients with cancer.
afferents and produces a neuropathic pain syndrome Neoplasms produce headache by injuring pain-sensi-
in some patients. tive intracranial structures, either directly or indirectly
through increased intracranial pressure. The headache
The postmastectomy syndrome, which is character- associated with this increased pressure may be dif-
ized by a tight, burning sensation in the medial fuse, hemicranial, or occipital, and is typically worse
aspect of the upper arm, the axilla, and the upper on awakening and improves throughout the day. It
aspect of the anterior chest wall, is caused by injury usually begins insidiously, is seldom severe, and pro-
to one or more cutaneous nerves in the chest. The gresses over time. A history of progressive headache
intercostobrachial nerve, a cutaneous nerve that should lead to appropriate imaging.
Interventions targeted to the etiology of the pain can An “analgesic ladder” approach to the selection of
have analgesic consequences and should be consid- analgesic drugs for cancer pain has been popularized
ered in every case. An extensive literature on the by the World Health Organization and is now widely
potential analgesic consequences of radiotherapy55 is accepted as a broad guideline and educational tool.58
being complemented by a small number of studies that According to this approach, analgesic selection
have documented the potential utility of chemother- should be guided by the usual severity of pain:
apy for pain control.56,57 To realize the potential bene- Patients with mild to moderate pain usually are first
fits of primary therapy, the pain assessment must treated with acetaminophen or a nonsteroidal anti-
include a competent examination and appropriate inflammatory drug (NSAID). This is combined with
imaging studies, which together clarify the extent of one or more adjuvant drugs if a specific indication
disease and the etiology of the pain. Once the underly- for one exists. These adjuvants include drugs
ing problem is characterized, decision-making is fur- selected to treat a side effect of the analgesic (eg, lax-
ther influenced by numerous other factors, such as the atives) and drugs with analgesic effects (the so-
availability, safety and efficacy of treatment; the called adjuvant analgesics).
potential of treatment to prolong life or reduce the
likelihood of further complications; and the overriding Patients with moderate to severe pain (including those
goals of care. 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
Pain Management:
Opioid therapy can provide adequate pain relief to cated. The most common approach in the United
more than three-quarters of patients with cancer States involves the administration of a combination
pain.58-60 This success rate justifies the widely held product containing an opioid plus either
view that long-term opioid therapy is the first-line acetaminophen or aspirin. The dose of this drug is
approach for moderate or severe cancer pain.58,59,61,62 increased as needed until the maximum safe dose of
the aspirin or acetaminophen is reached. For
Opioid analgesics can be classified as pure agonists or acetaminophen, this maximal safe dose is usually con-
agonist-antagonists, based on their interactions with sidered to be 4 g/d, and lower (eg, 2-3 g/d) in patients
opioid receptors. The agonist-antagonist drugs can be with known hepatopathy or heavy alcohol use.
further divided into a mixed agonist-antagonist sub-
class (including butorphanol, nalbuphine, penta- Patients with severe pain (including those who fail to
zocine, and dezocine) and a partial agonist subclass achieve adequate relief after appropriate administra-
(including buprenorphine). Drugs in the agonist- tion of drugs on the second rung of the analgesic lad-
antagonist subclass have a ceiling effect for analgesia der) receive an opioid conventionally selected for
and reverse the effects of pure agonists in patients who severe pain. This treatment may also be combined
are physically dependent; some produce psy- with acetaminophen or an NSAID, or an adjuvant
chotomimetic side effects more readily than do the drug as indicated.
pure agonist opioids. For these reasons, they are not
favored for the treatment of cancer pain. For the man- The analgesic ladder approach to drug selection must
agement of chronic pain, the pure mu agonist drugs be individualized. Some patients with generally mod-
are preferred (Table 10). 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.
Opioid Analgesics
Equi-
Morphine-like analgesic Half-life Duration
Agonists Dosesa (h) (h) Toxicity Comments
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.
(continued)
Opioid Analgesics
Equi-
Morphine-like analgesic Half-life Duration
Agonists Dosesa (h) (h) Toxicity Comments
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%.
For chronic therapy, the oral route for opioid delivery have been adapted to long-term treatment, and prop-
is usually attempted first and the transdermal route for erly selected patients can benefit greatly.71 The clearest
fentanyl is a widely accepted alternative.69,70 The avail- indication is intolerable somnolence or confusion in a
ability of oral controlled release oral formulations patient who is not experiencing adequate analgesia
allows convenient dosing, either once daily or twice during systemic opioid treatment of a pain syndrome
daily. Some patients require doses three times per day located below the level of mid-chest. Continuous
to optimize therapy, but this, too, is usually accommo- epidural infusion can be accomplished through either
dated well. The transdermal route offers a 48- to 72- a percutaneous or implanted epidural catheter. These
hour dosing interval, and is very useful for patients approaches are generally preferred if life expectancy
who are unable to swallow or absorb an orally admin- is measured in a few months. Intrathecal infusion
istered opioid, and those who perceive non-oral using a totally implanted pump should be considered
administration as a convenience. It allows a trial of for patients with longer life expectancies.
fentanyl during opioid rotation and appears to
improve adherence to therapy in some cases. The The use of intraspinal infusion in the management of
observation in open-label studies that transdermal cancer pain is likely to increase with further evidence
fentanyl produces less constipation than oral mor- of favorable outcomes in the oncology population. A
phine70 suggests that severe constipation may be recent controlled trial comparing neuraxial infusion
another indication for a trial. and comprehensive medical management demon-
strated that the spinal opioid treatment improved pain,
The use of the transdermal system is limited by the side effects, quality of life and even survival.71a
difficulties involved in delivering high doses and the
need for an alternative route to provide supplemental The potential for intraspinal infusion has increased
doses for breakthrough pain. It also is not preferred further with the use of drug combinations. The long-
when rapid dose titration is needed for severe pain. term administration of opioid, local anesthetic, and
Because drug delivery is influenced by temperature, clonidine is widely available. Ziconotide, a unique
frequent fever spikes could lead to unstable absorp- calcium-channel blocker, is now available in the
tion from the transdermal system and may also com- United States and has been shown to be effective for
plicate the use of this approach. cancer pain in controlled trials.71b As new drugs are
tested for intraspinal therapy, the indications for the
Patients who are unable to swallow or absorb opi- approach are likely to increase.
oid drugs and who do not experience intolerable
side effects from systemic administration also are An oral transmucosal formulation of fentanyl (oral
candidates for other approaches to long-term par- transmucosal fentanyl citrate or OTFC) has been
enteral dosing. Repetitive injections are painful and approved for the treatment of cancer-related break-
should be avoided. Continuous infusion techniques through pain. This formulation incorporates fen-
are generally preferred because they reduce the tanyl into a candy matrix that is sucked, allowing
need for nursing support, eliminate the potential for partial absorption through the buccal mucosa. The
bolus effects (side effects at peak concentration or formulation is effective and well tolerated, and
Fixed schedule dosing is preferred for continuous or coadministered (OTFC, which can be selected with
frequently recurring pain. An as-needed “rescue any baseline opioid, can be selected for use with trans-
dose” usually is combined with the fixed regimen to dermal fentanyl if there is a specific desire to limit opi-
treat breakthrough pains. As-needed dosing alone oid exposure to fentanyl).
should be considered at the start of therapy in rela-
tively opioid-naive patients (this is particularly appro- With the exception of OTFC, the size of the rescue
priate with methadone because of the risk of late toxi- dose is usually 5% to 15% of the total daily dose, and
city from drug accumulation); in patients with rapidly the dosing interval in the ambulatory population is
changing pain (eg, after radiotherapy to a painful bony usually 1 to 2 hours as needed. Controlled studies of
lesion); and in patients with intermittent pain sepa- OTFC did not confirm that the dose administered on a
rated by pain-free intervals. scheduled basis predicts the effective size of the res-
cue72 and guidelines for the use of this new formula-
For the patient with limited prior opioid exposure tion include a low starting dose in all cases (200 mcg
(eg, the use of an acetaminophen-oxycodone com- or, perhaps, 400 mcg), followed by dose titration.
bination product several doses per day), the starting
dose of an opioid conventionally used for severe The success of opioid therapy ultimately depends on
pain is usually equivalent to morphine sulfate 5-10 individualization of the dose through titration. The
mg intramuscularly every 4 hours. When a patient goal of titration is to identify a dose associated with a
is switched to a new opioid, the initial dose is calcu- favorable balance between analgesia and side effects.
lated from a table of equianalgesic doses (Table
10). This calculation is revised based on the spe- The opioid dose should be increased when pain is
cific drug, the medical status of the patient, and the inadequately controlled and there are no treatment-
degree of pain at the time of the switch.73 Because limiting side effects, The size of the increase usually is
of interindividual variability and the possibility of selected as either the total quantity of rescue drug con-
incomplete cross-tolerance, the dose of the new sumed during the previous day, or 30%-50% of the
drug should routinely be reduced by 30%-50%. The current total daily dose. The increment can be larger
usual two exceptions to this are methadone, which (75%-100% of the total daily dose) if pain is severe, or
may have a potency greater than anticipated and smaller if the patient is already experiencing opioid
should be reduced by 75%-90%, and transdermal toxicity or is predisposed to adverse effects because of
fentanyl, which typically is administered at the cal- advanced age or coexisting major organ dysfunction.
culated equianalgesic dose based on the conver- Caution is also reasonable if the patient has a limited
sions in the package insert. The dose of the new prior opioid exposure.
the sole driving force for declining effects. When The term non-opioid analgesic is conventionally
pain increases during long-term therapy, the devel- 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-
Table 11
Nonopioid Analgesics
Approach Options
is more likely to respond than pain of other types, such after publication of several studies documented a risk
as neuropathic pain. Metastatic bone pain appears to of adverse cardiovascular outcomes greater than com-
be relatively responsive to these drugs. parator drugs, and the U.S. Food and Drug Adminis-
tration decided to withdraw valdecoxib from the mar-
NSAIDs vary in the degree to which they each inhibit ket based on this risk and an unrelated risk of cuta-
COX-1 and COX-2. Relatively selective COX-2 neous hypersensitivity reactions.
inhibitors, including celecoxib, rofecoxib and valde-
coxib, have been developed in an effort to reduce gas- Additional studies, including secondary analyses of
trointestinal toxicity, including ulcer formation.76,77 This a series of trials and epidemiologic surveys, have
reduced risk is favorable, and, on theoretical grounds, altered this view, however, and suggest that the
supported the preferential use of these NSAIDs in med- potential for prothrombotic effects is linked to inhi-
ically frail populations, such as those with cancer pain. bition of COX-2, whether or not the drug is a selec-
tive COX-2 inhibitor or a nonselective COX-1 and
The role of the selective COX-2 drugs, and of the COX-2 inhibitor. The risk, therefore, attends the use
NSAIDs overall, is undergoing re-examination, how- of any NSAID, not only the selective COX-2
ever, as a result of recent safety concerns related to inhibitors. Moreover, risk appears to vary with the
cardiovascular toxicity.78 Early publications suggested specific drug, the dose and the duration of treatment.
that this risk, which takes the form of an increased Following a review of the available evidence on
incidence of myocardial infarction, transient ischemic safety, the U.S. Food and Drug Administration
attacks and stroke, and peripheral vascular disease, required a boxed warning on all NSAIDs that high-
was specifically associated with the selective COX-2 lights the potential for both serious cardiovascular
drugs. Rofecoxib was withdrawn by the manufacturer and gastrointestinal toxicity.
Recommended Recommended
Starting Maximum
Chemical Class Generic Name Dose (mg/d)* Dose (mg/d) Comment
(continued )
Recommended Recommended
Starting Maximum
Chemical Class Generic Name Dose (mg/d)* Dose (mg/d) Comment
* 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.
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
obstruction, pain caused by lymphedema, and 5-10 mg, or dexamethasone, 1-2 mg, is administered
headache caused by increased intracranial pressure. once or twice daily. Therapy is continued as long as
Current data are inadequate to evaluate drug-selec- potential benefits appear to outweigh adverse effects.
tive differences, dose-response relationships, predic- Dose escalation for worsening symptoms is appropri-
tors of efficacy, or the durability of favorable effects. ate if benefits decline with progressive disease, partic-
ularly at the end of life.
Because the risk of adverse effects associated with
corticosteroids increases with both the dose and dura- Another approach to corticosteroid therapy is consid-
tion of use, long-term therapy usually involves the ered for selected patients with severe pain. The usual
administration of relatively low doses to patients with scenario is the occurrence of rapidly worsening pain
advanced disease, whose overriding need for symp- related to a nerve injury, bony lesion, or duct obstruc-
tom control justifies the risk. Typically, prednisone, tion that has failed to respond promptly to an opioid.
Many adjuvant analgesics are primarily used in medi- reached if pain relief does not occur with routine
cally ill populations for the treatment of neuropathic dose escalation.
pain that fails to respond adequately to an opioid.
These drugs include anticonvulsants, antidepressants, The existing evidence suggests that the antidepres-
local anesthetics, and others. sant drugs are nonspecific analgesics90 and that the tri-
cyclic drugs are somewhat more efficacious for neu-
At the present time, gabapentin is the most common ropathic pain than gabapentin or pregabalin.88a An
adjuvant analgesic used for neuropathic pain. This antidepressant should be considered as the first adju-
drug is an anticonvulsant with proven efficacy in vant analgesic selected for neuropathic pain if depres-
different neuropathic pain syndromes.87,88 It has an sion is a significant comorbidity; if not, one of these
acceptable adverse effect profile, is not metabolized drugs is usually tried if gabapentin or pregabalin do
in the liver, and has no known drug-drug interac- not yield adequate results.
tions. Treatment usually starts with 100-300 mg/d,
and dose titration usually continues until benefit The tricyclic antidepressants (TCAs) have been
occurs, side effects supervene, or the total daily most extensively studied, and there is strong evi-
dose is at least 3,600 mg. Some patients respond to dence that both the tertiary amine TCAs (eg,
600 mg/d in divided doses, whereas others do not amitriptyline, doxepin, and imipramine), and the
reach a maximal response until the dose is increased secondary amine TCAs (eg, desipramine and nor-
to 6,000 mg/d. triptyline) can be effective analgesics. There is
good evidence that a serotonin and norepinephrine
Gabapentin’s analgesic effects are mediated reuptake inhibitor (SSNRI), duloxetine, is anal-
through modulation of the alpha-2-delta protein of gesic and this drug has been approved in the United
the voltage-gated calcium channel in the central States for neuropathic pain associated with dia-
nervous system. Pregabalin has the same mecha- betes.90a Limited evidence favors analgesic effects
nism and has been demonstrated to be safe and for venlafaxine, another SSNRI; several of the sero-
effective in varied neuropathic pains.88a,88b Unlike tonin-selective reuptake inhibitors, including
gabapentin, pregabalin has stable pharmacokinetics paroxetine, citalopram and trazodone; and several
through the clinically-relevant dose range and stud- other types of antidepressants, including bupropion
ies suggest that dose titration to the usual effective and maprotiline.84
dose of 300 mg to 600 mg per day in two divided
doses can be accomplished within one week. Clini- Amitriptyline is the best studied TCA and, on this
cal observations suggest that some patients who did basis, may be preferred when pain is the target symp-
not respond to gabapentin report more satisfactory tom. Patients who cannot tolerate amitriptyline, or are
effects from pregabalin. predisposed to its sedative, anticholinergic, or
hypotensive effects, should be considered for a trial
Many other anticonvulsant drugs have been evalu- with a secondary amine TCA such as desipramine.
ated as treatments for neuropathic pains.89 There is Given the relatively better side effect profile, how-
limited evidence in support of several older anticon- ever, a trial of duloxetine may be preferred initially
vulsant drugs, including carbamazepine, phenytoin, and should be strongly considered if a patient has
and divalproex, and several newer drugs, including poorly tolerated a TCA or is likely to do so.
Brief intravenous local anesthetic infusions also are The GABA agonist baclofen has been shown to be
analgesic.93,93a Treatment usually involves the infu- effective in the treatment of trigeminal neuralgia101
sion over 30 minutes of a dose that ranges from 1 and may be useful for neuropathic pain in the medi-
mg/kg to 4 mg/kg. Given the existence of a dose cally ill. The therapeutic dose appears to vary widely,
response, a prudent approach may be to start with a ranging from 30 mg to more than 200 mg per day.
low-dose infusion and follow it, if unsuccessful,
with infusions at incrementally higher doses. There Cannabinoid receptors have been identified in both
is no evidence that a brief local anesthetic infusion the peripheral and the central nervous system, and
is more effective than oral therapy, but the ability to there is now abundant data indicating that exoge-
give a larger dose more quickly may have clinical nous cannabinoid compounds have potential anal-
advantages. In the cancer population, this approach gesic effects.101a Tetrahydrocannabinol (THC) is
usually has been tried when neuropathic pain is now available and several other compounds are in
severe and progressive. development. Given the potential for adverse cogni-
tive and mood effects, and the still limited clinical
Several other drug classes may be useful in managing experience, a trial of THC is usually considered in
neuropathic pain. The alpha-2-adrenergic agonists, the setting of refractory neuropathic pain, after a
which in the United States include clonidine and number of other adjuvant analgesic trials have been
tizanidine, have established analgesic efficacy in a unsuccessful. The advent of new compounds may
variety of pain syndromes.94-96 and may be considered change this approach in the future.
nonspecific analgesics. Like the antidepressants, they
usually are considered as adjuvant analgesics for neu- Benzodiazepines also may have salutary effects in
ropathic pain in populations with cancer. Epidurally patients with chronic cancer pain, and it may be
administered clonidine has proven efficacy in cancer impossible to determine the degree to which psy-
pain and was shown to be relatively more effective chotropic or primary analgesic actions contribute
for neuropathic pain.96 to this outcome. As noted previously, clonazepam
often is tried for neuropathic pain despite limited
respond well to other benzodiazepines, such as Radiation therapy is usually considered when bone
diazepam. pain is focal and poorly controlled with an opioid or
is associated with impending fracture. Multifocal
Topical analgesic therapies may particularly benefit bone pain that has been refractory to opioid therapy
medically ill patients with chronic pain by providing may benefit from coadministration of an NSAID or
pain relief that complements a systemic analgesic reg- corticosteroid. Adjuvant analgesics that may be use-
imen without the risk of additional side effects. Topi- ful for this indication include bisphosphonate com-
cal therapies include local anesthetics, NSAIDs, cap- pounds,107,108 calcitonin,109,110 and bone-seeking
saicin, and numerous other compounds.103 radionuclides.55,111,112 There have been no comparative
trials of these adjuvant analgesics for bone pain, and
Topical local anesthetics can be administered by the selection of one over another is usually based on
patch or cream. A lidocaine-impregnated patch convenience, patient preference, and several clinical
(Lidoderm®) has been approved for use in patients indicators.
with postherpetic neuralgia.104 This formulation
appears to be well accepted by patients and should be Based on the abundance of supporting evidence, the
considered for any patient who is a candidate for topi- benefit to nonpainful skeletal comorbidities (such as
cal local anesthetic therapy. fracture rate), and convenience, the bisphosphonates
are generally preferred as the first-line approach.
A 1:1 mixture of lidocaine and prilocaine known as There is strong evidence that certain bisphospho-
EMLA (eutectic mixture of local anesthetics) can pro- nates, including pamidronate and clodronate, can be
duce dense cutaneous anesthesia if applied thickly analgesic.107,108 Pamidronate, zolendronate and iban-
under an occlusive dressing. Cutaneous anesthesia dronate are available in the United States and any of
may not be necessary to yield analgesic effects in these drugs may be considered for its analgesic
patients with neuropathic pains, however, and patients effects. Studies with pamidronate suggest that several
can use alternative methods of application, as well as doses may be needed to judge efficacy. The oral bis-
pure lidocaine creams (eg, lidocaine 5%), which are phosphonates alendronate and risedronate have not
far less costly than EMLA. been studied for malignant bone pain. They are highly
potent, however, and a trial may be warranted
There is substantial evidence that topical NSAIDs can because of their simpler modes of administration.
be effective for soft tissue pain and perhaps joint
pain.105 A trial of a compounded formulation contain- Recent evidence that treatment with the intravenous
ing diclofenac, ketoprofen, or another NSAID may be bisphosphonates may lead to osteonecrosis of the
considered, particularly when pain has a superficial jaw has altered the risk:benefit analysis applied to the
element of inflammation. use of these drugs.112a The cause of this lesion is not
known, and although the risk appears to be very
Patients with neuropathic pain caused by peripheral small, the complication can be serious in terms of
nerve injury also can be considered for a trial of topi- pain and functional consequences. Most cases have
cal capsaicin, a peptide that depletes peptides in small been associated with intravenous therapy over a
primary afferent neurons, including those that mediate period of years, and a link with prior dental extrac-
nociceptive transmission. Although anecdotal experi- tion or other procedures is likely, but not absolute.
ence with this compound has been mixed, there is evi- The potential for this adverse effect must be consid-
dence of efficacy from controlled trials.106 A therapeu- ered in positioning intravenous bisphosphonate ther-
tic trial of the high-concentration formulation apy for analgesic purposes in the population with
(0.075%) is reasonable in patients with neuropathic metastatic bone pain.
strontium-89 and samarium-153, should be consid- A small proportion of cancer patients will be unable
ered for patients with refractory multifocal pain to attain adequate analgesia from optimally adminis-
caused by osteoblastic lesions or lesions with an tered pharmacotherapy. A large number of non-phar-
osteoblastic component.111,112 Samarium-153 allows macologic approaches may be considered when this
imaging with bone scintigraphy during treatment for occurs (Table 15). These approaches are reviewed
bone pain. Patients who receive these drugs should elsewhere1,2,59,118-120 and may be broadly categorized.
have life expectancies greater than 3 months, ade- Interventional techniques include injection thera-
quate bone marrow reserve, and no further planned pies, neural blockade, and implant therapies (spinal
therapy with myelosuppressive chemotherapy. cord stimulation or neuraxial infusion). Another
Patients with a platelet count below 60,000 or a white group of invasive approaches—neurosurgical thera-
blood cell count below 2,400 generally should not be pies—involve surgical interruption of afferent neu-
treated. The onset of effect is often slow (2 weeks or ral pathways. With the advent of nondestructive pro-
longer), and peak effects may not be attained for more cedures, such as neuraxial analgesia, these proce-
than a month. Some patients experience a flare of pain dures now are rarely performed. Psychological ther-
before analgesic effects occur. 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
Adjuvant Analgesics for Bowel Obstruction
Patients with malignant bowel obstruction who are modalities such as heat, cold, ultrasound, and topical
not candidates for surgical decompression require stimulation. Finally, complementary modalities
intensive palliative interventions to reduce pain and include a very broad array of treatments, some of
other obstructive symptoms, including distention, which (acupuncture, therapeutic massage, a number
nausea, and vomiting.115,116 Surveys of patients with far of movement therapies, some nutritional interven-
advanced disease suggest that the use of opioids, a tions) are mainstream.
corticosteroid, anticholinergic drugs, and the somato-
statin analog octreotide can provide good symptom Although some of these modalities, such as trigger
control for most patients and, for many, obviate the point injections, are within the purview of oncolo-
need for tube drainage. gists, most require appropriate referral to either a
specialist who can perform a specific technique or a
A variety of anticholinergic drugs are used for this pain specialist, who may be able to provide a broader
indication. Scopolamine is available in a transdermal evaluation and help select the best course among
system and is often tried first. Hyoscyamine is avail- many options. To recommend wisely and assist in-
able in a sublingual formation, and glycopyrrolate has patient and family education, the oncologist should
lesser penetration through the blood-brain barrier and, have a working knowledge of the indications, risks
therefore, may be less likely to produce central ner- and potential benefits of all these approaches.
vous system toxicity.
Interventional Injections
Neural blockade
Implant therapies
Spinal cord stimulation
Neuraxial infusion
Surgical Cordotomy
Psychologicical Psychoeducational
Cognitive techniques
Psychotherapy
Numerous other symptoms must be addressed in pro- in diet is impeded by anorexia or some other inter-
viding palliative care to patients with cancer. The current medical problem. If uncomfortable flatu-
management of constipation and dyspnea exemplify lence or obstructive symptoms such as cramping or
the medical sophistication necessary to optimize the painful distention occur with increased fiber intake,
management of these problems. the amount should be adjusted.
Constipation is a symptom characterized by dimin- lems, such as bowel obstruction, have been
ished frequency of defecation associated with diffi- excluded and the clinician is reasonably certain that
culty or discomfort. It may contribute to abdominal impaction has not occurred. Low impaction can be
pain, distention, nausea, and worsening anorexia. In assessed by examination of the rectum; suspicion of
the cancer population, the etiology and pathophysi- a high impaction requires abdominal imaging for
ology is presumably multifactorial. Contributing evaluation. The management of impaction may
factors may include structural extraluminal or intra- require physical disimpaction; repeated enemas; and
luminal pathology, drugs (such as the opioids), a combination of rectal and oral laxatives, including
physiologic disturbances (such as hypercalcemia), a lubricant, softening agent, osmotic laxative, or
and neurologic disorders. A more detailed evalua- contact laxative.
tion of potential etiologies may be appropriate when
constipation develops or progresses without a clear There are many laxative therapies, but few have been
precipitant, or when it is more severe than expected. subjected to controlled comparative trials in medi-
In such cases, the history should explore a broad cally ill populations. Oral laxatives can be: 1) bulk-
range of possible causes, and the examination must forming agents; 2) osmotic agents (including the so-
include a digital rectal examination. The need for called saline cathartics, specifically magnesium and
imaging studies may be limited to a plain abdominal sodium salts, and poorly absorbed sugars, specifically
radiograph or may include a barium enema, an lactulose and sorbitol); 3) lubricants; 4) surfactants
upper gastrointestinal series, or computed tomogra- (specifically docusate); 5) contact cathartics (includ-
phy of the abdomen and pelvis. Occasionally, the ing the anthraquinones senna and cascara, and the
evaluation requires colonoscopy. diphenylmethanes phenolphthalein and bisacodyl);
6) prokinetic drugs (specifically cisapride and meto-
Although prophylactic laxative therapy is often con- clopramide); 7) agents for colonic lavage; and 8) opi-
sidered appropriate when constipation is likely to oid antagonist therapy.
occur, most notably when opioid therapy is initiated,
the need for prophylaxis should be determined on a Various strategies may be considered in combining
case-by-case basis. If multiple potential etiologies one or more of these approaches with other inter-
exist (eg, opioid therapy in the setting of debilitation, ventions (Table 16). In the absence of data from
poor diet, and the use of other constipating drugs), clinical trials, treatment selection is based on con-
prophylactic laxative therapy usually is warranted. ventional practices and good clinical judgment.
Patients should be well informed about the varying
There are many therapeutic strategies for managing options for therapy, and patient preferences should
constipation.121-123 The assessment may yield infor- influence recommendations.
mation about a potential etiology that can be
reversed. Simple approaches, including enhanced In most cases, routine management begins with either
fluid and fiber intake, usually should be encouraged. an osmotic laxative or a contact laxative such as
The consumption of increased fiber can be accom- senna. Alternative approaches, such as daily lactulose
plished by adding fruits or high-fiber cereals, or a or sorbitol, a prokinetic drug, or an approach involv-
fiber supplement, to the diet. A fiber intake of at least ing intestinal lavage, usually are reserved for patients
10 g/d is an appropriate goal. Additional fiber should who do not tolerate or benefit from the more widely
be avoided if the patient is extremely debilitated, if
partial bowel obstruction is suspected, or if a change
Management of Constipation
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
used interventions. Daily lavage therapy has recently therapy may provide a safe and effective alternative
been simplified by the availability of a powdered for larger numbers of patients with refractory consti-
polyethylene glycol (Miralax®). pation or other significant adverse opioid-induced
gastrointestinal effects. Alvimopan is likely to appear
Patients with refractory opioid-induced constipation on the United States market first, initially indicated for
now may benefit from oral naloxone therapy.124 The the treatment of postoperative ileus. Further studies
latter approach is feasible because naloxone has a very will be needed to clarify the positioning of these new
low oral bioavailability and oral administration and therapies among the many currently used to manage
therefore may reverse opioid bowel effects without opioid-related constipation.
producing systemic withdrawal. Treatment usually
involves a starting dose of 1 mg orally twice daily,
which is gradually increased until bowel function
Dyspnea
improves or side effects (typically just abdominal Dyspnea is an extremely distressing symptom and is
cramping but occasionally also symptoms of systemic highly prevalent in populations with advanced can-
opioid withdrawal) supervene. cer, particularly those with lung cancer. Significant
dyspnea is associated with a relatively short life
The use of other opioid antagonists, quaternary com- expectancy, and the management of this symptom is
pounds that do not cross the blood-brain barrier, in the often a critical part of comprehensive palliative care
treatment of opioid-induced bowel dysfunction is at the end of life.
under active investigation. Studies of oral alvi-
mopan124a and intravenous methylnaltrexone124b The pathophysiology of dyspnea is complex, and a
demonstrate efficacy in reversing opioid-related careful assessment is needed to clarify the existence of
bowel dysfunction and suggest that opioid antagonist potentially treatable etiologies or mechanisms (such
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