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Chapter29:Palliative care and symptom management
Table 29.4 Elements of a comprehensive pain assessment
Aspects of the domain to
Domain
Location Superficial vs. deep
assess
to use them as determined by safety, patient interest, aordability, and local availability.
Treatment– drug therapy
Localized or diffuse or radicular
Temporality Onset, duration, constant vs.
Severity Current, worst, best, average
Quality Sharp, dull, aching, burning,
Aggravating and alleviating
factors
Treatments Drug and non-drug, including
Functional limitations Pain impacts ability to move,
Concurrent symptoms Insomnia, anorexia, nausea,
Psychosocial aspects of pain Effect on relationships with
Treatment goal Severity level and functional goal
radiation pattern
intermittent, diurnal variation,
tempo of progression
severity
Rated on 0–10 scale
throbbing, numb
Change with position, certain
movements, and activities
complementary and alternative;
over the counter and prescription;
efficacy of treatments; adverse
effects of treatments
breath, talk, eat. Pain limits normal
vocational and recreational
activities
dyspnea, anxiety, mood
disturbance
family and friends; meaning of
pain to the patient; spiritual and
existential effects of the pain
(improved sleep, back to work,
etc.)
Non-opioid analgesics
Non-opioid analgesics include acetaminophen, non-steroidal
anti-inammatory drugs (NSAIDs), tramadol, and tapendatol.
Unlike opioids, all have dose-limiting side eects and analgesic
ceiling eects. NSAIDs, such as ibuprofen, diclofenac, etodolac,
naproxyn, and related drugs, work by inhibiting cyclooxygenase in damaged tissues, thereby decreasing tissue levels of
inammatory and pain-provoking arachidonic metabolites.46
ey all can worsen renal and heart failure, inhibit platelet
aggregation, and promote gastrointestinal bleeding, which
limits their use in many cancer patients. When used safely,
they are believed to act synergistically with opioid analgesics
in alleviating visceral and somatic pain,
46
and can limit opioid
dose escalation.47 Selective cyclooxygenase-2 inhibitors (e.g.,
celecoxib) have moderately lower gastrointestinal toxicity than
traditional NSAIDs, but are otherwise no safer or more ecacious and have no particular role in treating cancer pain.48
Acetaminophen’s mechanism of action remains unclear. It is
oen used in combination products with opioids. Its dose is
limited to approximately 3grams daily in healthy patients due
to a hepatotoxic metabolite. Tramadol has complicated pharmacodynamics:it is a weak opioid agonist that also modulates
norepinephrine and serotonin. It has been shown to be eective for mild to moderate cancer pain from a variety of sources,
but is inappropriate for severe pain.49 Side eects include nausea, dizziness, sweating, and a lowering of the seizure threshold; compared to opioids it is less sedating and constipating.
49
Opioid analgesics
Opioids are analgesics derived from the opium poppy plant–
or synthetic analogs– which agonize opioid receptors. Opioids
causing neuropathic pain; vertebral compression fractures; epidural metastases; referred pain from abdominal or retroperitoneal tumor; or muscle spasm from psychological stress or
pain elsewhere.
are the standard for treatment of moderate to severe cancer
pain.50 ey are most eective for somatic or visceral pain; neuropathic pain is oen more dicult to relieve with opioids, but
a therapeutic trial is usually appropriate.42 Opioids are available in a myriad of dosing formulations and by multiple routes,
Treatment– non-drug therapy
All patients should be evaluated for the potential use of
non-drug therapies. ese include education and counseling, relaxation techniques, physical modalities, and physical/
occupational therapy. Patient education by itself is an analgesic intervention. Patients feel a greater sense of control
and empowerment by understanding the cause and potential
treatment options. Simple counseling interventions include
reframing and normalization along with bedside imagery and
relaxation techniques. Physical modalities include application
of heat, cold, and massage, which are simple modalities suitable
for most patients with little associated risk. Finally, physical or
occupational therapy can be a useful adjunct for many pain
conditions. e role of complementary and alternative medicine treatments for cancer pain is less clear.
44,45
It is reasonable
including oral, rectal, buccal, transdermal, intravenous, subcutaneous, intramuscular, nasal, nebulized, epidural, and intrathecal. Opioids have no arbitrary ceiling dose; their use is mainly
limited by side eects.
Several principles apply to the use of opioids for cancerpain.
1. Oral morphine is considered the opioid of choice due to
its eectiveness, familiarity, ease of administration, and low
cost.42 ere is no evidence that any one opioid provides
superior analgesia, although patients may idiosyncratically
have fewer adverse eects with some opioids than others.
2. ere is little role for partial-opioid agonists such as pen-
tazocine or nalbuphine for cancer pain:they provide no
therapeutic or safety benet over pure opioid agonists and
can precipitate withdrawal in patients currently on opioid
agonists.
51
299
Section X:Specialized interventional techniques in cancercare
3. Meperidine and propxyphene should be avoided. ese
drugs are prone to neuroexcitatory side eects, especially
in the elderly and those with renal insuciency.
52
4. When available, the oral route is preferred. Intramuscular
injections are unnecessarily painful and oer no benet
over less painful subcutaneous injections and should be
avoided.
42
5. Patients with continuous moderate to severe pain are best
managed by a combination of both short- and long-acting
opioids. Short-acting formulations are used for breakthrough pain to supplement the long-acting opioid.
A variety of short-acting oral opioids are available in the USA
(Table29.5) as either pure opioid formulations or in combina-
tion with a non-opioid such as acetaminophen or an NSAID.
Combination products have a ceiling dose due to the nonopioid. All short-acting oral opioids have an onset of analgesia in 30minutes, with peak eect at 60–90minutes, providing
3–4hours of analgesia.42 Oral transmucosal fentanyl, an ultrashort-acting opioid, is absorbed through the buccal mucosa. It
has unique pharmacokinetic and dosing properties compared
to other short-acting opioids, providing an onset of analgesia
in 5–10minutes.
53
Multiple long-acting opioid preparations are available
in the USA; however, the transdermal fentanyl patch and
sustained-release morphine and oxycodone are the most commonly prescribed and available. erefore, they are considered
by most experts to be rst-line agents in this class. Clinicians
caring for cancer patients should have familiarity and expertise
in managing these agents. Most sustained-release morphine
and oxycodone formulations are dosed every 8–12hours. e
transdermal fentanyl patch is applied once every 72hours and
is indicated for continuous moderate to severe cancer pain in
patients with swallowing impairment or who are intolerant of
other long-acting opioids. Due to its long half-life, this product should not be dose-escalated more frequently than every
3days and thus is most appropriate for opioid-tolerant patients
on relatively stable opioiddoses.
Methadone is a unique opioid that it has a long and variable
half-life.54 Although it is a uniquely eective opioid for severe
pain (especially for patients who may have trouble swallowing pills or have renal insuciency) and it is relatively inexpensive compared with other opioids, its potency relative to
other opioids increases as the dose of other opioids increases.
us switching to and from methadone is problematic. For
these reasons methadone is usually considered a second- or
third-line agent in cancer-related pain. Methadone’s initial dosing and titration should be managed by experienced palliative
care specialists or pain management practitioners.
42
e frequency of dose adjustments depends on the opioid
product in use. Short-acting opioids can be dose-escalated
every 2–4hours; long-acting oral opioids every 24hours; and
the fentanyl patch or methadone every 72hours.55 For patients
with inadequately controlled pain, it is generally recommended
to increase their opioid dose 25–50% for ongoing mild to moderate pain and 50–100% for moderate to severe pain, irrespective of starting dose.55 Patients with severe or rapidly escalating
pain are best managed in the inpatient hospital setting where
rapid opioid titration can be performed under controlled
conditions.
Patients and practitioners frequently have concerns about
opioid safety and toxicity in cancer patients– concerns that
could result in inadequate dosing and undertreatment of pain.
Fortunately, patients usually become tolerant to many opioid
side eects, allowing ongoing upward titration of opioids for
pain.56 Central nervous system (CNS) depression is one such
feared side eect. It manifests rst as sedation and somnolence,
and later as respiratory depression. Risk factors for respiratory
depression include opioid naiveté, advanced age, use of other
CNS-depressant medications, rapid intravenous bolus dosing, deteriorating renal or liver function, and poor respiratory
reserve.56 Ongoing pain directly counteracts CNS depression,41
and tolerance to opioids’ CNS-depressant eects rapidly develops, limiting the risk of respiratory depression.42 Constipation,
nausea, and pruritus are also common side eects of opioids.
Morphine and hydromorphone are metabolized in the liver to
renally excreted active metabolites, many of which have unwelcome neuroexcitatory side eects, including hyperalgesia.57 It
is believed that fentanyl, methadone, and perhaps oxycodone
Table 29.5 Commonly used opioid preparations (USA)
Opioid Major routes Combination product Long-acting product
Codeine PO Acetaminophen No
Fentanyl TD, oral transmucosal No TD
Hydrocodone PO. Antitussive elixir available in
combination with an antihistamine
Only available as combination
product with acetaminophen or
No
ibuprofen
Hydromorphone PO, PR, IV, SQ No Not available in the USA
Methadone PO, PR, IV, elixir No See text
Morphine PO, PR, IV, SQ, elixir No Yes, dosed q8 to q24 hours
depending on formulation
Oxycodone PO, PR, elixir Yes, with acetaminophen and
Yes, dosed q8 to q12 hours
NSAIDs
PO = by mouth; TD = transdermal; PR = by rectum; IV = intravenous; SQ = subcutaneous; NSAIDs = non-steroidal anti-inflammatory drugs.
300
Chapter29:Palliative care and symptom management
are safer to use in renal failure, although this has not been clinically tested.
48
Practitioners and patients alike frequently have concerns
about opioid tolerance and addiction.58 Opioid tolerance
describes the need for a higher dose of an opioid in order to
achieve a similar eect. While tolerance develops to certain
adverse eects of opioids (nausea, CNS depression), it rarely
occurs with its analgesic eects.
42,59
Typically, patients’ requirements for increased opioid amount reect a worsening of their
underlying cancer, not tolerance.
41,60
e term addiction, oen
used synonymously with psychological dependence, describes
the “aberrant use of a substance in a manner characterized by
loss of control, compulsive or escalating use, preoccupation,
and continued use despite harm.”61 It is dierent from physical
dependence, which is dened by an abstinence, or withdrawal,
syndrome, which occurs following discontinuation or dose
reduction of the drug, or administration of a pharmacologic
antagonist. Physical dependence is a predictable and expected
Table 29.6 Dosing guidelines for second-generation anticonvulsants as
adjuvant analgesics
Usual eective
Drug Starting dose
Gabapentin 100 mg tid or
300 qhs
Pregabalin 150 mg daily 150–300 mg bid
Lamotrigine 25–50 mg daily 200–400 mg daily
Topiramate 25 mg daily 100–200 mg bid
Oxcarbazepine 75–150 mg bid 150–800 mg bid
Tiagabine 4 mg qhs 4 mg tid
Levetiracetam 250–500 mg bid 500–1,500 mg bid
Zonisamide 100 mg daily 100–200 mg bid
Reproduced with permission from McDonald AA, Portenoy RK. How
to use antidepressants and anticonvulsants as adjuvant analgesics in
the treatment of neuropathic cancer pain. J Supp Oncol. 2006; 4: 43–52.
Copyright 2006, with permission from Elsevier.
dose
900–3,600 mg daily
divided bid-tid
phenomenon aer ongoing opioid use, and should not be confused with psychological dependence, which is dened behav-
Table 29.7 Dosing and titration of gabapentin for neuropathic pain
a
iorally. Patients with past or current substance abuse problems
are best managed together with a pain management and/or
addiction specialist.61 ere are several assessment tools available to screen for opioid misuse.
62,63
However, most have been
validated in chronic non-cancer pain. e assessment tools
can be a helpful adjunct along with careful history taking, a
trusting relationship, and collaboration with other specialists
as needed.
64
Adjuvant analgesics
Adjuvant analgesics refers to a heterogeneous group of drugs
to treat neuropathic pain and other pain syndromes that do
not respond well to conventional analgesics. Anticonvulsant
and antidepressant agents are the most commonly used and
best-studied classes of adjuvants. Other classes of drugs are
more rarely used and will not be fully discussed here. ese
include gamma-aminobutyric acid agonists such as baclofen,
benzodiazepines, glucocorticoids, lidocaine, ketamine, and
clonidine.
Anticonvulsants have long been used for chronic neuropathic pain syndromes such as postherpetic neuralgia,
trigeminal neuralgia, and diabetic neuropathy.
40,65
Newer,
second-generation anticonvulsants are preferred for their
more desirable side-eect proles and ease of use (Table29.6).
Gabapentin is considered the rst-line anticonvulsant for
neuropathic pain for several reasons. It is better tolerated
than other anticonvulsants, has been studied extensively for
neuropathic pain including cancer pain, and has almost no
drug–drug interactions.
66,67
Common side eects include
somnolence, ataxia, and edema; doses should be started low,
increased slowly, and adjusted for renal function (Table29.7).
Pregabalin is a newer agent with pharmacodynamics and side
eects similar to gabapentin. It has greater oral bioavailability,
undergoes hepatic metabolism, and requires less dose titration
than gabapentin.
Antidepressants are also well established in the treat-
ment of neuropathic pain.65 Tricyclic antidepressants, such as
Starting dose
Routine 100–300 mg bid
Elderly, medically frail 100–300 mg qhs
Renal insufficiency (CrCl < 60 mL/
min, > 15 mL/min)
Renal failure (CrCl < 15 mL/min) 100 mg qhs
Dose increments
Routine 50–100% every 3 days
Elderly, medically frail Slower titration
Renal insufficiency/failure Slower titration
Usual eective dose
Routine 900–3,600 mg in 2–3 divided
Elderly, medically frail 300–1,800 mg in 2–3 divided
Renal insufficiency (CrCl < 60 mL/
min, > 15 mL/min)
Renal failure (CrCl < 15 mL/min) 100–300 mg qhs
a
Goal of titration: Continue dose escalation until treatment-limiting side
effects (ineffective therapy) or until dose increment yields no additional
benefit (maximal benefit).
CrCl = creatinine clearance.
Reproduced with permission from McDonald AA, Portenoy RK. How
to use antidepressants and anticonvulsants as adjuvant analgesics in
the treatment of neuropathic cancer pain. J Supp Oncol. 2006; 4: 43–52.
Copyright 2006, with permission from Elsevier.
100–200 mg qhs
doses
doses
300–1,800 mg in 2–3 divided
doses
amitriptyline, nortriptyline, and desipramine, all have analgesic
eects distinct from their antidepressant eects (Table29.8).
However, their use is limited by side eects, including somnolence, orthostatic hypotension, delirium, cardiac conduction
abnormalities, and constipation.40 ese are most problematic for the elderly and medically frail. Because of this, they
are not considered good rst-line agents, except for younger
people for whom nocturnal sedation is desirable. Some
301
Section X:Specialized interventional techniques in cancercare
Table 29.8 Dosing guidelines of antidepressants as adjuvant analgesics
Usual eective
Drug Starting dose
Tricyclic antidepressants
Amitriptyline 10–25 mg nightly 50–150 mg nightly
Nortriptyline 10–25 mg nightly 50–150 mg nightly
Desipramine 10–25 mg nightly 50–150 mg nightly
SSRIs
Paroxetine 10–20 mg daily 20–40 mg daily
Citalopram 10–20 mg daily 20–40 mg daily
Others
Venlafaxine 50–75 mg daily 75–225 mg daily
Buproprion 100–150 mg daily 150–450 mg daily
Duloxetine 60 mg daily 60 mg daily
SSRIs = selective serotonin reuptake inhibitors.
Reproduced with permission from McDonald AA, Portenoy RK. How
to use antidepressants and anticonvulsants as adjuvant analgesics in
the treatment of neuropathic cancer pain. J Supp Oncol. 2006; 4: 43–52.
Copyright 2006, with permission from Elsevier.
dose
newer antidepressants have analgesic properties (Table29.8).
Venlafaxine and duloxetine have the most evidence supporting
their use in cancer-related neuropathic pain syndromes such as
chemotherapy-induced neuropathy.
67,68
Newer antidepressants
are better tolerated than tricyclic antidepressants, although
their comparative ecacy has not been fully evaluated.
Bone metastases
Painful bone metastases are common in many cancers and oer
unique pain management challenges. Bone metastases need close
assessment and management to avoid complications such as
reduced mobility, fracture, spinal cord compression, and hypercalcemia. Acutely, most pain from bone metastases responds
to opioids and anti-inammatory agents, including NSAIDs
and corticosteroids.
long-term and denitive treatment of painful bony metastases.
Bisphosphonates reduce osteoclast activity at the tumor site, leading to analgesia aer approximately a month of use. ere is good
evidence these improve quality of life and reduce pain in lung,
prostate, and renal cancers. eir role for pain relief in other cancers, as well as how long to use them, remains controversial.
Radiation remains the gold standard for treatment of painful bone metastases; virtually all patients with painful bone
metastases should be referred to a radiation oncologist for
evaluation. External-beam radiation provides pain relief in up
to 90% of patients, with approximately 50% achieving complete relief in 1–2months.67 Many studies have shown that
single-fraction palliative radiotherapy can provide eective
pain relief, even when compared to multifraction therapy.
Patients can have marked improvement in quality of life with
low treatment burden. is is ideal for all patients, especially
those with limited life expectancy. Early studies have shown
that percutaneous radiofrequency ablation can be used to palliate bone metastases and can be eective in treating patients
who have failed radiation therapy or have already received
maximal radiation doses to a particular region.
46,69
Several interventions exist for more
73,74
70,71,72
e systemic administration of radioisotopes such as
strontium-89 is used for diuse, painful osseous metastases that cannot be treated solely by external-beam radiation.
Pain relief occurs in up to 70% of patients, starting within
1–4weeks aer radioisotope administration, and can last for
over a year.75 Myelosuppression is the most common limiting side eect. Additional interventional techniques are being
used to palliate metastases,76 such as kyphoplasty, vertebroplasty, and related procedures for malignant vertebral compression fractures.
77
Refractorypain
A minority of cancer patients will not achieve acceptable
analgesia with the appropriate use of conventional drug and
non-drug therapies. e rst steps in approaching patients with
inadequately controlled pain or pain not following an expected
course are: (1) complete a thorough multidimensional pain
assessment or reassessment to explore the reason for refractory pain, remembering that psychological and spiritual issues
are common in cancer patients and may be expressed as an
increase in pain; (2)ensure that sucient opioid, non-opioid,
and adjuvant analgesics have been tried; (3)consider chemical coping or opioid dependency in the dierential diagnosis
of poor pain control; and (4)seek consultation from a clinician
with pain management or palliative care expertise.
A variety of invasive procedures are available to meet the
wide range of dicult pain management problems. ese
include epidural or intrathecal administration of drugs
through implanted catheters or pumps; neurolytic procedures
to destroy autonomic aerent or autonomic nerves, such as
intercostal, celiac, or hypogastric plexus blocks; or neurosurgical procedures to interrupt pain pathways to the brain such as
a cordotomy.
78,79
e success of these procedures depends to
a large extent on a thorough and accurate assessment of pain
etiology combined with the technical skills of the practitioner.
Nausea and vomiting
Up to 60% of patients with advanced cancer will experience
nausea and half of these vomiting.80 Despite advances in the
prevention and treatment of chemotherapy-related nausea,
patients still rate nausea as one of the primary detriments to
quality of life while undergoing cancer therapy.81 Nausea and
vomiting may aggravate weight loss, can lead to aspiration
pneumonia and electrolyte disturbances, and can interfere with
timely cancer treatment.
e biochemistry and pathophysiology of nausea and vomiting are complex physiologic processes coordinated in the
brainstem vomiting center (VC). e VC lies in the nucleus
tractus solitarius, which receives input primarily from the
chemoreceptor trigger zone (CTZ) located rostral to the VC
at the base of the fourth ventricle. e CTZ is outside the
blood–brain barrier and acts as sampling port for emetogenic
toxins in the blood and cerebrospinal uid. Nausea from
chemotherapy, opioids, renal failure, and other metabolic disturbances are all mediated in part through this mechanism.
Dopamine, serotonin, and neurokinin-1 receptors are important in nausea-related signaling in theCTZ.
302
Chapter29:Palliative care and symptom management
Table 29.9 Causes of nausea and vomiting in the cancer patient
Drugs
Opioids
Chemotherapeutic agents
Digoxin
Antidepressants
Non-steroidal anti-inflammatory drugs
Antibiotics
Iron
Gastrointestinal causes
Esophagitis, reflux
Gastritis, peptic ulcer disease
Gastroparesis
Constipation, ileus
Bowel obstruction
Biliary obstruction
Pancreatitis
Metabolic
Uremia
Hypercalcemia
Adrenal insufficiency
Central nervous system
Elevated intracranial pressure (e.g., tumor metastases)
Meningitis
Vestibular disease
Aerent neural input to the CTZ comes from several
sources. Gastrointestinal aerent input, such as from distension or inammation, is mediated by the vagus nerve. Aerent
input from the cerebral cortex is involved in anticipatory
or anxiety-related nausea. Finally, the vestibular apparatus
sends input to the CTZ in motion-related and some cases of
opioid-induced nausea; acetylcholine and histamine receptors
are particularly important in this system. Because of these multiple potential causes of nausea it is important to consider a
wide dierential diagnosis and pursue appropriate diagnostic
workup that is focused on the most likely cause (Table29.9).
Two causes of nausea deserve special mention in the
cancer patient: chemotherapy- and opioid-induced. Acute
chemotherapy-induced nausea occurs within the rst 24hours
aer receiving emetogenic chemotherapy– usually within the
rst few hours. It has been studied extensively and there are
well-established prophylactic drug regimens. Most regimens
use a combination of dexamethasone and an antagonist of the
serotonin receptor subtype-3, such as ondansetron, granisetron, dolasetron, or others.82 More recently, the neurokinin-1
receptor antagonists aprepitant and fosaprepitant have become
part of the standard of care for moderate to highly emetogenic
chemotherapy.83 Delayed chemotherapy-induced nausea and
vomiting occurs for several days aer the initial chemotherapy
dose and is more common with certain chemotherapy agents
(e.g., cisplatin) than others. It responds less well to serotonin
antagonists,82 but glucocorticoids, neurokinin-1 antagonists,
and olanzapine have demonstrated ecacy as well.
83,84,85,86
Nausea is a normal response to opioid use; it is not an allergic reaction. Opioid-induced nausea occurs at the initiation of
therapy or– less commonly– following a dose increase. Some
patients idiosyncratically have more nausea with certain opioids and less with others. Among the opioids, morphine and
codeine appear to be the most emetogenic. For most patients,
nausea resolves within a few days and no dose or drug adjustment is necessary. For a small proportion of patients, nausea
continues and alternative opioids should be tried. Treatment
is empiric, and antidopaminergic antiemetics (e.g., prochlorperazine) are a reasonable rst choice. Ondansetron has shown
some ecacy in postoperative opioid-induced nausea,87 but
this has not been demonstrated in the treatment of cancerpain.
Table 29.10 lists commonly used antiemetic agents.
Dopamine antagonists are a good rst choice due to cost,
availability, and side-eect prole. Metoclopramide is perhaps
the most well studied, and has shown ecacy in managing
non-specic nausea associated with advanced cancer .
88,89,90
It
is a gastrointestinal prokinetic agent, making it particularly
useful in the setting of gastroparesis. Other agents in this class
include proclorperazine, haloperidol, droperidol, and chlorpromazine. Of these, haloperidol has been studied the most.91
Chlorpromazine is best used as an antiemetic when sedation is
also a goal.
88
One newer, atypical antipsychotic agent, olanzapine, has
shown such promising results in improving cancer patients’
quality of life through its antiemetic activity in patients receiving chemotherapy
92,93,94,95
that the American Society of Clinical
Oncology has recommended it for patients with nausea or
emesis despite optimal prophylaxis.96 In one study of patients
receiving highly emetogenic chemotherapy, olanzapine was
found to be superior to metoclopramide for control of breakthrough emesis and nausea.
97
Promethazine has some antidopaminergic eects but is also
a powerful antihistamine and anticholinergic and is not generally indicated for the cancer patient. All the dopamine antagonists can cause extrapyramidal reactions, as well as sedation,
xerostomia, and orthostasis.
Antihistamines have a limited role in cancer-related nausea, except for those patients with a vestibular component or
for whom sedation is desirable. Anticholinergic agents such
as scopolamine or glycopyrrolate have particular usefulness
in managing nausea, secretions, and colic related to bowel
obstruction, but as single agents they are weak antiemetics.80
Scopolamine is available as a transdermal patch, but can cause
delirium. Glycopyrrolate, a quarternary amine which does not
cross the blood–brain barrier and so causes less delirium, can
be used intravenously, orally, or subcutaneously.
Cannabinoids are eective for chemotherapy-induced
nausea and vomiting, although probably not for highly emetogenic chemotherapy.98 eir usefulness for other causes
of nausea is unclear and their eectiveness is strongly limited by CNS side eects such as dizziness and sedation.
Psychotomimetic side eects are also common, particularly in the elderly.99 Dronabinol and nabilone are synthetic
303
Section X:Specialized interventional techniques in cancercare
Table 29.10 Common antiemetic agents
Class Common dosing Comments
Dopamine antagonists
Prochlorperazine 5–10 mg PO tid–qid; 25 mg PR Available PO, IV, and PR
Metoclopramide 5–10 mg PO tid–qid; best given before meals. Up
to 120 mg/day has been used
Chlorpromazine 10–25 mg PO qid PO, IV, PR, SC. Very sedating
Haloperidol 0.5–2 mg PO q4 hours PO, PR, IV available
Droperidol 0.625–1.25 mg IV q3–4 hours IV only. Risk of QT prolongation – electrocardiogram
Serotonin antagonists Indicated for prophylaxis of chemotherapy-induced nausea
Ondansetron 4–8 mg PO qid; 24–32 mg prior to chemotherapy IV and orally disintegrating tablet available
Granisetron 1–2 mg PO daily IV available
Dolasetron 12.5–100 mg PO IV available. Extended dosing has not been described
Atypical antipsychotics
Olanzapine 5–10 mg PO Blocks multiple neurotransmitters
Cannabinoids
Dronabinol 2.5–5 mg PO q2–4 hours Limited by central nervous system side effects
Neurokinin-1 antagonists
Aprepitant 125 mg PO once, then 80 mg daily Unknown efficacy except as part of a regimen for
Glucocorticoids
Dexamethasone 2–4 mg q6 hours PO, IV, SC, PR
PO = orally; PR = per rectum; IV = intravenous; SC = subcutaneous.
Prokinetic. PO, IV, SC, and PR routes available
recommended for extended dosing
and vomiting
chemotherapy-induced nausea
cannabinoids available in the USA. Many states and the
District of Colombia have now legalized medical marijuana in
the USA.
100
Research suggests cannabis can be useful for many
common cancer-associated symptoms, including nausea and
vomiting.
101,102,103
e glucocorticoid dexamethasone is a well-established
antiemetic for chemotherapy-induced nausea. Additionally
it is oen used as part of a regimen for terminally ill people
with refractory nausea associated with advanced cancer, and
can be particularly useful for relieving symptoms associated
with bowel obstruction.
89,90
Nausea from cerebral edema may
respond rapidly to dexamethasone. Glucocorticoids are associated with serious side eects: delirium, gastric ulceration,
osteoporosis, insomnia, glucose intolerance, peripheral edema,
myopathy, and immunosuppression. Accordingly, their use is
best limited to the shortterm.
Benzodiazepines are eective for anticipatory nausea
related to chemotherapy, but have not shown ecacy in other
conditions.
104
Acupuncture or acupressure point stimulation
are at best modestly eective for chemotherapy-induced nausea, as adjuvants to pharmacologic agents.
105,106
Constipation
Estimates of rates of constipation range from 40% to 90%,
and its prevalence increases as the cancer advances.
Constipation, as a subjective complaint of inadequate passage
of stool, can reect a patient’s perception of increased hardness
107,108
of stool, decreased size or frequency of stools, or both. Besides
causing discomfort, constipation can lead to obstipation and
bowel obstruction, and contribute to anorexia and weight loss,
and delirium in the elderly and medically frail.
109
e consistency and frequency of stooling are a complex
balance of multiple external and internal factors. ese include
the amount and type of oral intake, gastrointestinal electrolyte
and uid transport, bowel motility, and interactions between
the sympathetic, parasympathetic, and somatic nervous systems. Any or all of these may contribute to a patient’s constipation, and adds to the challenge of its evaluation and treatment.
Constipation should be considered not only in patients with
actual complaints of constipation, but also in those with a variety of other symptoms, including nausea, anorexia, abdominal pain or bloating, delirium, and genitourinary complaints.
Diarrhea, especially in previously constipated patients, should
raise concern for overow diarrhea in which fecal material
liquees proximal to a mass of constipated stool and escapes
around it. In addition to a careful history and physical examination, plain-lm radiography of the abdomen can be helpful
to conrm a diagnosis of constipation, establish its extent, and
rule out bowel obstruction.
107
Table29.11 lists common causes of constipation in can-
cer patients. Opioid-induced constipation deserves special
mention as over half of opioid-treated patients report consti-
110
pation.
ere is some evidence that transdermal fentanyl
is less constipating than oral opioids
111
; however, in general
304
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Table 29.11 Common causes of constipation in the cancer patient
Drugs
Opioids
Serotonin antagonists (e.g., ondansetron)
Anticholinergic agents (e.g., tricyclic antidepressants, antisecretory drugs)
Antacids (calcium- or aluminum-containing)
Chemotherapeutic agents (particularly vinca alkaloids)
Iron
Non-steroidal anti-inflammatory drugs
Antihypertensive agents (e.g., calcium channel blockers, beta-adrenergic
blockers, diuretics)
Metabolic factors
Hypercalcemia
Uremia
Mechanical
Bowel obstruction
Bowel strictures
Fecal impaction
Other
Poor oral intake of solids or liquids
Patient inactivity
Inability to reach or use commode
Spinal cord compression/cauda equina syndrome
constipation is noted with all opioids and all routes. Opioids
reduce gastrointestinal motility via directly inhibiting peristalsis and increasing sphincter tone; they also decrease gastrointestinal secretions.
Treatment of constipation is largely empiric and the
best therapy is prophylaxis. Most agents have some ecacy
across a variety of etiologies of constipation. ere are four
major categories of pharmacological treatments: stimulants, bulk-forming agents, osmotics, and surfactant laxatives
(Table29.12). Decisions about which agents to use should be
based on rapidity of desired eect and severity of constipation.
Generally, if a patient is responding inadequately to one class
of laxative, a second class should be added. Doses should be
started low, then titrated upwards to prevent cramping and
diarrhea. Commonly used agents for prophylaxis include
mild stimulants (e.g., senna) or saline laxatives (e.g., Milk of
Magnesia). Surfactant laxatives such as docusate are not eective prophylactic agents for opioid-induced constipation.
Bulk-forming agents such as ber and psyllium have a limited role for the cancer patient. ey increase stool mass and
water content but do not promote motility and so are ineective for opioid-induced constipation and should not be used
as monotherapy.
110
Stimulant laxatives such as senna and bisacodyl stimulate the myenteric plexus and increase forward
peristalsis, and so are particularly eective for opioid-induced
constipation. Indeed, many recommend initiating scheduled
senna at the same time as scheduled opioids are prescribed as
prophylaxis.
110
Historic concerns about colonic damage from
long-term stimulant laxative use have not been substantiated.
Table 29.12 Commonly used laxatives
Drug Dosing Onset of action
Stimulant laxatives
Senna 8.6–68.8 mg daily, divided bid 6–12 hours
Bisacodyl 5–30 mg daily; oral or rectal 6–12 hours
Surfactant laxatives
Docusate 100–500 mg daily, divided up to qid 24–72 hours
Mineral oil 15–45 mL, divided 6–8 hours
Saline osmotic laxatives
Magnesium citrate (1.745 g/30 mL) 150–300 mL daily 0.5–3 hours
Magnesium hydroxide 30–60 mL daily, may divide bid 0.5–3 hours
Polyethylene glycol 17 g daily, taken in water 24 hours
Carbohydrate osmotic laxatives
Lactulose (10 g/15 mL liquid) 15–60 mL daily, divided up to tid 24–48 hours
Sorbitol 70% solution 30–150 mg daily or bid 24–48 hours
Opioid antagonist
Methylnaltrexone Dosing is weight-based and given
subcutaneously: 8–12 mg for most adults;
>114 kg 0.15 mg/kg, maximum 1 dose/24 hours
Chloride channel activator
Lubiprostone 24 mcg bid 30–60 minutes
Onset-of-action data modified from Fallon M, O’Neill B. ABC of palliative care: constipation and diarrhoea. BMJ. 1997;315:1293–1296 and Mancini I, Bruera
E. Constipation in advanced cancer patients. Supp Care Cancer. 1998; 6:356–364.
30–60 minutes (in responding patients)
305
Section X:Specialized interventional techniques in cancercare
Oil-based lubricants such as mineral oil are eective but
poor long-term choices as they can lead to fat-soluble vitamin
deciencies. Additionally they can lead to a severe chemical
pneumonitis if aspirated. Osmotic laxatives contain poorly
absorbable salts or carbohydrates, which osmotically retain
uid in the intestinal lumen, causing laxation. Saline osmotic
laxatives usually contain a magnesium salt. In higher doses
these can have cathartic eects, but in lower doses can be used
safely in the long term. For opioid-induced constipation they
can be a helpful addition to a stimulant laxative, but should
be used cautiously in renal failure. Carbohydrate laxatives such
as lactulose or sorbitol can also have cathartic eects at higher
doses. All oral laxatives can cause cramping, bloating, nausea,
and atulence, as well as diarrhea and concomitant electrolyte
disturbances.
Rectal therapies (enemas or suppositories) are best reserved
for refractory constipation. All enemas cause colonic distension, which stimulates rectal contraction and fecal evacuation. Electrolyte-containing enema solutions increase water
retention in the rectum and thus stool volume and soness.
Suppositories have either a stimulant (e.g., bisacodyl) or surfactant (e.g., glycerin) eect. Impaction should be treated
Table 29.13 Potentially treatable causes of anorexia and weight loss
Oral
Oropharyngeal mucositis
Xerostomia
Thrush
Treatment-related changes in smell and taste
Poor dentition, ill-fitting dentures
Gastrointestinal
Esophagitis
Dysphagia
Nausea, vomiting
Gastroparesis
Proximal gastrointestinal obstruction (tumor-related, stricture)
Constipation
Diarrhea, steatorrhea
Psychosocial
Depression
Anxiety
Inability to shop for, pay for, or prepare food
mechanically with manual disimpaction and with large-volume
enemas and stool soeners along with attention to pain management as the procedure can be quite distressing.
Opioid antagonists have been used successfully to treat
opioid-induced constipation.
112,113
In particular, methylnaltrexone is an opioid receptor antagonist which blocks opioid binding
at the mu receptor and is a quaternary derivative of naltrexone.
It has restricted ability to cross the blood–brain barrier due
to a permanently charged tetravalent nitrogen atom.
114
us,
it acts peripherally on the gastrointestinal tract to decrease
opioid-induced constipation but does not impact pain relief or
induce withdrawal symptoms. Several pharmaceutical-funded
studies demonstrated successful treatment of opioid-induced
constipation aer treatment with methylnaltrexone, with minimal adverse reactions.
115,116
Constitutional symptoms
Fatigue, lack of appetite, and weight loss are cardinal symptoms of an advanced cancer, especially in the last 3months of
life. Anorexia occurs in up to 70% of cancer patients,
117
and at
least half will experience weight loss in the course of their dis-
118
ease.
Patients and families usually nd anorexia and weight
loss particularly distressing. ey are “cancer stigmata,”
118
and
conict between family members, or family members and the
health care team, over issues of nutrition and oral intake occur
commonly. Education and emotional support provided by the
health care team are important in alleviating fears of starvation.
Health professionals can assist conicted families by focusing
“blame” for the anorexia on the cancer and not the patient.
Nutritional counseling is reasonable, especially if poor caloric
intake is suspected, although it has not shown any signicant
long-term benet.
119
e cancer anorexia–cachexia syndrome, characterized
by anorexia, early satiety, weight loss, muscle wasting, debilitation, and asthenia, is commonly referred to as a symptom
cluster. Cancer-induced derangements in the production of
inammatory cytokines, such as tumor necrosis factor-alpha,
interleukin-6, and others, are believed to underlie the syndrome. In contrast with starvation, in which bodily energy
consumption is conserved and fat is preferentially consumed
due to a caloric decit, in cancer cachexia bodily energy consumption increases and fat and muscle tissues are mobilized
equally, even without a caloric decit.
119,120
Unfortunately, this
means that increasing caloric consumption in cancer cachexia,
whether by hyperalimentation or appetite stimulation, has little
impact on lean body mass, quality of life, or longevity. Indeed,
it is not clear that treating cancer anorexia–cachexia with currently available therapies is of any meaningful benet, except
psychologically to the patient and family.
119
e cancer patient who begins to lose weight or is complaining of anorexia should be evaluated for potentially
reversible causes (Table 29.13). Orexigenic therapy can be
successful in increasing a patient’s appetite and caloric intake.
It can also increase weight, although only by increasing fat
mass. Several classes of orexigenic agents have been studied.
Progesterones, particularly megestrol and medroxyprogesterone acetate, are the most closely studied. Megestrol is an eective appetite stimulant at doses between 480 and 800mg/day.
Medroxyprogesterone acetate can lead to weight gain at doses
of 500mg twice daily.
121
Both can aggravate edema and elevate the risk of thromboembolic events. Mortality and quality
of life have not been shown to improve with either agent.
117,122
Glucocorticoids are also eective, but have not been studied
long-term and have severe, limiting side eects.
117
e cannabinoid dronabinol can improve appetite and weight at a dose
of 2.5mg given 1hour aer meals.99 However, its use is limited
by psychotomimetic side eects. Androgens have not shown
any ecacy.
122
ere is ongoing study into modulating the
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inammatory substrate of anorexia–cachexia with agents such
as omega-3 fatty acids, thalidomide, amino acids, pentoxifylline, mistletoe, NSAIDs, and other novel agents.
117,119,120
None
has yet shown strong promise clinically.
Fatigue shares much in common with cancer-related anorexia and weight loss, and some argue that they all are part of the
same pathophysiologic process of inammation and neurohormonal disruption that accompanies cancer.
123,124
It is generally
the most frequently cited symptom associated with cancer and
its treatment, occurring in virtually 100% of patients.
Fatigue can persist for years beyond curative treatment.
108,125,126
123
Cancer-related fatigue is distinct from exercise-induced
127
fatigue.
It is disproportionate to activity and poorly relieved
by rest and sleep. Patients feel globally limited– not only physically but emotionally, mentally, vocationally, and socially.
While frequently due to the cancer itself, other causes
include eects of chemotherapy or radiotherapy, weight
loss, depression, anxiety, poor sleep, poorly controlled pain,
anemia, and major organ failure (heart, liver, lung, or kidney).
Medication side eects, particularly opioids and other psychotropic drugs, oen contribute as well. Treatment of fatigue
starts with addressing underlying causes that are amenable to
intervention, such as anemia or depression. Anemia is well
studied and worth investigating and treating in the fatigued
cancer patient. Erythropoietin is routinely used to prevent
and treat anemia in the cancer patient, and has been shown
to reduce transfusions and improve fatigue and quality of life
in patients undergoing cancer treatment.
128,129,130
In advanced
cancer patients and the terminally ill, anemia and its correction play a much smaller role in impacting fatigue, as other
factors become more important.
131,132
Psychostimulants such as
methylphenidate have been used for severe fatigue in patients
with advanced cancer, with mixed results.
133
Education and support should be oered to all patients
uid resorption across the peritoneum.
the onset of malignant ascites is about 20 weeks.
Management of ascites diers based on its etiology. Salt
restriction and diuresis are the mainstays of therapy for portal
hypertensive ascites. Patients should be instructed to consume
a low-sodium diet (less than 2,000mg daily). Most patients with
cirrhosis and ascites respond well to oral diuretics, usually spironolactone alone or in combination with a loop diuretic such
as furosemide. Patients should be started on moderate doses
(50–100mg spironolactone and 20–40mg furosemide), which
can then be titrated upwards until eective. Gynecomastia can
be an intolerable side eect of spironolactone; amiloride can
be substituted in this case. Overly aggressive diuresis can have
serious complications, including acid–base and electrolyte
imbalance, as well as renal failure. Hypokalemia and metabolic
alkalosis are both risk factors for developing hepatic encephalopathy and so frequent monitoring of electrolytes and renal
function is wise.
141
Supportive measures should be undertaken
to prevent the more severe complications of liver failure, such
as spontaneous bacterial peritonitis, hepatic encephalopathy,
and gastrointestinal bleeding.
Treatment of malignant ascites is aimed at the underlying
cancer. Unfortunately, many patients will have advanced cancer which is poorly responsive to oncologic therapies. In these
cases management is empiric, and should be based on patients’
overall prognosis and how symptomatic they are from the ascites. Because there is no physiologic derangement of salt and
uid retention, the benet of salt restriction and diuretics is
unclear.
140
Otherwise, the management of malignant ascites
is drainage, usually via large-volume paracentesis of up to 6
liters at a time.
137
More durable interventions such as peritoneovenous shunting and peritoneal drainage catheters can be
immensely helpful in select patients, and are discussed elsewhere in this book (see Chapter31).
140
Mean survival from
138
137
complaining of fatigue. Inquiring about specic activities
that are limited by the fatigue can allow for troubleshooting
and goal setting, even if the fatigue itself cannot be ameliorated. For patients who are able, moderate aerobic exercise is
recommended as it paradoxically improves fatigue in patients
undergoing treatment, and helps prevent further decondition-
134,135,136
ing.
to “store up” energy for important activities– is helpful.
It is unclear whether energy conservation– resting
120
Ascites
Approximately 10% of all cases of ascites are due to malig-
137
nancy,
intestinal cancers.
peritoneal carcinomatosis, although a minority of patients will
have some element of portal hypertension from either massive
hepatic tumor inltration or underlying cirrhosis.
ascites is a rare occurrence, usually from lymphoma. As in the
general population, nephrosis, congestive heart failure, biliary
or pancreatic ductal leakage, and thrombotic events can also
cause ascites. e pathophysiology of ascites from peritoneal
carcinomatosis is poorly understood, but is believed to be due
to direct uid eux from tumor implants as well as impaired
most commonly due to genitourinary or gastro-
138
Malignant ascites is usually secondary to
139
Chylous
Psychiatric symptoms
Psychiatric symptoms are common, underdiagnosed, and yet
oen treatable in cancer patients. is section will focus on the
assessment and management of depression and anxiety in cancer patients.
Depression
Depressive symptoms are more common in cancer patients
than in the general population.
major depressive disorder (MDD) are between 10% and 25%
of patients with cancer compared to less than 5% of the general
population.
124,142,143
Depressive symptoms (including diminished mood, anhedonia, feelings of guilt and sadness, fatigue,
weight loss, sleep disturbance, and memory problems) are more
common than rates of MDD and may be due to the underlying
cancer, coexisting medical disease, expected feelings of loss and
sadness, or an adjustment disorder. Nevertheless, depression is
not an inevitable or normal part of having cancer. By denition,
MDD interferes with quality of life and functioning.
MDD is associated with worse overall and cancer-related mortality, and evidence suggests it interferes with appropriate
124
Most estimates of rates of
144
Indeed,
307
Section X:Specialized interventional techniques in cancercare
Table 29.14 Differentiating depression from expected sadness and grief in cancer
Patient characteristics less suggestive of depression Patient characteristics more suggestive of depression
Sadness, grief, and guilt which is intermittent and about specific losses and
limitations
Accepting and appreciative of support offered by family, caregivers Feels worthless, not deserving of offered help
Recognizes that can control many aspects of life Feels helpless, out of control, unable to effect any meaningful change
Feels hope about controllable aspects of the future Feels hopeless about most aspects of the future
States has periods of sadness and grief States: “I am depressed”
Ability to enjoy aspects of day-to-day personal, work, and family life despite
limitations and some “bad days”
Thoughts about mortality and death Thoughts about suicide; an active desire for death
cancer evaluation and treatment.
aggressive identication and management of depression are
mandatory.
Depression is underrecognized by most care providers
of cancer patients.
148
Diagnosis of depression is notoriously
complicated in cancer due to overlap of the somatic symptoms of depression with common somatic complaints in
145,146,147
erefore, early and
cancer (fatigue, anorexia and weight loss, sleep disturbances,
and sexual dysfunction). Additionally, feelings of grief, sadness, and loss, as well as thoughts about dying are common
in cancer patients and not necessarily pathologic. Assessment
of depression should take these diculties into account, giving less emphasis to somatic symptoms and more to psychiatric ones (mood, interest in previously pleasurable activities,
and social withdrawal). Persistent feelings of guilt, shame,
worthlessness, hopelessness, and suicidality are not characteristic of the expected emotional adjustments to a potentially life-threatening diagnosis, and are strongly suggestive
of depression (Table29.14).
149
Asimple bedside tool– asking “Are you feeling down, depressed, or hopeless most of the
time over the last 2weeks?”– has shown excellent sensitivity and specicity in screening cancer patients for depression, although it has yet to be fully validated in a range of
populations.
150,151
Both pharmacologic and non-pharmacologic therapies for
depression are helpful.
152,153
Indeed, psychotherapy together
with pharmacotherapy of depression is considered to be more
ecacious than either alone.
154
Once depression is identied, immediate involvement of a
patient’s primary physician, or referral to appropriate professionals is important. Many institutions have mental health professionals with specic training in cancer care. Additionally,
many palliative care teams are able to provide these services
and act as an extra layer of support. Arandomized controlled
trial of patients with metastatic non-small-cell lung cancer
showed that early integration of a palliative care specialist team
led to improvement in quality of life and was associated with
fewer depressive symptoms than patients in the usual care
155
arm.
As with all psychological problems, unwelcome somatic
symptoms such as pain or nausea will worsen depression, and
need to be aggressively managed.
ree main classes of pharmacologic agents are avail-
able: (1) tricyclic (and related) antidepressants; (2) newer,
Pervasive feelings of grief, guilt, and shame that are generalized to all
aspects of life
Persistent anhedonia; mood does not lift when around loved ones or when
performing previously enjoyable activities
selective neurotransmitter reuptake inhibitors; and (3) psychostimulants (Table29.15). Given the prevalence of depres-
sive symptoms in the cancer population, surprisingly little
cancer-specic research has been performed. What has been
completed conrms that cancer patients respond to antidepressant therapy and, as in the general population, no class of
antidepressants has superior ecacy.
143
Choice of antidepressant should be based on associated symptoms, past treatment
eects, preference, prognosis, and cost. With the exception
of psychostimulants, all antidepressants take 2–8 weeks to
ameliorate mood; however, the side eects are immediate.
Counseling patients regarding this is important to prevent premature treatment discontinuation. All antidepressants should
be started at low doses and titrated upwards until therapeutic
eect is obtained or side eects limit further use. e antibiotic linezolid is a monoamine oxidase inhibitor and is relatively contraindicated for patients on antidepressants; prompt
consultation with a psychiatrist is warranted in this setting.
156
Antidepressants should be gradually tapered when stopping to
avoid a discontinuation syndrome.
Tricyclic (and related) antidepressants, such as amitriptyline, nortriptyline, and desipramine, have signicant
anticholinergic side eects such as orthostatic hypotension,
xerostomia, dizziness, constipation, urinary retention, sedation, and delirium. In addition, they can cause cardiac conduction abnormalities such as atrioventricular nodal block and QT
prolongation. ey should be used with extreme caution in the
elderly and medically frail. For these reasons, they are not as
commonly prescribed as newer agents.
Newer agents include selective serotonin reuptake inhibitors (SSRIs) such as uoxetine, paroxetine, sertraline, and
citalopram, as well as novel agents which selectively and variably modulate adrenergic and dopaminergic reuptake along
with serotonin. ese include buproprion, venlafaxine, mirtazapine, and duloxetine. Gastrointestinal upset, sexual dysfunction, and xerostomia are common side eects of all these
agents. Seizures, serotonin syndrome, and a short-lived paradoxical increase in anxiety and suicidality are rare, but should
be considered. SSRIs are associated with a small increased
risk of bleeding and should be used cautiously in those with
thrombocytopenia.
157
Fluoxetine can be quite activating and is
best avoided in patients with prominent anxiety or insomnia.
Venlafaxine or duloxetine may be a particularly attractive agent
308