++
Analgesic adjuvants are rarely adequate analgesics when used
alone for cancer pain. They are used especially to relieve neuropathic
pain and to provide an opioid-sparing effect, thus lessening opioid-related
side effects. Many patients with neuropathic pain, however, can
be treated with opioids alone.25
++
Tricyclic antidepressants (TCAs) were used as analgesics shortly
after their introduction.52,53,54 The mechanism
of their analgesic action is not certain, but probably includes
enhancement of monoamine concentrations in the dorsal horn,55 and
stimulation of alpha2 receptors56 (See
Chapter 62, Adjuvant Analgesics). They are useful in treating neuropathic
pain, and have been proven analgesic in well-designed trials for
postherpetic neuralgia, diabetic neuropathy, atypical facial pain,
migraine headache, fibrositis, and central poststroke pain.53,54 There are
few controlled trials of TCAs for the treatment of cancer pain,
perhaps because cancer pain encompasses so many somatic, visceral,
and neuropathic entities (See Chapter 44, Cancer Pain Syndromes).
Amitriptyline has been shown effective in a placebo-controlled study
of 20 patients with neuropathic postmastectomy pain.57 The
analgesic effect of the TCAs on neuropathic pain seems to be separate
from their antidepressant or sedative effects.57–61
++
TCAs are most appropriate for cancer patients with neuropathic
pain, which is often described as burning, searing, aching, or dysesthetic,
and occurs in the setting of known or probable nerve injury. The
choice of drug is empiric; there is no clearly superior drug. A
patient having difficulty with sleep may benefit from a more sedating
drug, such as amitriptyline, imipramine, or doxepin. Nortriptyline
is less sedating, and desipramine has the fewest side effects.58,62 Trazodone
is not an effective analgesic for neuropathic pain, but may be indicated
in the cancer pain patient with a sleep disturbance. Probably fewer
than half of patients with neuropathic pain achieve greater than 50% pain
relief with an antidepressant,54 and a lack of
complete relief should not be interpreted as treatment failure.
++
Suggested dosing for the TCAs is shown in Table 45-4. Because
these drugs are usually sedating, they are best given in the evening.
If the initial low dose is not effective, it should be increased every
few days until an effect is seen or side effects become intolerable.
As with opioids, greater analgesia is seen with higher doses.59
++
++
Adverse effects with TCAs are common.54 They
are primarily anticholinergic, including sedation, constipation,
urinary retention and overflow incontinence, tachycardia, dry mouth,
blurred vision, dysphoria, and agitation. Antihistaminergic effects
are responsible for sedation and weight gain, and may exacerbate
hypotension. Alpha1 and alpha2 blockade contribute
to orthostatic hypotension and tachycardia. Most of these side effects
are not life-threatening and diminish with time. Dry mouth tends
to persist. The side effects are troubling, however, and often prevent
the continued use of TCAs. Cardiac conduction abnormalities and
seizures are more concerning effects. A history of seizure is a
relative contraindication to TCA use.63 An electrocardiogram
should be obtained prior to TCA initiation to rule out bundle branch block
and bifascicular block, which are also relative contraindications.64 Dose
adjustment according to drug levels may help to prevent these consequences
of antidepressant therapy.63 When a patient experiences
unwanted side effects, it is wise to switch to another TCA, since patient
responses are variable and often idiosyncratic. Persistence in treatment
is essential, as analgesic response may take 4 weeks to achieve.53
++
Selective serotonin reuptake inhibitors (SSRIs) are newer antidepressants
than TCAs. They are usually better tolerated than TCAs, but there
is little evidence to support their use in cancer pain. Although
SSRIs are commonly used to treat fibromyalgia and migraine headaches,
most studies have found them to be less effective in neuropathic
pain.54,61,62 SSRIs should be tried when TCAs are
not tolerated or relatively contraindicated.
++
Carbamazepine has long been used for treatment of trigeminal
neuralgia.65 Several anticonvulsants are now commonly
employed to treat lancinating and burning dysesthesias complicating
nerve injury (See also Chapter 62, Adjuvant Analgesics). In addition
to trigeminal neuralgia, glossopharyngeal neuralgia, tabes dorsalis,
diabetic neuropathy, postherpetic neuralgia, postamputation pain,
migraines, central pain, and other conditions have been reported to
respond to anticonvulsants in case reports, case series, and poorly
controlled trials.66 Two randomized, double-blind,
placebo-controlled studies support the use of gabapentin for diabetic
neuropathy and postherpetic neuralgia.67,68
++
Swerdlow studied 200 patients with lancinating pain in an open-label,
uncontrolled trial of carbamazepine, phenytoin, valproate, and clonazepam.66 Patients
were switched from one drug to another if they failed to obtain
relief. Most patients did respond to one of the drugs, but there
was no clearly superior medication in general or for any particular
condition. McQuay et al conducted a recent systematic review of
20 randomized, controlled anticonvulsant trials.69 Trigeminal
neuralgia responded to carbamazepine, and diabetic neuropathy responded
to both carbamazepine and phenytoin. Valproate and carbamazepine
were effective for migraine prophylaxis. While there are few prospective,
controlled trials of anticonvulsants for patients with cancer pain,
individual patients may respond dramatically, and these medications
should not be withheld from patients in pain, pending definitive
evidence of their efficacy. Yajnik et al compared phenytoin with
buprenorphine and the combination in three groups of 25 patients
with cancer pain resulting from various causes.70 A
low dose of phenytoin (100 mg twice daily) provided greater than
50% pain relief in most patients, and enhanced the effect
of buprenorphine without increasing side effects.
++
Gabapentin is receiving considerable attention in pain management,
and there is now convincing evidence to support its use in diabetic
neuropathy and postherpetic neuralgia.67,68 It
has not been studied in cancer pain, but it is commonly used because
of its few side effects and relative absence of drug interactions.
It is usually started at 300 mg at bed time, and increased as high
as 3600 mg/day in divided doses. Dosage should be reduced
in patients with renal failure. Side effects (somnolence, ataxia,
and dizziness) are not life-threatening and plasma concentrations
are not monitored, making this an easy anticonvulsant to use.71 Other
new anticonvulsants, lamotrigine, tiagabine, oxcarbazepine, and
topiramate are also being investigated for analgesic activity.
++
Carbamazepine is started at 100 mg twice daily, and is escalated
until toxicity occurs, pain is relieved, or the safe plasma level
is exceeded (12 μg/mL). Bone marrow suppression often manifests
as mild leukopenia or thrombocytopenia, and rarely aplastic anemia.
If bone marrow suppression is anticipated from radiation, chemotherapy,
or tumor replacement, carbamazepine should be avoided. Patients
receiving carbamazepine should have their complete blood counts
and hepatic transaminases monitored. Reversible hepatotoxicity,
resembling viral hepatitis, occurs rarely, and fatal hepatic necrosis
is less common.72 Cutaneous reactions may also
occur, and require cessation of the medication. Sedation, vertigo,
ataxia, hyponatremia, and nausea are more common effects.66
++
Phenytoin and valproate are available in oral and intravenous
forms. A new form of phenytoin, fosphenytoin, may be administered
intramuscularly. Treatment with phenytoin begins with an oral loading
dose, and maintenance therapy, starting at 100 mg three times daily,
is adjusted to control pain with a plasma concentration of less
than 20 μg/mL. Side effects may include
anemia, anorexia, nausea, somnolence, and ataxia. Bone marrow suppression
is less likely with phenytoin than carbamazepine. The potential
for hepatotoxicity mandates periodic monitoring of liver function
tests.66 Hypersensitivity to phenytoin is rare
but potentially fatal, and manifests with rash, fever, and hepatitis.
Up to 19% of patients on phenytoin develop cutaneous reactions,
usually without hypersensitivity.73 Oral valproate
therapy usually starts at 125 mg twice daily. The most common side
effects are nausea and epigastric pain,which are reduced by taking
it with food and with enteric-coated tablets. Hepatotoxicity is
rare.66
++
Clonazepam is available for oral or parenteral use, and is started
at 0.25 to 0.5 mg daily. It is the most sedating anticonvulsant,
and may be useful for patients with anxiety and insomnia. The dose is
increased as needed. Plasma concentrations are not measured and
the principal toxicity is sedation.
+++
Systemic Local
Anesthetics
++
Systemic local anesthetics are often used to treat neuropathic
pain (See also Chapter 62, Adjuvant Analgesics). Intravenous lidocaine
(5 mg/kg over 30 minutes) has been found effective for
postherpetic neuralgia (PHN) and diabetic neuropathy.74,75 Painful
peripheral neuropathies may also respond to oral mexilitine (10
mg/kg/day).76,77 Systemic local
anesthetics have not been studied for cancer pain.
++
Topical local anesthetics are often used in the treatment of
mucocutaneous pain states. Topical lidocaine and benzocaine provide
temporary relief of pain from oral mucositis. This is necessary to
allow the patient to eat and for oral hygiene. Likewise, Rowbotham
et al showed that topical application of 5% lidocaine gel
relieves the pain of PHN for up to 24 hours in a blinded, placebo and
site-controlled trial.78 The effect is greatest
when lidocaine is applied in the painful dermatome. A lidocaine
patch was recently approved in the United States for treatment of
PHN.
++
Capsaicin is the compound in chili peppers that makes them taste
hot. When it is applied to the skin or a mucus membrane, it produces
a burning sensation as a result of C fiber activation. Repeated
application causes desensitization.79 Although
it is promoted for relief of arthritis pain, topical capsaicin has
been found useful for some types of neuropathic pain.79,80 Postmastectomy pain,
diabetic neuropathy, and postherpetic neuralgia may respond. Studies
have been complicated by difficulty in blinding because only the
active preparation causes a burning sensation. Capsaicin is available
over the counter in 0.25% and 0.75% concentrations
in a cream vehicle and a roll-on. The cream should be used four
to five times daily. Unfortunately, many patients do not persist
in applying the cream after the first few treatments because of
the uncomfortable burning.80
++
Corticosteroids are used as coanalgesics when inflammation or
the mass effect of vasogenic edema causes pain.81 They
reduce inflammation by inhibiting phospholipase activity, and thus prostaglandin
synthesis. In addition, they may reduce axonal sprouting and neurokinin
concentration in sensory fibers near injured tissue.82 Regenerating
axons in neuromas discharge spontaneously or with minimal tactile
stimulation because of high sodium channel expression83;
locally injected corticosteroids reduce neuroma discharge in animal
models, and appear to be effective in humans as well. Acute neural
compression, intracranial hypertension, bony and soft tissue infiltration,
and visceral distention cause pain that may respond to steroids.
++
Corticosteroid therapy for cancer pain usually includes dexamethasone,
4 to 8 mg, methylprednisolone, 8 to 40 mg, or prednisone 10 to 50
mg. Multiple daily doses are not needed, except for hydrocortisone.81 High
initial doses are continued until a response is seen, then tapered
to the minimum effective dose. Concurrent use of phenytoin, carbamazepine,
or phenobarbital induces hepatic metabolism of corticosteroids,
increasing the required dose. Dexamethasone may be given in very
high doses (40 to 100 mg intravenously) for the initial treatment
of spinal cord compression and for selected patients with other
causes of crescendo pain.
++
Corticosteroids have numerous toxicities when taken chronically.81 These
include fluid retention and electrolyte disturbances, hypertension,
proximal myopathy, osteoporosis and aseptic necrosis, insomnia,
psychosis, gastritis, hyperglycemia, and impaired cellular immunity.
These adverse effects may be undesirable in cancer patients who
are expected to survive for more than several months. Mood elevation,
antiemesis, and appetite stimulation are often desirable side effects
of corticosteroids, but they may diminish with prolonged use.81
+++
Sedatives and
Tranquilizers
++
Most benzodiazepines and barbiturates have no significant primary
analgesic effect, but may reduce anxiety associated with uncontrolled
pain and cancer. Clonazepam, when used for lancinating neuropathic
pain and myoclonus, may be an effective coanalgesic (See Sections
entitled Anticonvulsants, and Myoclonus and Hyperalgesia). Benzodiazepines
may also be effective for reducing muscle spasm, which may accompany
pain and spinal cord injury, and have a coanalgesic role in these
conditions. Lorazepam has been used to prevent nausea associated
with chemotherapy.
++
Phenothiazines have been used commonly in conjunction with opioids
for acute pain management. Although they have a tranquilizing effect,
only methotrimeprazine, which is no longer marketed, is analgesic
when used alone.84 Extrapyramidal side effects,
sedation, and hypotension make chronic phenothiazine use impractical
for cancer pain treatment. They are more often indicated in the
treatment of nausea and anxiety.
++
Most antihistamines are mild analgesics. The mechanism of analgesic
activity is unknown. Hydroxyzine (50 to 100 mg intramuscularly)
is commonly used in conjunction with opioids for acute pain. It
is also effective in cancer pain.85 These drugs
are most useful for their sedative, muscle relaxing, and antiemetic
properties, though opioids are more effective analgesics.
++
Pain from osteolytic metastases may be caused by bony destruction
alone or by neural or soft tissue compression by pathologic fracture.
Bisphosphonates and calcitonin are noncytotoxic agents that inhibit
osteoclast activity. They are often used for the management of hypercalcemia
of malignancy.86 They have also been found to reduce
bone pain from metastases, and may induce healing of lytic lesions.87 Calcitonin
also inhibits malignant osteolysis, and reduces bone pain in patients
with advanced, progressive disease.88
++
Calcitonin has also been investigated for the treatment of neuropathic
pain. The mechanism of analgesia is uncertain, but binding of calcitonin
in the hypothalamus and limbic system, areas rich in serotonin,
may have a role. A double-blind crossover study of intravenous salmon
calcitonin (200 μg) in 21 patients with acute phantom
limb pain showed a decrease in pain intensity and frequency with
calcitonin.89
++
Clonidine, an alpha2 receptor agonist, may contribute
to analgesia by stimulating presynaptic or postsynaptic receptors in
the superficial dorsal horn, decreasing sympathetic outflow, and
enhancing noradrenergic inhibitory fibers from the brain stem.90 These
mechanisms may make clonidine a useful analgesic adjuvant for opioids,
especially in the setting of neuropathic pain.91,92 Max
et al found a single dose of oral clonidine (200 μg) superior to
placebo, ibuprofen (800 mg), and codeine (120 mg) in the treatment
of postherpetic neuralgia.90 The epidural route
appears to be more effective than the systemic route for clonidine.92 Side
effects associated with clonidine include orthostatic hypotension,
sedation, dry mouth, and constipation. Clonidine does not appear
to aggravate opioid-induced respiratory depression, however.
++
Tizanidine is a newer alpha2 agonist that has been used
to treat pain associated with muscle spasm,93,94 and
neuropathic pain.95 Because it causes less hemodynamic
disturbance than clonidine, it may be more useful in treating debilitated
patients. Animal studies suggest that tizanidine is also effective
when administered intrathecally.96 Tizanidine,
like clonidine, produces sedation.