The last decade has seen a dramatic increase in the availability of
nonopioid analgesics for the management of chronic pain. The change has
been especially great in the area of adjuvant analgesics, the diverse group
of drugs that have other primary indications but, in certain circumstances,
Dr. Russell K. Portenoy, md, co-chief of the Pain and Palliative Care
Service at Memorial Sloan-Kettering Cancer Center, provided an overview
of adjuvant analgesics at a recent conference on chemical dependence and
pain management in New York City. "The term 'adjuvant' is really a
misnomer because in many clinical settings these drugs are used as primary
analgesics, and they are not adjuvant to anything," Dr. Portenoy said.
The group includes antidepressants, anticonvulsants, local anesthetics,
and other types of drugs. They can be divided into categories based on
the way they are conventionally used, he said. "There are multipurpose
analgesics. There are also drugs that are typically used for neuropathic
pain. There are drugs that are typically used for musculoskeletal pain,
and drugs that have found particular use in the cancer pain population."
The multipurpose analgesics, including antidepressants, alpha-2-adrenergic
agonists, and corticosteroids, have been shown to provide relief for a
variety of pain syndromes. The tricyclic antidepressants have demonstrated
analgesic efficacy in controlled clinical trials evaluating populations
with low back pain, headaches, arthritis, cancer pain, painful diabetic
neuropathies, central pain, fibromyalgia, and psychogenic pain, Dr. Portenoy
The best studied drugs by far are the tricyclic antidepressants, and
the two best-studied tricyclics are amitriptyline and desipramine. Amitriptyline
is a tertiary amine tricyclic drug with both serotonergic and noradrenergic
effects and a relatively bad side effect profile because of its anticholinergic
and sedative toxicities, Dr. Portenoy noted. Desipramine, a secondary amine
tricyclic antidepressant, is predominantly a noradrenergic compound. "Although
it has a much better toxicity profile than does amitriptyline, in head
to head comparisons, the data would suggest that you have a greater likelihood
of getting analgesia with the tertiary amine tricyclics."
Serotonin-selective reuptake inhibitors, such as fluoxetine (Prozac),
paroxetine (Paxil), sertraline (Zoloft), and venlafaxine (Effexor), have
a safety profile that exceeds the tricyclic antidepressants, even the secondary
amine tricyclic antidepressants. But they have not been well studied in
terms of pain, Dr. Portenoy said. "There have been controlled trials
that have suggested that fluoxetine and paroxetine are, indeed, analgesic
for neuropathic pain, but it's limited to one controlled trial per drug."
Thus, for pain, he recommended using a tricyclic antidepressant (amitriptyline
or desipramine) if it were thought that the patient could tolerate such
a drug. In cases where the patient might be unable to tolerate any tricyclic,
paroxetine or fluoxetine might be appropriate.
When using a tricyclic, Dr. Portenoy advised starting patients on a
low initial dose and gradually escalating the dose until benefit occurs,
the patient experiences toxic effects like sedation, or the antidepressant
dose is reached. He suggested measuring the drug's concentration in the
blood, particularly as the dose approaches the antidepressant range. "In
my own personal experience, the major reason that antidepressants fail
as analgesics is because of the tendency not to push the dose high enough,"
Many patients require doses in the antidepressant range, eg, above 150
mg of amitriptyline, to experience analgesic effects, he said. "There
are data suggesting that there are concentration-dependent effects for
these drugs. So what I would suggest is that dose escalation continue until
one of these end points occurs."
The alpha-2-adrenergic agonists, limited in this country to clonidine,
are, in fact, multipurpose analgesics, Dr. Portenoy noted. Clonidine has
been shown to relieve postoperative pain, neuropathic pain, and headache.
When given intrathecally, clonidine has been shown to lessen cancer pain,
with a greater efficacy in neuropathic cancer pain.
"One could consider using clonidine for any patient with chronic
pain, either by giving them tablets or a patch, starting at the lowest
possible dose and gradually escalating to limiting side effects, which
usually are sedation, dry mouth, and, rarely, orthostatic hypotension,"
Anticonvulsants have been used for a long time for lancinating or paroxysmal
neuropathic pain, Dr. Portenoy said. Experience is greatest with carbamazepine,
but there is also experience with phenytoin, valproate, and clonazepam
(Klonopin), and growing anecdotal experience with gabapentin (Neurontin),
which is being studied in controlled trials in several pain syndromes.
As an alternative to an anticonvulsant for the treatment of lancinating
pain, the clinician may want to consider using baclofen, a gamma-aminobutyric
acid (GABA) agonist with proven efficacy in trigeminal neuralgia that is
now used for any lancinating pain. As with the antidepressants, baclofen
should be started at a low dose so that patients can better tolerate it,
but then the dose should be escalated until efficacy or dose-limiting toxicity
"Again, in my experience, the major reason for the failure of baclofen
to afford some relief is that clinicians don't aggressively push the dose
high enough. Doses sometimes have to go above 160 or even 200 mg before
some patients with lancinating or paroxysmal pain get relief," Dr.
Local anesthetics represent another very important advance in the treatment
of chronic neuropathic pain in this country. In the United States, mexiletine
(Mexitil) is preferred because it has a better toxicity profile than tocainide
(Tonocard) and flecainide (Tambocor). Both mexiletine and tocainide, which
are on the market as antiarrhythmics, have potential cardiac toxicity,
and significant cardiac disease is a contraindication.
The mexiletine dose is started low and gradually increased to the usual
dose of 300 mg tid. Plasma concentrations can be monitored commercially
to ensure that the dose is not approaching the toxic level, he said.
Infusing a local anesthetic intravenously is a technique that was used
for many decades and is being "rediscovered" lately, Dr. Portenoy
said. Local anesthetics have been demonstrated to provide analgesia for
diverse pain syndromes, including postoperative pain and headache. He predicted
that more uses will become accepted in the future.
In conventional practice, local anesthetics are being infused for neuropathic
pain. Pain relief following infusion can persist for a long period, and
some patients are treated with repeated infusions on a weekly or biweekly
basis, Dr. Portenoy noted.
The largest experience of this type is with lidocaine, and, generally,
it has been infused after other oral therapies fail, Portenoy said. Lidocaine
has been given at a dose somewhere between 2 to 5 mg/kg over 30 minutes.
Dr. Portenoy and colleagues at Sloan-Kettering recently developed IV guidelines
for use of this drug in cancer patients who have crescendo neuropathic
pain, ie, rapidly progressive severe neuropathic pain. Patients will receive
repeated infusions every 2 hours, starting at 1/2 mg/kg; then the dose
will be increased gradually every 1 to 2 hours in an attempt to find out
whether this therapy will work.
"There is evidence that there may be a threshold plasma concentration
associated with relief from this local anesthetic infusion," Dr. Portenoy
said. "There is very little relief until a certain point is passed
and then relief occurs rapidly."
NMDA Receptor Antagonists
Dr. Portenoy also spoke about the possibility that antagonists of the
N-methyl-d-aspartate receptor may be analgesic. The NMDA receptor is an
important receptor in the processing of nociceptive information in the
spinal cord. "There's evidence that blockers of this receptor are
antinociceptive in animal models....Case reports suggest that dextromethorphan
and ketamine [Ketalar], two commercially available NMDA antagonists, are
Currently, NMDA receptor antagonists are being used for refractory neuropathic
pain, Dr. Portenoy said. "IV ketamine is used in an inpatient setting
with cancer pain in the crescendo pain pattern. In our own anecdotal experience,
it's been a favorable approach." Ketamine can be administered as a
brief or prolonged infusion.
Dr. Portenoy also noted that oral dextromethorphan cough syrup can be
commercially obtained without alcohol or other compounds. The analgesic
dose reported in the literature ranges from 400 to 450 mg/d, and doses
as high as 1 g/d have been given.
"Unfortunately, when you try to give this kind of dose of cough
syrup to a patient, they often get a little disgusted. So everybody is
anxiously awaiting dextromethorphan and other NMDA receptor antagonists
in formulations that allow us to give these high doses in a more palatable
Topical Analgesics and Muscle Relaxants
Topical analgesics are also important to remember, Dr. Portenoy said,
and he described the use of an anesthetic creme called EMLA that can produces
a dense cutaneous anesthesia and has been used to treat peripherally based
pains. There is also a good evidence that capsaicin, which has been around
for a long time, provides relief for small joint arthropathy. This topical
compound has also been used for neuropathic pain, with mixed results.
Finally, the muscle relaxant drugs, including cyclobenzaprine, methocarbamol,
and orphenadrine, "are effective analgesics for acute musculoskeletal
pains," Dr. Portenoy noted. However, these agents also have sedative
and anticholinergic side effects, he warned, and there is evidence that
some patients can misuse them. Thus, use of these agents must be monitored