Use of Adjuvent Analgesics Profiled at Pain Conference

The last decade has seen a dramatic increase in the availability ofnonopioid analgesics for the management of chronic pain. The change hasbeen especially great in the area of adjuvant analgesics, the diverse groupof drugs that have other primary indications but, in certain circumstances,provide analgesia.

Dr. Russell K. Portenoy, md, co-chief of the Pain and Palliative CareService at Memorial Sloan-Kettering Cancer Center, provided an overviewof adjuvant analgesics at a recent conference on chemical dependence andpain management in New York City. "The term 'adjuvant' is really amisnomer because in many clinical settings these drugs are used as primaryanalgesics, 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 onthe way they are conventionally used, he said. "There are multipurposeanalgesics. There are also drugs that are typically used for neuropathicpain. 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-adrenergicagonists, and corticosteroids, have been shown to provide relief for avariety of pain syndromes. The tricyclic antidepressants have demonstratedanalgesic efficacy in controlled clinical trials evaluating populationswith low back pain, headaches, arthritis, cancer pain, painful diabeticneuropathies, central pain, fibromyalgia, and psychogenic pain, Dr. Portenoysaid.

Antidepressants

The best studied drugs by far are the tricyclic antidepressants, andthe two best-studied tricyclics are amitriptyline and desipramine. Amitriptylineis a tertiary amine tricyclic drug with both serotonergic and noradrenergiceffects and a relatively bad side effect profile because of its anticholinergicand sedative toxicities, Dr. Portenoy noted. Desipramine, a secondary aminetricyclic antidepressant, is predominantly a noradrenergic compound. "Althoughit has a much better toxicity profile than does amitriptyline, in headto head comparisons, the data would suggest that you have a greater likelihoodof getting analgesia with the tertiary amine tricyclics."

Serotonin-selective reuptake inhibitors, such as fluoxetine (Prozac),paroxetine (Paxil), sertraline (Zoloft), and venlafaxine (Effexor), havea safety profile that exceeds the tricyclic antidepressants, even the secondaryamine tricyclic antidepressants. But they have not been well studied interms of pain, Dr. Portenoy said. "There have been controlled trialsthat have suggested that fluoxetine and paroxetine are, indeed, analgesicfor neuropathic pain, but it's limited to one controlled trial per drug."

Thus, for pain, he recommended using a tricyclic antidepressant (amitriptylineor desipramine) if it were thought that the patient could tolerate sucha 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 alow initial dose and gradually escalating the dose until benefit occurs,the patient experiences toxic effects like sedation, or the antidepressantdose is reached. He suggested measuring the drug's concentration in theblood, particularly as the dose approaches the antidepressant range. "Inmy own personal experience, the major reason that antidepressants failas analgesics is because of the tendency not to push the dose high enough,"he said.

Many patients require doses in the antidepressant range, eg, above 150mg of amitriptyline, to experience analgesic effects, he said. "Thereare data suggesting that there are concentration-dependent effects forthese drugs. So what I would suggest is that dose escalation continue untilone of these end points occurs."

Alpha-2-Adrenergic Agonists

The alpha-2-adrenergic agonists, limited in this country to clonidine,are, in fact, multipurpose analgesics, Dr. Portenoy noted. Clonidine hasbeen 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 chronicpain, either by giving them tablets or a patch, starting at the lowestpossible dose and gradually escalating to limiting side effects, whichusually are sedation, dry mouth, and, rarely, orthostatic hypotension,"he advised.

Anticonvulsants

Anticonvulsants have been used for a long time for lancinating or paroxysmalneuropathic 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 lancinatingpain, the clinician may want to consider using baclofen, a gamma-aminobutyricacid (GABA) agonist with proven efficacy in trigeminal neuralgia that isnow used for any lancinating pain. As with the antidepressants, baclofenshould 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 toxicityoccurs.

"Again, in my experience, the major reason for the failure of baclofento afford some relief is that clinicians don't aggressively push the dosehigh enough. Doses sometimes have to go above 160 or even 200 mg beforesome patients with lancinating or paroxysmal pain get relief," Dr.Portenoy said.

Local Anesthetics

Local anesthetics represent another very important advance in the treatmentof 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, whichare 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 usualdose of 300 mg tid. Plasma concentrations can be monitored commerciallyto ensure that the dose is not approaching the toxic level, he said.

Infusing a local anesthetic intravenously is a technique that was usedfor many decades and is being "rediscovered" lately, Dr. Portenoysaid. Local anesthetics have been demonstrated to provide analgesia fordiverse pain syndromes, including postoperative pain and headache. He predictedthat more uses will become accepted in the future.

In conventional practice, local anesthetics are being infused for neuropathicpain. Pain relief following infusion can persist for a long period, andsome patients are treated with repeated infusions on a weekly or biweeklybasis, 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. Lidocainehas 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 guidelinesfor use of this drug in cancer patients who have crescendo neuropathicpain, ie, rapidly progressive severe neuropathic pain. Patients will receiverepeated infusions every 2 hours, starting at 1/2 mg/kg; then the dosewill be increased gradually every 1 to 2 hours in an attempt to find outwhether this therapy will work.

"There is evidence that there may be a threshold plasma concentrationassociated with relief from this local anesthetic infusion," Dr. Portenoysaid. "There is very little relief until a certain point is passedand then relief occurs rapidly."

NMDA Receptor Antagonists

Dr. Portenoy also spoke about the possibility that antagonists of theN-methyl-d-aspartate receptor may be analgesic. The NMDA receptor is animportant receptor in the processing of nociceptive information in thespinal cord. "There's evidence that blockers of this receptor areantinociceptive in animal models....Case reports suggest that dextromethorphanand ketamine [Ketalar], two commercially available NMDA antagonists, areanalgesic."

Currently, NMDA receptor antagonists are being used for refractory neuropathicpain, Dr. Portenoy said. "IV ketamine is used in an inpatient settingwith cancer pain in the crescendo pain pattern. In our own anecdotal experience,it's been a favorable approach." Ketamine can be administered as abrief or prolonged infusion.

Dr. Portenoy also noted that oral dextromethorphan cough syrup can becommercially obtained without alcohol or other compounds. The analgesicdose reported in the literature ranges from 400 to 450 mg/d, and dosesas high as 1 g/d have been given.

"Unfortunately, when you try to give this kind of dose of coughsyrup to a patient, they often get a little disgusted. So everybody isanxiously awaiting dextromethorphan and other NMDA receptor antagonistsin formulations that allow us to give these high doses in a more palatableway."

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 producesa dense cutaneous anesthesia and has been used to treat peripherally basedpains. There is also a good evidence that capsaicin, which has been aroundfor a long time, provides relief for small joint arthropathy. This topicalcompound 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 musculoskeletalpains," Dr. Portenoy noted. However, these agents also have sedativeand anticholinergic side effects, he warned, and there is evidence thatsome patients can misuse them. Thus, use of these agents must be monitoredcarefully.