American Pain Society
19th Annual Meeting
Zahid H. Bajwa, MD
As our understanding of the complex mechanisms of neuropathic pain grows, it is becoming clear that numerous pathways, receptors, and neurotransmitters underlie the phenomenon and, thus, expecting a single drug, whatever the drug, to provide complete relief of neuropathic pain is entirely unrealistic. In a noteworthy symposium at the 19th annual meeting of the American Pain Society, James Eisenach, MD, Wake Forest University, Winston-Salem, North Carolina, Mitchell Max, MD, National Institutes of Health, Bethesda, Maryland, and Michael Rowbotham, MD, University of California at San Francisco discussed approaches toward a rational polypharmacy for patients with neuropathic pain. Robert Dworkin, PhD, University of Rochester, New York, moderated the discussion.
These presenters reviewed the multiple neurobiologic and chemical pathways involved in specific neuropathic pain syndromes including postherpetic neuralgia, diabetic neuropathy, and complex regional pain syndromes (previously known as causalgia and reflex sympathetic dystrophy). They noted that each of these syndromes probably involves at least several mechanisms, hence explaining the variable and usually incomplete response to any single therapeutic agent.
Based on clinically and statistically significant randomized, controlled studies, gabapentin and tricyclic antidepressants seem to be most efficacious in the treatment of painful diabetic neuropathy and postherpetic neuralgia but none of the studied antidepressant or antiepileptic agents has provided complete analgesia as a single agent for any of the above neuropathic pain syndromes.
Fortunately, a polypharmaceutical approach to treating neuropathic pain is well within our reach, with research on compounds with a variety of mechanisms of action well represented at this meeting. Several new drugs have been marketed over recent years, most notably anticonvulsants, which could be potentially useful in a variety of neuropathic pain syndromes.
The practical message to clinicians is that, for patients with unsatisfactory relief from monotherapy, we should use our growing understanding of pain mechanisms and proven/potential analgesics to combine neuropathic analgesics that have different and potentially synergistic mechanisms.
Drawing on studies[2,3] suggesting a role for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA-KA) receptors in pain processing, Ian Gilron, MD, MSc, and colleagues from the National Institutes of Health, examined the effects of topiramate, an orally available anticonvulsant that blocks kainate-specific currents, on trigeminal neuralgia.
As discussed by Dr. Max in the symposium on rational polypharmacy, this very small study (N = 3) used a multiple crossover design comparing 12 weeks of topiramate therapy with placebo in the main study. Patients who responded to topiramate were then enrolled in a confirmatory study comprising 3 pairs of topiramate-placebo crossovers. This kind of study design may compensate for the traditionally low recruitment rates for studies for relatively rare pain syndromes and allows for "a more cautious" interpretation of study results than if the main study alone was considered.
In the main study, all 3 patients experienced pain relief; reductions of pain ranged from 5% to 87% (mean pain reduction, 46%). However, in the confirmatory study, pain relief was less significant, and the pooled results showed a mean pain reduction of 12%. Larger trials are needed to assess the efficacy of topiramate for trigeminal neuralgia.
In a related study, Michael Haugh, MD, and Gregory Connor, MD, from the Headache and Neurological Center in Tulsa, Oklahoma, conducted a retrospective analysis of all patients (N = 8) at their center who had been treated with topiramate for trigeminal neuralgia. Patients had experienced their pain for 1 to 16 years; 5 of the patients had been treated unsuccessfully with other drugs, including gabapentin (n = 2), carbamezepine (n = 1), phenytoin (n = 1), and baclofen (n = 1).
Four patients taking topiramate monotherapy and 2 taking topiramate plus carbamezepine reported good to excellent pain relief. Two patients discontinued topiramate -- 1 because of nausea and dizziness at a dose of 25 mg, and another for personal reasons.
Clonidine Topical Gel
The search for a medication providing pain relief without producing systemic side effects has been buoyed by studies showing that the topical lidocaine patch exerts significant effects on a variety of neuropathic pain syndromes.[6,7] Clonidine is an alpha2-adrenergic receptor agonist used for treating hypertension. The gel has also been found to produce a localized concentration-dependent analgesia.
Sherwyn Schwartz, MD, and colleagues from Albert Einstein College of Medicine, Bronx, NY, studied the safety and analgesic effect of topical clonidine gel for the treatment of pain in 10 patients with chronic diabetic neuropathy. Patients applied 0.05% clonidine gel to each foot/leg twice daily for 2 weeks, and then gradually increased the dosing frequency to 4 times daily until the end of the 6-week study. Patients were evaluated at enrollment and at 2, 4, and 6 weeks, rating their pain on an 11-point pain scale ranging from 0 (no pain) to 10 ("pain as bad as it could be.")
At the end of the study, all patients reported some pain relief, with 3 patients claiming complete relief and 7 moderate relief. Adverse events were mild, suggesting minimal systemic absorption of the drug.
Zonisamide is another anticonvulsant drug that may be useful in relieving neuropathic pain. The drug exerts its antiepileptic effects through sodium and calcium channel blockade as well as through dopaminergic and serotonergic activity. It has been found useful for relieving pain in animal models of neuropathic pain.[9,10]
Bradley Galer, MD, Beth Israel Medical Center in New York City, and Misha Ba ckonja, MD, University of Wisconsin Hospitals in Madison, are conducting a study to determine appropriate dose ranges and evaluate the safety of the drug in humans with neuropathic pain.
Thus far, 13 patients with neuropathic pain have been enrolled in this ongoing study. Doses were started at 25mg daily or every other day, according to patient weights, and were increased weekly until week 8 or maximum tolerated dose. Four patients have dropped out, 1 because of lack of efficacy of the drug, 1 for noncompliance, and 2 for adverse events not related to the study drug. Zonisamide has been well tolerated up to doses of 300 mg. Adverse events were primarily mild and most were not felt to be related to the zonisamide.
In this pilot study, zonisamide was considered safe and well tolerated at doses 25-300 mg daily. Larger studies to determine the efficacy, analgesic dose-range and safety of this drug for treating neuropathic pain are under way.
In another retrospective analysis, Dr. Connor from the Headache and Neurological Center in Tulsa, Oklahoma, identified 20 patients with neuropathic pain who had been treated with topiramate. Etiologies included diabetes (n = 12), Guillain Barre syndrome (n = 1), and idiopathic causes (n = 7). In some cases, pain had been intractable to treatment with gabapentin, amitriptyline, and carbamezepine.
At a mean dose of topiramate 260 mg/d, 3 patients experienced complete pain relief, 9 had an excellent response, and 5 a good response. Five patients discontinued the drug; 4 because of adverse events and 1 after experiencing no pain relief.
Studies evaluating efficacy and safety of pregabalin in treating neuropathic pain represent the most comprehensive and methodologically sound data of any pharmacologic agents presented at this meeting.
Two studies[13,14] conducted by Uma Sharma, MD, and colleagues from the Parke-Davis Pharmaceutical Research group examined relief of neuropathic pain by pregabalin, a synthetic GABA analog. These researchers set out to determine the relationship between neural function and pain relief associated with pregabalin, and to evaluate the safety and efficacy of pregabalin for the treatment of painful diabetic neuropathy.
In 2 safety and efficacy studies 584 patients with diabetic neuropathy of 1 to 5 years' duration were randomized to receive pregabalin or placebo 3 times daily. Patients had a weekly pain score rating of at least 4 on an 11-point scale. Compared with placebo, pregabalin 300 mg/d and 600 mg/d reduced endpoint weekly mean pain scores significantly. The drug likewise proved more effective than placebo on other measures, including sleep interference scores and the SF McGill Pain Questionnaire. Adverse events were mild to moderate dizziness and somnolence; 31 patients withdrew because of adverse events.
In another analysis of these studies, investigators asked whether there was a relationship between neural function and pain relief in patients taking pregabalin for painful diabetic neuropathy. The pooled data set totaled 549 patients. The group found that pregabalin significantly reduced pain in patients with diabetic neuropathy and that these reductions were not associated with worsening neuropathy (as assessed by neuropathy scores). Thus, they concluded that pregabalin is not toxic to peripheral nerves, that the analgesic effect is not related to an acceleration of the neuropathy, and that no direct relationship exists between pain and neural function in patients with diabetic neuropathy.