Saturday, October 3, 2009

Drug Combo Helps Relieve Neuropathic Pain

Pharmacotherapy for neuropathic pain may have incomplete efficacy and dose-limiting side effects when given as monotherapy. A new study by Canadian researchers found that combination treatment using the anticonvulsant gabapentin and the tricyclic antidepressant nortriptyline was significantly more effective and better tolerated than treatment with either drug alone.

The study, reported in The Lancet, enrolled 56 patients with postherpetic neuralgia or diabetic polyneuropathy who had a daily pain score of at least 4 on a 0 to 10 scale [Gilron et al. 2009]. They were randomly selected to be given gabapentin alone, nortriptyline alone, or both drugs. In a cross-over design, all subjects received each type of treatment for a period of 6 weeks (during which time drugs were titrated toward maximum tolerated doses). At the start of the study, the average daily pain level among participants was 5.4.

At study completion, 47 patients were analyzed for the primary outcome of mean daily pain relief. At maximum tolerated medication doses, average daily pain levels were 3.2 while patients were taking gabapentin, 2.9 while taking nortriptyline, and 2.3 while taking the combination treatment. Pain levels with combination treatment were significantly lower than with gabapentin (p=0.001) or nortriptyline alone (p=0.02). At maximum tolerated dose, the most common side effect was dry mouth, which was significantly less frequent with gabapentin than nortriptyline or combination treatment. No serious adverse events were recorded for any patients during the trial. Finally, in a Eureka Alert news report, lead investigator Ian Gilron, MD, observes, "It was also exciting to discover the effect of this combination on sleep interference"; patients rated sleep interference with the combined drugs as 1.0 on a scale of 10, compared with 2.2 when they took each drug individually. "That's a very important issue for this group of patients, whose debilitating, unrelenting pain often interferes with normal sleep."

Commentary: This study, funded by the Canadian Institutes of Health Research, suggests that combination therapies may be preferred over monotherapies for neuropathic pain. For example, an industry-sponsored meta-analysis of monotherapies for diabetic peripheral neuropathic pain reported last winter found gabapentin, pregabalin, and duloxetine were all comparable in effectiveness and superior to placebo [Quilici et al. 2009]; however, the magnitudes of effectiveness were less than combination therapy in the present study by Gilron and colleagues. Also of interest, average baseline pain scores among participants in the Gilron et al. study were moderate, which usually makes it more difficult to show dramatic improvements with pharmacotherapies; therefore, the 57% pain-score reduction with combination therapy was noteworthy, and the study was well-powered to demonstrate such effects. The researchers state, "Although development of more effective and better-tolerated monotherapies is much anticipated, our findings suggest that drug combinations represent the most effective strategy for many patients with neuropathic pain.” And, while this investigation focuses on diabetic neuropathy and postherpetic neuralgia, Gilron suggests that the methodology could also be applied to the study of other chronic conditions such as cancer-related pain, spinal disk disease, and the pain experienced after chemotherapy and mastectomies.

> Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. The Lancet. Early Online Publication, September 30, 2009 [
abstract here].
> Quilici S, Chancellor J, Lothgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurology. 2009;9(6). [Full article
available here.]