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For neuropathic pain, a combination of two common drugs works better than either one alone, researchers said.

In a randomized, blinded crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia had significantly less pain when they took the combination of nortriptyline and gabapentin than with either by itself, according to Ian Gilron, MD, of Queen's University in Kingston, Canada, and colleagues.

The finding, published online in The Lancet, suggests that patients who have a partial response to either medication should be put on the combination, Gilron and colleagues declared.

They added that future research should involve other drug combinations.

Nortriptyline is a second-generation, tricyclic antidepressant marketed under various brand names, while gabapentin (Neurontin) is an antiepileptic.

The two are first-line drugs for neuropathic pain, but the maximum tolerated doses rarely reduce pain by more than 60%, the researchers said, and only 40% to 60% of patients obtain relief, because of incomplete efficacy and side effects that limit dosing.

Previous research has indicated that a combination of morphine and gabapentin was better at pain relief than either by itself, so the researchers designed a trial to test gabapentin with nortriptyline.

Between Nov. 5, 2004, and Dec. 13, 2007, they enrolled 40 patients with diabetic polyneuropathy and 14 with postherpetic neuralgia in a single-center study.

Thee patients were randomized to gabapentin, nortriptyline, or the combination, and then crossed over to another medication after six weeks of treatment. After another six weeks, they were crossed over to the remaining treatment possibility.

All patients took an identical-appearing daily combination of orange and yellow capsules that could contain active drugs or placebo. During each treatment period, patients were titrated toward the maximum daily dose.

To be eligible for the trial, patients had to have daily pain of at least four on a scale from zero to 10 On average, daily pain was 5.4 for the 47 patients who completed the study.

The researchers found that, at the maximum tolerated dose:

• Average pain was 3.2 for gabapentin, 2.9 for nortriptyline, and 2.3 for the combination.
• Pain with the combination was significantly lower than with gabapentin at -0.9 (95% CI -1.4 to -0.3, P=0.001).
• Pain was also significantly lower with the combo than with nortriptyline at 0.6 (95% CI -1.1 to -0.1, P=0.02).
• The most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline or combination treatment (at P<0.0001 for both comparisons). There were no serious adverse events.

The study is "most welcome because improved treatment for patients with chronic types of pain is urgently needed," argued Troels Staehelin Jensen, MD, and Nanna Brix Finnerup, MD, both of Aarhus University Hospital in Aarhus, Denmark.

Writing in an accompanying comment article, they said less than two thirds of patients with chronic pain get sufficient relief with current drugs.

"Multifaceted" treatment makes sense, they said, but "surprisingly few attempts" have been made to use such an approach.

In this case, they said, it is known that tricyclic antidepressants have several mechanisms that differ from those used by gabapentin. The idea of using them together "is, therefore, a logical step forward."