Combined treatment with gabapentin and nortriptyline improves pain control in peripheral neuropathy more than either agent alone

OBJECTIVE: To determine whether gabapentin, nortriptyline, the combination, or both are better for treatment of neuropathic pain. DESIGN: Double-blind, randomized controlled, crossover trial. SETTING AND PARTICIPANTS: 56 patients at 1 site with diabetic polyneuropathy or postherpetic neuralgia with a pain score of at least 4 on a 0–10 scale. Patients were randomized in a balanced Latin square design in equal proportions. All subjects received each of the 3 treatments for 6 weeks at a time—gabapentin alone, nortriptyline alone, or gabapentin and nortriptyline in combination—according to a sequence designated by the randomization. Exclusion criteria included abnormal laboratory values (creatinine, alanine aminotransferase), evidence of neuropathy or other significant pain from another cause, major organ system disease, hypersensitivity to the drugs used in the trial, and symptoms commonly found as side effects from the medications being used in the trial. MAIN OUTCOME MEASURES: Mean daily pain at the maximum tolerated dose of the drug. MAIN RESULTS: Most of the patients (71%) had diabetic polyneuropathy. Demographic details of patients were reported separately for diabetic polyneuropathy and postherpetic neuralgia patients. Respectively, the mean age of subjects was 61 and 68 years, 35% and 44% were women, and 20% and 25% were using opiates. 47 patients completed at least 2 treatment periods, and 45 completed all periods. Mean daily pain at baseline was 5.4 (95% confidence interval [CI], 5.0–5.8). Treatment with any of the medication regimens improved pain control compared to baseline (P = 0.004). There was no significant effect from the treatment period or treatment sequence in the main analysis. Pain was lower with the combination treatment than with either individual agent alone. With combined therapy, mean daily pain was –0.9 lower (95% CI, –1.4 to –0.3; P = 0.001) compared with gabapentin and –0.6 lower (95% CI, –1.1 to –0.1; P = 0.02) compared with nortriptyline. Moderate to severe dry mouth was higher in both the combined and nortriptyline periods than the gabapentin period. Depression was higher in the nortriptyline period compared with the combination period, and vitality was lower compared with the combination and gabapentin periods. The maximum tolerated dose of gabapentin and nortriptyline were 2180 mg (standard deviation, SD 108) and 50.1 mg (standard deviation, SD 3.5) when the medications were used in combination. The maximum tolerated dose of medications was significantly higher when used alone. CONCLUSION: The combination of nortriptyline and gabapentin decreases pain more than either medication alone in the treatment of neuropathic pain from diabetic polyneuropathy or postherpetic neuralgia.