The treatment sequences used in the study were:
(a) gabapentin and placebo; gabapentin and nortriptyline; nortriptyline and placebo,
(b) nortriptyline and placebo; gabapentin and placebo; gabapentin and nortriptyline, and
(c) gabapentin and nortriptyline; nortriptyline and placebo; gabapentin and placebo.
In a double-blind crossover trial, 56 patients with diabetic polyneuropathy or post-herpetic neuralgia were randomly allocated to one of three possible treatment sequences. Treatments in each sequence were given consecutively, and each lasted for six weeks during which drug doses were titrated towards a maximum tolerated dose (MTD).
The study’s primary outcome was pain intensity on a scale of 1–10 rated three times daily, with a mean taken over seven days at the MTD (days 25–31 of each treatment). The analysis included data for the 47 patients who completed at least two treatment periods. Secondary outcomes included MTD of the study drug, patient-reported nocturnal pain and adverse events.
The mean daily pain intensity at the MTD was lower with combination treatment than with gabapentin (pain intensity rating –0.9, 95 per cent confidence interval –1.4 to –0.3) or nortriptyline (pain intensity rating –0.6, 95 per cent CI –1.1 to –0.1) alone.
Combination treatment also produced a 52.8 per cent reduction in pain intensity — which was greater than the reduction associated with gabapentin (38.8 per cent; P=0.01) or nortriptyline (31.1 per cent; P=0.0002) monotherapy — and reduced sleep interference and nocturnal pain compared with either drug administered alone.
The frequency of adverse events at MTD was similar for all three treatments.
“Our findings suggest that drug combinations represent the most effective strategy for many patients with neuropathic pain,” conclude the study authors. They recommend combined treatment for patients who have a partial response to either drug alone — but warn that it might not be possible to extend the trial results to all combinations of antidepressants and anticonvulsants, or to all neuropathic pain disorders.