An article published Online First and in a future edition of The Lancet reports that combination treatment using gabapentin and nortriptyline reduces neuropathic pain more than either drug alone. This treatment could be used in patients that only partly respond to one drug or the other. The article is the work of Professor Ian Gilron, Director of Clinical Pain Research, Queen’s University, and Kingston General Hospital, Kingston, Ontario, Canada, and colleagues.
Neuropathic pain has been defined as pain “initiated or caused by a primary lesion or dysfunction in the nervous system.” It affects more than 2 to 3 percent of the general population. Disorders causing neuropathic pain include nerve problems in the spine; diabetic polyneuropathy, in which damage to blood vessels in diabetes also causes damage to nerves; and postherpetic neuralgia (PHN) which is a nerve pain caused by the varicella zoster virus which can follow an outbreak of shingles. Gabapentin is an anticonvulsant and nortriptyline is an antidepressant. They are two of several first line drugs with the most positive therapeutic profiles. However, when given as monotherapy, the maximum tolerated doses of these drugs hardly ever reduce pain by more than 60 percent. In addition, they provide relief in only 40 to 60 percent of patients because of partial efficacy and dose-limiting side-effects. The authors in this study evaluated the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone.
A total of 56 patients with diabetic polyneuropathy or postherpetic neuralgia were included in this randomised controlled trial. They had a daily pain score of at least 4 (scale 0 to 10) and were enrolled and treated at one site in Canada between November 2004 and December 2007. Patients were assigned in a 1:1:1 ratio to one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In series, a different drug was given to each randomised group in three treatment periods. This trial is referred to as a ‘crossover’ design. All patients get to try all three treatments and each patient serves as his/her own control. During each of three six-week treatment periods, drug doses were gradually increased towards maximum tolerated dose. The primary outcome was an average daily pain at maximum tolerated dose.
Results indicated that 45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain was 5•4 at baseline, and at maximum tolerated dose, pain was 3•2 for gabapentin, 2•9 for nortriptyline, and 2•3 for combination treatment. Pain with combination treatment was considerably lower than with gabapentin (-0•9) or nortriptyline alone (-0•6). At maximum tolerated dose, the most frequent adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline or combination treatment. During the trial, there were no serious adverse events recorded for any patients.
The authors write in conclusion: “This trial shows that combination of an antidepressant and an anticonvulsant drug seems to be superior to monotherapy for neuropathic pain… 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. On the basis of our results, we recommend combined gabapentin and nortriptyline for patients who have a partial response to either drug alone and seek additional pain relief.”
In an associated note, Dr Troels Staehelin Jensen, Department of Neurology, Aarhus University Hospital, and Dr Nanna Brix Finnerup, Danish Pain Research Center, Aarhus University Hospital, Denmark, define Gilron and colleagues’ proposal to use the two drugs in this way as ‘a logical step forward’.
“Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial”
Ian Gilron, Joan M Bailey, Dongsheng Tu, Ronald R Holden, Alan C Jackson, Robyn L Houlden
Written by Stephanie Brunner (B.A.)