Combination treatment using gabapentin and nortriptyline reduces neuropathic pain more than either drug alone, and thus could be used in patients that only partially respond to one drug or the other. These are the conclusions of an Article published Online First (www.thelancet.com) and in an upcoming edition of The Lancet. The Article is written by Professor Ian Gilron, Director of Clinical Pain Research, Queen's University, and Kingston General Hospital, Kingston, ON, Canada, and colleagues.
Neuropathic pain has been described as pain ''initiated or caused by a primary lesion or dysfunction in the nervous system'', and affects more than 2% 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) – nerve pain caused by the varicella zoster virus which can follow an outbreak of shingles. Gabapentin (an anticonvulsant) and nortriptyline (an antidepressant) are two of several first line drugs with the most favourable therapeutic profiles. However, when given as monotherapy, the maximum tolerated doses of these drugs rarely reduce pain by more than 60% and provide relief in only 40% of patients because of incomplete efficacy and dose-limiting side-effects. In this study, the authors assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone.
In this randomised controlled trial, 56 patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0), 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 sequence, a different drug was given to each randomised group in three treatment periods. In this trial (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 6-week treatment periods, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose.
The researchers found 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 significantly lower than with gabapentin (•9) or nortriptyline alone (•6). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline or combination treatment. No serious adverse events were recorded for any patients during the trial.
The authors conclude: "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 accompanying Comment, Dr Troels Staehelin Jensen, Department of Neurology, Aarhus University Hospital, and Dr Nanna Brix Finnerup, Danish Pain Research Center, Aarhus University Hospital, Denmark, describe Gilron and colleagues' idea to use the two drugs in this way as 'a logical step forward'.
Professor Ian Gilron, Director of Clinical Pain Research, Queen's University and Kingston General Hospital, Kingston, ON, Canada. T) +1 613-549-6666 ext. 3963 E) gilroni@queensu.ca
Dr Troels Staehelin Jensen, Department of Neurology, Aarhus University Hospital, Denmark. T) +45 2616 7042 E) tsjensen@ki.au.dk
For full Article and Comment, see: http://press.thelancet.com/neuropain.pdf
Journal
The Lancet