Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a d

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Comment in: Lancet. 2009 Oct 10;374(9697):1218-9.

Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a

double-blind, randomised controlled crossover trial.

Gilron I, JM, Tu D, Holden RR, AC, Houlden RL.

Department of Anesthesiology, Queen's University, Kingston, ON, Canada.

BACKGROUND: Drugs for neuropathic pain have incomplete efficacy and

dose-limiting side-effects when given as monotherapy. We assessed the efficacy

and tolerability of combined nortriptyline and gabapentin compared with each

drug given alone.

METHODS: In this double-blind, double-dummy, crossover trial, patients with

diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain

score of at least 4 (scale 0-10), were enrolled and treated at one study site in

Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a

1:1:1 ratio with a balanced Latin square design to receive 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. During each 6-week treatment period, drug doses were titrated

towards maximum tolerated dose. The primary outcome was mean daily pain at

maximum tolerated dose. Analysis was by intention to treat. This trial is

registered, number ISRCTN73178636.

FINDINGS: 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 (0-10; numerical rating scale) was 5.4 (95% CI 5.0 to

5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (2.5 to 3.8) for

gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for

combination treatment.

Pain with combination treatment was significantly lower than with gabapentin

(-0.9, 95% CI -1.4 to -0.3, p=0.001) or nortriptyline alone (-0.6, 95% CI -1.1

to -0.1, p=0.02). At maximum tolerated dose, the most common adverse event was

dry mouth, which was significantly less frequent in patients on gabapentin than

on nortriptyline (p<0.0001) or combination treatment (p<0.0001). No serious

adverse events were recorded for any patients during the trial.

INTERPRETATION: Combined gabapentin and nortriptyline seems to be more

efficacious than either drug given alone for neuropathic pain, therefore we

recommend use of this combination in patients who show a partial response to

either drug given alone and seek additional pain relief. Future trials should

compare other combinations to their respective monotherapies for treatment of

such pain.

FUNDING: Canadian Institutes of Health Research.