Morphine Plus Gabapentin Better for Neuropathic Pain Than Each Drug Alone

The combination of morphine and gabapentin achieves better analgesia for neuropathic pain than each drug alone, according to the results of a randomized trial.

"The available drugs to treat neuropathic pain have incomplete efficacy and dose-limiting adverse effects," write Ian Gilron, MD, from Queen’s University in Kingston, Ontario, Canada. "Painful diabetic neuropathy and postherpetic neuralgia are two neuropathic pain syndromes that have been investigated in mechanism-based studies as well as in many clinical trials of analgesic agents. Both conditions have been shown to respond to opioids and to gabapentin."

In this double-blind, four-period crossover trial, patients were randomized to receive daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine, each given orally for five weeks. The primary outcome was mean daily pain intensity in patients receiving a maximal tolerated dose, rated on a scale from 0 to 10, with higher numbers indicating more severe pain. Secondary outcome measures were pain ratings on the Short-Form McGill Pain Questionnaire, adverse effects, maximal tolerated doses, mood, and quality of life.

Of 57 patients who were randomized, 35 had diabetic neuropathy and 22 had postherpetic neuralgia; 41 completed the study. Mean daily pain at a maximal tolerated dose of the study drug was 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with gabapentin plus morphine (P < .05 for the combination vs placebo, gabapentin, and morphine alone).

Total scores on the Short-Form McGill Pain Questionnaire, on a scale from 0 to 45, with higher numbers indicating more severe pain, at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with gabapentin plus morphine combination (P < .05 for the combination vs placebo, gabapentin, and morphine alone).

Compared with the maximal tolerated doses of each drug as a single agent, the maximal tolerated doses of morphine and gabapentin were lower (P < .05). At the maximal tolerated dose, frequency of constipation and of dry mouth was higher for gabapentin plus morphine than for gabapentin alone (P < .05 for both).

"Gabapentin and morphine combined achieved better analgesia at lower doses of each drug than either as a single agent, with constipation, sedation, and dry mouth as the most frequent adverse effects," the authors write.

The results of this trial unequivocally show that gabapentin significantly enhances the efficacy of morphine," the authors conclude. "Given the potential benefits (e.g., improved efficacy and fewer adverse effects) and drawbacks (e.g., adverse drug interactions) of any drug combination, trials are needed to compare other analgesic combinations with their respective single agents."

"This study clearly shows the advantages of concurrent titration of gabapentin and morphine, though the perceived risks of addiction and diversion with opioids and the fear of scrutiny by regulatory agencies may present barriers to the acceptance of this combination as first-line treatment," the authors write. "
N Engl J Med. 2005;352:1324-1334, 1373-1375

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