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Morphine, Gabapentin, or Their Combination for Neuropathic Pain

Background: Gabapentin and opioids are currently two agents used to treat neuropathic pain. The use of the agents individually is limited due to incomplete efficacy and/or dose-limiting side effects.

Objective: The objective of the study was to evaluate the combination of gabapentin and morphine in patients with diabetic neuropathy or postherpetic neuralgia.

Methods: This study used a placebo controlled, randomized, double-blind, cross-over design. Patients were included if they had diabetic neuropathy or postherpetic neuralgia, daily moderate pain for three months or more, an age of 18-89 years, a serum alanine aminotransferase or aspartate aminotransferase level less than 1.2 times normal, a creatinine level less than 1.5 times the upper limit of normal, and sufficient language skills to communicate with research staff. Exclusion criteria were hypersensitivity to study medications, another painful condition as severe as diabetic neuropathy or postherpetic neuralgia, a recent myocardial infarction, unstable angina, congestive heart failure, any central neurologic disorder (including seizures), a serious mood disorder, a history of serious drug or alcohol abuse, pregnancy, lactation, or lack of a primary care physician. Fifty-seven patients were randomized to receive placebo, gabapentin, sustained release (SR) morphine, or a combination of gabapentin and SR morphine for five weeks, each in a cross-over design. Target daily dose for each treatment period was 120mg for SR morphine given alone, 60mg SR morphine in combination with 2400mg gabapentin, and 3200mg gabapentin given alone. Smaller target doses were used for subjects 60 years of age or older or who weighed less than 60kg. An active placebo, lorazepam, was utilized with a target daily dose of 1.6mg. Subjects kept baseline and daily pain diaries. During the first three weeks of each treatment period, the dose was escalated toward the maximal tolerated dose or the target-ceiling dose. In the fourth week subjects received the maximal dose. Subjects underwent a four-day tapering schedule and a three-day drug-free washout in the fifth week. A research nurse contacted subjects by telephone twice a week to evaluate adverse effects and guide drug titration. The primary outcome measure was mean pain intensity on a scale of 0 to 10, with 0 as “no pain” and 10 as “worst pain imaginable”. Secondary measures included adverse effects, pain questionnaire responses, pain-related interference with several functions, mood, health status, mental status and global pain relief. Forty subjects were needed for an 80% power to detect a mean difference of one point in pain intensity at week four.

Results: Treatment period A included all 57 randomized subjects. Treatment period B included 46 patients, period C had 43 subjects, and period D had 42 subjects. Forty-one subjects completed all four treatments (25 with diabetic neuropathy and 16 with postherpetic neuralgia). Subjects had to complete two treatment periods to be included in efficacy studies. Morphine was more likely than placebo to have a carry over effect on the next treatment period (p=0.005). Pain treated with the drug combination was rated lower than morphine alone (p=0.04), gabapentin alone (p<0.001), or placebo (p<0.001). The maximal tolerated doses of the combination treatment were lower as compared to the individual agents. For the primary outcome, the percent reduction in pain intensity was greater with combination therapy than placebo (p=0.03). Other comparisons in pain intensity were not statistically significant. Pain assessed by the Short-Form McGill Pain Questionnaire was lower when receiving combination therapy than with placebo (p<0.05), gabapentin (p<0.05), or morphine (p<0.05). Pain-related interference with mood with combination therapy was lower than with placebo (p<0.001) or morphine (p=0.03). Pain-related interference with general activity, normal work, sleep, and enjoyment of life was lower for all active treatments compared to placebo. Combination therapy had higher scores for vitality (p=0.007) and social functioning (p=0.004) than placebo and higher scores than morphine for vitality (p=0.03) and social functioning (p=0.04). Active treatments were associated with improved scores for bodily pain, vitality, work or other daily activities, and mental health compared to placebo. Active treatments scored lower for depression than placebo. At maximal tolerated doses, combination therapy was associated with a higher frequency of constipation than gabapentin (p=0.006) but not morphine, and a higher frequency of dry mouth than morphine (p=0.03) but not gabapentin. At least moderate pain relief was experienced by 31% (p<0.05 for comparison with all treatments), 61%, 80%, and 78%, of subjects receiving placebo, gabapentin, morphine, or the combination, respectively. Authors concluded that the combination of morphine and gabapentin, as compared to the individual agents, produced better analgesia for neuropathic pain at lower doses than each separately.

Strengths: The study objective was appropriate because there are insufficient treatment options for neuropathic pain. The study was randomized and used an “active” placebo that would cause sedation without pain relief. Appropriate inclusion and exclusion criteria were used for subject selection.

Weaknesses: Although the study was double-blind, many of the subjects could correctly guess which treatment they were receiving. The cross-over design allowed for carry-over effects to occur, particularly from morphine. There was a three-day washout period, but the duration was insufficient. The duration of each treatment period should also have been longer to determine the full effects of each treatment. Patients were allowed to take nonopioid drugs other than gabapentin for pain control, which could have interfered with the results. Compliance was not addressed. Confidence intervals were not reported. Insufficient power may have led to an absence of statistically significant differences in the percent change in pain level between baseline and treatment with the combination and between baseline and treatment with the individual agents, and also in the adverse effects comparisons.

Conclusion: The combination of morphine and gabapentin may be a useful therapy for neuropathic pain. However, the possibility of additive adverse effects is an important consideration when deciding to use the combination therapy. Larger, long-term studies are needed to further establish the efficacy of the combination of morphine and gabapentin for the treatment of neuropathic pain.

Gilron, Ian, Joan Bailey, Dongsheng Tu, Ronald Holden, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 352;13:1324-1334.

Kelly Ellis, Pharm.D. Candidate