Clinical Question: Is the combination of gabapentin (Neurontin) and morphine more effective for neuropathic pain than either drug alone?

Setting: Outpatient (specialty)

Study Design: Crossover trial (randomized)

Allocation: Concealed

Synopsis: Gabapentin and morphine are widely used for neuropathic pain, but it is unclear whether the combination is better than either drug alone. The authors of this small study used a crossover design. Each patient took each drug or a combination of drugs and served as his or her own control. This study design makes it possible to identify statistically significant results with a relatively small sample size. The 57 patients in the study had diabetic neuropathy or postherpetic neuralgia that was at least moderate in severity and had been present for at least three months. Those with postherpetic neuralgia were somewhat older than those with diabetic neuropathy (mean age: 68 versus 60 years). They stopped taking any medications for neuralgia and kept a pain diary for seven days to establish their baseline level of symptoms.

Patients were then assigned randomly to one of four treatment sequences. Each sequence included the following maximal target dosages for the four treatment regimens: (1) sustained-release morphine in a dosage of 60 mg twice daily, (2) gabapentin in a dosage of 3,200 mg daily in three divided doses, (3) sustained-release morphine in a dosage of 30 mg twice daily plus gabapentin in a dosage of 800 mg three times daily, and (4) active placebo with a low dose of lorazepam (Ativan; not believed to be effective for neuropathic pain, but patients were more likely to believe they were taking an active drug because of its side effects). Each treatment period lasted five weeks, with the dosage slowly escalated during the first three weeks, outcomes measured during the fourth week, and the drugs tapered and stopped during the fifth week. Older and smaller patients had somewhat lower target dosages than the dosages listed above (60 mg for morphine alone and 2,400 mg for gabapentin alone). Most patients did not reach the maximal dosage; the mean final dosages for morphine and gabapentin when used in combination were 35 mg and 1,700 mg per day, respectively.

Only 41 of 57 patients completed the study; most of the others dropped out during the first treatment period. The primary outcome was the mean pain intensity on a scale from zero to 10 during the fourth week when patients were receiving the maximal dosage of each drug. Average pain intensity was 5.70 at baseline and was decreased to 4.50 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.10 with the combination of gabapentin and morphine. The differences between the individual active drugs and the combination were statistically significant but of marginal clinical significance. In general, on a 10-point scale, a difference of less than 1 to 1.5 points is not clinically important. Patients receiving morphine alone or in combination with gabapentin had significant side effects; 21 percent receiving the combination had constipation, sedation, and dry mouth.

Bottom Line: The combination of gabapentin and morphine provides a small but clinically unimportant benefit over either drug alone. Tricyclic antidepressants have been shown in other studies to be as effective as gabapentin and are much less expensive, but were not studied in this trial. (Level of Evidence: 1b)