A New Approach to an Old Problem
August 15, 2002
Abstract & Commentary
Synopsis: This study provides results of a prospective study of dextromethorphan or memantine in treating diabetic and postherpetic neuralgia.
Source: Sang CN, et al. Anesthesiology. 2002;96:1053-1061.
This trial evaluated the efficacy of dextromethorphan or memantine in the treatment of diabetic or postherpetic neuropathy. The trial enrolled 23 patients with diabetic and 21 patients with postherpetic neuropathy who had previously failed a trial of tricyclic antidepressants. In a 3-phase design, subjects were randomized to receive dextromethorphan, memantine, or an active placebo consisting of lorazepam. Over 7 weeks, subjects were titrated up to a maximum tolerated dose, followed by a 2-week maintenance period. The targeted maximal daily doses were dextromethorphan 960 mg, memantine 58 mg, and lorazepam 2 mg. The end point was the mean score of the Gracely pain intensity scale (0-16) during the last week of therapy. After a 2-week wash-out period, subjects then received another of the 3 study drugs.
Eighty-three percent of diabetic patients and 85% of postherpetic patients completed all 3 phases of the study, with a mean dextromethorphan dose of 400 mg/d, memantine 35 mg/d, and lorazepam 1.3 mg/d. In patients with diabetes, dextromethorphan reduced pain intensity by 33% from baseline; there was a 17% reduction from baseline with memantine. When compared to the active placebo, there was a nonsignificant trend toward improvement with dextromethorphan (mean reduction, 2%; 95% CI, -5-1%) and memantine (mean reduction, 2%; 95% CI, -2-1%). In patients with postherpetic neuralgia, there was a similar but less impressive reduction in pain.
In the second part of the trial, the minimum dose to achieve relief was assessed. Subjects who responded to one of the drugs were given different dosages of the drug that provided relief in the first trial. Dosages were 25%, 50%, and 100% of the maximally tolerated dose. In dextromethorphan-responders from the first trial, the maximum dose of dextromethorphan resulted in a 35% reduction in pain when compared to lorazepam.
Comment by Jeff Wiese, MD
Treatment of diabetic and postherpetic neuropathy refractory to tricyclic antidepressants is a frustrating problem for physicians and patients. This trial suggests that for some patients, high-dose dextromethorphan may be useful in the treatment of diabetic neuropathy. Memantine showed only a modest benefit in a few patients. There did not appear to be a benefit from either drug in the treatment of postherpetic neuropathy.
The results of this trial should be interpreted with caution. Although all patients given dextromethorphan showed a reduction in pain intensity compared to baseline, only a select few had relief greater than that experienced by lorazepam. In those who did respond, however, the effect was substantial. There was also considerable dropout in the trial; 17% of those in the diabetic arm and 15% in the memantine arm did not complete the trial.
The effect of dextromethorphan may be underestimated by this trial, as the wide confidence intervals suggest that this study was underpowered. The lack of power also prevents drawing conclusions about which subgroups receive the greatest benefit from the drug. Further studies with larger sample sizes will be required to identify which patients are most likely to benefit from dextromethorphan. In addition, most patients did not come close to the maximum tolerated dose due to the side effect of sedation.
The diabetic patients in this trial had reasonably good control of their diabetes. The mean HgbA1c was 8%; a level below which most patients in the DCCT trial did not have diabetic complications. A patient population with more severe diabetes may have shown greater benefit.
Other agents used for the treatment of diabetic neuropathy include tricyclic antidepressants, gabapentin, carbamazepam, and SSRIs.1 If a patient has failed these medications, dextromethorphan may be a viable option. Dextromethorphan is a non-specific MDMA antagonist, and its primary side effect is sedation. At the high doses (400 mg/d) required to achieve relief, sedation should be expected.2 Future development of specific MDMA antagonists may offer significant improvement in neuropathy symptoms.
References
1. Sindrup SH, Jensen TS. Pain. 1999;83:389-400.
2. Nelson KA, et al. Neurology. 1997;48:1212-1218.
Dr. Wiese, Chief of Medicine, Charity, and University Hospitals, Associate Chairman of Medicine, Tulane Health Sciences Center, is Associate Editor of Internal Medicine Alert.
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