Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain – results of a randomized double-blinded, placebo-controlled trial

Abstract

Phantom limb pain (PLP) associated neuroplastic changes are partly mediated by excitatory amino acids at NMDA receptor sites. This study was undertaken to deduce if NMDA-receptor antagonists may be effective in patients with chronic PLP. Therefore a four week double-blinded, randomized placebo-controlled trial was performed to evaluate the efficacy of 30 mg memantine/day, an orally administrable NMDA receptor antagonist.Thirty-six patients, 18 per group, with a history of at least 12 months PLP and an average pain of at least 4 on the 11-point numeric rating scale (NRS) were enrolled. The patients completed a standardized questionnaire before the trial. PLP intensity and the level of eight complaints were assessed during the trial. Number needed to treat (NNT) was calculated based on the average PLP during the 3rd week (steady state). In both groups, PLP declined significantly in comparison with the baseline (verum: 5.1 (+/-2.1) to 3,8 (+/-2,3), placebo from 5.1 (+/-2.0) to 3.2 (+/-1,46) NRS) without a re-rising of the PLP during the washout period. Mean pain relief was 47% in the memantine group (10 patients reported more than 50% relief), 40% in the placebo group (6>50%): NNT were 4.5 (KI: 2.1-10.6). Analysis of covariance demonstrated a significant impact only on the prior PLP intensity, but no treatment effect. Two patients have demonstrated long-term pain relief under memantine until now (16 months). The total number of slight adverse events were comparable in both groups, but the overall number of severe events was higher in the memantine group (P<0.05). This trial failed to demonstrate a significant clinical benefit of the NMDA-receptor antagonist memantine in chronic PLP. The administration of a higher dosage is probably not tolerable.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Clinical studies of dextromethorphan, which is metabolized to the more potent antagonist dextrorphan (Wong et al, 1988), suggest efficacy for short-term treatment of postoperative pain, phantom limb pain, and diabetic neuropathy but not postherpetic neuralgia (Ben- Weinbroum et al, 2000Weinbroum et al, , 2001Weinbroum et al, , 2002Weinbroum et al, , 2003Weinbroum et al, , 2004Sang et al, 2002;Ben Abraham et al, 2003;Siu and Drachtman, 2007). Memantine has modest or no efficacy for diabetic neuropathy and postherpetic neuralgia (Sang et al, 2002), pain after surgery (Nikolajsen et al, 2000), and phantom limb pain (Maier et al, 2003). Although positive results have been reported for complex regional pain syndrome (Sinis et al, 2007), more studies are needed .…”

Role of N-methyl-D-aspartate receptor antagonists in postoperative pain management

“…A couple of studies failed to demonstrate the efficacy of memantine in patients who had already established chronic phantom limb pain. Even though memantine cannot relieve chronic phantom limb pain status [26,27], a recent randomized, double-blind, placebo-controlled trial using memantine (20-30 mg/day) initiated immediately after upper limb amputation for 4 weeks revealed an almost four-fold decrease in the incidence of phantom limb pain 6 months after surgery [28 ]. In this trial, patients received postoperative continuous brachial plexus ropivacaine infusion for 7 days after surgery.…”

Management of Phantom Limb Pain

“…Memantine and ketamine have also been found to be ineffective in the management and prevention of chronic PLP (Maier et al 2003;Schley et al 2008). …”