Morphine versus mexiletine for treatment of postamputation pain: a randomized, placebo-controlled, crossover trial

Abstract

Background: Stump and phantom pains are debilitating sequelae of amputations that are often resistant to treatment. The efficacy of pharmacologic therapies, including opioids and sodium channel blockers, for postamputation pain is uncertain.

Methods: The authors conducted a double-blind, randomized, placebo-controlled, crossover study in adult patients with postamputation pain of 6 months or longer and greater than 3 on a 0-10 numeric pain rating scale. Each of the three treatment periods (morphine, mexiletine, or placebo) included a 1-week drug-free interval followed by 4-week titration, 2-week maintenance, and 2-week drug-taper phases. The primary outcome measure was change in average pain intensity from the drug-free baseline to the last week of maintenance.

Results: Sixty amputees were enrolled; data were analyzed from 56 subjects for one drug period, 45 subjects for two drug periods, and 35 subjects who completed all three drug periods. The mean morphine and mexiletine dosages were 112 and 933 mg, respectively. Morphine treatment provided lower pain scores compared with placebo and mexiletine (P = 0.0003). The mean percent pain relief during treatment with placebo, mexiletine, and morphine was 19, 30, and 53%, respectively (P < 0.0001, morphine vs. placebo and mexiletine). The numbers needed to treat to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively. Treatment with morphine was associated with a higher rate of side effects.

Conclusions: Therapy with morphine, but not mexiletine, resulted in a decrease in intensity of postamputation pain but was associated with a higher rate of side effects and no improvement in self-reported levels of overall functional activity and pain-related interference in daily activities.

Trial registration: ClinicalTrials.gov NCT00383682.

Figures

Fig. 1

Study design. This figure illustrates the study design (placebo-controlled, double-blind, randomized, crossover study) in which each subject would undergo a period of three treatment periods (sustained-release morphine, mexiletine, or placebo) with a 1-week washout period between treatment periods. The duration of each treatment period was approximately 8 weeks and consisted of 4-week titration, 2-week maintenance, and 2-week taper phases, which were followed by a 1-week drug-free period. A total of 81 patients were approached regarding enrollment in the study, and 60 patients were ultimately enrolled.

Fig. 2

Flow of study subjects. This figure shows the flow of subjects through the study once enrolled, the number excluded, and the number of dropouts at each stage.

Fig. 3

Average numerical pain ratings before and after treatment with morphine, mexiletine, and placebo. The figure compares self-reported baseline pain scores on a numeric rating pain scale (NRS; 0–10). All treatments resulted in significantly lower (* P < 0.0001, baseline vs. maintenance) pain scores compared with baseline; however, post hoc general estimating equation analysis showed that morphine resulted in significantly lower pain scores compared with mexiletine (P = 0.0003) and placebo (P = 0.0003).

Fig. 4

Percentage self-reported pain relief between placebo, morphine, and mexiletine. The use of morphine was associated (general estimating equation model) with significantly higher self-reported percentage pain relief error bars compared with mexiletine (P < 0.0001) and placebo (P < 0.0001).

Fig. 5

Percent of subjects with varying degrees of reduction in pain with morphine, mexiletine, and placebo. The graph presents the proportion of responders over the entire range of possible cutoff points to allow comparison of treatment groups at any responder level.