Methadone vs. morphine SR for treatment of neuropathic pain: A randomized controlled trial and the challenges in recruitment

Introduction: Accumulating evidence has identified a number of advantages for methadone over other opioids for the treatment of chronic pain including: agonist action at both μ and δ opioid receptors, N-methyl-d-aspartate (NMDA) antagonist activity and the ability to inhibit the reuptake of monoamines. It was hypothesized that with these three mechanisms of action methadone might be a good option for the treatment of neuropathic pain. Methods: This was a double-blind randomized controlled trial comparing methadone to controlled-release morphine. The primary objective was to determine whether methadone is clinically inferior versus noninferior to morphine as an analgesic. Results: We attempted recruitment at three academic pain centers over a 3-year period. In the end only 14 participants were able to be recruited; 5 withdrew and only 9 completed the trial. This study was underpowered. All participants showed a mean reduction in pain intensity according to the Numeric Rating Scale for Pain Intensity (morphine 5.86 to 4.38, methadone 6.11 to 4.5) and reported pain relief compared to pretreatment, but the sample size was too small for statistical analysis. Discussion: Reasons for challenges in recruitment included tight inclusion and exclusion criteria and high participant burden. In addition, there was significant heterogeneity of patients between the three sites, leading to differences in reasons for exclusion. This included seemingly disparate reasons at the different sites, including few participants who were methadone naïve vs. avoidance or fear of opioids. In the end, we were unable to answer the question of the study.