Predictors of methadone response in chronic neuropathic pain
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Background
Although opioids are frequently prescribed for refractory chronic neuropathic pain, few data are available on baseline factors that may identify individuals more likely to respond and inform individually tailored practice.
Methods
This was a post hoc, exploratory analysis of individual-level data from a placebo-controlled trial of methadone for chronic neuropathic pain ( NCT05235191 ). Baseline clinical, psychological, psychophysical and radiological variables were tested for association with ≥30% pain reduction in the methadone group. The correlation between expectation of improvement and pain reduction was examined in both groups.
Results
Of the 81 participants completing the 8-week follow-up, 28 (70%) on methadone and 14 (34.1%) on placebo achieved ≥30% pain reduction. In the methadone group, responders had higher baseline expectation of improvement (median 100 [80-100] vs. 55 [50-81]; p=0.004), which correlated moderately with percentage pain reduction (r s =0.508; p<0.001). Neither finding was observed in the placebo group (p=0.211 and p=0.161, respectively), although the correlation did not differ significantly between groups (p for interaction=0.728). Other clinical, sociodemographic, psychological and psychophysical variables were not associated with response. In the subsample with peripheral neuropathic pain and structural MRI (n=37), lower left precentral cortex volume was associated with response to methadone (p=0.041), and lower right paracentral volume with response to placebo (p=0.003).
Conclusions
Baseline expectation may influence treatment outcomes, supporting its inclusion as a covariate to improve the precision of treatment effect estimates in trials, and its use in clinical practice to help tailor treatment to individual patients. These exploratory findings require confirmation in larger studies.
Significance statement
Predictors of opioid response in chronic neuropathic pain remain poorly understood, and treatment expectation has received little attention in this setting. In this study, a single baseline rating of expected improvement identified methadone responders more consistently than pain phenotype, conditioned pain modulation or other psychological traits. These results support considering patient expectation both when interpreting opioid trials and when discussing likely benefit with patients before starting treatment.
