Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in μ and mixed μ/κ opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on μ-opioids there was no significant sex-analgesia association. Restricting the analysis to patient-controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n=15, effect size 0.22, 95% c.i. 0.02-0.42, P=0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n=11, effect size=0.36, 95% c.i. 0.17-0.56, P=0.003). Meta-regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on μ-opioids women had greater antinociception from opioids (n=11, effect size=0.35; 95% c.i. 0.01-0.69, P=0.047), which was predominantly due to 6 morphine studies. Female patients had greater μ/κ opioid analgesia (n=7, effect size 0.84; 95% c.i. 0.25-1.43, P=0.005), but no sex-analgesia association was present in experimental studies (n=7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine μ and mixed μ/κ-opioids are less convincing and require further study.

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