BackgroundNumerous experimental studies, conducted primarily over the past 10 years, show that there are sex differences in opioid analgesia. This review summarizes the published literature on sex differences in analgesia produced by acute administration of drugs acting at &mgr;-, &kgr;-, and &dgr;-opioid receptors, in animals and humans. Additionally, methodological issues in research into opioid sex differences are discussed.ConclusionsProcedural variables that may influence the outcome of studies examining sex differences in opioid analgesia include modality and intensity of the noxious stimulus used in the pain test, opioid type (efficacy and selectivity), and experimental design and data analytic techniques. Subject variables that may be important to consider include subject genotype and gonadal steroid hormone state of the subject at the time of analgesia testing. Evidence is provided for multiple mechanisms underlying sex differences in opioid analgesia, including both pharmacokinetic and pharmacodynamic factors. Future research directions are suggested, such as examining sex differences in opioid tolerance development, sex differences in opioid analgesia using models of acute inflammatory pain and chronic pain, and sex differences in effects of opioids other than analgesia, which may limit their therapeutic use.