Sex differences in opioid analgesia: clinical and experimental findings

Sex differences in analgesic responses to opioids have received increasing attention in recent years. This article examines the literature on sex differences in opioid analgesia, including the results of studies from the authors' own laboratories. In general, nonhuman animal studies suggest more robust opioid analgesic responses in males relative to females; however, the human studies completed to date seem to indicate greater opioid analgesia among females. The most consistent evidence of sex differences in analgesia comes from studies of kappa-agonist-antagonists administered to patients following oral surgery. These data indicate more robust analgesia in females, and dose-response characteristics suggest that these agents possess both analgesic and antianalgesic properties, and the agonists may produce these effects in different proportions for women versus men. In contrast, the data from laboratory pain models in humans suggest greater analgesic effects in women in response mu-opioid agonists but not kappa-agonist-antagonists. Multiple mechanisms may explain sex differences in opioid analgesia, including gonadal hormonal effects, pharmacokinetics and pharmacodynamics, genetic influences, balance of analgesic/antianalgesic processes, and psychological factors. However, the disparity of results obtained from different pain models--animals versus humans and clinical pain versus experimental pain in humans--suggests that the models themselves are mechanistically different. Additional investigation is warranted in order to further explicate the nature of sex differences in opioid analgesia and to elucidate the underlying mechanisms.