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| GENDER DIFFERENCES IN RESPONSES TO ANALGESIC MEDICATIONS Christine Miaskowski, R.N., Ph.D., Jon D. Levine, M.D., Ph.D., Robert Gear, D.D.S., Ph.D., Newton Gordon, D.D.S., and Steve Paul. Schools of Nursing, Medicine, and Dentistry, University of California, San Francisco, California Gender differences in responses to analgesic medications have largely been ignored. Many clinical trials of new analgesic medications limit the participation of women of childbearing years because of concerns regarding potential teratogenic effects on the fetus. However, recent data from our laboratory suggest that men and women respond differently to opioid analgesics that are relatively selective for the kappa-opioid receptor and that these responses warrant additional investigations. Therefore, the purpose of this paper will be to provide a historical perspective on the published literature regarding gender differences in responses to analgesic medications and to review the work from our laboratory on gender differences in responses to kappa-opioids. In our clinical trials, patients undergo standardized surgery, by the same oral surgeon, for removal of third molar teeth including at least one bony impacted mandibular molar. Prior to surgery, patients receive intravenous diazepam, nitrous oxide, and a local anesthetic. After surgery, each patient is randomly assigned to a specific treatment group and receives an intravenous injection of the study drug. The duration of the experiment, measured from the time of administration of the study drug, is approximately 3 hours. Criteria for administration of the study drug are: 1) an elapsed time of at least 80 minutes after the onset of the local anesthetic and 2) a pain rating that is greater than one quarter (2.5 cm) of the maximum possible visual analogue scale (VAS) rating. Baseline pain intensity is defined as the VAS pain rating just before administration of the test drug. The magnitude of the analgesic response for each patient is defined as the difference between the pain rating at each time point following test drug administration and the baseline VAS pain rating. Previously published work from our laboratory demonstrates that the kappa-opioid analgesic, pentazocine, produces significantly greater analgesia in females than in males (1). In another series of experiments, we demonstrated the nalbuphine and butorphanol produce significantly greater analgesia in females as compared to males (2). Our most recent work evaluated for gender differences in placebo responses and in the analgesic responses of males and females to increasing doses of nalbuphine (i,e., 5, 10, or 20 mg). The responses to placebo were similar in males and females. Comparison over the three hour post drug administration period revealed that females experienced significantly better responses than males to all doses of nalbuphine. Within gender comparisons to placebo showed that in males only the 20 mg dose of nalbuphine produced significant analgesia, an effect that diminished to placebo level within one hour. Males who received the 5 mg dose of nalbuphine experienced significantly greater pain that those who received placebo. A similar within gender comparison for females showed that only the 10 mg dose of nalbuphine produced significant analgesia. The results of these studies suggest that kappa opioid analgesics produce significantly greater analgesic effects in women compared to men. In addition, no differences in placebo responses were found between males and females. The mechanisms underlying the complex dose-response relationships to nalbuphine, in men and women, remain to be elucidated (This research was supported by NIH grant NR03923). 1. Gear, RW, Gordon, NC, Heller, PH, Paul, S, Miaskowski C, & Levine, JD. Gender differences in analgesic responses to the kappa-opioid pentazocine. Neuroscience Letters, 1996, 205:207-209. 2. Gear, RW, Miaskowski C, Gordon, NC, Paul, S, Heller, PH & Levine, JD. Significantly greater analgesia in females compared to males after kappa-opioids. Nature Medicine, 1996, 2:1248-1250.
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