Action of naloxone on gender-dependent analgesic and antianalgesic effects of nalbuphine in humans

Previously, we have shown that the kappa-opioid analgesic nalbuphine, when administered at a low dose to treat postoperative pain after extraction of impacted third molar teeth, produced a marked increase in pain in men, whereas in women the effect of this dose was similar to placebo. In the current study, employing the same postoperative model, we found that coadministration of naloxone, which had no analgesic action administered alone, not only reversed the expected pain-enhancing effect of nalbuphine in men, but produced a similar degree of long-lasting analgesia in both sexes. This result further suggests that, at the dose employed, although naloxone antagonizes the pain-enhancing effect, it does not antagonize the analgesic effect of nalbuphine. Although observed only in men, this antianalgesic action also might be present in women but offset by a similar degree of analgesia, thus explaining the lack of analgesia in women produced by this dose of nalbuphine alone. Such action would suggest that the previously reported gender differences in kappa-mediated analgesia might, in fact, be explained by a gender difference in kappa-mediated antianalgesia. By avoiding side effects associated with mu-opioid analgesics, this drug combination might become an important new pharmacological therapy for pain relief.