To evaluate the role of sigma receptors in the sexually dimorphic antianalgesic effect of agonist-antagonist kappa opioids, 2 neuroleptics, haloperidol, a sigma receptor antagonist, and chlorpromazine, which has minimal effect at sigma receptors, were administered with the agonist-antagonist kappa opioid nalbuphine in patients with postoperative pain. Before surgical extraction of bony impacted mandibular third molar teeth, patients received haloperidol (1 mg), chlorpromazine (10 mg), or placebo by oral administration. After surgery, the pain intensity did not differ significantly between the 3 treatment groups, suggesting lack of analgesic effect produced by either haloperidol or chlorpromazine. All patients were then administered nalbuphine (5 mg, intravenous). As previously reported, the group that did not receive a preoperative neuroleptic exhibited sexually dimorphic analgesia, with women experiencing greater analgesia than men. Antianalgesia was also observed, with men experiencing late onset increased pain compared with baseline, starting approximately 1 hour after nalbuphine administration. Both neuroleptics blocked nalbuphine antianalgesia, resulting in enhanced analgesia and elimination of the sex differences. Because chlorpromazine and haloperidol enhanced nalbuphine analgesia and eliminated sexual dimorphism, the receptor at which neuroleptics act to antagonize the "antianalgesia" might be a common site of action to both drugs.
Perspective: This study demonstrates that neuroleptics can block the antianalgesic effect of agonist-antagonist kappa opioids. These findings could help inform the development of novel analgesics.