Potentiation of opioid analgesia by the antidepressant nefazodone

Nefazodone is a new antidepressant related structurally to trazodone. In addition to its activity in preclinical assays for antidepressant activity, nefazodone was a potent analgesic in the mouse hotplate assay. At 50 mg/kg s.c. nefazodone doubled baseline latencies in 40% of mice but was inactive in the tailflick test at any dose tested. The hotplate analgesia seen with nefazodone alone was not reversed by naloxone (10 mg/kg s.c.). In the tailflick assay, nefazodone (50 mg/kg s.c.) enhanced morphine's analgesic response, shifting morphine's ED50 from 3.1 mg/kg alone to 0.86 mg/kg in conjunction with nefazodone (P less than 0.05). Two days after implantation of a morphine pellet (75 mg) no mice remained analgesic in the tailflick assay. Administration of nefazodone (50 mg/kg s.c.) restored analgesia to 60% of mice (P less than 0.03). In selective analgesic assays, nefazodone enhanced mu 1, mu 2 and delta analgesia, but not kappa 1 or kappa 3 analgesia. Nefazodone did not affect morphine's LD50 and, in assays of gastrointestinal transit, nefazodone increased morphine's potency only slightly. In conclusion, nefazodone alone is analgesic in certain animal models. In conjunction with morphine, nefazodone potentiated analgesia with no effect on lethality and little effect on gastrointestinal transit, resulting in an increase in morphine's therapeutic index. These results suggest that nefazodone and similar agents may have a significant role in the management of pain.