Potentiation of opioid analgesia by the antidepressant nefazodone

Chaim G. Pick, Dennis Paul, Michael S. Eison, Gavril W. Pasternak*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 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 < 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 < 0.03). In selective analgesic assays, nefazodone enhanced μ1, μ2 and δ analgesia, but not κ1 or κ3 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, rsulting 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.

Original languageEnglish
Pages (from-to)375-381
Number of pages7
JournalEuropean Journal of Pharmacology
Issue number3
StatePublished - 18 Feb 1992
Externally publishedYes


  • Gastrointestinal transit
  • Opiate lethality
  • Opiate receptors
  • δ-Opioid receptors
  • κ-Opioid receptors
  • μ-Opioid receptors


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