Interactions between the serotonin/norepinephrine uptake inhibitor clomipramine and mu opioid agonists in rhesus monkeys: role of mu agonist efficacy

Abstract

Adjunct medications may increase the efficacy or safety of μ opioid agonists for the treatment of pain. This study examined interactions between the serotonin/norepinephrine uptake inhibitor clomipramine and different efficacy μ‐opioid agonists (nalbuphine<morphine<fentanyl<methadone) in assays of thermal nociception (50 and 54°C warm water tail withdrawal) and schedule‐controlled responding (fixed‐ratio 30 schedule of food delivery) in rhesus monkeys. In the assay of thermal nociception, clomipramine was ineffective, and μ agonists produced efficacy‐dependent antinociception. Clomipramine produced superadditive effects in combination with the lower efficacy μ agonists nalbuphine and morphine, but only additive effects in combination with the higher‐efficacy μ agonists fentanyl and methadone. In the assay of schedule‐controlled responding, clomipramine was ineffective, and all μ agonists decreased response rates. Clomipramine produced additive effects in combination with all mu agonists. Clomipramine selectively enhanced the antinociceptive effects relative to the rate‐decreasing effects only for lower efficacy μ agonists. Research supported by NIH grants RO1‐DA11460 and T32‐DA007027.