Opioid-induced inhibition of the human 5-HT and noradrenaline transportersin vitro: link to clinical reports of serotonin syndrome

Background and Purpose Opioids may inhibit the 5-HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with 5-HT receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET and 5-HT receptors have not been sufficiently studied. Experimental Approach We determined the potencies of different opioids to inhibit the SERT and NET in vitro using human transporter-transfected HEK293 cells. We also tested binding affinities at 5-HT1A, 5-HT2A and 5-HT2C receptors. Additionally, we assessed clinical cases of the serotonin syndrome associated with each opioid reported by PubMed and a World Health Organization database. Key Results Dextromethorphan, l(R)-methadone, racemic methadone, pethidine, tramadol and tapentadol inhibited the SERT at or close to observed drug plasma or estimated brain concentrations in patients. Tapentadol was the most potent NET inhibitor. Pethidine, tramadol, l(R)-methadone, racemic methadone, dextromethorphan and O-desmethyltramadol also inhibited the NET. 6-Monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone did not inhibit the SERT or NET. Fentanyl interacted with 5-HT1A receptors and methadone, pethidine and fentanyl with 5-HT2A receptors, in the low micromolar range. Opioids most frequently associated with the serotonin syndrome are tramadol, fentanyl, tapentadol, oxycodone, methadone and dextromethorphan. Conclusions and Implications Some synthetic opioids interact with the SERT and NET at potentially clinically relevant concentrations. SERT inhibition by tramadol, tapentadol, methadone, dextromethorphan and pethidine may contribute to the serotonin syndrome. Direct effects on 5-HT1A and/or 5-HT2A receptors could be involved with methadone and pethidine.