Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

• Published in: British journal of pharmacology Vol. 175; no. 3; pp. 532 - 543
• Main Authors: Rickli, Anna, Liakoni, Evangelia, Hoener, Marius C, Liechti, Matthias E
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-02-2018; John Wiley and Sons Inc
• Subjects: Analgesia; Analgesics, Opioid - pharmacology; Buprenorphine; Codeine; Dextromethorphan; Drug overdose; Fentanyl; HEK293 Cells; Heroin; Humans; Inhibition; Methadone; Morphine; Narcotics; Noradrenaline; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins - antagonists & inhibitors; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Opioids; Oxycodone; Pain perception; Research Paper; Research Papers; Serotonin; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin receptors; Serotonin S1 receptors; Serotonin S2 receptors; Serotonin Syndrome - metabolism; Serotonin transporter; Toxicity; Tramadol
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14105

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.