Effects of opioids on human serotonin transporters

Barann, Martin; Stamer, Ulrike; Lyutenska, M.; Stüber, Frank; Bönisch, Heinz; Urban, B. W.

doi:10.1007/s00210-014-1056-3

Cited by 31 publications

(35 citation statements)

References 27 publications

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“…Tapentadol and tramadol were 2.6‐ and 1.6‐fold more potent inhibitors of the NET versus SERT respectively. Consistent with the present findings, tramadol and pethidine inhibited the human SERT in vitro , whereas morphine, hydromorphone and fentanyl were inactive (Barann et al, ). Also consistent with the present findings, dextromethorphan, methadone, pethidine, tramadol and tapentadol have previously been shown to block the rat SERT and NET in rat brain synaptosome in vitro assays (Larsen and Hyttel, ; Driessen et al, ; Codd et al, ; Frink et al, ; Giusti et al, ; Tzschentke et al, ).…”

Section: Discussionsupporting

confidence: 91%

“…Opioids primarily activate opioid receptors, but some atypical synthetic opioids have also been shown to interact with the noradrenaline transporter (NET) and/or the 5‐HT (serotonin) transporter (SERT) (Codd et al, ; Barann et al, ). The effects of opioids on noradrenaline and 5‐HT transport have previously been studied using rat brain synaptosomes (Larsen and Hyttel, ; Driessen et al, ; Codd et al, ; Frink et al, ; Giusti et al, ; Tzschentke et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, no data have been reported on the effects of different clinically used opioids on the human SERT, NET and dopamine transporter (DAT) using the same method, thus hindering direct comparisons of their transporter inhibition potencies. Only one recent study assessed the effects of a few opioids on the human SERT and showed SERT inhibition by tramadol and pethidine but not morphine, hydromorphone, fentanyl and alfentanil (Barann et al, ). More information on the non‐opioid effects of various opioids is needed because these analgesic substances are very widely used.…”

Section: Introductionmentioning

confidence: 99%

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

Rickli

Liakoni

Hoener

et al. 2018

British J Pharmacology

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Background and PurposeOpioids 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 ApproachWe 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 ResultsDextromethorphan, 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 ImplicationsSome 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.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Rickli

Liakoni

Hoener

et al. 2018

British J Pharmacology

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“…Although tramadol is not an analgesic frequently prescribed in the ICU, a recent case series by Ibister et al [22] suggested that tramadol does not seem to provoke serotonin toxicity clinically and a study by Barann et al [23] showed a concentration-dependent decrease in 5-HT reuptake, leading to an increase in serotonin.…”

Section: Discussionmentioning

confidence: 99%

Unsuspected serotonin toxicity in the ICU

Ewijk

Jacobs

Girbes

2016

Ann. Intensive Care

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Background: Delirium is a frequently occurring syndrome in patients admitted to the intensive care unit (ICU) or medium care unit (MCU), yet the pathophysiology remains poorly understood. An excess of central serotonin can lead to an altered mental status, associated with autonomic hyperactivity, and neuromuscular excitation. Drugs with serotonergic properties are frequently and for prolonged periods administered to ICU/MCU patients. Therefore, central serotonergic toxicity may constitute a predisposing, contributing or precipitating factor in the emergence of delirium. The purpose of the present study is to determine the number of patients admitted to the ICU or MCU who are diagnosed with delirium and who show characteristics of serotonin toxicity in association with the administration of serotonergic drugs.Methods: During a 10-week prospective observational cohort study in the ICU and MCU, patients aged 18 or older, diagnosed with delirium in the ICU or MCU, were included. Patients were considered as delirious in case of a positive CAM-ICU and/or at the start of haloperidol prescription on suspicion of delirium. Once included, patients were screened for recent administered serotonergic drugs and screened for physical signs associated with serotonin toxicity by a standardized physical examination by a specifically trained physician.Results: A total of 61 patients diagnosed with delirium were enrolled. In 44 out of 61 patients (72 %), the use of drugs potentially contributing to serotonergic toxicity was recorded. Out of 44 patients, seven (16 %) patients showed physical signs of serotonin toxicity and in addition met the Hunter serotonin toxicity criteria, suggesting the presence of serotonergic toxicity. None of these patients were recognized as such by the treating physicians.Conclusions: A significant proportion of delirious patients in the ICU might in fact be classified as suffering from central serotonin toxicity. The awareness of potential serotonin toxicity is low among physicians.

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“…Se ha observado que el fentanilo origina una regulación a la alta dosis dependiente de los receptores 5-HT 1A a nivel del hipocampo y de la amígdala de cerebro de rata. Se señala en la literatura que la estimulación de los receptores 5-HT 1A presenta efecto analgésico a nivel central (23)(24)(25) . Estos planteamientos concuerdan con nuestros resultados en los que los sujetos con asociación fentanyl-bupivacaína presentaron menor dolor postoperatorio y mayor tiempo de analgesia.…”

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