Dataset Information

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

ABSTRACT:

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-HT_1A , 5-HT_2A and 5-HT_2C 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-HT_1A receptors and methadone, pethidine and fentanyl with 5-HT_2A 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-HT_1A and/or 5-HT_2A receptors could be involved with methadone and pethidine.

SUBMITTER: Rickli A

PROVIDER: S-EPMC5773950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate the severity of neonatal opioid withdrawal syndrome (NOWS) in infants prenatally exposed to medications for opioid use disorder (MOUD) and serotonin reuptake inhibitors (SRI).MethodsA prospective cohort included 148 maternal-infant pairs categorized into MOUD (n = 127) and MOUD + SRI (n = 27) groups. NOWS severity was operationalized as the infant's need for pharmacologic treatment with opioids, duration of hospitalization, and duration of treatment. The association between prenatal SRI exposure and the need for pharmacologic treatment (logistic regression), time-to-discharge, and time-to-treatment discontinuation (Cox proportional hazards modeling) was examined after adjusting for the type of maternal MOUD, use of hydroxyzine, other opioids, benzodiazepines/sedatives, alcohol, tobacco, marijuana, gestational age, and breastfeeding.ResultsInfants in the MOUD + SRI group were more likely to receive pharmacologic treatment for NOWS (OR = 3.58; 95% CI: 1.31; 9.76) and had a longer hospitalization (median: 11 vs. 6 days; HR = 0.54; 95% CI: 0.33; 0.89) compared to the MOUD group. With respect to time-to-treatment discontinuation, no association was observed in infants who received treatment (HR = 0.59; 95% CI: 0.26, 1.32); however, significant differences were observed in the entire sample (HR = 0.55; 95% CI: 0.34, 0.89).ConclusionsUse of SRIs among pregnant women on MOUD might be associated with more severe NOWS.ImpactA potential drug-drug interaction between maternal SRIs and opioid medications that inhibit the reuptake of serotonin has been hypothesized but not carefully evaluated in clinical studies. Results of this prospective cohort indicate that the use of SRIs among pregnant women on MOUD is associated with more severe neonatal opioid withdrawal syndrome. This is the first prospective study which carefully examined effect modification between the type of maternal MOUD and SRI use on neonatal outcomes. This report lays the foundation for treatment optimization in pregnant women with co-occurring mental health and substance use disorders.