The role of 5-HT modulation in opioid withdrawal and neonatal opioid withdrawal syndrome: mechanisms and potential serotonergic targets.

Introduction: Opioid use disorder and neonatal opioid withdrawal syndrome are persisting consequences of the opioid epidemic in the United States. Current pharmacologic approaches primarily utilize opioid replacement therapy, but non-opioid therapeutics could have advantages. Preclinical and clinical data suggest modulation of the serotonergic system as a novel therapeutic approach in relieving opioid withdrawal syndromes.

Areas covered: Serotonin receptors that have been reported to mediate opioid withdrawal signs based on preclinical findings are identified and described. Extant clinical studies assessing the modulation of these receptors on opioid withdrawal outcomes are then summarized.

Expert opinion: While medications that serve as agonists or antagonists to serotonin receptor subtypes have the potential for treatment of opioid withdrawal and neonatal opioid withdrawal syndrome, much of the evidence is tenuous. The supportive data are mainly derived from preclinical studies, and the measured clinical efficacy has been variable, but reductions in symptom severity are consistently noted. Serotonergic modulation offers a non-opioid pathway to relieving opioid withdrawal manifestations, which is especially useful for neonates as changes in neuroplasticity have been noted with postnatal opioid use. Potential benefits warrant additional studies to clarify the mechanisms for their effect and for measuring how effective these agents are in human disease.