Treatment of opioid withdrawal in neonates with morphine, phenobarbital, or chlorpromazine: a randomized double-blind trial

Abstract

Three suitable compounds (morphine, chlorpromazine, and phenobarbital) to treat neonatal abstinence syndrome were compared in a prospective multicenter, double-blind trial. Neonates exposed to opioids in utero were randomly allocated to one of three treatment groups. When a predefined threshold of a modified Finnegan score was reached, treatment started and increased stepwise until symptoms were controlled. If symptoms could not be controlled with the predefined maximal dose of a single drug, a second drug was added. Among 143 infants recruited, 120 needed pharmacological treatment. Median length of treatment for morphine was 22 days (95% CI 18 to 33), for chlorpromazine 25 days (95% CI 21 to 34), and for phenobarbital 32 days (95% CI 27 to 38) (p = ns). In the morphine group, only 3% of infants (1/33) needed a second drug; in the chlorpromazine group, this proportion was 56% (24/43), and in the phenobarbital group 30% (13/44). Conclusion: None of the drugs tested for treating neonatal abstinence syndrome resulted in a significantly shorter treatment length than the others. As morphine alone was able to control symptoms in almost all infants, it may be preferred to the two other drugs but should still be tested against more potent opioids such as buprenorphine. Trial registration: At ClinicalTrials.gov NCT02810782 (registered retrospectively). What is Known: • Neonates exposed to opiates in utero and presenting with withdrawal symptoms should first be treated by non-pharmacological supportive measures. • In those who fail, drugs have to be given, but there is controversy which drug is best. What is New: • Among three candidates, morphine, chlorpromazine and phenobarbital, none resulted in significantly shorter treatment time. • As morphine alone was able to control symptoms in almost all infants, it may be preferred to the two other drugs.

Clinical pharmacology of morphine in infants and children

“…Morphine decreases the ticagrelor plasma concentration [30], the combination of gabapentin with morphine produces better anaesthesia even when administered at low dose [32], and morphine is associated with a delayed onset of action of oral antiplatelet agents [33]. The treatment of infants and children with morphine has been extensively studied [34][35][36][37][38][39][40][41][42][43].…”

“…Morphine is able to control withdrawal symptoms in infants exposed to opioids in utero [34]. Newborns, with neonatal abstinence syndrome, were treated with morphine which significantly produces higher scores in cognitive and gross motor domains compared to infants treated with methadone [35].…”

Efficacy of a Vibrating Crib Mattress to Reduce Pharmacologic Treatment in Opioid-Exposed Newborns

“…Given emerging concerns on the meaningfulness of the Finnegan score as a primary outcome, we focused analyses on pharmacotherapy (AMT, CMD, and LOT) and hospitalization duration (length of stay). We did not recalculate the sample size post hoc; calculations reported in other studies indicated our study sample size was adequate to detect differences (Supplement 1).…”

Maternal and iatrogenic neonatal opioid withdrawal syndrome: Differences and similarities in recognition, management, and consequences

“…Currently, morphine and methadone are recommended for opioid therapy of mNOWS for severe symptoms of withdrawal by the American Academy of Pediatrics (Hudak et al, 2012;Lacaze-Masmonteil & O'Flaherty, 2018), with morphine being the most widely used (Tolia et al, 2015). When compared in a multicenter, double-blind, prospective parallel group study in neonatal intensive care units, morphine, phenobarbital, and chlorpromazine show some efficacy, but morphine was more likely to treat symptoms of withdrawal in mNOWS without requiring a second agent (Zimmermann et al, 2020). Morphine and methadone show similar short-term and long-term (18 months of age) neurobehavioral outcomes when used for treatment of mNOWS (Czynski et al, 2020), but methadone is associated with shorter hospitalization (Tolia et al, 2018), while buprenorphine shows superiority over other opioids in decreasing both treatment duration and length of stay (Disher et al, 2019;Kraft et al, 2017;Lee et al, 2019).…”