Accelerated Weaning of Opioids to Reduce Pharmacologic Exposure for Neonatal Opioid Withdrawal Syndrome: A Randomized Clinical Trial

OBJECTIVE: To determine if newborns receiving morphine or methadone as the primary pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS) tolerate and receive fewer days of opioid using an accelerated wean protocol (15% decrements) compared with using a slower wean protocol (10% decrements). STUDY DESIGN: Newborns ≥36 weeks of gestation receiving morphine or methadone for NOWS were enrolled in a pragmatic blinded, randomized multicenter trial. Newborns underwent protocol-driven weaning with decreasing opioid doses of either 15% or 10% decrements. Weaning was encouraged every 24 hours, and if signs of NOWS worsened, the preceding dose was resumed. To maintain blinding, the last 3 dose levels of the 15% decrements were placebo. The primary outcome was the number of days of opioid treatment from the first weaning dose to cessation of opioids. RESULTS: Slow enrollment prompted early trial closure; 189 newborns were randomized, 98 (51.9%) to 15% decrements (mean ± SD, 38.8 ± 1.2 weeks gestation, 59.8% male) and 91 (48.1%) to 10% decrements (38.8 ± 1.3 weeks gestation, 61.5% male). Morphine was used most commonly. Intention-to-treat analysis included all but 4 infants withdrawn in the 15% decrement group. The durations of opioid treatment during weaning were 8.2 (7.2, 9.5) (adjusted mean [95% CI]) and 11.2 (9.7, 12.9) days for 15% and 10% decrement groups, respectively (P < .001). Adverse events were few in both groups. CONCLUSION: Pharmacologic treatment of NOWS using an accelerated wean protocol (15% decrements) was well tolerated with fewer days of opioid treatment compared with 10% decrements. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04214834.