Clonidine as Monotherapy for Neonatal Opioid Withdrawal Syndrome: A Randomized Trial

Abstract

Objective: We sought to determine whether clonidine, a non-opioid α-2-adrenergic agonist, would effectively treat neonatal opioid withdrawal syndrome (NOWS).

Methods: This was an intention-to-treat randomized clinical trial. Enrollment criteria included prenatal opioid exposure, age ≤7 days, gestational age ≥35 weeks, no other medical condition, and need for pharmacotherapy. Primary outcomes were length of treatment and neurobehavioral performance.

Results: A total of 1107 patients were screened for enrollment (645 ineligible, 91 parents or staff unavailable, 216 declined, 155 consented). Of 155 infants, 120 required treatment and were randomized to receive oral clonidine (n = 60) at 1 µg/kg/dose or morphine (n = 60), 0.06 mg/kg/dose, every 3 hours. Infants with no improvement had their doses increased by 25% of the initial dose every 12 to 24 hours. Those without improvement by the fourth dose increase, received adjunct therapy. Length of treatment did not differ between morphine and clonidine, with median (95% confidence interval [CI]) days, respectively, of 15 (13-17) and 17 (15-19), P = .48. More clonidine-treated infants (45%) needed adjunct therapy versus 10% in the morphine group, adjusted odds ratio (95% CI) = 8.85 (2.87-27.31). After treatment completion, the NICU Network Neurobehavioral Scales summary scores did not differ between clonidine-treated and morphine-treated infants.

Conclusions: Length of pharmacologic treatment and final neurobehavioral performance were not significantly different between the clonidine- and morphine-treated groups. Clonidine appears to be an effective non-opioid medication to treat NOWS. Future studies are needed to determine the optimal clonidine dosage for a quicker response and obviation of adjunct therapy.

FIGURE 1

CONSORT flow diagram showing the number of participants screened for eligibility who were consented for enrollment, enrolled, received allocation, were excluded or withdrawn from participation after the intervention initiated and the reasons, and included in the outcome analysis.

FIGURE 2

Trajectories of the Finnegan scores, mean, and 95% CI over the course of treatment of all infants in the treatment groups (Fig 2A) and for those who only received a single drug therapy and no adjunct medication (Fig 2B). The means and 95% CIs are descriptive and conditional on subjects still being treated on the given day.