Clonidine vs Morphine Pharmacotherapy for Significant NOWS

Source: Bada HS, Westgate PM, Sithisarn T, et al. Clonidine as monotherapy for neonatal opioid withdrawal syndrome: a randomized trial. Pediatrics. 2024;154(5):e2023065610; doi: 10.1542/peds.2023-065610.Investigators from multiple institutions conducted a randomized trial comparing the effectiveness of morphine and clonidine in managing infants with neonatal opioid withdrawal syndrome (NOWS). Newborns born at ≥35 weeks’ gestation with prenatal opioid exposure and meeting criteria for NOWS were enrolled when they were ≤7 days old. At enrollment, study participants were randomized to treatment with clonidine 1 μg/kg/dose or morphine 60 μg/kg/dose every 3 hours. Families and providers were blinded to treatment group. NOWS symptoms were monitored with Finnegan Neonatal Abstinence Scoring System Scores (FS). The dose of study medication was increased until FS were consistently <8, or until a predetermined maximum dose of each drug was reached. If the maximum dose was reached, an adjunct medication, usually phenobarbital, was added. When FS began dropping, the dose of study medication was weaned in a prescribed fashion. After the study drug was discontinued, infants were monitored for 48 hours prior to discharge. The primary study outcomes were length of treatment (LOT) with study medication and scores on NICU Network Neurobehavioral Scale (NNNS), which assesses neurologic, behavioral and stress/abstinence in newborns across 13 domains. The NNNS was administered when infants began weaning off their study medication and when it was discontinued. Secondary outcomes included need for adjunct therapy, FS scores, and LOS. Outcomes among infants in the 2 treatment groups were compared using a variety of statistical tests.A total of 120 infants were enrolled in the study, with 60 randomized to each treatment group. Prior to treatment the median maximum FS among infants randomized to clonidine was 14.5 and 14 among those randomized to morphine. By the third day of treatment, the maximum FS was significantly higher in newborns receiving clonidine than in those randomized to morphine (P <0.001). In addition, 27 (45%) of those randomized to clonidine required an adjunct drug for treatment compared to 6/60 (10%) infants receiving morphine (P <0.001). Overall, there were no significant differences for LOT and LOS in infants randomized to clonidine or morphine (median LOT, 17 and 15 days, respectively; P = 0.48; LOS, 22 and 19 days, respectively; P = 0.30). When NNNS initially was administered to study participants, scores for some domains were significantly worse among those receiving clonidine than in those randomized to morphine, but there were no significant differences between groups in NNNS scores when infants were assessed after discontinuation of study medication.The authors conclude LOT and final NNNS scores were not significantly different among infants with NOWS managed with clonidine or morphine.Dr Loyal has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The evidence supporting strategies to optimize maternal and child health during pregnancy and post-partum in response to the opioid epidemic has grown substantially.1-2A non-pharmacologic approach is the first line treatment for infants with NOWS, specifically rooming-in with the mother, a low stimulation environment, swaddling and breastfeeding.1 Assessing the severity of NOWS to guide treatment remains inconsistent with some institutions favoring a symptom-based scoring tool vs a functional assessment tool. Notably, the AAP does not endorse a single scoring tool for NOWS.2 At the Yale University School of Medicine, symptoms are measured with the functional Eat Sleep Console (ESC) approach, and pharmacotherapy is given on an as-needed basis; the average length of hospital stay is 5 days. (See AAP Grand Rounds. 2017;38[3]:28.)3 The ESC approach has been replicated in multiple institutions, with no significant adverse outcomes reported.4Despite differences in criteria, once pharmacotherapy is initiated, morphine generally is recommended as the first-line agent.1 In the current study, the comparable length of treatment and neurobehavior assessment of infants treated with clonidine in comparison with morphine suggests that a non-opioid alternative as a first-line medication for NOWS may be reasonable to consider. The increased use of adjunctive therapy when using clonidine and what appears to be a slower initial treatment response need to be investigated further in larger studies.Measuring response to NOWS treatment is complicated. There are unknown effects of in utero exposure to substances other than opioids, unknown dose effect in the setting of multiple exposures and timing of exposures, differences in placental transfer, and the contribution of small amounts of medication through the breastmilk. It is also unclear whether the use of non-opioid treatment post-delivery will mitigate the in utero long-term developmental effects of opioid exposure in these infants.In symptomatic infants with NOWS, treatment with clonidine compared with morphine results in similar LOT and comparable neurobehavioral outcomes.