Neonatal opiate withdrawal syndrome (NOWS) is an all-too-common reason for newborns to be hospitalized for prolonged lengths of stay. Although non-pharmacologic methods such as “Eat, Sleep, Console” are considered first line treatment, the American Academy of Pediatrics currently recommends opioid medications as the next step in management for infants who continue to have severe symptoms.
Unfortunately, opioids come with significant risks, including respiratory depression and slowed gut motility, and are associated with adverse effects on the developing brain.
The question is: can we find another medication that is effective, but with a better safety profile?
This week, Pediatrics is early releasing an article and accompanying video abstract by Dr. Henrietta Bada from the University of Kentucky and colleagues, entitled “Clonidine as Monotherapy for Neonatal Opioid Withdrawal Syndrome: A Randomized Trial” (10.1542/peds.2023-065610). Clonidine has been shown to decrease withdrawal symptoms, both as an adjunct therapy and, in small studies, as a primary agent. Clonidine not only has a more desirable safety profile but may lead to neurologic benefits by decreasing brain injury and cell apoptosis, and by suppressing inflammatory cytokines.
In this study, authors enrolled neonates who were:
- at risk of NOWS due to known prenatal opioid exposure
- ≥35 weeks gestational age
- ≤7 days of age
The authors randomized 120 neonates to either: 1) clonidine monotherapy or 2) morphine monotherapy. Finnegan Neonatal Abstinence Scores were used to guide treatment. If clinical improvement was not achieved at the maximum dose of either medication, adjunct therapy with phenobarbital—or, in situations where the clinical team preferred to avoid phenobarbital, either morphine or clonidine—was added.
When comparing the two treatment arms, authors found:
- No difference between morphine and clonidine in median duration of treatment (15 versus 17 days, p=0.48), or length of stay (19 versus 22 days, p=0.3).
- Significantly more clonidine-treated infants required adjunct therapy (45% versus 10% in the morphine group, p<0.001). In fact, the clonidine group had almost 9 times the adjusted odds of requiring adjunct therapy.
As noted in the accompanying invited commentary by Dr. Elisha Wachman from Boston University and Dr. Hayley Friedman from Washington University (10.1542/peds.2024-068359), it is unclear how these results will be integrated into current clinical practice. One interesting point was the use of phenobarbital as the primary adjunct therapy. Although it is effective treatment for NOWS and offers the benefit of a home-weaning option, concern exists for worsened developmental outcomes and behavioral issues in phenobarbital-exposed infants. These concerns were reflected in many clinical teams’ decisions to opt instead for either clonidine or morphine as an alternative adjunct therapy.
Perhaps the most interesting takeaway was that 55% of neonates who were randomized to clonidine were able to avoid post-natal opioids and/or phenobarbital, with similar treatment duration and length of stay as those receiving opioids. Given the harms of opioids and phenobarbital on the developing brain, this is a promising finding.
