Clonidine Comparable to Morphine for Infants With Opioid Withdrawal

Length of treatment and neurobehavioral scores did not significantly differ between infants with prenatal opioid exposure randomized to either clonidine or morphine, researchers found.

Among infants with neonatal opioid withdrawal syndrome (NOWS), median length of treatment was 15 days for infants who received morphine and 17 days for those who received clonidine (P=0.48), reported Henrietta Bada, MD, MPH, of the University of Kentucky in Lexington, and colleagues.

At the end of treatment, neurobehavioral performance, a predictor of childhood outcomes, also did not differ between groups, Bada and colleagues noted in Pediatrics.

However, more of the clonidine-treated infants needed adjunct therapy compared with those in the morphine group (45% vs 10%; adjusted odds ratio 8.85, 95% CI 2.87-27.31, P<.001).

"Future studies are needed to investigate the optimal dose and frequency of clonidine administration for improved efficacy and the decreased need for adjunctive therapy in NOWS," Bada and colleagues noted.

Increased use of prescribed and illicit opioids among women of childbearing age in the U.S. has contributed to an uptick in NOWS, with diagnosed infants at higher risk of hospital readmission after birth.

The researchers noted that smaller studies have suggested that clonidine -- a non-opioid alpha-2 adrenergic agonist -- can work in NOWS, as a single-drug therapy and as an adjunct therapy. Preclinical work has shown that it "has advantages over morphine" including the fact that it "stabilizes breathing and temperature control that is disrupted by morphine" and "downregulates opioid receptor expression in neonatal mononuclear cells."

In their earlier pilot study, clonidine was associated with shorter length of treatment and improved neurobehavioral performance compared with morphine for neonatal abstinence syndrome, which "supported evaluating a non-opioid drug as an alternative to treat NOWS," they wrote.

At initial testing, clonidine-treated infants scored worse on arousal, hypertonicity, and stress abstinence. But between initial and final assessments, this group showed significant improvement (less handing, excitability, and stress abstinence, and improved arousal and regulation), ultimately faring as well as their morphine-treated counterparts.

At final measure, median neurobehavioral scores based on the NICU Network Neurobehavioral Scale were not significantly different between groups.

There was also no significant difference in median length of hospital stay between clonidine and morphine groups (22 days vs 19 days; P=0.30).

The current study by Bada and colleagues "is a robust new clinical trial in the field of NOWS demonstrating efficacy of clonidine as a primary pharmacologic agent with comparative hospitalization outcomes to morphine, with the exception of higher secondary agent use," wrote Elisha Wachman, MD, of Boston University Chobanian & Avedisian School of Medicine, and Hayley Friedman, MD, of Washington University School of Medicine in St. Louis, in a commentary accompanying the study.

"Future studies should incorporate multicentered designs, examine longer-term neurodevelopmental outcomes, emphasize the importance of standardized nonpharmacologic care bundles as primary medical management, compare clonidine to methadone and buprenorphine, and incorporate symptom-triggered dosing and the [Eat, Sleep, Console] care approach for broadest generalizability into clinical practice," they added.

For this randomized clinical trial, enrollment criteria included gestational age of at least 35 weeks, ≤7 days postnatal age, prenatal opioid exposure, and no other medical condition. Infants were enrolled from December 2017 to February 2022 at a single children's hospital in the U.S.

There were 120 infants randomized to oral clonidine at a dose of 1 μg/kg or morphine at a dose of 0.06 mg/kg, every 3 hours. Those showing no improvement had their doses increased by 25% of the initial dose every 12 to 24 hours. Those without improvement by the fourth dose received adjunct therapy. All infants had non-pharmacological intervention, such as swaddling, low noise and lighting environment, rooming in, and infant massage.

Initiation and monitoring of treatment were guided by Finnegan Neonatal Abstinence Scoring System scores (FSs), which are used to monitor withdrawal symptoms. Clonidine or morphine started when an infant had three consecutive FSs ≥8 or two consecutive FSs ≥12. The aim was FSs consistently <8.

Prior to treatment, the median of maximum FSs was similar in infants who received clonidine (14.5, 95% CI 14.1-15.6) and those who received morphine (14, 95% CI 13.9-15.5). By the third day of treatment, the maximum FS was significantly lower in the morphine-treated group, with a median of 8 (95% CI 7.3-8.6) versus 11.5 (95% CI 11.0-12.5) in the clonidine-treated group (P<0.001).

Over time, though, similar patterns of mean FS emerged. After 6 days, mean daily scores for the clonidine group trended lower than the morphine group; however, CIs overlapped.

Limitations of the study included that it was not powered to show equivalence or non-inferiority, and that the pandemic affected plans to enroll a larger sample at an additional site.

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