Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial B Surran, P Visintainer, S Chamberlain, K Kopcza, B Shah and R Singh
To compare the efficacy of clonidine versus phenobarbital in reducing morphine sulfate treatment days for neonatal abstinence syndrome (NAS).
Prospective, non-blinded, block randomized trial at a single level III NICU (Neonatal Intensive Care Unit). Eligible infants were treated with a combination of medications as per protocol. Primary outcome was treatment days with morphine sulfate. Secondary outcomes were the mean total morphine sulfate dose, outpatient phenobarbital days, adverse events and treatment failures.
A total of 82 infants were eligible, of which 68 were randomized with 34 infants in each study group. Adjusting for covariates phenobarbital as compared with clonidine had shorter morphine sulfate treatment days (−4.6, 95% confidence interval (CI): −0.3, −8.9; P=0.037) with no difference in average morphine sulfate total dose (1.1 mg kg−1, 95% CI: −0.1, 2.4; P=0.069). Post-discharge phenobarbital was continued for an average of 3.8 months (range 1 to 8 months). No other significant differences were noted.
Phenobarbital as adjunct had clinically nonsignificant shorter inpatient but significant overall longer therapy time as compared with clonidine.
This prospective but non-blinded study randomized opioid-exposed infants with moderate to severe neonatal abstinence syndrome (NAS) to compare length of morphine sulfate therapy with clonidine as adjunct therapy or with phenobarbital as adjunct therapy. The dosing protocol utilized tiered initial dosing determined by the initial qualifying modified Finnegan score and adjunct therapy was started with initial morphine dosing. The primary outcome analyzed was the time taken to wean the infants off morphine for each group. The sample size was powered to detect a difference of 5 days in treatment time. This study was terminated early due to a detected difference in length of morphine therapy favoring phenobarbital adjunct dosing. Multivariable analyses showed an adjusted mean difference of 4.6 days (95% CI: 0.3, 8.9; p=0.03). Average total dose of morphine received was not significantly different between the two groups. Both groups had decreased lengths of therapy compared to the study site’s prior protocol using morphine alone, consistent with previous studies. It was observed that post-discharge phenobarbital therapy was continued for an average of 3.8 months (range 1-8 months). Given the growing evidence and concern for the possible negative cognitive and developmental effects of phenobarbital, additional studies utilizing different dosing protocols may be indicated to better assess the potential for clonidine adjunct therapy.
Aaron Germain, M.D.