Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: A randomized controlled trial

Context. Opioids are the standard treatment for neonatal abstinence syndrome (NAS). We hypothesized that clonidine, a centrally-acting alpha-adrenergic agonist useful in opioid detoxification in adults, would ameliorate the symptoms of opioid withdrawal in neonates.Objectives. To determine if clonidine in combination with diluted tincture of opium (DTO, 0.4 mg/mL/morphine equivalent) reduces the duration of opioid detoxification and to determine the pharmacokinetics of oral clonidine in neonates with NAS.Methods. Neonates (n=80) with intrauterine exposure to methadone or heroin and 2 consecutive modified Finnegan Scores (MFS) >9 were block-randomized into 2 parallel groups, to receive clonidine (Duraclon(TM), 1mcg/kg q4h) (n=40) or placebo (n=40) in addition to DTO orally, in double-blind fashion. Excluded were infants <35 weeks gestational age, <5th% birth weight or breastfeeding. All infants received DTO in dosages ranging from 0.2mL q4h to 0.9mL q4h according to a standardized algorithm. Infants requiring >0.9mL q3h were classified as treatment failure. Infants were monitored for hypotension, bradycardia, and oxygen desaturations. In a population pharmacokinetic (PK) analysis of 103 samples, clonidine clearance (CL/F), volume of distribution (V/F) and absorption rate constant (Ka) were determined.Results. The median length of therapy was 27% shorter in the clonidine group (11 days, 95%CI:8-15 days) than in the placebo group (15 days, 95%CI:12-17 days) the difference was statistically significant by the logrank test (p=0.035). Fewer infants in the clonidine group required high dosages of DTO. There were fewer infants with seizures (0 versus 3, p=0.24) or treatment failure (0 versus 5, p=0.05) in the clonidine group than in the placebo group. Hypertension, hypotension, bradycardia, or desaturations did not occur in either group. Three infants in the clonidine group died before 6 months of age, all after discharge from the hospital, due to myocarditis, sudden infant death syndrome, and homicide, respectively. A one-compartment PK model with dosing by weight determined the CL/F 0.26L/hr/kg (95%CI:0.24-0.29L/hr/kg), V/F 4.62L/kg (95%CI:3.90-5.34L/kg) and Ka 0.96/hr (95%CI:0.093-0.44/hr).Conclusions. In neonates requiring pharmacotherapy for NAS, addition of oral clonidine to standard opioid treatment results in a shorter length of treatment and sparing of opioids. This study provides a one-compartment pharmacokinetic model with weight based oral clonidine dosing.Keywords from the Medical Subject Headings (MeSH) Database. Neonatal Abstinence Syndrome, Clonidine, Analgesics, Opioid, Pharmacokinetics.