Agthe 2009.

Study characteristics
Methods	Randomised, double‐blind, placebo‐controlled trial in USA March 2002 to December 2005
Participants	Inclusion criteria Infants aged 0–14 days if they were exposed to opioids during the antenatal period and developed moderate‐to‐severe NAS (2 consecutive modified NASS scores ≥ 9) requiring pharmacotherapy Exclusion criteria Gestational age < 35 weeks Intrauterine growth retardation (birth weight < 5th percentile) Congenital anomalies Illness requiring oxygen, intravenous fluids or medications Breastfeeding 61% of infants were exposed to an opioid + cocaine in utero, 6/80 infants had positive benzodiazepine urine screens.
Interventions	Intervention 1: oral clonidine 1 μg/kg every 4 hours (6 μg/kg/day) and (clonidine/DTO) (n = 40) Intervention 2: DTO (placebo/DTO) (n = 40) DTO was given as a 1:25 dilution, 0.4 mg/mL (morphine equivalent). All infants started on 0.2 mL DTO (0.08 mg morphine equivalent) orally every 4 hours. NAS symptoms were uncontrolled if there were 2 consecutive MFSs ≥ 9. DTO was incrementally escalated to 0.3 mL, 0.4 mL and 0.5 mL every 4 hours, then to 0.5 mL, 0.7 mL and 0.9 mL every 3 hours, until withdrawal symptoms (MFS < 9) were controlled. (Dose range 0.48 mg/day titrated to maximum 2.88 mg/day.) Clonidine/placebo dose was based on weight (mL/kg) and maintained at that dose. When symptoms were controlled (mean daily MFS < 9), infants were continued on clonidine/placebo and DTO dose that controlled symptoms for ≥ 48 hours. Afterward, DTO was weaned by increments of 0.05 mL per dose, for each 24‐hour period.
Outcomes	Primary outcome Length of treatment for NAS Secondary outcomes Amount of DTO required to treat the NAS (with or without clonidine) Treatment failure (> 0.9 mL of diluted TO every 3 hours) Seizures Weight gain BP, heart rate and haemoglobin saturation measured by pulse oximetry Diagnosis of seizures made by the clinical team; all infants received an electroencephalogram after phenobarbital was administered and no infant had an abnormal electroencephalogram.
Notes	Funded by a Thomas Wilson grant, an institutional research grant from JHH, General Clinical Research Center, and was supported by National Institute on Drug Abuse. ClinicalTrials.gov identifier NCT00510016
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation.
Allocation concealment (selection bias)	Low risk	Infants were stratified according to hospital of birth and maternal methadone use before randomisation. After written parental consent it was reported that (quote): "eligible infants were randomly assigned by research pharmacist into 2 strata by a computerised random list in blocks of 4".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo (isotonic saline) used. Quote: "a clear, colourless, liquid formulation of clonidine was diluted".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "investigators, parents, and caretakers were blinded to group allocations until the study was completed".
Incomplete outcome data (attrition bias) All outcomes	Low risk	1 withdrawn infant reported in intention‐to‐treat analysis.
Selective reporting (reporting bias)	Unclear risk	Retrospective trial registration. Only primary outcome documented in registration.
Other bias	Unclear risk	Reported that infants in the clonidine + DTO group had significantly lower mean birthweight.