Multiple drug classes (opioids, benzodiazepines, barbiturates, and phenothiazines) have been used alone or in combination to manage NAS in infants born to drug addicted mothers.9,19
However, this is the first randomized, controlled trial of clonidine20
and the largest prospective double-blind, randomized trial of any kind in this patient population. Our findings that clonidine in combination with DTO stabilized and detoxified infants with moderate to severe NAS more rapidly than DTO alone confirms the findings of a previously published, small, open-label study in neonates17
and validates by using α2
-adrenergic receptor agonists in the management of opioid withdrawal symptoms.
Clonidine has successfully been used to treat the symptoms of opioid (and other drug) withdrawal in older children21
Being a central α2
-adrenergic receptor agonist acting at presynaptic receptors in the midbrain and medulla, clonidine inhibits sympathetic outflow by decreasing central catecholamine release, leading to reduced blood pressure and heart rate.25,26
Clonidine is well absorbed after oral and transdermal administration, is highly lipid soluble, and readily distributes in the central nervous system.27
Adverse effects include hypotension, rebound hypertension, atrioventricular block, and bradycardia. Concurrent use of β
-blockers increases adverse events in adults,28
and toxicity can result from accidental ingestion by children.29–31
The transient decrease in blood pressure when starting clonidine/DTO and increase after stopping it was within the range of blood pressure norms for term infants.18
The differences in blood pressure between the 2 groups may have been directly related to clonidine or attributed to better early control of NAS. Rebound of symptoms of NAS was limited to the clonidine/DTO group () and was controlled with small amounts of opioid for a short period. It is unclear if rebound was due to withdrawal from clonidine, DTO, or both. A 2-step reduction of the clonidine dose over 48 hours or weaning of opioids before stopping clonidine may result in fewer rebound events.
The 4 serious adverse events (1 episode of SVT and 3 deaths) all occurred in the clonidine/DTO group and happened after discontinuation of clonidine. The SVT episode occurred 3 days after stopping clonidine and was successfully treated with adenosine; it did not recur. Clonidine has been used to treat cardiac dysrhythmias32
and is associated with elevations of blood pressure and heart rate after abrupt discontinuation in children33
but has only caused SVT in 1 adult with severe heart and renal failure.35
Although we think it unlikely, we cannot say with certainty that stopping clonidine caused the single episode of SVT in this otherwise healthy infant. Furthermore, whether clonidine contributed to the 3 deaths caused by myocarditis, SIDS, and homicide is not known.
This study was not designed to detect differences in lengths of hospitalization, because hospitalization may be prolonged and discharge delayed even after pharmacotherapy is no longer required in this population. In agreement with other reports,36
methadone exposure was associated with longer pharmacotherapy for NAS than heroin exposure alone; clonidine shortened the length of treatment of methadone-exposed infants.
Interpretation of our results is limited by the small number of patients, which limited the statistical power to determine the true assessment of the effect of clonidine on short- and long-term adverse events. The short-term follow-up precluded assessment of long-term neurodevelopment. Although the study sample was diverse in gender, ethnicity, and exposure to methadone and heroin, the small number of hospitals in a limited geographic area limits broad generalization of our findings.
Because the pharmacokinetics of clonidine in newborn infants was not available to us at the time of this trial, we chose the dose of 1 μ
g/kg every 4 hours on the basis of the study of Hoder et al,17
our experience using clonidine in 8 infants with intractable NAS, and guidance of the Food and Drug Administration who granted the physician-sponsored investigational new drug to perform this trial. As part of the trial, population pharmacokinetics were performed and will be reported in a separate manuscript. The clonidine formulation (100 μ
g/mL, diluted to 5 μ
g/mL) administered orally in this study is commercially available for epidural injection; it was selected to ensure accurate dosing as opposed to a suspension made from tablets (0.2 mg).37
A clonidine transdermal patch is available (in 3 concentrations) but can have problems with bioavailability resulting in nonuniform dosing and has been associated with toxicity in infants.38
Dexmedetomindine has 8 times the affinity for the α2
-adrenergic receptor than clonidine and is approved for short-term sedation for adults. Its effective sedative, analgesic, and anxioloytic properties without respiratory depression are desirable properties39
also for infants,40
but randomized trials are essential to demonstrate its efficacy and safety.
The American Academy of Pediatrics recommends DTO for treatment of severe NAS, although diluted morphine is frequently used and has similar efficacy.41
Clonidine, when used in combination with intravenous opioids, reduces total opioid use in infants.42
Thus, clonidine is likely to be effective when combined with oral morphine. For infants requiring >0.5 mL of DTO or 0.2 mg ME every 4 hours, we added clonidine to facilitate NAS symptom control and weaning of the opioid.