Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants

Phase 2

Terminated

Conditions: Neonatal Abstinence Syndrome

Interventions: Drug: Clonidine HCL
Drug: saline

Registration Number: NCT01360450

Lead Sponsor: Johns Hopkins University

Brief Summary: Thousands of critically ill infants (and children) are exposed to opioids and benzodiazepines to achieve sedation and analgesia as part of routine care in neonatal and pediatric intensive care units. While the use of these agents are undisputedly beneficial in reducing pain and anxiety, improving ventilation, reducing pulmonary vascular resistance and improving outcomes; the consequence is often the development of tolerance and physiologic dependence - similar to prenatal exposure from these same classes of drugs. The investigators have recently reported the results of randomized placebo control trial showing that the addition of clonidine (central alpha 2 agonist) to tapering doses of opioids was efficacious and safe in treating opioid dependence in infants who had moderate to severe neonatal abstinence syndrome from prenatal drug exposure to opioids. Currently, the investigators propose to perform a double-blind, randomized placebo control trial in a cohort of critically ill infants without prenatal drug exposure at Johns Hopkins Hospital to test the overall hypothesis that early addition of clonidine to a cohort of critically ill neonates on mechanical ventilation who are receiving opioids and benzodiazepines for analgesia and sedation will be efficacious and safe in reducing both the incidence and severity of withdrawal symptoms (NICU-NAS); as well as, reducing the time to complete sedative and analgesic drug detoxification. The hypothesis will be tested by addressing 2 specific aims that will determine: 1) the efficacy and safety of clonidine in critically ill infants, and 2) pharmacokinetics and pharmacodynamics using population-based pharmacokinetics in this vulnerable infant population who have only been exposed to these drugs as part of their routine care. Many "standard of care practices" are incorporated in neonatal and pediatric care prior to evidence based studies. This proposal will fill a much needed gap in translating what the investigators have learned about basic mechanisms mediating dependence and withdrawal to proven therapies for vulnerable pediatric populations.

Detailed Description: The study will test the following 2 specific aims:

Specific Aim 1

To determine the efficacy and short-term safety of clonidine in reducing the severity of iatrogenic neonatal abstinence syndrome (NAS) by decreasing the time required for complete sedative and analgesic drug detoxification. The investigators will enroll 88 neonates at risk for having moderate to severe NAS in a randomized, double-blinded placebo controlled trial comparing opioid/benzodiazepine administration combined with a placebo (control) vs. opioid/benzodiazepine combined with clonidine. Principal outcome measure will be the difference in length of treatment for complete detoxification. Early safety of clonidine will be determined by monitoring for cardiorespiratory side effects that might be associated with clonidine use in this high risk population.

Specific Aim 2

To determine the pharmacokinetics and pharmacodynamics of clonidine in this critically ill infant population. The investigators will estimate the dose-exposure-response relationship of clonidine in neonates at risk for developing iatrogenic by using nonlinear mixed-effects population pharmacokinetic (PK)-pharmacodynamic (PD) analysis.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 12

Inclusion Criteria

>35 week Gestational Age (GA) at birth
<3 months (90 days) old chronological age at the time of enrollment
Exposed to a minimum five days of continuous narcotic infusion

Exclusion Criteria

Neurologic abnormality which would make Neonatal Abstinence Score (NAS) scoring inaccurate
Major chromosomal abnormality (with the exception of Trisomy 21)
Infant already enrolled in another randomized, controlled clinical trial

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	Clonidine HCL	Interventions: Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation: Duration: (Clonidine HCL) 1 mcg/kg/dose q4 either iv or po.
Control	saline	Intervention: Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally

Primary Outcome Measures

Name	Time	Method
Time to Complete Detoxification	up to 4 weeks	Time to complete detoxification is defined as 48 hrs off all opioids/benzodiazepines and study drug with acceptable withdrawal scores of \<9 (on average we expect the infant to be enrolled in the study for 2-4 weeks). The scale used to assess withdrawal was the Modified Finnegan Neonatal Withdrawal Scale, which ranges from 0-41, 0 represents no withdrawal and 41 represent maximum withdrawal.

Secondary Outcome Measures

Name	Time	Method
Cardiovascular Side-effects Changes HR and BP	48 hrs after starting study drug and for 48hrs after stopping study drug	Changes in Heart Rate (HR) and BP for 48 hrs after starting study drug and for 48hrs after stopping study drug
Cumulative Dose of Opioid and Benzodiazepine	2-4 weeks	We will determine the total amount of opioid and benzodiazepine needed from the start of detoxification to the end of the the detoxification.