Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants

Johns Hopkins University

Status and phase: Terminated; Phase 3; Phase 2

Conditions: Neonatal Abstinence Syndrome

Treatments: Drug: saline; Drug: Clonidine HCL

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01360450

R21DA029295-01 (U.S. NIH Grant/Contract)

Clonidine NICU-NAS

Details and patient eligibility

About

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.

Full 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.

Enrollment: 12 patients

Sex: All

Ages: 5 to 90 days old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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12 participants in 2 patient groups, including a placebo group

Treatment

Experimental group

Description:

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.

Treatment:

Drug: Clonidine HCL

Control

Placebo Comparator group

Description:

Intervention: Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally

Treatment:

Drug: saline