Neonatal Abstinence Syndrome
Conditions
Keywords
opioid withdrawal, Neonatal Pain, Agitation, and Sedation Scale (NPASS), duraclon
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.
Interventions
DRUGClonidine HCL
At day 5 on opioid and/or benzodiazepine (BZD), the infant will be randomized to receive either placebo (normal saline) or clonidine 1μg/kg/q 4 hrs to a maximum dose of 2μg/kg/q 4. Weaning from the study drug: When the opioid is no longer required, 24 hrs later the study drug (placebo or study drug) will be reduced by 50% and then discontinued 24 hours later provided that the Modified Finnegan scores remain between \< 9.
DRUGsaline
Infants randomized to placebo will be administered IV saline or oral sterile water in the same volume as study drug. The placebo will be give every 4 hrs as outlined in the algorithm for the study.
Sponsors
National Institute on Drug Abuse (NIDA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Days to 90 Days
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Infants recruited from the Neonatal Intensive Unit (NICU) and Pediatric Intensive Unit (PICU) at Johns Hopkins Hospital within 5 days of birth who needed sedation and analgesia as part of treatment. Recruitment period was from July 2011 to July 2014. Accrual was very low
Pre-assignment details
All patients who were enrolled participated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation
Clonidine HCL: At day 5 on opioid and/or benzodiazepine (BZD), the infant will be randomized to receive either placebo (normal saline) or clonidine 1μg/kg/q 4 hrs to a maximum dose of 2μg/kg/q 4. Weaning from the study drug: When the opioid is no longer required, 24 hrs later the study drug (placebo or study drug) will be reduced by 50% and then discontinued 24 hours later provided that the Modified Finnegan scores remain between \< 9. | 6 |
| Control Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally
saline: Infants randomized to placebo will be administered IV saline or oral sterile water in the same volume as study drug. The placebo will be give every 4 hrs as outlined in the algorithm for the study. | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Treatment | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Birth Weight | 3084 grams STANDARD_DEVIATION 0.59 | 3250 grams STANDARD_DEVIATION 0.9 | 3160 grams STANDARD_DEVIATION 0.76 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 1 Participants | 7 Participants |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Time to Complete Detoxification
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.
Time frame: up to 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Time to Complete Detoxification | total days on narcotics | 89.5 days | Standard Deviation 137 |
| Treatment | Time to Complete Detoxification | duration on study drug in days | 21 days | Standard Deviation 18.1 |
| Control | Time to Complete Detoxification | total days on narcotics | 37.2 days | Standard Deviation 10 |
| Control | Time to Complete Detoxification | duration on study drug in days | 14.2 days | Standard Deviation 8.5 |
p-value: >0.05ANOVA
Secondary
Cardiovascular Side-effects Changes HR and BP
Changes in Heart Rate (HR) and BP for 48 hrs after starting study drug and for 48hrs after stopping study drug
Time frame: 48 hrs after starting study drug and for 48hrs after stopping study drug
Population: No data is available for this outcome measure, as it was not collected.
Secondary
Cumulative Dose of Opioid and Benzodiazepine
We will determine the total amount of opioid and benzodiazepine needed from the start of detoxification to the end of the the detoxification.
Time frame: 2-4 weeks
Population: No data is available for this outcome measure, as it was not collected.