Iatrogenic Opioid Withdrawal in Hospitalized Infants

Introduction

Infants exhibit acute physiologic and hormonal responses to pain leading to increased neurologic morbidity and mortality.¹ Pain-mediated poor neurologic outcomes are mitigated by opioid-derived medication, yet, recent work finds that preterm infants receiving opioids during hospitalization can also exhibit increased morbidity and death.² Methadone treatment is commonly used to transition an infant off of intravenous opioids after prolonged treatment or in response to clinical signs of opioid withdrawal.³ Epidemiological studies of infant iatrogenic opioid withdrawal associated with clinician-prescribed opioid exposures during hospitalization are sparse. This study estimated the annual incidence of iatrogenic opioid withdrawal following opioid therapy indicated by methadone treatment for infants cared for in children’s hospitals over a recent 10-year period in the United States.

Methods

A retrospective cohort study using the Pediatric Health Information System® (PHIS) database was conducted using data from January 2005–October 2015. PHIS is maintained by the Children’s Hospital Association (CHA; Lenexa, KS) and includes clinical and resource utilization data for 52 children’s hospitals, representing 20% of all pediatric hospitalizations in the United States and approximately 50% of hospital discharges of children with the highest illness severity. All infants <1 year at discharge were identified, including term and preterm infants and inborn patients. Infants with NAS/NOWS due to in-utero opioid exposure as identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes (779.5, 760.7x) and infants who received methadone alone during hospitalization were excluded. Infants with ICD-9-CM code 779.5 and a comorbidity commonly associated with iatrogenic opioid withdrawal remained in the cohort. Infants who were weaned from opioid infusions and discontinued without methadone were not identified. Scoring tools for sedations weans (e.g. Finnegan Neonatal Abstinence Scoring System) are not captured in PHIS and were therefore not included. The study was approved by the Children’s Hospital Los Angeles Institutional Review Board.

Annual incidence of clinician-administered non-methadone opioids (e.g. intravenous morphine, fentanyl, hydromorphone) and methadone treatment was estimated from pharmacy charges. Hierarchical multivariable logistic regression with mixed effects was employed to determine odds of methadone treatment for infants receiving non-methadone opioids. Sociodemographics were included and disease severity was measured by using version 2 of the pediatric Complex Chronic Conditions classification system. Data was analyzed using SAS® software 9.4. A p-value <0.05 was considered significant.

Results

From 2005–2015, 2,487,472 hospitalized infants were identified, of whom 498,343 (20.0%) received non-methadone opioids during hospitalization (Supplemental Table 1). Overall, 20,056 received methadone, representing 0.8% of all hospitalized infants and 4.0% of infants receiving non-methadone opioids. Non-methadone opioid and methadone use decreased in parallel over 2005–2015 (p-value <0.001, Figure) but varied widely by hospital (Supplemental Figure). The most common comorbidities present in infants who required methadone treatment were cardiovascular (N=12,235, 61.0%), technology dependent (N=8,157, 40.7%), gastrointestinal (N=6,479, 32.3%), and premature/neonatal (N=5,436, 27.1%). Infants requiring methadone treatment demonstrated longer hospitalization, prolonged mechanical ventilation, and higher mortality.

Figure.

Annual Incidence of Non-methadone Opioid Use and Methadone Treatment in Hospitalized Infants (N=2,487,472)

Demographic factors associated with transition to methadone (Supplemental Table 2) were female sex (OR 1.05; 95% CI, 1.02, 1.09), Black race (OR 1.18; 95% CI, 1.13, 1.22), Hispanic/Latino ethnicity (OR 1.18; 95% CI: 1.12, 1.23), and public insurance (OR 1.33; 95% CI, 1.28, 1.39). Infants with cardiac conditions (OR 5.61; 95% CI, 5.43, 5.79), requiring organ transplantation (OR 7.92; 95% CI, 6.89, 9.10), and/or technology dependent (OR 2.38; 95% CI 2.28, 2.50) exhibited the greatest odds of requiring methadone treatment.

Discussion

In the present study, 1 in 5 infants cared for at a children’s hospital in the United States received a non-methadone opioid during hospitalization, and 0.8% required methadone treatment. Female and minority infants and infants with public insurance are more likely to require methadone. Finally, infants with cardiac and transplant comorbidities, and technology dependent infants are more likely to require methadone.

Inpatient opioid use and methadone treatment decreased in parallel over time, in line with national trends of decreased opioid prescribing for older children and adolescents.⁴ As infants requiring methadone therapy demonstrated longer hospital stays and prolonged ventilation, minimizing physiologic opioid dependence from clinician-prescribed opioids may result in improved outcomes overall. Discreet high-risk populations routinely requiring methadone during hospitalization, particularly infants requiring cardiac or gastrointestinal surgery, may be ideal targets for future interventions aimed at optimizing pain control. Finally, while methadone is the most common medication used to wean an infant from opioids,⁵ alternative medications (i.e. benzodiazepines, buprenorphine, dexmedetomidine, clonidine) were not evaluated in this study but may also impact health outcomes. Characterization of this critical epidemiologic issue will aid in changing practice patterns to optimize pain management protocols for hospitalized infants while minimizing opioid-associated risks.

Abbreviations:

NAS/NOWS

Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome

PHIS

Pediatric Health Information System

ICD-9-CM

International Classification of Diseases, Ninth Revision, Clinical Modification