Dataset Information

Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioid Withdrawal Syndrome.

ABSTRACT:

Background and objective

Buprenorphine has been shown to be effective in treating infants with neonatal opioid withdrawal syndrome. However, an evidence-based buprenorphine dosing strategy has not been established in the treatment of neonatal opioid withdrawal syndrome because of a lack of exposure-response data. The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic model to predict buprenorphine treatment outcomes in newborns with neonatal opioid withdrawal syndrome.

Methods

Clinical data were obtained from 19 newborns with a median (range) gestational age of 37 (34-41) weeks enrolled in a pilot pharmacokinetic study of buprenorphine. Sparse blood sampling, comprising three specimens obtained around the second dose of buprenorphine, was performed using heel sticks with dried blood spot technology. Standardized neonatal opioid withdrawal syndrome severity scores (Finnegan scores) were collected every 3-4 h based on symptoms by bedside nursing staff. Mean Finnegan scores were used as a pharmacodynamic marker in the exposure-response modeling. The blood concentration-Finnegan score relationship was described using a physiologic indirect response model with inclusion of natural disease remission.

Results

A total of 52 buprenorphine blood concentrations and 780 mean Finnegan scores were available for the pharmacokinetic/pharmacodynamic modeling and exposure-response analysis. A one-compartment model with first-order absorption adequately described the pharmacokinetic data. The buprenorphine blood concentration at 50% of maximum effect for the inhibition of disease progression was 0.77 ng/mL (95% confidence interval 0.32-1.2). The inclusion of natural disease remission described as a function of postnatal age significantly improved the model fit.

Conclusions

A buprenorphine pharmacokinetic/pharmacodynamic model was successfully developed. The model could facilitate model-informed optimization of the buprenorphine dosing regimen in the treatment of neonatal opioid withdrawal syndrome.

SUBMITTER: Mizuno T

PROVIDER: S-EPMC8489161 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportancePrescription opioids are often used during pregnancy even though they are associated with neonatal opioid withdrawal syndrome (NOWS). Most studies of adverse outcomes of opioid use for pain have assessed only the class-wide outcome despite the pharmacodynamic and pharmacokinetic heterogeneity across opioid medications.ObjectiveTo compare the risk of NOWS across common types of opioids when prescribed as monotherapy during the last 3 months of pregnancy.Design, setting, and participantsThis cohort study analyzed administrative claims data of Medicaid-insured mothers and newborns in 46 states and Washington DC from January 1, 2000, through December 31, 2014. Participants were mothers with 2 or more dispensed opioid prescriptions within 90 days before delivery and their eligible live-born neonates. Data were analyzed from February 2020 to March 2021.ExposureDifferent types of opioid medications were compared by agonist strength (strong vs weak) and half-life (medium vs short and long vs short) of the opioid active ingredient.Main outcomes and measuresThe primary outcome was NOWS, which was identified using an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code in the 30 days after delivery. Relative risks (RRs) were adjusted for an exposure propensity score, including demographic characteristics, comorbidities, other medication use, and opioid treatment characteristics (including morphine milligram equivalents), using fine stratification.ResultsThe cohort comprised 48 202 opioid-exposed pregnancies with live newborns. A total of 1069 neonates (2.2%) had NOWS and 559 (1.2%) had severe NOWS. Opioid exposure during pregnancy included 16 202 pregnancies exposed to codeine, 4540 to oxycodone, 1244 to tramadol, 260 to methadone (dispensed for pain), 90 to hydromorphone, and 63 to morphine compared with 25 710 exposed to hydrocodone. Demographic characteristics varied across opioids, with tramadol, oxycodone, methadone, hydromorphone, and morphine being more commonly dispensed at older maternal age (≥35 years). Compared with hydrocodone, codeine had a lower adjusted RR of NOWS (0.57; 95% CI, 0.46-0.70), with a similar adjusted RR for tramadol (RR, 1.06; 95% CI, 0.73-1.56), and 2- to 3-fold higher adjusted RRs for oxycodone (1.87; 95% CI, 1.66-2.11), morphine (2.84; 95% CI, 1.30-6.22), methadone (3.02; 95% CI, 2.45-3.73), and hydromorphone (2.03; 95% CI, 1.09-3.78). Strong agonists were associated with a higher risk of NOWS than weak agonists (RR, 1.97; 95% CI, 1.78-2.17), and long half-life opioids were associated with an increased risk compared with short half-life products (RR, 1.33; 95% CI, 1.12-1.56). Findings were consistent across sensitivity and subgroup analyses.Conclusions and relevanceResults of this study show higher risk of NOWS and severe NOWS among neonates with in utero exposure to strong agonists and long half-life prescription opioids. Information on the opioid-specific risk of NOWS may help prescribers select opioids for pain management in late stages of pregnancy.

Project description:The opioid epidemic in the United States has led to a significant increase in the incidence of neonatal opioid withdrawal syndrome (NOWS); however, the understanding of long-term consequences of NOWS is limited. The objective of this study was to evaluate post-discharge healthcare utilization in infants with NOWS and examine the association between NOWS severity and healthcare utilization. A retrospective cohort design was used to ascertain healthcare utilization in the first year after birth-related discharge using the CERNER Health Facts® database. ICD-9/ICD-10 diagnostic codes were used to identify live births and to classify infants into two study groups: NOWS and uncomplicated births (a 25% random sample). Evaluated outcomes included rehospitalization, emergency department (ED) visits within 30-days and one-year after discharge, and a composite one-year utilization event (either hospitalization or emergency department visit during that year). NOWS severity was operationalized as pharmacologic treatment, length of hospitalization, and medical conditions often associated with NOWS. In 3,526 infants with NOWS (restricted to gestational age ≥ 33 weeks), NOWS severity was associated with an increase in composite one-year utilization (OR: 1.1; 95% CI: 1.04-1.2) after adjusting for prematurity, sepsis, jaundice, use of antibiotics, infant sex, insurance status, race, hospital bed size, year of birth, and census division. In a subset of full-term infants (3008 with NOWS and 88,452 uncomplicated births), having a NOWS diagnosis was associated with higher odds of a 30-day (OR: 1.6; 95% CI: 1.03-2.4) and one-year rehospitalization (OR: 1.6; 95% CI: 1.1-2.4) after adjusting for infant sex, race, type of medical insurance, hospital location, census division, year of primary encounter, hospital bed size, and medical conditions. This study found higher healthcare utilization during the first year of life in infants diagnosed with NOWS, especially those with severe NOWS. Findings suggest a need for closer post-discharge follow-up and management of infants with NOWS.