Opioid Treatment for Neonatal Opioid Withdrawal Syndrome: Current Challenges and Future Approaches

Abstract

Chronic intrauterine exposure to psychoactive drugs often results in neonatal opioid withdrawal syndrome (NOWS). When nonpharmacologic measures are insufficient in controlling NOWS, morphine, methadone, and buprenorphine are first‐line medications commonly used to treat infants with NOWS because of in utero exposure to opioids. Research suggests that buprenorphine may be the leading drug therapy used to treat NOWS when compared with morphine and methadone. Currently, there are no consensus or standardized treatment guidelines for medications prescribed for NOWS. Opioids used to treat NOWS exhibit large interpatient variability in pharmacokinetics (PK) and pharmacodynamic (PD) response in neonates. Organ systems undergo rapid maturation after birth that may alter drug disposition and exposure for any given dose during development. Data regarding the PK and PD of opioids in neonates are sparse. Pharmacometric methods such as physiologically based pharmacokinetic and population pharmacokinetic modeling can be used to explore factors predictive of some of the variability associated with the PK/PD of opioids in newborns. This review discusses the utility of pharmacometric techniques for enhancing precision dosing in infants requiring opioid treatment for NOWS. Applying these approaches may contribute to optimizing the outcome by reducing cumulative drug exposure, mitigating adverse drug effects, and reducing the burden of NOWS in neonates.

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

“… 15 , 16 , 17 Challenges include dynamic drug disposition and elimination in the first days of life and PK variability for commonly used pharmacologic agents. 18 The biology of opioid withdrawal is not fully understood in newborns, and there is not general agreement on instruments to measure disease severity nor the severity of disease that should prompt use of pharmacologic therapy or accepted clinical trial end points. 19 Understanding these challenges, we sought to (1) build on prior work describing buprenorphine PK exposure in infants with control of NOWS symptoms, (2) simulate optimized dose regimens, (3) test these revised dose regimens, and (4) feed these data back into the PK‐PD model for use in future work.…”

“…Model‐based approaches are increasingly brought to bear in the quest to optimize treatment for NOWS 15–17 . Challenges include dynamic drug disposition and elimination in the first days of life and PK variability for commonly used pharmacologic agents 18 . The biology of opioid withdrawal is not fully understood in newborns, and there is not general agreement on instruments to measure disease severity nor the severity of disease that should prompt use of pharmacologic therapy or accepted clinical trial end points 19 .…”

Use of Phenobarbital to Treat Neonatal Abstinence Syndrome From Exposure to Single vs. Multiple Substances

“…The adverse effect profile of opioids has stimulated further research into the use of other agents, including benzodiazepines, barbiturates, naloxone, chlorpromazine, and clonidine (7,21,23,24,(29)(30)(31)(32). A Cochrane review of sedatives for NAS treatment recommends opioids as the initial therapy and phenobarbital as the preferred sedative if a sedative is used (29,30).…”

Economic Evaluation of Interventions for Treatment of Neonatal Opioid Withdrawal Syndrome: A Review

“…Substance use during pregnancy is a significant and growing global public health concern. In the United States (US), illicit drug use (specifically opioid use disorder) among pregnant women has increased almost four-fold between 2004 and 2012, with at least one infant born with signs of withdrawal or neonatal opioid withdrawal syndrome (NOWS), formerly known as neonatal abstinence syndrome (NAS), every 15 min [ 1 , 2 , 3 ]. Similar trends in the rate of NOWS have also been reported in other countries, including the United Kingdom and Canada [ 4 , 5 , 6 ].…”