Pharmacotherapy of neonatal opioid withdrawal syndrome: a review of pharmacokinetics and pharmacodynamics

ABSTRACT

Introduction

Neonatal opioid withdrawal syndrome (NOWS) often arises in infants born to mothers who used opioids during pregnancy. Morphine, methadone, and buprenorphine are the most common first-line treatments, whereas clonidine and phenobarbital are generally reserved for adjunctive therapy. These drugs exhibit substantial pharmacokinetic (PK) and pharmacodynamic (PD) variability. Current pharmacological treatments for NOWS are based on institutional protocols and largely rely on empirical treatment of patient symptoms.

Areas covered

This article reviews the PK/PD of NOWS pharmacotherapies with a focus on the implication of physiological development and maturation. Body size-standardized clearance is consistently low in neonates, except for methadone. This can be ascribed to underdeveloped metabolic and elimination pathways. The effects of pharmacogenetics have been clarified especially for morphine. The PK/PD relationship of medications used in the treatment of NOWS is generally understudied.

Expert opinion

Providing an appropriate opioid dose in neonates is challenging. Advancements in quantitative pharmacology and PK/PD modeling approaches facilitate identification of key factors driving PK/PD variability and characterization of exposure-response relationships. PK/PD model-informed simulations have been widely employed to define age-appropriate pediatric dosing regimens. The model-informed approach holds promise to aid more rational use of medications in the treatment of NOWS.

KEYWORDS:

• Buprenorphine
• clonidine
• methadone
• morphine
• neonatal abstinence syndrome
• neonatal opioid withdrawal syndrome
• pharmacodynamics
• pharmacogenetics
• pharmacokinetics
• phenobarbital

Article highlights

● Gestational age, postnatal age, and pharmacogenetics decisively affect the pharmacokinetics of drug therapies used in neonatal opioid withdrawal syndrome.

● Metabolic and physiological elimination pathways are underdeveloped in neonates and mature over time, though some significantly faster than others.

● Model-informed precision dosing has the potential to overcome current obstacles pertaining to pharmacokinetic and pharmacodynamic variability and is likely to improve clinical outcomes.

This box summarizes key points contained in the article.

Acknowledgments

The authors gratefully acknowledge the help of Björn Lohse, MD in translating the historical German papers cited in this work.

Declaration of interest

S Wexelblatt has received a research grant from Chiesi Pharmaceuticals and a consulting fee from Braeburn Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

M van Hoogdalem was supported by the Ritschel Doctoral Fellowship of the University of Cincinnati.