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

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.