Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments

Abstract

In this paper, we review the management of neonatal opioid withdrawal syndrome (NOWS) and clinical pharmacology of primary treatment agents in NOWS, including morphine, methadone, buprenorphine, clonidine, and phenobarbital. Pharmacologic treatment strategies in NOWS have been mostly empirical, and heterogeneity in dosing regimens adds to the difficulty of extrapolating study results to broader patient populations. As population pharmacokinetics (PKs) of pharmacologic agents in NOWS become more well-defined and knowledge of patient-specific factors affecting treatment outcomes continue to accumulate, PK/pharmacodynamic modeling and simulation will be powerful tools to aid the design of optimal dosing regimens at the patient level. Although there is an increasing number of clinical trials on the comparative efficacy of treatment agents in NOWS, here, we also draw attention to the importance of optimizing the dosing regimen, which can be arguably equally important at identifying the optimal treatment agent.

FIGURE 1

Comparative pharmacokinetic parameters and elimination of morphine in neonates/infants and adults. *Clearance increases with age (0–57 days). NE, not estimated; t_1/2, terminal half‐life

FIGURE 2

Comparative pharmacokinetic (PK) parameters and elimination of methadone in neonates/infants and adults. *Apparent parameter estimates from a population PK model by Wiles et al. NE, not estimated; t_1/2, terminal half‐life

FIGURE 3

Comparative pharmacokinetic parameters and elimination of buprenorphine in neonates/infants and adults. *Sublingual dosing. ^#Estimated in premature neonates. ^Relative ratio of buprenorphine to norbuprenorphine. NE, not estimated t_1/2, terminal half‐life

FIGURE 4

Comparative pharmacokinetic (PK) parameters and elimination of clonidine in neonates/infants and adults. *Dose‐dependent decrease in clearance. ^#Apparent parameter estimates from a population PK model by Xie et al., half‐life estimated in a typical neonate. GFR, glomerular filtration rate; NE, not estimated; t_1/2, terminal half‐life

FIGURE 5

Comparative pharmacokinetic parameters and elimination of phenobarbital in neonates/infants and adults. *Bioavailability was reported to be lower than in adults. ^#Half‐life estimates reported for term and preterm neonates. t_1/2, terminal half‐life