Interventions to reduce pharmacologic opioid exposure in neonatal opioid withdrawal syndrome: a systematic review and meta-analysis of randomized studies

Background Neonatal opioid withdrawal syndrome (NOWS) is increasingly prevalent and is frequently managed with pharmacologic opioid therapy, raising concerns regarding early-life opioid exposure and prolonged hospitalization. Interventions aimed at reducing pharmacologic exposure while maintaining safety have emerged, most notably care-model–based approaches. This study aims to systematically review the evidence evaluating interventions designed to reduce pharmacologic opioid exposure in neonates with NOWS compared with standard care. Methods A systematic review was conducted in accordance with PRISMA guidelines. PubMed/MEDLINE, Cochrane CENTRAL, and Google Scholar were searched from inception through the final search date. Randomized controlled trials, comparative observational studies, and quality-improvement studies evaluating exposure-reduction strategies were included. Interventions of interest primarily comprised care-model approaches such as Eat–Sleep–Console (ESC). Outcomes included duration of opioid therapy, cumulative opioid exposure, length of hospital stay, and safety outcomes. Due to substantial heterogeneity across studies, findings were synthesized narratively. Results Six studies met inclusion criteria, comprising three randomized studies and three observational or quality-improvement studies. Meta-analysis of randomized evidence showed ESC-based care significantly reduced hospital stay length (MD −6.50 days; 95% CI −9.63 to −3.36; p < 0.0001; I 2 = 0%) and decreased opioid therapy duration (MD −3.06 days; 95% CI −3.74 to −2.38; p < 0.00001; I 2 = 36%) compared to standard care. A subgroup analysis showed lower cumulative opioid exposure (MD −4.1 MME/kg; p = 0.001). Observational and quality-improvement studies consistently reported substantial reductions in opioid exposure and hospitalization following ESC implementation. Across all included studies reporting safety outcomes, no increase in adverse events or hospital readmissions was observed. Conclusions Care-model interventions emphasizing functional assessment and nonpharmacologic support—particularly the ESC approach—are associated with reduced pharmacologic opioid exposure and shorter hospitalization for infants with NOWS without compromising short-term safety. These findings support evolving guideline recommendations favoring exposure-reduction strategies in NOWS management.