A Scoping Review of Non‐Opioid Therapeutics for Opioid Withdrawal: Translational Relevance to Neonatal Opioid Withdrawal Syndrome ( <scp>NOWS</scp> ) Research

In the wake of the ongoing opioid epidemic, the incidence of neonatal opioid withdrawal syndrome (NOWS) has surged. While the short-term effects of NOWS are well-characterized, long-term physiological and molecular consequences remain unclear. First-line NOWS treatments include non-pharmacological interventions; however, most infants who require medication are primarily treated with more opioids, such as morphine, weaned over time. This practice may be counterintuitive given recent preclinical evidence linking prenatal opioid exposure (POE) to neuroinflammation, as well as cognitive deficits in both preclinical and clinical studies. Identifying alternative non-opioid therapeutic agents may be essential for future NOWS management. This scoping review evaluated non-opioid therapeutics for opioid withdrawal symptoms (OWSx) across clinical and preclinical populations to identify candidate agents for future NOWS treatment research. Forty-one articles met inclusion criteria, encompassing 16 different drug classes, with particular attention to alpha-2-agonists, enzyme inhibitors, NMDA receptor antagonists, and unregulated dietary supplements. Among these empirical studies, several promising therapeutics emerged, with a few demonstrating efficacy on par with standard opioid treatments. However, despite promising results, definitive conclusions from many studies were limited by small sample sizes, inconsistent methodologies, or confounding variables. Furthermore, most agents remain untested in neonatal populations, leaving critical safety and dosing parameters unknown. This underscores the need for rigorous, translational research of these agents, including neonatal safety, efficacy, pharmacokinetics, and pharmacodynamics, ideally benchmarked against standard-of-care treatments. Addressing these gaps is crucial for developing effective NOWS treatment and improving outcomes for this vulnerable population.