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Abstract

Aims: This study characterized the heterogeneity of opioid withdrawal by comparing naturally occurring withdrawal during opioid abstinence (spontaneous withdrawal) with abrupt, pharmacologically induced naloxone-precipitated withdrawal in adults with Opioid Use Disorder (OUD).   Methods: A secondary analysis was conducted on de-identified data from 86 adults meeting DSM-5 criteria for moderate-to-severe OUD. Participants either presented in spontaneous withdrawal (n = 28) or underwent naloxone challenge to precipitate withdrawal (n = 58). Withdrawal symptoms were rated using the Wang procedure. Principal Component Analysis (PCA) of binary symptom data was performed to identify dominant patterns of symptom co-occurrence. Separate PCAs were then conducted for the withdrawal syndrome types to delineate group-specific symptom clusters.   Results: In the combined sample, four principal components together accounted for 55.6% of the variance in withdrawal symptoms, with the highest loadings observed on autonomic (e.g., temperature change, sweating) and somatic (e.g., restlessness, yawning) domains. Subgroup analyses revealed distinct symptom-loading patterns: the spontaneous withdrawal group displayed a more pronounced autonomic profile dominated by temperature dysregulation and muscle aching, whereas the precipitated withdrawal group exhibited greater variability, with notable gastrointestinal (vomiting, stomach pain) and somatic features. Across analyses, inter-individual variability was substantial, underscoring the multidimensional nature of opioid withdrawal.   Conclusion: These findings suggest spontaneous and precipitated withdrawal are distinct clinical phenomena: the former emerges gradually, the latter produces diverse, acute symptoms, though both display heterogeneity. Moreover, relying solely on naloxone-challenge paradigms for treatment development may overlook key aspects of “real-world” spontaneous withdrawal, reinforcing the importance of broader experimental models and individualized care.

Document Type

Article

Publication Date

2026

Notes/Citation Information

0091-3057/© 2026 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.pbb.2026.174153

Funding Information

The authors are currently receiving funding from the National Institute on Drug Abuse through the following grants: K08DA058057 (S. M.), R01DA052937 (K.E.D.), R01DA047368 (J.A.L.), T32DA035200 (T. P.S), UH3DA048734 (A.S.H.), and UG3DA062907 (L.B. and K.E.D.). The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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