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. 2026 Mar:260:174153.
doi: 10.1016/j.pbb.2026.174153. Epub 2026 Jan 9.

Evidence of heterogeneity in the opioid withdrawal syndrome: Spontaneous and precipitated withdrawal

Suky Martinez  1 , Jermaine D Jones  2 , Kelly E Dunn  3 , Andrew Huhn  4 , Joshua A Lile  5 , Thomas P Shellenberg  5 , Laura Brandt  6
Affiliations

Evidence of heterogeneity in the opioid withdrawal syndrome: Spontaneous and precipitated withdrawal

Suky Martinez et al. Pharmacol Biochem Behav. 2026 Mar.

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.

Keywords: Heterogeneity; Interoception; Naloxone challenge; Opioid use disorder; Opioid withdrawal; Principal Component Analysis; Spontaneous withdrawal; Symptom profiles.

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Conflict of interest statement

Declaration of competing interest Within the past three years, Dr. Jermaine Jones has received compensation (partial salary support) from: the World Health Organization, the Hazelden Betty Ford Foundation, the American Psychological Association and BioXcel Therapeutics. During the same period, Dr. Kelly Dunn provided consulting services to Cessation Therapeutics and DemeRx; served on a study steering committee for Indivior; and received research funding through her university from the National Institute on Drug Abuse and Cure Addiction Now. Dr. Andrew Huhn received research funding from Indivior Inc. (via his university); grants from the National Institutes of Health and Ashley Addiction Treatment; consulting fees from Gilgamesh, Inc.; and non-financial support from Merck Sharp & Dohme LLC, all outside the scope of the submitted work. Drs. Suky Martinez, Laura Brandt, Joshua Lile, and Mr. Thomas Shellenberg report no relevant affiliations or financial involvement with any organization or entity that has a financial interest in or conflict with the subject matter of this manuscript.

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