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

Suky Martinez; Jermaine D. Jones; Kelly E. Dunn; Andrew Huhn; Joshua A. Lile; Thomas P. Shellenberg; Laura Brandt

doi:10.1016/j.pbb.2026.174153

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

Suky Martinez
, Jermaine D. Jones
, Kelly E. Dunn
, Andrew Huhn
, Joshua A. Lile
, Thomas P. Shellenberg
, Laura Brandt

Producción científica: Article › revisión exhaustiva

Resumen

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.

Idioma original	English
Número de artículo	174153
Publicación	Pharmacology Biochemistry and Behavior
Volumen	260
DOI	https://doi.org/10.1016/j.pbb.2026.174153
Estado	Published - mar 2026

Nota bibliográfica

Publisher Copyright:
© 2026 Elsevier Inc.

Financiación

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.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. 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.

Financiadores	Número del financiador
American Psychological Association
Ford Foundation
BioXcel Therapeutics
National Institutes of Health (NIH)
Merck Sharp and Dohme United Kingdom
World Health Organization
Author National Institute on Drug Abuse DA031791 Mark J Ferris National Institute on Drug Abuse DA006634 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA026117 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA028162 Elizabeth G Pitts National Institute of General Medical Sciences GM102773 Elizabeth G Pitts Peter McManus Charitable Trust Mark J Ferris National Institute on Drug Abuse	R01DA047368, UH3DA048734, T32DA035200, R01DA052937, UG3DA062907, K08DA058057

ASJC Scopus subject areas

Biochemistry
Toxicology
Pharmacology
Clinical Biochemistry
Biological Psychiatry
Behavioral Neuroscience

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@article{bc2f82b8b97644d4b61454efe498eccf,

title = "Evidence of heterogeneity in the opioid withdrawal syndrome: Spontaneous and precipitated withdrawal",

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",

author = "Suky Martinez and Jones, \{Jermaine D.\} and Dunn, \{Kelly E.\} and Andrew Huhn and Lile, \{Joshua A.\} and Shellenberg, \{Thomas P.\} and Laura Brandt",

note = "Publisher Copyright: {\textcopyright} 2026 Elsevier Inc.",

year = "2026",

month = mar,

doi = "10.1016/j.pbb.2026.174153",

language = "English",

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AU - Martinez, Suky

AU - Jones, Jermaine D.

AU - Dunn, Kelly E.

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AU - Lile, Joshua A.

AU - Shellenberg, Thomas P.

AU - Brandt, Laura

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N2 - 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.

AB - 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.

KW - Heterogeneity

KW - Interoception

KW - Naloxone challenge

KW - Opioid use disorder

KW - Opioid withdrawal

KW - Principal Component Analysis

KW - Spontaneous withdrawal

KW - Symptom profiles

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VL - 260

JO - Pharmacology Biochemistry and Behavior

JF - Pharmacology Biochemistry and Behavior

M1 - 174153

ER -

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

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Nota bibliográfica

Financiación

ASJC Scopus subject areas

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