Decreased Effectiveness of a Novel Opioid Withdrawal Protocol Following the Emergence of Medetomidine as a Fentanyl Adulterant

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

 

This retrospective study evaluates the effectiveness of an ED opioid withdrawal protocol initially developed for fentanyl-xylazine withdrawal after the emergence of medetomidine as a fentanyl adulterant. The study found that the original protocol became significantly less effective during the medetomidine era (ME), leading to higher ICU admissions and poorer symptom control. A revised protocol partially improved outcome. This report is timely although it has limited generalizability with data only from two ED in the same city.

 

Minor:

1. Tables: Unify the font style and spacing of p-values.
2. Figures: Add more descriptive legends to make the figures interpretable without the text.
3. Discussion: There are a few places where the authors only talk the medetomidine background. Please edit so every point is tightly linked back to the results of the study.

 

Major:

1. General: please make a clear statement that there is no individual toxicology confirmation. This is very important. And please discuss the potential bias from misclassification.

 

Author Response

I am so appreciative of your feedback.  Please see the point by point discussion, below.

 

Comment 1: 

Minor:

1. Tables: Unify the font style and spacing of p-values.
   1. I have changed all of these, thank you so much, it's embarrassing that I missed that initially.
2. Figures: Add more descriptive legends to make the figures interpretable without the text.
   1. I have added text to all figures, better explaining what they demonstrate
3. Discussion: There are a few places where the authors only talk the medetomidine background. Please edit so every point is tightly linked back to the results of the study.
   1. This is entirely fair.  I have revised the discussion, see revisions.

Major:

1. General: please make a clear statement that there is no individual toxicology confirmation. This is very important. And please discuss the potential bias from misclassification.
   1. I have actually added the toxicology data, which we now have back, and is being submitted as a separate manuscript (an invited one from a sister MDPI journal).  It will not be ready for this publication, but it will be soon.  I have also linked to our subsequent CDC MMWR which addresses toxicology as well.

Reviewer 2 Report

Comments and Suggestions for Authors

While the topic is clinically relevant and timely, especially given the evolving landscape of fentanyl adulterants and their impact on opioid withdrawal, the manuscript in its current form suffers from significant methodological and interpretive weaknesses that preclude publication.

Major Concerns:

1. Lack of Confirmed Exposure Data

The central premise of the study is comparison of clinical outcomes based on presumed exposure to xylazine vs. medetomidine. However, individual-level data on adulterant exposure were not collected. Classification was instead inferred solely by date ranges tied to public health surveillance. This results in substantial exposure misclassification bias, weakening the validity of all comparative analyses.

1. Inappropriate Outcome Measurement

The Clinical Opioid Withdrawal Scale (COWS), while validated for opioid withdrawal, is not appropriate for assessing withdrawal from alpha-2 agonist sedatives such as xylazine and medetomidine. Using COWS as the sole outcome measure to assess symptom relief or severity in this context is methodologically unsound. The authors acknowledge this limitation but still rely on it entirely.

1. No Adjustment for Confounding Variables

All statistical analyses appear to be univariate. The authors do not perform multivariable regression to adjust for key confounders such as age, sex, comorbidities, concurrent stimulant or alcohol use, or site-specific practice patterns. This leaves the observed associations vulnerable to bias and limits interpretability.

1. Subgroup and Time-Trend Analyses Poorly Defined

The authors state that a protocol revision occurred mid-study and that monthly trends were examined, yet these analyses are not clearly described or statistically formalized (e.g., interrupted time series, segmented regression). The subgroup analysis is neither adequately powered nor methodologically justified.

1. Vague Definition of Secondary Outcomes

ICU admission and discharge against medical advice (AMA) are context-dependent outcomes that may be influenced by factors unrelated to withdrawal severity. “Serious adverse events” are mentioned but not defined, and no adjudication or classification method is described.

1. Redundancies and Writing Quality

The manuscript contains duplicate content in several sections (e.g., primary outcome repeated verbatim), lacks flow diagrams for participant inclusion, and omits key information such as excluded patient counts and missing data rates. These issues raise concerns about attention to detail and overall readiness for publication.

Author Response

I entirely understand and greatly appreciate the concerns of this reviewer.  While these were the toughest I received, this type of feedback is most valuable to improve the overall work.  I hope these revisions are strong enough to get you to reconsider.

Major Concerns:

1. Lack of Confirmed Exposure Data    

The central premise of the study is comparison of clinical outcomes based on presumed exposure to xylazine vs. medetomidine. However, individual-level data on adulterant exposure were not collected. Classification was instead inferred solely by date ranges tied to public health surveillance. This results in substantial exposure misclassification bias, weakening the validity of all comparative analyses.

Response: This is fair and was a criticism of our initial paper as well, which did not have any xylazine confirmation.  Subsequently we have tested a small cohort using LC-MS/MS and found them all to be medetomidine positive.  This has been included.  I also included our recently published CDC MMWR which discusses this issue and was also published.  It is a limitation and is discussed as such.  

1. Inappropriate Outcome Measurement

The Clinical Opioid Withdrawal Scale (COWS), while validated for opioid withdrawal, is not appropriate for assessing withdrawal from alpha-2 agonist sedatives such as xylazine and medetomidine. Using COWS as the sole outcome measure to assess symptom relief or severity in this context is methodologically unsound. The authors acknowledge this limitation but still rely on it entirely.

Response: This is also fair, and while we have it noted, I think it's important that it was the same limitation as the initial paper (citation #4) and we addressed that then: we think it's a reasonable alternative due to the association of decreasing COWS and AMA rates, which are associated on face (patients in less agony leave on their own less times). There are no other approved means of assessing this syndrome as we are just describing it now.  I have added to the methods section to note this important caveat.

1. No Adjustment for Confounding Variables

All statistical analyses appear to be univariate. The authors do not perform multivariable regression to adjust for key confounders such as age, sex, comorbidities, concurrent stimulant or alcohol use, or site-specific practice patterns. This leaves the observed associations vulnerable to bias and limits interpretability.

Response: I asked our statistician about this and given the limited data set size and number of variables, this was not felt to increase the value of the data.  This is an incredibly important limitation and has been added to the limitations section.

1. Subgroup and Time-Trend Analyses Poorly Defined

The authors state that a protocol revision occurred mid-study and that monthly trends were examined, yet these analyses are not clearly described or statistically formalized (e.g., interrupted time series, segmented regression). The subgroup analysis is neither adequately powered nor methodologically justified.

Response: I think this reviewer is apt in their description that the analysis is not powered but I disagree with the justification.  I apologize to keep using the same terms, but this is a pragmatic, retrospective analysis of real world data.  The data changed dramatically around that time due to a systemic change we made -- not for research reasons -- but because our patients were suffering.  I have added to this section in the limitations.

1. Vague Definition of Secondary Outcomes

ICU admission and discharge against medical advice (AMA) are context-dependent outcomes that may be influenced by factors unrelated to withdrawal severity. “Serious adverse events” are mentioned but not defined, and no adjudication or classification method is described.

Response: This is again absolutely correct but these are tangible and available outcome values that we have.  The fact that the patient chief complaints markedly decreased for infections and greatly increased for withdrawal while ICU and admissions increase speak to this phenomenon.  I have tried to reduce the strength of my language as clearly all of these are just associations but to be honest, these questions feel similar to a before/after COVID intervention being asked if other variables could be responsible for changes.  Yes -- absolutely, unconfirmed variables may play a role.  It is plainly clear that medetomidine is responsible for all of this now, hence our CDC MMWR (citation #9) publication.

1. Redundancies and Writing Quality

The manuscript contains duplicate content in several sections (e.g., primary outcome repeated verbatim), lacks flow diagrams for participant inclusion, and omits key information such as excluded patient counts and missing data rates. These issues raise concerns about attention to detail and overall readiness for publication.

Response: This is the strongest of your criticisms and the most embarrassing for me.  I am so sorry, I have went through everything, including removing the redundant outcomes in the methods section.  I hope this is more satisfactory.

Thank you again, your critical eye is what improves papers and sustains peer review.  I am glad for it.

Reviewer 3 Report

Comments and Suggestions for Authors

Fentanyl abuse is a major public health crisis in the United States. It is now the leading cause of drug overdose deaths. Hence protocols for managing withdrawal are important to save victims of abuse. The current paper contributes to understanding withdrawal especially when Fentanyl is adulterated with other substances. 

I note a sudden rise in efficacy of the protocol after it was tweaked in Feb 2025. While the authors cite it as one of the few limitations of the study, it would have been better if they had waited for a month or two to include the data post tweak. May be that data could be even now entered in the paper, which would make the paper all the more valuable. 

Author Response

Your comments are too kind and I greatly appreciate your review!  Please see my below comments:

I note a sudden rise in efficacy of the protocol after it was tweaked in Feb 2025. While the authors cite it as one of the few limitations of the study, it would have been better if they had waited for a month or two to include the data post tweak. May be that data could be even now entered in the paper, which would make the paper all the more valuable. 

       - I entirely understand and appreciate this concern.  This data is extremely timely and this is just the first paper regarding this topic.  An entire separate manuscript will be developed describing the total treatment of patients during the medetomidine era (similar to citation #4 did for the xylazine era).  In deference and given another month has elapsed, I have added April and recalculated all of the data).  Thank you.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have revised the manuscript as suggested. This updated version is ready for publication. 

Author Response

You are so kind, thank you for reviewing our paper!

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for your detailed and thoughtful responses to the reviewer comments. I appreciate the revisions and additional data you’ve provided. The manuscript is improved, particularly with the added transparency around key limitations such as the lack of confirmed exposure data and the reliance on COWS as a proxy for alpha-2 agonist withdrawal. That said, some methodological concerns remain, particularly regarding the absence of adjustment for confounding variables and the limited rigor of subgroup analyses. I also noted a few minor editorial issues: for instance, the word "objective" should be singular if only one aim is stated, and the comma in line 89 should follow the reference, not precede it. Overall, I appreciate your responsiveness to critique.

  

Author Response

I cannot tell you how incredibly appreciative I am to have had you as a reviewer on this process. If there is some way I can write you a review or a positive salutation otherwise, I would be happy to do so.  Reading your revisions caused me mild shame because of how much better they were, I have accepted them en masse.  This journal is lucky to have you and so are we.   

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

thank you for your comment

good luck