Profound Opioid and Medetomidine Withdrawal: A Case Series and Narrative Review of Available Literature
, Maeve Montesi 1,2, Sejal H. Patel-Francis 4,5, Jamal Rashid 4,5, Oluwarotimi Vaughan-Ogunlusi 4, Kelly Goodsell 3,4, Jennifer L. Kahoud 3,4, Christopher Martin 2,3,6, Keira Chism 2,3,6, Paul Goebel 5, Karen Alexander 7, Dennis Goodstein 2,5 and Kory S. London 2,3,4,*
Kim Aldy
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have undertaken a small case series (4 patients) and a review of the literature. This is essentially the same as "case report and a review of the literature", which was once a common article format, but which is now outmoded.
The authors should separate that case series and the narrative review. It is OK to cite literature in the Discussion to give context to the observations.
"Due to the paucity of research", the authors expanded their review to dexmedetomidine, opioid (with or without an alpha-2-agonist), and alcohol withdrawal. Of these, only the first should be part of the discussion. Alcohol withdrawal is mechanistically quite different (affecting regulation of GABA-chloride channels). Its inclusion is very puzzling.
The authors cannot separate medetomidine withdrawal (if it exists) from opioid withdrawal. A patient receiving 62 mg of hydromorphone in 1 day may be getting treatment for opioid withdrawal. I am willing to believe that combined withdrawal is possible, but we lack so many details about the duration or frequency of medetomidine exposure (the patients likely do not know) or the absorbed doses of medetomidine.
The case series includes patients with "suspected medetomidine-adulterated fentanyl", but there is no proof of the presence of medetomidine among any of these four patients. The only bases are that they were in Philadelphia (which appears to have high penetrance of adulterants -- perhaps because the proximity of CSFRE enables more detection) and that they had difficult withdrawals. The latter is a circular argument. The authors should clearly state this limitation in the Discussion.
Irregular capitalization:
Generic medication names sometimes are capitalized when they are not the first word in a sentence. (Examples in lines 229, 263, 298. This list may be incomplete.)
Why do some diagnoses appear capitalized? (Lines 282, 283, 291, 338. List may be incomplete.).
Why does "Male" hae a capital letter in Line 248?
Why does "addiction medicine service" (or team) sometimes have no capital letters (lines 85, 187, 219, 227, ), one capital letter (line 319), or three capital letters (line 312)?
Line 172: "AP One View Chest X-Ray was read as no evidence of..." First, the correct term is chest radiograph and not the colloquial "chest X-ray". Second, when you say it "was read as...", you imply that the reading might not be accurate. If the radiograph showed no pneumonia, pneumothorax, or mediastinal abnormalities, then simply say so.
Line 216: Use the generic term "dexmedetomidine" and not the brand name "Precedex".
Line 241-242: Define "maximal doses of dexmedetomidine and fentanyl". Are these cumulative doses? Are these local limits for infusion rates? The only limit for fentanyl dosing is respiratory depression, so an intubated patient could receive grams instead of micrograms. The primary limit for dexmedetomidine is severe bradycardia (I define this as HR < 40 bpm since the bradycardia is benign and reversible with discontinuation of the drug.
LINE 244-246: Syntax is awkward. I dislike the passive voice, which separates the actor from the action. You should identify what kind of capacity. I think that you mean decision making capacity. The last clause should be a separate sentence (after eliminationg the vague and meaningless passive voice "was regarded". What does "her condition was regarded as poor" actually mean? This conveys a value judgement, but the criteria are opaque. Do you mean that she had unstable vital signs, unresolved symptoms, or something else. Is this a value judgement about the likelihood that this patient would soon use drugs again?
LINE 256: "dramatically" This description conveys a subjective judgement. Just state the fact.
LINE 275: What dose "micro induction" mean here? We use the term differently in my hospital. Case 3 never mentions any buprenorphine until this line. The patient received 12 mg/day of buprenorphine on Days 4, 5, and 6, so I do not understand how he
"completed his micro induction" on Day 6.
Also, there is no mention of the route, dose interval, and form of buprenorphine (with or without naloxone?).
LINE 276-277: "...what was deemed a persistent atrial tachycardia by cardiology." As written, this signifies that the writer doubted the diagnosis by the cardiologist. If it is so that the patient had persistent atrial tachycardia, then simply state that he received diltiazem for persistent atrial tachycardia.
Line 278-280: This information is not necessary for the reader's understanding of the case.
LINE 301: "repeat vitals" Please avoid the colloquial but incorrect use of "vitals" as a noun. The term is "vital signs".
LINE 323-314: Adjustments were made..." This sentence tells the reader almost nothing. What were the goals? Were these specific vital sign targets? Since they were the patient's goals ("his goals of care"), what did the patient identify as his goals? Normally, the term "goals of care" refers to the comfort or lifestyle goals and the limits of medical intervention requested by a patient with a terminal illness.
LINE 340: Is the mention of the bus pass from social work important to my understanding of medetomidine and its possible contribution to withdrawal?
LINE 364 / Section 4.3 is overly long and largely unnecessary.
LINE 390: "As previously stated" In the words of David Byrne of the Talking Heads, "Say something once. Why say it again?"
LINE 396: "is thought to contribute" Avoid "is thought to". Who thinks this? What references (if any) directly support this idea? All too often, I see authors cite a single case report to support "is thought to", but the expression sounds more determined as though the idea were established fact. If you are simply expressing your own thoughts about about the possibility then say "this synergism may contribute" (moderate confidence in the possibility) or "this synergism might contribute" (lower confidence in the possibility.
LINE 446: "aggressive" If I am doing something "aggressive" to my patients, I am doing something with the deliberate intent to cause harm. Also, although I get that you are very vaguely describing the quantities or numbers of drugs used, "aggressive" is in the eye of the beholder and has no objective meaning.
An anecdote to illustrate: I was consulting on a psychotic patient with psychiatric disturbance after a medication overdose. The patient required 7 or 8 staff in the room to prevent her from harming herself. When I suggested giving IM haloperidol or olanzapine, the primary team criticized this as "too aggressive" and instead gave IM diphenhydramine (which was unsurprisingly ineffective).
LINE 493 / Section 4.7: I have long wondered about why some use two oral medications (clonidine and tizanidine), which should have the same effect. This would be like giving both diphenhydramine and hydroxyzine for itching or giving both ondansetron and granisetron for nausea & vomiting.
LINE 507 / Section 4.8: This section on potential safety of dexmedetomidine infusion outside the ICU has nothing to say about medetomidine withdrawal or its treatment. I agree that patients with medetomidine (or xylazine) withdrawal (if it exists) would likely tolerate IV dexmedetomidine infusions very safely.
LINE 563: I live in a city (hundreds of miles from Philadelphia) where medetomidine has already entered the drug supply. Our medical examiner's office has detected it several times. However, our hospital laboratory does not test for this, so it is possible that I have seen some medetomidine exposed patients with no severe withdrawal state.
LINE 570: "often refractory" You have a case series of 4 patients selected by the severity of withdrawal. We do not know the proportion of patients with difficult-to-manage withdrawal out of the entire population of illicit drug users exposed to medetomidine.
Author contributions: Some of these seem to be inflated to justify why there are 17 authors for a case series and review of the literature.
Methodology: The case series is simply 4 case reports, so there are no methods. The narrative review has a straightforward description of the literature search.
Software: It is not clear what software the 16th author developed. Simply using Epic to search for all drug doses or COWS for a given patient is using the software but not creating a software.
Formal analysis: The manuscript explicitly states "No quantitative synthesis or formal risk-of-bias assessment was performed..."
Investigation: What investigation is there in a short case series?
Resources: What resources did this case series and review of the literature require besides access to the hospital computer system?
Data curation: There was no analysis of data because there were no data. The closest that I can see is that someone developed the graphs of cumulative medication doses and COWS for each patient.
Visualization: What was there to "visualize"? It is a small case series and a narrative review.
Project administration and funding acquisition: Two lines later on Line 584, the manuscript says "This research received no external funding."
Excessive use of the passive voice. The passive voice detaches the actor from the action, usually requires more words, and is less clear. Readers clearly prefer the active voice. The AMA Manual of Style strongly recommends using the active voice.
Variations in capitalization (generic drug names, name of the consulting service, patient sex, diagnoses, etc.) suggest different authors for different cases with at least one of the case authors likely not being a native English speaker/writer.
Author Response
Thank you for your comprehensive review, which will allow our paper to be much stronger if considered for publication. We have addressed each review, point by point, and attach a manuscript with tracked changes to follow.
The authors have undertaken a small case series (4 patients) and a review of the literature. This is essentially the same as "case report and a review of the literature", which was once a common article format, but which is now outmoded.
Our response: I apologize that this feels outmoded, but the relevance to the addiction community and hospital based care in communities affected by this is substantial. We have published larger case series, as referenced, but an narrative accounting of the agony these patients face deserves to be documented. These are unprecedented symptoms in those who are ultimately trying to use opioids. Similarly, the meager available literature prevents upgrading to a systematic review. If the journal is uncomfortable with the format, we have several other journals who are interested and would be willing to retract.
The authors should separate that case series and the narrative review. It is OK to cite literature in the Discussion to give context to the observations.
Our response: We strongly disagree with this, as the point of this paper, which we’ve been asked to write by several clinicians and hospitals to support the development of their own treatment protocols -- is to demonstrate the severity of this novel condition and then pair it to a narrative review of present and future research topics. The reviewer seems skeptical to the overall format of our manuscript and again, if this is disqualifying at this journal, we can submit elsewhere.
"Due to the paucity of research", the authors expanded their review to dexmedetomidine, opioid (with or without an alpha-2-agonist), and alcohol withdrawal. Of these, only the first should be part of the discussion. Alcohol withdrawal is mechanistically quite different (affecting regulation of GABA-chloride channels). Its inclusion is very puzzling.
Our response: The mechanistic concern about inclusion of alcohol is a fair critique but it appears absent to the context of the inclusion, which is to demonstrate the use of dexmedetomidine to treat sedative withdrawal toxidromes, which is not it's FDA approved indication. We removed the reference to alcohol in deference to the reviewer.
The authors cannot separate medetomidine withdrawal (if it exists) from opioid withdrawal. A patient receiving 62 mg of hydromorphone in 1 day may be getting treatment for opioid withdrawal. I am willing to believe that combined withdrawal is possible, but we lack so many details about the duration or frequency of medetomidine exposure (the patients likely do not know) or the absorbed doses of medetomidine.
Our response: This is assuredly true. Thank you for this feedback and a limitation section has been added to the manuscript.
The case series includes patients with "suspected medetomidine-adulterated fentanyl", but there is no proof of the presence of medetomidine among any of these four patients. The only bases are that they were in Philadelphia (which appears to have high penetrance of adulterants -- perhaps because the proximity of CSFRE enables more detection) and that they had difficult withdrawals. The latter is a circular argument. The authors should clearly state this limitation in the Discussion.
Our response: This is factually untrue (the first case report’s last sentence was: ‘Subsequent liquid chromatography-tandem mass spectrometry revealed positive detection of 3-hydroxy-medetomidine metabolites in her urine.’) Saying that, this is absolutely a limitation, and I have added this to the limitation section and re-written the passage for clarity. Secondly, this condition has been published in multiple locations, not just Philadelphia. Our colleagues published in the CDC in Pittsburgh and there are more and more reports from the US (Arizona, LA County, NYC) and Europe. This is not made up. And furthermore, we referenced the other papers and locations outside Philly. We are assuredly the hotspot, which is why we are trying to publish for when it inevitably spreads further.
Irregular capitalization:
Generic medication names sometimes are capitalized when they are not the first word in a sentence. (Examples in lines 229, 263, 298. This list may be incomplete.)
Our response: I’m very thankful and yes, there are lots of formatting improvements, we are so sorry for the state of the paper in that regard. I went through each and made sure all medications were generic and not capitalized unless first word in a sentence.
Why do some diagnoses appear capitalized? (Lines 282, 283, 291, 338. List may be incomplete.).
Our response: I have gone through each case and assured there are no capitalized diagnoses.
Why does "Male" hae a capital letter in Line 248?
Our response: In the USA, Sex is often capitalized in medical documentation, this has been fixed.
Why does "addiction medicine service" (or team) sometimes have no capital letters (lines 85, 187, 219, 227, ), one capital letter (line 319), or three capital letters (line 312)?
Our response: I have gone through each case and assured there are no capitalized addiction medicine entries.
Line 172: "AP One View Chest X-Ray was read as no evidence of..." First, the correct term is chest radiograph and not the colloquial "chest X-ray". Second, when you say it "was read as...", you imply that the reading might not be accurate. If the radiograph showed no pneumonia, pneumothorax, or mediastinal abnormalities, then simply say so.
Our response: Thank you for catching this, changed.
Line 216: Use the generic term "dexmedetomidine" and not the brand name "Precedex".
Our response: This was quoted from the medical documentation, but I have edited to remove the brand name.
Line 241-242: Define "maximal doses of dexmedetomidine and fentanyl". Are these cumulative doses? Are these local limits for infusion rates? The only limit for fentanyl dosing is respiratory depression, so an intubated patient could receive grams instead of micrograms. The primary limit for dexmedetomidine is severe bradycardia (I define this as HR < 40 bpm since the bradycardia is benign and reversible with discontinuation of the drug.
Our response: Great point, I have added a paragraph in the methods section denoting the maximal dosage. They are infusion rates that are delineated on our hospital formulary guidelines.
LINE 244-246: Syntax is awkward. I dislike the passive voice, which separates the actor from the action. You should identify what kind of capacity. I think that you mean decision making capacity. The last clause should be a separate sentence (after eliminationg the vague and meaningless passive voice "was regarded". What does "her condition was regarded as poor" actually mean? This conveys a value judgement, but the criteria are opaque. Do you mean that she had unstable vital signs, unresolved symptoms, or something else. Is this a value judgement about the likelihood that this patient would soon use drugs again?
Our response: We are required to document patient condition upon leaving the hospital, and hers was documented as poor. Physicians make value judgements about conditions all the time, not patients. I have removed this to help resolve this reviewer’s concerns with a passive voiced narrative.
LINE 256: "dramatically" This description conveys a subjective judgement. Just state the fact.
Our response: Agreed, removed.
LINE 275: What dose "micro induction" mean here? We use the term differently in my hospital. Case 3 never mentions any buprenorphine until this line. The patient received 12 mg/day of buprenorphine on Days 4, 5, and 6, so I do not understand how he
"completed his micro induction" on Day 6.
Also, there is no mention of the route, dose interval, and form of buprenorphine (with or without naloxone?).
Our response: Great point, this has been added to the methods section along with the infusion maximal dosages.
LINE 276-277: "...what was deemed a persistent atrial tachycardia by cardiology." As written, this signifies that the writer doubted the diagnosis by the cardiologist. If it is so that the patient had persistent atrial tachycardia, then simply state that he received diltiazem for persistent atrial tachycardia.
Our response: Fair, changed.
Line 278-280: This information is not necessary for the reader's understanding of the case.
Our response: Fair, changed.
LINE 301: "repeat vitals" Please avoid the colloquial but incorrect use of "vitals" as a noun. The term is "vital signs".
Our response: Fair, changed.
LINE 323-314: Adjustments were made..." This sentence tells the reader almost nothing. What were the goals? Were these specific vital sign targets? Since they were the patient's goals ("his goals of care"), what did the patient identify as his goals? Normally, the term "goals of care" refers to the comfort or lifestyle goals and the limits of medical intervention requested by a patient with a terminal illness.
Our response: Fair, changed.
LINE 340: Is the mention of the bus pass from social work important to my understanding of medetomidine and its possible contribution to withdrawal?
Our response: Many of our patients have vast social related health needs. I charitably believe this reviewer is writing this worried that we are stigmatizing our patients by including these details, but the fact that our patient left alone, without loved ones to pick them up, is not trivial. I have removed the reference but this is not stated to judge a patient, but to explain the common ways some hospital stays end.
LINE 364 / Section 4.3 is overly long and largely unnecessary.
Our response: I don’t understand why a review of the pharmacology of the drug is unnecessary, but I have edited the entire section without removing content.
LINE 390: "As previously stated" In the words of David Byrne of the Talking Heads, "Say something once. Why say it again?"
Our response: Removed
LINE 396: "is thought to contribute" Avoid "is thought to". Who thinks this? What references (if any) directly support this idea? All too often, I see authors cite a single case report to support "is thought to", but the expression sounds more determined as though the idea were established fact. If you are simply expressing your own thoughts about about the possibility then say "this synergism may contribute" (moderate confidence in the possibility) or "this synergism might contribute" (lower confidence in the possibility.
Our response: Yes, it was hypothesis, but I have just removed it as the conjecture is unnecessary
LINE 446: "aggressive" If I am doing something "aggressive" to my patients, I am doing something with the deliberate intent to cause harm. Also, although I get that you are very vaguely describing the quantities or numbers of drugs used, "aggressive" is in the eye of the beholder and has no objective meaning.
Our response: Now we are arguing semantics where the meaning seems clear from our end, I have removed 4/5 mentions of the word aggressive in the manuscript.
LINE 493 / Section 4.7: I have long wondered about why some use two oral medications (clonidine and tizanidine), which should have the same effect. This would be like giving both diphenhydramine and hydroxyzine for itching or giving both ondansetron and granisetron for nausea & vomiting.
Our response: Thank you. If this is actually a persistent question, yes; we give both medications to achieve lower doses of each, especially as you reach therapeutic ceilings.
LINE 507 / Section 4.8: This section on potential safety of dexmedetomidine infusion outside the ICU has nothing to say about medetomidine withdrawal or its treatment. I agree that patients with medetomidine (or xylazine) withdrawal (if it exists) would likely tolerate IV dexmedetomidine infusions very safely.
Our response: That is fair, we do have an abstract we have published that is directly relevant to opioid-a2a withdrawal, added as new reference #51.
LINE 563: I live in a city (hundreds of miles from Philadelphia) where medetomidine has already entered the drug supply. Our medical examiner's office has detected it several times. However, our hospital laboratory does not test for this, so it is possible that I have seen some medetomidine exposed patients with no severe withdrawal state.
Our response: Yes, that is why this is so challenging. There are likely people who don’t develop severe withdrawal, but we are seeing huge increases in presentations for severe withdrawal.
LINE 570: "often refractory" You have a case series of 4 patients selected by the severity of withdrawal. We do not know the proportion of patients with difficult-to-manage withdrawal out of the entire population of illicit drug users exposed to medetomidine.
Our response: Agreed, changed.
Author contributions: Some of these seem to be inflated to justify why there are 17 authors for a case series and review of the literature.
Our response: We have documented each person’s contribution. Caring for these individuals counts and we want to include all the clinicians who cared for these patients. I do not see an author maximum, and if everyone contributes, what’s the issue?
Methodology: The case series is simply 4 case reports, so there are no methods. The narrative review has a straightforward description of the literature search.
Our response: Our methods include a variety of information, I am not sure if this reviewer is asking for the methods to be removed, but I hope our additions bring more value to the reviewer of this section.
Software: It is not clear what software the 16th author developed. Simply using Epic to search for all drug doses or COWS for a given patient is using the software but not creating a software.
Our response: That is fair, this was removed.
Formal analysis: The manuscript explicitly states "No quantitative synthesis or formal risk-of-bias assessment was performed..."
Our response: We have removed all of the figures due to the numerous issues, but this was the an
Investigation: What investigation is there in a short case series?
Our response: This is who did the case series and figures, but we removed the figures.
Resources: What resources did this case series and review of the literature require besides access to the hospital computer system?
Our response: That is fair, removed.
Data curation: There was no analysis of data because there were no data. The closest that I can see is that someone developed the graphs of cumulative medication doses and COWS for each patient.
Our response: That is fair, yes, we meant all the data for the cases and figures, but removed the figures, so removed.
Visualization: What was there to "visualize"? It is a small case series and a narrative review.
Our response: This was the figures, again removed.
Project administration and funding acquisition: Two lines later on Line 584, the manuscript says "This research received no external funding."
Our response: Removed.
Excessive use of the passive voice. The passive voice detaches the actor from the action, usually requires more words, and is less clear. Readers clearly prefer the active voice. The AMA Manual of Style strongly recommends using the active voice.
Our response: This is fair but how many case reports are written. I have essentially rewritten every case to be more active and homogenous.
Variations in capitalization (generic drug names, name of the consulting service, patient sex, diagnoses, etc.) suggest different authors for different cases with at least one of the case authors likely not being a native English speaker/writer.
Our response: This is only partially true, each case was written by a different author, but all are native English speakers who trained in the USA and practice in the hospital.
Reviewer 2 Report
Comments and Suggestions for AuthorsGeneral comments:
While the topic of this manuscript is timely and relevant, the manuscript requires substantial revision before it can be considered for publication. At present, there are numerous grammatical errors and stylistic inconsistencies that significantly affect its readability. The introduction is difficult to follow, with sentences that are long and winding. Much of this is due to the frequent use of parentheses, which often contain extraneous information that interrupts the flow rather than clarifying it. In addition, dashes are used inconsistently and at times are oddly placed for little reason. Some of these dashes should be commas, and some of the dashes are between words where they should not be, for example within “against-medical-advice” which is not the correct use of dashes.
The presentation of data also requires attention. The figures have inconsistent decimal places and overall poor formatting, which makes them difficult to interpret. Similarly, abbreviations are used inconsistently throughout the manuscript, creating confusion for the reader.
Overall, the writing lacks clarity and cohesion, which makes it challenging for the reader to stay engaged. If this work is to move forward, it will need a careful, line by line revision to ensure consistency, clarity, and a more professional presentation.
Abstract:
1st sentence – in areas of the manuscript, a-2 agonists (no dash after 2) vs a-2-agonists (has a dash after 2) are used interchangeably. Recommend picking one and sticking with it. Personally, I think no dash is a better way to present it.
Introduction:
Page 1, line 44 – I would not call oxycodone and hydromorphone short-acting opioids. These have a longer half-life than fentanyl for all intents and purposes. Recommend removing the words short-acting and leaving it as “opioids”.
This whole sentence could be rewritten in a more streamlined way as the excess information does not add much in my opinion: “In response, hospitals in Philadelphia developed novel withdrawal protocols tailored to “tranq dope” (fentanyl/xylazine) users, employing opioids (e.g., oxycodone or IV hydromorphone), ketamine, antipsychotics (droperidol or olanzapine), and α-2-agonists (tizanidine, or guanfacine).”
Page 2, line 46 – remove comma after tizanidine for consistency.
Page 2, line 48 – The dashes in “against-medical-advice” do not need to be there. That is not the way it is ever written. Remove those dashes. Also, the parenthesis at the end with “also known as patient directed discharge” is not necessary and appears as an afterthought. Recommend rewriting the sentence as “Early data showed these protocols were effective during the xylazine era, achieving significant symptom relief and reducing patients leaving the hospital against medical advice.
Page 2, line 51 – The sentence starting with medetomidine and an immediate dash is not how things are written. Change it to a comma. The dash between 2 and adrenergic has a space, either remove the dash or remove the space. Rewritten it could be:
“Medetomidine, a highly α-2 adrenergic agonist used in veterinary anesthesia, largely supplanted xylazine as the dominant fentanyl adulterant.”
Page 2, line 58 – Closing parenthesis is missing after 30%. Also not sure there needs to be so many parentheses in the intro. This reads like someone is speaking in their head rather than stating what is known. Suggest comma after “contained medetomidine” and taking parenthesis out.
Page 2 line 60 – This sentence is highly typical for AI with a dash after crisis, which is fine as this is a tool that can be helpful in writing, but this is simply not how people write. Remove the dash after crisis and rewrite the sentence as:
“Reported features include intractable vomiting, diaphoresis, tremors, and sympathetic crisis, characterized by extreme tachycardia and hypertensive emergencies often refractory to even aggressive treatment for fentanyl and xylazine.”
Materials and Methods:
For a case series, this section is very oddly written. I suggest it completely be rewritten to make it easier for a reader to follow, and to take out unnecessary details. An example of an unnecessary detail is that “The senior/corresponding author reviewed each for accuracy and formatting.” This does not help the reader much. Also, the sentence prior to it says that one of the separate reviewers was the senior author.
The authors initials are denoting their involvement in every step, which is really not necessary. For instance, page 2 line 87, when I read this sentence, I had to scroll up to the authors and see what type of people reviewed the cases. This sentence about reviewers could be more effective and easier to understand if it explained the types of people that reviewed it, like this:
“All cases were reviewed retrospectively by three addiction medicine and one emergency medicine physician, providing a timeline from their arrival in the emergency department through departure from the hospital.”
The whole materials and methods should be streamlined as suggested above to change initials to descriptions or remove initials altogether in some places where it is unnecessary.
Results:
General comments about case presentations – the formatting throughout the cases needs to be redone. Sometimes the dosing (such as mg) is right after the number and sometimes there is a space. These should be consistent and typically a space is needed. The use of abbreviations like “q8” should not be used in a manuscript and need to be written out as “every 8 hours”. Sometimes “hrs” or “hours” are used interchangeably throughout the case presentations. ODT and IVF are written in case 1 (page 3, lines137-138) but were never properly abbreviated in the text with it written out on the first use with the abbreviation, and were not listed in the abbreviations table at the end.
Writing a case up for a manuscript is very different than what is seen in the chart and should be presented in a way that even a non-medical individual could understand. That means there should be minimal medical abbreviations unless they are fully explained. Medical use of q8 in a patients chart is ok, but in a manuscript should never occur.
Case one – all the sudden emergency department is presented as the acronym “ED”. Emergency department has been written out twice in the first paragraph of the methods. If the acronym “ED” is to be used, it needs to start on the first mention of emergency department in the methods, and every single time after that change it to ED.
Case three – Page 6 line 263, midazolam does not need to be capital. Page 7 line 279, the bridge clinic name should be removed and instead mention what it is (an “outpatient opioid use disorder treatment center” perhaps).
Case four – Page 7 line 282, opioid use disorder and alcohol use disorder do not need to be capitalized. This occurs in multiple areas of the manuscript and it should be lower case. Note, if you are writing a disease, it does not need to be capitalized unless it’s a pseudonym for someones name (like Alzheimer’s disease). To capitalized only opioid use disorder and not things like schizoaffective disorder (such as was done on page 7 line 282-284) makes no sense. Page 7 line 292, ICU is now spelled out and abbreviated, but this has been used 4 times as the abbreviation ICU since the introduction of this manuscript. Page 8 line 319, addiction is lower case and medicine is upper case. If the various services are to be capitalized, then it needs to be consistent. Page 8 line 325, IVPB is written and never explained and is not in the abbreviation table.
Discussion:
Page 8 line 345 - All the sudden a2 is used. This is inconsistent with the last 8 pages of text.
Page 13, like 565 – Its not sympathetic, its “sympathomimetic” when used in this way. This also needs to be fixed on page 2 line 61 and page 13 line 570.
Other:
Abbreviations page 15-16 – This list is not consistent with much of what is written in this manuscript. Emergency department as stated above in the results was not always presented as an acronym. In addition, alpha-2 being rewritten as a2 only occurred from the discussion forward. Sometimes it was written out as “alpha-2” and sometimes it was “a-2” (with the alpha symbol). Sometimes “heart rate” is written out (page 6 lines 256 and 265) and sometimes abbreviated as HR. MICU is written in multiple places but never abbreviated in this abbreviations table, and it seems like ICU was used a lot but then MICU suddenly becomes used in case two (ICU is also not in this abbreviations table). RR is written in multiple places but not on the abbreviation list. The authors need to go through the manuscript again from beginning to end and fix these details. After a manuscript is written someone should be responsible for ensuring that these inconsistencies are fixed prior to submission.
Figure 1 – The formatting is hard to get past. The decimal places and numbers running together are unsuitable. Also, the overlapping of the bars in the bar graph are apparent starting on HD 5 through the right side of the figure. This badly needs to be reformatted and cannot be used as it stands now.
Figure 3 – This figure also has many formatting issues. The numbers above the bars are very inconsistent. Some have two decimal places, some have one, some have none. Even if a number has no decimal, if the formatting is to be 1 decimal place, then the numbers would have that decimal place. For instance, 1114 would be written 1114.0. I would suggest no decimal places however because of this figure is already too crowded. The numbers are running into each other or winding to the line below (like in 6570 in hospital day 3).
Figure 4 – as in figure 3, the decimal units are not consistent. Rounding to whole numbers is a better option.
Author Response
Thank you for your comprehensive review, which will allow our paper to be much stronger if considered for publication. We have addressed each review, point by point, and attach a manuscript with tracked changes to follow.
Comments and Suggestions for Authors
General comments:
While the topic of this manuscript is timely and relevant, the manuscript requires substantial revision before it can be considered for publication. At present, there are numerous grammatical errors and stylistic inconsistencies that significantly affect its readability. The introduction is difficult to follow, with sentences that are long and winding. Much of this is due to the frequent use of parentheses, which often contain extraneous information that interrupts the flow rather than clarifying it. In addition, dashes are used inconsistently and at times are oddly placed for little reason. Some of these dashes should be commas, and some of the dashes are between words where they should not be, for example within “against-medical-advice” which is not the correct use of dashes.
Our response: We apologize, The other reviewer also mentioned these grammatical and formatting flaws. We have rewritten the entire paper to try to homogenize and better flow.
The presentation of data also requires attention. The figures have inconsistent decimal places and overall poor formatting, which makes them difficult to interpret. Similarly, abbreviations are used inconsistently throughout the manuscript, creating confusion for the reader.
Our response: We are so sorry. We have removed the figures for being difficult to read beyond fixing and re-edited the entire piece for consistency.
Overall, the writing lacks clarity and cohesion, which makes it challenging for the reader to stay engaged. If this work is to move forward, it will need a careful, line by line revision to ensure consistency, clarity, and a more professional presentation.
Our response: This is exactly what we did. Thank you for allowing us to improve the piece.
Abstract:
1st sentence – in areas of the manuscript, a-2 agonists (no dash after 2) vs a-2-agonists (has a dash after 2) are used interchangeably. Recommend picking one and sticking with it. Personally, I think no dash is a better way to present it.
Our response: Totally fair, we decided to use α2 agonist.
Introduction:
Page 1, line 44 – I would not call oxycodone and hydromorphone short-acting opioids. These have a longer half-life than fentanyl for all intents and purposes. Recommend removing the words short-acting and leaving it as “opioids”.
Our response: ‘Short acting opioids’ are an actual medical term, differentiating from methadone and extended release options such as oxycodone. Simplified either way.
This whole sentence could be rewritten in a more streamlined way as the excess information does not add much in my opinion: “In response, hospitals in Philadelphia developed novel withdrawal protocols tailored to “tranq dope” (fentanyl/xylazine) users, employing opioids (e.g., oxycodone or IV hydromorphone), ketamine, antipsychotics (droperidol or olanzapine), and α-2-agonists (tizanidine, or guanfacine).”
Our response: Agreed, we simplified it.
Page 2, line 46 – remove comma after tizanidine for consistency.
Our response: Agreed, removed.
Page 2, line 48 – The dashes in “against-medical-advice” do not need to be there. That is not the way it is ever written. Remove those dashes. Also, the parenthesis at the end with “also known as patient directed discharge” is not necessary and appears as an afterthought. Recommend rewriting the sentence as “Early data showed these protocols were effective during the xylazine era, achieving significant symptom relief and reducing patients leaving the hospital against medical advice.
Our response: Agreed, revised.
Page 2, line 51 – The sentence starting with medetomidine and an immediate dash is not how things are written. Change it to a comma. The dash between 2 and adrenergic has a space, either remove the dash or remove the space. Rewritten it could be:
Our response: Agreed, revised.
“Medetomidine, a highly α-2 adrenergic agonist used in veterinary anesthesia, largely supplanted xylazine as the dominant fentanyl adulterant.”
Page 2, line 58 – Closing parenthesis is missing after 30%. Also not sure there needs to be so many parentheses in the intro. This reads like someone is speaking in their head rather than stating what is known. Suggest comma after “contained medetomidine” and taking parenthesis out.
Our response: Great catch. Changed.
Page 2 line 60 – This sentence is highly typical for AI with a dash after crisis, which is fine as this is a tool that can be helpful in writing, but this is simply not how people write. Remove the dash after crisis and rewrite the sentence as:
“Reported features include intractable vomiting, diaphoresis, tremors, and sympathetic crisis, characterized by extreme tachycardia and hypertensive emergencies often refractory to even aggressive treatment for fentanyl and xylazine.”
Our response: This was not written with AI, in fact re-reading the sentence, there is a grammar error that needed correction (crisis should be crises). Sorry, some of our authors (myself included), really like using dashes and parentheses in writing. I have removed all the other dashes, except for the ones in the author contributions and references sections.
Materials and Methods:
For a case series, this section is very oddly written. I suggest it completely be rewritten to make it easier for a reader to follow, and to take out unnecessary details. An example of an unnecessary detail is that “The senior/corresponding author reviewed each for accuracy and formatting.” This does not help the reader much. Also, the sentence prior to it says that one of the separate reviewers was the senior author.
Our response: We have edited and improved the whole methods section.
The authors initials are denoting their involvement in every step, which is really not necessary. For instance, page 2 line 87, when I read this sentence, I had to scroll up to the authors and see what type of people reviewed the cases. This sentence about reviewers could be more effective and easier to understand if it explained the types of people that reviewed it, like this:
“All cases were reviewed retrospectively by three addiction medicine and one emergency medicine physician, providing a timeline from their arrival in the emergency department through departure from the hospital.”
Our response: Thank you, we have edited and revised the whole methods section.
The whole materials and methods should be streamlined as suggested above to change initials to descriptions or remove initials altogether in some places where it is unnecessary.
Our response: Thank you, we have edited and revised the whole methods section.
Results:
General comments about case presentations – the formatting throughout the cases needs to be redone. Sometimes the dosing (such as mg) is right after the number and sometimes there is a space. These should be consistent and typically a space is needed. The use of abbreviations like “q8” should not be used in a manuscript and need to be written out as “every 8 hours”. Sometimes “hrs” or “hours” are used interchangeably throughout the case presentations. ODT and IVF are written in case 1 (page 3, lines137-138) but were never properly abbreviated in the text with it written out on the first use with the abbreviation, and were not listed in the abbreviations table at the end.
Our response: We have fixed all of those, thanks for the heads up!
Writing a case up for a manuscript is very different than what is seen in the chart and should be presented in a way that even a non-medical individual could understand. That means there should be minimal medical abbreviations unless they are fully explained. Medical use of q8 in a patients chart is ok, but in a manuscript should never occur.
Our response: We entirely respect this and thank you for catching our errors. All abbreviations have been universalized and only used where appropriate.
Case one – all the sudden emergency department is presented as the acronym “ED”. Emergency department has been written out twice in the first paragraph of the methods. If the acronym “ED” is to be used, it needs to start on the first mention of emergency department in the methods, and every single time after that change it to ED.
Our response: Thank you, we absolutely missed this one.
Case three – Page 6 line 263, midazolam does not need to be capital. Page 7 line 279, the bridge clinic name should be removed and instead mention what it is (an “outpatient opioid use disorder treatment center” perhaps).
Our response: There were several of these, and we made them all lower case.
Case four – Page 7 line 282, opioid use disorder and alcohol use disorder do not need to be capitalized. This occurs in multiple areas of the manuscript and it should be lower case. Note, if you are writing a disease, it does not need to be capitalized unless it’s a pseudonym for someones name (like Alzheimer’s disease). To capitalized only opioid use disorder and not things like schizoaffective disorder (such as was done on page 7 line 282-284) makes no sense. Page 7 line 292, ICU is now spelled out and abbreviated, but this has been used 4 times as the abbreviation ICU since the introduction of this manuscript. Page 8 line 319, addiction is lower case and medicine is upper case. If the various services are to be capitalized, then it needs to be consistent. Page 8 line 325, IVPB is written and never explained and is not in the abbreviation table.
Our response: All of this is correct, we have fixed all of it.
Discussion:
Page 8 line 345 - All the sudden a2 is used. This is inconsistent with the last 8 pages of text.
Our response: We chose α2 for all of them.
Page 13, like 565 – Its not sympathetic, its “sympathomimetic” when used in this way. This also needs to be fixed on page 2 line 61 and page 13 line 570.
Other: Agree to disagree on this. We are discussing the sympathetic nervous system, the effect is a sympathetic crisis. It is similar to a sympathomimetic toxidrome but this is in the setting of withdrawal, not exposure, hence, it’s the lack of a sympatholytic drug in the setting of withdrawal, not intoxication.
Abbreviations page 15-16 – This list is not consistent with much of what is written in this manuscript. Emergency department as stated above in the results was not always presented as an acronym. In addition, alpha-2 being rewritten as a2 only occurred from the discussion forward. Sometimes it was written out as “alpha-2” and sometimes it was “a-2” (with the alpha symbol). Sometimes “heart rate” is written out (page 6 lines 256 and 265) and sometimes abbreviated as HR. MICU is written in multiple places but never abbreviated in this abbreviations table, and it seems like ICU was used a lot but then MICU suddenly becomes used in case two (ICU is also not in this abbreviations table). RR is written in multiple places but not on the abbreviation list. The authors need to go through the manuscript again from beginning to end and fix these details. After a manuscript is written someone should be responsible for ensuring that these inconsistencies are fixed prior to submission.
Our response: This is a great catch, we revied all of the abbreviations and made them consistent throughout the piece. We apologize.
Figure 1 – The formatting is hard to get past. The decimal places and numbers running together are unsuitable. Also, the overlapping of the bars in the bar graph are apparent starting on HD 5 through the right side of the figure. This badly needs to be reformatted and cannot be used as it stands now.
Our response: All figures were removed we ultimately did not think there was a viable way to format that didn’t confuse or add overall to the piece.
Figure 3 – This figure also has many formatting issues. The numbers above the bars are very inconsistent. Some have two decimal places, some have one, some have none. Even if a number has no decimal, if the formatting is to be 1 decimal place, then the numbers would have that decimal place. For instance, 1114 would be written 1114.0. I would suggest no decimal places however because of this figure is already too crowded. The numbers are running into each other or winding to the line below (like in 6570 in hospital day 3).
Our response: All figures were removed we ultimately did not think there was a viable way to format that didn’t confuse or add overall to the piece.
Figure 4 – as in figure 3, the decimal units are not consistent. Rounding to whole numbers is a better option.
Our response: All figures were removed we ultimately did not think there was a viable way to format that didn’t confuse or add overall to the piece.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThank you for your wonderful revisions! This manuscript looks great and the figures are much more clear for the reader! The discussion is really well done with strong references. The limitations section is well thought out for the same limitations I feel apply after reviewing this paper. I have a few comments below which are very minor grammatical edits.
Page 4, line 160 in case 1, heart rate and respiratory rate should be lower case.
Page 4, line 164, case 1, push should be lower case. IV was never shortened by itself and is sometimes written out as intravenous or IV throughout the manuscript. I suggest changing this to “intravenous push (IVP). Suggest revising line 166, change it to “intravenous fluid (IVF) lactated ringer’s solution 1000 mL”. Then to introduce IV itself on line 168 spell out intravenous in the sentence “…received all intravenous (IV) medications and fluid.” Then please add IV to the acronym list
Page 6, Line 239 – change intravenous to IV
Page 10, Line 425 – change intravenous to IV
Page 12, Line 492 – change intravenous to IV
Page 13, Line 585 – change intravenous to IV
Page 7, line 269 – This is the first time PO is written, and though it is in the acronym list, it is not written out in the paper itself. Most physicians do know what PO is, but some public health trained people reading this important paper may not know and it would make it more clear if its written out on first mention. PO is also missing for the dosing of tizanidine.
Page 10, line 425 –section 4.3 Pharmacology and comparison to xylazine – Consider revising this sentence with commas to prevent saying “and” twice: “Intravenous administration of dexmedetomidine and medetomidine have similar onset, duration, and half-lives between two and three hours [22,23].
The ED acronym is correctly placed at first mention in the materials and methods section 2.1 population. However on page 3 line 95, it is written out again, please change to “ED”. Also, on page 4 line 153 of the results in section “3.1 case one”, it is written out with the acronym in parentheses again, please change to just “ED”.
Abbreviations table – Should the abbreviations be in alphabetical order? Currently I am not sure if there is an order (its not alphabetical and does not seem to be ordered by first mention). Please refer to the journals guidance of how this table should be formatted.
Author Response
All the comments were excellent and accepted. Please see the tracked changes document. I did a point by point version of this but it timed out and essentially just said 'done' after each suggestion. They were all salient. Thank you
Author Response File: 
Author Response.pdf
