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

Abstract

Background/Objectives: Philadelphia has experienced a surge in illicit fentanyl adulterated with alpha-2 agonist sedatives. Initially, xylazine (“tranq”) was the predominant adulterant, and a novel multimodal withdrawal protocol was effective at mitigating symptoms. However, since mid-2024, medetomidine—a more potent sedative—has largely supplanted xylazine. Clinicians have reported more severe, treatment-resistant opioid withdrawal during this transition. To assess whether a previously effective withdrawal management protocol retained efficacy after the emergence of medetomidine as the primary fentanyl adulterant in a community. Methods: We conducted a retrospective cohort study of patients receiving protocol-based opioid withdrawal treatment at two emergency departments in Philadelphia between September 2022 and April 2025. Patients were divided into the xylazine era (September 2022–July 2024) and medetomidine era (August 2024–April 2025). The primary outcome was a change in Clinical Opioid Withdrawal Scale (COWS) score from pre- to post-treatment. Secondary outcomes included rates of discharge against medical advice (AMA) and ICU admission, as well as the impact of a revised treatment protocol. Results: Among 1269 encounters with full data, 616 occurred during the xylazine era and 770 during the medetomidine era. Median COWS reduction was greater in the xylazine group (−9.0 vs. −4.0 points, p < 0.001), with more patients achieving symptom relief (COWS ≤ 4: 65.6% vs. 14.2%, p < 0.001). ICU admission occurred in 8.5% of xylazine era patients and 16.8% of medetomidine era patients (p < 0.001). Rates of AMA were higher during the medetomidine era as well (6.5% vs. 3.6%) (p = 0.038). Revision of treatment protocols showed promise. Conclusions: The protocol was significantly less effective during the medetomidine era, though a protocol change may be helping. Findings highlight the need to adapt withdrawal treatment protocols in response to changes in the illicit drug supply.

1. Introduction

Philadelphia remains at the leading edge of the opioid crisis, with high rates of fentanyl use and associated morbidity. In recent years, the local illicit opioid supply has been increasingly adulterated with potent sedatives, intensifying the clinical challenges associated with withdrawal management [1]. Xylazine—a veterinary alpha-2 adrenergic agonist—emerged in 2022 as a frequent fentanyl adulterant, becoming present in up to 99% of the publicly checked dope samples by 2023 [2]. The combination of potent synthetic opioids and alpha-2 agonists wrought a series of challenges, including increasing reports of precipitated withdrawal, a serious and previously rare side effect when starting the medication buprenorphine [3]. This promoted the creation of emergency department (ED) protocols specifically tailored to manage the resulting complex withdrawal syndrome [4].

A multimodal opioid withdrawal treatment protocol was implemented at two Philadelphia EDs to address xylazine-associated withdrawal. This approach used multiple pharmacologic classes targeting distinct symptom domains: short-acting opioids (e.g., oxycodone, hydromorphone) for opioid cravings and bridging to partial agonists (low dose buprenorphine), ketamine for NMDA antagonism and analgesia, droperidol or olanzapine for anxiolytic and antiemetic effects, and alpha-2 agonists (tizanidine or guanfacine) for replacement of the xylazine. In an early evaluation, the protocol produced a median COWS score reduction from 12 to 4, with only 3.9% of patients leaving AMA compared to a 10.7% historical baseline [4].

In mid-2024, toxicology surveillance and clinical observations indicated a shift in adulterants, with medetomidine supplanting xylazine as the dominant alpha-2 agonist in the local fentanyl supply [5]. Medetomidine, an alpha-2 agonist sedative up to 200 times more potent than xylazine [6,7], entered the fray, possibly related to the scheduling of xylazine as a controlled substance by the Commonwealth of Pennsylvania [8]. Clinicians noted increasingly severe and atypical withdrawal symptoms, including profound vomiting, hypertensive crises, tremor without clonus or seizure, hypoactive encephalopathy, and refractory symptoms to conventional treatment [9]. These presentations often required ICU care and were poorly responsive to the previously successful xylazine focused protocol. Clinicians hypothesized that medetomidine-related withdrawal could mimic dexmedetomidine discontinuation syndrome, a well-documented phenomenon of sympathetic overactivity [10].

This study evaluated whether the novel opioid withdrawal protocol maintained effectiveness during and after the transition from the xylazine era (XE) to the medetomidine era (ME) in Philadelphia. We compared outcomes from the xylazine and medetomidine eras, hypothesizing a significant decline in treatment efficacy and increased rates of severe clinical secondary outcomes, following the emergence of medetomidine.

2. Materials and Methods

2.1. Study Design and Setting

We conducted a pragmatic retrospective cohort study of two urban EDs in Philadelphia, Pennsylvania, one academic and one community. The academic hospital, which sees approximately 76,000 visits annually, is a level 1 trauma center. The community hospital, which sees approximately 34,000 visits annually, is a stand-alone center 2.5 miles from the main hospital. Both sites serve large urban populations and care for a high volume of patients with opioid use disorder (OUD). Both hospitals were clinical sites for the retrospective analysis establishing evidence of order set efficacy, with the orders built into the electronic health record (EPIC Systems, Madison, WI, USA) [4].

The study protocol adhered to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational research, utilizing the guidelines prior to the development of the project. Institutional Review Board approval was obtained (IRB #1269), with a waiver of informed consent due to the retrospective nature and negligible risk of the study.

Two temporal cohorts were defined using 1 August 2024 as a transition point based on public health data identifying a shift from xylazine to medetomidine as the dominant fentanyl adulterant [5]. The XE cohort included encounters from 1 September 2022, when the order set debuted, to 31 July 2024. The ME cohort included encounters from 1 August 2024 to 30 April 2025.

On 11 February 2025, in response to local trends, the order sets were updated to address medetomidine adulteration. While education had been performed as early as December 2024 related to this adulterant change, this date represents the alteration of the treatment order sets. Doses of short-acting opioids were doubled (oxycodone 10 mg > 20 mg, hydromorphone 2 mg > 4 mg), and clonidine was added due to the rates of hypertensive crises (0.3 mg orally and 0.3 mg transdermal). Education about this change was made to staff during the standing faculty meeting and resident didactics as well as through virtual/asynchronous communication. While this period still represents part of the ME, given this defined change, it was analyzed as a subgroup.

2.2. Population

This study included adult patients (≥18 years) treated in the ED who received medications from the withdrawal protocol during the study period (1 September 2022–30 April 2025). This represents the total cohort and includes all patients who were present on the database report.

The final cohort are those from the total who had both pre- and post-treatment COWS scores and a disposition documented in their charts. Exclusion criteria included missing outcome data, pregnancy, and active enrollment in methadone or buprenorphine maintenance therapy (the latter of which were ineligible for order set usage).

Detection of xylazine and medetomidine exposure in humans is difficult and not performed routinely. Due to the conjoined nature of opioids and alpha-2 agonists in Philadelphia, fentanyl urine toxicology testing is used as a marker of street “dope” exposure. Adulterant classification was therefore based largely on temporal trends rather than individual toxicology testing, which was unavailable in the ED setting, aside from fentanyl testing. A small cohort did undergo liquid chromatography tandem mass spectrometry testing. A total of 59/59 individuals tested positive for 3-OH-medetomidine metabolite in their urine samples, following glucuronidase pre-treatment. A full accounting of toxicology analysis will be published separately; a subgroup was previously described [9].

2.3. Exposure Classification

Era classification was based on date of presentation and the predominant local adulterant, as identified through citywide drug surveillance. Xylazine predominated before 1 August 2024, while medetomidine became the dominant adulterant thereafter. A subgroup analysis of patients treated after a protocol revision on 11 February 2025 was also performed, as this represents when default orders were changed for providers.

2.4. Outcomes

The primary outcome was a change in Clinical Opioid Withdrawal Scale (COWS) score from pre- to post-treatment. COWS is a multi-item scale used as the standardized means of assessing withdrawal severity in the United States [11]. Notably, there are not standardized withdrawal severity tools for alpha-2 agonist withdrawal [12]. The initial study solely utilized COWS scores for holistic withdrawal evaluation, given that anxiety and vital sign abnormalities common in alpha-2 agonist withdrawal are included in COWS. There was an association of the order sets between both reducing COWS scores and reducing the risk of AMA disposition in the first study, indicating that it may be a reasonable alternative [4]. In the absence of other standardized withdrawal assessments, COWS was used as the sole criterion for fentanyl, xylazine, and medetomidine withdrawal severity. Secondary outcomes included the following: (1) percentage of patients with COWS ≤ 4 post-treatment (which signifies no longer classifying as having withdrawal); (2) disposition from the ED, including AMA discharge, hospital admission, and ICU transfer; and (3) occurrence of serious adverse events during ED care.

2.5. Measurements and Analysis

Data for this study were obtained by an automated database report. This report contains visit demographics, chief complaint, and diagnostic data (urine fentanyl screen results), pre- and post-treatment COWS scores, and disposition data.

Statistical analysis was performed using R Version 4.4.3 statistical software (R Core Team, 2023). Descriptive statistics were calculated utilizing demographic information documented in the codebook, including standard deviations for non-parametric data.

Continuous variables were summarized as medians with interquartile ranges and compared using Mann–Whitney U and Wilcoxon signed-rank tests. Categorical variables were reported as frequencies and compared using chi-square tests. A two-sided p-value < 0.05 was considered statistically significant. Monthly COWS trends and responder rates were graphed, with key inflection points noted.

3. Results

3.1. Patient Characteristics

A total of 1269 patient encounters met inclusion criteria, out of 2158 total encounters having received medications from the protocol during the period. Of the final cohort, 616 encounters were in the XE cohort (September 2022–July 2024) and 770 in the ME cohort (August 2024–April 2025); see Figure 1. The two cohorts were similar in demographic makeup both in their total and final cohort forms. Full demographics data, including race/ethnicity, are included in

Table 1. Demographic characteristics by era and cohort.

Characteristic	Xylazine Era (Total, N = 1160)	Medetomidine Era (Total, N = 998)	Xylazine Era (Final, N = 616)	Medetomidine Era (Final, N = 770)
Age, mean ± SD	39.8 ± 9.2	40.9 ± 9.6	39.6 ± 9.2	41.1 ± 10.0
Female, n (%)	408 (35.2%)	351 (35.2%)	213 (34.6%)	275 (35.7%)
White, n (%)	885 (76.3%)	779 (78.1%)	467 (75.8%)	599 (77.8%)
Black, n (%)	122 (10.5%)	117 (11.7%)	66 (10.7%)	87 (11.3%)
Latinx, n (%)	115 (9.9%)	69 (6.9%)	65 (10.6%)	55 (7.1%)
2 + Races, n (%)	13 (1.1%)	4 (0.4%)	6 (1.0%)	4 (0.5%)
Asian, n (%)	3 (0.3%)	4 (0.4%)	1 (0.2%)	3 (0.4%)
Other/Unknown, n (%)	19 (1.6%)	24 (2.4%)	9 (1.5%)	21 (2.7%)
Positive Urine Fentanyl Screen, n (%)	893 (97.0%)	807 (98.7%)	515 (96.6%)	649 (98.6%)
Missing Urine Fentanyl Screen	239	180	83	112

.

Notably, xylazine is well known to be associated with severe skin ulceration and eventual infection [11]. The chief complaints of all presentations are shown in

Table 2. Chief complaints of presentations between the xylazine and medetomidine eras.

	Xylazine Era N (%)	Medetomidine Era N (%)	p-Value
General Medical/Other	483 (41.6)	419 (42.0)	p = 0.905
Opioid Withdrawal	159 (13.7)	312 (31.3)	p < 0.001
Psychiatric, Behavioral and Social Needs	60 (5.2)	58 (5.8)	p = 0.578
Skin/Soft Tissue Infection	386 (33.3)	150 (15.0)	p < 0.001
Trauma	72 (6.2)	59 (5.9)	p = 0.845

Note: p-values reflect chi-square comparisons of category frequency by era. Categories were formed based on clinical similarity.

. They have been simplified for categorization sake; please see Appendix A for a full list of chief complaints and in which categories they were placed. It is therefore quite telling that rates of visits for skin and soft tissue visits fell from 33.3% to 15.0% (p < 0.001) between the eras, and that volume was made up for with a commensurate rise in visits purely for opioid withdrawal (13.7% to 31.3%, p < 0.001).

At presentation, median initial COWS scores were higher in the medetomidine cohort (15.0, IQR 10–21) than in the xylazine cohort (13.0, IQR 7–17), which was statistically significant (p < 0.001). Of note, there were also significantly more presentations per month in the ME than in the XE. See full COWS scores and encounter details in

Table 3. Withdrawal severity and treatment response by era.

Outcome Metric	Xylazine Era (n = 616)	Medetomidine Era (n = 770)	p-Value
Mean ED Encounters per Month	26.8	85.6	p < 0.001
Median Pre-Treatment COWS	13	15	p < 0.001
Median Post-Treatment COWS	4	11	p < 0.001
Median COWS Reduction (∆)	9	5	p < 0.001
Mean COWS Reduction ± SD	8.80 ± 7.41	4.39 ± 7.61	p < 0.001
% Achieving COWS ≤ 4	65.60%	16.40%	p < 0.001

.

3.2. Withdrawal Treatment and COWS Outcomes

The primary outcome of withdrawal severity improvement, measured by the change in COWS, differed markedly between the two eras. Figure 2 illustrates the COWS scores before and after treatment for each cohort (median and IQR). In the XE cohort, withdrawal scores improved substantially with protocol treatment. The median COWS decreased from 13.0 (IQR 10–17) on arrival to 4.0 (IQR 1–6) after treatment, a median reduction of −9 points (p < 0.001 for within-cohort pre/post comparison). This supports the efficacy of the protocol in mitigating withdrawal signs and symptoms in the XE, consistent with previously published outcomes [4].

In Figure 3 and Figure 4, a large majority of XE patients achieved a post-treatment COWS score of <5 (65.6%, indicating relief from withdrawal). In contrast, the ME cohort experienced more modest improvements. The median COWS in this group was 15.0 (IQR 10–21) before treatment and 11.0 (IQR 7–15) post-treatment, for a median reduction of only −4 points. While this reduction was still statistically significant compared to pre-treatment scores (p < 0.001), the magnitude of improvement was clearly smaller. Only 16.4% during the ME attained a post-treatment COWS < 5 (p < 0.001 vs. XE). The between-cohort comparison of ∆COWS was highly significant (p < 0.001), indicating that the protocol’s effectiveness in reducing objective withdrawal scores was significantly blunted in the ME.

To account for any baseline differences, we performed a two-way analysis of variance on COWS scores, with time (pre vs. post) and era as factors. This analysis demonstrated a significant interaction effect (p < 0.001), corroborating that the improvement in COWS over time depended on the era (XE vs. ME). In essence, patients in the ME did not respond as robustly to the standardized regimen as those in the XE did.

3.3. Secondary Outcomes: Subgroup, Disposition, and Adverse Events

To assess the impact of the revised withdrawal protocol introduced on 11 February 2025, we performed a subgroup analysis of ME encounters before (BPC) and after the protocol change (APC). Among the 998 total encounters in the ME, 770 met criteria for inclusion in the analytic cohort, of which 293 (38.1%) occurred after the updated protocol was implemented. Patients in this subgroup demonstrated significantly greater improvement in COWS scores; the median reduction in COWS was −6.0 (IQR: −9 to −3) after the revision (APC), compared to −4.0 (IQR: −6 to −2) prior to the revision (BPC, p < 0.001). The proportion of patients achieving a post-treatment COWS score ≤ 4 increased from 11.0% to 21.1% following the protocol update (p = 0.003). Although response rates remained lower than in the xylazine era, these findings suggest partial restoration of protocol efficacy after the revision.

We also examined emergency department dispositions across eras (see

Table 4. Emergency department disposition by era (including post-protocol change cohort).

ED Disposition	Xylazine Era (N = 616)	Medetomidine Era Before Protocol Change (BPC) (N = 477)	Medetomidine Era After Protocol Change (APC) (N = 293)	p-Value (XE vs. BPC, BPC vs. APC)
Admit	410 (66.6%)	348 (72.7%)	131 (75.3%)	p = 0.036, p = 0.566
ICU Admission	35 (8.5%)	88 (18.4%)	22 (16.8%)	p < 0.001, p = 0.107
Discharge	182 (29.5%)	99 (20.7%)	33 (19.0%)	p = 0.001, p = 0.712
AMA	22 (3.6%)	31 (6.5%)	9 (5.2%)	p = 0.038, p = 0.669
Transfer to Another Facility for Eval	2 (0.3%)	1 (0.2%)	1 (0.6%)	---

). The incidence of patients leaving against medical advice (AMA) was higher in the medetomidine cohort before the protocol change (6.5%) compared to the xylazine cohort (3.6%), and this difference reached statistical significance (p = 0.036). After the protocol update, AMA rates modestly improved to 5.2%, though the change from the pre-revision medetomidine subgroup did not meet statistical significance (p = 0.056). ICU-level admission occurred substantially more frequently in the medetomidine cohort; 88 patients (18.4%) were admitted to the ICU before the protocol revision, compared to 35 patients (8.5%) in the xylazine era (p < 0.001). After the protocol change, ICU admission remained common at 48 patients (16.4%), though this represented a nonsignificant reduction compared to the earlier medetomidine period (p = 0.527). Overall admission rates in the post-protocol group were 76.1%.

Hospital admissions for continued withdrawal management were more frequent in the ME. In the XE, nearly 30% of patients could be discharged home or to a treatment program after ED management. In contrast, in the ME cohort, only around 20% were discharged from the ED, while a significantly higher proportion (~75%) required inpatient admission for ongoing care of withdrawal, including almost double the amount who needed ICU care.

Regarding adverse events, the protocol was generally well-tolerated in both groups, with no serious adverse events directly attributable to the medications. There were zero instances of respiratory arrest or cardiac arrest due to the treatment in either era.

4. Discussion

This pragmatic, real world study demonstrates that the emergence of medetomidine as an adulterant in illicit fentanyl was associated with a decline in the effectiveness of a novel opioid withdrawal management protocol developed during the xylazine era. In the XE (September 2022–July 2024), the protocol was associated with reduced withdrawal severity, whereas during the ME (August 2024–April 2025) significantly smaller improvements in COWS scores were noted. Concurrently, ME patients had higher rates of intensive care unit (ICU) admission for withdrawal-related complications and more patients leaving the emergency department against medical advice (AMA).

These disparities suggest that medetomidine adulteration may be associated with clinical challenges not adequately addressed by a protocol tailored to manage opioid withdrawal with another potent alpha-2 agonist (xylazine). Xylazine, a veterinary alpha-2 agonist sedative, rose to prominence as a fentanyl adulterant in the mid-2010s and early 2020s. By 2019–2022, xylazine was detected in approximately 2.9–10.9% of fentanyl-involved overdose deaths in the United States [13]. Medetomidine—a pharmacologically similar but more potent alpha-2 agonist—has rapidly increased as a new adulterant over the past two years. The first confirmed cases of medetomidine exposure in U.S. overdose patients were reported in late 2023 [14]. Shortly thereafter, public health alerts in early 2024 announced the detection of medetomidine in local fentanyl supplies in Philadelphia and New York [15]. These alerts noted that medetomidine was identified in street “dope” samples alongside fentanyl and xylazine, and described overdose clusters involving profound sedation unresponsive to naloxone.

Forensic drug surveillance from mid-2024 further documented medetomidine’s proliferation, being identified in opioid samples across multiple states [16]. Medetomidine was almost invariably found in combination with xylazine [17], indicating a shift to an increasingly dynamic supply pattern in which fentanyl is co-mixed with multiple sedatives. This context likely contributed to the challenging clinical presentations observed during the ME. Patients were possibly exposed to two synergistic alpha-2 agonists (medetomidine plus xylazine) alongside fentanyl, a combination plausibly expected to produce more profound and prolonged CNS depression than either sedative alone [17]. It is plausible that illicit suppliers introduced medetomidine as a more potent or longer-acting replacement for xylazine once awareness and regulation of xylazine increased, thereby sustaining the enhanced sedative profile of adulterated fentanyl.

Medetomidine’s pharmacologic properties may help explain why its community presence may be associated with a reduction of withdrawal protocol effectiveness. Medetomidine produces similar effects to xylazine—including sedation, analgesia, bradycardia, and hypotension [18,19]—but tends to have a longer duration of action [20,21]. Given increased potency of medetomidine, it is unsurprising that the ME was therefore associated with an increase in ED presentations for withdrawal, as well as the increased need for ICU-level care, as patients often suffered more severe withdrawal, requiring higher intensity care.

In contrast to xylazine, which is notorious for causing necrotic skin ulcers in chronic users [22], medetomidine has not been linked to such tissue injury. Its chief hazards are systemic, exerting powerful sedating effects that complicate both overdose resuscitation and withdrawal management. This is notable given the decreased number of visits related to skin and soft tissue infections in the ME.

Chronic exposure to alpha-2 agonists can induce adaptive changes; abrupt cessation precipitates a rebound hyperadrenergic state. In the critical care literature, prolonged infusions of dexmedetomidine (the active enantiomer of medetomidine) have been shown to produce significant withdrawal symptoms upon discontinuation [23]. A recent meta-analysis reported that over one-third of patients developed hypertension and tachycardia after stopping long-term dexmedetomidine, and it advocated gradual weaning or adjunctive clonidine to mitigate such withdrawal effects [24,25]. By analogy, individuals using medetomidine-adulterated opioids may regularly develop dependence on this sedative. When they present to the ED in opioid withdrawal (having not used for several hours), they plausibly could simultaneously be in medetomidine withdrawal.

This scenario would likely manifest as severe autonomic hyperactivity (anxiety, vomiting, tremors, hypertension, tachycardia) that overlaps with opioid withdrawal but does not fully respond to opioid agonist therapy, which is exactly the impact that was demonstrated. Indeed, health officials have noted that frequent xylazine users experience a distinct withdrawal syndrome (irritability, anxiety, palpitations, and elevated blood pressure) when xylazine is discontinued [22]. It is likely that medetomidine causes a similar withdrawal phenomenon. Unrecognized alpha-2 agonist withdrawal in our ME patients is likely therefore a key factor in the blunted COWS score improvements—since certain withdrawal signs (e.g., tachycardia, diaphoresis, agitation) could persist due to persistent autonomic activation.

After appreciating these issues, we modified our ED withdrawal protocol in February 2025 to better address medetomidine co-exposure. While education regarding this challenge had been underway since December 2024, this change represents a tangible difference in the order sets providers utilized. Although detailed outcomes of the new protocol are beyond the scope of this discussion, and will be published separately, we observed the following associations in the APC compared to the BPC: withdrawal-symptom relief rates began to rise, and AMA discharge rates declined relative to earlier in the ME. While underpowered to determine causation, these associations should be assessed in future studies.

The protocol revisions included measures to counteract medetomidine withdrawal, such as more aggressive management of autonomic symptoms by use of clonidine and sympatholysis with higher doses of short-acting opioids. Clonidine is a more potent oral alpha-2 agonist than tizanidine or guanfacine, up to 50 times more vasoactive [23]. In essence, we attempted to pharmacologically bridge the sudden loss of alpha-2 agonist input—an approach analogous to using clonidine to taper patients off dexmedetomidine or xylazine [24,25].

The association with partial restoration of efficacy in the APC supports the possibility that more aggressive management may improve outcomes. However, even with adjustments, ME outcomes did not return fully to the baseline seen in the XE, indicating that significant challenges remain. Patients with medetomidine exposure may require prolonged observation and higher levels of care to completely normalize their withdrawal trajectory. Further study is needed to determine optimal strategies for managing withdrawal in the context of medetomidine and similar sedative adulterants.

Overall, our findings highlight the necessity for clinicians to rapidly adapt withdrawal management protocols in response to changes in the adulterant profile of illicit opioids, as well as the importance of community-based drug testing programs. A protocol that was effective for “tranq dope” (fentanyl + xylazine) had to be recalibrated for what some have termed “demon dope” (fentanyl + medetomidine ± xylazine). These conclusions align with emerging guidance urging emergency and critical care providers to recognize and manage polysubstance opioid withdrawal, including the effects of alpha-2 agonist adulterants [5,9,22]. By integrating clinical findings with public health intelligence on drug-supply trends, healthcare systems can better prepare for and respond to the next evolution of the opioid crisis.

5. Limitations

This study has several important limitations. First, as a pragmatic, real world, retrospective analysis, it is inherently subject to confounding, selection bias, and limited generalizability beyond the two emergency departments studied. While both institutions serve a high volume of individuals with opioid use disorder in Philadelphia, the findings may not reflect experiences in other regions or healthcare systems.

Second, not all patients receiving withdrawal protocol treatment during the study period could be analyzed due to missing data. Specifically, patients lacking either pre- or post-treatment COWS scores or documented ED disposition were excluded from the final cohort, and more than a third of eligible cases were excluded for missing data. This may have introduced bias if these excluded encounters differed systematically from those included. Given the demographic and disposition data showing similar total and final cohorts, the impact of this is likely mild.

Third, individual toxicologic confirmation of xylazine or medetomidine exposure was not available. Neither compound is included in routine clinical toxicology screening, and their detection requires specialized analytical techniques that were not performed in real-time ED care. Era classification was therefore inferred based on temporal association with drug-supply trends reported by public health surveillance, which may misclassify some cases—especially during transition months. A small cohort that received LC-MS/MS confirmation of medetomidine exposure strengthens the data but does not replace full individual-level toxicology. It is also possible that the combination of xylazine and medetomidine is responsible, more so than just medetomidine itself. Future studies should assess individuals who are exposed to xylazine, medetomidine, and both and compare outcomes.

Fourth, all statistical analysis was performed using univariate analysis, rather than the use of a multivariate regression analysis. This increases the risk that the association described is confounded by other variables and limits interpretation. Given the pragmatic, retrospective, and limited nature of the dataset, it was felt that simple descriptive analysis was most appropriate, and future studies should assess other possible granular reasons for the observed findings.

Fifth, chief complaint data relied on structured text documentation, which introduces limitations in symptom categorization. Complaints related to opioid withdrawal may have been inconsistently documented or underreported if patients presented with overlapping symptoms such as vomiting or altered mental status. As a result, the frequency of opioid withdrawal presentations may be underrepresented in our analysis.

Additionally, the Clinical Opiate Withdrawal Scale (COWS) was the sole tool used to assess withdrawal severity, though it was developed for opioid withdrawal and may not fully capture the autonomic or neuropsychiatric features of alpha-2 agonist withdrawal. There are currently no validated tools for medetomidine or xylazine withdrawal, and this likely underestimates the true symptom burden in such patients.

Finally, while the protocol revision in February 2025 showed promising improvements, this subgroup was pragmatically inserted for patient care reasons, rather than as a focused research question. It was therefore both underpowered to determine accurate comparisons and purely exploratory. Further data are needed to confirm effectiveness and safety of any treatment protocol in the context of medetomidine exposure.

6. Conclusions

In summary, this retrospective cohort analysis found that our opioid withdrawal protocol was significantly less effective during the period when fentanyl was adulterated with medetomidine, compared to the earlier xylazine-dominant era. Patients in the ME experienced poorer withdrawal symptom relief and higher rates of ICU admission and AMA disposition, indicating more severe and complex withdrawal presentations. Implementation of a revised protocol (in February 2025), which incorporated adjustments to address medetomidine’s alpha-2 agonist effects, was associated with partial restoration of efficacy. This suggests that adapting treatment strategies to account for medetomidine co-exposure can mitigate some of the negative impact.

However, even after protocol changes, medetomidine-exposed patients remained more difficult to treat than those in the XE, underscoring the formidable challenge posed by this new adulterant. For medical practice, these findings highlight the importance of dynamic protocol revisions in the face of an evolving drug supply. Standard opioid-centric withdrawal management approaches may fail when confronted with novel adulterants that produce additional non-opioid pharmacologic effects (such as profound sedation or autonomic instability). Clinicians should be alert to regional drug trends and be prepared to modify withdrawal treatment plans accordingly.

Looking ahead, enhanced surveillance of illicit drugs is crucial for early identification of emerging adulterants. Timely toxicological analysis of overdose cases and drug samples, coupled with rapid information-sharing through public health alerts, will enable clinicians to anticipate changes in withdrawal patient presentations [13]. Future research should focus on developing tailored withdrawal protocols for multi-substance exposures. This includes investigating optimal management of alpha-2 agonist withdrawal in patients with OUD—such as the role of clonidine or other sympatholytics in treating medetomidine/xylazine withdrawal—and determining best practices to reduce ICU utilization and prevent AMA dispositions in these complex cases. In conclusion, a proactive, evidence-based approach to new opioid adulterants is needed to maintain effective withdrawal care. Ongoing collaboration between clinicians and addiction medicine and toxicology experts, as well as public health authorities, will be essential to stay ahead of emerging trends and to safeguard the outcomes of patients with opioid use disorder.