Key Points

Question听 What are the clinical features of wounds among patients exposed to xylazine, a rapidly spreading adulterant in illicitly manufactured fentanyl?

Findings听 In this case series of 59 wounds among 29 hospitalized patients with confirmed xylazine exposure, wounds were commonly located on extensor surfaces of the extremities, frequently had devitalized wound beds, and were more likely to have larger and necrotic wound beds the longer wounds had persisted.

Meaning听 These distinguishing wound characteristics may help identify patients exposed to xylazine and guide research into the etiology and management of xylazine-associated wounds.

Importance听 The alpha-2 agonist xylazine is increasingly detected as an adulterant in illicitly manufactured fentanyl. There is concern that xylazine may be responsible for an emerging pattern of necrotizing wounds among people who use drugs, but the clinical features of wounds associated with xylazine remain poorly characterized.

Objective听 To systematically characterize the location, wound bed surface, and chronicity of wounds among persons with confirmed xylazine exposure.

Design, Setting, and Participants听 This case series at 3 academic medical hospitals in Philadelphia, Pennsylvania, included patients with emergency department or inpatient encounters from April 2022 to February 2023 who had a wound-related chief complaint and xylazine detected with urine gas chromatography鈥搈ass spectroscopy.

Exposure听 Xylazine.

Main Outcomes and Measures听 The location, size, wound bed, and chronicity of wounds associated with xylazine using electronic medical record abstraction and Fisher exact tests.

Results听 Of 59 wounds from 29 unique patients with confirmed xylazine exposure (mean [SD] age, 39.4 [8.8] years; 15 [52%] male; all using fentanyl, and 23 [79%] routinely injecting opioids), 53 wounds (90%) were located on extremities, and 41 (69%) involved extensor surfaces. Five wounds (9%) involved exposed deep structures such as bone or tendon. Of 57 wounds with photographs, 34 (60%) had wound beds of predominantly devitalized tissue (eschar or slough). Based on patient report, 28 wounds (48%) were acute (<1 month old), 12 (20%) were subacute (present for 1-3 months), and 17 (29%) were chronic (developed 鈮�3 months prior). Subacute and chronic wounds were more often medium or large in size (odds ratio, 48.5; 95% CI, 8.2-1274.8; P鈥�<鈥�.001) and more frequently had devitalized wound beds (odds ratio, 9.5; 95% CI, 2.9-37.0; P鈥�&濒迟;鈥�.001).

Conclusions and Relevance听 In this case series of hospitalized patients with confirmed xylazine exposure, wounds were commonly located on extensor surfaces of the extremities, frequently had devitalized tissue or exposed deep structures, and were more likely to have larger and necrotic wound beds the longer they had persisted. This systematic characterization of xylazine-associated wounds may inform identification, management, and research to address this emerging public health threat.

Across the US, the alpha-2 agonist xylazine is increasingly detected as an adulterant of illicitly manufactured fentanyl, the principle opioid involved in overdose deaths.¹ Xylazine is a veterinary sedative that acutely depresses the central nervous system and decreases heart rate and blood pressure.² There is rising concern that xylazine also causes a distinct pattern of devitalized skin and soft-tissue injury.³ Early reports of people using fentanyl-xylazine have described wounds in various locations and with diverse wound bed types.^4-8 Some of these studies did not confirm xylazine exposure, raising concern that other adulterants or medical conditions may be responsible for these wounds instead of xylazine itself.⁹

In this study, we describe the location, size, wound bed, and chronicity of wounds among hospitalized patients with confirmed xylazine exposure. Our goal was to systematically characterize these wounds to inform identification, management, and research on wounds associated with xylazine.

We conducted a case series of adult patients seen in the emergency department or admitted to 1 of 3 academic medical hospitals in Philadelphia, Pennsylvania, from April 2022 through February 2023. In Philadelphia during this period, xylazine was found in 98% of powdered opioid (ie, fentanyl) samples, with average xylazine purity (percent by weight) of 34% (range, 0%-65%).¹⁰

We identified patients with xylazine exposure using a urine gas chromatography鈥搈ass spectroscopy test with a limit of detection of 200 ng/mL. Xylazine testing was ordered at the discretion of treating physicians. Among patients with xylazine exposure, we included patients with a wound-related chief complaint (eTable in Supplement 1). For each patient, we selected up to 3 of the largest wounds. We extracted data from the electronic health record (Epic Systems) into a HIPAA (US Health Insurance Portability and Accountability Act)鈥揷ompliant database (REDCap, version 12.5.4 [Vanderbilt University]) using a structured codebook and standardized medical record abstraction tool.

For each patient, we reported demographics, hepatitis C and HIV status, serum inflammatory markers, and hospital outcomes. For each wound, we described location (using a body map of 64 unique areas) and size (small [approximately <1 cm²], medium [approximately 1 cm² to the size of a hand], or large [approximately larger than the size of a hand]). We characterized wound beds as predominantly (>60%) devitalized (eschar or slough), granulation, blister, or mixed/other tissue type. We described wounds as single or multifocal, and we documented the presence of exposed deep structures, erythema, or purulence; patient-reported wound chronicity and etiology; and wound culture results.

This study was approved by the University of Pennsylvania institutional review board with a waiver of informed consent for the use of deidentified data. We followed reporting guidelines for case series.¹¹

We used Fisher exact tests (using R, version 4.2.2 [R Project for Statistical Computing]) to assess associations between wound bed types, size, and chronicity. Statistical tests were 2-sided with a significance level of P鈥�&濒迟;鈥�.05.

There were 74 hospitalizations with xylazine detected in urine (eFigure 1 in Supplement 1). Thirty-one hospitalizations (42%) involved a wound-related emergency department chief complaint. Among 29 unique patients, we characterized the 59 largest wounds.

Of the 29 patients, 15 (52%) were male, and the mean (SD) age was 39.4 (8.8) years. Seven patients (24%) were unstably housed, and 9 (31%) experienced street homelessness (Table 1). Additionally, 28 patients (97%) used unregulated powdered opioids (鈥渇entanyl,鈥� 鈥渉eroin,鈥� or 鈥渄ope鈥�), and 23 (79%) injected opioids; 14 patients (48%) had untreated hepatitis C, and 3 (10%) tested positive for HIV. Among 21 patients with inflammatory markers measured, mean (SD) erythrocyte sedimentation rate was 78.0 (34.0) mm/h (upper limit of normal, 20 mm/h), and C-reactive protein was 10.2 (7.1) mg/dL (upper limit of normal, 0.80; to convert to mg/L, multiply by 10). On cross-sectional imaging, 8 patients (28%) had likely or definitive osteomyelitis, and 6 (21%) had soft tissue gas. Surgical and hospitalization outcomes are provided in Table 1.

Of the 59 wounds, 53 (90%) were on the extremities (Table 2 and Figure, A), and 41 (69%) involved extensor aspects of the limbs (ie, posterior upper or anterior lower extremities). Twelve wounds (20%) were small (<1 cm²), 33 (56%) were medium (1 cm² to the size of a hand), and 14 (24%) were large (larger than the size of a hand). Five wounds (9%) involved exposed structures such as bone, tendon, or vasculature. Additionally, 34 wounds (58%) had periwound erythema present, 15 (25%) had purulent exudate present, and 18 (31%) had neither.

Among 57 wounds with photographs, 34 (60%) had wound beds of predominantly devitalized tissue (eschar or slough), 6 (11%) were blisters, 5 (9%) had granulation tissue, and 12 (21%) had mixed tissue or other wound bed types (Figure, B-E). Devitalized tissue was more common in medium or large wounds compared to small wounds (odds ratio [OR], 5.2; 95% CI, 1.3-28.0; P鈥�=鈥�.02). Twenty-one wounds (37%) were multifocal.

Based on patient report, 28 wounds (48%) were acute (<1 month old), 12 (20%) were subacute (present for 1-3 months), and 17 (29%) were chronic (developed 鈮�3 months prior) (Table 2). Subacute and chronic wounds were more commonly medium or large compared to acute wounds (OR, 48.5; 95% CI, 8.2-1274.8; P鈥�<鈥�.001; eFigure 2 in Supplement 1). Additionally, subacute or chronic wounds more commonly had devitalized wound beds (OR, 9.5; 95% CI, 2.9-37.0; P鈥�<鈥�.001; eFigure 2 in Supplement 1). Of 39 wounds with patient-reported etiology, 34 (87%) were at sites of injection drug use. Of 7 wounds cultured, 5 were positive and grew Staphylococcus aureus (4 wounds; 3 methicillin resistant), group A Streptococcus (2 wounds), Proteus mirabilis (1 wound), and Providencia stuartii (1 wound).

In this case series of 59 wounds among 29 hospitalized patients with xylazine exposure, most wounds were located on extensor surfaces of the extremities and devitalized tissue was common, especially among large and chronic wounds. To our knowledge, this is the largest study of wounds among patients with confirmed exposure to xylazine and the first to systematically describe wound characteristics.

These findings highlight several distinguishing features of xylazine-associated wounds. Most wounds were on extensor surfaces of the limbs. Limbs are common sites for drug injection, and extensor surfaces with thin dermis and hypodermis might be particularly prone to injury from xylazine鈥檚 cytotoxic⁸ and vasoconstrictive² effects. Consistent with prior work,^2-7 wounds were often large with devitalized eschar or slough, especially among people who inject drugs. Eschar and slough are physical barriers to epithelialization and can precipitate the formation of a proinflammatory biofilm that inhibits healing.¹² At the same time, nearly a third of wounds were small to medium sized with nonnecrotic wound beds, and one-fifth of the cohort used opioids via noninjection routes. The finding that chronic wounds were more likely to be larger with devitalized tissue suggests that untreated xylazine-associated wounds might progress from small, multifocal blisters into larger, confluent areas of eschar and slough. This progression is consistent with at least 1 prior case report⁷ and deserves further investigation.

While clinical experience suggests that wound incidence rises with xylazine adulteration,⁷ it is not yet established whether xylazine causes these wounds. Wounds with devitalized, granulation, blister, or mixed-tissue wound beds can result from a range of conditions, including pyoderma gangrenosum, venous stasis, vasculitis, and infections; xylazine exposure may just be coincident. Alternatively, xylazine might inhibit healing of wounds initially caused by other conditions. Future studies should investigate the etiology of these wounds with histopathology and prospective designs that account for the route of xylazine administration.

Strengths of this case series include its size, its setting in Philadelphia, where xylazine exposure is common, and the use of gas chromatography鈥搈ass spectroscopy xylazine testing.¹⁰ Limitations include its retrospective design from a single city, which limits causal claims and generalizability. Second, selection of up to 3 of the largest wounds biased the sample toward larger wounds. Third, patient-reported wound chronicity may be subject to recall bias. Fourth, this study did not capture patient experience with wounds, which can be traumatic.¹³ Last, this case series did not describe wound progression over time. Clinical experience suggests that xylazine-associated wounds can heal with early and consistent wound care, stable housing, and, for wounds with extensive devitalization or exposed structures, tissue-sparing surgical debridement and synthetic dermal substitute.^7,14

In this case series among hospitalized patients exposed to xylazine, wounds were commonly found on extensor surfaces of the extremities with devitalized tissue. Wound chronicity was associated with larger size and necrotic wound beds. These findings may help identify xylazine exposure and can guide research on the etiology and management of these wounds.

Accepted for Publication: August 26, 2024.

Published Online: November 13, 2024. doi:10.1001/jamadermatol.2024.4253

Corresponding Author: Ashish P. Thakrar, MD, MS, Department of Medicine, University of Pennsylvania Perelman School of Medicine, 423 Guardian Dr, 1233 Blockley Hall, Philadelphia, PA 19104 (apthakrar@pennmedicine.upenn.edu).

Author Contributions: Dr Thakrar had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lutz, McFadden, Davis, Wei, Lowenstein, Thakrar.

Acquisition, analysis, or interpretation of data: Lutz, McFadden, Xu, Bhatia, Davis, Rohacs, Perrone, Thakrar.

Drafting of the manuscript: Lutz, McFadden, Davis, Thakrar.

Critical review of the manuscript for important intellectual content: Lutz, McFadden, Xu, Bhatia, Rohacs, Wei, Perrone, Lowenstein, Thakrar.

Statistical analysis: Lutz, Thakrar.

Administrative, technical, or material support: Lutz, McFadden, Xu, Davis, Rohacs, Thakrar.

Supervision: Thakrar.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Thakrar received support from the National Institute on Drug Abuse (R34DA057507-01A1). Dr Lowenstein received support from the National Institute on Drug Abuse (K23-DA055087-01).

Role of the Funder/Sponsor: The National Institute on Drug Abuse had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.