Xylazine: Epidemiology, Pathophysiologic Manifestations, and Clinical Management

RESEARCH ANALYSIS 

Xylazine: Epidemiology, Pathophysiologic Manifestations, and Clinical Management

APURVA PULI, BS 

Cooper Medical School of Rowan University

SUMMARY POINTS

-       The insidious permeation of xylazine, a non-opioid central nervous system depressant, in the U.S. illicit drug supply during the early 2000s has grown to become a present-day health crisis within the Greater Philadelphia Area and across the nation.

-       Xylazine is an alpha-2 agonist that lengthens the high experienced by fentanyl users through pre-synaptic receptor activation and ensuing sedation and analgesia.        

-       Intractable soft tissue wounds of the upper and lower limbs are an adverse effect of chronic xylazine use and are exacerbated in patients with limited access to personal hygiene resources.

-       Further research is necessary to improve the prevention and treatment of xylazine-associated complications, including assessments of hospital-specific treatment algorithms.

ANALYSIS

Background

Xylazine is a non-opioid alpha-2 adrenergic receptor agonist that has been increasing in prevalence as an adulterant in the U.S. illicit drug supply. Historically, it is the first substance to be designated as an “emerging threat” by the White House. Though routinely and legally used in veterinary medicine as a tranquilizer, xylazine is not FDA-approved for use in humans. In the unregulated drug market, it is being used as an additive to synthetic opioids—primarily fentanyl—for the purpose of prolonging the high experienced by users and reducing costs for suppliers. Colloquially known as “tranq,” xylazine has become a rapidly growing concern across the country, particularly in New Jersey and Philadelphia. Therefore, this analysis aims to detail the epidemiology of xylazine, its pathophysiologic manifestations, and clinical management.

Findings

The first reports of xylazine-laced fentanyl occurred in the early 2000s in Puerto Rico (1). In Philadelphia, the rate of fentanyl adulteration and heroin remained low through the early 2010s with only 2% of fatal overdoses testing positive for xylazine (2). After 2016, both Philadelphia and New Jersey experienced spikes in the proportion of deaths related to xylazine, increasing to 10% in New Jersey by 2022 and 31% in Philadelphia by 2019. In 2021, the region with the highest rate of xylazine-associated overdose deaths was Philadelphia, while New Jersey had the third-highest rate (Figure 1) (3). In New Jersey, there was a 3,192% increase in detected xylazine in seized heroin and fentanyl between 2015 and 2020. According to the CDC, the rate of xylazine-involved overdose deaths nationally increased 35-fold from 2018-2021. As of today, 48 of the 50 states have had xylazine-adulterated opioids confiscated by the DEA.

Physiologically, xylazine depresses the central nervous system by binding to presynaptic alpha-2 receptors and inhibiting the release of norepinephrine and dopamine. The symptoms of acute toxicity include sympatholytic sedation, muscle relaxation, respiratory depression, bradycardia, hypotension, and analgesia (4). The analgesia and prolonged sedation explain its addition to the illicit fentanyl supply, as it compensates for the “short-lived high” and ensuing rebound symptoms of fentanyl. This effect has created a more desirable product for users and reduces costs because less fentanyl is needed to achieve the same high. Chronic use, however, leads to postsynaptic alpha-2 agonism, which contributes to the development of xylazine wounds like soft tissue ulcerations and necrosis.

Xylazine wounds frequently manifest on the upper and lower extremities. They initially appear as smaller lesions of erythematous or discolored tissue with a central pinpoint or punched-out area. The clusters then progress by merging borders and developing into larger erosions. At this stage, the wounds may be scabbed, sloughing, or covered by a sizeable eschar overlying ulcerated tissue (6). Although not intrinsically microbial, the compromised tissues often become colonized (polymicrobial) and may produce purulent discharge. The wounds necrotize and deepen without proper care, leading to osteomyelitis with exposed bone and potential amputation in severe cases (7). The enduring nature of the wounds is hypothesized to be a result of the deoxygenation of tissues and concomitant alpha-2 adrenergic effects caused by xylazine, including peripheral vasoconstriction (8). The reduced perfusion is thought to delay healing and increase the risk of infection. Histopathology from a patient case indicated epidermal necrosis with fibrin thrombi and no evidence of vasculitis (8). However, further studies are necessary to establish a consistent diagnostic pathology and etiology, as findings differ across case studies.

The clinical management of opioid overdose and chronic outcomes must be adjusted when xylazine adulteration is involved. Xylazine is not an opioid. Therefore, naloxone lacks the pharmacologic properties necessary to negate xylazine-associated symptoms, including prolonged sedation (1). However, naloxone is still an essential intervention for patients who are overdosing on opioids, with or without adulterants, since a major cause of overdose death continues to be fentanyl-induced respiratory failure. Furthermore, xylazine has proven to be fatal as a single agent at high doses, raising new concerns about the future trends of multi-drug overdoses (9). Currently, no specific reversal agents exist, and treatment for xylazine overdose symptoms relies on supportive care.

As stated previously, chronic xylazine exposure leads to soft tissue wounds that are difficult to manage. Broadly, these erosions are treated similarly to burns using topical broad-spectrum antibiotics, such as Silvadene, and moist coverings that are frequently redressed (6). Typically, the persistence of these lesions stems from limited access to basic wound care and the progressive necrosis of involved tissues. Depending on the severity of the wound and infection, treatment with enzymatic debridement and antibacterial dressings may be indicated. In the most severe cases, synthetic dermal substitutes or skin grafts may be attempted as a final limb-sparing therapy prior to amputation (10).

Discussion

In summary, the introduction of xylazine to the illicit drug supply has altered the trajectory of the opioid crisis and worsened the disease outcomes of fentanyl addiction. A collective understanding of the adulterant’s history in the market and its clinical presentations will produce research questions and legislative efforts that provide solutions for affected patients and community members. Examples of promising advancements include the exploration of alpha-2 antagonists as potential xylazine reversal agents, the designation of xylazine as a Schedule III drug in Ohio and Pennsylvania, and the production and dissemination of xylazine test strips across the country. Additionally, the emergence of xylazine-associated wounds in Philadelphia and New Jersey has prompted rapid action from local hospital systems to develop stepwise treatment algorithms. These flowcharts (Figure 4), which are the product of individual patient cases during in-house encounters, are being produced by distinct health systems in the absence of a standardized care plan. Future research should aim to collect and compare the patient outcomes of different algorithms with the goal of creating an optimal approach. Ultimately, this would address the need for an established, evidence-based treatment regimen for xylazine wounds.

REFERENCES

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3.     Spencer M, Cisewski J, Warner M, Garnett M. Drug Overdose Deaths Involving Xylazine, United States, 2018–2021. National Center for Health Statistics (U.S.); 2023.

4.     Rose L, Kirven R, Tyler K, Chung C, Korman AM. Xylazine-induced acute skin necrosis in two patients who inject fentanyl. JAAD Case Rep. 2023;36:113-115. doi:10.1016/j.jdcr.2023.04.010

5.     Papudesi BN, Malayala SV, Regina AC. Xylazine Toxicity. StatPearls Publishing; 2023.

6.     Philadelphia Department of Public Health, Division of Substance Use Prevention and Harm Reduction. Recommendations for Caring for Individuals with Xylazine-Associated Wounds.; 2024.

7.     Oscherwitz ME, Trinidad J, Chen ST. Necrotic skin ulcerations caused by xylazine in people who inject intravenous drugs. J Eur Acad Dermatol Venereol. 2024;38(6):e551-e553. doi:10.1111/jdv.19817

8.     D’Orazio J, Nelson L, Perrone J, Wightman R, Haroz R. Xylazine adulteration of the heroin-fentanyl drug supply : A narrative review. Ann Intern Med. 2023;176(10):1370-1376. doi:10.7326/M23-2001

9.     Sue KL, Hawk K. Clinical considerations for the management of xylazine overdoses and xylazine‐related wounds. Addiction. 2024;119(4):606-608. doi:10.1111/add.16388

10.  Zagorski CM, Hosey RA, Moraff C, et al. Reducing the harms of xylazine: clinical approaches, research deficits, and public health context. Harm Reduct J. 2023;20(1). doi:10.1186/s12954-023-00879-7