Xylazine Added to Illicit Drugs: What Podiatrists Should Know

The practice of adulterating drugs of abuse is common, and can involve adding any of a wide range of active substances to the primary drug.¹ Although this adulteration for pharmacologic or profit purposes is not a new scenario, there are evolving and increasingly alarming public health implications.¹ The presence of substances—unbeknownst to the consumers of these illicit products—may lead to the users experiencing unexpected or even potentially fatal adverse effects.¹ As an example, levamisole may be a cutting agent into cocaine during manufacturing for intentional underdosing. In other cases, to enhance the effects of heroin, one may add fentanyl.¹ However, this practice carries additional consequences such as a synergistic effect and resultant higher toxicity.¹ In the previous example of levamisole-adulterated cocaine, there are reports of vasculitis as an example of this increased toxicity.^1-4

Late last year, the United States Food and Drug Administration (FDA) alerted health care professionals to an emerging adulterate/contaminant in illicit drug overdoses throughout the US—xylazine.^5,6 From 2015–2020, reports showed a 20-fold increase in fatal drug overdoses with xylazine, comprising nearly 7% of total overdose deaths.^5,7 However, one should note that the prevalence in some states is as high as 26%.^5,7

Of particular interest to podiatric physicians, one notable and increasingly reported complication of xylazine is a high prevalence of abscesses and painful skin ulcers, even in areas where the drug was not injected.⁸ Researchers hypothesize that this is due to local vasoconstriction and resultant local ischemia. Also relevant could be xylazine’s depressive effects possibly leading to systemic decreases in tissue oxygenation. These factors then contribute to the formation of these unique wounds, their impaired healing potential, and increased risk of infection.

Understanding the Pharmacology of Xylazine

Xylazine, an alpha-2 receptor agonist (Figure 1), is a large-animal veterinary tranquilizer, with reports of its presence on the illicit drug market dating back to the early 2000s.5,9,10 It has properties and effects comparable to clonidine, with severe central nervous system (CNS) depression and hypotensive effects contributing to lack of approval for human use.^11-14 It has sedative, anesthetic, analgesic, and muscle-relaxing properties, and may commonly be added to opioids or cocaine to enhance CNS depression.^5,7,9,11-13

In fact, these sedative properties allow manufacturers to decrease the amount of fentanyl or heroin in drug mixtures while still producing the user’s desired effect.¹¹ Purchasing xylazine is fairly easy over the Internet at a relatively low cost, making it appealing to drug traffickers.¹¹ Also adding to its appeal is the belief that some drug dealers hold that lacing xylazine into fentanyl or heroin may increase the primary drug’s  duration of action.^7,11,13 When combined with these specific drugs, it may be referred to as “tranq” or “tranq dope.”^7,13

When administered, xylazine leads to a decrease in norepinephrine and dopamine neurotransmission with action seen within 15–30 minutes.^7,13 Once xylazine gains access to the vascular system, it is distributed within the blood, and will circulate through the organs, penetrating the blood-brain barrier due its lipophilic nature.^7,13  

Veterinary xylazine comes in a liquid solution, which may be salted or dried into a powder to cut into the illicit drugs, and may be difficult to visually identify when used as an adulterant. Routes of administration on the illicit market include intravenous, intramuscular, intranasal, and oral with no current reports of vaping or smoking.^14,15 Due to its common use with opioids, it is important to know that xylazine’s effects are not reversible with naloxone.^7,13

Understanding Xylazine’s Adverse Effects

Ball and colleagues provided an excellent clinical review of xylazine toxicity in the prehospital and emergency medicine settings, noting no available standardized treatment algorithm, and the need for more research.¹³ In their review of 1409 records over 17 articles and 2 abstracts they only found descriptions of 98 patients from 1979 to 2020 across 9 countries. Common symptoms of exposure to xylazine on presentation included hypotension, bradycardia, drowsiness, lethargy, and less frequently, apnea with intubation and death.¹³

As previously mentioned, repeated xylazine use is also associated with skin ulcers, abscesses, and related complications, sometimes independent of the site of administration (Table 1 at top right).^9,14-17 These wounds may appear atypically, and often on the lower extremities, with a rapidly worsening course.

Skin and soft tissue infections are not a new phenomenon among people who inject drugs; however, xylazine-related wounds even more carry unique characteristics.¹⁸ They are often large (greater than 10 cm diameter), and may begin as several punched-out wounds that merge into one larger lesion. Clinicians often note granular tissue with central necrosis and features similar to burns.

One 2022 case report focused on a female in her 30s who regularly injected drugs and developed spontaneous, large, severe anterior lower leg wounds with evidence of osteomyelitis within 1–2 weeks of onset.⁸ Despite proper inpatient care for drug toxicity and withdrawal, along with intervention for the leg wounds, healing was complicated by continued injectable drug use upon discharge.

Xylazine as a Public Safety Concern

Xylazine poses a threat to public health, and the people being harmed by this drug deserve rapid, comprehensive, and high-quality health care. The White House Office of National Drug Control Policy declared xylazine, particularly the use of fentanyl adulterated or associated with xylazine (FAAX), an emerging threat on April 12, 2023.¹⁹ Such a declaration will likely bring a call for content and evidence on testing, treatment, mitigation, regulations, and more.¹⁹ Philadelphia and Connecticut seem to be current epicenters of xylazine use in the continental US, but reports are rapidly appearing throughout the country.²⁰ Over 90% of illicit drug samples tested in Philadelphia in 2021 contained xylazine,²¹ as did forensic toxicology samples from 36 states in June 2021.²² As of March 2023, drug seizures in 48 states found evidence of fentanyl mixed with xylazine.²¹

Presentation and Management of Xylazine-Involved Overdose

Opioid overdoses that also involve xylazine present similarly to opioid overdoses alone.²³ Xylazine may potentiate the effects of other depressants that it accompanies. The resulting profound mental status depression may lead to airway compromise. Although naloxone does not reverse xylazine toxicity, it may be useful to counteract the likely presence of substances like fentanyl.

There is no reversal agent for xylazine that is safe for use in humans; so supportive care is vital, including blood pressure monitoring and intervention.

Xylazine withdrawal is not well understood, but can include anxiety, irritability, hypertension, and restlessness. Clinicians should be prepared to manage these symptoms proactively along with the symptoms associated with opioid withdrawal.^7,24

A Harm Reduction Approach to Xylazine in Podiatric Patients

Careful and compassionate social history taking may allow clinicians to have productive conversations about xylazine in the illicit drug supply when appropriate, especially in the setting of atypical wounds. While cessation of illicit drug use is the best prevention of these complications, harm reduction education may be an option to reduce some of these risks, including using sterile syringes, swabbing with alcohol prior to injecting, and rotating the injection site among intact areas of skin. There are also local initiatives to provide test strips that can identify the contents of a drug sample so users will identify substances unknowingly cut with other substances.

I encourage clinicians to educate patients on overdose and complication risks no matter what drugs are used, and to advocate for consistent harm reduction practices. Providing updates to harm reduction service organizations and stakeholders, and advocating for additional focused training in illicit drug-related wound care are also important considerations.

One must also keep in mind that a harm reduction approach is not limited to the patient’s actual drug use.¹⁸ Best practice wound care treatment regimens may not always be feasible depending on a patient’s living environment and other factors. Standardized recommendations do not yet exist for these types of wounds, but cleansing and dressing pathways achievable for the patients and individualized to each case are paramount.

In Conclusion

The unexpected presence of certain psychotropic drugs may lead to incorrect treatment of intoxication cases or unusual presentations of other complications, such as atypical lower extremity wounds. Podiatric physicians should be aware of this emerging clinical and public health threat and connect with local organizations and resources to be ambassadors towards mitigation and prompt, focused care for impacted patients.

Dr. Smith’s research centers on podiatric implications, pharmacy implications, and social determinates of pain management and substance use disorder. He is a consultant to the National Board of Podiatric Medical Examiners. He is a contributing editor and reviewer to the Journal of the American Podiatric Medical Association in the area of podiatric clinical pharmacology. He has operated a solo practice, Shoe String Podiatry. He is the Founder and President of STOP (Studying Opioid Harm), Inc., a non-profit educational company to build and develop tools to educate and mitigate the harm from opioids. Dr. Smith has been the Chair of the Podiatric Academy for the National Academy of Practice since 2020.

References
1. Di Trana A, Montanari E. Adulterants in drugs of abuse: a recent focus of a changing phenomenon. Clin Ter. 2022;173(1):54-55.
2. Barbera N, Busardò FP, Indorato F, et al. The pathogenetic role of adulterants in 5 cases of drug addicts with a fatal outcome. Forensic Sci Int. 2013;227:74-76.
3. Rinaldi R, Negro F, Minutillo A. The health threat of new synthetic opioids as adulterants of classic drugs of abuse. Clin Ter. 2020;171 e107-e109.
4. Marquez J, Aguirre L, Muñoz C, et al. Cocaine-levamisole induced vasculitis/vasculopathy syndrome. Curr Rheumatol Rep. 2017;19:36.
5. Rock KL, Lawson AJ, Duffy J, Mellor A, Treble R, Copeland CS. The first drug-related death associated with xylazine use in the UK and Europe. J Forensic Leg Med. 2023;97:102542. doi: 10.1016/j.jflm.2023.102542.
6. United States Food and Drug Administration. FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs; 2022. Accessed June 3, 2023.
7. Friedman J, Montero F, Bourgois P, et al. Xylazine spreads across the US: a growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend. 2022;233:109380. https://doi.org/10.1016/j.
8. Malayala SV, Papudesi BN, Bobb R, Wimbush A. Xylazine-induced skin ulcers in a person who injects drugs in Philadelphia, Pennsylvania, USA. Cureus. 2022 Aug 19;14(8):e28160. doi: 10.7759/cureus.28160. PMID: 36148197; PMCID: PMC9482722.
9. Ruiz-Colon K, Chavez-Arias C, Díaz-Alcala JE, Martínez MA. Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: a comprehensive review of the literature. Forensic Sci Int. 2014;240:1–8. https://doi.org/10.1016/j.forsciint.2014.03.015.
10. Rodríguez N, Vargas Vidot J, Panelli J, Colon H, Ritchie B, Yamamura Y. GC-MS confirmation of xylazine (Rompun), a veterinary sedative, in exchanged needles. Drug Alcohol Depend. 2008;96(3):290–293. https://doi.org/10.1016/j.
11. United States Drug Enforcement Administration. The growing threat of xylazine and its mixture with illicit drugs. Published December 21, 2022. Accessed October 4, 2023.
12. Rubin R. Warning about xylazine, a veterinary sedative found in illicit drugs. JAMA. 2022;328:2296.
13. Ball NS, Knable BM, Relich TA, et al. Xylazine poisoning: a systematic review. Clin Toxicol (Phila). 2022;60(8):892-901.
14. Thangada S, Clinton HA, Ali S, et al. Notes from the field: Xylazine, a veterinary tranquilizer, identified as an emerging novel substance in drug overdose deaths - Connecticut, 2019-2020. MMWR Morb Mortal Wkly Rep. 2021;70(37):1303-1304. doi:10.15585/mmwr.mm7037a5
15. Reyes JC, Negrón JL, Colón HM, et al. The emerging of xylazine as a new drug of abuse and its health consequences among drug users in Puerto Rico. J Urban Health Bull N Y Acad Med. 2012;89(3):519-526. doi:10.1007/s11524-011-9662-6
16. Torruella RA. Xylazine (veterinary sedative) use in Puerto Rico. Subst Abuse Treat Prev Policy. 2011;6(1):7. doi:10.1186/1747-597X-6-7.
17. Ohio Department of Mental Health and Addiction Services. Drug trend reports. Accessed June 3, 2023.
18. 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 Sep 30;20(1):141. doi: 10.1186/s12954-023-00879-7. PMID: 37777769; PMCID: PMC10544173.
19. Gupta R, Holtgrave DR, Ashburn MA. Xylazine - Medical and Public Health Imperatives. N Engl J Med. 2023;388(24):2209-2212. doi: 10.1056/NEJMp2303120.
20. Alexander RS, Canver BR, Sue KL, Morford KL. Xylazine and overdoses: trends, concerns, and recommendations. Am J Public Health. 2022;112:1212-1216.
21. Philadelphia Department of Public Health. Substance use Philly: xylazine. Accessed October 4, 2023.
22. Kacinko SL, Mohr ALA, Logan BK, Barbieri EJ. Xylazine: pharmacology review and prevalence and drug combinations in forensic toxicology casework. J Anal Toxicol. 2022; 46: 911-917.
23. New York State Department of Health. Xylazine: what clinicians need to know.
24. Ehrman-Dupre R, Kaigh C, Salzman M, Haroz R, Peterson LK, Schmidt R. Management of xylazine withdrawal in a hospitalized patient: a case report. J Addiction Med. 2022;16(5):595–598.