ToxCard: Xylazine

Authors: Tony Spadaro MD MPH (@Tspadaro91, Medical Toxicology-Addiction Medicine Fellow, Rutgers New Jersey Medical School/New Jersey Poison Information and Education System); Howard A. Greller MD (@heshiegreshie, Associate Professor of EM, Co-Director Combined Addiction Medicine – Medical Toxicology Fellowship, Medical Toxicology Fellowship Program Director, Rutgers New Jersey Medical School/New Jersey Poison Information and Education System); Corey Hazekamp MD (@coreyhazekamp, Emergency Medicine Resident, Lincoln Hospital) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 28-year-old man is brought to the emergency department (ED) via emergency medical services (EMS) for suspected opioid overdose. EMS gave the patient 0.4 mg of intramuscular naloxone prior to arrival. EMS reports the patient was bradypneic when they arrived on scene and a bystander reported the patient had just used “Tranq Dope.” The patient began spontaneously breathing but remained sedated during transport. On arrival to the ED, the patient’s vital signs are: heart rate (HR), 50 beats per minute; blood pressure (BP), 102/65 mmHg; respiratory rate (RR), 10 breaths per minute. You notice the patient has pinpoint pupils and has small necrotic wounds on his forearms bilaterally without surrounding cellulitis and suspect that the patient has used xylazine.  

Questions:

1. What is xylazine, and how does it cause toxicity? 
2. How does xylazine impact the ED care of patients with opioid use disorder (OUD)? 
3. Is there wound care advice we can give to patients who have developed wounds from xylazine?

Background:

Xylazine is an α₂-agonist, with structural similarity to dexmedetomidine and clonidine (see image 1) and is used in veterinary medicine as a sedative for procedural sedation and anesthesia.¹ Unlike dexmedetomidine, xylazine does not contain an imidazoline ring and may not act as an imidazoline receptor agonist. The imidazoline receptor agonism of dexmedetomidine causes hypotension, which is much less prominent with xylazine due to its structural differences.^1-3 The pharmacology of xylazine has been studied in various animals with dose ranges of 0.1 mg/kg to 5 mg/kg needed for sedation depending on the species of animal.^4-6 From animal studies the half-life also varies according to species with a range from 20 minutes to 3 hours.^4-6 Less is known about its pharmacology in humans because it is not approved for human use.⁷ Until recently, most case reports of human exposures to xylazine were descriptions of self-harm attempts by people with access to veterinary medicines.^2,7–10 There are sporadic reports of xylazine being present in the illicit drug supply in Philadelphia and Puerto Rico prior to 2010.^11,12 However, there have been increasing reports of xylazine being present in the unregulated drug supply in the Northeast United States, and spreading across the country.^13,14 In post-mortem testing, xylazine most often accompanies fentanyl, with one study reporting that 99.1% of all xylazine associated deaths also involved fentanyl or fentanyl analogues.¹⁵ More recently in Philadelphia, xylazine is being found in up to 95% of drug samples.^15,16 The combination of xylazine and fentanyl is often referred to by the street name “Tranq” or “Tranq Dope.”¹⁶ Although the exact reason xylazine is being added to the illicit opioid supply isn’t entirely known, some have speculated that it accelerates, enhances, or prolongs the sedative effects of opioids, it may also be added as a bulking agent.^13,16,17

There are reports of xylazine-associated skin ulcers and wounds.^17-20 Xylazine may cause skin vasoconstriction, leading to poor tissue perfusion and wound development.^18,19  Other proposed mechanisms include pressure related injury after prolonged immobility from sedation or cytotoxic effects of xylazine .²¹ Whether xylazine-associated wounds are a distinct entity from other skin and soft tissue infections related to injection drug use has been debated.²² However, wounds have been reported in body sites where people do not inject drugs and in people who only report using drugs intranasally.¹⁷

Image 1: Structure of xylazine (A), clonidine (B), dexmedetomidine (C). Images courtesy of wikimedia commons.

Clinical Presentation:

Xylazine overdose is largely a clinical diagnosis.²¹ Xylazine overdose may be suspected in a patient who appears to be opioid intoxicated but has prolonged sedation with improved respiratory rate after naloxone administration.²¹ Knowing the common adulterants in the drug supplies in the catchment area of your hospital will help you know when to suspect a patient may have used xylazine.¹⁹ Harm reduction activists have started employing xylazine test strips to check local drug supplies. Individual hospitals may have developed Gas Chromatography/Mass Spectrometry (GC/MS) to test patients urine or blood for xylazine, but these tests are likely not available everywhere and the best practices for their use is not defined.²¹

Xylazine associated wounds have been described as having a unique progression and appearance.¹⁹ Most often they begin as small dark-purple blisters that coalesce in days to weeks and develop areas of patchy necrosis (image 2).¹⁹ The necrosis may progress to the full thickness of the skin and expose bone, tendon, and underlying tissue. These wounds may develop into surrounding cellulitis which can progress to systemic infection. The wounds may be painful or painless.

Image 2: Progression and healing of a xylazine associated wound: from McFadden R, Wallace-Keeshen S, Petrillo Straub K, et al. Xylazine-associated Wounds: Clinical Experience From a Low-barrier Wound Care Clinic in Philadelphia. J Addict Med. 2024;18(1):9-12. doi:10.1097/ADM.0000000000001245

Management:

Management of acute xylazine overdose is primarily supportive. No xylazine specific reversal agent is approved for human use.²¹ Naloxone should be given to patients with suspected xylazine intoxication with respiratory depression as xylazine exposure is almost always concurrent with opioids, particularly fentanyl.²¹ A recent prospective cohort study examined patients with suspected opioid overdose who had positive serum tests for xylazine versus overdose patients with negative serum tests for xylazine and found that suspected opioid overdose patients who were xylazine positive were less likely to present in cardiac arrest and require CPR, and hypothesize that this could be due to smaller quantities of opioids in illicit drugs containing xylazine.²³ Opioids such as fentanyl are more potent respiratory depressants than xylazine, and thus if xylazine is replacing some of the opioid that someone is using, they may be less likely to experience a respiratory arrest.²³ Although from existing studies it is not clear if patients exposed to xylazine present with more  hypotension, bradycardia, or respiratory depression, these patients may occasionally need supportive care to address these issues.^21,23 Intravenous fluids and vasopressors such as norepinephrine should be used to treat hypotension. Intubation and mechanical ventilation may be required for patients who are unable to adequately oxygenate independently.²¹

Xylazine withdrawal is another consideration for patients being treated in communities with high prevalence of xylazine in the unregulated drug supply. Although a distinct xylazine withdrawal syndrome has not been fully elucidated, some patients have reported symptoms such as anxiety, cravings, and restlessness that they attribute to xylazine withdrawal.¹⁷ A recent case report highlights successfully managing a confirmed xylazine withdrawal with dexmedetomidine, tizanidine, and phenobarbital.²⁴ The patient was later transitioned to clonidine and eventually discharged on clonidine, buprenorphine, and gabapentin.²⁴  Clonidine, tizanidine, lofexidine, and guanfacine are all oral α₂ agonists that could be used to manage xylazine withdrawal symptoms.²¹ Patients who report xylazine withdrawal also likely need buprenorphine or methadone for their OUD.²¹

Finally, ED clinicians should be familiar with managing xylazine associated wounds.¹⁹ Wound care and cessation of drug use are the cornerstone of wounds healing. Complications of these lesions could include abscesses, cellulitis, and systemic infection.^18-21 Management is mainly supportive including pain control, wound care, and possibly antibiotic coverage if necessary.¹⁹ The following steps (image 3) have been proposed for optimal wound care for xylazine associated wounds.^19,25

1. Premedicate the patient as needed for dressing changes, many of the wounds may be painful
2. Remove old or dirty dressings
3. Irrigate the wound with saline or water
4. Apply enzymatic or autolytic debridement to necrotic areas: agents such as Santyl™ or Medihoney™
5. If there is extensive and deep necrosis or exposed bone or tendon, surgical debridement may be considered
6. Apply a skin protectant to the peri-wound area such as A&D ointment to protect healthy tissue from maceration
7. Apply a non-adherent primary dressing to the wound such as Xeroform™ or Adaptic™
8. Apply an absorbent secondary dressing such as gauze or abdominal pads over the primary dressing to absorb exudate.
9. Secure the dressing
10. Supply patients with equipment to perform daily dressing changes.

Image 3 : Basic Wound Care for xylazine associated wounds. From Philadelphia Department of Public Health, Division of Substance Use Prevention and Harm Reduction. Recommendations for caring for individuals with xylazine-associated wounds. January, 8th, 2024.https://www.substanceusephilly.com/healthcare-providers.

In severe cases surgical debridement and skin grafting may be necessary, but which patients need these interventions over conservative wound care is not well defined.^19,20 Further guidance on care for xylazine associated wounds from the Philadelphia Department of Public Health can be found here.

Case Follow-up:

The patient was observed in the ED for several hours on end-tidal capnography. Before discharge they were noted to be in moderate opioid withdrawal and started on buprenorphine. They were discharged with an appointment at a bridge clinic to continue their buprenorphine and provide additional wound care.

Clinical Pearls:

• Xylazine is an alpha 2 agonist that can cause sedation in overdose
• Xylazine is becoming more prevalent, staying up to date on the makeup of the local drug supplies will help you manage patients with substance use disorders.
• At this time if you suspect xylazine overdose with respiratory depression, treatment includes naloxone (for likely concurrent opioid exposure) and supportive care.
• Xylazine withdrawal may exist and could be treated with α₂ agonists such as clonidine.
• Xylazine associated wounds can improve with diligent wound care.

References:

1. Ball NS, Knable BM, Relich TA, et al. Xylazine poisoning: a systematic review. Clin Toxicol (Phila). 2022;60(8):892-901. doi:10.1080/15563650.2022.2063135
2. Hoffmann U, Meister CM, Golle K, Zschiesche M. Severe Intoxication with the Veterinary Tranquilizer Xylazine in Humans. J Anal Toxicol. 2001;25(4):245-249. doi:10.1093/jat/25.4.245
3. Ruiz-Colón K, Chavez-Arias C, Díaz-Alcalá 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. doi:10.1016/j.forsciint.2014.03.015
4. Garcia-Villar R, Toutain P, Alvinerie M, Ruckebush Y. The Pharmacokinetics of xylazine hydrochloride: an interspecific study. Journal of Veterinary Pharmacology and Theraputics. 1981;4(2):87-92.
5. Kitzman J v, Booth NI, Hatch RC, Wallner B. Antagonism of Xylazine and Yohimbine in Cattle Sedation by 4-Aminopyridine.
6. de Carvalho LL, Nishimura LT, Borges LP, et al. Sedative and cardiopulmonary effects of         xylazine alone or in combination with methadone, morphine or tramadol in sheep. Vet Anaesth Analg. 2016;43(2):179-188. doi:10.1111/vaa.12296
7. Spoerke DG, Hall AH, Grimes MJ, Honea BN, Rumack BH. Human Overdose with the Veterinary Tranquilizer Xylazine.
8. Krongvorakul J, Auparakkitanon S, Trakulsrichai S, et al. Use of Xylazine in Drug-Facilitated Crimes. J Forensic Sci. 2018;63(4):1325-1330. doi:10.1111/1556-4029.13684
9. Velez LI, Shepherd G, Mills LD, Rivera W. Systemic toxicity after an ocular exposure to xylazine hydrochloride. Journal of Emergency Medicine. 2006;30(4):407-410. doi:10.1016/j.jemermed.2006.02.042
10. Moore KA, Ripple MG, Sakinedzad S, Levine B, Fowler DR. Tissue Distribution of Xylazine in a Suicide by Hanging. Vol 27.; 2003. https://academic.oup.com/jat/article/27/2/110/706288
11. Wong SC, Curtis JA, Wingert WE. Concurrent detection of heroin, fentanyl, and xylazine in seven drug-related deaths reported from the Philadelphia Medical Examiner’s Office. J Forensic Sci. 2008;53(2):495-498. doi:10.1111/j.1556-4029.2007.00648.x
12. 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. Journal of Urban Health. 2012;89(3):519-526. doi:10.1007/s11524-011-9662-6
13. 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. doi:10.1016/j.drugalcdep.2022.109380
14. Alexander RS, Canver BR, Sue KL, Morford KL. Xylazine and Overdoses: Trends, Concerns, and Recommendations. Am J Public Health. 2022;112(8):1212-1216. doi:10.2105/AJPH.2022.306881
15. Kariisa M, Patel P, Smith H, Bitting J. Notes from the Field: Xylazine Detection and Involvement in Drug Overdose Deaths — United States, 2019. MMWR Morb Mortal Wkly Rep. 2021;70:1300-1302.
16. Hoffman J. Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug Zones. New York Times. January 7, 2023.
17. Spadaro A, O’Connor K, Lakamana S, et al. Self-reported Xylazine Experiences: A Mixed-methods Study of Reddit Subscribers. J Addict Med. 2023;17(6):691-694. doi:10.1097/ADM.0000000000001216
18. Malayala S v, Papudesi BN, Bobb R, Wimbush A. Xylazine-Induced Skin Ulcers in a Person Who Injects Drugs in Philadelphia, Pennsylvania, USA. Cureus. 2022;14(8):e28160. doi:10.7759/cureus.28160
19. McFadden R, Wallace-Keeshen S, Petrillo Straub K, et al. Xylazine-associated Wounds: Clinical Experience From a Low-barrier Wound Care Clinic in Philadelphia. J Addict Med. 2024;18(1):9-12. doi:10.1097/ADM.0000000000001245
20. O’Neil J, Kovach S. Xylazine-Associated Skin Injury. N Engl J Med. 2023;388(24):2274-2274. doi:10.1056/NEJMicm2303601
21. 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
22. Hoffman RS. Closing the xylazine knowledge gap. Clinical Toxicology. 2023;61(12):1013-1016. doi:10.1080/15563650.2023.2294619
23. Love JS, Levine M, Aldy K, et al. Opioid overdoses involving xylazine in emergency department patients: a multicenter study. Clin Toxicol (Phila). 2023;61(3):173-180. doi:10.1080/15563650.2022.2159427
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 Addict Med. 2022;16(5):595-598. doi:10.1097/ADM.0000000000000955
25. Philadelphia Department of Public Health, Division of Substance Use Prevention and Harm Reduction. Recommendations for caring for individuals with xylazine-associated wounds. January, 8th, 2024.