US Pharm. 2024;49(10):24-27.

Xylazine is a nonnarcotic compound or tranquilizer that is used for pain and is FDA approved for use in veterinary medicine. It is also utilized for sedation and muscle relaxation in veterinary medicine, where it is often referred to as “horse anesthetic.” Xylazine is chemically known as N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine and is a clonidine analogue. It was developed in 1962 by German company Farbenfabrikin Bayer AG and promoted for use as an antihypertensive.1 Approval was not granted for human use as an antihypertensive due to profound hypotension and excessive central nervous system (CNS) depression.2

Xylazine is also used with ketamine as an anesthetic agent for experimental studies involving dogs, cats, horses, rabbits, and rats. Xylazine is often mixed with illicitly manufactured opioids, most frequently fentanyl, but it is not an opioid.

Recently, xylazine misuse has surged in the northeastern United States and has spread across many states, as evidenced by the rising number of samples testing positive for the drug. Additionally, xylazine has been found alongside cocaine and methamphetamine, and it has most recently been mixed with oxycodone and alprazolam. Xylazine was reportedly diverted from the veterinary market to the recreational drug market in Puerto Rico.3

The drug’s increased prevalence in the illegal drug industry poses a concern to the U.S. healthcare system and to those who use it knowingly or unknowingly. The lack of information and the absence of an approved antidote are a challenge.4

Background

Xylazine is available as a solution for injection in concentrations of 20 mg/mL, 100 mg/mL, and 300 mg/mL for veterinary usage. Xylazine or xylazine-containing drugs can be injected into muscles or veins, insufflated, ingested, or smoked.4,5

The solution may be dried into a powder that can appear white or brown. It may be challenging to distinguish xylazine based solely on appearance since it can be blended with other powders or crushed into tablets to adulterate a drug supply. The powder can be used as a cutting agent in drugs such as heroin and fentanyl to increase their bulk. The availability, low cost, and ability of xylazine to potentiate the opioid effect make it a profitable addition to the opioid supply, decreasing the net amount of heroin or fentanyl sold.6 When combined with stimulants, xylazine can decrease the adverse effects and withdrawal symptoms of the stimulant.4,7 The etiology of xylazine use in humans is complex, and further research is needed to understand the factors contributing to its abuse.7

Epidemiology

Xylazine use substantially increased before adequate research on its effects was completed. The State Unintentional Drug Overdose Reporting System has identified xylazine as an emerging impurity in illicit drug mixtures, amplifying the already devastating opioid overdose crisis.4,8

Public health professionals have observed xylazine as an increasingly common additive in the street opioid supply in Philadelphia since the mid-2010s.8

In 2014, xylazine was reported as an impurity in recreational drugs such as heroin or combined opioid stimulants—commonly called “speedball.” From 2015 to 2021, xylazine was reported to be coadministered primarily with fentanyl and cocaine, in addition to benzodiazepines, methamphetamine, and heroin. A 2022 study led by the Rhode Island government reported that in addition to cocaine, heroin, and fentanyl, xylazine was combined with reasonably prevalent drugs of abuse, such as Percocet (oxycodone plus acetaminophen) and Xanax (alprazolam). This pattern illustrates that xylazine is being combined with an increasing number of substances.4,9

A study revealed that xylazine existed in 10 jurisdictions throughout the four U.S. census regions. Among these locations, Philadelphia had the highest prevalence of xylazine-related deaths at 25.8%, followed by Maryland at 19.3% and Connecticut at 10.2%.10 In 2021, the Philadelphia Department of Public Health reported that 91% of samples of purported heroin or fentanyl from the local area contained xylazine, making it the most common adulterant in the drug supply.4,7

Xylazine toxicity is a critical and emerging public health concern associated with severe respiratory and CNS depression, significant cardiovascular effects, and potentially disfiguring and life-threatening skin ulcers. The increasing prevalence of xylazine as an adulterant in the opioid and nonopioid supply for patients with substance use disorder (SUD) is a public health emergency. The heightened risk of death due to xylazine toxicity and lack of a specific antidote urges the dire need for prompt identification, comprehensive evaluation, and appropriate management.7

Mode of Action

The chemical structure of xylazine is very similar to that of phenothiazines, tricyclic antidepressants, and clonidine. Xylazine is in the same drug class as clonidine, lofexidine, and dexmedetomidine and functions as an alpha-2 receptor agonist.4

Alpha-2 adrenoreceptors are found on the presynaptic and postsynaptic neurons of the central and peripheral nervous systems and are activated by norepinephrine and epinephrine. When the presynaptic receptors are activated, the release of norepinephrine onto the alpha-1 receptor in the postsynaptic neuron is inhibited due to a negative-feedback mechanism. This lack of norepinephrine activity leads to the sympatholytic effects of hypotension, bradycardia, sedation, analgesia, and muscle relaxation; however, activation of postsynaptic receptors leads to sympathomimetic effects. Xylazine has a high affinity for presynaptic alpha-2 receptors, making its sympatholytic effects more pronounced clinically.10

Pharmacokinetics

Xylazine is quickly absorbed.11 It has a large volume of distribution due to its lipophilicity and is rapidly concentrated in the CNS and kidney. Xylazine is metabolized by CYP450 enzymes in the liver and excreted through the kidney as 2,6-xylidine. Xylazine is quickly eliminated from the body, with an elimination half-life of 23 to 50 minutes. It is rapidly metabolized, and there is minimal elimination of intact xylazine by the kidney.2

Xylazine can cause toxicity and death in humans at dosages ranging from 40 mg to 2,400 mg, with plasma concentrations in nonfatal cases ranging from 0.03 mg/L to 4.6 mg/L and from trace to 16 mg/L in fatal cases.12 This significant overlap between fatal and nonfatal doses indicates that there may be no “safe” blood concentration of xylazine.2 Due to a lack of clear evidence regarding the pharmacokinetics of xylazine in humans, further studies in humans are required.

The primary metabolite of xylazine, 2,6-xylidine, has carcinogenic and genotoxic effects; long-term users of xylazine appear to be at increased risk for malignancies.13

Symptoms and Diagnosis

It is challenging to identify xylazine toxicity solely based on history and physical examination, as many other lethal substances may be present.4

Xylazine toxicity is characterized by CNS depression. Other symptoms may include a “high” feeling, sedation, dry mouth, dysarthria, hyporeflexia, disorientation, hypotension, bradycardia, hypothermia, and hyperglycemia. When combined with other CNS depressants such as opioids, benzodiazepines, or alcohol, xylazine overdose causes severe CNS and respiratory depression with signs and symptoms of muscle relaxation, hypotension or hypertension, apnea, cardiac arrhythmias, or cardiac arrest.2

The chronic use of heroin and fentanyl mixed with xylazine can lead to deep skin ulcers, abscesses, and infections.14 These xylazine-associated wounds may increase the risk of bacteremia, endocarditis, sepsis, limb amputation, and death. Any patient with a nonhealing ulcer, regardless of the use of injection as the route of administration, should be assessed for xylazine use.

Fentanyl is the drug most commonly combined with xylazine. Fentanyl and xylazine have an additive effect on the CNS and respiratory depression that can lead to arrest and death. Patients exhibiting signs of a fentanyl overdose who have shown little to no improvement with the administration of naloxone should be suspected of a xylazine overdose or another similar substance.15

Due to the ongoing xylazine crisis, lateral flow immunoassay has been used to develop testing strips for xylazine with a detection sensitivity of up to 1,000 ng/mL. The strips are used to test for xylazine within the drug supply. Testing strips used by patients with SUD are available through common online marketplaces and harm-reduction programs. These strips can play a prominent role as a harm-reduction tool.15

Differential Diagnosis

Opioid overdose is the most common coexisting diagnosis. Naloxone can reverse opioid overdose but will not affect the clinical effects of xylazine. Overlooking concomitant opioid overdoses can result in fatal outcomes. Benzodiazepine overdose can lead to CNS depression; however, compared with xylazine toxicity, there is less respiratory depression and little cardiovascular derangement. Other substances that may mimic xylazine toxicity include barbiturates and ethyl alcohol.2,4

Treatment and Management

Individuals suspected of xylazine overdose in the field should be administered naloxone and placed in the “recovery position.” Proper patient positioning is crucial in drug overdoses and is designed to maintain a clear airway and prevent aspiration in an unconscious, independently breathing person.4

As of September 2024, no pharmacologic antidote for xylazine intoxication has been approved by the FDA. Management of xylazine intoxication involves supportive care, monitoring for adverse effects, and interventional management as symptoms present. Supportive care includes supplemental oxygen and airway management, IV fluid administration, vasopressor administration for hemodynamic instability, assessment and replenishment of electrolytes to prevent dysrhythmias, and management of hyperglycemia. The use of medications inducing CNS depression should be avoided. Naloxone should be administered to treat any concomitant opioid toxidrome. Hemodialysis may not be effective in removing xylazine from the blood due to its lipophilic property.2,4

Routine wound care for xylazine-induced skin lesions comprises wound cleansing, evaluating potential secondary infection, applying a nonadherent gauze to the wound bed, and applying a topical ointment. Daily dressing changes with layered dressings are optimum. Full-thickness wounds may require reconstruction or, in severe cases, limb amputation. Antibiotic coverage for secondary infection must cover methicillin-resistant Staphylococcus aureus, and coverage for group A streptococcus should be considered.4

Avoiding xylazine use and providing prompt and appropriate treatment for xylazine-induced skin ulcers may result in wound healing; however, if the ulcers are not adequately cared for and become infected, the chances of acquiring sepsis from infection, the need for limb amputation, and mortality are very high.4

The Philadelphia Department of Public Health released recommendations for managing and alleviating xylazine withdrawal symptoms. The suggested approach includes replacement therapy with alpha-2 adrenergic agonists such as clonidine, dexmedetomidine, tizanidine, or guanfacine, paired with symptom management for pain using short-acting opioids, ketamine, gabapentin, ketorolac, acetaminophen, or nonsteroidal anti-inflammatory drugs.4

Deterrence

In light of the risks of xylazine being diverted as an anesthetic in veterinary medicine, it may be possible that halting the production of this drug, even for veterinary use, could have benefits for humans. Additionally, it may be worth exploring alternative anesthetics.4

Since xylazine initially entered the human market through redirection from veterinary use rather than illicit manufacturing, healthcare providers, particularly veterinarians, worldwide have a crucial role in preventing drug misuse. Primary care physicians can also reduce drug addiction by screening patients for SUDs and referring them promptly to addiction treatment services.2,4

Community-based initiatives can also contribute significantly to deterrence efforts. Building awareness about the dangers of drug misuse, providing resources for the safe disposal of unused veterinary medications, and promoting community programs for educating risk groups about xylazine and its harmful effects are very instrumental.4

REFERENCES
1. Greene SA, Thurmon JC. Xylazine—a review of its pharmacology and use in veterinary medicine. J Vet Pharmacol Ther. 1988;11(4):295-313.
2. Ruiz-Colón K, Chavez-Arias C, Díaz-Alcalá JE, et al. 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.
3. 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. 2012;89(3):519-526.
4. Papudesi BN, Malayala SV, Regina AC. Xylazine toxicity. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2024 Jan-. www.ncbi.nlm.nih.gov/books/NBK594271.
5. Hoffman SR. Closing the xylazine knowledge gap. Clin Toxicol. 2023:61(12):1013-1016.
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7. Rodríguez N, Vargas Vidot J, Panelli J, et al. GC-MS confirmation of xylazine (Rompun), a veterinary sedative, in exchanged needles. Drug Alcohol Depend. 2008;96(3):290-293.
8. Johnson J, Pizzicato L, Johnson C, et al. Increasing presence of Xylazine in heroin and/or fentanyl deaths, Philadelphia, Pennsylvania, 2010–2019. Inj Prev. 2021;27(4):395-398.
9. Kariisa M, Patel P, Smith H, et al. Notes from the Field: Xylazine Detection and Involvement in Drug Overdose Deaths—United States, 2019. MMWR Morb Mortal Wkly Rep. 2021;70(37):1300-1302.
10. Giovannetti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31-39.
11. Mittleman RE, Hearn WL, Hime GW. Xylazine toxicity—literature review and report of two cases. J Forensic Sci. 1998;43(2):400-402.
12. Silva-Torres L, Veléz C, Alvarez L, et al. Xylazine as a drug of abuse and its effects on the generation of reactive species and DNA damage on human umbilical vein endothelial cells. J Toxicol. 2014;492609.
13. Sakamoto H, Misumi K, Nakama M, et al. The effects of xylazine on intrauterine pressure, uterine blood flow, maternal and fetal cardiovascular and pulmonary function in pregnant goats. J Vet Med Sci. 1996;58(3):211-217.
14. Rose L, Kirven R, Tyler K, et al. Xylazine-induced acute skin necrosis in two patients who inject fentanyl. JAAD Case Rep. 2023;36:113-115.
15. Ehrman-Dupre R, Kaigh C, Salzman M, et al. Management of xylazine withdrawal in a hospitalized patient: a case report. J Addict Med. 2022;16(5):595-598.

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