Everyone knows the great energies running amok cast terrible shadows, that each of the so-called senseless acts has its thread looping Back though the world and into a human heart[horizontal ellipsis]

From the poem Shadows.

-Mary Oliver. Devotions-The Selected Poems of Mary Oliver. New York: Penguin Press;2017:348

Over the past 2 decades, drugs implicated in overdose deaths for the United States have switched from cocaine (2000-2006) to prescription opioids (2007-2013), then heroin (2014-2015), to illicit fentanyl beginning in 2016.1,2 Now, increasing numbers of deaths are linked to polysubstance abuse with powerful synthetic agents that include synthetic opioids, sedatives, and stimulants such as methamphetamine and benzodiazepines.1 Emerging evidence demands that clinicians add xylazine, a veterinary anesthetics to this lethal list of "popular recreational" drugs.3

Xylazine is gaining a foothold as an adulterant with heroin, speedball (cocaine and heroin mixture), and fentanyl use. Proven harmful to humans and even more dangerous when combined with drugs of abuse, xylazine sedates, intensifies, and lengthens the drug experience.4 Xylazine adulterated illicit opioid is growing at an alarming rate on the eastern United States and is appearing across the south and west. Xylazine was found in almost one-third of opioid overdose deaths reported in Philadelphia, Pennsylvania, in 20195 and has become the primary adulterant in fatal fentanyl drug overdoses.4,6,7

In veterinary medicine, xylazine is a nonnarcotic used for analgesia, sedation, muscle relaxation, and the treatment of tetanus acting as a central [alpha]2 agonist. Xylazine structure is similar to clonidine, phenothiazines, and tricyclic antidepressants and is often administered intramuscularly or intravenously before surgical procedures.4,6 Often used in combination with ketamine, xylazine is marketed worldwide as Rompun, Anased, Sedazine, and Chanazine.4

Effects of xylazine usually manifest 15 to 30 minutes after administration, and sedation effects can last up to 4 hours. Once xylazine accesses to the vascular system, xylazine diffuses widely and through the blood-brain barrier decreasing norepinephrine and dopamine transmission in the central nervous system. Xylazine is metabolized by cytochrome P450 enzymes in the liver and excreted in urine. Because of serious adverse effects in humans, xylazine is not approved by the US Food and Drug Administration (FDA). Therefore, knowledge of xylazine's mechanisms of action in humans is significantly limited. Xylazine is approved only for veterinary use for dogs, cats, horses, elk, and deer.4

In humans, when xylazine is used as an adulterant, observed effects will vary based on substance combinations. Common adverse effects for xylazine alone include bradycardia, premature ventricular contractions, brief hypertension related to [alpha]1 activation followed by hypotension and other negative hemodynamic effects. Other symptoms include ataxia, diminished reflexes, disorientation, slurred speech, respiratory depression, sedation, and urinary incontinence, all of which can last from 8 to up to 72 hours.4 Xylazine is becoming increasingly identified in the illicit drug supply of the United States and in opioid related deaths.8

Xylazine doses associated with toxicity and fatality in humans vary from 40 to 2400 mg. There is no antidote approved for human use. Hemodialysis has been suggested as a possible treatment. However, limited evidence suggests this intervention would not be effective. At this time, there is no standardized screening for xylazine overdose. Treatment must primarily focus first on ventilation and establishing hemodynamic stability and supportive treatment.4,7

First reported in 2019, physicians in Philadelphia reported some patients who had an overdose responded differently to naloxone (Narcan) and had tissue wounds so severe that amputation was sometimes required.9 Sadly, this observation remains true. In areas with high use of xylazine mixed with fentanyl or heroin, abscesses and painful skin ulcers are prevalent in persons using xylazine. Tissue injury is believed to be related to the direct vasoconstricting effect of xylazine on local blood vessels near injection sites and decreased tissue perfusion.4,10,11 Prolonged xylazine use can lead to tissue injury across the body independent of injection sites, resulting in abscesses, impaired wound healing, infection, sepsis, and amputation.11,12

Pharmaceutical-grade xylazine is now rapidly appearing in cities across the United States providing a new addictive agent with increased mortality and morbidity, without a reversal agent and associated with very difficult withdrawal. Because xylazine is not tracked, and testing is limited, xylazine use is underreported and underestimated at best.9

With this evidence and the difficulty of distinguishing opioid overdose and xylazine use, the FDA issued an alert in November 2022 to be aware of possible xylazine use in fentanyl, heroin, and other illicit drug overdoses and that naloxone may not be effective. Furthermore, it is unknown if reversal agents for use only in veterinary medicine (eg, yohimbine hydrochloride, tolazoline hydrochloride) are safe or even effective in humans; therefore, these should never be used for humans.13

Most healthcare toxicology screens do not screen for xylazine. Therefore, suspect xylazine exposure if naloxone is not effective and/or patient examination reveals necrotic skin ulcerations and provide cardiac and respiratory supportive care.13 Also consider that the patient may not even be aware of xylazine presence in his/her drug supply.7,14

At this time, it is unknown if the xylazine supply in the United States is being illegally produced or being diverted from animal supplies.13 Without testing capability to identify xylazine in drug supplies, public health interventions to reduce harms and develop treatments remain seriously undermined.8

Causal factors underlying xylazine's increasing use also remain unknown. Xylazine has similar physiological consequences as heroin and is increasingly found in speedballs or mixture of several drugs such as cocaine, morphine, and fentanyl. Further research is needed to gain more information on the distribution of xylazine in the body, physical symptoms, potential treatments, and factors predictive of chronic use.3

While investigation continues, the FDA encourages healthcare professionals and patients to report adverse events in humans associated with possible illicit xylazine exposure to FDA's MedWatch Adverse Event Reporting program. Complete and submit the report online at http://www.fda.gov/medwatch/report.htm, or download and complete the form and then submit it via fax at 1-800-FDA-0178.13

References