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Be Aware of Xylazine-Adulterated Fentanyl

package of xylazine

You give naloxone – a lot of naloxone – and the patient still has some CNS and respiratory depression and hypotension. What gives?

Fentanyl has almost replaced heroin in recreational drugs, but the creators of such experiences are always trying to improve the high, and perhaps the profits, by including additional ingredients. Xylazine is an up-and-coming tag-along with fentanyl that is causing clinically-significant toxicity. Xylazine-adulterated fentanyl has made its way to the Midwest. 

What is xylazine?

Xylazine is a non-opioid veterinary procedural sedative with anesthetic and muscle relaxant properties. It is a centrally-acting alpha-2 adrenergic agonist, similar to the sedative dexmedetomidine and the antihypertensive/ADHD medication clonidine. These drugs cause dose-related CNS and respiratory depression and reduced sympathetic outflow to the periphery resulting in decreased heart rate, respiratory rate, and blood pressure.

Where are patients getting xylazine? 

Mainly in illicit fentanyl, and sometimes in cocaine or meth. Although in the past the only source was diversion of veterinary supplies, xylazine is now easily synthesized and delivered to its illicit markets, which are growing by leaps and bounds. 

It is sometimes used recreationally by itself for CNS effects of euphoria and sedation or used for drug-facilitated sexual assault. However, its major market presence is in combination with fentanyl

And, since fentanyl alone is sometimes pre-mixed with a stimulant (to make up a speed-ball), xylazine also finds its way into drugs purported to be cocaine or methamphetamine. 

Xylazine is said to enhance or mimic some of the desired effects of fentanyl and it lasts longer than fentanyl. However, its addition to fentanyl has a mixed reception among users – desirable to some but not wanted by others. The presence of xylazine is often unknown to the fentanyl user.

Xylazine can be used by virtually every route of administration – orally, snorting, and injection.

What is the scope of the xylazine problem? 

Although urine drug screen tests to detect xylazine in patients have become available, they are not widely used; therefore, most non-fatal overdoses that involve xylazine are not being identified. However, forensic labs have been detecting and tracking xylazine presence in samples of illicit drugs and in autopsies for some time. This is what they are finding:

The DEA’s National Forensic Laboratory Information System (NFLIS) Drug database shows this dramatic increase in the presence of xylazine in illegal drugs:

Furthermore, according to the State Unintentional Drug Overdose Reporting System, the percentage of overdose deaths that have involved xylazine jumped 276% between January 2019 and June of 2022 (31 states and District of Columbia). In the Midwest region, 17% of fentanyl-overdose deaths involved xylazine. 

Clinical features of fentanyl-plus-xylazine 

It looks the same as fentanyl without xylazine: CNS depression, respiratory depression, miosis, possibly bradycardia and hypotension in severe overdose. The main difference? Incomplete response to naloxone. The patient may fail to wake up to full alertness, may temporarily lighten but quickly fall back into CNS and respiratory depression, or may show little apparent response to naloxone at all. 

There is no reversal agent or antidote for xylazine. After naloxone to antagonize any opioid effects, supportive care is given for any residual respiratory depression, hypotension, and bradycardia. 

Airway management and ventilation is needed for reduced respiratory drive or apnea. Fluid resuscitation and vasopressor support may be indicated for hypotension. Significant bradycardia may respond to atropine. 

As the xylazine is eliminated, the patient recovers. Kinetic data in humans are sparse, but available estimates of xylazine half-life are 1 to 5 hours. Because of the large volume of distribution, hemodialysis will not be useful in accelerating elimination.

Skin and soft tissue necrosis 

Repeated injection of xylazine has been associated with severe, extensive, and progressive wounds, typically at the site of injection, although they have been reported at distant sites. Xylazine is thought to be a partial alpha-1 agonist in addition to being a central alpha-2 agonist. Alpha-1 agonists constrict the vasculature and diminish blood flow in areas of locally-high concentration. Repeated tissue ischemia leads to a spectrum of wounds from ulcerations and cellulitis to necrotizing fasciitis or osteomyelitis. 

Care should include debridement, clean dressings, and wound management education. Antibiotics should be given if purulence, surrounding erythema or edema is present. Initial coverage should include group A strep (Strepococcus pyogenes) and methicillin-resistant Staphylococcus aureus (MRSA). Bacteremia and endocarditis are more likely with xylazine-associated wounds. Inpatient treatment may be necessary. Concurrent management of withdrawal might be helpful to encourage the patient to complete therapy. 

Withdrawal

Like clonidine, if xylazine is used regularly—knowingly or unknowingly — and abruptly discontinued, withdrawal symptoms may occur. Anxiety, irritability, restlessness, tachycardia and hypertension are possible. Management strategies for opioid withdrawal will not eliminate the symptoms of xylazine withdrawal. Suggested treatments include benzodiazepines and/or replacement therapy with alpha-2 adrenergic agonists such as clonidine, dexmedetomidine, tizanidine or guanfacine. 

 

Recognition of xylazine toxicity can be difficult in users of fentanyl and other recreational drugs as well as in inadvertent exposure in children. Have a high index of suspicion when CNS and respiratory depression do not resolve after naloxone, or the patient presents with unusually severe necrotic wounds. 

The Missouri Poison Center is here to help 24/7 by calling 1-800-222-1222. Our specially trained nurses, pharmacists, and toxicologist can offer information on xylazine and provide the most up-to-date information regarding exposures and treatment.

 

This Poison Alert was developed with contributing work by Dr. Michael Semple.

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