Tranq (Xylazine) Reversal Agents Could Save Lives.
Plausible candidate drugs for the newest fatal street drugs epidemic
Say what you will about fentanyl—at least naloxone (Narcan) is an effective reversal agent. Just as the FDA moves to re-classify the intranasal version as an OTC drug, another threat to the lives of those struggling with addiction is here to frustrate our efforts.
Xylaxine was developed as a veterinary anesthetic agent. However, when combined with fentanyl or other opioids, it creates profound sedation and hemodynamic instability, and death. And this cocktail isn’t reversible by Naloxone—an opioid receptor antagonist—which means not only more deaths of our fellow humans. It means more death and trauma for First Responders and to Emergency Medicine nurses, and physicians.
Overdose deaths are not just an emotional burden on the loved ones who are survivors of those who die while in the thrall of addiction. It’s a problem for helpers too.
I’m a psychiatrist by training. This means I am a physician who’s done all the same medical training as Emergency Medicine and ICU docs for the first four years of medical school. I’ve done chest compressions on many patients who didn’t make it. I've done them in the ER. I’ve helped save lives by holding pressure on wounds of young people with bullet wounds. They would have bled out without hands applying pressure.
I can say losing patients is trauma. But it’s also part of what we do. At best, we learn to manage loss and do it well. But the win/loss ratio of “saves” to losses for first responders is its own protective factor—or not. Speaking as someone who works with high-risk patients, the more I can help, the more I can stand the loss. We are not invulnerable, however.
Now, it’s time to introduce a new plague: xylazine, street name: Tranq.
Pardon the extensive quote from SubstanceUsePhilly, but it’s crucial:
1. What is xylazine?
Xylazine is a non-opioid medication used as a sedative and muscle relaxant in veterinary medicine. Although not approved for use in humans, xylazine is increasingly added to street drugs and is often found in combination with fentanyl (a powerful synthetic opioid).
2. Is xylazine approved for human use by the FDA?
No. It was first synthesized in 1962 for use in humans, but due to harmful side effects, the FDA has approved it only for veterinary use.
3. When was xylazine introduced into the illicit drug market?
While it’s unclear when xylazine first appeared in the illicit drug markets, reports suggest that its use began in Puerto Rico in the early 2000s, where it’s known as “Anestesia de Caballo ” or horse anesthetic. The Philadelphia Medical Examiner’s Office included xylazine in toxicology reports beginning in 2006.
4. Is xylazine a Philadelphia-specific public health issue?
No, other states including Ohio, Maryland, Massachusetts, and more recently Texas have identified xylazine in overdose deaths.
5. Why do people use xylazine with fentanyl?
The “high” from fentanyl lasts for a very short time compared to the high from heroin and other opioids. Xylazine may be added, at least in part, to extend the effects of fentanyl and mimic the high of heroin. However, not everyone who uses fentanyl is intentionally seeking out xylazine. In some cases, people are not aware that xylazine is in the drugs they are buying and using.
6. What are the signs and symptoms of a xylazine-involved overdose?
The main effect of xylazine is heavy sedation, so the person who has overdosed will likely be unresponsive. When xylazine is found in combination with fentanyl, the signs and symptoms can include blue/greyish skin and slowed breathing and heart rate.
7. Does naloxone (Narcan) reverse xylazine-involved overdoses?
No. Xylazine is not an opioid, so naloxone (Narcan) will not reverse a xylazine overdose. However, because xylazine is almost always found in combination with opioids, including fentanyl, naloxone (Narcan) should still be administered whenever an opioid-involved overdose is suspected.
8. Does xylazine cause skin ulcers?
Although research has yet to definitively prove that xylazine causes skin ulcers, there appears to be an association between the two. People who regularly use xylazine often have severe skin ulcers and abscesses. Since xylazine became more prevalent in Philadelphia’s drug market, local hospital systems have reported increased skin and soft tissue infections. These wounds present atypically, often all over the body (away from the site of injection), and appear to worsen more quickly than other skin infections.
9. Can a person experience withdrawal from xylazine?
Yes. People who use xylazine heavily and frequently are at risk of withdrawal. Xylazine withdrawal is often marked by irritability, anxiety, and unease. It may also cause a rapid heart rate and high blood pressure, though these are not always present.
It’s a miserable drug to have introduced into your life. A military veteran who got addicted to Tranq is quoted by Sky News:
This place eats everything that is good. All that joy you had in your heart. You’re going to change because this place forces you to change.
Tranq isn’t just a death sentence for those it kills. It’s poison for the resilience of first responders. It turns last year’s wins into bitter defeats. Many people have less compassion for those struggling with addiction than I’d like. But, we might still muster some compassion for the helpers and loved ones also traumatized by these Demons in chemical form.
I’m not working in drug development. If I were, however, here is my proposed approach:
Xylazine is approved in veterinary medicine, and its mechanism of action is as an agonist (aka binds to receptors in a way that makes them act just as if the natural neurotransmitter had been present).
It binds to centrally acting “alpha-2 adrenergic” receptors. These are the sites in your brain where adrenaline binds…but they work to turn down arousal and blood pressure. Under physiological conditions, adrenaline + norepinephrine binding to a-2 receptors “balances out” the effect of adrenaline in the peripheral circulation. However, out in the body, the same neurotransmitters increase heart rate and increase blood pressure at the “alpha-1” receptors.
This is a similar mechanism to human medicines like dexmedetomidine in the ICU setting (and now available for acute agitation management) and, at vastly lower potencies, clonidine and guanfacine (which I have written about in the context of ADHD)
When fentanyl is cut with xylazine on the street, the potential agonist effect at both alpha-2 and mu-opioid receptors creates both a more potent high and abrupt death. Opioids shut off the need to breathe (reparatory drive), and the combined sedative effect of xylazine makes the effect even more deadly. You need to breathe to live. One of the essential effects of naloxone is its rapid onset. The high affinity for the mu-opioid receptor abruptly puts people into withdrawal and makes them…gasp for breath. And thus start breathing. Being sedated by xylazine means the reversal effect doesn’t happen as robustly, and people die instead of getting another shot at life.
Naloxone (Narcan) is a widely recognized lifesaver recommended for reclassification as an over-the-counter medicine by the FDA.
Xylazine has a few potential reversal agents; some are human-approved, and others are not.
We need this now.
—Owen Scott Muir, M.D.