I have long argued that the true cause of the dramatic increase in overdose deaths experienced by the United States has two causes. First is the uncontrolled flow of Fentanyl through commercial checkpoints on our national southern border. Second is the DEA’s draconian destruction of doctors who treat pain and addiction, leaving their patients abandoned on the streets to die when they encounter fake pills made with this drug.
As bad as things were, they just got worse. A recent laboratory analysis of counterfeit oxycodone pills seized in Rhode Island in 2022 shows that 99.3% contained Fentanyl. As we would expect. But it was also commonly mixed with a newer drug, xylazine. The combination of these two drugs could have devastating, even deadly, consequences for recreational users and patients suffering from pain and addiction who encounter them.
Dr. Rachel Wightman, an associate professor of epidemiology and emergency medicine at Brown University in Providence, Rhode Island, led the research team. On May 6th, the findings were published in the Journal of the American Medical Association. Most of us are familiar with fentanyl, but xylazine is relatively newer to the American market. Xylazine is often referred to as a “horse tranquilizer,” and this time, the term is accurate.
Almost all medications used in humans can also be used in most animals, from antibiotics like penicillin to anesthetics like ketamine. Ketamine is often also referred to in the media by the DEA as a “horse tranquilizer.” This is sensationalism and implies that the targeted doctor was doing something wrong. That is not the case. Ketamine works fine in people and animals. The dose and frequency just need to be adjusted for size and metabolism.
Xylazine is another matter. It was discovered in 1962 by Bayer Pharmaceutical out of Germany. First investigated as an antihypertensive agent, human clinical trials later confirmed a sedative effect. Xylazine is now used mainly by veterinarians on larger animals like horses, where it provides pain relief, anesthesia, and relaxation for the animal. It’s not used for humans in the US because of side effects like hypotension and bradycardia.
How does xylazine relieve pain when it’s not a mu-opioid agonist like most pain medicines? And does it create the sensation of euphoria? Not for most people. But then, neither do opiate medications. The sudden sensation of euphoria when first taking a drug has been strongly correlated with the potential for later addiction. Dr. Siri Leknes of the University of Oslo believes this reaction to opiates is not that common, which makes sense.
Despite about twenty percent of people appearing to have a genetic predisposition to opiate addiction, this only accounts for 40 to 60% of a person’s overall risk of addiction. Which for opioid use disorder, has a prevalence of only about 2.35 to 4.0%. Indeed, some researchers argue that this is a much more reliable measure of future risk than any AI or “expert” generated calculation of childhood traumas and prior convictions.
So, how does Xylazine work? Once taken orally, xylazine spreads throughout the body in about half an hour, where it acts as an alpha-2 adrenergic agonist. We usually think of adrenergic agonists as increasing alertness and blood pressure, but it’s more complicated than that. Because xylazine works on alpha-2 receptors, it has a paradoxical effect. It actually suppresses the release of these catecholamines, which is confusing to me.
Alpha-2 adrenergic receptors or adrenoreceptors are found in both the peripheral and central nervous system on both pre- and post-synaptic neurons and are usually activated by norepinephrine and epinephrine. When the presynaptic alpha-2 neurons are activated, norepinephrine release onto the postsynaptic neuron where alpha-1 receptors reside is inhibited, reducing the activity of the post-synaptic neuron.
The effect is often referred to as sympatholytic, which means it reduces or blocks the sympathetic nervous system response, creating hypotension, bradycardia, sedation, analgesia, and muscle relaxation. Activation of alpha-2 adrenergic receptors also inhibits the release of other neurotransmitters, including glutamate, the major excitatory neurotransmitter in the brain, enhancing its overall sedative effect.
Medications with similar actions include tricyclic antidepressants (like trazodone), phenothiazines (promethazine), and clonidine. There are three types of alpha-2 adrenoreceptors: a, b, and c. Alpha-2a and 2c are in the locus ceruleus, and activating them shuts off norepinephrine in that area, creating the sedative effect. While in the dorsal horn of the spinal cord, their activation produces some analgesia or pain relief.
The alpha-2b type is found in the smooth muscles of blood vessels, controlling blood pressure by vasodilation. Xylazine activates alpha-2 over alpha-1 by a factor of 160x. The selectivity for the subtypes of alpha-2 is still being worked out, but we do know that the activation of alpha-2b receptors in the skin, especially in an area of injection, causes vasoconstriction, which can lead to ischemia, leading to the pathognomonic skin ulcers.
These can occur from any administration of the drug and do not require skin injection to manifest but almost always occur with subcutaneous injection. Common in Russia and now seen here. Very high doses of xylazine in animals seem to exhaust the hypotensive action, creating a rebound hypertensive emergency. This is something to be aware of as more Americans are being poisoned by this drug and dying.
I stress poisoning because it’s important to remember that these are not “overdoses” as we usually think of them, as people do not know which “oxycodone” pills have been adulterated. According to a CDC report, the rate of deaths involving xylazine has increased by 35x. I emphasize involving because it does not mean there is a proven cause and effect. Just because something is present doesn’t mean it was responsible for the death.
You see the DEA using this easily confused metric to send doctors away for life by saying, “There were deaths associated with their practice.” That’s always the case for any doctor treating any sick patient or, if you wait long enough, any patient at all. The question becomes muddled with multidrug-related deaths, as it is impossible to determine for any specific individual exactly how much contribution was made by any individual substance.
A simple antihypertensive like a beta-blocker or calcium channel blocker could just as logically be blamed for creating severe hypotension in combination with the xylazine. The CDC researchers recognized the limitations noted above and noted in their study, “…one limitation of the ICD–10 classification system is that, with a few exceptions, ICD–10 codes do not reflect specific drugs but, rather, broader categories.
For example, they relate that “the ICD–10 code for poisoning by antiepileptic and sedative-hypnotic drugs (T42.7) includes deaths involving xylazine and levetiracetam.” To remove this complication, they searched the full text of death certificates written by coroners and medical examiners. That’s better than going by nonspecific codes, but its accuracy is limited due to the lack of full medical evaluations in many multidrug-related deaths.
In some areas of the United States, coroners are not required to have any medical or forensic training. None at all. I practiced emergency medicine where the local mortician had been elected to the office. Granted, he would be skilled at knowing when someone was dead, we hope, but he had no other training or experience in determining the cause of death, and this is crucial. I’ll give you an example.
At the start of the opioid panic in 2019, two doctors who practiced on the border between Arkansas and Oklahoma were prosecuted. They had worked together once but then operated separate pain management clinics. After the DEA press release of their arrest, the media started off parroting what the government had said, reporting “1,803 pills per patient!” (over two years) as if that were a crime. but they didn’t do the math.
This works out to 2.5 pills per patient per day. Completely normal. That’s like saying your doctor advised you to drink 11,520 ounces! ( Accumulated from the recommendation to drink eight ounces of water up to four times a day every day for 12 months). Without the math and the context, it looks like they are either trying to drown you or kill you with hyponatremic seizures. Misleading sensationalism does not serve justice or medicine.
But this common tactic is very effective since, too often, we have reporters these days and not true journalists. The difference being that a journalist provides context to prevent exactly this kind of sensationalism, especially when it comes to a citizen’s liberty, whereas most others just repeat what they are told and refuse to even consider the possibility that the government might be misleading them or just plain wrong. It happens. Look closely.
A death involving one of these doctors was listed as “sepsis due to bacteremia,” but the examiner went on to say that the combination of alprazolam and hydrocodone produced “a fatal respiratory depression.” Well, which is it? Or is this a perfect example of a supposedly objective scientist trying to “help” the authorities in the crisis of the day? This common phenomenon is what I call Salem Syndrome, and it doesn’t always go well for the doctor.
As the Salem Witch Trials were heating up, a doctor named Toothaker jumped on the bandwagon, insisting that he had detected and killed witches for many years and trained his daughter to do the same. I assume he thought supporting the ridiculous exercise in mass hysteria would keep him safe. Sadly for him, the servant of his competitor Dr. William Griggs, pointed the finger directly back at Dr. Toothaker, who died in jail before trial.
The combination of hydrocodone and alprazolam was often used by doctors for people who had both severe chronic pain and panic attacks. PTSD is not uncommon in someone who has suffered a life-altering injury and often causes extreme attacks of anxiety. In fact, hundreds of thousands of Americans have safely taken this combination for half a century, which is why many patients came to us already on them, though you will see fewer now.
Of course, if you take more than you are supposed to, you can kill yourself with almost anything. Including Tylenol and aspirin. Context and accuracy matters. NSAIDs, taken as prescribed, kill three times more people per year than heroin. As does Tylenol by suicide. All that being said. Using prescription medications other than as prescribed or illegal drugs at all can get you killed. Especially now, with this new combination of fentanyl and xylazine.
That’s because some medications work synergistically to multiply their effect rather than just being additive. There were 102 deaths in 2018 where xylazine was found with fentanyl. By 2021that became 3,468. Of the 1,176 counterfeit pills evaluated by Wightman’s group, most of them fell into three categories: Oxycodone (686 pills), alprazolam (brand name Xanax, 312 pills), and amphetamines (174 pills).
Terrifyingly, the laboratory analysis showed that almost all the counterfeit oxycodone pills seized in 2022 contained fentanyl. Fentanyl was also detected in 2.6% of the Xanax pills. None of the amphetamine pills contained fentanyl. Xylazine was also found in almost all of the fake oxycodone pills. Out of 137 pills containing xylazine, 135 (98.5%) were counterfeit oxycodone while xylazine was detected with fentanyl in 136 of 137 pills.”
Dr. Kimberly Sue, an addiction medicine doctor at Yale Medicine in New Haven, Conn., said that “…for the majority of people, they don’t know they’re using it and they don’t intend to be using it…” Another complication is that xylazine does not respond to Narcan (naloxone), which is finally being made somewhat available about three decades later than it should have. This could dramatically limit EMT and ER treatments when patients are found alive.
The combination of fentanyl with a new drug that cannot be treated with Narcan, added to a medical environment where patients are abandoned after the DEA locks up their doctors for daring to try to treat pain and addiction, is a perfect storm for even more deaths. But is worse than that. Xylazine alters mRNA expression of protein phosphorylating AMPK signaling molecules, which could cause persistent changes in the brain.
A study from 2022 found a critical role for AMPK in addiction, specifically to cocaine, through actions in the motivation and reinforcement center, the nucleus accumbens. Finding that “AMPK-CRTC1 signaling regulates cocaine reinforcement and motivation.” This could imply that xylazine, when added to any habit-forming substance, could potentiate the risk of developing a full addiction, dramatically increasing the dangers of its use.
But all is not lost. A vaccine has been developed by researchers at Scripps Research in La Jolla, California. This could be used after a non-fatal overdose to guard against the effects of relapse. Can we make more of these vaccines? They have one for cocaine. Of at least one thing, I am sure. Addiction is more complicated than politicians would lead you to believe, and we need more doctors willing to try to help these patients, not fewer.
