Xylazine is the latest veterinary tranquilizer to be sold as a street drug. It has no approved human uses. It is used as both a light and general anesthetic for horses depending on the extent of the surgery. Xylazine is a presynaptic alpha-2 adrenoceptor agonist inhibiting the release of norepinephrine from synaptic vesicles. This leads to decreased postsynaptic activation of adrenoceptors, inhibited sympathetic activity, leading to analgesia, sedation and anxiolysis. This mechanism of action is also seen with clonidine and dexmedetomidine. Xylazine has low potency and affinity for Alpha-2 receptor adrenergic receptors. It has been demonstrated by the use of a knock out genetic mouse model that the clinical effects are mediated through the alpha-2A receptor subtype (5).
Alpha-2 receptor adrenergic receptor (AR) profiles
are complicated by the fact that there are 4 subtypes with central, peripheral
and behavioral effects but very little seems to be written about the D subtype so I have not included it here. The general
associated mechanisms include a decrease in adenyl cyclase activity, suppressed
voltage gated calcium currents, increased potassium currents and increased mitogen-activated
protein kinase (MAP kinase) activity. At steady state the α-2A and α-2B receptor types are at the cell surface
and the α-2C type is at the cell surface and intracellular. Some drugs like clonidine and guanfacine
promote α-2A internalization. The author (3) of the review suggests that this
may account for the unique duration of signaling. α-2AR trafficking and
signaling also undergoes complex regulation by a number of factors including
protein kinases, G protein coupled receptors (GPCRs), and scaffolding proteins. A table of receptor affinities for various drugs are listed below. These affinities are primarily from reference 2 and generally represent results for human cloned receptors of the averages of several experiments. Please note the very low affinities for xylazine. I have tried to corroborate these numbers from outside sources and have not been successful. If you have better affinities for xylazine please email me or post them here in the comments section.
From a pharmacodynamic standpoint there are several relevant Alpha-2 AR polymorphisms that have been tentatively linked disease states like ADHD and hypertension. They have also been studied in heart rate, heart rate variability, blood pressure control, obesity and insulin resistance (4). As expected, these polymorphisms also effect drug response.
Although Xylazine is approved only for veterinary uses,
reports of human use and accidental or inadvertent overdoses began to appear in
the 1980s. A review of initial reports
looking at the compound as an adulterant that was done in 2014 (7) and
concluded that half of the human overdoses resulted in death.
Central effects of alpha 2 agonists, results in decreased
sympathetic output and resulting imbalances in the peripheral autonomic nervous
system. Decreased sympathetic output
leads to the expected effects of bradycardia, hypotension, sedation and
decreased level of consciousness. Unopposed vagal parasympathetic effects can
lead to increasing heart block and arrhythmias.
In addition to the central effects of α-2 agonists there
are also peripheral effects. A common α-1
and α-2 agonist used peripherally is oxymetazoline
that is used as a topical nasal decongestant. It exhibits very high affinity
for both receptors and the following Kis α-2A (7.24 nM), α-2B
(483.5 nM), α-2C (144.07 nM), α-1 (402.75 nM).
Peripheral α-2 adrenergic effects can lead
to increased systemic vascular resistance due to effects at the level of
arterioles. This is important from a toxicological perspective because it can
cause hypertension and is probably the mechanism leading to soft tissue
necrosis at injection sites.
The epidemiology of xylazine use is discussed in a few
studies at this point (7,12,13). The original paper suggested it may have
started in Puerto Rico and spread Philadelphia with the highest prevalence of
overdoses in eastern states. It is well
described at this point both in terms of overdoses and as an adulterant when it
is added to heroin, fentanyl, cocaine, methamphetamine, alcohol or combinations
like heroin + cocaine. There are expected synergies with opioids including a
depressed level of consciousness, and decreased respiratory drive. Synergies
with stimulants would include increased likelihood of cardiac arrhythmias,
hypertension, and tissue necrosis.
The CDC recently published a study of xylazine in Cook
County, IL (Chicago area) in MMWR (12).
The study ran from January 2017 to October 2021. Xylazine associated deaths were defined as positive
post-mortem toxicology in any substance related death where the intent was unintentional,
undetermined or pending. The authors identified 236 xylazine associated deaths
that increased over the study period and are graphed below. The graph on the
right is the percentage of fentanyl associated deaths involving xylazine by
month. That graph peaks at 11.4% in October. Overall, fentanyl or its
metabolites was present in 99.2% of xylazine associated deaths. The authors
point out that naloxone does not reverse the effects of xylazine but it should
be administered for any suspected opioid use in a polypharmacy toxidrome. They
also state that better surveillance for this compound is probably indicated.
The toxidromes from these drug combinations can be complex so that on a clinical basis it will be hard to tell if the patient you are seeing has used xylazine. I was fortunate enough to attend a Hennepin County Medical Center Addiction Medicine Journal Club on 4/5/2022. In that presentation the pharmacology, clinical effects and toxicology of xylazine were discussed. The cases presented all had xylazine combined with other substances and severe necrosis of the lower extremities in two cases and hand and wrist in the other. In one case the patient no longer had venous access and was injecting into the area of necrosis. All of these patients required skin grafting wanted to leave the hospital after the acute phase of intoxication had passed. In these cases, the transition to detoxification and maintenance medications is complicated because of the possible synergy between opioids and α-2 adrenergic agonists and the question of rebound or withdrawal from preadmission use of xylazine. The question of Takotsubo cardiomyopathy was discussed because some patients the literature were described as using xylazine. Rebound or withdrawal from xylazine and the associated rapid increase in catecholamines was discussed as a potential mechanism. A toxicologist attending the meeting also pointed out that with overdoses the α-2 adrenergic agonists can cause hypertension by peripheral effects and this has caused some acute cardiac problems. That toxicologist was also familiar with local testing for xylazine and it was not currently being done. He pointed out that a half life of 5 hours was determined in humans as contrasted with a few minutes in several animal species. He suggested that in the case of a patient unresponsive to high dose naloxone, without hypercapnia via arterial blood gases, and normal brain imaging it would be reasonable to request xylazine toxicology.
In an interesting development, the FDA recently approved a dexmedetomidine
sublingual film for the treatment of acute agitation in schizophrenia and
bipolar disorder (14). Dexmedetomidine
has been available for intravenous use for 20 years with the indication “sedation
of non-intubated patients prior to and/or during surgical and other procedures”
(15). It also has a place in critical
care medicine – addressing all three aspects of the ICU triad of pain,
agitation, and delirium (16). The film comes in 120 mcg and 180 mcg doses with
a schedule in the package insert with dosing for adults and geriatric patients with
and without varying degrees of hepatic impairment. The clinical trials in the package insert
describe the medication as effective for this indication. As a psychiatrist who
spent most of his career in acute care there are fairly frequent situations
where medications that are typically used to treat agitation (antipsychotics
and benzodiazepines) do not work – even at high doses. It will be interesting
to see if acute care psychiatrists find dexmedetomidine preparation useful.
When I ran into that situation it was typically cases of severe mania with
agitation or delirious mania with catatonia and the only available option was
conscious sedation by anesthesiology. The other unknown at this point is how
effective this medication will be over time.
The package insert specifies a maximum of two or three doses. Clinicians will be on their own after that.
It reminds me of how another α-2 adrenergic agonist – clonidine is currently
used for anxiety, agitation, and insomnia. Many patients experience it as
transiently effective until a more sustained preparation (typically a
transdermal patch) is used.
The appearance and gradual increase in xylazine as a street
drug is not good news. It is clearly
used as an adulterant in both opioids and stimulants. Its use can result in severe complications
and death. The surveillance for this compound is not good at this time and
clinicians have to have a high index of suspicion to request toxicology for it.
People with substance use disorders need to be educated about this compound and
its use as an adulterant and that deciding to use it with an opioid or other CNS depressants (including alcohol) is very
dangerous and needs to be avoided. Using it with stimulants can also have significant negative effects. At this point it is also an unknown danger because like fentanyl - it can be sold as anything.
George Dawson, MD, DFAPA
References:
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Bergström U, Neil A. Interactions of xylazine and detomidine with
alpha2-adrenoceptors in brain tissue from cattle, swine and rats. J Vet
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PMID: 12755905.
2: PDSP Ki Database
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Robertson D, Biaggioni I, Burnstock G, Low PA, Paton JFR. 2012.
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Kobayashi T, Yamaguchi S, Otsuguro K. The α2A -adrenoceptor
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sodium retention and vasoconstriction, whereas activation of peripheral
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