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Trade names | Rompun, Anased, Sedazine, Chanazine |
AHFS/Drugs.com | International Drug Names |
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Routes of administration | By mouth, inhalation, or injection (intravenous, intramuscular, or subcutaneous) |
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ECHA InfoCard | 100.028.093 |
Chemical and physical data | |
Formula | C12H16N2S |
Molar mass | 220.33 g·mol−1 |
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Xylazine is a structural analog of clonidine and an alpha-2 adrenergic receptor agonist, [1] sold under many trade names worldwide, most notably the Bayer brand name Rompun, [2] as well as Anased, Sedazine and Chanazine. [3]
Xylazine is a common veterinary drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other mammals. [2] In veterinary anesthesia, it is often used in combination with ketamine. Veterinarians also use xylazine as an emetic, especially in cats. [4] Drug interactions vary with different animals. [5] [6] [7]
Xylazine has become a commonly abused street drug in the United States where it is known by the street name "tranq", particularly in Puerto Rico. [8] The drug is being diverted from stocks for equine veterinarians and used as a cutting agent for heroin and fentanyl, causing skin sores and infections at injection sites, as well as other health issues. [9] Fentanyl mixed with xylazine is known by the street names "sleep-cut", "zombie drug", "Iso" and "tranq dope". [10] [11] [12] [13]
Xylazine was discovered as an antihypertensive agent in 1962 by Farbenfabriken Bayer in Leverkusen, Germany. [1] Accounts of the actions and uses of xylazine in animals were reported as early as the late 1960s and early 1970s. [1] Results from early human clinical studies confirmed that xylazine has several central nervous system depressant effects. [1] Xylazine administration is used for sedation, anesthesia, muscle relaxation, and analgesia. [2] It causes a significant reduction in blood pressure and heart rate in healthy volunteers.[ failed verification ] [14] Xylazine was also studied for use in human beings, but due to hazardous side-effects, including hypotension and bradycardia, it was not approved by the Food and Drug Administration (FDA) for human use. [9]
In the United States, xylazine was approved by the FDA only for veterinary use as a sedative, analgesic, and muscle relaxant in dogs, cats, horses, elk, fallow deer, mule deer, sika deer, and white-tailed deer. [1] [3] The sedative and analgesic effects of xylazine are related to central nervous system depression. Xylazine's muscle relaxant effect inhibits the transmission of neural impulses in the central nervous system. [15]
In scientific research, xylazine is a component of the most common anesthetic, ketamine-xylazine (see rodent cocktail), which is used in rats, mice, hamsters, and guinea pigs. [16]
Xylazine is widely used in veterinary medicine as a sedative, muscle relaxant, and analgesic. It is frequently used in the treatment of tetanus. [1] It is not used in human medical treatment. Xylazine is similar to drugs such as phenothiazines, tricyclic antidepressants, and clonidine. [3] As an anesthetic, it is typically used in conjunction with ketamine. [14] In animals, xylazine may be administered intramuscularly or intravenously. [3] As a veterinary anesthetic, xylazine is typically only administered once for intended effect before or during surgical procedures. [1] Alpha-2 antagonists such as atipamezole and yohimbine may be used to reverse the effects of xylazine in animals. [17] [18] [19]
Side-effects in animals include transient hypertension, hypotension, and respiratory depression. [3] Further, the decrease of tissue sensitivity to insulin leads to xylazine-induced hyperglycemia and a reduction of tissue glucose uptake and utilization. [14] The effects in animals last up to 4 hours. [3]
In dogs, sheep, horses, and cattle, the half-life is very short: only 1.21–5.97 minutes. Complete elimination of the drug can take up to 23 minutes in sheep and up to 49 minutes in horses. [1] [3] In young rats the half life is one hour. [16] Xylazine has a large volume of distribution (Vd). [3] The Vd = 1.9–2.5 for horses, cattle, sheep, and dogs. [3] Though the peak plasma concentrations are reached in 12–14 minutes in all species, the bioavailability varies between species. [3] The half life depends on the age of the animal, as age is related to prolonged duration of anesthesia and recovery time. [16] Toxicity occurs with repeated administration, given that the metabolic clearance of the drug is usually calculated as 7–9 times the half-life, which is 4 to 5 days for the clearance of xylazine. [16]
Xylazine is a potent α2 adrenergic agonist. [21] [3] When xylazine and other alpha-2 adrenergic receptor agonists are administered, they distribute throughout the body within 30–40 minutes. [15] Due to xylazine's highly lipophilic nature, xylazine directly stimulates central α2 receptors as well as peripheral α-adrenoceptors in a variety of tissues. [1] [3] As an agonist, xylazine leads to a decrease in neurotransmission of norepinephrine and dopamine in the central nervous system. [3] It does so by mimicking norepinephrine in binding to pre-synaptic surface autoreceptors, which leads to feedback inhibition of norepinephrine. [22]
Xylazine also serves as a transport inhibitor by suppressing norepinephrine transport function through competitive inhibition of substrate transport. Accordingly, xylazine significantly increases Km and does not affect Vmax. [22] This likely occurs by direct interaction on an area that overlaps with the antidepressant binding site. [22] For example, xylazine and clonidine suppress uptake of MIBG, a norepinephrine analog, in neuroblastoma cells. [22] Xylazine's chemical structure closely resembles clonidine.
Xylazine is absorbed, metabolized, and eliminated rapidly. Xylazine can be inhaled or administered intravenously, intramuscularly, subcutaneously, or orally either by itself or in conjunction with other anesthetics, such as ketamine, barbiturates, chloral hydrate, and halothane in order to provide reliable anesthesia effects. [9] [14] The most common route of administration is injection. [9]
Xylazine's action can be seen usually 15–30 minutes after administration and the sedative effect may continue for 1–2 hours and last up to 4 hours. [3] Once xylazine gains access to the vascular system, it is distributed within the blood, allowing xylazine to enter the heart, lungs, liver, and kidney. [23] In non-fatal cases, the blood plasma concentrations range from 0.03 to 4.6 mg/L. [3] Xylazine diffuses extensively and penetrates the blood–brain barrier, as might be expected due to the uncharged, lipophilic nature of the compound. [3]
Xylazine is metabolized by liver cytochrome P450 enzymes. [16] When it reaches the liver, xylazine is metabolized and proceeds to the kidneys to be excreted in urine. [24] Around 70% of a dose is excreted by urine. [16] Thus, urine can be used in detecting xylazine administration because it contains many metabolites, which are the main targets and products in urine. [1] [25] Within a few hours, xylazine decreases to undetectable levels. [3] Other factors can also significantly impact the pharmacokinetics of xylazine, such as sex, nutrition, environmental conditions, and prior diseases. [16]
Xylazine-M (2,6-dimethylaniline) | Xylazine-M (N-thiourea-2,6-dimethylaniline) | Xylazine-M (sulfone-HO-) isomer 2 |
Xylazine-M (HO-2,6-dimethylaniline isomer 1) | Xylazine-M (HO-2,6-dimethylaniline isomer 2) | Xylazine M (oxo-) |
Xylazine-M (HO-) isomer 1 | Xylazine-M (HO-) isomer 1 glucuronide | Xylazine-M (HO-) isomer 2 |
Xylazine-M (HO-) isomer 2 glucuronide | Xylazine-M (HO-oxo-) isomer | Xylazine-M (HO-oxo-) isomer 1 glucuronide |
Xylazine-M (HO-oxo-) isomer 2 | Xylazine-M (HO-oxo-) isomer 2 glucuronide | Xylazine-M (sulfone) |
Xylazine-M (sulfone-HO-) isomer 1 |
In 1979, the first case of xylazine toxicity was reported in a 34-year-old male who had self-medicated for insomnia with injection of 1 gram (0.035 oz) of xylazine. [26] Intentional intoxication from ingesting, inhaling, or injecting xylazine has since been reported. Intravenous injection is the most common route of administration for those who use heroin with xylazine recreationally.
Since the early 2000s, xylazine has become popular as a drug in the United States.[ clarification needed ]. [25] Xylazine's street name in Puerto Rico is anestesia de caballo, which translates to "horse anesthetic". [3] [8] From 2002 to 2008, its use was associated with a high number of inmate deaths at the Guerrero Correctional Institution in Aguadilla, Puerto Rico. [27]
Xylazine's street name in the United States, particularly when it is mixed with fentanyl, is "tranq", "tranq dope" and "zombie drug". [28] From 2010 to 2019, the proportion of heroin and/or fentanyl deaths in Philadelphia where xylazine was detected rose from 3 to 28%. [29] [30]
As of 2012, xylazine users in Puerto Rico were more likely to be male, under age 30, living in a rural area, and injecting rather than inhaling xylazine. Because xylazine and heroin trigger similar behavioral outcomes, the former is often secretly mixed into illegal doses of heroin. The combination of heroin and xylazine produces a potentially more deadly high than administration of heroin alone. Xylazine is also frequently found in "speedball", a mixture of a stimulant drug such as cocaine with a depressant drug such as heroin, morphine and/or fentanyl. [9] As of 2012, causal factors underlying xylazine's increasing popularity were still unknown. [8]
As of 2022, more information on the distribution of xylazine in the body, physical symptoms, and factors predictive of chronic use was known: when used, frequency of use depended on social or economic factors, as well as each user's subjective response to the drug's addictive properties. [31] From November 2021 until August 2022, 80% of drug paraphernalia which tested positive for fentanyl at needle exchange programs in Maryland also contained xylazine. [32] As of 2022, xylazine was almost invariably combined with opioids when used recreationally, and the drug produced a characteristic withdrawal syndrome which complicates treatment of addicted users. [33] [34]
In April 2023, the Biden administration declared xylazine-laced fentanyl an official emerging drug threat to the nation, the first time such label has been given. Rahul Gupta, director of the Office of National Drug Control Policy (ONDCP), said he was troubled about what he learned "about the devastating impact of the fentanyl-xylazine combination, which is growing in youth across the nation". [35] According to Gupta, xylazine is the deadliest drug threat the United States has ever faced. The Drug Enforcement Agency (DEA) has seized xylazine and fentanyl mixtures in most states, finding 23% of seized fentanyl powder and 7% of fentanyl pills adulterated with xylazine. [12]
In July 2023, the first death following xylazine use outside of North America was reported to have taken place in Solihull, England in May 22. A 43-year-old male was found dead at home with postmortem toxicology detecting heroin, cocaine, fentanyl and xylazine. [36] Xylazine is anticipated to make inroads in the European illicit drug market once the most recent Afghanistan opium poppy harvest has been produced and delivered, the Taliban having banned poppy cultivation in 2023. [37]
In April 2024, xylazine was reported to be present in illicit THC e-cigarettes in the UK. [38] [39]
Xylazine overdose is often fatal in humans. [1] Because it is used as a drug adulterant, the symptoms caused by the drugs accompanying xylazine administration vary between individuals. [9]
The most common side-effects in humans associated with xylazine administration include bradycardia, respiratory depression, hypotension, transient hypertension secondary to alpha-1 stimulation, and other central and hemodynamic changes. [1] [9] [40] Xylazine significantly decreases heart rate in animals that are not pre-medicated with medications that have anticholinergic effects. [1]
Xylazine administration can lead to diabetes mellitus and hyperglycemia. [14] Other possible side-effects are areflexia, asthenia, ataxia, blurred vision, disorientation, dizziness, drowsiness, dysarthria, dysmetria, fainting, hyporeflexia, slurred speech, somnolence, staggering, coma, apnea, shallow breathing, sleepiness, premature ventricular contraction, tachycardia, miosis and dry mouth. [3] Rarely, hypotonia, urinary incontinence, and nonspecific electrocardiographic ST segment changes occur. [3] Following a human overdose, symptoms can last for 8–72 hours, varying based on xylazine's combined usage with other drugs. [1] [3]
Chronic intravenous use of xylazine in combination with opioids is reported to be associated with physical deterioration, dependence, abscesses, and skin ulceration, sometimes progressing to necrosis with eschar formation, which can be physically debilitating and painful. [3] [14] [30] Hypertension followed by hypotension, bradycardia, and respiratory depression lower tissue oxygenation in the skin. [9] Thus, chronic use of xylazine can progress the skin oxygenation deficit, leading to severe skin ulceration. [9] Lower skin oxygenation is associated with impaired healing of wounds and a higher chance of infection. [9] The ulcers may ooze pus and have a characteristic odor. [8] In severe cases, surgical amputations must be performed on the affected extremities. [8]
Since xylazine is not an opioid, it cannot be neutralized by naloxone (Narcan). However, experts still recommend administering naloxone during a suspected xylazine overdose because the drug is very frequently mixed with opioids like fentanyl. [12]
Human tolerance to xylazine varies widely with toxicity and fatality occurring between doses of 40–2,400 mg (0.62–37.04 gr). [3] Non-fatal blood or plasma concentration ranges from 0.03 to 4.6 mg/L. [23] In fatalities, the blood concentration of xylazine ranges from trace to 16 mg/L. [23] It is reported that there is no defined safe or fatal concentration of xylazine because of the significant overlap between the non-fatal and postmortem blood concentrations of xylazine. [3]
As of 2014, there is no specific antidote to treat humans who overdose on xylazine. Hemodialysis has been suggested as a form of treatment, but is usually unfavorable due to the large volume of distribution of xylazine. [3]
There are no standardized screenings to determine if an overdose has occurred. Detection of xylazine in humans involves various screening methods, such as urine screenings, thin layer chromatography (TLC), gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS). [25] [23] As of November 2022, detecting xylazine in a drug sample requires spectrophotometry. [41]
As of 1998, the alpha-2 antagonist atipamezole was used to reverse the effects of xylazine or the related drug dexmedetomidine in veterinary medicine, [42] but this is not an approved medical treatment for humans, despite Phase I clinical trials in 2005. [43]
As of 2001, the effects of xylazine in animals were also reversed by the analeptics 4-aminopyridine, doxapram, and caffeine, which are physiological antagonists to central nervous system depressants. [44] Further research is needed to accurately identify chronic xylazine usage and standardize effective treatments. [1] As of 2014, multiple drugs have been used for therapeutic intervention, including lidocaine, naloxone, thiamine, lorazepam, vecuronium, etomidate, propofol, tolazoline, yohimbine, atropine, orciprenaline, metoclopramide, ranitidine, metoprolol, enoxaparin, flucloxacillin, insulin, and irrigation of both eyes with saline. [3]
The treatment after a xylazine overdose primarily involve maintaining respiratory function and blood pressure. [3] In cases of intoxication, physicians recommend intravenous fluid infusion, atropine, and hospital observation. [1] Severe cases may require tracheal intubation, mechanical ventilation, gastric lavage, activated charcoal, bladder catheterization, electrocardiographic (ECG) and hyperglycemia monitoring. [3] Physicians typically recommend which detoxification treatment should be used to manage possible dysfunction involving highly perfused organs such as the liver and kidneys. [23]
In 2022, the Food and Drug Administration (FDA) issued an alert to American health care providers on the risks patients face if exposed to xylazine in illicit drugs. [45]
Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic. It is 20 to 40 times more potent than heroin and 100 times more potent than morphine; its primary clinical utility is in pain management for cancer patients and those recovering from painful surgeries. Fentanyl is also used as a sedative. Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose. Fentanyl works by activating μ-opioid receptors. Fentanyl is sold under the brand names Actiq, Duragesic and Sublimaze, among others.
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of opioid use disorder.
Carfentanil or carfentanyl, sold under the brand name Wildnil, is an extremely potent opioid analgesic used in veterinary medicine to anesthetize large animals such as elephants and rhinoceroses. It is typically administered in this context by tranquilizer dart. Carfentanil has also been used in humans to image opioid receptors. It has additionally been used as a recreational drug, typically by injection, insufflation, or inhalation. Deaths have been reported in association with carfentanil.
Sufentanil, sold under the brand names Dsuvia and Sufenta, is a synthetic opioid analgesic drug approximately 5 to 10 times as potent as its parent drug, fentanyl, and 500 times as potent as morphine. Structurally, sufentanil differs from fentanyl through the addition of a methoxymethyl group on the piperidine ring, and the replacement of the phenyl ring by thiophene. Sufentanil first was synthesized at Janssen Pharmaceutica in 1974.
Acepromazine, acetopromazine, or acetylpromazine is a phenothiazine derivative antipsychotic drug. It was used in humans during the 1950s as an antipsychotic, but is now almost exclusively used on animals as a sedative and antiemetic. A closely related analogue, chlorpromazine, is still used in humans.
Tiletamine is a dissociative anesthetic and pharmacologically classified as an NMDA receptor antagonist. It is related chemically to ketamine. Tiletamine hydrochloride exists as odorless white crystals.
Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and intranasal spray formulations. The tablet form is only used in dogs, cats and horses due to low bioavailability in humans.
Dexmedetomidine, sold under the trade name Precedex among others, is a drug used in humans for sedation. Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses. It is also used in humans to treat acute agitation associated with schizophrenia or bipolar I or II disorder.
Diprenorphine, also known as diprenorfin, is a non-selective, high-affinity, weak partial agonist of the μ- (MOR), κ- (KOR), and δ-opioid receptor (DOR) which is used in veterinary medicine as an opioid antagonist. It is used to reverse the effects of super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals. The drug is not approved for use in humans.
Veterinary anesthesia is a specialization in the veterinary medicine field dedicated to the proper administration of anesthetic agents to non-human animals to control their consciousness during procedures. A veterinarian or a Registered Veterinary Technician administers these drugs to minimize stress, destructive behavior, and the threat of injury to both the patient and the doctor. The duration of the anesthesia process goes from the time before an animal leaves for the visit to the time after the animal reaches home after the visit, meaning it includes care from both the owner and the veterinary staff. Generally, anesthesia is used for a wider range of circumstances in animals than in people not only due to their inability to cooperate with certain diagnostic or therapeutic procedures, but also due to their species, breed, size, and corresponding anatomy. Veterinary anesthesia includes anesthesia of the major species: dogs, cats, horses, cattle, sheep, goats, and pigs, as well as all other animals requiring veterinary care such as birds, pocket pets, and wildlife.
Medetomidine is a synthetic drug used as both a surgical anesthetic and analgesic. It is often used as the hydrochloride salt, medetomidine hydrochloride, a crystalline white solid. It is an α2 adrenergic agonist that can be administered as an intravenous drug solution with sterile water.
Atipamezole, sold under the brand name Antisedan among others, is a synthetic α2 adrenergic receptor antagonist used for the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. Its reversal effect works by competing with the sedative for α2-adrenergic receptors and displacing them. It is mainly used in veterinary medicine, and while it is only licensed for dogs and for intramuscular use, it has been used intravenously, as well as in cats and other animals(intravenous use in cats and dogs is not recommended due to the potential for cardiovascular collapse. This occurs due to profound hypotension caused by reversal of the alpha 1 effects while the reflex bradycardia is still in effect.). There is a low rate of side effects, largely due to atipamezole's high specificity for the α2-adrenergic receptor. Atipamezole has a very quick onset, usually waking an animal up within 5 to 10 minutes.
Romifidine is a drug that is used in veterinary medicine as a sedative mainly in large animals such as horses, although it may be used in a wide variety of species. It is not used in humans, but is closely related in structure to the commonly used drug clonidine.
Alpha-2 blockers are a subset of the alpha blocker class of drugs and are antagonists to the α2 adrenergic receptor. They are mainly used in research, having found limited clinical application in human medicine. Alpha-2 blockers increase noradrenaline release.
Sarmazenil (Ro15-3505) is a drug from the benzodiazepine family. It acts as a partial inverse agonist of benzodiazepine receptors, meaning that it causes the opposite effects to most benzodiazepine drugs, and instead acts as an anxiogenic and convulsant. It is used in veterinary medicine to reverse the effects of benzodiazepine sedative drugs in order to rapidly re-awaken anesthetized animals.
An opioid overdose is toxicity due to excessive consumption of opioids, such as morphine, codeine, heroin, fentanyl, tramadol, and methadone. This preventable pathology can be fatal if it leads to respiratory depression, a lethal condition that can cause hypoxia from slow and shallow breathing. Other symptoms include small pupils and unconsciousness; however, its onset can depend on the method of ingestion, the dosage and individual risk factors. Although there were over 110,000 deaths in 2017 due to opioids, individuals who survived also faced adverse complications, including permanent brain damage.
Acetylfentanyl is an opioid analgesic drug that is an analog of fentanyl. Studies have estimated acetylfentanyl to be 15 times more potent than morphine, which would mean that despite being somewhat weaker than fentanyl, it is nevertheless still several times stronger than pure heroin. It has never been licensed for medical use and instead has only been sold on the illicit drug market. Acetylfentanyl was discovered at the same time as fentanyl itself and had only rarely been encountered on the illicit market in the late 1980s. However, in 2013, Canadian police seized 3 kilograms of acetylfentanyl. As a μ-opioid receptor agonist, acetylfentanyl may serve as a direct substitute for oxycodone, heroin or other opioids. Common side effects of fentanyl analogs are similar to those of fentanyl itself, which include itching, nausea and potentially fatal respiratory depression. Fentanyl analogs have killed hundreds of people throughout Europe and the former Soviet republics since the most recent resurgence in use began in Estonia in the early 2000s, and novel derivatives continue to appear.
Thiafentanil is a highly potent opioid analgesic that is an analog of fentanyl, and was invented in 1986. Its analgesic potency is slightly less than that of carfentanil, though with a faster onset of effects, shorter duration of action and a slightly lesser tendency to produce respiratory depression. It is used in veterinary medicine to anesthetise animals such as impala, usually in combination with other anesthetics such as ketamine, xylazine or medetomidine to reduce the prevalence of side effects such as muscle rigidity.
Hanhong Pharmaceutical Technology Co. is a Chinese drug manufacturer. The company, its owner Du Changgen and some of its employees are indicted by the United States Justice Department for crimes relating to fentanyl, xylazine and methamphetamine production, distribution of synthetic opioids, and sales resulting from precursor chemicals. The indictments accuses Hanhong of exporting large quantities of fentanyl precursors and non-opioid additives like xylazine, to drug traffickers in Mexico and the United States. Its owner Du Changgen is the head of the Du Transnational Criminal Organization, which is listed on the United States Attorney General’s Consolidated Priority Organization Target (CPOT) list, which according to the DEA is a list of the leaders of the most prolific drug trafficking and money laundering organizations, having the greatest impact on the United States illicit drug supply.
Reports from social media and news outlets suggest that xylazine-containing products may be sold under the street names tranq, tranq dope, sleep-cut, Philly dope and zombie drug.