Review ArticleXylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature
Introduction
Xylazine is a non-narcotic drug synthesized in 1962 by Bayer (Leverkusen, Germany), used as a sedative, analgesic, and muscle relaxant in animals [1]. According to the Food and Drug Administration (FDA), xylazine is used exclusively in veterinary medicine, marketed as Rompun®, Anased®, Sedazine™, and Chanazine®. It is approved for use in dogs, cats, horses, fallow deer (dama dama), mule deer (odocoileus hemionus), sika deer (cervus nippon), white-tailed deer (odocoileus virginianus), and elk (cervus canadensis) [2]. Its chemical structure closely resembles the phenothiazines, tricyclic antidepressants, and clonidine (Fig. 1) [1]. Xylazine is a potent α2-adrenergic agonist that mediates via stimulation of central α2-receptors. The α2 stimulation decreases the release of norepinephrine and dopamine in the central nervous system resulting in sedation, muscle relaxation, and decreased perception of painful stimuli. Its actions may also involve cholinergic, serotonergic, dopaminergic, α-1-adrenergic, histaminergic, or opiate mechanisms [3]. Acknowledged side effects in animals include transient hypertension, hypotension, and respiratory depression. [1], [4].
The routes of administration in animals include intravenous, intramuscular and, subcutaneous. The dosage form and amount are available in liquid solution equivalent to 20, 100 and 300 milligrams of xylazine. The dose varies with animals ranging from 0.25 to 4 milligrams per pound intramuscularly or 0.5 milligrams per pound intravenously [2]. The ranges of these doses provide analgesia for 15–30 min, but the sedative effect may continue for 1–2 h [5].
Xylazine pharmacokinetic parameters are well-established in different animal species, but not in humans. Briefly described, xylazine is absorbed, metabolized and eliminated extremely rapid [4], [6]. After intravenous administration in animals, xylazine rapidly distributes, concentrating in the kidney and the central nervous system. The duration of effects begins within a few minutes and last up to 4 h. [4], [7], [8]. The pharmacokinetics of xylazine have been studied in the dog, sheep, horse, and cattle [9]. Pharmacokinetic parameters do not vary greatly between species following intravenous administration. In all four species after intravenous administration, the distribution half-life (t1/2α) was very short (1.21–5.97 min) and the elimination half-life (t1/2β) varied from 23.11 to 49.51 min. These values indicate that the xylazine concentration would decrease to an undetectable level within a few hours. Xylazine has a large volume of distribution (1.9–2.5 for horse, cattle, sheep and dog) suggesting that xylazine, as expected for the lipophilic nature of the compound, diffuses extensively. Xylazine bioavailability (intramuscular to intravenous) ranges from 52 to 90% in the dog, 17 to 73% in sheep, and 40 to 48% in the horse [9]. Peak plasma concentrations are reached in 12–14 min in all species. The LD50 for dogs and horses is 47 and 60–70 mg/kg intramuscularly, respectively [10].
There is limited information on the metabolism of xylazine. In rats, using radio-labeled xylazine, after intravenous (i.v) injection (0.2–1.0 mg/kg) the drug was rapidly distributed to different tissues and 70% of the radio-activity was eliminated in urine with a half-life of about 2–3 h, only 8% of the activity corresponded to the unchanged form of the drug [9]. In the urine of cattle, 1% unchanged xylazine was eliminated during the first 2 h, with apparent half-life of 40 min. [9]. Total drug elimination after a therapeutic dose occurs over 10–15 h in the animal model [4], [8]. The rapid elimination of xylazine is attributed to extensive metabolism, and not to rapid renal excretion of unchanged xylazine. Several metabolites have been identified in horses, rats and cattle [6], [11], [12], [13]. Recently, a study on human metabolism in urine was investigated by Meyer and Maurer. Xylazine was N-dealkylated and S-dealkylated, oxidized, and/or hydroxylated to 12 phase I metabolites. The phenolic metabolites were partly excreted as glucuronides or sulfates. All phase I and phase II metabolites identified in rat urine were also detected in human urine. In rat urine after a low dose as well as in human urine after an overdose, mainly the hydroxy metabolites were detected using the authors’ standard urine screening approaches by GC–MS and LC–MSn [14].
Illicit drugs, such as cocaine and heroin, are often adulterated with other agents to increase bulk and enhance or mimic the illicit drug's effects. In Puerto Rico, heroin is commonly adulterated with xylazine [15], [16]. Also, it is frequently found in speedball (a cocaine and heroin mixture) [15], [17]. It has also been reported to be misused as a horse doping agent, a drug of abuse, a drug for attempted sexual assault, and as source of accidental or intended poisonings [14]. From human reported cases, central nervous system depression, respiratory depression, bradycardia, hypotension, and hyperglycemia were observed. [16]. Literature shows some similar pharmacologic effects between xylazine and heroin in humans. Both drugs cause bradycardia, hypotension, central nervous system depression and respiratory depression [16], [18], [19], [20], [21]. Because of these similar pharmacologic effects, synergistic effects may occur in humans when xylazine is use as an adulterant of heroin. Therefore, fatalities among drug users may increase due to the use of xylazine as an adulterant, especially due to the potentiation of the respiratory depressant effects of heroin. Authorities must be on alert about the use of xylazine as an adulterant, but also of others α2-adrenergic agonists. For example, dexmedetomidine is approved in humans by the FDA, produce sedation, analgesia, anxiolysis, and sympatholysis with less respiratory depression than others α2-adrenergic agonist such as xylazine [22]. To the best of our knowledge, dexmedetomidine has not been found as an adulterant of illicit drugs, however due to its FDA legal usage in humans and increase availability at this time, it may also encounter as a drug of abuse or possible adulterant in future.
A comprehensive review of the literature regarding non-fatal and fatal xylazine intoxication cases including those in which the substance was used as adulterant of drugs of abuse is presented and discussed in order to increase the awareness in the forensic community, law enforcement, and public health agencies.
Section snippets
Search strategy
A literature review was performed with PubMed using the keywords “xylazine”, “xylazine and poisoning”, “xylazine and humans”, “xylazine and adulterant”, “xylazine and cocaine”, xylazine and morphine”, and “xylazine interaction”. Articles were also identified through searches of the authors’ own manuscripts and relevant publications. Only papers published in English language were reviewed.
Results
Forty-three intoxication cases (43) in humans were identified from the years 1966 to 2013 [1], [3], [4], [8], [10], [16], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38]. A brief history, general effects, supportive care, drug used during the treatment, uses, route/mode of administration, dose, toxicological results and analytical technique are presented in Table 1 for the non-fatal cases. A summary of a brief history, uses, route, toxicological
Xylazine and humans
Xylazine is not approved by the FDA for human use. It was investigated in humans as a sedative-hypnotic, analgesic and anesthetic drug, but it was rejected because of its frequent association with severe hypotension and central nervous system depression [7], [23]. From all the reported cases (43), 21 (49%) were non-fatal scenarios in which most required medical intervention and 22 (51%) resulted in fatalities. According to the history described in both tables, 14 (33%) of the individuals had
Conclusion
In conclusion, xylazine is a potentially hazardous drug in humans. From 43 xylazine published intoxication cases in humans, 21 cases (49%) occurred in non-fatal scenarios and most required medical intervention; 22 cases (51%) resulted in fatalities. 14 (33%) out of 43 of the individuals had easy access to supplies of xylazine, due to their type of job (veterinarian, veterinarian assistant, farmer, horse trainer or related field). From the total reported, 17 cases (40%) were associated with the
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