## 5 Combinations of Xylazine with Other Drugs  
Xylazine is often combined with ketamine as a sedative and analgesic during surgery in animals [134; 135], such as equines [136; 137], and with lidocaine [138; 139; 140; 141] since xylazine greatly enhances the anesthetic and sedative properties of these drugs. A synergistic interaction between ketoprofen and xylazine on the level of cyclooxygenase-2 in mice has been reported [142]. Moreover, the administration of carprofen in combination with xylazine in the castration process of male goats is likely beneficial, as it enhances plasma concentration of carprofen and decreases clearance in castrated male goat kids [143]. In a recent study in West African Dwarf goats, the combination of xylazine with propofol provided an analgesic duration higher than propofol alone [144]. Some diseases might be exacerbated by the use of xylazine in combination with ketamine, and some animals might be affected by its use. It has been recently reported that the administration of ketamine/xylazine in mice has increased the severity of influenza (A/Puerto Rico/8/34) [145].  
In the unregulated market, xylazine is generally used as an adulterant in recreational drugs, with synthetic opioids, mainly fentanyl [146], as it allows the illicit production costs to be lowered without losing the euphoric effects of the adulterated compounds [146]. The attraction of the mixture for drug addicts is that the xylazine-doped fentanyl drugs extend the relatively short-lived \"high\" of fentanyl. The first signs of xylazine occurred when clients noticed an unidentified adulterant in the unregulated opioid supply that produced rapid, tranquilizer-like sedation that was unlike fentanyl. Initially, it was thought that the new substance \"was just good fentanyl\" that produced more intense sedative effects. However, clients then began experiencing a more rapid onset of withdrawal symptoms; then, necrotic wounds were also evidenced [147]. Between 2015 and 2020, the presence of xylazine in toxicology testing of fatal opioid overdoses in the U.S. was greatest in Philadelphia, Maryland, and Connecticut [148]. [PERSON] et al. (2021) [35] reported that 98% of the cases in which xylazine was detected in fatal opioid overdoses in the U.S. were fentanyl. Moreover, in Philadelphia, there is an increasing presence of xylazine in the local fentanyl/heroin drug market [149]. In addition, it may be combined with cocaine and methamphetamine and, more recently, with oxycodone and alprazolam [46]. [PERSON] 2022 [26] summarized several examples of drugs reported in co-presence with xylazine, which included analgesics (heroin, fentanyl, carfentanyl, codeine, morphine, butorphanol, methadone, phenacetin, stimulants (cocaine, methamphetamine, methylphenidate, caffeine), anesthetics (ketamine, combination of tiletamine and zolazepam, detomidine, lidocaine, phencyclidine), antiepileptic (phenytoin, pentobarbital), antipsychoticsh (haloperidol), antimalarials (quinine), benzodiazep (alprazolam, etizolam, clorazepate), antihistaminic drugs (diphenylhydramine, hydroxyazine), selective serotonin reuptake in  
\begin{table}
\begin{tabular}{l l l l} \hline
**Method of Detection** & **LOD** & **Sample** & **Ref.** \\ \hline Monoclonal-antibody-based lateral flow & 0.1 ng/mL & Milk & [128] \\ immunoassay & & & \\ \hline Colorimetric assay using molecularly & 1.36 mM * & Gin and tonic drinks & [129] \\ imprinted polymers & & & \\ \hline Enzyme-linked immunosorbent assay & 0.1 ng/mL ** & Oral fluid & [130] \\ \hline Portable electrochemical test strips & & & \\ based on Au/graphene & 0.02 ug/L & Raw milk & [131] \\ \hline Portable amperometric sensor with & \textasci{-1 ppm} * & Alcoholic and & [133] \\ anti-fouling properties & & Non-alcoholic beverages & [133] \\ \hline \end{tabular}  
* Results obtained in 20 s; ** Results obtained in 24 h.  
\end{table}
Table 2: _Cont._hibitors (citalopram), tetracyclic antidepressant (mirtazepine), calcium channel blockers (dilitiaem), non-steroidal anti-inflammatory drugs (ibuprofen and naproxen).