Letter to the Editor—Response to “Opioid-related xylazine toxicity manifesting as myonecrosis, rhabdomyolysis, multifocal ischemic cerebral infarcts, and cerebral edema”

To the Editors,

We commend the authors on their presentation of “Opioid-related xylazine toxicity manifesting as myonecrosis, rhabdomyolysis, multifocal ischemic cerebral infarcts, and cerebral edema”.¹

However, we have significant concerns regarding their attribution of the adverse effects to xylazine. The case description is identical to that of a hypoxic, multiorgan system insult resulting from an opioid overdose, including liver injury, rhabdomyolysis, and cerebral infarcts. While the authors appropriately note that the unregulated fentanyl supply is increasingly adulterated with xylazine, “xylazine overdose” is currently always a xylazine–fentanyl overdose.² Therefore, the contribution of fentanyl in overdose victims cannot be overlooked or underestimated, and especially given hearing loss, it is far more likely that the patient's injuries were due to fentanyl.³

The authors hypothesize that xylazine toxicity resulted in hemodynamic changes that contributed to microvascular constriction and infarcts. They cite animal studies or case studies of intentional xylazine overdose, which are not clinically analogous to human exposure to fentanyl adulterated with xylazine. Interestingly, patients with consequential xylazine-adulterated fentanyl exposures may be relatively hemodynamically stable. In a study of patients with such overdoses in whom xylazine was detected, there was no increase in the incidence or degree of bradycardia, coma, or need for ventilatory support.⁴ In fact, xylazine-exposed patients had lower rates of cardiopulmonary arrest. A potential explanation for this finding is that due to the addition of xylazine to the street product, they were exposed to less fentanyl overall.

The authors rely on urine drug screen (UDS) results to support that xylazine is the cause of the patient's presentation. Fentanyl and xylazine were detected on the UDS; however, there was no quantitative measurement of either fentanyl or xylazine to explain their relative contributions to the outcome. Regardless, because the detection window of a xylazine UDS is not known, it is not possible to know the time of last use or the temporal relationship between xylazine-adulterated fentanyl use and the development of clinical effects. There may be utility in adding xylazine to a UDS for epidemiological or research purposes or for educating patients on the contents of the unregulated drug supply, but there is no clear clinical utility for the management of patients with acute drug intoxication. Furthermore, the xylazine UDS may lead to premature diagnostic closure with a time-sensitive conditions, such as altered mental status.⁵ Although the emergence of xylazine in the unregulated drug supply is a public health concern, it should not distract from the fact that fentanyl is the major contributor to drug overdose deaths and that ventilatory support and naloxone remain the treatments of choice.

The authors declare they have no conflicts of interest.

The authors received no specific funding for this work.