The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl's behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is not a noted fentanyl adulterant. Here we evaluated xylazine and lofexidine combined with self-administered fentanyl doses in male and female rats and evaluated fentanyl demand, body weight, and acute withdrawal. Consumption of fentanyl alone increased at various unit doses compared to saline. Xylazine but not lofexidine shifted fentanyl consumption downward at a number of unit doses, however, both lofexidine and xylazine suppressed fentanyl demand intensity as compared to a fentanyl alone control group. Further, both fentanyl + lofexidine and fentanyl + xylazine reduced behavioral signs of fentanyl withdrawal immediately following SA, but signs increased by 12 h only in the xylazine co-exposed group. Weight loss occurred throughout fentanyl SA and withdrawal regardless of group, although the xylazine group lost significantly more weight during the first 24 h of withdrawal than the other two groups. Severity of weight loss during the first 24 h of withdrawal was also correlated with severity of somatic signs of fentanyl withdrawal. Together, these results suggest that body weight loss may be an important indicator of withdrawal severity during acute withdrawal from the xylazine/fentanyl combination, warranting further translational evaluation.

中文翻译：

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赛拉嗪对大鼠芬太尼需求、体重和急性戒断的影响：与洛非西定的比较


阿片类药物的使用格局最近发生了变化，包括赛拉嗪（一种兽用麻醉剂）作为芬太尼供应中的掺杂剂。赛拉嗪作为一种新兴的芬太尼掺杂剂对健康的影响引起了人们对赛拉嗪作为公共卫生威胁的警觉，因此有必要研究赛拉嗪对芬太尼行为影响的影响。先前没有研究评估甲苯噻嗪对不同单位剂量芬太尼消耗量、芬太尼需求或戒断的影响，与美国食品和药物管理局批准的阿片类药物戒断药物洛非西定 (Lucemyra®) 相比。这一点很重要，因为洛非西定和赛拉嗪都是肾上腺素能 α2a (A2aR) 激动剂，但洛非西定并不是著名的芬太尼掺杂剂。在这里，我们评估了甲苯噻嗪和洛非西定与雄性和雌性大鼠自行给药的芬太尼剂量的组合，并评估了芬太尼的需求、体重和急性戒断。与生理盐水相比，不同单位剂量的单独芬太尼的消耗量有所增加。赛拉嗪而非洛非西定使芬太尼消耗量在多个单位剂量下下降，然而，与单独芬太尼对照组相比，洛非西定和赛拉嗪均抑制了芬太尼需求强度。此外，芬太尼+洛非西定和芬太尼+甲苯噻嗪均减少了SA后芬太尼戒断的行为症状，但仅在甲苯噻嗪共同暴露组中症状增加了12小时。无论哪组，在芬太尼 SA 和戒断过程中体重都会减轻，尽管甲苯噻嗪组在戒断后的前 24 小时内体重减轻明显多于其他两组。戒断后 24 小时内体重减轻的严重程度也与芬太尼戒断后躯体症状的严重程度相关。 总之，这些结果表明体重减轻可能是赛拉嗪/芬太尼组合急性戒断期间戒断严重程度的重要指标，需要进一步的转化评估。