Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Center for Drug Evaluation and Research, Food and Drug Administration, United States Department of Health and Human Services, Silver Spring, MD, USA.
Drug Alcohol Depend. 2023 Feb 1;243:109740. doi: 10.1016/j.drugalcdep.2022.109740. Epub 2022 Dec 16.
The opioid epidemic remains one of the most pressing public health crises facing the United States. Fentanyl and related synthetic opioid agonists have largely driven the rising rates of associated overdose deaths, in part, because of their surreptitious use as substitutes for other opioids and as adulterants in psychostimulants. Deaths involving opioids typically result from lethal respiratory depression, and it is currently unknown how co-use of psychostimulants with opioids affects respiratory toxicity. Considering psychostimulant overdoses have increased over 3-fold since 2013, and half of those co-involved opioids, this is a cardinal question.
Naloxone, d-amphetamine (AMPH), and (±)-methamphetamine (METH) were evaluated for their effects on basal and fentanyl-depressed respiration. Minute volume (MVb) was measured in awake, freely moving mice via whole-body plethysmography to quantify fentanyl-induced respiratory depression and its modulation by dose ranges of each test drug.
Naloxone immediately reversed respiratory depression induced by fentanyl only at the highest dose tested (10 mg/kg). Both AMPH and METH exhibited bidirectional effects on MVb under basal conditions, producing significant (p ≤ 0.05) depressions then elevations of respiration as dose increased. Under depressed conditions the bidirectional effects of AMPH and METH on respiration were exaggerated, exacerbating and then reversing fentanyl-induced depression as dose increased.
These results indicate that co-use of amphetamines with fentanyl may worsen respiratory depression, but conversely, monoaminergic components of the amphetamines may possibly be exploited to mitigate fentanyl overdose.
阿片类药物泛滥仍是美国面临的最紧迫的公共卫生危机之一。芬太尼和相关的合成阿片类激动剂在很大程度上导致了与过量相关的死亡人数上升，部分原因是它们被秘密用作其他阿片类药物的替代品，以及作为苯丙胺类兴奋剂的掺杂物。涉及阿片类药物的死亡通常是由致命的呼吸抑制引起的，目前尚不清楚阿片类药物与苯丙胺类兴奋剂共同使用如何影响呼吸毒性。鉴于自 2013 年以来，苯丙胺类兴奋剂的过量使用增加了 3 倍以上，且其中一半涉及阿片类药物，这是一个关键问题。
评估纳洛酮、右旋苯丙胺（AMPH）和（±）-甲基苯丙胺（METH）对基础呼吸和芬太尼抑制呼吸的影响。通过全身 plethysmography 在清醒、自由活动的小鼠中测量分钟通气量（MVb），以量化芬太尼引起的呼吸抑制及其受每种测试药物剂量范围的调节。
纳洛酮仅在测试的最高剂量（10mg/kg）下立即逆转了芬太尼引起的呼吸抑制。在基础条件下，AMPH 和 METH 均表现出双向影响 MVb，随着剂量增加，呼吸产生显著（p≤0.05）的抑制，然后升高。在抑制条件下，AMPH 和 METH 对呼吸的双向作用被夸大，随着剂量增加，加剧并逆转了芬太尼引起的抑制。
这些结果表明，阿片类药物与苯丙胺类兴奋剂共同使用可能会加重呼吸抑制，但相反，苯丙胺类兴奋剂的单胺能成分可能被利用来减轻芬太尼过量。
