Xu Deli, Kuai Lixin, Chen Yuanyuan, Zeng Xianbin, Wang Dan, Di Bin, Xu Peng
School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing, 100193, China.
Psychopharmacology (Berl). 2025 Jan;242(1):205-214. doi: 10.1007/s00213-024-06664-z. Epub 2024 Aug 7.
Isobutyryl-carfentanyl is the most recently discovered fentanyl analogue with a chemical structure that is similar to that of carfentanyl. Its analogue, carfentanyl, is regarded as one of the most lethal drugs in the world, with a potency of 10,000 times that of morphine. Therefore, isobutyryl-carfentanyl may possess a comparably high potency and its harmful effects cannot be ignored.
This study was designed to assess the analgesic effect of isobutyryl-carfentanyl and the potential risks associated with its misuse.
In this study, we assessed the acute toxicity of isobutyryl-carfentanyl by up-and-down-procedure, the analgesic efficacy by hot-plate test, the abuse potential by conditioned place preference (CPP), drug self-administration, and drug discrimination tests, and compared it with fentanyl and carfentanyl.
The estimated median lethal dose (LD) of isobutyryl-carfentanyl administered were 175 mg/kg (intragastric administration, IG), 15.84 mg/kg (intraperitoneal injection, IP), 15.84 mg/kg (subcutaneous injection, SC), and 1.6 mg/kg (intravenous injection, IV), respectively. The 50% maximal analgesic effect (ED) of isobutyryl-carfentanyl was determined to be 0.00319 mg/kg, with an analgesic potency 14 times that of fentanyl and 0.82 times that of carfentanyl. Isobutyryl-carfentanyl exhibited a significant positional preference at a minimum dose of 0.1 mg/kg, while fentanyl exhibited a significant positional preference at a minimum dose of 0.3 mg/kg. In the heroin (0.05 mg/kg/infusion) self-administration substitution experiment, isobutyryl-carfentanyl showed significant self-administration behaviour at doses of 0.0005-0.001 mg/kg/infusion, with the maximum number of infusions observed at a dose of 0.001 mg/kg. In the heroin (1 mg/kg) drug discrimination experiment, fentanyl (0.005-0.02 mg/kg), carfentanyl (0.0005-0.002 mg/kg), and isobutyryl-carfentanyl (0.001-0.005 mg/kg) were tested in the dose-effect curves. The results showed that all three drugs exhibit dose-dependent increase in the number of drug-associated nose pokes responses and reduction in the rate of nose pokes. The subjective effect potency of isobutyryl-carfentanyl was found to be 4.4 times that of fentanyl and 0.5 times that of carfentanyl.
In summary, isobutyryl-carfentanyl has high acute toxicity and analgesic effect, with strong psychological dependence approximately 5 times that of fentanyl and 0.5 times that of carfentanyl, and has extremely high abuse potency.
异丁酰卡芬太尼是最近发现的一种芬太尼类似物，其化学结构与卡芬太尼相似。其类似物卡芬太尼被认为是世界上最致命的毒品之一，效力是吗啡的10000倍。因此，异丁酰卡芬太尼可能具有相当高的效力，其有害影响不容忽视。
本研究旨在评估异丁酰卡芬太尼的镇痛效果及其滥用相关的潜在风险。
在本研究中，我们通过上下法评估异丁酰卡芬太尼的急性毒性，通过热板试验评估镇痛效果，通过条件性位置偏爱（CPP）、药物自我给药和药物辨别试验评估滥用潜力，并将其与芬太尼和卡芬太尼进行比较。
经口给予异丁酰卡芬太尼的估计半数致死剂量（LD）分别为175mg/kg（灌胃，IG）、15.84mg/kg（腹腔注射，IP）、15.84mg/kg（皮下注射，SC）和1.6mg/kg（静脉注射，IV）。异丁酰卡芬太尼的50%最大镇痛效应（ED）被确定为0.00319mg/kg，镇痛效力是芬太尼的14倍，是卡芬太尼的0.82倍。异丁酰卡芬太尼在最低剂量0.1mg/kg时表现出显著的位置偏爱，而芬太尼在最低剂量0.3mg/kg时表现出显著的位置偏爱。在海洛因（0.05mg/kg/输注）自我给药替代试验中，异丁酰卡芬太尼在剂量为0.0005 - 0.001mg/kg/输注时表现出显著的自我给药行为，在剂量为0.001mg/kg时观察到最大输注次数。在海洛因（1mg/kg）药物辨别试验中，对芬太尼（0.005 - 0.02mg/kg）、卡芬太尼（0.0005 - 0.002mg/kg）和异丁酰卡芬太尼（0.001 - 0.005mg/kg）进行剂量 - 效应曲线测试。结果表明，所有三种药物均表现出与药物相关的鼻触反应次数呈剂量依赖性增加，鼻触速率降低。发现异丁酰卡芬太尼的主观效应效力是芬太尼的4.4倍，是卡芬太尼的0.5倍。
总之，异丁酰卡芬太尼具有高急性毒性和镇痛效果，心理依赖性强，约为芬太尼的5倍，卡芬太尼的0.5倍，具有极高的滥用潜力。
