Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, Bünteweg 9, 30559, Hannover, Germany.
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559, Hannover, Germany.
BMC Vet Res. 2021 Jan 18;17(1):35. doi: 10.1186/s12917-020-02735-3.
The present study aimed to collect pharmacokinetic data of a methadone continuous rate infusion (CRI) and to investigate its effect on mechanical and thermal nociceptive thresholds. Seven, 47 to 54 months old beagle dogs, weighing 9.8 to 21.2 kg, were used in this experimental, randomized, blinded, placebo-controlled crossover study. Each dog was treated twice with either a methadone bolus of 0.2 mg kg followed by a 0.1 mg kg h methadone CRI (group M) or an equivalent volume of isotonic saline solution (group P) for 72 h. Mechanical and thermal thresholds, as well as vital parameters and sedation were measured during CRI and for further 24 h. Blood samples for methadone plasma concentrations were collected during this 96 h period.
Percentage thermal excursion (%TE) increased significantly from baseline (BL) until 3 h after discontinuation of CRI in M. Within P and between treatment groups differences were not significant. Mechanical threshold (MT) increased in M until 2 h after CRI discontinuation. Bradycardia and hypothermia occurred in M during drug administration and dogs were mildly sedated for the first 47 h. Decreased food intake and regurgitation were observed in M in five and four dogs, respectively. For methadone a volume of distribution of 10.26 l kg and a terminal half-life of 2.4 h were detected and a clearance of 51.44 ml kg min was calculated. Effective methadone plasma concentrations for thermal and mechanical antinociception were above 17 ng ml.
A methadone CRI of 0.1 mg kg h for 3 days after a loading dose results in steady anti-nociceptive effects in an acute pain model in healthy dogs. Main side effects were related to gastrointestinal tract, hypothermia, bradycardia and sedation.
本研究旨在收集美沙酮持续输注（CRI）的药代动力学数据，并研究其对机械和热痛觉阈值的影响。在这项实验性、随机、双盲、安慰剂对照交叉研究中，使用了 7 只 47 至 54 月龄、体重 9.8 至 21.2kg 的比格犬。每只狗都接受两次治疗，一次是 0.2mg/kg 的美沙酮推注，随后是 0.1mg/kg/h 的美沙酮 CRI（M 组），或等量的等渗生理盐水溶液（P 组），持续 72 小时。在 CRI 期间以及之后的 24 小时测量机械和热阈值以及生命参数和镇静。在 96 小时期间采集用于美沙酮血浆浓度的血样。
与基线（BL）相比，M 组在 CRI 停止后 3 小时内 %TE 显著增加。P 组和治疗组之间没有显著差异。M 组在 CRI 停止后 2 小时内 MT 增加。在药物治疗期间，M 组出现心动过缓和体温过低，并且狗在前 47 小时内轻度镇静。在 M 组中，观察到五只狗的食物摄入量减少和四只狗的呕吐。对于美沙酮，检测到分布容积为 10.26l/kg，半衰期为 2.4 小时，清除率为 51.44ml/kg/min。用于热和机械镇痛的有效美沙酮血浆浓度高于 17ng/ml。
在健康犬急性疼痛模型中，负荷剂量后 3 天每天输注 0.1mg/kg/h 的美沙酮 CRI 可产生稳定的镇痛作用。主要副作用与胃肠道、体温过低、心动过缓和镇静有关。
