Plasma levels of a methadone constant rate infusion and their corresponding effects on thermal and mechanical nociceptive thresholds in dogs

Abstract

Background 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\u2009months old beagle dogs, weighing 9.8 to 21.2\u2009kg, were used in this experimental, randomized, blinded, placebo-controlled crossover study. Each dog was treated twice with either a methadone bolus of 0.2\u2009mg\u2009kg −\u20091 followed by a 0.1\u2009mg\u2009kg −\u20091 \u2009h −\u20091 methadone CRI (group M) or an equivalent volume of isotonic saline solution (group P) for 72\u2009h. Mechanical and thermal thresholds, as well as vital parameters and sedation were measured during CRI and for further 24\u2009h. Blood samples for methadone plasma concentrations were collected during this 96\u2009h period. Results Percentage thermal excursion (%TE) increased significantly from baseline (BL) until 3\u2009h after discontinuation of CRI in M. Within P and between treatment groups differences were not significant. Mechanical threshold (MT) increased in M until 2\u2009h after CRI discontinuation. Bradycardia and hypothermia occurred in M during drug administration and dogs were mildly sedated for the first 47\u2009h. Decreased food intake and regurgitation were observed in M in five and four dogs, respectively. For methadone a volume of distribution of 10.26\u2009l\u2009kg −\u20091 and a terminal half-life of 2.4\u2009h were detected and a clearance of 51.44\u2009ml\u2009kg −\u20091 \u2009min −\u20091 was calculated. Effective methadone plasma concentrations for thermal and mechanical antinociception were above 17\u2009ng\u2009ml −\u20091 . Conclusion A methadone CRI of 0.1\u2009mg\u2009kg −\u20091 \u2009h −\u20091 for 3\u2009days 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.