Abstract
BackgroundThe 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− 1 followed by a 0.1 mg kg− 1 h− 1 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.ResultsPercentage 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− 1 and a terminal half-life of 2.4 h were detected and a clearance of 51.44 ml kg− 1 min− 1 was calculated. Effective methadone plasma concentrations for thermal and mechanical antinociception were above 17 ng ml− 1.ConclusionA methadone CRI of 0.1 mg kg− 1 h− 1 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.
Highlights
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
Nociceptive thresholds For Mechanical threshold (MT) only the data from six of seven dogs were included in the analysis due to technical problems with the measurements in one dog
A more frequent measurement of plasma levels after discontinuation of methadone CRI is recommended to exclude the possibility of underestimation of t0.5
Summary
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. Typical dose dependent adverse effects of μopioids have been described after IM or IV bolus injection of methadone in dogs. We hypothesized that dose dependent adverse effects could be reduced by administration via constant rate infusion (CRI), because thereby stable plasma levels can be achieved. The primary aim of this study was to evaluate a methadone CRI at a preset dose regarding its anti-nociceptive properties in an acute pain model and associated adverse effects. A secondary aim was to collect pharmacokinetic data of this methadone CRI and to establish methadone plasma levels, corresponding to an anti-nociceptive effect in healthy beagle dogs
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