• DOI:10.1093/bja/aet234
• Corpus ID: 4848640

Enhanced antinociceptive efficacy of epidural compared with i.v. methadone in a rat model of thermal nociception.

@article{Haroutiunian2014EnhancedAE,
  title={Enhanced antinociceptive efficacy of epidural compared with i.v. methadone in a rat model of thermal nociception.},
  author={Simon Haroutiunian and Leonid Kagan and I Yifrach-Damari and Elyad M. Davidson and Yael Ratz and A Hoffman},
  journal={British journal of anaesthesia},
  year={2014},
  volume={112 1},
  pages={
          150-8
        }
}

• S. Haroutiunian, L. Kagan, +3 authors A. Hoffman
• Published 2014
• Medicine, Biology
• British journal of anaesthesia

BACKGROUND
The properties of methadone suggest a potential advantage for epidural over i.v. administration for pain relief, but little supportive evidence exists.

METHODS
To investigate the pharmacokinetic and the pharmacodynamic properties of epidural and i.v. methadone, four doses of methadone (0.1, 0.25, 0.5, and 0.75 mg kg(-1)) were investigated by each route in a rat model. The tail-flick and hot water tail immersion test were used for thermal nociception. The magnitude of antinociceptive efficacy was expressed as per cent maximal possible effect (%MPE) of tail withdrawal latency, and the area under the %MPE vs time curve indicated the cumulative antinociceptive effect. A pharmacokinetic model describing the disposition and elimination of methadone was established.

RESULTS
The pharmacokinetic profiles of methadone were not significantly different after epidural and i.v. administration. A two-compartment model with saturable elimination provided a good fit of the experimental data. At equivalent doses, epidural methadone produced higher cumulative antinociceptive effect in both thermal models. Supraspinal opioid effect, assessed by pinna reflex presence, was significantly lower with epidural methadone at equivalent doses. The duration of antinociceptive effect was longer with epidural administration of 0.5 and 0.75 mg kg(-1) doses.

CONCLUSIONS
Epidural administration of methadone in rats resulted in systemic exposure similar to that after i.v. administration, but improved thermal antinociceptive efficacy, and reduced supraspinal undesired effects. The findings suggest the presence of local effect at the spinal cord level, in addition to the systemic effect produced by epidural methadone.