TY - CONF

T1 - Response surface analysis of synergistic interactions of morphine and gabapentin in a rat model of postoperative pain.

AU - Papathanasiou, Theodoros

AU - Juul, Rasmus Vestergaard

AU - Heegaard, Anne-Marie

AU - Kreilgaard, Mads

AU - Lund, Trine Meldgaard

PY - 2015/10/19

Y1 - 2015/10/19

N2 - ObjectivesDespite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacologic interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of the two drugs in a wide range of combination doses and investigate whether co-administration can lead to synergistic effects in a preclinical model of postoperative pain.MethodsThe pharmacodynamic effects of morphine (1, 3 and 7 mg/kg), gabapentin (10, 30 and 100 mg/kg) or their combination (9 combinations of the above doses) were evaluated in the plantar incision model in the rat using an electronic von Frey device (1). The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for the evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on three-dimensional response surface analyses based on the concept of Loewe additivity (2). Modeling of the pharmacodynamic data was performed using R (3). All models were fitted with generalized least squares modeling using the “gnls” function from the “nlme” library. Model selection was based on the AIC criterion.ResultThe combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58 % for the synergistic doses.ConclusionsThe finding of dose-dependent synergistic interactions might indicate that there is a high potential for gabapentin and morphine to be used in combination in the clinic, in order to optimize postoperative pain management and minimize side effects of morphine.1. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain [Internet]. 1996 Mar;64(3):493–501. Available from: http://www.ncbi.nlm.nih.gov/pubmed/87833142. Greco W, Bravo G, Parsons J. The search for synergy: A critical review from a responce surface perspective. Pharmacol Rev [Internet]. 1995 [cited 2014 Nov 27]; Available from: http://intl.pharmrev.org/content/47/2/331.full.pdf+html3. R Development Core Team R. R: A Language and Environment for Statistical Computing [Internet]. R Foundation for Statistical Computing. 2011. p. 409. Available from: http://www.r-project.org

AB - ObjectivesDespite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacologic interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of the two drugs in a wide range of combination doses and investigate whether co-administration can lead to synergistic effects in a preclinical model of postoperative pain.MethodsThe pharmacodynamic effects of morphine (1, 3 and 7 mg/kg), gabapentin (10, 30 and 100 mg/kg) or their combination (9 combinations of the above doses) were evaluated in the plantar incision model in the rat using an electronic von Frey device (1). The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for the evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on three-dimensional response surface analyses based on the concept of Loewe additivity (2). Modeling of the pharmacodynamic data was performed using R (3). All models were fitted with generalized least squares modeling using the “gnls” function from the “nlme” library. Model selection was based on the AIC criterion.ResultThe combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58 % for the synergistic doses.ConclusionsThe finding of dose-dependent synergistic interactions might indicate that there is a high potential for gabapentin and morphine to be used in combination in the clinic, in order to optimize postoperative pain management and minimize side effects of morphine.1. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain [Internet]. 1996 Mar;64(3):493–501. Available from: http://www.ncbi.nlm.nih.gov/pubmed/87833142. Greco W, Bravo G, Parsons J. The search for synergy: A critical review from a responce surface perspective. Pharmacol Rev [Internet]. 1995 [cited 2014 Nov 27]; Available from: http://intl.pharmrev.org/content/47/2/331.full.pdf+html3. R Development Core Team R. R: A Language and Environment for Statistical Computing [Internet]. R Foundation for Statistical Computing. 2011. p. 409. Available from: http://www.r-project.org

UR - http://kliniskfarmakologi.dk/uf/90000_99999/93571/49ef2bf2ed06700685fd6bd153577911.pdf

M3 - Poster

T2 - DSFTM Annual Meeting 2015: Pharmacokinetics: Driving Research at the Interface between

Y2 - 19 October 2015 through 20 October 2015

ER -