Theodoros Papathanasiou (1), Rasmus Vestergaard Juul (1), Anne-Marie Heegaard (1), Mads Kreilgaard (1,2), Trine Meldgaard Lund (1)
(1) Department of Drug Design and Pharmacology, University of Copenhagen, Denmark (2) Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
Objectives
Despite 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 dose combinations and investigate whether co-administration can lead to synergistic effects in a preclinical model of postoperative pain.
Methods
The 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 a rat plantar incision model 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.
Result
The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects. The synergistic combinations were 3+100, 7+10, 7+30 and 7+100 mg/kg for AUC and 1+100 and 3+100 mg/kg for %MPE. 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.
Conclusions
Combination of morphine and gabapentin resulted in dose-dependent synergistic antihyperalgesic effects in a preclinical model of postoperative pain. This finding highlight the theoretical advantage of using morphine and gabapentin in combination in order to minimize morphine related side effects and may encourage future clinical studies that will aim to clarify whether the synergistic interaction is present in post-operative pain in humans.
References:
[1] Brennan, T. J., Vandermeulen, E. P. & Gebhart, G. F. Characterization of a rat model of incisional pain. Pain 64, 493–501 (1996).
[2] Greco, W., Bravo, G. & Parsons, J. The search for synergy: A critical review from a responce surface perspective. Pharmacol. Rev. 47, 331-385 (1995).
[3] R Development Core Team, R. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing 1, 409 (2011).
Reference: PAGE 24 (2015) Abstr 3524 [www.page-meeting.org/?abstract=3524]
Poster: Drug/Disease modeling - CNS