title: Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.
abstract: Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. 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. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Papathanasiou
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Rasmus Vestergaard
authors.initials: RV
authors.lastname: Juul
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Heegaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Trine Meldgaard
authors.initials: TM
authors.lastname: Lund
mesh_terms: D000588:Amines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010149:Postoperative Pain / Q000188:drug therapy*; D010812:Physical Stimulation; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine
keywords: Drug–drug interactions; Gabapentin; Loewe; Morphine; Postoperative pain; Synergy; Von Frey