title: Fentanyl-trazodone-paracetamol triple drug combination: multimodal analgesia in a mouse model of visceral pain.
abstract: Multimodal or balanced analgesia is commonly used in the management of acute and chronic pain in humans, in order to achieve the best analgesic/safety profile. Here, by using a model of visceral acute tonic pain, the acetic acid-induced writhing test of mice, we show a synergistic interaction between fentanyl, trazodone and paracetamol on the inhibition of nociception. First of all, once assessed that all drugs induced dose-related antinociceptive effects, they were mixed in fixed ratio (1:1) combinations and a synergistic drug-drug interaction was obtained in all circumstances. Thereafter, we assayed the effects of the triple combination of fentanyl-trazodone-paracetamol and it was demonstrated that they displayed a potent synergistic interaction on the inhibition of acetic acid-mediated nociception. Interestingly, drug dosage reduction permitted to reduce the incidence of possible adverse effects, namely exploratory activity and motor coordination, thus it was demonstrated that it improved the benefit/risk profile of such treatment. Afterwards, we attempted to elucidate the mechanism of action of such interaction, by means of the non-selective opioid receptor antagonist naloxone. Interestingly, naloxone completely antagonized the antinociceptive effects of fentanyl, and it also partially reversed paracetamol and trazodone mediated analgesia. Furthermore, when naloxone was co-administered with the triple-drug treatment it blocked the previously observed enhanced antinociceptive effects of the combination. Thus, these results indicated that the endogenous opioid system played a main role in the present drug-drug interaction. Overall, the triple combination of fentanyl-trazodone-paracetamol induced a potent synergistic antinociceptive effect, which could be of interest for optimal multimodal clinical analgesia.
authors.affiliation: Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain. vfernandez@ub.edu
authors.forename: Víctor
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.forename: Raquel
authors.initials: R
authors.lastname: Poveda
authors.forename: Alejandro
authors.initials: A
authors.lastname: Fernández
authors.forename: Sílvia
authors.initials: S
authors.lastname: Sánchez
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Planas
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage*; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004338:Drug Combinations; D005283:Fentanyl / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D045442:Rotarod Performance Test; D014196:Trazodone / Q000008:administration & dosage*
chemical_list: D000700:Analgesics; D004338:Drug Combinations; D000082:Acetaminophen; D005283:Fentanyl; D014196:Trazodone