title: Isobolographic analysis of multimodal analgesia in an animal model of visceral acute pain.
abstract: Multiple analgesic-drug combinations are commonly used in the management of acute and chronic pain in humans during multimodal or balanced analgesia. At present, these combinations are used empirically in clinical practice and are considered to be beneficial for the patient. Interactions between two antinociceptive drugs have been thoroughly examined, but the nature of interactions between three analgesics has not been studied. The antinociceptive interaction of ketoprofen (K) with a mixture of morphine (M) and paracetamol (P) was evaluated using a model of visceral acute tonic pain, the acetic-acid writhing test in mice. The i.p. administration of the combination M/P+K resulted in a significant potentiation of the antinociception induced either by K or by the synergic two-drug mixtures M/K, P/K and M/P. The effect of opioid, cholinergic, adrenergic and serotonergic antagonists on the analgesic interaction was assessed. The pretreatment of mice with atropine (1 mg/kg) did not produce any change in the synergistic interaction of the triple combination. The pretreatment with naltrexone (1 mg/kg) or tropisetron (1 mg/kg) reduced the intensity of M/P+K synergic interaction, while prazosin (0.1 mg/kg) significantly potentiated the synergy. The findings of this work suggest that the two major pathways of descending inhibitory systems, noradrenergic and serotonergic are significantly involved in the mechanism of the antinociceptive synergy induced by the triple combination. On the other hand, opioid pathways also seem to participate, since pretreatment with naltrexone reduced the synergy. In conclusion, the triple combination M/P+K induced a strong synergistic antinociceptive effect, which could be of interest for optimal multimodal clinical analgesia.
authors.affiliation: Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Clasificador 70.000, Santiago 7, Chile.
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Miranda
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Prieto
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Puig
authors.forename: Gianni
authors.initials: G
authors.lastname: Pinardi
mesh_terms: D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000208:Acute Disease; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D007660:Ketoprofen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D011224:Prazosin / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D018727:Muscarinic Antagonists; D009292:Narcotic Antagonists; D000082:Acetaminophen; D009271:Naltrexone; D009020:Morphine; D001285:Atropine; D007660:Ketoprofen; D011224:Prazosin