Interacción sinérgica entre los dos mecanismos de de acción del tapentadol en analgesia
Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. Schröder W, Tzschentke TM, Terlinden R, De Vry J, Jahnel U, Christoph T, Tallarida RJ. Global Preclinical Research and Development, Department of Pharmacology, Grünenthal GmbH, Zieglerstrasse 6, 52078 Aachen, Germany. firstname.lastname@example.org J Pharmacol Exp Ther. 2011 Apr;337(1):312-20. Epub 2011 Jan 24. Abstract The novel centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the α(2)-adrenoceptor antagonist yohimbine. Two different pain models were used: 1) low-intensity tail-flick and 2) spinal nerve ligation. In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, NRI, and unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dose-dependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2- to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364495/?tool=pubmed http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364495/pdf/zpt312.pdf
Tapentadol de liberación rápida: una nueva opción de tratamiento en dolor agudo
Tapentadol immediate release: a new treatment option for acute pain management. Afilalo M, Stegmann JU, Upmalis D. Sir Mortimer B. Davis Jewish General Hospital, Montréal, Canada J Pain Res. 2010 Feb 8;3:1-9. Abstract The undertreatment of acute pain is common in many health care settings. Insufficient management of acute pain may lead to poor patient outcomes and potentially life-threatening complications. Opioids provide relief of moderate to severe acute pain; however, therapy with pure μ-opioid agonists is often limited by the prevalence of side effects, particularly opioid-induced nausea and vomiting. Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action, μ-opioid receptor agonism and norepinephrine reuptake inhibition. The analgesic effects of tapentadol are independent of metabolic activation and tapentadol has no active metabolites; therefore, in theory, tapentadol may be associated with a low potential for interindividual efficacy variations and drug-drug interactions. Previous phase 3 trials in patients with various types of moderate to severe acute pain have shown that tapentadol immediate release (IR; 50 to 100 mg every 4 to 6 hours) provides analgesia comparable to that provided by the pure μ-opioid agonist comparator, oxycodone HCl IR (10 or 15 mg every 4 to 6 hours), with a lower incidence of nausea, vomiting, and constipation. Findings suggest tapentadol may represent an improved treatment option for acute pain.