title: Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit.
abstract: BACKGROUND
  A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation). The present study investigated the nature of interaction of the two mechanisms on a surrogate measure for gastrointestinal adverse effect (inhibition of gastrointestinal transit).
  
  
  METHODS
  Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid receptor antagonist, naloxone, or the α2 -adrenoceptor antagonist, yohimbine, to reveal the effect of tapentadol based upon MOR agonism, NRI, and combined mechanisms.
  
  
  RESULTS
  The dose-effect curve of tapentadol was shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Analysis revealed a simple additive interaction between the two mechanisms on this endpoint, in contrast to the synergistic interaction previously demonstrated for antinociception.
  
  
  CONCLUSIONS
  We believe this is the first published evaluation of mechanistic interaction for a surrogate measure of adverse effect of a single compound with two mechanisms of action, and the results suggest that there is a greater separation between the analgesic and gastrointestinal effects of tapentadol than expected based upon its analgesic efficacy.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine and Center for Substance Abuse Research, Philadelphia, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cowan
authors.forename: R B
authors.initials: RB
authors.lastname: Raffa
authors.forename: C S
authors.initials: CS
authors.lastname: Tallarida
authors.forename: R J
authors.initials: RJ
authors.lastname: Tallarida
authors.forename: T
authors.initials: T
authors.lastname: Christoph
authors.forename: W
authors.initials: W
authors.lastname: Schröder
authors.forename: T M
authors.initials: TM
authors.lastname: Tzschentke
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005772:Gastrointestinal Transit / Q000187:drug effects*; D008297:Male; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010636:Phenols / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D000077432:Tapentadol; D015016:Yohimbine / Q000008:administration & dosage
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010636:Phenols; D017450:Receptors, Opioid, mu; D015016:Yohimbine; D009270:Naloxone; D000077432:Tapentadol