title: Synergistic antihypersensitive effects of pregabalin and tapentadol in a rat model of neuropathic pain.
abstract: Neuropathic pain is a clinical condition which remains poorly treated and combinations of pregabalin, an antagonist of the α2δ-subunit of Ca(2+) channels, with tapentadol, a μ-opioid receptor agonist/noradrenaline reuptake inhibitor, or with classical opioids such as oxycodone and morphine might offer increased therapeutic potential. In the rat spinal nerve ligation model, a dose dependent increase in ipsilateral paw withdrawal thresholds was obtained using an electronic von Frey filament after IV administration of pregabalin (1-10mg/kg), tapentadol (0.316-10mg/kg), morphine (1-4.64 mg/kg) and oxycodone (0.316-3.16 mg/kg), with ED(50) values (maximal efficacy) of 4.21 (67%), 1.65 (94%), 1.70 (96%) and 0.63 mg/kg (100%), respectively. Equianalgesic dose combinations of pregabalin and tapentadol (dose ratio 2.5:1), morphine (2.5:1) or oxycodone (6.5:1) resulted in ED(50) values (maximal efficacy) of 0.83 (89%), 2.33 (97%) and 1.14 mg/kg (100%), respectively. The concept of dose-equivalence suggested an additive interaction of pregabalin and either oxycodone or morphine, while a synergistic interaction was obtained with pregabalin and tapentadol (demonstrated by isobolographic analysis). There was no increase in contralateral paw withdrawal thresholds and no locomotor impairment, as measured in the open field, for the combination of pregabalin and tapentadol; while a significant increase and impairment was demonstrated for the combinations of pregabalin and either morphine or oxycodone. Because combination of pregabalin and tapentadol resulted in a synergistic antihypersensitive activity, it is suggested that, beside the use of either drug alone, this drug combination may offer a beneficial treatment option for neuropathic pain.
authors.affiliation: Grünenthal GmbH, Global Preclinical Research and Development, Department of Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany. thomas.christoph@grunenthal.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
authors.forename: Jean
authors.initials: J
authors.lastname: De Vry
authors.forename: Klaus
authors.initials: K
authors.lastname: Schiene
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Tallarida
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D008026:Ligation; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D010098:Oxycodone / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D010636:Phenols / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000069583:Pregabalin; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000187:drug effects / Q000503:physiopathology / Q000601:surgery; D000077432:Tapentadol; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D010636:Phenols; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D010098:Oxycodone; D000077432:Tapentadol