Pregabalin enhances the antinociceptive effect of oxycodone and morphine in thermal models of nociception in the rat without any pharmacokinetic interactions

Background Oxycodone is increasingly being used in combination with pregabalin. Pregabalin use is prevalent in opioid‐dependent individuals. A high number of deaths caused by the co‐use of gabapentinoids and opioids occur. It is not known whether pregabalin affects concentrations of oxycodone or morphine in the central nervous system. Methods Effects of pregabalin on acute oxycodone or morphine‐induced antinociception, tolerance and sedation were studied using tail‐flick, hot plate and rotarod tests in male Sprague–Dawley rats. Concentrations of pregabalin, opioids and their major metabolites in the brain were quantified by mass spectrometry. Results In the hot plate test, morphine (2.5 mg/kg, s.c.) caused antinociception of 28% maximum possible effect (MPE), whereas pregabalin (50 mg/kg, i.p.) produced 8–10% MPE. Co‐administration of pregabalin and morphine resulted in antinociception of 63% MPE. Oxycodone (0.6 mg/kg s.c.) produced antinociception of 18% MPE, which increased to 39% MPE after co‐administration with pregabalin. When pregabalin 10 mg/kg was administered before oxycodone (0.6 mg/kg, s.c.) or morphine (2.5 mg/kg), only the effect of oxycodone was potentiated in the tail‐flick and the hot plate tests. Brain concentrations of the opioids, their major metabolites and pregabalin were unchanged. Pregabalin co‐administration (50 mg/kg, i.p., once daily) did not prevent the development of morphine tolerance. Conclusions Pregabalin potentiated antinociceptive and sedative effects of oxycodone and morphine in acute nociception. Co‐administration of pregabalin with the opioids did not affect the brain concentrations of oxycodone or morphine. Pregabalin did not prevent morphine tolerance.