INTRODUCTION Combination therapy with two or more analgesics is widely used for conditions associated with moderate to severe pain. Combinations of diverse analgesics with different modes of action can improve the risk-benefit ratio of analgesic treatments. Tapentadol (TAP) is an atypical opioid with dual mechanisms of action; it is a l-opioid receptor (MOR) agonist and acts to inhibit norepinephrine (NE) reuptake1. Flupirtine (FLP) is a centrally acting non-opioid analgesic, without antipyretic or anti-inflammatory effects2. It inhibits the N-methyl-D-aspartate (NMDA) receptor indirectly. Molecules that inhibit the NMDA receptor are likely to have synergistic or additive effects with other analgesics, particularly opioids. The aim of this study is to evaluate the antinociceptive effect of tapentadol (TAP) and flupirtine (FLP), when administered separately or in combination, as well as their synergistic interaction in the orofacial formalin test in rats. MATERIALS AND METHODS The orofacial formalin test in rats was used in this study. Fifty microliter of 2.5% formalin solution was injected subcutaneously into the right upper lip. Thereafter the behavior (face rubbing) of the rats was recorded for 45 min. The degree of nociception was assessed as the area under the time course of response (face rubbing) curve (AUC). The isobologram was constructed by connecting the ED30 of the FLP plotted on the abscissa with the ED30 of TAP plotted on the ordinate to obtain the additive line. RESULTS AND CONCLUSIONS After IP injection of TAP at different doses (2, 5, 10 and 15 mg kg 1), the biphasic nociceptive behavior was reduced in a dose-dependent manner in both phase I and II. Conversely, IP injection of FLP at different doses (0.6, 1.6, 3.3, 6.6, 16.6 and 22.2 mg kg 1) induced a dose-dependent antinociceptive effect in phase II only. TAP was found to be more potent and effective than FLP. The interaction between TAP and FLP was synergistic in phase II with an interaction index (c) of 0.50 0.24. The data reported in this study indicate that FLP enhances the anti-nociceptive effect of TAP and this drug combination might be useful in the treatment of chronic pain.
SYNERGISTIC INTERACTION BETWEEN TAPENTADOL AND FLUPIRTINE IN THE RAT ORAFACIAL FORMALIN TEST
DE VITO, VIRGINIA;GIORGI, MARIO
2015-01-01
Abstract
INTRODUCTION Combination therapy with two or more analgesics is widely used for conditions associated with moderate to severe pain. Combinations of diverse analgesics with different modes of action can improve the risk-benefit ratio of analgesic treatments. Tapentadol (TAP) is an atypical opioid with dual mechanisms of action; it is a l-opioid receptor (MOR) agonist and acts to inhibit norepinephrine (NE) reuptake1. Flupirtine (FLP) is a centrally acting non-opioid analgesic, without antipyretic or anti-inflammatory effects2. It inhibits the N-methyl-D-aspartate (NMDA) receptor indirectly. Molecules that inhibit the NMDA receptor are likely to have synergistic or additive effects with other analgesics, particularly opioids. The aim of this study is to evaluate the antinociceptive effect of tapentadol (TAP) and flupirtine (FLP), when administered separately or in combination, as well as their synergistic interaction in the orofacial formalin test in rats. MATERIALS AND METHODS The orofacial formalin test in rats was used in this study. Fifty microliter of 2.5% formalin solution was injected subcutaneously into the right upper lip. Thereafter the behavior (face rubbing) of the rats was recorded for 45 min. The degree of nociception was assessed as the area under the time course of response (face rubbing) curve (AUC). The isobologram was constructed by connecting the ED30 of the FLP plotted on the abscissa with the ED30 of TAP plotted on the ordinate to obtain the additive line. RESULTS AND CONCLUSIONS After IP injection of TAP at different doses (2, 5, 10 and 15 mg kg 1), the biphasic nociceptive behavior was reduced in a dose-dependent manner in both phase I and II. Conversely, IP injection of FLP at different doses (0.6, 1.6, 3.3, 6.6, 16.6 and 22.2 mg kg 1) induced a dose-dependent antinociceptive effect in phase II only. TAP was found to be more potent and effective than FLP. The interaction between TAP and FLP was synergistic in phase II with an interaction index (c) of 0.50 0.24. The data reported in this study indicate that FLP enhances the anti-nociceptive effect of TAP and this drug combination might be useful in the treatment of chronic pain.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
