SYNERGISTIC INTERACTION BETWEEN TAPENTADOL AND FLUPIRTINE IN THE RAT ORAFACIAL FORMALIN TEST

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.