Painful diabetic neuropathy is difficult to treat. Single
analgesics often have insufficient efficacy and poor tolerability. Combination
therapy may therefore be of particular benefit, because it might provide optimal
analgesia with fewer adverse effects. This study aimed to examine the type of interaction between
levetiracetam, a novel
anticonvulsant with
analgesic properties, and commonly used
analgesics (
ibuprofen,
aspirin and
paracetamol) in a mouse model of
painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of
streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered
levetiracetam,
analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical
hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis.
Levetiracetam (10-100 mg/kg),
ibuprofen (2-50 mg/kg),
aspirin (5-75 mg/kg),
paracetamol (5-100 mg/kg), and
levetiracetam-
analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of
levetiracetam with
aspirin/
ibuprofen, and
paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in
levetiracetam-
ibuprofen and
levetiracetam-
aspirin/
levetiracetam-
paracetamol combinations, respectively. These results show synergism between
levetiracetam and
ibuprofen/
aspirin/
paracetamol in a model of
painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from
painful diabetic neuropathy.