title: Levetiracetam synergises with common analgesics in producing antinociception in a mouse model of painful diabetic neuropathy.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia. Electronic address: anamicov@pharmacy.bg.ac.rs.
authors.forename: Ana
authors.initials: A
authors.lastname: Micov
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia. Electronic address: majat@pharmacy.bg.ac.rs.
authors.forename: Maja
authors.initials: M
authors.lastname: Tomić
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia. Electronic address: upecikoza@gmail.com.
authors.forename: Uroš
authors.initials: U
authors.lastname: Pecikoza
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia. Electronic address: unprof@ufar.co.rs.
authors.forename: Nenad
authors.initials: N
authors.lastname: Ugrešić
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia. Electronic address: racabbr@eunet.rs.
authors.forename: Radica
authors.initials: R
authors.lastname: Stepanović-Petrović
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D003929:Diabetic Neuropathies / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006358:Hot Temperature; D007052:Ibuprofen / Q000627:therapeutic use; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects
chemical_list: D000700:Analgesics; D000082:Acetaminophen; D000077287:Levetiracetam; D001241:Aspirin; D007052:Ibuprofen; D010889:Piracetam
keywords: Acetylsalicylic acid (PubChem CID: 2244); Aspirin; Diabetic neuropathy; Ibuprofen; Ibuprofen (PubChem CID: 3672); Levetiracetam; Levetiracetam (PubChem CID: 5284583); Paracetamol; Paracetamol (PubChem CID: 1983); Streptozotocin (PubChem CID: 29327); Synergism