Levetiracetam synergizes with gabapentin, pregabalin, duloxetine and selected antioxidants in a mouse diabetic painful neuropathy model
We have reported that levetiracetam, a novel anticonvulsant with analgesic properties, synergizes with ibuprofen/aspirin/paracetamol in a model of diabetic painful neuropathy (DPN). Most guidelines recommend gabapentin, pregabalin, and duloxetine as first- or second-line agents for DPN.
We examined the effects of combination treatment of first-/second-line analgesics with levetiracetam in a model of DPN. Additionally, the levetiracetam’s combinations with antioxidants, low dose of aspirin, coenzyme Q10, or α-lipoic acid were evaluated.
Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin. The antinociceptive effects of orally administered levetiracetam, gabapentin, pregabalin, duloxetine (acute treatment) and aspirin, coenzyme Q10, and α-lipoic acid (preventive 7-day treatment), as well as combinations of levetiracetam with individual drugs were examined in the tail-flick test. In combination experiments, the drugs were coadministered in fixed-dose fractions of single-drug ED50; the type of interaction was determined by isobolographic analysis.
About 60-, 32-, 30-, 26-, 18-, and 6-fold reductions of doses of both drugs in levetiracetam combinations with pregabalin, gabapentin, coenzyme Q10, aspirin, duloxetine, and α-lipoic acid, respectively, were detected.
Combinations of levetiracetam with gabapentin/pregabalin/duloxetine that target different mechanisms/sites of action involved in DPN, as well as combinations of levetiracetam and low-dose aspirin/coenzyme Q10/α-lipoic acid that target underlying causes of DPN, produce marked synergistic interactions in reducing nociception in diabetic mice. This suggests that these combination treatments might be of great benefit for diabetic patients and should be explored further in clinical trials.
KeywordsLevetiracetam Gabapentinoids Duloxetine Antioxidants Synergism Diabetic painful neuropathy
- Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T (2010) European Federation of Neurological Societies: EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 17:1113–1e88. doi:10.1111/j.1468-1331.2010.02999.x CrossRefPubMedGoogle Scholar
- Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E (1998) Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 280:1831–1836. doi:10.1001/jama.280.21.1831 CrossRefPubMedGoogle Scholar
- Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, Feldman E, Iverson DJ, Perkins B, Russell JW, Zochodne D (2011) American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation: evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 76:1758–1765. doi:10.1212/WNL.0b013e3182166ebe CrossRefPubMedPubMedCentralGoogle Scholar
- Bulckaen H, Prévost G, Boulanger E, Robitaille G, Roquet V, Gaxatte C, Garçon G, Corman B, Gosset P, Shirali P, Creusy C, Puisieux F (2008) Low-dose aspirin prevents age-related endothelial dysfunction in a mouse model of physiological aging. Am J Physiol Heart Circ Physiol 294:H1562–H1570. doi:10.1152/ajpheart.00241.2007 CrossRefPubMedGoogle Scholar
- Garcia-Alcala H, Santos Vichido CI, Islas Macedo S, Genestier-Tamborero CN, Minutti-Palacios M, Hirales Tamez O, García C, Ziegler D (2015) Treatment with α-lipoic acid over 16 weeks in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose loading. J Diabetes Res 2015:189857. doi:10.1155/2015/189857 CrossRefPubMedPubMedCentralGoogle Scholar
- Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey B (2005) Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manag 30:374–385. doi:10.1016/j.jpainsymman.2005.04.009 CrossRefGoogle Scholar
- Lee WY, Orestes P, Latham J, Naik AK, Nelson MT, Vitko I, Perez-Reyes E, Jevtovic-Todorovic V, Todorovic SM (2009) Molecular mechanisms of lipoic acid modulation of T-type calcium channels in pain pathway. J Neurosci 29:9500–9509. doi:10.1523/JNEUROSCI.5803-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
- Mezawa M, Takemoto M, Onishi S, Ishibashi R, Ishikawa T, Yamaga M, Fujimoto M, Okabe E, He P, Kobayashi K, Yokote K (2012) The reduced form of coenzyme Q10 improves glycemic control in patients with type 2 diabetes: an open label pilot study. Biofactors 38:416–421. doi:10.1002/biof.1038 CrossRefPubMedGoogle Scholar
- Stepanović-Petrović RM, Micov AM, Tomić MA, Kovačević JM, Bošković BD (2014) Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents. Anesthesiology 120:737–750. doi:10.1097/ALN.0000435833.33515.ba CrossRefPubMedGoogle Scholar
- Tesfaye S, Vileikyte L, Rayman G, Sindrup SH, Perkins BA, Baconja M, Vinik AI, Boulton AJ (2011) Toronto expert panel on diabetic neuropathy: painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management. Diabetes Metab Res Rev 27:629–638. doi:10.1002/dmrr.1225 CrossRefPubMedGoogle Scholar
- Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tölle T, Bouhassira D, Cruccu G, Skljarevski V, Freynhagen R (2013b) Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”–a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 154:2616–2625. doi:10.1016/j.pain.2013.05.043 CrossRefPubMedGoogle Scholar
- Tomić MA, Vučković SM, Stepanović-Petrović RM, Micov AM, Ugrešić ND, Prostran MS, Bošković B (2010) Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice. Eur J Pharmacol 628:75–82. doi:10.1016/j.ejphar.2009.11.016 CrossRefPubMedGoogle Scholar
- Wang ZF, Li Q, Liu SB, Mi WL, Hu S, Zhao J, Tian Y, Mao-Ying QL, Jiang JW, Ma HJ, Wang YQ, Wu GC (2014) Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats. Neuroscience 273:65–78. doi:10.1016/j.neuroscience.2014.04.052 CrossRefPubMedGoogle Scholar
- Wei H, Saarnilehto M, Falck L, Viisanen H, Lasierra M, Koivisto A, Pertovaara A (2013) Spinal transient receptor potential ankyrin 1 channel induces mechanical hypersensitivity, increases cutaneous blood flow, and mediates the pronociceptive action of dynorphin A. J Physiol Pharmacol 64:331–340PubMedGoogle Scholar
- Zhang YP, Eber A, Yuan Y, Yang Z, Rodriguez Y, Levitt RC, Takacs P, Candiotti KA (2013a) Prophylactic and antinociceptive effects of coenzyme Q10 on diabetic neuropathic pain in a mouse model of type 1 diabetes. Anesthesiology 118:945–954. doi:10.1097/ALN.0b013e3182829b7b CrossRefPubMedGoogle Scholar
- Zhang YP, Song CY, Yuan Y, Eber A, Rodriguez Y, Levitt RC, Takacs P, Yang Z, Goldberg R, Candiotti KA (2013b) Diabetic neuropathic pain development in type 2 diabetic mouse model and the prophylactic and therapeutic effects of coenzyme Q10. Neurobiol Dis 58:169–178. doi:10.1016/j.nbd.2013.05.003 CrossRefPubMedGoogle Scholar
- Zhou M, Zhi Q, Tang Y, Yu D, Han J (1999) Effects of coenzyme Q10 on myocardial protection during cardiac valve replacement and scavenging free radical activity in vitro. J Cardiovasc Surg 40:355–361Google Scholar
- Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schütte K, Gries FA (1995) Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid: a 3-week multicentre randomized controlled trial (ALADIN study). Diabetologia 38:1425–1433. doi:10.1007/BF00400603 CrossRefPubMedGoogle Scholar