Levetiracetam synergizes with gabapentin, pregabalin, duloxetine and selected antioxidants in a mouse diabetic painful neuropathy model

Abstract

Rationale

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.

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

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Correspondence to Radica Stepanović-Petrović.

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The experimental protocols were approved by the Institutional Animal Care and Use Committee of the Faculty of Pharmacy, University of Belgrade and were carried out in compliance with the guidelines of European Communities Council Directive 2010/63/EU on the use of animals for scientific purposes.

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This work was supported by the Serbian Ministry of Education, Science, and Technological Development (24 Nemanjina St., Belgrade, Serbia), Grant No. 175045.

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Stepanović-Petrović, R., Micov, A., Tomić, M. et al. Levetiracetam synergizes with gabapentin, pregabalin, duloxetine and selected antioxidants in a mouse diabetic painful neuropathy model. Psychopharmacology 234, 1781–1794 (2017). https://doi.org/10.1007/s00213-017-4583-z

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Keywords

  • Levetiracetam
  • Gabapentinoids
  • Duloxetine
  • Antioxidants
  • Synergism
  • Diabetic painful neuropathy