, Volume 234, Issue 11, pp 1781–1794 | Cite as

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

  • Radica Stepanović-Petrović
  • Ana Micov
  • Maja Tomić
  • Uroš Pecikoza
Original Investigation



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.


Levetiracetam Gabapentinoids Duloxetine Antioxidants Synergism Diabetic painful neuropathy 


Compliance with ethical standards

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.

Research funding

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

Conflicts of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Radica Stepanović-Petrović
    • 1
  • Ana Micov
    • 1
  • Maja Tomić
    • 1
  • Uroš Pecikoza
    • 1
  1. 1.Department of Pharmacology, Faculty of PharmacyUniversity of BelgradeBelgradeSerbia

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