Comparison of the effects of zonisamide, ethosuximide and pregabalin in the chronic constriction injury induced neuropathic pain in rats

Abstract

Background:Evidence has been generated that various anticonvulsant agents provide relief of several chronic pain syndromes and therefore as an alternative to opioids, nonsteroidal anti-inflammatory, and tricyclic antidepressant drugs in the treatment of neuropathic pain. The results of these studies thus raise the question of whether all anticonvulsant drugs or particular mechanistic classes may be efficacious in the treatment of neuropathic pain syndromes.Aim:The aim was to compare the clinically used anticonvulsant drugs which are differ in their mechanism of action in a chronic pain model, the chronic constriction injury, in order to determine if all anticonvulsants or only particular mechanistic classes of anticonvulsants are analgesic.Materials and Methods:The study included zonisamide, ethosuximide and pregabalin. All compounds were anticonvulsant with diverse mechanism of actions. The peripheral neuropathic pain was induced by chronic constriction injury of the sciatic nerve in male Sprague-Dawley rats. Zonisamide (80 and 40 mg/kg), ethosuximide (300 and 100 mg/kg), pregabalin (50 and 20 mg/kg), and saline was administered intraperitoneally in respective groups in a blinded, randomized manner from postoperative day (POD) 7-13. Paw withdrawal duration to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency to mechanical allodynia and thermal hyperalgesia were tested before drug administration on POD7 and after administration on POD 7, 9, 11 and 13.Results:The present study suggests that these drugs could provide an effective alternative in the treatment of neuropathic pain. However, zonisamide and pregabalin appears to have suitable efficacy to treat a wide spectrum of neuropathic pain condition.Conclusion:The present findings suggest that the inhibition of N-type calcium channels or voltage-gated sodium and T-type calcium channels provides better analgesic potential instead of inhibition of T-type calcium channels alone.

Characterization of a rat model of bortezomib‐induced painful neuropathy

“…In our investigation, administration of another calcium channel blocker, ethosuximide, was shown to robustly inhibit bortezomibinduced mechanical hypersensitivity at 1 and 3 h after a single administration. Systemic administration of ethosuximide has previously been shown to induce a dose-dependent reduction in mechanical hypersensitivity in a rat model of paclitaxel-induced pain (Flatters and Bennett, 2004) and analgesic in rat models of traumatic nerve injury (Dogrul et al, 2003;Hamidi et al, 2012;Goyal et al, 2015). There is also evidence of calcium dysregulation in bortezomib-induced cell death, with bortezomib causing transient intracellular ER calcium release, resulting in mitochondrial-calcium influx and caspase activation (Landowski et al, 2005).…”

Effect of hangebyakujutsutemmato on pregabalin‐induced dizziness in a rat model of neuropathic pain

“…Pineda‐Farias et al performed the von Frey test 1 h after oral pregabalin treatment in a spinal nerve ligation model, while Lau et al performed the von Frey test 4 h after oral pregabalin treatment in the same model . In the Goyal et al study, pregabalin induced an analgesic effect at 50 mg/kg/day using the same CCI model as in the present study. They assessed mechanical allodynia sensitivity by hind paw withdrawal duration with a mild pinprick stimulus.…”

“…Despite the use of pregabalin, there were no changes in the mechanical allodynia threshold in the present study. We believe that this is due to the fact that the von Frey test was conducted 22 h after pregabalin treatment, in contrast to other studies in which it was conducted only a few hours afterward . Given that pregabalin reaches maximum blood concentration in 1 h and has a half‐life of 6 h, the timing of the von Frey test was not appropriate in the present study.…”

“…Given, however, that the primary outcome of this study was to evaluate equilibrium sense disturbances due to pregabalin, the BBT, instead of the von Frey test, was conducted a few hours later when pregabalin concentration was considered to be high. Based on previous studies, the pregabalin dose (50 mg/kg/day) should have a sufficient analgesic effect on neuropathic pain if tested within a few hours after treatment . Pineda‐Farias et al and Lau et al showed that pregabalin has an analgesic effect on neuropathic pain at 30 mg/kg/day .…”

An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy

“…A few cases in point illustrating the importance of false analgesic activity are the disappointing clinical trial outcomes of presumably promising drug candidates such as CB2 agonist, NK-1 receptor antagonist 50 and FAAH inhibitor 51 , despite strong evidence for efficacy in pre-clinical studies using behavioral tests, including thermal hyperalgesia 52 , 53 . Interestingly, thermal hyperalgesia continues to be considered as a primary outcome for the testing of pregabalin’s efficacy in neuropathic pain models including CCI 54 , 55 .…”