Evaluation of Anticonvulsants for Possible Use in Neuropathic Pain

Abstract

Neuropathic pain is a kind of pain related with functional abnormality of neurons. Despite large progress in pharmacotherapy, neuropathic pain is still considered an unmet need. Nowadays, there are few drugs registered for this condition, such as pregabalin, gabapentin, duloxetine, carbamazepine, and lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known antiepileptic drugs. Among the group of new antiepileptic drugs, which are addressed to 1% of human world population suffering from seizures, it turned out that 30% of the seizures resistant to pharmacotherapy has not enough market to justify the costs of drug development. Therefore, it is already a phenomenon that researchers turn their projects toward a larger market, related with possible similar mechanism. Anticonvulsant mechanism of action is in the first place among primary indications for drugs revealing potential analgesic activity. Therefore, many drug candidates for epilepsy, still in preclinical stage, are being evaluated for activity in neuropathic pain. This review is focusing on antiepileptic drugs, which are evaluated for their analgesic activity in major tests related with neuropathic pain. Relation between structure, mechanism of action and result in tests such as the Chung model (spinal nerve ligation SNL), the Bennett model (chronic constriction injury of sciatic nerve CCI) and other tests are considered. The first examples are carbamazepine, gabapentin, and lacosamide as drugs well established in epilepsy market as well as drug candidates such as valnoctamide, and other valproic acid derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical efficacy related with listed animal models has been discussed.

Ion Channels as Drug Targets in Central Nervous System Disorders

“…Fig. (8 [26,37]. Although well established position in pharmaceutical market, its mechanism of action is not yet completely understood.…”

“…Molecular modeling showed that the pharmacophore segments of CBZ and PHT are similar, and CBZ is also able to develop interaction with binding site in domain IV-S6 [46]. CBZ is used in the treatment of simple partial, complex partial and generalized tonic-clonic seizures but it is not effective against absence seizures [26,37].…”

“…(10) proved efficacy in several animal seizure test: MES, 6Hz test, corneal kindled mice, hippocampal kindled rats, sound induced seizures. Its mechanism of action involves inhibition of sodium and calcium channels [22,37]. Common pharmacophore concept for PTH enables to chose elements in the structure of LTG responsible for binding to the receptor site IV-S6.…”

“…Moreover, it had antipsychotic effect in an animal model of schizophrenia and mania [92]. It also showed activity in rat models of neuropathic pain [37]. Retigabine is thought to bind selectively to K V 7.2 -K V 7.5 channels, shifting the current-voltage curve to the left, which results that the channels open at more hyperpolarized membrane potentials [101].…”

Ultrastructural study of hippocampal cortex neurons in an experimental model of valproate encephalopathy

“…Additionally, VPA is widely used as a mood-stabilizer in bipolar disorder [2], in the treatment of schizophrenia [3], neuropathic pain [4] as well as migraine headache prophylaxis [5]. Due to its beneficial activity in reducing the incidence of both generalized and partial seizures in adults and children, the drug belongs to the so called "first-line" anticonvulsive agents and belongs to the most often prescribed antiepileptic drugs.…”