New Insights On Neuropathic Pain Treatment

Neuropathic pain is defined by the IASP – International Association for the Study of Pain – as “pain that arises as a direct consequence of a lesion or disease affecting the nervous system.” Any kind of disease or condition that damages the nervous system such as limb amputation, spinal cord injury, multiple sclerosis, nerve tumor, alcoholism, diabetes, or infections may give rise to neuropathic pain.

Dysfunctional or damaged nerve fibers send wrong signals to pain-processing centers in the nervous system, and some nerves even continue to send pain signals to the brain, even though there is no tissue damage. The latter defines allodynia, a pain that develops due to a non-painful stimulus. The second characteristic of neuropathic pain is hyperalgesia, defined as an increased response to a painful stimulus. That is why the tools assessing these mentioned pain behaviors are frequently used in the laboratories.

Whatever the reason is, neuropathic pain affects the patient’s life in many ways. For this reason, the treatment of neuropathic pain requires a multidisciplinary approach including both interventional and non-interventional (pharmacological, psychological, and physical therapy) therapies.

Neuropathic pain is normally unresponsive to common painkillers such as ibuprofen or paracetamol since the mechanisms of neuropathic pain are different from the underlying causes of other types of pain. Several groups of analgesic drugs have been found to be effective in the treatment of various neuropathic pain states when compared to placebo in clinical trials. These groups include tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin-noradrenaline reuptake inhibitors (SSNRI), anticonvulsants, local anesthetics, N-Methyl-D-aspartate (NMDA) receptor antagonists, opioids, cannabinoids, botulinum toxin, and topical capsaicin.

The World Health Organization (WHO) recommends antidepressants and anticonvulsants as the first-line in the stepwise treatment of neuropathic pain. Anticonvulsants that are developed for the treatment of seizures and epilepsy are also used to alleviate pain due to the similarity of pathophysiological mechanisms underlying epilepsy and neuropathic pain. The known, common problem is the neuronal hyperexcitability underlying both of the diseases. It is clear that effective anticonvulsants and analgesics act on one or more of the processes underlying this neuronal hyperexcitability. Anticonvulsants are used effectively in a variety of neuropathic pain conditions of peripheral origin, although they rarely provide full pain control. Today, the most commonly-used anticonvulsant drugs in neuropathic pain involve gabapentin, pregabalin, sodium valproate, carbamazepine, and lamotrigine.

Valnoctamide is the amide derivative of valproic acid (Depakote), one of the most commonly-used antiepileptic drugs. Since its anxiolytic actions, it was marketed as an anxiolytic drug in Europe from the 1960s until 2005, but it was withdrawn due to low sales (Wlodarczyk et al., 2015). This anxiolytic effect of the valnoctamide has been linked to chemical similarity to valerian, a plant used in the treatment of insomnia and anxiety disorders since ancient Greece and Rome (Bialer, 2012).

As is known, valproic acid is a drug widely used as a first-line antiepileptic, especially against generalized seizures. The mechanisms that valproic acid uses are the inhibition of voltage-dependent Na⁺ channels, increased GABAergic signal, decreased NMDA-receptor-mediated glutamate excitation and increased serotonergic inhibition (Winkler et al., 2005). In addition to being used as antiepileptic, valproic acid is also used in various neurological disorders such as migraine, bipolar disorder, neuropathic pain, anxiety, phobia, and depression. In fact, although these multiple effects appear to be highly advantageous, clinical use of valproic acid is limited due to two rare but life-threatening side effects as teratogenicity and hepatotoxicity.

The reason for the development of valnoctamide for the treatment of bipolar disorder and epilepsy is the better distribution of valnoctamide in the brain than valproic acid. Furthermore, valnoctamide is neither metabolized into its homolog acid, valnoctic acid, nor converted to valproic acid. For this reason, side effects and teratogenic effects due to valproic acid or its oxidative metabolites are not observed with valnoctamide. This compound has been of promising agents, since its anti-allodynic activity has also been demonstrated in relatively low plasma concentrations in previous studies (Kaufmann et al., 2010; Winkler et al., 2005) yet the antihyperalgesic effects of valnoctamide have not been assessed and its mechanisms of action have not been elucidated in these studies.

In our study, we aimed to determine the possible anti-allodynic and antihyperalgesic effects of valnoctamide, to compare with the reference drug, carbamazepine and to elucidate the role of serotonergic, adrenergic, opioidergic and GABAergic systems in its pharmacological action.

To answer these questions, we used the chronic construction injury rat model of neuropathic pain. This model which consists of unilateral loose ligation of the sciatic nerve demonstrates many pathophysiological characteristics of the human chronic neuropathic pain such as allodynia and hyperalgesia.

Figure 1. Steps of Chronic Constriction Injury Model. 1. Removal of the sciatic nerve 2. Four loose ligations in the sciatic nerve 3. Closure and sterilization of the wound. Credit: Dilara Nemutlu-Samur

Our study demonstrates that valnoctamide (70 and 100 mg/kg, i.p.) significantly increased the mechanical and thermal thresholds decreasing with the development of neuropathy and demonstrated anti-allodynic and antihyperalgesic activity. According to our findings, limited contribution of serotonergic, noradrenergic and opioidergic systems and significant contribution of the GABAergic system to the anti-allodynic activity have been identified whereas the limited contribution of opioidergic and GABAergic systems and significant contribution of serotonergic and noradrenergic systems to the antihyperalgesic activity have been identified.

It is known that pain modulation is a complex process involving the activation of various neuronal signaling pathways within the peripheral and central nervous system. Various neurotransmitters or neuromodulators coexist in this process and produce antinociceptive or pronociceptive responses.

In order to better contribute to new drug research and development studies for neuropathic pain that are currently going on because of side effects, tolerance, and tolerability problems of current drugs, we need to elucidate the whole mechanism of action of a compound with antinociceptive properties in more detail and complete the gaps. Therefore, further studies are required to elucidate the whole mechanism of action of valnoctamide, however, our findings reinforce that valnoctamide is a potential agent that might be used alone or in combination with the other effective therapies in the alleviating of neuropathic pain. Since valnoctamide is considered as a drug without any teratogenicity and is safe with side effect profile, this data makes its potential more valuable.

These findings are described in the article entitled Valnoctamide: The effect on relieving of neuropathic pain and possible mechanisms, recently published in the European Journal of Pharmacology.

This work was conducted by Dilara Nemutlu-Samur (Anadolu University, Faculty of Pharmacy, Eskisehir, Turkey), Rana Arslan (Anadolu University, Faculty of Pharmacy, Eskisehir, Turkey), Sule Aydin (Osmangazi University, Faculty of Medicine, Eskisehir, Turkey), and Nurcan Bektas (Anadolu University, Faculty of Pharmacy, Eskisehir, Turkey) and it is supported financially by the Anadolu University Research Foundation (Eskisehir, Turkey), Project no: AUBAP-1409S395.

References:

1. Bialer, M., 2012. Chemical properties of antiepileptic drugs (AEDs). Adv Drug Deliv Rev 64, 887-895.
2. Kaufmann, D., Yagen, B., Minert, A., Wlodarczyk, B., Finnell, R.H., Schurig, V., Devor, M., Bialer, M., 2010. Evaluation of the antiallodynic, teratogenic and pharmacokinetic profile of stereoisomers of valnoctamide, an amide derivative of a chiral isomer of valproic acid. Neuropharmacology 58, 1228-1236.
3. Winkler, I., Blotnik, S., Shimshoni, J., Yagen, B., Devor, M., Bialer, M., 2005. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain. Br J Pharmacol 146, 198-208.
4. Wlodarczyk, B.J., Ogle, K., Lin, L.Y., Bialer, M., Finnell, R.H., 2015. Comparative teratogenicity analysis of valnoctamide, risperidone, and olanzapine in mice. Bipolar Disord 17, 615-625.