Carbamazepine in osteoarthritis treatment: A novel approach targeting Nav1.7 channels

Abstract

Osteoarthritis (OA) presents a growing health concern, with substantial societal and healthcare burdens. Current management focuses on symptom relief, lacking disease-modifying options. Emerging research suggests the sodium channel Nav1.7 as a pivotal target in OA treatment. Preclinical studies demonstrate carbamazepine's efficacy in Nav1.7 blockade, offering significant joint protection in animal models. However, human trials are needed to validate these findings. Carbamazepine's repurposing holds promise for OA management, potentially revolutionizing treatment paradigms. Further research is essential to bridge the gap between preclinical evidence and clinical application, offering hope for improved OA management and enhanced patient quality of life.

Key Words: Osteoarthritis; Joint illness; Treatment approaches; Pain management; Healthcare expenses

Core Tip: Carbamazepine, a non-specific voltage-gated sodium channel blocker primarily used for epilepsy, has shown promising results in preclinical studies for treating osteoarthritis (OA). By targeting Nav1.7 channels, it not only reduces pain but also protects against joint degradation by modulating chondrocyte biology. However, further research is needed to confirm its efficacy in humans, potentially paving the way for innovative OA treatments beyond traditional analgesics.

TO THE EDITOR

Osteoarthritis (OA) is a degenerative disorder projected to affect a substantial increase in the number of individuals from 32.5 million presently to 78.4 million by 2040, primarily due to the rising incidence of obesity[1]. The disease is characterised by joint pain, tenderness, crepitus, stiffness, and restricted range of motion, as well as sporadic effusion and varying degrees of inflammation[2]. It is the most common kind of joint disease, leading to a decline in quality of life, impaired functioning, and significant societal and healthcare costs[3]. Notably, women are twice as likely as men to develop OA[4]. According to a report by the United States Bone and Joint Initiative, covering the period from 2008 to 2014, the mean annual expense for treating OA was $486.4 billion[1].

Several methods, including topical treatments like ice and heat, the combination of anesthetics and cannabidiol, and anti-inflammatories, are used in the management of OA. For more severe pain, oral drugs such as acetaminophen and ibuprofen are prescribed, alongside physical therapy involving strength and low-impact exercises[5]. Paracetamol can be used to treat mild to moderate OA. When combined with tramadol, COX-2 inhibitors, and Nonsteroidal Antiinflammatory Drugs, it can provide even greater pain relief, but it also raises the risk of cardiovascular events. Although opioids often cause side effects such as drowsiness, constipation, nausea, vomiting, and disorientation, they have demonstrated remarkable efficacy in pain management[6]. Currently, there are no effective treatment methods that simultaneously prevent joint degeneration and reduce pain in treating OA[7].

Voltage-gated sodium channels (Navs), which regulate neuronal excitability and pain signal transmission, are essential for the modelling of non-opioid medicines. Nav1.8 has been identified as a human pain target; it is primarily located in peripheral nociceptors. It has been demonstrated that blocking these Nav1.8 channels may reduce pain without having a major impact on other critical Nav isoforms that are vital for heart, lung, and central nervous system function[8].

Blocking nociceptive primary afferents in OA can also provide analgesia. A-803467, at times referred to as the Nav1.8 inhibitor, is a viable option for this method because it has demonstrated efficacy in reducing joint nociception induced by mechanical stimulation[9] It is discovered that functional Nav1.7 channels are expressed in human OA chondrocytes, suggesting a potential breakthrough in OA treatment[7]. The deletion of these channels in mouse chondrocytes has shown promising results by reducing structural damage, slowing OA progression, and alleviating pain-related behaviors[5]. Nav1.7 blockers influence chondrocyte biology and OA advancement by regulating the chondrocyte secretome and intracellular calcium signaling[7]. Notably, mutations in the NaV1.7 gene contribute to severe hereditary pain syndromes, highlighting its significance in pain disorders[10].

Carbamazepine, a non-specific Nav-blocking drug, primarily used as a first-line treatment for epilepsy, has shown noteworthy protective effects against joint degradation in experimental mice models with OA. Administering the dosage of 250 mg of the drug carbamazepine administered to mice models, demonstrated the potential to protect and reduce pain levels. It performs its action by upregulating the expression of COL2 and downregulating the production of enzymes that break down the matrix. Through increasing anabolic and suppressing catabolic effects in chondrocytes, this replication has been observed to mitigate cartilage loss, reduce OA pain, and protect against any changes. Non-specific VGSC blockers like carbamazepine have the potential to be innovative treatments for OA beyond mere analgesics[7]. This indicates that carbamazepine can have a great impact in treating OA.

It can be concluded that carbamazepine has the potential to significantly transform and bring a breakthrough revolution in the treatment of OA by blocking Nav1.7. Carbamazepine has shown great efficacy by inhibiting the Nav1.7 channels in the preclinical trials. However, due to a lack of evidence about the efficacy of carbamazepine in humans, additional research is required to promote its role in humans, which may lead to the possibility of a time when OA is more manageable and enables patients to lead a healthier and more productive life.