TRPV1 antagonists in the treatment of osteoarthritis pain

Abstract

Pain is the dominant symptom of osteoarthritis (OA) and available analgesic treatments offer inadequate pain relief. The capsaicin receptor, TRPV1 is considered to be a promising analgesic target. TRPV1 is expressed in multiple cell types of the joint. A variant of the TRPV1 gene is associated with the risk of developing symptomatic OA and synovial TRPV1 expression is increased in OA patients undergoing total joint replacement. Potent and selective small molecule TRPV1 antagonists have analgesic effects in preclinical models of OA highlighting the potential utility of TRPV1 antagonists in OA pain management. However, use of these compounds is associated with serious on-target-mediated side effects and analgesic efficacy in OA patients in clinical trials remains to be proven. This review article will discuss recent findings in this area and explore the potential utility of TRPV1 antagonists in the treatment of OA pain. Targeting TRPV1 in the treatment of OA painThere is now a significant body of evidence supporting targeting TRPV1), for the treatment of OA pain [7][8][9][10]. The relevance of TRPV1 to OA pain was highlighted by a recent human genetic study that discovered polymorphisms in the TRPV1 gene associated with symptomatic knee OA [11]. Persistent activation of TRPV1 by the agonist capsaicin causes TRPV1 desensitization and inactivation of TRPV1 expressing sensory neurones. These effects account for why TRPV1 agonists can produce paradoxical analgesia. Topical capsaicin is more effective than placebo for a 50% reduction in pain with a number needed to treat of 8.1 [5]. However, the use of topical capsaicin is associated with increased local adverse events and withdrawals due to these events [12]. The TRPV1 agonist 4975 (Adlea™) developed by Anesiva has been shown to cause a reduction in pain scores with no safety concerns following a single intra-articular injection in end-stage OA patients [13]. A recent Phase II clinical trial demonstrated analgesic efficacy of topic administration of civamide (cis isomer of capsaicin) in patients with knee OA pain [14] and has been approved for topical treatment as a 0.075% cream for the relief of pain in OA patients [14]. Qutenza ® an 8% capsaicin patch is indicated for the management of neuropathic pain associated with postherpetic neuralgia. The long-term analgesic efficacy of topical capsaicin cream in the treatment of knee OA pain [12] and of a capsaicin patch in postherpatic neuralgia provides clear evidence that the blockade of TRPV1 expressing nociceptive afferents at the periphery is a useful strategy to treat chronic pain, although this does not necessarily inform us of the role of TRPV1 itself. The relatively low effectiveness of capsaicin cream and the need to reapply, along with the associated skin irritation has limited civamides' use. Despite this, TRPV1 remains a potential target for OA pain treatment with accumulating preclinical data suggesting that TRPV1 has an important role in the maintenance of established OA pain [7][8][9][10]15]. Several pharma...

Identification and Quantification of Transient Receptor Potential Vanilloid 1 (TRPV1) in Equine Articular Tissue

“…Upregulation of TRPV1 in the articular tissue in connection with inflammation has been shown in multiple species, including humans, mice and rats, and the receptor has been proven to play an important role not only in the development of oedema and hyperalgesia, but also in the destruction of cartilage and surrounding bone, as seen in OA joints [15,[26][27][28][29]. These results highlight the potential of TRPV1 as a promising target for future DMOADs.…”

“…TRPV1 receptors have been found in chondrocytes, macrophages, osteoclasts, osteoblasts and synovial fibroblasts [22][23][24][25][26], and it is generally established that activation of the receptor has a proinflammatory effect and that inhibition will lead to decreased pain and inflammation. [15,16].Upregulation of TRPV1 in the articular tissue in connection with inflammation has been shown in multiple species, including humans, mice and rats, and the receptor has been proven to play an important role not only in the development of oedema and hyperalgesia, but also in the destruction of cartilage and surrounding bone, as seen in OA joints [15,[26][27][28][29]. These results highlight the potential of TRPV1 as a promising target for future DMOADs.Surprisingly, not only deactivation of TRPV1, but also prolonged activation of the receptor will lead to analgesia due to the depletion of neuropeptides and subsequent desensitization of the C-fibres [30], hence both TRPV1-antagonists and agonists have shown promising results in pain management [14,16,26,31].…”

“…In human medicine, so-called disease-modifying osteoarthritis drugs (DMOADs) are being investigated in an attempt to stop the disease progression, as well as being pain-relieving and anti-inflammatory. However, an effective disease-modifying drug has not yet been developed [13].Several authors point to the transient receptor potential vanilloid 1 (TRPV1) ion channel as a possible target for new ways of treating joint disease including OA [14][15][16]. TRPV1 is a nonselective cation channel which is expressed in various tissues.…”

“…Several authors point to the transient receptor potential vanilloid 1 (TRPV1) ion channel as a possible target for new ways of treating joint disease including OA [14][15][16]. TRPV1 is a nonselective cation channel which is expressed in various tissues.…”

“…TRPV1 receptors have been found in chondrocytes, macrophages, osteoclasts, osteoblasts and synovial fibroblasts [22][23][24][25][26], and it is generally established that activation of the receptor has a proinflammatory effect and that inhibition will lead to decreased pain and inflammation. [15,16].…”