fluid, and tissue macrophages of OA patients 112 and has been related to inflammatory pain in a rat model 113. LEVI-04, a p75 neurotrophin receptor fusion protein (p75NTR-Fc), is currently being investigated in a phase I clinical trial (NCT03227796), but results are not available yet. Ion channels Furthermore, ion channels like transient receptor potential (Trp) and Nav1.7/Nav1.8 voltage-gated sodium channels gained attention as potential drug targets 114, 115. TRP vanilloid 1 (TRPV1) channels expressed by sensory neurons might be targeted using receptor agonists like capsaicin or resiniferatoxin. In various animal models, these molecules resulted in long-term desensitization or nerve degradation, thus reducing pain and neuropeptide release, but conflicting observations have been reported 114. Currently, several active clinical trials are analyzing the use of topical and i.a. trans-capsaicin (CNTX-4975) in knee OA. Stevens et al. described a dose-dependent effect of i.a. CNTX-4975 that reduced pain compared to placebo over 24 weeks in patients with moderate-to-severe knee OA 35. The FDA assured Fast Track designation to CNTX-4975 for the treatment of OA knee pain in 2018. Several “small molecule” TRPV1 antagonists have been tested so far in healthy subjects but not in OA pain 116, 117, and some had to be stopped because of inefficiency or adverse effects, including NEO6860, which caused headache, nausea, fatigue, and increased blood pressure among other adverse effects 118, 119. A single dose of JNJ-39439335 (Mavatrep), a selective competitive TRPV1 receptor antagonist, was evaluated in phase I studies and successfully reduced pain and improved functional score in knee OA patients after 7 days, though future studies require dose adjustment owing to adverse events involving thermal perception 36, 37 . Animal models indicate involvement of voltage-gated sodium channels Nav1.7 and Nav1.8 in pathological pain states 120, and A-803467, a selective Nav1.8 channel-blocking agent, disrupted nociceptive signal transmission in monoiodoacetate (MIA)-induced OA 121. Furthermore, Vertex’s sodium-channel blocker VX-150 showed efficacy in acute pain reduction and was granted a breakthrough therapeutic potential by the FDA, though results of a completed phase IIa clinical study have not been published yet (NCT02660424) 122. Targeting peripheral opioid receptors Opioids are effective analgesics but their use is limited due to serious adverse side effects like constipation, respiratory depression, tolerance, and dependence. Currently, new opioid receptor (OR) agonists with an improved safety profile targeting the µ, δ, and κ subtypes are in development. Selectively targeting the peripheral κ-OR might avoid side effects observed when drugs target the µ-OR. Cara Therapeutics developed the selective κ-OR agonist CR845 and evaluated its efficacy in knee and hip OA (NCT02524197 and NCT02944448), reporting dose-dependent efficacy in the reduction of pain in hip OA over knee OA Evolving new targets Pain relief might also be achieved by targeting the nociceptin/orphanin FQ peptide receptor (NOP) 123. Cebranopadol (GRT6005), a dual agonist for the NOP/µ-OR, proved to be safe and efficient in chronic back pain 124 and was recently tested in patients with painful knee OA (NCT01357837 and NCT01709214). Other nerve-associated targets include the bradykinin B2 receptor (Fasitibant, NCT02205814 and NCT01091116) and the CB2 cannabinoid receptor (GW842166 [NCT00479427 and NCT00447486], LY2828360 [NCT01319929]). Direct blockade of the sensory neuropeptide α-calcitonin gene-related peptide using LY2951742 (galcanezumab) failed to reduce pain in patients with mild-to-moderate OA 39 . CR4056, an imidazoline-2 ligand with powerful analgesic properties, inhibited inflammation-induced PKCε phosphorylation and membrane translocation in sensory neurons 125 and effectively reduced allodynia and hyperalgesia in two rat OA models 126. A recent phase II trial in knee OA patients reported