Of note, CGRP plasma levels positively correlate with headache intensity and timing , and CGRP intravenous infusion causes migraine-like symptoms in migraine patients . The acute treatment of migraine relies on compounds specifically developed for the disease, such as the triptans . In contrast, prophylactic treatment has relied on drugs originally developed for other disorders, such as antihypertensive or antiepileptic drugs. Unfortunately, all of these compounds are only moderately effective, with side effects that limit adherence . The identification of CGRP as causative in migraine events has led to the development of different therapeutic strategies to specifically treat or prevent migraine. Four monoclonal antibodies targeting CGRP or its receptor have been approved by the U.S. Food and Drug Agency or the European Medicine Agency for the prophylactic treatment of migraine . With their extended time to reach the maximal concentration and long plasma elimination time , mAbs have proven to be effective. mAbs are relatively large molecules that usually do not cross the blood–brain barrier, so that they are more likely to act outside of the brain. Sites of action include the meningeal vasculature and certainly also the trigeminal ganglion, which is not protected by the blood–brain barrier . The results of a recent retrospective longitudinal study suggested that pa tients discontinued use of prophylactic therapies when they initiated CGRP receptor antagonist therapy with erenumab. Adherence to these novel therapies is higher than to the older medications,ebb and flow suggesting an increased real-world effectiveness . However, a proportion of migraine patients do not experience benefit from CGRP targeted treatments, suggesting the involvement of other pathways in migraine.
A preliminary study has indicated that those who do not benefit from their current CGRP-targeted therapy fare better by switching antibody class, but more rigorous double-blind studies are necessary . Gepants are small molecule CGRP receptor antagonists. The development of the so-called first-generation gepants was halted because of pharmacokinetic limitations or hepatotoxicity , but the second generation appears to be safe and tolerable, with several different compounds already FDA approved. Zavegepant is currently under clinical investigation for acute treatment or prophylaxis of migraine. Gepants with different pharma cokinetics along with mAbs could provide a continuum between acute and prophylactic approaches. Although these drugs all are effective in prophylactic or acute migraine treatment, real-life efficacy, long-term safety, and durability of the effects remain to be established. OA affects about 9.6% of older men and 18% of older women . Cartilage degradation is a hallmark of OA, with pain and reduced joint functionality. Treatment of OA pain remains an unmet medical need. This pain probably stems from the inflammatory response and release of inflammatory cytokines, including NGF. Indeed, NGF is present in sub-chondral bone of the human tibial plateau, cartilage, and synovium in OA and rheumatoid arthritis . Increased synovial NGF immunoreactivity, along with synovitis and morpholog ical changes in chondrocytes, also has been associated with symptomatic knee OA . It has become clearer that the NGF/TrkA pathway has a central role during the development of pain in OA , which has prompted research into therapeutic strategies targeting NGF in both animal studies and clinical trials . Pre clinical studies have shown encouraging results. Although several anti-NGF mAbs have been tested in the clinical setting, only fasinumab is currently in clinical development for treatment of painful lower extremity OA and low back pain . Tanezumab is another anti-NGF mAb, but its testing was stopped by the manufacturer in late 2021. Initially, following a proof-of-concept study showing improvement in joint pain and functionality , tanezumab was administered intravenously with and without NSAIDs . After the treatment, patients with knee or hip OA had significant pain reduction and improvement in joint function compared to either placebo or NSAID alone.
In 2010, however, the clinical development program for anti-NGF antibodies was put on hold after several serious adverse events emerged resembling joint osteo necrosis or rapidly progressive OA in patients treated with higher doses of both NGF antagonists alone or combined with NSAID. A detailed analysis identified most of these events as RPOA. This disorder is considered to be an accelerated form of OA leading to joint replacement. After a second clinical hold because of unclear and suspected peripheral neuropathy, clinical trials were eventually continued. Addi tional phase III studies with fasinumab and tanezumab were continued with a subcutaneous formulation. As in the previous studies with an intravenous formulation, these results also showed significantly reduced joint pain, but adverse events including RPOA were still present with the higher dose. The mechanism behind the development of RPOA is not completely understood, and the FDA and EMA both rejected approval of tanezumab for the treatment of OA pain, leading to the termination of the clinical tanezumab program in 2021. However, targeting patients with chronic low back pain and excluding medium to severe OA might be a promising alternative strategy for anti-NGF regimens. Fasinumab has completed phase II/III studies in patients with knee OA. Fasinumab also resulted in significant reduction in joint pain, with similar incidences of RPOA. Currently, studies with fasinumab at 1 mg every 4 weeks and 1 mg every 8 weeks are underway, and results should be reported soon. In summary, inhibition of NGF by systemic administration of antibodies appears to reduce pain and improve function in individuals with lower extremity OA. If fasinumab is approved, a longer acting non-opioid alternative will be available for the treatment of OA or perhaps chronic low back pain. CGRP and NGF have been successfully targeted in chronic pain pa thologies. In contrast, SP has not been as promising, and the results of studies are variable, preventing definite conclusions. SP is expressed in the spinal ganglion and released after stimulation of primary nociceptive neurons. SP binds the neurokinin-1 receptor found in the CNS , on the trigeminal and spinal ganglia , and immune cells, such as lymphocytes, macrophages, and mast cells .
SP leads to inflammation with vasodilation and edema after repetitive stimulation and anti-dromal transport with release at the nociceptor. In this way, SP causes neurogenic inflammation with recruitment of immune cells and the release of pro-inflammatory mediators . Genetic studies have pointed towards the role of the SP/NK-1 pathway in the development of pain. For instance,dry racks the absence of the NK-1 receptor in mice does not alter the perception of acute pain, but pain wind-up was absent. Furthermore, African naked mole rats have limited SP fibers in the skin and are not susceptible to some types of pain . Consequently, NK-1 receptor antagonists were developed with the idea of blocking SP neurotransmission . Although these antagonists showed promising results in animal models, results of clinical studies were disappointing . Aprepitant is a SP/NK-1 receptor antagonist approved as an antiemetic drug. Surprisingly, aprepitant did not show attenuation of pain after 2 weeks of treatment in patients with post-herpetic neuralgia or a decrease of sensitization in a human model of electrical hyperalgesia . This outcome raised the question of compound specificity in humans. Furthermore, blocking the NK-1 pathway might upregulate other neurotransmitters involved in nociception or activate alternative pathways such as NK-2 or NK-3. Findings of recent study suggest that SP released from primary afferents binds Mas-related G-protein–coupled receptor on mast cells, triggering the release of inflammatory mediators as well as immune cell recruitment . Thus, SP-mediated nociception involves not only the NK-1 receptor but also MrgprB2, suggesting that perhaps the other receptor should be a focus . MrgprX2, the human homolog of MrgprB2, may be a promising new target for chronic pain.
Despite our growing understanding of the pain landscape, novel treatment targets are necessary in light of the current scarcity of treatment options. Novel therapeutic regimens targeting more disease specific key molecules of chronic pain will have to be a focus in neuroscience and interdisciplinary research in rheumatology, neurology, and pain medicine. The lack of disease-specific treatment targets for chronic pain syndromes is in astounding contrast to a “mi nority” of inflammatory autoimmune diseases with targeted therapies against TNF-α, IL-1β, IL-6, IL-12/23, IL-17, IL-23, CTLA4, CD20, PDE4, or Janus kinases . Animal models of pain and the identification of novel therapeutic targets have led to development of new treatment strategies in the pre-clinical setting, but the translation into the clinic has been disappointing . Nonetheless, evidence is gradually accumulating of beneficial effects in subtypes of pain syn dromes. The poor translation between experimental models and clinical condition may trace to the clinical relevance of the model and assessment methods used . Several studies also suggest that the inflammatory response has a critical role during neuropathic and inflammatory pain by enhancing the expression or release of prostaglandins, sympathetic amines, endothelin, and NGF . With neurogenic in flammatory pain, target molecules can be related to inflammation itself or to pain, and it is crucial to evaluate the underlying inflammatory mechanisms. One of the mediators of inflammation in pain is TNF-α, a classical pro-inflammatory cytokine that enhances release of second order pro-inflammatory cytokines, such as IL-6 and other mediators, amplifying the inflammatory response . Like several other cytokines, IL-6 exerts its effects through JAK/signal transducer activation . A meta-analysis revealed that JAK inhibitors used for joint pain from rheumatoid arthritis improve outcomes, but in several patients, pain persists even when inflammation is contained . Patient-reported out comes such as health assessment questionnaire responses, physical function, and patient assessment of pain showed significant improvements in patients treated with baricitinib alone and in combination with methotrexate as compared to methotrexate alone . Therapies targeting inflammation in degenerative chronic pain syndromes have failed thus far. These chronic pain syndromes do not all rely on the same pathways as systemic inflammation, but anti inflammatory regimens may be beneficial for some chronic pain syndromes. For example, anti-TNF-α antibodies have been tested in patients with knee OA, and the treatment was well tolerated, with a significant improvement in pain . However, in another clinical trial, pain did not improve in patients with hand OA that had not responded to analgesics and NSAIDs . Thus, further studies are necessary to assess the therapeutic benefits of anti inflammatory compounds. Recently, the approach to pain has included revisiting old molecules, such as cannabinoids and capsaicin, and new synthetic compounds. Results of these studies suggest that cannabis and cannabis-based molecules may be effective and improve quality of life in a variety of chronic pain conditions . Cannabinoid receptors are localized on the sensory nerve, and their dual ability to reduce inflammation and neuronal activity might be a crucial mechanism in modulating neurogenic inflammation and pain. The legal consumption of cannabis and its use for pain management are already approved in several countries, despite limited evidence of their efficacy in pain management . Further clinical studies are needed to properly assess the benefits and pitfalls of cannabis-based therapies in pain management . Another relevant treatment for pain is capsaicin, the active ingredient in chili peppers. Capsaicin targets the TRPV1 receptor, which is prominent on nociceptors containing neuropeptides, and more specifically, it is enriched in nociceptors expressing SP and CGRP.A double blind multicenter study recently showed that intra-articularly injected synthetic capsaicin yielded improvement in pain in patients with knee OA . Of note, intra-articular injection of capsaicin did not cause side effects, as seen with the subcutaneous or intravenous administration of anti-NGF compounds. However, high doses of capsaicin can desensitize nociceptors, causing the loss of axon terminals . Another emerging therapeutic target candidate for chronic pain is BDNF, a crucial modulator of nociception. Although BDNF expression can contribute to plasticity in spinal neurons during controllable pain, spinal injury or chronic pain can lead to an altered response to BDNF, triggering central sensitization and pain hypersensitivity . Sustained BDNF levels may show noxious properties with chronic pain . Pro-inflammatory conditions in hyperalgesia also can induce upregulation of BDNF . A recent study showed that BDNF also plays a role in OA, with synovial expression of the BDNF receptor TrkB associated with higher OA pain . However, when administered as a pharmacolog ical treatment in the CNS, BDNF showed anti-inflammatory effects, suggesting an anti-nociceptive role .