People with active arthrofibrosis are all-too familiar with joint pain. Chronic pain is a serious problem for millions around the world, with no good solutions [1], but medical research is finally starting to catch up and offer hope with a new class of non-opioid painkillers on the horizon. Although these medications are not available just yet, the first of this type, called suzetrigine, has been given priority fast tracking by the FDA with a target action date of January 2025.
Suzetrigine (formerly VX-548) was developed by Vertex Pharmaceuticals for the treatment of moderate to severe acute pain and peripheral neuropathic pain, and it’s thought that it will be equally effective in the early post-operative period and for chronic pain. This oral medication blocks a type of sodium channel on the membranes of peripheral (outside the brain and spinal cord) nerves, interfering with their ability to transmit pain signals. Because suzetrigine selectively works on sensory peripheral nerves to provide pain relief rather than nerves in the brain or spine, the risk of addiction and other side effects associated with opioids such as oxycodone (OxyContin) are avoided. In addition, suzetrigine has a very different mode of action to non-steroidal anti-inflammatory medications (NSAIDs, for example Ibuprofen, Celebrex) and therefore doesn’t carry the increased risk of fibrosis that non-aspirin NSAIDs have when taken long-term. NSAIDs inhibit cyclooxygenases (COX) proteins and, when taken for more than a few days, non-aspirin NSAIDs interfere with the body’s natural pro-resolving pathways [2] for overcoming inflammation, in effect becoming “resolution toxic” [3].
Surgery and trauma stimulate the release of inflammatory cytokines and growth factors that act directly on nerves and cause hypersensitisation.
Pain is triggered by nerve and tissue injury and the resulting inflammation [4]. Surgery and trauma stimulate the release of inflammatory cytokines (small proteins for cell signalling) and growth factors that act directly on nerves and cause hypersensitisation [1]. Then, the overactive nerves release substances that increase inflammation and numbers of immune cells in a feedback effect [5, 6] (see our blog Why Pain Control is Important). This feedback between pain and inflammation is why an anaesthetic nerve block over several days post-surgery is important, assisting the recovery of nerves and tissues [6]. In healthy healing the body’s anti-inflammatory pathways kick in over the first days as cellular debris and pathogens are cleared from the injury site, reducing inflammation and pain. However, in arthrofibrosis these processes go awry, and healing and inflammation persist.
Long lasting inflammation creates maladaptive changes to peripheral nerves, including an increase in the number of sodium channels on cell membranes [6], that leads to peripheral and sometimes central sensitisation and hyperexcitability [1]. The hypersensitisation creates a heightened response to normal or mild stimuli (hyperalgesia), or a pain signal in the absence of a pain stimulus, for example in response to warmth and coolness (allodynia) [4].
Sodium channels in membranes of nerve cells are central to creating pain signals and transmitting them to the brain.
So, how does suzetrigine work? We’ll get a little technical, but don’t worry if you don’t understand some of the terms. Sodium channels (pores) in membranes of nerve cells (nociceptive neurons) are central to creating pain signals and transmitting them to the brain. These membrane channels act as cellular gates, opening when they sense inflammatory cytokines that are released after an insult, allowing positively charged sodium ions to enter the cell [6]. As sodium ions accumulate inside the nerve cell the charge changes and generates an electrical signal (action potential) that travels to the spinal cord and then the brain where it is felt as pain. This system is the body’s alarm system that warns us about dangers such as toxic chemicals, extreme temperatures and sharp objects [7].
There are two types of voltage-gated sodium channels that are almost exclusively expressed in peripheral nerves, and which are of interest for treating pathological pain: Nav1.7 and Nav1.8 [4, 8]. These are concentrated in the nerve endings of peripheral sensory nerves (not the brain), making them ideal therapeutic targets [7]. Nav1.7 activates very rapidly and initiates the pain signal while Nav1.8 regulates the signal, amplifying it in the presence of inflammatory cytokines [7]. Nav1.8 produces most of the pain signal and is strongly associated with pain perception [7, 8], hyperalgesia and allodynia. Interestingly, Amitriptyline also acts on these and other sodium channels [8] but is not selective, so it can have unwanted side effects.
Suzetrigine inhibits Nav1.8 sodium channels on nerve cells, reducing the amount of pain signal reaching the brain.
Suzetrigine inhibits Nav1.8 sodium channels on nerve cells, reducing the amount of pain signal reaching the brain. In clinical trials of early post-operative pain, it reduced pain by around 3 points on the 10-point pain scale, for example, reducing a pain score of 7 down to 4, which is a meaningful outcome. There are plans for a phase 3 trial for chronic diabetic neuropathy and Vertex already have a next-generation Nav1.8 inhibitor in clinical trials that may be even more effective. The success of suzetrigine has encouraged other pharmaceutical companies to investigate Nav1.7 and Nav1.8 as therapeutic targets using a variety of approaches, so there may be more options in the future.
Chronic pain is an enormous burden on sufferers, and these new pain pills are eagerly awaited by many. In the meantime, mindfulness, meditation and self-compassion can help, together with the tips outlined in our blog 10 Self-Care Tips for Arthrofibrosis Patients.
This blog was inspired by an article published in Scientific American (Sept 2024) with the same title.
References
Cheng, X., Choi, J. S., Waxman, S. G. & Dib-Hajj, S. D. Mini-review - Sodium channels and beyond in peripheral nerve disease: Modulation by cytokines and their effector protein kinases. Neurosci Lett 741, 135446 (2021). https://doi.org/10.1016/j.neulet.2020.135446
Little, P. Non-steroidal anti-inflammatory drugs and covid-19. BMJ 368, m1185 (2020). https://doi.org/10.1136/bmj.m1185
Serhan, C. N. & Levy, B. D. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest 128, 2657-2669 (2018). https://doi.org/10.1172/JCI97943
Hameed, S. Nav1.7 and Nav1.8: Role in the pathophysiology of pain. Molecular Pain 15 (2019). https://doi.org/10.1177/1744806919858801
Zieglgansberger, W. Substance P and pain chronicity. Cell Tissue Res 375, 227-241 (2019). https://doi.org/10.1007/s00441-018-2922-y
Cui, Y. et al. Ropivacaine Promotes Axon Regeneration by Regulating Nav1.8-mediated Macrophage Signaling after Sciatic Nerve Injury in Rats. Anesthesiology 139, 782-800 (2023). https://doi.org/10.1097/ALN.0000000000004761
Vasylyev, D. V., Zhao, P., Schulman, B. R. & Waxman, S. G. Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain. J Gen Physiol 156 (2024). https://doi.org/10.1085/jgp.202413596
Heinle, J. W. et al. Insights into the voltage-gated sodium channel, Na(V)1.8, and its role in visceral pain perception. Front Pharmacol 15, 1398409 (2024). https://doi.org/10.3389/fphar.2024.1398409
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