Journavx (suzetrigine) by Vertex Pharmaceuticals represents a major advancement in pain management, offering a non-opioid alternative for acute pain. Besides being the first non-opioid pain medication approved in over two decades, as an inhibitor of the voltage-gated sodium channel 1.8 (NaV1.8), it validates a completely new mechanism of action for pain relief. This innovation paves the way for future pain medications that can offer more effective treatment with fewer side effects compared to traditional opioids. By selectively inhibiting NaV1.8, Journavx provides effective pain relief without the addictive side effects of opioids, marking a significant milestone in the fight against opioid dependence and opening the door for a new era of pain management.
Targeting sodium channels: a safer path to pain relief
The opioid epidemic has underscored the urgent need for safer and more effective pain treatments, as opioids, despite being potent analgesics, carry addictive properties and significant side effects. Voltage-gated sodium channels are key players in pain transmission, generating electrical signals in response to pain stimuli. These signals are then transmitted from the peripheral nervous system to the central nervous system, where pain is perceived. These channels, especially NaV1.7 and NaV1.8, are considered excellent drug targets due to their exclusive expression in peripheral sensory neurons, reducing the risk of central side effects. Their involvement in pain is supported by strong genetic evidence, with mutations in these channels either causing painful neuropathies or, conversely, an inability to feel pain. However, developing selective inhibitors for these channels has proven difficult due to the structural similarities between the nine NaV subtypes, especially those expressed in critical tissues like the heart, which can lead to unwanted and dangerous side effects. Despite these challenges, targeting NaV1.8 specifically offers a promising avenue for pain relief without the risks associated with opioids.
The breakthrough of Journavx (suzetrigine)
Journavx, Vertex Pharmaceuticals’ latest pain medication, has received FDA approval for treating moderate-to-severe acute pain in adults. The drug targets NaV1.8 and what makes Journavx stand out is its remarkable selectivity: it is over 31,000 times more selective for NaV1.8 than for other NaV channels (NaV1.1, NaV1.7). By binding to the second voltage-sensing domain (VSD2) of NaV1.8, Journavx stabilizes the channel’s closed state, preventing the influx of sodium ions that initiate and propagate pain signalling. This specific binding mechanism allows for more precise control over pain transmission without interfering with other important functions, such as those controlled by NaV channels in the heart. In large phase 3 clinical trials involving more than 2,000 surgical patients, Journavx was tested against hydrocodone combined with acetaminophen (paracetamolo), the standard treatment for acute pain. The results? Pain relief was nearly identical, but Journavx had far fewer side effects like nausea, dizziness, and vomiting. Importantly, it also showed no signs of addictive potential, unlike opioids.
A new era in pain management
The approval of Journavx is not just a breakthrough for acute pain treatment; it also validates NaV1.8 as a promising target for pain relief. Vertex Pharmaceuticals has already initiated clinical trials for other NaV1.8 inhibitors, such as VX993, which could be administered at higher doses to improve efficacy in pain treatment. The success of Journavx could extend beyond acute pain, offering a potential treatment for chronic pain conditions like diabetic neuropathy. Additionally, ongoing research into alternative delivery methods for NaV inhibitors could further enhance their effectiveness and provide options for more targeted treatment in specific types of pain.
Vertex’s success with Journavx marks a turning point in the search for safer alternatives to opioids. By targeting NaV1.8 with high selectivity, Journavx offers a non-addictive, effective alternative to traditional pain medications. The approval of this drug is a significant step forward in addressing the opioid crisis while providing more effective pain relief. As more NaV1.8 inhibitors enter clinical trials, they could revolutionize pain management, offering a new class of drugs that minimize risks while maximizing therapeutic benefits.
By Federica Gorla, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan
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