Journavx: The New Pain Kid on the Block
The FDA just approved Journavx for treatment in moderate-to-severe acute pain in adults. It is the first-in-class non-opioid pain medication. Journavx targets the pain-signaling pathway, specifically the sodium channel NaV1.8, in the peripheral nervous system before pain signals reach the brain. Since NaV1.8 is not expressed in the central nervous system, it is not expected to have addictive potential. Previous research into similar drugs failed either at the pre-clinical or early clinical trial phase. The approval of Journavx is a game-changer for pain management.
Why is this important?
Opioids are the most effective treatment for pain. Unfortunately, due to their mechanism of action, opioids users are at risk for addiction. The American Medical Association estimates that 3% to 19% of people who take prescription opioids will develop an addiction to them. In 2022, over 70,000 Americans died from opioid overdoses. The rate of deaths due to opioid overdose increased dramatically from 2003 (0.5 deaths per 100,000) to 2022 (22.7 deaths per 100,000), although there is some evidence that this number has decreased slightly over the past few years. These statistics highlight the need for research in alternatives for pain medication.
How does Journavx work?
The PNS comprises nerves and ganglia that are located outside the brain and spinal cord, mainly functioning to connect the CNS to organs and limbs in our body. On the other hand, the CNS is composed of the spinal cord and the brain, which is mainly responsible for integrating and interpreting the information sent from the PNS, and subsequently coordinating all the activities in our bodies, before sending response towards the effector organs.
Neurons are connected with each other to form complex neural networks in our body, where the chemical and electrical signals are transmitted via specialized connections, which are called synapses. The synaptic signals sent from a neuron are received by the dendrites and soma (synaptic transmission) of another neuron, and these signals could be inhibitory or excitatory in nature, defined by the pharmacological effects resulting from the signal itself. After receiving the signals via the dendrites or soma, the signals are transmitted within the neurons by axons. This leads to brief pulses generated within the neuron, known as an action potential, which propagate from the soma, travel along the axons to activate the synapses, and are then sent to other neurons the action potential starts, when Na+ enters through a voltage-activated Na+ channel (Nav), which creates the depolarizing nature of the membrane potential. When threshold potential is achieved, all the Nav channels that are located in the axon hillock are stimulated to open, leading to a complete depolarization till achieving peak potential (+40 mV) of the neurons. At this point, the Nav channels return to their resting state, and the voltage-activated K+ channels (Kv) are activated and opened to allow the efflux of K+, causing repolarization of the neurons. The shape of the action potential is stereotypical, which means that the amplitude and the time course for all the action potentials occurring in the cells are the same. The continuous efflux of K+ through the Kv and K+ leakage channels causes the membrane potential to hyperpolarize, during the supposedly refractory period of the neurons. Eventually, the K+ channels close and the Na+/K+ transporters restore the resting potential by allowing the entrance of three Na+ and exit of two K+. When the action potential travels to the axon terminal, the Ca2+ enters into the presynaptic terminal through the voltage-operated Ca2+ channels (VOCC), hence causing the synaptic transmission. Blocking NaV halts the signal transmission, effectively blocking the pain signal from reaching the brain.
Although Journavx has been approved for acute pain, it has not yet been studied for chronic pain. Additionally, as the graph below shows (source: https://www.journavx.com/), it is not superior to opioids in acute pain reduction. There is much more research to be done to determine the limitations of Journavx and other potential NaV1.8 inhibitors; however, the discovery of this class of pain relievers is a huge step towards fighting the opioid epidemic.
Sources:
Hameed S. Nav1.7 and Nav1.8: Role in the pathophysiology of pain. Mol Pain. 2019 Jan-Dec;15. https://pmc.ncbi.nlm.nih.gov/articles/PMC6589956
Heinle J.W., et al: Insights into the voltage-gated sodium channel, NaV1.8, and its role in visceral pain perception. Frontiers in Pharm. 2024; 15. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1398409/full
Huan W., et al: Drug discovery targeting Nav1.8: Structural insights and therapeutic potential. Current Opinion in Chemical Biology. 2024; 83 (1020538).
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Morgan M.M., MacDonald J.C.: Analysis of opioid efficacy, tolerance, addictions, and dependence from cell culture to human. British Journal of Pharm. 2011; Oct (1322-1334). https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01335.x
Drug Overdose Deaths: Facts and Figures. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates#Fig2
Kiran G., et al: Structural and functional characterization of movel scorpion toxin that inhibits NaV1.8 via interactions with the DI voltage sensor and DII pore module. Frontiers in Pharm; 2022; 13. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.846992/full
Journavx. https://www.journavx.com