Penalty. Torment. Hardship. Suffering. Punishment. These definitions of poine and poena—the Greek and Latin words for pain—describe our complex relationship with pain, speaking to something beyond the physical discomfort, a phenomenon experienced in both body and mind. Pain is not a simple, unidirectional, linear process whereby a physical stimulus activates a nociceptor, triggering the propagation of a signal along a nerve to the brain to become salient. It is more akin to an ouroboric Gordian knot made of mental and physical fibers.
We all feel pain. In the U.S., pain annually affects 100 million Americans, amounting to half a trillion dollars in terms of economic burden. Still, the opioid epidemic rages on, a major cause for mortality among young adults—one in five in their 20s and 30s—and tamper-proof opioids that reduce addiction and risk continue to be developed as painkillers. Only ziconotide, developed into a therapeutic called Prialt by Elan Pharmaceuticals and approved by the FDA to treat pain in 2004, but due to side effects, is rarely used. Without question, the need for new non-addictive pain treatments is as critical now as ever.
Mind over Matter
During her pediatric residency at Albert Einstein College of Medicine’s Montefiore Medical Center, Kara Margolis, MD, treated patients who changed her career path. “Healthy kids would come in, and then suddenly they’d be blind or couldn’t walk,” Margolis told Inside Precision Medicine. Although the children did not show any signs of neurological damage, they were clearly experiencing symptoms of motor or sensory loss. But Margolis noticed a common thread—all of the children seemed to be living in challenging and stressful situations. It was as if they were experiencing such intense emotional pain that the children suddenly experienced symptoms typically caused by having a bundle of neurons severed or a chunk of brain removed.
Although Margolis did not end up studying this baffling condition, it did point her in the direction of studying the interaction between psychiatric conditions and pain. Margolis, who is the director of the New York University (NYU) Pain Research Center, believes that it is critical to capture not only the biological factors contributing to pain but also the psychological and social ones as they seem to be essential to the most up-to-date model for human pain, the neuromatrix (or the brain pain matrix). In this model, patterns of nerve impulses across several interacting networks in the brain (i.e., sensory, cognitive, and affective) create the multidimensional experience of pain not only through the physical stimulation of pain receptors but also via environmental and internal non-nociceptive stimuli.
Part of the Margolis lab at NYU focuses on gut signaling in mood disorders and abdominal pain-related disorders of gut-brain interaction (DGBIs), which affect as many as 20% of children and adolescents in the United states. The symptoms DGBI patients experience do not primarily result from gastrointestinal damage but from challenges associated with processing pain signals between the gut and the brain. “There are many factors that make pain highly diverse and complex, such as comorbidities like addiction and mood disorders,” Margolis said. “Understanding the shared mechanisms between pain and these other comorbidities could not only lead to novel targets but potentially targets that can treat multiple disorders at the same time.”
Of mice and men
Rajesh Khanna, PhD, a professor and director of the Pain and Addiction Therapeutics Collaboratory at the University of Florida, has been studying voltage-gated sodium channels (NaVs) as targets for non-opioid therapeutics. For decades, his darling has been Nav1.7, a nociceptor preferentially expressed in the cell bodies of neurons located within the dorsal root ganglion of the spinal cord. These receptors are critical for sensing pain and relaying the signal to the brain. NaV1.7 makes sense as a therapeutic target because patients with mutations in SCN9, the gene encoding the channel, display many pain-related phenotypes and conditions. For example, loss-of-function results in pain insensitivity whereas gain-of-function confers pain hypersensitivity.
Professor and Director
Pain and Addiction Therapeutics Collaboratory
University of Florida
A major issue limiting pain research is the poor translatability of existing preclinical models. “We have solved chronic pain in rodents a thousand times over—we and everybody else who works on it,” Khanna told Inside Precision Medicine. “But it doesn’t translate because humans have this feeling, the emotional aspect of pain, the affective dimension. How do you assess that in an animal? It’s been done, but it’s very difficult.” Even when the emotional dimension of pain is taken out of the equation, Khanna thinks the cellular and molecular complexity in the biology of pain relative to other diseases, such as cancer, is extraordinarily challenging. Khanna explained, “There’s so much about pain that has to be connected: the circuits, the cells, and the proteins. And it’s not all neurons, but also astrocytes, glia, and immune cells; there’s so much of a cross-talk that it becomes overwhelming to think about. It’s complicated. It’s not just [like cancer] where you can say, ‘Let me eliminate this thing and everything goes away.’”
Moving from preclinical to clinical, however, is like jumping from the frying pan into the fryer. One of the reasons for this, according to Margolis, is the dearth of pain biomarkers. “There’s no consistent reliable biomarkers for pain, so without those, it’s challenging to accurately, objectively, recruit for clinical studies and also to determine drug efficacy or other outcomes,” Margolis said. “How do you characterize and how do you personalize medicine when you have no biomarkers?”
The power to HEAL
Director
NIH’s Office of Pain Policy and Planning
In 2018, with Congressional support, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-term Initiative, or HEAL Initiative, as a comprehensive research endeavor aimed at expediting scientific solutions for opioid use disorder, overdose, and pain management. According to Linda Porter, PhD, a director at the NIH’s Office of Pain Policy and Planning, an initiative like HEAL was critical to rejigging their entire approach to the study and treatment of pain. While lots of pain research had been done at the NIH—for example, the National Cancer Institute did a lot of research on cancer pain, chemotherapy-induced pain, and post-cancer survivor pain—there had not been a centralized effort behind what Porter calls the “neurological disease of pain.”
In its first five years, the HEAL Initiative has put financial eggs into lots of baskets, like the Program to Reveal and Evaluate Cells-to-Gene Information that Specify Intricacies, Origins, and the Nature of Human Pain (PRECISION Human Pain) network that focuses on research efforts to identify and describe mechanisms underlying pain experiences in humans instead of animal models. The HEAL Initiative has also funded a clinical screening program for small molecules and biologics for pain therapeutic development. “The compounds, or the potential drugs, that have come through the pipeline so far are not really ready for the large effectiveness trials because it’s only been five years,” said Porter. “But what we’re hoping in the next five years of HEAL is that some of those could maybe move into larger trials. So we’ve got a number of approvals from the FDA of products to move forward.”
Another key area for the HEAL Initiative is to get at the heart of the many issues that have plagued the clinical study of pain treatments, whether therapeutics or devices. The HEAL initiative has built clinical trial networks that would take in trials at the early efficacy or proof of concept stage and also run effectiveness and implementation trials. “We also built large programs to provide a pipeline from start to finish of how we could find validated tests and then move into the implementation component of new therapeutics,” said Porter. “The game has really changed as far as how we were able to evaluate interventions.”
Khanna believes that initiatives like HEAL are critical to this new push to find non-addictive pain medications, in part because he does not think that Big Pharma wants to go on a wild goose chase to find and validate new targets. “This is a great service that the NIH is supporting in terms of either validating, de-risking, or eliminating potential new targets for pain. I see this as a way to fill the void left by [Big Pharma]. They want a blockbuster, but I believe they have been burned by so much investment that has not really paid off.”
A temporary reprieve
Paul Negulescu, senior vice president and disease area executive (pain) at Vertex, is leading an effort that stands to prove Khanna wrong by targeting a different sodium voltage-gated channel, NaV1.8, which is a nociceptor found in many of the same cells that carry NaV1.7. To do so, Vertex developed a pain-in-a-dish approach to model NaV1.8, or any other voltage-gated channel, with two key aspects. The first is studying the channel in isolation with very fine control and high-resolution measurements of channel dynamics. Vertex developed specific technology for expressing a single voltage-gated channel in HEK cells, enabling measurements of action potentials elicited by the channel. “We can vary the frequency and the intensity of the stimulus, and we can really see how the drug interacts in real time over repeated cycles,”
Senior Vice President and disease area executive (pain)
Vertex
Negulescu told Inside Precision Medicine. The second is to take the chemical entities identified as having the ideal properties for controlling a NaV and add them to a population of neurons from a human dorsal root ganglion (DRG). Studying the candidate molecules in this more complex context of a population of pain-sensing neurons is important because the firing of a neuron involves an orchestration of several voltage-gated channels, which work like a “bucket brigade,” as Negulescu likes to call it. DRGs are a heterogeneous place, made of neurons with nociceptors specific to heat, cold, pressure, chemical insults, and more. This setting allows the team at Vertex to study the flavor of pain signals their candidate molecules modulate. “Short of having a whole human dorsal root ganglion all the way to the fingertips and the spinal cord, this is as far as we’ve gotten at modeling pain in a dish, and it’s translated pretty well so far in terms of both the efficacy and the lack of effect on other sensory systems that are not pain sensors,” said Negulescu.
Formerly known as VX-548, suzetrigine targets sodium voltage-gated channel Nav1.8 to inhibit pain-signaling pathways in the peripheral nervous system, which, theoretically, should not pose a risk of addiction. “The mechanism is not in the brain, so we don’t interact with the reward centers of the brain like the opioids and some other analgesics do—it’s precisely treating pain,” Negulescu said. So far, that theoretical derisking of addiction has proven true, and suzetrigine has made the most clinical headway in treating irritated lumbosacral radiculopathy. This condition, where the nerve roots in the lower back are compressed, affects 3–5% of Americans throughout their lifetime, translating to several millions of patients. The Nav1.8 inhibitor has completed two Phase III clinical trials. A Phase II study of lumbosacral radiculopathy has been granted FDA Fast Track and Breakthrough Therapy designations and is under priority review with a target action date of January 30, 2025.
Negulescu said that this clinical work on suzetrigine, which could also treat peripheral neuropathic pain such as painful diabetic peripheral neuropathy, has served as a proof of concept for Vertex’s approach to developing pain therapeutics. “It’s a simple vision to precisely treat pain without risk of addiction, and we have a fairly straightforward strategy, which is to fully exploit the idea of selective sodium channel inhibition as the way to achieve that,” said Negulescu. “If possible, we’d like to be as efficacious as an opioid, to relieve the pain at the level of morphine. Whether we can do that, we don’t know. Ideally, people in the future may not have to take an opioid at all. But we’re far away from that today.”
Jonathan D. Grinstein, North American editor for Inside Precision Medicine, investigates the most recent research and developments in a wide range of human healthcare topics and emerging trends, such as next-generation diagnostics, cell and gene therapy, genome engineering, and AI/ML for drug discovery. Before IPM, Jonathan wrote for publications like Scientific American and Genetic Engineering and Biotechnology News (GEN). Jonathan earned his PhD in biomedical science from the University of California, San Diego, and a BA in neural science from New York University.
