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In January, the US Food and Drug Administration (FDA) approved the first new type of painkiller in more than two decades. The decision roused excitement across the healthcare sector for a key reason: the drug, which is called suzetrigine and sold under the brand name Journavx, is not an opioid.
Opioid painkillers such as oxycodone and morphine are still used to treat severe pain in the UK and US. But they come with an obvious downside: the risk of addiction.
Between 1999 and 2017, the number of overdose deaths in the US involving prescription opioids soared almost 400% from 3,442 to 17,029, according to the National Institute on Drug Abuse. In England and Wales the number of cases where opiates were mentioned on a death certificate rose from 1,332 in 1999 to 2,551 in 2023, according to the Office for National Statistics.
Pharma companies have been trying to develop safer painkillers since the start of the US opioid crisis. But these efforts have proven notoriously difficult, with a less than 1% chance that a novel pain drug will advance from phase 1 clinical trials to FDA approval.
One reason for this is that pain is not a purely physical phenomenon, but is also influenced by psychological factors.
The success of Journavx marks a welcome break from a long history of setbacks, but experts say it is just one piece of the puzzle. For starters, the medicine is only available for certain types of short-term pain, but there are many other kinds of pain that still need new treatments.
Further, the science behind some of those other types of pain is not clear, which makes designing treatments for them challenging. And pain relief is itself a rewarding experience. So opioid or not, is there even such a thing as a non-addictive painkiller?
What is pain?
When you think of pain, you might picture someone stubbing their toe. This type of pain – when something damages bodily tissue – is called nociceptive pain. Sensory neurons at the site of damage called nociceptors get activated, says Grégory Scherrer, associate professor at the University of North Carolina’s department of cell biology and physiology. The nociceptors send signals to the spinal cord, where other neurons process them.
Next, the signals travel through complex pathways into several parts of the brain. One of those parts, the cortex, is responsible for processing sensory information, says Anthony Dickenson, emeritus professor of neuroscience, physiology and pharmacology at University College London (UCL). It is only once this processing occurs that we “feel” the signal as pain.
A second type of pain – called neuropathic pain – happens as a result of damage to or disease of the nervous system outside the brain and spinal cord, Dickenson says. Damaged or defective neurons fire off signals that go through the same process. One example is diabetic peripheral neuropathy, where high blood sugar damages blood vessels that transport blood to the nerves, resulting in nerve damage and, potentially, death in the extremities.
In general, then, pain perception involves two systems. This first is a network of nerves running through the limbs, organs and other tissues, also known as the peripheral nervous system. Then there is the central nervous system, made up of the brain and spinal cord.
A third type of pain is less well understood. Nociplastic pain involves no obvious damage to tissues or neurons, but is thought to be driven by a problem with how the central nervous system processes signals. “Relatively normal stimuli produce pain when they shouldn’t,” Dickenson says. A key example is fibromyalgia, a disorder that mostly affects women.
Some researchers believe nociplastic pain is simply a more subtle form of nociceptive or neuropathic pain where the tissue or nerve damage is harder to detect, says Jeffrey Mogil, professor at McGill University’s department of psychology in Montreal.
In a medical setting, pain is treated according to how long it lasts, says Amanda Williams, professor of clinical health psychology at UCL. Pain that lasts for three months or less – after an injury or operation, for example – is generally classed as acute, while pain that lasts longer than three months is often considered chronic.
The amount of pain a person feels does not always correlate with physical signs of damage, Williams says. For instance, one person could have a little wear and tear in their knees and feel significant pain, while another person with even more damage could feel no pain.
Is pain relief addictive?
Regardless of the type and length, people are wired to dislike pain. Besides the cortex, pain signals also travel to another part of the brain called the limbic system, which is responsible for processing emotions, Dickenson says.
This triggers the feelings of fear, anxiety and depression that often accompany pain. Pain signals also switch off the release of dopamine, a neurotransmitter associated with feelings of reward, Dickenson adds. Relief from pain is “absolutely rewarding” in and of itself, says Mark Hutchinson, professor at the University of Adelaide’s school of biomedicine.
But there are many experiences that are rewarding without being addictive, from eating to seeing friends, Williams says. The “switch point”, at which a reward becomes an addiction, is defined by detriment to a person’s broader health and wellbeing, according to Hutchinson. Opioid painkillers can flip this switch because of how they work.
Opioids interrupt pain signalling by binding to and activating inhibitory opioid receptors in the brain and spinal cord. These receptors form part of the body’s endogenous opioid system, which helps regulate pain and mood. But one of the receptors – the μ-opioid receptor – can increase dopamine signalling between certain parts of the brain when activated.
The resulting dopamine dump creates a feeling of reward or pleasure that can be over and above the inherently rewarding nature of pain relief. The body can also build a tolerance to opioids over time, meaning that higher doses of the drugs may be required to experience the same feeling of pain relief or reward. This creates the basis for addiction.
But there are lots of painkillers that do not operate on the reward system, such as paracetamol and ibuprofen, says Christopher Eccleston, professor of psychology at the University of Bath. “Is pain relief always going to be addictive? I think the answer is no.”
What are the alternatives to opioids?
Journavx was developed by Vertex Pharmaceuticals and belongs to a class of drugs that block voltage-gated sodium channels (VGSCs).
VGSCs allow sodium ions to flow into certain cells of the body. Once inside the cells, the ions trigger electrical activity – or action potentials – that are responsible for a range of bodily functions, from heart beats to pain signalling.
Journavx selectively blocks a VGSC called Nav1.8 that is predominantly found in pain-sensing neurons in the peripheral nervous system, says David Altshuler, chief scientific officer of Vertex. The drug does not act on the brain the way opioids do and instead acts outside the brain, meaning there is no addiction risk.
Vertex has not applied for Journavx approval in the UK. In the US, the drug is only available for moderate to severe acute pain.
Some experts are sceptical about the need for a non-opioid in acute pain. It is relatively rare that someone taking an opioid for a few days after a surgery gets addicted to them, although it can happen, Scherrer says. There is also more communication about the risks of opioids these days and many patients request a minimal amount before switching to another medicine, he adds.
But Altshuler says the need is clear, citing estimates that 80,000 people a year in the US develop an opioid addiction just because they were given one for acute pain.
Experts agree that there is a significant need for non-opioid painkillers in chronic pain. There is little evidence of the effectiveness of opioids in treating chronic pain, according to the NHS, and using them long term only increases the risk of addiction.
Chronic pain is treated with much less success than acute pain, says David Andersson, professor of neuroscience at King’s College London. Each chronic pain condition has a different cause and in many cases, the cause is not well understood, he adds. To introduce a further layer of complication, placebos have been performing increasingly well in clinical trials of pain in recent decades, Mogil says, citing research published in 2015 on which he appeared as an author.
One potential explanation for this trend is the presence of a neural circuit in the brain that mediates people’s perception of pain based on their expectations of it, according to research co-written by Scherrer in 2024. People enrolled in clinical trials may expect to experience relief from pain. “When we’re expecting pain relief, we’re recruiting circuits in our brain that release endogenous opioids,” which itself suppresses pain, Scherrer explains.
In a study of patients with a chronic condition called lumbosacral radiculopathy, Journavx produced a level of pain reduction in the legs similar to that achieved by placebo. The drug did significantly reduce patients’ pain from their baseline level, which is what the trial was designed to show, according to Vertex. The company added that the placebo arm was included for “reference” and not for “statistical comparison”.
But experts largely remain unconvinced. The idea that Journavx works for lumbosacral radiculopathy seems “farcical” in the face of evidence that it does not work any better than placebo, Mogil says. Vertex said it plans to design future trials in a way that better controls placebo response.
Another new type of painkiller called cebranopadol is also angling for FDA approval after it succeeded in two late-stage clinical trials of acute pain after various surgeries. Cebranopadol activates the μ-opioid receptor, but also activates the nociceptin opioid receptor (NOP). The latter is structured very similarly to an opioid receptor but it behaves differently, says Scherrer.
Activating the NOP significantly reduces the effects of reward, tolerance and respiratory depression (slowness or shallowness of breathing) associated with μ-opioid receptor activation, according to Tris Pharma, the company behind cebranopadol. The result is a painkiller with similar effectiveness to an opioid but with much lower risk, the company said.
In what is known as a human abuse potential study, non-addicted recreational opioid users were given two types of opioids – oxycodone and tramadol – and cebranopadol to see which one they preferred. Cebranopadol was the least preferred of the three active drugs and only marginally preferred to placebo, says Tris’s chief executive, Ketan Mehta.
Another drug maker, Vertanical, recently reported phase 3 success for its non-opioid drug, VER-01, in patients with chronic back pain. The drug contains THC – the active ingredient in cannabis that causes a “high”. Patients in the trial did not experience intoxication because THC levels in their body were not high enough, the company said.
Despite all these new pharmaceutical approaches, most experts agree that there is no such thing as a magic bullet for pain. “We’re going to have to treat pain with multiple drugs that act in the peripheral nervous system, in the central nervous system, in the brain and on emotions and cognition, and not just on sensory systems,” Scherrer says. He adds that other types of treatments such as neurostimulation and cognitive behavioural therapy will also play a key role.
