An experimental drug developed at Duke University School of Medicine could offer powerful pain relief without the dangerous side effects of opioids.
Called SBI-810, the drug is part of a new generation of compounds designed to target a receptor on the nerves and spinal cord. While opioids flood multiple cellular pathways indiscriminately, SBI-810 takes a more focused approach, activating only a specific pain-relief pathway that avoids the euphoric “high” linked to addiction.
In tests in mice, SBI-810 worked well on its own and, when used in combination, made opioids more effective at lower doses, according to the study published in Cell.
Even more encouraging: it prevented common side effects like constipation and buildup of tolerance, which often forces patients to need stronger and more frequent doses of opioids over time.
SBI-810 is in early development, but Duke researchers are aiming for human trials soon and have secured multiple patents for the discovery.
There’s an urgent need for non-opioid pain relievers. Researchers said the drug could be a safer option for treating both short-term and chronic pain for those recovering from surgery or living with diabetic nerve pain.
SBI-810 is designed to target the brain receptor neurotensin receptor 1. Using a method known as biased agonism, it switches on a specific signal – β-arrestin-2 – linked to pain relief, while avoiding other signals that can cause side effects or addiction.
“The receptor is expressed on sensory neurons and the brain and spinal cord,” Ji said. “It’s a promising target for treating acute and chronic pain.”
SBI-810 effectively relieved pain from surgical incisions, bone fractures, and nerve injuries better than some existing painkillers. When injected in mice, it reduced signs of spontaneous discomfort, such as guarding and facial grimacing.
Duke scientists compared SBI-810 to oliceridine, a newer type of opioid used in hospitals, and found SBI-810 worked better in some situations, with fewer signs of distress.
Unlike opioids like morphine, SBI-810 didn’t cause tolerance after repeated use. It also outperformed gabapentin, a common drug for nerve pain, and didn’t cause sedation or memory problems, which are often seen with gabapentin.
Researchers said the compound’s dual action – on both the peripheral and central nervous systems– could offer a new kind of balance in pain medicine: powerful enough to work, yet specific enough to avoid harm.
An animated jellyfish floats through water in the PainWaive game.
Image: PainWaive
The first trial of an interactive game that trains people to alter their brain waves has shown promise as a treatment for nerve pain – offering hope for a new generation of drug-free treatments.
You’re staring at a jellyfish drifting through inky black water on a screen. As your mind calms, the water turns turquoise. Nothing else seems to change, but the headset you’re wearing has picked up a subtle shift in your brainwaves and the game responds by altering the imagery. Now, for the first time, you can see your brain activity change. And by seeing it, you can practice making it happen again.
The game is part of PainWaive, a drug-free treatment for nerve pain developed by UNSW. Combining a game-like app and a brain-monitoring headset, PainWaive teaches users how to regulate the abnormal brain activity linked to chronic nerve pain, offering a potential in-home, non-invasive alternative to opioids.
The study compared hundreds of measures across participants’ pain and related issues like pain interference before, during and after four weeks of interactive game play. Their brain activity was tracked via EEG (electroencephalogram) headsets, with the app responding in real time to shifts in brainwave patterns.
Three out of the four participants showed significant reductions in pain, particularly nearing the end of the treatment. Overall, the pain relief achieved by the three was comparable to or greater than that offered by opioids.
“Restrictions in the study’s size, design and duration limit our ability to generalise the findings or rule out placebo effects,” Dr Hesam-Shariati says.
“But the results we’ve seen are exciting and give us confidence to move to the next stage and our larger trial.”
The PainWaive project builds on UNSW Professor Sylvia Gustin’s seminal research into changes in the brain’s thalamus – a central relay hub in the brain – associated with nerve (neuropathic) pain.
“The brainwaves of people with neuropathic pain show a distinct pattern: more slow theta waves, fewer alpha waves, and more fast, high beta waves,” Prof. Gustin says.
“We believe these changes interfere with how the thalamus talks to other parts of the brain, especially the sensory motor cortex, which registers pain.
“I wondered, can we develop a treatment that directly targets and normalises these abnormal waves?”
The challenge was taken up by an interdisciplinary team at UNSW Science and Neuroscience Research Australia (NeuRA), led by Prof. Gustin and Dr Hesam-Shariati, and resulted in PainWaive.
The four participants in its first clinical trial received a kit with a headset and a tablet preloaded with the game app, which includes directions for its use. They were also given tips for different mental strategies, like relaxing or focusing on happy memories, to help bring their brain activity into a more “normal” state.
The user data, meanwhile, was uploaded to the research team for remote monitoring.
“After just a couple of Zoom sessions, participants were able to run the treatment entirely on their own,” says Dr Hesam-Shariati.
“Participants felt empowered to manage their pain in their own environment. That’s a huge part of what makes this special.”
Initially, Dr Hesam-Shariati says, the team planned to use existing commercial EEG systems, but they were either too expensive or didn’t meet the quality needed to deliver the project. Instead, they developed their own.
“Everything except the open-source EEG board was built in-house,” says Dr Hesam-Shariati. “And soon, even that will be replaced by a custom-designed board.”
Thanks to 3D printing, Prof. Gustin says, the team has cut the cost of each headset to around $300 – a fraction of the $1000 to $20 000 price tags of existing systems.
The headset uses a saline-based wet electrode system to improve signal quality and targets the sensorimotor cortex.
“We’ve worked closely with patients to ensure the headset is lightweight, comfortable, and user-friendly,” says Prof. Gustin.
“Owning the technology offers us the potential to one day offer PainWaive as a truly affordable, accessible solution for at-home pain management, especially for those with limited access to traditional treatments.”
The team is currently focussed on a randomised controlled trial of the PainWaive technology, aiming to recruit 224 people with nerve pain following spinal cord injury.
It’s part of more than a dozen active collaborations between UNSW Science and the Centre for Pain IMPACT at NeuRA, all building on Prof. Gustin’s foundational research into the brain.
Among these is a clinical trial of an eHealth therapy, called Pain and Emotion Therapy, that was shown to reduce chronic pain by retraining the brain to process emotions more effectively.
Another major project, Project Avatar, is inspired by Prof Gustin’s discovery that half of people with complete spinal cord injuries still have touch signals reaching the brain – though the brain can’t identify them.
The trial uses immersive virtual reality and real-world touch stimulation to help the brain relearn how to feel.
“Many of our team are clinician-scientists, and we’re focused on developing practical treatments that can be integrated into the healthcare system,” says Prof Gustin.
“It’s incredibly inspiring to see results that help unlock the brain’s potential to heal itself and bring back hope to people living with pain.”
The researchers are now calling for participants to register their interest in two upcoming trials of the neuromodulation technology: The Spinal Pain Trial, investigating its potential to reduce chronic spinal pain, and the StoPain Trial, exploring its use in treating chronic neuropathic pain in people with a spinal cord injury.
People who take over-the-counter pain relievers after a concussion may recover faster than those who do not take pain relievers, according to a preliminary study that will be presented at the American Academy of Neurology’s 77th Annual Meeting taking place April 5–9, 2025.
The study does not prove that pain relievers improve recovery after concussion; it only shows an association.
“These results are exciting as there are limited treatment options for concussion, and over-the-counter pain relievers are readily available and inexpensive,” said study author Kyle Arnold, MD, of the University of Washington in Seattle and a member of the American Academy of Neurology.
“If these results can be confirmed by a controlled study, they could guide us to possible treatment options for people after a concussion.”
The cohort study was conducted by the NCAA and US Department of Defense CARE Consortium and looked at NCAA athletes and military cadets who had concussions. A total of 813 people took over-the-counter pain relievers such as acetaminophen or ibuprofen and other non-steroidal anti-inflammatory drugs after their concussion and 848 people did not take any pain relievers.
Researchers looked at the amount of time it took the athletes to be cleared to return to activities with no restrictions at both 50% recovery and 90% recovery, meaning when 50% of the athletes in the study recovered and then later when 90% recovered.
People who took the pain relievers were 20% more likely to have a faster time before they were cleared to return to activities with no restrictions than those who did not take pain relievers. Those who took the medications were cleared at 50% recovery an average of two days faster, and at 90% recovery an average of seven days faster than those who took no medication.
People who took pain relievers were also about 15% more likely to return to having no symptoms more quickly than those who did not take pain relievers. At 50% recovery, those taking the medications had no symptoms one day sooner than those not taking the medications. At 90% recovery, they had no symptoms three days sooner.
Those who took pain relievers also had lower scores on tests of how severe their symptoms were overall and how severe their headaches were. The researchers also found that the earlier people took the pain relievers after the injury, the faster they recovered. For instance, at 50% recovery, those who started using pain relievers on the first day of their injury returned to play and had resolution of symptoms approximately eight days faster than those who started taking them after five or more days.
There was no difference between the type of pain reliever taken and how quickly people recovered.
“Early medication use appeared to be linked to shorter recovery times, but these findings require further validation through controlled trials,” Arnold said. “In the meantime, these preliminary results may help inform potential treatment options for people recovering from concussions, but additional studies are needed to provide more definitive recommendations.”
A new method has been developed that could non-invasively ease pain, avoiding the side effects of pain medication and the addiction problems associated with current opioid pain relievers.
This new study by Wynn Legon, assistant professor at the Fralin Biomedical Research Institute at Virginia Tech, and his team targets the insula, the location for pain reception deep within the brain. Their study, published in the journal PAIN, found that soundwaves from low-intensity focused ultrasound aimed at this spot can reduce both the perception of pain and other effects of pain, such as heart rate changes.
“This is a proof-of-principle study,” Legon said. “Can we get the focused ultrasound energy to that part of the brain, and does it do anything? Does it change the body’s reaction to a painful stimulus to reduce your perception of pain?”
Unlike ultrasound scans, focused ultrasound delivers a narrow band of sound waves to a tiny point. At high intensity, ultrasound can ablate tissue. At low-intensity, it can cause gentler, transient biological effects, such as altering nerve cell electrical activity
Neuroscientists have long studied how non-surgical techniques, such as transcranial magnetic stimulation, might be used to treat depression and other issues. Legon’s study, however, is the first to target the insula and show that focused ultrasound can reach deep into the brain to ease pain.
The study involved 23 healthy human participants. Heat was applied to the backs of their hands to induce pain. At the same time, they wore a device that delivered focused ultrasound waves to a spot in their brain guided by magnetic resonance imaging (MRI).
Participants rated their pain perception in each application on a scale of zero to nine. Participants reported an average reduction in pain of three-fourths of a point.
“That might seem like a small amount, but once you get to a full point, it verges on being clinically meaningful,” said Legon, also an assistant professor in the School of Neuroscience in Virginia Tech’s College of Science.
“It could make a significant difference in quality of life, or being able to manage chronic pain with over-the-counter medicines instead of prescription opioids.”
Researchers also monitored each participant’s heart rate and heart rate variability as a means to discern how ultrasound to the brain also affects the body’s reaction to a painful stimulus.
The study also found the ultrasound application reduced physical responses to the stress of pain – heart rate and heart rate variability, which are associated with better overall health.
“Your heart is not a metronome. The time between your heart beats is irregular, and that’s a good thing,” Legon said.
“Increasing the body’s ability to deal with and respond to pain may be an important means of reducing disease burden.”
The effect of focused ultrasound on those factors suggests a future direction for the Legon lab’s research – to explore the heart-brain axis, or how the heart and brain influence each other, and whether pain can be mitigated by reducing its cardiovascular stress effects.
Researchers have called for a reassessment of medical advice on analgesic use during pregnancy after a new study published in BMJ Openfound that pregnant women using over-the-counter analgesics are about 1.5 times more likely to have a baby with health issues.
The study found elevated risks for preterm delivery, stillbirth or neonatal death, physical defects and other problems compared with the offspring of mothers who did not take such medications.
Between 30% and 80% of women globally use non-prescription analgesics in pregnancy for pain relief. However, there is presently great variation in evidence for safety of use during pregnancy, with some drugs considered safe and others not.
“We would encourage a strong reinforcement of the official advice for pregnant women.”
Aikaterini Zafeiri, first author of the study
The study analysed data from more than 151 000 pregnancies over 30 years (1985–2015) which contained medical notes for non-prescribed maternal consumption of five common analgesic. These were paracetamol, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac, naproxen and ibuprofen – either as single compounds or in combinations.
Overall, 29% of women have taken over-the-counter analgesics during pregnancy, a figure which more than doubled to 60% during the last seven years of the 30-year study period.
When asked specifically at their first antenatal clinic visit, as opposed to later in pregnancy or after labour, 84% of women using painkillers reported use during the first 12 weeks after conception. However, the duration and dose of use and medical reason for use were not recorded.
Nevertheless, given that up to 60% of women reported using over the counter analgesics, they could not all have underlying medical conditions that would cause the increased risks seen in this study.
The study found increases in the following:
Neural tube defects: 64% more likely.
Admission to a neonatal unit: 57% more likely.
Neonatal death: 56% more likely.
Premature delivery before 37 weeks: 50% more likely.
Baby’s condition at birth based on APGAR score of less than 7 at five minutes: 48% more likely.
Stillbirth: 33% more likely.
Birthweight under 2.5 kg: 28% more likely.
Hypospadias, a birth defect affecting the penis: 27% more likely.
First author of the paper, Aikaterini Zafeiri of the University of Aberdeen said: “In light of the study findings, the ease of access to non-prescription painkillers, in combination with availability of mis-information as well as correct information through the internet, raises safety concerns.
“This is especially when mis-informed or partially-informed self-medication decisions are taken during pregnancy without medical advice.
“It should be reinforced that paracetamol in combination with NSAIDs is associated with a higher risk and pregnant women should always consult their doctor or midwife before taking any over-the-counter drugs. We would encourage a strong reinforcement of the official advice for pregnant women.”
Following a functional screen of extracts from US plants researchers found that plants with a long history of use by Native Americans as topical analgesics were often also used as gastrointestinal aids.
The study, published today in Frontiers in Physiology, found forest plants that activated the KCNQ2/3 potassium channel, a protein that passes electrical impulses in the brain and other tissues, showed a long history of use by Native Americans as topical analgesics, to treat conditions such as insect bites, stings, sores and burns. Less intuitively, the same plants that activated KCNQ2/3 and were used as traditional painkillers were often also used as gastrointestinal aids, especially for preventing diarrhoea.
“Done in collaboration with the US National Parks Service, this study illustrates how much there is still to learn from the medicinal practices of Native Americans, and how, by applying molecular mechanistic approaches we can highlight their ingenuity, provide molecular rationalizations for their specific uses of plants, and potentially uncover new medicines from plants,” said UCI School of Medicine professor Geoffrey Abbott, PhD. KCNQ2/3 is present in nerve cells that sense pain, and activating it would relieve pain by reducing pain signal transmission. The breakthrough \came when the team discovered that the same plant extracts that activate KCNQ2/3 have an opposite effect on the related intestinal potassium channel, KCNQ1-KCNE3. Previous studies on modern medicines showed that KCNQ1-KCNE3 inhibitors can prevent diarrhoea.
The Abbott Lab is currently screening native US plants, having shown already that quercetin and tannic and gallic acids explained many of the beneficial effects of the plants. The team also identified binding sites on the channel proteins that produce the effects.
Knowing that these compounds activate versus inhibit closely related human ion channel proteins, drug specificity and safety can be improved and therefore safety. More specifically, the plant compounds can be further optimised with the goal of treating pain and secretory diarrhoea.
“I personally am very excited about the paper; it was my lab’s first published collaboration with the National Park Service, and it shines a light on the incredible ingenuity and medicinal wisdom of Californian Native American tribes,” said Prof Abbott.
New analgesics are being sought to fight the opioid crisis. In addition, according to the CDC, diarrhoeal diseases account for 1 in 9 child deaths worldwide; incredibly, diarrhoea kills over 2000 children every day worldwide – more than AIDS, malaria and measles combined.
