Researchers advance drugs that treat pain without addiction
Opioids are one of the most common ways to treat pain. They can be effective but are also highly addictive, an issue that has fueled the ongoing opioid crisis. In 2020, an estimated 2.3 million Americans were dependent on prescription opioids.
Opioids bind to receptors at the end of nerve cells in the brain and body to prevent pain signals. In the process, they trigger endorphins, so the brain constantly craves more. There is a huge risk of addiction in patients using opioids for chronic long-term pain. Even patients using the drugs for acute short-term pain can become dependent on them.
Scientists have been looking for non-addictive drugs to target pain for over 30 years, but their attempts have been largely ineffective. “We desperately need alternatives for pain management,” says Stephen E. Nadeau, a professor of neurology at the University of Florida.
A “dimmer switch” for pain
Paul Blum is a professor of biological sciences at the University of Nebraska. He and his team at Neurocarrus have created a drug called N-001 for acute short-term pain. N-001 is made up of specially engineered bacterial proteins that target the body’s sensory neurons, which send pain signals to the brain. The proteins in N-001 turn down pain signals, but they’re too large to cross the blood-brain barrier, so they don’t trigger the release of endorphins. There is no chance of addiction.
When sensory neurons detect pain, they become overactive and send pain signals to the brain. “We wanted a way to tone down sensory neurons but not turn them off completely,” Blum reveals. The proteins in N-001 act “like a dimmer switch, and that's key because pain is sensation overstimulated.”
Blum spent six years developing the drug. He finally managed to identify two proteins that form what’s called a C2C complex that changes the structure of a subunit of axons, the parts of neurons that transmit electrical signals of pain. Changing the structure reduces pain signaling.
“It will be a long path to get to a successful clinical trial in humans," says Stephen E. Nadeau, professor of neurology at the University of Florida. "But it presents a very novel approach to pain reduction.”
Blum is currently focusing on pain after knee and ankle surgery. Typically, patients are treated with anesthetics for a short time after surgery. But anesthetics usually only last for 4 to 6 hours, and long-term use is toxic. For some, the pain subsides. Others continue to suffer after the anesthetics have worn off and start taking opioids.
N-001 numbs sensation. It lasts for up to 7 days, much longer than any anesthetic. “Our goal is to prolong the time before patients have to start opioids,” Blum says. “The hope is that they can switch from an anesthetic to our drug and thereby decrease the likelihood they're going to take the opioid in the first place.”
Their latest animal trial showed promising results. In mice, N-001 reduced pain-like behaviour by 90 percent compared to the control group. One dose became effective in two hours and lasted a week. A high dose had pain-relieving effects similar to an opioid.
Professor Stephen P. Cohen, director of pain operations at John Hopkins, believes the Neurocarrus approach has potential but highlights the need to go beyond animal testing. “While I think it's promising, it's an uphill battle,” he says. “They have shown some efficacy comparable to opioids, but animal studies don't translate well to people.”
Nadeau, the University of Florida neurologist, agrees. “It will be a long path to get to a successful clinical trial in humans. But it presents a very novel approach to pain reduction.”
Blum is now awaiting approval for phase I clinical trials for acute pain. He also hopes to start testing the drug's effect on chronic pain.
Learning from people who feel no pain
Like Blum, a pharmaceutical company called Vertex is focusing on treating acute pain after surgery. But they’re doing this in a different way, by targeting a sodium channel that plays a critical role in transmitting pain signals.
In 2004, Stephen Waxman, a neurology professor at Yale, led a search for genetic pain anomalies and found that biologically related people who felt no pain despite fractures, burns and even childbirth had mutations in the Nav1.7 sodium channel. Further studies in other families who experienced no pain showed similar mutations in the Nav1.8 sodium channel.
Scientists set out to modify these channels. Many unsuccessful efforts followed, but Vertex has now developed VX-548, a medicine to inhibit Nav1.8. Typically, sodium ions flow through sodium channels to generate rapid changes in voltage which create electrical pulses. When pain is detected, these pulses in the Nav1.8 channel transmit pain signals. VX-548 uses small molecules to inhibit the channel from opening. This blocks the flow of sodium ions and the pain signal. Because Nav1.8 operates only in peripheral nerves, located outside the brain, VX-548 can relieve pain without any risk of addiction.
"Frankly we need drugs for chronic pain more than acute pain," says Waxman.
The team just finished phase II clinical trials for patients following abdominoplasty surgery and bunionectomy surgery.
After abdominoplasty surgery, 76 patients were treated with a high dose of VX-548. Researchers then measured its effectiveness in reducing pain over 48 hours, using the SPID48 scale, in which higher scores are desirable. The score for Vertex’s drug was 110.5 compared to 72.7 in the placebo group, whereas the score for patients taking an opioid was 85.2. The study involving bunionectomy surgery showed positive results as well.
Waxman, who has been at the forefront of studies into Nav1.7 and Nav1.8, believes that Vertex's results are promising, though he highlights the need for further clinical trials.
“Blocking Nav1.8 is an attractive target,” he says. “[Vertex is] studying pain that is relatively simple and uniform, and that's key to having a drug trial that is informative. But the study needs to be replicated and frankly we need drugs for chronic pain more than acute pain. If this is borne out by additional studies, it's one important step in a journey.”
Vertex will be launching phase III trials later this year.
Finding just the right amount of Nerve Growth Factor
Whereas Neurocarrus and Vertex are targeting short-term pain, a company called Levicept is concentrating on relieving chronic osteoarthritis pain. Around 32.5 million Americans suffer from osteoarthritis. Patients commonly take NSAIDs, or non-steroidal anti-inflammatory drugs, but they cannot be taken long-term. Some take opioids but they aren't very effective.
Levicept’s drug, Levi-04, is designed to modify a signaling pathway associated with pain. Nerve Growth Factor (NGF) is a neurotrophin: it’s involved in nerve growth and function. NGF signals by attaching to receptors. In pain there are excess neurotrophins attaching to receptors and activating pain signals.
“What Levi-04 does is it returns the natural equilibrium of neurotrophins,” says Simon Westbrook, the CEO and founder of Levicept. It stabilizes excess neurotrophins so that the NGF pathway does not signal pain. Levi-04 isn't addictive since it works within joints and in nerves outside the brain.
Westbrook was initially involved in creating an anti-NGF molecule for Pfizer called Tanezumab. At first, Tanezumab seemed effective in clinical trials and other companies even started developing their own versions. However, a problem emerged. Tanezumab caused rapidly progressive osteoarthritis, or RPOA, in some patients because it completely removed NGF from the system. NGF is not just involved in pain signalling, it’s also involved in bone growth and maintenance.
Levicept has found a way to modify the NGF pathway without completely removing NGF. They have now finished a small-scale phase I trial mainly designed to test safety rather than efficacy. “We demonstrated that Levi-04 is safe and that it bound to its target, NGF,” says Westbrook. It has not caused RPOA.
Professor Philip Conaghan, director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine, believes that Levi-04 has potential but urges the need for caution. “At this early stage of development, their molecule looks promising for osteoarthritis pain,” he says. “They will have to watch out for RPOA which is a potential problem.”
Westbrook starts phase II trials with 500 patients this summer to check for potential side effects and test the drug’s efficacy.
There is a real push to find an effective alternative to opioids. “We have a lot of work to do,” says Professor Waxman. “But I am confident that we will be able to develop new, much more effective pain therapies.”
The Friday Five: An mRNA vaccine works against cancer, new research suggests
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
Here are the promising studies covered in this week's Friday Five:
- An mRNA vaccine that works against cancer
- These cameras inside the body have an unusual source of power
- A new theory for what causes aging
- Can bacteria make you excited to work out?
- Why women get Alzheimer's more often than men
Last minute holiday gifts for the bio-inspired
“Merry Christmas! Isn’t it fun to say Merry Christmas to everyone? Time for a party and presents and things that make children happy and give their hearts wings!” go the lyrics of the popular Christmas poem. But adults (of various religions) need their gifts this time of year, too. For the biologically inspired big children, the process of finding the right fit can be daunting. To inform your choices in both conventional and unconventional ways, Leaps.org is presenting a roundup of the coolest bio-products related to health, nutrition, gaming, lifestyle and more.
AYO Circadian Light Therapy Wearable
We don’t hear it tick, but we have our own clock inside our body–more precisely, circadian clocks. Our cells contain tiny molecular clocks that keep track of our circadian rhythms, or our sleep and metabolism pattern and activity levels, on a daily basis. Chronic circadian disruptions can lead to sleep disorders, poor energy levels, weight gain, lousy mood, and sped-up aging, as well as increased risk for every “modern” disease out there, from diabetes to cancer.
Now, high-tech glasses have been developed that attempt to mimic the benefits of sunlight. In the morning and afternoon, these glasses shed blue light into your eyes to stimulate the master clock at the base of your brain for less drowsiness. The technology's design draws from an area of research, chronobiology, that received a Nobel Prize in 2017 and has become increasingly active in recent years.
“We have been developing and testing the AYO Circadian Health solution for the past five years in collaboration with some of the world's leading experts and researchers in chronobiology, light therapy and health,” said Alexander Dimitrov, co-creator of AYO. “We have done studies with over 25,000 participants, and over one million light sessions,” Dimotrov continued, partnering with institutions such as Mount Sinai Hospital, City of Hope and the U.S. Department of Defense.
The technology could fundamentally reshape the way we view sleep, health and our daily calendars. And, when connecting to a mobile app, the glasses could minimize circadian disruptions for travelers between conflicting time zones.
($269)
myDNAge Test
It's not easy for many people to break free of their attachment to the concept of chronological age, which counts years by how many times we’ve circled the sun since the day we were born. Society lumps us all into one age bracket according to our date of birth but, lately, research is suggesting that we should do some serious deconditioning. According to these studies, the more accurate measure is your biological age, a measurement based on various biomarkers of the body’s overall health and resilience, regardless of your calendar age.
If you want to find out your “true” biological age, myDNAge is a test that focuses on epigenetics, or patterns of changes in DNA methylation, with some initial research pointing to its accuracy. It offers a snapshot of your epigenetic age as well as key biomarkers related to your metabolism, risk of Alzheimer's and more, according to Xiaojing Yang, group leader of epigenetics at myDNAge. “You can perform tests six to 12 months [apart] to track the impact of lifestyle changes,” Yang said. The kit could be a useful tool both for citizen scientists and biohacking veterans.
($299 for one kit–Use code NEWYEARNEWME to receive 50% off a second kit)
Prairie Sky Yak Cheese
Do you love cheese? Do you love exotic cheese? Do you have an interest in preserving biological and genetic diversity? If you answered yes to all three questions, yak cheese was made for you. This type of cheese typically comes from a free-range yak living 13,000 feet above surface level in the Tibetan Himalayas, a relative of the endangered Wild yak. (North America is home to at least 5,000 registered yaks.)
“When I learned that we had a piece of rare biodiversity to be preserved for future generations, I realized that the yak in North America needed a job,” said Nicole Geijer Porter, president of World Heritage Yak Conservancy (WHYC), an organization formed to protect heritage yak “If an animal cannot be beneficial to the rancher in some way, exclusively as pets and lawn ornaments, they will go extinct. Raised for meat they are often hybridized with cattle to grow bigger and faster, so they will also go extinct,” said Porter, an epigeneticist turned yak herder.
Each slice of cheese and piece of butter supports the genetic testing and tracking of Tibetan yak. (You can become a member of WHYC through the Adopt-A-Yak program). “This project is also of biological importance because of the low methane emission research on yak, and the high nutritional content of the milk and cheese,” said Porter.
As for flavor, the Prairie Sky Yak Gruyere is a semi-hard cheese with a nutty taste sometimes compared to chocolate; Tomme de Savoie is a semi-soft Alpine cheese reminiscent of a washed rind muenster; and the Yak Cheddar is made with yak milk following the classic English recipe from Wells Cathedral, with earthly and pungent flavors.
(Various prices; $59.95 for the Three Yak Cheese Flight Gift Box, $139.95 for the Regional Himalayan Yak Cheddar Gift Basket and more)
Bite Toothpaste Bits
The price of a healthy smile is steep. Each year over one billion plastic toothpaste tubes are thrown out, over 50 Empire State Buildings worth of these tubes end up in landfills or oceans, and many animals suffer and die each year in cruel tests for improving oral care in people.
Sustainable oral care is both an act of self-love and giving back to the environment. Bite is a toothpaste that boasts about its green practices for a reason: it uses recyclable glass bottles with aluminum lids that break down into sand after they’ve been used. For shipping, Bite uses kraft envelopes padded with recycled and compostable newspapers, and its boxes are made of fully recycled, corrugated cardboard and sealed with paper tape. Bite refills come in 100% home compostable pouches every four months (still no plastic).
Sustainability aside, there may be an element of fun to Bite – as you brush, a mint foam forms “like magic,” the company claims.
Fractional Laser Treatment for Skin
The environment is hard on our skin: from ultraviolet rays to pollution, a constant oxidative war is waged upon it, leading to loss of collagen and damage to the barrier function of the skin. A fractional laser treatment is a type of laser skin resurfacing procedure that essentially traumatizes the skin – in a good way - through subjecting a small area of it to tiny amounts of laser energy. The laser penetrates the second layer of skin, the dermis, leading to skin exfoliation, which stimulates collagen and elastin production.
The treatment may help with soothing acne scarring, correcting uneven skin tone and texture, and reducing wrinkles and fine lines, sun damage and age spots. Recent research suggests the fractional laser can help with improving skin elasticity and reducing the amount and depth of wrinkles, though there’s little to no evidence for any benefits for eyebags, dark circles, discolorations within the eye area and water retention.
(Typically, a single fractional laser treatment costs $750 for a small area, $1500 for a full facial treatment, and $2000 for full face.)
Gadgets and Apps to Measure Your Heart Rate Variability
Heart rate variability may sound like a condition that requires immediate medical treatment, but the more you have of it, the better for your health. Although you may think of the heart as a steadily beating metronome, there are actually small differences in the amount of time between each beat. These differences are called HRV, and having more HRV has been linked to better fitness and fewer diseases.
HRV is easy to measure with a range of gadgets on the market, including Fitbits and Oura Rings. Which product floats your boat is a matter of personal preference, but the Polar H10 chest strap offers some advantages. For example, you can measure your HRV with the Polar H10 while walking around, unlike some devices that require you to stay still while taking a reading.
Plus, the Polar sensor pairs with free apps such as Elite HRV that are great for tracking how your HRV changes over time. "HRV really helps you gauge if you're moving in a positive or negative direction" with your health, says Jason Moore, the CEO and founder of Elite HRV and Spren. Have fun experimenting over the holidays with different lifestyle habits that are associated with higher HRV, some studies show, such as intermittent fasting, regular exercise and just getting more sleep.
($89 for the Polar H10, $0 for the Elite HRV app)
FoodMarble AIRE2
Its predecessor, FOODMarble AIRE1 was a pocket-size breath-testing device that measured hydrogen on the breath. More hydrogen means less digestion, and the AIRE1 used advanced breathalyzer technology to figure out what exactly is going on with the gut. Now, the company has launched FoodMarble AIRE2, which also measures methane alongside with hydrogen. High levels of methane in the body may cause abdominal pain, bloating and constipation, cirrhosis of the liver and chronic pancreatitis. The AIRE2 also comes with haptic feedback to make it easier to use.
Research suggests that these breath tests are valid as at-home diagnostic tools for many digestive conditions. To get the most accurate results, though, it’s important to closely follow the recommended protocol - for example, you can’t eat or drink anything for 10 to 12 hours before the test.
($229)
Adventurist Backpack’s Classic Backpack
The Classic backpack is a perfect option for life science aficionados who enjoy getting outside and exploring in nature. Padding in the front and back provides extra protection for camera gear, laptop, and other electronics, and it's completely water-resistant so you can get outside in winter weather.
Nobility points: Adventurist Backpack Co. is partnered with national non-profit Feeding America, and every backpack sold helps provide 25 meals to families in need across the U.S.
($65)
This Saves Lives
Speaking of nobility points, you could load your new backpack with a food choice that helps feed others as well. In 2013, actors Kristin Bell, Ryan Devlin, Ravi Patel and Todd Grinnell teamed up to start This Saves Lives, which makes power bars full of vitamins and nutrients, and the company has a unique business model: for every bar you buy, a packet of food is sent to a child in need. In addition to offering essential nutrients, the bars are non-GMO, kosher and gluten-free. Note: This Saves Lives is owned by the same company, GOOD Worldwide, that owns Leaps.org.
(Wild Blueberry & Pistachio bars, $23.99)
NADI X Pants
Even if you’re a yoga zealot enjoying the benefits to your strength, balance and flexibility, chances are you're performing the movements sort of askew. Wearable technology wants to improve your yoga posture and these sleek yoga pants called NADI X have subtle electronic sensors that track how you place your hands, rotate your hips, and align your back. The leggings use haptic feedback (or vibrations on your skin) to slowly guide you into correct alignment. You can also combine the wearable with an app that contains 40 poses and fitting music. Even if you aren't into yoga, you could use the pants for a perfect stretching session. If you do use it for yoga poses, the pants will “speak” to you, letting out a soothing "om" sound once everything is perfect.
Meta Quest Pro VR headset
When it comes to perfecting virtual reality (VR), the Meta Quest Pro VR headset is one step ahead the rest. In a vibrant 3D virtual space, your Meta avatar has the ability to translate your real-life facial expressions into the virtual realm so the experience can feel more personal, while controllers track your movement and use haptic feedback to translate your hand gestures and finger actions into VR as well. Unlike its Quest 2 headset, Meta markets this Quest Pro headset, which was just released in October, as a great tool for work and business meetings, but you can also use it to play games, watch movies, or download fitness apps or mental-health related apps – some of which are designed to help you get boxing workouts with long-distance friends, fight your fear of heights or meditate in outer space.
Rouge Sur Mesure Custom Lip Color Creator
Beauty and artificial intelligence (AI) complement each other well in the new Yves Saint Laurent lip personalized color – which wants to put the final nail on the coffin of generic lipsticks. This is a lipstick printer at its core. You pair a device to your smartphone and then insert three lipstick cartridges into the base, each of which comes with a color palette (all four could create up to 4,000 lipstick shades). Particularly charming is the fact that you can take a photo of your outfit, and the app will suggest shades that match or clash it.
($299, cartridges $89 each)
Dairy-Free Cream Cheese and Meatless Breakfast Patties
On the environmental front again, meatless patties and dairy-free cream cheese constitute conscientious and delicious choices for vegans, vegetarians and pretty much anyone else. Chicago-based Nature's Fynd is worth checking out. It uses a microbe named Fusarium strain flavolapis, which has origins in an acidic hot spring at Yellowstone National Park.
“We use this remarkable microbe to grow Fy — a nutritional fungi protein that’s made into a wide variety of delicious and sustainable foods,” says Karuna Rawal, Nature’s Fynd CMO. Fy is grown via a breakthrough fermentation process using a fraction of the water, land, and energy compared to traditional protein sources.
It’s a sustainable way to grow food for Earth’s population,” but Nature’s Fynd isn’t just concentrating on Earth. The company recently partnered with NASA to send Fy to space. “As long as there’s an appropriately controlled environment, we can grow Fy anytime, anywhere. It could be a nutritious food source for astronauts on deep space missions," said Rawal.
CBD Oil
Biologically curious people may be especially interested in trying cannabinoid (CBD) oil. CBD is a natural and safe substance found in cannabis, which has been found to tackle anxiety and depression, reduce symptoms of post-traumatic stress disorder, help manage chronic pain and migraines, improve sleep patterns, and keep panic attacks at bay. Kanibi’s Isolate CBD Oil Tincture is a good choice as it is cinnamon-flavored and made in an FDA-inspected facility.
($109--25% off on your first order)
Govee RGBIC Floor Lamp
Another winner for anyone who's been hearing about the health benefits of obeying your circadian rhythms: "RGB" lights, or red-green-blue lights that can be operated by remote control to shine bright blue light during the day and then, with a few touches of your phone, bathe you in warmer, red light to get you ready for bed. Look for RGB bulbs to stick into the light fixtures you already have, or you could opt for the Govee floor lamp that syncs with an app on your phone (or Alexa) for circadian color changing. You can also put it on party mode and watch it shift across 16 million color shades in response to the rhythms and beats of Cuddle Up, Cozy Down Christmas and Hanukkah Oh Hanukkah.
($99)
PackPoint
If you suffer from packing anxiety (or incompetence), an app may take away the pain. PackPoint is an app that builds your packing list according to trip type, activities and weather. You add your trip details, select activities (fancy dinner, business meeting, or even workout are some examples), and PackPoint tells you what you need to bring to your destination. The app is free, but upgrading to Premium for a small fee lets you add your own activities and packing list items.
(Free, Premium Package $2.99)
Eternity Rose
Roses symbolize love, passion, innocence, friendship, and the disarming power of natural beauty. They wilt fast, though, and their spectacle is an unsettling reminder of the fragility of beauty and existence. Unless you dip the rose in 24 karat gold.
The Eternity Rose is put through an intricate three-month process of electroplating, or coating the rose with copper and then with other metals in micro-thin layers. You won’t have to see your flowers sag after a few days because these roses never die. The glitter of gold atop the natural rose (or platinum or silver–whatever you prefer) will fit right in with the Christmas Eve ambiance.
($169 for the gold rose)