Researchers advance drugs that treat pain without addiction
New therapies are using creative approaches that target the body’s sensory neurons, which send pain signals to the brain.
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.”
Neil deGrasse Tyson Wants Celebrities to Promote Scientists
Neil de Grasse Tyson wants fellow celebrities to point their followers to experts and organizations who know what they're talking about.
"President Kennedy was the first president to not wear a hat. Have you seen men wearing hats since then?" Neil deGrasse Tyson, one of the world's few astrophysicists with a household name, asks on the phone from his car. Well, no. "If I wear some cowboy hats, it's because it's the outfit, it's not because that's my standard equipment when I leave the home."
"We have classes on 100 things and none of them are on the ability to distinguish what is true and what is not."
But Tyson, who speaks in methodically reasoned paragraphs with lots of semi-rhetorical questions to make sure we're all still listening, isn't really making a point about Mad Men-era men's clothing trends. "Should a president influence fashion?" he says. "I think people sometimes don't know the full power they have over other people. So, that's the first prong in this comment. My second prong is, why would anyone take medical advice from a politician?"
Days before our conversation, news broke that President Trump said he was taking hydroxychloroquine, which he had hyped for months as a surefire magical cure for COVID-19 — the science just hadn't caught up to his predictions. But the science never did catch up; instead, it went the opposite direction, showing that hydroxychloroquine, when used to treat COVID-19 patients, actually led to an increased risk of death.
Alarm spread swiftly around the globe as experts cast the president's professed self-medicating as illogical and dangerous. However, it was just one of a series of wild pieces of medical advice espoused by Trump from his mighty pulpit, like that, hey, maybe disinfectants could cure people when injected into their bodies. (That also leads to death.)
But people do take medical advice from politicians. An Arizona man afraid of COVID-19 died after consuming chloroquine phosphate, which he and his wife had sitting on the back of a shelf after using it to treat koi fish for parasites. The pandemic has exposed many weaknesses in the feedback loop of society, government, the media, and science, including the difficulty of seeding accurate medical information with the masses. Many on the left and right decry a broken political and news media system, but Tyson believes the problem isn't mega-influencers like Trump. Rather it's the general public's desire to take their advice on complex topics – like the science of virology – that such influencers know nothing about.
Tyson's not upset with the public, who follow Trump's advice. "As an educator, I can't get angry with you," he says. Or even Trump himself. "Trump was elected by 60 million people, right? So, you could say all you want about Trump, kick him out of office, whatever. [There's] still the 60 million fellow Americans who walk among us who voted for him. So, what are you going to do with them?"
Tyson also isn't upset with Facebook, Twitter, and other social platforms that serve as today's biggest conduits for misinformation. After all, in the realm of modern media's history, these networks are tadpoles. "As an educator and as a scientist, I'm leaning towards, let's figure out a way to train people in school to not fall victim to false information, and how to judge what is likely to be false relative to what is likely to be true. And that's hard, but you and I have never had a class in that, have we? We've had biology classes, we've had English lit, we've had classes on Shakespeare — we have classes on 100 things and none of them are on the ability to distinguish what is true and what is not."
This is why Tyson himself doesn't engage in Trump bashing on his social feeds, but does try to get people to differentiate factual science from fake news. "I feel responsibility to participate in the enlightenment of culture and of civilization, because I have that access," says Tyson, who has 13.9M followers on Twitter, 1.2M on Instagram, and 4.2M on Facebook. He doesn't tell his followers not to inject themselves with Clorox ("no one likes being told what to do"), but tries to get them to visualize a pandemic's impact by comparing it to, say, a throng of rabbits.
"Left unchecked, 1,000 rabbits in 5 years, become 7-billion, the human population of the World. After 15 years, a 'land-ocean' of rabbits fills to one-kilometer depth across all of Earth's continents. Viruses can reproduce waaaay faster than Rabbits," he tweeted on April 6, after much of the nation had locked down to slow the pandemic's spread. For added viral impact, he attached a photo of an adorable, perhaps appropriately scared-looking, white bunny.
Of course, not all celebrities message responsibly.
Tyson is a rare scientist-turned-celebrity. His appeal isn't acting in movies or singing dance-pop anthems (if only). Rather, his life's work is making science fun and interesting to as many people as possible through his best-selling books on astrophysics and his directorship of the planetarium at the American Museum of Natural History in New York. His longstanding place in popular culture is an exception, not the rule.
And he believes his fellow celebrities, actors and pop music stars and internet influencers, should aid the public's quest for accurate scientific information. And in order to do that, they must point their followers to experts and organizations who know what they're talking about. "It could be to a website, it could be to a talk that was given. I would say that that's where the responsibility lies if you control the interests of a million people," he says.
One example of this is Lady Gaga's March 14 Instagram of herself on her couch with her three dogs with the caption, "So I talked to some doctors and scientists. It's not the easiest for everyone right now but the kindest/healthiest thing we can do is self-quarantine and not hang out with people over 65 and in large groups. I wish I could see my parents and grandmas right now but it's much safer to not so I don't get them sick in case I have it. I'm hanging at home with my dogs." (All the celebrities here in this article are my references, not Tyson's, who does not call out specific people.)
Of course, not all celebrities message responsibly. Jessica Biel and Jenny McCarthy have faced scorn for public stances against vaccines. Gwyneth Paltrow and her media brand GOOP have faced backlash for promoting homeopathic treatments with no basis in science.
"The New Age Movement is a cultural idea, it has nothing to do with religion, has nothing to do with politics, and it's people who were rejecting objectively established science in part or in total because they have a belief system that they want to attach to it, okay? This is how you get the homeopathic remedies," says Tyson. "That's why science exists, so that we don't have to base decisions on belief systems."
[Editor's Note: This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]
Masks and Distancing Won't Be Enough to Prevent School Outbreaks, Latest Science Suggests
The likely dominant mode of aerosol transmission cannot be ignored in school settings.
Never has the prospect of "back to school" seemed so ominous as it does in 2020. As the number of COVID-19 cases climb steadily in nearly every state, the prospect of in-person classes are filling students, parents, and faculty alike with a corresponding sense of dread.
The notion that children are immune or resistant to SARS-CoV-2 is demonstrably untrue.
The decision to resume classes at primary, secondary, and collegiate levels is not one that should be regarded lightly, particularly as coronavirus cases skyrocket across the United States.
What should be a measured, data-driven discussion that weighs risks and benefits has been derailed by political talking points. President Trump has been steadily advocating for an unfettered return to the classroom, often through imperative "OPEN THE SCHOOLS!!!" tweets. In July, Secretary of Education Betsy DeVos threatened to withhold funding from schools that did not reopen for full-time, in-person classes, despite not having the authority to do so. Like so many public health issues, opening schools in the midst of a generational pandemic has been politicized to the point that the question of whether it is safe to do so has been obscured and confounded. However, this question still deserves to be examined based on evidence.
What We Know About Kids and COVID-19
Some arguments for returning to in-person education have focused on the fact that children and young adults are less susceptible to severe disease. In some cases, people have stated that children cannot be infected, pointing to countries that have resumed in-person education with no associated outbreaks. However, those countries had extremely low community transmission and robust testing and surveillance.
The notion that children are immune or resistant to SARS-CoV-2 is demonstrably untrue: children can be infected, they can become sick, and, in rare cases, they can die. Children can also transmit the virus to others, especially if they are in prolonged proximity to them. A Georgia sleepaway camp was the site of at least 260 cases among mostly children and teenagers, some as young as 6 years old. Children have been shown to shed infectious virus in their nasal secretions and have viral loads comparable to adults. Children can unquestionably be infected with SARS-CoV-2 and spread it to others.
The more data emerges, the more it appears that both primary and secondary schools and universities alike are conducive environments for super-spreading. Mitigating these risks depends heavily on individual schools' ability to enforce reduction measures. So far, the evidence demonstrates that in most cases, schools are unable to adequately protect students or staff. A school superintendent from a small district in Arizona recently described an outbreak that occurred among staff prior to in-person classes resuming. Schools that have opened so far have almost immediately reported new clusters of cases among students or staff.
This is because it is impossible to completely eliminate risk even with the most thoughtful mitigation measures when community transmission is high. Risk can be reduced, but the greater the likelihood that someone will be exposed in the community, the greater the risk they might pass the virus to others on campus or in the classroom.
There are still many unknowns about SARS-CoV-2 transmission, but some environments are known risks for virus transmission: enclosed spaces with crowds of people in close proximity over extended durations. Transmission is thought to occur predominantly through inhaled aerosols or droplets containing SARS-CoV-2, which are produced through common school activities such as breathing, speaking, or singing. Masks reduce but do not eliminate the production of these aerosols. Implementing universal mask-wearing and physical distancing guidelines will furthermore be extraordinarily challenging for very young children.
Smaller particle aerosols can remain suspended in the air and accumulate over time. In an enclosed space where people are gathering, such as a classroom, this renders risk mitigation measures such as physical distancing and masks ineffective. Many classrooms at all levels of education are not conducive to improving ventilation through low-cost measures such as opening windows, much less installing costly air filtration systems.
As a risk reduction measure, ventilation greatly depends on factors like window placement, window type, room size, room occupancy, building HVAC systems, and overall airflow. There isn't much hard data on the specific effects of ventilation on virus transmission, and the models that support ventilation rely on assumptions based on scant experimental evidence that doesn't account for virologic parameters.
There is also no data about how effective air filtration or UV systems would be for SARS-CoV-2 transmission risk reduction, so it's hard to say if this would result in a meaningful risk reduction or not. We don't have enough data outside of a hospital setting to support that ventilation and/or filtration would significantly reduce risk, and it's impractical (and most likely impossible in most schools) to implement hospital ventilation systems, which would likely require massive remodeling of existing HVAC infrastructure. In a close contact situation, the risk reduction might be minimal anyway since it's difficult to avoid exposure to respiratory aerosols and droplets a person is exhaling.
You'd need to get very low rates in the local community to open safely in person regardless of other risk reduction measures, and this would need to be complemented by robust testing and contact tracing capacity.
Efforts to resume in-person education depend heavily on school health and safety plans, which often rely on self-reporting of symptoms due to insufficient testing capacity. Self-reporting is notoriously unreliable, and furthermore, SARS-CoV-2 can be readily transmitted by pre-symptomatic individuals who may be unaware that they are sick, making testing an essential component of any such plan. Primary and secondary schools are faced with limited access to testing and no funds to support it. Even in institutions that include a testing component in their reopening plans, this is still too infrequent to support the full student body returning to campus.
Economic Conflicts of Interest
Rebecca Harrison, a PhD candidate at Cornell University serving on the campus reopening committee, is concerned that her institution's plan places too much faith in testing capacity and is over-reliant on untested models. Harrison says that, as a result, students are being implicitly encouraged to return to campus and "very little has been done to actively encourage students who are safe and able to stay home, to actually stay home."
Harrison also is concerned that her institution "presumably hopes to draw students back from the safety of their parents' basements to (re)join the residential campus experience ... and drive revenue." This is a legitimate concern. Some schools may be actively thwarting safety plans in place to protect students based on financial incentives. Student athletes at Colorado State have alleged that football coaches told them not to report COVID-19 symptoms and are manipulating contact tracing reports.
Public primary and secondary schools are not dependent on student athletics for revenue, but nonetheless are susceptible to state and federal policies that tie reopening to budgets. If schools are forced to make decisions based on a balance sheet, rather than the health and safety of students, teachers, and staff, they will implement health and safety plans that are inadequate. Schools will become ground zero for new clusters of cases.
Looking Ahead: When Will Schools Be Able to Open Again?
One crucial measure is the percent positivity rate in the local community, the number of positive tests based on all the tests that are done. Some states, like California, have implemented policies guiding the reopening of schools that depend in part on a local community's percent positivity rate falling under 8 percent, among other benchmarks including the rate of new daily cases. Currently, statewide, test positivity is below 7%, with an average of 3 new daily cases per 1000 people per day. However, the California department of health acknowledges that new cases per day are underreported. There are 6.3 million students in the California public school system, suggesting that at any given time, there could be nearly 20,000 students who might be contagious, without accounting for presymptomatic teachers and staff. In the classroom environment, just one of those positive cases could spread the virus to many people in one day despite masks, distancing, and ventilation.
You'd need to get very low rates in the local community to open safely in person regardless of other risk reduction measures, and this would need to be complemented by robust testing and contact tracing capacity. Only with rapid identification and isolation of new cases, followed by contact tracing and quarantine, can we break chains of transmission and prevent further spread in the school and the larger community.
None of these safety concerns diminish the many harms associated with the sudden and haphazard way remote learning has been implemented. Online education has not been effective in many cases and is difficult to implement equitably. Young children, in particular, are deprived of the essential social and intellectual development they would normally get in a classroom with teachers and their peers. Parents of young children are equally unprepared and unable to provide full-time instruction. Our federal leadership's catastrophic failure to contain the pandemic like other countries has put us in this terrible position, where we must choose between learning or spreading a deadly pathogen.
Blame aside, parents, educators, and administrators must decide whether to resume in-person classes this fall. Those decisions should be based on evidence, not on politics or economics. The data clearly shows that community transmission is out of control throughout most of the country. Thus, we ignore the risk of school outbreaks at our peril.
[Editor's Note: Here's the other essay in the Back to School series: 5 Key Questions to Consider Before Sending Your Child Back to School.]