Mouse sensory neurons are shown in magenta. BH4, the molecule driving chronic pain, is shown in green. Hence, the neurons “in pain” are seen in green/white. CREDIT ©Cronin/IMBA

Pain is an important alarm system that alerts us to tissue damage and prompts us to withdraw from harmful situations. Pain is expected to subside as injuries heal, but many patients experience persistent pain long after recovery. Now, a new study published in Science Translational Medicine points to possible new treatments for chronic pain with a surprising link to lung cancer. The work was spearheaded by an international team of researchers at IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Harvard Medical School, and Boston Children’s Hospital. Their findings of the research, conducted in laboratory mouse models, open up multiple therapeutic opportunities that could allow the world to improve chronic pain management and eclipse the opioid epidemic.

Acute pain is an important danger signal. By contrast, chronic pain is based on persistent injury and can even be experienced in the absence of a stimulus, injury, or disease. Despite the hundreds of millions of people affected, chronic pain is among the least well-managed areas of healthcare. To improve how persistent pain is managed and considering the raging opioid crisis, it is paramount to develop novel drugs based on a fundamental understanding of the underlying mechanisms. “We had previously shown that sensory neurons produce a specific metabolite, BH4, which then drives chronic pain, such as neuropathic pain or inflammatory pain,” says project lead and co-corresponding author Shane Cronin, a staff scientist in the Penninger lab at IMBA and a former postdoc in the Woolf lab at Harvard Medical School and F.M. Kirby Neurobiology Center, Boston Children’s Hospital. “The concentrations of BH4 correlated very well with the pain intensity. So, we naturally thought that this was a great pathway to target.”

To identify drugs that reduce BH4 levels in pain neurons, the researchers performed a “phenotypic screen” of 1000 target-annotated, FDA-approved medications. This approach allowed the scientists to start their search using medications that are currently in use for various indications, and to identify undescribed, off-target analgesic properties. Among the first findings of this hypothesis-driven search, the team was able to link the previously observed analgesic effects of several drugs, including clonidine and capsaicin, to the BH4 pathway.

“However, our phenotypic screen also allowed us to ‘repurpose’ a surprising drug,” says Cronin. The drug ‘fluphenazine’, an antipsychotic, has been used to treat schizophrenia. “We found that fluphenazine blocks the BH4 pathway in injured nerves. We also demonstrated its effects in chronic pain following nerve injury in vivo.” The researchers also found that the effective analgesic dose of fluphenazine in their experiments in the mouse model is comparable to the low end of the doses safely indicated for schizophrenia in humans.

In addition, the screen uncovered a novel and unexpected molecular link between the BH4 pathway and EGFR/KRAS signaling, a pathway involved in multiple cancers. Blocking EGFR/KRAS signaling reduced pain sensitivity by decreasing the levels of BH4. The genes of EGFR and KRAS are the two most frequently mutated genes in lung cancer, which prompted the researchers to look at BH4 in lung cancer. Surprisingly, by deleting an important enzyme, GCH1, in the BH4 pathway, the mouse models of KRAS-driven lung cancer developed fewer tumors and survived much longer. Hence, the researchers uncovered a common signaling pathway for chronic pain and lung cancer through EGFR/KRAS and BH4, thus opening up new avenues of treatment for both conditions.

“Chronic pain is currently subjected to often ineffective palliative treatments. Furthermore, effective painkillers such as opioids can lead, if used inappropriately, to severe addiction. It is therefore critical to find and develop new and repurposed drugs to treat chronic pain,” says co-corresponding author Clifford Woolf, professor of neurology and neurobiology at Harvard Medical School and director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

One intriguing aspect of the study is the mechanistic link between pain and lung cancer. “The same triggers that drive tumor growth appear to be also involved in setting the path to chronic pain, often experienced by cancer patients. We also know that sensory nerves can drive cancer, which could explain the vicious circuit of cancer and pain,” adds co-corresponding author Josef Penninger, IMBA group leader and founding director, who is currently also the director of the Life Sciences Institute at the University of British Columbia (UBC), Vancouver, Canada. “Understanding these cross-talks is therefore not only critical for cancer treatments but might also help to improve the quality of life for cancer patients towards less pain.”

Researchers say that emotional pain and chronic pain are related, and painkillers, ultimately, make things worse.

A broken heart is often harder to heal than a broken leg. Now researchers say that a broken heart can contribute to lasting chronic pain.

In a reflections column published Dec. 21 in the Annals of Family Medicine, pain experts Mark Sullivan and Jane Ballantyne at the University of Washington School of Medicine, say emotional pain and chronic physical pain are bidirectional. Painkillers, they said, ultimately make things worse.

Their argument is based on new epidemiological and neuroscientific evidence, which suggests emotional pain activates many of the same limbic brain centers as physical pain. This is especially true, they said, for the most common chronic pain syndromes – back pain, headaches, and fibromyalgia.

Opioids may make patients feel better early on, but over the long term these drugs cause all kinds of havoc on their well-being, the researchers said.

“Their social and emotional functioning is messed up under a wet blanket of opioids,” Sullivan said.

The researchers said new evidence suggests that the body’s reward system may be more important than tissue damage in the transition from acute to chronic pain.

By reward system, they are referring, in part, to the endogenous opioid system, a complicated system connected to several areas of the brain, The system includes the natural release of endorphins from pleasurable activities.

When this reward system is damaged by manufactured opioids, it perpetuates isolation and chronic illness and is a strong risk factor for depression, they said.

“Rather than helping the pain for which the opioid was originally sought, persistent opioid use may be chasing the pain in a circular manner, diminishing natural rewards from normal sources of pleasure, and increasing social isolation,“ they wrote.

Both Sullivan and Ballantyne prescribe opioids for their patients and say they have a role in short-term use.

“Long-term opioid therapy that lasts months and perhaps years should be a rare occurrence because it does not treat chronic pain well, it impairs human social and emotional function, and can lead to opioid dependence or addiction,” they wrote.

What Sullivan recommends is if patients are on high-dose long-term opioids and they are not having clear improvement in pain and function, they need to taper down or switch to buprenorphine. If available, a multidisciplinary pain program using a case manager to monitor their care and well-being, similar to those for diabetes and depression care, may be of benefit.

On a quest to develop more effective pain medicines, scientists are studying how CBD inhibits pain-sensing neurons

Image: ArtistGNDphotography/iStock/Getty Images E+ Collection

• On a quest to develop more effective painkillers, scientists are studying how cannabidiol, or CBD, inhibits pain-sensing neurons
• Recent research suggests that CBD tamps down the activity of pain-sensing neurons by simultaneously blocking sodium channels and activating potassium channels
• The findings could inform the design of novel pain therapies that harness and optimize the beneficial properties of CBD

In recent years, cannabidiol, a compound derived from cannabis plants, has begun popping up more and more in everyday life. Now legal in most U.S. states, the cannabinoid commonly known as CBD can be found in supermarkets and drugstores, where it is often sold as a gummy, an oil, or a cream, and is praised by some for its pain-suppressing properties.

But does CBD actually relieve pain? If so, how precisely does it do so? And what would it take to harness the beneficial properties of CBD into a safe and effective pain medicine?

These are some of the questions that Bruce Bean, the Robert Winthrop Professor of Neurobiology in the Blavatnik Institute at Harvard Medical School, and Clifford Woolf, HMS professor of neurology at Boston Children’s Hospital, have teamed up to explore.

Their research so far, conducted in animal models and cells, suggests that CBD simultaneously acts on two targets in pain-sensing neurons. They are now using this information to develop drugs that work the same way as CBD and are similarly safe and nonaddictive, but are more effectively absorbed by the body

Untreated pain is a significant and widespread health issue that can interfere with daily activities, lead to poor mental health, and generally result in a reduced quality of life for those afflicted. The U.S. Centers for Disease Control and Prevention estimates that around 20.4 percent of U.S. adults, or 50 million people, suffer from chronic pain, defined as pain lasting longer than three to six months.

An earlier study suggests that the economic toll of chronic pain in the United States is between $560 and $635 billion per year. However, some of the currently available and commonly prescribed pain medicines have tremendous addictive potential, leaving those who use them vulnerable to becoming dependent.

“Something that would relieve pain that’s not addictive is a great unmet need, and remains one of the most formidable challenges in modern medicine,” Bean said.

A convergence of research

Bean and Woolf have long shared an interest in developing better pain medicines. Currently, effective treatments for pain are somewhat limited, Woolf said, and opioid-based drugs prescribed for pain carry a significant risk of addiction, contributing in part to the widespread opioid crisis. In fact, the CDC estimates that since 1999, more than 932,000 people have died from drug overdoses, and in 2021, opioids were involved in 75.1 percent of overdose deaths, claiming 80,816 lives.

Prescription opioids, while not directly involved in most overdose deaths, often serve as a gateway to more dangerous synthetic opioids such as fentanyl. Yet progress in developing new pain treatments has been slow, in large part because such drugs must precision-target only pain pathways while sparing other parts of the nervous system.

“Both of us are very interested in conditions for which there’s no effective treatment, and pain certainly happens to be that,” Woolf said. “We are trying to see if we can make a big impact on patients by coming up with novel classes of highly effective and safe analgesics.”

However, the researchers did not initially plan to work together on CBD. 

Bean conducts basic research on the mechanisms underlying electrical signaling in the brain. Specifically, he studies tiny channels in the membranes of neurons that open and close to control the flow of ions, which in turn determines whether neurons fire and transmit electrical messages.

Woolf’s work centers on discovering new drugs to treat pain and neurodegenerative diseases. He specializes in performing large-scale screens on human neurons to identify novel drug targets, as well as compounds that modify disease course. In particular, he focuses on membrane receptors and ion channels that mediate inflammation and pain.

In the course of his research, Bean became intrigued by experiments suggesting that CBD reduces pain-related behavior in mice and rats, as well as anecdotal reports of CBD as a painkiller in humans.

“There are no good clinical studies of CBD for pain, but a lot of people say that it helps them with their pain,” Bean said. “We started looking at CBD directly on the electrical activity of neurons to see what it did and how it did it.”

Working in mouse models, Bean and his team found that CBD inhibits two different kinds of sodium channels found in the membranes of nociceptors, the specialized neurons that sense and communicate pain. This inhibition prevents sodium from rushing inside nociceptors, which keeps the neurons in an inactive state and stops them from firing and transmitting a “pain” message via an electrical signal.

Meanwhile, Woolf and his lab had conducted a screen on thousands of bioactive compounds to see if any of them interacted with a particular potassium channel found in the membranes of nociceptors and is involved in suppressing pain signaling—and unexpectedly, they hit on CBD.

Together, Woolf and Bean figured out that CBD activates the potassium channel, allowing potassium ions to flow inside nociceptors. This influx of potassium reduces the firing activity of the neurons, thus blocking pain signaling. In fact, flupirtine, a pain medicine with restricted use due to liver toxicity, works by the same mechanism.

“We realized that CBD is really interesting because it actually acts on two different targets in pain sensing neurons,” Bean said.

The dual finding for CBD is especially exciting, Woolf added, because sodium channels and potassium channels work together to modulate the activity of nociceptors, yet there are no treatments that target both.

“There was nothing in the literature about it, but out it popped that CBD had this potassium channel-opening activity in addition to sodium channel-blocking activity,” Woolf said. “That’s exactly what we want if we want to control the excitability of this set of neurons.”

The future of CBD

CBD has several advantages as the possible basis of an eventual pain medicine. Most significantly, it does not seem to be addictive, and it appears to be relatively safe in humans, with few side effects. In fact, it is already approved by the FDA for use in children with severe, drug-resistant epilepsy.

Still, CBD is far from ready for prime time. As an herbal compound derived from cannabis plants, it is highly variable from batch to batch and may contain other ingredients with undesirable effects. Children with epilepsy take CBD orally, mixed with sesame oil, and because CBD is poorly absorbed by the body in this form, they must consume large quantities of it. Gaps remain in understanding the safety of CBD, including how it affects various organ systems as well as how it interacts with other drugs.

“CBD has features that we want, but it doesn’t have exactly what we want, so we have to work to improve it,” Woolf said. “We’re trying to take this herbal compound with a profile that we think is promising and make it even better and more reliable.”

“Although CBD is very effective in blocking the activity of pain-sensing neurons when applied directly to a neuron in a dish, we have no idea what concentration ultimately reaches nerve cells in the body, and the concentration is probably very low with oral administration,” Bean added, so it is unlikely that CBD itself will be useful as a painkiller. “We want to make new compounds that retain the properties and the activity that we found in CBD, but are more effective drugs.”  

It is also essential, he said, that any new compounds don’t act on CB1, the receptor that binds THC to give marijuana its psychoactive effects.

Importantly, the researchers noted, any CBD-based medicines would need to be rigorously tested and approved by the FDA to ensure both safety and efficacy.

Bean and Woolf are taking a two-pronged approach to their work. One avenue involves starting with the CBD molecule itself and trying to create derivatives based on that initial scaffold that improve the properties of the compound. They are also planning to use large-scale screens to identify new compounds with completely different chemistry that target the same sodium and potassium channels in pain-sensing neurons targeted by CBD.

The researchers emphasized that CBD is part of their broader push to change how drugs, including painkillers, are developed. In traditional drug development, Woolf said, researchers choose a single target and find compounds that act on that target. However, this approach has had limited success in translating results from the lab to the clinic: when compounds move into clinical trials, they often turn out to have low efficacy or unexpected side effects.

“We’re trying to identify new ways of developing therapeutics and we’ve recognized that an alternative strategy is a polypharmacological one,” Woolf said. “The idea is that multiple targets will give us greater selectivity and safety than compounds that only act on one target.”

This strategy is bolstered by growing evidence that different types of neurons in the body have different combinations of ion channels—knowledge that the researchers are trying to exploit to develop more targeted drugs with fewer side effects. CBD, for example, targets a combination of sodium and potassium channels that seems to be specific to nociceptors, which may reduce the compound’s off-target effects.

And while their research on CBD is largely a work in progress, the researchers are hopeful that they will eventually succeed in developing a drug based on CBD that is safe, effective, and easy to take—and in the process, accomplish their overarching goal of building a better pain medicine.