Taking Aim at New Pain Drugs

Sodium channels are a promising target for pain treatment, but researchers face a long road ahead. Image: Artistic rendering of the Nav1.7 sodium channel. Each channel has four domains that sit in the cell membrane of nerve cells. Credit: Elaine Alibrandi (www.elainealibrandi.net).

Sodium channels are a promising target for pain treatment, but researchers face a long road ahead. Image: Artistic rendering of a Nav1.7 sodium channel. Each channel has four parts that sit in the cell membrane of nerve cells. Credit: Elaine Alibrandi (www.elainealibrandi.net).

With an estimated 100 million adults living with chronic pain in the U.S., the need for more effective therapies for pain is of paramount importance. Pharmaceutical treatments available today are only partly effective in just a subset of patients. Meanwhile, massive over-prescribing of opioid drugs in the past twenty years has led to an epidemic of abuse and addiction without improving the outlook for chronic pain patients. Although the past several decades have yielded an unprecedented new understanding of chronic pain, that has yet to translate into new pain medications. But there may be light at the end of that tunnel. Researchers are hopeful that a new class of analgesic (pain-relieving) drugs directed at pain-sensing neurons might one day provide an effective weapon in the arsenal for fighting pain.

What are researchers striving for in new pain drugs? The holy grail is an agent that could effectively curb chronic pain without affecting normal sensations, and do so without side effects in the central nervous system (brain and spinal cord) or the heart, and without the risk of addiction. It’s a tall order. However, new drugs aimed at a class of proteins called voltage-gated sodium channels (Navs) could fit the bill, at least for some types of pain. Despite that continuing promise, clinical trials of new compounds aimed at Navs have not gone as smoothly as researchers had hoped based on the underlying science.

Nav1.7: A promising drug target emerges
“This sodium channel has to be the best opportunity [to develop a new therapeutic] for pain science in quite a while,” says Stephen McMahon, King’s College London, UK, referring to Nav1.7, the seventh among nine known voltage-gated sodium channels. Ion channels like Nav1.7 are tiny pore-shaped proteins that sit in the outer membrane of neurons and some other types of cells. Ions are electrically charged particles, such as sodium, potassium and calcium, which flow in and out of cells through ion channels, changing the cells’ electrical excitability. Ion channels that open and close in response to changes in voltage, such as Nav1.7, generate electrical signals and give neurons their capacity to communicate with one another.

In the absence of incoming signals, neurons sit in an electrical resting state, but when an excitatory signal comes along, they respond by “depolarizing,” or becoming electrically excited. When this excitation reaches a certain threshold, neurons fire an action potential, an electrical signal that rapidly spreads to the far ends of the neurons, where the signal gets passed along to neighboring neurons. That includes sensory neurons that detect pain and other sensations from the body and transmit them to neurons in the spinal cord.

“Intuitively, Navs are clear targets for pain,” says Sulayman Dib-Hajj, Yale University School of Medicine, New Haven and the Veterans Affairs Medical Center, West Haven, Connecticut, US, “because without them, you can’t get a [pain] signal from point A to point B.” Most people have experienced a loss of sodium channel function during a trip to the dentist’s office. Local anesthetics such as lidocaine (Xylocaine) and procaine (Novocaine) work to deaden sensation by blocking sodium channels non-selectively—meaning the drugs hit multiple types of Navs. The problem with using nonselective drugs like lidocaine or procaine to treat pain is that they block all sensations, which can lead to injury or disability. An even bigger problem with taking sodium channel blockers that spread throughout the body—when taken in pill form, for example—is that they would also affect voltage-gated sodium channels found in the heart and throughout the central nervous system. Turning off those sodium channels could be deadly.

But today, researchers are focused squarely on Nav1.7, a channel that appears in pain-sensing neurons (and a few other cell types), but not in the heart or in the brain. That means that side effects would likely be very limited compared to today’s painkillers such as opioids. If researchers could find a way to selectively block or dampen Nav1.7 activity, they reason that they should stop pain signals without negative consequences. This approach has proved much trickier than researchers expected, however.

Genetic discoveries
In the late 1990s, researchers discovered that one particular Nav channel, Nav1.7, was found mostly in pain-sensing neurons and not other cells. Since then, researchers around the world have made the critical link between this channel and pain in humans by studying families with extremely rare pain disorders.

First, in 2004, Chinese researchers studying two families with a rare pain disorder found mutations in SCN9A, the gene that directs the production of Nav1.7. The family members suffered from inherited erythromelalgia (IEM), a disease characterized by redness and severe burning pain, usually in the hands or feet, in response to warmth, exercise or even standing. (Although still a rare condition, erythromelalgia of unknown origin affects many more people.)

Later that year, together with Dib-Hajj, Stephen Waxman, also at Yale University School of Medicine and the Veterans Affairs Medical Center, showed that the mutations increased the activity of Nav1.7 channels. In 2005, the same team confirmed that the SCN9A mutations found in an American family caused nerve cells in a dish to become hyperactive, which could account for the painful condition.

Next, in 2006, Caroline Fertleman in collaboration with John Wood, University College London, UK, showed that other mutations in SCN9A that cause increased channel activity also caused another rare pain condition, called paroxysmal extreme pain disorder.

But the real leap from Nav1.7 to human pain came with a discovery by British researchers in 2006. Geoff Woods and James Cox at the University of Cambridge, UK, found that people with an extremely rare—and dangerous—condition called congenital insensitivity to pain (CIP) also carried a different mutation in SCN9A; people with CIP feel no pain whatsoever. This time, the mutation made Nav1.7 completely unable to function. That finding showed that Nav1.7 is crucial to the experience of pain.

Together, these findings have confirmed that Nav1.7 plays a vital role in pain signaling in people with rare diseases. But they extend to the much wider population of people living with chronic pain. In 2012, together with collaborators in the Netherlands, Waxman showed that mutations in SCN9A were also present in many people with small fiber neuropathy (SFN), a much more common pain condition that results from damage to peripheral nerves (those outside of the brain and spinal cord), often with no known cause. Moreover, the results of these studies indicate that drugs aimed at Nav1.7 might work for all types of pain originating in peripheral nerves (as most do), not just for pain in people with genetic differences in SCN9A.

The Nav story, Waxman says, parallels that of the development of cholesterol-lowering statin drugs, which have provided a major public health advance toward managing metabolic disorders.

“Statin development was propelled by the initial discovery of families with hypercholesterolemia,” a very rare, high-cholesterol condition. “Those patients desperately needed help, but they also helped show the way toward the molecules that were major players in metabolic diseases” more broadly, Waxman explains. In the same way, he says, people with rare pain diseases have generously shared their stories and their DNA, “which has led the way to discovering the Navs that play important roles in pain not just in those with rare genetic disorders but also in the broader population.”

By now, a landslide of evidence from cells, animals and people has contributed to the idea that Nav1.7 might be the best-ever shot researchers have at a potent new pain drug with minimal side effects. But early clinical trials of Nav1.7 inhibitors have not yet produced a wonder drug.

The hunt is on
Pharmaceutical and biotechnology companies are actively developing agents aimed at Nav1.7, as well as several other related Navs that also appear to participate in pain signaling. John Mulcahy, co-founder and vice president of research at SiteOne Therapeutics, San Francisco, US, estimates that at least a dozen companies—including his—are in pursuit of drugs that can selectively silence Nav1.7 to reduce pain.

Early clinical trials of drugs that quiet Nav1.7, however, have had mixed results. In a trial held by Pfizer in just five patients with IEM, who all had confirmed mutations in SCN9A, a Nav1.7 blocker drastically reduced pain in some but not all of the subjects.

Wider clinical trials “have failed in osteoarthritis,” says William Schmidt, a consultant to pharmaceutical companies with NorthStar Consulting, Davis, US. “But new trials in people with neuropathic pain—resulting from nerve damage—are in progress.” That includes trials conducted by Teva Pharmaceutical Industries and Xenon Pharmaceuticals in people with post-herpetic neuralgia, a painful condition caused by the virus responsible for chicken pox and shingles, Schmidt said.

The new drugs “are aiming at a single gene product, which is a tractable target,” says McMahon. Removal of the SCN9A gene in animals and people “leads to complete analgesia. You’d think we could recapitulate that pharmacologically.”

Why weren’t the trials more successful if the target seems so promising? One explanation might be that Nav1.7 simply isn’t as critical to sensing pain as the research suggests. “The problem is often more complex than you’d think. If it quacks like a duck, and walks like a duck, it still may not be a duck,” McMahon says. But few researchers are willing to give up on Nav1.7. “I still think it’s a fantastic target,” he says.

Another possibility is that inhibiting Nav1.7 might improve some types of pain and not others, Schmidt says. “Clinical trials have to look at specific individual conditions. Unfortunately, most companies test only one condition, and if [a new drug] doesn’t work [for that condition], they give up.” In reaching out to the biggest market—people with common conditions such as low back pain or osteoarthritis, for example—drug companies might miss the opportunity for success in less common conditions that still affect tens of millions of people, he says.

The trial results, Schmidt says, could suggest that blocking Nav1.7 alone will not reduce pain, but that the new drugs might work better in combination with other drugs already in use, such as opioids. That could allow patients to lower their opioid dose and achieve a better level of pain relief.

“Hopefully that would reduce opioid side effects like tolerance and addiction, if we could balance the two types of pain inhibition. This is a strategy that many of us working in this area strongly endorse,” Schmidt says. Traditionally, clinical trials have excluded subjects taking any drugs other than the one being tested, but Schmidt says that design may be outdated. “We can get more information by adding multiple drugs during trials.”

Some researchers believe that if inhibiting Nav1.7 is not sufficient to relieve chronic pain, the answer may be to inhibit multiple types of Nav channels, or even other types of channels, along with Nav1.7. Two other members of the sodium channel family, Nav1.8 and Nav1.9, are also considered potential drug targets because, like Nav1.7, they are mostly confined to sensory neurons and seem to contribute to triggering pain signals.

Theodore Cummins, Indiana University, Indianapolis, US, says that evolution might account for why multiple Nav channels generate pain signals. After an injury or during illness, pain lays us low so that we can rest and heal. “The interesting thing about pain-sensing fibers is that they have adapted so that they can work even in injured tissue,” because the sensation of pain is so important to healing. “Neurons do that by expressing more than one Nav,” says Cummins. “It provides a backup function. The sodium channels work together to make sure that pain sensations get through. That’s great during injury, but it makes it more difficult to treat chronic pain” that remains after the injury has healed.

Still, McMahon says, “just like in a good murder mystery, the obvious is still possible: that Nav1.7 may be a critical contributor to pain signaling.”

The problem with the new agents might be purely practical. It’s quite a tricky proposition to design a drug that has 100 times the selectivity for Nav1.7 over other Nav channels, low toxicity, and the ability to get into the body and reach the nerve fibers where the drugs work.

“This is a huge problem for the field,” says Justin Du Bois, a chemist at Stanford University, US. “The challenge is not just achieving selectivity [for Nav1.7], but getting the drug to the right cellular address.” In laboratory studies, he says, “we work with these channels made of recombinant, or genetically engineered, proteins in artificial cells. The situation in living organisms is so different: nerves are hard to reach, and they are wrapped in myelin,” a fatty substance that speeds nerve signaling. “It’s not easy to replicate that in a dish.”

Of the pharmaceutical companies working on the problem, Cummins says, “I’m optimistic they’re going to figure it out and get the right balance of all those properties to produce a drug that will work.”

Fast forward?
Despite the challenges and setbacks on the road to new pain drugs, researchers remain hopeful about future medicines aimed at Navs. All things considered, this line of research has actually progressed very rapidly.

“Drug discovery is full of challenges, not only scientific challenges but also the business challenges found in the drug development industry,” Waxman says. “This is a very exciting time, but that excitement doesn’t take away from the need for rigor, time and funding,” he says.

“Don’t think of these blockers as being the only game in town,” says Dib-Hajj. He points out that while present efforts are mainly aimed at developing “small molecules,” or chemical drugs that block the channel, “we’re not just relying on small-molecule approaches.” Drugs designed to interfere with the production of Nav1.7 channels—rather than just blocking their activity—could also work, as could viruses designed to alter the amount of Nav1.7 or the function of the channel. “Gene therapy is now within the realm of clinical trials, though not yet for targeting of sodium channels,” Dib-Hajj says.

The overall message? “Multiple approaches are being pursued. This work is the culmination of a huge effort by many groups,” according to Dib-Hajj.

Other researchers echo that sentiment. The sheer number of companies pursuing drugs directed at Navs, Mulcahy says, “indicates that a lot of smart people are working on this approach.”

It’s an approach that “still remains the best game in town; it has the best potential for reducing pain of peripheral origin,” says McMahon.

“I think that these new drugs will come along,” says Schmidt. “People are working very hard on this right now.”

While researchers are notoriously hesitant to put a timeline on when patients can expect new pain drugs, they seem to agree that this strategy might pay off within five to ten years.
