The Future of Painkillers

The human peripheral nervous system is a massive network of highways that carry signals from every part of the body back to the spinal cord and brain – the sister components of the central nervous system. Sensations such as pressure, temperature and pain cruise those highways in their own vehicles. At numerous gates along the way, called ion channels, each vehicle is either permitted to continue or is taken off the road and junked.

Now imagine those vehicles are actually electric impulses traveling from nerve endings to the central nervous system, where they will be processed as sensations when they reach the brain. When that signal is pain, sodium ions must travel through the gate known as the Nav1.7 sodium ion channel, which is present in all the neurons of the peripheral nervous system. Imagine shutting down those gates, and you will have a pretty good idea of what the future of painkillers looks like.

Now imagine being one of those 50 million Americans suffering from chronic pain every day. The most effective painkillers are opiates, such as morphine and its derivatives, which change the way the brain perceives pain signals. In doing so, it becomes addictive even while it impairs judgment and cognition.

But researchers at two drug companies – Icagen, a biotech firm in North Carolina, and Pfizer, the pharmaceutical giant – are developing a drug that would block the Nav1.7 sodium ion channel, essentially cutting pain off at its source by erecting a barrier at its gates.

Because it does not act on the central nervous system, Simon Halegoua, one of the scientists at Stony Brook University who helped to discover this ion channel over a decade ago, said that this painkiller would potentially have no side effects at all.

Richard D. Katz, Icagen’s chief financial officer, said this drug was designed with a special focus on patients with nerve damage from cancer and diabetes, as well as those with pain from joint inflammation, as in arthritis. While it theoretically could treat short-term injuries like bruises or headaches, Icagen’s priority is to find a workable alternative to opiates, he said.

The painkiller comes in pill form, and is not directed to specific areas but to the body as a whole, targeting only the Nav1.7 channel and leaving the others unaffected.

Dentists already use sodium ion channel blockers in the form of local anesthetics like Lidocaine, but that blocks all the channels it comes in contact with.

If Lidocaine were to be taken internally in a large enough dose, it would block all the sodium ion channels in the body. The patient would die because blocking those channels would mean shutting down many essential functions regulated by the central nervous system.

But Icagen has some competition from two other companies: Convergence Pharmaceuticals and Xenon Pharmaceuticals. Convergence, in Britain, is also testing a compound utilizing Nav1.7 ion channel blockers and Xenon in Canada is developing a topical ointment for treating painful viral diseases like shingles.

These painkillers are all based on research conducted in the early 1990s at Stony Brook University by neurobiologist Simon Halegoua, electrophysiologist Paul Brehm and molecular biologist Gail Mandel. In an early example of multidisciplinary collaboration, they established a lab in the basement of Stony Brook’s Life Sciences building and began studying how peripheral nerves transmit signals.

Halegoua, Brehm and Mandel discovered a sodium ion channel unknown to scientists before then. At the time, they called it PN1— Peripheral Neuron 1 because it appeared only in the parts of the nervous system outside the brain and spinal cord.

“The moment that we realized that that was a unique cellular channel, and that it was specifically expressed in peripheral neurons was a real eureka moment,” Halegoua said. He added that while they had known it was a significant development at the time, they did not know how much of an impact it would really have.

They went on to research a mechanism to block that channel. Icagen received the exclusive license to the research in 2007.

But why would pharmaceutical companies take so long to find a practical application for that discovery?

The significance of the Nav1.7 sodium ion channel became apparent in 2006 when researchers discovered three Pakistani families whose children were born with a congenital insensitivity to pain.

By analyzing their DNA, scientists found that this condition results from a mutation in the gene that encodes the Nav1.7 channel – proof positive that Nav1.7 really did regulate pain signaling and nothing else, not temperature or pressure or any other signals. The obvious next step: Blocking the channel could be a viable method of pain management in humans.

The discovery of the gene mutation was like a shot from a starter gun: Several pharmaceutical companies burst from the gate in a race to be first to develop a marketable Nav1.7 blocker.

“The drug companies couldn’t ask for more,” Halegoua said.

The new painkiller, which researchers call the Pfizer Collaboration Compound, or PCC, looks promising because it so clearly targets only pain signals. PCC is entering phase I clinical trials. In this step, researchers will split a group of healthy volunteers without pre-existing conditions into a trial group and a control group. The control group will receive a placebo and the trial group will receive the drug.

Both groups must be carefully observed for potential side effects. Once the drug is deemed non-toxic, it will move into the second phase of trials, when researchers are required to investigate whether the drug is effective and to identify the optimum dosage.

Ideally, Halegoua said, the drug would block only the Nav1.7 channels, and only when they’re open instead of at all times.

Convergence officials have claimed their experimental drug can do just that. Both the Convergence and Xenon versions are moving into phase II trials, just a little ahead of Icagen.

But a painkiller without side effects still poses risks. People born with congenital insensitivity to pain like those children in Pakistan do not live very long; when they receive a serious injury, they frequently do not know the extent of it and fail to find appropriate treatment. In the same way, someone taking the medication could develop a complication and not know it.

Brian Durkin, a director at the Stony Brook University Medical Center’s pain management center who specializes in cancer, wrote in an e-mail that acute pain is a line of defense, but “chronic pain has no protective mechanism and is really a disease in itself.”

Treating chronic pain is also not an easy task: patients face practical problems like unemployment because of their condition, as well as psychological conditions like stress, anxiety and a lowered sense of self-worth. Even after the pain is mitigated, physicians will need to continually monitor and work with the patient in order to restore their ability to function.

Durkin said the market for pain medications is enormous. “If this new drug works well and is safe, there is a huge potential for its use,” He added.

The potential for abuse of this painkiller is also high, though not in the same way opiates or recreational drugs are abused, Halegoua said. For example, an athlete injured in the middle of a competition might take a pill and power through, potentially worsening the damage.

“Drugs that would be targeted to block pain with no other side effects would have to be administered very carefully,” he continued. Halegoua said that he expects the painkillers to be prescription drugs when they hit the market, with tight restrictions on their use.

 

This article was first published in the Stony Brook Independent.