Chronic pain comes in many forms, from the ache of an arthritic knee, to the pins-and-needles sensation of diabetic neuropathy, to the all-over pain of fibromyalgia. And a single pain condition may affect people very differently. To complicate matters, individuals also vary in how they respond to medications. Together, these factors make successful treatment of chronic pain difficult, to say the least. Wouldn’t it be great if doctors could prescribe exactly the right medication to help each individual patient? That is the dream of precision medicine, an approach in which treatments are guided by researchers’ understanding of the molecular mechanism underlying a patient’s pain.
For most of the millions of Americans living with chronic pain, precision medicine remains a distant prospect at this point. But studies of individuals with rare genetic causes of chronic pain are leading the way toward making it a reality. Two papers published in April, which report results from drug treatment of patients with a rare chronic pain condition called inherited erythromelalgia, demonstrate two things, says Stephen Waxman, an author on both studies: one, that basic research carried out in the lab can guide successful treatments for human pain conditions; and two, that it takes a lot of work.
From mechanism to treatment
Erythromelalgia (EM) causes extreme burning pain—usually in the hands and feet—that is brought on by heat or exercise and typically is only alleviated by cooling. Most cases of EM have no known cause, but an inherited form (IEM) has been traced to genetic mutations in a gene for a voltage-gated sodium channel, a type of protein that makes nerve cells electrically excitable. The mutations make the channel, called Nav1.7, more active than it normally is, in turn increasing the activity of pain nerves. People with a different mutation that makes Nav1.7 nonfunctional are unable to feel pain.
In the first study, Waxman and his colleagues at Yale University School of Medicine, New Haven, and the Veterans’ Affairs Medical Center, West Haven, both in Connecticut, US, carried out a small clinical trial of carbamazepine, an anti-epileptic drug that blocks sodium channels, in patients with IEM. Carbamazepine does not help most people with IEM, but back in 2008, Waxman and his team identified a family with IEM caused by a specific mutation in Nav1.7 that did respond to the drug.
Later, in a 2012 study, the group used computer modeling to predict that people with another mutation in Nav1.7 might also respond to carbamazepine. In the new work, the researchers report a successful trial of two IEM patients with that mutation, which confirmed their prediction.
They found that one of the two patients who took carbamazepine reported spending an average of 232 minutes per day in pain compared to 424 minutes per day while taking placebo. The total time spent in pain during the course of the study dropped from 6360 minutes with placebo to 3015 minutes on carbamazepine.
Meanwhile, the second subject saw a daily reduction of time spent in pain from 61 minutes on placebo to just nine minutes on the drug, and a total reduction in time spent in pain from 915 minutes to 136 minutes. Both patients also reported reduced duration of painful episodes, and one subject who frequently experienced sleep disturbances due to pain reported 101 awakenings while on placebo and only 32 awakenings on carbamazepine.
The new findings were published online April 18 in JAMA Neurology.
A new drug helps, too
In a second study, Waxman together with researchers at Neusentis, a division of the pharmaceutical company Pfizer in Cambridge, UK, tested a novel drug aimed at quieting Nav1.7 in five patients with IEM caused by a variety of mutations.
The results were mixed: some patients experienced less pain with the drug compared to placebo, whereas others saw no difference. The findings were somewhat disappointing, considering that the new agent was aimed directly at the molecule known to cause the patients’ condition, and they point to the tremendous diversity in even such a specialized population of pain patients. The results were published April 20 in Science Translational Medicine.
The team also used a new tool to screen the drug: nerve cells generated from each individual patient. Cells isolated from the patients’ blood samples were genetically reprogrammed into induced pluripotent stem cells (iPSCs). These cells are adult cells that, after the genetic manipulation, take on an embryonic stem cell-like state. The iPSCs were then treated with a cocktail of chemicals to direct them to become nerve cells like those affected in the patients. Interestingly, just as the patients’ responses to the drug varied, so did the response of their cells containing Nav1.7.
“It was exciting to see the parallels between the results in the iPSCs and the human subjects,” Waxman says. “And that underscores the potential usefulness of the iPSCs.”
How close are we?
Stephen McMahon, a pain researcher at University College London, UK, who was not involved in either study, said that although the new stem cell technology has its limitations, it should help speed the development of effective—and perhaps even precision—pain medications. “The technique is not a panacea, but it is a step forward,” he says.
McMahon said that although precision pain medicine is in its infancy, there is a precedent for success. “The cancer field is way ahead in terms of the tractability of this approach.” Cancer researchers have an advantage in that they know precisely where to look for genetic changes to target: in cancerous tumor cells. Cancers with certain genetic changes are more susceptible to specific medications, so a patient with tumors bearing those mutations is more likely to respond to specific drugs.
Waxman says that although these new studies only apply to people with very rare genetic mutations, “I hope that they will hold lessons for the broader population” of patients with chronic pain. Precision medicine for the masses, however, is still years away, he says. —Stephani Sutherland
To read about the new research in more detail, see the related news story at Pain Research Forum here.