Eisenach's Research Garners NIH Merit Award

11/03/2011

Prestigious Award Provides up to $3.7 million over 10 Years

James C. Eisenach, MDJames C. Eisenach, MD, suspects the hormone oxytocin could prevent chronic pain that sometimes follows physical trauma, such as surgery. Determining whether oxytocin used this way is safe and effective will take about a decade—a challenging timeframe in an era of tighter research funding.

Eisenach can focus on science rather than funding after recently learning that the National Institutes of Health (NIH) selected him for the Method to Extend Research in Time (MERIT) award. The prestigious award, given to 5 percent or less of all NIH-funded investigators, will provide up to $3.7 million over 10 years. NIH created MERIT funding to give proven researchers the security they need to ask riskier questions and commit to longer investigations that could yield profound discoveries for better health.

“Oxytocin may become a very useful treatment to prevent chronic pain after surgery, or it may not, but it may tell us something important about how individuals respond to pain stimuli,” said Eisenach, who is the F.M. James III Professor of Anesthesiology. “Chronic pain following surgery is an important problem in its own right—more than 20 million new cases occur per year—but what we learn from this may also apply to other forms of trauma.”

Investigators cannot apply for MERIT awards. NIH officials identify candidates during the regular competitive grant process and consider only those with a superior record of accomplishment over at least 10 years of continuous funding. Eisenach, who joined the faculty in 1986, has won NIH grants to study chronic pain for 25 years. A scientific review committee scored his latest renewal application in the top 1 percent, and his grant manager nominated Eisenach for the MERIT award. When Eisenach seeks renewal in five years, he will bypass the competitive review process and report directly to the council that authorizes grants.

“We are fortunate to have Jim on our faculty and gratified to see his research recognized in this way by the NIH,” said Edward Abraham, MD, dean of Wake Forest School of Medicine. “The long-term funding provided by the MERIT award not only secures his ability to study chronic pain but supports our institutional mission to translate knowledge into improved health.”

Oxytocin and Pain Research

The idea to study oxytocin in connection with chronic pain emerged from Eisenach’s work as an obstetric anesthesiologist. He wondered whether women experience chronic pain after childbirth, particularly complicated vaginal deliveries or cesarean sections. In a multi-center study with partners at Columbia University in New York, and medical centers in Belgium and Switzerland, he found that less than 1 percent of women had chronic pain after delivery. That was notable, since typically about 10 percent of surgical patients later experience chronic pain.

Chronic pain differs from, say, the pain that prompts patients to have surgeries like knee or hip replacements. “It’s more of a nerve injury kind of pain,” Eisenach explained. “Nerve injury pain usually has an electric-shock feeling to it, like a burning sensation. It’s not the achy kind of feeling you would imagine with arthritis. Patients can distinguish the two. It is a pain that is new and different and begins at surgery.”

Because pain is subjective, researchers measure in both humans and animals what they call hypersensitivity to a light-touch stimulus. They touch the skin with filament bristles of increasing thickness and stiffness until the subject reports pain, or in the case of a rodent, it withdraws its hind paw to escape the bristle.

After his childbirth study, Eisenach tested rodents and found that they also showed a low incidence of chronic pain-like behaviors following delivery. To rule out pregnancy as the protective factor, he performed surgery on the animals well before delivery and found that their hypersensitivity response was normal. “After the surgical injury, we find that the bristle thickness they will respond to is much, much less,” Eisenach said. “They’re responding to very fine, almost imperceptible touches to their paw. We don’t know if it’s pain. We do know that they become hypersensitive to light touch.”

The animal results suggested something about delivery was the key, making oxytocin the prime suspect. The brain secretes oxytocin, sometimes called the “trust hormone,” from the pituitary gland. As a neurotransmitter, it plays a role in social bonding, but in women, it plays a special role in childbirth, causing the uterus to contract and stimulating the flow of breast milk. Doctors often give women oxytocin to speed up labor. Eisenach gave the test animals a drug that blocked their oxytocin receptors and found that it curtailed the reduced hypersensitivity associated with delivery.

Testing the Theory in Humans

“Ultimately, we want to ask whether a spinal injection of oxytocin just before surgery will protect people from having chronic pain afterward, just like we think the increased oxytocin released by the brain into the nervous system at the time of childbirth protects women from having chronic pain afterward,” Eisenach said. “It will probably take six to eight years to get that far.”

Spinal injection is required because oxytocin in the bloodstream cannot penetrate the blood-brain barrier. Eisenach will perform this part of the research under FDA supervision, since it is not currently an approved procedure. Eisenach has chaired an FDA advisory committee and over the course of 20 years has worked with the FDA to develop four drugs for spinal injection.

Eisenach expects Phase 1 trials will last six to nine months. This study, conducted in healthy volunteers, will look for any problems with safety and define the maximum dose below which people have no side effects. Afterward, he will give some healthy volunteers the maximum dose and others a placebo and test both groups for hypersensitivity using a chili pepper cream that induces a temporary sunburn-like sensation. Next, he will conduct experiments using spinal injection, probably in patients who are getting knee or hip replacements, to look for possible side effects not seen in the healthy volunteers. The last study will test whether the approach actually lowers the incidence of chronic pain.

“It will probably take us a couple of years before we get to the point that we know enough to design the study about preventing chronic pain,” Eisenach noted. “And then, the study will probably take three to four years to do, because only about 10 percent of people get chronic pain after knee surgery. Say the procedure cuts the incidence of chronic pain by half. To show the difference in a proportion between 10 percent and 5 percent requires hundreds of patients.”

Eyeing the Future

Beyond evaluating oxytocin as a spinal analgesic, Eisenach hopes to explore even more difficult questions, such as the role of stress in suppressing oxytocin production and whether a patient’s social state—being under high stress versus in a caring relationship—affects chronic pain after surgery.

“The life of a researcher is more challenging when you have to compete for funds every few years, so I am grateful to have the opportunity to pursue these long-range studies,” Eisenach said. “I have more questions about chronic pain than I or any one investigator could address in a single career.” 

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