Jane Martinsons, Staff Writer

Last May, the APS Translational Task Force released a position statement (see www.ampainsoc.org/advocacy/downloads/translationalpain.pdf) on translational pain research that listed seven obstacles blocking the path between scientific discovery in the lab and bedside practice. These obstacles range from avalanche-sized roadblocks—“inadequate funding for pain research” and “burdensome regulatory issues”—to the seemingly more traversable “inadequate incentives for junior faculty to pursue pain research.”

The task force also suggested ways that the National Institutes of Health (NIH) and APS and other national organizations can help circumvent these obstacles. For example, to overcome inadequate funding of translational research the task force recommended that, among other things, NIH increase funds for exploratory grants, training grants, and researcher-initiated grants through program announcements and request for applications.

Today, as NIH’s budget continues to tighten, funding requests like these go largely ignored. “Translational research is part of the NIH Road Map and to that extent the NIH has a commitment to it,” says APS President-elect Charles E. Inturrisi, PhD, professor at Weill Medical College of Cornell University, New York City. “However, given the extremely low percentage of applications currently being funded, 8%–10%, it is difficult to be optimistic about funding for translational or any other NIH-supported topic area.”

NIH’s budget crunch isn’t expected to ease anytime soon. At the APS Bulletin deadline time, the Senate was expected to vote on an appropriations bill that calls for increased funding for NIH and other federal agencies. President Bush had threatened to veto the bill if passed, saying the increased funding would exceed his proposed budget.

“This is not the first NIH tightening and it won’t be its last. These things are cyclical,” says Roger Fillingim, PhD, professor at the University of Florida’s School of Dentistry in Gainesville. Still, he concedes that the NIH budget crunch is substantially slowing the availability of funding to individual researchers and, more broadly, is prompting good translational researchers to leave academic research for other areas. With that, “we lose the edge that we once had,” he says.

Others believe the issue goes way beyond NIH funding. “This is a national issue, not just an NIH issue,” says Patrick Mantyh, PhD, professor and director of the Neurosystems Center at the University of Minnesota School of Dentistry. “I think that the pain community has to make a real effort to point out that this is a national priority,” he says. “You can’t let [U.S. soldiers] come back from war and basically tell them that they’re on their own. The Department of Defense and the Veterans Administration are making a major effort to address the issue of chronic pain in returning vets, but I think that it really needs to involve the entire pain community.”

The funding issue aside, is any headway being made on two other obstacles cited by the task force: inadequate clinician-researcher interactions, and inadequate access for researchers to clinical databases or tissues?

Clinician-Researcher Interactions

On the national level, Ron Dubner, DDS PhD, of the University of Maryland Dental School, says that NIH supports translational clinical research as well as the collaboration between researchers and clinicians through several major initiatives. First, he says, its Clinical and Translational Science Awards (CTSAs) recognize institutions that develop major programs in clinical and translational research. “[The awards] don’t go specifically to a particular disease or condition, such as pain or heart disease. It’s really more process-oriented—[namely] the process by which institutions develop programs that will facilitate clinical and translational research.” Major academic institutions that apply for CTSAs should incorporate pain as a component of their proposals, he says.

Dubner adds that translational pain researchers should also consider that NIH offers training grants as well as multicenter grants. His university is one of a group of four universities from different states to receive a multicenter grant to study temporomandibular joint dysfunction and pain.

Fillingim agrees that NIH has conceptually changed direction and now encourages translational research. But, he says, it’s hard to measure the extent to which NIH funding has filtered down to pain research. Still, at his institution, “most of us view translational research as an important focus of the future,” says Fillingim, who is also staff psychologist at Gainesville VA Medical Center. One project is a mouse-to-human pain-research project that tries to identify genes in mice that respond well to pain relievers and then translate those to human genes—so far, to genes in redheaded people.

What characterizes the interaction between clinician and researchers today? “To a great extent, there’s a culture clash between clinicians and scientists,” says Timothy Ness, MD PhD, professor at the University of Alabama at Birmingham and member of the ad hoc APS task force on translational pain research.

“When you’re working in the realm of basic science, what is important is the question—that uncertainty that you are striving to test and answer,” says Ness, who identifies with both groups as a practicing anesthesiologist who holds a PhD in pharmacology. “Clinicians struggle with the concept of uncertainty. They prefer their practice of medicine to be composed of black-and-white distinctions: what is the best [and worst] way to do something. In general, clinicians find it difficult to do their jobs in the absence of certainty.”

Because of these differing mindsets, Ness says that APS and other national organizations need to foster clinician-scientist interactions by holding national meetings that bring together both groups. Meanwhile, individuals in both groups should strive to learn about the other, with scientists getting to know patients and researchers presenting to clinicians.

That was precisely what Mantyh was doing when he spoke with APS Bulletin—presenting in Halifax, Nova Scotia, Canada, to members of an arthritis network comprised of physicians, nurses, and patients who experience pain from osteoarthritis (OA) and rheumatoid arthritis (RA).

“These people at the meeting all see and experience OA and RA daily, [while] I look at receptors, ions, channels, and nerves,” says Mantyh, who also served on the APS Translational Task Force. “You really have to make [your presentation] understandable to [clinicians], visualize it for them within an allocated time so that they can come away with data, images, or a concept of what is really going on in their patients.” He says that conference attendees, all experts in bone pain, tell him how much they appreciate his efforts to reach out to them.

The clinician-researcher interaction doesn’t stop there for Mantyh, however. Back in Minnesota, both he and clinicians at nearby Mayo Clinic occasionally will “carve out a morning to chat” and visit patients. During their visits to Minneapolis, Mayo clinicians look at researchers’ design models and suggest ways to adapt and refine them to reflect what they’re seeing in patients. Similarly, Mantyh visits patients at the Mayo Clinic, including those with hard-to-control pancreatic cancer pain. “When you see these patients and see them hunched over in chairs, you really get a concept of how bad the pain is, how much it interferes with their lives, and what we really have to control it. Then, when you put that all together, [the basic scientist] says, ‘Okay, I would need a model that would look like this.’”

Fillingim says that the biggest obstacle is creating time and opportunity for dialogue between both groups. “Clinicians are busy doing clinical things and basic scientists are in their labs. There’s no ‘preordained’ mechanism for those two groups of people to talk to each other and to interact, which slows translational research considerably,” he says. He says that major institutions are making an effort to make grand rounds interdisciplinary and to involve basic scientists.

“When a case is presented, for example, we have a clinician present the case and a basic scientist comment on mechanisms,” Fillingim says. “In my experience, if you start creating those opportunities [for interaction], collaboration naturally develops.”

At the hospital level, that may mean simply making it easier for both groups to meet. Laura S. Stone, PhD, assistant professor, McGill Centre for Research on Pain, Faculty of Dentistry, McGill University in Montreal, Quebec, says that plans are underway at her campus to provide transportation for basic researchers to meet with clinicians at the university’s hospitals.

Gavril W. Pasternak, MD PhD, laboratory head of the molecular pharmacology and chemistry program at the Memorial Sloan-Kettering Cancer Center, and professor at Weill College of Medicine of Cornell University in New York City, says that in academic environments, collaborations require intellectual resources and especially financial resources to succeed.

But clinicians’ time is also important. “Interactions depend on support and the likelihood of completing projects,” Pasternak says. “We currently suffer from woefully inadequate funding for trials and laboratories from traditional granting sources, but the more insidious issue is the lack of time available to clinicians to pursue academic issues,” he says. “In many cases, it is a ‘Catch 22’: You can have more time if you raise your salary, but to raise your salary, you need more time to generate the preliminary data, etc. There is less funding available, making it even more difficult for new investigators to generate preliminary studies that would help them obtain extramural support. Clinicians are working harder and harder just to cover salary, leaving them less time for academic pursuits.”

Limited Access to Clinical Databases and Tissue

Although federally funded studies are required to have some data-sharing plan, investigators often have difficulty accessing tissues and clinical databases.

Pasternak says that despite the proliferation of genetic studies and tissue banks, there’s often limited sharing at these facilities. Laboratories that maintain samples use them for their own research, he says, and when quantities of materials are limited, investigators are understandably reluctant to hand them out. Moreover, as competition over limited resources increases, some investigators fear that releasing samples will help their competitors.

Fillingim agrees, saying that mechanisms to share biological samples and tissues help, “but just how data sharing plans get constructed is still very much an individual investigator’s prerogative.” Most major academic centers that apply for CTSAs have a biological sample core facility or facilities, he says. “Here at the University of Florida, every Tom, Dick, and Harry who does research with biological samples has them stored somewhere, but there’s no integration of all this. As a researcher, I have no idea what is available and where I can get samples. CTSAs provide oversight and integration of tissue banking operations at individual institutions and, eventually, across universities.”

According to Stone, a group of researchers and clinicians at major pain clinics in Quebec are starting to build a patient registry that will include standardized assessment measures across their sites. Plans call for collecting and archiving patients’ serum to be used for future genetic analysis, and having a committee review requests for access to the samples.

Stone also notes a tie between increasing interaction between researchers and clinicians and improving access to patient samples. “Researchers need to make the time and effort to attend clinical meetings and present their research ideas,” she says. “My experience has been that they are generally very responsive and willing to assist with sample collections.”

Future Trends

Increasingly clinicians and researchers are bridging gaps in communication and data-sharing on their own, Stone says. “We will start to see some real impact in the next few years from these efforts, but they are isolated.”

Stone recommends that foundations and patient organizations help fund collaborative studies. “One of the major issues is the time and effort required to obtain enough preliminary data to submit a competitive NIH grant,” she says. “None of these projects will ever get off the ground without continued efforts to get us all in the same room.”

As for the future of translational pain research, that may be determined by the healthcare consumer, particularly aging Baby Boomers who demand quality services and accountability.

“What does the taxpayer want?” Ness asks. “We have a huge number of patients in pain in the United States and they feel very strongly that they are not getting their fair share of what they contribute to their federal government. The public has become very dissatisfied with the fact that they’re spending money on research, but what has it actually done to make their health better?” he says. “When it really comes down to it, the taxpayer only wants to pay for something that is going to help that individual taxpayer.”

Ness says that APS and other national organizations must arm themselves with reliable data as they seek funding. Meanwhile, he says, APS members would benefit from getting in touch with their own inner taxpayer and demanding focused support of what they feel is important.

“Every time clinicians and healthcare professionals see their patients they are reminded of their urgent and unmet needs,” notes Christine Sang, MD MPH, director, Translational Pain Research at the Brigham and Women’s Hospital. “The overall goals of translational research are not that different from clinical research, but they include strategies that clinical researchers should implement to expedite the development of improved therapies.”