Pain Research at a Threshold
By Bob Shepard
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Anesthesiology researchers Ursula Wesselmann and Timothy Ness are using imaging technology to take a closer look at the physiology of pain. The findings could benefit patients who experience different types of pain throughout their bodies.
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The National Institutes of Health (NIH), the leading federal agency supporting and conducting medical research, covers a lot of ground. Among its 27 different units, doling out some $29 billion in fiscal year 2008, are institutes for cancer, vision diseases, mental health, and aging.
Yet there is not a single NIH division dedicated to pain management—which is surprising because “pain is the number-one reason why people come into the health-care system,” says Keith “Tony” Jones, M.D., professor and chair of UAB’s Department of Anesthesiology. His colleague, anesthesiology professor Timothy Ness, M.D., puts it even more simply: “Every doctor is a pain doctor.”
Researching pain is no simple task, however, because it’s subjective and almost impossible to recreate in a laboratory setting. For Jones, the solution is to adapt the investigative approach used for other medical conditions: Recruit a cadre of top researchers and clinicians from across the medical and scientific spectrum. Organize them in a comprehensive, interdisciplinary pain-management program. Give them the tools and the funding they need. And then stand back.
“One of my priorities is to establish a behavioral medicine pain-treatment facility that involves neurology, rehabilitation, psychiatry, anesthesia, rheumatology, and other fields,” Jones says. “Patients treated using this multidisciplinary approach become more functional, increase their productivity, and get back to work sooner.”
Jones says pain—and pain research—can be divided into two broad categories. Perioperative pain is induced by trauma—either controlled trauma, as in surgery, or uncontrolled, as in a car wreck. Management focuses on reducing the amount of pain so that patients can rehabilitate quickly.
The second category is chronic pain. Jones says that for about 15 percent of these cases, an interventional procedure can treat the pain. “But the other 85 percent is not amenable to an invasive procedure because the pain is not localized; it’s a systemic problem such as fibromyalgia,” he says. “This is where we really need an interdisciplinary team. When a direct intervention is not a solution, a behavioral medicine approach to therapy is required.”
Anesthetic Mechanisms
As Jones begins to assemble his team, they are already addressing one investigative challenge: gaining a better understanding of how anesthetic drugs work.
Despite years of safe use, side effects still occur. Some anesthetics depress the respiratory system, others the cardiovascular system. Some can cause blood pressure to drop dramatically.
Ursula Wesselmann, M.D., talks about the misunderstandings surrounding chronic pelvic pain.
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One significant side effect is that many anesthesia drugs can trigger apoptosis, or programmed cell death. Each cell has latent programs in its DNA that instruct it to die when it is no longer needed. “We’re finding that when we anesthetize a very young child, for example, we may accelerate this normal neurodegenerative apoptosis process, potentially creating developmental problems,” says Jones. “We need to gain a deeper understanding of the basic ways these drugs function.”
Jones explains that anesthetic drugs bind to proteins, changing the way that they vibrate and wobble and interact with other proteins. The next step is to learn the basic underlying principles of how anesthetic molecules can affect the function of these proteins. That knowledge should help researchers design anesthetics that limit current side effects.
Jones, along with anesthesiologist Chuck Jetton, M.D., and pediatric hematology/oncology specialist Joseph Chewning, M.D., is pursuing another avenue to determine if anesthetic gases inhibit natural killer-cell function. Natural killer cells survey the body for abnormal cells, such as cancer, and destroy them. Recent research has suggested that breast cancer patients given local anesthesia have a better five-year survival rate than patients given general anesthesia.
“We think the reason is that the gases used in general anesthesia inhibit or block these natural killer cells,” Jones says. “We’re going to do a study in patients to see if that’s the case. We can’t do local anesthesia on every patient who needs cancer surgery. But for those who will need general anesthesia, we may be able to simultaneously use drugs that will boost the immune system during the surgery so that these patients don’t have a higher incidence of tumor recurrence later.”
New Views of Pain
Ursula Wesselmann, M.D., who joined the UAB anesthesiology research team last year after a long career at Johns Hopkins University, focuses on pelvic and urinary-genital pain, which is seen mostly in women but can affect men. Wesselmann says about 37 out of 1,000 people have chronic pelvic pain, a frequency similar to back pain or asthma.
“Historically it was thought that pelvic pain or urinary-genital pain was due to disease in the reproductive organs, so a lot of women had hysterectomies,” says Wesselmann. “But the results were often quite frustrating. Some patients were cured by those surgical interventions, but many were not. It was the gynecologists who turned to the pain specialists and said there is something else going on.”
Wesselmann says that looking beyond a specific pelvic organ such as the uterus or bladder has provided a new view into pain physiology. If the pain is not coming from the organ, then it must be coming from the central nervous system, so the focus is now on spinal cord and brain mechanisms, she says. In her laboratory, Wesselmann uses animal models to identify the nervous system pathways for these pains; the search then narrows to neurotransmitters that may be involved. Pinpointing those neurotransmitters will offer potential targets for drug design—an eagerly anticipated discovery because very few existing drugs are designed specifically for pelvic pain.
For clinical studies, Wesselmann is following up on research showing that many patients with visceral, or abdominal, pain have other pain syndromes as well. “The same patient might have vaginal pain and interstitial cystitis, which is a bladder pain syndrome,” she says. “They might have irritable bowel syndrome, fibromyalgia, or migraine headaches. We are now trying to identify subgroups of patients—those who have one type of pelvic pain and those who have many types—for future clinical trials.”
Timothy Ness is already taking an inside look at these subgroups. He recently received funding for a multicenter study to conduct brain imaging in patients with interstitial cystitis. Ness and his collaborators want to see what parts of the brain activate when these patients have a full bladder. “Some people in these subgroups appear to be hypersensitive to pain that manifests in different parts of their bodies,” he says. “Then there are some who seem to be bladder-specific; that’s the only part that is hypersensitive.”
The imaging shows that people with global pain hypersensitivity seem to have increased blood flow and activation on both sides of their brains, Ness says. Typically, stimuli to one side of the body will increase activity only in the opposite hemisphere of the brain. Ness adds that the findings illustrate a need for different treatments for patients with global hypersensitivity as opposed to those with bladder-specific pain.
Practical Outcomes
Meanwhile, Tony Jones is collaborating with the chairs of a number of UAB departments to create the integrated, multidisciplinary system he envisions. It’s key to both clinical care and research, he believes. By establishing an organized clinical pain practice, Jones says that UAB can create the critical mass of patients required for the important studies that need to be done.
It’s a crucial move because pain studies are one area well suited to carry out the NIH mandate for research that translates into practical treatments, Ness explains. “Some of the best examples of almost immediate translation in medicine have been in the pain field.”
Moreover, “everyone agrees that being able to treat pain better is a desirable goal. Besides the suffering, chronic pain has a huge economic impact from missed work and increased expenses for medical care such as surgeries or other treatments. It’s a big-ticket item in our society, and it’s incredible that our understanding of pain is so imprecise.
“Pain research offers a perfect opportunity,” he adds.