New Answers to Ancient Questions

By Laura Freeman and Matt Windsor

2009_pain1UAB researchers are seeking out the underlying causes of devastating pain syndromes and developing more effective treatments. Click the image for the full graphic.Pain is paradox. Although it is humanity’s most common bond, it can isolate us like no other sensation. Pain is a master communicator, alerting us to seek help when we’re wounded or ill, but it can also be a cruel chatterer, blaring its warnings long after the original danger has passed.

Alleviating pain has always been medicine’s primary goal, yet thousands of years of study have unraveled few of its mysteries. Why do people perceive pain so differently? How much of it is in our heads, our hearts, and our genes? Why can some women deliver children without a drop of medication, while others seek relief within the first few minutes of labor? Why does one accident victim heal, while another develops a disabling syndrome that all the remedies of modern medicine seem inadequate to ease?

For the first time, answers to these questions may be within our grasp. And looming beyond them could be a solution to the problem asked by sufferers throughout the centuries: Why me?

Help for the Hurting

More often than not, it is pain that drives us to seek medical help. “Pain is the primary complaint of 80 percent of all patients who enter the health-care system,” says Keith A. “Tony” Jones, M.D., chair of UAB’s Department of Anesthesiology. “If you talk to patients who are about to undergo a surgical procedure, the number-one thing they are concerned about isn’t the actual surgery, but the postoperative pain.”


Tony Jones, M.D., chair of UAB’s Department of Anesthesiology, discusses postoperative pain.

Ursula Wesselmann, M.D., talks about the misunderstandings surrounding chronic pelvic pain.

Helping patients avoid pain is a worthy end in itself, but research shows that effective relief actually improves surgical outcomes. “Better pain control after surgery gets patients back on their feet faster, so there is less risk of blood clots and fewer complications,” Jones says. “The same is true with lung function. If the pain is so bad that a patient can’t take a deep breath, there is a greater risk of pneumonia. Relieving the pain helps to prevent those problems and speed recovery. There’s rising evidence that pain management has a significant impact on reducing costs to our health-care system.”

The road to relief is not the same for every person, however. Clinicians at the Pain Treatment Clinic at UAB Highlands hospital combine different types of medication, along with rehabilitation and psychological counseling, to find the right mix for each patient. Narcotic drugs, the foundation of modern anesthesia, are still the most effective way to silence the wailing alarms of pain, says Jones. But research at UAB and elsewhere shows that patients benefit from a more varied approach. “New strategies to utilize regional anesthesia techniques combined with systemic, non-narcotic drugs have really entered into the forefront of our research and clinical practice,” Jones says.

Anti-inflammatory medications, for example, are playing a larger role. “A big component of pain is nerve damage, but the body reacts to that nerve damage with an inflammatory response,” Jones explains. “This creates a positive feedback loop—inflammatory cells come in and release substances that cause swelling, the tissue gets more damaged, and that causes more pain and more inflammation. But if you can block the inflammatory process, you can indirectly reduce the amount of pain that’s generated.”

Targeted anesthesia is another important advance, Jones says. UAB’s new Regional Anesthesia Pain Service specializes in threading catheters into precise locations around the body, such as the nerve sheaths around the wrist and knee, and infusing these areas with local anesthetic. “You feel nothing, absolutely nothing,” says Jones. “Not just reduced pain, but no pain.” Because they can begin rehabilitation exercises almost immediately, patients recover more quickly than those treated with narcotics alone.

Melding new techniques and proven medications into a “multimodal” attack allows anesthesiologists to treat pain in more sophisticated ways. Still, Jones says, drugs are not the only answer. That’s why the pain clinic includes specialists in physical medicine and rehabilitation, neurology, psychology, and psychiatry.

“Pain is a feed-forward phenomenon,” says Jones. “If you have arthritis, you may not feel like moving. But if you don’t move, the disease process worsens. That makes you depressed, which makes you focus on the pain, and then it just gets worse. You have to break that cycle by treating both the pain in the knee and the suffering in the head. You can get these people back, but it takes an interdisciplinary effort.”

Jones has plans to take his interdisciplinary approach even farther—perhaps all the way to the heart of some of pain’s most challenging puzzles. “We already offer state-of-the-art treatment for acute and chronic pain based on the best current knowledge,” Jones says. “Now we’re moving to the next level.” His goal is to develop a center of excellence in pain treatment, research, and education at UAB that will include internationally recognized experts from the schools of Medicine, Dentistry, and Public Health. “By bringing together clinicians, researchers, and educators under the same roof,” he says, “we can develop an even more comprehensive approach to pain control and move the benefits of new insights more quickly from the lab to the bedside.”

Chronic Conundrums

New insights are particularly vital for chronic pain syndromes, which receive comparatively little attention from clinicians and researchers, says Timothy Ness, M.D., Ph.D., director of pain treatment research in the Department of Anesthesiology. “The biggest challenge is persistent pain,” he says. “But it’s also the most dynamic area of current research.”

2009_pain3UAB researchers are seeking out the underlying causes of devastating pain syndromes and developing more effective treatments. Click the image for the full graphic.

Much of the mystery surrounding chronic pain is due to its maddening obliqueness. Acute pain usually offers straight lines between cause and effect: A gash in the forearm hurts more than a nick. In many chronic syndromes, however, the connection between the extent of visible trauma and the amount of discomfort a person feels is tenuous. Physicians are often unsure why their patients are feeling such significant pain—or why they are experiencing pain at all.

“Imagine a young woman, healthy as can be, who develops what seems to be a pretty benign bladder infection,” says Jones. “That is not unusual, and most of the time you go to the doctor, get some antibiotics, and the infection and pain go away. But every now and then, that bladder pain—even though you’ve treated it—progresses and becomes manifest as a chronic pain syndrome called interstitial cystitis, which is a debilitating disease that can utterly destroy your life. The pain is excruciating. And we have no idea why one patient, who has what appears to be the same bladder infection as 99 others, goes on to develop a chronic pain syndrome.”

In fact, Jones says, the underlying causes of everything from irritable bowel syndrome to low back pain to certain types of headache are still open questions: “Two people can be in a car accident, and both fracture their arms. They can have the exact same fracture, but one heals, and the other develops a complex regional pain syndrome that results in complete dysfunction of his hand. A hundred people can get chicken pox; some will go on to develop severe shingles, but most don’t. We don’t understand why.”

At the moment, chronic pain researchers have far more questions than answers, but they are starting to uncover some intriguing clues. Ursula Wesselmann, M.D., is an internationally renowned expert on pain syndromes who recently joined UAB from Johns Hopkins University. Along with co-investigator Peter Czakanski, M.D., Ph.D., she is working on the care and cure of two chronic pelvic conditions: interstitial cystitis and vulvodynia, a vaginal pain syndrome.

As is the case with many chronic syndromes, both conditions demonstrate “no clear relationship between the extent of the pathology and the extent of pain that the patients report,” says Wesselmann. Interstitial cystitis, for example, “seems to be related to the bladder, but it’s not 100 percent clear if the bladder is indeed involved.”

In the past, this lack of a causal link led many physicians to treat complaints of pelvic pain with skepticism—and little else. “Patients often undergo a lot of invasive diagnostic procedures, and nothing is found,” says Wesselmann. “Previously, such patients were often told that nothing was wrong with them, even though they still had the pain. Only recently have gynecologists and urologists acknowledged that these syndromes deserve treatments, even in the absence of clear pathology.”

In addition to the obvious benefits, prompt treatment offers another advantage to patients: Emerging research indicates that chronic pain could have the ability to spread from its original source to points across the body. “Patients who have chronic pelvic pain often have more than one chronic pain syndrome,” including migraine headaches, irritable bowel syndrome, or fibromyalgia, Wesselmann says. “That suggests the possibility that these chronic pains are a disease entity in themselves. It might be that chronic pain is a disease that starts locally and then spreads to other areas.”

One hypothesis attributes this expansion to changes in pain-modulating pathways that make it more likely that recurrent pain will appear elsewhere in the body. “It’s definitely not just something in the periphery,” Wesselmann says. “It is affecting the central nervous system.”

What’s Past Is Painful

Other new research validates the idea that pain can make permanent changes to the body. UAB psychologist Alan Randich, Ph.D., and anesthesiology researcher Meredith Robbins, Ph.D., are working with Timothy Ness to study the effects of pain experienced early in life on pain response as an adult. “From our research on bladder pain, it appears that early exposure to pain and inflammation may enhance the sensitivity of neurons,” Randich says. “These changes seem to increase the response to similar pain later in life, and this increased response may be a contributing factor in diseases characterized by hypersensitivity and pain.”

Advancing Medicine for Pain

Of all the approaches UAB researchers are taking to solve the puzzle of pain, the most intriguing may be a new project under way at the Gene Therapy Center. Working with anesthesiology’s Timothy Ness, M.D., and Meredith Robbins, Ph.D., center director David T. Curiel, M.D., Ph.D., is developing a novel method of pain control that uses the body’s own painkillers to ease intractable suffering, such as that seen in cancer patients with hard-to-treat malignancies.

Curiel’s goal is to use gene therapy techniques to increase production of endorphins and other natural pain-fighting substances or make the existing supply more effective. It might even be possible to send genes to specific target areas in the body that would create “molecular mini pumps” to attack pain at its point of origin, Curiel says.

As with many gene therapy strategies, this approach uses a benign version of the adenovirus to deliver therapies directly to specific areas in the body. Similar approaches to pain relief are also being studied at other major research centers, and preliminary reports are promising. “We’ve come a long way with gene therapy,” says Curiel. “Once we know an approach is working, moving from the lab to the patient can happen fairly quickly.”

Functional magnetic resonance imaging (fMRI) studies of patients with chronic pain disorders—who experience fatigue and widespread pain in deep tissues such as the viscera, muscles, and ligaments—suggest that these patients’ bodies process pain signals in a unique way. Whereas pain in the left arm usually registers on the right side of the brain during fMRI scans, ongoing studies at UAB suggest that chronic pain patients may register pain from one side of the body as activity on both sides of the brain. Whether this is a cause or result of their chronic pain is the subject of continuing research.

A patient’s history of pain is important, but many other things play a role in how an individual experiences suffering, says Wesselmann. Genetic differences are a major factor, she notes; they affect everything from pain sensitivity to how well a patient responds to different types of drugs. “There is also a great deal of literature, not only from our group but from many others, that shows that men and women have different responses to the same experimental stimuli,” says Wesselmann. “It could be that men and women might actually need different treatments for pain. And there’s an emerging field looking at the effects of race, ethnicity, and culture on pain.”

Even within gender or ethnic groups, however, there are widely differing responses to pain. Wesselmann’s lab is studying childbirth, which can induce some of the most intense agony that humans experience, “on a similar level to amputation pain,” she says. “We want to learn why some women have more pain than others during labor and delivery.”

That is essentially the same question that drives her research on vulvodynia and interstitial cystitis. “A patient might have interstitial cystitis and then at a later point might develop vulvodynia or irritable bowel syndrome or fibromyalgia, or migraine headaches,” she says. “But some patients who have interstitial cystitis never have anything else. Why are those patients different?”

The only way to find out, Wesselmann says, is to discover the root causes of chronic pain. And these won’t be the same for every patient, she predicts. This has already been shown to be true in the case of chronic headache. Leading researchers such as UAB’s John Rothrock, M.D., began to make great strides in developing effective therapies when they recognized that different types of headaches require tailored treatments, says Wesselmann.

When researchers looked at migraine headache, cluster-type headache, and tension headache together, she says, they had trouble finding effective remedies. “Only when clinical trials focused on specific subgroups were they able to identify treatment approaches that worked really well for these populations.”

Wesselmann hopes to re-create this success using the pain research expertise at UAB. “That is one of the primary reasons I came here,” she says. “We have different subspecialties working together to attack chronic pain from different angles: basic science, clinical research, genetics, neurophysiology, psychology, and drug development. We can identify subgroups of patients within these chronic pain syndromes, and then when we do drug trials, we should have a better idea of which drugs are likely to work best for which patients. It should also give us a better sense of which non-drug treatments might be helpful.”

What Works Best?

Once promising new treatments have been developed, most clinicians and researchers naturally turn their attention to other pressing problems. But investigators shouldn’t stop there, says Jones. “Imagine you’ve done a randomized trial with 50 patients, and you say, ‘This particular drug works better than that other one.’ But once you start using the drug out in the real world, does it really have an impact on health in our society?”

Questions such as this motivate Thomas Vetter, M.D., M.P.H., who leads the Department of Anesthesiology’s Division of Pain Treatment. “Not that much information has been gathered on what happens when we go from the bedside into the general population,” he says. “We need to talk more with patients and listen to what they have to say. A year after a joint replacement, has the patient’s quality of life improved? Has the pain decreased? Does he move more and enjoy interacting more with family and friends?”

Vetter is using data from a national study of perioperative outcomes to determine patterns in complications, infection rates, and patient satisfaction. He is also investigating health-care disparities in access to pain treatment, particularly cancer pain management in patients with limited resources. “Having solid data on outcomes,” says Vetter, “will help physicians and patients make better decisions on which therapies offer the most promising results from an ethical, practical, and economic standpoint.”

In the end, all of UAB’s research and educational efforts related to pain are being designed to reach that same goal. “The more we learn about the mechanisms of pain and the factors that influence it, the better equipped we are to develop new and better ways to improve treatment,” says Ness. “The discomfort of chronic conditions such as arthritis, cancer, low back pain, and pain syndromes can be difficult to treat. A center of excellence will allow us to combine optimal clinical care with research to make that care better.”