A Good Time for Pain?

Science is making progress with pain management and pain research

I know what you’re thinking: “There’s never a great time to be in pain.” But hang tight. Science is blowing away the boundaries that have limited our understanding of pain – not just why it happens but how it starts, how the brain interprets it and how it can be reduced through pain management. Pain research has allowed us to glimpse the inner workings of a system so sophisticated yet so primal: the nervous system.

It’s been there all along, but sometimes the nervous system gives many of us not-so-gentle reminders that it’s the boss. An estimated 20 percent of people in the United States live with chronic pain – now the country’s number one health problem, with a cost of more than $100 billion a year, according to the American Pain Society (APS). Yet despite the number of people it affects and the staggering costs it generates, pain has been largely under-treated.

Only 10 years ago, pain management was an almost incidental part of physician training. “When I was in training 25 years ago, pain wasn’t considered to be that important, probably because not enough was known about the biology of pain,” recalls rheumatologist Lee S. Simon, MD, associate professor of medicine at Harvard Medical School and previous director of the Division of Analgesic, Anti-Inflammatory and Opthalmalogic Drug Products for the FDA in Bethesda, Maryland.

Pain is now explored in medical schools in basic science classes such as biochemistry and pharmacology as well as in clinical courses such as psychiatry, rheumatology and surgery. In fact, the state Senate of Texas proposed a bill requiring Texas medical schools to review their pain curriculum to ensure training in aspects of pain management – including pain assessment and emotional impact of pain – is available to all students. Attitudes toward pain research have changed not only in medical school but in practice and society, as well.

Narcotics blot out pain like no other drug, but their use has been tinged with controversy and approached with caution. “There was a general avoidance of narcotics for pain relief because it could be difficult for doctors to distinguish patients who really needed them from patients who were seeking them [to abuse],” says Dr. Simon. (See “Neurotic about Narcotics?”) What doctors are learning now from the growing body of pain research is helping to shape new ways of looking at – and treating – pain.

Changing perspectives

The APS published the first-ever Guidelines for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis, signaling a turning point in the recognition of chronic joint pain. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO), a nonprofit organization that sets standards of care and evaluates health-care organizations every two to three years, requires health-care organizations to regularly assess and treat patients in acute or chronic pain or risk losing their JCAHO accreditation. Along with blood pressure, temperature, heart rate and breathing rate, pain – now considered the “fifth vital sign” – must be assessed by health-care personnel.

Doctors and patients aren’t alone in recognizing that pain is a major health problem in the United States. Congress has declared 2001 to 2010 the “Decade of Pain Control and Research” in an effort to raise public awareness about the impact of pain on productivity, quality of life and medical costs as well as to funnel more research money into the field of pain management. Additionally, the Pain Care Policy Act of 2003 was introduced in the House of Representatives and has since been re-introduced as the National Pain Care Policy Act of 2005 (HR 1020).

Passage of this legislation would provide important federal recognition of pain as a priority health problem in the United States, earmarking $61 million over three years to establish a national center for pain research at the National Institutes of Health as well as six regional pain research centers.

What is happening is nothing short of a revolution. “Previously, doctors wanted to end pain by healing the underlying problem. Now we think it’s important to treat the pain at the same time that we treat the underlying illness,” says Dr. Simon, a co-author of the APS guidelines. Biochemical research, genetic research and imaging technologies have catalyzed remarkable studies, the results of which are contributing to the development of new diagnostic methods and treatment options. “This next decade is going to be a golden era of pain therapies,” Dr. Simon says. That means more pain research will lead to new and better treatments.

On a fundamental level, researchers now understand that different diseases produce different kinds of pain and that pain is an individual and subjective experience. The pain from osteoarthritis (OA) is different from postoperative pain, for example. “Pain is not homogenous,” according to Clifford Woolf, MD, PhD, professor of anesthesia research at Harvard Medical School.

This conceptual shift has huge implications for pain treatment in the next decade being targeted to address the specific kind of pain a patient may be feeling, says Dr. Woolf. “We know it will be very unlikely that one magic bullet will be useful for all pain. Instead we need to identify an individual patient’s pain, determine which mechanisms are the predominant cause of their pain and target treatment to those mechanisms.”

Another shift in perspective has come with the recognition that pain does not arise only in the periphery of the body, such as limbs and joints, but can also arise from changes within the central nervous system (CNS), says Dr. Woolf. You may blame your condition for your pain, but what if the real culprit was your genes, your brain or your very nerves? Pain has long been thought of as a symptom of conditions affecting those areas of the body, but an emerging new way of thinking may attribute the occurrence of some of those conditions to the pain signals coursing through your nervous system.

Why you hurt

Don’t you wonder why you hurt and what pain does to your body? To really understand what’s going on in pain research, you need to know a little about the nervous system, which can seem as daunting as the electrical flow chart of a complex power grid. The entire nervous system has two main divisions: central and peripheral. The CNS consists of your brain and spinal cord. The peripheral nervous system (PNS) consists of everything else – all the nerves that project from the brain and spinal cord to the trunk and limbs, which are on the “periphery” of your body.

Pain itself has two major divisions: neuropathic and nociceptive. Neuropathic pain is caused by injury to the nervous system, such as nerve pain associated with diabetes or shingles. It is typically treated with antidepressants, anticonvulsants, antispasmodics, anesthetics and adrenergic blockers. 

Nociceptive pain results from injury to tissues outside the nervous system, such as a cut on your skin, pain after surgery or the chronic pain of arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, muscle relaxants, local anesthetics and opioids are used to treat nociceptive pain. Sometimes pain can be a mix of both types, such as a headache or a herniated disc in the back, requiring mixed treatments. Other times the source of pain remains a mystery, but researchers continue to sleuth.

Mean genes

Working at the molecular level, researchers isolating genes associated with pain are finding that certain genetic predispositions may make people more or less susceptible to developing pain syndromes, says Dr. Woolf.

Genes control the type and amount of proteins produced by cells, and proteins affect cells and tissues in a variety of ways, from acting as enzymes that speed up metabolic reactions to inhibiting the metabolic pathway. Genes associated with pain can produce higher or lower levels of proteins, with dramatic effects on cells and tissues. One example, says Dr. Woolf, is stimulation of the enzyme cyclooxygenase-2 (COX-2), which leads to the production of prostaglandins, which, in turn, promote pain. “People are born with genes that control the level of pain they experience, but the level of proteins being expressed by those genes can be turned upward or downward by diseases,” says Dr. Woolf.

Researchers are beginning to find genetic underpinnings in fibromyalgia, partly explaining why it tends to run in families. And fibromyalgia is teaching researchers important lessons about pain. “If someone has the genetic propensity toward fibromyalgia and experiences stress – anything from an infection to physical trauma to emotional stress – the combination figures into the development of the condition,” says Daniel Clauw, MD, professor of medicine at the University of Michigan and a leading researcher on fibromyalgia pain. 

How exactly a stressor figures into the development of fibromyalgia remains to be determined, he says. “Evidence shows that fibromyalgia is not a psychiatric disease and is not depression; it’s something totally different,” says Dr. Clauw. Is that “something” partly a genetic factor? Possibly, but genetic research relating to fibromyalgia will take years, he explains. “Fibromyalgia differs from diseases like RA or lupus because it is more a disorder of the central nervous system than of the immune system. Proteins of the immune system circulate in the blood, so they can easily be tested. But nervous system proteins don’t circulate, so testing them is tough.”

Sex and sensitivity

In addition to genetic scripting, the ways that people respond to pain depend on a range of factors, including cultural influences, past experiences and perhaps even gender, say researchers. As a result, the expression and experience of pain varies widely and is subjective. Culturally, some people are encouraged to vocalize when they are feeling pain; other societies promote stoicism. Society may be one factor that molds you; your life experiences are another.

“A person’s past experience of pain often impacts a person’s current response to painful stimuli,” says Robert Coghill, PhD, assistant professor in neurobiology and anatomy at Wake Forest University School of Medicine. For example, a man in Dr. Coghill’s study who had been stung many times during his years as a beekeeper did not feel as much pain as others in the test group when all received a stimulus that felt like a beesting. The beekeeper’s experience with stinging decreased the pain he felt from a similar sensation years later.

Learning how the brain processes pain signals may be a key to understanding why people respond to pain differently. Researchers are just discovering that one reason pain becomes chronic is because of a “memory imprint,” in which the pain experience is recorded in the CNS and can contribute to ongoing pain. Neurons in the CNS might remain hypersensitive for long periods and respond in an amplified way. 

Using imaging technology, Dr. Coghill found that of the 17 patients in his test group, all of whom received the same pain stimulus, those who were highly sensitive to pain had frequent activation in regions of the brain involving the processing of pain. The people who reported less pain had minimal activation in those areas of the brain. Could this be due to individual past experiences? (See “Can You Retrain Your Brain?”)

Individual differences may make sense, but what about gender differences? Why are more women than men affected by arthritis or fibromyalgia, and why do women often seem to experience more intense pain from these conditions? Researchers now know the pain sensory neurons that detect injury differ by sex. A woman’s pain sensory neurons tend to be highly refined, receiving more pain signals than a man’s. Estrogen receptors amp up the signaling of pain pathways, and researchers now believe this may contribute to women reporting more pain.

Amazing maze

The “ouch” type of pain – which protects us from danger by letting us know when, say, a pot on the stove is too hot – involves a dedicated high-threshold, high-speed pain pathway starting at the site of the pain, shooting its way to and through the spinal cord and ending in the brain, all within a split second. In contrast, inflammatory pain such as arthritis pain develops when neurons in the CNS and PNS become hypersensitive, says Dr. Woolf.

“Multiple chemicals interacting at the site of inflammation – including cytokines such as tumor necrosis factor-alpha (TNF-a) – act on peripheral “pain-sensing” neurons and sensitize them,” says Dr. Woolf. Studies show that in people with RA, the nerve fibers within the joints become hypersensitive with repeated stimulus and then require only the smallest stimulus to create severe pain – a phenomenon called peripheral sensitization. 

Pain arising from changes within the CNS is referred to as central sensitization. “If the pain pathway in the spinal cord is excessively activated, for example in response to injury or tissue damage, the central pathway becomes hypersensitive so that neurons begin to respond to things that normally wouldn’t activate them, like light touch, vibration, movement of a joint or even just rubbing the skin,” says Dr. Woolf.

Much more information processing goes on in the spinal cord than previously thought, says Tony Yaksh, PhD, vice chairman for research and anesthesiology at the University of California, San Diego. The spinal cord takes in all the information from the body, encodes it, sends it to the brain and decodes it. “In the face of continual peripheral pain, as from arthritis inflammation, there is ongoing input into the spinal cord. Neurons activated by this constant input become highly sensitized and keep firing messages to the brain,” says Yaksh.

“The pain process is much more complex than we thought,” says Jon Levine, MD, PhD, a professor of medicine at the University of California, San Francisco (UCSF), who is researching the mechanisms of pain on a molecular level and how they are affected in an inflammatory condition like arthritis. “We now realize that the multiple mechanisms involved in pain probably work in parallel so you can inhibit one kind of pain and still have only partial relief.”

In his laboratory at UCSF, Dr. Levine has identified a mix of molecules he calls an “inflammatory soup” – brimming with prostaglandins and cytokines – that bathes the cells and contributes to long-term, chronic pain. “Chronic inflammation changes your tissues,” says Dr. Levine. That’s why someone in the early stage of arthritis, for example, may feel much better when given NSAIDs, but years later the same patient may complain that NSAIDs no longer work. 

“Over time, some of the tissue changes result from inflammation, and some result from actual molecular changes that pain sensory neurons undergo. Those molecular changes – peripheral sensitization – alter the ways neurons produce pain signals. Meanwhile, an ever-increasing level of pain signals are being sent to the brain, increasing the amount of pain you feel,” explains Dr. Levine. The cascade of events triggered by peripheral injury explains, in part, the mystery of how aspirin manages to minimize pain wherever it occurs in the body.

Doctors understand that aspirin and other NSAIDs have an effect on the spinal cord. “It turns out there are connections between the injury site and the spinal cord called sensory fibers, which release neurotransmitters in the spinal cord,” says Yaksh. According to Dr. Simon, aspirin and other NSAIDs work on the CNS both peripherally and centrally to inhibit the production of prostaglandins – ingredients in the “inflammatory soup.”

Eyes on the prize, nose to the grindstone

Research unraveling the mystery and mechanisms of pain is paving the way for promising new treatments in the short term as well as several years down the road. Pain researchers are hopeful about P38 map kinase inhibitors – the next generation after TNF-a inhibitors that will target specific pain pathways. P38 map kinase is an enzyme that contributes to the production of inflammatory compounds. P38 map kinase inhibitors would decrease the body’s ability to make those pain-inducing compounds. 

Although one pharmaceutical company is completing phase two clinical trials, a number of these inhibitors are in pre-clinical phases and should be in clinical trials within five years. Also within the next five years, a number of new drugs that work by inhibiting the ability of certain cells to “talk” to each other are expected to be approved. Some of these drugs would block neurons, inhibiting the pain signal being sent among cells; others would block the release of certain chemicals that normally allow cells to communicate, says Dr. Simon.

Within 10 years, Dr. Woolf predicts a “mechanism-based” approach to pain as researchers continue to unlock the secrets of different kinds of pain and how they work. Dr. Woolf believes doctors will be able to identify the exact mechanism responsible for a patient’s pain and then apply the right tool to interrupt the mechanism.

What the current pain research means is incalculable. “We are evolving into a much more aggressive way of treating pain,” says Dr. Simon. With several pain-causing mechanisms identified and several clinical trials already under way for a number of drugs that will combat pain, Congress’s mandate that this be the decade of pain control and research is likely to be fulfilled.