A cure for pain

Pain is the great equalizer. It crosses geography, culture, language, religion, and socioeconomic status. You don’t need a PhD to feel the tingling pain of a banged elbow, or the blinding pain of a migraine headache. And while you may say “Ouch, that stings!” or “Ai! Doi demasiado!” words only approximate the experience.

Dr. Anne Louise Oaklander

But pain isn’t all bad. In fact, it’s healthy and necessary. Pain is what keeps a person with a broken leg from walking on it. Pain is the signal that tells someone to pull his hand away from a hot stove. “Pain is so essential to survival that virtually all living organisms, even amoebas, have primitive pain systems,” says Anne Louise Oaklander, MD, PhD, a neurologist and director of the Nerve Injury Unit in the Pain Center at Massachusetts General Hospital (MGH). “Pain is what keeps us out of harm’s way.”

But sometimes this helpful system goes into overdrive. Pain lingers, instead of disappearing with the injury or disease that produced it. It can persist for months beyond its original cause, taking on a life of its own. Today, doctors consider such chronic, or persistent, pain a disease in its own right. And it’s a global problem. In this article, HMI World takes a look at what we are learning about the origins of pain, and what we might be able to do in the future to alleviate it.

Because there is no agreed-upon definition for chronic pain, estimates about its prevalence vary greatly. Pain is largely a subjective experience, making it hard to pin down. Researchers at the Alberta Heritage Foundation for Medical Research in Canada reviewed 13 studies published between 1991 and 2002 and found that prevalence estimates ranged from around 12 to 55 percent of adults. When the investigators pooled the results of four studies that used a common definition provided by the International Association for the Study of Pain, they determined that over one-third (35.5 percent) of adults have chronic pain, and for 11 percent, the chronic pain is severe.

In 2001, the U.S. Congress declared this the “Decade of Pain Control and Research.” The World Health Organization (WHO) recognizes that chronic pain is “disabling and costly,” and ranks it among the top reasons for health care visits and health-related work absences. A WHO study of nearly 5,500 people in Asia, Africa, Europe, and the Americas found that people with persistent pain were over four times more likely to have an anxiety or depressive disorder than people without pain. Indeed, it is well known that chronic pain often leads to emotional problems, sleep disturbances, and relationship difficulties.

Neuropathic pain: A wiring problem
When patients complain of persistent pain, health care professionals often look first for tissue damage, observes Oaklander. Sometimes they find it, for instance, in a patient with arthritis. But for substantial numbers of chronic pain sufferers, there is no obvious explanation for their pain, such as an infection or fracture. All too often, these patients are sent on their way without treatment.

Because most health care providers are not trained in pain management, Oaklander says, “they feel inexperienced or uncomfortable managing severe, chronic pain.” And in some cases, they may believe the patient has psychiatric problems, or is looking for secondary gain, such as compensation or pain medication.

But for millions of patients, this invisible suffering is caused by wiring problems. The patients have damage to the pain pathways in the central or peripheral nervous system. This nerve injury results in a type of maladaptive pain known as neuropathic pain. According to some estimates, as many as half of the people with chronic pain have a neuropathic component.

Normal nerves transmit messages back and forth between the body and the brain. They relay sensations as gentle as a ligh touch, or as sharp as a knife cut. But when pain-transmitting nerves are damaged, the alarm may continue to go off even though the danger has passed, or it may send out repeated false alarms.

Neuropathic pain can occur anywhere in the body and often produces shooting, burning, or prickling sensations. It can also create numbness (or loss of sensation) or pain from light touch. Common causes include AIDS, alcoholism, carpal tunnel syndrome, shingles (postherpetic neuralgia), pinched nerves (e.g., sciatica), or the inability to absorb vitamin B12. It can also result from cancer and chemotherapy, stroke, or amputation. Or it can appear spontaneously, seemingly out of nowhere.

Neuropathic pain presents a particularly vexing challenge to clinicians. Even those who know what to look for are forced to take a trial-and-error approach to treatment. While neuropathic pain responds to drugs such as lidocaine, tricyclic antidepressants, anticonvulsants, and certain opioids, it is difficult to know which to try first, or what combinations will work best for which patient.

Mechanisms of pain
Scientists have been making great strides toward understanding pain’s underpinnings. Over the past decade, they have begun to tease out some of the neurobiological mechanisms that produce neuropathic pain. These insights have led to new ways of thinking about diagnosing and treating people who suffer from the chronic pain resulting from injured nerves (see sidebar).

Dr. Clifford Woolf

One of the principal researchers behind this paradigm shift is Clifford Woolf, MD, PhD, director of the Neural Plasticity Research Group and Professor of Anesthesia Research at Massachusetts General Hospital and Harvard Medical School.

Woolf has changed the way we think about pain sensation and transmission. He helped develop a concept called “central sensitization” that explains the way the nervous system changes in response to chronic pain, becoming more sensitive, rather than desensitized. He has spearheaded discoveries of several key pain mechanisms, including the reorganization of the synaptic architecture in the spinal cord after peripheral nerve injury (called central sprouting), transcriptional changes in sensory and spinal neurons (phenotypic switches), and loss of inhibitory interneurons (disinhibition).

His team is currently using molecular techniques to identify which genes are switched on or off in pain-related conditions, providing a means to identify new targets for the development of analgesics. These efforts and those of other scientists in the pain field may one day lead not only to drugs that control or suppresses pain symptoms, but treatments that can stop pain from developing in the first place.

While preventive treatments remain a daunting challenge for researchers, says Woolf, they are at last conceivable. And in the meantime, he says, there are at least 10 “novel forms of therapy” that are in some stage of development. But despite these advances, tremendous obstacles stand between the drugs and the patients who need them. “Neuropathic pain is receiving a lot of attention from the pharmaceutical industry,” Woolf says. “We have many new treatments. But we don’t have a good way of using them effectively.”

Not all patients respond to the same drug in the same manner. And some don’t respond to some drugs at all. What’s more, knowing that pain is caused by, say, cancer or postherpetic neuralgia, is not necessarily useful in choosing the best treatment. Today, Woolf explains, clinicians rely on their judgment and past experience to determine the appropriate combination of drugs for each patient. He calls this the “a la carte approach to pain management.” There is no way of predicting who will obtain relief from a particular treatment, and who will not respond. Moreover, there isn’t even an agreed-upon means of making a diagnosis.

“Right now, the diagnosis of neuropathic pain is confusing and controversial,” Woolf notes. Does it include only lesions of the nervous system, or does it also include dysfunction of the nervous system, “conditions where the nervous system is simply not working as it should? We need a new set of diagnostic criteria to say exactly what neuropathic pain is and how it is produced.”

Woolf has spent his career examining the mechanisms of pain in laboratory animals. But now, he says, he is about to embark on something new. “I’ve realized the only way to make a bigger impact, rather than study the mechanisms in a preclinical setting, is to find these diagnostic criteria and identify what mechanisms are causing pain.”

To that end, Woolf and his colleagues are conducting a trial at MGH involving 200 patients to determine what is responsible for their pain. The investigators are taking 100 different measurements and using statistical analysis to see whether there are features of the patients’ pain that, when grouped together, reflect the presence or absence of a mechanism generating the pain.

The research is based on the knowledge that out of 50 mechanisms that potentially could cause neuropathic pain, there are only five that are really important. Woolf hopes that the findings will lead to a new way to assess what causes a patient’s pain, which in turn will enable physicians to make a “rational decision” about who will respond to which therapy, and what therapy is best for each patient. More importantly, he adds, he hopes to create algorithms that determine the best way to give patients relief without causing major side effects.

One day, instead of simply asking “where does it hurt,” “how bad is it,” and “when did it begin,” a physician might find out how sensitized the neurons are, whether the sympathetic nervous system is involved, and what role the central nervous system plays. “By improving our diagnostic abilities, in particular, being able to identify what mechanisms are responsible for the production of pain, we will be able to discover and choose treatments that target those mechanisms rather than controlling the symptoms,” says Woolf. He expects the trial to be completed this year.

In the meantime, he is continuing his research into selective sodium ion channel blockers, and his lab has found hundreds of genes that change in response to nerve damage. The investigators have even identified a family of genes that are targets for drugs in development. The only thing that stands in the way, he says, is resources. “We have the technology and tools. It’s a matter of applying them. Neuropathic pain has to reach a point where funding bodies decide it’s worth investing in. Society needs to say this is a major problem worthy of our dollars and attention.”