Imagine you are a doctor treating a patient who has been in nearly constant pain for four years, ever since the day he sprained his ankle stepping off a curb. Physical therapy only briefly dulled the agony. Painkillers were not much better, and the most effective drugs made your patient exhausted and constipated. He is now depressed, sleeping poorly and having difficulty concentrating. As you talk with him, you realize that his thinking also seems impaired. Your exam confirms that the original injury has healed. Only pain and its consequences remain—and your options for helping this man are running out.

This scenario plays out every day in doctors’ offices around the world. Fifteen to 20 percent of adults worldwide suffer from persistent, or chronic, pain. Half the primary care patients who develop a chronic pain condition fail to recover within a year, according to surveys conducted by the World Health Organization. Common causes of such unrelenting discomfort include physical trauma, arthritis, cancer, and metabolic diseases such as diabetes that can damage nerves. In many cases, however, the pain’s origins are mysterious.

Indeed, despite decades of intense research into the biology of pain and how pain is perceived, many mysteries still surround chronic pain and its treatment. No one knows for sure why some injuries, even minor ones, result in persistent pain or why it occurs in some people but not in others. Nevertheless, researchers are pinpointing telltale changes in the neurons that underlie persistent pain. In particular, they have documented abnormal excitability among neurons at every level of the body’s pain network. For instance, in the spinal cord, some cells aberrantly amplify pain signals after undergoing a type of molecular “learning” that is similar to what happens in the brain during the formation of long-term memories.

Chronic pain is more emotionally fraught than acute pain—which comes on quickly but lasts a relatively short time. Changes in brain regions governing feelings and complex thoughts in chronic pain states may help explain some of the unwanted emotional and cognitive problems, from depression to attention deficits, that can sometimes emerge after years of suffering. Researchers have even uncovered signs that chronic pain might be a type of neurodegenerative disease, affecting parts of the brain that deal with attention, memory and decision making. A firmer understanding of these processes could lead to new treatments that would alleviate the relentless chronic pain experienced by millions of people worldwide.

Disease of Discomfort
We sense pain using specialized sensory neurons called nociceptors; these cells extend to most of the body, their fibers running alongside other sensory neurons in large bundles that make up peripheral nerves. Nociceptors normally respond selectively to strong stimuli, such as pressure, heat or cold. They then send their messages to neurons in the spinal cord, which, in turn, relay neuronal indications of potential or real tissue damage to the brain centers where pain perception occurs. Activation of this pain pathway is critical for reflexive and coordinated protective responses to escape something that could damage the body, such as a stinging insect or a hot stove. Detecting circumstances in which we might experience harm is a vital protective function of our nervous system.

But the protective pain we experience as a result of daily living is quite different from that which leads patients to seek medical attention. Instead of becoming active only in the presence of strong and potentially damaging stimuli, the pain transmission pathway can become pathologically revved up in reaction to movement of joints, light touch or other actions that are normally innocuous—a phenomenon termed allodynia. In some sufferers, donning clothes, taking a shower or going for a walk on a breezy day is excruciating because the fabric, water or wind on their skin abnormally stimulates pain pathways.

In other cases, pain can occur spontaneously, without any obvious cause. Patients who have endured nerve damage as a result of diabetes, for example, may feel intense burning pain while doing nothing more than sitting quietly in a chair.

Unlike ordinary pain messages, spontaneous pain and pain produced by mild stimulation do not signal impending damage to tissues and do not provide a survival advantage. Pain produced under these conditions reflects pathological changes in pain pathways and represents a disease in and of itself.

Too Much Excitement
In the early 1980s researchers began to learn the sources of such pathological pain. Studies in rats by neuroscientist Clifford Woolf of University College London and Harvard University and his colleagues revealed, for example, that following an injury to a rat’s paw, neuronal signals from nociceptors near the skin to neurons in the spinal cord became amplified, much like turning up the volume on an iPod. These altered neurons unleash exaggerated reactions to tissue-damaging input; in addition, they become more easily excited, responding to stimuli that are ordinarily too mild or weak to produce a reaction.

Hormones or inflammatory molecules that the body produces in response to injury may sensitize nociceptors, making them more impulsive, a change that could instigate the development of chronic pain and abnormal sensitivity to mild stimuli. (Such molecules also account for the aches a person may feel during normal movement a day after lifting weights, an activity that can lead to mild muscle damage.) Chronic pain conditions often begin when a peripheral nerve is injured, making that nerve—a bundle of fibers of which some are nociceptors—and neighboring ones more excitable. Hyperexcitability within the uninjured nerves that intermingle with the wounded nerve is probably paramount for the persistence of pain after the original injury is gone because many of the damaged nerves degenerate.

In addition to becoming more excitable, injured neurons may sometimes start signaling spontaneously. Injuries to peripheral nerves from trauma, diseases such as diabetes and cancer, drug treatments or excessive use of recreational drugs such as alcohol can spark such relentless electrical discharge, or ectopic activity, in the damaged nerves. These nerves then provide persistent input to the rest of the pain transmission pathway, a process that is believed to drive spontaneous pain. Often the recalcitrant signaling that underlies the pain remains long after an injury has healed.

In recent years researchers have revealed a molecular basis for this low-level ectopic activity. Voltage-gated sodium channels—proteins that conduct sodium ions into a cell in response to voltage changes—on the membranes of these neurons are essential for their ability to transmit electrical messages; their abundance and activity—how often they open and shut, for example—play an important role in how sensitive or excitable a neuron is. The latest data indicate that in chronic pain states these channels cluster where they count most, at the endings of the neurons near the skin and all along the nerve, most likely making the neurons more responsive to input.

For example, in a 2003 study one of us (Porreca) and his colleagues used fluorescent molecules to visualize a sodium channel called Nav1.8 in the peripheral nerve cells of rats after a type of nerve injury that leads to chronic pain. We saw that the nerve membrane undergoes a “remodeling” so that the Nav1.8 channels accumulate near the injury. This study suggests that injury prompts the nerve cells to ship lots of these proteins from their neuronal cell bodies near the spinal cord outward to the nerve terminal. This redistribution appears to be critical to the experience of neuropathic pain, because blocking the cells from producing this sodium channel made the rats’ pain disappear, as evidenced by a return to their normal behavior. Neuroscientists have also discovered support for a similar transport of sodium channels in human tissues from studies on patients who have nerve injuries that produce persistent pain.

Other researchers have been homing in on the underpinnings of chronic pain in the dorsal horn of the spinal cord, where the peripheral pain fibers end. In 1999 neuroscientist Patrick W. Mantyh, then at the University of Minnesota, and his colleagues found that a subset of these dorsal horn neurons—just 1 to 3 percent of cells in this region—of the spinal cord are major culprits in chronic pain. Using a Trojan horse strategy, they chemically coupled a toxin to a neurotransmitter, a neural signaling substance, so that when the neurotransmitter bound to its receptor on another cell, the receptor-transmitter complex served as a chemical “scalpel,” deleting (killing) the recipient cell. Without these dorsal horn neurons, rats failed to show signs of chronic pain after local inflammation or nerve injury—symptoms that plagued rats that still had these neurons. The elimination of this neuronal subset did not affect ordinary pain perception, however, implicating these cells primarily in pathological discomfort.

But what happens in these spinal cord neurons when pain becomes chronic? Recent data hint that they undergo a process called long-term potentiation (LTP), a long-lasting improvement in communication between two neurons that also underlies the formation of certain types of memories in the brain. Although LTP in the brain generally requires high-frequency input, 100 hertz or above, in a 2006 study neurophysiologist Jrgen Sandkhler of the Medical University of Vienna and his colleagues demonstrated that low-frequency stimulation from injured peripheral nerves in rats can lead to LTP in some dorsal horn neurons. In LTP, input from one neuron leads to a heightened response in the recipient cell, an effect that should enable spinal cord cells to amplify incoming pain signals. And just as LTP represents a molecular mechanism of memory storage in brain cells, it may underlie the ability of spinal cord neurons to sustain a state of chronic pain.

Nerve circuits that arise in the brain and lead down to the spinal cord can also profoundly influence the incoming pain signals and the resulting experience of pain. In this circuit, cells in the periaqueductal gray area of the midbrain receive input from the various regions of the brain’s outer layer (the cortex) as well as from interior sections, such as the amygdala and the hypothalamus. This midbrain region then relays information to the rostral ventromedial medulla (RVM) in the brain stem, the lower part of the brain adjoining the spinal cord. Activation of this circuit mediates the powerful suppression of pain that occurs during trauma, intense stress or excitement.

This same circuit, and in particular the RVM, also plays a major role when pain from an acute injury persists. Work from our laboratories has shown that when nerves are injured in rodents, a specific set of cells in the RVM sends out a signal that amplifies, rather than diminishing, incoming pain signals and sets the stage for chronic pain. In 2001, for example, a team led by Porreca used the toxin-based Trojan horse strategy to selectively snip out these RVM neurons in rats. Without these cells, the rats still developed pathological pain in their hind paw after a nerve injury, but that pain was short-lived, suggesting the RVM harbors a critical “switch” for the maintenance of chronic pain.

In an important 2008 study neuroscientist Irene Tracey of the University of Oxford and her colleagues found that neural activity in this brain stem region in human volunteers paralleled the duration of painful symptoms (induced by exposure to the hot pepper compound capsaicin) that were similar to those of chronic pain patients. Current evidence suggests that ectopic input from injured nerves may alter these RVM cells so that their messages to the spinal cord facilitate, instead of inhibiting, incoming pain signals.

Painful Feelings
In addition to operating the pain-control circuit, pain-processing regions of the brain interpret input from the spinal cord and from other brain regions to create an overall impression of the discomfort. This interpretation depends on the setting and on a person’s past experience, attentiveness and mood, among other psychological factors [see “The Psychology of Pain."] To that end, pain not only stimulates sensory areas of the brain but also powerfully activates brain areas involved in emotion, such as the anterior cingulate cortex (ACC), a region governing emotional aspects of pain, and the amygdala, which mediates fear and other feelings. These areas—which are part of a so-called pain axis in the brain—can become hyperactive in chronic pain conditions and may, in turn, play a significant role in enhanced responses to stimulation in these patients.

Various known triggers of chronic pain seem to alter the ACC in particular. Peripheral nerve injury and chronic inflammation precipitate neural restructuring in the ACC. In addition, psychological factors such as mood, expectation and hypnotic suggestion can modulate pain responses in the ACC, according to human imaging studies [see “The Truth and the Hype of Hypnosis,” by Michael R. Nash and Grant Benham; Scientific American Mind, June 2005]. Thus, the ACC may integrate sensory input with emotional state and may partially underpin some of the “affective” disturbances associated with chronic pain, such as depression, sleep disorders and pain catastrophizing, a condition in which patients expect and fear that pain will be intense and unmanageable. (Neuroscientists have shown that pain catastrophizing specifically engages the ACC.) The involvement of the ACC and the pain axis in general might also help explain the common occurrence of pain in patients with conditions such as depression and post-traumatic stress disorder.

A hyperactive pain axis not only increases pain intensity but also augments the aversive qualities of the experience. Chronic pain may thus reflect a switch from a bottom-up condition in which painful sensory information dominates to a top-down state in which emotional and cognitive assessments control pain behavior.

Certain cognitive deficits may also result from the toll chronic pain takes on patients. In 2004 neuroscientist A. Vania Apkarian of Northwestern University’s Feinberg School of Medicine and his colleagues demonstrated that individuals with chronic back pain or complex regional pain syndrome, a debilitating condition that can develop after trauma, showed a decreased ability to accurately assess risk and reward when making decisions. All the patients took part in the Iowa Gambling Task, a card game in which players choose between “bad” decks of cards that yield high immediate gain but substantial future losses and “good” decks that produce lower immediate gain but minimal losses later. Pain-free participants chose cards from the good decks—the most profitable strategy—more frequently than the pain patients did. The patients also tended to be fickle, frequently switching between decks, suggesting that the unpleasant emotions that accompany a state of persistent agony may interfere with judgments in other situations, such as weighing options in a gambling game.

In recent work presented at international pain meetings, neuroscientists Volker Neugebauer of the University of Texas Medical Branch and Vasco Galhardo of the University of Porto in Portugal showed that arthritic rats display a similar impairment. Given a choice between a “high-risk” food-dispensing lever that yields three food pellets in three out of 10 visits and a “low-risk” lever promising one pellet eight times out of 10, arthritic rats over time developed a preference for the high-risk lever (risking going hungry in seven of 10 visits), whereas normal rats more consistently picked the low-risk lever (missing only two snacks in 10). In this study the researchers associated a change in the brain with the inappropriate risk assessment: alterations in chemical signaling within neural circuits connecting the amygdala to the prefrontal cortex—a region governing higher cognitive functions, including attention, decision making and working memory—of the arthritic rats.

Previous work by Neugebauer and his colleagues suggests that chronic experimental pain in rats can lead to amplification of neural signals coming into the so-called nociceptive amygdala, a part of the amygdala governing pain. This augmented input then magnifies the messages—which are inhibitory in nature—that the nociceptive amygdala sends to the prefrontal cortex. The increased inhibition of the prefrontal cortex may impair an animal’s (or human’s) ability to accurately assess the risks of options when making important decisions.

More obvious brain changes may underlie other types of cognitive decline, among them muddled thinking and difficulty concentrating, in chronic pain patients. In 2004 Apkarian and his colleagues reported a shrinking of the prefrontal cortex in patients with very long-lasting back pain. The decreased brain volume was proportional to the duration of the pain in these patients but roughly equivalent to that seen in 10 to 20 years of aging. Since then, other research teams have revealed preliminary evidence of possible atrophy in the brains of some patients afflicted with other persistent pain conditions. These results hint that pain might actually be a neurodegenerative disease leading to remodeling of the prefrontal cortex and possibly other cognitive regions of the brain.

No one knows for sure how chronic pain could lead to neurodegeneration, but the increased neuronal excitability that we now know characterizes chronic pain may provide a clue. Such excitability often leads to excessive release of the neurotransmitter glutamate, and glutamate is known to be toxic to neurons in large quantities. At this point, however, the glutamate explanation is purely speculative, and researchers are actively investigating various possible molecular causes of this neurodegeneration.

Calming Nerves
The recent insights into the mystery of why pain becomes chronic may point to new therapies. Medical researchers are attempting to block amplification of neuronal signals at every stage of the body’s pain network. A few current and emerging medicines are geared toward countering abnormal activation of nociceptors. Some of these therapeutics act as “sponges” to absorb inflammatory proteins or nerve growth factors that are thought to boost the excitability of these pain-transmitting neurons. Other compounds that target neuronal hyperexcitability include sodium channel blockers and inhibitors of enzymes such as nitric oxide synthase that yield active neurotransmitters.

In the future, new analgesics might target the small subset of cells in the dorsal horn of the spinal cord that Mantyh, now at the University of Arizona, and his team tied to chronic pain or analogous cells in the RVM. A better understanding of the role of the ACC in chronic pain conditions might lead to novel therapeutic strategies that ameliorate pain, along with its psychological consequences. Ideally, these antiamplification therapies will not only ease patients’ suffering but also prevent structural brain changes and possibly neurodegeneration that accompany extreme forms of chronic pain. That is, the best treatments would not just reduce symptoms but also reverse the disease process.

Drug treatments might make up just a part of the eventual strategy for ending intractable pain. Advanced diagnostic techniques might help determine the underlying cause of persistent pain. Some researchers are trying to identify “biomarkers,” or molecular signs, of chronic pain that they could find in a blood or tissue sample, enabling early detection—and treatment—of abnormal changes in the nervous system that signal chronic pain. This technique could also point to the therapies most likely to work in an individual.

For patients who have a long-standing problem, doctors may want to prescribe behavioral techniques to address any emotional and cognitive fallout from the pain. Patients might be advised, for example, to supplement their medication with mind-preserving strategies, including intellectual challenges such as puzzle solving and physical exercise. Such a multipronged attack on relentless pain and its consequences should ultimately offer greater hope for the afflicted.

Note: This article was originally printed with the title, "When Pain Lingers."