Several years ago an elderly man came into the emergency room at Cook County Hospital in Chicago with a large, painful abscess (boil) on the back of his neck. When I told him he needed a minor procedure to lance the boil and drain it, he became ashen, asking, “Doc, is this going to hurt?” I told him that if at any time the treatment hurt too much, he could tell me to stop—and I would. I opened the boil with a very sharp scalpel. He did not make a sound for some time. “When are you going to start?” he finally asked. “It’s done,” I said. “How did you do that?” he replied. “I didn’t feel anything.”

Most people think of pain as resulting from physical injury or disease, but psychological factors play a huge role in pain perception. In the case of my elderly patient, my reassurance that the treatment would not significantly worsen his pain—because he could stop me if it did—produced an analgesic effect. In addition, reducing the man’s fear enabled him to look forward to pain relief instead, and that positive expectation also eased his pain.

The importance of mind-set to pain perception should come as no surprise. Pain is a warning sign of injury, but for such a sign to be useful, pain must influence human behavior in a way that increases survival. Thus, pain must be intimately tied to brain functions that govern behavior and decision making, including expectation, attention and learning. By way of these links, a painful blister on your foot can motivate you to stop walking or to protect the area with moleskin. It may also teach you to shop for more comfortable shoes or wear thicker socks in the future.

The interaction between the pain message and the brain centers that mediate motivation and learning accounts for the powerful effect of a person’s state of mind on the severity of pain he or she experiences with any injury. It explains the placebo effect: the expectation that a sugar pill will relieve pain reduces the extent of the agony even though the pill has no pharmacological effect. Conversely, if you are convinced that an injection, say, will be very painful, you are likely to unwittingly amplify the sting. Mood also interacts with agony. Depressed people, for example, may feel more pain as a result of their sour state of mind. In fact, worsening of a long-standing pain problem, such as headache, often is the first sign of depression or at least the complaint that first brings a depressed patient to the attention of a physician.

Recent investigations are unraveling the mystery of how and when factors such as expectation of reward or punishment, fear, stress and mood alter perceived pain intensity and affect our daily decisions. Some of these psychological factors also influence the risk of developing a chronic pain condition. The research not only reveals just how far pain reaches into our psyches but also may lead to better ways of controlling pain and hastening recovery from painful injuries.

Mind over Matter
In the classic view of pain perception, a stimulus to the body excites pain-sensitive sensory neurons in the body’s periphery; these neurons then transmit information in the form of electrical signals that eventually activate parts of the brain that enable us to perceive pain [see “When Pain Lingers,” by Frank Porreca and Theodore Price. But for decades doctors have noted that a person’s mental state can also dramatically affect pain perception.

For example, Harvard University anesthesiologist Henry K. Beecher noted in an article published in 1956 that soldiers who had been wounded in battle complained of much less pain than did patients with similar injuries in a civilian hospital. Beecher reasoned that in the context of having survived a battle and heading for home, an injury has a different meaning than it does for people hurt in the course of ordinary life. In the war scenario, a wound has honorable connotations, and such a positive spin on pain can lessen the sensation, Beecher speculated. Doctors have also long known about the analgesic powers of traumatic stress and of dummy pills that patients believe to be painkillers.

How could cognitive and emotional influences affect how much agony we feel? Over the past few decades researchers have uncovered a circuit in the brain and spinal cord that functions as a kind of volume control for pain, adjusting the amount a person perceives depending on the circumstances. In the early 1970s scientists at the University of California, Los Angeles, discovered that excitation of a small area in the midbrain of the rat produced profound pain relief. When they sent electricity through small wires implanted into that region of the brain, the rodent would no longer respond to intense, tissue-damaging stimuli that otherwise would make it squeak and flee. Later in the decade scientists showed that patients with severe chronic pain obtain significant, though temporary, relief from electrical stimulation of the same midbrain site, the periaqueductal gray.

Since then, researchers have mapped other parts of the body’s pain-control circuit. It stretches from the brain’s cerebral cortex in the frontal lobes through underlying brain structures, including the periaqueductal gray, to the spinal cord, where pain-sensitive nerve fibers connect to neurons that transmit pain signals from the rest of the body. Neurons in this pathway synthesize peptides known as endorphins that have pharmacological properties identical to the powerful opioid morphine. Endorphins, the body’s natural painkillers, and opioids (which also include opium and heroin) act at the same receptors, called mu opioid receptors, along this pain modulatory pathway to produce their analgesic effects.

Great Expectations
Neuroscientists are finding that cognitive influences on pain operate through this modulatory pathway. The circuit is the conduit for a variety of expectation effects, including the prospect of pain relief from a placebo pill. In 2004, for example, neuroscientist Tor D. Wager, now at Columbia University, and his colleagues found that a placebo produced increased activity in this pain-control circuit. Endorphins seem to be important in transmitting the pain-suppressing signal: my colleagues and I found that blocking mu opioid receptors with the drug naloxone erases the placebo effect in patients experiencing pain from a recent surgery. [For more on placebos, see “Cure in the Mind,” by Maj-Britt Niemi; Scientific American Mind, February/March 2009.]

Recent data from my laboratory implicate the same circuit in other forms of expectation while underscoring their power over pain. In a study published in 2006 my research team showed volunteers color cues generated on a computer monitor just before exposing them to a painful stimulus through a metal probe taped to their hand. The words “low temperature” against a blue background were followed by mildly painful heat, and the words “high temperature” against a red background by more intense heat. Afterward subjects were placed in a magnetic resonance imaging scanner and randomly shown the red-high and blue-low cues beginning just before the mild or intense painful stimuli were applied.

We found that the blue-low temperature cue, which had previously preceded milder discomfort, reduced the reported pain to the intense stimulus. In contrast, the red-high temperature cue, which had been paired with greater pain, amplified the discomfort of the mild stimulus. When the red-high cue preceded the intense stimulus, the pain magnitude was greatest. The brain sites known to be part of the pain transmission system in the thalamus and cortex were fully activated only when both stimulus intensity and high pain cues were given together. Thus, the pain we experience is a synthesis of what happens in our body and what we expect, which depends on what we are told or have otherwise learned.

We isolated the brain regions involved in the expectation effect by subtracting activity in the brain areas that lit up when the stimulus was intense and a person anticipated more pain from those excited by the same painful peripheral stimulus given when a person expected less pain. The net result was activation in cortical and brain stem regions that we now know are involved in the control of pain.

In addition to predictions about the pain itself, the expectation of a reward—say, from food or drugs—can profoundly affect pain intensity. In a classic 1984 experiment pharmacologists J. Dum and Albert Herz of the Max Planck Institute for Psychiatry in Munich fed rats every day while the rodents were standing on a metal plate, which was at room temperature. Some of the rats ate regular rat chow, whereas the others feasted on chocolate-covered biscuits. After two weeks, the researchers placed the rats on the plate, which they then gradually heated to a painful temperature. The rats that had previously consumed their regular chow responded to the pain after four seconds; the rats that expected to receive chocolate endured the heat for twice as long. When the rats received a drug that prevents endorphins from relieving pain, however, the animals would no longer wait twice as long for their chocolate treat. Thus, the anticipation of the food reward had served as an analgesic, effectively raising the rats’ tolerance for pain.

Food, sex and other natural enticements—and even the mere anticipation of such pleasures—activate the brain’s reward circuitry in both rodents and humans. In doing so, they can also produce pain relief. The effects of opioid drugs further suggest that reward and pain relief have a partially shared neural basis. After all, the most powerful of these drugs, such as morphine and oxycodone (OxyContin, a prescription painkiller that has been widely abused), can relieve severe pain but also unleash a “high”—leading to their addictive potential.

Painful Choices
Pain and reward interact at mu opioid receptors. Mice engineered to lack a functioning mu receptor experience neither pain relief nor reward from morphine. In addition, rats given naloxone (which blocks opioid receptors) no longer experience pain suppression when they are expecting a food reward such as chocolate. Thus, when a person anticipates a reward such as a delicious dinner, the body releases endorphins, activating the mu receptors along the descending pain-control pathway and controlling pain signals as they enter the central nervous system.

A brain region called the nucleus accumbens plays a critical role in both signaling reward and controlling pain. Inactivating this region, which contains mu receptors, prevents animals from experiencing pleasure from either recreational drugs or natural rewards such as food and sex. What is more, injecting rewarding substances into this region can suppress pain responses.

The ability of an imminent prize to suppress pain can influence decision making in situations in which reward seeking and escape from pain are in conflict. An athlete, for example, may face a choice between giving in to physical discomfort and enduring it in hopes of winning a race or a game. A person with a painful blister on his foot might have to choose between resting the injury and going out for pizza and a movie. Such decisions depend on a cost-benefit analysis inside the brain. How painful is the injury, and how much do you expect to enjoy the victory, movie or pizza? These expectations influence your decisions, in part through the pain-control circuit.

If you are a highly motivated athlete or you expect the pizza or movie to be extremely good, your expectation will—through the release of endorphins and their stimulation of mu receptors—not only enhance the predicted enjoyment of the victory, food or film but also suppress pain. The overall effect biases you toward tolerating the pain to reach your goal or reward. In addition, you will actually feel less pain as you compete or head to town.

Similarly, rats that anticipate chocolate subconsciously “decide” to bear the pain of a hot plate to get the chocolate, both because they expect it to taste delicious and because that expectation alone reduces their pain. Such a resolution of pain-reward conflicts may have survival value. Animals often must endure pain to fight off a competitor for food or for a desirable mate.

The analgesic properties of anticipated rewards are consistent with the placebo effect. If relief of pain is rewarding, then a placebo pill is a sign of a forthcoming reward, leading to pain suppression. Thus, the expectation of relief becomes a self-fulfilling prophesy. Conversely, predicting pain has the opposite effect, amplifying activity in the pain transmission pathway and leading to greater pain perception.

Positive expectations for healing from painful injuries can lead to faster actual recovery from those wounds. In 2009 epidemiologist J. David Cassidy of the University of Toronto and his colleagues reported that among 2,335 Saskatchewan residents who endured traffic-related whiplash injuries, which are a major source of neck pain, those who expected to get well enough to return to their regular job reported recovering 42 percent faster than did those who were less positive. Previous studies have also shown that expectations for recuperating are consistently associated with going back to work among patients who have lower back pain, suggesting that a person’s outlook on the future can strongly influence how much pain impinges on his or her life.

Skirting Danger
In addition to expectations of recovery or reward, a sense of danger can squelch pain. Researchers, including psychologists Fred. J. Helmstetter of the University of Wisconsin–Milwaukee and Michael S. Fanselow of U.C.L.A., have shown that rats do not respond to painful stimuli in the presence of a predator or when the rats are in an environment that provokes fear because, say, they had previously experienced a painful stimulus in it. Naloxone blocks this analgesic effect of fear in rats, indicating that the presence of imminent danger suppresses the experience of pain through release of an endogenous opioid.

People will often feel no pain during or immediately after severe trauma—say, a traffic accident or incident on a battlefield or during an athletic contest. Situations that produce acute tissue injury may signify an ongoing hazard and thus unleash fear or acute stress in humans and animals. The resulting suppression of pain may enable a person or animal to get to safety before being hobbled by agony.

Although acute stress can suppress pain, if stress persists and becomes chronic, pain usually intensifies. A bad mood may also increase pain. People who suffer from depression, for instance, may be more vulnerable to or less tolerant of pain. A 2007 study of 131,500 Canadians showed that among chronic pain patients, 11.3 percent had major depressive disorder as compared with just 5.3 percent of individuals who did not experience chronic pain. Being in pain may be depressing, and depression itself is also thought to affect pain perception. Neurochemical changes associated with depression—such as the depletion of the neurotransmitters serotonin and norepinephrine—may reduce normal inhibition or increase facilitation within the descending pain pathway.

In addition, catastrophizing, or interpreting pain as unbearable and likely to worsen, tends to increase the experience of pain. Patients who score high on catastrophizing on a standard questionnaire tend to experience more severe pain after surgery and show more sensitivity to experimentally induced pain than do those who score low on the questionnaire. Catastrophizing may worsen pain by making a person concentrate on it and attach additional emotion to it. In a study published in 2004 rheumatologist Daniel J. Clauw of the University of Michigan at Ann Arbor and his colleagues tested 29 fibromyalgia patients for their tendency to catastrophize and then measured their brain responses to blunt pressure on a thumbnail. They linked pain catastrophizing to increased activity in brain areas related to the anticipation of pain, attention to pain and emotional aspects of pain perception.

Psychological distress of various forms raises a person’s risk of developing a pain syndrome. In a study published in  2007 neurobiologist William Maixner of the University of North Carolina at Chapel Hill and his colleagues tracked 244 initially pain-free women for up to three years to see who developed temporomandibular joint disorder, a condition characterized by persistent jaw pain, to determine the traits that foretell its development. They linked being depressed and feeling stressed, for example, with a twofold to threefold rise in the chance of getting the disorder. In earlier work, scientists at the University of Washington tied somatization—a tendency to report numerous symptoms in excess of that expected from a physical injury—with more than a doubling of the incidence of the disorder and less improvement after five years.

Parting with Pain
Research into the psychology of pain may lead to new ways of helping people overcome or cope with pain caused by injury, medical treatment or disease, whether minor or significant. Already, increased knowledge of the brain circuits that mediate the interaction of reward and pain relief is beginning to provide clues for strategies to dissociate the addictive potential of drugs from their pain-relieving power. The findings may lead to effective painkillers that are significantly less addictive than opiates.

In addition, understanding the powerful effects of mood, expectation and other psychological factors on pain is important for helping friends, patients or loved ones deal with their pain. Telling people in pain about individuals who have done well can often ease their distress and discomfort, whereas informing them of others who have had serious illnesses with similar symptoms will very likely worsen their suffering.

Doctors should be on the lookout for mood-related factors such as depression or chronic stress that might be abetting a patient’s pain. They also need to carefully query patients about, or otherwise assess, their expectations regarding their discomfort. If a patient is overly pessimistic, a physician can reassure him or her by providing more accurate information, as I did with the man I treated for the abscess. Ultimately, the new understanding of the effects of mind-set on pain promises to revolutionize our approach to pain treatment.

Note: This article was originally printed with the title, "The Psychology of Pain."