Every runner is well acquainted with pain. Whether we medicate or endure it, whether we complain aloud or maintain a quiet stoicism, every runner has experienced myriad forms of pain.

Fear of pain prevents some from running or pursuing a marathon. For others, the pain of exertion is met as an old friend, a satisfying soreness confirming the intensity of effort. Experience teaches the runner to discern between pain that portends serious injury from the benign pain associated with a rigorous workout.

Pain can be frustratingly difficult to describe or characterize. It can be precise or deceptive, a tightly defined sensation or an amorphous, emotional feeling. Emotions and many other experiences influence the perception of pain. Soldiers in battle and athletes in competition may tolerate major injuries, nearly oblivious to any degree of pain. At other times, anxiety and expectation can exacerbate a relatively minor intrusion, such as the sting of a needle in a doctor’s office.

Dr. George Sheehan, physican and running philosopher, once said, “to keep from decaying, to be a winner, the athlete must accept pain—not only accept it, but look for it, live with it, learn not to fear it.” Understanding the physiology, psychology, and medication of pain can help the runner interpret the sensation and react appropriately.

THE SENSATION OF PAIN

The sensation of pain, nociception, involves a complex array of interactions that have been meticulously mapped and characterized. Tissue damage constitutes the initial stimulus for the sensation of pain via two classes of receptors. One type senses the sharp, prickling pain caused by thermal or mechanical injury. The other, overlapping with the first, responds to higher intensity mechanical, chemical, or hot stimuli. With endless resourcefulness, athletes find ways to trigger every possible pain receptor, in skin, deep tissues, and joints.

Once activated, these pain receptors relay the signal to the spinal cord via neurons, the elongated cells that comprise nerve fibers. From neuron to neuron, the signal is communicated up the spinal cord to the brain. No fewer than five distinct nociceptive pathways carry information along the spinal cord.

Upon reaching the brain, a web of signals is dispatched. In the brain, pain is comprehended, placed into context, and manipulated by several mental processes. Emotion, for example, powerfully influences the perception of pain. Childbirth is a classic example in which elation tempers the severity of pain. The extreme emotions engendered by athletic competition, from despair to euphoria, can magnify or dampen the perception of pain.

Remarkably, additional signals are sent from the brain back down the spinal cord to the site of injury. Stimulation of certain sites in the brain, such as the periventricular gray region, with a tiny electrical current, can induce analgesia. These areas of the brain project neurons back down the spinal cord to suppress the activity of pain-sensing pathways.

Pain is also modulated by other sensations, a phenomenon explained by the gate-control theory. Some neurons, relaying information about nonpainful sensations, block nearby neurons in pain-sensing pathways. Simplistically, the spinal cord and mind do not have the capacity to monitor all sensations equally, so transmission through some pain pathways may be intermittently inhibited. Runners are inundated with sensations, painful and otherwise, so plenty of noxious stimuli go unnoticed.

Given the intricate anatomy of pain-sensing pathways and the numerous inputs and manipulations, it is not surprising that the mind, on occasion, misperceives painful stimuli. Miscues and mixed signals result in phenomena such as referred pain, phantom pain, and some chronic pain syndromes.

Referred pain is the perception of pain in one part of the body, although the sensation originated elsewhere. Pain fibers in the spinal cord often receive input from more than one site, and the brain is sometimes unable to differentiate among inputs. Pain from a heart attack can be felt as pain in the left arm or jaw. Similarly, pain in a runner’s hip can be caused by arthritis of the knee.

Amputees can suffer from phantom pain in an absent limb. When a pain fiber is cut, traveling to the spinal cord, within the spinal cord, or within the brain, the pain pathway can become chronically activated instead of permanently silenced. Attempts have been made to cure chronic pain syndromes by surgically severing the pathways that conduct painful stimuli at virtually every level. These surgical interventions have proved unreliable and should not be considered as an effective option for athletes in pain.

In some chronic pain syndromes, the perception of pain is initiated in the brain; nociception is absent. Even if pain receptors are not activated by tissue damage, the perception of pain can be every bit as real and devastating and much more difficult to treat. Anti-inflammatory and opiate medications are excellent treatments for nociception, but they are poor therapy for other pain syndromes.

Pain begins as an objective sensation, nociception, and evolves into a highly subjective perception. The complex array of signals at the site of injury, in the spinal cord, and in the brain creates the potential for a multitude of responses to the same stimulus.

INFLAMMATION

The treatment of pain arising from athletic injuries is founded on the inextricable links among pain, injury, and inflammation. Rubor, calor, tumor, dolor, and functio laesa (redness, heat, swelling, pain, and loss of function) are the hallmarks of inflammation. Celsus, a Roman writer, enumerated the first four characteristics in the first century A.D.; Virchow, considered the founder of modern pathology, added the latter in the 19th century. From an insect bite to a sore knee, injury is universally recognized by these canonical symptoms.

Inflammatory responses are essential for healing. Damaged tissue, infections, and toxins are removed; tissues are repaired; and scar tissue is formed. However, in many cases, an overexuberant inflammatory response itself becomes the cause of injury. From arthritis to atherosclerosis, asthma to athletic injuries, maladaptive inflammation is the source of pathology.

From the moment of injury, inflammation is activated through chemicals, including bradykinin, serotonin, and prostaglandin E2 released from damaged cells and histamine released from immune cells, called mast cells. These chemicals cause an increase in blood flow to the site of injury, leaks in the walls of blood vessels allowing proteins and white blood cells to enter the tissues, and migration of white blood cells out of the circulation to the site of injury. The result is the characteristic inflammatory symptoms of redness, swelling, and warmth.

The very same chemicals, bradykinin chief among them, sensitize and activate pain receptors. As these chemicals leak into surrounding tissue, the entire area becomes more sensitive to pain, a phenomenon termed hyperalgesia. Substance P, a chemical used by nerve cells for the transmission of pain signals, helps further the inflammatory process.

The initial inflammatory response may be beneficial, but chronic inflammation becomes the cause of many athletic injuries. Local ice application is a safe, inexpensive, and effective way to attenuate the inflammatory process, particularly directly after exercise or injury. By constricting blood vessels and inhibiting inflammation at multiple levels, pain and further inflammatory injury are blocked.

The primary medications for pain and inflammation, particularly for athletic injuries, are nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, naproxen, and many others. The fundamental interconnection between inflammation and pain is the basis for the analgesic effects of these drugs. NSAIDs block the enzyme cyclo-oxygenase that produces prostaglandin E2 and other inflammatory chemicals.

NSAIDs also inhibit enzymes in the stomach that lead to protection against damage from acid. Thus, long-term use of NSAIDs can lead to ulcers and irritation of the stomach. Despite this caveat, NSAIDs are the effective and safe predominant pharmaceutical for all runners. Taking NSAIDs with meals helps avoid damage to the stomach’s lining. Avoiding NSAIDs during periods of dehydration helps prevent damage to the kidneys. High doses or long-term use of these medications should be taken under the guidance of a physician.

Cortisol is a steroid hormone produced in the adrenal glands. Drugs with similar properties, such as cortisone, powerfully shut down inflammatory processes. Injections of cortisone into a joint can extinguish inflammation and pain so effectively that an athlete can continue to use and (further) injure a severely damaged joint without feeling pain.

Acetaminophen (such as Tylenol), in contrast to NSAIDs or steroids, has analgesic but not anti-inflammatory properties. Mild pain may be alleviated, but the source of the pain, the underlying inflammation, is not affected.

Recognition that a nagging pain reflects underlying inflammation allows a runner to respond with rest, ice, or medication. Pain is a necessary alert to the presence of tissue damage, but inflammation can rapidly progress from a healing process to the source of ongoing injury.

USE AND ABUSE OF OPIATES AND OTHER PAIN MEDICATIONS

Morphine is named for Morpheus, the Greek god of dreams. Indeed, morphine was used in ancient Greece, Rome, and Egypt. For thousands of years before the advent of modern medical treatments, morphine was an effective treatment for pain, anxiety, insomnia, diarrhea, and coughing. Today, morphine and other members of the opiate family remain invaluable drugs, alleviating pain and suffering caused by injuries, surgery, and many terminal diseases.

Morphine is the prototype of the class of drugs called opiate agonists, compounds that bind to opiate receptors to inhibit the perception of pain. Other

opiate agonists include codeine, fentanyl, oxycodone, methadone, and heroin. Opiate antagonists, such as naloxone, have the reverse effect: They block and reverse the effects of agonists such as morphine. Within minutes of receiving naloxone, an unconscious patient who overdosed on heroin or another opiate will be awake, alert, and often quite displeased with the sudden sensation of withdrawal. Still other drugs have properties that lie part of the way between agonists and antagonists.

Use of opiates is limited because of concerns of addiction to these drugs, but this potential problem is often misunderstood by both the general public and physicians. Tolerance, physical dependence, and psychological addiction are three distinct concepts that are often confused. Tolerance means that gradually escalating doses of medication are required to achieve the same effect. Physical dependence refers to the syndrome of withdrawal from opiates that occurs when the medication is discontinued after prolonged treatment.

Psychological addiction is the compulsive use of a drug, usually caused by the sensations of euphoria, indifference, and sedation induced by the opiates. Addiction encompasses behaviors such as increasing opiate doses without the authorization of a physician or continued use despite negative consequences. While tolerance and physical dependence are inevitable consequences of opiate use, addiction is not.

Athletes who undergo surgery or who suffer serious injuries, such as a broken bone, will often be prescribed opiate medications. For this type of acute, severe, and reversible pain, opiates are excellent medications. For chronic injuries or chronic pain, opiates should be avoided due to tolerance, physical dependence, and the physiology of chronic pain syndromes.

ENDORPHINS AND THE RUNNER’S HIGH

Athletes willingly endure hardships that are strange and incomprehensible to nonathletes. Persevering through extremes of exhaustion and weather, long-distance runners seem partially anesthetized to physical discomfort. Studies show that when resting, athletes and more sedentary individuals have the same sensitivity to pain. Exercise itself powerfully raises the threshold of pain, mitigating soreness and pain during the intensity of exertion.

One of the most fascinating discoveries in the field of pain research was the identification of endogenous opioids, otherwise known as endorphins. Endorphins are small proteins produced by the body with effects similar to those of the opioid drugs. Three classes of endorphins have been identified, all with a similar structure, and they all act by binding to opiate receptors on the surface of cells. This discovery elucidates the tremendous efficacy of morphine and other opiate drugs: the drugs work because they mimic endogenous opioids.

Exercise increases the production of endorphins in certain areas of the brain. Naloxone, a drug that blocks opiate receptors and is often used to reverse the effects of morphine and heroin, also blocks exercise-induced analgesia. An incomplete response to naloxone in some studies has raised the possibility of endorphin and non-endorphin mechanisms contributing to exercise-induced analgesia.

The psychological and physiological effects of endorphins have not been fully characterized, but they are likely to be integral to countless sensations familiar to athletes. On some memorable occasions, perhaps after a burst of endorphin release, a runner is said to hit a stride, to experience a “second wind” or a runner’s high. The sensation of pain is diminished. The body glides with fluid efficiency, feet seeming barely to touch the ground. The runner becomes a detached observer, monitoring painful stimuli as a racecar driver follows gauges indicating engine performance. Perhaps endorphins are also partially responsible for the feeling of profound relaxation after a strenuous run, a state of calm satisfaction and equanimity.

Observation of patients in an emergency room or runners at a race provides ample evidence of disparate responses to pain. Differences in the activity of endorphins may explain part of this variation. The genes encoding the human endorphins and their receptors vary subtly among individuals. These genetic differences, or polymorphisms, may partially explain variability in pain thresholds among individuals.

Stoicism may be founded in biology and genetics in addition to being a psychological and philosophical perspective. For perseverance, runners owe at least some credit to endorphins that effectively buffer much of their potential suffering.

THE ATHLETE’S RESPONSE TO PAIN: NO PAIN, NO GAIN

Running is the source of innumerable noxious stimuli and bodily complaints. Most are harmless twinges, reminders of physical exhaustion. A catalog of the multitude of sports injuries is far beyond the scope of this article. Accurate diagnosis often requires a detailed history, physical examination, and radiographic imaging. The experienced marathoner compiles an extensive mental database correlating particular sensations of sore joints and aching muscles with specific injuries or benign soreness. The pain of impending injury is recognized and heeded while the pangs of severe exertion are calmly ignored.

Recognition of the connection between pain and inflammation is essential for appropriate treatment. Rest, ice, and anti-inflammatory medications are the mainstay of therapy for overuse injuries. A more sophisticated analysis of risks and benefits is required before using more serious medications, from cortisol to opiates. Overtreatment of pain, muting the critical systems that warn of ongoing damage, can unwittingly cause athletes to suffer severe or permanent damage.

Endorphins are extraordinarily valuable for making running tolerable and enjoyable. Without the release of endorphins during exercise, marathons and ultramarathons would be exceedingly unpleasant and unpopular. Release of endorphins in a controlled fashion in particular areas of the brain is a fascinating process with countless manifestations.

An interesting and ironic phenomenon develops as some people become serious athletes. Some athletes grow to anticipate, strive for, and even relish the sensation of pain. “No pain, no gain” is the oft-repeated maxim of competitive athletes. Those who “yearn for the burn” seek the accumulation of lactic acid in the muscles. The pain signifies an effort worthy of self-congratulation. Perhaps for some the painful effort may become associated, through Pavlovian conditioning, with the reward of an endorphin rush. To feel pain indicates the achievement of a level of intensity that athletes crave.

Even for those who deny frank masochism, perseverance through aversive stimuli may be requisite for the rewards of running. As physiological compensation, high levels of exertion are met with a release of endorphins and their attendant effects on pain and mood. Exploration of the limits of physical exhaustion and pain gives athletes access to a broad spectrum of human experience.

For some, triumph over the pain of exertion in a marathon or ultra provides a simple allegory for the trials and complex difficulties in everyday life.

Pain is the most subjective of sensations. A broad range of other sensations, thoughts, and emotions alter the perception of pain. The complex web of interacting pathways that govern the sensation of pain provides endless sites of regulation. Dozens of chemicals are involved, from those that mediate inflammation at the site of tissue damage to the endogenous opiates that modulate the perception of pain in the brain.

The complexity of pain makes it frustratingly difficult to describe, comprehend, and diagnose. Yet perhaps running requires just such a system. Only such a system can alert an athlete to the slightest tissue injury, yet not be a hindrance at the peak of exertion. Amidst the stress and pain of a marathon or ultra, endorphins provide both relief and reward.