Chapter 106: Pain

CHAPTER 106

Pain

Pain is an unpleasant sensation signaling actual or possible injury.

Pain is the most common reason people visit their doctor. Pain may be sharp or dull, intermittent or constant, or throbbing or steady. Sometimes pain is very difficult to describe. Pain may be felt at a single site or over a large area. The intensity of pain can vary from mild to intolerable.

People differ remarkably in their ability to tolerate pain. One person cannot tolerate the pain of a small cut or bruise, but another person can tolerate pain caused by a major accident or knife wound with little complaint. The ability to withstand pain varies according to mood, personality, and circumstance. In a moment of excitement during an athletic match, an athlete may not notice a severe bruise but is likely to be very aware of the pain after the match, particularly if the team lost.

Acute Versus Chronic Pain: Pain may be acute or chronic. Acute pain begins suddenly and usually does not last long. Chronic pain lasts for weeks or months. Usually, pain is considered chronic if it does one of the following:

Lasts for more than 1 month longer than expected based on the illness or injury

Recurs off and on for months or years

Is associated with a chronic disorder (such as cancer, arthritis, diabetes, or fibromyalgia) or an injury that does not heal

When severe, acute pain may cause anxiety, a rapid heart rate, an increased breathing rate, elevated blood pressure, sweating, and dilated pupils. Usually, chronic pain does not have these effects, but it may result in other problems, such as depression, disturbed sleep, decreased energy, a poor appetite, weight loss, decreased sex drive, and loss of interest in activities.

SPOTLIGHT ON AGING

Pain is common among older people. However, as people age, they complain less of pain. The reason may be a decrease in the body’s sensitivity to pain or a more stoical attitude toward pain. Some older people mistakenly think that pain is an unavoidable part of aging and thus minimize it or do not report it.

The most common cause is a musculoskeletal disorder. However, many older people have chronic pain, which may have many causes.

Effects of pain may be more serious for older people:

Chronic pain can make them less able to function and more dependent on other people.

They may lose sleep and become exhausted.

They may lose their appetite, resulting in undernutrition.

Pain may prevent people from interacting with others and from going out. As a result, they can become isolated and depressed.

Pain can make people less active. Lack of activity can lead to loss of muscle strength and flexibility, making activity even more difficult and increasing the risk of falls.

Older people are more likely than younger people to have side effects from pain relievers (analgesics), and some side effects are more likely to be severe. These drugs may stay in the body longer, and older people may be more sensitive to them. Many older people take several drugs, increasing the chances that a drug will interact with the analgesic, reducing the effectiveness of one of the drugs or increasing the risk of side effects.

Older people are more likely to have disorders that increase the risk of side effects from analgesics. Having a heart or blood vessel (cardiovascular) disorder or risk factors for these disorders increases the risk of heart attack, stroke, blood clots in the legs, and heart failure when NSAIDs are taken. Having a kidney disorder, heart failure, or a liver disorder makes people more vulnerable to kidney damage from NSAIDs and less able to handle the fluid retention caused by the drugs.

To reduce the risk of side effects, particularly when prescribing opioids, doctors give older people a low dose at first. The dose is increased slowly as needed, and its effects are monitored. Doctors also choose analgesics less likely to have side effects in older people. For example, acetaminophen is usually preferred to NSAIDs for treating chronic mild to moderate pain without inflammation. Certain NSAIDs (indomethacin and ketorolac) and certain opioids (such as pentazocine) are usually not given to older people because of the risk of side effects.

Nondrug treatments and support from caregivers and family members can sometimes help older people manage pain and reduce the need for analgesics.

During treatment for chronic pain, many people experience a brief, often severe flare-up of pain. It is called breakthrough pain because it breaks through in spite of regularly scheduled pain treatment. Typically, breakthrough pain begins suddenly, lasts up to 1 hour, and feels much like the original chronic pain except it is more severe. Breakthrough pain may differ from person to person and is often unpredictable.

Chronic pain can make the nervous system more sensitive to pain. For example, chronic pain repeatedly stimulates the nerve fibers and cells that detect, send, and receive pain signals. Repeated stimulation can change the structure of nerve fibers and cells or make them more active and can thus increase pain transmission to the spinal cord and brain. As a result, pain may result from stimulation that might not ordinarily be painful, or painful stimuli may be felt as more severe.

When pain occurs repeatedly, people may anticipate it by becoming fearful and anxious. These emotions can stimulate the body to produce substances that make pain feel more intense. An example is prostaglandins, which make nerve cells more likely to respond to pain signals. Fear and anxiety can also reduce the production of substances that reduce the sensitivity of nerve cells to pain. An example is endorphins, the body’s natural pain relievers. Fatigue can have the same effects on pain as fear and anxiety.

These changes in pain sensitivity partly account for pain that persists after its cause resolves and for pain that feels more severe than expected.

Pain Pathways: Pain due to injury begins at special pain receptors scattered throughout the body. These pain receptors transmit signals as electrical impulses along nerves to the spinal cord and then upward to the brain. Sometimes the signal evokes a reflex response (see art on page 633). When the signal reaches the spinal cord, a signal is immediately sent back along motor nerves to the original site of the pain, triggering the muscles to contract without involving the brain. For example, when people inadvertently touch something very hot, they immediately pull away. This reflex reaction helps prevent permanent damage. The pain signal is also sent to the brain. Only when the brain processes the signal and interprets it as pain do people become conscious of the pain.

Pain receptors and their nerve pathways differ in different parts of the body. For this reason, pain sensation varies with the type and location of injury. For example, pain receptors in the skin are plentiful and capable of transmitting precise information, including where an injury is located and whether the source was sharp, such as a knife wound, or dull, such as pressure, heat, or cold. In contrast, pain receptors in internal organs, such as the intestine are limited and imprecise. The intestine can be pinched, cut, or burned without generating a pain signal. However, stretching and pressure can cause severe intestinal pain, even from something as relatively harmless as a trapped gas bubble. The brain cannot identify the precise source of intestinal pain, which is difficult to locate and is likely to be felt over a large area.

Sometimes pain felt in one area of the body does not accurately represent where the problem is, because the pain is referred there from another area. Pain can be referred because signals from several areas of the body often travel through the same nerve pathways in the spinal cord and brain. For example, pain from a heart attack may be felt in the neck, jaws, arms, or abdomen. Pain from a gallbladder attack may be felt in the back of the shoulder.

There are several types of pain, including neuropathic pain (such as sciatica—see art on page 808), nociceptive pain (such as pain after surgery and pain due to cancer), and psychogenic pain.

Neuropathic pain is caused by damage to or dysfunction of the nerves, spinal cord, or brain.

Neuropathic pain may be felt as burning or tingling or as hypersensitivity to touch or cold. Causes include compression of a nerve (for example, by a tumor, by a ruptured intervertebral disk, or as occurs in carpal tunnel syndrome), nerve damage (for example, as occurs in a metabolic disorder such as diabetes mellitus), and abnormal or disrupted processing of pain signals by the brain and spinal cord. Processing of pain is abnormal in phantom limb pain, postherpetic neuralgia, and complex regional pain syndrome.

Phantom Limb Pain: Pain seems to be felt in an amputated part of the body, usually a limb. It differs from phantom limb sensation—the feeling that the amputated part is still there—which is much more common. Phantom limb pain cannot be caused by a problem in the limb. Rather, it must be caused by a change in the nervous system above the site where the limb was amputated. But the brain misinterprets the nerve signals as coming from the amputated limb. Usually, the pain seems to be in the toes, ankle, and foot of an amputated leg or in the fingers and hand of an amputated arm. The pain may resemble squeezing, burning, or crushing sensations, but it often differs from any sensation previously experienced. For some people, phantom limb pain occurs less frequently as time passes, but for others, it persists. Massage can sometimes help, but drug therapy is sometimes necessary.

Postherpetic Neuralgia: This disorder results from herpes zoster (shingles, which causes inflammation of nerve tissue), but occurs only after shingles resolves (see box on page 1248). What causes postherpetic neuralgia is unknown. The pain is felt as a constant deep aching or burning, as a sharp and intermittent pain, or as hypersensitivity to touch or cold. The pain may be debilitating. Pain relievers and other drugs may be required, but no treatment is routinely effective.

Complex Regional Pain Syndrome: This chronic pain syndrome is defined as persistent burning pain accompanied by certain abnormalities that occur in the same area as the pain. Abnormalities include increased or decreased sweating, swelling, changes in skin color, damage to the skin, hair loss, cracked or thickened nails, muscle wasting and weakness, and bone loss. This syndrome typically occurs after an injury. There are two types:

Sometimes complex regional pain syndrome is made worse by activity of the sympathetic nervous system, which normally prepares the body for stressful or emergency situations—for fight or flight. For this reason, doctors may suggest treatment with a sympathetic nerve block (see page 647). Physical therapy and drugs may also help.

The injury may be a cut, bruise, bone fracture, crush injury, burn, or anything that damages tissues. This type of pain is typically aching, sharp, or throbbing. Most pain is nociceptive pain. Pain receptors for tissue injury (nociceptors) are located mostly in the skin or in internal organs.

The pain almost universally experienced after surgery is nociceptive pain. The pain may be constant or intermittent, often worsening when a person moves, coughs, laughs, or breathes deeply or when the dressings over the surgical wound are changed.

Most of the pain due to cancer is nociceptive. When a tumor invades bones and organs, it may cause mild discomfort or severe, unrelenting pain. Some cancer treatments, such as surgery and radiation therapy, can also cause nociceptive pain. Pain relievers (analgesics), including opioids, are usually effective.

When people have persistent pain with evidence of psychologic disturbances and without evidence of a disorder that could account for the pain or its severity, the pain may be described as psychogenic. However, psychophysiologic pain is a more accurate term because the pain results from interaction of physical and psychologic factors. Psychogenic pain is far less common than nociceptive or neuropathic pain.

Any kind of pain can be complicated by psychologic factors. Psychologic factors often contribute to chronic pain and may contribute to pain-related disability. In such cases, the pain, disability, or both usually have a physical cause, but psychologic factors exaggerate or enhance the pain, making it worse than what most people with a similar physical disorder experience. For example, people with chronic pain know it will recur and may become fearful and anxious as they anticipate the pain. These emotions make them more sensitive to pain. Sometimes doctors describe chronic pain that is worsened by psychologic factors as a chronic pain syndrome.

The fact that pain is caused or worsened by psychologic factors does not mean that it is not real. Most people who report pain are really experiencing it, even if a physical cause cannot be identified. Doctors always investigate whether a physical disorder is contributing to pain.

Pain complicated by psychologic factors requires treatment, often by a team that includes a psychologist or psychiatrist. Treatment for this type of pain varies from person to person, and doctors try to match the treatment with the person’s needs. For most people who have chronic psychogenic pain, the goals of treatment are to improve comfort and physical and psychologic function. Doctors may make specific recommendations for gradually increasing physical and social activities. Drugs and nondrug treatments—such as biofeedback, relaxation training, distraction techniques, hypnosis, transcutaneous electrical nerve stimulation (TENS), and physical therapy—may be used. Psychologic counseling is often needed.

Neither examinations nor tests can prove that a person is in pain. Consequently, doctors ask the person about the history and characteristics of pain. The person’s answers help them identify the cause and develop a treatment strategy. Questions can include the following:

To evaluate the severity of pain, doctors sometimes use a scale of 0 (none) to 10 (severe) or ask the person to describe the pain as mild, moderate, severe, or excruciating. For children or for people who have difficulty communicating (for example, because of a stroke), drawings of faces in a series—from smiling to frowning and crying—can be used to determine the severity of pain.

Doctors always try to determine whether a physical disorder is causing the pain. Many chronic disorders (such as cancer, arthritis, sickle cell anemia, and inflammatory bowel disease) cause pain, as do acute disorders (such as wounds, burns, torn muscles, broken bones, sprained ligaments, appendicitis, kidney stones, and a heart attack). Doctors use specific techniques to check for sources of pain. Doctors move the person’s arms and legs through their normal range of motion to see if these motions cause pain. Injury, repetitive stress, chronic pain, and other disorders can make certain areas of the body (called trigger points) become hypersensitive. Doctors touch various spots to see whether they are trigger points for pain. Different objects (such as a blunt key and a sharp pin) may be touched to the skin to check for loss of sensation or abnormal perceptions.

Doctors also consider psychologic causes. Psychologic factors (such as depression and anxiety) can worsen pain. Sometimes pain is determined to be caused mostly or completely by psychologic factors. Such pain is called psychogenic pain. Because depression and anxiety may result from chronic pain, distinguishing cause and effect may be difficult.

Doctors ask about which drugs (including over-the-counter drugs) and other treatments the person has used to treat the pain and whether they are effective.

Few people exaggerate the pain they feel. Nonetheless, doctors usually also ask questions to make sure there are no ulterior motives for reporting pain, such as time off from work with pay or extra attention from family members. Such questions are routine.

In some cases, treating the underlying disorder eliminates or minimizes the pain. For example, setting a broken bone in a cast or giving antibiotics for an infected joint helps reduce pain. However, even if the underlying disorder can be treated, pain relievers (analgesics) may still be needed to quickly manage the pain. Doctors choose an analgesic based on the type and duration of pain and on the likely benefits and risks. Most analgesics are effective for nociceptive pain (due to ordinary injury of tissues) but are less effective for neuropathic pain (due to damage or dysfunction of the nerves, spinal cord, or brain), which often requires different drugs. For some types of pain, especially chronic pain, nondrug treatments are also important.

Analgesics fall into three categories: opioid (narcotic) analgesics, nonopioid analgesics, and adjuvant analgesics (drugs that are usually given for reasons other than pain but that sometimes relieve pain).

Opioid analgesics (sometimes called narcotics) are the most powerful analgesics. They are the mainstay for treatment of severe acute pain (as occurs after surgery or from burns or broken bones) and chronic pain due to cancer and other serious disorders. Opioids are preferred because they are so effective in controlling pain. Using opioids to treat chronic pain not due to cancer is becoming more acceptable but is still relatively uncommon. Opioids are not appropriate for everyone.

Opioids are chemically related to morphine, a natural substance extracted from poppies, although some opioids are extracted from other plants and other opioids are produced in a laboratory.

The dose of an opioid is increased gradually, in stages, until the pain is relieved or the opioid’s side effects cannot be tolerated. Older people and new-borns, who are more sensitive to the effects of opioids, are usually given lower doses. Nonopioid analgesics, such as acetaminophen, are often used with opioids, sometimes in tablets that contain both drugs.

Opioids are most effective when taken every few hours, before pain becomes severe. If more pain relief is required, the dose may be increased or another drug (such as a nonsteroidal anti-inflammatory drug) may be added, as in the following situations:

As the pain lessens, doctors reduce the dose of the opioid accordingly, and when possible, they stop the opioid and switch to a nonopioid analgesic.

Side Effects: Opioids have many side effects. Side effects are more likely to occur in people with certain disorders: kidney failure, a liver disorder, chronic obstructive pulmonary disease (COPD), dementia, or another brain disorder.

Drowsiness, constipation, nausea, vomiting, and itching are common when opioids are started.

Some people welcome the drowsiness provided by opioids, but others do not. For most people who take opioids, drowsiness disappears or decreases within a few days. If people continue to feel drowsy, they may be given stimulant drugs, such as methylphenidate, to keep them awake and alert. These drugs may be taken regularly or only before events that require alertness, such as a family gathering. For some people, drinking beverages that contain caffeine provides enough stimulation. When feeling drowsy after taking an opioid, people should avoid driving and take extra care to prevent falls and accidents. Opioids may also cause confusion, especially in older people.

Opioids often cause constipation, especially in older people. Stimulant laxatives (see page 121), such as senna, help prevent or relieve the constipation. Increasing the intake of fluids and the amount of fiber in the diet can also help. Some people need enemas.

Opioids can cause retention of urine, especially in men with benign prostatic hyperplasia. Trying to urinate a second time after a brief pause (double voiding) or applying gentle pressure on the lowest part of the abdomen (the area over the bladder) during urination may help. Sometimes a drug that relaxes muscles of the bladder (such as tamsulosin) is used.

Sometimes people with pain feel nauseated, and opioids can increase the nausea. Antiemetic drugs taken by mouth, suppository, or injection help prevent or relieve nausea. Some commonly used antiemetic drugs are metoclopramide, hydroxyzine, and prochlorperazine.

For most people, nausea and itching disappear or decrease within a few days. But constipation and retention of urine usually decrease much more slowly.

Taking too much of an opioid can have serious side effects, including a dangerous slowing of breathing and even coma. These effects can be reversed with naloxone, an antidote given intravenously. Nurses and family members should watch for side effects of opioids.

For most people, the same opioid dose remains effective for a long time. However, some people who take opioids repeatedly over time need higher doses because the body adapts to and thus responds less well to the drug. This phenomenon is called tolerance. Usually, the need for a higher dose means that the disorder is worsening, not that tolerance is developing.

OPIOID ANALGESICS

DRUG	LENGTH OF EFFECTIVENESS	COMMENTS
Morphine	By intravenous or intramuscular injection: 2 to 3 hours Immediate-release by mouth: 3 to 4 hours Controlled- and sustained-release by mouth: 8 to 24 hours	Morphine starts to work quickly. The oral form can be very effective for chronic pain. It is more likely to cause itching than other opioids.
Codeine	By mouth: 3 to 4 hours	Codeine is less potent than morphine. It is usually taken with aspirin or acetaminophen.
Fentanyl	By mouth: 3 to 4 hours By patch: up to 72 hours	Fentanyl lozenges and dissolvable tablets can be used to treat breakthrough pain. Fentanyl lozenges can also be used to relieve pain and provide sedation (before painful procedures) in children. A fentanyl patch is often used to treat chronic pain.
Hydrocodone	By mouth: 3 to 5 hours	Hydrocodone is similar to codeine in effectiveness.
Hydromorphone	By intravenous or intramuscular injection: 2 to 4 hours By mouth: 2 to 4 hours By rectal suppository: 4 hours	Hydromorphone begins to work quickly. It can be used instead of morphine and is useful for chronic pain.
Levorphanol	By intravenous or intramuscular injection: 4 hours By mouth: about 4 hours	The oral form is strong. It can be used instead of morphine.
Meperidine	By intravenous or intramuscular injection: about 3 hours By mouth: not very effective	Although meperidine can be effective for short-term use, it is not preferred for long-term use because it has side effects, such as muscle spasms, tremors, seizures, and confusion or psychosis (especially in older people).
Methadone	By mouth: 4 to 6 hours, sometimes much longer	Methadone is used for treating addiction to heroin and other opioids. It can also be used to treat chronic pain.
Oxycodone	By mouth: 3 to 4 hours	Oxycodone can be used instead of morphine to treat chronic pain. A long-acting, controlled-release formulation is available, lasting about 8 to 12 hours. The short-acting formulation is usually combined with aspirin or acetaminophen.
Oxymorphone	By intravenous or intramuscular injection: 3 to 4 hours By rectal suppository: 4 hours	Oxymorphone can be used instead of morphine to treat chronic pain. Like oxycodone, it is available in a long-acting, controlled-release formulation, lasting about 12 hours.
Pentazocine	By mouth: up to 4 hours	Pentazocine can block the pain-relieving action of other opioids. It is about as strong as codeine. The usefulness of pentazocine is limited because higher doses do not provide more pain relief and because the drug can cause confusion and anxiety, especially in older people. It is not a good choice for older people.
Propoxyphene	By mouth: 3 to 4 hours	At safe doses, propoxyphene provides little or no more pain relief than aspirin. At high doses, it is likely to have side effects. Thus, it is not often used.

People who take opioids for a long time usually become physically dependent on them. That is, they experience withdrawal symptoms if the drug is stopped. When opioids are stopped after long-term use, doctors reduce the dose gradually over a period of time to minimize the development of such symptoms. Physical dependence is not the same as addiction, which is characterized by a craving for the drug and compulsive, uncontrolled use of the drug despite the harm done to the user or other people. Although addiction is possible, it appears to be rare among people who take opioids to control pain and have not previously had problems with drug abuse. Too often, exaggerated concern about the addiction potential of opioids (see page 2096) leads to under-treatment of pain and needless suffering. People with severe pain should not avoid opioids, and adequate doses should be taken as needed. Doctors carefully weigh the benefits and side effects when they consider opioids for the treatment of chronic pain.

Administration: When possible, opioids are taken by mouth. When they need to be taken for a long time, they may be given through a patch placed on the skin. Opioids are given by injection when pain occurs suddenly or when people cannot take them by mouth or through a skin patch. If people are helped by an opioid but cannot tolerate its side effects, an opioid can be injected directly into the space around the spinal cord through a pump. This method gets high concentrations of the drug to the brain. For long-term pain relief, a device that slowly releases an opioid can be implanted in the space around the spinal cord.

Morphine, the prototype of these drugs, can be taken by mouth (orally) or by injection. There are three oral forms: immediate-release, controlled-release, and sustained-release. Different controlled-and sustained-release forms provide relief for 8 to 24 hours. These drugs are widely used to treat chronic pain. The immediate-release form provides short-lived relief, usually for less than 3 hours. In injected forms, 2 to 6 times less morphine is required than in oral forms because when morphine is taken by mouth, much of the drug is chemically altered (metabolized) by the liver before it reaches the bloodstream. Usually, the route used does not change the drug’s effects, even though different routes use different amounts of morphine. Pain relief with injected forms is quicker than that with oral forms, but relief does not last as long.

Morphine may be injected into a vein (intravenously), into a muscle (intramuscularly), or under the skin (subcutaneously).

Injections can be given every few hours, but repeated injections can become annoying. Alternatively, a catheter can be inserted in a vein or under the skin and connected to a continuous-infusion pump, which supplies morphine continuously. The continuous infusion can be supplemented with extra doses when needed. Sometimes a device that enables a person to release the drug by pressing a button is used. This technique is called patient-controlled analgesia. Usually, continuous infusion is used for people who have severe pain due to a serious disorder.

A variety of nonopioid analgesics are available. They are often effective for mild to moderate pain. People do not become physically dependent on these drugs or tolerant of their pain-relieving effects. Aspirin and acetaminophen are available without a prescription (over-the-counter, or OTC). Several other nonopioid analgesics (such as ibuprofen, ketoprofen, and naproxen) are available OTC and by prescription, usually in higher-dose formulations, with more active ingredient per dose than OTC formulations. OTC analgesics are reasonably safe to take for short periods of time, but their labels caution against taking them for more than 7 to 10 days to treat pain. A doctor should be consulted if symptoms worsen or do not go away.

Most nonopioid analgesics are classified as non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are used to treat mild to moderate pain and may be combined with opioids to treat moderate to severe pain. NSAIDs not only relieve pain, but they also reduce the inflammation that often accompanies and worsens pain. All NSAIDs are taken by mouth. One NSAID, ketorolac, can also be given by injection into a vein (intravenously) or muscle (intramuscularly). Indomethacin can be given by suppository.

Problems in the digestive tract: All NSAIDs tend to irritate the stomach’s lining and cause digestive upset (such as heartburn, indigestion, nausea, bloating, diarrhea, and stomach pain), peptic ulcers, and bleeding in the digestive tract (gastrointestinal bleeding). Coxibs (COX-2 inhibitors) are less likely to irritate the stomach and cause bleeding than other NSAIDs. However, if people take a coxib and aspirin, these problems are just as likely. Taking NSAIDs with food and using antacids may help prevent stomach irritation. The drug misoprostol can help prevent stomach irritation and ulcers, but it can cause other problems, including diarrhea. Proton pump inhibitors (such as omeprazole) or histamine-2 (H2) blockers (such as famotidine), which are used to treat peptic ulcers, can also help prevent stomach problems due to NSAIDs.

Bleeding problems: All NSAIDs except coxibs interfere with the clotting tendency of platelets (cell-like particles in the blood that help stop bleeding when blood vessels are injured). Consequently, NSAIDs increase the risk of bleeding, especially in the digestive tract if they also irritate the stomach’s lining.

Problems related to retaining fluids: NSAIDs cause fluid retention and swelling in 1 to 2% of people. Regular use of NSAIDs may also increase the risk of developing a kidney disorder, sometimes resulting in kidney failure (a disorder called analgesic nephropathy).

Increased risk of heart and blood vessel disorders: Recent studies suggest that with all NSAIDs except aspirin, the risk of heart attack, stroke, and blood clots in the legs may be increased. The risk appears to be higher with higher doses and longer use of the drug. The risk is also higher with some NSAIDs than with others. These problems may be related directly to the drug’s effect on clotting or indirectly to a small but persistent increase in blood pressure caused by the drug.

How Nonsteroidal Anti-Inflammatory Drugs Work

Nonsteroidal anti-inflammatory drugs (NSAIDs) work in two ways:

They reduce the sensation of pain.

At higher doses, they reduce the inflammation that often accompanies and worsens pain.

NSAIDs have these effects because they reduce the production of hormone-like substances called prostaglandins. Different prostaglandins have different functions, such as sensitizing pain receptors to mechanical and chemical stimulation and causing blood vessels to dilate.

Most NSAIDs reduce prostaglandin production by blocking both cyclooxygenase (COX) enzymes (COX-1 and COX-2), which are crucial to the formation of prostaglandins. One type of NSAID, the coxibs (COX-2 inhibitors), tend to block mainly COX-2 enzymes.

Only COX-2 enzymes are involved in the production of prostaglandins that promote inflammation and the resulting pain. These prostaglandins are released in response to an injury—burn, break, sprain, strain, or invasion by a microorganism. The result is inflammation, which is a protective response: The blood supply to the injured area increases, bringing in fluids and white blood cells to wall off the damaged tissue and remove any invading microorganisms.

Prostaglandins that are formed through the action of COX-1 enzymes help protect the digestive tract from stomach acid and play a crucial role in blood clotting. Most NSAIDs block COX-1 enzymes and thus reduce the production of these prostaglandins. Consequently, these NSAIDs may irritate the stomach’s lining and cause digestive upset, peptic ulcers, and bleeding in the digestive tract. Because coxibs block mainly COX-2 enzymes, they are less likely to cause these problems. However, coxibs block some COX-1 enzymes, so even coxibs may slightly increase the risk of these problems.

Taking NSAIDs for a short time is unlikely to cause serious problems. If NSAIDs are taken for a long time, certain tests are done regularly. They include blood pressure measurement, blood tests (such as a complete blood count and tests to check kidney and liver function), and tests for blood in stools.

For older people, the risk of side effects due to NSAIDs, particularly indomethacin and ketorolac, is increased. For people who drink alcoholic beverages regularly and take NSAIDs, the risk of digestive upset, ulcers, and liver damage may be increased. The risk of heart attacks and stroke may be higher for people with coronary artery disease, other heart and blood vessel (cardiovascular) disorders, or risk factors for these disorders. Older people and people who have heart failure, high blood pressure, or a kidney or liver disorder require a doctor’s supervision when they take NSAIDs. Some prescription heart and blood pressure drugs may not work as well when taken with these analgesics.

NSAIDs vary in how quickly they work and how long they relieve pain. Although NSAIDs are about equally effective, people respond to them differently. One person may find a particular drug to be more effective or to have fewer side effects than another.

Aspirin: Aspirin (acetylsalicylic acid) has been used for about 100 years. Aspirin is taken by mouth and provides 4 to 6 hours of moderate pain relief.

Because aspirin can irritate the stomach, it may be combined with an antacid (in a buffered product) to reduce this effect. The antacid creates an alkaline environment that helps aspirin dissolve and may reduce the time aspirin is in contact with the stomach lining. However, buffered aspirin can still irritate the stomach because aspirin also reduces the production of substances that help protect the stomach’s lining. These substances are a type of prostaglandin, which are similar to hormones.

Enteric-coated aspirin is designed to pass through the stomach intact and dissolve in the small intestine, thus minimizing direct irritation of the stomach. (Enteric refers to the small intestine.) However, enteric-coated aspirin may be absorbed erratically. If food and enteric-coated aspirin are ingested at about the same time, the aspirin is not absorbed as quickly because food delays the emptying of the stomach. Consequently, pain relief is delayed.

Aspirin increases the risk of bleeding throughout the body because it makes the particles that help blood clot (platelets) less likely to do so. People who bruise easily may be especially vulnerable to this effect. Anyone who has ever had a bleeding disorder or uncontrolled high blood pressure should not take aspirin except under a doctor’s supervision. People who take aspirin and anticoagulants (such as warfarin) are closely monitored to avoid life-threatening bleeding. Usually, aspirin should not be taken in the week before scheduled surgery.

Aspirin can aggravate asthma. People with nasal polyps are likely to develop wheezing if they take aspirin. A few people, who are sensitive (allergic) to aspirin, may have a severe allergic reaction (anaphylaxis), leading to a rash, itching, severe breathing problems, or shock (see page 350). Such a reaction requires immediate medical attention.

In very high doses, aspirin can have serious side effects such as abnormal breathing, fever, or confusion. One of the first signs of an overdose may be noise in the ears (tinnitus).

Most children and teenagers should not take aspirin because they could develop Reye’s syndrome if they have or have just gotten over influenza or chickenpox. Although rare, Reye’s syndrome can have serious consequences, including death.

TYPE	DRUG
Salicylates	Aspirin Choline magnesium trisalicylate Diflunisal Salsalate
Coxibs	Celecoxib
Others	Diclofenac Etodolac Fenoprofen Flurbiprofen Ibuprofen Indomethacin Ketoprofen Ketorolac Meclofenamate Mefenamic acid Meloxicam Nabumetone Naproxen Oxaprozin Piroxicam Sulindac Tolmetin

Ibuprofen, Ketoprofen, and Naproxen: NSAIDs such as ibuprofen, ketoprofen, and naproxen are generally believed to be gentler on the stomach than aspirin, although few studies have compared the drugs. Like aspirin, these drugs can cause digestive upset, ulcers, and gastrointestinal bleeding. They can make asthma worse and increase blood pressure. Taking one of these drugs probably slightly increases the risk of stroke, heart attack, and blood clots in the arteries of the legs.

Although ibuprofen, ketoprofen, and naproxen generally interfere with blood clotting less than aspirin does, people should not take these drugs with anticoagulants (such as warfarin) except under a doctor’s close supervision.

People who are allergic to aspirin may also be allergic to ibuprofen, ketoprofen, and naproxen. If a rash, itching, breathing problems, or shock develops, medical attention is required immediately.

Coxibs (COX-2 Inhibitors): Coxibs, such as celecoxib, differ from other NSAIDs. Other NSAIDs block two enzymes:

Coxibs tend to block mainly COX-2 enzymes. Thus, coxibs are as effective as other NSAIDs in the treatment of pain and inflammation. But coxibs are less likely to damage the stomach and to cause nausea, bloating, heartburn, bleeding, and peptic ulcers. They are also less likely to interfere with clotting than are other NSAIDs.

Because of these differences, coxibs may be useful for people who cannot tolerate other NSAIDs and for people who are at high risk of certain complications (such as gastrointestinal bleeding) from use of other NSAIDs. Such people include older people, people who are taking anticoagulants, those who have a history of ulcers, and those who must take an analgesic for a long time. However, blockage of COX-2 enzymes appears to make blood clots more likely to form. Thus, taking coxibs, like taking other NSAIDs, is likely to increase the risk of heart attack, stroke, and blood clots in the legs. How much the risk is increased depends on the drug used. The risk is higher when higher doses are taken and when the drug is taken for a longer time. Thus, before people who have a cardiovascular disorder (such as coronary artery disease), who have had a stroke, or who have risk factors for these disorders are given a coxib, they are told about the risk and the need to be closely monitored. Coxibs are not appropriate for people who have heart failure or who are at increased risk of heart failure (such as those who have had a heart attack).

Acetaminophen is roughly comparable to aspirin in its potential to relieve pain and lower a fever. But unlike NSAIDs, acetaminophen has virtually no useful anti-inflammatory activity, does not affect the blood’s ability to clot, and has almost no adverse effects on the stomach. How acetaminophen works is not clearly understood.

Acetaminophen is taken by mouth or suppository, and its effects generally last 4 to 6 hours. Acetaminophen appears to be a very safe drug. However, high doses can lead to liver damage, which may be irreversible. People with a liver disorder should use lower doses than those usually prescribed. Whether lower doses taken for a long time can harm the liver is less certain. People who regularly consume large amounts of alcohol are probably at highest risk of liver damage from overuse of acetaminophen. People who are taking acetaminophen and stop eating because of a bad cold, influenza, or another reason may be more vulnerable to liver damage. Taking high doses for a long time may lead to kidney damage.

Adjuvant analgesics are drugs that are not usually used for pain relief but may relieve pain in certain circumstances. When used to relieve pain, they are usually used with other analgesics or nondrug pain treatments.

The adjuvant analgesics most commonly used for pain are antidepressants (such as amitriptyline, bupropion, desipramine, fluoxetine, and venlafaxine—see table on page 868), anticonvulsants (such as gabapentin and pregabalin—see table on page 716), and oral and topical local anesthetics.

Antidepressants: These drugs can potentially relieve pain in people who do not have depression. Tricyclic antidepressants may be more effective for this purpose than other antidepressants, but newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and nor-epinephrine reuptake inhibitors (SSNRIs, such as duloxetine) are tolerated better. People may respond to one antidepressant and not to others.

Anticonvulsants: These drugs may be used to relieve neuropathic pain. Gabapentin is used most often, but many others, including carbamazepine, clonazepam, divalproex, lamotrigine, oxcarbazepine, phenytoin, pregabalin, and topiramate, may be tried. Pregabalin can be used to relieve pain caused by nerve damage due to diabetes (diabetic neuropathy) or a complication of shingles (postherpetic neuralgia). Anticonvulsants, such as divalproex, can prevent migraine headaches.

Anesthetics: Mexiletine, used to treat abnormal heart rhythms, is sometimes used to treat neuropathic pain. It is similar to local anesthetics that are placed directly on or near a sore area to help reduce pain. Doctors may inject a local anesthetic, such as lidocaine, into the skin to control pain due to an injury or even due to neuropathic pain. Local anesthetics can also be injected in nerves to block pain—a procedure called a nerve block. For example, a sympathetic nerve block involves injecting a local anesthetic into a group of nerves near the spine—in the neck for pain in the upper body or in the lower back for pain in the lower body.

Topical anesthetics, such as lidocaine applied as a lotion, ointment, or skin patch, can be used to control pain due to some conditions. These anesthetics are usually used for a short period of time. For example, gargling small amounts of an anesthetic mouthwash, limited to a few times a day, can relieve a sore throat. However, some people with chronic pain benefit from using topical anesthetics for a long time. For example, a lidocaine patch can relieve postherpetic neuralgia.

A cream containing capsaicin, a substance found in hot peppers, sometimes helps reduce the pain caused by such disorders as herpes zoster and osteoarthritis. It is most often used by people with localized pain due to arthritis. This cream must be applied several times a day.

In addition to drugs, many other treatments can help relieve pain. Applying cold or warm compresses directly to a painful area often helps (see page 46). Ultrasonography that provides deep heat (diathermy) may relieve the pain of osteoarthritis and muscle strain.

Some people benefit from transcutaneous electrical nerve stimulation (TENS). A gentle electric current is applied through electrodes placed on the skin’s surface. TENS produces a tingling sensation without increasing muscle tension. It can be applied continuously or several times a day for 20 minutes to several hours. The timing and length of stimulation vary because each person responds differently. Often, people are taught to use the TENS device, so that they can use it as needed. TENS may be useful for chronic pain. If pain is particularly severe and other treatments are ineffective, electrodes may be implanted along the affected nerves or in the space around the spinal cord.

Occasionally, pain due to nerve damage can be treated by disrupting a nerve pathway that transmits pain signals. The pathway is disrupted by injecting a caustic substance (such as phenol) into a nerve to destroy it, by freezing the nerve (in cryotherapy), or by burning the nerve with a radiofrequency probe. These procedures may be used to treat facial pain due to trigeminal neuralgia.

Acupuncture involves inserting tiny needles into specific areas of the body (see page 2061). How acupuncture works is poorly understood, and some experts still doubt the technique’s effectiveness. Some people find substantial relief with acupuncture, at least for a time.

Biofeedback and other cognitive techniques (such as relaxation training, hypnosis, and distraction techniques) can help people control, reduce, or cope with pain by changing the way they focus their attention. In one distraction technique, people may learn to visualize themselves in a calm, comforting place (such as in a hammock or on a beach) when they feel pain.

The importance of psychologic support for people in pain should not be underestimated. Friends and family members should be aware that people in pain suffer, need support, and may develop depression and anxiety, which may require psychologic counseling.