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.
The benchmark drug in this class is morphine — with other opioids falling above or below it in terms of pain-relieving potential. Near the bottom of the list is codeine, usually prescribed in combination with acetaminophen to relieve, for example, pain resulting from dental work. Codeine is only about 1/10th as powerful as morphine.
Opioids more powerful than morphine include hydromorphone (Dilaudid) and oxymorphone (Opana). But the strongest opioid in community use is fentanyl which, in its intravenous form, is 70 to 100 times more potent than morphine.
Fentanyl is also available as a long-release patch (Duragesic) and as a lozenge that dissolves in the mouth (Actiq). Sufentanil is even more powerful than fentanyl, but its use, at present is restricted to the intravenous route. However, a transdermal patch containing sufentanil is in clinical trials.
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
A variety of nonopioid analgesics are available. They are often effective for mild to moderate pain. These drugs are often the preferred drugs for treating 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.
Nonsteroidal Anti-Inflammatory Drugs
Most nonopioid analgesics are classified as nonsteroidal 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 may also reduce the inflammation that often accompanies and worsens pain. However, to reduce inflammation, NSAIDs usually need to be taken at high doses and for a relatively long time.
All NSAIDs can be taken by mouth. Two NSAIDs, ketorolac and diclofenac, can also be given by injection into a vein (intravenously) or muscle (intramuscularly). Indomethacin can be given by a suppository inserted in the rectum. Diclofenac is also available as a cream.
Although widely used, NSAIDs can have side effects, sometimes serious ones.
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 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. Coxibs are less likely to cause bleeding than other NSAIDs.
Increased risk of heart and blood vessel disorders: 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.
Taking NSAIDs for a short time is unlikely to cause serious problems. If people take NSAIDs for a long time, problems are more likely to occur. Such people need to have regular appointments with their doctor to check for high blood pressure, kidney failure, and ulcers or bleeding in the digestive tract and to evaluate their risk of heart disease and stroke.
The risk of side effects may be increased for some groups of people, such as the following:
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.
For people with coronary artery disease, other heart and blood vessel (cardiovascular) disorders, or risk factors for these disorders, the risk of heart attacks and stroke may be higher.
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.
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 is 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 platelets—cell fragments in the blood that help blood clot—less able 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. (Anticoagulants also interfere with blood clotting.) 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. 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 syndrome if they have or have just gotten over influenza or chickenpox. Although rare, Reye syndrome can have serious consequences, including death.
Some NSAIDs are available as creams or gels that are applied directly to the skin over the painful area. For example, diclofenac can be applied to a joint to relieve pain due to osteoarthritis and help improve movement. Diclofenac is also available as a patch, which can be used to relieve acute pain due to minor sprains, strains, and bruises.
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. The risk may be lower with naproxen than with other NSAIDs. Thus, naproxen may be a better choice when people with a high risk of these disorders require NSAIDs.
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.
Coxibs (COX-2 inhibitors)
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 the following:
People who are taking anticoagulants
Those who have a history of ulcers
Those who must take an analgesic for a long time
However, coxibs, like other NSAIDs, appear to increase the risk of heart attack, stroke, and blood clots in the legs. As a result, before people with certain conditions are given a coxib, they are told about the risk and the need to be closely monitored. These conditions include
Cardiovascular disorders (such as coronary artery disease)
Risk factors for these disorders
Has virtually no useful anti-inflammatory activity
Does not affect the blood’s ability to clot
Has almost no adverse effects on the stomach
How acetaminophen works is not clearly understood.
Acetaminophen is taken by mouth or a suppository inserted into the rectum, 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.
Opioids are chemically related to morphine, a natural substance extracted from poppies. Some opioids are extracted from other plants, and other opioids are produced in a laboratory.
Opioids are the mainstay for treatment of the following:
Opioids are preferred for these disorders because opioids are so effective in controlling pain.
Opioids may be underused in these situations because doctors
Underestimate the dose needed to be effective
However, in people with pain due to cancer or another terminal disorder or in hospice, concerns about side effects should not limit the use of opioids because side effects can usually be prevented or managed, and addiction is less of a concern.
If chronic pain is not due to cancer or a terminal disorder, opioids are usually not the first choice for treatment because the side effects of long-term opioid therapy can be serious. Opioid side effects include opioid use disorder (addiction), overdose, a dangerous slowing of breathing (respiratory depression), and death. Thus, when chronic pain is not due to cancer or a terminal disorder, other treatments, such as nonopioid drugs and nondrug treatments, are used first. If these treatments are ineffective, doctors may consider using opioids but only when the need for pain relief and improved functioning outweighs the risks of opioids.
Opioids are not appropriate for everyone.
Doctors ask people questions before prescribing opioids for them. The questions are designed to determine whether people are likely to
Misuse or abuse the drug
Use them for other purposes (such as selling them or using them to fall asleep)
Have side effects from the drug
Doctors also explain what the risks and side effects of opioids are and how to take and store opioids correctly.
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 newborns, who are more sensitive to the effects of opioids, are usually given lower doses.
Opioids are most effective when taken according to a schedule, before pain becomes severe.
For chronic pain, opioids are often used with nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), or adjuvant analgesics, such as gabapentin (an antiseizure drug) or tricyclic antidepressants. Nonopioid analgesics, such as acetaminophen, are sometimes combined with opioids in a single tablet.
Doctors usually monitor the response to opioids to determine whether opioids are effectively controlling the pain and/or people are having side effects. Based on this information, doctors determine whether continuing opioid therapy is appropriate. As the pain lessens, doctors reduce the dose of the opioid gradually, and when possible, they stop the opioid and switch to or continue to take a nonopioid analgesic.
Opioids provide long-term relief for only some people who are treated with them, and usually, they only partially relieve the pain. Some people decide to stop taking opioids because the pain relief is insufficient or because they cannot tolerate the side effects.
Side effects of opioids
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), untreated sleep apnea, dementia, or another brain disorder.
The following commonly occur when opioids are used:
Mental fuzziness or confusion
Nausea and vomiting
Less common side effects of opioids include
Retention of urine
Involuntary contraction of muscles (called myoclonus)
A dangerous slowing of breathing
Drowsiness is a common side effect of opioids. For some people who take opioids, drowsiness disappears or decreases within a few days. If people continue to feel drowsy, a different opioid can be tried because the degree of drowsiness caused by different opioids varies. Before an important event that requires alertness, people may be given a stimulant drug (such as methylphenidate or modafinil) to offset the drowsiness. For some people, drinking a caffeinated beverage helps offset the drowsiness. When feeling drowsy after taking an opioid, people should avoid driving and take extra care to prevent falls and accidents.
Confusion can also result from taking opioids, especially if people are older. Opioids increase the risk of falls in older people.
Nausea sometimes occurs in people with pain, 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.
The itching caused by taking opioids may be relieved by an antihistamine such as diphenhydramine, taken by mouth or given intravenously.
Constipation often develops, especially in older people. Stimulant laxatives, 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. Osmotic agents such as polyethylene glycol can also be useful. These agents pull large amounts of water into the large intestine to stimulate bowel movements. Some people need enemas. When these measures are not effective, doctors may prescribe a drug (such as methylnaltrexone) that blocks only the effects of opioids in the stomach and intestine and does not lessen the pain relief.
Retention of urine can result from taking opioids, especially in men with an enlarged prostate. 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.
For most people, nausea and itching disappear or decrease within a few days. But constipation and retention of urine usually decrease much more slowly, if at all.
Serious side effects can occur when people take too much of an opioid. These side effects include a dangerous slowing of breathing (respiratory depression), coma, and even death. The following adds to the risk of developing respiratory depression and of dying from respiratory arrest:
Having certain conditions (such as liver, kidney, or respiratory disorders)
Taking other drugs that cause drowsiness (such as benzodiazepines)
Some of these side effects can be reversed with naloxone, an antidote usually given intravenously or sprayed into the nose.
For people who are at increased risk of opioid side effects (including respiratory depression), doctors may prescribe naloxone when they prescribe the opioid. Nurses and family members or caregivers should watch for serious side effects of opioids and, if such side effects occur, be ready to inject naloxone or spray it into the person’s nose. Doctors or pharmacists usually teach the person taking the opioid and family members or caregivers how to administer naloxone.
Tolerance occurs in some people who take opioids repeatedly over time. They need higher doses because their body adapts to and thus responds less well to the drug. However, for most people, the same opioid dose remains effective for a long time. Often, the need for a higher dose means that the disorder is worsening, not that tolerance is developing.
Physical dependence usually develops in people who take opioids for a long time. That is, they experience withdrawal symptoms if the drug is stopped. Withdrawal symptoms include chills, abdominal cramping, diarrhea, trouble sleeping, and a jittery feeling. 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. Most people who take opioids to control pain and have not previously had problems with drug abuse do not become addicted to opioids. Nonetheless, doctors regularly monitor people who are taking opioid analgesics for signs of addiction.
Administration of opioids
When possible, opioids are taken by mouth (orally). When opioids are taken by mouth, the dose and time they are taken can be adjusted more easily. When they need to be taken for a long time, they may be given by mouth or through a patch placed on the skin (transdermally). Opioids are given by injection (into a muscle or vein) when pain occurs suddenly or when people cannot take them by mouth or through a skin patch.
If people who need to take opioids for a long time and are helped by an opioid taken by mouth but cannot tolerate its side effects, an opioid can be injected directly into the space around the spinal cord through a pump (intrathecally). This method gets high concentrations of the drug to the brain.
Morphine, the prototype of these drugs, can be taken by mouth or by injection. Morphine comes in sustained-, controlled-, and immediate-release forms that are taken by mouth.
The immediate-release form of morphine provides short-lived relief (about 4 hours) and is usually used to treat acute pain.
The controlled- and sustained-release forms provide relief for 8 to 24 hours. These forms have been widely used to treat chronic pain when nonopioid analgesics do not provide sufficient pain relief. However, if pain is not related to cancer, experts recommend limiting the use of these long-acting (controlled- and sustained-release) opioids.
Rapid-acting opioids (lozenges or dissolvable tablets) are placed under the tongue (sublingual) or between the gums and cheek (buccal). There, they are allowed to dissolve and are absorbed through the mucous membrane that lines the cheek or that lies under the tongue. These forms should not be swallowed. They provide relief very rapidly. Because they work rapidly, risk of side effects may be greater. They are used for breakthrough pain in people with cancer. Breakthrough pain is a brief, often severe flare-up of pain that may occur when regularly scheduled treatment does not control pain.
In injected forms, 3 times less morphine is required than in the immediate-release oral form 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. However, the doctor determines how much of the drug is released and how often it can be released. This technique is called patient-controlled analgesia. Usually, continuous infusion is used for people who are hospitalized and who have severe pain that occurs after surgery or that is due to a serious disorder such as cancer or a sickle cell crisis.
Problems with use of opioids
Opioids are now the leading cause of accidental death and fatal drug overdose in the United States. Problems with using opioids include opioid misuse, diversion, and abuse.
Opioid misuse may be intentional or unintentional. It includes any use that differs from what is prescribed.
Diversion involves selling or giving a prescribed drug to others.
Abuse refers to recreational use of the drug. That is, the drugs are taken for the feelings of pleasure or sensations they produce, rather than to treat pain or another medical condition.
Up to one third of people taking opioids for a long time to treat chronic pain may misuse them.
Opioid use disorder is the preferred term for what previously was called opioid addiction. It refers to compulsive use of opioids despite having problems caused by taking them. Also, people who have this disorder may require higher and higher doses to achieve the same effects and may experience withdrawal symptoms when they stop taking the opioid. They may try to stop taking opioids or reduce the amount they are taking but cannot. Taking high doses of opioids for a long time increases the risk of developing opioid use disorder.
Before prescribing opioids, doctors should evaluate people for risk factors for problems with taking opioids. Risk factors include
When the opioid is first prescribed, doctors explain the risks of opioids and the measures used to ensure that the drug is used safely. If problems occur, people are also told that they may be referred to a substance use specialist.
Doctors closely monitor all people who are treated with opioids to make sure opioid therapy is used safely. For example, they may test for other recreational drugs. Doctors also monitor interconnected state databases that track opioid prescriptions to check whether people are getting opioid prescriptions at more than one pharmacy. To prevent misuse, doctors typically restrict the person to a single pharmacy for filling opioid prescription.
To avoid misuse of their drug by others, people should keep opioids in a safe place and dispose of any unused drugs by returning them to the pharmacy.
Adjuvant analgesics are thought to work by changing the way the nerves process pain.
The adjuvant analgesics most commonly used for pain are
Oral and topical local anesthetics
Antidepressants can often relieve pain in people even when they do not have depression. Tricyclic antidepressants (such as amitriptyline, nortriptyline, and desipramine) may be more effective for this purpose than other antidepressants, but newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (SNRIs, including duloxetine, venlafaxine, and milnacipran) may have fewer of the side effects that limit how much of the drug can be taken.
Tricyclic antidepressants are effective for neuropathic pain, headaches, fibromyalgia, and visceral (organ) hypersensitivity syndromes (such as chronic abdominal or pelvic pain). The doses of tricyclic antidepressants used to treat pain are usually too low to treat depression or anxiety. Thus, if tricyclic antidepressants are used to treat pain, additional drugs are usually needed to treat depression or anxiety if present.
Duloxetine appears to be effective for neuropathic pain due to diabetes (called diabetic neuropathy), fibromyalgia, chronic low back pain, chronic musculoskeletal pain, and nerve pain due to chemotherapy. The doses of duloxetine used to treat pain are also adequate to treat depression or anxiety if present. Venlafaxine has similar effects. Milnacipran is effective for fibromyalgia.
People may respond to one antidepressant and not to others.
Antiseizure drugs may be used to relieve neuropathic pain. Gabapentin and pregabalin are most commonly used, but many others, including carbamazepine, clonazepam, lacosamide, lamotrigine, oxcarbazepine, phenytoin, topiramate, and zonisamide, help relieve pain in some people.
Pregabalin can be used to relieve pain caused by fibromyalgia or nerve damage due to diabetes (diabetic neuropathy), postherpetic neuralgia, or neuropathic pain due to a problem in the brain or spinal cord.
Antiseizure drugs, such as topiramate, can prevent migraine headaches.
A local anesthetic, such as lidocaine, may be injected into the skin to control pain due to an injury or even neuropathic pain. Local anesthetics can also be injected around nerves to block pain—a procedure called a nerve block. For example, a sympathetic nerve block involves injecting a local anesthetic around 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, an ointment, or a skin patch, can be used to control pain due to some conditions.
Mexiletine, used to treat abnormal heart rhythms, is sometimes used to treat neuropathic pain.
These anesthetics are usually used for a short period of time. For example, rinsing with small amounts of an anesthetic mouthwash a few times a day can relieve pain due to mouth sores. However, some people with chronic pain benefit from using topical anesthetics for a long time. For example, a lidocaine patch or gel can help relieve postherpetic neuralgia.
Tizanidine (a muscle relaxant), taken by mouth, and clonidine (used to treat high blood pressure), taken by mouth or applied to the skin as a patch, can help relieve neuropathic pain or prevent migraines.
High-strength capsaicin (a substance found in hot peppers), given in a patch, helps relieve neuropathic pain due to postherpetic neuralgia. A low-strength capsaicin cream may also help reduce the pain caused by postherpetic neuralgia and by other disorders such as osteoarthritis. The cream is most often used by people with localized pain due to arthritis. This cream must be applied several times a day.