Nonsteroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease. Well-known nonsteroidal anti-inflammatory drugs include aspirin, ibuprofen, diclofenac, and naproxen, all of which are available over the counter (OTC). Paracetamol (acetaminophen) is generally not considered an NSAID because it has only minor anti-inflammatory activity.
The term nonsteroidal, common from around 1960, distinguishes these drugs from corticosteroids, another class of anti-inflammatory drugs, which during the 1950s had acquired a bad reputation due to overuse and side-effect problems after their introduction in 1948.
Nonsteroidal anti-inflammatory drugs work by inhibiting the activity of cyclooxygenase enzymes (the COX-1 and COX-2 isoenzymes). In cells, these enzymes are involved in the synthesis of key biological mediators, namely prostaglandins, which are involved in inflammation, and thromboxanes, which are involved in blood clotting.
There are two general types of NSAIDs available: non-selective and COX-2 selective. Most NSAIDs are non-selective, and inhibit the activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also inhibit platelet aggregation and increase the risk of gastrointestinal ulcers and bleeds. COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote thrombosis, and some of these agents substantially increase the risk of heart attack. As a result, certain COX-2 selective inhibitors—such as rofecoxib—are no longer used due to the high risk of undiagnosed vascular disease. These differential effects are due to the different roles and tissue localisations of each COX isoenzyme. By inhibiting physiological COX activity, NSAIDs may cause deleterious effects on kidney function, and, perhaps as a result of water and sodium retention and decreases in renal blood flow, may lead to heart problems.
Medical uses Nonsteroidal anti-inflammatory drugs are often suggested for the treatment of acute or chronic conditions where pain and inflammation are present. Nonsteroidal anti-inflammatory drugs are generally used for the symptomatic relief of the following conditions: Osteoarthritis Rheumatoid arthritis Mild-to-moderate pain due to inflammation and tissue injury Low back pain Inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, reactive arthritis) Tennis elbow Headache Migraine Acute gout Dysmenorrhea (menstrual pain) Metastatic bone pain Postoperative pain Muscle stiffness and pain due to Parkinson's disease Pyrexia (fever) Ileus Renal colic Macular edema Traumatic injury
Chronic pain and cancer-related pain The effectiveness of nonsteroidal anti-inflammatory drugs for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear. There have not been sufficient numbers of high-quality randomised controlled trials conducted.
Inflammation Differences in anti-inflammatory activity between the various individual NSAIDs are small, but there is considerable variation among individual patients in therapeutic response and tolerance to these drugs. About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose, and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to three weeks. If appropriate responses are not obtained within these times, another NSAID should be tried.
Surgical pain Pain following surgery can be significant, and many people require strong pain medications such as opioids. There is some low-certainty evidence that starting NSAID painkiller medications in adults early, before surgery, may help reduce post-operative pain, and also reduce the dose or quantity of opioid medications required after surgery. Any increased risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied. When used in combination with paracetamol, the analgesic effect on post-operative pain may be improved.
Aspirin Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for antithrombosis through inhibition of platelet aggregation. This is useful for the management of arterial thrombosis, and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A2.
Dentistry Nonsteroidal anti-inflammatory drugs are useful in the management of post-operative dental pain following invasive dental procedures such as dental extraction. When not contra-indicated, they are favoured over the use of paracetamol alone due to the anti-inflammatory effect they provide. There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic.
Alzheimer's disease Based on observational studies and randomized controlled trials, NSAID use is not effective for the treatment or prevention of Alzheimer's disease.
Contraindications Nonsteroidal anti-inflammatory drugs may be used with caution by people with the following conditions: Persons who are over age 50, and who have a family history of gastrointestinal (GI) problems Persons who have had previous gastrointestinal problems from NSAID use
Adverse effects The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases the risk of a range of gastrointestinal (GI) problems, kidney disease, and adverse cardiovascular events. As commonly used for post-operative pain, there is evidence of increased risk of kidney complications. Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel anastomosis created.
An estimated 10–20% of people taking NSAIDs experience indigestion. In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding.
There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile, and balancing the risk of no treatment with the competing potential risks of various therapies should be considered. For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDs and the potential for adverse effects has not been well determined.
Side effects are dose-dependent, and in many cases, severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10–20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits.
Aspirin should not be taken by people who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using aspirin. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. People with kidney disease, hyperuricemia, or gout should not take aspirin because it inhibits the ability of the kidneys to excrete uric acid, and thus may exacerbate these conditions.
Combinational risk
If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time.
Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen. The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo—which caused a worldwide withdrawal of rofecoxib in October 2004.
Cardiovascular
NSAIDs, aside from aspirin, increase the risk of myocardial infarction and stroke. This occurs at least within a week of use. They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI. Evidence indicates that naproxen may be the least harmful out of these.
NSAIDs, aside from (low-dose) aspirin, are associated with a doubled risk of heart failure in people without a history of cardiac disease. In people with such a history, use of NSAIDs (aside from low-dose aspirin) was associated with a more than 10-fold increase in heart failure. If this link is proven causal, researchers estimate that NSAIDs would be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase mortality risk (hazard ratio) by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac.
In July 2015, the US Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin.
Possible erectile dysfunction risk
A 2005 Finnish survey study found an association between long-term (over three months) use of NSAIDs and erectile dysfunction.
According to a study published in 2011, men who use NSAIDs regularly are at significantly increased risk of erectile dysfunction. The study was observational and not controlled, with a low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusions regarding cause.
Gastrointestinal
The main adverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic effects on the epithelial mucosa.
Common gastrointestinal side effects include: Nausea or vomiting Indigestion Gastric ulceration or bleeding Diarrhea
Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have achlorhydria.Textbook of Gastroenterology, Tadataka Yamada, 2008, Ch.40, Peptic Ulcer Disease, page 941
Ulceration risk increases with therapy duration and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period—a practice that studies show is often not followed. Over 50% of patients on long term NSAID treatments of 6 or more months, sustained some mucosal damage to their small intestine.