Nonsteroidal anti-inflammatory drug


Non-steroidal anti-inflammatory drugs 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. The most prominent NSAIDs are aspirin, ibuprofen, diclofenac and naproxen, all available over the counter in most countries. Paracetamol is generally not considered an NSAID because it has only minor anti-inflammatory activity.
The term non-steroidal, 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.
NSAIDs work by inhibiting the activity of cyclooxygenase enzymes. 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. In addition, NSAIDs can blunt the production of erythropoietin, resulting in anaemia, since haemoglobin needs this hormone to be produced.

Medical uses

NSAIDs are often suggested for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs 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
  • Tennis elbow
  • Headache
  • Migraine
  • Acute gout
  • Dysmenorrhea
  • Metastatic bone pain
  • Postoperative pain
  • Muscle stiffness and pain due to Parkinson's disease
  • Pyrexia
  • Ileus
  • Renal colic
  • Macular edema
  • Traumatic injury

    Chronic pain and cancer-related pain

The effectiveness of NSAIDs 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 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

, 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

NSAIDs 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

NSAIDs 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 problems
  • Persons who have had previous gastrointestinal problems from NSAID use
NSAIDs should usually be avoided by people with the following conditions:
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 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.
NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and quinolone antibiotics may increase the risk of the adverse central nervous system effects of quinolones including seizure.
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.
There is some evidence suggesting that, for some people, use of NSAIDs may contribute to the initiation of chronic pain.
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 should not be taken at the same time.
Rofecoxib was shown to produce significantly fewer gastrointestinal adverse drug reactions compared with naproxen. The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs. 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.
Use of methotrexate together with NSAIDs in rheumatoid arthritis is safe if adequate monitoring is done.

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 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 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 by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac.
On 9 July 2015, the Food and Drug Administration toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs other than aspirin.