nonsteroidal anti-inflammatory drugs

Definition

Nonsteroidal anti-inflammatory drugs are medicines that relieve pain, swelling, stiffness, and inflammation.

Description

Nonsteroidal anti-inflammatory drugs relieve pain, stiffness, swelling, and inflammation, but they do not cure the diseases or injuries responsible for these problems. Two drugs in this category, ibuprofen and naproxen, also reduce fever. Some nonsteroidal anti-inflammatory drugs can be bought over the counter; others are available only with a prescription from a physician or dentist.

Among the drugs in this group are diclofenac (Voltaren), etodolac (Lodine), flurbiprofen (Ansaid), ibuprofen (Motrin, Advil, Rufen), ketorolac (Toradol), nabumetone (Relafen), naproxen (Naprosyn); naproxen sodium (Aleve, Anaprox, Naprelan); and oxaprozin (Daypro). They are sold as tablets, capsules, caplets, liquids, and rectal suppositories and some are available in chewable, extended-release, or delayed-release forms.

— Nancy Ross-Flanigan

Definition

Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications other than corticosteroids that relieve pain, swelling, stiffness, and inflammation.

Purpose

Nonsteroidal anti-inflammatory drugs are prescribed for a variety of painful conditions, including arthritis, bursitis, tendinitis, gout, menstrual cramps, sprains, strains, and other injuries. They may be used for treatment of post-surgical pain that either is too mild to require narcotic analgesics or follows a period of use of stronger analgesics. Ketorolac (Toradol) may be used in place of narcotics for treatment of acute pain in patients who should not receive narcotics.

Description

The nonsteroidal anti-inflammatory drugs are a group of agents that inhibit prostaglandin synthetase, thereby reducing the process of inflammation. As a group, they are all effective analgesics. Some, including the salicylates, ibuprofen, and naproxene, are also useful antipyretics (fever-reducers).

Although NSAIDs fall into discrete chemical classes, they are usually divided into the nonselective NSAIDs and the COX-2 specific agents. Among the nonspecific NSAIDs are diclofenac (Voltaren), etodolac (Lodine), flurbiprofen (Ansaid), ibuprofen (Motrin, Advil, Rufen), ketorolac (Toradol), nabumetone (Relafen), naproxen (Naprosyn), naproxen sodium (Aleve, Anaprox, Naprelan), and oxaprozin (Daypro). The COX-2 specific drugs are celecoxib (Celebrex) and rofecoxib (Vioxx).

Nonselective NSAIDS inhibit both cyclooxygenase 1 and cyclooxygenase 2 (COX-2). Cyclooxygenase 1 is important for homeostatic maintenance such as platelet aggregation, the regulation of blood flow in the kidney and stomach, and the regulation of gastric acid secretion. The inhibition of cyclooxygenase 1 is considered the primary cause of NSAID toxicity, including gastric ulceration and bleeding disorders. COX-2 is the primary cause of pain and inflammation. Both celecoxib and rofecoxib are relatively selective, and may cause the same adverse effects as the nonselective drugs, although with somewhat reduced frequency.

The analgesic activity of NSAIDs has not been fully explained. Antipyretic activity may be caused by the inhibition of prostaglandin E2 (PGE2) synthesis.

Although not all NSAIDs have approved indications for all uses, as a class, they are used for:

• ankylosing spondylitis
• bursitis
• fever
• gout
• headache
• juvenile arthritis
• mild to moderate pain
• osteoarthritis
• PMS
• primary dysmennorhea
• rheumatoid arthritis
• tendinitis

Recommended Dosage

Recommended doses vary, depending on the patient, the type of nonsteroidal anti-inflammatory drug prescribed, the condition for which the drug is prescribed, and the form in which it is used. The patient is advised to consult specific sources for detailed information or ask a physician.

Precautions

The most common hazard associated with NSAID use is gastrointestinal intolerance and ulceration. This may occur without warning and is a greater risk among patients over the age of 65. The risk appears to rise with increasing length of treatment and increasing dose. Patients should be aware of the warning signs of gastrointestinal (GI) bleeding.

Allergic reactions are rare, but may be severe. Patients who have allergic reactions to aspirin should not be treated with NSAIDs.

Because NSAID metabolites are eliminated by the kidney, renal toxicity should be considered. Clinicians should monitor kidney function before and during NSAID use.

Among the NSAIDs that are classed as pregnancy category B are ketoprofen, naproxen, naproxen sodium, flurbiprofen, and diclofenac. Etodolac, ketorolac, mefenamic acid, meloxicam, nabumetone, oxaprozin, tolmetin, piroxicam, rofecoxib, and celecoxib are category C. Breastfeeding is not advised while taking NSAIDs.

Many other rare but potentially serious adverse effects have been reported with NSAIDs. The consumer should consult specific references.

Interactions

Many drug interactions have been reported with NSAID therapy. The most serious are those that may affect the bleeding hazards associated with NSAIDs. Consumers are advised to consult specific references for further information. A partial list of interacting drugs follows:

• blood thinning drugs, such as warfarin (Coumadin)
• other nonsteroidal anti-inflammatory drugs
• heparin
• tetracyclines
• cyclosprorine
• digitalis drugs
• lithium
• phenytoin (Dilantin)
• zidovudine (AZT, Retrovir)

Resources

Books

AHFS: Drug Information. Washington, DC: Amer Soc Health-systems Pharm, 2002.

Brody, T., J. Larner, K. P. Minneman, and H. C. Neu. HumanPharmacology Molecular to Clinical. 2nd edition. St Louis: Mosby Year-Book,1995.

Karch, A. M. Lippincott's Nursing Drug Guide. Springhouse, PA: Lippincott Williams & Wilkins, 2003.

Reynolds, J. E. F., ed. Martindale, The Extra Pharmacopoeia. 31st Edition. London: The Pharmaceutical Press, 1996.

— Samuel D. Uretsky, PharmD

Key Terms: Cyclooxygenase-2 inhibitor, Enzyme, NSAIDs, Opioids.

Definition

Nonsteroidal antiinflammatory drugs (NSAIDs) are a type of drug that reduce pain and inflammation.

Purpose

NSAIDs often are used to relieve mild to moderate pain for all types of cancer, as well as the pain of arthritis, menstrual cramps, sore muscles following exercise, and tension headaches. Most NSAIDs are available in over-the-counter formulations.

Ibuprofen and naproxen are two NSAIDs that are also used to bring down fever and treat the side effects of radiation therapy.

Description

This class of drugs eases discomfort by blocking the pathway of an enzyme that forms prostaglandins (hormones that cause pain and swelling). By doing so, the drugs lessen the pain in different parts of the body.

Some of the NSAIDs used in cancer treatment include: ibuprofen (Motrin, Advil, Rufen, Nuprin), naproxen (Naprosyn, Naprelan, Anaprox, Aleve), nabumetone (Relafen), ketorolac, sulindac and diclofenac (Cataflam, Voltaren). The class of drugs known as Cyclooxygenase-2 inhibitors that emerged in the late 1990s for dealing with arthritis pain, such as the brand names Celebrex and Vioxx, is also considered part of the group of NSAIDS.

If NSAIDs are not strong enough to keep a cancer patient comfortable, physicians often will combine them with such opioids (narcotics) as codeine. In later stages, doctors also may combine NSAIDs with stronger opioids like morphine, to treat very severe pain.

NSAIDs also may be used to prevent colon cancer and other types of cancer, although scientists are still studying this experimental approach (see entry on chemoprevention).

Recommended Dosage

Patients typically take NSAIDs on an as-needed basis. Doses vary depending on the type of NSAID being used. For example, the most common type, ibuprofen, is available over the counter in 200mg caplets, which can be taken at regular intervals throughout the day. The maximum daily dose for ibuprofen is 1,200 mgs.

Precautions

Most doctors recommend taking NSAIDs with a full glass of water. Avoid taking these drugs on an empty stomach. Smoking cigarettes and drinking alcohol while taking NSAIDs may irritate the stomach.

People who take NSAIDs should notify their doctors before having surgery or dental work, since these drugs can prevent wounds from healing properly.

Women who are pregnant or breastfeeding should check with their doctor before taking NSAIDs, because they may be harmful to a developing fetus or a newborn.

Diabetics, people who take aspirin, blood thinners, blood pressure medications, or steroids also should check with their doctors before taking NSAIDs.

Side Effects

Many NSAID users experience mild side effects, such as an upset stomach. In 4 to 7% of cases, more serious complications develop, such as stomach ulcers. Typically, elderly people experience the most serious complications.

Common side effects include stomach upset, constipation, dizziness and headaches.

More severe side effects include stomach ulcers and bleeding ulcers. If a person has black, tarry stools or starts vomiting blood, it may be caused by a bleeding ulcer.

Kidney dysfunction is another severe complication of long-term NSAID use. Signs of kidney problems include dark yellow, brown or bloody urine. NSAID use also may cause liver function problems over longer periods of time.

To guard against ulcers, physicians may ask patients to take NSAIDs with such anti-ulcer medications as omeprazole or misoprostol. Another option is to take the NSAID in a different, non-oral form. Often topical creams or suppositories are available. Finally, doctors may decide to switch to a different type of pain killer, such as a cyclooxygenase-2 (COX-2) inhibitor like Celebrex, which may be easier on the stomach. Some studies indicate that the use of COX-2 inhibitors may postpone the need to prescribe narcotic medications for severe pain.

Some patients who have had problems with side effects from NSAIDs may benefit from acupuncture as an adjunctive treatment in pain management. A recent study done in New York found that older patients with lower back pain related to cancer reported that their pain was relieved by acupuncture with fewer side effects than those caused by NSAIDs.

Interactions

NSAIDs can be taken with most other prescription and over-the-counter drugs without any harmful interactions. Certain drug combinations, however, should be avoided. For instance, when ibuprofen is combined with methotrexate (used for chemotherapy and arthritis treatment) or certain diabetic medicines and anti-depressants, it can amplify negative side effects. Patients should check with a pharmacist before taking NSAIDs with other drugs.

NSAIDs may also interact with certain herbal preparations sold as dietary supplements. Among the herbs known to interact with NSAIDs are bearberry (Arctostaphylos uva-ursi), feverfew (Tanacetum parthenium), evening primrose (Oenothera biennis), and gossypol, a pigment obtained from cottonseed oil and used as a male contraceptive. In most cases, the herb increases the tendency of NSAIDs to irritate the digestive tract. It is just as important for patients to inform their doctors of herbal remedies that they take on a regular basis as it is to give the doctors lists of their other prescription medications.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Drug Therapy in the Elderly." Section 22, Chapter 304 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Pelletier, Dr. Kenneth R. The Best Alternative Medicine, Part I: Western Herbal Medicine. New York: Simon and Schuster, 2002.

Wilson, Billie Ann, RN, PhD, Carolyn L. Stang, PharmD, and Margaret T. Shannon, RN, PhD. Nurses Drug Guide 2000. Stamford, CT: Appleton and Lange, 1999.

Periodicals

Birbara, C. A., A. D. Puopolo, D. R. Munoz, et al. "Treatment of Chronic Low Back Pain with Etoricoxib, A New Cyclo-Oxygenase-2 Selective Inhibitor: Improvement in Pain and Disability—A Randomized, Placebo-Controlled, 3-Month Trial." Journal of Pain 4 (August 2003): 307–315.

Gordon, D. B. "Nonopioid and Adjuvant Analgesics in Chronic Pain Management: Strategies for Effective Use." Nursing Clinics of North America 38 (September 2003): 447–464.

Graf, C., and K. Puntillo. "Pain in the Older Adult in the Intensive Care Unit." Critical Care Clinics 19 (October 2003): 749–770.

Harris, R. E., R. T. Chlebowski, R. D. Jackson, et al. "Breast cancer and Nonsteroidal Anti-Inflammatory Drugs: Prospective Results from the Women's Health Initiative." Cancer Research 63 (September 15, 2003): 6096–6101.

Hatsiopoulou, O., R. I. Cohen, and E. V. Lang. "Postprocedure Pain Management of Interventional Radiology Patients." Journal of Vascular and Interventional Radiology 14 (November 2003): 1373–1385.

Meng, C. F., D. Wang, J. Ngeow, et al. "Acupuncture for Chronic Low Back Pain in Older Patients: A Randomized, Controlled Trial." Rheumatology (Oxford) 42 (December 2003): 1508–1517.

Perrone, M. R., M. C. Artesani, M. Viola, et al. "Tolerability of Rofecoxib in Patients with Adverse Reactions to Nonsteroidal Anti-Inflammatory Drugs: A Study of 216 Patients and Literature Review." International Archives of Allergy and Immunology 132 (September 2003): 82–86.

Raffa, R. B., R. Clark-Vetri, R. J. Tallarida, and A. I. Wertheimer. "Combination Strategies for Pain Management." Expert Opinion in Pharmacotherapy 4 (October 2003): 1697–1708.

Small, R. C., and A. Schuna. "Optimizing Outcomes in Rheumatoid Arthritis." Journal of the American Pharmaceutical Association 43, no. 5 Supplement 1 (September-October 2003): S16–S17.

Stephens, J., B. Laskin, C. Pashos, et al. "The Burden of Acute Postoperative Pain and the Potential Role of the COX-2-Specific Inhibitors." Rheumatology (Oxford) 42, Supplement 3 (November 2003): iii40–iii52.

Organizations

U. S. Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857. (888) 463–6332. .

—Melissa Knopper, M.S.; Rebecca J. Frey, Ph.D.

Definition

Nonsteroidal anti-inflammatory drugs are medicines that relieve pain, swelling, stiffness, and inflammation.

Description

Nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed for a variety of painful conditions, including arthritis, bursitis, tendonitis, gout, menstrual cramps, sprains, strains, and other injuries.

Although the NSAIDs are often discussed as a group, not all are approved for use in children. As of 2004, the following drugs are approved for pediatric use:

• Ibuprofen (Advil, Motrin, Nuprin).
• Indomethicin (Indocin), not recommended for children under the age of 14 except in circumstances that warrant the risk. Indomethicin has special application in some infants born with heart problems.
• Ketoprofen (Orudis, Oruvail), not given to children under the age of 16 unless directed by a physician.
• Ketorolac tromethamine (Toradol), not approved for use in children but has been reported safe by some pediatric authorities.
• Meclofenamate sodium, safety and efficacy in children under 14 years of age has not been established.
• Mefenamic acid (Ponstel), safety and efficacy in children under 14 years of age has not been established.
• Naproxen (Aleve, Anaprox, Naprosyn), safety and efficacy in children under two years of age has not been established.
• Tolmetin sodium (Tolectin), safety and efficacy in children under two years of age has not been established.

Other NSAIDs have been used in pediatric therapy, but should not be considered as first choice for treatment of children or adolescents.

A new class of NSAIDs, called COX-2 inhibitors, have a lower risk of causing ulcers than do the traditional NSAIDs. These drugs may be appropriate for use in older teenagers but have not been approved for use in younger children, and there is some evidence that they are inappropriate for infants.

General Use

Nonsteroidal anti-inflammatory drugs relieve pain, stiffness, swelling, and inflammation, but they do not cure the diseases or injuries responsible for these problems. Two drugs in this category, ibuprofen and naproxen, also reduce fever. Some nonsteroidal anti-inflammatory drugs can be bought without a prescription; others are available only with a prescription from a physician or dentist.

Precautions

Children with certain medical conditions and those who are taking some other medicines can have problems if they take nonsteroidal anti-inflammatory drugs. Before giving children these drugs, parents need to let the physician know about any of the following conditions.

Allergies

The physician needs to know about any allergies to foods, dyes, preservatives, or other substances. For children who have had reactions to nonsteroidal anti-inflammatory drugs in the past, parents should check with a physician before having these drugs prescribed again.

Pregnancy

Teens and young women who are pregnant or who plan to become pregnant should check with their physicians before taking these medicines. Whether nonsteroidal anti-inflammatory drugs cause birth defects in people is unknown, but some do cause birth defects in laboratory animals. If taken late in pregnancy, these drugs may prolong pregnancy, lengthen labor time, cause problems during delivery, or affect the heart or blood flow of the fetus.

Breastfeeding

Some nonsteroidal anti-inflammatory drugs pass into breast milk. Women who are breastfeeding their babies should check with their physicians before taking these drugs.

Other Medical Conditions

A number of medical conditions may influence the effects of nonsteroidal anti-inflammatory drugs. Parents of children and teens who have any of the conditions listed below should tell their physician about the condition before having nonsteroidal anti-inflammatory drugs prescribed.

• stomach or intestinal problems, such as colitis or Crohn's disease
• liver disease
• current or past kidney disease or current or past kidney stones
• heart disease
• high blood pressure
• blood disorders, such as anemia, low platelet count, low white blood cell count
• bleeding problems
• diabetes mellitus
• hemorrhoids, rectal bleeding, or rectal irritation
• asthma
• epilepsy
• systemic lupus erythematosus
• diseases of the blood vessels, such as polymyalgia rheumatica and temporal arteritis
• fluid retention
• alcohol abuse
• mental illness

Side Effects

The most common side effects are stomach pain or cramps, nausea, vomiting, indigestion, diarrhea, heartburn, headache, dizziness or lightheadedness, and drowsiness. As the patient's body adjusts to the medicine, these symptoms usually disappear. If they do not, the physician who prescribed the medicine should be contacted.

Serious side effects are rare, but do sometimes occur. If any of the following side effects occur, patients should stop taking the medicine and get emergency medical care immediately:

• swelling or puffiness of the face
• swelling of the hands, feet, or lower legs
• rapid weight gain
• fainting
• breathing problems
• fast or irregular heartbeat
• tightness in the chest

Other side effects do not require emergency medical care, but should have medical attention. If any of the following side effects occur, patients should stop taking the medicine and the physician who prescribed the medicine should be called as soon as possible:

• severe pain, cramps, or burning in the stomach or abdomen
• convulsions
• fever
• severe nausea, heartburn, or indigestion
• white spots or sores in the mouth or on the lips
• rashes or red spots on the skin
• any unusual bleeding, including nosebleeds and spitting up or vomiting blood or dark material
• black, tarry stool
• chest pain
• unusual bruising
• severe headaches

A number of less common, temporary side effects are also possible. They usually do not need medical attention and will disappear once the body adjusts to the medicine. If they continue or interfere with normal activity, the physician should be contacted. Among these side effects are:

• gas, bloating, or constipation
• bitter taste or other taste changes
• sweating
• restlessness, irritability, anxiety
• trembling or twitching

Interactions

Nonsteroidal anti-inflammatory drugs may interact with a variety of other medicines. When interaction occurs, the effects of the drugs may change, and the risk of side effects may be greater. Physicians prescribing this drug should know all other medicines the patient is already taking. Among the drugs that may interact with nonsteroidal anti-inflammatory drugs are:

• blood thinning drugs, such as warfarin (Coumadin)
• other nonsteroidal anti-inflammatory drugs
• heparin
• tetracyclines
• cyclosprorine
• digitalis drugs
• lithium
• phenytoin (Dilantin)
• zidovudine (AZT, Retrovir)

NSAIDs may also interact with certain herbal preparations sold as dietary supplements. Among the herbs known to interact with NSAIDs are bearberry (Arctostaphylos uva-ursi), feverfew (Tanacetum parthenium), evening primrose (Oenothera biennis), and gossypol, a pigment obtained from cottonseed oil and used as a male contraceptive. In most cases, the herb increases the tendency of NSAIDs to irritate the digestive tract. It is just as important for doctors to know which herbal remedies the patient is taking on a regular basis as it is for doctors to know the other prescription medications which are being taken.

Prevention

Many serious digestive system effects of NSAIDs can be prevented by taking mysoprostol (Cytotec), but this drug is only appropriate for patients with a high risk of ulcers. It is not called for when the NSAID is being used for a short period of time or in patients with other risk factors. Stomach upset can often be prevented by taking NSAIDs with food or milk.

Parental Concerns

NSAIDs are very safe when used properly over a short period of time. They should not be used for longer periods or in larger doses than indicated on the label. If NSAIDs are to be used for prolonged periods, as in juvenile rheumatoid arthritis, there is a risk of potentially serious stomach and intestinal problems.

Resources

Books

Pelletier, Kenneth R. The Best Alternative Medicine, Part I:Western Herbal Medicine. New York: Simon and Schuster, 2002.

Periodicals

Gordon, D. B. "Nonopioid and Adjuvant Analgesics in Chronic Pain Management: Strategies for Effective Use." Nursing Clinics of North America 38 (September 2003): 447–464.

Small, R. C., and A. Schuna. "Optimizing Outcomes in Rheumatoid Arthritis." Journal of the American Pharmaceutical Association 43, no. 5, suppl. 1 (September-October 2003): S16–S17.

Stempak, D., et al. "Single-dose and steady-state pharmacokinetics of celecoxib in children." Clinical Pharmacological Therapy 72, no. 5 (November 2002): 490–497.

Organizations

U. S. Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857. Web site: .

Web Sites

Pediatric Rheumatology Online Journal. Available online at www.pedrheumonlinejournal.org/ (accessed on September 29, 2004).

[Article by: Nancy Ross-Flanigan Rebecca J. Frey, PhD Samuel Uretsky, PharmD]

A group of drugs having analgesic, antipyretic and anti-inflammatory activity due to their ability to inhibit the synthesis of prostaglandins; abbreviated NSAID, NSAIDs. Includes aspirin, acetaminophen, phenylbutazone, indometacin, tolmetin, ibuprofen and related drugs. Excessive use in animals can lead to development of gastric and intestinal ulcers, especially in cats.

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, are drugs with analgesic, antipyretic (lowering an elevated body temperature and relieving pain without impairing consciousness) and, in higher doses, with anti-inflammatory effects (reducing inflammation). The term "non-steroidal" is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic.

NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs) or non-steroidal anti-inflammatory medicines (NSAIMs). The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen partly because they are available over-the-counter in many areas.

Contents 1 Mechanism of action 2 Examples 2.1 COX-2 inhibitors 2.2 Sulphonanilides 2.3 Others 3 Uses 4 Pharmacokinetics 5 Adverse effects 5.1 Combinational risk 5.2 Cardiovascular 5.3 Gastrointestinal 5.4 Inflammatory bowel disease 5.5 Renal 5.6 Photosensitivity 5.7 During pregnancy 5.8 Other 6 Chirality 7 Selective COX inhibitors 7.1 COX-2 inhibitors 7.1.1 Controversies with COX-2 inhibitors 7.2 COX-3 inhibitors 8 Veterinary use 9 References 10 External links

Mechanism of action

Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A₂). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (1927-2004), who later received a Nobel Prize for his work (see Mechanism of action of aspirin). A newly discovered^[when?] COX-3 may also have some role.^{[citation needed]}

Examples

NSAIDs can be broadly classified based on their chemical structure. NSAIDs within a group will tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among compounds tended to be with regards to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile. Some more common examples are given below.

COX-2 inhibitors

• Celecoxib (FDA alert ^[1])
• Etoricoxib FDA withdrawn
• Lumiracoxib TGA cancelled registration
• Parecoxib FDA withdrawn
• Rofecoxib (withdrawn from market ^[2])
• Valdecoxib (withdrawn from market ^[3])

Sulphonanilides

• Nimesulide (banned by several countries for the potential risk of hepatotoxicity)

Others

• Ibuprofen^[4]
• Naproxen
• Diclofenac
• Licofelone

Licofelone acts by inhibiting LOX (lipooxygenase) & COX (cyclooxygenase)and hence known as 5-LOX/COX inhibitor.

Uses

NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease.

NSAIDs are generally indicated for the symptomatic relief of the following conditions:^[5]

• Rheumatoid arthritis^[6]
• Osteoarthritis
• Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)
• Acute gout
• Dysmenorrhoea (menstrual pain)
• Metastatic bone pain
• Headache and migraine
• Postoperative pain
• Mild-to-moderate pain due to inflammation and tissue injury
• Pyrexia (fever)
• Ileus
• Renal colic
• They are also given to neonate infants whose ductus arteriosus is not closed within 24 hours of birth

Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation. This is useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane -A.

In 2001 NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States.^[7]

One study has suggested that taking NSAIDs while smoking marijuana may prevent the death of brain cells resulting from THC intoxication.^[8] However, neurotoxicity of marijuana is still a matter of dispute.

Pharmacokinetics

Most non-steroidal anti-inflammatory drugs are weak acids, with a pKa of 3-5. They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume. Most NSAIDs are metabolised in the liver by oxidation and conjugation to inactive metabolites which are typically excreted in the urine, although some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.

Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20–60 hours).

Adverse effects

The widespread use of NSAIDs has meant that the adverse effects of these relatively safe drugs have become increasingly prevalent. The two main adverse drug reactions (ADRs) associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents.

These 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.^[7]

Combinational risk

If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.^[9] In addition, patients on daily aspirin therapy (as for reducing cardiovascular risk or colon cancer risk^{[citation needed]}) need to be careful if they also use other NSAIDs, as the latter may block the cardioprotective effects of aspirin.

Cardiovascular

A recent meta-analysis of all trials comparing NSAIDs found an 80% increase in the risk of myocardial infarction with both newer COX-2 antagonists and high dose traditional anti-inflammatories compared with placebo.^[10]

NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of symptomatic heart failure in patients without a history of cardiac disease. In patients with such a history, however, use of NSAIDs (aside from low-dose aspirin) was associated with more than 10-fold increase in heart failure.^[11] If this link is found to be causal, NSAIDs are estimated to be responsible for up to 20 percent of hospital admissions for congestive heart failure.^[11]

Gastrointestinal

The main ADRs (adverse drug reactions) associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 reduces the levels of protective prostaglandins.

Common gastrointestinal ADRs include:^[5]

• Nausea/Vomiting
• Dyspepsia
• Gastric ulceration/bleeding^[12].
• Diarrhea

Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. Recent studies show that over 50% of patients taking NSAIDs have sustained damage to their small intestine.^[13]

There are also some differences in the propensity of individual agents to cause gastrointestinal ADRs. Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and Diclofenac appear to have lower rates.^[5]

Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations which are claimed to reduce the incidence of gastrointestinal ADRs. Similarly, there is a belief that rectal formulations may reduce gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration.^[5]

Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole, esomeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhea). While these techniques may be effective, they prove to be expensive for maintenance therapy.

Inflammatory bowel disease

NSAIDs are never to be used in individuals with Inflammatory Bowel Disease (e.g., Crohn's Disease or Ulcerative Colitis) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining. Pain relievers such as paracetamol or drugs containing codeine (which slows down bowel activity) are safer medications for pain relief in IBD.^{[citation needed]}

Renal

NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions (ADRs). The mechanism of these renal ADRs is due to changes in renal haemodynamics (blood flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Prostaglandins normally cause vasodilation of the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function. This is particularly important in renal failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent ateriole into the glomerulus in addition to the efferent arteriole one it normally constricts. Prostaglandins serve to dilate the afferent arteriole; by blocking this prostaglandin-mediated effect, particularly in renal failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased renal perfusion pressure. Horses are particularly prone to these adverse affects compared to other domestic animal species.

Common ADRs associated with altered renal function include:^[5]

• Salt and fluid retention
• Hypertension (high blood pressure)

These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect.^[14]

In rarer instances NSAIDs may also cause more severe renal conditions:^[5]

• Interstitial nephritis
• Nephrotic syndrome
• Acute renal failure
• Acute tubular necrosis

NSAIDs in combination with excessive use of phenacetin and/or paracetamol may lead to analgesic nephropathy.^[15]

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.^[16] It is somewhat ironic that these anti-inflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac and benzydamine.

Benoxaprofen, since withdrawn due to its hepatotoxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. While ibuprofen is somewhat of an exception, having weak absorption, it has been reported to be a weak photosensitising agent.

During pregnancy

NSAIDs are not recommended during pregnancy, particularly during the third trimester. While NSAIDs as a class are not direct teratogens, they may cause premature closure of the fetal ductus arteriosus and renal ADRs in the fetus. Additionally, they are linked with premature birth.^[17] Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies.^[18]

In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during pregnancy.^[19] Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses.^[20]

In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.^[21]

Other

Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness.^[5] Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash.^[5] Rapid and severe swelling of the face and/or body. Ibuprofen may also rarely cause irritable bowel syndrome symptoms.

Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness.

In very rare cases, ibuprofen can cause aseptic meningitis.

As with other drugs, allergies to NSAIDs exist. While many allergies are specific to one NSAID, up to 1 in 5 people may have unpredictable cross-reactive allergic responses to other NSAIDs as well.^[22]

Chirality

Most NSAIDs are chiral molecules (diclofenac is a notable exception). However, the majority are prepared in a racemic mixture. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically profens), an isomerase enzyme exists in vivo which converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely to be responsible for the poor correlation between NSAID efficacy and plasma concentration observed in older studies, when specific analysis of the active enantiomer was not performed.

Ibuprofen and ketoprofen are now available in single, active enantiomer preparations (dexibuprofen and dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has always been marketed as the single active enantiomer.

Selective COX inhibitors

COX-2 inhibitors

The discovery of COX-2 in 1991 by Daniel L. Simmons at Brigham Young University raised the hope of developing an effective NSAID without the gastric problems characteristic of these agents. It was thought that selective inhibition of COX-2 would result in anti-inflammatory action without disrupting gastroprotective prostaglandins.

COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. When non-selective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, these protective effects are lost and ulcers of the stomach or duodenum and potentially internal bleeding can result. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.

The relatively selective COX-2 inhibiting oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors, and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.

Controversies with COX-2 inhibitors

While it was hoped that this COX-2 selectivity would reduce gastrointestinal adverse drug reactions (ADRs), there is little conclusive evidence that this is true. The original study touted by Searle (now part of Pfizer), showing a reduced rate of ADRs for celecoxib, was later revealed to be based on preliminary data - the final data showed no significant difference in ADRs when compared with diclofenac.

Rofecoxib however, which has since been withdrawn, had been shown to produce significantly fewer gastrointestinal ADRs compared to naproxen.^[23] This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs - a statistically insignificant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a relative risk of cardiovascular events of 1.97 versus placebo - a result which resulted in the worldwide withdrawal of rofecoxib in October 2004.

COX-3 inhibitors

This article may require cleanup to meet Wikipedia's quality standards. Please improve this article if you can. (December 2008)

Simmons also co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to paracetamol (acetaminophen), arguably the most widely used analgesic drug in the world.^[24] The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.

The relevance of this research has been called into question as the putative COX-3 gene encodes proteins with completely different amino acid sequences than COX-1 or COX-2. The expressed proteins do not show COX activity and it is unlikely that they play a role in prostaglandin mediated physiological responses.^[25]

Veterinary use

Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves. The best effect is obtained by combining a short-term local anesthetic such as lidocaine with an NSAID acting as a longer term analgesic. However, most of the existing research data relates to ketoprofen while the only NSAID currently available for labelled use in the United States is flunixin meglumine, indicated for conditions other than post-operative pain.

References

1. ^ http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-hcp.htm^{[dead link]} FDA Alert for Practitioners on Celebrex (celecoxib)
2. ^ http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htm^{[dead link]}
3. ^ http://www.fda.gov/cder/drug/InfoSheets/HCP/valdecoxibHCP.htm^{[dead link]} Alert for Healthcare Professionals: Valdecoxib (marketed as Bextra)
4. ^ http://www.drugbank.ca/cgi-bin/getCard.cgi?CARD=APRD00372 Drugbank Card for Ibuprofen
5. ^ ^{a b c d e f g h} Simone Rossi, ed (2006). Australian medicines handbook 2006. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3. ^{[page needed]}
6. ^ Gøtzsche, Pc (Mar 1989). "Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis". Controlled clinical trials 10 (1): 31–56. doi:10.1016/0197-2456(89)90017-2. ISSN 0197-2456. PMID 2702836. 
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11. ^ ^{a b} Page, J; Henry, D (Mar 2000). "Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem" (Free full text). Archives of internal medicine 160 (6): 777–84. doi:10.1001/archinte.160.6.777. ISSN 0003-9926. PMID 10737277. http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=10737277. 
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13. ^ Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, Tokioka S, Arakawa T (Jul 2009). "Present status and strategy of NSAIDs-induced small bowel injury". Journal of Gastroenterology 44 (9): 879–888. doi:10.1007/s00535-009-0102-2. ISSN 1435-5922. PMID 19568687. 
14. ^ Thomas, Mc (Feb 2000). "Diuretics, ACE inhibitors and NSAIDs--the triple whammy". The Medical journal of Australia 172 (4): 184–5. ISSN 0025-729X. PMID 10772593. 
15. ^ De, Broe, Me; Elseviers, Mm (Feb 1998). "Analgesic nephropathy". New England Journal of Medicine 338 (7): 446–52. doi:10.1056/NEJM199802123380707. ISSN 0028-4793. PMID 9459649. 
16. ^ Moore, De (2002). "Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management". Drug safety : an international journal of medical toxicology and drug experience 25 (5): 345–72. doi:10.2165/00002018-200225050-00004. ISSN 0114-5916. PMID 12020173. 
17. ^ Østensen, Me; Skomsvoll, Jf (Mar 2004). "Anti-inflammatory pharmacotherapy during pregnancy". Expert opinion on pharmacotherapy 5 (3): 571–80. doi:10.1517/14656566.5.3.571. ISSN 1465-6566. PMID 15013926. 
18. ^ Cervera, R; Balasch, J (2004). "The management of pregnant patients with antiphospholipid syndrome". Lupus 13 (9): 683–7. doi:10.1191/0961203304lu1092oa. ISSN 0961-2033. PMID 15485103. 
19. ^ Graham, Gg; Scott, Kf; Day, Ro (2005). "Tolerability of paracetamol". Drug safety : an international journal of medical toxicology and drug experience 28 (3): 227–40. doi:10.2165/00002018-200528030-00004. ISSN 0114-5916. PMID 15733027. 
20. ^ Wilkes, Jm; Clark, Le; Herrera, Jl (Nov 2005). "Acetaminophen overdose in pregnancy". Southern medical journal 98 (11): 1118–22. doi:10.1097/01.smj.0000184792.15407.51. ISSN 0038-4348. PMID 16351032. 
21. ^ Dreillard, Audrey (March 2, 2009). "Grossesse - Mamans attention" (in French). France Soir. http://www.francesoir.fr/societe/2009/03/02/grossesse-mamans-attention.html. Retrieved June 1, 2009. 
22. ^ Allergy Capital: Adverse and allergic reactions to aspirin and NSAIDS. Accessed 2009.03.23.
23. ^ Bombardier, C; Laine, L; Reicin, A; Shapiro, D; Burgos-Vargas, R; Davis, B; Day, R; Ferraz, Mb; Hawkey, Cj; Hochberg, Mc; Kvien, Tk; Schnitzer, Tj; Vigor, Study, Group (Nov 2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis". New England Journal of Medicine 343 (21): 1520–8, 2 p following 1528. doi:10.1056/NEJM200011233432103. ISSN 0028-4793. PMID 11087881. 
24. ^ Chandrasekharan, Nv; Dai, H; Roos, Kl; Evanson, Nk; Tomsik, J; Elton, Ts; Simmons, Dl (Oct 2002). "COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression" (Free full text). Proceedings of the National Academy of Sciences of the United States of America 99 (21): 13926–31. doi:10.1073/pnas.162468699. ISSN 0027-8424. PMID 12242329. PMC 129799. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12242329. 
25. ^ Kis, B; Snipes, Ja; Busija, Dw (Oct 2005). "Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties" (Free full text). The Journal of pharmacology and experimental therapeutics 315 (1): 1–7. doi:10.1124/jpet.105.085431. ISSN 0022-3565. PMID 15879007. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15879007. 

External links

• US National Library of Medicine: MedlinePlus Drug Information: Anti-inflammatory Drugs, Nonsteroidal (Systemic)

v • d • e Pharmacology: Major drug groups Gastrointestinal tract/metabolism (A) stomach acid (Antacids, H2 antagonists, Proton pump inhibitors) • Antiemetics • Laxatives • Antidiarrhoeals/Antipropulsives • Anti-obesity drugs • Anti-diabetics • Vitamins • Dietary minerals Blood and blood forming organs (B) Antithrombotics (Antiplatelets, Anticoagulants, Thrombolytics/fibrinolytics) • Antihemorrhagics (Platelets, Coagulants, Antifibrinolytics) Cardiovascular system (C) cardiac therapy/antianginals (Cardiac glycosides, Antiarrhythmics, Cardiac stimulants) Antihypertensives • Diuretics • Vasodilators • Beta blockers • Calcium channel blockers • renin-angiotensin system (ACE inhibitors, Angiotensin II receptor antagonists, Renin inhibitors) Antihyperlipidemics (Statins, Fibrates, Bile acid sequestrants) Skin (D) Emollients • Cicatrizants • Antipruritics • Antipsoriatics • Medicated dressings Reproductive system (G) Hormonal contraception • Fertility agents • SERMs • Sex hormones Endocrine system (H) Hypothalamic-pituitary hormones • Corticosteroids (Glucocorticoids, Mineralocorticoids) • Sex hormones • Thyroid hormones/Antithyroid agents Infections and infestations (J, P, QI) Antibiotics (Antimycobacterials) • Antifungals • Antivirals • Antiparasitics (Antiprotozoals, Anthelmintics) • Ectoparasiticides • Intravenous immunoglobulin • Vaccines Malignant disease (L01-L02) Anticancer agents (Antimetabolites, Alkylating, Spindle poisons, Antineoplastic, Topoisomerase inhibitors) Immune disease (L03-L04) Immunomodulators (Immunostimulants, Immunosuppressants) Muscles, bones, and joints (M) Anabolic steroids • Anti-inflammatories (NSAIDs) • Antirheumatics • Corticosteroids • Muscle relaxants • Bisphosphonates Brain and nervous system (N) Anesthetics (General, Local) • Analgesics • Antimigraines • Anticonvulsants/Mood stabilizers (Lithium pharmacology) • Antiparkinson drugs Psycholeptics (Anxiolytics, Antipsychotics, Hypnotics/Sedatives) • Psychoanaleptics (Antidepressants, Stimulants) Respiratory system (R) Decongestants • Bronchodilators • Cough medicines • H1 antagonists Sensory organs (S) Ophthalmologicals • Otologicals Other ATC (V) Antidotes • Contrast media • Radiopharmaceuticals • Dressings

v • d • e Anti-inflammatory products (M01A) Pyrazolidine/Butylpyrazolidines Ampyrone · Clofezone · Kebuzone · Metamizole · Mofebutazone · Oxyphenbutazone · Phenazone · Phenylbutazone · Sulfinpyrazone Acetic acid derivatives and related substances Aceclofenac · Acemetacin · Alclofenac · Bromfenac · Bumadizone · Bufexamac · Diclofenac · Difenpiramide · Etodolac · Fentiazac · Indometacin · Ketorolac · Lonazolac · Oxametacin · Proglumetacin · Sulindac · Tolmetin · Zomepirac Oxicams Ampiroxicam · Droxicam · Lornoxicam · Meloxicam · Piroxicam · Tenoxicam Propionic acid derivatives Alminoprofen · Benoxaprofen · Dexibuprofen · Dexketoprofen · Fenbufen · Fenoprofen · Flunoxaprofen · Flurbiprofen · Ibuprofen · Ibuproxam · Indoprofen · Ketoprofen · Naproxen · Oxaprozin · Pirprofen · Suprofen · Tiaprofenic acid Fenamates Flufenamic acid · Meclofenamic acid · Mefenamic acid · Tolfenamic acid Coxibs Celecoxib · Etoricoxib · Lumiracoxib · Parecoxib · Rofecoxib · Valdecoxib Other Nabumetone · Niflumic acid · Azapropazone · Glucosamine · Benzydamine · Glycosaminoglycan · Magnesium salicylate · Proquazone · Superoxide dismutase/Orgotein · Nimesulide · Feprazone · Diacerein · Morniflumate · Tenidap · Oxaceprol · Chondroitin sulfate

v • d • e Non-steroidal anti-inflammatory drug (NSAID) products (primarily M01A and M02A, also N02BA) Salicylates Aspirin (acetylsalicylic acid) · Aloxiprin · Benorylate · Diflunisal · Ethenzamide · Magnesium salicylate · Methyl salicylate · Salsalate · Salicin · Salicylamide · Sodium salicylate Arylalkanoic acids Diclofenac · Aceclofenac · Acemetacin · Alclofenac · Bromfenac · Etodolac · Indometacin · Indometacin farnesil · Nabumetone · Oxametacin · Proglumetacin · Sulindac · Tolmetin 2-Arylpropionic acids (profens) Ibuprofen · Alminoprofen · Benoxaprofen · Carprofen · Dexibuprofen · Dexketoprofen · Fenbufen · Fenoprofen · Flunoxaprofen · Flurbiprofen · Ibuproxam · Indoprofen† · Ketoprofen · Ketorolac · Loxoprofen · Miroprofen · Naproxen · Oxaprozin · Pirprofen · Suprofen · Tarenflurbil · Tiaprofenic acid N-Arylanthranilic acids (fenamic acids) Mefenamic acid · Flufenamic acid · Meclofenamic acid · Tolfenamic acid Pyrazolidine derivatives Phenylbutazone · Ampyrone · Azapropazone · Clofezone · Kebuzone · Metamizole† · Mofebutazone · Oxyphenbutazone · Phenazone · Sulfinpyrazone Oxicams Piroxicam · Droxicam · Lornoxicam · Meloxicam · Tenoxicam · Ampiroxicam COX-2 inhibitors Celecoxib · Deracoxib‡ · Etoricoxib · Firocoxib‡ · Lumiracoxib† · Parecoxib · Rofecoxib† · Valdecoxib† Sulfonanilides Nimesulide Topically used products Bendazac · Diclofenac · Etofenamate · Felbinac · Flurbiprofen · Ibuprofen · Indometacin · Ketoprofen · Naproxen · Piroxicam · Suprofen COX-inhibiting nitric oxide donators Naproxcinod Others Fluproquazone Items listed in bold indicate initially developed compounds of specific groups. †Withdrawn drugs. ‡Veterinary use medications.

v • d • e Analgesic products (N02A, N02B) Opioids See also: Opioids template Opium & alkaloids thereof Codeine · Morphine · Opium · Laudanum · Paregoric Semi-synthetic opium derivatives Acetyldihydrocodeine · Benzylmorphine · Desomorphine · Dihydrocodeine · Dihydromorphine · Ethylmorphine · Diamorphine · Hydrocodone · Hydromorphinol · Hydromorphone · Nicocodeine · Nicodicodeine · Nicomorphine · Oxycodone · Oxymorphone · Dihydrocodeinone  · Buprenorphine · Synthetic opioids Alphaprodine · Anileridine · Butorphanol · Dextromoramide · Dextropropoxyphene · Dezocine · Fentanyl · Ketobemidone · Levorphanol · Methadone · Meptazinol · Nalbuphine · Pentazocine · Propoxyphene · Propiram · Pethidine · Phenazocine · Piminodine · Piritramide · Tapentadol · Tilidine · Tramadol · Pyrazolones Ampyrone/Aminophenazone · Metamizole · Phenazone · Propyphenazone Cannabinoids Ajulemic acid · AM404 · Cannabidiol · Cannabis · Nabilone · Tetrahydrocannabinol Anilides Paracetamol (acetaminophen) · Phenacetin · Propacetamol Non-steroidal anti-inflammatories See also: NSAIDs template Propionic acid class Fenoprofen · Flurbiprofen · Ibuprofen · Ketoprofen · Naproxen · Oxaprozin Oxicam class Meloxicam · Piroxicam Acetic acid class Diclofenac · Indometacin · Ketorolac · Nabumetone · Sulindac · Tolmetin COX-2 inhibitors Celecoxib · Rofecoxib · Valdecoxib · Parecoxib · Lumiracoxib Anthranilic acid (fenamate) class Meclofenamate · Mefenamic acid Salicylates Aspirin (Acetylsalicylic acid) · Benorylate · Diflunisal · Ethenzamide · Magnesium salicylate · Salicin · Salicylamide · Salsalate · Trisalate · Wintergreen (Methyl salicylate) Atypical, adjunct and potentiators, miscellaneous Befiradol · Bicifadine · Camphor · Clonidine · Cyclobenzaprine · Duloxetine · Flupirtine · Gabapentin · Glafenine · Menthol · Nefopam · Orphenadrine · Pregabalin · Scopolamine · Tebanicline · Trazodone · Ziconotide

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