NSAIDs relieve pain by blocking the effects of prostaglandins. Prostaglandins are substances synthesized from arachidonic acid, a fatty acid associated with cell membranes. The synthesis of prostaglandins from arachidonic acid is catalyzed by the cyclooxygenase or "COX" enzyme.

NSAIDS inhibit the normal enzymatic action of the COX molecule. There are two important forms of cyclooxygenase: COX-1 and COX-2.

• COX-1 has been identified in most tissues. The prostaglandins it produces contribute to tissue homeostasis, cytoprotection and cell-to-cell communication.
• COX-2 derived prostaglandins are found at sites of injury and inflammation. Their production is thought to induce and exacerbate the inflammatory process, in addition to sensitizing pain receptors.

Non-selective forms of NSAIDs block the action of both the COX-1 and COX-2 enzymes throughout the body. Unfortunately, inhibiting the COX-1 enzyme can produce potential life threatening complications, particularly in the gastrointestinal tract. In the GI tract, the prostaglandins have an important role in protecting the lining of structures and organs such as the esophagus, stomach, and intestine. When this protection is lost, the patient has an increased risk of a potentially life threatening GI bleed or gastrointestinal erosion and perforation. To reduce this risk, newer forms of NSAIDs, known as "selective" NSAIDs or "COX-2 inhibitors", are now used. They are especially used for long term NSAID use and/or for patients who are at risk of NSAID induced gastrointestinal problems. NSAIDs that selectively inhibit the COX-2 enzyme include Celecoxib (Celebrex), Rofecoxib (Vioxx), and Valdecoxib (Bextra).

Please note: On September 30, 1004, the Food and Drug Administration announced that Vioxx is being voluntarily withdrawn from the market by Merck & Co., the drug's manufacturer. The FDA also issued a Public Health Advisory to inform patients of this action and to advise them to consult with a physician about alternative medications. The drug is being withdrawn after safety data monitoring showed an increased risk of heart attack and stoke among patients taking Vioxx. The FDA reports that it will also monitor other COX-2 NSAIDs for similar adverse effects.

Source:Accessed 10/14/04: FDA Issues Public Health Advisory on Vioxx as Its Manufacturer Voluntarily Withdraws the Product. (2004). FDA News. U.S. Food and Drug Administration. http://www.fda.gov/bbs/topics/news/2004/NEW01122.html

Examples of non-selective NSAIDs:

Aspirin
Diclofenac (Voltaren, Athrotec)
Diflunisal (Dolobid)
Etodolac (Lodine)
Fenoprofen (Nalfon)
Flurbiprofen (Ansaid)
Ibuprofen (Motrin, Advil)
Indomethacin (Indocin)
Ketoprofen (Orudis, Orudis KT)
Ketorolac (Toradol)
Mechofenamate (Meclomen)
Mefanamic acid (Ponstel)
Meloxicam (Mobic)
Nabumetone (Relafen)
Naproxyn (Naprosyn, Aleve)
Oxaproxin (Daypro)
Piroxicam (Feldene)
Sulindac (Clinoril)
Tolmetin (Tolectin)

Selective (COX-2) NSAIDs:

Celecoxib (Celebrex)
Rofecoxib (Vioxx)
Valdecoxib (Bextra)

Uses, dosages and routes:

Nonopioid analgesics are used for a wide variety of acute and chronic painful conditions that cause pain of mild to moderate intensity. If a patient is experiencing mild pain, he or she may be given a nonopioid analgesic alone. For severe pain, a nonopioid analgesic may be combined with an opioid analgesic as part of a comprehensive analgesic plan. A basic principle of analgesic therapy is that whenever pain is severe enough to require an opioid analgesic, adding a nonopioid analgesic should be considered. Nonopioids are frequently used to help relieve nociceptive pain, especially muscle and joint pain.

• Lortab "5/500" (hydrocodone 5 mg and acetaminophen 500 mg)
• Percocet (oxycodone 5 mg and acetaminophen 325 mg)
• Tylenol # 3 (codeine 30 mg and acetaminophen 300 mg)
• Vicodin (hydrocodone 5 mg and acetaminophen 500 mg)
  

One of the disadvantages of opioid/nonopioid combinations is that the analgesic ceiling for acetaminophen limits the number of tablets an individual can take. The analgesic ceiling for acetaminophen is 4000 mg daily. Doses that exceed that level significantly increase the risk of liver damage. For example, if a patient is taking Vicodin, to avoid exceeding the maximum daily dose of acetaminophen, the patient cannot take more than 8 Vicodin tablets per day. Combining two NSAIDs increases the risk of side effects and drug interactions, so combinations of NSAIDs are not recommended. However, the small daily aspirin dose used for preventing a heart attack does not appear to increase combined NSAID risk.

Preventing and treating NSAID side effects:

Although acetaminophen and many NSAIDs can be purchased over-the-counter, their long-term use can result in serious side effects. In fact, side effects from long-term use of NSAIDs are more severe and potentially life threatening than regular doses of morphine or other opioid analgesics.

The most common side effect of opioid analgesics is constipation, as compared to NSAIDs, which can cause gastric ulcers, bleeding and perforation, increase bleeding time, and result in renal insufficiency. The nonopioid acetaminophen can cause serious hepatotoxicity. Gastrointestinal side effects associated with NSAID use can be both local and systemic.

• Local effects occur due to local irritation from an NSAID taken by mouth. Symptoms may include heartburn and upper abdominal pain. These symptoms often occur early in therapy. Local symptoms may be resolved by lowering the dose, changing to another NSAID, taking an enteric form of an NSAID and by taking each NSAID dose with food or a large glass of water.
• Systemic effects can be extremely serious. Regardless of the route of administration, NSAIDs (with the exception of the selective or COX-2 inhibiting drugs) interfere with prostaglandin synthesis throughout the entire body. Maintenance of the protective barrier in the gastrointestinal tract depends on normal prostaglandin synthesis. When this barrier is disrupted by a nonselective NSAID that interferes with prostaglandin synthesis, the patient is at risk of adverse events such as perforation and hemorrhage of the esophagus, stomach, and the small or large intestine. These potentially life-threatening side effects can occur at any time during therapy, most often without any warning signs. Enteric-coated NSAIDs, food, or antacids do not protect the patient from the risk of systemic side effects.
  
  Some patients are at higher than normal risk of experiencing life-threatening gastrointestinal complications from taking NSAIDs. Those individuals at highest risk include those who have the following characteristics:
  

• A prior history of an NSAID induced ulcer
• Previous gastric ulcer disease
• Older age (over 60)
• Concomitant corticosteroid or anticoagulant therapy
• Consuming high doses of an NSAID
• Individuals who are unlikely to survive a major gastrointestinal complication
  

To minimize the risk of gastrointestinal complications, NSAIDs should be used at the lowest effective dose for the shortest time they are needed. In addition, alcohol use while taking NSAIDs should be restricted. Patients taking NSAIDs should be advised to eat regularly and to avoid fasting because fasting can increase toxicity. Nonselective NSAIDs are inexpensive and usually appropriate for short term or intermittent use. For patients who use NSAIDs on a regular basis, the more expensive but safer selective NSAIDs may be more appropriate.

Patients who are at high risk of adverse gastrointestinal complications are preferably given drugs such as misoprostal (Cytotec), that help protect the gastrointestinal tract from the effects of NSAIDs. NSAIDs can also cause liver damage, which is usually detected by an increase in liver enzymes. Both nonselective and selective NSAIDs can cause renal insufficiency. Therefore, patients who take NSAIDs should be monitored carefully for renal impairment. Signs of renal insufficiency may include the sudden development of oliguria with sodium and water retention. NSAIDs can also cause some central nervous system (CNS) side effects, such as a decreased attention span or loss of short-term memory. Because nonselective NSAIDs interfere with normal bleeding time, they should be discontinued several days to one week before any surgical procedure. Selective NSAIDs do not decrease platelet aggregation. As a result, they can be used perioperatively and in other clinical situations in which bleeding is a concern.

• Don’t take an NSAID with alcohol.
• Don’t take more than one type of NSAID, with the exception of a small daily dose of aspirin for heart attack prevention.
• Take NSAIDs with a full glass of water or milk, with meals, or with a prescribed antacid. Remain upright 30 minutes after administration to reduce gastric irritation or ulcer formation.
• Unless contraindicated, drink 2-3 L of water a day.
• Report any changes in stool consistency or symptoms of gastrointestinal irritation, any bleeding episodes, ringing in the ears, skin rashes, sudden weight gain and decreased urine output, fever or increased joint pain.
• Use caution when operating machinery or when driving a car, as NSAIDs may cause dizziness or drowsiness.
• If the individual is a diabetic, he or she should be aware of interactions between specific NSAIDs and hypoglycemic agents.
• Notify all healthcare providers of all medications taken to avoid adverse drug interactions.
• Keep all medications, both prescription and over-the-counter, in a safe place out of the reach of children.