How NSAIDs work:

NSAIDs inhibit the normal enzymatic action of the cyclooxygenase (COX) molecule. COX catalyzes the conversion of membrane fatty acids (principally arachidonic acid) to prostanoids and thromboxane. Arachadonic acid is a ubiquitous membrane fatty acid released in response to injury or cell-to-cell signaling (see side panel).

Prostanoids are involved in diverse inflammatory and homeostatic processes
Vasodilator, Inhibits platelet aggregation
Inflammatory & neuropathic pain

Prostanoids have a short half life. They are used within the cells that produce them or are exported from the cell affecting cells close to the site of production.

There are two important forms of cyclooxygenase, COX-1 and COX-2. Cells use the COX molecules to synthesize specific prostanoids in response to specific stimuli. It is simplistic to infer that COX-1 or COX-2 perform an either/or function but for our purposes:

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, COX-1 produces PGI2 and PGE2 that reduce acid secretion, increase blood flow and stimulate the secretion of mucus in the esophagus, stomach, and intestine. When this protection is compromised, the patient is at increased risk for potentially life threatening gastrointestinal erosion, perforation and hemorrhage.

To reduce this risk, "selective" NSAIDs or "COX-2 inhibitors", were developed and marketed. They were targeted for long term NSAID use and/or for patients who are at risk of NSAID induced gastrointestinal or bleeding problems. NSAIDs that selectively inhibit the COX-2 enzyme include celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra).

Unfortunately, while these drugs had a greater affinity for COX-2, they were subsequently found to significantly increase the risk of potentially life threatening cardiovascular (CV) events. Inhibiting COX-2 reduced production of PGI2 by vascular endothelial cells. PGI2 has been found to be a potent vasodilator and an inhibitor of platelet aggregation. The side effects associated with COX-2 inhibitors, including hypertension and thrombotic cardiovascular events, prompted the FDA to offer the following advisory:

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Selective NSAIDS block the action of the COX-2 enzyme.

Examples of non-selective NSAIDs:

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)

Indications: (Oral route)

NSAID analgesics are used for a wide variety of painful nociceptive and neuropathic conditions of mild to moderate intensity. NSAIDS are frequently used to help relieve muscle and joint pain. If a patient is experiencing mild pain, he or she may be given an NSAID analgesic alone. For moderate to severe pain, an NSAID analgesic may be combined with an opioid analgesic as part of a comprehensive analgesic plan.

Combining an opioid analgesic and a nonopioid analgesic may provide more effective pain relief than either one alone; such drug combination may inhibit both the transduction and the transmission of pain signals to the brain. Whenever pain is severe enough to require an opioid analgesic, adding a nonopioid analgesic should be considered, is a basic principle of analgesic therapy.

NSAIDs are often combined with an opioid analgesic due to their "opioid dose-sparing" effect. Opioid dose sparing refers to the fact that when a nonopioid is combined with an opioid, the opioid dose can be lowered without compromising pain relief. A lower opioid dose decreases opioid related side effects.

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NSAIDs are frequently used alone to treat severe pain.

Examples of oral NSAID/Opioid Combos:

Preventing and treating NSAID side effects:

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.

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:

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 may be 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. Cox-2 NSAIDs do not decrease platelet aggregation. As a result, Celebrex may be used perioperatively and in other clinical situations in which bleeding is a concern.

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Fasting increases the risk of NSAID toxicity.

General guidelines for using NSAIDs:
Nurses can help patients achieve the benefits of NSAIDs while reducing adverse effects by ensuring that patients follow these guidelines:

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Patients should be encouraged to combine NSAIDs for optimum pain relief.