AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been prescribed extensively throughout the world. More than 30 billion NSAIDs are consumed annually in the US alone. For the most part, the most commonly ingested NSAIDs have few toxic effects, even when taken in significant quantities; however, with the numbers of both prescriptions and consumption of over-the-counter (OTC) NSAIDs increasing every year, so do the numbers of overdoses and NSAID-related complications reported to poison control centers around the country.

Pathophysiology

More than 20 drugs fall under the category of NSAID, and the major effect of all NSAIDs is to decrease the synthesis of prostaglandins by reversibly inhibiting cyclooxygenase (COX), an enzyme that catalyzes the formation of prostaglandins and thromboxanes from the precursor, arachidonic acid. This is in contrast to salicylates, which irreversibly bind to COX and inhibit production for the entire life of the cell. Prostaglandins enhance the inflammatory response and renal blood flow, and offer cytoprotection of GI mucosa.

Two isoforms of cyclooxygenases have been identified. Cyclooxygenase-1 (COX-1) has been proposed to generate prostaglandins that maintain organ function, protect the integrity of the gastric mucosa, and generate platelet-derived thromboxane responsible for platelet aggregation and vasoconstriction, and is expressed in all tissues, whereas cyclooxygenase-2 (COX-2), induced during the inflammatory response, produces prostaglandins that mediate pain and inflammation. COX-2 is also expressed in kidneys and vascular endothelium. Classic older NSAIDs (eg, ibuprofen) inhibit COX-1 more than COX-2, whereas the newer class of NSAIDs (eg, celecoxib, valdecoxib, rofecoxib) inhibits COX-2 predominately, decreasing gastrointestinal adverse effects.

Frequency

United States

The 2004 report from the American Association of Poison Control Centers (AAPCC) documents 71,000 toxic exposures to ibuprofen, of which, 19,000 were treated in healthcare facilities. Thirteen deaths were reported.

Mortality/Morbidity

Both acute and chronic poisoning with NSAIDs results in significant morbidity and mortality. The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) system has estimated that more than 100,000 hospitalizations and more than 16,000 deaths in the United States each year are due to NSAID-related complications with costs greater than $2 billion. Gastrointestinal (GI), renal, central nervous system (CNS), hematologic, and dermatologic symptoms may ensue (see Complications).

Race

No scientific evidence has demonstrated that outcomes of NSAID toxicity are based on race.

Sex

No scientific evidence has demonstrated that outcomes of NSAID toxicity are based on sex.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Agent ingested
• • The most toxic effects are reported after ingestion of phenylbutazone (Butazolidin), mefenamic acid (Ponstel), and meclofenamate sodium (Meclomen); however, all NSAIDS can have untoward effects.
  • Other NSAIDs are usually less toxic than those mentioned above. Doses of 100 mg/kg or less of ibuprofen, the most widely utilized NSAIDs, generally cause minimal symptoms; life-threatening situations typically occur with ingestions of 400 mg/kg or more.
• Amount ingested: The correlation between quantity ingested and toxic poisonings is poor; however, serious effects have occurred with more than 4 g of phenylbutazone, 6 g of mefenamic acid, and 400 mg/kg of ibuprofen.
• Time of ingestion
• • Nomograms that correlate time and amount of drug ingested have not been reliable for predicting outcome.
  • However, patients with recent significant ingestion of anthranilic acids, especially pyrazolones, require close observation for approximately 24 hours for signs of early severe poisoning.
• Considerable toxicity may result from interactions between NSAIDs and oral anticoagulants, lithium, oral hypoglycemic, phenytoin, methotrexate, digoxin, or aminoglycosides.
• Co-ingestions: The possibility of co-ingestants should always be investigated, especially if the patient becomes symptomatic.

Physical

Findings are most significant with the most toxic NSAIDs, phenylbutazone, mefenamic acid, and meclofenamate. However, also watch for these findings if suspicion of any NSAID toxicity exists.

• Vital signs
• • Bradypnea or tachypnea may suggest early respiratory or metabolic acidosis.
  • NSAIDs can promote salt and water retention and can antagonize beta-blockers, diuretics, and ACE inhibitors, resulting in an elevated blood pressure.
• An S₃ gallop or marked dysrhythmia may be noted.
• Central nervous system
• • Symptoms may be nonspecific such as headache. Also, subtle mental status changes, such as difficulty concentrating or mild anxiety, may be observed. Patients with severe toxicity may be agitated and delirious, or they may be comatose to the point of requiring endotracheal intubation.
  • Patients may have tremors or muscle twitching that could portend seizures or coma.
  • Case reports have also described tinnitus and transient hearing loss after NSAID use.
• Aspirin-sensitive individuals with asthma who ingest NSAIDs may present with wheezing or respiratory arrest. The reaction may also include flushed face and/or neck, conjunctivitis, rhinorrhea, and possibly angioedema.
• Gastrointestinal
• • Although ulcers are unlikely and perforations very rare in acute overdose, patients with gastrointestinal symptoms require thorough abdominal examination.
  • A rectal examination may reveal evidence of gastrointestinal bleeding and is mandatory in any patient who presents with acute or chronic toxicity.
• Delayed effects of severe poisonings include renal failure, hepatic failure, and platelet dysfunction. Look for generalized weakness, a sallow complexion, acidosis, heart failure, jaundice, liver tenderness, petechiae, and other signs of bleeding disorders.
• The less toxic NSAIDs (eg, ibuprofen) cause the above symptoms and signs very rarely.
• Poisoning by acute overdose of specific NSAIDs is best addressed by considering each of the 6 chemical classifications. Fenamates and, especially, pyrazolones (eg, phenylbutazone), are the most toxic and should be managed most aggressively.
• • Pyrazolones - Phenylbutazone (Butazolidin), one of the most toxic NSAIDs
    • Symptoms of mild poisoning include nausea, abdominal pain, and drowsiness.
    • Severe poisoning has multisystem effects that, early on, include the GI system (eg, nausea, vomiting, diarrhea), the CNS (eg, dizziness, seizures, coma), the cardiovascular system (eg, pulmonary edema, arrest), metabolic and respiratory acidosis, and electrolyte abnormalities.
    • Delayed severe toxicity (2-7 d) includes renal, hepatic, and hematologic dysfunction.
  • Anthranilic acids - Mefenamic acid (Ponstel) and meclofenamate sodium (Meclomen)
    • These drugs have not been studied thoroughly, but they have caused vomiting, diarrhea, muscle twitching, and seizures.
    • Most patients recover completely within 24 hours.
  • Diflunisal (Dolobid)
    • This NSAID commonly causes drowsiness, vomiting, and diarrhea.
    • Hyperventilation, tachycardia, diaphoresis, tinnitus, disorientation, stupor, coma, cardiopulmonary arrest, and fatality are rarely observed and occur only with doses exceeding 15 g.
    • The lowest reported dose resulting in fatality is 15 g.
  • Acetic acid derivatives - Diclofenac sodium (Voltaren), indomethacin (Indocin), sulindac (Clinoril), etodolac (Lodine), ketorolac (Toradol), nabumetone (Relafen), and tolmetin sodium (Tolectin)
    • These medications rarely have significant toxic effects and usually cause mild symptoms.
    • Sulindac overdoses are very rare, but case reports have shown effects on renal function.
    • Indomethacin poisoning can cause headache, lethargy, disorientation, seizures, nausea, vomiting, and GI bleeding.
    • Diclofenac can cause nausea, vomiting, tinnitus, hallucinations, and acute renal failure (3 cases).
  • Propionic acid derivatives - Ibuprofen (Motrin), fenoprofen (Nalfon), flurbiprofen (Ansaid), carprofen (Rimadyl), ketoprofen (Orudis), and naproxen sodium (Anaprox, Naprosyn)
    • Information regarding these relatively new agents is sparse.
    • Headache, tinnitus, drowsiness, nausea, vomiting, and abdominal pain are the most common symptoms, and commonly appear within 4 hours of ingestion.
    • Severe toxicity is reported mainly in children and can occur in ingestions of 400 mg/kg or more; symptoms include seizures, apnea, hypertension, and renal and hepatic dysfunction.
  • Oxicams - Piroxicam (Feldene)
    • Occasionally, these NSAIDs can cause dizziness, blurred vision, seizures, and coma.
    • Salicylates: See Toxicity, Salicylate for discussion of acetylsalicylic acid toxicity.

Causes

Patients who present with acute overdose and are suicidal should be chaperoned at all times while in the emergency department and never left alone for both medical and psychological reasons. A psychiatry consult should be obtained once the patient is medically stable.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Agitated delirium

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Routine determination of plasma concentration is not clinically useful in patients with NSAID toxicity. An ibuprofen nomogram for predicting ibuprofen toxicity exists, but it has been found to be inaccurate; thus, serum levels are not warranted.
• Asymptomatic patients with no co-ingestions generally do not require serum or urine studies. However, 4 hour acetaminophen should be ordered in every patient with suspected ingestion due to the notorious lack of signs and symptoms in initial 24 hours after ingestion.
• Consider obtaining baseline renal and hepatic function tests in patients with asymptomatic ingestions of phenylbutazone, mefenamic acid, and meclofenamate.
• In symptomatic patients, consider obtaining electrolytes, renal and liver function tests, a complete blood count (CBC), platelets, and arterial blood gases (ABGs), as indicated. Lactic acid levels, as well as ketones, should be obtained in patients with acidosis. Symptomatic patients frequently develop hypomagnesemia and hypophosphatemia within a day postingestion.

Imaging Studies

• No imaging tests are necessary unless the examination suggests a perforated viscus.

Other Tests

• An electrocardiogram (ECG) is required in hyperkalemic patients and should be obtained in any patient who presents with an acute overdose to help exclude cyclic antidepressant toxicity or exposure to cardioactive drugs.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Prehospital Care

• Initial assessment requires the clinician to assess for the secure airway, breathing, and circulation (ABCs).

Emergency Department Care

Management of acute NSAID poisoning is essentially supportive and symptomatic.

• Initial stabilization: Follow the ABC protocol.
• GI decontamination
• • Avoid ipecac syrup
  • If the patient has no clinical evidence of a perforated viscous, decontaminate with activated charcoal and a cathartic. The patient should be able to protect airway (eg, normal mental status, preserved gag reflex, absence of vomiting) in order to prevent aspiration of charcoal.
• No specific antidotes for NSAID poisoning exist. Patients with significant toxicity who develops severe acidosis may require supportive treatment with intravenous sodium bicarbonate.
• Elimination enhancement
• • Because NSAIDs are highly protein bound, hemodialysis and charcoal hemoperfusion are not beneficial for overdose treatments. The drug is mostly metabolized by the liver with less than 10% excreted unchanged by the kidney. For the majority of NSAIDs, the half-life of elimination is less than 8 hours; however, the half-life is anywhere from 8-30 hours for diflunisal, nabumetone, naproxen sodium, and sulindac, and even longer (approximately 30 h) for piroxicam and phenylbutazone.
  • Hemodialysis may not help clear the drug from the blood, but it may be indicated in patients who develop acute renal failure as a complication of their ingestion.
  • Acute renal failure is usually corrected after a few days.
  • Urine alkalinization and forced diuresis are unlikely to affect the clinical outcome in poisoning with NSAIDs because the kidney excretes only a small portion of the absorbed dose unchanged.
• Seizures induced by NSAIDs tend to be short lived. H2-antagonists and proton pump inhibitors (PPIs) may prevent GI irritation, but their usefulness in this situation is unproven.

Consultations

Consult a regional poison control center or local medical toxicologist (certified through the American Board of Medical Toxicology or the American Board of Emergency Medicine) for additional information and patient care recommendations.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The goals of pharmacotherapy are to reduce morbidity, prevent complications, and reduce the toxic levels of drug.

Drug Category: GI decontaminant

May bind and limit absorption of NSAIDs from the GI tract.

Drug Category: Alkalinizing agents

Used to accelerate excretion of the drug.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• Consider admission for all significant ingestions of phenylbutazone, mefenamic acid, and meclofenamate, whether symptomatic or not.
• Symptomatic patients with ingestion of the less toxic NSAIDs (eg, ibuprofen) should be observed for 6 hours, and safely discharge if there is no evidence of toxicity (eg, GI symptoms, change of mental status, acidosis).
• Patients with GI bleeding, hematemesis, or guaiac-positive stools may require endoscopic evaluation.
• Significant alteration in level of consciousness may require endotracheal intubation and admission to a critical care unit. Significant metabolic acidosis and episodes of acute renal failure have been reported.

Further Outpatient Care

• Asymptomatic patients who have ingested a less toxic NSAID may be discharged and followed as outpatient if they are reliable.
• Psychiatric evaluation is necessary for intentional ingestions.

Deterrence/Prevention

• As with paracetamol in the United Kingdom, limits on amount of NSAID purchased at one time and differences in packaging can possibly prevent toxicity from acute ingestion of NSAIDs.
• Practitioners can also prevent toxic effects of NSAIDs by searching for alternate medications for relief of pain and inflammation or suggesting alternate methods of pain relief such as acupuncture or other physical/rehabilitation therapies. Of note, the first-line recommendation of the American Arthritis Association for the treatment of osteoarthritis (the most common type of arthritis) is acetaminophen, rather than an NSAID, due to serious side effects common with chronic NSAID use.
• Product labels warn consumers to not use two products containing the same ingredients or the same class of drug at the same time and not to exceed recommended doses.
• Patients who are already taking medications that may impair renal blood flow (eg, ACE inhibitors, cotrimoxazole) should avoid NSAIDs.

Complications

• Acute ingestions
• • With acute ingestion, GI symptoms occur the most frequently, with dyspepsia being the most common. Peptic ulceration and its complications are relatively rare.
  • Renal effects are the second most common problem. Typically, these include salt and water retention, hyperkalemia, and acute renal failure that are reversible in the most instances. Acute interstitial nephritis, nephrotic syndrome, and papillary necrosis occur much less often than other renal symptoms. Elderly persons and individuals with underlying kidney problems or decreased intravascular volume from salt loss or hypoalbuminemia are at particular risk.
  • Dermatologic lesions include generalized exanthems, pruritus, and, rarely, Stevens-Johnson syndrome and toxic epidermal necrolysis.
  • CNS effects are also relatively common with NSAID toxicity. They include changes of mood and cognition (especially in elderly persons), seizures, headaches, and hallucinations. They are most frequent with the highly lipid-soluble NSAIDs such as ibuprofen, naproxen, and ketoprofen.
  • Hematologic complications are rare but have been described. Accounts of patients with subsequent aplastic anemia, agranulocytosis, hemolytic anemia, neutropenia, and thrombocytopenia exist.
  • Other adverse effects are rare, especially with acute ingestion; they include congestive heart failure in persons at risk, dysfunctional uterine bleeding, hepatic impairment, and platelet dysfunction.
• Chronic therapy
• • Many practitioners prescribe NSAIDs regularly for treatment of chronic conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA), and acute musculoskeletal injuries. With NSAIDs readily available in pharmacies, supermarkets, even liquor stores, many patients take these drugs assuming there is no real chance of damage.
  • The most common complications of chronic therapy with NSAIDs are gastrointestinal. Most of the deaths reported by the ARAMIS group involved GI bleeding. Most of the remainder were renal complications.
  • NSAIDS should be used with caution in older patients and in those with chronic medical problems, such as diabetes and congestive heart failure, due to a significantly increased risk of serious side effects.
  • Elderly individuals are at particular risk for the adverse effects of NSAIDs. One study showed that 30-40% of all elderly persons use NSAIDs, and that 10-13% of elderly persons use NSAIDs every day.
  • Serious, potentially fatal skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, may occur, and are most likely during the first 2 weeks of therapy but can happen anytime. Medication should be stopped immediately at the first sign of rash, mouth sores, or allergic reaction (eg, swelling, itching, shortness of breath).
  • With chronic use, neurologic symptoms, such as acute urinary retention, can occur. Also renal effects, such as interstitial nephritis, can occur with acute and chronic use.
  • H2 blockers and prostaglandins have been proposed to be used concomitantly with NSAIDs to block the irritating effects on the gastric mucosa; however, no substantial studies have shown any real protection, and, in fact, use of H2 blockers can possibly increase risk of subsequent serious GI complications. The only way to decrease destruction caused by NSAIDs is to not use them.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to note and treat GI hemorrhage
• Failure to note mild mental status changes, thereby allowing early discharge, with possible development of major mental status changes (eg, coma, delirium)
• Prescribing high-dose NSAIDs to patients at high-risk of complications (eg, elderly individuals, persons with alcoholism, diabetes, or other chronic medical conditions; those with active gastric ulcer disease) or patients who are taking medications that may impair renal flow

Special Concerns

• September 30, 2004, Merck & Co, Inc, announced a voluntary withdrawal of rofecoxib (Vioxx) from the United States and worldwide market because of its association with an increased rate of cardiovascular events (including heart attacks and strokes) compared with that of placebo. The decision to withdraw rofecoxib from the market was made after halting a long-term study of the drug due to an increased risk of serious cardiovascular events, including heart attacks and strokes. The APPROVe (Adenomatous Polyp Prevention on VIOXX) trial examined the ability of rofecoxib to decrease the risk of developing recurrent colon polyps when compared with placebo.
• Additionally, a major FDA study of rofecoxib found an apparent 3-fold increase in the risk of sudden cardiac death or heart attack among patients who had taken higher doses of the drug compared with the risk of patients who had not recently received similar medication. The report showed that even patients taking the standard starting dose of 12.5 mg or 25 mg of rofecoxib had a 50% greater chance of heart attack or sudden cardiac death than patients on any dose of celecoxib (Celebrex). The large-scale study was conducted after analyzing the medical records of 1.4 million people insured by Kaiser Permanente in Oakland, Calif, between 1999 and 2001. Note: The study has inherent limitations in that it is observational, rather than randomized and controlled.
• On April 7, 2005, valdecoxib (Bextra, by Pfizer, Inc) was voluntarily withdrawn from the US market, pending further discussion with the US Food and Drug Administration (FDA). The association of valdecoxib with potentially life-threatening risks, including myocardial infarction, stroke, and serious skin reactions, initiated an investigation to determine whether the benefits of the drug outweighed the risks. In 2004, the FDA had Pfizer add a boxed, bolded warning to the prescribing information to alert healthcare professionals and patients about the serious adverse effects.
• New data regarding cardiovascular risks are also highlighted, including data from more than 1500 patients treated after coronary artery bypass graft (CABG) surgery. The patients treated with valdecoxib showed an increased cardiovascular risk compared with those treated with placebos. Observed cardiovascular events included myocardial infarction, cerebrovascular accident, deep vein thrombosis, and pulmonary embolism.
• Pfizer submitted the final report of the new CABG study to the FDA on November 5, 2004. The report confirms the risk of the intravenous form (approximately 2% of patients experienced adverse cardiovascular events) and also shows that oral valdecoxib is associated with a lower risk (approximately 1% of patients) immediately following CABG surgery. In the placebo group, about 0.5% of patients had an adverse cardiovascular event.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Carlyn Ko, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Aug 22, 2006