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Toxicity, Nonsteroidal Anti-inflammatory Agents

Author: Timothy Wiegand, MD, Clinical Assistant Professor of Medicine, University of Vermont College of Medicine and Maine Medical Center; Associate Medical Director, Northern New England Poison Center
Coauthor(s): Jingjing Hu, MD, Attending Physician, Department of Internal Medicine, Maine Medical Center, Portland; Michele B Delenick, MD, Hospitalist, Maine Hospitalist Service, Department of Internal Medicine, Maine Medical Center, Portland
Contributor Information and Disclosures

Updated: Aug 17, 2009

Introduction

Background

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been prescribed extensively throughout the world. More than 70 million prescriptions for NSAIDs are written each year in the United States. With over-the-counter use included, more than 30 billion doses of NSAIDs are consumed annually in the United States alone. 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. Additionally, adverse events related to drug interactions, or exposure to vulnerable patients with disease states that predispose patients to NSAID toxicity, are common and may result in significant morbidity and mortality.  

NSAID toxicity in the setting of acute drug overdose as well as factors predisposing individuals to adverse effects from NSAIDs are described below.

Pathophysiology

More than 20 drugs fall under the category of NSAID. 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 (eg, aspirin), which irreversibly bind to COX and inhibit production for the entire life of the cell, or acetaminophen, which inhibits COX centrally. The result of NSAID-induced COX inhibition is decreased production of prostaglandins, which leads to decreased pain and inflammation. CNS, hemodynamic, pulmonary, and hepatic dysfunction may occur with certain agents, but the relationship to prostaglandin production remains uncertain. Prostaglandins are involved in maintaining GI mucosal integrity as well as regulating renal blood flow and both acute and chronic toxicity often involves the GI and renal systems.

Two isoforms of cyclooxygenase 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. COX-1 is expressed in all tissues, whereas cyclooxygenase-2 (COX-2) is induced during the inflammatory response and 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) inhibit COX-2 predominately, decreasing gastrointestinal adverse effects. Selectivity of inhibition may be lost during overdose, however.

Frequency

United States

In 2007, calls to US Poison Control Centers (as documented by the American Association of Poison Control Centers National Poison Data System [AAPCC NPDS]) included 307,590 number of case mentions with NSAIDs involved (other than salicylates). Of these calls, 205,245 cases were found to be due to single exposures. More than 100,000 NSAID calls involved co-ingestants, or more than one substance causing potential toxicity.1

Out of 79,130 case mentions for ibuprofen in the 2007 AAPCC NPDS Annual Report, 10,557 patients were treated in a health care facility. Of these patients, 537 patients were described as having moderate toxicity and 35 patients developed major toxicity (categories defined below). No deaths were reported. Out of 12,620 case mentions for naproxen, 2,379 patients were treated in a health care facility. Of these patients, 175 developed moderate toxicity and 6 patients developed major toxicity from naproxen overdose/poisoning. 

In 2007, according to AAPCC NPDS data, 2 deaths were attributed to acute NSAID overdose in 2007, both secondary to massive ingestion of naproxen.1  

Profile of single-substance NSAID exposures from ...

Profile of single-substance NSAID exposures from 2007 American Association of Poison Control Centers National Poison Data System (AAPCC NPDS).

Profile of single-substance NSAID exposures from ...

Profile of single-substance NSAID exposures from 2007 American Association of Poison Control Centers National Poison Data System (AAPCC NPDS).



AAPCC NPDS data are coded by outcome, as follows:

  • Outcome – None
  • Outcome – Minor toxicity:  Minimally bothersome with rapid resolution (eg, self-limited GI symptoms, drowsiness, skin irritation, sinus tachycardia without hypotension)
  • Outcome – Moderate toxicity: More pronounced, more prolonged, or more systemic in nature than minor symptoms. Usually, some form of treatment is indicated. Symptoms are not life-threatening, and the patient is without residual disability or effect (eg, acid-base disturbance, high fever, hypotension that responds to treatment, isolated brief seizures that respond to treatment).
  • Outcome – Major toxicity: Potentially life-threatening or that results in significant residual disability or disfigurement (eg, seizures with status epilepticus, respiratory compromise requiring endotracheal intubation, ventricular tachycardia with hypotension, cardiac or respiratory arrest)
  • Outcome - Death

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.

Age

Most NSAID exposures are in children younger than 6 years.


Age profile of single-substance exposures from 20...

Age profile of single-substance exposures from 2007 American Association of Poison Control Centers National Poison Data System (AAPCC NPDS).

Age profile of single-substance exposures from 20...

Age profile of single-substance exposures from 2007 American Association of Poison Control Centers National Poison Data System (AAPCC NPDS).

Clinical

History

Patient 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.  
  • Amount ingested
    • Most nonsteroidal anti-inflammatory drug (NSAID) exposures are mild-to-moderate ingestions with low levels of symptom severity including general GI symptoms such as nausea and vomiting and mild chemistry and electrolyte abnormalities that resolve rapidly with supportive care.
    • In large ingestions, some patients may develop an altered level of consciousness evolving to coma with progressive and sometimes refractory metabolic acidosis and evolving multisystem organ failure. Seizures may be involved and seen with increased frequency in certain classes of NSAIDs such as the pyrazolones and fenamates (eg, phenylbutazone and mefenamic acid, respectively).
    • Other NSAIDs are usually less toxic than those mentioned above. Doses of 100 mg/kg or less of ibuprofen, the most widely used NSAID, generally cause minimal symptoms; life-threatening situations do not typically occur until ingestions of 400 mg/kg or more.
  • Time of ingestion
    • Nomograms that correlate time and amount of drug ingested are not reliable for predicting outcome.
    • Patients with recent significant ingestion of anthranilic acids derivatives (fenamates), as well as pyrazolones, require close observation for approximately 24 hours for signs of early severe poisoning.
NSAIDs and adverse drug reactions (ADRs) and drug interactions
  • NSAIDs are implicated in nearly 25% of all adverse drug reactions, with the most commonly reported effects being GI irritation. NSAIDs increase the relative risk of gastrointestinal hemorrhage by approximately 3-fold, although estimations as high as 10-fold have been reported in the literature.2 The second most common type of adverse effect occurring with NSAID use involves the renal system. In the setting of high angiotensin and low intravascular flow (eg, congestive heart failure, cirrhosis, or dehydration), NSAID-induced decrease in prostaglandins leads to a decrease in renal blood flow and subsequently the glomerular filtration rate. Retention of salt, water, and potassium may ensue. Congestive heart failure may be exacerbated by concomitant use of NSAIDs.3
  • 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 considered and is based on the history and examination findings. In general, patients with NSAID overdose are asymptomatic or have mild GI upset (dyspepsia, nausea, vomiting, and abdominal pain). At higher doses, patients may exhibit CNS symptoms, including drowsiness, lethargy, ataxia, and nystagmus. Massive overdoses may cause the patient to present comatose with refractory acidosis and multisystem organ failure. Co-ingestants should be considered in any drug overdose.
  • Any individual presenting with a history of NSAID overdose should have a serum acetaminophen level obtained.

Physical

  • 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 if the patient presents with worsening heart failure.
  • Central nervous system (CNS)
    • Myoclonus, muscle twitching, or seizures are characteristic (but not specific) of symptomatic massive overdose. Seizures may be focal or general. In one series, 20% of 54 patients who developed abnormal neuromuscular activity described as, "twitching" developed seizures (generalized, grand mal [tonic-clonic]).4
    • Mild CNS symptoms may be nonspecific such as headache. 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.
  • Pulmonary: 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.
  • In a retrospective case series of 126 patients with ibuprofen overdose, 19% of patients developed symptoms, predominantly CNS depression and GI upset, typically within 4 hours. In a prospective study of 45 adults and 39 pediatric patients, all patients who became ill did so within 4 hours. In this study, coma, apnea, and/or metabolic acidosis occurred in 9% of adults and 5% of children. Ingestions of more than 400 mg/kg of ibuprofen are associated with seizures, apnea, hypotension, bradycardia, metabolic acidosis, and renal and hepatic dysfunction.5
  • Poisoning by acute overdose of specific NSAIDs is best addressed by considering each of the 7 chemical classifications (including salicylates). Fenamates and pyrazolones (eg, phenylbutazone) are the most toxic and should be managed most aggressively.

Table 1. Chemical Classifications of NSAIDs

Open table in new window

Table
NSAID Drug ClassMaximum Daily DoseHalf-LifeCommentsClinical Symptoms
Salicylates
Examples:
Aspirin and other salicylates, eg, sodium or magnesium salicylate (not covered in this article), diflunisal (Dolobid) – not metabolized to salicylic acid
1500 mg8-12 hSalicylates: See Toxicity, Salicylate for discussion of acetylsalicylic acid toxicitySalicylates: See Toxicity, Salicylate
Diflunisal: 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.
Pyrazolones
Examples:
Phenylbutazone
600 mg50-100 hPyrazolones:  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), 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.
Although the pyrazolones have been withdrawn from the market, phenylbutazone is available from veterinary sources and from other countries (eg, it has presented in southwestern United States)
Fenamates (anthranilic acids)
Examples:
Meclofenamate (Meclomen), mefenamic acid (Ponstel)
1000 mg2 hThese drugs have not been studied thoroughly, but they have caused vomiting, diarrhea, muscle twitching, and seizures. Most patients recover completely within 24 h.Myoclonus, muscle twitching, or seizures are characteristic of symptomatic overdose. Seizures may be focal or general. In one series, 20% of 54 patients who developed abnormal neuromuscular activity described as, "twitching" developed seizures (generalized, grand mal, tonic-clonic).
Acetic acids
Examples:
Diclofenac (Voltaren),
etodolac(Lodine),
indomethacin (Indocin),
ketorolac (Toradol),
sulindac (Clinoril)
PO ketorolac daily dosage limit is 40 mg.  Ketorolac should not be administered for longer than 5 days in a row.Typically 8-30 hSulindac is a prodrug. Peak concentrations may be delayed 2-5 h.  Sulindac overdoses are very rare, but case reports have shown effects on renal function. Indomethacin poisoning can cause headache, lethargy, disorientation, seizure, nausea, vomiting, and GI bleeding. Seizures were reported in the case of a 6-year-old who ingested, "a bottle" of indomethacin.
Diclofenac can cause nausea, vomiting, tinnitus, hallucinations, and acute renal failure (3 cases).
COX-2 inhibitors
Examples:
Celecoxib
400 mg -celecoxib3-11 hConsidered to be relatively safeOnly available Cox-2 inhibitor in the US
Propionic acids Examples:
Ibuprofen (Motrin, Advil), naproxen (Naprosyn, Anaprox), carprofen (Rimadyl), ketoprofen (Orudis)
For ibuprofen- 3200 mg and T1/2 3 h
For naproxen-
1500 mg and T1/2 12-17 h
 Severe toxicity  reported mainly in children and can occur in ingestions of 400 mg/kg or more; symptoms include seizures, apnea, hypertension, and renal and hepatic dysfunctionHeadache, tinnitus, drowsiness, nausea, vomiting, and abdominal pain are the most common symptoms, and commonly appear within 4 h of ingestion.
In a retrospective case series of 126 patients with ibuprofen overdose, 19% of patients developed symptoms, predominantly CNS depression and GI upset, typically within 4 h. In a prospective study of 45 adults and 39 pediatric patients, all patients who became ill did so within 4 h. In this study, coma, apnea, and/or metabolic acidosis occurred in 9% of adults and 5% of children. Ingestions of more than 400 mg/kg of ibuprofen are associated with seizures, apnea, hypotension, bradycardia, metabolic acidosis, and renal and hepatic dysfunction.
Oxicams Examples:
Piroxicam (Feldene)
20 mg45-50 h Occasionally, these NSAIDs can cause dizziness, blurred vision, seizures, and coma.
NSAID Drug ClassMaximum Daily DoseHalf-LifeCommentsClinical Symptoms
Salicylates
Examples:
Aspirin and other salicylates, eg, sodium or magnesium salicylate (not covered in this article), diflunisal (Dolobid) – not metabolized to salicylic acid
1500 mg8-12 hSalicylates: See Toxicity, Salicylate for discussion of acetylsalicylic acid toxicitySalicylates: See Toxicity, Salicylate
Diflunisal: 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.
Pyrazolones
Examples:
Phenylbutazone
600 mg50-100 hPyrazolones:  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), 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.
Although the pyrazolones have been withdrawn from the market, phenylbutazone is available from veterinary sources and from other countries (eg, it has presented in southwestern United States)
Fenamates (anthranilic acids)
Examples:
Meclofenamate (Meclomen), mefenamic acid (Ponstel)
1000 mg2 hThese drugs have not been studied thoroughly, but they have caused vomiting, diarrhea, muscle twitching, and seizures. Most patients recover completely within 24 h.Myoclonus, muscle twitching, or seizures are characteristic of symptomatic overdose. Seizures may be focal or general. In one series, 20% of 54 patients who developed abnormal neuromuscular activity described as, "twitching" developed seizures (generalized, grand mal, tonic-clonic).
Acetic acids
Examples:
Diclofenac (Voltaren),
etodolac(Lodine),
indomethacin (Indocin),
ketorolac (Toradol),
sulindac (Clinoril)
PO ketorolac daily dosage limit is 40 mg.  Ketorolac should not be administered for longer than 5 days in a row.Typically 8-30 hSulindac is a prodrug. Peak concentrations may be delayed 2-5 h.  Sulindac overdoses are very rare, but case reports have shown effects on renal function. Indomethacin poisoning can cause headache, lethargy, disorientation, seizure, nausea, vomiting, and GI bleeding. Seizures were reported in the case of a 6-year-old who ingested, "a bottle" of indomethacin.
Diclofenac can cause nausea, vomiting, tinnitus, hallucinations, and acute renal failure (3 cases).
COX-2 inhibitors
Examples:
Celecoxib
400 mg -celecoxib3-11 hConsidered to be relatively safeOnly available Cox-2 inhibitor in the US
Propionic acids Examples:
Ibuprofen (Motrin, Advil), naproxen (Naprosyn, Anaprox), carprofen (Rimadyl), ketoprofen (Orudis)
For ibuprofen- 3200 mg and T1/2 3 h
For naproxen-
1500 mg and T1/2 12-17 h
 Severe toxicity  reported mainly in children and can occur in ingestions of 400 mg/kg or more; symptoms include seizures, apnea, hypertension, and renal and hepatic dysfunctionHeadache, tinnitus, drowsiness, nausea, vomiting, and abdominal pain are the most common symptoms, and commonly appear within 4 h of ingestion.
In a retrospective case series of 126 patients with ibuprofen overdose, 19% of patients developed symptoms, predominantly CNS depression and GI upset, typically within 4 h. In a prospective study of 45 adults and 39 pediatric patients, all patients who became ill did so within 4 h. In this study, coma, apnea, and/or metabolic acidosis occurred in 9% of adults and 5% of children. Ingestions of more than 400 mg/kg of ibuprofen are associated with seizures, apnea, hypotension, bradycardia, metabolic acidosis, and renal and hepatic dysfunction.
Oxicams Examples:
Piroxicam (Feldene)
20 mg45-50 h Occasionally, these NSAIDs can cause dizziness, blurred vision, seizures, and coma.


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.

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References
Further Reading

References

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Further Reading

Tai WW. Nonsteroidal anti-inflammatory drugs. In: Olson KR, ed. Poisoning and Drug Overdose. 5. New York, NY: Lange Medical Books and McGraw-Hill; 2007:284-287.

Belson MT, Watson WA. Nonsteroidal anti-inflammatory drugs. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin NA, Nelson LS, eds. Goldfrank's Toxicologic Emergencies. 8. New York, NY: McGraw-Hill; 2006:573-579.

Keywords

NSAIDs toxicity, NSAIDs poisoning, nonsteroidal anti-inflammatory drugs overdose, NSAIDs, pyrazolones, fenamate, diflunisal, acetic acid derivatives, propionic acid derivatives, oxicams, mefenamic acid, Ponstel, meclofenamate, Meclomen, phenylbutazone, Butazolidin, diflunisal, Dolobid, diclofenac, Voltaren, indomethacin, Indocin, sulindac, Clinoril, etodolac, Lodine, ketorolac, Toradol, nabumetone, Relafen, tolmetin, Tolectin, ibuprofen, Motrin, fenoprofen, Nalfon, flurbiprofen, Ansaid, carprofen, Rimadyl, ketoprofen, Orudis, naproxen, Anaprox, Naprosyn, piroxicam, Feldene

Contributor Information and Disclosures

Author

Timothy Wiegand, MD, Clinical Assistant Professor of Medicine, University of Vermont College of Medicine and Maine Medical Center; Associate Medical Director, Northern New England Poison Center
Timothy Wiegand, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, American College of Physicians, and Maine Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Jingjing Hu, MD, Attending Physician, Department of Internal Medicine, Maine Medical Center, Portland
Disclosure: Nothing to disclose.

Michele B Delenick, MD, Hospitalist, Maine Hospitalist Service, Department of Internal Medicine, Maine Medical Center, Portland
Michele B Delenick, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Medical Editor

Lance W Kreplick, MD, MMM, FAAEM, FACEP, Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC
Lance W Kreplick, MD, MMM, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Chair, Department of Emergency Medicine, Director of Medical Toxicology - Allegheny General Hospital, Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

 
 
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