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Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity Differential Diagnoses

  • Author: Timothy J Wiegand, MD; Chief Editor: Asim Tarabar, MD  more...
Updated: Jun 29, 2016

Diagnostic Considerations

Other problems to consider in the differential diagnosis include the following:

Differential Diagnoses

Contributor Information and Disclosures

Timothy J Wiegand, MD Director, Ruth A Lawrence Poison and Drug Information Center, Associate Clinical Professor of Medicine and Emergency Medicine, University of Rochester Medical Center and Strong Memorial Hospital

Timothy J Wiegand, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, American College of Physicians

Disclosure: Nothing to disclose.


Constance M Vernetti, MD Resident Physician, Department of Emergency Medicine, University of Rochester Medical Center

Constance M Vernetti, MD is a member of the following medical societies: Society for Academic Emergency Medicine, Emergency Medicine Residents' Association

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and 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.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Attending Physician in Emergency Medicine, Excela Health System

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Lance W Kreplick, MD, FAAEM, MMM 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, FAAEM, MMM is a member of the following medical societies: American Academy of Emergency Medicine, American Association for Physician Leadership

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.

Neesha Suresh Desai, MD, MPH Staff Physician, Department of Emergency Medicine, New York University Hospital, Bellevue Hospital Center

Disclosure: Nothing to disclose.

Jingjing Hu, MD Attending Physician, Department of Internal Medicine, Maine Medical Center, Portland

Disclosure: Nothing to disclose.

Gregory S Johnston, MD Attending Physician, Beth Israel Medical Center

Disclosure: Nothing to disclose.

Carlyn Ko, MD Consulting Staff, Department of Emergency Medicine, Premier Healthcare

Disclosure: Nothing to disclose.

Fred Tilden, MD Consulting Staff, Department of Emergency Services, MidState Medical Center

Disclosure: Nothing to disclose.

  1. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015. 53 (10):962-1147. [Medline]. [Full Text].

  2. Laine L. Gastrointestinal safety of coxibs and outcomes studies: what's the verdict?. J Pain Symptom Manage. 2002 Apr. 23(4 Suppl):S5-10; discussion S11-4. [Medline].

  3. Riley DJ, Weir M, Bakris GL. Renal adaptation to the failing heart. Avoiding a 'therapeutic misadventure'. Postgrad Med. 1994 Jun. 95(8):153-6. [Medline].

  4. Hall AH, Smolinske SC, Conrad FL, et al. Ibuprofen overdose: 126 cases. Ann Emerg Med. 1986 Nov. 15(11):1308-13. [Medline].

  5. Balali-Mood M, Critchley JA, Proudfoot AT, Prescott LF. Mefenamic acid overdosage. Lancet. 1981 Jun 20. 1(8234):1354-6. [Medline].

  6. Marciniak KE, Thomas IH, Brogan TV, Roberts JS, Czaja A, Mazor SS. Massive ibuprofen overdose requiring extracorporeal membrane oxygenation for cardiovascular support. Pediatr Crit Care Med. 2007 Mar. 8(2):180-2. [Medline].

  7. Yuan JQ, Tsoi KK, Yang M, Wang JY, Threapleton DE, Yang ZY, et al. Systematic review with network meta-analysis: comparative effectiveness and safety of strategies for preventing NSAID-associated gastrointestinal toxicity. Aliment Pharmacol Ther. 2016 Jun. 43 (12):1262-75. [Medline].

  8. Chen HW, Chen KC, Chen JS. Colchicine and NSAID Combination Causing Acute Kidney Injury. J Coll Physicians Surg Pak. 2012 Nov. 22(11):737-9. [Medline].

  9. Gulmez SE, Larrey D, Pageaux GP, Lignot-Maleyran S, de Vries C, Sturkenboom M, et al. Methodology for a multinational case-population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT). Eur J Clin Pharmacol. 2012 Aug 10. [Medline].

  10. Rodriguez SC, Olguin AM, Miralles CP, Viladrich PF. Characteristics of meningitis caused by Ibuprofen: report of 2 cases with recurrent episodes and review of the literature. Medicine (Baltimore). 2006 Jul. 85(4):214-20. [Medline].

  11. Boelsterli UA, Redinbo MR, Saitta K. Multiple NSAID-induced hits injure the small intestine: Underlying mechanisms and novel strategies. Toxicol Sci. 2012 Oct 22. [Medline].

  12. Singh G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther. 2000 Mar. 7(2):115-21. [Medline].

  13. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med. 1996 Jul 22. 156(14):1530-6. [Medline].

  14. Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med. 2002 May 27. 162(10):1099-104. [Medline].

  15. Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet. 2008 Nov 15. 372(9651):1756-64. [Medline].

  16. Aithal GP, Day CP. Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Clin Liver Dis. 2007 Aug. 11(3):563-75, vi-vii. [Medline].

  17. Belson MT and Watson WA. Nonsteroidal Antiinflammatory Drugs. 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.

  18. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23. 343(21):1520-8, 2 p following 1528. [Medline].

  19. Bryson P. Nonsteroidal antiinflammatory agents. Comprehensive Review in Toxicology. 2nd ed. Aspen Publishers; 1989. 445-54.

  20. Colburn KK, Flores R. The Role of COX-2 Inhibitors in Emergency and Acute Care Medicine. Emergency Medicine Reports. 2000. 21(3):

  21. Garcia Rodriguez LA, Williams R, Derby LE, Dean AD, Jick H. Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med. 1994 Feb 14. 154(3):311-6. [Medline].

  22. Hillis WS. Areas of emerging interest in analgesia: cardiovascular complications. Am J Ther. 2002 May-Jun. 9(3):259-69. [Medline].

  23. Hoppmann RA, Peden JG, Ober SK. Central nervous system side effects of nonsteroidal anti-inflammatory drugs. Aseptic meningitis, psychosis, and cognitive dysfunction. Arch Intern Med. 1991 Jul. 151(7):1309-13. [Medline].

  24. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002 Jan 16. 287(3):337-44. [Medline].

  25. Konstam MA, Weir MR, Reicin A, et al. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation. 2001 Nov 6. 104(19):2280-8. [Medline].

  26. Laine L. Gastrointestinal safety of coxibs and outcomes studies: what's the verdict?. J Pain Symptom Manage. 2002 Apr. 23(4 Suppl):S5-10; discussion S11-4. [Medline].

  27. McElwee NE, Veltri JC, Bradford DC, Rollins DE. A prospective, population-based study of acute ibuprofen overdose: complications are rare and routine serum levels not warranted. Ann Emerg Med. 1990 Jun. 19(6):657-62. [Medline].

  28. Nephrotoxicity of non-steroidal anti-inflammatory drugs. Lancet. 1994 Aug 20. 344(8921):515-8. [Medline].

  29. Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol. 2005 May. 3(5):489-98. [Medline].

  30. Solomon DH, Goodson NJ. The cardiovascular system in rheumatic disease: the newest "extraarticular" manifestation?. J Rheumatol. 2005 Aug. 32(8):1415-7. [Medline].

  31. Tai, WW. Nonsteroidal Anti-inflammatory Drugs. Olson KR. Poisoning and Drug Overdose. 5. New York, NY: Lange Medical Books and McGraw-Hill; 2007. 284-287.

  32. U.S. Food and Drug Administration. Nonprescription Drugs Advisory Committee. September 2002. 19-20:[Full Text].

  33. Verhamme KM, Dieleman JP, Van Wijk MA, et al. Nonsteroidal anti-inflammatory drugs and increased risk of acute urinary retention. Arch Intern Med. 2005 Jul 11. 165(13):1547-51. [Medline].

Table 1. Chemical Classifications of NSAIDs
NSAID Drug ClassMaximum Daily DoseHalf-LifeCommentsClinical Symptoms

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.


Examples: Phenylbutazone

600 mg50-100 hPyrazolones: Phenylbutazone (Butazolidin), one of the most toxic NSAIDs

Symptoms of mild poisoning include nausea, abdominal pain, and drowsiness; no longer approved for human use in the US.

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


Diclofenac (Voltaren),


indomethacin (Indocin),

ketorolac (Toradol, Sprix),

sulindac (Clinoril)

PO ketorolac daily dosage limit is 40 mg. Not to exceed daily dose of 126 mg for intranasal ketorolac (63 mg/24 h if older than 65 y). Total cumulative ketorolac (any administration route) should not exceed 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.
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