Nonsteroidal Anti-inflammatory Agent Toxicity Follow-up

  • Author: Timothy J Wiegand, MD; Chief Editor: Asim Tarabar, MD   more...
 
Updated: May 20, 2010
 

Further Inpatient Care

  • Consider admission for all significant ingestions of phenylbutazone, mefenamic acid (Ponstel), and meclofenamate (Meclomen), whether symptomatic or not.
  • Symptomatic patients with ingestion of the less toxic NSAIDs (eg, ibuprofen) should be observed for 6 hours and may be safely discharged (or cleared for psychiatric assessment in cases of intentional overdose) if there is no evidence of toxicity (eg, GI symptoms, change of mental status, acidosis).
  • Patients with signs of GI bleeding, such as 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.
  • Psychiatric evaluation is necessary for intentional ingestions.
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Further Outpatient Care

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

  • Acute ingestions and adverse effects in chronic therapy
    • With acute ingestion, GI symptoms typically predominate, with dyspepsia being the most common. Peptic ulceration and its complications are relatively rare. Gastrointestinal adverse effects are due to inhibitory action on cyclooxygenase. Risk of adverse GI effect increases with increased dose and duration of NSAID therapy as well as with age, history of previous GI ulcers or bleeding, presence of untreated H pylori, concurrent use of anticoagulants, SSIRs, and glucocorticoids. Hepatotoxicity is uncommon, although transient elevation of hepatic transaminase levels may occur.
    • Renal effects are the second most common problem. Typically, these include salt and water retention. Hyperkalemia and acute renal failure are less common and 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.
    • Concomitant use with aspirin may negate the beneficial cardiovascular effects of aspirin. NSAIDs can exacerbate underlying hypertension and heart failure.
    • Dermatologic lesions include generalized exanthems, pruritus, and, rarely, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
    • Hematologic complications are rare but have been described. Accounts of patients with subsequent aplastic anemia, agranulocytosis, hemolytic anemia, neutropenia, and thrombocytopenia exist.
    • CNS effects are 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. With chronic use, urinary retention can occur. Aseptic meningitis has been reported secondary to NSAIDs.[7]
  • Chronic therapy
    • Many practitioners prescribe NSAIDs regularly for treatment of chronic conditions such as osteoarthritis and rheumatoid arthritis, 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.[8] Most of the remainder involved 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.[9]
    • 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 take 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 urinary retention can occur. Renal effects, such as interstitial nephritis, can occur both in 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.
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Patient Education

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Contributor Information and Disclosures
Author

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, and American College of Physicians

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.

Specialty Editor Board

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 and American College of Physician Executives

Disclosure: Nothing to disclose.

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  Director of Medical Toxicology, Allegheny General Hospital

Disclosure: Nothing to disclose.

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, 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

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Neesha Suresh Desai, MD, MPH, Gregory S Johnston, MD, Carlyn Ko, MD, and Fred Tilden, MD, to the development and writing of this article.

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Profile of single-substance NSAID exposures from 2007 American Association of Poison Control Centers National Poison Data System (AAPCC NPDS).
Age profile of single-substance exposures from 2007 American Association of Poison Control Centers National Poison Data System (AAPCC NPDS).
Table 1. Chemical Classifications of NSAIDs
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, 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 dysfunction Headache, 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 hOccasionally, these NSAIDs can cause dizziness, blurred vision, seizures, and coma.
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