Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity
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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 of the 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.
Most NSAID exposures are mild-to-moderate ingestions with low levels of symptom severity that include general gastrointestinal (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. See Presentation.
No specific antidotes for NSAID poisoning exist. Patients with significant toxicity who develop severe acidosis may require supportive treatment with intravenous sodium bicarbonate. See Treatment.
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.
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) inhibit COX-2 predominantly, decreasing gastrointestinal adverse effects. Selectivity of inhibition may be lost during overdose, however.
United States
The American Association of Poison Control Centers National Poison Data System (AAPCC NPDS) recorded 107,047 case mentions of NSAID ingestion and 77,179 single exposures in 2016. In the vast majority of these cases, the NSAID ingested was ibuprofen. [1]
The majority of NSAID ingestions occurred in children. There were 46,920 documented NSAID ingestions in children aged 5 years or younger. This is in contrast to only 14,352 ingestions in adults 20 years or older. Perhaps predictably, given that young children account for the majority of cases, most of the ingestions were documented as unintentional. [1]
The 2016 AAPCC NPDS Annual Report reveals that although over 100,000 NSAID ingestions are described, only 19,438 resulted in treatment in a healthcare facility, perhaps owing to the benign nature of most NSAID adverse effects. Of these individuals who received treatment, the majority had either no significant health outcome or only minor outcomes (see below for further definition of outcomes). However, there were 1680 moderate and 112 major toxicity outcomes—mainly secondary to either naproxen or ibuprofen ingestion. Nine deaths resulted from NSAID ingestion: five from colchicine, three from ibuprofen, and one from naproxen. [1]
AAPCC NPDS outcomes are defined as follows:
None
Minor: Minimally bothersome with rapid resolution (eg, self-limited GI symptoms, drowsiness, skin irritation, sinus tachycardia without hypotension)
Moderate: 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)
Major: 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)
Death
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).
No scientific evidence has demonstrated that outcomes of NSAID toxicity are based on race or sex. According to the AAPCC NPDS, the majority of NSAID ingestions occur in children, typically age 5 years or younger. [2] A review of AAPCC data from 2004 to 2013 found that of teenagers who attempted suicide by medication overdose, 9% had taken ibuprofen. [2]
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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].
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].
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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].
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NSAID Drug Class
Maximum Daily Dose
Half-Life
Comments
Clinical 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 mg
8-12 h
Salicylates: See Toxicity, Salicylate for discussion of acetylsalicylic acid toxicity
Salicylates: 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 mg
50-100 h
Pyrazolones: 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 mg
2 h
These 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 h
Sulindac 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 -celecoxib
3-11 h
Considered to be relatively safe
Only 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 mg
45-50 h
Occasionally, these NSAIDs can cause dizziness, blurred vision, seizures, and coma.
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.
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 and Medical Toxicology, Excela Health System
Fred Harchelroad, MD, FACMT, FAAEM, FACEP is a member of the following medical societies: American College of Medical Toxicology
Disclosure: Nothing to disclose.
Gil Z Shlamovitz, MD, FACEP Associate Professor of Clinical Emergency Medicine, Keck School of Medicine of the University of Southern California; Chief Medical Information Officer, Keck Medicine of USC
Gil Z Shlamovitz, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association
Disclosure: Nothing to disclose.
Lance W Kreplick, MD, FAAEM, MMM, UHM Staff Physician for Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC
Lance W Kreplick, MD, FAAEM, MMM, UHM is a member of the following medical societies: American Academy of Emergency Medicine, American Association for Physician Leadership
Disclosure: Nothing to disclose.
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.
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.
Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity
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