Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity

Updated: Dec 22, 2016
  • Author: Timothy J Wiegand, MD; Chief Editor: Gil Z Shlamovitz, MD, FACEP  more...
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Overview

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 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.

 

 

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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.

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.

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Epidemiology

Frequency

United States

The American Association of Poison Control Centers National Poison Data System (AAPCC NPDS) recorded 105,545 case mentions of NSAID ingestion in 2014. Over 75% of these cases were due to single exposures (77,122 cases). In the vast majority of these cases, the NSAID ingested was ibuprofen. [1]

The majority of NSAID ingestions occurred in children. There were 47,279 documented NSAID ingestions in children aged 5 years or younger. This is in contrast to only 14,251 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 2014 AAPCC NPDS Annual Report reveals that although over 100,000 NSAID ingestions are described, only 17,885 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 1352 moderate and 85 major toxicity outcomes—mainly secondary to either naproxen or ibuprofen ingestion. There were only two deaths from NSAID ingestion, both due to ibuprofen. [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

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-, Sex-, and Age-related Demographics

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. [1]

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