Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity

Updated: May 30, 2020
  • Author: Timothy J Wiegand, MD; Chief Editor: Gil Z Shlamovitz, MD, FACEP  more...
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Overview

Practice Essentials

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.

For patient education information, see First Aid for Poisoning in Children and Child Safety Proofing.

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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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Etiology

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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Epidemiology

Frequency

United States

The American Association of Poison Control Centers National Poison Data System (AAPCC NPDS) recorded 105259 case mentions of NSAID ingestion and 74,507 single exposures in 2018. In the vast majority of these cases, the NSAID ingested was ibuprofen. [1]

The majority of NSAID ingestions occurred in children. There were 43,429 documented NSAID ingestions in children aged 5 years or younger. This is in contrast to only 14,861 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 2018 AAPCC NPDS Annual Report reveals that although over 100,000 NSAID ingestions are described, only 19,823 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 1706 moderate and 107 major toxicity outcomes—mainly secondary to either naproxen or ibuprofen ingestion. Four deaths resulted from NSAID ingestion: two from colchicine, one from ibuprofen, and one from an unknown NSAID. [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

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]  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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Prognosis

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. Complications of NSAIDs differ with acute ingestions and long-term therapy.

Acure complications

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. [9, 10]  Typically, these include salt and water retention. Hyperkalemia and acute kidney injury 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. [11]

Adverse effects of long-term 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. [12]  Most of the deaths reported by the ARAMIS group involved GI bleeding. [13]  Most of the remainder involved renal complications. Other considerations are as follows:

  • 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. [14]

  • 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 at any time. Medication should be stopped immediately at the first sign of rash, mouth sores, or allergic reaction (eg, swelling, itching, shortness of breath).

  • With long-term use, neurologic symptoms and urinary retention can occur. Renal effects, such as interstitial nephritis, can occur both in acute and long-term use.

  • Histamine-2 (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 the risk of subsequent serious GI complications.

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