Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity

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 selective NSAIDs (eg, celecoxib) inhibit COX-2 predominantly, decreasing GI adverse effects. Selectivity of inhibition may be lost during overdose, however.

Frequency

United States

The American Association of Poison Control Centers National Poison Data System (AAPCC NPDS) recorded 65,805 single exposures to NSAIDs in 2021. In the vast majority of these cases, the NSAID ingested was ibuprofen. ^[3]

The majority of NSAID ingestions occurred in children. There were 32,666 documented NSAID ingestions in children aged 5 years or younger. This is in contrast to only 14,768 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. ^[3]

The 2021 AAPCC NPDS Annual Report reveals that only 20,549 exposures 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 1931 moderate and 154 major toxicity outcomes—mainly secondary to either naproxen or ibuprofen ingestion. Fatalities from NSAID ingestion included four deaths from ibuprofen, one from naproxen, and 2 from other types of NSAIDs. ^[3]

AAPCC NPDS outcomes are defined as follows:

• 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 resulting in significant residual disability or disfigurement (eg, seizures with status epilepticus, respiratory compromise requiring endotracheal intubation, ventricular tachycardia with hypotension, cardiac or respiratory arrest)

Race-, Sex-, and Age-related Demographics

No scientific evidence has demonstrated that outcomes of NSAID toxicity vary by race or sex. According to the AAPCC NPDS, the majority of NSAID ingestions occur in children, typically age 5 years or younger. ^[3]  A review of AAPCC data from 2004 to 2013 found that of teenagers who attempted suicide by medication overdose, 9% had taken ibuprofen. ^[4]

Both acute and chronic poisoning with NSAIDs can result 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. ^[5] Gastrointestinal (GI), renal, central nervous system (CNS), hematologic, and dermatologic symptoms may ensue. Complications of NSAIDs differ with acute ingestions and long-term therapy.

The US Food and Drug Administration (FDA) advises that NSAID use increases the risk of myocardial infarction (MI) or stroke. ^[6] Details are as follows:

• The risk can occur as early as the first weeks of using an NSAID, but may increase with longer use.
• The risk appears greater at higher doses.
• All NSAIDs may not pose a similar risk, but current data are insufficient for determining the relative risk of any particular NSAID.
• NSAIDs can increase the risk of MI or stroke in patients without heart disease or risk factors for heart disease, but those with heart disease or risk factors for it are at greater risk.
• In patients who have experienced a first MI, treatment with NSAIDs increases the risk of death in the first year afterward.
• NSAID use is also associated with increased risk of heart failure.

Acure complications

With acute ingestion, GI symptoms typically predominate, with dyspepsia being the most common. Peptic ulceration and its complications are relatively rare. 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 Helicobacter pylori infection, and concurrent use of anticoagulants, selective serotonin reuptake inhibitors (SSRIs), ^[7] and glucocorticoids. Hepatotoxicity is uncommon, although transient elevation of hepatic transaminase levels may occur. ^[8]

Renal effects are the second most common problem. ^[9] 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 (SJS) and toxic epidermal necrolysis (TEN). An analysis of the FDA's Adverse Event Reporting System (FAERS) database from 2004-2001 found 3489 cases of NSAIDs linked to SJS or TEN. This represented the second most common class of drugs associated with these disorders. ^[10] Within the NSAID class of drugs, oxicams (piroxicam, meloxicam, tenoxicam) have the highest risk of causing SJS or TEN. ^{[11, 12]}

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 long-term use, urinary retention can occur. Aseptic meningitis has been reported secondary to NSAIDs. ^[13]

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 people take these drugs assuming there is no real chance of damage.

The most common complications of long-term therapy with NSAIDs are gastrointestinal. ^[14]  Most of the deaths reported by the ARAMIS group involved GI bleeding. ^[5]  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 adverse effects. ^[15]

• 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 SJS and TEN, 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. ^[16] Renal effects, such as interstitial nephritis, can occur with 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, but 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.

• Proton pump inhibitors (PPIs) are often given along with NSAIDs to reduce the GI effects of NSAIDs. However, while coadministration of NSAIDs and PPIs decreases adverse events involving the upper GI tract, it has been associated with an increased frequency of lower GI tract events. ^[17] In addition, a machine-learning study suggested that a potentially hepatotoxic interaction might occur with concomitant use of meloxicam and the PPI esomeprazole. ^[18]