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.
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.
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.
Epidemiology
Frequency
United States
The American Association of Poison Control Centers National Poison Data System (AAPCC NPDS) recorded 76,411 single exposures in 2019. In the vast majority of these cases, the NSAID ingested was ibuprofen. [1]
The majority of NSAID ingestions occurred in children. There were 42,980 documented NSAID ingestions in children aged 5 years or younger. This is in contrast to only 16,332 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 2019 AAPCC NPDS Annual Report reveals that only 19,792 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 1741 moderate and 152 major toxicity outcomes—mainly secondary to either naproxen or ibuprofen ingestion. Six deaths resulted from NSAID ingestion: three from colchicine, one from ibuprofen, one from indomethacin, and one from naproxen. [1]
AAPCC NPDS outcomes are defined as follows:
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None
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Minor: Minimally bothersome with rapid resolution (eg, self-limited GI symptoms, drowsiness, skin irritation, sinus tachycardia without hypotension)
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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)
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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)
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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]
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:
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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]
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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..
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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).
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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.
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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.
Tables
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). |
|
|
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|
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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. |
