Chapter 115: Nonsteroidal Anti-inflammatory Drugs

• Nonsteroidal anti-inflammatory drugs (NSAIDs) are relatively devoid of toxicity in the overdose setting.

• Patients who develop toxicity exhibit central nervous system or gastrointestinal (GI) toxicity.

• Overdose of NSAIDs has been associated with an anion-gap acidosis.

• Long-term use of NSAIDs is associated with nephrotoxicity, including acute tubular necrosis, acute interstitial nephritis, and acute renal failure.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic, antipyretic, and anti-inflammatory effects and are among the most commonly used drugs in the world. While acute therapeutic use is regarded as safe in most patients, adverse reactions at therapeutic doses and with chronic use has resulted in a reevaluation of its safety in recent years. The introduction and, subsequent, withdrawal of cyclooxygenase (COX)-2-selective agents have resulted a decrease in the use of these agents. Ibuprofen and naproxen are currently the only nonprescription NSAIDs available in the United States. They are also available in combination cough and cold preparations as well as the prescription combination drug, Vicoprofen® (ibuprofen and hydrocodone). Other prescription forms of NSAIDs are also available in the United States and globally.

Due to its nonprescription status and wide use, unintentional and intentional ingestions are common. The 2011 Annual Report of the American Association of Poison Control Centers listed 48 deaths in which NSAIDs were a contributing factor with 2 deaths related to a single substance (ibuprofen and colchicine). NSAIDs accounted for more than 79,000 single exposures, of which more than 65,000 were attributed to ibuprofen. As expected, children younger than 6 years had the majority of exposures with over 51,000 single exposures to NSAIDs.¹ Symptoms in the overdose setting are rare; however, severe toxicity can occur.

NSAIDs have numerous classifications including their cyclooxygenase (COX) activity, biochemical properties and pharmacologic action.(Table 115-1)² Largely, NSAIDs are similar in their biochemical characteristics in that they are relatively lipophilic, weak acids. While most are absorbed readily in the GI tract, their pharmacokinetic properties differ. Thus the clinician can select for specific indications. The duration of action and half-life guides dosing with short half-life NSAIDs (e.g., ibuprofen) administered every 6 to 8 hours and longer half-life NSAIDs (e.g., naproxen) dosed once or twice daily. Metabolism and elimination are important pharmacokinetic properties to consider when dosing NSAIDs as adverse reactions are likely to occur with hepatic and renal disorders. In addition, drug interactions can result in adverse effects when taking into account metabolism, and other substrates that can affect enzyme function.

NSAIDs have analgesic, anti-inflammatory, and antipyretic properties through its binding to the COX enzyme.³ They work by preventing the binding of arachidonic acid to the COX enzyme active site resulting in inhibition of prostaglandin synthesis. It has been found to exist in several isoforms—COX-1, COX-2, and, possibly, COX-3. COX-1 is responsible for the synthesis of prostaglandins involved in many physiologic functions including maintenance of normal renal functions, protection in the GI tract, and thromboxane-A in platelets. COX-2 can be induced by cytokines and inflammation and has a role in the development of pain, inflammation, and fever. COX-3 has been poorly elucidated but is thought to be involved in the mechanism of acetaminophen. Many NSAIDs are nonselective in their binding to the COX enzyme. Newer forms of NSAIDs have marketed as selective COX-2 inhibitors but, with the exception of celecoxib, have been removed from use due to cardiac toxicity.

The majority of NSAID overdoses result in no to few symptoms that can be managed in the home setting. Most US poison control centers are comfortable managing asymptomatic children with inadvertent ingestions of less than 200 mg/kg of ibuprofen at home. Symptomatic children, persons with intentional ingestions and children ingesting more than 200 mg/kg are referred to a health care facility to be monitored. Most patients with an ingestion of a significant amount will develop symptoms within 4 to 6 hours. Significant toxicity has occurred with ingestions of greater than 400 mg/kg of ibuprofen. However, a study of 126 patients found no correlation between the amount of medication ingested and the development of toxicity.⁴

Typically, patients who ingest NSAIDs exhibit only CNS and/or GI toxicity. Common symptoms of CNS toxicity can include drowsiness, dizziness, and lethargy.⁵ Coma has been reported with ibuprofen ingestions,^6,7 as well as with piroxicam and diflunisal.⁸ The mefenamic acid compound, has a propensity to cause seizures.⁵ Other NSAIDs associated with seizures include piroxicam, naproxen, and ketoprofen. However, all NSAIDs may have this propensity at high doses. Mild CNS depression and headache are common after overdose. Seizures and coma can occur rarely after large ingestions (>400 mg/kg). In a prospective case series of 329 patients, 30% had CNS depression.⁹ Numerous case reports and studies have documented coma in children with large doses of ibuprofen and other NSAIDs.^4,10,11 Similarly, seizures have been documented after massive ingestions in children, which may have been secondary to metabolic derangement or acute renal failure.^12,13 Headache is more likely to occur after ingestion of indomethacin than other NSAIDs. Aseptic meningitis has been reported with NSAIDs, most typically with ibuprofen.^14,15

Symptoms of GI toxicity include nausea, vomiting, and epigastric pain, all of which can occur at therapeutic doses.¹⁶ Upper GI bleed can occur after acute or chronic ingestions. The gastritis associated with NSAIDs probably occurs secondary to inhibition of prostaglandin synthesis. While hepatotoxicity is more associated with acetaminophen, NSAIDs may also lead to elevated liver enzymes and liver failure.^10,17 However, this has been more associated with idiosyncratic reactions at therapeutic doses than in the overdose setting. Acute pancreatitis has also been reported.¹⁸

While mild GI symptoms are more likely to occur compared to other systemic effects, life-threatening drug toxicity occasionally occurs. If CNS or respiratory symptoms are present, the patient's acid–base status should be assessed. Acute, large ingestions of NSAIDs can result in a high–anion-gap metabolic acidosis secondary to the pKa of the drugs (weak acids) and their metabolites as well as their ability to cause mitochondrial dysfunction.¹⁹

Cardiovascular complications of NSAID overdose are generally limited to tachycardia and hypotension, usually secondary to volume depletion.²⁰ Multi-organ system failure can occur with anion-gap metabolic acidosis, elevated lactate concentrations, high-output renal failure resulting in cardiovascular collapse.¹⁰ In addition, ventricular tachycardia and prolonged QT interval have been reported after massive ibuprofen overdoses.^12,20 In addition, respiratory failure may occur in severe overdoses if the patient's acid–base status is not maintained.

Long-term use of NSAIDs is associated with nephrotoxicity, including acute tubular necrosis, acute interstitial nephritis, and acute renal failure. Renal papillary necrosis has been reported in children being treated with NSAIDs for juvenile rheumatoid arthritis. Renal insufficiency and, rarely, acute renal failure have been reported following overdose. While these are more likely to occur with concurrent use of nephrotoxic drugs and in the elderly, case reports have documented acute oliguric renal failure resulting in the need for dialysis.^10,12

Other systemic symptoms may present such as hematologic (thrombocytopenia and DIC), dermatologic (angioedema, urticaria, and hives), and fluid-electrolyte abnormalities (hypokalemia, hypophosphatemia, hyponatremia, and hyperkalemia associated with renal failure) have been reported following overdose.

While assay procedures for measuring plasma ibuprofen levels are available, most hospital laboratories do not have the ability to perform this test. There is a poor correlation between the absolute level and toxicity making the test unnecessary for clinical management in the overdosed patient.⁹

Laboratory tests include a complete blood count, electrolytes, glucose, creatinine, BUN, and coagulation profile. The patient should be monitored for GI bleeding. If CNS or respiratory symptoms are present, the acid–base status should be assessed. For patients with severe clinical symptoms, an arterial blood gas is indicated. A urinalysis may be useful to detect hematuria. Urine output should be monitored in patients with large overdoses.

Gastric decontamination with activated charcoal is indicated if the patient presents to the emergency room within an hour of the ingestion of a very large dose such as greater than 200 mg/kg of ibuprofen. There are no data to support multiple doses of activated charcoal. The high protein binding of NSAIDs renders extracorporeal methods of elimination ineffective. The treatment of NSAID overdoses is symptomatic and supportive.