Continuing Education Activity

Ibuprofen, 2-(4-isobutylphenyl)propionic acid, belongs to the class of drugs called nonsteroidal anti-inflammatory drugs and was discovered by Dr. Stewart Adams in 1961. The drug was first marketed in 1969 in the United Kingdom and in 1974 in the United States. Ibuprofen is commonly prescribed as an analgesic, antipyretic, and anti-inflammatory agent in conditions such as osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, and acute musculoskeletal pain. Off-label uses include slowing the progression of conditions such as cystic fibrosis. When considering ibuprofen toxicity, assessment for coingestions such as ethanol, toxic alcohols, acetaminophen, and aspirin should be based on a patient's presentation.

This activity reviews the basic pharmacological characteristics of ibuprofen, clinical presentations during an overdose, and management of ibuprofen toxicity. System-specific symptoms and signs delineate clinical correlations, and the next steps are recommended to narrow the cause of toxicity in undifferentiated patients. The interprofessional team consists of primary care, emergency medicine, internal medicine, and pharmacists, among other healthcare professionals, who are equipped to treat patients with ibuprofen toxicity successfully.

Objectives:

• Interpret the epidemiology of ibuprofen toxicity when encountering patients in clinical practice.

• Identify common history and physical examination findings in patients with ibuprofen toxicity.

• Compare the treatment options for ibuprofen toxicity based on the stage of presentation.

• Implement care coordination among interprofessional team members to improve patient outcomes with ibuprofen toxicity.

Introduction

Ibuprofen, 2-(4-isobutylphenyl) propionic acid, belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs) and was discovered by Dr. Stewart Adams in 1961. The drug was first marketed in 1969 in the United Kingdom and in 1974 in the United States.[1] Ibuprofen is commonly prescribed as an analgesic, antipyretic, and anti-inflammatory agent in conditions such as osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, and acute musculoskeletal pain. Off-label applications include its use in conditions such as cystic fibrosis to slow progression.[2][3] Ibuprofen is also used to close patent ductus arteriosus in neonates.[4][5] This resource serves to review ibuprofen's essential pharmacological characteristics, clinical presentations during an overdose, and management of ibuprofen toxicity.

Etiology

An overdose of ibuprofen may be intentional or accidental. Intentional overdoses are typically in the context of attempted suicide. Accidental overdoses may occur if an individual is taking more than the daily recommended dose of ibuprofen, often to treat acute or chronic pain. Young children may develop ibuprofen toxicity following exploratory ingestions.

Epidemiology

Ibuprofen is one of the most commonly used and prescribed medications in the world. According to the 2022 Annual Report of the American Association of Poison Control Centers’ National Poison Data System, analgesics were the most common drug class associated with adult exposures at 11.5% and the second most common among children at 9.54%. Among all analgesic overdoses, 28.5% had used ibuprofen exclusively or combined with other analgesics, making it the most common NSAID involved in the overdose.[6][7] In the United Kingdom, according to the annual report by the National Poison Information Service from 2022 to 2023, ibuprofen is the second most common substance, after acetaminophen, in telephone and TOXBASE inquiries. Another study in Croatia from 2009 to 2019 found that the most common NSAID involved in exploratory ingestions among preschool children was ibuprofen.[8]

Pathophysiology

The therapeutic effects of ibuprofen are mediated through reversible binding to cyclooxygenase (COX) receptors, including both COX-1 and COX-2, on prostaglandin synthase (COX enzyme), thereby preventing arachidonic acid from binding to these sites. This mechanism prevents the conversion of arachidonic acid into various prostaglandins, which are responsible for inflammation's 4 defining characteristic symptoms—redness (rubor), heat (calor), swelling (tumor), and pain (dolor). Prostaglandins also play a role in sensitizing pain-sensing nerve fibers, which explains the analgesic effect of ibuprofen and other NSAIDs.[9] Ibuprofen also works on the thermoregulatory center of the hypothalamus to control fever. Thromboxane A2, another substance produced by the COX enzyme,  plays a crucial role in platelet aggregation and coagulation. Therefore, the depletion of thromboxane A2 increases the risk of bleeding, especially in patients on anticoagulants or antiplatelets.

Adverse effects associated with chronic ibuprofen use result from the inhibition of prostaglandin synthesis. Chronic use is associated with dyspeptic symptoms and gastrointestinal ulcers at therapeutic doses. Recent findings indicate that specific CYP450 polymorphisms may predispose individuals to the development of ulcers and subsequent bleeding.[10][11] In the kidneys, prostaglandin inhibition can lead to decreased renal perfusion in the afferent renal vessels, especially in individuals with preexisting dehydration or renal impairment, resulting in reduced glomerular filtration rate and acute kidney injury.[12]

Toxicokinetics

Ibuprofen is available in various formulations, including tablets, capsules, suspensions, and oral solutions, with strengths ranging from 200 to 800 mg for tablets and capsules. Intravenous solutions are also available in these strengths.[13] These solutions are generally well absorbed and achieve peak plasma concentrations in 1 to 2 hours.[14] The onset of action after oral ingestion is 30 to 60 minutes for analgesia.[15] The onset of antipyretic action varies with age, ranging from less than 1 hour in adults to up to 3 hours in children.[16][17] At over-the-counter doses, ibuprofen may demonstrate somewhat superior antipyretic effects compared to acetaminophen.[18] Ibuprofen undergoes rapid metabolism, with a half-life of 1.8 to 2 hours, and is completely metabolized and eliminated in 24 hours.[19] The drug is almost completely protein-bound at 99%.[20]

Symptoms of ibuprofen toxicity are unlikely at doses of less than 100 mg/kg in children. Ingestion of more than 400 mg/kg in a child is associated with serious or life-threatening toxicity. No specific cutoff distinguishes asymptomatic from symptomatic overdose in adults, making the diagnosis challenging.[21]

History and Physical

Key points to consider in the medical history include the quantity of ibuprofen ingested, the time of ingestion, and any coingestions. In children, caregivers should be inquired explicitly about acetaminophen ingestion, which is commonly mistaken for ibuprofen. Most patients report no or mild symptoms following ibuprofen overdose.[22] The onset of symptoms typically occurs within 4 hours. Symptoms most commonly consist of gastrointestinal distress and hemorrhagic gastritis. More severe overdoses can result in central nervous system depression, seizure, and coma. On physical examination, for most ingestions, vital signs are normal. More severe toxicity can result in tachycardia and hypotension. Patients may have abdominal tenderness.

Ibuprofen toxicity can be discussed based on the organ system involved.

Gastrointestinal Toxicity

The COX-1 enzyme is found in the gastric mucosa and is instrumental in producing prostaglandins that regulate blood flow and bicarbonate production in the stomach. Ibuprofen, a nonselective inhibitor of COX, can disrupt the mucosal integrity of the gastric mucosa. Intramucosal hemorrhages occur within a few hours of ingestion of all NSAIDs, especially acidic types such as ibuprofen.[23] These hemorrhages may progress to erosions with continued use but are typically reversible. In susceptible individuals, they may progress to peptic ulcer. Although generally occurring after chronic use, a report occurs after single large ingestions.[24] The severity of gastrointestinal adverse effects can range from dyspepsia to life-threatening upper gastrointestinal hemorrhage or viscous organ rupture. Symptoms include nausea, vomiting, dyspeptic symptoms, and abdominal pain.[21] Gastrointestinal hemorrhage has been described in multiple case reports, particularly after large ingestions.[25][26] Perforation of the duodenum has been described in a patient after a single ingestion.[27]

Hepatotoxicity

Ibuprofen is commonly associated with drug-induced liver injury, both in overdose and in therapeutic use.[28] Symptoms include abdominal pain, nausea, vomiting, fever, rash and jaundice. Some cases may be associated with Stevens-Johnsons syndrome.[29]

Renal Toxicity

Renal impairment has been described in individuals who had consumed therapeutic and supratherapeutic doses of ibuprofen.[30][31] A report involving a 2-year-old child who consumed 640 mg/kg of ibuprofen revealed the onset of acute renal failure, characterized by a notable increase in creatinine levels and the presence of microscopic hematuria with no proteins or casts in urine. Normalization of creatinine occurred after 72 hours.[32] A prospective study conducted at Rocky Mountain Poison Control Center on ibuprofen poisoning showed that 2 out of 63 cases had elevated levels of creatinine after ingesting 4 and 4.5 g of ibuprofen, respectively, suggesting that this is an uncommon occurrence.[33] Renal impairment is typically reversible after supportive care and intravenous fluids.[34] The report of a patient requiring hemodialysis for months after developing renal failure followed ingestion of massive amounts of ibuprofen, with the eventual recovery of renal function.[35]

Neurotoxicity

Acute ibuprofen overdose leading to central nervous system toxicity is not uncommon, particularly when the ingestion is massive at more than 400 mg/kg. In a prospective population-based ibuprofen overdose study, central nervous system depression was the second most common clinical finding after gastrointestinal disturbances, affecting approximately 30% of cases, although symptoms were generally mild.[36] In another study, central nervous system depression was reported in 10% of cases.

In one case, a 50-year-old woman was admitted in a comatose state after consuming 40 to 60 tablets of 600 mg ibuprofen. The patient was unresponsive to verbal stimuli but responded to noxious stimuli. She was endotracheally intubated for airway protection. Subsequently, she developed renal failure and gastrointestinal hemorrhage, as indicated by a positive guaiac stool test. After a day in the intensive care unit, she clinically improved and was extubated with no further complications.[37] A similar case report of a male who reportedly ingested almost 20 g of ibuprofen developed central nervous system depression, metabolic acidosis, thrombocytopenia, acute renal failure, and gastrointestinal hemorrhage. His level of consciousness and other parameters improved with supportive management.[26]

Generalized seizures, depressed levels of consciousness, and apnea have been reported in children by various authors after large ingestions.[21][38][39] Aseptic meningitis is another reported effect of ibuprofen therapeutic use and overdose. Patients present with headache, fever, myalgias, neck stiffness, and confusion.[40][41]

Biochemical Toxicity

High anion gap metabolic acidosis is the most common abnormality reported, which typically occurs after massive ingestions.[39][42][43] This condition is due to the accumulation of acidic metabolites of ibuprofen, acute renal failure, and lactic acidosis from seizure activity.[44][45] Apnea from respiratory depression can result in concomitant respiratory acidosis. Life-threatening hypokalemia has been reported secondary to renal tubular acidosis after ibuprofen overdose.[46] Metabolic acidosis, accompanied by polyuria, has also been described.[47]

Hematological Toxicity

Thrombocytopenia is common following ibuprofen overdose.[48][49] Thrombocytopenia secondary to immune-mediated thrombocytopenia, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome from ibuprofen ingestion have all been described.[50][51][52][53] Prolonged prothrombin time may also occur. Pulmonary infiltrates with eosinophilia syndrome have been reported following ibuprofen overdose.[54] Severe pancytopenia has also been reported.[55]

Evaluation

Routine laboratory testing is unnecessary following an accidental overdose in asymptomatic patients, provided that there is no history of acetaminophen overdose. When acetaminophen overdose cannot be excluded, a serum acetaminophen level should be obtained 4 hours after the reported ingestion. In cases where a person has ingested a large amount of ibuprofen, if the ingestion is associated with self-harm or suicidal attempts, or if the person shows any symptoms, laboratory testing may be required. The tests may include a complete blood count, blood gas analysis, basal metabolic panel, and hepatic function panel.

Patients may have findings of leukocytosis, metabolic acidosis, acute kidney injury (as indicated by elevated levels of creatinine), and electrolyte abnormalities. Although less common, idiopathic drug-induced liver injury leading to elevated hepatic function tests, in the absence of acetaminophen toxicity, can also be observed.[28] Assessment for coingestions such as ethanol, toxic alcohols, acetaminophen, and aspirin should be performed based on a patient's presentation. Serum ibuprofen concentrations are typically not readily available in acute care and should not be used to guide management. If confirmation of ibuprofen exposure is necessary, these levels can be obtained from reference laboratories.

Treatment / Management

Management of ibuprofen toxicity is primarily supportive. Most patients have no symptoms or mild gastrointestinal symptoms that respond to symptomatic management. Asymptomatic patients with normal vital signs and no acetaminophen poisoning may be observed for 4 to 6 hours to develop symptoms.[33] Children who have consumed more than 400 mg/kg are at a higher risk of ibuprofen toxicity and generally should be admitted for further evaluation. In comparison, those who have ingested less than 100 mg/kg can be safely observed at home by their caretaker.

Gastrointestinal decontamination with activated charcoal is indicated with a history of recent (within 2 hours) clinically significant ibuprofen overdose in adults and children with ingestion of more than 400 mg/kg.[43][56] Patients with life-threatening manifestations such as respiratory depression, hypotension, seizures, and metabolic acidosis should be aggressively treated. Patients with profound central nervous system depression or airway compromise should be endotracheally intubated and placed on mechanical ventilation. Seizures should be treated with benzodiazepines. Hypotension should be treated with intravenous fluids and vasopressors as necessary. Corticosteroids can help alleviate the symptoms associated with hepatic injury.

Serial electrocardiograms and cardiac monitoring are essential for detecting arrhythmias, which can occur secondary to electrolyte imbalances such as hypokalemia. As ibuprofen is heavily protein-bound, hemodialysis is not effective in removing the drug from the serum. Hemodialysis should be considered if a patient develops renal failure and oliguria, has severe electrolyte abnormalities, or refractory metabolic acidosis.[45]

Differential Diagnosis

The differential diagnosis of symptoms caused by ibuprofen toxicity is broad and includes, but is not limited to:

• Peptic ulcer disease or gastritis
• Bleeding esophageal varices
• Pancreatitis
• Cholecystitis
• Sepsis
• Idiopathic thrombocytopenic purpura
• Thrombotic thrombocytopenic purpura
• Bacterial and viral meningitis
• Bacterial and viral encephalitis
• Acute cerebrovascular accident
• Intracranial hemorrhage
• Diabetic ketoacidosis
• Alcoholic ketoacidosis

Prognosis

Ibuprofen overdose is rarely fatal, although cases of death are reported.[21][42][57] The extent of recovery depends on the severity of the toxicity, but generally, full recovery is expected with appropriate supportive care.

Complications

Complications of ibuprofen overdose encompass gastrointestinal, hepatic, and renal problems. Gastrointestinal blood loss following ibuprofen intake is dose-related. The more serious gastrointestinal effects are not common and include occult blood loss, gastrointestinal hemorrhage, gastric ulcer, and pancreatitis. Elevations in liver function tests are commonly observed. However, more serious effects such as cholestasis, jaundice, hepatitis, and hepatic failure are rare. Renal complications include urinary retention or insufficiency, acute renal failure, nephrotic syndrome, and acute tubular necrosis. These complications are more likely in patients with impaired renal function. Other rare complications include cardiovascular effects, such as elevated blood pressure; nervous system complications, such as dizziness, drowsiness, and aseptic meningitis; and hematological issues, such as platelet dysfunction.[58]

Deterrence and Patient Education

Although ibuprofen is available over-the-counter and is relatively benign compared to many other analgesics, patients need to understand the appropriate dosing of medications to prevent accidental toxicity. Patients can refer to the labeling on the packaging or the instructions in their prescription to ensure they take ibuprofen appropriately. If an overdose is suspected, patients should promptly contact their regional poison center and seek immediate medical attention if experiencing symptoms. All medications should be stored in child-resistant containers and out of reach to prevent accidental exposures.

Enhancing Healthcare Team Outcomes

Managing ibuprofen overdose requires collaboration among various healthcare professionals, including the emergency clinician, intensivist, medical toxicologist or poison control center, pharmacist, and nursing staff.

The treating clinician's responsibilities encompass:

• Obtaining a detailed history of the substance ingested, any coingestion, time of ingestion, any suicidal intent behind the ingestion, and any previous similar history in the past.

• Initiating the management of airway, breathing, circulation, and decontamination if indicated.

• Ordering of initial laboratory tests, including acetaminophen levels, aspirin levels, blood gas, complete blood count (CBC), renal and liver function tests, electrolytes, and blood sugar.

• Initiating the correction of any electrolyte or blood gas abnormalities.

• Obtaining a psychiatric history to assess the risk of self-harm if the patient's condition permits.

• Seeking consultation with toxicology regarding further management of the patient.

• Consulting with nephrology if resistant metabolic acidosis, hyperkalemia, or renal failure is observed to consider hemodialysis.

The management of ibuprofen toxicity should continue after the patient is admitted to an appropriate level of care. Patients should be admitted to an intensive care unit for respiratory depression, shock, depressed mental status, severe metabolic acidosis, severe gastrointestinal hemorrhage, life-threatening electrolyte imbalances or arrhythmias, or if the presumed clinical course of the patient is predicted to worsen based on the dose of ibuprofen consumed. Symptomatic but otherwise stable patients may be admitted to a general medical floor. Asymptomatic patients may be observed in the emergency department for 4 to 6 hours before appropriate disposition.[33]

The admitting team should continue therapeutic interventions initiated in the emergency department with consultants such as medical toxicologists, the poison control center, nephrologists, and pharmacists. Consultation with a mental health counselor or psychiatrist is crucial to assess the risk of self-harm and determine if inpatient psychiatric admission is necessary. These interprofessional interventions can drive better outcomes irrespective of the underlying cause of toxicity.