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Nonsteroidal antiinflammatory drug (NSAID) poisoning

Nonsteroidal antiinflammatory drug (NSAID) poisoning
Literature review current through: Jan 2024.
This topic last updated: Nov 15, 2022.

INTRODUCTION — Millions of people worldwide take nonsteroidal antiinflammatory drugs (NSAIDs) on a regular basis to treat pain and inflammation. Patients with an acute overdose of NSAIDs often present to emergency departments and represent a sizable percentage of cases reported to regional poison control centers [1]. As aging populations increasingly rely on NSAIDs, chronic toxicity and acute poisonings have become more commonplace. Given the relative frequency of toxic NSAID exposures, emergency and primary care clinicians need to understand the diagnosis and management of this poisoning.

Acute NSAID poisoning is reviewed here. A summary table to facilitate emergent management is provided (table 1). A general approach to suspected drug intoxication and discussions of chronic NSAID toxicity are provided elsewhere.

(See "General approach to drug poisoning in adults".)

(See "Nonselective NSAIDs: Overview of adverse effects".)

PHARMACOLOGY — NSAIDs are competitive inhibitors of the enzyme cyclooxygenase (COX) (figure 1). NSAIDs prevent COX-mediated production of prostaglandins and thromboxanes but not leukotrienes and other eicosanoids. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

There are two COX isoforms, COX-1 and COX-2. The constitutive enzyme, COX-1, is expressed in most tissues and enables regulation of basal cellular homeostasis (platelet function, gastric mucosal integrity, and regulation of renal blood flow). The activity of the inducible COX-2 isoenzyme increases in inflammatory and pain states [2].

Numerous animal and human studies have demonstrated the role of COX-1 in inflammation [3,4]. In general, all NSAIDs inhibit both isoforms, with most adverse reactions believed to be attributable to COX-1 inhibition. The development of newer COX-2 selective NSAIDs arose from the desire to maintain therapeutic antiinflammatory function, while decreasing the rates of adverse drug effects, most notably gastrointestinal and renal toxicity. (See "Nonselective NSAIDs: Overview of adverse effects".)

KINETICS — Oral absorption of NSAIDs approaches 100 percent and peak serum levels usually occur within one to two hours. Large toxic ingestions or concomitant food consumption can delay peak levels up to three to four hours. NSAIDs are weak acids that are extensively (up to 99 percent) protein bound, with a small volume of distribution (0.1 to 0.2 L/kg). Diseases causing low protein levels or large NSAID ingestions can decrease plasma protein binding, resulting in an increased volume of distribution and greater penetration into body tissues, including the central nervous system.

Most NSAIDs are metabolized by hepatic biotransformation with urinary excretion. The elimination half-life is usually less than 8 hours, but it ranges from 1 to 50 hours depending on the specific class and initial dose [5]. The half-lives of some common NSAIDs are as follows:

Short half-life (<8 hours): ibuprofen, indomethacin, ketorolac, diclofenac

Long half-life (>8 hours): naproxen (9 to 20 hours), oxaprozin (25 to 50 hours), piroxicam (30 to 86 hours), phenylbutazone (50 to 100 hours)

HISTORY AND PHYSICAL EXAMINATION — Important historical information includes the name of the NSAID ingested, the amount ingested, the time of ingestion, and the presence of coingestants. Nausea, vomiting, and non-specific neurologic findings such as dizziness may occur. Patients should be specifically questioned about their use of acetaminophen and aspirin, as these are commonly mistaken for NSAIDs and can produce significant toxicity.

The physical examination in NSAID-poisoned patients is usually unremarkable or nonspecific. Severe poisoning may produce an acute alteration in mental status.

CLINICAL ASPECTS OF ACUTE TOXICITY

General — The clinical manifestations of acute NSAID overdose tend to be minimal. In a review of over 5000 NSAID overdoses, the most common signs and symptoms were nausea, vomiting, drowsiness, blurred vision, and dizziness [6]. Less than 0.5 percent of these patients experienced severe harm (eg, kidney injury); most required no medical intervention.

In general, ingestions of less than 100 mg/kg of most NSAIDs (except mefenamic acid and phenylbutazone) are unlikely to cause any significant toxicity. Massive overdoses that produce severe clinical toxicity are seen with ingestions greater than approximately 400 mg/kg (lean body weight) [7]. Hypothermia may develop following a large overdose, and has been reported in a child with a therapeutic dose [8,9].  

Acid base abnormalities — An increased anion gap metabolic acidosis may be seen after large ingestions of NSAIDs, particularly ibuprofen, naproxen, and phenylbutazone (a veterinary NSAID occasionally ingested by humans). This acidosis may represent a combination of lactic acidosis (from cellular hypoxia or seizures) and weakly acidic NSAID metabolites. Cardiac dysrhythmias and electrolyte abnormalities are thought to be due to the severe anion gap metabolic (lactic) acidosis resulting from massive NSAID ingestion [8,10-12].

Acute kidney injury — Acute kidney injury and renal papillary necrosis are reported but rare in NSAID overdose. Most commonly, these pathologic processes occur in patients with decreased effective arterial volume (heart failure, cirrhosis, protracted hypovolemia), age-related underlying renal dysfunction, or massive overdose.

Patients with NSAID-induced acute kidney injury usually present with evidence of decreasing renal function (increased serum creatinine, hyperkalemia, decreased urine volume, or weight gain). (See "NSAIDs: Acute kidney injury".)

The diagnosis of acute renal papillary necrosis may be more difficult. Patients classically present with gross hematuria and renal colic, secondary to ureteral passage of sluffed ischemic renal tissue. To confirm the diagnosis, the clinician must inquire specifically about a recent large ingestion of NSAIDs. (See "Clinical manifestations and diagnosis of analgesic nephropathy".)

NSAID-induced renal injury likely results from inhibition of vasodilatory prostaglandins. Prostaglandin inhibition leads to vasoconstriction and decreased renal perfusion. Discontinuation of NSAID therapy usually reverses the renal insult [13-17].

Cardiovascular toxicity — Hypotension and cardiovascular collapse have been reported following massive ibuprofen overdose [8]. In one case, a 14-year-old male with an intentional overdose of approximately 50 g of ibuprofen developed refractory hypotension, in addition to gastrointestinal bleeding and kidney injury but was successfully treated with extracorporeal membrane oxygenation [11]. (See 'Extracorporeal removal' below.)

Central nervous system toxicity — Acute central nervous system toxicity related to NSAID use is pervasive and varied. A prospective study looking at ibuprofen overdose noted that 30 percent of patients experienced CNS effects ranging from drowsiness to coma [18]. Case reports have identified numerous neurologic sequelae including ataxia, nystagmus, headaches, and disorientation [19].

Seizures have been reported with ingestions of propionic acids (ibuprofen), pyrazolones (phenylbutazone), acetic acids (diclofenac and indomethacin), and anthranilic acids (mefenamic acid and meclofenamate) [20-25]. Most cases occurred after large ingestions, but even small therapeutic doses have been associated with seizures in certain patients. The mechanism by which NSAIDs cause seizures is not clear. Some speculate that decreased cerebral prostaglandin and thromboxane synthesis may lower the seizure threshold [23,25].

Although drug-induced aseptic meningitis (DIAM) is a rare adverse CNS effect associated with NSAIDs, one case report describes its occurrence in a 29-year-old, healthy (non-atopic) woman [26]. DIAM is a type IV hypersensitivity reaction that has been reported in the past (as early as 1978), but this case is remarkable because it appears to be the first case in which dermatologic patch testing confirmed ibuprofen as the causative agent.

Hematologic toxicity — Aplastic anemia and agranulocytosis have been associated with the use of phenylbutazone and indomethacin [27,28]. In one case of aplastic anemia, the patient presented with bleeding gums and a diffuse petechial rash after ingestion of an herbal supplement containing phenylbutazone [28]. Phenylbutazones were removed from United States markets in the 1970s, but they are still available in veterinary formulations and in other countries. Discontinuation of the drug has been shown to reverse the hematologic disturbances.

Most hematologic toxicity from NSAIDs appears to be idiosyncratic (ie, not dose dependent). However, there are case reports of severe coagulopathy following overdose. One such report describes a 58-year-old woman who ingested 26 g of naproxen in a suicide attempt, became critically ill, and developed severe coagulopathy [29]. The patient's serum naproxen concentration at admission was 1320 mg/L (5729 micromol/L), and on hospital day seven, coagulopathy manifested with a prothrombin time below ten percent and platelet concentration of 45 g/L. Treatment with blood products led to resolution of the coagulopathy without significant bleeding. The authors theorized that thromboxane A2 inhibition and impaired activation of clotting factors by naproxen may have caused the coagulopathy.

Allergic reactions — NSAIDs may cause several types of allergic reactions, particularly in patients with chronic urticaria or asthma. Symptoms can range in severity from a worsening of chronic urticaria to full anaphylaxis. The management of anaphylaxis due to NSAID ingestion is the same as that of anaphylaxis from any cause. (See "Anaphylaxis: Emergency treatment".)

Patients with apparent allergic reactions to NSAID or aspirin should discontinue all NSAIDs until they have been specifically evaluated for this problem. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

LABORATORY EVALUATION

General diagnostic testing — Routine laboratory evaluation of the poisoned patient should include the following:

Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

Acetaminophen and salicylate levels, to rule out these common coingestions

Electrocardiogram, to rule out conduction system poisoning by coingestants that affect the QRS or the QTc intervals

Pregnancy test in all women of childbearing age

Testing for NSAID toxicity — Although measurement of NSAID serum concentrations provides one means to assess overdose severity, such measurement has no clear role in acute management. Concentrations correlate poorly with symptoms, rarely return in a timely fashion, and are not clinically useful [18,30].

Routine measurement of renal function (blood urea nitrogen [BUN] and serum creatinine) is not indicated in patients with minor, asymptomatic ingestions [30]. However, in symptomatic patients or those with massive ingestions, measurement of baseline renal function as well as serum electrolytes is prudent. A complete blood count to determine the hemoglobin and platelet levels is appropriate in patients with NSAID-induced bleeding. In massive ingestion (approximately >400 mg/kg in a child or >6 g in an adult) or when the etiology of mental status alteration is unknown, we recommend obtaining an arterial blood gas to determine acid-base status.

DIAGNOSIS — Diagnosis of NSAID poisoning is made on the basis of the history. In the large majority of NSAID poisoning cases, symptoms and signs are nonspecific, and often mild. The most common signs and symptoms are nausea, vomiting, drowsiness, blurred vision, and dizziness.

DIFFERENTIAL DIAGNOSIS — Patients with a suspected overdose can be a challenge for even the most experienced clinician. With an unreliable patient or an unclear history, the goal of the treating clinician is to construct a broad differential and ensure critical interventions are performed in a timely manner. These management issues are reviewed in detail separately. (See "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose".)

Medications commonly coingested or mistaken for NSAIDs, namely salicylic acid (aspirin) and acetaminophen, should always be considered in the differential diagnosis of a patient with purported NSAID poisoning. Both aspirin and acetaminophen are potentially lethal in overdose. Initial manifestations of acetaminophen toxicity are often mild, but poisoning can be determined through serial laboratory testing using an accepted nomogram if the time of ingestion is known. Early symptoms of acute aspirin toxicity include tinnitus, vertigo, nausea and vomiting, and diarrhea; subsequent symptoms portending a more severe intoxication include altered mental status (ranging from agitation to lethargy), hyperpyrexia, noncardiac pulmonary edema, and coma. In addition to clinical signs, salicylate toxicity can be diagnosed with laboratory testing. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Acetaminophen (paracetamol) poisoning: Management in adults and children" and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

Diagnosing a large, acute overdose of NSAIDs can be challenging in the absence of a history of the exposure. Patients presenting with altered mental status should be evaluated in a step wise manner, as is discussed in detail separately. (See "Stupor and coma in adults" and "Initial management of the critically ill adult with an unknown overdose".)

Complications of acute NSAID ingestion (eg, gastrointestinal bleeding, acute renal injury, seizures) may manifest without a clear history of ingestion, but these can be successfully treated with standard supportive measures. (See "Approach to acute upper gastrointestinal bleeding in adults" and "Overview of the management of acute kidney injury (AKI) in adults" and "Convulsive status epilepticus in adults: Management" and "Evaluation and management of the first seizure in adults", section on 'Early postseizure management'.)

MANAGEMENT OF ACUTE TOXICITY — A summary table to facilitate emergent management is provided (table 1).

Airway, breathing, circulation — As with any poisoned patient, the clinician's first responsibility is to secure the airway, breathing, and circulation. However, apnea and hypotension are rare so aggressive intervention is usually unnecessary. In the unusual circumstance where intubation and mechanical ventilation are necessary, it is important to adjust the ventilator appropriately to help compensate for any underlying acidosis. (See "Basic airway management in adults" and "Overview of advanced airway management in adults for emergency medicine and critical care" and "Mechanical ventilation of adults in the emergency department".)

Gastrointestinal decontamination — We suggest gastrointestinal decontamination with activated charcoal (AC) for patients with acute NSAID ingestion who present within two hours of ingestion, unless specific contraindications exist (bowel obstruction, perforation, etc). Aspiration risk, including mental status and the ability to protect the airway, must be assessed in all patients before any attempts to administer AC.

Multiple doses of AC (MDAC) are thought to be ineffective in acute NSAID ingestion because of the low enterohepatic recirculation and high protein binding of the majority of these drugs. Although certain NSAIDs have increased enterohepatic circulation (eg, naproxen, nabumetone, sulindac, and piroxicam), no clinical studies have demonstrated a benefit from MDAC, and the American Academy of Clinical Toxicology does not recommend its use in the treatment of NSAID overdose [31]. However, MDAC may be useful in patients with a massive overdose of a sustained release NSAID. In such cases, consultation with a medical toxicologist or regional poison control center is prudent. (See 'Additional resources' below.)

Other supportive measures — Supportive treatment is indicated for correction of metabolic acidosis after NSAID ingestion. The appropriate role of early volume correction and bicarbonate administration is debated [7,30,32-42]. Although we suggest the early use of crystalloid to correct volume depletion, we do not suggest routine use of bicarbonate therapy because of the lack of data demonstrating efficacy. Multiple case reports describe bicarbonate infusion as a temporizing measure for severe acidosis following massive NSAID ingestion. However, given the lack of evidence supporting this therapy, we recommend consultation with a poison control center or medical toxicologist before initiating treatment [8,10]. (See "Bicarbonate therapy in lactic acidosis".)

Seizures are treated in standard fashion with benzodiazepines. Hypothermia generally responds to active external warming (eg, heating blanket). (See "Accidental hypothermia in adults", section on 'Management' and "Convulsive status epilepticus in adults: Management", section on 'Emergency antiseizure treatment'.)

Antidote — There are no antidotes for NSAID toxicity.

Extracorporeal removal — Extracorporeal removal of NSAIDs via hemodialysis is ineffective due to the high degree of protein binding characteristic of all NSAIDs. One case report describes the efficacious use of plasmapheresis in a 15-year-old female with acute phenylbutazone toxicity, and another report describes extracorporeal membrane oxygenation (ECMO) in a 14-year-old male with massive ibuprofen ingestion. However, such invasive measures are not recommended or necessary in most cases [11,43,44]. We recommend consultation with a regional poison control center or medical toxicologist to determine if such therapeutic techniques are warranted, as may be the case in patients with severe metabolic acidosis or acute kidney injury. (See 'Additional resources' below.)

Patient disposition — Patients with ingestions under 100 mg/kg (excluding mefenamic acid and phenylbutazone) who are asymptomatic and not suicidal may be safely discharged following any needed supportive measures (gastrointestinal decontamination, hydration, etc.) and a four to six-hour period of observation, depending upon the agent ingested. Drugs with a longer half-life (eg, Naproxen) require longer observation. (See 'Kinetics' above.)

Suicidal patients, patients who manifest signs of severe intoxication (eg, pH <7.3, acute renal dysfunction, altered mental status), and those with other medical or psychosocial concerns should be admitted. As with all poisonings, determination of coingestions (eg, acetaminophen, aspirin) is important and will affect disposition.

Although there are little data regarding mefenamic acid and phenylbutazone ingestions, we recommend 24-hour observation in such cases because of the risk of seizures in the former and multiple potential complications in the latter [20-22,27].

CHRONIC TOXICITY — Most toxicity related to NSAIDs occurs after chronic use. An overview of chronic toxicity, including references to detailed discussions of specific toxicities, is provided elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects".)

SPECIAL POPULATIONS

Pediatrics — NSAIDs are commonly ingested by children and adolescents, and ibuprofen is the most commonly ingested NSAID [45]. For most NSAIDs (except mefenamic acid and phenylbutazone), when symptoms do occur, the onset is within four hours of ingestion and includes nausea, vomiting, abdominal pain, headache, drowsiness, blurred vision, tinnitus, ataxia, and dizziness [6,41]. Life-threatening toxicity is rare; can include coma, metabolic acidosis, apnea, and cardiovascular collapse; and occurs at ingested doses ≥400 mg/kg [11,36,37]. Young children (≤5 years old) are more likely to have exploratory, low-dose ingestions as compared with adolescents or adults, who are more likely to have intentional ingestions.

Assessment and management of children and adolescents with NSAID poisoning is similar to adults and generally supportive. Children who ingest an NSAID (except mefenamic acid and phenylbutazone) at a dose <200 mg/kg and who have either mild symptoms (eg, nausea, vomiting, or abdominal pain) that resolve or are asymptomatic do not need routine laboratory studies. If the ingestion was intentional or the formulation of the NSAID is unclear, acetaminophen and salicylate concentrations should be checked to rule out these common co-ingestants.

Home management of young children with exploratory ingestions of NSAIDs is frequently feasible as long as they remain asymptomatic, the formulation and maximum ingested dose is certain, and the caretaker is reliable. Consultation with a regional poison control center is frequently helpful in making this decision and should be undertaken if there is any uncertainty about the safety of home management. Regional poison control centers often suggest home monitoring and management of asymptomatic poisoned patients in whom toxicity is unlikely. (See 'Regional poison control centers' below.)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (The Basics)")

Beyond the Basics topic (see "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most common classes of medications prescribed. Despite high rates of acute NSAID overdose, few patients experience poor outcomes, and most require no medical intervention or supportive care alone. A summary table to facilitate emergency management is provided (table 1). (See 'Introduction' above and 'General' above.)

History – Patients should be specifically questioned about their use of acetaminophen and aspirin, as these are commonly mistaken for NSAIDs but can cause severe toxicity and may be life-threatening in overdose. (See 'History and physical examination' above and "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

Toxic and nontoxic doses – NSAID (except mefenamic acid and phenylbutazone) ingestions of less than 100 mg/kg are unlikely to cause significant symptoms in adults. Ingestions greater than approximately 400 mg/kg (lean body weight) can cause severe symptoms. (See 'General' above.)

Clinical features of acute toxicity – Symptoms and examination findings in NSAID intoxication are generally nonspecific. The most common signs and symptoms are nausea, vomiting, drowsiness, blurred vision, and dizziness. (See 'General' above.)

Increased anion gap metabolic acidosis – This may be seen after large ingestions, particularly those involving ibuprofen, naproxen, and phenylbutazone. (See 'Acid base abnormalities' above.)

Kidney injury and renal papillary necrosis – These are rare and occur most often in patients with decreased effective arterial volume, age-related underlying renal dysfunction, or massive overdose. (See 'Acute kidney injury' above.)

Acute central nervous system toxicity – Clinical manifestations are varied, ranging from drowsiness to seizure to coma. (See 'Central nervous system toxicity' above.)

Anaphylactic and anaphylactoid reactions – These can occur particularly in patients with chronic urticaria or asthma. (See 'Allergic reactions' above.)

Laboratory evaluationAcetaminophen and salicylate serum concentrations should be obtained in all patients with suspected NSAID poisoning. In symptomatic patients and those with large ingestions, tests of renal function (blood urea nitrogen [BUN], serum creatinine), serum electrolytes, and an arterial blood gas should be obtained. In bleeding patients, hemoglobin and platelet counts should be measured. NSAID serum concentrations are generally not helpful. (See 'Laboratory evaluation' above.)

Management – In patients with NSAID overdose, the clinician's first responsibility is to secure the airway, breathing, and circulation. Aggressive intervention is usually unnecessary. No antidote exists. Extracorporeal removal is ineffective. (See 'Management of acute toxicity' above.)

Gastrointestinal decontamination – In patients who present within two hours of an acute ingestion, we suggest gastrointestinal decontamination with activated charcoal (AC) (Grade 2C). Aspiration risk should be assessed in all patients before any attempts to administer AC. (See 'Gastrointestinal decontamination' above.)

Disposition – Patients with minor ingestions who are asymptomatic and not suicidal may be discharged safely after a four- to six-hour period of observation, depending upon the agent ingested. Suicidal patients, patients who manifest signs of severe intoxication (eg, pH <7.3, acute renal dysfunction, altered mental status), and those with other medical or psychosocial concerns should be admitted. (See 'Patient disposition' above.)

Observe patients for 24 hours in cases of the following NSAID ingestions (see 'Management of acute toxicity' above):

Mefenamic acid – Risk of seizures

Phenylbutazone – Risk of seizures, metabolic acidosis, aplastic anemia, and agranulocytosis

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References

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