Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity Clinical Presentation

Updated: Dec 20, 2017
  • Author: Timothy J Wiegand, MD; Chief Editor: Gil Z Shlamovitz, MD, FACEP  more...
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Presentation

History

Patient history

In nonsteroidal anti-inflammatory drug (NSAID) exposures, the clinician should elicit information on the agent ingested, the amount ingested, and the time of ingestion. The most toxic effects are reported after ingestion of phenylbutazone (Butazolidin; no longer available for human use in the United States), mefenamic acid (Ponstel), and meclofenamate sodium (Meclomen); however, all NSAIDS can have untoward effects.

Amount ingested

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. Seizures may be involved and are seen with increased frequency in certain classes of NSAIDs such as the pyrazolones and fenamates (eg, phenylbutazone and mefenamic acid, respectively).

Other NSAIDs are usually less toxic than those mentioned above. Doses of 100 mg/kg or less of ibuprofen, the most widely used NSAID, generally cause minimal symptoms; life-threatening situations do not typically occur until ingestions of 400 mg/kg or more.

Time of ingestion

Nomograms that correlate time and amount of drug ingested are not reliable for predicting outcome. Patients with recent significant ingestion of anthranilic acids derivatives (fenamates), as well as pyrazolones, require close observation for approximately 24 hours for signs of early severe poisoning.

NSAIDs and adverse drug reactions (ADRs) and drug interactions

NSAIDs are implicated in nearly 25% of all adverse drug reactions, with the most commonly reported effects being GI irritation. NSAIDs increase the relative risk of GI hemorrhage by approximately three-fold, although estimations as high as 10-fold have been reported in the literature. [3]

The second most common type of adverse effect occurring with NSAID use involves the renal system. In the setting of high angiotensin and low intravascular flow (eg, congestive heart failure, cirrhosis, or dehydration), NSAID-induced decrease in prostaglandins leads to a decrease in renal blood flow and subsequently the glomerular filtration rate. Retention of salt, water, and potassium may ensue. Congestive heart failure may be exacerbated by concomitant use of NSAIDs. [4]

Considerable toxicity may result from interactions between NSAIDs and the following drugs:

  • Oral anticoagulants
  • Lithium
  • Oral hypoglycemic agents
  • Phenytoin
  • Methotrexate
  • Digoxin
  • Aminoglycosides

Co-ingestions

The possibility of co-ingestants should always be considered and is based on the history and examination findings. In general, patients with isolated NSAID overdose are asymptomatic or have mild GI upset (dyspepsia, nausea, vomiting, and abdominal pain). At higher doses, patients may exhibit CNS symptoms, including drowsiness, lethargy, ataxia, and nystagmus. Massive overdoses may cause the patient to present comatose with refractory acidosis and multisystem organ failure. Co-ingestants should be considered in any drug overdose.

Any individual presenting with a history of NSAID overdose should have a serum acetaminophen level obtained.

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Physical

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 hours. In a prospective study of 45 adults and 39 pediatric patients, all patients who became ill did so within 4 hours. 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. [5]

Vital signs

Bradypnea or tachypnea may suggest early respiratory or metabolic acidosis. NSAIDs can promote salt and water retention and can antagonize beta-blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors, resulting in an elevated blood pressure.

An S3 gallop or marked dysrhythmia may be noted if the patient presents with worsening heart failure.

Central nervous system (CNS) findings

Myoclonus, muscle twitching, or seizures are characteristic (but not specific) of symptomatic massive overdose. Seizures may be focal or general. Tremors or muscle twitching may portend seizures or coma. Analysis of  NSAID overdose cases reported to the United Kingdom National Poisons Information Service, which included 10,398 single-drug exposures, found that mefenamic acid overdose is associated with a much larger and dose-related risk of CNS toxicity, especially convulsions, compared with overdose of ibuprofen, diclofenac, or naproxen. [6]

Mild CNS symptoms may be nonspecific (eg, headache). Subtle mental status changes, such as difficulty concentrating or mild anxiety, may be observed. Patients with severe toxicity may be agitated and delirious, or they may be comatose to the point of requiring endotracheal intubation.

Case reports have also described tinnitus and transient hearing loss after NSAID use.

Pulmonary findings

Aspirin-sensitive individuals with asthma who ingest NSAIDs may present with wheezing or respiratory arrest. The reaction may also include flushed face and/or neck, conjunctivitis, rhinorrhea, and possibly angioedema.

Gastrointestinal findings

Although ulcers are unlikely and perforations very rare in acute overdose, patients with gastrointestinal symptoms require thorough abdominal examination.

A rectal examination may reveal evidence of gastrointestinal bleeding and is mandatory in any patient who presents with acute or chronic toxicity.

Delayed manifestations

Delayed effects of severe poisonings include renal failure, hepatic failure, and platelet dysfunction. Look for generalized weakness, a sallow complexion, acidosis, heart failure, jaundice, liver tenderness, petechiae, and other signs of bleeding disorders.

Manifestations by NSAID class

Poisoning by acute overdose of specific NSAIDs is best addressed by considering each of the seven chemical classifications (including salicylates). Fenamates and pyrazolones (eg, phenylbutazone) are the most toxic and should be managed most aggressively.

Table 1. Chemical Classifications of NSAIDs (Open Table in a new window)

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).
         
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.

 

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Causes

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.

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