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Basics ⬇

Author(s): Kenneth P.Barnes, MD, MSc, CAQSM, FACSM and ShaneHudnall, MD, CAQSM

Epidemiology

Incidence

  • >20 million Americans take NSAIDs on a regular basis.
  • It is estimated that >30 billion OTC NSAID tablets are sold annually in the United States.
  • ~70 million NSAID prescriptions are written each year in the United States.
  • Acute NSAID poisoning is rare despite their extensive use.
  • In most fatalities involving NSAIDs, patients ingested other pharmaceutical agents as well.
  • Most poisonings are attributable to ibuprofen (>80,000 total yearly).

Etiology and Pathophysiology

  • Toxicity:
    • Only a small percentage of overdoses (<0.5%) lead to serious harm (i.e., gastrointestinal [GI] bleeding, renal failure).
    • Most are asymptomatic or have nonspecific symptoms (nausea, vomiting, dizziness, somnolence).
    • Generally, doses >400 mg/kg of NSAID are needed to cause severe toxicity.
  • GI:
    • Most common adverse effects are GI related (i.e., vomiting, abdominal pain, dyspepsia, diarrhea, constipation).
    • Gastric, duodenal, and large intestinal ulceration may occur (1–4% of users annually).
    • 3 to 10 times more likely to have serious hemorrhage with NSAIDs
    • COX-2 inhibitors have been shown to delay ulcer healing in animal studies, but this has not been elucidated in humans.
    • Celecoxib associated with fewer ulcers at 12 wk and 6 mo but no difference at 1 yr (presence of ulcer or complications) compared to ibuprofen and diclofenac (1)[A]
    • In patients requiring low-dose aspirin, celecoxib plus a proton-pump inhibitor (PPI) resulted in less recurrent bleeding and ulcers compared to naproxen plus a PPI (2)[A].
    • Celecoxib may be associated with decreased colon adenomas, duodenal polyps, and cancer from inhibiting COX-2 and tumor growth, especially in those with familial adenomatous polyposis.
  • Renal:
    • Second most common adverse effects
    • Inhibition of prostaglandins interferes with renal blood flow and glomerular filtration rate.
    • Leads to vasoconstriction (from blocking prostaglandin synthesis) and possibly acute renal failure or acute interstitial nephritis
    • Retention of sodium, potassium, and water may lead to congestive heart failure (CHF) exacerbation.
    • COX-2 inhibitors: adversely affect function in patients with volume depletion, underlying renal disease, heart failure, and cirrhosis (3)[A]
  • Central nervous system (CNS):
    • About 30% of patients with NSAID overdose experience CNS toxicity.
    • Elderly particularly at risk
    • Can cause headache, confusion, delirium, psychosis, hallucinations, nightmares, tremor, seizures, tinnitus, transient hearing loss, and aseptic meningitis
  • Cardiovascular:
    • Can raise blood pressure (BP) and worsen control of hypertension (HTN)
    • Increased risk of cardiovascular events in both nonselective NSAIDs and COX-2 inhibitors
    • Risk of bleeding and cardiovascular events further increased in patients on antithrombotic drugs concomitantly taking NSAIDs (4)[B]
    • Lowest risk NSAID based on current research appears to be naproxen (5,6)[A].
    • All are associated with increased risk of CHF exacerbation in those with a history of CHF.
  • Pulmonary:
    • Respiratory arrest is rare.
    • Asthmatics are at increased risk for bronchospasm owing to increased production of leukotrienes.
    • COX-2 inhibitors are much less likely to trigger bronchospasm.
    • Pulmonary infiltrates with eosinophilia are also possible.
    • Patients with clinical triad of asthma, nasal polyps, and allergic rhinitis are at increased risk of anaphylaxis to both salicylates and NSAIDs.
  • Hepatic:
    • Possibility (although rare) of fulminant hepatic failure, hepatitis, elevated transaminases
    • Generally, this is reversible and only rarely fatal.
  • Hematologic:
    • Aplastic anemia (now rare with decreased use of phenylbutazone and indomethacin), agranulocytosis, neutropenia, hemolytic anemia, thrombocytopenia possible
    • Decreased platelet aggregation may lead to increased GI bleeding.
    • COX-2 inhibitors have not been shown to decrease platelet function and are associated with a decreased risk of bleeding compared with nonselective NSAIDs.
  • Skin: Toxic epidermal necrolysis and Stevens-Johnson syndrome are uncommon, but relative risk is increased slightly with NSAID use (including celecoxib) compared with placebo.
  • Metabolic: may lead to anion-gap metabolic acidosis
  • Drug interactions:
    • Increased risk of GI bleeding when used with anticoagulants
    • Digoxin, lithium, sulfonylurea, and aminoglycoside levels are all increased with use of NSAIDs.
    • NSAIDs reduce antihypertensive effects of diuretics, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors.
    • Celecoxib contains a sulfa moiety and may have cross reactivity in those allergic to sulfa antibiotics.

Risk-Factors

  • Suicidal ideation
  • Untreated pain
  • Patients unclear of maximum allowed dosage of NSAIDs

Diagnosis ⬆ ⬇

History

  • Although significant symptoms may occur after 5 to 10 times the maximum dose has been ingested, there is a poor correlation between the amount ingested and toxic poisoning.
  • Timing of ingestion
  • Past medical history (i.e., peptic ulcer disease, chronic renal insufficiency)

Physical Exam

  • Airway, breathing, and circulation (ABCs)
  • Vital signs: Monitor BP, respiratory rate, and oxygen saturation.
  • Thorough neurologic examination (especially monitoring mental status)
  • Rectal examination for gross or occult blood

Diagnostic Tests & Interpretation

  • Complete blood count (CBC), comprehensive metabolic panel (CMP) (attention to transaminases), prothrombin time/partial thromboplastin time (PT/PTT); coagulation studies, arterial blood gas (ABG) (if patient has anion gap on CMP or altered mental status), fingerstick glucose (rule out hypoglycemia), pregnancy test (if child-bearing female)
  • Consider salicylate and acetaminophen levels, but do not check serum or urine levels of other NSAIDs. Just treat presumptively.
  • Electrocardiogram (ECG) to look for prolongation of QRS or QTc
  • Imaging generally not necessary unless concern for perforated ulcer is present

Treatment ⬆ ⬇

  • Acute treatment:
    • Supportive measures:
      • Call poison control.
      • Secure the ABCs.
      • There is no antidote for NSAID poisoning.
      • Close monitoring is warranted for almost all patients, and usually, this is the only treatment necessary.
      • Consider giving intravenous (IV) fluids if there is any volume deficit clinically.
      • Benzodiazepines IV if patient has seizures
    • Decontamination:
      • Gastric lavage if patient presents within 1 hr of ingestion or patient has massive overdose
      • Activated charcoal (1 g/kg adults, 0.5 to 1 g/kg in children) should be given to all patients with acute NSAID ingestion presenting within 2 hr unless contraindicated (i.e., bowel perforation).
      • Dialysis is unnecessary and ineffective.
  • Long-term treatment: disposition:
    • Admit patient for any signs of toxicity (e.g., renal failure, vital sign changes, somnolence, electrolyte abnormalities).
    • Asymptomatic patients should be monitored for 4 to 6 hr to ensure that they do not have any signs of toxicity before discharging home (possibly longer for drugs such as naproxen that have longer half-lives).
    • Obtain psychiatric consultation for suicide attempts once medically stable.

Additional Reading ⬆ ⬇

  • Hunter LJ, Wood DM, Dargan PI. The patterns of toxicity and management of acute nonsteroidal anti-inflammatory drug (NSAID) overdose. Open Access Emerg Med. 2011;3:39–48.
  • Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: a pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs. Am J Med. 2001;111(1):64–67.
  • Phillips RK, Wallace MH, Lynch PM, et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut. 2002;50(6):857–860.
  • TintinalliJE, KelenGD, StapczynskiJS, eds. Emergency Medicine: A Comprehensive Study Guide. New York, NY: McGraw-Hill; 2000.

References ⬆ ⬇

  1. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284(10):1247–1255.
  2. Chan FKL, Ching JYL, Tse YK, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet. 2017;389(10087):2375–2382.
  3. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med. 2000;133(1):1–9.
  4. Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA. 2015;313(8):805–814.
  5. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.
  6. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519–2529.

Clinical Pearls ⬆

  • There is no additional benefit to giving >1 dose of activated charcoal.
  • Ipecac has fallen out of favor for most acute ingestions and is not recommended for NSAID toxicity.