NSAIDs are a heterogeneous class of drugs, some carrying a unique toxicity profile. Fortunately, most nonselective NSAIDs behave similarly in overdose, although much of the medical literature specifically describes ibuprofen. Regardless of the particular NSAID ingested, symptoms typically manifest within 4 hours after ingestion.36,37,38,53,56,90
Initial clinical manifestations are usually mild and predominantly include GI symptoms, such as nausea, vomiting, or abdominal pain, or neurologic symptoms, such as drowsiness, headache, tinnitus, blurred vision, diplopia, and dizziness. More moderate and severe findings are rare and include coma, seizures, central nervous system (CNS) depression, metabolic acidosis, hypotension, hypothermia, rhabdomyolysis, electrolyte imbalances, cardiac dysrhythmias, and acute kidney injury.19,36,37,53,56,58,90 Massive NSAID ingestions may lead to multisystem organ failure and death.21,41,79,88,95
The neurologic effects of NSAID use vary from the mild drowsiness, headache, and dizziness with therapeutic dosing to the more life-threatening CNS depression, coma, and seizures in overdose. The mechanism associated with the decreased level of consciousness is unknown; however, several animal studies suggest a relationship with opioid receptors, and a human case report documents a dramatic return of consciousness in a child after intravenous (IV) administration of high-dose naloxone.27 Other reported neurologic manifestations of toxicity include optic neuritis, amblyopia, color blindness, transient diplopia, other visual disturbances, transient loss of hearing, acute psychosis, and cognitive dysfunction.39,67
Drug-induced aseptic meningitis is reported with several NSAIDs, including tolmetin, rofecoxib, naproxen, sulindac, piroxicam, and diclofenac, but ibuprofen is more commonly implicated, perhaps because of its widespread use.64 Clinical findings include fever and chills, headache, meningeal signs, nausea, vomiting, and altered mental status; cerebrospinal fluid findings include pleocytosis, elevated protein, and normal glucose.64 Studies suggest an immunologic mechanism behind NSAID-induced aseptic meningitis because it appears to be more common in patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease.39,64,67
Muscle twitching and generalized tonic-clonic seizures are described with mefenamic acid overdose and usually occur within 7 hours after ingestion.2 Seizures are also associated with ibuprofen overdose,69 although the specific mechanism for NSAID-induced seizures is unknown.
Renal and Electrolyte Effects
Both acute overdose and chronic therapeutic dosing of NSAIDs may have deleterious effects on kidney function, most of which are reversible. These include sodium retention and edema, hyperkalemia, acute kidney injury (AKI), membranous nephropathy, nephrotic syndrome, interstitial nephritis, and both acute and chronic renal papillary necrosis.39,71,94 General risk factors for NSAID-induced AKI include congestive heart failure, volume depletion, diabetes mellitus, underlying kidney disease, SLE, cirrhosis, diuretic therapy, and advanced age.54 There is also growing concern over the potential development of AKI with NSAID use in patients who are concurrently taking multiple antihypertensive medications, such as diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.50
Acute tubulointerstitial nephritis (ATIN) is one of the more common forms of NSAID-induced renal impairment, and it may occur with short-term therapeutic dosing.24,54 Many cases of ATIN probably go undiagnosed because clinical symptoms usually do not appear until significant renal impairment occurs.24,73 Significant elevations in blood urea nitrogen (azotemia) may occur in elderly patients within 5 to 7 days of initiating NSAID therapy and usually return to baseline within 2 weeks of discontinuation.34
Analgesic abuse nephropathy is a condition whose pathogenesis is not well defined, but it develops from excessive, chronic therapeutic consumption of NSAIDs. This results in AKI manifested by renal papillary necrosis, often requiring hemodialysis.78,94 Analgesic abuse nephropathy was originally described with the use of analgesic combinations including phenacetin and aspirin in addition to caffeine and has decreased in prevalence after the removal of phenacetin from many world markets.
Anion gap metabolic acidosis, with and without AKI, complicates many acute, massive ibuprofen ingestions and may be profound.25,41,95,96 The cause of the acidosis in this setting is most likely multifactorial, involving profound hypotension and tissue hypoperfusion with elevated lactate concentrations and the accumulation of ibuprofen and its two major metabolites, all weak acids.53 An elevated anion gap metabolic acidosis with elevated lactate concentrations is also described after naproxen overdose, suggesting this to be a class effect given that all NSAIDs are acid derivatives.13
Use of NSAIDs by pregnant women is associated with reversible oligohydramnios and is used therapeutically as a treatment modality for polyhydramnios. Decreased fetal urine output and neonatal acute and chronic kidney failure, including transient oligoanuria, are associated with gestational NSAID use, commonly indomethacin.5,29,45
Although the most common adverse GI effect of therapeutic NSAID use is dyspepsia, most patients with dyspepsia do not have ulcers.23 To help prevent the development of ulcers associated with NSAID therapy, concomitant use of misoprostol (a PGE1 analog), an H2-blocker, or a proton pump inhibitor (PPI) is often used; however, PPIs may be superior for both preventing and healing gastroduodenal ulcers resulting from chronic NSAID therapy.72 The most serious adverse GI effect is ulcer formation, which has the potential for life-threatening perforation and hemorrhage, and numerous studies reported an increased risk of these effects with therapeutic use of NSAIDs.32,51,68 The relative risk of developing gastroduodenal perforation, ulcer, or hemorrhage during chronic, therapeutic NSAID therapy ranges from 2.7 to 5.4, with ketorolac posing the greatest risk.68,87 Acute NSAID overdoses cause bloody emesis, fecal occult blood loss, and severe, life-threatening GI hemorrhage.
NSAID-induced hepatotoxicity is a well-known adverse effect that has prompted the removal of several NSAIDs from the market. Hepatotoxicity occurs with an incidence of less than 0.1% and can be quite difficult to diagnose because many patients on chronic NSAID therapy have underlying conditions, such as SLE or rheumatoid arthritis, which may cause hepatotoxicity. NSAID-induced hepatotoxicity is an idiosyncratic reaction primarily causing hepatocellular injury and does not depend on the chemical class. Diclofenac and sulindac are most commonly implicated.85
Immunologic and Dermatologic Effects
The nonimmunologic anaphylactoid and the IgE-mediated anaphylactic reactions that are reported with the use of NSAIDs are clinically indistinguishable from one another, producing flushing, urticaria, bronchospasm, edema, and hypotension.7 Evidence for anaphylactic reactions includes the presence of NSAID-specific IgE antibodies, positive wheal-and-flare skin reactions, and lack of cross-reactivity with oral challenges of aspirin and other NSAIDs.7 The proposed mechanism of NSAID-induced anaphylactoid reactions involves the inhibition of COX-1, which not only inhibits the production of PGE2 (which causes bronchodilation and inhibits the release of histamine from mast cells and basophils) but also shunts the AA metabolism to increased production of bronchoconstricting LTs.
The term aspirin-sensitive asthmati c is a bit of a misnomer because it refers to anaphylactoid reactions that may occur with any COX-1 inhibiting NSAID, not only aspirin.7,83 Selective COX-2 inhibitors cause similar clinical reactions but with an unclear mechanism. There appears to be very little cross-reactivity between NSAIDs and selective COX-2 inhibitors, and reports of reactions to one COX-2 inhibitor and not another suggest a predominant IgE-mediated mechanism.7,47,83
The most common skin reactions include angioedema and facial swelling, urticaria and pruritus, bullous eruptions, and photosensitivity.39 Although rare, toxic epidermal necrolysis and Stevens-Johnson syndrome are reported.39
As a class, NSAIDs are frequently implicated in the development of drug-induced thrombocytopenia and cause adverse effects on most other cell lines and function, including agranulocytosis, aplastic anemia, hemolytic anemia, methemoglobinemia, and pancytopenia.22,39,46,63,89 Specifically, phenylbutazone in chronic, therapeutic doses was associated with agranulocytosis and aplastic anemia,79 prompting its removal from the US market in the 1970s. The inhibitory effect of NSAIDs on granulocyte adherence, activation, and phagocytosis, along with the potential for masking signs and symptoms, has been suggested as the mechanism responsible for the association between NSAID use and necrotizing fasciitis.40
The ability of a particular type of NSAID to inhibit platelet aggregation and affect bleeding time depends on the dose and half-life because NSAIDs reversibly inhibit COX. One dose of ibuprofen prolongs the bleeding time within 2 hours and persists for up to 12 hours; however, this increase in bleeding time usually remains within the upper limit of normal range. This is in contrast to aspirin, which irreversibly inhibits COX, and typically doubles the bleeding time within 12 hours, returning to normal within 24 to 48 hours.75 Compared with placebo, flurbiprofen and indobufen clinically inhibit platelet function, thereby decreasing vascular reocclusion after angioplasty and preventing thromboembolic complications.9,15 The concern over whether ketorolac has clinically significant effects on postoperative bleeding remains controversial.1,20
NSAID use may also potentiate bleeding in patients already at higher risk. These patients include those with thrombocytopenia, coagulation factor deficiencies, or von Willebrand disease and those ingesting alcohol or on warfarin therapy.75
Although no evidence supports a direct cardiotoxic effect of NSAIDs or their metabolites, acute and massive NSAID overdoses may be complicated by persistent and severe hypotension; myocardial ischemia; and cardiac conduction abnormalities and dysrhythmias, including bradycardia, ventricular tachycardia or fibrillation, and prolonged QT interval.25,41,95 The cause of these findings is yet to be elucidated, although these effects are reported only in severely ill patients with acid–base abnormalities and multisystem organ involvement (see Cardiovascular Risk earlier).
Although there is no evidence of direct pulmonary toxicity, some case reports describe the development of acute respiratory distress syndrome similar to the clinical manifestations of salicylate toxicity, suggesting an NSAID class mechanism based process.25,41,52,58 Although chest radiographic findings such as bilateral pulmonary infiltrates appear to resolve rapidly, one study reported persistent clinical abnormalities associated with exertional dyspnea one month later (see Immunologic Effects earlier).58
Serum concentrations of most NSAIDs can be determined but usually only by a specialty laboratory requiring several days to report results. Although ibuprofen nomograms were constructed in an attempt to correlate serum concentrations with clinical toxicity,36,43 the utility of these nomograms proved limited.38,56
Laboratory measurements, including complete blood count, serum electrolytes, blood urea nitrogen, and creatinine, should be obtained for all symptomatic patients, patients with intentional ingestions, ibuprofen ingestion of greater than 400 mg/kg in a child, or ibuprofen ingestion of greater than 6 g in an adult.38 For patients presenting with significant neurologic effects, such as CNS depression, further evaluation of acid–base and ventilatory status by blood gas, hepatic aminotransferases, and prothrombin time should be obtained. A computed tomography scan of the head and a lumbar puncture may be clinically indicated in cases of suspected aseptic meningitis or when structural or infectious etiologies are suspected. An acetaminophen (APAP) concentration should always be determined in patients with intentional ingestions and in patients presenting with an unclear history because many people mistake APAP for NSAIDs because of confusing labeling and packaging or unawareness that they are completely different types of analgesics. For similar reasons, obtaining a salicylate concentration may also be considered.