Intolerance to NSAIDs is most likely in individuals with a history of asthma, nasal polyps, and chronic urticaria.66 A history of rhinorrhea, urticaria, angioedema, or bronchospasm occurring within 3 hours after exposure to a NSAID is an acceptable method of confirming intolerance. Even a single dose of a NSAID can precipitate asthma in susceptible patients.67 Intolerance is related to the inhibition of cyclooxygenase and the consequent shunting of arachidonic acid down the lipoxygenase pathway resulting in increased levels of leukotrienes, a family of inflammatory mediators.68
NSAIDs may cause nausea, vomiting, abdominal pain, diarrhea, dyspepsia. Mucosal injury related to the blockade of prostaglandin synthesis can exacerbate peptic ulcer disease (PUD).66,69 Ibuprofen appears to have the lowest risk of NSAID-associated gastrointestinal toxicity.39 NSAIDs also impair platelet function through the inhibition of thromboxane A2 (TXA2) synthesis.66 The risk of bleeding with PUD is increased with the concomitant use of aspirin, clopedigrel, and corticosteroids; with anticoagulants, NSAIDs increase the International Normalized Ration (INR) by as much as 15%.69,70
Hepatotoxicity has been reported in association with the use of NSAIDs, but it appears to be idiosyncratic and often dose-related.66,71 Predisposing factors for toxic reactions include advanced age, concomitant liver disease, decreased renal function, and collagen vascular diseases. Hepatotoxicity, like most ADRs, occurs within 6-12 weeks of initiation of long-term therapy.72 Patients with the liver disease also have impaired hemostasis associated with reduced synthesis of coagulation factors and the administration of NSAIDs may further increase the risk of bleeding.
NSAIDs decrease the synthesis of renal prostaglandins. Consequently, NSAIDs decrease renal blood flow causing fluid retention and increase blood pressure, and may precipitate renal failure in susceptible patients.66 Risk factors include old age, chronic renal insufficiency, congestive heart failure, hepatic cirrhosis, and the concurrent use of β-adrenergic receptor antagonists and angiotensin-converting enzyme inhibitors.73 Nephrotic syndrome, acute interstitial nephritis, and an increased incidence of end-stage renal disease have been reported in patients treated chronically with NSAIDs.74
COX-2 inhibition leads to less prostacyclin (PGI2) and more TXA2 synthesis. PGI2 is a vasodilator and blocks platelet aggregation; TXA2 is vasoconstrictive and promotes platelet aggregation. COX-2 inhibition allows TXA2 to function unopposed. Although NSAIDs block both COX-1 and COX-2 variably, the FDA considers cardiovascular risk a class effect.39 The risk appears to be related to dose and duration of treatment. In general, NSAIDs should be used with caution in patients with a history of hypertension, ischemic heart disease, stroke, or congestive heart failure.75
Rarely, NSAIDs may cause dizziness, anxiety, drowsiness, confusion, disorientation, depression, and severe headaches. These central nervous system-related adverse drug reactions may be seen with therapeutic doses of NSAIDs most commonly in older persons. Tinnitus appears to be a sign of high blood levels of NSAIDs.66 Aseptic meningitis has been reported in persons with systemic lupus erythematosus who were taking ibuprofen or naproxen.76,77
NSAIDs at the time of conception may increase the risk of miscarriage.66,78 During pregnancy, low dose intermittent administration of NSAIDs, in general, is considered to be safe. NSAIDs during the third trimester may prolong gestation and labor and increase peripartum bleeding.79,80 Potential fetal effects include premature closure of ductus arteriosus; pulmonary hypertension; renal dysfunction; reduced amniotic fluid volume; and increased cutaneous and intracranial bleeding. In breastfeeding women, ibuprofen and naproxen are considered safe.
In children, the primary concern when prescribing NSAIDs is dosing errors resulting in overdose, which may lead to significant morbidity and even death.66 Educating the caregivers (parents, guardians, others) about the importance of correct dosing and dosage intervals, avoiding concurrent use of other medications that may contain NSAIDs (e.g., combination cold remedies), and proper storage of analgesics (as other medications) in childproof containers can minimize the risk.
Drug-drug interactions all seem to have a pharmacodynamic or a pharmacokinetic basis. NSAIDs may decrease the antihypertensive effects (decreased prostaglandin synthesis) of β-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and diuretics; increase the toxicity of lithium and methotrexate (decreased renal excretion); increase the risk of peptic ulcer disease (additive) with corticosteroids; and increase the risk of bleeding (platelet inhibition) and increase the INR (mechanism unknown) with warfarin sodium.81-85
NSAIDs also interfere with the anti-platelet effect of low dose ASA (i.e., 81 mg per day) by blocking the access of ASA to its active site, potentially rendering ASA less effective when used for cardio-protection and stroke prevention.86 To avoid significant interference, oral healthcare providers should advise patients regarding the appropriate concomitant use of NSAIDs and ASA, i.e., at least 2 hours should elapse after ASA dosing before taking a NSAID and at least 8 hours should elapse after NSAID dosing before taking an ASA.87