What are the long-term effects of taking ibuprofen (Nonsteroidal Anti-Inflammatory Drug, NSAID)?

Long-Term Effects of Ibuprofen

Long-term ibuprofen use carries significant risks for cardiovascular events, gastrointestinal complications, renal damage, and hypertension, with these risks increasing substantially with duration of use and dose. 1, 2

Cardiovascular Effects

Ibuprofen increases the risk of serious cardiovascular thrombotic events, myocardial infarction, stroke, and death, with risk escalating with duration of use. 1, 3, 2

• The American Heart Association found that ibuprofen users had a 25% increased risk of recurrent MI and 50% increased mortality compared to non-users in registry data 1
• Patients with existing cardiovascular disease or risk factors face substantially greater risk 1, 3, 2
• The PRECISION trial demonstrated that ibuprofen users had a 38% higher risk of major toxicity compared to celecoxib users, translating to 1 in 82 patients experiencing major harm over 1-2 years 4

Hypertension and Heart Failure

Ibuprofen causes blood pressure elevation through impaired renal perfusion and sodium retention, which can precipitate or worsen heart failure. 3, 2

• COX inhibition by ibuprofen leads to increased blood pressure, contributing to adverse cardiovascular outcomes 3
• Heart failure hospitalizations approximately double with NSAID use compared to placebo 2
• Ibuprofen blunts the effects of antihypertensive medications including diuretics, ACE inhibitors, and ARBs 2

Aspirin Interaction

Ibuprofen interferes with aspirin's cardioprotective effects by blocking aspirin's ability to irreversibly acetylate platelet COX-1. 1, 3, 2

• This interaction can eliminate aspirin's cardiovascular benefits 1, 3
• To avoid this interaction, patients taking low-dose aspirin should take ibuprofen at least 30 minutes after aspirin or at least 8 hours before aspirin 3

Gastrointestinal Effects

Long-term ibuprofen use causes serious gastrointestinal events including ulceration, bleeding, and perforation, which can be fatal and often occur without warning symptoms. 1, 2

• Upper GI ulcers, gross bleeding, or perforation occur in approximately 1% of patients treated for 3-6 months and 2-4% of patients treated for one year 2
• Only one in five patients who develop serious upper GI events have warning symptoms 2
• Patients with prior ulcer disease or GI bleeding have a greater than 10-fold increased risk 2
• Risk factors include concomitant corticosteroids or anticoagulants, longer duration of therapy, smoking, alcohol use, older age, and poor general health 2

Renal Effects

Long-term NSAID administration results in renal papillary necrosis, other renal injury, and dose-dependent reduction in renal blood flow. 2

• Renal toxicity occurs particularly in patients where renal prostaglandins maintain renal perfusion 2
• Highest risk patients include those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly 2
• Treatment with ibuprofen is not recommended in patients with advanced renal disease 2

Hematologic Effects

Chronic ibuprofen use causes anemia, with hemoglobin decreases of 1 gram or more observed in 17-23% of patients on long-term therapy. 2

• Post-marketing studies showed hemoglobin decreases in 17.1% of patients on 1600 mg daily and 22.8% on 2400 mg daily 2
• Anemia may result from fluid retention, occult or gross GI blood loss, or effects on erythropoiesis 2
• Ibuprofen inhibits platelet aggregation and prolongs bleeding time, though this effect is reversible unlike aspirin 2

Hepatic Effects

Borderline liver enzyme elevations occur in up to 15% of patients on long-term NSAID therapy, with rare cases of severe hepatic reactions including fulminant hepatitis and hepatic failure. 2

• Notable ALT or AST elevations (≥3 times upper limit of normal) occur in approximately 1% of patients 2
• Rare severe reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure have been reported, some with fatal outcomes 2

Serious Skin Reactions

NSAIDs including ibuprofen can cause serious and potentially fatal skin reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). 2

• These reactions may occur without warning 2
• DRESS can present with fever, rash, lymphadenopathy, facial swelling, hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis 2

Pregnancy Considerations

NSAIDs including ibuprofen should be discontinued after gestational week 28 due to increased fetal risks including premature closure of the ductus arteriosus and oligohydramnios. 1, 2

• Early pregnancy exposure shows no evidence of increased miscarriage or teratogenicity, with most reassuring data for ibuprofen 1
• Short-term use (7-10 days) in the second trimester appears safe, but NSAIDs should be restricted to first and second trimester only 1
• After 30 weeks gestation, ibuprofen increases risk of premature closure of fetal ductus arteriosus 2
• Continuous periovulatory NSAID exposure can induce luteinised unruptured follicle syndrome, reducing fertility 1

Dose and Duration Considerations

The risk of all major toxicities increases with both dose and duration of ibuprofen use, making lowest effective dose for shortest duration the critical safety principle. 1, 2, 5

• At OTC doses (≤1200 mg/day), ibuprofen has a relatively favorable safety profile comparable to paracetamol 5, 6
• Higher prescription doses (1800-2400 mg/day) used long-term for rheumatic conditions carry substantially greater risks 5
• The short plasma half-life and lack of pathologically related metabolites contribute to ibuprofen's relatively lower toxicity at OTC doses compared to other NSAIDs 5, 6

Clinical Pitfalls

• Patients often underestimate risks of OTC ibuprofen and may use it chronically without medical supervision 7
• Many patients are unaware that ibuprofen is an NSAID and may inadvertently combine it with other NSAIDs 8
• The absence of warning symptoms for serious GI events means patients cannot rely on symptoms to guide safety 2
• Drug-drug interactions are common and dose-dependent, requiring careful medication review 7