Ibuprofen

General adverse effects and adverse reactions

Gastrointestinal adverse reactions are the most frequent. They occur in up to 30% of patients and range from abdominal discomfort to serious bleeding or activation of peptic ulcer. Nervous system effects, with headache and dizziness, are very common. Blood dyscrasias can occur when high dosage treatment is prolonged. There is no significant general hepatotoxicity, but both the liver and the central nervous system (meningitis) can be affected as part of a hypersensitivity reaction. Hypersensitivity reactions are uncommon, but they can be severe.

Observational studies

In a study of adverse reactions to long-term ibuprofen in the treatment of juvenile rheumatoid arthritis, gastrotoxicity was directly correlated with dosage and 5% of the patients withdrew early because they had gastrointestinal bleeding, vomiting, severe rash, hearing loss, and abnormalities of liver function tests [ ].

Systematic reviews

In a systematic review of 7 parallel-group comparisons of paracetamol and ibuprofen in 2241 participants after surgical removal of lower wisdom teeth, ibuprofen 400 mg was more efficacious than paracetamol 1000 mg []. Adverse events, which were mostly minor, included nausea, vomiting, headaches, and dizziness and were comparable between the treatment groups. No severe adverse events were thought to be definitely linked to the drugs.

Cardiovascular

Apart from the consequences of salt and water retention, ibuprofen does not affect myocardial or vascular function. Congestive heart failure has rarely been reported [ ].

All NSAIDs can cause or aggravate hypertension and inhibit the effects of antihypertensive drugs [ , ]. Data from a randomized trial have suggested that ibuprofen significantly increases blood pressure in patients taking ACE inhibitors, but that celecoxib and nabumetone do not [ ].

Compared with placebo, ibuprofen was associated with significantly greater increases in both systolic and diastolic blood pressure, whereas blood pressure increases with nabumetone and celecoxib were not significantly different to placebo. In addition, the proportion of patients with systolic blood pressure increases of clinical concern was significantly greater in those taking ibuprofen (17%) than in those taking nabumetone (5.5%), celecoxib (4.6%), or placebo (1.1%). However, the results of this study must be confirmed in a larger population of hypertensive patients on the basis of relevant clinical outcomes.

Pulmonary hypertension occurred in one of 169 preterm infants who were given lysine ibuprofen (10 mg/kg followed by 5 mg/kg after 24 and 48 hours) for closure of a patent ductus arteriosus; symptoms started within 1 hour of the second dose [ ].

In a small comparison of ibuprofen and indometacin in preterm infants with patent ductus arteriosus there was no apparent difference in the rate of patent ductus arteriosus closure; ibuprofen did not impair cerebral hemodynamics or oxygenation, while indometacin impaired cerebral oxygen delivery [ ].

Respiratory

Ibuprofen rarely provokes attacks of asthma in predisposed individuals. There is probably cross-sensitivity with aspirin; a death was reported after an asthmatic patient with no history of aspirin sensitivity took two ibuprofen tablets [ ].

Pulmonary infiltrates with eosinophilia have been described with ibuprofen [ ].

Two episodes of acute pulmonary edema and progressive pulmonary infiltrates without eosinophilia have been reported in a man with HIV infection after ibuprofen [ ].

Nervous system

Headache, vertigo, tinnitus, and insomnia are the most frequent nervous system effects, but are rarely severe. Depression and other psychotic reactions have been reported. Some nervous system reactions (meningism and meningitis, lethargy, and irritability) are thought to result from hypersensitivity [ , ]. This has been confirmed by a report of aseptic meningitis with increased intrathecal IgG synthesis and evidence of immune complexes in the cerebrospinal fluid [ ].

Analgesic-induced headache, not uncommon in adults, has also been described in children. One report [ ] described 12 children, aged 6–16 years, who gave a history of headaches on at least 4 days a week, for 3 months to 10 years. Eleven of the children had been taking paracetamol, six in combination with codeine, and one was taking ibuprofen alone. They were taking at least one dose of an analgesic for each headache and eight were taking analgesics every day. The headaches presented with increasing frequency and were related to overuse of analgesics, a typical finding in analgesic-induced headache. The analgesics were withdrawn; in six children the headaches resolved completely, another five children experienced a reduced frequency of headaches, and one resumed analgesic abuse.

The second report [ ] was a retrospective study of patients seen in a pediatric headache clinic. During 8 months 98 patients were seen for headache; 46 of them suffered from daily or near daily headache and 30 were consuming analgesics daily. Follow-up information was available in 25. The average number of doses of analgesics per week they consumed was 26. The most commonly used medications were paracetamol and ibuprofen. In addition, a minority were taking combinations that contained aspirin, codeine, caffeine, propoxyphene, or butalbital, or other NSAIDs. Abrupt withdrawal of all analgesics concomitant with the use of amitriptyline 10 mg/day (in 22 patients) prompted a significant reduction in the frequency and severity of headache.

Ibuprofen can cause aseptic meningitis [ ], the incidence of which is increasing, mainly among patients with underlying autoimmune disorders. Recurrent meningitis mimicking bacterial meningitis occurred in two women taking ibuprofen, one with dermatomyositis and one with autoimmune thyroiditis [ ]. In the authors’ review of 71 reported episodes of ibuprofen-related meningitis in 36 patients, 22 had an autoimmune disorder, mainly systemic lupus erythematosus, and 22 had recurrent episodes. Most of the episodes consisted of an acute meningeal syndrome with a predominance of neutrophils and raised protein in the cerebrospinal fluid in 26 patients.

Sensory systems

Ocular reactions described to date are reversible and not severe. They include blurred vision, changes in color perception, and toxic amblyopia [ ].

Ibuprofen significantly correlated with high-altitude retinal hemorrhages [ ].

Vortex keratopathy has been described in a woman taking oral ibuprofen [ ].

Optic neuritis with a visual field defect has been associated with ibuprofen [ ].

• A 41-year-old man took ibuprofen 400 mg tds for 3 weeks and developed blurred vision in his right eye and pain during eye and head movements that lasted 2 days. There was a marked reduction in visual acuity to 20/200 in the right eye, with quadrantanopia and absent visual-evoked potentials. After withdrawal of the drug and treatment with high-dose intravenous methylprednisolone and subcutaneous low-molecular-weight heparin, his vision improved to 20/70, the visual field defect vanished, and the visual-evoked potentials returned to almost normal values.

Although the authors could not rule out idiopathic optic neuritis, they thought that the absence of other susceptibility factors plus improvement after drug withdrawal suggested a toxic effect.

Psychiatric

Dementia has been attributed to ibuprofen.

• A 76-year-old man became confused and lost in familiar places and had short-term memory loss after taking ibuprofen 600 mg/ tds for osteoarthritic pain for 2 weeks [ ]. These symptoms continued for 2 weeks until he stopped taking ibuprofen, when his mental symptoms resolved within 1 week. Six months later he started taking ibuprofen again and within 1 week had the same symptoms. He stopped taking ibuprofen and his mental status again returned to normal.

Metabolism

An increase in serum concentrations of uric acid has been described with ibuprofen [ ].

Hematologic

Ibuprofen prolongs bleeding time, although less than aspirin [ ]. There are reports that a daily dose of less than 1 g does not affect the bleeding time [ ].

Blood dyscrasias, ranging from thrombocytopenia and granulocytopenia to agranulocytosis and fatal pancytopenia, have been reported [ ]. Reversible pure white cell aplasia with bone marrow plasmacytosis and complement-dependent IgG antibody has been observed in one patient [ ].

Fatal autoimmune hemolytic anemia has been attributed to ibuprofen in a patient who was taking other drugs [ ]. Reversible hemolytic anemia has been described during ibuprofen treatment, but tartrazine, the orange dye in the coating of the brand used (Motrin 400), may have been responsible [ ].

Gastrointestinal blood loss due to ibuprofen can cause iron deficiency anemia.

Gastrointestinal

When ibuprofen was first introduced, its gastrointestinal tolerance was regarded as better than with other NSAIDs, especially aspirin and indometacin. However, with the use of higher doses, which were probably equipotent with the usual doses of older agents, there seemed to be no significant differences. As with other NSAIDs there is a close correlation between efficacy and adverse effects. Gastrointestinal adverse effects include a variety of symptoms, such as irritation, nausea, anorexia, vomiting, dyspepsia, heartburn, abdominal discomfort, bleeding, hematemesis, and activation of peptic ulcer; 10–30% of patients taking prescription doses (for example for rheumatic conditions) develop these adverse effects [ ]. It is not possible to give a reliable estimate of the frequency when the drug is used as a self-medication analgesic in lower doses, since exact information on the complications of self-medication is rarely available and there is always likely to be a proportion of misuse (for example ingestion of higher or lower doses than recommended).

Bleeding from a Meckel’s diverticulum has been described with oral ibuprofen [ ].

Irritation of the rectal mucosa after ibuprofen suppositories has also been reported [ ]. Ulcerative proctitis has been reported in a patient with systemic lupus erythematosus [ ].

Liver

The liver can be damaged by as part of a generalized hypersensitivity reaction. Toxic hepatitis with Stevens–Johnson syndrome has been ibuprofen described [ ].

Ibuprofen has been rarely thought responsible for direct liver damage. A recent report has described three patients, 33–44 years old, with chronic hepatitis C infection, who developed more than five-fold increases in serum liver transaminases after taking ibuprofen for musculoskeletal pain. In all three there were no associated symptoms of hepatitis, and serum transaminases normalized after ibuprofen was withdrawn [ ].

Biliary tract

The vanishing bile duct syndrome has been associated with the use of ibuprofen in an atopic man, but the causal relation was not certain [ ].

Another report of this rare syndrome was associated with Stevens–Johnson syndrome in a 10-year-old girl who took ibuprofen in conventional doses (up to 30 mg/kg/day) for 2 days [ ]. She recovered uneventfully.