Ibuprofen: How Well Do You Know Your Favorite Drug?
by Carla Y. Falcon, D.M.D., M.D.S.
Ibuprofen was originally developed as an anti-rheumatic drug in 1961 and was first introduced by prescription in 1969 in Great Britain as Bufren. It became available by prescription in the United States in 1974, over-the-counter in Britain in 1983, and over-the-counter in the United States in 1984.
As an NSAID, ibuprofen is a non-selective inhibitor of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2). While the exact mechanism remains unknown, ibuprofen is known to be a potent inhibitor of prostaglandin synthesis, which controls pain, inflammation and fever. There are two stereo-forms of the drug, however the S-(+)-enantiomer accounts for the majority of the pharmacological activity, and has been found, in in vitro studies, to be 160 times more potent than its racemate, R-(-)-ibuprofen, in inhibiting prostaglandin synthesis, and two times more potent in inhibiting platelet aggregation and thromboxane generation. Its anti-inflammatory effect has been attributed almost entirely to the S-(+)-enantiomer.
Ibuprofen is rapidly absorbed, reaching peak serum levels one to two hours after administration, and has a half-life of 1.8 to two hours. Its primary distribution is in plasma albumin, with a volume of distribution of 0.12L/kg in adults, and significant levels are attained in synovial fluid, which is the proposed NSAID site of action. At doses greater than 600 mg, there is an increase in the unbound faction of the drug leading to an increased clearance. Ibuprofen is eliminated, after biotransformation to glucuronide conjugate metabolites, through urine and feces, with 45-79% as metabolites and <1% remaining unchanged. The maximum recommended daily dose is 3200 mg, and the therapeutic window of ibuprofen is wide: 10-50 mg/L and the toxic concentration is high (>100 mg/L).
Prescribing Precautions
The main prescribing precaution for NSAIDs is the risk of gastrointestinal (GI) tract injuries, which mainly occurs due to blockage of gastroprotective prostaglandin synthesis. Approximately 10-20% of patients taking NSAIDs may complain of dyspepsia, abdominal pain and GI discomfort, but these symptoms do not correlate with clinically significant ulcerations. It is recommended to take ibuprofen with a meal or a glass of milk if GI upset occurs, and while it has been shown that administering ibuprofen with meals reduces the absorption time, it does not affect the ultimate serum level concentration. While ibuprofen has the lowest GI bleeding risk of all NSAIDs, purportedly due to its short half-life, the risk of serious GI ulceration and bleeding is grave, and can be life threatening; therefore, NSAIDs should be avoided if the patient has a history of GI tract bleeding.
Cardiovascular complications such as worsening hypertension and an increased risk of myocardial infarction are also risks associated with using NSAIDs. As such, ibuprofen usage should be avoided in patients with congestive heart failure, and should be used with caution with patients who have hypertension, as a mean blood pressure increase of 5 mm Hg has been noted with NSAID use.
Primary hepatic complications are rare and usually reversible. However, ibuprofen should be avoided in patients with cirrhosis because of the decrease in functional capacity of the liver and its potential effects on the pharmacokinetics of ibuprofen and the potential for hematologic and renal complications. Interestingly, although ibuprofen is eliminated by oxidative metabolism, alcoholic liver disease appears to have minimal effect on the pharmacokinetics of ibuprofen.
As NSAIDs are eliminated through the kidneys, ibuprofen should be avoided in patients with renal disease. Concomitant use of anticoagulants increases the risk of GI bleeding by six times, and should therefore be avoided.
NSAIDs should be used with caution with patients who have a history of asthma, however hypersensitivity reactions most commonly are associated with patients who have severe asthma with greater medication requirements, such as dependence on corticosteroids.
Ibuprofen is not known to be a teratogen in humans. Use of low dose, intermittent ibuprofen in pregnancy is generally considered safe by the American Academy of Pediatrics as long as it is discontinued six to eight weeks before term. However, use in the third trimester of pregnancy has been cautioned against by some and as NSAIDs are used closer to term, risks to mother and child increase. Ibuprofen’s inhibition of prostaglandin synthesis may cause prolonged gestation and labor, increased peripartum blood loss, and increased anemia. Ibuprofen is the preferred NSAID for breast-feeding mothers as it has poor transfer into milk. In children, NSAIDs are considered to be just as safe as acetaminophen, with the main risk being dosing errors.
While ibuprofen has been shown to be highly effective as an analgesic, a ceiling dose has been noted by some researchers. As a result, supplemental analgesics to be taken in conjunction with ibuprofen have been advocated as a way to increase analgesia, such as concomitant administration of acetaminophen, which results in a statistically significant decrease in discomfort compared to 600 mg ibuprofen alone (Menhinick, 2004, IEJ). A quantitative systemic review found that the combination of ibuprofen and acetaminophen provided greater analgesic efficacy than opioids, as well as fewer adverse effects (Moore, 2013, JADA). With its tried and proven efficacy, it is easy to see why ibuprofen is one of the analgesics of choice by endodontists.
Dr. Falcon is an assistant professor in the Department of Endodontics at Rutgers, where she also completed her dental degree and endodontic training. She can be reached at falconcy@sdm.rutgers.edu.