Ibuprofen is a widely prescribed NSAID, is considered one of the safest drugs in this group and is generally well tolerated, but can nevertheless rarely cause clinically significant and serious acute liver damage. Ibuprofen has anti-inflammatory, analgesic, and antipyretic effects.

The drug is prescribed for symptomatic treatment of different types of pain, including headache, toothache, dysmenorrhea, neuralgia, back pain, joint pain, muscle pain, rheumatic pain, as well as signs of SARS and flu. Ibuprofen is prescribed as a monodrug or in combination with other analgesics, antihistamines, or anticholinergic drugs, usually in doses of 200, 400, 600, or 800 mg. Pediatric dosage forms of this drug are also available in pharmacies. Ibuprofen is part of many combination medications for the symptomatic treatment of dysmenorrhea, headache, allergies, and SARS.

Ibuprofen. FDA-approved indications

Ibuprofen is indicated and approved by the FDA for the symptomatic treatment of inflammatory conditions and rheumatoid arthritis. Ibuprofen was discovered while searching for an alternative non-corticosteroid treatment for rheumatoid arthritis. This disease was the impetus for the creation of the substance that eventually became known as ibuprofen. Patented by Dr. Stuart Adams and John Nicholson as 2-(4-isobutylphenyl)propionic acid (ibuprofen) became and remains one of the most widely used NSAIDs in the world (Halford G.M. et al., 2012). Today, ibuprofen is used as monotherapy for the symptomatic treatment of pain in rheumatoid arthritis and inflammatory diseases, with some research into the introduction of new treatments or dosage forms. One such study includes the development of complex drugs based on NSAIDs and a carbohydrate inhibitor for the symptomatic treatment of rheumatoid arthritis pain (Akgul O. et al., 2018).

Ibuprofen is FDA approved for symptomatic use in mild to moderate pain. As an over-the-counter medication, it is used as a symptomatic treatment for sprained muscles, joint pain, migraines, sore throat, and acute respiratory infections/influenza. Postoperative pain is a type of pain. One randomized, double-blind study demonstrated the therapeutic efficacy of IV ibuprofen; the comparison drug was IV acetaminophen. Drug efficacy was compared in the treatment of postoperative pain in patients undergoing laparoscopic cholecystectomy. A study in the first 24 h after the procedure found that IV therapy with ibuprofen reduced the severity of pain and thus there was an opportunity to reduce the dose of opioids (Ekinci M. et al., 2019). Ibuprofen is widely used as an effective medication for the symptomatic treatment of pain, but research is constantly focused on improving the effectiveness of its clinical use.

Ibuprofen is also approved by the FDA as an antipyretic used to lower body temperature in both adults and children. NSAIDs are much more commonly used in the treatment of fever in children, and many current studies are focused around creating greater efficacy in using ibuprofen for this purpose.

Dysmenorrhea is a condition accompanied by pain during menstruation, which can vary. Dysmenorrhea can be either primary, which is usually mediated by prostaglandin production during ovulation, or secondary to another condition such as endometriosis or pelvic inflammation (Durain D., 2004). NSAIDs are often the therapeutic choice and are FDA-approved for the treatment of primary dysmenorrhea. Transdermal drug delivery has been a topic of research in the context of using ibuprofen for symptomatic therapy for primary dysmenorrhea. One study examined the use of essential oils as penetration enhancers for transdermal delivery of ibuprofen in patients with dysmenorrhea. The study found that one of the essential oils (Chuanxiong oil) had a positive effect on permeation and relief of pain symptoms when administered with ibuprofen hydrogel (Chen J. et al., 2015).

Ibuprofen and other NSAIDs are also FDA approved for the treatment of osteoarthritis. The results of a comparative study of celecoxib (coxib group) and ibuprofen demonstrated similar tolerability and efficacy in the treatment of patients with osteoarthritis of the knee (Gordo A.C. et al., 2015).

The use of ibuprofen for symptomatic treatment of gout attacks has been studied. A 1978 study by Schweitz et al. documented rapid improvement and reduction in pain severity in 10 patients with acute gouty arthritis (patients were taking ibuprofen 2400 mg) (Schweitz M.C. et al., 1978). Ibuprofen is usually used as monotherapy for mild attacks, and colchicine is used as therapy for moderate to severe gout attacks.

NSAIDs and colchicine are also often used in combination in the treatment of pericarditis due to the anti-inflammatory and analgesic properties of NSAIDs. Since 2011, ibuprofen has been one of the most widely used NSAIDs in the treatment of pericarditis. Its efficacy has been demonstrated in the CORP and CORP-2 studies in the therapy and prevention of multiple recurrences of idiopathic pericarditis compared to acetylsalicylic acid. The study found no significant difference between the two drugs in the treatment or prevention of idiopathic pericarditis (Schwier N. et al., 2017). In a 2014 review, colchicine proved to be an effective drug in reducing the incidence of recurrent pericarditis when used as adjunctive therapy to NSAIDs such as ibuprofen, acetylsalicylic acid or indomethacin, but with limitations in the number of studies (Bayes-Genis A. et al., 2017).

The intravenous use of ibuprofen has been approved by the FDA as a therapy for patent ductus arteriosus in premature infants. Studies have reported similar efficacy of ibuprofen with indomethacin for this pathology. Differences exist in the number of cases of systemic vasoconstriction and renal toxicity; likely due to less selectivity for COX-1, ibuprofen was found to have reduced rates of both outcomes (Ferguson J.M., 2019).

Since 2007, the USPSTF guidelines have recommended the use of acetylsalicylic acid and NSAIDs to prevent colorectal cancer in certain populations. In 2016, they updated these recommendations as well as the 2009 recommendations on the use of acetylsalicylic acid and NSAIDs in the prevention of cardiovascular disease (Bibbins-Domingo K. et al., 2016). Although these recommendations are not specific to ibuprofen, they do provide a solid foundation for research that supports a potentially large role for NSAIDs in cancer treatment and prevention. The results of the NSAID efficacy study in cancer treatment, as well as some studies on the efficacy of ibuprofen, have shown promising results. A review by Hil’ovska et al. documented the potential use of NSAIDs in reducing cancer cell growth, morphology, and invasion; in inducing cancer cell death; and using a lower dose of cytotoxic drugs (Hiľovská L. et al., 2015). The studies reviewed were mainly focused on COX-2 inhibitors. As for ibuprofen specifically, some studies have suggested that it has a stronger antitumor effect compared to acetylsalicylic acid, namely in studies conducted in the therapy of breast and lung cancer (Harris R.E. et al., 2005). Also, the use of ibuprofen or acetylsalicylic acid reduces the risk of breast cancer (Cuzick J. et al., 2009).

Similar to the previous authors, Wawro et al. in their studies demonstrated potential indications for the use of NSAIDs, especially acetylsalicylic acid and ibuprofen, in cancer therapy in patients with colorectal cancer who are on vincristine monotherapy. The presumed role of NSAIDs is primarily to prevent chemoresistance by inhibiting proliferation of cancer-associated fibroblast formation. Vincristine stimulates the growth of cancer-associated fibroblasts through the secretion of tumor growth factor beta (TGF-β) and IL-6; when using acetylsalicylic acid and ibuprofen, scientists have documented the drug’s inhibitory effect on this pathological process. Their studies were based on the assumption that the likely mechanism of this inhibitory effect is associated with NSAIDs affecting the rate of regulation of microtubule polymerization dynamics (Wawro M.E. et al., 2019).

Ibuprofen. Pain in the pediatric population

Pain is a common symptom in children. The use of ibuprofen in the pediatric population has been the subject of research for over 30 years. The scientific literature has reviewed information on pediatric pain over the past 20 years, drawing conclusions about the efficacy and side effects associated with the use of ibuprofen as an analgesic. Ibuprofen has been shown to be effective for several pain conditions in children, such as skeletal muscle pain, earache and acute otitis media, toothache, and inflammatory conditions of the mouth and pharynx. The drug is a reasonable and effective alternative for postoperative pain, including tonsillectomies and adenoidectomies. It also remains a choice in symptomatic pain therapy for chronic inflammatory conditions such as arthritis. The side effects associated with ibuprofen are minor. It has the lowest gastrointestinal toxicity among NSAIDs, although some cases of GI toxicity (gastrointestinal toxicity) may occur. Kidney adverse reactions are minimal, but dehydration plays an important role in causing kidney damage, so ibuprofen should not be prescribed in patients with vomiting and diarrhea. Ibuprofen therapy has demonstrated a good safety profile and has provided evidence of efficacy in the symptomatic treatment of mild to moderate pain in children of various origins. The analgesic effect of NSAIDs, such as ibuprofen, lies mainly in the inhibition of prostaglandin biosynthesis. A decrease in prostaglandin synthesis leads to a decrease in glutathione production and renal perfusion.

The advantage of combined/shared use of ibuprofen and acetaminophen

The advantages of using NSAIDs and acetaminophen simultaneously or alternately have been suggested because of their potential synergistic antinociceptive effects and the convenience of using an additional analgesic drug for pain that cannot be treated with a single drug at any age-related dose. For acetaminophen, the Cmax in plasma is reached in 30 min compared to 60 min for ibuprofen. In studies of antipyretic effects, acetaminophen reduces high body temperature at most in 2 h, and ibuprofen in 3 h. The recommended dosing intervals are every 6 and 8 h for acetaminophen and ibuprofen, respectively; thus, they can theoretically be alternated every 3 h. Short-term use of an alternating dosing regimen may be considered for symptomatic treatment of pain that is not managed by monotherapy (Massimo Barbagallo et al., 2019)

There are several randomized controlled trials of symptomatic treatment of headache in children. Have concluded that ibuprofen and sumatriptan alone are significantly more effective than placebo in reducing headache severity.

One of the Cochrane reviews included 27 randomized controlled pediatric studies of the effectiveness of NSAIDs. Each compared the therapeutic efficacy of one of the drugs in this group with placebo. Efficacy was assessed 2 hours after administration of the study drug. Based on a systematic review, ibuprofen was more effective, making it the drug of choice for the symptomatic treatment of headache. If migraine is suspected, however, NSAIDs and triptans should be considered. In the case of nausea and vomiting, anti-emetics and IV rehydration should be used (Raucci U., 2019).

Conclusions

Ibuprofen first appeared on the market about 50 years ago and quickly became a popular drug. In April 2019, France’s National Agency for Drug and Medical Device Safety (ANSM) issued a warning about the use of NSAIDs in patients with infectious diseases, based on an analysis of 20 years of real-world safety data on ibuprofen and ketoprofen. Nevertheless, ibuprofen remains the baseline drug used in symptomatic therapy of pain of various origins, which has been clearly confirmed in numerous randomized clinical trials and clinical experience. There is a review of the literature on the safety of ibuprofen and how it compares favorably with other NSAIDs. Ibuprofen therapy is characterized by adverse reactions other than gastrointestinal reactions, which are dose-dependent and particularly common in some patient populations. Among NSAIDs, ibuprofen causes a relatively low risk of cardiovascular side effects.

Overall, ibuprofen has a favorable safety profile and is effective for many acute and chronic pain conditions