Side effects of ibuprofen – NHS

Common side effects of tablets, capsules, granules and liquid

These common side effects of ibuprofen taken by mouth happen in more than 1 in 100 people. There are things you can do to help cope with them:

Headaches

Make sure you rest and drink plenty of fluids. Try not to drink too much alcohol. It’s important not to take any other medicines for pain to help with headaches. Talk to your doctor if the headaches last longer than a week or are severe.

Feeling dizzy

If ibuprofen makes you feel dizzy, stop what you’re doing and sit or lie down until you feel better. Avoid coffee, cigarettes and alcohol. If the dizziness does not get better within a couple of days, speak to your pharmacist or doctor. Do not drive or ride a bike while you’re feeling dizzy.

Feeling sick (nausea)

Stick to simple meals. Do not eat rich or spicy food. Always take ibuprofen tablets, capsules, granules or liquid with a meal or snack or with a drink of milk.

Being sick (vomiting)

Have small, frequent sips of water to avoid dehydration. Speak to a pharmacist if you have signs of dehydration, such as peeing less than usual or having dark, strong-smelling pee. Do not take any other medicines to treat vomiting without speaking to a pharmacist or doctor.

If you take contraceptive pills and you’re being sick, your contraception may not protect you from pregnancy. Check the pill packet for advice.

Wind

Try not to eat foods that cause wind (like lentils, beans and onions). Eat smaller meals, eat and drink slowly, and exercise regularly. There are pharmacy medicines that can also help, such as charcoal tablets or simeticone.

Indigestion

If you get repeated indigestion stop taking ibuprofen and see your doctor as soon as possible. If you need something to ease the discomfort, try taking an antacid, but do not put off going to the doctor.

Speak to a doctor or pharmacist if the advice on how to cope does not help and a side effect is still bothering you or does not go away.

Common side effects of gel, mousse and spray

You’re less likely to have side effects when you apply ibuprofen to your skin than with tablets, capsules, granules or liquid because less gets into your body. But you may still get the same side effects, especially if you use a lot on a large area of skin.

Applying ibuprofen to your skin can sometimes cause your skin to become more sensitive than normal to sunlight. Speak to your doctor if this is a problem.

Serious side effects

Call a doctor or contact 111 straight away and stop taking ibuprofen if you have:

• black poo or blood in your vomit – these can be signs of bleeding in your stomach
• swollen ankles, blood in your pee or not peeing at all – these can be signs of a kidney problem

Go to 111. nhs.uk or call 111.

Immediate action required: Call 999 or go to A&E now if:

• you have severe chest or stomach pain – these can be signs of a hole in your stomach or gut
• you have difficulty breathing, or asthma symptoms that become worse
• you get a severe headache, a high temperature or stiff neck, and a dislike of bright lights – these can be signs or inflammation of the protective membranes that surround the brain and spinal cord (meninges)
• you have blurred vision or you see or hear things that are not real (hallucinations)

Find your nearest A&E

Serious allergic reaction

In rare cases, it’s possible to have a serious allergic reaction (anaphylaxis) to ibuprofen.

Immediate action required: Call 999 or go to A&E now if:

• you get a skin rash that may include itchy, red, swollen, blistered or peeling skin
• you’re wheezing
• you get tightness in the chest or throat
• you have trouble breathing or talking
• your mouth, face, lips, tongue or throat start swelling

You could be having a serious allergic reaction and may need immediate treatment in hospital.

Long term side effects

Ibuprofen can cause ulcers in your stomach or gut, especially if you take it by mouth for a long time or in big doses. If you need to take it for a long time your doctor may also prescribe a medicine to help protect your stomach.

Other side effects

These are not all the side effects of ibuprofen tablets, capsules and syrup. For a full list see the leaflet inside your medicines packet.

Information:

You can report any suspected side effect using the Yellow Card safety scheme.

Visit Yellow Card for further information.

Page last reviewed: 18 November 2021

Next review due: 18 November 2024

Recognizing the Risks of Chronic Nonsteroidal Anti-Inflammatory Drug Use in Older Adults

Ann Longterm Care. Author manuscript; available in PMC 2011 Aug 19.

Published in final edited form as:

Ann Longterm Care. 2010; 18(9): 24–27.

PMCID: PMC3158445

NIHMSID: NIHMS315767

PMID: 21857795

Author information Copyright and License information Disclaimer

Older adults commonly take nonsteroidal anti-inflammatory drugs (NSAIDs) chronically. Studies of older adults show that chronic NSAID use increases the risk of peptic ulcer disease, acute renal failure, and stroke/myocardial infarction. Moreover, chronic NSAID use can exacerbate a number of chronic diseases including heart failure and hypertension, and can interact with a number of drugs (eg, warfarin, corticosteroids). Preferred analgesics in older adults that may have a lower risk of these adverse drug reactions include acetaminophen, a nonacetylated salicylate (eg, salsalate), a short half-life NSAID (eg, ibuprofen), or low-dose opioid/opioid-like agents in combination with acetaminophen (in appropriate patients).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common class of analgesics used chronically for persistent pain due to osteoarthritis and other musculoskeletal disorders in older adults.^1-3 Specifically, an estimated 40% of people age 65 years and older fill one or more prescriptions for a NSAID each year.⁴ Considering that NSAIDs are also currently available over the counter, it is clear to see that even larger numbers of older adults are exposed to NSAIDs in the United States.

While these agents can be effective in treating inflammation and pain, older adults are at increased risk for adverse drug reactions (ADRs) due to age-related loss of physiological organ reserve, increased comorbidities, polypharmacy, and changes in pharmacokinetics.⁵ As a result, NSAID use causes an estimated 41,000 hospitalizations and 3300 deaths each year among older adults.² Some specific ADRs of concern with chronic use of NSAIDs include gastrointestinal (GI), renal, cardiovascular (CV), cerebrovascular, and central nervous system (CNS) adverse effects.⁶ This review will begin by describing key evidence for these organ-specific ADRs associated with the chronic use of NSAIDs in older adults and finish with general recommendations for healthcare providers to avoid/minimize these ADRs.

The spectrum of potential NSAID-related GI adverse effects is wide, ranging from dyspepsia to life-threatening gastric bleeding.² A nested case control study from nearly two decades ago (before the introduction of cyclooxygenase-2 [COX-2] selective NSAIDs) showed that NSAIDs increase the risk of fatal peptic ulcers by nearly fivefold in older adults;⁷ other studies have shown that the risk of peptic ulcer complications is increased by three- to fivefold in older adults using NSAIDs. ² This risk is much more pronounced in those taking concomitant systemic corticosteroids and warfarin.^8,9 In addition, the risk is increased as early as within the first month of treatment and is sustained over time.^3,10 Often, these peptic ulcers are asymptomatic but can lead to significant morbidity and mortality. The evidence for which NSAIDs are less risky is limited. One retrospective cohort study found that celecoxib, as compared to nonselective NSAIDs (ibuprofen, diclofenac, naproxen) carried the least risk of hospitalization for GI bleeding among elderly persons.¹¹ Of note, all NSAIDs (ie, nonselective and COX-2 selective) carry a boxed warning for adverse GI events. Overall, the rate of hospitalizations for peptic ulcer disease (PUD) increases with age, from 1 per 1000 per year in populations younger than age 50 years to 2-6 per 1000 per year in older adults (> 65 yr), with an estimated 15-35% of all peptic ulcer complications being due to NSAID use. ^2,12

Similar to NSAID-related GI adverse effects, NSAID-induced renal dysfunction has a wide spectrum of negative effects, including decreased glomerular perfusion, decreased glomerular filtration rate, and acute renal failure (ARF). While it is important to recognize that ARF can develop at any point during long-term NSAID therapy, the risk may be highest among those who have recently initiated therapy. Specifically, in a nested case control study of older adults, the risk of ARF was increased nearly twofold for all NSAIDs (nonselective and COX-2 selective NSAIDs) within 30 days of initial use/prescribing.¹³ This is consistent with previous studies reporting that NSAIDs increase the risk of ARF in the elderly.^14,15 This risk is further increased in those older adults with preexisting chronic kidney disease (CKD) and in those who use long half-life NSAIDs.¹⁶ Thus, diligent monitoring of renal function (eg, blood urea nitrogen/serum creatinine to estimate creatinine clearance) is critical in older adults receiving NSAIDs, especially those who are at increased risk. ¹⁴ Of note, salsalate may be preferred among the NSAIDs as it is rarely associated with nephrotoxicity.⁵ Overall, it is estimated that 2.5 million individuals in the United States experience adverse renal effects from NSAID use annually,¹⁷ with older adults being in the highest-risk group in the population.

NSAIDs have been shown to worsen/increase the risk of various CV and cerebrovascular outcomes, with some studies suggesting a greater risk associated with COX-2 selective NSAIDs as compared to nonselective NSAIDs.^11,18-23 One retrospective cohort study of older adults showed that naproxen carried the least risk of hospitalization for acute myocardial infarction (MI) among users of aspirin as compared to other nonselective NSAIDs (ibuprofen, diclofenac) and COX-2 selective NSAIDs (celecoxib, rofecoxib) used with aspirin.¹¹ In contrast, a prospective, population-based cohort study found an increased risk of stroke with the use of nonselective NSAIDs (including naproxen), as well as with COX-2 selective NSAIDs (including celecoxib) in those not taking aspirin. On an individual NSAID analysis, naproxen users were found to have more than a twofold increased risk of stroke.²⁰ Of note, all NSAIDs (ie, nonselective and COX-2 selective) carry a boxed warning for adverse CV events, including MI and stroke. Further research is needed to confirm individual NSAID adverse CV risk profiles.

One clinical trial of patients with hypertension (HTN) showed that piroxicam and ibuprofen blunted the effects of antihypertensive drugs (lisinopril/hydrochlorothiazide), significantly increasing systolic blood pressure (SBP) by 7.7-9.9%. An acetaminophen (APAP) period (in place of the NSAID) led to a significant decrease in blood pressure toward baseline, and a second exposure to the NSAIDs led to another significant increase in SBP of 7.0-7.7%, adding strong support to the evidence of causality.²¹ In addition, a cohort study of community-dwelling elderly individuals

The NSAID should be used at the lowest effective dose for the shortest period of time.

found that those who were taking antihypertensive therapy and NSAIDs had SBPs approximately 5 mmHg higher than those not taking NSAIDs, and were more likely to have SBP higher than 140 mmHg.¹⁸

NSAIDs have also been shown to cause or exacerbate heart failure (HF) in older adults. Specifically, a cohort study of older adults found that rofecoxib and nonselective NSAIDS (naproxen, ibuprofen, and diclofenac), but not celecoxib, were significantly associated with an increased risk of admission for HF as compared to those not taking NSAIDs.¹⁹ In contrast, another cohort study found that among patients who had survived their first hospitalization because of HF, subsequent use of any NSAID (including celecoxib, as well as ibuprofen, diclofenac, naproxen, and other NSAIDs) led to a significantly increased risk of death.²²

Finally, an important point of clinical debate is the interaction between low-dose, cardioprotective aspirin and NSAIDs potentially interfering with the antiplatelet effect of aspirin. The American Geriatrics Society⁵ recommends avoiding the coadministration of aspirin and ibuprofen based on a 2006 Food and Drug Administration warning. However, it is important to recognize that evidence suggests that this warning should also apply to naproxen, but not celecoxib.^23,24

NSAID use has been shown to be associated with a number of CNS effects including aseptic meningitis, psychosis, and cognitive dysfunction.^1,2 This latter point may seem to be inaccurate, but the literature suggests otherwise. At the time of this writing, the studies to date have not consistently shown a benefit from chronic NSAID use in reducing the risk of dementia or cognitive impairment.²⁵ Interestingly, though, several studies have shown that high-dose NSAIDs (ie, anti-inflammatory doses) may actually increase the risk of cognitive impairment.^26,27 In particular, indomethacin appears to cause more CNS effects than other NSAIDs in the elderly. ²⁸

One approach to reducing ADRs associated with NSAIDs is to avoid the use of specific agents and use preferred alternative analgesics (). This is particularly important in those older adults with preexisting HTN, CKD, HF, and/or PUD, or those taking concomitant warfarin or corticosteroids. An alternative option would be to use APAP, which has been shown to be equally effective to NSAIDs in a number of studies of patients with mild-to-moderate osteoarthritis pain. Of note, patients who say that APAP does not work for them may not have used an optimal dose (3-4 g/day in divided doses for at least 2 wk), which would be required in order to show a lack of effectiveness. If APAP does not work and NSAID use is not contraindicated, a trial of analgesic dosing of a nonacetylated salicylate (eg, salsalate) or ibuprofen or celecoxib may be acceptable. For those with moderate-to-moderately severe osteoarthritis pain, a trial of a low-dose opioid or opioid-like agent (eg, codeine, tramadol) in combination with APAP is another option. The rationale for this approach is to combine two different mechanisms of analgesic action. In those elderly persons who require chronic NSAIDs, a proton pump inhibitor or misoprostol should be used to avoid the risk of PUD.^9,12 In general, long half-life NSAIDs (eg, naproxen, oxaprozin, piroxicam) and specific other NSAIDs (eg, indomethacin, ketorolac) should be avoided because their risk outweighs their potential benefits.²⁸

Table

Preferred Analgesic Agents for Treatment of Nociceptive Pain in Older Adults

Drug	Initial Dosing	Special Considerations in Older Adults
Mild-to-Moderate Pain
APAP	325-500 mg every 4 h or 500-1000 mg every 6 h; maximum daily dose of 4000 mg	Does not interfere with platelet function; reduce maximum dose 50% to 75% in patients with hepatic insufficiency or history of alcohol abuse
Celecoxib	100 mg daily	Higher doses associated with higher incidence of GI and CV side effects; patients with indications for cardioprotection require aspirin
Ibuprofen	200 mg 3-4 times/day; maximum daily dose of 3200 mg	Risk of GI bleeding increased in persons > 75 yr; misoprostol or PPI should be prescribed for long-term users
Salsalate	500-750 mg every 12 h; maximum daily dose of 3000 mg	Does not interfere with platelet function; GI bleeding and nephrotoxicity are rare
Moderate-to-Moderately Severe Pain
APAP/Codeine	325/30 mg every 6 h; maximum daily dose of 12 tablets	Monitor for constipation, confusion, and falls; same considerations for APAP as listed above
APAP/Tramadol	325/37. 5 mg every 6 h; maximum daily dose of 8 tablets	Renally adjusted dose when estimated creatinine clearance < 30 mL/min: maximum of 2 tablets every 12 h; treatment should not exceed 5 days; same considerations for APAP as listed above

Open in a separate window

APAP = acetaminophen; GI = gastrointestinal; CV = cardiovascular; PPI = proton pump inhibitor.

Contains information from references ⁵and ⁶.

This review has summarized the potential risks associated with chronic NSAID use in older adults, including GI, renal, CV/cerebrovascular, and CNS adverse effects. Although only ADRs affecting these four organ systems were discussed in this review, it is important to recognize that NSAIDs can cause various other adverse effects (eg, hepatotoxicity, cutaneous toxicity).² Moreover, it is important to note that nonpharmacological approaches (weight reduction, increasing physical activity) may also help patients who are experiencing musculoskeletal pain. ²⁹ For patients already taking NSAIDS chronically, healthcare providers should assess whether the patient could switch to APAP or salsalate. If the patient still requires a NSAID, GI prophylaxis should be considered in all older patients, especially those with other risk factors; importantly, the NSAID should be used at the lowest effective dose for the shortest period of time.

As the aging population rapidly grows over the next few decades, the risks associated with chronic NSAID use will remain an important public health issue. Hopefully, health-care providers armed with the above information who carefully and consistently monitor chronic NSAID use in their older patients will avoid these preventable complications.

The writing of this paper was supported by National Institute on Aging grants (R01AG027017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056), a National Institute of Mental Health grant (R34 MH082682), a National Institute of Nursing Research grant (R01 NR010135), and an Agency for Healthcare Research and Quality grant (R01 HS017695).

The authors report no relevant financial relationships.

1. Hanlon JT, Fillenbaum GG, Studenski SA, et al. Factors associated with suboptimal analgesic use in community-dwelling elderly. Ann Pharmacother. 1996;30(7-8):739–744. [PubMed] [Google Scholar]

2. Griffin MR. Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury. Am J Med. 1998;104(3A):23S–29S. 41S–42S. [PubMed] [Google Scholar]

3. Gupta M, Eisen GM. NSAIDs and the gastrointestinal tract. Curr Gastroenterol Rep. 2009;11(5):345–353. [PubMed] [Google Scholar]

4. Ray WA, Stein MC, Byrd V, et al. Educational program for physicians to reduce use of non-steroidal anti-inflammatory drugs among community-dwelling elderly persons: A randomized controlled trial. Med Care. 2001;39(5):425–435. [PubMed] [Google Scholar]

5. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57(8):1331–1346. Published Online: July 2, 2009. [PubMed] [Google Scholar]

6. Hanlon JT, Guay DRP, Ives TJ. Oral analgesics: efficacy, mechanism of action, pharmacokinetics, adverse effects, and practical recommendations for use in older adults. In: Gibson SJ, Weiner DK, editors. Pain in Older Persons. IASP Press; Seattle, WA: 2005. pp. 205–222. [Google Scholar]

7. Griffin MR, Ray WA, Schaffner W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med. 1988;109(5):359–363. [PubMed] [Google Scholar]

8. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med. 1993;153(14):1665–1670. [PubMed] [Google Scholar]

9. MacLean CH, Pencharz JN, Saag KG. Quality indicators for the care of osteoarthritis in vulnerable elders. J Am Geriatr Soc. 2007;55(suppl 2):S383–S391. [PubMed] [Google Scholar]

10. Schaffer D, Florin T, Eagle C, et al. Risk of serious NSAID-related gastrointestinal events during long-term exposure: A systematic review. Med J Aust. 2006;185(9):501–506. [PubMed] [Google Scholar]

11. Rahme E, Nedjar H. Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: Does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. Rheumatology (Oxford) 2007;46(3):435–438. Published Online: January 25, 2007. [PubMed] [Google Scholar]

12. Lanza FL, Chan FK, Quigley EM. Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104(3):728–738. Published Online: February 24, 2009. [PubMed] [Google Scholar]

13. Schneider V, Lévesque LE, Zhang B, et al. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am J Epidemiol. 2006;164(9):881–889. Published Online: September 27, 2006. [PubMed] [Google Scholar]

14. Griffin MR, Yared A, Ray WA. Nonsteroidal anti-inflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol. 2000;151(5):488–496. [PubMed] [Google Scholar]

15. Winkelmayer WC, Waikar SS, Mogun H, Solomon DH. Nonselective and cyclooxygenase-2-selective NSAIDs and acute kidney injury. Am J Med. 2008;121(12):1092–1098. [PubMed] [Google Scholar]

16. Murray MD, Black PK, Kuzmik DD, et al. Acute and chronic effects of nonsteroidal antiinflammatory drugs on glomerular filtration rate in elderly patients. Am J Med Sci. 1995;310(5):188–197. [PubMed] [Google Scholar]

17. Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: Meta-analysis of randomized trials. JAMA. 2006;296(13):1619–1632. Published Online: September 12, 2006. [PubMed] [Google Scholar]

18. Chrischilles EA, Wallace RB. Nonsteroidal anti-inflammatory drugs and blood pressure in an elderly population. J Gerontol. 1993;48(3):M91–M96. [PubMed] [Google Scholar]

19. Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: A population-based cohort study. Lancet. 2004;363(9423):1751–1756. [PubMed] [Google Scholar]

20. Haag MD, Bos MJ, Hofman A, et al. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke. Arch Intern Med. 2008;168(11):1219–1224. [PubMed] [Google Scholar]

21. Pavlicević I, Kuzmanić M, Rumboldt M, Rumboldt Z. Interaction between antihypertensives and NSAIDs in primary care: A controlled trial. Can J Clin Pharmacol. 2008;15(3):e372–e382. Published Online: October 24, 2008. [PubMed] [Google Scholar]

22. Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med. 2009;169(2):141–149. [PubMed] [Google Scholar]

23. Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol. 2005;45(8):1295–1301. [PubMed] [Google Scholar]

24. Renda G, Tacconelli S, Capone ML, et al. Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease. Clin Pharmacol Ther. 2006;80(3):264–274. [PubMed] [Google Scholar]

25. Coley N, Andrieu S, Gardette V, et al. Dementia prevention: Methodological explanations for inconsistent results. Epidemiol Rev. 2008;30(1):35–66. Published Online: September 8, 2008. [PubMed] [Google Scholar]

26. Saag KG, Rubenstein LM, Chrischilles EA, Wallace RB. Nonsteroidal antiinflammatory drugs and cognitive decline in the elderly. J Rheumatol. 1995;22(11):2142–2147. [PubMed] [Google Scholar]

27. Hanlon JT, Schmader KE, Landerman LR, et al. Relation of prescription nonsteroidal antiinflammatory drug use to cognitive function among community-dwelling elderly. Ann Epidemiol. 1997;7(2):87–94. [PubMed] [Google Scholar]

28. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers criteria for potentially inappropriate medication use in older adults: Results of a U.S. consensus panel of experts. Arch Intern Med. 2003;163(22):2716–2724. published correction appears in Arch Intern Med 2004;164(3):298. [PubMed] [Google Scholar]

29. American Geriatrics Society Panel on Exercise and Osteoarthritis Exercise prescription for older adults with osteoarthritis pain: Consensus practice recommendations. A supplement to the AGS Clinical Practice Guidelines on the management of chronic pain in older adults. J Am Geriatr Soc. 2001;49(6):808–823. published correction appears in J Am Geriatr Soc 2001;49(10):1400. [PubMed] [Google Scholar]

Interactions Ibuprofen – what it is combined with, the effect of the use with other drugs

safety and efficacy in general clinical practice

ASA – acetylsalicylic acid

Gastrointestinal tract

IHD – ischemic heart disease

PM – medicines

NSAIDs – non-steroidal anti-inflammatory drugs

COX – cyclooxygenase

PG – prostaglandin

TxA2 – thromboxane

Modern clinical practice is difficult to imagine without the use of various non-steroidal anti-inflammatory drugs (NSAIDs). In ancient Greece, more than 3.5 thousand years ago, Hippocrates used willow bark extract as an antipyretic and analgesic. Much later, in the 17th century, a substance was isolated from it, which was called salicylic acid (from Latin salix – willow). At the end of the 19th century, the production of salicylic acid and acetylsalicylic acid (ASA) began in Germany. Currently, more than 20 different representatives of this group are known in clinical practice, with differences in chemical structure, features of the mechanism of action, indications for use and tolerability.

The mechanism of action of NSAIDs. NSAIDs inhibit the synthesis of prostaglandins (PG), which are important physiological and pathological mediators. PGs are involved in such processes as pain, inflammation, oncogenesis, osteoporosis, regulation of body temperature (hyperthermia) and kidney function, etc. From arachidonic acid, with the participation of the enzyme cyclooxygenase (COX), PGh3 is formed, which is the precursor of such PGs as thromboxane (TxA2), prostacyclin, or PGI ₂ , D ₂ , E ₂ and F ₂ (see illustration). Figure 1. The mechanism of action of NSAIDs [2, 3]. Two main isoforms of COX are known: COX-1 and COX-2. The issue of isolation under experimental conditions of the third isoform, COX-3, as a variant of COX-1 remains unresolved [1]. The first isoform (COX-1) is synthesized constantly and works according to a universal mechanism, i.e. regardless of the organ or tissue in which the synthesis takes place. Synthesis of the second isoform (COX-2) is stimulated by various inflammatory factors (lipopolysaccharides, interleukins, tumor necrosis factor α) in various cells of the human body, such as endothelium, osteoclasts, synoviocytes, monocytes, and macrophages [2].

The main pharmacodynamic properties of NSAIDs – anti-inflammatory, antipyretic and analgesic effects – are provided through the inhibition of COX-1 and COX-2. It is the inhibition of COX-1 and COX-2 that causes the main adverse reactions against the background of the use of NSAIDs. Prostaglandins PGE ₂ and PGI ₂ , which are synthesized with the participation of COX-1 in the gastrointestinal tract (GIT), are mucosal cytoprotectors by reducing the secretion of hydrochloric acid by parietal cells of the stomach, improving blood flow and stimulating mucus production. In addition, with the participation of COX-1, the synthesis of TxA ₂ in platelets with vasoconstrictive and proaggregant properties. NSAIDs, blocking the synthesis of COX-1, can lead to damage to the mucous membrane of the stomach and intestines and impaired platelet aggregation. Thus, NSAIDs increase the risk of developing severe gastrointestinal diseases such as inflammation, bleeding, and penetration of the stomach or intestines. The risk of developing such complications is higher in the elderly and does not depend on the duration of drug use [4].

The classification of NSAIDs is presented in Table . 1. Among the representatives of NSAIDs, there are differences in the chemical structure, features of action and in the degree of inhibition of COX-1 and COX-2. The selectivity of NSAIDs in relation to COX isoforms is usually assessed by the ratio of the degree of inhibition of COX-1 to COX-2 (selectivity coefficient). Selective inhibitors of COX-2 are those NSAIDs in which this coefficient is more than 5, highly selective inhibitors – if this coefficient is more than 50 (see table 1) . NSAIDs with high selectivity for COX-2 are called coxibs (from English – cyclo-oxygenase, abbreviated version of COX).

Clinical pharmacology of ibuprofen. One of the NSAIDs widely used in clinical practice is ibuprofen, which was synthesized by S. Adams and D. Nicholson in the UK in 1962. In the Russian Federation, it is registered under the trade name Nurofen (original drug). It has pronounced anti-inflammatory, analgesic and antipyretic effects, which, combined with good tolerability, predictability of side effects and a low risk of complications, has led to its widespread use in clinical practice.

According to its chemical structure, ibuprofen is a derivative of propionic acid, according to the mechanism of action, it is a non-selective inhibitor of COX-1 and COX-2, lipoxygenase involved in the synthesis of pro-inflammatory leukotrienes [6].

Ibuprofen is a racemic mixture of two optical left- and right-handed isomers, the S (+) and R (-) enantiomers. The clinical efficacy of ibuprofen is mainly due to the action of the S (+) form, however, the presence of the R (–) isomer explains some of the anti-inflammatory properties of ibuprofen [7].

Variety of dosage forms of ibuprofen. Modern opportunities for the use of ibuprofen are associated with advances in the field of pathophysiology of diseases and the development of new dosage forms of this drug. Currently, ibuprofen is represented on the drug market in a variety of dosage forms.

In addition to oral ibuprofen, it can also be used topically in the form of a gel, rectal (as suppositories) and parenteral (as solutions for intravenous administration) (Table 2). Modern technologies have also made it possible to develop new dosage forms – capsules containing a solution of ibuprofen (nurofen ultracap) and ibuprofen derivatives – sodium dihydrate and lysinate. The advantages of the lysine salt of ibuprofen are the rate of dissolution of this compound, the increase in bioavailability and the rate of onset of the maximum concentration in blood plasma (nurofen express) [8-10].

In clinical practice, new dosage forms with modified release are also presented, i.e. with a mechanism and nature of the release of the medicinal substance changed in relation to the usual form. Such forms of ibuprofen are known as the form of quick release (immediate release – IR) and the form of slow release (sustained release – SR).

Pharmacokinetics of ibuprofen. The main pharmacokinetic parameters of ibuprofen, in particular the concentration of enantiomers in plasma or the area under the pharmacokinetic curve, depend on the dosage form and dose of ibuprofen (see table. 2) .

When taken orally, ibuprofen is rapidly absorbed from the upper small intestine. The bioavailability of ibuprofen as a weak acid when taken orally is on average 80%. Eating, as a rule, reduces the rate of absorption of ibuprofen, however, it has been shown that some foods and drinks (for example, Coca-Cola) can cause an increase in the degree of absorption. The time to reach the maximum concentration of ibuprofen isomers in plasma or serum is on average 1-2 hours and depends on the dosage form of ibuprofen (see table 2) . According to the rate of absorption, dosage forms of ibuprofen can be distributed in ascending order: ibuprofen tablets → ibuprofen suspension → ibuprofen solution. The rapid absorption of ibuprofen from liquid forms (suspension, solution) provides a faster analgesic and antipyretic effect.

After oral administration, 40-60% of the R (-) form of ibuprofen is metabolized in the intestine and liver to the S (+) form. Further biotransformation of ibuprofen takes place in 2 phases. I – phase of oxidative reactions is associated with a system of microsomal cytochrome P-450 enzymes (2C9, 2C8 and 2C19), providing the formation of inactive carboxyl and phenolic compounds. Differences in the genotypes of the P-450 2C9 system lead to differences in ibuprofen metabolism, an increase in the area under the pharmacokinetic curve, and a change in hepatic clearance [7]. Phase II of ibuprofen metabolism includes the formation of inactive glucuronic and taurine compounds, which are subsequently excreted mainly through the kidneys. Impaired liver function due to cirrhosis of the liver leads to a slower inversion of the R form (-) of ibuprofen to the S form (+), as well as an increase in the half-life to 3.4 hours. Impaired renal function also reduces the rate of excretion of ibuprofen metabolites.

Ibuprofen is highly bound to plasma albumin (90-99%). In adults, ibuprofen, when taken orally and intravenously, has a short half-life of about 2 hours. Ibuprofen penetrates well into the synovial fluid of inflamed joints, which provides analgesic and anti-inflammatory effects. The antipyretic effect of ibuprofen is due to the inhibition of PGE2 synthesis in the central nervous system. Ibuprofen is a lipophilic substance, however, only its free (non-albumin-bound) fraction penetrates the blood-brain barrier.

With topical application of ibuprofen, there is a slight decrease in the systemic bioavailability of the drug to 14-30% of that when taken orally [12], while after topical application, higher concentrations are observed in subcutaneous and soft tissues, including muscle [13]. A number of studies in patients of different categories have shown that the effectiveness of topical application of ibuprofen (5% gel) and ibuprofen (1200 mg/day) orally in both acute traumatic injuries of soft tissues and chronic pain syndrome is the same, and the tolerability of topical forms is better. [12, 14, 15].

The pharmacokinetic curve for rectal use is comparable to the pharmacokinetic data for oral administration. Absorption with rectal administration of ibuprofen is characterized by a high degree of bioavailability and the rapidity of the onset of the maximum plasma concentration. In addition, the peculiarities of the blood supply to the rectal region lead to the fact that only part of the drug is metabolized in the liver, which leads to an increase in the half-life.

Pharmacokinetic parameters do not differ significantly in both men and women, and in different age groups. Pharmacokinetic parameters in children older than 2 years and adolescents do not differ from those in adults. The only exceptions are children under 2 years of age, in which the metabolism of ibuprofen is significantly lower than in adults, which requires the correct dosing regimen of the drug depending on the child’s body weight. With increasing age, there is a slight increase in elimination half-lives, which reflects age-related changes in metabolism and clearance, but in older people, ibuprofen excretion does not undergo significant changes.

Safety of ibuprofen. The development of selective COX-2 inhibitors was aimed at overcoming the limitations of the use of NSAIDs due to the risk of adverse gastrointestinal reactions. However, during the introduction of coxibs into clinical practice, another safety problem arose during long-term use – an increase in the risk of developing cardiovascular thrombotic complications, myocardial infarction and stroke [16]. At the heart of the increased risk of developing thrombotic complications against the background of selective COX-2 inhibitors is an imbalance between thromboxane and prostacyclin, which regulate endothelial function and platelet aggregation. Selective coxibs, due to the selective blockade of COX-2, disrupt the balance between the level of thromboxane and prostacyclin, which is the basis for the development of thrombotic complications [2]. However, the results of subsequent clinical observations have shown that the use of non-selective NSAIDs also increases the risk of developing cardiovascular complications [17, 18]. Current international recommendations based on the results of long-term clinical trials limit the use of both coxibs and non-selective NSAIDs in patients with coronary heart disease (CHD), stroke, or at high risk of developing CAD [3, 5].

Another adverse reaction associated with long-term use of NSAIDs is impaired renal function, since both COX isoforms play a significant role in the regulation of kidney function. PG regulate vascular tone, maintain normal blood flow, which is necessary to maintain normal kidney function. It is now known that inhibition of COX-1 leads to a decrease in glomerular filtration rate, and inhibition of COX-2 slows sodium reabsorption in healthy volunteers and the elderly. According to a meta-analysis, selective COX-2 inhibitors increase the risk of developing renal failure and arrhythmia [2, 19].

Ibuprofen has a strong evidence base for safety, making it available over the counter in many parts of the world (at dosages below 1200 mg).

The safety of ibuprofen has been demonstrated in many large clinical trials. Of greatest interest is a multicenter randomized study conducted in 1999 in France with the participation of 8677 patients (PAIN study), the purpose of which was to compare the efficacy and tolerability of over-the-counter analgesics: ASA, paracetamol and ibuprofen. It has been shown that ibuprofen (at a dose of less than 1200 mg) is tolerated as well as paracetamol, which was previously considered the standard of safety, and, compared with ASA, causes a significantly lower frequency of adverse reactions [20].

When comparing the frequency of adverse reactions of the gastrointestinal tract, it was noted that ibuprofen is characterized by high safety due to the presence of a low-active enantiomer R, which is a competitor for the active form S for the active center of COX-1, which is responsible for the synthesis of PG, which protect the gastrointestinal mucosa. In addition, the short half-life of ibuprofen may also provide a safety advantage for the use of this drug.

Ibuprofen does not form toxic metabolites, its toxicity after accidental or deliberate overdose is lower and it has a relatively higher therapeutic index (about 4 times higher than that of paracetamol). For ibuprofen, the development of Reye’s syndrome (acute hepatic encephalopathy in children while taking ASA) is also uncharacteristic [14, 21].

Clinical efficacy of ibuprofen. Ibuprofen is an effective analgesic for acute pain syndrome of various origins. At a dose of 400 mg, it has repeatedly proved its advantage over placebo in postoperative, toothache, sore throat, dysmenorrhea, tension headache and migraine, soft tissue injury, neuralgia and myalgia, as well as a number of other conditions accompanied by severe pain syndrome.

For headaches, ibuprofen as a first-line drug is included in the list of analgesics recommended by WHO, as well as by the European Federation of Neurological Societies (EFNS) for the treatment of mild to moderate migraine attacks (class A) [22, 23]. The effectiveness of ibuprofen in the treatment of cephalgia has been proven in many placebo-controlled clinical trials, as well as several meta-analyses, including in children and adolescents [24-28].

At a dose of 200–400 mg, ibuprofen is the “gold standard” for the treatment of moderate pain in patients with postoperative toothache [29]. A meta-analysis demonstrated high efficacy of ibuprofen compared to placebo in 72 studies. Ibuprofen significantly reduced pain in all patients by at least 50% at an average of 4.7 hours. Repeat analgesia was required in only 48% of patients who took ibuprofen at a dose of 200 mg, and in 42% at a dose of 400 mg [30] . Another meta-analysis based on 33 studies revealed the advantage of ibuprofen (400 mg) in relieving pain after tooth extraction compared with paracetamol (1000 mg), as well as a combination of paracetamol (600-650 mg) and codeine (60 mg) [31].

Particularly acute is the issue of choosing an effective and safe NSAID in pediatric practice, in view of the fact that fever and pain are leading in a number of diseases, including respiratory infections, most common in young children. Large multicenter randomized trials have shown that among all antipyretic analgesics, ibuprofen and paracetamol are the safest drugs. Thus, a meta-analysis combining 24 randomized and 12 observational studies in the period from 1950 to 2008, did not show statistically significant differences in the incidence of adverse reactions of the gastrointestinal tract and kidneys, as well as in the effect on the course of bronchial asthma when taking ibuprofen, paracetamol and placebo [32]. The largest systematic review of data on the efficacy and safety of ibuprofen compared with paracetamol in the treatment of fever and pain in children and adults was conducted in 2010. It included 85, including large randomized trials in the period 2008-2009. The authors made conclusion that ibuprofen is more effective than paracetamol in the treatment of fever and pain in all age groups with equal safety [33].

According to WHO recommendations, ibuprofen at a dose of 5–10 mg/kg, along with paracetamol, is the drug of choice as an antipyretic and analgesic (for mild to moderate pain) in children from 3 months of age. No other NSAIDs can be recommended for use in pediatric practice due to the lack of the necessary evidence base for their efficacy and safety [34, 35].

Ibuprofen is also currently the only drug on the WHO formulary for the treatment of patent ductus arteriosus in newborns [36]. New, potentially possible, indications for the use of ibuprofen are being studied.

Cystic fibrosis. Several clinical studies have demonstrated the effect of ibuprofen on slowing down the progression of the pulmonary process (slowing the decrease in forced expiratory volume in 1 second) in patients with cystic fibrosis with long-term use in various age groups [37-39]. The results obtained are probably associated with a decrease in the influx of polymorphonuclear cells into the lungs and, consequently, the inflammatory process [40]. Despite the fact that large doses of ibuprofen were used, the risk of developing adverse reactions of the gastrointestinal tract remained low [37, 38].

Parkinson’s disease. It is believed that one of the key links in the pathogenesis of Parkinson’s disease is neuroinflammation. Based on this assumption, several studies have been conducted, the purpose of which was to determine the role of NSAIDs in the development of the disease. A 2010 meta-analysis of 7 large epidemiological studies demonstrated a 15% reduction in the risk of developing Parkinson’s disease in the general group of patients taking NSAIDs, as well as 29% and 21%, respectively, with regular and long-term use of NSAIDs. The strongest neuroprotective effect was noted for ibuprofen, which was also confirmed by a number of other studies [41–43].

Breast cancer. Currently, there is great interest in the positive effects of NSAIDs, primarily ASA and ibuprofen, on the risk of developing various types of cancer [44-46]. According to the results of a meta-analysis (38 studies, n = 2 788715), conclusions were drawn about the possible oncoprotective effect of NSAIDs, primarily ibuprofen (relative risk 0.