What are the common side effects of ibuprofen. What are the severe side effects of ibuprofen. What are the long term side effects of ibuprofen.

Common Side Effects of Ibuprofen

Ibuprofen is a widely used over-the-counter medication that can provide relief for pain, fever, and inflammation. However, like any medication, it can also cause side effects. The common side effects of ibuprofen taken by mouth include headaches, dizziness, nausea, vomiting, wind, and indigestion. These side effects occur in more than 1 in 100 people.

To help cope with these common side effects, the NHS recommends the following:

• Headaches: Make sure to rest, drink plenty of fluids, and avoid alcohol. Do not take any other medicines for pain to help with headaches. Speak to your doctor if the headaches last longer than a week or are severe.
• Dizziness: Stop what you’re doing and sit or lie down until the dizziness passes. Avoid coffee, cigarettes, and alcohol. If the dizziness does not improve within a couple of days, speak to your pharmacist or doctor. Do not drive or ride a bike while feeling dizzy.
• Nausea: Stick to simple meals, avoid rich or spicy food, and always take ibuprofen with a meal or snack or with a drink of milk.
• 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.
• Wind: Try not to eat foods that cause wind, such as lentils, beans, and onions. Eat smaller meals, eat and drink slowly, and exercise regularly. There are also pharmacy medicines that can 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.

If the advice on how to cope does not help and a side effect is still bothering you or does not go away, it’s important to speak to a doctor or pharmacist.

Serious Side Effects of Ibuprofen

While the common side effects of ibuprofen can be managed, there are also more serious side effects that require immediate medical attention. 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

Immediate action is required if you have:

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

In rare cases, it’s also possible to have a serious allergic reaction (anaphylaxis) to ibuprofen. Call 999 or go to A&E immediately if you experience a skin rash, wheezing, tightness in the chest or throat, trouble breathing or talking, or swelling of the mouth, face, lips, tongue, or throat.

Long-Term Side Effects of Ibuprofen

Ibuprofen can also cause long-term side effects, particularly if it is taken for a long time or in large doses. The most significant long-term side effect is the risk of developing ulcers in the stomach or gut. If you need to take ibuprofen for an extended period, your doctor may prescribe a medication to help protect your stomach.

It’s important to note that the list of side effects provided is not exhaustive, and you should always refer to the leaflet inside your medication packet for a full list of potential side effects. Additionally, you can report any suspected side effects using the Yellow Card safety scheme.

Applying Ibuprofen to the Skin

When ibuprofen is applied to the skin in the form of a gel, mousse, or spray, you are less likely to experience the same side effects as with oral forms of the medication. This is because less of the active ingredient gets into your body. However, you may still experience some of the same side effects, especially if you use a large amount on a large area of skin.

One potential side effect of applying ibuprofen to the skin is increased sensitivity to sunlight. If this becomes a problem, it’s important to speak to your doctor.

Reporting Side Effects

If you experience any side effects, whether common or severe, it’s important to report them to your healthcare provider. You can also use the Yellow Card safety scheme to report any suspected side effects of ibuprofen or other medications.

Conclusion

Ibuprofen is a widely used medication that can be effective in managing pain, fever, and inflammation. However, it’s important to be aware of the potential side effects, both common and severe, and to take the necessary steps to manage them. By understanding the risks and taking the appropriate precautions, you can safely use ibuprofen to alleviate your symptoms while minimizing the likelihood of experiencing adverse effects.

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

How Much Ibuprofen is Too Much?

The Science of Health

View more from this blog

• 
  Topics
  • 
    Babies & Children
  • 
    Bones, Joints & Muscles
  • 
    Brain & Nerves
  • 
    Cancer
  • 
    Diabetes
  • 
    Diet & Nutrition
  • 
    Digestive
  • 
    Ear, Nose & Throat
  • 
    Eyes & Vision
  • 
    Family Medicine
  • 
    Heart & Vascular
  • 
    Integrative Medicine
  • 
    Lungs & Breathing
  • 
    Men’s Health
  • 
    Mental Health
  • 
    Neurology & Neurosurgery
  • 
    Older Adults & Aging
  • 
    Orthopedics
  • 
    Skin, Hair & Nails
  • 
    Spine & Back
  • 
    Sports Medicine & Exercise
  • 
    Travel Medicine
  • 
    Urinary & Kidney
  • 
    Weight Loss & Management
  • 
    Women’s Health

• 
  Categories
  • 
    Blog
  • 
    Patient Stories
  • 
    Podcasts
  • 
    Infographics
  • 
    Videos

Subscribe to Notifications

May 07, 2018

If you pull a muscle while running, are experiencing menstrual cramps or have a killer headache, you’re likely to reach for an ibuprofen pill, such as Advil or Motrin, to reduce the inflammation and quash the pain. When taken correctly, ibuprofen is a safe and effective choice.

Available both over-the-counter and by prescription, ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase enzymes to prevent or reduce pain and inflammation.

While ibuprofen works well when you take it as directed, taking more of the medicine or taking it too often is not helpful and can actually hurt you, says gastroenterologist Gerard Isenberg, MD.

“People who take it chronically are at risk of developing problems,” he says. “A recent study showed that incorrect use of NSAIDs is estimated to account for 107,000 hospitalizations and 15,600 deaths annually in the United States.”

Among the risks of chronic or incorrect ibuprofen use are:

• Ulcers, with an annual incidence of 2 to 4 percent
• Worsening kidney function
• Cardiovascular issues, such as heart attack, heart failure, stroke and increased blood pressure
• Gastrointestinal bleeding
• Stomach upset and – rarely – a condition called microscopic colitis, which can cause diarrhea
• Nausea
• Complications with childbirth and in the newborn, when the mother takes ibuprofen during the third trimester (but ibuprofen use is fine when breastfeeding)

Ibuprofen is an appropriate option for most people, but Dr. Isenberg says it can cause these complications when:

• Used by someone who has liver disease
• Taken with another NSAID, such as aspirin
• Taken with a blood thinner, such as Coumadin
• Taken with other medications, such as clopidogrel, phenytoin or cyclosporine
• Dosing instructions are ignored (i.e., taking too many at a time or taking subsequent doses too soon)
• Used during the third trimester of pregnancy

If you choose to take ibuprofen to help you through an injury or other painful condition, Dr. Isenberg says you can mitigate your risk of developing side effects by following these five guidelines:

1. Take the lowest dose that is effective for your symptoms.
2. Consult your doctor before taking ibuprofen if you have a history of stomach, kidney or heart issues, or if you are pregnant.
3. Ask your doctor about using a topical NSAID gel, such as Diclofenac, instead of oral ibuprofen for musculoskeletal pain. This gel, available in a patch, is a good choice for athletes.
4. Consider taking something to reduce acid when taking ibuprofen. Check with your doctor and/or pharmacist to make sure you’re not on other medications that can increase your chance for side effects.
5. Ask your physician whether ibuprofen or another NSAID best treats your symptoms and has the fewest potential side effects.

“Ibuprofen is one of the most commonly used meds in the United States,” Dr. Isenberg says. “It has many therapeutic benefits and, despite some of the risks, a very strong safety profile. You just need to be cognizant of how much you use, for how long and whether you have any issues that could cause an increased risk of side effects.”

Gerard Isenberg, MD is a gastroenterologist and associate chief and director, Clinical Operations, Division of Gastroenterology and Liver Disease, and chief medical quality officer, University Hospitals Digestive Health Institute, at University Hospitals Cleveland Medical Center. You can request an appointment with Dr. Isenberg or any other medical provider online.

Subscribe

RSS

Tags:
Pain, Over-the-Counter Drugs, Men’s Health, Men’s Health: Prevention

Related

The Best and Worst Foods for Acid Reflux

A hot burning in the chest, a bitter taste in the throat, a gassy bloating in the stomach – acid reflux is no picnic. What you eat, however, can…

4/15/2014

Read More

The Do’s and Don’ts of Treating Fevers in Children

Almost nothing makes parents feel more helpless than when their child is sick. Learn what to do when your child has a fever and when it is time to…

3/5/2015

Read More

The Science of Health E-Newsletter

You can get health news and information from The Science of Health blog delivered right to your inbox every month. For a free subscription, visit our Sign Up page.

Sign up for The Science of Health E-Newsletter

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 the 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 made it possible to develop new dosage forms – capsules containing ibuprofen solution (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 less than 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 intentional 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 the WHO recommendation, 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. 79 with a 95% confidence interval from 0.64 to 0.97) in relation to the development of breast cancer [ 47]. Another meta-analysis (26 studies, n=528,705) showed similar results [48]. Perhaps, after conducting large placebo-controlled studies, the use of ibuprofen will be recommended as a cancer prevention.

Thus, when prescribing therapy, it is important to make a choice in favor of a time-tested remedy. More than 40 years of experience with the use of ibuprofen in wide clinical practice in almost 80 countries as an over-the-counter drug is a good example of its effectiveness and safety [49].

On the occasion of the 40th anniversary of the creation of ibuprofen. The first international conference on the use of ibuprofen in pediatrics | Geppe N.A.

P The first International Conference on the Use of Ibuprofen in Pediatrics took place on March 2, 2002 in Prague. The creator of ibuprofen, Boots Healthcare International, invited pediatricians from 18 countries to discuss the role of ibuprofen in treating fever and pain in children. The guest of honor at the conference was Dr. Stuart Adams, who was the first to receive ibuprofen 40 years ago while working for Boots Pure Drug (Figure 1). The purpose of the conference was to discuss at the international level all the pros and cons regarding the use of ibuprofen in pediatrics.

Fig. 1. Stuart Adams with colleagues in the early 60s (on the right in the picture)

Development of ibuprofen

In 1957, Stuart Adams, together with chemist John Nicholson, began to investigate the group of phenylpropionic acids. In 1962, BTS 13621 was created, commonly known today as ibuprofen. The drug showed good efficacy, good tolerability and caused less pronounced gastrointestinal side effects than acetylsalicylic acid. Many clinical studies followed that confirmed these properties of ibuprofen. The drug was registered on January 12, 1962 by the British Patent Office under the name Brufen. It began to be used as a prescription drug for the treatment of rheumatoid arthritis. In the US, since 1974, ibuprofen has been used under the trade name Motrin. Since 1983, the drug has been marketed in the UK as an over-the-counter drug called Nurofen. Significant in the history of ibuprofen was 1985, when Boots was awarded the Queen’s Award in recognition of the scientific and technological achievements in the development of this drug. Currently, the drug has many names and is used in both adults and children for the relief of pain and fever. For children, ibuprofen suspension (20 mg / ml) is used – “Nurofen for Children”, which does not contain sugar, is approved for over-the-counter use in children aged 6 months and over.

In 1957, Stuart Adams, together with chemist John Nicholson, began to study the group of phenylpropionic acids. In 1962, BTS 13621 was created, commonly known today as ibuprofen. The drug showed good efficacy, good tolerability and caused less pronounced gastrointestinal side effects than acetylsalicylic acid. Many clinical studies followed that confirmed these properties of ibuprofen. The drug was registered on January 12, 1962 by the British Patent Office under the name Brufen. It began to be used as a prescription drug for the treatment of rheumatoid arthritis. In the USA since 19In 1974, ibuprofen began to be used under the trade name Motrin. Since 1983, the drug has been marketed in the UK as an over-the-counter drug called Nurofen. Significant in the history of ibuprofen was 1985, when Boots was awarded the Queen’s Award in recognition of the scientific and technological achievements in the development of this drug. Currently, the drug has many names and is used in both adults and children for the relief of pain and fever. For children, ibuprofen suspension (20 mg / ml) is used – “Nurofen for Children”, which does not contain sugar, is approved for over-the-counter use in children aged 6 months and over.

Ibuprofen safety

Tolerability and safety of a drug are one of the most important parameters when deciding whether it is appropriate to prescribe it to children. Antipyretic drugs are prescribed to children to reduce discomfort, dehydration, and eliminate febrile convulsions. At the same time, both antipyretics and non-drug measures are used, such as sufficient drinking, loose light clothing, temperature control in the room (no more than 20 ° C), a therapeutic bath with a water temperature 2 ° C below the body temperature of the child. The ongoing symptomatic therapy should have a quick and pronounced effect. In children, acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDs) are mainly used. In Russia, on the recommendation of the National Pharmacological Committee, acetylsalicylic acid is not indicated for the treatment of fever in children under 15 years of age, and the use of metamizole sodium (analgin) is also limited due to the high incidence of side effects.

All experts at the conference agreed that ibuprofen was comparable in tolerability to paracetamol and was shown to be safe. According to the data obtained by Professor Autret-Leca (France), ibuprofen is one of the best tolerated NSAIDs in adults, and in children the tolerance of the drug is even higher. She emphasized that treatment with ibuprofen was never accompanied by the occurrence of Reye’s syndrome. The professor summarized the literature data as follows: “Compared to paracetamol and acetylsalicylic acid, ibuprofen has less toxicity in overdose and therefore a wider therapeutic range.”

Professor Ioana Alina Anca (Romania) has seen from personal experience that ibuprofen is less toxic than paracetamol and other NSAIDs. Among other NSAIDs, ibuprofen causes the fewest gastrointestinal side effects. Professor Anka analyzed the use of ibuprofen in young children. For the period 1999–2001 at the Institute of Mother and Child in Bucharest, ibuprofen was prescribed to 576 children for the first 6 months. life according to the main indication – ARVI. Fever was reduced more quickly and for a longer time compared to acetaminophen. Out of 304 children in 1999, 9 had mild side effects. The use of ibuprofen in adjunctive therapy for bronchiolitis did not have a bronchospastic effect. The rapid onset and duration of antipyretic action, anti-inflammatory and analgesic effect explain the effectiveness of ibuprofen in children up to six months [10].

Clinical data presented by Professor Samuel Lesco (USA) showed that short-term use of ibuprofen is not associated with an increased risk of side effects in children. A large double-blind clinical trial compared ibuprofen (5 or 10 mg/kg) and paracetamol (12 mg/kg) in more than 84,000 children (aged 6 months to 2 years) treated for febrile conditions [12,13] . The results of the study demonstrated that ibuprofen did not increase the risk of hospitalization in children under 2 years of age compared with paracetamol.

Lesko and colleagues also studied the outcome of febrile illness in 1879 children with bronchial asthma (BA). Children were randomized into two groups – ibuprofen and acetaminophen. Since none of the children had a history of acetylsalicylic acid intolerance, the authors suggested that sensitivity to NSAIDs may not be recognized in young children with asthma. Among children treated with ibuprofen, the frequency of visits to the doctor was reduced and there was less likelihood of hospitalization for asthma than in the acetaminophen group. The results obtained debunk the hypothesis that ibuprofen, to a greater extent than acetaminophen, increases the risk of bronchospasm in children with bronchial asthma who do not have indications of intolerance to acetylsalicylic acid, and indicate the relative safety of ibuprofen treatment in children with asthma.

Professor John van den Ancker (USA) conducted a study on the safety of ibuprofen and paracetamol in children with overdose based on 10-year observations of the Center for Poison Control of the American Association. John van den Anker stressed that ibuprofen and paracetamol are relatively safe drugs when used correctly. Commonly used doses of ibuprofen in children are 4–10 mg/kg/dose, with a maximum of 40 mg/kg/day. When using ibuprofen at a dose of 100-200 mg / kg, most patients do not develop side effects or mild signs of an overdose appear (abdominal pain, nausea, vomiting, headache, drowsiness, ringing in the ears). When taking ibuprofen more than 400 mg / kg, severe overdose symptoms occur: apnea, metabolic acidosis, coma. When prescribing paracetamol, there is a risk of chronic overdose even when using the maximum daily dose in children (90 mg/kg). Chronic toxicity of paracetamol is difficult to detect and is therefore potentially harmful to children. John van den Anker concluded that the safety margin of ibuprofen is higher than that of paracetamol in both acute intoxication and chronic overdose.

Comparative analysis of the effectiveness of ibuprofen in relation to paracetamol and acetylsalicylic acid

Autret-Leca noted that a clinical study of ibuprofen and paracetamol (6 clinical studies) showed that the antipyretic activity of ibuprofen at doses of 7.5 and 10 mg/kg is equal to that of 10 mg/kg of paracetamol and that the effect of ibuprofen is longer ( Table 1). In 3 clinical studies, ibuprofen at doses of 6–10 mg/kg was shown to be equally effective as acetylsalicylic acid (10–15 mg/kg) in lowering fever, onset and duration of action. In a randomized, open, parallel, multicentre study of children aged 6 to 24 months with rectal temperature >39°C, ibuprofen (7.5 mg/kg, n=116), paracetamol (10 mg/kg, n=116) or acetylsalicylic acid (10 mg/kg, n=116) was prescribed. Dosing continued after 6 hours if necessary. Rectal temperature was measured before taking the first dose and after 1, 4, 6 hours. Ibuprofen has been shown to be more effective than paracetamol and acetylsalicylic acid. This was confirmed by a larger area under the curve, a large decrease in temperature after 4 hours, and a large number of children with rectal temperatures <38°C already after 4 hours (Fig. 2). The general condition was better in children who took ibuprofen rather than paracetamol. Significantly more parents reported good sleep on the second day in the ibuprofen group.

Fig. 2. Efficacy of ibuprofen versus paracetamol and aspirin

During the discussions, other experts also reported on their experience of treating fever with ibuprofen. They believe that the popularity of ibuprofen among pediatricians is growing. Lesco noted that in his practice, parents once given ibuprofen to their children did not go back to using paracetamol.

Diseases such as otitis media and pharyngitis/tonsillitis are painful in children and require the use of painkillers. Pons reported data from three clinical trials on the efficacy of ibuprofen as an analgesic in the treatment of otitis media and tonsillopharyngitis in infants. Bertin and others (1991) conducted a randomized, double-blind, controlled, multicentre study [4]. 231 children (6 to 12 years of age, outpatients) with tonsillitis or pharyngitis received one of three treatments: ibuprofen (n=77, 10 mg/kg 3 times a day), paracetamol (n=77, 10 mg/kg 3 times a day) or placebo (n=77). All children received phenoxymethylpenicillin. Ibuprofen was more effective than paracetamol or acetylsalicylic acid. Tolerance was also good, no one dropped out of the study (Table 2).

In another randomized, double-blind, multicenter study by Bertin et al. (1996), 219 children (1 to 6 years of age) with otoscope-proven otitis media received one of three drugs: ibuprofen (n=71, 10 mg/kg 3 times a day), paracetamol (n=73, 10 mg/kg 3 times a day) or placebo (n=75) [5]. All study participants additionally received cefaclor. After 48 hours, 25.3% of children in the placebo group were still in pain compared to 9.6% in the paracetamol group and 7% in the ibuprofen group.

Professor Gerhard Gaedicke (Germany) reported on the growing popularity of ibuprofen in the treatment of mild to moderate postoperative pain, eg after tooth extractions, tonsillectomy, myringotomy with tympanostomy. Compared to ibuprofen, paracetamol is less effective as an analgesic. In addition, there is a danger of overdose: doses of 120–150 mg/kg of paracetamol are hepatotoxic and should be avoided.

In the experience of Gaedicke and colleagues, ibuprofen is as effective as paracetamol when combined with codeine. This was confirmed by a randomized controlled trial conducted in 1997. In this study, treatment with ibuprofen and paracetamol/codeine was equally effective in relieving pain after tonsillectomy. But the tolerability of ibuprofen was better (no opioid side effects – constipation, vomiting).

Two other studies reported by Gaedicke suggest that ibuprofen has a sparing effect on opioid receptors. Maunuksela and others (1982) showed that after all operations in children receiving ibuprofen, the need for additional morphine intake is reduced in recovery rooms on the day of operation and during the three days of the study period. Kokki et al. (1994) found similar results. In their randomized, double-blind study, 81 children (1–6 years) with postoperative pain were given spinal anesthesia and given either ibuprofen (40 mg/kg, rectally) or placebo. 42.5% of children in the treatment group did not require morphine compared to only 19.5% of children receiving placebo.

Dr. Daniel Annequin, Head of Pediatric Pain at the Armand Trouseau Children’s Hospital in Paris, reported on the importance of identifying headaches in children, classifying them and choosing a treatment for acute and chronic headaches. According to Daniel Annequin, if migraine therapy is started as early as possible, then relief comes faster. Ibuprofen (10 mg/kg) is now believed to have advantages in attack treatment, being twice as effective as acetaminophen in relieving migraine within 2 hours [8] (Table 3).

Long-term use of ibuprofen for juvenile idiopathic arthritis

The experience of using ibuprofen in juvenile idiopathic rheumatoid arthritis (JRA) was presented by Dr. Richard Mouy (France). This is a disease in which patients receive NSAIDs for a long time. Ibuprofen has been used in children with JRA for more than 30 years [15], and its effectiveness has been confirmed in numerous studies. With long-term use of NSAIDs, the literature describes numerous side effects in almost 40% of patients (piroxicam, indomethacin), requiring discontinuation of treatment in 35-50% of patients. Among patients taking ibuprofen, side effects are described in 30% of cases, while treatment was interrupted in only 10%, and better results were achieved compared with other NSAIDs. Numerous studies have shown that ibuprofen is an effective drug for JRA and should be used as the first line of NSAID therapy.

The experience of using ibuprofen in juvenile idiopathic rheumatoid arthritis (JRA) was presented by Dr. Richard Mouy (France). This is a disease in which patients receive NSAIDs for a long time. Ibuprofen has been used in children with JRA for more than 30 years [15], and its effectiveness has been confirmed in numerous studies. With long-term use of NSAIDs, the literature describes numerous side effects in almost 40% of patients (piroxicam, indomethacin), requiring discontinuation of treatment in 35-50% of patients. Among patients taking ibuprofen, side effects are described in 30% of cases, while treatment was interrupted in only 10%, and better results were achieved compared with other NSAIDs. Numerous studies have shown that ibuprofen is an effective drug for JRA and should be used as the first line of NSAID therapy.

Intravenous ibuprofen in the treatment of patent ductus arteriosus in preterm infants

Indomethacin is a drug that is now often used to close the ductus arteriosus. But it disrupts cerebral, renal and mesenteric blood flow. The conference presented data on the use of ibuprofen in newborns (Bart van Overmeire, Belgium). Ibuprofen has been shown to be a novel drug for the treatment of newborns with patent ductus arteriosus, causing fewer side effects than indomethacin. This is due to the fact that although both drugs inhibit cyclooxygenase-1 and cyclooxygenase-2, ibuprofen has less effect on cyclooxygenase-1 and therefore has fewer side effects on cerebral, mesenteric and renal blood flow. In extensive clinical comparative studies of the prophylactic and therapeutic use of ibuprofen and indomethacin for closure of the ductus arteriosus in newborns, ibuprofen has been shown to have equal efficacy and fewer renal side effects [18,19]. Recent pharmacokinetic studies of ibuprofen in very low birth weight newborns have shown that clearance in this group of children is significantly slowed down and the half-life of the drug is increased.

Characteristics of ibuprofen

Compared to other NSAIDs or paracetamol, ibuprofen has the following advantages:

• Unlike paracetamol, ibuprofen does not form toxic metabolites. Its toxicity after accidental or intentional overdose is lower.
• Ibuprofen has a relatively large therapeutic index (about 4 times higher than that of paracetamol).
• Among the NSAIDs, ibuprofen is best tolerated by adults and even better tolerated by children.
• The use of ibuprofen does not lead to the development of Reye’s syndrome.
• Unlike paracetamol, ibuprofen has an anti-inflammatory effect.
• Ibuprofen is increasingly being used in infants and even premature babies.

1. Aksoylar S, et al. Evaluation of sponging and antipyretic medication to reduce body temperature in febrile children. Acta Paediatrica Japonica 1997; 39: 215–217

2. Autret E, et al. Evaluation of ibuprofen versus aspirin and paracetamol on efficacy and comfort in children with fever. Eur J Clin 1997; 51: 367–371

3. Autret E et al. Comparative efficacy and tolerance of ibuprofen syrup and acetaminophen syrup in children with pyrexia associated with infectious diseases and treated with antibiotics. Eur J Clin Pharmacol, 1994; 46:197–201.

4. Bertin, L., G. Pons, et al. Randomized, double-blind, multicenler, controlled Trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of symptoms of tonsillitis and pharyngitis in children. J Pediatr 1991, 119(5): 811–4.

5. Bertin, L, G. Pons, Athis P el al. A randomized, double-blind, multicentre controlled Trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children. Fundam Clin Pharmacol 1996.10(4): 387–92.

6. Brown R.D.et al Single dose pharmacokinetics of ibuprofen and acetaminophen in febrile children Journal Clin Pharmacol 1992; 32, 231-41.

7. Czaykowski D, et al. Evaluation of the antipyretic efficacy of single dose ibuprofen suspension compared to acetaminophen elixir in febrile children. Pediatric Research, April 1994; Vol. 35, No.4, Part 2, Abstr. 829

8. Hamalainen LM, Hoppu K, Valkeila E et al. Ibuprofen or acetaminophen for the acute treatment of migrain in children: a double-blind, randomized, placebo-controlled, crossover study Neurology 1997:48, 103–107

9. Kauffmann, RE, Sawyer L A, Scheinbaum ML. Antipyretic Efficacy of Ibuprofen vs Acetaminophen. AJDC. 1992; 146:622–625

10. Kelley MT, Walson P.D, Edge H et al. Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children. Clin. Pharmacol. Ther. 1992; 52:181–9

11. Joshi Y.M. et al. The comparison evaluation of the antipiretic efficacy of ibuprofen and paracetamol Ind Paeds 1990, 803–806

12. Lesko S.M., Mitchell A.A. An assessment of the safety of pediatric ibuprofen. A practitioner–Based Randomized Clinical Trial. JAMA 1995; 273(12): 929–33.

13. Lesko S.M The safety of acetaminophen and ibuprofen among children less than two years old. Pediatrics 1999; 104 (4) 1–5

14. Lesko S.M.,Louic C, Vezina R, Mitchell A.A Asthma morbidity after he short-term use of ibuprofen in children. Pediatrics 2002; 109 (2) 1–4

15. Mclntyre J., Hull D. Comparison efficacy and tolerability of ibuprofen and paracetamol in fever Arch Dis Child 1996:74, 164–167.

16. Nahata MC et al. Efficacy of ibuprofen in pediatric patients with fever. International Journal of Clinical Pharmacology, Therapy and Toxicology 1992; 30(3): 94–96.

17. Sidler J, et al. A double-blind comparison of ibuprofen and paracetamol in juvenile pyrexia. Br. J.Clin. Pract. 1–990; 44(Suppl. 70): 22–25

18. Varvarigou A., Bardin C.L., Beharry K. Et al Early ibuprofen administration to prevent patent ductus arteriosus in premature new–born infants J. Amer. Med. Assoc. 1996; 275(7): 539–44

19. Van Overmeire B., Pollens I., Hartmann S. et al Treatment of patent ductus arteriosus with ibuprofen Arch. Dis. child. 1997; 76: F179-F18419

20. Walson PD, et al. Ibuprofen, acetaminophen and placebo treatment of febrile children. Clin Pharmacol Ther 1989; 46:9–17

21. Walson PD et al. Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. AJDC, 1992; 146:626–632.

22. Wilson JT, et al. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children.