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Side effects of long term use of ibuprofen. The Comprehensive Guide to Ibuprofen Side Effects: From Common to Severe and Long-Term

by alexxlab

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? Explore the comprehensive guide on ibuprofen side effects.

Navigating the Common Side Effects of Ibuprofen

Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) that can provide relief for a variety of ailments. However, like any medication, it can also have side effects. The NHS website outlines the common side effects of ibuprofen taken by mouth, which occur in more than 1 in 100 people. These include headaches, dizziness, nausea, vomiting, wind, and indigestion.

To cope with these common side effects, the NHS provides helpful advice. For headaches, it’s recommended to rest, drink plenty of fluids, and avoid taking other pain relievers. If ibuprofen makes you feel dizzy, it’s important to stop what you’re doing, sit or lie down until the dizziness subsides, and avoid stimulants like coffee and alcohol. For nausea, sticking to simple meals, avoiding rich or spicy foods, and taking ibuprofen with a meal or snack can help. In the case of vomiting, staying hydrated with small, frequent sips of water is crucial, and speaking to a pharmacist is recommended if signs of dehydration arise.

Wind and indigestion can also occur as common side effects of ibuprofen. The NHS suggests avoiding foods that can cause wind, such as lentils, beans, and onions, and eating smaller, slower-paced meals. Antacid medications may provide relief for indigestion, but it’s important to consult a doctor if the issue persists.

Addressing Severe Side Effects of Ibuprofen

While the common side effects of ibuprofen can be managed, there are also more severe side effects that require immediate medical attention. The NHS advises calling 111 or a doctor straight away and stopping ibuprofen if you experience black poop, blood in your vomit, swollen ankles, blood in your urine, or a reduction in urination, as these can be signs of internal bleeding or kidney problems.

Even more serious side effects require immediate emergency care. If you experience severe chest or stomach pain, difficulty breathing, a severe headache, a high temperature, stiff neck, vision issues, or hallucinations, the NHS recommends calling 999 or going to the nearest A&E department immediately. These symptoms can indicate a hole in the stomach or gut, asthma complications, or inflammation of the protective membranes surrounding the brain and spinal cord.

Navigating the Potential for Serious Allergic Reactions

In rare cases, ibuprofen can also cause a serious allergic reaction known as anaphylaxis. The NHS advises calling 999 or going to A&E immediately if you experience a skin rash, wheezing, chest or throat tightness, trouble breathing or talking, or swelling of the mouth, face, lips, tongue, or throat. These are all signs of a potentially life-threatening reaction that requires prompt medical treatment.

Understanding the Long-Term Risks of Ibuprofen Use

Prolonged use of ibuprofen, particularly in high doses, can also lead to long-term side effects. The NHS notes that ibuprofen can cause ulcers in the stomach or gut, especially if taken by mouth for an extended period. If long-term ibuprofen use is necessary, a doctor may prescribe additional medication to help protect the stomach.

It’s important to be aware that the side effects listed are not exhaustive, and a full list of potential side effects can be found in the leaflet inside the ibuprofen medication packet.

Reporting Suspected Side Effects

If you experience any suspected side effects from ibuprofen, the NHS encourages you to report them using the Yellow Card safety scheme. This helps healthcare professionals and the Medicines and Healthcare products Regulatory Agency (MHRA) monitor the safety of medicines and identify any emerging issues.

Seeking Medical Advice

If the advice provided on coping with common side effects does not help, or if a side effect is still bothering you or does not go away, it’s important to speak to a doctor or pharmacist. They can provide further guidance and determine if any additional treatment or monitoring is necessary.

Conclusion

Ibuprofen is a widely used medication, but like any drug, it can have side effects. Understanding the common, severe, and long-term side effects of ibuprofen, as well as the steps to take if they occur, is crucial for ensuring safe and effective use. By being informed and proactive, you can navigate the potential risks and make the best decisions for your health.

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?

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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.

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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, both in acute traumatic injuries of soft tissues and in 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, whose 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 metabolic processes and clearance, however, in the elderly, the excretion of ibuprofen 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, 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. 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].

Ibuprofen – efficacy and safety in children with fever

Introduction

Fever is the leading symptom in acute respiratory viral infections (ARVI) in children. For its relief, each pediatrician has developed his own tactics, based on previously acquired knowledge and personal experience in the use of various drugs. In accordance with the recommendations of the World Health Organization, the main drugs used to reduce body temperature in children are paracetamol and ibuprofen, due to their effectiveness and safety. Paracetamol is prescribed by 65%, ibuprofen – by 35% of doctors (Lesko S.M. et al., 2002). The use of acetylsalicylic acid (ASA) for this purpose is not recommended due to the risk of developing Reye’s syndrome, as well as metamizole sodium, associated with a high incidence of agranulocytosis.

Another common symptom that accompanies SARS is pain of various localization: in the throat, ear, head, coughing. In this regard, the prescribed drug should be characterized, on the one hand, by a multilateral action, and on the other, by maximum safety.

Ibuprofen in pediatric practice

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) developed in 1962 as an alternative to ASA, the main NSAID used at that time. Ibuprofen was first registered in England in 1968, currently used in >30 countries. In the 1980s, ibuprofen was introduced into pediatric practice in a number of countries, including the US and the UK; it is currently used in children over 6 months of age as an over-the-counter drug and in children over 3 months of age on the recommendation of a physician.

Ibuprofen is a white or almost white crystalline substance with a characteristic odor, which is 4-isobutylphenyl-propionic acid (Figure).

Drawing

Structural formula of ibuprofen

Ibuprofen is the active ingredient of Nurofen ® for children in the form of a white, sugar-free orange-flavored oral suspension, 5 ml of which contains 100 mg of ibuprofen. The drug is used at a dose of 5-10 mg (average dose – 7.5 mg) per 1 kg of body weight.

Ibuprofen is a propionic acid derivative with antipyretic, analgesic and anti-inflammatory properties. The pharmacodynamics of ibuprofen is primarily due to the suppression of the biosynthesis of prostaglandins, which, along with thromboxanes and leukotrienes, are part of the group of oxygenation products of polyunsaturated long-chain fatty acids known as eicosanoids. Prostaglandins are present in all cells of the body and activate pain receptors for the effects of pain-initiating substances such as histamine, 5-hydroxytryptamine, and bradykinin. Prostaglandins are important mediators of inflammation and are involved in the pathogenesis of signs of inflammation – pain, swelling and hyperthermia. As a result of infection or inflammation, blood monocytes and tissue macrobacteriophages are activated with the formation of interleukin-1, which, through intermediate links (such as prostaglandin E 2 ) in the hypothalamus contributes to an increase in body temperature.

When taken orally, ibuprofen is partially absorbed in the stomach and then completely absorbed in the small intestine. The time to reach maximum plasma concentration (T max ) is approximately 1-2 hours after oral ibuprofen in the form of tablets or suspension, although, according to some reports, children aged 6-18 months have a higher T max (3 hours). Ibuprofen for 99% binds to plasma proteins resulting in a relatively low (0.1 l/kg body weight) volume of distribution. Although ibuprofen actively binds to albumin, this does not affect drug interactions.

Ibuprofen is extensively metabolized in the liver, rapidly eliminated from blood plasma with a relatively short (≈2 h) half-life; <10% is excreted unchanged in the urine. The two main metabolites, 2-hydroxy-ibuprofen and 2-carboxy-ibuprofen, formed as a result of hydroxylation and subsequent oxidation, do not have pharmacological activity. Urinary excretion of metabolites is usually completed within 24 hours of the last dose. The total excretion of ibuprofen and its metabolites in the urine is linearly dependent on dosage. In children >2 months of age, the kidneys are well developed to cope with the elimination of ibuprofen by glomerular filtration. Study including 49children aged 3 months to 12 years showed no age-related differences in the rate of absorption and excretion of ibuprofen (Brown R.D. et al., 1992).

The rapid metabolism and excretion of ibuprofen account to some extent for its relatively low toxicity compared to some other NSAIDs. A study involving >84,000 children aged 6 months to 12 years showed that the risk of serious side effects with its use does not exceed that of paracetamol (Lesko S. M., Mitchell A.A., 1995).

Effect of ibuprofen on fever

Ibuprofen reduces high body temperature quickly and effectively. The pharmacodynamics of ibuprofen contributes to the physiological processes that are important during therapy.

It is believed that the antipyretic effect of ibuprofen is due to the suppression of the synthesis and release of prostaglandins in the central nervous system, which leads to the normalization of thermoregulation, helping to reduce the severity of fever.

For fever, ibuprofen 5 mg/kg body weight is effective, but the most effective dose is 7-10 mg/kg, with ibuprofen at a dose of 7-7.5 mg/kg having an antipyretic effect similar to ibuprofen at a dose of 10 mg/kg kg. The antipyretic effect when taking ibuprofen begins as quickly as when taking paracetamol. Usually, the antipyretic effect of ibuprofen begins to appear within 30 minutes from the moment of administration, although in some patients the body temperature decreases within 15 minutes. A comparison of the effectiveness of paracetamol and ibuprofen showed that both drugs effectively reduce body temperature, but ibuprofen has a longer effect. This was confirmed by the results of a double-blind, parallel-group, repeated-dose study comparing the effects of ibuprofen at doses of 7 and 10 mg/kg with those of paracetamol at a dose of 10 mg/kg (Sidler J. et al., 1990). The study included 90 children aged 5 months to 13 years with rectal temperature ≥38.5 °C. Data were recorded at 10 min intervals for at least 12 h. Fewer than half of the children treated with ibuprofen required a second dose to control fever within 12 h (38% and 44% in the 7 and 10 mg/kg groups, respectively) , while in the paracetamol-treated group, a second dose was required in 59% of children. In patients treated with ibuprofen, the mean body temperature was lower than in patients treated with paracetamol.

Ibuprofen has also been reported to be more effective than paracetamol in reducing very high body temperature in children (Walson P. D. et al., 1989). This was demonstrated in a double-blind, parallel-group study of children treated with a single dose of ibuprofen suspension 5 and 10 mg/kg, paracetamol elixir 10 mg/kg, and placebo for fever. Ibuprofen 10 mg/kg was more effective in lowering body temperature than paracetamol 10 mg/kg in both the subgroup of children with very high (>39.2 °C) body temperature (p<0.05), and in children of the whole group as a whole (p<0.05).

Effect of ibuprofen on pain

Prostaglandins mediate the pain response by activating the sensitivity of pain receptors to pain stimuli. Ibuprofen relieves pain by reversing the inhibition of cyclooxygenase enzymes, which prevents the conversion of arachidonic acid to prostaglandin G 2 and thus suppresses the formation of prostaglandins in the area of ​​inflammation. This reduces the hyperalgesic effect of prostaglandins on pain receptors, reducing the inflammatory response and resulting tissue damage. Peripheral action is considered the main mechanism by which ibuprofen relieves pain, especially in clinical conditions associated with inflammation and tissue damage, which are accompanied by an increase in prostaglandin synthesis.

Less significant mechanisms that may contribute to the analgesic/anti-inflammatory effects of ibuprofen include direct inhibition of (experimentally induced) leukocyte migration to the area of ​​inflammation and direct central action on the central nervous system.

Various studies show that ibuprofen is an effective treatment for mild to moderate pain in children (eg toothache, acute sore throat, migraine, tonsillitis pain, acute otitis media).

The effectiveness of ibuprofen in reducing ear pain is due to both its anti-inflammatory and analgesic effects. In a multicentre, double-blind, controlled study in children, ibuprofen at a dose of 10 mg/kg was effective in reducing the severity of pain in otitis media (Bertin L. et al., 1996). Ibuprofen was significantly more effective than placebo in reducing pain (p < 0.01), while no significant differences were noted between paracetamol and placebo.

In a randomized, double-blind, multicenter study by L. Bertin et al (1991), children with tonsillitis and pharyngitis were treated with ibuprofen (10 mg/kg), paracetamol (10 mg/kg) or placebo 3 times a day for 7 days daily along with antibiotics. After treatment for 48 hours, 80% of children treated with ibuprofen did not complain of any spontaneous pain. In the group of children treated with paracetamol, pain was relieved in 70.5%, and in the placebo group, this figure was 55%. A similar trend was observed in relation to pain when swallowing. Thus, ibuprofen is an effective, well-tolerated short-term therapy for pain associated with acute tonsillitis and pharyngitis.

Safety and tolerability of ibuprofen in children

Short-term treatment with ibuprofen for fever and pain is well tolerated in children aged 6 months to 12 years. Serious adverse events from the gastrointestinal tract are very rare.

The safety of ibuprofen was demonstrated in a large, randomized, double-blind study by S.M. Lesko, A.A. Mitchell (1995), who assessed the risk of hospitalization in children (n=55,765) who used ibuprofen at a dose of 5 or 10 mg/kg for fever compared with children (n=28,130) who received paracetamol at a dose of 12 mg/kg. Of all participants 795 (0.9%) were admitted to the hospital within 4 weeks of inclusion in the study. Ibuprofen did not increase the risk of hospitalization associated with one of the serious treatment outcomes of gastrointestinal bleeding, renal failure, anaphylaxis, and Reye’s syndrome compared with paracetamol. Other gastrointestinal adverse events include dyspepsia, abdominal pain, nausea and vomiting.

No difference was noted in the number of adverse events or the total number of adverse events in a head-to-head comparison between ibuprofen and paracetamol for up to 28 days.

Detailed analysis of adverse events from various systems and organs in the use of ibuprofen showed that adverse events in all cases were minor and stopped when treatment was discontinued. Adverse events from the gastrointestinal tract when using ibuprofen did not statistically significantly differ from those that occurred when taking paracetamol, clinically significant gastrointestinal bleeding or cases of melena were not observed when using ibuprofen. There were no cases of death or hospitalization associated with side effects of drugs, as well as differences in the frequency of adverse events by age or gender.

The risk of bronchial obstruction or exacerbation of bronchial asthma (BA) in the treatment of ibuprofen is similar to that in the treatment of paracetamol. As the results of studies show, AD associated with the use of ASA is very rare in children (Lamb C., Cantrill J.A., 1995). There are no data on the development of asthma associated with the use of ibuprofen. In children with asthma who are sensitive to ASA, ibuprofen or NSAIDs, the use of any NSAID should be avoided.

No cases of Reye’s syndrome in children with ARVI treated with ibuprofen have been reported so far.

The widespread use of ibuprofen from 1969 to the present has shown that the drug is characterized by a high safety margin and low toxicity in overdose, manifested either as an increase in its therapeutic effect or as an established side effect. Overdose symptoms include nausea, vomiting, abdominal pain, headache, low blood pressure, dizziness, drowsiness, nystagmus, blurred vision, tinnitus, rarely – metabolic acidosis, renal failure, loss of consciousness. Since there is no clear correlation between the dose taken and the clinical effect, in such cases, symptomatic, if necessary, supportive therapy is carried out. You can take activated charcoal within 1 hour after an overdose of the drug or do a gastric lavage.

Conclusion

Ibuprofen (Nurofen ® for Children) is well tolerated by children and provides:

  • prolonged (up to 8 hours) antipyretic effect;
  • decrease in body temperature during fever for a longer period than when taking paracetamol in the form of a suspension;
  • fast analgesic action.

    • References

    Information for the professional activities of medical and pharmaceutical workers.
    Nurofen® for children
    R. s. No. UA/8233/01/01 dated August 23, 2012; No. UA/7914/01/01 dated August 23, 2012; No. UA/6642/02/01 dated 04.04.2008 Composition: suspension for oral administration with orange flavor containing ibuprofen 100 mg/5 ml; suspension for oral administration with strawberry flavor containing ibuprofen 100 mg/5 ml; rectal suppositories containing ibuprofen 60 mg. Pharmacotherapeutic group . Non-steroidal anti-inflammatory drugs. ATS code. M01A E01. Pharmacological properties. Has analgesic, antipyretic and anti-inflammatory effects, inhibits platelet aggregation. The mechanism of action is due to inhibition of the synthesis of prostaglandins – mediators of pain, inflammation and temperature reaction. Readings . Symptomatic treatment of fever and pain of various origins (including fever after immunization, acute respiratory viral infections, influenza, pain during teething, pain after tooth extraction and other types of pain, including inflammatory origin).