Common
side effects include
heartburn and a
rash.[9] Compared to other NSAIDs, it may have other side effects such as
gastrointestinal bleeding.[10] It increases the risk of
heart failure,
kidney failure, and
liver failure.[9] At low doses, it does not appear to increase the risk of
heart attack; however, at higher doses it may.[10] Ibuprofen can also worsen
asthma.[10] While its safety in early
pregnancy is unclear,[9] it appears to be harmful in later pregnancy, so it is not recommended during that period.[11] Like other NSAIDs, it works by inhibiting the production of
prostaglandins by decreasing the activity of the enzyme
cyclooxygenase (COX).[9] Ibuprofen is a weaker anti-inflammatory agent than other NSAIDs.[10]
Ibuprofen was discovered in 1961 by
Stewart Adams and John Nicholson[12] while working at
Boots UK Limited and initially marketed as Brufen.[13] It is available under a number of brand names, including Nurofen, Advil, and Motrin.[9][14] Ibuprofen was first marketed in 1969 in the United Kingdom and in 1974 in the United States.[9][13] It is on the
World Health Organization's List of Essential Medicines.[15] It is available as a
generic medication.[9] In 2021, it was the 36th-most commonly prescribed medication in the United States, with more than 17million prescriptions.[16][17]
Medical uses
Ibuprofen is used primarily to treat
fever (including postvaccination fever), mild to moderate
pain (including pain relief after
surgery),
painful menstruation,
osteoarthritis, dental pain,
headaches, and
pain from kidney stones. About 60% of people respond to any NSAID; those who do not respond well to a particular one may respond to another.[18] A Cochrane medical review of 51 trials of NSAIDS for the treatment of
lower back pain found that "NSAIDs are effective for short-term symptomatic relief in patients with acute low back pain".[19]
In some countries, ibuprofen
lysine (the lysine salt of ibuprofen, sometimes called "ibuprofen lysinate") is licensed for treatment of the same conditions as ibuprofen; the lysine salt is used because it is more water-soluble.[24]
Ibuprofen lysine is sold for rapid pain relief;[25] given in the form of its lysine salt, absorption is much quicker (35 minutes for the salt compared to 90–120 minutes for ibuprofen). However, a clinical trial with 351 participants in 2020, funded by Sanofi, found no significant difference between ibuprofen and ibuprofen lysine concerning the eventual onset of action or analgesic efficacy.[26][unreliable medical source]
In 2006, ibuprofen lysine was approved in the US by the
Food and Drug Administration (FDA) for closure of patent ductus arteriosus in premature infants weighing between 500 and 1,500 g (1 and 3 lb), who are no more than 32 weeks gestational age when usual medical management (such as fluid restriction, diuretics, and respiratory support) is not effective.[27]
Allergic reactions, including
anaphylaxis and anaphylactic
shock, may occur.[30] Ibuprofen may be quantified in blood, plasma, or serum to demonstrate the presence of the drug in a person having experienced an anaphylactic reaction, confirm a diagnosis of poisoning in people who are hospitalized, or assist in a medicolegal death investigation. A
monograph relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in people who have overdosed has been published.[31]
In October 2020, the US FDA required the
drug label to be updated for all NSAID medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[32][33]
Cardiovascular risk
Along with several other NSAIDs, chronic ibuprofen use has been found correlated with risk of progression to
hypertension in women, though less than for paracetamol (acetaminophen),[34] and
myocardial infarction (heart attack),[35] particularly among those chronically using higher doses. On 9 July 2015, the US FDA toughened warnings of increased
heart attack and
stroke risk associated with ibuprofen and related NSAIDs; the NSAID
aspirin is not included in this warning.[36] The
European Medicines Agency (EMA) issued similar warnings in 2015.[37][38]
Drinking alcohol when taking ibuprofen may increase the risk of
stomach bleeding.[44]
Aspirin
According to the FDA, "ibuprofen can interfere with the
antiplatelet effect of low-dose
aspirin, potentially rendering aspirin less effective when used for
cardioprotection and
stroke prevention". Allowing sufficient time between doses of ibuprofen and immediate-release (IR) aspirin can avoid this problem. The recommended elapsed time between a dose of ibuprofen and a dose of aspirin depends on which is taken first. It would be 30 minutes or more for ibuprofen taken after IR aspirin, and 8 hours or more for ibuprofen taken before IR aspirin. However, this timing cannot be recommended for
enteric-coated aspirin. If ibuprofen is taken only occasionally without the recommended timing, though, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal.[45]
Paracetamol
Ibuprofen combined with
paracetamol is considered generally safe in children for short-term usage.[46]
Overdose
Ibuprofen overdose has become common since it was licensed for
OTC use. Many overdose experiences are reported in the
medical literature, although the frequency of life-threatening complications from ibuprofen overdose is low.[47] Human responses in cases of overdose range from an absence of symptoms to a fatal outcome despite intensive-care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen, and include abdominal pain, nausea,
vomiting, drowsiness, dizziness, headache,
ear ringing, and
nystagmus. Rarely, more severe symptoms, such as
gastrointestinal bleeding,
seizures,
metabolic acidosis, hyperkalemia,
low blood pressure,
slow heart rate,
fast heart rate,
atrial fibrillation,
coma, liver dysfunction,
acute kidney failure,
cyanosis,
respiratory depression, and
cardiac arrest have been reported.[48] The severity of symptoms varies with the ingested dose and the time elapsed; however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs.
Correlation between severity of symptoms and measured ibuprofen plasma levels is weak. Toxic effects are unlikely at doses below 100mg/kg, but can be severe above 400mg/kg (around 150 tablets of 200mg units for an average man);[49] however, large doses do not indicate the clinical course is likely to be lethal.[50] A precise
lethal dose is difficult to determine, as it may vary with age, weight, and concomitant conditions of the individual person.
Treatment to address an ibuprofen overdose is based on how the symptoms present. In cases presenting early, decontamination of the stomach is recommended. This is achieved using
activated charcoal; charcoal absorbs the drug before it can enter the
bloodstream.
Gastric lavage is now rarely used, but can be considered if the amount ingested is potentially life-threatening, and it can be performed within 60 minutes of ingestion. Purposeful vomiting is not recommended.[51] Most ibuprofen ingestions produce only mild effects, and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and
kidney function monitored.[49] Since ibuprofen has acidic properties and is also excreted in the urine,
forced alkaline diuresis is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, the kidneys' excretion of unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit.[52]
Miscarriage
A Canadian study of pregnant women suggests that those taking any type or amount of NSAIDs (including ibuprofen,
diclofenac, and
naproxen) were 2.4 times more likely to
miscarry than those not taking the medications.[53] However, an Israeli study found no increased risk of miscarriage in the group of mothers using NSAIDs.[54]
Like aspirin and
indomethacin, ibuprofen is a nonselective COX inhibitor, in that it inhibits two
isoforms of cyclooxygenase,
COX-1 and
COX-2. The
analgesic,
antipyretic, and anti-inflammatory activity of NSAIDs appears to operate mainly through inhibition of COX-2, which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 instead would be responsible for unwanted effects on the gastrointestinal tract.[55] However, the role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain, and different compounds cause different degrees of analgesia and gastric damage.[56]
Ibuprofen is administered as a
racemic mixture. The R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer.[57] The R-enantiomer is converted through a series of three main enzymes. These enzymes include acyl-CoA-synthetase, which converts the R-enantiomer to (−)-R-ibuprofen I-CoA; 2-arylpropionyl-CoA epimerase, which converts (−)-R-ibuprofen I-CoA to (+)-S-ibuprofen I-CoA; and hydrolase, which converts (+)-S-ibuprofen I-CoA to the S-enantiomer.[43] In addition to the conversion of ibuprofen to the S-enantiomer, the body can metabolize ibuprofen to several other compounds, including numerous hydroxyl, carboxyl and glucuronyl metabolites. Virtually all of these have no pharmacological effects.[43]
Unlike most other NSAIDs, ibuprofen also acts as an inhibitor of
Rho kinase and may be useful in recovery from spinal-cord injury.[58][59] Another unusual activity is inhibition of the sweet taste receptor.[60]
Pharmacokinetics
After oral administration, peak serum concentration is reached after 1–2 hours, and up to 99% of the drug is bound to plasma proteins.[61] The majority of ibuprofen is metabolized and eliminated within 24 hours in the urine; however, 1% of the unchanged drug is removed through biliary excretion.[57]
Chemistry
Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like
ethanol (66.18g/100mL at 40°C for 90% EtOH),
methanol,
acetone and
dichloromethane.[62]
The original synthesis of ibuprofen by the Boots Group started with the compound
isobutylbenzene. The synthesis took six steps. A modern, greener technique with fewer waste byproducts for the synthesis involves only three steps was developed in the 1980s by the Celanese Chemical Company.[63][64] The synthesis is initiated with the acylation of isobutylbenzene using the recyclable Lewis acid catalyst hydrogen fluoride.[65][66] The following catalytic hydrogenation of isobutylacetophenone is performed with either Raney nickel or palladium on carbon to lead into the key-step, the
carbonylation of 1-(4-isobutylphenyl)ethanol. This is achieved by a PdCl2(PPh3)2 catalyst, at around 50 bar of CO pressure, in the presence of HCl (10%).[67] The reaction presumably proceeds through the intermediacy of the
styrene derivative (acidic elimination of the alcohol) and (1-chloroethyl)benzene derivative (Markovnikow addition of HCl to the double bond).[68]
The product sold in pharmacies is a
racemic mixture of the S and R-isomers. The S (dextrorotatory) isomer is the more biologically active; this isomer has been isolated and used medically (see
dexibuprofen for details).[62]
(S)-ibuprofen, the
eutomer, harbors the desired therapeutic activity. Interestingly, the inactive (R)-enantiomer, the
distomer, undergoes a unidirectional
chiral inversion to offer the active (S)-enantiomer. That is, when the ibuprofen is administered as a racemate the distomer is converted in vivo into the eutomer while the latter is unaffected.[72][73][74]
History
Ibuprofen was derived from
propionic acid by the
research arm of
Boots Group during the 1960s.[75] The name is derived from the 3 functional groups: isobutyl (ibu) propionic acid (pro) phenyl (fen).[76] Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to
aspirin.[13][77] The molecule was discovered and synthesized by a team led by
Stewart Adams, with a patent application filed in 1961.[13] Adams initially tested the drug as treatment for his
hangover.[78] In 1985, Boots' worldwide patent for ibuprofen expired and generic products were launched.[79]
The medication was launched as a treatment for
rheumatoid arthritis in the United Kingdom in 1969, and in the United States in 1974. Later, in 1983 and 1984, it became the first NSAID (other than aspirin) to be available
over the counter (OTC) in these two countries.[13][77] Boots was awarded the
Queen's Award for Technical Achievement in 1985 for the development of the drug.[80]
In November 2013, work on ibuprofen was recognized by the erection of a
Royal Society of Chemistry blue plaque at Boots' Beeston Factory site in Nottingham,[81] which reads:
In recognition of the work during the 1980s by The Boots Company PLC on the development of ibuprofen which resulted in its move from prescription only status to over the counter sale, therefore expanding its use to millions of people worldwide
and another at
BioCity Nottingham, the site of the original laboratory,[81] which reads:
In recognition of the pioneering research work, here on Pennyfoot Street, by Dr Stewart Adams and Dr John Nicholson in the Research Department of Boots which led to the discovery of ibuprofen used by millions worldwide for the relief of pain.
In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the brand name Caldolor.[86][87]
Ibuprofen can be taken
orally (by mouth) (as a tablet, a capsule, or a suspension) and
intravenously.[9]
Research
Ibuprofen is sometimes used for the treatment of acne because of its
anti-inflammatory properties, and has been sold in Japan in topical form for
adult acne.[88][89] As with other NSAIDs, ibuprofen may be useful in the treatment of severe
orthostatic hypotension (low blood pressure when standing up).[90] NSAIDs are of unclear utility in the prevention and treatment of
Alzheimer's disease.[91][92]
Ibuprofen has been associated with a lower risk of
Parkinson's disease and may delay or prevent it.
Aspirin, other NSAIDs, and
paracetamol (acetaminophen) had no effect on the risk for Parkinson's.[93] In March 2011, researchers at
Harvard Medical School announced in Neurology that ibuprofen had a
neuroprotective effect against the risk of developing
Parkinson's disease.[94][95][96] People regularly consuming ibuprofen were reported to have a 38% lower risk of developing Parkinson's disease, but no such effect was found for other pain relievers, such as aspirin and paracetamol. Use of ibuprofen to lower the risk of Parkinson's disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems.[97]
^"Brufen Tablets And Syrup"(PDF). Therapeutic Goods Administration. 31 July 2012.
Archived from the original on 20 August 2016. Retrieved 8 May 2014.
^
abcdefghijklm"Ibuprofen". The American Society of Health-System Pharmacists.
Archived from the original on 9 September 2017. Retrieved 12 October 2016.
^
abcdBritish National Formulary, March 2014–September 2014 (2014 ed.). London: British Medical Association. 2014. pp. 686–688.
ISBN978-0857110862.
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.
hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^Rostas SE, McPherson CC (2016). "Pharmacotherapy for Patent Ductus Arteriosus: Current Options and Outstanding Questions". Current Pediatric Reviews (Review). 12 (2): 110–119.
doi:
10.2174/157339631202160506002028.
PMID27197952.
^Beaver WT (April 2003). "Review of the analgesic efficacy of ibuprofen". International Journal of Clinical Practice. Supplement (135): 13–17.
PMID12723741.
^Seibel K, Schaffler K, Reeh P, Reitmeir P (2004). "Comparison of two different preparations of ibuprofen with regard to the time course of their analgesic effect. A randomised, placebo-controlled, double-blind cross-over study using laser somatosensory evoked potentials obtained from UW-irritated skin in healthy volunteers". Arzneimittel-Forschung. 54 (8): 444–451.
doi:
10.1055/s-0031-1296997.
PMID15460211.
S2CID592438.
^Fanos V, Antonucci R, Zaffanello M (2010). "Ibuprofen and acute kidney injury in the newborn". The Turkish Journal of Pediatrics. 52 (3): 231–238.
PMID20718179.
^Bergner T, Przybilla B (January 1992). "Photosensitization caused by ibuprofen". Journal of the American Academy of Dermatology. 26 (1): 114–6.
doi:
10.1016/0190-9622(92)70018-b.
PMID1531054.
^McElwee NE, Veltri JC, Bradford DC, Rollins DE (June 1990). "A prospective, population-based study of acute ibuprofen overdose: complications are rare and routine serum levels not warranted". Annals of Emergency Medicine. 19 (6): 657–662.
doi:
10.1016/S0196-0644(05)82471-0.
PMID2188537.
^Vale JA, Meredith TJ (January 1986). "Acute poisoning due to non-steroidal anti-inflammatory drugs. Clinical features and management". Medical Toxicology. 1 (1): 12–31.
doi:
10.1007/BF03259825.
PMID3537613.
S2CID25223555.
^Hall AH, Smolinske SC, Conrad FL, Wruk KM, Kulig KW, Dwelle TL, et al. (November 1986). "Ibuprofen overdose: 126 cases". Annals of Emergency Medicine. 15 (11): 1308–1313.
doi:
10.1016/S0196-0644(86)80617-5.
PMID3777588.
^Verma P, Clark CA, Spitzer KA, Laskin CA, Ray J, Koren G (July 2012). "Use of non-aspirin NSAIDs during pregnancy may increase the risk of spontaneous abortion". Evidence-Based Nursing. 15 (3): 76–77.
doi:
10.1136/ebnurs-2011-100439.
PMID22411163.
S2CID28521248.
^Kakuta H, Zheng X, Oda H, Harada S, Sugimoto Y, Sasaki K, et al. (April 2008). "Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor". Journal of Medicinal Chemistry. 51 (8): 2400–2411.
doi:
10.1021/jm701191z.
PMID18363350.
^
ab"Ibuprofen". DrugBank.
Archived from the original on 21 July 2014. Retrieved 24 July 2014.
^Nakagita T, Taketani C, Narukawa M, Hirokawa T, Kobayashi T, Misaka T (November 2020). "Ibuprofen, a Nonsteroidal Anti-Inflammatory Drug, is a Potent Inhibitor of the Human Sweet Taste Receptor". Chemical Senses. 45 (8): 667–673.
doi:
10.1093/chemse/bjaa057.
PMID32832995.
^
abBrayfield A, ed. (14 January 2014).
"Ibuprofen". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 26 June 2014.
^Tracy TS, Hall SD (March–April 1992). "Metabolic inversion of (R)-ibuprofen. Epimerization and hydrolysis of ibuprofenyl-coenzyme A". Drug Metabolism and Disposition. 20 (2): 322–327.
PMID1352228.
^Caldwell J, Hutt AJ, Fournel-Gigleux S (January 1988). "The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences". Biochemical Pharmacology. 37 (1): 105–114.
doi:
10.1016/0006-2952(88)90762-9.
PMID3276314.
^
abRainsford KD (April 2003). "Discovery, mechanisms of action and safety of ibuprofen". International Journal of Clinical Practice. Supplement (135): 3–8.
PMID12723739.
^Wong RC, Kang S, Heezen JL, Voorhees JJ, Ellis CN (December 1984). "Oral ibuprofen and tetracycline for the treatment of acne vulgaris". Journal of the American Academy of Dermatology. 11 (6): 1076–1081.
doi:
10.1016/S0190-9622(84)80192-9.
PMID6239884.
^Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Garatachea N, et al. (February 2015). "Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer's disease: a systematic review and meta-analysis of treatment effect". Drugs & Aging. 32 (2): 139–147.
doi:
10.1007/s40266-015-0239-z.
PMID25644018.
S2CID35357112.
^Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, et al. (2015). "Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis". Journal of Alzheimer's Disease. 44 (2): 385–396.
doi:
10.3233/JAD-141506.
PMID25227314.
^Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, et al. (December 2005). "Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease". Annals of Neurology. 58 (6): 963–967.
doi:
10.1002/ana.20682.
PMID16240369.
S2CID30843070.
^Gleason JM, Slezak JM, Jung H, Reynolds K, Van den Eeden SK, Haque R, et al. (April 2011). "Regular nonsteroidal anti-inflammatory drug use and erectile dysfunction". The Journal of Urology. 185 (4): 1388–1393.
doi:
10.1016/j.juro.2010.11.092.
PMID21334642.