Ibuprofen

• 1. Introduction

  ›

  Stewart Adams, a researcher at Boots the Chemists in Nottingham, first tried the compound that became ibuprofen as a cure for his own hangover. A patent application followed in 1961. Ibuprofen is a nonsteroidal anti-inflammatory drug, usually shortened to NSAID, and it is now used against pain, fever, and inflammation. Taken by mouth or given intravenously, it typically begins working within an hour. It also sits on the World Health Organization's List of Essential Medicines. Behind those plain facts are several puzzles. Why was a pharmacy company searching for a new painkiller in the first place? What does the molecule actually do once it enters the body? Why can the same tablet that eases a migraine also irritate the stomach, strain the kidneys, or worry cardiologists at high doses? And how did a compound born in one Nottingham laboratory become a medicine that millions of people reach for?

  1011841214

• 2. Rival To Aspirin

  ›

  The hunt for a safer alternative to aspirin drove research through the 1950s and into the 1960s. Out of that effort, the research arm of the Boots Group derived ibuprofen from propionic acid. A team led by Adams made the molecule, and John Nicholson worked beside him. The first product carried the brand name Brufen. The generic name is a compression of the chemistry: isobutyl gives ibu, propionic acid gives pro, and the phenyl group gives fen.

  In 1969, ibuprofen reached patients in the United Kingdom as a treatment for rheumatoid arthritis. The United States followed in 1974. American shoppers met it under the brand name Motrin from 1974 and under Advil from 1984. Elsewhere it was sold as Brufen and Nurofen, among other names.

  In 1983 and 1984, ibuprofen became the first NSAID besides aspirin to be sold over the counter in both countries. Then came 1985. Boots's worldwide patent expired that year, and generic products were launched. The company also received the Queen's Award for Technical Achievement in 1985 for developing the drug.

  In November 2013, the Royal Society of Chemistry marked the story with two blue plaques. One stands at the Boots Beeston Factory site in Nottingham and honors the 1980s work that moved ibuprofen from prescription-only status to over-the-counter sale. The other is at BioCity Nottingham, the site of the original laboratory on Pennyfoot Street, and it names Adams and Nicholson.

  A new form arrived in 2009, when the first injectable ibuprofen was approved in the United States under the brand name Caldolor. By 2023, ibuprofen was the 32nd most commonly prescribed medication in the United States, with more than 17 million prescriptions.

  8587889316

• 3. Blocking The Enzyme

  ›

  Ibuprofen works by blocking cyclooxygenase enzymes, known as COX, which convert arachidonic acid into a molecule called prostaglandin H2. Other enzymes then turn that molecule into prostaglandins, which mediate pain, inflammation, and fever. They also make thromboxane A2, which stimulates platelets to clump and helps blood clots form. Cutting COX activity therefore reduces the whole chain downstream.

  Like aspirin and indomethacin, ibuprofen is a nonselective inhibitor, meaning it hits both COX-1 and COX-2. In laboratory measurements, the concentration needed to halve enzyme activity, called the IC50, was 13 micromolar for COX-1 and 370 micromolar for COX-2. The pain-relieving, fever-lowering, and anti-inflammatory effects of NSAIDs seem to come mainly from blocking COX-2. Blocking COX-1 is instead tied to unwanted effects in the digestive tract. The source stresses that this split is uncertain, and different NSAIDs cause different degrees of pain relief and stomach damage. Ibuprofen is a weaker anti-inflammatory agent than other NSAIDs.

  The fever effect may involve the hypothalamus. Action there could raise blood flow near the skin, widen the vessels, and let heat escape.

  The liver does most of the processing afterward. Enzymes including CYP2C9, CYP2C8, CYP2C19, and CYP3A4 produce hydroxylated forms, and CYP2C9 produces carboxyl-ibuprofen. These products are inactive. Almost all of the drug is bound to plasma proteins, most of it is cleared in urine within 24 hours, and only 1 percent leaves unchanged through bile.

  Two stranger activities set ibuprofen apart from most NSAIDs. It inhibits Rho kinase, which may be useful for recovery from spinal cord injury. It also inhibits the sweet taste receptor.

  5558636567

• 4. A Molecule In Mirror Form

  ›

  The original Boots route to ibuprofen began with a compound called isobutylbenzene and took six steps. Chemists ran a Friedel-Crafts acylation with acetic anhydride, then a Darzens reaction with ethyl chloroacetate. After that came hydrolysis and decarboxylation to form an aldehyde, a reaction with hydroxylamine to make an oxime, and conversion to a nitrile. A final hydrolysis delivered ibuprofen.

  In the 1980s, the Celanese Chemical Company developed a greener method with only three steps. Its first step uses hydrogen fluoride as a recyclable Lewis acid catalyst. The key step is a carbonylation run with a palladium catalyst at around 50 bar of carbon monoxide pressure. Waste byproducts came to 23 percent of total product mass, against a theoretical 60 percent for the older route.

  The finished compound is practically insoluble in water but dissolves readily in ethanol, methanol, acetone, and dichloromethane. In 90 percent ethanol at 40 degrees Celsius, 66.18 grams dissolve in 100 milliliters.

  Ibuprofen shares a feature with ketoprofen, flurbiprofen, and naproxen: a stereocenter, so the molecule exists as two mirror-image forms. Pharmacies sell a racemic mixture of the S and R forms. The S form, which is dextrorotatory, carries the desired therapeutic activity and is called the eutomer. The R form is the distomer, and it is inactive on its own. The body converts R into S in one direction only, using the enzyme alpha-methylacyl-CoA racemase, and the S form is left untouched. Three enzymes carry out the full conversion: acyl-CoA-synthetase, 2-arylpropionyl-CoA epimerase, and a hydrolase. The pure S form has also been isolated and used medically as dexibuprofen.

  6970727679

• 5. What It Treats

  ›

  About 60 percent of people respond to any given NSAID, and someone who does not respond to one may respond to another. Ibuprofen is used mainly for fever, including fever after vaccination, and for mild to moderate pain. That includes pain after surgery, painful menstruation, osteoarthritis, dental pain, headaches, and pain from kidney stones.

  A Cochrane medical review pooled 51 trials of NSAIDs for lower back pain. Its conclusion reads: "NSAIDs are effective for short-term symptomatic relief in patients with acute low back pain".

  Inflammatory diseases form a second group, including juvenile idiopathic arthritis and rheumatoid arthritis. Doctors also use ibuprofen for pericarditis. And in premature babies it can close a patent ductus arteriosus, a vessel that normally seals after birth.

  In some countries, a version called ibuprofen lysine, or ibuprofen lysinate, is licensed for the same conditions. The lysine salt dissolves more easily in water. Later studies found no statistical difference between it and plain ibuprofen. In 2006, the United States Food and Drug Administration approved ibuprofen lysine for closing a patent ductus arteriosus in infants weighing between 500 and 1500 grams. These infants must be no more than 32 weeks gestational age, and the approval applies when usual management has failed. That management includes fluid restriction, diuretics, and respiratory support.

  1823252126

• 6. Risks And Cautions

  ›

  Heartburn, nausea, indigestion, and abdominal pain are the common complaints. Diarrhea, constipation, headache, dizziness, rash, salt and fluid retention, high blood pressure, and gastrointestinal ulceration also appear on the list. Less often, patients report esophageal ulceration, heart failure, high blood potassium, kidney impairment, confusion, or bronchospasm. Long-term use has been linked to kidney failure and, rarely, liver failure. Ibuprofen can worsen heart failure and asthma, and the asthma effect is sometimes fatal. Allergic reactions, including anaphylaxis, can occur.

  On the 9th of July 2015, the FDA toughened its warnings about heart attack and stroke for ibuprofen and related NSAIDs. Aspirin was left out of that warning. The European Medicines Agency issued similar warnings in 2015. Chronic use is correlated with progression to hypertension in women, though less so than with paracetamol, also called acetaminophen. At low doses, ibuprofen does not appear to raise heart attack risk, but higher doses may.

  Skin reactions are another concern. Ibuprofen has been associated with bullous pemphigoid, a blistering condition. It is a weak photosensitizing agent compared with others in its chemical class. It is an extremely rare cause of Stevens-Johnson syndrome and toxic epidermal necrolysis.

  In Britain, the National Health Service recommends against using ibuprofen for more than 3 days in pregnancy, because it can affect the fetus's kidneys and circulatory system. Paracetamol is considered the safer alternative. A 2012 Canadian study found that women taking NSAIDs were 2.4 times more likely to miscarry. A 2014 Israeli study found no increased risk. It noted that two earlier studies, including the Canadian one, "did not adjust for important known risk factors". In October 2020, the FDA required all NSAID labels to describe the risk of kidney problems in unborn babies, which can lead to low amniotic fluid.

  Aspirin raises a different problem. The FDA says ibuprofen "can interfere with the antiplatelet effect of low-dose aspirin, potentially rendering aspirin less effective when used for cardioprotection and stroke prevention". Timing matters for immediate-release aspirin. Ibuprofen should come 30 minutes or more after aspirin, or 8 hours or more before it. That timing cannot be recommended for enteric-coated aspirin. Occasional use without the timing reduces aspirin's protection only minimally.

  Drinking alcohol with ibuprofen may raise the risk of stomach bleeding. Combining ibuprofen with paracetamol is considered generally safe for short-term use in children.

  3638473243

• 7. When Doses Climb

  ›

  Toxic effects of ibuprofen become severe above 400 milligrams per kilogram, which for an average adult male is around 150 tablets of 200 milligrams each. Toxicity is unlikely below 100 milligrams per kilogram. Even so, a large dose does not mean the outcome will be lethal. A precise lethal dose is hard to pin down because age, weight, and other conditions all shift it.

  Overdose has become common since the drug gained over-the-counter licensing, and many cases fill the medical literature. Yet life-threatening complications remain infrequent. Responses range from no symptoms at all to death despite intensive-care treatment. Typical symptoms include abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, ringing in the ears, and nystagmus, an involuntary eye movement. Rare severe ones include seizures, metabolic acidosis, coma, atrial fibrillation, acute kidney failure, and cardiac arrest. The match between symptoms and measured blood levels is weak, and individual sensitivity plays a large role.

  Treatment follows the symptoms. For patients who arrive early, doctors recommend decontaminating the stomach with activated charcoal, which absorbs the drug before it enters the bloodstream. Gastric lavage is now rarely used, but it can be considered when the amount is potentially life-threatening and within 60 minutes of ingestion. Making the patient vomit on purpose is not recommended. Care centers on maintaining normal urine output and monitoring kidney function. Forced alkaline diuresis helps little, because ibuprofen binds so tightly to blood proteins that the kidneys excrete almost none of it unchanged.

  Blood tests can measure ibuprofen to confirm poisoning in hospitalized patients, to document the drug after an anaphylactic reaction, or to assist a medicolegal death investigation. A published monograph relates plasma concentration and time since ingestion to the risk of kidney toxicity after an overdose.

  4952535451

• 8. Beyond Pain Relief

  ›

  In Japan, a topical form of ibuprofen has been sold for adult acne, since the drug's anti-inflammatory properties may help. As with other NSAIDs, it may be useful against severe orthostatic hypotension, a drop in blood pressure on standing. For Alzheimer's disease, the value of NSAIDs for prevention and treatment remains unclear.

  Supplements raise another caution. Some may be dangerous when taken with ibuprofen and other NSAIDs, though more research is needed to be certain. The list includes ginkgo, garlic, ginger, bilberry, dong quai, feverfew, ginseng, turmeric, meadowsweet, and willow, all of which can prevent platelet aggregation. Coumarin-containing plants such as chamomile, horse chestnut, fenugreek, and red clover are also flagged. So is tamarind, which increases the risk of bleeding.

  In March 2011, researchers at Harvard Medical School announced that ibuprofen had a neuroprotective effect against Parkinson's disease. People who used it regularly had a 38 percent lower risk. Aspirin, paracetamol, and other pain relievers showed no such effect. The source cautions that using ibuprofen across the general population to lower Parkinson's risk would not be problem-free, given possible effects on the urinary and digestive systems.

  95989910097