2020, allopurinol is generally the recommended preventative treatment if medications are used. a number of other medications may occasionally be considered to prevent further episodes of gout, including probenecid, febuxostat, benzbromarone, and colchicine. long term medications are not recommended until a person has had two attacks of gout, unless destructive joint changes, tophi, or urate nephropathy exist. it is not until this point that medications are cost-effective. they are not usually started until one to two weeks after an acute flare has resolved, due to theoretical concerns of worsening the attack. they are often used in combination with either an nsaid or colchicine for the first three to six months. while it has been recommended that urate-lowering measures should be increased until serum uric acid levels are below 300–360 µmol/l (5.0–6.0 mg/dl), there is little evidence to support this practice over simple putting people on a standard dose of allopurinol. if these medications are in chronic use at the time of an attack, it is recommended that they be continued. levels that cannot be brought below 6.0 mg/dl while attacks continue indicates refractory gout. while historically it is not recommended to start allopurinol during an acute attack of gout, this practice appears acceptable. allopurinol blocks uric acid production, and is the most commonly used agent. long term therapy is safe and well-tolerated and can be used in people with renal impairment or urate stones, although hypersensitivity occurs in a small number of individuals. the hla-b*58:01 allele of the human leukocyte antigen b (hla-b) is strongly associated with severe cutaneous adverse reactions during treatment with allopurinol and is most common among asian subpopulations, notably those of korean, han-chinese, or thai descent. febuxostat is only recommended in those who cannot tolerate allopurinol. there are concerns about more deaths with febuxostat compared to allopurinol. febuxostat may also increase the rate of gout flares during early treatment. however, there is tentative evidence that febuxostat may bring down urate levels more than allopurinol. probenecid appears to be less effective than allopurinol and is a second line agent. probenecid may be used if undersecretion of uric acid is present (24-hour urine uric acid less than 800 mg). it is, however, not recommended if a person has a history of kidney stones. pegloticase is an option for the 3% of people who are intolerant to other medications. it is a third line agent. pegloticase is given as an intravenous infusion every two weeks, and reduces uric acid levels. pegloticase is useful decreasing tophi but has a high rate of side effects and many people develop resistance to it. using lesinurad 400 mg plus febuxostat is more beneficial for tophi resolution than lesinural 200 ml with febuxostat, with similar side effects. lesinural plus allopurinol is not effective for tophi resolution. potential side effects include kidney stones, anemia and joint pain. in 2016, it was withdrawn from the european market. lesinurad reduces blood uric acid levels by preventing uric acid absorption in the kidneys. it was approved in the united states for use together with allopurinol, among those who were unable to reach their uric acid level targets. side effects include kidney problems and kidney stones. treatment the initial aim of treatment is to settle the symptoms of an acute attack. repeated attacks can be prevented by medications that reduce serum uric acid levels. tentative evidence supports the application of ice for 20 to 30 minutes several times a day to decrease pain. options for acute treatment include nonsteroidal anti-inflammatory drugs (nsaids), colchicine, and glucocorticoids. while glucocorticoids and nsaids work equally well, glucocorticoids may be safer. options for prevention include allopurinol, febuxostat, and probenecid. lowering uric acid levels can cure the disease. treatment of associated health problems is also important. lifestyle interventions have been poorly studied. it is unclear whether dietary supplements have an effect in people with gout. nsaids nsaids are the usual first-line treatment for gout. no specific agent is significantly more or less effective than any other. improvement may be seen within four hours and treatment is recommended for one to two weeks. they are not recommended for those with certain other health problems, such as gastrointestinal bleeding, kidney failure, or heart failure. while indometacin has historically been the most commonly used nsaid, an alternative, such as ibuprofen, may be preferred due to its better side effect profile in the absence of superior effectiveness. for those at risk of gastric side effects from nsaids, an additional proton pump inhibitor may be given. there is some evidence that cox-2 inhibitors may work as well as nonselective nsaids for acute gout attack with fewer side effects. colchicine colchicine is an alternative for those unable to tolerate nsaids. at high doses, side effects (primarily gastrointestinal upset) limit its usage. at lower doses, which are still effective, it is well tolerated. colchicine may interact with other commonly prescribed drugs, such as atorvastatin and erythromycin, among others. glucocorticoids glucocorticoids have been found to be as effective as nsaids and may be used if contraindications exist for nsaids. they also lead to improvement when injected into the joint. a joint infection must be excluded, however, as glucocorticoids worsen this condition. there were no short-term adverse effects reported. others interleukin-1 inhibitors, such as canakinumab, showed moderate effectiveness for pain relief and reduction of joint swelling, but have increased risk of adverse events, such as back pain, headache, and increased blood pressure. they, however, may work less well than usual doses of nsaids. the high cost of this class of drugs may also discourage their use for treating gout. prognosis without treatment, an acute attack of gout usually resolves in five to seven days; however, 60% of people have a second attack within one year. those with gout are at increased risk of hypertension, diabetes mellitus, metabolic syndrome, and kidney and cardiovascular disease and thus are at increased risk of death. it is unclear whether medications that lower urate affect cardiovascular disease risks. this may be partly due to its association with insulin resistance and obesity, but some of the increased risk appears to be independent. without treatment, episodes of acute gout may develop into chronic gout with destruction of joint surfaces, joint deformity, and painless tophi. these tophi occur in 30% of those who are untreated for five years, often in the helix of the ear, over the olecranon processes, or on the achilles tendons. with aggressive treatment, they may dissolve. kidney stones also frequently complicate gout, affecting between 10 and 40% of people, and occur due to low urine ph promoting the precipitation of uric acid. other forms of chronic kidney dysfunction may occur. gouty tophi presenting as nodules on the finger and helix of the ear tophus of the knee tophii on the toe and ankle gout complicated by ruptured tophi, the exudate of which tested positive for uric acid crystals gout in the big toe of left foot, compared to the healthy right foot gout in the joint of the big toe gross pathology of a large tophus epidemiology gout affects around 1–2% of people in the western world at some point in their lifetimes and is becoming more common. some 5.8 million people were affected in 2013. rates of gout approximately doubled between 1990 and 2010. this rise is believed to be due to increasing life expectancy, changes in diet and an increase in diseases associated with gout, such as metabolic syndrome and high blood pressure. factors that influence rates of gout include age, race, and the season of the year. in men over 30 and women over 50, rates are 2%. in the united states, gout is twice as likely in males of african descent than those of european descent. rates are high among pacific islanders and the māori, but the disease is rare in aboriginal australians, despite a higher mean uric acid serum concentration in the latter group. it has become common in china, polynesia, and urban sub-saharan africa. some studies found that attacks of gout occur more frequently in the spring. this has been attributed to seasonal changes in diet, alcohol consumption, physical activity, and temperature. history antonie van leeuwenhoek described the microscopic appearance of uric acid crystals in 1679. the term "gout" was initially used by randolphus of bocking, around 1200 ad. it is derived from the latin word gutta, meaning "a drop" (of liquid). according to the oxford english dictionary, this is derived from humorism and "the notion of the 'dropping' of a morbid material from the blood in and around the joints". gout has been known since antiquity. historically, it was referred to as "the king of diseases and the disease of kings" or "rich man's disease". the ebers papyrus and the edwin smith papyrus, (c. 1550 bc) each mention arthritis of the first metacarpophalangeal joint as a distinct type of arthritis. these ancient manuscripts cite (now missing) egyptian texts about gout that are claimed to have been written 1,000 years earlier by imhotep. greek physician hippocrates around 400 bc commented on it in his aphorisms, noting its absence in eunuchs and premenopausal women. aulus cornelius celsus (30 ad) described the linkage with alcohol, later onset in women and associated kidney problems: again thick urine, the sediment from which is white, indicates that pain and disease are to be apprehended in the region of joints or viscera... joint troubles in the hands and feet are very frequent and persistent, such as occur in cases of podagra and cheiragra. these seldom attack eunuchs or boys before coition with a woman, or women except those in whom the menses have become suppressed... some have obtained lifelong security by refraining from wine, mead and venery. benjamin welles, an english physician authored the first medical book on gout, a treatise of the gout, or joint evil, in 1669. in 1683, thomas sydenham, an english physician, described its occurrence in the early hours of the morning and its predilection for older males: gouty patients are, generally, either old men or men who have so worn themselves out in youth as to have brought on a premature old age—of such dissolute habits none being more common than the premature and excessive indulgence in venery and the like exhausting passions. the victim goes to bed and sleeps in good health. about two o'clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. the pain is like that of a dislocation and yet parts feel as if cold water were poured over them. then follows chills and shivers and a little fever... the night is passed in torture, sleeplessness, turning the part affected and perpetual change of posture; the tossing about of body being as incessant as the pain of the tortured joint and being worse as the fit comes on. dutch scientist antonie van leeuwenhoek first described the microscopic appearance of urate crystals in 1679. in 1848, english physician alfred baring garrod identified excess uric acid in the blood as the cause of gout. other animals gout is rare in most other animals due to their ability to produce uricase, which breaks down uric acid. humans and other great apes do not have this ability; thus, gout is common. other animals with uricase include fish, amphibians and most non-primate mammals. the tyrannosaurus rex specimen known as "sue" is believed to have had gout. research a number of new medications are under study for treating gout, including anakinra, canakinumab, and rilonacept. canakinumab may result in better outcomes than a low dose of a glucocorticoid, but costs five thousand times more. a recombinant uricase enzyme (rasburicase) is available but its use is limited, as it triggers an immune response. less antigenic versions are in development.