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GOUT Is a Clinical Syndrome Resulting from The Vol. 334 No. 7 DRUG THERAPY 445 ecules are in the form of urate. Only in parts of the uri- DRUG THERAPY nary tract where the pH is less than 5.7 are most of the molecules in the form of uric acid, which because of its ALASTAIR J.J. WOOD, M.D., Editor poorer solubility may be present as uric acid crystals. TREATMENT OF ACUTE GOUTY ARTHRITIS Three treatments are available for patients with THE MANAGEMENT OF GOUT acute gouty arthritis. Colchicine is less favored now BRYAN T. EMMERSON, M.D., PH.D. than in the past, because its onset of action is slow and it invariably causes diarrhea.9 Nonsteroidal antiinflam- matory drugs, which are currently favored, are rapidly OUT is a clinical syndrome resulting from the dep- effective but may have serious side effects. Corticoster- G osition of urate (monosodium urate monohydrate) oids, administered either intraarticularly or parenteral- crystals. The crystals may be deposited in a joint, lead- ly, are used increasingly in patients with monarticular ing to an acute inflammatory response, or in soft tissues, gout,10-13 especially if oral drug therapy is not feasible. such as cartilage, causing no inflammation. Most cases Therapy that might alter serum urate concentrations of gout are characterized by the sudden onset of severe should not be initiated or changed as long as any gouty acute monarticular arthritis in a peripheral joint in the joint inflammation persists, because such treatment leg. The arthritis remits completely and then recurs with may delay the recovery. The choice of a drug depends increasing frequency. After approximately 10 years of on an assessment of its efficacy as compared with its recurrent gouty arthritis, tophi develop in cartilage, ten- toxic effects in the treatment of a particular attack in dons, and bursae in some patients. a particular patient. However, nonsteroidal antiinflam- Established criteria for the diagnosis of gout include matory drugs are generally favored unless the risk of the presence of urate crystals in joint fluid, the develop- side effects is judged to be too high. ment of a tophus, or the presence of the characteristic clinical pattern described above.1 Occasionally, a pa- Colchicine tient may have a more chronic or less severe arthritis The benefit of colchicine in treating gout is related affecting more than one joint at a time, in which case principally to its ability to inhibit phagocytosis of urate the diagnosis depends entirely on the detection of urate crystals by neutrophils (Table 2). Colchicine forms a crystals. In some patients, urate crystals have been de- tubulin–colchicine dimer that caps the assembly end tected in joints in which there has been no inflamma- of the microtubules, interfering with the transport of tion,2,3 but most of these patients have had at least one phagocytosed material to lysosomes. Colchicine also previous attack of gout. There are also reports of tophi blocks the release of chemotactic factor,14 reduces the developing without prior arthritis,4 chiefly in elderly mobility and adhesion of polymorphonuclear leuko- women with renal insufficiency who were taking diuret- cytes, and inhibits tyrosine phosphorylation and the 5 15 ic or nonsteroidal antiinflammatory drugs. generation of leukotriene B4. Although hyperuricemia is not a requirement for the The effective dose of colchicine in patients with acute diagnosis of gout1 and its presence in a patient with ar- gout is close to that which causes gastrointestinal symp- thritis does not necessarily establish that diagnosis, the toms. The drug is usually administered orally in a dose risk of gout increases with the degree and duration of of 1 mg initially, followed by 0.5 mg every two hours hyperuricemia (Table 1). However, among patients until abdominal discomfort or diarrhea develops or a with serum urate concentrations of 9.0 mg per deciliter total dose of 8 mg has been administered. Most patients (540 mmol per liter), the incidence of acute gout is only have some pain relief by 18 hours and diarrhea by 24 about 5 percent per year. 6,7 Hyperuricemia may occur hours; joint inflammation subsides gradually in 75 to 80 in a wide variety of conditions, genetic or acquired, percent of patients within 48 hours. 9 Except in patients metabolic or renal. Asymptomatic hyperuricemia does who have renal or hepatic dysfunction or are elderly not have any adverse effects before the development of and frail, colchicine given in this way is safe, although gout.6-8 Drug treatment is therefore not required, al- it entails some discomfort for the patient. though it is prudent to determine the causes of the hy- Colchicine may be given intravenously if oral admin- peruricemia and correct them, if possible. istration is not possible or if there is a need to avoid For simplicity and uniformity, the term “urate” is gastrointestinal side effects. The risk of systemic toxic used here instead of the more common term, “uric effects (marrow suppression and injury of renal, hepat- acid,” because, at physiologic pH, 99 percent of the mol- ic, and central nervous system cells) is much greater with intravenous therapy than with oral therapy. Safe intravenous therapy depends on the following guide- From the University of Queensland, Department of Medicine, Princess Alex- lines.38,39 An initial dose of 2 mg should be administered andra Hospital, Ipswich Rd., Woolloongabba, Brisbane, Queensland 4102, Aus- tralia, where reprint requests should be addressed to Dr. Emmerson. through an established intravenous catheter (to mini- 1996, Massachusetts Medical Society. mize the risk of extravasation); two additional doses of The New England Journal of Medicine Downloaded from nejm.org at UQ Library on August 5, 2018. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved. 446 THE NEW ENGLAND JOURNAL OF MEDICINE Feb. 15, 1996 Table 1. Annual Incidence of Gouty Arthritis tered only when nonsteroidal antiinflammatory drugs According to the Serum Urate and colchicine have been ineffective or are contraindi- Concentration. cated. There are reports of good responses, without a SERUM URATE ANNUAL rebound effect, to oral prednisone (30 to 50 mg per day CONCENTRATION INCIDENCE OF initially, with the dose tapered during a period of 7 to (mg/dl)* GOUT (%) 10 days), intramuscular corticotropin (40 U) or triam- Ͻ7.0 0.1–0.5 cinolone acetonide (60 mg), or intravenous methylpred- 7.0–8.9 0.5–1.2 nisolone (a daily dose of 50 to 150 mg administered у9.0 4.9–5.7 during a 30-minute period, with the dose tapered dur- 11-13 *To convert values for serum urate to micromoles per liter, ing a period of 5 days). multiply by 59.48. PROPHYLAXIS AGAINST ACUTE GOUT 1 mg each may be given at six-hour intervals, but the Acute attacks of gout may be prevented by small dos- total dose should never exceed 4 mg. The doses should es of either colchicine or nonsteroidal antiinflammatory be reduced by at least 50 percent in patients with he- drugs (Table 2). Prophylactic therapy should be admin- patic or renal disease and in elderly patients. The intra- istered before the initiation of measures to correct the venous preparation of colchicine is not available in many hyperuricemia. Prophylaxis with colchicine clearly di- countries, including Britain and Australia. minishes the rate of recurrent acute attacks, whether or Although colchicine has been used widely and for a not the serum urate concentration is normal. 22,23 In one long time, much remains to be learned about it. Its tox- study of 540 patients, colchicine was totally effective in ic effects are poorly understood, as is its metabolism, 82 percent of the patients, satisfactory in 12 percent, particularly the mechanisms whereby drugs such as ci- and ineffective in only 6 percent. Colchicine reduces metidine and erythromycin reduce its metabolism and the number of inflammatory cells in synovial fluid in increase its plasma and tissue concentrations and hence patients with gout who are asymptomatic, suggesting its toxic effects.16 that the drug interferes with the chemotactic response and reduces subclinical joint inflammation.24 Although Nonsteroidal Antiinflammatory Drugs the necessary duration of prophylaxis has not been es- Most potent nonsteroidal antiinflammatory drugs tablished, continuation of therapy for at least a year af- are rapidly effective in relieving pain and reducing in- ter the serum urate concentration has returned to a flammation in patients with acute gout (Table 2), par- normal level is usually sufficient. A myoneuropathy has ticularly if the drugs are taken soon after the onset of occasionally been reported during prophylaxis with col- the attack.40 Indomethacin, the first of these drugs to chicine in patients with a creatinine clearance of 50 ml be used extensively, provides some pain relief within per minute or less.47-50 two to four hours. Depending on the severity of the at- Nonsteroidal antiinflammatory drugs are also useful tack and its duration, the appropriate dose ranges for prophylactic therapy. No controlled comparison be- from 150 to 300 mg per day, given in divided doses, tween such drugs and colchicine has been undertak- with a gradual reduction during a period of five to sev- en,25 but colchicine probably has less serious toxic ef- en days as the attack subsides.41 Most other nonsteroi- fects. Prophylaxis with colchicine is therefore preferable, dal antiinflammatory drugs are effective but no better with a nonsteroidal antiinflammatory drug added if col- than indomethacin,42-45 although few comparative data chicine proves inadequate. are available.40,46 The usefulness of nonsteroidal antiin- flammatory drugs is limited by their side effects, but in CORRECTION OF HYPERURICEMIA general, the risks are greatest in elderly patients, par- Gout can be prevented by identifying and correcting ticularly those with renal dysfunction.17-21 the cause of hyperuricemia or by administering drugs that inhibit the synthesis of urate or increase its excre- Corticosteroids tion.
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