Newswise — Increasing the dose of allopurinol above the recommended dose can lead to a significant reduction in serum uric acid in people with gout, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Philadelphia, Pa.
Gout is a painful and potentially disabling form of arthritis that has been recognized since ancient times. Initial symptoms usually consist of intense episodes of painful swelling in single joints, most often in the feet (especially the big toe). Treatments are already available to prevent or control the arthritis associated with gout, but managing this disorder can be difficult, and treatment plans often have to be tailored for each person.
Allopurinol (Zyloprim®) is the most commonly used urate lowering therapy. Recommended dosing guidelines for this medication have been published, and are based in part on kidney function; however, many patients fail to achieve adequate serum uric acid reduction—which is needed to control gout—with the recommended doses.
Researchers from the University of Otago, Christchurch, New Zealand recently completed a study to determine whether using allopurinol above the recommended doses would lead to adequate reduction in serum urate without increasing toxicity. They recruited 90 people with gout who were on a stable dose of allopurinol for at least one month. The average age of the participants was 58.3 years; 87.8 percent of the participants were male.
At the initial visit, 52 participants had serum uric acid levels greater than 6 mg/dL, the critical level above which gout is more likely to occur.
Forty-five participants had their dose of allopurinol increased anywhere from 50 to 400 milligrams above the recommended range. Of these, three developed rashes and discontinued allopurinol or went back to taking a lower dose of the medication and six failed to attend follow-up appointments or developed intervening medical problems unrelated to gout. Of the 36 patients who completed the 12-month study, 86 percent dropped their serum urate levels to 6 mg/dl or less, which researchers attribute to the increased doses of allopurinol. In addition to a good response to the increased treatment, participants (with the exception of the three who experienced rashes) did not experience any significant side effects.
“While allopurinol is the mainstay of treatment, physicians have concerns about increasing the dose above recommended guidelines particularly in patients with impaired kidney function, “ explains rheumatologist and Lisa Stamp, FRACP, PhD; senior lecturer and rheumatologist; University of Otago, Christchurch, New Zealand, and lead investigator in the study. “This has led to poor control of gout which causes significant pain, impacts on quality of life and can lead to permanent joint damage. This study lends support to the practice of many rheumatologists in which the goal in gout treatment is to achieve a target urate less than 6 mg/dL rather than persisting with a perceived safe but inadequate allopurinol dose.”
Patients should talk to their rheumatologists to determine their best course of treatment and should never adjust their medication unless directed by their rheumatologist
The ACR is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with or at risk for arthritis and rheumatic and musculoskeletal diseases. For more information on the ACR’s annual meeting, see www.rheumatology.org/annual.
Editor’s Notes: Dr. Stamp will present this research during the ACR Annual Scientific Meeting at the Pennsylvania Convention Center at 5:30 PM on October 20 in the Auditorium. Dr. Stamp will be available for media questions and briefing at 1:30 PM on Monday, October 19 in the on-site press conference room, 109 A.
Presentation Number: 1950
Increasing Allopurinol Dose Above the Recommended Range Is Effective and Safe in Chronic Gout, Including in Those with Renal Impairment – a Pilot Study
Lisa Stamp, FRACP, PhD, University of Otago, Dunedin, New Zealand J.L. O'Donnell, MB, Immunology, Canterbury Health Laboratories, Christchurch M. Zhang, PhD, Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand C. Frampton, PhD, Department of Medicine, University of Otago, Christchurch, New Zealand M. Barclay, FRACP, Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand PT Chapman, FRACP, Rheumatology, Christchurch Hospital, Christchurch, New Zealand
Purpose: Allopurinol is the most commonly used urate lowering therapy. Recommended dosing guidelines based on creatinine clearance (CrCL) have been published. However, many patients fail to achieve adequate serum uric acid (SUA) reduction with recommended doses. The aim of this study was to determine whether using allopurinol above recommended doses leads to adequate reduction in SUA without increase in toxicity.
Methods: Patients with gout on stable dose allopurinol for at least one month were recruited. Recommended allopurinol dose was defined by the Hande criteria based on CrCL. Allopurinol dose was gradually increased to obtain the target SUA ≤6mg/dL. Patients were seen monthly until SUA was ≤6mg/dL for 3 consecutive months. Then patients were seen 3 monthly until at least 12 months after study entry. Data were analyzed using allopurinol mg/day above recommended dose in 50mg increments (R+).
Results: 90 patients were enrolled. Mean age 58.3years (27-83yrs), 87.8% male, and 78% European. At the initial visit, 52 had SUA >6mg/dL, of whom 7 were on lower than recommended doses of allopurinol. 45 patients had the dose of allopurinol increased above the recommended range. Baseline mean CrCl in the dose escalation group was 61.9mls/min (19-132) and mean SUA was 7.4 mg/dL (6-10.8mg/dL). Three patients developed rashes (2 receiving concomitant frusemide) and discontinued allopurinol or ceased dose escalation. Six patients were lost to follow-up. All patients were included in the analysis until lost or stopped allopurinol. Of the 36 patients who completed the entire 12-month study period, 31 (85%) patients achieved a SUA ≤6mg/dL at the 12 month end point. Of the 5 patients who had SUA>6mg/dL 2 had undetectable plasma oxypurinol indicating non-compliance. There was a significant reduction in SUA at all allopurinol doses above recommended (p<0.001). The percentage decrease in SUA from baseline was -12.6% R+50mg, -20.8% R+100mg, -25.9% R+150mg, -36.2% R+200, -30% R+250mg and -35.6% R+300mg. 18/45 patients were receiving frusemide or a thiazide diuretic. There was no significant difference between baseline SUA in those receiving diuretic treatment or not. Baseline doses of allopurinol were higher in those patients on frusemide (248 vs 180mg/d p=0.003). Patients on frusemide were just as likely to achieve SUA ≤6mg/dL as patients not on frusemide (72% vs 88.5% p=0.24). Other than the three patients with rashes there were no significant toxicities.
Conclusion: Increasing the dose of allopurinol above the recommended range led to a significant reduction in serum urate. 86% of patients achieved a SUA ≤6mg/dL. There was no increase in toxicity with higher doses of allopurinol in this cohort, including those with renal impairment.
Disclosure: L. Stamp, WYETH, 6 ; J. L. O'Donnell, None; M. Zhang, None; C. Frampton, None; M. Barclay, None; P. Chapman, None.
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