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Low-dose colchicine (Colcrys) was as effective as the commonly prescribed high-dose regimen for pain reduction in acute gout and had a much better side-effect profile, a multicenter randomized trial found.

A total of 37.8% of patients in the low-dose group were responders, compared with 32.7% of those in the high-dose group and 15.5% of those in the placebo group (P=0.005 and P=0.034, respectively, versus placebo), according to Robert A. Terkeltaub, MD, of the University of California, San Diego, and colleagues.

The overall rates of adverse events in the low-dose, high-dose, and placebo groups in the AGREE (Acute Gout Flare Receiving Colchicine Evaluation) study were 36.5%, 76.9%, and 27.1% respectively, the investigators reported in the April issue of Arthritis & Rheumatism.

"The results of the AGREE trial provide the first evidence basis, after centuries of colchicine use, for low-dose colchicine therapy in the treatment of early acute gout flare," they stated.

Only one randomized, placebo-controlled study -- published more than two decades ago -- evaluated colchicine in acute gout flare.

The mean dosage in that trial was 6.7 mg, and while significant pain reduction was seen, 100% of patients experienced diarrhea.

To determine if a lower dose could be both safe and effective, Terkeltaub and colleagues enrolled 575 patients who had had two or more gout flares during the previous year and randomized them to one of three groups:

• Low-dose colchicine, 1.2 mg followed by 0.6 mg at one hour (total 1.8 mg)
• High-dose colchicine, 1.2 mg followed by 0.6 every hour for six hours (total 4.8 mg)
• Placebo

Included in the intent-to-treat analysis were 184 patients who had a flare and took the study medication. The primary endpoint was a clinically significant reduction in pain of 50% or more in 24 hours.

"A critical feature of our design was the attempt to overcome the ethical issues of using a placebo control by limiting the time (one day) that a patient in the placebo group would be untreated," they noted.

Most patients were white men aged about 50 who had elevated urate levels and a ten-year history of gout.

Rescue medications were taken by 31.1% of patients during the first 24 hours in the low-dose group, by 34.6% of patients in the high-dose group, and by 50% of those in the placebo group. These patients were classified as nonresponders.

Patients receiving low-dose colchicine were significantly less likely to take rescue medication compared with those receiving placebo (OR 0.45, 95% CI 0.22 to 0.92, P=0.027).

The use of rescue medication was not influenced by baseline characteristics including demographic factors, concomitant use of allopurinol, number of flares in the past year, or alcohol use.

However, a post-hoc analysis revealed that patients whose baseline serum urate level was above 10 mg/dL were less likely to be responders (OR 0.29, 95% CI 0.12 to 0.74).

The most common side effect was diarrhea, which was reported by 76.9% and 23% of the high- and low-dose groups and by 13.6% of the placebo group.

Nausea was reported by 17.3%, 4.1%, and 5.1% of patients in the three groups, respectively.

Vomiting occurred in 17.3% of the high-dose group and severe diarrhea in 19.2%. Neither of these events was reported in the low-dose group.

"The benefit of treating acute gout flares with low-dose colchicine extends beyond a dramatic reduction in gastrointestinal side effects," the investigators observed. For example, it could minimize the potential for drug–drug interactions.

Colchicine is metabolized by P-glycoprotein and cytochrome P450, and severe adverse events and deaths have occurred when colchicine was combined with inhibitors of these pathways, such as clarithromycin.

Further studies should be carried out to more fully clarify dosing in combination with other drugs, because the patient population using colchicine is likely to be on multiple concurrent therapies.

Additional studies are needed to determine how other factors might affect dosing, such as the use of urate-lowering therapy and the patient's renal function.

A randomized study comparing colchicine, corticosteroids, and nonsteroidal anti-inflammatory drugs also would be valuable, according to the AGREE investigators.

"The results [of AGREE] are consistent with recent, expert opinion-based European League Against Rheumatism recommendations and support an immediate change in clinical practice from a high-dose colchicine regimen to a low-dose colchicine regimen for treatment of early gout flare," they concluded.

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