By Igor Wilderman, MD, CCFP, DAAPM, DCAPM

One of the most uncomfortable and painful conditions is arthritic joint pain. Gout is a specific arthritic disease with a predictable outcome. Because modern medicine has been active on the battlefield against this age-old condition, the disease is now understood better than ever and can be effectively treated. Though the basic elements of exercise and a healthy diet remain an invaluable tool to control gout flare-ups, the use of medication to control uric acid production offers the best current treatment.

Gout has been recognized as a painful disease since ancient times. Hippocrates called gout “the unwalkable disease” because it tended to manifest itself in the big toe and make walking difficult. Finding a treatment for gout has been slow, but steady observation of its symptoms has led to improvement in treatment options. At first, the avoidance of alcoholic beverages and purine-rich foods was recommended to avoid the painful flare-ups associated with gout. Over time, there has been a natural progression toward understanding the dynamics of gout pain and uric acid to target effective treatment. The use of colchicines (from the autumn crocus plant) was one of the first treatments for gout and has remained the standard treatment for the disease for decades. Because of its high toxicity and long half-life, colchicine is not considered an effective treatment for gout when given alone, but colchicine has shown efficacy in reducing the frequency of gout attacks when used in combination with medications like allopurinol or probenecid.

As effective as non-steroidal anti-inflammatory drugs and corticosteroids may be to modern medicine, they rarely constitute an effective treatment for gout. The evolution of gout treatment has led to the development of uricosuric agents such as probenecid and sulfinpyrazone, which lower the amount of uric acid in the blood by increasing its elimination by the kidneys. Their mechanism of action involves moderating the absorption of uric acid from the proximal tubules of the kidney back into the blood.

Uricosurics act by blocking URAT1, the protein involved in the transport of uric acid between the kidney and blood. A difficulty with this type of medication is its contraindication in patients with renal conditions. These medications tend to mal-perform in renal-impaired patients because their high binding affinity for blood proteins results in a bypass of glomerular filtration. Since uricosuric agents must secrete into the renal tubule and inhibit the URAT1 transporter to be effective, they are inadequate in patients suffering from renal impairment.

Another common treatment for gout involves the use of allopurinol to manage hyperuricemia. But when serum uric acid levels rapidly fall below about 6mg/dL, urate crystals become activated and cause inflammation of the joints. In such a scenario, acute gout flare-ups become more common because of frequent uric acid surges. The predicament lies in identifying a form of therapy that lowers uric acid levels at a rate that does not encourage flare-ups. Concomitant use of anti-inflammatory medication with allopurinol sometimes alleviates flare-up inflammation. Research has shown that allopurinol is more effective at managing chronic gout when given in combination with febuxostat rather than when prescribed alone. Allopurinol is especially useful in patients with renal impairment, as it is not a uricosuric. Though potentially beneficial to this subset of patients, a notable problem with allopurinol in other patient populations is its tendency to cause gastrointestinal side effects. Furthermore, the relative inefficacy of allopurinol is attributed to the fact that a large number of patients are hypersensitive to it, exhibiting symptoms of rash, fever and liver enzyme elevation. Like all drugs in the class of xanthine oxidase medications, the therapeutic effects of allopurinol are exerted through the inhibition of xanthine oxidase, leading to a decrease in uric acid production and overall purine levels.

Some xanthine oxidase medications offer fairly effective treatment options with a low side effect profile. One such medication is febuxostat, an effective agent to combat gout because it is efficient at reducing serum uric acid (SUA) levels. A phase III study comparing febuxostat and placebo to allopurinol concluded there was an effective reduction of SUA at three increasing doses. An SUA of less than 6mg/dl was recorded in up to 69% of patients. The general acceptable range of SUA is between 4mg/dL and 7mg/dL. Febuxostat, like allopurinol, exerts its therapeutic effect by inhibiting xanthine oxidase, and essentially lowering uric acid levels. This results in a marked decrease in serum uric acid levels, but often at a cost of initially increasing acute flare-ups.

Controlling hyperuricemia is critical in the long-term management of gout pain. Febuxostat is effective at managing gout in the long term. Another phase III study showed that after five years of treatment, 93% of remaining patients maintained a healthy SUA level. Less than ten per cent of patients taking febuxostat experience adverse reactions such as headache, diarrhea and rash. However, these side effects pale in comparison to the effects of untreated gout, which may include bone and cartilage damage and permanent kidney damage. Though the side effects of prolonged febuxostat treatment are not completely established, the medication is well tolerated and does not have a high rate of acute side effects. With febuxostat, long-term gout pain management seems to be a viable option. It is the first new gout medication in more than 40 years to offer such a specific spectrum of treatment.

One of the latest medications to undergo trials, and one that is being researched at the Canadian Centre for Clinical Trials, is MBX-102. After several phase I and II trials, this medication seems promising for effective treatment of gout. Originally developed to combat type 2 diabetes, MBX-102’s uricosuric properties are proving effective at lowering uric acid. It is being formulated as a once-a-day medication with the benefits of not altering kidney function while simultaneously reducing serum glucose and inflammation markers. Trials are underway to test the efficacy of MBX-102 administered in conjunction with allopurinol.

The most recent advancement in gout treatment is a novel medication called lesinurad, a urate transporter inhibitor. Lesinurad can be given to patients along with allopurinol or febuxostat to maximize therapeutic effects. A number of clinical trials have been conducted with this “next generation” medication. A recent study concluded that lesinurad in combination with febuxostat was very successful at reducing uric acid levels to below 6mg/dL. Moreover, lesinurad is very well tolerated and does not have a loss of efficacy in patients with renal impairment. The quest for effective gout pain management is ongoing, and will likely see an increase in approved medications in the near future. Chronic gout management research has made great strides in the past 40 to 50 years, and the development of newer and more effective medications remains an ongoing goal. The options for managing chronic gout pain are ever expanding as a result of diligent research into new medications.

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Dr. Igor Wilderman is a physician in Thornhill, Ontario with a focused practice in chronic pain. The founder and medical director of the Canadian Centre for Clinical Trials, he and his research team strive to improve available treatment options for people living with various chronic conditions. He also runs a series of free educational seminars to inform and raise awareness.