Gout

Description

Alternative Names

Medications

Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. They are the drugs of choice for young, healthy adults without any other serious medical condition. NSAIDs are usually taken orally at their highest safe dosage as long as gout symptoms persist and for three or four days after. Low doses of NSAIDs may be used to prevent gout attacks, including in patients who are starting anti-hyperuricemic therapies.

NSAIDs Used. There are dozens of NSAIDs available.

There are dozens of NSAIDs. The most common are the following:

• Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT). One study suggested that ibuprofen or naproxen is more effective than aspirin or acetaminophen for acute tension-type headache.
• Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), flurbiprofen (Ansaid), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil), indomethacin (Indocin).

Indomethacin (Indocin) is typically the first choice for patients who have no medical conditions that would preclude its use. Usually two to seven days of high-dose indomethacin will be sufficient to treat a gout attack. The first dose of indomethacin usually begins to act against the pain and inflammation within 24 hours and often much sooner.

Ibuprofen, naproxen, sulindac, or others are good alternatives particularly for elderly patients who might experience confusion or bizarre sensations with indomethacin. (Aspirin is an NSAID, but is associated with a higher risk for gout and should be avoided.)

Regular use of even over-the-counter NSAIDs may be hazardous for anyone and has been associated with the following side effects:

• Ulcers and gastrointestinal bleeding. This is the major danger with long-term use of NSAIDs. (indomethacin poses a higher risk than many others for this adverse effect.)
• Increased blood pressure. Most NSAIDs appear to pose this risk, with higher risks observed with piroxicam (Feldene), naproxen (Aleve), and indomethacin (Indocin). (Sulindac has the smallest effect and aspirin as no risk.) People with hypertension, severe vascular disease, kidney, or liver problems and those taking diuretics must be closely monitored if they need to take NSAIDs.
• May delay the emptying of the stomach, which could interfere with the actions of other drugs. The elderly are at special risk.
• Dizziness.
• Tinnitus (ringing in the ear)
• Headache.
• Skin rash.
• Depression has also been noted.
• Confusion or bizarre sensation (in some higher-potency NSAIDs, notably indomethacin).
• As with acetaminophen, high daily doses of aspirin have been associated with an increased risk of kidney failure, although the risk remains low in those with healthy kidney function. Kidney abnormalities have been reported in people taking other NSAIDs as well, which resolve when the drugs are withdrawn. Any sudden weight gain or swelling should be reported to a physician. Anyone with kidney disease should avoid these drugs.
• Patients with diabetes who take oral hypoglycemics may need to adjust the dosage if they also need to take NSAIDs because of possible harmful interactions between the drugs.

Note: Some studies have reported that ibuprofen (but not other NSAIDs) may blunt the heart-protective effects of low-dose aspirin, Additional research is needed to confirm these findings.

COX-2 Inhibitors (Coxibs).

Celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) are known as COX-2 (cyclooxygenase-2) inhibitors, or coxibs. They inhibit an inflammation-promoting enzyme called COX-2. Others, such as etoricoxib, are under investigation. Meloxicam (Mobicox) is a related drug known as a COX-2 preferential.

COX-2 inhibitors are increasingly being used for patients with gout. In 2004, etoricoxib (120 mg once daily) was shown to be as effective as indomethacin (50 mg three times daily) in patients with acute gout, but with significantly fewer side effects. Another 2004 study showed that rofecoxib 50 mg once daily was a more effective treatment for acute gout than once-a-day therapy with diclofenac sodium SR 150 mg or meloxicam 15 mg.

Evidence is increasing that the coxibs are somewhat less harmful to the GI tract than the common NSAID naproxen. Celebrex may be superior to Vioxx in this regard, although more studies are needed to confirm this. Some early evidence also suggests that, like NSAIDs, they may be partially protective against colon cancer and possibly even Alzheimer's disease.

In spite of their potential promise, some researchers theorize that inhibiting COX-2 may have some negative side effects over the long term. The effects of these drugs on the heart particularly require clarification. The following are possible adverse effects or complications:

• Some studies have reported twice the incidence of heart attacks in patients taking Vioxx compared to those taking standard NSAIDs. There were limitations to these studies, however, and 2003 study found no higher risk. Some (but not all evidence) suggests that the COX-2 inhibitors may increase the risk for blood clots. On the other hand some studies have suggested that the anti-inflammatory effects, at least in Celebrex and meloxicam (Movicox) may have beneficial effects on blood vessels, which would be heart protective.
• In one study, people who took Celebrex or Vioxx experienced an increase in blood pressure, with Vioxx having the greater effect.
• A few cases of neurologic side effects (hallucinations) have been observed with higher doses of Celebrex or Vioxx. There have also been reports of meningitis with Vioxx, which is reversible when the drug is stopped.
• COX-2 inhibitors may have some adverse effects on kidney function, particularly in elderly people, which is similar to the effects of standard NSAIDs. Liver abnormalities, which are side effects of many drugs, have also been reported with coxibs and need further follow-up.
• They may have negative effects on pregnancy and fertility.A 2004 study showed that COX-2 selective inhibitors may harm fetal and newborn kidney development, and therefore should be used with caution during pregnancy.
• Some severe allergic reactions have been reported in patients taking valdecoxib (Bextra). Anyone who develops a rash after taking these agents should stop taking them immediately.
• Patients who are sensitive to aspirin should discuss COX-2 inhibitors with their physician. Some may be safer for these individuals than others.

COX-2 inhibitors can interfere with other drugs taken concurrently. Patients taking anticoagulant drugs such as warfarin may experience a higher risk for bleeding with the use of these agents. The use of coxibs can interfere with many other drugs taken concurrently, including lithium, methotrexate, and many others taken for heart disease, high blood pressure, or epilepsy. Patients should discuss all other medications with their physician. Patients should discuss all other medications with their physician.

COX-2 inhibitors are also currently more expensive than traditional NSAIDs, however, costing about $80 per month, compared to about $15 for an NSAID like naproxen, and some insurers do not pay for them. More research is needed to confirm or refute any possible hazards from taking coxibs and also to determine whether their benefits are worth the higher cost.

Other Investigative Alternatives to NSAIDs

NO-NSAIDs. Experimental agents are being developed that combine nitric oxide (NO) with NSAIDs. These treatments are called NO-NSAIDs. NO increases blood flow in the mucous lining and secretions of mucus and bicarbonate. Combining nitric oxide with NSAIDs may reduce the adverse effects on the GI tract. In addition, according to one study, an experimental NO-aspirin also had the heart protective properties of aspirin without its gastrointestinal problems. (COX-2 inhibitors may have adverse effects on the heart.)

Arthrotec. Arthrotec is a combination of misoprostol and the NSAID diclofenac that may reduce the risk for gastrointestinal bleeding. One study found that patients taking Arthrotec had 65% to 80% fewer ulcers than those who took NSAIDs alone.

Colchicine

Colchicine, a derivative of the autumn crocus (also called the meadow saffron), has been used against gout attacks for centuries. It is highly effective though no longer the first drug of choice because of its frequent, unpleasant, and sometimes very serious side effects.

Oral Regimen. The oral regimen requires doses every hour until the symptoms either improves or side effects develop; improvement should be evident by the tenth dose. Oral colchicine usually eliminates the pain of an acute attack within 48 hours.

The drug is generally appropriate only for healthy adults. It should not be used elderly patients or those with kidney, liver, or bone marrow disorders. It can also effect fertility and should not be used during pregnancy.

Colchicine is unsuitable for many other patients as well, however, because of gastrointestinal side effects, which occur at the high doses necessary to relieve symptoms. They include nausea, vomiting, diarrhea, or abdominal cramps. Low doses do not pose as high a risk for gastrointestinal symptoms, and can prevent further attacks, including in patients who are starting anti-hyperuricemic therapies. Taking low doses has virtually no GI side effects. Note: The antibiotic erythromycin or H2 blockers, such as famotidine (Pepcid AC), cimetidine (Tagamet), ranitidine (Zantac), may intensify the gastrointestinal side effects of colchicine. A 2004 study showed that long-term colchicine therapy may also weaken the respiratory muscles, especially among patients with renal failure.

Intravenous. Intravenous administration of colchicine relieves episodes of gout without gastrointestinal effects and for a time, physicians hoped it could be used routinely. The intravenous route has some serious side effects, however, and poses an increased risk for injury to the kidney, liver, central nervous system, and bone marrow.

Warning Note: Overdose of colchicine can be fatal, and there have even been reports of fatalities. The agent may also suppress blood cell production and cause nerve and muscular injury in certain people, sometimes even in those not taking high doses.

Corticosteroids

Corticosteroids, known commonly as steroids, are used when patients cannot tolerate other anti-inflammatory drugs or they prove ineffective for an attack of gout. They are becoming popular in elderly people.

Corticosteroids can be administered in different ways:

• If only one joint is affected, an injection of the steroid triamcinolone directly into the affected joint can often bring rapid pain relief.
• A single muscular injection of ACTH or triamcinolone may be the most rapid and reliable method for terminating an attack. Oral doses of prednisone are usually given for seven to 10 days after the injection in tapered doses. This is to prevent a rebound attack, which can occur after the injection.

These drugs should only be administered for short periods and not used for long-term treatment. Corticotropin (ACTH), a drug that converts to a steroid, is effective and safe, according to some evidence, but is not widely available.

Uricosuric Drugs

The uricosurics prevent the kidney from reabsorbing uric acid and so increase the amount excreted in the urine. They are usually the choice for preventing gout in the following patients:

• Those under 60 years old.
• Those with normal diets.
• Those who have normal kidney function.
• Those who have no risk of kidney stones.

Uricosuric drug candidates should produce no more than 700 to 800 mg of uric acid in urine over a 24-hour period.

Specific Uricosurics. Probenecid (Benemid, Parbenem, Probalan) and sulfinpyrazone (Anturane) are the standard uricosurics. An investigative uricosuric, benzbromarone, may prove to be beneficial, even in patients with some renal insufficiency. In 2002 studies, benzbromarone was equal to or even more effective than allopurinol, the other standard maintenance drug. A uricosuric combined with allopurinol may be beneficial in cases where using just one drug is not.

Probenecid is taken two to three times a day and sulfinpyrazone begins at twice a day and increases to three or four times daily. The initial doses should be low and then gradually built up. Probenecid combined with colchicine is more effective than probenecid alone, but patients respond differently to this regimen depending on the dosage balance, so it needs to be carefully individualized.

Side Effects. The possible side effects of these two drugs include skin rashes, gastrointestinal problems, anemia, and kidney stone formation. To help reduce acidity and the risk for kidney stones, patients should drink plenty of fluids (ideally water, not caffeinated beverages). Sodium bicarbonate supplemented by acetazolamide can also reduce acidity and the risk for stones.

Interactions. Adding low-dose colchicine or an NSAID may help prevent gout attacks, but NSAIDs, particularly aspirin, as well as other salicylate drugs, interfere with uricosuric drugs and reduce effectiveness, so they should be avoided if possible. Patients who require minor pain relief should instead take acetaminophen (Tylenol and others). Uricosurics interact with many other drugs, and a patient should be sure to inform the physician of any medications they are taking.

Allopurinol

Allopurinol (Lopurin, Zyloprim) blocks uric acid production and is the drug most often used in long-term treatment for older patients and overproducers of uric acid (levels of excreted uric acid of more than 800 mg during a 14-hour period). It is also considered the drug of choice for patients with impaired kidney function, a history of kidney stones, and for tophaceous gout. Its use in patients with tophaceous gout can help reduce the need for later surgery.

Administration. Allopurinol is taken orally once a day in doses of 100 mg to 600 mg, depending on the patient's response to treatment. When it is first used, allopurinol can trigger further attacks of gout, and thus during the first months (or longer) of therapy the patient is also given a NSAID or colchicine to forestall that possibility.

Side Effects. Between 3% to 5% of patients experience severe side effects, diarrhea, headache, and fever. Among the more serious are blood cell abnormalities, including leukopenia (a reduction in the number of white blood cells) and thrombocytopenia (a reduction in the number of platelets). The drug may also increase the risk for cataracts. About 2% of patients experience an allergic reaction to allopurinol that causes a rash. In rare cases, the rash can become severe and widespread enough to be life threatening. Allergic individuals who had experienced only a mild rash may be able to build up their tolerance for the drug by undergoing a desensitization process.

Interactions. Allopurinol interacts with certain other drugs, such as azathioprine.

Other Agents

Hypertensive Agents. People with gout have a higher risk for high blood pressure. And some of the agents used for hypertension can increase the risk for gout attacks. Newer agents, such as losartan (known as an angiotensin II receptor antagonist), may have beneficial effects on both high blood pressure and gout.

Urate Oxidase. Recombinant urate oxidase (raburicase) is an agent being investigated to prevent hyperuricemia and gout in patients undergoing chemotherapy. It is proving to dramatically reduce uric acid levels and to be safe even in children.

Alternative Agents

Some people use so-called natural remedies for gout. Patients should be very cautious when using such agents and do so only after checking with their physicians.