Key Points
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Nonsteroidal antiinflammatory drugs (NSAIDs) (or cyclooxygenase-2–selective coxibs), systemic oral corticosteroids (prednisone or prednisolone), and colchicine are the primary therapy options for an acute gout attack. However, there remains no single standard of therapy for an acute gout attack.
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Selection of treatment should be individualized by taking into consideration comorbidities, potential drug-drug interactions, and duration and severity of the gout attack.
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Indomethacin, starting at 50 mg orally three times daily, is effective in acute gout but gastrointestinal and central nervous system side effects are limitations. Many NSAIDs are effective alternatives, but high doses of aspirin (acetylsalicylic acid) or nonacetylated salicylates are not recommended for acute gout.
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When prednisone or prednisolone is used to treat acute gouty arthritis, the starting dose should be at least 0.5 mg of prednisone or prednisolone/kg per day.
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The use of prednisone for acute gout attack is associated with the potential for rebound attacks of acute gout, and colchicine gout attack prophylaxis can be added as an adjunctive therapy.
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Oral colchicine appears most effective when given promptly in the first 12 to 36 hours of an acute gout attack.
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The dosing regimen of colchicine for treating an acute early attack of gout (defined as within 12 hours of onset) should be limited on day 1 to 1.2 mg orally followed by 0.6 mg 1 hour later. Twelve to 24 hours later, low-dose colchicine gout attack prophylaxis can be commenced. Higher colchicine doses do not add efficacy and increase toxicity.
Introduction
Acute gout is characteristically an intensely painful inflammatory arthritis. A quote from the English poet John Milton published in Samuel Johnson’s Lives of the Poets series (1779–1781) illustrates this: “Was he free from the pain the gout gave him, his blindness would be tolerable.” The goal of therapy in acute gout is prompt and safe termination of the acute attack. To terminate the acute gout attack, pharmacotherapy needs to be rapidly initiated and an appropriate dose be given for a sufficiently long duration. This chapter summarizes the main treatment options for acute gout, how commonly each is used in practice, and the clinical trials supporting use of each option. Importantly, substantially more detail on strategically choosing between these options is provided in Chapter 16 .
Without pharmacotherapy, the extreme pain of acute gout may resolve within a few days, but in many it may last longer, even up to several weeks. Using no medication for acute gout appears inappropriate and inhumane. Bellamy et al. evaluated the natural course of acute gout. This study serves as a benchmark for comparing the efficacy of treatments for acute gout. In this 7-day study, 2 of 11 patients withdrew because of severe persistent pain after 4 days. All of the remaining patients showed some improvement in pain by day 5 and in swelling by day 7. Tenderness improved in 7 of the 9 remaining patients; however, full resolution of pain was observed in only 3 patients. It is therefore necessary to give the patient with acute gout prompt treatment with antiinflammatory therapy.
The primary options available for the treatment of acute gout are nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, systemic corticosteroids (CSs), intraarticular CSs, and adrenocorticotropic hormone (ACTH). It is important to note that in a growing number of patients, one or more of the available treatments for acute gout are contraindicated (relative or absolute contraindication), largely due to the presence of comorbidities. Indeed, hypertension, cardiovascular disease including congestive heart failure, diabetes and renal impairment, peptic ulcer disease, the metabolic syndrome, and liver disease are all highly prevalent in individuals with gout and may lead to standard treatments being inappropriate. It is important to consider these comorbidities when treating acute gout. In this chapter, the new and the old treatments for acute gout, as well as drugs in development, are discussed.
Nonpharmacologic Treatment
Joint motion may increase inflammation in experimentally induced gout, whereas rest of affected joint(s) may aid in its resolution. Less medication is needed if the patient can rest the afflicted joint for 1 to 2 days.
Topical ice applications should be used as an adjunct to pharmacologic treatment of acute gout. In a prospective randomized trial, patients with acute gout in whom topical ice treatments were added to pharmacologic antiinflammatory treatment had a greater reduction in pain ( p = .021), joint circumference, and synovial fluid volume compared with the control group. In a study in dogs, heat application to inflamed joints exacerbated urate-induced synovitis.
Pharmacologic Treatment
There are few guidelines for the treatment of acute gout and only a few randomized controlled trials have evaluated the efficacy of the various treatments for acute gout. A task force of the European League Against Rheumatism (EULAR) Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT) published recommendations for gout management. These recommendations are based on 19 rheumatologists and one evidence-based medicine experts’ Delphi consensus approach for different propositions. Research evidence was searched systematically for each proposition. The following recommendations for acute gout management were published : oral colchicine and/or NSAIDs are first-line agents for the systemic treatment of acute gout. In the absence of contraindications, an NSAID is a convenient and well-accepted option; high doses of colchicine lead to side effects and low doses may be sufficient for some patients with acute gout; and intraarticular aspiration and injection of long-acting steroid provide an effective and safe treatment for an acute attack. The American College of Rheumatology (ACR) is developing practice guidelines for the treatment of gout so as to reduce inappropriate care, minimize geographic variations in practice patterns, and enable the effective use of health care resources.
Suboptimal prescribing practices may have an impact on the effectiveness of gout management. Neogi et al. reported an online prospective case-crossover study of 211 patients meeting ACR preliminary criteria for gout. They reported inappropriate therapy (not using antiinflammatory therapy) for acute gout in 26% of patients for some or all of their acute gout attacks. Prevalence of types of therapies among study participants with gout who had inappropriate treatment included (1) analgesia alone (22% of patients), (2) starting urate-lowering therapy (allopurinol 12%; probenecid 3%) acutely without having used it chronically, and (3) no medication given for the acute attack (60% of patients). In another study, 41% of 630 primary care physicians reported that they started allopurinol during the acute attack. In a recent Australian study, 9% of hospitalized patients with acute gout received no pharmacotherapy. This is surprising and concerning because pharmacotherapy should have been readily available for these hospitalized patients.
Combination Therapy to Treat Acute Gout
Most American rheumatologists use combination therapy to treat acute gout. In an American survey study evaluating the treatment of gout, most American rheumatologists (64%) were found to use combination therapy for acute gout, whereas American internists tended to use monotherapy ( p = .0005). The first three most frequently used combination therapies for acute gout in an otherwise healthy patient were NSAIDs with intraarticular CS (43%), NSAIDs with oral CSs (33%), and NSAIDs with oral colchicine (32%). NSAIDs alone were used in 27%. This was confirmed by a study evaluating the treatment of hospitalized patients with acute gout that found combination therapy was used in more than 50% of these patients. In a recent Australian study, combination therapy was used in 43% of patients with acute gout. The most frequently used combination therapies for acute gout included colchicine with oral CSs (35%), oral colchicine with an NSAID (39%), oral colchicine, NSAID, and oral CSs (16%), and NSAIDs with oral CSs (10%).
Colchicine and its metabolites are excreted through the urinary and biliary tracts, and the presence of renal or liver disease impairs clearance of colchicines, as reviewed in detail in Chapter 15 . It is well known that NSAIDs also should be used with caution in patients with renal disease to avoid renal toxicity. Gutman suggested in 1965 that there is some advantage to combining NSAID treatment with colchicine 2.0 mg daily in divided doses for the first 2 days of the attack and then tapering off. However, there still is little literature to support the use of such combination therapy in acute gout. Most studies in acute gout have evaluated monotherapy despite the regular use of combination therapy in clinical practice. This common practice merits study.
Monotherapy
Colchicine and NSAIDs are the most commonly used drugs in the treatment of acute gout. In the American survey study, NSAIDs were reported to be the most commonly used monotherapy (77%). Interestingly, in this study, intraarticular CS injections (47%) and oral prednisone (42%) were more commonly reported to be used to treat acute gout than was oral colchicine (37%). Triamcinolone intramuscularly (11%) and ACTH intramuscularly (5%) were also reported to be used uncommonly. In the United States, oral CSs were reported to be the most commonly used monotherapy by rheumatologists in patients with chronic kidney disease, which is a common comorbidity seen in patients with gout.
In an American study, monotherapy was used in 58% of hospitalized patients with acute gout. In the patients who were prescribed monotherapy, colchicine use (76%) exceeded NSAID (14%) and oral CS (10%) use. A recent Australian study found similar findings. Colchicine was the most common monotherapy (75%), followed by NSAIDs (32%) and oral CSs (28%). Oral CSs were used to treat acute gout in approximately 10% of patients. Interestingly, a recent Malaysian study of primary care physicians found oral CSs were used to treat acute gout in approximately 10% of patients, as was suggested by the two other studies.
NSAIDs were the most commonly used drugs in acute gout in other survey studies, too. Among Canadian physicians, only 11% of family physicians and 6% of rheumatologists would use colchicine in the acute situation. A similar preference for NSAIDs has been noted in Australia, New Zealand, and Malaysia. In contrast, in a French survey study evaluating the treatment of gout, colchicine was found to be the most commonly used drug as monotherapy. The most widely prescribed treatments for acute gout were colchicine alone (63%), colchicine with an NSAID (31.7%), and an NSAID alone (5.2%).
As shown in Table 10-1 , in survey studies, many clinicians claim to use NSAIDs, colchicines, or CSs alone or in combination therapy. Table 10-2 lists the mainstay therapeutic options for acute gout.
| Study Reference | Country | No. of Physicians | Colchicine as Primary Agent | Colchicine Plus NSAIDs | NSAIDs Alone | Corticosteroids |
|---|---|---|---|---|---|---|
| Canada | 71 | 6% | ? | ? | ||
| New Zealand | 26 | 12% | 25% | Indomethacin used in 73% | ||
| Brazil | 57% | |||||
| France | 750 | 63% | 32% | 5% | 0 | |
| USA | 100 | 69% | 33% | 27% | ||
| USA | 518 | 37% | 32% | 27% | 42% (71% if CKD) | |
| China | 82 | 77% | 17% | 1% (48% if CKD) | ||
| Malaysia | 128 Primary care physicians | 10.2% | 68% | 10% |
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Colchicine
Colchicine is an alkaloid derived from the autumn crocus (also known as meadow saffron; Crocus autoimmale ). Colchicum in the form of extracts from the bulb of C. autoimmale has been known since antiquity, although it came into widespread use only around 1800. As reviewed in Chapter 15 , colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and, consequently, at low (nanomolar) concentrations, interferes with many neutrophil functions, including adhesion to endothelium and chemotaxis. At higher concentrations, colchicine globally suppresses neutrophil functions.
Absorption of oral colchicine is rapid but incomplete (time to maximum is 2 hours; bioavailability is 25% to 50%). Colchicine is excreted in the urine and via the biliary tract after it is metabolized in the liver. However, absorption can be highly variable. The half-life of colchicine after an oral dose in patients with normal renal and hepatic functions is approximately 9 hours, whereas in patients with renal failure, it is 2 to 3 times normal (about 24 hours), and in cirrhotic patients with renal failure, it is 10 times normal (approximately 4 days). Hemodialysis does not remove colchicine.
Until recently, only one placebo-controlled trial of colchicine treatment in acute gout was reported. All other data reported were accumulated through review rather than through prospective studies. In this placebo-controlled study, Ahern et al. studied 43 patients (40 men, 3 women); 22 patients received colchicine 1 mg then 0.5 mg every 2 hours until complete response or toxicity and 21 patients were in the placebo group. No NSAIDs were used during the study. All participants had monosodium urate (MSU) crystal–proved gout. In this placebo-controlled study, two thirds of the colchicine-treated patients improved after 48 hours but only one third of the patients receiving placebo demonstrated similar improvement. Oral colchicine was shown to be efficacious in two thirds of patients presenting with acute gout. It was more effective when used within 24 hours of an acute attack. Importantly, more than 80% of patients experienced nausea, vomiting, diarrhea, and abdominal pain after oral administration before full clinical improvement.
Despite the widespread use of oral colchicine, it did not have U.S. Food and Drug Administration (FDA) approval until recently. It did not have FDA-approved prescribing information, dosage recommendations, or drug interaction warnings until August 2009. In the AGREE trial, a randomized, double-blind placebo-controlled study in which 184 patients with acute gout were treated for an acute attack within 12 hours of the onset of the attack, low-dose colchicine (1.2 mg then 0.6 mg 1 hour later for a total of 1.8 mg) was found to be equally effective and better tolerated than high-dose colchicine (1.2 mg then 0.6 mg hourly × 6 hours for a total of 4.8 mg). There was a significantly higher incidence of gastrointestinal adverse events (diarrhea, nausea/vomiting) with high-dose colchicine than with either low-dose colchicine or placebo. If needed on day 2 of early gout attack treatment, the patient can be started on gout attack prophylactic doses of colchicine (e.g., 0.6 mg PO twice daily if renal function and hepatobiliary function are preserved and there are no significant drug-drug interactions).
Previous recommendations for treatment of acute gout that involved repeated dosing of colchicine over multiple hours for acute gout until toxicity or pain relief developed are no longer tenable. To lessen colchicine side effects, Morris et al. suggested that in a patient with acute gout, colchicine should be used at lower doses: 500 mcg three times a day or less frequently, especially in those with renal impairment. However, the recommended dosage of colchicine depends on the patient’s age, renal function, hepatic function, and use of coadministered drugs. For treatment of acute gout attacks in patients with mild (glomerular filtration rate [GFR] of 50 to 80 ml/min) to moderate (GFR of 30 to 50 ml/min) kidney disease, adjustment of this recommended dose is not required. For patients with acute gout requiring repeated courses of colchicine, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of acute gout should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more often than once every 2 weeks. Treatment of gout attacks with colchicine is not recommended in patients with renal impairment who are receiving colchicine prophylaxis.
There has been little information on colchicine drug-drug interactions until recently (as reviewed in detail in Chapter 15 ). Colchicine was found to be a substrate for both the CYP3A4 enzyme and P-glycoprotein (P-gp) transporter. Therefore, coadministration with drugs known to inhibit CYP3A4 and/or P-gp increases the risk of colchicine-induced toxic effects. These drugs include cyclosporine, erythromycin, and calcium channel antagonists such as verapamil and diltiazem. Other examples of P-gp and strong CYP3A4 inhibitors include telithromycin, ketoconazole, itraconazole, HIV protease inhibitors, and nefazodone. The FDA required patients treated with P-gp or strong CYP3A4 inhibitor drugs within 14 days of colchicine use for acute gout to have a dose reduction in or interruption of colchicine treatment.
Colchicine appears most effective for acute gout when started in the first 1 to 2 days of the onset of the gout attack. It is important to note that a clinical response to colchicine is not pathognomonic for acute gout. A clinical response can be seen in patients with pseudogout, sarcoid arthropathy, psoriatic arthritis, and calcific tendonitis.
Oral Nonsteroidal Antiinflammatory Drugs
Currently, approximately 50 different NSAID preparations are available and, as a class, they are among the most commonly prescribed drugs worldwide. NSAIDs are structurally diverse and differ in pharmacokinetic and pharmacodynamic properties but share the same mode of action. NSAIDs exert their antiinflammatory action by inhibiting cyclooxygenase ( COX), an enzyme that transforms phospholipid-derived arachidonic acid into prostaglandins. NSAIDs may be nonselective, inhibiting both COX-1 and COX-2 (e.g., ibuprofen and naproxen), or may be more COX-1 (e.g., aspirin) or COX-2 (e.g., celecoxib) selective.
There are no randomized controlled trials comparing colchicine to NSAIDs. Even so, NSAIDs are the drugs of choice in patients with gout without underlying comorbidities. The most important determinant of therapeutic success is not which NSAID is chosen but rather how soon NSAID therapy is initiated—that proper dosages be given at the onset of symptoms or at the time of diagnosis and continued for a sufficiently long period (e.g., at least several days after complete resolution of the acute attack).
Unfortunately, the use of NSAIDs is limited by side effects. The gastrointestinal adverse effects of traditional NSAIDs are well known. Clinically important NSAID-related gastrointestinal side effects may lead to bleeding, hospitalization, and death. The gastrointestinal side effects of NSAIDs may be lessened by coadministration of a proton pump inhibitor. In addition, the use of NSAIDs confers increased cardiovascular risk in patients with known heart disease or those thought to be at high risk of heart disease. This is commonly the case in our patients with gout. All patients taking NSAIDs should be carefully monitored for the development of high blood pressure, worsening heart disease, worsening renal function, fluid retention, gastrointestinal bleeding, and elevations in liver enzymes.
A number of head-to-head controlled studies, including randomized controlled trials, in acute gout show equivalence between the different NSAIDs. Most were small trials ( Table 10-3 ). Most of these studies compared indomethacin with another NSAID. Indomethacin 50 mg orally three times daily has been held to be a gold standard for acute gout treatment, but the gastrointestinal and central nervous system side effects of indomethacin are often limiting. Naproxen 500 mg orally twice daily is one of the effective alternatives, and sulindac 150 or 200 mg orally twice daily also is FDA approved for the treatment of gout. High-dose salicylates are not advised for acute gout treatment, since the time to buildup of analgesic efficacy can be slow with acetylsalicylic acid and all high-dose salicylates lower serum urate via uricosuric effects, which has the potential to worsen the acute gout attack.
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