Black Box Warning: Nonsteroidal Antiinflammatory Drugs
NSAIDs may increase the risk for myocardial infarction, stroke, and other thromboembolic events.
NSAIDs increase the risk for dangerous gastrointestinal adverse effects such as bleeding, ulceration, and perforation.
For acute gouty arthritis, NSAIDs are considered agents of first choice. Compared with colchicine, NSAIDs are better tolerated and their effects are more predictable. Benefits derive from suppressing inflammation. Treatment should start as soon as possible after symptom onset. Most patients experience marked relief within 24 hours; swelling subsides over the next few days. Adverse effects of NSAIDs include gastrointestinal (GI) ulceration, impaired renal function, fluid retention, and increased risk for cardiovascular events. However, because the duration of treatment is brief, the risk for these complications is low. Which NSAID should be used? There is no good evidence that any NSAID is superior to the others for treatment of gout. Commonly used NSAIDs include indomethacin [Indocin] and naproxen [Naprosyn, Anaprox 
, others]. (See Table 58.1.)
TABLE 58.1
Preparations, Dosages, and Administration of Antigout Drugs
| Name | Preparation | Dosage | Administration |
| NONSTEROIDAL ANTIINFLAMMATORY DRUGS | |||
| Indomethacin [Indocin, Tivorbex] | Indocin: 50-mg rectal suppository, 25 mg/5 mL oral suspension Tivorbex: 20-mg, 40-mg capsule Generic: 25-mg, 50-mg capsule Generic ER: 75-mg capsule | 50 mg 3 times daily initially until pain is tolerable, then reduce dosage and continue dosing for 3–5 days | To decrease GI effects, administer with or after meals or with a snack. ER forms should be swallowed whole. |
Naproxen [Anaprox  , Naprosyn, Naprelan, many others] | Anaprox: 275 mg Anaprox DS: 550 mg Naprosyn: 500-mg scored tablets EC-Naprosyn: 375-mg, 500-mg enteric-coated tablets Generic: 250-, 375-, 500-mg tablets Naprelan (ER): 375-, 500-, 750-mg controlled-release tablets | Naprosyn: 750 mg initially, then 250 mg every 8 hours until attack subsides Naprosyn ER: 1 tablet initially, then one tablet daily until attack subsides Anaprox: 825 mg initially, then 275 mg every 8 hours until attack subsides | To decrease GI effects, administer with or after meals or with a snack. ER and EC forms should be swallowed whole. |
| ANTIGOUT ANTIINFLAMMATORY DRUG | |||
| Colchicine [Colcrys, Mitigare] | Colcrys: 0.6-mg scored tablet Mitigare: 0.6-mg capsule | Acute attack (Colcrys only): 1.2 mg at first sign of the flare, followed by 0.6 mg 1 hour later (maximum, 1.8 mg/24 hours) Prophylaxis (Colcrys, Mitigare): 0.6 mg once or twice daily (maximum, 1.2 mg/24 hours) | Administer with or without food. Do not take with grapefruit juice. |
| GLUCOCORTICOIDS | |||
| Prednisone (oral) [Deltasone] | Deltasone: 20-mg (scored) tablets | 30–50 mg once daily or in two divided doses until pain is tolerable; then gradually taper off the drug over 7–10 days | Administer at mealtime or with food to decrease GI upset. |
| Triamcinolone acetate (IM) [Aristospan, Kenalog] | Aristospan: 20 mg/mL in 1-mL and 5-mL vials Kenalog: 10 mg/mL in 5-mL vial; 40 mg/mL in 1-mL, 5-mL, and 10-mL vials | 40–60 mg; may repeat after 1–4 days if flare continues | Shake well to ensure homogeneous suspension of medication, then withdraw into syringe immediately. |
| XANTHINE OXIDASE INHIBITORS | |||
| Allopurinol [Zyloprim] | 100- and 300-mg tablets | Dosages should be individualized to decrease plasma urate to 6 mg/dL.* Chronic tophaceous gout: 100 mg once a day, then increase by 50- to 100-mg increments every few weeks until urate target level is reached. Standard maintenance dose: 300 mg a day up to a maximum of 800 mg/day Secondary hyperuricemia in adults: 100–800 mg/day | May be taken with or without food. |
| Febuxostat [Uloric] | 40-mg and 80-mg tablets | 40 mg/day initially, increase to 80 mg/day, if needed | May be taken with or without food |
| URICOSURIC AGENTS | |||
| Probenecid [generic only] | 500-mg tablets | 250 mg twice daily for 1 week. The maintenance dosage is 500 mg twice daily. | Administration with food decreases GI upset. |
| RECOMBINANT URIC ACID OXIDASE | |||
| Pegloticase [Krystexxa] | 8 mg/mL | 8 mg IV every 2 weeks | Dilute 1 mL in 250 mL NS or  NS IV solution and administer over 2 hours. Monitor for infusion reaction. |
| COMBINATION DRUGS | |||
| Colchicine and probenecid [generic] | Colchicine 0.5 mg + probenecid 500 mg | One tablet daily for 1 week, then 1 tablet twice daily | Do not begin therapy in the presence of an acute gout flare |
Glucocorticoids
Glucocorticoids (e.g., prednisone), given orally or intramuscularly, are highly effective for relieving an acute gouty attack—although NSAIDs are generally preferred. Candidates for glucocorticoid therapy include patients who are hypersensitive to NSAIDs, patients who have medical conditions that contraindicate use of NSAIDs, and patients with severe gout that is unresponsive to NSAIDs. Because of their effects on carbohydrate metabolism, glucocorticoids should be avoided, when possible, in patients prone to hyperglycemia. For oral therapy, prednisone can be used. For intramuscular (IM) therapy, triamcinolone acetonide can be used. Glucocorticoids are discussed in Chapter 56.
Colchicine
Colchicine [Colcrys, Mitigare] is an antiinflammatory agent with effects specific for gout. In the past, colchicine was considered a first-line drug for gout. However, owing to the common occurrence of GI toxicity and the availability of safe and effective alternatives, its use has declined.
Therapeutic Use
Colchicine has two applications in gout. First, it can be used short term to treat an acute gouty attack. Second, it can be used long term to prevent attacks from recurring. Colcrys is approved for both uses. Mitigare is approved only for prophylaxis.
Acute Gouty Arthritis
High-dose colchicine can produce dramatic relief of an acute gouty attack. Within hours, patients whose pain had made movement impossible are able to walk. Inflammation disappears completely within 2 to 3 days.
Prophylaxis of Gouty Attacks
When taken during asymptomatic periods, low-dose colchicine can decrease the frequency and intensity of acute flare-ups. Colchicine may also be given for prophylaxis when urate-lowering therapy is initiated because there is a tendency for gouty episodes to increase at this time.
Mechanism of Action
We do not fully understand how colchicine relieves or prevents episodes of gout. We do know that colchicine does not decrease urate production or removal. It may work, at least in part, by inhibiting leukocyte infiltration: in the absence of leukocytes, there is no phagocytosis of uric acid and no subsequent release of lysosomal enzymes. How does colchicine inhibit leukocyte migration? It disrupts microtubules, the structures required for cellular motility. Because microtubules are also required for cell division, colchicine is toxic to any tissue that has a large percentage of proliferating cells. Disruption of cell division in the GI tract and bone marrow underlies major toxicities of the drug.
Pharmacokinetics
Colchicine is readily absorbed after oral dosing, in both the presence and absence of food. Large amounts reenter the intestine through the bile and intestinal secretions and then undergo reabsorption. Final elimination occurs primarily through two processes: metabolism by hepatic CYP3A4 (the 3A4 isoenzyme of cytochrome P450) and renal excretion of intact drug.
Adverse Effects
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
Drugs for Gout
| Life Stage | Considerations or Concerns |
| Children | U.S. labeling for indomethacin recommends using the lowest dose that is effective at the shortest possible duration. Canadian labeling contraindicates its use for patients younger than14 years. When given for gout prophylaxis (as opposed to familiar Mediterranean fever), colchicine is not recommended for patients younger than 16 years. Febuxostat is not recommended for children. Allopurinol may be given to children younger than 6 years for the purpose of treating hyperuricemia associated with cancer therapy. Probenecid has been given to children as young as 2 years for purposes unrelated to gout. |
| Pregnant women | Although most NSAIDs are FDA Pregnancy Risk Category C, some studies have demonstrated fetal cardiovascular abnormalities and cleft palate after NSAID exposure. Exposure to indomethacin after 30 weeks’ gestation has resulted in a number of abnormalities, resulting in a Pregnancy Risk Category of D if taken later in pregnancy. Colchicine is Pregnancy Risk Category C. Of the xanthine oxidase inhibitors, both febuxostat and allopurinol are Pregnancy Risk Category C; however, animal studies with febuxostat have demonstrated an increase in fetal mortality. Probenecid has not been associated with increased fetal risk. |
| Breastfeeding women | U.S. labeling recommends against breastfeeding by mothers taking indomethacin and naproxen. Canadian labeling contraindicates breastfeeding by mothers taking these drugs. Breastfeeding is not recommended for other drugs taken for gout. For patients taking xanthine oxidase inhibitors, Canadian labeling contraindicates breastfeeding. |
| Older adults | The Beers Criteria list both indomethacin and naproxen among those drugs considered potentially inappropriate for patients 56 years and older and notes that, of all NSAIDs, indomethacin carries the greatest risk. Colchicine can be dangerous if the older patient has renal impairment. |
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