AUTHOR INFORMATION

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Authored by Joseph Kaplan, MD, FACEP, Clinical Assistant Professor of Emergency Medicine, Department of Emergency Medicine, Medical College of Georgia

Joseph Kaplan, MD, FACEP, is a member of the following medical societies: American College of Emergency Physicians

Edited by Edward A Michelson, MD, Program Director, Associate Professor, Department of Emergency Medicine, University Hospital Health Systems in Cleveland; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Gino A Farina, MD, Program Director, Associate Professor of Clinical Emergency Medicine, Department of Emergency Medicine, Long Island Jewish Medical Center, Albert Einstein College of Medicine; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Steven C Dronen, MD, FAAEM, Director of Emergency Services, Director of Chest Pain Center, Department of Emergency Medicine, Ft Sanders Sevier Medical Center

Author's Email:	Joseph Kaplan, MD, FACEP
Editor's Email:	Edward A Michelson, MD

eMedicine Journal, March 14 2007, VOLUME 8, Number 3

INTRODUCTION

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Background: Gout and pseudogout are the 2 most common crystal-induced arthropathies. They are debilitating illnesses in which pain and joint inflammation are caused by the formation of crystals within the joint space.

Gout is inflammation caused by monosodium urate monohydrate (MSU) crystals.

Pseudogout is inflammation caused by calcium pyrophosphate (CPP) crystals and is sometimes referred to as calcium pyrophosphate disease (CPPD).

Gout is the most common crystal-induced arthritis. Lowenhook first described symptoms in the 1600s. In 1848, Sir Alfred Garrod linked gout with hyperuricemia, but the pathophysiology of acute gouty arthritis was not described fully until 1962. Since then, gout has been associated with a large number of different autoimmune and metabolic disorders. Specific therapies and prophylactic measures have been developed to address the underlying problem.

Pseudogout, which may be clinically indistinguishable from gout, was recognized as a distinct disease entity in 1962. As with gout, pseudogout has been associated with a variety of metabolic disorders as well as with aging and trauma. Treatment of the acute phase of pseudogout is identical to that of gout. Unlike gout, however, no specific therapeutic regimen exists to treat the underlying cause of pseudogout, and no known prophylactic therapy exists.

Pathophysiology: Pain and joint edema of acute arthritis in patients with gout and pseudogout are caused by an inflammatory response triggered by the lysis of polymorphonuclear white blood cells that have ingested MSU crystals or CPP crystals. MSU crystals are formed in synovial fluid when the fluid becomes supersaturated with MSU. This supersaturation can result from overproduction or reduced excretion of MSU. Many conditions and drugs have been associated with an increase in plasma (and subsequent synovial) urate levels. A genetic predisposition for the disease exists. CPP crystals are produced by nucleoside triphosphate pyrophosphohydrolase (NTPPPH), a catalytic enzyme found in vesicles that develop within osteoarthritic cartilage. A genetic predisposition exists for the condition, but any process that leads to osteoarthritis also can be associated with subsequent pseudogout.

Frequency:

• In the US: Gout affects 2.7 of every 1000 adults. Prevalence is approximately 20% in patients with a family history of gout.

  Frequency of pseudogout varies with age. The annual incidence of acute attacks of arthritic pain and swelling is about 1.3 per 1000 adults, but nearly half of adults develop radiographic changes typical of CPPD by age 80 years.

  Gout has been noted to occur more frequently in the spring and less frequently in the winter, although the reason for this is unknown.

• Internationally: Prevalence of gout varies widely from country to country. In England, gout affects 16.4 of every 1000 men and 2.9 of every 1000 women.

Mortality/Morbidity:

• Pain and edema of inflammatory crystalline arthritis is extremely debilitating.

• Chronic injury to intra-articular cartilage leaves the joints more susceptible to subsequent joint infections.

Race:

• Limited data suggest an increased prevalence of gout in American blacks compared with whites; however, clinically recognized gout is extremely rare in blacks living in Africa.

• Diet may be linked to racial prevalence since diet has a large influence on the clinical expression of gout.

Sex:

• For gout, the male-to-female ratio is 9:1.

• For pseudogout, the male-to-female ratio is 1.5:1.

Age:

• The predominant age range is 30-60 years.

CLINICAL

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History:

• The history and physical examination alone cannot reliably determine the cause of new-onset acute monoarticular arthritis.

• Septic arthritis, gout, and pseudogout can present in very similar ways.

• The spontaneous onset of pain, edema, and inflammation in the metatarsal-phalangeal joint of the great toe (podagra) is highly suggestive of acute crystal-induced arthritis. This is the most common presentation of gout.

• Other than the great toe, the most common sites of gouty arthritis are the ankle, wrist, and knee. Consider the diagnosis in any patient with acute monarticular arthritis of any peripheral joint except the glenohumeral joint of the shoulder, in which a crystal-induced arthritis is more likely to be due to pseudogout.

• The most common sites of pseudogout arthritis are the knee, wrist, and shoulder. Case reports have documented carpal tunnel syndrome as an initial presentation of pseudogout. Case reports of pseudogout forming masses in the spinal ligamentum flavum have been documented. These have lead to both single and multi-level myelopathy.

• Crystal-induced arthritis is most commonly monarticular; however, polyarticular acute flares are not rare, and many different joints may be involved simultaneously or in rapid succession. Multiple joints in the same limb often are involved, as when inflammation begins in the great toe and then progresses to involve the midfoot and ankle.

• Although gout and pseudogout cannot reliably be distinguished on clinical grounds, a tendency exists for gout symptoms to develop rapidly over a few hours, whereas the onset of symptoms in pseudogout is usually more insidious and may occur over several days.

• When a patient presents with an identical recurrent attack of crystal-induced arthritis, the diagnosis is rarely in question, but the possibility of septic arthritis must always be considered.

• Fever, chills, and malaise do not distinguish cellulitis or septic arthritis from crystal-induced arthritis because all 3 illnesses can produce these signs and symptoms.

• A careful history may uncover risk factors for cellulitis or septic arthritis, such as possible exposure to gonorrhea, a recent puncture wound over the joint, or systemic signs of disseminated infection.

• Gout is also associated with hyperlipidemia, hypertension, hypertriglyceridemia, kidney failure, obesity, and insulin resistance. Social factors such as alcohol intake also increase the risk of gout.

• It has been suggested that a link exists between several autosomal dominant disorders and the development of gout. However, there has not been a specific genetic marker for those predisposed to developing gout.

• Pseudogout attacks have been reportedly induced by etidronate disodium therapy and post vascular angiography.

Physical:

• Patients with gout or pseudogout most often present with a single joint that is hot, erythematous, tender, and affected with asymmetric edema. If inflammation is severe, desquamation of overlying skin may be present.

• Extra-articular deposits of MSU, known as tophi, may be seen along the Achilles tendon or on the ear helix, olecranon bursa, or prepatellar bursa.

• Migratory polyarthritis is a rare presentation.

• An inflammatory synovial effusion may be present.

• Although uncommon, acute gout may present with signs of carpal tunnel syndrome.

Causes:

• Although the pathophysiology, clinical presentation, and acute-phase treatment of gout and pseudogout are very similar, the underlying causes of the 2 diseases are very different.

• Acute gouty arthritis results from overproduction or reduced secretion of uric acid. Thiazide diuretics and foods that are rich in purines will increase the frequency of attacks.

• Many cases of pseudogout are idiopathic, but pseudogout has also been associated with aging, trauma, and many different metabolic abnormalities, the most common of which are hyperparathyroidism and hemochromatosis.

• Lead poisoning

• Hemo-proliferative disorders

• Renal disease

DIFFERENTIALS

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Ankle Injury, Soft Tissue
Arthritis, Rheumatoid
Bursitis
Cellulitis
Dislocations, Interphalangeal
Fractures, Foot
Hyperparathyroidism
Knee Injury, Soft Tissue
Osteomyelitis
Paronychia
Reactive Arthritis
Tenosynovitis
Toenails, Ingrown

Other Problems to be Considered:

Acute sarcoidosis (rare)
Amyloidosis
Calcific periarthritis
Infectious or septic arthritis
Multicentric reticulohistiocytosis
Psoriatic arthropathy
Spondyloarthropathy
Trauma
Type IIa hyperproteinemia

WORKUP

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Lab Studies:

• Diagnostic arthrocentesis is indicated for every patient in whom a diagnosis has never been proven by joint aspiration and for those in whom a possibility of septic arthritis exists. A prior history of gout or pseudogout does not rule out the possibility of acute septic arthritis. In fact, the latter is more common in patients with a history of crystal-induced arthritis. Septic arthritis must be diagnosed and treated promptly. Irreversible damage can occur within 4-6 hours, and the joint can be completely destroyed within 24-48 hours.

• Joint fluid analysis

• Send joint fluid for fluid analysis, including cell count and differential, Gram stain, culture and sensitivity, and microscopic analysis for crystals. If crystals are seen, their shape and appearance under polarized light can aid in diagnosis.

• In gout, crystals of MSU appear as needle-shaped intracellular and extracellular crystals. When examined with a polarizing filter, they are yellow when aligned parallel to the axis of the red compensator, but they turn blue when aligned across the direction of polarization (ie, they exhibit negative birefringence).

• In pseudogout, CPP crystals appear shorter and often rhomboidal. Under a polarizing filter, CPP crystals do not change color depending upon their alignment relative to the direction of the red compensator.

• In crystal arthritis, the WBC count in the joint fluid is usually 50,000-100,000.

• Even in the presence of crystals in the joint fluid, blood cultures are indicated if any sign of systemic toxicity is present. Septic arthritis can occur in patients with active crystalline arthropathy.

• Gouty attacks are triggered by crystal formation in synovial fluid. They are not related to serum levels of uric acid. Thus, a normal serum uric acid level does not exclude the diagnosis of acute gout, and an elevated level does not prove the diagnosis.

• Pseudogout attacks can be triggered by many metabolic abnormalities. Thus, patients who have an initial attack of arthritis with CPP crystals should have a workup including a chemistry screen; magnesium, calcium, and iron levels; and thyroid function tests.

• WBC count usually is elevated.

• Erythrocyte sedimentation rate (ESR) usually is elevated during acute attacks.

• Hyperuricemia may be present but is not diagnostic. Renal uric acid excretion should be obtained in high-risk patients, including those with renal calculi, strong family history of gout, and first attack before age 25 years.

Imaging Studies:

• Radiographs

• Plain radiographs of the affected joint or joints are indicated.

• Radiographic lesions of chronic gout may appear as rat-bitten, sclerotic regions on the joint surfaces, with overhanging margins.

• Patients with new onset of acute gout usually have no radiographic findings.

• Patients with pseudogout usually have degenerative joint changes and may have calcifications in the soft tissues, tendons, or bursae.

• Bone scan reveals increased nuclide concentration at affected sites.

• MRI

• MRI is capable of detecting crystal deposits but is not part of any routine evaluation for acute arthritis.

• MRI can be very useful in determining the extent of the disease and may help in the differential diagnosis.

• MRI with gadolinium is recommended to evaluate any tendon sheath involvement and when osteomyelitis in the differential diagnosis.

• Large deposits of crystals may be seen in bursae or ligaments. Tophi usually are low or intermediate signal intensity on T1-weighted images.

Procedures:

• Aspiration and biopsy

• Joint aspiration is the principal procedure used to make the diagnosis of crystal-induced arthritis and to rule out septic joint effusion.

• Biopsy of synovial membrane or subcutaneous nodule includes an examination with polarizing optics.

TREATMENT

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Emergency Department Care:

• The temptation to treat patients without a proven diagnosis must be resisted. Unrecognized septic arthritis can lead to loss of life or of limb. Distinguishing septic arthritis from crystal-induced arthritis is not possible without an examination of joint fluid.

• Arthrocentesis is mandatory for all patients with new onset of acute monoarthritis and is very strongly recommended for those with recurrent attacks whose diagnosis has never been proven by microscopic visualization of crystals.

• Treatment of proven crystal-induced arthritis is directed at relief of the pain and inflammation. Narcotic pain relievers, nonsteroidal anti-inflammatory drugs (NSAIDs), and steroids are the mainstays of treatment.

• When comorbidities limit the use of NSAIDs or oral steroids (eg, a brittle diabetic with peptic ulcer disease), colchicine should be considered. However, a preferred option may be an intra-articular steroid injection, particularly when a large, easily accessible joint is involved.

• Patients should also be counseled to reduce comorbidities. They should be instructed to go on a diet if obese, to stop drinking beer, and to avoid purine-rich foods.

Consultations:

• Orthopedic consultation is indicated for any patient with septic arthritis or for any patient in whom a septic arthritis cannot be ruled out.

• If the diagnosis has not been proven by microscopic examination of crystals under polarized light, refer the patient to a rheumatologist as soon as possible.

• Rheumatologic referral should be made for patients with new-onset crystal-induced arthritis. This is not an emergency and should be completed on an outpatient basis.

MEDICATION

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The goal of pharmacotherapy is to terminate the acute attack, to prevent complications, and to prevent recurrent attacks.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) -- Most commonly used for the relief of mild to moderate pain. Although the effects of NSAIDs in the treatment of pain tend to be patient specific, indomethacin usually is the DOC for the initial therapy. Other options include ibuprofen and naproxen.

Drug Name	Ibuprofen (Ibuprin, Advil, Motrin) -- For treatment of mild to moderate pain if no contraindications are present. Inhibits inflammatory reactions and pain probably by decreasing activity of the enzyme cyclooxygenase, resulting in prostaglandin synthesis.
Adult Dose	400-800 mg PO tid for 5 d; continue treatment up to 2 wk prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding Patients in whom aspirin, iodides, or other NSAIDs induce hypersensitivity because of potential cross-sensitivity to other NSAIDs
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; closely monitor PT (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Drug Name	Naproxen (Anaprox, Naprelan, Naprosyn) -- Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of the enzyme cyclooxygenase, resulting in prostaglandin synthesis.
Adult Dose	250-500 mg PO tid for 5 d; continue treatment up to 2 wk prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; closely monitor PT (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Drug Name	Indomethacin (Indocin) -- Often DOC. Absorbed rapidly; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation.
Adult Dose	50 mg PO tid for 1 d, then 25-50 mg PO tid for the next 5 d; 25 mg PO tid may be continued for up to 2 wk prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; GI bleeding; renal insufficiency Patients in whom aspirin, iodides, or other NSAIDs induce hypersensitivity because of potential cross-sensitivity to other NSAIDs; senile dementia is a possibility (case report suggests it may cause severe behavioral change)
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; closely monitor PT (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	D - Unsafe in pregnancy
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if leukopenia, granulocytopenia, or thrombocytopenia persists)

Drug Category: Uricosuric agents -- These agents increase renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid.

Drug Name	Colchicine -- Reduces formation of uric acid crystals in affected joint, thereby reducing the amount of acute inflammation and pain. Also decreases levels of uric acid in the blood. Colchicine can be used either in combination with probenecid on a long-term basis to prevent gout or by itself to treat pain and inflammation of acute gout attacks. Colchicine has a very narrow window between toxic and therapeutic effects and should be used with caution for acute attacks. Generally other treatment options are available with less potential for toxic side effects. The traditional approach of giving colchicine until vomiting and/or diarrhea appear is to be discouraged as these are signs of toxicity.
Adult Dose	0.6 mg PO, repeated q1h; not to exceed 3 mg/d and a maximum of 8 mg/course; total dose should be reduced in elderly patients and in those with hepatic impairment or moderate renal insufficiency Braun has recommended modified protocol for stable renal transplant recipients, as follows: Day 1: 0.6 mg PO q1h X 2 maximum Day 2: 0.6 mg PO q1h X 2 maximum; stop if any dose causes diarrhea Days 3-9: 0.6 PO once daily; stop if diarrhea occurs
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias; use cautiously and at reduced dosage in patients with moderate impairment of renal function (creatinine clearance <50 mL/min; contraindicated if creatinine clearance <10 mL/min)
Interactions	Alters hepatobiliary and urinary excretion of many substances; known to cause interactions with more than 60 other medications; when coadministered, significantly increases both toxicity of sympathomimetic agents and effect of CNS depressants
Pregnancy	D - Unsafe in pregnancy
Precautions	Risk of renal failure, hepatic failure, permanent hair loss, bone marrow suppression, numbness or tingling in hands and feet, disseminated intravascular coagulopathy, and decreased sperm count; discontinue colchicine when pain of gouty attack begins to subside or when maximum dose has been reached, preferably before GI symptoms (eg, nausea, vomiting, diarrhea) indicate cellular poisoning has occurred; GI symptoms occur in most patients prescribed colchicine for an acute flare-up of gout, most likely because physicians have been taught to give the drug until GI symptoms develop; case reports have shown colchicine-induced myopathy leading to reversible respiratory muscle weakness from chronic colchicine use; overdose has been associated with a toxic epidermal necrolysis–like reaction and multisystem organ failure; fatalities have been reported with therapeutic administration of colchicine, generally at doses above 8 mg and/or in elderly patients and in patients with impaired renal or hepatic function

Drug Category: Corticosteroids -- These agents have anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. Oral corticosteroids may be used for patients with gout or pseudogout who cannot tolerate NSAIDs. Although case reports of adrenal crisis related to multiple interarticular injections of steroids for gout have been documented, this has not been clearly proven.

Drug Name	Triamcinolone (Aristocort) -- Treatment regimen of choice for pseudogout and for acute gouty attacks in patients with renal transplant and others who cannot be given NSAIDs or colchicine.
Adult Dose	2.5-40 mg (10 mg/mL or 40 mg/mL solutions) intra-articular or intrasynovial; repeat prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; fungal, viral, and bacterial skin infections
Interactions	Coadministration with barbiturates, phenytoin, and rifampin decreases effects of triamcinolone
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Multiple complications (eg, severe infections, hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression) may occur; abrupt discontinuation of glucocorticoids may cause adrenal crisis

Drug Name	Prednisone (Deltasone, Orasone, Sterapred) -- Useful in treatment of inflammatory and allergic reactions. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation.
Adult Dose	50 mg/d PO for 1 wk; a tapering dose of steroids is not necessary in this setting
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	D - Unsafe in pregnancy
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Corticotropic hormones -- These agents are used in diagnostic tests to differentiate primary adrenal insufficiency from secondary adrenal insufficiency. They have limited therapeutic value in conditions responsive to corticosteroid therapy where a corticosteroid should be the DOC.

Drug Name	Cosyntropin (Cortrosyn) -- An adrenocorticotropic hormone (corticotropin) that stimulates the production and release of endogenous steroids. Effective treatment of acute crystal-induced arthritis in postoperative patients and others who cannot take oral medications.
Adult Dose	80 IU IM once
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Prior to treatment, verify adrenal responsiveness through a rise in urinary and plasma corticosteroid values following cosyntropin administration; for treatment when disease is not very responsive to more conventional therapy; use as an adjunct and not as sole therapy

Drug Category: Narcotics analgesics -- Anti-inflammatory agents and other drugs that work against the intra-articular inflammatory process may take hours or days to relieve the pain of acute crystal-induced arthritis.

As in any severely painful condition, the pain of acute crystal-induced arthritis should be treated promptly in the ED. Narcotic analgesics should be used as necessary until the inflammatory process has begun to resolve.

Combinations of acetaminophen with oxycodone, hydrocodone, or codeine may be given orally every 4-6 hours as needed. In severe cases, morphine may be given IV or SC, or meperidine may be used IV or IM as indicated.

Drug Name	Acetaminophen and oxycodone (Percocet) -- Drug combination indicated for relief of moderate to severe pain. DOC for aspirin-hypersensitive patients.
Adult Dose	1-2 tab or cap PO q4-6h prn for pain
Pediatric Dose	0.05-0.15 mg/kg/dose oxycodone PO; not to exceed 5 mg/dose of oxycodone PO q4-6h prn
Contraindications	Documented hypersensitivity
Interactions	Phenothiazines may decrease analgesic effects of this medication; toxicity increases with coadministration of either CNS depressants or tricyclic antidepressants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Duration of action may increase in elderly persons; be aware of total daily dose of acetaminophen patient is receiving; do not exceed 4,000 mg/d of acetaminophen; higher doses may cause liver toxicity

Drug Name	Acetaminophen and hydrocodone (Vicodin, Lortab, Norcet) -- Drug combination indicated for relief of moderate to severe pain.
Adult Dose	1-2 tab or cap PO q4-6h prn for pain
Pediatric Dose	<12 years: 10-15 mg/kg/dose acetaminophen PO q4-6h prn; not to exceed 2.6 g/d of acetaminophen >12 years: 500 mg acetaminophen PO q4h; not to exceed 10 mg of hydrocodone bitartrate in a single dose; not to exceed 5 doses in 1 d
Contraindications	Documented hypersensitivity; elevated intracranial pressure
Interactions	Documented hypersensitivity; high altitude cerebral edema (HACE) or elevated intracranial pressure (ICP)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Tablets contain metabisulfite, which may cause hypersensitivity; caution in patients dependent on opiates because this substitution may result in acute opiate-withdrawal symptoms; caution in severe renal or hepatic dysfunction

Drug Name	Acetaminophen and codeine (Tylenol #3) -- A drug combination indicated for treatment of mild to moderate pain.
Adult Dose	30-60 mg/dose PO based on codeine content q4-6h or 1-2 tabs PO q4h; not to exceed 12 tabs per d
Pediatric Dose	0.5-1 mg/kg/dose PO based on codeine q4-6h; 10-15 mg/kg/dose based on acetaminophen content; not to exceed 2.6 g/d of acetaminophen
Contraindications	Documented hypersensitivity
Interactions	Toxicity increases with CNS depressants or tricyclic antidepressants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients dependent on opiates because this substitution may result in acute opiate-withdrawal symptoms; caution in severe renal or hepatic dysfunction

Drug Name	Morphine sulfate (Duramorph, MS Contin, Astramorph) -- DOC for narcotic analgesia because of its reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate administered IV may be dosed in a number of ways and is commonly titrated until desired effect is obtained.
Adult Dose	Starting dose: 0.1 mg/kg IV/IM/SC Maintenance dose: 5-20 mg/70 kg IV/IM/SC q4h Relatively hypovolemic patients: Start with 2 mg IV/IM/SC and reassess hemodynamic effects of the dose
Pediatric Dose	Neonates: 0.05-0.2 mg/kg/dose IV/IM/SC prn Children: 0.1-0.2 mg/kg/dose IV/IM/SC q2-4h prn
Contraindications	Documented hypersensitivity; hypotension; potentially compromised airway with uncertain rapid airway control; respiratory depression; nausea; emesis; constipation; urinary retention
Interactions	Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants, MAO inhibitors, and other CNS depressants may potentiate adverse effects of morphine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid in hypotension, respiratory depression, nausea, emesis, constipation, and urinary retention; caution in atrial flutter and other supraventricular tachycardias; has vagolytic action and may increase ventricular response rate

Drug Category: COX-2 inhibitors -- These are a relatively new type of anti-inflammatory drug that are currently under scrutiny. By inhibition of cyclooxygenase-2, the vicious cycle of inflammation and pain caused by gout is impeded. COX-2 expression in monocytes has been suggested to be induced in response to urate crystals.

Several drugs in this class are currently under investigation and are suspected to be linked to an increased risk of cardiac disease. One of these drugs, rofecoxib (Vioxx), has already been removed from the market.

Drug Name	Celecoxib (Celebrex) -- Several studies have found that this class of drug was more effective than NSAIDs for treating acute gouty arthritis. Unfortunately, Celebrex was not one of the COX-2 inhibitors studied. Given its drug class, it may be assumed to be helpful in the treatment of acute gout, but no clear evidence supports this. Currently under investigation for associated risk of accelerated cardiac disease. COX-2 inhibitors work similarly to NSAIDs, which possess both COX-1 and COX-2 inhibitory properties but with a lower risk of gastrointestinal side effects.
Adult Dose	100-200 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to sulfonamides
Interactions	Coadministration with fluconazole may cause increase in celecoxib plasma concentrations because of inhibition of celecoxib metabolism; coadministration of celecoxib with rifampin may decrease celecoxib plasma concentrations
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category D in third trimester of pregnancy; may cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, and conditions predisposing to fluid retention; caution in severe heart failure and hyponatremia because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs of infection; caution in the presence of existing controlled infections; evaluate therapy when symptoms or laboratory results suggest liver dysfunction

FOLLOW-UP

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Deterrence/Prevention:

• No prophylactic or deterrent regimen for patients with idiopathic pseudogout is known. If an underlying metabolic problem is responsible for pseudogout, the arthritis may be cured when the underlying problem is addressed.

• Consumption of purine-rich foods increases the frequency of attacks in patients with gout. Alcohol, yeasty foods, oily fish, and liver have been implicated in gout attacks. A consultation with a dietitian may be helpful for such patients.

• Gout prophylaxis may be carried out with allopurinol (100-300 mg/d) or with a combination of colchicine (0.6 mg qd/bid) with probenecid (250-500 mg bid). Increasing dosage of or starting patients on probenecid and allopurinol is contraindicated during an acute attack of gouty arthritis. Long-term continuation is controversial.

Complications:

• Gout patients who have a 24-hour urinary excretion of uric acid above 1100 mg have a 50% risk of developing urate and oxalate kidney stones. Those with a measured urate excretion greater than 800 mg per 24 hours may benefit from allopurinol prophylaxis to prevent urate nephropathy.

• Severe degenerative arthritis

• Secondary infections

• Recurrent painful episodes

• Carpal tunnel syndrome (rare)

• Urate or uric acid nephropathy

• Nerve or spinal cord impingement

Prognosis:

• Gout

• With early treatment, total control usually is attained.

• If attacks recur, successful uric acid adjustment (requiring lifelong use of uricosuric or allopurinol medication) usually is effective.

• During the first 6-24 months of uricosuric or allopurinol therapy, acute gout may occur.

• Pseudogout

• Acute attacks usually resolve within 10 days. Prognosis for resolutions of acute attacks is excellent.

• Some patients experience progressive joint damage with functional limitation.

Patient Education:

• Advise patients to begin a low-purine diet.

• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Gout.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to diagnose a septic joint in a patient with what is assumed to be an acute crystal-induced arthritis

• Failure to inform patient of the risks associated with medication used to treat crystal-induced arthritis

Special Concerns:

• Posterior interosseous nerve syndrome has been reported because of elbow inflammation causing compression of the nerve. In patients presenting with a swollen elbow and inability to extend the fingers actively, this should be considered. Treatment with intra-articular steroids has led to resolution of the nerve palsy in a case report.

• Allopurinol is a drug that is a hypoxanthine analog. It is not used in acute gouty arthritis but is a competitive inhibitor of xanthine oxidase at low doses and is a noncompetitive inhibitor at high doses. This decreases the amount of uric acid produced. However, it is not innocuous and is associated with allopurinol hypersensitivity syndrome. It is also associated with the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome.

• Allopurinol hypersensitivity syndrome occurs in 2% of those on the drug. It entails a slight rash, which will usually resolve with discontinuation of the drug.

• DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after beginning allopurinol. The underlying mechanism is thought to be a cell-mediated immunity to allopurinol and its metabolites. Although occurrence is 0.4 %, the rate of organ failure and death is high. Treatment is with intravenous N-acetyl cystine and steroids.

• Accumulation of allopurinol and its metabolite oxypurinol is felt to increase the risk of hypersensitivity reaction. Dosing guidelines are being developed to decrease their accumulation based on creatinine clearance while decreasing the amount of serum uric acid.

• Because of the hypersensitivity syndromes associated with allopurinol, other uricosuric drugs have been investigated. These include probenecid, sulfinpyrazone, and benzbromarone. Although probenecid (1-2 g/d) and sulfinpyrazone were shown not to be as effective in lowering uric levels as allopurinol, they are not associated with DRESS syndrome. However, they cannot be used in patients with renal impairment. Benzbromarone can significantly reduce uric acid levels but is associated with hepatic problems and, in some cases, hepatic failure. For this reason, its use is restricted in the United States.

• Recent research has indicated that the lipid-lowering drug fenofibrate, a fibric acid derivative, will lower serum uric acid levels while reducing very-low-density lipoprotein (VLDL), total cholesterol, and triglyceride levels. However, the creatinine level increases, and all effects are negated once the drug has been discontinued.

TEST QUESTIONS

Section 10 of 11

CME Question 1: What is the recommended treatment of acute gouty arthritis after renal transplant?

A: Indocin
B: Colchicine
C: Probenecid
D: Intra-articular prednisolone
E: Aspirin

The correct answer is D: Nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine endangers renal graft survival. Oral or intravenous steroids are not recommended for patients who already are immunosuppressed.

CME Question 2: What is the most important immediate concern regarding a patient who presents with an acutely warm, erythematous, edematous, and painful joint?

A: Severe pain
B: Septic arthritis
C: Severe degenerative joint disease
D: Renal stones
E: Compliance

The correct answer is B: Although the pain of acute arthritis can be severe and incapacitating, the primary concern must be to rule out septic arthritis, which can be life threatening or limb threatening. Renal calculi are a late complication of chronic gouty arthritis.

Pearl Question 1 (T/F): Arthrocentesis should always be performed on a patient who presents with an acutely warm and tender joint.

The correct answer is False: Arthrocentesis should be performed when a prior diagnosis of gout or pseudogout has not been proven by microscopic identification of crystals in the joint fluid and whenever the history or the physical examination suggests the possibility of septic arthritis.

Pearl Question 2 (T/F): Colchicine has no serious side effects or complications.

The correct answer is False: Colchicine has a very narrow window between therapeutic and toxic effects. Its use is associated with multiple side effects, including renal and hepatic failure and agranulocytosis.

Pearl Question 3 (T/F): Intra-articular steroids may be very effective in the treatment of acute gouty arthritis.

The correct answer is True: Intra-articular steroids are effective in the treatment of gout and pseudogout and are useful particularly when patients cannot tolerate oral agents and have a contraindication to parenteral steroids.

Pearl Question 4 (T/F): A patient with a septic joint may wait up to 72 hours before serious damage to the joint occurs.

The correct answer is False: Irreversible damage can occur within 4-6 hours, and the joint can be destroyed within 24-48 hours.

BIBLIOGRAPHY

Section 11 of 11

• Arroyo MP, Sanders S, Yee H, et al: Toxic epidermal necrolysis-like reaction secondary to colchicine overdose. Br J Dermatol 2004 Mar; 150(3): 581-8[Medline].
• Becker MA, Tate G, Schumaker HR: Primer on rheumatic disease. In: Gout. 9th ed. 1998: 195-206.
• Bleyer AJ, Hart TC: Genetic factors associated with gout and hyperuricemia. Adv Chronic Kidney Dis 2006 Apr; 13(2): 124-30[Medline].
• Braun WE: Modification of the treatment of gout in renal transplant recipients. Transplant Proc 2000 Feb; 32(1): 199[Medline].
• Cheng TT, Lai HM, Chiu CK, Chem YC: A single-blind, randomized, controlled trial to assess the efficacy and tolerability of rofecoxib, diclofenac sodium, and meloxicam in patients with acute gouty arthritis. Clin Ther 2004 Mar; 26(3): 399-406[Medline].
• Choi HK, Atkinson K, Karlson EW, et al: Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004 Apr 17; 363(9417): 1277-81[Medline].
• Dalbeth N, Kumar S, Stamp L, Gow P: Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol 2006 Aug; 33(8): 1646-50[Medline].
• Erickson AR, Enzenauer RJ, Nordstrom DM, Merenich JA: The prevalence of hypothyroidism in gout. Am J Med 1994 Sep; 97(3): 231-4[Medline].
• Joseph J, McGrath H: Gout or 'pseudogout': how to differentiate crystal-induced arthropathies. Geriatrics 1995 Apr; 50(4): 33-9[Medline].
• Lee YH, Lee CH, Lee J: Effect of fenofibrate in combination with urate lowering agents in patients with gout. Korean J Intern Med 2006 Jun; 21(2): 89-93[Medline].
• Lin SH, Hsieh ET, Wu TY, Chang CW: Cervical myelopathy induced by pseudogout in ligamentum flavum and retro-odontoid mass: a case report. Spinal Cord 2006 Nov; 44(11): 692-4[Medline].
• Mallet L, Kuyumjian J: Indomethacin-induced behavioral changes in an elderly patient with dementia. Ann Pharmacother 1998 Feb; 32(2): 201-3[Medline].
• Markel A: Allopurinol-induced DRESS syndrome. Isr Med Assoc J 2005 Oct; 7(10): 656-60[Medline].
• McCarty D: Pyrophosphate dihydreate crystal deposition disease. In: Gout. 9th ed. 1988: 207-210.
• Popovich T, Carpenter JS, Rai AT, et al: Spinal cord compression by tophaceous gout with fluorodeoxyglucose-positron-emission tomographic/MR fusion imaging. AJNR Am J Neuroradiol 2006 Jun-Jul; 27(6): 1201-3[Medline].
• Rosenthal AK, Ryan LM: Treatment of refractory crystal-associated arthritis. Rheum Dis Clin North Am 1995 Feb; 21(1): 151-61[Medline].
• Rubin BR, Burton R, Navarra S, et al: Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004 Feb; 50(2): 598-606[Medline].
• Schlesinger N: Acute gouty arthritis is seasonal: possible clues to understanding the pathogenesis of gouty arthritis. J Clin Rheumatol 2005 Aug; 11(4): 240-2[Medline].
• Taggarshe D, Ng CH, Molokwu C, Singh S: Acute pseudogout following contrast angiography. Clin Rheumatol 2006 Feb; 25(1): 115-6[Medline].
• Tan N, Lertratanakul Y, Barr WG: Acute gouty arthritis. Modern approaches to an ancient disease. Postgrad Med 1993 Aug; 94(2): 73-5, 78, 83-4 passim[Medline].
• Taniguchi Y, Yoshida M, Tamaki T: Posterior interosseous nerve syndrome due to pseudogout. J Hand Surg [Br] 1999 Feb; 24(1): 125-7[Medline].
• Tanios MA, El Gamal H, Epstein SK, Hassoun PM: Severe respiratory muscle weakness related to long-term colchicine therapy. Respir Care 2004 Feb; 49(2): 189-91[Medline].
• Towheed TE, Hochberg MC: Acute monoarthritis: a practical approach to assessment and treatment. Am Fam Physician 1996 Nov 15; 54(7): 2239-43[Medline].
• Watanabe H, Yamada S, Anayama S, et al: Pseudogout attack induced during etidronate disodium therapy. Mod Rheumatol 2006; 16(2): 117-9[Medline].
• Weishaupt D, Schweitzer ME, Alam F, et al: MR Imaging of inflammatory joint disease of the foot and ankle. Skeletal Radiology 1999; 28: 663-669[Medline].
• Wicki J, Droz M, Cirafici L, Vallotton MB: Acute adrenal crisis in a patient treated with intraarticular steroid therapy. J Rheumatology 2000; Feb; 27(2): 510-511[Medline].
• Wise CM, Agudelo CA: Gouty arthritis and uric acid metabolism. Curr Opin Rheumatol 1996 May; 8(3): 248-54[Medline].
• Zhang W, Doherty M, Bardin T, et al: EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006 Oct; 65(10): 1312-24[Medline].

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