Gouty arthritis and colchicine

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Colchicine is a unique plant alkaloid derived from Colchicum autumnale, commonly known as the Aautumn crocus or Meadow saffron. This remarkable compound has unique anti-inflammatory actions not yet completely understood nor duplicated by any other compounds derived synthetically. The first use of colchicine evolved from the application of the ancient "Doctrine of Signatures". This doctrine suggested that the shape, color and appearance of plant would implicate it's use. The bulbous root of the plant was thought to resemble the appearance of a gout deformed big toe. Gout, a painful form of acute and chronic arthritis responds very well to colchicine. In 1763, Baron Anton von Storck documented the effectiveness of colchicine in treating gout, and it still remains as the drug of choice for acute gout today.

Colchicine has a good safety profile and may be given orally or intravenously. The oral route may produce gastrointestinal irritation and diarrhea. The intravenous route is quite safe, if care is taken so that the colchicine does not leak from the vein and into surrounding tissue (called infiltration). Our use of colchicine goes beyond its use in treating acute gout attacks. Other forms of arthritis may also respond to colchicine. In 1989, Dr. Michael Rask reported in the Journal of Neurological and Orthopedic Medicine the results of his use of colchicine in the treatment of 6000 patients with back pain resulting from herniated spinal disks. This common painful affliction was markedly improved in 92% of the cases treated with colchicine! Positive results in treating the pain associated with sciatic neuritis, herpes zoster neuritis (shingles), diabetic neuropathy, and trigeminal neuralgia (tic douloureux) have also been reported.

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The frequency and duration of treatment are variable. We have seen marked improvement with a single treatment and others who respond after multiple treatments. Of course there's no guarantee that this therapy will be effective for you, but this alternative therapy is certainly worth a trial for those facing surgery for disk herniations, or the severe and unrelenting pain of other disorders and the conventional application of addictive narcotics to treat it.

The reimbursement of the costs of treatment by insurance companies varies. Some regarded the therapy as alternative or experimental and will not reimburse, and others will provide reimbursement. As with all of our therapies, payment is expected at the time of service. When colchicine is effective, patients are glad they invested in this low cost and safe treatment!

http://www.infoplease.com/ce6/sci/A0812831.html

Colchicine, alkaloid extracted from plants of the genus Colchicum and especially from the corms of the autumn crocus, Colchicum autumnale (see meadow saffron). The metabolic effect of colchicine is not known, but it is thought that it may decrease production of lactic acid and prevent accumulation of uric acid crystals in the body, making it useful in the treatment of gout. Colchicine and derivatives such as demecolcine inhibit mitosis, or cell division. As a mitotic poison, it inhibits rapidly proliferating cells and has been used in cancer therapy and as an immunosuppressive drug. Colchicine has also been used to visualize chromosomes photomicrographically and to induce mutations experimentally.

Meadow Saffron or Autumn Crocus,perennial garden ornamental (Colchicum autumnale) of the family Liliaceae (lily family). Native to Europe and N Africa, it has escaped from gardens to meadows and fields in some parts of the United States. Its poisonous corms and seeds were the source of the drug colchicine. The purplish flowers, which bloom in the fall when the leaves are gone, resemble those of the true crocus and true saffron (of the iris family) but have six stamens instead of three. Other species of Colchicum are also popular garden plants. Meadow saffron is classified in the division Magnoliophyta, class Liliopsida, order Liliales, family Liliaceae.

While tart cherries have proven to be one of the best sources of food to quickly and effectively help those with gout, a variety of other foods have been found to be low in what are called "purines" and a diet that is based on these can help to relieve the discomfort and reduce the incidence of gout attacks, as well.

What's a purine? It is a chemical compound found in our bodies that actually plays many important roles in the life process. After metabolism these Purines break down into uric acid. Unfortunately, those stricken with Gout have an overproduction of uric acid which then deposits as uric acid crystals in their joints. By lowering one's purine intake the resulting uric acid is lowered and reduces these deposits.

Gout is one of the most painful rheumatic diseases. It results from deposits of needle-like crystals of uric acid in connective tissue, in the joint space between two bones, or in both. These deposits lead to inflammatory arthritis, which causes swelling, redness, heat, pain, and stiffness in the joints. The term arthritis refers to more than 100 different rheumatic diseases that affect the joints, muscles, and bones, as well as other tissues and structures. Gout accounts for approximately 5 percent of all cases of arthritis.

Pseudogout is sometimes confused with gout because it produces similar symptoms of inflammation. However, in this condition, also called chondrocalcinosis, deposits are made up of calcium phosphate crystals, not uric acid. Therefore, pseudogout is treated somewhat differently and is not reviewed in here.

Uric acid is a substance that results from the breakdown of purines, which are part of all human tissue and are found in many foods. Normally, uric acid is dissolved in the blood and passed through the kidneys into the urine, where it is eliminated. If the body increases its production of uric acid or if the kidneys do not eliminate enough uric acid from the body, levels of it build up in the blood (a condition called hyperuricemia). Hyperuricemia also may result when a person eats too many high-purine foods, such as liver, dried beans and peas, anchovies, and gravies. Hyperuricemia is not a disease and by itself is not dangerous. However, if excess uric acid crystals form as a result of hyperuricemia, gout can develop. The excess crystals build up in the joint spaces, causing inflammation. Deposits of uric acid, called tophi (singular: tophus), can appear as lumps under the skin around the joints and at the rim of the ear. In addition, uric acid crystals can collect in the kidneys and cause kidney stones.

For many people, gout initially affects the joints in the big toe. Sometime during the course of the disease, gout will affect the big toe in about 75 percent of patients. It also can affect the instep, ankles, heels, knees, wrists, fingers, and elbows. The disease can progress through four stages:

Asymptomatic (without symptoms) hyperuricemia -- In this stage, a person has elevated levels of uric acid in the blood but no other symptoms. A person in this stage does not usually require treatment.

Acute gout, or acute gouty arthritis--In this stage, hyperuricemia has caused the deposit of uric acid crystals in joint spaces. This leads to a sudden onset of intense pain and swelling in the joints, which also may be warm and very tender. An acute attack commonly occurs at night and can be triggered by stressful events, alcohol or drugs, or the presence of another illness. Early attacks usually subside within 3 to 10 days, even without treatment, and the next attack may not occur for months or even years. Over time, however, attacks can last longer and occur more frequently.

Interval or intercritical gout -- This is the period between acute attacks. In this stage, a person does not have any symptoms and has normal joint function.

Chronic tophaceous gout -- This is the most disabling stage of gout and usually develops over a long period, such as 10 years. In this stage, the disease has caused permanent damage to the affected joints and sometimes to the kidneys. With proper treatment, most people with gout do not progress to this advanced stage.

Where high uric acid has been present for a long time and acute gout has been frequent and severe, deposits of uric acid salts may appear around the affected joint and even in tissues elsewhere such as the ears. These are seen as chalk coloured nodules called tophi. Their presence indicates the need for treatment with one or other of the long term uric acid lowering drugs mentioned above.

High uric acid levels and recurrent gout are often associated with high blood pressure which your doctor will check and treat as necessary. This combination of hyperuricaemia and high blood pressure can lead to kidney damage so it is all the more important, not just because of the effects on the joints, to correct this state of affairs through the proper use of all the measures mentioned above under your doctor's supervision.

A number of risk factors are related to the development of hyperuricemia and gout:

Genetics may play a role in determining a person's risk, since up to 18 percent of people with gout have a family history of the disease.

Gender and age are related to the risk of developing gout; it is more common in women and adults than in children.

Being overweight increases the risk of developing hyperuricemia and gout because there is more tissue available for turnover or breakdown, which leads to excess uric acid production.

Drinking too much alcohol can lead to hyperuricemia because it interferes with the removal of uric acid from the body.

Eating too many foods rich in purines can cause or aggravate gout in some people. An enzyme defect that interferes with the way the body breaks down purines causes gout in a small number of people, many of whom have a family history of gout.

Exposure to lead in the environment can cause gout.

Some people who take certain medicines or have certain conditions are at risk for having high levels of uric acid in their body fluids. For example, the following types of medicines can lead to hyperuricemia because they reduce the body's ability to remove uric acid:

Diuretics, which are taken to eliminate excess fluid from the body in conditions like hypertension, edema, and heart disease, and which decrease the amount of uric acid passed in the urine;

Salicylates, or anti-inflammatory medicines made from salicylic acid, such as aspirin;

The vitamin niacin, also called nicotinic acid;

Cyclosporine, a medicine used to suppress the body's immune system (the system that protects the body from infection and disease) and control the body's rejection of transplanted organs; and

Levodopa, a medicine used to support communication along nerve pathways in the treatment of Parkinson's disease.

Who Is Likely To Develop Gout?

Gout occurs in approximately 840 out of every 100,000 people. It is rare in children and young adults. Adult men, particularly those between the ages of 40 and 50, are more likely to develop gout than women, who rarely develop the disorder before menopause. People who have had an organ transplant are more susceptible to gout.

How Is Gout Diagnosed?

Gout may be difficult for doctors to diagnose because the symptoms may be vague, and they often mimic other conditions. Although most people with gout have hyperuricemia at some time during the course of their disease, it may not be present during an acute attack. In addition, having hyperuricemia alone does not mean that a person will get gout. In fact, most people with hyperuricemia do not develop the disease.

To confirm a diagnosis of gout, a doctor may insert a needle into an inflamed joint and draw a sample of synovial fluid, the substance that lubricates a joint. A laboratory technician places some of the fluid on a slide and looks for monosodium urate crystals under a microscope. Their absence, however, does not completely rule out the diagnosis. The doctor also may find it helpful to examine chalky, sodium urate deposits (tophi) around joints to diagnose gout. Gout attacks may mimic joint infections, and a doctor who suspects a joint infection (rather than gout) may check for the presence of bacteria.

Signs and Symptoms of Gout

Hyperuricemia

Presence of uric acid crystals in joint fluid

More than one attack of acute arthritis

Arthritis that develops in 1 day, producing a swollen, red, and warm joint

Attack of arthritis in only one joint, usually the toe, ankle, or knee

http://staff.washington.edu/momus/PB/gout.htm

I. Pathophysiology and epidemiology

A multi-organ disease resulting from inflammation and tissue damage triggered by precipitation of monosodium urate monohydrate (MUS) crystals

Uric acid metabolism

Produced by action of xanthine oxidase on the purines hypoxanthine and xanthine (mostly from breakdown of senescent cells; also some from diet).

Filtered at the glomerulus (filtration inhibited by diuretics)

Secreted by the tubules (secretion inhibited by pyrazinamide, low-dose ASA, and alcohol)

Also reabsorbed by the tubules (reabsorption inhibited by uricosuric drugs--probenecid, sulfinpyrazone, benzbromarone, ASA at doses> 2g/d).

About 33% of uric acid elimination is by bacterial degradation in the gut.

Chronic hyperuriciemia is necessary but not sufficient for the development of gout. Note that serum uric acid levels can be temporarily lowered during a gout attack.

Usually idiopathic (> 99%) but can be secondary to:
Increased urate production due to:

Rare inherited metabolic disorders causing increased uric acid production (PP-ribose-P synthetase over-activity; hypoxanthine-guanine phosphoribosyltransferase deficiency; G5PD deficiency)
Chronic hemolysis
Increased WBC turnover, e.g. leukemia
High dietary purine content (meats esp. organ meats; meat extracts & gravies; seafood; yeast; beer; legumes; oatmeal; spinach; asparagus; cauliflower; mushrooms)
Impaired renal urate secretion
Chronic renal insufficiency of any cause
Meds which inhibit urate secretion or enhance reabsorption
Diuretics (thiazide and loop)
Cyclosporine
Lead
Low-dose ASA
Pyrazinamide
Ethambutol
Niacin
Alcohol

More common in men than women; very rare before puberty; peak incidence around age 45 for men; for women; more common after menopause

Obesity is a risk factor; unclear why

Hypertension appears to be a risk factor, though this may be be confounded by diuretic use.

II. Clinical features

Gouty arthritis--an acute, inflammatory arthritis caused by intra-articular precipitation of MUS Predominantly PMN-mediated

Usually monoarticular; 50% involve the big toe MTP joint ("podagra")

Usually exquisitely tender

Can be accompanied by fever and elevation of WBC and ESR

Can last anywhere from hours to weeks without tx

Can be precipitated by exercise, trauma, physiologic stress e.g. surgery, alcohol, "dietary overindulgence," starvation, or start of uric acid-lowering meds

In recovery phase, desquamation of overlying skin may occur

Extra-articular manifestations

Deposition of monosodium urate monohydrate crystals in extra-articular locations ("tophi")

In cartilage (including ear), tendon sheaths, bursae, subcutaneous tissues, bone, renal interstitium, and rarely, cardiac valves or conduction system

Usually not associated with inflammation

Can cause stiffness and aching due to mechanical impingement on surrounding tissue and even, in rare cases, extensive joint destruction

Can get inflammatory tenosynovitis, bursitis, or cellulitis.

Gouty nephropathy

Deposits of monosodium urate monohydrate in renal interstitium with attendant monuclear and giant cel reaction

Renal failure due to gout is generally mild and slowly progressive

Can rarely get acute oliguric renal failure from bilateral tubular obstruction by uric acid crystals--typically in leukemia or lyphoma (esp. during chemotherapy--tumor lysis syndrome) or in setting of severe volume depletion and acidosis

Uric acid urolithiasis is seen in 10-25% of pts with gout

III. Diagnosis

Gold standard for diagnosis is observation of negatively birefringent, needle-shaped crystals on polarized light microscopy in synovial fluid.

WBC count in synovial fluid is usually 5-50k/mm3 in acute gout

Differential diagnosis for acute gouty arthritis

Pseudogout

Acute rheumatic fever

Rheumatoid arthritis

Traumatic arthritis

Osteoarthritis

Septic arthritis--Consider w/u with synovial fluid culture in acute gout, esp. first episode, to r/o alternate diagnosis of septic arthritis

Cellulitis

Bursitis

Thrombophlebitis

Acute sarcoidosis

Psoriatic arthritis.

Reiter's syndrome

IV. Treatment of acute gouty arthritis

Rest the affected joint

Ice significantly reduces pain (J. Rheum. 29:331, 2002--JW)

NSAIDs (don't use salicylates because decrease tubular secretion of uric acid) until attack subsides

Colchicine PO
Reduces PMN phagocytosis of urate crystals

0.6-1.2mg then 0.6mg Q1-2h until attack subsides or side f/x develop (us. 18-24h)

Reduce dose in pts with renal or hepatic disease

Side f/x include nausea, abdominal cramping, and diarrhea; may also cause alopecia, hepatotoxicity, reversible myopathy, and bone-marrow suppression in high doses

Monitor CBC in pts on long-term colchicine therapy

Colchicine IV--much higher risk of bone marrow suppression, nephrotoxicity, and hepatotoxicity--2mg then 1mg Q6h; max dose 4mg; reduce dose by 50% in elderly or pts with hepatic or renal disease

Systemic Corticosteroids if other meds are contraindicated (prednisone 20-40mg/d or intra-articular steroids)

Don't start hypouricemic therapy during acute attack--doesn't help and may induce a recurrent attack by mobilizing uric acid from the tissues. However, if pt is on hypouricemic tx, don't d/c during acute attacks.

Preventive Treatment
May result in diminution of tophi as well as prevention of acute attacks
Hypouricemic agents
Criteria for use
Frequent or severe attacks
Severe hyperuricemia
Tophi
Radiographc evidence of urate deposits
Urolithiasis
Urate overexcretion
Try to maintain serum uric acid at < 6mg/dl
The optimal duration of hypouricemic tx is unknown; may experts recommend lifelong treatment

Hypouricemic tx may precipitate acute gout (unclear why)--to prevent this, start Colchicine 1-2wks before and continue for several months after initiation of hypouricemic tx

Specific agents -- Pts with elevated urinary uric acid excretion are at increased risk for urolithiasis and should be tx'd with allopurinol rather than uricosuric agents; this would be the only reason to check urinary uric acid excretion (normal = 330-600mg/d; don't check during an acute attack b/c won't be accurate)

Allopurinol
Reduces serum uric acid levels by inhibiting xanthine oxidase
Dosing: 300mg QD, may increase to up to 900mg if needed; 100-200mg/d in pts with renal insufficiency

May cause gastric irritation, diarrhea, skin rash, and rarely, hypersensitivity syndrome (more likely in pts with renal insufficiency) with acute interstitial nephritis, hepatitis, fever, vasculitis, and severe skin injury

In a case-control study of 3,677 pts and 21,868 control, allopurinol use> 3y ass'd with RR for cataracts of 1.53 (sig.) (Arch. Ophth. 116:1652, 1998--JW)

Uricosuric agents
Ineffective--and more dangerous re: risk of uric acid urolithiasis--if CrCl < 30ml/min
Before starting tx, check to make sure 24h urine uric acid secretion is not high, b/c if it is, tx'ing with a uricosuric agent may raise the risk of uric acid stones as well as uric acid deposition in renal tubules

Consider co-treating with urine alkalinizing agents (e.g. acetazolamide 250mg HS)

Probenecid 500-1000mg BID--effectiveness reduced by salicylates

Sulfinpyrazone 100mg TID-QID--may cause HA, GI upset, rash; effectiveness reduced by salicylates

Encourage high fluid intake

Moderation in protein intake

Treat HTN if present

Avoid excessive alcohol intake

Colchicine 0.6-1.2mg/d can be used as preventive monotherapy

Ditto for low-dose NSAIDs

(Sources: Cecil Textbook of Medicine 20th ed.; NEJM 334:445, 1996)

Colchicine database

Prevent gout, use pearl powder!

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10-23-09

FDA-Approved Gout Drug Could Kill You

Gout comes with killer pain... but Colchys, the latest FDA-approved preventive treatment, could really kill you.

Knowing that this drug can cause fatal toxic reactions (especially when used at the same time as many common medications) -- even in approved dosages! -- the FDA still approved it. The agency issued a safety alert on July 30 because colchicine (the generic name) could cause death even when taken sporadically for treating acute flare-ups. But still, they gave Colchys the green light as a daily preventive just this week.

How deadly is this drug? The FDA found 169 deaths linked with colchicine... including 117 where the people took only the recommended, approved dose.

Apparently, Colchys can interact VERY BADLY with many other, very common drugs (like Lipitor, Prilosec, erythromycin, Prozac, and Imodium... just to name a few), increasing the risk of potentially fatal colchine toxicity.

On top of that, the potential for non-fatal but still horrific adverse events is pretty big -- the first page of the prescribing information is honestly terrifying: thrombocytopenia, aplastic anemia, neuromuscular toxicity.

How any doctor could prescribe such a dangerous drug when there are highly effective, totally safe natural remedies for gout is unthinkable. But you don't have to subject yourself to unreasonable risk to find relief.

Michele Cagan healthiernews.com

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