Colchicine vs Allopurinol

Colchicine (Colcrys) and Allopurinol (Zyloprim, Aloprim and generics) are used for gout treatment. This post compares their efficiency, dosage and intake methods, side effects and interactions in gout treatment when taking individually and together.

Colchicine

Colchicine is a drug which is commonly used for the treatment of gout. It is quite a toxic product and a secondary metabolite which is extracted from plants of the genus Colchicum (1). This drug can lead to some adverse effects like gastrointestinal problems but these effects are only seen at high doses of the drug. Colchicine is commonly used for the treatment of gout but it is also used for the treatment of several other diseases like Mediterranean fever, atrial fibrillation and pericarditis.

Recent evidence has suggested that colchicine effectiveness in treating gout is greater than the similar medicines of this class. The researches have indicated the common side effects of other drugs and how colchicine overcomes those side effects.

There are a few things which the health care professionals need to keep in mind when recommending colchicine. These things are mentioned below:

• The healthcare professionals should be aware of the recommended dosage of colchicine for treating gout.
• The health care professional should abstain from prescribing colchicine to those patients who have renal or hepatic impairment and those who are taking the drugs which react with colchicine.

Vomiting and diarrhea are the common side effects seen when colchicine is given repeatedly after 1 to 2 hours dosage gap (2).

These are the first indication of colchicine toxicity and many rare side effects may also occur like neuropathy, muscle damage, bone marrow suppression and multiple organs failure.

Patients suffering from renal and hepatic impairment are likely to suffer from colchicine toxicity.

Medical uses

Colchicine is commonly prescribed to those patients who are unable to tolerate NSAIDs in gout. The use of the drug is limited due to its side effects at high doses. But this drug is quite effective and tolerable at lower doses.

Colchicine is also used for the long term treatment of Behcet’s disease. This drug has a limited effect in relapsing polychondritis because it is only useful for the treatment of chondritis and mild skin symptoms.

Colchicine is also used for the constipation predominant irritable syndrome in women and also for the treatment of persistent or severe aphthous stomatis.

Colchicine is also used in the treatment of pericarditis (3). Pericarditis is the inflammation caused around pericardium which is a membranous sac surrounding the heart. The most common complication of acute pericarditis is recurrent pericarditis which causes severe chest pain.

A study was recently done whose main objective was to review the effect of all randomized and controlled studies. The data bases of different research companies was analyzed in the study. The researchers said in the conclusion of their study that colchicine is effective in reducing the number of pericarditis recurrences in patients suffering from acute pericarditis.

But the researchers also said that the study was done on a limited number of subjects.

Colchicine also has anti-inflammatory properties and it is used to reduce the recurrence of atrial fibrillation of the cardiac tissue.

Colchicine is also used for the treatment of familial Mediterranean fever (an inborn condition which causes several episodes of severe pain, fever and swelling of the lungs and joints) in adults with ages of 4 years and older (4).

You should know one thing here that colchicine isn’t a pain reliever and shouldn’t be used for the treatment of pain that isn’t caused by gout. Colchicine belongs to a class of medicines known as anti-gout agents. The mechanism of gout is naturally stopping the natural processes which cause swelling and other symptoms of gout.

Also at initial stages of gout in patients on Allopurinol medication, doctors may prescribe Colchicine. Taking Colchicine and Allopurinol together resulted in lower number of future gout attacks (5a, 5b) however still more research should be done to confirm whether Allopurinol and Colchicine should be used together or not.

Dosage and intake methods

The proper dosage for colchicine is described below (6, 7, 8):

• Oral use – the initial dosage for gout flare is about 1.2 mg at the first signs of gout followed by a dose of 0.6 mg about one hour later. The dosage with strong CYP450 3A4 inhibitors is about 0.6 mg followed by 0.3 mg dose one hour later. The dose shouldn’t be repeated earlier than 3 days. The dosage can also be 1.2 mg orally for one dose only. The dose can also be 0.6 mg for one dose only.
• Dosage for familial mediterranean fever – the dosage is about 1.2 mg to 2.4 mg to be administered in 1 to 2 divided doses. The dose can be increased according to the specific needs. Sometimes you can develop tolerance to the drug. You shouldn’t discontinue the drug at once in this case but the dosage should be decreased in increment of 0.3 mg/day.
• Dosage for gout – the dosage is about 0.5 to 0.6 mg to be administered once a day for 3 to 4 days a week. Some severe cases require doses of 1 to 1.8 mg/day.

Intake methods

Colchicine comes only in the tablet form. The following things should be kept in mind while taking colchicine:

• You should read the manufacturer’s label carefully inside the box before starting the treatment. This will give you more information about the drug and provide you with a detailed description of the side effects of the drug.
• You must take the drug exactly as instructed by the doctor. Most doctors will recommend to take the drug when severe gout arises. It is important that you shouldn’t take more than 12 tablets during one gout attack.
• The usual dosage for the treatment of colchicine is about one tablet to be taken twice a day.
• You should drink the colchicine tablets with a glass of water. It’s your choice to take the tablet with or without food.
• You should take the dose immediately if you have missed a dose. But you shouldn’t take the dose if it’s the time for your next dose. Never double dose.

The dosage of colchicine is based on your medical condition and the other drugs which you are taking along with it. You shouldn’t increase the dose to reduce the risks of side effects. You shouldn’t also take the dose more frequently or more than that recommended by the doctor.

Mechanism of action

Colchicine binds itself to tubulin and stops the microtubule polymerization. The availability of tubule is essential for mitosis. Therefore colchicine functions effectively as a spindle poison or mitotic poison (9).

The mitosis-inhibiting function of colchicine has become of great use in the study of cellular genetics. If you want to see the chromosomes of the cell under a microscope then it is important that they should be viewed near the point in the cell cycle in which they have the most density.

This happens in the middle of mitosis and that is why mitosis must be stopped before it is completed. The standard procedure for doing karyotype studies is to add colchicine in a culture during mitosis.

Colchicine also stops the neutrophil mobility and activity other than stopping the mitosis which leads to an anti-inflammatory effect which is quite useful for the treatment of acute gout flares.

Action after intake – pharmacokinetics

The following steps are involved in the pharmacokinetics of colchicine (10):

1. Absorption

Colchicine is absorbed when given orally to healthy subjects and reaches a mean Cmax of 2.5 ng/mL after one or two hours following a single dosage given under fasting conditions. Colchicine is readily absorbed when it is given orally as 1.8 mg colchicine over one hour to healthy young subjects under fasting conditions. Colchicine is readily absorbed in such a case and reaches a maximum plasma concentration of 6.2 ng/mL with a median 1.81 hours. The mean plasma concentration after the oral administration of the drug at high dose was 6.8 ng/mL with a median of 4.47 hours. The peak concentrations reach from 3.1 to 3.6 ng/mL after 10 days of giving 0.6 mg twice on daily basis.

Taking colchicine with food has no effect on rate of the absorption of colchicine but it decreases the extent of colchicine by 15%.

2. Distribution

The apparent mean volume of distribution in healthy young adults is about 5 to 8 L/kg. The binding of colchicine to serum protein is quite low which is 39+-5 due to albumin, regardless of the concentration. Colchicine crosses the placenta. It also distributes in the breast milk at concentrations similar to those found in maternal serum.

3. Metabolism

Colchicine is metabolized to two important metabolites which are 2-O-demethylcolchicine and 3-O-demethylcolchicine and one minor metabolite which is 10-O-demethylcolchicine. The vitro studies which involved the human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2- and 3-DMC. The plasma levels of these metabolites are at minimum levels.

4. Elimination

About 40% to 65% orally administered colchicine in healthy volunteers was recovered unchanged through the urine. A major role played in the colchicine elimination is by enterohepatic recirculation and biliary excretion. The mean half lives in individuals after the oral administration becomes from 26.6 to 31.2 hours. Colchicine acts as a substrate of P-gp.

Colchicine overdosage

The exact dosage of colchicine which produces colchicine toxicity isn’t yet known (11, 12, 13). There have been many cases of deaths after taking doses as low as 7 mg over a 4 day time period. But some patients have even survived after consuming doses of more than 60 mg. The mortality rate in the patients who ingested more than 0.8 mg/kg was 100%.

Some common signs and symptoms colchicine toxicity which occur in the first 24 hours are shown below:

• Gastrointestinal symptoms like vomiting, diarrhea
• Significant fluid loss which leads to fluid depletion
• Peripheral leukocytosis
• Multi organs failure
• Death due to respiratory depression and cardiovascular collapse

The treatment of colchicine overdose starts with gastric lavage and measures taken to prevent shock. The treatment is also symptomatic and supportive. There isn’t a specific antidote of colchicine yet known. Colchicine isn’t removed effectively through the process of dialysis.

Colchicine side effects

Some major side effects of colchicine intake include diarrhea, nausea, abdominal pain, vomiting and cramping (14). You should inform your doctor at once if any of these side effects worsen.

You should remember one thing that the doctor has prescribed this medicine for you because he thinks that its benefits are greater than its side effects. Most people using this medication don’t suffer from any serious side effects.

 You should stop taking this medicine and get medical help if any of the following severe side effects occur:

• Severe vomiting or diarrhea
• Unusual bruising and bleeding
• Numbness in the fingers
• Muscle pain or weakness
• Unusual tiredness
• Tingling in the fingers or toes
• Shortening of breath
• Change in the amount of urine
• Fast heartbeat

Sometimes serious allergic reactions are also caused due to this drug but it is quite rare.

However you should seek help immediately if you notice the symptoms of a serious allergic reaction which include rashes, severe dizziness, trouble breathing and swelling or itching.

Sometimes nervous system side effects are also caused due to the intake of colchicine which include seizures, mental state changes and neuropathy in patients. Neuromyopathy has been seen with or without the elevated muscle enzymes.

Some renal side effects of the intake of colchicine include the rare cases of rapid progressive glomerulonephritis. There have been several reports of chronic renal failure with a fatal outcome of colchicine toxicity. Acute renal failure with fatal outcome has been observed in a 78 year old man after having a 10 day course of 0.5 mg tablet 3 times a day.

A case of azoospermia (the absence of motile and viable sperms in the semen) has been seen in patients treated with colchicine.  The sperm count of the patient returned to normal on the discontinuation of colchicine. But the sperm levels again decreased when the drug was continued.

You should note here that this isn’t the complete list of side effects. You should immediately consult a doctor or pharmacist if you observe any other abnormality.

Decreased efficiency causes

The following things reduce the overall efficiency of colchicine (15):

• The efficiency of colchicine decreases when it reacts with other drugs. A total of 357 drugs are known to interact with colchicine. Some common drugs which can react with colchicine include aspirin low strength, vitamin B12, Nexium, fish oi, Lasix and Lipitor.
• The efficiency of colchicine is decreased when liver patients take the drug. Therefore patients suffering from liver problems should avoid the intake of colchicine.

Allopurinol

This drug is sold under the brand name Zyloprim and generics (16). This drug is mainly used to treat the high levels of uric acid in the blood and the complications associated with it which includes chronic gout. It is a xanthine oxidase inhibitor and is administered orally only. This drug is on the list of the World Health Organization’s list of Essential Medicines which is a list of important medications needed in the basic health care system (17).

This drug is also beneficial for people having uric acid and undergoing cancer treatment. Allopurinol has many other uses which will be discussed below.

You should know about some important things relating to allopurinol before knowing about the medical uses of allopurinol. The first thing is that you need to stop taking allopurinol if you previously had a strong allergic reaction to allopurinol. You should inform your doctor at once if you notice any symptoms and signs of rash even if they are mild. You should take each dose of allopurinol with a full glass of water. You should also drink up to 8 to 10 glasses of fluid every day to reduce kidney stones (18).

Allopurinol can lower the blood cells in the body needed for fighting infection. This can make you bleed as soon as you have an allergy. Your blood needs to be tested often in these cases. Therefore, you should visit your doctor often.

You should avoid drinking alcohol as this can make your condition worse than ever. Allopurinol can impair your thinking and reaction ability. So you need to be careful if you drive or do anything which needs you to be alert.

Medical uses

There are a number of benefits of allopurinol which have been mentioned below (19):

• Hyperuricemia and gout – Allopurinol is used for the treatment of chronic gout to prevent any kind of future attacks. This drug doesn’t rid oneself from the acute attacks of gout and right now there is an ongoing controversy on whether it can actually make the gout attacks worse.
• Tumor lysis syndrome – Allopurinol is used for the treatment of chronic tumor lysis syndrome in different chemotherapeutic treatments because it can rapidly produce severe acute hyperuricemia. But now-a-days it has been replaced by the urate oxidase therapy.
• Reperfusion injury – Some major established indications for allopurinol therapy include kidney stones having a uric acid component and protozoal infections.
• Epilepsy – Allopurinol is also used for refractory epilepsy as an add-on drug because it is an adenosine agonist which stops the glutamine release from excitatory neurons and doesn’t also change the concentration of plasma of other epilepsy drugs.
• Inflammatory bowel syndrome – The allopurinol cotherapy is used for the improvement of outcomes in people suffering from inflammatory bowel disease and Crohn’s disease who don’t respond to monotherapy (20). Cotherapy has greatly improved the hepatoxicity side effects in treatment of inflammatory bowel syndrome. The dose reduction of thiopurine is needed in cotherapy and the standard dose mainly depends upon the patient’s genetic status for thiopurine methyltransferase.

Dosage and intake methods

The dosage for allopurinol depends upon the specific patient and the specific problem. The dosing information of allopurinol has been mentioned below (21):

• The initial dosage of allopurinol for gout is 100 mg to be taken orally once a day. The maintenance dosage is about 200 to 300 g to be taken once a day or 400 to 600 mg/day in divided doses.
• The usual dose for patient suffering from calcium oxalate calculi is about 200 to 300 mg daily. The maintenance dosage is about 300 mg or less per day.
• The usual dosage for patients suffering from congestive heart failure is about 300 mg orally for one month.
• The adult dosage for cardiothoracic surgery is about 600 mg orally before the surgery and another 600 mg on the day of surgery.
• The usual dose of allopurinol for mania is about 300 mg orally every day.
• The usual pediatric dose for leishmaniasis is about 20 mg/kg/day plus low-dose of meglumine antimoniate for 20 days.
• The usual dosage for hyperuricemia which is before chemotherapy is about 200 to 400 mg/day and a maximum of 600 mg/day. The maintenance dosage is 200 to 300 mg/day orally until the patient doesn’t has a risk of developing hyperuricemia.

Intake methods

Allopurinol comes only in the tablet to taken orally. It is taken once or twice a day mostly after meals. But the choice depends upon you. You should take the medicine at the same time every day to help you remember to take the medicine.

You should follow the direction on the label carefully and ask the doctor anything which you don’t understand. Take allopurinol exactly as directed by the doctor. Don’t take the drug more or less than that prescribed by the doctor. The doctor will start from a low dose of the drug and continue increasing the dose not more than once a week.

The drug may take several weeks to take effect if you are suffering from gout. You might have more gout attacks for the first few months after starting the medicine when the body still removes the extra uric acid. You should remember here that allopurinol isn’t a pain reliever. You should continue to take the medicine for gout attacks if you want to relieve the pain from gout.

It may take you several months to see the full benefits of the drug. Allopurinol can increase the number of gout attacks in the first few months that you take it and it might also prevent the attacks. Your doctor might give you another medication like colchicine to prevent the gout attacks for the first few months that you take it. You should continue taking the medicine even if you feel well. Don’t stop taking the medicine without consulting the doctor.

Mechanism of action

Allopurinol is a purine analog which means that it is a structural isomer of hypoxanthine and it inhibits the enzyme xanthine oxidase (22). Xanthine oxidase is responsible for the oxidation of hypoxanthine and xanthine which results in the production of uric acid which is the product of human purine metabolism. The inhibition of xanthine oxidase also causes an increase in xanthine and hypoxanthine.

Mechanism of allopurinol – pharmacokinetics

The following steps take place after the intake of allopurinol (23):

1. Absorption

The peak plasma concentrations of allopurinol after 80 to 90 percent absorption are reached after 1.5 to 4 hours. The infusion takes place over 30 minutes and the peak plasma concentration of allopurinol is reached in about 30 minutes.

The serum urate concentrations in patients suffering from gout decreases slowly within 24 to 48 hours. The minimum concentrations may not reach for about one to three weeks. The substantial uric acid may be delayed up to 6 to 12 hours because of the continuous mobilization of the urate deposits.

People who suffer from geriatric disease have greater peak plasma concentrations and the allopurinol dosage in such patients is 50 to 60 percent higher than in young adults which is related to the renal function in older population.

2. Distribution

Allopurinol is uniformly distributed throughout the body except the brain where the concentrations are about 50% of the concentrations in other tissues. Allopurinol is distributed into the milk. Allopurinol isn’t bound to plasma proteins.

3. Metabolism

Allopurinol is metabolized by xanthine oxidase and it is metabolized to an active metabolite known as oxypurinol.

4. Elimination

The drug is excreted through urine and feces as an unchanged drug within 48 to 72 hours. Allopurinol is dialyzable. The half-life of allopurinol is about 1-3 hours.

Allopurinol overdosage

It is possible that a person accidentally or intentionally overdoses on allopurinol. An allopurinol overdose is likely to cause the same side effects as those which are possible with this medication (24). But still the experts don’t know exactly what to expect from allopurinol overdose. Some cases were reported in which no serious problems occurred.

There are a number of treatments of allopurinol overdose. The healthcare professional might provide you with certain medications if the overdose was recent. The doctor may also place a tube in your stomach to “pump the stomach”.  Another treatment is supportive care in which the symptoms of allopurinol overdose are treated. Dialysis can also be used to remove allopurinol from the blood.

It is very important that you seek immediate medical attention if you think that you have overdosed on allopurinol.

Allopurinol side effects

Some common side effects of allopurinol overdose are nausea, vomiting, stomach upset and diarrhea. You should inform the doctor or pharmacist immediately if any of these side effects persist or worsen (25).

You should remember that the doctor has prescribed the medication for you because he thinks that its health benefits are greater than its side effects. Most people using this drug don’t suffer from any serious kind of side effects.

You should inform your doctor right away if any of the following serious side effects occur:

• Numbness
• Tingling in the hands and feet
• Signs of infection
• Unusual tiredness
• Painful urination
• Yellowing of skin and eyes
• Change in the amount of urine
• Persistent vomiting
• Dark urine
• Vision changes
• Eye pain
• Unusual weight loss

Sometimes an allergic reaction can also be caused due to the intake of allopurinol but it is quite rare. But you should inform the doctor immediately if you notice any symptoms of an allergic reaction like rashes, swelling, dizziness, itching and trouble breathing.

Some patients are hypersensitive to this drug (26). Therefore it should be used carefully.

Allopurinol should be used in pregnancy only if clearly instructed by the doctor and it should be used with caution by breast feeding women. The benefits and the harmful effects to the fetus should be considered before the intake of this drug. Allopurinol should also be used with caution in certain patients with hyperuricemia.

Moderate side effects

The following is a list of less severe side effects of allopurinol consumption:

• Drowsiness
• Fever
• Feeling faint or dizzy
• General feeling of weakness or tiredness
• Incoherent speech
• Itching
• Metallic taste
• Sore throat
• Thirst
• Tightness in chest
• Sweating
• Hostility
• Dry mouth

Decreased efficiency causes

The following things reduce the overall efficiency of allopurinol (27):

• The efficiency of allopurinol is decreased when it reacts with other medicines. A total of 135 drugs are known to interact with allopurinol. Some common drugs which can interact with allopurinol include aspirin, Nexium, Vitamin B12, Synthroid, Lipitor and Lasix.
• Alcohol can reduce the overall efficiency of this drug. So you should quite alcohol as long as you are taking this drug.

Colchicine vs Allopurinol - final comparison and clinical trials

The following studies give a brief comparison between colchicine and allopurinol:

• A randomized study was done which involved 184 patients having acute gout flares of less than 12 hours duration. The patients were divided into three groups. One group was given high dose of colchicine whereas the second group was given a low dose of colchicine. The third group was the placebo group. The results showed that the low dose showed comparable peak plasma concentrations and efficacy and the side effects were quite similar to that of placebo. The researchers concluded in the results of the study that the side effects of colchicine are quite less. The half-life of the drug was found to be of 4 hours.
• A study was recently done to find the effects of allopurinol for the treatment of gout. The patients were divided into two groups. One group was given allopurinol whereas the other group was given colchicine. The results of the study showed that allopurinol was more beneficial for the treatment of gout as compared to the placebo. But it was found in the study that about 30% patients using allopurinol suffered from different side effects; the most common side effects were skin rashes and gastrointestinal intolerance. The half-life of allopurinol was found to be about 1 to 3 hours.

Conclusion

While Colchicine is normally used for treatment of acute flares of gout, Allopurinol is usually used for chronic gout treatment as it is an uric acid lowering drug. Sometimes doctors prescribe Colchicine and Allopurinol together, mainly in patients on Allopurinol treatment at the initial stages to prevent further gout attacks. Both drugs may have some serious side effects, therefore proper dosage is necessary and the drugs should not be overdosed as there is a risk of renal impairment and other serious problems. Interactions of Allopurinol and Colchicine include some commonly used medicines (such as aspirin or even vitamin B12). Alcohol is reducing efficiency of Allopurinol as well as Colchicine.