DRUGS AND INFLAMMATORY BOWEL DISEASE
Many drugs are used to treat inflammatory bowel disease (IBD). They may be given for a variety of reasons; to suppress inflammation in those with active disease, to prevent flare-ups in those with inactive disease, to control symptoms such as pain or diarrhoea, or to replace or supplement essential nutrients which are poorly absorbed because of extensive disease or surgery. They are given in a number of ways depending on the location and severity of disease; as tablets or capsules, by intravenous or intramuscular injection, or as enemas, rectal foam or suppositories.
All treatments used in medicine (drugs, surgery, radiation) have risks. Every time a doctor prescribes a drug, the risks of the drug must be weighed against the risks of continuing symptoms or complications if the drug is not used. As the cause of IBD is not known, drugs cannot be precisely targeted and even "specific" drugs used to suppress inflammation or prevent flare-ups have a wide range of effects, some beneficial and some not.
The following information describes the drugs used in IBD, how
they work, when they are used and their more common and important
side-effects. The list of side-effects is not all-inclusive. If
you think one of your drugs is causing a side-effect, consult
your doctor. It is important not to treat yourself. This
information does not discuss any non-drug therapies such as
diets, surgery or psychological support. You can obtain further
information about these forms of treatment through the Australian
Crohn's and Colitis Association.
A. SPECIFIC DRUGS
1. 5-Aminosalicylic Acid (5ASA) containing drugs
To be effective 5ASA must remain in the bowel until it reaches the area which is diseased. If pure 5ASA is taken by mouth, it is completely absorbed from the upper gut into the blood. As all ulcerative colitis and some Crohn's disease occurs in the large bowel (or colon), which is beyond the site of absorption, it is necessary to modify 5ASA to prevent it being absorbed in the upper gut. There are three 5ASA preparations available in Australia. Most studies have found them to be equally effective, both in the treatment of mild attacks of ulcerative colitis and in preventing flare-ups.
1.1 Sulphasalazine (Salazopyrin®
1.1.1 Side Effects of Sulphasalazine
The most common side-effects are abdominal pain, nausea and vomiting, and reduced appetite. These can be helped by taking the tablets with food, rather than on an empty stomach, or by using enteric coated tablets (Salazopyrin EN). The enteric coating prevents release of sulphasalazine from the tablet until after it has left the stomach.
Headache and skin rashes are also relatively common. Occasionally sulphasalazine causes anaemia by a process called haemolysis. Red blood cells normally have a life span of 120 days before they are destroyed by the spleen. In some patients sulphasalazine accelerates this destruction. Rarely it can suppress the production of different types of blood cells in the bone marrow. Other uncommon side-effects include inflammation of the lung, hair loss, blistering of the face and mouth, and a flare-up of colitis.
Sulphasalazine can occasionally cause male infertility by reducing the sperm count. This is due to sulphapyridine and always resolves when the drug is stopped. Rarely it reduces the body's ability to absorb folic acid, a vitamin necessary for blood formation. This is only significant if there is increased demand for folic acid (eg. during pregnancy) or another reason for impaired folic acid absorption (eg. surgical removal of part of the small bowel) and is easily controlled by taking a folic acid tablet. Some patients taking sulphasalazine notice that their urine has an orange colour. This is harmless.
1.2 Olsalazine (Dipentum®)
As there is no sulphur component most individuals who are unable to take sulphasalazine because of side-effects can take olsalazine. However, about 10% develop watery diarrhoea soon after commencing olsalazine. This can often be improved by starting with a lower dose or by taking the drug with food, and tends to resolve with time. However, some patients are unable to take olsalazine because of diarrhoea. Other side-effects are quite rare; nausea, headache, joint pains, abdominal pain and skin rash have been reported. You should tell your doctor if you think you are allergic to aspirin.
As olsalazine is considerably more expensive than sulphasalazine, its use is restricted by the Federal Government's requirement for an authority prescription. This means that it is only available at the normal prescription cost for individuals with colitis who are intolerant of sulphasalazine.
1.3 Mesalazine (Mesasal®)
As 5ASA is released in the ileum, the use of mesalazine for Crohn's disease affecting the ileum has been investigated over the past few years. Recent research suggests that it may have some effect, both for the treatment of mild attacks and for preventing flare-ups in those whose disease is inactive, including patients who have recently had surgery. However, it is much less effective than steroids in active disease and the preventative effect is less than that of 5ASA containing drugs in ulcerative colitis.
Most individuals unable to take sulphasalazine because of side-effects are able to take mesalazine. Side-effects are relatively uncommon but nausea, abdominal pain, headaches and rashes do occasionally occur. There have been a few reports of kidney damage, presumably due to the small amount of 5ASA absorbed from the small bowel. You should tell your doctor if you think you are allergic to aspirin. Mesalazine, like olsalazine, is considerably more expensive than sulphasalazine and can only be dispensed with an authority prescription. This means that it is only available at the normal prescription cost for individuals with colitis who are intolerant of sulphasalazine.
1.4 ASA Enemas
5ASA can also be given by enema to control attacks of ulcerative colitis affecting the lower part of the large bowel. Direct comparisons with steroid enemas suggest that 5ASA is more effective. Unfortunately there is no 5ASA enema on the market in Australia at the present time. 5ASA enemas are often useful for attacks of colitis not responding to other drugs and several hospital pharmacies (and a few local pharmacies) make up 5ASA enemas for use in this situation.
5ASA and sulphasalazine suppositories are more widely
available. However, they are only useful for disease confined to
the lowest part of the bowel (the rectum).
2. Corticosteroids (Steroids)
Corticosteroids have a wide range of actions but their major effect in IBD is to suppress inflammation. They can be given as tablets, enemas, rectal foams, suppositories or intravenous injections, depending on the site and severity of inflammation. Rectal steroids (eg. Predsol®, Colifoam®) are preferred for disease confined to the lower large bowel because they are poorly absorbed into the blood and therefore produce fewer side-effects. There is no point in using rectal steroids for more extensive disease, as only part of the inflamed bowel will be treated.
Although steroids are the most effective treatment for more severe IBD, their use is restricted by significant side-effects. Therefore high doses are used to bring attacks under control, after which they are gradually withdrawn over weeks to months. Steroids have no role in preventing flare-ups in those with inactive disease. However, a few patients with persistent "grumbling" disease require prolonged treatment with steroids. In these cases the lowest possible dose is used.
2.1 Side-Effects of Corticosteroids
Patients with IBD are often reluctant to take steroids because of their effects on bodily appearance. However, these side-effects do not always occur. The most common changes are weight gain (predominantly face and body - sometimes a "buffalo hump" of fat develops in the middle of the upper back), rounding (or "mooning") of the face, redness of the skin, acne, facial hair, easy bruising and ankle swelling. Rapid changes in weight can cause stretch marks. Some people develop wasting and weakness of the muscles of the upper arms and legs with long-term use. This can lead to difficulty with activities such as climbing stairs, getting out of a chair, combing hair or hanging out washing.
Many patients notice an increased appetite. Mood changes can also occur, usually a feeling of well-being but occasionally agitation, irritability or depression.
There are a number of less visible side-effects. Steroids weaken the body's resistance to infection. You should always consult your doctor if you develop an infection while you are taking steroids. They also cause thinning of the skin and impair healing after cuts or surgery.
Steroids may raise blood sugar levels; some people who have normal blood sugar levels develop diabetes while they are on steroids, those with pre-existing diabetes may have to increase their treatment. They can also raise blood pressure and lower the level of potassium in the blood, occasionally causing fatigue and weakness.
Prolonged use of steroids in children may retard growth. However, children with active IBD will not grow normally until the disease is brought under control. The long-term effects of withholding treatment are significantly greater than the side-effects of steroids. Children with IBD may experience a growth spurt after their disease is controlled.
All of the side-effects mentioned so far are reversible; they resolve when the steroids are stopped. There are also a small number of irreversible side-effects. These include development of cataracts and most importantly, bone damage. Corticosteroids can lead to osteoporosis, or softening of bones, with the result that bones break more easily. Osteoporosis develops gradually, particularly when high doses have been used for long periods of time and is more likely in those with other risk factors (eg. women after menopause). Rarely they cause a sudden loss of blood supply to the bone of the hip joint (avascular necrosis of the head of the femur).
The body's normal steroid production stops when you take corticosteroids. When an attack of IBD is under control the dose of steroids should be reduced gradually to allow the body to take over again. It may take up to 12 months to completely restore normal steroid production. As increased levels of corticosteroids are necessary for your body to cope with physical stresses such as surgery or illness, you should always tell your doctor, dentist or any paramedical person treating you if you have taken steroids over the previous 12 months. You should never stop steroids suddenly unless advised to do so by your doctor.
3. Immunosuppressive Drugs
These drugs work by suppressing the activity of the body's immune system. They were initially developed for use in transplantation and cancer treatment. Only a minority of IBD patients with more severe disease (more commonly Crohn's disease) need to take an immunosuppressive drug. The rationale behind their use is to suppress the immune system so that it is unable to mount an inflammatory response in the gut, but not so much that it is unable to defend the body against infections.
3.1 Azathioprine (Imuran®) and 6-mercaptopurine (6-mp,
Azathioprine has been shown to control difficult Crohn's disease and ulcerative colitis, and to prevent flare-ups of both diseases. It has a "steroid sparing" effect, allowing the dose of steroids to be reduced to a level that is less likely to cause side-effects. It is less commonly used in ulcerative colitis which can be cured by surgery. Azathioprine may take up to 6 months to have an effect.
3.1.1 Side-Effects of Azathioprine and 6mp
Other side-effects of azathioprine include nausea, loss of appetite, fever, rashes, inflammation of the liver and abdominal pain due to inflammation of the pancreas (pancreatitis). Approximately 10% of individuals are unable to continue taking azathioprine because of side-effects. However, they all resolve when the drug is stopped and, unlike corticosteroids, both drugs can be stopped immediately.
Transplant patients who take azathioprine or 6-mp for prolonged periods of time have an increased risk of developing certain cancers. Although this is a theoretical concern, there has not been an increased rate of these cancers in IBD patients taking these drugs.
There have been encouraging reports of a beneficial effect in severe active ulcerative colitis. It may allow some patients who are not responding to intravenous injections of corticosteroids to avoid surgery. However, it is not yet known how long-lasting this effect will be. There is also some evidence that it may help some patients with severe Crohn's disease. It is very expensive and is usually used when other medical therapies have failed.
Cyclosporin is a relatively toxic drug with a number of side-effects, many of which are more likely when blood levels of the drug are high. Regular blood level measurements are essential. Side-effects include high blood pressure, impaired kidney function, susceptibility to infection, nausea, loss of appetite, facial hair, tremor, pins and needles or numbness of the fingers and toes, headaches, gum swelling and epileptic seizures (fits).
3.3 Methotrexate (Ledertrexate®, Methoblastin®)
4.1 Metronidazole (Flagyl®)
The most common side-effects are nausea and loss of appetite, indigestion, a metallic taste in the mouth, diarrhoea and headache occur less frequently. Prolonged treatment with metronidazole can damage the nerves in the feet and arms, leading to tingling and numbness. This is reversible on stopping the drug but may take some months to return to normal. Some people have an unpleasant reaction to alcohol (flushing of the face, headache, palpitations, nausea, shortness of breath and drowsiness) while they are taking metronidazole. It is probably best to abstain from alcohol.
Tinidazole (Fasigyn®), a closely related antibiotic, has
fewer side-effects but has not been evaluated in patients with
IBD. There are a number of research projects in progress which
are evaluating other antibiotics for Crohn's disease.
B. NON-SPECIFIC DRUGS
5. Anti-diarrhoeal Drugs
These drugs should not be used in children or in a severe
attack of colitis, when they may cause the bowel to enlarge and
burst. They can be useful to control diarrhoea during milder
attacks of IBD, or in patients who have diarrhoea even though
their disease is inactive. The main side-effect is constipation.
Other side-effects are unusual, although probably more common
with codeine phosphate than with loperamide and Lomotil.
Drowsiness, headache, mood changes and skin rashes can occur.
Lomotil contains atropine, which can cause a dry mouth, blurred
vision, palpitations and difficulty passing urine, but usually
only when larger amounts are consumed.
6. Bile Salt Binders
Cholestylamine (Questran®) and colestipol (Colestid®
Cholestylamine (Questran®) and colestipol (Colestid®) are
two drugs that bind to bile salts, preventing them from causing
diarrhoea. Their most frequent side-effects are constipation,
abdominal discomfort and abdominal distension. Heartburn, nausea
and loss of appetite can also occur. They can also interfere with
absorption of food (in which case diarrhoea may be worsened) and
other medications. Both are powders which are dissolved in fluid
before consumption. Many patients find their taste unpleasant.
7. Analgesics (Pain Killers)
Pain most commonly occurs during a flare-up. The best treatment is to suppress the activity of the disease using one of the specific drugs already discussed. However, it is perfectly safe to use common analgesics such as paracetamol or mixtures of paracetamol and codeine (eg. Panadeine® and Panadeine forte®) for a short time to relieve pain. It is probably best to avoid aspirin which can cause damage to the stomach.
A minority of IBD patients have more persistent pain. Regular
analgesics can be helpful but it is important to discuss your
symptoms with your doctor as this sort of pain may be caused by a
complication which requires specific treatment.
8. Vitamins and Minerals
The most important is the use of regular vitamin B12 injections in some patients with Crohn's disease. Vitamin B12 is essential for blood formation and for nerve and brain function. It is absorbed from the lower part of the small bowel, the terminal ileum, a common site of Crohn's disease. If there is extensive Crohn's disease of the terminal ileum or if a significant length of terminal ileum has been surgically removed vitamin B12 absorption is compromised. The body has enough vitamin B12 in the liver to last 3 years but eventually deficiency causes anaemia or symptoms of nerve dysfunction such as tingling of the arms and legs. Deficiency is detected by a blood test to measure vitamin B12. If you develop vitamin B12 deficiency you will need to have an injection of vitamin B12 every 3 months for the rest of your life.
Most other vitamins and minerals are absorbed in the upper
part of the small bowel, which is less commonly affected by
Crohn's disease. However, a few individuals with extensive
disease or surgery require supplements, most commonly iron or
folic acid. Iron supplements may also be necessary in patients
who have bled from the bowel. Iron tablets cause the bowel
motions to turn black. They can also cause indigestion and
nausea. Some patients with extensive Crohn's disease absorb fat
poorly, particularly if they are taking bile salt binders. They
may require supplements of fat-soluble vitamins (vitamins A, D or
K). For further information refer to the AGI/ACCA publication Nutrition,
Diet and Inflammatory Bowel Disease.
9. Unconventional Therapies
10. Drug Treatment and Pregnancy
Flare-ups occurring during pregnancy should be treated aggressively, usually with corticosteroids, to bring the disease under control as quickly as possible. Enemas, foams or suppositories may be safer as the amount of steroid absorbed into the body is very small.
It is probably preferable not to conceive or carry a child while taking azathioprine but there is no evidence of an increased rate of abnormalities among children of male or female IBD patients taking this drug. There is very little information on methotrexate or cyclosporin, therefore they should not be taken during pregnancy. Anti-diarrhoeal agents (Ioperamide, Lomotil®, codeine) should be used with caution at all times. Dependence of the new-born and respiratory depression are possible side-effects of these agents.
If you are concerned about taking any of the drugs that may be
necessary for a flare-up during pregnancy, please do not hesitate
to discuss any issues with your doctor. For further information
refer to the AGI/ACCA publication, Inflammatory Bowel Disease,
a Guide to Sex, Fertility and pregnancy.
Further Patient Information Sheets & Updates at:- http://www.nevdgp.org.au/tbbase.htm