Azathioprine or 6-mercaptopurine for the treatment of active Crohn's disease

Prefontaine E, MacDonald JK, Sutherland LR

Published Online:

September 8, 2010

Azathioprine and 6-mercaptopurine may be effective for inducing remission in Crohn's disease among patients with chronically active disease. These drugs may reduce the need for steroid treatment and their use may therefore lead to a lower incidence of steroid related side effects. However, these drugs are slow acting and are associated with some rare, but serious side effects. In some patients they suppress formation of blood cells that fight off infection and allow blood to clot and they occasionally cause inflammation of the pancreas. These drugs have also been associated with an increased risk of lymphoma. For these reasons careful consideration needs to be given to the use of these drugs as the primary treatment for patients experiencing an acute flare of Crohn's disease.

Abstract (click to read)

Background:

The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting and controversial. A meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.

Objectives:

To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.

Search strategy:

Studies were selected using the MEDLINE database (1966 to July 2009), abstracts from major gastrointestinal meetings and references from published articles and review. The Cochrane Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. This search strategy was updated using the MEDLINE, EMBASE and the International Pharmaceutical Abstracts databases as well as the Cochrane Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.

Selection criteria:

Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with active Crohn's disease were selected for inclusion.

Data collection and analysis:

Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel.

Main results:

Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. The odds ratio (OR) of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.43 (95% CI 1.62 to 3.64). This corresponded to a number needed to treat (NNT) of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the OR was 2.06 (95% CI 1.25 to 3.39). Treatment of > 17 weeks resulted in an OR of 2.61 (95% CI 1.69 to 4.03). A steroid sparing effect was seen with an OR of 3.69 (95% CI 2.12 - 6.42), corresponding to a NNTof about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased with active therapy with an odds ratio of 3.44 (95% CI 1.52 to 7.77). The NNT to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.

Authors' conclusions:

Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. Adverse events were more common among patients on active therapy.

This record should be cited as:

Prefontaine E, MacDonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD000545. DOI: 10.1002/14651858.CD000545.pub3

Assessed as up to date:

July 31, 2009

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Primary Review Group:

Inflammatory Bowel Disease and Functional Bowel Disorders Group

PEARLS - Practical Evidence About Real Life Situations (click to read)

Clinical question:

Are antidepressants effective for neuropathic pain?

Bottom line:

Both tricyclic antidepressants (TCAs) and venlafaxine provide relief of neuropathic pain (NNT*= 3.6 and 3.1 respectively). This effect is independent of any effect on depression. There is very limited evidence that selective serotonin reuptake inhibitors (SSRIs) may be effective but numbers of participants were insufficient to calculate robust NNTs. *NNT= number needed to treat to benefit one individual.

Caveat:

The NNH* for major adverse effects, defined as an event leading to withdrawal from a study, was 28 for amitriptyline and 16.2 for venlafaxine. The NNH for minor adverse effects such as drowsiness, dizziness, dry mouth and constipation was 6 for amitriptyline and 9.6 for venlafaxine. *NNH = number needed to treat to cause harm in one individual.

Context:

Neuropathic pain can be very disabling, severe and intractable, causing distress and suffering for individuals, including dysaesthesia and paraesthesia. For many years antidepressants have been used to manage neuropathic pain, and are often the treatment of first choice. It is not clear, however, which antidepressant is most effective, what role the newer antidepressants, such as SSRIs and venlafaxine, can play in treating neuropathic pain and what adverse effects are experienced by patients.

Cochrane Systematic Review:

Saarto T and Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Reviews 2007, Issue 4. Art No: CD0005454.DOI: 10.1002/14651858. CD0005454.pub 2. The review contains 61 trials involving 3,293 participants

Authored by:

Brian R McAvoy

Cochrane Primary Health Care Field

Health topics:

Gastroenterology > Inflammatory bowel disease > Crohn's disease: induction of remission

Cochrane Summaries^beta

Independent high-quality evidence for health care decision making

Azathioprine or 6-mercaptopurine for the treatment of active Crohn's disease

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