Systematic review: is ingestion of paracetamol or non‐steroidal anti‐inflammatory drugs associated with exacerbations of inflammatory bowel disease?

AIM: To examine the published evidence on the association between paracetamol or non-steroidal anti-inflammatory drugs and relapse in inflammatory bowel disease. METHODS: Medline searches were performed till June 2004 and Embase till April 2003. Abstracts published in Gut and Gastroenterology from 1999 to 2004 were hand-searched. Twenty-nine relevant abstracts and papers were identified. RESULTS: Twenty-two patients with relapse of inflammatory bowel disease following exposure to non-steroidal anti-inflammatory drugs have been described in case-reports. Four patients were re-exposed to non-steroidal anti-inflammatory drugs and relapsed again. Two had relapsed after taking a cyclo-oxygenase 2 inhibitor. One study described increased inflammatory activity and clinical relapse in some patients after challenge with naproxen or nabumetone. Fifteen epidemiological studies were identified. All had small sample sizes and many had methodological problems. Six studies found evidence for an association between non-steroidal anti-inflammatory drug use and relapse of inflammatory bowel disease, but the association was significant in only two. Three studies suggested a relationship between paracetamol use and exacerbations of inflammatory bowel disease. CONCLUSIONS: Non-steroidal anti-inflammatory drugs may precipitate a relapse in some patients with inflammatory bowel disease. This may be an idiosyncratic reaction. The published evidence does not support the view that non-steroidal anti-inflammatory drugs are important in inducing relapse of inflammatory bowel disease. There is weak evidence that paracetamol may be more important.     

Systematic review: coxibs,non‐steroidal anti‐inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high‐risk patients?

Selective cyclooxygenase-2 inhibitors have been marketed as alternatives of conventional, non-steroidal anti-inflammatory drugs with the purpose of reducing/eliminating the risk of ulcer complications. Unexpectedly, randomized-controlled trials revealed that long-term use of coxibs, such as rofecoxib, significantly increased the risk of myocardial infarction and stroke, while the use of valdecoxib was associated with potentially life-threatening skin reactions. Subsequently, rofecoxib and valdecoxib were withdrawn from the market. Although more strict precautions for other coxibs, such as celecoxib, etoricoxib, lumiracoxib and parecoxib, may be accepted/recommended by regulatory agencies, a critical review of published data suggests that their use may not be justified - even in high-risk patients - taking benefits, costs and risks into consideration. Clinicians should, therefore, never prescribe coxibs to patients with cardiovascular risk factors, and should only reluctantly prescribe coxibs to patients with a history of ulcer disease or dyspepsia to overcome persistent pain due to, e.g. rheumatoid arthritis or osteoarthritis. Instead, they should consider using conventional non-steroidal anti-inflammatory drugs in combination with a proton pump inhibitor or a prostaglandin analogue, especially for patients with increased cardiovascular risks, i.e. established ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease, or alternatively acetaminophen. An evidence-based algorithm for treatment of a chronic arthritis patient with one or more gastrointestinal risk factors is presented.     

Should we eradicate Helicobacter pylori in non‐steroidal anti‐inflammatory drug users?

The interaction between Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) in ulcerogenesis has been visited by many studies. Apparently these studies yielded conflicting results. This is a result of a wide diversity of methodology, selection of patient groups and definitions of outcome used by different investigators. This review attempts to analyse separately studies dealing with new or chronic NSAID users, primary or secondary prophylaxis, complicated or uncomplicated ulcers in NSAID or aspirin users. Evidence suggests that eradication of Helicobacter pylori infection may reduce the risk of ulcer and ulcer complications in patients requiring NSAIDs and aspirin. Whether or not one should test-and-treat H. pylori before prescribing NSAIDs is a complicated issue. Factors such as the ulcer risk of patients, previous history of NSAID usage and the use of aspirin or NSAIDs would guide the strategy.     

Aspirin for the prevention and treatment of pre‐eclampsia: A matter of COX‐1 and/or COX‐2 inhibition?

Since the 1970s, we have known that aspirin can reduce the risk of pre‐eclampsia. However, the underlying mechanisms explaining this risk reduction are poorly understood. Both cyclooxygenase (COX)‐1‐ and COX‐2‐dependent effects might be involved. As a consequence of this knowledge hiatus, the optimal dose and timing of initiation of aspirin therapy are not clear. Here, we review how (COX‐1 versus COX‐2 inhibition) and when (prevention versus treatment) aspirin therapy may interfere with the mechanisms implicated in the pathogenesis of pre‐eclampsia. The available evidence suggests that both COX‐1‐ and COX‐2‐dependent effects play important roles in the early stage of aberrant placental development and in the next phase leading to the clinical syndrome of pre‐eclampsia. Collectively, these data suggest that high‐dose (dual COX inhibition) aspirin may be superior to standard low‐dose (selective COX‐1 inhibition) aspirin for the prevention and also treatment of pre‐eclampsia. Therefore, we conclude that more functional and biochemical tests are needed to unravel the contribution of prostanoids in the mechanisms implicated in the pathogenesis of pre‐eclampsia and the potential of dual COX and/or selective COX‐2 inhibition for the prevention and treatment of pre‐eclampsia. This information is vital if we are to deduce the suitability, optimal timing and dose of aspirin and/or a specific COX‐2 inhibitor (most likely using modified forms that do not cross the placenta) that can then be tested in a randomized, controlled trial instead of the current practice of empirical dosing regimens.     

Can drug injectors be encouraged to adopt non‐injecting routes of administration (NIROA) for drugs?

Drug use by injection can cause problems specific to this form of administration. Problems include an increased risk of drug overdose, drug dependence, the transmission of HIV, hepatitis B and hepatitis C and vein damage. Shifting drug injectors from injecting to another route of administration may minimize these problems. The aims of the study were to develop and trial an intervention to assist willing injecting drug users (IDUs) to shift to non-injecting routes of administration (NIROA) and to explore the acceptability and practicality of facilitating NIROA. IDUs were assessed and suitable subjects entered a cognitive behavioural trial consisting of five 1-hour sessions of individual therapy with a registered psychologist. Forty-two subjects were assessed (22 males and 20 females). Thirty subjects entered treatment. The mean age was 36 years. Twenty-one subjects were followed-up at 3 months and 10 subjects at 6 months. At 3 and 6 months, the proportion of subjects who had commenced using NIROA was 30% and 50%, respectively. This pilot study showed that it was possible to assist a minority of drug injectors to move from injecting to the non-injecting administration of drugs. However, many of these appeared to be already motivated to cease using drugs and adopting NIROA was one way of assisting this. Poor follow-up rate, lack of control group, questions about cost-effectiveness and the impact of market factors which possibly constrain shifting to NIROA suggest that further research is needed before it could be said that NIROA should be recommended as a viable harm reduction strategy in the Australian context.     

Can biological markers act as non‐invasive,sensitive indicators of radiation‐induced effects in the gastrointestinal mucosa?

Background Reliable, non‐invasive biological markers of the severity of radiotherapy‐induced damage to the gastrointestinal tract are not available. Clinicians continue to use symptom scores as surrogate indicators of toxicity. Aim To determine whether levels of potential biochemical markers of mucosal toxicity change during pelvic radiotherapy. Methods Fifty‐nine patients (30:29 males:females) with mixed pelvic malignancies, receiving 45–70 Gy were recruited. At baseline and weeks 4 or 5 of radiotherapy, blood samples for citrulline, C‐reactive protein, eosinophil cationic protein and stool samples for faecal calprotectin were obtained. Symptoms were measured using the Inflammatory Bowel Disease Questionnaire – Bowel Subset, Radiation Therapy Oncology Group and Vaizey Incontinence Questionnaires. Paired t‐tests of change in marker values were calculated. Results Citrulline (P = 0.02) and faecal calprotectin (P = 0.01) values changed significantly between baseline and 4/5 weeks. Inflammatory Bowel Disease Questionnaire – Bowel Subset fell significantly (mean fall = 10 points, s.d.: 8.9). Changes in markers did not correlate with symptoms. Conclusions Some biochemical markers of mucosal toxicity change significantly during treatment. Further studies must investigate the timing of changes of these biochemical markers, their relationship to gastrointestinal physiological change and the radiotherapy dose delivered to the gastrointestinal tract and whether changes in markers acutely can predict the degree of long‐term gastrointestinal dysfunction.