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Gut. 2007 August; 56(8): 1133.
PMCID: PMC1955490

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Opiate‐receptor blockade as therapy for Crohn's disease?

[filled triangle] Smith JP, Stock H, Bingaman S, et al. Low‐dose naltrexone therapy improves active Crohn's disease. Am J Gastroenterol 2007;102:820–8.

The search for new treatments in Crohn's disease never stops. Endogenous opiates are known to influence both growth and immunity, and Met5‐enkephalin has effects on a number of immune effector cells. Low‐dose naltrexone can produce intermittent blockade of opioid receptors, resulting in a rise in tissue levels of Met5‐enkaphalin and endorphins. Naltrexone has been used to aid healing of corneal abrasions and is known to block tumour necrosis factor (TNF)‐α synthesis. Stimulators of μ‐opioid receptors reduce inflammation in the trinitrobenzenesulphonic acid (TNB) colitis model in mice.

The authors designed a prospective, pilot study of low‐dose naltrexone (4.5 mg at night, compared with the usual 50 mg dose used in alcohol or opioid abuse) given for 12 weeks to a group of 17 patients with moderate to severe active Crohn's disease (Crohn's Disease Activity Index (CDAI) score >220). Most patients had previously received infliximab, but not for at least 8 weeks prior to the study. Other medications for Crohn's disease were kept stable during the study (47% were taking immunomodulators and 24% were taking corticosteroids).

Within 4 weeks, there was a significant fall in CDAI score, which was sustained throughout the study and still evident at 4 weeks after cessation of treatment. Eighty‐eight percent of patients responded to treatment (ie a fall in CDAI score of 70 points from baseline) at both 8 and 12 weeks. At 8 weeks 53% were in remission and at 12 weeks 47% were in remission (CDAI score <150). By 4 weeks after stopping treatment 33% remained in clinical remission. Both diarrhoea and pain scores improved independently during the study; quality of life (Inflammatory Bowel Disease Questionnaire and SF‐36 questionnaire scores) and inflammatory markers (C‐reactive protein and erythrocyte sedimentation rate) also improved. Low‐dose naltrexone certainly appears to cause more than a simple reduction in bowel motility. The treatment appeared safe and the commonest side effect was sleep disturbance (mainly insomnia), noted in seven patients.

Within all the usual limitations of interpreting open‐label, uncontrolled, pilot studies, the concept of low‐dose opiate receptor blockade seems to be a treatment worthy of further study in larger, double‐blind, placebo‐controlled studies.

Proton pump inhibitors for gastrointestinal bleeding: getting the timing right

[filled triangle] Lau JY, Leung WK, Wu JCY, et al. Omeprazole before endoscopy in patients with gastrointestinal bleeding. N Engl J Med 2007;356:1631–40.

A systematic review suggested that proton pump inhibitor (PPI) therapy reduces the risk of re‐bleed and surgery, but not mortality, when administered after a peptic ulcer bleed (Leontiadis et al. In: Cochrane Library. Issue 2. Oxford: Update Software, 2007). Many clinicians have extrapolated these findings to give PPI therapy for any gastrointestinal bleed before the cause is known, in the hope that earlier acid suppression will lead to better outcomes. Lau et al have tested this hypothesis in a randomised, controlled trial. Patients not taking low‐dose aspirin with haematemasis or melaena, that were either not in shock on admission or were stabilised with volume resuscitation, were randomised to intravenous PPI or placebo. Six hundred and thirty‐eight patients were randomised (319 in each group) and 60% were found to have a peptic ulcer bleed at endoscopy.

The PPI group had fewer actively bleeding ulcers at endoscopy (6% vs 15%) and a greater proportion spent less than 3 days in hospital (60% vs 49%). However, there were no statistically significant differences between the groups in transfusion requirements, re‐bleeds, surgery or mortality — findings identical to the first large trial of PPIs in gastrointestinal bleeding (Daneshmend et al. BMJ 1992;304:143–7). The authors conclude that PPI therapy should be given early in gastrointestinal bleeding on health economic grounds.

This is another excellent study from the Hong Kong group but caution should be used in interpreting the results. There were no differences in the clinically important secondary end‐points. The proportion of bleeds that were due to peptic ulcers was much higher than seen in most developed countries. Finally, previous systematic reviews have suggested that PPIs perform better in peptic ulcer bleeds in Asian studies compared with other countries (Leontiadis et al. In: Cochrane Library. Issue 2. Oxford: Update Software, 2007). Data suggest that PPIs do ameliorate peptic ulcer bleeding: the jury is still out on when the most cost‐effective time to give these drugs is.

Plus ça change, plus c'est la même chose

[filled triangle] Alves A, Panis Y, Bouhnik Y, et al. Risk factors for intra‐abdominal septic complications after a first ileocecal resection for Crohn's disease: a multivariate analysis in 161 consecutive patients. Dis Col Rectum 2007;50:331–6.

If surgery is to be a realistic alternative to the medical management of terminal ileal Crohn's disease, predicting those who are likely to do badly with surgery is clearly important. Alves and colleagues looked to identify predictive factors of postoperative intra‐abdominal septic complication in patients undergoing ileocaecal resection. From 1984 to 2004, 161 consecutive patients underwent, as a first operation, an elective ileocaecal resection without temporary stoma.

Fifteen patients (9%) developed abdominal septic complications, including abscess and anastomotic leaks. Multivariate analysis found only four independent factors associated with a higher risk of postoperative intra‐abdominal septic complication: poor nutritional status (OR 6.23 (CI 1.75 to 22.52)); intra‐abdominal abscess discovered during surgery (OR 7.47 (CI 1.5 to 37.69)); preoperative steroids use for more than 3 months (OR 5.95 (CI 1.04 to 34.1)); and recurrent clinical episodes of Crohn's disease (OR (per episode) 1.38 (CI 1.03 to 1.9)).

These factors are clearly recognisable as risks by any surgeon who is familiar with operating on Crohn's disease. However, the authors also show that the risk of sepsis is cumulative, with a 100% likelihood of sepsis if all four factors are present. Perhaps more importantly, the other clear message here must be that prolonged, unsuccessful medical treatment, in particular steroids, leading to fistula and/or abscess, and poor nutritional state is no substitute for early surgery. Indeed, one might argue that prolonged unsuccessful medical treatment may at least in part contribute to the reputation for high complication rates following surgery for Crohn's disease.


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