On the day of my diagnosis, the gastroenterologist I was seeing at the time told me that I should totally avoid nonsteroidal anti-inflammatory drugs* (NSAIDs). She mentioned that this class of medications was not safe for Crohn's patients because they could cause the disease to flare. Acetominophen (which you probably know as the active ingredient in Tylenol), though, was considered a safe alternative therapy for general aches and pains. I imagine many Crohn's patients were given similar recommendations by their GI physicians at or around the time of diagnosis.
In many regards, it seems plausible that NSAIDs could cause trouble for Crohn's patients. NSAIDs definitely cause other GI problems, including stomach ulcers and colitis (remember colitis is the general term for colonic inflammation... but it can be inflammation due to anything, not necessarily inflammatory bowel disease), and there is a clear mechanism by which NSAIDs act to screw up the GI mucosal barrier (i.e. the protective lining of the GI tract). But what gives... just because a doctor says its true doesn't make it true... the scientific data need to support the claim. Thus, I have set out to investigate the research on NSAID use and Crohn's disease. And this week I am in luck (or maybe not), because there are a plethora of publications on this topic... so much so that I might have to make this a two-post series. I want to ensure that I look at enough published science so as to not be biased in my presentation.
An aside... evidence-based living
In my blog post from a week ago, I brought up the concept of evidence-based medicine (EBM) as the ultimate standard for clincal practice. In this post I am going to mention another concept that I made up based off of EBM... evidence-based living (EBL)... basically, trying to make personal decisions for my own health based on strong scientific research.
Now, this is somewhat of an impossible goal... to live one's life in accordance with scientific evidence. Everyone has their biases and quirks (including and especially me), and there is simply too much scientific literature out there to keep track of it all. But, if I know that the scientific data support or refute some sort of behavior, I try my best not to ignore those results. For example, I don't take a multivitamin anymore, because studies have generally shown either no benefit, or in some cases, even detrimental effects of their use (Dolara et al. 2012). Also, new evidence from the Women's Health Initiative* that calcium supplementation may do more harm than good has prompted me to stop taking so much Viactiv (Jackson et al. 2011)... but these data are from older individuals and other published results disagree with this study. A Swiss clinical trial actually showed that the risk of fractures was reduced in healthy individuals with calcium supplementation (Bischoff-Ferrari et al. 2008). This latter study, and the maintained hope for the potential benefits of vitamin D (and the fact that the caramel flavor is actually quite tasty... not the chocolate, which tastes like chalk), have kept me taking the occasional Viactiv chew. (An important note... I would like to be clear that these studies for multivitamin and calcium supplementation are specifically for supplementation on top of a normal diet. Clearly, vitamins and minerals are important when consumed in foods as part of a healthy diet. The major question with these research trials is whether or not there is added benefit to taking vitamins and minerals as pure-ish compounds in amounts above what is in the normal diet). So, getting back to NSAIDs, my EBL intention is to make my personal decision about NSAID use based on the scientific evidence on the matter.
So how did this whole story about NSAIDs and Crohn's get started anyway?
Some of the first possible links between NSAID use and Crohn's exacerbations came in the form of case studies* stating that four individuals taking NSAID had their IBD flare up (Kaufmann and Taubin. 1987.). In addition to only being putative associations, in my opinion, several of the first supposed cases of NSAID use and Crohn's exacerbations are pretty weak. One patient had a diagnosis of Crohn's and was supposedly in remission for three years, when on one fateful day he was given the NSAID indomethacin for sciatica. Twenty-four hours later he developed bloody diarrhea, and then had a flexible sigmoidoscopy that revealed 60 cm of uniform colitis. Really, indomethacin was the cause of this guy's exacerbation? With 60 cm of uniform inflammation, isn't it more likely that he had active Crohn's disease that had been going for a long time? It seems possible to me that he maybe had some increased GI bleeding due to the indomethacin (NSAIDs are also well-known inhibitors of blood clotting... this is why "baby" aspirin is prescribed for the prevention of cardiovascular disease), but it seems unlikely that this single dose of medication played any role in his significant inflammation. Thus, I would generally say interpret case "studies" with a grain of salt; they shouldn't result in significant shifts in clinical practice recommendations, but may point out the need for controlled studies on the subject.
For what it's worth, there were a couple other case reports from the 1980s suggesting an association between exacerbations of ulcerative colitis (the other major form of IBD) and NSAIDs (Rampton et al. 1981., Rampton et al. 1983.)... neither of the others discuss Crohn's disease. Just want to mention that this sort of questionable association from my previous paragraph wasn't the only case report mention linking NSAIDs and IBD.
The other side of the NSAID coin (or pill)
Given that NSAIDs are part anti-inflammatory, it also seems conceivable that they could be beneficial in Crohn's disease. Crohn's disease is over-activation of the immune system (see my previous blog post for a more detailed explanation on the mechanisms of Crohn's), and if NSAIDs could suppress this inflammation, then they could inhibit disease activity. Unfortunately, the immune system is not quite so straightforward--there are many arms of it, and inhibiting one side could shift the balance too much toward the other, etc. Also, NSAIDs have a lot of effects other than just being anti-inflammatory. But, the potential benefit for NSAIDs in IBD was at least considered in some earlier publications (Campieri et al. 1980., Rask-Madsen et al. 1990.). In the end, though, NSAIDs don't work as Crohn's treatment and are not indicated for IBD therapy.
NSAIDs and Crohn's incidence
There are a few studies that have looked at the relationship between NSAID use and the development of inflammatory bowel disease (IBD). One cohort study* showed that there was a small (and I mean small) increase in the incidence (number of new cases in the population) of Crohn's disease and ulcerative colitis in women who were frequent NSAID users (Ananthakrishnan et al. 2012.)... fyi, the authors of this study defined frequent use as greater than 15 days per month. Now, this does not prove any sort of causal link between NSAID use and IBD. To borrow an analogy from Stephen Dubner, author of Freakonomics, just because a lot of people carry umbrellas on a rainy day does not mean umbrellas caused it to rain. Similarly, high NSAID use does not necessarily cause IBD. An alternative explanation might be that women with IBD experience more pain from their disease, and, therefore, take more NSAIDs. Also, this study showed no association between low NSAID use and IBD.
To be continued...
Due to the depth of this topic, it does seem deserving of more attention and justice than I can humanly summarize in a single blog post. Thus, next week I will continue this subject with the scientific data on NSAIDs and Crohn's flares and on the potential differences between COX-1 and COX-2 inhibitors (and any other important NSAID-related matters I find in the meantime). I will also weigh in on my own EBL decision about the use of NSAIDs. So please check back next weekend for more!
Bibliography:
Ananthakrishnan et al. (2012) Asprin, nonsteroidal anti-inflammatory drug use, and risk for Crohn's disease ulcerative colitis: a cohort study. Annals of Internal Medicine 156:350-359.
Bischoff-Ferrari et al. (2008) Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial. American Journal of Clinical Nutrition 87:1945-51.
Bjamason et al. (1988) Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures. Gastroenterology 94:1070-1074.
Dolara et al. (2012) Antioxidant vitamins and mineral supplementation, life span expansion and cancer incidence: a critical commentary. European Journal of Nutrition Jun 9 [Epub ahead of print].
Jackson et al. (2011) Calcium plus vitamin D supplementation has limited effects on femoral geometric strength in older postmenopausal women: the Women's Health Initiative. Calcified Tissue International 88:198-208.
Kauffman et al. (1987) Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Annals of Internal Medicine 107:513-516.
Rampton et al. (1983) Analgesic ingestion and other factors preceding relapse in ulcerative colitis. Gut 24: 187-189.
*Some more specific terminology explanations:
Case study: The more preferable term to refer to a case study might actually be "case report" because "study" is sort of a misnomer, at least in terms of how these reports are used in the biomedical literature, in my opinion. Case reports are basically descriptive or explanatory articles (i.e. published papers) on a single or small group of patients that have an interesting/unusual/rare medical issue. They enable physicians to share patient cases that might have greater relevance or may establish a potential interesting disease association (e.g. NSAIDs and Crohn's)... but this putative association will need to be investigated in larger, controlled studies.
Cohort study: This is a particular type of research study in which a large group of people without a particular disease are followed over time to see if they develop the disease. Then, basically, the researchers go back to see what kind of risk factors (e.g. smoking, dietary habits, etc.) might be present in those individuals who developed the disease of interest. These studies are purely correlational... they do not prove that the risk factor caused the disease.
Nonsteroidal anti-inflammatory drugs (NSAIDs): This is a class of medications that provide analgesic (pain relieving), anti-pyretic (fever reducing), and, at high doses, anti-inflammatory effects. Many of these medicines are available over the counter, and, chances are, most of you have taken them at some point in your lives. Common examples are aspirin, ibuprofen, and naproxen. The "NS" or "nonsteroidal" part of NSAIDs distinguishes these drugs from the steroid class of anti-inflammatory medications... steroids being a common class of anti-inflammatory drugs prescribed for a host of autoimmune diseases, including Crohn's disease. NSAIDs are the most prescribed of the anti-rheumatic drugs (i.e. drugs prescribed for arthritis), which suggests that they are very efficacious as anti-inflammatory analgesics (Takeuchi et al. 2006.).
Women's Health Initiative (WHI): The WHI is a program started by the NIH (see previous post for information about the NIH) in order to investigate the major health problems in older women. Some of the major WHI study topics include cardiovascular disease, osteoporosis, and cancer.
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