Gastrointestinal Endoscopy
Volume 69, Issue 6 , Pages 1117-1119, May 2009

Levitra for sphincter of Oddi dysfunction? Are you kidding?

Article Outline

Abbreviations: PT5I, phosphodiesterase type-5 inhibitor, SOD, sphincter of Oddi dysfunction

 

There are no clinical studies that investigated the effects of phosphodiesterase type 5 inhibitors on symptoms of sphincter of Oddi dysfunction.

In this month's Gastrointestinal Endoscopy, an article by Cheon et al1 entitled, “Effects of vardenafil on sphincter of Oddi motility in patients with suspected biliary sphincter of Oddi dysfunction” outlines a case-controlled study that demonstrated a decrease in sphincter of Oddi pressures as measured with biliary manometry after the administration of vardenafil (Levitra; Bayer Healthcare Pharmaceuticals, Montville, NJ), a phosphodiesterase type 5 inhibitor (PT5I). As I read the article, I thought of certain commercials I have seen and began to wonder: Do the investigators' findings mean that our patients with sphincter of Oddi dysfunction (SOD) will soon be sitting in outdoor bathtubs overlooking a lake? Or, as is shown in an even worse commercial, will they be desperately trying to wash their cars with a lawn sprinkler? Not so fast! We are all desperately seeking a medication to effectively relieve the symptoms in our patients with SOD, and this decrease in the sphincter of Oddi pressures is an interesting finding and likely a real response to the drug. But let us look at the facts and also the possible ramifications before we raid the sample cabinets in our nearby urology clinics.

First, at the present time, this is a physiologic finding only. There are no clinical studies that investigated the effects of PT5Is on symptoms in SOD (I did the Ovid database [Ovid Technologies Inc, New York, NY] search in mid September of 2008). So there is no basis for giving patients with SOD vardenafil, sildenafil, or any other PT5I at this time. Nevertheless, after reading about a decrease in the sphincter of Oddi pressures with vardenafil administration, it is tempting to “give it a whirl” in our patients with SOD. Sure, we can try it in our patients' off-label medications; it is “technically legal” to do so. But first take a good look at the list of adverse effects, then imagine trying to explain to one of these patients who is having an adverse effect that there are no studies to show that PT5Is have actually relieved symptoms in patients with SOD.

Moreover, even if we gave patients with SOD a trial of these medications and they said that it helped within the first few months, how do we know that it really helped? We scratch our heads when we see a beneficial placebo effect in up to 30% of the patients in some studies,2, 3 but when we realize how desperate these patients (and we) are to find symptom relief, it is easy to understand how some may convince themselves that they are having a positive outcome even though they are in the placebo arm.

Therefore, it is conceivable that we could start giving a PT5I to patients with SOD as an “empiric trial,” and some of the short-term “miracle cures” that follow could be reported anecdotally or in a small “select” series. Once that happens, you can bet that a pharmaceutical company executive knows what to do next. In short, not only is there no basis at this point for giving PT5Is to patients with SOD but to do so in any capacity other than in a well-designed, placebo-controlled study protocol may cause more confusion than clarity.

The public's perception of all this is also important to address. It is conceivable that individuals with SOD (or those who think that they have this problem) will come upon the information reported in the study by Cheon et al1 somewhere, somehow. “Googling” sphincter of Oddi dysfunction brings up some pretty interesting things, including blogs in which all sorts of remedies are discussed by people with various levels of medical knowledge. One of my favorites is at http://www.momathome.com.4 If you want a peek at what some of our patients with SOD are saying outside the examination room, check it out. You will find that one of our SOD heroes, Dr Glen Lehman, is mentioned in several places at that site, so it is pretty clear that many of these folks are reading or hearing about our journal literature. It is thus possible that someone will see this information about PT5Is in SOD somewhere and bring in the reference to their health care provider with the intent of getting a prescription. Perhaps they will have access to a patient with an erectile dysfunction medicine supply and try 1 or 2 pills during an episode of abdominal pain. The best way to minimize all of the above is to move as swiftly and as definitively as we can to determine whether PT5Is will effectively and safely treat the symptoms of SOD. It seems that simply repeating the study reported in this issue of Gastrointestinal Endoscopy would be the best next step.1 A project such as this is ideal for a group that does biliary manometry on a regular basis. It is the type of study question that we advise our trainees who are interested in research to seek, because a positive or negative result will provide valuable information and, therefore, will merit publication.

Wait a minute, you say. Do we want to start down this path? What about those adverse effects? Are we really going to have to learn what to do when we get the call from our patient who proudly announces that he has surpassed the 4 hours that he read about on the package insert? What kind of bizarre adverse effects might we be getting into here? Before our imaginations get too carried away, let us review the facts. Obviously, the adverse effects of PT5Is in men are infrequent enough that these drugs have been approved by the U.S. Food and Drug Administration, and it is pretty clear that since PT5Is have been available, the patient experience has included large numbers of men. We can also be reassured by our urology colleagues, who tell us that telephone calls like the one above are uncommon in their patients. Moreover, with proper patient selection and concurrent medication review, the serious adverse effects that we hear about, such as myocardial infarction and ischemic optic neuropathy, are quite uncommon.

As for the use of PT5Is in women, obviously, the experience is quite limited,5, 6 but it turns out that use in women with SOD might provide some interesting benefits in a roundabout way. The initial thought is that, if SOD symptoms are relieved by PT5Is, then prescribing these medications will somehow create situations reminiscent of those Hai Karate aftershave commercials. (I have provided a “YouTube” link7 for those of you who are too young to know what this means.) In fact, approximately 3000 women were studied to see whether Viagra could improve sexual function8; however, efforts were abandoned9 when studies did not demonstrate a perceived improvement of sexual behavior in women with a variety of sexual disorders.6 This was attributed to the complex nature of this behavior, so adverse effects of this nature are unlikely.

Interestingly though, Nurnberg et al5 studied women who were taking antidepressants and found that sildenafil treatment of these women reduced antidepressant-associated sexual dysfunction. Dr Heiman, one of the coauthors of that study, in an interview on National Public Radio,10 called for others to reproduce their results and emphasized how this phenomenon may reduce noncompliance among medicated patients with depression. The number of women patients who discontinue antidepressants because of medication-related sexual dysfunction is debatable. But it is interesting to wonder whether the combination of an antidepressant, which we sometimes give to our patients with SOD for pain control, and a PT5I might increase antidepression medication compliance and, in turn, accomplish better pain control. In these studies, the adverse effects from PT5Is in women appear to be minimal, such as headaches, flushing, rhinitis, nausea, and dyspepsia.5, 6 So, at first glance, it does not appear that the adverse-effects profile should prevent the pursuit of a well-designed clinical study of PT5Is in SOD.

These future studies will be interesting if the results of the study by Cheon et al1 are reproducible. They should be designed to use clearly defined study groups with enough patients so that the power of the study produces statistically meaningful results. Moreover, these investigations need to be long enough to let the placebo-effect phenomena described above extinguish. We also need to keep in mind that, for selected groups of patients with SOD, endoscopic sphincterotomy appears to be somewhat effective in relieving symptoms,11, 12 and it will be important to assess how any proposed medical therapy for SOD compares with this option. In this era of evidence-based medicine, we would also do well to design studies that meet criteria for a systematic review by organizations, eg, The Cochrane Collaboration, who reviewed our clinical investigations of SOD in the past.13 Having a safe, effective pill to treat patients with SOD would be great. For the time being, however, it is safe to say that we need to see a little more clinical data.

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Disclosure 

The author disclosed no financial relationships relevant to this publication.

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References 

  1. Cheon YK, Cho YD, Moon JH, et al. Effects of vardenafil, a phosphodiesterase type-5 inhibitor, on sphincter of Oddi motility in patients with suspected biliary sphincter of Oddi dysfunction. Gastrointest Endosc. 2009;69:1111–1116
  2. Brown WA, Dornseif BE, Wernicke JF. Placebo response in depression: a search for predictors. Psychiatry Res. 1988;26:259–264
  3. Dworkin RH, Katz J, Gitlin MJ. Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain. Neurology. 2005;65(Suppl 4):S7–19
  4. Sphincter of Oddi syndrome blog. Mom at Home Web site. Available at:http://www.momathome.com/2005/10/that_dang_sphincter_of_oddi_ag/. Accessed September 22, 2008.
  5. Nurnberg HG, Hensley PL, Heiman JR, et al. Sildenafil treatment of women with antidepressant-associated sexual dysfunction: a randomized controlled trial. JAMA. 2008;300:395–404
  6. Basson R, McInnes R, Smith MD, et al. Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther. 2001;27:411–420
  7. Hai Karate commercial video. YouTube Web site. Available at:http://www.youtube.com/watch?v=VAnU9zT87j4. Accessed September 22, 2008.
  8. Harris G. Pfizer gives up testing Viagra on women. The New York Times. Available at:http://query.nytimes.com/gst/fullpage.html?res=9906EED91E3CF93BA15751C0A9629C8B63. Accessed September 22, 2008.
  9. Mayor S. Pfizer will not apply for a licence for sildenafil for women. BMJ. 2004;328:542
  10. Silberner J. Study on Viagra for depressed women scrutinized. National Public Radio Web site. Available at:http://www.npr.org/templates/story/story.php?storyId=92809573. Accessed September 22, 2008.
  11. Toouli J, Roberts-Thomson IC, Kellow J, et al. Manometry based randomised trial of endoscopic sphincterotomy for sphincter of Oddi dysfunction. Gut. 2000;46:98–102
  12. Geenen JE, Hogan WJ, Dodds WJU, et al. The efficacy of endoscopic sphincterotomy after cholecystectomy in patients with sphincter of Oddi dysfunction. N Engl J Med. 1989;320:82–87
  13. Craig AG, Toouli J. Sphincterotomy for biliary sphincter of Oddi dysfunction. Cochrane Database Syst Rev. 2001;1:CD001509

PII: S0016-5107(08)02701-6

doi:10.1016/j.gie.2008.10.006

Gastrointestinal Endoscopy
Volume 69, Issue 6 , Pages 1117-1119, May 2009