Our EPISOD research project finishes after 9 years.

Our EPISOD research project finishes after 9 years.

 

This one is medical, but I will try to make it intelligible. EPISOD stands for “Evaluating Predictors and Interventions in Sphincter of Oddi dysfunction”. That pesky sphincter described by Mr Oddi is the valve that controls the flow of juices from the liver and pancreas into the small intestine (duodenum). If it overacts it can cause biliary pains or even pancreatitis because the duct pressure is increased. Biliary pains are more likely to occur in patients who have had the gall bladder removed (cholecystectomy) since they no longer have a reservoir that can accept the back-up of bile to reduce the pressure. This condition is called “sphincter of Oddi dysfunction” (SOD).

Thousands of such patients are seen each year by Gastroenterology specialists. When physical causes like bile duct stones or even tumors have been excluded by scanning, patients are usually investigated by ERCP (Endoscopic Retrograde CholangioPancreatography). This means passing a flexible endoscope through the mouth and into the duodenum, finding the sphincter and injecting dye to take x-rays of the ducts. It is possible also to measure the pressure in the sphincter (manometry). When the clinical suspicion for SOD is high, the sphincter can be cut (sphincterotomy) to prevent the rise in pressure which causes the pain. Sounds logical so far I hope. The devil is in the details.

Patients with “suspected SOD” vary. Some have findings on investigation that show that the biliary sphincter is overacting, ie the bile duct is bigger than it should be on scanning, and/or the liver blood tests are elevated. Patients with both these findings are labeled SOD type 1, those with only one SOD type II. Those whose tests are all normal but whose pains are impressive and sound “biliary” are called SOD type III.

We know from previous research and long practice that patients with SOD type 1 usually respond to cutting the sphincter at ERCP (biliary sphincterotomy). Some of the type II patients also respond, but not all. Some evidence suggests that the pressure measurements taken at ERCP help to show who will get better. Whether sphincterotomy helps patients with type III has been the most controversial area. Research to date has relied on simple “cohort studies” in which patients are treated and then followed to see how they do. They have suggested that half to two thirds of such patients benefit. There are several problems with such studies. They are usually done by the treating specialists (ie “believers”) on patients are desperate for help and anxious to please. Some of the apparent benefit may be due to all the nice attention (placebo effect). We know that the results of invasive interventions such as ERCP or surgery often appear less good when assessed by independent observers. Definitions of benefit have also varied widely, and may include “improved”. Improvement is not to be dismissed but we know that some patient’s symptoms improve with time without specific treatment.

A very important fact in this discussion is that ERCP intervention in these patients (usually healthy youngish women) is risky. At least 15% develop acute pancreatitis immediately after ERCP. Most recover in a few days, but some linger in hospital for weeks or months and a few have succumbed.

Working in one of the centers (Medical University of South Carolina) recognized for special interest in SOD, I was seeing more and more of these patients. I became concerned that we did not have enough evidence on which to decide which patients to offer the ERCP treatment.

The gold standard method for discovering whether a treatment works is the “sham-controlled randomized trial”. Patients (with their full knowledge and agreement) get the active treatment or a pretend “sham” treatment by random draw (by computer). Most important, the patients and the people caring for them and assessing their progress are “blinded”, ie they do not know if the treatment has been active or sham. We decided that we needed to do such a study in patients with SOD type III, the most controversial group, and were lucky to land a $6m grant from the National Institute of Health in 2007.

MUSC was the lead site, but patients were recruited in another 6 expert centers in the USA. We enrolled 214 patients in the EPISOD study, all with bad biliary type pains having previously had a cholecystectomy. They all got ERCP, but only those allocated to active treatment had a sphincterotomy. We followed them by phone initially for one year. We defined “success” as a marked reduction of their burden of pain as measured at 9 and 12 months, without needing another ERCP treatment.

The results were published in the prestigious Journal of the American Medical Association in 2014. It was not a big surprise that 37% of the patients with no treatment (sham) were successful, since that is about the usual figure for a placebo response in medical and surgical studies. What was startling was that only 23% of the actively treated patients were successful!

The grant funding allowed us to keep track of the patients for 3-5 years, and we recently showed that the outcomes were consistent. Sham treated patients were still doing better.

A lot of additional useful information came out of the study. For instance we could (unfortunately) not find any difference between the clinical characteristics of the success and failures, the pressure measurements were not predictive, and we (sadly) confirmed that ERCP is risky. 15% of patients in both groups developed pancreatitis, and one suffered a perforation needing surgery. None died.

Publication of these results has had a major impact on expert opinion and clinical practice, as we reviewed in detail recently for the Rome Foundation, an international body advising on “functional digestive disorders”. We recommended dropping the term SOD type III. The patients certainly exist, but they do not have “SOD” since cutting the sphincter does not help. Better now for the moment to call it “unexplained biliary pain”. Our hope is that our work will open minds to look at more effective and safer ways to help these unfortunate people who are often disabled with pain.

So, this research funding finishes at the end of this month. That does not mean that we will not continue to work hard in the same and related areas. We have pilot studies in SOD type II, and have applied for research grants to extend them and to explore the value of cholecystectomy for so-called “Gall bladder dyskinesia”, an equally controversial condition.

It has been a fun and fulfilling 9 years. My sincere thanks to all the many collaborators and contributors, not least Dr Valerie Durkalski-Mauldin, leader of the Data Coordination Unit at MUSC (and to anyone who has read this far!).

I am attaching two key references for anyone who wants to dig deeper.

 

Rome IV. Gallbladder and Sphincter of Oddi Disorders.

Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari ES.

Gastroenterology. 2016; 150:1420-1429 PMID: 27144629

 

Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial.

Cotton PB, Durkalski V, Romagnuolo J, Pauls Q, Fogel E, Tarnasky P, Aliperti G, Freeman M, Kozarek R, Jamidar P, Wilcox M, Serrano J, Brawman-Mintzer O, Elta G, Mauldin P, Thornhill A, Hawes R, Wood-Williams A, Orrell K, Drossman D, Robuck P.

JAMA. 2014 May;311(20):2101-9. doi: 10.1001/jama.2014.5220. PMID: 24867013

 

4 Responses

  1. Nicky Richardson says:

    Well done, Dad, very interesting.

  2. Ann Procter says:

    Cor ! What a huge effort. Evidence of placebo effect very interesting too.
    XX Ann

    • Geoffrey Gibson says:

      Thx. Peter interesting result but not unexpected Thr placebo effect is also of note and again confirmed the importance of placebo in clinical medicine and appropriate clinical trials. Geoffrey Gibson

  3. Ian L Taylor says:

    This was a very important study Peter. You are to be congratulated for providing a scientific basis for the care of this very troublesome and difficult condition. You deserve great credit for convincing the NIH to fund this large clinical study. Best, Ian

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