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Chronic Pancreatitis

What is pain like in chronic pancreatitis? Hereís a study from South Africa which, if you just focus on the patients, out of the 172 with chronic calcific pancreatitis due to alcohol: 80 with pain, roughly, and you can see that only a very small minority had persistent chronic pain. That most patients have recurrent or relapsing attacks of pain as the major manifestation of their painful pancreatitis. Out of 207 with again alcoholic chronic pancreatitis.

Everybody has intermittent pain but generally this is short-lived and they will often go months to years without any pain. In almost half of the patients, this is the only pattern of pain. These patients did not require surgery. Fifty-six percent of their cohort developed constant pain as defined here, needed an operation, but the operation typically revolved around correction.

Either pseudocysts or cholestasis in the late phase. And this did lead to pain relief. The argument here that persistent pain complicating chronic pancreatitis should suggest a complication. This is the classic work, again from Amman, that shows the natural history of alcoholic chronic pancreatitis, is that a lot of patients - what percentage is not known - will have cessation of pain and that generally correlates with the onset of pancreatic failure. As measured by calcification, steatorrhea or diabetes. This is a somewhat contentious point but I think that thereís at least some hope that in the natural history that the disease will take care.

Well, what about our experience? This is the study that came out a few years ago in Gastroenterology looking at our cohort of patients. There are at least three groups of chronic pancreatitis: the alcoholic with an onset in their 40ís, and then really two groups with idiopathic chronic pancreatitis. An early-age onset group and a late onset pancreatitis. These groups differ based by the amount of pain that they have. That is, the early onset idiopathic pancreatiticís almost all present with pain. Much less frequently in this late onset group, so they might present with pancreatic failure and the alcoholics were somewhere in the middle. But itís really this group that we all struggle with the management. This just in graphic form shows that this early onset tends to have the more severe pain associated with their pancreatitis, as opposed to late-onset and the alcoholic chronic pancreatitis.

Importantly, in terms of the natural history, those early onset chronic pancreatitis patients take a long time to develop calcification, steatorrhea and diabetes so they are going to have many years, or decades of pain before you can realistically expect the pain to resolve. Now if you look again at those three groups, what happens to them historically, they all have about the same rate of pancreatic surgical procedures. Again, the other important thing here is that out here at 20-25 years only about half of the patients have needed a surgical procedure. But importantly again, in that early onset group the operation was done for pain alone.

What about pancreatic hypertension? We know that the ductal and tissue pressures are increased, and itís probably not just the duct. But really this is a compartment syndrome because of fibrosis, entrapment, ischemia, which then leads to pain. Importantly, there is really a poor correlation between the major duct findings, the amount of dilatation and pain. A study from Howard Reber in his cat model shows that, in his model, the pressure in the gland as measured by the interstitial pressure is high as is the duct pressure in his model. And then if you only stent the main pancreatic duct there is really a modest change in the pressure.

Now what about enzymes? I think itís based on the theory that secretion causes pain in this compartment syndrome and that there is a feedback regulation in the duodenum whereby proteases inhibit pancreatic secretion by digestion of a CCK releasing factor. Easy to prove in the rat, more difficult to prove in man but I think most people would agree that this operates at least at the extremes of physiology. Does it work to treat pain? This from a metaanalysis of all of the enzyme trials. Four of these studies were negative studies, two were positive. Importantly the four negative studies used enterically coated enzyme preparations. That you have to deliver proteases into the duodenum, which these would potentially not do. This is from that metaanalysis and this is the study from Florida. This is a Scandinavian study. These are the only two. In fact this is the only one which reached statistical significance. Overall there was no benefit, but again, these four studies used enterically coated enzymes. So I think the jury is still out but I think we typically use them because itís pretty benign therapy.

What about octreotide? You probably all know, there was a multi-center controlled trial, 91 patients. Importantly, the placebo response was 40% overall in this study, for painful chronic pancreatitis. There was no significant differences overall. There was a trend in the very highest group - 200 micrograms t.i.d. - 65% versus 35%. In an open label study there was 50% pain relief at six weeks, but again, remember the placebo response was 40%.

What about endoscopic stenting? Unproven, experimental. Again the morbidity has to do with damaging the duct. Now if someone already has chronic pancreatitis thatís an arguable point, I suppose, but certainly you can get into infectious complications with these procedures. This is a summary of the uncontrolled trials, and Iíll just say that the overall benefit approaches about 50%. And the difficulty in interpretation is the intermittent nature of the pain, which weíve shown from the previous studies, and the placebo response of 40% seen in a drug study.

What about taking stones out of the ducts? It looks very attractive. Itís technically feasible. Does that do anything to help pain? I think you are all aware of uncontrolled studies from a variety of groups looking at both shock wave lithotripsy as well as just endoscopic treatment. The pain relief, complete or partial, runs in the 50-60% range. This gets at the pain relief so that patients at the end of the study had not pain, but then if you look at the pain that they had before the trial started, a few - 10% - had no pain, so Iím not sure why they were getting the stones out, and you can see the majority of patients who had intermittent pain often had infrequent attacks. Given the natural history, how does one know without a controlled study, if you are really doing any good? In the Cramier study, those patients are in the hospital on average 14 days with this intervention. So again I think it is a therapy that is of unknown benefit. So I think to summarize, itís uncertain if it is beneficial. He would argue that the complications are unacceptable unless you are doing a study, and it should certainly be done only by very experienced endoscopists and probably only in large centers.

The other thing that complicates this whole field is the CFTR mutation finding and how does that impact on the idea that somehow the sphincter of Oddi may be important in these diseases, and I think itís going to take some time to sort through how this fits into the management.

Just briefly, what about missed diagnoses? Donít forget there are other causes for pain. IDMT, or intraductal mucin tumor, narcotic addition, other disorders. We certainly see patients whose pancreatitis is defined by an abnormal sphincter of Oddi measurement, and abdominal wall pain. This is a CT finding of IDMT which could mimic chronic pancreatitis. Donít forget that of course the risk of pancreatic cancer is higher in these chronic pancreatitis patients so that one has to be alert to the possibility that they may have developed a complicating carcinoma.