CEimpact Podcast

Pancreatic Enzymes for Exocrine Dysfunction

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Exocrine enzyme dysfunction is far more common than many primary care practitioners realize. Using pancreatic enzymes can help with symptoms and vitamin absorption. Join host, Geoff Wall, as he reviews new guidelines on the appropriate use of pancreatic enzymes.
 
The GameChanger
Chronic pancreatitis is the most common cause of exocrine dysfunction in adults. All pancreatic enzymes are equally effective; however, the use of pancreatic enzymes to treat chronic pain is controversial.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Whitcomb DC, Buchner AM, Forsmark CE. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatic Insufficiency: Expert Review. Gastroenterology. 2023 Nov;165(5):1292-1301. doi: 10.1053/j.gastro.2023.07.007. Epub 2023 Sep 20. PMID: 37737818.

https://www.gastrojournal.org/article/S0016-5085(23)04780-7/fulltext
 
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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Discuss common symptoms and diagnoses associated with exocrine dysfunction.
2. Describe challenges associated with the use of pancreatic enzymes.

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-366-H01-P
Initial release date: 12/4/2023
Expiration date: 12/4/2024
Additional CPE details can be found here.

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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Hello and welcome to Game Changers clinical conversations. I am your host, jeff Wall. I'm a professor of pharmacy practice at Drake University and internal medicine clinical pharmacist at Iowa Methodist Medical Center. Welcome to our pod.

Speaker 2:

Today we are going to be talking about something that is a bit of a niche, but certainly something that I get questions about several times a year, and that's patients who have exocrine pancreatic insufficiency. So, for whatever reason, the extra and exocrine functions of the pancreas don't work anymore. And just in the last couple of weeks the American Gastroenterological Association came up with, I think, to my knowledge, the very first set of guidelines for this problem. And I because I've never suddenly read any guidelines before and there's always been a lot of questions about you know, when do you suspect it, how do you dose it?

Speaker 2:

As any pharmacist will tell you, pancreatic enzymes are about 15 different formulations. Insurances usually don't cover it, and if they don't, the patient will probably not be able to afford it, and et cetera, et cetera, et cetera. So I mean there are actually some pretty significant questions associated with this and, again, it isn't probably the most common disease state that the primary care practitioner pharmacist is going to run into but it is something that I, like, I see at least several times a year and get asked questions several times a year about it.

Speaker 2:

So I see these patients mostly with chronic pancreatitis.

Speaker 2:

So this is someone who's had pancreatitis over and over and over again to the point where they basically destroyed most of their pancreas and they essentially can't produce exocrine enzymes at that point of. As you might imagine, most of those patients have diabetes at that point because they've also knocked out all their beta cells. That's where I see these patients most commonly, but certainly that's not the only reason why patients develop exocrine insufficiency. The other, of course, is the big one that I don't see a ton of but my pediatric colleagues do, of course is cystic fibrosis. But some of the other things include pancreatic malignancy, where they say that the use of pancreatic enzymes in patients with pancreatic cancer is actually way underused and we should use it a lot more. And even in patients with bariatric surgery will sometimes develop exocrine dysfunction, depending on the surgical anatomy and kind of what happens. So it just kind of depends on a lot of that stuff and unfortunately a lot of these patients have overlapping issues that can kind of get confused with exocrine insufficiency, such as celiac disease. So it's an interesting disease state and, again, not the most common thing, but something that I think everybody runs into at least a couple of times a year.

Speaker 2:

These guidelines were pretty much your standard guidelines. They were approved by the AGA. They did do the standard formatting and reviews, so they did literature evaluation and stuff like that. They did not do their own systematic reviews, which is what the AGA and actually a lot of other medical organizations are doing nowadays for their official guidelines is they'll pull, you know, randomized control trials and do their own systematic reviews or meta-analyses to come up with their evidence. And unfortunately in this field there just aren't very many good randomized control trials. So they note that in their methods that because of that, they just basically took a look at best practice information and came up with best practice advice statements and so they looked at the literature, did their best to come up with a consensus of what the guidelines were. They did still give evidence based on the strength of the guidelines, based on the strength of the evidence. But they did not do and again, I think an increasing number of groups are doing which is basically doing their own kind of mini-men analyses on their recommendations to help guide what they're saying.

Speaker 2:

So they talk about the fact that this occurs in about one half of patients with chronic pancreatitis, and that's about what I think I've seen, again very common in cystic fibrosis, some other diseases as well. Chronic alcohol use then, of course, is one of the most common risk factors for developing excreta dysfunction, because that's the most common cause of pancreatitis. But they note that, again, other things such as pancreatic duct calcifications, diabetes, pancreatic malignancy and against cystic fibrosis all can lead to the excreta insufficiency. But the most common cause people are going to run into is chronic pancreatitis. They note that the more episodes of chronic pancreatitis, the higher the risk of excreta insufficiency, and they note that after several bouts of acute pancreatitis the risk is approximately 80-plus percent, and again, that's typically what I see. It usually occurs five to 10 years after the first incidence of pancreatitis and in cystic fibrosis it occurs much quicker. Smoking seems to accelerate the risk of excreta dysfunction, which I thought was kind of interesting, and so of course quitting smoking is good for this. There are 9,000 other things that we talk about and even though it's kind of beyond the scope of this pod, they note that, again, cf patients will have actual excreta insufficiency at birth. But again, we're going to focus and these guidelines, I think, are much more focused on adults than children with cystic fibrosis.

Speaker 2:

Symptoms of extraneous function unfortunately aren't the most pleasant to talk about, so I hope you're not eating when you hear this pod. But they unfortunately have to do with stool and so you know they talk about, you know, bloating gas, a steateria, which is super fatty stools, and that means that they're, that they float in the bowl and that they don't smell very good and stuff like that. Yeah, sorry, that's just kind of how I'm with the symptoms of, of, of, of pancreatic insufficiency, are they? They're gotten in the symptoms they list, flatulency. Didn't know that was a word, but apparently flatulency is a word. So, and we all know what that means, I won't, I won't belabor that, I think that's. You know that is distressing for patients and it can lead to abdominal pain. So I mean the bloating and abdominal pain that occurs with chronic angiotitis. At least part of it is associated with some of these symptoms.

Speaker 2:

But I think a little more seriously the other problem you run into is malabsorption. Again, if you're not secreting extra and enzymes, you're not absorbing, especially fat soluble vitamins. So many of these patients are deficient in ADE and K, also essential fatty acids, and even some studies suggesting that vitamin B12 deficiency is a little more common. So of course, because of that, you get all the issues associated with chronic enzyme or chronic vitamin deficiency. So you know patients with vitamin A and E deficiencies can develop, you know, visual problems, skin issues with vitamin A. You know neurologic things would be 12, coagulopathy would be E. Again, I'm not going to kind of belabor that, but the bottom line is that is that certainly something that is very serious so so X-ray dysfunction is, is particularly vitamin malabsorption.

Speaker 2:

Risk of osteoporosis, as you might expect in these patients, is quite high, not only because of X-ray dysfunction, but, again, many of these patients have chronic pancreatitis, probably aren't eating them. I write them out of calcium and vitamin D, so that's. That's another issue as well. So you know, yes, there are certainly GI issues associated with it and I certainly don't mean to downplay those. But the other, at least as important if not more important issue is the chronic vitamin malabsorption and deficiency.

Speaker 2:

How do we diagnose X-ray dysfunction?

Speaker 2:

Well, in the old days we used to do a fecal fat count, and so you do that by literally collecting 24 hours of stool and then measuring the fat in the stool, and I'm sure that was fun for everybody involved, from the patient who had to do it to the lab people who had to measure that.

Speaker 2:

However, they did that. That is no longer recommended and in fact the guidelines note specifically that the fecal elastase test is now the most appropriate initial test and should be performed on patients who you suspect have anachron dysfunction, x-ray dysfunction. So, again, patients with chronic pancreatitis who complain of some of these GI issues, patients who might have again some vitamin malabsorption if they have any of the disease states we've been talking about. It's very sensitive and very specific. So a fecal elastase level of less than 100 actually has a high predictive value of diagnosing X-ray dysfunction levels between 100 and 200 or more indeterminate above that you probably don't have that the good. The reason this is now recommended is obviously it's a lot, frankly, less messy than the fecal fat measurements and it's probably as or more sensitive and specific. It's relatively inexpensive. Most labs will do this test as well and the best part is that it is still a sensitive and specific test, even if patients were on pancreatic enzymes, which the fecal fat measurement was not.

Speaker 2:

So, for all those reasons, fecal elastase tests are the initial test you would want to check in patients who use suspected X-ray dysfunction and again, those numbers are simple enough that I don't think you need to be a GI physician to do that. In fact, I would argue that, given a simple treatment associated with this, while many of these patients will be seeing a gastroenterologist for other reasons, I don't think there's really any reason why a primary care provider can't do a lot of this, because it's relatively easy to diagnose and there's only one treatment and you can make some adjustments as time goes on, and measuring vitamin levels are fairly easy, stuff like that.

Speaker 2:

So again, fecal elastase is the way to go as far as diagnosis. Then the guidelines move into treatment and they note that pancreatic enzyme replacement is the treatment of choice, as you might imagine. And again, if you just ignore it, not only do they have continued GI symptoms but the malnutrition of other patients, including vitamin deficiencies, and they note that, especially in patients with pancreatic cancer, as we said before, that X-ray dysfunction is very common in these patients and that pancreatic enzyme replacement is vastly underused in studies, in some cases less than 20%. And there are studies that suggest that in those patients, giving them pancreatic enzymes actually does improve quality of life. It refixes nutritional deficiencies and it actually may.

Speaker 2:

Even I looked at the studies they noted on this and it's not. These aren't randomized controlled trials, but retrospective studies suggest that it might even improve mortality in these patients and actually extend life somewhat. Again, I think that's a little, that might be a bit of a stretch, but at a minimum I think you can say that it's going to improve what life, what quality of life they do have, and help with their vitamin absorption, stuff like that. So, as any pharmacist will tell you, there's about 15 different preparations of pancreatic enzymes. That's a bit of an exaggeration, but there's certainly several of them out there.

Speaker 2:

All of those preparations contain some sort of combination of lipase, amylase and proteases, so the three big enzymes that the pancreas secretes to help you digest food almost all of them are available as entericoded capsules, usually with microbeads in them, and the reason for that is that in the stomach all those enzymes will get destroyed or denatured and so you can have some sort of formulation that allows it to buy it to get through the gastric juices into where the small intestine or it should be secreted. The exception of that is vial case. Vial case comes as a non-entericoded tablet. It also comes or at least it used to come commercially as a powder as well, because it does not have an entericoding into it. Patients who are going to use vial case have to take an acid blocker with it, so either a proton pump inhibitor or H2 receptor antagonist, and studies have shown that improves absorption as well as improving efficacy.

Speaker 2:

Now many of these patients are already on H2 blockers or proton pump inhibitors for other reasons. Chronic pancreatitis patients are almost always on some sort of acid blocker, but if they aren't, then you're going to use vial case. Then you need to use some sort of an anti-secretary agent. In my world, the big place where we use these is in patients with chronic pancreatitis who have feeding tubes in, so they have intral tubes in and are getting fed that way. Unfortunately, as you might imagine, you can't just open up the other preparations and send them on the feeding tube, so you have to use that.

Speaker 2:

You have to use the non-entericoded tablets Also, as any hospital pharmacist will tell you we also commonly use the vial case to dissolve blockages in intral tubes, like blockages of dried food and stuff like that. It will help break that up as well. So you have multiple formulations on the market and, with the exception of vial case, they all have some sort of proprietary formulation that protects the capsules from getting being venerated in the stomach and going through. The guidelines note that there is probably no difference between them as long as you use them in equal potent doses. There's never been one that's been shown to be better than another, and they specifically say that there's generally no reason to switch from one to another based on response, because, again, they all basically contain the same things.

Speaker 2:

And all you should really have to do is adjust the dosages, and all of these preparations come in a wide variety of dosing formulations. Adjusting doses is usually relatively easy with even within one formulation. So, for example, pancrease, which is again one of the most common entericoded micro-tablets that's used for excreting deficiency, comes in six different dosage formulations, and so you should be able to adjust doses relatively easy within the same preparation, and in fact, the only reason that it's usually patients are usually switched is because their insurance no longer covers it or it's unavailable. For a long time, pagpangra and pancreate enzymes were not available, or only one or two different brands were available, so that's become less of an issue now and more of the enzyme formulations are available.

Speaker 2:

But again, that's the big thing. The others, all of these, are unbelievably expensive, and we'll talk about that here in just a little bit. There are some over the counter preparations for enzyme replacement and, as you might imagine, the AGA guidelines call them out and they say they should be used because, like all dietary supplements, we have no idea what's action them. And so their utility and safety is unknown.

Speaker 2:

So the dosing of pancreate enzymes is essentially based on the lipase account, and the reason for that is that humans have other mechanisms for protein and carbohydrate digestion, but they don't have any other mechanisms for digesting fat. So the focus on pancreatic enzyme replacement is on lipase, and that's why you go drugs based on lipase. The primary goal is to basically improve symptoms, so they have less GI symptoms, less diarrhea, less diattery, less abdominal pain, bloating and things along those lines, but also to ensure that the patient is absorbing particularly vitamins as well, and those are kind of the goals of therapy.

Speaker 2:

When you're doing this, if you look at the package and sort of any of these medications that give you an idea of kind of starting dose, it is worth noting that the pancreas makes about 900,000 units of lipase during an average meal. That's right, I said 900,000. And about 90,000 units about a tenth of that is needed to be used to prevent statteria and diarrhea. So it's worth noting that the doses we give of pancreate enzymes don't even come close to that. I mean they're high but it just we're not going to equal exactly what the pancreas secretes during a normal meal.

Speaker 2:

And so, because of that complete elimination of symptoms, gi symptoms is probably not a attainable goal and again they call that on the guidelines that you should definitely have improved symptoms, but it's probably unrealistic to expect completely absent GI symptoms even though, again, most of these patients will at least have some residual pancreatic function.

Speaker 2:

So even though a lot of their pancreas has been knocked out by, again, cancer, chronic pancreatitis, something along those lines, there should be at least a little bit of exocrine function left, and I think that's one of the reasons why they target lower doses of pancreatic enzymes, again based on the lipase content, and they say you should probably start at about 40,000 units, so about half of what the pancreas would normally secrete to prevent statteria. For a standard size meal and then for snacks you want to use about one half of that dose and then basically from there you adjust the dose up or down, largely based on symptoms and largely based on meals. So if a patient were to have a very, very fatty meal or a large fatty meal or coming up on Thanksgiving that might be an example You'd want to use a higher dose, kind of almost like people diabetic patients who carve down and know how many carbs they're going to eat kind of make some adjustments based on the amount of fat the patient is as likely to eat and that can sometimes help.

Speaker 2:

After that, doses should be titrated to basically resolve or greatly improve GI symptoms, particularly steatoria, and so while again, it's not really fun for patients to do, they should monitor their stools and make sure that their stools are not super floaty and super smelly, and as that goes down and as their gastrointestinal symptoms improve, that means they're probably doing a good job of the right dose of what we're using here.

Speaker 2:

The guidelines talk a bit about doses for cystic fibrosis, which are a little bit less, and of course they have to be dosed more by weight because we're dealing usually with kids, but again, that's kind of beyond the scope of this pod. The pancreatic enzymes are relatively well tolerated. However, one of the big side effects and has been reported numerous times in the literature is chronic fibrosis, and so taking too much of pancreatic enzymes can actually cause sclerocene and fibrosis of the colon.

Speaker 2:

There's also been reports of allergic reactions. All these agents are porcine origin and that might be another thing for religious or cultural reasons. It may be difficult to help those patients if they, for religious or cultural reasons, can't have porcine products and then some other really rare stuff. But I think the key piece there is to not overdose patients, because if you do overdose them, that you do run the risk of a chronic fibrosis, which obviously can be pretty serious as well.

Speaker 1:

So it really does require some.

Speaker 2:

It's not one of those set and forget things. It really does require you to have the patient monitor what's going on. If they start having constipation, something along those lines, you may have to back off on the dose instead of continually going up on the dose. They know that, again, prescription and pancreatic enzymes are really expensive. I did a little poking around on GoodRx and found that the average amount of a one month supply of any of these agents some in some routine two and $3,000 a month. So I mean obviously beyond the reach of almost all patients. And they know that insurances often don't cover it or they cover it only partially. And they call out and say that you know better insurance coverage is critically needed, especially for low income patients. Well, you could say that a lot of things, but I'm glad they at least call that out. You know it's worth like so many things.

Speaker 2:

I think insurance companies feel like, well, if this is a life threatening, you know, and it's super expensive, we're just not, we can't afford to cover it. And it is like so many things in the world of GI, you know, it isn't like pancreatic enzymes themselves are expensive and we're getting them from pigs who, I'm sure, have plenty of panic pancreatic enzymes to spare. But it's it's the delivery formulation. That's that is why these companies can charge whatever they want, because there really is no generic tanny of these medications, right, you know? Because it isn't the medication that's generic, it's actually the formulation of the delivery system and that is proprietary. And so because of that, you can't switch these, these medications back and forth, and so they can charge really kind of whatever they want to charge for it.

Speaker 2:

There's something similar with with ulcerative colitis and the various micellamine products that again, it isn't the micellamine, that's. That's. That's the problem. It's the delivery system that allows the drug companies to charge whatever they want. It's very similar here. They also note that that once you start pancreatic enzymes, you need to screen these patients for vitamin deficiencies, and so this is going to be one of the cases where you are going to want to do kind of a full vitamin panel, including looking for vitamins levels of vitamins A, d, e and K, because it goes on, sort of that type of vitamins, as well as vitamin B12, folate levels and they even note that that it's probably a good idea to check magnesium and iron studies as well, and there's even managed some reports of zinc deficiency and and promososic with zinc deficiency in these patients.

Speaker 2:

So I think that's a little more tricky, but I think certainly checking some of the common vitamins you know again, a, d, e, k and B12 certainly makes sense. And if the those levels are low then you're going to have to supplement with with, with extra vitamins. In particular they call out vitamin.

Speaker 2:

D and note that that these get it's significantly lower in these patients and they note some of the other issues associated with with both D and K and noticing, noting that, again, these patients are at high risk for osteoporosis anyway, and then having the levels of that is going to increase. That it's kind of in my experience that that these, these patients are sometimes difficult to get vitamin D levels above 30. And I've seen and I got asked about this where you know you have to sometimes give these patients some pretty high doses of vitamin D to get those levels up.

Speaker 2:

You know, I've seen as high as 10,000 units a day sometimes, which again is far beyond what we would give normally patients who have vitamin D deficiency.

Speaker 2:

So don't be surprised if you need to give higher than regular doses, trying to try and get vitamin D levels and kind of the normal range. Again, a specific A, d, e, k supplement like is used sometimes in real efficiency, wouldn't be a bad idea I don't think in these patients as well. And then more global assessment of of of malnutrition, including making sure that they're maintaining weight, that their muscle function and muscle mass is saying about the same, etc. Etc. So it isn't just levels you want to look at, but also look at weight, body mass index, things along those lines.

Speaker 2:

Quality of life measures the AGA guidelines recommend. Should that they should be done? I don't think that's it.

Speaker 2:

It's probably done commonly clinically just because it's just not something that kind of enters the brain. I think of most providers. But I think having some sort of standardized measure, especially for GI symptoms, it probably makes sense. And just to try and have some sort of documentation in the chart about okay, well, their score was this when we started pancreatic enzymes and the score has improved to this Now they've been on it for six months or a year. That might even be a tool you can use to convince insurance companies to continue coverage of these agents.

Speaker 2:

For the individual patient. They note that every one to two years at DEXA scan should also be done again to monitor for the development of osteoporosis. That, I think, gets a little tricky because again, if they do develop osteoporosis, one wonders how well oral bisphosonates would work in these patients, right? I mean, they're already barely absorbing anything anyway and you have a drug that's less than 1% absorbed. And in patients who often have gastric ulcers and other issues associated with it. And to my knowledge there are no studies looking specifically at oral bisphosonates in patients who have X-ray dysfunction. There may be some data in the cystic fibrosis literature but not in the chronic pancreatitis literature. So if you're interested to see, you know. Would you have to use intravenous bisphosonates or some, or DinoSMAB or something along those lines.

Speaker 2:

Be kind of interesting and so that's that that's kind of the you know the basic treatment strategies and goals for treatment. And again, this is unfortunately not a set it forget it sort of thing. You really do need to sit down and start therapy and adjust therapy to help with symptoms and making sure their their imon levels are normal. Now the other big part with cystic fibrosis that has kind of been controversial over the last 20 years is one of the big problems with chronic pancreatitis patients is chronic abdominal pain, which can be severe and it's due to get the inflammation of the pancreas.

Speaker 2:

And if you work in with patients who have continuous bouts of pancreatitis, they kind of go into this.

Speaker 2:

You know they have chronic levels of pain in kind of the six to seven out of 10 range and then you know, for whatever reason unfortunately it's they may be going back to drinking alcohol or some other reason.

Speaker 2:

They have an acute flare that gets their pain up to nine or 10. And we're able to, you know, hospitalize them, you know, and then maybe get their pain down back to the six or seven range and then we send them home. Unfortunately, that means that a lot of these patients are on chronic opioids and again, I don't think there's anything wrong with using opioids in appropriate patients, but because many of these patients do have substance abuse issues, I think there's some stigma associated with with with sending these patients home on long term opioids, even though it's been my experience that that that's sometimes the only thing that really helps these patients is chronic opioids, unfortunately. You know, tie it off and certainly use but but and osteoidals are often avoided in these patients, again because of the GI effects. So the controversial part is then do pancreatic enzymes help with the pain associated with osteoporotide or chronic pancreatitis? And the data has kind of been back and forth. We're going to talk about that piece of pancreatic enzymes treatment right after this word from CD impact.

Speaker 1:

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Speaker 2:

So we're back talking about the American Gastroenterological Association guidelines for exergent dysfunction, again usually due to either cystic fibrosis or chronic pancreatitis. We were talking about the use of pancreatic enzymes to treat pain in chronic pancreatitis, and again earlier studies suggested that there was an effect, but later ones did not. We now have two metanalyses that have kind of been tiebreakers, and both of them have come to the same conclusion that unfortunately, pancreatic enzyme replacement does not seem to have a significant benefit in pain associated with chronic pancreatitis. However, those same studies do point out that the pain associated with chronic pancreatitis is often interlinked with some of the GI symptoms. So if you have bloating and abdominal lestention, that can make the chronic pancreatitis pain worse. And so the AGA guidelines and my own kind of reading of the literature basically suggests that even though pancreatic enzymes by themselves don't seem to improve the pain associated with just an inflamed pancreas, if they can help with some of the other GI symptoms you still might get a little bit more relief on top of it. So while you probably don't want to use pancreatic enzymes solely for pain control in chronic pancreatitis, because the guidelines say that all patients with exergent dysfunction should be on pancreatic enzyme replacement, they should all be on it anyway.

Speaker 2:

So I have to admit, over the years I've started this kind of a desperation in patients. You know they've been admitted multiple times with pain, with chronic pancreatitis. We've at least tried it. I'm going to try. After reading all this I'm going to try and back away from doing that, though I am still going to recommend pancreatic enzymes in almost all of these patients just because we know especially the vitamin deficiencies they have. Again, assuming they can afford it.

Speaker 2:

Is there anything else you can try? Well, a actual, relatively well done study done a few years ago to look at the anti-oxygen supplementation and had a proprietary compound they used that contained various vitamins, selenium and some of them you know, some of the more big, you know antioxidants like methionine, and found in a relatively decent randomized double-blind placebo-controlled study that and most of the patients either had idiopathic pancreatitis or alcoholic pancreatitis. They found that anti-oxygen supplementation pancreatitis. They found that number of non-painful days was significantly higher and in the treatment group compared to placebo, it was seven versus three days and that 32% of patients in the antioxidant group compared to 13% of patients placebo group did report significant pain improvement. So unfortunately that means probably buying the specific antioxidant preparation, but I think it's reasonable to consider.

Speaker 2:

You know some sort of agent that has, you know, vitamin C, vitamin E and methionine, and I think it's reasonable to try. You know again, it's cheap. These patients are going to need vitamins anyway. So, you know again, you might be getting, you know, double bang for your buck there, as well as improving their symptoms. So, while pancreatic enzymes don't seem to be beneficial, I think antioxidants may have a role in the treatment of pain associated with chronic pancreatitis. So that's it for this episode of Game Changers. Thanks for listening. We will see you next week, but until then, remember time flies. I don't know where it's going, but the most important day is today. We'll see you then.