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Targeting Gastroparesis Treatments in 2012
UPMC's Dr. Klaus Bielefeldt discusses targeting gastroparesis treatments in 2012.
Upon completion of this activity, participants should be able to:
- Develop diagnostic skills to identify gastroparesis
- Advance patient safety and resource utilization by more selective use of diagnostic tests
- Improve patient outcomes through targeted medication use in patients with gastroparesis
- Abell, T. L., R. K. Bernstein, et al. (2006). "Treatment of gastroparesis: a multidisciplinary clinical review." Neurogastroenterology & Motility 18: 263-283
- Dudekula, A., M. O'Connell, et al. (2011). "Hospitalizations and Testing in Gastroparesis.." J Gastroenterol Hepatol 26: 1275-1282
- Bielefeldt, K: “Gastroparesis: Concepts, Controversies, and Challenges,” Scientifica, vol. 2012, Article ID 424802; doi:10.6064/2012/424802
Dr. Bielefedlt has no relevant financial interests with proprietary entity or entities producing health care goods or services.
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Release Date: 11/20/2012 | Last Modified On: 11/27/2013 | Expires: 11/27/2014
So what I want to do is start with a case that might remind you of patients you may have seen. This is a young woman who has known idiopathic gastroparesis, the most common form of gastroparesis where we know they have it but we don’t know why. She has had it stably for about 2 years, but then recently developed more symptoms, more anorexia, postprandial fullness, nausea and then the associated vomiting, lost quite a bit of weight and now comes to your office. She feels down, has problems sleeping and is less interested in some of her social interactions. She has been on Metoclopramide for a while, she added Erythromycin a while ago and she still is the same. When you examine her you feel a little bit or you notice a little bit of left lower quadrant tenderness, maybe some epigastric tenderness but truly no physical findings. You are struck by a flat affect but that’s about it.
So this brings us to a few issues that I want to touch on. So what seems to be wrong here? She is receiving outpatient treatment but seemingly fails. How common is this? Do we need to do tests if we face this scenario? She is on prokinetics, two actually of the prokinetics that we have available. She has a disease defined by gastric emptying delay and when we speed it up it doesn’t seem to work. Shouldn’t – is this, is this common, why is this the case? And then she is depressed, so maybe it is what we often think and don’t dare to say it all in her head, where basically everything I feel ends up anyway. So let’s look at this a little bit more in details.
How often do people fail outpatient therapy if they have gastroparesis? A few data have been published in this context. If you look at our own data the vast majority of patients looking here, looking here at a histogram of individuals followed for about 2 years the vast majority of them will be managed on an outpatient basis only, but you also see a scatter of people end up being admitted requiring some more intervention or at least modification of therapy which probably accounts for about 20 to 30% of individuals, data that have been shown also in other centers like the Mayo Clinic. If you look nationally once a person like the one that I described ends up in the ER shown here the likelihood of an admission exceeds 50%. So if they are bad they may still be okay on the outpatient environment, once they end up in the ER they will almost certainly be admitted.
So once they are admitted what do we do? Well we want to know what’s going on, why they are getting worse, so more often than not we do tests. So if we look again at our own data here we have a pretty good chance of getting these people into the endoscopy suite about a 30% chance per year, the likelihood of a CT scan largely driven by the emergency room department is even higher than that. And you heard beforehand about the cumulative risk of radiation exposure, which is certainly true for IBS and true in this functional disease. Our data are not unique because again nationwide here abstracted from a large data bank you see that once a person is admitted they would have about a 30% chance of undergoing an endoscopy. Now what is very important is we may hope for insight but we actually rarely ever get it. The endoscopy yield for truly relevant findings that will change what we do is about 5% or less. CTs look a little bit better but not good enough to justify the often significant radiation exposure you’ve heard about beforehand. So testing often done, little helpful in many instances. So we may need to learn how to screen more who to test and who not to subject to some of these interventions.
Now if we tested, didn’t find anything, or if we found something but nothing that really changes treatment what do we do? So let’s look at treatment that we typically use and here I have two larger samples, one from our own environment here and then one from a recently published NIH consortium study. As you see in both of those prokinetics as true for the patients I described are very commonly used. We probably apply them or use them, I see them used in 2/3 of the individuals with gastroparesis. We use more than prokinetics because you see a large list of medications and on average people with gastroparesis will have about 6 to 7 prescription medications to take at any given time, many of them as you can see here actually targets central processes and that’s where David and I overlap in our interest, or where we need to overlap in our approaches.
So let’s look at the prokinetics a little bit more because obviously they are often given and failed in this patient I described. So how well do they work if you look at the details? Let’s start with Metoclopramide, the most commonly used agent. There were only 3 randomized control trials comparing it to placebo, all of them done in relatively small patient samples, all of them focusing on idiopathic – on diabetic gastroparesis. The duration of all trials was 3 weeks, so that’s important to keep in mind. If we look at the data that are available, for example this study here, it shows that gastric emptying indeed did accelerate or was improved while patients were on Metoclopramide and in parallel to an improved gastric emptying we can indeed see there is an improvement of symptoms. Again, relatively short timeframe, diabetic patients only.
The flipside of this medication is certainly an important one we need to keep in mind and that is adverse effects. You all know this, the FDA warns everyone about it by now. If I look at my certainly skewed population of patients about half of them will report adverse effects that ultimately lead to discontinuation of the medication, and the effects are typ9cally in the area that relate to dopamine that David talked about before and in the context of Parkinson’s disease, so mostly extrapyramidal motor dysfunction of some sort. Relatively often not seen as much by the NIH consortium emotional problems with more anxiety or somewhat also worsening depression whether truly caused by the agent it’s sometimes difficult to discern because they also have symptoms that might affect their emotional state, but again the coincidence and improvement with discontinuation makes it a likely culprit. And then there are issues with fatigue, alertness, somnolence that are relatively commonly described. Now again this may be a skewed population I need to keep in mind, but it’s interesting that data from a randomized control trial comparing Metoclopramide to Domperidone demonstrated in a systematic assessment of several different side effects here that the incidence of all of these side effects is pretty high, typically exceeding 30% for each given side effect, sometimes even exceeding more than 50%. So the overall data there prospectively collected match actually my own experience seen in this sample that I described.
So what does the FDA tell patients? This is one of those things that we need to tell patients if we put them on Metoclopramide and actually the Neurogastroenterology Motility Society in the United States suggests that we should document discussion and consent once we use Metoclopramide. So the FDA says with a focus on tardive dyskinesia that one should not use Metoclopramide for longer than 12 weeks because it will increase the risk, the FDA also emphasizes that age and sex, meaning older individuals and women, are at a higher risk for tardive dyskinesia and side effects. That’s important because those criteria, those phenomena are the very ones that characterize the epidemiology of gastroparesis which is 80% women and if you look at the left side of these tiny, tiny images the prevalence increases with age. So we shouldn’t use it where we may need it the most.
The other aspect that the FDA emphasizes in their official description on the website and also in the label is that beyond tardive dyskinesia individuals taking this medication should be aware of central side effects that affect arousal, alertness and may need to curtail some of the activities that are essential in daily life like operating a car. So again we should monitor, inform and then have a decided informed decision with the patient as well as documenting it if we use this agent.
So if Metoclopramide is okay but not ideal to put it mildly may not be a good long term solution as the FDA at least tells us, do we have alternatives? The answer is as you know yes, and here I show you some data on motilin agonists. On the left side you see the data for Erythromycin from a study that was done I think more than 15 years ago in Belgium and there was indeed a significant acceleration of gastric emptying when used acutely. On the right side is a study from a nonantibiotic motilin agonist that never made it to market, it’s one of three that never made it to market because while there is an improvement if one compares baseline values that are always the higher bars to the lower bars which are after 4 weeks, the improvement between the two time points was not different between when one looked at the various drug dosages and placebo. So the motilin agonists do improve emptying but they do not seem to improve symptoms over placebo. So our prokinetics while having a rationale gone do they not have enough of an effect? The answer is we don’t know quite yet because there is a new kid on the block, Ghrelin or Ghrelin agonist.
Ghrelin is an interesting hormone produced in the gut typically in anticipation actually of food intake, and it seems to if you look at this side here it seems to accelerate gastric emptying. And what’s important speeding up emptying if you don’t feel better doesn’t help anyone, it seems to also when used in diabetics with gastroparesis it seems to improve the nausea score, so it seems to not just speed up also make people feel less uncomfortable once they eat. What is important in these now initial and still promising studies is that first the early improvement was actually also seen with placebo. And so we need to make sure that what we see as a prolonged response will not wear off with prolonger therapy because we deal with a chronic illness and we certainly need to have an effect that exceeds a four day window. Secondly, at this point the published data are all obtained with IV preparation an oral agent has been developed and is currently undergoing testing with initial results hopefully coming out relatively soon. So the prokinetics may still have an option, there is Ghrelin but we don’t have a very strong support once it comes to the efficacy of the currently available agents.
So what we need to do is perhaps move away from the endophenotype, namely the defining delay in gastric emptying and then look back at what’s the phenotype, what are the things that really people are bothered by and then target those and obviously nausea is one of the key symptoms, vomiting is one of the key problems and we have a whole array of different antiemetics, many of you use, most of you are familiar with and I therefore will not go into the details. None of them have been tested systematically in gastroparesis, that’s important to keep in mind. So whatever you do, whatever I do is off label basically.
But there are a few new things that might provide new rationale of new approaches. The first one now brings me back to David’s interest and that’s the brain. Now he is more interested in what’s going down from the brain, I see more, or we see more also what’s going up to the brain or goes with reciprocity both ways. So two different studies showed a significant correlation between depression and then severity of symptoms as rated by patients or severity of gastroparesis as rated by treating physicians. There was a significant correlation between worsening depressed sensation feelings and then worsening symptoms of gastroparesis or complications of the illness. Whether this is chicken or egg at some point doesn’t matter because it provides independent of causality a chance to improve a person’s wellbeing if we possibly improve the sense of depression. So people have looked at this in other diseases that are related to gastroparesis and currently there is an ongoing trial in gastroparesis to address this in a prospective fashion. So this one we only have reason by analogy looking at functional dyspepsia where we see at least some overlap between delay in emptying and symptoms.
So if we use the functional dyspepsia data that are available and then think about what we might do in patients or what might come out in some of the studies that are currently ongoing we may learn from the information that’s available.
So this here is one study that the late Ray Claus has published in individuals with significant nausea and vomiting. And what he used was a series of different tricyclics depending on patient tolerance trying to go to relatively high dosages and when he looked at his responses he reported response rates in a retrospective case here that are very, very impressive, so in the range of about 75%. Now what’s important is about 40% of these individuals had highly intermittent symptoms that are more reminiscent of cyclical vomiting, a totally different entity and independent of underlying cause his approach led to significant side effects in nearly 50%. What’s also important from my perspective that quite a few individuals are already on antidepressants so it becomes a bit more complex for us if we have an SSRI and now we want to go to a TCA, should we switch? How do we switch? When do we switch? So we certainly are in foreign territory.
A different approach is here depicted by a study that was recently published preliminarily by Jan Tack’s group from Belgium. What he used was a 5-HT1 agonist Buspirone with a rationale that this medication will not just affect the brain but also the gut and it will improve accommodation, meaning the accommodating relaxing response of the stomach in – of the good intake will be enhanced and therefore symptoms decreased. While this fundic relaxation was not as pronounced and not significant there was indeed a significant improvement of symptoms compared to the placebo arm, a very small study and only 17 patients that certainly needs to be replicated before one uses this more widely.
We know a little bit more about some of the other agents that are available, for example here on the left we know that SNRIs now represented by Venlafaxine and Effexor do not work in people with dyspeptic symptoms. Not in dyspepsia although a similar trial has been published in abstract form in individuals with significant nausea, in this case medication meaning anesthesia induced nausea, Mirtazapine, Remeron had a significant antiemetic effect and the study that I mentioned was published in abstract form actually showed a significant improvement also in weight of dyspeptic symptoms who had a tremendous weight loss in view of their impaired food tolerance. So there may be some options you can pick from, all of this again at this point reasoned by analogy in some ongoing studies we’ll hopefully see soon whether or not there is indeed a true benefit.
There is yet another reasoning by analogy that I think is interesting. You’ve probably all heard about gastric electrical stimulator the so-called pacer that initially was designed to accelerate gastric emptying but is now supposedly only a neuromodulator, so what happens is whatever happens in the stomach of PS2 influence the brain, that’s the current theory and then improves symptoms decreasing emesis. Now while I will talk a little bit about this later one of the interesting aspects that one needs to keep in mind the very same neurostimulation is actually used in depression with vagal stimulation, difference stimulator implantation site, different electrode site, not in the stomach, and data are controversial but suggest it may be beneficial. So what we may look at is something that has nothing to do with the stomach at least directly, what we may need to do is also select these people much less if we want to use electrical stimulation of the stomach, much less based on failure prokinetic but based on a more comprehensive assessment and I will touch on that in a second.
So let’s move on a little bit and talk about some other options that might become available. One is this is a person I mentioned before and there was a weight loss, does this person need nutritional support? Do we need to do more than just adjust her nutritional intake? So tubes are luckily rarely needed, so in nationwide studies and also in our experience a minority of individuals needs, will need nutritional support. And if they are needed the unfortunate thing is they don’t do that well no matter what tube you choose, whether we do a jejunal tube, whether we do a transgastric tube, tube related problems with dislocation, with leak and so on, need for re-interventions are unfortunately quite common. And it’s not just the tube related problems that are common, seemingly getting a tube is a mark of bad luck. And this is shown here where you see a hospitalization stays, the inpatient stay in gastroparesis once they get nutritional support or gastrostomy placed they are staying much longer, and they are not just staying longer, they are dieing more often, so we may select a high risk population or we may do something that actually has much less benefit than we hope we would see.
Lastly, we could even become more radical and move towards surgery and there are two different things, two different sides to the concept of surgery in gastroparesis. One, do we do it? The other one, should we do it? So let’s look at the do we do it? The answer from a collective that I looked at here is actually that in general, and that’s not just my population it’s done relatively frequently, often for feeding tube insertion which I alluded to before and rarely for radical solutions such as gastrectomy and then in a small subset to insert this pacemaker or gastric electrical stimulator that I talked about. So let’s look at this a little bit.
Gastric electrical stimulation was developed in the late ‘90s and then made it in the early 2000 into a multicenter trial that was then followed by a double blinded multicenter trial. What was happened is they used the – they inserted the stimulator and then after surgery did turn it on in half and did not turn it on in the other half of patients with patients and providers not knowing. And during the blinded phase of this trial when you look at this here only in diabetics did they only see a decrease in emesis episodes, none of the other end points changed. Later on when the trial was unblinded and everyone was treated everyone got better, so that sounds like sort of marginal effect and then later on a more impressive effect. Now based on these results the investigators decided let’s go for the group that responded the most, let’s exclude the time that is the most difficult, the immediate postoperative time and treat them after we give them the recovery let’s say after about 6 to 8 weeks. So they did exactly this, they used only diabetics, waited after the implantation and then randomly allocated. They got a very quick response which was different from the first trial and then again no, and this time no difference between the blinded and unblinded phase.
So overall there have now been 4 randomized control trials, only one showed the marginal difference that I mentioned before, and none of the others showing differences between the blinded or – the turn on, turn off of the gastric electrical stimulator. With the absence of convincing effect I need to look at the side effect ratio, and about 10% of these individuals will have re-operations within the first year. That’s important to keep in mind. So I at this point still am a skeptic and I’ve put a picture up of one of the reoperations that were needed because of electrodes leading to an obstruction.
So where does this leave me? We have prokinetics, they have their issues but they have some degree of efficacy and at this point with Ghrelin perhaps a future prospect that may be more promising. We have the antiemetics I only mentioned and didn’t touch on. There are interesting relationships between the central nervous system, mostly emotion and then the severity of gastroparesis. Trials are missing but are forthcoming. There is at least a rationale based on some analogy reasoning and a few agents with some positive signs and then a few like SNRIs and perhaps also SSRI’s where evidence is completely missing or evidence in efficacy, lack of efficacy is there. We have nutritional support that we should really be skeptical about but may at times need. Surgery once it comes to gastric electrical stimulation is one of those things that leaves me as a skeptic, in general should not be done very often. We have certainly the dietary issues I didn’t touch on but that often allow appropriate control of symptoms and maintenance of weight. Thank you.