Brian Lacy, MD, and Jay Pasricha, MD, on Chronic Nausea and Vomiting: Part 2

In part 2 of their podcast, Dr Lacy and Dr Pasricha continue their discussion on chronic nausea and vomiting, focusing on treatments for this debilitating condition.

Brian Lacy, MD, is a professor of medicine at the Mayo Clinic in Jacksonville, Florida. Jay Pasricha, MD, is a professor of medicine and director of the Johns Hopkins Center for Neurogastroenterology in Baltimore, Maryland.

TRANSCRIPT

Welcome to this Gastroenterology Learning Network podcast. My name is Brian Lacy. I’m a professor of medicine at the Mayo Clinic in Jacksonville, Florida. Today I’ll be speaking with Dr Jay Pasricha, and we will continue our discussion on chronic nausea and vomiting, with a focus on how we can treat this chronic, debilitating condition.

Jay, you mentioned medications, and many of our patients that we all see come to us first, and maybe they've tried over-the-counter medications. If we focus on that just for a second, do you think there's really any value to any of the over-the-counter medications that patients use or do you think it's more just placebo?

Dr. Pasricha:  No, I don't think it's placebo. I think it depends on the severity of the symptoms. There are some patients who do benefit from common, over-the-counter remedies. Ginger is a good example.

There are also nonmedicinal alternative therapies like acupuncture, which may be of benefit for patients with chronic nausea. There is experimental evidence to think that this acts via stimulation of autonomic reflexes. It may actually even accelerate gastric emptying, at least in animals. There's some basis for using these alternatives.

If you have a mild case of nausea chronically and you've been diagnosed, you've sought medical attention, if you can manage it over the counter, I will tell you right now, we do not have disease-modifying treatment, so whatever we do is also symptomatic. The simpler the treatment, if it's just going to be symptomatic, the more I'm in favor of it.

Unfortunately, as you know, for most specialists and particularly at the kinds of centers that you and I are in, these patients have usually exhausted not only these over-the-counter alternatives but a lot of the prescription medicines. That's where you start running into "What do I do next?" kind of question.

Dr. Lacy:  Let's take the patient then who maybe tried some of the over-the-counter agents, and ginger, and maybe the P36 pressure point bands, and things like that, and they haven't worked.

When you see these patients, let's assume they haven't tried any prescription medication because that will apply maybe for many of our listeners, recognizing we don't have 50 medications for nausea and vomiting. It's a shorter list. Is there one go-to first prescription you like to use, or is it individualized based on patient and comorbid conditions?

Dr. Pasricha:  There's only 1 approved medication for gastroparesis as you know, and that's metoclopramide. It has a black box. I don't think the black box is the main reason why I hesitate to use it because the tardive dyskinesia is pretty rare and happens with years of use and in a particular population, particularly in the elderly.

But one the reasons I don't like to use it is because of the other side effects. At doses that are effective, on the minimal dose that's effective of metoclopramide, at least 10 milligrams, not more. At 10 milligrams 3 times a day, or 4 times a day, a significant number of those, and I would say 20-plus percent, would start having some kind of CNS issues—depression, fatigue, malaise.

So it's not a drug that a lot of people can tolerate to have to be an effective dose. People can do fine with 5 milligrams. Five milligrams is not going to do much. But nevertheless, I think it's important to say it is the only approved drug.

In the short-term, a trial of that, if a patient has never been on that, is worth it, as long as you explain why there's a black box, what you're going to monitor them for, and monitor them carefully for that.

As you also know, a lot of people have been using domperidone, which is not approved in this country, and have obtained it either from outside the country because there are lots of pharmacies on the Internet that can ship that to you. Or if you go through officially the FDA-approved IND process, there's a dispensing pharma that can make it.

But for a long time, we used to think domperidone is much safer, because it doesn't cross the blood-brain barrier. And yes, it's true that neurological side effects are almost negligible, but we now know that there may be a cardiovascular risk. And so at least in Europe, they have restricted long-term use of domperidone, as well, for that reason. Neither of these agents is particularly satisfactory.

Now, my go-to agent beyond this, is typically something like mirtazapine. Mirtazapine, as you know, is an antidepressant, a special kind of antidepressant. But apart from the fact that it enhances the release of these two neurotransmitters, it's also an important antagonist of the 5-HT3 receptor.

Why do I prefer this over PRN use, for instance, of another 5-HT3 antagonist? For 2 reasons. An ondansetron-like drug is only partially effective in this particular situation, in my experience, number 1. Number 2, patients still have a hard time getting coverage for it. Number 3, it can cause constipation.

A lot of patients are already on it. I'm trying to distinguish between rescue medication use or chronic. For me, I use mirtazapine as chronic use.

Now, the problem with mirtazapine is weight gain. Why is that a problem? For most patients who are nutritionally depleted, it's not a problem. They want to gain weight, so it's OK. But as you know, increasingly, a large portion of our patient population with gastroparesis are either overweight or obese, and for them, it's a big problem. You have to be careful about using mirtazapine in the outset, because patients can gain a lot of weight.

The other drug that people use a lot in the psychotropic category is buspirone. Buspirone, at least in functional dyspepsia, in European trials which includes some patients with gastroparesis — and as I've said, now that distinction is moot — has been shown in a randomized controlled trial to be effective. We think it principally acts by improving gastric accommodation.

You would predict that a major effect would be on fullness and satiety, but if you actually decrease the pressure in the stomach, you might also decrease the amount of stimulation that the vagus nerve is receiving, and thereby attenuate nausea as well.

These are not hard and fast, well-established drugs that there's a lot of evidence in favor of them. But frankly, we are in a period where we think more effective drugs are coming in, but are not here yet. We have to do what we can with what's available.

Dr. Lacy:  For our listeners, that was a great teaching pearl. In the interests of time, we didn't talk about the very complicated physiology of nausea and vomiting with multiple neurotransmitters. But mirtazapine, because it acts on several different sites, can be a very good medication to use. For our listeners, you may want to start really employing that in your practice.

Jay, I want to do another segue here, because you brought it up. You've done some really interesting work on aprepitant, an NK1 antagonist. Some of our listeners may not be very familiar with that agent. Could you briefly explain its mechanism of action, and why it might be useful for patients with chronic nausea and vomiting?

Dr. Pasricha:  Aprepitant was first approved in this country many, many years ago, as a treatment for delayed nausea from chemotherapy. Aprepitant acts on a receptor for the neurotransmitter substance P. This receptor is called NK1, neurokinin-1 receptor.

It is present on the sensory nucleus of the vagus. The vagus has sensory neurons that terminate in this sensory nucleus and those receptors are present there, right next to the chemoreceptor trigger zone.

So this is where a lot of antiemetics and anti-nauseas impact, including the D2 receptor antagonists. That's around the same site. NK1 receptors play a particularly prominent role. We hypothesized that if aprepitant is used for chemotherapy-induced nausea, it might be useful for nausea related to gastroparesis, or gastric dysmotility.

As you know, we ran and published that study in Gastroenterology using aprepitant. We picked the wrong endpoint, frankly. We picked an endpoint that was not generally used in gastroparetic studies. We used a 1-100 scale, a visual analogue scale. Our endpoint didn't actually turn out to be statistically significant. But when we looked at all the other endpoints, the secondary endpoints, it was having a statistically significant effect. Now, that doesn't count in a heuristic statistical way, and that's fine.

But it was enough to inspire this pharma company, who's got another NK1 receptor antagonist, tradipitant, to go out and do a phase 2 study, which was also published in gastroenterology results that were truly positive and impressive. I believe they're now in phase 3 trials. I think this is going to be very helpful, and if it does get approved, we don't know, but if it does get approved, it will represent the first new class of antinauseants for GI problems.

Dr. Lacy:  Exciting times. Thank you.

Jay, as we wind down here, one last question. Hard to have any conversation about chronic nausea and vomiting without bringing up gastric electrical stimulation. You've been a pioneer in this field. You've been involved in this for 30 years. For our listeners, do you think this is still an option? Should it only be used in diabetic patients? Do you think it has a benefit, or should we start moving away from that?

Dr. Pasricha:  A complicated question, Brian. First of all, if there's one patient that gets benefit from one procedure, it's worth it for that patient, for sure. As academicians, sometimes, we tend to forget that, and we must be aware that there will always be somebody who responds to something. So we shouldn't be dismissive just because randomized controlled trials haven't shown a convincing benefit of the stimuli.

There are lots of anecdotal reports that some patients benefit, but if you look at the randomized controlled trials, the evidence that this is going to be particularly helpful isn't there. Now, should we use it for a subset?

People have shown that diabetics do better, but again, large-scale studies prospectively validated are not there for us to say with confidence, "I know exactly the kind of patient that's going to benefit." Like a lot of these treatments, it comes down to trial and error. You try it out and see if it helps, and that's where I think we are with the stimulator.

I used to use a stimulator a lot. I don't use it as much because my own experience with it has been not particularly encouraging, but that's my advice. I know lots of other people who have large practices around stimulators, and they attest to its efficacy. It's difficult to tell you for sure, but if you look at the science, the evidence is equivocal at best.

Dr. Lacy:  Great. It shows how much we still have to learn about nausea and vomiting, and the physiology and pathophysiology. To me, this is why it's such an exciting time in gastroenterology because I think we're going to learn some great things in the next decade.

Dr. Pasricha:   I want to add one more thing on the stimulator.

Dr. Lacy:  Yes.

Dr. Pasricha:  I don't want people to get the impression that I'm not in favor of neuromodulation. I think neuromodulation is the key. I think some kind of stimulation will work. We just don't know what that optimal method of stimulation is, but the approach it represents is very, very promising.

Vagus nerve stimulation of some kind, if we can understand exactly what we're doing and how to do it, may be a very important therapeutic option. Now, there's a lot of noninvasive devices that are coming out, and it'll be interesting to see what the results of that are.

The science behind all of this is still somewhat murky, and as we go forward, I think for me, a lot more of the basic scientists are starting to focus finally on the vagus nerve.

The next 10 years are going to be, like you said, very exciting, not just in terms of understanding what's happening in the periphery, in the stomach, and the entire enteric system, but what's happening within the gut and the brain, and the major highway there is the vagus nerve.

Dr. Lacy:  Absolutely. It will be an exciting time. For our listeners, stay posted, don't give up, and look for great, exciting things coming down the pike.

Jay, I can't thank you enough. I know our listeners really appreciate this. What a wealth of information we've heard today. I always learn something new by listening to you and your very thoughtful manner. Thank you so much.

Dr. Pasricha:  Thank you, Brian. It's been a pleasure to be here, and thank you for having me.