What changed in the management algorithm for chronic persistent RLS?

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KATIE DAVIS: Hi, everyone. Welcome. I am Katie Davis. On behalf of Azurity, I want to thank you all so much for joining us today. We recognize how busy your daily practice is, and we sincerely appreciate the enthusiasm and interest. Our presentation today is centered around restless leg syndrome, the disease state and treatment approach, and is sponsored by Azurity Pharmaceutical. We look forward to engaging presentation and discussion, and before I turn it over to Dr. Ellenbogen and Dr. Ondo, who are our speakers for today, I want to go over just a few housekeeping items. There will be a Q&A at the end of the presentation. So, please feel free to submit any questions that you may have throughout the presentation. You can enter them into the box at the bottom of your screen at any time. We do ask that any questions that you submit that are specifically for HORIZANT, that they are on-label, so that we can be sure to answer them appropriately. Again, I want to thank you all so much for joining, and thank you specifically to Doctors Ellenbogen and Ondo for being our presenters today, and with that, I turn it over to you all.

DR. AARON ELLENBOGEN: Okay. Well, good afternoon, everyone. I’m Aaron Ellenbogen. I’m a movement disorders neurologist in the Detroit area. Thank you for advancing that slide. It’s a pleasure to be here and thank you to everyone for joining us. It’s our hope today that you’ll learn a bit more about restless legs. Dr. Ondo does a really excellent overview, and then I’ll spend some time discussing HORIZANT as a treatment, and then we’ll run through a case presentation as well. So, welcome to everyone, and I will turn things over to Dr. Ondo.

DR. WILLIAM ONDO: All right, thank you very much. Next slide. My name is Bill Ondo. I’m a director of movement disorder clinic at Houston Methodist Hospital, professor of neurology at Weill, Cornell, and Texas A&M, and also, director of the RLS Center of Excellence here in Houston. So, as Dr. Ellenbogen discussed, we’re going to have a pretty comprehensive review of restless leg syndrome, and I’ll forward this now, and then we’ll talk about a little bit more, some specific treatment issues. Now, first of all, this is sponsored by Azurity Pharmaceuticals. Azurity Pharmaceuticals do sell HORIZANT or Gabapentin Enacarbil, one of the FDA approved medicines for restless leg syndrome. This is not a CME program. Dr. Ellenbogen and myself are being reimbursed to participate in this. Okay. So, table of contents. The first three sections are sort of an overview with some guidelines and treatment options, I’ll discuss, and again, Dr. Ellenbogen will talk a little bit more about Gabapentin Enacarbil and present a case at the end, which highlights some of the difficulties in treating restless leg syndrome. Our objectives are basically to get a better understanding of RLS disease state, and this will include epidemiology, a little bit of pathophysiology, and then again, some of the treatment options, and then talk about some more specific data with Gabapentin Enacarbil, and then a case, as we’ve alluded to. Okay, so, RLS overview. So, there have been a number of different diagnostic criteria for RLS over the years, and that’s because it’s largely a subjective disease. You know, we like things with blood tests or a scan of some sort that can make diagnosis, and that’s just not the case with restless leg syndrome. These all are fairly similar, and I think the gist of it is, to have a diagnosis of RLS, you need some sort of urge to move the legs. Okay? It’s not just pain. There has to be some sort of feeling. It may be a strong sensory component. It may be described a number of different ways, but there needs to be some different urge to move that makes you want to move. Those symptoms are worse if you are forced to be

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still, or for example, if you’re lying in bed trying to get sleep. They transiently improve with volitional movement and sometimes even intense cognitive activity, patients will tell you, and then finally, there’s a true circadian pattern to this. So, RLS symptoms are worse in the evening and at night, and perhaps, even more robustly, they’re improved early morning. So, 6:00 AM to 12 noon, very unusual to get RLS symptoms at that time, unless patients are augmented. We’ll go into a little bit of a differential diagnosis of RLS at the end, when we get back to some of the more specific nuances of diagnostic and actual symptoms that people present, but that’s basically it. Urge to move, gets better with movement, worse if you’re still, worse at night, better in the morning, and that’s really the diagnostic criteria for restless leg syndrome. Now, RLS is very common in predominantly Caucasian populations up to about 10% of people,

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and really very consistently, 10% in epidemiologic studies has RLS. Now, that doesn’t mean that 10% of people have RLS bad enough that you need to treat it. Those studies have been done as well using different cutoffs, and probably 2-3% of the population has RLS problematic enough that it should at least the consideration of treatment. If you do the math in the United States, that ends up with about 6 million people in the U.S. with RLS. So, again, it’s a pretty large number of patients. Women are affected more than men. I think it’s more like two to one. It depends on the different study, but there’s a number of potential reasons for that, including potentially iron deficiency, which we’ll talk about towards the end as one of the causes of restless leg syndrome, but definitely women more than men in every epidemiologic study. Age of onset can be any. I mean, it’s not rare to have pediatric RLS. Maybe 1% of kids in epidemiologic studies have been consistent with RLS. It can be a little bit more difficult to diagnose RLS in children, because they would have difficulty discussing the actual symptoms that they’re having, but from, say, the 20’s to 70’s, there does definitely have an increase prevalence of RLD. Now, sometimes, and this is predominantly anecdotal, in the 80’s and 90’s, people that had RLS, their RLS sort of resolves or lessens, and there aren’t that many diseases that improve in your 90’s, but this may be one of them, but overall, as we get older, at least through the course of the entire life, you have higher frequencies of RLS symptoms. Now, there’s a number of different studies and data points that have attested to the fact that RLS is significantly underdosed, underdiagnosed, and undertreated. Some of these are older studies, and I’m hoping we’re a little better these days, although that certainly can vary, but some of the data points, in one survey of patients treated with RLS, it took 21 years of symptoms before they were treated with RLS. In another study of patients who claimed to present or mention RLS symptoms to their physician, this is in 2005, only a third of them received a correct diagnosis of RLS. So, there are a number, still a number of problems with making this diagnosis and getting people appropriately treated. There are a number of different manifestations and consequences of RLS. One of the main ones is simply sleep deprivation. The majority of patients who present to a physician with RLS will have sleep deprivation or sleep problems, insomnia, as one of the main symptoms. The exact timing of RLS can vary. So, for some people, they have more difficulty getting to sleep, but there also is a subset of patients that actually fall asleep, and then they wake up at 2:00 AM because of RLS symptoms. So, sleep disturbance in general is one of the most common features of RLS, and like anything that causes sleep disturbance, that can then subsequently cause daytime symptoms with

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fatigue, daytime sleepiness, and reduced concentration and a whole series of manifestations associated with sleep deprivation. One of those is depression, okay? People that have sleep deprivation certainly get more depressed. There’s much higher rates of depression in patients with RLS, especially more severe RLS, compared to people without, and in fact, suicidal thoughts are fairly common in patients with RLS. That’s happened the same place last time. Okay. So, there are a number of different consequences of RLS. It’s a very common condition. It can impact sleep at night. It can impact daytime wakefulness. It can impact mood. It even has economic impact. At least one study tried to look at this, probably as a consequence of the sleep deprivation, decreased alertness, attention, that it estimated about a 20% reduction in economic activity in patients with RLS. Again, also, correlating with severity. Okay, now, I’m going to spend just a couple minutes on this slide, because it really is the only slide on pathophysiology, and I wanted to get into this just a little bit. This has always been kind of my, one of my main interests in this field. We’ll start with iron. So, if you do an autopsy on patients with RLS, the main brain abnormality that will be found is reduced iron in the brain. Now, this is even in the case in people that had documented normal iron levels in the blood, which is the typical way we assess iron. Iron is a very tricky thing to assess, and it turns out that patients that do have systemic iron deficiency are definitely at increased risk for restless leg syndrome or exacerbation of existing restless leg syndrome, but I just want to make a couple points about iron. It’s actually a very difficult thing to assess. Ferritin is our most

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common measure of iron. Ferritin is actually a protein. It’s a giant hollow, ball. It stores about 2,000 atoms of iron. It’s the main storage protein for iron, and if ferritin is low, you’re definitely iron deficient. One of the problems is, however, that ferritin also is artificially elevated by any inflammatory component. You know, mild infections, any sort of arthritis, inflammation will artificially elevate ferritin. So, a normal ferritin or a high ferritin tells you nothing. A low ferritin is low. So, if you have a low ferritin, you have low iron. If you have a normal ferritin, you have no idea what the iron status is. The other issue with ferritin is that it changes over life expectancy. So, the rule of thumb is ferritin definitely goes up as we get older. So, the rule of thumb is that ferritin should be greater than age if you’re considering it normal. Now, the sheet, the lab sheet you get will say 10-200 is normal. That’s absolutely false in someone who’s 70 years old, okay? Someone who’s 70 years old with a ferritin of 40 has low iron. So, it’s a very important point. Now, there’s another iron, we sometimes use iron percentage binding. That’s another assessment of iron. That is less associated with RLS symptoms, but it sometimes can help out. If they have a high ferritin, but an iron binding percentage of 12, well, to me, that patient is iron deficient, end of story, regardless of what the iron says, and furthermore, a CBC is definitely not a screening test for iron deficiency. You can have a normal hematocrit and be severely iron deficient. So, again, we usually do a CBC as part of this, but we certainly don’t rely on that to diagnose iron deficiency. Okay. So, low iron is an important component. We’ll get back to that at treatment at the very, very end. The next, dopamine. Three of the four FDA-approved medicines for restless legs are dopamine agonists. Clearly, dopamine is involved somehow, but it’s been fairly enigmatic. It’s been quite difficult to sort out exactly what’s going on. There clearly is no overt deficiency of dopamine. We can’t find that. In fact, if anything, a

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variety of paths and studies and imaging studies show that there seems to be increased turnover in dopamine systems. Now, we don’t know exactly why this is. My gestalt of this is the whole macro system is not working, and the brain is trying to compensate by turning dopamine over faster. Bottom line is we don’t really understand the dopamine deficiencies or abnormalities in restless legs. Clearly, it’s involved. There’s no way it’s not with the response that you can get from dopamine medications, but the exact anatomy, whether this is a different system that goes down to the spinal cord, which many of us postulated, versus the Parkinson system, it’s just not known. Okay? We do know that RLS is strongly genetic. In published studies, there are 19 genes with conferred risk to RLS. In an unpublished study with 10,000, no, I’m sorry, 100,000 participants, that’s gone up to 164 genes that confer some risk to RLS. Now, there was no RLS gene. You can test some of these genes even on 23 and Me type platforms, but they’re genes that are conferred risk. So, if you have this normal version of a gene, you have a 6% increased risk. There’s no genetic test that says yes or no. There’s no utility in doing genetic tests at this point. There may be some in the future, but suffice it to say, it’s a very robust genetic condition. It’s most common in Northern European ancestry. So, Scandinavian populations have the highest, followed by Germanic Anglo-Saxon, and then as you get more Mediterranean, and then as you go east and south from there, it’s less common. Okay, but again, a very robust genetic component. About six out of 10 people, if they really query their family members, will have some family history of RLS. Now, we classify this sometimes as primary, if there’s no other reason for it, versus associated conditions, end stage renal disease, pregnancy, probably iron deficiency, neuropathy, a little bit more controversially, are associated with restless leg symptoms, and they might be considered secondary or associated conditions as opposed to primary RLS. From a practical standpoint, unless it’s a treatable thing, like iron deficiency, treatments seem to be similar, whether it’s primary or secondary. We also codify RLS into chronic persistent versus intermittent. This is fairly arbitrarily cut at two days a week, and this was used in many of the studies, which is why it has some importance, because the data you see in studies is related to all these patients would’ve had at least two days a week of RLS to participate in any of the phase three trials that looked at drugs

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for restless leg syndrome. Now, a little bit more about the clinical description, because like I said, this is what the diagnosis is based on. There’s this, again, a strong circadian component. This will persist with biological circadian rhythms. For example, if you go from the U.S. to Japan, the RLS will stay in the parent, or the original circadian pattern, until you acclimate, which typically takes five to seven days. So, your RLS times will change when you first go to, you know, the trans-meridian flight. You also have a strong association of RLS with periodic limb movements of sleep. Periodic limbs of sleep are these kicking episodes, typically triple flexion. So, you flex the knee, the ankle, the hip. It’s most common in stage one, stage two sleep, much less common in slow wave sleep, and REM sleep. Almost everyone with RLS, if you measure POMS with a sleep study, will have periodic movements of sleep. However, it’s kind of an important point, many people have periodic movements of sleep that do not have restless leg syndrome. Okay? As we, you know, as we age, we’re more and more likely to have POMS. Over 75, about 30% of people, will have, you know, abnormal quote/unquote periodic

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movements of sleep. So, you don’t make RLS based on a sleep study. There’s actually, honestly, probably no role to directly diagnose RLS with a sleep study. We often do sleep studies throughout sleep apnea and things like this, other problems, or occasionally for mimics restless leg syndrome, but you don’t need a sleep study to diagnose RLS. The actual sensation is described in a number of different ways. There’s usually some sense of kinesis, okay? Crawling, creeping is the most common, you know, heebie-jeebies, Elvis legs. Don’t get caught up on what the terminology is. The key is do those Elvis legs make you want to move. The answer has to be yes. Now, pure nocturnal pain, I mean, I just, my legs hurt, but you can’t get them to say, it makes me want to move, is not restless leg syndrome, okay, and we do see that sometimes, you know, misdiagnosed as RLS, where people have just nocturnal pain. You have to have an urge to move. Legs are essentially always involved. You certainly can have arm involvement. Often, you know, 20 years of legs, then you start to get arms, or that may be a common manifestation of augmentation, which we’ll get to here in just a bit. It’s frequently, you know, one night it was left leg. The other night, right leg. Almost always, there’s bilateral leg involvement, but it certainly may be asymmetric, or one side may be worse, as the way patients report it. There is an acronym for the diagnostic criteria called urge. The first one is a bit of a cheat, urge to move, okay? So, again, this is the critical thing. There has to be an urge to move the legs. R means rest induced, so, again, when you’re not moving around. G means gets better with activity. So, improves when you move around. E means evening and night accentuated. So, worse in the evening, and then S is just you know, there’s nothing else that better explains it. So, the official criteria, you have this caveat. There’s no other diagnosis which better explains the symptoms, which is on essentially all sleep criteria. Okay, a couple of guidelines about treatment. Now, this has evolved over time, depending on studies that have shown efficacy for RLS. The first official treatment guidelines were American Academy of Sleep in 2004. These were updated eight years later. There have been some additional ones by RLS Foundation, Academy of Neurology, Academy of Sleep Medicine, again, and the most recent published guidelines were, again, from the RLS Foundation in 2021. So, again, these do evolve over time, depending on what studies are out there, and the evidence-based criteria as, and also, keeping in effect long-term side effects of medications. So, the initial medicines, which were shown to be beneficial, were dopaminergic medicines. Later on, the ASM for the first time in 2012, included the alpha two delta calcium channel ligands. So, these are sometimes called the gabapentin or gabapentinoid drugs, which we’ll tend to refer them, as opposed to alpha two delta calcium channel ligands. The only… there are three of these that are available. Gabapentin, everyone’s familiar with, Pregabalin, probably everyone’s familiar with, and then Gabapentin Enacarbil, which is marketed as HORIZANT. That’s actually the only one of the three that’s FDA approved to treat restless leg syndrome. So, most recently, in the 2021 criteria, it took into account some of the long-term problems with dopamine agonists, namely, augmentation, which we’re getting to soon here, and because of the long-term complications of dopamine

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agents, actually preferred the alpha two ligand drugs as first-line therapy for restless leg syndrome, with dopamine agonists still being strongly considered, especially in cases where there may be some contraindication to the gabapentinoid type medicines, or obviously, if they

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fail the gabapentinoid medicines, but mostly because of long-term complications with augmentation, in this treatment algorithm, the alpha two delta medicines are preferred to the dopamine agonist. All right, so, finally, what is augmentation? So, augmentation is, by definition, all definitions, and there’s multiple subtle variations in criteria here, but all definitions of augmentation require an earlier onset of symptoms. So, for years, the symptoms started at 10:00 PM. They were put on a dopamine medicine, because augmentation is strongly associated with dopamine medications, and for a number of years, they’re doing okay, but then they start to get symptoms at 8:00 PM, okay, and maybe later, at 5:00 PM. So, this is an earlier onset of symptoms, and this is a key diagnostic criteria for augmentation. Now, other symptoms may worsen as well. You can get just an increased severity of symptoms. You can get new anatomy. So, again, a very common scenario in which arms start to get involved. Torso involvement, much less common. Face involvement, very rare. So, it’s usually limbs. There was actually a movement at one point to change the name to restless limb syndrome, but, you know, we just got stuck with restless legs, and that’s fine, because our legs are always involved first. Then finally, the other thing that can really drive people crazy sometimes as an exacerbation is it no longer improves with movement. So, again, when patients are augmented, you can lose some of those core features of the criteria. So, you don’t get relief with movement, and you don’t… you can get symptoms 24 hours a day. So, that’s important to keep in mind, that you can actually lose the diagnostic criteria, official diagnostic criteria, as a consequence of augmentation, just symptoms. Okay. Now, augmentation is a little bit different than tolerance and rebound. Tolerance is just, you know, you had some benefit with the meds, you know, at midnight, but now, at midnight, you’re taking the meds the same way, and they’re just not working. So, that’s tolerance, and sometimes that just a little bit higher dose will work. That would be fine. Rebound’s a little bit of a misnomer here, but it’s stuck in, in the literature. Rebound means the medicine just wears off before the symptoms wear off. So, the biggest example of this is Ropinirole, which has a fairly short half-life. You take Ropinirole at 9:00 PM, and it’s working until about 2:30 AM, and then you’re having RLS symptoms. Well, that’s most likely because the Ropinirole just doesn’t last that that long, and that’s what we officially call rebound. So, it’s not really an exacerbation of symptoms like you sort of… rebound is the connotation of, but it’s just the wearing off of effects. So, tolerance and rebound, and then a third one, which is sometimes hard to sort out. I mean, the symptoms may just get worse on their own over time. So, those things are different than augmentation, and the key is that augmentation really requires an earlier onset of symptoms as its core feature. Now, there are other side effects of dopamine medicines. The side effect profile of dopamine medicines, however, is different in RLS than Parkinson’s disease. So, patients with RLS do not get dyskinesia, okay? They very rarely get hallucinations and delusions, which is very common in Parkinson’s disease. They typically don’t get orthostatic hypotension. That’s something fairly specific to Parkinson’s disease, but they do still get some of the other dopamine side effects, like nausea, potentially sleepiness during the daytime, if you’re taking the medicines during the daytime, and then also impulse control disorder. So, this is an interesting one, which in retrospect, makes sense. The anticipation or reward is dopaminergic. You know, pleasure is actually not dopaminergic, but the drive towards pleasure is very dopaminergic mediated. So, pleasurable things, sometimes, you can increase the desire for these with exogenous dopaminergic. So, the big ones that pop up are gambling, which is classic variable rate operant positive conditioning, just spending more money, which is fun for people,

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and then increased hypersexuality. Okay? So, these are all immediate gratification type things, and there are some patients, even after a long duration of being on these medicines that will develop these, and it can range from kind of patients like it, and it’s not that big a deal, to being a severe problem

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with these impulse control disorders. So, that’s something to keep an eye on in patients’ chronic therapy of dopamine agonists. The augmentation, however, is really the biggest problem that we have. There are some risk factors for augmentation in different studies that have popped up. In a couple of studies, higher doses of dopamine medicines are associated with augmentation. The problem with this is causality is hard to sort out, because there’s a reason they’re on higher doses. In some of the studies, low iron stores has been a risk factor for augmentation, and this is one of the reasons that we… one of the many reasons we aggressively treat patients with iron whenever we can. There’s also some evidence that shorter dopamine agonists, like Ropinirole may have higher rates of augmentation than longer dopamine agonists, such as Retigabine Patch. Now, Levodopa falls into this. We don’t use Levodopa that much for RLS, but it probably has the highest rates of augmentation, because it’s by far the shortest half-life of any of the dopamine medications. That’s the reason we rarely do use Levodopa, and when we use dopaminergic medications, it tends to be the dopamine agonists. Okay. So, the next couple of slides deal with what you do when you get augmentation. Now, I want to emphasize there is no standard formula here. I’m going to actually move on to the last part of this slide. We actually, at the last sleep meeting, there’s one just finished today. I’m not at it, obviously, but at the last sleep meeting in Charlotte, there was a course on RLS, you know, management issues, including augmentation, and John Winkleman, Chris Early, and myself, were doing that, and at the end of the, you know, at the end of the, what do you do about augmentation, the three of us had three completely different strategies. Okay? So, I want to emphasize there’s no absolute codified strategy here, but there are a couple things that we’ve sort of agreed on. So, number one, eventually, you have to stop the dopamine drug. Now, you can cheat for a while. You can move the dopamine drug earlier if they just have, like, maybe two hours earlier, and that will often work for a while, but ultimately, the strategy of increasing and increasing the dopamine agonist will fail, and it will tend to accelerate as it fails. So, as you go up on the dose over and over again, they get a shorter and shorter reprieve before the symptoms get out of out of hand. So, we all agree that the definitive treatment of augmentation always involves stopping the offending dopaminergic medication. Now, how you do that is where there’s a lot more disagreement. So, we generally agree that you want to top off iron as much as you can, and we’ll get to iron treatment here in a minute, but if at all possible, I would try to do a round of intravenous iron in someone that we’re going to stop the dopamine agonist. There are differences in whether you abruptly stop it. Do you go cold turkey to get it over with faster, or whether you try to down titrate it more slowly, but an important point is that the first night that you reduce the dopamine medicine, symptoms are going to be worse, okay, and you get this exacerbation, most commonly, I would say for three to seven days. So, it’s very, very important to talk to patients and to warn them and to plan this out, okay? I mean, the patients have to plan a time where they may be more sleep deprived than they’ve ever been to get off the medications. Now, almost always, again, the first couple of

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nights you stop dopamine, no matter what else you do, you’re going to get worsening of symptoms, and this is an important point, because this slide talks about cross titrating a gabapentinoid, you know, a gabapentinoid type medication, but I want to emphasize that’s not going to usually be immediately satisfactory. They’re going to have a worsening of symptoms. Even when we go to opioids, which is what we more commonly do for a short-term, to cover up this, this exacerbation, you’re still often going to have a bad, a really bad three to seven days. Now, an important point is, though, once you get over the augmentation, if they’re off the dopamine agonist for a couple weeks, then the gabapentinoid medicines will often work, but at that first day you swap over, if you’re just going right from a dopamine drug to gabapentin medicine, usually that’s not going to be a satisfactory, and again, another thing you got to educate the patient about, that just because it didn’t work if you do make that swap, it didn’t work now. A few weeks later these medicines may work. So, it is a challenge, okay? There’s no way around it. We do have patients that are pretty easy, but others that, wow, I mean, it is just a miserable week or so when you try to get off the dopamine medications. Now, there are a couple of other statistics

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about using dopamine medicines basically making the point that many people do eke up on the dose and escalate the dose and escalate the dose. I do this myself, okay? I cannot cast stones here, but many patients are on doses well above the FDA recommended doses for dopamine agonists, and again, although that transiently may work, ultimately, that strategy typically will fail. Okay, let’s talk about iron for just a minute as another sort of segueing into treatment options. A couple aspects about iron. So, there are some official recommendations, not really based on empiric data so much. Oral iron is often recommended for RLS, but a key point to this is that oral iron is highly regulated by ferritin levels. Whether they truly represent iron, or whether they’re part of an infection or, you know, just some osteoarthritis or whatever else will increase inflammation, increase ferritin. So, if you have a ferritin over 75, the chances of you absorbing iron pills is pretty slim, and probably, you’re wasting your time. Okay? If the ferritin is very low, you do absorb oral iron much better. Now, there are some tricks to oral iron. One, it should be given in a somewhat acidic milieu. So, vitamin C is often added to iron. It should be a two-plus preparation, okay, so, as opposed to three plus, and it should be taken by itself. So, both food and other divalent metals will inhibit the absorption of iron. So, iron in a multivitamin pill that contains calcium or magnesium, or manganese is not nearly as effective as the iron pill by itself, okay? Now, intravenous iron, which we frequently do use in, you know, our tertiary referral center, circumvents all of these problems with oral iron. I have no problem with oral iron, but like I said, if their ferritin is high, you’re probably really wasting your time. Okay, another important thing, if they come to you with a worsening of RLS, is look for exacerbating factors. Probably the most common one here is sedating antihistamine. So, a sedating antihistamine is an antihistamine that crosses the blood-brain barrier, okay? That’s the difference between sedating and non-sedating antihistamines. So, a diphenhydramine, for example, Benadryl, is probably the single most drug that that worsens RLS. Most of the patients will tell you this, because at some point, they tried over-the-counter sleeping pills, and they tried some Tylenol PM or something with diphenhydramine in it, and they had the worst night of their life.

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I’ll argue anyone that’s ever told you either allergic to Benadryl has RLS, okay, because that’s the main thing that gets worse with RLS. So, that’s important to keep in mind. Antihistamines are all over the place. They’re used for itching medicines, you know, again, many over-the-counter medicines, many prescription medicines not marketed as antihistamines have antihistaminergic properties. So, Mirtazepine, for example, which is a classic medicine that worsens RLS probably because of the antihistamine properties. So, again, that’s a big one here, things that can worsen RLS: over the counter or prescription medicines with antihistamine properties, alcohol, and frankly, anything that can relax you can worsen RLS. Okay? So, that’s a problem. SSRIs will consistently worsen periodic movements of sleep. I’m old enough that I was around when Fluoxetine or Prozac came out, and within six months, the sleep docs were all calling it Prozac legs, because everyone had PLMD. Now, that being said, I don’t personally think they’re contraindicated in restless legs. I think there’s less of an issue with urge to move than the actual kicking component, but just keep that in mind. SSRIs, of course, very common medicines. Dopamine antagonists, the interesting things about them is they don’t always worsen RLS, but they certainly can in some cases. Okay. So, in looking at the different therapies, there are some pros and cons of some of these, and again, some of this is based on evidence base or trials, and some of it is kind of anecdotal and assumptions. So, the alpha two delta ligands or the gabapentin type medications, you know, clearly show benefit in NYS-based three control trials, at least, Gabapentin Enacarbil does, and the biggest advantage compared to dopamine drugs is they don’t seem to have augmentation. Keep in mind they also can improve sleep paradigm, especially slow wave sleep, and they’re used for pain. Okay? I mean, and, you know, RLS may not be in a vacuum. So, if someone has back pain and RLS, well, that’s certainly part of the calculus that goes into deciding these things. Dopamine agonists are probably better at periodic movements of sleep. If you give a big dose of a dopamine agonist,

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it will knock the PLMS down to zero in most cases, but the disadvantage of them is the augmentation, and again, they don’t really help with sleep, per se, other than the PLMS. Okay? Opioids, we haven’t talked about them too much. They actually can be very effective for RLS, but there’s much, much less data on opioids for RLS, and the advantages, again, I think the efficacy and the fact they don’t cause augmentation. The disadvantages include the side effects profile. I mean, constipation being the most common, and just the general problems with chronic opioid therapy. Obviously, there’s been a big backlash against this, and when we do use these, it can be very problematic and difficult to use these medications. Also, there’s compelling evidence that, if they do have concurrent sleep apnea, that opioid medications will worsen that. Benzodiazepines, there’s actually almost no data supporting the use of benzodiazepines in restless leg syndrome. There is data that they will reduce awakenings from PLMS, although they actually, in the studies, if you look at them, they don’t really reduce the rates of PLMS. They just reduce the awakenings from PLMS. So, we occasionally use these medicines as adjunct therapy. If patients need a sleeping pill. I think benzos don’t worsen RLS as opposed to antihistaminergic sleeping pills, which definitely can actually worsen the RLS, and of course, worsen sleep. There’s some specific populations to look at as well. The biggest one, and the only one for which there’s much data, is end stage renal disease, but also, kidney disease that doesn’t require

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dialysis. Both of these populations of higher rates of RLS. It seems that the medicines work similarly, although they may be a little bit more refractory, and sometimes, they seem to require a bit higher doses than the general population, and then finally, pregnancy. This is a real problem. It’s common that, in the last third of pregnancy, the last trimester, that patients will get RLS, in about between a quarter and a third in various studies. It usually resolves with delivery. Like, the next day it resolves, but we don’t have any data in how to treat this. There never will be a study in the third trimester of pregnancy to treat restless leg syndrome. So, this can be problematic, other than folate and iron supplements and things like that, which are certainly generally considered safe. Okay. So, with that, I think it, I’ll hand it over to Dr. Ellenbogen to discuss a little bit more detail about Gabapentin Enacarbil and then present a case showing some of the difficulties of treatment with RLS.

DR. AARON ELLENBOGEN: Okay. Well, thank you, Dr. Ondo. That was a great review of all things RLS in terms of pathology and the treatment landscape and so on, and as you had mentioned, I’m going to now shift gears a little bit, and we’ll spend some time discussing HORIZANT, or Gabapentin Enacarbil. Just waiting for… can you advance my slide for me, please? Thank you. So, to begin with, HORIZANT or Gabapentin Enacarbil, is an extended-release tablet, and it actually is indicated for treatment of moderate-to-severe primary restless leg syndrome in adults. It is not recommended for people who are required to sleep during the day or who have shift work and are required to remain awake at night. The other thing is, it is also indicated for the treatment of postherpetic neuralgia in adults. As far as how this medication is administered, it should be swallowed whole. It shouldn’t be crushed or chewed in any way, and it should be taken with food. The reason that we ask people to take it this way is that the extended-release mechanism is such that, if you crush or cut the tablet, then this is a… it will destroy it, and it becomes an immediate release medication. For restless leg syndrome, the dose is 600 milligrams daily taken about 5:00 PM. This, of course, is dose adjusted for patients with renal impairment, and there is a table in the prescribing information to review exactly how that may be adjusted. For postherpetic neuralgia, it’s started at 600 milligrams in the morning for three days, and then ultimately titrated to 600 milligrams BID on day four. Again, the dose adjustments may be required for patients with impaired renal function. Next slide, please. For some reason, I’m unable to advance them. So, I think it’s important to understand the differentiation between Gabapentin and Gabapentin Enacarbil. Just as a reminder, Gabapentin Enacarbil is actually a pro-drug, and really, it’s a situation where necessity is the mother of invention. Conventional Gabapentin, while it can be an extremely effective medication for a variety of conditions,

[00:40:00]

and it has been used broadly both on-label and off-label, for those of us who have an experience with it, one of the things that we’ve come to understand is that there can be quite a varied response to the medication, and what this really is a result of is the fact that it is passively absorbed in the upper part of the small intestine through a pathway that is saturated quite easily. So, for some patients or some individuals, this may actually be saturated at very low doses of gabapentin. Others do have a higher capacity for absorption and can absorb higher doses much

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Transcript by TransPerfectmore regularly, but there’s a tremendous difference in bioavailability from one person to the next, and so, this can be quite challenging as we try to manage our patients, and so, because of this, we need something that’s a little bit more predictable, and hopefully, something that can provide more consistent response for our patients. Next slide, please. So, that was what led to the development of Gabapentin Enacarbil. It turns out that this pro-drug, by attaching a moiety that is recognized by a high volume, high-capacity transporter that’s actually present throughout the intestinal tract, really accomplishes two things. This transporter is called MCT1, and it’s expressed throughout the small intestine as well as a large intestine. So, by having a high-capacity transporter, number one, you’re not going to saturate the absorption, and it gets converted very quickly, once it passes through the luminal wall of the intestine, into just gabapentin. That that pro-drug piece is cleaved off, but the other thing is that this is what allows for an extended-release preparation, and so, in contrast to conventional gabapentin where you get saturation, we really don’t see saturation, and this has been studied at doses that are far beyond what we would use therapeutically in treating either restless leg syndrome or postherpetic neuralgia. Next slide, please. So, this is just a way of looking at the difference in bioavailability and what we’re able to achieve. These are equimolar doses of gabapentin. So, HORIZANT 1,200 milligrams gives you about 626 milligrams of conventional gabapentin in the fed state, comparing it to 600 milligrams of conventional gabapentin. Although the conventional gabapentin may rise a little bit more quickly, and this is a function of the time release mechanism, ultimately, we see that we have a higher peak plasma concentration, and we also find that it can last substantially longer. So, we have an improved area under the curve, and we take the pharmacokinetics of this drug and use it to our advantage. So, one of the reasons that people are actually typically advised to dose around 5:00 PM, as you can see, you start to achieve levels that are more likely to be therapeutic and help ameliorate symptoms within a few hours, and so, by hour four, we’re starting to approach what you would see with the conventional gabapentin, and that may very well be sufficient to start treating RLS symptoms in those evening hours, when people who experience them may be at their greatest, and then certainly we get this longer duration of effect, and so, can carry through and hopefully last until the time where people are less likely to have those symptoms occurring, around 6:00 AM to noon, and so, you see a tailing off of the drug, and then they re-dose the next day. Next slide, please. So, just to show in a different way pharmacokinetic studies, number one, we find that there is a better bioavailability, but additionally, this dose proportionality shows that, as you titrate the dose, you do certainly have an increase in the proportion, or increased availability based on that dose, and so, again, this looks at doses beyond what we use in treating either RLS or postherpetic neuralgia, and it certainly, the curve continues to even higher doses that were studied, and there’s certainly literature available to review this. Next slide, please, and in terms of the bioavailability, again, you get a dose proportional response in terms of exposure to gabapentin. This is just looking at the potential for BID dosing, and so, the 24-hour concentrations with the food and without. Next slide, please. So, to give you a little more precision in terms of what you can get in terms of bioavailability of HORIZANT versus conventional gabapentin, you can see that it’s really twofold in, when taken HORIZANTs in the fed state versus conventional gabapentin bioavailability in the fasted state, and so,

[00:45:00]

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the main point to understand here is really that these are not bioequivalent drugs. They’re not interchangeable. The label says they’re not interchangeable. However, sometimes, we have to deal with insurance companies who see the word gabapentin and assume all gabapentin is created equally, and because this is a pro-drug, it actually behaves in a very different fashion. Next slide, please. So, shifting gears now and actually talking a little bit about the randomized controlled trials. The way the trials were designed is people were randomized to receive either a placebo or 600 milligrams of HORIZANT, or 1200 milligrams of HORIZANT, and as you can see, there’s a fairly early separation between the two groups, placebo and active treatment arm, and this is sustained really throughout the 12 weeks, and we can see that, when you look a little more closely in the orange and the blue lines, which are the two doses of HORIZANT, those do not separate out. So, first of all, there is a clear and significant improvement in RLS symptoms, and there was a 40.8% reduction versus placebo. If you could advance, please, and it did meet both of the primary endpoints, and so, this is, first of all, an improvement on the International Restless Legs Rating Scale score at week 12, but also, the proportion of responders had actually rated their… had their symptoms rated as very much improved or much improved on an investigator clinical global impression improvement scale. So, it did meet both of those co-primary endpoints. Next slide, please. The one thing to point out, though, is because there is no separation between the doses of 600 and 1200 milligrams, ultimately, only the 600-milligram dose was approved for treatment of primary restless leg syndrome. Next slide, please. As I had pointed out when you were looking at the graphs, it’s fairly easy to see that there does seem to be a fairly early response, and at week one, there was a 42% reduction from baseline for the active treatment arm at 600 milligrams. There was a placebo response, which was about 25% improvement. So, clearly, there is a placebo response, which we expect in this population, but we do see improvement, and so, this is important in terms of setting expectations for our patients, and with the exception of the situation where we’re trying to manage someone with augmentation, where it can be a little bit more challenging in a quote/unquote clean RLS patient that isn’t experiencing those complications of treatment. We can usually guide them that they should expect to start seeing improvement within that first week. Next slide, please. So, what I want to do is share some of the warnings and precautions with you, because there are some safety issues that we need to cover. HORIZANT can be sedating for some people. Dr. Ondo had mentioned the impacts of gabapentinoids in general on sleep in the RLS population, and we know that HORIZANT certainly can be sedating for some individuals, and so, the general guidance is that people should see how this medication affects them prior to operating a car, for example. So, typically, I tell a patient when they are first starting the medication that they should be in a position where they don’t have plans to go out for the evening, or if they do, they shouldn’t be out driving. They should actually have someone else drive them and give themselves enough time, whether it’s a single dose or several days of dosing, to have a sense of how they respond to the medication in terms of a side effect such as sedation. Similarly, you know, we talk about the dizziness aspect as well. So, we just warn people that, before they resume or go about their normal activities, they should understand how this affects them. As I had mentioned, this is not interchangeable with generic gabapentin or any of those generic formulations, and again, this is a pro-drug, which has certainly very different properties in terms of its bioavailability, and so, we expect people may respond differently when you give equimolar

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Transcript by TransPerfectdoses. HORIZANT is a pro-drug of gabapentin and is an anti-convulsant drug. AEDs have actually been associated with increased risk of suicidal thoughts or behavior in patients taking these drugs for any indication, and so, because this is a pro-drug of gabapentin, that’s the parent compound, we do have the same warning. So, patients should be monitored for any signs of worsening depression, and certainly, suicidal behavior ideation, and patients and their families should be informed that this can be a potential challenge for this population. Next slide, please. With regard to respiratory depression,

[00:50:00]

there’s evidence from case reports and human studies and animal studies associating gabapentin with serious life threatening or fatal respiratory depression, particularly when co-administered with other CNS depressants, and so, this is something that, in particular, when administered with opioids in the RLS population, it’s something that we need to keep in mind, and so, patients need to be monitored carefully. There is also, a concern regarding DRESS, which is also, known as multiorgan hypersensitivity, and this has been identified in patients taking anti-convulsants, including gabapentin, and it can manifest with things such as lymphadenopathy, fever, or rash, and can have other organ involvement, including hepatitis and nephritis, and so, if there’s any evidence of hypersensitivity, even if a rash isn’t evident, this is something that the patient needs to be evaluated, and HORIZANT should be discontinued if there’s no alternative etiology that can be established. As far as discontinuing HORIZANT, this is a drug that, at the doses that are indicated for RLS, can be stopped immediately. However, if people are titrated to a dose beyond 600 milligrams, then they should be reduced to 600 milligrams once daily for a week prior to discontinuation. This reduces the risk of potential withdrawal seizure. There’s this other issue that’s been identified and really is of unclear significance, but in a rat model, there were actually an increase in pancreatic acinar cell adenomas. It hasn’t been identified in human use thus far. It wasn’t seen with generic gabapentin, and so, it remains an interesting finding, but it’s not something that we can really provide any clinical context for at this time. Next slide, please. So, again, just as a reminder, the most common adverse reactions for patients with RLS were somnolence and sedation and dizziness, and in the postherpetic neuralgia population, again, dizziness, somnolence, and headache. Just as a reminder, there are no pure drug-drug interactions. However, because alcohol can also be sedating, and is a central nervous system depressant, it’s advised not to take alcohol when using HORIZANT. Similarly, drugs such as morphine or the other opiates can also exacerbate that potential for somnolence and sedation, and I did mention the potential issue of respiratory depression, and so, just something to keep in mind if you are using these medications in combination. So, the patient would have to be monitored quite closely. Next slide, please. In terms of special populations, and Dr. Ondo had mentioned this, in terms of just how do we treat these folks. With pregnancy and lactation, it has not been studied. However, we do know that both in animal models and in humans, the conventional formulation of gabapentin has been identified as being expressed in breast milk, and so, it is something that can’t… if a person, if a mother who’s nursing is taking HORIZANT or gabapentin, it can be present in breast milk, and it’s not clear what impact that may have on the baby, and so, as a result, it’s certainly not considered safe to use in that population. Similarly, HORIZANT has not been studied in the pediatric population. With regard to geriatric use, I

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would just bring to your attention that, as I’d mentioned before, there may be some need to dose adjust based on creatinine clearance, and so, this population is at higher risk for having reduced creatinine clearance, and so, sometimes, that may be an issue. If you haven’t had recent labs, then some people will actually check this prior to initiation of the dose of medication. Similarly, in a patient population with renal impairment, because this is a drug that’s excreted almost exclusively by the kidney, dose adjustments need to be made, and as I had mentioned previously, this is available in the prescribing information, and so, you can find what dose adjustment needs to be made for various creatinine clearances, and then of course, there is additional safety information and prescribing information for HORIZANT as well. One thing that I do think is important is, if you have a patient with a suspected adverse event, you really, you know, Azurity would prefer that you report it, and you can report it to them at the 800 number listed there. It can be reported to the FDA or through the website for MedWatch, and again, this is important because it helps us, as clinicians, understand the full context and the full potential, as well as adverse events associated with a medication, and so, that helps us better treat our patients. Next slide, please. Next slide. So, what I wanted

[00:55:00]

to do is close with a case study, and this is based on a patient that, actually, I saw in my office, and so, I think this is something that actually rings fairly true. This is a patient who has been diagnosed with restless leg syndrome. She has very typical sort of symptoms. She has symptoms that typically occur on a daily basis around 8:00 PM, although if she’s seated and a little bit more confined or restrained in terms of her ability to move around, she may develop symptoms in the late afternoon. So, a long car ride, for example, might provoke that. Her symptoms she describes as a tingling sensation, so, paresthesia, and there is some pain to it, and, you know, the pain is difficult for her to describe. It does seem to be worse on one side than the other and typically occurs between the ankle and the knee. It’s certainly worse at rest and relieved with getting up and walking around. There is this diurnal variation. It’s worse in the evening and at night. She does see some benefit from counter stimulus, such as rubbing her leg, but it is still disruptive to sleep and lifestyle. So, she went to her primary care physician after the onset of symptoms, beginning about five years prior. She has no family history of restless legs, and she was placed on primary Paxil. Ultimately, she had an increase in symptoms, and so, she was gradually titrated from 0.125 and landed on 0.5 milligrams at night. After being titrated, she started to develop some issues that are concerning for impulse control disorders. She was making online purchases of items that she did not need, and this was brought to the attention of her primary care physician, who discontinued her medication and referred her to neurology. She was not on any other medications at the time of her presentation. Labs were drawn, and her ferritin, you can see here, was 178, and the remainder of her iron panel was normal, and so, the treatment plan was, because of her development of impulse control disorders, there was no signs of augmentation, she was started on HORIZANT 600 milligrams at 5:00 PM, and she was monitored for adverse events that we had discussed during the visit, so, the typical things that I’d mentioned: dizziness, somnolence, and sedation, and within a few weeks, she was reassessed and reported marked improvement in her symptoms. So, at this point, I don’t know if Dr. Ondo has anything to add to the case, but certainly, if you have any comments, please share, and then, you

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know, I’d certainly like to thank everyone for participating today, and just as a reminder to enter any questions that you have into the chat, and we can answer them.

KELLY DAVIS: Thank you, Dr. Ondo and Ellenbogen, for your fantastic presentations. We do have a couple of questions. Question number one: is there a vascular workup indicated for ruling out RLS?

DR. WILLIAM ONDO: I would generally say no. I mean, you know, there was an old hypothesis many years ago that vascular insufficiency was associated with RLS, and I still have some patients that get venous stripping done with RLS, but I’ve never had anyone that was really convinced there was any benefit to it. So, no, I don’t think there’s any role for that. I mean, the evaluation, we always do iron studies, and if there is nothing else indicated on the history or physical examination, that’s really our evaluation for RLS. If we think, again, we think they have sleep apnea, we might do a sleep study. If there’s reason to think they may have renal failure or neuropathy, you could pursue that, but for pure RLS with no other indications, it’s really just the iron studies that we do.
DR. AARON ELLENBOGEN: I agree with that. I mean, really, the iron studies are key. There’s very little other testing, as Dr. Ondo had mentioned. There’s rarely an indication for getting a polysomnogram. I think the biggest thing and the place where people get hung up the most is by failing to identify concomitant medications that may be exacerbating their situation.

DR. WILLIAM ONDO: Yeah.

KELLY DAVIS: Great. We have one more question. For a breakthrough of HORIZANT, would you consider low dose naloxone instead of methadone?

DR. WILLIAM ONDO: Well, I’m not sure about naloxone. Well, I take it back. There is a small study suggesting naloxone could be beneficial. I’ve never used naloxone by itself. Okay? Methadone’s a slow opioid. You know, I’m not sure if I commonly use opioids as a PRN therapy. I mean, usually, when we decide to bite the bullet and go to opioids, it’s, you know, it’s just a standard therapy, and there’s not much data to support one, but personally, no, I’ve not used naloxone by itself for restless leg syndrome.

[01:00:00]

For PRN therapy, there’s, again, zero data. We occasionally do use dopamine drugs as PNM in addition to a gabapentinoid, but even that’s a little bit risky, that you could potentiate augmentation in the long run. There are people that might give a little bit extra gabapentin, okay, or sort of a faster acting, milder opioid, you know, tramadol or something along those lines could be an option as well.

DR. AARON ELLENBOGEN: I agree with Dr. Ondo. Again, I have no experience with naloxone in treating restless leg syndrome. I am aware of the small paper but don’t have any

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personal experience, and I am someone who will actually use additional gabapentin, whether it’s immediate release formulation, to try to supplement what they’re doing with their HORIZANT.

KELLY DAVIS: Great. Those appear to be our last questions.

DR. WILLIAM ONDO: Okay.