Good afternoon and welcome to this APA virtual immersive day of SILI. I am going to be talking about less the site syndrome and the lesser extensively related movement disorders over the next 45 minutes to an hour. Please consider these potential conflicts of interest when listening to the content of this talk. Two things that I would like you to leave with from this talk. Dopamine agonists, which have been the mainstay of treatment for restless like syndrome for 20 years are associated with worsening of restless like symptoms called augmentation. And according to the recently released American Academy of sleep medicine, clinical practice guidelines are no longer first-line therapy for our lives. Number two, those individuals who you are seeing in practice who have a worsening of restless legs due to prior use of dopamine agonists can be managed with other RLS treatments. One of the alpha to delta agents, gabapentin, pregabalin, gabapentin and carbol, use of iron in appropriate patients, or opioids. The goal when you see somebody with augmentation is to use those medications, adding them first before changing the dopamine agonists. And then extremely slowly over a matter of many months, papering and discontinuing the dopamine agonist, which is associated with iatrogenic worsening of RLS. I want to introduce you to a new website that we have developed at Mass General called rlsherbside.org. This is a free HIPAA compliant non-commercial website, like a Reddit forum, where you can sign up using your health care license. You have to provide that. This is not for patients. And then fill out a template information about the patient, the variety of questions that you put on the website. We make sure that it is de-identified. And then a variety of other providers will respond to your question, giving you some guidance about how to manage these patients. rlsherbside.org. So, backing up. Restless leg syndrome. The acronym for diagnosis is URGED. You need to have all of these features to have restless leg syndrome. You have to have an urge or a need to move, usually the legs, sometimes the arms, that are oftentimes that need is associated with dysesthesia, uncomfortable, unpleasant feeling. You ask people what it feels like, the most common thing they will say is, I can't describe it, but I just have to move my legs. These feelings are present at rest, generally lying down or sitting. If they start while somebody was standing or walking, not restless legs. G, they get better while you are moving, not permanently, but while moving, they get better. And then interestingly, because this is unusual for most medical disorders, they have a strict circadian rhythm, unless people have severe symptoms, in which case they are predominantly present in the evening or at night. And these are not leg cramps, this is not akathisia, this is not joint pain, and those are potentially. So, RLS is the third most common sleep disorder in adults, by far the most common is insomnia, chronic basis, DSM, called insomnia disorder, sleep apnea, second most common, clinically significant RLS present in 2.5% of adults, and about 1% of kids, you can see much more common than adults. When you look at the prevalence over lifespan and divided by sex, you can see that women have about twice the prevalence of RLS as men, and that for both sexes, that prevalence goes up substantially with age. We have oftentimes divided RLS into primary and secondary, secondary being those that are associated with another medical disorder, often which is reversing. So, primary RLS, we don't have one of those associated medical problems, and it's reversible. Secondary RLS, the things we need to think about are iron deficiency, we'll talk about the exact numbers in a moment, renal failure, pregnancy, particularly second and third trimester, peripheral neuropathy and MS, serotonergic antidepressants, certainly worse, rheumatoid arthritis, and a high prevalence of RLS in those undergoing opioid withdrawal. As we will see, opiates treat RLS, not a surprise that opioid withdrawal brings out. For those individuals who have severe RLS, it is usually not going to go away, unfortunately, in the idiopathic ones, unless they get a renal transplant or we fix their iron. Those people with moderate RLS, then you may see waxing and waning, so people may have periods when they go into RLS. And many people with mild RLS only have it intermittently under certain conditions, long plane rides and car rides, and so necessity for chronic treatment needs to be carefully considered. We know two things about the pathophysiology problem. One, we know that there's a strong genetic component. And if you do GWAS and you add up all the genes that contribute to the prevalence of RLS, the incidence of RLS, the genetics stands for about 20% of RLS. So you're going to hear from patients that they have a family member or multiple family members with RLS. The other thing that we know about pathophysiology of RLS is associated with low brain iron. And on the right side here, you can see one study looking at CSF ferritin on the y-axis, serum ferritin on the right axis. And then you can see for a given serum ferritin stored iron in someone without RLS, it's roughly a quarter of what you're going to see in those individuals with RLS. I'm sorry, CSF ferritin is much higher in those individuals with normal GWAS than patients with RLS. So there is something about transport of iron into the brain or metabolism of iron within the brain that is abnormal in individuals with GWAS. This has been demonstrated on MRI, at post, by CSF here, and by Transcranial Doppler. However, when you check your patients with RLS, when you check their serum finances, you're going to see that the majority of them have normal, within normal range. But for RLS, we want to push their irons higher than just the lower level of normal. We want them at least in the middle of the normal range, which does seem to assist with restlessness symptoms. When people with RLS go to sleep, they commonly have periodic limb movements of sleep, which is called periodic because the intermovement interval is relatively stable, as you can see here in this figure that I took from my patients. These are generally small movements of the foot and knee, but can be much larger and more violent in more severe RLS. You can see that with each of these movements, there's an increased heart rate, and oftentimes an EEG or breathing arousal in sleep. Please note that a significant percentage of the population, particularly older and those on serotonergic antidepressants, will have PLMS. That doesn't mean that they have RLS. So a lot of people, if you look at a Venn diagram, a lot of people with PLMS, only a minority of those will have RLS, and everybody with RLS will have PLMS. So why do we care about RLS? Well, it's certainly sleep disturbance. Feelings that you have to move your legs and associated with discomfort that occur at night are going to interfere with sleep, and that's what brings most people into your office, instead of sleep. It's also reduced quality of life, increased risk of major depression and anxiety disorders, and we have demonstrated in a number of studies, increased risk of cardiovascular disease, incident cardiovascular disease. The American Academy of Sleep Medicine has just released new guidelines. These are the first guidelines for RLS in 12 years, and we're going to go through those guidelines. And we have good practice statements that are at the beginning of the guidelines that say you want to try to, before adding any treatment for RLS, you want to try to address those things that are making RLS worse. In particular, alcohol makes RLS worse, number of medications including antihistamines, centrally acting antihistamines, whether those are traditional antihistamines or antihistamine effects from antidepressant or stabilizing medications, serotonergic reuptake inhibitors, dopaminergic antagonists. We've talked about iron, and anybody with RLS should have an attempt to treat their obstructive sleep apnea because that can improve. We're going to talk about the exact ferritin and transparent saturation levels that we want to reach in patients with RLS and recognize that RLS is common in pregnancy. At this point in time, we probably just use IV iron in those women rather than patients. So the grade criteria that the American Academy of Sleep Medicine used divided all randomized controlled trials into four boxes. Medications that we recommend for, medications we recommend against, and in each of those two, they're strong for and conditional for, and conditional against and strong against. First-line agents for RLS, and they no longer include the dopamine agonists. They are the Alpha-2-Delta-Calcine channel blockers, which are gabapentin, gabapentin-phenylparval, and preavil, as well as one particular form of IV iron for which a number of controlled trials had been performed. Those four are first-line treatments. Second-line treatments are another, this other form of IV iron, dextran, oral ferrous sulfate, and we'll talk about when you should use oral iron versus IV iron. There is one randomized controlled trial for diperidamol, which demonstrated efficacy in RLS, and opioids. Any of the new agonist opioids are conditionally recommended for RLS, given, of course, the limitations and the caution that you need to express in prescribing these medications for anybody. And this is where these recommendations dramatically changed from those 12 years ago. The dopaminergic agents, levodopa and Paxil, transdermal reticulatine, Pinerol, are now recommended conditionally against. American Academy of Medicine, Sleep Medicine, conditionally recommends against their use. However, you'll see in the caveat below, for patients who place a higher value on the reduction in RLS symptoms in the short term, and a longer value on adverse effects, particularly augmentation with long-term use, these medicines could be selected for treatment, as long as you see people regularly and keep the dose below the maximum dose that the FDA recommends for RLS. The reason why they're conditionally against is because, you can see highlighted here, they've all been associated with augmentation with RLS. A worsening of the underlying disorder over a period, usually a year, is insidious worsening that, unfortunately, then you find yourself involved. So, there are four classes that have good efficacy, significant numbers of studies that have demonstrated efficacy. We're going to go through each one of those in turn. Calcium channel, alpha 2 delta ligands, and I mentioned 4-gallopentin gallopin today, arbol-3-gallon. These are the range of doses that we would recommend for RLS, starting certainly at the lower end, depending upon patient's vulnerability to their specific side effects of these meds. Side effects, of course, include sedation, dizziness, weight gain, gait instability, and cognitive dysfunction. There's no evidence of augmentation with these agents. However, for gabapentin in particular, one thing that pharmaceutical companies who commercialized these did not make clear to providers is that gabapentin has non-linear pharmacokinetics. So, if you can see, even by the time you get to a single dose of 400 milligrams, you've fallen off the linear dose. The serum concentration in the area under the curve is about 30, whereas it should be around 40. By the time you get to 800, serum AUC should be about 80 or 90, and is about 40. The gut receptors can only absorb so much at a time. So, if you want to use gabapentin at higher doses, you need to split the dose, allowing the receptors to empty their contents into the bloodstream, and then be ready for more. Gabapentin in a carbol is a controlled release pro-drug of gabapentin, which avoids the non-linear pharmacokinetics. It has linear pharmacokinetics. It usually is administered once a day at 5 p.m. with food. So, if you take it with a fatty meal, you're going to get better absorption, and the dose of that is anywhere from 600 to 1,200 milligrams a day, and that will give you pretty much 24-hour coverage, or RLS, if you need it. Regabal is the third alpha-2-delta, one that's commonly used at this point in time. You can see here, new in the Journal of Medicine paper that we published in 2014, head-to-head trial of placebo, pramopexol at two doses, 0.25 and 0.5, and pregabalin at 300 milligrams. And you can see that pregabalin beat both doses of the pramopexol, and the higher dose of pramopexol and pregabalin beat placebo. Then everybody was on placebo at the end of three months, got re-randomized to either pregabalin or one of those two doses of pramopexol, and then followed for the next nine months. And blindly, augmentation was assessed at the end of the 12 months, and at the higher dose of pramopexol, about 8% risk of a worsening of RLS, find very strictly 5% in the lower dose, 2% with pregabalin. I don't think that that's a true augmentation. I think that that's natural worsening, disease, and limitations in the methodology by which we assess augmentation. When we looked at those individuals who had been on the pramopexol for a whole year, not just nine months, the rates of augmentation were about nine and a half. So pregabalin does not have the absorption issues of gabapentin, very similar half-life to gabapentin. So if you want to treat people who have symptoms 12 hours a day, you may very well need to dose twice a day. So dopaminergics are no longer recommended for RLS. I think that's clear at this point. These agents are FDA approved. They, in the short term, they are miraculous in terms of their efficacy, and in suppressing periodic weakness of sleep. They also improve subjective, not objective, but subjective sleep quality. But augmentation, over time, occurs in many people who take these medications. What is augmentation? Augmentation was characterized by earlier appearance of symptoms during the day, before treatment, they started at 10 o'clock. So you gave the medicine at nine, things were good for a year, maybe two. Then they came back and said, you know, symptoms are starting at six or seven. So you increase the dose, giving some of it at five, the rest of it at nine. And that went for a while, until a couple of years later, they say, you know, now symptoms are starting at four or five, or maybe two o'clock. So this expansion, augmentation, increased size, temporarily, timely. You also get an increased size. Symptoms move from the legs to the upper extremities, or torso, which are very disturbing symptoms. Symptoms also have increased severity, and happen more quickly with ability. We don't have a good sense of what percentage of people with RLS are augmented. I'm not going to belabor this point here, but in trying to understand this, I got data from a company called IQVIA, who knows everything that you're prescribing, and I'm prescribing as well. And they have de-identified data there, crossed with diagnosis. For over a million healthcare practitioners in the United States, and we looked at those individuals who had breast cystic syndrome, with diagnosis of breast cystic syndrome. That's 670,000 individuals. We excluded anyone with Parkinson's disease, and looked just at those people on dopamine agonist, which is about 60% of the total. And then we looked at doses. And you can see that if you add these up, about 20% of individuals taking a dopamine agonist, are taking it above what the FDA says should be the maximum dose. In fact, the Pranifexol, we didn't use 0.5 as the maximum dose, we used 0.75. So I'm sure it's substantially higher than this 20%. There's only one reason people get to those doses. And it's because they have augmented symptoms. My guess is around 40%, maybe more of individuals with breast cystic syndrome are currently on them. Psychiatrists use dopamine agonists less commonly than the specialists. This is from that same data, and the lighter colored blue here is dopamine agonists. And only about 30% of prescriptions for RLS patients prescribed by psychiatrists are for dopamine agonists. Whereas as you can see in sleep doctors, it's 75%. And including those practitioners and VAs, it's about 60% neurologists also that's. So augmentation is the primary challenge currently facing clinicians treating RLS. It's easy to treat RLS if you give a dopamine agonist. People are very, very happy for a short period. It's been so good acute. However, when things go south, most doctors say, well, you know, that was so good at the beginning, let's just give you more. And that works again for a while. But higher doses lead to more rapid and more severe augmentation. So you get into this vicious cycle. And I say to people, this is like trying to put out fire with gasoline. And anybody for whom you're prescribing anything for RLS is like, certainly at the first appointment and I would recommend at any later appointments, try to figure out the shape of their arms. By that, I mean it's temporal appearance and severity. So I say to people, I'm gonna divide the day into four equal parts, anywhere from six or seven in the morning till noon. How many days a week do you get it during that time period? And when you get it during that time period is mild, moderate, severe, or very severe. I can say noon to 6 p.m., same thing, 6 p.m. to 11 p.m., same thing. And then 11 p.m. to 6, 7 a.m. So I'm getting a shape of its appearance and severity. And then you can monitor this with therapy over time. You also, in addition to monitoring for augmentation, you wanna ask about impulse control. So there's a wide range of ICDs prevalence in people with RLS, anywhere from seven to 40%, as you can see. And ICDs, as you may or may not be aware, are an increase in these impulsive or compulsive behaviors, increased interest in gambling, spending money, binge eating, or increased sexual activity or watching pornography. And people will say, I'm not sure why I'm doing these things. I'm really not getting much pleasure from it, but I feel this drive to do it. This is an impulse control. And there are some potential risk factors for this, but I think that these studies are really kind of too slow, too small to establish risk factors. You really need to ask about ICDs when you're prescribing dopamine agonists for RLS, which I'm hoping you will do less and less of. Iron. Number of good studies showing that oral iron and IV iron are good for patients who have low iron at base. So ferritin in your labs, probably lower limit of normal ferritin is maybe 10 to 15. In these studies of RLS patients, the mean ferritin was 38 for oral iron, for IV iron here mean was about 45. So these are normal level. And you can see there was a dramatic improvement with the oral on. The placebo group really didn't get much better at all, minus one, whereas the oral iron group had minus 10 in the RLS severity scale. And you can see the same RLS severity scale here, placebo in blue, really not much change with IV saline versus IV paravoxymaltose, where about a 10 point change in the RLS severity score. What's interesting is that IV iron does not work immediately at week one, just about no effect. At week four, you really get good effect, but maximum benefit was at week 12. So the guidelines for IV iron in RLS, anyone with a serum ferritin under 100 and a transparent saturation, which is iron divided by TIPC under 45% is potential candidate for IV iron, particularly if oral iron has failed. If they had a ferritin of 50, 40, and you gave them a couple months of oral iron and didn't produce any benefit. And in fact, the ferritin didn't improve, then I would go with IV iron. Ferritin did improve, but say to over a hundred, then it's not clear that IV iron is going to be valued. What's important to recognize is that oral iron is very poorly absorbed in individuals that have ferritin above 50. So we're recommending treatment with ferritin below a hundred but between 50 and a hundred, really not a lot of point in taking oral iron because it's not absorbed. Body protects us by releasing a peptide called pepsidin to suppress absorption of iron. So between 50 and a hundred, these are people who are going to get IV iron. Below 50 on the ferritin, I would encourage giving a shot to oral iron. Most people don't follow me. We just did a study recently showing that carboxymaltose, one of the IV iron formulations was quite effective in individuals who did not have augmentation here. So the IRLS score, we've done it by 11 with IV iron and we've done it by about five with saline. But for those individuals who had augment, IV iron did not seem to be effective. Opioids, and this is a thorny issue for many doctors given what's going on in the United States with the opioid crisis. And opioids can be prescribed responsibly or treatment per factory augmented restless leg syndrome. We've got a lot of options and just to be clear, these are very low doses that are used for RLS. Most of the patients that I see who I give opioids to have symptoms over 12 hours a day. I'm not going to use short-acting agents in those individuals because they'll have to dose multiple times a day and I don't want them to do that. So I'm going to use extended release formulations. Oxycodone ER has a duration of action of about eight hours. What I generally use for people with augmented or refractory RLS are the really long acting agents, methadone or buprenorphine. And we look here at the usual dose in my hands, usual dose is about 10 milligrams. That's a 10th of what people get or even a 20th of what people get for chronic pain disorders or for opioid use disorder. Very low doses of very effective for RLS. And the same is true for buprenorphine. And most of my patients are around one milligram of buprenorphine. As you know, 16 or maybe 24 what's recommended for opioid use disorder. So here to make that point, here's doses for methadone and you can see opioid use disorder anywhere in this range, chronic pain in this range and severe RLS is going to be way down here. I don't give more than 20 milligrams of methadone for RLS because I don't need to. Before prescribing an opioid for RLS, there are a number of things you need to do to confirm that the patient is a good candidate for this approach. You should ask questions related to the ORT, opioid risk, which ask about a family history of substance abuse, personal history of substance abuse, younger age, history of preadolescent sexual abuse or certain psychiatric conditions. You add up those numbers and you get a risk score. You certainly want to check your state's prescription monitoring program. Make sure at every visit that you're the only one prescribing opioids. If you have concerns, you should do a urine tox screen. And we have to sign an opioid agreement which discloses all of our responsibilities as prescribers and the responsibilities of patients for whom we're prescribing. To prescribe methadone for RLS, you should write in the notes for chronic RLS pain. That way they can get it filled at a pharmacy rather than methadone. As I'm sure you're aware, you do not need an X license anymore for prescribing buprenorphine. I write three one-month prescriptions so that I only need to write them every three months. Today, this is in the EMR. I have a start date a month from today for 30 days and then start date two months today for 30 days. And then I meet with all of my patients for whom I'm prescribing opioids every three to four months. So for opioid treatment, slow dose opioid treatment, augmented or treatment-resistant RLS, you need to think about how many hours a day people need treatment and then think about which opioid matches that. Just the same way you would work for a hypnotic. Do they have problems falling asleep? Well, then no point in using a long-acting benzodiazepine receptor agonist. Use a short-acting. If they have problems falling and staying asleep, then you can make symptoms longer. For people who have symptoms about four hours a day, oxytocin, tramadol, ibuprofen. For symptoms six to 10 hours a day, I use oxytocin and expanded valise. Anybody with RLS symptoms more than 10 hours a day, I'm gonna use these very safe medications, methadone and buprenorphine in very low dose. Of course, opioids have many potential side effects. Most common is constipation. It's almost always manageable with the use of stool softeners and bowel stimulants, Miralax, occasionally people need prescription medications like naloxagel, which are peripheral opioid antagonists. Some people have sleepiness during the day. They may sleep more hours than they did. I sleep eight hours, certainly when they had RLS, they sleep a few, and they may be tired during the day. Itching can happen nauseably. Sweating is probably the most common reason that I have change in an opioid or even discontinuity. Opioids interfere with the metabolism, sorry, the synthesis of reproductive hormones. And so if you have a patient for whom they develop bad sweating, check a testosterone level of men and substituting exogenous testosterone as long as the urologist feels that it's safe, that can be very helpful. Some people develop central sleep apnea, though this is uncommon at this low dose. We have a national RLS opioid registry, 500 patients that we recruited from around the United States about 3% of them are mine, they're all from other practitioners around the country. We recruited them about six years ago and we have very elaborate surveys that we use every six months to assess ongoing efficacy of the opioid and dose of the opioid. And you can see here that the majority of people, we're looking at MME, morphine milligram equivalents, about 50% of people are at the same dose that they were when we recruited them into the registry. Somewhere around 20% have increased their MME by zero to 10, so that's four milligram increase of methadone, about a six milligram increase in nitrocodone. We've now analyzed data out to five years and writing that data up into very similar. The ones that we're particularly concerned about are the ones that have increased their dose of the opioid substantially. And so we're keeping a close eye on those, looking at independent predictors of those patients so we can make recommendations about who should get opioid for RLS and maybe who should not. And here you see four-year data, as I said, similar about a third of people, this is four-year data, about a third of people, no change in their MME, about 25% have a small change, a little more than 10% have an MME increase of 10 to 20. Again, this is about four milligrams of methadone, probably about 10 milligrams of oxycodone, and about 20% of individuals decreased their dose. Many of these people have increased their dose, did so because the dopamine agonist was weaned off and now they need something to replace it. I do wanna mention neurostimulation treatments for RLS because these are important. Variety of treatments are being investigated. The one that really at this point has the most data by far is high-frequency bilateral perineal nerve stimulation. And here you see data here for the device which is used 30 minutes a day, usually in the evening, and you see a substantial benefit of the device compared to sham treatment where there is stimulation for 30 seconds instead of 30 minutes. So I'm gonna briefly talk about augmentation and how to manage that. Certainly introduced this before. In those individuals who you think have dopamine agonist induced worsening of RLS, you can try to administer the agonist earlier or split the dose. You can switch from a short to intermediate acting agonist that's inter-all, maybe to an extended release dopamine agonist. My experience has not been good with it. It's just a matter of time before that produces augmentation. And so you're really going to be thinking about, do I want to, what's going on with their iron? Can I maximize that? And if that doesn't do it, going to add one of the alpha to delta agents to the dopamine agonist. Maintaining the dopamine agonist does say first, and as you see, then very, very, very slowly reduce the agonist. And this old Will Rogers saying, if you find yourself in a hole, the first thing to do is stop digging. Don't increase the dose of dopamine agonist. That's a mistake. Just gonna make the, initially things will be fine. You'll be back at the honeymoon, but within a year, maybe two, things are going to go south again for most people. So you would add those agents, the iron or the alpha to delta, and then you very slowly need to reduce the dopamine agonist roughly by 10% a month after you have the agent that you're going to be using instead on board, whether it's alpha to delta or an oak. I went into great detail in a recent paper, the Chest Journal, Pulmonary Journal, and requested me to write on management of severe refractory and augmented RLS in this section and how I do it that they, every month they have different pulmonary issue or just a sleep issue with a real how-to on management. And so I would refer you to this paper, which is very much operation management for these patients. Again, if you have such patients, you're not sure what to do, register for RLS curbside, put some details about your patient there. Don't worry, we will scrub a bit of any HIPAA information in case you didn't. And this is free to you. I don't get paid. None of the other people on the executive committee on RLS curbside get paid. There's no outside influence from commercial influences. It's free, as I said, this was paid for by a neuroscience foundation, the leader of which has RLS. So in conclusion, in anybody with RLS, correct the underlying contributor, medications that make RLS worse or care, iron, sleep apnea, alcohol. Initial treatment should be with a calcium channel alpha to delta ligand or iron, unless there's significant contraindications there. Dopamine agonists are third line in treatment. If you do use a dopamine agonist, keep doses within the FDA range. Amopexol, 0.5 milligrams or below. Lipinrol, four milligrams. Lutigotine patch, three milligrams or below. And be vigilant, meeting with people regularly for augmentation. Goal for augmented patients is to eventually discontinue the dopamine agonist. And you do that by first adding the new medication and then reducing very slowly the dopamine agonist. Of that note, I'd say thank you for your attention. And I hope you all sleep very well. Here's the next question. Hi, Dr. Winkleman. We actually, we have one question in the chat. The question reads, what about treatment of periodic limb movement disorder without RLS? Are dopaminergic advised against? Can you tell us more about that? Yes. So it's not clear if you really mean periodic leg movements, sleep, or periodic limb movements. Periodic leg movements and sleep are very common in people for sleep study, particularly in older people who are going to see a lot of PLMS. PLMD are those people with a lot of PLMS where you are fairly convinced that the PLMS, periodic leg movements and sleep, are responsible for sleep disturbance or next day dysfunction. That's PLMD, it's supposed to be PLMS. So for PLMS, if you see that on sleep study, I would generally, unless you really can be convinced that that's responsible, we don't treat PLMS. You can do a brief trial for, in somebody with periodic leg movements and sleep who has nighttime sleep disturbance or daytime non-restorative sleep, can do a brief trial of a dopamine agonist, getting to 0.5 milligrams for about two weeks. You're not going to have augmentation in that very short period of time. And then you can determine, because those will wipe out the leg movements, you can determine whether you think the leg movements are responsible for the nighttime or daytime symptoms. If they have no response to the dopamine agonist, then it's not the PLMS. If they do have a response to the dopamine agonist, then you say, okay, I do think this is periodic leg movement disorder. That therapeutic trial kind of somewhat proved that. We're now going to taper you off the dopamine agonist and we're going to use one of the other agents to address the PLM. And whether that is, at this point in time, we really don't have good guidance on treatment of PLMD, but I'm still recommending against dopamine agonist because you definitely can see people who had leg movements during sleep, no RLS. And over time on the dopamine agonist, they augment right across the sleep-weight barrier and develop RLS. And that's really bad and embarrassing. So in those people where the dopamine agonist worked, you could use pregabalin or daffodil. You could even try a short-term intermediate acting benzodiazepine receptor agonist, whether it be nesapone or lorazepam to suppress the arousals from these leg movements. Certainly check iron and replete if it's within ranges that are abnormal for somebody with RLS. But we don't, we have very, very little data on in terms of randomized controlled trials on treatment of PLMD because it's actually pretty rare. We have a few more questions coming in on the Q&A. Next question is, is there a role for magnesium supplementation and RLS? Many of my patients ask and are already on magnesium hoping to improve their sleep. Yes. The data for magnesium does not demonstrate efficacy. However, I have had patients who say that it benefits them as well. You should recognize, as you saw in a number of the RCTs that I showed you, there's a powerful placebo effect in RLS. And so if people want to try magnesium, I say, yeah, give it a shot. Let's hope that it works. I'm not going to tell them I don't think it works, but I say, give it a shot, just watch out for diarrhea, high doses. And if it works, great. Doesn't work, okay, we'll move on to something else. But in terms of the controlled trials, there really isn't evidence that it is effective. Next question, can you clarify dosing schedule if gabapentin used to treat RLS? Of gabapentin used to treat RLS? Can you repeat that? That didn't sound like a question, it sounded like a statement. Yes, the attendee is requesting if you can clarify the dosing schedule of gabapentin, which is used to treat RLS. Gotcha, so for gabapentin, I usually start at 300 milligrams a couple of hours before bedtime. I write the initial prescription for one to two QHS and tell them the factor a couple of weeks they're not getting anywhere. They can go to two caps a couple of hours before bed. If they're not finding any benefit then, then we're kind of getting to the point where those nonlinear pharmacokinetics matter. And at that point, if I'm gonna use gabapentin, at that point, usually I'm gonna transition to Gregal, because now we're talking about two different dosing times of gabapentin. So they have them take it, if you wanna use gabapentin at let's say seven o'clock or eight o'clock and 10 o'clock, but adherence becomes an issue when you're using two doses a night. But if you like gabapentin, I would go 300 to 600 an hour or two before bedtime. And if you wanna stick with gabapentin and that dose is not working, then a couple hours before that administration, I'll add 300 to the 600 that's already there, then go up to 600. So then I've got 600 and 600. Problem is in the clinical trials, you needed to get to higher doses than that. So I have patients who have been on gabapentin with good efficacy, but they're taking it at seven, nine and 11. People with RLS are usually pretty adherent because these symptoms are quite salient and bothersome. But really at this point in time, if you have to use more than once a night dosing of gabapentin, I'd probably transition to pregabalin, picking about a three to four to one ratio of gabapentin to pregabalin milligrams. And so starting at maybe seven, depending upon sensitive people have side effects, starting at 75 or 100 and increasing the dose of the target should be 300 milligrams. And it may take you a while to get there because people can have side effects transiently and they do need to get accustomed to those. And I hope that answers your question. We have another question that came in. Is it reasonable to request for a sleep medicine referral right away for eval and management of RLS or PLMD, or is the first step to refer to a PCP? It depends whether you trust the PCP to follow the guidelines and not just start a doping annex. If you do, then it's reasonable to send them to the PCP. But otherwise I'd probably send them to sleep medicine who hopefully will increasingly recognize that dopamine additives are not virtually free. So I see a question. Why do you think so many providers are not up to date with current recommendations for RLS still prescribing DAs? These recommendations just came out this week. There has been an evolution away from our recommendations for DAs, but there hasn't been an explicit recommendation saying that these are not first line treatments. So I think that this will evolve and develop and be manifested in prescribing practices over the next few years. But I don't understand it. Some doctors say to me, I've never seen an augmented patient with RLS. And I say, well, either you're not prescribing RLS you're not seeing patients with RLS or you're not asking them the right question. This is common. Will insurances cover gabapentin in a carbol or do they usually require a PA? I'm really not sure. If you want to use gabapentin in a carbol, I would just see and see whether you get a bounce back for a PA and then see what the step edit is requiring you to do before you prescribe the carbol. My advice on the gabapentin in a carbol is it's for patients who have symptoms a significant percentage of the day. It's a controlled release formulation there all day and all night. If they don't have symptoms most of the day, most of the night, it's not really the right medicine. If they have symptoms four hours a day, why are you giving them a drug that's present 24 hours? I think that's it. Yes, thank you so much, Dr. Winkleman. My pleasure. Wonderful seeing all of you. Thank you for all your really nice questions. I appreciate it. Thank you all. And be sure to join our next presentation on Disordered Sleep and Rhythms by Dr. Benka, which is starting now.

Restless Leg Syndrome

dopamine agonists

augmentation

alpha-2 delta agents

iron supplementation

rlsherbside.org

pathophysiology

periodic limb movements

magnesium supplementation