Sleep 2023.01.25 Winkelman

February 19, 2023

ID9520

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00:00Today I have the pleasure of
00:03introducing Doctor John Winkleman. Dr.
00:05Winkleman received his PhD in psychobiology
00:08from Harvard University and his medical
00:10degree from Harvard Medical School.
00:12He then completed both a residency in
00:14psychiatry and a fellowship in Sleep
00:16Medicine at Mass General Hospital.
00:18He was a medical director of the Sleep
00:20program at McLean Hospital and subsequently
00:22did was a medical director of the Sleep
00:24Lab at Brigham and Women's Hospital.
00:26He's currently a professor of
00:28psychiatry at Harvard Medical
00:29School and Chief of the Sleep.
00:31Disorders clinical research
00:32program in the Department of
00:34Psychiatry at Mass General Hospital.
00:37Doctor Winkelmann's research is
00:38primarily focused in two areas,
00:40epidemiology, Physiology,
00:41cardiovascular consequences and
00:43treatment of restless leg syndrome,
00:45and neurobiology and treatment of insomnia.
00:48He has lectured in and directed postgraduate
00:51medical education courses and sleep
00:54disorders nationally and internationally.
00:56Dr.
00:56Winkelman serves on the editorial
00:58boards of Sleep Medicine.
00:59He's also received many awards published.
01:01More than 150 articles,
01:03reviews,
01:04book chapters and is also the editor of the
01:06Textbook Foundations of Psychiatric Medicine.
01:09Is also the current President of
01:11International Restless Leg Syndrome study
01:13Group and has also helped leadership
01:15position in many national societies.
01:17Thank you for so much for being with us
01:19Doctor Winkelman and without further delay,
01:21I would like like to hand it over
01:22to you to share your expertise on
01:24putting out the fire of refractory
01:26or augmented restless leg syndrome.
01:28Thank you.
01:29Thank you. I appreciate that
01:32that kind introduction.
01:37So I think without further ado,
01:40I'll get going.
01:41As you can see here,
01:42this is going to be the theme,
01:43or at least one of the thing I'm stuck on.
01:45Kind of analogies.
01:47Oftentimes really stretched analogies, but.
01:52They provide some value I think,
01:55and this is restless leg syndrome,
01:57the fire and this gasoline
02:00is dopamine agonists.
02:04Here's a slide that I was asked
02:07to put up by. Whatever it says,
02:11I of course completely agree with.
02:13Here my conflicts of interest specifically,
02:17and some of them have to do.
02:22None of them have to do with
02:24commercialized products for RLS.
02:29So two things I want you to take home,
02:31if nothing else.
02:34One, dopamine agonists are
02:36no longer first line therapy.
02:39That should say first line,
02:41not first therapy,
02:42first line therapy for RLS.
02:45So if you're seeing patients with
02:48RLS and you're turning to one of the
02:51dopamine agonists as the first line.
02:53Stop doing it.
02:55As we as there's already one
02:58guideline that's published in Mayo
03:00Clinic proceedings and the American
03:02Academy of Sleep Medicine is going
03:05to be coming out with another one
03:07that Brian and I are are both on the
03:11clinical practice guidelines of the
03:13ASM for RLS and dopamine agonists are
03:16no longer going to be first line therapy.
03:20So if you want to be current,
03:21if you want to be practicing
03:26standard treatment.
03:27Don't start with a dopamine agonist
03:29unless you're going to be giving some
03:32justification in your in your Note 2.
03:34Opioids are a safe and generally
03:37well tolerated treatment treatment
03:39for patients with severe
03:41refractory or augmented RLS.
03:43Those will be the two main things.
03:47You'll hear those kinds of
03:48messages throughout my talk.
03:52For this group, I do not have to
03:54describe what RLS symptoms are,
03:56but there's this nice acronym
03:57that you can tell patients.
03:59And when you're giving talks to other docs,
04:02you can use this urged acronym,
04:05which I think is pretty nice.
04:08RLS is not uncommon.
04:10And certainly every patient
04:12with insomnia that you see,
04:14you should ask them as
04:16simple screening question,
04:17something like do your legs
04:19bother you at night whether
04:21they're coming in for sleep apnea.
04:23Certainly, if they're coming in for insomnia,
04:25if they're coming in for narcolepsy,
04:27abnormal behaviors at night,
04:28circadian rhythms, single questions,
04:30all you have to do.
04:32If they say no, move on.
04:34If they say yes,
04:35then you need to ask a few more
04:38questions to see if it's RLS.
04:40If it's not ternal my clonus, I'm sorry.
04:44Nocturnal leg cramps or something else,
04:49but always ask.
04:51Not going to spend a lot of time
04:54on this nosological description of
04:56primary and reversible RLS other
04:58than to say these are things,
05:01many of them that can be fixed
05:05and therefore we don't have to
05:08do a big therapeutic evaluation
05:10because if they're iron deficient,
05:13we're going to give them iron.
05:14If they have renal failure and
05:16on dialysis and waiting for a
05:18kidney when they get the kidney,
05:20things are going to improve
05:21when they deliver.
05:22Generally,
05:22things are going to improve if they're
05:24on a serotonergic antidepressant.
05:26You're going to talk to whomever is
05:28prescribing it and to the patient
05:30to see whether it can be modified.
05:34One of the cool things about RLS that I
05:37think attracted me initially to it is
05:40that unlike almost all medical problems,
05:43it has a time of day dependence,
05:47almost all the things we treat.
05:49Are present throughout the day and night.
05:53But RLS has this clear circadian rhythm,
05:56at least prior to us screwing things up
06:00with our dopamine agonists such that it's
06:04mostly present in the evening or at night.
06:08The first time I meet with patients and
06:11pretty much every visit there after,
06:14I get the following information.
06:18Somebody's trying to get in.
06:19I'll admit them up. They did.
06:22I divide the day into 4 equal parts.
06:26I'm gonna, I say to the patients,
06:27I'm going to divide it into 4 equal parts.
06:29I can ask you how often do you have
06:32RLS during that particular time
06:33of day and how bad is it?
06:36Mild, moderate, severe, very severe.
06:38So I'll say from 7:00 AM to noon,
06:41how many days a week do you get RLS?
06:43They'll say 2 mild, moderate,
06:45severe or very severe. Mild.
06:47OK, noon to 6:00 o'clock.
06:49How many quickly?
06:50Just takes a minute or two
06:51to go through this.
06:53And then you have a snapshot almost even.
06:57Video maybe of the course of the RLS
07:00treatments over the day and their severity,
07:03and this is key because.
07:06We're going to focus our treatments on
07:08the time of day that they have symptoms.
07:11I can't tell you how often I see
07:15patients who had RLS symptoms.
07:17I said they they come to me on
07:21pramipexole .25 milligrams TID.
07:22I say you're taking it three times a day.
07:25Do you have symptoms in the morning? No.
07:27Did you ever have symptoms in the morning?
07:29No.
07:29Why are you taking this medicine three times?
07:32Why are you taking it in the morning?
07:34Why are you taking it again at noon?
07:35I don't know.
07:36That's my doctor told me to do.
07:38Why, why,
07:40why is that happening?
07:43I think it's because that's kind of
07:44the treatment for Parkinson's disease.
07:46Pramipexole is used for Parkinson's disease.
07:49Therefore we're going to follow the same.
07:53Menu the same description there to treat RLS,
07:56which doesn't make sense.
07:57We treat the symptoms when they're present.
08:00Don't waste medications at times
08:02that that people don't have.
08:07Don't have symptoms. So the workup is.
08:12Is not particularly onerous.
08:16Certainly nobody leaves the office without
08:20having lab rec position for iron indices.
08:25And the key here is don't
08:28just check ferritin.
08:30Ferritin's unreliable in so many instances.
08:34You've got to check ferritin iron TIBC.
08:39Iron and TIBC are also are unreliable.
08:43So This is why we have both sides of it.
08:45And as you I'm sure are aware iron divided
08:48by TI BC is transferrin saturation,
08:52T said here.
08:53So we want to keep ferritin over 75,
08:56transferrin saturation over about 20%.
08:59These are not carved in stone,
09:01these are just rough guidelines.
09:03Think about medications,
09:05particularly serotonergic antidepressants,
09:07dopamine antagonists.
09:08Think about whether people just
09:11stopped an opioid post surgery.
09:14Nowadays, of course,
09:15no one gets opioids post surgery.
09:18People just go home and are
09:19supposed to take Tylenol.
09:20But for those people who do
09:23take opioids post surgery,
09:25think about whether they've just
09:27stopped them in the last week or two.
09:29Physical examination has some value,
09:31particularly to assess obstructive
09:34sleep apnea.
09:35Think about comorbid sleep disorders.
09:37Generally, we don't do sleep
09:40studies for people with RLS.
09:42Unless we of course suspect obstructive
09:45sleep apnea or central sleep apnea.
09:49I do this a lot.
09:50See the four fingers there.
09:52I do this a lot. Patience,
09:53I'm sure, are totally secured.
09:55And I say to them,
09:58there are four classes of medicines that
10:00work for our list that we know work.
10:02Dopaminergic medications,
10:04the calcium channel, A2D ligands,
10:07gabapentin and pregabalin,
10:09opioids and iron.
10:10Usually I say iron and opioids and I say,
10:15so we don't have unlimited choices.
10:17We certainly have a number of them,
10:19but we need to make sure that we
10:22take the fact that we don't have
10:26unlimited choices seriously and
10:28therefore before we give up on
10:31the medication we make sure that.
10:33You've given it a good college try,
10:35a Yale College try,
10:37if you will,
10:39to make sure that it's not going
10:41to be effective or tolerated
10:43or or poorly tolerated.
10:45And maybe we went up too fast
10:47on the pregablin.
10:48Maybe we need to slow it down.
10:54So here are some guidelines that were
10:56published by the AN 2016 that was
10:59quite involved with these guidelines
11:01really just had to do with efficacy.
11:04They didn't talk about a balance
11:07of efficacy and side effects.
11:09So there's it's a weakness of the
11:12A and guidelines at that point
11:15in time just talking about what
11:18works for various symptoms so.
11:20I have more faith in those guidelines
11:22that the American Academy of Sleep
11:24Medicine that we're working on,
11:26that Brian and I are working on and in the
11:30recommendations that will be coming out.
11:34Probably later this year.
11:38So here you see the timeline of various
11:40medications and when they were approved.
11:42It's been more than 15 years
11:45since Requip was approved.
11:4716 plus years since Mirapex was approved,
11:51more than 10 years since gabapentin,
11:54HORIZANT, gabapentin and Congress
11:56Carnival horizon was approved,
11:58and about 10 years since
12:00Reticulating knew Pro was approved.
12:01Nothing since then.
12:04Ten years with nothing new.
12:08And this is something that we in
12:11the international restless Leg
12:12Syndrome study group have convened
12:14a bunch of people to get together
12:17to try to figure out why this
12:19is and what we can do about it.
12:22So here's a.
12:27Little picture of the pivotal trial
12:30that was published for the FDA
12:33approval of Pramipexole mirapex,
12:35you see it came out in 2006.
12:37And I was just a young man.
12:40I was basically just out of high school
12:42at the time, 15 years ago, and naive.
12:46And that's going to be my defense is
12:49all I can say is that I was naive.
12:53This was a pivotal trial for an FDA approved
12:57drug that was 12 weeks in duration.
13:00For a lifetime disorder.
13:04What I was thinking or what anyone
13:07else was thinking is unclear.
13:09Lifetime disorder.
13:10We're going to make a decision about its
13:13approval in for in a three month trial.
13:16That clearly, at this point,
13:17has been demonstrated to be a mistake.
13:21And I apologize whenever I can to
13:24patients that for any responsibility that
13:28I played in having them use a dopamine
13:32agonist without adequate warning.
13:36And what's the warning?
13:38Here you see somebody taking
13:40another analogy here,
13:42taking a pill that's got this fuse.
13:44Again, I don't know how long the fuse is,
13:47but at some point for most people
13:50this is going to blow up on them.
13:53And it's going to blow up with respect
13:56to the fact that augmentation develops.
13:59Augmentation is a worsening of
14:02the underlying RLS disease.
14:05Symptoms appear earlier in the day.
14:08There have increased severity,
14:10they go from the legs to the arms and
14:13they have a shortened latency to onset.
14:16Instead of happening after you've
14:17been sitting for an hour watching TV,
14:19now it's after 10 minutes.
14:25So even before I published that
14:27pivotal trial in 2006, it was clear
14:30that there were problems in 2004.
14:34I recognized that this augmentation
14:37process was occurring.
14:38Richard Allen had already published a
14:40paper a couple of years beforehand with
14:43levodopa demonstrating augmentation
14:45levodopa and I looked at about 60
14:48patients that I was prescribing
14:51pramipexole for and demonstrated.
14:53That there was about 1/3 of the people.
14:57Over just even two years had developed.
15:02Augmentation.
15:03Again, apologies.
15:04Augmentation and tolerance are more
15:07common than have been previously reported.
15:11However, these complications are
15:13generally manageable by earlier dosing
15:16or small dose increases of this agent,
15:19and only rarely require
15:22medication discontinuation.
15:28Again, two years is too short.
15:32To make that conclusion,
15:35and again I apologize for the
15:38mistake that I made 20 years ago.
15:42By 2008, it was clear to me that we
15:45had problems and here's the NIH RLS
15:48scientific meeting that happened in 2008.
15:51And this is my slide.
15:54Clinicians have become
15:55addicted to the predictable,
15:57rapid and nearly complete response seen
15:59in our patients with dopamine agonists.
16:03Increasing concern in Rs community that
16:06dopaminergic agents are addictive.
16:09And I don't use that word lightly.
16:11It created a need for medication at
16:14times that were unaffected beforehand.
16:16Increasing doses are required
16:18and symptoms are really bad when
16:20you stop the medication.
16:24So last 15 years I've spent a
16:26lot of time talking about this
16:28and I'm glad that the ASM now and
16:31the guidelines are finally coming
16:34to more appropriate conclusions.
16:37Augmentation is not all or none.
16:40It is a continuum of severity
16:43starting with loss of efficacy,
16:46then going to somewhat earlier
16:48appearance and then really early
16:50appearance such that people have
16:52symptoms by the time they have.
16:54Fear augmentation to about 12 hours a day.
16:59Last year I got I got a hold of
17:02prescription data from the United States.
17:06And basically all commercial providers
17:09as well as non commercial providers and.
17:14We found 670,000 people from about a
17:20million prescribers who had medication
17:23treatment for restless leg syndrome.
17:26Anybody with Parkinson's disease was
17:29excluded, about 2 thirds, 60% of the
17:32people getting any medication for RLS,
17:34we're getting a dopamine agonist.
17:37And as you can see almost 20% of
17:40the people take getting a topamax,
17:42dopamine agonist.
17:43We're taking doses at above the FDA
17:48and guideline recommended maximum
17:51dose that's 4 milligrams for requip.
17:56.75 milligrams mirapex above those doses.
18:0110%.
18:02We're getting more than 6 milligrams of
18:07requip or 1.25 milligrams of mirapex.
18:12There's only one way you get to this.
18:15And that's through augmentation.
18:19So as I said,
18:21these medications are seductive.
18:23But make no mistake about it,
18:25dopaminergic agents are no longer first
18:28line treatment for RLS and the ASM will
18:32be coming out with those guidelines.
18:34Probably around the end of the year.
18:36What are our alternatives?
18:41Forefingers. Dopamine agonists
18:44first alternative I think would be
18:48we'll talk about iron in a minute,
18:50but will be the A2D agents gabapentin,
18:53gabapentin, Anna Carbol and pregabalin.
18:57These medicines and here you see
19:00the range of effective doses here.
19:03These medicines are not without side effects.
19:05Therefore in many people you're going
19:07to have to start low and go slow.
19:09But that's fine.
19:12Sedation, dizziness, weight gain,
19:15gait instability,
19:16any of those things actually can
19:19interfere with people's tolerability
19:21and therefore you may have to
19:23pull the plug in some patients and
19:25go to one of the next options.
19:28But there's really no evidence,
19:29no published evidence in
19:31my clinical experience,
19:33no evidence of augmentation
19:35with these agents.
19:39And when we think about comparative trials,
19:42which of course are rarely done in medicine,
19:45but thankfully we were able to do
19:48a comparative trial of pregabalin
19:50Lyrica versus Pramipexole,
19:52mirapex for restless leg syndrome 12
19:55week placebo-controlled. Section 1.
20:00Dose of pregabalin, 300 milligrams,
20:022 doses of pramipexole .25 and .5
20:06versus placebo and you can see that
20:09pregabalin and the higher dose.
20:12Of primary pexel,
20:13the FDA maximum approved dose were roughly
20:17equivalent and in fact pregabalin was
20:20somewhat better on the IRS severity scale.
20:24Then everybody on placebo was re
20:26randomized to one of these three arms
20:29and we followed them for a year and
20:33you can see augmentation rates at
20:35about 8% for the higher pramipexole dose.
20:40You prima pixel dose and 2% for pregabalin.
20:43I don't think that was actually augmentation.
20:46I think that that was just
20:49variance in their scores.
20:51Even though we were pretty strict
20:54on our augmentation criteria or
20:56maybe progression of disease,
20:58I do think that these values are real.
21:02And that somewhere 5 to 10% of
21:05patients on PRAMIPEXOLE will
21:07develop augmentation every year.
21:15The thing to remember about gabapentin,
21:17if you want to prescribe it for RLS,
21:19and I do frequently, is that it has
21:23non-linear pharmacokinetics, something
21:25that the manufacturers never told us.
21:29And so here you would see what linear
21:32pharmacokinetics would look like,
21:34double the dose,
21:35double the serum concentration.
21:37This is what gabapentin looks like.
21:40Look at how it flattens out.
21:42So when you increase the dose,
21:44you're not going to get increased
21:47serum concentrations if you give
21:49the medication all at once.
21:51So therefore, if you want to get doses,
21:54I generally cut it off
21:55at about 600 milligrams.
21:56If you want to give doses
21:59above 600 milligrams,
22:00I split the dosing,
22:02give it once and then two hours later.
22:06Give another dose.
22:08This way you can approximate more
22:11linear pharmacokinetics because the
22:14receptors in the gut are not saturated.
22:19Let's talk about iron. As you can see,
22:22I'm kind of rushing through these other
22:24treatments because I'm going to spend a
22:26lot of time talking about opioids and
22:28about the management of augmentation.
22:30But just to give us some basis here
22:33on the four treatments for RLS.
22:36So. Iron has been shown to be
22:43efficacious in patients. Who have?
22:48Iron indices that are within certain ranges.
22:52So for PO iron and those individuals
22:57with ferritin less than 75,
22:59in fact the mean was 38.
23:01You can see the two groups at baseline
23:04were right around that 40 and 36.
23:07You can see what happens to
23:11the IRS score it went from.
23:1523 to 25 and the two groups,
23:18Iron Group and the placebo group
23:20dropped 10 points on the IRS scale
23:23in the Iron Group and dropped only
23:26one point in the placebo group.
23:28Really dramatic difference there.
23:32For IV iron.
23:35Umm.
23:36Generally,
23:37again we recommend that it be
23:40used in individuals with ferritin
23:43level less than 100.
23:46Here you can see a clinical trial
23:49of IV ferric carboxy maltose
23:52one 1000 milligram dose.
23:54And again here you see placebo.
23:57It went from whatever it
23:59went to my lost four points,
24:01improved 4 points at week one,
24:04but then really didn't change over that time.
24:06On that and look what happens in
24:09the ferric carboxy maltose group
24:11and these are blinded patients.
24:13You're in a setting where the IV bag
24:16is and the line are both covered,
24:19so they can't tell because FCM
24:21and most iron formulations are
24:23brown whereas saline was.
24:25The placebo is obviously not brand.
24:28So you can see here that IV
24:31iron takes a while to work.
24:34Doesn't work quickly.
24:36Seem to have its maximum benefit
24:38here at 12 weeks in fact.
24:42And #4. Finger would be opioids and
24:46you can see of course we have a wide
24:49range of opioids available to us.
24:54And really, I've divided
24:56them based on half life.
24:59We have these shorter agents in here,
25:02Tramadol, codeine, morphine,
25:04oxycodone, hydrocodone.
25:06A couple of them have ER formulations
25:10which make them not so much short acting.
25:14And then the two long acting agents
25:18oftentimes once a day because of long
25:22half lives methadone and buprenorphine.
25:25And I'm not going to go into the
25:27details here of where you start the
25:29dose and the usual effective dose,
25:31but opioids are extremely effective for RLS.
25:38However. Most doctors in the
25:42United States are very, very.
25:46Umm. Let me change that.
25:49About 1/3 of the United States
25:52physicians will no longer,
25:54and during this period from 2012 to 2017,
25:58stopped writing prescriptions for opioids.
26:011/3 of doctors say,
26:04I don't prescribe them for anything.
26:07Which I think is problematic.
26:09That's not our role as doctors.
26:11We balance risks and benefits.
26:14That's what our training led us to do.
26:17And 1/3 of doctors are saying there
26:20is no benefit that outweighs the risk.
26:25And that's unfortunate.
26:26So those of us who are prescribing
26:29opioids for RLS are really kind of
26:32swimming upstream here going against
26:34what many other docs are doing, but.
26:37I think we need to recognize the
26:40pendulum has swung and the CDC kind of
26:43stated that just earlier at the end of
26:46last year and it will swing back and
26:49opioids will find a reasonable use in
26:52medicine and for the treatment of RLS.
26:55For doctors really is comes down to our
26:59fear versus our care of our patients.
27:03Everybody's got to find their own place
27:06where they feel comfortable with that.
27:08And so I'm not going to.
27:12Suggest that if your concern
27:14or discomfort with prescribing
27:16these medications is excessive,
27:19that you should do it.
27:21If you're uncomfortable,
27:22of course you shouldn't do it.
27:25However,
27:25you should know that a number of
27:29analysis have looked at doctors who
27:34did prescribe opioids inappropriately.
27:37And they identified these three
27:41CD's that predict who's going
27:43to be a problematic prescriber.
27:45People who are careless,
27:47doctors who are careless,
27:49corrupt or compromised.
27:51If you're not one of those things,
27:54you can prescribe opioids appropriately
27:57and safely to your patients.
28:02Before starting an opioid for restless legs,
28:05there are few things you're going to
28:07want to do or that you're required to do.
28:09You want to think about the
28:11features and the opioid risk tool.
28:13This is really not been validated,
28:15but it's the best that we've got.
28:18Think about the individuals history
28:20of substance abuse, their family
28:22history of substance abuse, their age.
28:25Any history of pre adolescent sexual abuse?
28:30Certain psychiatric diseases.
28:31And then you add these numbers up
28:35and it'll come up with a risk score.
28:38How likely the person is to
28:41misuse one of these medications?
28:44Always check the PDMP.
28:45I'd love checking the prescription
28:48monitoring program in my state.
28:50I don't know,
28:50maybe I you know I when I was a
28:52kid I wanted to be a cop and you
28:54get to combine kind of medicine
28:55and police work here and try to
28:58see what people are doing and.
29:01Umm.
29:01And you can identify people who are
29:05using medications inappropriately.
29:08I generally do not do it.
29:10You're in talk screen unless
29:12I have particular concerns.
29:14And at mass general we are required
29:18to review an opioid agreement and have
29:21patients verbally assent or sign it.
29:27When you're writing an
29:30opioid prescription for RLS.
29:33I always put these words in
29:35the notes for chronic RLS pain.
29:42#1 #2 you no longer need an X
29:45license to prescribe buprenorphine.
29:48They've just gotten rid of that.
29:50That is no longer relevant for for you.
29:54And if somebody says you need an extra
29:56license, say not anymore you don't,
29:58and you could also say it's for pain.
30:02I only write one month prescriptions.
30:04Obviously that's all you're able to write.
30:06No refills other than for buprenorphine.
30:10But I write 3 sequential one
30:13month prescriptions in EPIC.
30:16Dated one month sequentially,
30:17and I see people every three to four months,
30:21as is required by mass general
30:23and the state of Massachusetts.
30:26That's fine. I'm happy to see
30:28them every three or four months.
30:30And.
30:32Keep an eye on their RLS,
30:35their General Medical health and
30:37their use of these medicines.
30:40So how would I use opioids for RLS so?
30:47Opioid treatment is based on the 24
30:49hour distribution of RLS symptoms.
30:51All RLS treatments are based
30:54on the 24 hour distribution.
30:56As they pointed out,
30:57people only have RLS symptoms at night.
31:00And if, God forbid,
31:01you want to start a dopamine agonist,
31:04don't start a TID.
31:05Start at an hour or two
31:07before symptoms start.
31:08Same thing with gabapentin or pregabalin.
31:13Opioids differ predominantly,
31:14and they're half life.
31:17And therefore I'm going to base
31:19the opioid choice on the pattern
31:22distribution of bothersome RLS symptoms.
31:26If they had just a few hours
31:27a day of our less symptoms,
31:30I may give them a short acting opioid,
31:33oxycodone, tramadol, hydrocodone, codeine.
31:36But remember these are
31:38oxycodones like 4 hours codeine.
31:41You're not going to get
31:42even four hours out of it.
31:44So these are short term and the concern is,
31:46is that when they wear off.
31:48There's going to be a rebound
31:50of RLS or that you're going
31:52to create a rebound of RLS.
31:54For people who have symptoms,
31:55let's say that start at 10:00 o'clock
31:57at night and they are still waking up at
32:003:00 o'clock in the morning with RLS.
32:03I may use an extended release formulation,
32:06for instance oxycodone ER.
32:08But for people of symptoms more
32:11than 10 hours a day,
32:12I'm going to use methadone or buprenorphine.
32:17I want to briefly review data
32:20from the national Restless
32:22leg syndrome opioid registry,
32:24a study that I started five years ago.
32:27With funding from the Rs Foundation
32:29and now is primarily funded through
32:32the Bazooka Brain Research Foundation,
32:34we put, we contacted providers,
32:39Rs providers around the United States.
32:41Brian Koo was very,
32:43very helpful in this regard.
32:45We putting them in something in
32:50the RLS Foundation website and we
32:52got a 500 people within about one
32:55year who wanted to participate.
32:57The date of 1 hour interview at the
33:00beginning followed up immediately by
33:02about a 30 to 45 minute survey and
33:05every six months thereafter since then.
33:08We have been.
33:11Sending surveys out to individuals
33:15in the registry and we've had
33:19enormous commitment from people,
33:20so we have about a 95%.
33:25Persistent involvement in our registry,
33:29of course few people have died,
33:30some people have stopped opioids,
33:32but we've lost very few people.
33:34Otherwise it's you can see at baseline the
33:37majority of people were taking methadone,
33:40some were taking oxycodone or hydrocodone
33:43and then lesser numbers of other opioids.
33:47About 60% female majority are over 60.
33:52Vast majority are white.
33:55Baseline median MDMA morphine
33:58milligram equivalent was thirty.
34:00It's 20 milligrams of oxycodone,
34:037 1/2 milligrams of methadone.
34:0780% of people taking an ME less than 50,
34:10so that's.
34:1435 milligrams of oxycodone,
34:1612 1/2 milligrams of methadone,
34:1980% taking less than that.
34:24We just had our paper two
34:28year longitudinal data.
34:31Accepted to neurology and you can see here,
34:35let's just focus on dosing and you can
34:37see here from baseline to two years.
34:39And let me make clear,
34:41when people entered the registry,
34:43the median time on opioids was already
34:46one to three-year, two to three years.
34:49The there were some who
34:51were less than one year,
34:52some there were more than three years.
34:54A number of there were even
34:55more than five years.
34:56But from baseline to two years,
34:59here's change in opioid.
35:01See about 45% of people had no
35:04change in their opioid dose.
35:06About 25% had an IME increase
35:09of less than 10.
35:12That's 7 milligrams of oxycodone
35:15increased 2 1/2 milligrams of methadone
35:18increase we were particularly.
35:20Interested in those people
35:23who had large increases?
35:25In opioid dose,
35:26those are the ones that we
35:28would be concerned about.
35:30Obviously they're bumping up in
35:32two years of substantial increase.
35:34In ME this is 35 milligram
35:38increase of oxycodone,
35:4012 1/2 milligram increase of methadone
35:42and these were the independent predictors.
35:45And so at baseline people with these
35:48things or people who are on opioids,
35:51these are people you want to
35:54have more vigilance about.
35:55People who are using an opioid
35:57for comorbid pain condition,
35:59well,
35:59it's probably the comorbid pain condition
36:01that's leading to the increase in dose.
36:03People who stopped another
36:05medication for RLS, well,
36:07if there were two medicines before working
36:09for RLS and you took one of them away,
36:12it makes sense that one of them might need
36:14to increase people who switched opioids.
36:16These were oftentimes people
36:19who switched to methadone.
36:21And what we found was that there
36:24RLS severity scores went way down,
36:26but the ME went up in these individuals
36:30and some of that has to do with.
36:34Some unusual characteristics of
36:36methadone equivalencies in figuring
36:39out the MMA male sex was a predictor,
36:42people with depressive disorder
36:44at baseline was a predictor,
36:45and younger people.
36:48Younger.
36:49At this point, I guess I have to say
36:52that less than 45 is younger people.
36:54It was also a predictor.
36:56As I talked about,
36:58no change in median dose from
37:01baseline for methadone for oxycodone,
37:04ateny increase for hydrocodone,
37:06somewhat of an increase for tramadol,
37:10but you can see for most of
37:13the medications there was no
37:15median increase dose.
37:16Let's talk about augmentation,
37:18because this is where the rubber
37:20hits the road with your patients.
37:21Now we've talked about the
37:23four classes of medicines.
37:24Let's talk about what the
37:26mechanism is for using them.
37:30You see somebody with augmentation on
37:32a dopamine agonist, most docs just say,
37:35well, just increase the dose. Bad idea.
37:39You're putting out the fire with gasoline,
37:42or as Will Rogers Will Rogers said.
37:47If you find yourself in a hole.
37:50The first thing to do is stop digging.
37:53And I'll see many patients whose
37:55doctors started on the dopamine agonist
37:57digging a hole, digging a hole.
37:59Things are getting worse digging,
38:00and at a certain point they realize
38:03that they're in the hall looking up.
38:05And now the patient is on a high dose.
38:09Bad. Powerless again. What do I do?
38:12They say.
38:13And that's when they say to the patient,
38:15I'm sorry,
38:16I'm not going to increase your dose.
38:19You really should go see somebody else.
38:24The workup for worsening RLS is very similar
38:27to the workup for at your first visit.
38:30Iron medications, sleep disorders.
38:32Make sure that the medications are
38:35being taken at the appropriate time.
38:37Make sure they don't have sleep apnea.
38:41For mild augmentation.
38:44Maybe you can split the dose.
38:46You can take that same dose and move some
38:50of it earlier and keep the rest of it later.
38:54Maybe you can switch to a short to
38:57intermediate acting dopamine agonist to
39:00a longer acting dopamine agonist from
39:03mirapex or requip pramipexole ropinirole.
39:06To an extended release version of one
39:08of those medicines, or to retigabine.
39:10My experience has been you're just
39:13kicking the can down the road.
39:16You're going to treat those earlier symptoms,
39:18yes, because you're giving drug all day long.
39:21But it's only a matter of time before
39:24Rs comes back at various times of day.
39:28I would strongly encourage you to
39:31not increase the dopamine agonist
39:33dose above FDA maximum.
39:36I'll give you pramipexole up to .75,
39:39ropinirole to four, rotigotine to three,
39:43but if you're above those doses.
39:47Patients in trouble?
39:49They're augmented.
39:51And hopefully you've discussed
39:52this with them,
39:54but it's time to do something more dramatic.
39:59Think about iron.
40:01Think about adding gabapentin,
40:04pregabalin, gabapentin in a carbal.
40:08If these approaches to mild
40:11augmentation aren't effective,
40:13this is when you need to
40:15do something radical,
40:16and this is not easy.
40:21You're not just going to be tinkering here,
40:23you're going to be making major changes.
40:26You're going to eventually to try
40:28to reduce the dopamine agonist.
40:30And that is not easy because each time
40:33you drop down on the dopamine agonist,
40:36people have a withdrawal.
40:39Their Rs comes back with a vengeance.
40:42So you need to provide them something
40:45else to manage that withdrawal.
40:47They are detoxing and I use that word.
40:52With the full understanding
40:53of what it suggests,
40:54they are detoxing from the
40:56dopamine agonist and you need to
40:58give them something to treat the
41:00RLS that worsens as they detox.
41:05So how do you switch from the dopamine
41:07agonist to either an A2D or an opioid?
41:11Don't try taking the dopamine agonist
41:13away without giving them something else.
41:16All that does is convince the patient.
41:18I can't do that, Doc.
41:20I tried to reduce the medicine
41:21once and it was terrible.
41:23I didn't sleep for days and days and
41:25days and then I had to go back on it.
41:27So first give them something
41:29to manage those symptoms.
41:31Worsen symptoms that are going to develop.
41:35And either that's going to be an A2D.
41:38Or it's going to be an opioid after
41:42you've added that second medication then?
41:46Only then start chipping away
41:49at the dopamine agonist.
41:51Other people have different
41:53approaches to this.
41:54Some doctors will stop the
41:56dopamine agonist like that.
42:00Have patients go cold Turkey either
42:03before adding the other medication
42:05or after adding the other medication.
42:08My experience has not been good with that.
42:11Because the withdrawal is bad
42:14and people just. Can't achieve.
42:21Staying off these medications,
42:23staying off the dopamine agonist.
42:28So the order and the the approach
42:31to this considerate can correct any
42:34underlying exacerbating factors,
42:36ones we've talked about. Add and maximum,
42:40maximize the A2D to a tolerable dose
42:43that may take a little bit of time.
42:45Then taper the dopamine agonist slowly.
42:48If that doesn't work,
42:50then I add the opioid.
42:52So at this point,
42:53they're on 3 medicines for our list.
42:55They say Doc, I'm on 3 medicines for RLS.
42:57I say, yeah, we got to get all of
42:59our reinforcements here if we want
43:01to get you off the dopamine agonist.
43:04They say OK.
43:05And keep tapering the dopamine
43:08agonist to discontinuation.
43:11And in many people you're going
43:13to be able to discontinue the
43:15dopamine agonist then.
43:17They're on the A2D and the opioid
43:19and maybe then you can taper the
43:21A2D now that the dopamine agonist
43:24is no longer worsening their Rs,
43:28it's worsening it.
43:29The Agonist is always helping and
43:32worsening helping and worsening always.
43:37We so I wondered whether this approach
43:43which is basically guideline approach.
43:49I wondered whether this approach worked,
43:51and so I did something that's stupid,
43:53which was to assess its
43:57efficacy in retrospectively.
44:01So I looked at roughly 60 or 70
44:04patients who I saw over a few
44:07year period who came in with
44:10augmentation on the dopamine agonist.
44:13And I looked at how this approach worked.
44:16And here you see severity at baseline
44:19and severity at the final visit,
44:22which was you can see about 2 1/2 years
44:26later and 80% were very much or much better.
44:30You can see the dark colors here,
44:33more severe changed into the lighter colors,
44:37less severe at the final visit.
44:41Lot of data here.
44:42You can look up this paper that
44:43was published last year in sleep.
44:4878% were responders at the
44:50final visit and the responders.
44:52They were borderline to mildly ill.
44:55Only 60% of the patients that I.
45:00Who started on dopamine agonists
45:02and everybody was on a dopamine
45:04agonist at the beginning,
45:05were able to discontinue
45:07those by the final visit.
45:09Some of them have now after we did this,
45:12data analysis continued to chip away,
45:15chip away,
45:16chip away and so more are discontinued,
45:18but there are still going to
45:20be 25% of patients who I just
45:22can't get off their agonist.
45:24The median the mean time to dopamine
45:28agonist discontinuation was nine months.
45:32This is going bad .3 milligrams per month.
45:38OK. It's ripping oral equivalence.
45:43So it takes a long time.
45:44Don't rush it.
45:45You'll fail, I think,
45:47if you rush it.
45:50Here's the question.
45:51Can addition of the this
45:52is from this data set?
45:54Can addition of just an A2D allow
45:58you to stop the dopamine agonist?
46:00You can see that.
46:0523 out of 60 ish people were
46:08able to discontinue. Umm.
46:12There's something weird about
46:14this picture here. But.
46:16A number of them could not.
46:19Ohh yeah 7 here was these were able
46:21to cut the blue was able to come off.
46:24The people that weren't able to
46:26come off the dopamine agonist
46:28with the A2D was either because
46:31it didn't have efficacy,
46:33it was not tolerable or both.
46:36Here's the same data for an opioid.
46:39About 1313 out of 31 were able
46:42to come off the dopamine agonist
46:44with just an opioid.
46:48But you can see that more than 50%
46:51needed something else or weren't
46:53able to come off The Agonist,
46:55either due to lack of efficacy,
46:58lack of tolerability, or both.
47:02And I'm not going to show this as a
47:04pie chart of what people ended up on
47:07at the end of this 2 1/2 year period.
47:10And you can see about 1/4 of patients
47:13were on an A2D with or without an agonist.
47:16About a sixth were on opioids and an
47:20eighth were on an A2D and an opioid.
47:24That it was common to have people
47:25at the end to be on all three.
47:29Think this is my next to last slide.
47:32This is kind of my.
47:35What do you call it when
47:37you're making a recipe?
47:41From. God blinking underwear.
47:45Anyway, you want to make
47:48whatever you're making food
47:50wise and you're following a.
47:55I'll just call it a road map now,
47:57but that's not what you
47:58use when you're cooking.
48:00This is my recommendations
48:03for how to treat severe,
48:07refractory, and augmented RLS.
48:12And is kind of an expanded
48:14version of this talk.
48:15It was published just this
48:17last year in the journal Chest.
48:19They have a section called how I
48:21do it and this is how I do it.
48:25For those of you who are interested.
48:27So in conclusion.
48:31Always assess your patients for
48:33underlying contributors because RSI
48:35is reversible and some people you
48:38can make it go away by giving iron by
48:41stopping a serotonergic antidepressant.
48:44Um, etcetera.
48:46Initial treatment is not.
48:50A dopamine agonist.
48:51Hope I made that clear.
48:53Generally you should start with a A2D ligand,
48:58pregabalin, gabapentin,
48:59gabapentin and a carpool.
49:02If you do use a dopamine agonist,
49:05keep dosages within the approved
49:07range and ask those questions.
49:10How many days a week do you have
49:11it at this time?
49:12How bad is it at that time?
49:14OK.
49:14Next period of time between noon and five,
49:17how many days a week and mild,
49:19moderate, severe or very severe?
49:21This will allow you to
49:24have a moving chart of.
49:27Daily severity and timing of
49:30symptoms in augmented patients.
49:32The goal is to stop the dopamine agonist.
49:39Just making things worse.
49:40And you do that by adding a new
49:44medication first, maximizing its dose,
49:47and then slowly withdrawing The Agonist.
49:51On that note, I'm going to stop
49:56and answer any and all questions.
50:03And I think I had some in the chat,
50:06so I'll just start with those.
50:07But mayor, because he is mayor,
50:10gets first shot.
50:13So before some of these drugs were
50:16introduced and I can I can mention
50:19this because of my advanced age.
50:22Anyways, we used to use
50:24clonazepam at very low doses.
50:26And it was actually in a lot
50:28of patients very effective,
50:31especially in patients
50:32that used to get restless
50:35legs, for example, on an airplane.
50:37And the rest of the time it was
50:38kind of controlled. Is there a role
50:41for clonazepam? At all.
50:42So I think for a PRN use, it's OK.
50:47I mean, for PRN use,
50:49I'd rather use a dopamine
50:50agonist if you're going to
50:51use it just on an airplane,
50:52or when they're getting acupuncture,
50:55or getting your, you know, Mayor,
50:57mayor, when you're getting your
50:59hair done at the hairdresser,
51:01I think it's reasonable to use a
51:02dopamine agonist in those contexts.
51:06I don't use clonazepam #1,
51:09it's got a 40 hour half-life.
51:12I don't use clonazepam
51:14within sleep disorders.
51:16Just doesn't make any sense for insomnia.
51:1840 hour, half life at the end of a week,
51:21you're at steady state.
51:22What kind of a sleep drug is that?
51:25So I don't use clonazepam if I'm going
51:27to use a benzo just to help people
51:29fall asleep because lying there for
51:31an hour we'll provoke our lesson.
51:33Some people for sure.
51:34So I'm going to treat their insomnia
51:37so they're not just lying there waiting
51:39for RLS to come get them in the dark.
51:42There's no evidence that clonazepam works.
51:44The clinical trials were
51:46negative for clonazepam.
51:48Sure if you put people to sleep they're
51:50not going to complain about RLS.
51:52But you know,
51:53we could use propofol if while we're at it.
51:55So I would encourage you to avoid
51:58benzodiazepines in these people
52:00unless you think anxiety is
52:03playing a substantial part in the
52:05emergence of their symptoms or they
52:08have a daytime anxiety disorder.
52:09And if you do want to use a benzo.
52:12There's a short acting one.
52:16We have a few questions here in the
52:18chat room if you want to read those.
52:20Sure. Yeah, yeah.
52:21First one is from Doctor Karen Johnson.
52:24For the people who you can't
52:25get off the dopamine agonists,
52:26do you try to convert using long
52:28acting formulation or will you
52:30continue them on short acting?
52:34I don't believe that the long
52:37acting provides any advantage.
52:39It does treat their symptoms
52:41in terms of augmentation.
52:43I don't think it produces
52:46a tremendous advantage.
52:48So if I can't get them off it,
52:50they still have symptoms,
52:51quite a bit of the day,
52:53and that context I will switch them
52:56to from a IR to an ER or to the patch.
53:01But I don't fool myself into thinking
53:04and I don't I make very clear to them.
53:08These dopamine agonists are still
53:09doing their bad things to your brain,
53:12and so we need to be really
53:16aware of that and.
53:18And they're scared because I've
53:20made them scared of this and so
53:22they're vigilant for it as well.
53:24But yes,
53:24I will move from a an IR to an ER only
53:28if they have symptoms that weren't it.
53:30They just have symptoms at night.
53:33There,
53:33I really don't think there's an
53:36advantage of the extended release
53:38medicines in terms of less augmentation.
53:41I just think they mask augmentation,
53:44at least at the beginning.
53:47Second question from T Kumar,
53:49people who may have mild OSA and are
53:52not willing to treat it and with RLS,
53:54will it get better with
53:56dopamine agonists or A2D?
53:58What's the maximum dose of
54:00methadone you would use?
54:01And she says I may have
54:03missed a variety of questions.
54:04Thank you. Yes, as far as I know,
54:09every kind of RLS responds to dopamine,
54:12I guess. I mean, they're remarkable.
54:14They're remarkable medicines for our lives,
54:16for the short term. So OSA,
54:19if you think OSA is causing their RLS or
54:23causing sleep disturbance causing RLS,
54:25dopamine agonists will work,
54:26that still doesn't mean I'm
54:28going to want to use them.
54:29As first line treatments.
54:34The maximum dose of methadone that
54:36I prescribe. I rarely go above 20
54:39milligrams I maybe twice in the last.
54:4415 years have I gone above 20 milligrams and
54:48one of them was a patient with severe RLS,
54:51end stage renal disease and.
54:55From basement, memory and disease
54:57actually lost most of her heart muscle
55:00and both kidneys in at the age of 40 and
55:04she got transplanted a few years ago.
55:06RLS and she was on 25 maybe of
55:11methadone and transplanted. Now,
55:14on no opioid and a little bit of gabapentin,
55:17I mean, our great story.
55:18So I rarely go above 20.
55:20I say to people at the beginning,
55:21most people are going to be between 5 and 15.
55:25It's my experience.
55:26And I go up by 2 1/2 milligrams
55:28at a time because I'm cheap.
55:31I'm really cheap with these
55:33medicines because small dose
55:34increases can make a big difference.
55:38So the next question we
55:40have is from Daniel Ellie.
55:41There's two question.
55:42Number one, what do you think is
55:45the mechanism for augmentation #2
55:47for patient with evening bedtime
55:48early sleep time symptoms in light
55:51of the nonlinear pharmacology
55:52of gabapentin thing at the end?
55:54How do you handle dosing for
55:56patients who need more than 600
55:58of gabapentin to control symptoms?
56:00OK, what's the? Brain mechanisms of RLS.
56:06I don't know. I stopped thinking about
56:07those kinds of questions long ago.
56:09I'm just mostly a. Practical person.
56:12I leave the higher level analysis
56:16of causes and mechanisms to others
56:19who are much smarter than me.
56:21What do I do with people who have an
56:23early bedtime? They go to bed at 8:30.
56:26And they get home from work at 5:30, so.
56:30So I'll give them some at
56:326 and some at eight.
56:34People are going to bed before 8:30.
56:37You know you have to.
56:40Troubleshoot with them and
56:41say can you take a little bit?
56:43You know early,
56:44and I understand that it may
56:47interfere with your alertness when
56:50you're doing that very important
56:52exercise after after you eat dinner.
56:54This exercise,
56:55the thumb exercise,
56:56clicking the channel changer.
57:00You want people to have a quality of life.
57:02You want them to be able to change that,
57:04to stay awake with their partner,
57:06to watch TV.
57:09But do you want to try
57:10to get ahead of things?
57:11I if if it's basically what I would
57:13do would be to give them pregabalin.
57:16Now that Lyrica has gone generic,
57:18I'm I've switched many, not all,
57:21but many of my gabapentin patients
57:24to pregabalin because it's just.
57:26I know what I'm getting, gabapentin.
57:28I don't know what I'm getting.
57:34Next question, what was the lowest
57:38level of pramipexole that you
57:40see caused augmentation example,
57:42have you seen it at 0.125 milligram?
57:46I think it can happen at .125.
57:49Maybe it happens more slowly.
57:52Umm. But I think it can happen
57:55and I think you say to patients,
57:57you know this is a very low dose and
58:00sometimes I see patients on half
58:02of 1 of of a .125 and you say it's
58:05a really low dose and your risk of
58:07augmentation is less than other people,
58:08but it is certainly not 0. And. So.
58:16You know, in the end the decision is theirs.
58:20And if they don't tolerate the
58:23other medicines, if they don't
58:24respond to the other medicines,
58:26they're really the ones driving this.
58:29You give them the risks and
58:31benefits and you say to them.
58:35You know you have a risk of this,
58:37but I understand your symptoms
58:38didn't respond to anything
58:39else or you didn't tolerate it.
58:40It's up to you and,
58:43and I'll see you very regularly,
58:44I don't see the people,
58:46these people on dopamine agonist once
58:48a year because things move too fast
58:51at no less than every six months,
58:54and maybe even more often than
58:56that because we want to try
58:58to avoid this problem.
59:03OK. And then does a higher ferritin
59:05level protect against augmentation?
59:08Well, low ferritin levels seem to promote.
59:13Augmentation. However,
59:14going from there's no evidence that
59:18going from 100 to 300 is protective.
59:21Ferritin is funky, as I'm sure you're aware.
59:25It's an acute phase reactant,
59:27and it doesn't take much to bump it up.
59:30So you can't trust the ferritin and I,
59:33you know, even the fellows I
59:35see them just are are fellows.
59:36They're just getting a fair 10, I say.
59:38You're just missing the boat.
59:39That 3:20, your ferritin means nothing.
59:42I don't know.
59:43I have no idea what it means,
59:44but it probably doesn't have to do with iron.
59:47And so.
59:50This is why I always get ferritin iron
59:53TIBC and I tell people I want you to
59:56take no iron containing vitamins and
59:58no red meat for at least 24 hours
01:00:02before you get your blood test.
01:00:06I want your iron level.
01:00:07I do not want the bacon from your
01:00:10bacon and eggs this morning level.
01:00:16I had a quick question.
01:00:17So if if you see someone
01:00:19who's on dopamine agonist,
01:00:20would you preemptively change them
01:00:23to alpha do to like delta, you know,
01:00:26so that you can avoid augmentation?
01:00:28Probably yes.
01:00:29I'll explain to them my concerns,
01:00:33but I'm not doing anything to anybody.
01:00:38I'm not changing their medicine.
01:00:41I'm providing them with guidance.
01:00:43That's what we do, right?
01:00:45And in the end, it's their body.
01:00:48And you know,
01:00:48at a certain point if they're on super
01:00:50high doses or something and they say
01:00:52I'm not going to make any changes,
01:00:54I'll say, you know,
01:00:55I don't think that I can care for
01:00:58you appropriately, but I rarely,
01:01:01rarely do that but.
01:01:03Give them the best odds that I can
01:01:07and allow them to make a decision.
01:01:10But I'm gonna keep nagging
01:01:13them every time I see them,
01:01:15because that's my job is to nag.
01:01:19Any further questions? I don't see
01:01:24any questions, no hands raised.
01:01:26I just, I just didn't want to say,
01:01:27John, thanks so much for that
01:01:28talk and it's always nice to hear
01:01:30from somebody that's been in the
01:01:32field a really long time, so.
01:01:36But I do. I know I do want to say that
01:01:39this message is so important it it's
01:01:43it's important for even people who are
01:01:45in the sleep field to here because I
01:01:47think it is a real change in how we
01:01:50think about how we treat restless legs.
01:01:52And and the first thing is to educate.
01:01:54Educate, to make people aware
01:01:55that this is a really big problem.
01:01:58And you know you first have to change the
01:02:00practice of the people that are in the
01:02:02field and then you can maybe begin to change.
01:02:05The practice of people that
01:02:06are outside of the field.
01:02:07But this is going to take a
01:02:09monumental effort and you know,
01:02:11I'm glad that that that, you know,
01:02:13we can do it kind of that we're
01:02:15on the same page.
01:02:16That's a great comment and I want
01:02:19to point out for all of you there
01:02:22in New Haven that you've got a
01:02:25world expert right there.
01:02:28Right.
01:02:28That is home today with his kids
01:02:30who went home early from school.
01:02:32So when you have questions about your
01:02:35RLS patients, your augmented RLS patients,
01:02:38you're difficult RLS patients.
01:02:40Just to e-mail Brian,
01:02:41you're I'm sure you're going to give
01:02:44them your home phone number just e-mail
01:02:47or call Brian at home because you
01:02:49know it's there are not many experts,
01:02:54Rs experts and you're really
01:02:56lucky to have one right there.
01:02:58So take advantage of him.
01:03:03Well, thank you. Thank you so much
01:03:05Doctor Winkleman for this excellent talk.
01:03:08I'm sure everybody enjoyed and learned a lot.
01:03:10Thank you everyone for your time. Bye, bye,
01:03:15bye, all. Good to see you all.
01:03:17See you soon, Brian.
01:03:18See you. Bye, bye, bye.