Sleep 2023.01.25 Winkelman
February 19, 2023ID9520
To CiteDCA Citation Guide
- 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.