Update on RLS 2026 Part 2: S8-Ep12

[00:00:00][music] [music] >> Welcome to Mayo Clinic Sleep Medicine Podcasts, a series for physicians, advanced practice providers, nurses, and other health practitioners treating sleep disorders or interested in learning about state-of-the-art advances in sleep medicine and sleep health.

[00:00:27]I'm your host, Dr. Michael Silber.

[00:00:29]>> And I'm your co-host, Dr. Mairaj Juna.

[00:00:33]We are both consultants at the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minnesota.

[00:00:39]Thank you all for joining us for today's podcast titled "Update on the Management of Restless Legs Syndrome, Part Two".

[00:00:46]It has been about 2 years since we last did a podcast on Restless Legs Syndrome, and since then the American Academy of Sleep Medicine has published new clinical guidelines for the management of RLS, and the scientific and medical advisory board of the Restless Legs Syndrome Foundation has revised their algorithm for the management of this condition.

[00:01:07]In our last podcast, Dr. Michael Silber, who chaired the task force of the foundation responsible for the recent update, discussed first-line therapies for the management of RLS, and today he returns to discuss second-line approaches.

[00:01:23]Mike, in our last podcast you discussed iron and gabapentinoids as first-line therapies for chronic persistent restless legs symptoms.

[00:01:32]What are the reasons why a provider might move on to second-line therapies, and what agents or modalities would you consider here?

[00:01:41]>> Well, um a patient may have tried iron oral or intravenous and it really hasn't worked or it was contraindicated in the first place, and then have tried gabapentinoids and a number of things might have happened. It may be ineffective. You recall that 30% of patients gabapentinoids are not effective for restless legs, or there may be intractable and unacceptable side effects.

[00:02:07]Alternatively, by joint decision-making, the patient and the provider may have decided the gabapentinoids should not be used in that patient. For instance, we did discuss that someone with a previous history of opioid dependency may be at greater risk from dependency with gabapentinoids, or someone who's in respiratory failure already should probably not or be careful using the drug.

[00:02:32]Even though only 20% of patients on gabapentinoids increase weight, if you have a patient who's already struggling, BMI 39, they may be extremely unwilling to consider any drug in which is even a low probability that this would contribute to difficulties losing weight. And similarly, someone who has a background of major depression who's at last under control on antidepressants may understandably be very wary about using a drug which could precipitate a relapse. So, there are reasons why patients and their providers together might decide gabapentinoids are not for that patient. So, for all these reasons, we must have second-line therapies.

[00:03:12]Now, the two medication groups that would have to be considered at that point are the low-dose opioids and the dopamine agonists.

[00:03:21]Um we have also now a neuromodulatory form of therapy, peroneal nerve stimulation, which we'll talk about a little later, but generally, that's adjunctive therapy for medications. Um though, some patients may choose to try that alone first. And then finally, we should talk just briefly about the drug dipyridamole, although there's much less information about it.

[00:03:50]>> So, after the opioid epidemic, many providers are understandably uncertain about prescribing long-term opioids.

[00:03:58]Can you tell us a little bit about why it's safe to use these drugs in restless leg syndrome? And And do we have any data in regard to efficacy and long-term safety with the use of these drugs in RLS?

[00:04:10]>> Mhm.

[00:04:11]Yes, we do. I'm happy to say that more more and more physicians are becoming comfortable in using low-dose opioids for restless legs.

[00:04:23]Um This has evolved as more and more physicians have understood the risks of long-term high-dose opioid use for chronic pain and thankfully moved away from it, but restless legs is a condition in which low-dose chronic use is certainly indicated and is relatively safe. The best data we have is the long-term opioid registry for restless legs, which is coordinated by Dr. John Winkelman at Harvard University, involving about 500 patients taking opioids of various types for restless legs, and we now have 5-year follow-up data. And I think the best way of looking at it is that only 13% of the patients had by 5 years increased their dose of opioid by more up to greater than 25 morphine milligram equivalents. Now, that may be a difficult statistic for people who haven't done a lot of opioid prescription to understand, but 25 milligrams morphine is actually very low dose. We are only concerned about morphine when it goes above 50 milligrams, and certainly patients who who ran into trouble in the chronic opioid epidemic were using, you know, well over a hundred generally and sometimes far above that. Only 6% of those 500 patients by 5 years had increased their dose to greater than 50 morphine milligram equivalents. So, for the majority of patients it was little or no change after 5 years and they continued to use those doses suggesting that both there's both efficacy and very little risk of tolerance and in and increasing doses. So, that's good and encouraging data to suggest that these drugs are safe and effective in restless legs in the right people.

[00:06:30]>> So, with this in mind, what opioids might you consider and and what does low dose really mean?

[00:06:37]>> Well, the only good controlled large controlled trial of opioids in restless legs was on oxycodone, actually controlled-release oxycodone.

[00:06:48]Very good trial and undoubtedly effective for people with otherwise refractory restless legs. There are long-term studies of methadone and otherwise short-term studies, but a lot of clinical experience. Now, there is not one single opioid which different experts would say is the one to start with. I personally start with it short-acting oxycodone. It's cheap. It's easy to use.

[00:07:15]A lot of experience with it, but other colleagues start with methadone and others start with buprenorphine. They're all reasonable choices and it really depends on the provider's familiarity, the patient's wishes, and the cost and side effects. Now, if one starts with oxycodone, as I do, I might start with 5 mg before bed um and another five during the night. Or depending on the age of the patient, maybe 10 mg. The average patient needs a total of 20 mg oxycodone um to get control of restless legs. We do go up to 30 mg daily. For oxycodone, or alternatively for those familiar and liking using hydrocodone rather, or for that matter controlled release morphine, which I find is very effective in people controlled release, we a low dose would be considered certainly under 50 morphine mg equivalents. Um so, these doses I'm telling you about are definitely low dose. Methadone is a little different. Under a daily dose of 20 mg would be low dose. And buprenorphine again it's hard to compare with the others, certainly under 6 mg daily. Most patients need considerably less. So, we are talking low dose, and there's a range of people of what people can use.

[00:08:45]>> Most sleep providers are unfamiliar with buprenorphine. Could you tell us how you use this drug, Mike?

[00:08:52]>> Yes, um there's very little published data on buprenorphine in restless legs, really just one abstract at the moment. But a fair amount of experience is being developed, and the attractiveness of buprenorphine is that it's a mixed agonist antagonist, and it's being used very frequently now to wean people who are addicted to opioids such as heroin or fentanyl. Um it's not I wouldn't say replace, but I think it's used more frequently than methadone for these patients. So, it has less tolerance, less euphoria, less respiratory depression. So, all these are very attractive features, even though these um side effects are relatively rare in the low doses we use with the more conventional opioids. Now, the problem with buprenorphine is it's not well absorbed from the elementary tract and really has to be absorbed through oral mucosa or through the skin. There is a skin patch, but that's put on sort of once a week and it's very hard to regulate doses. So, we tend to use the oral mucosa forms.

[00:09:56]For somebody who is naive to opioids with starting buprenorphine at the beginning as the first opioid, we really need to use the buccal um patch um which is called Belbuca and it's quite expensive. So, one starts low at about 75 micrograms at night and builds up every two to three nights. By the time we get to near 250 micrograms, we should really convert to the much cheaper sublingual um form and that is usually marketed in the form of Suboxone. It does it include some um naloxone with it to prevent it being um used as an abuse agent.

[00:10:43]It comes the lowest dose only as a 2 mg film, which is too high to start with, but you can cut it into quarters, which would be 0.5 mg, 500 micrograms, or even into eighths. One could even start at 125 micrograms. And as I said, we change Belbuca to this as soon as possible because of cost.

[00:11:04]Um we then increase it slowly. Most people need about 2 mg, but some need up to 6 mg.

[00:11:11]The Most people need it just before bed.

[00:11:15]It's got a long half-life, but some do need a second dose at some stage during the day.

[00:11:21]The important thing is if you are already on another opioid and you want to convert, you can go straight then to um the Suboxone starting at 0.5 mg and you must stop the other opioid 24 hours before because otherwise it can precipitate withdrawal. So, you stop 24 hours before you start the buprenorphine.

[00:11:44]Conversion from methadone is more complex and probably best left for specialists with experience in that conversion.

[00:11:53]In higher doses, buprenorphine can damage teeth enamel, and we do recommend that patients brush their teeth after the film has dissolved, and then also see a dental hygienist every 6 months.

[00:12:07]So, that's in summary is how we use buprenorphine. As I said, I don't usually use it as my first-line opioid, but if patients are not tolerating, say, oxycodone well, or not getting a good effect, that would be the second one I go to, and it's perfectly reasonable to start it in lower dose for a patient who's opioid-naive if a provider so wishes.

[00:12:32]>> So, what side effects do you warn patients about, and and what precautions should providers take when prescribing opioids?

[00:12:40]>> Side effects can occur.

[00:12:43]Many people will get constipation on even low-dose opioids, and we talk about diet modifications.

[00:12:50]Nausea is rare, but when it does happen, can be very intractable and difficult to manage. Many people get an itch, not from an allergy, it's from mast cell degranulation, and often it's just perfectly tolerable, but patients should be warned about it.

[00:13:05]Opioids can cause unsteadiness at night in older people, risk of falls, sometimes drowsiness in the morning, but most people with severe restless legs actually become more alert because for the first time in months or even years, they're getting adequate sleep at night, which is wonderful.

[00:13:23]Um there can be changes in testosterone, which can cause sweating, which can be very uncomfortable for patients, and sometimes sexual dysfunction.

[00:13:34]But, generally, the drugs are well tolerated. They can convert obstructive sleep apnea to central sleep apnea. So, patients with sleep apnea need to be monitored, check the downloads in the machine that sleep apnea isn't creeping in again if the central form, and if necessary, do overnight oximetry. So, that's important to bear in mind, and they should not be combined with benzodiazepines.

[00:14:00]I warn patients that opioids are dependence-producing drugs. Most patients know that pretty well, but in practice, in these low doses, especially in people with auto positive history of drug abuse, that is exceptionally rare.

[00:14:14]Now, what precautions do we take? Well, all our patients sign an opioid contract, saying, basically, they will get opioids from only one provider, they will not increase the dose without discussing us with us, they will look after their opioids. We don't like a patient to call in and say, "I lost my opioid supply. Can you give me an earlier repeat prescription?" We'll give them one chance on that, usually.

[00:14:39]And a few other things on the contract, but those are the main things. Um we uh see our patients back regularly, initially within a month of starting opioids, and then, usually, every 6 months. Now, in at Mayo, we've got this so well put together with nurses who supervise management, that in stable patients, we see them back once a year, but I think most practitioners would want to do that every 6 months.

[00:15:05]Please don't ask your patients to have to come in personally every month to get their prescription. It's humiliating for the patients, and generally not required by regulatory authorities. Though, of course, we we can't um Um, talk about that if it is required.

[00:15:23]Usually, they they could should be able to renew each month electronically.

[00:15:27]Um, then urine drug screens are controversial. We're required to do them every 6 to 12 months, but I've never found it particularly helpful. Sometimes the drug doesn't show up. Methadone and buprenorphine may need special screens.

[00:15:44]Um, occasionally we pick up cannabis in the screen and that's not essentially a contraindication to opioids that we prefer them not to use cannabis.

[00:15:53]And it just hasn't been terribly helpful in my hands, but sometimes it's required um, by the hospital or other regulatory authorities.

[00:16:04]>> Now let us discuss the controversies regarding dopamine agonists. The American Academy of Sleep Medicine gave a conditional recommendation advising against the use of dopamine agonists for restless legs. What was the reason for this, Mike? Do you think they still play a role in management of this condition?

[00:16:21]And if so, what precautions should providers take when using these medications?

[00:16:27]>> Well, this was a huge change in that ASM practice parameter. They gave a conditional recommendation against the use of dopamine agonists uh, based on only moderate evidence at best. Um, they do qualify that by saying that some patients may choose to use them if they value short-term benefit um, balanced with perhaps long-term harm. And elsewhere in the discussion of the in the paper, they say that it could can certainly be used for patients who failed other drugs. So, it's not an absolute um, prohibition by any means. I was not on the ASM task force, but um, five of the members of the task force served on the Restless Legs Foundation task force bringing out the new algorithm and we reached a a compromise on the use of dopaminergic agonists.

[00:17:23]This is an acceptable alternative to low-dose opioids for patients who failed first-line therapy as long as several very important conditions are fulfilled.

[00:17:34]But let's first talk about why did the ASM come up with this um finding and it was based on augmentation as most um physicians who use the drugs know and I think most are familiar with augmentation.

[00:17:48]Um with the passage of time restless legs moves early in the day up into the arms and is less effective at night and the more agonist you then add in the worse the augmentation paradoxically becomes.

[00:18:02]Now how frequently is how frequent is this? Well, let me summarize a number of studies by saying that and let me turn it a little on its head at least 30% of patients with using dopamine agonists chronically will not develop augmentation over 8 to 10 years.

[00:18:23]So there is that 30% group who will never develop it or at least by 10 years. We don't know after that. It's very hard ab initio to predict those group. In fact, we can't do that easily.

[00:18:36]But that is the main reason why the ASM was very understandably very concerned because once augmentation is established and in our next podcast we'll talk about this in more detail, it is exquisitely hard to get the patients off the dopamine agonists. So what are the conditions? Well, number one, we have to make do joint decision-making with the patient, explain very carefully to them what augmentation means and the other side effect of impulse control disorders. 6 to 12% of patients. They must understand it and accept that this is a risk. Number two, they must guarantee to us they will not increase the dose without telling us irrespective of how symptoms worsen and will report immediately should symptoms of augmentation develop.

[00:19:24]Um number three, we must follow those patients. These are not drugs that you as a sleep specialist can prescribe and say go back to your primary care doctor who will continue the prescription. If you prescribe a mean agonist, you take on the responsibility of seeing your patient back at least every months and questioning them about augmentation symptoms.

[00:19:46]And then perhaps most important, the most important thing we can do to reduce the risk of augmentation is keep the doses low. Pramipexole should never be used in a daily dose of more than 0.5 mg, ropinirole 2 mg, and the rotigotine patch 3 mg. We should really never go above those levels. So, if we take those precautions and the patient and you together have made a careful decision they don't want to use opioids, stigmas, um concerns about addiction, or any other factor, and you and they both believe it's perfectly reasonable to try the dopamine agonists, I think it can certainly be done and done safely, but one has to be careful and fulfill these criteria.

[00:20:38]>> As you mentioned earlier, the new algorithm also indicates a role for neuromodulation in the form of peroneal nerve stimulation.

[00:20:47]Could you tell us a little bit about this technique and the data supporting its use?

[00:20:52]>> Yes, this is bilateral high-frequency peroneal nerve stimulation by bands around the peroneal nerve around the knee on both sides. Patients tolerate this very well on the whole. We think it stimulates the efferent fibers up into the spinal cord, and then there's an efferent discharge causing a little bit of subclinical contraction of the anterior tibial muscles, which simulates movement. Um it can be used up to four times a day for 30 minutes at a time. It seems to work best if you put it on when if you know what time your RLS is going to start, you put it on just before that time rather than when they have already started, but it can be used that way.

[00:21:36]The controlled trial of 130 patients showed benefit um in about I think it was 60 um oh I think by 4 weeks 45% of the patients had benefit, and in the open-label extension up to close to 6 months, there was 73% benefit. So, that sounds very reasonable. Um there is a study suggesting the dose of opioids can be reduced if you add in the pair peroneal nerve stimulation. It is FDA approved for what they call refractory restless legs, which is defined as failure of one drug.

[00:22:15]Can it be used alone? Um certainly. Most clinical experience so far seems to be that it works best in association with another drug, but there's nothing to stop the patient trying it alone first and see if it is sufficiently beneficial.

[00:22:31]Um and we know we don't know a lot about using it at initial if they've not failed a drug, that's not an FDA indication at the moment. I believe it is now available in almost all US states. The company producing it deals with the prescription, working with insurance payment issues, and sets it all up with somebody coming to see the patient and working out how to do the stimulation. It's actually fairly straightforward. There seems to be no downside except sometimes patients get a irritation around the knee, but that's unusual. We need to build up more experience with this technique, but it's very nice to have a neuromodulatory technique.

[00:23:11]Um perhaps this is also a good opportunity for me to say that I have not been involved in that in these trials at all for this device or actually in in um company-sponsored trials of any of the drugs we've talked about last time or today.

[00:23:31]>> Now, the revised algorithm also discusses a dipyridamole. Could you tell us a little bit about this drug and its role?

[00:23:40]>> Well, dipyridamole is an old drug. It's an antiplatelet agent. Um it increases adenosine and there's some theoretical evidence that adenosine may be low in restless legs. There's one small Spanish controlled trial. I think it was 28 patients for over 2 weeks, which seemed to show benefit, but that's it. We don't have long-term studies. We don't have bigger trials. And there are some difficulties with dipyridamole because it's an antiplatelet agent. If your patient's also taking low-dose aspirin or an anticoagulant, you have to be careful.

[00:24:16]And it also drops blood pressure, so patients on antihypertensive agents might get light-headedness, dizziness.

[00:24:23]So, those are concerns. Um I've had very little experience with the drugs.

[00:24:29]Colleagues who've used it a little more extensively have not been terribly impressed with its effectiveness, but it's available as an alternative, which certainly can be tried as second-line therapy.

[00:24:41]>> Mike, thanks so much for sharing your expertise today and to our listeners for joining us.

[00:24:46]In our next podcast, Dr. Silber will will return to discuss the management of patients with dopamine agonist-induced augmentation, the perioperative management of this condition, and RLS in renal failure.

[00:24:59]>> We hope you enjoyed this podcast. If so, please tune in again through wherever you receive your podcasts as we discuss further topics in sleep medicine and sleep health. Thank you.

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