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We dive into the evolving landscape of treatment for restless legs syndrome (RLS) with neurologist Andrew Spector. For decades, patients have been prescribed dopamine agonists like ropinirole and pramipexole, often unaware that these medications could worsen their symptoms over time. Andrew discusses the new clinical practice guidelines from the American Academy of Sleep Medicine, which mark a significant shift in RLS treatment and offer hope for better alternatives. Learn about the risks of long-term dopamine agonist use, patient experiences, and promising new therapies.
Andrew Spector is a neurologist.
He discusses the KevinMD article, “The unexpected truth about restless legs syndrome treatments.”
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Transcript
Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today, we welcome back Andrew Spector. He’s a neurologist. Today’s KevinMD article is “The Unexpected Truth About Restless Leg Syndrome Treatments.” Andrew, welcome back to the show.
Andrew Spector: Thank you very much, Kevin. Glad to be here.
Kevin Pho: All right. So, your most recent KevinMD article is about restless leg syndrome. Before talking about the treatments for it, just give us some background in terms of what restless leg syndrome is.
Andrew Spector: Restless leg syndrome is an unpleasant sensation that affects mostly the legs. People often describe it as an urge to move, and it tends to get worse at night, worse when you’re resting and holding still, and better if you’re up and moving. So, it’s a pretty simple, straightforward, subjective criteria for diagnosis.
Kevin Pho: And what typically causes that?
Andrew Spector: We think the most common cause is a low iron state in the brain. A lot of people are brain iron deficient, and that triggers a cascade of changes in the receptors and several different pathways in the brain, leading to the symptoms that we talk about.
Kevin Pho: OK, so your article is about “The Unexpected Truth About Restless Leg Syndrome Treatments.” Tell us about that article for those who haven’t had a chance to read it.
Andrew Spector: For the last 20 or more years, the first-line therapy for restless leg syndrome has been dopamine agonists, specifically ropinirole, pramipexole, and rotigotine. Those three drugs have been widely used by many patients with restless leg syndrome, and unfortunately, often to their detriment.
These drugs are highly effective when you start them, and so you get this profound sense of relief that finally something is treating the restless legs. But as treatment goes on over the course of months to years, more and more people develop this complication that we call augmentation. Augmentation is when the symptoms of restless legs get worse. Maybe it’s spreading to other parts of the body or starting earlier in the day. This is a result of the long-term use of those three drugs.
When I talk about the surprising truth, the issue is the drugs that we’re using are actually probably making the problem worse for many people.
Kevin Pho: Just so I understand, someone comes in, gets diagnosed with restless legs, and traditionally they’d be put on one of these dopamine agonists. It would work for a couple of years, but then the symptoms eventually get significantly worse. Is that what you’re saying?
Andrew Spector: Right. It’s a seductive drug. If you go back to the doctor and say, “You know what, this drug’s been working great for me for the last year, but it’s starting to not work as well,” the doctor’s reaction is to say, “All right, let’s bump your dose up a little bit.” It’s going to work again, and you’re going to feel great again—until you don’t. It’s a vicious cycle.
Then you start accumulating more side effects of the drugs. Maybe you develop orthostatic hypotension and get lightheaded when you stand up. Maybe you start to develop daytime sleepiness. One of the most dreaded complications of these drugs is what we call impulse control disorders. You can become a compulsive gambler, a compulsive shopper, a compulsive eater, or a compulsive pornography user. These are well-known complications of the drugs as the dose goes up.
Every time you go back and say, “My legs are worse,” your dose goes up. You’re increasing the risk that your restless legs will get worse, and you’re increasing your risk of one of these terrible complications.
Kevin Pho: When patients come to you in that scenario you just described, where they’re in that vicious cycle, what are your options as a neurologist when you see them?
Andrew Spector: The first step is convincing patients that these are harmful drugs. They’ve been on them, and they’ve been working, so their perception is, “Every time I get a dose increase, it works.” You have to walk that back and say, “Yes, it may be helping, but it’s actually making it worse.” Then we look at the iron.
As I said earlier, this is a disease of iron deficiency—not necessarily blood iron deficiency. If you check the blood levels of iron for these people, they’re often normal based on what the lab defines as normal. But in our world, treating restless leg syndrome, we don’t want normal. We want high iron. We want to push that level up because a lot of times, people have trouble moving the iron from the blood into the brain, across the blood-brain barrier.
For people who have trouble moving iron from the blood into the brain, restless legs can develop as a result. So, we do a lot of iron infusions to push the iron level up, giving it directly in the IV to make that high level of iron. That creates a better environment to try to get off these dopamine agonist drugs—pramipexole, ropinirole, and rotigotine—and move to safer options.
Kevin Pho: In terms of weaning patients off that drug in the setting of IV iron infusion, what kind of timeframe are we looking at? How successful are you in doing that?
Andrew Spector: There are a lot of different schools of thought on this. Speaking from my practice, I tend to be a little slower with the wean. I know there are people who really go aggressively to wean off these drugs, but I tend to be patient. Coming off a dopamine agonist can be miserable, and you go through a terrible withdrawal sometimes.
So, I try to set the stage for success. I get the iron in, and that could take two months for the iron to have its full effect. It doesn’t work immediately. Then I try to find a drug to help mitigate the symptoms. That might be a gabapentin or pregabalin medication, or it could be an opioid medication like methadone or buprenorphine, which are highly effective. I try to cushion the symptoms of restless legs while I very gradually take the dopamine agonist away.
I’ll be more aggressive if they’ve got compulsive gambling or compulsive shopping. I don’t want to wait around to get them off the drug if that’s going on. But if it’s just an issue with augmentation and they’re suffering from bad restless legs, I’ll more gradually take them off to avoid as much withdrawal as I can.
Kevin Pho: To be clear, how often is it that patients eventually develop some of these complications to dopamine agonists? Are we talking about the majority of patients or a small subset? What kind of numbers are we looking at?
Andrew Spector: The majority—and there are some out there who will say that everybody will eventually develop it if given enough time. I don’t know if it’s truly everybody, but it could be 70 percent of patients who eventually have a problem with augmentation if left on the drugs long enough. So, it’s a high enough number that we really need to be thinking twice about using these drugs.
Kevin Pho: How about in the primary care setting, then? If I see a patient that I suspect has restless legs, what are the options available to me?
Andrew Spector: Number one: iron. Number two: remove triggers—antihistamines, anti-nausea drugs, anything with anti-dopamine properties, antidepressants, especially the serotonin drugs. They can all make restless legs worse. So can caffeine, alcohol, nicotine, and sugar.
You can counsel patients about removing the triggers. You can also start gabapentin or pregabalin, and you can get iron treatment going. Those are all great things at the primary care level. I wouldn’t advise using dopamine agonists at this point in the primary care setting. I will use them in select patients, knowing I’ve got to keep the doses very low and try to use them as needed, maybe not as a daily medication. But I think it’s safer not to use dopamine agonists in primary care.
Kevin Pho: When you say iron, would oral iron be good enough? And how would I start oral iron in patients?
Andrew Spector: Ironically, oral iron is better if your iron is very low. Sometimes we think, “Oh, it’s really low, better do an infusion.” In fact, it’s the opposite logic with iron. That’s because the lower the iron level, the better your gut will absorb the oral iron.
People who have not just brain iron deficiency but also blood iron deficiency, with low ferritin levels—a ferritin of 7 or 10—will often do really well with oral iron because their bodies are so starved for iron that they’ll absorb it all. Once you get to ferritin levels like 75 or 100, the body’s just not going to absorb a lot more iron. Those are the folks where I’d say we should go for an iron infusion.
The thresholds we use—the guidelines suggest that if your ferritin is less than 100 or your transferrin saturation is less than 20 percent, you should go ahead with an iron infusion. We use both because ferritin is an acute-phase reactant, so it’ll go up just because you have inflammation. We can’t always rely on the ferritin, which is why we use the percent saturation as well. That’s not an inflammatory marker.
It’s also important to note that iron levels need to be tested in a fasting state in the morning. Those levels fluctuate throughout the day. So, testing iron in the morning—not after taking an iron pill—is the best way to do it.
Kevin Pho: What can a patient expect after getting an iron infusion in terms of relief of their symptoms?
Andrew Spector: Iron infusions are not as scary as they once were. When I was in med school, we were told not to do them because of the risk of anaphylaxis. Those risks are not present to nearly the degree they used to be.
The immediate effect is that patients will probably tolerate it very well. Maybe they’ll experience a headache afterward or some muscle aches. But restless legs don’t tend to improve for about six to eight weeks. I tell people they need to be patient—it’s not an immediate process.
Kevin Pho: Do patients eventually need iron infusions on a continuous basis? Are they going to be on iron infusions long-term to maintain relief of their restless leg syndrome?
Andrew Spector: That’s a great question, and I get it a lot. The answer is no. A lot of times, when we take a patient’s iron up to a nice high level, they’re good to go. We’ve really just changed their baseline level of iron, and they can stay there for quite a while. Maybe a couple of years down the road it’ll be time for another infusion, but there’s no set rule that says you have to do it every year or every six months.
We just monitor the levels. If the iron drops again, we’re open to doing another infusion, but there’s no set frequency or guarantee. The population most likely to need repeat infusions would be menstruating females who are losing blood each month—they may need iron infusions more often. Postmenopausal women and men tend to hold on to their iron pretty well.
Kevin Pho: Let’s talk about augmentation again. In the primary care setting, if we have patients who are on these dopamine agonists for a period of time for their restless legs, what kinds of things are patients saying that would make me think this is, in fact, augmentation? What are some typical phrases, sentences, or symptoms they would report?
Andrew Spector: I’d say there are three common ones. First, they’ll say, “It’s just not working as well as it used to.” Second, they need the medication earlier. For example, they’re not making it to their nighttime dose. Normally, their restless legs might kick in around 8 p.m., but now it’s starting at 7 or 6. So, the symptoms are occurring earlier. The third red flag is spreading. It was just in the legs, but now they’re starting to feel it in the arms too, or another part of the body.
Those are the big three indicators that they’re developing augmentation: reduced efficacy, earlier onset of symptoms, and spreading to new areas.
Kevin Pho: How about non-pharmacological treatments? You mentioned peroneal nerve stimulators. Are there any device-based approaches to restless legs? What do we have to look forward to?
Andrew Spector: Earlier this year, we got our first really effective device treatment, which is exciting. As I mentioned earlier, some of the advanced drug therapies include methadone and buprenorphine. While they work, we’d rather avoid opioids if we can.
This new device is a band that you place around the leg just below the knee. It stimulates the peroneal nerve, specifically the afferent fibers, creating a spinal reflex arc. This stimulation results in tonic motor activation, simulating what voluntary movement of the leg would feel like. I’ve tried it on myself—it almost feels like a very mild vibration in the leg.
It’s not the same as a TENS unit, which people often ask about. It doesn’t create a muscle contraction that you can see, and your leg doesn’t visibly move. It’s more like the sensation of a vibration in the leg. The patients I’ve used it on have been pleased so far. It’s still early—since it only came out this year—but anecdotal evidence from my patients has been quite good.
Most importantly, it’s very well-tolerated with no major side effects.
Kevin Pho: We’re talking to Andrew Spector. He’s a neurologist, and today’s KevinMD article is “The Unexpected Truth About Restless Leg Syndrome Treatments.” Andrew, as always, we’ll end with some take-home messages to the KevinMD audience.
Andrew Spector: My biggest take-home message is to take restless legs seriously because it makes patients absolutely miserable. It’s one of the conditions that can completely destroy quality of life. That’s message number one.
Message number two: it’s very treatable. These folks who come to me with severe augmentation, they all get better by the time we get them off the dopamine agonists. Augmentation is reversible, and there are good treatments available. Never give up, because if you can get to a restless leg specialist, we can help almost everyone, if not everyone, feel better.
Kevin Pho: Andrew, thank you so much for sharing your perspective and insight. Thanks again for coming back on the show.
Andrew Spector: Thank you very much, Kevin.
