Treatment of Restless Legs Syndrome (RLS) with Methadone Versus Buprenorphine: Who Wins?
A ReLACSing Blog #34
Tyrannosaurus rex versus spinosaurus, who wins? King cobra versus red-tailed hawk, who wins? Wolverine versus buckeye, who wins? OK, that third one I made up…This past year, my son has been reading a lot of these interesting science books that pit one creature against another, as if they were in a UFC fight and we were analyzing the strengths and weaknesses of each combatant to determine who would be victorious. For whatever reason, none of my patients asks me about who would win between a raccoon and a possum. They don’t even ask me about Tempur-Pedic versus Sleep Number, as if I had any clue, so I am glad they usually don’t. However, those with restless legs syndrome (RLS) always want to know: methadone versus buprenorphine, who wins? This blog addresses the pros and cons of both of these commonly prescribed opioids in the treatment of severe RLS.
Those with a severe degree of RLS, the vast majority of whom have, or previously suffered from, the scourge of dopaminergic augmentation, often require opioid therapy to control RLS symptoms and improve sleep and overall quality of life. In fact, the American Academy of Sleep Medicine (AASM) lists opioids as one of only five treatment groups recommended in the 2024 Clinical Practice Guidelines.
Why opioids? Briefly, RLS is a condition primarily involving unpleasant sensations generated in the brain, similar to pain. In fact, a subset of those with RLS have a painful variation of it. Previous and even recent research has shown that the opioid system in the brain of those with RLS may not work properly or have deficiencies. This may help to explain why low doses of opioids are perhaps the most powerful treatment for RLS, dating back to the 17th century. In modern times, opioids, aka narcotics, pain medicines, analgesics, etc. like methadone and oxycodone have been used for severe cases of RLS, for 3–4 decades now. In my own clinical practice, I see a large proportion of very severe cases of RLS and thus have to prescribe opioids quite often. Methadone and buprenorphine (bup) are the two opioids I would recommend first to the majority of those with RLS who need to start one. But I have a clear favorite. Let’s break this down by each feature, just like in those “Who Wins” books that might start out with claw sharpness or something.
For those who do not want to read through this blog, here is a table that summarizes the relative positive strengths between these two agents:
1) Risk of death with overdose: Life or death is kind of a big deal. The biggest difference between methadone and buprenorphine chemically is that methadone is a traditional opioid that is a full agonist at the mu-opioid receptor. In layman’s terms, opioids are chemicals that attach to microscopic receptors—sort of like shipping ports—located on neurons (brain cells). The attachment of the drug to the receptor creates a signal throughout the brain through communications through a network of brain cells. In this case, it would be to create a signal that reduces the sensation of RLS, or lessens the pain, in other contexts. Methadone fully stimulates the receptor, but buprenorphine only partially stimulates the mu-opioid receptor and is thus called a partial agonist.
This is extremely important because there happen to be mu-opioid receptors in the brainstem in areas that control breathing. If those receptors are overstimulated, it can cause breathing to slow down, and in some cases, stop completely. Methadone, if taking too much all at once, can lead to breathing slowing down, possibly to the point of death. This is exactly the cause of the opioid-related deaths in the US from drugs like fentanyl and heroin that also impair breathing in the same fashion. Buprenorphine, however, due to the partial stimulation of the receptor, has what is called a “ceiling effect” on breathing. It may have a small effect at first, but beyond that, truckloads of buprenorphine will have no further effect and be unlikely to lead to serious breathing problems and death. Potential risk of death versus unlikely risk of death, who wins? Buprenorphine.
An important note, this may not be the case if buprenorphine is used in combination with other drugs that affect breathing. This can include RLS drugs like gabapentin and former RLS drugs like clonazepam that are used for anxiety or sleep as well. On this list is good ol’ alcohol, muscle relaxants like baclofen, and hypnotics/sleeping pills like your Ambiens and Lunestas. If used irresponsibly or in bad combinations, even buprenorphine can add on to the dangerous breathing risk. This is why it is so important not to experiment with taking controlled substances or changing doses outside of medical guidance.
2) Respiratory depression and central sleep apnea (CSA) during sleep: This is the same mechanism that could lead to a drug poisoning, but respiratory depression occurs much more frequently and usually without any apparent effect. The slowing of breathing could be the number of times one takes a breath per minute (respiratory rate) or the amount of air one breathes with each inspiration (tidal volume). Some of this reduced breathing rate and amount can occur while asleep, when breathing is fully controlled by the brain unconsciously. Another related phenomenon is CSA. Most have heard of obstructive sleep apnea (OSA), which is the very common snoring condition in which the throat collapses while one is sleeping, cutting off airflow. CSA is “central” in that the breathing is cut off by the brain itself. The brain takes pauses in breathing, which are called central apneas. Methadone is more likely to cause respiratory depression and CSA as it is a full agonist versus bup as a partial agonist. There is the ceiling effect with bup in that there can be a slight decrease in breathing, but beyond that, the bup does not further affect breathing no matter how much one uses. Buprenorphine can cause a slight degree of CSA or breathing reduction during sleep, but to a much lesser degree and less frequently. There are currently no studies of this at RLS doses, but I have personally transitioned several patients to bup who were on methadone, fentanyl, and extended-release oxycodone who had CSA, and it disappeared after they went on buprenorphine. Who wins? Buprenorphine.
3) Effectiveness: Despite the landmark randomized clinical trial a decade ago on extended-release oxycodone, methadone has probably been the most widely used opioid among RLS specialists. Buprenorphine is gradually gaining popularity due to some of the above safety factors and other features as below. Methadone and buprenorphine both work extremely well for RLS at low doses. There are no randomized controlled trials of either drug, and there probably won’t be one any time soon. (No one wants to fund studies promoting opioids, certainly not the opioid manufacturers!) There are no observational studies of methadone that evaluate RLS severity in a before and after fashion but the indirect evidence is overwhelming. My group has done a longitudinal study of buprenorphine demonstrating significant effectiveness over one year for those with severe RLS and augmentation. The study is in abstract form and simply waiting for this person to spend time writing up the paper and submitting it to a journal instead of writing blog posts on buprenorphine. (Actually, most of the time went into publishing the 2024 AASM Clinical Practice Guidelines; as proof, you see how long it’s been since the last blog post! Shhhh).
Part of the benefit of both drugs is the long-acting nature of these two agents. One dose of these drugs can last in the body for more than a day or two. They are steady in and steady out without the ups and downs of short-acting opioids like the immediate release forms of hydrocodone or oxycodone. With as few as one dose per evening, these medications can get those suffering with RLS through the entire evening and night, often enough to last into the next afternoon. This may provide enough relief to go on a plane flight or long car ride the next day. Who wins? Tie.
4) Ease of use: Methadone comes in a tablet form as well as an oral solution. The lowest strength tab is 5 mg, which is often stronger than many need for RLS, but the oral solution that is 5 mg/5mL can be finitely adjusted. Buprenorphine comes in three forms—more or less—for RLS: buprenorphine-naloxone sublingual films/tablets (Suboxone®), buprenorphine buccal films (Belbuca®), and transdermal patch (Butrans®). The patch is pretty easy to use as it works for 7 days and gives the drug 24/7 quite steadily, though with any patch there is a risk of skin irritation or allergy. The films and tablets placed in the mouth cannot be swallowed or the bup will be destroyed or not absorbed, so it must get into the bloodstream through the blood vessels in the mouth. This can be a bit of a hassle compared to going bottoms up with a sip of water for methadone like most other pills. There are also reports of a slightly increased risk of dental issues with the oral preparations of buprenorphine. Who wins? Methadone.
5) Risk of irregular heart rhythm: Methadone and buprenorphine, particularly in combination with other drugs that also affect heart conduction, can cause a delay in what is called the QT interval. This is measured on an electrocardiogram (ECG/EKG) in the doctor’s office. If the QT interval becomes too long, it could lead to the risk for a serious irregular heartbeat pattern called Torsades des Pointes. This can be of more concern at doses of these medications that are much higher than are used in RLS. The risk is stronger with other medications and health conditions like electrolyte imbalances, certain antidepressants and antibiotics that affect the QT interval, and other heart medications that are used for conduction. Buprenorphine has a much lower risk of this. It may be best to have a baseline ECG prior to starting methadone just to be sure one does not have a long QT interval. Who wins? Buprenorphine.
6) Cost: Methadone is dirt cheap (if the cost of dirt is adjusted for inflation, of course). It’s an old generic and costs pennies. Bup has three tiers. The Suboxone film can be as little as $1/day with some discount programs or pharmacy discounts and is often covered by insurance plans including Medicare. The generic form of the transdermal patch can run $50-100/month through cash pricing, but it is sometimes covered by insurance with lower costs at times (though for some, it costs more by going through insurance!). The Belbuca film can run > $300/month out-of-pocket and has considerably less insurance coverage as a newer brand name drug. Who wins? Methadone.
7) Availability and accessibility: Methadone tablets are in fairly good supply nationwide though at times it is hard to find the oral solution. I have no research data to support this, but I have rarely had an issue getting patients the Suboxone 2-0.5 mg buprenorphine-naloxone film or tablet. The patch is frequently available once shipped to the pharmacy from the warehouse, and the Belbuca has the most shortages from my experience.
Accessibility: So what is the difference between availability and accessibility? Methadone may be slightly more available, but it may actually be considerably less accessible to an individual who needs it. The biggest reason is that methadone is a Drug Enforcement Agency (DEA) Schedule II drug, as are most opioids, and buprenorphine is Schedule III. Bup is less regulated due to the reduced safety risks as above. Methadone requires a single, new monthly prescription from the doctor and no refills are allowed. Some states do not allow Schedule II drugs like methadone to be prescribed without an in person visit. This is a major barrier to clinics like ReLACS Health that are 100% telemedicine. This is a major barrier for patients not living near an area with an RLS specialist (generally hard to find) or other clinicians who are willing to prescribe these medications (very few are). Bup can be given for 90 days or 30 days with additional refills. It can be prescribed without an in person visit in most states. At the time of this blog post, the DEA is still figuring out what to do about the Ryan Haight act that had required an in person visit to prescribe controlled substances. There were exemptions made by the DEA for this law in 2020 due to the COVID-19 pandemic and they are still in place. A decision (or just a further moratorium) on telemedicine prescribing of controlled substances is expected at the end of 2024.
Additionally, both drugs are infrequently prescribed for pain and conditions not related to opioid use disorder (though in this view, they should be more frequently prescribed than other opioids). There is a general lack of education among clinicians on the benefits of these drugs. Not only are the drugs poorly understood, some clinicians have the impression that these are more dangerous than other opioids. Others are not even aware that they can prescribe them for pain conditions and RLS. Some think special licensing or certification is required or that their clinic “does not allow” them to prescribe these drugs. The fact is that only a regular DEA license that most doctors already have is needed. If the doctor can prescribe Percocet, the same doctor can prescribe methadone and buprenorphine. Who wins? It’s a draw.
8) Opioid withdrawal with opioid transitions: Regular opioids like methadone can be used interchangeably without major interactions. Someone can be taking oxycodone for several weeks and then start methadone the next day. If the dose is correct, there are no major problems. Oxycodone kindly leaves and methadone slips inside with no issues. With buprenorphine, however, due to its unique action at the mu-opioid receptor, it can bind more tightly to the receptor than other opioids and displace them. Instead of kindly opening the door and letting the previous opioid pack up and walk out, buprenorphine can do an eviction, with police and sirens and flashing lights. Buprenorphine, if initiated in those on a high enough dose of opioids for a long enough time, can lead to a withdrawal reaction of the previous opioid. The opioid system has to be clear of opioids for the buprenorphine to come in and make itself at home or there can be a bit of a kerfuffle. Can this happen at the low doses of opioids use for RLS? We do not know, but it is possible. This really only pertains to those taking higher doses of short-acting opioids like oxycodone multiple times throughout the day for many weeks or, more commonly, those on long-acting opioids like methadone, extended-release opioids, or the fentanyl patch. One must temporarily switch to a shorter-acting opioid for a few days to let the long-acting drug “wash out” and then stop the short-acting drug for several hours so that the system is clear of opioids before buprenorphine can be started. Another way is to stay on the same dose of the previous dose of opioids and slowly add buprenorphine in increasing amount each day. This latter method is used more often in those with opioid use disorder on higher doses, but it really has not be tested much in RLS. This is not an issue for most people on other opioids but the possibility of creating a drug withdrawal is still there, where it is not an issue with starting methadone. Who wins? Methadone.
9) Chemical dependence: A huge concern among those starting on opioids and for those prescribing them is whether the person will get “addicted.” This is addressed in painful (pun intended) detail in a previous three-part blog. Opioids can cause a chemical dependence with long-term use if one is on a high enough dose. Buprenorphine, however, causes less dependence than methadone. This may be because bup stimulates the ORL-1 receptor in the brain. Have you had enough receptor talk? I will spare you. The bottom line is this area of the brain can counteract some of the negative effects of stimulating the opioid system and reduce dependence. Who wins? Buprenorphine.
10) Constipation: As a common opioid adverse effect, I had intended to put this at the beginning of the blog, but it took a long time to come out…(rim shot). Opioids typically cause constipation by binding to the mu-opioid receptors in the bowels and slow the contractions and movements in the gut that move food through. Usually, this can be combated with increased water and plant matter intake or bulk-forming stool softeners that can help the slower bowels move digested food through. Bup, unlike methadone, counteracts another opioid receptor called delta. How many opioid receptors are there? Are there more opioid receptors than variants of COVID? Are there enough Greek letters in the world to sustain this? By blocking the delta-opioid receptor, it can have an effect that reduces constipation whereas full agonists opioids like methadone actually stimulate the delta receptor a little. Who wins? Buprenorphine.
11) Euphoria (aka “getting high”): Another risk that contributes to “addiction” to opioids is the fact that opioids can cause a euphoric effect. This is one of the main reasons the drugs are abused—to get high off them. Sometimes it can be unintentional, such as someone taking opioids for surgery but then getting used to the pleasant side effect and craving more of it over time. Methadone and buprenorphine are very low risk for euphoria. Part of this is due to the long-acting nature of the drugs. There is no rush in and out of the system. There are other chemical factors as well. Buprenorphine, again, is a partial agonist of the mu-opoid receptor, where most of the euphoria is generated, and it is an inverse agonist/antagonist (nevermind) at the kappa-opioid receptor (to name another receptor for you that I won’t bother explaining). The antagonism at the kappa receptor helps with reduction in other effects on mood including feeling bad when the opioid is out of the system (dysphoria). Though methadone is used for opioid use disorder, it is still higher risk of euphoria for these reasons than bup. Who wins? Buprenorphine, but methadone is not that bad.
12) Pronunciation: Methadone is easy to pronounce. It’s phonetic. Buprenorphine rhymes a bit with morphine. No one can pronounce it the first time they hear it. That’s why the brand names of Suboxone, Belbuca, Butrans, and even older ones like Subutex are made easier to pronounce than the generic. I cannot even remember the old brand name for methadone. Who wins? Methadone.
Well, that is enough of the similarities and differences between the two giants of opioid treatment for RLS. They are both excellent treatments for severe cases of RLS if opioids are needed, and in my view should be 1a and 1b among opioids. In the previously mentioned Guidelines for RLS, these two were not mentioned specifically until the discussion section, and fall under “oxycodone and other opioids” that are conditionally recommended. Again, this is because extended-release oxycodone with naloxone was a fancy new drug in Europe at the time and the company funded a large, high-quality research study. However, most RLS experts are using these two drugs before pulling out the oxycodone ER because of the benefits listed above. Final Results: Methadone versus buprenorphine, who wins? Buprenorphine, but methadone is a close second, earning the silver medal.
-Andy Berkowski, MD of ReLACS Health: writing a blog post versus publishing a large research study of buprenorphine: who wins?
