Should Sleep Specialists Prescribe Opioids for Restless Legs Syndrome?

Should Sleep Specialists Prescribe Opioids for Restless Legs Syndrome?

John Winkelman, MD, PhD, was fooled as soon as by an RLS remedy. Now he’s launched a registry to do the long-term analysis that gained’t let the sleep medication neighborhood be fooled twice.

As a clinician scientist, John Winkelman’s analysis tasks have virtually at all times been pushed by the perplexing circumstances he sees in clinic at Massachusetts Basic Hospital, notably by sufferers who reside with the neurological sleep problem stressed legs syndrome (RLS).

A professor of psychiatry at Harvard Medical College and a frontrunner within the research of the mechanisms behind the situation, Winkelman, MD, PhD, has made monumental contributions to the medical area over the previous few many years. He’s investigated therapy choices for sufferers with kidney failure and RLS. He noticed how limb actions throughout sleep can improve coronary heart price and blood strain, which may have cardiovascular implications for folks with RLS. Now, in gentle of research linking RLS augmentation with dopamine agonist remedy, he’s taking a look at opioid therapies.

Regardless of revealed medical trials exhibiting the efficacy of opioids in treating extreme RLS, the nationwide opioid epidemic has made many clinicians cautious of prescribing these medicines, and sufferers typically report problem acquiring opioid prescriptions for RLS, in line with a suggestion paper revealed in Mayo Clinic Proceedings in January 2018.1

“Quite a lot of medical doctors are abrogating their duty as a result of they’re scared,” says Winkelman, coauthor of the rules. “I perceive that as a result of I’m additionally nervous about prescribing these medicines, however I wish to do all the pieces that I can to be sure that my sufferers’ RLS is safely and successfully managed.”

John Winkelman, MD, PhD, sees sufferers with stressed legs syndrome at Massachusetts Basic Hospital. He’s additionally a professor of psychiatry at Harvard Medical College and has performed in depth analysis on the mechanisms behind RLS.

David Rye, MD, PhD, a neurologist primarily based in Georgia who treats RLS, has discovered that a few of his sufferers can profit from opioids, however writing prescriptions for these medicines comes with purple tape. Many pharmacies don’t take prescriptions from out of state—and since many individuals come from distant to see him, prescribing turns into a problem, he says.

“Some physicians have simply determined that they aren’t going to prescribe [opioids]. A number of folks in my workplace refuse to prescribe the medicines. It’s not solely a burden to the sufferers, it’s a burden to me as a result of I find yourself seeing these sufferers,” he says.

Ought to sleep medication medical doctors prescribe opioids for RLS? It’s a query that Winkelman is organizing a medical workshop round on the annual SLEEP assembly in June in San Antonio, Texas. There, he hopes that outstanding researchers, physicians, and regulators will debate the problem, share concepts, and doubtlessly bridge gaps in understanding.

Proceed this dialogue in particular person at SLEEP 2019. The medical workshop group, entitled “Ought to Sleep Medication Suppliers Prescribe Opioids for RLS?” will happen Tuesday, June 11, 2019, from eight am to 10 am (room quantity to be determined; examine this system nearer to the date). 

The query of RLS and opioids is one which he has already been exploring with funding from the Stressed Legs Syndrome Basis, which in 2017 awarded him a grant for a pilot research. With that funding, he has been constructing a registry of individuals in america who’re prescribed opioids for RLS (registry data is offered at In February, the RLS Basis introduced it’s giving Winkelman a further grant to increase his work on this space.

“That is the primary research wherein sufferers with RLS who use opioids are monitored over time to judge the effectiveness and tolerability of this therapy long-term, and by far the biggest observational research of such sufferers,” says Karla Dzienkowski, govt director of the muse, in a press release.

Evaluating this remedy has turn into extra necessary than ever since dopamine agonists, medicine that had lengthy been thought-about the gold normal of therapy, are not a viable possibility for a lot of sufferers. In recent times, it’s come to gentle that as many as 50% to 70% of sufferers utilizing these medicines develop a extreme worsening of signs referred to as augmentation inside 10 years.2,3 In such circumstances, RLS signs unfold to the higher extremities and begin earlier and earlier within the day.

Winkelman contributed to a number of the first medical trials exhibiting the efficacy of two medicines that had been authorized by the FDA in america for the therapy of RLS within the 2000s: pramipexole and ropinirole, that are dopamine agonists bought below the model names Mirapex and Requip.
At first, these medicines appeared like miracle medicine. “They, at the very least within the short-term, are extremely efficient for RLS, similar to placing a bit of butter on a scorching pan. The RLS actually melts away in virtually everyone,” he says.

The medical trials for FDA approval had been solely Three months lengthy however years later it grew to become obvious in longer therapy that, sadly, in many individuals RLS turns into worse over time on these medicines. “It grew to become clear as I used to be treating these those who we had made a mistake,” says Winkelman. “I started seeing extra sufferers who had been on high-dose dopamine agonists and had this very clear and really extreme augmentation. So it grew to become a problem as to easy methods to deal with these folks.”

Winkelman sets up a sleep study device.

Winkelman units up a sleep research machine.

Physicians who don’t acknowledge the phenomenon of augmentation proceed to extend the dopamine agonist doses for sufferers whose signs worsen, unknowingly inflicting doubtlessly everlasting harm. “My expertise is that a point of augmentation is reversible, however for many individuals it isn’t,” Winkelman says, “so you’ll want to deal with what’s now the extra extreme facets of stressed legs syndrome.”

Winkelman joined a global job pressure, established by the Worldwide Stressed Legs Syndrome Research Group at the side of the European Stressed Legs Syndrome Research Group and the RLS Basis, to develop evidence-based suggestions for the prevention and therapy of dopaminergic-induced augmentation. In 2016 the group revealed a paper within the journal Sleep Medication, stating that in probably the most extreme RLS augmentations circumstances, when all else fails, methadone or oxycodone needs to be thought-about.4

“There are solely 4 actually well-established therapy classes for RLS. One are the dopamine agonists; the second, alpha-2-delta brokers: gabapentin and pregabalin. The third class is [intravenous] iron or oral iron in individuals who have lowish serum iron, and the fourth is opioids. So we don’t have limitless choices,” says Winkelman.

To carry consciousness to this concern, Winkelman has visited Washington, DC a number of instances over the past 6 months to speak to regulators from businesses together with the US Division of Well being and Human Providers and the US Meals and Drug Administration.

In  November,  Winkelman,  traveled  with representatives  from  the  Restless  Legs  Syndrome  Foundation  to  Washington,  DC,  to  visit  legislators  and  federal  agencies  involved  in  health  care  policy.  Left  to  right:  Lina  Kilani,  legislative  correspondent, Sen. Lamar Alexander’s office, Winkelman, Karla Dzienkowski, executive director of the RLS Foundation, Sandra Katanick, member of the RLS Foundation Board of Directors. Photo courtesy of the RLS Foundation.

In November, Winkelman, traveled with representatives from the Stressed Legs Syndrome Basis to Washington, DC, to go to legislators and federal businesses concerned in well being care coverage. Left to proper: Lina Kilani, legislative correspondent, Sen. Lamar Alexander’s workplace, Winkelman, Karla Dzienkowski, govt director of the RLS Basis, Sandra Katanick, member of the RLS Basis Board of Administrators. Photograph courtesy of the RLS Basis.

Throughout these journeys, he’s requested the query: “How can we proceed to deal with the numerous opioid drawback we’ve on this nation, however on the identical time acknowledge that medical doctors must know that there are official makes use of of opioids, resembling RLS?”

Low doses of opioids can supply some reduction, however Winkelman desires to proceed with warning. Extra information is required concerning the long-term results of opioids on RLS sufferers. This is the reason he developed the Nationwide RLS Opioid Registry, primarily based at Massachusetts Basic Hospital in Boston. The venture has grown bigger than anticipated, enrolling roughly 400 individuals within the final 12 months, far surpassing the unique objective of simply 200.

The RLS Registry will stay open to new individuals till roughly late June. Enrollment is proscribed to people who’ve a analysis of RLS, are taking an opioid remedy to deal with their RLS signs, and have beforehand taken or are at present taking a dopamine agonist for RLS therapy. For details about collaborating, go to or name 617-643-2082 

In his medical observe, Winkelman makes use of the Opioid Danger Device, a well-established ranking scale to assist clinicians decide sufferers’ chance of misusing or abusing opiates. The shape is offered without cost on-line ( from the Nationwide Institutes of Well being.5

Winkelman usually prescribes methadone for RLS, an artificial opioid that’s recognized to deal with ache, with out producing the identical intoxication that pure opiates are recognized for. Based on the Mayo Clinic Proceedings paper, opioid medicines mostly used for RLS are oxycodone and methadone, however tramadol, codeine, morphine, and hydrocodone will also be thought-about. Efficient doses are significantly decrease than these used for power ache, 10-30 mg every day for oxycodone or 5-20 mg for methadone.1

Based on Winkelman, researchers nonetheless have extra to study. The Nationwide RLS Opioid Registry already has 6 to 12 months of knowledge for about half of those that have enrolled and retention charges have exceeded expectations.

The workforce has recognized physicians who’re keen to supply brochures concerning the registry to their sufferers. Those that are curious about collaborating can contact the researchers at Massachusetts Basic. The registry is enrolling new individuals till late June 2019.

“We’re going to proceed to comply with the individuals for at the very least 5 years and hopefully longer,” says Winkelman. “We actually want long-term security and efficacy information to supply to sufferers, to medical doctors, and to regulators.”

Contributors are given an preliminary telephone interview and a web based questionnaire. The researchers then comply with up with them each 6 months with surveys on-line. Knowledge collected pertains to opioid remedy, dose, severity of signs, opioid unintended effects, sleep high quality, and augmentation.

Thus far, “Opioids seem like efficient, long-term, with out dose escalation, they’re well-tolerated, and we use them solely in circumstances wherein folks developed augmentation and don’t reply to different approaches: iron, gabapentin, pregabalin,” says Winkelman, “so [opioids] are actually last-ditch therapies.”

One earlier double blind, randomized research within the journal Lancet Neurology discovered that extended launch oxycodone-naloxone was efficient for short-term therapy in sufferers with extreme stressed legs syndrome not managed with different therapies.6 “The research adopted sufferers for a 12 months, however that isn’t lengthy sufficient,” says Winkelman.

“I’ve been by means of this as soon as with the dopamine agonists, doing what I believed was finest for my sufferers, and what was skilled normal of care. Nevertheless it turned out to not have been factor,” he says. “Lots of people did get super reduction from the dopamine agonists, however we didn’t anticipate that in the long run it could make their RLS worse. So having been by means of that when, I actually really feel like it’s my duty to look at this in additional element simply so we don’t make the identical mistake once more.”

The Mayo Clinic paper concludes, “Numerous opioid medicines in low dose seem efficient in refractory RLS. The dangers of opioid use are comparatively low, considering the a lot decrease doses used for RLS in contrast with these in sufferers with ache syndromes. So long as affordable precautions are taken, the risk-benefit ratio is appropriate and opioids shouldn’t be unreasonably withheld from such sufferers.”

Lisa Spear is affiliate editor of Sleep Assessment.


1. Silber MH, Becker PM, Buchfuhrer MJ, et al. The suitable use of opioids within the therapy of refractory stressed legs syndrome. Mayo Clinic Proceedings. 2018 Jan;93(1):59–67.
2. Lipford MC, Silber MH. Lengthy-term use of pramipexole within the administration of stressed legs syndrome. Sleep Med. 2012 Dec;13(10):1280-5.
3. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal evaluation of dopamine agonists and methadone within the therapy of stressed legs syndrome. Sleep Med. 2011 Might;12(5):440-4.
4. Pointers for the first-line therapy of stressed legs syndrome/Willis-Ekbom illness, prevention and therapy of dopaminergic augmentation: a mixed job pressure of the IRLSSG, EURLSSG, and the RLS-Basis. Sleep Med. 2016 Might;21:1-11.
5. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated sufferers: preliminary validation of the Opioid Danger Device. Ache Med. 2005 Nov-Dec;6(6):432-42. Device out there on-line at
6. Trenkwalder C, Beneš H, Grote L, et al. Extended launch oxycodone-naloxone for therapy of extreme stressed legs syndrome after failure of earlier therapy: a double-blind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013 Dec;12(12):1141-50.

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