By Alyx Arnett
Dopamine agonists make up three of the four US Food and Drug Administration (FDA) approved medications for restless legs syndrome (RLS), and they are the most commonly prescribed drugs for RLS.1 The American Academy of Sleep Medicine (AASM) now recommends against them.
The pivot in the AASM’s clinical practice guideline, newly published in The Journal of Clinical Sleep Medicine, overhauls its previous guideline, issued in 2012, which recommended dopamine agonists as first-line treatment for RLS.2,3 The leap away from this drug class stems from longer-term evidence on the risk of augmentation—a gradual worsening of RLS symptoms—that occurs in many patients after starting dopaminergic agents.4
“Whatever part I played in saying these medications should be first-line, now I feel I really need to put out these new guidelines,” says John W. Winkelman, MD, PhD, first author of the AASM’s 2024 guidelines.
Winkelman didn’t co-author the 2012 AASM guideline but feels some responsibility due to his role in RLS studies in the early 2000s. Though a paper published in 1996 documented augmentation concerns,5 Winkelman and a colleague reported in a 2004 publication that augmentation and tolerance were more common with extended pramipexole treatment of RLS than had been previously reported, but that the complications were “manageable” and “only rarely require medication discontinuation.”6
Perhaps even more influential was a paper co-authored by Winkelman in 2006 that contributed to the approval of pramipexole, initially approved in 1997 for Parkinson’s disease, for RLS treatment.7
“I was naive,” says Winkelman, chief of the Sleep Disorders Clinical Research Program in the Department of Psychiatry at Massachusetts General Hospital. “Twelve-week trials are not long enough for disorders that can last a lifetime.”
Augmentation is now estimated to occur in about 40% to 70% of RLS patients using pramipexole and ropinirole during a 10-year period. It may be slightly lower with the rotigotine patch (estimated at 36% after five years).8
First-Line Therapy Drugs for RLS
The AASM now recommends the alpha-2-delta ligand medications gabapentin enacarbil (the other FDA-approved drug for RLS), gabapentin, and pregabalin (the latter two when prescribed off-label) as first-line therapy and recommends against the three FDA-approved dopamine agonists—pramipexole, rotigotine, and ropinirole—as well as dopaminergic agent levodopa.
The guidelines also recommend intravenous iron (ferric carboxymaltose) in patients with low iron stores and emphasize the importance of regularly screening iron indices, including ferritin and transferrin saturation. Iron was not a focus of the earlier guidelines.
Andy Berkowski, MD, a neurologist specializing in sleep medicine who practices independently at ReLACS Health and a co-author of the AASM guidelines, says this is “almost the exact opposite” of the earlier guidelines—but they’re not completely out of left field. Consensus guidelines published by a task force of the International Restless Legs Syndrome Study Group, European Restless Legs Syndrome Study Group, and the RLS Foundation in 2016 suggested starting treatment with an alpha-2-delta ligand to prevent augmentation.9
The RLS Foundation published an updated algorithm in 2021 stating that alpha-2-delta ligands are first-line drugs, with dopamine agonists as second-line.8
Still, Berkowski notes the medical community has been slow to shift away from dopamine agonists, with most clinicians “still prescribing drugs that we’re not recommending.” A 2022 drug utilization study by Winkelman found nearly 60% of RLS patients, amounting to approximately 400,000 patients, were on dopamine agonists.1
Creating a New Generation of Patients Without Augmentation
Berkowski hopes the new guidelines—which address newly diagnosed patients—“will create a new generation of people with restless legs who don’t have severe conditions.”
He urges that clinicians begin by considering iron before “reflexively prescribing dopamine agonists.” Brain iron deficiency is now understood to play a major role in causing RLS, but this knowledge is “still lacking among clinicians and third-party payers,” according to the guidelines. Berkowski also notes a general resistance to iron treatments, which may stem from misconceptions of their adverse effects when “they’re actually probably the safest treatment.”
“We have so many individuals who are iron deficient whose condition might have been completely eliminated with an iron supplement or an iron infusion, and instead, they were put on a drug that’s going to make their condition permanently worse for the rest of their life,” he says.
After assessing iron, Berkowski says alpha-2-delta ligands should be considered. He says that “the vast majority of people should never start” on dopamine agonists.
What About Patients Already on Dopamine Agonists?
The task force wasn’t charged with determining what to do for patients who are on dopamine agonists already. However, from a clinical perspective, Berkowski says that stable patients who are on relatively low doses of these drugs need to think about coming off them.
For patients who are either on very high doses or having adverse effects, “they really need to find a different treatment and then slowly taper off the dopamine agonist treatment,” Berkowski says. Winkelman says the decision is ultimately up to the patient as “they’re the ones who have to go through the, I call it, ‘detox.’”
William Ondo, MD, director of the Movement Disorders Clinic, a tertiary referral center for RLS at the Houston Methodist Neurological Institute, sees mostly patients already experiencing augmentation from dopamine agonists and works with them to discontinue the medications. While there’s no standard algorithm for how to stop the drugs, Ondo first advises patients to choose a time when they can handle several nights of worsened symptoms.
He first tries administering intravenous iron. After that, he will typically start patients with an opioid medication, such as methadone or buprenorphine, one to two days before discontinuing dopamine medication. He will then typically very rapidly discontinue the dopamine drug. “There is some debate on that last section, as some experts like to taper the dopamine drugs more slowly, but in my opinion, we like to rapidly discontinue the medications and get this exacerbation period over with,” he says.
Simply adding a delta-2 alpha ligand or an opioid for a patient experiencing augmentation doesn’t typically work well, but once they are off the dopamine agonist and are no longer augmented, “these medications often will work quite well,” says Ondo, who was not involved in the development of the new guidelines.
‘Too Strongly Worded’ Approach
Still, Ondo expresses he is “somewhat opposed” to the recommendations against the use of dopamine agonists, describing them as “too strongly worded.” His perspective aligns more with the RLS Foundation’s algorithm that positions delta-2 alpha ligands as first-line while reserving dopamine agonists as a second-line option.
“We go for gabapentin medicines first. And if they weren’t satisfactory, they weren’t tolerated—which is not that rare—then I would go to dopamine meds,” Ondo says. He estimates that for every five patients he discontinues from a dopamine agonist, he starts one patient on them. These cases include patients who may have a relatively low risk of augmentation, such as elderly patients, where long-term concerns are less likely to become an issue.
Since issuing the new guidelines, Winkelman says he has heard from clinicians who are concerned about potential legal issues for prescribing dopamine agonists. “I say, ‘These are guidelines. They are not requirements. They are not prohibited. We are making recommendations that this is best practice,” he says.
The guidelines include a clear caveat: Dopamine agonists “may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).”
While clinicians can still prescribe the drugs, Winkelman stresses that they must explain augmentation and warn patients of the risk. Berkowski emphasizes that clinical judgment remains key, with treatments needing to be tailored to individual patients.
Jacob Teitelbaum, MD, a board-certified internist and expert in pain and sleep, who was not involved in developing the guidelines, says the new guidance aligns with the approach he has long taken in his clinical practice and research. “I am pleased that the AASM guidelines continue to more closely approximate the recommendations I have made for this area over the last quarter-century,” he says.
Karla Dzienkowski, RN, BSN, executive director of the RLS Foundation, says the organization does “not have a position on these guidelines.”
Non-Pharmacological Treatment Option
As of last year, RLS patients have an FDA-cleared non-pharmacological treatment option: the Nidra tonic motor activation (TOMAC) system by Noctrix Health, which received a conditional recommendation in the guidelines for its effectiveness in reducing symptom severity in patients with RLS.
The prescription therapy includes a pair of devices worn on the lower legs that electrically activate the peroneal nerves bilaterally to produce tonic muscle activation to suppress RLS symptoms. Shriram Raghunathan, PhD, president and CEO of Noctrix Health, says that being included in the guidelines offers another stamp of validation that will likely help get the therapy into the hands of more patients.
“From a payer perspective, having the guidelines call out bilateral high-frequency peroneal nerve stimulation is a big deal for them. It gives them one more reason to check the box and say, ‘Hey, this is medically necessary for some of these patients,’” he says. “For us and the patient, that is the true win.”
Raghunathan notes that Nidra has been helpful for patients with augmentation. What surprised him during recruitment and enrollment of clinical trials was how many patients were on doses of dopamine agonists above the FDA label recommendations—which further raises the risk and severity of augmentation. “The worst patients that we wind up putting on Nidra therapy usually have come from being up-titrated several times on dopamine,” he says.
Nidra is now available in 14 states, and the company continues to roll it out.
Payer and Prescribing Hurdles
There are several barriers to the clinical implementation of the new guidelines, including cost and insurance coverage. Ironically, “the only FDA-approved drug we recommend, almost nobody has ever tried,” Berkowski says. “It’s a very expensive drug, and no insurance company wants to pay for it.” Iron infusion for RLS also isn’t covered by insurance.
Part of the benefit of the guidelines, Berkowski notes, is that insurance companies can’t deny coverage for treatments that are strongly recommended in favor of treatments no longer recommended. His hope now is that payers will require patients to try gabapentin or pregabalin first rather than, for example, requiring patients to try and fail a dopamine agonist before covering pregabalin or intravenous iron infusion.
“Ferric carboxymaltose is the iron that’s strongly recommended, but [payers] won’t cover it unless you try pramipexole first,” he says. “The guidelines should change that because then the insurance is…going completely against what is recommended medically.”
Ondo believes that seeing less augmentation would be advantageous for him and everyone else in tertiary referral centers, but he has reservations. “Yes, less dopamine agonist use will cause less augmentation, and that will result in less difficult situations where you have to stop the medication. But patients’ immediate ability to treat the RLS may suffer,” Ondo says.
That is in part because, in the US, pregabalin is designated as a Schedule V controlled substance, while gabapentin is a controlled substance in some states.10Opioids, which received a conditional recommendation, also are controlled substances. “So now you’ve got drugs that are more difficult to prescribe and administer that are listed ahead of the easy drug to prescribe, like the dopamine agonist,” Berkowski says. “It will take more effort to prescribe these drugs, more monitoring, so it’s going to cause more of a hassle.”
Still, Winkelman hopes sleep specialists will help increase awareness of the new guidelines to physicians in other specialties, noting that “we’re influencers, and so we need to spread the word and proselytize.”
References
- Winkelman JW. High national rates of high-dose dopamine agonist prescribing for restless legs syndrome. Sleep. 2022;45(2):zsab212.
- Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2024 Sept 26.
- Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults–an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep. 2012;35(8):1039-62.
- Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2024 Sept 26.
- Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996;19(3):205-13.
- Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med. 2004;5(1):9-14.
- Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006;67(6):1034-9.
- Silber MH, Buchfuhrer MJ, Earley CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc. 2021;96(7):1921-37.
- Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1-11.
- Schifano F, Chiappini S. Pregabalin: A range of misuse-related unanswered questions. CNS Neurosci Ther. 2019;25(5):659-60.
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