Physicians who regularly manage RLS patients offer real-world advice on ways to prevent augmentation. For patients already experiencing augmentation, new therapy options may be on the way.
By Alyx Arnett
Dopamine agonists are a popular choice for treating restless legs syndrome (RLS), but an increased understanding that their long-term use can cause augmentation has led some physicians to prescribe other treatments.
Characterized by an intense and unpredictable worsening of symptoms, augmentation caused by dopaminergic medications typically occurs six months after beginning therapy and affects up to 50% of patients after five years.1 Once it occurs, adjusting therapies can be excruciating, says William Ondo, MD, whose patients typically come to him already experiencing augmentation. “The most difficult part is ultimately stopping the dopamine agonists because patients have symptoms where they literally will not sleep for two or three nights,” says Ondo, director of movement disorders at Houston Methodist Neurological Institute. “I’ve had patients that have actually gone psychotic from sleep deprivation when we’ve tried to do this, so it is not an easy thing to do.”
The only definitive way to significantly reduce the risk of augmentation, Ondo says, is to avoid dopaminergic medications. New guidelines, research, and therapies have emerged over the last several years, shaping some physicians’ approaches to finding relief for patients from RLS symptoms without unduly risking augmentation.
The Restless Legs Syndrome Foundation released an updated algorithm for treating RLS patients in 2021 that sharply pivoted from dopamine agonist medications as first-line treatment.2 The guidelines recommend alpha-2-delta ligands (gabapentin enacarbil, pregabalin, and gabapentin) as first-line agents for the treatment of chronic RLS, with dopamine agonists (including ropinirole, pramipexole, and rotigotine) as second-line drugs.
Trialing Non-pharmacological Therapies First
Shalini Paruthi, MD, medical co-director of the St. Luke’s Sleep Medicine and Research Center, first considers non-pharmacological therapies—including iron supplementation, behavioral strategies, and identifying triggers—for her patients before resorting to prescription drugs.
Research has shown that patients with RLS have lower-than-normal iron stores in some regions of the brain and that iron therapy can be beneficial. Iron replacement is suggested in patients whose fasting serum ferritin level is 75 ng/mL or less, according to recommendations from UpToDate.3
Both oral and intravenous iron therapies are available. The oral route typically leads to slower symptom relief; patients may wait several months before experiencing the full benefits. The response to intravenous iron can be much quicker, taking just several days, especially for those with iron deficiency. “Iron deficiency is definitely our number-one part of our evaluation and treatment,” says Paruthi.
Physicians should regularly check iron stores in patients already being treated as well. Low iron might result in worsening augmentation, says Ondo, “So we do typically aggressively treat with iron…but there’s also evidence that you will delay augmentation if they have copious iron stores.” Trials of intravenous iron find that it is effective in approximately 40% to 60% of patients.4
Behavioral Strategies and Triggers
Implementing behavioral strategies and identifying triggers also can be effective in reducing patients’ symptoms and preventing augmentation. Recommendations include mental alerting activities—such as video games or crossword puzzles— at times of rest or boredom and regular exercise—like walking or bicycling. Warm baths, pneumatic compression devices, and leg massage can also be helpful.
Paruthi sometimes will have patients with RLS track factors like sleep, alcohol intake, caffeine intake, and quality of the day. “That way people can start to say, ‘Oh, I didn’t realize every time I have two glasses of wine, I have much more restless legs,’ or, ‘Every time I have caffeine after 5 pm I have more restless legs,’” she says.
Identifying other sleep issues also is important, as concurrent sleep disorders, sleep fragmentation, and sleep deprivation can exacerbate symptoms. The Restless Legs Syndrome Foundation recommends clinicians inquire about symptoms of obstructive sleep apnea. “In some cases, sleep apnea treatment results in improvements in RLS, eliminating the need for medications,” according to the foundation.
Paruthi says, “I’ve had several patients that we tried a whole lot of different therapies and could not get very great control. We did a sleep study or the home sleep apnea test, and we treated the sleep apnea. And they had just a remarkable improvement in their sleep and their restless legs.”
Monitoring which medications patients take also plays a role in treatment. In addition to dopaminergic medications, other drugs like antidepressants, neuroleptic agents, and sedating antihistamines (including those found in over-the-counter medications) may be associated with worsening RLS symptoms. An exception for antidepressants is bupropion, according to the Restless Legs Syndrome Foundation, which may be less likely to induce or worsen RLS.
Turning to Pharmacological Options
If non-pharmacological therapies are ineffective for patients, Paruthi will work with them to decide if a medication should be introduced. If symptoms are occurring around twice a week, she may prescribe an alpha-2-delta medication.
There are patients for whom alpha-2-delta medications aren’t appropriate, including those with kidney failure on hemodialysis, moderate to severe depression, gait instability, or respiratory disease. In those cases, a dopamine agonist may be considered. “We do want to stay on the lowest dose of dopamine agonist that we can,” says Ondo.
When prescribing a dopamine agonist, Ondo says patients should be warned of the risk of augmentation and carefully monitored. The first indication of augmentation typically is the earlier onset of symptoms, he says. Other signs could include the patient requesting a dose increase, symptoms spreading to other body parts, or 24-hour occurrence of symptoms.
“What point you decide you need to discontinue the dopamine medicines is a matter of opinion because you can manipulate the dose and treat for a while. But ultimately that fails, and…they’ll need to discontinue the dopamine agonist in order to stop the augmentation,” says Ondo. “And the worse the augmentation is, the harder it is to just continue to use dopamine agonists. But it is an individual decision at what point you would adjust a dopamine agonist or switch to something else. Some people would do this very early at the first sign of augmentation. Others will manipulate the dose of the dopamine agonist to treat the augmentation for a while.”
Opioids are another group of medications prescribed for RLS. For Ondo, he uses them for some patients coming off dopamine agonists to help them “get over the hump” when they have withdrawal exacerbations. Paruthi, who says there is “a time and a place” for opioids, cautions that the opioid tramadol also has been linked to augmentation.5
Be sure everybody has the same expectations, says Paruthi, who also has RLS. “We would love to completely get rid of the restless legs syndrome, but chances are there might be just a little bit left or that it kind of comes and goes despite being, for the most part, really well treated with either nonpharmacologic therapy or pharmacologic therapy,” she says.
Breakthrough Therapies for RLS Augmentation
It’s been over a decade since the US Food and Drug Administration (FDA) approved Horizant (gabapentin enacarbil) for the treatment of moderate to severe RLS, marking the last drug approval. There’s been even less innovation for ways to help RLS patients experiencing augmentation. However, new breakthroughs offer hope.
New Non-pharmacological Option
In April, the FDA granted marketing authorization to Noctrix Health’s wearable NTX100 Tonic Motor Activation System to treat symptoms of moderate to severe RLS and improve sleep quality in patients refractory to medications.
The FDA grant makes the system—which previously received a Breakthrough Device Designation in May 2020—the first and only therapy for patients with moderate to severe drug-refractory RLS, says Shriram Raghunathan, PhD, CEO of Noctrix Health.
The prescription therapy includes a pair of devices worn on the lower legs that electrically activate the peroneal nerves bilaterally to produce tonic, sustained muscle activation to suppress symptoms of RLS.
The marketing authorization follows the completion of a randomized study (The RESTFUL Study) of 133 patients experiencing augmentation, in which all seven efficacy outcomes met statistical significance. The company also met recruitment goals for the clinical trials ahead of schedule in all seven states, “a testament to the fact that there is a large, unmet need in this population,” says Raghunathan. “It moved our clinical team to darn near tears because we’ve worked on a number of therapeutic areas as a team…and we’ve never seen a patient population that receptive to participating in trials for new products.”
What surprised him during recruitment and enrollment was the number of patients on doses of dopamine agonists above the FDA label recommendations. “It was not insignificant,” he says.
Raghunathan says patients in the trials experienced both acute benefits and significant improvement in symptoms. “Our patients actually, at the end of the trial, had fewer nights of RLS per week than when they started,” he says.
Noctrix Health plans to have a limited commercial release of the NTX100 Tonic Motor Activation System this fall, launching at select sites.
New Drug Candidate
Stefan Clemens, PhD, from the department of physiology at Brody School of Medicine at East Carolina University, was awarded a patent in 2020 for his novel method for treating RLS, and the drug candidate is currently being developed.
Dopaminergic medications target the dopamine-3 receptor, which has a calming effect on the nervous system. However, research conducted by Clemens’ laboratory using animal models showed that long-term use of these treatments can result in increased levels of the dopamine-1 receptor, which has an excitatory effect and may be the cause of augmentation.6
Clemens proposed a new treatment approach that targets the increased dopamine-1 receptor levels in RLS patients who experience augmentation, thereby reducing activation of dopamine-1 receptors while still providing symptom relief. “Lofty goal, but it could get rid of the augmentation,” says Clemens.
East Carolina University issued Emalex Biosciences Inc patent rights of ecopipam (EBS-101) in March 2022, the investigational, first-in-class dopamine-1 receptor antagonist to advance clinical studies for the treatment of RLS with augmentation. The drug candidate is now approaching phase 2 clinical trials.
While EBS-101 shows promise, any long-term side effects remain to be seen, Clemens says. “To some extent, it’s really, really cool, but then pramipexole had also a huge effect as soon as it was being prescribed,” he says.
- Augmentation: diagnosis and treatment. Restless Legs Syndrome Foundation brochure. Available at https://www.rls.org/file/member-publications/handouts/RLS-AUGMENTATION-5-3-22.pdf
- Silber MH, Buchfuhrer MJ, Earley CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clinic Proceedings. 2021 July;96(7):1921-37.
- Management of restless legs syndrome and periodic limb movement disorder in adults. UpToDate website. Available at https://www.uptodate.com/contents/management-of-restless-legs-syndrome-and-periodic-limb-movement-disorder-in-adults?csi=6e770f7e-ca27-446d-b542-eb260cc8d0ac&source=contentShare
- Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018 Jan;41:27-44.
- Vetrugno R, La Morgia C, D’Angelo R, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord. 2007 Feb 15;22(3):424-27.
- Clemens S, Ghorayeb I. D3 and D1 receptors: The Yin and Yang in the treatment of restless legs syndrome with dopaminergics. Adv Pharmacol. 2019 Feb 18;84:79-100.
Photo caption: Known for his restless legs syndrome expertise, William Ondo, MD, cares for many patients who are already experiencing augmentation when they first enter his practice.
Photo credit: Humberto Jamie/Houston Methodist