Restless Legs Syndrome and Dopamine Agonists

The Restless Legs Syndrome Foundation updates its algorithm for the management of RLS. The most notable change is a firm pivot away from dopamine agonist medications as first-line treatments.

By Lisa Spear

Many physicians turn to dopaminergic medications to quickly soothe the limb restlessness and discomfort that plagues restless legs syndrome (RLS) patients, but for many of those being treated, the fast relief is gone all too soon. Physicians have observed that these dysesthesias of RLS return to their patients with greater intensity, and spread to once unaffected parts of the body after taking these medications.

In time, dopamine agonists—medications that stimulate dopamine receptors commonly used to treat RLS and other neurological disorders—including pramipexole, ropinirole, and rotigotine may lead to a phenomenon called augmentation. Augmentation occurs when pharmacological treatment triggers a downstream cascade of worse symptoms in RLS patients, including an increase in intensity of the restlessness and sensations and their spread to once unaffected limbs.1

No one is certain as to why exactly dopamine agonists first work extremely well, but then over time begin to exacerbate RLS symptoms. Mounting evidence shows that augmentation is common.2,3 

A new paper published in the Mayo Clinic Proceedings by the scientific and medical advisory board of the Restless Legs Syndrome Foundation details an updated algorithm for the management of restless legs syndrome, and a major change is that dopamine agonists are no longer considered a first-line therapy.

“Dopamine agonists are so effective in the short-term that they are seductive, and they can lead prescribers to use them without thinking about the significant long-term consequences, particularly of augmentation,” says coathor John Winkelman, MD, PhD, chief of the Sleep Disorders Clinical Research Program in the Department of Psychiatry at Massachusetts General Hospital.

Once hailed as miracle medications for patients experiencing RLS, dopaminergic medications have been used for at least three decades to treat the sleep disorder, but now the scientific and medical advisory board of the Restless Legs Syndrome Foundation’s new algorithm explains that these drugs should only be considered if alpha2-delta calcium channel ligand medications, including pregabalin and gabapentin, fail or are poorly tolerated.

“Dopamine agonist medications are no longer first-line due to untoward effects such as augmentation, impulse control disorders, and rebound,” says Karla Dzienkowski, RN, BSN, executive director of the Restless Legs Syndrome Foundation.

David Schulman, MD, MPH, FCCP, professor of medicine—pulmonary, allergy, critical care, and sleep medicine at Emory University School of Medicine and who was not involved with developing the algorithm, says the updated algorithm is consistent with a treatment strategy to which many providers have already transitioned. “While dopamine agonist therapies are generally quite effective for treating RLS, we have all seen a number of our patients go on to develop augmentation, necessitating an escalation of dosing, often followed by a transition to alternative agents. Given the frequency which this occurs (sometimes even years after therapy was initiated), using alpha-2-delta agents as initial therapy just makes sense,” Schulman says.

When RLS patients’ symptoms worsen, the most common clinical response is to increase the dose. Although a higher dose often produces a temporary improvement in RLS symptoms, higher doses are associated with greater risk and severity of augmentation, and over time RLS symptoms may increase, perpetuating a “cycle of progressively worsening augmentation” says Winkelman, professor of psychiatry at Harvard Medical School.  His recent national prescription audit of 400,000 RLS patients in the US prescribed dopamine agonists demonstrates that roughly 20% are prescribed doses above the FDA and guideline maximums, most likely as a result of augmentation.5

“These medications need to be used extremely carefully, and should be considered in some senses as addictive,” says Winkelman. “Higher doses are required over time, significant rebound symptoms occur upon discontinuation, and there is the worsening of the underlying course of the disorder.”

The new algorithm paper specifies that only when the use of an alpha2-delta ligand is ruled out should dopamine agonists be considered. For example, alpha2-delta ligands should be used carefully for patients with obesity, depression, gait instability, disorders causing respiratory failure, and those with a history of substance use disorder. In these cases, the guideline says, it may be appropriate to try a dopamine agonist first. Also, in instances when alpha2-delta ligands are ineffective or poorly tolerated, clinicians may also consider a dopamine agonist.

“Regular follow-up of RLS patients receiving medications long term is important. The frequency depends on the response to treatment; initially, this should be at least every 3 months, with stable patients reassessed at least every year,” the new algorithm authors write. Winkelman also notes that RLS patients on dopamine agonists should be warned about the risks of augmentation and should tell their prescribing physician if this complication develops.

The paper also highlights that even before pharmacological intervention is considered, iron levels should be evaluated. There is substantial clinical research showing that RLS patients have lower than normal iron stores in some regions of the brain and that iron therapy can be beneficial, even if the patient is not anemic.6

Schulman says, “While I support the evaluation of iron levels in all patients with RLS, the amount of time it takes for iron-deficient patients to appreciate meaningful symptomatic improvement with the use of oral iron supplementation is quite long. In general, I prefer to use adjunctive pharmacotherapy while waiting for the iron to work its magic, or alternatively use intravenous iron instead of oral iron.”

The paper specifically recommends a full iron assessment, including measurements of serum iron, ferritin, total iron-binding capacity, and percentage transferrin saturation. All the tests should be conducted in the early morning after an overnight fast and off of iron-containing vitamins for 24 hours, according to the treatment algorithm.

Aarthi Ram, MD, a sleep neurologist at Houston Methodist Willowbrook Hospital, who was not involved with developing the algorithm, says the updated information will change how she practices. “I will now do an early morning iron level after an overnight fast. Previously, I did not have my patients fast for this lab,” she says.

Ram also says that one important question to her practice remains unanswered in this new paper: “How would off-label medication get covered, if not FDA approved for RLS? This is my biggest roadblock for not being able to use Lyrica.” Winkelman notes that pregabalin (Lyrica) is now generic, as is gabapentin.

Aside from medication recommendations, the new RLS treatment algorithm provides physicians and advanced practice providers with a comprehensive guide to RLS diagnosis and clinical management, including when to consider use of low-dose opioid therapy for refractory RLS, clinical management of RLS in children, adolescents, as well as in pregnancy.

The open-access article incorporates tools to aid in the clinical management of RLS and improve patient outcomes, including decision trees and tables that work as visual guides, says Dzienkowski.

“The last update of the RLS treatment algorithm by the foundation’s scientific and medical advisory board occurred in 2013,” she says. “Since then, scientific discoveries have led to a better understanding of the condition and to new clinical approaches, and we have seen fundamental changes in RLS disease management.”

Lisa Spear is associate editor of Sleep Review. 

References

1. Trenkwalder C, Paulus W. Pharmacological treatments of augmentation in restless legs syndrome patients. Adv Pharmacol. 2019;84:255-65.

2. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med. 2011;12: 440-4.

3. Lipford MC, Silber MH. Long-term use of pramipexole in the management of restless legs syndrome. Sleep. 2012;13:1280-5.

4. Silber MH, Buchfuhrer MJ, Christopher JE, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clinic Proceedings. 2021;96(7): 1921-1937.

5. Winkelman JW. High national rates of high-dose dopamine agonist prescribing for restless legs syndrome. Sleep. 2021, zsab212, published online ahead of print.

6. Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). Sleep Med. 2014;15: 1288-1301.

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