The SLEEP 2025 conference represented a funeral for the dopaminergic drug class for treating restless legs syndrome (RLS). How long will it take to change practice patterns in other fields like primary care and neurology? In this week’s 39th Annual Meeting of the Associated Professional Sleep Societies, the conference was “buzzing” about RLS (and not just due to the peroneal nerve stimulator, the condition’s newest recommended treatment!). The print publication of the landmark 2025 Clinical Practice Guidelines for the Treatment of RLS by the American Academy of Sleep Medicine (AASM) was published on January 1. This update took a 180-degree turn from its anachronistic predecessor in 2012. The AASM now suggests against the standard use of dopaminergic medications (DAs): ropinirole, pramipexole, transdermal rotigotine, and the dopamine precursor levodopa. DAs cause a phenomenon called augmentation, in which patients suffer an often horrific worsening of symptoms with long-term use including earlier onset of normally nighttime symptoms, spread to other regions of the body, severe tolerance and dependence, and inability to be at rest. Augmentation may eventually occur in a vast majority of individuals, is only partially irreversible, and makes other treatments less effective. Despite their demotion from first line in 2016, a 2022 study showed that RLS patients still received DAs at a rate of nearly 60% in the U.S., often at doses above the FDA maximum.
From a single lecture in 2023, the SLEEP conference had a half-dozen full sessions on RLS this year, including a discussion section by the Guidelines Task Force members and multiple other presentations on the guidelines. The emphasis was that augmentation could be prevented with the right approach at the initial presentation, which is usually done by a PCP or neurologist, not by a sleep-RLS specialist, when it may already be too late. In nearly all cases, DAs should not prescribe PCPs. Instead, The Good Practice Statement in the AASM Guidelines states patients should first address exacerbating factors, including “substances of vice” (e.g., caffeine, alcohol, nicotine, and sedating antihistamines). Clinicians should look to modify prescription treatments where possible, including a reduction in antiemetics, antipsychotics, and unnecessary antidepressants (trazodone, anyone?). Obstructive sleep apnea (OSA) should be identified and treated, along with behavioral interventions to improve sleep and insomnia, including low-hanging fruit like waking up at the same time every morning. Serum iron should be assessed annually, including a morning, fasting iron + TIBC (TSAT%), and ferritin. The AASM strongly recommends IV iron infusion for any patient with ferritin < 100 ng/mL OR TSAT% < 20%. Oral iron may also be considered for ferritin < 75 ng/mL, though it is absorbed poorly above this level. It is important to note that these loose thresholds are much different than for a typical adult without RLS, given that we now know that RLS is caused by a brain iron deficiency, even in those with normal serum levels.
As has been the case since 2016, gabapentinoids (gabapentin, gabapentin enacarbil, and pregabalin) are STRONGLY recommended medications with CONDITIONALLY recommended treatments being low-dose opioids, the more experimental dipyridamole, and the novel bilateral, high-frequency peroneal nerve stimulation device, which is increasingly available and garnering insurance approval in numerous U.S. states. As mentioned, DAs are CONDITIONALLY recommended AGAINST for standard use due to the risk of augmentation of roughly 75% within 10 years of use. Behavioral health can deteriorate, including depression and suicidal ideation, along with high rates of impulse control disorders, including compulsive sexuality, gambling, eating, and substance use disorder from the artificial overstimulation of the CNS reward pathways.
In a well-attended Tuesday afternoon session, a two-hour workshop called “The Critical Role of Opioids for RLS” included presentations by Drs. Brian Koo, John Winkelman, Mark Buchfuhrer, and myself. Koo presented his research on the biological basis of low-dose opioids, which are effective in the treatment of severe RLS and necessary in most of those with dopaminergic augmentation. The session guided the audience through the outcomes of the Winkelman-led National RLS Opioid Registry, which has tracked 500 real-world RLS patients on opioids for five years now. Unlike in other areas of medicine like chronic pain, those taking opioids for RLS do not seem to develop tolerance or dose escalation, with the Registry showing that more than half of patients were on the same or lower opioid dose after five years with a median dosage change of only ~1 mg morphine equivalent (MME). Koo’s research has demonstrated deficiencies in the endogenous opioid system in RLS, and opioids may function to replete the opioid system deficits. Buchfuhrer guided clinicians through the daunting process of tapering patients completely off dopaminergic medications. I rounded out the session by presenting research showing the longitudinal effectiveness of buprenorphine in the treatment of severe RLS. In 55 patients prescribed buprenorphine and observed for up to 1.5 years, ~75% of those were on buprenorphine at the final visit, with 81% eliminating their DA and 14% with significant dose reduction on their way to elimination. Patients showed marked clinically and statistically significant improvements in RLS severity, sleep quality, quality of life, and mental health over one year. Buprenorphine is a partial agonist at the mu-opioid receptor and has the advantages of having a very low abuse potential, ceiling effect on respiratory depression, stable long-acting duration of action, and ease of prescribing as a DEA Schedule III drug (e.g., 90-day supplies and telemedicine prescription in most states).
However, if patients are not exposed to DAs, then opioids can be avoided. The message is clear and needs to pervade the primary care level. SLEEP 2025 has shown the field of sleep medicine has reached a consensus that these agents should be used sparingly, if at all, and PCPs need to start RLS patients on the right leg.
Dr. Berkowski has no conflicts of interest to report.
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