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Restless Legs Syndrome Often Treated with Excessively High Doses of Dopamine Agonists

Key findings

  • Long-term use of dopamine agonists (DAs) by patients with restless legs syndrome (RLS) is commonly associated with augmentation, a dose-related iatrogenic worsening of symptoms, which can lead to a vicious cycle of dose escalation and further worsening
  • This retrospective observational study investigated the frequency of high-dose DA therapy for RLS, using data on 485,565 patients (projected to a nationwide estimate of 670,404) from a longitudinal U.S. prescription database
  • 19% of DA prescriptions were for doses above the FDA-approved or guideline-recommended maximums (10.5% were for ≥150% of the maximum recommended dose)
  • The odds of high-dose or very high dose prescribing by neurologists was double that in other specialties
  • According to new guidance from the RLS Foundation, alpha2-delta calcium channel ligands (e.g., gabapentin, pregabalin, gabapentin enacarbil) are now the first-line agents for treatment of chronic RLS, and DAs should be a second-line therapy

The efficacy of dopamine agonists (DA) often wanes when they are used long-term to treat restless legs syndrome (RLS). What's worse, in 30% to 50% of cases, these agents cause augmentation—progressive exacerbation of RLS. Augmentation is marked by daytime appearance of symptoms, more severe symptoms, shorter duration of medication benefit and/or symptom spread to upper extremities.

Clinicians often respond to the loss of DA efficacy or augmentation by increasing the DA dose. This may produce temporary improvement, but higher DA doses are associated with greater risk and severity of augmentation. As the underlying iatrogenic process worsens, symptoms worsen further, and ultimately, DAs may be prescribed at doses far higher than those approved for RLS.

High doses of DAs also increase the risk of acute adverse effects, notably orthostatic hypotension, peripheral edema, sleep attacks, impulse control disorders, hallucinations and psychosis.

In a retrospective observational study, John W. Winkelman, MD, PhD, chief of the Sleep Disorders Clinical Research Program in the Department of Psychiatry Massachusetts General Hospital, determined that inappropriately high dosing of DAs for RLS is a national problem that cuts across specialties. The findings are published in Sleep.

Study Methods

The data source was LRx, a longitudinal prescription database that covers about 65% of all U.S. retail and mail-order prescriptions. 485,565 patients with RLS had prescriptions included in LRx between October 2017 and September 2018; this figure was projected to a nationwide estimate of 670,404 patients.

Dose levels for DAs were defined as:

  • Low/Mid (within FDA-approved or guideline-recommended maximum doses)—pramipexole, 0 to ≤0.75 mg; ropinirole, 0 to ≤4 mg; rotigotine, 0 to ≤3 mg
  • High (101% to 149% of FDA approved/recommended maximums)—pramipexole, >0.75 to ≤1.25 mg; ropinirole, >4 to ≤6 mg; rotigotine, >3 to ≤6 mg
  • Very high (≥150% of approved/recommended maximums)—pramipexole, >1.25 mg; ropinirole, >6 mg; rotigotine, >6 mg

Prevalence of High Dosing

With or without concomitant non-DA therapy, 8.6% of the 670,404 projected patients were prescribed high DA doses and 10.5% received very high doses.

Specialty of Prescriber

59% of the prescriptions for high or very high DA doses were written by primary care physicians and 17% were written by nurse practitioners or physician assistants. Neurologists wrote 14% of such prescriptions, but the odds of high-dose or very high dose prescribing by neurologists was double that in other specialties (OR=2.1).

Neurologists are accustomed to prescribing much higher DA doses for patients with Parkinson's disease, which may lead to increased comfort with higher doses in RLS. However, such high doses were never tested in RLS, and although the acute side effects of high DA doses may be similar in PD and RLS, augmentation is a uniquely harmful iatrogenic issue in RLS.

Change in Clinical Guidance

In July 2021, the Scientific and Medical Advisory Board of the RLS Foundation published a revised management algorithm in Mayo Clinic Proceedings. Unless otherwise contraindicated, alpha2-delta calcium channel ligands are now the first-line agents for the treatment of chronic persistent RLS. DAs should be second-line therapy.

The alpha2-delta ligands—gabapentin, gabapentin enacarbil and pregabalin—have all demonstrated efficacy for RLS in clinical trials, although only gabapentin enacarbil is currently FDA-approved. Their major adverse effects are sedation, dizziness, altered mental status, increased risk of falls and weight gain.

of prescriptions for dopamine agonists in restless legs syndrome were for doses above the recommended maximum

of prescriptions for dopamine agonists in restless legs syndrome were for doses ≥150% of the recommended maximum

greater odds compared with other specialists that neurologists would dose dopamine agonists above the recommended maximum in restless legs syndrome

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