Restless Legs Syndrome

The cardinal feature of restless legs syndrome (RLS) is an urge to move the limbs, often accompanied by uncomfortable sensations, which come on in the evening and nighttime, and which are relieved by moving the limbs. A family history of RLS, history of periodic leg movements during sleep (seen in ~ 90% of patients with RLS), and symptomatic improvement with dopamine agonist medications are supporting features. In cases where the history is unclear, a sleep study assessing for the presence of periodic limb movements of sleep may be useful.

A.

Antihistamines, caffeine, nicotine, and selective serotonin receptor inhibitors (SSRIs), selective norepinephrine inhibitors (SNRIs), and tricyclic antidepressants (TCAs) may exacerbate symptoms of RLS. Bupropion, mirtazapine, and trazodone are antidepressants considered “safe” for RLS. Although the pathophysiology of RLS is not fully understood, overt iron deficiency or a relative deficiency of brain iron have been implicated, possibly through downstream effects on dopaminergic transmission. For this reason, patients should be evaluated for iron deficiency. Treat for ferritin < 75 mcg/mL with ferrous sulfate 325 mg bid + vitamin C (to aid iron absorption) or other iron formulations that give the equivalent dose of elemental iron (total of 130–195 mg of elemental iron daily). Consider polysomnography if comorbid obstructive sleep apnea (OSA) is suspected, since OSA can cause further sleep fragmentation and make management of RLS more difficult.
B.

Various forms of counterstimulation (limb-rubbing, stretching, and other movements) provide transient, and in some cases sufficient, relief for some patients.

First-line treatments for RLS include dopamine agonists (pramipexole, ropinirole, rotigotine) or alpha 2 delta ligands (gabapentin, extended-release gabapentin, pregabalin, gabapentin enacarbil) ( Table 79.1 ). The choice of drugs can be guided by comorbidities. Consider an alpha 2 delta ligand for patients with pain, ropinirole for patients with renal insufficiency, and rotigotine patch for patients who do not tolerate oral agents. Note that only pramipexole, ropinirole, rotigotine, and gabapentin enacarbil are approved by the Federal Drug Administration for treatment of RLS, though many other medications are used off label. For long-term follow-up, observe for side effects. With dopamine agonists, these include nausea, loss of efficacy, compulsive behaviors, and augmentation (see section D); alpha 2 delta ligands can cause sedation, weight gain, depression, and edema.

Table 79.1

Dosing and Titration of Medications for Restless Legs Syndrome

Drug	Starting dose	Titration	Maximum dose
Ferrous sulfate	325 mg bid	Take with vitamin C
Vitamin C	250 mg bid	Taken with iron supplement
Ropinirole	0.25 mg qhs	Increase 0.25 mg q3–4 d	4 mg
Pramipexole	0.125 mg qhs	Increase 0.125 mg q3–4 d	1 mg
Gabapentin	100 mg qhs	Increase in 100–300 mg increments	1200 mg tid or qhs
Codeine	30 mg qhs	Increase in 30 mg increments	30 mg tid
Oxycodone	2.5 mg qhs	Increase in 2.5–5 mg increments	10 mg tid
Methadone	2.5–5 mg qhs	Increase in 2.5–5 mg increments	15 mg bid
Pregabalin	25–50 mg qhs	Increase in 50 mg increments	300 mg
Gabapentin enacarbil	300 mg	Increase in 300 mg increments	1200 mg at 6.00 p.m.
Rotigotine patch	1 mg	Increase in 1 mg increments daily	3 mg