Nonergot dopamine(Drug information on dopamine) agonists such as pramipexole(Drug information on pramipexole), ropinirole(Drug information on ropinirole), and rotigotine have been found effective in double-blind studies.17 In fact, 2 dopamine agonists, pramipexole and ropinirole, are the only medications that are approved by the FDA for treatment of moderate to severe RLS. The maker of rotigotine—another dopamine agonist delivered through a transdermal patch—filed for approval to market the drug for RLS. However, rotigotine was recently recalled in the United States and some European countries because of problems with the delivery mechanism.
Ergot-derived agonists, such as bromocriptine(Drug information on bromocriptine), pergolide(Drug information on pergolide), and cabergoline(Drug information on cabergoline), have also been found to be effective in treating RLS.17 However, potentially serious adverse effects, such as heart valve abnormality, limit their use. Generally, treatment with dopamine agonists should start with the lowest dose possible followed by slow titration. Adverse effects—including nausea, orthostatic hypotension, dizziness, and daytime somnolence—should be monitored carefully.17
(L-dopa) is also effective in treating RLS.18 Until nonergot dopamine agonists were available, (L-dopa) was the most popular pharmacological agent, particularly for intermittent symptoms, because of its rapid onset of action. However, long-term treatment of RLS with (L-dopa) is frequently associated with augmentation and rebound. Augmentation refers to the clinical phenomenon of earlier onset, increased severity, or involvement of other parts of the body with RLS symptoms.19 Unlike long-term complications of (L-dopa)–induced dyskinesia in patients with Parkinson disease, augmentation usually resolves with cessation of (L-dopa) in patients with RLS. The rebound effect causes increased restlessness at night or in the morning as the dose wears off, or as tolerance to the drug builds up. While the risk may be less with dopamine agonists than with (L-dopa), augmentation has been associated with dopamine agonists.20,21
Opiates, particularly oxycodone(Drug information on oxycodone), are considered second-line agents for patients with moderate to severe RLS.16 Because of concerns about the risk of opioid dependency, sedation, and exacerbation of sleep apnea, opiates have been primarily prescribed for RLS patients who cannot tolerate dopaminergic agents. Among opiates, codeine(Drug information on codeine) is considered to have the least abuse or dependency potential and has been reported to be effective in treating RLS.22
The efficacy of the anticonvulsant gabapentin has also been demonstrated in controlled studies, and a prodrug of gabapentin—gabapentin enacarbil—is in the FDA pipeline with an indication for RLS treatment.23 In controlled trials, efficacy has also been reported for other anticonvulsants, such as carbamazepine(Drug information on carbamazepine) and valproic acid, but these are rarely prescribed.24,25
Psychiatric comorbidities of RLS
Previous clinic-based studies reported a high prevalence of comorbidity between RLS and depression or anxiety disorders.3 Notably, Winkelmann and colleagues26 used a structured psychiatric measure, the Munich–Composite International Diagnostic Interview for DSM-IV, to assess psychopathology among 130 RLS patients. Compared with 2265 community residents, those with RLS had an increased risk of having panic disorder (odds ratio [OR], 4.7; 95% confidence interval [CI], 2.1 to 10.1), generalized anxiety disorder (OR, 3.5; 95% CI, 1.7 to 7.1), and MDD (OR, 2.6; 95% CI, 1.5 to 4.4) over a 12-month period.27
Several population-based studies have reported increased rates of anxiety and depression in patients with RLS.3 Data from the Baltimore Epidemiologic Catchment Area study showed strong associations between RLS and MDD (OR, 4.7; 95% CI, 1.6 to 14.5) and panic disorder (OR, 12.9; 95% CI, 3.6 to 46.0) among 1024 community residents over 12 months.27
The underlying cause for the high prevalence of comorbidities between RLS and depression is unclear. Certainly, symptomatic overlap exists between MDD and RLS because RLS can trigger or exacerbate at least 4 of the 9 depressive symptoms listed in DSM-IV for MDD.3 Dysphoria, insomnia or excessive sleepiness (particularly during the day), decreased concentration, fatigue or loss of energy, and psychomotor retardation are common among RLS patients. Alternatively, an underlying shared pathophysiological mechanism between RLS and MDD might be responsible for the comorbidity.
Many studies have established the role of dopaminergic pathology in RLS.28 A recent systematic review supported a role for diminished dopaminergic neurotransmission in major depression based on the following evidence29:
• Diminished dopamine release from presynaptic neurons or impaired signal transduction has been implicated.
• Animal models of depression have shown considerable responsiveness to dopamine neurotransmission.
• Several studies have shown reduced concentration of dopamine metabolites in cerebrospinal fluid and in brain regions that mediate mood and motivation.
• Neuroimaging studies have shown reduced dopamine transmission and compensatory up-regulation of D2 receptors.
In fact, bupropion, which has proven efficacy in the treatment of depression, acts, at least in part, by promoting dopaminergic function. Several clinical trials recently reported a potential role for dopamine agonists—the first-line agents for RLS—in managing treatment-resistant depression or bipolar depression.30
Potential associations between other psychiatric disorders and RLS have been reported recently. Several studies found that RLS and PLMS are common among children or adults with attention-deficit/hyperactivity disorder (ADHD).31,32 It is still unclear whether sleep disruption from RLS rather than RLS itself is associated with ADHD-like symptoms of restlessness, overactivity, and inattention. High rates of RLS-like symptoms in patients with schizophrenia33 and somatoform pain disorder34 have been reported as well.