Restless Legs Syndrome
Conventional Pharmacologic Treatment
The main pharmacologic agents used to treat primary RLS are dopamine agonists, levodopa (L-DOPA), benzodiazepines, gabapentin, and opioids. However, treatment of primary RLS should not be considered until possible causes of secondary RLS are ruled out, especially venous disorders (Miletic 2011).
- Dopamine Agonists. Dopamine agonists are drugs that directly activate dopamine receptors in the nervous system. They are currently considered the first-line therapy for severe RLS and are typically less associated with augmentation or rebound than high doses of L-DOPA (see below). Several different dopamine agonists are used to treat RLS, including:
- Ropinirole. The efficacy of rop-inirole has been demonstrated in two large randomized, double-blind, placebo-controlled tri-als. In both studies, standardized assessment showed that 1) symptoms were significantly less, and 2) both quality and quantity of sleep were significantly improved in the ropini¬role-treated groups compared with controls (Walters 2004; Garcia-Borreguero 2004).
- Pramipexole. Pramipexole is highly effective in the reduction of periodic limb movements as well as improving subjective severity of RLS and sleep quality (Benbir 2006; Inoue 2010). Compared to ropinirole, pramipexole is equally effective but with significantly lower incidence of nausea, vomiting and dizziness (Quilici 2008).
- Rotigotine - on April 3, 2012 the FDA approved topical delivery of rotigotine for the treatment of RLS (Bell 2012). Branded Neupro®, the topical delivery system represents a paradigm shift in the delivery of a dopamine agonist in the treatment of RLS. By delivering the drug in a sustained manner, Neupro® may lessen side effects common with orally administered dopamine agonists, which bombard dopamine receptors with a single, quickly absorbed dose (Farlow 2011; Elshoff 2012; Boroojerdi 2010).
- Levodopa (L-DOPA). L-DOPA serves as a precursor for dopamine in the human body. L-DOPA crosses the protective blood-brain barrier, whereas dopamine itself cannot. Once L-DOPA has entered the central nervous system, it is converted into dopamine with the aid of pyridoxal 5'-phosphate (the active form of vitamin B6) (Allen 2009). In studies, L-DOPA reduced the number of periodic limb movements during sleep and improved sleep quality compared to placebo (Benes 1999; Trenkwalder 2007; Scholz 2011). L-DOPA can provide relief within 20 minutes; however, it does not provide sustained relief for those with persistent symptoms. Levodopa/carbidopa is generally reserved for patients with infrequent symptoms, because of problems with augmentation and rebound (Bayard 2008). Therefore, L-DOPA is recommended for intermittent treatment (less than three times a week) of bedtime symptoms or as prophylaxis during infrequent sedentary activities such as long plane trips, car rides, or theater events (Gamaldo 2006). L-DOPA has a relatively benign side effect profile, though there is some concern that it can cause symptoms to occur earlier in the day and more quickly at rest, and spread to the upper limbs (Garcia-Borreguero 2007).
A pitfall of dopaminergic drugs is that, paradoxically, they may cause or exacerbate RLS symptoms – a phenomenon known as augmentation. As many as 20% to 60% of patients treated with L-DOPA or dopamine agonists develop augmentation; so “it is important for physicians to carefully screen patients for changes in RLS symptoms for as long as they are on dopamine agents, with particular attention paid to those patients who present with the most severe RLS symptoms prior to treatment initiation” (Allen 2011; Hogl 2010).
- Benzodiazepines. Benzodiazepines (e.g., clonazepam and lorazepam) enhance the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), giving them sedative, sleep-inducing, anti-anxiety, anticonvulsant, and amnesic qualities (Rudolph 1999). These drugs are often useful for treating insomnia associated with RLS (Yee 2009). A small placebo-controlled study measured the acute effects of 1 mg clonazepam on sleep and awakening quality in 10 RLS and 16 periodic limb movement disorder (PLMD) patients. Insomnia associated with both RLS and PLMD was improved by clonazepam (Saletu 2001). Benzodiazepines are sometimes combined with dopamine agonists in patients with refractory RLS (Bayard 2008). These drugs can adversely impact cognitive ability and coordination and may rarely exacerbate anxiety and irritability.
- Gabapentin. Gabapentin is a medication often used to treat epilepsy and peripheral neuropathy; and some studies have also found that it may be useful in treating painful variants of RLS (Yee 2009; Kushida 2009; Happe 2001; Garcia-Borreguero 2002). Gabapentin may be effective in individuals with RLS-associated neuropathic pain that has not responded to dopaminergic drugs (Bayard 2008). The U.S. FDA approved Horizant® (gabapentin enacarbil) for the treatment of moderate-to-severe RLS in April 2011.
- Low-dose opioids have been used successfully in some cases of RLS (Kaplan 1993; Walters 1993). However, the mechanism by which they provide relief is not clear and the role of the endogenous opioids system in RLS is complex (von Spiczak 2005). Opioids are typically reserved as a last-resort treatment for refractory RLS.