Wednesday, October 4, 2023
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Avoidance of caffeine, alcohol, or nicotine may help improve symptoms in some patients. Offending medications (see numbered list above) should be discontinued. Physical measures that may partially or temporarily help include a hot or cold bath, rubbing the limbs before sleep, or vibratory or electrical stimulation of the distal lower limbs before bedtime.
Correction of a vitamin deficiency (eg, folate) or an electrolyte deficiency (eg, magnesium) can improve symptoms in RLS. Those with low ferritin levels or iron deficiency can benefit from oral iron supplementation, or in some cases intravenous infusion of iron.[28] Sclerosing agents may improve RLS symptoms in individuals with prominent varicose veins in the legs.[29] Uremic patients with RLS usually improve upon correction of anemia with erythropoietin, or after renal transplantation.[30]
The goal of pharmacotherapy is symptomatic relief in primary or idiopathic RLS, given that a cure is only possible in secondary RLS. Medications are best initiated at low doses and taken 1-2 hours before bedtime to allow for sufficient absorption and action. Additional doses can be given in the middle of the night if the patient awakens. If tolerance develops to one drug, another class of drugs may be substituted. Severe cases of RLS may benefit from polypharmacy with 2 or more drugs. One strategy to help prevent tolerance is to find 2 or 3 effective medications and then rotate them every few months.
Levodopa. Carbidopa-levodopa can improve sensory symptoms and PLMS in RLS. For symptoms that start before sleep, one 25-mg/100-mg carbidopa-levodopa tablet can be taken 1-2 hours before bedtime. If the symptoms occur later during the night, a controlled-release (CR) carbidopa-levodopa tablet (either 25 mg/100 mg or 50 mg/200 mg CR) can be used. Even low doses of levodopa (50-200 mg/day) are effective in most patients. Only rarely do patients require more than 600 mg/day. Nausea and constipation are the most common side effects of levodopa.
The major drawback with levodopa is that about 80% of patients will develop "augmentation" as early as a few months after initiation of the drug.[31] Augmentation manifests as earlier onset of RLS symptoms during the evening, shorter latency to onset after assuming a restful position, increased intensity, or extension of the symptoms to the upper body. "Rebound" refers to an increase in severity of symptoms occurring in the morning. Augmentation often leads to escalating doses of levodopa. Once augmentation or rebound occurs, adjunctive therapy or substitution of levodopa with other drugs is an alternative treatment strategy.
Dopamine Agonists. The most commonly prescribed dopamine agonists for RLS are pramipexole and ropinirole. Both are nonergots, and have been determined to be effective in double-blind, placebo-controlled studies.[32,33] Doses as low as 0.125 mg of pramipexole (D2, D3 agonist) at bedtime or 0.25 mg of ropinirole (D2 agonist) can be effective in controlling nocturnal symptoms in mild-to-moderate cases of RLS. The majority of patients require less than 2 mg/day of pramipexole or 6 mg/day of ropinirole. Piribedil, a nonergot D2 and D3 dopamine agonist, is effective even at a low dose of 25 mg/day.[34] Cabergoline, a long-acting ergot dopamine agonist, can provide symptomatic relief of RLS symptoms (at doses of 2 mg/day or less) for the entire day despite the need for once-daily dosing due to its long half-life.[35] Rotigotine, the only dopamine agonist that is available as a patch, can provide relief of RLS both day and night with once-daily dosing.[36]
The side effects of dopamine agonists include nausea, light-headedness, drowsiness, and postural hypotension. Dopamine agonists are less likely to produce augmentation or rebound, and can be of benefit in patients treated with levodopa who develop these complications.
Benzodiazepines. Clonazepam can alleviate sensory symptoms and PLMS in RLS patients.[37] The initial dose is 0.25 mg at bedtime, with a maximum dose of 3-4 mg/day in divided doses. Other benzodiazepines, such as temazepam and alprazolam, have also been used anecdotally with success. The major side effects of benzodiazepines include daytime drowsiness, confusion, unsteadiness, falls, and aggravation of sleep apnea. Benzodiazepines may be used in patients with mild or intermittent symptoms.
Opioids. Low-potency opioids, such as codeine and propoxyphene, can be of benefit for those with mild and intermittent symptoms, whereas higher potency agents, such as oxycodone, methadone, or levorphanol, may be useful in refractory cases.[38] Opioids are best used in RLS patients who have painful symptoms, especially those with associated sensory neuropathy.
Anticonvulsants. Carbamazepine (200-400 mg daily) has been shown to be effective in reducing RLS sensory symptoms, especially among young patients with recent-onset and severe symptoms.[39] Gabapentin (100-2400 mg/day) may be effective in relieving sensory symptoms[40] and PLMS in RLS, even in refractory cases. Topiramate (25-150 mg/day) and sustained-release valproate (600 mg/day) have also been reported to be effective in some patients.[41,42]
Other Medications. Clonidine (0.1-1 mg/day), a presynaptic alpha2-adrenergic agonist, is effective in idiopathic and secondary RLS.[43] The sleeping pill zolpidem (5-10 mg per night) has also been reported to be effective in improving sleep, sensory symptoms, and PLMS in RLS patients.[44] Amantadine (100-300 mg/day), a drug that is used to treat the flu and PD, can be effective in treating idiopathic and neuropathic RLS, even in those with severe symptoms.[45]
In PD patients with RLS, subthalamic deep brain stimulation has been noted to improve not only the motor symptoms of PD but also RLS.[46] RLS in these patients improves significantly despite a drop in postoperative doses of dopaminergic drugs. Whether RLS in non-PD patients will respond to deep brain stimulation is uncertain.
