Treatment Options for Restless Legs Syndrome

Drug Therapy for Restless Legs Syndrome

Not all patients with restless legs syndrome will require pharmacological (drug) therapy. The decision whether or not to implement an individual treatment plan for idiopathic restless legs syndrome is based upon a variety of clinical factors including:

  • Type and severity of the symptoms
  • Frequency of symptoms
  • How long the symptoms last
  • Are symptoms related to restless legs syndrome or PLMD
  • Are symptoms present during waking, sleeping, or both
  • Is the patient experiencing leg pain, or leg discomfort
  • Extent and type of sleep disturbances
  • Effect of symptoms on the patient's overall function and quality of life
  • Presence of other comorbidities such as neuropathy or heart disease, which may influence type and dose of medication chosen for therapy.

In general, the following classes of drugs may be used for the management of patients with restless legs syndrome:

  • Dopaminergic agents
  • Benzodiazepines
  • Opioid medications
  • Anticonvulsants

Dopaminergic Agents

Dopaminergic agents enhance the levels of dopamine which is the neurotransmitter (naturally produced chemical) that regulates the messages for movement between nerve cells in the central nervous system. They inhibit abnormal movement by enhancing the level of dopamine available and this facilitates the ease of messages passing between brain cells in the central nervous system. Dopaminergic agents are the first line treatment for restless legs syndrome and alleviate all major features of restless legs syndrome symptoms including:

  • Restlessness
  • Abnormal sensations
  • Involuntary movements
  • Sleep disturbances

Two important side effects associated with dopaminergic agents that must be continually assessed include:

  • Rebound - the reappearance of symptoms when the dose wears off typically in the middle of the night or during early morning hours assuming the patient took medication before bedtime. This is often followed by a symptom-free period during the day and then symptoms re-emerge (sometimes stronger) at night. Rebound is preventable by using controlled release formulation or by adding a dose in the middle of the night.

  • Augmentation - this is a more significant side effect and occurs in 50-80% of patients using levodopa. Some patients may have to change medication when augmentation occurs. It may begin within a few months after initiating treatment with levodopa and consists of :

    • initiation of restless legs syndrome symptoms earlier in the day
    • a more rapid onset of symptoms when the patient is at rest
    • increased severity of symptoms
    • shorter relief from dopaminergic medications
    • symptoms may spread from the legs to the arms.

The severity of restless legs syndrome symptoms and dosage of dopaminergic agents are related to the likelihood of augmentation occurring. In the short term, augmentation may be treated by increasing the frequency of administration of levodopa but over time, the period of effectiveness may continue to shorten. At that point, the medication may have to be discontinued and a new one initiated. Administration of single medications is recommended as the first choice, however, switching medications and/or combining them until the most effective regimen is established, may be necessary in the treatment of restless legs syndrome. If restless legs syndrome is intractable, combination therapy or use of opioids may be needed. There is little data regarding drug combinations for treating restless legs syndrome but it appears that side effects are more likely to occur when drugs are combined than when taken alone.

Medication is initiated at low doses which are then increased gradually to the minimum level of effectiveness. The timing of medication administration is very important in order to ensure relief at the time of greatest need when the symptoms are strongest, such as the early evening hours. Medications may be given only on an as needed basis or on a more regular schedule. If one drug is not sufficiently effective in reducing symptoms, the dose may be adjusted or another medication may be initiated as treatment either from the same or from a different class of drugs. A drug may also be suspended temporarily if the patient develops a tolerance for it and needs to keep increasing the dose in order to get relief. Some patients experience remission and then medications may be withdrawn or their dose may be reduced.

The response to dopaminergic agents in patients with restless legs syndrome is almost universal. Two types of drugs included in this class of medications:

  • Dopamine precursors
  • Dopamine agonists
Dopamine Precursors

Levodopa has been used for over 20 years and its effectiveness has been confirmed in many studies. It is usually given in combination with carbidopa (a dopa-decarboxylase inhibitor) in a formulation called Sinemet. While levodopa increases the level of dopamine in the brain, carbidopa prevents other enzymes from breaking down the available dopamine, thus increasing the amount of time that dopamine can remain active in the central nervous system. As a result, the dose of levodopa can be reduced and as well as the subsequent side effects. Sinemet is formulated with varying ratios of the two medications and a controlled-release formulation (Sinemet CR) is also available.

Sinemet is taken orally either on an as-needed basis or on a regular schedule. It is usually taken on an empty stomach in order to increase absorption and it is recommended that Sinemet not be taken with a high protein meal since protein interferes with the absorption into the blood. Restless leg syndrome is typically so responsive to levodopa that when the patient improves after commencing this drug, that is a confirmation that the diagnosis of restless legs syndrome is correct. The medication is typically taken shortly before going to sleep (about one hour) and results in:

  • Reduction of periodic limb movements
  • Reduction of severity of restless legs syndrome symptoms
  • Improved sleep quality
  • Reduced daytime sleepiness

When taken on an empty stomach, levodopa is fast acting, usually within 15-20 minutes. Because of its short half-life (amount of time it takes for the body to eliminate half of the medication), levodopa is effective in preventing symptoms from developing when taken shortly before an event in which the patient wants to be symptoms free, such as a movie or a meeting. When taken shortly before bedtime, its effect may wear off quickly and patients may wake up during the night with symptoms of paresthesia and the need to move their legs. In order to combat this problem, an additional dose of levodopa may be prescribed before bedtime. Alternatively, a controlled release form of levodopa/carbidopa (Sinemet CR) has been developed in order to extend the effectiveness of the medication since it delivers a steady supply of levodopa over an extended period of time and this also prevents the levels from falling too low in the blood which would bring on additional symptoms. However, the duration between taking the extended release form and the initiation of symptom relief is longer than for the standard form of Sinemet so the patient may need to also take a standard form of the medication in order to get relief for the immediate short term duration.

Levodopa is generally well tolerated in patients with restless legs syndrome and does not cause side effects such as dyskinesia which is felt when it is taken for other conditions (e.g., Parkinson's disease). Prolonged use does not appear to cause toxicity. Some patients can take levodopa for 5-10 years with minimal side effects - whereas patients with Parkinson's disease often experience side effects from Sinemet such as involuntary movements and psychiatric problems.

Daytime augmentation is very common side effect and is reported in up to 80% of patients taking levodopa. Up to 50% of patients who experience augmentation must change medications. It has been noted that augmentation is more likely to occur with higher doses of levodopa. As mentioned before, the only other major side effect early morning rebound which occurs in approximately 20-35% of patients on levodopa treatment. For this reason, many physicians prefer to prescribe dopamine agonists as they have a longer half-life and fewer problems with augmentation and rebound.

Dopamine Agonists

Dopamine agonists act like dopamine and produce dopamine-like effects. Dopamine agonists are usually selected as the first-line treatment for idiopathic restless legs syndrome and have been found to produce significant improvements in restless legs syndrome symptoms in randomized, controlled clinical trials. They are particularly effective when used for advanced restless legs syndrome. Dopamine agonists are much slower acting than levodopa and are taken up to 2 hours before symptoms would typically develop, however, they also are effective for a longer period of time.

When taken at night, 1-2 hours before bedtime, dopamine agonists relieve motor and sensory symptoms until the morning so that sleep quality is significantly improved. If symptoms of restless legs syndrome intensify in the first two years of treatment with dopamine agonists, then it may be due to the progression of restless legs syndrome or to augmentation. This must be evaluated carefully. Augmentation is thought to occur in approximately 20-30% of patients being treated with dopamine agonists and is often milder than for levodopa.

In general, side effects of dopamine agonists include:

  • Insomnia
  • Nasal congestion
  • Bloating
  • Edema (swelling) of hands and feet
  • Nausea/vomiting
  • Chest pain
  • Mild augmentation

When dopamine agonists are discontinued, the patient typically shows signs of withdrawal where symptoms intensify for up to 48 hours and then return to baseline levels after 4-7 days. The intensity of withdrawal symptoms is related to the duration of drug use and the dose.

Examples of dopamine agonists that may be used for the treatment of restless legs syndrome include:

  • Pergolide mesylate (Permax) - This medication was considered to be a first line treatment for moderate or severe restless legs syndrome. In March 2007, however, the FDA notified healthcare professionals and patients that pergolide has been withdrawn from the market because it has been linked to serious damage to heart valves.

  • Pramipexole (Mirapex) - Pramipexole is effective in individuals who do not respond to other dopamine agonists. It is initiated at low doses which are increased up to the point of maximum effectiveness. Pramipexole is taken with food. Benefits of pramipexole include:

    • significant reduction of periodic limb movements during sleep and wakefulness
    • relief from sensory symptoms and leg discomfort
    • reduction of motor symptoms
    • may be effective for patients who failed to respond to other dopaminergic medications.

  • Ropinirole (Requip) - In May 2005, the U.S. Food and Drug Administration (FDA) approved ropinirole (Requip) for the treatment of moderate to severe restless legs syndrome and it is now recommended by the AASM. There was a 55% improvement of symptom severity and sleep disturbance noted on a restless legs syndrome questionnaire filled out by a group of patients taking ropinirole after 4 months of use. This drug was first approved for the treatment of Parkinson's disease in 1997.

  • Bromocriptine (Parlodel) - This medication is often effective for patients with restless legs syndrome who have not responded to therapy with levodopa/carbidopa.

  • Rotigotine (Neupro) - A novel transdermal delivery system (Neupro patch) has recently emerged for the treatment of patients with restless legs syndrome with a dopamine receptor agonist drug called rotigotine . The patch is applied once a day to the skin and continuously releases the drug through the skin for a period of 24-hours.

In March 2008, the manufacturer of Neupro (Schwarz Pharma) informed healthcare professionals and patients of the recall of Neupro because of the formation of rotigotine crystals in the patches. When the rotigotine crystalizes, less drug is available to be absorbed through the skin and, therefore, the efficacy of the product may vary. Neupro will not be available in the U.S. by the end of April 2008. Healthcare professionals should not initiate any new patients on Neupro and should begin to gradually down-titrate all patients currently using the product per the guidelines in the product labeling. Patients should not abruptly discontinue therapy because abrupt withdrawal of dopamine agonists has been associated with a syndrome resembling neuroleptic malignant syndrome or akinetic crises.

Benzodiazepines

Benzodiazepines do not act directly upon restless leg syndrome but may be used to alleviate related symptoms. They reduce communication between nerve cells by interfering with chemical activity and are used for:

  • Relaxing muscles
  • Relieving anxiety
  • Reducing restlessness
  • Promoting sleep

This class of drugs is usually used for the treatment of restless legs syndrome symptoms that are mild or intermittent and occur primarily during sleep. Benzodiazepines are also used as adjunctive therapy in patients with restless legs syndrome who are being treated with other medications but who are still experiencing sleep disturbances even while on medication. For patients with severe symptoms, benzodiazepines are effective when used together with Sinemet or dopamine agonists.

Benzodiazepines are effective on a long term basis and have a low incidence of side effects or buildup of tolerance over time. Benzodiazepines may be used to help with insomnia but must be used with caution especially in older people. They are not particularly effective for paresthesia related to restless legs syndrome or for PLMS. Side-effects of benzodiazepines may include:

  • Drowsiness especially in the morning
  • Dizziness, unsteadiness and elevated risk of falling
  • Reduced libido (sexual desire)
  • Sleep apnea (may develop or become exacerbated)
  • Drug dependence (low risk)

Benzodiazepines should not be taken with alcohol or any other medication that depresses the central nervous system.

Examples of benzodiazepines that may be used for the treatment of restless legs syndrome include:

  • Clonazepam (Klonopin) - this is the most commonly used drug in this category. Its side effect is early morning sedation.
  • Diazepam (Valium) - helpful in up to 75% of patients
  • Alprazolam (Xanax)
  • Temazepam (Restoril)

Opioid Medications

Opioid medications possess both analgesic (pain-relieving) and sedative properties and have been found to be useful for the treatment of both restless legs syndrome and periodic limb movement. Low potency opioids such as propoxyphene hydrochloride (Darvon) alleviate all major symptoms of restless legs syndrome and have been shown to be effective for up to 15 years with little risk of dependence and few side effects. Higher potency opioids such as oxycodone hydrochloride (Percocet) are effective for patients with severe restless legs syndrome who have not responded to other types of medications. In a study of 500 patients with restless legs syndrome, approximately 20% reported taking opioids at some point either as a solo drug or in combination with other drugs for an average of 6 years. Opioids can also be taken as a single dose to prevent symptoms for a specific period of time (e.g. plane trip or going to the theatre).

Examples of drugs in this category include:

  • Morphine
  • Codeine
  • Oxycodone
  • Hydrocodone
  • Propoxyphene
  • Methadone - this drug usually provides longer-acting relief and is given for the most refractory cases of restless legs syndrome (i.e., individuals who don't respond to other medications)

Side-effects of opioid medications include drowsiness, constipation, confusion, and the potential for drug addiction (a major concern). Daytime augmentation is rare but symptoms return when the medication is withdrawn and sometimes they are temporarily worse than before.

There is no general consensus as to whether opioids should be used as second-line treatment or reserved to be used as a last resort. Since each individual responds differently to specific medications, sometimes it takes several "trial and error" attempts before the right drug and the right dose is identified.

Anticonvulsants

This class of drugs has also been found to be helpful for controlling some of the symptoms of restless legs syndrome, such as restlessness, sensory abnormalities, sleep problems, and painful peripheral neuropathy. The most commonly drugs in this category include:

  • Gabapentin (Neurontin)
  • Carbamazepine (Tegretol)

Both of these drugs are usually well-tolerated although gabapentin has become preferred because of lower risk of side effects which may include:

  • Fatigue (more of a problem with carbamazapine)
  • Dizziness
  • Gastrointestinal upset (this is minimized by taking the medication with food)
  • Carbamazepine carries a warning concerning the risk of aplastic anemia