Dopamine Agonists
Dopamine agonists (DAs) bind to dopamine receptors, producing dopamine-like effects. These medications include the ergot derivatives bromocriptine mesylate (Parlodel®) and pergolide mesylate (Permax®) and the nonergotoline drugs pramipexole dihydrochloride (Mirapex®) and ropinerole hydrochloride (Requip™). As with several treatment regimens used to treat RLS, most DAs were developed as anti-Parkinsonian agents. Although RLS patients do not have PD, the observation that RLS was found more frequently in PD patients, and that RLS symptoms improved with levodopa lead to trials of DA for idiopathic RLS. (Levodopa treatment was found to cause side effects including rebound and augmentation. DA are much less likely to cause these side effects and currently are preferred over the use of levodopa) The DA are currently recommended for RLS patients with mild to severe symptoms sufficient to impair their quality of life. DAs may be used as first-line therapies in patients with moderate or severe RLS or as appropriate alternatives or supplements to carbidopa/levodopa. Reports have indicated that long-term therapy with DAs remains effective for many RLS patients.
Ergot Derivatives–Bromocriptine (Parlodel®) and Pergolide (Permax®)
Bromocriptine is a semisynthetic DA that is a derivative of ergot alkaloids and lysergic acid. The drug, which was approved by the FDA in 1978 for secondary amenorrhea or galactorrhea due to hyperprolactinemia, is most commonly used in the treatment of Parkinson's disease. Bromocriptine stimulates D2 receptors and antagonizes D1 receptors in the neostriatum of the CNS and hypothalamus. Following oral administration, approximately 28% of the drug is absorbed from the GI tract. Due to significant hepatic metabolism, only about 6% reaches the systemic circulation. Bromocriptine has an elimination half-life of approximately 4.0 to 4.5 hours in the initial phase and about 40 to 50 hours in the terminal phase.
Pergolide, a long-acting DA, is also a semisynthetic ergot alkaloid derivative. The drug was approved by the FDA in 1988 for the management of Parkinson's disease and has received an orphan drug designation for the treatment of TouretteÕs syndrome. On a milligram basis, pergolide has about 10 times the potency of bromocriptine. Pergolide is an agonist at D1, D2, and D3 receptors, stimulating postsynaptic dopamine receptors in the nigrostriatal system. Following oral administration, the drug is well absorbed and has an elimination half-life that may be as long as 27 hours.
Daytime augmentation occurs less frequently and to a milder degree with bromocriptine or pergolide therapy than with carbidopa/levodopa therapy, thereby allowing a greater degree of dopaminergic treatment. Consequently, bromocriptine or pergolide are first-line therapies for patients with severe or moderate RLS or may serve as effective second-line treatments for patients who must discontinue carbidopa/levodopa therapy due to augmentation. Pergolide may also be used in combination with levodopa formulations to provide additive effects while allowing decreased dosages of carbidopa/levodopa. While comparative studies have not been done, there have been more studies of pergolide than of bromocriptine, giving greater support to the usefulness of this agent in RLS.
These DAs are initially prescribed in small dosages and require slow upward titration over several weeks to minimize adverse effects. In addition, the medications should be administered with food to reduce nausea. Recommended starting dosages are typically 1.25 to 2.50 mg of bromocriptine at bedtime or 0.05 mg/day of pergolide. Pergolide is best divided into two equal doses, one taken with the evening meal and the other approximately one hour before bedtime. Average effective total daily dosages range from approximately 2.5 to 20.0 mg of bromocriptine or 0.1 to 1.0 mg of pergolide. Both bromocriptine and pergolide may cause gastrotoxicity and orthostatic hypotension (OH). Pergolide therapy typically causes fewer episodes of OH and less nausea, and such symptoms usually resolve with ongoing treatment. Pergolide therapy may cause additional side effects including nasal congestion, insomnia, dizziness, and lightheadedness. If these side effects occur, the use of a benzodiazepine may control insomnia (and simultaneously manage RLS symptoms) and a nasal decongestant may relieve congestion. In addition, temporarily discontinuing and then reinstating pergolide therapy may help to minimize associated side effects.
Rare or uncommon side effects associated with the use of pergolide include double vision, confusion, anxiety, restlessness, hallucinations, mental changes, or uncontrollable movements (i.e., dyskinesias of the arms, face, hands, head, mouth, shoulders, or upper body). Uncommon side effects of bromocriptine include blurred vision, difficulty breathing, lightheadedness, irregular heartbeat, or convulsions. Side effects that are more common include hallucinations or severe weakness or tiredness.
In one small study, domperidone (Motilium®), a peripherally acting antagonist at type D2 dopaminergic receptors, was used in combination with pergolide (mean dose of 0.4 mg). Researchers reported that this combination was effective in the treatment of sleep disturbances as well as daytime symptoms associated with RLS. Domperidone may help to relieve some side effects associated with the use of pergolide, but has not been approached by the FDA for sale in the U.S. In one small, open-label trial, investigators found that cabergoline (Dostinex), a D2 receptor agonist that is used to treat galactorrhea, has the potential to reduce RLS symptoms in patients who were discontinuing levodopa therapy due to augmentation. The therapeutic dosage used was 2.1 mg daily.
Ergotoline DAs should not be prescribed for patients with a known sensitivity to ergot alkaloids. In very rare cases, prolonged therapy with such medications may be associated with pulmonary or retroperitoneal fibrosis and pleural thickening and effusion. Such effects typically resolve upon discontinuation of drug therapy.
Non-Ergot Derivatives–Pramipexole (Mirapex®) and Ropinirole (Requip™)
Other DAs may also be effective in treating some patients with RLS. Such medications include nonergotoline drugs, such as pramipexole and ropinirole, as well as amantadine. Pramipexole (Mirapex®), a DA that stimulates D2 and D3 receptors in the striatum and substantia nigra, was approved by the FDA in 1997 for the treatment of idiopathic Parkinson's disease. Pramipexole has been shown to alleviate RLS symptoms such as motor restlessness, involuntary movements, and sleep difficulties in patients who have not responded to treatment with other DAs. In studies of pramipexole for RLS, patients reported that PLMS were reduced by 98% and, in some affected individuals, RLS symptoms disappeared completely after pramipexole therapy.
This medication is typically initiated at a low dose such as 0.125 mg or lower and then gradually titrated up to a therapeutic range (e.g., 0.25 to 1.0 mg). The primary adverse effect reported is a mild, transient nausea, typically experienced by patients after they have been titrated to doses between 0.375 mg/day and 0.75 mg/day. Another adverse effect that has been reported in patients with Parkinson's disease is peripheral edema, which resolves when therapy is discontinued.
The absolute bioavailability of pramipexole is over 90%. Although food does not affect the drug's absorption, administering pramipexole with food may help minimize potential nausea. Because the drug is more selective for D3 receptors than bromocriptine or pergolide, pramipexole may cause fewer episodes of OH than other DAs. However, patients should be closely monitored for such episodes; in addition, slow titration may reduce the risk of OH. Side effects associated with pramipexole therapy include fatigue, stiffness, or dizziness. The drug is primarily eliminated through urinary excretion. However, because clearance is approximately 60% to 70% lower in patients with severe or moderate renal impairment, dosage adjustments are necessary in such cases.
Ropinirole, another nonergotoline DA, stimulates D2 and D3 receptors, such as post-synaptic D2 receptors in the caudate and putamen. As with pramipexole, ropinerole was approved by the FDA in 1997 for the treatment of Parkinson's disease. In several small trials of ropinerole for the treatment of RLS, patients reported symptom reduction ranging from 59% to 75%.
In patients with RLS, ropinirole therapy is usually initiated at a low dose and then slowly titrated up to a therapeutic dosage, typically in the range of 3 mg/day. Its bioavailability is approximately 55%, and its elimination half-life is about 6 hours. Food does not affect the medication's absorption. Side effects associated with ropinirole therapy may include nausea, dizziness, or OH.
Since all DAs studied to date have been found useful in RLS, it is likely that other agonists, as developed or available, may also benefit RLS. Amantadine (Symmetrel®) and selegiline (Eldepryl®) have been noted to be helpful in preliminary reports. In small trials on amantadine, patients reported symptom reductions averaging 69%. When used to treat RLS, amantadine therapy is typically started at a dose of 100 mg daily, and titrated to a maximum dose of 300 mg per day. The most common adverse effects associated with amantadine are drowsiness, fatigue, and insomnia.
Some retrospective studies have also shown that selective serotonin receptor uptake inhibitors (SSRIs), which are typically prescribed as psychotropics, may be able to alleviate RLS symptoms. These may include fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). In some patients, SSRIs may exacerbate PLMD, which is often associated with RLS.
All contents Copyright © http://www.wemove.org 2003. Last Update: February 24, 2003
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About WE MOVE
WE MOVE (Worldwide Education and Awareness for Movernent Disorders) is a not for profit organization whose primary mission is to increase awareness of movement disorders among health care professionals and the public. WE MOVE recognizes the role that patient advocate organizations play in providing valuable information and emotional support to patients and their families. It is the goal of WE MOVE to promote these organizations in all possible ways.
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