Levodopa is used in the symptomatic treatment of idiopathic Parkinson's disease (paralysis agitans), parkinsonian syndrome (postencephalitic parkinsonism), and symptomatic parkinsonism resulting from carbon monoxide intoxication and/or manganese intoxication. Levodopa is currently the most effective drug for relieving the symptoms of parkinsonian syndrome and is considered by many clinicians to be the drug of choice in the management of idiopathic parkinsonian syndrome. Most clinicians delay introduction of symptomatic therapy until the patient begins to experience functional limitation. Although levodopa traditionally has been considered the drug of choice for the initial symptomatic management of idiopathic parkinsonian syndrome, long-term administration of levodopa is associated with motor complications (dyskinesia and motor fluctuations). One strategy to reduce the risk of motor complications associated with long-term levodopa therapy is to initiate levodopa therapy in combination with a catechol-O-methyltransferase (COMT) inhibitor (entacapone, tolcapone). Another strategy to reduce the risk of motor complications and to improve long-term outcome is to initiate symptomatic therapy with a dopamine receptor agonist (bromocriptine mesylate, pramipexole dihydrochloride, pergolide mesylate, ropinirole hydrochloride) and to add levodopa as supplemental therapy when dopamine receptor agonist monotherapy no longer provides adequate symptom control. However, clinical studies evaluating this strategy are limited both in number and duration, and it remains to be determined whether initiating therapy with a dopamine receptor agonist rather than levodopa results in a more favorable long-term outcome. Factors to consider when choosing an agent for the initial symptomatic management of idiopathic parkinsonian syndrome include patient age, cognitive status, disease severity, and cost. Most clinicians would use levodopa for initial therapy in individuals older than 70 years of age (since these individuals are less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease. A dopamine receptor agonist may be preferred for initial therapy in patients 70 years of age or younger.
The effectiveness of levodopa reportedly decreases substantially after the third year of treatment and symptoms of the disease may return to pretreatment levels after 6-7 years of levodopa therapy. Concurrent administration of selegiline hydrochloride, a selective monoamine oxidase (MAO)-B inhibitor, may improve therapeutic response in patients who exhibit a deteriorating response to levodopa-carbidopa therapy. Selegiline therapy appears to be most beneficial when used during the early stages of the '' wearing off'' effect; patients with advanced parkinsonian syndrome and those exhibiting severe ''on-off'' phenomena during levodopa therapy are less likely to benefit from selegiline therapy.
Concomitant administration of levodopa and a decarboxylase inhibitor such as carbidopa generally decreases levodopa dosage requirements by 70-80%, reduces the incidence of levodopa-induced nausea and vomiting, allows a more rapid dosage titration, and may provide a smoother response to levodopa. Therefore, most clinicians currently state that carbidopa used in conjunction with levodopa is the treatment of choice for patients with parkinsonian syndrome who require levodopa. Certain patients who responded poorly to levodopa alone (no longer commercially available in the US as a single-entity preparation) have improved when carbidopa and levodopa were administered concomitantly; however, patients with markedly irregular ''on-off'' responses to levodopa
(see Cautions: Nervous System and Muscular Effects)usually have not benefited from combination therapy. Carbidopa has no therapeutic effect when given alone to patients with parkinsonian syndrome and should be used only in conjunction with levodopa. Combination preparations containing levodopa in fixed combinations with carbidopa are commercially available. Carbidopa is also available alone from the manufacturer for use in conjunction with the combination preparations in patients who do not have adequate reduction in nausea and vomiting with the fixed-dosage preparations.
Levodopa completely or partially relieves akinesia, rigidity, and tremor in about 80% of patients treated. Levodopa may be useful in the management of other symptoms of parkinsonian syndrome including dysphagia, sialorrhea, and seborrhea. Levodopa improves functional ability and other secondary motor manifestations such as gait, postural stability, facial expression, swallowing, speech, and handwriting. Levodopa therapy often produces a general alerting response, increased vigor, and a sense of well-being.
In the treatment of parkinsonian syndrome, levodopa-carbidopa may be used in conjunction with amantadine; ergot- and nonergot-derivative dopamine receptor agonists such as apomorphine hydrochloride, bromocriptine, pramipexole dihydrochloride, or ropinirole hydrochloride; antihistamines such as diphenhydramine; or anticholinergic antiparkinsonian agents such as benztropine mesylate, trihexyphenidyl hydrochloride, or procyclidine hydrochloride. When levodopa is administered with an anticholinergic agent, the dosage of each drug may need to be reduced.
(See Drug Interactions: Anticholinergic Agents.)Combined therapy with amantadine and levodopa has been reported to be more effective than levodopa alone in some patients who cannot tolerate large dosages of levodopa; however, the addition of amantadine does not usually provide substantial additional benefit when patients are already receiving full therapeutic dosages of levodopa.
Levodopa-carbidopa may be used in conjunction with a COMT inhibitor (i.e., entacapone, tolcapone) for the symptomatic treatment of idiopathic parkinsonian syndrome. Concomitant administration of entacapone or tolcapone with levodopa-carbidopa enhances the efficacy of levodopa in patients with motor fluctuations and in those with stable responses to levodopa. However, tolcapone therapy has been associated with severe hepatocellular injury in some patients. Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone generally should be reserved for patients receiving levodopa who are experiencing symptom fluctuations and are not responding adequately to other adjunctive therapies. Some clinicians consider entacapone the COMT inhibitor of choice. For additional information on such combined therapy, .
Levodopa may be useful in the management of reserpine-induced parkinsonian symptoms; however, levodopa is not effective in controlling extrapyramidal effects induced by antipsychotic agents such as phenothiazines or butyrophenones.
Although levodopa is not effective in the management of extrapyramidal effects induced by antipsychotic agents and is not generally useful in the management of other neurologic diseases, the drug may be of some benefit in conditions in which marked akinesia is present. Levodopa is not useful in the treatment of mental disorders.