Levodopa is used in the symptomatic treatment of parkinsonian syndrome (e.g., parkinsonism, idiopathic Parkinson disease [paralysis agitans]); the drug also is used in the symptomatic treatment of parkinsonian syndrome resulting from encephalitis (postencephalitic parkinsonism), carbon monoxide intoxication, or manganese intoxication.
Levodopa (in combination with carbidopa) currently is the most effective drug for relieving the motor symptoms of parkinsonian syndrome and is considered by many clinicians to be the drug of choice for this use. Levodopa completely or partially relieves akinesia, rigidity, and tremor in about 80% of patients treated, and improves functional ability and other secondary motor manifestations such as those affecting gait, postural stability, facial expression, swallowing, speech, and handwriting. Levodopa also may be useful in the management of other symptoms of parkinsonian syndrome including dysphagia, sialorrhea, and seborrhea. Levodopa therapy often produces a general alerting response, increased vigor, and a sense of well-being. However, the effectiveness of levodopa tends to decrease over time and most patients develop motor complications such as motor fluctuations (e.g., end-of-dose failure, ''on-off'' phenomenon, akinesia) and dyskinesias (drug-induced involuntary movements) with long-term use.
(See Cautions: Nervous System and Muscular Effects.)Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine), selective monoamine oxidase (MAO)-B inhibitor (e.g., rasagiline, safinamide, selegiline), catechol-O-methyltransferase (COMT) inhibitor (entacapone, tolcapone), or amantadine; the goal of adjunctive therapy is to improve motor fluctuations without exacerbating dyskinesia. Another strategy to reduce the risk of motor complications and to improve long-term outcome in patients receiving levodopa is to initiate symptomatic therapy with other antiparkinsonian agents first and then add levodopa when these other therapies no longer provide adequate symptom control. This delayed approach is often used in younger patients who have a higher risk of developing motor complications and a longer life expectancy. Levodopa generally is used 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. Treatment must be individualized; factors to consider when selecting a drug for the initial symptomatic management of parkinsonian syndrome include patient age, cognitive status, disease severity, and cost.
Carbidopa, a decarboxylation inhibitor, is used in conjunction with levodopa to inhibit the decarboxylation of peripheral levodopa and increase the amount of levodopa available for transport to the brain. Concomitant administration of levodopa and 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. 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.
In the treatment of parkinsonian syndrome, levodopa-carbidopa therapy may be used in combination with selective MAO-B inhibitors (e.g., rasagiline, safinamide, selegiline), dopamine agonists (e.g., pramipexole, ropinirole, rotigotine), amantadine, antihistamines (e.g., diphenhydramine), or anticholinergic agents (e.g., benztropine, trihexyphenidyl). When used as adjunctive therapy to levodopa in patients with advanced parkinsonian syndrome, MAO-B inhibitors and dopamine agonists can reduce motor fluctuations and permit the use of lower dosages of levodopa. Although anticholinergics may be useful for controlling tremor and drooling, the adverse effects of these drugs may limit their use. 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 also 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.