Treatment centers on alleviating motor symptoms
The general guiding principle of therapy (TABLE16,17) is to alleviate the motor symptoms (bradykinesia, rigidity, and postural instability) associated with the disease. Experts recommend that treatment commence when symptoms begin to have disabling effects or become a source of discomfort for the patient.1
Carbidopa/levodopa is still often the first choice
Multiple systematic reviews support the use of carbidopa/levodopa as first-line treatment, with the dose kept as low as possible to maintain function, while minimizing motor fluctuations (also referred to as “off” time symptoms) and dyskinesia.11,16 Initial dosing is carbidopa 25 mg/levodopa 100 mg tid. Each can be titrated up to address symptoms to a maximum daily dosing of carbidopa 200 mg/levodopa 2000 mg.17
“Off” time—the return of Parkinson symptoms when the medication’s effect wanes—can become more unpredictable and more difficult to manage as the disease advances.11 Of note: The American Academy of Neurology (AAN) says there is no improvement in the amount of off time a patient experiences by changing to a sustained-release form of carbidopa/levodopa compared with an immediate-release version.11 In addition to the on-off phenomenon, common adverse effects associated with carbidopa/levodopa include nausea, somnolence, dizziness, and headaches. Less common adverse effects include orthostatic hypotension, confusion, and hallucinations.17
Other medications for the treatment of motor symptoms
Second-line agents include dopamine agonists (pramipexole, ropinirole, and bromocriptine) and monoamine oxidase type B (MAO-B) inhibitors (selegiline, rasagiline) (TABLE16,17). The dopamine agonists work by directly stimulating dopamine receptors, while the MAO-B inhibitors block dopamine metabolism, thus enhancing dopaminergic activity in the substantia nigra.
The pros/cons of these 2 classes. Research shows that both dopamine agonists and MAO-B inhibitors are less effective than carbidopa/levodopa at quelling the motor symptoms associated with PD. They can, however, delay the onset of motor complications when compared with carbidopa/levodopa.16
One randomized trial found no long-term benefits to beginning treatment with a levodopa-sparing therapy; however, few patients with earlier disease onset (<60 years of age) were included in the study.18 Given the typically longer duration of their illness, there is potential for this group of patients to develop a higher rate of motor symptoms secondary to carbidopa/levodopa. Thus, considering dopamine agonists and MAO-B inhibitors as initial therapy in patients ages <60 years may be helpful, since they typically will be taking medication longer.
Dopamine agonists. Pramipexole and ropinirole can be used as monotherapy or as an adjunct to levodopa to treat bradykinesia, postural instability, and rigidity. Bromocriptine, an ergot-derived dopamine agonist, is considered an agent of last resort because additional monitoring is required. Potential adverse effects mandate baseline testing and annual repeat testing, including measures of erythrocyte sedimentation rate and renal function and a chest x-ray.16 Consider this agent only if all second- and third-line therapies have provided inadequate control.16
Adverse effects. Dopamine agonists cause such adverse effects as orthostatic hypotension, drowsiness, dizziness, insomnia, abnormal dreams, nausea, constipation, and hallucinations. A Cochrane review notes that these adverse effects have led to higher drop-out rates than seen for carbidopa/levodopa in studies that compared the 2.19
Patients should be counseled about an additional adverse effect associated with dopamine agonists—the possible development of an impulse-control disorder, such as gambling, binge eating, or hypersexuality.1 If a patient develops any of these behaviors, promptly lower the dose of the dopamine agonist or stop the medication.16
The MAO-B inhibitors selegiline and rasagiline may also be considered for initial therapy but are more commonly used as adjunct therapy. Use of selegiline as monotherapy for PD is an off-label indication. Adverse effects for this class of agents include headache, dizziness, insomnia, nausea, and hypotension.