The ideal medication for Parkinson disease (PD) would reduce disability and halt or slow disease progression without intolerable adverse effects. Although such an agent is not yet available, current treatments offer significant symptom control for most patients. The decision about when to start therapy is highly individual; however, delaying treatment because of fear of adverse effects may not be in the patient's best interest.
Options for initial treatment of motor symptoms include levodopa(Drug information on levodopa), dopamine(Drug information on dopamine) agonists, anticholinergic agents, amantadine(Drug information on amantadine), and selective monoamine oxidase B (MAO-B) inhibitors (Table).
DOPAMINERGIC AGENTS
Since 1959, when brain dopamine deficiency was identified as a key factor in PD, medical treatment has centered on methods to enhance dopamine transmission. Dopamine agonists currently available in the United States include ropinirole (Requip), pramipexole(Drug information on pramipexole) (Mirapex), pergolide(Drug information on pergolide) (Permax), and bromocriptine(Drug information on bromocriptine) (Parlodel). Another, rotigotine (marketed as Neupro in Europe), will likely be available soon in the form of a daily skin patch. Ropinirole(Drug information on ropinirole) and pramipexole are the 2 most widely prescribed dopamine agonists. Pergolide and bromocriptine are used less because, as ergot derivatives, they have been associated with rare instances of fibrosis of the heart valves, lungs, and retroperitoneum.1
Levodopa and the dopamine agonists remain the mainstays of PD treatment. However, soon after these agents went into widespread use, reports of adverse events began to appear, including short duration of benefit and involuntary choreic movements (dyskinesia) with levodopa and abnormal psychiatric states with bromocriptine. As awareness of the adverse effects of these and other medications that were introduced later grew, it became evident that physician familiarity with the use of levodopa and 1 or 2 dopamine agonists was crucial to satisfactory patient outcomes.
Levodopa and dopamine agonists complement one another and are often used together to maximize efficacy and minimize adverse effects. Probably because of its short half-life, levodopa is more likely to produce dyskinesia and other motor complications when used as monotherapy. The dopamine agonists have long half-lives and are less likely to produce these effects; however, they are not as effective as levodopa. Dopamine agonists must be introduced more slowly; they are more likely to cause adverse effects such as drowsiness, hypotension, hallucinations, and compulsive behavior.
Two large-scale studies that compared initial therapy with levodopa and initial therapy with a dopamine agonist established that initial treatment with a dopamine agonist reduces or delays the appearance of motor complications—specifically dyskinesia—and end-of-dose wearing off.2,3 However, in both studies, most patients eventually received levodopa in conjunction with the dopamine agonist. Unfortunately, these results were misinterpreted by some clinicians to mean that levodopa is to be avoided, a phenomenon dubbed levodopa phobia.2-4 Clinicians who fail to prescribe levodopa withhold from their patients the single most effective agent for symptomatic treatment.
According to the practice parameters of the American Academy of Neurology, treatment may be started with either levodopa or a dopamine agonist.5 To minimize the risk of motor complications, many movement disorder specialists suggest that it may be preferable to start therapy with a nonergot dopamine agonist for patients aged 65 years or younger and to add levodopa later as necessary to optimize mobility. For patients older than 75 years, levodopa may be used first and, in many cases, as monotherapy. Younger patients appear to be at greater risk for dyskinesia, and motor complications may take years to develop.
In patients aged 65 to 75 years, the choice depends on the patient. Determine whether the patient is likely to comply with the dosing changes involved in the titration of a dopamine agonist, which requires 3 to 8 weeks, or whether prompt relief of symptoms is needed. In the latter case, levodopa would be the appropriate choice.
SECOND-LINE AGENTS
Anticholinergic medications, such as trihexyphenidyl (Artane) and benztropine (Cogentin), were the mainstays of therapy before levodopa became available. However, these agents are not superior for tremor and are often associated with distressing adverse effects, such as dry mouth, blurred vision, and exacerbation of constipation and cognitive dysfunction.
Amantadine (Symmetrel). This agent is thought by some experts to be effective for patients with mild symptoms who do not yet require levodopa or a dopamine agonist. However, amantadine does not effectively reduce symptoms in many patients, and it has been associated with hallucinations and peripheral edema, as well as with livedo reticularis, a benign skin discoloration. Amantadine is the only medication that effectively relieves dyskinesia.6
MAO-B inhibitors. Agents that selectively inhibit MAO-B are far less likely to cause the adverse drug and food interactions associated with nonselective (type A) monoamine oxidase inhibitors. Selegiline(Drug information on selegiline), available since 1989, has been reformulated in a new freeze-dried orally disintegrating form (Zelapar), which dissolves rapidly and is absorbed directly through the buccal mucosa.7 This allows once-daily administration with a lower dose than the older tablet or capsule form. Selegiline is approved as an adjunct to carbidopa/levodopa for patients who experience a loss of effectiveness with the latter therapy.
Rasagiline (Azilect) has recently been approved as monotherapy for mild PD and as an adjunct to levodopa for patients who are experiencing symptom fluctuations.8,9 This once-daily formulation is currently being investigated as a possible disease progression-slowing agent.
Both selegiline and rasagiline may interact with other medications. Concomitant use of either drug with antidepressants may be problematic or dangerous. Neither drug should be used within 14 days of administration of meperidine, tramadol, methadone(Drug information on methadone), or dextromethorphan(Drug information on dextromethorphan); neither drug should be used concomitantly with over-the-counter (OTC) cold and allergy remedies. Although the "cheese effect" of tyramine-containing foods is less likely to occur with MAO-B inhibitors, rasagiline carries a warning about this effect.
Catechol-O-methyltransferase (COMT) inhibitors. Attempts to address the short half-life of levodopa include concurrent administration of COMT inhibitors, which inhibit a degradative pathway of levodopa. The COMT inhibitors entacapone(Drug information on entacapone) (Comtan) and tolcapone(Drug information on tolcapone) (Tasmar) increase the effective plasma half-life of levodopa, allow enhanced delivery to the CNS, and prolong the efficacy of levodopa. Entacapone has been combined with levodopa and carbidopa in one tablet that is marketed as Stalevo.
Cholinesterase inhibitors (ChEIs). Patients with cognitive impairment may benefit from ChEIs. A review of data on ChEI therapy for cognitive impairment in PD concluded that rivastigmine(Drug information on rivastigmine) (Exelon) and donepezil(Drug information on donepezil) (Aricept) are modestly beneficial.10 However, of the ChEIs, only rivastigmine has been examined in a large trial of patients with PD and dementia.11 Although it was modestly effective in some patients, it was also associated with nausea, vomiting, and increased tremor. It was recently approved for the treatment of mild to moderate dementia in patients with PD. A new patch form of rivastigmine that may cause fewer adverse effects will soon be available.
Coenzyme Q10 (CoQ10). Many patients inquire about CoQ10, an OTC supplement that has received a great deal of attention based on the results of one well-designed but small study.12 The study demonstrated apparent slower progression of early PD in patients who were otherwise untreated for 16 months. The outcome reached statistical significance only at the highest dosage studied (400 mg/tid). The results of this study require corroboration. A larger trial that has been organized and is being funded by the NIH has not yet begun. Pending additional results, we neither encourage nor discourage the use of this agent by our patients.
