Updates in the medical management of Parkinson disease
ABSTRACTMost, if not all, currently available drugs for Parkinson disease address dopaminergic loss and relieve symptoms. However, their adverse effects can be limiting and they do not address disease progression. Moreover, nonmotor features of Parkinson disease such as depression, dementia, and psychosis are now recognized as important and disabling. A cure remains elusive. However, promising interventions and agents are emerging. As an example, people who exercise regularly are less likely to develop Parkinson disease, and if they develop it, they tend to have slower progression.
KEY POINTS
- Parkinson disease can usually be diagnosed on the basis of clinical features: slow movement, resting tremor, rigidity, and asymmetrical presentation, as well as alleviation of symptoms with dopaminergic therapy.
- Early disease can be treated with levodopa, dopamine agonists, anticholinergics, and monoamine oxidase-B inhibitors.
- Advanced Parkinson disease may require a catechol-O-methyltransferase (COMT) inhibitor, apomorphine, and amantadine (Symmetrel). Side effects include motor fluctuations, dyskinesias, and cognitive problems.
EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE
Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.
A number of agents have been tested for neuroprotective efficacy:
Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.
Pramipexole, a dopamine agonist, has also been studied without success.
Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.
Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.
Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.
Rasagiline: Protective effects still unknown
A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.12 A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.
The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.
EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE
For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.
As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.
Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.
Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.13 Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.14–17
Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.18,19
Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.
Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.
Managing dyskinesias
Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.
Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.20,21
Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.
