Currently, all pharmacologic treatments of Parkinson disease are based on attempts at eliminat- ing or minimizing symptoms. There are no neuroprotective or disease-modifying pharmacologic therapies available. The medications each have significant adverse effects, making treatment frus- trating. The medications do serve to improve and maintain function, thus allowing patients to continue in their daily activities with as little impairment as possible. Since all medications have significant adverse effects and seem to have a finite period of peak effectiveness, initiation of therapy should be postponed until symptoms become significant or troubling to the patient. If a patient has a minimal resting tremor in one hand and does not complain of any impaired func- tion of that hand, there is little reason to initiate therapy.
People respond differently to the Parkinson disease drugs, so finding the right medication at the optimal dose for each individual takes time and patience. As the disease progresses, it is nec- essary to increase the dosage, and sometimes it is necessary to combine medications. There are six important classes of drugs used to treat Parkinson symptoms as well as one approved surgical option.
Levodopa. Levodopa or l-dopa remains the most commonly prescribed medication and the gold standard for the treatment of Parkinson disease. It was introduced in 1967 and held promise as a cure for Parkinson disease. It works simply by replacing the depleted dopamine with levodopa. Unfortunately, the adverse effects and waning effectiveness over time have limited its usefulness. Despite these limitations, l-dopa is the most important medication and is effective in nearly all patients with idiopathic Parkinson disease. In fact, because it is so highly effective, it is often employed in diagnosing the condition in addition to its use in treatment.
Most of the adverse effects are related to the toxicity of levodopa in periphery, especially gastrointestinal tract. This has resulted in the necessity to combine levodopa with carbidopa, a
Table 7.9 • Differential Diagnosis of Parkinson Disease
n Idiopathic Parkinson disease
n Drug-induced Parkinsonism
n Vascular Parkinsonism
n Essential tremor
n Normal pressure hydrocephalus
n Parkinson-plus syndromes
n Progressive supranuclear palsy
n Multiple system atrophy (Shy–Drager syndrome)
n Corticobasal degeneration
n Dementia with Lewy bodies
compound that inhibits the peripheral conversion of levodopa to its active metabolite, therefore assuring that a greater percentage of the levodopa crosses the blood–brain barrier, minimizing the gastrointestinal side effects.
Levodopa/carbidopa (Sinemet) is highly effective in helping with the motor symptoms of Par- kinson disease. In most cases, it should be the initial medication prescribed when it is determined that the functional status is such that medication should be utilized. The usual starting dose is levodopa/carbidopa (Sinemet) 25/100 three times daily with modifications based on effect and side effects. Over time, there is an inevitable need to increase the dose. There are multiple formu- lations with a variety of combinations; there is a controlled release formulation of levodopa/car- bidopa (Sinemet) that is particularly useful when taken at night and often serves to diminish the morning stiffness. Chronic use of l-dopa in Parkinson disease does not enhance the progression of disease pathology as far as can be determined by observations with substancia nigra neuronal counts and Lewy body densities (Parkkinen et al., 2011).
The most commonly encountered side effect of l-dopa is gastrointestinal intolerance with nausea, vomiting, and anorexia. A more complete list of the side effects can be found in Table 7.10. The first step in attempting to improve these symptoms is to take them with food.
The one caution here is that the absorption of levodopa is greatly reduced in the presence of a high-protein meal. Therefore, it is best taken with light meals that are not high in protein content. If nausea persists, taking extra doses of Carbidopa helps prevent dopamine effects in the periphery. Finally, one might have to lower the dose and very slowly taper the dose up to effectiveness.
Patients who develop compulsive behavior will need to undergo a dose reduction with the possible addition of a second agent. Daytime sleepiness is often a symptom of depression or of poor nighttime sleep. Attempts at treating depression and improving the sleep hygiene should be tried. Melatonin and modafinil are not recommended.
The on–off phenomenon is a frightening but very common occurrence in patients after long- term treatment with l-dopa. It is characterized by unpredictable, abrupt fluctuations in motor state from when the medication is effective and symptoms are controlled (“on”) to when par- kinsonian symptoms worsen (“off”). These motor complications can be treated by adding a do- pamine agonist, monoamine oxidase-B (MAO-B) inhibitor, or catechol-O-methyltransferase (COMT) inhibitor.
Table 7.10 • Levodopa/Carbidopa Adverse Effects
Nausea and vomiting Hallucinations Paranoia Nightmares Compulsive behavior Drowsiness/daytime sleepiness
Long-term use results in dyskinesias (involuntary movements) On–off phenomenon
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As mentioned earlier, in most patients there is a wearing off in the effectiveness that occurs over time. This is initially managed with increasing the dose and dose frequency of the medica- tion. Eventually, however, other side effects make further dose increases impossible, and other therapies should be employed.
Dopamine Agonists. Dopamine agonists directly stimulate dopamine receptors. They mainly work to reduce motor complications, and work best when they are not combined with any other drug. They are, however, often added to levodopa/carbidopa in an effort to improve the overall function and reduce the “on–off” phenomenon. There are several dopamine agonists on the market, including Ropinirole (Requip, Ropark, Adartrel), Bromocriptine (Parlodel, Cycloset), Pergolide (Permax, Pergotoliderived), Pramipexole (Mirapex), and Apomorphine (Apokyn).
Each of the above medications is used orally with the exception of Apomorphine, which is used subcutaneously. While they can be effective when used alone, they are often used early in an effort to delay the need for l-dopa. They are also effective when used in combination with l-dopa when motor effects and side effects become more problematic.
As with all medications used to treat Parkinson disease, these drugs have particularly trouble- some adverse effects, including psychosis, edema, nausea and vomiting, fibrosis, and orthostatic hypotension. The side effects can sometimes be managed with changing the time and frequency of administration or by trying a different dopamine agonist. In the case of edema and orthostatic hypotension, patients should be educated on ways to reduce the impact of the effect. Psychosis and hallucinations are the adverse effect that most often results in having to abandon the dopa- mine agonists as a class in the treatment of that particular patient. Patients should be warned about the potential for dopamine agonists to cause impulse control disorder and excessive day- time somnolence. They should be informed of the implications of driving/operating machinery while on these medications.
Catecol-O-Methyltransferase Inhibitors. The COMT inhibitors are particularly useful in the treatment of Parkinson disease because they work by increasing the bioavailability of levodopa.
Metabolic reactions allow only about 1% of administered levodopa taken in pill form to reach the brain. Adding COMT inhibitors reduces the metabolic actions that break down levodopa, including inhibiting an enzyme that degrades the drug, which leads to more levodopa entering the brain. Clinical trials have shown that l-dopa works for a longer time in the presence of a COMT inhibitor (Waters, 2000).
The currently available COMT inhibitors include Entacapone (Comtan) and Tolcapone (Tas- mar). Entacapone is taken as a 200-mg tablet with each dose of levodopa/carbidopa, up to eight times per day. Tolcapone is taken as 100 to 200 mg three times a day. Liver function tests should be done every 2 to 4 weeks, and the drug should be discontinued if there is no benefit after 3 weeks of therapy.
There is a combination drug, Stalevo, which includes levodopa, carbidopa, and entacapone.
There are multiple combinations available, with dosing recommended at up to eight times per day.
The adverse effects of this class of drugs include psychosis, diarrhea, abdominal pain, dry mouth, urine discoloration (entacapone), and orthostatic hypotension. In addition, when first introduced there may be accumulation of levodopa, resulting in dyskinesias. This should prompt the clinician to reduce the dose of l-dopa.
Monoamine Oxidase-B Inhibitors. Selegiline and Resagiline are the primary MAO-B inhibitors currently on the market. Monamine oxidase is one of the enzymes involved in the breakdown of dopamine, so these drugs are thought to work by preventing the metabolism of dopamine. Initially, these drugs were thought to slow the progression of the disease. These claims have not been substantiated, and this class is used primarily as adjuncts to levodopa/carbidopa.
The adverse effects of the MAO-B inhibitors include insomnia, hallucinations, and orthostatic hypotension.
Amantadine. A randomized, double-blind trial of amantadine in patients with Parkinson disease and dyskinesia showed a 45% reduction in dyskinesia with amantadine compared with placebo. However, the benefit lasted for less than 8 months, and withdrawal of amantadine caused a 10% to 20% rebound increase in the presence of dyskinesias (Thomas et al., 2004). In addition, amantadine is often not well tolerated, limiting its usefulness. The recommended dose is 100 mg twice daily.
Anticholinergics. Anticholinergic drugs appear to improve motor function in Parkinson disease, but effects on individual outcomes are inconsistent across studies (Holloway & Frank, 2004). The primary symptom that anticholinergic drugs appear to affect is tremor. Patients with tremor-predominant Parkinson disease who wish to delay the initiation of l-dopa would be reasonable individuals to try anticholinergics. The side effects include dry mouth, somnolence, and delirium.
Deep Brain Stimulation. Neurosurgical interventions such as deep brain stimulation (DBS) have essentially replaced all other previous forms of surgery, including pallidotomy. The procedure involves placing an electrode in the subthalamic nucleus bilaterally. The electrode is set to provide stimulation aimed at improvements in motor function. While the mechanism of action is not fully known, DBS is thought to result in functional blockade of the site implanted.
Patients who have undergone DBS often have more “on” time and fewer dyskinesias. Although there are many instances where DBS has resulted in remarkable and long-lasting improvements, there is considerable cost as well as potential morbidity associated with this procedure. Therefore, selecting the ideal candidate is the key to getting the best results. Patients with cognitive deficits, dementia, atypical Parkinson disease, or significant psychiatric problems are poor candidates for this procedure. Younger age, shorter disease duration, and good preoperative response to levodopa are good predictors of favorable outcomes (Pahwa et al., 2006).
Stem Cell Therapy
Genetic therapies like stem cell therapy hold out hope in diseases like Parkinson disease that have a genetic and cellular basis. There is great hope that such therapies might result in true disease- modifying or curative options for the future.
Alternative Therapies
Ayurvedic medicine—Parkinson disease symptoms are mentioned in an ancient text under the name Kampavata. Ayurvedic medicine is a comprehensive system placing equal emphasis on diet, exercise, meditation, massage, and herbal remedies. One such herb, Mucuna pruriens, is
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gaining attention in conventional circles as its effects mimic synthetic l-dopa, with fewer side effects.
Broad beans—Australian researchers discovered that broad beans are also an extremely effec- tive natural source of levodopa. The highest concentration of levodopa is found in the pod, so they are most effective when consumed whole.
St.John’s Wort—Dopamine influences positive feelings in the brain, and since dopamine levels are low in patients with Parkinson disease, depression is often a symptom. St. John’s Wort is a herb that has been used in Europe for many years. It has been proven to be effective in alleviating depression and insomnia, but should be used with caution in patients on SSRIs (Selective sero- tonin reuptake inhibitor).
Botulinum toxin A—This is a bacterium that causes food poisoning (botulism), but has proven to be effective in reducing hand, head, and voice tremors when used in a weak solution (Trosch
& Pullman, 1994).
Coenzyme Q10 (CoQ10)—This has been shown to have an effect on the symptoms of Parkin- son disease; however, it is unclear whether it actually slows the disease or simply temporarily alle- viates symptoms. The drawback is the massive dose required. The effective dose is approximately 1,200 mg/day, well above the 60 to 90 mg recommended by many alternative therapy advocates (Suchowersky et al., 2006).
Acupuncture—Used for centuries in China to correct energy disturbances in the body, acu- puncture has become a popular method of treatment for Parkinson sufferers in other parts of the world. So far, there are no placebo-controlled studies that show acupuncture can treat the motor control symptoms of the disease, but there is some evidence that it can assist with sleep distur- bances. There is much anecdotal evidence to suggest that it may be effective in increasing feelings of well-being and relaxation.
Massage—While not treating the symptoms directly, it can help reduce some of the discomfort associated with muscle stiffness that is commonly experienced by patients.
Although there may be no cure, there are several Parkinson disease drugs that will improve the quality of life. These drugs do not work to cure the disease, but rather to alleviate symptoms. A lot of research is still underway, in the hope of developing more helpful drugs, and better yet, maybe a cure.
Additional Treatment Strategies
The first step in the clinical management of Parkinson disease is a full discussion of the diagnosis with the patient and family. They should be informed that Parkinson disease is a progressive disease and that most people with this disease have near-normal life expectancy. Patients should be encouraged to participate in physical therapy, have a home exercise program, and engage in a multidisciplinary team approach to the maintenance of functional independence.
When functional status and symptom severity worsen to the point where treatment is indi- cated, the clinician should consider drug therapy. The efficacy and side effect profile of the drugs along with the patient’s age, cognitive status, and degree of motor disability as well as the drug cost should be taken into account.
The clinical trial literature on this subject suggests that levodopa treatment in early Parkinson disease results in greater motor improvement and performance, but also more motor fluctua- tions and dyskinesias, whereas initial treatment with a dopamine receptor agonist results in less symptom relief, but with a lower incidence of fluctuations and dyskinesias. The practice param- eter from the American Academy of Neurology (AAN) considers either levodopa or a dopamine
receptor agonist to be a reasonable choice for patients with Parkinson disease who require the ini- tiation of dopaminergic treatment (Miyasaki et al., 2002). In either case, it is best to start with low doses to gauge the effect of the drug and the patient’s ability to tolerate the drug. In certain subsets of patients, other therapies may be considered first line. For instance, in the patient with tremor- predominant disease who can tolerate the anticholinergic side effects, these drugs may be helpful.