Conventional Medical Treatment
For decades, the conventional standard of care for Parkinson's disease has focused on symptomatic relief. Pharmaceutical treatments for Parkinson's accomplish this by either increasing dopamine levels or mimicking its action. While conventional therapeutics are indispensable for improving quality of life in Parkinson's patients, they do not provide fundamental neuroprotection or support for neuronal mitochondria. Thus, mainstream pharmaceutical treatments cannot be expected to address the underlying cause of disease progression—neurodegeneration.
Treatment with L-DOPA causes patients to be less responsive to the medication over time and can evoke a number of adverse side effects. However, careful dosing strategies, and utilization of ancillary medications may help limit side effects and maintain the effectiveness of conventional pharmaceutical therapies.
Pharmaceutical treatment of Parkinson's disease symptoms is usually initiated when the patient has already developed some disability for which he/she needs to be treated. This is typically referred to as the initial stage of therapy. The primary goal of treatment during the initial stage is to limit symptoms arising from progression of the disease. However, with time, adverse side effects of the medications arise, which leads into the secondary treatment stage. The aim of the secondary treatment stage is to reduce Parkinson's symptoms, as well as counterbalance the adverse side effects of levodopa.
Since its FDA approval in 1970, Levodopa (L-DOPA) has been a staple for the management of Parkinson's disease symptoms.
L-DOPA (the precursor to dopamine) is metabolized into dopamine in the body by an enzyme called aromatic L-amino acid decarboxylase (AADC). Dopamine itself cannot pass through the protective blood-brain barrier, but L-DOPA can. When L-DOPA is administered orally, a small percentage passes into the brain and is converted into dopamine. This temporary increase in dopamine levels within the brain offers relief of Parkinson's disease symptoms for a short period.
However, the body presents many obstacles that limit the efficiency of oral L-DOPA therapy. First, AADC exists outside the brain as well, which means that the majority of orally administered L-DOPA will be converted into dopamine peripherally (not in the central nervous system). Therefore, L-DOPA is typically administered with an inhibitor of peripheral AADC, called carbidopa. Carbidopa (or another AADC inhibitor) helps preserve orally administered L-DOPA for conversion to dopamine in the brain.
Regrettably, the use of orally administered L-DOPA over time results in diminished production of endogenous (naturally occurring within the body) L-DOPA. L-DOPA therapy is further complicated by the development of movement disorders called dyskinesias after 5–10 years of use in most cases.
Dyskinesias are movement disorders in which neurological discoordination results in uncontrollable, involuntary movements. This discoordination can also affect the autonomic nervous system, resulting in, for example, respiratory irregularities.82 Dyskinesia is the result of L-DOPA-induced synaptic dysfunction and inappropriate signaling between areas of the brain that normally coordinate movement, namely the motor cortex and the striatum.83
With long-term L-DOPA use (usually after about five years), responsiveness declines and dose adjustment is often necessary. This phenomenon leads to fluctuations in the effectiveness of L-DOPA therapy that cause the patient to experience dyskinesia as the post-dose concentration of L-DOPA peaks, and rapid reversion to severe Parkinsonism towards the end of the dosing period.
Several strategies exist for enhancing L-DOPA effectiveness. Some of these include varying combinations of L-DOPA and other medications discussed in this section as well as altering dose timing and amount. Other strategies can involve "rest periods" or "drug holidays" during which the patient abstains from L-DOPA for a short time; as little as skipping a single dose each day may help lessen the damage caused by oxidation products of L-DOPA metabolism and maintain dopamine receptor sensitivity. A patient should never adjust their L-DOPA dose without close supervision by their physician.
Other strategies for stabilizing dopamine levels include combining L-DOPA with inhibitors of enzymes that breakdown dopamine. Medications of this type include monoamine oxidase-B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors. By combining L-DOPA with COMT and/or MAO-B inhibitors, a physician may be able to reduce the dose of L-DOPA required to relieve symptoms, and widen dose intervals, which is more convenient for the patient.
There are a variety of ways that pharmaceuticals can be combined to deliver optimal effects in each Parkinson's case, but the needs of each patient may vary widely. Therefore, patients should always consult an experienced physician to discuss medication combinations that may be ideal for their unique situation.
L-DOPA can produce several adverse side effects, including:
- Gastrointestinal discomfort (taking L-DOPA with low protein snacks may help avoid stomach upset)
- Breathing disturbances
- Hair loss
- Extreme emotional variability with prevalent anxiety
- Vivid dreams
- Impaired social behavior
- Excessive libido
- Compulsive behavior (ie, reckless gambling)
L-DOPA-induced elevations in homocysteine, a potentially harmful amino-acid derivative, are another major concern for Parkinson's patients. High levels of homocysteine have been implicated in various cardiovascular diseases, including cerebral small vessel disease, as well as brain atrophy.84,85 A comprehensive review of 16 studies found that elevated homocysteine was associated with dementia and markers of neurodegeneration in patients with Parkinson's patients.86
Parkinson's disease patients taking L-DOPA should read Life Extension's “Homocysteine Reduction” protocol and strive to maintain homocysteine levels of less than 7–8 µmol/L.
L-DOPA Drug Holidays
Regular, chronic use of L-DOPA causes dopamine receptors within the brain to become less sensitive, leading to the eventual need for increased dosages of L-DOPA. Research suggests taking a "drug holiday" from L-DOPA may re-sensitize dopaminergic receptors and lower the patient’s L-DOPA requirements, or at least prevent the need for increasing L-DOPA in the near future. In a three-year study, 15 Parkinson's patients were submitted to a seven-day L-DOPA drug holiday. Within the first six-months following the drug holiday, symptoms improved dramatically, and all of the study subjects were able to maintain a L-DOPA dose regimen of 50–70% of their pre-holiday dose for the entire three-year period.87
Despite these promising results, there are serious risks associated with stopping L-DOPA therapy, one of which is neuroleptic malignant syndrome, a potentially life-threatening situation. Therefore, a drug holiday should only be initiated under the close supervision of a physician. However, at least one study suggests use of amantadine, another drug used to alleviate Parkinson's symptoms, during an L-DOPA drug holiday may limit the severity of side effects associated with stopping L-DOPA therapy. In this study, 12 Parkinson's patients were submitted to a three-day L-DOPA drug holiday, and during that time they were given I.V. infusions of amantadine. The subjects were then started back on the pre-holiday L-DOPA dose and symptomatic improvements lasting up to four months were noted.88
Another method used to restore dopaminergic signaling in Parkinson's disease is medicating with a dopamine agonist. A dopamine agonist is a drug containing a molecule that binds to and activates dopamine receptors, similar to dopamine itself, thus compensating for low dopamine levels. Dopamine agonists are often used in younger patients, or in very early Parkinson's disease.
Research comparing the results of initial therapy with a dopamine agonists or L-DOPA is conflicting. Some studies suggest that initiating therapy with a dopamine agonist may delay the onset of dyskinesias as the disease progresses, while some seem to indicate that this may not be the case. Other studies suggest initial dopamine agonist therapy delivers results similar to those seen in L-DOPA plus COMT inhibitor therapy.89 Results from a 14-year follow up study found that initial therapy with a dopamine agonist offered no greater benefit over standard L-DOPA therapy in the long term.90
Dopamine agonists pose a greater risk of serious side effects than L-DOPA and are therefore not as tolerable for some patients. Some side effects of dopamine agonists include:
- Orthostatic hypotension (low blood pressure upon standing)
- Increased orgasmic intensity
- Weight loss
- Unusual tiredness or weakness
- Dizziness or fainting
- Twitching, twisting, or other unusual body movements
- Pathological addiction and compulsive behavior (ie, hyper-sexuality, gambling)
Selegiline and Rasagiline
Selegiline is a MAO-B inhibitor that, due to its unique chemical structure, also exerts other neuropharmacological actions via its metabolites. By blocking the breakdown of dopamine, selegiline helps compensate for the diminished production of dopamine in Parkinson's disease. This can lead to symptomatic improvement, especially in early-stage Parkinson's.
Numerous clinical trials have confirmed the efficacy of selegiline alone and in combination with L-DOPA in early Parkinson's disease.91-93 One study showed that selegiline was highly effective if initiated within five years of Parkinson's disease diagnosis, but less effective if initiated 10 years or more after diagnosis.91
Selegiline exerts a number of other benefits as well, including maintenance of whole-brain blood flow in depressed Parkinson's disease patients.94 Moreover, selegiline may reduce the formation and toxicity of alpha-synuclein aggregates.95
Rasagiline is a newer generation medication based upon selegiline. Laboratory studies suggest that, in addition to functioning very similarly to selegiline, rasagiline may exert a greater neuroprotective effect.96
Rasagiline was superior to placebo in slowing progression of Parkinson's disease in a cohort of 1,176 early-stage patients. In this study, subjects receiving rasagiline were less likely than those taking placebo to need additional anti-Parkinson drugs to manage symptoms.97 More trials need to be conducted to determine if rasagiline is significantly more effective than selegiline for treating Parkinson's disease.
Selegiline is available via prescription in a clinically studied transdermal patch called Emsam. Selegiline and rasagiline may cause dizziness, dry mouth, sleeplessness, and an overall stimulating effect.