Research Insights

The comparative effects of medical therapies for Parkinson’s Disease

Horn, S. & Stern, MB (2004) The comparative effects of medical therapies for Parkinson’s Disease , 2004 Oct 12;63(7 Suppl 2):S7-12

This article looks at medical therapies for PD divided into three different phases, 1. therapy to slow progression of the disease, 2. Treatment of early PD, and 3. treatment of advanced PD. Medications to slow PD A neuroprotective (a treatment that "might modify the course of PD by interfering with the underlying disease process.") agent has not been identified for PD for many reasons (e.g. not knowing the cause of PD, variability in symptoms among patients, etc.) but many have shown promise. Selegiline (Eldepryl), is a monoamine oxidase inhibitor (selectively inhibits monoamine oxidase type B; MAO-B helps break down dopamine; inhibiting it prolongs the action of dopamine in the brain) that has been studied as a neuroprotective agent for PD. The results on Selegiline are mixed. A large, "double-blind, placebo-controlled trial by the Parkinson’s Study Group" (PSG, 1993) looked at how much time it took for patients taking and not taking the drug to reach disability and their need for levodopa. They found that patient’s treated with Selegiline reached disability at "a slower rate" and received some symptom relief from the medication. Other studies (PSG, 1996) mentioned in the article found that patients taking Selegiline had equal levels of disability in the long term as compared to patients that did not take the drug. It is also notable that experimental and animal studies have shown some protective factors for this medication. Coenzyme Q10 (CoQ) is a strong antioxidant (Agents that inhibit or neutralize potentially harmful compounds known as free radicals. Free radicals are produced during metabolic activity. High levels of free radicals may eventually lead to impaired functioning and destruction of neurons and other bodily cells. Certain antioxidants are thought to neutralize free radicals before cellular damage occurs). It has not been shown to have symptom relief effects for PD. A multicenter double-blind, placebo controlled study of 80 patients with early PD showed that patients taking 1,200 mg/day of CoQ were found to have less disability after 16 months of treatment as compared to lower doses of CoQ or placebo. Dopamine Agonists have also shown neuroprotective effects. One study (Whone, et al. 2003) looked at PET scans of PD patients over a 2 year period. The found that subjects initially treated with ropinirole (Requip) had "a diminished rate of decline" as compared to subjects taking levodopa. It is notable that there wasn’t a placebo group used for comparison in this study. Another study using SPECT showed slower decline on pramipexole (Mirapex) than the levodopa group.The consistent finding amongst all of these studies is that more research needs to be conducted on finding the cause of as well as neuroprotective agents for PD. Treatment of Early PD Treatment of PD usually begins when the patient is experiencing symptoms that are either socially or functionally disabling. The authors suggest that clinicians should take "age, most problematic symptom, functional status of the patient, co-morbid medical conditions, and cognitive state" into account when deciding on appropriate treatment for the patient with PD. Current medical treatments include "MAO inhibitors, anticholinergic medications, amantadine, DA agonists, and levodopa." There is a very informative table in this article that lists different information about each of the aforementioned classes of drug, including if it can be used as monotherapy or adjunctive therapy, common adverse events, and dosing information. As mentioned previously, the MAO inhibitor, Selegiline has shown modest benefit in treating symptoms of PD as has rasagiline, another MAO inhibitor. The authors cite multiple studies showing improvement in UPDRS ratings on either medication as compared to placebo-treated patients. The authors also suggest that the MAO inhibitors may also have antidepressant effects, which may improve some of the nonmotor symptoms of PD. Anticholinergic medications have also shown benefit in treating PD, especially tremor, but due to the adverse effects are limited in usage. Amantadine (Symmetrel; An antiviral drug used also in the treatment of Parkinson’s disease) typically is used to treat tremors in early PD. It is usually well tolerated but there are adjustments that need to be made for patients with renal impairment and all patients monitored for adverse events. Dopamine agonists (Pergolide, ropinirole, and pramipexole) were initially used to treat advanced PD but have shown benefits for early symptoms of PD. The authors suggest that recent research suggests DA agonists delay the onset of motor complications from levodopa therapy. The authors cite multiple studies suggesting that patients experienced improvement in motor symptoms and their ability to complete activities of daily living. Treatment of early symptoms of PD with levodopa has been controversial. Typically treatment for PD starts with a drug other than levodopa as it is has been hypothesized that levodopa is either neurotoxic or that it causes motor complications (e.g. dyskinesia). The authors cite a study from 1999 (Fahn) that looked at various dosages of levodopa administered for 9 months. Patients were then given the UPDRS after 2 weeks of medication washout and those treated with the highest dosage of levodopa showed the lowest UPDRS scores but also had a higher rate of dyskinesias. Treatment of Advanced PD As PD progresses patients taking medications for PD typically experience motor fluctuations (on/off, wearing off phenomenon, etc.) and dyskinesias. Patients may also experience nonmotor symptoms (dementia, hypotension) that limit the medications that they may take. Many of the medical treatments for advanced PD are used in combination with levodopa (adjunctive therapy). However, the long term benefits or weaknesses of adjunctive therapies are relatively unknown as most clinical trials of adjunctive therapies are only up to 6 months in duration. MAO inhibitors have shown benefit as an adjunctive therapy. Specifically the authors cited studies showing MAO inhibitors improved clinical assessment of functioning, motor functioning, reduced "off" time, and reduced dyskinesias. Adverse events include nausea and headache. The authors suggest that there are few differences between the available DA agonists in advanced PD. Typically the DA agonists reduce "off" time by 1-2 hours, improve UPDRS score, and reduce the necessary dose of levodopa. Adverse events typically include nausea, hallucinations, somnolence (Sleepiness, the state of feeling drowsy, ready to fall asleep), and orthostatic hypotension (A sudden decrease in blood pressure that occurs when the affected individual sits up or stands. In some cases, it may occur as a side effect of certain medications). Catechol-O-methyltransferase (COMT) inhibitors are a group of new medications considered adjunctive for PD that have been shown to reduce the "off" time for patients with PD. COMT inhibitors slow the body’s breakdown of levodopa in the brain. Adverse events include diarrhea, dyskinesias, insomnia, somnolence, and hallucinations. Additionally, tolcapone has a "black box warning because of several cases of liver failure associated with its use." Amantadine is another medication that has shown benefit for dyskinesias in advanced PD. Adverse events with this medication include dry mouth, constipation, confusion, and hallucinations. Again, the consistent finding in many of the studies mentioned is that the treatment of advanced PD continues to evolve and clinical trials need to be continued to evaluate their efficacy as well as adverse events.

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