Am Fam Physician. 2007 Apr 1;75(7):1045-1048.
What are the effects of drug treatments in persons with early stage Parkinson's disease?
Immediate-Release Levodopa (Compared with Placebo or No Treatment [the term levodopa used throughout the article refers to a combination of levodopa and a peripheral decarboxylase inhibitor])
One randomized controlled trial (RCT) in persons with early Parkinson's disease found that levodopa was effective in treating motor impairments and disability compared with placebo. This is supported by many years of clinical experience, which has led to the consensus that levodopa is effective for early Parkinson's disease, but that long-term use causes dyskinesias and motor fluctuations that are irreversible. Two RCTs in persons with early Parkinson's disease found no significant difference between immediate- and modified-release levodopa in dyskinesia, motor fluctuations, and motor impairment after five years. The first RCT found no significant difference in the Unified Parkinson's Disease Rating Score activities of daily living scores. The second RCT found that modified-release levodopa improved the activities of daily living score and was better tolerated than immediate-release levodopa. (Categorization based on evidence and consensus opinion.)
UNLIKELY TO BE BENEFICIAL
Modified-Release Levodopa (No More Effective Than Immediate-Release Levodopa)
Two RCTs in persons with early Parkinson's disease found no significant difference between modified- and immediate-release levodopa in dyskinesia, motor fluctuations, and motor impairment after five years. The first RCT found no significant difference between modified- and immediate-release levodopa in Unified Parkinson's Disease Rating Score activities of daily living scores. The second RCT found that modified-release levodopa improved the activities of daily living score and was better tolerated than immediate-release levodopa.
TRADE-OFF BETWEEN BENEFITS AND HARMS
Dopamine Agonists Plus Levodopa (Reduced Dyskinesia Compared with Levodopa Alone, but Increased Disability)
One systematic review and additional RCTs provided evidence that dopamine agonists plus levodopa reduced dyskinesia or motor fluctuations compared with levodopa alone. One small additional RCT found no significant difference between lisuride plus levodopa and levodopa alone in motor complications at five years. However, some of the RCTs found that levodopa alone improved motor impairments and disability compared with dopamine agonists plus levodopa. One RCT found that pramipexole plus rescue levodopa increased somnolence and hallucinations compared with levodopa alone.
Dopamine Agonists (Reduced Dyskinesia and Motor Fluctuations Compared with Levodopa, but Were Associated with Increased Treatment Withdrawal and Poorer Motor Scores)
One systematic review and one subsequent RCT (published only as an abstract) found that dopamine agonist monotherapy (bromocriptine or pergolide) reduced the incidence of dyskinesias and motor complications compared with levodopa monotherapy. However, the review and the subsequent RCT found that dopamine agonist monotherapy was associated with greater motor impairment than levodopa monotherapy and an increased risk of treatment withdrawal.
We found one systematic review in persons with early Parkinson's disease (some of whom were taking levodopa or other antiparkinsonian drugs) and one subsequent RCT in persons not taking levodopa or other antiparkinsonian drugs. The review and the subsequent RCT found that monoamine oxidase-B (MAO-B) inhibitors improved the symptoms of Parkinson's disease, reduced the need for levodopa, and reduced motor fluctuations compared with placebo or no MAO-B inhibitor treatment. However, the review found an overall increase in adverse events with MAO-B inhibitors compared with placebo or no MAO-B inhibitor treatment. Although one RCT identified by the systematic review found evidence of increased mortality in persons treated with selegiline, pooled analysis of all available trials by the review did not find a significant increase in mortality. We found insufficient evidence to compare MAO-B inhibitors versus other drug classes in early Parkinson's disease.
What are the effects of adding other treatments in persons with motor complications from levodopa?
TRADE-OFF BETWEEN BENEFITS AND HARMS
Adding a COMT Inhibitor to Levodopa
One systematic review found that in persons taking levodopa, the catechol O-methyl-transferase (COMT) inhibitors entacapone and tolcapone reduced “off” time, reduced levodopa dose, and modestly improved motor impairment and disability. Tolcapone was withdrawn from the European market and its use was restricted in other countries because of three cases of fatal hepatic toxicity. It has recently been reintroduced for use in those who fail on entacapone, provided that stringent liver function test monitoring is performed.
Adding a Dopamine Agonist to Levodopa
Systematic reviews found that in persons with response fluctuations to levodopa, certain dopamine agonists reduced off time, improved motor impairment and activities of daily living, and reduced levodopa dose, but it increased dopaminergic adverse effects and dyskinesia.
What are the effects of surgery in persons with later Parkinson's disease?
TRADE-OFF BETWEEN BENEFITS AND HARMS
Two RCTs identified by two systematic reviews found that unilateral pallidotomy improved motor examination and activities of daily living compared with medical treatment. There is a high incidence of adverse effects with pallidotomy. One RCT found insufficient evidence to assess the effects of pallidotomy compared with those of pallidal deep brain stimulation. One RCT found that unilateral pallidotomy was less effective than bilateral subthalamic stimulation in improving parkinsonian symptoms.
Pallidal Deep Brain Stimulation
We found no RCTs comparing pallidal deep brain stimulation versus medical treatment. One RCT found insufficient evidence to assess the effects of pallidal deep brain stimulation compared with those of pallidotomy. Adverse effects are probably less common with pallidal deep brain stimulation than with pallidotomy. Three RCTs provided insufficient evidence to assess the effects of pallidal deep brain stimulation compared with those of subthalamic nucleus deep brain stimulation.
Subthalamic Nucleus Deep Brain Stimulation
Three systematic reviews found no RCTs of sufficient quality comparing subthalamic nucleus deep brain stimulation versus medical treatment. Three RCTs provided insufficient evidence to assess the effects of subthalamic nucleus deep brain stimulation compared with those of pallidal deep brain stimulation. One RCT found that bilateral subthalamic stimulation was more effective than unilateral pallidotomy in improving parkinsonian symptoms.
One systematic review found no RCTs of subthalamotomy in persons with Parkinson's disease.
Thalamic Deep Brain Stimulation
Two systematic reviews identified no RCTs comparing thalamic deep brain stimulation with medical treatment. One RCT found that thalamic deep brain stimulation improved functional status and caused fewer adverse effects than thalamotomy.
Three systematic reviews found no RCTs comparing thalamotomy with medical treatment. One RCT found that thalamic deep brain stimulation improved functional status and caused fewer adverse effects than thalamotomy. Case series found that, in 14 to 23 percent of persons, thalamotomy was associated with permanent complications, including speech disturbance, apraxia, or death.
What are the effects of nursing and rehabilitation treatments in persons with Parkinson's disease?
LIKELY TO BE BENEFICIAL
Parkinson's Disease Nurse Specialist Interventions
Two RCTs provided limited evidence of the benefits of Parkinson's disease nurse specialist interventions.
One systematic review provided insufficient evidence to assess the effects of occupational therapy in later Parkinson's disease.
Two systematic reviews and two subsequent RCTs found insufficient evidence of the effects of physiotherapy in Parkinson's disease.
Speech and Language Therapy for Speech Disturbance
One systematic review provided insufficient evidence to assess the effects of speech and language therapy for speech disturbance in later Parkinson's disease.
Swallowing Therapy for Dysphagia
One systematic review identified no RCTs of swallowing therapy for dysphagia.
Idiopathic Parkinson's disease is an age-related neurodegenerative disorder, which is associated with a combination of asymmetric bradykinesia, hypokinesia, and rigidity, and is sometimes combined with rest tremor and postural changes. Clinical diagnostic criteria have a sensitivity of 80 percent and a specificity of 30 percent (positive likelihood ratio [LR] of 1.1; negative LR of 0.67) compared with the preferred method of diagnosis at autopsy.1 The primary pathology is progressive loss of cells that produce the neurotransmitter dopamine from the substantia nigra in the brainstem.
Treatment aims to replace or compensate for the lost dopamine. A good response to treatment supports, but does not confirm, the diagnosis. Several other catecholaminergic neurotransmitter systems also are affected in Parkinson's disease. There is no consistent definition of early- and late-stage Parkinson's disease. In this chapter, we consider persons with early-stage disease to be those who have not yet developed motor complications associated with long-term levodopa treatment (such as dyskinesias and motor fluctuations, also known as “on/off ” fluctuations). Late-stage Parkinson's disease is taken to mean that motor complications of long-term levodopa treatment are present.
Incidence and Prevalence
Parkinson's disease occurs worldwide, with equal incidence in both sexes. In 5 to 10 percent of persons who develop Parkinson's disease, the condition appears before 40 years of age (young onset), but the mean age of onset is about 65 years. Overall, age-adjusted prevalence is 1 percent worldwide and 1.6 percent in Europe, rising from 0.6 percent at 60 to 64 years of age to 3.5 percent at 85 to 89 years of age.2,3
The cause of Parkinson's disease is unknown. It may represent different conditions with a final common pathway. Persons may be affected differently by a combination of genetic and environmental factors (e.g., viruses, toxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine, well water, vitamin E, smoking).4–7 First-degree relatives of affected persons may have twice the risk of developing Parkinson's disease (17 percent lifetime chance) compared with persons in the general population.8–10 However, purely genetic varieties probably affect a small minority of persons with Parkinson's disease.11,12 The parkin gene on chromosome 6 may be associated with Parkinson's disease in families with at least one member with young-onset Parkinson's disease, and multiple genetic factors, including the tau gene on chromosome 17q21, may be involved in idiopathic late-onset disease.13,14
Parkinson's disease is currently incurable. Disability is progressive and associated with increased mortality (relative risk [RR] of death compared with matched control populations ranges from 1.6 to 3.0).15 Treatment can reduce symptoms and slow progression, but it rarely achieves complete control. The question of whether treatment reduces mortality remains controversial.16 Levodopa seemed to reduce mortality in the United Kingdom for five years after its introduction, before a “catch-up” effect was noted and overall mortality climbed toward previous levels. This suggests a limited prolongation of life.17
An Australian cohort study followed 130 persons treated for 10 years.18 The standardized mortality ratio was 1.58 (P <.001). At 10 years, 25 percent had been admitted to a nursing home, and only four were still employed. The mean duration of disease until death was 9.1 years. In a similar Italian cohort study conducted over eight years, the RR of death for affected persons compared with healthy controls was 2.3 (95% confidence interval [CI], 1.60 to 3.39).19 Age at initial census date was the main predictor of outcome (RR of death for persons younger than 75 years was 1.80; 95% CI, 1.04 to 3.11; and RR of death for persons older than 75 years was 5.61; 95% CI, 2.13 to 14.80).
editor's note: Lisuride is not available in the United States.
search date: August 2005
Adapted with permission from Clarke CE, Moore AP. Parkinson's disease. Clin Evid 2006;16:531–5.
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This is one in a series of chapters excerpted from Clinical Evidence, published by the BMJ Publishing Group, London, U.K. The medical information contained herein is the most accurate available at the date of publication. More updated and comprehensive information on this topic may be available in future print editions of Clinical Evidence, as well as online athttp://www.clinicalevidence.com (subscription required). Those who receive a complimentary print copy of Clinical Evidence from United Health Foundation can gain complimentary online access by registering on the Web site using the ISBN number of their book.
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