The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, good practice point) are defined at the end of the "Major Recommendations" field.
Early Untreated Patients
The optimal time frame for onset of therapy has not been clearly defined. Once parkinsonian signs start to have an impact on the patient's life, initiation of treatment is recommended. For each patient, the choice between the numerous effective drugs available is based on a subtle combination of subjective and objective factors. These factors include considerations related to the drug (efficacy for symptomatic control of parkinsonism/prevention of motor complications, safety, practicality, costs, etc.), to the patient (symptoms, age, needs, expectations, experience, co-morbidity, socioeconomic level, etc.), and to his/her environment (drug availability according to national markets in the European Union, variability in economic and health insurance systems, etc.). However, based on the available level of evidence alone, two main issues are usually considered when initiating a symptomatic therapy for early Parkinson's disease (PD): the symptomatic control of parkinsonism, and the prevention of motor complications (see Table below).
Currently, there is no uniform proposal across Europe on initiating symptomatic medication for PD. Options include starting treatment with:
- Monoamine oxidase isoenzyme type B (MAO-B inhibitor), like selegiline or rasagiline (level A). The symptomatic effect is more modest than that of levodopa and (probably) dopamine agonists, but they are easy to administer (one dose, once daily, no titration).
- Amantadine or an anticholinergic (level B). The impact on symptoms is smaller than that of levodopa. Anticholinergics are poorly tolerated in the elderly and their use is mainly restricted to young patients.
- Levodopa, the most effective symptomatic antiparkinsonian drug (level A). After a few years of treatment, levodopa is frequently associated with the development of motor complications. As older patients are more sensitive to neuropsychiatric adverse reactions and are less prone to developing motor complications, the early use of levodopa is recommended in the older population (good practice point). The early use of controlled release (CR) levodopa formulations is not effective in the prevention of motor complications (level A).
- Orally active dopamine agonist. Pramipexole and ropinirole are effective as monotherapy in early PD, with a lower risk of motor complications than levodopa (level A). Older drugs like bromocriptine are supported by lower class evidence, giving a level B recommendation. However, there is no convincing evidence that they are less effective in managing patients with early PD. The benefit of agonists in preventing motor complications (level A, with data up to 5 years only) must be balanced with the smaller effect on symptoms and the greater incidence of hallucinations, somnolence, and leg edema, when compared with levodopa. Patients must be informed of these risks (e.g. excessive daytime somnolence is especially relevant to drivers). Younger patients are more prone to developing levodopa-induced motor complications, and therefore initial treatment with an agonist can be recommended in this population (good practice point). Ergot derivatives such as pergolide, bromocriptine, and cabergoline are not recommended as first-line medication because of the risk of fibrotic reactions. Subcutaneous apomorphine is not appropriate at this stage of the disease. The early combination of low doses of a dopamine agonist with low doses of levodopa is another option, although the benefits of such a combination have not been properly documented.
- Rehabilitation. Because of the lack of evidence of the efficacy of physical therapy and speech therapy at this stage of the disease, a recommendation cannot be made.
Table. Recommendations for the Treatment of Early PD
| |
Recommendation Level |
| Therapeutic Interventions |
Symptomatic Control of Parkinsonism |
Prevention of Motor Complications |
Levodopa
Levodopa controlled release (CR)
Apomorphine
Bromocriptineb
Cabergolineb
Dihydroergocryptineb
Lisurideb
Pergolideb*
Piribedil
Pramipexole
Ropinirole
Selegiline
Rasagiline
Entacaponed
Tolcaponed
Amantadine
Anticholinergics
Rehabilitation
Surgery
|
Effective (level A)
Effective (level A)
Not useda
Effective (level B)
Effective (level B)
Effective (level A)
Effective (level B)
Effective (level A)
Effective (level C)
Effective (level A)
Effective (level A)
Effective (level A)
Effective (level A)
No recommendationc
No recommendationc
Effective (level B)
Effective (level B)
No recommendationc
Not used
|
Not applicable
Ineffective (level A)
Not useda
Effective (level B)
Effective (level A)
No recommendationc
Effective (level C)
Effective (level B)
No recommendationc
Effective (level A)
Effective (level A)
Ineffective (level A)
No recommendationc
No recommendationc
No recommendationc
No recommendationc
No recommendationc
No recommendationc
Not used
|
aSubcutaneous apomorphine is not used in early PD.
bPergolide*, bromocriptine, cabergoline and, precautionarily, other ergot derivates, cannot be recommended as a first-line treatment for early PD because of the risk of valvular heart disorder.
cNo recommendation can be made due to insufficient data.
dAs Catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone should always be given with levodopa. Due to hepatic toxicity, tolcapone is not recommended in early PD.
*Note from the National Guideline Clearinghouse (NGC): On March 29, 2007, Permax (pergolide) was withdrawn from the market in the U.S. and worldwide due to safety concerns of an increased risk of cardiovascular events. See the U.S. Food and Drug Administration (FDA) Web site for more information.
Adjustment of Initial Monotherapy in Patients without Motor Complications
Patients Not on Dopaminergic Therapy
If a patient has started on a monoamine oxidase isoenzyme B (MAO-B) inhibitor, anticholinergic, amantadine, or a combination of these drugs, a stage will come when, because of worsening motor symptoms, there is a requirement for:
- Addition of levodopa or a dopamine agonist (good practice point). Just like in de novo patients, at this stage, the choice between levodopa and an agonist again mainly depends on the impact of improving motor disability (better with levodopa) compared with the risk of motor complications (less with agonists) and neuropsychiatric complications (greater with agonists). In addition, there is the effect of age upon the occurrence of motor complications (more frequent in younger patients), and neuropsychiatric complications (more frequent in older and cognitively impaired patients). In general, dopaminergic therapy could be started with agonists in younger patients, whereas levodopa may be preferred in older patients (good practice point, see previous section).
Patients on Dopaminergic Therapy
Once receiving therapy with a dopamine agonist or levodopa, adjustments of these drugs will also become necessary over time because of worsening motor symptoms.
If on dopamine agonist therapy:
- Increase the dopamine agonist dose (good practice point). However, even when the dopamine agonist dose is increased over time, it cannot control parkinsonian symptoms for more than about 3 to 5 years of follow-up in most patients.
- Switch between dopamine agonists (level C).
- Add levodopa (good practice point).
If on levodopa:
- Increase the levodopa dose (good practice point).
- Add a dopamine agonist (good practice point), although the efficacy of adding an agonist has been insufficiently evaluated.
Patients with Persistent or Emerging Disabling Tremor
If a significant tremor persists despite usual therapy with dopaminergic agents or amantadine, the following treatment options exist for tremor at rest:
- Anticholinergics (good practice point: possibly useful, although no full consensus could be made). Cave: anticholinergic side effects, particularly cognitive dysfunction in older patients. (See the "Potential Harms" field.)
- Clozapine (level B). Because of safety concerns (see Part II of the guidelines on the treatment of psychosis), clozapine is not advised for routine use, but it is considered as an experimental approach for exceptionally disabled patients requiring specialized monitoring (good practice point).
- Beta-blockers (propranolol). Beta-blockers can be effective in both resting and postural tremor (level C). However, because of methodological problems, a Cochrane review found it impossible to determine whether beta-blocker therapy is effective for tremor in PD. Further studies are needed to judge the efficacy of beta-blockers in the treatment of tremor in PD (no recommendation can be made).
- Consider deep brain stimulation. Usually subthalamic nucleus stimulation, rarely thalamic stimulation (good practice point, see Part II of the guidelines).
Occupational, Physical, and Speech Therapy
Physical therapy, especially exercise and cueing strategies, are probably effective (level B). Speech therapy is possibly effective (level C). However, the long-term benefits of these therapies remain to be proven. The studies discussed in the original guideline document and the conclusion address physical and speech therapy as adjunctive therapy in PD. No recommendation can be made regarding the effect of physiotherapy as monotherapy in early PD.
Definitions:
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
Good practice point When only class IV evidence is available, or there is no scientific evidence, a good practice point is given.
