Website Edition: February/March 2012

Evidence Based Medicine

Update on treatments for motor symptoms of Parkinson's disease

Contributed by Susan H. Fox, MRCP (UK), PhD
Associate Professor Neurology
University of Toronto
Toronto Western Hospital

The recent MDS EBMR on treatments for motor symptoms of PD updates the original comprehensive EBM reviews published in 2002 and 2005. This new review incorporates data on efficacy, safety and implications for clinical practice of treatments up to December 2010. The methodology used was the same as in prior reports. Inclusion criteria included pharmacological, surgical and non-pharmacological therapies, available in at least one country, assessed using level 1, randomized controlled trials (RCTs); where motor symptoms were the primary endpoint measured with an established rating scale or well described outcome A quality assessment for each article was calculated using predetermined criteria; each drug was assigned 'efficacious, likely efficacious; unlikely efficacious; non-efficacious or 'Insufficient evidence' according to the level of evidence. Safety was assessed and assigned as 'acceptable risk with no specialized monitoring, or with specialized monitoring; unacceptable or Insufficient evidence'. The overall implications for clinical practice were then assessed and classed as 'clinically useful, possibly useful, investigational, unlikely useful or not useful'.

Each intervention was considered for the following indications: prevention/delay of clinical progression; symptomatic monotherapy, symptomatic adjunct therapy to levodopa, prevention/delay of motor complications (motor fluctuations and dyskinesia), treatment of motor complications (motor fluctuations and dyskinesia). For the treatment of the motor symptoms, sixty-nine new studies qualified for review and the updates, according to indication presented in Tables 1 - 5 (see below).

To date, several pharmacological and surgical therapies have been shown to be clinically useful, with acceptable safety, as symptomatic monotherapy; add on symptomatic therapy to levodopa or treat motor fluctuations. However, other indications are lacking in therapeutic options. These include therapies to slow disease progression; prevent or delay motor complications and treat dyskinesia. Many novel agents for these indications have been assessed but few to date have progressed to clinical use. Non-pharmacological treatments do not fare well in EBMR due to the inherent issues with study design; however, despite these problems, physical therapy and speech therapy are possibly clinically useful. However, well designed level 1 studies are still needed in this field.

Table 1 Treatments that may delay/prevent disease progression

Drug Class Drug Efficacy conclusions Implications for clinical practice Safety
MAO-B inhibitor Selegiline Insufficient evidence Investigational  
Rasagiline Insufficient evidence Investigational
Dopamine Agonist Ropinirole Insufficient evidence Investigational
Pramipexole Insufficient evidence Investigational
Pergolide Unlikely efficacious Unlikely useful

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'

Table 2 Treatments for symptomatic Monotherapy

Drug Class Drug Efficacy conclusions Implications for clinical practice Safety
Dopamine agonists Non-ergot Piribedil Efficacious Clinically useful  
Pramipexole Efficacious Clinically useful
Pramipexole ER Efficacious Clinically useful
Ropinirole Efficacious Clinically useful
Ropinirole PR Likely efficacious Possibly useful
Rotigotine Efficacious Clinically useful
Apomorphine Insufficient evidence Investigational
Ergot Cabergoline Efficacious Clinically useful Acceptable risk with specialized monitoring
DHEC Efficacious Clinically useful
Pergolide Efficacious Clinically useful
Bromocriptine Likely efficacious Possibly useful
Lisuride Likely efficacious Possibly useful
Levodopa/peripheral decarboxylase inhibitor Standard formulation Efficacious Clinically useful  
Controlled release Efficacious Clinically useful
Rapid-onset Insufficient evidence Investigational
Infusion Insufficient evidence Investigational
MAO-B inhibitors Selegiline Efficacious Clinically useful  
Rasagiline Efficacious Clinically useful
Others Anticholinergics Likely efficacious Clinically useful  
Amantadine Likely efficacious Possibly useful
Zonisamide Insufficient evidence Investigational

Table 3 Treatments for symptomatic adjunct therapy to Levodopa

Drug Class Drug Efficacy conclusions Implications for clinical practice Safety
Dopamine agonists Non-ergot Piribedil Efficacious Clinically useful  
Pramipexole Efficacious Clinically useful
Pramipexole ER Insufficient evidence Investigational
Ropinirole Efficacious Clinically useful
Ropinirole PR Efficacious Clinically useful
Rotigotine Efficacious Clinically useful
Apomorphine Efficacious Clinically useful
Ergot Bromocriptine Efficacious Clinically useful Acceptable risk with specialized monitoring
Cabergoline Efficacious Clinically useful
Pergolide Efficacious Clinically useful
DHEC Insufficient evidence Investigational
Lisuride Likely efficacious Possibly useful
Levodopa/peripheral decarboxylase inhibitor Rapid-onset Insufficient evidence Investigational  
Infusion Insufficient evidence Investigational
COMT inhibitors Entacapone Efficacious (in patients with motor complications) Clinically useful  
Non-efficacious (in patients without fluctuations) Not useful
Tolcapone Efficacious Clinically useful Acceptable risk with specialized monitoring
MAO-B inhibitors Selegiline Insufficient evidence Investigational  
Oral disintegrating selegiline Insufficient evidence Investigational
Rasagiline Efficacious Clinically useful
Others Anticholinergics Likely efficacious Clinically useful  
Amantadine Likely efficacious Possibly useful
Zonisamide Efficacious Clinically useful
Surgery Bilateral STN DBS Efficacious Clinically useful Acceptable risk with specialized monitoring
Bilateral GPi DBS Efficacious Clinically useful
Unilateral pallidotomy Efficacious Clinically useful
Unilateral thalamotomy Likely efficacious Possibly useful
Thalamic stimulation (uni or bilateral) Likely efficacious Possibly useful
Subthalamotomy Insufficient evidence Investigational
Human fetal transplantation Non-efficacious investigational Unacceptable risk
Non pharmacological Physical therapy (all types) Likely efficacious Possibly useful  
Speech therapy Insufficient evidence Possibly useful  
Occupational therapy Insufficient evidence Possibly useful  
Acupuncture Insufficient evidence Investigational  

Table 4. Treatments to prevent/delay of motor fluctuations (F) or dyskinesia (D)

  Drug Efficacy conclusions Implications for clinical practice Safety
Dopamine agonists Non-ergot Pramipexole Efficacious (F,D) Clinically useful (F,D)  
Ropinirole Efficacious (D) Insufficient evidence (F) Clinically useful (D) Investigational (F)
Pramipexole ER Insufficient evidence Investigational
Ropinirole PR Insufficient evidence Investigational
Rotigotine Insufficient evidence Investigational
Piribedil Insufficient evidence Investigational
Apomorphine Insufficient evidence Investigational
Ergot Cabergoline Efficacious (F,D) Clinically useful (F,D) Acceptable risk with specialized monitoring
Bromocriptine Likely efficacious (D) Insufficient evidence (F) Possibly useful (D) Investigational (F)
Pergolide Likely efficacious (D) Insufficient evidence (F) Possibly useful (D) Investigational (F)
DHEC Insufficient evidence Investigational
Lisuride Insufficient evidence Investigational
Levodopa/peripheral decarboxylase inhibitor Infusion Insufficient evidence Investigational  
COMT inhibitors Entacapone Non-efficacious (F,D) Not useful (F,D)  
Tolcapone Insufficient evidence Investigational Acceptable risk with specialized monitoring
MAO-B inhibitors Selegiline Non-efficacious (D) Insufficient evidence (F) Not useful (D) Investigational (F)  
Oral disintegrating selegiline Insufficient evidence Investigational
Rasagiline Insufficient evidence Investigational

Table 5a Treatments for motor fluctuations (F)

Drug Class Drug Efficacy conclusions Implications for clinical practice Safety
Dopamine agonists Non-ergot Pramipexole Efficacious I Clinically useful < 
Ropinirole Efficacious Clinically useful
Ropinirole PR Efficacious Clinically useful
Rotigotine Efficacious Clinically useful
Apomorphine Efficacious Clinically useful
Piribedil Insufficient evidence Investigational
Pramipexole ER Insufficient evidence Investigational
Ergot Pergolide Efficacious Clinically useful Acceptable risk with specialized monitoring
Bromocriptine Likely efficacious Possibly useful
Cabergoline Likely efficacious Possibly useful
DHEC Insufficient evidence Investigational
Lisuride Insufficient evidence Investigational
Levodopa/peripheral decarboxylase inhibitor Standard formulation Efficacious Clinically useful  
Controlled release Insufficient evidence Investigational
Rapid onset Insufficient evidence Investigational
Infusion Likely efficacious Investigational
COMT inhibitors Entacapone Efficacious Clinically us  
Tolcapone Efficacious Possibly useful Acceptable risk with specialized monitoring
MAO-B inhibitors Selegiline Insufficient evidence Investigational  
Oral disintegrating selegiline Insufficient evidence Investigational
Rasagiline Efficacious Clinically useful
Others Amantadine Insufficient evidence Investigational  
Zonisamide Insufficient evidence Investigational
Surgery Bilateral STN DBS Efficacious Clinically useful Acceptable risk with specialized monitoring
Bilateral GPi DBS Efficacious Clinically useful
Unilateral pallidotomy Efficacious Clinically useful
Unilateral thalamotomy Insufficient evidence Investigational
Thalamic stimulation (uni or bilateral) Insufficient evidence Investigational
Subthalamotomy Insufficient evidence Investigational
Human fetal transplantation Non-efficacious investigational Unacceptable risk

Table 5b Treatment for dyskinesia

Drug Class Drug Efficacy conclusions Implications for clinical practice Safety
Dopamine agonists Non-ergot and ergot Ergot All Insufficient evidence Investigational As above
Levodopa/peripheral decarboxylase inhibitor Infusion Likely efficacious Investigational  
Others Amantadine Efficacious Clinically useful  
Clozapine Efficacious Clinically useful Acceptable risk with specialized monitoring
Zonisamide Insufficient evidence Investigational  
Surgery Bilateral STN DBS Efficacious Clinically useful Acceptable risk with specialized monitoring
Bilateral GPi DBS Efficacious Clinically useful
Unilateral pallidotomy Efficacious Clinically useful
Unilateral thalamotomy Insufficient evidence Investigational
Thalamic stimulation (uni or bilateral) Insufficient evidence Investigational
Subthalamotomy Insufficient evidence Investigational
Human fetal transplantation Non-efficacious investigational Unacceptable risk

Update on treatments for non-motor symptoms of Parkinson's disease

Contributed by Klaus Seppi, MD
Consultant and Senior Lecturer
Medical University Innsbruck

The recent MDS EBMR on treatments for non-motor symptoms of Parkinson's Disease (PD) updates the original comprehensive evidence-based review on 'Management of Parkinson's Disease' published in 2002. In this revised version the MDS task force decided it was necessary to extend the review to non-motor symptoms, thus this review incorporates data on efficacy, safety and implications for clinical practice of treatments from January 2002 up to December 2010. The methodology used was the same as in prior reports. Inclusion criteria included pharmacological, surgical and non-pharmacological therapies, available in at least one country, assessed using randomized controlled trials (RCTs); where non-motor symptoms were the primary endpoint measured with an established rating scale or well described outcome, including a minimum of 20 subjects that were treated for a minimum duration of 4 weeks. In cases where the above listed inclusion criteria were not fulfilled, special exceptions were made when there was justification for inclusion. A quality assessment for each article was calculated using predetermined criteria; each drug was assigned 'efficacious, likely efficacious; unlikely efficacious; non-efficacious or Insufficient evidence' according to the level of evidence. Safety was assessed and assigned as 'acceptable risk with no specialized monitoring, or with specialized monitoring; unacceptable or Insufficient evidence'. The overall implications for clinical practice were then assessed and classed as 'clinically useful, possibly useful, investigational, unlikely useful or not useful'. Fifty-four new studies qualified for efficacy review, and several others covered safety issues. According to indication the review results are presented in Tables 1-7 (see below).

Although PD is generally considered a paradigmatic movement disorder, a majority, if not all PD patients also suffer from non-motor symptoms adding to the overall burden of parkinsonian morbidity. Non-motor symptoms in PD are numerous and include mood and affect disorders, cognitive dysfunction and dementia, psychosis, autonomic dysfunction, and disorders of sleep-wake cycle regulation. They become increasingly prevalent and obvious over the course of the illness and are a major determinant of quality of life, progression of overall disability, and of nursing home placement of PD patients. In their various combinations, non-motor symptoms may become the chief therapeutic challenge in advanced stages of PD. Despite the high prevalence and associated disability of non-motor symptoms in PD, many of the non-motor symptoms may not have effective treatment options. One mechanism of assisting clinicians in decision-making is the use of evidence-based medicine (EBM), whose principles allow clinically meaningful conclusions to be drawn from clinical trials, and therefore the comparison of results from these different trials is simplified. By using the current evidence in the medical literature, EBM helps to provide the best possible care to patients.

TABLE 1: CONCLUSIONS ON DRUGS TO TREAT DEPRESSION INCLUDING DEPRESSIVE SYMPTOMS IN PD

DRUG CLASS DRUG EFFICACY PRACTICE IMPLICATIONS SAFETY
DOPAMINE AGONISTS Pramipexole Efficacious Clinically useful  
Pergolide Insufficient evidence Not useful Acceptable risk with specialized monitoring
TRICYCLIC ANTIDEPRESSANTS (TCA) Nortriptyline Likely efficacious Possibly useful  
Desipramine Likely efficacious Possibly useful  
Amitriptyline Insufficient evidence Investigational  
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) Citalopram Insufficient evidence Investigational  
Sertraline Insufficient evidence Investigational  
Paroxetine Insufficient evidence Investigational  
Fluoxetine Insufficient evidence Investigational  
NEWER ANTIDEPRESSANTS Atomoxetine Insufficient evidence Investigational  
Nefazodone Insufficient evidence Not useful Unacceptable risk
ALTERNATIVE THERAPIES Ω-3 fatty acids Insufficient evidence Investigational  
NON-PHARMACOLOGICAL INTERVENTIONS rTMS Insufficient evidence Investigational  
ECT Insufficient evidence Investigational Insufficient evidence

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'.

TABLE 2: CONCLUSIONS ON DRUGS TO TREAT FATIGUE IN PD

DRUG EFFICACY PRACTICE IMPLICATIONS SAFETY
METHYLPHENIDATE Insufficient evidence Investigational Insufficient evidence
MODAFINIL Insufficient evidence Investigational Insufficient evidence

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'.

TABLE 3: CONCLUSIONS ON DRUGS TO TREAT PATHOLOGICAL GAMBLING IN PD

DRUG EFFICACY PRACTICE IMPLICATIONS SAFETY
AMANTADINE Insufficient evidence Investigational  

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'.

TABLE 4: CONCLUSIONS ON DRUGS TO TREAT DEMENTIA IN PD

DRUG CLASS DRUG EFFICACY PRACTICE IMPLICATIONS SAFETY
ACETYLCHOLINESTERASE INHIBITORS Donepezil Insufficient evidence Investigational  
Rivastigmine Efficacious Clinically useful  
Galantamine Insufficient evidence Investigational  
  MEMANTINE Insufficient evidence Investigational  

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'.

TABLE 5: CONCLUSIONS ON DRUGS TO TREAT PSYCHOSIS IN PD

DRUG EFFICACY PRACTICE IMPLICATIONS SAFETY
CLOZAPINE Efficacious Clinically useful Acceptable risk with specialized monitoring
OLANZAPINE Unlikely efficacious Not useful Unacceptable risk
QUETIAPINE Insufficient evidence Investigational  

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'.

TABLE 6: CONCLUSIONS ON DRUGS TO TREAT DISORDERS OF SLEEP AND WAKEFULNESS IN PD

DISORDERS OF SLEEP AND WAKEFULNESS DRUG EFFICACY PRACTICE IMPLICATIONS SAFETY
INSOMNIA Controlled-release formulation of levodopa/carbidopa Insufficient evidence Investigational  
Pergolide Insufficient evidence Not useful Acceptable risk with specialized monitoring
Eszopiclone Insufficient evidence Investigational  
Melatonin 3-5 mg Insufficient evidence Investigational  
Melatonin 50 mg Insufficient evidence Investigational Insufficient evidence
EXCESSIVE DAYTIME SOMNOLENCE AND THE SUDDEN ONSET OF SLEEP Modafinil Insufficient evidence Investigational Insufficient evidence

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'.

TABLE 7: CONCLUSIONS ON DRUGS TO TREAT AUTONOMIC DYSFUNCTION IN PD

  DRUG EFFICACY PRACTICE IMPLICATIONS SAFETY
ORTHOSTATIC HYPOTENSION Fludrocortisone Insufficient evidence Investigational Insufficient evidence
Domperidone Insufficient evidence Investigational Insufficient evidence
Midodrin Insufficient evidence Investigational Insufficient evidence
Dihydroergotamine Insufficient evidence Investigational Insufficient evidence
Etilefrine hydrochloride Insufficient evidence Investigational Insufficient evidence
Indomethacine Insufficient evidence Investigational Insufficient evidence
Yohimbine Insufficient evidence Investigational Insufficient evidence
L-threo-3.4-dihydroxy-phenylserine Insufficient evidence Investigational Insufficient evidence
SEXUAL DYSFUNCTION Sildenafil Insufficient evidence Investigational Insufficient evidence
CONSTIPATION Macrogol Likely efficacious Possibly useful  
ANOREXIA, NAUSEA AND VOMITING ASSOCIATED WITH LEVODOPA AND/OR DOPAMINE AGONIST TREATMENT Domperiodone Likely efficacious Possibly useful  
Metoclopramide Insufficient evidence Not useful Unacceptable risk
SIALORRHEA Ipratropium Bromide Spray Insufficient evidence Investigational Insufficient evidence
Glycopyrrolate Efficacious Possibly useful Insufficient evidence
Botulinum Toxin B Efficacious Clinically useful Acceptable risk with specialized monitoring
Botulinum Toxin A Efficacious Clinically useful Acceptable risk with specialized monitoring
URINARY FREQUENCY, URGENCY, AND/OR URGE INCONTINENCE Oxybutynin Insufficient evidence Investigational Insufficient evidence
Tolteradine Insufficient evidence Investigational Insufficient evidence
Flavoxate Insufficient evidence Investigational Insufficient evidence
Propiverine Insufficient evidence Investigational Insufficient evidence
Prazosin Insufficient evidence Investigational Insufficient evidence
Desmopressin Insufficient evidence Investigational Insufficient evidence

Note; In all tables, where no safety findings are indicated, outcome conclusion was 'Acceptable risk without specialized monitoring'.