1. Initial Treatment of Idiopathic Parkinson’s Disease
Sandra Derghazarian
August 2013

2. Treatment in PD Complex because of Motor and non-motor features
Disease is progressive
Both early and late side effects

3. Goals of treatment in PD
Prevention of disease progression
Symptomatic treatment of motor symptoms
Management of motor complications
Wearing off/motor fluctuations
Dyskinesias
Symptomatic treatment of non-motor symptoms

4. Prevention of progression

5. Prevention of disease progression
“Neuroprotection is an unmet need in Parkinson’s disease and no drug can be recommended yet for this purpose in practice.”

6. Canadian PD Guidelines 2012
Following should not be used for neuroprotection
Vitamin E
Following should only be used as neuroprotection in context of clinical trials
Coenzyme Q10
Dopamine agonists
MAO B inhibitors
Insufficient evidence to make recommendations for:
Amantadine
Thalamotomy
No evidence on L-dopa for neuroprotection
Canadian PD Practice Guidelines

7. Initial treatment of MOTOR SYMPTOMS

8. Motor symptoms Symptoms that are being targeted by medications Tremor
Rigidity
Bradykinesia
Gait/postural instability

9. What to take into account?
Know that no single medication is recommended for initial treatment
Remember goals
Reduce motor symptoms
Improve QOL
Avoid side effects
Guidelines
Canadian PD Practice Guidelines

10. What to take into account?
Consider following factors
Symptom severity
Ability/desire to continue to work
Patient preference
May have fears that meds will cause deterioration
There is NO evidence to suggest this
In fact, L-Dopa may spare dopaminergic neurons
Canadian PD Practice Guidelines

11. What are the options?
“It is not possible to identify a universal first-choice drug for early PD.”
Canadian PD Practice Guidelines

12. Levodopa Remains the most effective for motor symptoms
Converted into dopamine
Always combined with either
Carbidopa (Sinemet) or
Benserazide (Prolopa)
They prevent peripheral decarboxylation  avoid peripheral side effects of dopamine

13. Levodopa L-dopa/carbidopa formulations Regular (Sinemet R)
Usually use tablets of 100/25
L-dopa = 100mg, Carbidopa = 25mg
Can break tablets if necessary
Sustained–release (Sinemet CR)
100/25 or 200/50
Not used in early treatment
25-30% less bioavailable than Sinemet R
Remember to adjust dose!
L-dopa/bensazeride (Prolopa)
Less used
50/12.5,100/25, 200/50

14. Levodopa How to start? Should see considerable improvement
No guidelines
Usually 1 tab (100/25) po tid
Should see considerable improvement
Beware of undertreating
If no effect  likely not idiopathic PD

15. Levodopa Side-Effects
Early side effects – most common
Peripheral
Nausea, orthostatic hypotension
If severe –> Domperidone 10 mg tab
Central
Somnolence, confusion, hallucinations
Punting – repetitive purposeless behavior
Dopamine dysregulation syndrome – “addiction” to dopamine
Late side effects
Motor complications
DDS typically involves male patients with early onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-induced dyskinesia [79,80]. DDS can be associated with a cyclical mood disorder characterized by hypomania or manic psychosis. Tolerance (or frank dysphoria) to the mood elevating effects of dopaminergic therapy develops, and a withdrawal state occurs with dose reduction or withdrawal. Impulse control disorders including hypersexuality and pathologic gambling may accompany DDS

16. Motor complications What are motor fluctuations/off time?
Periods of alteration of symptom control
On/off time – initially predictable, later unpredictable
What are dyskinesias?
Drug-induced involuntary movements that include chorea and dystonia
Risk factors for development
Younger age at onset of PD, severity, higher L-dopa dose and longer disease duration

17. Levodopa
Try to keep dose at lowest effective possible to help avoid motor complication
No evidence that sustained-release form reduces motor complications
No evidence that entocapone delays motor complications
Canadian PD Practice Guidelines

18. Levodopa - Recommendations
May be used as a symptomatic treatment for early PD
Dose should be kept as low as possible to maintain good function, in order to reduce development of motor complications
Modified-release levodopa should not be used to delay onset of motor complications in early PD
Canadian PD Practice Guidelines

19. What are the options?
“It is not possible to identify a universal first-choice drug for early PD.”
Canadian PD Practice Guidelines

20. Dopamine Agonists Stimulate dopamine receptors directly
Do not need to be converted
2nd most potent for control of motor symptoms after L-dopa
Can be used with success in early PD
Titrate slowly to effective dose
Less risk of fluctuations but higher risk of side-effects
Canadian PD Practice Guidelines

21. Dopamine Agonists Ergot agonists Non-ergot agonists
Bromocriptine (only one available in Canada)
Non-ergot agonists
Pramipexole (Mirapex)
Ropinirole (Requip)
[Rotigotine (patch, Neupro)]
Canadian PD Practice Guidelines

22. Ergot Dopamine Agonists
Bromocriptine
Risk of pleuropulmonary and cardiac valve fibrosis
ESR, renal function, cardiac echo and CXR before starting and q-yearly
Risk of erythromelalgia
Because of complications and need for monitoring, rarely used
If possible, switch to a non-ergot DA-agonist
Canadian PD Practice Guidelines

23. Non-Ergot Agonists Principle of start low, go slow
Pramipexole (Mirapex)
Titrate to 0.5mg po tid over 3 weeks
E.g tid x 1 wk, 0.25 tid x 1 week, then 0.5 tid
Maintenance dose: 0.5 – 1.5 mg po tid
Ropinirole (Requip)
Titrate to 2-3 mg po tid over 6-9 weeks
Start at 0.25 tid, 0.5 tid, 0.75 tid, 1 tid, 1.25 tid etc

24. Non-Ergot Agonists Clinical effect Side effects Moderate
Of long duration (don’t notice wearing off)
Side effects
Nausea
Can treat with domperidone
Somnolence (“sleep attacks”)
Hallucinations
Behavioral changes
Peripheral edema

25. Behavioral Complications
Behavioral changes with DA-agonists– overall 13%
Gambling (50%)
Hypersexuality (40%)
Excessive spending (10%)
Management
ASK about symptoms – patients will not offer
Reduce dose or discontinue

26. DA-Agonists Recommendations
Dopamine agonists may be used as a symptomatic treatment in early PD
Titrated to a clinically efficacious dose
If side effects prevent this  use another agonist or drug from another class
If use an ergot-derived dopamine agonist
Minimum of RFTs, ESR, and chest X-ray before starting treatment, and annually thereafter.
Given monitoring required with ergot-DA agonists, non-ergot agonist preferred
Canadian PD Practice Guidelines

27. What are the options?
“It is not possible to identify a universal first-choice drug for early PD.”
Canadian PD Practice Guidelines

28. Monoamine Oxidase (MAO)
Group of enzymes involved in monoamine metabolism
Dopamine, serotonin, norepinephrine
Two enzyme subtypes
A and B
In basal ganglia  80% is MAO-B
MAOI and the “cheese reaction”
Hypertensive crisis if eat foods rich in tyramine
Does not happen with selective MAO-B inhibitors

29. MAO-B Inhibitors Selective MAO-B inhibitors Selegiline Rasagiline
Start at 5mg daily
Increase to 5mg bid (maximum dose)
Start at 0.5mg daily
Increase to 1mg daily (maximum dose)
Note: almost no MAO activity in neurons of the SN

30. MAO-B Inhibitors Clinical effects Side effects Moderate but definite
Long duration
No evidence of neuroprotection
Side effects
Nausea
Confusion
Headache

31. MAO-B Inhibitors - Recommendations
May be used as a treatment for people with early PD
Canadian PD Practice Guidelines

32. What are the options?
“It is not possible to identify a universal first-choice drug for early PD.”
Canadian PD Practice Guidelines

33. Amantadine Used in PD for over 40 years
Antiparkinsonian MoA not fully known
Partial NMDA receptor antagonist
Partial dopamine agonist

34. Amantadine - Use Dose Clinical effect Side effects
100 mg po daily to qid
Clinical effect
Modest for motor symptoms
Side effects
Livedo reticularis, leg edema,
Same side effect profile as dopamine agonists
Generally well-tolerated

35. Amantadine - Recommendations
May be used as treatment in early PD but should not be drug of first choice
Canadian PD Practice Guidelines

36. What are the options?
“It is not possible to identify a universal first-choice drug for early PD.”
Canadian PD Practice Guidelines

37. Anticholinergics Mechanism of Action in PD Use in PD Options
Not clearly known
Degeneration of DA-ergic nigrostriatal neurons  imbalance between striatal dopamine and Ach
Anticholinergics help counteract the imbalance
Use in PD
Typically for tremor-predominant young patients
Options
Benztropine, Ethopropazine, Procyclidine, Trihexyphenidyl
ounteracting the imbalance between striatal dopamine and acetylcholine activities caused by the degeneration of dopaminergic nigrostriatal neurons in Parkinson´s disease

38. Anticholinergics Main ones (start low, go slow): Side effects
Trihexyphenidyl (Artane)
Start 0.5-1mg bid, increase to 2mg tid
Benztropine (Cogentin)
Start mg bid, increase to 2mg bid
Side effects
Confusion, hallucinations, blurry vision, increased intraocular pressure, dry mouth, urinary retention, constipation

39. Anticholinergics May be used in symptomatic treatment
Typically in young patients with early PD and severe tremor
Should not be drug of first choice due to limited efficacy and side-effect profile
Canadian PD Practice Guidelines

40. A few words on Motor complications – Late effect

41. Motor Symptoms Later in PD
Levodopa remains the most effective
Over years, duration of benefit decreases
Patients feel “wearing off” before next dose
Eventually  unpredictable on/off, freezing
Also, start to develop dyskinesias
As per recommendations, it is not possible to identify a universal first-choice adjuvant therapy for late PD
Canadian PD Practice Guidelines

42. What are the options?
Canadian PD Practice Guidelines

43. COMT Inhibitors Entocapone (Tolcapone
Blocks key enzyme responsible for breaking down levodopa before it reaches the brain
(Tolcapone
Not used due to hepatotoxicity )
Improves duration of response to levodopa
Hence its usefulness in wearing off
Adds 1-2 hours of on-time/day

45. Entocapone (Comtan) How to start Will increase peak levodopa
1 tab of 200 mg with each dose of L-dopa
Will increase peak levodopa
often recommend 30% reduction in levodopa
practically difficult - often cannot
Side effects
Same as increasing Sinemet
Increased dyskinesias possible
Stalevo (L-dopa, carbidopa, entocapone)
50 Ldopa/12.5 carbidopa/200 mg entacapone
Advantage is convenience

46. Motor Complications - Recommendations
To reduce off time
Entocapone and rasagiline should be offered
Pramipexole and ropinirole should be considered
Sustained-release L-dopa may be used but should not be first choice
To reduce dyskinesias
Amantadine may be considered
Canadian PD Practice Guidelines

47. Two Words on Surgery DBS of the STN may be considered to
Improve motor function
Reduce dyskinesias
Reduce medication usage
Candidates for bilateral GPi stimulation
Motor complications refractory to med mgmnt
Healthy, no significant comorbidity
L-dopa responsive
No psychiatric problems
Canadian PD Practice Guidelines

48. Two Words on Surgery
No evidence to state whether GPi or STN is preferred target of DBS
DBS of thalamus may be considered
Patients with predominantly severe disabling tremor
STN DBS cannot be performed
Canadian PD Practice Guidelines

49. Non-motor symptoms Note: I didn’t update these based on the canadian guidelines. All from AAN 2006 guidelines.

50. Non-motor symptoms
“Non-motor symptoms dominate the clinical picture of advanced Parkinson’s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy”

51. Pathophysiology
Non-dopaminergic-cell dysfunction thought to play a major part in the development of the non-motor symptoms
However, neuroanatomy and neurochemistry of non-motor symptoms are unknown

53. Non-motor symptoms Neuropsychiatric symptoms Sleep disorders
Depression, apathy, anxiety, hallucinations, dementia, impulsive behavior (usu drug-induced)
Sleep disorders
Restless legs and period limb movements, REM-sleep behavior disorder, excessive daytime somnolence
Autonomic symptoms
Bladder (urgency, nocturia, frequency), sweating, orthostatic hypotension, sexual dysfunction
GI symptoms (overlap with dysautonomia)
Dribbling saliva, constipation, dysphagia, ageusia,
Sensory symptoms
Olfactory disturbance, pain, paresthesias

54. Management Depression Anxiety Psychosis Orthostatic hypotension
Dementia
Sexual dysfunction
Sleep dysfunction

55. Management - Depression
Can affect from 10-45% of patients
Likely has a biological contribution
May be a result of impaired 5HT transmission
What is best pharmacological treatment? (AAN 2006)
The highest level of evidence is for amitriptyline
Although it may be considered, it is not necessarily the first choice for treatment of depression associated with PD.
Insufficient evidence to make recommendations regarding other treatments for depression
SSRIs and SNRIs are used but little published data in PD
amitriptyline,
nortriptyline, citalopram, fluoxetine, sertraline, pergolide, pramipexole, and nefazodone

56. Management – Anxiety and Apathy
Anxiety disorder common
Often coexists with depression
Panic attacks, phobias, GAD, related to motor fluctuations
AAN practice parameters regarding treatment
Insufficient evidence to make any recommendations

57. Management - Psychosis
What is the best treatment for patients with PD and psychosis?
Clozapine should be considered
Remember: associated with agranulocytosis that may be fatal. The absolute neutrophil count must be monitored.
Quetiapine may be considered
Olanzapine should not be routinely considered
No proven efficacy and may worsen motor function
Note that not FDA approved because of increased risk of death in pts with dementia
Side effects are worsening of motor function, weight gain, insulin resistance and diabetes

58. Management - Dementia
What are the most accurate screening tools in PD?
MMSE and CAMCog (Cambridge cognitive assessment)
MMSE as sensitive but not as specific
What is the most effective treatment for dementia in PD?
Rivastigmine probably effective in improving cognitive function. Modest effect and may exacerbate tremor
Donepezil is probably effective in improving cognitive function. Modest effect.
Donepezil – non-competitive ACHesterase inhibitor (Aricept)
One study – measured at 20 weeks, MMSE, improved by 2 points
Galantamine – ACHesterase inhibitor, centrally acting, competitive and reversible. (Reminyl)
Rivastigmine – competitive inhibitor of ACHesterase (Exelon)

59. Management – Orthostatic Hypotension
Defined as a 20mmHg drop in systolic BP or a 10mmHg drop in diastolic BP
Challenge in PD
DA-ergic agents often worsen OH
Reducing dose usually insufficient to treat
What treatments are effective? (AAN 2006)
Insufficient data to recommend to any particular treatment
Symptoms variable – can be disabling
Lightheadedness, syncope, fatigue, cognitive slowing, neck tightness, headache, unsteadiness

60. Management – Orthostatic Hypotension
Compression stockings
Increasing water intake
Fludrocortisone
Dose: 0.1 – 0.3mg daily + high Na intake
Supine hypertension, peripheral edema
Midodrine
Peripheral alpha1 receptor agonist
Dose: 2.5 to 5mg tid
Others: domperidone, pyridostigmine, indomethacin
Domperidone – peripheral DA antagonist therefore blocks peripheral effects of DA

61. Management – Sexual Dysfunction
Common in both men and women
Multifactorial
Motor dysfunction, medication side effects, mood disorders, and dysautonomia
Dysautonomia  erectile dysfunction
One study looked at sildenafil in ED
12 patients with PD, BP > 90/50
Sildenafil at 50mg significantly improved ED

62. Management – Sexual Dysfunction
AAN Practice Parameter
Sildenafil possibly efficacious
Need to ensure that other treatable causes of ED/sexual dysfctn have also been addressed
Note: hypersexuality can be seen in PD associated with DA-ergic agents

63. Management – Sleep Dysfunction
Range of sleep dysfunction
REM sleep behavior disorder (RBD)
Excessive daytime somnolence (EDS)
Insomnia
Restless legs syndrome and periodic limb movement

64. Management – RBD
A type of parasomnia characterized by patients acting out dramatic or violent dreams during the REM sleep stage.
What treatments are effective in PD?
Insufficient data
What treatments are available for RBD?
Clonazepam to 1mg po qhs
Melatonin

65. Management - EDS
May be 2ary to disease process or medication side effect
Dopaminergic agents can cause mild to severe somnolence
Falling asleep at wheel of car
Agonists > L-dopa
FDA warnings for pramipexole and ropinirole
Patients should be advised to d/c DA agonists if marked increase in sleepiness

66. Management - EDS What treatments are available?
Modafinil improves SUBJECTIVE feeling of sleepiness but doesn’t change OBJECTIVE measurements of somnolence
Dose: 200mg daily in am

67. Management - Insomnia Etiology is multifactorial
Mood disturbances, persistent tremor, nighttime PD symptoms, nocturia, and reversal of sleep patterns
Practice parameter: Insufficient data
Available treatments
Bedtime L-dopa – may improve nocturnal PD sx
Melatonin – Improves perception
Sedating antidepressants (trazodone)
Mild sedatives – zopiclone, zolpidem
Over-the-counter sleeping aids – beware of side effects (anticholinergic effect)

68. Management - RLS Occurs in up to 20% of patients
No evidence on how to treat of RLS in PD
May use ropinirole and pramipexole
FDA approved treatment in primary RLS

69. Summary L-dopa Dopamine agonists Entocapone
Most effective, early and late PD
Associated with motor complications
Dopamine agonists
Second most effective, early PD
2nd line for motor complications, late PD
Entocapone
First-line adjunct for wearing off
May increase dyskinesias

70. Summary MAOB Inhibitors Anticholinergics Amantadine
Monotherapy, early PD
Rasagiline to reduce off time
Anticholinergics
Young patients with predominant tremor
Not for motor complications
Amantadine
Monotherapy, early PD (not first choice)
May use to reduce dyskinesias

71. Summary Depression Psychosis Dementia Orthostatic hypotension
Consider amitryptilline
Psychosis
Clozapine > quetiapine
Dementia
Rivastigmine and donepezil
Orthostatic hypotension
Non-pharm; fludro, midodrine, domperidone

72. Summary RBD EDS RLS Clonazepam Warn patients! Remove offending agent
Pramipexole and ropinirole

73. Thank you