Transcript Treatments in Parkinson’s disease

Initial Treatment of Idiopathic
Parkinson’s Disease
Sandra Derghazarian
August 2013
Treatment in PD
• Complex because of
– Motor and non-motor features
– Disease is progressive
– Both early and late side effects
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
PREVENTION OF PROGRESSION
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.”
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
INITIAL TREATMENT OF MOTOR
SYMPTOMS
Motor symptoms
• Symptoms that are being targeted by
medications
– Tremor
– Rigidity
– Bradykinesia
– Gait/postural instability
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
Canadian PD Practice Guidelines
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
What are the options?
“It is not possible to identify a universal firstchoice drug for early PD.”
Canadian PD Practice Guidelines
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
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!
Levodopa
• How to start?
– No guidelines
– Usually 1 tab (100/25) po tid
• Should see considerable improvement
– Beware of undertreating
• If no effect  likely not idiopathic PD
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
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
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
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
What are the options?
“It is not possible to identify a universal firstchoice drug for early PD.”
Canadian PD Practice Guidelines
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 sideeffects
Canadian PD Practice Guidelines
Dopamine Agonists
• Ergot agonists
– Bromocriptine (only one available in Canada)
• Non-ergot agonists
– Pramipexole (Mirapex)
– Ropinirole (Requip)
– [Rotigotine (patch, Neupro)]
Canadian PD Practice Guidelines
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
Non-Ergot Agonists
• Principle of start low, go slow
• Pramipexole (Mirapex)
– Titrate to 0.5mg po tid over 3 weeks
• E.g. 0.125 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
Non-Ergot Agonists
• Clinical effect
– Moderate
– Of long duration (don’t notice wearing off)
• Side effects
– Nausea
• Can treat with domperidone
–
–
–
–
Somnolence (“sleep attacks”)
Hallucinations
Behavioral changes
Peripheral edema
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
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
What are the options?
“It is not possible to identify a universal firstchoice drug for early PD.”
Canadian PD Practice Guidelines
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
MAO-B Inhibitors
• Selective MAO-B inhibitors
– Selegiline
– Rasagiline
• Selegiline
– Start at 5mg daily
– Increase to 5mg bid (maximum dose)
• Rasagiline
– Start at 0.5mg daily
– Increase to 1mg daily (maximum dose)
MAO-B Inhibitors
• Clinical effects
– Moderate but definite
– Long duration
– No evidence of neuroprotection
• Side effects
– Nausea
– Confusion
– Headache
MAO-B Inhibitors - Recommendations
• May be used as a treatment for people with
early PD
Canadian PD Practice Guidelines
What are the options?
“It is not possible to identify a universal firstchoice drug for early PD.”
Canadian PD Practice Guidelines
Amantadine
• Used in PD for over 40 years
• Antiparkinsonian MoA not fully known
– Partial NMDA receptor antagonist
– Partial dopamine agonist
Amantadine - Use
• Dose
– 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
Amantadine - Recommendations
• May be used as treatment in early PD but
should not be drug of first choice
Canadian PD Practice Guidelines
What are the options?
“It is not possible to identify a universal firstchoice drug for early PD.”
Canadian PD Practice Guidelines
Anticholinergics
• Mechanism of Action in PD
– 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
Anticholinergics
• Main ones (start low, go slow):
– Trihexyphenidyl (Artane)
• Start 0.5-1mg bid, increase to 2mg tid
– Benztropine (Cogentin)
• Start 0.5-1 mg bid, increase to 2mg bid
• Side effects
– Confusion, hallucinations, blurry vision, increased
intraocular pressure, dry mouth, urinary
retention, constipation
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
A FEW WORDS ON MOTOR
COMPLICATIONS – LATE EFFECT
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
What are the options?
Canadian PD Practice Guidelines
COMT Inhibitors
• Entocapone
– 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
Entocapone (Comtan)
• How to start
– 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
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
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
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
NON-MOTOR SYMPTOMS
NOTE: I DIDN’T UPDATE THESE BASED ON THE CANADIAN GUIDELINES. ALL
FROM AAN 2006 GUIDELINES.
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”
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
Non-motor symptoms
• Neuropsychiatric symptoms
– 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
Management
•
•
•
•
•
•
•
Depression
Anxiety
Psychosis
Orthostatic hypotension
Dementia
Sexual dysfunction
Sleep dysfunction
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
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
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
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.
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
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
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
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
Management – Sleep Dysfunction
• Range of sleep dysfunction
– REM sleep behavior disorder (RBD)
– Excessive daytime somnolence (EDS)
– Insomnia
– Restless legs syndrome and periodic limb
movement
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 - 0.25 to 1mg po qhs
– Melatonin
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
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
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)
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
Summary
• L-dopa
– 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
Summary
• MAOB Inhibitors
– 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
Summary
• Depression
– Consider amitryptilline
• Psychosis
– Clozapine > quetiapine
• Dementia
– Rivastigmine and donepezil
• Orthostatic hypotension
– Non-pharm; fludro, midodrine, domperidone
Summary
• RBD
– Clonazepam
• EDS
– Warn patients!
– Remove offending agent
• RLS
– Pramipexole and ropinirole
THANK YOU