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

Initial Treatment of Idiopathic Parkinson’s Disease

Sandra DerghazarianAugust 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


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


What are the options?


“It is not possible to identify a universal first-choice drug for early PD.”

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


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





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


Dopamine Agonists

• Ergot agonists– Bromocriptine (only one available in Canada)

• Non-ergot agonists– Pramipexole (Mirapex)– Ropinirole (Requip)– [Rotigotine (patch, Neupro)]


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


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 preferredCanadian 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





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





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


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




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


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


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


NON-MOTOR SYMPTOMSNOTE: 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

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

Documents

effects slide

idiopathic pd slide

canadian pd guidelines

effects of dopamine

motor symptoms symptoms

effects motor complications

early pd dose

onset of pd