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

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Presentation on theme: "Initial Treatment of Idiopathic Parkinson’s Disease Sandra Derghazarian August 2013."— Presentation transcript:

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


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


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

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!

14 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

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

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

20 Dopamine Agonists Stimulate dopamine receptors directly – Do not need to be converted 2 nd 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 – 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. 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

24 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

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

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 Selegiline – Start at 5mg daily – Increase to 5mg bid (maximum dose) Rasagiline – Start at 0.5mg daily – Increase to 1mg daily (maximum dose)

30 MAO-B Inhibitors Clinical 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? Canadian PD Practice Guidelines “It is not possible to identify a universal first- choice drug for early PD.”

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 – 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? Canadian PD Practice Guidelines “It is not possible to identify a universal first- choice drug for early PD.”

37 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

38 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

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


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 – 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 – 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


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 – 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

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

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.

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

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

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

70 Summary MAO B 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

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

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


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