A review of the role of dopamine agonists in advanced parkinsons disease, its merits and demerits.

1. Dopamine receptor agonists
in advanced Parkinson’s
disease
BNET Webinar: 27.11.2020
Dr Pramod Krishnan
Consultant Neurologist and HOD Neurology
Manipal Hospital, Bengaluru.

2. Dopamine receptor
agonists
Non-ergot derivatives
Ergot derivatives
Cabergoline
Pergolide
Pramipexole
Ropinirole
Piribedil
Rotigotine
Bromocriptine Apomorphine
Lisuride

3. Drug Route of adm Dosage
Ropinirole Tablet (regular, ER)
Transdermal patch
Initial dose: 3 X 0.25 mg, maximum 24
mg/d.
Prolonged release: initial dose: 6 mg,
maximum 24 mg/d.
Pramipexole Tablet (regular, ER) Initial dose: 3 X 0.125 mg,
maximum 24 mg/d.
Prolonged release: initial dose 0.52 mg,
maximum 3.15 mg/d.
Rotigotine Transdermal patch Initial dose: 2 mg/24 h, maximum 16
mg/24 h.
Apomorphine Subcutaneous,
infusion pump

4. Adverse effects of dopamine receptor agonists
Adverse effects Comment
Impulse control disorders in upto 40%
patients on oral dopamine agonists.
Eg. gambling, compulsive spending, abnormal sexual
and eating behaviours, compulsive medication use,
hobbyism.
Dopamine agonist withdrawal
syndrome (DAWS) in 15-20% of
patients)
Anxiety, panic attacks, irritability, diaphoresis, pain,
drug cravings. Strong association with ICD.
Orthostatic hypotension
Confusion, hallucinations Use with caution in elderly, those with cognitive
deficits.
Somnolence, sleep attacks.
Pedal edema
Pulmonary and valvular fibrosis With older ergot dopamine agonists.
Pisa syndrome

5. Role of dopamine agonists in PD
• The fear of developing side effects is
the main reason why dopamine
agonists are not frequently used in
advanced PD, and not due to loss of
efficacy.
Challenges in advanced PD:
• Dyskinesias, motor fluctuations.
• Non-motor symptoms.
• Cognitive disturbances.
• Autonomic disturbances.
• Disturbances of mood and
behaviour.
• Sleep disturbances.
• Monotherapy for use in early and mild PD.
• To reduce dyskinesias and motor fluctuation related to Levo-dopa.

7. Relevant pathophysiology of advanced PD
• Dopamine receptors are normally continuously exposed to dopamine, but in
PD they are exposed to alternating high and low concentrations (pulsatile
stimulation).
• Pulsatile or discontinuous replacement of dopamine further destabilises a
denervated and unstable striatum inducing further disruptions of basal
ganglia activity leading to motor complications.
• The degree of dopamine denervation and the half-life of the dopaminergic
agent employed contribute to the likelihood that pulsatile stimulation of
dopamine receptors will occur.

8. • Duodopa pump: best result in
reducing dyskinesia and increasing
‘on’ period.
• Apomorphine pump: half life of 20
min (shortest acting dopamine
agonist) but very effective when
used as a pump.
• Both are invasive, very expensive
have significant adverse effects.
Continuous dopamine replacement therapy
More than Levo-dopa per se, it is the peaks and troughs that result in dyskinesia and
motor fluctuations.

9. Int J Clin Pract, April 2009, 63, 4, 613–623
• 15 RCTs (n=4380) of dopamine receptor agonist or placebo added to L-dopa
therapy for advanced PD were evaluated.
• Dopamine receptor agonist use resulted in improvement of UPDRS for ADL,
motor score, reduction of “off” time measured in hours/day and reduction of
L-dopa dose versus placebo.
• Incidence of dyskinesia and hallucinations were higher.
• Conclusion: Adjunctive dopamine receptor agonist use with L-dopa is superior
to L-dopa alone in patients not controlled with monotherapy. They are very
useful in PD patients with wearing off phenomenon from levodopa therapy.

10. Advantage of extended release preparations
• Continuous delivery of dopamine agonists can reduce nausea, vomiting,
somnolence or symptoms of a dopamine dysregulation syndrome.
• The relatively constant medication levels in the blood and also at the
dopamine receptors prevent these side effects.
• In contrast, the plasma levels of ordinary dopamine agonists increase steeply
shortly after intake, resulting in adverse effects.
• Thus, extended release formulation of dopamine agonists permits their use in
advanced stages of PD.

11. • Once daily tablet.
• Plasma concentrations decrease
slightly over 24 hours.
• If taken in the morning, the
plasma level of Ropinirole
decreases over night, which
mimics the physiological
situation in healthy persons: the
Ropinirole level in the blood in
the morning is still high enough
to guarantee a good start without
early morning dystonia or
akinesia.
• Well tolerated, effective and can
be titrated rapidly.

12. • To evaluate the efficacy of Ropinirole PR as an adjunct to levodopa in patients
with advanced PD and motor fluctuations.
• Double blind placebo controlled 24 week study.
• 393 patients were randomized to Ropinirole PR (n=202) or placebo (n=191).
• At 24 weeks, the mean dose of Ropinirole was 18.8 mg/day with a mean
reduction in daily L-dopa of 278 mg.
• There was a mean reduction in daily “off” time of 2.1 hours with Ropinirole
PR and 0.3 hours with placebo.

13. EASE PD adjunct study: results
Secondary outcome measures were significantly improved:
• Change in hours and percent of daily “on” time, “on” time without
troublesome dyskinesia.
• UPDRS motor and ADL subscales.
• Beck Depression Inventory-II.
• PDQ-39 subscales of mobility.
• PD Sleep Scale.
Adverse events: dyskinesia, nausea, dizziness, somnolence,
hallucinations, and orthostatic hypotension.
• Adverse events led to study withdrawal in 5% of both active and placebo
groups.

14. • A randomized, double-blind, parallel-group, placebo-controlled trial.
• To evaluate superiority of Ropinirole hydrochloride patch over placebo and
noninferiority of Ropinirole patch to Ropinirole ER tablet.
• 229 PD patients on levodopa received Ropinirole patch (up to 64 mg/d), 229
received Ropinirole ER tablets (up to 16 mg/d), and 129 received placebo.
• The patch comes in five sizes (8, 16, 24, 32, and 40 mg of Ropinirole).

15. Results
• The primary endpoint was the change from baseline in the total score for the
UPDRS Part III (on state) at week 16.
• There was a significant change in the UPDRS favouring Ropinirole patch and
tablet over placebo.
• Ropinirole patch was non inferior to Ropinirole ER tablet.
• In all three groups, most adverse events were mild or moderate and there were
no serious safety concerns.

16. • 465 subjects completed the advanced-PD double blind study, 391 entered the
advanced-PD open label extension.
• Reported AEs were dyskinesia (27.4%) and somnolence (13.6%), impulse
control disorders in 1.4%.
• Adjusted mean UPDRS Parts II + III scores remained substantially improved
from baseline prior to pramipexole introduction after 113 weeks.

17. Rotigotine TP (transdermal patch)
• It is available as 10, 20, 30 and 40
cm2 patches containing,
respectively, 4.5, 9, 13.5 and 18 mg of
Rotigotine, and designed to release,
respectively, 2, 4, 6 and 8 mg of
Rotigotine per 24 h.
• Approved as monotherapy in early
PD, or in combination with levodopa
throughout the course of the disease
even in late stages.

18. • Prospective Randomized Evaluation of a new Formulation: Efficacy of Rotigotine
(PREFER).
• Randomised double blind placebo controlled trial.
• Advanced PD with > 2.5 hrs of daily ‘off’ time.
• Rotigotine 8mg/24 hrs (n=120), Rotigotine 12 mg/24hrs (n=111), Placebo (N=120).
• The primary efficacy measures compared changes from baseline to the end of
week 24 in the number of daily hours “off ” and responder rates for subjects
achieving >30% reduction in “off” time.
Neurology 2007;68:1262–1267

19. PREFER study: Results
• Compared with placebo, there was a significant decrease in mean “off” time
of 1.8 hours/day for rotigotine 8 mg/24 hours and 1.2 hours/day for those on
12 mg/24 hours.
• >30% responder rates were 56.6% and 55.1% compared to placebo (34.5%).
• “On” time without dyskinesia after awakening was more than doubled in both
Rotigotine treatment groups versus the placebo group.
• Drug-related adverse effects included typical dopaminergic side-effects,
which were generally mild to moderate in intensity.
• Patch application site reactions including erythema and pruritus were mild to
moderate and transient in the majority of instances.
Neurology 2007;68:1262–1267

20. Movement Disorders, Vol. 26, No. 1, 2011
• Multinational, double-blind, placebo- controlled trial.
• 287 PD patients with unsatisfactory early-morning motor symptom control were
randomized 2:1 to receive Rotigotine 2–16 mg/24 hr (n=190) or placebo (n=97).
• Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose
maintenance for 4 weeks.
• Early-morning UPDRS Part III and modified Parkinson’s Disease Sleep Scale
(PDSS-2) were recorded.

21. RECOVER study: results
• Mean UPDRS Part III score decreased by -7.0 points with Rotigotine (from a
baseline of 29.6) and by -3.9 points with placebo (baseline 32.0).
• Mean PDSS-2 total score decreased by -5.9 points with Rotigotine (from a
baseline of 19.3) and by -1.9 points with placebo (baseline 20.5).
• This represented a significantly greater improvement with Rotigotine
compared with placebo on both UPDRS Part III (p<0.0002) and PDSS-2
(p<0.001).
• Adverse effects: The most frequently reported adverse events were nausea
(placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%;
rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%).

22. Lancet Neurol 2007; 6: 513–20
• Clinical Efficacy of Pramipexole And Transdermal Rotigotine in Advanced PD
(CLEOPATRA-PD) study.
• Aim: To assess the efficacy of adjunct treatment with Rotigotine in comparison
with placebo and with Pramipexole in levodopa-treated patients with advanced
PD and wearing-off type motor fluctuations.
• Rotigotine TP (up to 16 mg/24 h), Pramipexole (up to 4.5 mg/day), or placebo
for 6 months.
• Rotigotine TP (n=204), Pramipexole (n=201), Placebo (n=101).

23. CLEOPATRA PD study: results
• 427 (84%) completed the trial. The number of discontinuations in each group
was similar; most were for adverse events.
• The mean dose of Rotigotine was 12.95 mg/24 h, the mean dose of
Pramipexole was 3.1 mg/day.
• Mean absolute change in off time from baseline was –2.5h with Rotigotine, –
2.8h with Pramipexole, and –0.9 h with placebo (statistically significant).
• Responder rates were 67% for Pramipexole, 59.7% for Rotigotine, and 35% for
placebo.
• Conclusion: Rotigotine TP was non inferior to oral Pramipexole.

24. • Nine RCT (n = 2857) which assessed the Rotigotine TP, Pramipexole ER, and
Ropinirole PR were included.
• Compared with placebo, they achieved greater improvements in UPDRS ADL
score, motor score, and the ADL and motor subtotal score, as well as a reduction
in ‘‘off’’ time, and an increase in ‘‘on’’ time without troublesome dyskinesia.
• Compared with placebo, they were associated with a higher risk of nausea, but
no difference was found in headache incidence.
• Higher risks of dyskinesia and hallucination were only found in advanced PD.

25. The Cochrane Library 2010, Issue 7
• 44 eligible trials, involving 8436 participants were identified.
• Indirect comparisons of the three drug classes suggested that dopamine agonists
were more efficacious in reducing off-time and levodopa dose.
• UPDRS scores also improved more with dopamine agonists than with COMTI or
MAOBI, but more dyskinesia were seen with dopamine agonists than with MAOBI.
• Although the increase in the overall incidence of side-effects was generally more
marked with dopamine agonists and COMTI than with MAOBI, was only of
borderline significance.

26. Conclusion
• Dopamine receptor agonists are useful in advanced PD.
• Conflicting data that long acting formulations are superior to the immediate
release forms.
• They reduce motor fluctuations, dyskinesias, reduce ‘off’ time and improve
‘on’ time when used as adjunct to Ldopa.
• Apomorphine injection and pump has excellent efficacy in advanced PD.
• Careful patient selection, slow titration and dose adjustments of
comedications can improve tolerability and improve outcomes.

27. THANK YOU