Choosing the Right Dopamine Agonist for Patients With Parkinson's Disease

C. Lebrun-Frenay, M. Borg


Curr Med Res Opin. 2002;18(4) 

In This Article

How to Choose a Dopamine Agonist

The therapeutic value of dopamine agonists being clearly established now in PD, physicians might wonder which dopamine agonist is the most convenient for their parkinsonian patients in daily practice. In order to answer this question, we have reviewed the literature on our selection of five dopamine agonists, i.e. ropinirole, pramipexole, pergolide, bromocriptine and piribedil, taking into particular consideration the flexibility of their indications in the different PD stages, their titration schedule and their safety profile.

The first step before any selection consists of being sure that the available dopamine agonists are indicated at all stages of PD. Nevertheless, careful examination of both clinical data and prescribing information shows some differences between them. These differences concern, in particular, the flexibility of their respective prescription in PD, i.e.:

  • In monotherapy in the early stages of PD.

  • In early combination with levodopa, which is defined as adding a dopamine agonist to L-dopa treatment within the first months in stable, non-fluctuating patients.

  • In late combination with levodopa, which is defined as adding a dopamine agonist after patients have received several years of L-dopa therapy in patients with motor fluctuations.

In Monotherapy in the Early Stages of PD. An important new development in the pharmacotherapy of PD today is the possibility of using dopamine agonists as first-line therapy for patients with early PD, prior to the introduction of levodopa. Dopamine agonist use first-line prevents levodopa-induced motor complications, and especially the 'priming' effect. This benefit on dyskinesia has been recently linked with the long elimination half-life that leads to a continuous stimulation of dopaminergic receptors. It has fuelled interest in the notion that it may be better to initiate symptomatic therapy in PD with a relatively long-acting dopamine agonist rather than with a relatively short-acting formulation of levodopa ( Table 1 ).[7] Thus, a long elimination half-life may vouch for a more stable plasmatic balance, and better clinical efficacy.

Both ropinirole and pramipexole have been demonstrated to have significant efficacy on the symptoms of PD, and substantially delay the need for the addition of levodopa.[8,9] Nevertheless, available in 17 countries, pramipexole is only indicated in monotherapy in four countries (Argentina, Korea, Russia and the USA).

The dopamine agonists bromocriptine and pergolide have also shown comparable efficacy or tolerability.[10,11] However, pergolide is only indicated in combination with levodopa. Piribedil is active as monotherapy on all the cardinal signs of PD, and is the treatment of choice for parkinsonian tremor.[12,13,14] Its use at an early stage can also delay the need to start levodopa and hence delay the onset of iatrogenic motor disorders.

In Early Combination With Levodopa in PD. The wearing-off of medication effects or motor fluctuations associated with levodopa are the most common causes for the use of a dopamine agonist.[15,16,17]

Yet another important indication is the emergence of levodopa-related dyskinesia. The use of a dopamine agonist together with a lower dose of levodopa will usually maintain or improve the amount of 'on' time that the patient is experiencing throughout the day without exacerbating dyskinesia.[18,19]

More than all the other types of prescriptions in PD, early combination with levodopa highlights the flexibility of dopamine agonists. Indeed, few dopamine agonists have been assessed in randomised and controlled trials. Moreover, fewer again have the indication in their prescribing information.

Pergolide and pramipexole are not indicated in early combination with levodopa, as there are no randomised and controlled trials to support this indication.[20,21]

Ropinirole has been widely assessed in early combination with levodopa, but strangely its prescribing information underlines only its use in combination with levodopa when dopa therapy gradually fails, and the 'on-off' phenomenon occurs.[22]

Bromocriptine and piribedil have conclusive data in early combination with levodopa, and they are clearly indicated.[23]

In Late Combination With Levodopa in PD. In late combination with levodopa, there are no difficulties encountered when dopamine agonists are used in late combination with levodopa, and, indeed, all the above drugs are appropriate and efficient in this indication.

Nevertheless, although ropinirole has the indication, no randomised and controlled trials support this, since the two published trials conducted in advanced L-dopa-treated patients only assessed time spent 'off' and/or reduction in L-dopa daily dose.[24,25]

After considering the indication status in PD, the second step should be to investigate the updated safety profile of each drug. Regarding this major point, the first comment is that all the dopamine agonists present the same classical dopaminergic peripheral adverse reactions, such as nausea, vomiting and hypotension. However, concerning possible severe side-effects, even if they remain rare, dopamine agonists are not equal.

Acute Side-Effects. The acute side-effects of dopamine agonists are similar to those observed with levodopa. They include nausea, vomiting, postural hypotension and psychiatric symptoms.[26] They tend to occur with the initiation of treatment and to abate as tolerance develops over several days to weeks.

Neuropsychiatric Problems. Neuropsychiatric problems, specifically hallucinations and psychosis, are more common with dopamine agonists than with levodopa in most studies and are particularly prone in elderly or cognitively impaired patients. Moreover, the serotoninergic properties of ergot-derived drugs may enhance these symptoms.[27] Thus, a balance must be reached between the adverse effect of the drug on mental function and its beneficial effect on PD.

Erythromelalgia, pulmonary or retroperitoneal fibrosis, and Raynaud's-like phenomena have been described in association with the ergot-derived dopamine agonists (bromocriptine, pergolide).[28,29,30,31,32] Even if they are relatively uncommon, they remain severe enough to be kept in mind, looked for carefully at each patient visit and investigated by

X-ray at any suspicion of pleural fibrosis, or by ECG if the ergot derivative has to be increased to its highest dosage in the case of a parkinsonian patient with an obvious coronary history.

Episodes of suddenly falling asleep while at the wheel of a motor vehicle have been described in a case report of eight PD patients who received the dopamine agonists pramipexole and ropinirole.[33] The authors termed these episodes 'sleep attacks' because they were reported to have occurred without warning. It is now evident that such events are more common than was previously appreciated and that they can be associated with any dopaminergic drug, including levodopa.[34,35] The notion that these episodes are sleep attacks has been questioned,[36] because sleep episodes without antecedent sedation are not known to occur under physiologic or pathologic conditions, and, indeed, the term has been abandoned in narcolepsy.[37] It has been proposed that these episodes represent an extreme form of somnolence related to the sleep disturbances that are so common in PD, coupled with the propensity of dopaminergic drugs to induce dose-related sedation.

However, it remains clear that dopamine agonists are not equal in producing sleepiness. However, it remains clear that dopamine agonists are not equal in producing sleepiness. Shäfer shows that the sedative effects of pramipexole and ropinirole are greater than that of other dopamine agonists. A strong body of clinical data supports the claim that Piribedil is associated with a non-significant incidence of somnolence when compared with placebo ( Table 2 ).[38]

In the light of the different sedative effects of pramipexole,[39] which presents one of the largest numbers of event reports, and piribedil,[40] which presents the least reports of somnolence, the opposite adrenergic properties of both should be underlined. Pramipexole is an 2-adrenergic presynaptic receptor agonist[41,42] and decreases the noradrenergic pathway, which induces a decrease in vigilance. Conversely, piribedil is an 2-adrenergic presynaptic receptor antagonist which raises noradrenergic activity and provides an increase in vigilance ( Table 3 ).[43,44]

The consideration given above to both the safety profiles and the flexibility of various dopamine agonists in their indications in PD, proved to be very valuable. However, it is also very important to consider their ease of use. This is vital for two reasons. Firstly, in order to ensure that the prescription will be easy to follow in daily practice. Secondly, since it is essential that the treatment regimen will be easily understood by patients with PD, so as to help to guarantee their compliance with their individual antiparkinsonian treatment.

According to data presented recently by Shulman,[45] there is a huge variation in the range of titration schedules ( Table 4 ).

Indeed, the common therapeutic efficacy dose range of pramipexole goes from 3 weeks to 7 weeks (1.5-4.5 mg). Ropinirole reaches its common therapeutic efficacy in 4-18 weeks (3-24 mg), and pergolide and bromocriptine reach theirs in 3-33 weeks (0.75-4.5 mg and 7.5-45 mg, respectively).

The titration schedule of piribedil appears easier to manage in daily practice. Certainly, only 3-7 weeks are required to achieve its common therapeutic efficacy range (150-250 mg) in monotherapy. More importantly, however, in combination with levodopa, only 1-3 weeks are needed.


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