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During the past decade new direct acting dopamine agonists (DAs) have become widely deployed for the treatment of the early stages of Parkinson’s disease (PD), because randomised controlled trials (RCT) have demonstrated that their use is associated with a reduced incidence of motor fluctuations and dyskinesias compared to levodopa therapy.1–5 In addition, direct acting DAs have been used in combination with levodopa in the later stages of the disease as levodopa sparing agents, to reduce these side effects.6
However, published randomised controlled trials of DAs with levodopa have tended to focus on the development of motor fluctuations and dyskinesias as primary end points.1–4 Curiously these studies have also shown that the effect of levodopa on motor function or activities of daily living (measured by Unified Parkinson’s Disease Rating Scale (UPDRS) parts II and III) was superior to that obtained by the DAs, irrespective of whether the latter were administered as monotherapy or with open label levodopa supplementation.1–4
Our understanding of the reasons behind why the DAs were consistently less effective than levodopa on the UPDRS is poor, particularly as these RCTs were performed double blind. Two plausible explanations are: (1) the UPDRS does not capture the whole picture; for example, the DAs and levodopa may have differential effects on mood; or (2) the dose ranges (therapeutic levels) deployed in these studies were set so that the DAs were slightly suboptimal compared to levodopa, but this difference was not apparent to the blinded clinicians assessing the trial patients.
The latter notion encouraged us to examine the dose of the DAs used to treat PD in routine clinical practice. Thus we systematically reviewed the database of all the PD patients under our care in order to identify those receiving DA therapy (cabergoline, pergolide, pramipexole, or ropinirole) above their maximum recommended therapeutic daily dose (respectively 6 mg, 5 mg, 4.5 mg, and 24 mg per day).7
We identified 18 patients fulfilling these criteria. All were either on cabergoline (n = 11) or pergolide (n = 7), which are ergoline derived dopamine agonists. This represents about 23% and 27% of PD patients in the practice receiving cabergoline or pergolide respectively. In these patients the dose of the appropriate dopamine agonist had been titrated upwards against clinical response (as would be the case with levodopa). There were no patients on “high” doses of the non-ergolide DAs pramipexole or ropinirole, even though the distribution of patients on each DA within the practice was: 45% cabergoline, 21% pergolide, 17% pramipexole, 17% ropinirole. This was probably because of our greater duration of therapeutic experience with the two former drugs.
Table 1 illustrates the clinical characteristics of these patients and shows that cabergoline and pergolide are tolerable, over mean follow up periods of 2.3 and 2.5 years respectively, at dosages well above those recommended in their data sheets. Indeed it is clear from these data that the therapeutic windows of the ergoline derived dopamine agonists are at least twice that presently acknowledged.7
Consequently, we speculate that the ergoline derived dopamine agonists (cabergoline and pergolide) may not have been deployed to their full therapeutic potential, either in the major RCTs comparing DAs with levodopa or in current clinical practice. However, we do not know whether this capacity is confined to the ergoline derived DAs. As the direct acting DAs are now considered to be first line therapy for younger people with Parkinson’s disease, we would be very interested to hear of other neurologists’ experiences of using these drugs for prolonged periods above their recommended doses. There is a case for further studies involving high dose dopamine agonist treatment for people with PD.
Finally, it should be noted that serosal inflammation is a rare, probably idiosyncratic, potentially reversible complication of ergoline derived dopamine agonist administration, which typically develops about two years after introducing this class of drug.7 However, we have not encountered this problem in our practice.
We would like to thank Patrick O’sullivan (drug information pharmacist, Charing Cross Hospital), Janet Munro (Lilly), and Kevin Bridgman (Pharmacia) for assisting with our search for data on serosal inflammatory disorders associated with pergolide and cabergoline therapy in Parkinson’ disease.
Competing interests: PN was reimbursed by Pharmacia for attending the XIV International Congress on Parkinson’s disease (Finland, 2001). The authors also conducted two double blind trials comparing the antitremor effects of pergolide with pramipexole, to which Pharmacia freely supplied the masked medications.