We define the meaning of early and late treatments and present arguments opposed to early treatment with levodopa. These are based on the development of complications with long-term Sinemet which include clinical fluctuations, loss of efficacy, and painful dystonic cramps. By delaying the onset of levodopa therapy until the symptoms require this most potent of antiparkinsonian agents, we can delay the onset of these disabling problems. Also, using as low a dosage as possible should reduce the risk of any long-term complication related to accumulative dose.

We also present the serial evaluations of 26 patients followed for as long as 7.5 years before levodopa therapy was initiated. Three scoring scales on these patients are compared. Arguments are presented which suggest that the Columbia University and the ADL scales are superior to the UCLA scale, and more closely approximate the curve of the progressive clinical disability of the disease as assessed by global evaluation. We conclude that the ultimate answer to any clinical debate must come from well-designed, controlled studies to assess the differences between two treatment modalities.

Complete withdrawal of all levodopa compounds “drug holiday” for a period of at least one week in severely disabled, unresponsive Parkinson patients may influence receptor blockade by resensitizing and can alter denervation hypersensitivity.

Twenty four patients with 31 holidays were evaluated. Transient improvement was noted in most patients, however significant long term benefit of over 1 years duration occurred in only 6 individuals.

In view of the unpredictability and limited responsiveness, drug holiday has not yet been established as a satisfactory treatment for the severe, intractable problems associated with chronic levodopa administration in Parkinson patients. Further trials appear to be warranted.

Parkinson’s disease is associated with a variety of neurotransmitter disturbances which may be further altered by its treatment with dopamine agonists. Based on this information a wide range of pharmacological approaches have been used in search of newer treatment alternatives and in hopes of reducing complications of long-term levodopa use. This paper reviews the various therapies which have had some success in the management of Parkinson’s disease, other than levodopa and dopamine agonists. Special emphasis is placed on the many unresolved questions and controversies that exist in this area of neuropharmacology.

Dopamine agonists have yielded two important advances to our understanding of the basal ganglia – they have facilitated the subdivision of different classes of dopamine receptors, and they have established the fact that important dopaminergic effects can be achieved by activation of dopamine receptors in a manner that is unrelated to anoxal impulse traffic in dopaminergic neurons – a phenomenon similar in its diffuse, slow, characteristics to an endocrine effect.

The tangible clinical benefit of dopamine agonists has been evident in patients with prominent dyskinesia or wearing off reactions. It is possible that earlier use of agonists, in low doses combined with similarly low doses of levodopa, may improve the long term treatment of Parkinson’s disease, but as yet there is no firm evidence.

In the future, we can expect to see agonists with more prolonged effects, deriving from the formation of active metabolites. We can also hope to gain further insight into the correlations between the various animal models of dopaminomimetic activity, and specific aspects of drug efficacy and toxicity in parkinsonian patients. Such information should allow the design of improved pharmacotherapy.

The results obtained with high and low dose bromocriptine therapy were compared in a review assessing the per cent of patients showing improvement (not taking account of the extent of improvement). It is concluded that the response rate with low dose bromocriptine is as good as that obtained with high dose therapy for both de novo and levodopa treated patients. The incidence of adverse effects is similar in the high and low dose treatment groups: More levodopa reduction results in a higher daily bromocriptine requirement. A statistical analysis of 61 bromocriptine-levodopa treated patients showed no positive correlation between bromocriptine dose and severity or duration of Parkinson’s disease.

The long term consequences of the use of a dopamine agonist, bromocriptine, in the treatment of Parkinson’s disease are reported. In a first study in 82 patients showing late side effects of levodopa, bromocriptine permitted a significant decrease of the gastro-intestinal adverse effects. In contrast, no significant improvement of end of dose deterioration from levodopa was noted. In cases where levodopa had ceased to be active, bromocriptine produced an improvement in the clinical state. The drug was ineffective in the very advanced stages of the disease or in the cases of dyskinesias without “on-off” effects. Bromocriptine did not significantly improve freezing or “on-off” effects, but reduced other side effects of levodopa, in particular dystonia. In a second group of 29 patients who had never received levodopa treatment, bromocriptine was shown to be very effective as a first treatment of the disease. The most important finding was the absence of long term side effects similar to those usually observed under levodopa: in this group and in comparison with 38 patients taking levodopa, dyskinesia, dystonia, oscillations in performance and especially “on-off” effects were not noted. However, a partial loss of efficacy of bromocriptine was observed in 27% of cases. In a third group of 10 patients, bromocriptine introduced according to a low and slow protocol was found to be active in a limited number of patients only.

Experience with bromocriptine in 106 patients treated over nine years was reviewed. Most of the patients were already being treated with levodopa (combined with a peripheral decarbosylase inhibitor). These patients, after having initially achieved a good response to levodopa, were no longer responding satisfactorily. Most of the patients were also experiencing diurnal oscillations in performance: “wearing off” and “on-off” phenomena. In these patients previous attempts at changing the dose (increasing or decreasing) or changing the scheduling of levodopa had been unsuccessful. Bromocriptine was added to levodopa beginning at a dose of 5mg/day, and each week was increased by another 5mg/day. At a dose of bromocriptine of at least 25 mg/day, there was a decrease in disability in the majority of patients with a decrease in the severity of the diurnal oscillations in performance (especially “wearing off” phenomena). In most patients, the addition of bromocriptine resulted in an approximately 10% reduction in the dose of levodopa. The majority of patients sustained their improvement at least one year. In some patients improvement was sustained for up to five years. The therapeutic efficacy of bromocriptine was limited in many patients by the occurrence of adverse effects including mental changes, dyskinesias, orthostatic hypotension, and nausea. These adverse effects could often be minimized by reducing the dose of bromocriptine or levodopa. All adverse effects were reversible upon stopping the drug. We have found bromocriptine to be a valuable adjunct in the treatment of these patients.