Uncertainties in the Pharmacotherapy of Parkinson's Disease and how to solve them

The causative relationship between levodopa and the long-term motor complications of therapy, along with the possibility that levodopa may be toxic to dopaminergic neurones in vivo, has led to a move away from its use in early Parkinson's disease. Alternatives such as amantadine and the anticholinergics suffer from poor efficacy in comparison and a high side effect profile. Selegiline is probably less effective than levodopa and the issue of its safety versus neuroprotective properties remains unresolved. Long-term trials with the old and newer dopamine agonists as monotherapy have shown that as a class they can delay the development of dyskinesia and probably response fluctuations. However, major uncertainties remain about their use as monotherapy in all patients instead of levodopa. No data on their effect on quality of life and health care costs are available. Most of the trials were heavily biased towards younger patients with Parkinson's disease, so little data in the elderly are available. In later disease when patients have already developed motor complications on levodopa, the choice rests between adjuvant therapy with a dopamine agonist, a catechol-O-methyltransferase inhibitor (COMT; e.g. entacapone), and a monoamine oxidase B inhibitor (MAO B; e.g. selegiline). Trials with the former two classes have confirmed that they can reduce 'off' time, reduce levodopa dose, and improve motor impairments and disabilities with acceptable increases in adverse events including dyskinesia. Trials with selegiline as adjuvant therapy were less rigorous but it can allow a reduction in levodopa dose and motor impairments. No studies have compared these three classes of drug as adjuvant therapy so there is no evidence on which to base rational decisions in this type of patient. A large pragmatic trial which includes older patients is needed to clarify which treatment is best for different stages of the disease.