Time-Lag between Establishing Clinical Pharmacology Principles and Advances in Practice: The Case of Tolerance to Levodopa

Levodopa is widely used, but rarely is the topic of tolerance raised. Escalating requirement and ‘on/off’ fluctuations are often ascribed to disease progression, rather than admitted to be iatrogenic. The risk should be discussed before introduction, since ‘weaning off’ levodopa is difficult and usually unsuccessful. Dependence on the mood elevation and relief of anxiety might add to the difficulty. Tolerance develops rapidly, especially after infusion or oral sustained release formulation. It is, in part, pharmacokinetic, being associated with the accumulation of the long t1⁄2 metabolite, 3-O-methyldopa. Therefore, effective use of catechol-O-methyl transferase inhibition should reduce tolerance.