Management of response fluctuations - Practical guidelines

More than 50% of patients with Parkinson's disease (PD) develop response fluctuations following prolonged treatment with levodopa. Some are due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of post synaptic dopaminergic receptors. Other fluctuations, especially the "delayed on" (increased time latencies from dose intake to turning "on") and "no on" (complete failure of levodopa dose to induce an "on" response) are caused by peripheral pharmacokinetic mechanisms. Patients with PD, especially those with response fluctuations, have gastric atony. The reduced motility of the stomach, combined with the poor solubility of levodopa, is the cause for the delayed and incomplete absorption of levodopa. The best strategy to overcome central pharmacodynamic mechanisms and to increase daily "on" hours can be achieved by using dopamine agonists, controlled release preparations, MAO-B and COMT inhibitors. Therapeutic strategies that improve levodopa absorption are needed to overcome response fluctuations that are caused by peripheral mechanisms. This can be achieved by crushing levodopa and drinking it as a suspension. Administration of crushed levodopa or levodopa/carbidopa/ ascorbic acid solutions orally or through gastroduodenal or gastrojejunostomy tubes may also be helpful. Prokinetic drugs, such as prepulsid, improve absorption of levodopa by enhancing gastric motility. Bypassing the stomach by subcutaneous dopamine agonists (apomorphine and lisuride pumps) or by the novel prodrug of levodopa, i.e., levodopa ethylester, may produce dramatic rescue from incapacitating "off" states.