of levodopa must be reduced over time to avoid adverse effects at doses that were well tolerated initially. Some patients become less responsive to levodopa, perhaps because of loss of dopaminergic nigrostriatal nerve terminals or some pathologic process directly involving striatal dopamine receptors. For such reasons, the benefits of levodopa treatment often begin to diminish after about 3 or 4 years of therapy, regardless of the initial therapeutic response. Although levodopa therapy does not stop the progression of parkinsonism, its early initiation lowers the mortality rate. However, long-term therapy may lead to a number of problems in management such as the on-off phenomenon discussed below. The most appropriate time to introduce levodopa therapy must therefore be determined individually.
When levodopa is used, it is generally given in combination with carbidopa (Figure 28–3), a peripheral dopa decarboxylase inhibitor, which reduces peripheral conversion to dopamine. Combination treatment is started with a small dose, eg, carbidopa 25 mg, levodopa 100 mg three times daily, and gradually increased. It should be taken 30–60 minutes before meals. Most patients ultimately require carbidopa 25 mg, levodopa 250 mg three or four times daily. It is generally preferable to keep treatment with this agent at a low level (eg, carbidopa-levodopa 25/100 three times daily) when possible, and if necessary, to add a dopamine agonist, to reduce the risk of development of response fluctuations. A controlled-release formulation of carbidopalevodopa is available and may be helpful in patients with established response fluctuations or as a means of reducing dosing frequency. Even more helpful for response fluctuations is a new extended-release formulation (Rytary) that is now available in the USA. A formulation of carbidopa-levodopa (10/100, 25/100, 25/250) that disintegrates in the mouth and is swallowed with the saliva (Parcopa) is available commercially and is best taken about 1 hour before meals. The combination (Stalevo) of levodopa, carbidopa, and a catechol-O-methyltransferase (COMT) inhibitor (entacapone) is discussed in a later section. Finally, therapy by infusion of carbidopa-levodopa into the duodenum or upper jejunum appears to be safe and is superior to a number of oral combination therapies in patients with advanced levodopa-responsive parkinsonism with response fluctuations. A permanent access tube is inserted via a percutaneous endoscopic gastrostomy in patients who have responded well to carbidopa-levodopa gel administered through a nasoduodenal tube. A morning bolus (100–300 mg of levodopa) is delivered via a portable infusion pump, followed by a continuous maintenance dose (40–120 mg/h), with supplemental bolus doses as required.
Levodopa can ameliorate many of the clinical motor features of parkinsonism, but it is particularly effective in relieving bradykinesia and any disabilities resulting from it. When it is first introduced, about one third of patients respond very well and one third less well. Most of the remainder either are unable to tolerate the medication or simply do not respond at all, especially if they do not have classic Parkinson’s disease.
A. Gastrointestinal Effects