Altering Oral PD Regimens Versus Using On-Demand Therapy

Peter A. LeWitt, MD: I mentioned the different roles of tinkering with meditation or the experiments we can do to help a patient adjust medication to the best effect. I think the decision of whether to alter oral drugs, levodopa being the short-acting agent, but also to add longer-acting therapies, such as dopaminergic agonists, represents one way of handling motor fluctuations, especially the kind that can have an intermingling of delayed ON episodes and the wearing OFF episodes.

Knowing that the pharmacokinetics of levodopa immediate release last about 2.5 to 3 hours, it's quite logical to think of ways to attain a more extended release through a sustained-release formulation, of which there are several available. Unfortunately, these don't behave exactly as their title tells us. Sustained-release levodopa also has the same problems of getting out of the stomach and absorbed, as well as possible interference by protein and amino acid intake.

By and large, the experience that I've had with sustained-release formulations has been relatively unsatisfactory. You don't get 4 or 5 or 6 hours of effect with currently available products. You have delay in uptake. I think the most reliable intake of levodopa is with the immediate-release form. Sometimes it's necessary to take such doses at intervals closer than 4 hours. Three hours, 2.5 hours, or even 2 hours might be the ideal spacing, as inconvenient as that may be for patients.

To get the most constant effect of levodopa, sometimes it's necessary to increase the dose. It just so happens that 100 mg in the typical 25mg/100mg formulation of carbidopa/levodopa can achieve a therapeutic blood level, but not for everybody. An optimal dose can be 150 mg or even 200 mg per dose, even for someone with relatively mild Parkinson disease, because the efficiency of their GI [gastrointestinal] tract may be different than other patients who've experienced mild Parkinson disease.

Fortunately, the absorption of the drug doesn't seem to change over long periods. What works today is probably going to be effective 2 years from now. But what about the option of on-demand therapy? In this patient scenario, apomorphine injections were used. The problem of delayed onset of effect is one that can be very frustrating to patients, especially if they've just forgotten to take a dose. If it's an hour beyond their usual dosing cycle and they're OFF, the fastest that they're going to get back ON is in 15 or 20 minutes by oral intake.

But they have that option of an on-demand therapy with injection of apomorphine, that within 10 minutes in many instances—or certainly 15 minutes—they can reliably be back ON, in contrast to the problem of taking an oral rescue dose. I would consider that option for patients to be important, even if it's carried around and used infrequently. It might be a security blanket to be able to safely go out into the world and not worry about safety issues or getting stuck in unfamiliar places.

At work, a patient can feel confident that within a few minutes, if they happen to go OFF, they could be back ON at an optimal level. They know what to expect if they've worked out a titration effect with a drug such as apomorphine injections. It is a fairly uniform response that will occur time after time. In addition, possible adverse effects of therapy such as hypotension, nausea, and perhaps other adverse effects can be largely avoided by using a medication such as trimethobenzamide.