This post raises two related questions:

Why do many PwP go unmedicated with levodopa/carbidopa at night?

Is the apparent failure of levodopa/carbidopa to address the non-motor symptoms of PD due to an insufficient dose being used?

Many PwP take drugs overnight, but many don't. For these, typically the last dose of levodopa/carbidopa of the day is at 1900 and the first dose is at 0700. This gives a gap of 12 hours between doses which, since the half life of levodopa is about 90 minutes, means that very little is left by the morning.

I used to think that it made sense not to "waste" a dose overnight or even in the late evening. My "off" is still, 12 years post diagnosis, fairly good: I can walk at normal speed, but my typing is very slow. So, often, if I'm just watching television, I'll choose to go without a dose.

Of course, the problem with this regimen is that the non-motor symptoms of PD, such as constipation, are not being addressed. The processes underlying constipation are continuous, 24/7. They require a job to be done over a few days. In a sense, their success depends on the integral (sum) of dopamine levels over time. Thus, time spent "off" likely affects constipation.

The Braak hypothesis says that PD starts in the gut, before spreading to the brain. It is reasonable therefore to suggest that the dopaminergic neuron loss is higher in the gut than in the brain, and hence that the dose required to relieve the symptoms in the gut is higher. So, titrating the dose using only the motor symptoms as the measure leads to a dose which may be sufficient for an "on" for the motor symptoms, but which I suspect is insufficient to bring therapeutic relief for the non-motor symptoms of PD.

If this is the case, two approaches to consider are: increasing the daily dose of levodopa/carbidopa, especially by using the overnight slot; trying to target the dose, so that one amount goes to the brain, and a different amount goes to the ENS.

Any comments?

John