Levodopa/carbidopa: dose required for non-motor symptoms?
 

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

Hi John,
Sounds like you're going well 12 yrs on. I think if you don't need the evening dose unless perhaps you were out and about or needed to type then just leave it as is.
The fact that you can comfortably with a degree of normality turn over easily in bed go to loo etc is my thinking on that.
Are you ok with say 100 mg Sinemet first thing in the morning?
If not enough the fact that you've gone 12 hrs with no levodopa you might not move as well?
If thats the case perhaps increase your morning first dose by 50 mg if still unable to dance around the room maybe an extra 100 mg?
Not sure what ENS is.
Your bowels would IMO open more easily when on I'm sure.
Anyway been meaning for ages to tell you I enjoy your posts.

Firstly, thanks very much for sharing your thoughts on this topic, johnt.

"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, ...".

I may be wrong, but my understanding is that it doesn't work that way. My understanding is that the dopaminergic neurons in the substantia nigra produce dopamine, and that dopamine is used in the striatum, for control of muscles. Whether those muscles include the muscles associated with the GI tract, and if not, where the GI-tract muscles are controlled from, I'm not sure.

Also, it is my understanding that the neurons of the Enteric Nervous System (ENS) can tolerate the presence of alpha-synuclein aggregates. It is the dopaminergic neurons of the substantia nigra (and the cholinergic neurons of the locus coeruleus) which can not.

However, the hypothesis that medicating during the night might improve non-motor symptoms such as constipation, is worthy of investigation (IMHO).

made it up,

Thank you for your kind words.

I'm sorry that I slipped into jargon. ENS is the enteric nervous system. It basically controls the gastrointestinal tract. It has been called a second brain.

According to Wikipedia [1]:

"The enteric nervous system in humans consists of some 500 million neurons ... one two-hundredth of the number of neurons in the brain, five times as many as the one hundred million neurons in the human spinal cord ... The enteric nervous system is embedded in the lining of the gastrointestinal system, beginning in the esophagus and extending down to the ****."

[The **** above has been generated automatically to replace the name of a part of the body. Perhaps some people think that some people may find it offensive!]

The gut contains "about 50% of the body's dopamine".

The ENS is protected in a way similar to how the BBB (blood brain barrier) protects the brain.

The higher accessibility of the ENS compared to the brain may make it a better location for surgical intervention. An ENS equivalent of DBS, for instance?

It seems to me that because we can't see the non-motor symptoms of PD we ignore them. PwP, and medics, and researchers need to focus more on the non-motor symptoms of PD.

Reference:

[1] Enteric nervous system - Wikipedia

John

johnt said: "The gut contains 'about 50% of the body's dopamine'."

Humm... I can see now that there is clearly a gap in my understanding of how "gut" dopamine is produced, and how it is used.

John, once again you've raised a very interesting question. I can't say that I know much about PD and constipation, as luckily this is one symptom I haven't had to deal with. However, if we're just making some educated assumptions, or guessing, these would be my thoughts:

1. There hasn't been much, if any, research that has shown the L/C has had any beneficial impact on constipation, as a symptom. In fact, it's the opposite, as many studies on L/C have shown it to cause constipation as a side effect (as do many of the other drugs we take).

2. You are absolutely correct in your statements about the ENS, which functions as a second brain, autonomous to the CNS. The large majority of all of our neurotransmitters that the body uses (as much as 95%) are produced and used here.

3. The dopamine produced in the ENS doesn't pass through the BBB. This is the reason we take Levodopa (a dopamine precursor) along with Carbidopa (or Entacapone also) to get it through the BBB so it can be turned into dopamine.

4. If the above assumptions are generally accurate, then it is unlikely that consuming extra L/C will have much, if any, impact on constipation as it is mostly bypassing synthesis in the gut. Once it's synthesized in the brain, it can't pass through the BBB back to the gut.

I do wonder what the effect on the gut would be if levodopa was taken without carbidopa. Would that have any impact on constipation?

Just some thoughts which I honestly can't say are accurate.

Gary

This is so interesting! I've just come from my family doctor who has been trying to figure out why I have so much mucus clogging up my throat at night that I spend half the night trying to cough it up. We've looked at food allergies, environmental allergies, septal deviation, tried various meds. In the six months it's been plaguing me we've travelled quite a bit, eaten completely different food in different places. Nothing ever made sense and none of the meds worked. I've been exhausted from lack of sleep and steadily more frustrated. Today he did some more research and discovered that rhinorrhea (runny nose, my mucus just goes back instead of forwards). is a non-motor symptom of PD. I was horrified because there is no proven treatment for it. They do suggest ipratropium nasal spray.

But maybe all I need is to take my PD meds in the late evening and maybe during the night. I 've always thought it was a good thing to lminimize the number of doses, but maybe not. I've only considered the motor symptoms until now

On the subject of whether levodopa helps or hinders constipation the message from the literature is mixed.

According to Poirier et al. [1]:

"Anismus, the abnormal contraction of the external **** sphincter and puborectalis muscle during attempted defecation, is another problem that can occur in synergy with constipation in approximately 65% of PD patients, which is more frequently observed during “off” periods".

[Once again let me report that **** has been generated by the system. It must be a truly scary word.]

On the other hand, the Merck information sheet for Sinemet [2] says that constipation has been reported as an adverse reaction to Sinemet.

As an aside, I used to assume that for something, X, to be described as a "side effect" of a treatment, T, then T had to cause X, or at the very least T had to make X worse. Instead time after time I see many of the less noted symptoms of PD listed as side effects. It's as though causality can no longer be assumed. This is not just a technical point, whether causality is implied affects my decision to take or not to take L/C when I'm constipated.

Reference:

[1] "Gastrointestinal Dysfunctions in Parkinson’s Disease: Symptoms and Treatments"
Andrée-Anne Poirier,1,2 Benoit Aubé,1 Mélissa Côté,1,3 Nicolas Morin,4 Thérèse Di Paolo,1,2 and Denis Soulet
Hindawi Parkinson's Disease 2016
https://www.hindawi.com/journals/pd/2016/6762528/

[2] https://www.merck.com/product/usa/pi...sinemet_pi.pdf

John

I've spent some time trying to fill that "gap in my understanding of how 'gut' dopamine is produced, and how it is used". I can't say that I've got very far yet, but there are a couple of things worth mentioning.

Firstly, I spotted an error in my first post. When I said "It is the dopaminergic neurons of the substantia nigra (and the cholinergic neurons of the locus coeruleus) which can not [tolerate the presence of alpha-synuclein aggregates]", that should have been "It is the dopaminergic neurons of the substantia nigra (and the locus coeruleus) which can not [tolerate the presence of alpha-synuclein aggregates]".

Secondly, I came across an interesting research paper, which seems relevant [1]:

"The principal components of the enteric nervous system (ENS) are two neuronal networks, the myenteric and submucosal plexus (SMP) ..."

"A recent autopsy survey indicated that there was no global or dopaminergic loss in the myenteric plexus in PD ..."

"Our results indicate that there is no evidence of dopaminergic and noradrenergic neuronal loss in the SMP in PD, thereby suggesting that neuropathology in submucosal neurons is unlikely to be a causative factor for GI dysfunction in PD."

[1] Appraisal of the Dopaminergic and Noradrenergic Innervation of the Submucosal Plexus in PD, Corbille et al., J Parkinsons Dis. 2014;4(4):571-6.

Appraisal of the dopaminergic and noradrenergic innervation of the submucosal plexus in PD. - PubMed - NCBI

I forgot to include a summary in my previous post, so here it is:

If I've understood johnt correctly, his hypothesis is based on the following premise:
"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, ...".

If I have understood reference [1] correctly (see previous post), PD researchers (up until 2014 at least) can find no evidence of dopaminergic neuron loss in the gut.

As always, I'm happy to be corrected.