Boxtel et al. write [1]:

"Classically, the worsening of clinical signs in patients given very low dose antiparkinsonian drugs is explained by a preferential stimulation of presynaptic dopaminergic receptors ... limiting release of endogenous dopamine."

This observation complicates the prescribing process: a baseline result, followed by a negative result is not, in itself, adequate to conclude that an antiparkinson medication is not efficacious.

It may also explain why I perform fairly well in the morning before taking the first dose of the day, but get worse briefly while the drug's absorbed up to working levels. I often go 12 hours, 8 half-lives of levodopa, overnight between doses, so the drug has almost been washed out.

It also suggests that too much exogenous levodopa may lead to a decrease in endogenous dopamine production. This would favour the "runway" hypothesis of dosing, rather than the, I think, currently favoured "use or lose" hypothesis.

Reference:

[1] "Drug Benefits and Risks: International Textbook of Clinical Pharmacology"
edited by C.J. van Boxtel, B. Santoso, I.R. Edwards

John

John,

I'm not familiar with the "runway" hypothesis or the "use or lose" hypothesis (and I couldn't make Google understand what I was searching for).

Can you provide a link, or a brief explanation?

thanks,
Jeff

Jeffreyn,

I'm sorry that my use of double quotes was unclear. I did not intend for them to indicate a direct quote, but, rather to indicate common-place metaphors. Like you, I couldn't find any direct examples on Google, so they are not as common in this context as I'd expected.

What I was trying to get at was that there are two approaches to the timing of initiating levodopa treatment, as Fox and Lang write [1]:

"Preventing the development of motor complications is one of the
principal concerns when treating patients with Parkinson’s disease,
and ‘levodopa-sparing’ approaches have been commonly touted
as the best method of achieving this. Early use of dopamine agonists,
rather than levodopa, was the preferred management strategy
in the 1990–2000s, and several large randomized controlled trials
reported delayed development of motor complications with this
approach. However, follow-up studies revealed that once patients
were started on levodopa, they developed motor complications of
the same severity and at the same rate irrespective of whether
levodopa had been initiated earlier or later."

Reference:

[1] "‘Don’t delay, start today’: delaying levodopa does not delay motor complications"
Fox S., Lang A.
Brain, 2014
‘Don’t delay, start today’: delaying levodopa does not delay motor complications | Brain | Oxford Academic

John

Hi John

Yes I also experience a worsening of pd symptoms after the fist dose, but then I do after every dose at times, though mainly my 1st and 2nd. I was told it was because of wearing off between doses. I pointed out the fact that the main one was the first and that the stalevo had been nil for some hours. I was ignored. I said I'm often better first thing than during the night. I was told of course sleep recharges any remaing cells, I said it's the same if I've not slept or had only 2 hr. I was ignored.

OCD and panic attacks so bad I was taken to hospital have resulted in me suddenly having to reduce ropinirole. It was increasing this and switch to stalevo that brought me to the forum. Early 2016 I posted finally mastered 12mg. I was then ramped up to 16 mg and now back to 10 mg !
Another 1.5 yrs wasted !
Tuning a Ferrari they say ? This post illustrates what I've always believed Parkinson's is all smoke and mirrors. There are more theories created, challenged, archived and re-done than I'd ever believe. I don't know but I certainly believe there are some fundamental faults in the current bible of all things parkinsonian.

Hope everyone's as well as possible
Keep batting folks !

Nigel

Nigel,

I'm sorry to hear of your experience.

I'm a great fan of making changes in small steps, measuring the effect of the changes, and always having a previous state to go back to if a new regimen proves unsuccessful. I think that while a PwP is looking for a new stable regimen, changes need to be made frequently, perhaps weekly. Waiting the typical 6 months between consultations means that some PwP may never get close to an optimal treatment.

John

Hi John,

Chemistry seems subject to so many variables and though top down hierarchical logic can prove useful I feel it is good to see chemistry in the context which recognizes there are unknown factors (which leaves us with what can be observed -what modalities effect a better or worse response). Having said that I hold as a constant in my way of seeing things that the body possesses the ultimate intelligence in economy and how to distribute and circulate nutrient etc...( but even that is subject to a context of evolution verses devolution/ anabolic vs catabolic ) which is why I wait as long as possible to repeat dose and attempt to dose according to NEED with a general strategy of every 3 to 4 hours...and have been able to delay 1st morning dose till sometimes 10:30 AM (not this morning) and last dose usually by 4PM . I will watch to see if I experience feeling worse after dosing (hard to tell if I am lying down because lying down itself discourages endogenous dopamine production for me)....I do notice that if I eat right after (but not before) taking med I often will end up vomiting . Do you think it would be useful to identify and pay closer attention to ones own unique circadian rhythms etc.? I think that some individuals may do better with periodicity and others need change in their routines...(and this also holds true with nutrition and environmental temperature requirements) because what provides balance is different for each of us. I remember you mentioned you fare better in the summer...traditionally its been the Spring for me ! Thankyou for this post!!
Kind Regards,
MD

Thank you John,

I was reduced from 16mg requip to 12mg over a 4 week period, then the drop was compensated by increasing my 4 x daily stalevo 150's to 4 x 175's. The change in my mental well being has been both dramatic and interesting. I am so much my old self now and could 'feel' the change happening, very weird.
I presented at the clinic such a positive change they decided to tweek the ropi down to 10mg. I had to tease it out of them but their rationale is the agonist is causing anxiety = worsening PD. (Something I raised 3/12 after dx)
So now I'm on 10mg requip xl and 4 x stalevo 175mg, I think the LED is slightly lower than the original.
It takes me an age to adjust dose alteration, eg I dropped to 10mg 3 weeks ago and only now am I hitting the withdrawals, it'll be 2 weeks more to see if I can live with it, at which time they may up stalevo again.
These are the positives of reducing requip xl for me

Improving peripheral oedema, foot discolouration
anxiety levels normal
nausea, gut motility improved
although stalevo increased now when I'd dropped from 16mg to 12mg I felt no worse on 12mg.
periods of greater fluidity which are increasing.

I'll post back with updates in case anyone is in a similar position.

One final point, it was the nurse specialists who have instigated this drop and the neurologist who ramped me up to 16mg and did so without ever testing me with taps, tuning, gait observation etc.

When I first started taking it I felt worse initially, that went away after a month or so.