Spiking and sinemet dosage question
 

Hello, I am posting this question for a friend, but I have a similar interest (I'm currently taking 2 or 3 25/100 sinemet a day and not always at the same time each day):

I am concerned, like everyone else prescribed medication for Parkinson's, to minimise my risk of developing levodopa-induced dyskinesia. There seems to be a fairly established position that the risk is a function of how old you were when you first developed symptoms, how long you've had the disease, and how much levodopa you're taking. No-one can do anything about the first two, so we focus on the third.

There seems to be a newer view emerging, that perhaps the key mechanism causing dyskinesia is not so much the total consumption of levodopa as such, but rather the process of "spiking" between "on" and "off" periods, when the level of dopamine in the brain rises and falls in between levodopa doses. I have seen some academic papers discussing the biological mechanisms (that I am definitely not qualified to understand!), but my consultant has mentioned this theory as well, and has prescribed a 24 hour agonist patch partly to smooth out the spiking.

It does raise a practical question that I'm struggling with. Most days I can get by with his recommended regimen of one Sinemet tablet three times a day (12/50) plus a Neupro patch once a day (4mg), and deal with the slowness of movement as the effects wear off until the next dose of levodopa. However, some days a fourth dose of levodopa would enable me to do so much more – go out in the evenings, day trips out by public transport or extended driving without problem. Should I stick to 3 and adapt my lifestyle accordingly, or can I tweak it to 4 some days to keep my life as active as I want … in which case is it safer just to change my regimen to 4 a day all the time?

I am really interested in whether other people have heard about this idea that spiking is a major factor in the development of dyskinesia, and what the practical implications might be for levodopa treatment.

MeAndPD,

You may be interested in an app that I've written:

Parkinson's Disease Measurement: PwP, surveys, trials, analysis

You input details (time, size, drug) of each dose that you take in a day, and using pharmacokinetic parameters it draws a graph showing how your levodopa equivalent levels change minute by minute during the day. (Unfortunately it doesn't, as yet, deal with the Neupro patch.)

You can reduce the spikes by:
- taking more, but smaller doses;
- taking meds with a longer half-life;
- using meds with continuous delivery, e.g. the patch;
- timing your doses;
- basing your dosing on need, not time.
- combining with food, but not protein.

Regarding my own daily regimen, I have strong foundations of drugs which have limited variability (8mg ropinirole CR, 1mg rasagiline). Then I have five 75mg Stalevo to take as required. Often I take fewer, rarely I take more. The trick is to read your body so that you take the medication before it's needed, but in time to come on stream when it's required. For me, basing this on tremor and stiffness seems to work. (I'm trying to develop an automated decision making system, but progress is slow.)

I'm no doctor, but the limitations on the QOL that you describe seem to me to make a good case for increasing your daily dose.

John

dupdopa pump results support the theory that even levels of ldopa reduce the risk of dyskinesia, people on the pump actually get more l-dopa 'than orally, but have less dysk - 1 reason they're on the pump and the trend is if one discontinues the pump and goes back to oral l-dopa the benefit of less dysk lasts a few weeks. keep in mind that taking l-dopa probably changes the number/distribution of dopaminne receptors throughout your brain and DNA that controls dopamine production so if your dosing is irregular your're not reaching a smooth equilbrium. this doesn't matter in the early stages since your're able to mfg/store your own dopamine and that evens out the brain concentration. keep in mind your brain needs only a tiny amount of dopamine, people on agonists need less than 20mg of drug and assuming molecular weights are similar that's probably all the dopamine your brain needs.

i started on l-dopa in 2005, now up to 1gram/day and no dyskinesias, i do worry about BP going too low so i have to manage it.. i'm 63 so not holding out hope i'll be young enough for the "cure" but i think there will be a "cure" in the next 5 years so take whatever dose of l-dopa gives you the best results. especially if you believe exercise slows down progression and adding 100mg enables you to exercise "better". i wouldn't worry for a second about varying between 200-300mg/day especially since you are on the neupro. if you get dyskinesias in the future you can manage it. what i would worry about more is what are you going to do if your insurance doesn't pay for the neupro one day or you can't get it, what's the plan? sorry, i'm just a worry wort. there's always DBS which hopefully will improve.

Diphasic dyskinesia might be the case. I experienced dyskinesia only 1 yr after starting Sinemet. Some PWP never get dyskinesia. I changed treatment to adopt the Hinz protocol. This protocol claims dyskinesia is caused by carbidopa. using Mucuna Pruriens to provide levodopa removed carbidopa from the equation. It worked for me. I agree with John.

Atttempting to find balance....
 

[QUOTE=john "Often I take fewer, rarely I take more. The trick is to read your body so that you take the medication before it's needed, but in time to come on stream when it's required. For me, basing this on tremor and stiffness seems to work. (I'm trying to develop an automated decision making system, but progress is slow.)
"

John[/QUOTE]

Hi John , Meandpd and soccertese, Hercules et al,

This is very very interesting to me and I am experimenting too.

I find that if i take too much mucuna in the morning my stomach wont tolerate any food taken within 30 minutes of the first dose...so now my breakfast time is after taking first and/or 2nd dose of med which is probably a good thing as I hear that fat in the liver is metabolized with a fast between 6 pm to 12 noon.

If I wait till tremor and stiffness set in to take next dose sometimes I have to wait quite a while for dose of med to metabolize up to an hour. I have had better luck just dosing according to a 2 to 2 and one half hour schedule...and protein doesn't always seem to bother it (perhaps a blood type issue? I'm O- )......but possibly the half and half (with my fresh nectarines) does? (Please don't let it be the nectarines.....tho I do love whip cream ..... :p
) also I notice taking an effervescent form of vitamin C with small quantity B6 and vitamin E sometimes helps to activate the med...basically i'm struggling with consistency but necessity is becoming more an issue commanding me to pay closer attention and to discipline myself more carefully. Also I notice I do generally better in the Spring time.....making sense of the various cycles requires a lot of attention that seems to come very naturally to you! I notice my appetite changes also with the seasons as well as sleep patterns (which are sensitive to moon cycles!) which also may impact how med dosing goes as it seems I do better (med activates faster and smoother) following a good nights' sleep.

My med regimen is just one half pill of 10/100 sinemet and a 100mg LD capsule of mucuna...several times /day Do you notice you use up the first morning dose faster? and I'm thinking i could possibly experiment with taking just mucuna for 2nd dose though in the past have not been succesful with that. Also, i'd love to find a specific variety of cannabis that could possibly replace the sinemet...tried CBD oil (no THC)...find it great for strains and bumps from falls but not for bradykinesia and proprioception deficit. sigh...

Thanks for your posts and great thread too! any suggestions welcome...
Kind Regards,
Moondaughter

This is an old article which points to relation between weight, levodopa and dyskinesia
Relationship between weight, levodopa and dyskinesia: the significance of levodopa dose per kilogram body weight - Sharma - 28 - European Journal of Neurology - Wiley Online Library

I am amazed at how everyone (except me) can feel the sinemet kick in and feel it wearing off. I can't tell if it's working or not. It's all the same to me. Has anyone heard of someone who also has this experience? I would really appreciate any feedback you have! Many thanks.

KPNV- I was tremoring with stiffness for 16 years before I started any medication---I figured why take it before it became a quality of life issue...at first on/off transitions were very smooth but I could definitely feel a sense of groundedness and well being from the med...do you? There are some who do not have levadopa responsive parkinsons. Why take the med if it makes no difference? MD

Hi,
I was diagnosed with P.D. in my mid thirties and my then neuro was reluctant to prescribe levodopa and his reason was dyskinesia.
Eventually (5 yrs after his diagnosis) I got to the stage where my quality of life was awful.
I hadn't realised how poor it was until I like the neuro very reluctantly took my first Sinemet.
The freedom and ability to carry out normal everyday things, tasks and as a mother to 3 young children etc was such a joy to me!
I wished I'd given in to it sooner but took it slowly i.e. 50 mg each dose and titrated up slowly and with caution.
Dyskinesic movement came very quickly, within months of commencing the levodopa and after 10 yrs (5 with dyskinesia) living with PD I had DBS and to this day I've never had any dyskinesia.
So I'm now almost 14 yrs post DBS and not a wriggle or wiggle since!
I just wanted you and others to know that sometimes there is a light at the end of the tunnel with conventional evidence based medicine!
Cheers

KNPV,

Some possible reasons for not noticing any differences when taking levodopa:
- your symptoms are so mild that "normal" is little different;
- your dose is too low to take you over the therapeutic threshold;
- the absorption of the dose is affected by protein in your diet;
- you don't have PD.

Sometimes I will "lose" a dose: it just has no effect. Other than thinking that it may be linked to constipation, which I suffer from badly, I don't know the cause of this.

To measure your PD you can do a side-to-side tap test.

Parkinson's Disease Measurement: PwP, surveys, trials, analysis

There's a definite learning effect. So, do the test 10 times and throw away the results. Then do the test immediately before a dose and again 60 minutes later. Adding together the left and right hand components gives me a total score of about 40 when I'm "off" and about 60 when I'm "on".

John

Thanks very much! I will give it a try. Very helpful.

i apologize moondaughter if this reply offends you, just trying to help. i haven't taken the time to read your old posts to see how l-dopa affects you so why the 10/100 pill rather than the 25/100 carbidopa/levodopa? i've read a number of posters who take C/L with mucana mainly to get the carbidopa so the l-dopa from the mucana lasts longer, the carbidopa is just as important as the l-dopa. one other thing which i bring up is if you can't tolerate the 25/100 have you tried a different generic? i loved the TEVA generic which you can't get anymore and switched to the mylan generic, not many choices left. i think this is the same formulation as brand SINEMET, pill looks identical except sinemet isn't scored and the mylan is scored and MYLAN as far as i can tell makes SINEMET.

keep in mind that as far as eating reducing the affect of C/L, you want to have the fastest gastric emptying as possible since L-DOPA is converted by enzymes in the stomach, have to look up the enzyme and the end product, so the longer it stays in your stomach the less gets to your small intestine. so if you take C/L with any food in your stomach, even foods with little protein, it is going to slow down getting C/L out of your stomach. if you eat say more than 4grams of protein then you may not get any affect from the C/L, and you may want to take 50mg sooner, if that doesn't get you on in 45min then take another 50mg, i'm not a doctor but that's what i do if i really need to get going, i also have to check my BP when taking extra C/L.

after 14 years i still just take C/L and .75mg total generic mirapex which is sub-therapeutic but it seems to have no major side affects and my OFF condition is slightly less OFF. I do take 50/200CR and in that case you want to slow gastric emptying so i'll take it with half an apple or something else with low protein and a FISH OIL capsule if i remember since fat slows gastric emptying. so my first dose is 100 to 150mg C/L, after an hour i take 50mg of regular C/L + 50/200CR. it take 90min for the CR to start kicking in so the 50mg of C/L is needed for me at least to keep me ON for 90 more minutes. This is pretty predictable as long as i haven't eaten anything. After 90minutes i'll have a bowl of oatmeal, 1/2cup dry, and some fruit. the CR will give me 2.5-3hrs, and i repeat the pattern, regular C/L followed by CR, i have found that taking CR twice in a row can occasionally result in too much L-DOPA since food actually extends how long it can last so it can be unpredictable. most people would think i'm crazy following this dosage regime, maybe i am. i keep planning on trying mucana, just lazy i guess. so not knocking mucana as an adjunct and just wanted to describe what i do if it might give you some ideas. and suffice it to say i get most of my calories/protein at night.

i will say this about carbidopa, a study was done a few years ago where i think the amount of carbidopa was increased at least 100%, maybe it was 400%, to see if there was a chance high doses could penetrate the BBB, and the result was no, patients tolerated it ok and had tiny improvement in their pd symptoms. and without carbidopa we'd be taking 1gram pills of L-DOPA and we just wouldn't take it due to side affects - extreme nausea - and cost.

A recent post on the SoPD blog contains a good overview (IMHO) of mucuna pruriens. It seems that there is some evidence to support a possible anti-dyskinetic element.

Plan B: Itchy velvet beans – Mucuna pruriens | The Science of Parkinson's disease

Less can be more!
 

Thanks so much for your thoughtful reply Soccertese.....Managing C/L in/up take with gastric emptying speed is a juggling effort for me too.... I'm so glad you have found some consistency from your regimen....I find my dietary needs/responses seem to change with the seasons....and who knows what else....Why is it that food and supplements can provide a positive effect for awhile.. then lose their effectiveness?

I used to take 6 doses of 25/100 generic sinemet but reached a point where it was becoming less and less effective so I revisited mucuna. I had tried mucuna years earlier (w and w/o straight carbidopa) and didn't like it but for whatever reason my body does really well with it now . If I take mucuna with just carbidopa I don't feel it..so it seems there is something about the LD in the sinemet that catalyzes the LD in mucuna ?

I am always looking for opportunity to decrease sinemet and when I found that I could get a positive response with 10/100 I was really happy...no need to take more .

Recently in the news there has been talk of microdosing cannabis/marijuana .....that very small doses increase focus and energy and overall have an antiaging effect in older people where as large doses cqn have the opposite in younger people... Why Microdosing Is Taking Over Medical Marijuana - Rolling Stone

I think the same could apply to parkinsons med intake..that less can be more...but I think in order to achieve this one has to be very judicious and take only what is needed...(and, at the risk of what might appear as a contradiction )which, at times, IS more ... otherwise you become addicted ( which scrambles the messages in a negative feedback loop) ... I take this approach in an effort to listen to my bodys' intelligent signalling.

will note your observation of generic brands...

With Kind Regards,
MD

moondaughter, i assume eventually we lose the ability to convert l-dopa to dopamine in our brains but the success of intravenous l-dopa via a patch pump and duodopa delivered l-dopa sows that this is a much more complicated situation. if inhaled l-dopa ever gets approved it will be interesting to see if bypassing the gastric system can give a consistent ON and can be a tool in investigating if you have digestive system problems, remember the heliobacter bacteria claims. ON'S seem be more consistant in advanced pd'ers with IV and intestinal (duodopa) delivery. the patch pump product hasn't reached the market yet, i think.

tap test good indicator for testing effects of various foods and supplement for PWP?
 

Dear JohnT,

Have you experimented with tap testing combinations of food and supplements ( taken
WITH/or before or after) the meds such as circumin , magnesium etc etc? Seems to me this could be helpful for testing increased dopamine levels resulting from these in combination with med regimen, depending how subtle of a signal that would be picked up - timing too. Sort of like biokinesiology (commonly referred to as "muscle testing") but specific to dopamine levels instead of an overall strengthening/weakening response.

MD