The question of immediate release versus controlled-release carbidopa levodopa is a frequent topic here, so it is high time to have a post specifically addressing this issue. Chart source: ingentaconnect.com/contento...
With reference to the above chart, if a person is dosing at 5 hour or greater intervals, the controlled-release formation provides a much more even level of levodopa. On the other hand, if a person with more advanced Parkinson's is dosing at 4 hour intervals or less, the immediate release version is more appropriate, because the controlled-release levels will overlap, causing a "stacking" effect of increasing levodopa levels.
To get a graph of your Levodopa Equivalent Plasma Levels, use the excellent application created by fellow member johntPM, available at this link: parkinsonsmeasurement.org/t...
Regarding food, according to the Sinemet CR label: dailymed.nlm.nih.gov/dailym... "The extent of availability and peak concentrations of levodopa after a single dose of SINEMET CR 50-200 increased by about 50% and 25%, respectively, when administered with food."
Also from the label: "In elderly subjects, the average trough levels of levodopa at steady state after the CR tablet were about 2 fold higher than after the standard SINEMET (163 vs. 74 ng/mL).... In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with SINEMET CR fluctuated in a narrower range than with SINEMET. "
Update 10/21/2021 - CR vs IR, the Debate
I personally favor the controlled-release version. By all means those who are better served by immediate release should continue with it.
It is not true that immediate release is always better. Doctors tend to prescribe immediate release by default, for infrequent dosing, without educating the patient as the pros and cons of the different versions, and this is wrong.
This study followed 618 patients over a period of five years. Half of them took CR and the other half took IR Sinemet:
It found:" Activities of daily living scores in the Unified Parkinson Disease Rating Scale (UPDRS) consistently favored the Sinemet CR treatment group and a number of the NHP scales also favored the CR group. ... There was a statistically significant difference (p < 0.05) in activities of daily living as measured by the UPDRS in favor of Sinemet CR." On other measures the results of the two formulations were similar.
Since publication this study has been cited 304 times by various researchers:
I did not see any of these contradict the above study. So is has stood the test of time.
If doctor's opinions were as good as double-blind studies we would not need to bother with them. That is not the case - investigator bias is all too real a factor, and an M.D. busy in clinical practice is not in the position to carefully test, monitor and tabulate results, particularly of similar reasonably good treatments. Opinions are not evidence and that includes the renowned Doctor Ahlskog. He alleges the following drawbacks to the CR formulation:
"1. Effect: 60-90 minutes longer than regular carbidopa / levodopa
2. Slow to kick-in and more erratic
3. Complex interactions with food
4. Not a mg-to-mg correspondence with regular carbidopa/levodopa"
Taking these point by point:
1. Yes that is the point of CR which is why it is better for infrequent dosing
2. Yes it is slower to kick in. We take levodopa on a schedule, which allows for time needed to kick in. We do not wait for the moment we think we need another dose. I have not seen any evidence that is "more erratic"
3. No evidence cited to support this allegation
4. True it is not a milligram to milligram correspondence. It is is a simple matter to take a bit more. Better yet, simply starting with the CR version moots the issue of needing to find an equivalent dosage.
Further details for data wonks:
In searching for the appropriate chart, there were an excess of hits for "ER CD-LD", which is actually Rytary and therefore not relevant to the discussion. The terminology used in the title for this post follows that used in the reference for the chart. The actual names for medications are "Sinemet CR" for the original medication, and "carbidopa levodopa ER" for the generic.
More from the Sinemet CR label: "In healthy elderly subjects (56-67 years old) the mean time-to-peak concentration of levodopa after a single dose of Sinemet CR 50-200 was about 2 hours as compared to 0.5 hours after standard SINEMET. The maximum concentration of levodopa after a single dose of Sinemet CR was about 35% of the standard SINEMET (1151 vs. 3256 ng/mL)."
These levels are different than the chart because dosage used here was twice the dosage in the chart. Note in the chart that peak CR level is 67% of that of the IR formulation vs. 35% per the label. This discrepancy is due to different sources of data – the chart comes from "database within IMPAX Laboratories, Inc., based on studies conducted by IMPAX Laboratories", whereas this Sinemet label comes from the Sinemet sponsor Merck Sharp & Dohme Corp. Adjusting for different dosages, the CR levels are comparable, but the peak IR level measured by Merck is about twice that measured by Impax. I am inclined to credit the Impax number because I have not seen information elsewhere that supports the Merck number.
Continuing with the label text: "The extent of availability of levodopa from Sinemet CR was about 70-75% relative to intravenous levodopa or standard SINEMET in the elderly. ... Because the bioavailability of levodopa from SINEMET CR relative to SINEMET is approximately 70-75%, the daily dosage of levodopa necessary to produce a given clinical response with the sustained-release formulation will usually be higher."
Update 6/2/2023 - Gender Differences in Plasma Levels
The foregoing concerns plasma levels of levodopa. That is not the same as the level of dopamine in the affected neurons. There is a delay getting through the blood-brain barrier, and another delay turning levodopa into dopamine. Following that, the dopamine persists for some time. I've noticed I still receive some benefit even hours after my plasma levodopa is gone.
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park_bear
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Individual circumstances vary, but it is often cheaper to pay cash at Costco mail-order pharmacy than to get meds via a profit-seeking medical insurer.
The graph in this study on Rytary is a better representation. ncbi.nlm.nih.gov/pmc/articl... There are 3 components in Rytary including an immediate release portion.
"In searching for the appropriate chart, there were an excess of hits for "ER CD-LD", which is actually Rytary and therefore not relevant to the discussion. "
"Official study" is a misnomer. The officialdocument that is generated as a result of FDA approval is the label. It summarizes the studies that resulted in approval. I cited the label extensively in my post:
It looks like CR version is very tricky. I think I would choose to stay on immediate release. Kind of scary reading that information. thanks for the information
Is ERc/l the samec/l as IRc/l. Is the ER a different drug. Currently on c/l IR (25-100) every 6 hr. I don't want to get more side effects from something different.The c/l was increased because I an having issues with constipation,gas and bloating. I have been waking up with gas,bloating and intense tremors.I asked to have a stool analysis to see if I have IBS or parasites. Both the neurologist and movement specialist deferred to PCP. The PCP ordered a CT scan instead of a stool analysis. The additional problem with constipation,gas and bloating is that it causes pressure on my right side which results in the right side tremoring,and cramping. All of that is usually resolved afterI have a bowel movement or passing gas .Previously on c/l (25-100) every 8 hrs. your thoughts. Thank you! the other recommendation Is to take c/l every 4hrs and ER c/l at night .I think that is too much.
IR stands for immediate release and ER stands for extended release. Both versions have the same amounts of carbidopa/levodopa, just the timing is different.
I take immediate release Sinemet five times a day I put it under my tongue instead of swallowing it. some gets into my bloodstream almost immediately and what I swallow last little longer going through my digestive system.Also take mucuna puriens five times a day. I take b1 twice a day. Alternate and take something every 2 hours.
I'm with you ,Coot. Sometimes didn't have water handy so started letting pill dissolve in my mouth. Doesn't taste too bad, but I think my teeth have gotten a bit discolored so I use one of those tooth whitener adhesive strips once a day. I've also given up on the fasting thing. Taking the pill after meals frequently doesn't work because the stomach empties too slowly and the medicine is competing with food for absorption. Same applies to before meals. No question that meds are absorbed faster on an empty stomach but a 1/2 hour should be plenty of time to wait for pill absorption if one goes that route. If I'm really hungry and it's time to take the meds, I frequently break off an extra 1/4 and add that to my regular dose of 25/100 every 3 hours.
Thanks park_bear for starting a discussion on this topic. After all, levodopa affects most PwP on a daily basis. Having a well tuned regimen can make a large difference to the QOL. I see all versions of levodopa as being useful. There isn't a one size fits all. What matters is what works for you. What works for me could be different.
I have found Ahlskog well worth reading [1]:
"The carbidopa/levodopa formulation with the most predictable and consistent responses is regular (immediate release) carbidopa/levodopa. ... The controlled-release formulation of carbidopa/levodopa (Sinemet CR) was developed a couple of decades ago and proved to have only limited advantages and several disadvantages. Thus, the effect only lasted about 60 to 90 minutes longer and often took twice as long to take effect. It proved to be incompletely bioavailable and required larger doses, which were often difficult to estimate when converting from the regular formulation".
John
Reference:
[1] "Common Myths and Misconceptions That
Sidetrack Parkinson Disease Treatment, to the Detriment of Patients"
The Ahlskog piece seems to generally contain good information. Moreover it appears to have been highly influential, so thanks for bringing it to my attention.
That said, the reference he cites for this: "Myth: Sustained-Release Carbidopa/Levodopa Is the Preferred Formulation When Starting Treatment" – Is his own book! If he had something better to cite, like a study, surely he would have done so.
Personally I have found the longer interval to take effect and the lesser bioavailability are small prices to pay for a much more even level of levodopa. I have also found that my response to this medication is consistent and little affected by food.
I do agree that the best choice varies by individual. People should at least be aware there is a controlled-release/extended release option, especially if they are experiencing dyskinesia shortly after taking a dose, which has been reported here more than once.
Could you explain in detail what examples of dyskinesia might be? I'm guessing that most people who are newly diagnosed have no idea what that looks like. It is probably very disconcerting to experience it and not have a clue as to what it is or what to do about it.
Dyskinesias are involuntary, unintended muscle movements. In mild cases it may be experienced as occasional twitches. Michael Fox has severe dyskinesia as shown in the video below. In early-stage Parkinson's, in my experience, the solution is simply switching from the IR to the CR version of Sinemet. In late stage Parkinson's it is not so easy, because the amount of levodopa it takes to be therapeutic can result in dyskinesia. There is a time release version of amantadine that is supposed to help.
Mine is not that bad. Its mainly a severe twitching of my right leg which makes walking and even thinking difficult. I was taking 2 tablets of c/l 25/100 (generic for Sinemet) every 6 hours but recently have been trying Mucuna Puriens (Barlow's) which gives me about 225 mg of levodopa 3 times a day and one tablet of c/l at bedtime. I have played with the dosage (less) and timing (more often) but no real improvement so decided to try the MP because others said there may be a benefit from a natural product vs the chemicals. My nuero prescribed Amantadine twice a day which seemed to help at first ( a year ago) but no longer is effective. This is why I am interested in the Artane.
Please avoid Artane. Add 1/2 t Carbidopa to your Barlow's MP so that MP can cross the BBB. Our MDS suggested it to my husband.
Another MDS at Mayo asked my husband who was on Artane at that time why and who prescribed Artane. He told my husband to stop it. This Mayo MDS told us that he would NEVER prescribe Artane (if I remember correctly he said it is a century old med. ) Artane causes memory problems. . .
Personally I have found the longer interval to take effect and the lesser bioavailability are small prices to pay for a much more even level of levodopa. I have also found that my response to this medication is consistent and little affected by food.
That is not my experience, the longer interval to effect and the less bioavailability impact my life considerably. Food does affect my response
Smitty there are two posts below i have written on my meds. If you are worried about dyskenisia can you say a bit more about that? What form the dyskenisia takes and when you get it. But most important is your age. I take amantadine 2 day for dyskenisia and it controls it but it has affected my memory.
I am 72.i get shoulder shrugs, lip tremors, and sometimes muscle spasms in my affected leg.its been happening within 2to3 hrs after my medication sometimes It lasts for a short time and subsides. Sometimes it will continue on and off for about an h r.Sometimes after walking or exercising Sometimes my tremors in my arm and hand get worse.
Hi Smitty (Smithy?)Well you arent getting dyskinesia because of your age ie young onset who are more prone to it. Sounds like peak dose dyskenesia. You would do best to follow your neurologist rather than people here. Each person has their pet topic which they push often at every opportunity. I have not seen anyone have miraculous results, despite peoples efforts with supplements or fast walking. Added to this the placebo effect is very strong in PD.
You take drugs 100/25mg every eight hours. That is very little, 300mg levadopa in 24 hours. If it is causing dyskenesia then take less ie break the pill in half.
Also i am 13+ years into treatment for PD, my needs are quite different to yours. You cannot compare with people at different stages
Thanks for sharing your thoughts and information. I also appreciate your advice. What is your dyskinesia? One suggestion from a neurologist was to consider amantadine. After reading the side effects I am hesitant to consider that. How is it affecting your memory? Are you able to drive taking amantadine? How much do you take? What other medication are you on?
I'm taking instant release Carbidopa levodopa 25 mg to 100 mg and I have started to experience dyskinesia. I be afraid to go on the controlled release. I understand too much levodopa can cause dyskinesia.
I believe it would reduce your dyskinesia. If you are taking levodopa at frequent intervals it could cause a stacking effect. Is that what you are afraid of or something else?
I'm taking the carbidopa-levodopa one tablet 25 mg to 100 mg every 8 hours it is the immediate release forum. I'm trying to determine if a dyskinesia that I started to experience is related to too much of the carbidopa-levodopa. Don't want it to get worse but not sure how to adjust thank you for your input
Yes dyskinesia is due to too much levodopa. For starters try replacing one of the immediate release doses with Sinemet CR or carbidopa levodopa ER and observe the change. If it works then replace the other doses as well.
Would it be the same dosage? Currently one Carbidopa levodopa every 8 hours. My neurologist I guess we'll have to write another prescription. Sorry I seem so stupid. I'm just trying to take the right steps and not get any worse. Thanks again for your help ! How long will it take for me to see an improvement?
Which would you increase? The carbidopa-levodopa immediate release or extended or controlled release? Won't increasing 1/2 pill also increase the Carbidopa levodopa thereby causing more dyskinesia
My experience is that levadopa long acting worked well for a few years but doesnt now. It takes 2-3 hours to go from the off state to the on state which can mean I’m off most of the day. Just taking the medication puts me into the off state. If I increase the LA to get over the hump I am experiencing I invariably end up over medicated and with dyskenesia. The exception to this is the morning dose on an empty stomach. However if I take a short acting pill with the long acting I can usually be on again in an hour.
I agree with what you have set forth in this comment. Early on controlled-release can be sufficient. As time progressed and you needed more frequent dosage, the stacking effect caused dyskinesia due to excess levels, and immediate release became appropriate.
I am in favor of whatever version works for the individual.
My post is especially addressed to patients receiving an initial prescription for immediate release who are typically not even informed that there is a controlled-release version. In such cases they are not even aware there is another version which may work better for them.
Really interesting to hear your reflections on this. I've been on CR only since diagnosis 7yrs ago but have been struggling with some dyskinesia over the last year I think due to what you call "stacking". Adding in a bit of dispersible levodopa a couple of times a day if the CR has not kicked in. Bit of a complicated balancing act!
Hi buzbycI wish I knew the answer to medication but just when I think I have got it right I have a bad day or days. What I can say is that I believe my gut activity is the key to how well my meds work.
We cant get long acting meds where I live except for long acting levadopa. I find a mixture of short acting with long acting works best for me. With LA it seems that the longer I can go between doses the better but with IR it is best to have a dose before the previous dose wears off which can make my meds 2hrly and even then the fluctuating levels make me go off too much.
Just an update from me. I was still struggling with the lack of predictability of CR (after being on it for 7years), and have now gradually swapped each dose over to IR. Maybe a little more dyskinesia and if I go "off" the drop off is much quicker. However the advantages of taking a drug that kicks in much quicker and seems a lot more reliable outweigh the negatives. Have also recently started on Opicapone which also seems to be helping. Just my experience though.
Thanks buzbtc, very interesting. Unfortunately we dont have opicopone here but I recently started Azilect which we have only just got! It is hard to know what is having the positive effect but I am a little more stable on my meds. I tried just short acting but the on offs were too dramatic so I now have madopar extended release 100/25 three times a day with Madopar 100/25 immediate release I had to get the build up of Sinemet LA out of my system which took a while. I also tried to reduce my dopamine agonist but all kinds of aches and pains emerged making mobility difficult at times. DA’s have a positive effect on my arthritis of the knee it seems.
My MDS came up with a 5 dose regimen because of splitting headaches from IR tablets about 3 year ago and now I take 1/2 IR ( up to 1 whole tablet if needed) and 1-CR 25/100 and 1- 50/200 CR Generic . The IR version is to smooth the jitters that my wife keeps her eye out when I am doing hard labour like cutting wood for the stove or putting up sheet rock on the walls, etc. if I go too long to take a booster IR, I have to sit down and rest.
Strangely if I am on one of my dogs 1 mile walks it does not affect my walking.
Right now I am sitting and my feet are both "dancing " away under my swivel chair at their leisure.
I recently have changed the times to this:.
AM, 7:00 when I have my first coffee, then 11:00,
PM, 3:00 to no later than 5:00 , and then between 9 and 10
The fifth dose was ~~~3 AM but since I am taking 70 mg of Melatonin I am still sleeping till 6 AM or later.
Hope this makes sense to you, seems to work well for me.
Please excuse my ignorance but I'm assuming c/l(25-100) is the immediate release. 1 pill every 8 hrs.Could cutting back of the c/l eliminate the involuntary movements? How long will it take to eliminate the involuntary movements? Thanks for your help.
Sorry I missed this when you posted it. If you are still taking C/L at eight hour intervals I believe switching to the Sinemet CR controlled-release or the generic C/L ER extended release would be an improvement.
What happens if a pill causes more dyskinesia. My understanding is it too much levodopa causes dyskinesia. I need to eliminate the dyskinesia something to control the tremors. Is switching to controlled release or extended release affect my ability to drive. That's the other important part. Thanks for your help
Hopefully my neurologist can walk me through this. I'm afraid to make an adjustment on own. I definitely don't want to go back to where I was a couple months ago. I was doing great making lots of improvements and physical therapy and occupational therapyThen the dosage was increased by 1/2 pill in the am and the dyskinesia started.
I do not understand your comment. It says you were doing great but you do not want to go back to that? If the extra half dose caused dyskinesia why did you not drop it?
In August and September I was a mess. I started on c/l in October. When I first started on c/l it was 1/2 pill twice a day. Then 1/2 three times a day. Then 1three times a day. I made great progress in both PT and OT. When I was told to add an additional 1/2 pill in the am the involuntary movements started. January I cut back the extra 1/2 pill and I still get the involuntary movements they occur within 2-3 hours after taking c/l,walking and exercising,then subside. Shoulder shrugs, increased tremors, lip quiver.Sometimes it is short and sometimes it hangs on or comes and goes for awhile. Thanks for your help and patience. I really appreciate it.
Smittybear,I really think all this information will not solve your problems but increase them. For instance you will get entirely different advice from parkbear than from me. You will notice that over half his posts have advised you to go contrary to your neuros advice and switch (albeit slowly) to long acting c/l. If you track his posts across HU you will see this is his theme.
I am concerned that you are very anxious and prone to worry and when that gets addressed these other concerns will fade. You are likely to be pulled into many peoples pet theory of cause and cure right now so I would suggest a holiday from HU and if you want to do something monitor your symptoms and look for patterns. Get prepared for your next neuro appt.
Good luck.
Yes I still drive but not long distance. But at 13 years post diagnosis can that tell you anything about you and your form of Parkinsons ?
Peak dose dyskinesia involves the upper body as reported by Smittybear. Diphasic dyskinesia involves the legs, which Smitty did not report. Peak dose dyskinesia is due to excessive peak levels of levodopa. Such levels are reduced by using a time release version instead of immediate release. This is not a "pet theory". These are facts.
3 hours is a long time post ingestion of half a pill for someone to have peak dose dyskinesia, no? If cutting back has not assisted in this regard it could be wearing off that is causing this.
Breaking this stuff down over the Web is very difficult imo. Dyskinesia is difficult to distinguish with language but easily spotted when you see it, in my experience.
He says he was taking one plus one half pills and has now cut back to one full pill. Also he says "within 2-3 hours" - unclear when it starts. There is also some delay for levodopa to get from the plasma through the blood-brain barrier and turned into dopamine. I cannot claim to know for sure what is going on with Smitty but it seems to me a timed release version is at least worth a try.
PB I would contend that PD is a whole body systems condition and focusing on one element is not exactly wholistic care. The presenting issue is not always THE issue.
Thankyou for the reference (which I hope to find somewhere I don't have to pay for it).
LoL beautiful metaphor Hikoi, but are you sure? because I see here two fish now. However, I see that you appreciate the research done by Italians on dyskinesia , excellent preference. Like the artist of your avatar, very refined, Gustav Klimt the only recent artist I appreciate.
Enjoy the reading! (also recommended to the other; and TY to PB)
I saw a spreadsheet a few days ago that had lots of different products with a graph that you could enter what you take and when and it plots an overlay. I can’t find it now. Do you happen to know who posted it please?
Content on HealthUnlocked does not replace the relationship between you and doctors or other healthcare professionals nor the advice you receive from them.
Never delay seeking advice or dialling emergency services because of something that you have read on HealthUnlocked.
However, I see that you appreciate the research done by Italians on dyskinesia , excellent preference. Like the artist of your avatar, very refined, Gustav Klimt the only recent artist I appreciate.
Switching from generic Carbidopa/Levodopa to Rytary
Any guidance on how to switch from IR C/L to CR C/L during the day?
