I wonder whether there is agreement amongst us in the forum on how best to medicate for the motor symptoms of PD.

When it comes to Parkinson's, it is common to say that we are all different. This is true. But what strikes me is how similar are the dosing regimes that people have. At its simplest, it seems to me that dopamine replacement therapy (DRT) comes down to these principles:

1. Many PwP have health needs in addition to motor problems, e.g. anxiety. Medications for these needs are not covered here.

2. DRT is not the only therapy to deal with motor problems: exercise and DBS can have good results, but usually they are not enough in themselves to avoid DRT all together. These approaches are not considered here.

3. Even late into the disease PwP are continuing to produce and store some of the dopamine they require. These factors should be estimated.

4. The aim of DRT is to keep PwP mobile for as long as possible.

5. There is no conclusive evidence that presently available drugs can slow the progression of the disease. So, DRT is for symptom relief only.

6. There is no benefit from undermedicating, except in order to avoid overmedicating.

7. Overmedicating should be avoided. It can lead to dyskinesia, impulse control problems, psychosis.

8. The underlying cause of the disease affects a person in many ways, but as far as DRT is concerned it leaves us with an inability to produce enough dopamine AND/OR a reduced ability to store it.

9. The disease is progressive, so dosing will typically increase with time.

10. DRT dugs, even when of a different type have an additive effect. (An exception is rasagiline where beyond 1mg it usually has no improved effect.)

11. To estimate the combined effect of two or more doses, three factors are required for each dose: the levodopa equivalent dose (LED), the time it is taken and the duration of its effectiveness.

12. The reason for taking different combinations of DRT drugs is two-fold. First, some PwP are unable to stomach some DRT drugs. Second, is to make use of the differing properties of the drugs so as to smooth out the graph of combined LEDs over time. A DRT based on immediate release levodopa is, unless advanced control features are introduced, likely to lead to large variations during the day, Whereas a DRT based exclusively on drugs which are long lasting, such as rasagiline or ropinirole controlled release, is unlikely to match changing needs during the day.

13. The time it takes a dose taken by mouth to take effect is contingent on protein in the diet, constipation and gastric emptying. In bad cases a whole dose can be "lost".

14. Doses should not be increased rapidly. They should be increased over a period of a few weeks until optimum levels are found.

15. Doses should not be reduced rapidly because of the danger of neuroleptic malignant syndrome.

John

well thought out

Conjecture 16 most PwP can be better medicated with existing drugs than they are now.

Is the drug cocktail that you're on optimal?

To the extent that Parkinson's is a disease characterized by a shortage of dopamine in the brain, it seems reasonable to suppose that the aim of any dopamine replacement therapy (DRT) should not just be to supply the missing amount, but to supply it just when it is needed.

The consequences of getting it wrong include:

- under-medicated: slowness, stiffness;

- over-medicated: dyskinesia;

- peaks and troughs in DRT levels [1]:

"Evidence from preclinical and clinical studies indicates that pulsatile stimulation of striatal dopamine receptors is a key factor in the development of levodopa-associated motor complications."

Many of us are chronically under-medicated, so as to avoid complications, but this leads to a lower quality of life than that needed.

I would estimate that in the ideal world, where dopamine/agonist levels could be monitored continuously and could be controlled dynamically, doses could be doubled without any increase in complications. This estimate is based on evidence about Rytary and Duodopa.

Regarding Rytary [2]:

"The final total daily dose of levodopa from RYTARY was approximately double that of the final total daily dose of levodopa from immediate-release tablets." However, we also need to take into account: "The bioavailability of levodopa from RYTARY in patients was approximately 70% relative to immediate-release carbidopa-levodopa."

Regarding Duodopa, doctors in Denmark report the following percentage changes in levodopa equivalent consumption on being introduced to Duodopa on 14 patients [3]:
+64, +281, +261, -18, +222, -53, +477, +25, -29, +19, +438, +6
Some of these changes are due to the differences in the technology involved, some will be due to the sub-optimality of the dosing regeme before taking levodopa.

As I see it, many PwP live, metaphorically speaking, in a house with a central boiler and a supply of wood, that once was adequate, but with no way to adapt, other than through interventions by a heating engineer every 6 months, to changes of weather or changes of need in different rooms or changes in the efficiency of the boiler.

Clearly it should be an expectation that the DRT is monitored frequently (every week, perhaps), and changes made with smaller granularity than at present. If the health system does not provide this regular updating, we should deliver it ourselves.

References:

[1] "Continuous dopaminergic stimulation in early and advanced Parkinson’s disease"
Fabrizio Stocchi, MD PhD and C. Warren Olanow, MD FRCPC
Neurology January 13, 2004 vol. 62 no. 1 suppl 1 S56-S63
http://www.neurology.org/content/62/...1/S56.abstract

[2] Rotary Full Prescribing Information
http://www.accessdata.fda.gov/drugsa...312s000lbl.pdf

[3] "Duodopa pump treatment in patients with advanced Parkinson‘s disease"
Merete Karlsborg, Lise Korbo, Lisbeth Regeur & Arne Glad
Dan Med Bull, June 2010
http://www.danmedj.dk/portal/pls/por...me=5274860.PDF

John

Conjecture 17. Dopamine agonists increase the risk of somnolence as compared to levodopa.

Etminan et al. write [1]:

"Four trials were included in the analysis of patients taking pramipexole or ropinirole compared with those taking placebo. The pooled relative risk of somnolence in this analysis was 4.98 [95% confidence interval (CI) 1.79 to 13.89]. Seven trials were included in the analysis of patients taking levodopa and pramipexole or ropinirole compared with those taking levodopa alone. The pooled relative risk was 2.06 (95% CI 1.47 to 2.88)."

Salawu and Olokoba write [2]:

"The importance of addressing EDS [excessive daytime sleepiness] in PD was highlighted by a report of eight patients who suddenly fell asleep while driving a motor vehicle. ... These episodes were termed "sleep attacks" by the author because they seemed to have occurred without warning, and were attributed to dopamine agonists because they disappeared when the drugs were withdrawn."

References

[1] Abstract only.
Drug Saf. 2001;24(11):863-8.
"Increased risk of somnolence with the new dopamine agonists in patients with Parkinson's disease: a meta-analysis of randomised controlled trials."
Etminan M1, Samii A, Takkouche B, Rochon PA.
http://www.ncbi.nlm.nih.gov/pubmed/11665873

[2] "Excessive Daytime Sleepiness and Unintended Sleep Episodes Associated with Parkinson’s Disease"
Fatai Salawu1,* and Abdulfatai Olokoba
Oman Med J. 2015 Jan; 30(1): 3–10
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371466/

John

Hi John

My own experience leads me speculate whether the agonist associated daytime sleepiness is compounded by or caused by agonist induced insomnia. My regular 4 hours out, 2 hours awake has suddenly decreased to 2 hours out, 2 hours awake in line with increased requip dosage, I wonder if due to increased activity of the D3 receptor. If Iv remembered which one is linked to mood/serotonin ?
This perhaps links with point 3, our remaining ability to generate and store dopamine which is effectively done over night during sleep (I often feel good without meds between 2am - 5am) With insomnia,whatever the cause, we are probably not replenishing our natural supply efficiently and as the sleep deficit increases so the meds need to compensate. Small effect but part of the whole.

Nigel

"Clearly it should be an expectation that the DRT is monitored frequently (every week, perhaps), and changes made with smaller granularity than at present. If the health system does not provide this regular updating, we should deliver it ourselves."

Thoughtful summary john. I could agree with all your points.
The quote above I think is in the domain of self care. Personally I can never see a time when updating and adjusting my Meds will deliver a consistent response because of no 13 and that will vary from person to person. Our challenge must be to have our observations validated and to be accepted as equal partners in our health care.

Our challenge must be to have our observations validated and to be accepted as equal partners in our health care.[/QUOTE]

Dilmar,

You've hit the nail on the head and I could'nt agree more. Just a few hours on forums such as this would provide any researcher with enough leads to start joining some dots and finally make some progress.

Nigel

John

Can I ask you for your thoughts on point 13. Rapid gastric emptying is understandable. But what is the likely inhibiting process with constipation ? Is it fecal matter physically blocking absorption, a slowing of the digestive process that prevents the meds getting to the right part of the gut or something else.
How much do we estimate this would alter drug levels and would this be primarily a constant release specific problem ?

I guess this is why exercise,diet,fluid intake is so important .




Nigel

Niggs, a good set of questions. We could answer those questions if we could answer the following question.

What is the mechanism by which constipation affects the bioavailability of levodopa?

I must admit that when I wrote the conjectures I was mainly thinking about my personal experience which, in this context, and put simply, is that my PD is worse when I am constipated.

These matters have been discussed before. See the thread, "Docs Ignore Constipation in Parkinson's", started by GerryW:

http://neurotalk.psychcentral.com/sh...t=constipation

My constipation is worse now than it was when I posted to that thread. It is now unusual for me to "go" in less than five days. (Or, rather, it was before I started taking enemas regularly. But, that will be the subject of another post.)

I can't find a scientific paper that explicitly reports that constipation reduces the bioavailability of levodopa. The closest I can get is:

"Since levodopa is absorbed from the small intestine ... bowel dysfunction in PD may interfere with levodopa absorption, worsen the motor disorder, or even lead to malignant syndrome ..." [1]

But, I suggest two mechanisms that may cause it:

1. Toxin build up due to constipation, as posted in the thread referenced above by Rick.

2. The presence of stool at the absorption sites.

Note: as I understand it, in terms of the normal flow of materials, food goes through the stomach, followed by the small intestines, followed by the large intestines.

Based on dog studies, Sasahara et al. [2] report that "the major absorption site of levodopa in the intestine resides in the upper small intestine", with the jejunum, ileum and duodenum all playing a part. The case then rests on whether under conditions of severe constipation stool gets into the small intestine.

Certainly, the large intestine can be blocked by a "hard mass of stool" [3]. But it can go further back.

"An obstruction can occur ... anywhere in the small or large intestine, and there can be a partial or complete blockage. ...
About 20% of hospital admissions for acute abdominal pain are due to a bowel obstruction and the majority of these occur in the small intestine." [4]

References

[1] Parkinson's Disease
Volume 2011 (2011), Article ID 924605, 21 pages
http://dx.doi.org/10.4061/2011/924605
"Bladder, Bowel, and Sexual Dysfunction in Parkinson's Disease"
Ryuji Sakakibara,1 Masahiko Kishi,1 Emina Ogawa,1 Fuyuki Tateno,1 Tomoyuki Uchiyama,2 Tatsuya Yamamoto,2 and Tomonori Yamanishi
http://www.hindawi.com/journals/pd/2011/924605/

[2] J Pharm Sci. 1981 Oct;70(10):1157-60.
"Dosage form design for improvement of bioavailability of levodopa V: Absorption and metabolism of levodopa in intestinal segments of dogs."
Sasahara K, Nitanai T, Habara T, Morioka T, Nakajima E.
http://www.ncbi.nlm.nih.gov/pubmed/7299652

[3] http://www.webmd.com/digestive-disor...topic-overview

[4] http://www.webmd.boots.com/digestive...el-obstruction

John

John

Thankyou for replying..

I am also worse when constipated, fortunately I'm rarely longer than 3 days between movements. Also I often feel very much like I do during dose reduction ie. not good. The bounce back appears to be rapid and depends on dose timing/achieving bowel movement.
Eg. if meds taken 2.00 pm & movement after 3 days achieved at 8.00 pm no parkinsonian improvement til next day.
But if meds taken at 4.00 pm and movement at 7.00 pm the improvement can be noticed at 8.00 pm onwards.
This is a purely personal observation and the above is for illustration rather than based on actual experiment.
However it leads me to favour the blockage/meds not getting to the correct place theory.

Nigel