In this post I put together a group of related ideas that I've written about on this forum in the past. In short, I think that:
- we should see the placebo effect as a friend;
- we should devise methods to increase the power of the placebo effect;
- we should measure symptoms continuously;
- we should assume that there are many types of PD;
- we should run trials on PwP as individuals, not as part of a cohort;
- we should be very careful not to needlessly do anything which diminishes peoples' expectations of the therapeutic value of their treatments.

Placebo

A placebo is something which is not expected to have any "real" impact on an illness. Nevertheless, when used in the right context, placebos can relieve both the perception and the objective measurement of the disease. The BBC reporting work done in Canada states that "when [a PwP] responds well to a placebo, it isn't the case that he's simply coping better with his symptoms, or somehow battling through them. Instead, the placebo is triggering the release of dopamine in his brain." [1]

Therebo

Why limit ourselves to placebos? There are many potential therapies which are likely to be both safe and offer the possibility of true therapeutic benefit. As an example, consider water. Dehydration is a common problem with PwP. Anything which addresses this problem goes beyond being a placebo.

To avoid confusion with standard placebos, let's introduce a new word: "therebo". A therebo is defined to mean something that may have therapeutic power or may be just a placebo (THERapy or placEBO). In the context of Parkinson's, coffee and curcumin are examples of therebos; levodopa is not a therebo, it is a therapy. A therebo doesn't have to be a drug, it's anything that can possibly affect the symptoms or progression of the disease. For instance, transcranial magnetic stimulation and the forced exercise of the arms are therebos. Even ideas can be therebos, even the concept of a therebo is a therebo. A therebo doesn't have to be static, it can be a process, e.g. the act of following this forum from day to day involves reading both good news and bad news items, and commenting on some of these, often following a study of the literature, creating a sense of empowerment.

As defined above, there are an infinite number of therebos for PD, most of these should be free or almost free. They are readily available. They could be in use in weeks. The main problem is to get the buy-in of the medical establishment.

Therebo distillation

1. A committee of PD experts is formed to recommend what therebos should be considered. This would be influenced by theoretical concerns, the results of test tube experimentation, animal trials and any human trial data that is available. As time goes by, new information will arrive (not least through the therebo distillation process itself) and this may lead to changes in the therebos.

2. People who join the scheme should:
- continuously monitor their symptoms;
- report their symptom measurements to the database;
- to start with take no therebos, so as to build a baseline of results against which to measure progress;
- once basedlined they can decide whether or not to take a therebo, whether or not to continue with a therebo, whether or not to change therebos. Any decisions are reported to the database.

3. The database stores symptom data and all the therebo choices made. Software would be written to show the effectiveness of the therebos.

The claim is made that:
- good results would enhance the placebo effect;
- people will migrate to therebos which have better results;
- therebos with true therapeutic effect will gradually rise to the top;
- therebos which in spite of the screening turn out to do harm, will fall off the bottom of the list and cease to be used;
- people will stick with therebos which are giving good results for them, even when their overall score is poor, providing patient-centric treatment.

Ethics of therebos

One of the issues that doctors have when prescribing placebos (for instance, suggesting antibiotics to treat a suspected viral infection or, more seriously, performing sham surgery as part of a clinical trial) is that there is a degree of deception. One of the nice things about therebos is that there is evidence to support the therapeutic value of the treatment. Although this evidence is not conclusive, a rational case can be made that taking a therebo is in the patient's interest. There is no advantage in deception; everything should be open.

However, without strong reasons, one must be careful not to rubbish people's therebos. Even true therapies will have a placebo component increasing their effectiveness. Lidstone et al. report [2]:
"The strength of belief of improvement can directly modulate dopamine release in patients with PD."
This benefit can be lost, and harm done to the PwP, by reporting negatively on the treatment. This is not say that negative reporting is always wrong. A balance needs to be struck taking into account all the circumstances.

I'll be grateful for your comments.

References

[1] "The medicine in our minds"
Olly Bootle, BBC, 17 Feb, 2014

[2] Arch Gen Psychiatry. 2010 Aug;67(8):857-65. doi: 10.1001/archgenpsychiatry.2010.88.
"Effects of expectation on placebo-induced dopamine release in Parkinson disease."
Lidstone SC1, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, de la Fuente-Fernández R, Phillips AG, Stoessl AJ
http://www.ncbi.nlm.nih.gov/pubmed/20679593

John

In a recent paper in Neurology [1] Tiago et al. present the results of a meta-analysis of placebo results collected from drug trials.

Unfortunately, most of their report is behind a pay-wall, but the paper's tables can be read. These show, for a number of drugs, the improvement in motor UPDRS scores of both the active and placebo arms of the trials for that drug.

For instance,
Pramipexole, mean improvement: Active = 7.79, Placebo = 6.68
Ropinirole, mean improvement: Active = 7.17, Placebo = 7.16
Levodopa, mean improvement: Active = 8.89, Placebo = not given

A few points to note:
- the confidence intervals are wide, suggesting that for each category of data there is not statistical significance;
- the placebo results appear to be almost as good as the active control; this could be due to chance, but given this, I wouldn't have expected them to be given regulatory approval - perhaps the drugs did better in other measures;
- note that part of the power of a placebo is contextual, so the same sugar pill could have a different effect if used in a placebo controlled trial of an effective drug or of a weak drug.

A less promising, but still positive measure of the effectiveness of placebos at reducing the symptoms of PD, is given by Pham and Nogid [2]. Reporting on rotigotine they write:

"Changes on the UPDRS III (motor examination) at 6 months ranged from -3.58 to -8.7 with rotigotine transdermal system, compared with +0.38 to -4.3 in the placebo group and -10.3 in the pramipexole group (P < 0.001 vs placebo; P = NS vs pramipexole). The change in "off" time at 6 months ranged from -2.1 to -2.7 hours with rotigotine transdermal system, compared with -0.9 hour with placebo and -2.8 hours with pramipexole (P < 0.001 vs placebo; P = NS vs pramipexole). The proportion of patients achieving a >30% reduction in "off" time ranged from 55.1% to 59.7% of patients receiving rotigotine transdermal system, compared with 34.5% to 35.0% of patients receiving placebo and 67.0% of patients receiving pramipexole (P<0.001 vs placebo; P = NS vs pramipexole)."

So what? If a basic placebo can have these positive effects, just wonder what an optimally engineered placebo, or better still therebo, could have. But let's not use the possibility of making better placebos as an excuse to delay implementing the routine therapeutic use of placebos and therebos for Parkinson's. Let's make it happen NOW!

References

[1] "Another face of placebo: The lessebo effect in Parkinson disease. Meta-analyses"
Tiago A. Mestre, MD, MSc,
Prakesh Shah, MBBS, MRCP, MRCPCH,
Connie Marras, MD, FRCPC, PhD,
George Tomlinson, PhD and
Anthony E. Lang, MD, FRCPC, FAAN
Neurology April 22, 2014 vol. 82 no. 16 1402-1409
http://www.neurology.org/content/82/16/1402/suppl/DC1
Click on Tables e-1 to e-2

[2] Clin Ther. 2008 May;30(5):813-24. doi: 10.1016/j.clinthera.2008.05.007.
"Rotigotine transdermal system for the treatment of Parkinson's disease."
Pham DQ1, Nogid A
http://www.ncbi.nlm.nih.gov/pubmed/18555929

John

I think you may be misinterpreting the point of the analysis. They were studying the "Lessebo" effect more so than the placebo effect. Basically, Lessebo is sort of the opposite of Placebo. Essentially, the argument has been made that patients in PD studies which have a placebo group may experience a negative expectation of benefit due to the possibility getting the placebo. The net effect, according to the Lessebo theory, is that patients getting the active drug will change less when in a placebo controlled trial as opposed to when there is no chance of getting placebo. Lessebo reduces the recorded effect of and active ingredient. Placebo increases the effect of an inactive ingredient.

There have now been several studies where results showed that having a placebo arm reduces the measured efficacy of an active treatment significantly. The result would mean that a drug may have a larger magnitude of effect than that which was measured in the trial.

Tiago Mestre is a leading proponent of this theory. The meta analysis you linked is his latest attempt to prove that Lessebo exists, that a placebo controlled study will reduce the magnitude of change after drug treatment for PD patients.

Tupelo3,

Thank you for your comments.

Whatever "the point of the analysis" presented in the paper, it also contains measurements of the size of the placebo effect. I think I've used these correctly to support the point of my analysis that placebos can have a substantial effect on PwPs.

Why not take the benefits that placebos have to offer?

Why not engineer placebos to be even more effective?

John

This is a very interesting subject and analysis.
I only wish to add that I believe that we all possess natural healing powers which are empowered or diminished depending on our beliefs and perceptions.
I will not loose hope that I will find a kind of healing that makes life worth living!
Imad

Based on the analysis of results from sham surgery, Ko et al., using brain imaging, claim to be able to identify PwP who are particularly susceptible to the placebo effect.

"Approximately 35% of the participants would fall into this category".

Identifying such people and excluding them from the clinical trial

"substantially lowers the number of randomized participants needed to demonstrate treatment efficacy ... [Here it] resulted in a net reduction in sample size of over 56%."

For the sham responders, 6 months after sham surgery, and still unblinded, the size of the effect was a reduction in the UPDRS motor score of approximately 8 (note a decrease in UPDRS score is good) as compared to an average baseline score of 39.4.

Turning this finding on its head, it seems to me that it makes it easier to target placebo/therebo therapies at those who are most likely to benefit.

Reference

[1] "Network modulation following sham surgery in Parkinson’s disease"
Ji Hyun Ko1, Andrew Feigin1, Paul J. Mattis1, Chris C. Tang1, Yilong Ma1, Vijay Dhawan1, Matthew J. During2, Michael G. Kaplitt3 and David Eidelberg1
J Clin Invest. doi:10.1172/JCI75073, 2014
http://www.jci.org/articles/view/75073

John

I would like to see a study when one group of subjects is given for some time medication and another say sugar pill and then there is an exchange and the group who has received medication is given sugar pill and vice verse. Subjects are not told which of them is receiving medication first or sugar pill first. I wonder if it is ever done and dose it show different results then study when subjects continue with medication or sugar pill through the whole time, and would this exchange affect lessebo or placebo effect.