Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Placebolotherapy
- Nick J Woodhead (2 May 2008)
-
An excellent and innovative perspective on placebo
- Robert W Leckridge (2 May 2008)
-
Re: Placebolotherapy
- D B Double (4 May 2008)
-
The placebo effect put into context
- David E Linden (5 May 2008)
-
Will patients given placebos be expected to benefit from a placebo effect?
- Peter J Flegg (6 May 2008)
-
Re: Will patients given placebos be expected to benefit from a placebo effect?
- ian D Rubenstein (6 May 2008)
-
Placebo response, temporal trends and regression towards the mean
- David J Torgerson (6 May 2008)
-
Re: Re: Will patients given placebos be expected to benefit from a placebo effect?
- D B Double (7 May 2008)
-
The thinking doctor’s guide to very low doses
- James P McCormack (8 May 2008)
-
Reply to rapid responses
- Rudiger UJ Pittrof, Ian Rubinstein (21 May 2008)
|
|
|||
|
Nick J Woodhead, Mental Health Act Coordination Manager Mallard Court, Bridgwater, Somerset, TA6 4RN
Send response to journal:
|
I am thinking of setting myself up as a placebolotherapist: Placebolotherapy The standard by which all other treatments are measured. At least as equally effective as all types of psychotherapy and all ‘alternative’ healthcare treatments. Treats physical health conditions and mental health problems (especially mood disorders). Evidence based. No spurious claims or pseudo scientific explanations. No reliance on ill-defined terms such as ‘energy’, ‘auras’, ‘crystal power’ or ‘spirituality’. Placebolotherapy is not a replacement for any proven treatment, it is an enormously helpful adjunct. The placebolotherapist spends an hour with the ‘patient’ in a pleasant room, giving them their full and undivided attention. They explain that what they are doing is backed up by rigorous scientific evidence, is extremely effective and that the patient will feel better afterwards. That’s it. £50.00 a session. Research into placebo shows that the more value the patient puts on it, the more effective it is. (A placebo injection is more effective than a placebo pill), so an expensive session will be more effective than a cheap one. Or should I set myself up as a homeopathist? Competing interests: I often use hot lemon cold cures |
|||
|
|
|||
|
Robert W Leckridge, Locum Consultant Glasgow Homeopathic Hospital. G12 0XQ
Send response to journal:
|
Congratulations. This is indeed a thinking doctor's guide. What is highlighted by this article is that the "placebo" response is not a sham response - the treatment might be sham (a dummy drug, or pretend acupuncture, or whatever) but the response is REAL. It's such a shame that this phenomenon has been ignored for so long because people have dismissed it as unreal or, at best, insignificant. As you rightly point out, the response can be significant and can be long lasting. In other words it can bring real value to the patient - and with minimal potential for harm and very small cost. One point I would like to make, however, is that for each patient who receives, say, a chemical drug, it is impossible to say how much of the outcome will be due to the chemical and how much to this mechanism (whatever this mechanism is!), so, as doctors, we are never in a position of being able to say to a patient - the benefit you will get from this drug will be due to the effects of the chemicals. In other words, in every single intervention, for full disclosure, a doctor should make clear that the outcomes may be due in whole, or in part, to the placebo effect. There's a misunderstanding on the part of many doctors and patients that there are drugs which work and placebos which don't. The world is not like that. ALL interventions will have some degree of specific effect and some of placebo. Ethically, shouldn't we seek to maximise our use of this effect for every single patient? Competing interests: None declared |
|||
|
|
|||
|
D B Double, Consultant Psychiatrist Norfolk & Waveney Mental Health NHS Foundation Trust, Norwich, NR6 5BE
Send response to journal:
|
Thanks for your excellent response. Satire seems to be the best way to deal with this article. Whatever has happened to the BMJ? Still, some people obviously take the issues raised seriously. This reflects a sorry state of modern medicine, with so much confusion about the role of the doctor-patient relationship. We avoid looking at how much current recognised treatments may be inadvertent placebos. Competing interests: None declared |
|||
|
|
|||
|
David E Linden, Professor of Biological Psychiatry School of Psychology, Bangor University and North Wales Clinical School, Bangor LL572AS
Send response to journal:
|
Pittrof and Rubinstein (1) make the important point that the “placebo effect” is actually an effect – people often do get better on placebo. However, most if not all of the evidence for placebo effects comes from studies where patients expected to have a reasonable chance (generally 0.5) of receiving the active treatment. There is therefore no evidence base for prescribing placebos in a standard clinical setting, which is what the authors seem to advocate. We do not know whether placebos will have an effect if patients are aware of what they are receiving. Such studies will probably never be conducted. However, the most likely explanation for the placebo effect, particularly in mental disorders, is that it works as a proto- psychotherapy, utilising the patients’ conviction that they are being helped and mobilising their own positive resources. We still know very little about the brain mechanisms of the placebo response, but the available evidence suggests that, like psychotherapy, it partly operates through the same pathways as the relevant active drugs (2). I would therefore expect the patient’s belief that some aspect of their brain chemistry is actually being changed to be a crucial part of the placebo effect. There may still be ways in which patients can benefit from placebos, even if they cannot be prescribed like ordinary drugs. First, in a setting that recreates the original trial, including randomisation to placebo or active treatment, but then the physician would not have control over who receives the “reduced benefits for much reduced risks” (1); second, if physicians were to deceive patients, telling them that they are receiving an active treatment when they are not, but this would face both ethical and practical challenges; third, by administering placebo-like substances in the context of a quasi-medical model such as homoeopathy, but this will only work if the patient (and probably the physician as well) believes in this model. 1) Pittrof R, Rubinstein I. The thinking doctor's guide to placebos. BMJ 2008;336:1020 2) Linden DE. How psychotherapy changes the brain--the contribution of functional neuroimaging. Mol Psychiatry 2006;11:528-38. Competing interests: None declared |
|||
|
|
|||
|
Peter J Flegg, Consultant physician Blackpool FY3 8NR
Send response to journal:
|
Pitroff and Rubinstein may think they have devised an ethically acceptable framework in which a clinican could justifiably prescribe a placebo, but it is based upon a false premise. The primary benefit of a placebo comes from the patient's belief that he will receive a biologically-active intervention and the consequent expectation of clinical benefit. Once he is aware that the doctor wishes to give him something that is therapeutically inactive, there will be no expectation of benefit and the placebo response will be expected to significantly diminish, or indeed disappear altogether. In essence, once a patient is aware he is taking a placebo, he cannot be expected to show a placebo effect. The only way to morally justify Pitroff and Rubinstein's approach would be on the basis of study evidence that has demonstrated that patients derive benefit even though they know they are taking placebos, and as yet there is no such evidence. Competing interests: None declared |
|||
|
|
|||
|
ian D Rubenstein, GP eagle House Surgery 291 High Street Ponders end Enfield Middx EN3 4DN
Send response to journal:
|
"Once he is aware that the doctor wishes to give him something that is therapeutically inactive, there will be no expectation of benefit"
I think the point we are trying to make is that the placebo in the trial was not therapeutically inactive. There is clear evidence of an effect. As physicians we make certain assumptions: i.e. biologically inert = therapeutically inactive. The point you make about the fact that the patient does not know what he is receiving in the trial is valid. However, it is my contention that the evidence-base for a therapeutic effect to some extent lets us off the hook. The chief problem with placebo is that it involves us in deception. I would say that it all depends on how you sell it! Here's a scenario: "Look we can try you on a non-pharmacologcal therapeutic agent which has been shown to have a beneficial effect and, by the way, there are no drugs involved" "so how does it work then doctor?" "Well no one quite understands, but it seems to stimulate the body's natural ability to overcome this particular problem" I can guarantee that many of my patients would jump at the chance! Competing interests: I wrote this article |
|||
|
|
|||
|
David J Torgerson, Director, York Trials Unit University of York YO10 5DD
Send response to journal:
|
For patients who appear to improve when being given a placebo treatment there are three alternative explanations. The placebo phenenomenon, regression to the mean and temporal changes[1]. This article did not consider 2 of the 3 competing explanations for an improvement. A placebo controlled trial of the type the authors mention in erectile dysfunction cannot control for regression or temporal change effects and an examination of the cited paper shows that the design cannot exclude these competing explanations. Regression to the mean occurs when you identify patients (in this case men) who are at the extreme of a clinical measure with error [1] (a questionnaire on sexual functioning will be error prone). Intervening and then remeasuring will appear to show an effect irrespective of any other therapetic effects - placebo or otherwise. Similarly there may be a temporal effect. Both of these need to estimated and eliminated before we can ascribe a placebo effect. The trial by Kaptchuk and colleagues is good evidence to suggest there is a placebo effect in IBS with acupunture - the evidence cited in this article is not so robust and therefore should be treated with caution. 1 Torgerson DJ, Torgerson CJ. Designing randomised trials in health, education and the social sciences. Palgrave MacMillan, 2008. Basingstoke. 2 Kaptchuk et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome BMJ 2008;336:999-1003 Competing interests: None declared |
|||
|
|
|||
|
D B Double, Consultant Psychiatrist Norfolk & Waveney Mental Health NHS Foundation Trust
Send response to journal:
|
What's your evidence that placebo "seems to stimulate the body's natural ability"? Is it "biologically inert" or not? Competing interests: None declared |
|||
|
|
|||
|
James P McCormack, Professor, Faculty of Pharmaceutical Sciences, Therapeutics Initiative, UBC, Vancouver, BC, Canada V6T0A7
Send response to journal:
|
Pittrof and Rubenstein make a clear and convincing argument for the potential value of placebos. However, I would like to suggest an approach that would likely get almost all, if not more of the value of what one could get by using placebos, but eliminate almost all the ethical and other issues associated with the use of placebos. It is an approach I, and a number of colleagues, have been endorsing for years. http://www.ti.ubc.ca/node/90. The approach is starting with “very” low doses of medications. While many clinicians obviously endorse the “start low, go slow” approach, in my experience, this usually means starting with the lowest available dose (or at best maybe ½ that dose). So first off, “very” low dose needs to be defined. 1) I am not talking about homeopathic doses – that’s a whole other topic. 2) As mentioned above, I am also not talking about starting with the lowest marketed dose – I am talking typically about a ¼ to an 1/8 or sometimes even less of the lowest marketed dose of a medication. A few of the many principles on which this approach is based are as follows: 1) For the clear majority of conditions seen in family practice (insomnia, depression, elevated blood pressure, mild depression, mild asthma, anxiety, osteoarthritis, menopausal symptoms etc) there is rarely a hurry to get a response. 2) For many marketed drugs (especially when they first come on the market) the recommended starting doses are too high [1] 3) The initially marketed dose, is a dose that by design works for most people. Clinicians need to be aware when drugs are put on the market, very rarely have doses on the true lower end of the dose response curve been studied. 4) The placebo group response for many conditions is in the 20-40% range. 5) Almost all side effects of drugs are dose related. 6) If you look at dose response curves for drugs, they are NOT typically effect vs dose but rather effect versus the LOG of the dose. This explains why you rarely lose much effect by cutting the dose in half. 7) We have all had patients come and tell us that for side effect or cost issues they are using just ¼ of the tablet we initially suggested and it works just fine. 8) In animal research (virtually genetically identical rats) there are clear dose response relations. Relatively, humans are genetic mongrels so the dose response is obviously even more variable. There really is no way a clinician can tell how a patient will respond to a drug or how they will metabolise a drug etc A few of the many examples for low if not very low doses include: 1) 50-200 mg of HCTZ used to be the recommended daily dose - 12.5 mg is the typical starting dose now – 6.25 mg or even lower should be the maximum initial starting dose 2) A ¼ of the dose of Viagra works as well as a full dose – why not try even lower doses? 3) When sumatriptan (Imitrex) first came on the market the dose was 100 mg. We now know 25 mg and 50 mg works pretty much as well as100 mg - is there any reason why 12.5 mg or 6.25 mg shouldn’t be considered? 4) Fluoxetine (Prozac) 5 mg daily has been shown to have an effect - why not start with 2.5 or 1.25 mg daily [2]. 5) One excellent recent example is ezetimibe (Ezetrol/Zetia). While one can debate whether or not this drug does anything to cardiovascular disease I bet very few clinicians are aware of the fact that 0.25 mg (1/40th of the recommended initial staring dose of 10 mg) provides 50% of the LDL lowering effect [3]. The recommended starting dose (10 mg) for ezetimibe has little to do with what is actually the best starting dose, but much more on regulatory and drug company issues. Some of the discussion with patients that is needed if one wishes to try very low doses includes the following: 1) There is no urgency to the treatment 2) We really have no idea what dose will work for you. 3) The typical recommend starting doses are too high. 4) Starting with ¼ to an 1/8 of the dose should considerably decrease the chance of side effects. 5) You (the patient) will determine the correct dose. 6) After a while, if you get a good response, we will reassess the whole issue because there is no way to really tell if you got better because of the drug or because of the placebo and/or tincture of time effect. We sometimes say to the patients they should – half-jokingly obviously - for the first few days just look at the tablet; if the problem isn’t improving, then lick the tablet every day for a week or so and see how that goes. Then if that doesn’t work, start taking an 1/8 of a tablet a day and so on. This low dose approach (as well as the placebo approach) obviously does not apply to acute life-threatening conditions or conditions for which a therapeutic effect/endpoint cannot easily be determined – or example reduction in seizures in a patient who only has seizures 1-2 times a year. Some obvious advantages of this very low dose approach are: 1) There is no deception. 2) The patient is completely engaged in the process, and in my experience, really buys into the concepts of “just a little bit to start off with”. 3) Cost savings can be considerable. 4) Almost all drug interactions can be avoided Some dose cutting tips 1) Not all drugs come in dosage forms that allow small doses to be used – however the vast majority of tablets can be split especially if one uses a pill cutter. One doesn’t need to be too spastic that every piece is exactly the same size. 2) Some capsules can be opened or potentially, as for instance the proton pump inhibitors, the frequency of the dosing could be increased – instead of daily go to ever 2-3 days etc. 3) Many drugs do come in a liquid form - fluoxetine for instance is available as a 20 mg/5 ml liquid dosage form so doses of just a few mg could easily be used. 1. Cohen JS. Over Dose: The Case Against the Drug Companies: Prescription Drugs, Side Effects, and Your Health, 2001 2. N Engl J Med. 1994;331:1354-61 3. Clin Ther 2001;23:1209-30 Competing interests: None declared |
|||
|
|
|||
|
Rudiger UJ Pittrof, Consultant in integrated sexual health and HIV Enfield EN1 1NJ, Ian Rubinstein
Send response to journal:
|
There were only 4 rapid responses that were not in favour of placebo treatment when such treatment is supported by evidence. This is less than anticipated and could indicate that placebo treatment is not as controversial as generally suspected. Dr Flegg’s point: “Once he is aware that the doctor wishes to give him something that is therapeutically inactive, there will be no expectation of benefit and the placebo response will be expected to significantly diminish, or indeed disappear altogether” assumes that placebos are therapeutically inactive. For many conditions placebos have been demonstrated to be therapeutically active. Often the placebo effect can persist over time (Khan et al 2007) and is thus not explained by regression towards the mean.
As we explain in our e-paper, RCTs are likely to systematically underestimate the efficacy of placebo treatment: Placebo controlled RCTs are only ethical if there is no known effective treatment accessible (Helsinki declaration). Following informed consent the trial participants knows that they are either receiving a placebo or a potentially ineffective treatment. This is likely to reduce the placebo effect. In real life, the effectiveness of placebo treatment is likely to be higher than the efficacy as shown in RCTs. Rather than receiving a potentially useless drug or inactive drug, the patients will receive an individualized treatment of known efficacy following an informed trade-off of a lower risk of benefit (as compared to active drug) for a minimal risk of harm. Prof McCormack suggests replacing placebo treatment with low dose treatment of drugs known to be effective. As he points out it is not the same as placebo treatment and could keep most the benefits of placebo treatment. The only disadvantages we can see are costs, allergic reactions and the potential “loss of placebo effect” as the patient may associate 1/8th of a tablet with a lower effectiveness when compared to a full tablet. Once the placebo effect is gone it may not become part of the patient’s response to the standard dose. Prof McCormack’s approach deserves its own review paper. References: Khan A, Redding N Brown WA . The persistence of the placebo response in antidepressant clinical trials. J Psychiatr Res . 2007 Nov 23. [Epub ahead of print] Competing interests: None declared |
|||