Bad Science’s Dr Ben Goldacre has collaborated with Radio 4 to produce a 2-part exploration of the potent, intriguing power of placebo. Both Part 1 and Part 2 discussed the history, science and theatre of this fascinating phenomenon and it has been notable that the examples spanned from Perkins Tractors, Mesmer and animal magnetism, to work that was published only this year. Placebo has such an extensive and rich history and encompasses so many issues aside from medicine such as social influence and trust that it isn’t practical to present more than a tasting menu of it in 2 half-hour programes. Nonetheless, at the risk of sounding like Brillat-Savarin, it was strangely unsatisfying that neither of the programmes addressed the issue that some researchers argue that the placebo is both over-rated and ineffective and that there is no role for it in medicine, outside the context of a clinical trial.
As my handwave for the content and themes of the programmes, the Shapiros gave an excellent overview of the history of medicine and placebo:
It is a mystery how a treatment used since antiquity was unknown, unnamed, and unidentified until recently. It is even more remarkable because this is the only treatment common to all societies and cultures. When we examine the long history of medicine, it is the only common denominator between the Egyptian physician who prescribed crocodile dung and the modern physician who prescribes penicillin. Moreover, its effectiveness has been attested to, without exception, for more than two millennia.
One of the many secrets enshrouding this remarkable treatment is that when its effectiveness wanes, it metamorphoses into a new, seemingly different, and culturally more appropriate form of effective treatment-somewhat as bacteria develop a resistance to antibiotics. Trousseau (1833) discerned this covert mischievousness in the middle of the nineteenth century, and he urged healers to hurry and use new drugs while they still worked. [Shapiro AK, Shapiro E. 1997. The Powerful Placebo: From Ancient Priest to Modern Physician.]
It is clear that a healing response in patients seems to be enhanced by confidence in the doctor/healing figure and a meaningful theatrical ritual (whether physician, herbalist or shaman, depending upon history or culture, as Goldacre’s discussion of Quesalid indicates). Dr Houston wrote: “the placebo has always been the norm of medical practice” and suggested that, doctors themselves:
were the therapeutic agent by which cures were effected. Their therapeutic procedures, whether they were inert or whether they were dangerous, were placebos, symbols by which their patients’ faith and their own was sustained. [Houston WR (1938). Doctor himself as therapeutic agent. Annals of Internal Medicine, 11, 1416–1425.]
Houston’s description may seem a little hyperbolic but it seems to be borne out by the many interesting studies, experiments and anecdotes that Goldacre reports in the programmes. What the doctor says, how the doctor behaves and what the doctor believes, all have an effect on healing. This probably explains why, despite some of the ethical issues associated with the use of placebo, the placebo is still in use in clinical practice. At the beginning of 2008, Sherman and Hickner[1] announced that the placebo is still in (occasional) use among academic physicians in Chicago. 45% reported that they had used it to calm a patient or as supplemental treatment. Only 12% thought that placebo use in routine medical care should be prohibited.
Goldacre discussed ethical issues surrounding the use of placebo in Part 2. Sir Ian Chalmers has a long-standing interest in the evidence underpinning healthcare. He explored the notion that full information about the administration of placebos in a trial may have a downside for patients as well as advantages. Chalmers gave the example of a trial in which some participants were warned that the active drug might cause stomach upsets as part of the side-effects. When the results were analysed, more patients who received the placebo but had been warned about the stomach upsets reported this side-effect than those who took the drug or were not warned (it was slightly unclear).
Goldacre explored whether there is an ethical dilemma if honesty, transparency and fully informed consent mitigate against the use of placebo but thereby deny patients some of the most effective therapeutic techniques and diminish the full effectiveness of treatments. Goldacre stated his own distaste at the notion of deception but explored whether it was possible “to provoke placebo researchers into justifying mild deception, overstating the benefits of a treatment, perhaps, or underplaying the potential risks”.
None of the placebo researchers considered that deceiving a patient could be justified and considered that the long-term damage to the relationship of trust with medicine would outweigh any short-term advantage to the patient. Various clinicians discussed a form of words that allowed them to present the facts about a placebo treatment to patients. Goldacre wondered whether medicine was prevented from exploiting placebo by knowledge of the efficacy and quantification of treatment effects and concerns for patient autonomy, but CAM practitioners were less inhibited because their interventions had not been disproven, so there were notionally free to present their therapy in reassuring terms and perhaps exaggerate its expected efficacy, which, paradoxically, might provide a degree of confidence, authoritativeness and reassurance that is more effective for patients. A slightly convoluted argument for ‘ignorance is bliss if it gives you plausible deniability for your recommendations’.
Professor George Lewith is a researcher and practises both CAM and medicine. When Goldacre presented this idea to him, Lewith argued that a lack of funding for CAM in the UK makes it an evidence-free zone, and so, when it is offered, it is mostly done so on the basis of a practitioner’s prior experience that such interventions have been helpful. Lewith argued that that might be an example of a placebo effect but, in the absence of evidence to the contrary, it is a legitimate use of it. Goldacre demurred that when doctors try to enhance the effect of a treatment that they recommend, they do so with a knowledge that there is an evidence-base to support their recommendations but Lewith countered that that is not always true and offered the example of the use of SSRIs for depression in primary care.
Goldacre then said that he would be clear that “prescribing SSRI antidepressants for mild depression…is a bad idea because the evidence for benefit is very limited”. He asked Lewith: “Do you think it is acceptable…to prescribe a homeopathic sugar pill for mild depression; given that the evidence of benefit there is equivalently poor?”. Lewith argued that in the case of mild depression:
Very often, the homeopathic consultation…will be focusing on why the patient got depressed. What their overwhelming emotion is. How they might be thinking about managing that emotion. What kind of remedy picture that might fit and that might give you other clues. And then at the end of your 35-45 minutes you’ll make a symbolic gesture. You’ll say, “I think we might be able to help you a little bit with this particular sugar pill for this particular reason”. It’s almost even shamanistic.
Goldacre objected that in that case, the doctor/practitioner was recommending a pill for which there was no established efficacy but Lewith rejected that and claimed that the therapeutic effect lay in the whole package, which includes the consultation. Goldacre expressed his concern that in the scenario that Lewith outlined, “the patient has been reassured by a white lie”. Lewith said that it isn’t a white lie if the practitioner is clear with the patient that s/he is not sure whether it is the process of homeopathy or the proferred remedy that works.
Professor Irving Kirsch objected to the long-term harm that would result from violating patient trust by deception or less than transparency. Professor Edzard Ernst is a CAM researcher and was adamant that the only ethical use of placebos would be if they were used openly and with fully informed patient consent, in which case he denied that they would work. Ernst claimed that as an experienced clinician he is capable of forming a good, therapeutic alliance with a patient “without being bogus”.
Goldacre mused that although he fully accepts the admirable ethical arguments against placebos, there are times when it is difficult for doctors to hold the line: e.g., in the face of patients requesting antibiotics for a viral cold. Professor Walter Brown took a somewhat robust attitude and said that some patients would be indifferent to what actually relieved their symptoms, they would just be grateful for the relief. He says that there are times when doctors should feel comfortable with prescribing placebos because it can be done without deceiving patients. Brown offered some forms of words but Goldacre argued that although the sentiments were fine as they stood, in the context of a patient’s expectations of a doctor, there was a reasonable assumption of clinical research to support the recommendation.[a] Brown countered that with the argument that there is good quality research to support the placebo. Which may be true, but at this point, the discussion felt like semantic point-scoring rather than a genuine engagement with the issue although Brown gave several fine examples to support his stance.
Goldacre worried away at the issue of whether all of the above might be true but, at the heart of the matter, the patient is still deceived, and it may be difficult to disentangle this from a sense of medical paternalism. Brown give a good answer, but again, it seemed to rely upon framing and word games that sound manipulative in discussion but may not appear so in practice.[a] There was further exploration of whether a pill or specific intervention was necessary or whether it was the whole process of the visit, the consultation, the interaction, the evaluation, diagnosis, confidence about the treatment (as referred to by Lewith) that combined to make the placebo effective.
Goldacre suggested that the best proof of concept for the efficacy of placebo would be if it could be demonstrated that they work, even when openly and honestly prescribed.[b] Fortunately, just such a study was published earlier this year.
Brown gave a fine overview of the Sandler and Bodfish pilot study of open-label placebos in the treatment of ADHD.[2] All of the children were receiving a drug therapy and they were randomised into three groups. Group 1 continued to take their usual dose. Group 2 received half the usual dose but were also given a placebo capsule that they were told was a placebo that would extend the effect of the drug – a “dose extender”. Group 3 received half the usual dose but no additional placebo capsule. Group 2 fared as well as Group 1 and better than Group 3 (some of whom experienced symptom exacerbation and deterioration) although they only received the same effective dosage as Group 3 suggesting that the placebo extender was effective. If this result is replicated in a longer trial, there are obvious implications for being able to reduce the dose of medications while amplifying their effects.
It was reassuring to learn that in an analysis of the perspectives of children and parents,[3] both were generally accepting of the use of the placebo and the parents were particularly pleased at the reduced risk of side-effects. The authors concluded:
Open-label use of placebos as part of CPDR treatment may represent an innovative, ethical way of harnessing the power of placebos in clinical therapeutics.
There was some interesting discussion of trust issues but the issue is too broad to be covered in a satisfactory manner in a few sentences. Maybe Goldacre’s forthcoming and shortly-to-be-available book will cover this area in greater depth and explore why there is a history that may explain why some groups of people would find the issue of trust to be so insurmountable for historical reasons (e.g., Tuskegee, or the historical collusion of the medical and legal systems in sequestering women in asylums for scant grounds of public health or for reasons that do not seem to have applied to men[c] ).
Perhaps unfairly, given the time constraints, it felt a little superficial to imply that most patients had no feelings of outrage at being duped when they discovered that they had been in the placebo arm of a trial and it is unclear whether (unlike the Sandler and Bodfish[2]) it is typical for there to be some form of follow-up that collects and analyses the perspectives of the participants (although, from Brown’s reference to anecdotes, it seems not). The Sandler and Bodfish[2] trial involved a treatment for children, it would be interesting to know if there is a difference when considering the value of a placebo for others, than for oneself: further, whether there is a special consideration both for parents and children that both generations would be happier if the dosage of the drug were to be reduced because of the stigma associated with the disorder and the medication.
Last week we learned of a study that reports that the placebo effect is greater in children.[4] Beyond the immediate significance for studying placebo, there is the interesting implication for the impact that this finding may have on the power and sample size for trials involving young children, which are already as scarce as hen’s teeth.
Children with drug-resistant partial epilepsy receiving placebo in double-blind RCTs demonstrated significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric clinical trial designs should account for these age-dependent variations of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials.
The clear message from the programme seemed to be that the placebo is powerful and mysterious and it works for most demographics. However, we heard no discussion about whether there are agreed characteristics of patients for whom the placebo doesn’t work or if it is expected to work for everyone in some contexts. If anything, it seems that it is popular with patients who consider pharmaceuticals to be synthetic and intrinsically undesirable and potentially harmful, and frequently express their desire for a ‘natural remedy’.
Social anthropologist Professor Moerman suggested that placebo had been circumscribed by the medical profession who see it as something that applies to sugar pills or the placebo arms of clinical trials, isolating it from mainstream medicine. Chalmers summarised the difficulties of assessing and evaluating all of the contributory factors that contribute to the placebo effect and remarked that it is easier to make a case for a specific drug than for (say) an intervention such as an extended consultation time with GPs.
Goldacre finished by summarising the current interest in evidence-based medicine both as a means of providing good quality treatment for patients but also best return on financial investment for health services but flagged up that both of these may be compromised by medicine’s inability to harness the placebo. Disappointingly, he left the final word to Professor Kaptchuk who gave rather a reductionist view of medicine as a process of establishing a diagnosis of a specific disease and knocking it down with a drug. He reported that many chronic diseases “don’t have knock out drugs that work with that kind of refinement and precision” and it is possible that there never will be that perfect drug for each of those conditions.
The ideology of specificity and scientific precision sometimes clouds the need for the art of medicine…[The value of my research is] to influence health care policy to not trim the amount of time a patient receives from a doctor, will not devalue the doctor-patient relationship. Will understand that it’s not just handing a pill like you’re throwing feed to a chicken in a chicken coop but that the pill, the medication is part of an elaborate drama and that drama has an impact on people’s illness and health.
I’m sure that Dr Crippen, in line with other family GPs throughout the UK will be delighted by that depiction of their typical interaction with a patient albeit it is coupled with an acknowledgement of their powerful role as primary care doctors in a therapeutic alliance with their patients. This was a profoundly irritating and trite bunch of sentiments.[d] to end this interesting pair of programmes. Goldacre might have nipped into any surgery’s waiting-room and interviewed patients and he would probably have heard similar banalities from some patients while others extolled the virtues, keen interest and kindness of their GPs and Practice Nurses. I might have been more sympathetic had there been any suggestion as to how research findings from NCCAM might be translated into a form that would influence health care policy in general and not be restricted to an even more circumscribed part of the ghetto of influence that Moerman described.
My irritation with the conclusion was possibly exacerbated because there was no strong voice of dissent in either of the programmes, with the strongest disagreement being reserved for whether or not it is ethical to use a placebo even with a patient’s consent. What was missing from the discussion was an acknowledgement that there are researchers who argue that the placebo is both over-rated and ineffective and that there is no role for it in medicine, outside the context of a clinical trial. And they have a systematic review of placebo trials to support their stance.
In 2001 Professors Hróbjartsson and Gøtzsche of the Nordic Cochrane Institute in Stockholm, carried out a meta-analysis of 130 clinical trials to compare the outcomes of the placebo group with a no-treatment group, to reveal and quantify the placebo effect.[5] The studies ranged from investigations into alcohol dependence to Parkinson’s disease, encompassing 40 medical conditions, around 7500 patients and placebos that were pharmacologic (e.g., a tablet), physical (e.g., a manipulation), or psychological (e.g., a conversation). The authors concluded that with some small-scale exceptions, placebos have no significant effects.
We found little evidence in general that placebos had powerful clinical effects. Although placebos had no significant effects on objective or binary outcomes, they had possible small benefits in studies with continuous subjective outcomes and for the treatment of pain. Outside the setting of clinical trials, there is no justification for the use of placebos.
A follow-up review included data more trials and patients[6] and the conclusions remained the same.
There was an apparent effect of placebo interventions on pain (SMD -0.25 (95% CI -0.35 to-0.16)), and phobia (SMD -0.63 (95% CI -1.17 to -0.08)); but also a substantial risk of bias. There was no statistically significant effect of placebo interventions in eight other clinical conditions investigated in three trials or more: nausea, smoking, depression, overweight, asthma, hypertension, insomnia and anxiety, but confidence intervals were wide.
In keeping with most of the studies that Goldacre discussed, it seems that if you restrict your examination to only those studies where the outcomes are dependent upon patients’ reports and subjective experiences, such as their level of pain, then placebos may have a small but significant effect, although Hróbjartsson and Gøtzsche caution that the quality of the studies introduces a high risk of bias. Depending upon the condition and how it is measured, it seems that the placebo effect can make patients feel better – even if there are no observable clinical differences.
Hróbjartsson was recently interviewed as part of an article about the power of the placebo effect in the New Scientist. He reports that there will shortly be another update to the systematic review of placebo interventions for all clinical conditions but that the results are more or less the same. Hróbjartsson argues that there is no justification for offering placebos outside a clinical setting.
“My concern is not so much whether effects of placebo are real or not, but whether there is evidence for clinically relevant effects.”
Giving patients plenty of TLC is where placebo intervention should end, he thinks. “Most of us working in the field think that’s just another way of saying ‘be a good doctor’.”
Skepdic outlines some of the methodological objections in Hróbjartsson and Gøtzsche’s systematic reviews. It might have been useful for Goldacre to mention the bias of compliance and whether this is a characteristic of placebo responders. Again, it is possible that there was simply not enough room in the programmes and this may be fully addressed in the book.
Yes, maybe medical practice might be substantially improved by incorporating some of the more attractive and exciting findings from placebo research (or at least the implications for higher-quality patient-doctor interactions) and Goldacre presented a fine array of them. However, the audience for the programme needed to be told that there are strong dissenting voices that argue that the placebo is less powerful than its publicity would have us believe and that, beyond the considerations of white lies, Clinical placebo interventions are unethical, unnecessary, and unprofessional.[7] Skepdic has a good discussion of placebo, including some of these dissenting elements and an excellent series of links and references.
The placebo is intriguing and interesting and seductive, yet, like most health-related interventions, it needs to be placed in a sophisticated context that fully incorporates social, contextual and other factors. There is a nagging feeling that this didn’t quite happen in the radio programmes hence the Brillat-Savarin sense of being sans fromage or gazing upon a beautiful woman with only one eye. It will be interesting to see whether or not these dissenting viewpoints receive an airing in Goldacre’s book.
Update: to include Skepdic discussion and link to Gary Taubes’ article: Do We Really Know What Makes Us Healthy?. I’ve also included a link to Glymour and Stalker.
Notes
[a] Philosophers Clark Glymour and Douglas Stalker contributed a classic paper on this issue: Engineers, cranks, physicians, magicians. Fortunately, Dr Kim Atwood has provided some lengthy extracts of this paper: Science, Reason, Ethics and Modern Medicine, Part 4: Is CAM the Only Alternative? It would have been useful if Goldacre had asked Brown or Lewith to rebut the concerns that Glymour and Stalker expressed so eloquently.
If holistic-health advocates were content with encouraging sensible preventive medicine or with criticizing the economic organization of American medicine, we might be enthusiastic, but they are not. If the movement were without influence on American life, we would be indifferent, but it is not. Holistic medicine is a pablum of common sense and nonsense offered by cranks and quacks and failed pedants who share an attachment to magic and an animosity toward reason. Too many people seem willing to swallow the rhetoric—even too many medical doctors—and the results will not be benign.
[b] Again, it might have been useful if there had been an allusion to the need not only to design an ethical form of words that allows for full consent while not wholly undermining the placebo response, but also some way of encapsulating a willing acceptance of magic to enhance a healing response that should not be transferred elsewhere in life or used to undermine the public understanding of science.
[c] There are too many examples of instances where there was or is an institutional blindness to the reporting of symptoms by particular groups to the extent where flagrant instances of disease are being missed. Denise Grady gave a fine account of women’s hidden heart disease risk that had been dismissed for too long because ‘everyone knew that women’s risk of heart disease is less than men’s and the male presentation of heart disease is the only genuine symptom profile’. Constant reassurances and patient management rather than investigation had delayed recognition of significant gender differences for too long as in this story: In heart disease, the focus shifts to women.
“I was treated like a crazy woman,” Ms. Kachmann-Geltz said, noting that one doctor offered her tranquilizers, implying that her problems were all in her head.Her symptoms began during her third pregnancy, and her heart function deteriorated so much that she nearly died during labor, she said, recalling that a nurse in the delivery room actually asked whether she was an organ donor.
After her son was born, she suffered from angina for almost two years and had attacks that woke her up at night, before she found her way to Dr. Pepine.
Tests showed a blood flow deficit in her heart.
“It was 30 seconds that changed my life,” she said. “It was the first time I felt acknowledged. This is real, it’s not in my head, it’s not some pregnancy thing. I shake when I think about it.”
There is a present distrust in the US that is grounded in the comparatively recent sterilization abuse of black women and similar horrors.
[d] Glymour and Stalker as per note a.
What ties together the diverse practices [of CAM]…? In part, a banal rhetoric about the physician as consoler;… In part, familiar and rather useless admonitions about not overlooking the abundance of circumstances that may contribute to one condition or another. Such banalities are often true and no doubt sometimes ignored, with disastrous consequences, but they scarcely amount to a distinctive conception of medicine…
Insofar as it extends beyond banality, the holistic medical movement constitutes both a deliberate attempt to substitute a magical for an engineering conception of the physical and an attack on scientific understanding and reasoning. Although the holistic movement does not contain a conception of medicine distinct from those we have discussed, it does contain a reactionary impetus to return the practice of medicine to the practice of magic and to replace logic and method with occultism and obfuscation.
References
[1] Sherman R, Hickner J. Academic physicians use placebos in clinical practice and believe in the mind-body connection. J Gen Intern Med. 2008 Jan;23(1):7-10.
[2] Sandler AD, Bodfish JW. Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Health Dev. 2008 Jan;34(1):104-10.
[3] Sandler A, Glesne C, Geller G. Children’s and parents’ perspectives on open-label use of placebos in the treatment of ADHD. Child Care Health Dev. 2008 Jan;34(1):111-20.
[4] Rheims S, Cucherat M, Arzimanoglou A, Ryvlin P. Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial Epilepsy. PLoS Med. 2008 Aug 12;5(8):e166.
[5] Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001 May 24;344(21):1594-602. Review. Erratum in: N Engl J Med 2001 Jul 26;345(4):304.
[6] Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2004;(3):CD003974.
[7] Hróbjartsson A. Clinical placebo interventions are unethical, unnecessary, and unprofessional. J Clin Ethics. 2008 Spring;19(1):66-9.
21 Comments
August 26, 2008 at 12:40 pm
“Group 2 received half the usual dose but were also given a placebo capsule that they were told was a placebo that would extend the effect of the drug – a “dose extender”…”
I did wonder during the broadcast how sophisticated the understanding of placebo was among the participants in this trial – the introduction of the term ‘dose extender’ seemed to me to be approaching sleight-of-hand but perhaps my grasp of these issues is faulty. It’s a fascinating subject and I enjoyed the broadcasts but share your regret that the dissenting view was not explored more. Though my view is no doubt coloured by personal family medical history where, perhaps, less reassurance and more “specificity and scientific precision” might have led to a better outcome.
August 26, 2008 at 3:12 pm
OK, that was a weird experience. I listened to the programme and apart from some objections that sound like Claire’s, I was happy with it. I intensely disliked the weasel wording used by some participants because it sounded exactly like what people loathe about politicians but it can be difficult to discuss these issues in sound-bite form. (Radio 4 is remarkable for doing this sort of programme at all and it is inevitable with the format.)
But – now I’ve followed some of your links and I realise that that there are principled objections to placebo and even a Cochrane review I feel that I was only give a partial glimpse of the topic. Even if Ben Goldacre does write up the arguments against placebo in the book, it must have left the programme unbalanced as a stand-alone event.
I enjoyed the programme and I learned about some good stories. I’m currently feeling a little discontented about what was missing but I’ll work through it. :-)
August 26, 2008 at 11:53 pm
Fair point. Now, the Hróbjartsson and Gøtzsche systematic review doesn’t incorporate many of the studies that Goldacre included in his programmes because they needed trials with both a placebo and a non-treatment arm. Skepdic gives a good overview of some of the methodological problems with other studies that led to their exclusion.
However, even if it means that there are some areas of endeavour or demographics for which placebo is more suited, then it would have been helpful if this had been mentioned as part of the implications for researching or implementing its use.
@Claire, yes – it does depend on the wording of the informed consent as to whether it was absolutely clear that there was nothing to the “drug extender”. Maybe Ben Goldacre will eventually clarify this in his piece.
August 27, 2008 at 1:30 am
If I’ve understood your links then Professor Kaptchuk is a doctor of Oriental Medicine, he doesn’t have any qualifications in medicine, nor does he have any listed degrees, far less research degrees? However, judging by his bio and Pubmed he does have an extraordinary publication record, particularly for someone who says he didn’t get into science until 1999.
I’m just a little confused because I read an interesting post by Mike Stanton who seems to think that Kaptchuk is a medical doctor.
I found Professor/Dr Kaptchuk distracting rather than thought-provoking and felt that too much time had been alloted to him in the programmes. I’m more convinced of that now that I know that there was more that should have been included, even if it was just to acknowledge awareness of it before briefly explaining why it wasn’t relevant. It’s important to show that you are aware of dissenting opinions or it looks very like you have been cherry-picking your studies and your commenters.
Some of the suggested wording sounded clever-clever and would be the sort of thing that would raise my hackles. I invariably find that the people who need people-handling skills or think that they have them have no insight into their impact on others. I can see some people using that wording and feeling very smug about it but not understanding how much they were irritating the patient whom they are addressing – and then blaming the patients as difficult or unco-operative if the irritation overflowed.
I’ll stop here. I am going to say that female commenters seemed to be singularly absent from that programme and there is probably a reason for that. You have touched on it in your discussion as to why there are groups, like some women, who would find this approach tantamount to dishonesty and disrespectful.
Sorry for the length.
August 27, 2008 at 1:37 pm
As far as we can tell, that is an accurate view of Professor Kaptchuk – who does have an astonishing number of publications on PubMed (most are multiple-authored but even so, it is impressive and remarkable for such a short career as a scientist).
I’m not entirely sure what you mean about female commenters in the programme. I had expected Prof Anne Harrington to be involved as she had edited a well-received book (that would bear some updating): The Placebo Effect: An Interdisciplinary Exploration.
On the point of dishonesty and disrespect, I think that Goldacre mentioned several times that he would have some ethical qualms about using/recommending placebo and at some point declared that he ‘wasn’t sure what he thought about it’. However, I’m not too sure that any of the respondents (in the parts that were broadcast) addressed the concerns that you express or that occurred to me.
August 27, 2008 at 3:42 pm
“It might have been useful for Goldacre to mention the bias of compliance and whether this is a characteristic of placebo responders.”
Not the first time you’ve linked to the Taubes NYT piece – nor is it the first time you’ve lamented its absence from discussions of placebo. [I checked]
From the article, it appears that the bias of compliance affected the placebo group [being compared to the clofibrate group in the Coronary Drug Project] to roughly the same extent as it affected those taking clofibrate. David Freeman: “faithfully taking the placebo cuts the death rate by a factor of two [...] people who take their placebo regularly are just different than the others. The rest is a little speculative. Maybe they take better care of themselves in general. But this compliance effect is quite a big effect.” Freeman seems to be supported in his views by Jerry Avorn: “Girl Scouts in the group, the compliant ongoing users, who are probably doing a lot of other preventive things as well” in his comments on the Nurses’ Health Study.
Slightly OT, perhaps but… Holford made the point that “the more strictly they [YorkTest users] followed their allergy-free diet, the better their results.” Those results seem to me to be compatible with the ‘bias of compliance’ effect.
He has also trumpeted the Gladys Block study as evidence for the benefits of supplements, but I would have thought that the bias of compliance could have been an important factor in that study too.
August 27, 2008 at 3:50 pm
There were a couple of comments on the Bad Science blog I found interesting too.
Gazza made the point that “no comment was really made in the programmes on the limits of placebo for ’serious’ illnesses (let’s say most cancers, heart disease, HIV, etc).” Which I was interested in mainly because I think a major problem with Alt Med is that (at least some) healers seem to have fantasies in which they can cure cancer and AIDS. What’s The Harm lists a few of those who have refused conventional treatment in the belief that, for example, homeopathy could treat their cancer (or heart disease, or AIDS…) and as long as these people have their healer fantasies I don’t see how it is possible to discuss the possibility of incorporating Alt Med into our healthcare system.
And that is quite apart from the ethical dilemma – is it OK (or necessary) to lie to patients? Ben Goldacre says “the answer, from me at any rate, is “no”.”
Admin edit: Gazza’s comment on BS post.
August 27, 2008 at 5:15 pm
I am interested in whether or not there is a higher rate of compliance amongst placebo responders but I hope not obsessed although, obviously, predictable.
And, again, feeling very predictable, it does seem as if people who can take pills/supplements on a regular basis or constantly monitor their food intake (e.g., 2 squares of dark chocolate, 3 fruits, 10 vegetables a day with no wheat, no dairy, but fish 3x a week) are different and unusual (judging by national snap-shots of dietary intakes). It would be fascinating to know if there is a tie-in there between compliance and response.
I think that it would be useful to establish if someone is inherently good with compliance or whether people can acquire the habit and, if so, does this make a difference to their response. If you are habitually ‘non-compliant’ does the strain of acting in a ‘compliant’ way outweigh any of the benefits?
I’m suggesting that because one of the suggestions for the unexpectedly poor outcomes of the aggressive lifestyle modification programme for diabetes is that it was difficult to follow. Similarly for the ACCORD programme some physicians speculated (to be confirmed) that the stress of following this gruelling regime may have contributed to the outcomes (perhaps a time when compliance worked against the interest of the patients).
August 27, 2008 at 6:05 pm
“I am interested in whether or not there is a higher rate of compliance amongst placebo responders but I hope not obsessed although, obviously, predictable.”
Ha, no – it only stood out because I’ve never seen anyone else link to it. Er, and because the first time I saw you link to it I went and read it and stuck references to it in some of my blog posts and comments. Especially those dealing with Patrick Holford’s “evidence” for the efficacy of supplements and food intolerance tests.
“Could it be the stress of ‘I’m trying so hard, but I can’t get it done’?”
I can still remember being accused of “not really trying” when I knew damn well I was – also the frustration of being unable to do something even when giving 100% – and I think, at least for me, these are instances that can be very stressful indeed. If you are put in the same position of being unable to achieve something despite your best efforts and it is something that you believe failing to achieve will have a negative impact on your health then it must be incredibly stressful. I imagine if I were in that situation, I would be not simply frustrated by my inability to succeed, but also scared by the implications of my failure to succeed.
August 27, 2008 at 9:40 pm
Yes – because with diabetes, it’s not ‘just’ the diabetes, it’s the concomitant co-morbidities such as CVD, macrovascular and microvascular disorders contributing to sequelae such as chronic renal disease or loss of function, chronic infection leading to amputation of toes, feet etc.
However, I don’t have a feeling for whether diabetes is a special case because it seems to be quite well-established that stress has a role in exacerbating blood sugar disturbances.
All of which is why I have a sense that compliance and associated issues might be relevant confounders for the placebo response. I’d like to read a good discussion of that but I’m not too sure how many suitable data-sets are out there. Moerman managed to put together some provocative analyses of placebo by re-purposing data on ulcers that already exist: I don’t know if there are large-scale studies that would be suitable for analysis that would yield data on compliance as well as placebo.
Moerman DE. Cultural variations in the placebo effect: ulcers, anxiety, and blood pressure. Med Anthropol Q 14:1-22, 2000.
Moerman DE. General Medical Effectiveness and Human Biology: Placebo Effects in the Treatment of Ulcer Disease. Medical Anthropology Quarterly, Vol. 14, No. 4 (Aug., 1983), pp. 3-16.
de Craen AJ, Moerman DE, Heisterkamp SH, Tytgat GN, Tijssen JG, Kleijnen J. Placebo effect in the treatment of duodenal ulcer. Br J Clin Pharmacol. 1999 Dec;48(6):853-60.
August 28, 2008 at 11:27 am
I’m definitely on thin ice here knowledge-wise but in the context of the compliance/placebo response discussion, it occurs to me that one group I’ve seen characterised as at risk of poor compliance/prone to risk taking (in the context of chronic disease such as asthma or epilepsy where daily meds are prescribed) is young people in teens/early 20s, particularly males. It would be interesting to know if there was any data on placebo response in this group.
August 28, 2008 at 11:34 am
Re above, this articledescribes some teens/poor compliance issues. Feeling in control, even when they’re not, seems to induce a false sense of security.
August 28, 2008 at 12:21 pm
Also true of type I diabetics, in my (anecdotal) experience of the half-dozen I have known reasonably well. Of course, it is understandable there in the context of young diabetics having to “restrict” the behaviour that is normal for their age / peer group (irregular eating, eating crap food, getting boozed up / hung over, taking illegal substances etc etc). You can call all of this “risk-taking” behaviour, but it is pretty standard stuff from 15-25 (at least!).
Another important distinction in any study would have to be “diseases with perceptible and inconveniencing symptoms” (like a peptic / duodenal ulcer) versus “diseases with no very perceptible symptoms at present but possible nasty consequences down the line”.
Diabetes in young people might serve as an example of the latter – not-the-very-best blood glucose control may not have that many immediate consequences for a teenager , but it would probably be speeding them towards experiencing all the nasty “co-morbidities” (see DVNutrix’s post above) significantly earlier than someone with “tight blood glucose control”.
As has already been mentioned, the medical sociologists are clear that you have to approach compliance issues through this “risk vs. benefit as perceived by the patient“ framework. But the question of how that interacts with the effectiveness of placebo interventions is definitely interesting.
August 28, 2008 at 6:22 pm
I’ve taken another look through the final Moerman ref above.
So, it looks like there was a higher rate of placebo response among people who were compliant enough to take 4 tablets a day than those who were willing to take 2 per day: your Girl Scouts v. your muddle-through+s as it were.
However, the authors do remark:
Which looks like they think that compliance may be an interesting confounding factor. But, it is almost impossible to track the figures because these trials happened in the 70s and 80s and it doesn’t look like they were at all hot on establishing NNTs or using the intention to treat analysis what with NNT not being popularised until 1988.
Of course, with Helsinki and everything – it’s probably very tricky to come up with a study design involving placebo for a significant illness that would pass an IRB nowadays. By and large, lots of people (rightly) frown on using a placebo in such trials, because you are expected to evaluate your proposed novel treatment against the current best practice treatment.
Which is why there probably needs to be some creative thinking about data-sets that exist for another purpose.
And, I think evaluating placebo/compliance issues in young men, in particular, would be a nightmare.
However – it might be worthwhile having a poke around. Not that there is much chance of getting access to the raw data, but this is where the ‘allergy’/intolerance studies would be interesting because of the remarkable level of compliance that is needed to follow an exclusion diet. (However, iirc, Hunter argued that if the Gut paper had used an intention to treat analysis, then the NNT was 9 and therefore less effective than the usual exclusion diet and not the claimed 2.5 – which the Gut authors accepted). However, as the Gut paper demonstrated, it is not that straightforward to come up with a plausible sham diet – and measuring diet compliance would be considerably more difficult than evaluating whether someone has taken their scheduled drugs/placebos.
August 28, 2008 at 8:22 pm
Just to add to the mix if you haven’t seen it in the miniblog – h/t to Dr Vaughan Bell for the medical anthropology blog Somatosphere. As Bell says, Somatosphere brings together:
As if that didn’t offer enough placebo-related goodness – they have a fascinating link to Vasectomania, and Other Cures for Sloth with some novel and fad placebos from early C20.
September 3, 2008 at 11:30 am
Came across this recently, which included, briefly, some discussion (and links) on people likely to respond to placebo:
“…Recent functional brain imaging by University of Michigan researchers, headed by neuroscientist Jon-Kar Zubieta, has confirmed this finding. Their model is straightforward. Healthy young volunteers agreed to receive a painful injection into a jaw muscle. Prior to the injection, the volunteers were asked to gauge how much pain reduction they would experience if they were also administered a painkiller. Would they feel a 20 percent reduction in pain? Fifty percent? Then, simultaneously, they received the painful jaw muscle injection and a painkiller injection — only the “painkiller” was a placebo — an inert saline solution.
In patients reporting pain relief, PET scans showed an activation of their opioid receptors, where both narcotics and endorphins ply their trade, and a decrease in activity in several brain regions vital for feeling pain. The scans also showed that the placebo effect isn’t confined to endorphin release; the neurotransmitter dopamine receptor sites critical for the brain’s primary reward system also lighted up.
In an elegant follow-up study, Zubieta and colleagues looked at how subject expectation of pain relief was associated with a more generalized expectation of good results. The volunteers were invited to play a game; if they won, they’d get a small monetary reward. Before playing the game, they were asked to estimate their chances of winning. The study showed that those who felt they were most likely to win were the same folks who predicted the greatest relief from their “painkiller” injection. Scans confirmed that the activation of brain reward regions correlated with both general anticipation of winning and degree of expectation of pain relief…”
I wonder how this interacts with the risk perception/compliance questions discussed above.
September 3, 2008 at 2:16 pm
There might be an interesting association between the sort of people Prof Wiseman wrote about in The Luck Factor and this study. It’s possibly also relevant to the positive expectation-attribution paradigm written about by Ross and Olsen.
Beyond that however, although there can be one-off good placebo responses in controlled settings like the experiment – I wonder if, paradoxically, they are the people who might rely on ‘luck’ to tide them through and might not be the people who would reliably take medication – as per diabetes, asthma, epilepsy.
Intriguing research area that must be getting much harder to explore in a ‘real world setting’ because Helsinki is (rightly) stacked against placebo where an appropriate best-practice treatment exists.
September 4, 2008 at 9:23 am
You’re right, it’s intriguing and all the angles raised in this discussion make it hard (for me anyway) to decide how big a deal this really is.
Pulse has a recent article on how a GP surgery tackled the problem of frequent attenders with no obvious pathology. Such patients were offered a referral to the local MIND centre and there seems to have been benefit for those who accepted:
“…Nine patients out of the 20 we wrote to attended the special one-to-one appointments. The meetings were felt to be useful by both parties and the historical need to attend the surgery was discussed. Resolutions involved a range of ideas including volunteer work, subsidised reflexology, anxiety groups and subsidised counselling.
The main attraction of this project was the possibility of a dramatic reduction in our workload but the implications of somatisers for secondary care are significant and raised some commissioning possibilities.”
It’s possible the ’subsidised reflexology’ was suggested/provided by MIND, rather than GPs, and it’s probably mean-spirited of me to wonder if it is really necessary to include a modality which makes claims about human physiology and disease which have been found to have little basis in reality.
October 6, 2008 at 5:24 pm
[...] and the growth of the personal testimonial feels as if it is very important. Returning to the placebo discussion that we have had recently, the advertising, the home-grown qualifications and the moving [...]
October 23, 2008 at 12:51 pm
[...] Although HolfordWatch has not reviewed Bad Science, it has a related discussion: Ben Goldacre and Placebo (Part 2) Radio 4: Lacking In Cheese or Missing An Eye. [...]