MD, PhD, FMedSci, FSB, FRCP, FRCPEd

placebo

As promised in the last post, I will try to briefly address the issues which make me uncomfortable about the quotes by Anthony Campbell. Readers will recall that Campbell, an ex-director of what was arguably the most influential homeopathic hospital in the world and a long-time editor of the journal HOMEOPATHY, freely admitted that homeopathy was unproven and its effects were most likely not due to any specific properties of the homeopathic remedies [which are, in fact, pure placebos] but largely rely on non-specific effects.

I agree with much that Campbell wrote but I disagree with one particular implication of his conclusions:Homeopathy has not been proved to work but neither has it been conclusively disproven….” and “…it is impossible to say categorically that all the remedies are without objective effect…”

This is an argument, we hear from proponents of alternative medicine with unfailing regularity:MY TREATMENT MAY NOT BE SUPPORTED BY GOOD SCIENCE [BECAUSE GOOD SCIENCE IS EXPENSIVE, AND WE CANNOT AFFORD IT] BUT IT HAS NOT BEEN DISPROVEN EITHER – AND, AS LONG AS IT IS NOT DISPROVEN, NOBODY SHOULD STOP US USING IT”

Campbell does not explicitly draw this latter conclusion but he certainly implies it. In his book, he explains that, even though homeopathic remedies probably are placebos, homeopathy does a lot of good through the placebo effect and through its spiritual aspects. And that is, in his view, sufficient reason to employ it for healing the sick. The very last sentence of his book reads: “Love it or loathe it, homeopathy is here to stay”

So the implication is there: alternative therapies can be as bizarre, nonsensical, implausible, unscientific or idiotic as they like, if we scientists cannot disprove them, they must be legitimate for general use. But there are, of course, two obvious errors in this line of reasoning:

  1. Why on earth should scientists waste their time and resources on testing notions which are clearly bonkers? It is hard to imagine research that is less fruitful than such an endeavour.
  2. Disproving homeopathy [or similarly ridiculous treatments] is a near impossibility. Proving a negative is rarely feasible in science.

In the best interest of patients, responsible health care has to follow an entirely different logic: we must consider any treatment to be unproven, while it is not supported with reasonably sound evidence for effectiveness; and in clinical routine, we employ mostly such treatments which are backed by sound evidence, and we avoid those that are unproven. In other words, whether homeopathy or any other medicine is unproven or disproven is of little practical consequence: we try not to use either category.

While I applaud Campbell’s candid judgement regarding the lack of effectiveness of homeopathic remedies, I feel the need to finish his conclusion for him giving it a dramatically different meaning: Homeopathy has not been proved to work but neither has it been conclusively disproven; this means that, until new evidence unambiguously demonstrates otherwise, we should classify homeopathy as ineffective – and this, of course, applies not just to homeopathy but to ALL unproven interventions.

There are numerous types and styles of acupuncture, and the discussion whether one is better than the other has been long, tedious and frustrating. Traditional acupuncturists, for instance, individualise their approach according to their findings of pulse and tongue diagnoses as well as other non-validated diagnostic criteria. Western acupuncturists, by contrast, tend to use formula or standardised treatments according to conventional diagnoses.

This study aimed to compare the effectiveness of standardized and individualized acupuncture treatment in patients with chronic low back pain. A single-center randomized controlled single-blind trial was performed in a general medical practice of a Chinese-born medical doctor trained in both western and Chinese medicine. One hundred and fifty outpatients with chronic low back pain were randomly allocated to two groups who received either standardized acupuncture or individualized acupuncture. 10 to 15 treatments based on individual symptoms were given with two treatments per week.

The main outcome measure was the area under the curve (AUC) summarizing eight weeks of daily rated pain severity measured with a visual analogue scale. No significant differences between groups were observed for the AUC (individualized acupuncture mean: 1768.7; standardized acupuncture 1482.9; group difference, 285.8).

The authors concluded that individualized acupuncture was not superior to standardized acupuncture for patients suffering from chronic pain.

But perhaps it matters whether the acupuncturist is thoroughly trained or has just picked up his/her skills during a weekend course? I am afraid not: this analysis of a total of 4,084 patients with chronic headache, lower back pain or arthritic pain treated by 1,838 acupuncturists suggested otherwise. There were no differences in success for patients treated by physicians passing through shorter (A diploma) or longer (B diploma) training courses in acupuncture.

But these are just one single trial and one post-hoc analysis of another study which, by definition, cannot be fully definitive. Fortunately, we have more evidence based on much larger numbers. This brand-new meta-analysis aimed to evaluate whether there are characteristics of acupuncture or acupuncturists that are associated with better or worse outcomes.

An existing dataset, developed by the Acupuncture Trialists’ Collaboration, included 29 trials of acupuncture for chronic pain with individual data involving 17,922 patients. The available data on characteristics of acupuncture included style of acupuncture, point prescription, location of needles, use of electrical stimulation and moxibustion, number, frequency and duration of sessions, number of needles used and acupuncturist experience. Random-effects meta-regression was used to test the effect of each characteristic on the main effect estimate of pain. Where sufficient patient-level data were available, patient-level analyses were conducted.

When comparing acupuncture to sham controls, there was little evidence that the effects of acupuncture on pain were modified by any of the acupuncture characteristics evaluated, including style of acupuncture, the number or placement of needles, the number, frequency or duration of sessions, patient-practitioner interactions and the experience of the acupuncturist. When comparing acupuncture to non-acupuncture controls, there was little evidence that these characteristics modified the effect of acupuncture, except better pain outcomes were observed when more needles were used and, from patient level analysis involving a sub-set of 5 trials, when a higher number of acupuncture treatment sessions were provided.

The authors of this meta-analysis concluded that there was little evidence that different characteristics of acupuncture or acupuncturists modified the effect of treatment on pain outcomes. Increased number of needles and more sessions appear to be associated with better outcomes when comparing acupuncture to non-acupuncture controls, suggesting that dose is important. Potential confounders include differences in control group and sample size between trials. Trials to evaluate potentially small differences in outcome associated with different acupuncture characteristics are likely to require large sample sizes.

My reading of these collective findings is that it does not matter which type of acupuncture you use nor who uses it; the clinical effects are similar regardless of the most obvious potential determinants. Hardly surprising! In fact, one would expect such results, if one considered that acupuncture is a placebo-treatment.

Several sceptics including myself have previously commented on this GP’s bizarre promotion of bogus therapies, his use of disproven treatments, and his advocacy for quackery. An interview with Dr Michael Dixon, OBE, chair of the ‘College of Medicine’, and advisor to Prince Charles, and chair of NHS Alliance, and president of the ‘NHS Clinical Commissioners’ and, and, and…was published on 15 November. It is such a classic example of indulgence in fallacies, falsehoods and deceptions that I cannot resist adding a few words.

To make it very clear what is what: the interviewer’s questions are in bold Roman; MD’s answers are in simple Roman; and my comments are in bold italic typeface. The interview itself is reproduced without changes or cuts.

How did you take to alternative medicine?

I started trying out alternative medicine after 10 years of practising as a general physician. During this period, I found that conventional medicine was not helping too many patients. There were some (patients) with prolonged headaches, backaches and frequent infections whom I had to turn away without offering a solution. That burnt me out. I started looking for alternative solutions.

The idea of using alternative treatments because conventional ones have their limits is perhaps understandable. But which alternative therapies are effective for the conditions mentioned? Dr Dixon’s surgery offers many alternative therapies which are highly unlikely to be effective beyond placebo, e.g. ‘Thought Field Therapy’, reflexology, spiritual healing or homeopathy.

But alternative medicine has come under sharp criticism. It was even argued that it has a placebo effect?

I don’t mind what people call it as long as it is making patients better. If the help is more psychological than physiological, as they argue, all the better. There are less side-effects, less expenses and help is in your own hands.

I have posted several articles on this blog about this fundamental misunderstanding. The desire to help patients via placebo-effects is no good reason to employ bogus treatments; effective therapies also convey a placebo-response, if administered with compassion. Merely administering placebos means denying patients the specific effects of real medicine and is therefore not ethical.

Why are people unconvinced about alternative medicine?

One, there are vested interests – professional and organizational impact on it. Two, even practitioners in conventional medicine do not know much about it. And most importantly, we need to develop a scientific database for it. In conventional medicine, pharmaceutical companies have the advantage of having funds for research. Alternative medicine lacks that. Have people who say alternative medicine is rubbish ever done research on it to figure out whether it is rubbish? The best way to convince them is through the age-old saying: Seeing is believing.

1) Here we have the old fallacy which assumes that ‘the establishment’ (or ‘BIG PHARMA’ ) does not want anyone to know how effective alternative treatments are. In truth, everyone would be delighted to have more effective therapies in the tool-kit and nobody does care at all where they originate from.

2) GPs do not know much about alternative medicine, true. But that does not really explain why they are ‘unconvinced’. The evidence shows that they need more convincing evidence to be convinced.

3) Dixon himself has done almost no research into alternative medicine (I know that because the few papers he did publish were in cooperation with my team). Contrary to what Dixon says, there are mountains of evidence (for instance ~ 20 000 articles on acupuncture and ~5000 on homeopathy in Medline alone); and the most reliable of this evidence usually shows that the alternative therapy in question does not work.

4) Apologists lament the lack of research funds ad nauseam. However, there is plenty of money in alternative medicine; currently it is estimated to be a $ 100 billion per year business worldwide. If they are unable to channel even the tiniest of proportions into a productive research budget, only they are to blame.

5) Have people who say alternative medicine is rubbish ever done research on it to figure out whether it is rubbish? Yes, there is probably nobody on this planet who has done more research on alternative medicine than I have (and DM knows it very well, for about 15 years, he tried everything to be associated with my team). The question I ask myself is: have apologists like Dixon ever done rigorous research or do they even know about the research that is out there?

6) Seeing is believing??? No, no, no! I have written several posts on this fallacy. Experience is no substitute for evidence in clinical medicine.

Will alternative medicine be taught in UK universities?

US already has 16 universities teaching it. The College of Medicine, UK, is fighting hard for it. We are historically drenched in conventional medicine and to think out of the box will take time. But we are at it and hope to have it soon.

1) Yes, the US has plenty of ‘quackademia‘ – and many experts are worried about the appalling lack of academic standards in this area.

2) The College of Medicine, UK, is fighting hard for getting alternative medicine into the medical curriculum. Interesting! Now we finally know what this lobby group really stands for.

3) Of course, we are ‘drenched’ in medicine at medical school. What else should we expose students to?

4) Thinking ‘out of the box’ can be productive and it is something medicine is often very good at. This is how it has evolved during the last 150 years in a breath-taking speed. Alternative medicine, by contrast, has remained stagnant; it is largely a dogma.

What more should India do to promote integrated medicine?

India needs to be prouder of its institutions and more critical of the West. The West has made massive mistakes. It has done very little about long-term diseases and in preventing them. India needs to be more cautious as it will lead the world in some diseases like the diabetes. It should not depend on conventional medicine for everything, but take the best for the worst.

To advise that India should not look towards the ‘West’ for treating diabetes and perhaps use more of their Ayurvedic medicines or homeopathic remedies (both very popular alternatives in India) is a cynical prescription for prematurely ending the lives of millions prematurely.

Can one design a clinical study in such a way that it looks highly scientific but, at the same time, has zero chances of generating a finding that the investigators do not want? In other words, can one create false positive findings at will and get away with it? I think it is possible; what is more, I believe that, in alternative medicine, this sort of thing happens all the time. Let me show you how it is done; four main points usually suffice:

  1.  The first rule is that it ought to be an RCT, if not, critics will say the result was due to selection bias. Only RCTs have the reputation of being ‘top notch’.
  2.  Once we are clear about this design feature, we need to define the patient population. Here the trick is to select individuals with an illness that cannot be quantified objectively. Depression, stress, fatigue…the choice is vast. The aim must be to employ an outcome measure that is well-accepted, validated etc. but which nevertheless is entirely subjective.
  3.  Now we need to consider the treatment to be “tested” in our study. Obviously we take the one we are fond of and want to “prove”. It helps tremendously, if this intervention has an exotic name and involves some exotic activity; this raises our patients’ expectations which will affect the result. And it is important that the treatment is a pleasant experience; patients must like it. Finally it should involve not just one but several sessions in which the patient can be persuaded that our treatment is the best thing since sliced bread - even if, in fact, it is entirely bogus.
  4.  We also need to make sure that, for our particular therapy, no universally accepted placebo exists which would allow patient-blinding. That would be fairly disastrous. And we certainly do not want to be innovative and create such a placebo either; we just pretend that controlling for placebo-effects is impossible or undesirable. By far the best solution would be to give the control group no treatment at all. Like this, they are bound to be disappointed for missing out a pleasant experience which, in turn, will contribute to unfavourable outcomes in the control group. This little trick will, of course, make the results in the experimental group look even better.

That’s about it! No matter how ineffective our treatment is, there is no conceivable way our study can generate a negative result; we are in the pink!

Now we only need to run the trial and publish the positive results. It might be advisable to recruit several co-authors for the publication – that looks more serious and is not too difficult: people are only too keen to prolong their publication-list. And we might want to publish our study in one of the many CAM-journals that are not too critical, as long as the result is positive.

Once our article is in print, we can legitimately claim that our bogus treatment is evidence-based. With a bit of luck, other research groups will proceed in the same way and soon we will have not just one but several positive studies. If not, we need to do two or three more trials along the same lines. The aim is to eventually do a meta-analysis that yields a convincingly positive verdict on our phony intervention.

You might think that I am exaggerating beyond measure. Perhaps a bit, I admit, but I am not all that far from the truth, believe me. You want proof? What about this one?

Researchers from the Charite in Berlin just published an RCT to investigate the effectiveness of a mindful walking program in patients with high levels of perceived psychological distress.

To prevent allegations of exaggeration, selective reporting, spin etc. I take the liberty of reproducing the abstract of this study unaltered:

Participants aged between 18 and 65 years with moderate to high levels of perceived psychological distress were randomized to 8 sessions of mindful walking in 4 weeks (each 40 minutes walking, 10 minutes mindful walking, 10 minutes discussion) or to no study intervention (waiting group). Primary outcome parameter was the difference to baseline on Cohen’s Perceived Stress Scale (CPSS) after 4 weeks between intervention and control.

Seventy-four participants were randomized in the study; 36 (32 female, 52.3 ± 8.6 years) were allocated to the intervention and 38 (35 female, 49.5 ± 8.8 years) to the control group. Adjusted CPSS differences after 4 weeks were -8.8 [95% CI: -10.8; -6.8] (mean 24.2 [22.2; 26.2]) in the intervention group and -1.0 [-2.9; 0.9] (mean 32.0 [30.1; 33.9]) in the control group, resulting in a highly significant group difference (P < 0.001).

Conclusion. Patients participating in a mindful walking program showed reduced psychological stress symptoms and improved quality of life compared to no study intervention. Further studies should include an active treatment group and a long-term follow-up

This whole thing could just be a bit of innocent fun, but I am afraid it is neither innocent nor fun, it is, in fact, quite serious. If we accept manipulated trials as evidence, we do a disservice to science, medicine and, most importantly, to patients. If the result of a trial is knowable before the study has even started, it is unethical to run the study. If the trial is not a true test but a simple promotional exercise, research degenerates into a farcical pseudo-science. If we abuse our patients’ willingness to participate in research, we jeopardise more serious investigations for the benefit of us all. If we misuse the scarce funds available for research, we will not have the money to conduct much needed investigations. If we tarnish the reputation of clinical research, we hinder progress.

In 2010, NICE recommended acupuncture for chronic low back pain (cLBP). Acupuncturists were of course delighted; the British Acupuncture Council, for instance, stated that they fully support NICE’s (National Institute for Health and Clinical Excellence) decision that acupuncture be made available on the NHS for chronic lower back pain. Traditional acupuncture has been used for over 2,000 years to alleviate back pain and British Acupuncture Council members have for many many years been successfully treating patients for this condition either in private practice or working within the NHS. In effect, therefore, these new guidelines are a rubber stamp of the positive work already being undertaken as well as an endorsement of the wealth of research evidence now available in this area.

More critical experts, however, tended to be surprised about this move and doubted that the evidence was strong enough for a positive recommendation. Now a brand-new meta-analysis sheds more light on this important issue.

Its aim was to determine the effectiveness of acupuncture as a therapy for cLBP. The authors found 13 RCTs which matched their inclusion criteria. Their results show that, compared with no treatment, acupuncture achieved better outcomes in terms of pain relief, disability recovery and better quality of life. These effects were, however, not observed when real acupuncture was compared to sham acupuncture. Acupuncture achieved better outcomes when compared with other treatments. No publication bias was detected.

The authors conclude that acupuncture is an effective treatment for chronic low back pain, but this effect is likely to be produced by the nonspecific effects of manipulation.

In plain English, this means that the effects of acupuncture on cLBP are most likely due to placebo. Should NICE be recommending placebo-treatments and have the tax payer foot the bill? I think I can leave it to my readers to answer this question.

Massage is an agreeable and pleasant treatment. It comes in various guises and, according to many patients’ experience, it relaxes both the mind and the body. But does it have therapeutic effects which go beyond such alleged benefits?

There is a considerable amount of research to test whether massage is effective for some conditions, including depression. In most instances, the evidence fails to be entirely convincing. Our own systematic review of massage for depression, for instance, concluded that there is currently a lack of evidence.

This was ~5 years ago - but now a new trial has emerged. It was aimed at determining whether massage therapy reduces symptoms of depression in subjects with human immunodeficiency virus (HIV) disease. Subjects were randomized into one of three groups to receive either Swedish massage (the type that is best researched amongst the many massage-variations that exist), or touch, or no such interventions. The treatment period lasted for eight weeks. Patients had to be at least 16 years of age, HIV-positive, suffering from a major depressive disorder, and on a stable neuropsychiatric, analgesic, and antiretroviral regimen for > 30 days with no plans to modify therapy for the duration of the study. Approximately 40% of the subjects were taking antidepressants, and all subjects were judged to be medically stable.

Patients in the Swedish massage and touch groups visited the massage therapist for one hour twice per week. In the touch group, a massage therapist placed both hands on the subject with slight pressure, but no massage, in a uniform distribution in the same pattern used for the massage subjects.

The primary and secondary outcome measures were the Hamilton Rating Scale for Depression score and the Beck Depression Inventory. The results showed that, compared to no intervention and/or touch, massage significantly reduced the severity of depression at week 4, 6 and 8.

The authors’ conclusion is clear: The results indicate that massage therapy can reduce symptoms of depression in subjects with HIV disease. The durability of the response, optimal “dose” of massage, and mechanisms by which massage exerts its antidepressant effects remain to be determined.

Clinical trials of massage therapy encounter formidable problems. No obvious funding source exists, and the expertise to conduct research is minimal within the realm of massage therapy. More importantly, it is difficult to find solutions to the many methodological issues involved in designing rigorous trials of massage therapy.

One such issue is the question of an adequate control intervention which might enable to blind patients and thus account for the effects of placebo, compassion, attention etc. The authors of the present trial have elegantly solved it by creating a type of sham treatment which consisted of mere touch. However, this will only work well, if patients can be made to believe that the sham-intervention was a real treatment, and if somehow the massage therapist is prevented to influence the patients through verbal or non-verbal communications. In the current trial, patients were not blinded, and therefore patients’ expectations may have played a role in influencing the results.

Despite this drawback, the study is one of the more rigorous investigations of massage therapy to date. Its findings offer hope to those patients who suffer from depression and who are desperate for an effective and foremost safe treatment to ease their symptoms.

My conclusion: the question whether massage alleviates depression is intriguing and well worth further study.

Acupuncture remains a highly controversial treatment: its mechanism of action is less than clear and the clinical results are equally unconvincing. Of course, one ought to differentiate between different conditions; the notion that acupuncture is a panacea is most certainly nonsense.

In many countries, acupuncture is being employed mostly in the management of pain, and it is in this area where the evidence is perhaps most encouraging. Yet, even here the evidence from the most rigorous clinical trials seems to suggest that much, if not all of the effects of acupuncture might be due to placebo.

Moreover, we ought to be careful with generalisations and ask what type of pain? One very specific pain is that caused by aromatase inhibitors (AI), a medication frequently prescribed to women suffering from breast cancer. Around 50 % of these patients complain of AI-associated musculoskeletal symptoms (AIMSS) and 15 % discontinue treatment because of these complaints. So, can acupuncture help these women?

A recent randomised, sham-controlled trial tested whether acupuncture improves AIMSS. Postmenopausal women with early stage breast cancer, experiencing AIMSS were randomized to eight weekly real or sham acupuncture sessions. The investigators evaluated changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain visual analog scale (VAS). Serum estradiol, β-endorphin, and proinflammatory cytokine concentrations were also measured pre and post-intervention. In total, 51 women were enrolled of whom 47 were evaluable (23 randomized to real and 24 to sham acupuncture).

Baseline characteristics turned out to be balanced between groups with the exception of a higher HAQ-DI score in the real acupuncture group. The results failed to show a statistically significant difference in reduction of HAQ-DI or VAS between the two groups. Following eight weekly treatments, a significant reduction of IL-17 was noted in both groups. No significant modulation was seen in estradiol, β-endorphin, or other proinflammatory cytokine concentrations in either group. No difference in AIMSS changes between real and sham acupuncture was seen.

Even though this study was not large, it was rigorously executed and well-reported. As many acupuncturists claim that their treatment alleviates pain and as many women suffering from AM-induced pain experience benefit, acupuncture advocates will nevertheless claim that the findings of this study are wrong, misleading or irrelevant. The often remarkable discrepancy between experience and evidence will again be the subject of intense discussions. How can a tiny trial overturn the experience of so many?

The answer is: VERY EASILY! In fact, the simplest explanation is that both are correct. The trial was well-done and its findings are thus likely to be true. The experience of patients is equally true – yet it relies not on the effects of acupuncture per se, but on the context in which it is given. In simple language, the effects patients experience after acupuncture are due to a placebo-response.

This is the only simple explanation which tallies with both the evidence and the experience. Once we think about it carefully, we realise that acupuncture is highly placebo-genic:

It is exotic.

It is invasive.

It is slightly painful.

It involves time with a therapist.

It involves touch.

If anyone had the task to develop a treatment that maximises placebo-effects, he could not come up with a better intervention!

Ahhh, will acupuncture-fans say, this means that acupuncture is a helpful therapy. I don’t care how it works, as long as it does help. Did we not just cover this issues in some detail? Indeed we did -  and I do not feel like re-visiting the three fallacies which underpin this sentence again.

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