On 25 and 26 May of this year I wrote two posts about an acupuncture trial that, in my view, was dodgy. To refresh your memory, here is the relevant part of the 2nd post:
This new study was designed as a randomized, sham-controlled trial of acupuncture for persistent allergic rhinitis in adults investigated possible modulation of mucosal immune responses. A total of 151 individuals were randomized into real and sham acupuncture groups (who received twice-weekly treatments for 8 weeks) and a no acupuncture group. Various cytokines, neurotrophins, proinflammatory neuropeptides, and immunoglobulins were measured in saliva or plasma from baseline to 4-week follow-up.
Statistically significant reduction in allergen specific IgE for house dust mite was seen only in the real acupuncture group. A mean (SE) statistically significant down-regulation was also seen in pro-inflammatory neuropeptide substance P (SP) 18 to 24 hours after the first treatment. No significant changes were seen in the other neuropeptides, neurotrophins, or cytokines tested. Nasal obstruction, nasal itch, sneezing, runny nose, eye itch, and unrefreshed sleep improved significantly in the real acupuncture group (post-nasal drip and sinus pain did not) and continued to improve up to 4-week follow-up.
The authors concluded that acupuncture modulated mucosal immune response in the upper airway in adults with persistent allergic rhinitis. This modulation appears to be associated with down-regulation of allergen specific IgE for house dust mite, which this study is the first to report. Improvements in nasal itch, eye itch, and sneezing after acupuncture are suggestive of down-regulation of transient receptor potential vanilloid 1.
…the trial itself raises a number of questions:
- Which was the primary outcome measure of this trial?
- What was the power of the study, and how was it calculated?
- For which outcome measures was the power calculated?
- How were the subjective endpoints quantified?
- Were validated instruments used for the subjective endpoints?
- What type of sham was used?
- Are the reported results the findings of comparisons between verum and sham, or verum and no acupuncture, or intra-group changes in the verum group?
- What other treatments did each group of patients receive?
- Does anyone really think that this trial shows that “acupuncture is a safe, effective and cost-effective treatment for allergic rhinitis”?
In the comments section, the author wrote: “after you have read the full text and answered most of your questions for yourself, it might then be a more appropriate time to engage in any meaningful discussion, if that is in fact your intent”, and I asked him to send me his paper. As he does not seem to have the intention to do so, I will answer the questions myself and encourage everyone to have a close look at the full paper [which I can supply on request].
- The myriad of lab tests were defined as primary outcome measures.
- Two sentences are offered, but they do not allow me to reconstruct how this was done.
- No details are provided.
- Most were quantified with a 3 point scale.
- Mostly not.
- Needle insertion at non-acupoints.
- The results are a mixture of inter- and intra-group differences.
- Patients were allowed to use conventional treatments and the frequency of this use was reported in patient diaries.
- I don’t think so.
So, here is my interpretation of this study:
- It lacked power for many outcome measures, certainly the clinical ones.
- There were hardly any differences between the real and the sham acupuncture group.
- Most of the relevant results were based on intra-group changes, rather than comparing sham with real acupuncture, a fact, which is obfuscated in the abstract.
- In a controlled trial fluctuations within one group must never be interpreted as caused by the treatment.
- There were dozens of tests for statistical significance, and there seems to be no correction for multiple testing.
- Thus the few significant results that emerged when comparing sham with real acupuncture might easily be false positives.
- Patient-blinding seems questionable.
- McDonald as the only therapist of the study might be suspected to have influenced his patients through verbal and non-verbal communications.
I am sure there are many more flaws, particularly in the stats, and I leave it to others to identify them. The ones I found are, however, already serious enough, in my view, to call for a withdrawal of this paper. Essentially, the authors seem to have presented a study with largely negative findings as a trial with positive results showing that acupuncture is an effective therapy for allergic rhinitis. Subsequently, McDonald went on social media to inflate his findings even more. One might easily ask: is this scientific misconduct or just poor science?
END OF QUOTE
This and the previous post created lots of discussion and comments. However, the question whether the study in question amounted to scientific misconduct was never satisfactorily resolved. Therefore, I decided to write to the editor of ‘Ann Allergy Asthma Immunol‘ where the trial had been published. He answered by saying I would need to file an official complaint for him to address the issue. On 13 June, I therefore sent him the following email:
Thank you for your letter of 3/6/2016 suggesting I make a formal complaint about the paper entitled ‘EFFECT OF ACUPUNCTURE ON HOUSE DUST MITE…’ [ Ann Allergy Asthma Immunol 2016] by McDonald et al. I herewith wish to file such a complaint.
The article in question reports an RCT of acupuncture for persistent allergic rhinitis. It followed a parallel group design with 3 groups receiving the following interventions:
3. No treatment
There was a plethora of outcome measures and time points on which they were measured. A broad range of parameters was defined as primary endpoints.
The conclusion reached by the authors essentially was that acupuncture affected several outcome measures in a positive sense, thus supporting the notion that acupuncture is efficacious [“Symptoms and quality of life improved significantly and were still continuing to improve 4 weeks after treatment ceased.”] This conclusion, however, is misleading and needs correcting.
The main reasons for this are as follows:
· Despite the fact that the authors did many dozens of statistical tests for significance, they did not correct for this multiplicity of tests. Consequently, some or most of the significant results are likely to be false positive.
· Many of the positive results of this paper were not obtained by comparing one group to another but by doing before/after comparisons within one group. This approach defies the principle of a controlled clinical trial. For doing intra-group comparisons, we obviously do not need any control group at all. The findings from intra-group comparisons are prominently reported in the paper, for instance in the abstract, giving the impression that they originate from inter-group comparisons. One has to read the paper very carefully to find that, when inter-group comparisons were conducted, their results did NOT confirm the findings from the reported intra-group comparisons. As this is the case for most of the symptomatic endpoints, the impression given is seriously misleading and needs urgent correction.
On the whole, the article is a masterpiece of obfuscation and misrepresentation of the actual data. I urge you to consider the harm than can be done by such a misleading publication. In my view, the best way to address this problem is to withdraw the article.
I look forward to your decision.
END OF QUOTE
I had to send several reminders but my most recent one prompted the following response dated 7/11/ 2016:
- Our editorial team recognizes that this is not the best clinical trial we have published in the Annals of Allergy, Asthma and Immunology. However, neither is is the worst. As in most published research studies, there are always things that could have been done better to make it a stronger paper. Never-the-less, the criticism falls fall short of any sort of remedy that would include withdrawal of the manuscript.
- Regarding your accusation that the multiple positive endpoint resulted in the authors making specific therapeutic claims, our assessment is that no specific therapeutic claim was made but rather the authors maintained that the data support the value of acupuncture in improving symptoms and quality of life in patients with AR. We do not believe there was overreach in those statements.
- The authors’ stated intent was to show immune changes associated with clinical markers of improvement in the active acupuncture group compared to controls. The authors maintain (and our editors agree) that their data assessments were primarily based upon three statistical tests not “dozens” (as stated in your original letter of complaint). The power analysis and sample size calculations were presented to us and deemed adequate , making the probability of a type I error quite low.
- The authors acknowledge in their paper that there could be limitations to their data interpretation based upon potential disparities between intra- and intergroup comparisons. The editors felt their transparency was adequately disclosed.
I have been alerted to the fact that my former medical school in Munich at one of Germany’s highest-ranked universities is currently running an elective course in homeopathy. For those who do not read German (the original announcement [apparently posted all over Munich university hospitals] is copied below), it teaches the use of homeopathy in/for:
- INTERNAL MEDICINE
- RECURRENT OTITIS MEDIA
- PALLIATION OF RESPIRATORY PROBLEMS
- PROSTATE CANCER
- POST-TRAUMATIC SYNDROMES
- BIPOLAR DISEASE
- MULTIMORBID PATIENTS WITH UVEITIS
- DISEASES OF THE FEMALE BREAST
- SUPPORTIVE CANCER CARE
- PAEDIATRIC ASTHMA
The course is being organised by Dr. med. Sigrid Kruse, von Haunersches Kinderspital des Klinikums der Universität München in co-operation with the ‘Landesverband Bayern des Deutschen Zentralvereins homöopathischer Ärzte’. The lecturers of this course seem to be mostly homeopaths from practices in and around Munich.
This article provides further explanations:
The project „Homeopathy in pediatrics“ was established in the Dr. von Hauner’s Children’s Hospital University of Munich in 1995 to integrate homeopathy into a university hospital. Selected children (outpatients and in the wards) are treated conventionally and homeopathically. The Karl and Veronica Carstens-Foundation initially financed the project over six years. An association of parents, whose children were treated for cancer, funded the project for one year. Since 2002, for the first time in Germany, the National Health Insurance is providing the financial background for two consultants for Homeopathy at this University hospital.
Who are we?
Dr. Mira Dorcsi-Ulrich, who initiated the project and carries out the supervision. She is a pediatrician in her own practice with 23 years of experience.
Dr. Sigrid Kruse has managed to integrate homeopathy into the clinic, starting at first in 1995 as a resident for pediatrics. Now she fulfills the requests of doctors and parents in the wards demanding concomitant homeopathic treatment.
Dr. Christian Lucae mainly treats the outpatients while focussing on his research project with children showing attention-deficit-hyperactivity-syndrome (ADHS).
Concomitant homeopathic therapy was successful in the following cases: intracerebral bleeding 3rd degree in premature babies, drug withdrawal in neonates addicted mothers, epilepsy, handicapped children, ADHS, migraine, tic, recurrent infections, asthma and atopic eczema, complications in wound healing and other problems. Homeopathic treatment of children parallel to conventional methods is particularly well accepted in the treatment of cancer. The side effects of oncological treatment like vomiting and stomatitis can be relieved, aggressions and anxiety intercepted and life quality improved.
END OF QUOTE
Which journal with a modicum of self-respect or rigor allows a homeopath to publish anything like the last paragraph without providing a jot of evidence? The answer is the ‘ALLGEMEINE HOMOEOPATHISCHE ZEITUNG’ – no further explanation needed, I think.
Courses like the one above, run at university level, make me first a little speechless and then more than a little angry. Medical schools should have other roles than teaching impressionable students things that fly in the face of science and evidence. They should guide them to become responsible doctors not misguide them to turn into irresponsible quacks. The fact that this comes from the medical school where I, many years ago, studied, graduated, worked and made both my MD and PhD theses renders the whole thing painfully sad for me personally.
But let’s not get depressed… ‘always look on the bright side of life’!!!
Luckily, there are glimpses of a bright side here. For instance, the fact that doctor Quak is one of the lecturers of this course (see below) is not without jollity, I must admit. Also amusing – at least to me – is be the vision of Dr. med. Mira Dorcsi-Ulrich (see below) standing in front of her students explaining the findings of one of the few RCT of individualised homeopathy for paediatric asthma. This study from my team found no evidence that “adjunctive homeopathic remedies, as prescribed by experienced homeopathic practitioners, are superior to placebo in improving the quality of life of children with mild to moderate asthma in addition to conventional treatment in primary care.”
Here is the German original announcement of the course:
RINGVORLESUNG IM WINTERSEMESTER 2016/2017
HOMÖOPATHIE VON DER THEORIE ZUR PRAXIS MIT PRAXISBEISPIELEN UND PATIENTENVORSTELLUNGEN
1. 20.10.2016 … IN DER INNEREN MEDIZIN: MÖGLICHKEITEN UND GRENZEN Dr. med. Ulf Riker
2. 27.10.2016 … IN DER NEONATOLOGIE: IKTERUS, ASPHYXIE UND UNRUHE Dr. med. Monika Grasser
3. 03.11.2016 … BEI PATIENTEN MIT SINUSITIS Dr. med. Michael Schreiner
4. 10.11.2016 … BEI KINDERN MIT REZIDIVIERENDER OTITIS MEDIA Dr. med. Christian Lucae
5. 17.11.2016 … BEI SCHLAFSTÖRUNGEN Dr. med. Brigitte Seul
6. 24.11.2016 … BEI PALLIATIV-PATIENTEN MIT RESPIRATORISCHEN PROBLEMEN Herbert Michalczyk
7. 01.12.2016 … IN DER BEGLEITUNG VON PATIENTEN MIT EINEM PROSTATA-CARCINOM Uwe Kraemer-Hoenes
8. 08.12.2016 … BEI POSTTRAUMATISCHER BELASTUNGS-STÖRUNG Dr. med. Ingrid Pfanzelt
9. 15.12.2016 … BEI EINER PATIENTIN MIT BIPOLARER AFFEKTIVER STÖRUNG Dr. med. Stephan Gerke
10. 12.01.2017 … BEI EINEM MULTIMORBIDEN PATIENTEN MIT UVEITIS Dr. med. Thomas Quak
11. 19.01.2017 … BEI PATIENTEN MIT HUSTEN Dr. med. Renate Grötsch
12. 26.01.2017 … BEI ERKRANKUNGEN DER WEIBLICHEN BRUST Dr. med. Ute Bullemer
13. 02.02.2017 … IN DER BEGLEITUNG VON KREBSPATIENTEN MIT Q-POTENZEN Miclós Takács
15. 09.02.2017… BEI KINDERN MIT ASTHMA BRONCHIALE Dr. med. Mira Dorcsi-Ulrich
Organisation: Dr. med. Sigrid Kruse, Dr. von Haunersches Kinderspital des Klinikums der Universität München
E-Mail: email@example.com in Zusammenarbeit mit dem Landesverband Bayern des Deutschen Zentralvereins homöopathischer Ärzte,
Prince Charles’ views on health have repeatedly taken centre stage on this blog. And rightly so; they are often weird and wonderful. In 2013, for instance, I quoted them extensively:
Charles stands for…”the kind of care that integrates the best of new technology and current knowledge with ancient wisdom. More specifically, perhaps, it is an approach to care of the patient which includes mind, body and spirit and which maximizes the potential of conventional, lifestyle and complementary approaches in the process of healing”. Charles believes that conventional medicine aims “to treat the symptoms of disease” his vision of a post-modern medicine therefore is “actively to create health and to put the patient at the heart of this process by incorporating those core human elements of mind, body and spirit…This whole area of work – what I can only describe as an ‘integrated approach’ in the UK, or ‘integrative’ in the USA – takes what we know about appropriate conventional, lifestyle and complementary approaches and applies them to patients. I cannot help feeling that we need to be prepared to offer the patient the ‘best of all worlds’ according to a patient’s wishes, beliefs and needs“. Charles also points out that “health inequalities have lowered life-expectancy” in parts of the UK and suggests, if we “tackle some of these admittedly deep-seated problems, not only do you begin to witness improvements in health and other inequalities, but this can lead to improvements in the overall cost-efficiency and effectiveness of local services.“
Sounds alright? Well – at least it is touching to see how he is concerned about inequalities in the UK!
But the royal and no doubt well-intended views need to be followed by royal actions. If not, such words might degenerate into royal BS. If Charles is so keen on giving us all THE BEST OF BOTH WORLDS, he should stop promoting outright quackery such as homeopathic remedies. They contain nothing but sugar! But that is one substance Charles seems to be rather fond of, regardless of the harm it can do in high doses to public health.
Recently, Prince Charles has been criticised by health campaigners for the high sugar content of his Duchy Organic ice cream. The Duchy Organic vanilla ice cream contains 14.5g of sugar per 100g, almost double the amount of Asda’s ‘smart price’ vanilla ice cream which has 7.9g sugar per 100g. If that wasn’t enough of a blow to the Prince’s brand, the Asda ice cream is also much more affordable at 85p for two litres – compared with £3.49 for every 750ml tub of the Duchy Organic product. Charles’ Dutchy Originals products are sold by Waitrose, and a spokesman of the retailer said: “Waitrose Duchy Organic vanilla ice cream is an indulgent product which is not aimed at children.”
Indulgent like in ‘expensive’? So much for inequalities, Charles.
But let’s not go there; let’s be constructive; after all, the man is full of good will, isn’t he?
I recommend the R&D department of Dutchy Originals put their profits and Charles convictions to good use. Specifically, I suggest they start a research programme on the homeopathic cure for sugar-induced obesity. If Charles is correct, and LIKE CURES LIKE, the obesity epidemic in the UK should be treatable with the very cause of excess body weight. It follows that potentised sugar ought to be a cure for obesity.
I can see it now: DUTCHY ORIGINALS – ‘SUGAR C30’, £15.99 per 10g.
This website tells us that ‘Stopain Migraine’ is the first topical product to effectively relieve migraine pain. It is a safe alternative to other migraine relief products that begins to work as soon as it’s applied. And the press release informs us that Troy Healthcare extended its Stopain line with a Stopain Migraine offering – a topical pain relieving gel that is massaged onto the back of the neck and behind each ear.
“Many of the women we shopped with told us they like that Stopain Migraine lacks systemic side effects and can be used in conjunction with other products – whether that’s natural remedies like peppermint essential oil, Epsom salts and ginger tea, or even prescription drugs or other over-the-counter products,” stated Anthony Cicini, VP Troy Healthcare.
Stopain Migraine begins to work as soon as it’s applied, can be reapplied after 30 minutes, and can be used up to four times daily, the company noted. It’s unique in that it can be used alone, or in addition to other ingestible migraine products to relieve migraine pain.
The homeopathic blend of ingredients follow the guidelines of The Homeopathic Pharmacopoeia of the United State and is recommended by both by primary care physicians and OBGYNs, the company stated.
In addition to providing effective relief quickly, Stopain Migraine offers peace of mind for migraine sufferers, knowing the product is free from aspirin, acetaminophen and caffeine, has no known drug interactions and contains no dyes or preservatives.
Consumers can now find Stopain Migraine nationwide for the suggested retail price of $11.99
END OF PRESS RELEASE
Any evidence, you’d probably ask. A quick Medline search located this abstract:
To determine whether topical menthol 6% gel will relieve a migraine attack.
MATERIALS AND METHODS:
A single-center, open-label pilot trial of 25 patients with at least 1 year of diagnosed episodic migraine and <15 headache days per month. Patients treated one migraine attack with STOPAIN topical menthol 6% gel to skull base within 2 h of headache onset. Headache pain severity was assessed prior to and after gel application.
Thirty-two patients enrolled and 25 completed the study. Prior to treatment, 7 patients had mild pain, 13 moderate pain, and 5 severe pain. Two hours following gel application, 7 (28%) patients had no pain, 7 (28%) mild pain, 6 (25%) moderate pain, and 5 (20%) severe pain. The majority of patients had similar pain intensity (8; 32%) or improvement (13; 52%). At 24-h, only two non-rescued patients still had mild headache. Of the 25 completers, 2 patients took rescue medication prior to the 2-h period, and an additional 10 patients rescued between 2 and 24 h.
Study results showed a significant improvement in headache intensity by 2 h after gel application. This pilot study shows STOPAIN gel may be effective in treating an acute migraine attack.
A pilot study! I thought pilots were for testing feasibility, not effectiveness!
No control group! The observed effect is therefore not attributable to ‘Stopain’ at all!
But there is more! Iranian researchers published this RCT:
To investigate the efficacy and safety of the cutaneous application of menthol 10% solution for the abortive treatment of migraine.
Peppermint and its active ingredient menthol have long been used for the treatment of various pain conditions including headache.
This is a randomised, triple-blind, placebo-controlled, crossed-over study conducted in the neurology Clinic of Nemazee Hospital, affiliated with Shiraz University of Medical Sciences, Shiraz, southern Iran, from March 2007 to March 2008. The patients were recruited via local newspaper advertisements. Eligible patients were categorised into two groups and a 10% ethanol solution of menthol (as drug) and 0.5% ethanol solution of menthol (as placebo) were applied to the forehead and temporal area in a crossover design. Pain free, pain relief, sustained pain free and sustained pain relief end-points were measured by questionnaires using a visual analogue scale.
The intent-to-treat population consisted of 35 patients (80% women, 20% men, mean age: 29.6 +/- 6.2) with 118 migraine attacks. In the intent-to-treat population, the menthol solution was statistically superior to the placebo on 2-h pain free (p = 0.001), 2-h pain relief (p = 0.000), sustained pain free and sustained pain relief end-points (p = 0.008). The menthol solution was also more efficacious in the alleviation of nausea and/or vomiting and phonophobia and/or photophobia (p = 0.02). In the per-protocol population, there was significantly higher number of patients who experienced at least one pain free/pain relief after the application of menthol rather than the placebo (p = 0.002). No significant difference was seen between the adverse effects of the drug and the placebo groups (p = 0.13).
Menthol solution can be an efficacious, safe and tolerable therapeutic option for the abortive treatment of migraine.
Yes, you are quite right; this must be a different product. It contains just menthol and at a higher concentration than ‘Stopain’.
So what does ‘Stopain’ actually contain? I must say that 6% menthol does not sound very homeopathic to me! The website of Troy Healthcare tells us that it has a total of 4 ingredients:
|Mentholum 1X HPUS – 50.00%|
|Belladonna 3X HPUS – 1.33%|
|Iris Versicolor 6X HPUS – 1.33%|
|Sanguinaria Canadensis 6X HPUS – 1.33%|
And what do the three homeopathically diluted ingredients do?
Is the term ‘homeopathic’ used here merely to attract a certain type of customer?
And why do they claim that ‘Stopain’ is effective when there is no evidence?
Or perhaps there is evidence and they haven’t published it?
And why do they claim that ‘Stopain’ is the first topical product?
Wasn’t a German topical menthol product marketed years ago?
Search me! I am not sure I know all the answers.
I hope someone from Troy Healthcare reads this and cares to explain.
The risks of consulting a chiropractor have regularly been the subject of this blog (see for instance here, here and here). My critics believe that I am alarmist and have a bee in my bonnet. I think they are mistaken and believe it is important to warn the public of the serious complications that are being reported with depressing regularity, particularly in connection with neck manipulations.
It has been reported that the American model Katie May died earlier this year “as the result of visiting a chiropractor for an adjustment, which ultimately left her with a fatal tear to an artery in her neck” This is the conclusion drawn by the L.A. County Coroner.
According to Wikipedia, Katie tweeted on January 29, 2016, that she had “pinched a nerve in [her] neck on a photoshoot” and “got adjusted” at a chiropractor. She tweeted on January 31, 2016 that she was “going back to the chiropractor tomorrow.” On the evening of February 1, 2016, May “had begun feeling numbness in a hand and dizzy” and “called her parents to tell them she thought she was going to pass out.” At her family’s urging, May went to Cedars Sinai Hospital; she was found to be suffering a “massive stroke.” According to her father, she “was not conscious when we got to finally see her the next day. We never got to talk to her again.” Life support was withdrawn on February 4, 2016.
Katie’s death certificate states that she died when a blunt force injury tore her left vertebral artery, and cut off blood flow to her brain. It also says the injury was sustained during a “neck manipulation by chiropractor.” Her death is listed as accidental.
Katie’s family is said to be aware of the coroner’s findings. They would not comment on whether they or her estate would pursue legal action.
The coroner’s verdict ends the uncertainty about Katie’s tragic death which was well and wisely expressed elsewhere:
“…The bottom line is that we don’t know for sure. We can’t know for sure. If you leave out the chiropractic manipulations of her neck, her clinical history—at least as far as I can ascertain it from existing news reports—is classic for a dissection due to neck trauma. She was, after all, a young person who suffered a seemingly relatively minor neck injury that, unbeknownst to her, could have caused a carotid artery dissection, leading to a stroke four or five days later… Thus, it seems to be jumping to conclusions for May’s friend Christina Passanisi to say that May “really didn’t need to have her neck adjusted, and it killed her.” … Her two chiropractic manipulations might well have either worsened an existing intimal tear or caused a new one that led to her demise. Or they might have had nothing to do with her stroke, her fate having been sealed days before when she fell during that photoshoot. There is just no way of knowing for sure. It is certainly not wrong to suspect that chiropractic neck manipulation might have contributed to Katie May’s demise, but it is incorrect to state with any degree of certainty that her manipulation did kill her.”
My conclusions are as before and I think they need to be put as bluntly as possible: avoid chiropractors – the possible risks outweigh the documented benefits – and if you simply cannot resist consulting one: DON’T LET HIM/HER TOUCH YOUR NECK!
The placebo response might be important in clinical practice, but it is certainly difficult to study and the findings of such investigations can be confusing. This seems to be exemplified by two new trials.
The first study examined the possibility of using theatrical performance tools, including stage directions and scripting, to reproducibly manipulate the style and content of a simulated doctor-patient encounter and influence the placebo response (defined as improvement of clinical outcome in individuals receiving inactive treatment) in experimental pain.
A total of 122 healthy volunteers were exposed to experimental pain using the cold pressor test and assessed for pain threshold and tolerance before and after receiving a placebo cream from a “doctor” impersonated by a trained actor. The actor alternated between two distinct scripts and stage directions. One script emulated a standard doctor-patient encounter (scenario A), while the other emphasized elements present in ritual healing such as attentiveness and strong suggestion (scenario B).
The placebo response size was calculated as the % difference in pain threshold and tolerance after exposure relative to baseline. Subjects demonstrating a ≥30% increase in pain threshold or tolerance relative to baseline were defined as responders. Each encounter was videotaped in its entirety.
Inspection of the videotapes confirmed the reproducibility and consistency of the distinct scenarios enacted by the “doctor”-performer. Furthermore, scenario B resulted in a significant increase in pain threshold relative to scenario A. This increase derived from the placebo responder subgroup; as shown by two-way analysis of variance (performance style, F = 4.30; p = 0.040; η(2) = 0.035; style × responder status interaction term, F = 5.21; p = 0.024) followed by post hoc analysis showing a ∼60% increase in pain threshold in responders exposed to scenario B (p = 0.020).
Performance style and response size in placebo responders and non-responders. Bars represent mean ± SE of % change in CPT threshold of 60 subjects in scenario A: 53 non-responders vs. 7 responders and 62 subjects in scenario B: 51 non-responders and 11 responders. Two-way ANOVA by performance style and responsiveness revealed significant effects of doctor’s performance (F = 4.30; p = 0.040; η2 = 0.035) and responsiveness (F = 134.71; p < 0.001) as well as a significant interaction term (F = 5.21; p = 0.024). ∗p = 0.020, Fisher’s least significant difference post hoc test.
The authors concluded that these results support the hypothesis that structured manipulation of physician’s verbal and non-verbal performance, designed to build rapport and increase faith in treatment, is feasible and may have a significant beneficial effect on the size of the response to placebo analgesia. They also demonstrate that subjects, who are not susceptible to placebo, are also not susceptible to performance style.
In the second study, the authors investigated if an implicit priming procedure, where participants were unaware of the intended priming influence, affected placebo analgesia.
In a double-blind experiment, healthy participants (n = 36) were randomized to different implicit priming types; one aimed at increasing positive expectations and one neutral control condition. First, pain calibration (thermal) and a credibility demonstration of the placebo analgesic device were performed. In a second step, an independent experimenter administered the priming task; Scrambled Sentence Test. Then, pain sensitivity was assessed while telling participants that the analgesic device was either turned on (placebo) or turned off (baseline). Pain responses were recorded on a 0-100 Numeric Response Scale.
Overall, there was a significant placebo effect (p < 0.001), however, the priming conditions (positive/neutral) did not lead to differences in placebo outcome. Prior experience of pain relief (during initial pain testing) correlated significantly with placebo analgesia (p < 0.001) and explained 34% of placebo variance. Trait neuroticism correlated positively with placebo analgesia (p < 0.05) and explained 21% of placebo variance.
The authors concluded that priming is one of many ways to influence behaviour, and non-conscious activation of positive expectations could theoretically affect placebo analgesia. Yet, we found no SST priming effect on placebo analgesia. Instead, our data point to the significance of prior experience of pain relief, trait neuroticism and social interaction with the treating clinician.
The two studies are similar but generate somewhat contradictory results. In the discussion section, the authors of the first paper stress that “replication of our findings in clinical populations; employing professional physicians of both sexes, are necessary in order to establish their generality and possible application in medical training, with the aim of improving patient outcome across diseases and treatment modalities.” This is certainly true. They continue by stating that “future studies using performance tools in clinical trial settings could demonstrate the potential of borrowing performance principles and techniques from traditional healing and applying them to physician–patient encounters in Western medicine, following certain necessary modifications. Performance tools could thus eventually be incorporated into the systematic training of physicians and medical students, possibly to complement programs in Narrative Medicine and Relational Medicine.”
These ideas are not dissimilar to what we have been discussing on this blog repeatedly. For instance, I have previously tried to explain that “the science and the art of medicine are essential elements of good medicine. In other words, if one is missing, medicine is by definition not optimal. In vast areas of alternative medicine, the science-element is woefully neglected or even totally absent. It follows, that these areas cannot be good medicine. In some areas of conventional medicine, the art-element is weak or neglected. It follows that, in these areas, medicine is not good either.”
The fact that the two studies above show contradictory findings is not easy to interpret. Possibly, this shows how fragile the placebo response can be. It can be influenced by a multitude of factors related to an experiment or the clinical setting. If that is so, and placebo effects are truly unreliable, it would be yet another argument for not relying on them in clinical routine. In my view, clinicians should try to maximize them where they can. Yet placebo effects are not normally a justification for employing placebo therapies in clinical practice. In other words, the fact that a bogus treatment can generate a placebo response is not a good reason for using it on patients who need help.
Good clinicians have probably always been good ‘performers’. Alternative practitioners tend to be excellent ‘performers’, and I am sure their success is mainly due to this ability. I see little reason why conventional practitioners should not (re-)learn the skills that once upon a time were called ‘good bed-side manners’. Maximizing the placebo effect in this way might maximize the benefit patients experience – and for that we do not require the placebo-therapies of alternative medicine.
Stable angina is a symptom of coronary heart disease which, in turn, is amongst the most frequent causes of death in developed countries. It is an alarm bell to any responsible clinician and requires causal, often life-saving treatments of which we today have several options. The last thing a patient needs in this condition is ACUPUNCTURE, I would say.
Yet acupuncture is precisely the therapy such patients might be tempted to employ.
Because irresponsible or criminally naïve acupuncturists advertise it!
Take this website, for instance; it informs us that a meta-analysis of eight clinical trials conducted between 2000 and 2014 demonstrates the efficacy of acupuncture for the treatment of stable angina. In all eight clinical trials, patients treated with acupuncture experienced a greater rate of angina relief than those in the control group treated with conventional drug therapies (90.1% vs 75.7%)….
I imagine that this sounds very convincing to patients and I fear that many might opt for acupuncture instead of potentially invasive/unpleasant but life-saving intervention. The original meta-analysis to which the above promotion referred to is equally optimistic. Here is its abstract:
Angina pectoris is a common symptom imperiling patients’ life quality. The aim of this study is to evaluate the efficacy and safety of acupuncture for stable angina pectoris. Clinical randomized-controlled trials (RCTs) comparing the efficacy of acupuncture to conventional drugs in patients with stable angina pectoris were searched using the following database of PubMed, Medline, Wanfang and CNKI. Overall odds ratio (ORs) and weighted mean difference (MD) with their 95% confidence intervals (CI) were calculated by using fixed- or random-effect models depending on the heterogeneity of the included trials. Total 8 RCTs, including 640 angina pectoris cases with 372 patients received acupuncture therapy and 268 patients received conventional drugs, were included. Overall, our result showed that acupuncture significantly increased the clinical curative effects in the relief of angina symptoms (OR=2.89, 95% CI=1.87-4.47, P<0.00001) and improved the electrocardiography (OR=1.83, 95% CI=1.23-2.71, P=0.003), indicating that acupuncture therapy was superior to conventional drugs. Although there was no significant difference in overall effective rate relating reduction of nitroglycerin between two groups (OR=2.13, 95% CI=0.90-5.07, P=0.09), a significant reduction on nitroglycerin consumption in acupuncture group was found (MD=-0.44, 95% CI=-0.64, -0.24, P<0.0001). Furthermore, the time to onset of angina relief was longer for acupuncture therapy than for traditional medicines (MD=2.44, 95% CI=1.64-3.24, P<0.00001, min). No adverse effects associated with acupuncture therapy were found. Acupuncture may be an effective therapy for stable angina pectoris. More clinical trials are needed to systematically assess the role of acupuncture in angina pectoris.
In the discussion section of the full paper, the authors explain that their analysis has several weaknesses:
Several limitations were presented in this meta-analysis. Firstly, conventional drugs in control group were different, this may bring some deviation. Secondly, for outcome of the time to onset of angina relief with acupuncture, only one trial included. Thirdly, the result of some outcomes presented in different expression method such as nitroglycerin consumption. Fourthly, acupuncture combined with traditional medicines or other factors may play a role in angina pectoris.
However, this does not deter them to conclude on a positive note:
In conclusion, we found that acupuncture therapy was superior to the conventional drugs in increasing the clinical curative effects of angina relief, improving the electrocardiography, and reducing the nitroglycerin consumption, indicating that acupuncture therapy may be effective and safe for treating stable angina pectoris. However, further clinical trials are needed to systematically and comprehensively evaluate acupuncture therapy in angina pectoris.
So, why do I find this irresponsibly and dangerously misleading?
Here a just a few reasons why this meta-analysis should not be trusted:
- There was no systematic attempt to evaluate the methodological rigor of the primary studies; any meta-analysis MUST include such an assessment, or else it is not worth the paper it was printed on.
- The primary studies all look extremely weak; this means they are likely to be false-positive.
- They often assessed not acupuncture alone but in combination with other treatments; consequently the findings cannot be attributed to acupuncture.
- All the primary studies originate from China; we have seen previously (see here and here) that Chinese acupuncture trials deliver nothing but positive results which means that their results cannot be trusted: they are false-positive.
My conclusion: the authors, editors and reviewers responsible for this article should be ashamed; they committed or allowed scientific misconduct, mislead the public and endangered patients’ lives.
Antrodia cinnamomea (AC) is a fungus which is used in Taiwan as a remedy for cancer, hypertension, hangover and other conditions. There are several commercial AC products and the annual market is worth over $100 million in Taiwan alone.
Several studies have suggested anti-cancer properties in vitro but few clinical trials have been reported. Now Taiwanese researchers published a double-blind, randomized clinical study to investigate whether AC had acceptable safety and efficacy in advanced cancer patients receiving chemotherapy.
Patients with advanced and/or metastatic adenocarcinoma, performance status (PS) 0-2, and adequate organ function who had previously been treated with standard chemotherapy were randomly assigned to receive routine chemotherapy regimens with AC (20 ml twice daily) orally for 30 days or placebo. The primary endpoint was 6-month overall survival (OS); the secondary endpoints were disease control rate (DCR), quality of life (QoL), adverse event (AE), and biochemical features within 30 days of treatment.
A total of 37 subjects with gastric, lung, liver, breast, and colorectal cancer (17 in the AC group, 20 in the placebo group) were enrolled in the study. Disease progression was the primary cause of death in 4 (33.3 %) AC and 8 (66.7 %) placebo recipients. Mean OSs were 5.4 months for the AC group and 5.0 months for the placebo group (p = 0.340), and the DCRs were 41.2 and 55 %, respectively (p = 0.33). Most hematologic, liver, or kidney functions did not differ significantly between the two groups, but platelet counts were lower in the AC group than in the placebo group (p = 0.02). QoL assessments were similar in the two groups, except that the AC group showed significant improvements in quality of sleep (p = 0.04).
The above figure shows the survival curves for both groups.
The authors concluded as follows: Although we found a lower mortality rate and longer mean OS in the AC group than in the control group, AC combined with chemotherapy was not shown to improve the outcome of advanced cancer patients, possibly due to the small sample size. In fact, the combination may present a potential risk of lowered platelet counts. Adequately powered clinical trials will be necessary to address this question.
I agree, the survival curve looks promising. But we must not get carried away: this was a tiny sample size and a relatively short treatment period. Thus the difference could be a coincidence or an artefact.
The investigators are sufficiently cautious in the interpretation of their findings, and most of us would probably agree that it is necessary to submit such traditional remedies to proper scientific tests. Yet, I feel a sense of unease when I read such articles.
On the one hand, it is possible that such investigations meaningfully contribute to progress. On the other hand, I wonder whether they merely end up providing a significant boost to the trade of bogus remedies sold at high prices to desperate patients. Do the benefits really out-weigh the risks? We will probably never know.
But to minimize the risk, the authors should now swiftly conduct a more definitive trial and create some clarity about the value or otherwise of this traditional cancer remedy.
A new study tested the efficacy of chiropractic spinal manipulative therapy (CSMT) for migraine. It was designed as a three-armed, single-blinded, placebo -controlled RCT of 17 months duration including 104 migraineurs with at least one migraine attack per month. Active treatment consisted of CSMT (group 1) and the placebo was a sham push manoeuvre of the lateral edge of the scapula and/or the gluteal region (group 2). The control group continued their usual pharmacological management (group 3).
The RCT began with a one-month run-in followed by three months intervention. The outcome measures were quantified at the end of the intervention and at 3, 6 and 12 months of follow-up. The primary end-point was the number of migraine days per month. Secondary end-points were migraine duration, migraine intensity and headache index, and medicine consumption.
The results show that migraine days were significantly reduced within all three groups from baseline to post-treatment (P < 0.001). The effect continued in the CSMT and placebo groups at all follow-up time points (groups 1 and 2), whereas the control group (group 3) returned to baseline. The reduction in migraine days was not significantly different between the groups. Migraine duration and headache index were reduced significantly more in the CSMT than in group 3 towards the end of follow-up. Adverse events were few, mild and transient. Blinding was strongly sustained throughout the RCT.
The authors concluded that it is possible to conduct a manual-therapy RCT with concealed placebo. The effect of CSMT observed in our study is probably due to a placebo response.
Chiropractors often cite clinical trials which suggest that CSMT might be effective. The effects sizes are rarely impressive, and it is tempting to suspect that the outcomes are mostly due to bias. Chiropractors, of course, deny such an explanation. Yet, to me, it seems fairly obvious: trials of CSMT are not blind, and therefore the expectation of the patient is likely to have major influence on the outcome.
Because of this phenomenon (and several others, of course), sceptics are usually unconvinced of the value of chiropractic. Chiropractors often respond by claiming that blind studies of physical intervention such as CSMT are not possible. This, however, is clearly not true; there have been several trials that employed sham treatments which adequately mimic CSMT. As these frequently fail to show what chiropractors had hoped, the methodology is intensely disliked by chiropractors.
The above study is yet another trial that adequately controls for patients’ expectation, and it shows that the apparent efficacy of CSMT disappears when this source of bias is properly accounted for. To me, such findings make a lot of sense, and I suspect that most, if not all the ‘positive’ studies of CSMT would turn out to be false positive, once such residual bias is eliminated.
This new study is amazing in several respects. It was conducted in Spain by otolaryngologists, and one of its authors is an employee of Boiron, the world’s biggest manufacturer of homeopathic products. It was designed as a double blind, placebo-controlled RCT. Patients aged 2 months to 12 years suffering from otitis media with effusion (OME), as diagnosed by pneumatic otoscopy (PNO) and tympanometry, were randomized into two groups. Both groups received aerosol therapy (mucolytics and corticosteroids). In addition, the experimental group received a homeopathic remedy of Agraphis nutans 5CH, Thuya Occidentalis 5CH, Kalium muriaticum 9CH and Arsenicum iodatum. The placebo group received placebos instead. Both of the treatments were continued for 3 months. Patients were evaluated by PNO examination and tympanometry at baseline, at 45 and 90 days.
A total of 97 patients were enrolled in this study. In the homeopathy group, 61.9% of individuals were cured according to PNO results by the 3rd visit compared with 56.8% of patients treated with placebo. 4.8% of patients in the homeopathy group suffered a recurrence (positive PNO in the 2nd visit changed to negative in the 3rd visit), while 11.4% did in the placebo group. These inter-group differences were not statistically significant. Adverse events were distributed similarly, except in the case of upper respiratory tract infections, which were less frequent in homeopathic group.
The authors of this new RCT concluded that the homeopathic scheme used as adjuvant treatment cannot be claimed to be an effective treatment in children with OME.
No surprises then – we already know that homeopathic remedies are placebos!
Sure, but at least two amazing features need to be pointed out:
- I am delighted that the authors did not try to spin the results such that they appear to be positive. Some investigators might have emphasised the fact that there was a (non-significant) trend in favour of homeopathy, and that, for a secondary outcome measure (upper respiratory infections), it even reached the level of statistical significance.
- Considering that this study was obviously Boiron-sponsored and its list of authors included an employee of this firm, such honesty can’t have been easy to maintain.
- The design of this RCT is also worth a mention: most alt med proponents seem to think that ‘adjunctive’ use of alt med needs to be tested via the infamous ‘A+B vs B’ design which fails to control for placebo effects and therefore invariably produces false positive findings. The authors of this trial did the right thing by randomising their patients into usual care + homeopathy vs usual care + placebo. This is very simple and has the advantage to actually provide a meaningful result.
In view of all this, I raise my hat to the Spanish researchers: very well done!!!
If all trials of homeopathy were conducted and reported in this honourable fashion, the collective evidence would be in a much better state and far less confusing.