Placebo effect works even if patients know they're getting a sham drug
Study suggests patients benefit from the placebo effect even when told explicitly that they're taking an 'inert substance' Ben Goldacre: Can a placebo have side-effects?

ymptoms of irritable bowel syndrome improved despite pill bottles being labelled 'placebo'. Photograph: Nitschkefoto/Alamy
Patients can benefit from being treated with sham drugs even if they are told they contain no active ingredient, scientists have found. The finding suggests that the placebo effect could work without the need for any deception on the part of the doctor, as had been previously thought.
When a patient undergoes a sham treatment for a disorder - such as taking a sugar pill - but still experiences a measurable improvement in their condition this is known as the
placebo effect. It was widely thought, however, that the effect only works if the patient believes that the treatment they are receiving contains an active ingredient. Dummy treatments that might elicit the placebo effect are often used in clinical trials as a comparison group to allow scientists to measure the additional effects of experimental medicines.
To investigate the limits of placebo, Prof
Ted Kaptchuk of Harvard Medical School's Osher Research Center divided 80 patients suffering from irritable bowel syndrome (IBS) into two groups: one received no treatment and the other was given dummy pills to take twice a day. The second group was told by the doctors that they would be taking "placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS-symptoms through mind-body self-healing processes".
"Not only did we make it absolutely clear that these pills had no active ingredient and were made from inert substances, but we actually had 'placebo' printed on the bottle," said Kaptchuk. "We told the patients that they didn't have to even believe in the placebo effect. Just take the pills."
The results,
published in the scientific journal PLoS ONE, showed that the placebo pills were more effective at relieving symptoms compared with doing nothing at all.
"I didn't think it would work," says senior author Anthony Lembo of the Beth Israel Deaconess Medical Center and an expert on IBS. "I felt awkward asking patients to literally take a placebo. But to my surprise, it seemed to work for many of them."
In the trial, the IBS patients were monitored for three weeks. The group on placebo pills showed improvements both at the half way point and at the end of the period, when compared with the no-treatment group. By the end of the trial, almost twice as many patients treated with placebo showed adequate relief of symptoms compared with the control group. Patients taking the placebo also doubled their average rate of improvement to that achieved with the most powerful IBS medications.
"Directly harnessing placebo effects in a clinical setting has been problematic because of a widespread belief that beneficial responses to placebo treatment require concealment or deception," wrote the researchers in PLoS ONE. "This belief creates an ethical conundrum: to be beneficial in clinical practice placebos require deception but this violates the ethical principles of respect for patient autonomy and informed consent."
Nevertheless, a recent survey of doctors in the US,
published in the British Medical Journal, found that while only small numbers of American physicians use inert placebo pills and injections, around half prescribed treatments that they considered to have no specific effect on patients' conditions and are used solely as placebos. "Given this situation, finding effective means of harnessing placebo responses in clinical practice without deception is a high priority," wrote the researchers.
Kaptchuk and his colleagues warned that there were limitations with their study, given its small size and limited time span. They called their result a "proof-of-concept" pilot study that would need to be repeated with larger numbers of people and over longer periods, to investigate the long-term effects of the placebo.
"Nevertheless," said Kaptchuk, "these findings suggest that rather than mere positive thinking, there may be significant benefit to the very performance of medical ritual. I'm excited about studying this further. Placebo may work even if patients know it is a placebo."

Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS).
Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes” or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL).
Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08).
Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent.

Homeopathy and the nocebo effect
Dr Peter Fisher from the Royal London Homeopathic Hospital (funded by the NHS) says homeopathic pills have physical side-effects. Can a sugar pill have a side-effect?

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This week the parliamentary science and technology committee looked into the the funding of homeopathy on the NHS and the evidence behind the decision of the MHRA, which regulates medicines, to allow homeopathy sugar pill labels to make medical claims without evidence of efficacy.
There were comedy highlights, as you might expect from any serious inquiry into an industry where sugar pills have healing powers conferred upon them by being shaken with one drop of the ingredient which has been diluted so extremely that it equates to one molecule of the substance in a sphere of water whose diameter is roughly the distance from the Earth to the sun.
The man from Boots said he had no evidence that homeopathy pills worked, but he sold them because people wanted to buy them. The man from the pill manufacturers' association said negative trials about homeopathy were often small, with an average of 65 people, and "all statisticians" agreed you need 500 people for a proper trial. Not only is it untrue that you necessarily need this many people ; he then cited, in his favour,
a positive homeopathy trial with just 25 patients in it.
The best moment was Dr Peter Fisher from the (NHS-funded) Royal London Homeopathic hospital explaining that homeopathic sugar pills have physical side-effects – so they must be powerful.
Can a sugar pill have a side-effect? Interestingly, a
paper published in the journal Pain next month looks at just this issue. It found every single placebo-controlled trial ever conducted on a migraine drug, and looked at the side-effects reported by the people in the control group, who received a dummy "placebo" sugar pill instead of the real drug. Not only were these side-effects common, they were also similar to those of whatever drug the patients thought they might be receiving.
This is nothing new. A
study in 2006 sat 75 people in front of a rotating drum to make them feel nauseous, and gave them a placebo sugar pill: 25 were told it was a drug that would make the nausea worse. It did get worse, and they also exhibited more gastric tachyarrhythmia, the abnormal stomach activity that frequently accompanies nausea.
paper in 2004 took 600 patients from three different specialist drug allergy clinics and gave them either the drug that was causing their adverse reactions, or a dummy pill with no ingredients: 27% of the patients experienced side-effects such as itching, malaise and headache from the placebo dummy pill.
a classic paper from 1987 looked at the impact of listing side-effects on the treatment consent form. This was a large trial comparing aspirin against placebo, conducted in three different centres. In two, the form outlined various gastrointestinal side-effects, and in these centres there was a sixfold rise in the number of people reporting such symptoms and dropping out of the trial. This is the amazing world of the nocebo effect, where negative expectations can induce unpleasant symptoms, in the absence of a physical cause.
And in any case, it doesn't help homeopaths:
In 2003 Professor Edzard Ernst conducted a systematic review, finding every homeopathy trial that reported side-effects. There was no significant difference in the rates of side-effects between patients given placebo and those given homeopathic remedies.
The world of the homeopath is reductionist, one-dimensional, and built on the power of the pill: it cannot accommodate the fascinating reality of connections between mind and body which have been elucidated by science.
The next time you find yourself trapped at dinner next to some bore who's decided in middle age that they have secret mystical healing powers, while they earnestly explain how their crass efforts at selling sugar pills represent a meaningful political stand against the crimes of big pharma, just think: some lucky person, somewhere in the world, is sat next to a nocebo researcher.

Read the full article at:

Differential Effectiveness of Placebo Treatments: A Systematic Review of Migraine Prophylaxis.
Meissner K, Fässler M, Rücker G, Kleijnen J, Hróbjartsson A, Schneider A, Antes G, Linde K.
Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany2Institute of Medical Psychology, Ludwig-Maximilians-University Munich, Munich, Germany.
IMPORTANCE When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most effective one. Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak. OBJECTIVE To investigate whether different types of placebo treatments are associated with different responses using the studies of migraine prophylaxis for this analysis. DESIGN, SETTING, AND PARTICIPANTS We searched relevant sources through February 2012 and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine with an observation period of at least 8 weeks after randomization that compared an experimental treatment with a placebo control group. We calculated pooled random-effects estimates according to the type of placebo for the proportions of treatment response. We performed meta-regression analyses to identify sources of heterogeneity. In a network meta-analysis, direct and indirect comparisons within and across trials were combined. Additional analyses were performed for continuous outcomes. EXPOSURE Active migraine treatment and the placebo control conditions. MAIN OUTCOMES AND MEASURES Proportion of treatment responders, defined as having an attack frequency reduction of at least 50%. Other available outcomes in order of preference included a reduction of 50% or greater in migraine days, the number of headache days, or headache score or a significant improvement as assessed by the patients or their physicians. RESULTS Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47]) and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only significant predictors of response in placebo groups in multivariable analyses (P = .005 and P = .001, respectively). Network meta-analysis confirmed that more patients reported response in sham acupuncture groups than in oral pharmacological placebo groups (odds ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed similar findings. CONCLUSIONS AND RELEVANCE Sham acupuncture and sham surgery are associated with higher responder ratios than oral pharmacological placebos. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be due to nonspecific effects and that the size of such effects might differ between treatment modalities.

J Clin Epidemiol. 2014 Apr 25. pii: S0895-4356(14)00089-4. doi: 10.1016/j.jclinepi.2014.02.021. [Epub ahead of print]
Clinically meaningful nocebo effect occurs in acupuncture treatment: a systematic review.
Koog YH1, Lee JS2, Wi H3.
Author information

To investigate the nocebo effect using randomized acupuncture trials that include sham and no-treatment groups.
Electronic databases were searched to retrieve eligible trials from their inception until June 2013. Risk differences were then calculated using the acupuncture and sham groups to determine the treatment effect and the sham and no-treatment groups to determine the nocebo effect.
In total, 58 eligible trials were analyzed. On the basis of the rate of patients with any adverse event in 31 trials reporting available data, the treatment effect was 0.012 (95% confidence interval [CI]: 0.003, 0.021), with a number needed to harm (NNH) of 83 (95% CI: 48, 333). The nocebo effect was 0.049 (95% CI: 0.012, 0.086), with an NNH of 20 (95% CI: 12, 83). By contrast, the rate of dropouts due to adverse events in 39 trials reporting available data showed no differences for both effects. In addition, nearly 70% of the trials reported zero dropouts in the sham and no-treatment groups.
Our findings suggest that (1) the nocebo effect of acupuncture is clinically meaningful and (2) the rate of patients with any adverse event may be a more appropriate indicator of the nocebo effect.
Copyright © 2014 Elsevier Inc. All rights reserved.
Acupuncture, Adverse event, Dropout, Nocebo effect, Randomized trial, Systematic review

Acupunct Med. 2014 Dec 30. pii: acupmed-2014-010679. doi: 10.1136/acupmed-2014-010679. [Epub ahead of print]
Association of pre- and post-treatment expectations with improvements after acupuncture in patients with migraine.
Zheng H1, Huang W2, Li J1, Zheng Q1, Li Y1, Chang X3, Sun G4, Liang F1.
Author information

To study whether a higher expectation of acupuncture measured at baseline and after acupuncture is associated with better outcome improvements in patients with migraine.
We performed a secondary analysis of a previous published trial in which 476 patients with migraine were randomly allocated to three real acupuncture groups and one sham acupuncture control group. All the participants received 20 sessions of acupuncture over a 4-week period. The primary outcome was the number of days with a migraine attack (NDMA) assessed at 5-8 weeks after randomisation. The secondary outcomes were visual analogue scale, headache intensity and quality of life assessed at 4, 8 and 16 weeks after randomisation. Expectations of the acupuncture effect were assessed at baseline and at the end of treatment and categorised into five levels, with 0% the lowest and 100% the highest. Outcome improvement was first compared among the participants with different expectation levels using an analysis of variance model. The association between expectations of treatment and outcome improvement was then calculated using a logistic regression model.
Patients with 100% baseline expectations did not report significantly fewer NDMA than those with 0% baseline expectations after adjusting for the covariates (at 5-8 weeks, 1.7 vs 3.9 days, p=0.987). High baseline expectations had no significant impact on improvement of the primary outcome (100% vs 0%: OR 8.50, 95% CI 0.89 to 191.65, p=0.682). However, patients with 100% post-treatment expectations reported fewer NDMA than those with 0% expectations (primary outcome: 1.3 vs 5.0 days, p<0.001) and were more likely to have a favourable response (100% vs 0%: OR 68.87, 95% CI 6.26 to 1449.73, p=0.002). Similar results were found when analysing the impact of expectation on the secondary outcomes.
A high level of expectation after acupuncture treatment rather than at baseline was associated with better long-term outcome improvements in patients with migraine.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

Evid Based Complement Alternat Med. 2016;2016:3925878. doi: 10.1155/2016/3925878. Epub 2016 Feb 11.
The Effects of Positive or Neutral Communication during Acupuncture for Relaxing Effects: A Sham-Controlled Randomized Trial.
Rosén A1, Lekander M2, Jensen K1, Sachs L1, Petrovic P1, Ingvar M1, Enblom A3.
Author information

Introduction. The link between patient-clinician communication and its effect on clinical outcomes is an important clinical issue that is yet to be elucidated. Objective. Investigating if communication type (positive or neutral) about the expected treatment outcome affected (i) participants' expectations and (ii) short-term relaxation effects in response to genuine or sham acupuncture and investigating if expectations were related to outcome. Methods. Healthy volunteers (n = 243, mean age of 42) were randomized to one treatment with genuine or sham acupuncture. Within groups, participants were randomized to positive or neutral communication, regarding expected treatment effects. Visual Analogue Scales (0-100 millimeters) were used to measure treatment expectations and relaxation, directly before and after treatment. Results. Participants in the positive communication group reported higher treatment expectancy, compared to the neutral communication group (md 12 versus 6 mm, p = 0.002). There was no difference in relaxation effects between acupuncture groups or between communication groups. Participants with high baseline expectancy perceived greater improvement in relaxation, compared to participants with low baseline levels (md 27 versus 15 mm, p = 0.022). Conclusion. Our data highlights the importance of expectations for treatment outcome and demonstrates that expectations can be effectively manipulated using a standardized protocol that in future research may be implemented in clinical trials.
JAMA Intern Med. 2013 Oct 14. doi: 10.1001/jamainternmed.2013.10391. [Epub ahead of print]