Unethical informed consent caused by overlooking poorly measured nocebo effects

Unlike its friendly cousin the placebo effect, the nocebo effect (the effect of expecting a negative outcome) has been almost ignored. Epistemic and ethical confusions related to its existence have gone all but unnoticed. Contrary to what is often asserted, adverse events following from taking placebo interventions are not necessarily nocebo effects; they could have arisen due to natural history. Meanwhile, ethical informed consent (in clinical trials and clinical practice) has centred almost exclusively on the need to inform patients about intervention risks with patients to preserve their autonomy. Researchers have failed to consider the harm caused by the way in which the information is conveyed. In this paper, I argue that the magnitude of nocebo effects must be measured using control groups consisting of untreated patients. And, because the nocebo effect can produce harm, the principle of non-maleficence must be taken into account alongside autonomy when obtaining (ethical) informed consent and communicating intervention risks with patients

Positive messages may reduce patient pain: A meta-analysis

Introduction Current treatments for pain have limited benefits and worrying side effects. Some studies suggest that pain is reduced when clinicians deliver positive messages. However, the effects of positive messages are heterogeneous and have not been subject to meta-analysis. We aimed to estimate the efficacy of positive messages for pain reduction. Methods We included randomized trials of the effects of positive messages in a subset of the studies included in a recent systematic review of context factors for treating pain. Several electronic databases were searched. Reference lists of relevant studies were also searched. Two authors independently undertook study selection, data extraction, risk of bias assessment, and analyses. Our primary outcome measures were differences in patient- or observer-reported pain between groups who were given positive messages and those who were not. Results Of the 16 randomized trials (1703 patients) that met the inclusion criteria, 12 trials had sufficient data for meta-analysis. The pooled standardized effect size was −0.31 (95% confidence interval [CI] −0.61 to −0.01, p = 0.04, I2 = 82%). The effect size remained positive but not statistically significant after we excluded studies considered to have a high risk of bias (standard effect size −0.17, 95% CI −0.54 to 0.19, P = 0.36, I2 = 84%). Conclusion Care of patients with chronic or acute pain may be enhanced when clinicians deliver positive messages about possible clinical outcomes. However, we have identified several limitations of the present study that suggest caution when interpreting the results. We recommend further high-quality studies to confirm (or falsify) our result. FUNDING Alexander Mebius research has been funded through the ERC grant "Philosophy of Pharmacology: Safety, Statistical Standards, and Evidence Amalgamation" (GA: 639276

Me ei tea, kas enamik ravimeetodeid toimib, ja veel vähem teame, kas need põhjustavad kahju, on väidetud uues uuringus*

Eesti Arst 2022; 101(9):521–52

Why include humanities in medical studies: comment

Five reasons why teaching medical humanities in medical schools improves student performance, enhances wellbeing, and ameliorates patient outcomes

Philosophical essentials in evidence-based medicine: Evaluating the epistemological role of double blinding and placebo controls.

The Evidence-Based Medicine (EBM) movement endorses a hierarchy of evidence that places randomized controlled trials at the top. More specifically, double-blind, placebo- controlled trials are often considered to be the 'best of the best'. This view leads to the paradox that treatments that seem to be most strongly supported by evidence, ranging from tracheotomies to rabies vaccines, have never been tested in randomized trials of any description and are hence supported by (allegedly) sub-optimal evidence. Moreover many of these treatments do not seem supportable by best evidence - how, for example do we keep the surgeons who perform tracheotomies 'blind'. After a brief introduction (chapter 1), and review of the literature (chapter 2), I argue that criticisms of the EBM hierarchy can be launched from the simple basis that best evidence rules out the most plausible rival hypothesis (chapter 3). To examine the relative evidential weight of placebo controlled trials compared to 'active' controlled trials (in which the control treatment is an existing established treatment) requires a good deal of conceptual work. I defend a modified version of Grunbaum's (1981/1986) definition of placebos (chapter 4), then provide constraints on what can count as a 'legitimate' placebo control (chapter 5). Next, I explain why double-blinding does not always rule out additional rival hypotheses. I then argue that the arguments for the superiority of placebo controls are flawed. The 'assay sensitivity' argument is limited in scope and based on a misconception about the nature of placebo controls (chapter 7), while the claim that only placebo controlled trials measure the absolute effect size relies on the questionable assumption that placebo and non-placebo effects add rather than interact (chapter 8). I conclude that the evidence hierarchy endorsed by EBM does not stand on solid foundations

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVES: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. SEARCH METHODS: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. SELECTION CRITERIA: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. DATA COLLECTION AND ANALYSIS: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116). AUTHORS' CONCLUSIONS: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence

Beyond empathy training for practitioners: Cultivating empathic healthcare systems and leadership

Empathic care benefits patients and practitioners, and empathy training for practitioners can enhance empathy. However, practitioners do not operate in a vacuum. For empathy to thrive, healthcare consultations must be situated in a nurturing milieu, guided by empathic, compassionate leaders. Empathy will be suppressed, or even reversed if practitioners are burned out and working in an unpleasant, under‐resourced environment with increasingly poorly served and dissatisfied patients. Efforts to enhance empathy must therefore go beyond training practitioners to address system‐level factors that foster empathy. These include patient education, cultivating empathic leadership, customer service training for reception staff, valuing cleaning and all ancillary staff, creating healing spaces, and using appropriate, efficiency saving technology to reduce the administrative burden on healthcare practitioners. We divide these elements into environmental factors, organisational factors, job factors, and individual characteristics

Problematic placebos in physical therapy trials

The function of a placebo control in a randomised trial is to permit blinding and reduce risk of bias. Adopting Grűnbaum’s definitional scheme of a placebo, all treatments must be viewed as packages consisting of characteristic and incidental features. An adequate placebo for an experimental treatment contains none of the characteristic features, all of the incidental features, and nothing more. For drug treatments, characteristic features can be readily identified, isolated, and separated. By contrast, physical therapy treatments often involve features such as patient-therapist contact and sensory feedback that make this separation difficult both conceptually and practically. It is therefore unsurprising that attempts to construct placebos for physical therapy treatments have in the past led to biased estimates of treatment effects. In this perspective piece, we describe the problem with constructing placebos for physical therapy trials drawing upon Grűnbaum’s definition and using paradigmatic examples from existing literature. We conclude by submitting that in the many cases where an adequate placebo cannot be achieved, alternative trial designs, e.g. dose-response or comparative-effectiveness trials, carry a lower risk of bias and should be favoured

How evidence‐based medicine is failing due to biased trials and selective publication

Evidence-based medicine (EBM) was announced in the early 1990s as a 'new paradigm' for improving patient care. Yet there is currently little evidence that EBM has achieved its aim. Since its introduction, health care costs have increased while there remains a lack of high-quality evidence suggesting EBM has resulted in substantial population-level health gains. In this paper we suggest that EBM's potential for improving patients' health care has been thwarted by bias in the choice of hypotheses tested, manipulation of study design and selective publication. Evidence for these flaws is clearest in industry-funded studies. We argue EBM's indiscriminate acceptance of industry-generated 'evidence' is akin to letting politicians count their own votes. Given that most intervention studies are industry funded, this is a serious problem for the overall evidence base. Clinical decisions based on such evidence are likely to be misinformed, with patients given less effective, harmful or more expensive treatments. More investment in independent research is urgently required. Independent bodies, informed democratically, need to set research priorities. We also propose that evidence rating schemes are formally modified so research with conflict of interest bias is explicitly downgraded in value

Evidence based medicine: a movement in crisis?

Trisha Greenhalgh and colleagues argue that, although evidence based medicine has had many benefits, it has also had some negative unintended consequences. They offer a preliminary agenda for the movement’s renaissance, refocusing on providing useable evidence that can be combined with context and professional expertise so that individual patients get optimal treatment