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Harmful placebos

Harmful placebos

11 Dec 2018

How could a sugar pill placebo cause harm? A new review of data from 250,726 trial participants has found that 1 in 20 people who took placebos in trials dropped out because of serious adverse events (side effects). Almost half of the participants reported less serious adverse events. The adverse events ranged from abdominal pain and anorexia to burning, chest pain, fatigue, and even death.

The study found that the apparently strange phenomena of sugar pills producing harm can be explained by misattribution and negative expectations.


Someone in a trial might have a symptom like a stomachache for any number of reasons that are not related to the trial. Because they are in a trial, they think the trial intervention caused the ache. This gets reported as an adverse event when it would have happened anyway.

Negative expectations

The way patients are warned about adverse events can sometimes cause an adverse event. Effects of negative expectations are called ‘nocebo’ (‘negative placebo’) effects. ‘Our study provided preliminary data indicating that some trial participants experience nocebo effects,’ reports lead author Jeremy Howick. Other studies provide more definitive evidence that the way patients are warned about adverse events can affect whether they report them. For example, a study found that patients in a randomised trial of aspirin or sulfinpyrazone for treating unstable angina who were warned about gastrointestinal adverse events were six times more likely to withdraw from the study due to reported gastrointestinal adverse events. A more recent study published last year in The Lancet found that patients were more likely to report adverse events when they knew they were taking statins, compared to when they didn’t. This is probably because the belief that statins cause adverse events like muscle pain can actually produce the muscle pain.

Finding ways to reduce adverse events among patients in placebo groups is important for improving trial quality (since fewer participants will drop out), and improving trial ethics (by avoiding harm). The question is: how?

‘Misattribution can be hard to avoid,’ says Jeremy Howick, ‘because it’s hard for someone to know whether a symptom like a stomachache would have occurred anyways or whether it was because of the trial. However, I believe we can reduce the harm caused by negative expectations.’

For example, telling patients that a new treatment is safe for 90% of patients contains the same information as saying it causes adverse events like headaches in 10% of patients. But the second way may be more likely to actually cause the adverse events than the first.

Unfortunately, guidance for informing trial participants about trial intervention harms, in a way that is ethical, understandable, and does not produce nocebo effects, is currently under-researched. A recent study suggested that information provided to trial participants often fails to tell them what they wish to know, and that it is presented in a way that is difficult to understand. Ongoing research at the Universities of Oxford and Cardiff is looking at ways to inform patients in trials about the best way to provide balanced information about the benefits and harms of participating in trials. Their preliminary research suggests that patients are provided more information about trial harms than trial benefits.

Says co-author Professor Kerry Hood (Director of Cardiff Centre for Trials Research): ‘We believe it is possible to balance the information about trial benefits and harms in a way that is fact-based and that does not cause unnecessary harm. This can be achieved by ensuring that the benefits, as well as the harms, are explained in a way patients understand.’

The full paper, 'Rapid Overview of Systematic Reviews of Nocebo Effects Reported by Patients Taking Placebos in Clinical Trials,' can be read in Trials.

Instruments on InSight's spacecraft deck

A UK instrument, co-designed by the University of Oxford, has captured the first sounds ever recorded directly from Mars.

The NASA InSight lander, which is supported by the UK Space Agency, has recorded a haunting, low rumble caused by vibrations from the wind. These vibrations were detected by an ultra-sensitive seismometer, developed in the UK, and an air pressure sensor sitting on the lander's deck.

Both recorded the Martian wind in different ways. The seismometer recorded vibrations as the wind moved over the lander's solar panels, each of which is more than 2 metres in diameter and sticks out from the sides of the lander like a giant pair of ears. The air pressure sensor recorded the vibrations directly from changes in the air.

This is the only time during the mission that the seismometer - called the Seismic Experiment for Interior Structure, or SEIS - is capable of detecting these sounds. In a few weeks, it is due to be placed on the Martian surface by InSight's robotic arm. For now, it is recording wind data that scientists will later be able to cancel out of data from the surface, allowing them to separate "noise" from actual Marsquakes.

These sensors can detect motion at sub-atomic scales, including the wind on Mars, which is barely within the lower range of human hearing.

Dr Neil Bowles, from the University of Oxford’s Department of Physics, said: 

'To get the first data from the seismometer instrument package has been fantastic and even with a short test run the analysis is now full swing.  To "hear" the low frequency rumble of the Martian wind on the lander being picked up by the SEIS-SP is really eerie and provides a strangely human connection to this very different environment.'

Population health:Forget tech, modifying social structures should be our collective focus

Following the World Health Organisation/UNICEF Global Conference on Primary Health Care, Dr Luke Allen, from Oxford’s Department of Primary Care Health Sciences explains how to improve population health

I write from Astana – capital city of Kazakhstan. Hundreds of health ministers, policymakers, academics, and campaigners have braved the cold to reaffirm their commitment to a 40-year-old WHO/UNICEF declaration. The Declaration of Alma-Ata was forged in the geopolitical turmoil of the late 70s and committed countries to social, political, economic and health sector reform, propelled by a sense of democratic social justice.

Today health inequalities  continue to widen and the richest in our societies enjoy much longer and healthier lives than the most disadvantaged. Why?

We often tend to think that the main ingredient for better health is access to high quality healthcare: doctors, nurses, hospital beds and fancy scanners. In reality, healthcare is only responsible for around 10% of the health improvements we have experienced over the past 50 years or so. Genetics play a role, but much more important are non-medical factors like education, clean water, transport, the local food environment, access to green space, pollution, and cultural factors that influence the likelihood that locals smoke, drink harmfully, exercise, and eat healthily.

This ensemble of ‘social determinants of health’ are responsible for approximately 80% of deaths due to cardiovascular disease, chronic respiratory disease, type 2 diabetes, and cancers – earning this tetrad the moniker ‘socially transmitted diseases’. It stands to reason that however promising the next precision medicine blockchain nano-delivery VR widget is, interventions that do not fundamentally address socio-political building blocks of towns and neighbourhoods will only ever tinker at the fringes.

That’s not to say that medical tech can’t make big differences to individuals, it’s just that new tech breakthroughs often take a long time to reach the scale where they influence population means, and even then benefits are disproportionately enjoyed by the wealthy. Conversely, interventions aimed at socioeconomic conditions, e.g. welfare, smoke-free spaces, free school meals, fluoridising water or reducing salt in bread, often make a negligible difference to individuals but lead to large aggregate reductions in death and disability with the least advantaged benefitting the most.

The Alma-Ata Declaraton (and the new Astana Declaration) commit governments to the basic, slightly boring work of reorienting their health systems to focus investment on public health measures, communities, and the economic and political environment. This is potentially inflammatory for countries pursuing radical capitalist policies, and for autocracies that struggle with viewing individuals and communities as partners rather than potential threats to stability. Alma-Ata’s audacious vision for health systems also challenges the British health research paradigm, reminding us that even the biggest pharma RCTs are never going to make that much of a difference. We need more interdisciplinary research combining health, politics, economics, and social science, as well as better methods to understand which interventions are most effective in the messy, confounded, complex, and dynamic systems of public life.

Dr Luke Allen (@drlukeallen) is a GP academic clinical fellow working at the Nuffield Department of Primary Health Care Sciences in the Interdisciplinary Research in Health Sciences group. He is also a primary care consultant for the World Health Organisation.

Scientists swap labs for Westminster

Professor Deborah Gill from the Radcliffe Department of Medicine and Dr Luke Jostins-Dean from the Kennedy Institute at the University of Oxford recently swapped lab coats for legislation at the House of Commons for a week in Westminster. The week is part of a unique pairing scheme run by the Royal Society – the UK’s national academy of science, with support from the Government Science & Engineering (GSE) profession.

During her visit, Deborah, who is a Professor of Gene Medicine, and Co-Director of the Gene Medicine Research Group, shadowed Tony Whitney, senior policy advisor for Public Engagement with Science for the Department of Business, Innovation and Strategy. Dr Jostins-Dean shadowed local MP for Oxford East, Annaliese Dodds.

As well as attending seminars and panel discussions about how evidence is used in policy making, the two researchers also attended a mock Select Committee.

The visit provided the Oxford academics with a behind the scenes insight into how policy is formed and how their research can be used to make evidence-based decisions. It was also to give the politicians the opportunity to investigate the science behind their decisions and improve their access to scientific evidence.

Professor Gill said: 'Science is a shared endeavour in society and communicating with the public is crucial to agreeing future research directions. In my research, using gene technologies, responsible public engagement builds trust and transparency. The Royal Society pairing scheme is a fantastic opportunity see this in action.'

Speaking of his pairing, Dr Jostins-Dean said: 'In my research I work directly with patients' genetic and healthcare data, and my work is heavily influenced by government policy around data sharing, treatment decisions and confidentiality. I am excited to learn from Anneliese how new laws are made, and how we as scientists can provide evidence to help parliamentarians make and scrutinise government policy.'

'I'm very grateful to the Royal Society for pairing me with a scientist, for a second year. It has been really interesting to spend time with Dr Jostins-Dean, in order both for him to find out more about how parliament works but also for me to find out more about his life as a scientist! It is very important that we build more links between science and politics, and I think the Royal Society scheme is an excellent way of doing that. I am looking forward to getting some hands-on experience of Dr Jostins-Dean's work when I do the reciprocal visit with him back in Oxford,' added Anneliese Dodds.

The MP for East Oxford will find out about Dr Jostins-Dean research, which focuses on identifying genes that increase our risk of developing inflammatory bowel disease (IBD), and on coming up with new mathematical and experimental ways to understand how these genes impact the human immune system.

Tony Whitney will get hands on experience of Professor Gill’s work, which includes developing gene therapy for lung conditions such as cystic fibrosis, in a reciprocal visit next year. Researchers at the University of Oxford’s Radcliffe Department of Medicine also hope to learn more about engaging the public with their work during his visit.

The Royal Society’s pairing scheme, which started in 2001, aims to build bridges between parliamentarians, civil servants and some of the best scientists in the UK.

Shazeaa Ishmael, a Diamond CDT (Centre for Doctoral Training) student working within the NQIT programme

By Julia Flynn, NQIT Communications Manager

Earlier this month the Engineering and Physical Sciences Research Council’s (EPSRC) UK National Quantum Technology Hubs successfully delivered the third annual Quantum Technologies Showcase, demonstrating the technological progress emerging from the national research programme.

There were over 80 exhibits, together with briefing sessions that asked ‘Are you ready for quantum?’ For the exhibitors it was a chance to discuss their work and highlight the achievements in quantum technologies in what has been a coordinated national effort. The 700 plus visitors could see the advance of quantum technologies and the potential to benefit their businesses and organisations, as well as for society as a whole.  

Quantum Technologies ShowcaseQuantum Technologies Showcase

The Showcase was divided into zones, from transport to defence and healthcare and many more. The Networked Quantum Information Technologies Hub (NQIT), led by the University of Oxford, had nine exhibits showcasing the multiple approaches to building quantum machines based on high performance qubit systems, and emerging quantum information processing technologies. They also had a busy Hub stand that explained the whole work of NQIT, inbuilding the essential systems for the Q20-20 quantum computer demonstrator and creating a world-leading quantum computing economy in the UK.

Participants were able to see demonstrations, showing the enormous engineering progress being made to build the complex systems and components for scalable quantum computers based on different architectures  including ion traps and superconducting circuits.

One of NQIT’s stands ‘Create your own qubit in diamond’ demonstrated how its researchers are developing methods to write qubits into diamond using ultrashort laser pulses. Visitors were excited to be able to remotely connect to the laser writing lab in Oxford and control the set up to write their own quibits, creating a single Nitrogen Vacancy in a synthetic high quality diamond.

While many of the exhibits looked at the advances in research, hardware and engineering that are core to building a scalable quantum computer, NQIT spin out applications and companies were also present, such as the random number generator, a patented application from NQIT’s photonics work stream. Oxford Quantum Circuits, one of the three NQIT spinout companies, had a prototype quantum computer at the Showcase, giving visitors the opportunity to perform some quantum logic, based on superconducting quantum hardware.

As well as the buzz and interest in the many exhibits visitors also heard more about the UK Government’s pledge of a further £235 million to support the development and commercialisation of quantum technologies, including up to £70 million from the Industrial Strategy Challenge Fund, and £35 million to support a new national quantum computing centre. This investment is in addition to the government’s £80million extension of the Quantum Technology Hubs and takes overall funding for the second phase of the UK’s world-leading National Quantum Technology Programme to £315 million.

Phase I of the UK Quantum Technology Programme has been a pioneering programme that has transferred scientific leadership into innovation and technological leadership. Phase 2 will build on that work to make the UK the ‘go-to’ economy, creating opportunities for industry and the development of new skills geared toward exploiting these new quantum technologies.