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Top position for German placebo research

Placebo research at Tübingen University is part of a German network that is a world leader in the field. One of the research priorities relates to the perception of pain and the underlying neurobiological mechanisms.

Prof. Dr. Paul Enck has been the director of research in the Department of Psychosomatic Medicine and Psychotherapy (Internal Medicine IV) at Tübingen University Hospital since 2004. © Enck, University Hospital Tübingen

“In most countries, placebo research is only a minor field of research and there are no pan-regional research consortia outside Germany working on this issue,” says Prof. Dr. Paul Enck highlighting Germany’s role as a global player in placebo research. Enck is the director of research in the Department of Psychosomatic Medicine and Psychotherapy at Tübingen University Hospital and one of four spokespersons of the DFG research unit “Expectations and conditioning as basic processes of the placebo and nocebo response – from neurobiology to clinical applications” that aims to analyse the mechanisms of placebo effects using experimental and clinical models. The transregional research unit consists of scientists from the universities and university medical centres in Tübingen, Hamburg, Marburg and Essen. The German Research Foundation (DFG) has been supporting the unit’s eight subprojects since 2010 with funding of over two million euros. 

The results obtained thus far were presented at a conference held in Tübingen in January 2013. “The meeting was aimed at drawing attention to the subject, and also at obtaining intellectual input for subsequent funding applications,” Enck says. The financial resources for the meeting were provided by the Volkswagen Foundation, which had previously provided funding for a large-scale placebo research project also involving researchers from Tübingen that ended in 2011. Enck is specifically focused on the field of gastroenterology and his subproject deals with placebo effects in the gastrointestinal tract. The first question Enck and his team wanted to solve was whether placebos are in principle able to relieve pain in the gastrointestinal tract. Enck is now able to answer this question with a resounding yes: “Our group here in Tübingen, and above all our colleagues in Prof. Eisenbruch’s team at the University of Essen, now have excellent data to substantiate our assumptions. However, we are not yet a hundred percent sure whether the observed analgesic effect is of a somatic or neurocognitive nature. This was one of the issues discussed at the recent conference in Tübingen,” Enck explains. 

Placebo effect depends on the neurological processing of sensory perceptions

Enck’s initial findings suggest that the perception of pain is due to how the discomfort is subjectively interpreted by those affected. And this interpretation takes place in the brain, which is why the assessment is a neurocognitive one. Most of the clinical results were obtained in Essen and Tübingen using, amongst other things, special probes that were placed into the intestinal tract of volunteers who participated in the study. The team from Tübingen also brings data obtained in peripheral pain research into the project. The researchers mainly use heat stimuli for making basic statements on the effect placebos have on how people experience pain. “We generally use thermode technology, which involves attaching a hollow metal bar to the lower arm. Heated water flows through this bar. We then test how the volunteers perceive pain when they are given placebos,” Enck says explaining that the placebo effect is assessed by applying a supposedly analgesic cream between the skin and the metal plate. The rest of the procedure is relatively simple: the study participants with and without placebo are then questioned about the intensity of heat perceived.

The major challenge is to design the experimental set-up in a way that enables scientifically reliable results to be obtained. In order to do this, the researchers talk with the patients to glean information on the effects experienced as well as using a broad range of different biomedical analysis methods. The composition of saliva, for example, provides information about the level of excitation, which changes with the pain perceived. The researchers also record electrogastrograms (EGGs) in the gastrointestinal tract. Similar to electroencephalograms (EEGs), which record the electrical activity in the brain and are also used for the investigations, EGGs record the electrical signals that occur in response to pain stimuli in the gastrointestinal tract.

Relatively little is yet known about the effect of placebos in the treatment of chronic diseases, and the DFG-funded researchers are now working to improve this situation. “We will initially focus on finding out whether the mechanisms identified in connection with acute pain can be transferred to patients suffering from chronic pain. We are also interested in finding out whether chronically ill people react differently to acute pain than healthy people,” said Enck.

Tübingen research team is specifically focused on placebo effects in children

Functional magnetic resonance imaging (fMRI) data provide the researchers from Tübingen with insights into how visceral signals (from the gastrointestinal tract) are cognitively processed. © Enck, University Hospital Tübingen
Enck and his team of researchers are specifically focused on elucidating the effects of placebos in children. “Research strongly suggests that children display greater placebo effects than adults. We now want to study this in detail and identify the underlying mechanisms,” says Enck, who hopes to obtain general results on several mechanisms that can evoke a response to placebo treatment, including patient expectations that trigger the release of endorophins, as well as Pavlovian conditioning using the colour of pills in a similar way to Pavlov’s bell that triggered a response in dogs. “Research suggests that Pavlovian conditioning is probably the most fundamental mechanism to trigger the positive effect of placebos, but it has not yet been studied in detail,” said Enck. Although Enck’s investigations are non-clinical, he nevertheless needs to be very careful in planning his experimental set-up, especially as his analyses involve children. “In general, we always make sure that our analyses are as uninvasive as possible, especially when we are dealing with children,” said Enck. Enck is particularly excited by the analysis of social learning, which is possibly another important mechanism for provoking placebo responses. For example, Enck wants to find out how children’s response to pain is influenced by role models. Do children respond differently if the role models are of the same gender? Does the age of the role models play a role? Is the impact of parents greater than that of strangers? And what influence does belonging to a particular social group have? “As the answers to these questions are also of high clinical relevance, we now want to focus on these issues despite the complex and time-consuming investigations that are involved,” said Enck.

Implant development stands to benefit from placebo research

The placebo effect is probably best known from pills. However, placebo research is also of importance in the development of prostheses and implants. Placebo stimulation of certain body areas using implanted electrodes has also been shown to provoke placebo effects. “I am sure that further progress will also be made in this area. Placebos can be quite powerful, especially when doctors and their patients believe in their therapeutic effect,” said Enck.

Enck and his group of researchers are also focusing on a completely different aspect: Enck would like to optimise clinical trials in which the efficacy of new medicines is compared to that of placebos. “A relatively frequent occurrence is that an investigational drug fails to achieve significant efficacy in a clinical trial because the placebo worked better than expected, resulting in the drug not being placed on the market. We do not want the process of clinical development of new compounds to be put at risk due to the effect of placebos,” said Enck. In addition, there are many ethical objections to carrying out placebo-controlled clinical trials, one concern being that patients who receive the fake treatment do not benefit from the therapy. “And this is the reason why countries like Canada and Brazil require clinical trials to compare a new drug with an existing drug and not with a placebo,” Enck explained. In order to avoid such problems, Enck therefore sees great demand for new, adaptive clinical trial designs, which means, for example, that the dosing of the drug is increased during the course of the trial.

Need for action: placebo effects in drug trials and package inserts

Enck also believes that package inserts need to address the issue of placebo effects. Information given on package inserts can lead to a dilemma as patients might experience adverse drug effects purely as a result of the fact that the package insert informs patients of potential treatment complications. Worsening symptoms caused by negative expectations on the part of a patient are referred to as nocebo effect. Enck believes that the inserts do not communicate the advantages of a certain drug well enough. “The information provided on package inserts should also be used to prevent nocebos from occurring, for example by positively formulating the frequency of possible adverse events and other issues.” In order to find solutions for the dilemma, Enck is interested in developing innovative solutions in cooperation with partners from the pharmaceutical industry.

Further information:
University Hospital Tübingen
Department of Internal Medicine VI
Psychosomatic Medicine and Psychotherapy
Prof. Dr. Paul Enck
Frondsbergstr. 23
72076 Tübingen
Tel.: +49 (0)7071/ 29-89118
E-mail: Paul.Enck(at)med.uni-tuebingen.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/top-position-for-german-placebo-research