The 100 Billion Dollar-Euro Question: Is There A Placebo Effect In Medicine Outside Drug Trials?

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A common cold lasts for 7 days without medicines and for one week with medicines, but a day less with an empathic doctor

Everybody knows about the placebo effect: Patients given placebos during a test for a novel medication will show improvement of their condition – sometimes more, sometimes less. But almost always to the annoyance of the drug industry that has to subtract this effect from the drug effect seen in the same trial, to value the new treatment (1), although this is often forgotten in the marketing department of the company. Because daily medical routines where the drug is subsequently used does (or should) not use placebos and value the placebo effect. Does this mean there is no placebo effect in medicine outside drug trials?

We know about the size of the placebo effect from two different kinds of sources (2): Meta-analyses of clinical trials that have used drugs and placebos (randomized, placebo-controlled trials, RCT) on the one hand (e.g. with analgetics in patients with a chronic pain condition), and from experimental (laboratory) research on the other hand, where the placebo response of individuals (patients, volunteers) is tested under controlled conditions (e.g. with an experimental pain stimulus, and with a definitive placebo that is purposely given with false information, such as saying. “This is a strong pain killer.”). Let’s leave ethics aside for now.

When both RCT and experimental studies were compared to calculate the size of the placebo effects (3), it turns out that in RCT it is substantially smaller than in the lab; this implies that the information given to a patient in an RCT (“You have a 50% chance of receiving the drug.”) results in much smaller responses than in the laboratory, based on lower and more realistic expectations of the patients. On the other hand, to investigate the mechanisms of the placebo response it may be useful to enhance the placebo effect in the laboratory, even though this may not reflect reality.

This immediately raises the question about the size of the placebo effect in medical routines outside RCT and the laboratory. Is it larger as compared to RCT, because doctors can substantially enhance the response to any drug using verbal reinforcement (“This drug will definitively eliminate your symptoms.”), as in the laboratory? Or is it smaller than in RCT, because in a clinical trial a patient will see his/her doctor on a regular, e.g. monthly, basis for extensive interviewing and investigations, while in daily medical routine consultations, time ranges between 5 and 15 minutes every few months, at best (4)? Time is money, and in RCT doctors get paid for their time by the drug industry, while in routine they are reimbursed by health care plans and insurances.

Two quasi-experimental patient studies shed some light on the issue. In the first study (5), 262 acupuncture-naive patients with irritable bowel syndrome (6) were recruited for treatment of their symptoms by a specialized academic center (Harvard Medical School); they were randomized to a 3-week waiting list before treatment (Group 1), to a standard sham acupuncture treatment (Group 2), and to an “augmented” sham-acupuncture therapy (Group 3). A subset (50%) of patients received true acupuncture after 3 weeks. The patient information was, therefore, truthfully stating that they had a 50% chance to receive acupuncture during the six-week study.

While the waiting list (Group 1) controls for spontaneous fluctuations of symptoms, establishing a comparison between a standard therapeutic setting (with limited communication between doctor and patient) (Group 2) and an augmented practitioner-patient communication (Group 3) was the goal of the study. Augmented communication was operationalized as follows: practitioners were trained to follow a rule book that determined the interaction with respect to  both content (four aspects: intestinal and extra-intestinal symptoms, their impact on lifestyle and relationships, patients perception of origin, and explanation of symptoms) as well as style (five aspects: warm and friendly, active listening, empathy, thoughtful silence, transmitting confidence). For the limited interactions in contrast (Group 2), the practitioner “… introduced themselves and stated they had reviewed the patient’s questionnaire and “knew what to do.” They then explained that this was “a scientific study” for which they had been “instructed not to converse with patients” and performed mostly in silence.

As predicted, the augmented interaction with the patient resulted in significantly better clinical outcomes than the limited interaction, and both were better than the results of the waiting list control. This was true for global overall improvement, for adequate relief of symptoms in comparison to before the study, for symptom severity, and for quality-of-life. But as the authors state, their measures were subjective rather than objective, and it remains unclear whether these improvements were related to any biochemical, neuroendocrine, neurophysiological or neuroanatomical correlates of the disease. It also remained inconclusive whether these findings relate to any other illnesses.

The second study from the University of Wisconsin (7) follows a similar design but with a different group of patients: 350 patients older than 12 years and with a common cold, consulting at university outpatient clinic, were asked to participate in a study testing Echinacea (coneflower) for their immune system. While waiting to see a doctor, they received a set of questionnaires, among which was the “Consultation and Relational Empathy” (CARE) scale that asked to rate the empathy of the physician that had just completed their initial anamnesis and investigation. What they did not know was that six of the physicians had explicitly been trained before for this experiment. They had to either treat patients in a very limited but schematic way or follow a rulebook (PEECE) with elaborate standards: Positive prognosis, Empathy, Empowerment, Connection, and Education.

Which patient would be treated according to which treatment strategy was disclosed to the doctors only shortly before the visit and according to a pre-defined experimental plan. The patients were randomly assigned to one of three groups: they either did not see a doctor at all but other medical personnel (Group 1), a doctor instructed to execute the limited treatment scheme (Group 2), or a doctor following the PEECE rules (Group 3). In all patients, the actual treatment was the same: Anamnesis, and collection of nasal exudate for measures immune parameters. In case of seeing a doctor, interviews were done, in one case more, in the other less. After the patient had filled out the questionnaires and left, they returned after two days and after the cold had ceased.

Doctors were subdivided according to the patient’s rating of their empathy on the CARE scale, into a group with a perfect score (50 points, N=84) and a group with a less-than-perfect score (ranging between 10 and 49, N=266). And as it turns out, patients with a maximally empathic physician reported significantly less symptom severity than the other group. But more importantly, they also showed a significantly lower interleukin-8 (IL-8) value of nasal wash specimen (an inflammatory immune marker), and cold duration that was significantly shorter (7.1 + 3.5 versus 8.1 + 3.36 days), even when adjusted for age, gender, education, race, and a number of psychometric measures.

While we still do not know what the effect size of the placebo response in daily medical routine is, this example now allows us reasoning about its value: Assuming the total (adult, > 16 years of age) population of the US (or Europe) to be 200 Million, and each individual affected by a common cold once every year, this accumulates to 200 Million disease days saved, if all physicians would be maximally empathic, and if each disease day equals a working day off,  and costs (directly and indirectly) 250 $/€, then empathy-associated placebo effects are worth 100 Billion $ and € in annual savings for the society for the US & Europe only. However, this is rather simple-minded reasoning!

This is part 2 of a series covering “placebo” provided by Paul Enck and Sibylle Klosterhalfen from the Tübingen University Hospital. Continuous updates on placebo research can be found at www.jips.online.

References

  1. Schedlowski M, Enck P, Rief W, Bingel U. Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice. Pharmacol Rev. 2015 Jul;67(3):697-730.
  2. Weimer K, Enck P. Traditional and innovative experimental and clinical trial designs and their advantages and pitfalls. Handb Exp Pharmacol. 2014;225:237-72.
  3. Vase L, Riley JL 3rd, Price DD. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain. 2002 Oct;99(3):443-52
  4. Irving G, Neves AL, Dambha-Miller H, Oishi A, Tagashira H, Verho A, Holden J.  International variations in primary care physician consultation time: a systematic review of 67 countries. BMJ Open. 2017 Nov 8;7(10):e017902.
  5. Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE, Kirsch I, Schyner RN, Nam BH, Nguyen LT, Park M, Rivers AL, McManus C, Kokkotou E, Drossman DA, Goldman P, Lembo AJ. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008 May 3;336(7651):999-1003.
  6. Enck P, Aziz Q, Barbara G, Farmer AD, Fukudo S, Mayer EA, Niesler B, Quigley EM, Rajilić-Stojanović M, Schemann M, Schwille-Kiuntke J, Simren M, Zipfel S, Spiller RC. Irritable bowel syndrome. Nat Rev Dis Primers. 2016 Mar 24;2:16014.
  7. Rakel DP, Hoeft TJ, Barrett BP, Chewning BA, Craig BM, Niu M. Practitioner empathy and the duration of the common cold. Fam Med. 2009 Jul-Aug;41(7):494-501.
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