MD, PhD, FMedSci, FSB, FRCP, FRCPEd

The placebo response might be important in clinical practice, but it is certainly difficult to study and the findings of such investigations can be confusing. This seems to be exemplified by two new trials.

The first study examined the possibility of using theatrical performance tools, including stage directions and scripting, to reproducibly manipulate the style and content of a simulated doctor-patient encounter and influence the placebo response (defined as improvement of clinical outcome in individuals receiving inactive treatment) in experimental pain.

A total of 122 healthy volunteers were exposed to experimental pain using the cold pressor test and assessed for pain threshold and tolerance before and after receiving a placebo cream from a “doctor” impersonated by a trained actor. The actor alternated between two distinct scripts and stage directions. One script emulated a standard doctor-patient encounter (scenario A), while the other emphasized elements present in ritual healing such as attentiveness and strong suggestion (scenario B).

The placebo response size was calculated as the % difference in pain threshold and tolerance after exposure relative to baseline. Subjects demonstrating a ≥30% increase in pain threshold or tolerance relative to baseline were defined as responders. Each encounter was videotaped in its entirety.

Inspection of the videotapes confirmed the reproducibility and consistency of the distinct scenarios enacted by the “doctor”-performer. Furthermore, scenario B resulted in a significant increase in pain threshold relative to scenario A. This increase derived from the placebo responder subgroup; as shown by two-way analysis of variance (performance style, F = 4.30; p = 0.040; η(2) = 0.035; style × responder status interaction term, F = 5.21; p = 0.024) followed by post hoc analysis showing a ∼60% increase in pain threshold in responders exposed to scenario B (p = 0.020).

fpsyg-07-00874-g003

Performance style and response size in placebo responders and non-responders. Bars represent mean ± SE of % change in CPT threshold of 60 subjects in scenario A: 53 non-responders vs. 7 responders and 62 subjects in scenario B: 51 non-responders and 11 responders. Two-way ANOVA by performance style and responsiveness revealed significant effects of doctor’s performance (F = 4.30; p = 0.040; η2 = 0.035) and responsiveness (F = 134.71; p < 0.001) as well as a significant interaction term (F = 5.21; p = 0.024). p = 0.020, Fisher’s least significant difference post hoc test.

The authors concluded that these results support the hypothesis that structured manipulation of physician’s verbal and non-verbal performance, designed to build rapport and increase faith in treatment, is feasible and may have a significant beneficial effect on the size of the response to placebo analgesia. They also demonstrate that subjects, who are not susceptible to placebo, are also not susceptible to performance style.

In the second study, the authors investigated if an implicit priming procedure, where participants were unaware of the intended priming influence, affected placebo analgesia.

In a double-blind experiment, healthy participants (n = 36) were randomized to different implicit priming types; one aimed at increasing positive expectations and one neutral control condition. First, pain calibration (thermal) and a credibility demonstration of the placebo analgesic device were performed. In a second step, an independent experimenter administered the priming task; Scrambled Sentence Test. Then, pain sensitivity was assessed while telling participants that the analgesic device was either turned on (placebo) or turned off (baseline). Pain responses were recorded on a 0-100 Numeric Response Scale.

Overall, there was a significant placebo effect (p < 0.001), however, the priming conditions (positive/neutral) did not lead to differences in placebo outcome. Prior experience of pain relief (during initial pain testing) correlated significantly with placebo analgesia (p < 0.001) and explained 34% of placebo variance. Trait neuroticism correlated positively with placebo analgesia (p < 0.05) and explained 21% of placebo variance.

The authors concluded that priming is one of many ways to influence behaviour, and non-conscious activation of positive expectations could theoretically affect placebo analgesia. Yet, we found no SST priming effect on placebo analgesia. Instead, our data point to the significance of prior experience of pain relief, trait neuroticism and social interaction with the treating clinician.

The two studies are similar but generate somewhat contradictory results. In the discussion section, the authors of the first paper stress that “replication of our findings in clinical populations; employing professional physicians of both sexes, are necessary in order to establish their generality and possible application in medical training, with the aim of improving patient outcome across diseases and treatment modalities.” This is certainly true. They continue by stating that  “future studies using performance tools in clinical trial settings could demonstrate the potential of borrowing performance principles and techniques from traditional healing and applying them to physician–patient encounters in Western medicine, following certain necessary modifications. Performance tools could thus eventually be incorporated into the systematic training of physicians and medical students, possibly to complement programs in Narrative Medicine and Relational Medicine.”

These ideas are not dissimilar to what we have been discussing on this blog repeatedly. For instance, I have previously tried to explain that “the science and the art of medicine are essential elements of good medicine. In other words, if one is missing, medicine is by definition  not optimal. In vast areas of alternative medicine, the science-element is woefully neglected or even totally absent. It follows, that these areas cannot be good medicine. In some areas of conventional medicine, the art-element is weak or neglected. It follows that, in these areas, medicine is not good either.”

The fact that the two studies above show contradictory findings is not easy to interpret. Possibly, this shows how fragile the placebo response can be. It can be influenced by a multitude of factors related to an experiment or the clinical setting. If that is so, and placebo effects are truly unreliable, it would be yet another argument for not relying on them in clinical routine. In my view, clinicians should try to maximize them where they can. Yet placebo effects are not normally a justification for employing placebo therapies in clinical practice. In other words, the fact that a bogus treatment can generate a placebo response is not a good reason for using it on patients who need help.

Good clinicians have probably always been good ‘performers’. Alternative practitioners tend to be excellent ‘performers’, and I am sure their success is mainly due to this ability. I see little reason why conventional practitioners should not (re-)learn the skills that once upon a time were called ‘good bed-side manners’. Maximizing the placebo effect in this way might maximize the benefit patients experience – and for that we do not require the placebo-therapies of alternative medicine.

17 Responses to Two fascinating new studies of the placebo response

  • “In my view, clinicians should try to maximize them where they can. Yet placebo effects are not normally a justification for employing placebo therapies in clinical practice. In other words, the fact that a bogus treatment can generate a placebo response is not a good reason for using it on patients who need help.”

    Spoken like a true skeptic. Do you have any clue about the power of the mind over the body?

    A placebo can be as effective as a drug for reducing lower back pain—even when the person knows he’s being given a dummy pill. Back pain patients who are told they’re taking a placebo still report a 30 per cent reduction in pain and disability.
    Around half of the 97 patients with chronic lower back pain were given a pill bottle, with the word ‘Placebo’ printed on it—after they had been told that a placebo contains no active ingredient—along with a standard NSAID (non-steroidal, anti-inflammatory drug) painkiller, and the rest of the group was given just the painkiller.
    After taking the pills twice a day for three weeks, the patients given the placebo reported a 30 per cent reduction in pain compared to a 9 per cent decrease among those given only an NSAID.
    Other chronic problems such as fatigue, depression, and common digestive or urinary symptoms might also respond well to placebo where the patient is told beforehand, say researchers from the Beth Israel Deaconess Medical Centre.
    Lead researcher Ted Kaptchuk, who is also a professor of medicine at Harvard Medical School, reckons that the placebo works because it’s part of a process that includes interaction with a nurse or physician, taking pills and “all the rituals and symbols of our healthcare system,” he says.
    The results “turn our understanding of the placebo effect on its head,” says Prof Kaptchuk. In most medical trials, the patient isn’t told that he or she has been given a placebo so that any benefits must therefore be all “in the mind.”

    But it seems our mind doesn’t care whether or not it knows we’re taking the dummy pill.

    • ” Do you have any clue about the power of the mind over the body?” yes, I do!
      perhaps you care to read my previous posts on this topic and try to understand: ONE DOES NOT NEED PLACEBOS TO GENERATE PLACEBO EFFECTS!

  • The difference between the two studies in how patients were primed is not clear but it looks as if the first study involved explicit priming by contrast with the implicit priming employed in second study. This might explain the difference in priming effectiveness found in the two studies.

    The Kaptchuk study mentioned in the comments employed heavy-duty explicit priming throughout and even before the trial, advertising itself to prospective participants as an experiment in “mind-body” medicine: Self-selecting placebo responders were likely to have been well represented in the trial.

    The placebo responder/non-responder dichotomy is exemplified in the first study mentioned here. The ANOVA analysis is instructive. Doctor’s performance just scraped statistical significance; interaction was far more significant but far and away the most significant factor was – responsiveness. The placebo response relies heavily upon the suggestibility of patients.

    I think this fact makes the systematic employment of the effect highly problematic in terms of ethics. Explicit suggestion by medical professionals of possible benefits of a purported treatment which depends entirely on the effectiveness of suggestion itself on a small sub-group of the general population seems like an extremely dubious way to go, as a general practice.

  • I don’t think these studies show any reduction in the pain experienced by the subjects, just a modification of the point at which they complain. Similar to studies that found reduced pain reported but no change in on-demand painkiller use. If this is a possible explanation then there is very little “mind-body” effect and a lot of reporting effect. Clinical use of placebo in that case is shutting the patient up not helping them. That has contributed to difficult to diagnose patients going for years without effective help.

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