Concepts of placebo, dating back to medieval times, are becoming increasingly important today for understanding the efficacy and limitations of pain management therapies. For example, we most recently discussed in Pain-Topics UPDATES major influences of placebo effects in acupuncture [here] and transcutaneous electrical nerve stimulation (TENS) [here] as therapies for pain. With the newly reported discovery that the unconscious mind may play a key role in placebo effects, researchers have proposed a novel mechanism that helps to further explain the power of placebos and their sinister sister, nocebo.
Writing online in the Proceedings of the National Academy of Sciences (PNAS), Karin Jensen, PhD — of Massachusetts General Hospital and the Program in Placebo Studies at Beth Israel Deaconess Medical Center/Harvard Medical School — and colleagues report a novel study that demonstrated how placebo and nocebo (negative placebo) effects may rely on brain mechanisms that are not dependent on conscious awareness [Jensen et al. 2012]. They enrolled a total of 40 healthy volunteers (24 female, 16 male; median age 23) in 2 experiments:
- In the first experiment, researchers administered a heat stimulus to participants' arms while simultaneously showing them images of male human faces on a computer screen. The first face was associated with low pain stimulation and the second image with high pain. Subjects were then shown the faces again, along with a heat stimulus, and asked to rate their pain on a 0-to-100 scale; however, unknown to the subjects, all heat stimulations had the same moderate intensity. As predicted from classical conditioning theory, the pain ratings correlated with the previously learned associations, with an average pain rating of only 19 when subjects viewed the low-pain face and a mean rating of 53 (nocebo effect) associated with the high-pain face.
- In the second experiment, a different group of participants were first administered the same high and low levels of thermal heat stimulation in association with different faces. Following that, the facial images were again projected on the computer screen, along with the moderate-intensity stimulus; however, this time the images were flashed by so quickly that subjects could not consciously recognize them. Despite this lack of visually recognizable cues, when participants were asked to rate their pain they still reported a mean pain rating of only 25 associated with the low-pain face (placebo effect) and a mean pain rating of 44 in response to the high pain face (nocebo effect).
The researchers believe these new findings demonstrate that a patient may have a favorable (placebo) or a negative (nocebo) response to a therapy even if he/she is not consciously unaware of any suggestion of therapeutic benefit or anticipation of getting worse. This process, operating below the level of cognition, may be automatic, rapid, and powerful, and does not rely on conscious deliberation or judgment. It adds a new level of complexity to understandings of placebo and nocebo effects in research and medicine in general.
COMMENTARY: This unique study by Jensen et al., suggesting an influence of non-conscious conditioned stimuli on placebo/nocebo effects could be of significant consequence, since the results challenge the exclusive role of awareness and conscious cognition in placebo responses. At the same time, however, this was a small laboratory experiment in a select group of subjects and needs further verification.
Traditional thought has contended that placebo responses are related to conscious beliefs or thoughts and, when given an inert pill or therapy, patients may improve because they have the expectation that they will get better. Or, in the case of nocebo, patients get worse because of anticipation some harm, such as due to knowledge of possible adverse effects. This new research proposes that patients may learn to expect or anticipate either benefit or harm quickly and automatically, without needing to consciously register the idea in their brains.
The implication is that a host of factors beneath conscious awareness, operating “under the radar” so to speak, may influence patient responses. Among other things, it highlights the absolute necessity of blinding in clinical trials — whereby neither practitioners nor patients know whether the actual intervention of interest is being administered — to avoid biased outcomes. Yet, this is often problematic or impossible to achieve, and placebo or nocebo effects will continue to be a difficult to control confounder in research.
In an interesting review of the biological, clinical, and ethical aspects of placebos, Finniss et al.  observed that placebos in medical research and practice have been defined by their inert content. However, “recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings.” They further noted that placebo effects can exist, even if no placebo is given, which appears to portend these latest findings by Jensen and colleagues of a subconscious context.
Finniss and colleagues  also offer some fascinating and important commentary regarding the origins of placebos, which is abstracted here for interested readers:
The notion of a “placebo” started with St Jerome's mistranslation of the 9th line of Psalm 116; instead of translating the Hebrew as “I will walk before the Lord,” St. Jerome wrote, “Placebo Domino in regione vivorum” (“I will please the Lord in the land of the living”). By the 13th century, Finniss et al. continue, when hired mourners awaited Vespers for the Dead to begin, they often chanted that mistranslated 9th line, and so were called “placebos” to describe their faked behavior. Later, in The Canterbury Tales, Chaucer named his sycophantic, or falsely flattering, courtier “Placebo.”
The idea of placebo controls were introduced in the 16th century, when progressive Catholics administered fake procedures to separate the effects of imagination from reality. To discredit the validity of exorcisms, individuals “possessed” by the devil were given false holy objects and if they reacted with violent contortions — as if those were genuine religious relics — it was concluded that their possession was in their imagination. This concept of a placebo control was later applied to medical experiments, beginning with the Franklin commission's debunking of the psychic force of mesmerism or animal magnetism in 1784.
Finniss and colleagues further note that use of the word placebo in a medical context to describe innocuous treatments to make a patient comfortable dates from at least the end of the 18th century. The earlier, unsavory connections likely led to the tainted reputation of placebos and placebo effects as being undesirable, which persisted until relatively recently.
Mainstream interest in placebo effects only began with the widespread adoption of the randomized controlled trial (RCT) after World War II. It was then noticed that people improved — sometimes dramatically — in placebo-control groups. Soon after, in his legendary work during the 1950s, Henry Beecher claimed that about 30% to 35% of pain patients responded positively to placebo treatment [previously discussed in an UPDATE here].
Beecher, however, encouraged an inflated notion of the “powerful placebo” because he failed to distinguish the placebo response from other confounding factors, Finniss et al. contend. Since that time, there has been increasing interest in investigating placebo effects by rigorous research methods, especially during the past decade or so, and this has included recognition of the importance of nocebo effects.
> Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. The Lancet. 2010;375(9715),686-695 [abstract].
> Jensen KB, Kaptchuk TJ, Kirsch I, et al. Nonconscious activation of placebo and nocebo pain responses. Proceedings of the National Academy of Sciences (PNAS). 2012(Sep 25);109(39):15959-15964 [abstract here].
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