Placebo Effect: More than just a spoonful of sugar
You have probably heard of the placebo effect before. And now you are probably thinking of some unwitting patient being given a sugar pill and told it will cure their ailment… and voila, they feel cured. And you may think that somehow they have fooled themselves into feeling better, but not really being cured. And you may even think of the word psychosomatic.
But there is a lot more to placebo than that. And there may be more uses for this effect than just as a simple way to control a study…
wait what? Yes. Placebos in the common recognized way are identical to a drug treatment, only they don’t contain any active drug.
Here’s some definitions
Placebo – a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient
-placebos are given as control treatments and depend on the use of measured deception
-common placebos are inert tablets, sham surgery, and other procedures based on false information.
Nocebo – harmful, unpleasant, or undesirable effects a subject manifests after receiving an inert dummy drug or placebo
-not chemically generated, due to subject’s belief and expectation that the inert drug will produce negative consequences
-a nocebo response occurs when a drug-trial’s subject’s symptoms are worsened by the administration of a placebo
Wait, what? Nocebo? Yeah, like a placebo only instead of trying to get positive results, but a “fake” treatment that is supposed to elicit the negative effects of the drug… tease out the psychosomatic part of the study.
And that could be useful and important when dealing with possibly painful or unpleasant treatments.
But what I really wanted to talk about here was the usefulness of the placebo effect.
The placebo effect points to the importance of perception and the brain’s role in physical health.
There is accumulating evidence from different fields of mechanistic placebo research that placebo effects result from REAL neurobiological processes.
Is the placebo effect a real neurobiological phenomenon?
One way to understand whether the placebo effect is ‘real’ is to define particular physiological and functional outcomes that are in themselves meaningful.
–Psychosocial signals => behavioral/clinical changes
–behavioral, neuroimaging, and psychophysiological
•“Open-Hidden paradigm” – comparing whether a patient can see injection/cannot see injection and measure how the expectations that shape response.
–Placebo-related brain measurement decreases during pain, or regions in which placebo-related brain measurement decreases were correlated with placebo analgesia
Is placebo analgesia mediated via reduced negative emotions?
•Recent research has suggested that placebo analgesia may be mediated via reduced negative emotions (Flaten et al., 2011).
•Pain increases negative emotions like nervousness and anxiety, and negative emotions increase pain, whereas a reduction in negative emotions has been shown to reduce pain
•Testing for tense/relaxed and nervous/calm finds that stress leads to pain (EEG studies, ERP studies).
•Conversely, higher fear of pain leads to decreases in the placebo effect. Therefore, increasing stress can abolish placebo (peptide driven). So decreasing fear and stress can increase the placebo effect.
•When treatment for pain is administrated, the patient expects the unpleasant symptoms to decrease. Thus, it could be hypothesized that the expectation of having received effective treatment reduces nervousness and anxiety, which in turn reduces unpleasant symptoms like pain.
•placebos—administered with information that they were powerful painkillers—reduced stress in the absence of pain and before the placebo analgesic response to painful stimulation was observed.
•event-related potentials (ERPs) to painful stimulation were also reduced in the placebo condition compared to a natural history condition where pain was applied, but no pills and no information were administrated.
•If placebo responses are due to reductions in stress levels, then the nocebo response, often considered the opposite of placebo responses, could be due to increases in stress levels.
CNS mechanisms of placebo analgesia – the role of cortical-subcortical-spinal interactions.
•Inhibition of pain related to sensory brain areas, increasing activity with less pain.
•Spinal Cord fMRI shows involvement in placebo effect (ascending is inhibitor) – BOLD response is significantly reduced under placebo
•Also, there is a perceived expectation of brand name versus generic effect as well as price difference effect (higher the price = higher the placebo effect).
From expectations to experience: brain mechanisms and targets of placebo analgesia
•45% of patients use prayer for health, $34+ billion is used on alternative medications.
•Previous studies have shown that the areas in the brain that are active with placebos are similar to the areas of the brain that are also active for opioids and dopamine.
–2 systems are involved:
•frontoparietal (attention, expectation)
•medial oribitofrontal sub cortical (emotion/memory) – effects value system, level of optimism, personality.
•These are highly individual, variable, so when studying, must compare within subject.
•The most predictive regions were those associated with emotional appraisal, rather than cognitive control or pain processing.
•During pain, decreases in limbic and paralimbic regions most strongly predicted placebo analgesia.
The cognitive and emotional dynamics of placebo analgesia: correlating EEG with behavior
•Several studies have now shown that you can have a reduced perception of pain with the use of an inert substance.
•The average pain ratings (+ SE) for pre and post-treatment and LEP plots of the N2–P2 grand average. There was a significant reduction in pain rating post-treatment.
•Placebo analgesia is related to the pathway used in expectation and that it is mediators of expectation that contribute to the reduction of pain.
•This theory has interesting implications into the pathway of why in clinical studies the placebo is sometimes perceived to be at least as efficacious as the active formula.
The placebo effect and the autonomic nervous system: an investigation of peripheral responses
•Powerful verbal suggestion alone is in driving responses in the body.
•Gastric motility
•Patients given placebo 3 different statements
•Electrogastrogram, electrocardiogram, electrodermal activity and respiration measurements
•After being given the “stimulant” pill, 11 out of 18 reported rumbles and growls (sign of increased gastric activity) and while 3 of those given the “relaxant” pill reported rumbles or growls. Reports of “heaviness,” “fullness,” “bloating,” or “decreased activity” of the stomach were rated as signs of dampened stomach activity and were reported by eight participants following the relaxant and none following the stimulant intervention.
•Reported changes matched measured changes in gastric activity.
•This has implications in the complexity of driving consumer perception in clinical studies with the use of products, in particular, the use of questionnaires and how we structure and word our questionnaires.
•Within the neuroscience field, questionnaires with consumers are typically developed and validated before being put in practice to ensure that the information generated from the questionnaires is accurate and that consumers are not being misled by wording within the questionnaire.
Neural correlates of placebo analgesia modulation by value
•Strength of placebo analgesia can be modulated by individual expectations regarding certain placebo attributes.
•They investigated the neuronal basis of the relationship between value and placebo analgesia using fMRI in 40 volunteers.
•Two identical placebo creams were introduced to the subjects as cheap and expensive pain relief creams, respectively, and compared against a control cream on two separate days in a thermal pain stimulation paradigm. Participants rated their perceived pain.
•Assessed the willingness-to-pay (WTP) for all three creams as a measure of subjective value.
•Importantly, placebo analgesia was stronger in the expensive compared to the cheap placebo condition. Stronger analgesia in the expensive condition was paralleled by highest WTP for the expensive cream and high WTP correlated with low pain ratings.
•On the neural level, rACC activity was significantly increased in response to the pooled placebo conditions compared to control. In addition, we observed a significant interaction in the subgenual ACC (sACC) showing a steeper increase for expensive versus control compared to cheap versus control cream.
•The anatomical segregation of the placebo related activation in the rACC and the treatment by value interaction in the sACC suggest distinct underlying neuronal circuits for placebo triggered pain inhibition and placebo valuation. However, these circuits probably interact, since higher WTP for one cream was correlated with stronger pain relief.
•Pain reduction is extremely complex and has been linked to expectation, in particular price. Previous work by Waber et al (JAMA, March 5, 2008—Vol 299, No. 9) has shown that patients given a pill that was priced higher was perceived to be more efficacious in the reduction of pain (table). Implications into how goods are priced can influence consumer expectations and thus perceptions of performance.
So why is this important? When designing studies or designing products, it is important to understand how placebo effect may affect the results. But further, it may be possible to use the placebo effect to increase the likelihood that a product with give positive results. In science, we spend a lot of time trying to eliminate the placebo effect, seeing it as a confound. When in fact, the placebo effect may just be an asset.
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