Placebo Flashcards
Definition of placebo and placebo analgesic response; active “ingredients” of treatment context
Placebo: an inert medical treatment (pharmacological, medical device, etc.) that has therapeutic benefit
The ‘active ingredients’ of placebo effects come from the treatment context
Vase et al, 2004
Placebo analgesic agent: external context of the therapeutic intervention that can be perceived by the patient or experimental subject: pills, instruments, white coat, doctors, nurses, hospital, verbal suggestion, observation of pain relief in others
Placebo analgesic effect : the measured difference in pain comparing an untreated group and a placebo-treated group (or between placebo and non-placebo conditions within the same group)
Placebo analgesic response : analgesic response in an individual that results from his/her perception of the therapeutic intervention (may also encompass natural history or spontaneous fluctuations of pain)
Methodological problems in evaluation of placebo effects:
- regression to the mean
- natural history
Regression to the mean
A - Time course of a relapsing or remitting condition such as headache; successive episodes vary widely in their peak intensity. Occasionally, a very severe episode will exceed the threshold intensity for seeking medical attention.
B - A hypothetical situation in which there is a normal distribution of peak severities around a mean value. Because mean values are more common than extreme values, the most severe episodes are likely to be followed by less intense episodes (central tendency). Assuming that there is a high threshold for seeking medical care (TM), it is very likely that the episodes immediately following the physician visit will be of lower intensity. Thus even an ineffective treatment initiated during an episode of peak severity is likely to be followed by improvement.
Natural history
A - A hypothetical painful episode such as an idiopathic headache, which starts at a low level and subsides in the absence of treatment.
In this example, giving a placebo is followed by improvement, but to show that this manipulation actually had an effect one must compare the time course of pain in a group of patients receiving the placebo from that in a no treatment group. The difference is the placebo effect. An active analgesic agent produces an even more rapid or complete pain reduction. The difference between placebo and active treatment is the relief due to the active constituent of the treatment.
Theories of “internal context” of placebo:
Conditioning
Response expectancy
Unconcious conditioning can cause conscious expectation, Conditioning is the learning of unconscious expectations
Conditioning theory of placebo
Hospital, doctors, nurses, medical instruments might have helped us to relieve pain: we unconsciously expect pain relief in medical environment = conditioning
Voudouris et al. 1990
Examined the relative contribution made by conditioning and verbal expectancy. Group 1 received a Combined Expectancy and Conditioning Manipulation; group 2 received Expectancy Alone; group 3, Conditioning Alone; and group 4 was the control group. Subjects’ responses were compared with and without a placebo cream, using iontophoretic pain stimulation. The results suggest that conditioning was more powerful than verbal expectancy in creating a placebo response.
Colloca 2010
Tested the effects of either one or four sessions of conditioning on the modulation of both non-painful
and painful stimuli delivered to the dorsum of the foot. Subjects were told that the lights (Red = noncebo and Green placebo) and would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. The four sessions group had robust
placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.
Response expectancy theory of placebo
Conscious expectancy of pain relief will cause diminution of pain
Demonstrated in conditioning experiments in which the placebo manipulation is disclosed to the subject: this resulted in disappearance of placebo analgesia (Montgomery and Kirsch, 1971)
Expectancy of pain relief is combined with desire for pain relief, and their non-linear combination determines the placebo effect (Vase et al., 2004)
Clinical pain: Administration of four common analgesics (tramadol, ketorolac, metamizol, buprenorphine) in the form of open or hidden administration (intravenous infusions) in patients in pain. Pain reduction was stronger when patients could view the infusions compared to a hidden administration.
Benedetti et al.
Found that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo responses are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.
Role of social context in placebo
analgesia (e.g. Colloca 2009)
(Lancet, 1985)
In clinical settings, doctors were informed that the pill is a placebo or a likely painkiller (placebo or painkiller).
The patients were always given placebo.
When the doctor was told it was a placebo, there was no pain relief, when they believed it could be real, pain relief was seen. The doctor is doing something.
Colloca 2009
Observing the beneficial effects in the demonstrator induced substantial placebo analgesic
responses, which were positively correlated with empathy scores. Moreover, observational social learning
produced placebo responses that were similar to those induced by directly experiencing the benefit
through the conditioning procedure. These findings show that placebo analgesia is finely tuned by social observation and suggest that
different forms of learning take part in the placebo phenomenon.
The placebo analgesic effect can only be measured with an untreated control group
Aspects of external context such as social cues are required for placebo analgesia
Conditioning and expectation are important aspects of the internal context driving placebo effects
How does the brain mediate the internal context of placebo analgesia?
Brain mechanisms of placebo and
the role of endogenous opioid
system (e.g. Fields 2004)
Wager and Fields, 2013
Consistent de-activation across 19 studies during placebo analgesia in: amygdala, basal forebrain, anterior insula, medial thalamus, basal ganglia, anterior cingulate cortex, and prefrontal cortex
Placebo has a real physiological effect.
Effects of placebo on spinal processing: Descending nociceptive controls
Brain structures (PAG, RVM, DLPT) (Fields 2004)
Eippert et al. 2009)
Recorded fMRI from the spinal cord during noxious heat stimulation to their right arm
Two identical creams were administered, either labelled “Lidocaine” (a powerful pain-killer) or “neutral”. Pain ratings were smaller when the heat was combined with the cream labelled “Lidocaine” than with “neutral”.
Spinal cord activation to the pain was also reduced
Both pain matrix and spinal cord activity during pain is decreased by placebo
PAG mediates anti-nociception of pain (Blocks sensory pain), via OFF cells in the RVM, and this is opioid-dependent
Electrical stimulation of PAG causes suppression of behavioural response to pain (Reynolds, 1969)
Two neuronal populations in RVM:
OFF cells: show suppression of activity about 0.4 s
before motor withdrawal reaction
ON cells: show increase of activity prior to and
during nociceptive stimulation
Wager and Fields, 2013
Placebo analgesia has been linked with activity in the prefrontal cortex and opioid release in both
descending antinociceptive systems and forebrain structures.
Thus, placebo responses can affect pain via both inhibition of ascending nociceptive pathways and modulation of forebrain and limbic pain-generation circuits.
PAG is activated and binds opioids during anticipation of pain and during placebo analgesia - Provides a potential mechanism by which expectation can cause pain relief
Placebo and clinical pain: meta-analytic studies
Vase et al., Caperda et al.
Vase et al. 2002)
Two meta-analyses, one in which 23 studies used only placebo as a control condition, and one in which 14 studies investigated placebo analgesic mechanisms. Magnitudes of placebo analgesic effects were much higher in the latter.
This difference may be partly explained by differences in expected pain levels produced by placebo suggestions and by conditioning.
Some of the studies of mechanisms indicate that placebo analgesia is higher when the effect is induced via suggestion combined with conditioning than via suggestion alone or conditioning alone.
Explain whether and how could
placebo be used in pain therapy
Placebo cannot be considered as a substitute for the treatment, patients must be treated actively
Drugs have dual effect: 1) physiological, 2) psychological = placebo
Using the knowledge of placebo effects in helping patients is ethical, and represents one of the future assets in personalised pain therapy
Translate experimental knowledge into clinical practice
Boost placebo effects, ethically?
Expectancy:
Boost positive expectancy of pain relief
Reduce negative expectancies (avoid stressing negative effects)
Inform patients about positive effects of placebo, and effects of placebo on brain (educate the patient)
Knowledge of placebo will boost patient’ self-management capacity
Mention the value and cost of treatment to the patient
Learning / Conditioning:
Apply analgesics in open manner
Turn patients’ attention towards the drug itself (multisensory)
Accumulate pain relief experience (number of reinforcements!)
Use social cues, such as observing other patient benefiting
Intermittent application of a drug allows a better use of placebo effect
