Placebo Flashcards
Placebo-definition
“a substance or procedure… that is
objectively without specific activity for
the condition being treated”.
Placebo examples
- pharmacological (dummy medication)
- procedure including sham surgery
- psychological (conversation/homeopathy)
Placebo effect (definition)
Any improvement in a symptom or physiological condition of a subject after placebo treatment
Placebo response (definition)
Neurobiological and psychophysiological response of an individual to an inert substance
Placebo effect in active treatments
Placebo response can modulate effectiveness of active treatments (active–i.e. non-dummy medicines can work better if you believe they will)
Nocebo effect (definition)
The harmful, unpleasant, or undesirable reactions (or responses) manifested as a result of administering a placebo, due to the subject’s pessimistic belief and expectation that the drug would produce harmful,
injurious, unpleasant, or undesirable consequences.
Nocebo (examples)
Includes statements such as “This medication may worsen your symptoms” or “this medication may give you a headache”
Placebos have _____ effectiveness
HIGHLY variable (10-60%)
Beecher’s The powerful placebo” (1955)
Book
~ 35% of people respond to placebo
Placebo effectiveness is dependent on…
Placebo effect
- doctor-patient communication
- expectation
- conditioning
Things that may give false sense of getting better:
- natural history of disease (spont. getting better)
- regression to mean
- Biases and false positives
- Co-interventions and other non-specific effects
___% of physicians would recommend
sugar pill treatment for difficult to treat
conditions such as fibromyalgia
25%
Pain killing and anxiety reducing drugs that are infused secretly without an individual’s knowledge are ____ effective than when a patient knows they are receiving them
LESS effective; placebo effect increase efficacy of an active drug
Patient expectations
Often a consequence of physician – patient relationship and trust (if u trust your physician and they say it will work –> more likely to have placebo due to positive expectation)
Patient expectation example: marijuana sample
Name of marijuana strain may alter the high you get due to expectation
Conditioning: _____ is a conditioned stimulus and _______ are conditioned responses.
According to classical conditioning theory
PLACEBO = conditioned stimulus
PLACEBO EFFECT = conditioned responses.
Classical conditioning placebo example
1) Start with high level of nociceptive stim
2) then pair inactive cream with decreasing noicieptive stimulation
3) patient associates decreased pain w/ cream
4) inactive cream will start to have an analgesic effect
IS THIS CONDITIONING OR EXPECTANCY–debated
Issues with conditioning theory in placebo
Role of conditioning has been questioned, and some describe placebo effect purely in terms of expectancy
For FDA approval drug must be…
more effective than placebo
CLinical trials with placebo should be
- double blind
Double blind
physician doesn’t know what they are
administering, patient doesn’t know what they are receiving
Placebo is best in
patient-reported outcomes (subjective health issues)
Placebo works best in these conditions:
• Pain • Depression • Anxiety • Drug abuse • Gastric Ulcers • Crohn’s Disease Note: GI disorder effects may be related to anxiety
Placebo in crohn’s disease
• Placebo can improve endoscopic assessment of disease activity in 20% of cases (placebo response)
“Honest placebo” effect in IBS
Patients with IBS experienced a significant beneficial effect even though THEY KNEW THEY WERE TAKING PLACEBO
as compared to a control group who received no pills.
In Gastric and duodenal ulcers placebo was ____ (more/less) effective than H2 blocker (cimetidine) confirmed with ____
Placebo was less effective, but comparable
Healing of ulcer was confirmed with endoscopy = physiological mechanism for placebo
WEAKest palcebo effect in conditions where outcomes are _____. Examples:
Objective
infections, blood poisioning
neurological disorders (ex. epilepsy)
Pitfalls in placebo clinical trials
- Natural history of disease
- Regression to mean
- biases and false positives
- effect of co-interventions and non-specific effects
Natural history of disease
a pitfall in clinical trials
Spont remission can lead to false-positive placebo effects
Regression to mean
Meta-analysis shows little placebo effect= but looked at objective AND subjective diseases
But subpopulations can show great benefits
Biases and false positives
ex. physicians report better effects in depressed patients than the depressed patients report themselves
Non specific effects
-patient charcteristics–placebos may work better in some cultures (germans vs Brazilians) ; alterations in life circumstance can alter depressive scores etc. (bereavement, financials)
Co-interventions
Patients may self medicate or change lifestyle–influences disease state
How to prevent pitfalls in placebo trials
Add a 3rd arm to the study
- drug, placebo AND no treatment
- “no treatment” group will allow for any changes in life circumstance, disease course, biases, co-interventions, etc.
Animal model of placebo: set up
Used an “operant model” where animals would be subjected to mild thermal facial pain when they went for a reward (sugar
water)
Process: animal placebo
1) Rats learn that putting their head through the “thermode” at 37oC (non noxious) = reward (sugar water)
2) “Thermode” @ 48oC, (noxious) get baseline score of how often rats go for reward
3) Morphine + handling = analgesia therefore rats learning SubQ injection + handling = analgesia; Morphine treated rats will seek sugar more often
4) Inject saline + handle rats –> go for sugar more frequently.
BUT Effect blocked by naloxone (therefore must have physiological basis in endogenous opioids)
Animal model of placebo: short version
COndition rats to associate morphine (analgesia) with handling
WHen given subQ injection and handling –> analgesia
Analgesia is measured by how much the animal goes for the reward in the noxious hot
effect blocked by naloxone (b/c of physiological placebo response)
Why does naloxone block animal model of placebo
In this case release of endogenous opioids seems to be involved in the placebo effect
–> naloxone will prevent binding and therefore effect of these endogenous opioids –> prevent analgesia
if the substance is viewed as helpful it can ___; if it is viewed as harmful, it can cause ______ aka _____
HEAL; negative effects; nocebo
placebo effect is related to the perceptions and expectations of
the patient
Pain matrix structures
• Anterior cingulate and prefrontal, cortices • Nucleus accumbens • Amygdala • Brainstem periaqueductal gray matter • Spinal cord.
What is the pain matrix
a group of structures that are activated during pain
Pain matrix and placebo
Activity of all components of the “pain
matrix” is altered during placebo
analgesia–> decrease activation with placebo analgesia
Pain matrix: PFC role
related to recalling the placebo and maintaining its cognitive presence
Pain matrix: cingulate cortex role
could be related to the expectation of potential pain stimuli
NAc and placebo
High placebo responses link with enhanced dopamine and mu-opioid activity in the circuitry for reward responses and
motivated behavior of the nucleus accumbens
Analgesic placebos activate _____ through the ______ activation of ____________
descending inhibition ; PAG; spinal nociceptive reflexes
Activation of ____ explains the naloxone sensitivity of placebo
descending inhibition through the PAG activation of spinal nociceptive reflexes
How a neutral stimulus saccharin can cause immunosuppression in animals
1) learn taste of saccharin
2) Saccharin is paired in a drink with cyclophosphamide that causes immunosuppression
3) saccharin alone causes hypothalamic activation –> CRH release onto ant pit –> ACTH release onto adrenal cortex –> corticosteroids cause immunosuppression
Placebos in pain
- Can also sometimes see respiratory depression (further support for endogenous opioid involvement)
- Placebo analgesia more effective the more severe the pain
- placebo saline was said to be a powerful pain killer and had same effects as morphine
Placebo in Depression
- tests for new ADs are benchmarked against placebo
- some ADs like prozac had to run 5 trials before they beat placebo –what is the physiological mechansim
Placebo effect involves…
- Clinician – Patient Relationship
- Expectancy and conditioning
- Effects in the brain
- Brain-body interactions
Example of active drugs with a placebo component
ADs
