Problem 3
PLACEBO ANALGESIA (WAGER, FIELDS)
- analgesia: inability to feel pain
- determinants of the analgesic efficacy of a placebo are:
o presence of sensory cues associated with effective treatment or pain relief in
the past
o expectation of pain relief
- placebo implies a mismatch between what patient expects and the treatment’s
actual intrinsic efficacy
- placebo effect can occur in several situations: with deception, with conscious
expectations, following conditioning, associated with psychosocial context
Terminology
- placebo: dummy treatment such as sham surgery and sugar pill
- placebo effect: observable difference between groups that is attributable to the
efficacy of the placebo (e.g. difference in mean treatment effect between groups)
- placebo analgesic response: pain relief in an individual that results from the
expectation of effectiveness of therapeutic intervention
Active placebo responses vs statistical artifacts:
- patients in placebo groups can improve for several reasons:
o improvement would have happened w/ treatment bc of history of disease
o patients tend to enroll when the pain is worst, improvement can be a
consequence of regression to mean
o patients benefit from the positive psychosocial context of being in a study
(more attention, additional social support)
Evidence for placebo analgesia
Placebo effects in experimental and clinical studies
- “clinical trials” report larger effect sizes (compared to experimental)
- most convincing evidence is seen for low back pain and IBS
- placebo effects are larger with sustained pain and in the presence of hyperalgesia
- enthusiasm of physician, verbal communication, conditioning effects from previous
exposure, and physical properties of the placebo and how it’s administered are
critical factors
Cognitive bias as a source of placebo effects
- patients can establish a lower anchor point for pain
- patients can overweigh moments with lower pain to match expectations
- patients may desire report what they believe experimenter expects
- patients may desire to be consistent with previous behavior
- patients may bias their reports towards what they would like to happen
- although placebo treatment decreases reported pain, it doesn’t affect sensory
discriminability
, Placebo effects on brain correlates of pain
- studies show that with placebo treatment:
o reductions in pain-related activity in most brain correlates of pain experience
o activation of areas and circuits important for modulation of pain
o activation of the endogenous opioid and dopamine systems
- placebo effects on fMRI responses to noxious stimuli
o reduced processing of noxious somatic stimuli with placebo treatment
o placebo induced reductions in contralateral anterior insula, medial thalamus
and rostral dorsal anterior cingulate (rdACC) accompanying large behavioral
placebo effects
- placebo effects on event-related potential responses to noxious stimuli
o evidence against a habituation related explanation for the placebo effects
o placebo treatments can modulate responses to early nociceptive processes
- placebo effects on spinal nociceptive processes
o limited direct evidence for spinal inhibition
o placebo treatment significantly reduced spinal fMRI activity in response to
heat
Ingredients of placebo analgesia: what makes a placebo responder?
- promising psychological correlates of placebo response include: suggestibility,
optimism, expectation, behavioral activation, desire for relief, reductions in
anticipatory anxiety, sensitivity to opiate drugs
- placebo effects are influenced both by individual differences and experiences with
treatments, context and cues
- conditioning: process of learning that drug cues signal pain relief or drug-induced
changes in the brain’s neurochemistry
- conditioning can work in at least 2 ways:
o by eliciting conscious expectations of drug relief
o by brain mechanisms independent of conscious expectations
- nocebo effect: conditioning can also produce negative expectations and brain
changes that increase pain
- nocebo instructions have larger and longer-lasting effects than placebo instructions
and produce stronger physiological responses such as on cortisol
Mechanisms of placebo analgesia
Engagement of the evaluative and visceromotor brain systems
- consistent increases in placebo conditions are found in: bilateral posterior
dorsolateral prefrontal cortex (DLPFC), anterior prefrontal cortex, orbitofrontal
cortex (OFC), the pre-genual anterior cingulate cortex (pgACC) and the midbrain
periaqueductal gray (PAG)
- these regions form a control circuit that generate expectations of pain relief and alter
appraisals of ongoing pain
- involvement of PAG points to possible activation of descending control systems and
altered affective-motivational states
- strongest links during anticipation of pain were found in the anterior prefrontal
cortex and superior parietal cortex
PLACEBO ANALGESIA (WAGER, FIELDS)
- analgesia: inability to feel pain
- determinants of the analgesic efficacy of a placebo are:
o presence of sensory cues associated with effective treatment or pain relief in
the past
o expectation of pain relief
- placebo implies a mismatch between what patient expects and the treatment’s
actual intrinsic efficacy
- placebo effect can occur in several situations: with deception, with conscious
expectations, following conditioning, associated with psychosocial context
Terminology
- placebo: dummy treatment such as sham surgery and sugar pill
- placebo effect: observable difference between groups that is attributable to the
efficacy of the placebo (e.g. difference in mean treatment effect between groups)
- placebo analgesic response: pain relief in an individual that results from the
expectation of effectiveness of therapeutic intervention
Active placebo responses vs statistical artifacts:
- patients in placebo groups can improve for several reasons:
o improvement would have happened w/ treatment bc of history of disease
o patients tend to enroll when the pain is worst, improvement can be a
consequence of regression to mean
o patients benefit from the positive psychosocial context of being in a study
(more attention, additional social support)
Evidence for placebo analgesia
Placebo effects in experimental and clinical studies
- “clinical trials” report larger effect sizes (compared to experimental)
- most convincing evidence is seen for low back pain and IBS
- placebo effects are larger with sustained pain and in the presence of hyperalgesia
- enthusiasm of physician, verbal communication, conditioning effects from previous
exposure, and physical properties of the placebo and how it’s administered are
critical factors
Cognitive bias as a source of placebo effects
- patients can establish a lower anchor point for pain
- patients can overweigh moments with lower pain to match expectations
- patients may desire report what they believe experimenter expects
- patients may desire to be consistent with previous behavior
- patients may bias their reports towards what they would like to happen
- although placebo treatment decreases reported pain, it doesn’t affect sensory
discriminability
, Placebo effects on brain correlates of pain
- studies show that with placebo treatment:
o reductions in pain-related activity in most brain correlates of pain experience
o activation of areas and circuits important for modulation of pain
o activation of the endogenous opioid and dopamine systems
- placebo effects on fMRI responses to noxious stimuli
o reduced processing of noxious somatic stimuli with placebo treatment
o placebo induced reductions in contralateral anterior insula, medial thalamus
and rostral dorsal anterior cingulate (rdACC) accompanying large behavioral
placebo effects
- placebo effects on event-related potential responses to noxious stimuli
o evidence against a habituation related explanation for the placebo effects
o placebo treatments can modulate responses to early nociceptive processes
- placebo effects on spinal nociceptive processes
o limited direct evidence for spinal inhibition
o placebo treatment significantly reduced spinal fMRI activity in response to
heat
Ingredients of placebo analgesia: what makes a placebo responder?
- promising psychological correlates of placebo response include: suggestibility,
optimism, expectation, behavioral activation, desire for relief, reductions in
anticipatory anxiety, sensitivity to opiate drugs
- placebo effects are influenced both by individual differences and experiences with
treatments, context and cues
- conditioning: process of learning that drug cues signal pain relief or drug-induced
changes in the brain’s neurochemistry
- conditioning can work in at least 2 ways:
o by eliciting conscious expectations of drug relief
o by brain mechanisms independent of conscious expectations
- nocebo effect: conditioning can also produce negative expectations and brain
changes that increase pain
- nocebo instructions have larger and longer-lasting effects than placebo instructions
and produce stronger physiological responses such as on cortisol
Mechanisms of placebo analgesia
Engagement of the evaluative and visceromotor brain systems
- consistent increases in placebo conditions are found in: bilateral posterior
dorsolateral prefrontal cortex (DLPFC), anterior prefrontal cortex, orbitofrontal
cortex (OFC), the pre-genual anterior cingulate cortex (pgACC) and the midbrain
periaqueductal gray (PAG)
- these regions form a control circuit that generate expectations of pain relief and alter
appraisals of ongoing pain
- involvement of PAG points to possible activation of descending control systems and
altered affective-motivational states
- strongest links during anticipation of pain were found in the anterior prefrontal
cortex and superior parietal cortex
