the placebo effect

limitations of placebo study CT

- depends primarily on patient's self report bias: people tend to over react (aka Bayesian response bias) and they want to please experimenter (demand characteristics)

supporting study - Wager et al. 2004 - brain areas associated with opioid release due to expectation

- increased neural activity in expectation-related areas just before administration of placebo frontal cortex: - orbitofrontal cortex (OFC) - control - affective/motivational responses - dorsolateral prefrontal cortex - maintenance of information needed for cognitive control - found activity correlated with perception of pain reduction - suggests activation of areas triger opioid release in the midbrain

pain

- mechanisms easily understood and well researched - it is an unpleasant sensory/motor experience associated with actual or potential tissue damage - sensation formed by brain - damaged tissues send signals to the brain and brain interprets them (e.g.phantom pain) - highly individual and subjective - best to measure by self reports

placebo due to reward expectation?

- placebo operates as a reward - the anticipation that pain will reduce is rewarding) Bingel et al. 2011 - response depends on expectation - positive expectation reduces pain intensity on self reports - but does it reduce intensity in brain regions? - state it is dependent on expectation if it is rewarding we expect it to be associated with dopamine

analgesia

- when placebo reduces pain - placebo analgesia - if it actually reduces pain we expect to see associated neurotransmitters and brain regions affects neurotransmitter: opioids - endogenous opioids are opioids produced in the brain to relive pain (aka endorphins) - brain releases lots of endorphins to release pain - opium, heroine, morphine..

paradigms for assessing placebo effect

1. parallel group desgin - compare placebo to control 2. open vs hidden drug design - people are aware of treatment vs not 3. response conditioning design - 2 creams - told one is beneficial (placebo) and the other isn't, painful stimuli applied to both arms and told the same intensity but placebo sight is less (reinforcing) - asked to assess pain level when equal pain is applied - most commonly say placebo is better 4. pharmacological conditioning design - combine instructions and cues with active drug during conditioning phase - then take away drug and just cues -> see if still works without active drug

two key types of response to pain

1. sensory aspect of pain -- thalamus to somatosensory cortex (S1, S2) -- painful stimulus sends information through spinal cord to thalamus, then thalamus tells somatosensory cortex which part of the body is in pain 2. emotional aspects of pain -- anterior cingulate cortex -- insular cortex -- amygdala -- PFC

examples - WW2 - knee surgery

Beecher - american surgeon - WW2 - treated soldiers with morphine - one day ran out and treated soldiers with saline (salt water) and stopped the patient from screaming after injection •surgery for osteroarthitis (painful inflation) of the knee under general anaesthetic Study: Moseley et al., 2002 oPlacebo can be as good as medical surgery oUS - expensive to clean knee and sow up = 31% in improvement and 33% after placebo surgery after 2 weeks o2 years after = real = 27% recovery, and placebo = 28% oUse placebo as controls to compare effect of placebo

study on response conditioning

Nakamura et al. 2012 - assess pain, autonomic responses and electroencephalography - received 3 identical placebo creams and told they varied in strength -then painful stimuli applied to skin after treatment - training: painful stimuli varied amongst creams - reinforcement - test phase: same strength = placebo effect - found change in autonomic responses (e.g. pupil diameter and skin irritation) - linked placebo analgesia to changes in autonomic activity

opioids in pain matrix study

Scott et al. 2008 - two pain challenges: 1. absence of placebo 2. with placebo with expected analgesic properties (tell them it will reduce pain) - investigated activity in 2 different neurotransmitters in nocebo and placebo effects found: opioids found in condition 2 in some of the pain matrix areas (ACC, PFC, insular cortex, amygdala) opioid neurotransmission increases in areas associated with the emotional aspect of pain - how we deal with it (however can relief pain in all pain related regions - most consistent = acc, tHALAMUS, INS)

looking at increase in neurotransmitters after placebo

Wager, Scott and Zubieta (2007) - looked at opioid release during placebo treatment using PET - pain: heat - pain someone experiences with heat - opioids activity increased in anticipation of pain and in response to pain - opioid activity was correlated with subjects report of pain - more opioid = less pain -> placebo = opioid increased to relieve pain

pain matrix - areas of the brain

areas involved in pain processing: thalamus somatosensory corticles insular cortex anterior cingulate cortex

immune response

autonomic and neuroendocrine systems work together with the immune system - can be seen in pharmacological conditioning studies -> taste cues paired with immunosuppressive drugs - little is known about process but associated with forebrain - Moseley et al. 2002 and Beecher WW2

what is a placebo effect?

beneficial effects that are attributed to the brain-mind responses rather than a specific action of a drug in treatment. - procedure aimed to please rather than exerting a specific event - can produce physcial effects - positive (placebo) and negative (nocebo - symptoms worsen in response to substance)

neuroendocrine response

can affect hormonal responses that are mediated via forebrain control of hypothalamus-pituitary-hormone system - hormones that regulate appetite - ghrelin Crum et al. 2011 - drank milk shake 'indulgent' vs 'sensible' - indulgent = reduction in pro-hunger hormones - ghrelin

what cues affect the strength of placebo and why?

colour - red associated with stimulants, and blue associated with sleep number of pills size price packaging administration method - drugs less than injections - more invasive better

types of cues

external: verbal cues/place/social (body language) treatment: syringe internal: this will work - expect a good outcome

what happens in the brain? what was the initial thought

initially people thought it was just a change in subjective symptom reporting (they aren't actually feeling a relief of pain they just think they are) - neural evidence has shown that there are actual changes

DOPAMINE

involved in reward expectation Scott et al. 2008 - also looked at dopamine as well as opioids - results: sig activation of dopamine neurotransmission after placebo - they expect it to work so get a hit of dopamine areas: CAU, NAC, PUT (areas involved in reward processing)

Nociception analgesia

neural process of encoding/processing stimuli that have the potential to damage tissue - does not always lead to feeling pain analgesia - pain relief

examples of treatment

parkinson's disease - tremors - treatment: inject electrodes deep intp the brain to stimulate dopamine neurons to improve motor symptoms of patients - this deep brain stimulation has a good impact of motor symptoms BUT if you do this operation and tell the patients the electrodes are on even though they are not, the patient will stop shaking. Like wise when you turn it off but they are still on - powerful placebo effect not just in pain but in motor

how do neurotransmitters work?

they inhibit the neurons that release pain neurotransmitters

form of classical conditioning

you are pairing cues with expectations - like Pavlov and dogs e.g. morphine causes with pain relief, needle associated with morphine -> needles become conditioned stimulus and make you feel better - evidence suggest nocebo effect can happen when these are negative cues