cognitive influences on pain

Question 1

what is the placebo effect?

Answer 1

a positive psychological and physiological response, following the administration of a sham treatment or intervention

2 central mediators of placebo hypoalgesia (& nocebo): expectation & experience/learning

Question 2

what is the nocebo effect?

Answer 2

opposite to the placebo effect - inert substance is given along with a negative context to induce negative expectations about the outcome

leads to worsening of symptoms

Question 3

what are hyperalgesia, hypoalgesia and analgesia

Answer 3

hyperalgesia = an increase in pain sensitivity

hypoalgesia = a decrease in pain sensitivity

analgesia = abscence of pain

Question 4

negative expectations may lead to clinical worsening

Nocebo and pain (Amanzio, 2016)

Answer 4

neg diagnoses, neg communication & distrust → can lead to amplification of pain intensity and reduce/conceal efficacy of treatments and affect patients’ emotions

perceived intensity of a painful stimulus following negative expectation of pain increase is higher than in the absence of negative expectations
- expectation of painful stimulation amplifies perceived unpleasantness of innocuous stimulation

Question 5

open vs hidden administration/interuption of treatment & their effects on pain

Answer 5

open: medication given by doctor (e.g. doctor hands a pill) - doctor tells patient that treatment is over
* tends to have better treatments effects & stronger placebo (but also nocebo) effects
* due to expectation of the patient - they know when they are being given the drug = expect to work now

hidden: medication given by a machine - patient doesn’t know when its given or when it has been discontinued

study: effects of open (expected) versus hidden (unexpected) interruptions of morphine in postoperative patients
* after having received morphine for 48hrs, p’s underwent either open or hidden interruption
* after interruption of morphine → pain increase larger in open group than hidden group
* hidden interruption of morphine prolonged the post-interruption analgesia
* suggests that the open-hidden difference relates to the fact that in the open condition fear and negative expectations of pain relapse play an important role

Question 6

nocebo effect and observational learning

Answer 6

nocebo effects can be learned through observation and social interaction (social learning)

nocebo suggestions of a negative outcome can produce both hyperalgesic and allodynic effects (perception of pain in response to innocuous stimulation)

social observational learning can lead to a negative emotional contagion across individuals, with the consequent activation of nocebo mechanisms

Question 7

what is the role of cholecystokinin (CCK) in nocebo hyperalgesia

Answer 7

CCK = a nonspecfic neurostransmitter
proglumide = antagonist to CCK

study found that proglumide prevented nocebo hyperalgesia in a dose-dependent manner, even though it is not specifically a painkiller → suggests that the nocebo hyperalgesic effect is mediated by CCK

another study suggested a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect

a close relationship between anxiety and nocebo hyperalgesia exists - but proglumide does not act by blocking anticipatory anxiety, as previously hypothesized
- proglumide interrupts a CCK link between anxiety and pain

Question 8

Direct evidence for spinal cord involvement in placebo analgesia (Eippert, 2009)

(BOLD responses)

Answer 8

hypothesis: spinal cord blood oxygen level–dependent (BOLD) responses related to painful heat stimulation are reduced under placebo analgesia

method: combined fMRI scans of the spinal cord with a placebo analgesia paradigm

results:
* pain ratings were significantly lower under the placebo condition compared with control = placebo induction was successful
* reduction of BOLD responses under placebo compared with control was evident

discussion:
* provides direct evidence that psychological factors can influence nociceptive processing at the earliest stage of the CNS - namely the dorsal horn of the spinal cord
* one mechanism of placebo analgesia is inhibition of spinal cord nociceptive processing, possibly mediated by the descending pain control system in a gate-control manner
* spinal cord as a gatekeeper of nociceptive signals: placebo analgesia may modulate this “gate,” reducing nociceptive transmission from the spinal cord to higher brain regions

Question 9

enhancing expectancy to improve pain interventions

Placebo analgesia: clinical application (Klinger, 2014)

Answer 9

• strength and certainty of pos expectancies will increase self-control beliefs and attention to positive effects → can reduce anxiety and stress
• placebo effects can be enhanced by educational informative approaches - informing about placebo mechanisms & explaining effects
• health care providers can shape the context in which therapeutic interventions are given = can influence the outcome via maximizing expectancy
• neg expectancy can reduce its efficacy and increase side effects and induce a nocebo effect when info is focused on adverse events

Question 10

enhancing learning to improve pain interventions

Placebo analgesia: clinical application (Klinger, 2014)

Answer 10

• learning pov: an originally neutral stimulus (e.g. sight, taste or smell of a medication) when associated with the pharmacological effect of a drug → elicit’s the analgesic effect on its own
• analgesic interventions can have an additional pos effect based on their association with previously experienced successful treatments
• study: the prior experience of a beneficial effect of a drug led to a higher placebo response than the experience that a drug had been ineffective, and these effects last several days

Question 11

Psychological placebo and nocebo effects on pain rely on expectation and previous experience (Reicherts, 2016)

aim & method

Answer 11

aim: test whether a purely psychological placebo-nocebo manipulation would be feasible to induce placebo hypoalgesia and nocebo hyperalgesia

method:
* thermal pain stimulation, skin conductance recording & pain intensity & unpleasantness rating
* experiment 1: compared 3 groups: group 1 expectation, group 2 experience, group 3 expectation + experience
* in a subsequent test phase, placebo and nocebo responses were measured by applying identical thermal pain stimuli
* experiment 2: an additional neutral control stimulus was introduced to determine whether manipulation resulted in placebo or nocebo effect

Question 12

Psychological placebo and nocebo effects on pain rely on expectation and previous experience (Reicherts, 2016)

results & conclusions

Answer 12

results:
* experiment 1: significant placebo and nocebo responses + indicated that their magnitude was predicted by the difference between high and low pain ratings during the learning phase - ONLY in combined condition
* results from experiment 2 replicate findings from 1 → suggests that the manipulation of expectation together with experience induces stronger nocebo than placebo effects

conclusions:
* study showed a significant placebo and nocebo effect on pain that resulted from a purely psychological placebo–nocebo manipulation
* this effect was only observed when both expectation and experience were manipulated
* suggest an overadditive interaction of experience and expectancy - most likely a result of reinforced expectations

Question 13

what is algesia?

Answer 13

algesia = sensitivity to pain

nocebo algesia = occurs when changes in individual pain perception cause a lowering of the specific positive effects associated with a particular medical treatment or intervention

Question 14

what are the 3 kind of algesic nocebo that are possible in clincal practice?

Answer 14

1. the patient’s expected neg outcome in regard to a treatment reduces the pos outcomes
2. when a patient’s overvalued expected pos outcome of a treatment is not confirmed after treatment → this neg experience reduces the effectiveness of a subsequent treatment
3. patients can fail to expect a pos outcome from their treatment because of deficient information about the pain-reducing effects → limits the occurrence of additional pos outcomes related to placebo analgesia

Question 15

how can patient-clinician communication affect patient outcomes?

Nocebo effects in clinical studies: hints for pain therapy (Klinger, 2017)

Answer 15

the way of informing patients about painful medical procedures, pain medication or other pain interventions influences patients expectations and thereby the response to the particular intervention
- nocebo effects could be prompted by knowledge of adverse effects + could potentially last for long periods of time

informed consent practices may be inadvertently inducing nocebo effects through the explanation of possible adverse effects related to medication use
- need to balance ethical principles with the possibility of unintentionally triggering nocebo effects

Question 16

what are the 5 contextual aspects of treatments which are related to algesic nocebo effects

Nocebo effects in clinical studies: hints for pain therapy (Klinger, 2017)

Answer 16

1. neg patient-clinician communication: can suppress the complete effectiveness of a treatment
2. patients’ emotional burden while going through treatment: can interfere with the intervention’s pos effects
3. neg info provided via leaflets: neg info can cause a neg effect on mood that leads to decreased willingness to take medication
4. cued and contextual conditioning nocebo effects
5. lack of information: unintentional ‘hidden’ administration of analgesic treatment - open administration is crucial to prevent algesic nocebo effect

Question 17

what are statistical artifcats that can occur in placebo affect research?

Answer 17

assumption that patients in clinical trials under placebo condition improve because they received a placebo → assumption is often unwarranted

patients in placebo groups can improve for several reasons:
1. improvement would have happened without treatment because of natural history of the disease
2. patients tend to enrol in trials when pain is at its worst → improvement with time can be a consequence of regression to mean
3. patients benefit from the pos psychosocial context of being in a study (more medical attention, care, additional social support)

Question 18

3 key findings from studies investigating whether placebo responses reflect altered transmission in pain pathways

Placebo Analgesia (Wager, 2013)

Answer 18

1. reductions in pain-related activity in most brain regions correlated w pain experience
2. placebo treatments cause activation of areas and circuits important for modulation of pain
3. placebo treatments cause activation of the endogenous opioid and dopamine systems

Question 19

placebo effects on brain responses to noxious stimuli

Placebo Analgesia (Wager, 2013)

Answer 19

reduced processing of noxious somatic stimuli found in the brain with placebo treatment - opioid system implicated

decreased processing of noxious stimuli in typical “pain-processing regions,” including the ACC, insula, and medial thalamus
+ reductions in pain-responsive regions of the ventral striatum, amygdala, sensorimotor cortex, S1 and S2

Question 20

placebo effects on spinal nociceptive processes

Placebo Analgesia (Wager, 2013)

Answer 20

• limited direct evidence for spinal inhibition in placebo analgesic effects
• placebo treatment significantly reduced spinal fMRI activity in response to heat

Question 21

mechanisms of placebo analgesia

engagement of the evaluative and visceromotor brain systems

Placebo Analgesia (Wager, 2013)

Answer 21

brain circuits important for creating and maintaining expectations, re-evaluating the significance of noxious stimuli and activating endogenous antinociceptive systems are likely to show increased activity when anticipating and experiencing pain under placebo conditions

consistent increases in placebo conditions are found in: prefrontal cortex, ACC and PAG
* increases in activity correlated with the magnitude of placebo analgesia in reported pain
* these regions form a control circuit that generate expectations of pain relief and alter appraisals of imminent and ongoing pain
* involvement of PAG suggests activation of descending control systems and altered affective-motivational states

Question 22

mechanisms of placebo analgesia

evidence of the relationship between brain activity and analgesia

Placebo Analgesia (Wager, 2013)

Answer 22

• correlations between individual differences in the magnitude of changes in brain activity with placebo analgesia
• both placebo analgesia and pre-scan expectations of analgesia also associated with reduced anticipatory activity in the pgACC
• DLPFC may play a role in establishing the cognitive set that generates placebo analgesia

Question 23

mechanisms of placebo analgesia

neurochemical mechanisms of placebo analgesia

Placebo Analgesia (Wager, 2013)

Answer 23

• evidence of increased opioid system activation associated with placebo effect
• placebo effects can be reversed by opiate antagonist naloxone
• naloxone reversed placebo-related increases in the pgACC, DLPFC, PAG, pons and rostral ventral medulla
• PAG is a major source of opioids in the brain - placebo treatment causes central opioid release