Week 5-Mechanisms of pain relief (incl. placebo and hypnotic analgesia)

Question 1

Why is placebo important? (Enck & Zipfel, 2019)

Answer 1

-Can compare the therapeutic effect of the drug by comparing it to the therapeutic effectiveness of the placebo

Question 2

What is placebo analgesia? (Wager & Atlas, 2015)

Answer 2

 Placebo: an inert medical treatment (pharmacological, fake medical device to convince a therapeutic effect is taking place etc.) that has therapeutic benefit

 The ‘active ingredients’ of placebo effects come from the treatment context (external context = the context in which the treatment is actually given e.g., verbal cues, place cues etc., internal context = the psychological factors which mediates between the external context e.g., emotions, pre-cognitive associations etc.,)

Question 3

Define Placebo analgesic agent

Answer 3

The 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.

Question 4

Define Placebo analgesic effect

Answer 4

The measured difference in pain comparing a placebo-treated group and an untreated group (or between placebo and non-placebo conditions within the same group)

Question 5

Define Placebo analgesic response

Answer 5

An analgesic response in an individual that results from his/her perception of the therapeutic intervention (may be confounded by natural history or spontaneous fluctuations of pain)

Question 6

Placebo confounds: What is its Natural history? (McMahon & Koltzenburg) Give an example

Answer 6

A: A hypothetical painful episode such as an
idiopathic (unknown cause) headache, which starts at a low level and subsides in the absence of treatment.

B: 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 (line b) from that in a no treatment group (line a). The difference (a - b, area 1) is the placebo effect.

 An active analgesic agent produces an even more rapid or complete pain reduction (line c). The difference between placebo and active treatment (b - c, area 2) is the relief due to the active constituent of the treatment.

 This is reason number 1 why we need an untreated control group to study placebo effects

Question 7

Placebo confounds: What is Regression to the mean? (McMahon & Koltzenburg) Give an example

Answer 7

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 (TM).

B: A hypothetical situation in which there is a normal distribution of peak severities around a mean value.

 Central tendency: Because mean values are more common than extreme values (close to no pain or extremely high levels), the most severe episodes are likely to be followed by less intense episodes.

 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.

 This is reason number 2 why we need an untreated control group to study placebo effects.

Question 8

What was found in Vase et al’s (2002) meta-analysis study on the clinical effectiveness of placebos?

Answer 8

■ Placebo is most effective in patients, when it is the main treatment, and when the pain is experimental (rather than clinical).

■ Vase et al. (2002): Separated studies according to whether they specifically investigated placebo mechanisms, or just
studied the placebo arm of a clinical trial.

1. Placebo as main treatment (studies focusing on mechanisms): d = 0.95 (very strong)
2. Placebo as control group: effect size d = 0.15 (weak)

Question 9

What was found in Forsberg et al’s (2017) meta-analysis study on the clinical effectiveness of placebos?

Answer 9

Compared effect sizes for patients (experimental pain and clinical pain) and healthy volunteers (experimental pain).

1. Healthy volunteers: d = 1.24
2. Patients: d = 1.49

■ In patients, also compared:
1. Experimentally induced pain: d = 1.73
2. Clinical pain: d = 1.05

Question 10

Are placebos used often? (Fassler et al., 2010)

Answer 10

■ Common examples:
– Plaster for a headache
– Antibiotics for flu

From twenty-two studies from 12 different countries investigating placebo use:
– Between 17% and 80% among physicians and between 51% and 100% among nurses have admitted giving placebos (until 2009)

– The most common placebo cited was
the use of antibiotics (43%) followed by
vitamins (23%) and herbal supplements
(12%). Pure placebos were infrequently used

Question 11

Can placebo be used as a treatment? (Klinger et al., 2014)

Answer 11

■ Conventional view: Placebo on it’s own cannot be considered as a substitute for the real physiological treatment; patients must be treated actively.

■ But, using the knowledge of placebo effects in helping patients is ethical

■ So, we need to understand what causes placebo effects

Question 12

What are the Key learning points of Placebo effects?

Answer 12

■ The ‘active ingredients’ of placebo effects come from the treatment context.

■ The placebo analgesic effect can only be measured by comparison to an untreated control group

■ Placebo effects in clinical trials are strong and more effective in patients with clinical pain symptoms

■ Placebos can work even if the patient is aware it is a placebo

Question 13

What are the main 2 components on how placebo analgesia works?

Answer 13

1. Conditioning (i.e., aspects of the external context)
2. Expectancy (i.e., aspects of the internal context)

Stewart-Williams & Podd (2004):
Unconscious conditioning can cause conscious expectation = Conditioning is the learning of unconscious expectations (i.e., 2 sides of the same coin)

Question 14

What is Conditioning Theory?

Answer 14

 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) tested subjects in three conditions:
1. Pre-test: Painful stimuli
2. Conditioning: Inert cream applied, Pain turned down
3. Post-test: Pain turned up (without the participant knowing)

 The conditioning group compared to the control subjects (no conditioning) showed reduced pain at post-test.

Question 15

Conditioning: How does exposure to pain relief affect the placebo effect? (Colloca et al., 2010)

Answer 15

-During the conditioning phase, when someone was about to feel a high intensity pain stimulus, a red light would flash, medium was yellow and light was green (people learnt through association).

-During the testing phase the light colours were the same, but it was always medium intensity pain stimuli.

-If there were 10 reinforcements (i.e., red is high pain), people reported higher levels of pain in the testing phase. If there were 40, the effect was much larger. The more times you associate an aspect of the external context, the bigger the pain relief effect (In favour for conditioning as a mechanism for placebo analgesia).

Question 16

Conditioning: What was found about continuous and partial reinforcement? (Au et al., 2014)

Answer 16

 Subjects told that effects of TENS on pain
will be tested

 TENS never switched on but signaled by a
tone or vibration

 Conditioning achieved by surreptitious
reduction of pain during conditioning

3 regimes:
 A: continuous 100%
 B: partial 62%
 C: control (0%)

Question 17

Role of social cues: the doctor

Answer 17

-Non-verbal social cues were studied
by Gracely et al. (Lancet, 5: 43, 1985). In
clinical settings, doctors were informed that the pill was a placebo or a likely painkiller (placebo or painkiller).

-The patients were always given placebo

Group 1: doctor told placebo, patient given placebo = no pain relief outcome

Group 2: doctor told placebo or painkiller, patient given placebo = pain relief outcome

Question 18

Role of social cues: vicarious learning (Colloca et al., 2009)

Answer 18

Group 1: viewed other person undergoing the experiment; no physical conditioning

Group 2: conditioning: stimulus intensity
reduced surreptitiously on green lights

Question 19

What’s Response/outcome expectancy theory?

Answer 19

■ 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, 1997)

■ However, more recent work in patients with IBS shows that placebo analgesia can survive disclosure (Kaptchuk et al., PLoS One, 2010)

■ Placebo analgesia may be getting more potent over time but only in the USA!
-Results from RCTs of drugs for neuropathic pain (Tuttle et al., 2015)
– Possibly due to greater public knowledge of placebo efficacy

Question 20

What’s the Evidence for expectancy theory:
Open vs. hidden treatment

Answer 20

 A hidden injection of morphine (6-8mg) yielded analgesia that was equal to an open injection of saline with suggestion that the injection will relieve pain. Expectation is as strong as morphine! (Levine et al., 1981)

 Administration of four common analgesics (tramadol, ketorolac, metamizol, buprenorphine) in the form of open or hidden administration (intravenous infusions) (Amanzio et al., 2001)

Question 21

Placebo analgesia: What are the effects on pain processing? (Wager & Fields, 2013)

Answer 21

Decreases in brain activation:
 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

Increases in brain activation and opioids:
-Consistent changes in dorsal pons, subgenual anterior cingulate cortex,
nucleus accumbens, hypothalamus, and
periaqueductal gray (PAG)

Question 22

The placebo analgesic effect: What evidence is there for Opioid-dependency?

Answer 22

-Naloxone abolished placebo analgesia

■ Naloxone is an opioid antagonist (blocks the action of opioids)

■ Reverses placebo analgesia (Levine
et al., 1978)

■ Figure: effect on pain from tourniquette ischaemia (Benedetti et al., 1996)

■ Suggests the role of endogenous opioid peptides in placebo analgesia

Question 23

Descending nociceptive control: endogenous opioids (Tracey & Mantyh, 2007)

Answer 23

 How much analgesia to apply?
Periaqueductal gray matter (PAG)

 Execution: Rostroventromedial medulla (RVM), dorsolateral pontine tegmentum (DLPT)

Evidence?
 Electrical stimulation of PAG/RVM causes suppression of behavioural response to pain (Reynolds, 1969)

 Microinjections of morphine – (long u shape)- opioid receptor agonist has the same tantinociceptive effect

Question 24

What evidence is there that Placebo analgesia attenuates spinal cord
nociception?

Answer 24

 Eippert et al. (Science, 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 heat was combined with the cream
labeled “Lidocaine” than with “neutral”.

 Spinal cord activation to the pain was reduced.

Question 25

How can you boost placebo effects, ethically? (Klinger et al., 2014)

Answer 25

■ Boost expectancy of pain relief
– Apply analgesics in open manner
– Turn patients’ attention towards the drug itself (multisensory)
– Inform patients about positive effects of placebo, and effects of placebo on brain (educate the patient; but also educate the doctor!)
– Knowledge of placebo will boost patients’ self-management capacity
– Mention the value and cost of treatment to the patient
– Reduce negative expectancies (avoid stressing negative effects)

■ Facilitate learning / conditioning
– Accumulate pain relief experience (number of reinforcements!)
– Intermittent application of a real drug allows a better use of placebo effect
– Use social cues, such as observing another patient benefiting

Question 26

What are the Key learning points about Placebo Mechanisms?

Answer 26

■ Aspects of external context such as treatment cues and social cues drive conditioning effects

■ Other aspects of external context such as verbal suggestions drive expectancy effects

■ Placebo attenuates brain and spinal nociception via the release of endogenous opioids

■ It is possible (and ethical) to boost these
mechanisms to improve the effectiveness of real treatments

Question 27

What is hypnosis? (Kihlstrom, 1985)

Answer 27

“A social interaction in which one person,
designated the subject, responds to suggestions offered by another person,
designated the hypnotist, for experiences involving alterations in perception, memory, and voluntary action.”

Question 28

What causes hypnotic responses? (Landry et al., 2017)

Answer 28

1. Hypnotic Susceptibility
2. Hypnotic Induction
3. Hypnotic Suggestion

Question 29

What’s the method of hypnosis?

Answer 29

1. Induction:
   – Requires a relaxed state
   – Attracts and narrows the attention of the patient
   – Decreases awareness of surroundings
   – Decreases monitoring and censorship of thoughts and feelings
   – Increases automaticity and receptivity
2. Hypnotic/post-hypnotic suggestion:
   – Interim (short-term) suggestions
   ■ Effects over minutes/hours
   – Extended post-hypnotic suggestions
   ■ Effects over days/weeks
   ■ E.g. suggestion that benefits will continue; use of a cue to self-hypnotise.

Question 30

What’s the model of hypnotic induction? (McMahon & Koltzenburg, 2006)

Answer 30

Experiential model of hypnosis
 Positive (+) and negative (-) functional interactions are proposed
 Full lines represent relations that have been confirmed statistically in groups of naive subjects.

Question 31

Give examples of Hypnotic Suggestions to alleviate pain (Elkins et al., 2012)

Answer 31

Dissociated imagery - disconnection from the body (e.g. imagination of floating out of the body, instruction of not to feel painful body part)

Focused analgesia - replacement of pain with other sensation such as pressure, cold, warmth, or as if the hand would be placed in a glove.

Analgesia/Anaesthesia – suggestions to decrease the pain and increase the level of comfort
“… notice the feeling as the area becomes numb …. Let the numb feeling transfer from
the hand to the back…”

Safe place imagery – to achieve a comfortable feeling of safety and to reduce the tensions related to pain
“… and this place is so absorbing, and interesting … and so comfortable, that you hardly notice any other sensation…”

Question 32

Does hypnosis work for acute
(procedural) pain? Review: Stoelb et al., (2009)

Answer 32

■ Hypnosis research for acute pain focuses mainly on pain related to scheduled medical procedures (procedural pain) or labour/childbirth.
■ Prior reviews involving about 20 studies included conditions such as:
– Burn wound dressing change and debridement
– Labour pain
– Bone marrow aspiration
– Invasive surgical procedures, e.g., angioplasty or arteriograms
-Chemotherapy

Conclusions - hypnosis consistently resulted
in:
* Significant reductions in pain.
* Decreased anxiety.
* Shorter hospital stays.
* Reduced duration of Stage 1 labour in
childbirth.
Reducing acute pain may speed up wound
healing due to decreased physiological

Question 33

What are the Factors affecting response to hypnotic analgesia for acute pain? (Stoelb et al., 2009)

Answer 33

■ Hypnotic suggestibility often linked to positive hypnosis outcomes but not always. Even patients with ‘low’ hypnotisability can benefit from hypnosis.

■ Perceived control over pain and treatment outcome expectancy have been positively linked with treatment outcomes.

■ Severe acute pain might increase motivation for hypnotic analgesia treatment, potentially boosting the
effectiveness

■ Therapist skill not found to be a significant factor. Also, a critique of the hypnosis literature is the lack of accounting for non-specific factors like therapist
attention or collaboration.

Question 34

Does hypnosis work for chronic pain? (Review: Dillworth & Jensen, 2010)

Answer 34

 Examined about 25 well-controlled clinical
trials

 Studies analysed effects of hypnosis on pain and related outcomes in a variety of pain syndromes

 Studies usually compared hypnosis with no-treatment, standard treatment or active
treatment (e.g. progressive relaxation)

 Conclusions from review:
– hypnotic treatment is always better in terms of pain reduction and other outcomes (e.g., drug consumption) than
no treatment or standard treatment (showing support)

– hypnosis with pain-specific and pain-nonspecific suggestions gives comparable results as other active treatments having
hypnotic components (progr. muscle relax., biofeedback)

– the use of post-hypnotic suggestion increases impact of hypnotic treatment

Question 35

What are the advantages of hypnotic analgesia?

Answer 35

 Multiple outcomes positively affected: pain, anxiety, sleep, reduced analgesia

 Long-term effects, on a scale of months

 Boosts effects of other types of therapies

 Can be effective when other treatment has failed

Question 36

What are the disadvantages of hypnotic analgesia?

Answer 36

 Not everyone can be hypnotised

 Requires individual approach

 Demands on skilled therapists

Question 37

What’s the importance of suggestion in
Temporomandibular disorders (TMD)? (Abrahamsen et al., 2009)

Answer 37

Effect of hypnosis on pain and oral
function in temporomandibular disorders patients.
 Randomized control trial in 40 females with temporomandibular disorder (TMD).

 Participants were randomly assigned to
either four 1-hour sessions of hypnosis or
four 1-hour sessions of relaxation.

Participants in both conditions were given
audio recordings for home practice.
1. Hypnosis condition:
■ Induction: progressive muscle
relaxation followed by guided imagery
■ Hypnotic suggestions (see text box)

2. Relaxation condition:
   ■ Induction step only.

Hypnotic suggestions used:
* Generic suggestions for experiencing feelings of success, calm, peace of mind, inner strength

• Pain relief suggestions through metaphor (e.g., changing the colour of pain) and substitution (e.g., changing pain with
  warmth), create feelings of anaesthesia.
• Post-hypnotic suggestions, including the suggestion to use pain as a cue to become occupied with good memories and using the experience of muscle tension as a cue to relax.

■ Results: effects on pain
– Hypnosis decreased pain intensity relative to the relaxation group
– No change in medication use was shown for either treatment condition,
– Hypnotisability was not found to predict outcome for either group

Question 38

What’s Hypnotic suggestion, with and without hypnotic induction, in fibromyalgia? (Derbyshire et al., 2009)

Answer 38

■ Suggestion can modulate chronic pain even without induction, but induction boosts the effect

■ Patients claimed significantly more control over their pain and reported greater pain reduction when hypnotised

■ Activation of the “pain matrix” correlated with reported changes in pain in both cases, with stronger effects under induction

Question 39

What is the Hypothetical model of descending analgesic effects during hypnosis? (Price & Rainville, 2006)

Answer 39

■ Nociceptive afferents activate spinal nociceptive reflexes as well as ascending neurons projecting to various areas of
the brain.

■ Descending projections modulate nociceptive processes in the brain stem
and the spinal cord
– Two distinct descending pathways to spinal cord

■ Hypnosis may affect the output of autonomic nuclei of the brain stem – could modulate spinal nociceptive motor
reflexes.

Question 40

What evidence is there for Hypnotic suppression of spinal nociception?

Answer 40

■ Kiernan et al. Pain, (1995) applied painful electrical stimuli to the foot and measured the EMG amplitude during reflexive
flexion of the leg (RIII reflex).

■ Stimuli were applied during:
1. hypnotic state
2. baseline waking
3. voluntary attempt to suppress pain
■ The RIII reflex was significantly smaller during hypnotic state compared to other two conditions

-RVM-PAG pathway? Naloxone abolished the placebo effect but not hypnosis-induced analgesia (Goldstein and Hilgard, 1975)

Question 41

What are the Key Learning points about Hypnosis?

Answer 41

■ Hypnotic suggestion has benefits for chronic pain beyond induction

■ Likewise, hypnotic induction has benefits for chronic pain beyond suggestion

■ Hypnosis may modulate spinal activity in a similar way to placebo, but involve additional non-opioid pathways.

Question 42

Isn’t hypnotic analgesia just a
placebo effect? What are the arguments for and against?

Answer 42

Arguments for:
1. Hypnosis has been described as “placebo without deception” (Raz, 2007)
2. “Suggestion” in hypnosis is designed to change expectations of analgesia – similar to placebo
3. Placebo and hypnosis both modulate pain via similar brain regions and via descending inhibition.

Arguments against:
1. Hypnotic induction is qualitatively different from expectation, yet increases the impact of suggestions designed to change expectations
2. Hypnotisability affects only hypnotic-induced analgesia but not placebo analgesia.
3. Hypnotic analgesia is not opioid-dependent (Goldstein & Hilgard, 1975)

Question 43

What evidence is there to show Hypnotic analgesia affects similar brain regions to placebo analgesia?

Answer 43

 Overlaps with placebo changes in ACC

-Hypnotically induced changes in pain unpleasantness are encoded in the mid-cingulate cortex (Rainville et al., 1997)

Question 44

What evidence is there for Hypnotic suggestion, with and without
hypnotic induction, in fibromyalgia? (Derbyshire et al., 2009)

Answer 44

■ Suggestion can modulate chronic pain even without induction, but induction boosts the effect

■ Patients claimed significantly more control over their pain and reported greater pain reduction when hypnotised

■ Activation of the “pain matrix” correlated with reported changes in pain in both cases, with stronger effects under induction

Question 45

What are the Key learning points: Hypnosis vs. placebo mechanisms?

Answer 45

■ Likely to be some overlap between hypnosis mechanisms and placebo
mechanisms

– Not least because ALL treatments have a “non-specific” (i.e. placebo) component in that patients will always have an expectation about the treatment outcome

– Endogenous opioids may be involved in both, although hypnotic analgesia is less dependent on this pathway.

– Overlap in brain regions affected – but this is not in itself very good evidence for shared mechanisms

■ Hypnosis uniquely involves an induction procedure, which might explain some
physiological differences (e.g. less opioid dependency), and boosts the effect of
suggestion.