Week 3-Pain Assessment and Sex & Gender Differences in Pain

Question 1

What are some reasons for needing a Pain Assessment?

Answer 1

• Therapeutic decisions (i.e., clinically)
• Progress of therapy check
• Evaluation of effects of different treatments e.g., clinical trial to evaluate efficacy of drugs (looks as a group)
• Individualised pain therapy: phenotype of patients e.g., neuropathy with/without pain (looks as an individual)
• Insurance, compensation claims, legal issues
• To identify the presence of pain in vulnerable people, such as people with communication disorders

Question 2

What are some possible markers of pain?

Answer 2

• Self-reports (incl. McGill Pain Questionnaire)
• Behavioural measures (pain behaviour, facial expressions)
• Brain and autonomic changes
• Pain thresholds (i.e., when can that person feel that pain)

Question 3

Define Pain Threshold (PT)

Answer 3

The minimum amount of stimulation that
reliably evokes a report of pain.

Question 4

Define Pain Tolerance Threshold (PTT)

Answer 4

The time that a continuous stimulus is endured, OR the maximum tolerated intensity is endured (ethically more appropriate to do research-wise)

Question 5

What are some of the Pain Threshold Methods?

Answer 5

1. Method of Limits (classical): series of ascending level and descending level stimuli of pain (P knows what level is next = expectation effects)
2. Method of Limits (Marstock’s modification for thermal pain): same as 1. but done through temperature
3. Method of Adjustment: tune the stimulus intensity to painful level (show on screen to let P’s screen up and down)
4. Method of Constant Stimuli: stimuli of fixed intensity are presented in random order (to reduce expectation effects)

Question 6

What are the Advantages of the Pain Threshold Methods?

Answer 6

1. Simple to administer
2. Pain expressed in physical units (gives us something numerical)

Question 7

What are the Disadvantages of the Pain Threshold Methods?

Answer 7

1. Not suitable for clinical pain (asking someone to detect the lowest level of pain is not the same as chronic pain)
2. Depends on reaction time (ask lecturer)
3. Response bias: “stoic” style of responding

Question 8

Pain Tolerance: What are some suprathreshold measures?

Answer 8

Measures the amount of time for which the pain was endured (suprathreshold=above the pain tolerance level)

1. Cold pressor test: T[s] to endure cold pain when hand dunked in ice bath
2. Tourniquet ischaemia: T[s] to endure ischemic pain, can use a standard blood pressure cuff used for bp readings

Question 9

Quantitative sensory testing: What are the different types of fibres?

Answer 9

The German Research Network on Neuropathic Pain (DFNS):
* Warm threshold
* Cold threshold
* Heat pain threshold
* Cold pain threshold
* Vibration threshold

-Test different fibres (as seen above)

Question 10

What are the Advantages of Quantitative sensory testing? (DFNS)

Answer 10

1. Diagnostic value (can detect neuropathic and non-neuropathic pain)
2. Phenotyping patients based on QST profiles (e.g., normal warm threshold but above average vibration threshold)
3. Can be compared to standardised reference data from various populations (Magerl et al., 2010)

Question 11

What is a Disadvantage of Quantitative sensory testing?

Answer 11

Does not measure spontaneous background pain (i.e., ongoing fluctuating pain which is what happens with chronic pain patients)

Question 12

Self-report instruments: Name some response-dependent measures (i.e., not everyone can communicate this information)

Answer 12

• Categorical scale ([no - yes], [no - mild - strong])
• Verbal scales
• Numerical scales
• Visual analogue scales
• Combined verbal-numeric instruments

Question 13

What are Numerical Rating Scales?

Answer 13

• Ordinal scale: a number is assigned to a pain
• Simple to use, suits well for rapidly changing pain, sensitive to pain intensity
• Good reliability: (+0.7 test-retest, Kahl & Cleland; 2005)
• BUT…The boundaries between categories (levels) are not known and are only assumed to be equal (i.e., the difference between 1 and 2)
• Tendency towards stereotyped responses

Question 14

What is Direct magnitude scaling (visual analogue scale, VAS)?

Answer 14

• Ratio scales, pain is represented as a continuum that is matched with some other modality (from no pain to worst possible pain)
• Subjects are given a reference continuum (intensity of sound, light, length of line) e.g., the sensory usage is meant to represent the level of pain to make it easier for individuals to express their pain levels
• The position of reported pain is proportional to the pain continuum

Question 15

What are the Advantages of VAS?

Answer 15

1. True ratio-based scale (can say because it is a continuum that the boundaries between numbers are equal e.g., 4 & 5, 9 & 10)
2. Easy to administer and score
3. Sensitive to variations of pain due to therapy interventions
4. Good reliability: (~0.7 test-retest, Kahl & Cleland; 2005)

Question 16

What are the Disadvantages of VAS?

Answer 16

1. Unidimensional (all you get is one report)
2. Some patients do not understand the scale
3. Subject to bias (e.g. tendency to not use the full range of the scale i.e., not using the extreme ends)

Question 17

What is The McGill Pain Questionnaire
(Melzack, 1975)?

Answer 17

-78 pain words organised into 20 categories (i.e., multidimensional)

-Present Pain Intensity (numerical)

-Location of pain

Question 18

MPQ: describe the measures within the questionnaire

Answer 18

• PRI = pain rating index (rank values of the words)
  – Sensory dimension: categories 1-10
  – Affective dimension: categories 11-15
  – Evaluative: category 16
  – Miscellaneous: categories 17-20
• Present Pain Intensity (0 – 5) Good reliability: (+0.7 test-retest, Kahl & Cleland; 2005)
• Can capture multiple dimensions (Kahl & Cleland; 2005) HOWEVER takes a long time (15 minutes typically which is a rare slot to have in the hospital)
• The number of words chosen

Question 19

What is the Short-form McGill Pain Questionnaire (Melzack, 1987)?

Answer 19

• 15 more representative words (11 from sensory and 4 from affective categories)
• Takes <1 min to fill
• More ideal in clinical settings to use

Question 20

What are Behavioural Assessment Methods?

Answer 20

Pain manifests in behavioural changes (acquiring help, giving a sign of warning)

Pain behavior: any behaviour informing that pain is being experienced (Fordyce, 1976)

Behavioural analysis is important because:
* It helps to pinpoint the pain problem
* It enables to set the baseline level of behaviour against which the effects of treatment will be compared
* It predicts the patient’s response to therapy

Question 21

Name some types of Pain Behaviour?

Answer 21

• Facial expressions
• Verbal pain statements
• Reduced social interactions
• Use of support (cane or walker)
• Guarding = cradling sore limb, interrupted movements
• Rubbing sore limb
• Avoiding the use of a limb where otherwise appropriate
• Bracing = pain-avoidant, stiff posturing (i.e., holding themselves to prepare and prevent pain)

Question 22

What are some Observation Methods (Keefe et al., 1992; 2001)?

Answer 22

Continuous observation of the whole behaviour in a variety of situations

Different scientific measures of pain behaviours:
1. Duration measure: time spent demonstrating behaviour
2. Frequency counts: number of instances of each target behaviour

Reliability outcome if well-trained:
Inter-observer reliability : r = ~ 0.8
Test-retest reliability : r = 0.5 - 0.7

Question 23

What are some Advantages of Behavioural Methods? (Ask lecturer what classes as BMs)

Answer 23

• Useful to identify important features of pain
• Can be recognised in natural settings
• Unbiased (in terms of the patient)

Question 24

What are some Disadvantages of Behavioural Methods? (Ask lecturer what classes as BMs)

Answer 24

• Time-consuming
• Observer training needed
• Ethics - complement rather than replace the self-report instruments

Question 25

What are the Facial Expressions of Pain (Charles Darwin, 1872)? (Some of the slide cut off check rest of info on slides in lecture)

Answer 25

• Facial pain expressions: patterns of
  facial activity modified by social and family
  influences (i.e., to illicit a social response)
• Less dependent on subject’s willingness
  to admit pain
• Not confound by labels or abstract concepts (e.g., numerical scale, “excruciating pain”) Therefore > inclusivity (ask lecturer what this means?)

Question 26

How is the Facial Expression of Pain measured in adults nowadays?

Answer 26

• Facial Action Coding System (Ekman
  and Friesen, 1978) is used to measure
  Action Units (small movements of facial
  structures) in an objective manner.
• New methods (e.g., Machine learning)
  utilize FACS to evaluate pain or emotional representations in facial expressions

Question 27

Give examples of FACS- Facial expressions of pain in adults

Answer 27

• Brow lowering
• Narrowing of the eye orbit
• Raising the cheek
• Eyes closed or blinking
• Raising the upper lip
• Parting the lips or dropping the jaw

Question 28

Why are Pain Assessments important?

Answer 28

Prevalent clinical conditions represent risk of self-unreported pain suffering:
1. Immaturity: Infants, toddlers, preschool children

2. Disability: Down’s syndrome, Dementia
3. Temporary or permanent restriction of
   consciousness: general anesthesia, intoxication, sedatives, disturbances of consciousness
4. Inability to communicate: language deficits, mutism, (non-verbal) ASD

Question 29

What is the Disturbances of Consciousness (DoC)?

Answer 29

• Unresponsive wakeful state. A state of partial arousal without self-awareness (eyes track moving objects, swallowing, smiling, grunting, moaning in absence of external stimuli)
• Common causes: traumatic brain injury, neurodegenerative disorder, and congenital abnormities of the brain

-Therefore they might be in huge amounts of pain that cannot be told

– Can be classified according to duration, Persistent/Permanent

Question 30

What is the Nociceptive Coma Scale (Schnacker et al., 2010)?

Answer 30

-Used to counteract issues with DoC

-Brief evaluation (1-2 min) of patient’s
behaviour at rest or during nociceptive
stimulation (Chatelle et al., 2012)

-They administer stimulation to the patient to see any motor, visual, facial and verbal responses

-Sub-threshold mechanical threshold (tapping) shows the same to rest in healthy control but pain was seen in both healthy control and coma patients (Chatelle et al., 2012)

Question 31

What are the Consequences of a Poor Pain Assessment for those who are unable to communicate?

Answer 31

• Risk of under-assessment and under-treatment
  – people with cognitive deficits receive less medication (Kaasalainen, 1998)
• Risk of overtreatment if the level of pain is overestimated
  – Side effects of opioids include slowing of bowel motility – obstructions.
  – Death due to intestinal obstruction 34x more frequent in people with intellectual disabilities (Roy and Simons, 1987)
• Untreated pain in people who are unable to communicate pain may worsen their cognitive abilities and executive functions

Question 32

What are the adapting existing methods of
assessment for vulnerable groups?

Answer 32

• About 35% of people with cognitive deficits cannot understand the question when aiming for self-reports of pain
• Simplified scales, adapted from those assigned for children can help in acquiring self-reports persons with communication
  disorders or impaired cognitive capabilities

Example: Wong-Baker (1998, PsycTEST) ‘FACES Scale’ for children (+3 yrs) where no pain has a happy face but progressively the face gets sadder as the pain level increases

Question 33

What’s involved in the Behaviour Observations for clinically vulerable
groups?

Answer 33

Behavioural methods offer a potential method to evaluate pain. Identifying units of pain behaviour using validated observational scales:

-PACSLAC, DOLOPLUS: specialised observation scales to assess pain in patients
with dementia

-DEPS: Dalhousie Everyday Pain Scale (Fearon et al., Pain, 68: 55-62, 1996) is a
short instrument enabling collection of reports from caregivers about intensity of
distress, anger, protective behaviours, and social response.

-FACS: Facial action coding scale (e.g. LaChapelle et al., 1999)

-There are shared units among various observation scales (i.e., similar observation types like facial expressions, body movements etc., (Hadjistavropoulos et al., 2014)

Question 34

What are some Recommendations for pain assessment and pain management in non-verbal people (Booker et al., 2016)?

Answer 34

• Facilitate self-reports in those patients who can respond non-verbally (nodding, eye blinks)
• Identify sources of pain and evidence (leads, tubes, monitoring devices), and check if a patient had a pre-existing pain condition
• Consult any symptoms of pain and changes in mood with a family members, caregivers, and other health-care professionals
• Observe indicators of pain (facial, mood, movements, behavioural scales useful)
• If clear signs of pain present, initiate an analgesic trial (e.g., analgesic drugs)
• If the analgesic trial confirmed pain being present, a collaborative pain treatment plan should be designed

Question 35

What are some non-invasive objective measures of pain that could be used in the future?

Answer 35

• We are working on methods to integrate machine learning analyses of EEG data to predict subjective pain experience.
• Mari et al (Sci Rep; 2023) achieve ~70% accuracy of binary classification of high pain, versus low pain experimental pain stimuli in healthy people
• Some clinical potential for vulnerable groups (not there yet!)

Question 36

How does the definition of Sex and Gender differ? (Canadian Institute of Health Research, 2022)

Answer 36

“Sex is often associated with biological factors, such as genetics, sex hormones, and physiology, and usually involves comparisons between men and women. Conversely, gender is associated with
psychological and sociocultural factors, such as beliefs, expectations, and stereotypes, and how men and women behave and interact with one another. Binary categories are commonly used (e.g.,
male/female, man/woman, and boy/girl), although gender is not constrained to this and encompasses broader aspects”

Question 37

Give an example of Experimental Pain (Chesterton et al., 2003)

Answer 37

-Analysed sex differences in pressure pain threshold (pressure on the interossei muscles - back of hand).

-Pain threshold differences were stable over one-hour period

-Males typically require higher levels of pressure before they report pain compared to females (and these differences are consistent when repeated with the same P’s)

Question 38

What was found in a Meta-Analysis of Experimental Pain?

Answer 38

Females pain thresholds lower, pain endurance shorter compared to males.

Riley et al. (1998):
* Meta-analysis of 21 studies analysing differences between females and males in
experimental pain threshold and pain tolerance.

• Largest differences in pain thresholds and pain tolerance for electrical and pressure
  stimulation: males showed higher thresholds than females.
• The mean effect size over different types of stimuli was 0.55 and 0.57 for pain
  threshold and pain tolerance, respectively.
• Authors calculated sample sizes required for these size effects; the groups should
  count at least 41 subjects each. Thus, early studies that have not reported statistically significant differences might suffer from low power.
• N.B.: Greenspan and Taub (2013) performed a similar calculation including newer studies and raised the recommended cohort sizes to 49 subjects

Question 39

What was found in Racine et al’ s review (1998-2008) of sex differences in experimental pain?

Answer 39

Racine et al. (2012 Part 1) analysed 172 papers on sex differences in experimental pain over a 10 year period with a systematic literature review

Pain threshold, pain tolerance, pain intensity:
* no consistent differences in pain intensity (do we agree with them?) or pain thresholds in various pain modalities
* pain tolerance was greater in males than females for cold (in 81% of studies), heat
(80%), and pressure pain (86%)
* Many studies had low statistical power

Question 40

True or False: A number of studies show greater or smaller pain thresholds and
pain tolerance thresholds in males and females (Mogil, 2012)

Answer 40

True!

• Re-analysis of 122 studies originally reviewed by Racine et al. (2012).
• The number of studies showing increased pain threshold and pain tolerance in males
  compared to females is much larger than for a reverse direction.

-Females are more sensitive in terms of their PT & PTT

Question 41

True or False: A 4.8 times greater proportion of females than males among
10% of pain most sensitive people (Greenspan and Taub, 2013)

Answer 41

True!

-Data on pain sensitivity were derived from the large scale OPPERA study (+4000 P’s)
which considered males and females.

-Among the most sensitive 10%, 83% of women were most sensitive to pressure pain

Question 42

What Biological Factors can explain why we perceive pain differently?

Answer 42

■ Endogenous pain mechanisms

■ Hormones

■ Brain (central nervous) perception differences

■ CAVEAT - many other factors (skin dermis thickness differences, nerve innervation, diet and lifestyle etc.,)

Question 43

What is the conditioned pain modulation test?

Answer 43

• A painful conditioning stimulus (e.g., water of 1 ̊C) in one loci will attenuate the pain
  associated with the test stimulus in another
  location.
• A non-painful conditioning stimulus (e.g., water of 30 ̊C) will not attenuate the pain associated with the test stimulus on opposite hand.
• The drop in pain ratings to the test stimulus under a painful and non-painful conditioning stimulus is the measure of conditioned pain modulation.
• Conditioned pain modulation activates the
  endogenous opioid system and inhibitory
  synapses in dorsal horn neurons in the spinal cord (meaning you will feel less pain from the pain stimulus)

-Test stimulus is a brief painful stimuli applied to a different limb (in this image the
left hand), e.g. laser heat, pressure, electrical current. Participant rates the pain of this stimuli.

-Conditioning stimulus is the cold pressor test applied here to right hand.

Question 44

What are the Sex Differences in conditioned pain modulation (Popescu et al., 2010; Zubieta, 2002)?

Answer 44

• Popescu et al. (2010) reviewed 17 studies comparing effects of pain modulation in males and females
  – Males showed stronger inhibitory control of pain intensity in most studies
• Zubieta (2002) Males activate m-opioid receptors during pain more strongly
  than females

Question 45

What’s the link between hormones and pain?

Answer 45

• Contraceptive pill artificially elevates levels of oestrogen and progesterone in females.
• Meta-analyses indicate no convincing data on differences in experimental pain sensitivity in females taking or not taking
  oral contraceptives (Racine et al., 2012/2; Greenspan and Taub, 2013)
• Hormonal replacement therapy (HRT) in menopausal period:
  – reduced experimental pain (increased thresholds and decreases sensitivity) in females receiving HRT than those not receiving (Racine et al., 2012/P2)

Question 46

What’s the link between the Menstrual Cycle and Pain?

Answer 46

• Meta-analysis of 19 pain studies (Riley et al., 1999):
• Pain thresholds for pressure, and cold pain were greater in the follicular than in the luteal phase (but this is a small-to-moderate effect).
• Pain modality specific? Painful electrical stimulation yielded contradictory results

Question 47

What are the Menstrual cycle (MC) effects on CPM?

Answer 47

• 0 of 12 studies performed between 1998-2008 reported significant effect of MC on pain thresholds (Racine et al., 2012/2)
• MC effects on conditioned pain modulation (Rezaii et al., J. Pain, 2012)
  suggest greater pain inhibition during ovulation period (so individual phases do have an impact but further research needed)
• Pressure pulses (test stimuli) to masseter muscle during concurrent cold pressor (conditioned stimulus) pain in contralateral arm in 3 periods of MC (early follicular, ovulatory, mid-luteal)
• No effects of MC on cold pressor test – MC appears to modulate only the pain modulation mechanism.

Question 48

What are the painful brain activation differences in males and females?

Answer 48

-Straube (HBM, 2009) applied painful electrical stimuli to the dorsum of the
hand in males and females.

-Females had greater activation in the medial pre-frontal cortex –related to
pain anticipation.

-Males showed more activation in anterior insula (more sensory regions).

Question 49

What are the Brain Activation Sex Differences (Greenspan and Taub, 2013)?

Answer 49

• Greenspan and Taub (2013) summarised results of 11 brain imaging studies in experimental pain
• Variable patterns of activations across studies, with perhaps only the insula consistently yielding greater activation during painful stimulation in males than females (in line with Straube)
• A methodological problem: stimulus intensity was matched to be subjectively identical in males and females in some (but not all) studies

Question 50

What are the Clinical Pain Sex Differences?

Answer 50

Females compared to males:
1. have greater prevalence of chronic pain syndromes.

2. experience more intense pain for comparable pathology (e.g. injury, surgery).
3. show stronger analgesic effects following administration of opioids (showing therapeutic differences)

Question 51

What is the prevalence of Chronic Pain Syndromes? (Fillingim et al., 2009)

Answer 51

• There are types of pain which do not show sex differences, e.g., cancer pain

-Population studies across countries show a greater prevalence of chronic pain in females compared to males

Question 52

What is the Preponderance of chronic pain syndromes in females?

Answer 52

-Excess prevalence in females broken down by chronic pain type: Mogil (2012) (supports the idea that women experience chronic pain conditions more than males)

-However males had a greater prevalence of back pain compared to females.

Question 53

True or False: Stronger post-operative pain is seen more in females than males

Answer 53

True!

• Tighe et al. (2014) analysed sex
  differences in post-operative pain by
  collecting numerical rating scales (0-10)
  from 330,000 patients in Florida over one
  year.
• Serious surgeries: amputations, cardio-
  thoracic, orthopedic.
• Measured numerical pain rating scores.
  From day 1 to 5 post-operatively.
• Females had consistently greater scores
  than males e.g., day 5: statistically significant difference (mean score 4.1 for
  females and 3.74 for males)

Question 54

What was found in the Meta-analysis of opioid analgesia in males and females in experimental pain? (Niesters et al., 2010)

Answer 54

-Morphine induces greater opioid analgesia in females than males in experimental
pain

-This was studies looking at acute experimental pain

Question 55

How does opioid use for clinical pain relief differ regarding the sexes? (Chia et al., 2002)

Answer 55

-Chia et al. (2002) analysed consumption of
morphine in patient-controlled analgesia.

-2298 patients undergoing abdominal,
chest or limb surgery. Consumption of opioids was screened from 12 to 72 hours post-operation.

-Males self-administered higher doses (even accounting for weight).

-Campesi et al. (2012): Results are because females require less opioids than males to reach comparable level of analgesia.

Question 56

What was found in the Meta-analysis of opioid analgesia in males and females in acute pain? (Niesters et al., 2010)

Answer 56

Patient-controlled analgesia shows reduced morphine doses in females than males (probably a difference in the analgesic effects of opioids between the sexes as these results are shown despite females experiencing higher levels of pain)

Question 57

What’s the evidence for problematic opioid usage?

Answer 57

• Serrdarevic (2017) evaluated gender studies of opioid use (8 total) and data from +8000 people in a health engagement program in USA.
• Half reported use of prescription
  opioids
• USA gender prevalence review of
  studies: Women are more likely to
  use prescription opioids compared to
  men (despite a lower dosage, it seems there is a higher responsiveness to opioids in women meaning a greater risk for them with addiction and the side effects associated with opioid usage)
• Health data outcome: females significantly higher usage of opioids in past and present.

Question 58

What was found in Non-pharmacological pain relief regarding the sexes? (Keogh et al., 2005)

Answer 58

-Keogh et al. (2005) - inferior outcomes for females, relative to males, following interdisciplinary chronic pain management programs (which is a problem as most chronic pain patients tend to be females)

-Replicated in analysis of Pain Management
Program treatment for veterans in the USA
(Improvements in a range of domains were
sustained at follow-up for both sexes, but
females did not maintain improvements in pain intensity or sleep) (Murphy et al., 2016)

Question 59

What’s the link between Experimental Pain and Gender? (Wise et al., 2002)

Answer 59

-Wise et al. (2002) analysed pain tolerance in males and females - cold pressor task.

-Gender Role Expectations of Pain
questionnaire (GREP) measured gender-specific expectations about pain (willingness to endure and communicate pain).

-GREP scores was a significant, although not
exclusive, predictor of pain tolerance

-Similar findings for pain threshold
(not shown)

Question 60

What’s the link between Gender and Pain? (Pool et al., 2007)

Answer 60

-Pool et al. (Pain, 2007) administered questionnaires to measure how males and females identified themselves with “ideal men” or “ideal women” roles.

-Split into low identification with roles vs high

-Greater experimental pain tolerance in men identifying with traditional male roles,
compared with women identifying with traditional female roles + lower gender difference gaps between those in the low group

Question 61

How can Stereotypical Beliefs play a role?

Answer 61

• Stereotypes can be damaging, e.g., men
  are considered less expressive and more
  likely to engage in avoidance when in pain, whereas women are perceived to be more likely to catastrophize and cry (Keogh, 2022).
• Hirsh et al., (2009): when viewing virtual
  patients, observers rated women as
  having more pain and being worse at
  coping.
• Schafer et al., (2016) found that clinicians viewed female patients more negatively in
  clinical scenarios relative to males.

Question 62

What is the Evolutionary perspective in Sex and Gender differences?

Answer 62

Mogil (2006) hypothesised an evolutionary basis for sex differences in pain:
1. Females might have an additional antinociceptive circuit that is being implemented during childbirth, and this pattern might interfere with the default
pain processing mode leading to greater pain in various scenarios.

2. Males have been exposed more frequently to injuries, and natural selection contributed to affirmation of less sensitive pain genes.