Kvinnligt och manligt i ett smärtperspektivIréne LundInsitutionen för fysiologi och farmakologiKarolinska InstitutetStockholm

SEX biologisk konstrukt (djur, människor)Reproduktionsorgan, kromosomer, könshormones och genetiska skillnader. ‘‘There is no body without a sex.’’

GENDER socio-kulturell konstrukt (människor)spektrum av kvinnlighet eller manlighet som bestäms av socio-miljö faktorer -alla individer påverkas av kultur och förväntningar

“THE CONCECEPT OF SEX AND GENDER ARE INTERTWINED” – vi är biologiska, sociala och kulturella individer i

komplicerade och föränderliga kombinationer

Alex et al. 12 Beyond a Dichotomous View of the Concepts of ‘Sex’ and ‘Gender’ Focus Group Discussions among Gender Researchers at a Medical Faculty. PLoS One. 2012;7(11):e50275.

Epidemiologiska aspekter av smärta i ettgender perspektiv

”Married women suffer from more pain than unmarried”

- +

Män Övervikt Jogging

Arbetslöshet Högt utbildada

Långvarig sjukskrivning

Women Övervikt Hårt arbete

Oro om ekonomi

Halvtids arbete Singel, frånskild

Långvarig sjukskrivning

Bingefors. Epidemiology, co-morbidity, and impact on health-related quality of life of self-reported headache and musculoskeletal pain--a gender perspective. Eur J Pain. 2004;8:435-450.

”Kvinnor använder komplementär och alternativ medicin, CAM, inklusive akupunktur oftare än män”.

Klingberg et al. The use of complementary and alternative medicine in outpatients withinflammatory rheumatic diseases in Sweden. Scand J Rheumatol 2009;38:472480

Ben-Arye E et al. Gender Medicine 2009;6(2).

Vincent et al. Utilisation of acupuncture at an academic medical centre. Acupunct Med 2010;28:189–190

Skillnad i användning av analgetika

Kvinnor vs Män >

yngre > äldre

Isacson. Epidemiology of analgesic use: a gender perspective. Eur J Anaesthesiol Suppl. 2002;26:5-15

Hargreave et al. Factors associated with a continuous regular analgesic use—a population-based study of more than 45 000 Danish women and men 18–45 years of age. Pharmacoepidemiology and drug safety 2010; 19: 65–74.

Experimentell smärta

Cold pressor

Ischemi

Värme stimulering

Klatzkin RR et al. Menstrual cycle phase does not influence gender differences in experimental pain sensitivity. Eur J Pain. 2009 Feb 11.

Elektrisk

Lund et al. Gender differences in electrical pain threshold responses to transcutaneous electrical nerve stimulation (TENS) Neuroscience Letters 2005;375:75–80.

Smärttröskel <

Smärttolerans <

Cold pressor

Schmitz et al. Pain tolerance in children and adolescents: Sex differences and psychosocial influences on pain threshold and endurance. Eur J Pain2013;17:124-131

Marchand and Arsenault Odors modulate pain perception. A gender-specific effect. Physiol & Behav 2002;76:251-256.

Neutrala Behagliga Obehagliga

Vatten Mandelextrakt Permanentolja

Apelsinvatten Massage-/babyolja Vinäger

Påverkar andra sinnen smärtupplevelsen?

Doft

Hippocampus - affinitet av glucocorticoidreceptorer – hälften hos kvinnor än hos män

Melchior et al. INSIGHTS INTO THE MECHANISMS AND THE EMERGENCE OF SEX-DIFFERENCES IN PAIN.Neuroscience 2016;338:63–80.

“Differential activation in the pain matrix in men and women”

”Specifically, men seem to have more access to an amygdale-mediated recruitement of the endogenouspain inhibitory system.”Linman et al. Sex similarities and diffrences in pain-related periqueductal gray connectivity. Pain 2012;153:444-454

Cahill. Why sex matters for neuroscience. Nat Rev Neurosci 2006;may:1-8

Fillingim RB. Sex, Gender and Pain. Progress in pain research and management, vol 17. IASP press 2000Bekker MHJ, vn Mens-Vershulst J. Anxiety disorders: Sex differences in prevalence, degree, and background but gender-neutraltreatment. Gend Med 2007;4:S178-S193. Kajantie E. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinol2006;31:151-178.Accortt et al. Women and major depressive disorder: Clinical perspectives on causal pathways. J Womens Health 2008;17:1583-1590.Melchior et al. Insightes int the mechanisms and the emergence of sex-differences in pain. Nuerosci 2016; 338:63-60.

Klinisk smärta > •Högre nivå av upplevd smärta

•Smärta från fler kroppsregioner

•Längre duration av smärta

•Högre förekomst av smärtsamma tillstånd

t.ex. knäartros, fibromyalgia, TMD, migraine, RA, IBS, post-traumatic stress syndrome (PTSD), depression

Berkley KJ, Zalcman SS, Simon VR. Sex and gender differences in pain and inflammation: a rapidly maturing field. Am J Physiol Regulatory Integrative Comp Physiol 2006;291:241-244. Mogil JS. Sex, gender and pain. In: Cervero F, Jensen TS. Handbook of clinical Neurology 2006. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J anaesthesia 2013;111:52-58Fillingim RB. Sex, Gender and Pain. Progress in pain research and management, vol 17. IASP press 2000.

GenetiskaKroppsorgan

Kulturella

Molekulära

Psykologiska

Cellulära

Sociala

Fysiologiska

KONCEPTION DÖD

Pubertet Partersökande Graviditet Menopaus Pensionering

Mekanismer av sex/gender skillnader – komplexa interaktioner

Campesi I. Sex and Gender Aspects in Anesthetics and Pain Medication Sex and Gender Differences in Pharmacology, Handbook of Experimental Pharmacology 214, 2012. Miaskowski C. Gender differences in pain, fatigue, and depression in patients with cancer. J Natl Cancer Inst Monogr 2004;(32):139-43.Chen W, Woods SL, Puntillo KA. Gender differences in symptoms associated with acute myocardial infarction: a review of the research. Heart Lung 2005;34(4):240-7.

Forskningsprojekt – likaförekommande av kvinnor och män?

Män/Manliga individer harvarit/är norm!NIH föreslog inkluderande av kvinnor i humanakliniska studier 1993.

Mössen kommer från det så kallade International

Mouse Phenotyping Consortium. Bild: Thinkstock

•VETENSKAP

Labbmössens

kön kan ha

stor betydelseNatasha Kapr et al. Prevalence of sexual dimorphism in

mammalian phenotypic traits. Nature Communications, 2017. DOI:

10.1038/ncomms15475

InflammationVärme Svullnad Rodnad Smärta Nedsatt funktion

Köns-beroende aktivering av inflammatoriska processer

•Plasma extravasation

•Leukocyt adhesion

•Hyperalgesi

•Produktion av pro-inflammatoriska cytokiner (IL-6)

Levine et al. Neurogenic inflammation and arthritis. Ann N Y Acad Sci 2006;1069:155-67.

Prather et al. Gender differences in stimulated cytokine produktion following acute psychological stress. Brain Beh Immun 2009

Nisell, Lundeberg.

Smärta och inflammation

Ballong distension hos IBS patienterAktivitet i limbiska strukturer♂ , ♀

Naliboff et al. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology 2003;124:1738-1747

--------------------------------------------------------------------------------------------------------Influens av könshormonder på gastrointestinal aktivitet och sensorisk funktion

Ouyang, Wrzos. Contribution of gender to pathophysiology and clinical presentation of IBS: should management be different in women? Am J Gastroenterol. 2006 Dec;101(12 Suppl):S602-9.

Visceral smärta

Könshormoner vid smärtaInfluens på perifera och centrala neurala strukturer (variation med menscykel)

Testosteron Anti-nociception

Östrogen Pro-nociception

Aloisi et al. Cross-sex hormone administration changes pain in transsexual women and men.

Pain 2007; 132:Suppl 1:S60-S67.

Craft RM et al. Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain 2004;8:397-411

McEwen et al. Understanding the Broad Influence of SexHormones and Sex Differences in the Brain. J NeuroscieResear 2017;95:24–39

Effects of gonadal hormones on cells of the innate and

adaptive immune system leading to modulation of pain.

Rosen S, Ham B, Mogil JS. Sex differences in neuroimmunity

and pain. J Neurosci Res. 2017 Jan 2;95(1-2):500-508

Skillnader i smärtreglerande systemÖkat antal NMDA receptorer hos kvinnor jämfört med män?NMDA receptorer aktiveras av kvinnliga könshormoner?Sensitiserad smärt system beroende upprepad visceral smärta (mens, förlossning)?Wind-up mer förekommande hos kvinnor än män (termisk hud smärta)?

Cairns. The influence of gender and sex steroids on carniofacial nociception. Headache Curr 2007 feb. 319-324

Fillingim et al. Sex differences in temporal summation but not sensory-discriminative processing of thermal pain. Pain 1998;75.121-127

Nisell, Lundeberg

Könsskillnader i organisation och funktion i PAG-rostralaventrala medulla,RVM Descenderande inhibitoriska smärt kontrollerande banor

Loyd DR, Murphy AZ.The role of the periaqueductal gray in the modulation of pain in males and females: are the anatomy and physiology really that different? Neural Plast. 2009;2009:462879.

Brodin et al. Norsk tandläkartidningen 2016

Inverkan av konstitutionen?

Genetiska skillnaderRödhåriga kvinnor med ljus hud + melanocortin-1 (MC1R) gen –

•Högre smärttrösklar

•Bättre effekt av kappa opioid agonisterMogil et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. PNAS 2003;100:4867-4872

Zubieta et al.”At matched pain intensities the μ-opioid receptor system is less active during the follicular phase of women than in men”. J Neurosci 2002;22.5100-5107.

Könsberonde aktivering av opioid receptorer?

Staud R, et al. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 2003;101:167–174.

Skillnader i endogena smärthämmande system?

Stark smärt stimulering gerhämning på flera nivåer i nervsystemet dvs. minskad smärta bilateralt + i andra kroppshalvan

Colloca, Benedetti. Placebos and painkillers: is mind as real as matter? Nar Rev Neurosci 2005;6: 545-552.

NoceboTerapeutiska effekter

Uppgivenhet, oro, ångestAktiverar endogena substanser i CNS, Cholecystokinin (CCK) som motverkar opioider och icke-opioider (dopamin)

Mer smärta, sämre motorik

PlaceboTerapeutiska effekter

Förväntan medvetna fysiologiska funktioner (smärta, motorik)

Individens grad av förväntan Utformning av förväntan

Konditionering (betingning) omedvetna fysiologiska funktioner (hormoner)

Okonditionerat stimulus (aktiv substans)Konditionerat stimulus (distraktionsform + omständighet)Aktiverar endogena opioider, icke-opioider(dopamin), cannabinoider

Mindre smärta, bättre motorik

Högre hjärnaktivitet kan aktivera två system

Carlino, Frisaldi, Benedetti, Pain and the context. Nature 2014;10:348-355

Ordens betydelse

Vambheim SM, Flaten MA. 2017

1) males responded more strongly to placebo treatment, and females responded more strongly to nocebo treatment

2)males responded with larger placebo effects induced by verbal information

3)females responded with larger nocebo effects induced by conditioning procedures.

Fysiologiska stress reaktioner

slagvolym, hjärtminutvolym

vaskulär resistans (adrenerg sensitivitet)

frisättning av cortisol

Girdler and Light, 1994

Hinojosa-Laborde et al., 1999

Zimmer, 2003

Bangasser et al. Biology of Sex Differences 2013, 4:2. Sex differences in CRF1 trafficking in LC dendrites. Bangasser et al. Molecular Psychiatry (2013) 18, 166 – 173. Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression.

Corticotropin-Releasing Factor, CRF

Robinson et al. Altering Gender Role Expectations: Effects on pain tolerance, pain threshold, and pain ratings. J Pain, 2003;4:284-288

Psyko-sociala aspekter

Spelar förväntan någon roll?

0

10

20

30

40

Same Opposite

Gender of examinator

Pain

rat

ing

Men

Women

Levine et al. The effects of experimenter gender on pain report in male and female subjects. Pain 1991;44:69-72

Gijsbers K, Nicholson F. Experimental pain thresholds influenced by sex of experimenter. Perc Mot Skills 2005;101:803-807

Influens av undersökaren?Psyko-sociala aspekter

Alaksen. The effect of experimenter gender on autonomic and subjective responses to pain stimuli.Pain 2007;129:260–268

Gear et al. Neurosci Lett 1996;205:207-209 Gear et al. Pain 1999; 83: 339-345

Farmakologisk smärtlindrande behandling

Genderberoende svar på sensorisk stimulering?

Lund et al. Gender differences in electrical pain threshold responses to transcutaneous electrical nerve stimulation

(TENS) Neuroscience Letters 2005;375:75–80.

Ökad smärttröskel hos kvinnor men inte hos män

HF TENS – påverkan på elektrisk smärttröskel

0 10 20 30 40 50 60 70

Pre TENS

0

10

20

30

40

50

60

70

10

' po

st T

EN

S

♀, n=25

0 10 20 30 40 50 60 70

Pre TENS

0

10

20

30

40

50

60

70

10

' po

st T

EN

S

♂, n=27

0.0 0.2 0.4 0.6 0.8 1.0

Pre TENS

0.0

0.2

0.4

0.6

0.8

1.0

10

' po

st T

EN

S

Men

Women

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

PM

val

ues

Pre TENS TENS 10' TENS 20' 10' post TENS

EST women

EST men

EPT women

EPT men

♀

♂

RP 0.43 (95% CI 0.27 to0.60)

RV 0.20 (95% CI 0.01 to 0.39)

RP -0.01 (95% CI -0.13 till 0.10)

RV 0.09 (95% CI 0.00 till 0.22)

Women, n=23

Before 10' 20' 10' after 0

20

40

60

80

100

Pain

Matc

her v

alu

es

Median

25%-75%

Min-Max

Raw Data

Men, n=22

Before 10' 20' After0

20

40

60

80

100

Pain

Matc

her v

alu

es

Median

25%-75%

Min-Max

Raw Data

0

2

4

6

8

10

12

14

16

18

20

22

Before Stim 10' Stim 20' 10' after

Pain

Matc

her

valu

es, m

ed

ian

Men

Women

RP 0.39 (95% CI 0.23 to 0.56)

RV 0.24 (95% CI 0.00 to 0.49)

RP 0.09 (95% CI -0.06 to 0.24)RV 0.13 (95% CI0.00 to 0.30

Increased pain threshold in women but not in men

Lund I, Lundeberg T. On the threshold - evaluation of variability in effects of acupuncture in a gender perspective. Chin Med 2010; 5:32 (4 September 2010)

Electroakupunktur; influens på elektrisk smärttröskel

”A one size fits all” eller

Gender beroende svar på akupunktur?

Genderberoende svar på akupunktur?

Brain Research 2010;1362:56-67.

“Our study suggests that brains with sex dimorphism may process the acupuncture stimulation differently between women and men.”

PLoS ONE 2017;12(4): e0175737

Purpose

The aim of this study is to explore differences between male and female patients

entering a rehabilitation program at a pain clinic in order to gain a greater

understanding of different approaches to be used in rehabilitation.

Method

1371 patients referred to a specialty pain rehabilitation clinic, completed

sociodemographic and pain related questionnaires. They rated their pain acceptance

(CPAQ-8), their kinesiophobia (TSK), the impact of pain in their life (MPI), anxiety and

depression levels (HAD) and quality of life scales: the SF-36, LiSat-11, and the EQ-5D.

Results

Analysis showed that when both sexes experience the same pain severity, women

report significantly higher activity level, pain acceptance and social support

while men report higher kinesiophobia, mood disturbances and lower activity

level.

Conclusion

Pain acceptance (CPAQ-8) and kinesiophobia (TSK) showed the clearest differences

between men and women. Pain acceptance and kinesiophobia are behaviorally

defined and have the potential to be changed.

Concordance of two pain rating scales

0 100

VAS

0

1

2

3

4

VR

S

Women

0 100

VAS

0

1

2

3

4

VR

S

Men

0 100

VAS

0

1

2

3

4

VR

S

Lund I et al. BMC Med Res Methodol 2005 Oct 4;5:31

Worst possible pain

Severe pain

Moderate pain

Mild pain

No pain

I L

Stimulus Context Individual Response measures

Modalaty Threat/safety History Threshold

Location Stress Age Tolerance

Timing Time of testing Coping Suprathreshold scaling

Tissue type Experimenter gender Genetic background

Stimulus discriminability

Phasic/tonic Contingency Race/etnicity Reflex

Sleep history Hormonal status Imaging

Co-stimulation

odor, sounds etc.)

Anxiety (trait and state)

Cardiovascular system

Social environment Reproductive status (females)

Communication (extent and style)

Attention

Expectation

Mood state

Factors decidedly or likely relevant to sex differences in experimental studies of human pain

Greenspan et al. Studying sex and gender differences in pain and analgesia: A concensus report.

Pain 2007;132:S26-S45.

Melchior et al. INSIGHTS INTO THE MECHANISMS AND THE EMERGENCE OF SEX-DIFFERENCES IN PAIN. Neuroscience 2016;338:63–80.

Sammanfattning•Smärta uppträder olika hos män och kvinnor - från neurobiologiska till sociokulturella aspekter

•Kvinnor rapporteras vara överrepresenterade i de flesta smärtsamma tillstånd

•Observationer på män kan inte med automatik generaliseras till kvinnor och vice versa.

•Inverkan av genderrelaterade effekter bör övervägas vid utformning, analys och rapportering av smärtstudier

•Fler studier som separera könen vid utvärdering behövs

•Studier som utvärderar mekanismer som ligger till grund för köns skillnader börprioriteras