Kvinnligt och manligt i ett smärtperspektiv. Iréne Lund Insitutionen för fysiologi och farmakologi Karolinska Institutet Stockholm

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1 Kvinnligt och manligt i ett smärtperspektiv Iréne Lund Insitutionen för fysiologi och farmakologi Karolinska Institutet Stockholm

2 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.

3 Epidemiologiska aspekter av smärta i ett gender 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:

4 Kvinnor använder komplementär och alternativ medicin, CAM, inklusive akupunktur oftare än män. Klingberg et al. The use of complementary and alternative medicine in outpatients with inflammatory rheumatic diseases in Sweden. Scand J Rheumatol 2009;38: 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: 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 Danish women and men years of age. Pharmacoepidemiology and drug safety 2010; 19:

5 Experimentell smärta Smärttröskel < Smärttolerans < Elektrisk Cold pressor Lund et al. Gender differences in electrical pain threshold responses to transcutaneous electrical nerve stimulation (TENS) Neuroscience Letters 2005;375: Ischemi Cold pressor Värme stimulering Schmitz et al. Pain tolerance in children and adolescents: Sex differences and psychosocial influences on pain threshold and endurance. Eur J Pain2013;17: Klatzkin RR et al. Menstrual cycle phase does not influence gender differences in experimental pain sensitivity. Eur J Pain Feb 11.

6 Påverkar andra sinnen smärtupplevelsen? Doft Neutrala Behagliga Obehagliga Vatten Mandelextrakt Permanentolja Apelsinvatten Massage-/babyolja Vinäger Marchand and Arsenault Odors modulate pain perception. A gender-specific effect. Physiol & Behav 2002;76:

7 Differential activation in the pain matrix in men and women Melchior et al. INSIGHTS INTO THE MECHANISMS AND THE EMERGENCE OF SEX-DIFFERENCES IN PAIN. Neuroscience 2016;338: Hippocampus - affinitet av glucocorticoidreceptorer hälften hos kvinnor än hos män Cahill. Why sex matters for neuroscience. Nat Rev Neurosci 2006;may:1-8 Specifically, men seem to have more access to an amygdale-mediated recruitement of the endogenous pain inhibitory system. Linman et al. Sex similarities and diffrences in pain-related periqueductal gray connectivity. Pain 2012;153:

8 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 Fillingim RB. Sex, Gender and Pain. Progress in pain research and management, vol 17. IASP press 2000 Bekker MHJ, vn Mens-Vershulst J. Anxiety disorders: Sex differences in prevalence, degree, and background but gender-neutral treatment. Gend Med 2007;4:S178-S193. Kajantie E. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinol 2006;31: Accortt et al. Women and major depressive disorder: Clinical perspectives on causal pathways. J Womens Health 2008;17: Melchior et al. Insightes int the mechanisms and the emergence of sex-differences in pain. Nuerosci 2016; 338:63-60.

9 Mekanismer av sex/gender skillnader komplexa interaktioner Sociala Psykologiska Kulturella Kroppsorgan Genetiska Fysiologiska Molekulära KONCEPTION Cellulära DÖD Pubertet Partersökande Graviditet Menopaus Pensionering 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: Mogil JS. Sex, gender and pain. In: Cervero F, Jensen TS. Handbook of clinical Neurology Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J anaesthesia 2013;111:52-58 Fillingim RB. Sex, Gender and Pain. Progress in pain research and management, vol 17. IASP press 2000.

10 Forskningsprojekt lika förekommande av kvinnor och män? Män/Manliga individer har varit/är norm! NIH föreslog inkluderande av kvinnor i humana kliniska studier Mössen kommer från det så kallade International Mouse Phenotyping Consortium. Bild: Thinkstock VETENSKAP Labbmössens kön kan ha stor betydelse Natasha Kapr et al. Prevalence of sexual dimorphism in mammalian phenotypic traits. Nature Communications, DOI: /ncomms15475 Campesi I. Sex and Gender Aspects in Anesthetics and Pain Medication Sex and Gender Differences in Pharmacology, Handbook of Experimental Pharmacology 214, Miaskowski C. Gender differences in pain, fatigue, and depression in patients with cancer. J Natl Cancer Inst Monogr 2004;(32): 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.

11 Inflammation Värme Svullnad Rodnad Smärta Nedsatt funktion Köns-beroende aktivering av inflammatoriska processer Plasma extravasation Leukocyt adhesion Hyperalgesi Produktion av pro-inflammatoriska cytokiner (IL-6) Nisell, Lundeberg. Smärta och inflammation Levine et al. Neurogenic inflammation and arthritis. Ann N Y Acad Sci 2006;1069: Prather et al. Gender differences in stimulated cytokine produktion following acute psychological stress. Brain Beh Immun 2009

12 Visceral smärta Ballong distension hos IBS patienter Aktivitet i limbiska strukturer, Naliboff et al. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology 2003;124: 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 Dec;101(12 Suppl):S602-9.

13 Könshormoner vid smärta Influens på perifera och centrala neurala strukturer (variation med menscykel) Testosteron Östrogen Anti-nociception Pro-nociception Effects of gonadal hormones on cells of the innate and adaptive immune system leading to modulation of pain. McEwen et al. Understanding the Broad Influence of Sex Hormones and Sex Differences in the Brain. J Neuroscie Resear 2017;95:24 39 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: Rosen S, Ham B, Mogil JS. Sex differences in neuroimmunity and pain. J Neurosci Res Jan 2;95(1-2):

14 Nisell, Lundeberg killnader i smärtreglerande system kat antal NMDA receptorer hos kvinnor jämfört med män? MDA receptorer aktiveras av kvinnliga könshormoner? ensitiserad smärt system beroende upprepad visceral smärta (mens, förlossning)? ind-up mer förekommande hos kvinnor än män (termisk hud smärta)? airns. The influence of gender and sex steroids on carniofacial nociception. Headache Curr 2007 feb illingim et al. Sex differences in temporal summation but not sensory-discriminative processing of thermal pain. Pain 1998;

15 Könsskillnader i organisation och funktion i PAG-rostrala ventrala medulla,rvm Descenderande inhibitoriska smärt kontrollerande banor Brodin et al. Norsk tandläkartidningen 2016 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:

16 Inverkan av konstitutionen? Genetiska skillnader Rödhåriga kvinnor med ljus hud + melanocortin-1 (MC1R) gen Högre smärttrösklar Bättre effekt av kappa opioid agonister Mogil et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. PNAS 2003;100:

17 Könsberonde aktivering av opioid receptorer? 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;

18 Skillnader i endogena smärthämmande system? Stark smärt stimulering ger hämning på flera nivåer i nervsystemet dvs. minskad smärta bilateralt + i andra kroppshalvan 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:

19 Colloca, Benedetti. Placebos and painkillers: is mind as real as matter? Nar Rev Neurosci 2005;6: Högre hjärnaktivitet kan aktivera två system Placebo Terapeutiska 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 Nocebo Terapeutiska effekter Uppgivenhet, oro, ångest Aktiverar endogena substanser i CNS, Cholecystokinin (CCK) som motverkar opioider och icke-opioider (dopamin) Mer smärta, sämre motorik Mindre smärta, bättre motorik

20 Vambheim SM, Flaten MA Ordens betydelse 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 Carlino, Frisaldi, Benedetti, Pain and the context. Nature 2014;10: )females responded with larger nocebo effects induced by conditioning procedures.

21 Fysiologiska stress reaktioner slagvolym, hjärtminutvolym vaskulär resistans (adrenerg sensitivitet) Corticotropin-Releasing Factor, CRF 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, Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression.

22 Psyko-sociala aspekter Spelar förväntan någon roll? Robinson et al. Altering Gender Role Expectations: Effects on pain tolerance, pain threshold, and pain ratings. J Pain, 2003;4:

23 Pain rating Psyko-sociala aspekter Influens av undersökaren? Men Women 10 0 Same Opposite Gender of examinator 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: Alaksen. The effect of experimenter gender on autonomic and subjective responses to pain stimuli. Pain 2007;129:

24 Farmakologisk smärtlindrande behandling Gear et al. Neurosci Lett 1996;205: Gear et al. Pain 1999; 83:

25 Genderberoende svar på sensorisk stimulering? PM values HF TENS påverkan på elektrisk smärttröskel 10' post TENS , n= Pre TENS RP 0.43 (95% CI 0.27 to0.60) RV 0.20 (95% CI 0.01 to 0.39) 10' post TENS , n= Pre TENS RP (95% CI till 0.10) RV 0.09 (95% CI 0.00 till 0.22) Ökad smärttröskel hos kvinnor men inte hos män Pre TENS Lund et al. Gender differences in electrical pain threshold responses to transcutaneous electrical nerve stimulation (TENS) Neuroscience Letters 2005;375: ' post TENS Men Women EPT men EPT women EST men EST women Pre TENS TENS 10' TENS 20' 10' post TENS

26 A one size fits all eller Gender beroende svar på akupunktur? PainMatcher values, median 100 Electroakupunktur; influens på elektrisk smärttröskel Women, n=23 Men, n= PainMatcher values Before 10' 20' 10' after RP 0.39 (95% CI 0.23 to 0.56) RV 0.24 (95% CI 0.00 to 0.49) PainMatcher values Median 25%-75% Min-Max Raw Data Before 10' 20' After RP 0.09 (95% CI to 0.24) RV 0.13 (95% CI0.00 to 0.30 Median 25%-75% Min-Max Raw Data Men Women Before Stim 10' Stim 20' 10' after 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)

27 Genderberoende svar på akupunktur? Brain Research 2010;1362: Our study suggests that brains with sex dimorphism may process the acupuncture stimulation differently between women and men.

28 PLoS ONE 2017;12(4): e 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.

29 Concordance of two pain rating scales Worst possible pain 4 Severe pain 3 Moderate pain Mild pain 2 VRS 1 No pain VAS Lund I et al. BMC Med Res Methodol 2005 Oct 4;5: VRS 1 2 VRS VAS Women VAS Men I L

30 Factors decidedly or likely relevant to sex differences in experimental studies of human pain 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.) Social environment Anxiety (trait and state) Reproductive status (females) Communication (extent and style) Attention Expectation Mood state Cardiovascular system Greenspan et al. Studying sex and gender differences in pain and analgesia: A concensus report. Pain 2007;132:S26-S45.

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

32 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 bör prioriteras