1. Sex Differences in Pain Perception Department of Pharmacology
Integrating the Life Sciences from Molecule to Organism
The American Physiological Society
Sex Differences in Pain Perception
Todd Vanderah, Ph.D.
Head and Professor
Department of Pharmacology
University of Arizona
Presented on April 22, 2017
Experimental Biology 2017
Chicago, IL April 2017

2. The American Physiological Society
This presentation is part of
the 2017 Refresher Course on
Curricular Innovation in Sex and Gender Based Medical Physiology Education
Organized by the APS Education Committee
For more information and to listen to other presentations:

3. Todd Vanderah, Ph.D. vanderah@email.arizona.edu
The American Physiological Society
Todd Vanderah, Ph.D.
Dr. Vanderah received his Ph.D. in Pharmacology and Toxicology at University of Arizona. He completed a post-doctoral fellowship in neuropharmacology in the Department of Pharmacology at The University of Colorado Health Sciences Center. Dr. Vanderah returned to the University of Arizona where he currently serves as Professor and Head of the Department of Pharmacology with joint appointments in Anesthesiology and Neurology. Dr. Vanderah maintains a productive research program focused on understanding mechanisms of acute and chronic pain, and has published over 155 original research articles on the topic. He is also an award winning instructor in both graduate and medical education, authoring a leading Human Neuroscience text book titled “Nolte’s the Human Brain” and was recently awarded the Lifetime Achievement Award for Teaching at the University of Arizona.

4. Sex Differences in Pain Perception
Todd W. Vanderah, Ph.D.
Professor and Chair
Department of Pharmacology
Joint Appointment Anesthesiology & Neurology
THE UNIVERSITY OF ARIZONA
COLLEGE OF MEDICINE TUCSON
Pharmacology

5. Pain Education in North America Medical Schools
A total of U.S.(104) and Canadian(13) medical schools were included in the study.
Inclusion Criteria - U.S. and Canadian medical schools were assessed using the Association of American Medical Colleges’ (AAMC) CurrMIT.32 (28 schools excluded)

6. Pain Education in North America Medical Schools
U.S. Medical Schools
Canadian Medical Schools
Lina Meze, et al., The Journal of Pain, Vol 12, No 12, 2011: pp

7. Major Topics in Pain Taught in 117 US and Canadian Medical Schools
Lina Meze, et al., The Journal of Pain, Vol 12, No 12, 2011: pp

8. Major Topics in Pain Taught in 117 US and Canadian Medical Schools
Continued
Lina Meze, et al., The Journal of Pain, Vol 12, No 12, 2011: pp

9. Conclusions: Pain Education in North America Medical Schools
Approximately 80% of U.S. medical schools require 1 or more pain sessions.
Among Canadian medical schools, 92% require pain sessions.
Median hrs of instruction on pain for Canadian schools was twice the U.S. median hrs.
U.S. medical schools allot a median of 9 teaching hours on pain education
Canadian schools allot a median of 19.5 teaching hours on pain education
In the U.S., that's approximately 0.3% of the total curriculum hours.
We conclude that pain education for North American medical students is limited, variable, and often fragmentary.
There is a need for innovative approaches and better integration of pain topics into medical school curricula.
Students in veterinary schools spend five times as many education hours focused on pain management as students in medical schools.

10. Pain Education in Medical Schools
Comprehensive cross-sectional analysis of pain education undergraduate medical school curricula across Europe,
97% of all medical schools in 15 European countries
Median number of hours spent teaching pain was 12 hr (range 4-56 hr)

11. Pain Education in Medical Schools
% of Schools with a Pain Module
Spain
Italy UK
France
Romania
Germany
Sweden
Bulgaria
Portugal
Ireland
Poland
Total (N=242)
Belgium
Switzerland
Denmark
Netherlands
Emma V Briggs, et al., BMJ Open, 2015 (5), 8, 1-10

12. Pain Education in Medical Schools
Teaching Method
Assessment Method
Emma V Briggs, et al., BMJ Open, 2015 (5), 8, 1-10
Conclusions: there needs to be more time spent on pain education

13. U.S. Pain Research Portfolio
in 2012, the NIH spent $5.6 billion on cancer research compared to $396 million on pain research. (15 fold greater)
chronic pain affects 100 million people, while cancer affects 13.7 million

14. Sex Differences and Pain Research Support
IPRCC-Pain-Research-Portfolio-Analysis-Report

15. Increased Research into Sex Differences in Clinical Pain
Fillingim et al. J Pain May ; 10(5): 447–485

16. Increased Research into Sex Differences in Clinical Pain
Fillingim et al. J Pain May ; 10(5): 447–485

17. Sex‐Based Differences and Pain Syndromes
Pain Syndromes F:M Ratio
Fibromyalgia :1
Irritable Bowel Syndrome :1
Interstitial cystitis/painful bladder syndrome 9:1
Migraine :1
Chronic tension type headache :1
Tempomandibular disorders :1
Female Pain Syndromes
Vulvodynia
Chronic Pelvic Pain
Primary Dysmenorrhea
Comorbidity with chronic pain includes Stress and Anxiety, Depression
(2015 White Paper on COPCs, Chronic Pain Research Alliance)

18. Migraine is the most common neurological disease
Affects 15 percent of the world population (Vos, T., et al. 2012)
3 out of 4 migraine sufferers are women (Hu, X.H., et al. 1999)

19. Increased Research into Sex Differences in Clinical Pain
Fillingim et al. J Pain May ; 10(5): 447–485

20. Female cluster headache in the United States of America:
What are the gender differences?
Results from the United States Cluster Headache Survey
Todd D. Rozen a,⁎, Royce S. Fishman Journal of the Neurological Sciences 317 (2012) 17–28

21. Sex‐Differences in Age of Onset of Cluster Headaches
Rozen & Fishman, Journal of the Neurological Sciences 317 (2012) 17–28

22. Sex‐Differences in Age of Onset of Cluster Headaches
Rozen & Fishman, Journal of the Neurological Sciences 317 (2012) 17–28

23. Sex‐Differences in Cluster Headache Associated Symptoms
Rozen & Fishman, Journal of the Neurological Sciences 317 (2012) 17–28

24. Sex‐Differences in Cluster Headache Triggers
Rozen & Fishman, Journal of the Neurological Sciences 317 (2012) 17–28

25. Sex‐Differences in Medical Conditions that Occur in Cluster Headache Patients
Rozen & Fishman, Journal of the Neurological Sciences 317 (2012) 17–28

26. Sex‐based Differences in Animal Model of Migraine
Sex differences in KCl-induced (0.5µL, 1M) periorbital allodynia- Headache
Courtesy of Largent-Milnes, UofA, Tucson

27. Sex Differences in Postoperative Pain
Fillingim et al. J Pain May ; 10(5): 447–485

28. Increased Research into Sex Differences in Analgesics
Fillingim et al. J Pain May ; 10(5): 447–485

29. Sex Differences and the Efficacy of Narcotic Analgesics in Humans
Opioid Receptor Reference
Morphine (MOR agonist)
Acute injury M > F [50]
Thermal, pressure, and ischemic pain (experimental) M = F [51]
Postoperative pain M > F, M = F, M < F [32,33][58-60][30,61-64]
Buprenorphine (Partial MOR agonist and some KOR antagonist properties)
Postoperative pain M < F [47-49]
Butorphanol (Partial MOR and KOR agonist)
Acute injury M = F [50]
Thermal, pressure, and ischemic pain (experimental) M = F [51]
Postoperative dental surgery M < F [52]
Cold-water stimulus (experimental) M > F [53]
Fentanyl (MOR agonist)
Postoperative pain M < F, M = F [54][55]
Methadone (MOR agonist)
Cancer pain M = F [57]
Heroin (MOR agonist)
Addiction epidemic M > F [8,37]
Adolescent drug users M < F [38]
Lee and Ho, Molecular Pain 2013, 9:45

30. Sex Differences and the Modulation of Opioid Receptors by Estrogen
Schematic representation of the facilitation of KOR/MOR heterodimerization by E2.
Biochemical and behavioral experiments suggest that ERs work cooperatively to increase KOR/MOR expression. We postulate that E2 triggers a signaling complex containing one or multiple ERs, which via an unknown mechanism enhances the formation of KOR/MOR heterodimers and thereby creates the sex difference in opioid actions.
Lee and Ho, Molecular Pain 2013, 9:45

31. Sex Differences and the Modulation of Opioid Receptors by Estrogen
Diagram of the postulated cross-talk between estrogen and opioid receptors.
Although numerous reports have addressed gender differences of opioid receptor agonists, very few directly examined the mechanism.
Lee and Ho, Molecular Pain 2013, 9:45

32. Sex‐Based Differences in Drug Abuse of Narcotics
Recent evidence suggests that the progression to dependence and abuse may differ between women and men
Females appear to be more vulnerable than males to the reinforcing effects of opiates during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse)
Preclinical and Clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse

33. Sex‐Based Differences in Drug Abuse
Conclusions: females seem to be more sensitive to the rewarding effects of drugs than males, and estrogen is a major factor that underlies these sex differences.

34. Sex‐Based Differences in Fear of Pain
Sara M Vambheim and Roald A Øien
April 7, 2017, –831
- 185 healthy college students were included in the study
(49.7% females, mean age: 21, 62, range: 18–30 years)
(50.3% males, mean age: 24, range: 19–32 years)
- FPQ-III measures pain-related fear on a 30-item questionnaire
Conclusions: There are sex differences in severe Fear of Pain,
Fear of Pain females > males.
Potential explanations are sex differences in the
1) psychosocial mechanisms of fear and anxiety, and
2) emotional reactions to and interpretation of FPQ-III Severe Pain items.

35. Sex‐Based Differences in Neuroimmunity and Pain
- Women suffer from chronic pain at rates higher than men.
- Sex differences in pain may be due to sex differences in the immune system

36. Sex‐Based Differences in Neuroimmunity and Pain
Robert E. Sorge and Stacie K. Totsch
Journal of Neuroscience Research (2016)
Rosen et al., J of Neuroscience Research 95, 2017

37. Sex‐Based Differences in The Brain

38. Sex‐Based Differences in The Brain
Robert E. Sorge and Stacie K. Totsch
Journal of Neuroscience Research (2016)
Conclusions: Ample evidence for a role of immune system cells in modulating the transition to and maintenance of chronic pain.
- Good support for roles of sex hormones in shifting the activity of the immune system cells. - Women (high levels of estrogen and low levels of testosterone) predisposition to greater proinflammatory Th1 cells.
- Men, with higher testosterone levels, suppress the activity/differentiation of CD41 T cells, shifting the distribution of these cells toward the anti-inflammatory Th2 subtype.

39. Sex‐Based Differences in Brain Alterations Across Chronic Pain Conditions Using Neuroimaging
Number of articles with human studies and imaging
Sex Differences
Female Specific
Male Specific
IBS
GERD
Whiplash
Mixed Sex
Fibromyalgia
Osteoarthritis
Facial Pain
Vulvodynia
Cluster Headache
Back/Limb Pain
Dysmenorrhea/Endometriosis
Migraine/Headache
Chronic Fatigue Syndrome
Urologic Pain/Bladder Cystitis
Journal of Neuroscience Research Volume 95, Issue 1-2, pages , 7 NOV 2016 DOI: /jnr

40. Sex‐Based Differences in Brain Alterations Across Chronic Pain Conditions Using Neuroimaging
Journal of Neuroscience Research Volume 95, Issue 1-2, pages , 7 NOV 2016 DOI: /jnr

41. Increased Research into Sex Differences in Clinical Pain
Fillingim et al. J Pain May ; 10(5): 447–485

42. Sex‐Based Differences in The Brain

43. Sex‐Based Differences in The Brain
Bruce S. McEwen and Teresa A. Milner
Journal of Neuroscience Research 95:24–39 (2017)

44. Sex‐Based Differences in The Brain
Bruce S. McEwen and Teresa A. Milner
Journal of Neuroscience Research 95:24–39 (2017)

45. Sex‐Based Differences in The Brain
Sex differences in CA1 steroid hormone receptor distribution.
Females nuclear ERs are in GABAergic neurons,
Males ARs are in pyramidal cell neurons.
Bruce S. McEwen and Teresa A. Milner
Journal of Neuroscience Research 95:24–39 (2017)

46. Summary
1) There is a lack of pain and analgesics taught in our medical schools;
2) Pain research (specially sex differences in pain) is underfunded;
3) There are differences between males and females in pain conditions
(i.e., headache, fibromyalgia, IBS)
4) There are differences between males and females in analgesic efficacy and addiction probabilities.
5) There may be sex differences in the Fear of Pain, as well as differences in the comorbidities
6) There are sex differences in neuro-immune with females having more of a proinflammatory state and males more of a anti-inflammatory state.
7) There are sex differences in areas of the CNS that respond to different types of pain
8) Estrogen and Androgen receptors are located on different types of neurons and result in differences in function.

47. Persistent Challenges in Researching Sex Differences and Pain
including identifying hormonal versus chromosomal contributions to sex differences in pain/analgesia;
understanding the contribution of local (versus gonadal release) hormonal effects;
elucidating the role of psychological factors;
understanding whether pain chronicity contributes to sex differences;
distinguishing the roles of sexual dimorphism in ascending versus descending modulatory pathways;
determining the cellular and molecular bases of sex differences in pain/analgesia;
understanding sex differences across the lifespan;
considering whether diagnostic criteria for some pain disorders should be sex-specific.

48. Questions/Discussion

49. For more information, to listen to other presentations,
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