Sex and Gender Differences in Pain Management: Do we Need Pink and Blue Pills

Sex and Gender Differences in Pain Management: Do We Need Pink and Blue Pills?

Roger B. Fillingim Director, University of Florida Pain Research and Intervention Center of Excellence (PRICE) Research Health Scientist, North Florida/South Georgia Veterans Health System

Disclosure • Stockholder and Vice President of Clinical Research Services at Algynomics, Inc. • Consulting: Medscape, Curatio, Cytogel • Research Supported by NIH: NIA (AG033906), NIDCR (DE017018), NINDS (NS41670), and CTSA Grant (RR029890)

Disclosure This presentation was developed to be in full compliance with all ACCME rules and guidelines.

Learning Objectives Upon completion of this course, the learner will be able to: • Describe the nature of sex differences in clinical and experimental pain responses • Enumerate multiple biological and psychosocial factors that contribute to sex differences in pain • Describe current findings regarding sex differences in responses to medical and nonmedical treatments for pain

In other words‌Let’s discuss how and why pain differs by sex and whether men and women may need different pain treatments.

Case Scenario • Pat: 48 year old presenting with chronic, recurrent, low back pain • Will the diagnosis be influenced by Pat’s sex?

• Do treatment goals differ if Pat is a male versus a female?

• Does Pat’s sex matter in developing a treatment plan?

Overview of Presentation • Conceptual issues • Sex differences in clinical and experimental pain responses • Mechanisms contributing to sex differences in pain • Sex differences in responses to treatment – Analgesic medications – Non-pharmacologic therapies

• Conclusions and clinical implications

The Translational Research Cycle Clinical Observation (There are more women in my clinic than men)

Intervention Studies (Clinical trial to compare treatment efficacy in women vs. men)

Translational Research (Human studies to translate mechanisms of sex differences in pain)

Observational Research (Epidemiologic studies on sex differences in pain)

Mechanistic Research (Preclinical studies on sex differences in nociceptive processing)

Myths About Sex, Gender and Pain • Sex and gender are synonyms • Sex differences in pain are due to reporting biases (underreporting of pain in men and over-reporting of pain in women) • Sex differences in laboratory pain responses in humans are inconsistent and small in magnitude • Gender roles are determined exclusively by environmental factors, particularly social learning

Ann Rev Neurosci 2011, 34:69-88

Human gender development begins before birth and is influenced by levels of testosterone prenatally, and perhaps neonatally. Sex-typed play in childhood relates to levels of testosterone before birth, and evidence indicates that the prenatal hormone environment also contributes to variability in sexual orientation, gender identity, and some, but not all, personality traits that differ on average for males and females.

BIOPSYCHOSOCIAL MODEL OF PAIN Psychological Factors Mood, Pain Coping, Catastrophizing

Biological Factors Hormones, Genetics, Endogenous Opioids

Sex, Gender and Pain Social Factors Gender Roles, Provider Bias

Overview of Presentation • Conceptual issues • Sex differences in clinical and experimental pain responses • Mechanisms contributing to sex differences in pain • Sex differences in responses to treatment – Analgesic medications – Non-pharmacologic therapies

• Conclusions and clinical implications

Fillingim, et al, 2009, J Pain, 10: 447-485

Sex Differences in Chronic Pain Prevalence Across Different Categories (Mogil, in press)

Pain scores for women were higher in 18/25 (72%) ICD diagnosis sections with 41 to 68 patient encounters per sex group. This proportion reached 21/22 (95%) when the minimum number of encounters per diagnosis was increased to 69 or more.

Prevalence of Migraine by Sex and Age (Lipton, et al, 2001, Headache 41:646-57)

Population Prevalence (%)

30 25 20 15

Male Female

10 5 0 12-17

18-29

30-39

40-49

Age Group

50-59

> 60

Why Study Sex Differences in Experimental Pain Responses?

• Sex differences in in clinical pain could be influenced by numerous factors that are difficult to control, including: disease severity or duration, differential diagnostic and treatment histories, differential treatment efficacy, and psychosocial aspects of disease burden.

• That is, in clinical pain, we often don’t know or can’t quantify the painful stimulus, but experimentallyinduced pain allows control over the stimulus

Common Experimental Pain Modalities and Measures Stimulus Modalities

Pain Measures

Electrical Contact Thermal (heat, cold) Immersion Thermal (heat, cold) Mechanical/Pressure Ischemic Chemical (e.g. capsaicin, hypertonic saline, glutamate)

Pain Threshold Pain Tolerance Suprathreshold Scaling (e.g.

VAS, NRS) Temporal Summation Conditioned Pain Modulation Cerebral Responses (e.g. EEG, fMRI, PET) Muscle Reflexes (e.g. R3 reflex)

Are There Consistent Sex Differences in Experimental Pain Sensitivity?

Consistent with our previous reviews, current human findings regarding sex differences in experimental pain indicate greater pain sensitivity among females compared with males for most pain modalities, including more recently implemented clinically relevant pain models such as temporal summation of pain and intramuscular injection of algesic substances.

Are There Consistent Sex Differences in Experimental Pain Sensitivity?

In summary, 10 years of laboratory research have not been successful in producing a clear and consistent pattern of sex differences in human pain sensitivity, even with the use of deep, tonic, long-lasting stimuli, which are known to better mimic clinical pain.

STANDARDIZED PAIN MEASURES ACROSS MULTIPLE PAIN TASKS FOR FEMALES AND MALES Male (96)

0.5

Female (n=111)

0.25

0

-0.25

-0.5 HPTH Heat Pain

HPTO

IPTH

IPTO

Ischemic Pain

Mean=0, higher numbers reflect higher pain threshold or tolerance

CPTH

CPTO

Cold Pain

PPTTrap PPTMass Pressure Pain

Sex Differences in Pain Sensitivity Across Experimental Pain Measures (Mogil, in press)

Sex Differences in Endogenous Pain Modulation

Popescu, et al, 2010, Pain, 150: 309-318

Overview of Presentation • Conceptual issues • Sex differences in clinical and experimental pain responses • Mechanisms contributing to sex differences in pain • Sex differences in responses to treatment – Analgesic medications – Non-pharmacologic therapies

• Conclusions and clinical implications

Menstrual Cycle Effects on TMD Pain (LeResche, et al., 2003, PAIN 106:253-61)

Normally cycling women

Oral contraceptive women

Men

Exogenous Hormone Use and Pain • HRT use was associated with increased risk of TMD: OR=1.64 (1.38-1.94), and risk increased with estrogen dose (Fig. 1: LeResche, et al, PAIN 1997 69:153-60). • HRT use has also been associated with increased risk of back pain, widespread pain, and severity of orofacial pain (Brynhildsen, et al, 1998; Musgrave, et al, 2001; Macfarlane, et al, 2002; Wise, et al, 2001).

Sex Hormones and Experimental Pain Responses • A meta-analysis indicated that pain sensitivity was greater in the premenstrual vs. the postmenstrual phase for most pain stimuli (Riley, et al., 1999, PAIN, 81: 223-35)

R3 Reflex Threshold

Menstrual Cycle Effects on the R3 Reflex

(Tassorelli, et al, 2002 Psychosom Med 64:621-26)

Pain Threshold

• 32 healthy women tested at 3 cycle phases: – Menstrual (days 1-3) – Ovulatory (days 12-14) – Premenstrual (days 19-23)

• Assessed heat pain responses and DNIC induced using a 2minute cold pressor

No cycle phase effects on heat pain threshold or tolerance, or ratings of suprathreshold heat or cold pain emerged

No sex differences in baseline pain, but DNIC responses were more robust during the ovulatory vs. menstrual and luteal phases.

• Heat pain threshold and tolerance were assessed in 73 older adults (mean age 62.5 years).

• Three groups were tested: – Women on HRT (35) – Women not on HRT (15) – Men (23)

Thermal Pain Responses in Women as a Function of HRT Use and in Men

Temperature (deg C)

52 50

*

48

HRT No-HRT

46 44

Men

*

42 40 HPTH

* HRT group differs from other groups, p < .05

HPTO

Catastrophizing and Sex Differences in Pain Catastrophizing refers to an exaggerated negative mental set brought to bear during actual or anticipated painful experience (Sullivan et al, 2001, Clin J Pain. 17: 52-64).

Women typically report greater catastrophizing than men.

Sex Differences in Pain Catastrophizing (Sullivan, et al, 2000 Cog Ther Res, 24:121-34) 14 12 10 8

Men

6

Women

4 2 0

Rumination

Magnification

Helplessness

Does Catastrophizing Explain Sex Differences in OA Pain?

(Keefe, et al, 2000, PAIN 87:325-34)

â&#x20AC;˘

Women with OA reported greater pain, disability and showed higher pain behavior and greater catastrophizing.

When catastrophizing was controlled, gender differences in pain-related outcomes became non-significant.

Sex Differences in Depression Among Persons with Chronic Pain (Munce & Stewart, 2007, Psychosomatics, 48: 394-99)

â&#x20AC;˘ Data from a national representative sample from Canada that examined persons with chronic pain.

Depression Prevalence (%)

25 20 15 10 5 0 Mild

Moderate Severity of Chronic Pain

Severe

Overview of Presentation • Conceptual issues • Sex differences in clinical and experimental pain responses • Mechanisms contributing to sex differences in pain • Sex differences in responses to treatment – Analgesic medications – Non-pharmacologic therapies

• Conclusions and clinical implications

Meta Analysis of Sex Differences in Opioid Responses (Niesters, et al, 2010, PAIN, 151:61-68) 0.9 Standardized mean difference

0.8

(Higher values indicate greater â&#x20AC;&#x153;analgesiaâ&#x20AC;? in females)

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

-0.1 -0.2

All Studies

Morphine PCA Studies Studies

Clinical Studies

Morphine PCA

All Studies

Morphine

Experimental Studies

Niesters, et al 2010, Pain, 151: 61-68

Sex Differences in Side Effects of Morphine (Riley, et al, 2010, Pain Med., 11: 195-206)

Scale Score

5

4

Male (n=46)

3

Females (n=68)

* 2 * * 1 Sedation

Dry Mouth

* Significant sex difference (p < 0.05)

Nausea

Sex Differences in Side Effects of Pentazocine (Riley, et al, 2010, Pain Med., 11: 195-206)

Scale Score

5

4

3

*

Male (n=44) Females (n=54)

2 *

*

*

1 Sedation

Dry Mouth

* Significant sex difference (p < 0.05)

Nausea

Tremors

Sex Differences in Subjective Effects of Oxycodone (Zacny & Drum, 2010, Drug & Alc Depend, 107: 209-214)

Scale Score

Males

Females

Males

60

70

50

60

Females

50

40

40

30

30

20

20

10

10

0

0 Placebo

10 mg Like Drug

20 mg

Placebo

10 mg Take Again

20 mg

Sex Differences in non-Medical Use of Opioids (Back, et al, 2010, Addictive Beh 35: 1001-07)

18 16

% of People

14 *

12 10

Male

8

Female

6

*

4 2 0 * p < 0.0001

Lifetime

Past year

Gender Differences in Risk Factors for Aberrant Opioid Use (Jamison, et al, 2010, J Pain, 11:312-20) 9

1.2

8.5

1

8

0.8

*

7.5 7

Males

0.6

Males

Females

0.4

Females

6.5

0.2

6

0 PDUQ Score

Prescription Drug Use Questionnaire Assesses pain-related, psychosocial, family and personal history of substance use factors.

Higher scores indicate greater risk for substance abuse. * pâ&#x20AC;&#x2122;s < 0.05

*

POTQ Total Prescription Opioid Therapy Questionnaire Assesses past behaviors indicative of aberrant substance use (e.g. unsanctioned dose escalations, lost or stolen prescriptions).

Higher scores indicate greater risk for substance abuse.

• 10 M, 10 F subjects underwent electrical pain testing before and after administration of placebo or ibuprofen (800 mg) under two different conditions – They were told they were receiving placebo (negative expectancy) – They were told they were receiving ibuprfen (positive expectancy)

In males, positive expectancies produced greater analgesia, whether ibuprofen and placebo was administered.

Females failed to show analgesic responses in any condition.

Sex Differences in Responses to Ketorolac

(Compton, et al, 2003, Clin Exp Pharm Phys, 30: 759-63)

Sex Differences in Placebo Responses

(Aslaksen, et al, 2011, Psychosom Med, 73: 193-99)

Males showed significant reductions in pain unpleasantness after a placebo medication, while no placebo response occurred in females.

Males (%)

Females (%)

Odds Ratio

Being able to accept that you can no longer do what you were able to do in the past

41

46

1.6 (1.05-2.5)

Having fewer problems with household activities

29

58

4.0 (2.5-6.4)

Coping better with being a spouse

30

21

0.5 (0.3-0.9)

Having the cause of the pain found

29

21

0.6 (0.4-0.9)

Expectation

Sex Differences in Maintenance of Improvement After Multidisciplinary Treatment â&#x20AC;˘ Females did not maintain their improvement for some outcomes in this study. â&#x20AC;˘ Loss of improvement was associated with increased catastrophizing Present pain intensity 6.5 6 5.5 5 4.5 4 3.5

Pre-Tx

Post-Tx Males

3-mos

Females

Keogh, et al, 2005, PAIN, 114: 37-46

Distress in the past week 7 6.5 6 5.5 5 4.5 4 3.5

Pre-Tx

Post-Tx Males

3-mos

Females

Sex Differences in Responses to Multimodal Pain Treatment (Pieh, et al, 2012 PAIN, 153: 197-202)

• 496 patients (51% F) underwent a 5-week multimodal pain program

• Women also showed greater reduction in depression than men (32% vs. 19.9%)

25%

Percent Improvement

• Women showed significantly larger reductions in painrelated disability and pain severity compared to men

30%

20%

15%

10%

5%

0% Disability

Pain

Overview of Presentation • Conceptual issues • Sex differences in clinical and experimental pain responses • Mechanisms contributing to sex differences in pain • Sex differences in responses to treatment – Analgesic medications – Non-pharmacologic therapies

• Conclusions and clinical implications

Case Scenario • Pat: 48 year old presenting with chronic, recurrent, low back pain • Will the diagnosis be influenced by Pat’s sex?

• Do treatment goals differ if Pat is a male versus a female?

• Does Pat’s sex matter in developing a treatment plan?

Is There Any Actionable Information Here?

• The evidence does not support tailoring treatment based on gender, but the following findings merit consideration: – Women are at greater risk for may forms of chronic pain, therefore, preventive efforts may need to target women – Women experience greater side effects and perhaps greater analgesia from opioids, therefore dosing may vary by sex – Also, men appear to be at greater risk of opioid analgesia, due to the more positive subject effects of opioids – Some evidence suggests greater placebo responses in men, and this should be exploited where possible – Women may benefit more from multimodal treatment, which should be offered whenever possible

Other Factors to Consider • Gender-related biases in pain diagnosis and treatment do exist and should be guarded against • The quality of pain symptoms may differ for women and men, which can cloud diagnosis (e.g. coronary heart disease) • Women and men may have different goals and expectations when seeking pain care • Pain treatment needs to be tailored for each patient, and sex/gender is only one of many factors that can influence the treatment plan

Summary and Conclusions • Sex differences in clinical and experimental pain responses are consistently reported • Multiple biopsychosocial factors contribute to these sex differences • Women and men may respond differently to pain treatments – ↑ opioid analgesia and side effects in women – ↑ placebo effects in men – Sex differences in multimodal treatment inconsistent

• We don’t yet need pink and blue pills, but this is foreseeable in the future

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