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11 Articles in Volume 16, Issue #2
Gender and the Pain Experience
Sex and Gender Differences In the Pain Experience
Medical Management of Diabetic Neuropathy
Comorbid Substance Use Disorders: Primer for Pain Management
Marijuana Use Disorder: Common and Often Untreated
Acupuncture: New Approach for Temporomandibular Disorders
Opioid-Maintained Patients Who Require Surgery
Natural Protein Points to New Inflammation Treatment
Lessons from the Murder Conviction of Dr. Hsiu-Ying “Lisa” Tseng
Zohydro vs Hysingla: What is the Difference in These Extended-Release Agents?
Letters to the Editor: Opioid Calculator, Testosterone for SCI

Sex and Gender Differences In the Pain Experience

New insights from Roger B. Fillingim, PhD, into why the sexes experience pain differently

Q Why is research into sex and gender differences in the assessment and treatment of pain so important?

Dr. Fillingim: This area of research may help us understand why men and women seem to have different pain experiences. If there are fundamental differences in what drives pain in women versus men, we might need to think about different treatments tailored to the source of pain—this is a new way of thinking for most of us.

Epidemiological evidence has clearly shown that pain is distributed differently in women and men. Overall, pain is reported more frequently by women than men, and specific pain conditions (eg, migraine, fibromyalgia, irritable bowel syndrome, and temporomandibular disorders) are considerably more common in women than in men.1 We need to understand the underlying cause of these differences in order to fully understand how to better treat patients. (see Gender and the Pain Experience.)

Tug of war—how sex and gender influence how men and women experience pain differently.

Q How can these differences in the pain experience contribute to the undertreatment of pain in women?

Dr. Fillingim: If a clinician has developed his or her whole view of pain based on the average man, anyone who responds differently to pain or analgesics than the average man seems unusual. Thus, we need to expand our expectations for what the “average” patient’s pain experiences might be, because it varies wildly across people, and gender is one of the factors that seems to contribute to these differences.

I hope that as we learn more about women’s and men’s pain as potentially different entities, we will have less of this potential bias and a better understanding of the varied presentations of pain that we might expect in a provider’s office.

Roger B. Fillingim, PhD

Q What are the key biopsychosocial contributors to sex differences in pain?

Dr. Fillingim: Women have higher levels of estrogen and progesterone, and also are subject to more dramatic cyclic fluctuations in those and other hormones than men. It is clear that sex hormones are related to pain; however, this relationship is complicated. The relationship appears to be related to the timing of the hormones—for example, it might be estrogen withdrawal that precipitates pain rather than the average level of estrogen across the cycle. In addition, while some evidence suggests that estrogens are associated with higher levels of pain, other studies have found that estrogens are associated with lower levels of pain.

The organizational effects of sex hormones—the permanent effects of hormones in early development on the structure and function of our brains and bodies—also may play a role in sex differences in pain. Rodent models suggest that those early effects of hormones on pain can be even stronger than the effects of current hormone levels.2 In addition, research shows that other aspects of pain processing may vary between women and men. For example, evidence suggests that men show greater activation of μ-opioid receptors when subjected to pain compared to women.3

Brain imaging studies reveal some similarities, but also some differences between men and women in how the brain processes pain.4 Furthermore, some evidence suggests that women have more densely innervated skin.5 While this relationship doesn’t seem strongly related to pain, it is still something to consider.

Furthermore, there are a variety of psychosocial contributors to pain. For example, women in the general population are more likely to have higher levels of depression and anxiety, both of which are known to potentially increase the risk for pain. Pain catastrophizing—magnification, rumination, and feeling of hopelessness—also is typically higher in women than men. Higher pain catastrophizing scores have been found to correlate with greater pain intensity, pain-related disability, fear avoidance, and psychosocial distress.

In contrast, women appear to have a broader repertoire of coping skills for pain, some of which are likely effective and some of which are characterized as being maladaptive.

Stereotypic gender roles—masculinity and femininity—are correlated with pain as well. The extent to which gender roles are responsible for the sex difference in pain is hard to tell, but these roles may help explain why men tend to under-report pain or why women over-report pain, because of what is acceptable versus not acceptable according to gender roles.

Q What are the clinical implications of your recent study of sex differences in postoperative pain in patients undergoing a variety of surgical procedures?

Dr. Fillingim: On average, women report higher levels of pain after surgery than men. However, some studies have shown conflicting findings. Our study was notable given the large number of patients included (3,739 women and 3,992 men) and the large number of pain scores evaluated (n=333,446).6

On postoperative day 1, mean pain scores were 4.20 for women and 3.98 for men—a small but statistically significant difference (mean difference 0.22, P<0.0001). This difference was highly statistically significant because of the large patient population. The actual magnitude of the difference between women and men was very small—less than 1 point on a scale of 0 to 10—and is not likely to have a clinical impact on treatment decisions.

However, what is particularly interesting about the study is that women were 14% more likely to have severe pain events, which almost always require an intervention. It would be helpful if we could identify which patients are at risk for severe pain events, so that we can either prevent these events or better prepare to aggressively manage them.

Q Are there gender differences in how the sexes respond to pharmacological and nonpharmacological pain interventions?

Dr. Fillingim: Studies suggest sex differences in response to some pain medications, the most studied of which are opioids. On balance, the evidence suggests that women use less opioids than men after surgery.7 This is particularly true in studies of patient-controlled analgesia (PCA) where patients are delivering their own medication.7

This difference could be because women are getting better pain relief from opioids, so they need less medication. Indeed, we and other researchers have found that women in general show better pain relief in response to μ-opioid analgesics, particularly morphine.7 It also could be that women are taking lower doses of opioids because they experience more side effects than men.

On the other hand, it could be that women are only pushing the button on PCA devices when the pain is really bad, and men are pushing the button and maintaining a consistently lower pain level, although we don’t have any evidence thus far suggesting this to be true.

We do not have a clear picture of sex differences in response to nonpharmacological treatments. It would be extremely helpful if investigators on drug trials would report clinical findings by gender. Even if researchers don’t perform a statistical test, but at least provide data on means, we could perform a meta-analysis. However, that is currently not standard in the literature.

Q What is the most important recent study on gender difference in pain that health care providers should know?

Dr. Fillingim: A recent study found that different immune cells drive pain responses in male versus female mice.8 Mechanical pain hypersensitivity in male mice appears to be driven by microglia, while in female mice appears to be driven by adaptive immune cells, such as T lymphocytes.8

The point of the study was not that male or female mice had more or less pain. The point was that the causes of the pain from an immune perspective were fundamentally different. And so, if we are going to design an immunotherapy to treat pain, we have to design a different one for female versus male mice. These types of qualitative differences in the experience of pain may have stronger clinical implications than studies just showing that one gender has more pain than the other.

Q What lead you to this area of research?

Dr. Fillingim: In 1993, I was at University of North Carolina doing a post-doctoral fellowship under William Maixner, DDS, PhD, who was studying temporomandibular disorder (TMD) pain. Because this condition is significantly more common in women than men, we started a side project studying sex differences in pain in healthy people. We thought that maybe part of what contributes to the excess prevalence of TMD and other pain conditions in women is a difference in the way that the female pain processing system works compared to that in males.

Next, I started looking at sex differences in acute dental pain, and ultimately received my own funding to examine sex differences in both experimental pain responses and in response to opioids.

During the past 20 years, I’ve seen the status of sex difference in pain in biomedical research get elevated further and further. The National Institutes of Health (NIH) requires that funded studies include men and women, unless there is a compelling reason not to.

In 2015, the NIH issued a notice stating that even basic animal studies have to justify the use of only one sex in order to secure grant funding.9 That is a dramatic shift, given that historically the overwhelming majority of preclinical research have used male animals, even in studies of clinical conditions that are more prevalent in women than men.

On the other hand, clinical applications in this area of research are still lagging behind, and that is where we really need to make some inroads.

About the Expert: Roger B. Fillingim, PhD, is a Distinguished Professor at the University of Florida, College of Dentistry, and the Director of the University of Florida Pain Research and Intervention Center of Excellence (PRICE), Gainesville, Florida. Dr. Fillingim also is Immediate Past President of the American Pain Society.

Last updated on: March 15, 2016
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Medical Management of Diabetic Neuropathy

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