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5 Articles in this Series
Breaking Down Barriers, Including Potential Trauma, When Treating Women in Chronic Pain
Key Goals, Including Healthcare Equity, Emerge from the Chronic Pain in Women Summit
Pain and Sleep: Why It Is So Crucial and How CBT May Help
Sex Differences in Pain Response Matter
Women in Chronic Pain Need More from their HCPs

Sex Differences in Pain Response Matter

From preclinical studies to clinical practice, males and females require unique assessments. with Jeffrey Mogil, PhD, Roger B. FiIlingim, PhD, and Julie Pilitsis, MD, PhD

The literature is full of studies around pain response, and both researchers and providers alike are aware that women are more sensitive to pain than men, but that is not really the issue. The issue is how women are modeled in research and how those results impact the course of treatment, according to speakers at the July 2019 HealthyWomen Chronic Pain Summit, held in Ellicott City, MD.


Animal Studies Often Start and End with Males Alone

Even as of the year 2015, 80% of preclinical pain research studies featured only male rodents, noted speaker Jeffrey Mogil, PhD, a psychology professor at McGill University (see detail at Mogil, Nature, 2016). While the NIH required females to be included in clinical research trials (particularly Phase 3) back in 1993, it was not until 2016 when the institute changed the rules, forcing federally funded scientists to use female animals and female cell lines in their preclinical research (ie, the NIH’s “sex as a biological variable campaign). Since then, said Dr. Mogil, “the floodgates have opened—and we are finding big, robust sex differences.”

For instance, microglia cells are known to play a major role in chronic pain and researchers now know they primarily act in those with high testosterone levels (ie males). One day, there may very well be certain drugs for each sex as a standard, especially in the pain domain, but clarified Dr. Mogil, “There is still advocacy left to do in the clinical trial world among pharma and others.”

The pain community at large is still in the early stages of female-centered research. Even within the FDA’s Office of Women’s Health (OWH), established in 1994, only 31% of its research projects have looked at sex differences to date, according to summit speaker Kaveeta Vasisht, MD, PharmD, acting associate commissioner of OWH.

The Clinical Implications of Sex Differences Found in Pain Research

Roger B. Fillingim, PhD, a distinguished professor at the University of Florida’s Pain Research and Intervention Center of Excellence in Gainesville, addressed the HealthyWomen summit audience by reviewing the clinical implications of individual differences in pain responses.

Time and again, laboratory tests time have trialed different types of pain stimuli on healthy people and demonstrated different reactions and responses based on the individual, he noted. While there is common overlap between the sexes, pain sensitivity also differs between men and women. In unpublished data from the well-known OPPERA Study, for example, Dr. Fillingim noted that females exhibited more pain conditions, including more overlapping pain conditions, showing that women are at greater risk than men for having pain and for having multiple pain conditions. “While differences between sex are smaller than differences within sex, that doesn’t mean the differences are unimportant, especially at the public health level,” he said.

In terms of clinical implications, understanding the risk factors that explain sex differences in pain and pain prevalence is key, as is understanding whether treatments work differently in women than they do in men. This knowledge and integration into practice will help lead healthcare providers toward precision medicine. As an example, Dr. Fillingim referred to a study conducted by his lab on the OPRM1 A118G genotype in correlation with heat pain ratings (see Fillingim, et al, J Pain, 2005). No overall genotype effect was found, but there was a sex by genotype interaction with opposite responses for males and females. He noted that the results were repeated in a similar study in Norway, in which the allelle studied was protective in males with pain due to lumbar disc herniation but associated with higher pain ratings in females. There have also been demonstrated sex differences in analgesic responses to mixed action opioids, and the redhead gene was associated with better analgesia from these medications in women only (see Gear, et al, Nature Med, 1996, and Mogil, et al, 2003, PNAS).

Overall, concluded Dr. Fillingim, there are many robust individual differences in pain and “sex must be considered in personalized pain treatment.”

Sex Differences as Part of Pain Management Approaches

In the same session, Julie Pilitsis, MD, PhD, a professor of neurosurgery at Albany Medical College in New York, spoke about some advances in chronic pain treatment with a focus on neuromodulation use in men and women. (She disclosed that she has relationships with some neuromodulation device manufacturing companies.)

“It’s more complicated than just men and women, diversity also plays a role in pain disorders,” said Dr. Pilitsis. We have to keep in mind both genetics and individual differences when assessing and treating for pain. Decision-making is very complicated as the reasons behind development of chronic pain and treatment response could be one of many things. The diagnosis we really need to seek is the one that explains what patient will develop chronic pain and which patient will respond to which treatment. Phenotype includes sex, ethnicity and multiple other factors—all key to treating pain in the future, she explained.

Clinicians know that pain is multifactorial and are able to test for those aspects, added Dr. Pilitsis. “How we use those results in meaningful ways is not easy,” she added, noting that providers cannot continue to chase pain scores. “My pain level of 7 could be different than person X’s pain level of 7. Functional improvement [rather than the rating] needs to be the target.”

Dr. Pilitsis shared her team’s work in Albany regarding the follow-up of spinal cord stimulation (SCS) implants in male versus female patients. Overall, she noted that her patients performed better at 2-year follow-up compared to what is often reported in the literature (72% reporting pain relief compared to 50% on average). She credits this difference to the approach applied by her clinic’s holistic team, where patients receive not only neuromodulation treatment but also methods to help reduce stress and anxiety, and overall support. (See more on this subject by Dr. Pilitsis in Neuromodulation, 2016,  and Neurosurgery, 2019.)

Overall, Dr. Pilitsis said that there are many options for women in pain but, in her opinion, targeting the right patients with a multidisciplinary team is essential for long-term outcomes.


Update: An additional 2019 recent study by Dr. Pilitsis and team examined sex differences in back pain response with regard to spinal cord stimulation (SCS). The study reviewed 63 patients who had their spinal cord stimulator removed due to non-infection related causes found that most implants were removed because of inadequate pain relief or discomfort caused by the generator. Implant removal due to discomfort of the device itself was found to be much more common among female patients, while there were no sex-related differences when looking at patients who had an implant removed due to insufficient pain relief. The underlying cause of the increased discomfort experienced among women may be related to the size and placement of the device or differences in neural processing.

Another interesting finding from the study demonstrated that women who had a stimulation device removed had more untreated depression compared to male counterparts despite no statistically significant difference in post-operative pain ratings. These results further support a multimodal approach to pain management with an adequate focus on psychological health and well-being. More research is needed to fully understand how SCS can provide maximal benefit to female patients. 


PPM polled its online audience on taking sex differences into consideration when assessing patients. See the results.

Next summary: Women in Chronic Pain Need More from their HCPs
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