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Sex-Specific Differences in Responses to Painkillers

Author: Suhani Patel

Editor: Shirley Chen and Hanson Xuan

Artist: Serena Yung

Sex-specific disparities are highly prevalent in society, but as subjectivity transitions to objectivity in the medical field, such differences can still be observed and materialized in an alternate form: the physiological differences between men and women cause females to respond differently to pain medications. Researchers have consistently studied this phenomenon and attributed the observed differences to three main reasons: hormonal, immune, and genetic differences.

Estrogen–a hormone that controls the development of the uterus, ovaries, and breasts and regulates menstruation–significantly influences pain perception. Depending on the location and concentration of estrogen, it can either worsen or lessen pain. Testosterone–the hormone involved in developing the penis, testes, and prostate–can dull pain. Some patients even take testosterone treatments for chronic pain. Dr. Meera Kirpekar, clinical assistant professor of anesthesiology, perioperative care, and pain medicine at NYU Langone, explains, “women can have worsened pain because of their high estrogen levels. And men with low testosterone can process pain similarly to women.”

The second finding that explains the difference in pain sensation lies with immune cells called microglia–the macrophages of the brain. The theory is that blocking microglia also blocks pain.

When microglial functions are inhibited in men, pain is similarly reduced. However, such results were not replicated in women. Why? Women use immune cells called T-cells instead of microglia to control their pain response. Moreover, immune cells known as peripheral macrophages contribute to neuroinflammatory pain by activating an enzyme known as cyclooxygenase-2 (COX-2). High levels of macrophage activity in specific areas thus lead to inflammatory-related pain. Non-steroidal anti-inflammatory drugs (NSAIDs) target inflammation by reducing COX-2 activity.

Recognizing this, researchers at Duquesne University in Pittsburgh, Pennsylvania, suspected that dedicating additional focus on macrophage activity could tell them a lot about different pain responses between males and females. They thus created a nanomedicine that could deliver celecoxib, an NSAID, directly to these macrophages — and specifically to the site of pain — to monitor sex-based differences in response.

The final cause of differential painkiller response resides within ribonucleic acid (RNA), the secondary genetic material of the human body. “Women have elevated levels of RNA in the bloodstream compared to men,” explained Dr. Kirpekar.

“It’s theorized that these elevated levels lead to a predisposition for chronic pain. Many of these RNA molecules are encoded by genes on the X chromosome. As women have two X chromosomes, they are more predisposed to develop chronic pain,” she added.

When asked to explain what may lie behind the sex-based differences in response to pain treatments in the study, Dr. John A. Pollock, professor and co-director of the Chronic Pain Research Consortium at Duquesne University and one of the study’s authors, told MNT: “every time that we look carefully, we find that there are subtle differences in the underlying physiology of females versus males. As we have noted in this study, pain [hypersensitivity] arising from the peripheral nervous system relies on a dialogue between neurons, activated glia (support cells), and the immune/ inflammatory response, which provides a dynamic milieu of cytokines and chemokines.” Dr. Pollock and his team believe that by studying model species like rats, we can better understand how these processes differ across the sexes and how to treat pain and promote long-lasting recovery in people.

Agreeing with this perspective, Dr. Jelena M. Janjic, associate professor at the School of Pharmacy at Duquesne University, states that “knowing more about the differences in pain response among males and females at the molecular level is a first step towards designing such treatments, and nanomedicines are crucial for this due to their dual-use for diagnostics and as a therapeutic.”



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