The Physiology of Pain and Pain Relief In Sex

The more I research this subject, the more I come to understand that women aren’t just more “sensitive” to pain than men. They actually process pain differently than men—physiologically, biologically, and psychologically, from the cellular level up.
It seems obvious, therefore, that women’s pain must be treated, managed, and even identified according to different criteria. However, because the majority of our current pain research is based on male models, this is not currently being done.
A major reason, of course, for these differences is our sex hormones. Most cells produce and respond to sex hormones (such as androgens, estrogens, and progestins)—including nerve cells in the central nervous system (CNS). More, sex hormones directly affect both the organization and function of the CNS, starting in the womb. This means that neurotransmission—including the perception of and response to pain—is biologically different in men and women.
The areas of the brain that control perception of pain and analgesia (pain reduction or suppression) have receptors for both estrogens and androgens. Estradiol, a variant of estrogen, seems to be particularly important in controlling the structural and molecular aspects of the CNS because it regulates proteins involved in signal transduction. Estrogen in the bloodstream also appears to affect other neurotransmitters like dopamine and serotonin. This is why, for example, migraines are more prevalent during certain points in the menstrual cycle; decreased estrogen levels lead to decreased receptivity to serotonin.
Sex hormones also bind to nerve receptors in the brain, the spine, and peripherally throughout the body. They help to modulate the perception of and response to pain and can even lead to the formation of additional receptors that control pain response.
When something happens to cause pain, nociceptors—the sensory nerves responsible for recognizing pain—are stimulated. It’s the job of nociceptors to transmit a pain signal to the CNS, where a response is formulated. However, along the way, different factors may modify the signal (i.e., the sensation), either intensifying or alleviating it.
In essence, pain medications intercept or ameliorate in some way the signals sent from the nociceptors to the brain. But because pain reception and perception is so strongly affected by sex hormones, because of the unique nature of female inflammatory responses, and because of differences in the ways that female cells communicate pain to the central nervous system, women respond differently than men to many treatments.3 In fact, what works in men is not guaranteed to work to the same degree—or at all—in women.
This was demonstrated in animal models by Robert E. Sorge, PhD, an assistant professor at the University of Alabama in Birmingham, and his colleagues. In male and female mice with persistent pain and inflammation, they injected one of three drugs that inhibit microglial function (the mediation of immune response in the central nervous system). All three drugs reversed pain sensitization in the male mice but had no effect whatsoever in the females.4
While it’s understood in the medical community that results in animal models may not be replicated exactly in humans, the fact that this study showed an entirely different process between male and female mice was highly intriguing and demonstrated the need for similar studies in humans.
Another groundbreaking study, conducted in Texas, looked at patients with metastatic spinal tumors that were pressing on dorsal root ganglia (clusters of neurons in the dorsal roots of spinal nerves). Dorsal root ganglia are the main signaling centers for the central nervous system. In essence, they take information from various parts of the body and relay it to the brain. Researchers found that after the tumors were removed in these study patients, there were differences in male and female inflammatory responses to pain. In fact, they identified different gene expressions related to pain and inflammation in their male and female subjects. This means, in essence, that men’s and women’s bodies signal their brains differently when there is a problem. This led researchers to conclude that there are sex-based differences to neuropathic chronic pain responses.5
This is an intriguing concept to study, particularly in relationship to women’s pain management. Unlike some other pain medications (like the microglial inhibitors studied by Dr. Sorge and his team), opiates do seem to work to manage women’s pain—although women are more likely than men to experience unpleasant side effects from their use. This efficacy may explain why prescription rates for opiates like oxycodone (Percocet, OxyContin), hydrocodone (Vicodin), and many others are so much higher for women, particularly women of reproductive age. It may also partially explain why women are more likely than men to use opiates without a prescription to cope with chronic pain or to self-treat for emotional conditions like anxiety. Unfortunately, this prevalence can also create a pathway for addiction and misuse.
Like so much else in medicine, nearly all our pain protocols, medications, and treatment procedures are still based on male models, male animal experiments, and male-centric research. In fact, a recent review in the journal Pain noted that at least 79 percent of animal studies published in that journal over the last ten years included only male subjects, while 8 percent studied only female subjects, and 4 percent studied sex differences.6 And yet, as we’ve observed, the results of these male-centric studies are then applied to women as if their biology were interchangeable with men’s.
In order to give women more and better treatment options for their acute and chronic pain, we need to understand how their pain is sensed, transmitted, and managed internally—particularly when it comes to ongoing pain and chronic pain disorders. Because we don’t understand women’s specific pain pathways, we are essentially fire-hosing the problem, hoping that something will work. Imagine if we could develop medicine to target sex-specific pain signals and inflammatory patterns. Could we relieve women’s pain with lower doses, fewer side effects, and fewer addiction issues?
Women have exponentially higher rates of pain disorders tied to neurological function, including fibromyalgia, lupus, and chronic fatigue syndrome. Could this be because of the ways in which our bodies process pain?
Men and women are both able to produce their own internal analgesics—compounds that help take the “edge” off the pain and reduce inflammation. This process is called diffuse noxious inhibitory control (DNIC). However, people with chronic pain or with pain disorders like fibromyalgia have lesser, or “blunted,” DNIC activity. Also, mu receptors in the brain and spinal cord (which diminish pain sensation and are the receptors that opioids bind to) are more prevalent in men than in women and do not respond as robustly in women because they are dependent on estradiol levels, which fluctuate during the menstrual cycle. This may explain why both chronic pain and pain disorders are more common in women and respond less well to treatment.
There are drugs that appear to work for chronic pain in women, particularly neuropathic pain; for example, Neurontin (gabapentin) and Lyrica (pregabalin) are often prescribed for fibromyalgia, diabetic nerve pain, and other pain disorders. However, the exact mechanisms by which these drugs dampen nerve response in the female body are not well understood. (In fact, Neurontin is an antiseizure drug, not a pain reliever, and was not originally intended for use in nerve pain patients.) Because we don’t fully understand female pain pathways, it often feels to me that we are throwing drugs at the problem to see what “sticks.” This is obviously not ideal for patients—but it’s not ideal for our medical system either, particularly because these drugs come with a laundry list of potentially serious side effects that often complicate an already problematic situation.
Another common practice is to prescribe antidepressants and/or antianxiety medication for chronic pain disorders. Increasing serotonin and dopamine levels does help make chronic pain more bearable—but, in the long run, it’s not a cure. Until we understand more about the underlying causes and mechanisms of chronic pain conditions like fibromyalgia, offering relief is the best we can do.
The fact is, until we understand the physiology of female pain, we will not be able to treat it effectively, and we will keep coming up with “halfway there” solutions for the conditions that are dramatically affecting women’s lives. Broadening our understanding will help us not only to finally give women the relief they’re seeking from their acute and chronic pain but also to understand the differing mechanisms of drug metabolism, efficacy, and addiction between the sexes.

References:

  • Robert E. Sorge and Larissa J. Strath, “Sex Differences in Pain Responses,” Current Opinion in Physiology 6 (2018): 75–81. doi: 10.1016/j.cophys.2018.05.006.
  • Robert E. Sorge et al., “Different Immune Cells Mediate Mechanical Pain Hypersensitivity in Male and Female Mice,” Nature Neuroscience 18, no. 8 (2015): 1081–1083. doi: 10.1038/nn.4053.
  • R. Y. North et al., “Electrophysiological and Transcriptomic Correlates of Neuropathic Pain in Human Dorsal Root Ganglion Neurons,” Brain 142, no. 5 (2019): 1215–1226. doi: 10.1093/brain/awz063
  • Joel D. Greenspan et al., “Studying Sex and Gender Differences in Pain and Analgesia: A Consensus Report,” Pain 132, Suppl. 1 (2007): S26–S45. doi: 10.1016/j.pain.2007.10.014.
  • Elena H. Chartoff and Maria Mavrikaki, “Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction,” Frontiers in Neuroscience 9 (2015): 466. doi: 10.3389/fnins.2015.00466

 

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