The patient-specific individual experience and treatment of pain is currently a highly debated point of discussion. No longer are pain management consultants using a “standardized” concept to manage pain in their patients.
It is well known that many variables such as our personal immune system and our individual unique gene expressions alter our pain experience even when given identical pain stimuli. This article will discuss the science behind the concept of the individual selective patient-specific approach to pain management.
This topic requires an initial review of important definitions. First, it is essential to point out that the terms “sex” and “gender” are not synonymous. Sex is a characteristic defined by biological or chromosomal traits, whereas gender is a continuum of self-identified traits, which can be influenced by societal and cultural factors. Furthermore, gender refers to a person identifying themselves as being either male or female with many variations in the middle. It is essentially a modifiable, socio-culturally shaped behavior unrelated to your chromosomal makeup. It is your own personal self-representation of who you are.
There is a range, with self-identified males being on one end and self-identified females on the other. Because it is a subjective and modifiable category, many of the older research studies on pain utilizing the term “gender” were not always scientifically objective.
The term “sex” is a purely phenotypical definition related to the expression of either two “X” chromosomes or an “X” and a “Y” chromosome. It is easily definable when comparing two people and placing them into a research (trial). Using the term “sex” you are defined as either male or female specifically by your chromosomes and studies using this identifier have more scientifically objective and less variable discussion. Clearly there are a myriad of chromosomal variations that can occur and cause difficulty placing a subject into either male or female categories, but for the purpose of this discussion, we will focus on the traditional “X” and “Y” categories.
This topic may appear new in the clinical arena of the anesthesiologist, but the pain research world has studied this concept since the late 1990’s. Historically the first landmark paper that introduced the concept of gender differences in pain was by Bartley in 1997 termed “Sex Differences in Pain”. This paper concluded that females had 1) lower pain thresholds, 2) higher pain ratings, 3) less tolerance to noxious stimuli and 4) a greater ability to discriminate pain.
They also concluded that females had pain in a greater number of body regions than their male counterpart. They reported three proposed mechanisms leading to these findings 1) sex specific hormones acting as neuroactive agents affecting various pain physiologic processes such as the opioid and nonopioid systems, nerve growth factor, and the sympathetic nervous system; 2) the vaginal canal being a route for trauma and invasion by pathogens leading to hyperalgesia and 3) females having different patterns of pain for example a temporal pattern correlating with the menstrual cycle – which ultimately may influence how females “learn pain” and interpret painful stimuli.
So what are the specific differences found in the published literature when comparing the sexes? Females have 1) Greater pain discrimination 2) Less pain tolerance 3) Higher pain intensity 4) More rapid withdrawal reflex 5) Greater pupil dilation 6) Greater temporal summation 7) Less diffuse noxious inhibitory control (pain in one part of the body leads to pain in another part of the body) 8) Greater pain related fears and depression 9) Less self-efficacy 10) Greater disability.
In 2007 the International Association for the Study of Pain (IASP) Special Interest Group on Sex and Pain published a review of the previous ten years of publications on pain and they found that 79% of the papers used 100% male subjects in their research and only 8% of pain papers published used 100% female subjects. This made researchers aware of the importance of using female/male subjects in the study designs of their future pain research in an effort to understand “individual patient specific “pain. Some authors suggest that this propensity for male only research subjects was an attempt to remove the variability of hormonal influences on their pain specific research outcomes. Since then, researchers make strong efforts to have equal representation of males and females in their study designs.
What types of pain are “sex” specific? Female specific pains include: 1) pelvic pain, vulvodynia, post mastectomy, dysmenorrhea, labor pain, and endometriosis. As far as pain in general – females (compared to males) more frequently experience migraine, temporomandibular pain, irritable bowel syndrome, and fibromyalgia. Male specific pains include 1) Prostatitis 2) Prostadynia and less frequently 3) Chronic pelvic pain.
What are the physiological differences between the sexes? There are four categories to consider 1) Bioavailability, 2) Distribution 3) Metabolism and 4) Excretion.
These four categories will affect medication management of your female patient. As far as bioavailability – females have lower body weight and higher body fat content in general which will affect drug bioavailability. They have a variety of drug catabolic enzymes that stored in less quantities compared to males.
An example is the long-held notion that females become more quickly and heavily intoxicated compared to males, which was subsequently found to be secondary to a deficient amount of alcohol dehydrogenase in females compared to males. Distribution in females is also different compared to males. The volume of distribution is less, the amount of albumin is less and the amount of protein binding in females compared to males is less.
Drug metabolism is different secondary to a higher amount of cytochrome P3A, which will metabolize certain drugs more quickly, such as Midazolam. Lastly, renal clearance is slower in females compared to males.
Female hormones affect many drugs. If you look at a variety of drug classes utilized in pain management and then look at their neurobiological precursors, you will find interactions with several female hormones.
Examples include: Opioids (Enkephalins), anticonvulsants (Gamma amino butyric acid), antidepressants (Serotonin), ketamine (Glutamate), clonidine (Angiotensin), THC (Cannabinoids). This has been demonstrated in the literature with females having a greater side effect profile with opioids particularly its sedative and respiratory depressive properties, which in turn limits the opioid dosing necessary for adequate pain control.
If opioids perioperatively are influenced by female hormones, wouldn’t it be better to remove ourselves from the habit of generalized postoperative dosing of the female who is at the beginning of her menstrual cycle exactly in the same manner as a male dose per kilogram? This is an example of where patient specific pain management begins to cross into our clinical arena.
Additionally, not only a greater analgesic drug -dose per kilogram in females compared to males but considering a different class of analgesic in females compared to males based on progesterone and estrogen levels. We are beginning to look at individualized medicine. The genetics and hormones of our patients and how that affects our patients pain experience and outcomes. Leaving the idea of treating everyone as a “hip replacement” or a “total knee” and taking into consideration our individual patient characteristics.
What are the hormone characteristics of females? In general when estrogen decreases during the hormonal cycle – pain is increased. Alternatively, the hormone progesterone is an analgesic pain-relieving affective hormone and is found at about the halfway point in the female hormone cycle. If you compare the three hormones Estrogen, Progesterone and Testosterone (males) you will find very specific effects on 1) immune system, 2) brain 3) spinal cord 4) peripheral nerves 5) musculoskeletal system and 6) cardiovascular system. Progesterone is an anxiolytic. It is also a sedative, an analgesic, an anticonvulsant and is considered neuroprotective as well. Testosterone is analgesic, modulates endogenous opioids, and decreases norepinephrine. Unfortunately, estrogen has a number of nociceptive properties. It increases glutamate in the dorsal horn and changes facilitating pain pathways.
The physiological differences have been studied using the transgender and neutral sex populations. These groups allow specific physiologic hormone replacement environments to occur without correlation to genetic chromosomes allowing research to look in more detail at how hormones affect pain.
In 2007, a publication reported cross-sexual hormone replacement changes in transgender women and men. These are patients that undergo gender reassignment surgery as well as hormonal replacement to reflect their desired gender identity. The first category included transgender women (biological males undergoing the transition process to women.) They were given estrogens and anti-androgens. The second category included transgender men (biological females undergoing the transition process to men) and was given androgens. In this paper, 25% of the transgender women developed painful conditions including headaches, muscle aches and breast pain. When the transgender men (female to male) underwent the male-hormonal transition process, 54% of that group reported a global reduction of their previously reported pain. Although the study had some flaws, it was an interesting trend and made researchers want to study the role of testosterone and estrogen in analgesia more clearly.
There are psychological differences in males vs females. The prevalence of major depression and anxiety is significantly higher in females compared to males (5.3 vs 3.2% worldwide). In addition, coping mechanisms are also different between men and women with women more likely to verbalize their pain. Particularly, women are more likely to catastrophize and ruminate during painful experiences. These psychosocial factors more often found in women all play a role in not only how pain is experienced but subsequently how itub managed. Additionally, sociocultural differences include 1) childbirth stereotypes and 2) historical stereotypes (sedentary desk job in females vs manual labor in males).
Where does the immune system fit in when we discuss the difference in male and female pain pathways? Although social and psychological factors certainly play a role in the differences in prevalence and incidence of pain suffering in females – biological differences in the functioning immune system likely underlie these observed effects. Biological sex differences in the functioning of the innate and adaptive immune systems are related to the pain experience. With rodent models male mice utilize microglia in the spinal cord to mediate pain, whereas females preferentially use T cells in a similar manner.
The difference can be traced to differences in cell populations, differences in suppression by hormones, and disparate cellular responses in males and females. These sex differences also translate into human cellular responses and may be the mechanism by which the disproportionate chronic pain experience is based. Recognition of the evidence underlying sex differences in pain will guide development of treatments and provide better options for patients that are tailored to their physiology.
The key phrase in this review is pain experience “variability”. There is tremendous inter-individual variability in the pain experience. As we have stated above – multiple biological and psychosocial variables contribute to individual differences in pain including demographic variables, genetic factors, and psychosocial processes.
This paper did not cover other variables such as culture, ethnicity and race but those factor heavily as well in the variability of pain. Even in experimentally-induced pain, many variables can be manipulated to reproduce the results we have discussed.
Additionally, the different biopsychosocial factors interact with each other in complex ways to influence the experience of our individual pain. Genetic associations with pain vary across ethnic and sex groups. Genetic factors also interact with psychosocial factors including stress and pain catastrophizing, to influence pain. The individual and combined influences of these biological and psychosocial variables result in a unique combination of factors that contributes to each of our individual pain.
Understanding these interactions is a critically important process in providing optimal pain treatment, and future research is needed to understand the crucial need to provide individualized, personalized pain care to our patients.
In the most fundamental terms, sex differences in perception, expression and coping with pain exist. Understanding these differences is instrumental to how we as pain physicians assess and manage pain. Future articles detailing how other factors including culture, race and ethnicity influence our understanding and management of pain are in the works but our hope with this article is to change the “one size fits all” approach to pain and develop pain management plans which allow us to provide the best possible individualized care to our patients.
- Bartley KJ. Sex differences in pain. Behav Brain Sci. 1997; 20:371-80; discussion 435-513.
- Whitley, Heather P., and Wesley Lindsey. “Sex-Based Differences in Drug Activity.” American Family Physician, 1 Dec. 2009, www.aafp.org/afp/2009/1201/p1254.html.
- Aloisi AM et al. Cross-sex hormone administration changes pain in transsexual women and men. Pain 2007: 132:560-567.
- Albert, Paul R. -sex hormone administration changes paomen?” Journal of Psychiatry & Neuroscience: JPN, 8872147 Canada Inc., July 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4478054/.
- Sorge RE et al. Sex Differences in Pain. Journal of Neuroscience Research 2017: 95:1271-1281.
- Fillingim RB. Individual Differences in Pain: Understanding the Mosaic that Makes Pain Personal. Journal of Pain. 2017: Apr 158 (Supp 1) S11-S18.