Men,Women,and Pain

Abstract

Pain is one of the cardinal signs of illness or injury of a body part or organ system. Healthcare providers from antiquity to the present ostensibly have been sensitized and educated to perceive, evaluate, diagnose, treat, and relieve pain. Sadly education in pain medicine in medical school and resident trainees' curricula is often limited to faculties' grading students on their use of pain scales and expressions of “empathy” in simulations and actual patient encounters. There seems to be a widely accepted belief that people who choose to become healthcare providers will have “natural empathy” and an instinctive ability and desire to recognize and alleviate pain in their patients. Unfortunately this ill-considered hope has no grounds in scientific research or pedagogic practice.

Healthcare providers come to the profession with empathy (it is hoped), but also with a lifetime of internalized beliefs, social constructs, expectancies, and lenses through which they perceive their worlds, evaluating and choosing actions based on these perceptions, including a preformed, predigested, premeditated understanding of the relationship of pain and the symptom of pain to sex and gender. While most providers mean well and believe that they are unbiased in their perceptions and understanding of their patients, good intentions are not sufficient. Furthermore in spite of the primal importance of pain in the recognition and management of disease, the neuroscience of pain, including approaches to the valid and accurate evaluation, and effective treatment of pain, particularly with respect to sex and gender, is in its early stages.

Many disciplines of medical research have turned their attention to issues of sex and gender in the presentation, evaluation, diagnosis, and treatment of disease. For generations women and men had been seen as medically identical, apart from their reproductive systems, and internal and external sex organs. Of course this notion and the medical practice that it spawned are patently false. Women and men are different. Every cell in their bodies contains sex chromosomes and these chromosomes influence a myriad of biochemical, biophysical, and biopsychologic functions.

Most cells produce and respond to sex hormones, such as androgens, estrogens, and progestins, including neurons in the central nervous system (CNS) itself. It is well-recognized that sex hormones affect both the developmental organization and functional dynamics of the CNS, particularly neurotransmission. So-called neurosteroids control neuron excitability, neurotransmitter receptors, and their associated ion channels.^1–3 Sex hormones, either produced endogenously in the CNS or exogenously, regulate the transcription of ion channels and neurotransmitter receptors. This “genomic” action that requires hours to days to effect transmission, includes the perception of pain. Sex hormones can also bind to membrane receptors directly and alter transmitter receptors by stimulating the synthesis of second-generation messengers such as G-proteins, nucleotides, and kinases. This nongenomic effect is rapid in onset—seconds to minutes.⁴ The nature and extent of that interaction vary depending on the type of cell and the “sex” of the cell. The complete effect of these hormones on the pain associated with illness or injury has not yet been discovered.

One of the most challenging issues facing researchers in this field is the varying plasma level of sex hormones temporally in individual research participants and across participant groups. For example, it is well-established that women have a greater prevalence of inflammatory disorders than men (such as fibromyalgia and systemic lupus erythematosus). It is also well-established that falling estrogen levels in the premenstrual period are associated with “flares” of these disorders as well as greater reported pain caused by these disorders and women seeking treatment for the pain of these flares. However, the absolute relationship between levels of estrogen and progestin, and a flare or the intensity of pain from a flare, or the need to seek treatment is very difficult to prove.

Areas of the brain that control perception of pain and analgesia have receptors for estrogens and androgens, and can synthesize estrogens and androgens from cholesterol. These neurosteroids are produced in the mitochondria and microsomes of neurons and glial cells and, unlike other neurotransmitters, are released by passive diffusion.⁵ Estradiol in particular controls many structural and molecular aspects of the CNS, regulating proteins involved in signal transduction, increasing concentrations of nerve growth factor in dorsal root ganglia,⁶ stimulating neuronal plasticity in the hippocampus, increasing dendritic spines and excitatory synapses,⁷ and activating mitogen-activated protein kinase. Structural and functional changes in the cerebral cortex, cerebellum, dorsal ganglia, and hippocampus in response to varying levels of estradiol can change susceptibility to stress and pain.⁸

Estradiol-linked modulation of pain in the CNS seems to be linked to suppression of gamma-aminobutyric acid (GABA)–mediated inhibition of pyramidal cells⁷ and estradiol decreases GABA related inhibition in the hippocampus.⁹ Plasma estrogen affects other neurotransmitters, such as endorphins, dopamine, serotonin, and acetylcholine. Decreasing estrogen levels in the premenstrual period is associated with decreasing serotonin and the increased occurrence of (migraine) headache.¹⁰ The anterior and posterior horns of the spinal cord have androgen receptors. However, androgen can be converted to estradiol in the CNS, increasing concentrations in the extracellular (and perhaps intracellular) environment of neurons.¹¹

Sex hormones bind to nerve receptors, both in the brain and peripherally, modulate the perception and response to pain, and lead to the production of neurotransmitters and additional receptors¹² that control central- and peripheral pain–related responses. Some of these affect the concentration of mu opioid receptors on cell membranes,¹³ the relationship to these mu receptors to the ion channels that mediate their effects,¹⁴ the synthesis of cytokines and prostaglandins that are key to chronic inflammatory pain,¹⁵ and the production of other, still unknown, endogenous neurosteroids.¹⁶

It could be that the hypothalamic–pituitary–adrenal (HPA) axis, the hypothalamic–pituitary–gonadal (HPG) axis, and the concomitant control of the production of glucocorticoids—including cortisol in response to stress and pain—might comprise the key to discovering some of the more-intriguing sex-related differences in the response to pain. Women with histories of trauma, chronic pain, fibromyalgia, and cigarette smoking showed decreased estradiol levels and blunted salivary cortisol responses to corticotropin-releasing hormone stimulation¹ and decreased resilience of the HPA axis with hippocampal defects in feedback inhibition related to decreased glucocorticoid receptor function.¹⁷ This effect was demonstrated at the cellular level¹⁸ in female athletes who adapted to the stress of intensive training regimens with increased glucocorticoid-receptor synthesis and function likely related to estradiol levels.

At the macro level, when treating patients in the clinical setting, confounding factors—such as patient age; parity; duration of illness or number and intensity of previous flares (chronicity); histories of trauma or sexual abuse¹⁹; and comorbidities, including depression, severe anxiety, and post-traumatic stress disorder (PTSD)—all affect the incidence, prevalence, degree, and morbidity associated with each pain episode. Women have a greater prevalence of mood disorders, physical disorders associated with chronic pain, and (in general) somatic symptoms than men.²⁰ Depression and anxiety are much more common in women and seem to be associated with pain symptoms, treatment-seeking, and responses to treatment.^21,22 These associations may be directly related to HPA and HPG axis functions as well as estrogen and estradiol levels, which all are affected by depression, trauma, and chronic illness with pain. The role of selective serotonin reuptake inhibitors in the treatment of subacute and chronic pain in women with comorbid mood disorders has yet to be defined.^23,24

Gender is socially constructed and leads to self and societal perceptions of the individual along a spectrum of behavior, appearance, and roles that an individual will live out in society. Of course the provider treating the patient also has a sex and a gender and has grown up and developed in a milieu that is far from sex- and gender-neutral. Human perception of self and of others is affected both by external and learned influences. Human behavior is a response to expectation and learned influences as well. These influences affect providers' perceptions of treatments of their patients, particularly with respect to diagnoses, understanding, and treatment of pain. Sadly until recently, the majority of medical research subjects were men or male animals. Researchers chose male-centric research designs specifically to avoid the allegedly more-variable influence of hormonal rhythms in women and the risk of injuring a fetus in pregnant participants, all the while believing that the results found in male participants could be applied to women without modification.

Pain is a perception, but patients' expression and communication of their pain is behavior. The structure of the central and peripheral nervous system is coded in an organism's DNA. However, the function of that hardwired system is very variable, responding to previous and contemporaneous events. For example, pain and the expression of pain during labor and childbirth are the result of the stimulation of hard-wired receptors in the pelvis. The woman's perception of the pain of labor and her response to that pain reflect cultural, familial, and personal expectations. Furthermore, intercurrent neurologic input can have a significant dampening or heightening effect on a patient's experience and perception of pain, as well as the need for pharmacologic intervention and treatment. Distractions (music therapy during suturing in an emergency department) or seemingly unrelated neural activations (self-stimulation on extremity heat perception) have surprising effects on a patient's expression of pain and need for analgesia. Yet stress and fear can magnify and intensify a patient's perception of the suffering. Of course the provider has a life's history of socially, culturally, and medically constructed expectations about pain and the expression of pain during labor and childbirth as well.

It is useful to examine a pain scenario from both the patient and provider sides, with attention to sex and gender differences. The patient has an injury or illness that creates painful stimulation of nociceptors, the peripheral sensory nerves responsible for recognizing pain. This sensation is transmitted to the CNS. Along the way different neurons may modify the afferent stimulation, intensifying or ameliorating the “sensation.” Chronic pain states may develop when the patient is unable to produce his or her own endogenous analgesics, a process known as diffuse noxious inhibitory control (DNIC).

Women and patients with fibromyalgia (who report chronic pain and disability caused by stimuli that would not elicit these responses in a “normal” patient) have absent or blunted DNIC activity. The prevalence of fibromyalgia is much greater in women, perhaps reflecting this phenomenon.²⁵ Mu opioid receptors in the brain (which blunt pain sensation) do not respond as robustly to peripheral pain stimulation in women as they do in men. These mu receptors are dependent on estradiol levels, which cycle in women with the menstrual cycle. Furthermore the spinal mu receptor and endorphin receptor activity in the spinal cord is more robust in men than in women.^26,27 The relationship of depression and anxiety to pain perception and treatment may also be a function of the balance of descending inhibition and descending facilitation in the spinal cord (of pain perception and conduction from the peripheral nervous system to the brain) as well as central sensitization.²⁸ This yin and yang balance that keeps an organism aware and responsive to noxious stimuli, but not overwhelmed and impaired by excessive input, might be disrupted particularly in women with mood disorders and chronic pain.

The patient then has a full palette of bodily and linguistic modes for expressing discomfort as well as certain expressions that are out of the control of consciousness (e.g., the autonomic nervous system). The provider also has a variety of receptors to perceive the patient's pain: eyes to see visual cues such as facial grimacing or crying; ears to hear the linguistic expressions of discomfort; et cetera. However, the information that the provider receives is filtered and evaluated. It is the authors' experience that most providers form conscious and subconscious preconceptions of their patients instantly upon walking into the examination room. These preconceptions are often as much a reflection of the provider's upbringing, social exposure, training, and biases and belief systems, as they are true representations of the patient, and have significant impacts on the therapeutic choices that the provider will make.

This interplay of patient and provider has not been well-studied yet and exerts tremendous influence on the actions of both and on the judgments that will be made leading to diagnoses, treatment, and healing (or not). The more “subjective” and difficult to measure the patient's complaint, the more this interplay comes to dominate the evaluation, treatment, and outcome. A two-inch scalp laceration is objective. Lower back pain that's “killing me” is subjective and instantly invokes the interplay of patient and provider. The recognition, evaluation, and treatment of pain are carried on in this interplay and thus create fertile ground for examining the roles of sex and gender. The subjectivity of pain also creates great obstacles to empirical scientific research. Thus, it is not surprising that the published research focusing on the role of sex and gender in the evaluation and treatment of pain is complex and often contradictory.

A number of studies have suggested that women perceive a lesser degree of negative stimulation as “pain” (a lower pain threshold) and they perceive a greater amount of “pain” in association with a given degree of stimulation than men (pain tolerance).^29–31 Women respond differently to analgesic treatment^32,33 than men. Women have reported more severe pain than men with similar illnesses and injuries.^29,32 It is difficult to draw conclusions from these studies about causation or, even, validity, as modes of communicating, socialization, and the control of the expression of feelings and emotions differ between women and men. Furthermore, extraneural modulators, including estrogen and testosterone, affect nociceptor function. As estrogen levels fall in the premenstrual period, pain thresholds and pain tolerance decrease, likely due to neuromodulation of postreceptor fibers. However, other central or peripheral effects could also be responsible.³⁴

Healthcare providers and hospital administrators have focused attention on pain interventions. Concomitant studies have revealed that certain patient groups are more likely to have their pain undertreated, including women, minorities, people in lower socioeconomic positions, and elders.^29,35–37 In the acute-care setting women are less likely to have their complaints of pain addressed.³⁸ In another study of hospitalized patients, nonwhites, the elderly, and women had significantly higher pain ratings and higher proportions of negative Pain Management Index scores. Logistic regression predicted adequate pain management with 0.89 accuracy. The study findings support conceptualizing mismanagement of pain as a medical error. Ravn et al. created an intervention model that described the use of a systems approach to identify high-risk patients and ensure effective pain-management practices for all patients.³⁹

Healthcare providers who are undertreating their patients' pain either cannot “hear” or interpret the information being communicated to them by their patients (afferent deficit), or these providers have resistance to responding appropriately (efferent deficit). No studies have reported the effect of same- or opposite-sex providers or the effect of same- or opposite-sex support persons accompanying patients, although in the laboratory, women who were accompanied in the experimental milieu by same-sex friends and who participated in a cold-exposure pain trial were more likely to report more discomfort.⁴⁰ These deficits may influence healthcare providers' inadequate analgesic treatment of minorities, patients in lower socioeconomic brackets, and elders, although the root cause of provider behavior for each group may be different.

One study has shown that both males and females perceive themselves (and their own sex in general) to be less sensitive to pain and less willing to report pain than the opposite sex.⁴¹ While this research did not investigate healthcare providers' attitudes and cannot be generalized to this group, these expectations suggest that female healthcare providers might consider their women patients to be less sensitive to pain and therefore requiring less analgesia for any condition. In contrast male healthcare providers might consider women patients to be more sensitive to pain and more willing to report their pain than men. The male healthcare providers might undervalue their female patients' attempts to communicate their pain and would therefore underestimate and undertreat their discomfort. No researchers have examined healthcare providers' differential responses to their patients' pain complaints based on sex disparities or sex similarities between providers and patients. However a virtual reality simulation collected data that suggested that male and female providers had a differential in their responses to the pain complaints of their virtual patients, depending upon the sex of those patients (as well as other disparate characteristics such as age and ethnicity).

Acute pain from an illness or injury that is not treated adequately can lead to the need for increased analgesia in the subacute treatment phase, and the late development of chronic pain syndromes and other symptoms, such as depression and anxiety.⁴² Furthermore inadequate treatment of a patient's pain during an acute episode of illness or injury will create a negative expectation on the part of that person, which will accompany that person to his or her next acute medical encounter, influencing that patient's approach to communicating the nature, quality, and intensity of the pain. It is likely that there will be an amplification effect. As the patient speaks louder about the pain (gives the pain more voice, metaphorically speaking), the healthcare provider may reflexively “turn down the volume” on their receptors, becoming less and less able to hear the patient's expressions of pain. The interpretation of this voice of pain rising in tone and timber will increasingly be tempered by the belief that the patient is exaggerating (which in a sense he or she is doing). Other important pieces of the medical conversation might then also be misconstrued, leading to delayed or inadequate diagnosis, mistreatment, and increased morbidity and mortality for the patient.

The tendency to underdiagnose and undertreat the pain of certain groups of patients, especially women, is greater when patients present with symptoms that are less objective and more grounded in complaints of pain (coronary artery disease, collagen vascular disease, nonspecific abdominal or pelvic pain). Undertreatment of a patient's pain causes patient dissatisfaction, patient distrust, a form of PTSD, and anxiety associated with the medical visit. Thus a vicious cycling and amplification of behavior is engendered that is self-defeating for the patient and significantly undermines the provider–patient relationship. The behavior, once initiated, leads to misdiagnosis and mistreatment that is damaging to the patient and costly to the healthcare system.⁴³ This miscommunication is the result of:

(1) inadequate sex- and gender-specific instruments for pain assessment

(2) sex- and gender-specific myths and beliefs on the part of healthcare providers about patients and their perceptions and communications of pain

(3) inadequate true scientific understanding of the roles of sex and gender in the physiology and psychology of pain

(4) inadequate healthcare provider education in understanding and communicating with patients of different sexes and genders, ethnicities, and ages about their pain, and how best to treat it in a variety of acute, subacute, and chronic clinical settings.

Solutions to this dangerous problem can and will be found in expanding sex- and gender-specific research into the mechanisms, modifiers, and treatment of pain, expanding and deepening sex- and gender-specific medical education initiatives with a focus on evaluating and treating patients' pain, and developing innovative approaches to evaluating provider performance with respect to their assessment and treatment of their patients' discomfort. Such approaches should be nonthreatening and positively oriented, and facilitate the connection between provider and patient as partners collaborating to facilitate the relief of suffering for the patient rather than casting the patient and provider as adversaries battling to establish whether the patient's pain is real (it is), how severe it is, and whether the pain is responding to the provider's treatment.

Footnotes

Author Disclosure Statement

No conflicts of interest exist.

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