Pain/Expert

Incidence/Prevalence

Sex related differences are scientifically proven with regard to pain and pain disorders as well as inflammation-related diseases. [1] Various studies show that women suffer more frequently from different types of pain compared to men and have a higher pain sensitivity and tend to have a lower pain threshold. Especially in the case of supra-threshold pain stimuli, women show lowered tolerance thresholds significantly more often than men. [2] In addition, women are more likely than men to receive medical treatment for pain. [3] Related to this, women are associated with a significantly increased risk of suffering from acutely severe pain and the development of persistent pain postoperatively. [4] [5] It is estimated that the prevalence of pain in women is approximately 1.5 times higher than in men, and [6] that there are significantly higher prevalence rates for women than men with regard to pain disorders such as migraine/headache, craniomandibular dysfunction, irritable bowel syndrome, rheumatoid arthritis and osteoarthritis. For many of these pain disorders it has been reported that women suffer more often from severe pain and that pain episodes last longer. Typical disorders include fibromyalgia and irritable bowel syndrome. [7] [8]

However, not all pain disorders are more strongly associated with the female sex, e.g. neuropathic pain occurs equally in women and men. The following table depicts sex-related differences in the prevalence of pain-associated diseases. These are either diseases characterized by pain symptoms or accompanied by specific pain. [9]

Table 1: Sex differences in the prevalence of pain-associated diseases. [Source: Hurley & Adams (2008)]

Type/Localization

Women > Men

Men > Women

Head

Chronic tension headaches, migraine with aura, temporomandibular pain syndrome, trigeminal neuralgia, burning mouth syndrome, odontalgia ("phantom tooth pain")

Cluster headache, migraine without aura, post-traumatic headache, post-herpetic trigeminal neuralgia

Visceral

Irritable bowel syndrome, esophagitis (inflammation of the mucous membrane of the esophagus) chronic constipation, gall bladder diseases, proctalgia fugax (painful disease of the rectum)

Duodenal ulcers, diseases of the pancreas

Extremities

Carpal tunnel syndrome, Raynaud's syndrome, complex regional pain syndrome (CRPS), chronic venous insufficiency, scleroderma, piriformis syndrome

Brachial plexus neuralgia, gout, intermittent claudication

Autoimmune diseases

Lupus erythematosus, Multiple Sclerosis, Rheumatoid Arthritis

Rider's disease

Other

Fibromyalgia

 

Risk and protective factors

Based on studies on the prevalence and incidence of pain and pain-related diseases, [4] [10] the female sex can be identified as an important risk factor in the development of pain symptoms. Sex differences in the exogenous and endogenous modulation of pain can be assumed. Mechanisms underlying the sex-related variability in pain responses are often understood as having either biological or psychosocial determinants. This dualistic concept should be considered obsolete and inappropriate for practical application and should rather be used only for analysis at the different levels. For example, from a psychosocial perspective, gender-specific expressions of pain are often attributed solely to stereotypical gender roles. Biological aspects are then ignored as the object of investigation. If the influence of sex-related hormonal and neurobiological factors and their interaction with the respective gender role is overlooked, fundamental aspects of the nociceptive response cannot be understood. The following table shows which factors can cause (social and/or biological) sex differences.

Table 2: Sex differences in biological and psychosocial factors.

Biological factors

Psychosocial factors

Sexual hormones:

Especially during their reproductive years, women are more frequently affected by chronic pain syndromes than men. [10]

In contrast, hormonal changes during pregnancy lead to an increased insensitivity to pain. [3]

Testosterone may protect men from chronic pain and contributes to differences in the effectiveness of drug treatment for pain. [11] Patients with rheumatoid arthritis have reduced testosterone levels in the body, and exogenous testosterone supplementation can reduce arthritis-associated pain in men and women. Low testosterone levels have also been shown in patients with cluster headache [11] and neck pain. [12]

Gender roles:

Among other things, studies show that men report lower pain levels when they are cared for by a female investigator (rather than a male investigator). In keeping with their stereotypical gender role, they want to be strong and immune to pain. [13]

Endogenous opioid system:

Women appear to have reduced endogenous pain inhibition compared to men. [14]

These reduced inhibition mechanisms act as a factor influencing the development of chronic pain and increased sensitivity to pain. [15]

Coping and catastrophizing:

Women seem to be more likely to have catastrophizing thoughts, which correlate with a poor subjective state of health [16] and modulate the sex difference in pain perception. [17] Female patients are more likely to use social support and positive self-affirmation to cope with pain; male patients are more likely to use distraction strategies. [18]

Dopamine:

Estrogens and progestins have a complex influence on the fluctuation of dopamine. Some studies confirm a higher sensitivity of the dopamine transporter (DAT) in women. [19] Dopaminergic sex differences, for example, seem to explain the primary clinical symptoms of fibromyalgia. [20]

Affective distress:

Stress leads to higher pain sensitivity in women. [21] In many studies, women report higher anxiety levels, which can then lead to an increase in clinical pain and increased experimental pain sensitivity. [22]

Serotonin:

Serotonergic functions are modulated by ovarian hormones. For example, there is a significantly increased serotonin synthesis in patients with irritable bowel syndrome. The increased serotonin synthesis correlates with visceral hypersensitivity. In irritable bowel syndrome there is a clear dominance of the female sex. [23]

Depressive symptoms:

Depression and pain are highly comorbid, with women reporting depressive symptoms (especially of a somatic nature) significantly more often than men. [24] In addition, women with certain chronic pain (e.g. oncological pain) appear to be more likely to be affected by depression than men.

NMDA receptor functionality:

Estrogen contributes to an increase in NMDA receptor excitability. This can then contribute to significantly greater central sensitization in women compared to men. Sex-related NMDA receptor functionality may help explain the wind-up phenomenon in pain and, as a consequence, central hypersensitivity or hyperalgesia. [25] [26]

 

Immune system:

Estrogen, progesterone and other gonadal hormones play a complex role in inflammatory processes and pain reactions. Microglia cells in the central nervous system (CNS) have receptors for sex hormones and are activated by inflammatory stimuli, release cytokines and other mediators and can enhance the pain response.[27] Regarding the qualitative sex differences during the pain process, Sorge et al (2015) could demonstrate that female and male rodents process pain in the spinal cord through completely different immune cells: Thus, the involvement of microglia cells in male rodents and T-cells in female rodents was established. [28]

 

The importance of hormonal factors in pain-related sex differences is of particular scientific interest. While women are affected by pain most frequently during their reproductive years, [10] hormonal changes in the course of pregnancy lead to an increased insensitivity to pain. Under the hormonal influence, the female nervous system seems to be geared to maximally protect the woman from pain during pregnancy and childbirth [3]. Under post-menopausal hormone replacement therapies, some pain syndromes worsen while others are attenuated (e.g. migraine). 

The observation that sex differences in pain only begin at puberty (when hormonal changes begin) supports the involvement of sex hormones in pain phenomena. Many studies have investigated the influence of ovarian hormones on women's perception and modulation of pain during different phases of the cycle. [29] [30] The intensity of clinical pain, as well as the acute onset of pain syndromes (such as headaches or migraines), varies during different phases of the cycle. Migraine-related pain often begins during low or rapidly falling estrogen levels (after ovulation). [31] A similar relationship has been observed between hormonal levels and irritable bowel syndrome. [32] [33] In contrast, the influence of the menstrual cycle on pain is inconsistent in patients with fibromyalgia. [34] [35] While some authors state that women with fibromyalgia in particular suffer less pain during the luteal phase (increase and peak of progesterone), [36] other studies show that women are affected by more intense pain during the follicular phase and menstruation (highest plasma levels of the four main sex hormones LH, FSH, estrogen and progesterone).

Current meta-analyses have shown that pain sensitivity varies throughout the menstrual cycle and that the pain threshold is lowest during menstruation. Most studies confirm that women with low progesterone and high estrogen levels do not differ from men in their pain threshold, whereas women with low estrogen levels evaluate pain stimuli as significantly more painful than men. It is possible that these findings may be attributed to the fact that the activity of opioid receptors in the brain is influenced by estrogen levels. [6] Due to methodological problems (for example, hormone levels are not recorded at all in many studies, or inaccurate cycle diaries are preferred over hormone concentrations in the blood), reliable data on the role of hormones under clinical pain conditions are lacking to date. [15]

Pathophysiology

Sex hormones have a key function in inflammatory processes. It has been shown that women have an increased inflammatory response compared to men. This increased inflammatory response appears to lead to a significantly higher risk of painful inflammatory autoimmune conditions in women such as rheumatoid arthritis or lupus. The effect of estrogen on inflammatory responses is very complex and depends on estrogen levels, the timing of the inflammatory process and several other factors. For example, a very high concentration of estrogen seems to inhibit the inflammatory response, while lower estrogen levels seem to have no or a pro-inflammatory effect. Additionally, estradiol may cause a divergent effect when administered systemically or centrally.

Sex hormones can influence signaling pathways in the central nervous system in various ways such as the opioid system, dopaminergic and serotonergic activity and other endogenous components involved in nociception. Sex differences in neurotransmitter levels, receptor binding and reactivity to medication have already been identified. For example, the dysfunction of dopaminergic neurotransmission seems to be related to the development of clinical symptoms of fibromyalgia. Fibromyalgia is much more common in women than in men. Dopamine could therefore represent a very important starting point in the treatment of fibromyalgia. 

It can be concluded that sex differences in opioid, dopaminergic, serotonergic and other pain-associated systems can be clearly demonstrated, but the concrete mechanisms underlying the sex differences in pain and analgesia have not yet been fully identified. [27]

Although poorly studied so far, androgens and in particular testosterone seem to have an effect on the sensation of pain: Testosterone may protect men from chronic pain and contributes to differences in the effectiveness of drug treatment of pain.[11] Patients with rheumatoid arthritis have reduced testosterone levels and exogenous intake of testosterone may reduce arthritis-associated pain in women and men. Low testosterone levels have also been observed in patients with cluster headache [11] and neck pain. [12] Definitive conclusions are not yet possible at this stage.

Management of patients

Therapy

Inflammatory processes play an important role in the mediation of pain. Nutritional factors that influence the inflammatory response offer a promising option for the prevention and treatment of chronic pain disorders. Of particular interest is the potential role of moderate to high doses of vitamin D and omega-3 fatty acids, both of which have a strong anti-inflammatory effect and can modify certain pain conditions. These supplements reduce the level of circulating pro-inflammatory cytokines, decrease chronic pain and appear to reduce the risk of autoimmune diseases. This can be of particular benefit to women who have a significantly higher prevalence of chronic inflammatory pain disorders. [27]</ref>

Physician-patient interaction

Medical care is not sex neutral. Not only the sex of the patient influences the care process. It can also be crucial whether the respective specialist staff is female or male and which gender specific interaction occurs:

The relationship between the sexes of the person conducting the experiment and the subject influences the expressions of pain and can lead to distortions in reporting. Experimental studies show that men report lower pain levels when they are asked by their pain levels by a female researcher (and not by a male researcher). In accordance with their gender role, they want to be less sensitive to pain and appear strong. [1]</ref> Women do not seem to be influenced by the sex of the professional in their expression of pain and generally rate their pain higher than men. [37] Often, socially influenced expressions of pain cannot be traced back, and studies often do not reveal the sex of the researcher. [15]</ref> In summary, the following applies: At present, only clinical experimental studies and only one retrospective clinical study on researcher dependence are available. Prospective data from clinical routine are currently lacking.

In addition, male family physicians and internists prescribe analgesics more frequently and in higher doses than their female colleagues (and female patients are prescribed these more frequently than male patients). Male physicians also interpret female health complaints more often as psychosomatic than male complaints. Medical students are more likely to make a non-specific somatic diagnosis, address psychosocial variables in the patient's history and prescribe analgesic and psychoactive medications in female patients compared to male patients with neck pain. [38]

Psychosocial factors

Psychosocial differences and their interaction with biological factors can influence pain in different ways. Psychological factors include, for example, placebo and nocebo effects, expectation or experience learning, and attention control. There are currently only a few studies on sex-specific psychological factors of pain. [1]</ref> There are sex differences regarding correlations between psychological symptoms such as stress, anxiety or depression and pain. [39] For example, stress appears to lead to higher pain sensitivity in women. [40] The interaction of pain and anxiety is complex and depends on pain-related anxiety constructs (e.g. pain-related anxiety or anxiety sensitivity) and the type of (experimental) pain. Women report higher levels of anxiety in various studies, which can lead to an increase in clinical pain and increased experimental pain sensitivity. [22] But there are also studies that show higher pain-associated anxiety in men. [41] Besides sex aspects, personality traits also appear to play an important regulatory role in the interaction of pain and psychological factors. It is suspected that higher neuroticism levels correlate with higher activation of certain brain regions. These brain regions are involved in emotional and cognitive arousal during the anticipation of pain. [42]

Open research questions

Qualitative sex differences of pain processes exist everywhere: In the stress-induced inhibition of pain, the effect of genes on pain, the social modulation of pain and pain memory. In fact, it seems that the pain sensitivity of a rodent can even be influenced by the sex of the person performing the experiment. [43]

Therefore, since 2014, the NIH (National Institutes of Health in the USA) has been demanding that sex be treated as a biological variable in preclinical research and that a 50/50 solution be implemented. Nevertheless, pain researchers and other researchers tend to still insist on experiments that only consider male laboratory animals: Of 71 research articles investigating pain in rodents in 2015, 56 articles included only male rodents, six tested only females (four of which investigated female-specific topics) and six did not reveal the sex of the animals. Only three papers (4.2 percent) reported that both sexes were included. Thus, there is hardly any improvement compared to preclinical studies in the period from 1996 to 2005 [44] The consideration of only male laboratory animals seems particularly paradoxical against the fact that the majority of pain patients are female. A 50/50 solution would allow not only women but also men with pain to benefit positively.[45]

What is the reason for so much resistance to the inclusion of female laboratory animals? The pain researcher Mogil has identified three main reasons for this and tried to refute them (see Table 3). [45]

Table 3: Reasons for the exclusion of female laboratory animals and the refutation thereof. [Source: Mogil (2016)]

1. The fear of too much variability:

Due to fluctuating gonadal hormone levels, scientists fear an increased variability and the related need to study more animals. However, this would not seem justified from an empirical point of view. For example, the variability in female rodents is not higher than in male rodents. The reason for a high variability in male animals seems to be related to dominance hierarchies. Male laboratory animals fight against each other for their status in the cage. Thus, experiments can be influenced by different hierarchical ranks of the laboratory animals (which animal is dominant, which submissive?). Another important factor is the length of time elapsed since the aggressive state of the male animals at the beginning of the study.

2. The fear of excessive financial burdens:

Often there is a fear that the 50/50 solution would require a doubling of the sample size, which would mean an immense increase in costs. However, there is no need to increase the sample size to have enough statistical power to study all sex differences. Rather it is suggested that first the fundamental sex discrepancies be identified, for which a larger sample size is not necessary.

3. The worry of having to repeat the tests for each phase of the female cycle

In general, the first step in a study investigating sex differences should be a comparison between gonadally intact adult animals of both sexes. If there is no previous evidence of cycle-related variations in the respective measurement, it is not an absolute necessity to study female animals in certain cycle phases. There are also other and sometimes more appropriate ways to study the effect of gonadal hormones on pain. Many sex differences in pain are also due to testosterone effects.

The same applies to studies in humans: Women were excluded from clinical studies for many years, especially in the early phase of drug development. Those responsible feared that women could jeopardize the success of a study or distort the findings by a possible pregnancy or hormonal fluctuations. As a result, the influencing factor ''female sex'' was not or only slightly included in pharmacological studies for many years. [46] Although an evaluation from 2001 showed that more women were included in studies in recent years, a sex-specific subgroup analysis was only conducted in nine percent of all studies. [47]

Concerning medication for pain, the dosage recommendations for acetaminophen are a good example. The dosing recommendations continue to be based on decades old studies that were only conducted on men, although it is now known that the elimination half-life of acetaminophen in women is only 60 percent compared to that of men. Numerous studies also prove that morphine has a stronger analgesic effect in women than in men. [48] Men need about 40 percent more morphine than women to achieve an analgesic effect. From these findings it is clear that a sex-specific dose adjustment of morphine, i.e. a reduced dose in women, could be a step towards a pharmacotherapy tailored to men and women. A dose reduction is also reasonable and necessary due to the fact that women suffer more than men from side effects such as respiratory depression, nausea and vomiting at the same morphine dose (see also Pharmacological Principles/Technical Articles).

External Links

Mogil J. S., 2016: Equality need not be painful.

 

 

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