Article

Women with dysmenorrhoea are hypersensitive to experimentally induced forearm ischaemia during painful menstruation and during the pain-free follicular phase: Women with dysmenorrhoea are hyperalgesic to ischaemia

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Abstract

Background Monthly primary dysmenorrhoeic pain is associated with increased sensitivity to painful stimuli, particularly in deep tissue. We investigated whether women with dysmenorrhoea, compared with controls, have increased sensitivity to experimentally induced deep-tissue muscle ischaemia in a body area distant from that of referred menstrual pain.Methods The sub-maximal effort tourniquet test was used to induce forearm ischaemia in 11 women with severe dysmenorrhoea and in nine control women both during menstruation and in the follicular phase of the menstrual cycle. Von Frey hair assessments confirmed the presence of experimental ischaemia. Women rated the intensity of menstrual and ischaemic pain on a 100-mm visual analogue scale.ResultsWomen with dysmenorrhoea [mean (SD): 68 (20) mm] reported significantly greater menstrual pain compared with controls [mean (SD): 2 (6) mm; p = 0.0001] during the menstruation phase. They also rated their forearm ischaemic pain as significantly greater than the controls during the menstruation [dysmenorrhoeics vs. controls mean (SD): 58 (19) mm vs. 31 (21) mm, p < 0.01] and follicular [dysmenorrhoeics vs. controls mean (SD): 60 (18) mm vs. 40 (14) mm, p < 0.01] phases of the menstrual cycle.Conclusions These data show that compared with controls, women who experience severe recurrent dysmenorrhoea have deep-tissue hyperalgesia to ischaemic pain in muscles outside of the referred area of menstrual pain both during the painful menstruation phase and pain-free follicular phase. These findings suggest the presence of long-lasting changes in muscle pain sensitivity in women with dysmenorrhoea. Our findings that dysmenorrhoeic women are hyperalgesic to a clinically relevant, deep-muscle ischaemic pain in areas outside of referred menstrual pain confirm other studies showing long-lasting changes in pain sensitivity outside of the painful period during menstruation.

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... 44 Women with PD have also reported higher peak pain during the menstrual phase than women without PD following a saline injection into the forearm, 37 and in a subsequent study testing muscle ischemia, the authors found that women with PD reported higher pain ratings compared to controls during menstruation. 47 Women with PD have higher heat pain thresholds when tested on the forearm during menstruation, 39 and report more pain from a bladder distension during menstruation, 48 We were able to identify only one study that did not find significant differences between women with and without PD in areas outside of referred pain during menstruation. That study included 56 women with menstrual pain and 18 women without menstrual pain and subjected them to ischemic pain by using a blood pressure cuff on the nondominant arm. ...
... A critical problem is the lack of consensus regarding the threshold of pain severity allowing classification as PD. Most studies have not reported the level of pain using either a visual analog scale (VAS) or numeric rating scale (NRS) required to be classified as having PD. 44,45 For studies where menstrual pain was rated using a VAS or NRS, no consistent scales (e.g., 0-10 versus 0-100) nor criteria (e.g., 4/10 versus 6/10) were used to categorize women with PD. 6,[35][36][37]40,41,47 Others have used responses on the Menstrual Symptom Questionnaire, 46,49,51 indicating "mild/no menstrual pain" or "moderate/severe menstrual pain." 50 This ambiguity suggests the possibility that some participants would be classified as having PD in some studies, while being classified as non-PD in other studies, thus making it very difficult to compare results. ...
... In fact, evidence in this review suggests that pain responding may be related to the "degree" of menstrual pain, rather than just the presence or absence of menstrual pain. 6,35,42,43,48 Study methodology and exclusion of demographic information Studies have used a wide variety of pain stimuli, ranging from thermal pain 4,36,45,46,50 to ischemic pain 47,49,51 at different parts of the body. This variability in pain induction stimuli and degree of pain provoked makes it difficult to draw conclusions about the nature of pain responsivity in women with PD. ...
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Laura A Payne,1 Andrea J Rapkin,2 Laura C Seidman,1 Lonnie K Zeltzer,1 Jennie CI Tsao1 1Pediatric Pain and Palliative Care Program, 2Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Abstract: Primary dysmenorrhea (PD) has been the focus of a number of experimental pain studies. Although a number of reviews exist, few have critically evaluated the existing body of research on PD and experimental and procedural pain. Data from 19 published research articles that include women with PD and responses to an experimental or procedural pain stimulus (or stimuli) suggest that women with PD may have elevated pain reactivity, as compared to women without PD. This pattern appears to be true across different phases of the menstrual cycle. However, there is an abundance of conflicting findings, which may be due to significant methodological issues such as inconsistent definitions of PD, wide variation in experimental pain methodologies, and inaccurate assessment of the menstrual cycle. Future research should focus on identifying specific symptoms (i.e., pain threshold ratings) to more clearly define what constitutes PD, establish reliable and valid laboratory testing protocols, and assess the menstrual cycle with greater precision. Keywords: primary dysmenorrhea, menstrual pain, acute pain, menstrual cycle, central pain mechanisms
... The range of stimulations to induce experimental pain in women with dysmenorrhea include: pressure (Amodei and Nelson-Gray, 1989;Bajaj et al., 2002), heat (Granot et al., 2001;Bajaj et al., 2002;Vincent et al., 2011), cold pressor stimulation (Hapidou and De Catanzaro, 1988), electrical stimulation (Giamberardino et al., 1997), ischemia (Aberger et al., 1983;Amodei and Nelson-Gray, 1989), pinch (Bajaj et al., 2002), tactile stimulation (Bajaj et al., 2002), pain-evoked potentials by laser stimuli (Granot et al., 2001), and deep-muscle pain by means of an i.m. injection of hypertonic saline (Iacovides et al., 2013) and ischemia (Iacovides et al., 2015). The choice of experimental pain stimuli used in studies is fundamental for several reasons: when assessing pain, the pain stimulus needs to be (i) reproducible, (ii) strong enough to elicit a measurable response, (iii) moderate enough to highlight individual differences and (iv) either meaningful enough to resemble a natural physiological or clinical pain, or precise enough to elucidate the basic mechanism of a response to pain (Sherman and LeResche, 2006). ...
... It is likely that each painful stimulus results in differential processing of nociceptive afferents (Lynn and Perl, 1977). Electrical stimuli, for example, activate all classes of afferent neurons (i.e. both nociceptive and non-nociceptive fibers), and hence produce both painful and non-painful sensations (Gracely, 1990;Keefe et al., 1991), while i.m. injection of Iacovides et al. (2015) 11 dysmenorrheic, 9 non-dysmenorrheic Dysmenorrheic women had sensitivity to muscle ischemia ( Primary dysmenorrhea: not just period pain hypertonic saline is believed to excite wide dynamic range neurons (Ro and Capra, 1999), possibly via activation of group III (thinly myelinated A-delta fibers) and group IV (unmyelinated C-fibers) muscle nociceptors to produce both a local area of transient pain and referred pain (Paintal, 1960;Iggo, 1961;Kumazawa and Mizumura, 1977;Graven-Nielsen et al., 1997. Theories on tourniquet-induced ischemic pain support the role of C-fibers in the transmission of pain, while A-fiber conduction is believed to be abolished during an ischemic event (Chabel et al., 1990;Loram et al., 2007). ...
... Type, location, and depth of experimental pain stimulation are important factors that can influence study results. The variety of sites that have been used to induce experimental pain in women with dysmenorrhea include: the thumb (Haman, 1944), index finger (Amodei and Nelson-Gray, 1989), forearm (Goolkasian, 1983;Iacovides et al., 2015), upper arm (Giamberardino et al., 1997;Bajaj et al., 2002), leg (Giamberardino et al., 1997;Bajaj et al., 2002), abdomen (Giamberardino et al., 1997;Bajaj et al., 2002) and lower back (Bajaj et al., 2002;Iacovides et al., 2013). Several aspects of pain assessment have been shown to vary according to body location; particularly with respect to the proximity to the reproductive organs (Robinson and Short, 1977;Klonoff et al., 1993;Giamberardino et al., 1997). ...
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Article
BACKGROUND Primary dysmenorrhea, or painful menstruation in the absence of pelvic pathology, is a common, and often debilitating, gynecological condition that affects between 45 and 95% of menstruating women. Despite the high prevalence, dysmenorrhea is often poorly treated, and even disregarded, by health professionals, pain researchers, and the women themselves, who may accept it as a normal part of the menstrual cycle. This review reports on current knowledge, particularly with regards to the impact and consequences of recurrent menstrual pain on pain sensitivity, mood, quality of life and sleep in women with primary dysmenorrhea.
... Since then, several studies have investigated pain sensitivity in dysmenorrhea, with mixed findings (Table I) partly due to differences in methodology. Without taking menstrual cycle phase into consideration, studies have reported mixed findings with some showing no differences in the perception of experimental pain, including ischemic pain, heat pain, and electrical stimulation of the skin, between dysmenorrheic and non-dysmenorrheic women (Aberger et al., 1983; Amodei and Nelson-Gray, 1989; Brinkert et al., 2007), and others reporting that women with dysmenorrhea have an enhanced perception of laser pain-evoked potentials (Granot et al., 2001), heat pain (Goolkasian, 1983; Bajaj et al., 2002; Vincent et al., 2011), pressure pain (Bajaj et al., 2002), ischemic pain (Iacovides et al., 2015) and ...
... The inconsistent findings in the current literature regarding pain sensitivity in women across the menstrual cycle have been attributed to various experimental methodological concerns including: differences in the choice of experimental pain stimuli; where, and at what tissue-depth, these stimuli are applied (Sherman and LeResche, 2006 ; Vincent and Tracey, 2010); different outcome measures (thresholds versus tolerance) used; the arbitrary division of the menstrual cycle into functionally distinct phases, based either on the ovarian or endometrial cycle (Sherman and LeResche, 2006; Vincent and Tracey, 2010; Pogatzki-Zahn, 2013 ); and lack of consideration of menstrual cycle phase or measurement of gonadal hormones (Hapidouand De Catanzaro, 1988; Amodei and Nelson-Gray, 1989; Giamberardino et al., 1997; Bajaj et al., 2002). The range of stimulations to induce experimental pain in women with dysmenorrhea include: pressure (Amodei and Nelson-Gray, 1989; Bajaj et al., 2002), heat (Granot et al., 2001; Bajaj et al., 2002; Vincent et al., 2011), cold pressor stimulation (Hapidou and De Catanzaro, 1988), electrical stimulation (Giamberardino et al., 1997), ischemia (Aberger et al., 1983; Amodei and Nelson-Gray, 1989), pinch (Bajaj et al., 2002), tactile stimulation (Bajaj et al., 2002), pain-evoked potentials by laser stimuli (Granot et al., 2001), and deep-muscle pain by means of an i.m. injection of hypertonic saline (Iacovides et al., 2013) and ischemia (Iacovides et al., 2015). The choice of experimental pain stimuli used in studies is fundamental for several reasons: when assessing pain, the pain stimulus needs to be (i) reproducible, (ii) strong enough to elicit a measurable response, (iii) moderate enough to highlight individual differences and (iv) either meaningful enough to resemble a natural physiological or clinical pain, or precise enough to elucidate the basic mechanism of a response to pain (Sherman and LeResche, 2006). ...
... Type, location, and depth of experimental pain stimulation are important factors that can influence study results. The variety of sites that have been used to induce experimental pain in women with dysmenorrhea include: the thumb (Haman, 1944), index finger (Amodei and Nelson-Gray, 1989), forearm (Goolkasian, 1983; Iacovides et al., 2015), upper arm (Giamberardino et al., 1997; Bajaj et al., 2002), leg (Giamberardino et al., 1997; Bajaj et al., 2002), abdomen (Giamberardino et al., 1997; Bajaj et al., 2002) and lower back (Bajaj et al., 2002; Iacovides et al., 2013). Several aspects of pain assessment have been shown to vary according to body location ; particularly with respect to the proximity to the reproductive organs (Robinson and Short, 1977; Klonoff et al., 1993; Giamberardino et al., 1997). ...
Article
Primary dysmenorrhea is the most common gynecological condition among women of reproductive age. Although dysmenorrhea has been reported to affect the ability of women to carry out daily activities, the impact of primary dysmenorrheic pain specifically on quality of life (QoL), has yet to be elucidated. We investigated whether QoL varies between women with and without severe primary dysmenorrhea, and whether QoL is impaired only during menstruation or also during pain-free phases of the menstrual cycle. Twelve women with severe primary dysmenorrhea and nine control women completed the quality of life enjoyment and satisfaction questionnaire (Q-LES-Q-SF) during menstruation and during the late follicular phase. Women with dysmenorrhea had a significant reduction in Q-LES-Q-SF scores (mean ± SD: 54 ± 18%, percentage of the total maximum possible score) when they were experiencing severe menstrual pain compared with their own pain-free follicular phase (80 ± 14%, p < 0.0001) and compared with controls during menstruation (81 ± 10%, p < 0.0001). They also rated their overall life satisfaction and contentment as poorer during menstruation. Severe menstrual pain associated with primary dysmenorrhea, therefore, impacts health-related of QoL.
... It is classified into two broad categories: primary dysmenorrhea (occurring without pelvic pathology) and secondary dysmenorrhea (caused by identifiable organic diseases). Primary dysmenorrhea is characterized by recurrently painful menstruation in the absence of underlying pelvic pathology (Iacovides et al., 2015). It is highly prevalent among menstruating women where a percentage ranging from 21% to 26% experience severe menstrual pain (Grandi et al., 2012). ...
... In addition to pain, women suffering from primary dysmenorrhea also experience sleep disturbance and reduced quality of life. High levels of menstrual pain are associated with significant economic burdens caused by absenteeism, reduced productivity, and two-to three-fold increased healthcare costs (Akiyama et al., 2017;Iacovides et al., 2015). the levels of steroid hormones in the blood circulation of women in reproductive ages (Jahromi et al., 2008). ...
... Past research has demonstrated enhanced pain sensitivity in women with dysmenorrhea, both in areas of referred pain 3,5,12,21,35,44,46 and remote body regions. 1,2,4,5,12,13,17,20,21,23,35,46 These data provide support for the concept that PD is associated with lasting changes in pain processing. However, little is known about potential mechanisms in this episodic condition. ...
... Consistent with the majority of other reports, 2,12,13,17,20,21,23,44,49 we found significant group differences in heat pain responses across all cycle phases. Although some recent studies have shown enhanced pain modulation (indicative of successful pain inhibition) in healthy women during the ovulatory phase, 34 most laboratory research in women with menstrual pain has demonstrated either no group differences or heightened pain sensitivity in women with PD across the menstrual cycle (for review, see Ref. 30), suggesting the stability of group differences independent of hormonal variations. ...
Article
Abstract Primary dysmenorrhea (PD; menstrual pain without an underlying medical condition) is associated with enhanced pain sensitivity and temporal summation in adult women, which may reflect the presence of central pain processes. Research in this area has been limited by focusing on only adult populations and incomplete assessments of central sensitization. The current study explored both excitatory and inhibitory measures of pain processing in girls and young adult women with and without PD. Thirty-two girls with PD and 34 healthy controls underwent laboratory pain testing during each of three menstrual cycle phases (menstrual, ovulatory, and mid-luteal), which included measures of pain tolerance and threshold, temporal summation, and conditioned pain modulation. Results indicated enhanced pain sensitivity in girls with PD as measured by heat pain tolerance and threshold, compared to healthy controls. These group differences were evident at all phases of the menstrual cycle. No group differences in cold pain tolerance, temporal summation, or conditioned pain modulation were evident at any phase of the menstrual cycle. These data suggest some evidence of central sensitization in girls with PD, although no evidence of deficient pain modulation was observed. Future research should focus on identifying other potential phenotypes for PD to identify those at risk for developing other pain problems.
... For example, Payne et al. (2019)) described significantly lower heat tolerance in adolescent and young adult women with PD. Amodei and Nelson-Gray (1989)) reported significantly higher degrees of pain and distress in both pre-menstrual and menstrual phases of the menstrual cycle, while Bajaj et al. (2002)) uncovered significantly lower heat and pressure thresholds in women suffering from PD. Iacovides et al. (2013Iacovides et al. ( , 2015b) uncovered increased sensitivity in the deep-tissue outside of abdominal area during the painful menstrual phase and the painless follicular phase of the menstrual cycle. ...
Article
Background: Dysmenorrhea is a prevalent pain condition that affects women of reproductive age, who are monthly exposed to this pain, usually until they reach the adult age, or even after that, which can predispose them to Central Sensitization. The present study aimed to observe the association between menstrual characteristics and central sensitivity symptoms in women. Methods: Cross-sectional study. Brazilian women (n=10,402) answered an online form comprised of questions regarding their gynecological history, the Numerical Rating Scale for pain and the Central Sensitization Inventory, part A. For the analysis, we separated women into two groups: Central Sensitivity Symptoms group (n=5,200) and No-Central Sensitivity Symptoms group (n=5,202). We performed a binary logistic regression with the backward insertion method for the variables with p<0.05 in the bivariate analysis between groups. The significance level was set at 5%. Results: Prevalence of dysmenorrhea was 67.3%, and 32.2% of women in the Central Sensitivity Symptoms group reported pain >8 during their menstrual period. The logistic regression showed that greater levels of menstrual pain (Odds Ratio 1.12), gynecological diseases (Odds Ratio 1.51), presence of dysmenorrhea since adolescence (Odds Ratio 1.20) and irregular menstrual cycles (Odds Ratio 1.47) increased the likelihood of women presenting with Central Sensitivity Symptoms (p<0.05 for all comparisons). Conclusions: The present study shows that Central Sensitivity Symptoms are present in about 50% of women and are associated with menstrual characteristics such as dysmenorrhea-related pain intensity, cycle regularity, presence of dysmenorrhea since adolescence accompanied by gynecological diseases. Significance: Central sensitivity symptoms occur in 50% of women, and are more present in women with dysmenorrhea. They are associated with cycle regularity, presence of dysmenorrhea since adolescence, and gynecological diseases. Limitations: Women that suffer from dysmenorrhea and of higher socioeconomic and educational levels may have been more propense to respond to the invitation; as such, the findings of the present study should be carefully interpreted.
... However, the authors noted that the more well-controlled studies mostly did not find any effect of the menstrual cycle phase on pain sensitivity, although these studies were not without some of the methodological limitations as pointed out by Sherman and LeResche (2006). To the best of our knowledge, nine recent studies have been published since the time of the last review in 2015 (Bartley et al., 2015;Iacovides et al., 2015b;Cankar et al., 2016;Palit et al., 2016;Alves et al., 2017;Nayak et al., 2017;Jasrotia et al., 2018;Payne et al., 2019;Pogatzki-Zahn et al., 2019); these findings also appear to be inconsistent. There is a roughly equal number of studies that observed variations in pain sensitivity across the menstrual cycle (5/9 studies) and those that did not (4/9 studies). ...
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Article
Chronic pain - pain that persists for more than 3 months - is a global health problem and is associated with tremendous social and economic cost. Yet, current pain treatments are often ineffective, as pain is complex and influenced by numerous factors. Hypohydration was recently shown to increase ratings of pain in men, but studies in this area are limited (n = 3). Moreover, whether hypohydration also affects pain in women has not been examined. In women, changes in the concentrations of reproductive hormones across menstrual phases may affect pain, as well as the regulation of body water. This indicates potential interactions between the menstrual phase and hypohydration on pain, but this hypothesis has yet to be tested. This review examined the literature concerning the effects of the menstrual phase and hypohydration on pain, to explore how these factors may interact to influence pain. Future research investigating the combined effects of hypohydration and menstrual phase on pain is warranted, as the findings could have important implications for the treatment of pain in women, interpretation of previous research and the design of future studies.
... In the first, women with dysmenorrhea had increased sensitivity to experimentally induced deep-tissue muscle ischemia compared with controls, both during the painful menstruation phase and pain-free follicular phase, and demonstrated long-lasting changes in pain sensitivity outsite the painful period during menstruation. [72] In the second, Iacovides et al. certified that women with PDM were hyperalgesic to experimental muscle pain, both at the site of referred pain and at a remote nonpainful site, compared to women without dysmenorrhea. [73] dIscussIon Nowadays, fMRI study is thriving and on an uptrend. ...
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Article
Primary dysmenorrhea (PDM) is the painful menses with spasmodic cramping in the lower abdomen in the absence of any discernable macroscopic pelvic pathology. The prevalence of dysmenorrhea changes between 16% and 91% in women. About 2%–29% of the women studied suffer from severe pain. This review focuses on the current knowledge, particularly with regard to the latest research on the etiology of PDM. Full‑text manuscripts on PDM were searched on PubMed and Google Scholar. One or more of the following search terms were used to obtain articles published: PDM, pain, functional magnetic resonance imaging, brain image, etiology, epidemiology, metabolism, hormone, gene variation, and quality of life. In this review, we detailed four potential etiology aspects of PDM: brain abnormality, gene expression, metabolism, and hyperalgesia. We highlighted the latest brain research on PDM patients and investigated genetic aspects. We are dedicated to identifying more metabolic variations and expand the previous knowledge on the sensitive pain threshold.
... 28 Enhanced neurotransmission with long lasting molecular changes in both the spinal cord and brain may result in pain perception that no longer reflects, and is independent of, peripheral pain nociceptive signaling. 26 Altered central processing of nociception in women with dysmenorrhea, both during menses and on pain-free days, as measured by serum cortisol, response to thermal stimuli, and functional MRI investigation, has been demonstrated by Vincent et al, Arendt-Nielssen et al, and Iacovides et al, [29][30][31] with literature review by Payne et al. 32 Central sensitization has the potential to affect both pelvic and extra-pelvic pain symptomatology. With regard to pelvic symptoms, there is ample evidence for the convergence of sensory information from discrete pelvic organs of the gastrointestinal or genitourinary tract in the dorsal root ganglia, spinal cord, and brain, 33,34 result- ing in viscero-visceral hyperalgesia and the experience of multiple pain symptoms across pelvic organs. ...
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Article
This article investigates 14 additional symptoms present in women with dysmenorrhea. It discusses central sensitization, migraine, stabbing pains.
... In the first, women with dysmenorrhea had increased sensitivity to experimentally induced deep-tissue muscle ischemia compared with controls, both during the painful menstruation phase and pain-free follicular phase, and demonstrated long-lasting changes in pain sensitivity outsite the painful period during menstruation. [72] In the second, Iacovides et al. certified that women with PDM were hyperalgesic to experimental muscle pain, both at the site of referred pain and at a remote nonpainful site, compared to women without dysmenorrhea. [73] dIscussIon Nowadays, fMRI study is thriving and on an uptrend. ...
Full-text available
Article
Primary dysmenorrhea (PDM) is the painful menses with spasmodic cramping in the lower abdomen in the absence of any discernable macroscopic pelvic pathology. The prevalence of dysmenorrhea changes between 16% and 91% in women. About 2%–29% of the women studied suffer from severe pain. This review focuses on the current knowledge, particularly with regard to the latest research on the etiology of PDM. Full-text manuscripts on PDM were searched on PubMed and Google Scholar. One or more of the following search terms were used to obtain articles published: PDM, pain, functional magnetic resonance imaging, brain image, etiology, epidemiology, metabolism, hormone, gene variation, and quality of life. In this review, we detailed four potential etiology aspects of PDM: brain abnormality, gene expression, metabolism, and hyperalgesia. We highlighted the latest brain research on PDM patients and investigated genetic aspects. We are dedicated to identifying more metabolic variations and expand the previous knowledge on the sensitive pain threshold.
... 28 Enhanced neurotransmission with long lasting molecular changes in both the spinal cord and brain may result in pain perception that no longer reflects, and is independent of, peripheral pain nociceptive signaling. 26 Altered central processing of nociception in women with dysmenorrhea, both during menses and on pain-free days, as measured by serum cortisol, response to thermal stimuli, and functional MRI investigation, has been demonstrated by Vincent et al, Arendt-Nielssen et al, and Iacovides et al, [29][30][31] with literature review by Payne et al. 32 Central sensitization has the potential to affect both pelvic and extra-pelvic pain symptomatology. With regard to pelvic symptoms, there is ample evidence for the convergence of sensory information from discrete pelvic organs of the gastrointestinal or genitourinary tract in the dorsal root ganglia, spinal cord, and brain, 33,34 result- ing in viscero-visceral hyperalgesia and the experience of multiple pain symptoms across pelvic organs. ...
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Article
Purpose Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. The frequency of 14 associated symptoms both within and outside the pelvis was determined. Patients and methods Symptom questionnaires were completed by 168 women with dysmenorrhea, allocated to three groups based on their diagnostic status for endometriosis confirmed (Endo+), endometriosis excluded (Endo−), or endometriosis diagnosis unknown (No Lap). Those with endometriosis confirmed were further divided into current users (Endo+ Hx+) and non-users of hormonal treatments (Endo+ Hx−). Users of hormonal treatments were further divided into users (Endo+ Hx+ LIUCD+) and non-users (Endo+ Hx+ LIUCD−) of a levonorgestrel-releasing intra-uterine contraceptive device (LIUCD). The frequency and number of symptoms within groups and the effect of previous distressing sexual events were sought. Results Women with and without endometriosis lesions had similar symptom profiles, with a mean of 8.5 symptoms per woman. Only 0.6% of women reported dysmenorrhea alone. The presence of stabbing pelvic pains was associated with more severe dysmenorrhea (P=0.006), more days per month of dysmenorrhea (P=0.003), more days per month of pelvic pain (P=0.016), and a diagnosis of migraine (P=0.054). The symptom profiles of the Endo+ Hx+ and Endo+ Hx− groups were similar. A history of distressing sexual events was associated with an increased number of pain symptoms (P=0.003). Conclusion Additional symptoms are common in women with dysmenorrhea, and do not correlate with the presence or absence of endometriosis lesions. Our study supports the role of central sensitization in the pain of dysmenorrhea. The presence of stabbing pelvic pains was associated with increased severity of dysmenorrhea, days per month of dysmenorrhea, days per month of pelvic pain, and a diagnosis of migraine headache. A past history of distressing sexual events is associated with an increased number of pain symptoms.
... Aberger, Denney, & Hutchings, 1983;Amodei & Nelson-Gray, 1989) over reduced (Giamberardino, Tana, & Costantini, 2014;Hapidou & De Catanzaro, 1988) to increased pain sensitivity (e.g. Bajaj et al., 2002;Iacovides, Avidon, & Baker, 2015b;Vincent et al., 2011) in PDM patients. This heterogeneity is likely due to differences between pain models and/or modalities, methodological differences in experimental procedures, small sample sizes in most studies, and differences between study samples in psychosocial patient characteristic (Iacovides et al., 2015a). ...
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Article
Background Chronic pelvic pain, in particular dysmenorrhea, is a significant yet unresolved healthcare problem in gynecology. As interoceptive sensitivity and underlying neural mechanisms remain incompletely understood, this functional magnetic resonance imaging (fMRI) study assessed behavioral and neural responses to visceral stimuli in primary dysmenorrhea (PMD). Methods Women with PMD (N=19) without psychological comorbidity and healthy women (N=20) were compared with respect to visceral sensory and pain thresholds, and to neural responses to individually‐calibrated mildly‐painful and painful rectal distensions implemented during scanning. Trial‐by‐trial ratings of perceived intensity were accomplished with visual analogue scales (VAS). Results Although women with dysmenorrhea reported significantly higher chronic pain intensity and pain interference with daily life activities (p < .01, assessed with the West Haven‐ Yale Multidimensional Pain Inventory), there were no differences between groups in visceral sensitivity and mean trial‐by‐trial VAS ratings were virtually identical. Analysis of neural responses revealed activation in brain regions previously shown to be involved in the processing of visceral stimuli with differences between painful and mildly‐painful stimulation, but no group differences were found even when using a liberal statistical threshold. Conclusions Dysmenorrhea patients show unaltered perceptual and neural responses to experimental interoceptive stimuli. Despite limited sample size, these negative results argue against a generalized sensitization towards interoceptive stimuli in patients without psychological comorbidities. Future studies should clarify the role of psychosocial factors in central sensitization using more pain region‐specific models in larger and clinically more heterogeneous samples. This article is protected by copyright. All rights reserved.
... The evidence for centralized components of chronic pelvic pain has been provided by brain neuroimaging studies, many from the MAPP Research Network, showing significant structural and functional anomalies in patients including white and gray matter differences (Bagarinao et al., 2014;Farmer et al., 2015;Huang et al., 2016;Kairys et al., 2015;Woodworth et al., 2015), altered resting state functional connectivity (Kilpatrick et al., 2014;Kleinhans et al., 2016;Kutch et al., 2017;Kutch et al., 2015;Martucci et al., 2015), and heightened painevoked brain activity in and functional connectivity between painprocessing brain regions Kleinhans et al., 2016). Furthermore, quantitative sensory testing has demonstrated widespread hyperalgesia, allodynia, and impaired endogenous analgesia in individuals with chronic pelvic pain, including UCPPS, (As-Sanie et al., 2016;Clauw et al., 1997;Grinberg et al., 2017;Iacovides et al., 2015;Ness et al., 2014;Ness et al., 2005;Powell-Boone et al., 2005;Slater et al., 2015;Stratton et al., 2015), which also strongly suggest involvement of the central nervous system. Altered levels of brain metabolites have been observed in chronic pain patients with endometriosis (As-Sanie et al., 2016) and in other non-pelvic pain Fig. 3. Correlations between ACC choline levels and moodrelated psychosocial measures, including a) HADS Depression, b) MPQ affective-to-sensory pain, c) PANAS Negative, and d) recent negative mood (past 24 h) in UCPPS patients. ...
Article
Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy (¹H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p = 0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p = 0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome.
... 63 Although it has not been demonstrated directly, evidence of central sensitization within dysmenorrhea includes increased referred pain, 64 and heightened experimentally evoked thermal, ischemic, muscular, and pressure pain sensitivity. [65][66][67][68] Dysmenorrheic women also exhibit altered gray matter volume in key cortical regulatory pain regions. [69][70][71] Since NSAIDs are not known to affect central sensitization, 72 further research is needed to confirm whether dysfunctional central sensitization occurs in NSAID-resistant dysmenorrhea. ...
Article
Although non-steroidal anti-inflammatory drugs can alleviate menstrual pain, about 18% of women with dysmenorrhea are unresponsive, leaving them and their physicians to pursue less well-studied strategies. The goal of this review is to provide a background for treating menstrual pain when first-line options fail. Research on menstrual pain and failure of similar drugs in the antiplatelet category has suggested potential mechanisms underlying non-steroidal anti-inflammatory drug resistance. Based on these mechanisms, alternative options may be helpful for refractory cases. This review also identifies key pathways in need of further study to optimize menstrual pain treatment.
... However, a review of recent well-controlled studies failed to find evidence of an effect of menstrual cycle phase on the perception of pain sensitivity. 44 There is little evidence of an estrogenic influence in pain processing caused by crosstalk between the estrogen and opioid receptors through classic secondary messengers and downstream gene transcriptional regulators. 45 Several studies support a role for testosterone in dampening pain and raising the pain threshold. ...
Article
Recently, more and more studies have found that pain generation, transmission and modulation are under hormonal regulation. Indeed, hormonal dysregulation is a common component of chronic pain syndromes. Studies have attempted to determine whether the relationship between the pain and its perception and hormones is a causative relationship and how these processes interrelate. This review summarizes and analyzes the current experimental data and provides an overview of the studies addressing these questions. The relationship between pain perception and endocrine effects suggests that hormones can be used as important biomarkers of chronic pain syndromes and/or be developed into therapeutic agents in the fight against pain.
Article
Primary dysmenorrhea (PDM) is not only a painful experience but also affects the psychological and affective states of women. Neuroimaging studies have revealed shared neural substrates for somatic and empathic pains in healthy subjects. However, little is known about the relationship between pain intensity and pain empathy in pain disorders. The cyclic nature of PDM makes it a unique model for investigating this issue during a patients' pain phase. To study how long-term pain modulates empathy for pain, T1-weighted MRI scans were obtained in 39 PDM patients and 41 matched female healthy controls during menstruation. Subjects viewed static visual stimuli of the limbs submitted to painful and non-painful stimulation to solicit empathy. The visual analogue scale for pain intensity and the Interpersonal Reactivity Index for empathic ability were also obtained. We found that women with PDM exhibited higher pain empathy compared with the controls. The anterior insula and brain regions related to sensory discrimination with decreased gray matter volumes were not only shared but also acted as a mediator between pain intensity and pain empathy in PDM patients. In addition, the general linear modeling analysis revealed that long-term pain experience was a more important factor to pain empathy compared with pain intensity. This indicated that long-term pain may cause maladaptive brain structural plasticity, which may further affect psychological adjustment to bring patients more vivid pain when they witness suffering and distress in others.
Article
Background and aims: Exercise-induced hypoalgesia (EIH) is a well-established phenomenon in pain-free individuals that describes a decrease in pain sensitivity after an acute bout of exercise. The EIH response has been demonstrated to be sub-optimal in the presence of persisting pain. Menstrual pain is a common recurrent painful problem with many women experiencing high levels of pain each cycle. However, the EIH response has not been examined in a cohort of women with high levels of menstrual pain. This research aimed to examine whether EIH manifests differently in women with varying levels of menstrual pain. The primary hypothesis was that women with high levels of menstrual pain would demonstrate compromised EIH. Secondary aims were to explore relationships between EIH and emotional state, sleep quality, body mass index (BMI) or physical activity levels. Methods: Pressure pain thresholds (PPT) were measured in 64 participants using a digital handheld algometer before and after a submaximal isometric-handgrip exercise. EIH index was compared between low (VAS 0-3), moderate (VAS 4-7) and high (VAS 8-10) pain groups, using a linear mixed model analysis with participant as a random effect, and site, menstrual pain category and the interaction between the two, as fixed effects. Results: EIH was consistently induced in all groups. However, there was no statistically significant difference between the pain groups for EIH index (p=0.835) or for any co-variates (p>0.05). Conclusions: EIH was not found to differ between women who report regular low, moderate or high levels of menstrual pain, when measured at a point in their menstrual cycle when they are pain free. Implications: This study provides insight that EIH does not vary in women with differing levels of menstrual pain when they are not currently experiencing pain. The current findings indicate that, although menstrual pain can involve regular episodes of high pain levels, it may not be associated with the same central nervous system dysfunctions as seen in sustained chronic pain conditions.
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Article
Some studies suggest that women with primary dysmenorrhea have distinct emotional or personality features. For example, they might exaggerate their responses to external stimuli, such as to intensity-increasing auditory stimuli. Fifteen women with primary dysmenorrhea and 15 healthy women were invited to undergo tests of the intensity dependence of auditory evoked potentials (IDAEP), the Functional and Emotional Measure of Dysmenorrhea, and the Plutchik-van Praag Depression Inventory. Study participants with dysmenorrhea displayed higher Functional and Emotional scale scores and stronger IDAEP. Regarding the IDAEP generation, the source inversion of N1/ P2 disclosed the activated bilateral Superior Temporal Gyri; Medial and Superior Prefrontal Gyri in all participants; and additionally, the Middle Frontal Gyri in dysmenorrhea patients. We report a pronounced IDAEP in primary dysmenorrhea, which indicates the decreased cerebral serotonergic innervations and points to increased activations in the prefrontal and frontal areas in the disorder. Perspective Using an intensity dependence of auditory evoked potential technique, the authors found decreased serotonergic innervation and altered cerebral activation in women with primary dysmenorrhea, which might offer some pharmacotherapeutic clues for the disorder.
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Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF<5%) influencing pain sensitivity, we explored the genetic variation in individuals' responses to experimental pain. Quantitative sensory testing to heat pain was performed in 2,500 volunteers from TwinsUK (TUK): exome sequencing to a depth of 70× was carried out on DNA from singletons at the high and low ends of the heat pain sensitivity distribution in two separate subsamples. Thus in TUK1, 101 pain-sensitive and 102 pain-insensitive were examined, while in TUK2 there were 114 and 96 individuals respectively. A combination of methods was used to test the association between rare variants and pain sensitivity, and the function of the genes identified was explored using network analysis. Using causal reasoning analysis on the genes with different patterns of SNVs by pain sensitivity status, we observed a significant enrichment of variants in genes of the angiotensin pathway (Bonferroni corrected p = 3.8×10(-4)). This pathway is already implicated in animal models and human studies of pain, supporting the notion that it may provide fruitful new targets in pain management. The approach of sequencing extreme exome variation in normal individuals has provided important insights into gene networks mediating pain sensitivity in humans and will be applicable to other common complex traits.
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. Studies have shown that women are more likely to have irritable bowel syndrome (IBS) and more women seek healthcare because of IBS than men. Aim . We wanted to examine the natural history of IBS and dysmenorrhea in women over a 10-year period and to assess the change in IBS after menopause. Method . A population-based postal study. A questionnaire was mailed to the same age- and gender-stratified random sample of the Icelandic population aged 18–75 in 1996 and again in 2006. Results . 77% premenopausal women had dysmenorrhea in the year 1996 and 74% in 2006. 42% of women with dysmenorrhea had IBS according to Manning criteria in the year 2006 and 49% in 1996. 26% of women with dysmenorrhea had IBS according to Rome III 2006 and 11% in the year 1996. In 2006 30% women had severe or very severe dysmenorrhea pain severity. More women (27%) reported severe abdominal pain after menopause than before menopause 11%. Women without dysmenorrhea were twice more likely to remain asymptomatic than the women with dysmenorrhea. Women with dysmenorrhea were more likely to have stable symptoms and were twice more likely to have increased symptoms. Conclusion . Women with IBS are more likely to experience dysmenorrhea than women without IBS which seems to be a part of the symptomatology in most women with IBS. IBS symptom severity seems to increase after menopause.
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Viscero-somatic referral and sensitization has been well documented clinically and widely investigated, whereas viscero-visceral referral and sensitization (termed cross-organ sensitization) has only recently received attention as important to visceral disease states. Because second order neurons in the CNS have been extensively shown to receive convergent input from different visceral organs, it has been assumed that cross-organ sensitization arises by the same convergence-projection mechanism as advanced for viscero-somatic referral and sensitization. However, increasing evidence also suggests participation of peripheral mechanisms to explain referral and sensitization. We briefly summarize behavioral, morphological and physiological support of and focus on potential mechanisms underlying cross-organ sensitization.
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Most patients who undergo surgery recover uneventfully and resume their normal daily activities within weeks. Nevertheless, chronic postsurgical pain develops in an alarming proportion of patients. The prevailing approach of focusing on established chronic pain implicitly assumes that information generated during the acute injury phase is not important to the subsequent development of chronic pain. However, a rarely appreciated fact is that every chronic pain was once acute. Here, we argue that a focus on the transition from acute to chronic pain may reveal important cues that will help us to predict who will go on to develop chronic pain and who will not. Unlike other injuries, surgery presents a unique set of circumstances in which the precise timing of the physical insult and ensuing pain are known in advance. This provides an opportunity, before surgery, to identify the risk factors and protective factors that predict the course of recovery. In this paper, the epidemiology of chronic postsurgical pain is reviewed. The surgical, psychosocial, socio-environmental and patient-related factors that appear to confer a greater risk of developing chronic postsurgical pain are described. The genetics of chronic postsurgical pain are discussed with emphasis on known polymorphisms in human genes associated with chronic pain, genetic studies of rodent models of pain involving surgical approaches, the importance of developing accurate human chronic postsurgical pain phenotypes and the expected gains for chronic postsurgical pain medicine in the post-genomic era. Evidence is then reviewed for a preventive multimodal analgesic approach to surgery. While there is some evidence that chronic postsurgical pain can be minimized or prevented by an analgesic approach involving aggressive perioperative multimodal treatment, other studies fail to show this benefit. The transition of acute postoperative pain to chronic postsurgical pain is a complex and poorly understood developmental process, involving biological, psychological and social-environmental factors.
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Reactions to radiant heat stimuli were measured in dysmenorrheic and nondysmenorrheic women across a 4-week period. (Dysmenorrhea is a condition in which pain accompanies menstruation.) Receiver operating characteristic (ROC) curve parameters were computed for each of the phases of the menstrual cycle. When painful stimuli were used, a group × phase interaction was found in the analysis on the d’e scores. Nondysmenorrheic women were found to vary cyclically in their ability to discriminate painful from nonpainful stimuli, whereas dysmenorrheic women showed consistent pain reactions throughout the whole cycle. Cyclic effects were not apparent in the analyses on the response criteria or in those on reactions to thermal stimuli. The results suggest that women who experience pain with menstruation differ from women who do not differ in their perception of pain across the menstrual cycle. The sensory differences between the groups of women were not characteristic of responses to thermal stimuli and were not accompanied by shifts in willingness to report pain. Biochemical differences between dysmenorrheic and nondysmenorrheic women are believed to be the cause of the differences in pain reactions across phase.
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Article
The rat tail ischaemia--reperfusion model of acute hyperalgesia described by Gelgor et al. (Pain 24 (1986) 251) has been investigated pharmacologically and electrophysiologically. Despite the advantages of this reusable animal model, biochemical changes associated with the behavioural response have not been determined. After injury+/-subcutaneous diclofenac pretreatment, we investigated the behavioural response (changes to thermally-induced tail flick latency) and measured diclofenac, prostaglandin E(2), 6-keto-prostaglandin F(1 alpha) and thromboxane B(2) concentrations in the tail, spinal cord and brain. Subcutaneous injection of 40 mg kg(-1) diclofenac sodium abolished the hyperalgesic response, suppressed the increased eicosanoid production in the tail, inhibited eicosanoid synthesis in the brain, but gave equivocal effects on eicosanoid concentrations in the spinal cord. Injection of 10 and 20 mg kg(-1) diclofenac reduced the duration of hyperalgesia but did not abolish the behavioural response. Diclofenac concentrations in all three tissues were similar, being approximately 5--10% of the corresponding plasma concentrations. We propose that both central and peripheral mechanisms are associated with the hyperalgesia and that the findings lend indirect support to a central action for non-steroidal anti-inflammatory drugs.
Chapter
In the folklore of many cultures, the menstrual fluid is believed to be endowed with magical properties. The concept of toxins in the menstrual fluid is evident in many historical writings. Schick1 remarked that his maidservant caused withering of cut flowers when she touched them during her menstrual period. Similar observations were noted by Macht and colleagues.2,3 Acetone extracts of menstrual fluid were found toxic to primulas and could potentiate the epinephrine-induced contractions of the rat vas deferens in vitro.4 Pickles5 ushered in the era of prostaglandins in menstrual fluid when he showed that menstrual fluid extracts induced smooth muscle contractions in vitro; the term “menstrual stimulant” was coined, and this was later shown to be prostaglandins F and E.6 Later, women with primary dysmenorrhea were collectively shown to have a higher amount of menstrual fluid prostaglandins than normal women.7 During the 1970s, a few groups, including our laboratory, showed that endometrial and menstrual fluid prostaglandins were increased in dysmenorrhea women and could be reduced to below normal levels with nonsteroidal anti-inflammatory drugs while concomitant relief of the dysmenorrhea occurred.8–11
Article
Four different testing methods were used to estimate the sensitivity of body surfaces to pain-causing stimuli for a group of 24 healthy male subjects. These methods were (a) determination of the heat pain threshold, (b) determination of the pain threshold for pinching of a skin fold, (c) discrimination of a sharp prick from a blunt contact, and (d) estimation of the pain caused by application of an ice-cold cylinder.Three different body regions were tested: the abdomen, the anterior surface of the neck and the lateral surface of the thigh. Of the three body regions, the thigh area required the strongest stimulation for pain in all 4 tests. The neck was the most sensitive for cold pain, and the abdomen had the lowest threshold for heat pain.There was a barely statistically significant tendency for subjects relatively sensitive on one test to be also relatively sensitive on other tests. Correlation coefficients between any two tests on the same subject were always less than 0.6. Possible reasons for the relative lack of agreement among the results of the different pain tests are discussed.
Article
Unlabelled: Primary dysmenorrhea is a common painful condition in women that recurs every month across the reproductive years. The recurrent nociceptive input into the central nervous system that occurs during menstruation each month in women with dysmenorrhea is hypothesized to lead to increased sensitivity to painful stimuli. We investigated whether women with primary dysmenorrhea are hyperalgesic to deep muscle pain induced by a cleanly nociceptive method of hypertonic saline injection. Pain stimulation was applied both within an area of referred menstrual pain (lower back) and at a remote site outside of referred menstrual pain (forearm) in 12 healthy women with severe dysmenorrhea and 9 healthy women without dysmenorrhea, at 3 phases of the menstrual cycle: menstruation and follicular and luteal phases. Women rated their pain severity on a 100-mm visual analog scale every 30 seconds after injection until the pain subsided. In both groups of women, menstrual cycle phase had no effect on the reported intensity and duration of muscle pain. However, women with dysmenorrhea had increased sensitivity to experimental muscle pain both at the site of referred pain and at a remote nonpainful site, as assessed by peak pain severity visual analog scale rating, area under the visual analog scale curve, and pain duration, compared to women without dysmenorrhea. These data show that women with severe primary dysmenorrhea, who experience monthly menstrual pain, are hyperalgesic to deep muscle pain compared to women without dysmenorrhea. Perspective: Our findings that dysmenorrheic women are hyperalgesic to a clinically relevant, deep muscle pain in areas within and outside of referred menstrual pain indicates lasting changes in pain sensitivity outside of the painful period during menstruation.
Article
A rat model of tourniquet-induced ischemia was created to observe the changes in sciatic afferent neuronal activity associated with prolonged tourniquet inflation on the hind leg. The sciatic nerve was divided in the proximal thigh and a two-electrode microfilament recording technique and signal averaging computer were used to survey afferent neuronal activity prior to and after tourniquet inflation. This method was able to determine both firing rate and conduction velocity of spontaneously active or mechanically sensitive nerve fibers. In 14 rats observed prior to tourniquet inflation there was much spontaneous activity. These fibers all had rapid conduction velocities (30 +/- 6.9 m/s) (mean +/- SD) and firing rates (16.3 +/- 1.9 H). All fibers could be stimulated by movement of distal joints or by probing the skin of the leg. After tourniquet inflation, a pressure-induced conduction block occurred stopping all spontaneous and mechanically induced activity. After a short interval, (55 +/- 16 min) a different group of spontaneously active fibers were observed that had both slow conduction (2.04 +/- 0.77 m/s) and firing rates (0.54 +/- 0.9 H). These fibers did not respond to mechanical stimulation of the limb distal to the tourniquet, or local anesthetic or cold block of the nerve distal to the tourniquet. Blockade of the sciatic nerve just proximal to the tourniquet and deflation of the tourniquet did abolish activity in these fibers. In ten separate rats in which tourniquets were placed but no surgical incision made, mean arterial blood pressure rose significantly after tourniquet inflation. With tourniquet deflation, blood pressure fell significantly from levels observed during tourniquet inflation. This study showed the presence of a group of spontaneously active fibers with velocities in the C-fiber range that were not observed prior to tourniquet inflation. The receptive fields of these fibers were most likely in the ischemic tissue or axons directly under or just proximal to the tourniquet. The neurophysiologic changes noted in this experimental model could represent the physiologic basis of tourniquet pain.
Article
Objectives: In the present quantitative and methodological study we systematically investigated the variability and sensory aspects of experimental muscle pain induced by hypertonic saline 'as proposed by Kellgren. Methods: Four experiments were carried out: 1. intra-individual variability in saline-induced muscle pain, 2. the influence of saline concentration [0.9%, 5%, 11.5% and 20%], 3. the Influence of infusion time [20 and 100 seconds] and volume [0.1 ml and 0.5 ml] and 4. the influence of tissue type [periosteum, muscle, subcutis]. The infusion of hypertonic saline was standardized using a computer-controlled infusion pump. Pain intensity, quality, distribution and cutaneous sensory changes were assessed. Results: It was possible to obtain reproducible intra-individual [variability < 15.6% ± 54.3] scores of pain intensity, quality, distribution and cutaneous changes. There was a significant correlation between pain intensity and the infused volume [R = 0.51, P < 0.001] and concentration [R = 0.76, P < 0.0001] of hypertonic saline. The onset of pain was correlated to the infusion time [R = 0.57, P < 0.001] and concentration [R = − 0.40, P < 0.02]. The pain offset and peak time were significantly [P < 0.05] influenced by the concentration and infusion time. The infusions close to the periosteum caused a higher pain intensity compared to infusions in muscle and subcutis. Infusions in subcutis produced a “scalding” pain quality that was different compared to the “drilling” and “taut” quality of muscular pain. Cutaneous hypoesthesia to pin-prick and touch close to the injection site were the most commonly observed changes in sensation. Conclusion: The findings indicate that the hypertonic saline muscle pain model is useful when studying basic physiological aspects-of human muscle pain.
Article
Pain symptoms of many disorders are reported to vary with menstrual stage. This study investigated how pain thresholds to electrical stimulation of the skin, subcutis and muscle tissue varied with menstrual stage in normal women and compared these variations with those in women with dysmenorrhea and in healthy men at matched intervals. Thresholds of the three tissues were measured four times during the course of one menstrual cycle at four sites. Two of the sites were on the abdomen within the uterine viscerotome (abdomen-rectus abdominis, left and right) and two were outside it on the limbs (leg-quadriceps, arm-deltoid). Calculated from the beginning of menstruation (day 0), the menstrual phases studied were menstrual (days 2–6), periovulatory (days 12–16), luteal (days 17–22) and premenstrual (days 25–28). Spontaneous pain associated with menstruation was measured from diary estimates on a VAS scale. Menstrual phase, dysmenorrhea and tissue: Whereas the highest thresholds always occurred in the luteal phase regardless of segmental site or stimulus depth, the lowest thresholds occurred in the periovulatory stage for skin, whereas those for muscle/subcutis occurred perimenstrually. Dysmenorrhea accentuated the impact of menstrual phase. For non-dysmenorrheic women menstrual trends were significant only in abdominal muscle and subcutis, but for dysmenorrheic women the trends were also significant in abdominal skin and in limb muscle and subcutis. Dysmenorrhea also lowered thresholds mainly in muscle and sometimes in subcutis, but never in skin, with the greatest hyperalgesic effects in left abdominis muscle. Segmental site: Abdominal sites were more vulnerable to menstrual influences than limb sites. Muscle thresholds, but not skin or subcutis thresholds, were significantly lower in abdomen than in limbs, particularly in dysmenorrheic women. The amount of abdominal muscle hyperalgesia correlated significantly with the amount of spontaneous menstrual pain. Sex differences: Only minor sex differences were observed for pain thresholds of the arm and leg, but there was a unanimous refusal by men, but not by women, to be tested at abdominal sites. These results indicate that menstrual phase, dysmenorrhea status, segmental site, tissue depth and sex all have unique interacting effects on pain thresholds, thus adding more items to the lengthy and still-growing list of biological factors that enter into an individual's judgment of whether or not a stimulus is painful.
Article
Chronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15%-20% of women in the United States. Endometriosis is often associated with CPP, however, other factors, such as preexisting or concomitant changes of the central pain system, might contribute to the development of chronic pain. We applied voxel-based morphometry to determine whether women with CPP with and without endometriosis display changes in brain morphology in regions known to be involved in pain processing. Four subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6 with CPP without endometriosis, and 23 healthy controls. All patients with endometriosis and/or CPP were surgically confirmed. Relative to controls, women with endometriosis-associated CPP displayed decreased gray matter volume in brain regions involved in pain perception, including the left thalamus, left cingulate gyrus, right putamen, and right insula. Women with CPP without endometriosis also showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in patients with endometriosis who had no CPP. We conclude that CPP is associated with changes in regional gray matter volume within the central pain system. Although endometriosis may be an important risk factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data support the notion that changes in the central pain system also play an important role in the development of chronic pain, regardless of the presence of endometriosis.
Article
Patients with chronic pain conditions demonstrate altered central processing of experimental noxious stimuli, dysfunction of the hypothalamic-pituitary-adrenal axis, and reduced quality of life. Dysmenorrhoea is not considered a chronic pain condition, but is associated with enhanced behavioural responses to experimental noxious stimuli. We used behavioural measures, functional magnetic resonance imaging, and serum steroid hormone levels to investigate the response to experimental thermal stimuli in otherwise healthy women, with and without dysmenorrhoea. Women with dysmenorrhoea reported increased pain to noxious stimulation of the arm and abdomen throughout the menstrual cycle; no menstrual cycle effect was observed in either group. During menstruation, deactivation of brain regions in response to noxious stimulation was observed in control women but not in women with dysmenorrhoea. Without background pain (ie, in nonmenstrual phases), activity in the entorhinal cortex appeared to mediate the increased responses in women with dysmenorrhoea. Mean cortisol was significantly lower in women with dysmenorrhoea and was negatively correlated with the duration of the symptom. Additionally, women with dysmenorrhoea reported significantly lower physical but not mental quality of life. Thus, many features of chronic pain conditions are also seen in women with dysmenorrhoea: specifically a reduction in quality of life, suppression of the hypothalamic-pituitary-adrenal axis, and alterations in the central processing of experimental noxious stimuli. These alterations persist when there is no background pain and occur in response to stimuli at a site distant from that of the clinical pain. These findings indicate the potential importance of early and adequate treatment of dysmenorrhoea.
Article
The present paper describes various experimental techniques to induce and assess pain in the musculoskeletal system. Advantages and limitations of the human muscle pain models are discussed. The existing literature suggests that such models provide valuable information on basic and clinical muscle pain mechanisms.
Article
Primary dysmenorrhea (PDM) is the most prevalent gynecological disorder for women in the reproductive age. PDM patients suffer from lower abdominal pain that starts with the onset of the menstrual flow. Prolonged nociceptive input to the central nervous system can induce functional and structural alterations throughout the nervous system. In PDM, a chronic viscero-nociceptive drive of cyclic nature, indications of central sensitization and altered brain metabolism suggest a substantial central reorganization. Previously, we hypothesized that disinhibition of orbitofrontal networks could be responsible for increased pain and negative affect in PDM. Here, we further tested this hypothesis. We used an optimized voxel-based morphometry (VBM) approach to compare total and regional gray matter (GM) increases and decreases in 32 PDM patients with 32 healthy age and menstrual cycle matched (peri-ovulatory phase) controls. Abnormal decreases were found in regions involved in pain transmission, higher level sensory processing, and affected regulation while increases were found in regions involved in pain modulation and in regulation of endocrine function. Moreover, GM changes in regions involved in top-down pain modulation and in generation of negative affect were related to the severity of the experienced PDM pain. Our results demonstrate that abnormal GM volume changes are present in PDM patients even in the absence of pain. These changes may underpin a combination of impaired pain inhibition, increased pain facilitation and increased affect. Our findings highlight that longer lasting central changes may occur not only in sustained chronic pain conditions but also in cyclic occurring pain conditions.
Article
Co-existing algogenic conditions in two internal organs in the same patient may mutually enhance pain symptoms (viscero-visceral hyperalgesia). The present study assessed this phenomenon in different models of visceral interaction. In a prospective evaluation, patients with: (a) coronary artery disease (CAD)+gallstone (Gs) (common sensory projection: T5); (b) irritable bowel syndrome (IBS)+dysmenorrhea (Dys) (T10-L1); (c) dysmenorrhea/endometriosis+urinary calculosis (Cal)(T10-L1); and (d) gallstone+left urinary calculosis (Gs+LCal) (unknown common projection) were compared with patients with CAD, Gs, IBS, Dys or Cal only, for spontaneous symptoms (number/intensity of pain episodes) over comparable time periods and for referred symptoms (muscle hyperalgesia; pressure/electrical pain thresholds) from each visceral location. In patients' subgroups, symptoms were also re-assessed after treatment of each condition or after no treatment. (a) CAD+Gs presented more numerous/intense angina/biliary episodes and more referred muscle chest/abdominal hyperalgesia than CAD or Gs; cardiac revascularization or cholecystectomy also reduced biliary or cardiac symptoms, respectively (0.001<p<0.05). (b) IBS+Dys had more intestinal/menstrual pain and abdomino/pelvic muscle hyperalgesia than IBS or Dys; hormonal dysmenorrhea treatment also reduced IBS symptoms; IBS dietary treatment also improved dysmenorrhea (0.001<p<0.05) while no treatment of either conditions resulted in no improvement in time of symptoms from both. (c) Cal+Dys had more urinary/menstrual pain and referred lumbar/abdominal hyperalgesia than Cal or Dys; hormonal dysmenorrhea treatment/laser treatment for endometriosis also improved urinary symptoms; lithotripsy for urinary stone also reduced menstrual symptoms (0.001<p<0.05). (d) In Gs+LCal, cholecystectomy or urinary lithotripsy did not improve urinary or biliary symptoms, respectively. Mechanisms of viscero-visceral hyperalgesia between organs with documented partially common sensory projection probably involve sensitization of viscero-viscero-somatic convergent neurons.
Article
Brain imaging studies have identified abnormal rectal-evoked responses and cortical thinning in patients with irritable bowel syndrome (IBS). However, it is not known whether these abnormalities are pre-existing or develop as result of long-term IBS. Therefore, we tested whether abnormal structural gray matter integrity in IBS correlates with individual disease symptoms, duration of the IBS, or the personality characteristic of pain catastrophizing. Eleven IBS patients and 16 age-matched healthy subjects underwent structural magnetic resonance imaging. Voxel-based morphometry and cortical thickness analysis were used to identify abnormalities in subcortical and cortical regions, respectively, and their correlation to individual characteristics. The IBS group showed increased hypothalamic gray matter and cortical thinning in the anterior midcingulate cortex compared with controls, a strong negative correlation between dorsolateral prefrontal cortex thickness and pain catastrophizing, and a positive correlation between anterior insula thickness and pain duration. In the insula, there was cortical thinning in patients with short-term IBS, but long-term IBS pain was associated with a more normal insula thickness. Our findings provide new insight into IBS and chronic pain through evidence for structural changes that could fit with functional abnormalities. We report that patients with IBS have increased hypothalamic gray matter, which may be related to the association among IBS, stress, and the hypothalamic-pituitary-adrenal axis. Furthermore, we have identified some supraspinal abnormalities that may be pre-existing and contribute to vulnerability, and others that may develop over time, possibly because of chronic abnormal inputs.
Article
Dysmenorrhoea may begin soon after the menarche, after which it often improves with age, or it may originate later in life after the onset of an underlying causative condition. Dysmenorrhoea is common, and in up to 20% of women it may be severe enough to interfere with daily activities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for dysmenorrhoea? We searched: Medline, Embase, The Cochrane Library and other important databases up to July 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupressure, acupuncture, aspirin, behavioural interventions, combined oral contraceptives, compound analgesics, fish oil, herbal remedies, magnesium, magnets, non-steroidal anti-inflammatory drugs, paracetamol, spinal manipulation, surgical interruption of pelvic nerve pathways, thiamine, toki-shakuyaku-san, topical heat, transcutaneous electrical nerve stimulation (TENS), vitamin B12, and vitamin E.
Article
Primary dysmenorrhea (PDM, menstrual pain without pelvic abnormality) is the most common gynecological disorder for women in the reproductive age. It is characterized by cramping pain and enhanced pain sensitivity during the menstruation period. PDM has been associated with peripheral and central sensitization. Abnormal brain mechanisms may further contribute to development and maintenance of the state. Using fluoro-deoxyglucose positron emission tomography, increased activity was observed in prefrontal/orbitofrontal regions and left ventral posterior thalamus while decreased activity mainly was observed in sensorimotor regions of the left hemisphere at onset compared to offset of PDM. These results were specific to menstrual pain and were not found in menstrual matched controls. Orbitofrontal activities were positively related to while somatosensory activities where negatively related to subjective pain ratings. These results show that ongoing menstrual pain in PDM is accompanied by abnormal brain metabolism. Disinhibition of thalamo-orbitofrontal-prefrontal networks may contribute to the generation of pain and hyperalgesia in PDM possibly by maintaining spinal and thalamic sensitization while increasing negative affect. Excessive excitatory input during menstrual pain may induce compensatory inhibitory mechanism in several somatic sensorimotor regions.
Article
1. Unitary activities of muscular thin fibre afferents, which were not sensitive to muscle stretching, were recorded from the nerve of the medial gastrocnemius muscle of the dog. Responses to mechanical stimulation, intra-arterial injection and local application of chemical solutions, and thermal stimulation of the surface of the muscle were studied. It was observed that polymodal receptors which responded to all types of stimulation existed in the thin fibre afferents of the muscle.2. The receptive area of these units tested by mechanical stimulation was spot-like and appeared to be located not only on the surface but in the midst of the muscle.3. The mechanical response varied among these units with respect to the threshold and the pattern of discharges.4. In these units, NaCl, KCl, and bradykinin consistently evoked responses, with differences in the latencies and discharge patterns, while solutions of histamine, acetylcholine and sodium citrate caused responses less consistently and less effectively. In the stretch receptors, chemical stimulation applied in the same way as tested in the thin fibre afferents produced quite different features in their responses.5. Heating the receptive area of the muscle surface caused responses in twenty-five out of thirty-six units, which were sensitive both to mechanical and to chemical stimulations. The threshold varied from 38.0 to 48.3 degrees C, with a mean of 43.1 degrees C for C fibre units and 41 degrees C for A-delta fibre units.6. The responses to heating were consistently obtained in the units responding to the surface application of chemical solutions. However, the above response was never obtained in the units which did not respond to surface chemical stimulation but responded to intra-arterial injection. These results suggest a large population of polymodal receptors in the muscular thin fibre afferents.
Article
A comparison is made between the General Health Questionnaire (GHQ) and the Symptom Checklist (SCL) as psychiatric screening tests in community-based research projects. Both are shown to correlate equally well with independent clinical assessment, and the differences between them mainly reside in the form of their response scales. The GHQ works best as a screening test, since it has fewer false positives associated with its use, but it may miss those with long-standing disorders. The SCL tends not to miss long-standing disorders and furnishes diagnostic sub-scales if these are required. Both tests function better with men than with women and with whites than with blacks, but neither is affected by social class or age of the respondent. The study revealed high correlations between the symptoms of anxiety and depression, and indicated some possible differences between the symptom clusters seen in whites and in blacks.
Article
The relationship between cardiovascular responses and pain produced by the submaximal-effort tourniquet procedure was evaluated in healthy humans. Graded increases in ischemic pain were associated with graded elevations in arterial blood pressure, forearm vascular resistance, and venous tone. Many of the vascular responses to muscle ischemia were typical of the cardiovascular components of the defense reaction and correlated with both the sensory and affective aspects of ischemic pain. The cardiovascular responses to arm ischemia were distinguishable from those produced by rhythmic hand exercise used to produce ischemia. Dynamic hand exercise produced a transient increase in arterial blood pressure, heart rate, and measures of hand discomfort. These responses were enhanced when dynamic hand exercise was conducted under ischemic conditions. The tightly coupled and coordinated cardiovascular responses elicited by ischemic pain represent integrated adaptive responses to painful stimulation.
Article
A rat model of tourniquet-induced ischemia was created to observe the changes in sciatic afferent neuronal activity associated with prolonged tourniquet inflation on the hind leg. The sciatic nerve was divided in the proximal thigh and a two-electrode microfilament recording technique and signal averaging computer were used to survey afferent neuronal activity prior to and after tourniquet inflation. This method was able to determine both firing rate and conduction velocity of spontaneously active or mechanically sensitive nerve fibers. In 14 rats observed prior to tourniquet inflation there was much spontaneous activity. These fibers all had rapid conduction velocities (30 +/- 6.9 m/s) (mean +/- SD) and firing rates (16.3 +/- 1.9 H). All fibers could be stimulated by movement of distal joints or by probing the skin of the leg. After tourniquet inflation, a pressure-induced conduction block occurred stopping all spontaneous and mechanically induced activity. After a short interval, (55 +/- 16 min) a different group of spontaneously active fibers were observed that had both slow conduction (2.04 +/- 0.77 m/s) firing rates (0.54 +/- 0.9 H). These fibers did not respond to mechanical stimulation of the limb distal to the tourniquet, or local anesthetic or cold block of the nerve distal to the tourniquet. Blockade of the sciatic nerve just proximal to the tourniquet and deflation of the tourniquet did abolish activity in these fibers. In ten separate rats in which tourniquets were placed but no surgical incision made, mean arterial blood pressure rose significantly after tourniquet inflation. With tourniquet deflation, blood pressure fell significantly from levels observed during tourniquet inflation.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
It has been proposed that dysmenorrheic women have a heightened pain sensitivity compared to nondysmenorrheic women, although previous studies investigating this hypothesis have yielded conflicting results. This study investigated the pain sensitivity of nondysmenorrheic women and of women suffering from spasmodic, congestive, and combined dysmenorrhea, across three phases of the menstrual cycle: premenstrual, menstrual, and intermenstrual. No interaction between type of dysmenorrhea and menstrual phase was found for either pain threshold or pain tolerance, using three procedures of experimentally induced pain. On a self-report measure of pain, however, the congestive and combined dysmenorrheics reported the highest degree of pain and distress, especially during the premenstrual and menstrual phases; nonsufferers reported the lowest degree and were stable across phases.
Article
Pain responses (threshold, tolerance, and visual analog ratings) to the cold pressor task were studied in 46 normally menstruating dysmenorrheic and non-dysmenorrheic women during 2 phases of the menstrual cycle. Twenty-six women provided measurements during the follicular (days 8-14) and 20 during the luteal (days 15-21) phases of the menstrual cycle. A significantly lower pain threshold was obtained during the luteal as compared to the follicular phase. Pain tolerance showed a similar but non-significant trend. Visual analog ratings were significantly lower in dysmenorrheic women during the follicular than the luteal phase. Also, these ratings were lower than those of non-dysmenorrheic women in the follicular phase. This finding may support an adaptation-levels model, in that dysmenorrheic women report less pain than do non-dysmenorrheic women because they compare cold pressor pain with internal menstrual pain.
Article
Ischemic pain was produced by a blood pressure cuff placed to the arm of healthy human subjects for 15 min which produced a mean pain score of 59% (visual analogue scale). Ischemia induced a significant dental pain threshold elevation (mean 67%) and 2 mg of naloxone did not reduce it. Thermal sensitivity of the upper lip had a tendency to reduction during ischemia and 2 mg of naloxone reduced this effect. Tactile thresholds in the forehead or in the contralateral arm were not markedly elevated. Neither ACTH nor prolactin level in the plasma was related to the dental pain threshold elevation during ischemia. The findings of the present study suggest that ischemic pain nonsegmentally produces a predominant inhibition of responses to thin afferents. Endogenous opioids may markedly contribute to the reduction of thermal sensitivity induced by ischemia, but their contribution to dental pain threshold elevations seems to be less important. Stress or other adenohypophyseal mechanisms involving the release of ACTH or prolactin do not explain the effects of ischemia found in the present study.
Article
Samples of spasmodic, congestive and combined dysmenorrheic women and non-dysmenorrheic women were subjected to an ischemic pain procedure to measure their pain threshold, pain tolerance and self-reported pain. Cognitive and behavioral strategies that subjects had spontaneously used during the pain procedure were later assessed. A classification system was derived for categorizing subjects' responses to the interview and questionnaire used in this assessment. Contrary to previous claims that dysmenorrheic women may be hypersensitive to pain, no differences in pain sensitivity were discovered among the four groups of subjects. A few differences in cognitive and behavioral strategies did emerge, but these were of insufficient magnitude to contend that dysmenorrheic women are disadvantaged in their strategies for coping with pain.
Article
A common type of study performed by anesthesiologists determines the effect of an intervention on pain reported by groups of patients. The goal of this study was to evaluate the effectiveness of t, analysis of variance (ANOVA), Mann-Whitney, and Kruskal-Wallis tests to compare visual analog scale (VAS) measurements between two or among three groups of patients. These results may be particularly helpful during the design of studies that measure pain with a VAS. One VAS measurement was obtained from each of 480 nulliparous women in labor who were receiving oxytocin (149), nalbuphine (159), or epidural bupivacaine (172). Multiple simulated samples were then drawn from these data. These simulated samples were used in computer simulations of clinical trials comparing VAS measurements among groups. t and ANOVA tests were performed before and after an arcsin transformation was used, to make the data closer to a normal distribution. VAS measurements were also compared after they were divided into five ranked categories. The statistical distributions of VAS measurements were not normal (P < 10(-7)). Arcsin transformation made the distributions closer to normal distributions. Nevertheless, no statistical test incorrectly suggested that a difference existed among groups, when there was no difference, more often than the expected rate. t or ANOVA tests had a slightly greater statistical power than the other tests to detect differences among groups. Because arcsin transformation both decreased differences among means and reduced the variance to a lesser extent, it decreased power to detect differences among groups. Statistical power to detect differences among groups was not less for a five-category VAS than for a continuous VAS. We conclude that t and ANOVA, without an accompanying arcsin transformation, are good tests to find differences in VAS measurements among groups.
Article
In this paper, the author's long history with somatosensation is overviewed with special emphasis on the creation of objective tests of sensibility. Objective testing is discussed using numerous examples from the author's experiences. The creation of the Semmes-Weinstein monofilaments is discussed. Tests employing the Semmes-Weinstein monofilaments, two-point discrimination, and point localization are discussed with reference to the fact that these tests reflect specific differences between the central and peripheral nervous systems. Towards that end, contrasts are made between the Semmes-Weinstein esthesiometer and both the two-point discrimination and the point-localization tests. A new enhancement of the original Semmes-Weinstein monofilament test, the Weinstein Enhanced Sensory Test (WEST), is introduced. Advantages of the WEST are discussed.
Article
Daily ratings of symptoms are essential to confirm a diagnosis of premenstrual syndrome (PMS). The 17-item Daily Symptom Report (DSR) is relatively brief and appropriate for clinical and primary care settings. We report the reliability, factor structure and relationships with other standard mood measures of the DSR as a measure of PMS. The sample includes 170 women who sought medical treatment for severe PMS and a non-clinical comparison group of 54 healthy women in the same age range. Cronbach's coefficient alpha was 0.92 for the premenstrual DSR scores, indicating very high internal consistency for the 17 symptoms. Factor analysis yielded four factors describing mood, behavioral items, pain, and physical symptoms. In the PMS sample, there were moderate correlations between the DSR and the Hamilton Rating Scale for Depression, the Profile of Mood States, and the Premenstrual Assessment Form. The moderate correlations of the DSR with other standard symptom measures add to the evidence that PMS overlaps with other mood disorders at the premenstrual time but is not simply a brief depression or a truncated anxiety disorder.
Article
One way to ensure adequate sensitivity for analgesic trials is to test the intervention on patients who have established pain of moderate to severe intensity. The usual criterion is at least moderate pain on a categorical pain intensity scale. When visual analogue scales (VAS) are the only pain measure in trials we need to know what point on a VAS represents moderate pain, so that these trials can be included in meta-analysis when baseline pain of at least moderate intensity is an inclusion criterion. To investigate this we used individual patient data from 1080 patients from randomised controlled trials of various analgesics. Baseline pain was measured using a 4-point categorical pain intensity scale and a pain intensity VAS under identical conditions. The distribution of the VAS scores was examined for 736 patients reporting moderate pain and for 344 reporting severe pain. The VAS scores corresponding to moderate or severe pain were also examined by gender. Baseline VAS scores recorded by patients reporting moderate pain were significantly different from those of patients reporting severe pain. Of the patients reporting moderate pain 85% scored over 30 mm on the corresponding VAS, with a mean score of 49 mm. For those reporting severe pain 85% scored over 54 mm with a mean score of 75 mm. There was no difference between the corresponding VAS scores of men and women. Our results indicate that if a patient records a baseline VAS score in excess of 30 mm they would probably have recorded at least moderate pain on a 4-point categorical scale.
Article
Results from animal and human studies suggest that disregulations of the hypothalamus-pituitary-adrenal (HPA) axis are involved in several behavioral, circulatory, endocrine, and immune disorders with clear-cut gender differences in disease prevalence. The aim of the present study was to investigate sex-specific HPA response patterns with a focus on the contribution of gonadal steroids as possible mediators. A total of 81 healthy adults were investigated in the present study. Twenty men, 19 women in the follicular phase of the menstrual cycle, 21 women in the luteal phase, and 21 women using oral contraceptives (OC) were exposed to a brief psychosocial stress test (Trier Social Stress Test; TSST) and injected with 0.25 mg ACTH1-24 on consecutive days. Basal HPA activity was investigated by repeatedly measuring cortisol levels immediately after awakening, as well as in 30-minute intervals from 9:00 AM to 9:00 PM. Additionally, questionnaires were used to assess psychological state and trait parameters. Results show that the TSST induced significant increases in ACTH, salivary-free cortisol, total plasma cortisol, and heart rates, as well as increased wakefulness and reduced calmness in the total group. Significant group differences emerged for ACTH and salivary-free cortisol stress responses: Although men showed higher ACTH responses to the TSST compared with each of the three groups of women, salivary cortisol responses showed the following response pattern: Luteal = Men > Follicular = OC. The salivary cortisol responses to ACTH1-24 showed a similar response pattern: Luteal > Men > Follicular > OC. In contrast, total blood cortisol levels did not reveal any group difference between sexes or follicular versus luteal phase in either test. Although a similar salivary-free cortisol increase after awakening was found in the four groups, the circadian cortisol profile was significantly different throughout the first 4 hours of sampling. Questionnaire-derived psychological variables, as measured in the present study, could not explain the observed results. We conclude that gender, menstrual cycle phase, and OC use exert important effects on HPA responsiveness to psychosocial stress in healthy subjects. Although men seem to have a stronger hypothalamic drive in response to stressful stimulation than women, differences in salivary-free cortisol levels, at least in part, may be explained by estradiol-induced changes in corticosteroid-binding protein levels. ACTH and cortisol secretion is not affected by OC use per se but the amount of bioavailable unbound cortisol ("free") is greatly reduced in this group of women after stimulation. Inasmuch as none of these differences between the study groups emerged in total blood cortisol levels, we strongly advocate for the simultaneous measurement of free and total cortisol levels in future studies on HPA functioning.
Article
Primary dysmenorrhea is defined as cramping pain in the lower abdomen occurring just before or during menstruation, in the absence of other diseases such as endometriosis. Prevalence rates are as high as 90 percent. Initial presentation of primary dysmenorrhea typically occurs in adolescence. It is a common cause of absenteeism and reduced quality of life in women. The problem is often underdiagnosed and undertreated. Women with primary dysmenorrhea have increased production of endometrial prostaglandin, resulting in increased uterine tone and stronger, more frequent uterine contractions. A diagnostic evaluation is unnecessary in patients with typical symptoms and no risk factors for secondary causes. Nonsteroidal anti-inflammatory medications are the mainstay of treatment, with the addition of oral contraceptive pills when necessary. About 10 percent of affected women do not respond to these measures. It is important to consider secondary causes of dysmenorrhea in women who do not respond to initial treatment. Many alternative treatments (ranging from acupuncture to laparoscopic surgery) have been studied, but the supporting studies are small, with limited long-term follow-up.
Article
The subnucleus interpolaris (Vi) has been identified as a major recipient for trigeminal ganglionic input from jaw muscles, and contains neurons with nociceptive properties similar to those in the subnucleus caudalis (Vc). Therefore, Vi may be another important site for processing craniofacial muscle nociception. The aims of present study were to define functional properties of Vi neurons that receive input from masseter muscle afferents by characterizing their responses to electrical, mechanical, and to chemical stimulation of the muscle. Ninety cells were identified as masseter muscle units in 11 adult cats. Most of these units (79%) received additional inputs from orofacial skin. Following the intramuscular injection of 5% hypertonic saline, 49% of the cells showed a significant modulation of either the resting discharge and/or responses to innocuous mechanical stimulation on their cutaneous receptive fields (RFs). The most common response to saline injection was an induction or facilitation of resting discharge which declined as an exponential decay function, returning to pre-injection level within 3-4 min. Forty-five percent of the muscle units that were tested with mechanical stimulation (13/29) showed a prolonged inhibition of mechanically-evoked responses. In most cases (8/13), the inhibitory response was accompanied by initial facilitation. The observations that Vi contained a population of neurons that receive small diameter muscle afferent inputs, responded to noxious mechanical stimulation on the muscle and to a chemical irritant that is known to produce pain in humans provide compelling evidence for the involvement of Vi in craniofacial muscle pain mechanisms.
Article
This study investigated the impact of algogenic conditions of the reproductive organs upon urinary pain perception in women. A 5-year survey was conducted among 69 fertile women with calculosis of one upper urinary tract via an ad-hoc questionnaire. At both retrospective (3 years) and prospective (2 years) investigation, dysmenorrheic women (D) reported more colics than non-dysmenorrheic women (ND) (P<0.001) and women with previous dysmenorrhea treated with estroprogestins (DH)(P<0.05). Pain thresholds (electrical stimulation) of the oblique musculature ipsilateral to the stone (L1, site of referred hyperalgesia from upper urinary tract) were lower in D than in ND (P<0.01) and DH (P<0.05). Calculosis women with asymptomatic endometriosis / ovarian cysts also reported more colics (6-month prospective study) and greater threshold lowering (P<0.05) than women with calculosis alone. The results show enhancement of urinary pain / hyperalgesia by both manifest and latent algogenic conditions of the female reproductive organs. This enhancement could derive from neuronal sensitization in spinal segments of common projection of the two visceral districts (T10-L1).
Article
This study was undertaken to investigate the overlap between chronic pelvic pain, dysmenorrhea, dyspareunia, irritable bowel syndrome, and genitourinary symptoms in the community and also to examine associated investigations and diagnoses. A postal questionnaire was used to survey 3916 women aged 18 through 49 randomly selected from the Oxfordshire Health Authority Register. The number of responders was 2304 (74% of 3106 questionnaire recipients). Chronic pelvic pain was described as recurrent or constant pelvic pain of > or =6 months' duration unrelated to periods, intercourse, or pregnancy. Case patients (n = 483) were subgrouped as follows: (1) chronic pelvic pain only, (2) chronic pelvic pain and irritable bowel syndrome, (3) chronic pelvic pain and genitourinary symptoms, and (4) chronic pelvic pain, genitourinary symptoms, and irritable bowel syndrome. Half the women with chronic pelvic pain also had either genitourinary symptoms or irritable bowel syndrome, or both. Prevalences of dysmenorrhea and dyspareunia were higher among women with chronic pelvic pain (81% and 41%, respectively) than among women without chronic pelvic pain (58% and 14%, respectively); rates did not differ among the chronic pelvic pain subgroups. Irritable bowel syndrome and stress were the most common diagnoses received by patients with chronic pelvic pain, but 50% had never received a diagnosis. There is substantial overlap between chronic pelvic pain and other abdominal symptoms in the community. Despite a high prevalence of chronic pelvic pain, many women have never had the condition diagnosed.
Article
To determine if systemic processing of pain differs in women with and without dysmenorrhea. Twenty-two dysmenorrheic women and 31 nondysmenorrheic women were studied by pain threshold and supra-threshold magnitude estimation to heat stimuli, pain-evoked potentials by laser stimuli, and anxiety scores four times across their menstrual cycles. Significant differences were found between dysmenorrheic and nondysmenorrheic women. In all four examinations across the menstrual cycle, dysmenorrheic women had longer latencies of pain-evoked potentials (383.08 +/- 6.8 msec versus 345.05 +/- 7.0 msec, P <.001), higher magnitude estimations on visual analog scale of supra-threshold pain (83.29 +/- 2.87 versus 63.50 +/- 3.82, P <.001), and higher state anxiety scores (37.69 +/- 1.7 versus 29.20 +/- 1.9, P =.002). Women with dysmenorrhea show enhanced pain perception compared to nondysmenorrheic women. This augmentation of pain perception may be part of the development of dysmenorrhea.
Article
Can either a history of previous similar injury, including recurrence of injury, or an individual's symptoms, including time off work, predict chronic pain and/or chronic pain disability? The literature search identified one systematic review and six observational studies (5 low back pain and 1 chronic shoulder pain) to provide evidence about these questions. Only one study evaluated subjects before a painful event. Other studies evaluated subjects over a range of time from onset of pain, including some selected for clinic treatment. This variability as well as the use of different outcome measures without blinding limited the quality of the evidence. The studies provide moderate evidence (level 2) that a history of previous similar pain predicts subsequent reports of pain and limited evidence (level 3) that a history of similar pain predicts poorer outcomes after recurrent injury. The studies also provide moderate evidence (level 2) that longer duration of pain predicts the occurrence of subsequent reports of pain and limited evidence (level 3) that longer time off work before treatment predicts poorer activity and poorer participation outcomes after recurrent injury.
Article
The objective was to evaluate somatosensory thresholds to a multimodality stimulation regimen applied both within and outside areas of referred menstrual pain in dysmenorrheic women, over four phases of confirmed ovulatory cycles, and to compare them with thresholds in nondysmenorrheic women during menstruation. Twenty dysmenorrheic women with menstrual pain scoring 5.45 +/- 0.39 cm (mean +/- standard error of mean) on a visual analog scale (10 cm) participated. Fifteen nondysmenorrheic women with a menstrual pain score of 0.4 +/- 0.2 cm participated as controls. Ovulation was confirmed by an enzyme-multiplied immunoassay technique. Menstrual pain was described with the McGill Pain Questionnaire. Areas within menstrual pain referral were two abdominal sites and the midline of the low back, and the arm and thigh were the control areas. The pressure pain threshold (PPT) and pinch pain threshold were determined by a hand-held electronic pressure algometer, the heat pain threshold (HPT) by a contact thermode, and the tactile threshold with von Frey hairs. In dysmenorrheic women the McGill Pain Questionnaire showed a larger sensory and affective component of pain than the evaluative and miscellaneous groups. The HPT and PPT were lower in the menstrual phase than in the ovulatory, luteal, and premenstrual phases, both within and outside areas of referred menstrual pain (p <0.01), with a more pronounced decrease at the referral pain areas. The pinch pain threshold was lower in the menstrual phase than in the ovulatory phase (p <0.02), and the tactile threshold did not differ significantly across the menstrual phases or within any site. Dysmenorrheic women had a lower HPT at the control sites and a lower PPT at the abdomen, back, and control sites, than in those of nondysmenorrheic women in the menstrual phase. The results show reduced somatosensory pain thresholds during menstruation to heat and pressure stimulation, both within and outside areas of referred menstrual pain in dysmenorrheic women. Dysmenorrheic women showed a lower HPT at the control sites and a lower PPT at all the sites than those for nondysmenorrheic women in the menstrual phase. The altered somatosensory thresholds may be dependent on a spinal mechanism of central hyperexcitability, induced by recurrent moderate to severe menstrual pain.
Article
Musculoskeletal pains are often characterised by referred pain and hyperalgesia. The aim of the present study was to examine the sensitivity to pressure and pinprick at sites ipsi- and contralateral to capsaicin-induced pain in the tibialis anterior (TA) muscle. Visual analogue scale (VAS) scores of the sensation to sub- and supra-pain threshold stimuli by pressure and pinprick were recorded before, during and after experimental muscle pain. It was found that pressure stimulation (120% of baseline pain threshold) delivered over the ipsilateral deep peroneal nerve between the 1st and 2nd metatarsal bones showed a significant increase in VAS scores during muscle pain. The referred pain did not overlap this hyperalgesic site. Ipsilateral test sites at the TA muscle, great toe and between the 3rd and 4th metatarsal bones did not show any changes in response to pressure stimulation during pain. In contrast, test sites at the ipsilateral ankle showed hypoalgesia to pressure during muscle pain. In the contralateral leg hypoalgesia to pressure was found at all sites during pain. The decreased sensitivity to pressure was confirmed with both sub- and supra-pressure pain-threshold stimuli. VAS scores to pinprick were either decreased or unchanged during pain compared to before pain. Naloxone administrated in a placebo-controlled manner had no effect on hypoalgesia to pressure or pinprick during muscle pain. Thus, the generalised decreased sensitivity may reflect activation of non-opioid endogenous pain inhibitory systems. The lack of change in sensitivity at some sites could indicate a competitive balance between excitatory and inhibitory mechanisms. The deep peroneal nerve specifically innervates both the TA muscle and the only site of hyperalgesia indicating spatial summation of afferent activity from these structures.