Visceral pain: gender differences in response to experimental and clinical pain

European Journal of Pain 8 (2004) 465–472 www.EuropeanJournalPain.com

Visceral pain: gender differences in response to experimental and clinical pain Lars Arendt-Nielsen a

a,*

, Priti Bajaj

a,b

, Asbjørn Mohr Drewes

a,c

Laboratory for Experimental Pain Research, Department of Health Science and Technology, Center for Sensory-Motor Interaction, Aalborg University, Fredrik Bajers Vej 7, D3, DK-9220 Aalborg, Denmark b Department of Obstetrics and Gynaecology, Aalborg University Hospital, Denmark c Department of Medical Gastroenterology, Center for Visceral Biomechanics and Pain, Aalborg University Hospital, Denmark Received 15 December 2003; accepted 30 January 2004 Available online 8 April 2004

Abstract Gender differences in response to visceral pain have important implications for experimental studies and when evaluating clinical pain. Few studies have in details explored specific gender differences in response to experimental stimulation of selected visceral organs or specific visceral diseases. Lower pain threshold to e.g. oesophageal distension has however been shown in females. The effect of female sex hormones on visceral function and pain is studied in greater details in both experimental and clinical studies. Pronounced differences in pain sensitivity are found across the menstrual phases. This may also interact with pharmacological interventions. For clinicians assessing the pain level of female patients in the reproductive age group should take into consideration the physiological and clinical effects of the menstrual cycle and the somatic segmental sites related to the uterus and cervix when clinically evaluating the pain and assessing for disease activity. Ó 2004 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Gender differences; Experimental pain; Visceral pain

1. Introduction Pain arising from the visceral organs is one of the most common forms of pain in the clinical setting, and one of the most frequent reasons why patients seek medical attention (Cervero and Laird, 1999). As an example of visceral pain does health surveys in both America and Europe show that menstrual and pelvic pain account for the most common complaints during the reproductive period, with 40% of women’s overall morbidity and use of health care predominantly related to gynaecological and obstetrical problems (Gijsbers van Wijk et al., 1992). Gender differences in pain responses involve the interactions among multiple biological, psychological, and sociocultural factors (Fillingim, 2000; Sanford et al., 2002). These factors include previous experiences, cul*

Corresponding author. Tel.: +45-9635-8830; fax: +45-9815-4008. E-mail address: [email protected] (L. Arendt-Nielsen).

tural influences, internal hormonal environment, nociceptive input integration in the central nervous system, as well as modulation of the afferent input by descending supraspinal pathways. They are to some extent linked to the differences in the actions of sex hormones and the more complex nature of the reproductive function in females than in males. In females, although the physiological and hormonal status related to menarche, menstrual cycle phase, pregnancy and dysmenorrhea are well known, the modifying effects of these factors on the variability in the pain perception are not particularly well understood. The menstrual cycle phase, dysmenorrhea status, segmental site of pain, and pregnancy all have unique interacting effects on pain thresholds and the individual’s judgement of whether or not a stimulus is painful (Bajaj, 2002). Extensive evidence indicates that females and males differ greatly in their nociceptive processing (Berkley, 1997; Fillingim et al., 1999; Bajaj et al., 2001). Clinical

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research demonstrate that women report more severe levels of pain, more frequent pain, and pain of longer duration than men do (Fillingim and Maixner, 1995; Berkley, 1997; Riley et al., 1998). A female predominance is demonstrated in many pain conditions from non-sex-specific organs, such as irritable bowel syndrome, biliary colic, oesophagitis, interstitial cystitis, fibromyalgia, rheumatoid arthritis, and temporomandibular disorders (Unruh, 1996). Our knowledge about the pathways and mediators of pain arising from the viscera is incomplete due to the current limitations of experimental studies. Hence, the majority of studies has focused on skin pain, and there is now convincing evidence that gender differences exist to a variety of somatic stimuli. For experimentally delivered somatic nociceptive stimuli, females have lower thresholds, less tolerance, greater ability to discriminate, and higher pain ratings than males (Berkley, 1997). Women report lower levels of both pain threshold and tolerance to electrical stimuli as compared with men (Giamberardino et al., 1997a; Riley et al., 1998). Using contact heat, lower thermal pain threshold is reported in females as compared with males (Bajaj et al., 2001). Reports are inconclusive with regards to menstrual phase variation in cold pressor pain thresholds (Veith et al., 1984; Hapidou and De Catanzaro, 1988). The tactile threshold is significantly reduced in females as compared with males at presumed menstrual pain referral sites (Bajaj et al., 2001). For muscle pain consistent reports of higher pressure pain thresholds in males as compared with females are reported (Otto and Dougher, 1985; Brennum et al., 1989). Recently showed (Cairns et al., 2001) that females rated the pain intensity to intramuscular glutamate much higher than men. In addition, the size of the evoked pain areas were significantly larger in females. These data were supported by findings in animals. The role of peripheral glutamate receptors could be important for development of musculoskeletal pain and to some degree explain gender differences in musculoskeletal disorders such as temporoman-dibular disorders (Carlsson and LeResche, 1995). Another aspect which we recently unveiled is gender differences in descending inhibitory control following experimental muscle pain (injection of hypertonic saline in shoulder muscles). Males seem to be better to inhibit muscle pain than females (Ge et al., 2003), which again could be important in explaining gender differences in musculoskeletal disorders. Males developed more hypoalgesia to pressure stimulation in the referred muscle pain areas. This could be one aspects explaining why more females develop chronic neck and shoulder pain as compared with males. Gender differences are found in basic visceral functions such as gallbladder emptying (Fried et al., 1984), gastrointestinal (GI) transit, and colonic activity (Hinds et al., 1989; Meier et al., 1995). In healthy subjects, men seem to have generally shorter GI transit time, particular in the right colon (Meier et al., 1995), although these results

have recently been disputed (Soffer et al., 2000), and postprandial gastric relaxation is prolonged in females compared with males (Mearadji et al., 2001). There may also be some gender differences in the conscious perception and brain processing to visceral stimuli (Berman et al., 2000; Kern et al., 2001). In diseases of the visceral organs pain is often related to bowel movements and sphincter functions, and if normal gut transit time and sphincter functions can be altered by sex hormones, it is evident that visceral pain may be also be altered (Hinds et al., 1989; Heitkemper and Jarrett, 1992; Meier et al., 1995). Hence, functional visceral pain disorders are two to four times more prevalent in females relative to males (Chang and Heitkemper, 2002). Experimental studies have given conflicting results, and the existing data give sparse evidence that healthy females have increased perception thresholds to experimental visceral stimuli (Sloots et al., 2000; Mearadji et al., 2001). Most previous experimental studies relating to visceral functions and gender have been restricted to animal models. The ultimate goal of human experimental pain research is to obtain a better understanding of the mechanisms involved in transduction, transmission, and perception of visceral pain. Experimental visceral pain research involves standardised activation of the nociceptive system and measurement of the evoked responses. This is, however, far more complicated than delivering a cutaneous stimulus due to the relative inaccessibility of the deep-seated visceral organs and the inadequate definition of a nociceptive visceral stimulus. Although a group of visceral pain patients may have the same clinical diagnosis, they will be in different phases of the illness and on variable degrees of therapeutic interventions. When standardised experimental stimuli are applied to a standardised group of healthy individuals, these confounding factors are minimal and controllable, providing more standardised conditions for experimental pain research (Arendt-Nielsen, 1997; Drewes et al., 2003a). The aim of this paper is to present and discuss gender differences in response to (1) standardised experimental visceral pain stimuli and (2) visceral clinical pain conditions. As relatively few studies exist in this field of gender differences in experimental and clinical visceral pain, we will also discuss specifically the effect of female sex hormones on experimental/clinical pain and introduce a new experimental model developed specifically for the study of pain in females utilising dilatation of the uterine cervix as a model for gynaecological pain. 2. Gender differences in response to experimental visceral stimuli 2.1. Animal studies Support for gender differences in pain and visceral functions has largely come from animal studies, pro-

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viding insight into basic pain mechanisms and receptor functions. More detailed information can be obtained in animal studies, as e.g., micro-electrode recordings from the spinal cord are possible, and the spinal cord can be isolated from higher central nervous system (CNS) centres through spinal cord transection. This is obviously not possible in humans, where pain research is based on psychophysical and/or electrophysiological responses evoked by activation of dorsal horn neurones through stimulation of peripheral receptors. However, it is not known to what extent results from animal studies can be extrapolated to humans, as even different animal species may not show the same reactions to stimulation of the nociceptive system. Mogil (2000) found that as compared to males, female rats were more sensitive to electrical and chemical stimuli, but not to heat stimulation. An influence of the menstrual cycle was seen in studies where the sensory responses were assessed during colorectal distension with lowest threshold in the proestrus phase (Holdcroft et al., 2000). The same study showed that the visceromotor responses were increased in female rats. Giamberardino et al. (1997b) studied the effect of the menstrual cycle on artificial ureteral calculosis in rats and found an enhancement of ureteral pain sensitivity in metestrus/diestrus. Thus, animal studies suggest that gender differences and hormonal fluctuations are of importance in visceral functions and pain perception.

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2.2. Human studies There is a lacuna in the knowledge of visceral pain mechanisms in humans due to the limitations associated with human experimental studies. Furthermore, women have traditionally been avoided as subjects in pain research, partly because of the assumption that results derived from males can be transferred to females, and partly because of the potential variability introduced by fluctuations in hormones associated with menstruation (Fillingim and Maixner, 1995; Holdcroft, 1997). Even animal studies for the development of analgesic drugs for use in obstetrics and gynaecology have been mostly based on results from males (Holdcroft, 1997), and most basic studies of pain mechanisms related to the female reproductive organs have been conducted in animals (Wesselmann et al., 1998). Experimental visceral pain studies in humans have been contradictory with respect to gender differences (Table 1), and such studies have only to a limited degree been used to explore the gender differences in the visceral organs in healthy subjects. A lower pain threshold to oesophageal distension was demonstrated in females (Nguyen et al., 1995), whereas rectal studies showed no gender differences in the mechanical thresholds (Soffer et al., 2000; Sloots et al., 2000; Kern et al., 2001). In the stomach there were no gender difference between the sensation and pain thresholds to mechanical stimulation, but females had

Table 1 Gender differences for visceral sensation and pain responses Subjects

Organ

Method

Extract of main findings

Healthy subjects 9M:10F (Nguyen et al., 1995) Healthy subjects 42M:57F (Mearadji et al., 2001)

Oesophagus

Latex balloon with rapid/slow distensions Barostat system with stepwise pressure-controlled distensions

F had lower pain threshold. No effect of menstrual cycle or body size Perception of fullness and abdominal pressure increased more rapidly in F, but no differences were seen for the mean values No difference between gender for first sensation, urge to defecate and maximal tolerated volume No difference between genders for sensation of gas, urge to defecate and pain No difference between genders for perception threshold. Painful sensations not evoked. Gender differences in cortical clusters of fMRI activity Greater decrease in postprandial pain threshold in women, but no overall gender effect in threshold to maximal tolerable distension level No difference in unpleasantness rating to inflation at fixed pressure. PET showed greater blood flow to the insula during the distensions in males

Stomach

Healthy subjects 11M:17F (Sloots et al., 2000)

Rectum

Barostat system with rapid/slow distensions

Healthy subjects 9M:9F (Soffer et al., 2000) Healthy subjects 13M:15F (Kern et al., 2001)

Rectum

Barostat system with stepwise pressure-controlled distensions Barostat system with stepwise pressure-controlled distensions

Rectum

Patients with IBS 13M:39F (Ragnarsson et al., 1999)

Rectum

Manovolumetric method with stepwise pressure-controlled distensions

Patients with IBS 15M:12F (Berman et al., 2000)

Rectum

Latex balloon in the rectum with moderate rectal pressure

M: males; F: females; IBS: irritable bowel syndrome; fMRI: functional magnetic resonance imaging; PET: positron emission tomography.

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higher overall perception scores (Mearadji et al., 2001). Kern et al. (2001) investigated the cortical activation to rectal distension using functional magnetic resonance imaging (fMRI). In their study there were no gender differences between the pressures used to evoke the nonpainful rectal sensations. However, male subjects showed clusters of activity in the sensory and parietooccipital regions, whereas females also showed activity in the anterior cingulate and insular regions. In patients with irritable bowel syndrome (IBS), experimental distension of the rectum did not show consistent gender differences (Ragnarsson et al., 1999; Berman et al., 2000), although there were regional differences in cerebral blood flow to the stimulation, with males showing higher insular activation (Berman et al., 2000). Methodological problems may to some degree explain these contradictory findings, and as in somatic pain studies, the use of a single stimulus modality may be insufficient to show an effect on the viscera (Drewes et al., 2002). Thus, there is a need for new experimental studies to examine gender differences in visceral pain, using more controlled and differentiated stimulation paradigms as well as improved methods to assess the evoked pain. Previous experimental pain models were mainly based on distension of the organs with methods based on determination of pressure and volume. However, such models suffer from major methodological limitations (Drewes et al., 2003a) and biases are easily introduced in the measurements. Recently, new models for visceral stimulation based on more advanced mechanical stimulation have been developed and an example is given below. Other models using controlled electrical, thermal and chemical stimuli in the viscera have recently been developed. These models combined with assessment of the evoked responses using robust psychophysical and neurophysiological methods are available, and have been used in basic and clinical studies (for review see Drewes et al., 2003a). Such models should also be used to explore the gender differences to visceral pain.

3. Effect of female sex hormones on visceral function and pain Hormonal alterations associated with the menstrual cycle produce multiple central and peripheral effects that can influence pain modulation and neurotransmission, although the exact mechanisms are far from being fully elucidated. Binding sites for gonadal hormones are distributed throughout regions of the central nervous system involved in pain perception and pain inhibition, and sex steroids alter spinal nociceptive processing by influencing levels of multiple pain neuromodulators, indicating that these hormones play a role in pain modulation (Papka et al., 1998). In the GI tract, animal

studies have demonstrated sex steroid receptors throughout the entire gut, with direct effects of estrogen and progesterone on visceral organs (Waliszewski et al., 1997). This suggests that hormonal factors also can influence visceral pain perception in females. Progesterone is a smooth muscle relaxant, and the different hormonal milieu between the genders and the menstrual phases in females may alter bowel function and hence perception from the gut. In experimental studies oestrogen delayed gastric emptying, whereas progesterone had the opposite effect (Winborn et al., 1987; Chen et al., 1995; Waliszewski et al., 1997), and gastrointestinal (GI) motility was decreased by both estrogen and progesterone (Winborn et al., 1987). 3.1. Studies in healthy volunteers Humans studies have shown that the menstrual cycle influences GI transit with prolonged transit times in the luteal phase (where progesterone levels are increased) (Wald et al., 1981), although there were no differences between the phases in other studies (Hinds et al., 1989; Turnbull et al., 1989). Sex hormones may also affect the oesophageal muscle function and emptying, but controversies exist (Van Thiel et al., 1976; Nelson et al., 1984). Finally, Kamm et al. (1989) showed that the blood flow in the colon mucosa increased in the luteal phase. Jackson et al. (1994) investigated the stool consistency and found it to be significantly looser during menses. The diarrhoea reported at menses may be related to prostaglandin production (Arthur et al., 1992). As these symptoms can be reduced by cessation of menses by chemical or surgical methods (Mathias et al., 1989; Prior et al., 1992), hormonal factors are most likely to affect the symptoms. Outside the GI organs, blood pressure or heart rate did not show changes across the menstrual cycle, but women have a lower sympathetic tone with the vagal tone increased in the follicular phase (Sato et al., 1995). Pregnant women without pelvic pain demonstrate localised hypoalgesia in late pregnancy restricted to the uterocervical segmental dermatomes, whereas the hypoalgesia is generalised in pregnant women with pelvic pain (Bajaj Priti et al., 2002). This suggests that an endogenous antinociceptive system may be activated in late pregnancy and/or the descending noxious inhibitory system is activated in late pregnancy, more so when pregnancy is associated with pelvic pain. 3.2. Studies in patient groups Many female patients report changes in their bowel habits or worsening of the GI symptoms in relation to the menstrual cycle (Heitkemper and Jarrett, 1992; Jackson et al., 1994). Most clinical visceral pain studies have been carried out in patients with functional gut

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disorders, especially in patients with IBS, a functional disorder which is approximately two times as prevalent in females compared with males in the Western World (Chang and Heitkemper, 2002). In patients with IBS, symptoms increase at menses (Heitkemper et al., 1993). Kane et al. (1998) examined the menstrual effects in women having inflammatory bowel diseases. In this study premenstrual symptoms were reported by 93% of women, mostly affecting patients with Crohn’s disease.

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female reproductive organs and other organs as seen in animal experiments (Crowell et al., 1994; Giamberardino et al., 1997b). These findings are in line with the clinical observation in fertile women with urinary calculosis have a greater incidence of colics in the perimenstrual period (Giamberardino et al., 2001). Viscerovisceral hyperalgesia can also explain that bowel related symptoms are even more prevalent in IBS patients who also have dysmenorrhoea (Whitehead et al., 1990; Houghton et al., 2002).

3.3. Menstrual cycle variations and experimental visceral In healthy women greater ischemic pain sensitivity is reported during the luteal phase of the cycle (Fillingim et al., 1997; Pfleeger et al., 1997). Females also demonstrate significantly reduced pressure pain thresholds at presumed menstrual pain referral sites during ovulation, suggesting that increased levels of oestrogen and luteinising hormone at ovulation may modulate the pain thresholds (Bajaj et al., 2001). GI pain seem to fluctuate during the different menstrual phases (Fried et al., 1984), but in healthy controls no cyclic variations to experimental stimuli were found. Thus, Jackson et al. (1994) found no changes in rectal sensitivity in healthy subjects in response to rectal distension at the different menstrual phases. Similarly, Nguyen et al. (1995) found no differences in the pain threshold to distension of the oesophagus across the menstrual phases in healthy volunteers. Thus, in healthy subjects, the existing evidence does not consistently support an effect of the menstrual cycle on visceral sensation and pain responses, and further studies are needed to confirm these preliminary observations. In patients there seem to be differences across the menstrual cycle. Houghton et al. (2002) studied the rectal sensation to distension with a latex balloon in IBS during the different menstrual phases. The volume required evoking the ‘‘first sensation’’, ‘‘desire to defecate’’, ‘‘urgency’’ and ‘‘discomfort’’ was significantly lower during menses compared with the other phases. Although differences in vigilance may be important in functional disorders, the authors speculated that the increased prostaglandin production during menses might induce afferent sensitisation in IBS, where the nervous system is already sensitised. In dysmenorrheic women, reduced somatic pain thresholds during the menstrual phase of the cycle, both within and outside areas of menstrual pain referral, are suggestive of a spinal mechanism of central hyperexcitability induced by recurrent moderate to severe menstrual pain (Bajaj et al., 2002a). Changes in excitability and response properties of dorsal horn neurons, which receive input from diseased organs have been documented in animal studies. These neurons receive convergent input from other viscera, and the resulting viscero-visceral hyperalgesia may explain the clinical interaction between

4. Clinical implications From a therapeutic viewpoint, the clinician should be aware that symptoms might be presented differently between the genders. Although the clinical evidence is still sparse, fluctuations of symptoms with menstrual cycle, gender related differences in pain intensity and presentation may be important in the judgment of various diseases. Gender differences should also be considered in the design of clinical studies. Hence, gender differences are present in responses to analgesics, such as the opioid agonist–antagonist pentazocine, which appears to be more effective for women than for men (Gear et al., 1996a; Gear et al., 1996b). Ibuprofen, a widely used nonsteroidal anti-inflammatory drug, is less effective in women than in men for its ability to reduce experimental pain (Walker and Carmody, 1998). Moreover, serotonergic agents are more effective for visceral pain in females (Camilleri et al., 1999; Winborn et al., 1987). Hence, in patients with diarrhoea-predominant IBS, the 5-HT3 antagonist alosetron was more effective in women (Camilleri et al., 1999), and the 5-HT4 agonist tegaserod was more effective in women with constipation-predominant IBS (Muller-Lissner et al., 2001). The differentiated effects of these new treatment regimens emphasize the importance of recognizing gender differences for the clinician.

5. A novel experimental model for gynaecological pain: balloon distension of the uterine cervix In order to further elucidate the pain mechanisms specific to females, there is a need for experimental models to study pain arising from the vagina, uterus or cervix. Mechanical stimulation produced by balloon distension is so far the best characterised and least ambiguous stimulus for human visceral pain studies (Ness and Gebhart, 1990). Recently, our group has developed and evaluated a dilatation model of the uterine cervix whereby a safe, controlled, graded, and quantifiable mechanical stimulus is applied to the uterine cervix and reliable reports of discomfort, pain, and referred sensations are evoked (Bajaj et al., 2002b). The

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Fig. 1. A comparison of the words chosen in the McGill pain questionnaire (MPQ) to describe the pain induced by experimental acute cervical dilatation with those chosen by dysmenorrheic women to describe menstrual pain. Data retrieved from Bajaj et al. (2002b).

experimentally evoked sensations were to a major degree similar to the clinical pain associated with menstruation, abortion and labour, thus supporting the validity of the model in evoking pain similar to the clinical situation (cf. Fig. 1). The model has applicability for examining the pain responses in women with various gynecological pain conditions, and may lead to a better understanding of these pain mechanisms. Recently a rat model of acute uterine cervical distension (Shin and Eisenach, 2003) has been developed for the purpose of screening antinociceptive procedures and drugs. This may together with our human model provide a new basis for studying obstetric and some gynecologic pain and its management.

6. Future recommendations for experimental visceral pain studies One of the major limitations of most experimental visceral pain models is that they may not mimic clinical pain as they are relatively short lasting without the inflammation and subsequent activation of the many peripheral and central nervous mechanisms that are typically activated during diseases. To overcome such problems, a multimodal testing approach must therefore be used. A test battery, where multimodal stimuli are used, will increase the probability for activation of a range of relevant nervous mechanisms. Such models have clearly shown their value in somatic pain models, where single modality models have been inadequate to test pathophysiological changes and effects of specific drugs (Arendt-Nielsen, 1997; Curatolo et al., 2000;

Enggaard et al., 2001). The multi-modal sensory testing approach has mainly been applied for cutaneous stimuli (Arendt-Nielsen et al., 1995), but a multimodal stimulation probe (cold, warm, mechanical, chemical, electrical) was recently developed for visceral stimulation (oesophagus) (Drewes et al., 2002). This multimodal approach gives the possibility for a differentiated stimulation of receptors in the superficial and deep layers of the gut, and hence, provides a new possibility to further explore gender differences in response to standardised visceral stimulation. Recently, we have developed a technique where the multimodal stimulation is combined with sensitisation of the human oesophagus by acid perfusion (Drewes et al., 2003b). The possibility for induction of hyperalgesia and evoking central phenomena such as summation, allodynia and referred pain makes the model highly clinical relevant. Such models are clinically relevant with respect to increasing the knowledge of peripheral and central pain mechanisms. Future studies should be performed where more comprehensive and robust models are used to explore the differences in experimental visceral pain and hyperalgesia between sexes and across the menstrual cycle. Future visceral studies investigating the effects on analgesics should also specifically take into consideration possible hormonal and gender differences in pain responses.

References Arendt-Nielsen L. Induction and assessment of experimental pain from human skin, muscle, and viscera. In: Jensen TS, Turner JA, Wiesenfeld-Hallin, editors. Proceedings of the 8th World Congress on Pain: Progress in Pain Research and Management. Seattle (WA): IASP Press; 1997. p. 393–425. Arendt-Nielsen L, Petersen-Felix S, Fischer M, Bak P, Bjerring P, Zbinden AM. The effect of N-methyl-D -aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: a placebocontrolled experimental human study. Anesth Analg 1995;81:63–8. Arthur C, Ament ME, Song MK. Prostaglandin metabolism in relation to the bowel habits of women. Prostaglandins Leukot Essent Fatty Acids 1992;46:257–9. Bajaj P. Quantitative sensory assessment and development of a model for pelvic pain in women: special reference to the menstrual cycle and pregnancy. Ph.D. Thesis, Department of Health Science and Technology, Aalborg University, 2002. Bajaj Priti, Bajaj P, Madsen H, Moller M, Arendt-Nielsen L. Antenatal women with or without pelvic pain can be characterized by generalized or segmental hypoalgesia in late pregnancy. J Pain 2002;3:451–60. Bajaj P, Arendt-Nielsen L, Bajaj P, Madsen H. Sensory changes during the ovulatory phase of the menstrual cycle in healthy women. Eur J Pain 2001;5:135–46. Bajaj P, Bajaj P, Madsen H, Arendt-Nielsen L. A comparison of modality-specific somatosensory changes during menstruation in dysmenorrheic and nondysmenorrheic women. Clin J Pain 2002a;18:180–90. Bajaj P, Drewes AM, Gregersen H, Petersen P, Madsen H, ArendtNielsen L. Controlled dilatation of the uterine cervix – an experimental visceral pain model. Pain 2002b;99:433–42. Berkley KJ. Sex differences in pain. Behav Brain Sci 1997;20:371–80.

L. Arendt-Nielsen et al. / European Journal of Pain 8 (2004) 465–472 Berman S, Munakata J, Naliboff BD, Chang L, Mandelkern M, Silverman D, et al. Gender differences in regional brain response to visceral pressure in IBS patients. Eur J Pain 2000;4:157–72. Brennum J, Kjeldsen M, Jensen K, Jensen TS. Measurements of human pressure-pain thresholds on fingers and toes. Pain 1989;38:211–7. Cairns BE, Hu JW, Arendt-Nielsen L, Sessle BJ, Svensson P. Sexrelated differences in human pain and rat afferent discharge evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2001;86:782–91. Camilleri M, Mayer EA, Drossman DA, Heath A, Dukes GE, McSorley D, et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Aliment Pharmacol Ther 1999;13:1149–59. Carlsson GE, LeResche L. Epidemiology of temporomandibular disorders. In: Sessle BJ, Bryant P, Dionne R, editors. Temporomandibular disorders and related pain conditions. Seattle (WA): IASP Press; 1995. p. 497–506. Cervero F, Laird JM. Visceral pain. Lancet 1999;353:2145–8. Chang L, Heitkemper MM. Gender differences in irritable bowel syndrome. Gastroenterology 2002;123:1686–701. Chen TS, Doong ML, Chang FY, Lee SD, Wang PS. Effects of sex steroid hormones on gastric emptying and gastrointestinal transit in rats. Am J Physiol 1995;268:G171–6. Crowell MD, Dubin NH, Robinson JC, Cheskin LJ, Schuster MM, Heller BR, et al. Functional bowel disorders in women with dysmenorrhea. Am J Gastroenterol 1994;89:1973–7. Curatolo M, Petersen-Felix S, Arendt-Nielsen L. Sensory assessment of regional analgesia in humans: a review of methods and applications. Anesthesiology 2000;93(6):1517–30. Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, et al. Multimodal assessment of pain in the esophagus: a new experimental model. Am J Physiol Gastrointest Liver Physiol 2002;283:G95–G103. Drewes AM, Gregersen H, Arendt-Nielsen L. Experimental pain in gastroenterology: a reappraisal of human studies. Scand J Gastroenterol 2003a;38(11):1115–30. Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L. Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus. Eur J Pain 2003b;7(6):539–49. Enggaard TP, Poulsen L, Arendt-Nielsen L, Hansen SH, Bjornsdottir I, Gram LF, Sindrup SH. The analgesic effect of codeine as compared to imipramine in different human experimental pain models. Pain 2001;92:277–82. Fillingim RB. Sex, gender, and pain: women and men really are different. Curr Rev Pain 2000;4:24–30. Fillingim RB, Edwards RR, Powell T. The relationship of sex and clinical pain to experimental pain responses. Pain 1999;83:419– 25. Fillingim RB, Maixner W. Gender differences in the response to noxious stimuli. Pain Forum 1995;4:209–21. Fillingim RB, Maixner W, Girdler SS, Light KC, Harris MB, Sheps DS, et al. Ischemic but not thermal pain sensitivity varies across the menstrual cycle. Psychosom Med 1997;59:512–20. Fried GM, Ogden WD, Fagan CJ, Wiener I, Inoue K, Greeley Jr GH, et al. Comparison of cholecystokinin release and gallbladder emptying in men and in women at estrogen and progesterone phases of the menstrual cycle. Surgery 1984;95: 284–9. Ge HY, Madeleine P, Wang K, Arendt-Nielsen L. Hypoalgesia to pressure pain in referred pain areas triggered by spatial summation of experimental muscle pain from unilateral or bilateral trapezius muscles. Eur J Pain 2003;7(6):531–7. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med 1996a;2:1248–50.

471

Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD. Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 1996b;205:207–9. Giamberardino MA, Berkley KJ, Iezzi S, de Bigontina P, Vecchiet L. Pain threshold variations in somatic wall tissues as a function of menstrual cycle, segmental site and tissue depth in non-dysmenorrheic women, dysmenorrheic women and men. Pain 1997a;71:187– 97. Giamberardino MA, Affaitati G, Valente R, Iezzi S, Vecchiet L. Changes in visceral pain reactivity as a function of estrous cycle in female rats with artificial ureteral calculosis. Brain Res 1997b;774:234–8. Giamberardino MA, De Laurentis S, Affaitati G, Lerza R, Lapenna D, Vecchiet L. Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women. Neurosci Lett 2001;304:61–4. Gijsbers van Wijk CM, Kolk AM, van den Bosch WJ, van den Hoogen HJ. Male and female morbidity in general practice: the nature of sex differences. Soc Sci Med 1992;35:665–78. Hapidou EG, De Catanzaro D. Sensitivity to cold pressor pain in dysmenorrheic and non-dysmenorrheic women as a function of menstrual cycle phase. Pain 1988;34:277–83. Heitkemper MM, Jarrett M. Pattern of gastrointestinal and somatic symptoms across the menstrual cycle. Gastroenterology 1992;102:505–13. Heitkemper MM, Jarrett M, Caudell KA, Bond E. Women with gastrointestinal symptoms: implications for nursing research and practice. Gastroenterol Nurs 1993;15:226–32. Hinds JP, Stoney B, Wald A. Does gender or the menstrual cycle affect colonic transit. Am J Gastroenterol 1989;84:123–6. Holdcroft A. Females and their variability. Anaesthesia 1997;52:931–4. Holdcroft A, Sapsed-Byrne S, Ma D, Hammal D, Forsling ML. Sex and oestrous cycle differences in visceromotor responses and vasopressin release in response to colonic distension in male and female rats anaesthetized with halothane. Br J Anaesth 2000;85:907–10. Houghton LA, Lea R, Jackson N, Whorwell PJ. The menstrual cycle affects rectal sensitivity in patients with irritable bowel syndrome but not healthy volunteers. Gut 2002;50:471–4. Jackson NA, Houghton LA, Whorwell PJ, Currer B. Does the menstrual cycle affect anorectal physiology? Dig Dis Sci 1994;39:2607–11. Kamm MA, Farthing MJ, Lennard-Jones JE. Bowel function and transit rate during the menstrual cycle. Gut 1989;30:605–8. Kane SV, Sable K, Hanauer SB. The menstrual cycle and its effect on inflammatory bowel disease and irritable bowel syndrome: a prevalence study. Am J Gastroenterol 1998;93:1867–72. Kern MK, Jaradeh S, Arndorfer RC, Jesmanowicz A, Hyde J, Shaker R. Gender differences in cortical representation of rectal distension in healthy humans. Am J Physiol Gastrointest Liver Physiol 2001;281:G1512–23. Mathias JR, Ferguson KL, Clench MH. Debilitating functional bowel disease controlled by leuprolide acetate, gonadotropin-releasing hormone (GnRH) analog. Dig Dis Sci 1989;34:761–6. Mearadji B, Penning C, Vu MK, van der Schaar PJ, van Petersen AS, Kamerling IM, et al. Influence of gender on proximal gastric motor and sensory function. Am J Gastroenterol 2001;96:2066–73. Meier R, Beglinger C, Dederding JP, Meyer-Wyss B, Fumagalli M, Rowedder A, et al. Influence of age, gender, hormonal status and smoking habits on colonic transit time. Neurogastroenterol Motil 1995;7:235–8. Mogil JS. Interactions between sex and genotype in the mediation and modulation of nociception in rodents. In: Fillingim R, editor. Progress in pain research and management: sex, gender and pain. Seattle (WA): IASP Press; 2000. p. 25–40. Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F, Pecher E, Nault B, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves

472

L. Arendt-Nielsen et al. / European Journal of Pain 8 (2004) 465–472

symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001;15:1655–66. Nelson III JL, Richter JE, Johns DN, Castell DO, Centola GM. Esophageal contraction pressures are not affected by normal menstrual cycles. Gastroenterology 1984;87: 867–71. Ness TJ, Gebhart GF. Visceral pain: a review of experimental studies. Pain 1990;41:167–234. Nguyen P, Lee SD, Castell DO. Evidence of gender differences in esophageal pain threshold. Am J Gastroenterol 1995;90 901–5. Otto MW, Dougher MJ. Sex differences and personality factors in responsivity to pain. Percept Mot Skills 1985;61:383–90. Papka RE, Williams S, Miller KE, Copelin T, Puri P. CNS location of uterine-related neurons revealed by trans-synaptic tracing with pseudorabies virus and their relation to estrogen receptor-immunoreactive neurons. Neuroscience 1998;84:935– 52. Pfleeger M, Straneva PA, Fillingim RB, Maixner W, Girdler SS. Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation. Int J Psychophysiol 1997;27:161–6. Prior A, Stanley KM, Smith AR, Read NW. Relation between hysterectomy and the irritable bowel: a prospective study. Gut 1992;33:814–7. Ragnarsson G, Hallbook O, Bodemar G. Abdominal symptoms are not related to anorectal function in the irritable bowel syndrome. Scand J Gastroenterol 1999;34:250–8. Riley JL, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain 1998;74:181–7. Sanford SD, Kersh BC, Thorn BE, Rich MA, Ward LC. Psychosocial mediators of sex differences in pain responsivity. J Pain 2002;3:58– 64. Sato N, Miyake S, Akatsu J, Kumashiro M. Power spectral analysis of heart rate variability in healthy young women during the normal menstrual cycle. Psychosom Med 1995;57:331–5.

Shin SW, Eisenach JC. Intrathecal morphine reduces the visceromotor response to acute uterine cervical distension in an estrogenindependent manner. Anesthesiology 2003;98(6):1467–71. Sloots CE, Felt-Bersma RJ, Cuesta MA, Meuwissen SG. Rectal visceral sensitivity in healthy volunteers: influences of gender, age and methods. Neurogastroenterol Motil 2000;12:361–8. Soffer EE, Kongara K, Achkar JP, Gannon J. Colonic motor function in humans is not affected by gender. Dig Dis Sci 2000;45:1281–4. Turnbull GK, Thompson DG, Day S, Martin J, Walker E, LennardJones JE. Relationships between symptoms, menstrual cycle and orocaecal transit in normal and constipated women. Gut 1989;30:30–4. Unruh AM. Gender variations in clinical pain experience. Pain 1996;65:123–67. Van Thiel DH, Gavaler JS, Stremple J. Lower esophageal sphincter pressure in women using sequential oral contraceptives. Gastroenterology 1976;71:232–4. Veith JL, Anderson J, Slade SA, Thompson P, Laugel GR, Getzlaf S. Plasma beta-endorphin, pain thresholds and anxiety levels across the human menstrual cycle. Physiol Behav 1984;32:31–4. Wald A, Van Thiel DH, Hoechstetter L, Gavaler JS, Egler KM, Verm R, et al. Gastrointestinal transit: the effect of the menstrual cycle. Gastroenterology 1981;80:1497–500. Waliszewski P, Blaszczyk M, Wolinska-Witort E, Drews M, Snochowski M, Hurst RE. Molecular study of sex steroid receptor gene expression in human colon and in colorectal carcinomas. J Surg Oncol 1997;64:3–11. Walker JS, Carmody JJ. Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg 1998;86:1257–62. Wesselmann U, Czakanski PP, Affaitati G, Giamberardino MA. Uterine inflammation as a noxious visceral stimulus: behavioral characterization in the rat. Neurosci Lett 1998;246:73–6. Whitehead WE, Cheskin LJ, Heller BR, Robinson JC, Crowell MD, Benjamin C, et al. Evidence for exacerbation of irritable bowel syndrome during menses. Gastroenterology 1990;98:1485–9. Winborn WB, Sheridan PJ, McGill Jr HC. Sex steroid receptors in the stomach, liver, pancreas, and gastrointestinal tract of the baboon. Gastroenterology 1987;92:23–32.