{"paper_id":"ab029aff-0eaa-44ba-b19d-64a8d8ea9113","body_text":"Background: Chronic pelvic pain (CPP) is a complex pain syndrome. Since its pathogenesis is still \npoorly understood and structural alterations in pain related brain regions may be present, there is \na greater acceptance that sensitization of the central nervous system (CNS) plays an important role \nin the development and maintenance of chronicity. \nObjective: The purpose of this study is to systematically review the scientific evidence regarding \ncentral sensitization (CS) in female patients with urogynecological CPP .\nStudy Design: Systematic review of the literature.\nMethods: A systematic literature search was conducted in PubMed and Web of Science using \ndifferent keyword combinations related to urogynecological CPP and central sensitization. Full \ntext clinical reports addressing CS in adult women with urogynecological CPP were included and \nassessed for methodological quality by 2 independent reviewers.\nResults: After screening for the eligibility, a total of 29 full-text articles with low to good \nmethodological quality were retained. All studies were observational, 27 of which were case-\ncontrol and 2 of which were cohorts. Sensitivity of the CNS was investigated by using a variety \nof methods. Although different central mechanisms seem to be involved in pain processing, the \npresent evidence suggests hyperexcitability of the CNS in patients with urogynecological CPP . \nAltered brain morphology and function, generalized hyperalgesia to different type of stimuli, \noveractive bottom-up nociceptive mechanisms, and autonomic dysregulation were established \nin patients with urogynecological CPP . Nevertheless, diffuse noxious inhibitory control seemed \nnormal, and therefore the contribution of an impaired endogenous pain inhibition mechanism to \nCPP requires further study. The same goes for the contribution of psychological factors.\nLimitations: The level of evidence of retained studies is low due to the observational study \ndesigns and a wide range of diagnoses and assessment methods.\nConclusion: Although the majority of the literature provides evidence for the presence of CS in \nurogynecological CPP with changes in brain morphology/function and sensory function, it is unclear \nwhether these changes in central pain processing are secondary or primary to CPP , especially since \nevidence regarding the function of endogenous pain inhibition and the role of psychosocial pain \nfacilitation is scarce. Further studies with good methodological quality are needed in order to clarify \nexact mechanisms.\nKey words: Urogynecological pain, pelvic pain, chronic pelvic pain, hyperalgesia, sensitization, \ncentral sensitization, pain processing, pain modulation, pain inhibition, systematic review\nPain Physician 2013; 16:291-308\nLiterature Review\nCentral Sensitization In Urogynecological \nChronic Pelvic Pain: A Systematic Literature \nReview\nFrom: 1Department of \nPhysiotherapy and Rehabilitation, \nFaculty of Health Sciences, \nHacettepe University, Ankara, \nTurkey; 2Rehabilitation Sciences \nand Physiotherapy, Ghent \nUniversity and Artevelde \nUniversity College, Ghent, \nBelgium; 3Pain in Motion (PIM) \nresearch group, Department \nof Rehabilitation Sciences \nand Physiotherapy, Faculty of \nMedicine and Health Sciences, \nUniversity of Antwerp, Belgium\nAddress Correspondence: \nSerap Kaya, MSc\nHacettepe University\nFaculty of Health Sciences,\nDepartment of Physiotherapy \nand Rehabilitation\n06100, Samanpazarı\nAnkara, Turkey\nE-mail:  \nserapky@yahoo.com \nDisclaimer: Serap Kaya was \nfinancially supported by the \nErasmus Programme of Turkish \nNational Agency during her \nstudy period in Ghent University. \nMira Meeus was awarded the \n2012 early research career grant \nof the International Association \nfor the Study of Pain (IASP), \nfunded by the ScanDesign \nFoundation by INGER & JENS \nBRUUN.\nConflict of interest: None.\nManuscript received:02-23-2013  \nAccepted for publication: \n03-19-2013\nFree full manuscript:\nwww.painphysicianjournal.com\nSerap Kaya, MSc, PT1,2, Linda Hermans, MSc, PT2, Tine Willems, PT, PhD2, Nathalie Roussel, PT, \nPhD3,  and Mira Meeus, PT, PhD2,3\nwww.painphysicianjournal.com\nPain Physician 2013; 16:291-308 • ISSN 1533-3159\n\nPain Physician: July/August 2013; 16:291-308\n292  www.painphysicianjournal.com\nIn visceral hyperalgesia, visceral stimuli that are \nnormally sub-threshold may be perceived in the case of \nCS (28). Of particular importance is that these changes \nmay result in sensory and functional abnormalities not \nonly of the end organ subjected to initiating factors, \nbut also of other organs within the region. This cross-\ntalk between the organs is complicated and can prob-\nably happen in any direction (27,29). Cross-sensitization \namong pelvic structures may contribute to CPP of un-\nknown etiology and involves convergent neural path-\nways of noxious stimulus transmission from 2 or more \norgans (viscero-visceral sensitization). Besides the vis-\ncera, somatic areas may also be involved. Given enough \ntime, trigger points can develop in peripheral somatic \ntissue in response to increased nociceptive visceral \ninput (viscero-somatic sensitization) (2,30). Especially \nincreased sensitivity at asymptomatic remote areas, \nreferred to as secondary hyperalgesia, rather than pri-\nmary hyperalgesia (at asymptomatic places), is sugges-\ntive for CS (31). In addition, CS entails much more than \ngeneralized hypersensitivity to pain: It is characterized \nby an increased responsiveness to a variety of stimuli \nincluding mechanical pressure (32), chemical substances \n(33), cold (34), heat (20), electrical stimuli (32,35), stress, \nemotions, and mental load (15).\nIn summary, like many chronic disabling pain \nsyndromes, CPP may be the result of an incompletely \nunderstood dysfunction in peripheral and/or central \nneural processing (36). Although, it has already been \nsuggested that many of the mechanisms for the CPP \nsyndromes are based within the CNS (37), there is a \nneed to evaluate and summarize findings of the \nliterature.\nTo the best of our knowledge, studies evaluating \nCS in urogynecological CPP have not been reviewed sys-\ntematically until now. Therefore, the aim of the present \nstudy is to systematically review the current evidence \nregarding central nociceptive processing in women \nwith urogynecological CPP. It is hypothesized that the \nsensitization of the CNS is responsible for the develop-\nment and/or maintenance of pain and other symptoms.\nMethods\nThis systematic review is reported following the \nPRISMA (Preferred Reporting Items for Systematic \nReviews and Meta-Analyses) guidelines which is an up-\ndated reporting guidance addressing the conceptual, \nmethodological, and practical issues of the original \nQuality of Reporting of Meta-analyses (QUOROM) \nStatement (38). \nC\nhronic pelvic pain (CPP) is defined as chronic \nor persistent pain perceived in structures \nrelated to the pelvis for at least 6 months \n(1). Like many other chronic pain syndromes, CPP is a \nmultifactorial condition with possible sources of pain \nlocated in the urogynecological, gastrointestinal, \nmusculoskeletal, and/or in the nervous system, making \nthe differential diagnosing challenging (2). \nThis multifactorial trait means that CPP mecha-\nnisms may include ongoing acute peripheral pain \nmechanisms involving somatic or visceral tissue, \nchronic pain mechanisms which especially involve the \ncentral nervous system (CNS) and emotional, cogni-\ntive, behavioral, and sexual responses and mecha-\nnisms (3-6).  \nAlthough in the majority of cases of CPP, ongo-\ning tissue trauma, inflammation, or infection are not \nidentifiable (7-11), conditions that cause recurrent \ntrauma, infection, or ongoing inflammation may re-\nsult in CPP in a small proportion of cases. Activation \nof acute pain mechanisms by a nociceptive event may \nsensitize peripheral nociceptive afferents, magnifying \nthe afferent signaling (12,13).\nWhile peripheral sensitization is a local phenom-\nenon, central sensitization (CS) is a central process of \nthe nervous system with the enhanced responsiveness \nof the central neurons to input from unimodal and po-\nlimodal receptors (14-16). This central hypersensitivity \ncould also explain the chronic pain in the absence \nof peripheral pathology (17) and the discrepancy \nbetween the magnitude of tissue damage and magni-\ntude of pain and disability in CPP syndrome (18). \nCS indeed encompasses altered sensory processing \nin the brain (19), malfunctioning of descending pain \ninhibitory mechanisms (20), increased activity of pain \nfacilitatory pathways, temporal summation of second \npain or wind-up (19,21), and long-term potentiation \nof neuronal synapses in the anterior cingulate cortex \n(22). Both top-down and bottom-up mechanisms play \nan important role in the pathophysiology of CS. For \nexample, peripheral injury or other stressors trigger \nthe release of proinflammatory cytokines, with the \nconsequent activation of spinal cord glia with cyclo-\noxygenase-2 and prostaglandin E2 expression in the \nCNS (23-26). The outcome of these changes within the \nperipheral nervous system and CNS is a hypersensitive \nstate and amplification of perception of a peripheral \nstimulus; painful perception of nonpainful stimuli (al-\nlodynia) and increased sensitivity for painful stimuli \n(hyperalgesia) (1,27). \n\nwww.painphysicianjournal.com  293\nCentral Sensitization in Chronic Pelvic Pain\nEligibility Criteria\nTo be included in the present systematic review, \npapers had to report the results of clinical studies (S) \nevaluating the clinical, radiologic, and neurophysiologic \nmanifestations of CS (I), assessed by experimental out-\ncome measures (O), in women with urogynecological \nCPP (P), compared to healthy controls (C).\nMore specifically, an article had to meet following \neligibility criteria: (1) human adult women (> 18 years) \nsuffering from urogynecological CPP were evaluated; \n(2) central pain processing was assessed; (3) patients \nwere compared to healthy controls; (4) published in \nEnglish in the last 20 years; and (5) full-text reports, and \nnot abstracts, case-reports, letters, or editorials. The \nstudies not fulfilling any of the 5 inclusion criteria were \nexcluded. The articles assessing only primary hyperal-\ngesia or peripheral sensitization were not included, as \nthese are not supposed to represent CS (31).\nInformation Sources and Search Strategy\nTo identify relevant articles regarding CS in urogy-\nnecological CPP, PubMed (www.ncbi.nlm.nih.gov/sites/\nentrez) and Web of Science (http://apps.webofknowl-\nedge.com) were searched. The last search was run on  \nNovember 14, 2012. Two groups of key words were de-\ntermined related to “urogynecological CPP” and “cen-\ntral sensitization.” Key words from group 1 were com-\nbined with key words from group 2. The construct of \nthe search strategy is presented in Table 1. Additionally, \nthe reference lists of all included full-text reports were \nhand searched. Literature search was developed by the \nfirst author (SK), who achieved the degree of Master \nof Science, is experienced in pelvic physiotherapy, and \nwas trained in conducting a systematic review by the \nlast author (MM), who obtained the degree of PhD with \na dissertation regarding chronic pain and CS  and has \npublished 4 systematic reviews in this domain (39-42). \nData Collection Process\nAt first, the studies were screened according to \nthe title and abstract with the inclusion and exclusion \ncriteria. As a second step, the remaining papers were \nscreened on a full-text basis.\nData Items\nInformation was extracted from each included trial \non: 1) characteristics of trial participants (including diag-\nnosis, age, and pain duration) and the study’s inclusion \nand exclusion criteria, 2) method of assessment (brain \nimaging, neurophysiological tests, quantitative sensory \ntests, subjective pain ratings, psychosocial measures, \netc.), 3) type of outcome measure (brain morphology/\nfunction, sensation/pain threshold or tolerance, pain \nratings, psychosocial scores, etc.) and 4) main results. \nThe first author (SK) extracted the data from included \nstudies and the last author (MM) reviewed the ex-\ntracted data.\nRisk of Bias in Individual Studies\nMethodological quality was assessed by 2 inde-\npendent researchers (SK and LH), who were blinded \nto each others assessments. The second rater was also \ntrained in assessing methodological quality. In case of \nuncertainty between these 2 raters, a third decisive \nopinion was provided by the last author (MM).\nMethodological quality was evaluated using \nNewcastle-Ottawa Scale (NOS). The NOS has been rec-\nommended by the Cochrane Non-Randomized Studies \nMethods Working Group and it is partly validated and \nprimarily used to appraise cohort studies and case-\ncontrol studies (43,44). The NOS uses a star rating sys-\ntem (range 0 to 9 stars)  to judge the quality of a study \nbased on 3 broad perspectives: the selection of the study \ngroups, the comparability of the groups, and the ascer-\ntainment of either the exposure or outcome of interest \nfor case-control or cohort studies respectively (44). \nTable 1. Search strategy\nKeywords\nGroup 1 Group 2\npelvic pain OR\nchronic pelvic pain OR\ndysmenorrhea OR\nendometriosis OR\nadenomyosis OR\ninterstitial cystitis OR\npainful bladder syndrome OR\nbladder pain syndrome OR\nurethral pain syndrome OR\ngenital pain syndrome OR\nvaginal pain syndrome OR\nvulvar pain syndrome OR\nvulvodynia OR\nvulvar vestibulitis syndrome OR\nperineal pain syndrome OR\nvaginismus OR\npudendal neuralgia OR\npudendal pain syndrome OR\npelvic floor muscle pain OR\nmyofascial pelvic floor \ndysfunction OR\nmyofascial pelvic pain syndrome \nOR\npelvic organ prolapse\nsensitization OR\n(sensitization AND \nhyperalgesia) OR\nperipheral sensitization OR\ncentral sensitization OR\n(sensitization AND algometry) \nOR\n(pain threshold AND central) \nOR\nquantitative sensory testing OR\ncentral sensitivity OR\ncentral hypersensitivity OR\ncentral hyperexcitability OR\npain processing OR\npain modulation OR\nneural inhibition OR\nnociception OR\nhyperalgesia OR\nallodynia OR\nwindup OR\ntemporal summation OR\nspatial summation OR\nconditioned pain modulation\n\nPain Physician: July/August 2013; 16:291-308\n294  www.painphysicianjournal.com\nLevel of Evidence\nAfter pooling the results, the overall quality of \nevidence for each outcome was rated with the Grades \nof Recommendation, Assessment, Development, and \nEvaluation (GRADE) approach (45).\nGrading the evidence was done by 3 researchers \n(SK, TW, and MM) by means of internal discussion and \nconsensus.  \nResul ts\nStudy Selection and Study Characteristics\nThe flow-chart in Figure 1 shows the selection \nprocess. The initial search resulted in 805 hits. Finally, \n29 full-text articles were included in the qualitative \nsynthesis of this review. Of the 29 articles, 27 were case \ncontrol studies and 2 were cohort studies. The charac-\nteristics of the included studies are presented in Table 2.\nFig. 1. Flow chart study selection\n\nwww.painphysicianjournal.com  295\nCentral Sensitization in Chronic Pelvic Pain\nTable 2. Evidence table\nStudies/ \nDesign/ NOS\nPatients (P); Age; Pain \nDuration\nControls \n(C) Outcome Measures Main Results\nSutton et al\n(2012) (54)/\nCase control/\nNOS (5)\nProvoked vestibulodynia; \n23.78±5.04 (18-36); 3.66  \n(0.75-10); n= 23\n26.52±8.56 \n(19-44); n= \n23\n•   Pain intensity ratings during \ngynecological examination\n•   HPT, HP-Tol, ratings for  pain \ntolerance\n•   Peak pain ratings during \ntemporal summation \nprocedure\nP↔C\n•   ↑ pain intensity ratings during gynecological \nexamination\n•   ↓ HP-Tol before conditioning stimulus\n•   ↑ magnitude of DNIC responding\nP = C\n•   HPT \n•   HP-Tol during conditioning stimulus\n•   Ratings for pain tolerance before or during \nconditioning stimulus\n•   Peak pain ratings before or during conditioning \nstimulus in the number of  DNIC responders\nAs-Sanie et al \n(2012) (17)/\nCase control/\nNOS (7)\n1. Endometriosis (+) CPP \n(+); \n26.1±1.5; 5.5 [3.5-9.5]; \nn= 17\n2. Endometriosis (+) CPP \n(-); \n36.8±2.2;  0[0,0]; n= 15\n3. Endometriosis (-) CPP \n(+) ; 24.2±1.9;  3.75[0.90-\n9.9]; n= 6\n25.9±1.6; \nn=17\n36.2±2.6; \nn= 14\n24.8±1.2; \nn= 12\n•   Gray matter (GM) volume \nin regions involved in pain \nprocessing\n•   Clinical pain; pain intensity \nand unpleasantness\n•   Experimental pain testing; \npressure- pain values required \nto elicit faint, mild and \nslightly intense pain\n•   Measures of mood and \nfunction \nP1, P3↔C\n•   ↓ GM volume \nP2↔C\n•   ↑ GM volume \nZhang et al\n(2011) (56)/\nCase control/\nNOS (4)\nVulvodynia; n= 12\n1. Women with a shorter \nhistory of pain\n34.6±4.3; 3.4±1.3; n= 5\n2. Women with a longer \nhistory of pain\n35.7±3.2; 9.3±1.4; n= 7\n-\nn= 20\n•   Vibrotactile detection \nthreshold\n•   Amplitude discrimination \ncapacity\n•   A metric of adaptation (the \nimpact of conditioning \nstimuli on amplitude \ndiscrimination capacity)\nP2↔ (P1=C)\n•   ↓ adaptation metric\nP1=P2=C\n•   Vibrotactile detection threshold\n•   Amplitude discrimination capacity\nVincent et al\n(2011) (50)/\nCase control/\nNOS (4)\nDysmenorrhea; 30±7; no \nyears menstruation:\n17±6; n= 12\n32±10; \nno years \nmenstruation: \n19±10; n= 12\n•   Behavioral measures\n*  the temperature needed to \nobtain a pain intensity 5 of 10\n*  pain intensity and \nunpleasantness ratings during \nheat stimulation\n•   Serum cortisol levels\n•   Brain activity with FMRI\n•   Psychological profile and \nquality of life\nP↔C\n•   ↓ temperature \n•   ↓ serum cortisol levels\n•   no deactivation of  brain regions during \nmenstrual phase\n•   ↑ brain activity (entorhinal cortex)  during \nnonmenstrual phases\n•   ↓ quality of life\nP=C\n•   pain intensity and unpleasantness ratings\n•   brain activity during menstrual phase\nNeziri et al\n(2010) (18)/\nCase control/\nNOS (5)\nEndometriosis; 33{30-36}; \n> 6 month; n= 20\n27{24-37}; \nn= 25\n•   Reflex receptive fields\n•   Pain and nociceptive \nwithdrawal reflex thresholds \nafter a single and during \nrepeated electrical stimulation\n•   Measures of  mood and \nfunction\nP↔C\n•   ↑ reflex receptive field areas\n•   ↓ thresholds for the subjective feeling of  pain \n/increasing pain sensation and to evoke a \nnociceptive reflex after a single stimuli and \nduring repeated stimulation\nHe et al\n(2010) (70)/\nCohort/\nNOS (7)\nEndometriosis; 34.4±7.4; 33 \n(23-52); n= 100; PD Ø\n33.4±7.1; \n32 (25-51); \nn= 70\n•   Dysmenorrhea (DM ) \nseverity \n•   Electrical pain test (EPT) \nsensory and pain threshold\n•   The pain intensity score that \nmatches with patients own \nDM severity\n•   Ischemic pain test (IPT)\nBefore surgery\nP↔C\n•  ↓ EPT pain threshold\n•  ↑ IPT scores\nP=C\n•  EPT sensory threshold\n6 months after surgery\nP=C\n•  IPT scores\n•  EPT sensory and pain thresholds\nPost-op 6th month↔Pre-op\n•  ↓ DM severity \n•  ↓ EPT DM matching score\n\nPain Physician: July/August 2013; 16:291-308\n296  www.painphysicianjournal.com\nStudies/ \nDesign/ NOS\nPatients (P); Age; Pain \nDuration\nControls \n(C) Outcome Measures Main Results\n Tu et al\n(2010) (46)/\nCase control\nNOS (7)\nPrimary dysmenorrhea; \n23.84±2.99; 10.19±3.25; \nn=32\n23.81±2.80; \nn=32;\n•   Psychological measures \n•   Total and regional gray \nmatter (GM) volume\nP = C\n•  psychological measures\n•  total GM volume\nP↔C\n•   ↓ GM  volume in regions involved in pain \ntransmission, higher level sensory processing, \nand affect regulation\n•   ↑ GM volume in regions involved in pain \nmodulation and regulation function of endocrine\nSutton et al\n(2009) (53)/\nCase control/\nNOS (6)\nProvoked vestibulodynia; \n26.08±8.34; 3.77±2.93 (0.8-\n10.0); n= 20\n23.72±4.90; \nn= 25\n•   Pain intensity ratings during \ngynecological examination\n•   QST (PPT, HD, HPT, HP-\nTol), pain/sensory  intensity \nand unpleasantness during \nQST\n•   Psychosocial measures\nP↔C\n•   ↑ pain intensity ratings during gynecological \nexamination\n•   ↓ vulvar PPTs, HPTs, HP-Tols\n•   ↑ self-report ratings for HD\n•   ↑ somatization, catastrophization\n•   ↓ sexual self-efficacy, sexual functioning\nP = C\n•   PPTs, self-report ratings during pressure testing, \nthermal thresholds and  self-report ratings at \nthe forearm for thermal stimuli\n•   vulvar HD\n•   self-report ratings for vulvar  HPT, HP-Tol\nTu et al\n(2009) (49)/\nCase control/\nNOS (5)\nPrimary dysmenorrhea; \n23.1±3.03 (19-29); \n9.17±3.06 (4-16); n= 17\n21.7±2.6; \nn= 16\n•   Psychological assessment \n•   Regional brain metabolism/ \nactivity with PET scan\nP↔C\ncomparing pain state with the pain-free state\n•   ↑ regional metabolism in thalamic, prefrontal/ \norbitofrontal regions\nTwiss et al\n(2009) (73)/\nCase control/\nNOS (4)\nInterstitial cystitis/painful \nbladder syndrome; \n45.7±3.2; PD Ø; n= 13\n37.2±3.0; \nn=16\n•   Psychometric measures \n•   Acoustic startle reflex (ASR)\n•   Intensity and unpleasantness \nratings of abdominal \nstimulation\nP = C\n•   perceptual ratings of abdominal stimulation\n•   ASR during context threat and imminent threat \nconditions\nP↔C\n•   ↑ ASR at baseline, safe and anticipation \nconditions\n•   ↑ anxiety and depression scores\nLowenstein \net al\n(2009) (55)/\nCase control/\nNOS (5)\nPainful bladder syndrome\n50 (22-69); 4 (1-20); n= 11\n46 (35-54); \nn= 10\nO’Leary-Sant scale\nPain catastrophizing scale\nThermal and vibratory sensory \nthresholds\nSupra-threshold habituation to \nthermal stimuli\nP↔C\n•   ↑ thermal thresholds at T12\n•   ↓ habituation to supra-threshold thermal \nstimuli\n•   ↑ sensation intensity  during tonic heat stimulus\n•   ↑ catastrophization\nP=C\n•   thermal thresholds at all testing sites except T12\n•   vibratory thresholds at all testing sites\nFrasson et al\n(2009) (68)/\nCase control/\nNOS (5)\n1. Primary idiopathic \nlifelong vaginismus\n34.1±2.2; DD: lifelong; \nn=10\n2. Vulvar vestibulitis \nsyndrome accompanied by \nvaginismus; 34.6±2.6; DD: \n1-12 y; n=10\n37.6±5.5; \nn=10\n•   Electromyographic activity \nfrom pelvic floor muscles\n•   Bulbocavernosus reflex \n- The fırst early response (R1)\n- Second late response (R2)\n•   Pudendal-nerve \nsomatosensory evoked \npotentials (SEP)\n•   Pudendal-nerve SEP recovery \nfunctions\nP↔C\n•   ↑ muscular activity at rest and straining\n•   ↑ R2 amplitude and duration\n•   ↑ cortical P40-N50 amplitude at 20 ms \ninterstimulus interval\nP=C\n•   R1 latency, amplitude, duratıon\n•   R2 latency\n•   Sensory threshold to electrical stimuli on the \ndorsal nerve\n•   SEP amplitudes and latencies in response to \nsingle stimuli\nSchweinhardt \net al\n(2008) (47)/\nCase control/\nNOS (6)\nProvoked vestibulodynia; \n25.7±5.1 (19-36); > 6 \nmonths; SD: 5±2.9 (1-9); \nn= 14\n25.6±6.0; \nn= 14\nTT and PPT at the posterior \nvulvar vestibule\n•   Pain intensity ratings during \nQ-tip test\n•   Pain catastrophizing scale\n•   Total gray matter (GM) volume\n•   Regional GM densities\nP↔C\n•   ↓ TTs and PPTs \n•   ↑ pain intensity ratings\n•   ↑ non-vulvar pain catastrophizing\n•   ↑ GM density in pain modulatory and stress \nrelated areas\nP = C\n•   Total GM volume\nTable 2 (cont.). Evidence table\n\nwww.painphysicianjournal.com  297\nCentral Sensitization in Chronic Pelvic Pain\nStudies/ \nDesign/ NOS\nPatients (P); Age; Pain \nDuration\nControls \n(C) Outcome Measures Main Results\nJohannesson \net al\n(2007) (60)/\nCase control/\nNOS (5)\nProvoked vestibulodynia; \n24.9 (20-33); ≥ 6 months; \nn= 20\nCOC group\n24.4 (18-34)\nn= 20\nnon-COC \ngroup\n23.8 (18-33)\nn= 20\n•   PPTs at peripheral sites\n•   Pain intensity ratings \n•   Other measures \nP↔C\n•   ↓ score on vitality and general health\n•   ↑ anxiety and depression\n more bodily pain\n•   Before cold pressor test\n•   ↓ PPTs\nDuring cold pressor test\n•   ↓ PPTs\nP=C\n•   increase in PPTs during cold noxious stimulation\n•   pain ratings before and during cold noxious \nstimulation\nPukall et al\n(2006) (63)/\nCase control/\nNOS (8)\nVulvar vestibulitis \nsyndrome; 27.4 (22-37); > \n6 months; SD: 86.1±55.1 \nmonth; n=16\n26.3 (21-40); \nn=16\n•   Body pain questionnaire \nscores\n•   General Health Problems \nquestionnaire scores\n•   Pain Catastrohizing \n•   Anxiety Score\n•   Pain behavior, Pain intensity \nand unpleasantness ratings \nduring tender point (TP) \nexamination\nP↔C\n•   ↑ magnitude of non-vulvar pain\n•   ↑ pain interference with daily activities\n•   ↑ number of regularly experienced pains and ↑ \nratings for the seriousness and interference of \nthese pains and lifetime health problems\n•   ↑ vulvar and non-vulvar pain catastrophizing\n•   ↑ trait anxiety\n•   ↑ number of painful areas during TP \nexamination\n •   ↑ pain intensity and unpleasantness ratings \nduring TP examination\nP=C\n•   Total number of lifetime health problems\n•   State anxiety\nFoster et al \n(2005) (71)/\nCase control/\nNOS (7)\nVulvar vestibulitis \nsyndrome; 31.6; ≤ 4 y (for \n4 cases), \n≥ 10 y (for 6 cases); n= 10\n31.9; n=10 •   Post-capsaicin pain response\n•   Spontaneous pain level\n•   Surface area of punctate \nhyperalgesia\n •   Surface area of dynamic \nallodynia\n•   Cutaneous blood flow\n•   Regional skin temperature\n•   Vital signs\nP↔C\n•   ↑ post-injection spontaneous pain\n•   ↑ area of punctate hyperalgesia\n• ↑area of dynamic allodynia\n•   ↑ resting pulse rate\n•   ↓ resting mean systolic pressure\nP = C\n•   Cutaneous blood flow\n •   Regional skin temperature\nGranot &Lavee\n(2005) (64)/\nCase control/\nNOS (5)\nVulvar vestibulitis \nsyndrome; 22.88±2.27; > 6 \nmonths; n= 28\n24.60±4.11; \nn= 50\n•   Thermal pain threshold\n•   The magnitude estimation of \nphasic suprathreshold pain\n•   The magnitude estimation of \ntonic pain\n•   Psychological measures\nP↔C\n•   ↓ pain threshold at forearm\n•   ↑ magnitude estimation of phasic \nsuprathreshold stimuli\n•    ↑ trait anxiety\n•   ↑ somatization\n•   ↓ body image\nP = C\n•   Magnitude estimation of tonic stimuli\n•   State anxiety\n•   Experimental pain catastrophizing\nNess et al \n(2005) (62)/\nCase control/\nNOS (4)\nInterstitial cystitis; 36±8; \nPD Ø; n=13\n33±8; n=13 •   Psychological questionnaires\n•   Thermal pain threshold and \ntolerance\n•   Muscle PPT\n•    Ischemic pain threshold \n(I-THR)\n•   Ischemic pain tolerance \n(I-TOL)\n•   The pressure and volume \nvalues during bladder filling \n(cystometrogram)\n•   Pain intensity and \nunpleasantness ratings during \nbladder filling\nP↔C\n•   ↓ Quality of life\n•   ↑ reactivity and hypervigilance\n•   ↑ catastrophizing\n•   ↓ muscle PPTs\n•   ↓ I-TOL\n•   ↑ bladder sensitivity \nP = C\n•   Thermal measures\n•   I-THR\nTable 2 (cont.). Evidence table\n\nPain Physician: July/August 2013; 16:291-308\n298  www.painphysicianjournal.com\nStudies/ \nDesign/ NOS\nPatients (P); Age; Pain \nDuration\nControls \n(C) Outcome Measures Main Results\nLaursen et al\n(2005) (57)/\nCase control/\nNOS (8)\n1. Fibromyalgia/Whiplash/\n46 (37-54)/ 53 months/ \nn=10\n2. Endometriosis; 44 (35-\n61); 96 months; n=10\n3. Low back pain; 45 (28-\n58); 48 months; n=10\n4. Rheumatoid arthritis; 43 \n(28-58); 42 months; n=10\n42 (25-61); \nn=41\n•   Pain intensity of the habitual \npain \n•   PPTs\n•   Quality of life score\nP1,2,3,4↔C\n•   ↑ habitual pain intensity\n •   ↓ PPTs\nP1=P2=P3=P4\n•   median PPT values\nP1↔P2,3,4\n•   ↑ habitual pain intensity\nPukall et al\n(2005) (48)/\nCase control/\nNOS (8)\nVulvar vestibulitis \nsyndrome; 25.7 (19-39); > 6 \nmonths; n=14\n25.7 (19-39); \nn= 14\n•   Intensity and unpleasantness \nratings during mild \nand moderate pressure \nstimulation\n•   Regional brain activity \nduring non-painful and \npainful stimuli with FMRI\nP↔C\n•   ↑ intensity and unpleasantness ratings\n•   ↑ activation of pain-related brain regions\nGranot\n(2005) (65)/\nCase control/\nNOS (6)\nVulvar vestibulitis \nsyndrome; 24.1±4.1 (18-\n36); > 6 months; n= 98\n23.3±2.4 \n(18-31)\nn= 135\n•   Personality traits \n- harm avoidance (HA)\n- novelty seeking (NS)\n- reward dependence (RD)\n•   Thermal pain threshold\n•   The magnitude estimation \nof perceived phasic supra-\nthreshold pain (V AS)\nP↔C\n•   ↓ Thermal pain thresholds\n•   ↑ V AS scores in response to the supra-threshold \npainful stimuli\n•   ↑ Scores in HA and RD\nP = C\n•   Scores in NS\n•   Sig. correlations between pain sensitivity  and \npersonality trait variables (HA and RD)\nGiesecke et al\n2004 (58)/\nCase control/\nNOS (8)\nVulvodynia; 33.41±9.39 \n(18-60); PD Ø; n= 17 37.17±11.43; \nn= 23\n•   PPTs in the vulvar areas\n•   PPTs at peripheral sites\n•   The pressures required to \nproduce different levels of \nsubjective pain at the thumb\nP↔C\n•   ↓ PPTs in the vulvar region\n•   ↓ PPTs at peripheral sites\n•   ↓ pressures required to elicit faint, mild and \nslightly intense pain at the thumb\nBajaj et al\n(2003) (52)/\nCase control/\nNOS (5)\nEndometriosis; 37.7±2.9; \n15±3.5; n= 10\n30.1±2.3; \nn=10\n•   Post-saline pain intensity \n(V AS)\n•   Post-saline pain areas\n•   PPTs and TTs before and \nafter injection\nP↔C\n•   ↑Peak pain V AS after injection into the first \ndorsal interosseus muscle (FDI) of the hand\n•   ↑ Post-saline pain areas after injection into the FDI\n•   ↓ PPTs and before and after injection\nP = C\n•   Peak pain V AS after injection into the back\n•   Post-saline pain areas after injection to the back \n•   TTs before and after injection\nGranot et al\n(2002) (66)/\nCase control/\nNOS (5)\nVulvar vestibulitis \nsyndrome; 27.1±7.6; PD \nØ; n= 44\n25.4±5.2; \nn= 41\n•   Anxiety scores \n•   Heat pain intensity and \nunpleasantness thresholds\n•   The magnitude of perceived \nintensity and unpleasantness \nof phasic and tonic supra-\nthreshold stimuli\n•   The cardiovascular \nparameters\nP↔C\n•   ↑ state anxiety, trait anxiety\n•   ↓ heat pain and unpleasantness thresholds\n•   ↑ magnitude estimation of supra-threshold  \nphasic pain  and ↑ unpleasantness ratings at \n47ºC and 48 ºC.\n•   ↑ scoring of tonic pain perception and ↑ \nunpleasantness ratings\n•   ↑ increase in systolic blood pressure during \ntonic pain stimuli\nP=C\n•   Magnitude estimation of perceived intensity \nand unpleasantness at 44ºC, 45ºC and 46ºC\n•   Heart rate\nBajaj et al\n(2002) (61)/\nCase control/\nNOS (4)\nDysmenorrhea; 25.5±1.1; \nPD Ø; n= 20\n28±1.9\nn= 15\n•   McGill Pain Questionnaire\n•   PPT, PiPT, HPT, TT\nP↔C (menstrual phase)\n•   ↓ HPT at the control sites\n•   ↓ PPT at referral and control sites\nP = C (menstrual phase)\n•   HPT at referral areas\nMenstrual phase↔other phases\n•   ↓ HPT and PPT at referral and control areas\nMenstrual phase↔ovulatory phase\n•   ↓ PiPT\nTable 2 (cont.). Evidence table\n\nwww.painphysicianjournal.com  299\nCentral Sensitization in Chronic Pelvic Pain\nStudies/ \nDesign/ NOS\nPatients (P); Age; Pain \nDuration\nControls \n(C) Outcome Measures Main Results\nPukall et al \n(2002) (51)/ \nCohort/\nNOS (8)\nVulvar vestibulitis \nsyndrome; 25.85 (21-44); \n> 6 months; 50.08±38.37 \nmonth; n= 13\n26.31 (21-\n41); n= 13\n•   Pain ratings during \ngynecological examination\n•   Tactile and PPTs\n•   Pain and distress ratings \nduring supra-threshold pain \nand sustained pressure\n•   PP-Tol at peripheral sites\n•   Psychological measures \nP↔C\n•   ↑pain ratings during gynecological examination\n•   ↑ catastrophization scores related to intercourse \npain\n•   ↓ TT and PPT for the vestibular sites and \nlabium minus\n•   ↓TT, PPT and PP-Tol over the deltoid muscle\n•   ↑ distress ratings for supra-threshold pain and \nsustained pressure\nP = C\n•   TT at forearm and tibia\n•   PPT at tibia\nsession 1= session 2\n•   TTs at vestibular sites, thigh and labium minus\nsession 2↔session 1\n•   ↑ mean PPTs of vestibular sites\nGranot et al\n(2001) (67)/\nCase control/\nNOS (4)\nDysmenorrhea; 23.7±2.8; \nPD Ø; n= 22\n24.1±3.1 (19-\n30); n= 31\n•   Anxiety scores \n•   Self-reports of pain\n•   HPT\n•   Supra-threshold magnitude \nof perceived pain (V AS)\n•   Pain-evoked potentials \nby laser stimuli (latency, \namplitude) \n•   V AS score in response to \nsupra-threshold laser\nP↔C\n•   ↑ state anxiety\n•   ↑ V AS score for supra-threshold pain\n•   ↑ latency of the laser-evoked potentials\n•   ↑ V AS score in response to supra-threshold \nlaser stimuli\nP=C\n•   Trait anxiety\n•   HPT\n•   Amplitude of the laser-evoked potentials\nGiamberardino \net al \n(1997) (69)/\nCase control/\nNOS (5)\nDysmenorrhea; 29±5.6; \nPD Ø; n= 10\n28.7±5.9 ; \nn= 10\n•   EPT of skin, subcutis and \nmuscle\nP↔C\n•   ↓ EPT of subcutis and muscle\nP=C\n•   EPT of skin\nClauw et al \n(1997) (59)/\nCase control\nNOS (6)\nFibromyalgia; 43.8; PD Ø; \nn= 60\nInterstitial cystitis; 44; PD \nØ; n= 30\n45.6; n= 30 •   Questionnaire regarding \ncurrent symptomatology\n•   PPT\n•   PP-Tol\nIC↔C\n•   ↓ PPT, PP-Tol at tender and control points\nFM↔IC\n•   ↓ PPT, PP-Tol at tender points\nFM = IC\n•   Frequency of current symptoms\n•   PPT, PP-Tol at control points\n(COC: Combined Oral Contraceptive, CPP: Chronic Pelvic Pain, DD: Disease Duration, DNIC: Diffuse Noxious Inhibitory Control, EPT: Electri-\ncal Pain Threshold, FMRI: Functional Magnetic Resonance Imaging, HD: Heat Detection, HPT: Heat Pain Threshold, HP-Tol: Heat Pain Tolerance,   \nPET: Positron Emission Tomography, QST: Quantitative Sensory Testing, PPT: Pressure Pain Threshold, PP-Tol: Pressure Pain Tolerance, PiPT: \nPinch Pain Threshold, PD: Pain Duration, SD: Symptom Duration, TT: Tactile Threshold, V AS: Visual Analog Scale)\nTable 2 (cont.). Evidence table\nRisk of Bias and Level of Evidence\nThe methodological quality ratings of the reviewed \nstudies are presented in Table 2. In most cases (91.57% \nor 239 of the 261 items), the 2 researchers agreed. After \na second review and a discussion of the 22 differences, \nthe raters reached a consensus for 21 items. The last \nauthor (MM) solved the remaining point of difference. \nMethodological scores ranged from 4 to 8 points \n(maximum score 9). The most common flaws for the \ncase control studies were the representativeness of the \npatients and the comparability of cases and controls.\nSince all studies are observational (case-control \nor cohort) in the present systematic review, the level \nof evidence for each relevant outcome began as low-\nquality evidence according to the GRADE system. Then, \nfor most of the outcomes, the quality of evidence was \ndowngraded to low quality or to very low quality due \nto the limitations of the study design (risk of bias) and \ninconsistency of the study results. \nEvidence for Central Sensitization\nIn the following section, the results of this review \n\nPain Physician: July/August 2013; 16:291-308\n300  www.painphysicianjournal.com\nAlthough the differences in brain activity increases \nduring the menstrual phase were not significant be-\ntween the groups, deactivation of brain regions in \nresponse to noxious thermal stimulation of the control \nsite was observed in control women but not in dys-\nmenorrheic women. In response to stimulation of pain \nreferral site, dysmenorrheic women had higher activ-\nity in the left entorhinal cortex and inferior/middle \ntemporal gyrus than controls during non-menstrual \nphases (without background pain) (50). Women with \nVVS showed higher activation in the right cerebellum \nduring non-painful tactile vestibular stimulation and \nhigher activation in the insular and frontal cortical re-\ngions during painful stimulation compared to control \nsubjects (48).\nThere is a change in brain activity/function in \npatients with urogynecological CPP (very low level of \nevidence) but the evidence is too limited to draw con-\nclusions concerning the regions. \nAlteration in Sensory Perception \nTactile Stimuli\nThree research papers with low (51) and moderate \nrisk of bias (47,52) examined the response to tactile \nstimuli with von Frey filaments. Although Bajaj et al \n(52) did not find any significant difference between \ngroups for punctate tactile thresholds at referral and \nnonreferral areas of menstrual pain, other studies re-\nported lower punctate tactile thresholds at vestibular \nsites (47,51), labium minus, and over the deltoid muscle \nbut not at other peripheral sites (forearm, tibia) in PVD \npatients and these results were reliable over time in \nsymptomatic areas (51). \nIn patients with PVD, higher distress ratings to \nsustained supra-threshold pain stimuli in the vestibular \nregion (51) and higher pain intensity ratings during \ncotton-swab test (47,51,53,54) and speculum insertion \n(53,54) were also established.\nThe evidence based on the selected articles is \nlimited and too conflicting to draw conclusion for the \nresponse to tactile stimuli in patients with urogyneco-\nlogical CPP (very low level of evidence).\nVibratory Stimuli \nIn response to vibratory stimuli, 2 studies with \nmoderate (55) to high risk of bias (56) did not provide \nevidence for the hypersensitivity at both local and \nremote dermatomes in patients with painful bladder \nsyndrome (PBS) (55) and vulvodynia (56).  \nare categorized according to the neural, neurophysi-\nological, and clinical correlates of CNS alterations.\nAlteration in Brain Morphology and Function\nBrain Morphology\nUsing voxel-based morphometry, 3 studies with \nmoderate risk of bias reported changes in regional gray \nmatter (GM) density/volume in patients having CPP \nwith and without endometriosis and in the other CPP \nconditions including primary dysmenorrhea and pro-\nvoked vestibulodynia (PVD) (synonym “vulvar vestibu-\nlitis syndrome”) (17,46,47). Schweinhardt et al (47) re-\nported only regionally increased GM density compared \nto both GM volume decreases and increases in other \nstudies (17,46). Studies reported greater decreases in \nGM volume in regions of the pain system including \nthalamus, cingulate cortex, putamen (17), precuneus, \nsecondary somatosensory cortex, superior temporal \ngyrus, cerebellum (46), and insular cortex (17,46) and/or \nthose involved in pain modulation (prefrontal cortex) \n(17,46) in patients compared to controls. Endometriosis \npatients without CPP and PVD patients showed no evi-\ndence of a GM decrease within the pain system (17,47). \nRegional increase in GM density/volume was found in \npain modulatory, stress, and endocrine function related \nareas including right inferior/middle frontal gyrus, left \namygdala (17), cingulate cortex,  hypothalamus,  precu-\nneus, superior/middle temporal gyrus, cerebellum (46), \nmesencephalon (17,46), basal ganglia (47), and hippo-\ncampus/parahippocampus (46,47).  \nThere is limited evidence suggesting the change \nin regional brain morphology in patients with urogy-\nnecological CPP, but location and direction (increase or \ndecrease) are conflicting (very low level of evidence). \nBrain Function\nTwo different imaging methods were used to ex-\namine CNS activity in 3 studies with low (48), moderate \n(49), or high risk of bias (50). Using fluoro-deoxyglucose \npositron emission tomography, Tu et al (49) found that \ncramping menstrual pain is associated with increased \nactivity in prefrontal/orbitofrontal regions and left \nventral posterior thalamus and with decreased activity \nmainly in sensorimotor regions of left hemisphere in \npatients with primary dysmenorrhea.\nFunctional magnetic resonance imaging was used \nto investigate the cerebral response to experimental \nthermal and tactile stimuli in patients with dysmenor -\nrhea (50) and vulvar vestibulitis syndrome (VVS) (48). \n\nwww.painphysicianjournal.com  301\nCentral Sensitization in Chronic Pelvic Pain\nEvidence regarding the use of vibratory stimuli is \ntoo limited, but hypersensitivity to vibratory stimuli \ndoes not seem to be present (very low level of evidence).\nPressure Stimuli\nPressure algometry was used as one of the outcome \nmeasures in 10 of the 29 studies with low (51,57,58), \nmoderate (47,52,53,59,60), or high risk of bias (61,62). \nOne study with low risk of bias also used manual tender \npoint examination (63). \nSchweinhardt et al (47) assessed pain thresholds \nin response to pressure at only the symptomatic site \n(vestibular site) in their brain morphometry study and \nprovided evidence for primary hyperalgesia. All remain-\ning studies examined both local and remote (52,53,57-\n59,61) or remote sites only (51,60,62,63) and all of \nthem except one (53) established widespread pressure \nhyperalgesia in women with urogynecological CPP (see \nTable 2 for details). \nPukall et al (51) assessed the genital thresholds \nalso in a second session (3-12 months later) to test the \nstability of thresholds over time and reported a similar \nincrease in punctate pain thresholds in the PVD and \ncontrol groups. This increase at the second session can \nbe explained by reduced anxiety focused on the testing \nbecause of the familiarity with the test procedure.\nThere are 2 studies comparing CPP patients with \nother chronic pain patients (57,59) such as fibromyal-\ngia/whiplash, low-back pain, and rheumatoid arthritis \npatients. No significant differences were reported in \nmedian pressure pain thresholds between endometrio-\nsis patients and other chronic pain patients (57). In the \nother study, compared to fibromyalgia patients, women \nwith interstitial cystitis reported higher pressure pain \nthresholds at tender points (9 paired areas) but not at \ncontrol points (59).\nThe presence of generalized hyperalgesia in re-\nsponse to pressure stimuli is supported by a low level of \nevidence in women with urogynecological CPP.\nThermal Stimuli\nThermal stimuli were used in 10 studies, with mod-\nerate (53-55,64-66) to high risk of bias (50,61,62,67), to \nevaluate CS in women suffering from urogynecological \nCPP. All studies examined the response to heat stimuli at \nboth local and remote sites (50,53,55,61) or at remote \nsites only (54,62,64-67). Five of them (50,61,64-66) pro-\nvided evidence for widespread thermal hyperalgesia, \nwhile 2 others did not (53,62). Besides this, inconsistent \nresults at peripheral sites (54,67) and hypoesthesia at \npain-referral area (55) were also reported (see Table 2 \nfor details). \nPVD patients showed peripheral hypersensitiv-\nity for pain tolerance but not for pain thresholds (54). \nEven though Granot et al (67) did not report decreased \nheat pain thresholds at the thenar eminence of the \nhand of dysmenorrhea patients, the authors reported \nhigher magnitude estimations on a visual analog scale \nof supra-threshold pain elicited by thermal and water-\ncooled CO2 laser stimuli to the hand. \nElevated thermal detection thresholds, indicative \nfor the presence of hypoesthesia, were established at \nthe suprapubic area but not at remote dermatomes \nin patients with painful bladder syndrome (55). In \nthe same study, supra-threshold thermal stimuli were \nalso applied at T12 (suprapubic) and S3 (remote) der -\nmatomes for 60 seconds to assess the habituation to \nsomatic stimuli. The authors found that habituation \nto suprathreshold stimuli is less common in patients \nthan in controls, suggesting the impaired habitua-\ntion (55). \nThere is conflicting evidence regarding the re-\nsponse to thermal stimuli in patients with urogyneco-\nlogical CPP, although the majority suggest widespread \nthermal hyperalgesia (very low level of evidence).\nElectrical Stimuli\nThere are 4 papers with moderate risk of bias as-\nsessing the response to electrical stimuli (18,68-70). No \nhypersensitivity was reported at local (68) or at asymp-\ntomatic sites for electrical detection thresholds (70). \nGiamberardino et al (69) investigated the electrical \npain thresholds (EPT) at 3 stimulus depths: skin, sub-\ncutis, and muscle tissue within the uterine visceretome \nand on the limbs, and reported similar thresholds for \nskin, and lower thresholds for subcutis and muscle \ncompared to controls. EPTs were  also examined in \npatients with endometriosis before and following \nexcisional surgery for all visible endometriotic lesions \n(70). Three and 6 months after surgery, it is reported \nthat patients’ generalized hyperalgesia to electrical \nstimuli significantly and progressively improved, along \nwith their dysmenorrhea severity. In another study by \nNeziri et al (18), EPTs during sural nerve stimulation \nwere significantly lower in patients with endometrio-\nsis than in controls, also demonstrating the general-\nized hyperalgesia. \nThere is evidence supporting the generalized elec-\ntrical hyperalgesia in patients with urogynecological \nCPP (low level of evidence). \n\nPain Physician: July/August 2013; 16:291-308\n302  www.painphysicianjournal.com\nInjection of Specific Pain Mediators\nIn one study with moderate risk of bias, after \nintradermal injections of capsaicin in the forearms \nand feet of VVS patients, they reported greater spon-\ntaneous pain, area of punctate hyperalgesia, and \ndynamic allodynia compared with pain-free controls \n(71). In another study with moderate risk of bias (52), \npatients with endometriosis reported higher pain \nintensity and larger pain areas after injection of hy-\npertonic saline to the control site (into the first dorsal \ninterosseus muscle of the hand). These hyperalgesic \nresponses were not observed following the injection \nto the menstrual pain referral site (the multifidus \nmuscle at the low back). \nThe limited available evidence suggests the pres-\nence of CS in women with urogynecological CPP with \nincreased response to injection of pain mediators (very \nlow level of evidence). \nIschemic Stimuli\nThe ischemic pain test (IPT) is a tonic pain stimulus \ninvolving multiple noxious input (e.g., pressure and \nischemia) (70). Two studies with moderate (70) to high \nrisk of bias (62) used a modified procedure and provid-\ned conflicting evidence for the presence of generalized \nhyperalgesia. In the study of He et al (70), endome-\ntriosis subjects had significantly higher IPT visual analog \nscale scores than controls, but after removing ectopic \nimplants with surgery, their IPT scores were significantly \nand progressively improved. Six months after surgery, \nthere was no difference in IPT scores between patients \nand controls anymore. \nNess et al (62) showed that the subjects with in-\nterstitial cystitis tolerated the ischemic forearm pain \n(ischemic tolerance) for a shorter duration than normal \nsubjects, while the difference was not statistically sig-\nnificant for the ischemic threshold duration. \nThe evidence in response to ischemic stimuli in pa-\ntients with CPP is too limited and conflicting (very low \nlevel of evidence). \nDistention Stimuli\nOne study (62) with high risk of bias used cystomet-\nrogram to assess bladder sensitivity, and reported that \nthe subjects with interstitial cystitis are more sensitive \nto bladder distention than healthy subjects, demon-\nstrating the presence of primary hyperalgesia. \nThere is limited evidence that sensitivity to disten-\ntion stimuli in CPP patients is increased (very low level \nof evidence).\nNeurophysiological Changes\nOveractive Bottom-up Mechanisms\nFour studies with moderate (18,68) to high risk of \nbias (56,67) evaluated excitability and responsiveness of \nthe CNS by using different kinds of neurophysiological \ntests. \nThe spinal withdrawal reflex was used to evaluate \nreflex receptive fields of spinal cord neurons in patients \nwith endometriosis associated CPP. In comparison with \npain-free participants, patients showed larger reflex \nreceptive fields on the foot sole, providing evidence \nfor the expansion of nociceptive reflex receptive fields. \nLower thresholds to induce subjective feelings of in-\ncreasing pain sensation and lower nociceptive reflex \nthresholds by repeated electrical stimulation (temporal \nsummation) of the cutaneous area of the sural nerve \nwere even so reported, indicating generalized spinal \ncord hypersensitivity and generalized facilitated tem-\nporal summation (18). \nCNS excitability was also assessed by measuring \nelectromyographic activity of pelvic floor muscles, \nbulbocavernosus reflex (BCR), and pudendal nerve so-\nmatosensory evoked potentials in women with primary \nidiopathic lifelong vaginismus. In comparison with the \nhealthy controls, the patients had greater electromyo-\ngraphic activity, higher amplitude and duration for the \none component of bulbocavernosus reflex, and higher \namplitude of cortical P40-N50 in the pudendal nerve so-\nmatosensory evoked poatentials recovery cycle. This ab-\nnormal excitability suggests concomitant CNS changes \nin vaginismus (68). \nPatients with dysmenorrhea showed longer laten-\ncies of pain-evoked potentials and higher pain ratings \nin response to supra-threshold pain evoked by the laser \nstimuli to a non-gynecological site (67).\nOn the other hand, compared with healthy controls \nand patients with a shorter history of pain, vulvodynia \npatients with a longer history of pain demonstrated a \nsignificantly reduced effect of adaptation on sensory \nperception, suggesting central hyperexcitability (56). \nAvailable evidence suggests overactivity of bottom-\nup CNS mechanisms in the pathophysiology of urogyne-\ncological CPP (low level of evidence).\nDysfunctional Top-down Mechanisms\nTwo studies with moderate risk of bias found no \nevidence of impaired diffuse noxious inhibitory control \nresponse in patients with PVD. There was no significant \ndifference in the number of diffuse noxious inhibi-\n\nwww.painphysicianjournal.com  303\nCentral Sensitization in Chronic Pelvic Pain\ntory control responders between the groups (54,60). The \nmagnitude of the response (increase in pressure pain \nthreshold) was similar in both patients and controls in \none of the studies (60), while the other study (54) report-\ned a higher magnitude of response (increase in heat pain \ntolerance) in patients with PVD as compared to controls.\nEvidence suggests an intact diffuse noxious inhibi-\ntory control function in patients with PVD (low level of \nevidence). \nDysfunction of Hypothalamic-pituitary-adrenal \n(HPA) Axis\nOnly one study which has a high risk of bias inves-\ntigated whether menstrual pain is a sufficient stressor \nto affect HPA axis function. Women with dysmenor -\nrhea had significantly lower mean cortisol levels than \ncontrols. Also, a significant negative correlation was \nobserved between the number of years that dysmen-\norrhea had been present and the mean serum cortisol \nlevels (50).\nThere is limited evidence to support the dysfunc-\ntion of the HPA axis in urogynecological CPP (very low \nlevel of evidence).\nAlteration in Psychosocial Functioning\nPsychological factors such as anxiety, somatiza-\ntion, catastrophizing, and other personality traits are \ninvolved in pain processing (64) and enhanced pain \nfacilitation may be caused by cognitive emotional sen-\nsitization (72). Eight studies with low (51,63), moderate \n(47,53,60,64,65), or high risk of bias (73) reported con-\nflicting results regarding the alteration of psychosocial \nfunctioning and/or its association with pain perception. \nIn 3 studies, no association was found between higher \nanxiety scores and pain response in patients with PVD \n(60,64) or interstitial cystitis/painful bladder syndrome \n(73). Other components of psychosocial function includ-\ning somatization and catastrophization were examined \nin a variety of ways in women with PVD and results \nhave demonstrated that affected women report more \nsomatic and/or catastrophic symptoms in comparison to \ncontrol women (47,53,63,64), suggesting that a higher \ntendency to catastrophize about pain may enhance the \npain perception and increase emotional distress related \nto pelvic pain syndromes (63). Two studies reported an \nassociation between enhanced pain perception and \npsychological factors (53) and personality traits (65) in \nwomen with VVS. On the other hand, Granot and Lavee \n(64) found 4 subgroups of VVS women on the basis of \nhigh/low anxiety and high/low pain perception, indi-\ncating that not all women with VVS have greater pain \nsensitivity and anxiety levels. What’s more, women with \nVVS were more sensitive to noxious stimuli regardless \nof their personality traits (65). \nBesides certain psychological factors, the role of \nself-efficacy and body image in the perception of pain \nwas investigated in 2 studies (53,64). The VVS women \ndemonstrated lower body image, lower sexual func-\ntioning, and lower sexual self-efficacy than controls \nassociated with higher pain perception at vulvar and \nperipheral sites. \nTwiss et al (73) examined the acoustic startle \nresponses, which is mediated by output from the \namygdala complex, to investigate the responsiveness \nof affective circuits during visceral related threat. The \nwomen with interstitial cystitis/painful bladder syn-\ndrome showed significantly greater startle magnitudes \nthan controls during non-imminent threat conditions, \nindicating increased activation of a defensive emo-\ntional circuit and so hypersensitivity to visceral stimuli.\nAs mentioned in the first part of the results section \nof this review, the brain imaging studies also point to \nthe importance of cognitive emotional sensitization \nwith changes in morphology and activity of brain re-\ngions involved in pain modulation, cognition, stress, \nand emotions (17,46-50).\nAlthough there are changes in psychosocial func-\ntioning of women with urogynecological CPP (very \nlow level of evidence), the literature for the associa-\ntion of them with pain perception is too limited and \ninconclusive. \nAutonomic Dysregulation\nOne study with moderate risk of bias showed that \nVVS cases had higher heart rates and lower systolic \nblood pressures in the resting state compared to pain-\nfree controls. Following capsaicin injection, systolic \nblood pressure and mean arterial blood pressure in VVS \npatients increased more rapidly compared to controls \n(71). This autonomic hyperactivity was confirmed by an-\nother study with moderate risk of bias, which showed \nhigher increase in systolic pressure during heat pain \nstimuli in the same patient group (66).\nAutonomic dysregulation has been shown in 2 \nstudies in women with urogynecological CPP (very low \nlevel of evidence). \nMenstrual Phase Variations\nThere are 4 studies with moderate (69) to high \nrisk of bias (50,61,67) regarding the influence of the \n\nPain Physician: July/August 2013; 16:291-308\n304  www.painphysicianjournal.com\nmenstrual phase on pain perception in dysmenorrheic \nwomen. Studies reported inconsistent results for the \npain sensitivity in menstrual pain referral or control \nsites with different types of stimulation, including pres-\nsure, pinch, heat, laser, or electrical.  Although Bajaj \net al (61) reported higher sensitivity in the menstrual \nphase, no menstrual cycle effect was observed in the \nother 2 studies for the heat stimulation (50,67). Lower \nsensitivity, not for tactile, but for pressure and pinch \nstimuli, was also demonstrated by Bajaj et al (61) dur -\ning the menstrual phase. In response to laser stimuli, \ndysmenorrhea patients had the longest latency and \nthe highest amplitude of pain-evoked potentials (that \nis higher pain sensitivity) during the follicular phase, \nwhereas the shortest latency and the lowest amplitude \nwere observed in the luteal phase (67). Another study \nexamined the pain response to electrical stimuli at \n3 stimulus depths (skin, subcutis, and muscle) and re-\nported higher pain sensitivity during the periovulatory \nphase for skin and during the perimenstrual phases for \nmuscle and subcutaneous tissue (69).\nThe available evidence regarding the effect of \nmenstrual cycle phase on pain perception in women \nwith urogynecological CPP is limited and inconclusive.\ndiscussion\nThe present study systematically reviewed scientific \nliterature addressing central hypersensitivity in women \nwith urogynecological CPP. The mechanisms contribut-\ning to pain amplification and chronicity in urogyneco-\nlogical CPP seems heterogeneous and likely to occur at \nvarious levels of the nervous system. \nVoxel-based brain morphometry studies appear to \nagree with changes in regional brain morphology of \nwomen with urogynecological CPP, regardless of the \ndirection of change (increases and decreases in gray \nmatter density/volume) (17,46,47). Variability of the \nresults between studies may be attributed to many fac-\ntors such as the etiology of pain, pain duration, pain \noccurrence (intermittent vs. persistent), patient charac-\nteristics (age, personality traits), and pain medications \n(17,46,47). The stress on pain processing systems might \nbe less in menstrual or provoked pain than in continu-\nous pain and this might affect the direction of gray \nmatter changes (47). In addition, gray matter changes \nmay be dynamic and may change over time within an \nindividual. The initial increase in gray matter as an acute \nadaptive mechanism may be followed by a decrease in \ngray matter depending on the duration and persistence \nof the nociceptive input (17). Thus, longitudinal studies \nare required to evaluate possible bi-directional changes \nof gray matter in the progression of urogynecological \nCPP.\nBesides change in brain morphology, studies also \nreport alteration in brain function in patients suffering \nfrom urogynecological CPP. Hypersensitivity associated \nwith urogynecological CPP is reflected in increased ac-\ntivation (48-50) or no deactivation (50) in pain related \nbrain regions. In dysmenorrhea patients, absence of \nsignificant deactivations of certain pain related brain \nregions in response to noxious stimulus in the men-\nstrual phase can be attributed to dysmenorrhea-pain \nassociated maximally deactivated brain regions where \ndeactivation would usually occur during pain experi-\nence (74), so further deactivation  in response to a \nnoxious heat stimulus is not observed. Alternatively, \nalterations in resting state activity may be present in \nwomen with dysmenorrhea (50). One study also re-\nported regional cerebral hypometabolism in somatic \nsensorimotor regions as well as hypermetabolism in \nthalamo-orbitofrontal-prefrontal regions during \ncramping menstrual pain (49). This hypometabolism \nmay display a compensatory inhibitory mechanism in \nresponse to excitatory input and the generalized hy-\nperalgesia in primary dysmenorrhea (67,69). Although \nexisting evidence suggests increased activation in pain-\nrelated brain regions in women with urogynecological \nCPP, further investigation of other observations (lack of \ndeactivation, hypometabolism) in certain brain regions \nrequires further study specifically adressing activity in \nthese regions.  \nIn most of the included studies, different methods \nwere used to establish primary and secondary hyper -\nalgesia. Reflex hypersensitivity at outside of the area \nof pain in response to repeated electrical stimulation \nindicates generalized facilitated temporal summa-\ntion in patients with menstrual pain (18). Enhanced \npost-capsaicin and post-saline pain responses extend-\ning far beyond the anatomic location of the primary \ncomplaint may also reflect an expanded field of neural \nhypersensitivity consistent with the presence of CS in \nVVS and endometriosis (52,71). Nevertheless, revers-\nibility of generalized hyperalgesia is suggested, given \nthe normalization after surgical removal of peripheral \nnociceptive sources (70). Therefore, further research \nis warranted to assess whether the presence of clini-\ncal pain and tissue damage is the crucial factor in the \nmanifestation of CS. \nOne study also reported cutaneous hyposensitivity \nat the pain referral area in patients with painful blad-\n\nwww.painphysicianjournal.com  305\nCentral Sensitization in Chronic Pelvic Pain\nder syndrome (55). This hyposensitivity is thought to \nreflect either activity of the diffuse noxious inhibitory \ncontrol system (75) and/or adaptation (69), in which \nadditional stimuli are perceived as relatively mild be-\ncause they occur against a background of chronic pain \n(55). Findings of impaired habituation to non-noxious \nstimuli in local and remote dermatomes in the same \npatient group may also underlie increased awareness \nof visceral events and may facilitate chronic pain (55). \nIn general, findings for the presence of generalized \nhyperalgesia are inconclusive because of the differences \nin the nature of these pain syndromes or differences in \nthe methodology of studies. Available evidence seems \nto suggest generalized hyperalgesia in response to \npressure and electrical stimuli and injection of capsaicin \nand hypertonic saline, but the response to other stimuli \nsuch as tactile, vibratory, thermal, ischemic, and disten-\ntion, definitely deserves further attention.\nNeurophysiological studies also proved overactivity \nof bottom-up mechanisms. Reduced adaptation metrics \nmay indicate increased hyperexcitability in longstand-\ning vulvodynia (56). The generalized hyperexcitability is \nreported to be associated with an increased number of \nresponsive spinal neurons or with an expansion of the \nreceptive fields of the spinal neurons (18). In patients \nwith vaginismus or VVS accompanied with vaginismus, \nconcomitant CNS changes may be understood from \nabnormal and excessive functioning of pelvic floor \nmuscles, reduced inhibition of cortical somatosensory \nevoked potentials, and hyperexcitable bulbocaverno-\nsus reflex (68). The increased latency of pain-evoked \npotentials by laser stimuli to the hand also confirm the \nsystemic phenomenon rather than a regional change \nin the pelvis of dysmenorrheic women (67). The limited \nnumber of studies with a wide variation of assessment \nmethods requires further neurophysiologic research to \nconfirm these results.\nThe intact diffuse noxious inhibitory control in \nvulvodynia patients may be explained by provoked or \nintermittent pain (with pain-free intervals) of this pa-\ntient group. It is possible that diffuse noxious inhibitory \ncontrol dysfunction may play less of a role in chronic pain \nconditions in which the pain is recurrent (54,60). Zhang \net al (56) also suggest that women with vulvar pain for a \nlong duration or with unprovoked pain have more CNS \ninvolvement or dysregulation.  Alternatively, an excess \nin descending facilitatory mechanisms may provide an \nexplanation for the pain experienced in PVD (60). \nAlthough an altered psychosocial and sexual pro-\nfile in women with VVS (or PVD) and interstitial cystitis/\npainful bladder syndrome has been reported in several \nstudies, only 2 studies demonstrated that augmented \npain perception is associated with psychological fac-\ntors (53) and personality traits (65). On the other hand, \nreported changes in brain morphology and function \nmay be responsible not only for the development and/\nor maintenance of the chronic pain, but might also \ncontribute to other common comorbid clinical features, \nsuch as mood disorders and cognitive impairment (17). \nNonetheless, it is clear that more research is warranted \nto define the precise influence of psychological factors \non the central pain processing. \nIt is reported that the menstrual phase, segmental \nsite, dysmenorrhea status and depth, and modality of \npain stimulation all have interacting effects on pain \nsensitivity (61,67,69). The inconsistent results of men-\nstrual cycle effects may be partly due to the lack of \nconfirmation of ovulation (61). Well-designed future \nstudies are needed in order to more fully explain these \ninteractions on central pain sensitivity.\nThe same goes for the precise mechanism of auto-\nnomic dysregulation and association between pain and \nblood pressure.\nWomen with VVS have been shown to have an \nelevated heart rate and reduced systolic pressure in the \nresting state (71) and higher increase in systolic blood \npressure in response to experimental pain stimuli  sug-\ngesting an autonomic dysregulation (66,71). In pain-\nfree subjects, reduced blood pressure has also been \nshown to be associated with increased pain thresholds \n(76).\nGiven the inconclusive findings and the low levels \nof evidence in the present review, due to the observa-\ntional study designs, definitely more research is war -\nranted to draw conclusions regarding CS in CPP. In most \nof the studies, there is also a lack of information about \nparticular factors (comorbid chronic pain syndromes, \npsychiatric conditions, use of analgesic medication \nbefore or during study period, menstrual cycle regu-\nlarity, oral contraceptive use) known to be involved in \npain processing. The variation in study results can be \nattributed to not only these factors, but also different \ndiagnoses of CPP, using a variety of assessment meth-\nods, frequency of pain, pain duration, age, and person-\nality characteristics of study participants. The design \nof included studies does not allow us to state whether \naltered brain morphology and function, generalized \nhypersensitivity, or impaired psychosocial functioning \narise from the experience of CPP, or whether they pre-\ndispose a patient to CPP. Without longitudinal studies, \n\nPain Physician: July/August 2013; 16:291-308\n306  www.painphysicianjournal.com\nit is not possible to know whether these alterations are \na cause or an effect of pain. Based on these method-\nological issues, further study designs with a sufficient \nand justified sample size are needed. \nThe recognition of the possible involvement of \nCS has important implications for the development of \nspecific therapies and better clinical management of \nurogynecological CPP. The traditional practice of fo-\ncusing on peripheral pathology may not be adequate \nand needs to be analyzed carefully since several CNS \ndysfunctions are now indicated in women with urogy-\nnecological CPP. A multidisciplinary approach is needed \nto understand pain variability in this chronic pain syn-\ndrome, in which cognitive and emotional factors may \nplay a role together with augmented pain sensitivity. \nBut also, these hypotheses should be the subject of \nfuture studies. \nUp to now, it seems that generalized hyperalgesia \nis present in response to pressure and electrical stimuli \nand bottom-up nociceptive mechanisms are overactive, \ngiven the enhanced reflex responses and temporal \nsummation. Also, brain function and brain activation \nchanges are revealed in CPP patients, but the direction \nand the localization deserves further attention. \nOn the other hand, evidence for impaired top-\ndown mechanisms (pain inhibition or pain facilitation) \nis inconclusive. 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