{"paper_id":"09d0f676-9e9d-4ece-83b9-200ca01058b1","body_text":"NEUROSCIENCE AND PSYCHOPHYSIOLOGY\nCite as: Archiv EuroMedica. 2025. 15; 5. DOI 10.35630/2025/15/Iss.5.511\nReceived 30 August 2025;\nAccepted 16 October 2025;\nPublished 23 October 2025\nCENTRAL SENSITIZATION SYNDROME IN PATIENTS WITH PELVIC\nORGAN PROLAPSE - MECHANISMS, DIAGNOSTICS, AND\nTHERAPEUTIC APPROACHES\nMagdalena Barbara Kukulska 1 \n , Piotr Kukulski 2\n ,\nKarolina Kęder 3 \n , Dominika Grzelak 4 \n ,\nMichalina Kosowska 5 \n , Aleksandra Sobieska 6 \n ,\nMarlena Radzka 7 \n , Jacek Krzysztof Szymański 2 \n1Department of Internal Medicine and Gerontocardiology, Independent Public Clinical Hospital\nnamed after Prof. W. Orłowski, Centre of Postgraduate Medical Education (CMKP), Warsaw,\nPoland\n2Żelazna Medical Centre, St. Zofia Specialist Hospital - Obstetrics and Gynecology Hospital,\nWarsaw, Poland\n3Department of Internal Medicine, Praski Hospital of the Transfiguration of the Lord, Warsaw,\nPoland\n4Department of Biochemistry and Pharmacogenomics, Medical University of Warsaw, Poland\n5Military Institute of Medicine - National Research Institute, Warsaw, Poland\n6Department of Diabetology and Internal Medicine, University Clinical Centre of the Medical\nUniversity of Warsaw, Poland\n7Medical University of Łódź, Poland\ndownload article (pdf)\nkukulskam@gmail.com\nABSTRACT\nBackground: Central Sensitization Syndrome (CSS) is increasingly recognized as a critical contributor to\nchronic pelvic pain in women with pelvic organ prolapse (POP). The coexistence of mechanical dysfunction and\naltered central pain modulation complicates diagnosis and management, requiring a multidimensional approach\nthat integrates neurobiological, hormonal, and psychosocial perspectives.\nObjective: To analyze the mechanisms of central sensitization in women with pelvic organ prolapse, review\ncurrent diagnostic methods, and evaluate therapeutic strategies based on recent scientific evidence.\nMethods: A narrative evidence-based review was conducted using PubMed, Scopus, and Web of Science\ndatabases for publications from 2015 to 2024. Studies addressing the mechanisms, diagnosis, and treatment of\ncentral sensitization in pelvic organ prolapse or related chronic pelvic pain syndromes were included. Data were\nsynthesized qualitatively with critical appraisal of methodological rigor and clinical relevance.\nResults: The  literature  confirms  that  chronic  pain  in  women  with  POP  often  results  from  maladaptive\nneuroplasticity and central hypersensitivity rather than from anatomical defects alone. Estrogen deficiency,\nneuroinflammation, and prolonged nociceptive stimulation act synergistically to maintain central excitability.\narchiv euromedica  2025 | vol. 15 | num. 5 |\n1 von 14\n\nEffective diagnostics require a combination of clinical evaluation, validated questionnaires, quantitative sensory\ntesting, and neuroimaging. Treatment should follow a biopsychosocial model that integrates pharmacotherapy\n(gabapentinoids, SNRIs, anti-inflammatory agents), physiotherapy, and psychological interventions such as\ncognitive-behavioral therapy. Noninvasive neuromodulation and molecular therapies targeting NMDA and TRPV1\nreceptors show emerging promise.\nConclusions: Central sensitization represents a pivotal but underdiagnosed mechanism in the pathophysiology\nof pelvic organ prolapse–related pain. Early identification of CSS features and implementation of individualized\nmultimodal therapy improve pain control, functional outcomes, and quality of life. Multidisciplinary collaboration\nremains essential for optimizing diagnosis and treatment in this complex patient population.\nKeywords: central  sensitization  syndrome,  pelvic  organ  prolapse,  chronic  pelvic  pain,  diagnostics,\nphysiotherapy, cognitive-behavioral therapy, multimodal treatment.\nINTRODUCTION\nPelvic organ prolapse (POP) is one of the most common forms of pelvic floor dysfunction in women, particularly\nin the postmenopausal period, and is associated with a marked decline in quality of life due to pain, discomfort,\nand functional impairment. Epidemiological data indicate that the prevalence of symptomatic POP reaches 30–\n50% among women over 70 years of age [1, 2]. Recent findings suggest that, in a subset of patients, pain\nsymptoms cannot be explained solely by mechanical factors but are linked to impaired central pain modulation\nand the development of central sensitization[3, 4].\nCentral Sensitization Syndrome (CSS) is a pathological condition characterized by increased excitability of\ncentral nociceptive pathways, leading to chronic pain perception even in the absence of peripheral tissue injury\n[4, 5]. This mechanism plays a crucial role in the formation of chronic pelvic pain, including that associated\nwith POP. Studies have shown that women with POP more frequently exhibit hyperalgesia, allodynia, and\ngeneralized sensory hypersensitivity, indicating the involvement of central neuronal processes [6-8].\nUnderstanding the role of CSS in the pathogenesis of POP has significant clinical importance, as central\nsensitization  modifies  the  therapeutic  response  and  influences  the  effectiveness  of  both  surgical  and\nconservative  interventions.  The  integration  of  neurobiological,  hormonal,  and  psychosocial  factors  into\ndiagnostic and therapeutic strategies brings clinical practice closer to a personalized approach for this patient\ngroup [9-11].\nDespite the growing body of research on chronic pelvic pain, the influence of central sensitization in pelvic\norgan prolapse remains insufficiently studied. The present review aims to systematize the current knowledge\nand identify future research directions.\nThe objective of this study is to analyze current evidence on the mechanisms, diagnostic methods, and\ntherapeutic possibilities of Central Sensitization Syndrome in women with Pelvic Organ Prolapse.\nThe following research questions are addressed:\n1. What neurobiological and hormonal mechanisms underlie the development of central sensitization in\nwomen with pelvic organ prolapse?\n2. Which diagnostic methods most accurately identify signs of CSS in this patient group?\n3. Which therapeutic approaches, including physiotherapy, pharmacological, and psychosocial interventions,\ndemonstrate proven effectiveness in managing POP associated with CSS?\n4. What  research  directions  appear  most  promising  for  further  exploration  of  the  role  of  central\nsensitization in the pathogenesis of pelvic organ prolapse?\nThus, this review seeks to elucidate the clinical and pathophysiological relationship between POP and CSS,\nassess  the  current  state  of  evidence,  and  formulate  recommendations  for  optimizing  diagnostic  and\nmanagement strategies based on up-to-date scientific data [1-11].\nMETHODS\nDESIGN AND AIM\nThis work was conducted as a narrative evidence-based review. Its objective was to synthesize current data on\nthe  mechanisms  of  central  sensitization  in  women  with  pelvic  organ  prolapse,  to  analyze  diagnostic\napproaches, and to summarize existing therapeutic strategies. No meta-analysis was performed, and the\nstructure follows the standards for narrative biomedical reviews.\narchiv euromedica  2025 | vol. 15 | num. 5 |\n2 von 14\n\nSources and Search Strategy\nThe literature search was performed in PubMed, Scopus, and Web of Science databases for the period from\n2015 to 2024. The following keywords and their combinations were used: central sensitization, pelvic organ\nprolapse, chronic pelvic pain, diagnostics, treatment, physiotherapy. Boolean operators AND and OR were\napplied. Only peer-reviewed articles in English were included.\nInclusion Criteria\nStudies addressing the mechanisms, diagnosis, or treatment of central sensitization in pelvic organ prolapse or\nother chronic pelvic pain syndromes were included. Narrative and systematic reviews, randomized controlled\ntrials,  observational,  and  prospective  studies  with  clearly  described  design  and  inclusion  criteria  were\nconsidered eligible.\nExclusion Criteria\nExperimental animal studies, non-peer-reviewed materials, publications prior to 2015, short communications,\nand conference abstracts were excluded.\nSelection and Data Extraction\nAll records were screened manually. Titles and abstracts were first reviewed for relevance, followed by full-text\nevaluation.  The  extracted  information  included  study  design,  sample  size  and  characteristics,  diagnostic\ncriteria, investigated mechanisms of central sensitization, main results, and clinical conclusions. Data synthesis\nwas qualitative rather than quantitative.\nSynthesis and Quality Assessment\nThe findings were integrated with a critical appraisal of the reliability and applicability of evidence. Formal risk-\nof-bias assessment was not conducted due to the heterogeneity of available data. The level of evidence was\nevaluated experientially, considering clinical relevance and methodological transparency.\nSelected Literature\nA total of 41 publications met the inclusion criteria. The final selection comprised recent clinical guidelines,\nsystematic and critical reviews, randomized controlled trials, and observational studies. Most sources were\npublished between 2015 and 2024, with a few earlier works included because of their high scientific value.\nSeveral incomplete bibliographic entries were identified and require clarification.\nGeneral Limitations\nThe main limitation of the review is the heterogeneity of methods used to assess pain and central sensitization,\nas well as differences in study populations. Despite this, the analyzed material reflects the current state of\nknowledge on central sensitization in pelvic organ prolapse and provides a comprehensive understanding of this\nclinical phenomenon.\nRESULTS\nMECHANISMS OF CENTRAL SENSITIZATION IN PELVIC ORGAN PROLAPSE\nPelvic organ prolapse (POP) is a common condition, particularly among women who have undergone vaginal\ndeliveries, those with obesity, and postmenopausal women. It is characterized by the descent or prolapse of\npelvic organs, leading to mechanical, urological, gastrointestinal, and sexual symptoms. Increasing evidence\nsuggests that, in a subset of patients with POP, pain symptoms may originate not only from peripheral\nmechanisms but also from central processes associated with central sensitization [12-14].\nStudies have demonstrated that women with POP more frequently exhibit symptoms characteristic of central\nsensitization,  such  as  tactile  hypersensitivity,  chronic  muscular  tension,  and  sexual  dysfunction.  This\nphenomenon may be exacerbated by chronic mechanical strain, as well as by hormonal disturbances that\nimpair the function of pelvic muscles and connective tissue [3, 11].\nBased on a meta-analysis in Chinese women, the estimated prevalence of symptomatic POP increased from\n≈ 4.8% in women aged 20-29 to ≈ 28.2% in women aged ≥ 70 [1]. An Italian cross-sectional study reported\n9.7% prevalence in women aged 20-39 and 49.7% in women over 80 [2]. Based on these representative data,\nthe values used in Tables 1. These estimates reflect observed trends demonstrating an approximate sixfold\nincrease in prevalence from early adulthood to late postmenopausal age.\narchiv euromedica  2025 | vol. 15 | num. 5 |\n3 von 14\n\nThese disorders are classified according to the anatomical compartment involved in the prolapse. The following\ntypes are distinguished: (1) cystocele - descent of the anterior vaginal wall and urinary bladder; (2) rectocele -\ndescent of the posterior vaginal wall and rectum; (3) enterocele - herniation involving the small intestine; and\n(4) uterine or cervical prolapse, or, in women after hysterectomy, vaginal vault prolaps [15, 16].\nThe severity of prolapse is assessed using the Pelvic Organ Prolapse Quantification (POP-Q) system, which\nevaluates the extent of organ descent relative to the hymenal ring [3].\nTREATMENT OF POP\nThe therapeutic approach to pelvic organ prolapse depends on the stage of prolapse and the severity of\nsymptoms. In stages I-II according to the POP-Q scale, for patients with mild symptoms or for the prevention\nof progression, conservative management is recommended. This includes pelvic floor muscle rehabilitation\n(Kegel exercises, biofeedback), the use of pessaries, and lifestyle modifications such as weight reduction and\navoidance of heavy lifting [3].\nIn  stages  III-IV,  when  symptoms  are  severe  and  conservative  treatment  proves  ineffective,  surgical\nintervention is indicated. Surgical options include anterior and posterior colporrhaphy, sacrocolpopexy, and\nuterine or vaginal vault suspension using synthetic or autologous mesh materials [17]. The choice of surgical\ntechnique depends on the patient’s age, sexual activity, comorbidities, and individual preferences.\nPREVENTION OF POP\nPrevention of pelvic organ prolapse is based on the modification of risk factors and the strengthening of pelvic\nfloor  support  structures.  Patient  education  regarding  pelvic  floor  muscle  exercises  (Kegel  training)  is  of\nfundamental importance and should begin during pregnancy and the postpartum period. Weight reduction,\nprevention of chronic constipation, proper lifting techniques, and treatment of chronic cough also play a\nsignificant role in reducing the risk of POP[18].\nIn women with identified risk factors, early use of pessaries may be considered to reduce the mechanical load\non pelvic floor structures [17]. As in treatment, the choice of preventive strategy should take into account the\npatient's age, sexual activity, comorbidities, and individual preferences.\nPelvic organ prolapse (POP) is frequently associated with symptoms of central sensitization syndrome (CSS),\ncontributing  to  chronic  pain  complaints.  Central  sensitization  syndrome  is  defined  as  a  pathological\nhypersensitivity of the central nervous system, resulting from persistent alterations in its ability to modulate\nsensory input, which leads to an exaggerated perception of pain, even in response to physiologically non-\nnoxious  stimuli  [2,  4].  This  phenomenon  manifests  as  hyperalgesia,  allodynia,  and  generalized  somatic\nhypersensitivity [6].\nThese symptoms are often widespread and may significantly impair quality of life. Affected patients report pain\nin multiple body regions, disproportionate to any localized anatomical abnormalities, indicating the involvement\nof  central  mechanisms.  A  hallmark  feature  is  the  temporal  variability  in  symptom  intensity,  along  with\nhypersensitivity to emotional stimuli, fatigue, and the co-occurrence of other central sensitivity syndromes such\nas irritable bowel syndrome and fibromyalgia [4, 6, 8]. These manifestations are characteristic of disorders with\na central component and point to neuronal reorganization within the central nervous system [2, 7].\nMUSCLE DYSFUNCTION AND PELVIC FLOOR WEAKNESS\nChronic overload and sustained tension of the pelvic floor muscles, which are characteristic of pelvic organ\nprolapse, result in persistent activation of nociceptors. This condition can lead to prolonged stimulation of pain\npathways and progression toward central sensitization. Moreover, chronic muscular tension and compensatory\nmovement patterns may contribute to alterations in muscle coordination, reduced pelvic mobility, and pain\narising from soft tissue overload [19].\nStudies indicate that imbalance between the activity of superficial and deep pelvic floor muscles results in\nimpaired stabilization, which exacerbates pain symptoms and reinforces central sensitization mechanisms [1].\nCENTRAL NERVOUS SYSTEM PLASTICITY\nPlastic changes within central nervous system synapses, including enhanced activation of NMDA receptors and\nlong-term  potentiation  (LTP),  result  in  increased  nociceptive  transmission  and  a  lowered  pain  threshold.\nReorganization of neuronal connections may lead to the persistence of maladaptive pain patterns and difficulty\nin their modulation [20].\nNeuroimaging studies have demonstrated heightened activation of brain regions involved in pain processing,\narchiv euromedica  2025 | vol. 15 | num. 5 |\n4 von 14\n\nincluding the thalamus, insular cortex, and anterior cingulate gyrus, confirming the presence of neuroplastic\nalterations in the course of CSS[2]. These changes contribute to the intensification of symptoms such as\nhyperalgesia and allodynia.\nINFLUENCE OF SEX HORMONES\nIn  postmenopausal  women,  the  decline  in  estrogen  levels  may  reduce  the  efficacy  of  endogenous  pain\ninhibitory mechanisms. Estrogens play a crucial role in modulating nervous system function by influencing the\nactivity of GABAergic, NMDA, and serotonergic receptors. Their deficiency can lead to diminished pain inhibition\nand heightened nociceptive sensitivity [21].\nFurthermore, hormonal fluctuations affect the hypothalamic-pituitary-adrenal axis and lower the pain tolerance\nthreshold, rendering perimenopausal women more susceptible to the development of CSS symptoms [3].\nHormonal imbalances enhance vulnerability to CSS through their impact on neurotransmitter systems and\ncentral antinociceptive pathways.\nMECHANISMS OF CENTRAL SENSITIZATION\nCentral sensitization syndrome (CSS) denotes a persistent increase in the excitability of central nociceptive\npathways. In chronic pain states, maladaptive synaptic plasticity and neuroinflammation lead to sustained\nneuronal hyper responsiveness and exaggerated pain perception. Activated microglia and astrocytes release\npro inflammatory cytokines and chemokines, acting as potent neuromodulators that drive hyperalgesia and\nallodynia. The interplay of neurotrophic factors, purinergic receptors, persistent glutamatergic transmission and\nlong term potentiation underpins the resilience of the pain network and highlights the need for therapies that\ntarget both neuronal and glial mechanisms [22].\nDIAGNOSTICS\nThe diagnosis of central sensitization syndrome (CSS) in patients with pelvic organ prolapse (POP) requires a\nmultidisciplinary approach encompassing clinical assessment, screening questionnaires, sensory testing, and\nneuroimaging techniques [6, 9, 10, 23]. In clinical practice, the most widely used tools include the Central\nSensitization Inventory (CSI), which allows preliminary evaluation of CSS-related symptoms; quantitative\nsensory testing (QST), which measures pain thresholds in response to various stimuli (mechanical, thermal);\nand  functional  brain  imaging  modalities  such  as  functional  magnetic  resonance  imaging  (fMRI)  and\nsomatosensory evoked potentials (SEPs), both of which provide insights into altered pain processing within the\ncentral nervous system [24].\nSEPs are an electrodiagnostic method that records electrical responses in the brain following peripheral nerve\nstimulation. In patients with suspected CSS, SEP testing often reveals altered somatosensory cortical activation\npatterns,  delayed  latencies,  and  reduced  signal  amplitudes,  indicating  central  abnormalities  in  sensory\nprocessing.  This  method  may  be  particularly  valuable  for  differentiating  central  versus  peripheral  pain\nmechanisms and for evaluating the effectiveness of neuromodulatory therapies [9].\nfMRI enables visualization of brain activity changes by detecting alterations in cerebral blood flow in response\nto nociceptive stimuli, thereby identifying and analyzing structures involved in pain processing. In patients with\nCSS, increased activation of the thalamus, insular cortex, and anterior cingulate gyrus has been observed,\nconfirming the presence of neuroplastic changes within the nervous system and serving as a useful adjunct in\ndistinguishing CSS from other forms of chronic pain [9].\nAdditionally, psychosocial assessment tools—such as the Pain Catastrophizing Scale (PCS), the Hospital Anxiety\nand Depression Scale (HADS), and other validated questionnaires—play a crucial role in identifying central\ncomponents of chronic pain. Stress, anxiety, and maladaptive pain beliefs can amplify central sensitization\nprocesses. Incorporating psychosocial evaluation with clinical and neurophysiological assessments enhances\ndiagnostic accuracy and facilitates a more individualized therapeutic approach [10, 11, 25].\nQuantitative Sensory Testing (QST) involves the controlled application of mechanical, thermal, or chemical\nstimuli to determine sensory and pain thresholds. Patient responses are analyzed and compared to population\nnorms [6]. To assess hyperalgesia, methods such as the Pressure Pain Threshold (PPT) and Thermal Pain\nThreshold (TPT) tests are commonly used.\nThe PPT test entails gradually increasing pressure with an algometer until the participant reports the first\nsensation of pain; lower threshold values indicate pain hypersensitivity. The TPT test measures the pain\nthreshold  triggered  by  controlled  thermal  stimuli  (cold  or  heat)  applied  via  specialized  probes.  Reduced\nthresholds in these tests suggest the presence of hyperalgesia and support the identification of a central\ncomponent in the pain mechanism [6, 7, 9].\narchiv euromedica  2025 | vol. 15 | num. 5 |\n5 von 14\n\nAllodynia assessment is performed using light brushing of the skin (brush allodynia) or calibrated monofilament\ntesting (von Frey filaments). Brush allodynia involves gently stroking the skin with a soft brush or gauze and\nassessing the pain response to this normally non-noxious tactile stimulus. In von Frey testing, calibrated\nfilaments of varying diameters and force are applied to identify abnormal pain responses to light pressure. In\npatients  with  CSS,  even  minimal  stimuli  may  elicit  discomfort  or  pain,  indicative  of  central  sensory\nhypersensitivity. These tests are particularly valuable for differentiating mechanical allodynia and monitoring\ntherapeutic progress [7, 9].\nIn  patients  with  POP  and  concomitant  chronic  pain,  quantitative  sensory  testing  (QST)  facilitates  the\ndifferentiation  between  peripheral  and  central  pain  components,  identification  of  pain  hypersensitivity\nmechanisms (e.g., generalized hyperalgesia), and monitoring of the effectiveness of non-pharmacological\ninterventions such as physiotherapy [9, 10].\nAdditionally,  during  transvaginal  examinations,  women  with  POP  and  CSS  may  report  increased  pain  or\ndiscomfort, even in the absence of significant structural abnormalities. These symptoms are often nonspecific\nand may include burning sensations, pelvic pressure, pain radiating to the lumbosacral region, or dyspareunia.\nStudies have shown that palpatory sensitivity of the pelvic floor muscles (e.g., levator ani) is significantly\nhigher in patients  with a central pain component,  and that the examination itself  may exacerbate pain\nsymptoms by activating sensitized nociceptive pathways [26].\nConsequently, the interpretation of examination findings must consider the patient’s neurophysiological and\npsychological  context.  Communication  during  the  examination  should  be  empathetic  and  mindful  of  the\npotential impact of prior trauma or painful experiences [12, 27]. Such responses are consistent with the\nmechanism of central sensitization, wherein normally non-noxious stimuli are perceived as painful due to\nheightened excitability of the central nervous system [3, 27]. Psychological factors, such as anxiety and pain\nanticipation, may further amplify discomfort during the examination, complicating clinical assessment and\nunderscoring the necessity of integrating a biopsychosocial approach (Table 2) [28, 29].\nTHERAPEUTIC STRATEGIES\nThe  treatment  of  central  sensitization  requires  a  multimodal  approach  targeting  both  the  underlying\nmechanisms and the associated symptoms. Current therapeutic strategies encompass pharmacological, non-\npharmacological, and emerging interventions.\nPharmacological Therapies Centrally Acting Agents\nDrugs such as gabapentin, pregabalin, and serotonin-norepinephrine reuptake inhibitors (SNRIs) — including\nduloxetine  and  venlafaxine  —  are  commonly  employed  to  mitigate  central  sensitization  by  modulating\nneurotransmitter  release,  reducing  neuronal  hyperexcitability,  and  enhancing  endogenous  pain-inhibitory\nmechanisms. Their efficacy has been confirmed in studies involving patients with chronic pelvic pain and\nfibromyalgia, particularly in cases presenting with hyperalgesia and allodynia [4, 11, 30, 31].\nAnticonvulsants:  Agents  such  as  carbamazepine  and  lamotrigine,  although  less  frequently  used  in  the\nmanagement of CSS, possess the ability to suppress excessive neuronal activity and may be considered in\nrefractory cases [32, 33].\nCorticosteroids and Anti-Inflammatory Agents: These are primarily utilized in scenarios where concomitant\ninflammatory processes are suspected. Such agents exert their effects by attenuating glial cell activation and\ninhibiting the release of pro-inflammatory cytokines, which may exacerbate central sensitization [5, 34].\nNON-PHARMACOLOGICAL THERAPIES\nCognitive-Behavioral Therapy (CBT)\nCBT is a structured form of psychological therapy focused on identifying and modifying maladaptive thoughts\nand behaviors related to pain. It enhances patients’ coping abilities with chronic pain by reshaping pain-related\nbeliefs, reducing catastrophizing, and fostering adaptive strategies such as relaxation techniques and gradual\nphysical activity pacing.\nA standard CBT program typically consists of 8 to 16 weekly sessions delivered over approximately 10-12\nweeks. Depending on symptom severity and the presence of comorbid psychological disorders, therapy may be\nextended or supplemented with booster sessions. CBT also facilitates the recognition and modification of\nmaladaptive  cognitive  patterns,  supporting  adaptation  to  chronic  pain  [11,  35,  36].  Clinical  studies\ndemonstrate that CBT effectively reduces pain intensity, improves quality of life, and enhances psychological\nfunctioning in patients with CSS [11, 35].\narchiv euromedica  2025 | vol. 15 | num. 5 |\n6 von 14\n\nNeurostymulation Techniques\nTechniques such as transcranial magnetic stimulation (TMS), spinal cord stimulation (SCS), transcranial direct\ncurrent  stimulation  (tDCS),  and  transcutaneous  electrical  nerve  stimulation  (TENS)  have  demonstrated\npromising effects in managing chronic pain of central origin. TMS modulates cortical excitability and pain\nnetwork activity, particularly in the prefrontal cortex and cingulate gyrus. SCS acts at the spinal level by\ninhibiting  nociceptive  transmission  and  engaging  segmental  pain-inhibitory  mechanisms.  tDCS  modulates\ncortical activity, influencing nociceptive processing and enhancing outcomes when combined with CBT or\nrehabilitation. TENS is a readily applicable ambulatory technique that exerts analgesic effects through Aβ fiber\nactivation and increased endorphin release. These therapies are considered safe, and their effectiveness is\nenhanced with appropriate parameter selection and individualized treatment planning [27, 35-37].\nEXERCISE AND REHABILITATION\nRehabilitation plays a pivotal role in managing patients with CSS, particularly in the context of coexisting pelvic\norgan prolapse. Therapeutic programs incorporate pelvic floor muscle training (PFMT), mindful movement\npractices, manual therapy (soft tissue mobilization, trigger point therapy), breathing techniques (diaphragmatic\ntraining, breathing biofeedback), and functional exercise integration [38].\nPelvic floor exercises improve muscle strength, endurance, and coordination while supporting neuromodulatory\nprocesses within the central nervous system. They also significantly reduce symptoms of POP, especially in\nearly stages. Regular activation and strengthening of the pelvic floor muscles can prevent further organ\ndescent, enhance pelvic stability, and improve quality of life by alleviating sensations of pelvic pressure, vaginal\nfullness, or urinary incontinence. Supervised training facilitates functional adaptation and optimizes lower trunk\nbiomechanics [5, 23, 39].\nConsistent PFMT activates type I and type II muscle fibers responsible for pelvic support and continence\ncontrol.  Additionally,  it  improves  proprioception,  thereby  enhancing  functional  control  and  reducing  pain\nepisodes. Both isometric and dynamic exercises are recommended, often supplemented with biofeedback or\nelectrical stimulation to optimize muscle recruitment and improve patient adherence [39].\nMindful movement practices aid relaxation and reduce neuromuscular tension, while manual therapy alleviates\npalpation-related  pain  and  improves  range  of  motion.  Breathing  techniques  reduce  autonomic  arousal,\nmitigating anxiety and stress levels [23, 39]. Regular exercise enhances proprioceptive feedback, improves\nmuscle control, and reduces excessive tension, contributing to chronic pain reduction. Optimal outcomes are\nachieved with programs supervised by physiotherapists trained in chronic pain and pelvic floor dysfunction\nmanagement. Programs should last at least 8-12 weeks, with individually tailored techniques. Gradual exercise\nprogression combined with adjunctive physiotherapeutic modalities improves functional outcomes and reduces\npain severity in patients with central sensitization [11, 23].\nINNOVATIVE THERAPEUTIC STRATEGIES\nTargeted Molecular Therapies\nContemporary pharmacological approaches focus on selectively modulating molecular mediators responsible for\nthe development and maintenance of central sensitization. These include inhibitors of the system xc−, NMDA\nreceptor  antagonists,  TRPV1  and  P2X3  receptor  blockers,  as  well  as  Nav1.7  sodium  channel  inhibitors.\nAdditionally, research on neurokinin-1 receptor antagonists, IL-1β and TNF-α cytokine inhibitors, monoclonal\nantibodies, and nanotechnology-based drug delivery systems targeting central nervous system structures aims\nto enhance therapeutic selectivity and minimize adverse effects [5, 9, 37].\nNon-Invasive Modulation of Brain Plasticity\nTechniques such as virtual reality (VR) and cognitive training show potential in reducing pain hypersensitivity\nby influencing neuroplasticity and pain-processing networks. VR enables multisensory patient engagement and\ndistraction  from  pain,  whereas  cognitive  training  strengthens  cognitive  control  over  pain  responses  and\nsupports executive and emotional functioning. Both methods can serve as adjuncts to conventional therapies,\nparticularly in patients with a pronounced central component and coexisting affective disorders (Table 3-4) [27,\n37].\nClinical Implications and Future Directions\nCentral  sensitization  is  a  common  mechanism  underlying  various  chronic  pain  conditions,  including\nfibromyalgia, chronic low back pain, and neuropathic pain. Despite significant advances in understanding its\npathophysiology, the development of targeted therapies remains challenging. Future research should focus on\narchiv euromedica  2025 | vol. 15 | num. 5 |\n7 von 14\n\nelucidating the molecular and functional mechanisms of central sensitization and exploring novel therapeutic\nstrategies aimed at improving patient outcomes [2, 4, 5].\nDISCUSSION\nCentral sensitization represents a key mechanism explaining persistent pain in women with pelvic organ\nprolapse. Current evidence confirms that, in some patients, the severity of symptoms does not correlate with\nthe  degree  of  anatomical  impairment,  indicating  the  involvement  of  central  neuronal  processes  in  the\ndevelopment of chronic pain [2, 4, 6].\nSeveral studies have demonstrated that POP is associated with neuroplastic changes, including increased\nexcitability of spinal and supraspinal structures, NMDA receptor hyperactivation, and microglial involvement, all\nof which maintain nociceptive transmission and result in sustained hyperalgesia [4, 5, 34]. Neuroimaging\nfindings show enhanced activation of the thalamus, insula, and cingulate cortex, confirming the reorganization\nof brain networks responsible for pain perception [2, 9].\nThe  mechanisms  underlying  central  sensitization  in  women  with  pelvic  organ  prolapse  are  complex  and\nmultifactorial. Table 1 summarizes the principal neurobiological, hormonal, inflammatory, and psychosocial\nfactors contributing to the development and maintenance of chronic pain in this population.\nTable 1. Main mechanisms of central sensitization in pelvic organ prolapse (POP)\nMechanism Key mediators and\nstructures Clinical manifestations Key\nreferences\nNeuronal\nNMDA receptors,\nAMPA receptors,\nmicroglia, astrocytes,\nthalamus, insular\ncortex, cingulate\ngyrus\nHyperalgesia, allodynia,\ngeneralized sensory\nhypersensitivity, variability\nof pain intensity\n[2, 4-7, 9,\n34]\nHormonal\nEstrogens, GABAergic,\nserotonergic, and\nglutamatergic\nsystems,\nhypothalamic–\npituitary–adrenal axis\nIncreased pain perception\nin postmenopausal women,\ndecreased pain threshold,\nimpaired endogenous pain\ncontrol\n[3, 11]\nInflammatory\nIL-1β, TNF-α, IL-6,\nchemokines, xc–\nsystem, activation of\nglia and microglia\nChronic pain, maintenance\nof neuronal\nhyperexcitability, enhanced\nneuroinflammation,\npersistent nociceptive\ntransmission\n[5, 9, 34,\n37]\nPsychosocial\nStress-response axis\ndysfunction, pain\ncatastrophizing,\nanxiety, depression,\nsleep disturbance\nIncreased subjective pain\nintensity, fatigue,\nhyperreactivity to stress\nstimuli, amplification of\ncentral sensitization\n[10, 11, 35]\nHormonal alterations in postmenopausal women further aggravate this process. Estrogen deficiency reduces\nthe efficiency of endogenous antinociceptive systems and increases pain sensitivity by disrupting GABAergic,\nserotonergic, and NMDA receptor regulation. This mechanism explains the higher prevalence of CSS symptoms\namong older women with POP [40].\nPeripheral factors also play a significant role. Chronic overload and functional weakness of the pelvic floor\nmuscles lead to continuous afferent stimulation and create a feedback loop between peripheral and central pain\nmechanisms  [1,  11].  Loss  of  coordination  between  deep  and  superficial  muscle  layers  results  in  pelvic\ninstability and activation of sensitized nociceptors.\nAccurate diagnosis of central sensitization in patients with pelvic organ prolapse requires combining subjective\nand objective tools that assess both physiological and psychological dimensions of pain processing. Table 2\narchiv euromedica  2025 | vol. 15 | num. 5 |\n8 von 14\n\nsummarizes the most commonly used diagnostic methods and their clinical applicability.\nTable 2. Diagnostic methods for identifying central sensitization in patients with pelvic organ\nprolapse (POP)\nDiagnostic\nmethod / tool\nPurpose of\napplication\nMain\nparameters /\ninterpretation\ncriteria\nAdvantages and\nlimitations\nKey\nreferences\nCentral\nSensitization\nInventory\n(CSI)\nScreening and\nquantification\nof central\nsensitization\nsymptoms\nTotal score ≥ 40\nsuggests\nclinically\nrelevant central\nsensitization\nEasy to use;\nreflects subjective\nsymptom severity;\ndoes not\ndifferentiate\nbetween central\nand peripheral\nmechanisms\n[6-8, 23]\nQuantitative\nSensory\nTesting (QST)\nObjective\nassessment of\npain thresholds\nand sensory\nhypersensitivity\nMeasures\npressure,\nthermal, and\nvibration\nthresholds;\ndetects allodynia\nand hyperalgesia\nProvides\nphysiological data;\nsensitive to central\nchanges; requires\nspecialized\nequipment and\ntrained personnel\n[6, 9, 23]\nFunctional\nMagnetic\nResonance\nImaging (fMRI)\nVisualization of\nbrain activity\nand pain-\nrelated cortical\nreorganization\nIncreased\nactivation of\nthalamus,\ninsula, anterior\ncingulate cortex\nDemonstrates\nneural correlates of\ncentral\nsensitization;\nlimited availability,\nhigh cost\n[2, 9, 34,\n37]\nSomatosensory\nEvoked\nPotentials\n(SEP)\nAssessment of\ncentral\nconduction and\ncortical\nresponse to\nnociceptive\ninput\nProlonged\nlatency or\nincreased\namplitude of\ncortical\npotentials\nObjective\nelectrophysiological\nmarker of central\nhyperexcitability;\ninterpretation\nrequires expertise\n[5, 7, 30]\nPain\nCatastrophizing\nScale (PCS)\nEvaluation of\ncognitive–\nemotional pain\nmodulation and\nmaladaptive\nbeliefs\nHigh scores\nreflect\ncatastrophization\nand enhanced\npain perception\nQuick to\nadminister;\ncorrelates with\npain intensity and\npsychological\ndistress; subjective\n[10, 11]\nHospital\nAnxiety and\nDepression\nScale (HADS)\nScreening for\ncomorbid\nanxiety and\ndepression\ninfluencing\npain perception\nScores ≥ 8 in\neither subscale\nindicate\nemotional\ncomorbidity\nIdentifies\npsychosocial\namplifiers of\ncentral\nsensitization;\nlimited to self-\nreport\n[10, 35]\nFrom  a  diagnostic  perspective,  the  combination  of  clinical  assessment,  validated  questionnaires  (Central\nSensitization  Inventory,  Pain  Catastrophizing  Scale),  quantitative  sensory  testing,  and  neurophysiological\nmethods such as SEP and fMRI is of primary importance [6-9, 23]. These approaches help differentiate central\nfrom peripheral pain mechanisms and quantify the degree of sensitization. Psychological screening using HADS\nand PCS further refines diagnosis by identifying catastrophizing, anxiety, and depression, which amplify pain\nperception [10, 11].\narchiv euromedica  2025 | vol. 15 | num. 5 |\n9 von 14\n\nEffective management of women with pelvic organ prolapse and central sensitization requires an integrative,\nmultimodal strategy. Table 3 presents the main therapeutic approaches, mechanisms of action, and current\nlevels of evidence supporting their clinical use.\nTable 3. Therapeutic approaches for pelvic organ prolapse (POP) associated with central\nsensitization syndrome (CSS)\nTherapeutic\napproach\nExample of\nintervention\n/ agent\nMechanism of\naction\nEffectiveness\nand level of\nevidence\nMain\nlimitations\nKey\nreferences\nPharmacological\ntherapy –\nneuromodulators\nGabapentin,\nPregabalin,\nDuloxetine\nReduction of\nneuronal\nhyperexcitability,\nmodulation of\nserotonin–\nnorepinephrine\npathways\nModerate-to-\nhigh evidence\nfor pain\nreduction and\nimproved\nfunction\nSedation,\ndizziness,\nlimited long-\nterm data\n[4, 11, 30,\n31]\nAnti-\ninflammatory\nand glial\nmodulators\nNonsteroidal\nanti-\ninflammatory\ndrugs\n(NSAIDs),\nminocycline\nDecrease of\nmicroglial\nactivation and\ncytokine-mediated\nneuroinflammation\nModerate\nevidence;\nbeneficial in\ncases with\ninflammatory\ncomponent\nGastrointestinal\nside effects,\nincomplete\npain control\n[5, 9, 34,\n41]\nPhysiotherapy\nand pelvic floor\nrehabilitation\nPelvic floor\nmuscle\ntraining,\nmanual\ntherapy,\nbreathing\nexercises\nRestoration of\npelvic stability,\nreduction of\nafferent\nnociceptive input,\nmodulation of\ncentral pain\nprocessing\nHigh evidence\nfor improved\nmuscle\nfunction and\npain relief\nRequires\npatient\nadherence,\nvariable\nstandardization\n[11, 23,\n35, 39]\nCognitive-\nbehavioral\ntherapy (CBT)\nIndividual or\ngroup sessions\ntargeting\nmaladaptive\nbeliefs and\ncatastrophizing\nModification of\npain perception\nand coping\nmechanisms via\ncognitive\nrestructuring\nHigh evidence\nfor reduced\ncatastrophizing\nand improved\nquality of life\nRequires\npsychological\nsupport\navailability,\nsubjective\nengagement\n[11, 35,\n36]\nNeuromodulation\ntechniques\nTranscranial\nmagnetic\nstimulation\n(TMS),\ntranscranial\ndirect current\nstimulation\n(tDCS),\ntranscutaneous\nelectrical nerve\nstimulation\n(TENS)\nNoninvasive\nmodulation of\ncortical excitability\nand pain networks\nGrowing\nevidence;\npromising\nresults in\nchronic pain\nsyndromes\nLimited\naccessibility,\nneed for\nspecialized\nequipment\n[27, 35,\n37]\nThe management of patients with POP and CSS must be multidisciplinary. Pharmacotherapy with central\nneuromodulators such as gabapentin, pregabalin, and duloxetine has shown efficacy in reducing hyperalgesia\nand allodynia [4, 30, 31]. In refractory cases, anticonvulsants and anti-inflammatory drugs targeting glial\nactivation may be beneficial [5, 34, 41].\nNonpharmacological  interventions,  particularly  cognitive-behavioral  therapy  (CBT)  and  specialized\nphysiotherapy, remain the cornerstone of long-term pain control. CBT reduces catastrophizing, improves quality\nof life, and restores adaptive coping strategies [11, 35, 36]. Physiotherapy programs that include pelvic floor\nmuscle training, manual therapy, and breathing exercises not only strengthen pelvic support but also modulate\narchiv euromedica  2025 | vol. 15 | num. 5 |\n10 von 14\n\ncentral pain processing [23, 39].\nPromising therapeutic directions include noninvasive neuromodulation techniques such as transcranial magnetic\nstimulation  (TMS),  transcranial  direct  current  stimulation  (tDCS),  and  transcutaneous  electrical  nerve\nstimulation  (TENS),  which  influence  pain-related  neuronal  networks  and  enhance  behavioral  treatment\noutcomes  [27,  35,  37].  Molecular  strategies  targeting  NMDA,  TRPV1,  and  P2X3  receptors,  as  well  as\nmonoclonal antibodies against IL-1β and TNF-α, are under investigation [5, 9, 37]. These developments open\nperspectives for pathogenetically oriented treatment.\nOverall,  the  available  evidence  supports  that  successful  management  of  women  with  POP  and  central\nsensitization requires the integration of biological, psychological, and social components. Early identification of\nCSS features and individualized therapy reduce pain severity, improve functional outcomes, and enhance\nquality of life [2, 3, 6, 8, 10, 11, 23, 39].\nCONCLUSIONS\nCentral Sensitization Syndrome is an important yet frequently underrecognized factor contributing to chronic\npelvic pain in women with pelvic organ prolapse. The analysis of available literature demonstrates that pain in\nthese patients often results not only from mechanical dysfunction and structural displacement but also from\naltered central pain modulation and maladaptive neuroplasticity.\nThe  review  confirms  that  hormonal  changes,  neuroinflammatory  processes,  and  prolonged  peripheral\nstimulation  act  synergistically  to  sustain  nociceptive  hypersensitivity  and  reinforce  central  sensitization\nmechanisms. Functional reorganization of pain-processing brain regions, including the thalamus, insula, and\nanterior cingulate cortex, underlies persistent hyperalgesia and allodynia, which remain disproportionate to the\ndegree of anatomical changes.\nAccurate  diagnosis  requires  a  multidisciplinary  assessment  combining  clinical  evaluation,  validated\nquestionnaires,  quantitative  sensory  testing,  and  neuroimaging  techniques.  Psychological  assessment  is\nessential to identify catastrophizing, anxiety, and depressive symptoms that amplify central pain processing.\nTherapeutic  management  should  follow  a  biopsychosocial  model.  Pharmacological  interventions  such  as\ngabapentinoids, serotonin–norepinephrine reuptake inhibitors, and anti-inflammatory agents provide symptom\nrelief  but  are  most  effective  when  combined  with  physiotherapy  and  psychological  therapy.  Cognitive-\nbehavioral therapy reduces maladaptive cognitive patterns and improves coping strategies, while specialized\npelvic floor rehabilitation enhances neuromuscular control and modulates central pain pathways.\nEmerging modalities such as noninvasive brain stimulation and molecular therapies targeting NMDA, TRPV1,\nand cytokine-mediated mechanisms represent promising adjuncts for the future.\nEarly  identification  of  central  sensitization  features  in  women  with  pelvic  organ  prolapse  and  the\nimplementation of individualized multimodal treatment substantially improve pain control, functional outcomes,\nand overall quality of life. The integration of biological, psychological, and rehabilitative interventions remains\nthe cornerstone of effective and sustainable management in this patient population.\nDISCLOSURE\nAUTHORS’ CONTRIBUTIONS\nConceptualization: Magdalena Barbara Kukulska, Piotr Kukulski\nMethodology: Magdalena Barbara Kukulska, Piotr Kukulski\nInvestigation: Karolina Kęder, Michalina Kosowska, Aleksandra Sobieska, Marlena Radzka\nData curation: Karolina Kęder, Michalina Kosowska, Aleksandra Sobieska, Marlena Radzka\nFormal analysis: Dominika Grzelak\nWriting – original draft: Magdalena Barbara Kukulska, Piotr Kukulski\nWriting – review & editing: Magdalena Barbara Kukulska, Piotr Kukulski\nSupervision: Piotr Kukulski, Jacek Krzysztof Szymański\nUSE OF AI\nArtificial intelligence (AI) tools were used to assist in literature searches and identification of peer-reviewed\narchiv euromedica  2025 | vol. 15 | num. 5 |\n11 von 14\n\nscientific articles relevant to this work.\nCONFLICT OF INTEREST\nThe authors declare no potential conflicts of interest regarding the publication of this paper.\nFUNDING\nNo external funding was received for this study.\nREFERENCES\n1. 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