Central sensitization in patients with chronic pelvic pain resistant to hormonal therapy: A cross-sectional study of prevalence and clinical correlates in a tertiary referral cohort

Introduction Chronic pelvic pain (CPP) affects over 25% of women, with endometriosis being a predominant cause. Central sensitization, particularly pelvic and perineal pain central sensitization (PPCS), is increasingly recognized as a key mechanism in CPP, yet its prevalence and clinical implications across the broader CPP population are underexplored.

The aim was to determine the prevalence of PPCS among patients with CPP unresponsive to hormonal therapy and to assess its impact on symptomatology, analgesic consumption, and quality of life. This retrospective study included 270 consecutive patients presenting for the first time with CPP resistant to hormonal therapy, with or without endometriosis, at a tertiary referral center in France (2024–2025). PPCS was defined using the Convergences PP criteria (score ≥5), and neuropathic-like features using the DN4 score (≥4). Data collected included pain features, comorbid symptoms, quality of life (EHP-5), history of violence, and prior treatments. Multivariable logistic and linear regression analyses were conducted to assess associations with analgesic use and EHP-5 scores.

PPCS was present in 54.4% of patients and associated with more severe, multisystem symptoms, including urinary, gastrointestinal, and sexual dysfunction. Patients with PPCS had significantly higher use of strong analgesics (adjusted OR 2.48, 95% CI: 1.05–5.83, p = 0.038) and markedly impaired quality of life (+5.19 EHP-5 points, p < 0.001). A history of gender-based violence, reported by 25.9% of patients, was independently associated with higher analgesic consumption (aOR 2.56, p = 0.028) and was more prevalent among those with PPCS. Neuropathic-like features were associated with lower quality of life but not with increased analgesic use.

These findings support routine screening for central sensitization and trauma history in gynecological practice and advocate for multidisciplinary, trauma-informed, and neuromodulation-focused approaches to CPP management. Abbreviations | | | |---|---| | | | | | | | | | Key message Over half of patients with chronic pelvic pain showed signs of central sensitization, linked to greater symptom severity and analgesic use. Gender-based violence emerged as a key factor, underscoring the need for trauma-informed, multidisciplinary care in gynecology. 1 INTRODUCTION Chronic pelvic pain (CPP) affects more than one in four women, with endometriosis being the leading cause, affecting an estimated 10% of women of reproductive age.1-3 The presentation and progression of the disease vary widely, contributing to a diagnostic delay estimated at approximately 7 years.4 Although certain forms of endometriosis (such as deep infiltrating or ovarian involvement) are readily detectable through imaging, nearly 50% of cases are limited to superficial lesions which remain undetectable without surgical exploration.5, 6 About 30%–50% of women experiencing cyclic chronic pelvic pain are believed to have endometriosis, and the prevalence of endometriosis in asymptomatic women is also substantial.5-7 Although the management of symptomatic patients is ideally multidisciplinary, it remains largely guided by the presumption of endometriosis, as the diagnosis should not routinely rely on surgery. Furthermore, even in confirmed cases of endometriosis, around 30% of patients reportedly experience no relief despite appropriate hormonal therapy.6 Therefore, a positive diagnosis of endometriosis does not reliably predict either the presence or severity of symptoms, nor the response to standard treatments. In patients with cyclic CPP, after excluding other identifiable organic causes, management should shift from a diagnosis-centered to a symptom-centered approach. CPP is characterized by long-term incapacitating pain and is complexified by the frequent co-occurrence of neuropathic pain and/or pelvic and perineal pain central sensitization (PPCS), a neurophysiological phenomenon characterized by a heightened pain response.8 The effective treatment of these complex CPP syndromes necessitates a multidisciplinary team comprising physicians, nursing personnel, and pharmacists from various specialties at tertiary care centers.9 Literature recently focused on these aspects specifically for patients with endometriosis, but little is known about the prevalence of PPCS in all CPP.10 The aim was to report the prevalence of PPCS in patients presenting with CPP. The secondary goals were to explore how these symptoms could influence patients' management. 2 MATERIAL AND METHODS This retrospective study, based on a standardized clinical registry, was conducted at the University Hospital Center of Nice (France), a tertiary referral center for endometriosis and chronic pelvic pain management. Medical records from January 1, 2024 to December 31, 2024 were screened. Study population and data collection: All patients presenting for the first time with chronic pelvic pain that can be attributed to endometriosis resistant to hormonal therapy, with or without a diagnosis of endometriosis, were included if no other organic causes of pain were found, primarily through pelvic imaging (transvaginal ultrasound and pelvic MRI). This inclusion criteria could be called “chronic endometriosis-like pelvic pain.” Hormonal treatment resistance (oral, intrauterine device, or implant) was defined as the persistence, after at least 6 months of therapy, of at least one of the following criteria: pain with an intensity ≥8/10, resistance to step 1 analgesics, or the presence of one of the following associated symptoms: deep dyspareunia, cyclic dysuria, cyclic dyschezia, or school/work absenteeism. In our referral center, as part of their medical care, all these patients undergo a full assessment, including a precise evaluation of pain (intensity, validated DN4 questionnaire,11 screening for PPCS according to validated Convergences PP score8), a search for other urinary, digestive or sexual functional signs, medical history evaluation, and specifically the existence of a history of violence during the first consultation with a gynecologist. An evaluation of quality of life at the time of the consultation using the validated EHP-5 score was performed (which consists of 11 items, each scored from 0 to 4; the total raw score ranges from 0 to 44, where 0 indicates the best possible health status and 44 indicates the worst possible health status).12 A diagnosis of neuropathic-like features was given for patients with a DN4 score greater than 4. While the DN4 was originally validated for pain localized to a specific somatosensory neurological territory, we applied it in our center to the pelvic area to screen for neuropathic-like symptoms. In the context of visceral and pelvic pain, a high score may reflect neuro-inflammatory processes rather than a strictly defined peripheral nerve lesion. Consequently, in this study, the DN4 score is used as a clinical indicator of “neuropathic-expressive” pain components within the pelvic region. The PPCS was retained in the case of Convergences PP score greater than 5.8 Evaluation of previous medical and surgical management was also performed to consider therapies already tried, with success or not to increase quality of life. Use of analgesics by class was also recorded. Occupational status was assessed as a binary variable: “with professional activity” (including any full-time or part-time employment) and “without professional activity” (including voluntary absence of work or unemployment). 2.1 Statistical analysis Statistical analyses were performed with Stata MP 15.1. Categorical data were presented as absolute and relative frequencies. Data distribution was assessed using the Shapiro–Wilk test. Means and standard deviations were used even if Shapiro–Wilk test indicated nonnormal distribution because our large sample size allows for robust estimation according to the central limit theorem. Minimum and maximum values were also systematically provided to reflect the full range of the data. A comparative analysis was first performed between patients with PPCS and those without. Comparisons were performed using the chi-squared test or the Mann–Whitney U test as appropriate. Multivariable analyses were then conducted in two steps: (1) a logistic regression model was used to assess the association between central sensitization and the use of step 2 or 3 analgesics, adjusting for the following confounding variables: parity, history of endometriosis surgery, age, history of violence, maximum pain score, professional activity, PPCS, neuropathic-like features and EHP-5 score; (2) a multiple linear regression model was performed to evaluate the relationship between central sensitization and quality of life (EHP-5 score), adjusting for the same set of covariates. Robust standard errors were used in both models, and results from logistic regressions were reported as odds ratios (ORs) with their 95% confidence intervals. Statistical significance was defined as a p < 0.05. All tests were two-tailed. The calculation of the variance inflation factor after each multivariate analysis was used to ensure the robustness of the model by assessing the risk of multicollinearity. 3 RESULTS From January 1, 2024 to December 31, 2024, 270 new patients with chronic pelvic pain resistant to hormonal therapy, with or without endometriosis, and without other organic causes of pain were included. Patients were 32.4 ± 8.5 years old (minimum: 15.0 years; maximum: 52.7 years). Population characteristics are detailed in Table 1. Information about the history of violence against women was declarative, during the first consultation, and 15/270 (5.6%) patients did not wish to respond. | Total cohort N = 270 | Patients with PPCS n = 140 | Patients without PPCS n = 130 | p-value | | |---|---|---|---|---| | General characteristics | |||| | Age (years) | 32.4 ± 8.5 (15–52) | 31.6 ± 8.3 (16–50) | 33.5 ± 8.6 (15–52) | 0.057a | | Parity ≥1 | 81/270 (30.0%) | 42/140 (30.0%) | 39/130 (30.0%) | >0.999b | | Previous cesarean section | 32/270 (11.8%) | 19/140 (13.6%) | 13/130 (10.0%) | 0.823b | | Tobacco (n = 257) | 113/257 (44.0%) | 74/132 (56.1%) | 39/125 (31.2%) | <0.001 b | | Active | 61/257 (23.8%) | 44/132 (31.4%) | 17/125 (13.1%) | 1 month | 52/257 (20.2%) | 30/132 (21.4%) | 22/125 (16.9%) | 0.348b | | History of abdominal or pelvic surgery | 97/270 (35.9%) | 53/140 (37.9%) | 44/130 (33.9%) | 0.492b | | Surgery for endometriosis (suspicion or resection) | 59/270 (21.8%) | 30/140 (21.4%) | 29/130 (22.3%) | 0.861b | | History of violence against women (n = 255) | 66/255 (25.9%) | 41/129 (31.8%) | 25/126 (19.8%) | 0.029 b | | Context of infertility (n = 182) | 46/182 (25.3%) | 18/89 (20.2%) | 28/93 (30.1%) | 0.125b | | Patient undergoing assisted reproductive therapy | 29/270 (10.7%) | 12/140 (8.6%) | 17/130 (13.1%) | 0.232b | | Physical activities (hours per week) | 1.8 ± 2.0 (0–10) | 1.7 ± 2.0 (0–10) | 1.9 ± 2.1 (0–7) | 0.767a | | Without professional activity (n = 255) | 46/255 (18.0%) | 28/136 (20.6%) | 18/119 (15.1%) | 0.258b | | Clinical symptoms | |||| | Duration of menstrual cycles (days) | 27.6 ± 5.3 (14–60) | 28.4 ± 4.8 (20–55) | 26.8 ± 5.7 (14–60) | 0.033 a | | Duration of menstruation (days) | 6.2 ± 3.1 (2–30) | 5.9 ± 2.1 (2–15) | 6.5 ± 3.7 (3–30) | 0.357a | | Dysmenorrhea (VAS) | 7.3 ± 2.6 (0–10) | 7.6 ± 2.3 (0–10) | 6.9 ± 2.8 (0–10) | 0.170a | | Intermenstrual pain (VAS) | 5.7 ± 3.1 (0–10) | 6.4 ± 2.5 (0–10) | 5.0 ± 3.4 (0–10) | 0.004 a | | Pain starting at menarche (n = 135) | 84/135 (62.2%) | 36/57 (63.2%) | 48/78 (61.5%) | 0.848b | | Presence of at least one urinary symptom | 232/270 (85.9%) | 131/140 (93.6%) | 101/130 (77.7%) | <0.001 b | | Presence of at least one digestive symptom | 219/270 (81.1%) | 130/140 (92.9%) | 89/130 (68.5%) | <0.001 b | | Overall sexual evaluation (VAS) | 5.1 ± 3.1 (0–10) | 4.7 ± 3.0 (0–10) | 5.5 ± 3.3 (0–10) | 0.002 a | | Libido evaluation (VAS) | 5.0 ± 3.2 (0–10) | 4.6 ± 3.1 (0–10) | 5.5 ± 3.2 (0–10) | 0.004 a | | Neuropathic-like features | 95/270 (35.2%) | 69/140 (49.3%) | 26/130 (20.0%) | <0.001 b | | EHP-5 score | 22.6 ± 8.8 (0–40) | 25.8 ± 7.4 (0–40) | 19.1 ± 8.9 (0–38) | <0.001 a | | Medical management prior to the first consultation | |||| | Hormonal treatment at the time of the consultation | 226/270 (83.7%) | 124/140 (88.6%) | 102/130 (78.5%) | 0.025 b | | Oral | 170/270 (63.0%) | 92/140 (65.7%) | 78/130 (60.0%) | | | Intra-uterine device | 38/270 (14.1%) | 24/140 (17.1%) | 14/130 (10.8%) | | | Implant | 18/270 (6.6%) | 8/140 (5.7%) | 10/130 (7.8%) | | | Step 1 analgesic (n = 232) | 204/232 (87.9%) | 112/118 (94.9%) | 92/114 (80.7%) | 0.001 b | | Step 2 and/or 3 analgesic (n = 232) | 153/232 (66.0%) | 96/118 (81.4%) | 57/114 (50.0%) | <0.001 b | | Specific neuromodulating therapy | 5/270 (1.9%) | 2/140 (1.7%) | 3/130 (2.6%) | 0.623b | - Note: Numbers (n) and percentages (%) are indicated for categorical variables. Means and standard deviation, with minimum and maximum, are shown for continuous variables. When data were not available for all patients, the number of patients for whom the information was available is indicated after the name of the variable and the specific denominator was explicitly reported. Bold values indicate statistical significance (p < 0.05). - Abbreviations: EHP-5, Endometriosis Health Profile 5; PPCS, pelvic and perineal pain central sensitization; VAS, visual analog scale. - a Calculated using Mann–Whitney U test. - b Calculated using chi-squared test. Comparison of patients with and without PPCS is also reported in Table 1. Patients with PPCS were more exposed to tobacco (74/132 (56.1%) vs. 39/125 (31.2%) patients; p < 0.001) and had a history of violence more often (41/129 (31.8%) vs. 25/126 (19.8%) patients; p = 0.029). In the presence of central sensitization, symptoms were more severe and exhibited broader clinical manifestations, affecting multiple domains, including urinary, gastrointestinal, and sexual functions, as well as neuropathic-like features and overall quality of life. Patients with a Convergence PP score over 5 were more frequently receiving hormonal treatment and had higher consumption of level 1, 2, or 3 analgesics. In multivariate logistic regression, several factors were evaluated for their association with the use of step 2 or 3 analgesics (Table 2). After adjusting for parity, age, profession, history of endometriosis surgery or violence, maximum pain intensity, neuropathic-like features, and EHP-5 score, patients with a PPCS were significantly more likely to report use of strong analgesics (adjusted odds ratio [aOR] 2.48 [95% CI: 1.05–5.83], p = 0.038). Additionally, a history of violence against women was also associated with higher analgesic use (aOR = 2.56, 95% CI: 1.11–5.93, p = 0.028). Other variables, such as parity, history of endometriosis surgery, age, and maximum pain score, were not significantly associated with analgesic consumption in this model. | Variables | aOR | 95% CI | p-value | |---|---|---|---| | Parity | 0.84 | 0.54–1.30 | 0.438 | | History of endometriosis surgery | 1.67 | 0.70–4.03 | 0.250 | | Age | 0.99 | 0.95–1.04 | 0.750 | | History of violence | 2.56 | 1.11–5.93 | 0.028 | | Maximum pain score | 1.06 | 0.92–1.23 | 0.408 | | With professional activity | 1.83 | 0.70–4.77 | 0.218 | | PPCS | 2.48 | 1.05–5.83 | 0.038 | | Neuropathic-like features | 0.85 | 0.35–2.12 | 0.734 | | EHP-5 score | 1.13 | 1.07–1.18 | <0.001 | - Note: This model is adjusted for parity, history of endometriosis surgery, age, history of violence, maximum pain score, professional activity, PPCS, neuropathic-like features, and EHP-5 score. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI). Bold values indicate statistical significance (p < 0.05). - Abbreviations: EHP-5, Endometriosis Health Profile 5 (raw score 0–44); PPCS, pelvic and perineal pain central sensitization. In the linear regression model evaluating the determinants of quality of life (EHP-5 score) after adjusting for other confounding factors, the presence of PPCS was independently and strongly associated with poorer quality of life: patients had an increase of +5.19 points on the EHP-5 scale (95% CI: 3.01–7.37, p < 0.001) (Figure 1). Notably, while presenting neuropathic-like features score was also significantly associated with worse quality of life (β = +2.43, 95% CI: 0.19–4.66, p = 0.033), it was not independently associated with the use of stronger analgesics in the logistic model (aOR = 0.85, 95% CI: 0.35–2.12, p = 0.734). Maximum pain intensity was also significantly associated with poorer quality of life (β = +0.56, 95% CI: 0.11–1.01, p = 0.014). Other factors such as parity, age, and surgical history did not significantly impact EHP-5 scores. After each multivariate analysis, variance inflation factor values for all multivariate models were below 1.38, indicating a very low risk of multicollinearity. 4 DISCUSSION This study highlights the significant clinical and therapeutic implications of PPCS for patients with CPP unresponsive to hormonal therapy. PPCS was associated with a distinct and more severe clinical phenotype, with more than a twofold increase in consumption of opioids or strong nonopioid analgesics and a significant association with alterations in quality of life. The average age in our cohort was 32.4 years, reflecting a young, reproductive-aged population consistent with the typical epidemiology of CPP.10, 13, 14 Notably, over one-third of patients exhibited neuropathic-like features, and more than half met criteria for PPCS, suggesting widespread alterations in central pain processing mechanisms. Despite this high burden of neurogenic and sensitization-related pain, only five patients (1.9%) had received specialized pain management—such as tricyclic antidepressants, anticonvulsants, or referral to a pain clinic—before their first consultation in our center. This underlines a major gap in the recognition and management of these complex pain syndromes. Furthermore, more than one in five had undergone surgery for endometriosis, which highlights the frequency of prior therapeutic escalation before specialized consultation, in particular before resistant pain management. This emphasizes the risk of potentially unnecessary or deleterious invasive interventions when mechanisms of central sensitization are not adequately considered. Indeed, for many years, a nonsurgical approach was recommended as the first-line management, due to the absence of a consensus on the factors predicting surgical failure.15 In recent years, however, specific types of pain, symptoms, and clinical contexts have been clearly identified as being associated with a higher risk of surgical treatment failure.16 Our findings advocate for earlier and systematic screening for neuropathic and sensitization-related pain features in gynecological practice, as recommended in recent French national guidelines, and underscore the urgent need to improve access to multidisciplinary, specialized pain care for this underserved patient population.17 Strikingly, 25.9% of patients reported a history of violence against women, a figure that exceeds estimates in the general population in Western Europe18 and suggests a potential enrichment of trauma-related pain mechanisms. The prevalence of violence was significantly higher among patients with pelvic pain and signs of central sensitization (37.8% vs. 19.8%, p = 0.029), further reinforcing the importance of systematic screening for gender-based violence, but also the need for integrated, trauma-informed care pathways tailored to the specific needs of this vulnerable subgroup.19-21 Women with PPCS reported a broader symptomatology affecting urinary, gastrointestinal, and sexual domains, along with higher rates of neuropathic-like features. These findings were consistent with the concept of centralized pain, wherein pain processing becomes amplified and less dependent on peripheral nociceptive input.8 The significantly higher EHP-5 scores in patients with PPCS (+5.2 points, p < 0.001) underline the substantial association between PPCS and health-related quality of life. Interestingly, PPCS remained independently associated with quality-of-life impairment even after adjustment for maximum pain score, suggesting that the chronic pain burden in these patients may not be fully captured by intensity-based assessments alone. PPCS was the variable most strongly associated with a higher EHP-5 score after adjusting for key covariates, reflecting a significant negative impact on quality of life. PPCS was also independently associated with increased consumption of step 2 or 3 analgesics (aOR 2.48, 95% CI: 1.05–5.83), even after adjusting for known confounders. This underscores the challenge of managing CPP in patients with central sensitization, who may remain refractory to standard analgesic strategies. Notably, a history of violence against women emerged as another independent predictor of stronger analgesic use (aOR 2.56, p = 0.028). This aligns with prior work indicating that adverse life experiences may be linked to central sensitization and persistent pain states through neuroendocrine and inflammatory pathways.22, 23 While patients with a high DN4 score (≥4/10) exhibited significantly higher EHP-5 scores, suggesting poorer quality of life, neuropathic-like features were not independently associated with stronger analgesic use (WHO steps 2 or 3). Crucially, specific neuromodulators were rarely prescribed in this cohort despite the presence of neuropathic symptoms. This discrepancy underscores a significant diagnostic blind spot in identifying neuropathic components within CPP. Furthermore, the fact that analgesic escalation fails to mirror symptom severity suggests that this specific patient population is intrinsically nonresponsive to conventional pharmacological pathways. It reinforces the necessity of treating neuropathic features as a distinct clinical entity, requiring targeted diagnostic tools and specialized therapeutic interventions rather than a generic intensification of standard analgesics. It also suggests that centralized pain and neuropathic features, though overlapping, are not interchangeable entities and should be assessed independently.17 These findings support the integration of structured screening tools for central sensitization (e.g., the convergence PP score8), trauma history, and neuropathic pain features into the routine evaluation of women with CPP. Traditional gynecological evaluations that focus solely on hormonal or anatomical factors may miss key contributors to pain chronicity. In addition, the data suggest that central sensitization and trauma-related mechanisms are significantly associated with the overall analgesic burden. This has important implications for opioid stewardship and highlights the potential role of neuromodulatory therapies, particularly in a context where overuse and dependence on these agents constitute a major public health concern.14, 24, 25 However, the evidence remains debated. A large randomized controlled trial (GaPP2) did not demonstrate a significant benefit of gabapentin over placebo for chronic pelvic pain in a general population of women without obvious pelvic pathology.26 However, our findings highlight that 35% of patients exhibit neuropathic-like features. This suggests that gabapentinoids should not be used systematically but may be more appropriately reserved for a highly selected subgroup of patients where a neuropathic component or central sensitization is clearly identified, in line with a more individualized and multimodal management strategy. Our study has several limitations. Its monocentric design and reliance on self-reported data may introduce selection and reporting biases. However, these limitations were partially mitigated by the prospective and systematic nature of data collection integrated into routine clinical practice. Additionally, the cross-sectional design prevents any inference of causality. Future research should aim to replicate and validate these findings in multicentric prospective cohorts and explore the effectiveness of tailored, nonpharmacologic interventions that specifically target central sensitization mechanisms. This study included all first-time consultations in our center for patients presenting with chronic “endometriosis-like” pelvic pain resistant to hormonal treatment, with a deliberate focus on patients' symptomatology and lived experience rather than relying solely on imaging or surgical diagnosis. This patient-centered approach is more clinically relevant and reflective of real-world practice. Multivariate statistical analyses were performed to account for potential confounding variables, and methodological controls including variance inflation factor checks were used to ensure the robustness and validity of the results. 5 CONCLUSION This study highlights the consequences of central sensitization in chronic pelvic pain resistant to hormonal therapy. PPCS was associated with more severe symptoms, impaired quality of life, and increased use of strong analgesics. These findings support the need for systematic screening and multidisciplinary, patient-centered care approaches in the management of complex pelvic pain syndromes. AUTHOR CONTRIBUTIONS Hajar Alawadi, Marie Cid, and Pierre-Alexis Gauci conceived and designed the study. Pierre-Alexis Gauci analyzed the data. Hajar Alawadi and Pierre-Alexis Gauci drafted the manuscript. JD critically revised the manuscript. All authors approved the final manuscript. ACKNOWLEDGMENTS We thank all the Nice Endocentre Team of Nice University Hospital, its coordinator Mrs Ludivine Charbonnier, and its secretary Corinne Berder for their help and cooperation throughout the research period. FUNDING INFORMATION This work has been supported by the French government through the UCAJEDI Investments in the Future project managed by the National Research Agency (ANR) with the reference number ANR-15-IDEX-01. This work also received the support of the GCS GIRCI Méditerranée through the funding of a research grant. The funders had no role in studsy design, data collection and analysis, decision to publish, or preparation of the manuscript. CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest. ETHICS STATEMENT This single-center retrospective study was performed following the ethical standards of the 1964 Declaration of Helsinki, and Université Côte d'Azur Research Ethics Committee approval was obtained under the number 2024-128 obtained on January 20, 2025. Patients were informed in writing of the anonymous use of their data and could object to its use. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available on request from the corresponding author. T he data are not publicly available due to privacy or ethical restrictions.