Central sensitization in patients with deep endometriosis

Dear Editor,

Introduction

The association between endometriosis and pelvic pain is widely known, but the specific mechanisms by which endometriosis causes pain are still poorly understood [1].

Central sensitization (CS) is a phenomenon in which alterations in the central nervous system cause changes in the perception of pain [2], and these changes have the potential to exacerbate pain symptoms and predispose women with endometriosis to the development of other chronic conditions.

Previous research suggested that endometriosis-associated chronic pelvic pain is often related to the presence of CS [3] and could lead to worse response to treatments or lower health-related quality of life (HRQoL) and a higher risk of depression and anxiety.

The Central Sensitization Inventory (CSI) was designed to apply the concept of CS to the clinical management of patients with chronic pain [4]. The CSI questionnaire has been validated to differentiate between centrally sensitized and non-sensitized patients in the chronic pain literature, having strong psychometric properties, good internal consistency, and good test–retest validity [4]. A recently published study has shown that CSI could serve as a tool to help identify patients with endometriosis who have pain contributors related to central nervous system sensitization [5]. On the other hand, previous studies evaluating patients with endometriosis did not take into account the severity and type of disease. Moreover, to our knowledge, no previous study has evaluated the presence of CS-related symptoms in patients with deep endometriosis (DE), the type of endometriosis associated with higher levels of pain [1].

The objectives of the present study were to assess the prevalence of CS-related symptoms in patients diagnosed with DE compared with healthy controls and to analyze the clinical and epidemiological characteristics of patients with DE with CS-related symptoms and their effect on HRQoL and mental health.

Methods

A single-center comparative cross-sectional study was conducted at the Department of Gynecology of a tertiary teaching hospital. The study was approved by the Clinical Research Ethics Committee. All women gave written informed consent before initiation of the study.

All consecutive premenopausal women with recently suspected DE referred for first evaluation were included. Healthy patients were recruited during routine gynecological visits for contraception or cervical cancer screening, and they underwent transvaginal ultrasound (TVU) to exclude the presence of DE. Exclusion criteria were malignancy or a history of malignancy; endocrine, cardiovascular, autoimmune, or systemic inflammatory diseases; premature ovarian failure; or menopausal status.

All the women underwent a clinical examination and a two-three dimensional TVU with an endovaginal probe (type RIC5-9, Voluson S10; GE Healthcare, Milwaukee, WI, USA). The ultrasound examination was performed to diagnose the presence of DE, as it has been reported that performing a systematic evaluation of endometriosis by TVU can accurately replace diagnostic laparoscopy [6]. Among patients with DE, description of the sonographic features of the different phenotypes of endometriosis lesions was performed, following the consensus obtained by the International Deep Endometriosis Analysis (IDEA group) [6].

Clinical and epidemiological data were collected from all of the patients. Moreover, all the participants were also asked to quantify the severity of pain symptoms on a numeric rating scale from 0 (no pain) to 10 (unbearable pain).

All of the recruited patients completed the validated versions of three questionnaires: the CSI [4], the Short-Form 36-item survey (SF-36) [7], and the Hospital Anxiety and Depression Scale (HADS) [8].

CS-related symptoms were measured with the CSI questionnaire. The CSI questionnaire assesses 25 symptoms. Scoring ranges from 0 to 100, with a CSI cutoff point ≥40 considered the threshold of clinical relevance [9].

The power analysis was calculated on the basis of a previous study [10]. The minimum number of patients needed was 60. We established a ratio of 2:1, with 120 patients and 60 healthy controls. A total of 190 women with suspected DE were invited to participate in the study, and of these, 169 were diagnosed with DE by TVU examination and were accepted to participate. Sixty-six healthy participants were included (Non-DE group). Statistical analysis was performed with the Statistical Package for the Social Sciences software, release 25.0 for Windows (SPSS, Chicago, IL, USA). The Student t test was used for comparison of normally distributed continuous variables, and the Kruskal-Wallis test was used for comparison of non-normally distributed continuous variables. The chi-squared test was used for comparison of categorical variables. Statistical significance was set at P < 0.05.

Results

A total of 169 women were diagnosed with DE by TVU examination and accepted to participate (DE group). Sixty-six healthy participants were included (Non-DE group).

As expected, women in the DE group reported more pain symptoms, lower scores in all the dimensions of the SF-36, and higher mean scores for both subscales according to the screening for depression and anxiety than those of the control group (P < 0.001). CSI scores were significantly higher in the DE group (P = 0.015) (Table 1).

Table 1.

Main results of the DE group and healthy controls according to clinical and epidemiological characteristics, HRQoL (SF-36), and mental health (HADS)

	DE Group	Non-DE Group	P Value
	(n = 169)	(n = 66)
Age, years	37.9 ± 6	36.3 ± 7.2	0.087
Body mass index, kg/m2	24.7 ± 4.4	23.5 ± 3.3	0.09
Pain intensity (NRS)
Dysmenorrhea	5.9 ± 3.2	1.6 ± 2.5	<0.001
Chronic pelvic pain	4.1 ± 3.1	0	<0.001
Dyspareunia	3.7 ± 3.7	0.6 ± 1.6	<0.001
CSI total score	44.7 ± 16.3	17.6 ± 11.9	0.015
CSI ≥40	100 (59.2)	5 (7.6)	<0.001
SF-36 Questionnaire
Physical functioning	80.3 ± 23.5	98.5 ± 4.8	<0.001
Physical role	62.8 ± 30.4	92.5 ± 15	<0.001
Body pain	49.3 ± 28.8	88 ± 15.5	<0.001
General health	45.8 ± 22.6	91.5 ± 50.1	<0.001
Vitality	46.6 ± 13.9	63.7 ± 7.2	<0.001
Social functioning	61.9 ± 10.5	92.7 ± 11.5	<0.001
Emotional role	72.8 ± 26.7	89.4 ± 14.6	<0.001
Mental health	57 ± 23.3	80.4 ± 12.2	<0.001
HADS
HADA	9.11 ± 4	4.7 ± 2.1	<0.001
HADD	5.8 ± 3.8	1.3 ± 2	<0.001

Values are given as mean ± standard deviation or number (percentage) unless otherwise stated.

Abbreviations: NRS= numeric rating scale (0–10); HADA= Hospital Anxiety Scale; HADD= Hospital Depression Scale.

A CSI cutoff ≥40 has been shown to distinguish patients with CS-related symptoms from controls [9].

There were no differences in the clinical and epidemiological characteristics among patients with DE according to a CSI cutoff point ≥40. No statistically significant differences were found according to the presence of ovarian endometrioma (P = 0.077) or adenomyosis (P = 0.313) or with the number of previous endometriosis surgeries (P = 0.99). No correlation was found between the CSI value and the duration of pain (data not shown). Patients with DE and a CSI value ≥40 reported higher scores in pain symptoms (P < 0.001 and P = 0.005) (Table 2).

Table 2.

Analysis of the DE group according to the cutoff score above or below 40 of the CSI questionnaire in relation to clinical and epidemiological characteristics and the results of the HRQoL (SF-36) and mental health (HADS) questionnaires

	CSI ≥40	CSI <40	P Value
	(n = 100)	(n = 69)
Age, years	37.8 ± 6	38 ± 6	0.63
Ovarian endometrioma	50 (50)	44 (63.7)	0.077
Adenomyosis	33 (33)	28 (40.5)	0.313
Previous endometriosis surgery	55 (55)	38 (55)	0.99
Pain intensity (NRS)
Dysmenorrhea	6.69 ± 2.9	4.7 ± 3.3	<0.001
Chronic pelvic pain	4.9 ± 3	2.9 ± 2.9	<0.001
Dyspareunia	4.3 ± 3.7	2.7 ± 3.5	0.005
SF-36 Questionnaire
Physical functioning	71.6 ± 26.5	92.9 ± 8.5	<0.001
Physical role	49.9 ± 10.6	81.61 ± 20.3	<0.001
Body pain	36.7 ± 24.3	67.6 ± 24.8	<0.001
General health	45.8 ± 22.6	91.5 ± 50.1	<0.001
Vitality	41 ± 12.6	54.7 ± 11.5	<0.001
Social functioning	50.1 ± 25.2	78.9 ± 21	<0.001
Emotional role	64.5 ± 28.3	84.7 ± 18.7	<0.001
Mental health	49.15 ± 24	68.4 ± 16.6	<0.001
HADS
HADA	10.6 ± 3.9	6.9 ± 3	<0.001
HADD	7.4 ± 3.8	3.5 ± 1.4	<0.001

Data are provided as mean ± standard deviation or number (percentage) unless otherwise stated.

Abbreviations: NRS= numeric rating scale; HADA= Hospital Anxiety Scale; HADD= Hospital Depression Scale.

A CSI cutoff ≥40 has been shown to distinguish patients with CS-related symptoms from controls [9].

On a comparison of DE patients with a CSI score below the cutoff point with those with a score above the cutoff, the latter had a poorer HRQoL in all dimensions of the SF-36 questionnaire (P < 0.001) and presented a higher risk of depression and anxiety according to the HADS questionnaire scores (P < 0.001) (Table 2).

Discussion

The main finding of the present study was that patients with DE with greater pelvic pain more frequently presented CS-related symptoms. Patients with DE and a CSI value ≥40 had a poorer HRQoL and a higher risk of depression and anxiety. It is well known that the etiology of chronic pelvic pain is multifactorial, and, in this context, mental health can act either as a trigger or as a consequence. It should be taken into account that psychopathological symptoms can lead to a more complicated clinical prognosis. In contrast to other diseases related to CS, in endometriosis, CS can be initiated and perpetuated by peripheral nociceptive signaling, related to the endometriosis lesions in the pelvis, and drive central amplification [3]. It remains unknown whether these CS-related symptoms are causative, a consequence, or a coincidence in patients with DE with pelvic pain, as shown in the literature.

Endometriosis is a very prevalent pathology, and therefore, apart from adequate management of DE, it is important to establish tools for early detection and specific treatment of CS-related symptoms. A CSI score ≥40 should alert health care professionals to thoroughly evaluate endometriosis-associated pain and assess HRQoL and mental health with a multimodal approach in patients with DE.

The present study has several strengths. First, to our knowledge, this is the first study to determine the prevalence of CS-related symptoms via the CSI questionnaire, which is easy to perform to assess CS-related symptoms in daily practice, among patients with DE. Second, all the questionnaires used were standardized and validated in Spanish.

This study also has several limitations. First, as this was a preliminary study, it had a relatively small sample size, which was calculated according to a previous study [10]. Second, it included a group of patients with DE from a tertiary referral center. This could have contributed to an overestimation of the reported prevalence of CS-related symptoms, and therefore, the results of the present study might be applicable only to other large referral centers with similar patient populations and demographics. Third, this was a comparative cross-sectional study, and we could not analyze the influence of medical or surgical treatment on CS-related symptoms.

To conclude, a large proportion of patients with DE present CS-related symptoms. Performing an assessment of CS-related symptoms in patients with DE might allow a better understanding of the cause of endometriosis-associated pain and could suggest that treatments believed to target CS should be initiated. In these patients a multidisciplinary care program addressing central pain should be considered, including pelvic floor physiotherapy, psychological interventions, pain education, and pharmaceutical or interventional treatments, for chronic pain.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest: The authors report no conflicts of interest and have nothing to disclose.