This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.
Chronic pelvic pain is a common and disabling condition in women living with endometriosis. Pharmacological and surgical treatments are not always effective at controlling pain and present important restrictions. Digital therapeutics (DTx) are emerging as major nonpharmacological alternatives that aim to extend the analgesic therapeutic arsenal of patients.
In this randomized controlled trial (RCT), we aimed to measure the immediate and 4-hour persisting effects of a single use 20-minute DTx (Endocare) on pain in women experiencing pelvic pain due to endometriosis.
A total of 45 women with endometriosis participated in a randomized controlled study comparing the analgesic effect of a single use of a virtual reality digital treatment named Endocare (n=23, 51%) to a 2D digital control (n=22, 49%). Perceived pain and pain relief were measured before the treatment and 15, 30, 45, 60, and 240 minutes after the end of the treatment.
The clustered posttreatment pain was significantly reduced compared to the pretreatment for both Endocare and the control group (all
Our study aimed to test the effects of a single use of a DTx treatment on reported pain at different time points in women diagnosed with endometriosis experiencing moderate-to-severe pelvic pain. Importantly, our results support that Endocare, a virtual reality immersive treatment, significantly reduce pain perception compared to a digital control in women living with endometriosis. Interestingly, we are the first to notice that the effect persisted up to 4 hours posttreatment.
ClinicalTrials.gov NCT04650516; https://tinyurl.com/2a2eu9wv
Endometriosis is characterized by lesions occurring outside the uterus whose appearance and behaviors are close to those of the endometrium mainly on the pelvic peritoneum, ovaries, and rectovaginal septum [
The mean prevalence of endometriosis in women with CPP has been estimated at 70% (SD 3%) [
Current management of endometriosis pain involves pharmacological (eg, hormonal therapy) and surgical treatments [
Hormonal therapies or surgeries are not adapted for women willing to get pregnant. Therefore, the development of nonpharmacological alternatives for the management of endometriosis pain is critical to extend the treatment arsenal for women with pelvic-perineal pain and endometriosis [
In the past few decades, the emergence of digital therapeutics (DTx) aimed at the use of informatic tools to aid the diagnosis and therapy of various pathologies has led to the creation of many new therapeutic devices [
On these bases, a new digital therapeutic approach, Endocare, was created by combining various therapeutic procedures based on several modalities in a VR environment, individually known to reduce pain [
This was a randomized, controlled, comparative, open-label, 2-parallel-group interventional study comparing the effect of Endocare and a digital control on endometriosis-related pain after a single use. This RCT was conducted between December 2020 and May 2021 at the Franco-European Multidisciplinary Endometriosis Institute (IFEMEndo), Clinic Tivoli-Ducos in Bordeaux, France.
This study was conducted in compliance with good clinical practice guidelines, the principles of the Declaration of Helsinki, and French laws and regulations. It was reviewed and approved on November 6, 2020, by the Comité de Protection des Personnes. All participants completed and signed the informed consent form before inclusion in the study and before any study-related procedure began. Before commencing participant enrollment, this study was registered on ClinicalTrials.gov (NCT04650516).
Standard operating procedures were applied for the conduct and analysis of the clinical investigation. This study was monitored regularly according to the specifically designed monitoring plan. Furthermore, data were captured following the double entry procedure in the dedicated case report form and compared. Discrepancies were reviewed and corrected by a third entry clerk. A data validation document specifically written for this study aimed to list all data checks to be performed. A data manager programmed the checks with Ennov Clinsight, and the sponsor validated the checks. In case of inconsistencies, a query was edited during the quality analysis beyond data entry. The investigator or another authorized person from the clinical staff was asked to answer the query by confirming or correcting the data.
The selection criteria were women over 18 years old with a magnetic resonance imagery (MRI) diagnosis of endometriosis who were willing to participate in the study and signed the informed consent form. All patients were recruited from a highly specialized center (ie, IFEMEndo). These patients experienced mostly severe pain related to their chronic pain condition and presented a long medical history concerning their endometriosis, which was often deep endometriosis.
To be included in this study, the screened participants who met the selection criteria had to be living with moderate-to-severe endometriosis-related pain with a score ≥4 on an 11-point numerical rating scale (NRS) at the time of inclusion, a criterion shared among various studies [
The exclusion criteria were women who (1) were pregnant or breastfeeding; (2) had consumed painkillers within 8 hours prior to inclusion; (3) were participating in an interventional study or had participated in an interventional study within 30 days before enrolment; (4) were employed by the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator; and (5) had a contraindication to Endocare or the digital control, such as severe visual, hearing or cognitive impairments, color blindness, photosensitivity, epilepsy, or motion sickness.
This study aimed to evaluate the short-term pain evolution after a single use of Endocare compared to a digital control in participants experiencing endometriosis-related pelvic pain. The primary end point was the mean pain intensity 60 minutes after the beginning of treatment (or last evaluation if the participant dropped out of the study or started any rescue medication). Gerlinger et al [
With a 2-sided 95% CI, the study achieved 81% power to detect a difference between the group means at the last time of 20 mm on a 100-mm VAS with a 25-mm standard deviation. The correlation between measurements within a participant was estimated at 0.500. A test based on a mixed-model analysis was anticipated at a significance level of 5%. Assuming that about 25% of women would not experience an endometriosis-related pain ≥4 on NRS at time of inclusion, we planned to screen 50 women. Consequently, at least 40 women were planned to be included in the study.
Finally, 46 participants were screened, of which 45 were included and randomized; 1 was a screen failure because she never went back for the study visit (
Size of the sample.
Sample | Value |
Participants screened, n | 46 |
Participants randomized, n (%) | 45a (100) |
Participants who completed study, n (%) | 44b (97.8) |
aOne participant was lost to follow-up between the screening visit and the randomization visit and their inclusion criteria could not be checked.
bThe self-administered questionnaire of 1 participant was never received for analysis.
Pain medications were stopped at least 8 hours prior to participation. If pain persisted after treatment (Endocare or control), the patient could take their pain management rescue treatment, thus ending the data collection at that time.
We developed the Endocare treatment (Lucine, Bordeaux, France) specifically for this study (
Visual display of the 3D virtual reality treatment (ie, Endocare) and the 2D tablet control.
The digital control was also developed by Lucine specifically for this study (
Women living with endometriosis pain were recruited from IFEMEndo
When patients returned to the clinic on the day of the inclusion visit, their pain level needed to be at least 4 on an 11-point numeric pain rating scale to participate in this study. Patients reporting a pain of <4 on this scale were considered as screen failures and withdrawn from the study. This pain intensity evaluation represented the pretreatment evaluation just before the use of Endocare or control and is considered the baseline (T0).
If the patient consented to participate and met the inclusion criteria, they were randomized to 1 of the 2 groups, Endocare or control. The treatment (either Endocare or control) consisted of a single use of the VR headset on the day of the visit, as presented in
The research team accompanied the patient to distinct isolated rooms and then handed them either the headset (ie, Endocare) or the tablet (ie, control). Patients were then guided orally by the investigator for up to 5 minutes until the beginning of the treatment (ie, Endocare or control).
Study flowchart.
Study procedures | Screening | Care and follow-up | Follow-up until 240 minutes after treatment |
Informed consent | ✓ |
|
|
Eligibility criteria (without pain assessment) | ✓ |
|
|
Demographics | ✓ |
|
|
History and management of endometriosis | ✓ |
|
|
Typology of pain crises | ✓ |
|
|
Baseline pain assessment (T0) (just before the start of Endocare or control treatment) |
|
✓ |
|
Assessment of general status | ✓ | ✓ | ✓ |
Endocare or control treatment |
|
✓ |
|
Pain evolution (pain relief and intensity) |
|
✓a | ✓b |
Satisfaction |
|
|
✓b |
Concomitant treatments |
|
✓c | ✓c |
Adverse events |
|
✓ | ✓ |
aEvaluation 15 minutes (T15), 30 minutes (T30), 45 minutes (T45), and 60 (T60) minutes posttreatment.
bEvaluation 240 minutes (T240) posttreatment.
cIncludes rescue treatment if needed.
Once the treatment was completed, each participant was asked to rate on a paper questionnaire their pain perception on an 11-point NRS (0: no pain, 10: unbearable pain) and their perceived pain relief on a 5-point categorical scale 15 minutes (T15), 30 minutes (T30), 45 minutes (T45), and 60 minutes (T60) after administration of the allocated study treatment. During the first hour, participants remained under the direct supervision of the study site staff. After the first hour, and if cleared by the study site staff, participants were free to leave the study site and go home to complete next assessment 240 minutes (T240) after the end of the treatment. Adverse events (AEs), if any, were collected during the entire duration of patients’ participation. Before leaving the clinic, participants underwent a general health status check to ensure they were not experiencing any AEs and were able to go home.
At home, patients were asked to rate on a paper questionnaire their pain relief on a 5-point categorical scale and pain intensity based on the 11-point NRS at T240 or at the last time point if the participant dropped out the study or began taking a rescue medication before the end of the follow-up period.
Pain intensity was evaluated on an 11-point NRS at T0, T15, T30, T45, T60, and T240. This scale is the reference tool to assess pain in most clinical trials, and it has been used in various recent studies, including those related to endometriosis [
Pain relief was evaluated on a 5-point categorical scale (0: no relief, 1: slight relief, 2: moderate relief, 3: lots of relief, and 4: complete relief) at T0, T15, T30, T45, T60, and T240.
If rescue medication was needed, the participant was asked to rate their pain intensity or pain relief just prior to the intake of the rescue medication. Study follow-up was terminated upon the intake of rescue medication.
Patients who dropped out before the end of the 240-minute follow-up period were not replaced.
A linear mixed-model framework was used for statistical analysis (SPSS 2020, IBM Corp). The selected covariance matrix of the repeated measurements that better fitted the data based on the Akaike Information Criterion was the first-order ante-dependence. There were 3 explanatory fixed factors: group (Endocare, control), time (T0, T15, T30, T45, T60, T240), and group*time, as well as a random effect on the intercept of each participant. In the first analysis, time (fixed effect) was parametrized as baseline (T0) versus all other times (T15 to T240). The analysis consisted of comparing T0 with the 5 posttreatment data clustered for both groups and looking at the interaction term (group*time). A contrast analysis was also performed to verify the difference between baseline (T0) and posttreatment times (clustered) in the 2 separate groups. In the second analysis, time was parametrized as T0, T15, T30, T45, T60 and T240. A contrast analysis was also performed to test the difference between T0 and all other times (separated) in both groups. Bonferroni corrections were applied for multiple comparisons.
For pain relief, data were analyzed using R software. Because data did not satisfy to normality when assessed with the Shapiro-Wilk normality test, Wilcoxon unilateral unpaired tests corrected for multiple comparisons with a false discovery rate (FDR) were used.
Of the 45 women that participated in the study, 1 (2%) did not return the questionnaire. Among the patients included, 1 (2%) from the treatment group and 4 (9%) from the control group took rescue medication after T60 but before T240. Therefore, in accordance with the study design, no results at T240 were collected for these 5 patients. Participants from both groups were comparable in terms of age, height, and weight (
All participants were recruited from a clinic that specializes in endometriosis and were living with severe endometriosis-associated symptoms (
Most of the patients were taking different classes of medications for their endometriosis condition, including hormones, analgesics, and antidepressants (
Participant demographics.
Characteristics | Total (N=45) | Endocare (n=23) | Control (n=22) | |
|
||||
|
Ma (missingb) | 45 (0) | 23 (0) | 22 (0) |
|
Mean (SD) | 32.7 (8.02) | 32.2 (8.02) | 33.2 (8.12) |
|
Median | 31 | 32 | 30.5 |
|
Minc | 21 | 21 | 21 |
|
Maxd | 53 | 53 | 51 |
|
|
|||
|
M (missing) | 44 (1) | 22 (1) | 22 (0) |
|
Mean (SD) | 162.7 (7.22) | 162.6 (6.72) | 162.8 (7.84) |
|
Median | 165 | 165 | 164 |
|
Min | 148 | 148 | 150 |
|
Max | 175 | 175 | 175 |
|
||||
|
M (missing) | 44 (1) | 22 (1) | 22 (0) |
|
Mean (SD) | 63.8 (12.51) | 67.2 (12.46) | 60.4 (11.88) |
|
Median | 60 | 63.5 | 57 |
|
Min | 45 | 50 | 45 |
|
Max | 95 | 95 | 92 |
aM: total number of cases.
bMissing: total number of cases with missing data.
cMin: minimum.
dMax: maximum.
Participants’ history of endometriosis.
Variable | Total (N=45) | Endocare (n=23) | Control (n=22) | ||
|
|||||
|
Ma (missingb) | 45 (0) | 23 (0) | 22 (0) | |
|
Mean (SD) | 45.2 (54.9) | 43.4 (59.3) | 47.2 (51.1) | |
|
Median | 23.8 | 16.6 | 23.8 | |
|
Minc | 2.2 | 2.5 | 2.2 | |
|
Maxd | 277.8 | 277.8 | 199.7 | |
|
|||||
|
Superficial peritonea | 10 (22.2) | 6 (26.1) | 4 (18.2) | |
|
Deep infiltrating endometriosis | 34 (75.6) | 17 (73.9) | 17 (77.3) | |
|
Digestive locations | 1 (2.2) | 1 (4.3) | 0 (0) | |
|
Other | 2 (4.4) | 1 (4.3) | 1(4.5) | |
Presence of adenomyosis, n (%) | 11 (24.4) | 6 (26.1) | 5 (22.7) | ||
History of surgical management of endometriosis, n (%) | 31 (68.9) | 14 (60.9) | 17 (77.3) | ||
|
|||||
|
M (missing) | 31 (14) | 14 (9) | 17 (5) | |
|
Mean (SD) | 40.6 (43.9) | 40.5 (36.5) | 40.6 (50.2) | |
|
Median | 24.4 | 38.8 | 23.8 | |
|
Min | 0.1 | 2.1 | 0.1 | |
|
Max | 199.7 | 136.0 | 199.7 | |
|
|||||
|
Yes | 13 (41.9) | 3 (21.4) | 10 (58.8) | |
|
No | 18 (58.1) | 11 (78.6) | 7 (41.2) | |
|
|||||
|
M (missing) | 13 (0) | 3 (0) | 10 (0) | |
|
Mean (SD) | 35.1 (55.2) | 9.5 (15.5) | 42.8 (61.1) | |
|
Median | 21.1 | 1.7 | 22.0 | |
|
|||||
|
|
|
|
|
|
|
|
None | 10 (22.2) | 6 (26.1) | 4 (18.2) |
|
|
Combined hormonal contraceptives | 14 (31.1) | 7 (30.4) | 7 (31.8) |
|
|
Progestogens | 18 (40.0) | 9 (39.1) | 9 (40.9) |
|
|
Gonadotrophin-releasing hormone agonists | 1 (2.2) | 0 (0) | 1 (4.5) |
|
|
Other | 2 (4.4) | 1 (4.3) | 1 (4.5) |
|
Chronic analgesic treatment | 26 (57.8) | 14 (60.9) | 12 (54.5) | |
|
Other treatment | 16 (35.6) | 7 (30.4) | 9 (40.9) | |
|
|||||
|
Chronic pelvic pain not related to menses | 41 (91.1) | 21 (91.3) | 20 (90.9) | |
|
Dysmenorrhea | 24 (53.3) | 12 (52.2) | 12 (54.5) | |
|
Dysuria | 14 (31.1) | 6 (26.1) | 8 (36.4) | |
|
Dyschesia | 1 (2.2) | 1 (4.3) | 0 (0) | |
|
Dyspaneuria | 29 (64.4) | 15 (65.2) | 14 (63.6) |
aM: total number of cases.
bMissing: total number of cases with missing data.
cMin: minimum.
dMax: maximum.
We first analyzed the differences between the baseline pain (T0) and the 5 clustered posttreatment measurements covering 15 minutes to 4 hours after the treatment (ie, T15, T30, T45, T60, and T240) in both groups using a linear mixed model (
Difference in pain perception between baseline and the 5 clustered posttreatment measurements.
Mean pain perception (± standard error) in both groups (ie, Endocare, control) at baseline (black: T0) and the 5 clustered posttreatment measurements (white: T15, T30, T45, T60, and T240). ##
We then aimed to analyze the differences between the baseline (T0) and each of the 5 posttreatment measurements separately (ie, T15, T30, T45, T60, or T240) in both groups using a mixed model (
Difference in pain perception before and each of the 5 posttreatments measurements.
Mean pain perception (± standard error) in both groups (bold line: Endocare; dash-line: control) at baseline (T0) and each of the 5 posttreatment measurements (T15, T30, T45, T60, or T240). +
A total of 31 (70%) participants had surgery related to endometriosis (14 in the Endocare group and 17 in the control), and 11 (25%) suffered from adenomyosis (6 in the Endocare group and 5 in the control). Thus, we introduced 2 covariates, surgery and adenomyosis, into the linear mixed model. Neither surgery (
At each posttreatment measurements, participants were asked to measure their perceived pain relief on a 5-point numerical scale from no relief to total relief (
Difference in pain relief at each of the 5 posttreatment measurements.
Percentage of pain relief (± standard error of the mean) in both groups (circles and bold line: Endocare; squares and dash-line: control) at each of the 5 posttreatment measurements (T15, T30, T45, T60, or T240). +
Finally, we analyzed the maximum reduction of pain intensity in both groups. The mean maximum effect was 42% (95% CI 30.82-53.18) for Endocare and 22% (95% CI 15.38-28.53) for the control group. The maximum effect was significantly higher for the treatment group (Endocare; Cochran
Seven (15%) participants reported mild-to-moderate AEs, of which 4 (8%) were evaluated as probably unrelated and 3 (6%) as possibly related to the Endocare treatment. The 3 possibly related events were within the treatment group and described as a mild headache and nausea related to motion sickness.
In this RCT, we aimed to measure the immediate and 4 hours persisting effects of a single use of a 20-minute DTx (Endocare) on pain in women living with pelvic pain related to endometriosis. We showed that Endocare was able to significantly reduce the overall pain perception when comparing the pain at baseline (T0) with the combined 5 posttreatment measurements from 15 minutes (T15) to 4 hours (T240).
We found that our digital control was also able to significantly reduce the overall pain perception but significantly less than the Endocare treatment. Next, we wanted to evaluate whether the pain reduction was significant at each posttreatment measurement (ie, T15, T30, T45, T60, and T240) compared to baseline (T0) in each group. We showed that this was the case for the Endocare group but not for the control group, thus confirming the analgesic effect of the Endocare treatment. To our knowledge, our study is the first to demonstrate an effect on pain reduction in women living with moderate-to-severe pelvic pain due to endometriosis by using a nonpharmacological treatment that combined VR with visual and auditory stimuli.
Numerous studies have shown that VR is an effective way to reduce acute pain intensity, especially pain experienced during medical procedures, by burn victims, or by women during childbirth [
Thus, the combination of these stimulations potentialized with the VR experience could lead to the decrease in pain observed in the Endocare group immediately after and up to 4 hours posttreatment.
In the field of VR research, while some studies do not use a control group [
In this study, we chose to use a digital control program displayed through a 2D tablet with a headset, allowing us to control for the Endocare treatment and not solely the VR apparatus or the stimuli. Indeed, our digital control contained the same composition as the Endocare treatment (ie, context, environment, duration) without the immersive aspect of VR or the auditory and visual stimuli of the treatment. However, to preserve an immersive-like session, we chose to keep a soundtrack composed of nature sounds related to the projected image in the control group, which could potentially explain the positive outcome observed. This slight decrease in pain intensity observed in the control group indicates that our control is relevant.
One limitation of our study may be the population, as we decided to work with patients living with mostly severe pain related to a complex and chronic pain condition, which could represent a selection bias. We likely could have had slightly better treatment results with less severe pain conditions. However, to assess this potential selection bias and analyze whether the beneficial effect would be lessened in populations with complex pathologies related to endometriosis, we covariated for surgery and adenomyosis, 2 conditions with potentially more pain and less responses to the treatment. We found that the results were equivalent, suggesting a similar effect in all subpopulations, including those with a more complex pathophysiology. Nevertheless, an effect in the range of 30% for Endocare can ultimately be considered moderately significant according to the IMMPACT guidelines [
In conclusion, this pilot study on the Endocare treatment shows encouraging results for developing a digital therapy to relieve patients of pelvic and perineal pain associated with endometriosis. Moreover, Endocare treatment can be a great alternative to hormonal treatment or surgery for women who wish to get pregnant. These results will be further investigated in a second study evaluating the analgesic effects of the repeated use of Endocare at home with a larger population of women living with chronic pelvic pain associated with endometriosis. In the future, Endocare could benefit patients diagnosed with endometriosis during their everyday life to reduce the acute and chronic pain encountered in this pathology, thus improving their quality of life.
CONSORT eHEALTH checklist (V 1.6.1).
adverse event
chronic pelvic pain
digital therapeutics
false discovery rate
Franco-European Multidisciplinary Endometriosis Institute
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
magnetic resonance imagery
numerical rating scale
randomized controlled trial
virtual reality
None declared.