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In two randomized trials, two different doses of the oral gonadotropin-releasing hormone antagonist elagolix significantly reduced endometriosis-related dysmenorrhea and nonmenstrual pelvic pain but had hypoestrogenic adverse effects.

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 P<.01). Endocare was significantly more effective than the control group (all P<.01). Endocare decreased the mean pain intensity from 6.0 (SD 1.31) before the treatment to 4.5 (SD 1.71) posttreatment, while the control only decreased it from 5.7 (SD 1.36) to 5.0 (SD 1.43). When comparing each posttreatment measures to the pretest, Endocare significantly reduced pain perception for all points in time up to 4 hours posttreatment. The differences did not reached significance for the control group. Moreover, Endocare was significantly superior to the control group 15, 30, and 45 minutes after the treatment (all P<.001). The mean perceived pain relief was significantly higher for Endocare at 28% (SD 2%) compared to the control, which was 15% (SD 1%) for all the posttreatment measurements (all P>.05). 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.

To evaluate the effect of melatonin supplementation on sleep quality and pelvic pain in infertile women with endometriosis and sleep disturbances. A randomized, triple-blind, placebo-controlled trial was conducted among 80 infertile women with endometriosis and sleep disturbances. Participants were randomly assigned to receive either 5 mg melatonin or placebo for 2 months. The primary outcome was change in overall sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included changes in specific PSQI domains and chronic pelvic pain. Among 80 infertile women with endometriosis and sleep disturbances, melatonin significantly improved overall sleep quality compared to placebo, with a large effect size (p < 0.001, η² = 0.20, Cohen's d=1). The mean difference in sleep quality was a reduction of -1.7 on the PSQI, although it did not reach the clinically meaningful threshold of 3 points. Melatonin also led to considerable improvements in specific PSQI domains including: a substantial increase in sleep duration and a marked reduction in sleep disturbances. Furthermore, melatonin significantly decreased sleep latency, exhibiting a large effect size, and contributed to a medium reduction in the use of sleep medications. However, no significant improvements were noted in sleep efficiency, daytime dysfunction, or subjective sleep quality. Additionally, melatonin significantly reduced chronic pelvic pain, with a large effect size (p < 0.001, η² = 0.18, Cohen's d = 0.93). While melatonin may improve sleep quality and reduce pelvic pain, further investigation is needed to assess its clinical relevance in this population. ClinicalTrials.gov IRCT20171209037794N4.

AbstractObjectivesTo evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain.DesignThe PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial.Setting34 UK hospitals.Participants405 women of reproductive age undergoing conservative surgery for endometriosis.InterventionsParticipants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill.Main outcome measuresThe primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment).Results405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference −0.8, 95% confidence interval −5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00).ConclusionsPostoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some.Trial registrationISRCTN registry ISRCTN97865475.

Chronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology. We performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762. Participants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group. This study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology. National Institute for Health Research.

Endometriosis is defined by the presence of endometrial-like tissue (lesions) outside the uterus, commonly on the pelvic peritoneum. It affects 6-10% of women and is associated with debilitating pelvic pain. Current management options are often unsatisfactory. Omega-3 polyunsaturated fatty acids (O-PUFA) have the potential to reduce the painful symptoms associated with endometriosis, reduce lesion size, preserve the patient's ability to conceive, and have minimal side effects. We performed a two-arm, parallel double-blinded randomised controlled trial to inform the planning of a future multicentre randomised controlled trial to evaluate the efficacy of O-PUFA for endometriosis-associated pain. The primary objectives of the trial were to assess recruitment and retention rates. The secondary objectives were to determine the acceptability to women of the proposed methods of recruitment, randomisation, treatments and questionnaires, to estimate the variability in the proposed primary endpoints to inform the sample size calculation and to refine the research methodology for the future definitive trial. We recruited women with endometriosis from June 2016 to June 2017 and randomised them to eight weeks of treatment with O-PUFA or olive oil. Pain scores and quality of life questionnaires were collected at baseline and eight weeks. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to eight weeks. Acceptability questionnaires were used to evaluate women's experiences of the trial. The proportion of eligible participants who were randomised was 45.2% (33/73) and 81.8% (27/33) completed the study. The majority of participants described their overall trial experience favourably and there were no adverse events in either group. Our pilot trial supports the feasibility of a future larger trial to definitively evaluate the efficacy of O-PUFA for endometriosis-associated pain. The trial was registered on the ISRCTN registry (registration number ISRCTN44202346).

Background Endometriosis presents as endometrial tissue growths outside the uterine cavity with its major symptoms including dysmenorrhea and infertility. Progestin preparations, such as dienogest, are the first-line therapy for endometriosis symptoms, but may cause abnormal uterine bleeding. A gonadotropin-releasing hormone (GnRH) agonist may also be used to ease symptoms, but may induce flare-ups. Relugolix is a non-peptide GnRH antagonist that does not induce flare-ups. This study aims to compare the efficacy of relugolix with that of dienogest for reducing endometriosis-associated pain, and to evaluate if relugolix, administered prior to dienogest, decreases abnormal uterine bleeding. Methods A multicenter, open-label, active-controlled, non-inferiority randomized study will be conducted at 11 sites in Japan. A total of 100 premenopausal patients aged ≥ 18 years with endometriosis, a maximum visual analog scale (VAS) score > 30 for endometriosis-associated pain, and dysmenorrhea or pelvic pain of at least moderate severity on the Biberoglu & Behrman (B&B) scale will be randomized in a 1:1 ratio to either a relugolix group or dienogest group. Patients in the relugolix group will receive 40 mg oral relugolix once daily for 16 weeks, followed by 1 mg oral dienogest twice daily for 24 weeks. Patients in the dienogest group will receive oral dienogest 1 mg twice daily for 24 weeks. The primary outcome will be change in maximum VAS score for endometriosis-associated pain from baseline to 13–16 weeks after start of treatment. The secondary outcomes will include VAS score for dyspareunia, B&B score for dysmenorrhea, severity of induration in the pouch of Douglas, restricted uterine mobility, pelvic tenderness, quality of life, analgesic use, and ovarian endometrioma diameter. The safety outcomes will include treatment-emergent adverse events, bone density, bone markers, menstrual status, genital bleeding, and endometrial thickness. Discussion This study will determine the efficacy of relugolix for improving endometriosis-associated pain and dienogest-induced abnormal uterine bleeding. The results will support treatment decisions regarding endometriosis-associated pain, and the introduction of new treatments to reduce dienogest-induced abnormal uterine bleeding. Trial registration Japan Registry of Clinical Trials ID jRCTs061230064. Registered on 29 September 2023.

Introduction and hypothesisBotulinum toxin (BoNT) is increasingly used for pain, especially with muscle spasm. We describe our methodology for BoNT treatment of chronic pelvic pain (CPP) in women and place it in the context of the literature on techniques for this use.MethodsDatabases were searched using terms “botulinum toxin,” “pelvic pain,” and “vaginismus.” Reports on vaginismus/vulvodynia/vestibulodynia (included if pelvic floor muscles were injected) were grouped as “vaginismus/vulvar pain disorders” (V/VPD). We analyzed the type of report, condition, toxin serotype/brand, dose/dilution, muscle selection, guidance technique, and anesthesia. Publications from the same authors without unique information were combined for specific analyses.ResultsThirty-eight reports had analyzable information; many lacked complete information. Most were open-label prospective reports; there were four technical reports, one randomized comparison of doses and one placebo-controlled study of efficacy. Pelvic floor muscles were approached transvaginally, transperineally or transgluteally. BoNT brand/dose/dilution varied widely. Muscle localization techniques included anatomical landmarks only, electromyography, electrical stimulation with/without ultrasound, and fluoroscopy/CT scanning. Papers discussing analgesia utilized general anesthesia, conscious sedation with/without topical/local anesthesia, topical/local agent alone or pudendal block before or after injection. Cumulatively, 58–100% of patients with CPP and 71–100% of those with V/VPD improved. Serious adverse events (transient fecal incontinence/constipation, urinary incontinence/retention) were more frequent with higher doses.ConclusionsBoNT can be safely and tolerably injected into pelvic floor muscles in women as an out-patient procedure. This study identifies methodological factors to be considered in future studies and the critical need for high-quality clinical trials for this emerging treatment.

Chronic pelvic pain (CPP) affects 2.1-24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700 mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women's experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012-2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07-3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97-6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial.

PurposeIn this placebo-controlled trial, we aimed to evaluate the clinical results of using PDE-5 inhibitor, tadalafil 5 mg OD, for management of CP/CPPS.Patients and methods140 patients ≤ 45 years old with moderate/severe CP/CPPS associated with ED (IIEF-5 < 22) were randomly divided and received either tadalafil 5 mg OD (tadalafil-group) or placebo (control-group) for 6 weeks. Post-treatment CPSI scores were compared to baseline and to placebo. Clinically significant responders (≥ 25% reduction from baseline score) were calculated. Tadalafil-induced changes in IIE-5 were evaluated in correlation to that of CPSI scores.ResultsBy the 6th week, 59 and 56 patients were available in both groups respectively. Compared to baseline, tadalafil-group patients showed significant improvement in total, pain, urinary and Qol domains of CPSI (19.1 ± 5.26, 10.42 ± 3.55, 4.2 ± 1.72 and 4.47 ± 1.64 vs. 24.21 ± 5.05, 12.14 ± 3.57, 6.08 ± 1.53 and 6.22 ± 1.76), p < 0.5. When compared to placebo, all 6th week CPSI domains scores, except for pain, were significantly better in tadalafil-group (p < 0.05). Post-treatment pain score didn't significantly differ between both groups (10.42 ± 3.55, vs. 11.71 ± 3.9, p > 0.05). Clinically significant responders were 30 patients (50.8%) in tadalafil-group vs. 3 patients (5.4%) in control. Tadalafil-induced changes in IIEF-5 score had weak but significant correlation to Qol domain (r = − 0.28, p < 0.05).ConclusionTadalafil 5 mg OD can significantly improve all CPSI domains as compared to baseline. Post-treatment CPSI scores, except for pain, were better than placebo. About 50.8% of patients can develop ≥ 25% reduction in their total CPSI scores after treatment. Apart from Qol domain, these changes are not significantly correlated to tadalafil-induced IIEF-5 scores changes.