All studies reporting the assessment and outcomes of selected holistic management for pelvic pain were included (randomised and non-randomised controlled trials, cohort studies and case series).

We performed a PubMed search with terms to include holistic management strategies for endometriosis, including the search terms applied of: endometriosis with nutrition, diet, cognitive behavioural therapy, mindfulness, yoga, progressive muscle relaxation, physiotherapy, acupuncture, devices, TENS, cannabis, Chinese medicine.

We did not perform formal risk of bias assessment, but reported bias risks like high attrition rates for individual studies.

The role of nutrition in managing chronic pain conditions is investigated in two SRs. ^{12 , 13} A high intake of anti-inflammatory nutrients reduces pain severity by modulating inflammation. ¹⁴ Gut microbiome dysbiosis is hypothesised to cause incorrect immune responses resulting in pain from central sensitisation pathways in inflammatory conditions such as endometriosis. Probiotics and FODMAP diets (omitting fermentable oligo-, di-, monosaccharides and polyols), are beneficial in treating visceral pain. ¹⁵ More research into diet in endometriosis is recommended, ¹⁶ given small population sizes with heterogeneity between intervention groups.

One SR (one RCT and five observational studies) of low FODMAP, gluten-free and low-nickel diets as well as high intake of omega-3 polyunsaturated fatty acids (average treatment dose palmitoylethanolamide 400 mg & polydatin 40 mg twice daily for 3 months) ^{17 – 19} reported that all diets, with the exception of low FODMAP reduced pain. ²⁰ However, those with endometriosis and irritable bowel syndrome (IBS) may benefit from low-FODMAPs; observational data (n=160) demonstrated symptom improvement compared to patients with IBS alone (72% vs. 40%, respectively, P=0.001). ²¹

Interestingly, women with endometriosis are approximately three times more likely to develop IBS, ²² posing diagnostic challenges since symptoms (bloating and diarrhoea) may overlap. Velho et al reviews the benefits of anti-inflammatory (e.g. plant based) diets and antioxidant vitamins supplements including vitamin D. ²³

Compared to controls, endometriosis patients appear to have more allergic nickel contact mucositis (odds ratio: 2.474; 95% confidence interval: 1.023~5.988; P=0.044), ²⁴ causing IBS-like symptoms. Reducing nickel-rich foods e.g. tomatoes, whole wheat, and soy, resulted in improvement of CPP ( P<0.05) in a prospective 3-month observational study of 31 endometriosis patients with gastrointestinal symptoms. ²⁵

Krabbenborg et al ²⁶ observed 157 endometriosis patients asking which of their own dietary modifications had improved their QoL using the EHP-30 score. The commonest diets were the endometriosis diet (omitting foods that appeared to worsen symptoms), gluten free, low-FODMAP, low-lactose and weight loss diets. Although EHP-30 scores did not significantly alter with dietary modification, pain reduction was noted in 71.3% of patients, with gluten-free showing the greatest impact. Dietary modifications have a greater impact with longer adherence.

In a placebo-controlled triple-blind RCT (n=120) garlic extract (400 mg daily over 12 weeks) showed a significant reduction in ERPP ( P<0.05). Purported mechanisms are reduction in oxidative stresses, prostaglandin production, endometriosis cell proliferation and increased oestrogen elimination. ²⁷

Both low and high BMI appear to be associated with endometriosis severity, ²⁸ a confounding factor for both endometriosis and obesity being systemic inflammation. ²⁹

It is tempting to speculate whether maintaining a normal BMI is beneficial for ERPP, and further studies are needed.

Poor mental health may be a result of the impact endometriosis has on physical, sexual, and psychological well-being. ³⁰ Strategies such as cognitive behavioural therapy (CBT), yoga and relaxation techniques can be valuable. Increasing evidence suggests psychosocial factors, such as preoperative pain catastrophising independently impact pain experience, severity of symptoms and recurrence of endometriosis. ^{31 , 32} Patient awareness and self-uptake of psychological approaches for ERPP are increasingly popular, with 93.8% of women sampled in a cross-sectional survey distributed via The Endometriosis Network Canada (n=434) utilising at least one psychological management strategy. ³³

Please see Table 1 for a summary of the body and mind therapies.

CBT

CBT is recognised as an effective treatment for chronic pain and associated mental health conditions, including CPP. ³⁴ Three recent RCT protocols assessing efficacy of CBT ^{35 , 36} and yoga with CBT ³⁷ on QoL of patients with endometriosis indicate current interest. Boersen’s RCT ³⁶ aims to assess CBT in 100 postoperative endometriosis patients.

Wu et al ³⁸ assessed CBT with usual care compared to usual care alone in post-surgical endometriosis patients in a case-control study (Interventions n=48, Controls n=48), utilising one CBT session before and six sessions post-surgery. During a 6-month follow-up, participants scored on the depression, anxiety, and stress scale (DASS-21). Anxiety scores improved significantly ( P=.0091).

Authors highlight the important role of patient education in self-management of ERPP following CBT.

Mindfulness

Mindfulness is a psychological technique that draws on awareness and non-judgemental acceptance of present personal experience. The mindfulness-based stress reduction (MBSR) programme, developed by Kabat-Zinn ³⁹ is an adjunct to treatment for chronic pain, through relating physical and psychological conditions.

Moreira et al ⁴⁰ assessed the impact of mindfulness on ERPP in an RCT: They adapted the MBSR programme, forming a brief mindfulness-based intervention (bMBI, n=31, usual care controls n=32) with reduced intensity and duration (4-weeks instead of 8-weeks). Formal meditation was practised around the theme of ‘reconceptualising pain.’ The intervention group showed reduction in pain scores, pain unpleasantness and dyschezia.

Hansen et al ⁴¹ found that psychological intervention, improved QoL in a three-armed RCT, without reducing ERPP perception. Endometriosis patients were randomised to three groups: mindfulness and acceptance-based intervention (n=20), non-specific psychological intervention without mindfulness (relaxation and guided physical therapy) (n=19), or waitlist control with usual treatment only (n=19). All participants received usual treatment including analgesia. The ten-week programme (MY-ENDO) combined Kabat-Zinn’s MBSR programme and acceptance and commitment therapy (ACT). There was no significant reduction in ERPP between the MY-ENDO and non-specific psychological intervention ( P=0.144, d=0.59). Psychological intervention significantly improved QoL-subscales ‘control and powerlessness’ ( P=0.019, d=0.78), ‘emotional well-being’ ( P=0.003, d=1.01), and ‘social support’ ( P=0.042, d=0.66).

QoL was improved through the positive effects on bowel symptoms, specifically diarrhoea ( P=0.035, d=0.25), within the two intervention groups, likely due to physical activity undertaken.

Further studies are needed to determine whether psychological interventions in general improve QoL or whether it is the mindfulness intervention.

Yoga

Yoga has a long tradition in managing chronic pain. In an AB-design pilot study (patients served as their own control group) 42 endometriosis patients by Ravins et al, ⁴² participants underwent eight-weeks of conventional therapy followed by eight-weeks of 90-minute endometriosis yoga sessions, bi-weekly. EHP-30 scores and numerical pain rating scale were lower after the yoga sessions ( P=0.001).

Gonçalves’ RCT, ⁴³ randomised 40 women with ERPP to 90-minutes of yoga bi-weekly for 8 weeks (n=28) or no yoga (n=12). Daily pain was significantly lowered by yoga ( P=0.0007). EHP-30 domains were assessed at the time of presentation and at 8-weeks; scores for pain ( P=0.0046), well-being ( P=0.0009), and self-image ( P=0.0087) improved significantly over time only in the yoga group. Only 57% of participants in the intervention group completed the yoga programme, highlighting the challenges faced of adhering to regular yoga practice.

Saxena et al ⁴⁴ also demonstrated benefits of yoga over conventional care; 30 women with CPP were randomised to yoga therapy and 30 to conventional therapy (non-steroidal anti-inflammatory painkillers (NSAIDs). Pain scores (VAS score) and QoL (World Health Organization WHOQOL-BREF questionnaire) were assessed at baseline and 8-weeks. In contrast to the controls the yoga group showed a significant decrease in pain intensity ( P<0.001) and QoL improvement with a significant increase ( P<0.001) in physical, psychological, social, and environmental domain scores of WHOQOL-BREF.

Enriched environments (more space to move about, increased physical activity and social interactions) suppresses the development of endometriosis in mice by attenuating adrenergic signalling, enhancing autophagy, and reducing leptin levels. ⁴⁵ Extrapolating this to humans, Flores et al ⁴⁶ reported a significant reduction in pelvic pain, perceived stress and improved mood and emotional wellbeing in endometriosis patients who were randomised to outdoor physical activities such group yoga to optimise environmental enrichment as compared to controls.

Progressive muscle relaxation (PMR)

PMR is an exercise that reduces stress and anxiety through slowly tensing and relaxing muscle groups throughout the body. PMR improved anxiety and depression ( P<0.05), and health-related QoL ( P<0.05) for patients with endometriosis in an RCT of 100 women receiving Gonadotrophin-releasing hormone (GnRH) agonist treatment, randomly assigned to 12 weeks of PMR training or a control group. ⁴⁷

Psychological and physical interventions positively impact on QoL in patients with ERPP. However, there remains a lack of high-powered trials in mind and body therapies. Consideration must be taken for the barriers to accessing psychological interventions. Particularly, patients should not feel their pain is less validated if a physiological approach is offered. Nowadays smart-phone applications are often suggested to simplify access to Mindfulness. However, those approaches require co-development with stakeholders to be acceptable and used regularly. ⁴⁸

Pelvic floor muscle physiotherapy

Pelvic floor muscle dysfunction (specifically levator ani hypertonia and incomplete relaxation) contributes to ERPP with deep infiltrative endometriosis (DIE). ^{49 – 51}

Pelvic floor physiotherapy (PFP), assessed by 3D/4D trans-perineal ultrasound, increased levator hiatus area (LHA) which in turn improved dyspareunia and pelvic floor muscle relaxation (PFMR) reduced ERPP. Following a successful pilot study, ⁵² Forno et al used trans-perineal ultrasound to assess LHA before and after PFP in an RCT of 34 women with ERPP. ⁵³ Participants were assigned to treatment with five PFP sessions (n=17) or no intervention (n=17). Physiotherapy sessions involved the Thiele massage, using digital pressure to elongate and relax muscles, restoring normal tone. PFMR improved on maximum Valsalva manoeuvre in the intervention group compared to the control (20.0 ± 24.8% vs –0.5 ± 3.3%, respectively; P=0.02), and superficial dyspareunia pain scores reduced ( P<0.01)

Injection of botulinum toxin may have a role in easing CPP, however existing research lacks standardisation of the toxin brand, site of injection, dose and outcome measures. ⁵⁴

A cohort study of 13 women with endometriosis and pelvic floor spasm reported that 4-8 weeks following injection of 100 units of onabotulinumtoxinA into the pelvic floor muscles reduced pain in all women (median VAS=2, range 0–5/10, P<0.0001). ⁵⁵

Previous studies have shown acupuncture to be a suitable tool in reducing ERPP, and is considered a safe therapy with minimal side effects. ^{56 , 57} Several recent case studies have shown symptomatic improvement with acupuncture. ^{58 , 59} Yan et al published a protocol for SR and meta-analysis of RCTs on acupuncture benefits for endometriosis symptoms. ESHRE guidelines ⁶⁰ acknowledge that acupuncture may be a beneficial tool, however the studies that were available at that time were limited and not free from bias.

Wang et al ⁶¹ recently published a SR of 15 RCTs (sample sizes between 10 and 54), which assessed the effectiveness of acupuncture and/or moxibustion for the treatment of endometriosis. Compared with sham acupuncture, actual acupuncture was more effective at reducing dysmenorrhea VAS pain score (mean difference [MD] − 2.40, 95% CI [− 2.80, − 2.00]; moderate certainty evidence), pelvic pain VAS score (MD − 2.65, 95% CI [− 3.40, − 1.90]; high certainty evidence) and dyspareunia VAS scores (MD − 2.88, [− 3.83, − 1.93]), lessened the size of ovarian cysts (MD − 3.88, 95% CI [− 7.06, − 0.70]), and improved quality of life. These promising results suggest that acupuncture may be an effective adjunct to treating ERPP.

In a multicentre, randomised, single-blind, placebo-controlled trial ⁶² assessing the effects of acupuncture on endometriosis related symptoms (n=106), acupuncture was delivered to the intervention group (n=51) as 30-minute sessions once daily, three times a week, starting one week before expected onset of menstruation, for a total duration of 12-weeks. The control group (n=53) received sham acupuncture. Lower VAS scores were seen in the intervention group at 12 weeks for dysmenorrhoea (-2.82 (-3.47, -2.18) and QoL, (EHP score) -18.88 (-31.88, -5.87)), but not for pelvic pain and dyspareunia. At 24 weeks no statistical benefits were seen, suggesting acupuncture is a suitable immediate therapy for endometriosis related dysmenorrhoea, however the effects of acupuncture may not be sustainable over a long period of time and repeated therapy would be necessary. Notable limitations of this study include the lack of blinding and the inability to assess non-menstrual CPP.

Phallus length reducing devices

The Ohnut© device is a phallus length reducer worn over the penis or penetrating object with the intention to reduce endometriosis-associated deep dyspareunia, sparing the cervix and retro-cervical area from direct pressure. The effectiveness of this device is currently being assessed in a pilot RCT of 40 participants with ERPP by Zhang ⁶³ who will be randomised into an intervention group or a waitlist control group.

Transcutaneous electrical nerve stimulation (TENS)

A TENS unit passes an electrical current through skin electrodes for targeted pain relief. The spinothalamic nerve tract transmits both pain and touch, but not at the same time (gate control theory). ⁶⁴ Its use has been shown to reduce pain in primary dysmenorrhoea ⁶⁵ and CPP. ^{66 , 67}

Mira et al ⁶⁸ conducted a multicentre RCT of 101 participants with deeply infiltrating endometriosis. The study aimed to identify whether the addition of a TENS unit to hormonal therapy (n=53) would provide a greater therapeutic benefit than hormonal treatment alone (n=48). TENS was used twice a day, 20 minutes per day, for 8 weeks. CPP improved in the intervention group (VAS decreased from 7.11 ± 2.40–4.55 ± 3.08, P<0.001, 36% decrease), but not in controls (VAS from 7.33 ± 2.09–7.06 ± 2.33, P=0.554, 3.68% decrease). A greater improvement in deep dyspareunia was found in the intervention group, 32.67% reduction vs. 13.84% reduction in the controls. There was a decrease in the number of days participants experienced pain from the first week to the eighth week (from 3.27 to 2.22, P=0.028, 32.11% decrease), which was not identified in the control group (from 4.55 to 4.07, P=0.203, 10.54% decrease). This study was conducted over a relatively short time interval, therefore due to the chronic nature of endometriosis, further research is needed to assess whether benefits from TENs units are sustained longer-term.

CBD has antioxidant, antifibrotic and anti-inflammatory effects, and has been shown to reduce th diameter, volume and area of endometrioma as well as lesion morphology in endometriosis. ⁶⁹ A SR suggests that CBT use can relieve CPP in up to 95.5% of its users. ⁷⁰

A cross sectional survey ⁷¹ of 113 women with pelvic, perineal pain, dyspareunia or endometriosis was conducted to gather information regarding patient cannabis use. 26/113 (23%) participants reported cannabis use, of which only 5/26 obtained cannabis through a medical programme, 25 had complete data and were analysed. 15/25 (60%) used a combination of CBD and tetrahydrocannabinol (THC). There was no significant difference between the demographics of cannabis users and nonusers. Overall, 24/25 (96%) of participants reported improvement in symptoms such as pain, depression and sleep disturbance with the use of cannabis. It is important to note that participants from both groups also utilised alternative medications and therapies, and therefore reported symptom improvement cannot be confidently solely attributed to cannabis use.

Cannabis use was found to be the most effective form of self-management in an Australian online survey completed by 484 women with endometriosis. Women reported pain relief of 7.6 on a scale of 0-10 with cannabis use (SD 2.0), and 6.3 with hemp oil/CBD oil use (SD 3.0). ⁷²

Zhao et al ⁷³ performed a non-blinded RCT of 320 patients undergoing endometriosis surgery to investigate the effects of TCM (activating blood circulation and removing blood stasis treatment based on syndrome differentiation; n=131) and Western medicine (GnRH agonist or progesterone’s; n=141) on QOL postoperatively.

Pre-treatment WHOQOL-BREF scores, a QOL assessment tool with four domains including physical health, psychological, social relationships and environment, showed no significant difference between the two groups ( P>0.05), however post-treatment scores in the TCM group were significantly improved ( P<0.05) and the scores of 4 items (mobility, activities of daily living, sexual activity, QOL score) were also statistically significantly better ( P<0.05).

A Cochrane review by Flower et al ⁷⁴ assessed the effects of Chinese herbal medicine (CHM) for endometriosis. Only two RCTs were included (n=158), neither of which compared CHM with placebo. The first showed no significant difference in ERPP between CHM and gestrinone administration following laparoscopic treatment (95.65% vs. 93.87%; risk ratio (RR) 1.02, 95% confidence interval (CI) 0.93 to 1.12, one RCT). Combined oral CHM and herbal enemas provided better improvement in dysmenorrhoea than with danazol (RR 5.06, 95% CI 1.28 to 20.05; RR 5.63, 95% CI 1.47 to 21.54, respectively). There was no significant difference in lumbosacral pain, rectal discomfort, or vaginal nodule tenderness between CHM and danazol. Flower raises concern about the paucity of robust studies assessing on CHM in endometriosis and that the small size of the current studies.