Questionnaires for the Assessment of Central Sensitization in Endometriosis: What Is the Available Evidence? A Systematic Review with a Narrative Synthesis.

It has been suggested that central sensitization (CS) may be involved in the failure of standard medical and surgical treatment to relieve endometriosis-related pain. However, there is no gold standard for the diagnosis of CS, and self-reported questionnaires are used as diagnostic surrogates. The main objective of this review was to identify all CS questionnaires used in clinical endometriosis studies. The secondary objective was to qualitatively analyze strengths and weaknesses of each questionnaire. A PubMed and EMBASE systematic literature search conducted in April 2023 using the terms "endometriosis; central pain; central sensitization; questionnaire; patient-reported outcome measure; screening tool" identified 122 publications: six articles were included in the review. The Central Sensitization Inventory (CSI) is the most frequently used questionnaire for the detection of CS in patients with endometriosis. It has been validated in patients with endometriosis, in whom it appears to have good psychometric proprieties. The Fibromyalgia Survey Questionnaire (FSQ) has also been used, although it has not been specifically validated in endometriosis patients. The debate regarding these questionnaires' construct validity is still open and will be so until a gold standard diagnostic tool for CS is found. In fact, some authors argue these questionnaires are measuring psychological vulnerability and a hypervigilant state that is associated with pain, rather than CS itself. However, their use should not be discouraged as they are able to identify chronic pain patients which warrant further attention and who may benefit from broader treatment strategies.

Mitigating the economic burden of GnRH agonist therapy for progestogen-resistant endometriosis: why not?

STUDY QUESTION: Is it possible to reduce the cost of GnRH agonist treatment for endometriosis by using non-standard dosing regimens? SUMMARY ANSWER: An extended-interval dosing regimen of a 3.75 mg depot formulation of triptorelin injected every 6 weeks instead of every 4 weeks reduces the cost by one-third without compromising the effect on pain relief. WHAT IS KNOWN ALREADY: Cost constitutes a limit to prolonged GnRH agonists use. Alternative modalities to reduce the economic burden of GnRH agonist treatment have been anecdotally attempted. STUDY DESIGN SIZE DURATION: A systematic review was conducted to evaluate and compare the effect of three alternative modalities for GnRH use in women with endometriosis, i.e. intermittent oestrogen deprivation therapy, reduced drug dosage, and extended-interval dosing regimens of depot formulations. A PubMed and Embase search was initially conducted in October 2022 and updated in January 2023 using the following search strings: (endometriosis OR adenomyosis) AND (GnRH-agonists OR gonadotropin-releasing hormone agonists OR triptorelin OR leuprorelin OR goserelin OR buserelin OR nafarelin). Full-length articles published in English in peer-reviewed journals since 1 January 1980, and reporting original data on GnRH agonist treatment of pain symptoms associated with endometriosis were selected. PARTICIPANTS/MATERIALS SETTING METHODS: Information was extracted on study design, GnRH-agonist used, dosage, total duration of therapy, side effects, treatment adherence, and pelvic pain relief. Reviews, commentaries, conference proceedings, case reports, and letters to the editor were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1664 records screened, 14 studies regarding clinical outcomes associated with the 3 considered alternative modalities for GnRH agonist use were eventually included (intermittent oestrogen deprivation therapy, n = 2; low-dose or 'draw-back' therapy, n = 8; extended-interval dosing regimen, n = 4). Six studies were randomized controlled trials (RCTs) (double blind, n = 2) and eight adopted a prospective cohort design (non-comparative, n = 6; comparative, n = 2). A total of 776 women with endometriosis were recruited in the above studies (intermittent oestrogen deprivation therapy, n = 77; low-dose or 'draw-back' therapy, n = 528; extended-interval dosing regimen, n = 171). Robust data demonstrating cost saving without detrimental clinical consequences were available for the extended-interval dosing regimen only. In particular, the 3.75 mg triptorelin depot preparation inhibits ovarian function for a longer period compared with the 3.75 mg leuprorelin depot preparation, allowing injections every 6 instead of 4 weeks. Based on the cost indicated by the Italian Medicine Agency for the 3.75 mg triptorelin depot preparation, this would translate in a yearly saving of €744.60 (€2230.15-€1485.55; -33.4%). LIMITATIONS REASONS FOR CAUTION: The quality of the evidence reported in the selected articles was not formally evaluated and a quantitative synthesis could not be performed. Some studies were old and the tested therapeutic approaches were apparently obsolete. Only cost containment associated with GnRH analogue use, and not cost-effectiveness, has been addressed. WIDER IMPLICATIONS OF THE FINDINGS: Consuming less resources without negatively impacting on health outcomes carries ethical and practical implications for individuals and the community, as this approach may result in overall increased healthcare access. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Italian Ministry of Health (Ricerca Corrente 2023, IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano). E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest. REGISTRATION NUMBER: N/A.

A critical perspective on patient groups and industry funding

Patient groups are non-profit organizations that focus on the needs of people affected by a specific disease. Over the years, patient groups have assumed an increas-ingly decisive role in the healthcare decision-making process, and may influence the governments' decisions on key cru-cial health matters. Financial support for patient groups can come from different sources, including the pharmaceutical and medical device industries. Although patient groups may certainly benefit from drug companies economic support, in this commentary we address concerns regarding the pres-ence of potential conflict of interests (COIs), which may affect the independence, objectivity, integrity and reputation of the organizations.

Industry funding of patient and health consumer organisations: systematic review with meta-analysis.

OBJECTIVE: To investigate pharmaceutical or medical device industry funding of patient groups. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Ovid Medline, Embase, Web of Science, Scopus, and Google Scholar from inception to January 2018; reference lists of eligible studies and experts in the field. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Observational studies including cross sectional, cohort, case-control, interrupted time series, and before-after studies of patient groups reporting at least one of the following outcomes: prevalence of industry funding; proportion of industry funded patient groups that disclosed information about this funding; and association between industry funding and organisational positions on health and policy issues. Studies were included irrespective of language or publication type. REVIEW METHODS: Reviewers carried out duplicate independent data extraction and assessment of study quality. An amended version of the checklist for prevalence studies developed by the Joanna Briggs Institute was used to assess study quality. A DerSimonian-Laird estimate of single proportions with Freeman-Tukey arcsine transformation was used for meta-analyses of prevalence. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to assess the quality of the evidence for each outcome. RESULTS: 26 cross sectional studies met the inclusion criteria. Of these, 15 studies estimated the prevalence of industry funding, which ranged from 20% (12/61) to 83% (86/104). Among patient organisations that received industry funding, 27% (175/642; 95% confidence interval 24% to 31%) disclosed this information on their websites. In submissions to consultations, two studies showed very different disclosure rates (0% and 91%), which appeared to reflect differences in the relevant government agency's disclosure requirements. Prevalence estimates of organisational policies that govern corporate sponsorship ranged from 2% (2/125) to 64% (175/274). Four studies analysed the relationship between industry funding and organisational positions on a range of highly controversial issues. Industry funded groups generally supported sponsors' interests. CONCLUSION: In general, industry funding of patient groups seems to be common, with prevalence estimates ranging from 20% to 83%. Few patient groups have policies that govern corporate sponsorship. Transparency about corporate funding is also inadequate. Among the few studies that examined associations between industry funding and organisational positions, industry funded groups tended to have positions favourable to the sponsor. Patient groups have an important role in advocacy, education, and research, therefore strategies are needed to prevent biases that could favour the interests of sponsors above those of the public. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017079265.

Preliminary insights on the relation between endometriosis, pelvic pain, and employment.

AIMS: The economic burden of endometriosis and pelvic pain involves direct and indirect healthcare costs due to work loss and decreased productivity. However, the relation between endometriosis, pelvic pain, and employment remains underinvestigated. This study aimed at providing preliminary insights into this topic. METHODS: We compared the employment status (having vs. not having a job) in 298 consecutive endometriosis patients and in 332 women without a history of endometriosis (control group). We also examined the association between pelvic pain and employment status. RESULTS: Women with endometriosis were less likely to be employed compared to women without endometriosis (OR 0.508; 95% CI 0.284-0.908; p = 0.022). Women with symptomatic endometriosis were less likely to be employed relative to controls (OR 0.345; 95% CI 0.184-0.650; p = 0.001), as well as to asymptomatic endometriosis patients (OR 0.362; 95% CI 0.167-0.785; p = 0.01). No significant differences emerged between asymptomatic endometriosis and the control group (p > 0.05). Greater severity of dysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia was found in unemployed endometriosis patients (vs. employed endometriosis participants). CONCLUSION: Endometriosis symptoms may significantly affect women's professional life, with important socioeconomic, legal, and political implications. Community-based participatory research is encouraged.

Elagolix for endometriosis: all that glitters is not gold.

Elagolix, an orally active non-peptidic GnRH antagonist, has been approved by the Food and Drug Administration for the management of moderate to severe pain associated with endometriosis. As the degree of ovarian suppression obtained with elagolix is dose-dependent, pain relief may be achieved by modulating the level of hypo-oestrogenism while limiting side effects. Elagolix may thus be considered a novelty in terms of its endocrine and pharmacological properties but not for its impact on the pathogenic mechanisms of endometriosis, as the target of this new drug is, yet again, alteration of the hormonal milieu. Given the oestrogen-dependent nature of endometriosis, a reduction of side effects may imply a proportionate decrease in pain relief. Furthermore, if low elagolix doses are used, ovulation is not consistently inhibited, and patients should use non-hormonal contraceptive systems and perform serial urine pregnancy tests to rule out unplanned conception during periods of treatment-induced amenorrhoea. If high elagolix doses are used to control severe pain for long periods of time, add-back therapies should be added, similar to that prescribed when using GnRH agonists. To date, the efficacy of elagolix has only been demonstrated in placebo-controlled explanatory trials. Pragmatic trials comparing elagolix with low-dose hormonal contraceptives and progestogens should be planned to verify the magnitude of the incremental benefit, if any, of this GnRH antagonist over currently used standard treatments. The price of elagolix may impact on patient adherence and, hence, on clinical effectiveness. In the USA, the manufacturer AbbVie Inc. priced elagolix (OrilissaTM) at around $10 000 a year, i.e. $845 per month. When faced with unaffordable treatments, some patients may choose to forego care. If national healthcare systems are funded by the tax payer, the approval and the use of a new costly drug to treat a chronic condition, such as endometriosis, means that some finite financial resources will be diverted from other areas, or that similar patients will not receive the same level of care. Thus, defining the overall 'value' of a new drug for endometriosis also has ethical implications, and trade-offs between health outcomes and costs should be carefully weighed up.

Management of Endometriosis: Toward Value-Based, Cost-Effective, Affordable Care.

Endometriosis management seems to be influenced by outcome-independent biomedical, pharmacological, and technological developments. The propensity towards doing more affects several aspects of care, sometimes translating into proposals that are not based on sound epidemiological principles and robust evidence. Different stakeholders share the interest for doing more testing and using novel and costly drugs or devices in patients with endometriosis. Although some women may benefit from such an approach, the majority do not, and some may be harmed. Moreover, an uncontrolled increase in expenditures for endometriosis management without demonstrated and proportional health benefits would waste the finite resources of national health care services and would risk cost-related non-adherence. Cost-effectiveness analyses should be systematically pre-planned in future trials on endometriosis, and the concept of "value" of medical interventions should guide investigators and health care policymakers. Reducing low-value care, financial toxicity, and the burden of treatment is respectful not only of endometriosis patients, but also of the entire society. Whenever possible, long-term therapeutic strategies should be tailored to each woman's needs, and high-value tests and treatments should be chosen based on her priorities and preferences. Moreover, listening to patients, understanding their concerns, avoiding disease labelling, explaining plainly what is known and what is unknown, and giving constant reassurance and encouragement may be exceedingly important for the successful management of endometriosis and may change the patient's perception of her clinical condition. Physician empathy has no untoward effects, does not cause harms, and may determine whether a woman successfully copes or desperately struggles with her disease during reproductive life.

'Money for nothing'. The role of robotic-assisted laparoscopy for the treatment of endometriosis.

Despite higher costs for robotic-assisted laparoscopy (RAL) than standard laparoscopy (SL), RAL treatment of endometriosis is performed without established indications. PubMed/MEDLINE was searched for 'robotic surgery' and 'endometriosis' or 'gynaecological benign disease' from January 2000 to December 2016. Full-length studies in English reporting original data were considered. Among 178 articles retrieved, 17 were eligible: 11 non-comparative (RAL only) and six comparative (RAL versus SL). Non-comparative studies included 445 patients. Mean operating time, blood loss and hospital stay were 226 min, 168 ml and 4 days. Major complications and laparotomy conversions were 3.1% and 1.3%. Eight studies reported pain improvement at 15-month follow-up. Comparative studies were all retrospective; 749 women underwent RAL and 705 SL. Operating time was longer for RAL in five studies. Major complications and laparotomy conversions for RAL and SL were 1.5% versus 0.3% and 0.3% versus 0.5%. One study reported pain reduction for RAL at 6-month follow-up. RAL treatment of endometriosis did not provide benefits over SL, overall and among subgroups of women with severe endometriosis, peritoneal endometriosis and obesity. Available evidence is low-quality, and data regarding long-term pain relief and pregnancy rates are lacking. RAL treatment of endometriosis should be performed only within controlled studies.