Endometriosis and Contemporary Pain Science: Five "Simple Rules" for Managing Symptoms With Different Neurobiological Mechanisms

Moreira and Oliveira highlight the shortcomings of the current management of endometriosis symptoms based on exclusively lesion-centred models, and promote patient categorisation according to an individual's predominant neurobiological mechanism, that is, nociceptive, neuropathic, or nociplastic pain [1]. This should allow the tailored targeting of the different pain components, thus potentially optimising clinical outcomes. We agree with the authors' conceptual framework [2, 3] but, as accurately discriminating between the above pain phenotypes may not be straightforward, we propose five “simple rules” to guide inexperienced clinicians. Moreover, a comprehensive multimodal therapeutic approach is resource intensive, as physiotherapists, pain specialists, psychotherapists, gastroenterologists, urologists, and dieticians may be involved. Selected interventions, appropriately prescribed for patients with specific pain mechanisms, could avoid undue burden on already overstretched public health systems. First, suspect early-onset endometriosis in adolescents complaining of painful periods and abdominopelvic pain (primarily nociceptive pain), as its prevalence in severely symptomatic teenagers is high even when ultrasound is negative [2, 4]. Diagnostic delay promotes afferent hypersensitivity and fosters the transition from peripheral to central sensitisation [2]. Second, at diagnosis, suppress recurrent ovulatory cycles with continuous bioequivalent oestradiol–progestogen combinations or progestogen monotherapies. Generally, ethinyl-oestradiol is pro-inflammatory, whereas progestogens are anti-inflammatory [4]. Prompt secondary prevention could avoid disease progression, symptom worsening, and the transition from localised pelvic pain to widespread nociplastic pain. Third, along with potentially different neurobiological mechanisms, evaluate symptom type. Menstrual pain should be relieved by establishing amenorrhoea; deep dyspareunia may benefit from the excision of deep lesions and treatment of pelvic floor hypertonicity. Fourth, try a three-month course of a GnRH agonist or antagonist without ‘add-back’ therapy in non-responders to first-line medical treatment to differentiate between hormone-dependent (presumably mostly nociceptive) and hormone-independent (presumably mostly nociplastic) pain [4]. This pharmacological test is practicable in any clinical setting, overcomes the potentially confusing uncertainties regarding progesterone resistance, and identifies the best candidates for additional interventions such as aerobic exercise, cognitive behavioural therapy, anti-inflammatory diet, pelvic floor rehabilitation, acupuncture, and non-hormonal pharmacological therapies. In GnRH analogue non-responders, the role of endometriosis as the sole or main pain trigger should be carefully reconsidered [2, 4]. Fifth, administer yourself as a medication [3]. Listening with a warm and non-judgmental approach, providing clear explanations and reassurance, avoiding pessimistic predictions, offering practical advice on treatment plans and self-management strategies can reduce the ‘maladaptive cognitive affective responses to pain episodes that exert a direct influence on peripheral nociceptive processing via descending pathways’ [1, 3]. Words can help coping with pain, reduce catastrophising, anxiety, and depression, facilitate resumption of social activities and improve relationships. There is a pressing need to raise awareness of the multifaceted nature of endometriosis-associated pain. However, this should be combined with timely diagnosis, secondary prevention of disease progression, primary prevention of peripheral and central sensitisation and nociplastic pain onset, and appropriate empathy. Humanistic medicine is inexpensive, does not consume precious resources, and could be available everywhere without disparities. A neurobiological pain phenotype categorisation approach is crucial but demanding, requiring physician knowledge, motivation, and sufficient time for consultation. These simple rules may ease the transition toward a holistic approach to “the pains of endometriosis”. Paolo Vercellini conceived the text and drafted the original version of the letter. Giulia Emily Cetera, Noemi Salmeri, Paola Viganò and Edgardo Somigliana participated in conceiving and drafting part of the letter and critically revising it. All authors approved the final version of the letter. Paolo Vercellini is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate; and maintains both a public and private gynaecological practice. Paola Viganò is Co-editor-in-Chief of the Journal of Endometriosis and Uterine Disorders. Edgardo Somigliana is Editor-in-Chief of Human Reproduction Open; discloses payments from Ferring and Theramex for research grants and personal honoraria from Merck-Serono, Ibsa, and Gedeon-Richter; and maintains both a public and private gynaecological practice. Giulia Emily Cetera and Noemi Salmeri declare they have no conflicts of interest. The authors have nothing to report.