{"paper_id":"899eee6d-6590-4dcd-91f5-e1ed1dc58e40","body_text":"Editorial\nIs it the Ideal Time to Start Prescribing Cannabis Derivatives to\nTreat Endometriosis-associated Pain?\nOmero Benedicto Poli-Neto 1 Jaime Eduardo Cecílio Hallak 2 Julio Cesar Rosa-e-Silva 1\nJ o s éA l e x a n d r ed eS o u z aC r i p p a2\n1 Gynecological and Obstetrics Department, Ribeirão Preto Medical\nSchool, University of São Paulo, Ribeirão Preto, SP, Brazil\n2 Neurosciences and Behavioral Sciences Department, Ribeirão Preto\nMedical School, University of São Paulo, Ribeirão Preto, SP, Brazil\nRev Bras Ginecol Obstet 2022;44(5):449 –451.\nEndometriosis affects /C245%-10% of women of reproductive\nage and is often associated with painful symptoms like\ndysmenorrhea, dyschezia, dyspareunia, and even non cycli-\ncal pain.\n1 The disease is diagnosed in at least 20% of women\nwith dysmenorrhea and/or non-menstrual pelvic pain,\nreaching a prevalence of 50% among adolescents.\n2 There is\nan alignment among international societies 3,4 that the pre-\nsumed diagnosis of this disease is enough to start clinical\ntreatment. Moreover, there seems to be a consensus that\nfirst-line treatment should be hormonal contraceptives since\nthe ef ficacy is similar to that of surgery but with lower\ncomplication rates and costs.\n5 However, these drugs are\neffective in only approximately two-thirds of patients, 6\nhave limited long-term ef ficacy,7 and may occasionally\nlead to undesirable side effects. Additionally, there are seri-\nous limitations in the interpretation of clinical trials. 8 Ac -\ncordingly, evidence on the best therapeutic regimens has not\nyet been established.\n9 Other clinical options exist, but the\ncost, side effects, and similarity of results compared with\nhormonal contraceptives give them limited utility. 10 Thus,\ndue to the persistence of pain, a significant portion of women\nundergo surgery, which is obviously capable of eliminating\nvisible endometriotic lesions, but not curing the disease.\n11\nDespite short-term clinical improvement, postoperative re-\ncurrence is common, especially if hormone therapy was not\ninitiated.\n12\nThus, the clear clinical demand for more effective or\nlasting options for symptomatic relief, together with an\nincreasing recognition of the participation of the central\nnervous system in the genesis and/or modulation of chronic\nendometriosis-associated pain,\n13 has aroused growing in-\nterest in novel therapeutic modalities. 14 Among these treat-\nments, drugs derived from the Cannabis sativa plant, which\nwe will call cannabinoids in the following text, currently\nseem to be the main topic. In fact, increasing attention has\nbeen directed to the potential bene ficial effects of these\nmedicines in controlling the symptoms of patients with\nchronic pain.\n15 Cannabis contains over a hundred chemical\ncompounds that act on the endocannabinoid system, yet\ntwo are rather distinct, delta-9-tetrahydrocannabinol\n(THC), which is responsible for the psychoactive effects\nassociated with the use of this plant, and cannabidiol\n(CBD), which does not produce psychomimetic symp-\ntoms.\n16 Overall, unlike THC, CBD is not addictive or tolerant\nand has a very favorable safety and adverse effect pro files.\nAt first, it was believed that cannabinoids produced their\nanalgesic effects by the direct activation of speci fic recep-\ntors (CB1 and CB2). However, it is now known that they can\nreduce pain by interacting with a wide range of cannabi-\nnoid, opioid, vanilloid, serotonergic, and anti-in flammatory\nreceptors.17 Furthermore, preclinical studies have shown\nthat CBD can interfere with the levels of cytokines poten-\ntially involved in the pathophysiology of endometriosis-\nassociated pain 18; CBD has been shown to decrease the\nsecretion of pro-in flammatory cytokines, including IL-6 and\nTNF-α, and increase levels of anti-in flammatory cytokines,\nincluding IL-10. 19 In addition to these broad potential pain-\nrelated mechanisms of action, there is a vast evidence on its\nanxiolytic, antidepressant, neuroprotective, mood-stabiliz-\ning, sleep-modulating effects of cannabinoids, along with\nmany other bene fits,\n20 which may be useful in the concom-\nitant treatment of non-painful symptoms as the aforemen-\ntioned comorbidities are also frequent among patients with\nendometriosis. This makes cannabinoids potentially useful\nin treating patients with pelvic pain secondary to\nendometriosis.\nAddress for correspondence\nOmero Benedicto Poli-Neto, MD,\nPhD, Bandeirantes Avenue, 3900,\n8th Floor, 14049-900, Ribeirão\nPreto, SP, Brazil\n(e-mail: polineto@usp.br).\nDOI https://doi.org/\n10.1055/s-0042-1749430.\nISSN 0100-7203.\n© 2022. Federação Brasileira de Ginecologia e Obstetrícia. All rights\nreserved.\nThis is an open access article published by Thieme under the terms of the\nCreative Commons Attribution License, permitting unrestricted use,\ndistribution, and reproduction so long as the original work is properly cited.\n(https://creativecommons.org/licenses/by/4.0/)\nThieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de\nJaneiro, RJ, CEP 20270-135, Brazil\nTHIEME\nss\nTHIEME\nEditorial 449\nArticle published online: 2022-06-13\n\nA recent Australian national survey found that 13% of\nwomen with surgically con firmed endometriosis reported\nsignificant positive effects of using cannabis in natura both\non relieving pain and reducing the use of pharmaceutical\ndrugs as a form of self-medication. However, as the study was\nnot controlled and the investigational products did not have\na pharmaceutical grade as a standardized formulation, the\nconclusions and the reproducibility of findings are limited.\n21\nNevertheless, similar findings have been reported in other\nlongitudinal studies. 22 However, at least two meta-analyses\nfocusing on different types of pain 23,24 clarified the limita-\ntion of the methodological designs available thus far. Fur-\nthermore, they raised a legitimate concern about the\nsignificantly higher prevalence of the adverse effects on\nthe nervous system and psychiatric disorders associated\nwith THC use, 24 particularly including psychosis, depressive\nepisodes, and cognitive alterations commonly. More speci fi-\ncally, regarding the treatment of endometriosis-associated\npain, two clinical trials registered on the clinicaltrials.gov\nplatform (NCT03875261 and NCT04527003) were retrospec -\ntively proposed by researchers from Barcelona and Pennsyl-\nvania to assess the effect of cannabinoids on hyperalgesia in\nwomen with deep endometriosis, yet both are currently “not\nyet recruiting. ” To the best of our knowledge, in Brazil, we\nalready have a clinical trial in progress and another that will\nsoon start recruiting and is under our responsibility.\nConsidering the popular saying that “not everything that\nglitters is gold ” there has been a growing concern in the\nspecialized scientific community regarding the increasingly\nfrequent use ofcannabisor its derivatives for pain relief, despite\nthe potential adverse effects, the lack of robust evidence on\nbenefits and, consequently, the absence of clear recommenda-\ntions on doses and/or composition to be used. In 2021 the\nInternational Association for the Study of Pain (IASP) published\na statement position\n25 recognizing the legitimacy of the life\nexperience of people who report an improvement in pain\nfollowing the use of cannabis and cannabinoids. Nevertheless,\nthe association made it explicit that it does not endorse the use\nof cannabinoids until rigorous investigations and robust results\nclearly show the benefits and harms of its use in humans. The\nPAIN journal has even allocated an entire collection of 13\nscientific articles representing the IASP ’s Presidential Task\nForce on Cannabis and Cannabinoid Analgesia and calling for\nhigh-quality clinical trials to be initiated. Some of the concerns\nregarding the use of cannabinoids are potential reductions in\nneurocognitive performance, macrostructural and microstruc -\ntural brain development, and alterations in brain\nfunction secondary to heavy use by adolescents,\n26 who have\na higher risk of early onset psychosis,27 and addiction.28\nIn Brazil, cannabinoid-based medications are of ficially\napproved for use only in patients with refractory epilepsy\nwith a THC concentration <0.2%. These drugs have a very\nhigh cost and any use outside the approved indication is off-\nlabel. In any case, we have seen a growing supply ofcannabis-\nderived products on the market linked to the promise of pain\nrelief. Many serious groups and companies have devoted\nefforts to drug development, but international quality stand-\nards are not followed by all, which poses a health risk as it is\nimpossible to guarantee a high level of quality, adequate\npharmacovigilance, and extensive monitoring of adverse\nreactions. This can also lead to abusive and illegal use.\nNevertheless, the prospect of good results is an encour-\nagement to women with persistent symptoms and profes-\nsionals who assist them to use cannabinoids, but it is\nnecessary to be aware of the temptation of the premature\nclinical use of medication. Unfortunately, from a strictly\nmedical and scientific point of view, it is currently impossible\nto guarantee the ef ficacy, safety and tolerability of cannabis\nor its derivatives in the treatment of pain symptoms in\nwomen with endometriosis. Incentives have been made to\ndisseminate the need for large clinical trials in this domain.\nTo finish, I will restate a part of a text written by Michael\nEisenstein\n29 which seems to me to be very lucid, sensible and\nrelevant for the situation that we are currently living in:\n“Unfortunately, if studies such as these are not done —or not\ndone properly —then consumers will be left to fend for\nthemselves in a poorly monitored marketplace. In that\nscenario, the signal of true clinical bene fit would almost\ncertainly be drowned out by the noise from personal anec -\ndotes and the placebo effect, which could jeopardize the\nfuture of a potentially valuable medicine. ”29\nConflicts to Interest\nNone to declare.\nAcknowledgments\nWe acknowledge the Coordination for the Improvement\nof Higher Education Personnel (CAPES) for supporting our\npost-graduate program. We would like to thank Editage\n(www.editage.com) for English language editing.\nReferences\n1 Eisenberg VH, Weil C, Chodick G, Shalev V. Epidemiology of\nendometriosis: a large population-based database study from a\nhealthcare provider with 2 million members. BJOG. 2018;125\n(01):55–62. Doi: 10.1111/1471-0528.14711\n2 Janssen EB, Rijkers AC, Hoppenbrouwers K, Meuleman C,\nD’Hooghe TM. Prevalence of endometriosis diagnosed by lapa-\nroscopy in adolescents with dysmenorrhea or chronic pelvic pain:\na systematic review. Hum Reprod Update. 2013;19(05):570 –582.\nDoi: 10.1093/humupd/dmt016\n3 Dunselman GA, Vermeulen N, Becker C, et al; European Society of\nHuman Reproduction and Embryology. ESHRE guideline: man-\nagement of women with endometriosis. Hum Reprod. 2014;29\n(03):400–412. Doi: 10.1093/humrep/det457\n4 Kuznetsov L, Dworzynski K, Davies M, Overton CGuideline Com-\nmittee. Diagnosis and management of endometriosis: summary\nof NICE guidance. BMJ. 2017;358:j3935. Doi: 10.1136/bmj.j3935\n5 Chaichian S, Kabir A, Mehdizadehkashi A, Rahmani K, Moghimi M,\nMoazzami B. Comparing the ef ficacy of surgery and medical\ntherapy for pain management in endometriosis: a systematic\nreview and meta-analysis. Pain Physician. 2017;20(03):185 –195\n6 Vercellini P, Buggio L, Frattaruolo MP, Borghi A, Dridi D, Somigli-\nana E. Medical treatment of endometriosis-related pain. Best\nPract Res Clin Obstet Gynaecol. 2018;51:68 –91. 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Cannabis Cannabinoid Res. 2020;5(01):12 –31. Doi:\n10.1089/can.2018.0073\n20 Crippa JA, Guimarães FS, Campos AC, Zuardi AW. Translational\ninvestigation of the therapeutic potential of cannabidiol (CBD):\ntoward a new age. Front Immunol. 2018;9:2009. Doi: 10.3389/\nfimmu.2018.02009\n21 Sinclair J, Smith CA, Abbott J, Chalmers KJ, Pate DW, Armour M.\nCannabis use, a self-management strategy among australian\nwomen with endometriosis: results from a National Online\nSurvey. J Obstet Gynaecol Can. 2020;42(03):256 –261. Doi:\n10.1016/j.jogc.2019.08.033\n22 Liang AL, Gingher EL, Coleman JS. Medical cannabis for gyneco-\nlogic pain conditions: a systematic review. Obstet Gynecol. 2022;\n139(02):287–296. Doi: 10.1097/AOG.0000000000004656\n23 Chang Y, Zhu M, Vannabouathong C, Mundi R, Chou RS, Bhandari\nM. Medical cannabis for chronic noncancer pain: a systematic\nreview of health care recommendations. Pain Res Manag. 2021;\n2021:8857948. Doi: 10.1155/2021/8857948\n24 Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-\nbased medicines for chronic neuropathic pain in adults. Cochrane\nDatabase Syst Rev. 2018;3:CD012182. Doi: 10.1002/14651858.\nCD012182.pub2\n25 IASP Presidential Task Force on Cannabis and Cannabinoid Anal-\ngesia. International Association for the Study of Pain Presidential\nTask Force on Cannabis and Cannabinoid Analgesia position\nstatement. Pain. 2021;162(Suppl 1):S1 –S2. Doi: 10.1097/j.\npain.0000000000002265\n26 J a c o b u sJ ,T a p e r tS F .E f f e c t so fc a n n a b i so nt h ea d o l e s c e n t\nbrain. Curr Pharm Des. 2014;20(13):2186 –2193. Doi:\n10.2174/13816128113199990426\n27 Pardo M, Matalí JL, Sivoli J, et al. Early onset psychosis and\ncannabis use: Prevalence, clinical presentation and in fluence of\ndaily use. Asian J Psychiatr. 2021;62:102714. Doi: 10.1016/j.\najp.2021.102714\n28 Rup J, Freeman TP, Perlman C, Hammond D. Cannabis and mental\nhealth: Prevalence of use and modes of cannabis administration\nby mental health status. Addict Behav. 2021;121:106991. Doi:\n10.1016/j.addbeh.2021.106991\n29 Eisenstein M. The reality behind cannabidiol ’s medical hype.\nNature. 2019;572(7771):S2 –S4. Doi: 10.1038/d41586-019-\n02524-5\nRev Bras Ginecol Obstet Vol. 44 No. 5/2022 © 2022. Federação Bras ileira de Ginecologia e Obstetrícia. All rights reserved.\nEditorial 451","source_license":"CC0","license_restricted":false}