{"paper_id":"1c672f11-bde3-497a-b030-66aeab8ccff0","body_text":"1 \n \nStudy of the recommended dosage of the N-Acetyl Cysteine, \nAlpha Lipoic Acid, Bromelain and Zinc preparation as a \ntreatment for dysmenorrhea \nZuramis Estrada1 and Francisco Carmona2,3, \n1 Obstetrics and Gynecology Service, University Hospital of Southeast of Madrid, and Centro internacional \nde Investigación, Médico estético, uro-Ginecológico (CIMEG) Madrid, Madrid, Spain. \n2Department of Gynecology, Institut Clinic of Gynecology, Obstetrics and Neonatology, Hospital Clinic, \nInstitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.  \n3Faculty of Medicine, University of Barcelona, Barcelona, Spain. \n \nContact information:  \nFrancisco Carmona, MD, PhD  \nEndometriosis Unit, ICGON, Hospital Clinic of Barcelona, University of Barcelona, Villarroel \n170, 08036 Barcelona, Spain. Email: fcarmona@clinic.cat \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n2 \n \n1. Abstract \nAIM: Dysmenorrhea, defined as pain during menstruation , is the most common gynecological \ncondition, affecting a large percentage of women with varying degrees of pain.  In recent years, \nthe management of dysmenorrhea has become increasingly important because of the emotional, \nhealth and economic burden it entails and because of the need for new studies and research for \neffective treatments to alleviate its symptoms . The most common treatments for dysmenorrhea \nare NSAIDs or  oral contraceptives, although gynecologists also recommend the preparation \ncomposed of N -acetyl cysteine (NAC), alpha lipoic acid (LA), bromelain (Br) and Zinc (Zn), \n(NAC/LA/Br/Zn) due to its anti -inflammatory and anti -oxidative properties and efficacy in  \nreducing pain. However, there is no data on what dosage of the preparation should be \nrecommended for patients with dysmenorrhea. Therefore, the aim of this study is to determine \nhow the NAC/LA/Br/Zn preparation is recommended for the treatment of dysmenorrhea in daily \nclinical practice and what specialists base their decision on. \nMethods and Results: A survey was conducted among gynecologists with extensive experience \nrecommending the preparation, with a participation rate of 97% (N=73). The most frequently \nrecommended regimen is to begin with continuous administration for 90 days with 10-day breaks \n(69%) or without breaks (31%). Specialists recommend the preparation for any type of pain and \nmay recommend discontinuous administration (in the days around menstruation) when the pain \nis moderate or mild. In patients with primary dysmenorrhea with mild pain , the most \nrecommended approach is discontinuous therapy in the days around menstruation (50.7%) \nfollowed by continuous administration for 90 days with 10 -day breaks (24.7%). When pain is \nmoderate or severe, the most recommended approach is 90 -day continuous therapy with 10-day \nbreaks (47.9% and 71.2%, respectively). In the case of secondary dysmenorrhea, the most \nrecommended approach is 90-day continuous therapy with 10-day breaks for any degree of pain \n(41.1%, 57.5% and 76.7% for mild, moderate and severe pain, respectively). Most gynecologists \n(79%) adapt the regimen after clinical assessment of the degree of pain towards discontinuous \nadministration patterns, on the days around menstruation. Most of the specialists consulted do not \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n3 \n \nmodify the recommended regimen if the patient is being treated with other drugs such as NSAIDs, \nhormonal contraception or a combination of progestogens (78%, 59% and 58% , respectively). \nThe preparation is recommended in conjunction  with hygienic -dietary measures without \nmodification of the dosage (90%).  \nConclusion: This is the first study that addresses how specialists recommend the NAC/LA/Br/Zn \npreparation to patients with dysmenorrhea. The most common regimen for dysmenorrhea is to \nstart treatment with continuous administrati on of the preparation for 90 days with 10 days of \nbreak, continuing the regimen or adapting it according to the degree of pain reported by the patient \nduring treatment. \nKeywords \nDysmenorrhea; N-Acetyl cysteine; Alpha lipoic acid; Bromelain; Zinc; Antioxidants.  \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n4 \n \n2. Introduction \nDysmenorrhea, defined as pain during menstruation (1,2), is the most common gynecological \ncondition, affecting a large percentage of women with varying degrees of pain (3,4). Although \nthere is no consensus in the literature on the prevalence of dysmenorrhea, its prevalence lies \nbetween 17 and 81% of women, with severe dysmenorrhea occurring in 12 to 14% (5). \nDysmenorrhea is classified as primary, when the underlying anomaly is unknown, or secondary, \nwhich is usually strongly associated with endometriosis or pelvic inflammatory disease, a mong \nother causes (4,6-16). In recent years, the management of dysmenorrhea has become increasingly \nimportant because of the emotional, health and economic burden it entails and because of the need \nfor new studies and research for effective treatments to alleviate its symptoms (1,5,17). \nTreatments for dysmenorrhea can be classified as pharmacological, such as non -steroidal anti-\ninflammatory drugs (NSAIDs) a nd combined hormonal contraceptives (18-22), or non -\npharmacological, such as complementary treatments to reduce pain (23-26). Currently, \ngynecologists recommend the preparation of N -acetyl cysteine (NAC), alpha lipoic  acid (LA), \nbromelain (Br) and zinc (Zn) ( NAC/LA/Br/Zn), due to its antioxidant, anti -inflammatory and \nanalgesic properties (27,28). \nDue to the lack of evidence on how the NAC/LA/Br/Zn preparation is used in daily clinical \npractice, we decided to conduct a survey to gather information on the experience of gynecologists \nwho recommend it as a treatment for dysmenorrhea. Therefore, the aim of the study is to find out \nthe most frequent doses of the preparation recommend ed for both primary dysmenorrhea (PD) \nand secondary dysmenorrhea (SD) and other causes of pain in relation to the reasons for \nrecommending it, the characteristics of the patients and the adaptation according to the response \nto treatment.  \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n5 \n \n \n3. Materials and Methods  \n3.1. Survey approach  \nThe study involved a total of 75 gynecologists with extensive professional experience in the \ntreatment of dysmenorrhea, from different geographical areas of Spain. The survey developed \nwas sent to gynecologists with experience treatin g patients with the preparation of N -acetyl \ncysteine (NAC), alpha lipoic acid (LA), bromelain (Br), Zinc (Zn). All identities were kept \nconfidential during data collection and analysis. The participation of the specialists was voluntary, \nfree and unconditional. \nThe data on treatment times and concentration of preparation components reported in patients \nwith endometriosis by Lete et al. (27) were used as a reference for developing the survey. The \nspecialists were invited to participate by responding to a structured survey aimed at revealing the \nrecommended dosage of the NAC/LA/Br/Zn preparation for patients with menstrual pain. The \nsurvey was structured in five sections: [1] previous considerations (reason for use of the \npreparation and patient characteristics) [2] Primary Dysmenorrhea (patient management and \ndosage) [3] Secondary Dysmenorrhea and other causes of pain (patient management and dosage); \n[4] association of the NAC/LA/Br/Zn preparation with other drugs; [5] final considerations and \ncomments from the specialist consulted. The survey consisted of 37 questions in total, 32 of which \nwere single-answer questions, 5 of which were multiple-choice questions. In all questions, open \ntext fields were available to enter responses not included in the list, except in five questions where \nthe proposed options were categorical. The complete survey can be found in the supplementary \nmaterial. \n3.2. Data analysis and statistics  \nGynecologists' responses were collected using the Google Forms tool (Google LLC), and \ndownloaded into a Microsoft Excel 2019 file (Microsoft Office, Redmond, WA) for analysis. \nOpen-ended questions were manually coded into general response categories by a s ingle author \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n6 \n \nusing inductive coding with iterative sampling and recoding. In the multiple-choice questions, the \nnumber of times each answer was selected was analyzed. None of the participants' responses were \nexcluded from the analysis. Descriptive statisti cs including absolute numbers, frequencies (%) \nand means were used to explore the data.  \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n7 \n \n \n4. Results   \nA high level of participation was attained from the gynecologists identified, 73 responses out of \nthe 75 invited to participate (97.3%) having completed all sections of the survey. The \ngynecologists consulted recommend the NAC/LA/Br/Zn preparation to patients with any cause \nof menstrual pain, especially to women who want to reduce the consumption of NSAIDs (48 \nresponses), who wish to become pregnant (46 responses), and patients with pain who do not want \nto take contraceptives (32 responses) (possibility of multiple responses) (figure 1A). The majority \nof gynecologists recommend the NAC/LA/Br/Zn preparation to patients who report any degree \nof pain (49%), followed by the recommendation to patients who report moderate pain (between 4 \nand 7 pain on the Visual Analogue Scale (VAS), 37%) or patients with severe pain (>7 VAS, \n14%) (Figure 1B).  \n4.1. Recommended Dosages \nAt the beginning of treatment with the preparation, gynecologists recommend the administration \nof NAC 600 mg/day, LA 200 mg/day, Br 25 mg/day Zn 10 mg/day (71.2% for PD, 80.8% for \nSD), while the rest start treatment with half the concentration, with the possibility of doubling the \ndose if the patient does not respond to treatment (2 7.8% for PD and 19.2% for SD) ( Figure 1A \nsupplementary material). \nThe regimens recommended by specialists at the beginning of treatment may be continuous or \ndiscontinuous. The most commonly recommended continuous regimen is continuous therapy with \nbreaks (10 days of rest per 90 -day treatment cycle) recommended by 69% of the specialists, \ncompared to continuous therapy without breaks (31% of the specialists) (Table 1). Discontinuous \nregimens entail administration of the pre paration 7-15 days before menstruation (54%), 5 days \nbefore and 5 days after menstruation (24%), only 5 days before menstruation (15%) or other \nvariations (7%) (Table 1). \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n8 \n \nFor the treatment of dysmenorrhea, the most commonly recommended therapy at the start of \ntreatment is continuous administration with 10-day breaks every 90 days of treatment (54.8% for \nPD and 65.8% for SD). In the case of PD, 34.2% recommend long-duration therapies (>90 days) \nand 11% short -duration (<90 days). In the case of SD, 32.9% also  recommend continuous \nadministration without breaks at the start of treatment, and 1.4% recommend short -duration \ntherapies (<90 days). \nGynecologists decide the regimen they recommend based on the pain reported by patients. For \nPD patients with mild pain , m ost specialists recommend discontinuous therapies (50.7%), \nfollowed by continuous therapy with breaks (24.7%) and administration for 90 days with change \nto discontinu ous therapy (19.2%). For patients with moderate or severe pain , the most \nrecommended option is continuous therapy with breaks (47.9% and 7 2.6%, respectively), \nfollowed by administration for 90 days with change to discontinuous (35.6% and 20.5% , \nrespectively) (Figure 1C and Table 2).  \nIn contrast to PD, for SD patients,  for patients with mild pain, most specialist recommended 90 \ndays with change to discontinuous (41,1%), followed by continuous therapy with breaks (39.7%) \nand discontinuous therapy (13.7%) (Figure 1C and Table 2). For patients with moderate or severe \npain, the most  recommended option is continuous therapy with breaks ( 58.9% and 76.7%, \nrespectively), followed by administration for 90 days with change to discontinuous ( 34.2% and \n17.8%, respectively) (Figure 1C and Table 2).  \nFor other causes of pain , 63% of gynecologists recommend the preparation, while 33% only \nrecommend it for endometriosis or dysmenorrhea associated with endometriosis, and the \nremaining 4% recommend it when all other treatments fail. Among those who do recommend the \npreparation, the most commonly recommended dosage is continuous therapy with 10-day breaks \n(47.4%), followed by administration for 90 days with a change to discontinuous therapy (31.6%), \nand 17.6% recommend discontinuous therapies (7-15 days before menstruation or 5 days before \nand 5 days after, both recommended with the same frequency). \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n9 \n \nRegarding dosage adaptation, 79.5% of gynecologists recommend switching from continuous to \ndiscontinuous administration, while other gynecologists recommend switching from \ndiscontinuous to continuous administration (13.7%), not adapting the regimen (5.5%) or choosing \nother options (1.4%) (Figure 1D). Among specialists who recommend switching to discontinued \ntherapies, the most recommended regimens are administration in the 7 -15 days before \nmenstruation (44%), 5 days before (19%) or 5 days before and after menstruation (16%). \n4.2. Association of the preparation with other pharmaceuticals  \nSome patients who are recommended the NAC/LA/Br/Zn preparation are being treated with other \npharmaceuticals. Gynecologists recommend the preparation without modification of the dosage \nwhen they are treated with NSAIDs, gestagens or the combination of hormonal contraception \n(79.5%, 57.5% and 58.9%, respectively), compared to those who do modify the dosage of the \npreparation ( 8.2%, 16.4% and 15.1%, respectively) . Some specialists do not recommend the \npreparation when the patient is being treated with NSAIDs, gestagens, combination of hormonal \ncontraceptives (11%, 24.7% and 23.3% respectively). In cases in which patients are being treated \nwith hypoglycemic drugs, 67.1% of gynecologists recommend the NAC/LA/Br/Zn preparation \nwithout modifying the regimen, compared to 20.6% who do not recommend it in these cases and \n11% who reduce the daily dose (Figure 1E supplementary material).  \n4.3. Combined use with hygienic-sanitary measures \nIn most cases, in addition to treatment, patients are recommended a series of hygienic -dietary \nmeasures, based on healthy eating, exercise and avoiding stress. Ninety percent of gynecologists \nrecommend the NAC/LA/Br/Zn preparation along with all hygienic -dietary measures, 6% \nrecommend the preparation alone and 4% recommend the preparation with a healthy diet. Ninety \npercent of specialists do not modify the dosage of the preparation when recommending hygienic-\ndietary guidelines (1C supplementary material). \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n10 \n \n4.4. Patient satisfaction and reported adverse effects \nDepending on the progression of pain reported by patients, 92% adapt the dosage of the \npreparation compared to those who do not (8%), adaptation to discontinuous treatment being the \nmost frequent. For gynecologists who do adapt the dosage, the most frequen t change is from \ncontinuous to discontinuous treatments (60%) compared to those who report changes from \ndiscontinuous to continuous regimens (26%). Finally, the participants in this study stated that the \nNAC/LA/Br/Zn preparation is well tolerated by patien ts, with gastrointestinal discomfort being \nthe only adverse effect, detected by 11% of the gynecologists consulted (Figure 1D supplementary \nmaterial).  \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n11 \n \n5. Discussion  \nThis study describes for the first time which dosages of the NAC/LA/Br/Zn preparation are most \nrecommended by gynecological experts for patients with dysmenorrhea. The most frequently \nrecommended regimen is to begin with continuous administration for 90 days with 10-day breaks. \nIn subsequent evaluations, specialists may maintain this dosage or change it if the patient reports \na reduction in pain.  In addition, this study sheds light on how gynecologists recommend the \nNAC/LA/Br/Zn preparation depending on patients' characteristics, degree of pain, the type of \ndysmenorrhea and the association with other pharmaceuticals.  \nGiven the lack of data in the literature on the guidelines for recommending the preparation in \nclinical practice, it is necessary to conduct studies to produce pertinent data. It is important to \nknow the opinion of gynecologists who have experience recommending the preparation to \npatients with dysmenorrhea in order to learn how they prescribe it. The chosen methodology, an \napproach validated and used in other clinical areas, was a survey of gynecologists i n Spain (29–\n31). \nAt the beginning of the treatment for dysmenorrhea, the most frequently recommended regimen \nis continuous administration for 90 days with 10-day breaks, although one third of those consulted \nrecommend continuous administration without breaks. In subsequent evaluations, the specialist \nmay recommend continuing with this regimen or changing it to a discontinuous dosage if the pain \nhas subsided. In the instance of patients who initially report mild pain, the specialist may \nrecommend starting therapy w ith a discontinuous administration of the preparation. The most \nfrequently recommended discontinuous regimens involve administering the preparation 7-15 days \nbefore menstruation or 5 days before and 5 days after. Administering the preparation around the \ndays of menstruation results in a reduction in menstrual pain. Some specialists have stated that it \nis possible to switch to a continuous dosage in the event that the patient reports an increase in pain \nfollowing a discontinuous dosage. \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n12 \n \nFor primary dysmenorrhea, gynecologists recommend and adapt the dosage of the preparation \naccording to the patient's pain. When the pain is moderate or severe, gynecologists mostly opt for \ncontinuous treatment, and when the pain is mild, discontinuous treatment is more frequen tly \nrecommended. Upon reevaluation, the tendency is to reduce the number of doses of the \npreparation because it continues to be effective in reducing pain, although in some cases it can be \nchanged from a discontinuous to a continuous regimen if the patient  reports increased pain with \na discontinuous regimen. However, in secondary dysmenorrhea, for patients with any degree of \npain, the most recommended guideline is continuous therapy followed by re-evaluation. This may \nbe due to the fact that in secondary dysmenorrhea the patient has been previously diagnosed with \nendometriosis, which is the probable cause of the pain, so gynecologists more often recommend \nlong-acting regimens to reduce pain following the dosage reported in the study by Lete et al (27). \nThis study also addressed the issue of how the preparation is recommended for patients with other \ncauses of pelvic pain , since it was also found to be effective in reducing their pain. The most \ncommonly recommended therapy for other causes of pelvic pain, as well as for PD and SD, is the \nadministration of the preparation for 90 days with 10-day breaks. \nThere is evidence of the effectiveness of this preparation in patients diagnosed with pelvic pain \nassociated with endometriosis when the regimen is NAC 600 mg/day, LA 200 mg/day, Br 25 \nmg/day and Zn 10 mg/day for 6 months (27). In this prospective, open-label clinical study, it was \nobserved that patients taking the preparation reported a reduction in pain from 6.7 to 3.5 on the \nVAS scale and a reduction in the intake of NSAIDs, whether regularly administered or on \nmenstrual days. The evidence available to date indicates that the individual compounds separately \nare beneficial for patients with endometriosis-associated menstrual pain, but at different doses or \ntreatment times than those recommended in daily clinical practice. Trea tment with NAC \nsignificantly reduced pain caused by dysmenorrhea and vaginal bleeding when administered at \nthe same concentration as in this study for 90 days (32,33). Lower doses of NAC (150 mg/day), \nshort treatments (60 days) and  in combination with other molecules also favor the reduction of \npainful symptoms associated with endometriosis (34). LA as a treatment for dysmenorrhea and \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n13 \n \nchronic pelvic pain associated with endometriosis reported greater efficacy in reducing pain when \nadministered in combination with other compounds (35). Continuous treatment and treatment on \nthe days before menstruation have shown positive results in reducing pain (35,36). A case report \ndescribes that administration of Br (2000 mg/day changing to 3000 mg/day 3 days before menses) \nin combination with other compounds and acupuncture significantly reduced pain (from 8 to 2 on \nthe VAS scale) (37). Other studies administering bromelain extract (1.5 mg/mL in PBS, 5 minutes \nvaginal irrigation) showed immediate relief in 6 2% of patients (38,39). Zn supplementation has \nbeen reported to prevent uterine spasms and cramps, inducing a reduction in prostaglandin \nsynthesis by reducing cyclooxygenase -2 (COX-2) activity and an improvement in endometrial \ntissue microcirculation (40-42). The administration of Zinc, at concentrations between 20 and 126 \nmg/day for 3-6 days before and after menstruation, reduces pain in the first menstrual cycle after \nthe first intake, although the reduction in pain w as greater in subsequent cycles  (42–45). \nRegarding dosage, concentrations higher than 30 mg/day did not report better additional effect, \nprobably due to the poor absorption of zinc in the intestine (42,46).  \nNumerous therapeutic strategies and drugs approved by regulatory agencies are currently \navailable to treat endometriosis and associated symptoms such as dysmenorrhea. In most cases, \nspecialists recommend the preparation in conjunction with the prescribed treatment (between 60% \nand 80%) as opposed to those who do not (between 10% and 25%). Gynecologists more \nfrequently recommend the preparation when it is associated with NSAIDs, probably because of \nthe anti-inflammatory properties of the preparation and because it can complement or reduce the \nadministration of NSAIDs (27). Less frequently, they recommend the preparation when the \npatient is being treated with hormonal contraception or with a combination of progestogens. This \nmay be because oral contraceptive treatments are able to inhibit ovulatio n and endometrial \nproliferation, reducing or eliminating menstrual pain, resulting in specialists recommending the \ncombination less frequently in these cases.   \nClinical guidelines for the management of patients with menstrual pain also include some non -\npharmacological strategies or recommendations, such as exercise, healthy diet and natural \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n14 \n \nremedies. Although there is no solid scientific evidence in this regard, the components of the \npreparation have antioxidant, anti-inflammatory and analgesic properties (35,41,47). Therefore, \nspecialists recommend the preparation for its effectiveness in reducing pain as a complement to \npromoting healthy habits. \nThe NAC/LA/Br/Zn preparation is well tolerated by patients, with adverse reactions reported in \nonly 11% of patients. Adverse reactions reported were mild gastrointestinal discomfort, such as \nepigastralgia, gastralgia, abdominal  bloating, gastric intolerance or heartburn. Among the \ncomponents of the preparation, gastric problems such as nausea, vomiting, diarrhea, pain and \nheartburn have been reported as adverse effects of NAC, occurring infrequently (1:1000) (48). \n6. Conclusions  \nThe most common regimen for the treatment of dysmenorrhea with th e NAC/LA/Br/Zn \npreparation (600 mg/day, 200 mg/day, 25 mg/day and 10 mg/day)  is to start treatment with 90 \ndays of administration with 10 -day breaks. In subsequent evaluations with the specialist, the \ntreatment can be continued with the same continuous regimen with breaks or adapted according \nto the degree of pain. In the case of adapting the pattern to a discontinuous dosage, the regimen \nmost frequently recommended by specialists is the administration of the preparation 7 -15 days \nbefore menstruation.  \nThe study obtained a wide participation of gynecologists who are experienced in treating \ndysmenorrhea and who recommend the NAC/LA/Br/Zn preparation in daily clinical practice.  The \ngynecologists responded freely and without any prior consideration, including all their answers \nin the analysis. A lot of information has been collected o n how the preparation is recommended \nfor patients with any degree of pain at the beginning of treatment and after re-evaluations, as well \nas the association with other treatments or therapies. In addition, details were obtained on how \npatients with dysmeno rrhea are evaluated, segmented and followed up so that they receive the \nmost appropriate dosage.  The results obtained would justify and support further studies on the \neffectiveness of the preparation in patients with dysmenorrhea. \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n15 \n \nLimitations  \nThis study did not include the testimony of patients, nor clinical data of patients with \ndysmenorrhea who are being treated with the preparation. Due to the main objective of the study, \nthe survey was directed specially to gynecologists who had experience recommendin g the \npreparation. \nConflicts of interest  \nThe authors declare they have no conflict of interest. \nAcknowledgements  \nThe study was funded by a grant from Adamed Spain S.L.U, who was not involved in the \ndesign of the study, and data  collection or interpretation.  \nThe authors would like to thank our colleagues that responded to the survey: I. Adiego Calvo; M. \nAl Adib Mendiri; R. Alania López; A. Alonso García; C. Alonso García; J. Armengol Santacreu; \nA. Bahillo Varela; R. Baltà i Arandes; R. M. Barc eló Tortella; A. I. Barqueros Ramírez; R. \nBarrientos Naz; A. Biterna Tejeiro; I. Bonal Cea; P. Burguete Fenollosa; E. S. Cabo Silva; R. \nCampos Caballero; A. Cañadas Molina; A. Carazo Piñeiro; A. Carballo García; M. J. Carballo \nMartínez; M. Carrascoso Altar es; T. Casanova Sanchis; A. Cearsolo Michelena; C. Chacón \nAguilar; A. Chassignet Martin; M. C. Chicharro Cassuso; R. Curiel Rodado; J. Dapena González; \nMiriam de la Flor López; Lucia Diaz Meca; V. Domínguez Rubio; M. J. Fernández Ramírez; E. \nFresnadillo Humet; R. Galvan García; O. Gómez Pardo; N. Fernández Aller; M. González Jareño; \nE. González Rodríguez; C. Grau Bravo; E. Grau Civit; F. Hamadache Chabouni; R. Herrera \nRecio; A. Jodar Santibáñez; M. Juárez Cuervo; I. Juárez Pallarés; S. Landeo Agüero; M. Lapresta \nMoros; E. López Pérez; J. López Pérez; D. Lubian López; C. Marcos Santos; C. Miyares \nErausquin; F. Moreno Aguayo; M. J. Moreno Pérez; T. Muñoz Fernández; I. Navarro Alonso; M. \nC. Paladino Decile; M. I. Parra Ribes; M. D. Pérez -Jaraíz López-Zaballa; A. Prades Sanchis; C. \nPuertas; M. A. Quiñones Chávez; B. Ramos Balbona; R. Reboredo García; E. Recari Elizalde; F. \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n16 \n \nRubio Fernández; E. Ruipérez Pacheco; J. Sánchez Orta; C. Caninzzo Naccarato; J.F. Subiris \nGonzález; C. Troncoso Miranda.  \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n17 \n \n7. References  \n1.  Dawood M. Primary Dysmenorrhea, Advances in Pathogenesis and Management. \n2006;108(2):428–41.  \n2.  Chan WY, Fuchs F, Powell AM. Effects of naproxen sodium on menstrual \nprostaglandins and primary dysmenorrhea. Obstet Gynecol [Internet]. 1983 Mar 1 [cited \n2022 Jun 3];61(3):285–91. Available from: https://europepmc.org/article/med/6571974 \n3.  Ferries-Rowe E, Corey E, Archer JS. Primary Dysmenorrhea: Diagnosis and Therapy. \nObstet Gynecol. 2020;136(5):1047–58.  \n4.  Ylikorkala O, Dawood MY. New concepts in dysmenorrhea. Am J Obstet Gynecol. \n1978;130(7):833–47.  \n5.  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A randomised controlled trial of oral \nzinc sulphate for primary dysmenorrhoea in adolescent females. Aust New Zeal J Obstet \nGynaecol. 2015;55(4):369–73.  \n44.  Farrah AM, Halim B, Kaban Y. Effectiveness of Zinc Supplementation in Treating \nDysmenorrhea. Bali Med J. 2017;6(1):34.  \n45.  Sangestani, G., Khatiban, M., Marci, R., & Piva I. The Positive Effects of Zinc \nSupplements on the Improvement of Primary Dysmenorrhea and Premenstrual \nSymptomsA Double-blind, Randomized, Controlled Trial. J Midwifery Reprod Heal. \n2015;3(3):378–84.  \n46.  Teimoori B, Ghasemi M, Hoseini ZSA, Razavi M. The efficacy of zinc administration in \nthe treatment of primary dysmenorrhea. Oman Med J. 2016;31(2):107–11.  \n47.  Hikisz P, Bernasinska-Slomczewska J. Beneficial properties of bromelain. Nutrients. \n2021;13(12).  \n48.  Kerr F, Dawson A, Whyte IM, Buckley N, Murray L, Graudins A, et al. The \nAustralasian clinical toxicology investigators collaboration randomized trial of different \nloading infusion rates of N-acetylcysteine. Ann Emerg Med. 2005;45(4):402–8.  \n \n \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n22 \n \n \n  \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n23 \n \nFigure 1. Recommended dosage of NAC/LA/Br/Zn with respect to patient characteristics, \ndegree of pain and associations with other treatments. (A) Expert opinion on the indication \nfor which the preparation is recommended regarding the patient characteristics , (B) \nrecommendations of the preparation according to pain reported by the patient following the VAS \nscale (Visual Analogue Scale, from 0 to 10). (C) Recommended posology according to the disease \ndiagnosed (PD: upper bars; SD: bottom bars) and the pain reported by the patients following the \nVAS scale. (D) Adaptation of the posology in PD according to expert opinion and the patient \nreport to discontinued therapies 79%; to continuous therapies 14%; no therapy changes 5%; dose \nreduction 1%).  (E) Associations w ith treatments (NSAIDs: Non -steroidal anti -inflammatory \ndrugs; CHCs: Combined hormonal contraception). (A) was posed as multiple -choice questions; \nthe number of votes for each answer is shown. (B, C, D and E) responses are represented as a \npercentage of responses, N=73. Percentages are shown in the figures. PD: primary dysmenorrhea. \nSD: secondary dysmenorrhea. \n  \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n24 \n \n \nTable 1: Recommended dosages of the NAC/LA/Br/Zn preparation at the start of treatment \nof dysmenorrhea. N=73. \n \n \n \n \nTable 2. Recommended posology according to the disease diagnosed and the pain reported \nby the patients following the VAS scale. [1] Continuous therapy without breaks; [2] Continuous \ntherapy with breaks (10 days off per 90 -day treatment cycle); [3] 90 -days administration and \nswitch to discontinuous therapy; [4] Discontinuous therapy (5 days before menstruation and 5 \ndays after or 7-15 days before menstruation). N=73. \n \n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint \n\n . CC-BY-NC 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.08.22278399doi: medRxiv preprint","source_license":"CC0","license_restricted":false}