Objectifying acute effects of acupuncture for pelvic pain due to endometriosis: A clinical research protocol using a novel pain assessment system study design and case report

Khadija Bashir Ibar Objectifying acute effects of Acupuncture for pelvic pain due to endometriosis: A clinical research protocol using a novel pain assessment system - study design and case report. Dissertação de Candidatura ao grau de Mestre em Medicina Tradicional Chinesa submetida ao Instituto de Ciências Biomédicas de Abel Salazar da Universidade do Porto. Main supervisor: Prof. Dr. Henry Johannes Greten Director of the Specialization and Master Program in Traditional Chinese Medicine Institute for Biomedical Sciences Abel Salazar, University of Porto, Portugal - ICBAS / UP Supervisor: Dr. Nuno Cândido Maia Correia Assistant in Internal Medicine, Service of Emergency, Hospital Center São João, Porto Master in Traditional Chinese Medicine Institute for Biomedical Sciences Abel Salazar, University of Porto, Portugal - ICBAS / UP Page | I Dedication To my Dear Mother Rahma Ahmed, and my lovely brother Abdullahi Ibar, for the love and support. Page | II Page | III Acknowledgments First of all I would like to thank Allah for giving me everything in my life. To my Family for being always on my side emotionally and physically. To my professors; Johannes Greten, Jorge Machado, Nuno Montenegro, for their unconditional support. Special Thanks to my supervisor, Dr Nuno Correia for his support and guidance. To Drª Ana Rosa Costa for being kind and helpful. To Maria João Santos for her creativity and problem solving. To Engineer Rui Correia for his creativity to invent the pressure-sensitive machine which is the backbone of this protocol. To my Dear Friend Abdul Razak Ibrahim, for all his support, being understanding, helpful. A great example of kindness. Page | IV Page | V Abstract Background: Endometriosis (EM) is a common health problem affecting women worldwide and often undiagnosed. It is estimated that 7% -10% of women in the general population suffer from EM. According to conventional medicine, treatment of EM needs life-long management including medical or surgical treatments, hormonal therapy being mostly used. However, prolonged administration of these therapies remains challenging due to the plethora of serious adverse effects. Acupuncture has been studied in Gynecological disorders but its effectiveness for pain in endometriosis remains uncertain. Few studies have been published on acupuncture for “Endometrialgia”. Current data suggests that acupuncture may be helpful in relieving the chronic pelvic pain which in turn may improve EM patient's quality of life. Objectives: To develop a clinical research protocol for a randomized, sham-controlled preliminary study that evaluates the acute effects of acupuncture for endometriosis-related pain. To objectively measure the effect of acupuncture in pain, by using a new pressure sensitive sensor device. To assess feasibility of the study protocol, and collect preliminary data, for a larger study. To evaluate whether acupuncture can significantly improve pelvic pain in patients with pelvic endometriosis. Methods: Study type: a clinical protocol of a preliminary, prospective, randomized, controlled, singleblinded clinical trial in a cross over design. Inclusion Criteria: women from 18-55 yrs. with pelvic pain due to EM beyond the time of menstrual bleeding at Sao Joao Hospital EM clinic, mentally fit and co-operative with the study. Patients are naïve to acupuncture. Exclusion criteria: women with menses (to exclude dysmenorrhea), chronic pelvic pain due to non-endometriosis causes, active infectious disease, congenital diseases or any other severe disease. Intervention: The verum acupuncture consists of leopard spot technique on Gb 41 and Sp6, sham acupuncture, however in non-acupoints 1Cun distant from the Acupoints of the verum group. Setting: Endometriosis outpatient consultation office, Service of Gynecology and Obstetrics of Hospital Center São João. Page | VI Ethics Committee: The protocol was approved by the institutional local Ethics Committee. Sample: 30 patients, diagnosed with pelvic Endometriosis, and have pelvic pain secondary to EM. Randomization: patients are assigned into two groups by coin flip into Experiment and Control group. All patients’ consents are obtained before the beginning of the intervention. Crossover of the two groups will be performed after one week of wash out. o Experiment group: patients will undergo verum acupuncture in points chosen according to the Heidelberg model of Traditional Chinese Medicine (Gb 41 and Sp6). o Control group: patients will undergo sham acupuncture in non-acupoints 1 cun distant from the verum acupoints, outside the conduits. Experimental procedure: The first step is pain assessment by VAS and by using specially designed sensor for this study while applying deep pressure on the pelvic region until the maximum pain intensity. The second step consists of one type of Intervention as defined above (verum or sham). Needling consists of applying the bloodletting “leopard spot” technique in both groupsExpected Results: The effect of acupuncture as analgesic is demonstrated extensively in the literature. Recruitment for this study has recently started at Hospital São João, a major central university hospital in Porto. The study may reveal that a significant relief could be achieved after the application of acupuncture in patients with chronic pelvic pain due to endometriosis in the specific point according to Heidelberg model and this decrease of the pain intensity can be detected by the pain scales and tools such as VAS and the pain sensor machine. Discussion: This study is currently in course. We have introduced a novel pressure sensitive device in order to measure the objective effect of acupuncture in pain. Results from this study may in the future grant a larger prospective, controlled, multi-blinded, randomized protocol with longer follow-up period. This may add more evidence to the growing number of evidences and prove that Acupuncture is another interesting tool to manage this condition responsible for a great discomfort and reduced quality of life for affected women and their partners and could be included in the guidelines for the management of chronic pain due to endometriosis guidelines. Keywords: Endometriosis, Chronic Pain, Acupuncture, Traditional Chinese Medicine. Page | VII Resumo Enquadramento: A endometriose (EM) é um problema de saúde comum que afecta as mulheres mundialmente e com frequência subdiagnosticado. Estima-se que 7-10% das mulheres na população geral padecem de EM. De acordo com a medicina convencional, o tratamento da EM necessita de uma abordagem para toda a vida, incluindo tratamento médico ou cirúrgico, sendo a hormonoterapia a mais usada. Contudo, a administração prolongada dos tratamentos convencionais permanece um desafio devido à pletora de efeitos adversos sérios potencialmente associados. A acupunctura tem sido aplicada no tratamento de distúrbios ginecológicos mas a sua eficácia no tratamento da dor na endometriose permanece incerta. Poucos estudos foram publicados sobre acupunctura para “Endometrialgia. Os dados actuais sugerem que a acupuntura poderá ser útil no alívio da dor pélvica crónica, o que por sua vez poderá melhorar a qualidade de vida das doentes com EM. Objectivos: 1) Desenvolver um protocolo de investigação clínica para um estudo preliminar, randomizado, controlado com acupuntura falsa, que avalie os efeitos da acupunctura na dor relacionada com a endometriose. 2) Medir objectivamente o efeito da acupunctura na dor, usando umnovo sensor sensível à pressão. 3) Avaliar a viabilidade do protocolo de estudo, recolher dados preliminares para um suportar um estudo posterior de maior escala. 4) Avaliar se a acupunctura pode melhorar significativamente a dor pélvica em doentes com endometrioses. Métodos: Tipo de estudo: ensaio clínico preliminar, prospectivo, randomizado, controlado, cego, com desenho tipo “cross-over”. Critérios de inclusão: mulheres entre 18-55 anos de idade, com dor pélvica devida a EM fora do cataménio; doentes da consulta de Endometriose no Hospital São João, sem doenças psiquiátricas ou neurológicas que impeçam acupuncturam; pacientes que nunca tenham realizado acupuncturam previamente; assinam consentimento informado. Critérios de exclusão: mulheres na altura da menstruação (para excluir dismenorreia primária), com dor crónica por causas diversas. Doença infecciosa activa; doenças congénitas ou outras doenças graves Page | XIV Page | XV Index of Tables Table 1: Agents in HM of TCM 34 Table 2: Locations of Acupoints (verum group) 52 Table 3: Location of Skin Points (Sham group) 53 Table 4: Study chronogram 62 Table 5: Pain evaluation VAS results 66 Table 6: pressure sensor device results 66 Page | XVI Page | XVII Index of Figures Figure 1: Revised ASRM classification of Endometriosis 22 Figure 2: Endometriosis Stages 23 Figure 3: General view of all CAM therapeutic approaches 26 Figure 4: Proportional body measurement for acupuncture 28 Figure 5: Fou qi emblem 30 Figure 6: Regulation in Sinusoidal curve 31 Figure 7: postulated nerves & hormonal mechanisms of the phases 32 Figure 8: Chinese medicine complex network regulation 33 Figure 9: The twelve ORBs 35 Figure 10: Acupuncture traditional use in Gynecological disorders 38 Figure 11: Development of EM in HM 43 Figure 12: GB 41 Acupoint 45 Figure 13: SP 6 Acupoint 45 Figure 14: cross over design 50 Figure 15: Verum acupuncture group 52 Figure 16: Sham acupuncture group 53 Figure 17: schematic demarcation of dermatomes 54 Figure 18: Insulin needle 55 Figure 19: Subjective pain assessment VAS 56 Figure 20: pressure sensitive sensor machine connected to Laptop 57 Figure 21: schematic of software development 58 Figure 22: schematic of hardware development 59 Figure 23: Sensor start up screen 59 Figures 24, 25: Sensor recording pressure screen 60 Figure 26: Sensor data saving and reporting 61 Page | XVIII Page | 19 I. Introduction 1.1. Definition and epidemiology Endometriosis is a disorder in which abnormal growths of tissue, histologically resembling the endometrium are present in locations other than uterine lining[1]. Although Endometriosis can occur very rarely in post-menopausal women, it is found almost exclusively in women of reproductive age and it is divided according to the site of implementation, the lesions are usually found on the peritoneal surfaces of the reproductive organs and adjacent structures of the pelvis, but they can occur anywhere in the body. The size of the individual lesions varies from microscopic to large invasive masses that erode into the underlying organs and cause extensive adhesion formation. The most common symptom is chronic pain, notably dysmenorrhea, dyspareunia, and infertility, which all my lead to a reduction in the patient’s quality of life[2]. Endometriosis is a common and important health problem of women. It is estimated that 7% to 10%[1] of women in the general population have endometriosis. Pelvic endometriosis is present in 6% to 43% of women undergoing sterilization, 12% to 32% of women undergoing laparoscopy for pelvic pain, and 21% to 48% of women undergoing laparoscopy for infertility. Endometriosis occurs more often in women who have never had children[3]. Some evidence suggests that endometriosis may have a genetic component. Women with first degree relatives with endometriosis have nearly a 10-fold increased risk of developing endometriosis. The proposed mechanism of inheritance is polygenic multifactorial [4]. 1.2. Pathogenesis The cause of endometriosis is unknown. However, there are Three major theories by which Endometriosis may develops.[1, 5] 1. Direct implantation of endometrial cells, typically by means of retrograde menstruation. This mechanism is consistence with the occurrence of pelvic endometriosis and its predilection for the ovaries and pelvic peritoneum, as well as for sites such as an incision or episiotomy scar. Direct implantation is commonly referred to as Sampson’s theory because of his experimental work in 1920s that showed the possibility of such a mechanism. 2. Vascular and Lymphatic dissemination of endometrial cells (Halban’s theory). Distant sites of endometriosis can be explained by this process (i.e., endometriosis in locations such as lymph nodes, the pleural cavity, and kidney). Page | 20 3. Coelomic theory of multi potential cells in the peritoneal cavity (Meyer’s theory) states that, under certain conditions, these cells can develop into functional endometrial tissue. This could even occur in response to the irritation caused by retrograde menstruation. The early development of endometriosis in some adolescents before the onset of menstruation lends credence to this theory. It is probable that more than one theory is necessary to explain the diverse nature and locations of endometriosis. Underlying all these possibilities is a yet undiscovered immunological factor that would explain why some women develop endometriosis whereas others with similar characteristics do not. 1.3. Diagnosis and classification of Endometriosis Endometriosis is a chronic, multifactorial disease, and has significant impact on a women's quality of life. Pelvic pain, infertility, dyspareunia, dysmenorrhea and intestinal disorders, are the most common clinical manifestations. The diagnosis of EM is often strongly suspected from the initial history of the patient, most patients complaining from constant pelvic pain, infertility, dysmenorrhea and dyspareunia, in those patients EM have to be excluded. Cancer Antigen (CA-125) is often elevated in women with endometriosis. However, it has been shown that this marker is elevated in many other pelvic diseases and therefore has little specificity in the diagnosis of endometriosis. After medical or surgical treatment CA-125 return to normal value and in this case it can be helpful to evaluate recurrence.[6] Laparoscopy is considered the primary diagnostic modality for endometriosis. Histologic demonstration of a combination of endometrial glands and stroma in biopsy specimens obtained from outside the uterine cavity is required to make the diagnosis of endometriosis [7]. The following in descending order are the most common sites of involvement found during laparoscopy [1, 7, 8]: - Ovaries ( almost have of the cases) - Posterior cul-de-sac - Broad ligament - Uterosacral ligament - Recto-sigmoid colon - Bladder - Distal ureter Page | 21 There are some staging systems to assist in describing the anatomic location and severity of endometriosis at operation, although they are not entirely satisfactory, these scoring systems are useful for reporting operative findings and for comparing the results of various treatment protocols. One of the reliable tools is the American society for reproductive medicine revised classification of endometriosis. Page | 22 Figure1: Revised ASRM classification of Endometriosis. Page | 23 Figure 2: Endometriosis Stages 1.4. Chronic pelvic pain Chronic pelvic pain (CPP) could be defined as the presence of non-cyclic pain of 6 months duration or longer, that localizes to the anatomic pelvis and is severe enough to cause functional disability and require medical or surgical treatment. That means we can make diagnosis of CPP when the pain started from the pelvic area and remain for at least 3-6 months. CPP etiology could be related to different situations. It is well evidenced by Howard[9] and Vercellini et al [10] that pain may be due to nociceptive, inflammatory, or neuropathic mechanisms and probably all three of these mechanisms are relevant to endometriosisassociated pelvic pain. Chronic pelvic pain in Endometriosis patients is mostly related to the adhesions and pelvic scaring found in association with pelvic endometriosis. The severe pain is associated with deeply infiltrating lesions, and it is thought that the degree of pain is perhaps determined by the depth of invasion. Pelvic EM is present in 6% to 43% of women undergoing sterilization, and up to 12% to 32% of women undergoing laparoscopy for pelvic pain. Page | 30 Figure 5: Fou qi emblem Most of the regulatory processes describe periodical fluctuations of the actual value around a target value. Accordingly as vegetative system is a regulatory process; the symptoms are categorized leading to ORB “Group of diagnostically relevant signs that indicate the functional state of a body region, which correlates the functional properties of a conduit. The technical and regulatory dimension of Yin/Yang and the evolutionary phases (EP), i.e., Wood, Fire, Earth, Metal, Water, can be seen in an analogous example of the regulation of temperature in a water basin by a thermostat system. Due to the inherent fluctuations, the actual temperature value moves around the set point approximately in a sinus wave. Page | 31 Figure 6 Regulation in sinusoidal curve. Regulation as a technical process. The temperature profile of the pool is not constant (straight line), but rather sinusoidal. Temperature is on the y-axis and time plotted on the x-axis, which corresponds to the desired temperature Heidelberg Model of TCM hypothesizes a relation between this sinusoidal-pattern and the autonomic nervous system activities and it is major molecular effects (hormones, neurotransmitters). Page | 32 Figure 7 Postulated assignment of phases of Chinese medicine into the autonomic nervous system with respective analogies between the phases and the neuro-hormonal mechanisms. W – Wood phase. F – Fire phase. M – Metal phase. WWater phase. This theory is supported by several scientifically proofed studies all using the Heidelberg Model as backbone and common ground to drown conclusions regarding their respective objectives. Some of these studies are; pain following tonsillectomy Sertel, et al., 2009), Gait improvement (Hauer K. 2011), Qigong effects (Sousa, et al., 2012), polyneuropathy (Schroeder, Lieper, Remppis, & Greten, 2007), walking distance in peripheral occlusive disease (Forschungsemeinschaft, 2006). Page | 33 Mechanisms to become sick in Heidelberg Model of TCM 1Excess of an Agent 2Problem of transition from one phase to the next 3Imbalance of antagonist between phases 4Yin deficiency ( in our example of water Basin Yin deficiency means less water causing high variation of the temperature) Figure 8: Chinese medicine complex network regulation Page | 34 The functional TCM diagnosis has 4 components: 1Constitution: a tendency to express the signs of one orb predominantly so that they show in the physical phenotype. 2Agent: a pathogenic factor eliciting specific signs and symptoms. These may resemble and therefore promote orb patterns. There are external; internal and natural agents. Table 1: Agents in HM of TCM External Agents Internal Agents Neutral Agents Ventus(‘wind’),algor (‘cold’), humour (‘humidity’), ariditas (‘dryness’),aestus (‘summer heat’), ardour (‘glow”) Ira(‘anger’),voluptas (‘lust’), cogitatio(‘excessive thinking’),maeror (‘grief’), solicitudo(‘worriedness’), timor(‘anxiety’),pavor (‘shock’) Overwork, malnutrition, trauma, infections. 3Orb: a group of diagnostically relevant signs indicating the functional state of body island (body region) which correlates with the functional properties of a conduit. Page | 35 Figure 9: The twelve ORBs 4Guiding criteria (GC): main interpretationmatrix of symptoms in TCM, based on four regulatory models of physiology: Page | 36  1st GC – Repletion (fullness)/ depletion (emptiness) describes Qi content of the body by terms of orbs, Qi, Phases. In western medical view this describes symptoms predominantly originating from Neuro-vegetative system.  2nd GC - Calor( heat)/ Algor (cold) this describes the activity of Xue (blood), as western medical view this describes the clinical signs predominantly originating from Humoro-vegetative system, including the regional and systemic effects of microcirculation.  3rd GC – Extima (exterior)/Intima (interior) describes the course of a disease caused by an exterior agent invading the body. Most important model within TCM is the model of the six stages (Shan Han Lun). In western medical view this is interpretation of clinical signs predominantly induced by Neuro-immunological mechanism.  4th GC - Yin/Yangthis is to distinguish the origin of signs and symptoms, yin (structural deficiency). Yang (primary deregulation). Diseases described by guiding criterion Yin, there symptoms are due to deficiency of functional tissue (body substance). diseases described as yang, however symptoms are primary due to dysregulation described by the first three guiding criteria.[20] Page | 37 4. TCM approach to Endometriosis According to a survey of TCM treatment for endometriosis, TCM strategies may include[21]: 1. TCM internal treatment, including: 1.1. Syndrome-differentiation treatment 1.2. The periodic therapy (application of different prescriptions and treating principles at different periods of the menstrual cycle.) 1.3. The special-prescription treatment (prescription specially formulated for this disease based on the differential theory and clinical experience) 2. TCM external treatment, including: 2.1. Chinese herbal enemas 2.2. Medicinal plaster therapy 2.3. Acupuncture treatment Acupuncture is a type of treatment that stimulates certain locations or points of the body, by manipulating needles. All the methods in acupuncture treat diseases by exerting a certain stimulation on the body especially in the acupoints by which to free the conduits in order to move Qi and activate Xue (blood) so as to regulate the balance between Yin and Yang to coordinate the Function of Zang Fu; and to support the health of Qi and eliminate the Evil Qi.[22] Acupuncture therapy has been known as a practice associated with oriental and complementary medicine, and it has been recently identified in the field of complementary medicine as a potential therapeutic procedure for which there is good scientific evidence.[12] Based on TCM acupuncture is used widely around the world, but other methods of acupuncture exist, and numerous variation of acupuncture therapy has been developed.[23] Scientific research into the mechanism of action of acupuncture began around 1950 when an important pharmacological study was published by a group at Peking University. They demonstrated that an induction time of 15 to 20 minutes is required for the development of an analgesic effect and proposed the participation of chemical substances in the analgesic actions of acupuncture [4]. Before the 1990s, most experts agreed on the concept that in normal animal models, lower frequency electroacupuncture (EA) stimulates the release of beta-endorphin, encephalin and endomorphic, which in turn activates the muand delta-opioid receptors, and that higher frequency EA stimulates dynorphin which activates the kappa-opioid receptor.[24] Page | 38 Acupuncture in endometriosis – literature review: Acupuncture has been studied in gynecological disorders but it is effectiveness for pain in endometriosis is uncertain (Figure 10).[25] However the use of acupuncture for chronic pelvic pain is suggested to be helpful in relieving the pain and in turn improving patient’s quality of life.[26] More than 50% among women with chronic pelvic pain used at least one complementary health approach in the past year, including acupuncture 8%, special food or diet 22%, herbs 27%, and Vitamins and minerals 29%.[27] Figure 10: Acupuncture traditional use in Gynecological disorders[28]. Acupuncture has satisfactory results of relieving dysmenorrhea, especially the primary type, but also in secondary dysmenorrhea.[28]. Page | 39 Lewers et al. applied acupuncture-like transcutaneous electrical nerve stimulation (TENS) in treating 21 cases of primary dysmenorrhea and found an average pain relief of at least 50% immediately post-treatment[28]. Helms investigated the effectiveness of acupuncture in primary dysmenorrhea pain in a randomized controlled trial, with 43 women for one year and allocated to 4 groups. The verum acupuncture group was given random point acupuncture on weekly basis for 3 menstrual cycles. In the Verum group, 10/11 (90.9%) women showed improvement that was much higher than the placebo group or in other 2 control groups. There was 41% reduction of analgesic medication used by the women in the real acupuncture group after their treatment series and no change or increased use of medication seen in the other groups[28]. A study by Maric applied acupuncture in 32 patients with primary dysmenorrhea, showing a relief of the pain already after the first menstruation; one year after the completed therapy, there was a full disappearance of dysmenorrhea pain in 93% and a partial one in 75 of the cases[28]. A study by Tsenov included 48 women in reproductive age, 24 with primary dysmenorrheal in the first group and 24 women with secondary dysmenorrheal in the second group. The results were that in the first group effect was very good after one course of 2-4 acupuncture sessions before menstruation. In the second group, effect was satisfactory in 50% of the cases after two courses of acupuncture treatment [29]. LI Yuan-feng [21] used auricular seed-embedding and herbal prescription for dysmenorrhea due to EM with “quite good” results. The auricular seed-embedding with vaccaria seeds was applied starting from 5 days before the menstrual period on the auricular points of Sub cortex, Endocrine, Sympathetic Nerve, Ear-Shenmen, Liver, Kidney, Internal Genitalia, and Tingzhong. The embedded seeds were pressed 3–5 times a day, lasting 30 min each time. The seed-embedding was done every 2 days alternately on both ears, altogether 5 times, with two menstrual cycles forming one therapeutic course. DING Zhe [21] applied vaccaria seed-embedding on the auricular points of Internal Genitalia, Endocrine, Liver, Kidney, Ear-Shenmen, and Sympathetic Nerve. The treatment began 3–5 days before the menstrual period, and lasted 3–5 menstrual cycles. The total effective rate was 97%. RUAN Ji-yuan [21] defend that point-injection therapy with Chinese phytotherapy can improve the ectopic endometrial adhesion and fibrosis. For that purpose, they applied point-injection with salvia injection at Zusanli (ST 36) and Xuehai (SP 10), or at Ciliao (BL 32) and Sanyinjiao (SP 6), with the two groups of points alternately used every other day, during 2 months, achieving good symptom relief. Page | 46 Page | 47 II. CLINICAL RESEARCH PROTOCOL Title: Objectifying acute effects of Acupuncture for pelvic pain due to endometriosis. A clinical research protocol using a novel pain assessment system 1. Background: Endometriosis (EM) is a common health problem affecting women worldwide and often underdiagnosed. It is estimated that 7% -10% of women in the general population suffer from EM. Pelvic endometriosis is present in 6% to 43% of women undergoing sterilization, 12% to 32% of women undergoing laparoscopy for pelvic pain, and 21% to 48% of women undergoing laparoscopy for infertility. According to conventional medicine, treatment of EM needs life-long management including medical or surgical treatments, hormonal therapy being mostly used. However, long administration of these therapies remains challenging due to the plethora of serious adverse effects. Acupuncture has been studied in Gynecological disorders with few studies have been published on acupuncture for Endometriosis induced pain but its effectiveness for pain in endometriosis remains uncertain. The use of acupuncture is suggested to be helpful in relieving the chronic pelvic pain which in turn improves patient's quality of life. 2. Research team 2.1.1 Main investigator: Khadija Bashir Ibar • Physician graduated from Faculty of Medicine Benadir University Mogadishu – Somalia. • Resident house officer in Obstetrics and Gynecology department Benadir Teaching Hospital. • Master student of Traditional Chinese Medicine at the Instituto de Ciências Biomédicas Abel Salazar (ICBAS) 2.2 Research supervisors: 2.2.1 Main supervisor: Prof. Dr. Henry Johannes Greten Page | 48  Invited Associated Professor; Director of the Specialization and Master Program in Traditional Chinese Medicine; Department of Acquatic Production; Abel Salazar Institute for Biomedical Sciences, University of Porto, Portugal. • Head of the Heidelberg School of Traditional Chinese Medicine • President of the German Society of Traditional Chinese Medicine (DGTCM), Heidelberg, Germany  President of the German-Chinese Research Foundation for TCM, Heidelberg, Germany 2.2.2 Supervisor: Dr. Nuno Cândido Maia Correia • Assistant in Internal Medicine, Service of Emergency, Hospital Center São João, Porto • Invited Assistant Professor of General Pathology – Nursing School of Porto • Master in Traditional Chinese Medicine - ICBAS / UP • Heidelberg School of Health and Sciences 2.2.3 Co-supervisor: Dra. Ana Rosa Costa.  Hospital Assistant of the Service of Gynecology and Obstetrics, Hospital Center São João. Responsible for the outpatient consultations of Endometriosis, Family Planning and Climatery. 2.2.4 Co-supervisor: Dra. Maria João Santos.  Teacher at TCM Master Program ICBAS/UP  Heidelberg School of Health and Sciences Page | 49 3. Objectives: 3.1 General objectives:  To develop a clinical research protocol for a randomized, sham-controlled preliminary study that evaluates the acute effects of acupuncture for endometriosis-related pain.  To assess feasibility of the study protocol, and collect preliminary data, for a larger study. 3.2. Specific objectives:  To assess if acupuncture can improve pelvic pain in patients with endometriosis.  To objectively measure the effect of acupuncture in pain, by using a pressure sensitive sensor device. 4. Methods: 4.1. Setting Local: Hospital Center São João, Service of Gynecology and Obstetrics, Consultation of Endometriosis. 4.2. Ethics assessment: The study protocol was approved by the Ethical Committee of Hospital Center São João (See Annex 1). Data recruitment already started. 4.3. Study sample: 30 patients, diagnosed with pelvic endometriosis and having chronic pelvic pain secondary to EM. 4.4. Informed consent. All patients’ consents were obtained before the beginning of the intervention.(see annex 2) 4.2 Study design The study is designed has preliminary, prospective, randomized, controlled, singleblinded clinical trial in a cross-over methodology. Page | 50 Figure 14: cross over design. A cross-over design is defined in order to avoid possible carry over effects. Experimental group: verum acupoints. Control group: false acupoints.  Experiment group: 15 patients will first undergo true acupuncture in points chosen according to HM of TCM followed by sham acupuncture  Control group: 15 patients will undergo sham acupuncture first and then verum acupuncture. 4.3. Eligibility Criteria Inclusion Criteria: women from 18-55 yr .with pelvic pain due to EM beyond the time of menstrual bleeding at Sao Joao Hospital EM clinic, mentally fit and cooperative with the study; naïve to acupuncture. Exclusion criteria: women with menses (to exclude dysmenorrhea), chronic pelvic pain due to non-endometriosis causes, active infectious disease, congenital diseases or any other severe disease. Page | 51 4.4. Blinding methodology This study follows a single blinded methodology: - Patients are blinded to acupuncture since they are naïve to acupuncture. As such they cannot distinguish between true or false acupoints during needling. - The acupuncturist is not blinded. A trained acupuncturist will do the acupuncture and the palpation of the pelvic with the sensor measuring the pressure. - The VAS will be measured by another researcher, before and 5 min after the treatment, which is also not blinded. 4.5. Randomization Coin flip will divide the patients into the verum (true) and sham (control) acupuncture groups. Patient’s document sheet is marked with different colors according to which group the patient belongs to. 4.6 Experimental protocol Step1: Before the Intervention, data recruitment using clinical questionnaire (see annex 3), VAS will be measured baseline (see annex 4), and pelvic palpation with pressure application in a region two fingers above the superior anterior iliac spine and three fingers from the midline. This location was selected on the basis that it is common to have pain in this region on palpation specially women with endometriosis (Greten H., Understand TCM Scientific Chinese Medicinethe Heidelberg Model, 2013, 6th edition). Step 2: acupuncture intervention with leopard spot technique on GB41 and Sp6. Step3: 5 minutes after the treatment the measurements with the VAS and pressure sensitive device will be done to be compared and analyzed. Step 4: Cross-over of the two groups: after one week of washout period for the previous acupuncture intervention the two groups will be exchanged. Step 5: Experimental group will become control group and will undergo the same process of VAS measurement and Pelvic palpation and measuring the pressure with the pressure sensor, and in the intervention step the points will be Page | 52 Sham points with leopard spot technique. The Control Group will become experimental group and subject to same evaluation process. 4.6.1 Intervention: The verum acupuncture consists of needling following the leopard spot technique on Gb 41 and Sp6. Table 2: Acupoints locations and areas of innervation. D – Dermatome, M – myotome, S - sclerotome Acupoints Location and target Neurotomes Sp6 3 cun superior to the most prominent part of the medial malleolus on the medial border of the tibia Target: flexor digitorum longus D L4 /S1/S2 M L2/L3/L4 S L3 Gb41 In the depression distal to the junction of the 4th and 5th metatarsals, lateral to the tendon of extensor digitorum longus that passes to the 5th toe Target: 4th dorsal interosseus D L5/S1 M S1/S2 S S2 Figure 15: Verum acupuncture group The false acupuncture consists of needling following the leopard spot technique in nonacupoints 1 cun distant from the true acupoints (see figure 16). Needles are inserted according to the leopard spot technique (same stimulation as verum-group), using the same number of needles at skin points outside the conduits. Page | 53 Figure 16: Sham acupuncture group Table 3: Location of Skin point (sham group) Skin Points Location Skin Point 1 1 cun medial to GB 39 in between GB and ST conduit in the same level with GB39 and SP6 Skin Point 2 1 cun medial to GB 41 in between GB and ST conduit in the same level with GB 41 lateral side Page | 54 Figure 17: schematic demarcation of dermatomes .The dermatomes map allows understanding the segmental effect of acupuncture needling stimuli. (inhttp://www.backpainguide.com/Chapter_Fig_folders/Ch06_Path_Folder/Ch06_Images/064%20Radiculopathy.jpg, consultation on the 2014/09/3) The leopard spot technique consists of 5 rapid in-and-out bloodletting strokes with acupuncture needles over the point’s skin area. Patients are subject to 2 session of acupuncture with one week of interval (verum or false acupuncture) VAS pelvic pain is assessed at baseline (before acupuncture) and 5minutes after the acupuncture. Page | 55 Pain is elicited by pelvic palpation with pressure on region above the anterior superior iliac spine and measurement of the pressure needed to reach the maximum pain by a pressure sensitive sensor specially designed to do this study. Acupuncture treatments: Verum group (experimental group): “real” acupuncturebased on a concept of acupuncture according to Heidelberg Model of Chinese Medicine, aiming to relief the Qi and Blood (xue) stagnation which are the main causes of Endometriosis it is self and also the Chronic Pelvic Pain. . (Greten H., Understand TCM Scientific Chinese Medicinethe Heidelberg Model, 2013 6th Ed). - GB41, instantium lacrimarum pedis, Zu lin qi. - Sp6, copulatiotrium yin, San yin jiao. False group (control group): an invasive control using acupoints outside the conduits, 1 cun distant from the acupoints used in the verum group. Both treatments will be performed using the same number of needles, applied on the leg on the same side as the pelvic side with more pain as assessed at baseline (ipsilateral needling). Insulin needles are used for leopard spot technique in a calm room located at the Outpatient office of Gynecology. Sterile Single use needles will be used in both groups. Figure 18: Insulin needle. To perform the “leopard spot” needling technique insulin needles were used measuring X mm of length. Page | 62 Data to be analyzed: 1. VAS before and after the acupuncture with-out applying pressure on the pelvic. T0 and T3. 2. VAS before and after the intervention with pressure application on the pelvic.T1 and T2 3. Analysis of the data recorded in the computer with the pain events and the force needed to induce the maximum pain before and after the treatment. 4. Analysis of both VAS and the saved data from the Sensor and comparison after the cross-over between the groups. 4.8 Study Chronogram: Table 4: Study Chronogram Time period Main tasks and goals September 2013 to January 2014 Literature research; preparation of the research protocol. February to May 2014 Submission of the research project to Hospital Centre São João for Ethics Committee assessment (already approved see Annex 1). May – June 2014: Patient selection according to the inclusion criteria of this study, and data recruitment recently started at the Hospital. Since June Study protocol practical work and continuous patient recruitment and enrolments. October Master thesis delivery December 2014 Predicted end of the study January 2015 Data analysis and article writing February-March 2015 Submission and publication of results Page | 63 5. Research partnership: Cooperation between ICBAS TCM Master Program and the Service of Gynecology and Obstetrics of Hospital Center São João was established. Agreement for the research project was obtained from the Director of the Service of Gynecology and Obstetrics, Prof. Doctor Nuno Montenegro. Page | 64 6. Expected Results: This proposed clinical protocol has been submitted for approval by the Ethics Committee of São João Hospital (appendix 1), the authorization to work on the Endometriosis clinic has been granted (appendix 3), and steps towards its completion are being accomplished. Enrollment of the patients in currently in course. Until the present date, 20 patients were contacted. Only 6 could be selected due to the eligibility criteria. Mains reasons for exclusion: - Not interested in acupuncture - Patients underwent surgical treatment for endometriosis - No pain under medication - Patients had other medical conditions and treatment that did not allow for visits to the hospital or participation in acupuncture treatments. - Professional reasons not allowing their coming for a research study. In addition, summer time traditional Portuguese holidays (July-August-September) limited the voluntarily adherence of the patients to the study until the thesis delivery deadline. From 6 patients that were selected, we had 5 drop outs generally due to: - No pain with pressure at baseline on the first visit assessment in office or at the second session of acupuncture. - Missed 2nd session of acupuncture after 1 week (some could only come 2 weeks after which did not follow the protocol). So far we have one case report which showed clinical improvement with verum acupuncture that we describe. 6.1. Case report A 44 years-old woman diagnosed with pelvic endometriosis two years ago. She developed chronic pelvic pain with dysmenorrhea secondary to endometriosis and was taking NSAIDs plus analgesics Paracetamol 1000 mg 3 times daily and Tramadol 50 mg two times daily since 7months with limited improvement. After randomization, the patient was firstly enrolled to the verum acupuncture group. Page | 65 After one week, she was subjected to the sham acupuncture in her second session. During the pain assessment (VAS baseline T0) she reported that she didn’t felt the pain during the week and so did not use the drugs. The results of the VAS and Pressure maximum-induced pain measurements are shown in table 5 (VAS) and table6 (sensor). Table 5: Pain evaluation VAS results Type of pain measurement VAS Stages of the pain measurement T0 T1 T2 ΔT2-T1 T3 Verum acupuncture 0 7 3 4 0 Sham acupuncture 1 4 3 1 0 Table 5.1Pain evaluated by VAS. T0: baseline and patient reported taking Paracetamol 1000mg and Tamadol 50mg 3hr attending the session; T1: after pressure to maximum pain at pelvic point before acupuncture; T2: after acupuncture; T3: after treatment, at rest. ΔT2-T1: magnitude of VAS before and after acupuncture. The above table is showing the result of VAS both before and after intervention. Table 6: Pressure sensor device results Pressure induced maximal pain Stages of the pain measurement T1 T2 Δ (T2-T1) Verum acupuncture 1.740 kg 2.501 kg 0.761 Sham acupuncture 1.027 kg 1.576 kg 0,549 Table 2 –Maximum pain after pressure as measured by a pressure-sensitive sensor. T1: before: after pressure to maximum pain at pelvic point before acupuncture; T2: after acupuncture; Δ (T2-T1): magnitude of pressure maximum-induced pain before and after acupuncture. Page | 66 7. Discussion The scientific approach is the best way to increase knowledge and understanding of acupuncture in the future, because it is self-critical by its very nature. Only through a scientific approach, acupuncture and TCM may be validated as a therapeutic option for patients. Acupuncture analgesic effects are widely described in literature, mainly for musculoskeletal conditions (upper limb pain, neck pain, back pain, osteoarthritis of the knee or hip), headache (migraine, tension-type), myofascial pain, fibromyalgia, pelvic pain in pregnancy, dental pain, or postoperative pain. These neurophysiologic effects have been described by acting at 5 levels[37]: - Local effects in the tissue o Acupuncture promotes local healing - Segmental effects at a particular level in the spinal cord (depression of the dorsal horn activity, thereby reducing the painful stimuli) o Acupuncture reduces pain in the segment where the needles are inserted - Extra-segmental effects by stimulating pain-suppressing endogenous mechanisms on the brainstem pathways thereby promoting a systemic pain reduction response. o Acupuncture reduces pain on the whole body - Central regulatory effects at the cortex, hypothalamus and limbic system, thereby exerting regulatory effects o Acupuncture promotes a general wellbeing and relaxing sensation Unfortunately, pharmacological approaches often render limited effects and also provoke potentially serious side effects. Hence, many patients try complementary medicine treatments. Amongst the non-pharmacological approaches, the use of acupuncture has increased consistently during the past few decades. Regarding dysmenorrhea, from which 90% is primary, acupuncture seems to have satisfactory results according the present literature[28]. However, for dysmenorrhea secondary to endometriosis few studies have been performed. There is preliminary evidence to support acupuncture as an effective treatment for endometriosis, with one small sham controlled trial ([23]) and a few comparative studies against Western medication ([38], [39], [6]). Page | 67 Currently, it is thought that acupuncture treatment may improve pain due to endometriosis by: 1. providing pain relief - by stimulating nerves located in muscles and other tissues, acupuncture leads to release of endorphins and other neuro humoral factors, and changes the processing of pain in the brain and spinal cord ([40], [41], [42], [43]). 2. reducing inflammation - by promoting release of vascular and immune modulatory factors [44], [42]). 3. rregulating levels of prostaglandins ([45])· combining acupuncture with Chinese herbal medicine for endometriosis has been shown in animal studies to down regulate the abnormal increase of matrixmetalloproteinase-2 (MMP-2) levels that is associated with ectopic activity of endometrial cells. The treated rats had reduced areas of ectopic tissue (Chen 2008). MMP-2 is required for the anchoring of the placenta to the uterine wall in pregnancy but over-production can lead to endometriosis. Further research is needed to confirm these observations. In common to all acupuncture studies, we found methodological flaws in these studies of acupuncture for endometriosis including: - lack of an adequate control for acupuncture - absence of a double-blinding methodology - lack of objective measurements of the acupuncture effect in pain modulation We defined the needling of skin non-acupoints as the control acupuncture. Some researchers prefer to compare true acupuncture to a waiting list. However, by comparing true acupoints with non-acupoints, we wanted to assess whether true acupuncture effects are specific since it is known that needling any point on the skin elicits unspecific body responses. Interestingly, our selected control points share same segmental nerve roots with verum acupoints. If we observe specific effects of verum acupoints, then we must raise the hypothesis of an additional mechanism beside the neurological theory of “western medical acupuncture”. Our case report suggests that the effect of true acupuncture is superior to sham, indicating possibly a specific effect of verum acupoint needling. However, this observation must be skeptically considered, since we need more cases, more data, to exclude that this particular clinical case observation was not merely due to chance. Page | 68 Due to lack of time, financial and human resources, we could not develop a doubleblinded methodology. For this, we believe we could follow the Heidelberg double-blind assay, in which the individual inserting needles would be a non-acupuncturist, and therefore could not distinguish from true or sham acupoints that were marked on the skin with different alternating colors[46]. It is widely discussed, proved and recommended in the literature to use pain measurement tools like VAS to measure overall pain in clinical practice. However, problems exist in objective measuring the effect of acupuncture in pain. All studies in acupuncture for endometriosis have only applied VAS to measure pain. This tool has been criticized because it is highly subjective and therefore may not represent real effects of acupuncture. We wanted to introduce in our protocol a new method to objectively evaluate the effect of acupuncture in pain. In strict cooperation with the Engineer Faculty colleagues, we develop a novel pressuresensitive sensor device which allows objective measurement of acupuncture's effect in pain in endometriosis patients. By measuring how much pressure the patient can tolerate by abdomeno-pelvic palpation until maximum pain, we can achieve results of pressure in kg units that could indicate changes in pain by acupuncture. By analysing the resulted data from the sensor and the VAS we could get more accurate, reproducible measurement of the extent of the reduction induced by the treatment. We have seen in some cases, that VAS changes not always follow the same direction of change as with pressure-sensitive sensor assessment. Therefore, pain perception and real pain are different phenomena for patients. Our study could add information regarding these differences. Most importantly, the pressure maximum induced pain methodology allows an objective measurement of acupuncture effects, which in turn will contribute to the demystification of acupuncture. Since the study is in the beginning and there is not enough data yet available at the time of this thesis submission in order to take out conclusion regarding acupuncture effect in endometriosis. It is expected that the real acupuncture could show decrease in pain even after one treatment and this effect could be assessed with the visual pain scale and the sensor measurement before and after each session. Page | 69 It is foreseen that the real acupuncture could demonstrate a significant reduction in pelvic pain sensation, compared to the sham group keeping in mind that the both groups should be with no statistically significant differences regarding age, gender, and use of medication (this last factor may be difficult to control). Limitations Our study protocol has some limitations that we want to dissect. In a practical level some problems were detected. Since we are inviting patient out of their scheduled consultations, it was almost impossible to get the patient at the right time for the 2nd session one week after the 1st session. Availability of a room in the Gynecology outpatient sector in the hospital was limited to two days per week only in the afternoon 3hrs per day (6hrs per week) which also restricted the researcher’s availability for patient’s participation bearing in mind their own time-table availability to participate. As we mentioned in the results section, the recruitment of the patient already started and we faced several problems. So far we had 6 cases included into the study that signed the consent. From these, recruitment data and the first session were done, but only one of these six patients completed the second session in the right time (1 week apart from the first assessment), due lack of right timing between patients availability and the availability of the rooms in the hospital, some technical problems with the sensor that were meanwhile improved, and some patients just disappeared and did not come to the second session. In addition, most of the contacted patients did not have spontaneous pelvic pain, because they were controlled with pain killers. Ethically, we are not allowed to ask them to stop their medication in order to try acupuncture instead. Because it is a short time study, action of external factors such as change in medicaments, change of lifestyle, diet, alcohol intake, smoking status are less likely to happen and influence results. Also, crossover designs are prone to carry-over effects. Although it is generally accepted that the effect of one acupuncture session has vanished one week later, we cannot rule out residual carry-over effects based on an empirically notion. Statistically analyses may help to clear this doubt. We cannot also exclude that baseline pain may be different in the two sessions (1st or 2nd). However, comparison of the magnitude of the effects of acupuncture (true or false) Page | 70 between the 1st and 2nd session will serve as the index to avoid possible baseline differences. Although we include patients with chronic pain, the pain due to endometriosis may fluctuate in relation to its hormonal influences. This may limit the cross-over method. In order to overcome this limitation, a parallel two group study (verum vs. false acupuncture) with at least 8 to 12 sessions of acupuncture would be needed. This study protocol was conceived to evaluate acute effects of acupuncture in endometriosis pelvic pain in order to have a preliminary study to support a further larger study. As such, we are unable to infer the long-term or cumulative effects of repeated applications. A long-term study evaluating the chronic impact of acupuncture for endometriosis would then be needed and it can be done using the Endometriosis health profile (EHP-30, EHP-5) (Annex 5) which recognized to be the best questionnaire to evaluate the pain in endometriosis and patient's quality of life. We did not blind the acupuncturists for the reasons expressed previously. For a subsequent study evaluating long-term effects of acupuncture in endometriosis, we believe it would be important to blind the acupuncturist following the Heidelberg doubleblinded assay [46] Finally, the controversy over acupuncture extends to the issue of the most effective method of acupuncture. Some practitioners favor a “modern medical /western acupuncture”, treating patients according to a standardized set of points based on the areas of innervation. Other practitioners adhere to an individualized “classical acupuncture”, which selects acupuncture points based on assessment of disease patterns (syndrome differentiation) and a physical examination, including Chinese tongue and pulse diagnosis and the localization of par aesthetic pressure points. While the data support the notion that the choice of needling points matters, the relevant aspects of the Chinese diagnosis still remain to be elucidated[46]. This, however, cannot be addressed in this work. In this context, we opted to choose acupoints and the leopard spot technique on the basis of a general common treatment within the TCM Heidelberg model approach considering the need to treat qi and xue stasis which is present in all endometriosis patients according to TCM theory. As such, it is an open question to study an Page | 71 individualized acupuncture treatment based on neuro vegetative pattern differentiation, i.e., following an individual functional diagnosis. Hypothetically, acupuncture treatment based on an individualized selection of acupoints may be superior to a general standardized acupuncture treatment approach as we need which was not the goal of this study protocol. This study should, therefore, be considered a proof of concept study. • Blinding the patients to avoid the effects of their beliefs and expectations because these can influence the response to the therapy. . (Kaptchuk, 2002)(Flaten, Simonsen, & Olsen, 1999). DICUSSION 8. Future perspectives: This study may reveal that acupuncture may significantly decrease chronic pain due to endometriosis in comparison to the sham group, therefore possibly indicating specific physiological effects of acupuncture. The introduction of a novel pressure sensor to evaluate pain is a pioneer methodology that we want to further explore. Preliminary experience showed that this device is working successfully by objectifying pressure tolerance as a measure of pain reduction. Therefore, at the conclusion of this study protocol we may show that this device can be used as step towards objective research on acupuncture and of EM induced pelvic pain, thus validating the effects of acupuncture. This assessment could then be useful for additional research with larger sample and longer acupuncture treatment and follow up periods to assess the real effect of acupuncture. This study can be used as step toward the inclusion of acupuncture in the future guidelines for the management of EM induced pelvic pain. Results from this study may in the future grant a larger prospective, controlled, doubleblinded, and randomized protocol with longer follow-up period. Acupuncture may prove to be another interesting tool to manage this condition responsible for a great discomfort and reduced quality of life for affected women and their partners. Page | 78 Page | 79 Annex 1: Approval Letter from The Hospital Ethical committee Page | 80 Page | 81 Page | 82 Page | 83 Annex 2: Patient informed Consent letter & Patient invitation letter Page | 84 Page | 85 DECLARAÇÃO DE CONSENTIMENTO Considerando a “Declaração de Helsínquia” da Associação Médica Mundial (Helsínquia 1964; Tóquio 1975; Veneza 1983; Hong Kong 1989; Somerset West 1996 e Edimburgo 2000) Designação do Estudo (em português): Eu, abaixo-assinado, (nome completo do doente ou voluntário são) , declaro não ter participado em nenhum outro projecto de investigação durante este internamento, tendo compreendido a explicação que me foi fornecida acerca do meu caso clínico e da investigação que se tenciona realizar. Foi-me ainda dada oportunidade de fazer as perguntas que julguei necessárias, e de todas obtive resposta satisfatória. Tomei conhecimento de que, de acordo com as recomendações da Declaração de Helsínquia, a informação ou explicação que me foi prestada versou os objectivos, os métodos, os benefícios previstos, os riscos potenciais e o eventual desconforto. Além disso, foi-me afirmado que tenho o direito de recusar a todo o tempo a minha participação no estudo, sem que isso possa ter como efeito qualquer prejuízo na assistência que me é prestada. Por isso, consinto que me seja aplicado o método, o tratamento ou o inquérito proposto pelo investigador. Data: ____ / _________________ / 201___ Assinatura do doente ou voluntário são: ___________________________________________________ O Investigador responsável: Nome: Assinatura: Comissão de Ética do Centro Hospitalar de S. João – Modelo CE 01 Annex 3: Clinical Questionnaire Projecto de Investigação Page | 86 Efeito da acupunctura na dor pélvica na endometriose – estudo de viabilidade Questionário Clínico Nota: Os questionários serão mantidos sob confidencialidade Questinário nº____ A. Identificação: 1. Nome (iniciais):__________ 2. Nº processo clínico:_________ 3. Data de nascimento: ___ /___/______ 4. Estado Civil a. Solteira b. Casada c. Divorciada d. Viúva e. União de facto 5. Profissão:_______________ 6. Contacto telefónico:______________ B. História clínica da Endometriose a. Data do diagnóstico:___/___/___ b. Tipo de endometriose i. Pelvica: S ___ N___ ii. Extra-pelvica S ___ N___ c. Dor pélvica i. Intensidade (0-10) ii. Nº agudizações / semana iii. Predomínio diário: Manhã ___ Tarde___ Noite____ iv. Uso de analgésicos /AINEs:________________ d. Outros sintomas /problemas associados i. Dispareunia S___ N___ ii. Disuria S___ N___ iii. Fadiga S___ N___ iv. Dor abdominal S___ N___ v. Diarreia S___ N___ vi. Obstipação S___ N___ vii. Infertilidade S___ N___ e. CA -125 Data Resultado Page | 87 C. História Ginecológica e Obstétrica a. Menarca:_____ (anos) b. Cataménios i. regulares: ____ dias ii. irregulares: ___ a ____ (ex: 12 a 50 dias) iii. duração:____ dias c. Menorragias: S__ N___ d. Metrorragias: S__ N___ e. Primerio dia da última mentruação:___/__/___ f. Dor associada à menstruação? S___ N____ i. Se sim: antes da menstruação S__ N__; Durante S__ N___; Antes e durante S__ N___ g. Nunca esteve grávida: ___ h. Gravidez: Ano Abortamento S /N Tipo Parto Eutócito (E) Cesarina (C) Duração da gestação (semanas) Nados vivos Nados mortos Complicações do parto D. História de contracepção a. Método:____________ E. História sexual a. Tem parceiro sexual: S __ N___ (Homem ____; Mulher____) F. História médica passada: a. VIH ___ b. VHB ___ c. VHC ___ d. Sífilis___ e. Gonorreia____ f. Clamidia____ g. Infecções vaginais___ Page | 94 Please check that you have ticked one box for each question before moving onto the next page. ENDOMETRIOSIS, 12. Generally felt unwell? 8 . Been unable to sleep pro perly because of the pain? 9 . Had to go to bed/lie down because of the pain? 10. Been unable to do the things you want to do because of the pain? 11. Felt unable to cope with the pain? 13. Felt frustrated because your symptoms are not getting better? 14. Felt frustrated because you are not able to control your symptoms? Page | 95 Please check that you have ticked one box for each question before moving onto the next page. ENDOMETRIOSIS, 19. Felt weepy/tearful? 15. Felt unable to forget your symptoms? 16. Felt as though your symptoms are ruling your life? 17. Felt your symptoms are taking away your lif e? 18. Felt depressed? 20. Felt miserable? 21. Had mood swings? 22. Felt bad tempered or short tempered? Page | 96 Please check that you have ticked one box for each question before moving onto the next page. ENDOMETRIOSIS, 27. Felt alone? Felt frustrated as you cannot 28. always wear the clothes you would Please check that you have ticked one box for each question. 23. Felt violent or aggressive? 24. Felt unable to tell people how you feel? 25. Felt others do not understand what you are going through? 26. Felt as though others think you are moa ning? choose? 29. Felt your appearance has been affected? 30. Lacked confidence? Page | 10 nex 6: Summary of Studies done about Acupuncture in Endometriosis Authors Title Study type Conclusions Ref. Zhu X, Hamilton KD,McNicol ED. Acupuncture for pain in endometriosis. Review The evidence to support the effectiveness of acupuncture for pain in endometriosis is limited, based on the results of only a single study that was included in this review. This review highlights the necessity for developing future studies that are well-designed, double-blinded, randomised controlled trials that assess various types of acupuncture in comparison to conventional therapies. Cochrane Database Syst Rev. 2011 Sep 7;(9):CD00786 4. doi: 10.1002/1465 1858.CD00786 4.pub2. Xiang DF, Sun QZ, Liang XF. Effect of abdominal acupuncture on pain of pelvic cavity in patients with endometriosis Clinical study (acupuncture vs CM herbs) Effect of abdominal acupuncture on relieving pain of pelvic cavity caused by endometriosis, reducing the level of serum CA125 is superior than Tianqi Tongjing Capsule (radix notoginseng capsule for dysmenorrhea). However, the effects on reducing the size of the ovarian endometrial cyst and the size of uterus with adenomyosis are not significant. Therefore, it is concluded that abdominal acupuncture is a better choice for endometriosis with pain as the chief complaints. Zhongguo Zhen Jiu. 2011 Feb;31(2):1136. Chen M, Zhang H, Li J, Dong GR. Clinical observation on acupuncture combined with acupoint sticking therapy for treatment of dysmenorrhea caused by endometriosis Clinical s. Acup. vs medication group The therapeutic effect of acupuncture combined with acupoint sticking therapy is very significant for dysmenorrhea caused by endometriosis, and it is a good therapy for this kind of disease. Zhongguo Zhen Jiu. 2010 Sep;30(9):7258 Rubi-Klein K, KuceraSliutz E, Nissel H, Is acupuncture in addition to conventional medicine Clinical s. RCT, cross-over N=101 Acup (n=47) vs Acupuncture treatment on specific acupuncture points appears to be an effective pain treatment for endometriosis, but this has to be confirmed in further study. Eur J Obstet Gynecol Reprod Biol. 2010 Page | 11 Bijak M, Stockenhub er D, Fink M, Wolkenstein E effective as pain treatment for endometriosis? A randomised controlled cross-over trial. Non-specific acup (n=54) Nov;153(1):903. doi: 10.1016/j.ejog rb.2010.06.02 3. Epub 2010 Aug 21 Ahn AC, Schnyer R, Conboy L, Laufer MR, Wayne PM. Electrodermal measures of Jing-Well points and their clinical relevance in endometriosisrelated chronic pelvic pain. RCT Electrodermal measures may be significantly associated with clinical outcome and acupuncture treatments in adolescent women with chronic pelvic pain. Altern Complement Med. 2009 Dec;15(12):12 93-305. doi: 10.1089/acm.2 008.0597 Chen YF, et al Effects of acupuncture combined with medicine on expression of matrix metalloprotein ase-2 in the rat of endometriosis] Rat EMs model Combination of acupuncture with medicine has a better therapeutic effect on endometriosis and down-regulates the abnormal increase of MMP-2 level to inhibit the invasion of ectopic tissue to extracellular matrix, so as to reduce the ectopic tissue, hence cure of endometriosis. Zhongguo Zhen Jiu. 2008 Sep;28(9):67580. Wayne PM, et. All.. Japanese-style acupuncture for endometriosisrelated pelvic pain in adolescents and young RCT; feasibility study Preliminary estimates indicate that Japanese-style acupuncture may be an effective, safe, and well-tolerated adjunct therapy for endometriosis-related pelvic pain in adolescents. A more definitive trial evaluating Japanese-style acupuncture in this population is both feasible and warranted. J Pediatr Adolesc Gynecol. 2008 Oct;21(5):24757. doi: 10.1016/j.jpag. 2007.07.008. Page | 12 women: results of a randomized shamcontrolled trial. Lundeberg T, Lund I. Is there a role for acupuncture in endometriosis pain, or 'endometrialgia '? Review Management of pain in women with endometriosis is currently inadequate for many. Possibly acupuncture and cognitive therapy may be used as an adjunct. Acupunct Med. 2008 Jun;26(2):94110. Sun YZ, Chen HL Controlled study on ShuMu point combination for treatment of endometriosis RCT N=30 vs n=30 Acup vs Danazol Shu-Mu point combination needling method has an obvious therapeutic effect on endometriosis, with lower adverse effect than that of the western medicine group. Reduction of pain and CA125 levels Zhongguo Zhen Jiu. 2006 Dec;26(12):86 3-5. Highfield ES,et al. Adolescent endometriosisrelated pelvic pain treated with acupuncture: two case reports. Case report N=2 These case reports provide preliminary evidence that acupuncture may be an acceptable and safe adjunct treatment therapy for some adolescents with endometriosis-related pelvic pain refractory to standard antiendometriosis therapies. These observations suggest that a prospective, randomized controlled trial of the safety and efficacy of acupuncture for this population may be warranted. J Altern Complement Med. 2006 Apr;12(3):31722. Xiang D et al. Ear acupuncture therapy for 37 cases of dysmenorrhea due to endometriosis. Case report N=37 Not available J Tradit Chin Med. 2002 Dec;22(4):2825. Page | 13 Tsenov D The effect of acupuncture in dysmenorrhea N=48 Primary (1st Group) vs secondary dysmenorrhoe a (2nd group) In the 1st group effect was very well after one course of 2-4 acupuncture procedures before menstruation. In the 2nd group effect was satisfactory in 50% of the cases after two courses acupuncture treatment. In conclusion effect of acupuncture treatment on dysmenorrhoea depend on its kind--primary dysmenorrhoea is influenced very well, while secondary dysmenorrhoea is influenced satisfactory. Akush Ginekol (Sofiia). 1996;35(3):245.