Protocol of randomized controlled trial of potentized estrogen in homeopathic treatment of chronic pelvic pain associated with endometriosis

Marcus Zulian Teixeira; Podgaec Sérgio; Edmund Chada Baracat

doi:10.1016/j.homp.2016.03.002

Homeopathy, Table of Contents

Homeopathy 2016; 105(03): 240-249
DOI: 10.1016/j.homp.2016.03.002

Original Paper

Protocol of randomized controlled trial of potentized estrogen in homeopathic treatment of chronic pelvic pain associated with endometriosis

Marcus Zulian Teixeira

,

Podgaec Sérgio

,

Edmund Chada Baracat

Abstract

Background: Endometriosis is a chronic inflammatory disease that causes difficult-to-treat pelvic pain. Thus being, many patients seek help in complementary and alternative medicine, including homeopathy. The effectiveness of homeopathic treatment for endometriosis is controversial due to the lack of evidences in the literature. The aim of the present randomized controlled trial is to assess the efficacy of potentized estrogen compared to placebo in the treatment of chronic pelvic pain associated with endometriosis.

Methods/design: The present is a randomized, double-blind, placebo-controlled trial of a homeopathic medicine individualized according to program ‘New Homeopathic Medicines: use of modern drugs according to the principle of similitude’ (http://newhomeopathicmedicines.com). Women with endometriosis, chronic pelvic pain and a set of signs and symptoms similar to the adverse events caused by estrogen were recruited at the Endometriosis Unit of Division of Clinical Gynecology, Clinical Hospital, School of Medicine, University of São Paulo (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo – HCFMUSP). The participants were selected based on the analysis of their medical records and the application of self-report structured questionnaires. A total of 50 women meeting the eligibility criteria will be randomly allocated to receive potentized estrogen or placebo. The primary clinical outcome measure will be severity of chronic pelvic pain. Statistical analysis will be performed on the intention-to-treat and per-protocol approaches comparing the effect of the homeopathic medicine versus placebo after 24 weeks of intervention.

Discussion: The present study was approved by the research ethics committee of HCFMUSP and the results are expected in 2016.

Trial registration: ClinicalTrials.gov Identifier: https://clinicaltrials.gov/ct2/show/NCT02427386.

Keywords

Endometriosis - Pelvic pain - Estrogen - Protocol - Homeopathy - Clinical symptoms - Randomized controlled trial

Full Text

References

References
1 Bellelis P., Podgaec S., Dias Jr. J.A., Gonzalez M., Baracat E.C., Abrão M.S. Epidemiological and clinical aspects of pelvic endometriosis – a case series. Rev Assoc Med Bras 56 (04) 2010; 467-471.
2 Podgaec S. Coleção Febrasgo: Endometriose. 2014. Elsevier; Rio de Janeiro.:
3 Abrao M.S., Gonçalves M.O., Dias Jr. J.A., Podgaec S., Chamie L.P., Blasbalg R. Comparison between clinical examination, transvaginal sonography and magnetic resonance imaging for the diagnosis of deep endometriosis. Hum Reprod 22 (12) 2007; 3092-3097.
4 Goncalves M.O., Dias Jr. J.A., Podgaec S., Averbach M., Abrão M.S. Transvaginal ultrasound for diagnosis of deeply infiltrating endometriosis. Int J Gynaecol Obstet 104 (02) 2009; 156-160.
5 Goncalves M.O., Podgaec S., Dias Jr. J.A., Gonzalez M., Abrao M.S. Transvaginal ultrasonography with bowel preparation is able to predict the number of lesions and rectosigmoid layers affected in cases of deep endometriosis, defining surgical strategy. Hum Reprod 25 (03) 2010; 665-671.
6 Vimercati A., Achilarre M.T., Scardapane A. et al. Accuracy of transvaginal sonography and contrast-enhanced magnetic resonance-colonography for the presurgical staging of deep infiltrating endometriosis. Ultrasound Obstet Gynecol 40 (05) 2012; 592-603.
7 Exacoustos C., Manganaro L., Zupi E. Imaging for the evaluation of endometriosis and adenomyosis. Best Pract Res Clin Obstet Gynaecol 28 (05) 2014; 655-681.
8 Dmowski W.P., Lesniewicz R., Rana N., Pepping P., Nowisalehi M. Changing trends in the diagnosis of endometriosis: a comparative study of women with pelvic endometriosis presenting with chronic pelvic pain or infertility. Fertil Steril 67 (02) 1997; 238-243.
9 Luisi S., Lazzeri L., Ciani V., Petraglia F. Endometriosis in Italy: from cost estimates to new medical treatment. Gynecol Endocrinol 25 (11) 2009; 734-740.
10 Giudice L.C., Kao L.C. Endometriosis. Lancet 364 2004; 1789-1799.
11 Harris H.R., Costenbader K.H., Mu F. et al. Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses’ Health Study II. Ann Rheum Dis 0 2015; 1-6.
12 Kvaskoff M., Mu F., Terry K.L. et al. Endometriosis: a high-risk population for major chronic diseases. Hum Reprod Update 21 (04) 2015; 500-516.
13 Guo S.W. Endometriosis and ovarian cancer: potential benefits and harms of screening and risk-reducing surgery. Fertil Steril 2015. pii: S0015-0282(15) 01760-4.
14 Lu Y., Cuellar-Partida G., Painter J.N. et al. Australian Ovarian Cancer Study; International Endogene Consortium (IEC). Shared genetics underlying epidemiological association between endometriosis and ovarian cancer. Hum Mol Genet 24 (20) 2015; 5955-5964.
15 Cavaggioni G., Lia C., Resta S. et al. Are mood and anxiety disorders and alexithymia associated with endometriosis? A preliminary study. Biomed Res Int 2014 2014; 786830.
16 Laganà A.S., Condemi I., Retto G. et al. Analysis of psychopathological comorbidity behind the common symptoms and signs of endometriosis. Eur J Obstet Gynecol Reprod Biol 194 2015; 30-33.
17 Friedl F., Riedl D., Fessler S. et al. Impact of endometriosis on quality of life, anxiety, and depression: an Austrian perspective. Arch Gynecol Obstet 292 (06) 2015; Jun 26 1393-1399.
18 Matalliotakis I., Cakmak H., Matalliotakis M., Kappou D., Arici A. High rate of allergies among women with endometriosis. J Obstet Gynaecol 32 (03) 2012; 291-293.
19 Bungum H.F., Vestergaard C., Knudsen U.B. Endometriosis and type 1 allergies/immediate type hypersensitivity: a systematic review. Eur J Obstet Gynecol Reprod Biol 179 2014; 209-215.
20 Ferrero S., Pretta S., Bertoldi S. et al. Increased frequency of migraine among women with endometriosis. Hum Reprod 19 (12) 2004; 2927-2932.
21 Tietjen G.E., Bushnell C.D., Herial N.A., Utley C., White L., Hafeez F. Endometriosis is associated with prevalence of comorbid conditions in migraine. Headache 47 (07) 2007; 1069-1078.
22 Nyholt D.R., Gillespie N.G., Merikangas K.R., Treloar S.A., Martin N.G., Montgomery G.W. Common genetic influences underlie comorbidity of migraine and endometriosis. Genet Epidemiol 33 (02) 2009; 105-113.
23 Yang M.H., Wang P.H., Wang S.J., Sun W.Z., Oyang Y.J., Fuh J.L. Women with endometriosis are more likely to suffer from migraines: a population-based study. PLoS One 7 (03) 2012; e33941.
24 Nunes F.R., Ferreira J.M., Bahamondes L. Pain threshold and sleep quality in women with endometriosis. Eur J Pain 19 (01) 2015; 15-20.
25 Campin L., Borghese B., Marcellin L., Santulli P., Bourret A., Chapron C. Urinary functional disorders bound to deep endometriosis and to its treatment: review of the literature. J Gynecol Obstet Biol Reprod (Paris) 43 (06) 2014; 431-442.
26 Hansen K.E., Kesmodel U.S., Baldursson E.B., Kold M., Forman A. Visceral syndrome in endometriosis patients. Eur J Obstet Gynecol Reprod Biol 179 2014; 198-203.
27 Rodgers A.K., Falcone T. Treatment strategies for endometriosis. Expert Opin Pharmacother 9 2008; 243-255.
28 Vercellini P., Crosignani P.G., Somigliana E., Berlanda N., Barbara G., Fedele L. Medical treatment for rectovaginal endometriosis: what is the evidence?. Hum Reprod 24 (10) 2009; 2504-2514.
29 Febrasgo. Endometriose em mulheres com dor pélvica crônica: tratamento clínico [Endometriosis in women with chronic pelvic pain: clinical treatment]. Associação Médica Brasileira e Conselho Federal de Medicina: Projeto Diretrizes 2011 Available at: http://www.projetodiretrizes.org.br/diretrizes10/endometriose_em_mulheres_dor_pelvica_cronica.pdf.
30 Teixeira M.Z., Guedes C.H., Barreto P.V., Martins M.A. The placebo effect and homeopathy. Homeopathy 99 (02) 2010; 119-129.
31 Nuhn T., Lüdtke R., Geraedts M. Placebo effect sizes in homeopathic compared to conventional drugs – a systematic review of randomised controlled trials. Homeopathy 99 (01) 2010; 76-82.
32 Shang A., Huwiler-Müntener K., Nartey L. et al. Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet 366 9487 2005; 726-732.
33 Shaw D.M. Homeopathy is where the harm is: five unethical effects of funding unscientific ‘remedies’. J Med Ethics 36 (03) 2010; 130-131.
34 Brien S., Lachance L., Prescott P., McDermott C., Lewith G. Homeopathy has clinical benefits in rheumatoid arthritis patients that are attributable to the consultation process but not the homeopathic remedy: a randomized controlled clinical trial. Rheumatology 50 (06) 2011; 1070-1082.
35 Linde K., Clausius N., Ramirez G. et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 350 9081 1997; 834-843.
36 Taylor M.A., Reilly D., Llewellyn-Jones R.H., McSharry C., Aitchison T.C. Randomised controlled trials of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ 321 7259 2000; 471-476.
37 Jonas W.B., Anderson R.L., Crawford C.C., Lyons J.S. A systematic review of the quality of homeopathic clinical trials. BMC Complement Altern Med 1 (01) 2001; 12.
38 Jacobs J., Jonas W.B., Jiménez-Pérez M., Crothers D. Homeopathy for childhood diarrhea: combined results and metaanalysis from three randomized, controlled clinical trials. Pediatr Infect Dis J 22 (03) 2003; 229-234.
39 McCarney R.W., Linde K., Lasserson T.J. Homeopathy for chronic asthma. Cochrane Database Syst Rev 1 2004; CD000353.
40 Mathie R.T., Lloyd S.M., Legg L.A. et al. Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis. Syst Rev 3 2014; 142.
41 Webster’s new world medical dictionary. 3a edn. New Jersey:Wiley Publishing, 2008.
42 Teixeira M.Z. Semelhante cura semelhante: o princípio de cura homeopático fundamentado pela racionalidade médica e científica [Like cures like: the homeopathic cure principle based on medical and scientific reason]. 1998. Editorial Petrus; São Paulo.:
43 Teixeira M.Z. Similitude in modern pharmacology. Br Homeopath J 88 1999; 112-120.
44 Teixeira M.Z. Evidence of the principle of similitude in modern fatal iatrogenic events. Homeopathy 95 2006; 229-236.
45 Teixeira M.Z. NSAIDs, myocardial infarction, rebound effect and similitude. Homeopathy 96 2007; 67-68.
46 Teixeira M.Z. Bronchodilators, fatal asthma, rebound effect and similitude. Homeopathy 96 2007; 135-137.
47 Teixeira M.Z. Antidepressants, suicidality and rebound effect: evidence of similitude?. Homeopathy 98 2009; 114-121.
48 Teixeira M.Z. Statins withdrawal, vascular complications, rebound effect and similitude. Homeopathy 99 2010; 255-262.
49 Teixeira M.Z. Rebound acid hypersecretion after withdrawal of gastric acid suppressing drugs: new evidence of similitude. Homeopathy 100 2011; 148-156.
50 Teixeira M.Z. Antiresorptive drugs (bisphosphonates), atypical fractures and rebound effect: new evidence of similitude. Homeopathy 101 2012; 231-242.
51 Teixeira M.Z. Rebound effect of drugs: fatal risk of conventional treatment and pharmacological basis of homeopathic treatment. Int J High Dilution Res 11 (39) 2012; 69-106.
52 Teixeira M.Z. Immunomodulatory drugs (natalizumab), worsening of multiple sclerosis, rebound effect and similitude. Homeopathy 102 2013; 215-224.
53 Teixeira M.Z. Rebound effect of modern drugs: serious adverse event unknown by health professionals. Rev Assoc Med Bras 59 2013; 629-638.
54 Teixeira M.Z. ‘Paradoxical strategy for treating chronic diseases’: a therapeutic model used in homeopathy for more than two centuries. Homeopathy 94 2005; 265-266.
55 Teixeira M.Z. ‘Paradoxical pharmacology’: therapeutic strategy used by the ‘homeopathic pharmacology’ for more than two centuries. Int J High Dilution Res 13 (48) 2014; 207-226.
56 Bond R.A. Is paradoxical pharmacology a strategy worth pursuing?. Trends Pharmacol Sci 22 2001; 273-276.
57 Yun A.J., Lee P.Y., Bazar K.A. Paradoxical strategy for treating chronic diseases where the therapeutic effect is derived from compensatory response rather than drug effect. Med Hypotheses 64 2005; 1050-1059.
58 Page C. Paradoxical pharmacology: turning our pharmacological models upside down. Trends Pharmacol Sci 32 2011; 197-200.
59 Davies C.J., Davies D.M. Paradoxical reactions to commonly used drugs. Adverse Drug React Bull 211 2011; 807-810.
60 Bond R.A., Giles H. For the love of paradox: from neurobiology to pharmacology. Behav Pharmacol 22 2011; 385-389.
61 Smith S.W., Hauben M., Aronson J.K. Paradoxical and bidirectional drug effects. Drug Saf 35 2012; 173-189.
62 Bristow M.R. Beta-adrenergic receptor blockade in chronic heart failure. Circulation 101 2000; 558-569.
63 Ho C.Y. Hypertrophic cardiomyopathy in 2012. Circulation 125 2012; 1432-1438.
64 Dickey B.F., Walker J.K., Hanania N.A., Bond R.A. Beta-adrenoceptor inverse agonists in asthma. Curr Opin Pharmacol 10 2010; 254-259.
65 Cui X., Kobayashi Y., Akashi M., Okayasu R. Metabolism and the paradoxical effects of arsenic: carcinogenesis and anticancer. Curr Med Chem 15 2008; 2293-2304.
66 Platanias L.C. Biological responses to arsenic compounds. J Biol Chem 284 2009; 18583-18587.
67 Loffing J. Paradoxical antidiuretic effect of thiazides in diabetes insipidus: another piece in the puzzle. Am Soc Nephrol 15 2004; 2948-2950.
68 Kovács I. Examination of the rebound effect of biphasic oral contraceptives. Ther Hung 38 1990; 110-113.
69 Adám J. How rapid is the return of fertility after the use of Tri-Regol oral contraceptive?. Ther Hung 40 (01) 1992; 16-19.
70 Seeman P., Madras B. Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis. Behav Brain Res 130 2002; 79-83.
71 Engert V., Pruessner J.C. Dopaminergic and noradrenergic contributions to functionality in ADHD: the role of methylphenidate. Curr Neuropharmacol 6 (04) 2008; 322-328.
72 Teixeira M.Z. Homeopathic use of modern medicines: utilisation of the curative rebound effect. Med Hypotheses 60 2003; 276-283.
73 Teixeira M.Z. New homeopathic medicines: use of modern drugs according to the principle of similitude. Homeopathy 100 2011; 244-252.
74 Teixeira M.Z. Homeopathic use of modern drugs: therapeutic application of the organism paradoxical reaction or rebound effect. Int J High Dilution Res 10 (37) 2011; 338-352.
75 Teixeira M.Z. ‘New Homeopathic Medicines’ database: a project to employ conventional drugs according to the homeopathic method of treatment. Eur J Integr Med 5 2013; 270-278.
76 The United States Pharmacopeial Convention. The United States pharmacopeia dispensing information. 24th edn. Easton: Mack Printing Co, 2004.
77 Teixeira M.Z. New homeopathic medicines: use of modern drugs according to the principle of similitude. Vol 3 2010. Marcus Zulian Teixeira; São Paulo: Available at: http://www.newhomeopathicmedicines.com.
78 Teixeira M.Z. Estudo quali-quantitativo para avaliar a eficácia e a efetividade do tratamento homeopático individualizado na rinite alérgica perene [Quali-quantitative clinical trial to evaluate the efficacy and the effectiveness of individualized homeopathic treatment in perennial allergic rhinitis]. [thesis] 2009. Faculdade de Medicina, Universidade de São Paulo; São Paulo: Available at: http://www.teses.usp.br/teses/disponiveis/5/5159/tde-10062009-102220/en.php.
79 Teixeira M.Z. Effectiveness of individualized homeopathic treatment in perennial allergic rhinitis (PAR). Int J High Dilution Res 8 (28) 2009; 141-143.
80 Bignamini M., Bertoli A., Consolandi A. et al. A controlled double-blind clinical study of 15 CH barium carbonate vs. placebo in a group of hypertensive inmates of 2 homes for the aged. Clin Ter 122 (06) 1987; 429-436.
81 Frei H., Everts R., von Ammon K. et al. Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial. Homeopathy 96 2007; 35-41.
82 Hill P.B., Hoare J., Lau-Gillard P., Rybnicek J., Mathie R.T. Pilot study of the effect of individualised homeopathy on the pruritus associated with atopic dermatitis in dogs. Vet Rec 164 (12) 2009; 364-370.
83 Lorençatto C., Vieira M.J.N., Pinto C.L.B., Petta C.A. Avaliação da frequência de depressão em pacientes com endometriose e dor pélvica [Evaluation of the frequency of depression in patients with endometriosis and pelvic pain]. Rev Assoc Med Bras 48 (03) 2002; 217-221.
84 Fernandez I., Reid C., Dziurawiec S. Living with endometriosis: the perspective of male partners. J Psychosom Res 61 (04) 2006; 433-438.
85 Sepulcri R.P., Amaral V.F. Depressive symptoms, anxiety and quality of life in womem with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 142 (01) 2009; 53-56.
86 Thoth B. Stress, inflammation and endometriosis: are patients stuck between a rock and a hard place?. J Mol Med (Berl) 88 (03) 2010; 223-225.
87 Beck A.T., Steer R.A. Beck anxiety inventory manual. 1993. Psychological Corporation (Harcourt Brace and Company); San Antonio.:
88 Beck A.T., Steer R.A., Brown G.K. Manual of beck depression inventory – II. 1996. Psychological Corporation (Harcourt Brace and Company); San Antonio.:
89 Farmacopéia Homeopática Brasileira [Brazilian homeopathic pharmacopoeia]. 3rd edn. Brasilia: Anvisa. Available at: http://www.anvisa.gov.br/hotsite/farmacopeiabrasileira/conteudo/3a_edicao.pdf 2011.
90 Ware J.E., Sherbourne C.D. The MOS 36-Item Short-Form Health Survey (SF-36). I. Conceptual framework and item selection. Med Care 30 1992; 473-483.
91 Ciconelli R.M., Ferra M.B., Santos W., Meinão I., Quaresma M.R. Tradução para a língua portuguesa e validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF-36) [Brazilian-Portuguese version of the SF-36. A reliable and valid quality of life outcome measure]. Rev Bras Reumatol 39 (03) 1999; 143-150.
92 Bayoglu Tekin Y., Dilbaz B., Altinbas S.K., Dilbaz S. Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: levonorgestrel-releasing intrauterine system versus gonadotropin-releasing hormone analogue. Fertil Steril 95 (02) 2011; 492-496.
93 Kirwood B.R., Sterne J.A.C. Essential medical statistics. 2nd edn 2006. Blackwell Science; Massachusetts: pp 502.
94 Begg C., Cho M., Eastwood S. et al. Improving the quality of reporting of randomized controlled trials – The CONSORT statement. JAMA 276 (08) 1996; 637-639.
95 Dean M.E., Coulter M.K., Fisher P., Jobst K.A., Walach H. Reporting data on homeopathic treatments (RedHot): a supplement to CONSORT. Homeopathy 96 (01) 2007; 42-45.