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Introduction

Irritable bowel syndrome, IBS, is a diagnosis that is difficult to understand and difficult to treat [8]; [30]. Its definition is vague: IBS is a syndrome that incorporates symptoms of several functional gastro-intestinal disorders [8] that should have been experienced by patients´ for at least 3 months [3]. As a description, this is non-inclusive of the vast array of symptoms that have been identified as characteristic of IBS [16]; [21]; [24] [See Table 2]. Further complication arises with the fact that “the nature of symptoms [also] can vary amongst patients with IBS and within the same patient over time” [8] (p.1697).

Doctors and therapists therefore, find themselves confronted with variable aspects that make it difficult to diagnose the syndrome and complicate the process of identifying a curative treatment [8]. A precise etiology of IBS does not exist [4]; [24]; [26]; [30] and the diagnosis of IBS is largely achieved by exclusion of other more serious ailments [3]; [8]; [23]. IBS is associated with numerous burdens for the patient, ranging from physical and emotional impact to increased medical costs and decreased quality of life [8]; [13] [20].

In conventional medicine the treatment of IBS is “notoriously unsatisfactory”, [18]; [1] no curative agent is known [4]; [18]; [19]; [20]; [1] and no conventional treatment has educed efficacy in research [8]; [24]; [23]. As a consequence, “therapy for IBS is palliative and supportive, targeting specific symptoms” [18] (p. 2650) only.

Management of symptoms is in CAM, likewise, the main focus in the quest for improvement. CAM too, has to date not produced an effective treatment for the expressions of IBS [4]; [15], albeit offering aspects of treatment such as patient centeredness and individualisation that have been identified as prospective influential components of patient improvement and compliance [12]; [22].

The initial aim of this essay had been to identify evidence of efficacy of homeopathy for IBS. Unfortunately, respective studies and trials were scarce and available as abstracts only, such that the field of investigation had to be broadened to allow a critically examination of research in complementary and alternative medicine (CAM). Yet, focus had to be diverted again, due to the lack of evidence of efficacy of CAM treatments. Consequently this essay seeks to critically analyse research in CAM using the example of IBS. The aim is to identify improvements to research models employed for CAM that acknowledge the philosophical principles underlying holistic, complementary health care, whilst meeting the demand for evidence based proof of efficacy that is fundamental to research in conventional medicine. It is sought to extrapolate from these findings implications for future investigations into the efficacy of homeopathy, for IBS and in general.

Identification of existing literature on IBS

Studies, trials, systematic reviews and meta-analyses were included in this critical analysis. A search for relevant publications was performed on several databases namely, on Sciencedirect, Ebscohost, Pubmed, the Archives of Internal Medicine, the National Institute of Mental Health, Sage publications, the British Medical Journal and the Cochrane collaboration, as well as Google and Google-scholar. The search was performed in the English, German and French language. The initial search terms were: Irritable bowel, irritable bowel syndrome, IBS, complementary and alternative medicine, CAM, alternative therapies, and respective terminology in French and German. These terms were used separately or in differing conjunctions.

Most studies and publications were found via Science-direct, Wiley Online Library, and BMJ. Results in German and French were mainly pay on demand and were only available as abstracts, and were therefore excluded.

The search for articles on research methodology in general, in conventional medicine, CAM and homeopathy was conducted principally via Sciencedirect and Ebscohost. Keywords were: Study design, qualitative research method, methodology of trials, challenges to RCT, random controlled trial, research in CAM, research in homeopathy, whole system research.

Via the references of studies and reviews, the selection of the search-option `similar articles´ on Sciencedirect, and citations of articles, further publications and information were obtained. The selection of articles was restricted to the years 1978 until 2011. The final update of references for this essay was in April 2011.

With respect to the publications included in this analysis, what was considered as CAM were disciplines conform with Chang and Lu´s [4] definition of CAM, as:  “medical practices that are not currently considered a part of conventional medicine” (p.295).

Critical examination of selected studies on IBS

Table 1 – Selected Studies

What becomes evident from the analysis of sourced publications is that there exists a fundamental problem with research on IBS. The absence of consensus of definition of what irritable bowel syndrome precisely describes, flaws trials and studies from the very beginning.

Bommelaer et al. [2] have clearly demonstrated this with the outcomes of their study. Whether IBS is identified by use of the Manning, or evaluated by the ROME I, II or III criteria has impact on the prevalence measure of IBS (See table 2 for criteria describing IBS). Cabré [3] and Pavan et al. [19] also voice this criticism.

Bommelaer et al. [2] further point out that the inclusion of a factor descriptive of “frequency and duration of disorder is highly discriminating” (p.559), as prevalence is influenced by such data and consequently cannot be judged as precise. Biased outcome may also result if participants of the trial or study are expressing symptomatology of IBS at different stages [7]; [9]. Furthermore, in multi-national trials, prevalence, as is noted by Quigley et al. [20] may be flawed due to differing patient and practitioner awareness of the syndrome from one country to another.

Table 2 – Criteria defining IBS

Complementing the above, Whitehead [30] points out in his review of studies on the evidence of efficacy of hypnosis for IBS, what is critical for all studies, equally, if not more so for meta-analyses and systematic reviews in CAM, on IBS and in general. When comparing the efficacy of numerous studies, it “requires basic comparability in outcome measures” (p.17). This is not only of relevance concerning the definition of IBS, but likewise when investigating other measures, such as quality of life or emotional impact, especially when comparing studies from different disciplines.

The meta-analysis of Dorn et al. [6] abstracted the diagnostic criteria in their analysis. Their analysis was indifferent of the bias underlying the employment of differing definitions of IBS, and therefore of prevalence, as their focus was on “placebo response in CAM trials of IBS” (p.630). For identification of their outcome, the authors used 10 trials on herbal remedies, 1 on the use of melatonin and 1 on psychotherapy. Their results can hardly be generalized for all of CAM, and due to the superiority in number of studies on herbal therapy are at best representative of an evaluation in herbal treatment. Further, as the authors themselves point out, the inclusion of a study from the field of psychotherapy is critical, as this treatment approach is one considered to belong into the realms of conventional medicine.

Dorn et al. [6] contradict themselves in discussion and conclusion, when they point out in one that some consideration has to be given the nature of CAM treatments, with a possibly enhanced placebo response in CAM due to the therapeutic relationship, yet exclaim in the other that in CAM and conventional medicine placebo response rates are similar and therefore “independent of the type of therapy used” (p.634). Dorn et al. [6] take the evidence for these statements from different sources, showing clearly that research in this field is still inconclusive. This raises the question whether it is appropriate, in investigations into CAM, to employ research models that fall short of identifying and considering non-specific, but influential factors such as the therapeutic relationship in a treatment. RCTs deliver only one answer to a question and are non-multi-factorial in design [28] and therefore seem insufficient for investigations into CAM.

Shi et al. [21] have restricted focus, in their review, on the “effectiveness and safety of herbal medicine” (p.454) for IBS. They too have noted that prevalence differs depending on criteria employed and mention yet another evaluation criteria employed in China. They have evaluated RCT´s only, but have not insisted on blinding of the trials and studies selected. Shi et al. [21] concluded that 82% of studies reviewed were of poor methodological quality and consequently herbal treatment should “not be reliably recommended” (p.461). They further criticize that duration of study and respective treatment and follow-up were too short in most studies to be able to identify efficacy of herbal treatment. They make the point that in practice too, with short treatment duration, “it is hard to reach the therapeutic goal in IBS” (p.460). Although they did not focus on the placebo-response rate Shi et al. [21] further remind of the therapeutic relationship as possible causative factor of a high rate.

The importance of a longer duration of a study is also an aspect implied from the McFarland and Dublin [18] meta-analysis on the use of probiotics for IBS.  They too point out that current research suffers many methodological flaws and future trials should be designed for longer duration, and should be conducted with more rigor.

Hussain and Quigley [11] stress that in CAM few studies have been subject to RCT´s, and if investigated employing the `gold standard´ of conventional scientific research, the quality of trials has been low. They point out that in as many as 5000 trials, as little as 10% were actually properly blinded and randomized. They conclude that studies in CAM are complicated by higher placebo response rates and consequently little progress has been made in CAM research in general and for IBS.

An RCT, performed on the efficacy of acupuncture on IBS, by Kaptchuk et al. [12] demonstrates the difficulty in association to blinding in some treatment approaches of CAM. Kaptchuk et al. [12] have blinded their trial by using sham acupuncture and although Kaptchuk et al. [12] claim that their blinding has been successful, Mason et al. [17] state that such blinding in CAM “should be treated with caution” (p.833). They point out that the patient experience of a sham treatment does differ to that in regular practice.

In conclusion to their study Kaptchuk et al. [12] emphasize “that an enhanced relationship with a practitioner, together with the placebo treatment” studied in one of their 3 groups, provided “the most robust effect” (p.6). The therapeutic relationship therefore could be rated as the strongest of non-specific effects of the study. Its dominance is markedly and proves of clinical significance in the management of IBS. Kaptchuk et al. [12] in fact stress person-centred modalities as elemental to the patient-practitioner interaction, and consequently acknowledge these as significant to the clinical outcome, although they recommend further research to verify this. They further point out that they suspected in a trial on IBS, with a markedly subjective symptomatology, to be able to best demonstrate the relevance of such non-specific effects as the therapeutic relationship. They acknowledge as a limit to their trial, that it could not be identified whether the placebo outcomes originated from true pathological improvement or were due to a mere shift in patient focus away from their symptoms of IBS, and further admit that they experienced difficulty separating observation and assessment effects.

None of the above publications provided generalisable, conclusive evidence of efficacy of the therapeutic approaches for the treatment of IBS.

The potential contribution of other research designs on understanding IBS

What can be extrapolated from the above its that, beyond consensus in criteria used to identify IBS, it is essential, that in order to provide evidence for the efficacy of CAM for IBS, research models are adopted that are not ignorant of non-specific effects, and in fact identify such influential factors.  The gold-standard RCT cannot provide this. The above has shown that the possibility exists that “the non-specific components of treatment may be vehicles for the delivery of clinical benefits” [29] (p.187). RCTs are designed to investigate into one single quantitative effect [5]; [27], an aspect that entirely ignores the qualitative idiosyncratic approach of CAM [17]; [27]. A research methodology investigating into CAM must meet the demand of high scientific rigor and must be able to merge this with the holistic principles underlying the practices of CAM disciplines [17]; [29].

The identification of a blind-able placebo is another aspect complicating RCT approaches to research in CAM [17]; [27]; as could be extrapolated above in the study by Kaptchuk et al. [12].  Randomization may also be difficult, the patients prepared to participate in this type of trial, may be influenced in their decision by their own preference and belief [17]; [27]; [28].

It has been attempted to modify RCTs to adopt a more qualitative assessment. In what is termed `pragmatic RCT´, it was sought to create a model that investigates the entire system of a discipline within its individualised context [27]. Unfortunately, this format is restrictive and only partially meets the demand for a trial assessing multiple aspects of a holistic treatment approach [27]. Randomization, a blind-able placebo, as mentioned above, and the exclusion of influence of the therapeutic relationship with the practitioner are only marginally achievable [27]. Other variations of RCT´s, such as `preference trials´ [27] and `n-of-1 trials´ [28], have been identified to be likewise restrictive.

The `formal case study´ is a model for investigation that seeks to combine the conventional RCT design with the homeopathic patho-genetic trial, the homeopathic proving [25]. RCTs on homeopathy are flawed as the control with placebo is identifiable at follow-up level and the patient-practitioner relationship may be influential on the outcome [25], as is shown in the above analysis of studies in CAM. The formal case study delivers information on the contextual effects of the researched intervention and is adaptable to other alternative treatment approaches, nonetheless it is also criticised as being inconclusive [25]. A still unmet requirement for the `FCS´, is to master the divergence of the interpretative outcomes established by the different researchers analysing the same data [25].

In opposition to Thompson [25], Weatherley-Jones et al. [29] understand homeopathy as a discipline of CAM that “appears to lend itself well to placebo-controlled trials of efficacy”. They do not acknowledge the identification of the placebo upon progression into follow-up. Nonetheless they consent that the effect of the multiple components belonging to therapeutic interventions of CAM cannot be identified using the RCT, and as such outcomes in homeopathy cannot be generalised [29].

The ANOVA model is a research design that permits identification of two therapeutic aspects, yet Weatherley-Jones et al. [29] have identified its restriction. This model is flawed by the inaptitude of creating a study arm that can provide a group with an individualised treatment, devoid of a consultation [29]. Weatherley-Jones et al. [29] make the suggestion that focus of research on individualised therapies, such as homeopathy, should be diverted to the question of usefulness to health care in general. The relevance of an intervention to patients and practitioners may be valuable in the analysis of effectiveness of a whole system [29]. They suggest pragmatic trials for this purpose, yet these have limits as was noted by Verhoef et al. [27] and described above.

Most investigations have their focus on identification of efficacy or effectiveness of a treatment approach, the principles according to which CAM treatments work are in conventional research neglected [28]. Restoration to health in a holistic CAM treatment is influenced by multiple, individualised factors that are interconnected [5]; [17]; [28] and cannot be separated. Like Weatherley-Jones et al. [29] above, Verhoef et al. [28] postulate the adaptation of research models that take a whole system approach. This form of research must value to equal terms qualitative and quantitative methodologies in order to do justice to both, the nature and the holistic principles of the CAM approach and at the same time the demand for scientific rigor. A mixed-method-research model, therefore, “has most potential to effectively evaluate whole systems of health care” [28] (p.209). Such a model would incorporate patient experience and value attributed to the context within which a treatment is delivered, and would merge this with the evaluation of effectiveness gained through statistical appraisal of RCTs. Not only for disciplines of CAM, such as homeopathy, with its individualised case-taking and prescribing, but indeed also for “complex interventions in conventional health care” [28] (p.211), is a whole system research approach increasingly valuable.

Conclusion

In conventional medicine the striving is for `evidence-based´ approaches to treatment, yet with IBS, according to Thompson et al. [26] it should be stressed to make patient-centred, individualised decisions, an aspect belonging much more into the realms of CAM. The patient-practitioner relationship has been augmented as a factor important to the management of IBS [10]; [11] and research has delivered evidence of the therapeutic relationship as a non-specific effect of RCT´s undertaken in CAM [12]. The quest of finding an effective treatment for IBS requires understanding of patient experiences [1]; [24]. In the disciplines of CAM employing a holistic view of patient condition [22], practicing an idiosyncratic treatment approach [1] promoting a therapeutic relationship [23], and allowing patient empowerment [11]; [14]; [15], have been recognized as influential in a successful treatment of IBS.

Research in CAM needs to be as rigorous as that of conventional medicine, but failure to take into account the impact of the holistic nature of CAM produces, with RCTs, flawed results [17]. Consequentially a new model of research needs to be adapted for investigations into CAM. Future research into CAM should be sensitive to such elements that are increasingly being recognized as influential to patient treatment. Whole system research is an approach aiming to incorporate scientific rigor and qualitative experience [28]. Verhoef et al. [28], state that investigations into such models are currently being undertaken. Therefore, as IBS is considered a disorder that affects patients all their life [1], for the sake of the suffering patients, a consensus on a research model considering implications of whole systems should, preferably, be found soon.

Consequentially, future studies and trials investigating into the efficacy of CAM therapies for IBS could then possibly, with the utility of a modified research methodology, eventually elicit a successful treatment for IBS.

[Thanks to Kate Chatfield, University of Central Lancashire, for the assistance with this assignment.]

© U.M. at Clever Homeopathy

References:

[1] Agrawal, A. & Whorwell, P. (2006) Irritable bowel syndrome: Diagnosis and management [online] British Medical Journal Learning Vol.332, pp.280-283, article from British Medical Journal, last accessed 04 February 2011 at URL http://www.bmj.com

[2] Bommelaer, G., Poynard, T., Le Pen, C., Gaudin, A., Maurel, F., Priol, G., Amouretti, M., Frexinos, J., Ruszniewski, P. & El Hasnaqui, A. (2004) Prevalence of irritable bowel syndrome (IBS) and variability of diagnostic criteria [online] Gastroenterol Clin Biol Vol.28 pp.554-561, article from Oxford-journals, last accessed 07 April 2011 at URL http://www.e2med.com/gcb

[3] Cabré, E. (2011) Clinical nutrition University: Nutrition in the prevention and management of irritable bowel syndrome, constipation and diverticulosis [online] e-SPEN, the European e-Journal of clinical nutrition and metabolism pp.e1-e11, article from Elsevier, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[4] Chang, F. & Lu, C. (2009) Treatment of irritable bowel syndrome using complementary and alternative medicine [online] Journal of the Chinese medical association Vol.72, No.6, pp.294-300, article from Sciencedirect, last accessed 03 February 2011 at URL http://www.sciencedirect.com

[5] Dannheisser, I. (2009) An Investigation into Whole Systems Research as an Appropriate Methodology for the Advancement in Understanding of Homeopathy as a Complex Therapeutic Intervention [online] Hpathy, article from Hpathy, last accessed 04 February 2011 at URL http://hpathy.com

[6] Dorn, S., Kaptchuk, T., Park, J., Nguyen, L., Canenguez, K., Nam, B., Woods, K., Conboy, L., Stason, W. & Lembo, A. (2007) A meta-analysis of the placebo response in complementary and alternative medicine trials of irritable bowel syndrome [online] Neurogastroenterology and Motility Vol.19, pp.630-637, article from Wiley Online Library, last accessed 04 February 2011 at URL http://onlinelibrary.wiley.com

[7] Drossmann, D. (1999) Do psychosocial factors define symptom severity and patient status in irritable bowel syndrome? [online] The American journal of medicine Vol.107, No.5A, pp.41s-50s, article from Sciencedirect, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[8] Gilkin, R. (2005) The spectrum of irritable bowel syndrome: A clinical review [online] Clinical therapeutics Vol.27, pp.1696-1709, article from Sciencedirect, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[9] Hawkey, C. (1999) Irritable bowel syndrome clinical trial design: Future needs [online] The American journal of medicine Vol.107, No.5A, pp.98S-102S, article from Sciencedirect, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[10] Horst, H v. d., Schellevis, F., Eijk, J. v., & Bleijenberg, G. (1998) Managing patients with irritable bowel syndrome in general practice. How to promote and reinforce self-care activities [online] Patient education and counselling Vol.35, pp.149-156, article from Elsevier, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[11] Hussain, Z. & Quigley, M. (2006) Systematic review: Complementary and alternative medicine in irritable bowel syndrome [online] Alimentary Pharmacology & Therapeutics Vol.23, pp.465-471, article from Wiley Online Library, last accessed 03 February 2011 at URL http://onlinelibrary.wiley.com

[12] Kaptchuk, T., Kelley, J., Conboy, L., Davis, R., Kerr, C., Jacobson, E., Kirsch, I., Schyner, R., Nam, B., Nguyen, L., Park, M., Rivers, A., McManus, C., Kokkotou, E., Drossmann, D., Goldman, P. &  Lembo, A. (2008) Components of placebo effect: Randomized controlled trial in patients with irritable bowel syndrome [online] British Medical Journal n.p. article from British Medical Journal, last accessed 04 February 2011 at URL http://www.bmj.com

[13] Kearney, D. & Brown-Chang, J. (2008) Complementary and alternative medicine for IBS in adults: mind-body interventions [online] Nature reviews Gastroenterology & Hepatology Vol.5, No.11, pp.624-636, article from Nature, last accessed 04 February 2011 at URL http://www.nature.com/clinicalpractice/gasthep

[14] Kennedy, A., Robinson, A. & Rogers, A. (2002) Incorporating patients´ views and experiences of life with IBS in the development of an evidence based self-help guidebook [online] Patient education and counselling Vol.50, pp.303-310, article from Elsevier, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[15] Lewith, G. (1995) Irritable bowel syndrome: The complementary approaches considered [online] Complementary therapies in medicine Vol.3, pp.220-223, article from Sciencedirect, last accessed 03 February 2011 at URL http://www.sciencedirect.com

[16] Manning, A., Thompson, W., Heaton, K. & Morris, A. (1978) Towards positive diagnosis of the irritable bowel [online] British Medical Journal Vol.2, pp.653-654, article from British Medical Journal, last accessed 04 February 2011 at URL http://www.bmj.com

[17] Mason, S., Tovey, P. & Long, A. (2002) Evaluating complementary medicine: Methodological challenges of randomized controlled trials [online] British medical journal Vol.325, pp.832-834, article from Ebscohost, last accessed 06 April 2011 at URL http://www.sciencedirect.com

[18] McFarland, L. & Dublin, S. (2008) Meta-analysis of probiotics for the treatment of irritable bowel syndrome [online] World Journal of Gastroenterology Vol.14, No.17, pp.2650-2661,     article from National Centre for Biotechnology Information, last accessed 04 February 2011 at URL http://www.ncbi.nlm.nih.gov

[19] Pavan, M., Mehta, G. & Thillainayagam, A. (2008) The clinical evaluation of abdominal pain in adults [online] Medicine Vol.37, No.1, pp.11-16, article from Elsevier, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[20] Quigley, E., Bytzer, P., Jones, R. & Mearin, F. (2006) Irritable bowel syndrome: The burden and unmet needs in Europe [online] Digestive and Liver disease Vol.38, pp.717-723, article from Sciencedirect, last accessed 04 February 2011 at URL http://www.sciencedirect.com

[21] Shi, J., Tong, Y., Shen, J. & Li, H. (2008) effectiveness and safety of herbal medicines in the treatment of irritable bowel syndrome: A systematic review [online] World Journal of Gastroenterology Vol.14, No.3, pp.454-462, article from National Centre for Biotechnology Information, last accessed 04 February 2011 at URL http://www.ncbi.nlm.nih.gov

[22] Smart, H., Mayberry, J. & Atkinson, M. (1986) Alternative medicine consultations and remedies in patients with the irritable bowel syndrome [online] Gut Vol.27,pp.826-828, article from British Medical Journal, last accessed 03 February 2011 at URL http://www.gut.bmj.com

[23] Spanier, J., Howden, C. & Jones, M. (2003) A systematic review of alternative therapies in the irritable bowel syndrome [online] Archives of Internal Medicine Vol.163, pp.265-274, article from Archives of Internal Medicine, last accessed 04 February 2011 at URL http://archinte.ama-assn.org/

[24] Stenner, P., Dancey, C. & Watts, S. (2000) The understanding of their illness amongst people with irritable bowel syndrome: a Q methodological study [online] Social Science and Medicine Vol.51, pp.439-452, article from Elsevier, last accessed 14 February 2011 at URL http://www.elsevier.com

[25] Thompson, T. (2004) Can the caged bird sing? Reflections on the application of qualitative research methods to case study design in homeopathic medicine [online] BMC Medical Research Methodology Vol.4, No.4, n.p., article from BioMed Central, last accessed 06 April 2011 at URL http://www.sciencedirect.com

[26] Thompson, G., Hungin, A., Neri, M., Holtmann, G., Sofos, S., Delvaux, M. & Caballero-Plasencia, A. (2001) The management of irritable bowel syndrome: a European, primary and secondary care collaboration [online] European Journal of Gastroenterology & Hepatology Vol.13, pp.933-939, article from Ovid, last accessed 03 February 2011 at URL http://ovidsp.uk.ovid.com

[27] Verhoef, M., Casebeer, A. & Hilsden, R. (2002) Assessing efficacy of complementary medicine: Adding qualitative research methods to the “gold standard” [online] The journal of alternative and complementary medicine Vol.8, No.3, pp.275-281, article from Mary Ann Liebert, last accessed 06 April 2011 at URL http://www.sciencedirect.com

[28] Verhoef, M., Lewith, G., Ritenbaugh, C., Boon, H., Fleishman, S. & Leis, A. (2005) Complementary and alternative medicine whole systems research: Beyond identification of inadequacies of the RCT [online] Complementary Therapies in Medicine Vol.13, pp.206-212, article from Elsevier, last accessed 06 April 2011 at URL http://www.sciencedirect.com

[29] Weatherley-Jones, E., Thompson, E. & Thomas, K. (2004) The placebo-controlled trial as a test of complementary and alternative medicine: Observations from research experience of individualized homeopathic treatment [online] Homeopathy Vol.93, pp.186-189, article from Sciencedirect, last accessed 06 April 2011at URL http://www.sciencedirect.com

[30] Whitehead, W. (2005) Hypnosis for irritable bowel syndrome: The empirical evidence of therapeutic effects [online] International Journal of clinical and experimental hypnosis Vol.54, No.1, pp.7-20, article from Ebscohost, last accessed 04 February 2011 at URL http://web.ebscohost.com

© U.M. at Clever Homeopathy

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