Impact Matrix Analysis and Cost-Benefit Calculations to Improve Management Practices Regarding Health Status in Organic Dairy Farming (IMPRO)

FP7 - 311824 IMPRO Deliverable D 9.1

Impact matrix analysis and cost -benefit calculations to improve management pr actices regarding health status in organic dairy farming

Project Number: 311824

- Deliverable - D9.1 – Report on research projects in the field of homeopathy, cooperation between research bodies and initiatives to reduce use of antibiotics by using homeopathic remedies

Due Date of Deliverable: 31.10.2014 Actual submission to EC date: 31.10.2014 Deliverable Lead Partner: University of Kassel (UKS) Deliverable Author(s): Caroline Doehring and Albert Sundrum Dissemination Level PU

FP7 - 311824 IMPRO Deliverable D 9.1

Executive Summary

The use of homeopathy in food producing animals is discussed highly controversially with strong view- points expressed from different perspectives. On the other hand, the issue is very complex and cannot be covered by focussing on single aspects. The role of homeopathy when striving for options to treat diseased animals and reduce the use of antibiotics in organic and conventional livestock farming (cattle, pig and poultry production) has been assessed by a review on preconditions for the use of homeopathy in farm practice (Part A); a review of published research studies in the field of homeopathy (Part B), and by investigations regarding the cooperation between research bodies in this field (Part C). The analysis revealed the following outcomes: Part A: There is evidence that homeopathic remedies are widely used in treating food producing animals, independent of the production method. According to the EU Regulation on organic agriculture, homeopathic products shall only be used in preference to chemically-synthesised veterinary treatment if their therapeutic effect is effective . However, there is reason to assume that the prerequisites for an appropriate diagnostic and treatment procedure as well as the control of therapeutic effects, essential for an effective therapy with homeopathic remedies, often do not exist. This increases the risk of poor results in cure rates and prolonged suffering of diseased animals. Part B: To gain a comprehensive knowledge on the current state of the art, a systematic search of published articles has been conducted. From a total number of 4448 records screened by title and key- words, 327 abstracts/full text articles have been evaluated for further eligibility. Only articles in peer reviewed journals and doctoral theses have been considered for further analysis, revealing a total number of 62 studies, dealing with homeopathy in cattle, pigs and poultry. Study descriptions were assessed according to various criteria, among others: purpose of application, disease in focus, exclusion of experimental animals, diagnostic method and diagnosing person, used remedy, as well as origin, ingredients and potency of the remedy, way of administration, study design and control groups, methods of measurement, and finally the outcome of the studies. Regarding the efficacy of homeopathic remedies in livestock, a considerable number of the reviewed studies showed a significantly higher efficacy of the administered homeopathic remedy in comparison to a control group, whereas many other studies showed no medicinal effect. However, the fact that there has been an effect under certain conditions does not necessarily imply that a homeopathic remedy is effective under different conditions or in different individuals suffering from the same disease. Cure rates for the treatments with allopathy, homeopathy or placebo in the studies showed a wide range and the administered remedy did not seem to make a big difference. Taking into account all considered studies, not even one study has been repeated under comparable conditions. Thus, they can be assessed as single case studies. Consequently, the use of homeopathy is lacking any reproducibility and therewith cannot claim to have a sufficient prognostic validity concerning therapeutic efficacy. When striving for a high therapeutic effect in curing diseased animals, it cannot be recommended to make use of homeopathy in favour of allopathy, unless homeopathy is administered by highly skilled experts / veterinarians who are able to identify the most appropriate option for a successful treatment while considering the context in which the remedies are being used. Both, remedies and ther- apists should be measured by the therapeutic success achieved at the farm level. Otherwise, the use of homeopathy risks being blamed for increasing health and welfare problems instead of solving or reducing them. Part C: The analysis on homeopathic research showed that only few research bodies in Europe are dealing with the issue of homeopathy in farm animals. The currently existent research network of homeopathy can be regarded as poor, although a need for research is being seen by over 75% of the responding institutes. Lack of funding is mentioned as a big constraint in addition to a dismissive attitude towards homeopathy of the scientist community.

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Table of Contents Executive Summary ...... 2 Table of Contents ...... 3 1 Foreword ...... 4 2 Part A: Preconditions for the use of homeopathy ...... 7 2.1 Introduction into the topic of homeopathy ...... 7 2.2 Use of homeopathy ...... 9 2.2.1 “Lege artis ” procedure ...... 9 2.2.2 Factors affecting the availability of remedies ...... 12 2.2.3 Use of homeopathy in farm practice ...... 15 2.2.4 Quality of the remedies ...... 19 2.2.5 Critical notes ...... 20 3 Part B: Review on previous research on the effectiveness of homeopathy ...... 21 3.1 Material and methods ...... 21 3.2 Results ...... 23 3.2.1 Overview regarding the considered studies: ...... 23 3.2.2 Species specific results: ...... 33 3.3 Discussion...... 36 3.4 Conclusions ...... 40 4 Part C: Institutions, engaged in research with homeopathy ...... 41 4.1 Material and methods ...... 41 4.2 Results ...... 41 4.2.1 Research bodies ...... 41 4.2.2 Collection of research bodies/universities/higher education institutions ...... 43 4.2.3 Initiatives aiming for reduction of the use of antibiotics ...... 45 4.2.4 Co-operations between the institutions ...... 45 4.2.5 Need for research in future ...... 48 4.2.6 Constraints in research work with alternative remedies ...... 48 4.2.7 Conclusions ...... 49 5 Acknowledgement ...... 49 6 References ...... 50 7 Glossary ...... 57 8 Annex 1 (Cattle) ...... 60 9 Annex 2 (Pigs) ...... 65 10 Annex 3 (Poultry) ...... 66 11 Annex 4 (Questionnaire) ...... 68

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1 Foreword Continuous reports in the media on food associated scandals are currently enforced by reports on livestock-associated antimicrobial resistance of bacteria that may have an impact on food safety and have thereby created an environment of uncertainty amongst consumers. To regain consumers’ trust, legislative bodies, retailers, food processors, and other actors in the food supply chain are the main drivers to react with enforcements and solutions on this societal pressure and forward the pressure to livestock producers. On the other hand, a high prevalence level of diseased animals in need of an appropriate treatment is a direct issue of animal welfare. This issue has given rise to a second, not less important concern of consumers, forcing the same stakeholders to react towards the increasing demands. We would expect general agreement when concluding that prevention of diseases would fit best to meet both demands, the food safety and the animal welfare issue.

Farmers and veterinarians are encouraged to work together to reduce the risk of disease challenge on farms by implementing preventive measures which in turn will minimise the need to use medicines. However, preventive measures can be expensive in terms of invest-ments and labour time, while the use of antimicrobial drugs often appears the less expensive option. Continuously increasing amounts of last resort antimicrobials used over the last decades in livestock production indicate the benefits these drugs have provided to increase cost efficiency. While there is general agreement in society that prophylactic and metaphylactic use of antimicrobials should not be used as a substi- tute for good housing, comprehensive hygiene and management practices, this wishful thinking ig- nores the fact of a severe competitiveness between livestock farms on a global base for the lowest productions costs. Many farmers struggle a great deal to prevent bankruptcy and often fail to be successful. Thus, the issue is complex and cannot be restricted to the use and non-use of specific remedies.

Treating animals with remedies is to some degree ambivalent in itself. While treatments should be most effective regarding their supportive effect in curing the animal, basic causes of diseases should be rectified and possible negative side effects for the animals and the issue of food safety should be prevented. While reflecting on the use of medicine, it has to be recognised that it is the organism in the first place which is challenged by pathogens and which has to defeat the invaders by relying on unspecific and specific immune mechanisms. There is no doubt that the immune system possesses the most effective competence to defeat invaders and to support the recovering process. However, for various reasons, immune competence is not always capable to appropriately deal with pathogens. Therefore, supportive therapeutic measures are indicated to safeguard the organism from losing the battle towards the invaders and to cut short the suffering. In the very complex and interactive feedback loop when pathogens threaten the life of animals, there is in general more than one option to deal with the challenges. No option can claim to be the best solution in all cases. Indeed, the efficacy of options depends to a high degree on the context in which they are taken.

In the case of infectious diseases with bacteria, antibacterial drugs have been seen for decades as the first and often only interventional option for individual or group treatment, control of infections to prevent further spread, prevention of infections in at risk populations and to increase weight gain or improve feed efficiency. Nowadays antibiotics are not the only option anymore. The overuse of antibiotics has created resistant strains of bacteria. It not only takes courage but particularly knowledge to leave a broad spectrum and relatively cheap option for a much more complex, often more expensive and not always failure proof, approach. Responsible use of antimicrobial drugs means: ‘using remedies as little as possible and as much as necessary’. However, this simple and general guide-

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FP7 - 311824 IMPRO Deliverable D 9.1 line gives rise to more questions than answers. Remedies are in the first place means to an end. Questions arise, who is defining when a purpose justifies the use of which remedies, and to which degree? Who is able by which means and making use of which efforts to assess what is possible and what is necessary? Both efficacies of remedies as well as possible negative side effects are influenced to a high degree by the context in which they are used. What might be possible and effective depends on the options given in the specific situation. Cost-benefit-relationships between different options are needed to strive for the most efficient option. What might look efficient from the one perspective (e.g. farmers aiming at low productions costs) might be in conflict with the perspectives of other stakeholders (e.g. consumers demanding food safety).

The drivers of antibiotic use in livestock production are a complex mixture of various factors; e.g. prevalence and incidence of diseases, perception of health problems, presence or absence of regulatory systems, availability and costs of preventive measures and, probably more important than we realise, tradition. Prevalence and incidence of diseases are highly correlated to the living conditions, in which farm animals have to sustain themselves, to the resources they can rely on and to the pathogens they have to face and deal with. Thus, options in tightening biosecurity, enhancing the power of the immune system next to other preventing approaches are the first relevant options for an alternative-to-antibacterial intervention strategy.

Nevertheless, animals get sick even under good living conditions, although less so. Sick animals have the right to be treated. Due to various reasons there is no doubt that diseased animals are not always treated at all. When it comes to treatment, the veterinarian is obliged to use the most effective medicine at the right time, in the right dose and for the full course of treatment until the animals have recovered at least to some degree. However, an appropriate treatment depends on a comprehensive and profound diagnosis, which is often lacking.

While the negative side effects of cost reducing strategies in livestock production and the predominant use of antimicrobial drugs become more and more obvious so does the need for finding alternative options. Due to the high level of complexity, it should not be surprising that controversial debates have arisen between different stakeholders, and even within science about the possible alternatives. One group is blaming the other for not taking into account their own perspective.

Alternatives are always questioning the predominant approaches. Thus, it is the duty of applied science not to give right to those positions that represent the most powerful group but to identify the most convincing and evidence-based arguments in the defined context where remedies come into force. The duty is complicated by the fact that science itself has failed so far to identify and define the areas of uncertainties, therewith leaving ample room for the development of speculations and pseudo-science. Weighing heavier though is the fact that many lay people (particularly consumers and to some degree farmers) become more and more attracted and obviously love what many scientists despise. This controversial development cannot be ignored, especially when on the one side consumers are clients and on the other veterinarians are service providers whereas farmers are both, however, to different stakeholders.

Scientists paid by tax payers are dedicated to strive for common goods. When dealing with conflict- ing aims it should be clear to whom they owe responsibility. According to Pestre (2007), there is need to stress the obvious: that science, whatever its achievements, is human-made; that science has always been linked to powers and interests; that science has limits and is not socially ‘neutral’. Innovation and the direction of progress has always been a matter of dispute and it has always been subsequent to the dispute that safer technologies have emerged. In policy terms, this means

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FP7 - 311824 IMPRO Deliverable D 9.1 that the power of science has to be compensated by a renewed attention to other forms of knowledge, to alternative values and to social debates. For this reason, policies – like the sciences – are not only tentative solutions to problems; they might also be part of the problem.

It is not on behalf of scientists to decide which options should be taken but they are requested to focus their efforts and their time on the reflection which options are available and which are to be recommended in the specific context in which they should be used, and whether there is need for modifying conditions to provide better options when striving for common goods. However, there is the general impression that the majority of scientists refuse to deal with other arguments that are seen as “rubbish” from their point of view and they do not want to waste their limited time. While there is no doubt that the world is full of stubbornness, this position is reasonable. On the other hand, who can blame others for their stubbornness when one refuses to deal with arguments from different perspectives? The different perspectives and different options force scientists to sharpen their own arguments and to prevent themselves from overgeneralising statements which are valid in certain but not under all conditions. Thus, the challenge is to make the difference where necessary and to demand evidence wherever possible. “At the frontiers of science, nothing becomes more obvious than what is at issue in the core area of science” (Galison, 2003).

In line with the European Parliament resolution of 12 May 2011 on antibiotic resistance in which it called for the use of antibiotics in livestock farming to be reduced and for alternative methods to be used, a pilot project was initiated to coordinate research on the use of homeopathy and phytotherapy in livestock farming. In the pilot project, the role of alternative methods when striving for options to reduce the use of antibiotics in organic and conventional livestock farming (cattle, pig and poultry production) will be assessed by:

• Reviews on research projects in the field of homeopathy and phytotherapy, • Investigations regarding the cooperation between research bodies, • Workshops with proponents and detractors of alternative methods, • Research on the preconditions and diagnostic procedure for the use of homeopathic and phytotherapeutic treatments according to the state of the art in pig and poultry production, • Economic impacts of the use of homeopathic and phytotherapeutic treatments in conventional pig and poultry production, • Summarising report, conclusions and recommendations for assisting policy.

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2 Part A: Preconditions for the use of homeopathy

2.1 Introduction into the topic of homeopathy

Principles of homeopathy Homeopathy is a method developed by Samuel Hahnemann in the year 1796 to treat diseases in humans. It is based on three main principles.

The first is the principle of Similarity, so called “Simile-Rule” according to which a substance that causes certain symptoms when administered to healthy subjects will be able to cure the manifestation of disorders and corresponding symptoms in sick individuals. Single remedies were tested by Hahnemann in a native or low diluted form on a healthy human to capture all occurring symptoms that finally define the “ homeopathic drug picture ”.

The second principle is individualisation. It refers to the fact that in the case of illness every individual shows specific person-related symptoms, the “ clinical picture ”. While individuals suffer from the same causes of diseases they can considerably differ in some, if not in all, symptoms. The characteristics of the “homeopathic drug picture ” of the chosen remedy should be as similar as possible to the “clinical picture ” symptoms the patients show. The closest match is called the “simillium”.

A third principle is the use of the Smallest Dose. It is the way to choose a minimum dose of a substance that is still sufficient to cause a reaction in an organism without being harmful. Homeopathic remedies are used in a more or less diluted form due to the potentiation procedure described in the homeopathic pharmacopoeia. The doses range from those that are similar in concentration to some conventional medicines to very high dilutions (above C12 or D24 resp. a 1: 10 24 dilution) containing no material trace of the starting substance. “D” for decimal, means a dilution by a factor of 10 and “C” for centesimal for diluting a substance by a factor of 100 at each stage.

Diagnostic procedure While conventional treatments focusses in the first place on the general symptoms of a disease caused by an infection with pathogens or disturbance of organ functions, e.g. inflammation or fever, homeopathy tries to capture a more “holistic view” of the individual. It considers also the individual reactions of a patient towards the causes of diseases (individualised treatment). The approach of a “clinical picture ” covers inter alia the causa (any influences that caused the disease), modalities (timely, physically, physiological or psychological circumstances under which the symptoms increase or decrease), (extraordinary) behaviour, constitution, general symptoms, organ symptoms, frequency of symptoms and the tendency or disposition for infection (miasma).

An appropriate homeopathic remedy corresponds to the principle (most striking) symptoms observed on the patient. According to Hahnemann (1810), every remedy has to be proven by a specific homeopathic drug test. Typical characteristics and effects of a specific remedy observed at the drug test form the “homeopathic drug picture”. The knowledge of different drug pictures is a precondition for identifying the appropriate remedy for a specific case and a certain “clinical picture”, respectively. Correspondingly homeopathic treatment requires a profound diagnostic procedure and comprehensive knowledge about the homeopathic drug pictures.

Hahnemann (1810) described health as a dynamic process and homeopathy as a possibility to stimulate self-healing or -regulation processes in the body. Thus limitations of treatment conditions for homeopathy are given when the body system is no longer able to react, e.g. in the case of se-

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FP7 - 311824 IMPRO Deliverable D 9.1 vere tissue damage or organ failure. If the cause of a disease is still evident and the organism weakened, the effects of homeopathic remedies are jeopardised.

Homeopathy in animals In 1813, Hahnemann lectured on the use of homeopathy in animals in Leipzig (Germany) and stated that the principles and applications in animals were broadly similar to those in humans (Pinkus, 2009). A few years later Donauer (1815) published the first scientific paper on homeopathic treatment of animals, in which he adapted Hahnemann’s results to treat dogs. While homeopathic remedies have been comprehensively tested on humans and documented in the repertories, there is no information available in the literature if and to which extent homeopathic drug pictures have been elaborated by tests on healthy animals.

Veterinary homeopathy has been developed and used since then, particularly in Britain and Germa- ny beginning at the early 1900s (Vockeroth, 1999). In 1982 the British Association of Homeopathic Veterinary Surgeons (BAHVS) was founded by George MacLeod, Christopher Day, Francis Hunter, John Saxton and others. Two years later, the Faculty of Homeopathy (UK) started a veterinary teaching and examination programme, later developing standards, syllabus and ‘code of practice’. The first veterinary homeopathic qualification in the world (VetMFHom) was granted by them in 1987 (British Association of Homeopathic Veterinary Surgeons, 2012). At an international level, the International Association for Veterinary Homeopathy (IAVH) was founded in 1986. It has since gone on to conduct teaching programmes worldwide and to set examinations leading to the qualification “CertIAVH” on veterinary homeopathy (BAHVS, 2012).

Use of homeopathy in food producing animals According to the results of questionnaires, homeopathic remedies are widely used to treat food producing animals (Löscher, 2006; Ullman, 2010). Application of homeopathy is used independently of the production system but in general more in organic than in conventional livestock production.

Organic farmers are even encouraged by legislation to consider the use of homeopathy. The Euro- pean Council Regulations 834/2007/EC/Art.14(1) and 889/2008/EC/Art.24(2) on organic livestock production support the use of phytotherapeutic and homeopathic remedies compared to antibiotics and other chemical-synthesised drugs:”… chemically synthesised allopathic veterinary medicinal products including antibiotics may be used where necessary and under strict conditions, when the use of phytotherapeutic, homeopathic and other products is inappropriate...” (834/2007EC/Art.14(1)); “ Phytotherapeutic, homeopathic products, … shall be used in preference to chemically-synthesised allopathic veterinary treatment or antibiotics, provided that their therapeutic effect is effective for the species of animal, and the condition for which the treatment is intended ” (889/2008EC/24(2).

Although the strategy to treat animals with homeopathic remedies can look back on a long history, so far veterinary homeopathy has not been able to establish itself as a commonly accepted treatment method but remained captured in a more or less small niche (Clausen et al., 2013). One reason for considerable interest in homeopathy might be due to the concerns and doubts in relation to conventional treatment strategies. Indeed, apart from considerable success in diagnostic methods, surgery and some special disciplines, mainstream veterinary medicine is far from being able to claim that it has written a complete successful story. Despite a tremendous increase in knowledge about the causes and pathophysiological developments of diseases, prevalence and incidence of productions diseases have not declined but increased and often therapeutic success fails to appear

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(Rauw et al., 1998; Østerås et al., 2007; Knaus, 2009; Schwarz et al., 2010; Sundrum, 2012; Perry et al., 2013). Also, consequences of the use of considerable amounts of antibiotics in animal production threaten the efficacy potential of antibiotics to successfully treat humans and animals by an ongoing increase of antibiotic resistance of bacteria.

The question is whether the homeopathic treatment method offers options that conventional strategies do not or whether the expectations in relation to homeopathy are excessive optimistic and un- realistic. Alternative methods might lead expectations into a wrong direction or prevent the realisa- tion of necessary fundamental changes and might hamper the search for other more successful options. On the other hand, restricting the issue of homeopathy to the question whether a highly diluted substance can have an effect on a living organism does not do justice to the challenges and problems we are facing with respect to the treatment of farm animals.

Efficacy of homeopathic remedies is not necessarily questioned in the case of ingredients of plants or other substances used in a low diluted form. A considerable increase in the use of homeopathy also in conventional livestock production (Hovi, 2001) reflects the demand for options apart from synthetically chemically produced remedies. Thus, reflections on the use of homeopathy should not restrict on single aspects only but should take into account the conditions in which farm animals are living and how they are diagnosed and treated.

The aim of a comprehensive approach within the IMPRO project is to evaluate the preconditions of the use of homeopathy in cattle, pigs and poultry in theory and practice. This includes among others the availability of veterinary homeopathic remedies as well as European and National regulations (Part A). Furthermore, an analysis of scientific literature regarding the effectiveness of homeopathy in relation to antibiotic treatments in livestock is performed (Part B). The conditions of scientific net- works and research work, possible constraints and needs of research on homeopathy are addressed by questionnaires sent to research bodies that dealt with the topic before (Part C).

The objective is to provide information to the European Commission to questions of preconditions for an effective use of veterinary homeopathy and if they are present on farms in practice.

2.2 Use of homeopathy

2.2.1 “Lege artis ” procedure Reviewing the available literature, a wide range of different recommendations on how to treat human beings and animals appropriately with homeopathic remedies exists. However, no comprehensive lege artis use could be found for the homeopathic treatment procedure in livestock, although homeopathy has been applied on animals for more than 180 years. The following sections will make an attempt to describe the most plausible procedure in making use of homeopathy based on the existing knowledge and information available while relying on the principles of the homeopathic treatment method.

Homeopathic therapy is based on a diagnostic procedure regarding not only the pathologic symptoms of a specific disease but also the context of the disease expressed by the reactive symptoms and the behaviour of the individual animal, and by taking into account the surrounding living conditions. This may lead to the situation that two different individuals with the same disease, e.g. acute catarrhal mastitis but different key symptoms might give reason for the use of different remedies while the same remedy might be recommended in quite different clinical cases. Thus, it is not the

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FP7 - 311824 IMPRO Deliverable D 9.1 clinical case that is treated. Diseased animals are supported in their individual reactions towards disturbances to sustain themselves.

The treatment depends on a profound diagnostic procedure and a well-considered decision, if a sufficient therapeutic effect can be expected when animals are treated with homeopathic remedies in the given case. As homeopathy aims for inducing self-healing processes in the body, it should be used only if healing seems to be possible (e.g. by stimulation immune system, metabolic regulation). This is not the case with fractures, irreversible organ damage, exhausted body system or if the cause of the disease persists (Striezel, 2001). Especially in any kind of animal welfare challenging and in order to provide the most appropriate treatment (conventional or complementary) to the diseased animal, a veterinarian should be consulted without delay to avoid unnecessary suffering of the animal (834/2007/ EC (Art. 14e)) and “ Any animal which appears to be ill or injured must be cared for appropriately without delay and, where an animal does not respond to such care, veterinary advice must be obtained as soon as possible ” (98/58/EC, Annex (4)).

Anamnesis The homeopathic anamnesis (MacLeod, 1997) includes the investigation of:

1. The Causa: all causes for the sickness, like moisture, environment, injuries, change of food composition and causing pathogens. 2. The Modalities: conditions that cause aggravation or amelioration like daytime, temperature and exercise. 3. The Behaviour: remarkable changes of behaviour of the single animal, but also social behaviour in groups. 4. The Constitution: age, weight, previous diseases, prone to an illness, type of build, colour of fur, positive or negative dispositions. 5. The Symptoms: general symptoms, organ symptoms, abnormal/extraordinary symptoms, concomitant symptoms, frequency of symptoms.

Only a comprehensive anamnesis and thorough examination is expected to support an adequate selection of the appropriate remedy, potency, dosage, application frequency and treatment duration (MacLeod, 1997).

Examination The examination should start with observation from a distance and continue at close range. A full and proper conventional examination and aetiology should be performed and good clinical notes should be kept (British Association of Homeopathic Veterinary Surgeons, 2012). Further diagnostic procedures should be performed if necessary. It is recommended by the BAHVS that cases which prove difficult should be referred to a veterinarian specialised in homeopathy, if the farmer wishes to pursue a homeopathic option.

Choice of the remedy The choice of a remedy by experience and knowledge should always be accompanied by consulta- tion of a repertory like Synthesis (Schroyens, 2009), Kent’s repertory (Kent and Kent, 1986) or Hah- nemann’s Organon (Hahnemann and Haehl, 2004). To experience the effect of the single remedy on the disease, the application of only one drug is preferred, but also a combined administration of different remedies (e.g. with complex remedies) could be useful, e.g. for syndromes. A combination

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FP7 - 311824 IMPRO Deliverable D 9.1 with conventional remedies, e.g. antibiotics, cortisone or narcotics is rejected by some authors (Schmidt and Bär, 1998).

Potency and frequency of administration The choice for a specific homeopathic potency ß complies with the duration of the disease. Low Potencies (D4-D12 and 1:10.000 up to 1:10 12 dilutions, respectively) are in general used for acute infections and local lesions and are often applied in higher doses (every 30-60 minutes, 4-6 times daily). Middle potencies (D12-D23 and 1:10 12 up to 1:10 23 ) are used for longer lasting diseases and functional disorders. High potencies (from D24 and 1: 10 24 ) are used for chronic diseases and are applied rarer and in small doses (once a day, week or month). According to Burgard (1991) and Pinkus (2009) the general rule is that the higher the potency, the greater the stimulus and the faster the response precede. Lower potencies were used at the beginning of a disease and to avoid a suppression of the natural immune response (Pinkus, 2009; Burgard, 1991) and are regarded as simple and lower in risk (for an overreaction). The effect of a certain remedy can change with the chosen potency.

Dosage Which dose of the chosen remedy is going to be used (e.g. 5 globules or 10 drops/each day) is not defined. Only in commercially available veterinary homeopathic remedies, recommen-dations on dosage have to be indicated by the manufacturer.

Administration Homeopathic remedies are administered by contact with mucous membranes (mouth, nose, vulva, eyes) or according to the medical product leaflet. Oral administration is given best to the sober animal or 30 minutes before or after feeding and drinking (Schmidt and Bär, 1998). If possible, the remedy should be administered directly to the animal without touching, because, e.g. in form of homeopathic globules, the active substance only coats the sugar globules.

Duration and adaption of treatment The duration of the homeopathic treatment depends on the development of the symptoms and the healing process. The remedy is given until the body reacts to it. Only if no reaction appears or when the healing process stops or is regressive, the treatment should be repeated or adapted by a change of remedy or potency.

The course of the disease and changes in behaviour, modalities or symptoms have to be followed- up to react in good time to changed circumstances with an adaption in remedy, potency or dosage. The remedy may change over early, middle and later stages of a disease (Pinkus, 2009). The farmer has to spend time on observation of the treated animal if new symptoms appear, present symptoms vanish or if the behaviour of the animal changes (Deiser, 1997). A disagreement exists between different authors about the phenomenon of the initial aggravation: Some describe the oc- currence of an initial aggravation of symptoms (while the patient feels better) as a sign for a positive body reaction and necessary for a successful treatment (Kent and Kent, 1986; Deiser, 1997; Hah- nemann and Haehl, 2004). Other authors see them as a sign for a potency chosen that was too high or low (Wolter, 1986; MacLeod, 1997).

In the follow-up control of the disease a decision is required if the effect of the given remedy is still lasting or if a second administration of the same remedy is required or if a new remedy has to be selected.

See further explanations in the glossary with terms marked by the symbol ß 11 IMPRO FP7-KBBE-2012-6 Page 11 of 70

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Control of success As an essential part of the treatment, a success control is crucial. Indicators for success are the disappearance of pathologic symptoms. These symptoms can be visible, e.g. like vanishing of abnormal behaviour, flakes in the milk and lameness or supported by diagnostic tests, e.g. a physiological somatic cell count at a California Mastitis Test or absence of the causing pathogen in a mi- crobiological test. In case of mastitis, only the absence of symptoms and causing pathogen and a somatic cell count < 100.000 at the same time define a complete healing (Werner, 2006).

Nosodes Nosodes are manufactured of diseased matter and are mainly designed for the prophylactic treatment of a specific disease. Therefore, apart from treating a single animal, treatment of a group of animals by homeopathic nosodes is possible. Preparations of nosodes should be specified according to the herd pathogens or even the single animal (McCrory and Barlow, 2006). That means a nosode is ideally manufactured with diseased material of the specific animal or herd to be treated.

Storage of remedies Like most conventional remedies, homeopathic drugs should be stored at a dry, dark, cool place. Other authors also advise the storage far from strong electromagnetic fields, metal or strong odours, e.g. menthol, peppermint or coffee, because of the subtle energy of homeopathic remedies might be possibly damaged by exposure to electromagnetic radiation ( Schmidt and Bär, 1998; Montserrat, 2013).

Education and knowledge A precondition for choosing the appropriate remedy is the experience of the user and his sufficient knowledge of at least the most relevant homeopathic drug pictures. At minimum 50 remedies should be known as well as the inimicals (drugs that should not follow each other) and antidots (Schmidt and Bär, 1998). An effective treatment requires knowledge on the diversification of diseases, their specific background and on physiological behaviour and processes of different species to recognise deviations from signs shown by healthy animals. Qualification for providing a profound diagnosis is achieved in the first place by a study in veterinary medicine. Experiences and qualifications on veterinary homeopathy should be acquired by a minimum three-year-course (120 hours tuition provided), part-time and run alongside courses in teaching centres as required from the most European countries that approve additional veterinary homeopathic titles or diploma (ECCH, 2007; Öster- reichische Gesellschaft für veterinärmedizinische Homöopathie, 2014).

2.2.2 Factors affecting the availability of remedies

2.2.2.1 Regulatory approvals The European Medicines Agency (EMA) is responsible for drug approval in Europe. A homeopathic veterinary medicinal product is defined as “ any veterinary medicinal product prepared from products, substances or compositions called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in the absence thereof, by the pharmacopoeias currently used officially in the Member States” (2004/28/EC/Art.1(8). Like all veterinary medicinal products for food producing animals they require a veterinary prescription for dispensing to the public (2001/82/EC/Art.67). Remedies dedicated for another species or a different indication demand a prescription of a veterinarian following the “rules of cascade” according to the directive 2004/28/EC/Art.11. The use of homeopathic remedies approved for a different indication or species (including humans) is only permitted if no authorised remedy for this species and indication

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FP7 - 311824 IMPRO Deliverable D 9.1 is available. For food producing animals only remedies included in the annex of Directive 37/2010/EC from a D4 dilution (one part per 10 000 of the mother tincture) up and only under responsibility of a veterinarian are allowed to be used (2004/28/EC/Art.17). Some substances are completely forbidden, such as aristolochia and colchizine due to their toxic effects and the fact that a maximum residue limit cannot be established for these substances (37/2010/EC/Annex/Table 2). Directive 2006/130/EC allows an exception of a veterinary prescription for food-producing animals, if the remedies pose no direct or indirect risk for animals, humans or the environment, even if administered incorrectly. However, the use of remedies in food producing animals shall always be documented (96/23/EC and 90/676/EEC).

For homeopathic remedies a simplified registration procedure (in comparison to the officially approved registration) is possible. This procedure takes into account the particular characteristics of homeopathic products, such as the very low level of active substances and the difficulty of applying to them the conventional statistical methods (2004/28/EC (20)). Registration schemes are operated nationally and involve the submission of a relatively limited amount of information. Such information shall ensure the pharmaceutical quality and a batch-to-batch homogeneity. The information needed to register a veterinary homeopathic remedy include the scientific name, route of administration, pharmaceutical form, degree of dilution, a dossier on the biological substance, manufacturing and control methods, e.g. to ensure absence of bacteria, and the stability of the product (2001/82/EC Art.18 amended by 2004/28/EC). Homeopathic products not meeting the registration criteria or diluted below D4 must go through a process similar to conventional veterinary medicinal products. Information on therapeutic indications on the product leaflet is forbidden with homeopathy, due to the lack of tests regarding their effectiveness (2004/28/EC Art.17).

Specific national regulations that consider homeopathic medicinal products for food producing animals are not established in every European country (European Committee for Homeopathy). As a result, the availability and use of homeopathic remedies in food producing animals also differ considerably depending on the existing national regulation.

The topic of different legal and factual conditions in Europe will be addressed within the IMPRO project in work package 4.5 (WP4.5) by the International Association for Veterinary Homeopathy (IAVH).

In Ireland, Germany, Austria and France, only veterinarians are permitted to prescribe homeopathic drugs to food producing animals. Legislation in United Kingdom permits not only veterinarians and pharmacists but also an additional category of “suitably qualified persons” to prescribe and dispense veterinary drugs for use in food producing animals (Sager et al., 2011). A “Suitable Qualified Per- son” must pass a set of exams to demonstrate animal health knowledge and an understanding of the legal system, and be registered with the Animal Medicines Training Regulatory Authorities and the Veterinary Medicines Directorate (Veterinary Medicines Directorate - Regulations SI 2013/2033).

For veterinarians in Sweden it’s strongly recommended not to prescribe homeopathic remedies to their patients as homeopathy is not a therapy with a scientifically proven effect (Verdier et al., 2003). Also the British Veterinary Association (BVA) does not endorse the use of homeopathic medicines, because of making therapeutic claims without proven therapeutic efficacy. The BVA claims that veterinary medicinal products have to be proven evidence-based with any medicinal claims made by the manufacturer.

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The national medical association of the Czech Republic has officially declared homeopathy to be ineffective and has discouraged their members from utilising it. In Hungary, homeopathy was forbidden by law from 1949 until 1990 (Takács, 2000) and has now been allowed since 1991. In the United States, the American Veterinary Medical Association (AVMA) provided the statement that homeopathy has been demonstrated to be ineffective and does not support the education, titles or further activities without an evidence of efficacy for alternative veterinary medicine. The association wants veterinarians to take a stand against the practice of homeopathy in veterinary medicine (AVMA Guidelines for Complementary and Alternative Veterinary Medicine, 2013).

2.2.2.2 Availability of remedies on the commercial market Currently, no homeopathic remedy for livestock is authorized on European Level (European Medi- cines Agency, 2014). The German drug agency “Bundesinstitut für Arzneimittel und Medizinproduk- te” currently lists 188 approved homeopathic remedies for animals (DIMDI, 2014). In Spain, 21 veterinary homeopathic drugs are officially registered, 14 of them approved for livestock (Agencia Es- pañola de Medicamentos y Productos Sanitarios - AEMPS , 2014).

Most homeopathic remedies are available over the counter at national pharmacies in form of globules, tablets, powders, dilutions (alcoholic solutions) or ointments. However, only a small amount is available specifically for livestock and available by prescription of veterinarians. The veterinary repertorium “Synthesis 9.1 V” (Radar, 2014) lists 1.313 different remedies with 829 specific veterinary symptoms. However, only 41 substances are listed for food producing animals by the European Directive (37/2010/EC/Annex).

Most of the registered homeopathic remedies for livestock are preparations, with more than one active ingredient in mother tinctures (so-called complex remedies). Common producers of homeopathic remedies for livestock in Europe are:

Table 1: List of manufacturing companies of homeopathic remedies for food producing animals

Producer Country Preparations DHU (Vetsan) Germany 2 complex, 9 single Schaette Germany 1 complex Heel Germany, Belgium, NL, Spain and other 8 complex Ziegler Germany 8 complex, 12 single Biokanol (Dr. Assmann) Germany 15 complex Plantavet Germany 15 complex Dr. Reckeweg & Co. Germany 17 complex Mastavit GmbH (Vetokehl) Germany 20 single nosodes Boiron (Dolisos) France 20 complex Bonapp France 32 complex Ainsworths UK 22 single remedies Omida Switzerland 64 single remedies Ovejero Spain 2 complex ECOstyle BV Netherlands 3 complex, 1 single Feed Farm BV Netherlands 3 complex Holland Animal Care BV Netherlands 3 complex Vee-Service Idac Netherlands 7 complex

It can be concluded that the current widely different national legislations complicate the use of veterinary homeopathy within a European framework. Regardless of the restricted use of veterinary ho-

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FP7 - 311824 IMPRO Deliverable D 9.1 meopathy in livestock in Europe, registered homeopathic drugs are available for all veterinarians in all European countries over European pharmacies by “cascade –regulation”.

An increasing demand for organic products and the recommendation for the use of homeopathy in organic production in Europe (and the ban of antibiotics for animals where the products are certified as organic in the United States), increases the request for alternative treatment possibilities. The simplified registration for homeopathic products without performing all tests that conventional medicine has to pass could provide the opportunity to open the market to low quality products because no certain quality standards have to be met.

In the case of homeopathy, exemptions for a veterinary prescription according to Directive 2006/130/EC may provide a legal grey zone. Depending on the interpretation of the risk for environment, humans and animals when using homeopathic remedies, most of these remedies could be obtainable without a veterinarian prescription.

On the commercial market, the proportion of homeopathic complex remedies available for livestock is higher than of single remedies. Homeopathic complex remedies may not require such extensive knowledge on the single drug picture as single remedies, and are, for this reason, more present on the commercial market.

2.2.3 Use of homeopathy in farm practice According to the European legislation (889/2008/EC; Art.24, No.2 )”…phytotherapeutic, homoepathic products, trace elements and products listed in Annex V, part 3 and in Annex VI, part 1.1.shall be used in preference to chemically-synthesized allopathic veterinary treatment or antibiotics, provided that their therapeutic effect is effective for the species of animal, and the condition for which the treatment is intended…” .

Different national programmes (addressed in PART C of this report) aim to reduce the consumption of antimicrobials in livestock farming in general, due to the increase of antibiotic resistance worldwide. In the United States of America it is not permitted to “sell, label, or represent as organic any animal or edible product derived from any animal treated with antibiotics, any substance that contains a synthetic substance not allowed under §205.603, or any substance that contains a non- synthetic substance prohibited in §205.604.” (CFR/Title7/§205.238 - Livestock health care practice standard, U.S. Government, 2000).

Reasons for use The persistent high incidence of production diseases in farm animals and perceived limited success in the use of conventional treatment procedures may provoke a demand for alternatives to treat diseased animals (Hektoen, 2004). Homeopathy is that sort of alternative that is very present and often chosen by European farmers. According to a survey of Anderson and Leon (2000) performed in Germany, the main reasons for using homeopathic drugs were in 49% of the cases the observation of therapeutic effectiveness, in 25% of the cases the wish of the animal owners or interest in homeopathy of them (20%) and other reasons (7%).

Other reasons to explain the popularity of homeopathic treatment might be financial considerations, because homeopathic remedies have in general no withdrawal time and are available at a lower price. Also no contraindications, e.g. not to use it on pregnant female animals, or drug-food- interactions are known for homeopathic remedies. From a farmer’s perspective, homeopathic remedies might appear as an alternative to synthetic-chemically produced remedies, as they show no

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FP7 - 311824 IMPRO Deliverable D 9.1 drug residues in tissues or secretions, do not promote antibacterial resistance, and give the user the possibility to take action, especially if a disease seems to be not manageable with conventional medicine. In certain circles, homeopathy has a good reputation and positive image among consumers as opposed to antibiotics, and farmers might have experienced or assumed healing by homeopathy personnel or in their animals. The recommendations of other farmers and the availability of training courses on homeopathy with farm animals might attract them to give homeopathy a try. So a significant number of organic and also conventional farmers try to make use of homeopathic treatment.

Application of homeopathy Very little is known about the current use of homeopathy on European farms. According to a survey conducted by the (ECCH, 2007), homeopathic remedies are frequently used on organic and conventional livestock farms in Germany, United Kingdom, Spain and Sweden, whereas the use is limited in Belgium, Bulgaria, Finland, Greece and Israel. However, no clear descriptions on how this information has been gathered and evaluated have been provided. The survey was elaborated with support from an appointed sub-committee, consisting of homeopaths actively involved in the homeopathic treatment of animals in 16 member countries. The references mainly consist of personal communications with members of associations for homeopathy in the different countries.

Around 72 % of German organic farmers make use of homeopathic treatment and 3-30% of all German farmers independent from the production system do so (ECCH, 2007). In Sweden, 14 % of all farmers use homeopathic remedies to treat their animals. Concerning specific indications, e.g. mastitis in dairy cows, 41% of all UK farmers have been reported to use homeopathic remedies to treat mastitis on their farms (Hovi, 2001). More than 20% of all Irish farmers and 15% of Norwegian organic farmers stated to use homeopathic remedies for mastitis (Williamson and Lacy-Hulbert, 2014).The numbers correlate with the results of workpackage 2 (WP2) within the “IMPRO”- Europe- an Project for the countries France, Germany, Spain and Sweden (Delivery IMPRO D2.3 Farm Characteristics, 2014; FP7 EU project, 2012). In the ongoing study on organic dairy farms, 80% of the German farmers, 79% of the French farmers, 39% of the Spanish farmers and 7% of the Swe- dish farmers stated that they make use of homeopathy on their animals, varying in a wide range from sometimes to regularly.

Diagnosis and treatment on farms Although basic knowledge of homeopathic treatment and remedies may be available on many farms, diagnostic procedures are not performed completely on most farms. Remedies are often chosen only by established indications, e.g. mastitis, experience of the farmer or the vet, by intui- tion, experiences or availability on farm (Krömker, 2004). Modalities, causes and behavioural altera- tions or conventional diagnostics are often not considered. Persons who perform a detailed diagnostic procedure often consult a Materia Medica (Kent and Danciger, 1986; Hahnemann and Haehl, 2004; Schroyens, 2009). In Europe, many veterinary homeopaths prefer the Kent Repertory (Labre, 2005). Apart from shorter and often national published handbooks on established indications for homeopathic drugs and certain species, also veterinary repertories, based on human repertories and adapted to animals are available like the “New World Veterinary Repertory“ (Pitcairn and Jen- sen, 2013) and the computer-based repertory “Synthesis 9.1V” (Radar, 2014).

Although the administration of homeopathic remedies to farm animals is only legally permitted after prescription by a veterinarian and the drug has to be approved for the determined species (2001/82/EC), remedies, mostly approved only for humans, are often bought by the farmers in

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FP7 - 311824 IMPRO Deliverable D 9.1 pharmacies. Problems to find a veterinarian willing to work with homeopathy and giving a prescription is certainly one reason for this (Striezel, 2001).

Looking at different species and indications, 40% of the homeopathic remedies were used for dairy herds for the treatment of mastitis, fertility disorders or locomotion disorders. Thirty-three percent used homeopathic remedies for pigs suffering from the mastitis-metritis-agalactia-syndrome (MMA) or respiratory diseases and 10% of them used homeopathic remedies for poultry with diarrhoea (Andersson and Leon, 2000). The most common route of administration on farms was subcutaneous (50%), orally (35%) or intravenous (13%). More than half of the treatments (65%) were applied for prophylactic reasons (Andersson and Leon, 2000).

Homeopathic remedies often have to be given directly to mucous membranes and more than once per day. For this reason the single animal has to be fixed. Sometimes farmers refuse the homeopathic treatment of cows during the grazing period, because of the extra effort to fix the cows or to put them in house for a frequent administration of the remedies.

Some ways of administration were considered to be unacceptable for some farmers, like group treatment over drinking water (no separated water sources or possibilities for separation; no control of intake; no pipe cutting system, that prevents reflux of substances to the water system) or oral administration (no easy fixation possibilities) (McCrory and Barlow, 2006), but chosen as convenient in other farming systems. Especially the prevention of specific diseases by nosodes for large herds/groups is often used and can be easily administered by drinking troughs.

No information could be found in by publications if it was more common to treat only an individual animal or a group of animals, how homeopathic remedies were stored at farms and who usually diagnosed the clinical picture and chose the homeopathic remedy in practise. Furthermore, it is not known if and to which extent the follow-up of the course of disease, medication changes and a success control are performed and recorded.

Education on homeopathy Veterinary education in homeopathy at European universities is offered, if at all, only by optional courses for veterinary students (Germany, Hungary, Italy, Spain, Netherlands, Switzerland, and United Kingdom). This depends primarily on the interest of the university and the initiative of individual teachers. Postgraduate training is the most common way to receive an education in homeopathy. It is provided at universities, private teaching centres or at homeopathic associations in these countries (ECCH, 2007). Also homeopathy education courses for human physicians are being at- tended by veterinarians to receive further education. Full courses on animal homeopathy (like in Finland, Germany, Austria, France, Belgium, Norway, Sweden, Spain, Switzerland and United Kingdom) for veterinarians or others require at least 2-5 years (in a full- or part-time education programme), including 1200 – 1300 hours of lecture on topics and at least one year clinical training with an exam in the end (Deutscher Zentralverein homöopathischer Ärzte, 2014; Österreichische Gesellschaft für veterinärmedizinische Homöopathie, 2014).

On the European level, the IAVH offers one-year courses in many European countries with around 80-120 hours of lecture (IAVH, 2014). An additional title or diploma on homeopathy for veterinarians can be acquired. Approved are in Germany 187 active veterinarians qualified (Annual Report of the German Veterinary Chamber, 2013), in Austria (Annual report 2013 Austrian Veterinary Chamber) 38 veterinarians qualified for a specialist title on homeopathy, in Spain the specific number is un-

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FP7 - 311824 IMPRO Deliverable D 9.1 known and in the United Kingdom (Annual Report of the BAHVS 2009) approximately 50 veterinarians qualified for a specific homeopathic diploma.

In Sweden, no recognised homeopathic title for veterinarians exists. Food-producing animals may be treated with registered homeopathic medicinal products intended for either veterinary or human use. However, administration should only take place once a veterinarian has decided that no other measures need to be taken in the interest of animal welfare or preventing the spread of infectious diseases (Medical Products Agency Sweden, 2014). In general, it is not accepted to use homeopathy as a veterinarian in Sweden as this is not considered evidence based medicine (Swedish Veter- inary Association, 2014). Few veterinarians use homeopathy but as there are no approved homeopathic remedies in Sweden it is according to cascade principle and their own responsibility. No knowledge exists, how many veterinarians or other persons practice this.

In Spain, postgraduate courses for veterinarians are offered and after passing the exams a title (Master or Diploma) can be required, but this title is not officially approved.

Ten percent of the French veterinarians (n=700) prescribe homeopathic medicines (Finne and Viksveen, 1999). This does not, however, mean that they consider themselves homeopaths. Some give their patients homeopathic medicines only, but most of them do it to a variable degree. Four French schools of veterinary medicine provide structured training in homeopathy (Lyon, Maisons- Alfort, Nantes, and Toulouse). The French “Association pour la Promotion de la Médecine Ho- méopathique” currently lists 132 veterinary homeopaths.

In 2000, only 25 veterinary surgeons qualified by exams for the VetMFHom (Veterinary Member of the Faculty of Homeopathy) were listed in UK (and only 3 of them with wide experience in farm practice) (BAHVS, 2014). The British Association of Veterinary Surgeons lists 40 veterinary surgeons experienced in homeopathy in the United Kingdom, two in Ireland and one each in Denmark and France (BAHVS). The International Association for Veterinary Homeopathy (IAVH) listed 71 members in the Netherlands, 69 members in Germany, 48 in United Kingdom, 14 in Spain, four in Italy and two each in France and Ireland (IAVH, 2014). In Switzerland nine veterinarians working with homeopathy were registered at the IAVH while 1,631 veterinary surgeons were registered at the Society for Swiss Veterinarians (GST, Report 2013). However, veterinarians are licensed to prescribe their patients homeopathic remedies in the most European countries without profound knowledge on homeopathy or remedy pictures.

Training courses on animal homeopathy are also available for farmers, pet owners and others. They last from one to three days and are established in Germany, Austria, UK, Sweden, Finland, Norway and Switzerland. The courses are offered by veterinarians, advisors, non-medical practition- ers/homeopaths, farmers and officially by agricultural ministries and agricultural technical schools. The quality of the courses is unknown, because an official control or standard does not exist. The costs per course range between 70 € and 315 €.

It can be concluded that there is a large discrepancy between an appropriate use of homeopathy and the use in practise. A big proportion of farmers use homeopathy with insufficient expertise or treatment procedures. The lack of veterinarians educated and able to apply and prescribe homeopathic remedies aggravates the deficits and may be one reason for veterinarians to refuse the use or prescription of homeopathic drugs to farm animals. Altogether this leads to the situation that the farmers have often no specialised veterinarian for advice and prescription of a licensed drug and feel driven to seek advice from a non-medical-practitioner and “healer” or to train themselves on the

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FP7 - 311824 IMPRO Deliverable D 9.1 topic and to buy homeopathic remedies only approved for humans. The deficits in treatment procedure and abandonment of a control of healing or animal health may result in a low probability of a curing effect and a prolonged suffering of the animal.

2.2.4 Quality of the remedies The manufacturing specifications under which homeopathic remedies have to be produced are written down in the European Pharmacopoeia (Löscher and Frey, 2010). It covers active substances and preparations of chemical, animal, human or herbal origin, homoeopathic preparations and homoeopathic stocks as well as dosage forms and containers. Only regulations that are not captured in the European Pharmacopoeia and in national Pharmacopoeias are described in specific National Homeopathic Pharmacopoeias. The two main homeopathic pharmacopeia available and used in Europe are the German homeopathic pharmacopeia “Homöopathisches Arzneibuch” and the French homeopathic pharmacopeia “Pharmacopée Homéopathique Francais” (Andersson and Le- on, 2000). It is a collection of regulations on, e.g., quality, drug interactions, storage and terms for homeopathic remedies and their manufacturing as well as tests of the ingredients, materials and methods (e.g. potentization). The books are part of the official pharmacopoeia and therefore legally binding. The quality and standards of homeopathic remedies have to be ensured by origin and quality tests of the starting materials and a standard of further processing especially with toxic mother tinctures (MacLeod, 1997; Schmidt and Bär, 1998).

The European Directive 2001/82/EC, Art.18 requires a pharmaceutical quality and homogeneity in the produced batches of veterinary medicinal products including homeopathic remedies and provides rules relating to manufacture, control and inspection of these products. It demands to provide the user of homeopathic products with sufficient guarantees of their quality and safety. The materials have to be controlled at start and in the final dilutions, especially with toxic substances present at the beginning. In case dilutions are involved, these dilution steps shall be done in accordance with the homeopathic manufacturing methods laid down in the relevant monograph of the European Pharmacopoeia or, in absence thereof, in an official pharmacopoeia of a Member State. Control tests on the finished medicinal product and stability tests have to be performed and proven by the manufacturing company. Measures taken to ensure the absence of pathogens in case they contain biological substances have to be described. The regular monitoring of homeopathic products, regarding e.g. metal contamination, is necessary due to their frequent and mostly unsupervised use (Tumir et al., 2010). Notifications of adverse or unexpected drug reactions according to the “Guide- line on pharmacovigilance for veterinary medicinal products” (EMEA, 2004) have to be made by manufacturing companies and veterinarians also for homeopathic remedies.

With different source materials (e.g. plants, minerals, animal components) for homeopathic drugs possible contamination with microbes, insects, pesticides, heavy metals, fumigants, mycotoxins and radioactivity has to be considered by adequate control of source material, storage and processing (WHO, 2009).

In comparison to conventional remedies, homeopathic drugs can be viewed as low in risk in respect to toxic effects, residues and overdoses. One reason for this is the extensive dilution of the origin (sometimes toxic) substance below a hazardous level.

Manufacturing companies that provide registered homeopathic remedies for animals are obliged to produce and act according to the principles and guidelines of Good Manufacturing Practice (GMP) of veterinary medical products as described in the Directive 91/412/ECC. It encompasses require- ments for qualification of personnel, documentation of processes/procedures and batch documenta-

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FP7 - 311824 IMPRO Deliverable D 9.1 tion at least for 5 years. Manufacturing methods, implementation of a quality assurance system, hygiene programs esp. avoidance of (cross) contaminations, samples of each batch of finished products and starting materials shall be retained. Furthermore, a system for recording and reviewing complaints and product recall and the conduction of repeated self-inspection should be implement- ed.

External controls of these GMP principles are conducted by local authorities every one to three years. On European level the European Commission represents the supreme authority for the cen- tralised procedure for approval of medical products and its surveillance. The European Medicine Agency (EMA) mainly has the task of a coordinating agency by providing expert reports to the Eu- ropean Commission for decision support.

The required control of the amount of contained starting material and potency in homeopathic remedies is complicated due to the special principles of homeopathic dilutions and limited by the current possibilities to detect molecules of a substance above a dilution of 1:10 23 . A test on the potency of a product is usually performed up to a dilution of 1:10.000 (D4) according to personal correspondence with several quality assurance departments of manufacturers. Herbal starting materials that vary in content of active substances depending on harvest time and local conditions etc., are tested for sensory quality, ingredients e.g. flavones, essential oils, loss on drying, and residues of pesticides and metals as well as bacterial contamination to provide the same or similar starting materials.

2.2.5 Critical notes From the previous explanations, different points can be identified as being critical when comparing the principles of homeopathy with the conditions generally found in farm practices:

• Due to a lack of a “golden standard” for the use of homeopathy, no clear recommendations for action are available, neither with respect to an appropriate diagnostic and treatment procedure with homeopathy, nor regarding the control of therapeutic effects. • No fully fledged repertory with homeopathic drug pictures based on animal tests is available. Most drug pictures were developed with humans and later adapted to animals. Some critics doubt the transferability of human and veterinary homeopathy (Röhr, 2005). • Time capacity, demanded to perform a profound homeopathic diagnostic procedure and to follow the development after treatment and the control of the effectiveness of the treatment, may often not be available to an adequate level on many farms. • Laypeople are lacking expertise to assess whether animals are able to react to a stimulus by homeopathic remedies. The potential of animals to react on stimuli might be aggravated by the persistence of the main causes of the disease and deficits in relation to unbalanced nutrient supply or poor hygienic conditions. • A qualified education on veterinary homeopathy is often not offered at veterinary schools, and where provided, the quality might vary a lot. • Elaborating a profound diagnosis, identifying a correspondence between the specific symptoms of individual farm animals with the large number of homeopathic remedy pictures and controlling the efficacy of therapeutic measures require an expertise that laypeople cannot provide. To prevent farm animals from suffering due to improper treatment, the use of homeopathy should be retained in the hands of professionals.

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3 Part B: Review on previous research on the effectiveness of homeopathy

3.1 Material and methods The aim was to systematically evaluate the existing knowledge on the effectiveness of homeopathic remedies used for prevention or treatment in livestock published in scientific publications. Due to the fact that the development of antibiotic resistance is increasing and the demand for alternatives for treatment of bacterial diseases is growing, the main focus was on studies dealing with homeopathic remedies which could possibly replace antibiotics in the case of infections. Additionally, we looked for studies on homeopathic treatments against parasites because resistance is rising here too.

The search for scientific publications was carried out in the following databases: PubMed, Sci- enceDirect, and Web of Science. Specific databases on homeopathy were available at Hom (VetCR) (database of the Carstens Stiftung), Vetion:oekovet.de database or AudeSapere database and also taken into account. Further publications were found by relying on the reference list of considered studies.

The searches were performed between 17 th and 21 th February 2014. The search terms (see Table 1) were defined according to the PICOS approach (Liberati et al., 2009).

Table 2: Search terms according to PICOS

Population “livestock” OR “dairy” OR “cows” OR “cattle” OR “bovine” OR “heifer” OR “calves” OR “pigs” OR “sows” OR “piglets” OR ”poultry” OR “swine” OR “por- cine” OR “turkeys” OR “broiler/s” OR “chicken” OR “hen/s” AND Intervention “homeopathy” OR “veterinary homeopathy” OR “homeopathic” OR “dilution” OR “complementary veterinary medicine” OR “isopathy” OR “nosodes” AND Comparison “prevention” OR “prophylaxis” OR “metaphylaxis” OR “treatment/s” OR “therapy” OR “comparison” AND Outcome “efficacy” OR “effectiveness” OR “effect/s” OR “efficiency” AND Setting “clinical trial” OR “review” OR “trial/s” OR “study”

Only publications in peer-reviewed scientific journals and doctoral theses were taken into account. “Peer review” means the evaluation of work by one or more independent person of similar competence to the producers of the work to maintain a high standard of quality, to improve performance and ensure credibility for the publishing journal.

The considered studies for this report addressed the efficacy of homeopathic drugs in cattle, pigs or poultry in production diseases under European conditions. The term “Production diseases” refers to those diseases induced by management practices. The term was defined at the first „International Conference on Production Diseases in Farm Animals“ in Illinois (ICPD, 1968). It describes multifac- torial diseases of livestock induced by insufficient management practices, poor hygiene, nutritional deficiencies, inappropriate housing conditions, high performance, breeding and stress meeting infectious agents in an industrial production system. Examples for production diseases are mastitis, lameness and infertility in cows, MMA in sows, respiratory and gastrointestinal diseases in pigs and poultry.

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The time frame of publications considered was from year 1980 to 2014. Accessible languages were English and German.

The search and filtering process was performed on the basis of the PRISMA guidelines (Liberati et al., 2009). The “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) aims to ensure the transparent and complete reporting of systematic reviews and meta-analyses by providing a structure and checklist for the authors.

Extraction process of records

Figure 1: Search process based on the PRISMA guidelines

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All articles were evaluated by the same person. The following information was extracted from each study according to a predefined protocol

• author • publication year and source • research body • species • farming system • purpose of application • disease in focus • exclusion of experimental animals • diagnostic method and diagnosing person • used remedy, as well as origin, ingredients and potency of the remedy • producer of remedy • way of administration • study design and control groups • methods of measurement • outcome of the study

Studies with more than one clinical trial included, e.g. different homeopathic remedies for different diseases, and were regarded as separate studies for the evaluation and comparison of data. Sever- al publications on the same trial, if known, were considered as one clinical study.

3.2 Results

3.2.1 Overview regarding the considered studies: From 4,448 publications gathered, 62 publications (37 publications in English language and 26 in German) were identified dealing with the efficacy of homeopathic remedies in livestock when used to treat production diseases and which met the given criteria. In the progressed screening process on abstracts, most studies were excluded because of dealing with the wrong species or because they were not peer-reviewed. The publications were based on 60 individual clinical trials and 4 summarising reports on the topic. In two cases the identical clinical trial resulted in two publications (thesis and article). One publication included three individual clinical trials, and two publications included each two individual clinical trials. The publications focussed mainly on cattle while only a small proportion dealt with pigs and poultry (see table 3).

It is noteworthy that within the considered studies no repetitions were conducted concerning the use of the same remedy administered to the same species with a comparable indication.

Table 3: Number of trials for different species

Species Number of trials performed Cattle 40 Pigs 13 Poultry 7 Summary 60

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Sources Twenty doctoral theses on homeopathy in livestock were available and performed at veterinary or agricultural universities. The 42 scientific papers were primarily published in homeopathic journals (e.g. Homeopathy, British Homeopathic Journal, International Journal of High Dilution Research, Alternative Therapies in Health and Medicine, Zeitschrift für Ganzheitliche Tiermedizin), and only marginally in veterinary scientific journals (e.g. Veterinary Record, Journal of Dairy Science, Journal of Animal Science, Berliner und Münchener Tierärztliche Wochenzeitschrift, Transboundary and Emerging Diseases).

Time period Most studies were performed or published between the years 2003 and 2011 (n= 26). The time period before this decade seemed less productive with 18 publications in the time period 1980 till 1990 and 15 publications between 1991 and 2000 ( see fig.2). The four summarising reports were published in the years 1989, 2005, 2007 and 2008.

0 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

Figure 2: Number of publications per year

Production system In most of the studies (67%), the farming system/production method was not specified. The remaining studies were defined as conventional (20%) (particularly pig and poultry farms) or as organic (8%) (exclusively dairy farms). Five percent of the studies had taken place in both farming systems.

Purpose of treatment The main purpose to apply homeopathic remedies in clinical trials was prevention of diseases (28 studies, including 5 studies aiming for health in general or growth promotion ß). Furthermore, 24 studies refer to the therapeutic treatment of diseases while eight studies focused on metaphylactic ß treatment.

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Indication The indication for using homeopathic remedies in term of diseases was different for each species (see fig.3 ). In studies dealing with cattle, treatment was directed against mastitis or fertility disorders in dairy cows. The indication diarrhoea was exclusively tested on calves. The studies on pigs when using homeopathic remedies were balanced between fertility disorders, especially the MMA- syndrome in sows, and respiratory infections and diarrhoea in piglets, as well as growth promotion and health in general in fattening pigs. In the case of poultry, the main indication to use homeopathy was to support growth promotion or to treat diarrhoea. Three studies dealt with the treatment of parasitic manifestation in chicken or cattle. Studies that were aiming for more than one indication to treat were counted for each indication. Nearly all animals treated with remedies had become sick by natural infection. Only in three studies on chicken was an infection artificially induced. Camphausen (2002) inoculated a fixed dose of the parasite Eimeria tenella on a certain day, Velkers et al. (2005) induced an E.coli -infection to the chickens on day 8 and Berchieri et al. (2006) challenged chicken on day 17 after birth by a broth culture of Salmonella enteritidis .

Exclusion criteria Criteria for the exclusion of experimental animals from participating in the trial were only defined only in eight studies. Animals were excluded for the following reasons:

• systemic signs of infection including high temperature or low appetite (Williamson and Lacy-Hulbert, 2014) • additional diseases apart from the studied indication (Varshney and Naresh, 2005) • additional clinical diseases, pre-treatments, gangrenous mastitis, teat injuries and fever (> 41 °C) or loss of appetite (Hektoen et al., 2004) • additional treatment or additional quarter infected (Aubry et al., 2013) • fever (>39.5 °C) or systemic signs of depression o r watery milk or teat lesions and when mastitis was caused by Staphylococcus aureus (Werner et al., 2010) • additional treatment, severe injuries at parturition or caesarean section or palpable adhe- sions of the uterus (Arlt et al., 2009) • additional treatment (Verdier et al., 2003) • severe mastitis requiring intensive therapeutic measures and systemic symptoms e.g. ato- ny of rumen or exsiccosis (Sonnenwald, 1986)

In these studies, animals were primarily excluded for showing systemic symptoms or severe damage of organs, considering the ability to react to a stimulus by the immune system of an animal.

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100%

90%

80% Indications

70% Parasitic Diseases

60% Respiratory Diseases Growth promotion 50% Diarrhoea 40% Fertility disorders Mastitis 30% Health in general 20%

10%

0% Cattle Pigs Poultry

Figure 3: Distribution of the indications in relation to the use of homeopathy

Diagnosis Diagnostic procedures to evaluate the amelioration and deterioration of parameters for health or growing and to measure the effect of the applied remedy were quite heterogeneous in the various studies. The diagnostic methods were divided into four groups:

1. Clinical signs: e.g. optical control of milk for clots, observation of symptoms like 35 changed faeces consistency, cough etc. Clinical signs

2. Indirect tests: e.g. California-Mastitis-Test or conductivity milk test, rectal palpation Measurements 26 of the uterus, general blood parameters

3. Direct tests: e.g. laboratory tests for de- Direct tests 24 tection of pathogen in milk, test for parasites in faeces Indirect tests 18 4. Measurements: e.g. body temperature, bodyweight, milk yield

Figure 4: Diagnostic measures taken

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In half of the trials two or more parameters were considered when diagnosing diseases or possible effects of the use of remedies. The most frequently taken diagnostic measure was the record of clinical signs, followed by additional measurements and direct tests. Indirect tests, often available as on-site tests, were performed to a smaller degree (see fig. 4 ). The question regarding by whom a disease or symptom was diagnosed, remained unanswered in 38 of 60 studies. In the studies of Velkers (2005), Enbergs and Sensen (2007), Arlt et al. (2009) and Williamson et al. (2014) a veterinarian, specialised in homeopathy or veterinarian accompanied by a trained homeopath (Hektoen, 2005), performed the diagnostic procedure. In the study of Werner (2006), the diagnosis was performed by a veterinarian, supervised by an external veterinarian experienced in the use of homeopathy.

Remedies In general, two types of homeopathic remedies are available: Remedies including only one active ingredient in the starting tincture (used for classic homeopathy ß) and remedies combining two or more active ingredients in the starting tincture (used for complex homeopathy ß). In 47% of the studies complex remedies (with combined ingredients) were used, and in 42% of the studies single remedies. In the remaining studies (11%), the type of homeopathic remedy was unknown or not differentiable (e.g. parallel use of single and complex remedies). Producers of the applied remedies were not described in 47% of the trials. In the other cases, most often mentioned were the producing companies Heel ® (18%) and DHU ® (8%) apart from various small producing companies or local pharmacies (27%) mentioned one to three times. The homeopathic dilutions ß and potencies of the applied drugs, respectively, were in the slight majority (n=24) high potencies from D60 (resp.C30) and D400, followed by low potencies (n=22) from D1-D30. A number of 12 trials did not mention the potency. Two studies considered high and low potencies (Vohla, 1991; Werner, 2006). The ingredients used in the studies were of herbal, mineral or animal origin, for the nosodes ß, substances of diseased matters or the pathogen were used.

Methods of Administration The way of administration differed depending on whether individuals or groups of animals were treated. For groups, the administration was solely orally by drinking water or mineral salt. On individuals the drugs were usually administered orally and infrequently by subcutaneous or intramuscu- lar injection, topical (e.g. vulva spray or udder cream) or by intra-mammary injection.

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Study design ßßß The approach of an “evidence-based medicine” is premised on the current knowledge based on clinical studies and scientific publications, which prove or disprove a certain effect – the so-called external evidence (Panesar et al., 2010). According to the Oxford Centre of Evidence-based Medi- cine (CEBM, 2011) the levels of evidence are graded 1 through 5 in decreasing order of quality:

Level 1: (highest quality) consists of systematic reviews or meta-analyses of randomised controlled trials and high-quality, single, randomised controlled trials. Systematic review of RCTs Level 2: Randomised trial or observational study with with or without dramatic effect. meta-analysis RCTs Level 3: Non-randomised controlled cohort / follow-up Cohort studies study Case-Control Studies Case series Level 4: Case-series, case-control studies, or historical- ly controlled studies Case reports (Expert) Opinions Level 5: Evidence is expert opinion not based on critical appraisal but based on reasoning from physiol- Figure 5: Hierarchy of evidence for ogy, bench research, or underlying principles questions about the effectiveness of a treatment (modified accord. to Akobeng, (mechanism-based reasoning). 2005)

In single clinical trials, double-blinded Randomised-Controlled-Trials (RCT) are regarded as the “gold standard” for proving an empiric evidence of effectiveness of a tested remedy (Kaptchuk, 2001; EMEA, 2001). The study designs of the trials found were examined with respect to their ability to measure efficacy of homeopathy on an evidence-based-medicine-level.

Seventy-seven percent of the single clinical trials were intervention studies, including only “Random- ised Controlled Trials ß”, 23% were “Observational studies”. The RCT (n=46) could be divided in 23 non-blinded trials, 12 single-blinded trials and 11 double-blinded trials. “Single-blind” means that the patient is not aware of the true nature of the applied drug. As this is not applicable to animals, a single-blind experiment means that the person administering the drug is not aware of the true nature or the ingredients. Double-blinded trials include a “blinding” of the user as well as the assessor of the samples (Schulz and Grimes, 2002). The assessor of the samples and the scientist, who analysed the results, was the same person in some double-blinded trials. The blinding eliminates effects such as observation bias and wishful thinking that might occur if the samples were evaluated by someone who knew the group constellation and treatment.

The implementation of control groups, e.g. an untreated group, placebo group or antibiotic treated group were also taken into consideration. More than half of the trials (65%) included only one control group, 23% included two control groups and one study included even four control groups (Cam- phausen, 2002). Six of the observational studies enclosed no control or parallel group at all. Con- sidering the number of 67 control groups, 43% were treated with a placebo, 37% with a different treatment, e.g. antibiotics, hormones, teat-sealers or a phytotherapeutic drug and only 20% included an untreated group.

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Outcome for efficacy In medicine, efficacy indicates the capacity for beneficial change (or therapeutic effect) of a given intervention (e.g. a drug). When talking in terms of efficacy vs. effectiveness, effectiveness relates to how well a treatment works in the practice of medicine, as opposed to efficacy, which measures how well treatment works in clinical trials or laboratory studies (Thaul, 2012).

A “positive” outcome of a trial was defined by proof of a statistically significant higher efficacy of the homeopathic remedy compared to a placebo or an untreated group. “Negative” was defined when the efficacy of the homeopathic remedy was not significantly different to placebo or an untreated group or even worse. “Neutral” or “inconclusive” was chosen, when the efficacy was not significant different between the homeopathic and the antibiotic group (without a further control group) or when the homeopathic remedy only showed a significant effect on a specific group of animals (e.g. only on high yielding cows) or in a specific time frame (and vanished later) or when only single parameters improved while others deteriorated or when the authors did not come to a clear result.

In total, nearly the same number of studies with a positive (50%) as with negative out- Positive Outcome come 40%) or inconclusive outcome (10%) were published ( see fig.6 ). When looking at the single species ( see table 4 ) only outcome 40% Neutral 50% Outcome of the studies dealing with pigs were more positive, while the outcomes in studies with cattle and poultry were nearly evenly distrib- Negative Outcome uted between positive and negative. 10%

Figure 6: Percentage of studies with a positive result for efficacy of the used homeopathic remedy

Table 4: Number of trials and outcome regarding efficacy

Species Number of Positive Neutral Negative Trials Outcome Outcome Outcome Cattle 40 18 4 18 Swine 13 8 2 3 Poultry 7 4 0 3 Summary 60 30 6 24

Altogether 30 trials out of 60 had a positive outcome, meaning that they revealed a significant higher efficacy of the homeopathic treatment in comparison to the treatment in the control group in the conducted trial. The same number of trials failed to prove a significant efficacy of the homeopathic treatment in question. Trials with a significantly positive outcome were mainly published in scientific journals (22 out of 30 positive trials), as well as studies with a negative outcome (15 out of negative 24). Results described in a doctoral thesis were nearly evenly distributed between negative (n=9) and positive (n=8) outcomes concerning the efficacy of homeopathic remedies, apart from three theses which revealed an inconclusive outcome.

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Cure success In order to provide information about cure rates, 23 clinical trials with the purpose of therapeutic treatment were analysed. A number of 37 out of 60 clinical trials dealt with prophylaxis or metaphylaxis and were not taken into account. Only 12 of 23 trials dealt with therapeutic treatment and provided information on cure rates ( see Table 5).

A wide range of different criteria for defining a recovery or cure by the researchers, e.g. in case of mastitis was found: “full recovery” with or without cyto-bacteriological recovery or clinical recovery with or without cyto-bacteriological recovery or only bacteriological recovery etc. (see footnotes be- yond the table). This makes a comparison and interpretation of the results more difficult. Thus the different cure rates cannot be compared directly to each other. Eleven trials did not define cure rates at all. Instead, the effectiveness of the homeopathic remedy was evaluated on the basis of other criteria, e.g. number of re-treatment, mortality rate, duration of diarrhoea, fertility parameters, milk yield etc.. Overall, the cure rates in the 8 studies which focussed on mastitis ranged between 5% and 87% for a treatment with homeopathic remedies, between 17% and 95% when using an allopathic remedy and between 4% and 56% for the administration of a placebo.

Results for diarrhoea in calves were nearly the same for a treatment with homeopathic remedies and with a placebo in the two studies, which defined a cure rate. For sows with MMA and chicken with coccidiosis only one trial each performed a therapeutic treatment and defined a cure rate. The results for MMA were in favour of homeopathy compared to allopathy and vice versa for chickens with coccidiosis.

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Table 5: Curing rates for therapeutic use of different remedies

Healing effect of Author Species Indication Homeopathy Allopathy Placebo (Year) a a 34% 26% ______Sonnenwald Cows Mastitis d d 18% 24% (1986) a a 34% 26% ______Merck et al. Cows Mastitis d d 18% 24% (1989) a, o a, o 33% 67% ______Tiefenthaler Cows Mastitis a, p a, p 80% 50% (1990) 19% a 20% a 6% a e e e Hektoen et al. Cows Mastitis 47% 45% 56% (2004) 29% f 35% f 13% f m m ______Varshney & Naresh Cows Mastitis 87% 59% (2005) b b b 47% 24% 30% Werner Cows Mastitis c c c 31% 24% 4% (2006) a,g a,g 5% 17% ______Walkenhorst Cows Mastitis a,h a,h 10% 65% (2006) e e 63% 95% ______Williamson et al. Cows Mastitis n n 36% 74 % (2014) l ______l Kayne Calves Diarrhoea 83% 80% (1994) i ______Hornig Calves Diarrhoea 69-77% 69% (2014) ______Seifert Sows MMA 61% 35% (1987) j ______Camphausen Chicken Coccidiosis 43% 77% (2002) a [Full recovery = no pathological findings of milk and udder and negative cyto-bacteriological results of milk samples] b [Full recovery = no pathological findings of milk and udder with negative bacteriological results of milk samples on 1st day of disease] c [Full recovery = no pathological findings of milk and udder with positive bacteriological results of milk samples on 1st day of disease] d [Clinical recovery = no pathological findings of milk and udder and with positive bacteriological or/and positive cytological results of milk samples] e [Clinical recovery = no pathological findings of milk and udder] f [Bacteriological recovery = negative bacteriological result of milk samples after treatment and negative California Mastitis Test] g [Cows with clinical mastitis at min. one udder quarter] h [Cows without clinical signs, but positive bacteriological result of milk samples at min. one udder] i [Range of results due to the use of different homeopathic remedies] j [Efficacy was defined as the percentage oocysts which are impaired in their development] l [Clinical recovery = change from watery to pasty faeces; animals treated by homeopathy recovered 1 day earlier] m [Clinical recovery = no pathological findings of milk and udder and negative California Mastitis Test] n [Bacteriological recovery = negative bacteriological result of milk samples after treatment] o [test group = cows with acute mastitis with disturbed general condition] p [test group = cows with acute mastitis without disturbed general condition]

Outcome and potency Comparing the outcomes of the trials with the type of remedy (single or complex remedies) used, no differences could be found. Remedies with low potencies (D1-D12) showed more positive results, while homeopathic treatments with high potencies (>D24) were nearly evenly distributed in showing evidence or no evidence regarding the efficacy of homeopathy (see fig. 7 ). Differences in the use of high or low potencies did not depend on the purpose of use (prevention, treatment, metaphylaxis) nor the indication (e.g. mastitis, diarrhoea) or species.

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Number of studies

8 Positive 6 Negative 4

0 Low potency High potency

Figure 7: Outcome depending on the potency of the used homeopathic remedies

Outcome and study design Figure 8 shows the results of the evaluated studies in relation to the study designs. The double- blinded RCTs resulted in more negative than positive trials. Single-blinded RCTs and observational trials had a tendency to be positive . Non-blinded RCTs had the highest probability to result in a positive outcome.

Study design

RCT double-blind

Outcome RCT single-blind Negative Neutral RCT non-blind Positive N Observational

Number of N 0 2 4 6 8 10 12 14 studies

Figure 8: Study design and result for effectiveness of homeopathy in the studies

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3.2.2 Species specific results:

3.2.2.1 Studies on cattle (see Annex 1 for more detailed information)

Altogether 40 trials matched the selection criteria described above. The main focus (85%) was on dairy cows, the other studies dealt with calves. The findings concerning effectiveness of homeopathy was negative for 19 studies, positive for 18 studies and neutral or inconclusive for four of them. Six of eight studies performing randomised controlled trials with double-blinding (n=8) revealed negative results for efficacy while one inconclusive (Fidelak et al., 2007) and one positive (Enbergs, 2000) result were achieved.

Dairy cows (34 studi es): Twenty studies dealt exclusively with udder health, including prevention or treatment of acute or subclinical mastitis, drying off (Spranger, 2000) or udder health in general (Schlecht, 2004). Apart from mastitis, fertility disorders, especially around the parturition like retained placenta and endometritis, were addressed in 12 studies. Remarkably, almost all studies on fertility disorders used homeopathy for prevention. Only Enbergs and Sensen (2007) examined the use of two different homeopathic complex remedies to treat chronic endometritis with a positive result. Wirth (1990) and Erbe (1990) applied a metaphylactic homeopathic treatment to their experimental groups to reduce retained placenta and endometritis, both with a positive outcome. Concerning other diseases, the treatment of tick infested grazing dairy cows was only addressed once, showing a positive outcome (Gazim et al., 2010). Of the total of 35 studies on dairy cows, the outcome for effectiveness was positive for 17 studies, negative for 15 studies and undefined for three studies. Three of the studies failed in showing a clear result: (Fidelak, 2003), dealing with prevention of peripartal fertility and health disorders, showed that the experimental group performed only slightly better than a placebo group. Dealing with the same indication in another trial, he experienced similar results (Fidelak et al., 2007). While the oestrus cycle started earlier and average daily milk yield increased, the submission rate de- creased. The actual milk yield, mastitis, lameness and culling rate revealed no differences between placebo and homeopathy. Fidelak et al. (2007) concluded that the treatment might only be appropriate for high yielding cows. The study of Sonnenwald (1986) also struggled with undefined results for the homeopathic and the antibiotic treatment in acute mastitis. The homeopathic treatment presented better results with gram-negative bacteria causing mastitis and antibiotics were more effective with Streptococcus subspecies .

Calves (six studies): Four of the six studies on calves were dealing with the treatment of diarrhoea (Frerking and Ro- mansky-Rieken, 1981; Kayne and Rafferty, 1994; Verdier et al., 2003; Hornig, 2014). Of these studies only the study of Kayne and Rafferty (1994) showed an efficacy of the single homeopathic drug Arsenicum album 30C, resulting in a one day faster recovery of the homeopathy treated calves than in a placebo group. Boerms (1981) tested the effectiveness of the single homeopathic remedy “Echinacea” in combination with the standard allopathic remedies for treating pneumonia and enteritis in calves in comparison to the "pure" standard antibiotic treatment with inconclusive results. One single study aimed at preventing a Dictyocaulus worm infection in calves with a “homeopathic vaccination”, but had similar infection rates in the placebo group as in the blinded RCT group (Taylor et al., 1989). Only one study on parasitic infections performed a direct test for detection of the larvae to verify a possible

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3.2.2.2 Studies on pigs (see Annex 2 for more detailed information)

Thirteen studies were identified. Eight of the trials led to a positive outcome, three to a negative and two had an inconclusive outcome. The outcomes showed no relationship to the study design. Ob- servational trials and open RCTs as well as single- or double-blinded RCTs were performed with a positive, negative or inconclusive outcome. Between the evaluated trials, the age of the animals varied considerably: Five studies were performed with sows, four studies with pigs and three with piglets. The reason for applying homeopathic remedies was nearly evenly distributed. Four studies addressed fertility disorders in sows (Both, 1980; Day, 1984; Seifert, 1987; Drösemeier, 1989), three were dealing with respiratory infections and three with diarrhoea while two were focussing on growth promotion or two aimed for a general good state of health. The three mentioned disease complexes cover the most common reasons for the use of antibiotics on pig farms in practise (Christensen et al., 1995; Petersen et al., 2008). The prevention or treatment of fertility disorders, in particular prolonged anoestrus, stillbirth and the mastitis-metritis-agalactia-syndrome (MMA) with homeopathic remedies was effective in three out of four trials in sows. It should be noted that the trials that showed an efficacy were observational trials (Both, 1980; Day, 1984) or a non-blinded RCT (Seifert, 1987), while the one study that failed to show evidence of efficacy to prevent MMA in sows performed an double-blinded RCT (Drösemeier, 1989). In a study on respiratory disease and general state of health, homeopathy was significantly more effective than low dosage of antibiotics and a placebo in fattening pigs, but not over an antibiotic metaphylaxis in a therapeutic dosage (Albrecht and Schütte, 1999). In an earlier single-blinded trial of (Schütte, 1991), a metaphylactic treatment with two different homeopathic complex remedies showed a significantly higher effectiveness compared to a placebo. A second non-blinded trial of the author, performed at the same time, with two other complex remedies failed to present a significant effectiveness compared to an antibiotic treatment. Two of the studies dealt with growth promotion: Guarjardo-Bernal et al. (1996) administered a very high dilution (C201) of Sulphur to pregnant sows and examined the weight and performance of the new born piglets in a single-blinded RCT. He found no significant difference in the weight at birth and the further development of the piglets in comparison to a placebo group. Da Silva et al. (2011) treated the pigs directly with a complex remedy in two different treatment schemes in an observational trial with the aim of growth promotion. The measured weight between the groups was different within the testing period, but could not present a clear outcome; a control group was lacking. Stud- ies of Soto et al. (2008), Coelho et al. (2009) and Camerlink et al. (2010) had the objective to prevent E.coli - or post weaning diarrhoea. Coelho et al. (2009) and Camerlink et al. (2010) performed a double and single blinded RCT, respectively, and both came to a positive result for homeopathy in comparison to an antibiotic or placebo treated control group. Soto et al. (2008) showed that homeopathic treated piglets had less weight losses compared to an untreated control or placebo, but the difference between placebo and homeopathy group was not significant. The only study on pigs evaluating the influence of homeopathy to health in general measured by clinical signs, course of illness, therapeutic results and antibiotic consumption showed that with the use of homeopathy the consumption of antimicrobials could be reduced by 60% (over three years) on the participating farms in an observational trial (Schütte, 2003).

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3.2.2.3 Studies on poultry (see Annex 3 for more detailed information)

Only few studies were found dealing with homeopathic treatment in poultry production. Seven studies were performed exclusively on chickens. The effect of homeopathic treatment was positive in four studies and negative in three studies in comparison to an antibiotic treatment or an untreated control. In four trials the objective to administer homeopathy was diarrhoea caused by Salmonella (Sandoval et al., 1998; Berchieri et al., 2006) or E.coli -infection (Velkers et al., 2005) or coccidiosis (Camphausen, 2002). The remaining three studies aimed for a growth promoting effect (Amal- caburio et al., 2009; Hadipour et al., 2011) in one study in combination with the aim of an improved immune system (Sato et al., 2012). The four studies that showed an effect of homeopathy were performed as randomised controlled trials in a non-blinded form (Camphausen, 2002; Berchieri et al., 2006; Hadipour et al., 2011) or double-blinded (Sato et al., 2012). Camphausen (2002) treated chickens, challenged by an induced coccidian infection, with a D6 dilution of Acalypha indica and showed 12% reduced oocysts in faeces compared to an untreated group, but a lower effect than the compared conventional coccidiostatic (49%). Berchieri et al. (2006) induced an infection to test the preventive effect of a Salmonella nosode also, which he administered before to the chickens and found a significant lower faecal excretion of Salmonella enteritis compared with an untreated group. Hadipour et al. (2011) evaluated the growth promoting effect of a combined homeopathic remedy with undefined potency in comparison to a group, treated with a standardised treatment with antibiotics and vaccines. They found a 5% lower mortality rate and a significant higher weight gain in the homeopathic experimental group. Sato et al. (2012) performed a double-blinded RCT with chicken and showed an immune stimulating and growth promoting effect effect of Thymulin in a D5 dilution compared to an untreated group. The three studies with a negative outcome were performed as observational studies (Sandoval et al., 1998; Velkers et al., 2005) or as a non-blinded RCT (Amalcaburio et al., 2009). Two of them used high dilutions (C12 or C30) of single or combined homeopathic remedies in comparison to an antibiotic or untreated group. The third study administered three different combinations of homeopathic drugs combined with an E.coli nosode, all in a high dilution (C30, C200), with no effect compared to an untreated or antibiotic control group (Velkers et al., 2005). 3.2.2.4 Results of similar reports on homeopathic efficacy in animals: Four reports summarising a limited number of trials and matching the search criteria were found which considered various species, including livestock. Three of them evaluated the efficacy of homeopathy as insufficient; one of the reports did not come to a clear result: • Kowalski (1989) evaluated homeopathic treatment in veterinary literature in her doctoral thesis and found certain effects of homeopathy, but only in one trial a proof of efficacy of homeopathic treatment. She assessed 14 controlled, clinical trials, apart from experimental trials on single animals and general treatises on remedy pictures. Ten of the trials considered cattle or pigs, while the rest dealt with cats, dogs or horses. • Hektoen (2005) took three single clinical trials and one review on veterinary homeopathy (Kow- alski, 1989) into account to evaluate an efficacy of homeopathy in animals. The remaining sources were broader literature and conference proceedings or grey literature on the topic homeopathy and placebo effect, considering predominantly human medicine. The “Review of the current involvement of homeopathy in veterinary practice and research” did not result in a clear decision on the efficacy of homeopathy, because of the poor quality of the available studies, but suggested to keep an active dialogue between academic medicine and alternative medicine to ensure a high level of animal welfare.

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• Rijnberk and Ramey (2007) considered 10 publications on human medicine, e.g. reviews on homeopathy, while only 4 clinical trials including animals (3 on cattle, 1 on dogs) were taken in- to account. They published a report on the lack of effectiveness of veterinary homeopathy point- ing out inter alia the existence of no significant differences of homeopathic remedies and place- bos when compared in studies. • Ruegg (2008) compared different treatment strategies of mastitis and its efficacy. She considered four publications (Egan, 1998; Hektoen et al., 2004; Holmes et al., 2005; Rijnberk and Ramey, 2007), three of them also included in this report, and concluded that efficacy data for veterinary homeopathy appear to be almost completely lacking.

3.3 Discussion Taken into account the long existence and use of homeopathy in livestock production, only a relatively small number of studies focussing on the efficacy of homeopathy and following scientific standards have been conducted so far. In comparison to the four summarising reports previously published and dealing with the effectiveness of homeopathy in farm animals, a clearly higher number of trials have been taken into account in the current review. One reason for a higher number of studies involved here is due to the fact that much time has passed between the first review of Kow- alski (1989) and today. Apart from publications in peer reviewed journals, the current review also included doctoral theses in German language. This reflects the situation in German speaking countries, where for some unknown reasons homeopathy is more frequently used than in other countries (Kayne, 2006; Albrecht, 2013; Institut für Demoskopie Allensbach, 2014). Due to the extended search of literature at multiple sources, it can be assumed that nearly all peer-reviewed articles on homeopathy in livestock matching the search criteria have been considered. Thus, the current report can claim to encompass so far the most comprehensive review on homeopathy in farm animals.

Comparing the previous summarising reports (Kowalski, 1989; Hektoen, 2005; Rijnberk and Ramey, 2007; Ruegg, 2008) with findings of this report, three of them considered only a very small number of trials on animals. Hektoen (2005) considered mainly publications on human homeopathy, apart from three individual clinical trials and the doctoral thesis of Kowalski (1989) on veterinary homeopathy. She did not come up with a clear conclusion on the efficacy of homeopathy and justified this by emphasising the poor quality of the studies. A wide variation of scientific quality in the performed trials was also experienced in the present evaluation.

Rijnberk and Ramey (2007) considered only four clinical trials on animals (3 on cattle, 1 on dogs). They concluded from the results that no significant differences existed between the effectiveness of homeopathy and placebo in animals. However, the selective choice of studies does not allow far- reaching conclusions. Ruegg (2008) evaluated the efficacy of homeopathy within the treatment of mastitis of dairy cows, considering only four publications which have been concluded also in the current report.

On the contrary to the summarising reports or review of the previous authors, Mathie and Clausen (2014) evaluated the medical conditions of RCT on veterinary homeopathy and their risk of bias according to the evidence-based-medicine principles by applying Cochrane methods. They examined 18 records for methods concerning randomisation, allocation concealment of this randomisation, blinding of personnel, animal owner and outcome assessors, complete consideration of all randomised patients’ results as well as evidence of a selective reporting of the results and other possible bias, e.g. extreme data imbalances or vested interest by a funding source. They found many

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FP7 - 311824 IMPRO Deliverable D 9.1 deficiencies in the RCTs and only one trial was found to have a low risk for bias. It was assumed by the authors that there is an obvious need for a higher quality research on veterinary homeopathy.

Homeopathic remedies with a low potency were more likely to show a positive effect than highly diluted remedies. Remedies with lower potencies are more or less comparable with concentrations of substances in remedies in conventional medicine. Therefore, they are more easily accepted to show a possible effectiveness, as the mode of action is according to known basic physical principles (Löscher, 1992). However, also trials performed with high dilutions that are far from showing an active molecule at all, could prove an efficacy in terms of a significantly higher therapeutic success in eleven cases, including almost only RCTs, two of them also double-blinded (Coelho et al., 2009; Sato et al., 2012).

Trials performed in a single-blinded or non-blinded RCT or observational trial (see fig.9) more likely resulted in a positive outcome than a double-blinded RCT, indicating that the positive outcome may partly be due to a wish bias. The biggest proportion of the trials (77%) accounted for a RCT – a high quality level according to the principles of evidence-based-medicine (EBM) and currently regarded to be the golden standard (van Sluijs, 2005) for clinical proof of efficacy of a remedy by the scientific community. This may lead to the general conclusion that homeopathic remedies are able to support the healing process under certain conditions. However, the EBM-method is also prone to error by producing misleading conclusions or results for efficacy where there might be none (Weymayr, 2013).

A critical point of the current methods to perform trials on efficacy is that it does not consider the contextual situation of animals on the farms. The focus is mainly on the remedy without looking particularly at the animal or the context and the preconditions on the farm, for instance with respect to the appropriateness of diagnostic or treatment procedure.

No differences concerning the outcome were found in relation to the way of publication in scientific journals or as doctoral theses. The number of not peer-reviewed publications found was nearly double the number of peer-reviewed journals. Similar results were made by (Clausen et al., 2013), who evaluated all studies, collected by the 2006 launched database VETCR on veterinary homeopathy with focus on the content of placebo-controlled trials and a summary on placebo effects in animals. The peer-reviewed studies were published to a bigger proportion in journals dedicated to homeopathy or alternative therapies than in journals on veterinary medicine in general. It can be assumed that journals which focus on alternative therapies like homeopathy are rather more likely to receive articles dealing with homeopathy. There is an increased risk for publication bias, e.g. that reports with positive results are usually more likely to be published than those with negative results (Arlt and Heuwieser, 2010). But when comparing the outcome of doctoral theses and articles in journals this did not seem obvious, but cannot be ruled out completely.

Comparing the purpose to use homeopathic remedies, positive results tended to be more for a preventive use (n=15 of 30) than for a therapeutic (n=10 of 30) or a metaphylactic use (n=5 of 30). Re- markably, when strictly following the simile-rules of homeopathic treatment a preventive effect is difficult to achieve, because a complete homeopathic clinical picture is lacking and so is the matching remedy picture. The results of the trials contradict this principle, but may be an effect of an unspecific reaction of the immune system to the stimulus in form of a homeopathic remedy. A special form of homeopathic remedies are nosodes, which are manufactured on the base of diseased matter, highly diluted (usually of a certain animal of the herd that is to be treated) and used only for pre-

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FP7 - 311824 IMPRO Deliverable D 9.1 vention. The dilution process reduces the amount of infective pathogens against zero and may possibly also work as an inducer of unspecific humoral immunity.

The most objective way to assess the outcome after treating a diseased animal is to perform an acknowledged test, e.g. on the presence or absence of the causing pathogens, best performed by an official laboratory. More or less weaker assessments to evaluate the outcome are from a more objective to a more subjective manner: indirect tests performed onsite > clinical signs > measurements. Also the person, who performs the diagnostic procedures, will vary in its judgement according to its education and experience. This complexity and the performance of different qualities of diagnostic measures might distort the result of the effectiveness of an applied remedy.

A high level of expertise/education in veterinary medicine and homeopathy will not be sufficient alone to reach a high level of animal health in farm animals, but is essential for the serious decision if any and what therapeutic treatment may be appropriate in a certain case. This expertise is also a precondition to find the appropriate remedy and to intervene by changes or adaptions of the treatments when necessary. However, when existing causes are not discerned and eliminated and when farm animals are kept under living conditions where the immune system is overstrained and exhausted, neither conventional nor alternative treatments will be able to provide a sufficient cure rate.

While conventional medication is focusing on the indication, homeopathy is addressing the individual reactions and symptoms in first place. Correspondingly, the conventional approach is to a certain degree context-invariant whereas the homeopathic approach is highly context-variant . Homeopathic treatment might be able to replace antimicrobials in certain situations and under specific preconditions, however, definitively not in all cases. Although there is still a need to assess the efficacy of homeopathic remedies under experimental and standardised conditions, medication should also consider the context in which homeopathic remedies are used.

Differences in the therapeutic effect between homeopathy and placebo, when compared to each other in the same trial ranged between 0% and 25% (Kayne and Rafferty, 1994; Hornig, 2014). Sometimes relatively small and not significant differences were found between the homeopathic remedy and the placebo groups in clinical trials (Kayne and Rafferty, 1994; Hornig, 2014). This rais- es the question if the effects of homeopathy are comparable to a placebo effect? Nevertheless, eleven trials were performed above a dilution of 1:10 24 and showed a positive outcome for the efficacy of the administered homeopathic remedy in relation to a control treatment.

The efficacy of a placebo is mainly regarded as corresponding with the self-healing forces of the body system without the influence of an active substance. Therefore, a placebo and an untreated group are more suitable to distinguish between a placebo and a self-healing effect. When aiming for a replacement of an alternative for an existing remedy to treat animals with the most effective therapy, a comparison of the usual treatment with conventional remedy and a placebo seems quite more appropriate to provide valid results (EMEA, 2001).

Homeopathic remedies ought to have at least the same effectiveness as antimicrobials on diseases to be considered as an alternative to the use of antimicrobial remedies. A comparison of a homeopathic treatment and a treatment with antimicrobials were performed in 20 studies. In several cases, the effectiveness of the chosen homeopathic remedy was better than the conventional treatment with antimicrobials. Differences between the cure rate of homeopathic and antibiotic treatment ranged between 6% and 28% in favour for homeopathy in the same trial (Merck et al., 1989; Varsh- ney and Naresh, 2005) while also a comparable amount of trials found poorer cure rates of homeo-

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FP7 - 311824 IMPRO Deliverable D 9.1 pathic remedies compared to the conventional treatment, with differences ranging between 1% to 55% in the same trial (Hektoen et al., 2004; Walkenhorst, 2006). In other studies, no significant differences could be found in the cure rate between experimental and antibiotic control group (Sando- val et al., 1998; Velkers et al., 2005). Furthermore, it has to be considered that in most trials no sen- sitivity tests on bacterial resistance patterns were performed which might have led to a change in the selected drug and a higher effectiveness.

A comparison of the individual clinical trials within a systematic review according to the principles of evidence-based medicine was not possible ( see Figure 5 ). These principles involve a randomisation, blinding and several clinical trials performed on the same species, disease and remedy to be evaluated in a systematic way. Additional blinding of personnel or/and outcome assessors were applied only in 23 out of 60 trials.

A large heterogeneity among all clinical trials was found. Differences emerged on various areas: 1. Patients. The patients included in the trials differed with respect to: species and within species in relation to age of farm animals, performance level, resilience, and thus different individual abilities to respond to pharmaceutical active ingredients. 2. Remedy. The remedies used in the trials differed with respect to: ingredients in single and combined remedies, high and low dilutions (potencies), ways of administration, pharmaceutical active ingredients (not standardised). Potencies have been administered in different ways for different indications to achieve a preventive, metaphylactic, therapeutic, growth promoting or immune system stimulating effect. 3. Context. The trials were performed in a different context, distinguished among others by diseases, causing pathogens, way of infection (naturally occurred or artificially induced), living conditions for the farm animals regarding hygiene, feeding regimen and treatment procedures. In 67% of the studies, the living conditions were not even described. 4. Expertise: Diagnostic procedures in the trials were performed by persons who differed considerably in education, expertise and knowledge on treatment strategies. Choice of the remedy and ways of measuring the therapeutic effect of the applied homeopathic remedy differed between trials. This was also the case regarding the assessments of effects, e.g. visu- al improvement in milk to objective assessments, e.g. fully performed clinical examinations accompanied by external laboratory tests ( see fig.4 ). Taking into account the total number of studies, not even one study was repeated under comparable conditions. Consequently, preconditions to perform a meta-analysis are not given. The use of homeopathy is lacking reproducibility and therewith cannot claim to have a sufficient prognostic validity. No general conclusions can be drawn as to whether a homeopathic remedy that has shown to be significantly more effective in a specific context than a control treatment is effective also in a different context and under different conditions as found in the previous trial, let alone if it might be better or less effective or effective at all.

The efficacy of a remedy cannot be reduced to the concentration of pharmaceutical active ingredients alone and cannot be isolated from the context in which it is used but is highly context-variant. Efficacy is the result of complex interactions of various factors which include among others: the immune competence of the individual and the capacity to react to stimuli, the degree of elimination of the main and secondary causes, a profound diagnosis and an appropriate treatment no matter of

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FP7 - 311824 IMPRO Deliverable D 9.1 which kind, and last but not least, the given living conditions of farm animals, especially in relation to nutrient supply and hygiene conditions.

According to the results found in Part A, a general use of homeopathy according to a certain standard in diagnostic, treatment and education is not applied in practice. However, it is also questionable if conventional medicine, e.g. antibiotics, is always used in farm practice according to the guidelines on 'The prudent use of antibiotics in veterinary medicine' as communicated by (Federation of Veteri- narians of Europe). Various publications indicate that diagnostic tests to detect the causing pathogen are rarely investigated on farms (Ouweltjes et al., 2008; Doehring and Sundrum, 2013).

3.4 Conclusions As a considerable number of studies demonstrated a significant higher efficacy of the administered homeopathic remedy in comparison to a control group, a general potential concerning the medical efficacy of homeopathy under certain conditions cannot and should not be ruled out. However, this does not necessarily imply that a homeopathic remedy is effective under different conditions or in different individuals suffering from the same disease.

So far, all single trials have been conducted under very specific conditions while no trial has been repeated in a comparable manner. Thus, no reproducibility of the efficacy of a certain remedy has been proven and cannot be claimed without providing evidence within the specific farm conditions diseased animals are living in. Due to the complex interactions of the various factors affecting the efficacy of remedies in the farm specific context, the results of the previous studies lack the power for generalisation. Thus, the previous studies should be assessed as single case studies. The first target in medical treatment of animals should always be to apply the most effective treatment or remedy to prevent unnecessary suffering for the animal for animal welfare reasons. In the absence of a 100% effective treatment possibility for all therapeutic strategies, preconditions that may influence the success of a treatment, e.g. the expertise of the treating person, should be considered.

Due to a lack of prognostic validity, it cannot be recommended to make use of homeopathy in favour of allopathy, unless homeopathy is only administered by highly skilled persons who are able to perform a profound diagnosis and to follow the development of diseases, so that they can intervene if the animals show no sufficient reactions of recovery when treated with homeopathic remedies. Otherwise, the use of homeopathy risks being blamed for increasing health and welfare problems instead of solving or reducing them. Prognosis of a disease and possibility for a treatment requires expertise and experience to diagnose the disease, knowledge on the most probable development of the disease in a certain individual, and expertise on the efficacy of different remedies. Only an adequate educated veterinarian is able to provide this amount of knowledge and experience. This demand is in contrast with the current farming practice, described in Part A.

According to the EC Regulation 834/2007 on organic livestock production, homeopathic products “… shall be used in preference to chemically-synthesised allopathic veterinary treatment or antibiotics, provided that their therapeutic effect is effective for the species of animal, and the condition for which the treatment is intended”. Reflecting on the complex interactions in the diagnosing and healing processes of diseased animals, efficacy of homeopathic remedies cannot be proven alone by randomised clinical control trials but requires evidence of the therapeutic effects in the farm specific context. This is true also for the use of chemically-synthesised drugs. Previous knowledge provided by on-farm assessments reveals that the therapeutic effects of treatments, independent of the remedies used, indicate ample room for improvements.

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4 Part C: Institutions, engaged in research with homeopathy

4.1 Material and methods Identification of research bodies Research bodies and persons experienced in the field of homeopathy were identified by publications on homeopathy in livestock (see Part B). Conference lectures on homeopathy in livestock was a second important criteria for identification. Only research bodies which are located in Europe or that performed research under European conditions were included in this review. Finally, partici- pants of research projects on homeopathy or alternative treatments in livestock were identified by internet search or publications. Questionnaire design A questionnaire that covered questions on the topic of collaboration, needs and constraints within the research on phytotherapy and homeopathy (see Annex 4) was developed within the work group consisting of scientists from Sweden, Germany and Spain. The questionnaire consisted of 12 questions. Before sending the questionnaire to research bodies a test run was performed by researchers in the departments where the working groups are active. The questionnaire was reworded based on comments and answers before being sent out. Sending the questionnaires In total, 31 questionnaires were sent on the 23.06.2014 to the identified research bodies or persons located in 10 countries (Austria, United Kingdom, Netherlands, New Zealand, Denmark, USA, Swit- zerland, Brazil, Sweden and Germany). The time for response was set to three weeks. A reminder was sent approximately a week after the last due date of the questionnaire. Data Handling At Lime Survey, a free online software specifically designed for survey evaluations, a template of the questionnaire was made. All answers from the returned questionnaires were integrated and analysed using the software. Afterwards all collected data were extracted to Excel (Microsoft Office 2010).

4.2 Results In total 12 of 31 sent out questionnaires were received and analysed. Seven research bodies did not fill in the questionnaires, because they do not work any longer in the field of homeopathy. One respondent also stressed that “in biomedical sciences is unanimity on the ineffectiveness of homeopathy” and the research on it is superfluous. Ten requests for the filling in the questionnaire remained unanswered. The response rate for the questionnaires was approximately 39%.

4.2.1 Research bodies The average length of research activity within the area that the institutions had been involved in was 16 years, with a range from 0 to 50 (Question 1) and the average number of people (e.g. scientists, assistants, PhD students, etc.) were currently involved in research on homeopathy was two, but with only two person month per year (Table 6 ).

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Table 6: Number of researchers, currently involved in homeopathy at the responding research bodies

Persons Person month/year Average 2.08 2.16 Range (Minimum-Maximum) 0-10 0-12

The most important main drivers were the improvement of animal health (83.3%) followed by reducing the use of antimicrobials (75%; see fig.8). The third most important reason was the demand by stakeholders, such as vets, farmers and consumers (50.0%). In the category “Others”, education of veterinarians, improving the guidance base for homeopathy and the effectiveness etc. were repre- sented.

Figure 9: Main drivers to perform research on homeopathy

With respect to the amount of scientific production ( Q9 - see fig.10), these institutions published 39 and 45 articles in scientific journals, 5 and 6 publications as PhD theses in the last 5 and 10 years, respectively. Additionally, 51 and 69 conference posters/papers were presented in the last 5 years and in the last 10 years, respectively.

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51 45 39

5 6

Scientific journal Doctoral/PhD thesis Conference papers /posters

in the last 5 years in the last 10 years

Figure 10: Number of publications on homeopathy

The knowledge transfer of these institutions of research on homeopathy into practice (Q10, fig. 11) took place in most cases by publications in scientific journals (66.7%) and less often by publications on web pages (33.3%). Publications in grey literature (books, newsletter/articles/bulletins in farmer magazines) and direct contact with farmers, vets or advisors (stable schools, further education courses, congress presentations, seminars, workshops) were used in equal parts as a way of knowledge transfer.

Way of knowledge transfer into practice

67% 50% 50% 33%

Publications in Publications in grey Publications on Direct contact with scientific journals literature webpages farmers, vets or advisors

Figure 11: Way of knowledge transfer chosen by the research bodies

4.2.2 Collection of research bodies/universities/higher education institutions in Europe with research projects on homeopathy Table 7 presents a collection of institutions in Europe which are dealing with veterinary homeopathy and that were found by scientific publications, conference activity, internet research or direct correspondence.

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Table 7: Institutions involved in research on veterinary homeopathy

AVMC The “Alternative Veterinary Medicine Centre” uses alternative medicine since 1972 and has performed much clinical research into homeopathy and its efficacy in different species.

BAH The “British Homeopathic Association Research” provides factual information, also through supporting education and research.

BAHVS The “British Association of Homeopathic Veterinary Surgeons”, formed in 1982, aims to advance the understanding, knowledge and practice of veterinary homeopathy. It encourages and provides training for veterinary surgeons in the practice of homeopathy. Members follow a Code of Practice, adopted in 1998, which is regularly reviewed. It holds an annual three-day congress since 1986 and is involved in major issues such as nosode use, prescribing by pharmacists, product licences, etc. It is also contributing to the compilation of a Veterinary Materia Medica and of a Veterinary Repertory, in association with the IAVH. It supplies names and addresses of veterinary surgeons with the homeopathic qualification: Veterinary Member of the Faculty of Homeopathy (VetMFHom) and others using homeopathy, that have undergone some of the recognised training.

Carstens The Carstens Foundation provides financial support of homeopathy studies and Foundation cooperates with other institutes on research on homeopathy.

ECCH “European Council for Classical Homeopathy” represents the majority of profes- sional homeopaths in Europe and publishes a “Guideline for Homeopathic Edu- cation” since 1993.

FiBL The “Research Institute for Organic Agriculture” has expertise in holistic animal health, animal ethology and organic animal breeding. Along with practical research, it places a high priority to knowledge transfer into agricultural practice through advisory work, training courses and expert reports through many means of dissemination, including magazines, technical leaflets, reference books, video and internet.

FOH Founded in 1844, the “Faculty of Homeopathy” provides internationally recognised training pathways in homeopathy for vets, doctors, dentists, podiatrists and other statutorily regulated healthcare professionals. Training courses are provided by our accredited teaching centres in the UK and overseas. After training and examinations the title “VetMFHom” can be acquired.

HRI The Homeopathy Research Institute is an international charity created to address the need for high quality scientific research in homeopathy.

IAVH The “International Association for Veterinary Homeopathy” performs and sup- ports clinical research, publications and knowledge exchanges in conferences and congresses and provides education (certifications) and further training for vets on homeopathy. It organises a world congress for veterinary homeopathy every two years (CH).

Louis Bolk I n- Independent international knowledge institute to advance sustainable agriculture, stitute nutrition and health.

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4.2.3 Initiatives aiming for reduction of the use of antibiotics Table 8 presents initiatives that aim for a reduction in the consumption of antibiotics in order to decrease antimicrobial resistance. They were found by scientific publications, conference activity or internet research.

Table 8: Initiatives on reduction of the use of antibiotics

REPLACE The European funded project “Replacing Antibiotics in Animal feed” aiming to find plants and their extracts and other natural alternatives to replace antimicrobials in animal feed.

EPRUMA The European Platform for the Responsible Use of Medicines in Animals is a mul- ti-stakeholder platform collecting the best practices with animal health and public health and developing broad principles of responsible use at EU Level.

RUMA The Responsible Use of Medicines in Agriculture Alliance involving organizations on all stages of “farm-to-fork” production to promote an approach to best practise in use of medicines.

ESVAC European Surveillance on Veterinary Antimicrobial Consumption with annual report on consumption.

DART German Antimicrobial Resistance Strategy for human and animal medicine elaborated by the ministry for health and the ministry for nutrition, agriculture and con- sumer protection.

EARS -Net The European Antimicrobial Resistance Surveillance Network is a European wide network of national surveillance systems, providing European reference data on antimicrobial resistance for public health purposes.

AURES Austrian report on antimicrobial resistance in humans and animals.

NAP -AMR National Austrian action plan on antimicrobial resistance in human and animal health.

DANMAP National Danish Survey on the development of antibiotic resistance in livestock, food and human population. It was the base for the introduction of VETSTAT database for antibiotic consumption on livestock farms and the “Yellow Card Initia- tive”. RUMEN UP RUMEN UP project (universities, technology centres and private companies) with the aim of developing new plants or plant extracts as dietary supplements for ru- minants to replace chemical additives and growth-promoting antibiotics. Yellow Card The “Yellow Card Initiative” on Antibiotics was established by the Danish Veteri- nary and Food Administration and targets the highest consumers of antibiotics in the pig production to reach a reduction of antibiotic consumption.

4.2.4 Co-operations between the institutions Four of the 12 responders (33.3%) work together in the same discipline with universities, and two (16.7%) in other types of disciplines (Q4). Eleven research bodies (91.6%) collaborated with other research centres that were not universities or higher education centres (83.3% of them in the same discipline and 8.3% in other disciplines). None of the research respondents collaborated with higher education centres (fig. 12).

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Collaboration between institutions

Other research centres 83.3% 8.33% 8.33%

Higher education centres 100%

Universities 33.3% 16.7% 50.0%

0% 20% 40% 60% 80% 100%

Same Discipline Other Disciplines No answer

Figure 12: Institutions, which collaborated with respondents

Most of the research was predominantly performed with other national or European centres (Q5; fig.13).

Location of research centres

8.3% 16.7% Other departments in my 16.7% organisation Other national centres

Other European centres

50.0% Research centres outside 83.3% Europe Other

Figure 13: Locations, where collaborating research centres were located

The most usual way to connect with other research partners for research on homeopathy was through associations or membership bodies, direct contact or on conferences on the topic homeopathy and alternative medicine (Q6; fig.14).

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Networking with research partners

7 8 5 4 1 2 No contact at Research Conferences Direct contact Asssociations Webpages of all gate, LinkedIn on the topic e.g. after or other institutes or other published membership with contact social media journal bodies information for scientists papers

Figure 14: Chosen way of networking with research partners

The personal evaluation of the research network on homeopathy ranged from poor to excellent. 75.0% of the respondents considered the research network as insufficient or poor and only 8.33% as excellent. The option “good” was not given by any respondent (Q7; fig.15).

Are you satisfied with the existing research network on homeopathy?

Exellent 8% 17% Sufficient Insufficient 58% 17% Poor

Figure 15: Satisfaction with existing research network

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4.2.5 Need for research in future

If there is a possible need for future research work in homeopathy was answered positively by nine of the 12 respondents (75.0%) (Q12; fig.16).

Do you see a need in research on homeopathy in future?

25%

75% Yes No

Figure 16: Need for research on homeopathy

The need in research work was further defined in open answers and these were:

• Basic research, e.g. in (double-blinded) case studies, • Terms of high quality study protocols, • Efficacy of homeopathy in animal health on a broader basis, • All fields and facets of homeopathic medicine – especially in individualised treatment, preventive health management, livestock farming and humans to reduce the use of antibiotics and to provide new, safe, effective approaches to effectiveness gap conditions.

Only three respondents (25.0%) saw no need of research work in homeopathy.

4.2.6 Constraints in research work with alternative remedies Respondents were asked to rank a number of causes of constraints from no constraint to very high constraints (Q11; table 9). The most important constraint was lack of support by funding bodies (rated as "high" or "very high" by 91.7%), followed by attitudes of research colleagues/superiors (41.7%) and general attitudes of practising veterinarians (41.6%). No constraints were seen in the quality of remedies (58.3%) and the availability of remedies (50.0%).

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Table 9: Constraints for the research on homeopathy

No Low Average High Very High constraint constraint constraint constraint constraint Public prejudices 25.0% 41.7% 16.7% 8,3% 8.3% Attitudes of research colleagues / 16.7% 8.3% 33.3% 25.0% 16.7% superiors Non existing network 8.3% 25.0% 33.3% 33.3% 0% Availability of remedies 50.0% 41.7% 0% 8.3% 0% (legally/market) Quality of the remedies 58.3% 16.7% 8.3% 16.7% 0% No/insufficient support by funding 0% 0% 8.3% 41.7% 50.0% bodies General attitude of practising 0% 25.0% 33.3% 33.3% 8.3% veterinarians General attitude of farmers and 8.3% 66.7% 25.0% 0% 0% advisors Demand and attitudes of consumers/ 25.0% 50.0% 16.7% 8.3% 0% retailers

Additional comments revealed that also the poor quality of existing studies is seen as a big constraint. Offers by homeopathic research bodies or institutes to present their results or facultative lectures, even when free of charge, are not used or appreciated at veterinary universities, although students show a huge interest in the topic. Requests for doing doctoral theses on homeopathy or phytotherapy could not be answered positively, because at the universities no supervisor could be found or was willing to supervise the student.

4.2.7 Conclusions No comprehensive conclusion can be drawn for the research situation on the European level, because of the small amount of received answers. However, the answers from different institutions indicated that only few institutes and persons are involved in active research on veterinary homeopathy and research network was regarded as poor or insufficient by three-quarter of the respondents. Also three-quarters of them saw a need for research on homeopathy, especially in terms of high quality studies. The main constraints were seen due to the lack of funding and the reluctant attitude of research colleagues/superiors or practising veterinarians towards homeopathy.

5 Acknowledgement We wish to thank various people for their contribution to this project: Diana Keller, for being a huge support on the tables and figures and Christina Werner for a lot of helpful comments. Special thanks should also be given to the European project partners: Lena-Mari Tamminen, Dr. Isabel Blanco- Penedo and César Fernandez Gonzalez for extensive discussions on all unclear questions concerning the report; Prof. Ulf Emanuelson for reviewing the report and his valuable and very helpful comments, especially to keep the report short and precise. We would also like to extend the thanks to the manufacturing companies of homeopathic remedies, which provided information on their quality assurance practices, quality tests etc. and answered a lot of additional questions.

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Tiefenthaler, D. 1990. Der klinische und bakteriologische Euterbefund von homöopathisch und allo- pathisch therapierten, an akuten Mastitiden erkrankten Rindern. Doctoral Thesis, Wien. Tumir, H., J. Bošnir, I. Vedrina-Dragojevi ć, Z. Dragun, S. Tomi ć, and D. Puntari ć. 2010. Preliminary investigation of metal and metalloid contamination of homeopathic products marketed in Croatia. Homeopathy 99(3):183–188. http://dx.doi.org/10.1016/j.homp.2010.05.001. U.S. Government. 2000. CFR — Code of Federal Regulations. Accessed Oct 24, 2014. http://www.ecfr.gov/cgi-bin/text-idx?rgn=div5&node=7:3.1.1.9.32. Ullman, D. 2010. Homeopathic Medicine: Europe's #1 Alternative for Doctors. Accessed Oct 23, 2014. http://www.huffingtonpost.com/dana-ullman/homeopathic-medicine-euro_b_402490.html. van Sluijs, F. J. 2005. Can homeopathy withstand scientific testing? Proceedings of DVG-Forum 2005, 2005. http://www.vetscite.org/publish/articles/000051/index.html. Varshney, J. P., and R. Naresh. 2005. Comparative efficacy of homeopathic and allopathic systems of medicine in the management of clinical mastitis of Indian dairy cows. Homeopathy(94):81–85. Velkers, F. C., A. t. Loo, F. Madin, and J. van Eck. 2005. Isopathic and pluralist homeopathic treatment of commercial broilers with experimentally induced colibacillosis. Research in Veterinary Science 78(1):77–83. http://dx.doi.org/10.1016/j.rvsc.2004.06.005. Verdier, K. de, P. Ohagen, and S. Alenius. 2003. No effect of a homeopathic preparation on neonatal calf diarrhoea in a randomised double-blind, placebo-controlled clinical trial. Acta Vet Scand 44(1-2):97–101. VetCR. Veterinary Clinical Research-Database in Homeopathy. Accessed Oct 25, 2014. http://www.carstens-stiftung.de/clinresvet/suche.php. Veterinary Medicines Directorate. Veterinary Medicines Regulations 2013 SI 2033 (VMR) and Veter- inary Medicines Guidance Notes (VMGN). Vetion:oekovet.de. Ökovet bei Vetion. Accessed Oct 25, 2014. http://www.vetion.de/oekovet/publikationen/indexpub.htm. Vockeroth, W. G. 1999. Veterinary homeopathy: an overview. Can Vet J 40(8):592–594. Vohla, A. 1991. Zur vorbeugenden Anwendung von Sabina in unterschiedlichen Potenzen beim- hochtragenden Rind zur Reduktion puerperaler Störungen sowie Erkrankungen der Kälber. Hannover, Tierärztliche Hochsch., Diss., 1991. Wagenaar, J.-P., P. Klocke, G. Butler, G. Smolders, J. H. Nielsen, A. Canever, and C. Leifert. 2011. Effect of production system, alternative treatments and calf rearing system on udder health in organic dairy cows. NJAS - Wageningen Journal of Life Sciences 58(3–4):157–162. http://dx.doi.org/10.1016/j.njas.2011.06.001. Walkenhorst, M. 2006. Vergleich von homöopathischer und antibiotischer Laktationstherapie zur Behandlung von Mastitiden des Rindes. Dissertation, Zürich. Werner, C. 2006. Klinische Kontrollstudie zum Vergleich des homöopathischen und chemothera- peutischen Behandlungsverfahrens bei der Therapie der akuten katarrhalischen Mastitis des Rindes. Dissertation, Leipzig. Werner, C., A. Sobiraj, and A. Sundrum. 2010. Efficacy of homeopathic and antibiotic treatment strategies in cases of mild and moderate bovine clinical mastitis. Journal of Dairy Research, 2010:460–467. Weymayr, C. 2013. Scientabilität – ein Konzept zum Umgang der EbM mit homöopathischen Arz- neimitteln. Zeitschrift für Evidenz, Fortbildung und Qualität im Gesundheitswesen 107(9- 10):606–610. http://dx.doi.org/10.1016/j.zefq.2013.10.022. WHO. 2009. Safety issues in the preparation of homeopathic medicines. World Health Organization, [Geneva]. Williamson, J. H., and S. J. Lacy-Hulbert. 2014. Lack of efficacy of homeopathic therapy against post-calving clinical mastitis in dairy herds in the Waikato region of New Zealand. N Z Vet J 62(1):8–14. http://dx.doi.org/10.1080/00480169.2013.796435. Wirth, F. 1990. Metaphylaxe puerperaler Erkrankungen beim Rind, insbesondere Retentio secundi- narum und Endometritis, durch Anwendung von Pulsatilla miniplex. Wolter, H. 1986. Homöopathie für Tierärzte. 3. Auflage. Schlütersche Verlag, Hannover.

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7 Glossary Allopathy :(from the Greek: “állos” resp. "other or different", “pathos” resp."suffering") is a term coined in the 19th century by Samuel Hahnemann, the founder of homeopathy, as a synonym for mainstream medicine and is nowadays used to describe conventional chemical-synthesized medicine or non-homeopathic treatment.

Evidence based medicine: emphasizes the use of evidence from well designed and conducted research in medicine decision-making. The term was originally used to describe an approach to teaching the practice of medicine and improving decisions by individual physicians. In 1972, Archie Cochrane published “Effectiveness and Efficiency”, which described the lack of controlled trials supporting many practices that had previously been assumed to be effective. The term "evidence- based medicine", as it is currently used, has two main tributaries. Chronologically, the first is the insistence on explicit evaluation of evidence of effectiveness when issuing clinical practice guidelines and other population-level policies. The second is the introduction of epidemiological methods into medical education and individual patient-level decision-making.

Growth promoter: Substances added to a nutritionally balanced diet which provoke response towards the exploitation of maximum genetic potential of the host, in terms of growth as well as improvement in feed conversion efficiency. The term "antibiotic growth promoter" is used to describe any medicine that destroys or inhibits bacteria and is administered at a low, subtherapeutic dose (FAO). They are used to “help growing animals digest their food more efficiently, get maximum benefit from it and allow them to develop into strong and healthy individuals” (NOAH, 2001), helping animals to achieve their full genetic potential. There are different types of growth promoters like antibiotics, probiotics, prebiotics, exogenous enzymes, antioxidants, coccidiostatics and herbs. EU- wide ban on the use of antibiotics as growth promoters in animal feed enters into effect in 2006.

Homeopathy: is a system of alternative medicine created in 1796 by Samuel Hahnemann, based on his doctrine of “ like cures like ”, according to which a substance that causes the symptoms of a disease in healthy individuals will cure similar symptoms in sick individuals (“Simile-Rule”). The remedies are used in a diluted form according to the potentiation procedure described in the homeopathic pharmacopoeia. Ingredients for homeopathy can be of herbal, mineral or animal origin.

a. Classical homeopathy or individualized homeopathy:

Every individual and illness is unique and so is the chosen remedy. Holistic approach in respect to body, soul and spirit. It covers inter alia 1. causa (any influences that caused the disease), 2.modalities (timely, physically, physiological or psychological circumstances under which the symptoms increase or decrease), 3. (extraordinary) behaviour, 4. constitution , 5. general symptoms , 6. organ symptoms, 7. frequency of symptoms, 8. miasma (tendency or disposition for infection).

b. Clinical homeopathy or Organotrophic homeopathy:

Remedy will be chosen because of the symptoms of single organs.

c. Complex homeopathy or Combined-remedies-homeopathy:

Foregoes the holistic approach – different ingredients for the disease and its symptoms will be combined. Often used for livestock, because of the lack of information about modalities/symptoms… of every single animal.

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Homeopathic dilution: also known as potency of a homeopathic remedy and produced by a process known as “potentization” or "dynamization". The potency defines to which extent the original substance or mother tincture is diluted with alcohol or distilled water and then vigorously shaken in a process called "succussion". Two groups of potencies are used in homeopathic remedies: “D” for decimal, means a dilution by a factor of 10 and “C” for centesimal for diluting a substance by a factor of 100 at each stage. Hahnemann advocated 30C dilutions for most purposes (Hahnemann S (1921), The Organon of the Healing Art (6th ed.), aphorism 128). In his time it was reasonable to assume that remedies could be diluted indefinitely, as the concept of the atom or molecule as the smallest possible unit of a chemical substance was just beginning to be recognized. We now know that the greatest dilution that is reasonably likely to contain one molecule of the original substance is C12, if starting from 1 mole of original substance according to the rules of the Avogadro constant.

Isopathy: (iso - all the same, pathy – treatment/exposure) was introduced by Dr. Lux in 1823 who along with Hering taught that the toxins were capable of a cure. It is the term that describes using the individual's own discharges (urine), bodily fluids (mucus), or disease matter and potentize this substance and take this in the 'minimal dose' as prescribed by Homeopathic Principle. Some people use it as a shortcut to repertorizing. You can see the similarity between the isopathic approach to healing and Vaccinations, which also introduce an allergen or diseased which causes a physical response to a foreign body and boosts the immune system to fight this type of invader in the future.

Metaphylaxis: The timely mass medication of a group of animals to eliminate or minimize an expected outbreak of disease, if single animals are already infected or the group is expected to be at high risk for an infection (e.g. extremely unfavorable environmental conditions, long transport together with animals of different origin, stressful conditions).

Nosodes: The nosodes, which are studied as miasmic conditions come from diseased matter and given in the very minimal dose, mainly in ultra-high potency. They are used in general for protective treatment of a group of animals. The nosodes used in homeopathy may be considered a type of isopathy. The difference between nosode and isopathy is that the nosode remedy does not come from the individual to whom it is given. In this way, it conforms to the 'similar' principle. Thus, it is not 'exactly' from the individual's own tissue or cells, but comes from someone who had a similar illness.

Placebo: is a remedy or medical treatment, that imitates another remedy, but without any active ingredients compared with the tested remedy. Sometimes animals given a placebo treatment will have as actual improvement in a medical condition, a phenomenon commonly called the placebo effect. The explanation for this could be conditioning of the animals, methods of administration may be important (unspecific immune responses) as well as the owner, that is willing to invest time and efforts to observe and treat his animals with more attention.

Prophylaxis: Preventive use of remedies or vaccines without an extraordinary high risk to get infected, e.g. after surgery, dry-cow-treatment or to eliminate or minimize the possible infection.

RCT – Randomized Controlled Trials: is a specific type of scientific experiment and the gold standard for a clinical trial. RCTs are often used to test the efficacy or effectiveness of various types of medical intervention within a patient population. Randomization means that study subjects before the intervention to be studied begins are randomly allocated to receive one or other of the alternative treatments. After randomization, the two (or more) groups of subjects are followed in exactly the same way, except for the different treatments. The most important purpose of proper randomization

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FP7 - 311824 IMPRO Deliverable D 9.1 is to minimize allocation bias and balancing known and unknown prognostic factors in the assign- ment of treatments. Additionally control groups are included in Randomized-Controlled-Trials to minimize the effects of variables other than the single independent variable. This increases the reliabil- ity of the results, often through a comparison between control measurements and the other measurements. Control-Groups like a group treated with a placebo, a conventional drug or without a treatment are performed parallel to the experimental group (e.g. treated with a homeopathic drug).