Development and feasibility assessment of an integrated medical care rehabilitation (IMCR) program for patients with continuing health complaints after amalgam removal

A feasibility pilot trial

Frauke Musial

Nasjonalt forskningssenter innen komplementær og alternativ medisin – NAFKAM

Institutt for samfunnsmedisin, Det helsevitenskapelige fakultet,

UIT Norges arktiske universitet

E-mail: nafkam@helesefak.uit.no Web: www.nafkam.no Tlf: 47 77 64 66 50

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Tittel: Development and feasibility assessment of an integrated medical care rehabilitation (IMCR) program for patients with continuing health complaints after amalgam removal

Undertittel: A feasibility pilot trial Oppdragsgiver: Helsedirektoratet

Prosjektperiode: 1. Juni 2012 to 31. October 2016

Prosjektleder: Frauke Musial

Forfatter: Frauke Musial

Professor innen helsetjenesteforskning - alternativ behandling Forskningsleder NAFKAM / Head of Research NAFKAM National Research Center in Complementary and Alternative Medicine, NAFKAM Department of Community Medicine Faculty of Health Science UiT, The Arctic University of Norway 9037 Tromsø Dato: 31. October 2016

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Contents Abstract ................................................................................................................................................... 6

Background: An integrated medical care rehabilitation (IMCR) program for patients with continuing health complaints after amalgam removal ............................................................................................. 7

The dental amalgam issue and attributed health complaints............................................................. 7

The development of the illness coping program (ICP), a group based intervention .......................... 8

The individualized treatment component ........................................................................................... 8

User participation ................................................................................................................................ 9

The “Integrated Medical Care Rehabilitation” program ................................................................... 10

The challenges of the IMCR program ................................................................................................ 11

Feasibility assessment of the IMCR program .................................................................................... 12

Aims and objectives ........................................................................................................................... 12

Methods ................................................................................................................................................ 13

Participants and settings ................................................................................................................... 13

Interventions ..................................................................................................................................... 13

The general design of the treatment program .............................................................................. 13

The illness coping program (ICP) ................................................................................................... 15

The iCAM (individualized CAM therapies) ..................................................................................... 16

Organization of the IMCR program in the Oslo area ......................................................................... 16

Outcome measures ........................................................................................................................... 17

Study outcomes ............................................................................................................................. 17

Feasibility outcomes ...................................................................................................................... 18

Statistics ............................................................................................................................................ 19

Ethics ................................................................................................................................................. 19

Results ................................................................................................................................................... 20

Recruitment and enrollment ............................................................................................................. 20

Sociodemographics ........................................................................................................................... 21

Results, related to the intervention .................................................................................................. 22

Expectation .................................................................................................................................... 22

Symptom-pattern .......................................................................................................................... 22

Quality of life ................................................................................................................................. 23

Mental health ................................................................................................................................ 24

Feasibility outcomes .......................................................................................................................... 25

Participants satisfaction with the rehabilitation program ............................................................ 25

Participants experience with the intervention .............................................................................. 26

Acceptability of conditions of randomization ............................................................................... 26

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Discussion .............................................................................................................................................. 27

Feasibility of the IMCR program ........................................................................................................ 27

Outcome measures of the IMCR program ........................................................................................ 28

Conclusion ............................................................................................................................................. 29

Recommendation .................................................................................................................................. 29

Final remarks ......................................................................................................................................... 30

References ............................................................................................................................................. 32

List of abbreviations .............................................................................................................................. 34

List of tables .......................................................................................................................................... 35

List of figures ......................................................................................................................................... 36

Note of thanks ....................................................................................................................................... 37

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Abstract

This report presents the results of a feasibility trial, conducted from 2012 to 2016, investigating a newly developed intervention program for patients with amalgam attributed health complaints, whose complaints continued after amalgam removal. The program consisted of a life style oriented group program, and an individualized program, where the study participants could choose between six different types of therapies (“kinesiology”, “reflexology”, “homeopathy”, “ear acupuncture & acupuncture”, “healing”, and “physiotherapy”) by means of vouchers. These therapies were derived from a survey among the target group and were selected according to the “use”-“safety”-“benefit” principle. Special emphasis was placed on patient participation and patient empowerment in this trial. The main therapists, who were leading the groups in the group program, were trained in how to use the manual developed for this program in a two-week training session. The education of the practitioners focused particularly on the development of a non-directive, accepting, non-pedagogic approach. The main goal of the group program was to support patients in making experiences, regain competence and control, feel confident with their own decisions, and rely on themselves as experts for their situation.

The trial was conducted in three different study locations in the greater Oslo area. A total of n=18 participants, mostly women, completed the study. The administrative and organizational effort was considerable, however, all locations conducted the study successfully. Feasibility outcomes indicate, that the IMCR trial is feasible, and that the study participants were satisfied with the study and experienced a transfer value of the program for their everyday lives. The study outcomes themselves, mainly symptom load and quality of live, have to be interpreted with care, as this was not an effect study. Evaluated with due care, the study outcomes indicate a reduction of symptom load and an increase in quality of live.

In conclusion the treatment program was stable over different study locations and was conducted successfully. The program had a high acceptance among the target group and the results indicate that a pilot study aiming at the effect of the intervention can be recommended. Such a study should include more patients groups, with similar symptom patterns and with a similar challenge, that no cure is to date available.

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Background: An integrated medical care rehabilitation (IMCR) program for patients with continuing health complaints after amalgam removal

The dental amalgam issue and attributed health complaints

As many as 5% to 8% of the participants of a representative survey of the adult Norwegian population (n=2000 participants) believed to suffer from amalgam induced health problems. In 8% of the participants, who had removed their amalgam fillings (out of 43% in total) the motivation for removal was related to amalgam attributed health concerns (1). Thus, amalgam attributed health complaints have been an issue in Norway for many decades even though amalgam is generally considered to be a safe dental material. Nonetheless, due to a general concern about environmental effects from mercury, amalgam was banned in Norway in 2008. To date it is still controversial, whether mercury exposure from dental amalgam is sufficient to lead to chronic health issues.

According to the literature, fatigue/exhaustion, dizziness, mental symptoms (concentration and memory disturbances, anxiety, irritability, restlessness, depression), pain (muscle, joint, neck and shoulder, teeth/jaws/facial pain; headache), functional gastrointestinal symptoms (e.g. constipation, diarrhoea, bloating), mouth blisters, metallic taste, and susceptibility to infections (2-11) are the most common symptoms attributed to dental amalgam. These findings were confirmed in a survey, conducted in connection with the study presented here (see appendix I: Kristoffersen et al. Manuscript under review at The Open Dentistry Journal).

In 1990 a dental patient association (NDPA/FTH) was founded in Norway, whose aims among others, included the development of a treatment and rehabilitation program for patients suffering from harmful effects from dental treatment (12, 13). As a consequence, the Norwegian Ministry of Health and Care Services initiated a collaborative treatment project for patients with suspected adverse effects from dental materials ("Samarbeidsprosjekt mellom tannhelsetjenesten og helsetjenesten om utprøvende behandling ved mistanke om bivirkninger av odontologiske biomaterialer") which was executed through the Norwegian Directorate of Health. The aim of the project was to support patients with health complaints attributed to amalgam, and to improve their health and quality of life.

Part of the collaborative treatment project was the design of a rehabilitation program for patients, who have had their amalgam fillings removed but still experienced health complaints. The report presented here describes the results of this treatment project, the “integrated medical care rehabilitation” (IMCR) program for patients with continuing health complaints after amalgam removal.

Setting up such a treatment program for patients who have had their amalgam fillings removed, but still experience health complaints was a particular challenge for several reasons, mainly: i) there is to date no good pathophysiological explanation available for amalgam-related health complaints, and even though many patients experience symptom relief after amalgam removal, a substantial number of patients do not. ii) There is no causative treatment and as such no cure available, in particular for those patients who continue to experience symptoms after amalgam removal.

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The development of the illness coping program (ICP), a group based intervention

The most common complaints attributed to amalgam fillings, such as exhaustion and fatigue, pain from muscles and joints, gastrointestinal symptoms, taste disturbances and symptoms from ear/nose/throat (14) occur also in other chronic, debilitating diseases, such as chronic fatigue syndrome and fibromyalgia. Patients suffering from fibromyalgia typically show symptoms of widespread musculoskeletal pain, fatigue, insomnia, and impairment of physical and psychological quality of life (15, 16).

Furthermore, stress related or depressive symptoms are also common in these syndromes (17-20) and they seem to be relevant for the course of the disease (21, 22). Due to frequent unsatisfying results of conventional treatment, the use of complementary and integrative approaches such as Mind-Body medicine, supplements, acupuncture, massage and various nutritional therapies among fibromyalgia patients is common. Moreover, the scientific evidence for these therapies has increased over the last decade. Consequently, evidence based guidelines for the treatment of fibromyalgia recommend multimodal, multidisciplinary therapeutic approaches involving medication, exercise, relaxation, stress management, patient education, and behavioral therapies (15, 16, 23).

Due to the similarities in symptom patterns, a treatment program was developed in analogy for patients with amalgam attributed health complaints. The intervention consisted of a structured group program based on Mind-Body medicine approaches (Illness Coping Program, ICP). The ICP consisted of 12 modules, each covering a day (24) (see appendix II: von Scheidt et al. 2015 (24)

The individualized treatment component

Many of the patients with amalgam attributed health complaints report good experience with therapies from the spectrum of complementary and alternative medicine (CAM) (25) (see appendix III: Kristoffersen et al. 2016; BMC Complementary and Alternative Medicine). Since a major principle and cornerstone of this trial was patient participation, the results of the survey among the target group, namely patients, who had their amalgam fillings removed yet still experienced health complaints they related to former amalgam fillings, were utilized in order to integrate patient preferences into the intervention. Thus, a choice of therapies out of the CAM spectrum, from which patients were free to choose, was operationalized as part of the rehabilitation program. An individualized treatment part, where the participants received 12 vouchers to be used during the 12 weeks of the ICP and which they could use to choose from a selection of CAM therapies (iCAM) was developed. This procedure aimed at taking patient preferences on a principle basis (survey among the target group) and on an individual basis (self selection of interventions) into account.

The selection process of the therapies out of the results of the survey followed a predetermined principle, aiming to evaluate the CAM therapies according to the “use-safety-benefit” (USB) principle (see appendix IV: Musial et al. Manuscript under review at BMC Complementary and Alternative Medicine). In this way, it was intended to safeguard patient safety in a situation, where therapies are in widespread use, even though there is little scientifically sound information available.

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User participation

The particular focus of the IMCR trial on user participation was grounded in Norwegian health strategic documents, the “Coordination reform”(26) which emphasizes patient participation. The principal understanding that formed the basis for the coordination reform is that ".... Patients, who participate in the planning and monitoring of their health care, are better able to mobilize their own resources. This can improve the prospects for good results" (27). Moreover, it says “The issue of patient participation, whether it comes to building direct decision-making authority, or other forms of participation or influence, manifests itself on two levels:

• participation by the patients themselves in their own prevention, treatment, rehabilitation and care programs

• participation by the patient and user organizations in processes at the system level. That is, in the development and design of the system itself and the overarching decisions, which provides the framework”. (Translation from the Samhandlingsreform, Kapittel 5: Pasientrolle og pasientforløp; Side 47) (27).

(original: «…Spørsmålet om pasientmedvirkning, enten dette gjelder å bygge direkte beslutningskompetanse, eller andre former for medvirkning eller innflytelse gjør seg gjeldende på to nivåer:

• deltakelse fra pasienten i eget forebyggings-, behandlings-, rehabiliterings- og omsorgsopplegg

• deltakelse fra pasient- og bruker- organisasjoner i prosesser på systemnivå. Det vil si i utvikling og utforminger av systemer og overordnede beslutninger, som gir rammene

…..» (Samhandlingsreform, Kapittel 5: Pasientrolle og pasientforløp; Side 47, (27).

User participation was a cornerstone of this project and the design of the intervention itself, as well as regarding the processes developing the program. User participation was operationalized on three levels:

• System • Population • Patient/participant

System level: NDPA/FTH played an active role in i) advocating the collaborative treatment project ("Samarbeidsprosjekt mellom tannhelsetjenesten og helsetjenesten om utprøvende behandling ved mistanke om bivirkninger av odontologiske biomaterialer") and was ii) involved and consulted from the very beginning of and throughout the project.

Population level: The individualized treatment part of the IMCR program, the iCAM,was directly developed out of a survey conducted among the target group. The survey was developed and conducted in cooperation with NDPA/FTH.

Patient/participant level: Within the iCAM, patients were given a budget of vouchers they could use in order to construct their own treatment program. The limits set were the choice of

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therapies available as part of the iCAM, and the individual counselling by the program doctor. This counselling focused on safety concerns related to the health condition of the individual, as was thus focused on patient safety. Therefore, the program doctors should give advice related to individual safety concerns, which therapies out of the choice not to use. However, the program doctors were instructed not to give any advice on what therapies to choose with regard to the symptom pattern. Within the ICP part of the program, a non-directive, accepting, non-pedagogic approach was central, supporting the participants to make their own choices and experiences, and thus regain a sense of control (see further description below).

The “Integrated Medical Care Rehabilitation” program

Special emphasis was placed on patient participation and patient empowerment in this trial and intervention (28). The main therapists, who were leading the ICP groups, were trained in how to use the ICP manual (see appendix II: von Scheidt et al., 2015 (24) in a two-week training session. The education of the practitioners focused particularly on the development of a non-directive, accepting, non-pedagogic approach. The main goal of the ICP was to support patients in making experiences, regain competence and control, feel confident with their own decisions, and rely on themselves as experts for their situation. Therapists were educated to avoid instructions, but support patients in finding and developing their own solutions. The non-directive approach was extended to the individualized part of the program in that patients were free to use their “budget” of 12 therapy vouchers for the group of therapies available within the program.

The strategy to combine the ICP with an individualized, symptom oriented treatment approach was expected to have the advantage, that the ICP should be “relieved” from the high symptom load of the participants. The aim of the ICP was to support patients to find positive and supportive things in their lives in a situation, where many experience major restraints related to their symptoms. It was expected, that the possibility to address the individual symptom pattern through the iCAM part of the program, would make it easier to focus away from symptoms and illness and towards the supportive things in life within the ICP.

Moreover, the IMCR approach allowed for a sensible use of resources as the ICP part of the program was developed specifically for this trial, but was for the most part generic, meaning, that the ICP can principally and with minor adjustments, be used for all groups of chronically ill patients. At the same time, the integration of the iCAM part allows for specific adjustments to different groups of patients with different symptom patterns and is not restricted to CAM therapies. In situations, where there is scientific evidence for the effect of a specific intervention, the obvious recommendation would be to combine the ICP with the best practice individualized treatment approach. Nonetheless, in situations where there is no evidence based specific intervention available, the conduction of a survey among the target group and the construction of an individualized treatment package according to the USB approach was deemed feasible. The aim of the development of the ICP was to be able to offer an intervention, which could be delivered in the same quality in many different circumstances and under varying conditions. Thus, a high standardization of the ICP was required and a non-negotiable matter of quality assurance.

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Table 1 summarizes the framework of the IMCR program. Besides conducting a survey in order to select the iCAM therapies, user involvement was implemented within the ICP and, by using the voucher concept for the iCAM. It is principally possible, to use an individualized conventional medical approach within the IMCR framework. In that situation, user participation within the individualized part is most likely limited, however, such an individualized intervention should then be based on scientific evidence.

Table 1: Framework of the IMCR program

IMCR program

main target / focus resources symptoms

setting group individual

purpose generic symptom / disease specific

operationalization ICP iCAM

Scientific evidence, given yes no (principally possible, disease

dependent)

target/user group generated no yes

participant involvement yes yes, if use of vouchers

The challenges of the IMCR program

The particular challenge with the construction of the IMCR program was, that it could only in part be grounded in scientific evidence, as there is virtually no scientific evidence for a successful intervention for this particular patient group (patients who suffer from Amalgam attributed health complaints after they have had all fillings removed). Furthermore, the consequent operationalization of patient participation through the iCAM part of the program led inevitably to a situation, were patients preferences were not based on scientific evidence. Beyond that, the program in itself was very complex and involved many different groups of therapists and other personnel, in three different locations in the Oslo area. Thus, the planning of the intervention and the study design revealed that this was a complex, multimodal intervention, which involved many different professions. It was in part based on patient preferences with no experiences on how to operationalize the self-selection of therapies by the study participants. In addition, the fact that patients should have access to a center not too far from where they lived led to three, very different study locations in the greater Oslo area. Taken all this into account, it was decided, that the newly developed intervention in addition to the challenging study conditions made it impossible to conduct a clinical trial at this point in time.

The British medical council advocates in the case of newly developed, complex interventions, an iterative process, using so-called “feasibility studies” or “vanguard trials”. Their

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recommendations emphasize the iterative nature of the piloting approach of the processes of development, feasibility and piloting, evaluation and implementation (29). Therefore, it was decided to conduct a pilot study in order to evaluate whether the IMCR program was at all feasible.

Feasibility assessment of the IMCR program

The terms “pilot study”, “feasibility study”, and “feasibility pilot study” are often mixed and not separated clearly. Pilot studies are as a general rule very similar to the main study, and according to (30) a pilot study is a miniature version of the main study, which is supposed to test whether the components of the main study harmonize. Pilot studies can be performed when the concept of the main study is clear and the focus is on its processes (e.g. that recruitment, randomization, treatment, and possible follow-up run smoothly). Feasibility Studies are miniature trials, performed before a main study, and sometimes even before a pilot study is planned. They are used to estimate important parameters that are needed to design the main study such as the available patient population, the likelihood of patients agreeing to participate in the clinical trial (31), the likelihood of the patients to agree to randomization, conditions of agreement to randomization (waiting list, non-treatment control, other treatment conditions etc.), potential modifications to clinical trial design and eligibility criteria to enhance enrollment, compatibility of the clinical trial treatments and assessments with current patterns of care, site capabilities, research infrastructure, personnel, regulatory requirements and timelines, projected patient enrollment rates, the standard deviation of the outcome measure, which is needed to estimate sample size, follow-up rates adherence/compliance rates, etc.. Pilot studies are a useful tool in order to identify and avoid threats to the implementation of a larger trial and are highly recommended for complex interventions (29).

According to Arain et al (30) feasibility studies for randomized controlled trials may not themselves be randomized. Moreover, feasibility studies do not evaluate or statistically analyze the outcome of interest (30, 31). However, performing a feasibility trial as a first step can help to identify and avoid threats to the implementation of a larger trial. Delays in study startup and patient enrollment are the major contributors to cost overruns in clinical trials. A properly designed and executed feasibility study can provide a comprehensive assessment of a clinical trial’s specific challenges.

Aims and objectives

Thus, the primary objective of the trial presented here was to investigate the feasibility of the IMCR program for patients with amalgam attributed health complaints after amalgam removal. Focus was placed on the practicability of the newly developed intervention, which was strongly based in user participation. Thus, the main target of this feasibility pilot trial was placed on the acceptance of, and satisfaction with the intervention among the target group, the workability of the implementation routines and processes, the practicability of the outcome measures, and the expected enrollment rates and inclusion procedures. Quantitative as well as qualitative methodologies were utilized. The outcomes of the embedded clinical investigation will be part of this report, but are not the main focus of the study.

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Methods Participants and settings

Recruitment started January 2014, the interventional part of the study started in March 2014, the program lasted 3 month (12 group sessions, one day per week) until early June 2014, and there was a last group meeting three month after the 12th group session. Three different study locations were chosen, which were strategically placed over the greater Oslo area. The aim was to increase accessibility and reduce travel time for the study participants. Furthermore, with regard to the investigation of the feasibility of the treatment program, three study locations were chosen, which fulfilled basic requirements with regard to facilities, but had a very different organizational structure. Since the aim was, to investigate, whether the intervention was workable under very different organizational conditions, the study locations varied in size, organizational and administrative structure, and availability of alternative practitioners. Some centers had the vast majority of alternative practitioners fast employed, while others had to cooperate with self-employed alternative practitioners in order to provide the interventions necessary for the individualized treatment packages of the iCAM part of the intervention.

The inclusion criteria were: The research population should be permanent residents in Norway and be between 20 to 70 years of age, and they should be able to comply with the protocol. The study participants should have had all dental amalgam fillings removed (screening by study dentist) and they should still have health complaints which did not disappear after the removal of the dental amalgam fillings. These health complaints should have continued a minimum of 12 months since the removal of the last amalgam filling, and there should not be any biological/medical explanation for the health complaints. Moreover, the participants should be willing and motivated to take part in the IMCR program as it was described. Exclusion criteria were: ongoing cancers, severe cardiopulmonal, neurological, or psychiatric diseases or mental retardation (screening by study GP), life threatening diseases, dental conditions requiring treatment before entering the program (screening by the study dentist). Patients were recruited to participate in the study through invitations sent out to the members of NDPA/FTH, and through other sources, such as mouth-to-mouth advertising and one newspaper advertisement in the greater Oslo area.

Motivation to participate in a program focusing on lifestyle changes was checked by an extensive, semi standardized telephone interview prior to the inclusion of the participant into the enrollment procedures (see Figure 4, CONSORT flow chart). After the telephone interview, potential participants were screened by a study dentist according to a predefined checklist, and if they fulfilled the dental inclusion criteria, participants underwent a standardized screening by the study doctor.

Interventions

The general design of the treatment program As described above, the IMCR-program consisted of two core elements, a group program, ICP, focusing on life-style changes, and an individualized part, iCAM, where patients could choose

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CAM therapies, selected from the survey conducted. The ICP consisted of 12 sessions, which were held once per week for a whole day (For a detailed description of the ICP interventions see (see appendix II: (24). The end of the initial treatment phase (3 month) was followed by another 3 month period before the final meeting of the group. This temporal organization was assumed to be critical, since the participants should have a time period in which they could establish the intended behavioral changes and where they could identify challenges and threats to compliance. These potential problems could then be discussed in the last ICP group meeting. Figure 1 shows the design of the program for one group. Note that there were three groups with three different groups of therapists in three different centers in the Oslo area.

Figure 1: Structure of the IMCR-program, for one group.

Each day of the group meetings consisted of elements of information, nutrition, exercise, relaxation, and different topics on how to deal with psychosocial challenges. Figure 2 gives an overview over the 12 weeks.

Figure 2: Overview over the 12 group sessions

To illustrate the concept, a study participant would have the following time table on day 8:

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Table 2: Example of day 8 of the program

Modul 8 time activity 60 min Reflection over the last week 15 min break 60 min Self-help strategies 45 min Exercise (e.g. go for a walk out in nature, Yoga) 15 min break 60 min Nutrition (information, cooking, prepare a meal together etc.) 15 min break 90 min How to handle difficult feelings 45 min relaxation

The illness coping program (ICP) The group program, ICP, included elements of information, education, exercise, relaxation, and symptom oriented self-help strategies (see appendix II: (24). Special emphasis was placed on stress management and nutrition. The main goal was to enable the patients to take control over their situation and improve their ability to cope with their symptoms.

Development of the handbook for group leaders The handbook for the 12 group sessions was organized into 12 modules. In addition, the handbook contained general material which was in part information (e.g. on nutrition) and in part instructions for self-help practices, such as massage, as well as physical exercises, and relaxation exercises. Soundfiles for the relaxation exercises were given and are now available through a special website on the internet (see appendix II: (24). Each module was structured in the following way: 1) step by step instructions for the group leaders, 2) material needed for the day (powerpoint, paper & pencil etc.) 3) material to be given out to the participants. The handbook was developed in 2014.

Training of the group leaders The main therapists were trained in how to use the manual in a two-week training session. Therapists were educated to not give instructions, but support patients in finding and developing solutions they themselves felt comfortable with. Considerably more therapists than the three group leaders were trained, because it was deemed important to have a certain group size for the training of the group leaders, and it should be secured, that in case that a group leader would drop out during the running trial, it was possible to recruit among several others with the same training. In the course of the training, the participants first “played” the role of a patient group, led by an experienced group leader, supervisor and trainer. After that, the group returned to a meta level and discussed the module, their experiences with it, and anticipated problems while trying to conduct the session as a group leader themselves. The training took place in 2014. The two training sessions of one week each were placed about three month apart. It was expected that the future group leaders should use this time period

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to implement the contents of the program into their daily routines and in this way to experience for themselves, how easy or difficult this process was.

The training course conducted for the group leaders/main therapist is to be understood as an integral part of the ICP. The ICP should not be conducted by a person who did not receive special training in its application. Such a situation would be seen as a major threat to the quality of the delivery of the ICP.

The iCAM (individualized CAM therapies) As described above, many patients with amalgam attributed health complains use therapies out of the CAM spectrum. The results of the survey among the target group were utilized in order to develop the indicvidualized treatment part, the iCAM. A choice of therapies derived from the survey was operationalized as part of the rehabilitation program. The participants received 12 vouchers to be used during the 12 weeks of the ICP which they could use to freely choose from this selection of CAM therapies.

Selection of therapies for the (iCAM) The selection of the therapies was based on the results of the survey conducted in 2012. The survey included a list of 26 different therapies. A total of n=324 participants answered questions about the use of therapeutic interventions mostly from the spectrum of complementary and alternative medicine. The selection process followed a predetermined principle, aiming to evaluate the therapies according to the “use-safety-benefit” (USB) principle in order to ensure patient safety (see appendix IV: Musial et al. Manuscript under review at BMC Complementary and Alternative Medicine). The therapies, which came best out of the selection process were “supplements recommended by a therapist”, “special diet”, “herbs” , which were operationalized within the nutritional part of the program, and “kinesiology”, “reflexology”, “homeopathy”, “ear acupuncture & acupuncture”, “healing”, and “physiotherapy”. Vouchers were valid for the latter group of CAM therapies.

Safety assurance within the iCAM Patients received information taken from the NIFAB website as printouts about the available CAM therapies, which included a section on scientific evidence and potential risk (http://www.nifab.no/behandlingsformer). Moreover, all patients received counselling from a medical doctor at the beginning and the end of the program (patients had been checked for exclusion criteria before entering the trial). This counselling was restricted to safety issues, as the doctors should not recommend therapies for their effect, but should check for potential particular risks related to the individual patient and instruct them accordingly. The doctor who did the counselling was available for the participants throughout the trial, in case any adverse effect should occur.

Organization of the IMCR program in the Oslo area

The central organization, which means recruiting, contracting, administration etc. was located at NAFKAM in Tromsø. However, the complex organization of the enrollment procedures (see Figure 3), as well as the organization and administration of the three centers, made a second study office in Oslo necessary. Thus, the recruitment of the patients into the study and the prescreening procedures were administrated at NAFKAM. Patients included after telephone

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screening were then send to the Oslo study office for further screening by the study dentist and the study doctor (see also Figure 4: CONSORT statement).

Figure 3: Overview over the organizational structure of the IMCR trial

Outcome measures

Study outcomes

Expectations Expectations about the effect of the intervention are important to document, because they are likely to have an impact on the study results. Thus, it is advised to use them as a possible covariate in a statistical analysis. Expectations were measured at baseline (mean on a scale from 0=”not at all” to 10=absolutely right) with two simple questions: “I expect that my health issues will be better after treatment”, “I would recommend this treatment to my friends or family”.

Symptoms Several questionnaires related to symptoms were used: MYMOP, GBB-24, and Munich Amalgam Checklist. Only the MYMOP and the GBB were sufficiently answered. The GBB-24 asks to rate a number of symptoms from 0 to 4 how bothersome the symptom is, where 4 is the most bothersome situation. In the MYMOP (32, 33), patients define two symptoms themselves, which they experienced to be most bothersome. The severity of symptoms is then rated from 0 to 6. The next question asks about how much the situation had a bad impact on an activity, relevant for the patient. The fourth question asks about how much the situation had a bad impact on the patients’ well-being. Both scales are also rated from 0 to 6. With regard to the MYMOP it is important to keep in mind, that low values indicate a favorable situation for the patient.

Quality of life The quality of life measures included the SF-36 which is one of the most well established and elaborate instruments currently available, and the Cantril Ladder Scale, a very simple, three item questionnaire. The

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SF-36 provides a detailed health profile on the basis of eight health dimensions as well as sum scores for physical and mental health (34). It consists of 36 Items to be answered on a 5 point Likert scale. Higher scores indicate an increase in function.

The Cantril Ladder scale asks on a 10 scale “Ladder”, how life is perceived at the moment, 12 month ago, and how it will be in 12 month. “Please imagine a ladder with steps numbered from zero at the bottom to ten at the top. Suppose we say that the top of the ladder represents the best possible life for you and the bottom of the ladder represents the worst possible life for you. If the top step is 10 and the bottom step is 0, on which step of the ladder do you feel you personally stand at the present time?” Consequently, a higher score reflects higher life satisfaction (35).

Mental health With regard to mental health issues, two tests were chosen, which are in common use and deemed to be relevant for this group of patients, who often have a yearlong disease history. With regard to the data presented here, mean and variance measures were not considered to be informative. The questions of interest in this study was rather, do study participants suffer clinical deviations from the norm. Therefore, the study participants were classified according to the suggested cut off points.

The Whiteley index or test measures health anxieties and worries with 14 Item questionnaire using a 5-point Likert scale. It is sometimes also called the hypochondria index. Generally, the higher the Whiteley Index, the more health worries and anxieties people have. Persons without health anxiety generally have a score of 21 +/- 7 (14 to 28), while patients with hypochondria have score around 44 +/- 11 (32 to 55). The maximum possible score is 70, the minimum 14.

The Hospital Anxiety and Depression Scale (HADS) and is commonly used as a screening instrument to determine the levels of anxiety and depression in a person or patient (36, 37). The HADS is a fourteen item scale using a 4 point Likert scale. Seven of the items relate to anxiety and seven relate to depression. A sum score is calculated for each of the scales and values from 0-7 are considered normal, from 8-10 borderline abnormal, and from 11-21 clinically relevant.

Feasibility outcomes

Participants satisfaction with the program

One of the most important feasibility outcomes was patient satisfaction with the intervention. At post 1, which means directly after the intervention, and at post 2, 3 month later, the study participants were asked on scale from 0 (very dissatisfied) to 5 (very satisfied) about how satisfied they were with the intervention. Moreover, at post 2, which means at the very ending of the program, the participants were ask again on a visual analogue scale (VAS) ranging scale from 0 (not at all / ikke i de tele tatt) to 10 (totally agree / helt riktig), if they would recommend the program to their friends and family members. Furthermore, the participants were asked in the same manner, if they would recommend the program for other patients, and about their quality of life (“Has your quality of life changed throughout the program?”) on a VAS ranging scale from 0 (worse / verre) to 10 (better / bedre). Participants experience with the intervention In addition, four open questions about the experiences with the program were asked after completion of the final treatment session:

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1. How did you experience the IMCR program? (Norwegian: Hvordan opplevde du programmet?)

2. Have you taken some parts of the program into your daily living? If yes please describe these. (Norwegian: Dersom du har tatt med noe fra programmet med inn i hverdagen, beskriv hva dette er.)

3. Has your everyday life changed in any way after you started this program? If yes, please describe (Norwegian: Har livet ditt (hverdagen din) forandret seg på noen måte etter at du startet med programmet? I så fall hvordan?)

4. How did you experience your body and your symptoms during and after the program? (Norwegian: Hvordan opplevde du kroppen din og symptomene dine under og etter programmet?)

These questions were analyzed with qualitative methodology (systematic text condensation) and a manuscript about the results is currently under review in a scientific journal (see Appendix V: Alræk et al. Manuscript under review with Research in Complementary Medicine). The aim of this qualitative part was to explore, whether the intentions of the ICP were validly reflected in the participants daily practice after the intervention.

Acceptability of conditions of randomization Lack of adherence to a trial and participant compliance can impose a major threat to a clinical study, since they lead to high drop out rates. One of the major issues related to adherence is the acceptability of the control conditions. Therefore, one aim of the feasibility assessment was to investigate, which type of control condition was found acceptable by the study participants. We asked, whether the following conditions were acceptable / not acceptable: Waiting list control group, the group program alone, the individualized treatment package alone, no treatment, or standard medical care.

Statistics Since the study was planned as a feasibility study with the aim to investigate the practicability and acceptance of a newly developed intervention program, and to investigate the routines necessary for clinical pilot study, data are presented purely descriptive and are to be understood as such. Data are only presented, if at least 50% (> n=9) of the participants answered the questions.

Ethics The Regional Committee for Medical and Health Research Ethics (REK) assessed the study (REK reference 2012/2135) and decided that no ethic approval was needed because the project was not considered to be a medical and health related research project that complies with the Health Research Act. Therefore, the study was registered with The Norwegian Data Inspectorate (NSD) (NSD reference 34974). Written informed consent was obtained from the study participants. The trial was registered with ClinicalTrials.gov. (ClinicalTrials.gov Identifier: NCT02081664).

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Results Recruitment and enrollment

A total of n=25 of the potential participants screened qualified for the study and were included. Of these n=5 dropped out because of practical reasons. The main reason was that it was too complicated to reach one of the three study locations. After entering the program, n=2 participants dropped out. One participant was diagnosed with cancer, the other needed to travel for two hours to reach the study location and gave up (see Figure 4). Of the remaining n=18 participants, n=13 women (mean age 57.3 yrs) and n=5 men (mean age 40.4 yrs).

Figure 4: CONSORT flow chart of recruitment and study phases.

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Sociodemographics

Considerably more women than men participated in the study. The vast majority of the participants hold a university degree. Out of n=14 participants who were willing to answer detailed questions on their work situation it turned out that n=5 were working and n=9 were not working due to many different reasons (sick leave, disability pension, retirement, other).

Table 3. Basic characteristics of the participants. Due to the small sample size, data are collapsed over gender.

Sociodemografics (n) or mean + SD

Gender

Women 13

men 5

Age

women 57.31 (+8.23)

men 40.4 (+9,92)

Education (total sample)

Secondary School 3

High School 1

University, lower grade 6

University, higher grade grade 8

Civil status (n=17)

married 6

Living with a partner 2

Not married 6

divorced 3

Working (n=14)

Yes 5

No 9

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Results, related to the intervention

Expectation With scores on a scale from 0 to 10 of almost 8, the study participants had high expectations to the effect of the intervention.

Table 4: Expectations to the effect of the interventions of the study participants

Expectations (mean on a scale from 0=”not at all” to 10=absolutely right)

I expect that my health issues will be better after treatment (n=17)

7.79 (+1.8)

I would recommend this treatment to my friends or family (n=16)

7.8 (+1.8)

Symptom-pattern All symptom related scores went down from baseline to directly after the program, with a slight increase towards post 2. For the GBB-24, the difference from baseline post 1 corresponds to 28.32% reduction and 25.67% to post 2. At the same time, activity is less disturbed by symptoms at post1, and even less at post 2. The same trend is seen for the well being scale, where well being is improved at post 1 and even more so at post 2. The change in symptom load for MYMOP symptom 1 from baseline to post 1 is 35%, and from baseline to post 2 is 25.6%. The numbers for MYMOP symptom 2 are 21.2 % (post1) and 15.5 % (post 2). The difference in the score for the item MYMOP activity corresponds to 26% improvement from baseline to post 1, and 36,8% improvement from baseline to post 2. Well being improved with 22,85% and 28.57% respectively (it is important to keep in mind, that lower values indicate an improvement).

Table 5: Results of the symptom related questionnaires MYMOP and GBB-24.

Scale (n) Baseline

(mean + SD) Post 1

(mean + SD) Post 2

(mean + SD) GBB-24 sum score (n=14) 40.36 + 15.17 28.93 +19.93 30.00 +18.49

MYMOP symptom 1 (n=17) 4.00 + 1.28 2.59 +1.58 2.94 +1.35

MYMOP symptom 2 (n=16) 3.31 + 1.45 2.63 +1.50 2.75 +1.48

MYMOP activity (n=14) 3.93 + 1.49 2.93 +1.59 2.29 +1.27

MYMOP well being (n=16) 3.44 + 1.32 2.63 +1.54 2.56 +1.31

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Quality of life

The SF-36 showed increased scores from baseline to post 1 and post 2 on all subscales. Sometimes, the scores increased further between post 1 and post 2. An increased score indicates a better quality of life in this dimension. The Cantril ladder scale showed the same trend in that there was an increase of how satisfied the study participants are with their lives from baseline to post 1 and post 2. On a descriptive basis, the study participants exhibited an increase in Quality of life, which sustained from post 1 to post 2.

Table 6: Results of the quality of life related questionnaires SF 36 and Cantril Ladder Scale

Scale (n) Baseline

(mean + SD) Post 1

(mean + SD) Post 2

(mean + SD)

Cantril Ladder “right now” (n=16) 5.63 + 1.93 6.38 + 2.45 6.25 + 2.05

Cantril Ladder “12 month ago” (n=16) 5.94 + 1.69 5.19 + 1.68 4.87 + 2.0

Cantril Ladder “in 12 month” (n=16) 8.19 + 1.22 8.56 + 1.50 8.31 + 1.62

SF-36 Physical Functioning (n=13) 44.24 + 9.27 46.84 + 10.09 48.61 + 7.73

SF-36 Role Physical (n=15) 34.49 + 10.47 39.87 + 12.87 42.49 + 10.95

SF-36 Bodily Pain (n=17) 38.35 + 8.23 41.16 + 11.53 41.56 + 10.27

SF-36 General Health Perception (n=17) 39.64 + 13.37 43.96 + 12.84 44.66 + 13.62

SF-36 Vitality (n=15) 37.11 + 11.27 41.89 + 15.27 43.35 + 14.17

SF-36 Social Function (n=16) 34.01 + 14.66 40.15 + 15.75 41.17 + 14.62

SF-36 Role Emotional (n=15) 44.0 + 12,04 46.29 + 10.6 46.29 + 10.68

SF-36 Mental Health (n=16) 41.67 + 12.75 48.02 + 12.06 47.90 + 12.23

SF-36 Physical Component Score (n=10) 38.54 + 10.95 41.78 + 11.13 44.28 + 9.52

SF-36 Mental Component Score (n=10) 40.73 + 13.96 47.00 + 13.29 45.11 + 14.08

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Mental health

Figure 5 shows, that almost half of the patients answering the questionnaire reported clinical health anxieties (6 out of 14). These numbers went down after the program to 3 out of 16 at post 1 and 4 out of 15 at post 2. This finding indicates, that clinically relevant health worries are likely not a trait, but can be modified by an intervention (Figure 5).

Figure 5: Study participants classified according to the Whitely index. The dark blue bars indicate the numbers of patients without health anxieties, the light blue bars indicate the number of participants with relevant health anxieties. The numbers correspond to the absolute numbers of participants.

With regard to clinical anxiety, the number of study participants without borderline or clinical anxieties changed from n=8 at baseline to n=14 at post 1 and n=11 at post 2. The change was related to the fact that study participants with borderline clinical anxiety became less anxious. Participants suffering from clinically relevant anxieties did not benefit from the intervention (Figure 6).

Figure 6: Study participants classified according to the HADS Anxiety scale. The dark blue bars indicate the numbers of patients without anxieties, the light blue bars indicate the number of participants with borderline clinical anxieties, and the grey bars indicate the number of patients with manifest clinical anxieties. The numbers correspond to the absolute numbers of participants.

8

1311

6

3 4

BASELINE POST 1 POST 2

No Yes

8

14

11

7

2 33 2 3

BASELINE POST 1 POST 2

None Borderline Clinical

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The number of study participants without borderline or clinical depression changed from n=11 at baseline to n=13 at post 1 and n=12 at post 2. Depression was generally not as common as could be suspected considering that these were person, suffering from chronic symptoms over many years (Figure 7).

Figure 7: Study participants classified according to the HADS Depression scale. The dark blue bars indicate the numbers of patients without depressive symptoms, the light blue bars indicate the number of participants with borderline clinical depressive symptoms, and the grey bars indicate the number of patients with manifest clinical depressive symptoms. The numbers correspond to the absolute numbers of participants.

Feasibility outcomes

Participants satisfaction with the rehabilitation program Most of the participants were satisfied with the program (Figure 8). At post 1, n=17 (95%) were very satisfied, or satisfied and three month later, after a period of no group meetings and interventions, still n=15 (83%) answered accordingly.

Figure 8: Participant’s satisfaction with the IMCR program. The numbers above the columns indicate the number of patients with that particular rating (total n=18).

11

1312

3 3 32 1 2

BASELINE POST 1 POST 2

None Borderline Clinical

13

4

01

0

10

5

21

00

2

4

6

8

10

12

14

Very satisfied Satisfied Neutral Dissatisfied Very dissatisfied

post 1 post 2

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At post 2, which means at the very ending of the program, the participants were asked again on a visual analogue scale (VAS) ranging scale from 0 (not at all / ikke i de tele tatt) to 10 (totally agree / helt riktig), whether they would recommend the program to their friends and family members and answered with 7.8+2.66 (n=18). This value compared well to 7.8+1.8 (n=16) at baseline. At post 2, the participants were also asked in the same manner, whether they would recommend the program for other patients. The answer was on average 8.34+2.18 (n=17). When the participants were very globally asked about their quality of life (“Has your quality of life changed throughout the program?”on a VAS ranging scale from 0 (worse / verre) to 10 (better / bedre), the answer was on average 7.26+1.88 (n=18).

Participants experience with the intervention In addition, four open questions about the experiences with the program were asked after completion of the final treatment session and analyzed with qualitative methodology (systematic text condensation). Most participants were very satisfied with the program and appreciated the resource oriented focus of the program. Many of them found that it had provided them with a variety of instruments to cope better with everyday challenges in their lives. After completion of the training, many participants integrated relaxation and breathing exercises into their daily routine. Data from this qualitative study suggests that a program with several modalities such as life style advices, complementary therapies, relaxation exercises and stress management tools is beneficial for chronically ill patients with amalgam attributed health complaints. Beyond that, we conclude that the IMCR program can be useful for chronically ill patients with a similar symptom profile. A manuscript describing the full results is currently under review in a scientific journal, Research in Complementary Medicine” (see Appendix V: Alræk et al. Manuscript under review with Research in Complementary Medicine). These experiences with the program are also reflected in participants reports published in medlemsbladet “Tenner og Helse” (see Appendices VI, and VII).

Acceptability of conditions of randomization The responses to standard medical care are difficult to interpret as we received feedback, that patients had very different opinions about what was meant by “standard medical care”. Generally, the study participants found the individualized treatment, as well as a waiting list control most acceptable.

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Figure 9: Acceptance of randomization to possible control conditions

Discussion Feasibility of the IMCR program

The site capabilities were excellent in all three study locations, which was not necessarily expected as all the locations were very different in their structure. No loss of participants occurred related to study locations or site capacities. This finding was confirmed by the unusually high satisfaction of the study participants: The vast majority of the patients was satisfied or very satisfied with the program. Moreover, this finding was reflected in the reports about the study in the magazine of the patient organization (See appendices VI and VII).

Patients appreciated the resource oriented focus of the program and many reported that they were able to implement elements of the program into their daily life and routines. They found the instruments the ICP provided helpful in order to cope better with challenges in their lives. The participating patients themselves emphasized the possible high impact and relevance the IMCR program could have for chronically ill patients with a similar symptom profile.

In opposite to the positive attitude many participants had towards the program, the compliance with the questionnaires was insufficient and loss to follow up in the questionnaires was significant. Even patients who showed up to all meetings did not fill in all the questionnaires sufficiently. One reason for this was probably the high number of outcome measures. Thus, clear routines ensuring compliance with the study conditions need to be implemented in a possible follow up study.

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Moreover, it turned out, that the 12 sessions were difficult to operationalize with regard to vacation times. As a result, the program was shortened and is now available in a 10 module version.

Patient enrollment rates were considerably lower than anticipated. The reasons for that are complex. Probably most important was feasibility related to travel time. Even though the three study locations were strategically distributed over the Oslo area, the travel times towards the nearest location was sometimes more than two hours, which is unacceptable for persons who are chronically ill.

Randomization and the question of control groups were an issue in the discussions with the target group of this trial and their representatives. Therefore, one of the aims of this study was to investigate, what kind of control conditions would be acceptable for participants in a potential controlled clinical trial. Asked about what kind of control conditions the study participants would find acceptable with regard to a controlled clinical trial, most patients found randomization to a waiting list control or the iCAM part of the program most acceptable. The options of a group receiving no treatment, or standard medical care, or the group program alone were not preferred.

Outcome measures of the IMCR program

It is important to keep in mind, that this trial was designed as a feasibility study and not as a trial on clinical effectiveness. Thus, the results of outcomes related to the intervention have to be interpreted with care, as there was no control group in this feasibility trial (for reasons see discussion above). Therefore, data are presented and are to be interpreted purely descriptively. Nonetheless, with regard to the question, if it is advisable to continue investigating the IMCR program, it is of relevance to evaluate, whether the results of the outcomes related to the intervention point to a potential effect in a controlled, possibly randomized, clinical trial.

The results reveal that all symptom related scores went down from baseline to directly after the program. For symptom 1 of the MYMOP, this change from baseline to post 1 was 35% and for the GBB 28.32%. The difference was slightly smaller from baseline to 3 month after the program, as symptom scores increased slightly from post 1 to post 2. At the same time, the study participants reported less interference of their symptoms with their daily activities at post1, and even less at post 2 while at the same time, well being was improved at post 1 and continued to improve at post 2. Generally, a difference of more than 30% on a 10 point VAS scale is considered to be clinically relevant (38).

Given, that all interpretations are difficult to make, and that the structure of the trial does not allow for significance testing, the pattern of results indicates, that the intervention did have a limited, but beneficial impact on symptom load. The main outcome, however, is that patients felt less disturbed by their symptoms after the intervention. Symptoms seemed to have less impact on their daily activities and their well-being. This finding corresponds well with the fact, that the study participants exhibited an increase in Quality of life mesasured with the SF-36 and the Cantril ladder scale. Although this increase has to be interpreted cautiously, it nevertheless is interesting that this effect sustained from directly after the intervention to three month after the end of the program.

Depression was generally not as common as could be suspected considering that the study participants were persons, suffering from chronic symptoms over many years. This

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phenomenon was possibly due to the intense screening procedure at the beginning of the recruitment phase. Nonetheless, almost half of the patients reported clinical health anxieties before the intervention, while most of the patients showed normal values after the intervention. If this finding can be replicated in a confirmatory study, it may indicate, that clinically relevant health worries are likely not a trait, but can be modified by an intervention. A similar trend was seen for clinical anxiety measured by the HADS. Study participants with borderline anxieties showed no indication of anxiety after the intervention. However, participants suffering from clinically relevant anxieties did not benefit from the intervention and should be excluded in future trials with the same intervention. For those patients, a therapeutic approach directed directly to their anxieties is probably more appropriate.

Conclusion The conduction of the IMCR program is feasible and the acceptance among the user target group was high. The program was valid with regard to its intention and even though the organizational and administrative efforts were considerable, the program was implemented successfully in all three study locations. In conclusion, the implementation of the IMCR was successful under varying study conditions. Descriptive data analysis of the trial outcomes indicates, that the intervention has the potential to change symptom patterns and affect quality of life positively. Qualitative data indicate that the program did have transfer potential and value into the study participants’ daily routines.

Recommendation As discussed extensively in the introduction, pilot studies are often very similar to the main study (30) and can be performed when the concept of the main study is clear and the focus is on its processes (e.g. that recruitment, randomization, treatment, and possible follow-up run smoothly). Typically, this type of pilot studies are called “Feasibility Studies” and they ask the question, whether such a study or intervention/treatment is principally possible. They are often performed before a main study, or before a clinical pilot study is planned. Pilot studies are a useful tool in order to identify and avoid threats to the implementation of a larger trial and are highly recommended for complex interventions (29).

Figure 10: Phases of piloting for a full clinical trial

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The results of this feasibility trial are encouraging insofar as the implementation of the IMCR program was possible and not dependent on study locations. The acceptance among the target group was high and the target group itself recommended the continuation of the program as an offer for themselves, but also for other chronically ill groups of patients (See appendices V, VI and VII). However, it is important to keep in mind, that this study was not designed to answer the question, whether a clinical effect can be found, even though the clinical outcomes support the expectancy that the IMCR program is beneficial for patients with chronic health complaints.

Thus, the recommendation is to continue to investigate the IMCR program and conduct a clinical pilot trial which is clearly designed towards the question, whether a clinical effect can be expected in a large, confirmatory trial (see Figure 10). Clinical pilot studies are often conducted, analyzed and interpreted as confirmatory trials, even though this approach is not appropriate (30, 31). The correct statistical approach would be that of a separation test, which aims to find an indication that further research is justified, or that it is not. That type of question is the correct question to ask in early phases of research, where both budgetary and safety considerations argue for a small sample size (39). Since the structure of the IMCR program is in part generic (the ICP), it can easily be adjusted to other patient groups. Thus, it is recommended that the clinical pilot study should include other patient groups with similar chronic health complaints and a similar symptom load, such as e.g. Irritable bowel syndrome or Fibromyalgia in addition to patients with amalgam attributed health complaints. For some of the targeted patient groups there is considerable scientific evidence available to construct an individualized treatment package, so that no survey would have to be conducted in order to provide a selection of suitable therapies (15, 16, 23).

A greater number of different target groups would allow for more study locations. It is recommended, that the travel time for the participants should remain significantly less than one hour, considering that many participants struggled with fatigue. If the trial were to be conducted in the Oslo area, the existing competence could be utilized in order to reduce the implementation costs. Study personnel could be organized in rotating teams, serving different locations on different days of the week. In this way, the implementation costs could be significantly reduced and the existing expertise could be used efficiently. In addition, using a small number of teams would increase the consistency of the intervention. It can be evaluated, if such a pilot study can and should be conducted in cooperation with, e.g. communal agencies such as NAV.

Final remarks The planning, development, implementation, and conduction of the IMCR trial involved an exceptionally high number of professionals, with different expertise and qualifications. This was related tot the fact, that it was a scientific study, but it was also related to the fact, that the intervention was newly developed and had to be implemented for the first time. Several research institutions and study locations were involved, and last, but not least, NDPA/FTH and its representatives as well as the study participants themselves. At the end of this project, the main conclusion is, that most of the individuals and organisations, and most important, the study participants, have experienced this trial as a success.

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Not everything was perfect and there are numerous, very concrete recommendations, on how to improve routines and procedures in a possible next trial. However, there seemed to be a common understanding, that everybody involved in this study was determined to contribute in the most professional way and with all expertise that could be mustered. Moreover, the study participants were most dedicated to the intervention and were in part willing to invest tremendous efforts in order to participate (e.g. travel times of more than 2 hours!).

This exceptional dedication can in fact, imply a threat to future trials, as it is impossible to exclude, that some of the results are more related to the impressively high commitment of personnel and participants to the IMCR trial, than to the intervention itself. This phenomenon is, however, as a resume at the end of the IMCR trial, most appreciated!

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21. Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum. 2003;48(5):1420-9. 22. Häuser W, Schmutzer G, Brähler E, Glaesmer H. A cluster within the continuum of biopsychosocial distress can be labeled “fibromyalgia syndrome”—evidence from a representative German population survey. The Journal of rheumatology. 2009;36(12):2806-12. 23. Langhorst J, Hauser W, Bernardy K, Lucius H, Settan M, Winkelmann A, et al. [Complementary and alternative therapies for fibromyalgia syndrome. Systematic review, meta-analysis and guideline]. Schmerz. 2012;26(3):311-7. 24. von Scheidt C, Bruset S, Michalsen A, Alræk T, Drageset BJ, Musial F. IMCR-studien – et helseprogram med egeninnsats. Håndbok for gruppeledere [The IMCR stydy - a health program with individual efforts. Handbook for group leaders]. Tromsø, Norway: National reseach center in complementary and alternative medicne; 2015. 25. Kristoffersen AE, Musial F, Hamre HJ, Bjorkman L, Stub T, Salamonsen A, et al. Use of complementary and alternative medicine in patients with health complaints attributed to former dental amalgam fillings. BMC Complement Altern Med. 2016;16:22. 26. The Coordination Reform. Proper treatment – at the right place and right time. Oslo: Norwegian ministry of health and care services; 2012. Contract No.: St.meld. nr. 47. 27. Patient's Role in Health Care - relationship to participation. The Coordination Reform Proper treatment – at the right place and right time. 47. Oslo: Norwegian ministry of health and care services; 2012. p. 51. 28. Musial F. Patients as Active Partners in Research - a Fashionable Phrase or a Fundamental Paradigm Shift? Forsch Komplementmed. 2015;22(4):224-5. 29. Craig P, Dieppe P, Macintyre S, Michie S, Nazareth I, Petticrew M. Developing and evaluating complex interventions: the new Medical Research Council guidance. Int J Nurs Stud. 2013;50(5):587-92. 30. Arain M, Campbell MJ, Cooper CL, Lancaster GA. What is a pilot or feasibility study? A review of current practice and editorial policy. BMC Med Res Methodol. 2010;10:67. 31. Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, et al. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol. 2010;10:1. 32. Paterson C, Britten N. In pursuit of patient-centred outcomes: a qualitative evaluation of the 'Measure Yourself Medical Outcome Profile'. J Health Serv Res Policy. 2000;5(1):27-36. 33. Paterson C. Measuring outcomes in primary care: a patient generated measure, MYMOP, compared with the SF-36 health survey. BMJ. 1996;312(7037):1016-20. 34. McHorney CA, Ware JE Jr. Construction and validation of an alternate form general mental health scale for the Medical Outcomes Study Short-Form 36-Item Health Survey. Med Care. 1995;33(1):15-28. 35. Murdaugh C, Moneyham L, Jackson K, Phillips K, Tavakoli A. Predictors of quality of life in HIV-infected rural women: psychometric test of the chronic illness quality of life ladder. Qual Life Res. 2006;15(5):777-89. 36. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-70. 37. Dzata GD, Wyckoff JH, Confer AW. Immunopotentiation of cattle vaccinated with a soluble Brucella abortus antigen with low LPS content: an analysis of cellular and humoral immune responses. Vet Microbiol. 1991;29(1):15-26. 38. Turner JA, Turk DC. The significance of clnical significance. Editorial Pain. 2008;137:467-8. 39. Aickin M. Separation Tests for Early-Phase Complementary and Alternative Medicine Comparative Trials. Evid Based Integrative Med 2004;1(4): 225-31.

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List of abbreviations

IMCR Integrated Medical Care Rehabilitation

NDPA/FTH Norwegian Dental Patient Organisation / Forbundet Tenner og Helse

ICP Illness Coping Program

CAM complementary and alternative medicine

iCAM individualized CAM therapies

USB Use Safety Benefit

34

List of tables

Table 1: Framework of the IMCR program 11

Table 2: Example of day 8 of the program 15

Table 3. Basic characteristics of the participants. Due to the small sample size, data are collapsed over gender 21

Table 4: Expectations to the effect of the interventions of the study participants 22

Table 5: Results of the symptom related questionnaires MYMOP and GBB-24 22

Table 6: Results of the quality of life related questionnaires SF 36 and Cantril Ladder Scale 23

35

List of figures

Figure 1: Structure of the IMCR-program, for one group. 14

Figure 2: Overview over the 12 group sessions 14

Figure 3: Overview over the organizational structure of the IMCR trial 17

Figure 4: CONSORT flow chart of recruitment and study phases. 20

Figure 5: Study participants classified according to the Whitely index. The dark blue bars indicate the numbers of patients without health anxieties, the light blue bars indicate the number of participants with relevant health anxieties. The numbers correspond to the absolute numbers of participants. 24

Figure 6: Study participants classified according to the HADS Anxiety scale. The dark bue bars indicate the numbers of patients without anxieties, the light blue bars indicate the number of participants with borderline clinical anxieties, and the grey bars indicate the number of patients with manifest clinical anxieties. The numbers correspond to the absolute numbers of participants. 24

Figure 7: Study participants classified according to the HADS Depression scale. The dark blue bars indicate the numbers of patients without depressive symptoms, the light blue bars indicate the number of participants with borderline clinical depressive symptoms, and the grey bars indicate the number of patients with manifest clinical depressive symptoms. The numbers correspond to the absolute numbers of participants. 25

Figure 8: Participant’s satisfaction with the IMCR program. The numbers above the columns indicate the number of patients with that particular rating (total n=18). 25

Figure 9: Acceptance of randomization to possible control conditions 27

Figure 10: Phases of piloting for a full clinical trial 29

36

Note of thanks

Many thanks go to all the different professionals and contributors to this work for their commitment and dedication to the study….

The study participants for stort engasjement og deltagelse i studien.

The researchers Harald J. Hamre, ph.d. (professor, Institute for Applied Epistemology and Medical Methodology, the University of Witten/Herdecke, Freiburg, Tyskland)

Lars Björkman, ph.d. (professor, forskningsleder ved Uni Research Helse, leder for Bivirkningsgruppen, forsker I ved Bivirkningsgruppen for odontologiske biomaterialer, Bergen).

Terje Alræk, ph.d., Seniorforsker, NAFKAM

Christel von Scheidt, M.S., Leder for Mind Body Medisin Immanuel Krankenhaus Berlin

Andreas Michalsen, lege, ph.d., Professor, klinisk naturmedisin Universitätsmedizin Berlin

Vinjar Fønnebø, Professor, direktør NAFKAM

Agnete Kristoffersen, Seniorforkser, NAFKAM

Trine Stub, seniorforsker, NAFKAM

The cooperating partners Stig Bruset, (lege) og team, Regnbuen helsesenter, Lierskogen

Audun Myskja (lege ph.d.) og team, Senter for livshjelp, Ski

Randall Sexton (lege ph.d.) og team, Heggeli helhetsmedisin, Oslo

Forbundet Tenner og Helse (FTH)

Liljan Smith Aandahl (tidligere seniorrådgiver i Helsedirektoratet, avdeling omsorg og tannhelse) som var sentral i utviklingen av prosjektet for mennesker med mistanke om bivirkninger av amalgam som denne studien er en del av.

37

The group leaders

Karin Jansen, Regnbuen helsesenter; Karen von der Starre, Heggeli helhetsmedisin; Kristin Wang, Senter for livshjelp.

The other ICP instructors

The iCAM therapists

The study dentist

Inger-Lise Mathiesen (tannlege)

The administrative and technical coworkers

Brit J. Drageset, B.Sc. Rådgiver NAFKAM; Inger Lise Pettersen, Regnbuen helsesenter; Annette D-S. Marcussen, Heggeli helhetsmedisin; Reidun Stadven, Senter for livshjelp; Kari Riddervold, NAFKAM; Solveig Johansson, NAFKAM; Åsa Sohlén, NAFKAM for utrettelig praktisk bistand.

The Directorate og Health (Helsedirektoratet)

38

Innhold

Appendix I Health complaints attributed to dental amalgam: A retrospective survey exploring perceived health changes related to amalgam

removal

Appendix II IMCR- studien – et helseprogram med egeninnsats Håndbok for gruppeledere. Appendix III Use of complementary and alternative medicine in patients with health

complaints attributed to former dental amalgam fillings Appendix IV Operationalizing the use of patient experiences for the selection of treatment

options in a clinical trial: The “USB” (Use – Safety - Benefit) principle and the Integrated Medical Care Rehabilitation trial for patients with amalgam attributed health complaints

Appendix V «Everyone with a chronic disease should be offered this program» - participants experience with an Integrative Medicine group program. “Jeder mit einer chronischen Erkrankung sollte an diesem Program teilnehmen” – Teilnehmererfahrungen mit einem integrativmedizinischem Gruppenprogramm.

Appendix VI Tenner & helse Medlemsblad for forbundet Tenner og helse 20. Årgang – nr. 2 juni 2014

Appendix VII Tenner & helse Medlemsblad for forbundet Tenner og helse 22. Årgang – nr.3

september 2016

Appendix I

Health complaints attributed to dental amalgam:

A retrospective survey exploring perceived health changes related

to amalgam removal Short title: Health complaints attributed to amalgam

AGNETE EGILSDATTER KRISTOFFERSEN1*, TERJE ALRÆK1, TRINE STUB1, HARALD

JOHAN HAMRE2, LARS BJÖRKMAN3 AND FRAUKE MUSIAL1

1The National Research Center in Complementary and Alternative Medicine

(NAFKAM), Department of Community Medicine, Faculty of Health Sciences,

UiT The Arctic University of Norway, Tromsø, Norway

2Institute for Applied Epistemology and Medical Methodology at the University of Witten-

Herdecke, Freiburg, Germany

3Dental Biomaterials Adverse Reaction Unit, Uni Research Health, Bergen, Norway

* Corresponding author

Manuscript under review in The open dentistry Journal.

1

Health complaints attributed to dental amalgam: A retrospective

survey exploring perceived health changes related to amalgam removal

Short title: Health complaints attributed to amalgam

AGNETE EGILSDATTER KRISTOFFERSEN1*, TERJE ALRÆK1, TRINE STUB1,

HARALD JOHAN HAMRE2, LARS BJÖRKMAN3 AND FRAUKE MUSIAL1

1The National Research Center in Complementary and Alternative Medicine

(NAFKAM), Department of Community Medicine, Faculty of Health Sciences,

UiT The Arctic University of Norway, Tromsø, Norway

2Institute for Applied Epistemology and Medical Methodology at the University of

Witten-Herdecke, Freiburg, Germany

3Dental Biomaterials Adverse Reaction Unit, Uni Research Health, Bergen, Norway

* Corresponding author

E-mail addresses:

Agnete Egilsdatter Kristoffersen: agnete.kristoffersen@uit.no

Terje Alræk: terje.alrak@uit.no

Trine Stub: trine.stub@uit.no

Harald Johan Hamre: harald.hamre@ifaemm.de

Lars Björkman: lars.bjorkman@uib.no

Frauke Musial: frauke.musial@uit.no

Correspondence:

Agnete E. Kristoffersen

National Research Center in Complementary and

Alternative Medicine, NAFKAM,

Department of Community Medicine,

Faculty of Health Science,

UiT The Arctic University of Norway

9037 Tromsø, Norway

Tel. (+47) 77 64 61 47 (Agnete Kristoffersen)

Tel. (+47) 77 64 66 50 (NAFKAM)

Fax. (+47) 77 64 68 66

E-mail: agnete.kristoffersen@uit.no

The manuscript include 3 tables and 5 figures

2

Abstract

Objective: Many patients has complex health complaints they attribute to dental

amalgam. There is some evidence of symptom relief after removal of amalgam. The aims of

this study were to assess the total symptom load in patients with all their amalgam fillings

removed and to investigate the self-reported improvement of health with regard to precautions

taken under amalgam removal and time since removal. Material and methods: The survey

was distributed to all members (n=999) of the Norwegian Dental patients association in 2011.

The study participants returned the questionnaires anonymously by means of a pre-stamped

envelope. The questionnaire asked for sociodemographic data, subjectively perceived health

status, complaints persisting after amalgam removal and self-reported changes in symptoms

after amalgam removal. Results: A total of 324 participants were included in the study. The

majority of the participants reported improved health after amalgam removal, even though the

mean degree of severity of complaints was still high. Exhaustion and musculoskeletal

complaints were most severe, which reflects the fact that 38% of the participants reported poor

to very poor current health. With regard to amalgam removal, associations between improved

health, number of precautions applied, and time since removal were found. Conclusions: Most

of the participants in this study reported improvement of health after amalgam removal even

though they still suffered a high complaint load. Since absolute symptom load is a robust

predictor for general health outcome and socioeconomic burden for society, a possible

intervention, which enables patients to further improve their health status is desirable.

Key words: Dental amalgam; health complaints; restoration

3

Introduction

Many patients present to their General Practitioner (GP) with a high symptom load and

considerable psychological distress. Often, the underlying pathophysiology remains unclear

and sometimes these patients receive a diagnosis such as irritable bowel syndrome, chronic

fatigue syndrome or fibromyalgia. Common to all these diagnoses is that their pathophysiology

remains unclear and therefore often called “functional”. Patients do not die from these

syndromes, but they suffer, and they often feel that they are stigmatized, and that their suffering

is not accepted [1]. Moreover, the associated direct and indirect socioeconomic costs are

substantial [2].

A number of different symptoms have been attributed to dental amalgam [3]. Although

often transient, a sizeable proportion is persistent and associated with a considerable reduction

in these patients’ quality of life. The most commonly reported complaints attributed to amalgam

are neurological symptoms such as fatigue and dizziness, mental symptoms such as

concentration and memory disturbance, anxiety, irritability, restlessness and depression.

Moreover, pain in muscle joints and pain in neck, shoulder, teeth, jaws, face and headache as

well as gastrointestinal symptoms such as constipation, diarrhoea, bloating, mouth blisters,

metallic taste, as well as increased susceptibility to infections are also commonly reported [4-

11]. Many patients who had their amalgam fillings removed experience less severe symptoms

after removal [8, 12-15]. Best results (higher degree of symptom improvement, general

improvement or recovery) were seen in patients who had all their amalgam fillings removed.

In Norway amalgam removal procedures in patients with health complaints attributed

to dental amalgam are supposed to follow the recommendations from the Directorate of Health

guidelines for assessment and treatment for suspected adverse effects from dental materials

4

[16]. These recommendations intend to minimise exposure to mercury and other heavy metals

during the removal procedures. They consist of: a) removal of the whole amalgam filling in

chunks without any pulverizing, b) application of water cooling during the procedure, c) use of

a sharp drill, d) use of protective equipment including rubber dam, suction at the tooth and

appropriate ventilation of the treatment room [16, 17].

In addition to these guidelines, The Norwegian Dental Patient Association (NDPA),

(Forbundet tenner og helse (FTH) in Norwegian) claims, that it is important to combine the

removal of amalgam fillings with additional preventive therapies [18]. NDPA recommends

patients to take supplements such as selenium, zinc, vitamin C and E in order to improve

immune system functioning before, during and after the removal of amalgam. Just before the

removal, e.g. the intake of charcoal tablets and one unit of alcohol [17, 18] is expected to be

protective. Moreover, several other additional therapies are recommended [19]. These

recommendations are often based on extrapolations from laboratory experiments in animals

(e.g. alcohol inhibits uptake of mercury vapour from the lung through inhibition of the catalase

enzyme [20]) and anecdotal experiences. Systematic scientific evidence that these precautions

are associated with improved health outcomes in humans is however, currently missing. One

randomized trial found no difference in general health complaints in patients who replaced

amalgam and used additional “detoxification therapy” compared to patients who removed

amalgam and did not used such therapy [5].

The aims of the present study were therefor to 1) assess the total symptom load in

patients who have had all their amalgam fillings removed and 2) investigate the self-reported

improvement of health with regard to precautions taken under amalgam removal and time since

removal.

5

Material and methods

Study population

This study was a part of a larger research program on potential negative health effects

of amalgam commissioned by the Norwegian Directorate of Health to the National Research

Center in Complementary and Alternative Medicine (NAFKAM). Patient participation was a

cornerstone of this project and one of the questionnaires used in the present survey was

developed in close cooperation with NDPA. The Norwegian Data Inspectorate (NSD) has been

notified about the study and the Regional Committee for Medical and Health Research Ethics

(REK) has considered the study (REK reference 2011/1281) and decided that no ethic approval

was needed due to full anonymity of the participants.

The survey was distributed through NDPA to all their members in December 2011 with

a reminder in February 2012. The study participants returned the questionnaires anonymously

to NAFKAM by means of a pre-stamped envelope. The anonymous questionnaire asked for

sociodemographic data, subjectively perceived health status, complaints persisting after

amalgam removal (based on Norwegian version of the Giessen Subjective Complaints List

(GBB-24)), self-reported changes in symptoms after amalgam removal, and experience with

therapeutic interventions. It includes also questions with regard to the use of Complementary

and Alternative Medicine (CAM), which are reported elsewhere [21]. The only criteria for

inclusion were that the patients had previously amalgam fillings, which all were removed, in

addition to membership in the patient association NDPA. No information on possible medical

diagnoses was obtained.

6

Health complaints according to the GBB-24

The Giessen Subjective Complaints List (GBB-24) consists of 24 different health

complaints. The severity of each complaint is rated according to a five point scale; 0 (not at all),

1 (slightly), 2 (somewhat), 3 (considerably) and 4 (very much) [22]. The complaints are

grouped and summarized into four subscales with six complaints in each of the following

groups: Cardiovascular complaints, gastrointestinal complaints, musculoskeletal complaints

and exhaustion. Furthermore, the scores of the 24 single complaints are summed up in a total

score ("complaints load") ranging from 0-96 where 0 is no complaints at all while 96 represent

all listed complaints at highest severity. In addition to the 24 items in the GBB-24 questionnaire,

the participants were asked for severity of pain in the face and/or the jaw. This additional item

was included because it reflects a symptom known to be relevant for the patient group in

question (Table II).

Since the average score for each item includes also participants who answer 0 (not at

all), it is difficult to estimate the severity of the health complaint in individuals suffering from

the actual complaint. A low mean could reflect that many participants suffer this symptom, but

not very intensely, or that only a few are affected, who report a high intensity. Therefore, a

second item analysis was performed, which included only data from participants, who answered

minimally 1 (slightly) or higher for a complaint. The reason for this was to explore the burden

of each individual symptom among the individuals who reported it.

Self-reported changes in health following amalgam removal

In the survey, possible changes in self-reported health following the amalgam removal

were addressed in two different questions:

For the main analyses, a general question with three response categories (+ don't know) was

7

used: “If you have replaced your amalgam fillings, do you consider your health to have changed

as a consequence of this? 1. The health has improved, 2. The health has worsened, 3. The health

is unchanged, 4. Don’t know.

In addition, another question addressed long-term changes with five response categories: "Have

you experienced long-term (longer than 6 months) effects or changes following amalgam

removal? 1. Worsening, 2. No change 3. Some improvement, 4. Major improvement 5. Total

recovery / symptom free, 6. Don't know. The breakdown into five categories made this question

less suitable for subgroup analysis. However, these or similar response categories have been

used in a number of other studies of amalgam removal, therefore the question is included in this

paper.

Factors perceived as being related to amalgam removal

Data on possible precautions made before, during and after the amalgam removal were

collected via the following item:

If you have had dental fillings with amalgam removed, was there any precautions taken

in connection with the replacement of fillings? (drugs / minerals / vitamins / protective

equipment) Multiple answers possible. 1. Yes I had prophylactic treatment, 2. Yes,

protective equipment was used during the dental treatment, 3. Yes, I had post treatment,

4. No, no precautions were made, 5. Don’t know.

Since this item allowed multiple answers, the analysis was performed according to the number

of precautions (out of the responses 1, 2, 3 or 4 above) the participants reported: 0 (no

precautions), 1 (one precaution), 2 (two precautions), 3 (three precautions). Table III includes

a detailed analysis of the various combinations.

8

Statistics

Between-group differences were analysed using chi-square tests for binary data

analysing one variable at the time, one-way ANOVA test for continuous data and in SPSS for

Windows (version 22.0, SPSS, Inc., Chicago, IL). Significance level was defined as p <0.05

without p-value adjustment for multiple comparisons.

Ethics

The Norwegian Data Inspectorate (NSD) has been notified about the study and the

Regional Committee for Medical and Health Research Ethics (REK) has considered the study

(REK reference 2011/1281) and decided that no ethic approval was needed due to full

anonymity of the participants.

Results

Inclusion

A total of n=999 envelopes with questionnaires were sent out, of which 46 were returned

unopened to sender. Overall, 953 members of NDPA received the questionnaire, 347 responded

(36.4% response rate) and 324 fulfilled all eligibility criteria and were included in the study

(Figure 1).

9

Figure 1. Flow chart demonstrating the selection process of the study population.

Basic characteristics of the participants

The majority of the participants were female (71.6%), mean age was 60 years and

43.7% of the participants were holding a university degree. The women were slightly older

than the men (2.5 years, p=0.001) and men were more often still working (p=0.014). Most

participants reported normal (neither good nor poor) to good current health (62.4%) and

improved health after amalgam removal (75.2%). However, a substantial number of

participants reported poor to very poor current health (37.6%). No significant gender

differences were found with regard to education or self-reported current health. (Table I) In

order to avoid low cell frequencies, gender differences were not included in the further

analysis.

10

11

Table I. Basic characteristics of the participants Total Men Women p-value

%(n) %(n) %(n)

Gender Women 71.6 (232)

Men 28.4 (92)

Age

Mean 60.0 58.8 (SD

11.12)

61.3 (SD

10.26) 0.001^

Education

Primary School 13.4 (42) 7.9 (7) 15.6 (35) 0.252*

Secondary School 27.4 (86) 32.6 (29) 25.3 (57) High School 15.6 (49) 13.5 (12) 16.4 (37)

University, lower grade 22.0 (69) 25.8 (23) 20.4 (46) University, higher grade grade 21.7 (68) 20.2 (18) 22.2 (50)

Working

Yes 59.0 (128) 71.0 (49) 53.4 (79) 0.014*

No 41.0 (89) 29.0 (20) 46.6 (69)

Self-reported current health 0.203*

Very good 9.7 (31) 15.4 (14) 7.5 (17) Good 25.4 (81) 26.4 (24) 25.0 (57)

Neither good nor poor 27.3 (87) 23.1 (21) 28.9 (66) Poor 28.5 (91) 28.6 (26) 28.5 (65)

Very poor 9.1 (29) 6.6 (6) 10.1 (23)

Changes in health after amalgam removal 0.024*

Worsening of health 8.4 (26) 7.8 (7) 8.6 (19) Unchanged health 9.4 (29) 4.4 (4) 11.4 (25)

Improved health 75.2 (233) 85.6 (77) 70.9 (156) Don't know 7.1 (22) 2.2 (2) 9.1 (20)

^One-way ANOVA test * Pearson Chi-Square test

12

Health complaints according to the GBB-24

Mean severity score of the main 24 complaints in the GBB-24 (range 0-96) was 36.1,

with 47.8 in the group with less than one year since removal of amalgam, 39.6 one to four years

after removal and 35 and 36.5 five to nine years and more than ten years after removal,

respectively. A total of 8.3% (n=27) had a sum score of 0 (no complaints reported) while one

participant reported highest possible degree of complain load, 96. The most commonly reported

single symptoms among the participants were tendency of rapid exhaustion (80.9%) followed

by tiredness (79.6%), concentration disturbances (77.5%) and pains in joints or limbs (75.6%).

These four complaints were also the complaints with highest mean severity in the total sample

(2.42, 2.18, 2.12 and 2.14 respectively, 2 indicating “somewhat” and 3 “considerable”), with

mean severity of the remaining complaints ranging from 0.42 (vomiting) to 2.00 (pain in neck

and shoulders). When grouped into the following four subscales exhaustion, musculoskeletal

complaints, cardiovascular complaints and gastrointestinal complaints, with six complaints

in each groups (see Table II), we found that all symptom complexes were reported by more

than 75% of the participants. When the intensity of the complaints were taken into

consideration, exhaustion and musculoskeletal complaints were the most severe complaints

with a mean severity score in the total sample of 12.46 and 10.65 respectively (Table II). A

considerably lower mean severity score in the total sample was found for cardiovascular and

gastrointestinal complaints (7.34 and 5.65 respectively). The additional symptom Pain in the

face or jaws was reported by 58.3% of the participants with a mean severity score in the total

sample of 1.53 and a mean severity score among the participants actually suffering from it of

2.62 (Table II). As shown in Figure 2 there was a linear correlation between symptom load and

self-reported health in all groups of complaints, in particular for exhaustion and

musculoskeletal complaints.

13

Table II. Results of the GBB. The severity of each item is rated to a five point scale; 0 (not

at all), 1 (slightly), 2 (somewhat), 3 (considerably) and 4 (very much) [30] and

summarized into four subscales (exhaustion, gastrointestinal complaints, musculoskeletal

complaints and cardiovascular complaints) as well as a total sum score (complaints load).

14

* “Feeling numb or benumbed” in the standard English translation from German

Symptom/ GBB scale

%

reporting n

Mean severity in the

total sample

Mean severity in

participants reporting

the symptom

TOTAL GBB-24 sum score 91.7 297 36.1 58.41

Exhaustion 88.6 287 12.46 16.57

Tendency to rapid exhaustion 80.9 262 2.42 2.99

Tiredness 79.6 258 2.18 2.74

Excessive need for sleep 71.3 231 1.93 2.71

Weariness 71.3 231 1.91 2.68

Physical weakness 70.1 227 1.90 2.72

Concentration disturbance * 77.5 251 2.12 2.73

Musculoskeletal complaints 88.3 286 10.65 15.84

Pains in joints and limbs 75.6 245 2.14 2.83

Backache 65.4 212 1.71 2.61

Headaches 62 201 1.56 2.51

Pains in neck and shoulders 70.4 228 2.00 2.84

Head pressure 62.7 203 1.63 2.60

Heaviness or tiredness in the legs 66.4 215 1.62 2.45

Cardiovascular complaints 82.4 267 7.34 13.33

Dizziness 64.5 209 1.48 2.30

Heavy, rapid or irregular heart-throbbing 64.2 208 1.47 2.29

Sudden bouts of heart-trouble 48.5 157 1.03 2.13

Twinges, pains or aching in the chest 53.7 174 1.18 2.19

Attacks of breathlessness 48.8 158 1.06 2.16

Sensation of tightness, choking or lumpiness in

the throat 49.7 161 1.12 2.26

Gastrointestinal complaints 76.5 248 5.65 12.67

Stomach aches 60.2 195 1.31 2.18

Pressure or heaviness in the stomach 51.2 166 1.17 2.28

Heartburn 46.6 151 1.04 2.24

Nausea 44.1 143 0.88 2.00

Belching 38 123 0.82 2.17

Vomiting 23.5 76 0.42 1.80

Other, added to the GBB-24 complaints

Pain in the face or jaws 58.3 189 1.53 2.62

15

Figure 2. Self-reported health in relation to symptom load

Factors, perceived as being related to amalgam removal

Self-reported changes in health after amalgam removal

In response to the general question about changes in health after amalgam removal, most

of the participants (75.2%, n=233) reported improvement of health, 8.4% (n=26) reported

worsening of health while 9.4% (n=29) reported no change. Seven percent (n=22) could not say

whether their health has changed or not (Table I). In a subgroup analysis according to current

16

health, this was also the case in all subgroups except in the group reporting very poor health, in

which more participants reported worsening of health (n=13) than improvement of health

(n=11) after amalgam removal (Figure 3).

Figure 3. Changes in health after amalgam removal in subgroups according to current

health. Numbers are actual numbers of participants.

In response to the additional question about long-term changes after amalgam removal,

8.6% (n=24) reported to be recovered / symptom free, 59.3% (n=166) reported major

improvement, 17.5% (n=49) some improvement, 2.5% (n=7) no change, 8.9% (n=25)

worsening, and 3.2% (n=9) 'don't know'.

Experienced changes in health after amalgam removal related to time since removal

When the changes in health after amalgam removal (general question, see above) were

analysed according to time since removal, we found that the highest number of participants

reporting improved health after amalgam removal was found among the participants who have

had their amalgam removed more than nine years ago (82.2%, n=129). The lowest report of

improved self-reported health was found among the participants who had removed their

amalgam within the last year (28.6%, n=2). Worsening of self-reported health after amalgam

removal was highest (12.1%, n=19) in participants with more than 9 years since removal and

lowest in the group who have had their amalgam removed within the last year (0.0%, n=0)

(p<0.001, Fig. 4)

17

Figure. 4. Changes in health after amalgam removal in subgroups according to time since

amalgam removal.

Experienced changes in health after amalgam removal depending on the conditions related to

the removal

Among participants who had used no precautions neither before, during nor after the

amalgam removal, 62.5% reported improved health, 6.3% reported no change and 18.8%

reported worsening of health after amalgam removal. Among those who had used both

prophylactic treatment, protective equipment and post-treatment, 90.4% reported improved

health, 4.1% reported unchanged health, while 2.7% reported worsening of health after

amalgam removal (p<0.001, Figure 5). The changes in health after amalgam removal for the

different combination of precautions made are described in Table III.

18

Figure 5. Changes in health after amalgam removal in subgroups according to number of

precautions made under amalgam removal.

19

Table I. Changes in health after amalgam removal in subgroups according to the number

and combinations of precautions made under amalgam removal.

Number of Combination of

Improved

health

(n=233)

Unchanged

health (n=29)

Worsening

of health

(n=26)

Don't

know

(n=22)

precautions precautions n % n % n % n %

0 No precautions 40 60.6 4 6.1 12 18.2

1 Only prophylactic treatment 11 78.6 1 7.1 1 7.1 1 7.1

Only protective equipment 62 65.3 17 17.9 6 6.3 10 10.5

Only post treatment 7 87.5 0 0.0 1 12.5 0 0.0

2

Prophylactic treatment and protective

equipment 28 82.4 4 11.8 2 5.9 0 0.0

Prophylactic treatment and post treatment 6 100 0 0.0 0 0.0 0 0.0

Protective equipment and post treatment 13 81.3 0 0.0 2 12.5 1 6.3

3

Prophylactic treatment and protective

equipment and post treatment 66 90.4 3 4.1 2 2.7 2 2.7

20

Discussion

Main findings

This was a retrospective survey among members of a Norwegian dental patient

association with health complaints, which they attributed to former dental amalgam fillings.

Most of the participants reported some degree of health improvement after amalgam removal,

but the mean degree of severity of symptoms was still high, with the subscales exhaustion and

musculoskeletal complaints exhibiting the highest severity. This finding corresponds well with

the fact that 37.6% of the participants reported poor to very poor current health. Improved health

was more frequently reported among participants with the longest time interval since removal

and with the highest number of precautions made in connection with amalgam removal.

Other studies

The most commonly reported single symptoms in this study were tendency to rapid

exhaustion followed by tiredness, concentration disturbance, and pain in joints and limps. This

finding is in line with other Scandinavian studies on similar populations [12, 13, 23]. Lygre et

al. [12], found that the most reported complaints were local symptoms around the mouth, in

addition to general complaints such as pain from muscles and joints, fatigue, and memory

disturbance, a symptom pattern, which is confirmed in the present study. Moreover, half of the

participants in our study reported pain in the face, a category, which included symptoms around

the mouth as described in Lygre et al [12].

Our finding of improved self-reported health in 74.4% of the participants after removal of

amalgam, with 67.9% indicating major improvement or total recovery, is also in accordance

with findings in other studies [8, 12-15]. Hanson reported better or much better health after

removal of amalgam fillings in 73% of all participants across 25 studies (n=5821) [24]. A Sum

score of 35 on the GBB-24 complaint scale four to nine years after removal of amalgam is

21

somewhat higher than what was found in another Norwegian population 7 years after removal

of amalgam, where a sum score of 28.9 was found [13]. The higher mean complaint score in

the present study might be related to the membership in a patient organization [25, 26].

Our finding of worsening of health in 8.4% (n=26) of the participants after removal of amalgam

is in accordance with other studies. Long-term health deterioration following amalgam removal

has been reported in 9.5% of members of a Swedish patient organisation and in 13% of patients

examined at two different referral institutions [8, 27]. The differences in worsening of health

across these studies may be related to differences in clinical settings. Similar deterioration rates

were found in the present study of NDPA members (8.3%) and the survey of members of the

Swedish dental patient organisation (9.5%).

The reasons for worsening in self-reported health after amalgam removal are poorly

understood. A study from a referral institution found that patients reported health deteriorations

had altered mercury concentrations in erythrocytes and plasma, compared to patients who

reported improvement of health status after amalgam removal [28]. Sjursen et al. [29]

concluded in a qualitative study that: “The dental amalgam was certainly important to get rid

of, but it is uncertain how important the removal was for the experienced changes in health

complaints”. Also Nerdrum et al. [13], who reported improvement of health after amalgam

removal, state that the amalgam might not have been the main cause of the patient’s subjective

health complaints. These statements together with the fact that the majority of the participants

in this study still report complaints after removal of amalgam (and some even worsening of

existing symptoms), suggest that a multifactorial explanation for the complex symptom pattern

experienced by the patients cannot be ruled out. We did not collect information about, nor

adjusted for, other chronic medical disorders in the studied participants.

The reason for the increased frequency of self-reported improvement of health over time

22

is not obvious and is not in line with a study finding no difference in sum score on the GBB

scale between 2 and 7 years after the removal [13]. As the main difference in the present study

is found before and after one year since the removal of amalgam, one explanation may be that

the body needs time to restore after the amalgam removal. Another explanation may be that the

long recall time since removal in most of the groups could have led to inaccuracy in reported

health before removal.

The increased self-reported health found in this study when precautions were taken

during amalgam removal is interesting. This could be relevant for treatment procedures and for

the recommendations from The National guidelines for assessment and treatment for suspected

adverse effects from dental biomaterials [16] and the recommendations of NDPA [17]. It is,

however not in line with a randomised controlled trial where no differences in health outcome

were found between the groups where precautions (high doses of vitamins and trace elements,

similar to our prophylactic treatment and post-treatment) were taken and the group where no

precautions were taken [5]. This discrepancy can be related to different types and numbers of

precautions, different settings and follow-up periods as well as differences in health status in

the studied participants. Notably, in our study, health improvement increased with time since

removal, suggesting that follow-up duration may be a relevant factor for assessed health change

after amalgam removal.

Limitations

The main limitation of this study is the highly selected group of participants due to

membership in a patient association and a rather low response rate. In order to identify patients

with persistent health complaints attributed to former amalgam fillings (which was one aim of

the survey commissioned by the Norwegian Directorate of Health), study participants were

recruited from a specific patient association. The study population may therefore not be

23

representative for the total patient group. Moreover, the only criterion for inclusion was that the

patients had removed all their amalgam fillings. No information about possible clinical

diagnoses was obtained, hence is it not possible to distinguish study participants without a

medical diagnosis from participants with a diagnosed medical condition.

The fact that no data were available on symptom load related to amalgam before removal

of dental fillings, limits the results to symptoms remaining after amalgam removal. The

majority of the participants had replaced their amalgam fillings more than nine years ago, so

recall bias, meaning some inaccuracy reporting the experienced health changes cannot be

excluded. Recall bias may therefore have influenced the reported differences in self-reported

changes in health.

The low response rate (36.4%) may be a threat to the validity for the results of this study,

because non-responders may differ significantly from those who responded. Our findings are,

however in line with findings from other studies investigating symptoms and health changes in

patients after removal of amalgam [24]. This might suggest that a potential non-response bias

has not imposed a major threat to the validity of the results in the present study [30].

Clinical and socio economic significance

Turner and Turk [31] suggest an improvement of 30% on a visual analogue scale as a

clinically meaningful outcome. Seventy-four percent of the participants in our study reported

improvement of symptoms after amalgam removal on a 3 point categorical scale (improved- ,

unchanged-, or worsening of health), an outcome which is thus most likely clinically

meaningful for the individual patients. The data show a linear connection between symptom

load and perceived health status and are therefore in line with data from other patient groups

with a similar symptom load. Since the absolute complaint load is a predictor of functional

24

outcome [32, 33], these results are socioeconomically highly relevant [1, 2]. Even though

patients in the present study still report a substantial symptom load after removal, the reported

changes in experienced healthiness are of importance in the light of a health economic

perspective.

Possible interpretations

The experienced improvement of health was lowest within the first year after amalgam

removal, it increased substantially after the first year, and was still continuously high several

years later. It is not possible to conclude from a cross-sectional survey, which reflects just one

point in time, the possible reasons for this, however some possible hypothesis may be discussed.

The fact that the treatment is complicated and expensive increases the probability for an

expectation dependent placebo effect, which likely plays a role in many medical interventions

[34, 35]. The placebo effect is e.g. reportedly stronger for devices and invasive procedures [36,

37], which are similar procedures to the removal of dental amalgam. The fact that the

experienced improvement of health is directly dependent on the number of precautions taken,

could account for a strong expectation dependent placebo effect but could also be related to

biological effects of the precaution measures.

However, more than 70% of participants reported improved health after amalgam

removal at one to 4 years after removal, and the effect was still stable after more than ten years.

Thus, it cannot be excluded that the placebo effect played a role in the evaluation of health

status. However, considering the time course of the experienced health improvements, this

effect would not be distinguishable from a biologically mediated effect.

Conclusions

Most of the participants in this study reported a substantial improvement of health after

25

amalgam removal. However, they still suffer a variety of complaints. Since absolute complaint

load is a robust predictor for general outcome and socioeconomic burden for society, a possible

intervention, which enables patients to further improve their health status is desirable.

The findings in this survey are in line with a multifactorial origin of persistent health complaints

attributed to former dental amalgam fillings in members of dental patient associations: The

experienced improvement of health increased over time after removal and was linearly

dependent on the number of precautions taken. The latter effect is compatible with potential

placebo effects as well as biological effects. At the same time, the time course seems to be less

in accordance with a potential placebo effect.

Declarations

The authors declare that they have no competing interests.

Acknowledgements

We thank the leader and the administration of NDPA for posting the questionnaires to

their members. Subsequently we are grateful to the members of NDPA who filled in and

returned the questionnaires. The study was funded through a grant from the Norwegian

Directorate of Health. A special thanks to Liljan Smith Aandahl, retired Senior Advisor at the

Norwegian Directorate of Health, who was instrumental in setting up the project for people

with suspected adverse effects from dental amalgam, which this study is part of.

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Appendix II

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Appendix III

Use of complementary and alternative medicine in patients with health complaints attributed to former dental amalgam fillings Agnete E. Kristoffersen1*, Frauke Musial1, Harald J. Hamre2, Lars Björkman3, Trine Stub1, Anita Salamonsen1 and Terje Alræk1 Published in: Kristoffersen AE, Musial F, Hamre HJ, Bjorkman L, Stub T, Salamonsen A, et al. Use of complementary and alternative medicine in patients with health complaints attributed to former dental amalgam fillings. BMC Complement Altern Med. 2016;16:22.

RESEARCH ARTICLE Open Access

Use of complementary and alternativemedicine in patients with healthcomplaints attributed to former dentalamalgam fillingsAgnete E. Kristoffersen1*, Frauke Musial1, Harald J. Hamre2, Lars Björkman3, Trine Stub1, Anita Salamonsen1

and Terje Alræk1

Abstract

Background: The dental filling material amalgam is generally well tolerated. However, a small proportion of dentalpatients experience health complaints which they attribute to amalgam. The symptom pattern is often similarto patients with medically unexplained physical symptoms (MUPS) and the health complaints may persist afteramalgam removal. Among patients with MUPS, the use of complementary and alternative medicine (CAM) seemsto be high. The aim of this survey was to describe the prevalence and range of CAM use among people withhealth complaints attributed to dental amalgam fillings in which the health problems persist after the removalof all amalgam fillings. Specific attention was paid to (1) self-reported effects of CAM, (2) differences in CAM usedependent on self-reported health, and (3) gender differences in self-reported CAM use.

Methods: A survey was distributed to all members of The Norwegian dental patient association (NDPA) (n = 999),the response rate was 36.4 %. The anonymous questionnaire asked for socio-demographic data, health complaintsrelated to former amalgam fillings, subjectively perceived health status, symptoms, and experience with therapeuticinterventions, mostly from the spectrum of CAM. Only participants who had all their fillings removed, which wasthe vast majority, were analysed.

Results: A total of 88.9 % of included respondents had used at least one CAM modality, with a higher proportionof men (95.7 %) compared to women (86.2 %, p = 0.015). The most frequently used therapies were dietarysupplements, vitamins and minerals recommended by a therapist (used by 66.7 %) followed by self-prescribeddietary supplements, vitamins and minerals (59.0 %), homeopathy (54.0 %), acupuncture (48.8 %) and special diets(47.5 %). Use of CAM was similar for participants reporting normal to good health compared to participantsreporting poor health. For all but two CAM modalities, the self-reported treatment effect was better in the groupreporting normal to good health compared to the group reporting poor health.

Conclusions: CAM was widely used by participants in our study, a finding similar to findings from studies of MUPSpatients. To date, health problems associated with the use of dental amalgam is not an accepted diagnosis in thehealthcare system. Consequently, people suffering from such complaints experience a lack of adequate treatmentand support within conventional health care, which might have contributed to the high number of CAM users inthis study.

* Correspondence: agnete.kristoffersen@uit.no1The National Research Center in Complementary and Alternative Medicine,(NAFKAM), Department of Community Medicine, Faculty of Health Sciences,UiT The Arctic University of Norway, Tromsø, NorwayFull list of author information is available at the end of the article

© 2016 Kristoffersen et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Kristoffersen et al. BMC Complementary and Alternative Medicine (2016) 16:22 DOI 10.1186/s12906-016-0996-1

BackgroundAmalgam, an alloy of mercury and other metals, hasbeen used as a dental filling material since the 19th cen-tury and is well tolerated by most people [1]. However, aproportion of people experience health complaints,which they attribute to amalgam [2–4]. Moreover, forsome of these patients the health complains persist evenafter removal of amalgam fillings. The question whetherdental amalgam can cause general health complaints,apart from very rare cases of type-1 hypersensitivity, re-mains controversial [1]. Following removal of all dentalamalgam fillings, an average of three-fourth of peoplewith amalgam-attributed health complaints report im-provement or recovery, while the remainder report noor little improvement or even deterioration [1] (deterior-ation rates are 0.5 %–2 % in population-based surveys[5, 6] and up to 15 % in selected samples [7–9]).Health complaints persisting after amalgam removal

are often similar to symptom patterns associated withmedically unexplained symptoms (MUPS), such as fibro-myalgia and myalgic encephalomyelitis (ME). Many ofthese patients use complementary and alternative medi-cine (CAM) [10–12]. A study of fibromyalgia patients inthe U.S. found that 92.6 % of the participants (mostlywomen) reported to have used some kind of CAM [10].CAM is also frequently used by patients with healthcomplaints related to amalgam [9, 13–16]. In recent stud-ies, the most commonly reported CAM modalities for thispatient group were dietary supplements/vitamins (58–92 %) [9, 14, 15, 17], homeopathy (17–26 %) [9, 13, 14],acupuncture (13–28 %) [2, 9, 14, 16] and chiropractic(18–21 %) [14, 16]. In Norway the most commonly re-ported CAM modalities used for amalgam-related healthcomplaints are dietary supplements, acupuncture and hom-eopathy (65 %, 28 % and 26 % respectively) [9, 17]. The lit-erature has revealed that the prevalence and associationsfor use of CAM differs between men and women withregard to several socio demographic variables [18–23] andunderline the importance of gender-specific analyses [24].The dental amalgam safety issue has been debated

since the 19th century in the U.S [25], since the 1920sand 1930s in Germany [26, 27] and Denmark [28, 29],and since the 1970s internationally [30–35] with patientorganizations active in a number of European countries,North America, Australia and New Zealand [25]. InNorway the debate started in the early 1980s [36, 37]and in 1990 The Norwegian dental patient association(NDPA, Forbundet Tenner og Helse in Norwegian) wasfounded. NDPA is a non-profit patient organizationworking for a non-toxic dentistry. The association alsoworks to ensure that people, who experience themselvesas being hurt/injured by dentistry, shall be entitled torehabilitation and community support. The survey re-ported here was conducted in close cooperation with

NDPA and is thus in accordance with the emphasis onpatient involvement in recent health strategy documentsfrom Norwegian health authorities.In a representative survey of the adult Norwegian

population from 2006, between 5 % and 8 % of the par-ticipants expressed the belief that their amalgam fillingshad affected their health adversely. Further, a total of43 % of adults with amalgam fillings had some or allamalgam fillings removed and in 8 % of these partici-pants, the reasons for the removal of the fillings wereexclusively due to general health concerns [5]. Moreover,knowledge about the use of CAM among Norwegianswith health complaints attributed to amalgam, is limitedto a few studies that describe a limited number of CAMmodalities [9, 17].This cross-sectional survey is part of a collaborative

treatment project for people with suspected adverseeffects from dental amalgam and serve as a basis for thedevelopment of a treatment program, especially designedfor this group of patients. The overall aim of this studywas to describe the prevalence and range of CAM useamong people with health complaints attributed toamalgam fillings, in which these health complaints per-sist after the removal of all amalgam fillings. Specificattention was paid to (1) self-reported effects of CAMtreatments on health complaints, (2) potential differencesin CAM use between participants with self-reported goodvs. poor health, and (3) possible gender differences inself-reported CAM use.Since there is no well-established, general patho-

physiological explanation for the experienced symptomsin this group, we will use the term “amalgam-attributedhealth complaints” throughout the manuscript to denotegeneral symptoms or health complaints for which thepeople affected or other concerned persons suspect thecause to be amalgam fillings, regardless if such a causalassociation has been substantiated or not.

MethodsThe survey was distributed to all members of NDPA inDecember 2011 with a reminder in February 2012. Noinquiry about medical diagnoses was made, thus, noinformation on whether the amalgam-attributed healthcomplaints of the participants could be explained byspecific diseases or were medically unexplained (MUPS)was possible. Common to all participants was the attribu-tion of their health complaints to former dental amalgamfillings.The study participants returned the questionnaires an-

onymously to The National Research Center in Comple-mentary and Alternative Medicine (NAFKAM) by meansof a pre-stamped envelope. The anonymous questionnaireincluded socio demographic data, conditions related tothe amalgam removal, subjectively perceived health status,

Kristoffersen et al. BMC Complementary and Alternative Medicine (2016) 16:22 Page 2 of 8

symptoms, and experience with therapeutic interventions,mostly from the spectrum of CAM. Participants withremaining amalgam fillings were not asked to completethe survey and were therefore excluded from the study.In this study a participant was defined as a CAM user,

according to his or her answer to the following question:

If you have removed all your amalgam fillings becauseof health complaints, which other treatment modalities(forms) have you specifically tried for those healthcomplaints? (Tick (x) for every modality you have triedor not tried. Specify the name of the medication, dietsand treatment institutions you have tried.

Dietary supplements, vitamins and mineralsrecommended by therapist (DSVMT), Dietarysupplements, vitamin and minerals self-prescribed(DSVMS), Homeopathy, Acupuncture, Special diet,Reflexology, Massage, Herbs, Healing, Ear Acupuncture,Kinesiology, Magnetic field therapy, Naprapathy,Biopathy, Thought field therapy, Rehabilitation in aCAM institution, Craniosacral therapy, Lighteningprocess.

Participants answering “I have tried” for at least one ofthe CAM modalities listed above were defined as users.Participants who answered “I have not tried” or hadmissing values in combination with no statement ofeffect for all listed CAM modalities were defined as non-users of CAM. The perceived effect of the treatment wasindicated for each treatment as either “good effect”,“small/no effect” or “worsening”.The CAM modalities were classified in accordance

with the recommendation from The National Center forComplementary and Integrative Health (NCCIH) intothe following five categories: 1) alternative medical sys-tems, or complete systems of therapy and practice suchas Traditional Chinese Medicine and homeopathy; 2)mind-body interventions, or techniques designed to fa-cilitate the mind's effect on bodily functions and symp-toms such as meditation; 3) biologically-based systems,including herbalism; 4) manipulative and body-basedmethods, such as chiropractic and massage therapy and5) energy therapies such as healing [2].Between-group differences were analyzed using chi-

square tests for binary data analyzing one variable at thetime and one-way ANOVA test for continuous data inSPSS for Windows (version 22.0, SPSS, Inc., Chicago, IL).Significance level was defined as p <0.05 without p-valueadjustment for multiple comparisons.The Norwegian Data Inspectorate has been notified

about the study and the Regional Committee for Medicaland Health Research Ethics (REK) has approved thestudy (REK reference 2011/1281).

ResultsA total of 999 envelopes with questionnaires were sentout, of which 46 were returned unopened to sender.Overall, 953 members of NDPA received the question-naire and a total of 347 responded (36.4 % response rate)(Fig. 1).

Basic characteristics of the participantsThe majority of the participants were women (71.6 %)and most participants reported normal to good health(62.4 %). Half of the participants were holding a univer-sity degree and mean age was 60 years. The women wereslightly older than the men (p = 0.001) and men weremore often still working. No significant gender differ-ences were found with regard to education nor self-reported health (Table 1).

CAM use and perceived effect of CAM in the totalpopulationThe mean number of different CAM therapy modalitiesused per participant was 5.7 with a median of 5 in bothmen and women, ranging from 0 to 15 modalities. Themost commonly used CAM modalities were DSVMT (in66.7 % of participants), DSVMS (59.0 %), homeopathy(54.0 %), acupuncture (48.8 %), reflexology (42.3 %),massage (40.1 %) and healing (33.6 %). The perceivedeffects of dietary supplements, vitamins and minerals(DSVMT/DSVMS) were mostly reported to be good(63.0–74.7 %). Roughly half of users reported good effectof homeopathy (57.4 %), reflexology (48.6 %) and mas-sage (41.4 %). By contrast, only one third of users re-ported good effects of healing (33.8 %) and acupuncture

Fig. 1 Flow chart showing the selection of the studied population.NDPA: Norwegian Dental Patients Association

Kristoffersen et al. BMC Complementary and Alternative Medicine (2016) 16:22 Page 3 of 8

(38.8 %). Of the studied population, 12.3 % (n = 40) re-ported worsening of symptoms that they related to theiruse of one or more CAM modalities. In seven out of 18treatment modalities worsening of symptoms were re-ported by 5 % or more. Lightning process and thoughtfield therapy were the only treatment modalities with noworsening of symptoms reported (Table 2).

Gender specific CAM use and perceived effect of CAMOverall CAM use was more frequently reported by men(95.7 %) than women (86.2 %) (p = 0.015). Among men, themost commonly used CAM modalities were DSVMT(72.8 %) followed by DSVMS (71.7 %), homeopathy(56.5 %) and special diet (55.4 %). Among women, DSVMTwas most commonly used (64.2 %), followed by DSVMS(53.9 %), homeopathy (53.0 %) and acupuncture (48.7 %).Comparing the use of individual CAM modalities

between women and men, women were significantly morelikely to use DSVMS (71.7 % vs. 53.9 %, p = 0.003) and lesslikely to use naprapathy (6.5 % vs. 15.9 %, p = 0.024). Nosignificant gender differences were found in regard toCAM categories, though with a trend towards more fre-quent use of biological-based systems by men (p = 0.064).No significant gender differences were found with

regard to self-reported effect of the received CAM treat-ment (Table 3).

CAM use and perceived effect of CAM: subgroup analysisaccording to self-reported healthWhen men and women were divided into groups of self-reported health, no gender differences were found in thegroup reporting normal to good health. In the poorhealth group, on the other hand, the gender differencesreported above remained, with the addition of anothertherapy, magnetic-field therapy, which was significantlymore often used among women than men.There were no significant differences in overall CAM

use between the groups reporting normal to good healthand poor health. However, the CAM category “alterna-tive medical systems” was more commonly used amongparticipants who reported poor health compared to partic-ipants who reported normal to good health (p = 0.032).With regard to individual CAM modalities, the poorhealth group was more likely to use special diets, spiritualhealing, biopathy and Lightning Process than the groupreporting normal to good health. The self-reported effectsof the CAM therapy modalities were reported to be betterin the normal to good health group than in the poorhealth group (Table 3).

DiscussionIn this cross-sectional survey of members of NDPA withpersistent health complaints attributed to former amal-gam fillings, 89 % had used CAM for their health com-plaints. DSVMT was the most commonly used CAMmodality followed by DSVMS, homeopathy, acupunctureand special diet. Similar use was found in participantsreporting normal to good health and participants report-ing poor health. The self-reported effect of differentCAM modalities was highest in the group with normalto good health. More men than women reported use ofCAM in this study. Thus, similar to patients with MUPS,patients with amalgam attributed health complaints arefrequent users of CAM.Health care providers often find patients with medic-

ally unexplained symptoms difficult to handle, andmisunderstandings between health care providers andpatients seem to be common [38]. Since adverse effectsfrom dental amalgam is not an accepted diagnosis in thehealthcare system, the reasons why people with amalgamattributed health complaints turn to CAM modalities, asreported in our study, may be similar.Our findings of high use of CAM in general and diet-

ary supplements and vitamins/minerals in particular arein accordance with findings in other studies of patientswith amalgam-attributes health complaints [9, 13–15, 17].This high use might be partly caused by the fact thatpatient associations and some doctors and therapists rec-ommend vitamins and minerals in conjunction with amal-gam removal [39–41]. Our finding of rather frequent useof homeopathy was also reported in another Norwegian

Table 1 Basic characteristics of the participants

Total Men Women p-value

% (n) % (n) % (n)

Gender

Women 71.6 (232)

Men 28.4 (92)

Age

Mean 60.0 58.8 (SD 11.12) 61.3 (SD 10.26) 0.001*

Education

Primary school 13.4 (42) 7.9 (7) 15.6 (35)

Secondaryschool

27.4 (86) 32.6 (29) 25.3 (57)

High school 15.6 (49) 13.5 (12) 16.4 (37)

University,lower grade

22.0 (69) 25.8 (23) 20.4 (46)

University,higher grade

27.1 (68) 20.2 (18) 22.2 (50) 0.252**

Self-reported health

Normal to good 62.4 (199) 64.8 (59) 61.4 (140)

Poor 37.6 (32) 35.2 (32) 38.6 (88) 0.568**

Working

Yes 59.0 (128) 71.0 (49) 53.4 (79)

No 41.0 (89) 29.0 (20) 46.6 (69) 0.014**

*One-way ANOVA test**Pearson Chi-Square test

Kristoffersen et al. BMC Complementary and Alternative Medicine (2016) 16:22 Page 4 of 8

study of patients with amalgam-attributed health com-plaints [9]. The possible lack of adequate conventionaltreatment available for these health problems might be thereason for the high number of CAM users in this study.Also the fact that the period for CAM use in this studywas “since onset of the health complaints” (instead ofcommonly “in the past year” or similar), might have con-tributed to the high frequency of CAM use.The higher use of CAM among men than women in

our study is not in accordance with findings in previousstudies of other patient groups [18–22]. The reason forthis might be the highly selected group of male partici-pants due to membership in a patient association andremoval of their amalgam filling at their own expense.The fact that more men than women were still workingmight have given more of the men the financially abil-ities to finance CAM use, since CAM is mainly paidout-of-pocket in Norway. The lower use of CAM amongmen than women in most other studies is often attributed

to a presumption that men’s health care needs are bettermet within conventional health care [42], while we heresee CAM use in a population that do not find their healthcare needs met within conventional health care [10]. Edu-cational level and self-reported health were similar in menand women and these factors can therefore not explainthe differences in CAM use.The better self-reported effect of the CAM treatment

among the participants with normal to good health com-pared to those with poor health is an interesting findingand not easy to explain. Generally, since this is a cross-sectional survey, it is impossible to make causal interpre-tations. Possibly, differential effects of CAM therapycould lead to different degrees of health improvement inparticipants with similar health status before therapy.Worsening of symptoms following CAM treatment

was reported by 12.3 % of the participants in our study.For homeopathy, worsening was reported by 2.8 % ofusers, which is much lower than in another Norwegian

Table 2 CAM use and perceived effect in the total population (n = 324)

Reported use Good effect No effect Worsening

% (n) % (na) % (na) % (na)

Over all CAM use 88.9 (288)

Alternative medical systems 68.5 (222)

Homeopathy 54.0 (175) 57.4 (81) 39.7 (56) 2.8 (4)

Acupuncture 48.8 (158) 38.8 (52) 58.2 (78) 3.0 (4)

Ear acupuncture 32.7 (106) 38.8 (33) 58.8 (50) 2.4 (2)

Mind-body interventions 16.0 (52)

Thought field therapy 12.0 (39) 37.5 (12) 62.5 (20) 0 (0)

Lightning process 4.9 (16) 46.2 (6) 53.8 (7) 0 (0)

Biologically-based systems. including herbalism 84.3 (273)

DSVMT 66.7 (216) 74.7 (139) 23.1 (43) 2.2 (4)

DSVMS 59.0 (191) 63.0 (92) 32.2 (47) 4.8 (7)

Special diet 47.5 (154) 74.4 (96) 23.3 (30) 2.3 (3)

Herbs 37.7 (122) 55.6 (50) 38.9 (35) 5.6 (5)

Biopathyb 13.3 (43) 40.6 (13) 56.3 (18) 3.1 (1)

Manipulative and body-based methods 61.4 (199)

Reflexology 42.3 (137) 48.6 (52) 45.8 (49) 5.6 (6)

Massage 40.1 (130) 41.4 (41) 43.4 (43) 15.2 (15)

Kinesiology 29.3 (95) 43.3 (29) 50.7 (34) 6.0 (4)

Naprapathyc 13.3 (43) 46.4 (13) 46.4 (13) 7.1 (2)

Craniosacral therapy 8.6 (28) 42.9 (9) 47.6 (10) 9.5 (2)

Energy therapies 41.7 (135)

Healing 33.6 (109) 33.8 (26) 63.6 (49) 2.6 (6)

Magnetic field therapy 19.1 (62) 29.5 (13) 61.4 (27) 9.1 (4)

Rehabilitation in a CAM institution 9.3 (30) 80.0 (20) 16.0 (4) 4.0 (1)aDue to missing responses to the question about effect, the n regarding effect might be lower than for use of the CAM modalitybBiopathy is a treatment system that encompasses several different alternative diagnostic tools and therapies such as homeopathy, herbs, reflexologycNaprapathy is a system of specific examination, diagnostics, manual treatment and rehabilitation of pain and dysfunction in the neuro-musculoskeletal system

Kristoffersen et al. BMC Complementary and Alternative Medicine (2016) 16:22 Page 5 of 8

Table 3 Gender- and health specific use and effect of CAM

Use of CAM Good effect of CAM Use of CAM Good effect of CAM

Men Women p-value Men Women p-value Normal togood health

Poor health p-value Normal togood health

Poor health p-value

% (n) % (n) % (n) % (n) % (n) % (n) % (n) % (n)

Overall CAM use 95.7 (88) 86.2 (200) 0.015 89.9 (179) 88.3 (106) 0.650*

Alternative medical systems 68.5 (63) 68.5 (159) 0.992 64.3 (128) 75.8 (91) 0.032*

Homeopathy 56.5 (52) 53.0 (123) 0.568 52.3 (23) 59.8 (58) 0.403* 50.3 (100) 60.0 (72) 0.091* 68.4 (54) 42.4 (25) 0.002*

Acupuncture 48.9 (45) 48.7 (113) 0.973 33.3 (13) 41.1 (39) 0.405* 46.2 (92) 54.2 (65) 0.170* 49.3 (37) 25.9 (15) 0.006*

Ear acupuncture 31.5 (29) 33.2 (77) 0.851 32.0 (8) 41.7 (25) 0.405* 34.2 (68) 30.8 (37) 0.539* 43.4 (23) 29.0 (9) 0.191*

Mind-body interventions 14.1 (13) 16.8 (39) 0.553 15.1 (30) 18.3 (22) 0.445*

Thoughtfield therapy 10.9 (10) 12.5 (29) 0.684 42.9 (3) 36.0 (9) 0.740* 12.6 (25) 11.7 (14) 0.813* 47.6 (10) 18.2 (2) 0.139**

Lightening process 4.3 (4) 5.2 (12) 0.757 33.3 (1) 50.0 (5) 1.000** 2.5 (5) 9.2 (11) 0.008* 60.0 (3) 37.5 (3) 0.592**

Biologically-based systems. including herbalism 90.2 (83) 81.9 (190) 0.064 86.9 (173) 80.8 (97) 0.143*

DSVMT 72.8 (67) 64.2 (149) 0.139 74.2 (46) 75.0 (93) 0.905* 68.8 (137) 64.2 (77) 0.389* 80.7 (96) 63.6 (42) 0.011*

DSVMS 71.7 (66) 53.9 (125) 0.003 66.1 (37) 61.1 (55) 0.546* 60.3 (120) 58.3 (70) 0.729* 72.2 (70) 43.8 (21) 0.001*

Special diet 55.4 (51) 44.4 (103) 0.073 76.1 (35) 73.5 (61) 0.746* 42.7 (85) 56.7 (68) 0.016* 79.5 (58) 67.3 (37) 0.119*

Herbs 35.9 (33) 38.4 (89) 0.676 63.0 (17) 52.4 (33) 0.355* 35.7 (71) 41.7 (50) 0.286* 58.8 (30) 50.0 (19) 0.408*

Biopathy 10.9 (10) 14.2 (33) 0.422 50.0 (5) 36.4 (8) 0.699** 10.1 (20) 19.2 (23) 0.021* 35.7 (5) 44.4 (8) 0.618*

Manipulative and body-based methods 60.9 (56) 61.6 (143) 0.898 59.3 (118) 65.5 (79) 0.245*

Reflexology 41.3 (38) 42.7 (99) 0.822 41.9 (13) 51.3 (39) 0.378* 40.2 (80) 45.8 (55) 0.324* 51.6 (32) 43.2 (19) 0.392*

Massage 33.7 (31) 42.7 (99) 0.137 58.3 (14) 36.0 (27) 0.053* 38.7 (77) 43.3 (52) 0.413* 46.3 (25) 36.4 (16) 0.321*

Kinesiology 29.3 (27) 29.3 (68) 0.995 40.0 (8) 44.7 (21) 0.723* 27.1 ((54) 33.3 (40) 0.240* 40.6 (13) 44.1 (15) 0.774*

Naprapathy 6.5 (6) 15.9 (37) 0.024 75.0 (3) 41.7 (10) 0.311** 12.1 (24) 14.2 (17) 0.586* 50.0 (8) 40.0 (4) 0.619**

Craniosacral therapy 5.4 (5) 9.9 (23) 0.196 80.0 (4) 31.3 (5) 0.119** 9.0 (18) 8.3 (10) 0.828* 75.0 (9) 0.0 (0) 0.001**

Energy therapies 40.2 (37) 42.2 (98) 0.739 40.7 (81) 44.2 (53) 0.544*

Healing 35.9 (33) 32.8 (76) 0.593 37.5 (9) 32.1 (17) 0.641** 29.1 (58) 41.7 (50) 0.022* 47.2 (17) 20.0 (8) 0.012*

Magneticfield therapy 14.1 (13) 21.1 (49) 0.149 36.4 (4) 27.3 (9) 0.706** 22.6 (45) 14.2 (17) 0.065* 38.7 (12) 7.7 (1) 0.068**

Rehabilitation in a CAM institution 7.6 (7) 9.9 (23) 0.519 66.7 (4) 84.2 (16) 0.562** 10.6 (21) 7.5 (9) 0.366* 94.4 (17) 42.9 (3) 0.012**

*Pearson Chi-Square test**Fisher's Exact test

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study where 26 % reported worsening after homeopathictreatment regardless of health complains [43]. The de-terioration rate following CAM therapy for amalgam-attributed health complaints in this study (12.3 %) wassimilar to deterioration rates in three studies of amalgamremoval for the same indication, also in highly selectedpatient groups (9.5 % of members of a Swedish dentalpatient association [7]; 14.7 % and 13 % of patientsreferred to dental material adverse reaction units inSweden [29] and Norway [30], respectively) [7–9]. Pos-sibly, deterioration following CAM treatment in thisstudy could be related to characteristics of the selectedpatient group and not just to features of the CAMinterventions.

LimitationsThe main limitation of this study is the highly selectedtarget group: In order to identify and reach patients withpersistent health complaints attributed to former amal-gam fillings, subjects were recruited from a specific pa-tient association and may therefore not be representativefor the total patient group. A German study shows thatmembers of fibromyalgia self-help groups use signifi-cantly more CAM than patients not affiliated with self-help groups [11] while in a Norwegian study of peoplewith amalgam-attributed health complaints, those whohad removed all their amalgam fillings were significantlymore likely to use homeopathy and natural therapy thanthose who still had amalgam fillings [9]. The survey hada modest response rate (36.4 %) which may influence thegeneralizability of the findings. This survey did not con-tain diagnoses of the health complaints; therefore, theprevalence of related conditions such as MUPS cannotbe assessed. Since the CAM use was not limited in time,but related to the amalgam health complaints, regardlessof when they started, the recall period concerning CAMuse might have been long and resulted in inaccuracieswith regard to the reported use of CAM therapies. Also,the reported subgroup differences with regard to CAMuse and self-reported CAM effects should be treatedwith caution, because of multiple hypothesis testing anddue to low sample sizes in some subgroups.

InterpretationThis is the first survey of CAM use among people withamalgam-attributed health complaints in Norway ad-dressing a broad range of CAM modalities. To our know-ledge, it is the first study of CAM use worldwide to focuson the subgroup of people with amalgam-attributed healthcomplaints, in which the health complaints persist follow-ing complete amalgam removal, and is therefore a dooropener to the field. The results from this study were usedfor the development of an Integrated Medical Care

Rehabilitation program for this patient group, in whichCAM is given as a part of the program.

ConclusionFindings from this study suggest that CAM was widelyused by people with health complaints attributed to den-tal amalgam fillings, and who had removed all amalgamfillings, and were member of a patient organization,NDPA. The reasons for the considerably high use ofvarious CAM modalities may be related to the experi-enced lack of support and treatment offers within theconventional health care system.

AbbreviationsMUPS: Medically unexplained physical symptoms; ME: Myalgicencephalomyelitis; CAM: Complementary and Alternative Medicine;NAFKAM: National Research Center in Complementary and AlternativeMedicine; OTC: Over the counter; NDPA: Norwegian Dental PatientsAssociation (Forbundet tenner og helse in Norwegian); NCCIH: NationalCenter for Complementary and Integrative Health; DSVMT: Dietarysupplements, vitamins and minerals recommended by therapist;DSVMS: Dietary supplements, vitamin and minerals self-prescribed;REK: Regional Committee for Medical and Health Research Ethics.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsTA conceived the study, TA; HJH and LB compiled the questionnaires, AEKand FM performed the initial and final analyses. All authors helped draft themanuscript and reviewed subsequent versions; and all authors read andapproved the final manuscript.

AcknowledgementsWe acknowledge the leader and the administration of NDPA with postingthe questionnaires to the members of NDPA. Subsequently we are gratefulto the members of NDPA who filled in and returned the questionnaires.The study was funded through a grant from the Norwegian Directorate ofHealth. Special thanks to Liljan Smith Aandahl, retired Senior Advisor at theNorwegian Directorate of Health, who was instrumental in setting up theproject for people with suspected adverse effects from dental amalgam,which this study is part of.

Author details1The National Research Center in Complementary and Alternative Medicine,(NAFKAM), Department of Community Medicine, Faculty of Health Sciences,UiT The Arctic University of Norway, Tromsø, Norway. 2Institute for AppliedEpistemology and Medical Methodology at the University ofWitten-Herdecke, Freiburg, Germany. 3Dental Biomaterials Adverse ReactionUnit, Uni Research Health, Bergen, Norway.

Received: 26 August 2015 Accepted: 12 January 2016

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Kristoffersen et al. BMC Complementary and Alternative Medicine (2016) 16:22 Page 8 of 8

Appendix IV

Operationalizing the use of patient experiences for the selection of

treatment options in a clinical trial: The “USB” (Use – Safety - Benefit)

principle and the Integrated Medical Care Rehabilitation trial for patients

with amalgam attributed health complaints

Frauke Musial1*, Agnete Egilsdatter Kristoffersen1, Terje Alræk1, Harald Johan Hamre2,

Trine 6 Stub1, Lars Björkman3 & Vinjar Fønnebø1

Under review in BMC Complementary and Alternative Medicine

Operationalizing the use of patient experiences for the selection of 1

treatment options in a clinical trial: The “USB” (Use – Safety - Benefit) 2

principle and the Integrated Medical Care Rehabilitation trial for patients 3

with amalgam attributed health complaints 4

5

Frauke Musial1*, Agnete Egilsdatter Kristoffersen1, Terje Alræk1, Harald Johan Hamre2, Trine 6

Stub1, Lars Björkman3 & Vinjar Fønnebø1 7

8

1The National Research Center in Complementary and Alternative Medicine (NAFKAM), 9

Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University 10

of Norway, Tromsø, Norway 11

2Institute for Applied Epistemology and Medical Methodology at the University of Witten-12

Herdecke, Freiburg, Germany 13

3Dental Biomaterials Adverse Reaction Unit, Uni Health, Uni Research, Bergen, Norway 14

* Corresponding author 15

16

E-mail adresses: 17

Frauke Musial: frauke.musial@uit.no 18

Agnete E. Kristoffersen: agnete.kristoffersen@uit.no 19

Terje Alræk: terje.alrak@uit.no 20

Harald J. Hamre: harald.hamre@ifaemm.de 21

1

Trine Stub: trine.stub@uit.no 22

Lars Björkman: lars.bjorkman@uib.no 23

Vinjar Fønnebø: vinjar.fonnebo@uit.no 24

25

26

2

Abstract 27

BACKGROUND: 28

The patients’ role has changed from being the object of healthcare interventions to an active 29

decision maker. Consequently, more patient involvement in clinical research has become a 30

demand in Norway, but reflects also a general trend. We suggest a rational strategy for a 31

patient driven selection of treatments, framed by the numbers of users, safety, and benefit. 32

The selected interventions were used as part of a rehabilitation program, the Integrated 33

Medical Care Rehabilitation (IMCR) trial, for patients with amalgam-attributed health 34

complaints. 35

36

METHODS: 37

An anonymous questionnaire asking for experience with therapeutic interventions was 38

distributed to all members of The Norwegian dental patient association (NDPA) (n = 999; 39

response rate: 36.4 %). The anonymous questionnaire. Step I: Therapies were ranked 40

according to the number of users. Treatments where the confidence interval of a proportion 41

would be up to ± 10% at a reported proportion of 20% were included. Step II: In order to 42

minimize risk, the percentage of all participants reporting worsening was used as the criterion 43

to rank the therapies according to risk. The threshold for exclusion was set at 2% or more of 44

the total sample at risk. Step III: The remaining therapies were ranked according to benefit 45

and a criterion of at least 20% reporting benefit was set for inclusion. Moreover, therapies 46

were assessed for feasibility within the framework of the program. A quantitative 47

methodology for the measurement of patients’ experiences and preferences of a patient 48

population the “Patient Experience-based Benefit/Risk Index” (PEBRI) was developed in addition. 49

3

RESULTS: 50

The following therapies remained after the selection process,: dietary supplements, vitamins 51

and minerals recommended by therapist (DSVMT); special diet; herbs; reflexology; 52

kinesiology; acupuncture; ear acupuncture; physiotherapy; healing; homeopathy and 53

medications over the counter. With the exception of the last, these therapies were included in 54

the IMCR trial. 55

56

CONCLUSIONS: 57

The conduct of a survey among the target group is a probate and feasible methodology in 58

order to operationalize patient participation in clinical studies. In a situation where there is no 59

scientific evidence for the risk/benefit profile of the preferred interventions available, the USB 60

(use-safety-benefit) approach provides a helpful guide for decision making. 61

62

Keywords 63

64

Patient participation; safety; decision making; design clinical trial; Patient Experience-based; 65

Benefit/Risk Index 66

67

4

Background 68

Over the last decade, the patients’ role in their treatment has changed dramatically. The 69

availability of medical information, in particular through the Internet, has led to a situation 70

where patients are increasingly taking over the role of decision makers. Patient empowerment 71

and the role of an active patient is a relatively new concept, but the scarce evidence available 72

suggests that patients can play a distinct role in promoting their own health and that this 73

approach may even be cost effective in the long run [1]. 74

Norway is currently in a process of implementing a higher degree of patient participation in 75

health care. According to the “Coordination reform” patients shall participate in their own 76

preventive, treatment, rehabilitation and care programs, and patient and user organizations 77

shall be involved at the system level [2]. The principal understanding, which formed the basis 78

for such a fundamental position is that ".... Patients who participate in the planning and 79

monitoring of their health care, are better able to mobilize their own resources. This can 80

improve the prospects for good results" [3]. 81

One of the consequences of this fundamental change is a growing demand for patient 82

involvement in clinical research in Norway [4]. Patient participation on the individual and 83

system level in all phases of planning and execution of clinical trials or health services 84

research, is now mandatory. 85

The dental amalgam safety issue has been debated in Norway since the early 1980ies [5, 6] 86

and in 1990 the Norwegian dental patient association (NDPA, Forbundet Tenner og Helse in 87

Norwegian) was founded. NDPA is a non-profit patient organization working for a non-toxic 88

dentistry. The association also works to ensure that people, who experience themselves as 89

being hurt/injured by dentistry, shall be entitled to rehabilitation. Since the 1990ies the use of 90

amalgam in Norway has declined substantially, and in 2008 the use of amalgam was 91

5

prohibited in Norway for environmental reasons [7]. In 2011 the Norwegian Ministry of 92

Environment proposed a global ban on the use of mercury [8]. 93

In 2006, a population survey among 2000 adult Norwegians revealed that between 5% and 94

8% of the respondents expressed the belief that their amalgam fillings had affected their 95

health adversely. Nearly half of the adults with amalgam fillings had had some or all amalgam 96

fillings removed. In 8% of those who had had their amalgam fillings removed, the given 97

reason for the removal was exclusively “general health reasons” [9]. 98

In 2009 the Norwegian Ministry of Health and Care Services asked the Norwegian 99

Directorate of Health to initiate a collaborative treatment project for patients with suspected 100

adverse effects from dental materials ("Samarbeidsprosjekt mellom tannhelsetjenesten og 101

helsetjenesten om utprøvende behandling ved mistanke om bivirkninger av odontologiske 102

biomaterialer"). The aim of the Collaborative Treatment Project was to achieve improved 103

health and/or quality of life in patients with health complaints which they relate to dental 104

materials. Part of this project was the development of a rehabilitation program for persons 105

with persistent health complaints after amalgam removal, the so called integrated medical care 106

rehabilitation trial (IMCR trial). 107

Even though the possible pathophysiology for amalgam related health complaints is to date 108

not understood, some experience a high symptom-load and in some cases these symptoms 109

persist even after the removal of the amalgam fillings. The symptoms can be severe, interfere 110

with everyday activities, and can impose a major burden to the patients’ quality of life. 111

Moreover, it is known from other conditions, that a high symptom load can represent a 112

socioeconomic burden [10] and is associated with a poor functional prognosis [11, 12]. Thus, 113

to develop an intervention that might ameliorate the high symptom load of these patients and 114

that supports them with strategies in order to cope better with their everyday challenges, could 115

be of high socioeconomic relevance. 116

6

No treatment studies directed specifically at this patient group have been performed [13], and 117

there is therefore no established intervention available. As a consequence, we decided to 118

develop a resource and lifestyle oriented intervention which should be based on available 119

scientific evidence from patients with similar symptom patterns [14-23]. Moreover, the 120

intervention would also be built on the experience and preferences of the target patient group. 121

We planned this intervention program (the details of which will be published elsewhere) as a 122

group program [24], focusing on lifestyle and the strengths of the participants (resource 123

oriented/), combined with an element of optional symptom-focused individualized 124

interventions. 125

In the symptom oriented, individualized part of the intervention, patients would be free to 126

choose a selection of conventional- and Complementary and Alternative Medicine (CAM) 127

therapies. The selected therapies should ideally be based on patient experience and 128

preferences, and were derived from the results of a cross-sectional survey conducted among 129

the members of NDPA who had had all their amalgam fillings removed, but were still 130

experiencing a high symptom load. The survey was developed in close cooperation with 131

NDPA, and is thus in accordance with the emphasis on patient involvement and the demand 132

for patient participation in clinical research in Norway, as mentioned previously. The results 133

of the survey confirmed and extended earlier findings [25-28] namely that patients with 134

amalgam-attributed health complaints use CAM to a considerable degree [29]. 135

It was clear at the time of the survey that not all of the 26 therapies listed in the questionnaire 136

would be included in the intervention program. The goal was to select interventions in order 137

to accommodate patient preferences to the largest extent possible, while at the same time 138

ensuring patient safety as well as rigorous methodological standards and quality. 139

This paper describes the selection procedure for the therapies to be included in the IMCR trial 140

based on the NDPA survey. 141

7

Methods 142

Survey of self-reported use, safety and benefit of treatments for amalgam-attributed 143

health problems 144

The survey methodology has been described in detail previously [29]. Common to all 145

participants was the attribution of their health complaints to former dental amalgam fillings. 146

Information about the study was sent out together with the questionnaire. The study 147

participants returned the questionnaires anonymously to The National Research Center in 148

Complementary and Alternative Medicine (NAFKAM) by means of a pre-stamped envelope. 149

No informed consent was required since the questionnaire was anonymous. 150

Briefly, a total of 999 letters were sent through NDPA to all their members, of which 46 were 151

returned to sender. Overall, 953 members of NDPA received the questionnaire and a total of 152

347 responded (36.4%). Of these, n=23 were excluded due to remaining amalgam fillings. 153

Figure 1 depicts the inclusion flow chart. 154

8

155

Figure 1: Inclusion flow chart. 156

157

The survey included a section about use of various treatments for the persistent health 158

complaints attributed to the previous amalgam fillings (26 interventions in total). Most of 159

these therapies (n=18) were CAM interventions and the results of the survey regarding their 160

utilization among the target patient group are presented elsewhere [29]. Others are not 161

considered CAM (8 out of the 26) or standard treatment, but are in wide use among patients 162

with amalgam attributed health complaints (most of these therapies will be known, with the 163

exception of “chelators”. Chelators indicate off-label use of chelating agents, which are 164

medications otherwise used for treatment of acute heavy metal poisoning). However, they are 165

of relevance in this context, because patients have found them helpful, or have experienced 166

worsening of their condition during these interventions. 167

9

The question "If you have removed all your amalgam fillings because of health complaints, 168

which other treatment modalities (forms) have you specifically tried for those health 169

complaints?" was followed by the list of 26 therapies. The participants were asked, for each 170

of these, whether they had used it or not. If they answered “yes”, they were asked whether the 171

therapy had “good effect”, “no effect” or if it had caused a “worsening”. 172

When selecting therapies to be included in the intervention trial, the consideration of the 173

harm/benefit relation was most fundamental. We operationalized the selection procedure into 174

a sequence of three steps, corresponding to a hierarchical set of three criteria based on use, 175

safety and benefit (USB): 176

Use: Sufficient number of therapy users as basis for the selection

Safety: Minimize risk

Benefit: Maximize benefit

177

This principle and the rationale for the three criteria and their hierarchical order was to set a 178

priori before selecting therapies to be included. 179

The principle of "safety first" or "safety [Step II] coming before benefit [Step III]" is 180

fundamental in modern medicine [30] and implemented in health-related legislation in many 181

countries and at the European level. However, in order to enable an adequate assessment of 182

risks and benefit of a therapeutic intervention, a minimum amount of knowledge must be 183

available. That is the rationale for evaluating whether the data set includes a sufficient number 184

of users as in Step 1. 185

10

Criteria for sufficient number of users for judgment: (Step I) 186

Defining the minimum number of users needed is of course a matter of judgment. There needs 187

to be a narrow enough confidence interval for both relevant groups, around the proportion 188

reporting benefit, as well as around the proportion reporting worsening in response to the 189

treatment. We chose to only include treatments where the confidence interval of this 190

proportion would be up to ± 10% at a reported proportion of 20%. 191

𝑛𝑛 =0,2 ∗ 0,8

0,052 193

192

Standard sample size calculation [31] shows that this requires a minimum of 64 individuals 194

reporting use of the therapy in question. 195

196

Criteria to minimize risk (Step II) 197

With regard to patient safety, the question whether participants felt worse after the 198

intervention is most relevant, and was regarded as highly important information for the design 199

of the intervention. However, it is relevant to keep in mind that the judgment “worse” in this 200

questionnaire does not only relate to possible adverse effects induced by the therapy; 201

“worsening” can also be a consequence of a non-helpful treatment during a progressive or 202

fluctuating disease course [32]. Nonetheless, regarding the interpretation of the outcome of 203

the survey, self-reported “worsening” is the variable which is most suitable for risk 204

assessment. 205

The percentage of ALL users reporting “worsening” as a criterion was chosen with the rationale 206

that risk should be assessed as conservatively as possible and risk assessment should have the 207

highest priority with regard to the choice of therapies selected for inclusion in the IMCR trial. 208

11

Therefore, the standpoint was taken, that when a total of n=324 participants are asked about a 209

group of interventions, that number of participants in the total sample is at risk, irrelevant of 210

how many participants actually used the intervention. Therefore, the percentage of ALL 211

participants reporting worsening was used as the criterion to rank the therapies according to 212

risk. The choice of threshold is again a judgment. Our choice was to set this percentage at 2%. 213

This corresponds to n=7 or more participants reporting worsening. 214

215

Criteria to maximize benefit (Step III) 216

The therapies were lastly ranked according to the percentage of users who experienced 217

symptom relief (“good effect”) after utilization. Thus, if e.g. a high percentage of participants 218

who used the therapy experienced benefit, then that therapy would rank high, even though the 219

absolute number of participants who tried this therapy might be lower than for another 220

intervention. Again, the choice of a criterion is a matter of judgement. We chose a proportion 221

of at least 20 % reporting good effects from the respective treatment to be sufficient for 222

inclusion. 223

224

Feasibility assessment 225

Theoretically, all therapies remaining after step III of the selection process might be included 226

into a trial. However, a trial usually has limitations such as e.g. the financial framework, or 227

limitations due to practicability. Therefore, the final selection of which therapies to include in 228

a trial will depend on how feasible that particular therapy is within the framework of the trial. 229

12

A criterion for adequate benefit? 230

Usually one can assume, that there is room for a certain number of therapeutic choices in a 231

trial. Since Step I ensures a sufficient number of users, it is appropriate to include from the top 232

of the list as many therapies as the framework of the trial allows. 233

However, a particular patient population may express particular preferences for or against 234

interventions and most likely these are based on experience. These preferences may vary 235

according to the symptom complex. A quantitative methodology for the measurement of 236

patients’ experiences and preferences of a patient population could be the index of number of 237

patients experiencing good effect divided by the number of patients experiencing worsening 238

of symptoms. We call this the “Patient Experience-based Benefit/Risk Index” (PEBRI). Even 239

though not applied in the IMCR trial, the PEBRI could have been used as a fourth selection criterion. 240

Results 241

Step I 242

The ranking of the therapies according to the percentage of participants using the therapy in 243

the total sample (n=324) is presented in Figure 2. The percentages behind the bars relate to 244

the total of n=324 while the numbers in brackets report the absolute numbers of participants 245

using the therapy. Dietary supplements, vitamins and minerals recommended by therapist 246

(DSVMT) was with 66.7 % (n=216) the most frequently used intervention, while Lightning 247

process was used the least by only 4.9 % (n=16) of the participants. 248

According to our criteria, n=64 individuals are needed in order to secure sufficient sample 249

size for judgment. This resulted in the inclusion of all therapies from Chelators upwards (cf 250

Figure 2) into the following Step II. 251

252

13

253

Figure 2: The list of therapeutic interventions ranked according to frequency of use in percent 254

from a total of n=324 participants. The numbers in brackets show the absolute numbers of 255

participants, the numbers without brackets indicate percentages of the frequencies in relation 256

to the total sample. (DSVMT = Dietary supplements, vitamins and minerals recommended by 257

therapist, DSVMS = dietary supplements, vitamins and minerals, self-prescribed) 258

259

260

Step II 261

Participants, who answered “yes” with regard to utilization, were then asked, whether the 262

therapy had “good effect”, “no effect” or if it had caused a “worsening” of the health 263

complaints. Figure 3 shows the therapies included into Step II because they were used by a 264

sufficient number of patients, ranked according to the percentage of the total number of all 265

14

324 informants who experienced worsening of symptoms. Medicines prescribed by a doctor 266

with 37 of the participants experiencing worsening was the most “risky” therapy, followed by 267

chelators (n=21), massage (n=15) and DSVMS (n=7). 268

269

270

271

Figure 3: The list of therapeutic interventions ranked according to the absolute numbers of 272

participants who experienced worsening of the symptoms. (DSVMT = Dietary supplements, 273

vitamins and minerals recommended by therapist, DSVMS = dietary supplements, vitamins 274

and minerals, self-prescribed) 275

276

According to the criterion for Step II, therapies were excluded for which n=7 or more 277

participants reported worsening. As a consequence, the interventions Medicine prescribed by a 278

15

doctor, Chelators, Massage, and DSVMS were excluded, while the other interventions were 279

included into the following Step III (Figure3). 280

281

Step III 282

Figure 4 shows the therapies ranked according to the percentage of users of the respective 283

therapy who experienced symptom relief (“good effect”) after utilization. Note that the 284

percentages are related to the number of users of the therapy in question (not to the whole 285

sample). The self-reported most beneficial therapeutic intervention was, Dietary supplements, 286

vitamins and minerals recommended by therapist (DSVMT). 287

288

Figure 4: The list of therapeutic interventions ranked according to the percentage of 289

participants who experienced symptom relief after utilization. The numbers in brackets show 290

16

the absolute numbers of participants, the numbers without brackets indicate the percentages 291

related to the number of participants who stated having used the therapy in question. 292

293

Interventions related to nutrition, such as dietary supplements, vitamins and minerals 294

recommended by therapist (DSVMT), special diet, and herbs were perceived as being very 295

helpful with regard to symptom relief. Moreover, patients reported good experiences with 296

homeopathy, reflexology, acupuncture, ear acupuncture, kinesiology, physiotherapy, 297

medications over the counter and healing. All 11 therapies fulfilled the criterion of at least 298

20% of users reporting good effects, and were thus assessed for feasibility in the trial. 299

300

Feasibility 301

Of the 11 therapies assessed for feasibility, 10 could be included into the IMCR trial. 302

Medications over the counter was not included for lack of feasibility within the trial 303

conditions. 304

305

Adequate benefit 306

The PEBRI not only takes the experienced benefit within a particular patient population into 307

account, it sets this benefit in relation to potential worsening. Figure 5 depicts the PEBRI for 308

patients with amalgam attributed health complaints in this survey. 309

310

311

312

17

313

Figure 5: The “Patient Experience-based Benefit/Risk Index” (number of patients 314

experiencing good effect divided by the number of patients experiencing worsening of 315

symptoms) of the remaining therapies for this particular patient population. 316

317

The results show, that the PEBRI gives a slightly more differentiated picture of patients 318

preferences, even though the general tendency conforms the ranking according to benefit. 319

However, here e.g. healing ranks considerably higher (place 3) then if just the benefit was 320

taken into account, where healing was ranked lowest. 321

18

322

Discussion 323

We developed a three-step algorithm for selection of treatments to include into a rehabilitation 324

program. In the first step, 11 therapies of 26 were excluded because not enough patients had 325

experience with them. In step II, safety, 4 of the remaining 15 therapies were excluded, 326

because 2% or more of all respondents reported a worsening of symptoms. In step III, all 327

remaining therapies were included because more than 20% of patients had reported benefit. 328

329

Moreover, we suggest a patient experience based index, PEBRI, potentially providing a 330

quantitative methodology for the measurement of patients’ experiences of benefits and risks 331

with therapies within a particular patient population. The PEBRI is basically independent 332

from the USB principle of the selections process, but provides a patient centered risk/benefit 333

profile of the population of therapies to be investigated. 334

335

As pointed out above, interventions related to nutrition, such as dietary supplements, vitamins 336

and minerals recommended by a therapist (DSVMT), special diet, and herbs ranked high in 337

the preference of the patients responding to the survey. Nutrition is known to have a 338

substantial impact on health and is therefore generally a core part or “building block” in all 339

illness coping and health behavior programs [33-35]. This was also the case in the group 340

program developed for the intervention trial and accordingly, these interventions were not 341

included in the individualized part of the treatment program, but the focus on nutrition in the 342

group program was extended. 343

344

19

Even though there is no high-quality scientific efficacy/effectiveness documentation available 345

for some of the remaining therapies, none of them are known to impose a particular risk upon 346

patients, if they are applied correctly (http://www.nifab.no/). “Medications over the counter” 347

was not considered to be an intervention which could be operationalized within the 348

framework of the treatment program and was therefore excluded for lack of feasibility. 349

In the light of patient safety, a hierarchy of three criteria 1) Keep a sufficient number of 350

therapy users as basis for the selection (Use), 2) Minimize risk (Safety), 3) Maximize benefit 351

(Benefit), which we call the “USB-principle”, is in our view non-negotiable. However, we are 352

aware, that some of the cut-off limits set can be debated. To our knowledge, this is the first 353

attempt to apply this kind of design requiring such a selection strategy, and there are therefore 354

no established rules and cut-off limits. We acknowledge that for interventions with other risk 355

structures, our cut-off limits may have to be modified. 356

Conclusions 357

In conclusion, if patient participation and patient experiences are to be taken into account 358

while developing a treatment program, the conduct of a survey among the target group is in 359

our view a probate and feasible methodology in order to learn about their preferences and 360

perceived benefits and risks. In a situation where there is no scientific evidence for the 361

risk/benefit profile of the preferred interventions available, we found the USB-principle 362

described above which may or may not be combined with the PEBRI which provides a 363

quantifiable measure for patients experiences of benefits and risks, a helpful guide for 364

selecting which treatment interventions to be included. 365

366

20

367

Declarations 368 369

Abbreviations 370

IMCR trial: Integrated medical care rehabilitation trial 371

USB: use-safety-benefit 372

NAFKAM: National Research Center in Complementary and Alternative Medicine; 373

NDPA: Norwegian Dental Patients Association (Forbundet tenner og helse in Norwegian); 374

CAM: Complementary and Alternative Medicine; 375

NSD: Norwegian center for research data, (Norsk senter for forskningsdata) 376

REK: Regional Committee for Medical and Health Research Ethics. 377

DSVMT: Dietary supplements, vitamins and minerals recommended by therapist; 378

DSVMS: Dietary supplements, vitamin and minerals self-prescribed; 379

P E B R I : Patient Experience-based Benefit/Risk Index 380

381

Ethics 382

The Regional Committee for Medical and Health Research Ethics (REK) has considered the 383

study (REK reference 2011/1281) and decided that no ethic approval was needed due to full 384

anonymity of the participants. Therefore, the study was registered at The Norwegian Data 385

Inspectorate (NSD). No informed consent was required since the questionnaire was 386

anonymous. 387

388

21

Availability of data and materials 389

The dataset on which the analyses were performed can be obtained from the corresponding 390

author, while the raw dataset is not available due to Norwegian privacy regulations. 391

Applicants must be prepared to conform to Norwegian privacy regulations. 392

393

Competing interests 394

The authors declare that they have no competing interests. 395

396

Funding 397

The study was funded through a grant from the Norwegian Directorate of Health. 398

399

Authors’ contributions 400

FM and TA conceived the IMCR trial; TA; HJH and LB compiled the questionnaires; FM 401

and VF developed the selection strategy; FM; AEK and VF performed the analyses. FM, VF, 402

TS, and AEK drafted the manuscript. All authors reviewed and developed subsequent versions; 403

and all authors read and approved the final manuscript. 404

405

Acknowledgements 406

We acknowledge the leader and the administration of NDPA with posting the 407

questionnaires to the members of NDPA. Subsequently we are grateful to the members of 408

NDPA who filled in and returned the questionnaires. Special thanks to Liljan Smith 409

Aandahl, retired Senior Advisor at the Norwegian Directorate of Health, who was 410

22

instrumental in setting up the project for people with suspected adverse effects from dental 411

amalgam, which this study is part of. 412

413

414

415

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28. Olsson G, Lindh U: Veränderung des allgemeinen Gesundheitszustand nach 493 Amalgamentfernung - eine zähnjährige Studie. GZM Ganzheitl Zahnmed 1997, 1. 494

29. Kristoffersen AE, Musial F, Hamre HJ, Björkman L, Stub T, Salamonsen A, Alraek T: Use of 495 complementary and alternative medicine in patients with health complaints attributed to 496 former dental amalgam fillings. BMC Complement Altern Med 2016, 16(1):22. 497

24

30. Smith CM: Origin and Uses of Primum Non Nocere—Above All, Do No Harm! The Journal of 498 Clinical Pharmacology 2005, 45(4):371-377. 499

31. Kirkwood BR, Sterne AC: Calculation of required sample size. In: Essential Medical Statistics. 500 edn. Oxford: Blackwell Science Ltd; 1988: 413-428. 501

32. Stub T, Salamonsen A, Kristoffersen A, Musial F: How to Handle Worsening of Condition 502 during Treatment - Risk Assessment in Homeopathic Practice. Forschende 503 Komplementärmedizin / Research in Complementary Medicine 2015, 22(1):30-35. 504

33. Sköldstam L, Hagfors L, Johansson G: An experimental study of a Mediterranean diet 505 intervention for patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 2003, 506 62(3):208-214. 507

34. Ornish D, Magbanua M J M, Weidner G, Weinberg V, Kemp C, Green C, Mattie M D, Marlin R, 508 Simko J, Shinohara K et al: Changes in prostate gene expression in men undergoing an 509 intensive nutrition and lifestyle intervention. Proceedings of the National Academy of 510 Sciences 2008, 105(24):8369-8374. 511

35. Ornish D: Intensive lifestyle changes and health reform. The Lancet Oncology 2009, 10(7):638-512 639. 513

514

25

Appendix V

«Everyone with a chronic disease should be offered this program» - participants experience with an Integrative Medicine group program. “Jeder mit einer chronischen Erkrankung sollte an diesem Program teilnehmen” – Teilnehmererfahrungen mit einem integrativmedizinischem Gruppenprogramm. Alræk, T. 1, Stub T. 1, Kristoffersen A. 1, von Scheidt C. 2, Bruset S. 3, Michalsen A. 4

& Musial F. 1*

Under review in Research in Complementary Medicine / Forschende

Komplementärmedizin

«Everyone with a chronic disease should be offered this program» - participants experience with an Integrative Medicine group program.

“Jeder mit einer chronischen Erkrankung sollte an diesem Program teilnehmen” – Teilnehmererfahrungen mit einem integrativmedizinischem Gruppenprogramm.

Alræk, T. 1, Stub T. 1, Kristoffersen A. 1, von Scheidt C. 2, Bruset S. 3, Michalsen A. 4 & Musial F. 1* 1The National Research Center in Complementary and Alternative Medicine (NAFKAM),

Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University

of Norway, Tromsø, Norway

2Mind Body Medicine, Immanuel Krankenhaus, Berlin, Germany

3Regnbuen helsesenter, Lierskogen, Norway

4Charité – Universitätsmedizin Berlin, Berlin, Germany

* Corresponding author

Frauke Musial, Ph.D.

National Research Center in Complementary and Alternative Medicine, NAFKAM, Department of Community

Medicine, Faculty of Health Science

UiT, The Arctic University of Norway

9037 Tromsø

Norway

Tel. (+47) 77 64 92 82 (Frauke Musial)

Tel. (+47) 77 64 66 50 (NAFKAM)

Fax. (+47) 77 64 68 66

E-mail: frauke.musial@uit.no

1

Abstract

BACKGROUND: The Integrated Medical Care Rehabilitation (IMCR) program was designed for patients with

amalgam-attributed health complaints. Special emphasis was placed on patient participation

and patient empowerment. The aim of this qualitative study was to describe personal feedback

on mental, emotional, and bodily experiences with the program.

METHODS: Qualitative data were drawn from the study participants (n=18) from the three intervention

groups. Four open questions were asked as part of a anonymized questionnaire, which

presented a possibility to describe personal experiences with the IMCR program. The

questionnaires were sent back to the research team in sealed envelopes. Analysis method was

systematic text condensation.

RESULTS: Most participants were very satisfied with the program. They appreciated the resource

oriented focus of the program. After completion of the training, many participants integrated

relaxation and breathing exercises into their daily lives and reported calmness and a more

positive view on life.

CONCLUSION: Data from this qualitative study suggests that a program with several modalities such as life

style advices, complementary therapies, relaxation exercises and stress management tools is

beneficial for chronically ill patients with amalgam attributed health complaints. Beyond that,

we conclude that the IMCR program can be useful for chronically ill patients with a similar

symptom profile.

Keywords

Integrative medicine, rehabilitation, qualitative research, Amalgam attributed health complaints, Mind-Body medicine, group intervention Integrativmedizin, Rehabilitation, Qualitative Forschung, Amalgam attribuierte Beschwerden, Mind-Body medicine, Gruppenprogramm

2

Zusammenfassung

Hintergrund: Das Integrated Medical Care Rehabilitation (IMCR) Programm wurde für Patienten mit

Amalgam attribuierten gesundheitlichen Beschwerden entwickelt. Besonderes Augenmerk

wurde bei der Entwicklung der Intervention auf die Patientmitwirkung und „Empowerment“

gelegt. In dieser qualitativen Untersuchung wurde den Studienteilnehmern die Möglichkeit

gegeben, ihr ganz persönliches Feedback über die mentalen, emotionalen und körperlichen

Erfahrungen mit dem Programm zu geben.

METHODE: Qualitative Daten wurden von n = 18 Studienteilnehmern aus drei Interventionsgruppen

erhoben. Im Rahmen eines anonymisierten Fragebogens wurden neben standardisierten

Fragebögen auch vier offene Fragen gestellt, in denen die Studienteilnehmer ihre persönlichen

Erfahrungen mit dem IMCR Programm beschreiben konnten. Die Fragebögen wurden in

versiegelten Umschlägen an das Forschungsteam zurückgeschickt und mittels „systematic text

condensation“ analysiert.

Ergebnisse: Die meisten Teilnehmer waren sehr zufrieden mit dem Programm und schätzten die

ressourcenorientierte orientierte Ausrichtung des Programms. Die Teilnehmer berichteten,

dass sie Entspannungs- und Atemübungen in ihr tägliches Leben integrieren konnten und dass

die Teilnahme an dem Programm zu mehr Ruhe und einer positiveren Sicht auf das Leben

geführt habe.

Schlussfolgerung: Die Ergebnisse legen nahe, dass ein multimodales Therapieprogramm bestehend aus

Lebensstilveränderung, symptomorientierten komplementären Therapien,

Entspannungsübungen und psychosozialen bzw. Stressbewältigungsstrategien von chronisch

kranken Patienten mit Amalgam attribuierten Gesundheitsproblemen als nützlich und hilfreich

erlebt wurde.

3

Introduction In Norway, amalgam attributed health complains have been an issue for many decades and

as many as 5% to 8% of the participants of a representative survey of the adult Norwegian

population (n=2000 participants) believed that they suffered from amalgam induced health

problems. In 8% of the participants, who had removed their amalgam fillings (out of 43% in

total) the motivation for removal was related to amalgam attributed health concerns [1].

Generally, amalgam is considered to be a safe dental material. However, amalgam was

banned in Norway in 2008 due to a general concern about environmental effects from

mercury. It is to date still controversial, if mercury exposure from dental amalgam is

sufficient to lead to chronic health complaints. The fact that amalgam is not used in dentistry

in Norway to date is not related to suspected negative health effects, but purely due to

environmental concerns. The most common symptoms patients who suspect their health

problems to be related to amalgam report, are: fatigue/exhaustion, dizziness, mental

symptoms (concentration and memory disturbances, anxiety, irritability, restlessness,

depression), pain (muscle, joint, neck and shoulder, teeth/jaws/facial pain; headache),

functional gastrointestinal symptoms (e. g. constipation, diarrhoea, bloating), mouth blisters,

metallic taste, and susceptibility to infections [2-11]. In 1990 a dental patient association

was founded in Norway, whose aims among others, included the development of a

treatment and rehabilitation program for patients suffering from harmful effects

from dental treatment [12, 13]. As a consequence, the Norwegian Ministry of Health

and Care Services initiated a collaborative treatment project for patients with

suspected adverse effects from dental materials ("Samarbeidsprosjekt mellom

tannhelsetjenesten og helsetjenesten om utprøvende behandling ved mistanke om

bivirkninger av odontologiske biomaterialer") which was executed through the

Norwegian Directorate of Health. The aim of the project was to support patients with

health complaints attributed to amalgam, and to improve their health and quality of

life.

Part of the collaborative treatment project was the design of a rehabilitation program

for patients, who have had their amalgam fillings removed but still experienced

4

health complaints, the “integrated medical care rehabilitation” (IMCR) program for

patients with continuing health complaints after amalgam removal.

Setting up such a treatment program for patients who have had their amalgam

fillings removed, but still experience health complaints was a particular challenge for

several reasons, mainly: i) there is to date no good pathophysiological explanation

available for amalgam-related health complaints, and even though many patients

experience symptom relief after amalgam removal, a substantial number of patients

do not. ii) There is no causative treatment and as such no cure available, in particular

for those patients who continue to experience symptoms after amalgam removal.

Many of these patients report good experience with therapies from the spectrum of

complementary and alternative medicine (CAM) [14] therefore a choice of therapies

out of the CAM spectrum, from which patients were free to choose, was

operationalized as part of the rehabilitation program.

The most common complaints attributed to amalgam fillings, such as exhaustion and

fatigue, pain from muscles and joints, gastrointestinal symptoms, taste disturbances

and symptoms from ear/nose/throat [15] occur also in other chronic, debilitating

diseases, such as chronic fatigue syndrome and fibromyalgia. Patient suffering from

fibromyalgia typically show symptoms of widespread musculoskeletal pain, fatigue,

insomnia, and impairment of physical and psychological quality of life [16, 17].

Furthermore, stress related or depressive symptoms are also common in these

syndromes [18-21] and they seem to be relevant for the course of the disease [22, 23].

Due to frequent unsatisfying results of conventional treatment, the use of

complementary and integrative approaches such as Mind-Body medicine,

supplements, acupuncture, massage and various nutritional therapies among

fibromyalgia patients is common. Moreover, the scientific evidence for these

therapies has increased over the last decade. Consequently, evidence based

guidelines recommend multimodal, multidisciplinary therapeutic approaches

5

involving medication, exercise, relaxation, stress management, patient education,

and behavioral therapies [16, 17, 24].

Therefore, a treatment program was developed, which consisted of a structured

group program of 12 modules, each covering a day [25] based in Mind-Body

medicine approaches, and an individualized treatment part, where the participants

received 12 vouchers they could use to choose from a selection of CAM therapies.

This selection was derived from a survey conducted among the relevant patient

group [14, 26]

Special emphasis was placed on patient participation and patient empowerment. The

main therapists were trained in how to use the manual in a two-week training

session. The education focused particularly on a non-directive, accepting, non-

pedagogic approach. The main goal of the group intervention was to support

patients in making experiences, regain competence and control, feel confident with

their own decision, and rely on themselves as experts for their situation. Therapists

were educated to not give instructions, but support patients in finding and

developing solutions they themselves felt comfortable with. The non-directive

approach was extended to the individualized part of the program in that patients

were free to use their “budget” consisting of 12 therapy vouchers for the group of

therapies available within the program. All patients received counselling from a

medical doctor at the beginning and the end of the program (patients had been

checked for exclusion criteria before entering the trial). This counselling was

restricted to safety issues, as the doctors should not recommend therapies for their

effect, but should check for potential particular risks related to the individual patient

and instruct them accordingly.

The particular focus of the IMCR trial was grounded in Norwegian health strategic

documents, such as the “Coordination reform”[27] which emphasizes patient

participation. The principal understanding that formed the basis for the coordination

6

reform is that ".... Patients, who participate in the planning and monitoring of their

health care, are better able to mobilize their own resources. This can improve the

prospects for good results" [28].

The aim of this study was to give the participants a possibility to give us their

personal feedback taking part in the IMCR program. Since we were asking for

mental, emotional, and bodily experiences, a qualitative design was considered most

adequate to explore this. Hence, our questions reflected a possibility to describe in

their own words their personal experience with the IMCR program.

Design, Material and Method Qualitative data were drawn from a group of participants who took part in a study

named Integrative Medicine Care Rehabilitation (IMCR). The clinical goal of that

study was to develop a rehabilitation program for patients with continuing health

complaints after amalgam removal. Details and quantitative results from the study

are published elsewhere (ref).

The IMCR program combined a lifestyle oriented group program with

individualized CAM therapies. The group program consisted of 12 sessions, held

once per week for a whole day. The end of the initial treatment phase (3 month) was

followed by another 3-month period before the final meeting of the group. The

program was conducted with three groups of patients in three different locations.

The group sizes varied from n=7 to n=10. Every group was led by a main therapist,

which was there the whole day and throughout all other activities. Specialized

therapists conducted sessions with special topics, such as yoga or nutrition. Thus, the

three different locations included also with three different groups of therapists.

7

Hence, our sample was drawn from participants in the aforementioned study. After

completion of the final treatment session, the participants were asked to answer

several questionnaires; four questions were related to the present qualitative study:

1. How did you experience the IMCR program? (Norwegian: Hvordan opplevde

du programmet?)

2. Have you taken some parts of the program into your daily living? If yes please

describe these. (Norwegian: Dersom du har tatt med noe fra programmet med

inn i hverdagen, beskriv hva dette er.)

3. Has your everyday life changed in any way after you started this program? If

yes, please describe (Norwegian: Har livet ditt (hverdagen din) forandret seg

på noen måte etter at du startet med programmet? I så fall hvordan?)

4. How did you experience your body and your symptoms during and after the

program? (Norwegian: Hvordan opplevde du kroppen din og symptomene

dine under og etter programmet?)

Participants answered by using their own words. Hence our material consisted of

pages of text vary from only a few sentences to two dens handwritten pages of

information. The authors of the present study were not personally involved in the

rehabilitation study, and participants in the qualitative study provided their answers

anonymously. Questionnaires were distributed during the last group meeting sent

back by mail in sealed envelopes. In this way, we could guarantee the participants

anonymity.

Analysis was accomplished by systematic text condensation [29] (1) reading all the

material to obtain an overall impression and bracketing previous preconceptions; (2)

identifying units of meaning, representing different aspects of participant’s

experiences (reflected from answering the four questions) associated with the

rehabilitation program, and coding for these; (3) condensing and summarizing the

contents of each of the coded groups; and (4), generalizing descriptions and concepts

8

concerning experiences associated with the rehabilitation program. All the authors

were involved in the analysis, negotiating interpretations and categories along the

process.

Ethics

The Regional Committee for Medical and Health Research Ethics (REK) has considered the study (REK reference 2012/2135) and decided that no ethic approval was needed because the project was not considered to be a medical and health related research project that complies with the Health Research Act. Therefore, it was not mandatory to submit an application.

Therefore, the study was registered with The Norwegian Data Inspectorate (NSD) (NSD reference 34974). Written informed consent was obtained from the study participants.

9

Results

Figure 1. Flow chart of the inclusion process A total of n=25 of the potential participants screened qualified for the study and were

included. Of these n=5 dropped out because of practical reasons. The main reason

was that it was too complicated to reach one of the three study locations. After

entering the program, n=2 participants dropped out. One participant was diagnosed

with cancer, the other needed to travel for two hours to reach the study location and

gave up. All participants were invited to take part in the qualitative study and n=18

responded. Of these were n=13 women (mean age 57.3 yrs) and n=5 men (mean age

40.4 yrs). Most of the participants were on disability pension (not working).

Participants included in the program (n=25)

Participant that dropped out during the study (n=2)

Participants included in the study (n=18)

Participants who did not actually enter the program n=5. Reasons: Mostly feasibility, such as travel time to the study location.

10

Experiences with the rehabilitation program

On a general level, most of the participants (83%) were satisfied with the program.

N=10 were very satisfied, n=5 were satisfied, n=2 were neutral, n=1 was dissatisfied

while no one was very dissatisfied (figure 2).

Figure 2. Participant’s satisfaction with the IMCR program

Many of the participants reported calmness throughout the program. They were very

satisfied with the leaders of the different group therapies and their focus on

strengthening the participants ‘inner life’ and that the illness/sickness part of

everyone was not a part of the ‘talk of today’. Several of the participants also

mentioned a good balance between the group based program and the individualized

CAM treatments. According to the participants, there was a good mixture of practical

things to do and sitting down listening to different meaningful theories about health

and happiness.

11

Quotation 1:

I experienced the program as very positive and inspiring - in all aspects. The program

was varied and very well structured, and the tutor did a very good job. I also

experienced good effects and benefits from the treatment I received.

Experienced change in everyday life

The majority of the participants were more than happy to bring aspects of relaxation

exercise, including breathing exercises into their daily living. Added to this was also

meditation, relaxation and other exercises related to physical movement. This

experience also showed the participants the importance of scheduling the day, which

allowed for systematically practicing different mind- body techniques also on

‘difficult’ days. A smaller group of the participants acknowledged the use of healthy

foods in the program and likewise wanted to introduce this into their daily living.

Quotation 1:

I had done much of this before. However, the program has increased my insight and

motivation as to how important it is to give oneself room every day to do exercises,

rest, mindfulness, and to be conscious of breathing and nutrition (12).

Several persons were happy that they got information, teaching and tools on how to

handle everyday life with a chronic illness. Others learned the importance of having

friends and would continue to meet after the program had finished.

Has your everyday life changed after you started with the program? If yes, how

Many of the participants stated that they now had ‘a bright side of life’ attitude. They

felt more capable in caring about what was important in their life – more at peace

12

within themselves, stress situations were now handled in better ways and they

experienced a more optimistic attitude to life in general, due to having more

resources and tools available after the program.

Quotation 1:

Over time my progression is slow. All in all, that is including the treatments, my

interest has increased. It brings great values/personal growth, regardless of the

implementation of or need for medical care. This is a lesson for life that is useful for

anyone regardless of their health situation.

Others wrote that they now after the program paid more attention to dietary issues

and exercise in daily life. The experiences of ‘being together’ brought on thoughts

about the importance of sharing and being with people in daily life. Hence, and in

line with this, some used more time being ‘on the go’ due to more energy both

mentally and physically.

How do you experience your body and your symptoms during and after the program?

Although our question did not mentioned “mind” many of the participants included

that in their answers, hence also included under this heading. Some of the

participants mentioned here the specific CAM treatments they had received, e.g.

acupuncture that helped against depression and tiredness. However, the majority of

the participants referred to the IMCR treatment program in general. Many bodily

symptoms were present before the start of the program, some of these lasted through

the program. A few participants reported also a kind of stress and restlessness

during the program. However, after completing the program, these feelings of

unsettledness calmed down and i.e. bodily symptoms were gone. Several described

the program as being tough to them, both physically and mentally, because they

were taken out of their comfort zone. However they reported that afterwards, having

13

the sense of being able to cope better, and having a better understanding of oneself

and experiencing an increased ability to participate in daily life – they felt it was

worth it.

Others described bodily symptom changes related to being more energetic, having

better digestion and better sleep; these were the three most reported symptoms. One

participant reported that there was no change in the symptoms and the participant

felt bored, angry and stressed.

Quotation 1

During the program I was very stressed and anxious. However, I managed to follow

the program. After a while we learnt techniques that felt good. Breathing exercises

have become a part of my daily routine. The inner peace is a good feeling. As we were

talking, many things fell into place.

Quotation 2

My body functioned quite well, that is the pains did not get worse and several of the

techniques functioned well so that the symptoms decreased during the program. After

the program I continued to use these techniques and what I got from input corrections

and the therapists. Yes, I feel better.

Discussion Our results present a variety of perceived experiences from the IMCR program.

Several of those were related to the program itself and the group leaders e.g. due to

that leaders focused on strengthening the participants ‘inner life’ and that the

illness/sickness part of everyone was not a part of the program. Other changes were

related to the increased ability to attend and engage in activities of daily life after the

program. This was reflected by the use of breathing exercise, meditation and

different relaxation techniques, which they looked upon as important tools for

handling and living with a chronic disease/illness. Views about health issues had

14

changed as well. The participants felt a more positive attitude and more strength in

order to evaluate what was important in life. Reported changes of bodily symptoms

were attributed to the individualized CAM treatments, the group based program,

and/or to the program as a whole treatment package. Initially many of the

participants experienced the program to be challenging and somewhat hard to them.

However, those feelings disappeared as more energy, better sleep and improved

digestion was reported as changes in bodily symptoms.

Many patients with diseases, whose pathophysiology remains to date unclear such

as e.g. fibromyalgia utilize complementary and integrative approaches such as

Mind-body medicine, supplements, acupuncture, massage and various nutritional.

The reasons for this are often that these patients experience unsatisfying results of

conventional treatment. Moreover, the scientific evidence for integrative

therapeutic approaches has increased over the last decade. Consequently, evidence

based guidelines recommend multimodal, multidisciplinary therapeutic

approaches involving medication, exercise, relaxation, stress management, patient

education, and behavioral therapies [16, 17, 30] Patients with amalgam attributes

health complains suffer some of the same experiences [31] and symptom patterns.

Thus, it can be assumed that similar therapeutic approaches are likewise

experienced to be helpful in this particular patient group.

Over the last years, techniques such as meditation or yoga exercise are increasingly

utilized in multimodal treatment approaches in chronic diseases, which have a high

symptom load, but little perspective of cure e.g. [32, 33]. These Mind/Body

therapies are defined according to the American national institutes of health as

“Mind and body practices focus on the interactions among the brain, mind, body,

and behavior, with the intent to use the mind to affect physical functioning and

promote health.”[34].

15

Mind-body therapies have been shown to have a good effect in many diseases,

including fibromyalgia, but also for example, in cancer patients [32, 33, 35-37].

Moreover, many of these patients with amalgam related health complaints report

good experiences with therapies from the spectrum of CAM [14]. Thus, in

conclusion, the benefits reported by patients with amalgam attributed health

complaints in this study, are in line with the scientific evidence from other patient

groups.

Strengths and limitations of the study design

The reports albeit handwritten from our participants’ were found to be appropriate

and stable to conclude that our questions had been adequately understood.

Saturation was indicated by repeated statements about the same phenomena,

although some detailed variation would still occur. Generally, positive experiences

were reported from the participants in the IMCR program. However, our material

included also a few negative statements. This allow us to conclude that answers

presenting negative treatment effects indicate that participants did not feel obliged to

report only beneficial experiences. Therefore, we anticipate that we received

authentic stories that were not just designed to meet our expectations. The

openhearted answers might be a reflection of that we could secure the participants

anonymity throughout this qualitative study. Our sample was representing people

with a considerable symptom burden. Even though our participants do believe that

their problems are caused by amalgam, we think that our sample might be

representative for patients with similar symptom burden in chronic

diseases/illnesses, at least in Norway. Hence we think that the IMCR program can be

worth studying in other patient groups with similar symptom profile.

16

Acknowledgements Very special thanks go to the participants for sharing their stories with us.

Furthermore, we acknowledge the leader and the administration of NDPA for

supporting the IMCR trial and recruiting participants. Special thanks to Liljan

Smith Aandahl, retired Senior Advisor at the Norwegian Directorate of Health, who

was instrumental in setting up the project for people with suspected adverse effects

from dental amalgam, which this study is part of.

Conflicts of interests

The authors declare that they have no conflicting interests.

Funding The study was funded through a grant from the Norwegian Directorate of Health.

17

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Appendix VI

Tenner & helse

Medlemsblad for forbundet Tenner og helse 20. Årgang – nr. 2 juni 2014

Appendix VII

Tenner & helse

Medlemsblad for forbundet Tenner og helse 22. Årgang – nr. 3 sept. 2016