Understanding and restoring dopaminergic function in fibromyalgia patients using a mindfulness-based psychological intervention: a [18F]-DOPA PET study. Study protocol for the FIBRODOPA study—a randomized controlled trial

Fibromyalgia (FM) is a chronic, painful, musculoskeletal disorder characterized by widespread pain, accompanied by a broad spectrum of associated somatic and psychological manifestations, including fatigue, sleep disturbances, stiffness, anxiety, and cognitive dysfunction [72]. It is one of the most prevalent chronic pain conditions [67] with an estimated prevalence between 0.5 and 4% with a ratio of 3.5% in women to 0.5% in men [47]. Like other chronic pain conditions, FM often leads to disability, affective disturbance, and poor quality of life and is also associated with high direct and indirect disease-related costs [58]. The etiology of FM is largely unknown. However, several factors appear to underlie the disorder, including dysfunction of the central nervous system (CNS) and autonomic nervous systems, neurotransmitters, hormones, immune system, and external stressors and psychological factors [6]. More generally, chronic pain is commonly associated with comorbid affective disorders (e.g., anxiety, depression) and cognitive deficits (e.g., memory impairment), suggesting on one hand critical involvement of higher order neural brain processing [13] and on the other the necessity to develop specific interventions targeting comorbid mental disorders, mood, and cognitive dysfunctions (see for instance [17]). Among the neural changes observed in chronic pain, there is increasing evidence for alterations in the dopaminergic (DA) system. Evidence supporting a hypodopaminergic state in chronic pain comes from both preclinical [56] and clinical data [46, 52]. Furthermore, accumulating evidence suggests that the mesolimbic DA system modulates the perception of nociceptive information and the affective symptoms of chronic pain [3]. Taken together, there are now multiple lines of evidence showing that chronic pain, including FM, leads to a hypodopaminergic state that results in enhanced pain sensitivity and might impair positively motivated behavior [64]. In addition, DA is involved in descending inhibitory modulation of pain transmission, which is an additional link between hypodopaminergia and chronic pain [59]. In a previous project of our group that aimed at investigating DA function in FM, we found a reduced DA function in FM patients and showed group differences in DA receptor binding in striatal regions between FM participants with and those without depression compared to healthy subjects [50]. In addition, we found a differential modulation of pain by DA in healthy controls and FM participants [50]. Findings from functional neuroimaging studies indicate that a network of brain regions, including the orbitofrontal cortex, the ventral (specifically the nucleus accumbens) and dorsal striatum, the amygdala, and the anterior cingulate gyrus form the so-called reward system [57]. In chronic pain, alterations in brain structural features, functional connectivity, or activity of these regions have been reported, compared to healthy controls, or people who tend to recover from acute pain ([3, 42, 74, 75]. The neural changes observed in regions associated with the brain reward system could provide a possible explanation for the high incidence of comorbid affective disorders in chronic pain patients [49]. In conclusion, the exact mechanisms by which the brain reward network modulates chronic pain have not been established yet. More specifically, although there is first evidence for a hypodopaminergic state in FM ([50, 74, 75], the effects of chronic pain on the ability to enjoy rewards and hence anhedonia have insufficiently been investigated. Finally, the exact role of DA in the modulation of chronic pain remains unclear. On another note, the current evidence-based guidelines for the treatment of patients with FM are inconsistent [66]. Recent meta-analyses conclude that optimal treatment interventions should include components aimed at enhancing adaptive cognitive and behavioral responses [1, 39], and broad improvements have been observed with treatment plans that include non-pharmacologic interventions [1]. This is in line with the current international guidelines that recommend aerobic exercise, cognitive-behavioral therapy (CBT), and multicomponent treatment as the first choice for the care of FM patients [66].

A growing body of research has demonstrated that mindfulness-based interventions are clinically effective for a wide range of conditions (for a review, see [40]) leading to them increasingly being used for the treatment of chronic pain conditions including FM ([60, 69]. A recent systematic review indicates that mindfulness-based interventions produce statistically significant, moderate effect size improvements in mood-related outcomes in FM [65]. However, most studies of mindfulness-based interventions have concentrated on negative affective-related constructs and have not given sufficient attention to the effects of mindfulness on positive affect and reward [27].

In contrast, Mindfulness-Oriented Recovery Enhancement (MORE) is a mind-body intervention specifically designed to enhance positive emotion regulation and natural reward processing by uniting complementary aspects of mindfulness training, CBT, and positive psychological principles into an integrative treatment strategy. MORE was originally designed as a behavioral medical intervention for addictive behaviors ([23, 28, 29], but was more recently adapted to address chronic pain among individuals receiving long-term opioid analgesic therapy. Two stage 2 randomized clinical trials (RCTs, N = 115 and N = 95) showed that MORE significantly reduces pain severity and pain-related functional interference [26, 31, 33‐35], as well as opioid dosing [36], among chronic pain patients. In addition, the effects of MORE on reducing pain severity and opioid misuse were associated with increases in positive emotional processes, including positive affect, savoring, and meaning in life [24, 25, 30, 33‐35]. In addition to these psychological effects, RCTs demonstrate that MORE is also associated with behavioral and neurophysiological changes in reward processing [26, 27, 31], including increases in the late positive potential of the EEG and enhanced corticostriatal activity during savoring of natural rewards [21, 33‐35], suggesting that MORE might improve clinical outcomes by enhancing reward system function. It is however not clear whether or not the experimental modification of reward experiences represents a mechanism of change in MORE. Because our previous results showed dysfunctional DA responses to rewards in FM [49], the use of MORE in this group of patients could be very promising. Furthermore, no study so far has investigated the molecular underpinnings of MORE on the dopaminergic reward system.

In addition, daily measures of self-reported stress experiences and self-reported pain symptoms in FM indicate that stress exacerbates the pain feelings in everyday life of FM patients [20]. Furthermore, it has been hypothesized that FM patients may find it more difficult to mount a resilient affective response to stressful events if the force of negative affect (NA) compromises their resources of positive affect (PA) [76, 77]. In turn, PA is a source of resilience against pain and negative affectivity [76, 77], and momentary positive emotions, rather than more general satisfaction with life, are associated with increased psychological resilience [16]. In addition, in FM, deficits in PA regulation have been reported [76, 77]. Using ambulatory assessments (AA), MORE and mindfulness have been shown to significantly boost PA regulation and momentary positive emotions and enhance responsiveness to pleasant daily life activities [24, 25, 30, 33‐35, 38]. The overall objective of this project is to investigate whether FM participants differ from healthy participants with regard to DA function, pain perception, neural responses to reward FM-related symptoms (including mood disturbances), and daily life affects, reward, stress, and pain experiences and with regard to emotion regulation and pain coping strategies before participating in the MORE intervention. Furthermore, we aim to investigate the effects of the MORE intervention for the first time in FM, and to measure its ability to restore DA function at a neurochemical level, to reduce pain, to enhance neural responses to reward; to reduce FM-related symptoms and to affect the experience of pain, stress, and reward in everyday life in FM patients; and to change emotion regulation and pain coping strategies. We will also investigate the short-term effects of MORE on FM-related symptoms and pain after 3 months. In an exploratory way, we will perform microbiota and genetic analyses to investigate emerging pathophysiological models of FM that could be associated to the DA dysfunction observed in FM as well the changes in mindfulness associated with MORE.

The objectives are as follows:

Our hypotheses are:

The study is a multi-center study with 3 centers and includes the University Fribourg, Department of Psychology; the University Hospital Lausanne (CHUV), Center for Integrative and Complementary Medicine & Pain Center; and University Hospital Zurich, Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine. All 3 centers are based in accredited Swiss Universities, two of them are located in University Hospitals. The MORE intervention will be given in each of these centers in order to access a larger pool of participants. The PET scans will be performed at the PET-Center of the Department of Nuclear Medicine at the University Hospital Zurich. The fMRI measures will be performed at the Department for Neuroradiology at the University Hospital Zurich. Data collection takes place in Switzerland only.

The following groups of participants will be included: (a) 64 female subjects fulfilling the classification criteria of the American College of Rheumatology for FM (ACR 2011 criteria) [73] and without any psychiatric condition according to the ICD-10 and (b) 20 healthy women without a history of chronic pain or any mental disorder for the PET measures, and a total of 15 healthy women for the daily ambulatory assessments. The groups will be matched on age. All participants will be right-handed and older than 18 years old. Subjects will be excluded if they are pregnant; if they have a history of neurological disorders, current substance or tobacco abuse, current and past substance dependence, schizophrenia spectrum disorder, and any other form of chronic pain (except FM for the FM group); and if they have been treated with a medication affecting the central DA system in the 3 months preceding the scanning session (including opioids, neuroleptics, antileptics, antidepressants, and lithium). Participating in another RCT or some form of individual or group psychotherapy focusing on pain management is prohibited.

Informed consent will be obtained by trained and authorized study personal. The investigator will explain to each participant the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits, and any discomfort it may entail. Each participant will be informed that the participation in this study is voluntary and that she may withdraw from the study at any time and that withdrawal of consent will not affect her subsequent medical treatment. All participants will be provided with a participant information sheet and a consent form describing the study and providing sufficient information for participants to make an informed decision about their participation in the study.

Consent for each participant will be obtained that in case of withdrawal, the biological materials and health-related data collected before withdrawal will be stored and analyzed in coded form and used in the analyses. Anonymization of the biological material and personal data may be dispensed with if the person concerned expressly renounces this right when revoking consent.

We have the following reasons to justify the use of a design with a non-intervention control group and not an active control group. Placebo group interventions without specific effects can elicit so-called resentful demoralization [61], leading to increased drop-out risk in this group. With regard to the study of [26, 31] indicating more than 20% drop-out during the treatment, it is important to minimize this risk. Providing a non-efficacious treatment to patients having a long history of mostly not efficacious treatment behind them as it is the case for FM patients is questionable. Because of their symptomatology, it is difficult for them to commit to a treatment and they often encounter mobility difficulty due to pain symptoms, so it would be a waste of time and energy for them to come to our centers for an intervention without any specific effects. From a methodological point of view, it is difficult to provide comparable support group interventions among different groups as the interaction between the participants and the reaction of the therapist to them cannot be fully controlled. This is particularly complicated when the intervention is given in 3 different centers and might impair the validity of the intervention. For these reasons, RCTs in patients with somatic diseases use in the great majority non-intervention designs to assess the effects of psychological interventions.

FM participants will participate in the MORE intervention or in a non-intervention control group. The non-intervention control group does not include any intervention. The MORE treatment is manual-based [28], consists of 8 sessions, and offers instruction in applying mindfulness and related skills to the following topics: discriminating between nociception, pain, and suffering; gaining awareness of automaticity and coping habits in chronic pain; disrupting the link between negative emotions, catastrophizing, and pain experience through reappraisal; refocusing attention from pain and life stressors to savor pleasant experiences; promoting acceptance instead of suppression of experience; and developing a mindful recovery plan. Mindfulness training will involve mindful breathing and body scan techniques, with an emphasis on developing metacognitive awareness and shifting attention from affective to sensory processing of pain and craving sensations. Sessions will be audio recorded for control of therapists’ adherence with the manual. MORE participants will be asked to engage in daily 15-min mindfulness practice sessions at home guided by a MP3 recording of the meditations. MORE is a manualized intervention that is centered on three therapeutic processes: mindfulness, reappraisal, and savoring. The MORE manual and the meditations are translated in French and in German. The non-intervention control group includes continuation of treatment as usual.

Discontinuing or modifying allocated interventions is not possible.

FM participants will be withdrawn from the study if they receive treatment with medication affecting the central DA system, including opioids, neuroleptics, antileptics, antidepressive, and lithium, or if they have to undergo an examination with radiopharmaceutical or radioactive marked substances or if they begin another regular psychotherapeutic treatment or participate in another clinical trial during the course of the study until completion of the post-test measures. All other treatments are allowed during the course of the study. For healthy participants participating in PET measures at pre-test, the same conditions are applicable until the end of pre-test measures. For healthy participants not participating in the PET measures, the same conditions are applicable with exception of the examination with radiopharmaceutical or radioactive marked substance. Concomitant treatment will be recorded at each study visit in the eCRF.

Not foreseen.

To minimize bias, we will use only standardized questionnaires to assess the primary outcomes as recommended by Outcome Measures in Rheumatology Clinical Trials (OMERACT) [10].

The overall study duration is 4 years from June 2021 to June 2025. Recruitment will take place during the entire study duration as we will perform 4 successive groups of the MORE intervention. The study duration per participant will be between 6 and 8 months, depending on scanner availability for the pre- and post-test measures. As soon as we have a minimum of 10 FM participants (minimum 5 participants and maximum 10 participants per MORE group), we will start with the first MORE group. The first measures will ideally be performed on healthy participants. The FM participants will be randomized after screening, and the ones assigned to the MORE intervention will undergo the pre-test measures of FM first. We plan 4 to 5 weeks to perform the pre-test measures for the participants allocated to the MORE group (2 participants per week). The first MORE will take place in the center where we will have first recruited the necessary number of participants. During the duration of the first MORE group (8 weeks), we will make the pre-test measures for the non-intervention control group and begin the pre-test measures for the second MORE group. This will allow us to begin with the second group as quickly as possible after the completion of the first group. During the second MORE group, we will perform the post-test measures for the first MORE group participants and test the non-intervention controls of the second MORE group. During fall 2021, we will test participants of the healthy control group and recruit the participants for the next two MORE groups that will take place in winter/spring 2022, according to a similar schedule for the first 2 groups. In parallel, we will perform the follow-up measures for MORE 1 and MORE 2. FM participants allocated to the non-intervention group will have the possibility to participate in a MORE group at the earliest after all participants of the group have completed follow-up measures, i.e., around 20 weeks after pre-test-measures (8 weeks delay for post-test measures + 12 weeks after post-test measures). In the years 2023 and 2024, we will complete the measures for the control group as well as the follow-up measures for the FM groups.

Sample size justification:

The power analysis for the primary outcome is based on the following results:

• A study comparing 18F-DOPA influx between FM participants (N = 6) and a healthy control (N = 8) group [74, 75] yielded a mean effect size of 1.17; using this effect size, a power analysis with G*Power [19] showed that a group of 12 participants is optimal to obtain significant results with T-test comparing 18F-DOPA uptake between FM and healthy participants at baseline. We would round up to 20 to accommodate for technological problems, as the first measures will be done in healthy participants.

• Garland et al. [32] found significant neurophysiological changes after MORE treatment with EEG measure in 29 participants (F1,26 = 4.47; ηpartial² = .15) in response to reward before and after the MORE intervention in chronic pain patients with sample sizes of N = 11 (active group) and N = 18 (support group). Using this effect size, a power analysis with G*Power [19] showed that 14 participants are necessary for an ANOVA with 2 factors and repeated measures to be significant. However, results obtained with EEG cannot be directly compared to PET measures, and there are so far no available studies with FDOPA in that context.

The power analysis for the secondary outcomes is based on the following results:

• A randomized controlled study of the MORE intervention by Garland et al. [26, 31] evidenced significant reductions in self-reported pain severity with medium effect size (Cohen’s d = 0.5, effect size F = 0.46) after the MORE intervention in a starting group of 115 participants and of 69 at post-intervention measures (N = 31 for MORE and N = 38 for support group). Based on these estimates, an ANOVA to be significant should have a minimal sample of N = 20 participants after treatment in each group.

• A randomized controlled study by Garland et al. [33‐35] found significant effects of MORE on self-reported pain, stress, and positive affects in daily life (with AA measures) in a group of N = 30 using multilevel analyses, with effect sizes yielding to a minimal sample of 20.

• In their randomized clinical trial of the MORE intervention in chronic pain patients with opioid abuse, [26, 31] found a 20% drop-out between the beginning and completion of the intervention.

• In order to have a sample size sufficient to obtain significant results for the primary outcomes (FDOPA) and clinical pain measures as well as for the secondary outcomes (in particular daily life measures), we consider a minimal sample of N = 20 in each FMS group. Considering a 20% drop-out in total yields to a starting sample of 25 participants in each FMS group (MORE and non-intervention control). To account for data loss related to technical problems as well as for the average size of the MORE group of N = 8, we will round up to N = 32 in each FMS group.

Patients will be recruited from the interdisciplinary outpatient clinic for pain at the University Hospital Zurich, from the Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine at the University Hospital Zurich, from the Neurology Department and interdisciplinary outpatient clinic for pain at the Canton Hospital Fribourg, from the outpatient pain clinic at the Division of Anesthesiology as well as the service of rheumatology at the Lausanne University Hospital, from private practices, and from adds on websites of the Rheumaliga, as well as patient groups such as the Fibromyalgieforum Schweiz in the German-speaking and French-speaking parts of Switzerland. The healthy controls will be recruited through ads, word of mouth, and from our previous and current studies as well. When interested participants call into one of the study telephone lines, they will be told about the study and screened for eligibility using predetermined scripts. If potentially eligible, an in-person visit (90-min duration) at the study center will be scheduled. This first visit can be the start of the study, or this start can be reported, depending on the clinical situation. At the study start, eligibility will be confirmed, consent provided, and the initial assessment completed.

We will use a simple randomization procedure with a blocked size of 5, 6, or 8 according to the recruitment flow. Randomization will be performed with an online program (sealed envelope, https://​www.​sealedenvelope.​com) with the following randomization scheme: FMS MORE/FMS non-treatment control. The randomization will be performed for each group independently, before the pre-test measures by the data manager. Randomization tables will be deposited on RedCAP. There is no randomization of the healthy control groups for allocation in the PET or AA group.

The list is concealed by instructed office personnel in the study center of the University Fribourg, Switzerland, who is unaware of any patient information. The randomized participants will join the MORE group or non-intervention control.

Because there is no active control group or no placebo intervention in this study, the study staff and the participants will be unblinded.

N.A.

A detailed overview of questionnaires and measures is given in Table 1. The schedule of enrolment, interventions, and assessments is provided in Table 2. Data management including data entry, coding, security, and storage will be provided by the Web-based application Research Electronic Data Capture (REDCap) https://​doi.​org/​10.​5195/​jmla.​2018.​327 that is available at the University of Fribourg. It is Health Insurance Portability and Accountability Act (HIPAA)-compliant and highly secure.

Data to be collected at baseline include age, sex, marital status, education level, and professional status. Measures of functioning include a measure of quality of life with the World Health Organization quality of life questionnaire WHOQOL Brief questionnaire [62] and the Fibromyalgia Impact Questionnaire-Revised (FIQ-R [7];) that also includes a measure of fatigue. Measures of sleep quality include the medical outcomes study sleep scale (MOS [63]; [44]) that has been widely used in rheumatology research and is recommended by OMERACT-10.

Participation in this study is voluntary. If a participant wishes to retain from participating, she can stop the study without justification. In case of withdrawal, the biological materials and health-related data collected before withdrawal will be stored and analyzed in coded form and used in the analyses.

All study data must be archived for a minimum of 10 years after study termination or premature termination of the clinical trial. Study data will be archived at the University Fribourg.

For data recording, we will use electronic case report forms (eCRF) from REDCap which are available at the University Hospital Zurich, University Fribourg, and at the CHUV. For each participant, an individual CRF is maintained. The CRF is coded for each participant with protocol identifier plus randomization number based on the guidelines for an acceptable coding of trial subjects available on www.​swissethics.​ch. Source data in this study is all information in original records, certified copies of original records of clinical findings, questionnaires, observations, or other recorded activities collected during the study only. All collected data during the study will be transferred to the participant’s CRF. Direct access to source documents will be permitted for purposes of monitoring, audits, or inspections. Access to the project plan, dataset, and statistical code, during and after the research project (publication, dissemination), will be determined by the PI. Coding will be done using participant numbers and participants will be given a number in a chronological order with the first number differentiating between healthy controls and FM participants in the screening log. Data exchange between the centers will be done using coded data. For interim and for the main analyses, the (coded) data of the study centers will be merged into one file to perform the analyses.

The investigators are liable to treat the entire information related to the study and the compiled data strictly confidential. Any passing-on of information to persons that are not directly involved in the study must be approved by the owner of the information. Direct access to source documents will be permitted for purposes of monitoring, audits, and inspections. Data generation, transmission, archiving, and analysis of personal data within this study strictly follow the current Swiss legal requirements for data protection. Prerequisite is the voluntary approval of the participant given by signing the informed consent prior start of participation of the clinical trial. Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. Participant’s confidentiality will be further ensured by utilizing participant identification code numbers to correspond to treatment data in the computer files. Such medical information may be given to the participant’s personal physician or to other appropriate medical personnel responsible for the participant’s welfare, if the patient has given his/her written consent to do so. Data generated as a result of this study are to be available for inspection on request by the monitors and by the Cantonal Ethics Committee.

Biological specimens obtained under this protocol will be stored in coded form (protocol identifier plus randomization number), in freezers located in an access-controlled room at the University Fribourg. The cooling of the freezer system is guaranteed as an increase in temperature will lead to an alarm that goes directly to the PI’s designee’s phone or any other predetermined person in charge for the cooling system. When coded data is shared, the key to the code will not be provided to collaborators, but will remain in the hands of the PI and her designees. Saliva samples will be collected in coded form and sent to the Department of Psychology at the University Fribourg with a prepared envelope for storage. Coded saliva samples for cortisol and amylase analyses will be frozen and stored at −20 °C in a freezer located in the access-controlled room at the University Fribourg. After collection of saliva samples from all participants, the samples will be shipped to the Dresden Lab Service located at the University of Dresden, an institution operating under the Declaration of Helsinki.

Saliva samples will be destroyed from the laboratory after the analyses. If a participant withdraws from the study, all collected data will be kept and used for data analyses.

Safety analysis includes the report and observation of potential side-effects of the MORE intervention. Should side-effects occur, we will analyze the characteristics of the participants concerned.

Interim analyses will include pre-test comparisons (healthy controls versus FM) on the main and secondary outcomes after completion of the first MORE group as well as exploratory pre-post comparisons on the main outcomes to control whether methodological adjustments have to be made. Data of the pre-test comparisons (healthy controls versus FM) after completion of the second MORE group will be used for first data presentation and if possible publication of pilot data.

In an exploratory way, we will perform exploratory correlational analyses between the changes observed on our measures with the changes observed in 18F-DOPA influx to analyze the relationship between the neural and psychological mechanisms of change.

Using an intent-to-treat analysis strategy allows to include all participants having completed the pre-test measures in case of drop-outs. In case of drop-outs, last observations will be carried forward.

Full protocol, anonymous participant-level data, and statistical code are available from the corresponding author upon request.

The coordinating center is at the University of Fribourg and the trial steering committee is led by CMS and KL. Regular meetings are taking place between (1) the study staff involved in the recruitment, screening, and conductance of the study on a weekly basis (online meetings) and (2) all investigators

Monitoring visits at the investigator’s site prior to the start and during the course of the study will help to follow up the progress of the clinical study, to assure the utmost accuracy of the data, and to detect possible errors at an early time point. The sponsor organizes professional independent monitoring for the study. All original data including all patient files, progress notes, and copies of laboratory and medical test results will be available for monitoring. The monitor will review all or a part of the eCRFs and written informed consents. The accuracy of the data will be verified by reviewing the above referenced documents. The investigator’s site will collaborate with the Appletree CI group.

During the entire duration of the study, all serious and non-serious adverse events (SAEs) that may be causally related to the study intervention are collected and documented in source documents. Reportable events are recorded in the case report form (CRF). Study duration encompassed the time from when the participant signs the informed consent until the last protocol-specific procedure has been completed including a safety follow-up period of 12 weeks (see follow-up measures). The recording of serious and non-serious adverse event (SAE and AE) information includes the time of onset, duration, resolution, action to be taken, assessment of intensity, and relationship with study treatment. Participants will be asked about health problems, mood worsening, and negative thoughts as well as any emergency medical or hospitalization that could have happened between 2 study visits at each visit, beginning at pre-test. Participants who prematurely stop the study will be asked for adverse events at the time, when they stop at the end of the study visit.

A quality assurance audit/inspection of this study may be conducted by the Cantonal Ethics Committee (CEC). The quality assurance auditor/inspector will have access to all medical records, the investigator’s study-related files and correspondence, and the informed consent documentation that is relevant to this clinical study.

The investigator will allow the persons being responsible for the audit or the inspection to have access to the source data/documents and to answer any questions arising. All involved parties will keep the patient data strictly confidential.

Substantial protocol amendments (significant changes) are only implemented after approval of the CEC. Under emergency circumstances, deviations from the protocol to protect the rights, safety, and well-being of human participants may proceed without prior approval of the sponsor and the CEC. Such deviations shall be documented and reported to the sponsor and the CEC as soon as possible. A list of substantial amendments is also available on www.​swissethics.​ch.