Background Chronic prescription opioid use is a major international public health issue associated with significant harms, including increased risk of hospitalisation, morbidity and death. Guidance for healthcare professionals on when and how to deprescribe or reduce opioids is required. A key step for guideline development for deprescribing pharmacotherapy is to understand the perspectives of stakeholders. The aim of this study was to explore the perspectives of healthcare professional stakeholders on the challenges associated with opioid deprescribing and factors to be considered in the development of opioid deprescribing guidelines.
Methods A qualitative study was undertaken with a purposive sample of healthcare professionals including prescribers, pharmacists and nurses. An initial cohort of participants was identified at the 2018 Australian Deprescribing Network annual meeting and two focus groups were conducted (n=20). Individual interviews were conducted with a further 11 healthcare professionals. Focus groups and interviews were audio-recorded and transcribed verbatim. Data underwent inductive thematic analysis using a phenomenological perspective.
Results Healthcare professionals viewed opioid deprescribing as a challenge and identified several key barriers to deprescribing in clinical practice. Medication, patient, prescriber and health system level challenges were identified. Participants requested evidence-based guidance on the withdrawal of opioid therapies and suggested that prospective opioid deprescribing guidelines require a multitarget, multimodal intervention strategy that addresses patient psychosocial factors and incorporates behavioural change techniques.
Conclusion Opioid deprescribing was perceived as a complex and challenging practice with continued prescribing the default behaviour. Evidence-based opioid deprescribing guidelines may be a valuable resource for clinicians to support clinical decision-making and reduce suboptimal opioid use.
- clinical practice guidelines
- healthcare quality improvement
- qualitative research
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The current international analgesic landscape is characterised by significant opioid use. Media outlets regularly report on the ‘opioid epidemic’ plaguing the USA, however, increases in the use of prescription opioids have been observed globally.1 2 In Australia, over 1.9 million adults initiate opioid therapies each year,3 with the vast majority of prescriptions issued for maintenance therapy in chronic non-cancer pain.4 Utilisation of opioids for acute pain is associated with increased risk of chronic use,5 further amplifying the potential for opioid-related morbidity and mortality. Escalating opioid use and subsequent harm has been recognised as an international public health concern and there is impetus for action to reduce opioid prevalence and to re-evaluate prescribing practices.
Problematic prescription opioid use has resulted in individuals and organisations advocating for legislative reform, additional training for healthcare professionals and greater patient education and support.6–9 Similarly, the formulation of practice-specific guidelines has been suggested as a mechanism to curb current prescribing trends.10 In Australia, existing clinical guidance from the Royal Australian College of General Practitioners,11 the Therapeutic Guidelines (Analgesic)12 and the Australia and New Zealand College of Anesthetists13 focus primarily on pain management and the prescription of analgesia. However, there is a need for evidence-based guidance on when and how to deprescribe opioid therapies.
Deprescribing is ‘the process of withdrawal of an inappropriate medication, supervised by a healthcare professional with the goal of managing polypharmacy and improving outcomes’.14 Successful deprescribing has been demonstrated for individual drug classes, including risk-modifying medications such as antihypertensives15 and statins16 and symptom-modifying medication classes such as antipsychotics17 and benzodiazepines.18 Clinical trial data show lower withdrawal success rates for symptom-modifying classes of medications, including opioid analgesics,19 suggesting there are additional considerations and barriers when deprescribing these medications. Furthermore, it is postulated that opioid deprescribing may be additionally complicated by medication-related factors such as euphoria, tolerance and physical and psychological dependence.20
Deprescribing guidelines have been developed for a range of medication classes such as proton pump inhibitors21 and benzodiazepines22 to assist clinicians in assessing the appropriateness of therapy continuation and to provide guidance on how to safely reduce or cease pharmacotherapy. Recent efforts have seen the development of resources for clinicians on dose reduction and discontinuation of opioids,23–25 however, explicit evidence-based recommendations derived through a validated multidisciplinary systematic guideline development process have not yet been formulated. The aim of this study was to explore the perspectives of healthcare professional stakeholders on the challenges associated with opioid deprescribing and factors to be considered in the development of opioid deprescribing guidelines.
Reporting of methodology is in accordance with the Consolidated Criteria for Reporting Qualitative Research checklist.26
An exploratory qualitative study design was employed to elucidate healthcare professionals’ beliefs and attitudes towards opioid deprescribing and identify perceived facilitators and barriers to achieving successful outcomes. Focus groups were used to identify areas of importance to healthcare professionals and subsequent individual interviews were employed to enable in-depth exploration of themes.
Recruitment and data collection
Data collection was undertaken by four pharmacy academics with experience in qualitative research. A semi-structured interview guide (online supplementary file A) was developed from a review of the literature and discussion with experienced multidisciplinary healthcare professional and academic co-investigators to ensure face and content validity. Open-ended questions focused on beliefs, attitudes and behaviours surrounding opioid deprescribing and the content and utility of prospective opioid deprescribing guidelines.
A multistage purposive sampling technique was used. Initial recruitment involved identifying a sample of healthcare professionals at the Australian National Deprescribing Network conference in December 2018, Adelaide. Healthcare professionals with an interest and/or expertise in deprescribing were recruited. Purposive sampling resulted in the recruitment of healthcare professionals from relevant and diverse practice settings including direct clinical roles in community-based and hospital-based settings, research and policy development. Two focus groups were conducted by independent pharmacy academic facilitators with experience in qualitative and deprescribing research (LKO and SE). Focus groups were audio-recorded and transcribed verbatim. The duration of each focus group was 60 min.
The second stage of sampling involved the recruitment of individual clinicians including pain and addiction specialists, general practitioners, geriatricians, registered nurses and pharmacists who met the inclusion criteria of being a registered healthcare professional and having experience in the treatment of patients using opioid analgesics. The study was advertised through the Australian Pain Society website and community advertisements. Healthcare professionals known to the research team were also contacted directly and invited to participate. Participants who agreed to partake were contacted via phone or email to schedule a convenient interview time at their place of work. Each participant received a copy of the participant information statement and provided written or verbal consent to participate. Interviews were conducted by authors AVL and CS who possessed training and experience in qualitative research methods. AVL is a pharmacist and PhD candidate and CRS is a registered nurse, pharmacist and pharmacy academic. Neither researcher had an established relationship with participants prior to the research. Interviews were conducted face-to-face or over telephone between June and September 2019 and ranged in duration from 30 to 60 min. All transcripts were audio-recorded, transcribed verbatim and de-identified to maintain participant confidentiality.
Initial analysis was conducted in parallel with ongoing recruitment to allow for evaluation of sample size requirements in relation to thematic saturation.27 Recruitment continued until new themes relevant to the central focus of the research ceased to be observed.
A phenomenological approach was adopted, the aim of which is to describe the significance of the experience from the perspective of the individuals who have lived it.28 It is through exploring the experience of healthcare professionals that we can gain a deeper understanding of the challenges of deprescribing of opioids and subsequently, aspects of importance when developing opioid deprescribing guidelines.
Multiple phases of inductive thematic analysis were conducted,29 using NVivo V.12 software as a data management tool. Initial analysis involved a discussion of major themes among researchers, followed by independent open coding by AVL and CRS. A coding index was developed and applied to subsequent transcripts with coding consistency regularly assessed across transcripts. The coding index was refined throughout analysis to ensure that the themes derived adequately represented the obtained data.
Two focus groups (n=11 and 9) and subsequent individual interviews (n=11) were conducted with healthcare professionals. A summary of participant professional roles organised by style of interview is provided in table 1. In Australia, community-based physicians are routinely referred to as general practitioners (GPs).
Perceptions of healthcare professionals
Two main themes were identified: (i) the ‘too hard’ basket: challenges of deprescribing and (ii) even if I want to, I do not know how: development of opioid deprescribing guidelines. The first theme relates to the range of reported challenges which influence healthcare professionals’ willingness and ability to deprescribe opioids. Subthemes explore medication, patient, prescriber and health system-related challenges. The second theme acknowledges that participants feel current practices surrounding opioid management are suboptimal and that opioid deprescribing guidelines are required to direct and support clinical practice. Subthemes explore the need, scope, content and utilisation of prospective opioid deprescribing guidelines. Excerpts from participants’ responses have been included to provide understanding of healthcare professionals’ experiences and perspectives. Online supplementary file B contains a summary of themes and subthemes and additional participant quotes.
Theme 1: The ‘too hard’ basket: challenges of deprescribing
I think we know we should be deprescribing opioids, but sometimes it just gets placed in the ‘too hard’ basket. (Participant 5, semi-structured interview)
There was consensus among participants that deprescribing opioids is important, with participants highlighting a range of concerns when continuing opioids for patients including the potential for medication-related side effects, long-term health impacts, escalation and deviation. Despite participants’ recognition of value in opioid tapering and discontinuation, opioid deprescribing was viewed as a challenging and time-intensive activity with little incentive and substantial effort required from both healthcare professionals and patients.
Subtheme 1: Medication-related challenges
It’s always more of a compromise when you are talking about deprescribing centrally acting drugs compared to non-centrally acting ones. (Participant 6, semi-structured interview)
In some situations, the opioids do make people feel better in more ways than just relieving pain and I think that they are susceptible to maintaining that drug. (Participant 13, focus group 1)
Participants’ perceived limited clinical utility in the continuation of opioids in chronic non-cancer pain and identified an array of side effects warranting cautious use. Despite this, opioid deprescribing was not regarded as routine practice. Opioid deprescribing was considered by participants to be more complex than the deprescribing of other medication classes. Physical and psychological dependence were perceived as key barriers to the withdrawal of opioids. It was suggested that some individuals consume opioids for euphoric effects rather than for physical analgesia and would therefore be less receptive to deprescribing. A lack of alternative pharmacotherapy options was deemed a contributing factor for opioid continuation. Paracetamol and non-steroidal anti-inflammatory agents were identified as possible alternative analgesics; however, participants saw limited clinical utility of these agents as opioid substitutes due to a perceived lack of efficacy, clinical contraindications in specific patient cohorts and concerns about long-term use.
Subtheme 2: Patient-related challenges
People get to this stage and they become very medication focussed and ‘only a medicine will fix my problem’. Part of the treatment of chronic pain is getting them to shift to a more holistic view of pain…this is a psychological and sociological problem as well. (Participant 3, semi-structured interview)
Specific vulnerable patient populations were identified by participants as being at higher risk of opioid-related harms. These included persons with mental health issues, chronic pain and those with existing or previous substance use disorders. Clinicians felt most concerned about continuing opioids for these populations but also felt that they would be the most difficult groups to engage in deprescribing. Consideration of individual patient psychosocial factors was emphasised as being integral to the deprescribing approach. Due to the variability of patients and their individual circumstances, participants highlighted that prospective opioid deprescribing guidelines would need to address patient psychosocial factors while allowing clinicians to tailor care to patients’ personal circumstances.
Individual patients’ perceptions of pain and analgesics was thought to influence opioid-taking behaviours. Opioid-related stigma was thought to prevent patients from initiating conversations with clinicians about deprescribing, potentially limiting the opportunity for intervention, engagement and education. It was highlighted by multiple healthcare professionals that some patients refuse to trial opioid medications due to ‘opioid phobia’, limiting clinicians’ pain management options. Participants emphasised that a balance was required between curtailing opioid misuse and adequately managing patients’ pain.
Subtheme 3: Prescriber-related challenges
I think it’s hard. Maybe hard isn’t a good excuse, but deprescribing is more difficult than prescribing, it takes more effort. (Participant 6, semi-structured interview)
I am not going to rock the boat and probably most of us (general practitioners) would take that pragmatic approach. (Participant 5, semi-structured interview)
I think it’s hard. Maybe hard isn’t a good excuse, but deprescribing is more difficult than prescribing, it takes more effort. (Participant 6, semi-structured interview)
I am not going to rock the boat and probably most of us (general practitioners) would take that pragmatic approach. (Participant 5, semi-structured interview)
Participants believed that many prescribers refrain from opioid deprescribing as it may disrupt the prescriber-patient therapeutic relationship. Similarly, fear that a patient may experience an adverse outcome from opioid deprescribing such as withdrawal symptoms, pain exacerbations, reductions in physical function or a decreased quality of life was a perceived barrier. Participants did not raise concerns of patients seeking illicit or alternative sources of opioids. Some participants believed that continuation was less likely to cause harm than discontinuation. It was acknowledged that clinicians would be more willing to deprescribe opioids if the patient actively raised the topic with them. Other commonly suggested catalysts for prescriber-initiated opioid deprescribing included medication-related side effects or treatment failure. Alternatively, one participant suggested that discussing deprescribing with patients may in fact be beneficial for the therapeutic relationship and considered it a form of patient advocacy. Some physicians expressed that they felt an obligation to provide pain relief and often opted to continue therapies if patients were deemed ‘stable’. Many hospital prescribers did not view opioid deprescribing as their responsibility and often prioritised management of acute pain rather than modification of existing opioid therapies in an in-patient setting.
Subtheme 4: Health system-related challenges
That has been pointed out year after year—the disconnect between the hospital and the community. (Participant 1, semi-structured interview)
Workload pressures, inadequate remuneration for healthcare professionals and insufficient resources for clinicians and patients were viewed as barriers to opioid deprescribing. Specialist and multidisciplinary care were largely seen as enablers to opioid deprescribing; however, effectiveness of a multidisciplinary approach was thought to be limited by accessibility and lengthy wait times for referrals to pain clinics. Some participants expressed concern that specialised and multidisciplinary services, once engaged, decrease general practitioner agency to deprescribe opioids. Significant costs associated with alternate pain management strategies such as pain psychoeducation and physiotherapy which were thought to accompany successful opioid deprescribing, limited their applicability.
Transitions of care were identified as critical points in determining if opioids would be continued or deprescribed. Many participants suggested that opioids initiated in hospital for acute pain were then continued in the community setting. Targeting of routine opioid prescribing practices in acute surgical and emergency care settings was suggested to prevent pre-emptive opioid prescribing without adequate assessment of appropriateness and need. Many participants highlighted discontinuity in the health system and a need for improved communication between hospitals and community prescribers at the point of care transfer. Community-based practitioners requested clearer guidance on anticipated weaning of analgesics after hospital discharge. However, some hospital prescribers highlighted the limitation of this request, as it may be difficult to predict an individual’s pain ahead of time. Within the community setting, it was suggested that prescribers need to be more proactive in initiating opioid deprescribing when they ‘inherit’ a patient from another prescriber. It was thought that opioid deprescribing guidelines could be used to improve consistency in opioid management across various care settings.
Theme 2: Even if I want to, I do not know how: development of opioid deprescribing guidelines
I think there is an assumption that everyone knows how to—but the reality is they don’t. I mean not everyone would take the advice, but I think it would be good to have it available. (Participant 10, semi-structured interview)
Participants identified that current opioid prescribing guidelines provide advice regarding initiation of treatment, yet they rarely address monitoring or medication discontinuation. Participants felt that currently available resources provide inadequate cessation guidance and support, requesting novel approaches to ensure appropriate opioid use. Evidence-based opioid deprescribing guidelines were viewed as a mechanism to mitigate inappropriate use of opioids and related harms. Healthcare professionals felt that specific opioid deprescribing guidelines could address many challenges thought to inhibit opioid deprescribing and improve prescriber self-efficacy to implement interventions.
Subtheme 1: Guideline characteristics
I think the good thing about the community is the patient is exposed to all their usual triggers, in hospital you don’t have that, it’s sort of an unreal environment. (Participant 11, semi-structured interview)
The big concern is people who have chronic pain—and they have probably been on opioids for a while. (Participant 7, semi-structured interview)
Community-based care was considered by most participants as the preferred setting for opioid deprescribing due to patient accessibility and the opportunity for regular follow-up. Participants considered that those taking opioids for chronic non-cancer pain were the target patient population for prospective guidelines, however many participants suggested benefit in deprescribing opioids for all patients for which risks outweighed benefits.
Subtheme 2: Guideline content
It might seem impossible, but I do think it’s important it’s not a one size fits all approach. (Participant 11, semi-structured interview)
Healthcare professionals suggested that opioid deprescribing guidelines should include content on when and how to deprescribe opioids, when to refer to specialist care and outcome measures to assess the effectiveness of opioid deprescribing. Some participants saw deprescribing as an essential component of prescribing and advocated for a treatment agreement to be made between each patient and prescriber at the point of initiation regarding how opioids are going to be used, when to assess efficacy and when to withdraw. Planned opioid reduction at the point of prescribing was thought to create an expectation to deprescribe, minimising potential disruptions to therapeutic relationships during therapy withdrawal. A structured and holistic approach to deprescribing was considered optimal, with adjunct or alternate analgesic agents, non-pharmacological pain management strategies and involvement of multidisciplinary healthcare members. There was some concern about guidelines and their ability to be applicable to the heterogeneous group of individuals who consume opioids. As such, it was thought that prospective opioid deprescribing guidelines would require a multitarget, multimodal intervention strategy. Healthcare professionals suggested that functional measures, quality of life measures and overall risk reduction should be considered when assessing the effectiveness of opioid deprescribing in addition to pain outcome measures.
Subtheme 3: Guideline dissemination and implementation
I don’t think a guideline on its own will fix this problem…you need to think about how to get people to actually use the guideline. (Participant 13, focus group 2)
Participants expressed concern about the utility of deprescribing guidelines and emphasised that a robust implementation strategy would be required to ensure uptake and translation of evidence into practice. There was some concern that an opioid deprescribing guideline would limit prescribers’ practice or discourage use of opioids, leading to pain mismanagement. Suggested avenues for guideline dissemination included Healthpathways (an online condition management database for community-based physicians) and through bodies such as NPS Medicinewise (a national independent not-for-profit organisation which aims to improve the quality use of medicines in Australia). Resources for patients to assist in the implementation of guidelines were also suggested.
Healthcare professionals with an interest or expertise in deprescribing and/or pain medicine perceived value in opioid deprescribing yet highlighted an array of barriers to opioid deprescribing in clinical practice. Many challenges have been reflected in previous stakeholder perspective research on medication withdrawal, including resource and time barriers, fear of jeopardising therapeutic relationships and the complexities of care transitions.30–32 However, there are key aspects of participants’ responses which appear unique to opioids. Factors such as physical and psychological dependence, patient psychosocial factors and stigma surrounding opioid use suggest that specific guidance on the withdrawal of opioids is required to address challenges and support clinicians in implementing appropriate and effective deprescribing interventions.
Despite iatrogenic harms of opioids being central to participants’ responses, opioid deprescribing was not considered routine practice. A disconnect was revealed between participants’ perceived benefit of opioid deprescribing and deprescribing behaviours. Although a range of justifications for opioid continuation were presented, overall, the cognitive load associated with deprescribing appeared greater than that for continuation. Guidelines routinely impact on knowledge to standardise practices and improve concordance with evidence-base, with a criticism of guidelines being their inability to ensure transformation in attitudes or behaviours.33 Participants’ responses suggested that the desire to deprescribe opioids already exists. However, clinicians may benefit from guidance on the approach and execution of opioid deprescribing, thereby easing the cognitive load and shifting the default behaviour from prescribing to deprescribing. As such, guidelines on their own may not change a clinician’s willingness to deprescribe opioids, but for those who are willing, guidelines will likely influence their ability and confidence to effectively deprescribe.
Participants’ responses aided in defining the scope for prospective opioid deprescribing guidelines, identifying community-based physicians as the healthcare providers with the greatest opportunity to deprescribe opioids. Individuals consuming opioids for chronic non-cancer pain were the suggested patient target population. A specific subpopulation was identified for which participants expressed an enhanced need for opioid deprescribing and enhanced prescriber hesitancy; those deemed to be ‘opioid-dependent’. Prescriber hesitancy towards deprescribing for opioid-dependent persons, despite identifying greater need for intervention, suggests that practitioners lack deprescribing self-efficacy in this cohort. While prospective deprescribing guidelines may require specific interventions and strategies for those with opioid use disorders, it remains important to identify suitable candidates for opioid deprescribing prior to the point of dependence. Vulnerable patient population groups thought to be at greater risk of ongoing opioid use, including individuals with mental health issues or other substance use disorders were identified. However, given the increased exposure of opioids within the whole population, it is difficult to predict which patients are most likely to experience significant opioid-related harms. Although there is a gradient of risk and estimated individual risk should be considered, judicious use of opioids will likely require ‘universal precautions’.34 This concept suggests that all patients would benefit from judicious prescribing and monitoring as ‘there is no definite test or physical sign that will predict which patient will do well’.34 Prospective opioid deprescribing guidelines with a universal precautions approach could encourage opioid deprescribing in all patients for which the risk-benefit profile of continuation becomes non-favourable, rather than only those who are dependent or thought to be at the greatest risk of harm. A universal precautions approach could contain overall opioid-related risk while allowing for identification of patients progressing along the pain-addiction continuum.
Stigma associated with opioid use was identified as a significant factor which may inhibit patients from actively engaging in conversations with healthcare professionals about opioid deprescribing. Although healthcare professionals acknowledged this stigma and its detrimental impact on patient care, the language used by participants during interviews was perhaps stigmatising in itself, with terms such as ‘addict’ identified. Although these terms may not be used when interacting with patients, it appears there is implicit bias among healthcare professionals towards chronic opioid users, a concept which has been widely explored in the literature.35 36 This is of concern as stigmatising attitudes of healthcare professionals may undermine effective healthcare and deter individuals from seeking treatment.37 38 For this reason, opioid deprescribing guidelines will need to encourage a proactive deprescribing approach to ensure that patients are provided opportunities for treatment cessation, and acknowledge and address issues relating to opioid stigma and appropriate language of addiction to optimise the chance of successful outcomes.
Patient psychosocial factors were considered paramount when managing pain conditions and as such, participants felt that prospective guidelines need to focus on pharmacotherapy and address patient psychosocial factors. Specific intervention strategies for inclusion in prospective opioid deprescribing guidelines were suggested, however, there was some concern about the ability of strategies to be applicable to all pain patients. As such, it is likely that prospective guidelines will require a multitarget, multimodal intervention strategy to account for identified challenges at the medication, patient, prescriber and health system level, and also be flexible in nature to allow clinicians to tailor intervention strategies to individual patient needs. Like any strategy, it is unlikely that opioid deprescribing guidelines in isolation will solve the ‘opioid epidemic’. The current healthcare environment, both in Australia and internationally, is not incentivised by patient-centred outcomes and opioid deprescribing is time and labour intensive. Institution of system-wide changes will likely be impeded by factors such as the discontinuity of care between healthcare settings and prohibitive costs in a largely for-profit healthcare system. However, with a strong implementation strategy, evidence-based guidelines may be able to support clinical decision making, reduce variability in practice and improve opioid use and patient outcomes.
Strengths and limitations
To our knowledge, this is the first qualitative study to examine healthcare professionals’ perspectives on the scope and content of prospective opioid deprescribing guidelines. Rigorous methods for data collection and thematic analysis were used and it is believed that thematic saturation was achieved. A range of perspectives from different health disciplines were included, however, data were not analysed at the provider level. This means the findings, while broad, are not specific to individual professional groups. Furthermore, current health models emphasise the importance of shared decision making between healthcare professionals and patients in deprescribing practices, yet patients were not included in this study. As such, it is important that the perspectives of patients on the deprescribing of opioids are obtained prior to the development of guidelines. Although this study involved a variety of healthcare professionals, the recruitment of participants was via self-selection and it is possible that this may have resulted in under-representation of participants that would be resistant to the concept of deprescribing. Furthermore, there was additional selection bias as the two focus groups were conducted with participants who had chosen to attend an Australian Deprescribing Network event. To strengthen representativeness of the findings, we conducted individual interviews with practising healthcare professionals in the community who have frequent interactions with opioid users. Transcripts were not returned to participants after transcription for comment or correction nor were findings which may be a further limitation.
Opioid deprescribing was perceived as a complex, challenging practice with continuation of treatment being the default behaviour. Healthcare professionals recommended development of guidelines with the inclusion of psychosocial guidance, followed by a multitarget, multimodal intervention strategy that incorporates behavioural change techniques. The next step is to gauge the perspectives of patients to triangulate the findings and incorporate the perspectives presented into the development of opioid deprescribing guidelines.
The authors would like to thank all healthcare professionals who participated in this research. The authors would also like to thank Dr Lisa Kouladjian O’Donnell and Dr Sarira El-Den for facilitating the focus groups.
Twitter @AiliLangford, @jonpenm
Contributors All authors participated in the design and conduct of the research, writing and/or editing of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.DG and C-WCL are supported by fellowships from the National Health and Medical Research Council, Australia.
Competing interests C-WCL reports non-financial support from Pfizer Australia, outside the submitted work.
Patient consent for publication Not required.
Ethics approval The study was approved by The University of Sydney Human Research Ethics Committee (approval no. 2018/563).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available. The authors do not have permission to share data.