SAGE (safer analgesia): a protocol for a pragmatic cluster randomised controlled trial to reduce the use of high-risk medicines in people with chronic back and/or neck pain

Abstract

Introduction

Chronic back and neck pain are commonly treated with opioid analgesics, gabapentinoids and benzodiazepines, despite their high-risk profile and potential limited efficacy. Deprescribing interventions (aimed at medicine reduction or cessation) have shown some effectiveness in reducing the use of these medications, but similar approaches tailored to individuals with complex chronic back and/or neck pain are lacking and urgently needed. This trial will evaluate the effect of the safer analgesia (SAGE) intervention (training of general practitioners (GPs) in deprescribing and support to deprescribe) on cessation and/or reduction of the target high-risk medicine (a benzodiazepine, gabapentinoid or opioid) for people with chronic back and/or neck pain.

Methods and analysis

SAGE is a pragmatic cluster randomised trial that will be conducted with at least 30 general practices in Australia randomly assigned in a 1:1 ratio to the SAGE intervention or no intervention (usual care control group). The SAGE intervention is a GP-facing intervention comprising (i) training for GPs in deprescribing and access to deprescribing resources and (ii) deprescribing support—to assist the deprescribing process for their patients, GPs can conduct a long GP consultation (20–40-min duration), refer to trained physiotherapists for the provision of psychologically informed physiotherapy sessions and provide alternate pain management options including heat wrap and diclofenac gel. A total of 320 adult patient-participants experiencing chronic back and/or neck pain (≥ 3 months duration) prescribed a target high-risk medicine (benzodiazepine, gabapentinoid or opioid) persistently for this pain will be recruited via participating general practices. The primary outcome is cessation of dispensation of the trial participant’s high-risk medicine (a benzodiazepine, gabapentinoid or opioid) prescribed by their trial GP. The primary time-point for the primary outcome will be 1-year post-enrolment with an observation window of the preceding 4 weeks. Secondary outcomes include self-reported outcomes such as pain, quality of life and adverse events. Analyses will follow an intention-to-treat approach with a nested economic evaluation and per-protocol analysis planned separately.

Ethics and dissemination

The study received approval from the University of Sydney Human Research Ethics Committee (2024/HE001706). The results will be disseminated via publication in a peer-reviewed scientific journal, presentation at conferences and media.

Trial registration number

ANZCTR: ACTRN12625000953437.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• A key strength of this study is that it is targeting three classes of high-risk medicines (opioids, gabapentinoids and benzodiazepines) commonly used for chronic back and/or neck pain.

• Another strength of this study is that research team members involved in outcome collection and assessment will be blinded.

• A potential limitation of the study is that due to the nature of the trial, it will not be possible to blind study general practitioners or patient-participants to treatment.

Introduction

Back and neck pain are common conditions and key contributors to disability worldwide.^{1 2} Chronic back and neck pain are commonly treated with opioid analgesics, gabapentinoids (eg, pregabalin) and benzodiazepines (eg, diazepam), despite their high-risk profile and potential limited efficacy.13,9 In Australia, opioid analgesics are prescribed in approximately half of the 3.7 million annual general practitioner (GP) encounters for chronic back pain.^{1 10} Globally, opioids are prescribed for 15%–42% of chronic back and/or neck pain cases,^{1 10} often at moderate to high doses. Other drugs, such as pregabalin and diazepam, are also commonly prescribed by GPs for the management of chronic back and/or neck pain.^{4 11 12} Pregabalin, for instance, surpassed opioids as the most dispensed analgesic under Australia’s Pharmaceutical Benefits Scheme (PBS) in 2020.13,15

The persistent use of opioid analgesics, gabapentinoids and benzodiazepines, particularly if taken concomitantly, is a major global health concern and can lead to harms, such as dependence, tolerance, overdose deaths, hospitalisations and falls.^{16 17} Approximately 80% of individuals taking opioid analgesics for 3 months or more experience harm.¹⁵ In Australia, hospitalisation from prescription opioid poisonings has increased by 25% in the past 15 years,¹⁵ and nationally, opioid-related harms are costing Australia over $4.7 billion annually.¹⁸ Studies have also shown that one in seven Australians who are dispensed pregabalin misuse the medicine.¹⁶

Despite clinical guidelines discouraging or recommending cautious prescribing of these medications for conditions such as chronic back and/or neck pain, they continue to be commonly prescribed.^{6 9 19}

Given that persistent use of these medicines may lead to harms which outweigh the potential benefits, urgent action is needed to identify effective and safe interventions to reduce the use of high-risk medicines for chronic back and/or neck pain. Supporting GPs to safely deprescribe high-risk medications for the treatment of chronic back and/or neck pain is crucial to reduce potential harms. However, to date, there have been limited efforts to support GPs to achieve this.

A systematic review of 36 studies found that deprescribing strategies, such as prescriber-focused interventions and pain self-management programmes, have shown promise in reducing opioid use.²⁰ However, the results should be interpreted with caution as the evidence was of low certainty and the sample sizes were small. A large randomised controlled trial (n=608 adults) of a multicomponent intervention to reduce opioid use showed a reduction in self-reported opioid use in adults on strong opioids for chronic non-malignant pain.²¹ However, this trial recruited participants from electronic medical records from general practices, and the deprescribing was not led by a treating GP. There have been few efforts to support deprescribing of gabapentinoids, and no study examined outcomes at long-term follow-up.²² Collaborative, multidisciplinary models of care involving physicians and allied health professionals have shown efficacy in reducing benzodiazepine use in older adults.^{23 24} Furthermore, provision of psychologically informed physiotherapy was successful in reducing pain in people with chronic low back pain,²⁵ but interventions designed to support GPs to deprescribe high risk medicines for individuals with complex, chronic back and/or neck pain are lacking.

Important barriers to deprescribing of potentially high-risk medicines include sub-optimal communication, low prescriber confidence in initiating conversations around deprescribing and a lack of affordable and accessible alternatives for pain relief.^{22 26 27} The SAGE trial aims are therefore to evaluate whether a GP-facing deprescribing intervention, designed to address barriers to deprescribing by facilitating training of GPs in deprescribing skills and providing support to deprescribe, leads to greater cessation of the target high-risk medicine (a benzodiazepine, gabapentinoid or opioid analgesic) prescribed by study GPs for people with chronic back and/or neck pain compared with the usual care control group.

Methods and analysis

Study design and setting

SAGE is a pragmatic cluster randomised trial with nested economic evaluation that will be conducted with general practices in Australia randomly assigned in a 1:1 ratio to the SAGE intervention or no intervention (usual care control group). The trial protocol has been reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement.²⁸

Eligibility criteria

General practices

General practices will be considered for the trial based on the following criteria:

Inclusion

• Able to provide study GPs within the practice, with access to practice software or prescription monitoring information, such as SafeScript to screen for regular use of the target high-risk medicines.

GPs

GPs in participating practices will be eligible based on the following criteria:

• Consults patients with chronic back and/or neck pain (with or without radiation to the arm and leg).

• Be registered and maintain currency during the trial with the Australian Health Practitioner Regulation Agency (Ahpra).

• Have no restrictions on prescribing drugs of dependence, including opioids.

• Holds adequate insurance (public and professional liability).

• Willing to be trained in a GP-led deprescribing model of care.

• Willing to consider tapering of the target high-risk medicine(s) for patients with chronic back and/or neck pain.

Exclusion

• Received an educational outreach visit on deprescribing of the target high-risk medicine(s) within the past 6 months.

Patient-participants

Adults with chronic back and/or neck pain will be screened for eligibility by a participating GP either during a face-to-face or telehealth consultation. Participating GPs will determine patient-participant eligibility using a study screening form. Patient-participants will be considered for the trial based on the following criteria:

Inclusion

• Adults (≥ 18 years).

• Experiencing chronic back and/or neck pain (pain duration>3 months) with or without radiation to the leg or arm.

• Using a target high-risk medicine persistently (≥3 dispensations of the same high-risk medicine (a benzodiazepine, gabapentinoid or opioid)), prescribed by the study GP within the last 4 months for chronic back and/or neck pain with at least one of those dispensations within the last month.

• Sufficient understanding of English or translation available (in Arabic or Mandarin) to provide informed consent to participate and understand written and verbal study information.

• Holds a current Australian Medicare card number (for data linkage purposes) and allows access to their Medicare Benefits Schedule (MBS)/PBS data.

• Willingness to provide informed consent to participate in the trial.

• Willing to consider their GP’s recommendations regarding how to safely reduce the use of high-risk medicines.

Note: Patient-participants in an opioid pharmacotherapy treatment programme for opioid use disorder will be eligible if the target high-risk medicine is a benzodiazepine or gabapentinoid (non-opioid).

Exclusions

• Currently on a tapering plan with the GP for the target high-risk medicine for chronic back and/or neck pain.

• Receiving active treatment for cancer or palliative care.

Physiotherapists

Physiotherapists will be eligible based on the following criteria:

• Be registered and maintain currency during the trial with the Ahpra.

• Currently practising or working as a physiotherapist with at least 5 years’ experience.

• Has access to the internet or telephone (to deliver the sessions remotely).

• Holds adequate insurance (public and professional liability).

• Willingness to commit to the trial-funded training modules and webinars (~20 hours total) to prepare them for delivering the psychologically informed physiotherapy session to patient-participants in the intervention arm.

Intervention

The SAGE intervention is a GP-facing intervention (see figure 1) that supports GP-led deprescribing and involves the following components:

Figure 1. SAGE trial flow diagram. ^aIntervention only within 2 weeks of screening/consent; ^b10 psychologically-informed physiotherapy sessions (up to 8 sessions within 20 weeks of the longer GP consultation and two sessions for possible flare-ups up to 1 year post enrolment). ^cProcess Evaluation interview for intervention participants only. To be conducted within approximately 20 weeks after enrolment for patient-participants. GP, general practitioner; SAGE, safer analgesia.

1. GP training in deprescribing skills, including communication training using the motivational interviewing approach and access to evidence-based deprescribing resources, such as tapering algorithms.

2. To assist the deprescribing process for their patients, GPs can (at no cost to the patient).

   1. Conduct a long GP consultation (trial-funded).

   2. Refer to trained physiotherapists for the provision of evidence-based, psychologically informed physiotherapy sessions.

   3. Provide alternative pain management options.

These components of the intervention are elaborated further below.

GP training in deprescribing and communication

To support GPs in communicating medication-related harms with patient-participants and provide tapering strategies informed by the evidence, we will use a communication support bundle comprising videos, communication support guidance documents and tapering algorithms, which will be packaged and delivered during an outreach visit to each recruited GP practice.

The communication support bundle comprises the NPS MedicineWise ‘Opioids: Communication Videos’²⁹ (also applicable to benzodiazepines and gabapentinoids) alongside a 5–10 min educational video developed by the research team featuring an experienced GP, which will be presented during the face-to-face training with the study GPs. Together, the videos discuss conversations between GPs and patients and describe 'motivational interviewing’ (the recommended evidence-based communication approach for these conversations),²⁹ including its underlying ethos, four main principles (empathy, developing discrepancy, rolling with resistance, supporting self-efficacy) and five key skills (open-ended questioning, affirmations, reflections, summarisations, elicit shared understanding).²⁹ While the NPS MedicineWise communication videos discuss tapering in the context of opioid medicines, we will explain to GPs that the messages presented are applicable to other high-risk medicine classes, including benzodiazepines and gabapentinoids.

During this training, GPs will also be given access to trusted, up-to-date deprescribing resources developed by our partners, for example, ‘Medicines Conversation Guide’³⁰ and Opioid Deprescribing Guideline³¹ and other deprescribing resources hosted on the New South Wales Therapeutic Advisory Group Website (https://www.nswtag.org.au/deprescribing-tools/) to support safe tapering of the target medicine(s). GPs will also be given access to trusted tapering algorithms for opioids, gabapentinoids and benzodiazepines, for example, those developed by NPS MedicineWise, the National Health Service and Royal Australian College of General Practitioners.32,34 These resources offer GPs guidance on safe dose reduction, tailoring the deprescribing plan to the patient-participant, monitoring for withdrawal symptoms, making dose adjustments and supporting patient-participants to identify and report withdrawal symptoms.

Where outreach and delivery of the communication support bundle cannot feasibly occur face-to-face, they may be conducted via video call (eg, Zoom).

Deprescribing support

To support the GP to deliver GP-led deprescribing, the trial will provide the following support.

Funding of a long GP consultation

The trial will fund a ‘longer”’ GP consultation payment at the rate of an Australian Medicare Benefits Schedule Item 36 ‘Level C’ consultation (20 to 40 min in duration). This consultation will be provided once and scheduled within 2 weeks of identifying regular patient use of the target medicine and receiving patient-participant consent. The ‘longer’ consultation is intended to support the effective management of chronic conditions and is intended to facilitate a deep discussion about strategies to taper the high-risk medicine (informed by the resources developed by the team).

GPs will be asked to discuss with the patient-participant the use and tapering of the target high-risk medicine, using the guidance provided in the Medicines Conversation Guide,³⁰ Opioid Deprescribing Guide³¹ and tapering guides,32,34 and provide verbal education. Study physiotherapists will be asked to provide patient-participants with verbal education. The education combines evidence-based messages on judicious use, harms and safe disposal of opioids with management strategies endorsed in international back and/or neck pain guidelines, for example, advice to stay active and avoid bed rest.³⁵ These strategies assist with pain relief and can speed recovery from back and/or neck pain.² Patient-participants will be encouraged by their treating GPs to ask questions about pain, discuss a pain management plan, including a tapering plan; and set achievable goals.

Alternate pain management assistance

To reduce reliance on the high-risk medicine and further support the tapering process, GPs can provide patient-participants with heat wraps, topical diclofenac gel and referral for psychologically informed physiotherapy sessions at no cost (funded by the trial). These alternatives are described below.

GPs will be asked to provide an initial 1-week supply of heat wraps and where appropriate (depending on the patients’ medical history), a 100 g tube of diclofenac gel (a topically applied non-steroidal anti-inflammatory drug (NSAID)). The heat wraps (ARTG #209075) are a low-risk device providing low-level continuous heat. Topically applied NSAIDs have been shown to provide equivalent relief to oral NSAIDs for common musculoskeletal conditions (eg, osteoarthritis and spinal pain) and are associated with fewer adverse events.³⁶ Where requested, further supply of the heat wraps and topical diclofenac gel (up to 12 week’s supply at no cost to the patient-participant) will be provided in staged supplies (eg, monthly) via direct post to the patient-participant’s home.

Provision of evidence-based psychologically informed physiotherapy

GPs in the SAGE intervention can provide patient-participants with a written referral for up to 10×1-hour trial-funded physiotherapy consultations to provide education and training to manage pain. Trained study physiotherapists will deliver up to eight physiotherapy consultations within approximately 20 weeks following the long GP consultation, with a further two consultations reserved for managing flare-ups after this time, and within 1 year of the initial GP consultation.

Study physiotherapists will be trained in aspects of a psychologically informed treatment approach³⁷ shown to be effective and cost-effective in reducing pain for people with disabling chronic low back pain (LBP), but not routinely tested in people using high-risk medicines regularly.²⁵ The sessions will be delivered by trial physiotherapists trained in chronic pain assessment and management skills and are aligned with the biopsychosocial approach to management, as supported by the guidelines.²⁵ The sessions will be delivered via video (or alternatively via telephone in circumstances where the individual does not have readily available access to online platforms, such as Zoom).

Physiotherapy sessions will be collaboratively structured between the physiotherapist and participant to ensure the treatment plan is customised to the specific needs and goals of the participant, maximising the potential for best clinical outcomes.³⁸ The same physiotherapist will conduct all sessions for a single patient (except in circumstances where another physiotherapist may be required). We will aim to recruit at least one bilingual physiotherapist who speaks English and each of Arabic or Mandarin, to facilitate inclusion of and communication with culturally and linguistically diverse patient-participants. These were chosen as they are among the top non-English languages spoken at home in Australia. Our decision to deliver physiotherapy consultations/sessions via telehealth also enhances inclusivity for people for whom face-to-face consultations are less accessible (e.g. those unable to drive due to pain or medicine use).

Physiotherapists will be trained (~20 hours training in total) to deliver the physiotherapy sessions using a package of online learning modules delivered by pain titled physiotherapists (physiotherapists who have recognised advanced knowledge and skills in managing complex chronic pain). The training package is based on pedagogical principles used to facilitate learning and maximise engagement.³⁹ The online delivery will be multimodal using a blend of didactic written material, online self-paced modules, audiovisual lectures, specialist skill demonstrations and patient stories, interactive discussion platforms, problem-solving activities and formative assessment with quizzes. This hybrid model, comprising asynchronous independent online learning and live online Masterclass webinar sessions, aims to facilitate and consolidate the learning of knowledge and skills in the assessment, treatment planning and management of chronic pain.³⁹ A specific focus will be on providing patients with skills to manage pain and therefore enable reductions in medications. All content relates to clear learning objectives and is aligned with reflective practice principles. By providing a hybrid model of independent online learning together with Masterclass sessions, physiotherapists will have the opportunity to learn content and skills, implement these and reflect on their knowledge and skill development with guidance and feedback from the trainers and peers during Masterclass sessions.

Funded case conferences between the GPs and the physiotherapists (optional) will facilitate effective multidisciplinary care.

Control group

Study GPs in the usual care control group will be asked to treat patient-participants with their usual care methods and will receive no training from study researchers or researcher support for deprescribing.

Consumer medicines information leaflet provided by study team

Following enrolment, each patient-participant in the trial will be provided with the Consumer Medicines Information (CMI) leaflet for the target high-risk medicine currently being used for the chronic back and/or neck pain following the baseline contact. The appropriate CMI⁴⁰ will be determined during the baseline contact between the researcher and the patient-participant and provided by the study team. Further, a letter accompanying the CMI leaflets will also be provided by the study team, advising patient-participants to discuss any queries or concerns regarding the CMI leaflets with their doctor or pharmacist.

ICH-GCP training and refresher training

The International Council for Harmonisation Good Clinical Practice (ICH-GCP) training will be provided as a 7-min training video to all participating GPs at the start of the trial. GPs will be provided with refresher training (eg, in trial processes) every 6 months throughout the trial period they enrol the participants.

Co-interventions

No patient-participants in either arm will be prohibited from using other treatments that may assist with pain relief throughout the study (eg, personally funded physical therapies, the use of other analgesics). Any treatment outside of the study intervention which may impact study outcomes will be recorded and considered a co-intervention. The use of co-interventions will not be funded by the trial.

Study outcomes

Data for primary and secondary outcomes will be obtained using patient-participants’ self-reported data, linked data via the Centre for Health Record Linkage (CHeReL), or via access of their PBS and/or MBS data via Services Australia. A summary of outcomes collected is presented in table 1.

Table 1. A summary of study events and outcomes collected for SAGE trial.

Data	Timepoint
	Pre-enrolment	Baseline	Week 6	Week 12	Week 26	Week 52
Informed consent	✓
Patient information statement	✓
Eligibility criteria	✓
Demographic details		✓
Data linkage		✓	✓	✓	✓	✓
Self-reported
Medication diary		✓	✓	✓	✓	✓
†Heat wrap, NSAID gel use		✓	✓	✓
Harms (AE and SAE)			✓	✓	✓	✓
Global rating of change		✓	✓	✓	✓	✓
Quality of Life		✓	✓	✓	✓	✓
Interventions for pain		✓	✓	✓	✓	✓
Withdrawal symptoms			✓	✓	✓	✓
Other medicine use		✓	✓	✓	✓	✓
Planned back/neck surgery		✓	✓	✓	✓	✓
Emergency department presentations			✓	✓	✓	✓
Medicine-related poisoning			✓	✓	✓	✓
Process outcomes
Target medicine cessation			✓	✓	✓	✓
Return of unused medicines				✓		✓
Clinician questionnaires	✓‡				✓‡

^*Data linkage: for PBS, MBS, admitted patient and emergency department data, poisons and deaths data to occur at end of follow-up of last patient-participant, or in batches. Although the data will be accessed after completion of the follow-up period, it will cover the period from study enrolment to end of 1-year follow-up.

^†Intervention only.

^‡GP questionnaires will be collected pre-training, post-GP recruitment, and at 6 months. Physiotherapist questionnaire will be collected at pre-training, post-training and upon completion of delivering the sessions to 10 participants (ie, at the completion of the 10th participant’s final report) or at site close out if less than 10 participants.

AE, Adverse Event; GP, general practitioner; MBS, Medicare Benefits Schedule; NSAID, Non-Steroidal AntiInflammatory Drug; PBS, Pharmaceutical Benefits Scheme; SAE, Serious Adverse Event.

Primary outcome

The primary outcome is cessation (box 1) of dispensation of the trial participant’s high-risk medicine (a benzodiazepine, gabapentinoid or opioid) prescribed by their trial GP. The primary time-point for the primary outcome will be 1 year post-enrolment with an observation window of the preceding 4 weeks to ensure we adequately measure cessation.²¹ The primary outcome will be assessed using PBS data via Services Australia. These data capture >87% of dispensed prescription opioid and pregabalin use in Australia and at least 71% of benzodiazepine use.341,43

Box 1. Definition of key terms.

Persistent use: At least three dispensations of the same high-risk medicine prescribed by the study general practitioner (GP) within the last 4 months and at least one of those dispensations within the last month. The target high-risk medicine could be either a benzodiazepine, gabapentinoid or opioid analgesic.

Cessation: The absence of dispensation of the trial participant’s high-risk medicine (a benzodiazepine, gabapentinoid or opioid) prescribed by their trial GP at one year post enrolment with an observation window of the preceding 4 weeks.

Complete cessation: The absence of dispensation of the trial participant’s high-risk medicine (a benzodiazepine, gabapentinoid or opioid) sustained for three consecutive months immediately prior to the 1 year follow-up period. This includes a lack of substitution with another medicine from the same high-risk medicine class.

Substitution: A new dispensation of a high-risk medicine from a drug class other than that selected at study entry.

Secondary outcomes

Using self-report data and/or PBS, MBS data via Services Australia and/or data via the CHeReL, we will determine the following outcomes per group over 1 year:

• Cessation of the target high-risk medicine prescribed by any clinician. The proportion of participants who cease the same target high-risk medicine (a benzodiazepine, gabapentinoid or opioid) prescribed by any clinician in the 4 weeks prior to the 1-year follow-up.

• Complete cessation of the target high-risk medicine prescribed by any clinician. The proportion of participants who completely ceased the target high-risk medicine. Complete cessation is defined as the absence of dispensation of the trial participant’s high-risk medicine (a benzodiazepine, gabapentinoid or opioid) sustained for three consecutive months immediately prior to the 1-year follow-up period. This includes a lack of substitution with another medicine from the same high-risk medicine class.

• Reduced dose of the target high-risk medicine. Proportion of participants for whom there is any reduction in the dose of the target medicine(s) (based on strength and quantity dispensed in the 4 weeks prior to the 1-year follow-up) compared with baseline.

• Substitution to another high-risk medicine from a different drug class. Proportion of participants who substituted the target high-risk medicine to another medicine from a similarly high-risk drug class in the 4 weeks prior to the 1-year follow-up.

• Adjuvant anti-depressants dispensed on the PBS determined using the Defined Daily Dose (DDD)/1000 population/day.

• Adjuvant NSAIDs dispensed on the PBS determined using the DDD/1000 population/day.

• Cumulative dose of opioids dispensed, calculated as the cumulative oral morphine milligram equivalent⁴⁴ dose dispensed over 1 year using dispensed strength, quantity and type of opioids over this period.

• Cumulative dose of gabapentinoids dispensed, by dispensed strength and quantity over 1 year.

• Cumulative dose of benzodiazepines dispensed, by dispensed strength and quantity over 1 year.

• DDD/1000 population/day of gabapentinoids dispensed over 1 year.

• DDD/1000 population/day of benzodiazepines dispensed over 1 year.

• Healthcare use. We will capture all instances of subsidised services from health providers, including Home Medicines Review (HMR) by HMR accredited pharmacists (MBS item number 900). We will capture instances of emergency department (ED) presentations and hospitalisations through linked and/or self-report data.

• Total cost of MBS and PBS usage.

• Total cost of MBS usage.

• Total cost of PBS usage.

• Number of medicine-related poisonings and deaths, for example, using the NSW Poisons Information Centre and death registry (via the NSW registry of births, deaths and marriages).

• Cumulative anticholinergic and sedative medication exposure via the Drug Burden Index.⁴⁵

Secondary patient-reported outcomes

The following self-reported patient-participant reported outcomes will be collected at baseline and/or at weeks 6, 12, 26 and 52.

• Global rating of change (using the Global Perceived Effect scale; scored from -5 to +5): A measure with acceptably high test-retest reliability (interclass coefficient of 0.99).⁴⁶ This will be determined using the following item; ‘Compared to when this episode first started, how would you describe your back and/or neck these days?’

• Number and nature of harms (serious and non-serious adverse events), as defined in Section 9, and will include the following:

• Proportion of patient-participants who experience any adverse event.

• Frequency and nature of any adverse event.

• Proportion of patient-participants who experience any serious adverse event (any untoward medical occurrence resulting in death; is life-threatening; requires hospitalisation or prolongation of the existing hospitalisation; results in persistent or significant disability or incapacity; is a congenital abnormality or birth defect; is a medically significant or important event or reaction).⁴⁷

• Frequency and nature of any serious adverse event.

• Cause of serious adverse event.

• Quality of life using the Patient-Reported Outcomes Measurement Information System - 29 items (PROMIS-29) v2.1, a 29-item quality of life measure (with dimensions including physical function, participation, cognitive, anxiety, depression, fatigue, sleep disturbance, pain interference, pain intensity, with good internal consistency and validity).⁴⁸

• Over-the-counter analgesics, non-pharmacological interventions and other interventions for pain, categorised by type using an inductive approach at the time of analysis.

• Use of medicinal cannabinoids, reported as proportions (n/N (%)).

• Medication withdrawal using a publicly available version of the 16-item subjective opioid withdrawal scale (SOWS).⁴⁹ Although the SOWS has been validated for opioid withdrawal,⁴⁹ the symptoms included are documented withdrawal symptoms for each drug class we are targeting.

• Planned or unplanned back or neck surgeries.

• Other interventions for back and/or neck pain.

• ED presentations. Proportion of people experiencing and frequency of hospital ED presentations.

• Medicine related poisoning. Proportion of people experiencing and frequency of medicine related poisoning (poisoning is defined as experiencing harmful effects from taking too much of a medicine).

Process measures

The following process outcomes will be collected at reported specific time points (see table 1):

• The proportion of participants who ended a course of the target high-risk medicine(s) within the first 6 weeks: This will be determined using the self-report patient-participant medication diary. The course of medicine will be considered to have ended after seven continuous days of no high-risk medicine use.

• Return of unused high-risk medicine: At 12 weeks and 1 year, we will ask patient-participants whether they returned any unused high-risk medicines that they acquired whilst on the trial to the pharmacy for disposal. This will be presented as a proportion of participants who did return their study medicines per group (n/N (%)).

• Use of heat wraps and topical diclofenac gel (Intervention arm only): Patient-participants will be provided with a diary (paper or administered via research electronic data capture (REDCap)) and will be asked to document the number of days the heat wrap and diclofenac gel were used up to 12 weeks following the screening consultation and after patients have provided consent. The diary will be collected at week 12.

• Intervention costs. The cost of the intervention will be collected using trial logs, financial records and site monitoring data and will include costs associated with: training to GPs and physiotherapists, provision of alternative pain management (heat wrap/diclofenac, including express post-delivery), GP long consultation and physiotherapy sessions

• GP Study Clinician Questionnaires.

• Opioid therapy survey: A 10-item questionnaire to assess practice behaviour and confidence related to opioid therapy for the treatment of chronic pain, a measure of good reliability (Cronbach’s alpha of 0.28).⁵⁰ Responses will be collected pre-training, post GP recruitment and at 6 months.

• Concerns about analgesic prescription: a 21-item questionnaire to measure and predict both the frequency of prescribing opioids and reluctance to prescribe opioids, demonstrating both reliability and validity.⁵¹ Responses will be collected pre-training, post GP recruitment and at 6 months.

• Physiotherapist Study Clinician Questionnaire

Psychologically Informed Practice (PIP) questionnaire⁵² to measure four domains of practice, including knowledge about (components of) PIP treatment; confidence to implement (components of) PIP; likelihood to incorporate PIP treatment; and current practice. Collected at pre-training, post-training and upon completion of delivering the intervention to 10 participants (ie, at the completion of the 10th participant’s final report), or at site close out if less than 10 participants.

Sample size

An analysis sample of 320 patient-participants is required (160 in each arm) to detect a minimal 20% (absolute difference) for the primary outcome of medication cessation (as determined via previous trials), than that achieved via the usual care control,²¹ with 90% power, an α of 0.05 and an intracluster correlation of 0.05.²⁴ Allowing for a withdrawal rate of 15% and a rate of non-adherence of 10% (adherence by the GP to the intervention is the patient-participant being provided the long consultation), we will need 320 patient-participants. The study will recruit at least 30 general practices, and each practice will be asked to recruit ~15 patient-participants.

Strategies for achieving adequate patient-participant enrolment

The research team will conduct monthly phone calls and quarterly site visits (where possible) with study GPs to provide ongoing support, follow up on progress and facilitate continuing professional development points for GP participation. Both GPs and patient-participants will be remunerated for their involvement. Recruitment targets will be compared against milestones and a study steering committee will be engaged quarterly (where necessary) to address any challenges with recruitment.

Randomisation

Randomisation will be at the site (general practice) level. Individual clinicians and patient-participants will not be randomised. General practices (minimum of 30 practices) will be randomly assigned in a 1:1 ratio to either the SAGE intervention or control. For general practices that include more than one participating GP, the study GPs will be required to be trained in and deliver the same intervention to which the practice has been randomly assigned. The randomisation sequence will be determined by a blinded statistician using randomisation software and include permuted blocks of size 2 and 4. The randomisation schedule will be stratified by geographic remoteness (eg, urban and regional/remote/very remote) and area-level socioeconomic status of area in which the practice site is located (based on Socio-Economic Indexes For Areas) (see online supplemental file 1 for more details).

Blinding

As the study is a pragmatic cluster randomised controlled trial, there will be no treatment blinding of patient-participants, study GPs or physiotherapists. However, patient-participants, study GPs and physiotherapists will be blinded to the study hypothesis. Members of the study team coordinating patient-participant follow-up will be blinded. Statistical analysis will be performed by an independent statistician who will be blinded to group allocation. To minimise outcome measurement bias, the primary outcome (cessation of the dispensation of the same target high-risk medicine in the 4 weeks prior to the 1-year follow-up) has been chosen as an objective measure.

Data collection methods

The participating GP will notify the study team when a patient-participant is enrolled into the trial. The study team will follow up with the patient-participant, ideally within 24 hours, to complete the baseline telephone survey. Each patient-participant will be followed (by phone and/or online survey via REDCap) over 1 year. In addition, the study team will also follow-up with participating GPs and physiotherapists to complete questionnaires via REDCap (or paper based) at specified time points detailed above. Data will be entered and where appropriate, verified by the study team for data accuracy.

We will obtain consent from patient-participant and study GPs to access MBS and PBS data, admitted patient data (hospitalisations), ED presentations and poisons and deaths data via the following data custodians: Services Australia, CHeReL and NSW Poisons Registry (the latter where required). This information will also be supplemented with patient reported outcomes collected at baseline, week 6, 12, 26 and 52.

We will also collect assessment and summary reports from physiotherapists for each psychologically informed physiotherapy session via REDCap (ideally within 72 hours of the consultation).

Other data collected

Patient-participants, participating GPs in the intervention group and physiotherapists, will also be invited to complete a process evaluation interview (reported as a separate protocol). The study team will also keep field notes on any observations of particular importance to the trial during their interactions with study participants or others.

Data management

Data collected from patient-participants, study GPs and physiotherapists will be monitored for any inadvertent errors or omissions and recorded using a secure database hosted by the University of Sydney. An electronic data capturing system, REDCap, will be used to store participant self-reported data, and data collected over the phone will be directly entered into the database where possible, while surveys completed online will be automatically transcribed into the database. Information recorded using paper case report forms will be entered into the database and verified by another study team member.

All data collected during the trial including data from Services Australia and other data obtained via data linkage will be stored in secure databases hosted by the University of Sydney. The data will only be accessed by the approved study team. The record linkage process will be separated from the data analysis to minimise any risk to the participant’s privacy.

Statistical methods

To analyse the effect of the intervention vs control on study outcomes, trial group will be entered as a fixed effect in a mixed effects model, with a random intercept for cluster (GP practice) to account for correlation among participants recruited from the same practice. Primary analyses will follow the intention- to-treat principle with the study statistician blinded to treatment group.

Primary analysis

Primary analysis will be performed using a mixed effects regression to estimate risk difference and risk ratios⁵³ using trial group as the main covariate. Missing data are likely to be very low as our primary outcome is based on linked data, but any missing data will be imputed in order to comply with the intention-to-treat principle. Analysis of secondary outcomes will follow the same procedure, but where possible will include baseline observations of the outcomes, with models including an additional main effect for time, an interaction between group and time to allow change over time to vary between groups, and nested clustering to account for the use of multiple observations for individual participants.

Subgroup analyses will be performed on primary and secondary outcomes per (i) medicine class (opioid analgesics, benzodiazepines and gabapentinoids or combinations of these) and (ii) pain condition (back or neck pain or both).

Appropriate model checking will be conducted for all analyses. Balance of baseline patient-participant characteristics will be assessed, and any characteristics not well balanced will be included as covariates in the model, as a secondary analysis.

Secondary analysis

Secondary outcomes will be analysed using the same methodological approach.

Binary logistic regression will be conducted for binary outcomes.

Dichotomous variables will be reported as proportions, n/N (%). Continuous variables will be reported using point and variability estimates (eg, means and SD or median and IQRs). Outcomes will also be reported descriptively as appropriate, for example, proportion of participants per group reporting adverse events.

Reporting will follow the Consolidated Standards of Reporting Trials (CONSORT) guidelines.⁵²

Sensitivity analysis

Sensitivity analyses of the impact of missing data will be conducted using multiple imputation, and under a range of ‘missing not at random’ scenarios (eg, assumed success, assumed failure, last value carried forward).⁵⁴ Sensitivity analysis will also be carried out to account for any new indication for use of the target high-risk medicine which is unrelated to the index condition.

Per protocol analysis

A per protocol analysis involving a comparison of treatment groups including only patient-participants whose GPs adhered to the study intervention (operationalised as providing a long consultation) will be performed. This will be reported separately to the main paper.

Health economic analysis

Economic analysis, including a within trial cost-effectiveness and cost-utility analysis, will be conducted from the healthcare system perspective. Intervention-related costs and healthcare utilisation costs will be included in the analysis. Intervention related costs (ie, training outreach visits, heat wrap therapy, diclofenac gel, physiotherapy sessions, long GP consultation, resources production costs and costs of posting the heat wraps/diclofenac gel) will be collected using trial logs and financial records. Healthcare utilisation will be collected using administratively linked MBS, PBS and ED presentation and hospital admission costs, which will be valued using relevant state and national data. The health outcome measure for the cost-utility analysis will be quality-adjusted life years (QALY) at 52 weeks, calculated from PROMIS 29 using an Australian mapping algorithm.⁵⁵ Incremental cost-effectiveness ratio (ICER) will be expressed as additional cost per: (i) QALY gained at 52 weeks and (ii) additional patient with complete cessation, using linear mixed models for both costs and outcomes. Statistical uncertainty in cost and outcome estimates will be assessed through bootstrapped resampling techniques, which will be used to construct CIs for ICERs. Cost-effectiveness acceptability curves will then be used to depict the probability of cost-effectiveness across alternative willingness-to-pay thresholds. The full economic analyses will be detailed in the statistical analysis plan and be carried out separately to the main paper.

Statistical analysis plan

The final statistical analysis plan will be developed by the trial statistician, health economist and study team before the completion of participant follow up data, and prior to the breaking of the blind. We will publish the statistical analysis plan separately with details of the statistical analysis and handling of missing data where appropriate.

Data monitoring

The Data and Safety Monitoring Board (DSMB) has been formed by the steering committee and comprises experienced clinicians with skills relevant to the trial. A DSMB charter has been developed and reviewed by the DSMB.

The DSMB will review SAEs, assess causality where appropriate, review clinical trial data and provide recommendations (ie, trial progress and/or if changes for the trial are recommended). A meeting with the DSMB will be held around 6 months once the trial has commenced study recruitment, and annual follow-up meetings will be arranged, or as agreed by the DSMB and study team.

Harms

Collection of data on adverse events and serious adverse events via patient-participant self-report is described above. Harms data may also be documented for patient-participants in the intervention arm during the physiotherapy sessions. SAEs will be reported to the Sydney University Human Research Ethics Committee (HREC) within the required time frame, and causality will also be reviewed and adjudicated by the DSMB where appropriate.

Auditing

Independent auditing of the trial has not been arranged and will be arranged if requested.

Patient and public involvement

We involved the Painaustralia Consumer Advisory Group in the conception and design of the trial. Painaustralia will continue to support the project via high-level advocacy of the trial and dissemination. A consumer is a co-author on the work.

Ethics and dissemination

Ethics and other approvals

The study received approval from the University of Sydney Human Research Ethics Committee (project number: 2024/HE001706). Where appropriate, requests for ethics approval will also be submitted to the relevant committee, for example, NSW Population and Health Service Research Ethics Committee (PHSREC) to access linked data via CHeReL (eg, hospitalisations, ED presentations). Separate approval will be obtained by Services Australia to access PBS/MBS data for both patient-participants and GPs.

Protocol amendments

Proposed changes to the study protocol must be agreed on by the trial’s steering committee and be submitted to the University of Sydney HREC for approval prior to being implemented.

Informed consent process

The study team will train the study GPs on the informed consent process. An example of the consent form that will be provided to patient participants is presented in online supplemental file 2. For potential patients presenting to a study GP who fulfil the eligibility criteria, the study GPs will discuss the trial with them and provide a copy of the study patient information sheet and consent forms for consideration. During this process, the study GP (and/or member of the study team) will discuss and go through any queries regarding the trial. Potential patient-participants will be able to provide consent during the face-to-face or telehealth consultation, or at a later date (eg, once they have reviewed the patient information statement in further detail).

Two consent forms will be required to be completed from patient-participants. One consent form will be from the University of Sydney for study participation and health service usage data linkage and the second will be the Services Australia consent form to collect both MBS and PBS data to determine medicines dispensed and/or health care use. Study GPs will also need to complete two consent forms when they are recruited for the trial: the University of Sydney consent form and the Services Australia consent form. The Services Australia consent form will enable linkage of prescribing data to patient MBS and PBS information as part of the study. Physiotherapists will complete the University of Sydney form only for study participation.

Study withdrawals

At any stage, participants (patients, clinicians or sites) can withdraw their consent without repercussion, and the number of participants who withdraw (and reasons for withdrawal if provided) will be recorded. To account for potential study withdrawals, the study will recruit additional sites (eg, two additional sites in each arm) as a risk mitigation strategy in the event of under-recruitment of patient-participants. As described above, the sample size estimation for patient-participants has accounted for a withdrawal rate of 15% and non-adherence rate of 10%. Adherence by the GP to the intervention is the patient-participant being provided the long consultation.

Confidentiality

Study data will be securely stored in either locked cabinets (paper records) or electronically (electronic data files) and accessed only by the study team.

Access to data

The study team will have access to the final dataset, and a blinded (to treatment allocation) copy of the dataset will be provided to the trial statistician to perform the study analysis.

Ancillary and post-trial care

Costs of treatments outside of the trial will not be covered by the study. The trial will provide heat wraps, topical diclofenac gel and access to physiotherapy sessions at no cost to patient-participants in the intervention arm. Non-negligent harm associated with the protocol will be covered by the trial’s insurance. This includes cover for additional healthcare, compensation or damages.

Dissemination policy

The study will be disseminated via publication in a peer-reviewed scientific journal, presentation at conferences and media. All study authors will be required to meet the International Committee of Medical Journal Editors authorship criteria.