Mindfulness in Fracture Recovery and Reduction of Opioid Reliance: Evaluating the Feasibility of Implementing a Brief, Mindfulness-based Intervention to Manage Pain and Anxiety Before and After Fracture Surgery

1.0 INTRODUCTION 1.1 Pain, Anxiety, and Opioid Use After Fracture Fracturing a bone is both physically traumatic and psychologically distressing. Anxiety is common as patients awaiting fracture surgery struggle to quickly process what has happened to them and consider the risks and uncertainties that now lie ahead. In addition to this acute psychological distress, fracture patients often suffer from severe physical pain both before and after surgical treatment. During their post-operative hospitalization, fracture patients often receive both opioid-based and neuromodulating medications to manage their pain. Patients are then discharged from the hospital with instructions for rehabilitation and a prescription for analgesic medications - most often opioids. In fact, orthopaedic surgeons prescribe more opioid medications than any other surgical specialty and North American orthopaedic surgery patients take far more opioids than patients in other parts of the world. Despite the widespread use of opioids, patients often continue to struggle with severe pain and are not more satisfied with their pain management. In the context of the current opioid epidemic, the lack of non-pharmacological interventions available to address pain in fracture patients necessitates an urgent evaluation of alternative treatment strategies that could feasibly be integrated into current care pathways.

1.2 Mindfulness-Based Interventions Randomized controlled trials (RCTs) indicate that mindfulness-based interventions (MBIs) can effectively manage pain in many populations. Unfortunately, many challenges exist when considering how to implement an MBI in-hospital shortly after a traumatic event, such as a fracture. What fracture patients need is an intervention that is brief enough to be delivered at strategic times during their hospital stay, yet comprehensive enough to teach them pain self-management strategies capable of encouraging meaningful improvement in pain during the sensitive, subacute recovery period (i.e., weeks 1-6).

1.3 Need for a Pilot Trial To successfully implement a multicentre, randomized controlled trial that would evaluate the effects of a brief, perioperative mindfulness-based intervention on pain, anxiety, and opioid use before and after fracture surgery, a pilot trial is necessary to inform the trial's design and feasibility. The proposed pilot trial will (1) determine if participant recruitment is feasible, (2) assess key aspects of the protocol including treatment allocation compliance and follow up, and (3) assess the proportion of patients who are experiencing pain at six weeks post-randomization to support the sample size calculation for a larger, definitive trial.

2.0 OBJECTIVES 2.1 Feasibility Objectives

The primary objective is to assess the design and feasibility of the trial in preparation for a definitive multi-center trial. Specifically:

1. Determine the feasibility of participant enrollment;
2. Assess compliance with the intervention; and
3. Assess and refine data collection methods. 2.2 Primary Clinical Objective The primary clinical objective is to determine whether the brief MBI, compared to control, decreases pain intensity and interference over 6 weeks post-randomization.

2.3 Secondary Clinical Objectives

The secondary clinical objectives are to determine whether the MBI, compared to control:

1. Decreases acute pain over the perioperative period;
2. Decreases acute anxiety over the perioperative period;
3. Decreases pain catastrophizing over 6 weeks post-randomization; and
4. Decreases opioid use over 6 weeks post-randomization. 3.0 TRIAL DESIGN This pilot trial will use a randomized controlled trial design to evaluate the feasibility of implementing a trial that involves offering a brief, 2-part mindfulness-based intervention (MBI) to patients while in hospital before and after fracture surgery.

4.0 METHODS 4.1 Setting This trial will be coordinated by the Data Coordinating Centre at the Surgical Methods Centre, McMaster University, Hamilton, Ontario. The Surgical Methods Centre will be responsible for trial oversight, data management, data analysis, and knowledge dissemination. The Hamilton Health Sciences orthopaedic trauma research team at Hamilton General Hospital will oversee participant recruitment, follow-up and all data collection.

4.3 Patient Screening and Informed Consent All patients 18 years or older with an open or closed fracture of the appendicular skeleton who present to the hospital prior to internal fixation surgery will be screened. Patients who meet eligibility criteria will be asked to participate in the trial while they await fracture surgery. If they agree, written informed consent will be obtained. The process of obtaining and documenting informed consent forms will be completed in accordance with local Good Clinical Practice recommendations. Participants may withdraw their consent at any time.

4.4. Randomization Methods To ensure concealed allocation, eligible patients who provide informed consent will be randomized using the randomization function within the REDCap Cloud system. Eligible participants will be randomized to 1 of 2 groups: (1) 2-phase MBI treatment arm or (2) time-matched, audio recording control arm.

4.5 Intervention The MBI consists of two phases: a pre-surgery phase (Phase 1) and a post-surgery phase (Phase 2). Data will be collected before and after each phase of the intervention. Research personnel will facilitate the pre-operative intervention by providing participants with an iPad and headphones. After surgery, research personnel will once again arrange to facilitate the post-operative intervention before the participant is discharged from hospital.

Pre-Surgery Intervention (Phase 1): Participants in the MBI treatment arm will be provided with an iPad and headphones to listen to a 7-minute, audio-guided mindful breathing practice while waiting for surgery.

Post-Surgery Intervention (Phase 2): During their post-operative hospital stay, participants will once again be provided with an iPad and headphones to listen to another 7-minute, audio-guided mindfulness practice focused on pain management. Research personnel will ensure that patients have fully recovered from surgical anesthesia before facilitating the post-surgery intervention.

4.6 Comparator Participants randomized to the control arm will be provided with an iPad and headphones to listen to time-matched audio recordings at the pre-surgery phase (Phase 1) and the post-surgery phase (Phase 2). Research personnel will ensure that patients have fully recovered from surgical anesthesia before facilitating the post-surgery intervention.

4.7 Outcomes 4.7.1 Feasibility Outcomes (Primary)

The feasibility of participant enrollment will be assessed by monitoring screening and enrollment metrics, including:

1. Proportion of eligible patients who provide informed consent.
2. Length of time it takes to enroll 50 participants.
3. Review of reasons for exclusion.

The feasibility of the intervention and data collection will be assessed using the following metrics:

1. Proportion of participants assigned to the treatment arm who complete both phases of the MBI.
2. Proportion of complete data in all case report forms. 3. Proportion of participants who withdraw consent to participate. 4.7.2 Clinical Outcomes (Exploratory):
3. Pain intensity/interference over 6 weeks post-randomization will be measured by the Pain, Enjoyment of Life and General Activity (PEG) questionnaire.20
4. Acute pain over the perioperative time period will be measured using the Numeric Pain Rating Scale (NPRS).
5. Acute anxiety over the perioperative time period will be measured using a visual analogue scale (Anxiety VAS) from 0 (no anxiety) to 10 (the most anxiety you can imagine).
6. Pain catastrophizing over 6 weeks post-randomization will be measured using the Pain Catastrophizing Scale.
7. Opioid use over 6 weeks post-randomization will be measured in Morphine Milligram Equivalents (MME) per day, which will be assessed using the timeline follow-back (TLFB) method.

4.8 Data Collection and Follow-Up 4.8.1 Perioperative Data Collection Procedures After obtaining informed consent, participants will complete the baseline case report forms (CRFs) with support from research personnel as needed. Injury data will be obtained from the participant, the participant's medical chart, or the participant's treating physician(s). Baseline data collection points include participant characteristics and injury details such as age, sex, gender, co-morbidities, mechanism of injury, smoking status, and pre-injury opioid use. Participants will be screened for depression, anxiety, and chronic pain using the brief Patient Health Questionnaire (PHQ-2), brief General Anxiety Disorder (GAD-2) and Pain, Enjoyment of Life and General Activity (PEG) questionnaires respectively. Additionally, participants will complete the acute pain (Numeric Pain Rating Scale) and anxiety (Anxiety Visual Analogue Scale) questionnaires immediately before and after receiving each phase of the intervention. Baseline questionnaires consist of a total of only nine questions, so the investigators anticipate baseline data collection to take less than five minutes. Subsequent perioperative data collection (after Phase 1 intervention; before and after Phase 2 intervention) will only include two questions and should therefore take less than one minute.

4.8.2 Follow-Up Data Collection Procedures Follow up visits will occur at 2- and 6-weeks after randomization, which aligns with the timeline that patients return to the fracture clinic for standard of care visits with their surgeon. At each follow-up visit, participants will complete the Pain, Enjoyment of Life and General Activity (PEG) and Pain Catastrophizing Scale (PCS). Additionally, the following information will also be recorded at each follow-up visit: 1) any at-home mindfulness practice; 2) pain management medications, and 3) serious adverse events (SAEs) potentially related to participation in the trial.

Participant follow-up visits may be conducted via the participant's preference and convenience, i.e. in-person at a regularly scheduled clinic visit, or by a combination of telephone, email correspondence, text message, mail, alternate contact and/or online via REDCap Cloud Survey. Participants may be contacted via text, telephone, or email with reminders of upcoming follow-up visits. Questionnaires may be completed online directly by the participant or over the telephone with research personnel.

5.0 SAMPLE SIZE The primary objective of this pilot trial is to demonstrate enrollment feasibility (meet eligibility criteria and provide consent). The investigators anticipate that the study will achieve 40% enrollment in this pilot trial. If the study approaches 100 eligible patients for consent over eight weeks, the study will obtain a 95% confidence interval with a 15% margin of error (25%, 55%) around our point estimate of 40%. This will equate to approximately 41 participants. The investigators will round up to 50 participants for a meaningful analysis.

DATA ANALYSIS 6.1 Feasibility Outcomes Analysis The primary outcome of feasibility will be determined using a 'traffic light' system. If all results fall within the 'green light' range, the definitive study will be considered feasible as planned. Any results falling into the 'yellow light' range will require review and changes to the relevant protocol sections before proceeding to the definitive phase. If any results fall within the 'red light' range, the trial will be considered not feasible unless major modifications to the protocol are implemented. The investigators will use descriptive statistics, reported as count and percentage or mean and standard deviation depending on the type of variable, to summarize the feasibility objective results of this pilot study. Feasibility outcomes will be based on descriptive statistics reported as a percentage with the 95% Confidence Interval (CI).

6.2 Clinical Outcomes Analysis The exploratory clinical outcomes will be analyzed using descriptive statistics reported as count and percentage or mean and standard deviation depending on the type of variable. Clinical outcomes will be compared using mixed effects models and reported as estimates of effect (95% CI). The study statistician will prepare a detailed statistical analysis plan that will describe the analyses for the definitive study at the time the definitive study is initiated. The analyses for the pilot phase will be conducted using R statistical software.

7.0 DATA MANAGEMENT 7.1 Case Report Forms (CRFs) Required data, as detailed on the CRFs, will be collected using an Electronic Data Capture (EDC) system. Clinical site personnel will receive a unique login and password for the EDC system and will be able to view and modify data for participants recruited at their clinical site. Questionnaires will be completed directly by participants on a tablet, as much as possible, to ensure confidentiality.

7.2 Data Integrity This study will use the REDCap EDC system, which uses a variety of mechanisms for checking data at the time of entry including skip logic, range checks, and data type checks. Upon receipt of new data, the McMaster Methods Centre personnel will query all missing, implausible, or inconsistent data. Clinical site personnel will be able to review open queries in the system and are required to respond promptly.

7.3 Records Retention Records and documents pertaining to the conduct of this study, will be retained by the Principal Investigators and McMaster Methods Centre for 10 years after completion or discontinuation of the study. After that period, the documents may be destroyed, subject to local regulations. No records may be disposed of without the written approval of the McMaster Methods Centre.

8.0 ETHICS 8.1 Research Ethics Approval This protocol will be reviewed and approved by the Hamilton Integrated Research Ethics Board (HiREB) prior to the initiation of the study.

8.2 Confidentiality Information about trial participants will be kept confidential and will be managed in accordance with the below rules:

1. All trial-related information will be stored securely.
2. All trial participant information will be stored in locked file cabinets or access-restricted databases and accessible only to site research personnel.
3. All CRFs will be identified only by a coded participant number. If a participant revokes authorization to collect or use personal health information, the clinical site retains the ability to use all information collected prior to the revocation of participant authorization.

8.3 Protocol Amendments Protocol amendments that alter the conduct of the study will require approval by both HiREB and the Principal Investigators.

8.4 Adverse Event Reporting and Definitions Any SAEs that are potentially related to participation in the trial will be recorded in the REDCap EDC system. Significant new information on ongoing SAEs that are potentially related to participation in the trial should also be provided promptly to the Methods Centre via the REDCap EDC system.

SAEs will be reported to the local REB in accordance with local reporting requirements.

An SAE is defined as any adverse event that is any of the following:

• Fatal
• Life threatening
• Requires or prolongs hospital stay
• Results in persistent or significant disability or incapacity
• A congenital anomaly or birth defect
• An important medical event

Safety Monitoring This trial will not require a Data Safety and Monitoring Committee (DSMC) as the intervention is low risk to trial participants, and major morbidity, mortality, or other severe outcomes are not expected or evaluated. This decision aligns with the Food and Drug Administration guidelines for involving a DSMC in an RCT.

9.0 DISSEMINATION OF RESULTS The results of this study will be submitted for publication in a peer-reviewed journal and may also be shared in poster or presentation format at relevant orthopaedic conferences and/or research meetings. A patient-friendly summary of the aggregate results will be made available to trial participants who have consented to be contacted with the results. This summary will also be posted in the clinic and on our website.

10.0 SIGNIFICANCE OF RESULTS If successful, this project would provide strong evidence for the rapid implementation of a definitive trial to determine the effectiveness of incorporating brief MBIs into care pathways for fracture patients, potentially complementing or replacing traditional pharmacologic approaches to pain management following surgical fixation.