Article Text
PDF
Abstract
Introduction Chronic pain increases the risk of prescription opioid misuse or opioid use disorder (OUD). Non-pharmacological treatments are needed to dually address pain and opioid risks. The purpose of the Mobile and Online-Based Interventions to Lessen Pain (MOBILE Relief) study is to compare a one-session, video-based, on-demand digital pain relief skills intervention for chronic pain (‘Empowered Relief’ (ER); tailored to people at risk for opioid misuse or with opioid misuse/OUD) to a one-session digital health education intervention (‘Living Better’; no pain management skills).
Methods and analysis MOBILE Relief is an international online randomised controlled clinical trial. Study participants are adults with chronic, non-cancer pain (≥6 months) with daily pain intensity ≥3/10, taking ≥10 morphine equivalent daily dose and score ≥6 on the Current Opioid Misuse Measure. Participants are recruited through clinician referrals and clinic advertisements. Study procedures include electronic eligibility screening, informed consent, automated 1:1 randomisation to the treatment group, baseline measures, receipt of assigned digital treatment and six post-treatment surveys spanning 3 months. Study staff will call participants at baseline and 1-month and 3 months post-treatment to verify the opioid prescription. The main statistical analyses will include analysis of covariance and mixed effects model for repeated measurements regression.
Main outcomes Primary outcomes are self-reported pain catastrophising, pain intensity, pain interference, opioid craving and opioid misuse at 1-month and 3 months post-treatment. We will determine the feasibility of ER (≥50% participant engagement, ≥70% treatment appraisal ratings). We hypothesise the ER group will be superior to the Living Better group in the reduction of multiprimary pain outcomes at 1-month post-treatment and opioid outcomes at 1-month and 3 months post-treatment.
Ethics and dissemination The study protocol was approved by the Stanford University School of Medicine Institutional Review Board (IRB 61643). We will publish results in peer-reviewed journals; National Institute of Drug Abuse (funder) and MOBILE Relief participants will receive result summaries.
Trial registration number NCT05152134.
- Chronic Pain
- Telemedicine
- Substance misuse
- Behavior
- Psychosocial Intervention
- Cognition
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
STRENGTHS AND LIMITATIONS OF THIS STUDY
Mobile and Online-Based Interventions to Lessen Pain (MOBILE) Relief is a remote randomised clinical trial that uses a novel, rigorously tested digital platform to complete enrollment, randomisation, data collection and treatment delivery online.
MOBILE Relief will be advised by a virtual national patient advisory board (N=100) composed of people with chronic pain taking prescription opioids and with opioid misuse or opioid use disorder and assist with branding, advertising, operations and patient engagement.
One limitation is that MOBILE Relief will involve a largely US community-based sample and does not involve access to medical records or prescription databases; as such, opioid medication data and pain diagnoses will be self-reported.
To minimise input errors, self-reported opioid medication types, doses and frequency of use will be confirmed via telephone at baseline, and 1-month and 3 months post-treatment.
While enrolment will be open to eligible individuals in the USA, Canada, the UK and Australia, the study is not powered to conduct between-country analyses.
Introduction
Globally, rates of opioid overdose have increased in the last decade, with the largest increases observed in North America.1 2 Patients with chronic pain taking daily prescription opioids who evidence opioid misuse behaviour are at particular risk.3 As a result, there is a growing need for better integration of behavioural medicine into pain care pathways to reduce pain, opioid prescriptions and opioid-related mortality.4–7 As pain is a sensory and emotional experience,8 9 effective treatment requires an integrated approach that equips individuals with self-regulatory skills to manage pain and pain-related distress. Psychosocial factors, including pain-related worry, anxiety and depression, are associated with opioid craving and misuse.10–19 For some people, a failure to address these psychosocial factors may result in increased prescription opioid use, craving, misuse and opioid use disorder (OUD).20 21
Behavioural pain management approaches can effectively reduce symptoms associated with chronic pain.22 Cognitive–behavioural therapy for chronic pain (pain-CBT) and Mindfulness-Based Stress Reduction (MBSR) are interventions that teach self-regulatory skills to support pain self-management.23 MBSR and CBT-related improvements in self-regulation mediate psychological and physical improvements in people with chronic pain24–26 and significantly reduce opioid misuse.27 28 Mindfulness-Oriented Recovery Enhancement can also reduce pain and opioid misuse in people with chronic pain.29 30 These efficacious treatments typically involve multiple sessions and 16–20 hours of treatment time,31 thus rendering them inaccessible for many people. To best ensure broad access to effective, low-burden, non-pharmacological pain care, a range of treatment options are needed, including on-demand formats that are scalable and convenient for patients.
Brief home-based treatments can transcend several existing barriers to in-person behavioural pain care, such as limited trained therapists, need for referral, poor insurance coverage, costs and the time burden associated with multisession treatment and related travel.31 Additionally, pain-related stigma is a key barrier to treatment engagement,32 and consists of having pain dismissed or disbelieved.33 Pain care disparities and stigma could be minimised with greater access to home-based, confidential treatments that address factors that amplify pain and contribute to prescription opioid misuse and OUD.
One such brief treatment is Empowered Relief (ER), a 2-hour, one-session pain management skills intervention that includes pain neuroscience education, mindfulness principles and CBT-based self-regulatory skills.34–36 ER compresses many key aspects of evidence-based chronic pain treatments into a single didactic session. Published efficacy data from four randomised controlled trials (RCTs) show the benefits of ER across different patient populations and intervention formats. When compared with eight-session CBT (16 hours), in-person ER imparted clinically meaningful pain and symptom reduction that was non-inferior (equivalent) to eight-session CBT at 3 months34 and 6 months post-treatment among people with chronic low back pain.37 A second RCT conducted in mixed-aetiology chronic pain showed that compared with a waitlist control, online ER (delivered by a live instructor via Zoom) evidenced clinically meaningful and superior reductions in Pain Catastrophising Scale (PCS), pain bothersomeness, pain interference and sleep disturbance 3 months post-treatment.38 A third RCT tested a digital, on-demand version of ER that was tailored to surgical patients called ‘My Surgical Success’ (MSS) and was found to substantially reduce time to postsurgical opioid cessation after breast cancer surgery when compared with a digital health education control.39 Finally, a fourth RCT in orthopaedic trauma surgery patients showed that patients randomised to MSS reported clinically meaningful and superior analgesia 3 months after surgery.40
Several healthcare organisations have adopted ER as standard care for chronic pain and surgery patients (eg, Cleveland Clinic Spine Surgery,41 Cedars Sinai Spine Surgery, several VA Medical Centers, Lehigh Valley Health Network, Allegheny Health Network and Stanford Healthcare). Six active RCTs in the USA and Canada are testing the feasibility, acceptability and preliminary efficacy of instructor-delivered ER in different chronic and acute patient populations42–47 as well as the comparative effectiveness of live-instructor online-delivered ER to online 8-session CBT in 1650 adults with mixed-aetiology chronic pain.48
Recognising that even one-session live-delivered ER may be inconvenient, unwanted or unavailable to some individuals, on-demand and self-directed versions would expand options and provide convenient access to effective behavioural pain care. Additionally, while asynchronous, digital pain interventions exist,49 very few are designed to dually address chronic pain and risk for opioid misuse. One study is underway assessing a digital pain intervention for people with chronic pain and OUD, however, this intervention lasts 7–10 weeks and requires weekly clinician messages.50 There is an urgent need for less burdensome, tailored and scalable digital treatment options.
Study aims and hypotheses
The MOBILE (Mobile and Online-Based Interventions to Lessen Pain) Relief study is a parallel-group, two-arm, double-blind, superiority virtual RCT for people in the USA, UK, Canada or Australia who have comorbid chronic pain and opioid use behaviours (subthreshold), prescription opioid misuse or OUD. We aim to determine the feasibility and preliminary efficacy of an on-demand version of ER for pain and opioid use outcomes.
Primary aim 1
Characterise the comparative efficacy of on-demand ER to a digital health education control (Living Better) in reducing multiprimary pain metrics. We hypothesise that participants randomised to the on-demand ER arm will significantly reduce PCS, pain intensity or pain interference scores at 1-month post-treatment than participants randomised to the control arm.
Primary aim 2
Determine whether on-demand ER more effectively improves multiprimary opioid use metrics in comparison to the control at 1-month post-treatment. We hypothesise that the ER arm will report less opioid craving or opioid misuse at 1-month post-treatment than the control arm.
Secondary aim 1
Secondary aim 1 determines the feasibility of on-demand ER. We will summarise and estimate participant engagement and treatment appraisal ratings in the ER arm. We hypothesise ≥50% participant engagement rate and ≥70% treatment appraisal rating for treatment satisfaction, perceived utility and likelihood to use information/skills.
Secondary aim 2
Secondary aim 2 determines whether 3-months post-treatment reductions in pain intensity, pain interference, PCS, opioid craving and misuse are greater for ER compared with the control. We hypothesise reduced pain intensity, pain interference, PCS, opioid craving and misuse at 3 months post-treatment in the ER arm compared with the control arm.
Exploratory aims
We will estimate group differences in opioid dose escalation at 3-month post-treatment. We hypothesise that a smaller number of ER participants will report opioid dose escalation at 3 months post-treatment compared with the control arm. We will also explore patient characteristics (including biological sex) as predictors of treatment engagement and responsiveness in each arm.
Methods
Reporting of this protocol is in line with the Standard Protocol Items for Randomised Trials guidelines.51
Study setting and recruitment
We will enrol 220 adults with chronic pain, daily prescription opioid use and misuse behaviour (COMM>6) or OUD in the USA, Australia, Canada and the UK using the following sources: (1) a convenience database of people with chronic pain who are taking prescription opioids with current or past involvement in our research or who sought clinical care in our tertiary outpatient pain clinic, all of whom consented to be contacted for future research opportunities (N=12 000); (2) clinicians and clinics who treat patients with opioid misuse and OUD and (3) select online chronic pain patient groups. We chose the participating countries given their substantially higher prevalence of prescription opioid use and opioid overdose rates compared with the global average.1 The majority of recruitment will be from US sources, and the study will not be powered to detect country-level differences in outcomes. Study staff will send recruitment emails directly to individuals in the research database, and contact clinics to distribute materials to clinicians, who may refer interested patients to the study. IRB-approved recruitment materials include brochures, flyers, a website advertising the study and financial incentives. Interested individuals will be directed to the MOBILE Relief website (https://mobilerelief.stanford.edu/) where they can complete an online screening form to determine eligibility. The website advertises the study as testing two types of online, video-based interventions for pain. A study phone number and email will also be provided, which study staff will monitor to answer any questions, or on request, conduct study screening via telephone. Screening survey responses will be reviewed by study staff for evidence of fraudulent activity. Any records that have evidence of fraud are removed from enrolment consideration. After the screening, staff will call eligible participants to confirm their opioid medication information and review the informed consent form. After verbal consent, participants will be instructed to complete an electronic informed consent form to officially enrol in the study.
Eligibility criteria
Study inclusion criteria include (1) ≥18 years of age, (2) pain intensity ≥3 on an 11-point Numeric Rating Scale, (3) current chronic non-cancer pain (≥6 months in duration) diagnosis, (4) daily prescription opioid use (≥10 morphine milliequivalent daily dose) for ≥3 months, (5) opioid misuse behaviours (≥6 on COMM),52 English fluency and (7) internet access. Study exclusion criteria are (1) gross cognitive impairment, (2) inability to complete electronic study surveys and (3) currently enrolled in another ER clinical trial. There are no exclusions for seeking outside treatment while enrolled in the study. Of note, the initial COMM score threshold of 9 was reduced to 6 to examine and intervene on the potential progression of opioid use behaviour in people evidencing subthreshold behaviour52 (eg, potentially hazardous behaviours that alone are not indicative of opioid misuse, such as time spent thinking about opioid medications). A lower threshold also can address the needs of an important segment of the population that is often overlooked in opioid research and facilitate timely completion of the project.
After completing eligibility screening, informed consent and baseline measures, participants will be e-randomised 1:1 to a digital treatment group (ER or Living Better) within the MOBILE Relief informatics platform53 and immediately receive a link to their assigned treatment. We will blind participants, the principal investigator and coinvestigators to treatment group allocation; the study coordinator(s) will be unblinded.
Interventions
Digital ER
The tailored interactive ER intervention is 80 min, delivered online (via computer, tablet or smartphone) and includes brief video modules interspersed with medical animations, exercises and real-time participant ratings and prompts to create a daily personalised plan. The ER platform stores participant experience ratings and completed personalised plans for future use and revisions. The platform includes multiple resource documents, such as scientific references and downloadable tip sheets on opioid safety, trauma, crisis support and buprenorphine use. On-demand ER includes access to a Calm Tool App (guided binaural relaxation recordings) and daily text messages that reinforce the ER content and provide positive reminders of core concepts (scheduled for 90 days with an option to extend further). While the content is pain-focused, foundational self-regulatory skills are explained in relation to pain medication use.
Digital health education (‘Living Better’)
Prior work showed that general health education was beneficial when delivered to in-person groups of people with back pain.34 For this study, we expanded on this content to create a version that more closely matches digital ER in duration and video format, yet lacks pain education, self-regulatory skills and has no actionable strategies or worksheets.54 The content covers topics such as proper pain medication storage, and weight management and hydration for health and pain. Similar to ER, the Living Better narrator is BD, who introduces herself as a Stanford pain psychologist, scientist and pain treatment expert. As treatment length confers participant burden, Living Better is a slightly briefer format (65 min). See table 1 for common and distinct elements between the two digital treatments.
Common and distinct elements of the study treatment arms
Patient and public involvement
ER was developed in 2013 and has been delivered to more than 10 000 patients with acute and chronic pain. Stanford University (copyright and trademark owner) offers interprofessional CME ER clinician certification workshops; to date, 1500 clinicians are certified to deliver ER in 29 countries and in 7 languages (English, Dutch, Danish, Spanish, German, Canadian French and Italian). Patient and clinician feedback collated over the past decade supported seven iterations of ER, and each iteration ensured terminology is patient-centred and the content reflects scientific updates. For example, early versions of the intervention included PCS in the title and content; based on feedback, the intervention was renamed and branded ER to reflect the purpose and goal result and not a target issue that may confer stigma.55 Specific to the current ER version tailored to opioid misuse, five patient advisors (one a national advocate) advised on the digital adaptations and rejected early plans to include an animated allegory. Adhering to their advice, character sketches were eliminated and replaced with medical animations and expert-delivered content designed to create a warm, personal and adult didactic experience. Advisors also provided feedback on the length of the intervention and suggested content be 60–90 min to reduce the treatment burden.
In regard to the study design, patients advised a focus on pain outcomes and decoupling the study from medical care as there is stigma and risk associated with reporting aberrant behaviours for prescription opioids. As such, MOBILE Relief has no access to patient medical records or outside data sources. A virtual national patient advisory board (N=100) composed of people with chronic pain taking prescription opioids and with opioid misuse or OUD will advise the study team ongoingly related to study advertising, recruitment, operations and patient engagement. Advisor feedback was used to further refine our study systems prior to the formal launch of the clinical trial.
Outcomes
Table 2 describes the primary and secondary outcome measures, as well as other risk factors and correlates that are collected. Table 3 shows all self-report measures collected at each time point. Baseline demographics include age, sex, gender, race, ethnicity, education, zip code, household annual income, employment status, relationship status and living status (alone or cohabitating). Healthcare utilisation includes a number of healthcare provider visits, emergency room visits, overnight hospital stays and initiation of any new pain treatments.
Study outcome measures
Full self-report measurement plan by study time point
Participant flow and compensation
See figure 1 for study participant flow. All participants will be compensated for completing study surveys (table 4) and can receive up to US$170 (or its international currency equivalent) in the form of an electronic Amazon gift card code. The digital health literature (and our prior work) confirms that a fraction of participants will not engage with digital interventions56; however, we will offer non-engagers an additional US$30 to provide qualitative data on reasons for non-engagement to inform future studies. After study completion, those assigned to Living Better will be invited to cross over to the ER intervention arm (and be compensated for each survey completed) or they can choose to receive ER at no cost without further research participation.
Participant compensation schedule
Participant flow.
Power analyses
Primary aims
For primary aim 1, we will use analysis of covariance (ANCOVA) to compare between arms (ER vs Living Better) from baseline to 1-month post-treatment reduction in PCS, pain intensity and pain interference scores (multiprimary endpoint). 100 participants per arm provide 70% power for detecting a mean difference of 0.416 SD at the two-sided significance level of 0.05/3 using two-sample t- test, which is less powerful than the ANCOVA. The more stringent significance level of 0.05/3 was considered due to the need to adjust for multiple tests. Based on results from our prior RCT in patients with chronic pain,34 the observed between-group difference in PCS scores (ER vs Living Better) is 4 points with an SD of 10 points (difference of 0.40 SD). Therefore, the proposed study has approximately 70% power to detect a similar difference for individual endpoints. Assuming ≥0.40 SD difference for all three endpoints, we have 96% power to reject at least one hypothesis, and 73% power to reject at least two hypotheses, and 43% power to reject all three hypotheses.
For primary aim 2, we will use mixed model repeated measures (MMRM) regression to compare opioid craving and COMM scores between treatment arms from baseline to 1-month post-treatment. Similarly, based on a simple two-sample t-test, 100 participants per arm provide 80% and 70% power for detecting a mean difference of 0.44 SD and 0.39 SD,34 respectively, at the statistical significance of 0.05/2 accounting for multiple testing. Based on a 10-point opioid craving scale, Garland et al 57 reported 3-month post-treatment average opioid craving reductions of 1.75 points for a behavioural pain treatment group compared with 0.73 points for their study control group. Assuming a correlation coefficient of 0.5 between the pretreatment and post-treatment opioid craving scores, this difference in the reduction of opioid craving score is 0.31 SD. Based on the COMM, Garland et al 57 also reported an average reduction of 5.92 points in the behavioural pain treatment group and 2.94 points in the control group after treatment, representing a difference of 0.32 SD. In another study comparing web-CBT to a control arm, Guarino et al reported a difference of 0.393 SD in COMM score 1-month post-treatment between web-CBT and control arms.28 Therefore, the reported difference in opioid craving and COMM ranges from 0.31 SD to 0.39 SD and the proposed sample size provides adequate power to detect differences on the higher end of effects reported in the literature for individual endpoints. Assuming ≥0.35 SD for both endpoints, the proposed sample size provides 83% power to reject at least one hypothesis and 34% power to reject both hypotheses.
Secondary aims
For secondary aim 1, we will estimate the engagement rate (ie, completion of the treatment appraisal survey) in each digital treatment. Based on our prior digital behavioural medicine RCTs and assuming a true engagement rate of 56%, 100 participants yield an exact 95% CI with an average length of 0.20 and provide 86% power to conclude that engagement rate >40%, (ie, the lower end of the 95% CI is >0.40). For secondary aim 2, we will use a two-sample t-test to compare between arm (ER vs Living Better) pain intensity, pain interference, PCS, opioid craving and COMM scores at 3-months post-treatment. Similar to primary aim 2, 100 participants per arm provide 70% power for detecting a mean difference of 0.353 SD. The observed difference in COMM scores at 3 months post-treatment is 0.384 SD between web-CBT and control arms.28
Statistical analyses
Baseline covariates will be summarised by treatment arm. Categorical variables will be summarised by count and proportion, and continuous variables will be summarised by mean and SD or median and IQR.
Primary aims
For primary aim 1, we will compare the baseline to 1-month change in PCS, pain intensity or pain interference scores (multiprimary endpoints) between treatment arms using ANCOVA as the primary analysis to estimate the treatment effect adjusting for baseline PCS, pain intensity or pain interference scores, respectively. To adjust for multiple testing, we will construct 95% simultaneous CIs for the between-group difference in 1-month change of PCS, pain intensity and pain interference scores based on the resampling method accounting for the correlations among estimated differences. The treatment effect is statistically significant if the corresponding simultaneous CI excludes zero in the hypothesised direction. The same ANCOVA will be repeated as a sensitivity analysis to adjust for additional (potentially imbalanced) confounders. These confounders in the analysis will be selected based on their associations with outcomes of interest (PCS, pain intensity or pain interference). Note that although the outcomes may not follow a Gaussian distribution, the validity of ANCOVA is ensured by large sample approximations. Regardless, assumptions will be checked with each outcome. For primary aim 2, we will compare the between arm (ER vs Living Better) change in opioid craving scores (10-point scale) or COMM scores (0–68) from baseline to 1-month post-treatment using MMRM regression, where the change from baseline to 1 month and change from baseline to 3 months are treated as correlated longitudinal outcomes. Unstructured variance–covariance matrix will be used to model the covariance. The MMRM regression will adjust for baseline opioid craving scores and opioid misuse scores, respectively. Similarly, we will construct 95% simultaneous CIs for the between-group difference in 1-month change in opioid craving score and opioid misuse score. The treatment effect is statistically significant if the corresponding simultaneous CI excludes zero in the hypothesised direction.
Secondary aims
For secondary aim 1, we will estimate the treatment arms’ engagement rate (ie, percentage of participants to complete the treatment appraisal survey) separately. The 95% exact CI will be constructed. We will test whether the engagement rate in the digital ER arm is greater than 50%. We will also separately estimate and summarise the treatment appraisal ratings for each arm. For secondary aim 2, we will compare the between arms (ER vs Living Better arms) pain intensity, pain interference, PCS, opioid craving and misuse scores (range: 0–68) at 3 months post-treatment using the same MMRM regression as in primary aims 1 and 2.
Exploratory
As an exploratory analysis, we will estimate the rate of opioid dose escalation at 3 months post-treatment by treatment arm, and a 95% exact CI will be constructed. We will also compare patients’ characteristics between engagers and non-engagers by treatment arm (including examination of sex/gender differences). We will build regression models to predict patient’s response to the treatment by arms, where the post-treatment PCS, pain intensity, opioid craving and opioid misuse scores measure the response. Multivariate linear regression or ordinal regression with baseline covariates as the independent variables will be used to identify potential subgroups of patients who may benefit more from the intervention, including the impact of engagement in any new pain treatments over the course of the trial. Per National Institute of Health requirements, we will estimate the treatment effect in males and females separately and compare them, treating biological sex and gender as separate variables. Based on the sex/gender prevalence estimates reported for US adults with chronic pain,58 we estimate 56% females and 44% males for our proposed study; this will allow the estimation of the sex-specific and gender-specific treatment effect. Lastly, if international participants are enrolled in the study, we will conduct sensitivity analyses to assess their potential influence on the study findings.
Since this is a phase 2 study intended to test preliminary efficacy (testing ER in a new format, new population and new outcomes), the analysis for the secondary aims will not be adjusted for multiple testing. However, we will report all results regardless of their statistical significance. In the presence of missing data or loss of follow-up, we will use multiple imputations to impute missing values to study the treatment effect, which is valid under the missing at-random assumption.
Data collection and management
Study screening, consent, randomisation and all study surveys will be completed online using CHOIR,53 a secure, HIPAA-compliant, data collection, randomisation and treatment delivery platform. On randomisation, a link to their assigned treatment will be immediately delivered. Data collection via CHOIR will help to minimise participant entry errors by using web-based validation tools (eg, drop-down menus, number range restrictions) to ensure completeness. Reminders (text or email based on preference) to complete surveys will be sent to participants. Incomplete surveys will trigger automatic reminders at 24, 48 and 72 hours postsurvey deployment. The study coordinator will issue a final telephone call reminder if the participant has not completed the survey after 4 days. The week 1 survey will lock at 3 days, and the week 2 survey will lock at 7 days. All other surveys will lock at 10 days. Study staff will confirm prescription opioid medication details via telephone at baseline, 1 month and 3 months, and if necessary, correct data based on patient verbal report.
Data monitoring, harms and auditing
Informed consent
Informed consent is obtained electronically in compliance with the Stanford University Institutional Review Board through the MOBILE Relief informatics platform (CHOIR53). The study is not connected to the participant’s medical care, no medical records are accessed and all information is self-reported or participant engagement metrics from the CHOIR platform.
Potential participants risks and protections
The main risk of this research is unintentional disclosure of personal and protected health information. All data are captured electronically within CHOIR, with data stored within the secure computing environments of the Stanford School of Medicine. Study staff complete training in HIPAA, Human Subjects Protections and responsible conduct of research regulations. They will be clearly instructed not to divulge confidential information regarding subjects. The system will also be following FDA Part 11 (21CFR11) guidelines. If a breach of confidentiality occurs, it will be reported as an unanticipated problem. Participant records are electronically stored and confidential, with the study database and electronic records stored on a password-protected secure server, available only to the study staff, and requires double authentication to access. Within CHOIR, data transport is SSL-encrypted, data storage and access are HIPAA compliant (uses two-factor authentication).
While no prior ER studies have recorded such an adverse event, there is a small risk that participants assigned to ER may experience discomfort when using the Calm Tool App. Participants will be advised to stop use if discomfort or distress is experienced. There is also a small risk participants may experience discomfort from personal questions asked on the study surveys. Participants may refuse to answer any question.
Participant protections for worsening symptoms
At enrolment, all study participants will receive a resource document including information about 24-hour national crisis telephone hotlines, suicide hotlines and social media accounts that offer online and 24-hour text support. Participants will also receive general information on mental health, opioid discontinuation and opioid withdrawal symptoms, along with the recommendation to speak with one’s doctor if symptoms occur related to opioid use.
We will monitor participant data monthly to identify participants who report increased depression symptom severity. We will apply the PROMIS Depression T-score of ≥64.8 to categorise severe depression (the T-score threshold is based on publicly available cross-walk calculations derived from Prosetta Stone).59 For participants who enrol in the study with PROMIS Depression scores already exceeding this threshold, we will monitor for increased symptom severity of any level. In both cases, identified cases will trigger (1) automated emails that acknowledge their reported symptoms and encourage them to discuss their symptoms with their doctor; (2) review by the principal investigator, a licensed clinical psychologist, to determine if the participant should be called, with clinical decision-making based on severity and symptom escalation from previous report. We will not monitor for suicidality in our assessment batteries, though in cases where phone calls are made, this will be verbally assessed and appropriate communications will be made regarding safety actions (eg, call 911, identify support person).
Ethics and dissemination
Trial oversight includes adherence to the Stanford IRB reporting system for clinical trials, including adverse events reporting and annual reporting. The IRB covers all participating countries. This trial includes an external data safety and monitoring board (DSMB) who will review a data safety and monitoring protocol prior to trial initiation. The DSMB comprises members independent of those conducting and funding the trial, and they will meet biannually. This trial will be conducted following the requirements of the National Institute of Health, with National Institute of Drug Abuse receiving annual reports.
Dissemination will include peer-reviewed publications, press releases, media coverage and promotion of study findings through social media and scientific conferences. All patient advisors and study participants will receive a report of the study results. The study dataset will be available on committee-approved request 1 year after the primary trial findings are published. Results from this trial will inform broad dissemination and adoption of a scalable, digital behavioural pain intervention into community care pathways for people with comorbid pain and opioid misuse, an at-risk population with few on-demand, evidence-based non-pharmacological treatments.
Ethics statements
Patient consent for publication
Acknowledgments
We thank our current and past patient advisors for their contributions to the current study. We thank David Andis for directing and producing the Empowered Relief digital content; Andrea Anderson for coproducing the ER content. The Stanford MedEd team for creative and technical development of the digital ER script; the Stanford Research IT team (Garrick Olsen and Glenna Mayo) for digital platform design, development and integration; Kelly Adams for financial management, and Ashley Gomez for administrative support.
References
Footnotes
X @drkarlynedwards
Contributors BD is the guarantor. The MOBILE Relief study was designed by BD, the principal investigator, with support from DSY; KE contributed to the Empowered Relief digital treatment (BEATS) and manuscript drafting; DSY, MZ, LP and PP contributed to the drafting of the protocol manuscript. MZ contributed to the refinement of the Living Better pain education intervention. SM oversees the CHOIR development platform and drafted CHOIR-related protocol content. LP, PP, EA and CJ contributed to the regulatory and ethics aspects of the protocol (IRB, clinicialtrials.gov), adherence to NIDA protocols and protocol manuscript drafting. LT drafted the protocol analytical plan.
Funding Primary funding for work was supported by the National Institute on Drug Abuse (NIDA; K24DA053564; PI Darnall). NIDA had no role in the design of the study; the study is in compliance with NIDA’s published policies and procedures. NIDA had no role in the approval of the manuscript or the decision to submit this manuscript for publication. Additional funding support is as follows: KE (NIDA T32DA035165 and K12DA050607); DSY (NIDA K23DA048972); MZ (NIDA K23DA047473); SM (NINDS K24NS126781 and NINDS R61NS11865).
Competing interests Stanford University receives fees for continuing medical education ER clinician certification workshops; BD receives no personal monies for the ER certification workshops, nor for dissemination or adoption of ER. BD is the Chief Science Advisor at Applied VR, and her consulting role with this company (personal fees) is unrelated to the current research. BD receives royalties for four pain treatment books she has authored or coauthored. She is the principal investigator for two pain research awards from the Patient-Centered Research Outcomes Research Institute, one of which involves the study of ER. BD is the principal investigator for two NIH grants that are investigating the efficacy of ER (one is the MOBILE Relief study). BD serves on the Board of Directors for the Institute for Brain Potential (which is licensed by Stanford University to offer ER clinician certification workshops), and is on the Medical Advisory Board for the Facial Pain Association. BD is a scientific member of the NIH Interagency Pain Research Coordinating Committee, a former member of the Centers for Disease Control and Prevention Opioid Workgroup (2020–2021), and a current member of the Pain Advisory Group of the American Psychological Association. SM receives research funding from the NIH, Food and Drug Administration and Patient-Centered Outcomes Research Institute (administered through Stanford University). He is an unpaid advisor to both ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks) on their oversight committee and the American Chronic Pain Association (ACPA) for their scientific oversight. All other authors report no disclosures or conflicts of interest.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.