Chronic musculoskeletal pain (CMP) is among the most prevalent and disabling health conditions worldwide, affecting up to one-third of the global population and significantly diminishing quality of life and workplace productivity [1-3]. In the United States, CMP is a major contributor to health care expenditures and long-term disability [1,2,4]. Given the well-documented risks associated with pharmacologic treatments, such as gastrointestinal complications from nonsteroidal anti-inflammatory drugs and the potential for addiction and overdose with opioid analgesics, guidelines from the American College of Physicians recommend nonpharmacologic treatments, such as massage, acupuncture, and mindfulness, as preferred first-line therapies for managing CMP [5]. Nonpharmacologic approaches not only offer a safer alternative to pharmacologic treatment but also more directly address the complex biopsychosocial factors that contribute to chronic pain [6]. Among the notable psychological consequences of chronic pain is its potential to alter an individual’s sense of self [7-9]. Persistent pain may become enmeshed with personal identity through repeated and simultaneous activation of self- and pain-related schemas (eg, “I am [ie, self-schema] in pain [ie, pain schema]”) [7]. Over time, this repeated activation leads to a pain-laden self-concept [8,10,11] which may be reflected in corresponding changes within the brain’s default mode network (DMN) [12-14]. The DMN is a system involved in both self-representation and pain processing, potentially trapping individuals in a self-perpetuating “pain perception box” [7,10,11].

Mindfulness-based interventions (MBIs) offer a promising means of disentangling chronic pain from the sense of self, thereby disrupting the maladaptive cycle that sustains the pain individuals endure [9]. Rather than providing mere distraction or placebo effects, mindfulness engages specific neural and psychological mechanisms that fundamentally alter pain perception and appraisal [15-17]. Central to this process is a reduction in self-referential processing, a shift supported by neuroimaging evidence showing decoupling between the thalamus and DMN hubs such as the precuneus and medial prefrontal cortex during mindfulness practice [9,15,18,19]. This decoupling may represent a loosening of the neural circuits that enmesh pain in the sense of self, facilitating a more open, present-centered awareness [9,15,18,19]. The Mindfulness-to-Meaning Theory deepens this perspective by suggesting that mindfulness initiates a recursive cycle of positive psychological processes, including decentering, attentional broadening, cognitive reappraisal, and savoring, that synergistically promote self-transcendent states [9]. These transient states, characterized by diminished self-salience and expansive positive affect (eg, awe, bliss, and compassion), weaken the cognitive and emotional enmeshment between the individual and their pain experience [9,20]. Through momentary dissolution of the subject-object dichotomy, self-transcendence can reduce the centrality of pain in consciousness and cultivate a renewed sense of meaning [9,20]. In this way, mindfulness-induced self-transcendence may not only reshape the brain’s functional architecture but may also reframe the lived experience of pain, offering a path toward relief that is both neurologically grounded and psychologically liberating [9].

Emerging empirical evidence supports this theoretical framework. Two randomized controlled trials (RCTs) have examined the therapeutic value of self-transcendent states elicited during brief (ie, 15-20-minute), single-session mindfulness-based interventions (MBIs) for adults undergoing knee or hip replacement surgery (n=196, n=118) [21]. In both RCTs, the MBIs incorporated direct pointing (DP), an ancient yet underexplored contemplative technique designed to evoke self-transcendence by guiding attention away from self-specifying information and toward the nature of awareness itself [22-24]. Specifically, DP instruction encourages deidentification with thoughts, emotions, sensations, and sensory input as a means of accessing a nondual form of awareness in which the usual subject-object distinction dissolves [22-24]. Across both RCTs, groups involving mindfulness paired with DP consistently evoked the highest levels of self-transcendence relative to the psychoeducation control group, which in turn predicted immediate pain relief and improved postoperative outcomes, including reduced pain intensity and interference during the first month after surgery and better physical functioning 6 weeks after surgery [21,25,26]. These findings highlight the potential of DP to enhance the analgesic effects of brief MBIs by targeting self-related mechanisms of pain. However, because all mindfulness groups in these RCTs included DP instruction, the specific contribution of this technique remains to be isolated.

The therapeutic value of self-transcendence has also been examined in 4 RCTs evaluating the 8-week Mindfulness-Oriented Recovery Enhancement (MORE) program as a treatment for adults with chronic pain receiving long-term opioid therapy (n=95, n=187, n=62, and n=165) [27-30]. MORE incorporates DP throughout its protocol and has been shown to increase self-transcendent experiences both in daily life [27,30] and during lab-based, self-guided mindfulness practice [28,29]. In these RCTs, self-transcendent experiences were associated with reductions in pain, opioid misuse, and opioid dosing out to 9-month follow-up, as well as increases in frontal midline theta activity, which is thought to be a neurophysiological marker of meditative absorption and self-dissolution [27-30]. Collectively, these findings suggest that self-transcendence, along with its neurophysiological correlates, may serve as a core mechanism through which mindfulness improves chronic pain-related outcomes. Yet, due to the multimodal nature of MORE, the specific effects of DP remain confounded and warrant further investigation.

To isolate the specific effect of DP to mindfulness-based pain relief, the Pointing Beyond project will randomize 173 adults with CMP into one of three groups: (1) 4 weekly 30-minute sessions of traditional mindful breathing (MB) instruction, (2) 4 weekly 30-minute sessions of MB combined with DP (MB+ DP) instruction, or (3) a waitlist control group (WLC). The specific aims are:

The following are our hypotheses:

This will be a single-blind, randomized, 3-arm, parallel-group, clinical trial (2:2:1 allocation ratio). The planned flow diagram for this single-site RCT is presented in Figure 1. The protocol is reported according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials; Checklist 1) [41] checklist. This study was prospectively registered with the Open Science Framework on April 25, 2023.

We will recruit and enroll 173 adults with CMP who meet established eligibility criteria. Sample size estimation was conducted in 2 stages, reflecting an expansion from a sole focus on mechanistic sensitivity to the joint consideration of mechanistic and clinical relevance. The first stage was designed to detect changes in self-transcendence in order to elucidate an emerging therapeutic mechanism of MBIs, whereas the second stage broadened the scope of the study to contribute to a growing body of research evaluating the effects of brief MBIs on chronic pain.

First, our original power analysis using G*Power (Heinrich Heine University Düsseldorf) indicated that a total sample of 138 participants would provide sufficient power (β=.80) to detect changes in self-reported and psychophysiological indices of self-transcendence [42]. This target reflected a required analyzable sample of 110, inflated by 25% to account for expected attrition. To promote robust detection of mechanistic effects, we specified a conservative effect size ( Cohen d=0.30), representing half the smallest effect observed in our preliminary data (Cohen d=0.60). This approach was intended to support the more stringent comparison between the MB and MB+DP groups, while incorporating corrections for multiple comparisons.

Second, to enhance the clinical interpretability of the intervention effects, we added a waitlist control group. This adjustment was made prior to participant enrollment. Inclusion of this no-treatment comparison group provides a benchmark against which to evaluate the specific impact of the MBIs on both mechanistic and clinical outcomes, relative to the natural progression of symptoms in the absence of additional intervention. This control arm was designed to be half the size of each active treatment group (n=35), resulting in a total sample size of 173 and preserving a 2:2:1 randomization ratio. This total sample size (n=173) is consistent with a G*Power estimate for a 3 (group)×2 (time) mixed design, assuming a small effect (Cohen d=0.30), 80% power, and a Bonferroni-adjusted alpha of .0125 for 4 pairwise comparisons (ie, self-reported self-transcendence; 2 psychophysiological indices of self-transcendence, including frontal midline theta activity and DMN activity, and acute pain). Beyond these primary group-level effects, the planned sample size also supports Aims 2 and 3. Specifically, a G*Power analysis (2-tailed, α=.0167, corrected for multiple comparisons; power=0.80) indicated that 112 participants are sufficient to detect a moderate association (r=0.30) among phenomenological and psychophysiological indices of self-transcendence, well below the planned sample of n=173. Finally, this sample size is adequate for the planned mediation analyses; the parallel multiple-mediator model for acute pain includes 19 estimated parameters, yielding approximately 9.1 observations per parameter with n=173, consistent with the commonly cited 5‐10 observations per parameter convention.

Participants will be eligible for inclusion in the study if they meet the following criteria (Textbox 1):

Relevant concomitant care is restricted during the trial. Patients are welcome to continue their usual medical care but are asked to refrain from beginning any new treatments during the study. Cortisone and hyaluronate injections are prohibited during the trial.

All mindfulness training sessions and psychophysiological assessments will be conducted at the Complementary Health Innovation Lab (CHIL), located within Florida State University’s (FSU) College of Nursing. CHIL is equipped with a dedicated psychophysiology laboratory that integrates EEG and fNIRS systems, allowing for simultaneous data acquisition via a unified interface.

Sessions involving psychophysiological data collection (Sessions 1 and 4) will be conducted in a low-light environment to optimize the quality of fNIRS signal acquisition and more closely approximate real-world mindfulness settings. During these sessions, the participant, study therapist, and trained research assistant (RA) will be present. For Sessions 2 and 3, which do not involve psychophysiological data collection, only the participant and the therapist will be in the lab room. The treatment environment remains identical across all sessions, with the sole distinction being that the simultaneous EEG and fNIRS recording cap is worn only during the psychophysiology sessions.

Self-report measures will be administered during sessions, including assessments of self-transcendence and acute pain. All in-session measures will be completed using a tablet-based survey via the Qualtrics (Qualtrics International Inc) platform. Broader clinical assessments, including baseline and follow-up surveys at 1 week, 1 month, and 3 months, will be conducted remotely through Qualtrics at a time and location convenient for each participant.

Participants will be randomly assigned to intervention groups using a computer-generated randomization sequence created in Microsoft Excel. Randomization is stratified by opioid use (yes or no) to ensure balance across treatment arms on this clinically relevant variable. Within each stratum, participants are allocated using permuted block randomization with a fixed block size of 6 to maintain allocation concealment and prevent prediction of assignment. Treatment allocation is generated by personnel uninvolved in assessment or treatment and concealed on the private, password-protected computer of the uninvolved research member.

To preserve blinding, the randomization sequence will not be accessible to either assessment staff or the principal investigator (PI) until the study’s completion. Treatment allocation, for active treatment groups, will only be revealed to the interventionist immediately before the participant’s first treatment appointment. Outcome assessor blinding will further be ensured through the use of online, asynchronous self-report surveys, preventing any direct interaction between study personnel and participants.

Unblinding will only occur in exceptional circumstances where knowledge of the assigned intervention is essential for the clinical safety of the participant or to address a serious adverse event (AE). The request for unblinding must be made by the PI or a designated senior clinical investigator after determining that unblinding is necessary for participant safety or ethical oversight. The PI will document the rationale for unblinding and notify the institutional review board (IRB) if the event involves a serious adverse reaction or protocol deviation that may impact participant safety or data integrity.

Participants will be recruited through a combination of clinical and community-based outreach strategies to ensure a diverse sample of adults with CMP. Primary recruitment will occur through an orthopedic specialty clinic located in the Southeastern United States. Potential participants will be identified through direct referrals from clinicians or may self-refer after viewing recruitment materials displayed in the clinic. To supplement clinic-based recruitment, we will implement community outreach strategies designed to engage individuals with CMP who may not be actively seeking specialty care. These strategies will include the distribution of digital and print advertisements across local community centers and libraries. Targeted social media campaigns (eg, Facebook and Instagram [Meta Platforms]) will further expand recruitment reach. All advertisements will include a brief study description, eligibility criteria, and a link to a secure online screening form. Interested individuals will be directed to complete a brief web-based prescreening questionnaire to determine initial eligibility. Those who appear eligible will be contacted by study staff for a structured telephone interview to confirm inclusion and exclusion criteria.

Participant safety and data integrity will be monitored on an ongoing basis by the PI and designated study team members. Any reported events, whether physical, psychological, or behavioral, will be documented in a standardized case report form and evaluated for severity, duration, and potential relationship to the study intervention. The PI will assess each AE for relatedness and seriousness and determine whether the event qualifies as an unanticipated problem involving risk to participants.

Any AE or unanticipated problem involving risk to participants will be reported in accordance with the local IRB policies and applicable regulatory requirements. Nonserious but study-related AEs will be recorded and reviewed regularly by the study team to identify any emerging patterns that could indicate risks associated with the intervention or trial procedures. Participants who experience distress or negative effects related to the intervention (eg, heightened anxiety) will be provided with appropriate support. All documentation of AEs will be maintained in a secure, confidential manner and reviewed periodically to ensure prompt and appropriate response.

Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this research.

Participants in the 2 active treatment arms (MB and MB+DP) will attend 4 weekly, 30-minute, manualized mindfulness training sessions. Each session will be delivered in person by a PhD-level interventionist. In addition to the in-session mindfulness practice, all participants will be assigned daily at-home mindfulness practice throughout the 4-week intervention period. The at-home mindfulness practice will be a 15-minute, audio-recorded mindfulness practice recorded by a clinician and sent to participants via email. Each participant in the active treatment groups will receive a 15-minute audio recording that corresponds to the specific mindfulness practice style of the group to which they were randomized.

Each session will follow a consistent structure. The first session will begin with a 5-minute introduction to the intervention. In Sessions 2 through 4, the initial 5 minutes will be used to review participants’ experiences with their at-home mindfulness practice. All sessions will then include a 15-minute guided mindfulness practice and conclude with 10 minutes of therapist-led inquiry and reflective discussion. This structure is informed by established and empirically supported brief mindfulness intervention models [43]. To ensure treatment fidelity, all sessions will be audio-recorded. A study supervisor will review session recordings and provide regular supervision, ensuring adherence to the treatment manual and consistency in intervention delivery across participants. The specific elements of each session in both programs are described in Table 1.

Outcomes will be evaluated at two primary timescales: (1) during and immediately surrounding the mindfulness training sessions to assess mechanistic changes, including self-reported self-transcendence and psychophysiological responses, and (2) at baseline and follow-up intervals to examine the durability of clinical effects. Psychophysiological data (EEG and fNIRS), along with session-specific self-report measures, will be collected during the first and final training sessions (Sessions 1 and 4) to assess within-participant changes over the course of the intervention (see Table 2). Broader clinical outcomes, including pain interference, pain catastrophizing, and sleep disturbance, will be assessed remotely via online surveys at baseline and again at 1-week, 1-month, and 3-month postbaseline to evaluate the persistence of any treatment-related improvements (Table 3).

To promote participant retention and ensure complete follow-up, the study will implement a structured, participant-centered engagement strategy grounded in best practices for behavioral trial management. All follow-up assessments (at 1-week, 1-month, and 3-month posttreatment) will be conducted remotely via secure, web-based surveys to enhance flexibility and reduce burden. A dedicated RA will serve as each participant’s primary point of contact, maintaining regular communication and providing reminders and technical support based on participant preference (eg, phone, text, or email). Participants will receive modest compensation at baseline, each follow-up, and upon treatment completion, consistent with ethical standards for noncoercive remuneration.

Adherence will be further supported by weekly audio-guided mindfulness recordings and at-home practice diaries. Flexible scheduling will be offered for in-person EEG and fNIRS assessments to accommodate work and caregiving responsibilities. Missed sessions or assessments will be followed up within 48 hours, with up to 3 recontact attempts using alternate methods. Participants may re-engage at the next appropriate activity without penalty and may request a personalized summary of their self-report data poststudy. This approach aims to promote retention and data completeness while minimizing participant burden.

The Florida State University IRB approved all study procedures prior to participant enrollment (STUDY00004506). All procedures comply with institutional and international ethical standards. AEs will be monitored and reported per IRB policy. This study was prospectively registered on Open Science Framework (OSF): DOI 10.17605/OSF.IO/3UY2C. Trial results will be disseminated via peer-reviewed publications, academic conferences, and stakeholder engagement efforts. A summary of findings will also be offered to participants following study completion.

All participants provided informed consent prior to the participation in the study, in accordance with institutional guidelines and the 1964 Declaration of Helsinki. Any publications resulting from this research will not contain any identifiable information in any form. A model consent form will be made available from the corresponding author on reasonable requests to qualified individuals.

After eligibility has been established, individuals who express interest in participating in the study will complete the informed consent process under the guidance of a trained RA, in accordance with IRB requirements and ethical research standards. Participants will have the option to receive a copy of the signed consent form via email for their records. All consent documentation will be stored securely in compliance with institutional data protection policies.

Data will be deidentified and stored on secure servers at CHIL. Any paper data (questionnaires, sociodemographic, and clinical info) will have identifiers removed and banked for a minimum of 3 years. Deidentified data will be available to the research team, including the PI (AWH), the research coordinator, and the RAs. Any electronic data will be stored on a password-protected computer. Computers will be stored in locked rooms. Any data collected online will be stored on an encrypted data server at the College of Nursing. Any downloaded data will be stored on a password-protected computer. The RA supervised by the PI will be responsible for data receipt. AWH will be responsible for data analysis and results interpretation.