Can a specific biobehavioral-based therapeutic education program lead to changes in pain perception and brain plasticity biomarkers in chronic pain patients? A study protocol for a randomized clinical trial

Silvia Di Bonaventura; Josué Fernández Carnero; Raúl Ferrer-Peña

doi:10.1371/journal.pone.0289430

. 2024 Jan 19;19(1):e0289430. doi: 10.1371/journal.pone.0289430

Can a specific biobehavioral-based therapeutic education program lead to changes in pain perception and brain plasticity biomarkers in chronic pain patients? A study protocol for a randomized clinical trial

Silvia Di Bonaventura ^1,^2,³, Josué Fernández Carnero ^2,^3,^4,^5,^*, Raúl Ferrer-Peña ^3,^4,^5,⁶

Editor: Stephen D Ginsberg⁷

PMCID: PMC10798500 PMID: 38241249

Abstract

Background

Chronic pain conditions are complex multifactorial disorders with physical, psychological, and environmental factors contributing to their onset and persistence. Among these conditions, the role of brain-derived neurotrophic factor (BDNF) and the impact of a specific therapeutic education (TE) on pain management have emerged as important areas of research.

Objective

This study aims to investigate the effects of a specific type of therapeutic education on pain levels and BDNF concentrations.

Methods

In this single-blind, randomized clinical trial, patients will be randomly assigned to one of two groups: one will receive exercise with TE and the other without TE. Assessments will be made at baseline, mid-treatment, post-intervention, and at one and eight months.

Outcomes

This study will shed light on the effectiveness of a therapeutic education (TE) program in pain management. Additionally, it will provide information on its effects on BDNF levels, a biomarker of brain plasticity, as well as on various psychosocial variables that can influence pain experience.

Conclusion

By comprehensively addressing the need to quantify brain changes more precisely in individuals with chronic pain during interventions like TE and recognizing the importance of establishing a more structured and comprehensive protocol, this study lays a solid and replicable foundation for future evidence-based treatment developments.

Background

Chronic pain is a widely prevalent health problem that affects one in five people worldwide [1]. It is a debilitating condition with a potentially significant impact on one’s quality of life, affecting one’s ability to perform daily activities and decreasing one’s emotional and physical well-being [2], as well as the resources needed to cope therewith [3]. One serious drawback that accompanies chronic pain is the frequent dependence on drugs for pain relief. In particular, opioids have become one of the main medications for treating pain, as also one of the causes of the increase in mortality due to overdose [4] However, physiotherapy modalities that include therapeutic education and exercise are a common non-pharmacological therapeutic approach for chronic pain and its maladaptive plasticity [5–7], defined as a change in the structure or function of the nervous system resulting in increased pain sensitization [8, 9]. Specifically, therapeutic education (TE) plays a crucial role in reversing maladaptive plasticity, reducing pain and disability, fear avoidance, and pain catastrophizing, inter alia [10] TE is a fundamental component of chronic pain management and addresses several aspects essential for improving patients’ quality of life [11, 12]. These include understanding pain and its mechanism of production [13], promoting self-regulation and self-care strategies [14], acquiring coping skills [15], reducing fear-avoidance and pain catastrophizing [16], promoting healthy lifestyles, and optimizing physical functionality [17]. One of the main goals for the patient is to reconfigure maladaptive beliefs associated with their chronic pain, involving a change in the structure and function of the nervous system that has contributed to increased pain sensitization [18, 19].

However, no random educational approach is appropriate for this. There are several types of TE, addressing different topics [20, 21] and using different dosages [22–24], which inevitably lead to different results [25–27]. A specific approach is required that considers both the biological and behavioral aspects of chronic pain. Further, to accurately determine the true impact of such non-only-informative intervention, it is imperative to measure and evaluate the effects of the TE not only in terms of perceived pain and psychosocial factors but also through the lens of brain plasticity biomarkers and draw correlations within these domains.

In this sense, biological components like brain-derived neurotrophic factor (BDNF) and its relationship to cerebral plasticity in patients with persistent pain [28, 29]. BDNF, a protein that plays an important role in pain sensitization and neuronal plasticity, has been associated with neuronal hyperexcitability in chronic pain [30]. Understanding its relationship to pain is crucial for developing new therapies. Manipulating BDNF expression could offer options for modulating neuronal plasticity and relieving pain in patients with chronic pain. However, the impact of these interventions on the adaptive changes in the brain, which are crucial in patients with persistent pain, remains largely unknown. Additionally, a lack of adherence to established guidelines for reporting interventions, such as the TIDieR checklist for general interventions [31], or GREET checklist for educational interventions [32] and the Consensus on Exercise Reporting Template (CERT) checklist for exercise interventions [33] hinders their replication and adaptation to individual patients, thus limiting their practical utility [34].

In summary, despite the challenges in the field of education and exercise for chronic pain management, this model of pain TE will address the aforesaid needs, providing a comprehensive and evidence-based approach that considers changes in brain plasticity learning-related, biobehavioral aspects, appropriate dosing, and objective evaluation of results.

Materials and methods

Study setting

The proposed study is a single-blind, parallel-group, randomized control trial. Its protocol follows the structure based on the PICO question (Population, Intervention, Comparison, Outcome) [35] and adheres to the recommendations of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline [36]. In addition, specific interventions were described based on the Template for Intervention Description and Replication (TIDieR) checklist [31], the Guideline for Reporting Evidence-based Practice Educational Interventions and Teaching (GREET) [32], and the Consensus on Exercise Reporting Template (CERT) checklist [33]. The trial was approved by the ethics committee of Rey Juan Carlos University (Ethical number: 1901202202822) and the entire study will be conducted at the Universidad Rey Juan Carlos located in Alcorcón, Madrid (Spain). The trial identifier code is NCT05623579, registered on November 18, 2022, in ClinicalTrials.gov.

Eligibility criteria

Patients will be recruited from the physical therapy clinics located in Madrid, Spain, based on the following inclusion criteria: aged between 18 and 65, having a history of pain lasting more than twelve weeks, pain corresponding to at least 3 out of 10 on the visual analog scale, possessing the ability to comprehend, speak, and write in Spanish, not currently undergoing any other treatments for 3 months before the study, and explicitly consenting to not being allowed to initiate new treatments till the end of the follow-up period. The exclusion criteria are neurological cognitive alteration that prevents understanding the contents of the educational program (in case of doubt, assessment with the Mini-Mental test will be conducted, requiring a minimum score of 25), systemic, oncological, or inflammatory diseases, psychiatric pathologies, pregnancy, diabetes type II and inability to adhere to the protocol.

The following professionals were selected to conduct the study: two physiotherapists with more than 15 years of experience in the treatment of chronic pain for the pain education and exercise therapy component, two nurses for blood collection, another physiotherapist for administering questionnaires on psychosocial variables and quantitative sensory testing, and two biochemists for BDNF analysis.

Interventions

All patients who meet the inclusion criteria and agree to participate in the study will be informed verbally and in writing, with the delivery of the information sheet listing the specific characteristics of the study. They will be asked to sign the written informed consent form.

Sociodemographic data will then be collected, as well as psychosocial variables on their current pain process. This data collection will be carried out in a room in the physiotherapy gymnasium of the university center, previously designated for measurements by the evaluating researcher as well as blood extraction.

Once the specific questionnaires and the pressure pain threshold (PPT) at the joints of the elbow and tibialis anterior are measured, a trained professional will collect 5 ml of blood from the ulnar vein of the participants in a citrate vacutainer. The blood collection will always take place between 6 p.m. and 7 p.m., to minimize the possible effects of circadian changes [37–39]. Blood samples will be collected in tubes containing K3-EDTA and centrifuged at 1000 g for 10 min at 4°C. The supernatants for the total plasma (TP) condition will be frozen at -80°C. Blood collection will be performed in both groups at rest before the intervention, 15 days after the intervention, at the end of the intervention period, and at 1 month and 8 months after the intervention.

After the initial data collection, a researcher other than the initial evaluator, and the physiotherapist-therapist who will apply the subsequent treatment to ensure blinding, will proceed to randomly assign the subjects to one of the two study groups through a list previously generated with GraphPad software (version 5.01 Graphpad software, Inc. San Diego, California, USA).

Intervention group (Exercise + POBTE)

Patients assigned to the intervention group will be instructed by a physiotherapist in the performance of the TE sessions according to their functional capacity, with reference to their HRmax [40]. They will be prescribed the reference intensity measures for the expected increase in training time indications on potential risks and references for the interruption of the exercise in their case. The duration of the exercise program will be 4 weeks, with 3 sessions lasting a maximum of 45 minutes per session. On alternate days, twice a week, the patient will receive Pain Oriented Biobehavioral Therapeutic Education (POBTE) sessions, focusing on the specific parameters described below. The duration of the sessions will be a maximum of 45 minutes each day [41], and the education program will be spread across 8 sessions over 4 weeks. The intervention group will be instructed to refrain from discussing treatment details with participants assigned to the control group until the end of the treatment and follow-up periods.

The main learning areas that to be addressed and the biobehavioral interventions proposed are summarized in Fig 1, and the conceptual framework of the POBTE intervention is explained in detail in Fig 2 and S1 File. The specific cognitive components of the intervention are listed in the general intervention checklist, following the TiDier checklist (see S1 Checklist) and the exercise intervention is presented in S2 Checklist with the CERT checklist, while the Therapeutic Educational Intervention is presented in S3 Checklist with the GREET checklist.

A chronological representation of the tasks to be performed during the POBTE intervention is displayed in Fig 2. This figure is arranged to correspond to the stages of the meaningful learning phase in the intervention design.

Active control group (Exercise)

Patients assigned to the active control group will be instructed by a physiotherapist in the performance of TE sessions according to their functional capacity, with reference to their HRmax. They will be prescribed the reference intensity measures for the expected increase in training time, indications of potential risks, and references for the interruption of the exercise in their case. The duration of the exercise program will be 4 weeks, with 3 sessions lasting a maximum of 45 minutes per session. Contents of the exercise intervention are described in the CERT checklist (S2 Checklist).

Intervention modifications

The criteria for discontinuing or modifying allocated interventions for a given trial participant would include participant request, adverse events, or harms, improvement in or worsening of the disease, and non-compliance. In the context of this study, criteria will be adapted to the specific needs and characteristics of the study population.

Intervention adherence

To improve adherence, we will provide clear instructions, personalized feedback, and support, simplify the intervention as much as possible without losing scientific rigor, and monitor attendance, self-reports, and reminders. Written materials and videos will be provided, along with personalized feedback, progress reports, and regular check-ins. Attendance, self-reports, and reminders will be used to monitor adherence.

Outcomes

Primary outcome

Pain intensity

Visual Analogue Scale (VAS). Pain intensity will be measured using a 100 mm visual analog scale where 0 represents ‘no pain’ and 100 the ‘worst pain imaginable’. Participants draw a mark at a point on the line that best reflects the pain they are experiencing at the time of measurement. Higher scores indicate higher pain levels. The sensitivity and specificity of this questionnaire and the acceptability of its psychometric properties have been approved [42].

Secondary outcomes

Biochemical

Plasma BDNF levels. Within 30 minutes of collection, the blood samples will be centrifuged and the plasma separated into 0.5 ml aliquots for further analysis. Plasma BDNF levels will be determined by enzyme-linked immunosorbent assay (ELISA) test using monoclonal antibodies specific to neurotrophin (R&D Systems, Minneapolis, MN), using the manufacturer’s protocol. All samples will be tested in duplicate to avoid intra-assay variations. The lower limit of detection for BDNF from the kit is 7.8 pg/mL. Assay (ELISA) will use a ChemiKine BDNF ELISA kit, CYT306 (Chemicon/Millipore, Billerica, MA). Optical density will be measured using an ELISA reader at a wavelength of 450 nm (GloMax-Multi Microplate Reader, Promega, Madison, WI) for multiplex assay measurements. Data will be expressed in pg/mg protein.

Psychosocial

Anxiety and depression will be assessed using the Spanish-validated version of the HADS self-completion scale. This scale is divided into two subscales of 7 items each: 1) depression (HADSDep) and 2) anxiety (HADSAnx). The HADS has demonstrated good reliability and validity in various pathologies [43].

Quality of life. Measured with the EuroQoL-5D questionnaire (EQ-5D), this is a self-report instrument to assess the health-related quality of life comprised of three items, a 5-factor descriptive scale, a second item comprising a vertical VAS and a third one about social values index generated by the instrument. The EQ-5D has shown good psychometric characteristics [44].

Catastrophism will be measured by the Spanish version of the Pain Catastrophism Scale (ECD). This has demonstrated adequate psychometric characteristics for the assessment of this construct with internal validity (Cronbach’s alpha 0.81) [45].

Chronic Pain Grading Scale (CPGS) is a self-report instrument consisting of an 8-item scale. It has a high internal consistency, with a Cronbach’s α of 0.87, similar to that of other language versions, and an intraclass correlation coefficient of 0.81. The average administration time is 2 min 28 s [46].

Tampa Scale for Kinesiophobia (TSK) is a self-report questionnaire comprising 17 items. The internal consistency of the TSK is high, with Cronbach’s alpha coefficients ranging from 0.74 to 0.93, indicating strong reliability. Test-retest reliability is also good, with correlation coefficients ranging from 0.75 to 0.88 [47].

Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire of 19 items categorized into seven components, viz., subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. The internal consistency of the PSQI is high, with Cronbach’s alpha coefficients ranging from 0.77 to 0.83, indicating strong reliability. Test-retest reliability is also good, with correlation coefficients ranging from 0.85 to 0.87 [48].

Perceived Stress Scale is a self-report questionnaire comprising 10 items, each rated on a 5-point Likert scale ranging from 0 (never) to 4 (very often). The internal consistency of the PSS is high, with Cronbach’s alpha coefficients ranging from 0.78 to 0.91, indicating strong reliability. Test-retest reliability is also good, with correlation coefficients ranging from 0.67 to 0.85 [49].

International Physical Activity Questionnaire (IPAQ) is a self-reported questionnaire of 27 items to assess the frequency, duration, and intensity of physical activity. The internal consistency of the IPAQ is moderate to high, with Cronbach’s alpha coefficients ranging from 0.73 to 0.95. Test-retest reliability is good, with correlation coefficients ranging from 0.70 to 0.88 [50].

Chronic Pain Self-Efficacy Scale (CPSS) is a self-reported questionnaire comprising 22 items rated on a 0–10 scale, with higher scores indicating greater self-efficacy in managing pain. The internal consistency of the CPSS is high, with Cronbach’s alpha coefficients ranging from 0.89 to 0.95, indicating strong reliability. Test-retest reliability is also good, with correlation coefficients ranging from 0.63 to 0.90 [51].

Knowledge questionnaire on specific aspects of pain, ad hoc, includes 5 questions in multi-choice test format on the contents used in the education sessions.

Global Perception of Change is the only one that will be tested after the intervention. This instrument consists of a 100mm line numbered in centimeters from -5 to 5 where the left end reads "Much Worse", 0 is printed as "no change" and 5 is marked as "fully recovered". Relative to these values, the patient is asked to answer the following question: "In relation to your pain, how would you describe your current state of health compared to when your pain began?" This version of the change perception scale has been assessed in the literature as the most appropriate in musculoskeletal pain processes, and as a valid and reliable instrument [52].

Others

Pressure Pain Thresholds (PPT). Pressure pain thresholds will be assessed through a pressure algometer. The algometer will be applied to different points in the body (elbow and knee) and participants will be asked to indicate the point at which pressure changes to pain. The pressure will be gradually increased at approximately 1 kg/s until the participant indicates feeling pain. The threshold pressure at which the sensation changes from pressure to pain will be recorded in kilograms (kg) and used as an indicator of PPT. Higher PPT values indicate higher pain thresholds. The validity and reliability of using a pressure algometer to measure PPT have been established [53].

Height and weight. Both these variables will be determined by patient estimation, with no exploration of them in the measurement process.

Sociodemographic. This comprises Age, Marital status (Single, Married, Divorced, Widowed), Employment status (Active, Unemployed, Retired, Temporary disability, Student, Homemaker, Other), Educational level (none, primary, secondary, university), and Gender.

Exercise. Among the exercise variables, the parameters described below will be considered:

Blood pressure and respiratory rate. Measured with the Anura application, which has demonstrated reliability with a conventional blood pressure measurement of 98% [54].

Saturation and HR are Measured with an Oxylink finger pulse oximeter.

All the outcome measurements will be assessed in a random order at baseline, at the halfway point of the treatment, post-intervention, and one- and eight-months post-intervention (Figs 3–5).

Participants’ timeline

We have included a schematic diagram outlining the time frame for participant enrolment, interventions, assessments, and visits, as shown in the following figures (Figs 4 and 5).

Sample size

The determination of the sample size used a t-test for independent means, calculated using G*Power software (Universität Düsseldorf, Germany). The significance level was set at 0.05, and a power of 90% was targeted. The effect size, assessed by Cohen’s d, was predicted based on a mean difference of 2 points in the Visual Analog Scale (VAS), as it is commonly considered the minimum clinically relevant change in many chronic pain conditions [55], and the pooled standard deviation (SD_pooled). This was derived from the standard deviations of the intervention and control groups in a preliminary study, which were 1.29 and 2.61, respectively.

In recognition of the potential underestimation of standard deviations in the pilot study, the original SD values were adjusted using the Upper Confidence Limit (UCL) method, as described by Whitehead et al. [56], based on Browne’s [57] approach. This adjustment, accounting for a 95% confidence level, yielded an SD of 3.227 using the formula [56, 57]: s_UCL^2 = [k/(X_(1-X,k)^2)] s^2.

Consequently, the effect size (d) was calculated as 0.619195 (derived from 2/3.23). With a 1:1 allocation ratio between groups, G*Power [58] indicated a requisite minimum of 56 subjects per group to detect a 2-point difference in VAS with 90% power. Considering a 15% dropout rate, the final sample size was set at 66 subjects per group, totaling 132 subjects for the study to maintain the desired statistical power.

Recruitment

Allocation

Sequence generation, concealment mechanism, and implementation. Individuals meeting the inclusion criteria will be randomly allocated to one of two treatment arms: (1) POBTE plus exercise or (2) exercise therapy alone. Randomization will be conducted using computer-generated random numbers in block sizes ranging from 8 to 12, accommodating the requirements of the group intervention and ensuring that each group consists of 4 to 6 participants for the intervention to be feasible. The allocation will be concealed in an opaque, sealed envelope. A research assistant will open these envelopes and assign patients to their respective treatment arms. Multiple randomizations will be performed corresponding to the number of intervention-control groups formed. The randomization process will take place after obtaining informed consent and conducting baseline assessments.

Blinding

Masking

In this trial, both outcome assessors and data analysts will be blinded after intervention assignment. They will not know the participants’ intervention group affiliations during outcome assessment or data analysis. Due to the intervention’s nature, involving educational sessions and exercises requiring interaction, participants and educators cannot be blinded.

Emergency unmasking

A secure process, such as a password-protected system, will be employed for the emergency unmasking. Unbinding should only occur when deemed necessary, with the objective of preserving the trial’s integrity.

Data collection plan

The trial will collect baseline and outcome data through questionnaires, laboratory tests, and physical assessments, using standardized and validated instruments to ensure data quality. The instruments used in the trial are validated, and information on them can be found in the protocol.

Data collection plan: Retention

To ensure that participants remain engaged and complete the follow-up procedure in our trial, several strategies have been implemented. Firstly, clear and concise information is provided to participants, explaining the trial’s details, potential benefits, and associated risks, to help them understand the importance of their participation. Secondly, clear communication channels were established between the research team and participants to encourage an open and trusting relationship. The environment encourages participants to ask questions and provide feedback comfortably. Additionally, regular follow-up phone calls or emails are conducted to remind participants of upcoming study visits and to address any concerns they may have.

Data management

All data will be entered into a secure database system with restricted access. Data quality will be maintained through the implementation of range checks and double data entry processes. Tight data security and storage plans are in place, including regular backups, restricted access, and secure transfer methods.

Statistics: Outcome

Data analysis will be conducted using the statistical software SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). A descriptive analysis of the demographic characteristics and pain intensity of the sample size will be performed, presenting continuous variables as mean ± standard deviation (SD) and 95% confidence interval (CI), while categorical variables will be presented as number (n) and percentage (relative frequency, %). In instances where quantitative variables follow a non-normal distribution, they will be described using the median and interquartile range.

For the comparison between groups, parametric tests based on the central limit theorem will be chosen, since the sample size of both groups will be greater than 30 [56]. A mixed-model Analysis of Covariance (ANCOVA) will be used including baseline as the covariate, to obtain between-group adjusted mean differences at each follow-up point, controlling for type I error rate using Bonferroni’s correction. The chi-square test will be used for nominal variables. If the criteria for parametric testing cannot be met, robust methods will be applied [57]. A p-value < 0.05 will be accepted as statistically significant.

Statistics: Additional analyses

We will employ a multiple linear regression model to evaluate the strength of the associations between multiple predictor variables and the outcome variable at baseline. By using this method, we aim to discern the relative contribution of each predictor to the outcome, controlling for the potential influence of other variables, which will provide a comprehensive understanding of the factors that are most significantly associated with the baseline measures. We have calculated the sample size required to ensure a minimum power for each of the individual regression coefficients of the model. The sample size calculation was based on Hsieh et al. [59]. It was expected a minimum correlation coefficient of 0.6 between the predictors and the dependent variable, and an interpreter correlation of 0.5, along with a total of 8 predictors and a statistical significance level of 0.05, we determined that a minimum of 53 subjects is needed to achieve a desired power of 90% (beta of 0.1), assuming a loss rate of 15%. Thus, we ensured the feasibility of these tests with the previously reported sample size calculation for the main outcome.

Statistics: Analyzes population and missing data

The analysis will be based on the intention-to-treat principle, including all randomized participants in the analysis, regardless of their compliance with the intervention protocol. Missing data will be addressed using appropriate imputation methods, such as multiple imputations or the last observation carried forward. Sensitivity analyses will be conducted to evaluate the impact of different imputation methods on the results. The analysis population will be clearly defined, and any deviations from the intention-to-treat principle will be reported and justified.

Data monitoring: Formal committee

This small-scale, low-risk intervention trial does not require a Data Monitoring Committee (DMC). Instead, the study investigators will take on the responsibility of monitoring trial data. The primary investigator will regularly review study data to ensure protocol adherence and to maintain the safety and well-being of participants. In the event of significant safety concerns or other issues, the primary investigator will collaborate with the study team and, if deemed necessary, seek guidance from an independent expert to determine the best course of action. Any concerns or protocol deviations will be promptly reported to the relevant regulatory authorities.

Data monitoring: Interim analysis

Although data and blood samples will be collected for 15 days during the intervention period, no interim analyses are planned for this trial. Nevertheless, it could be of interest to check potential changes in BDNF levels, which serve as a biomarker of brain plasticity, in relation to the learning curve [60] observed in patients. It is expected that the learning process during the intervention will lead to significant changes in BDNF levels.

Harms

The research team will vigilantly monitor participants for adverse events related to the intervention or trial conduct. Solicited events will be assessed during follow-up visits, while spontaneously reported events will be identified during unscheduled interactions.

Adverse events will be documented, and the principal investigator will conduct a thorough review to determine whether they require reporting to the ethics committee and regulatory authorities. Unintended effects coming from the trial interventions or conduct will also be closely monitored and appropriately managed. All events will be reported in the trial report, publication, and to the ethical committee.

Research ethics approval

To get approval for our study from a research ethics committee (REC), we developed a detailed protocol, submitted the requisite documentation, addressed any queries or concerns raised by the REC, obtained REC approval, and will ensure ongoing compliance. Additionally, we have established plans to communicate important protocol modifications to investigators, the REC, trial participants, trial registries, journals, and regulators.

Consent or assent

Informed consent or assent will be obtained from potential trial participants or authorized surrogates by trained research staff. The consent process will involve the use of written informed consent documents, which will be provided to the potential participants or their authorized surrogates in advance of the trial. These documents will include a detailed description of the study, the associated risks and benefits of participation, as well as the rights and responsibilities of the participants. Research staff will also be readily available to answer any questions or concerns that may arise during the consent process.

Consent or assent: Ancillary studies

We have included provisions in the informed consent form to cover potential ancillary studies involving participant data and biological specimens. The form clearly states that data and specimens may be used for future research with ethical approval, and participants have the right to withdraw their consent at any time. This approach ensures that participants are fully informed and that their rights and privacy are protected.

Confidentiality

Throughout the trial, we will protect participants’ personal information. During the screening process, only essential information will be collected, and any unused data will be destroyed. Personal information will be kept secure and restricted to authorized members of the study team, identified solely by participant ID numbers. Upon completion of the trial, identifying information will be removed, and data will be securely stored for a specified period. Participants will be informed of our confidentiality policies during the informed consent process.

Data access

No datasets were generated or analysed during the current study. All relevant data from the RCT will be made available upon study completion.

Ancillary and post-trial care

The study team will develop a plan to provide ancillary or post-trial care for any harm experienced by participants during a clinical trial. Participants will be informed about these plans during the informed consent process and will work with regulatory authorities and review boards to ensure the implementation of appropriate provisions.

Dissemination policy: Trial results

We will communicate the trial results to participants, healthcare professionals, and the public. Results will be published in a peer-reviewed journal, presented at conferences, and reported in publicly accessible databases. Lay summaries will be provided to participants, and healthcare professionals will receive information. We will publish results regardless of the outcome, share the protocol, dataset, and statistical analysis, and adhere to responsible research guidelines. Our communication will be clear, timely, and accurate, with integrity and transparency.

Dissemination policy: Authorship

Authorship eligibility guidelines will follow international standards [61]. The contributions of eligible individuals will be clearly stated in publications, and professional writers will only be acknowledged if they meet the authorship eligibility guidelines.

Dissemination policy: Reproducible research

After the study, we will share the complete protocol, de-identified participant-level dataset, and statistical analysis, encouraging transparency and enabling further research. To enhance the accessibility and reproducibility of study findings, we will provide technical support and educational resources.

Discussion

The current randomized controlled trial (RCT) seeks to examine the impact of a specific therapeutic education program, combined with exercise, on BDNF levels and perceived pain intensity among individuals suffering from chronic musculoskeletal pain. This article not only seeks to offer a more rigorous approach to therapeutic education from a biobehavioral perspective but also assesses the outcomes of an intervention that encompasses both the cognitive aspects and pain-related plasticity biomarkers, such as BDNF. Consequently, it represents a valuable contribution to low-cost, non-pharmacological treatments in physiotherapy. Although the study design and methods have been meticulously planned, several practical and operational considerations need to be addressed.

One potential limitation of our study pertains to the heterogeneity of chronic pain. Despite having well-defined inclusion criteria, it is important to acknowledge that chronic pain is a complex and multifactorial condition [62–64]. While we have not imposed restrictions on the specific site of pain in our selection criteria, a stance supported by evidence suggesting that chronic pain is centrally mediated rather than solely dependent on the location of the injury [65–68], it is evident that various individual factors influence the pain experience in each patient [69–71]. These factors may impact the results obtained. To address this limitation, in addition to the inclusion criteria, we will consider conducting subgroup analysis if deemed necessary and feasible. This analysis will enable us to examine possible clusters of patients with similar characteristics, thereby enhancing our understanding of differences and treatment responses within our sample. It is also important to highlight that, regarding the proposed statistical analysis, it is assumed that categorical variables with more than five categories can be considered as continuous variables. This approach has been extensively considered in scientific literature and previously validated [72]. However, this could influence the final choice of the analysis method selected for the study.

Another concern is the potential confounding effects of medications and other interventions that participants might be undergoing. To address this issue, participants will be strongly advised to maintain their regular medication regimen (if applicable) but will not be permitted to initiate any new treatments during the program and follow-up period. This measure is implemented to minimize potential confounding factors and ensure the integrity of the study results. The study team will diligently screen and monitor participants to ensure compliance with this requirement. Additionally, the statistical analysis will consider adjusting for any emerging confounding variables.

Finally, it is important to note that the measurement of BDNF levels can pose challenges due to the inherent variability in sample collection, storage, and analysis. In this study, BDNF levels will be specifically measured in plasma samples, as they have been found to be more stable during analysis compared to serum samples [73]. To ensure precise and reliable results, the study team will adhere to rigorous protocols for plasma sample collection, processing, and storage. The analysis will be conducted using standardized ELISA kits, with regular calibration and quality control checks implemented to minimize potential sources of variation. These measures are crucial for ensuring the accuracy and validity of the BDNF measurements and upholding the integrity and reliability of the study’s findings.

In conclusion, this randomized controlled trial serves as a significant milestone in two important aspects. Firstly, it contributes to the development of a more structured and rigorous therapeutic education model for individuals with chronic musculoskeletal pain by implementing validated checklists and protocols [31, 32]. This standardized approach ensures the delivery of effective interventions tailored to the specific needs of these patients.

Secondly, the study investigates the changes occurring at the central nervous system level by measuring biomarkers such as BDNF. This provides valuable insights into the underlying mechanisms of chronic pain and the impact of non-pharmacological interventions on brain plasticity. By elucidating the relationship between therapeutic education, BDNF levels, and pain outcomes, this research can pave the way for novel and targeted strategies to enhance treatment efficacy and improve the quality of life for individuals suffering from chronic pain.

Supporting information

S1 Checklist. TiDier checklist.

(DOCX)

Click here for additional data file.^{(18.2KB, docx)}

S2 Checklist. CERT checklist.

(DOCX)

Click here for additional data file.^{(18.3KB, docx)}

S3 Checklist. GREET checklist.

(DOCX)

Click here for additional data file.^{(23.6KB, docx)}

S4 Checklist. SPIRIT checklist for this protocol.

(DOC)

Click here for additional data file.^{(121.5KB, doc)}

S1 File. POBTE explanation.

(DOCX)

Click here for additional data file.^{(128KB, docx)}

S2 File. Informed consent in Spanish.

(DOCX)

Click here for additional data file.^{(31.1KB, docx)}

S3 File. Informed consent in English.

(DOCX)

Click here for additional data file.^{(22.4KB, docx)}

Acknowledgments

Special acknowledgment is extended to the Spanish Ministry of Education’s FPU program (FPU20/00041) for supporting the predoctoral contract of Silvia Di Bonaventura. This support has significantly contributed to the progress of this research. It is important to note that the program has not provided direct funding for the study itself.

Informed consent materials

The model consent form and related documentation will be appended to the supporting information section of our study (S2 and S3 Files), ensuring a clear record of the consent process that can be easily accessed and verified by future reviewers.

Biological specimens

We will collect and label blood samples, isolate plasma, and measure BDNF levels using an ELISA kit. Quality control measures will be implemented to ensure accurate measurements. Specimens will be stored in secure, monitored freezers (-80°) at the research site and laboratory and tracked using unique participant identifiers. With proper ethics approval and participant consent, stored specimens may be used in future ancillary studies. This plan ensures the proper handling and availability of biological specimens for future research.

Data Availability

No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

Funding Statement

The authors received financial support for the future randomized clinical trial from the CSEU La SALLE (Universidad Autónoma de Madrid) with grant number: 2022A36005 but not for this protocol. The authors who have received funding are not part of the present study as it is a shared project.

References

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PLoS One. doi: 10.1371/journal.pone.0289430.r001

Decision Letter 0

Stephen D Ginsberg

7 Nov 2023

PONE-D-23-22066Can a specific biobehavioral based therapeutic education program lead to changes in pain perception and brain plasticity biomarkers in chronic pain patients? A study protocol for a randomized clinical trial.

PLOS ONE

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

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Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that (such) study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance]. I look at the manuscript in/with statistical view point, other reviewer(s) look(s) at it with different angle so that in totality the review is very comprehensive. However, there should be efforts from authors side to improve (may be by taking clues from reviewer’s comments). Therefore, please do not limit the revision only (with respect) to comments made here.

COMMENTS: I note that this manuscript is well drafted [and the study protocol is alright with respect to few aspects], I have certain definite observations/concerns (different opinion) which are given below:

Firstly, the account given in section ‘Sample Size’ (lines 354-368) appears alright, however, mind you that the effect size of 0.94 assumed is very large [your calculations are correct but the assumption regarding effect size in not at all reasonable, in my opinion]. Whereas details given of “POBTE’s intervention” are appreciable, difference from “Active Control group (Exercise)” [as indicated/implied by effect size assumed] cannot be that large [generally for such studies on non-pharmacological interventions], I guess. Effect size assumed here while estimating required sample size is very large [most likely], by any standard and please note that the ‘effect size’ assumed should be reasonable/realistic, else the study is very likely ‘not to be able to’ detect a difference despite its presence. In this case ‘effect size’ can at best be ‘medium’. The quoted reference [56] by Cohen J. ‘Statistical power analysis for the behavioral sciences’ is excellent, however, it not properly used {used to estimate SDpooled, but data used were from some pilot study, as this reference [Cohen’s] never comment(s) on likely ‘effect size’}.

According to table-2 on page 158 of Jacob Cohen’s paper “A power primer” in Psychological Bulletin, 1992, vol.:112, pp 155-159 [which is a sort of summary of the above quoted excellent book by Cohen himself for medium effect size you need n=64 per group (type-I error=0.05, power=80%). Your answer is [lines 364-5] “resulting in the need for at least 25 subjects per group to be able to detect a 2-point difference in VAS with 90% power” and in line 367, you said “Consequently, the study will require a total of 64 subjects to reach the required statistical power”. Note that my question is not about software used [G*Power or reference 57] as this software is excellent. For the same assumption of drop-out rate {25% is in fact, which is much more than generally allowed in any standard clinical trial(s)}, the study will require a total of 160 subjects to reach even 80% power.

In the context of ‘Statistics: additional analyses’ section (lines 430 onwards), mind you that ‘Multiple linear regression models (this technique [in fact any regression technique(s) for that matter] is/are not originally developed for testing the ‘Group difference(s)’. Head-to-head comparison is expected, as this is an indirect/secondary/by-product testing, in my opinion). You said [lines 432-33] “Subgroup analyses will consider age, gender, and duration of pain” is very good but do you think that this sample size will suffice to do this? Moreover, note that though the measures/tools used are appropriate [examples: Pain intensity - Visual Analogue Scale (VAS); Plasma BDNF levels; HADS self-completion scale; EuroQoL-5D questionnaire (EQ-5D); Pain Catastrophism Scale (ECD); Chronic Pain Grading Scale (CPGS)], most of them are likely to yield data that are in ‘ordinal’ level of measurement [and not in ratio level of measurement for sure {as the score two times higher does not indicate presence of that parameter/phenomenon as double}]. Then application of suitable non-parametric (or distribution free) test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (also called ‘normal’)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s), but should be used whenever/wherever they are available. Therefore, in short use suitable non-parametric test(s)/technique(s) while dealing with data that are in ‘ordinal’ level of measurement even if [despite that] the distribution may be ‘Gaussian’. Testing ‘normality’ in sample [by using any normality test(s)} is not required/desired while dealing with data that are in ‘ordinal’ level of measurement [as most of the normality tests are not valid for ‘ordinal’ data].

In ‘Conclusion’ section of abstract [lines 24-25] you conclude that “The rigorous scientific methods used ensure that the proposed interventions will be clinically applicable across different health care systems” is not understood. What type of conclusion it is? How this study helped the authors to conclude this? In any case, remember/mind you that this is a scientific/academic document and so all details should be clearly/correctly communicated (do not take readers’ for granted).

Refer to line 379 [stratified permuted block (block size of 4 and 6)], Please explain the role of ‘stratification’ in ‘permuted block’ randomization’? {i.e. how you used/executed in this study?} Moreover, please note that while using ‘permuted block randomization’, we generally do not reveal ‘block size’ [which is randomly chosen]. Further, please refer to lines 425-27 [ANOVA test will be used to analyze the group factor in the quantitative variables and if the ANOVA reveals statistical significance, a post-hoc analysis with Bonferroni correction will be performed], according to my understanding, you may not need ANOVA and subsequent any post-hoc analysis as there are only two groups.

In the beginning of the article (line 29) there is a list ‘Strengths and limitations of this study’ where there is hardly any limitation(s). Does that mean {according to authors} there are none?

As pointed out in ‘important note’ above “This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ should be assessed separately/independently [one should carefully consider/look at the clinical implications of the study]. In my opinion, to make this article acceptable (which is not impossible), large amount of re-vision (re-drafting) may be needed. However, please do not limit the revision only (with respect) to comments made here [as this is a protocol and is possible now to accommodate suggestion by other respected reviewers. ‘Major revision’ is recommended.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Attachment

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Click here for additional data file.^{(18.1KB, docx)}

PLoS One. 2024 Jan 19;19(1):e0289430. doi: 10.1371/journal.pone.0289430.r002

Author response to Decision Letter 0

13 Nov 2023

Dear Journal Editors,

First and foremost, we would like to express our deepest gratitude for your detailed corrections and suggestions, which have been immensely helpful in enhancing our manuscript. Below, we detail the revisions made in response to each of your requirements:

Compliance with PLOS ONE Style Requirements and Figure Corrections: We have reviewed and adjusted our manuscript to ensure it meets the style requirements of PLOS ONE, including those related to file naming, using the provided templates. Additionally, we have corrected the figures using the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool to ensure they meet the required standards. Furthermore, the entire paper has been meticulously reviewed and edited by a specialized editor (PaperTrue) for English language and composition to ensure clarity and coherence.

Funding Information: We have made the necessary corrections in the 'Funding Information' sections to accurately reflect it. It is important to highlight that we have clearly differentiated two sources of funding:

a. Funding from CSEU La Salle: In the 'Funding Information' section, we have indicated that CSEU La Salle, with grant number: 2022A36005, will provide the necessary funds for acquiring the material for the study we are going to conduct.

b. Acknowledgment to the Spanish Ministry of Education: As per the requirement of the Spanish Ministry of Education, we should acknowledge the predoctoral contract (FPU20/00041) of one of the authors in the “Acknowledgments” section. However, this contract does not provide any direct financial contribution to the study. If it is not permissible to include this acknowledgment in that section due to the journal's policies, we kindly request guidance on where you would prefer it to be included and we will change it.

Supplementary Figures: We have removed the supplementary figures (Fig S1-S5) from the manuscript file and uploaded them as 'Supporting Information', ensuring that each has an appropriate legend listed after the references.

Removal of Institutional Logo from Project Report: Regarding the Supporting Information file containing the project report, we have removed the institutional logo from both the English version and the original Spanish version, to avoid copyright issues.

Protocol Registration in Pprotocols.io: Our protocol was initially registered in MedRxiv. Following your advice, we have now also registered it in protocols.io.

Additionally, we have addressed all the reviewer's comments in a separate document, ensuring a thorough and detailed response to each point raised.

We are fully willing and available to make any additional adjustments that may be necessary. We look forward to your comments and guidance to proceed towards the publication of the manuscript.

Responses to Reviewer’ comments:

Dear Reviewer,

Thank you for your insightful commentaries aimed at enhancing the quality of our manuscript. We have undertaken a comprehensive and detailed modification process in accordance with your valuable suggestions.

In the following lines, we will explain in detail, question by question, how we have addressed and modified the manuscript in response to each specific point you raised.

REVIEWER

1. In response to “Firstly, the account given in section ‘Sample Size’ (lines 354-368) appears alright, however, mind you that the effect size of 0.94 assumed is very large [your calculations are correct but the assumption regarding effect size in not at all reasonable, in my opinion]. Whereas details given of “POBTE’s intervention” are appreciable, difference from “Active Control group (Exercise)” [as indicated/implied by effect size assumed] cannot be that large [generally for such studies on non-pharmacological interventions], I guess. Effect size assumed here while estimating required sample size is very large [most likely], by any standard and please note that the ‘effect size’ assumed should be reasonable/realistic, else the study is very likely ‘not to be able to’ detect a difference despite its presence. In this case ‘effect size’ can at best be ‘medium’.

We would like to express our sincere gratitude for your comments, which have resulted in a thorough revision of the initial assumptions of our manuscript regarding effect size. Considering them, we recognize that the initially proposed effect size of 0.94 was indeed ambitious for nonpharmacological interventions, despite being based on the results of our pilot study. Accordingly, we have recalibrated our calculations, adopting a "medium" effect size in line with the standard literature and better reflecting the expected results in such studies. You can find in line 419-441.

2. In response to “The quoted reference [56] by Cohen J. ‘Statistical power analysis for the behavioral sciences’ is excellent, however, it not properly used {used to estimate SDpooled, but data used were from some pilot study, as this reference [Cohen’s] never comment(s) on likely ‘effect size’}. According to table-2 on page 158 of Jacob Cohen’s paper “A power primer” in Psychological Bulletin, 1992, vol.:112, pp 155-159 [which is a sort of summary of the above quoted excellent book by Cohen himself for medium effect size you need n=64 per group (type-I error=0.05, power=80%). Your answer is [lines 364-5] “resulting in the need for at least 25 subjects per group to be able to detect a 2-point difference in VAS with 90% power” and in line 367, you said “Consequently, the study will require a total of 64 subjects to reach the required statistical power”. Note that my question is not about software used [GPower or reference 57] as this software is excellent. For the same assumption of drop-out rate {25% is in fact, which is much more than generally allowed in any standard clinical trial(s)}, the study will require a total of 160 subjects to reach even 80% power”:

According to the calculations adjusted for the Standard Deviations previously mentioned, the effect size (d) obtained was 0.619195, based on that and performing again the calculation in G*Power to maintain the desired power of 90% we obtained a total of 56 subjects per group, very close to the recommendation made in your commentary. In addition, we have incorporated a 15% loss rate in our sample size calculation (132 total subjects, rounding up to the next even number), more in line with what is to be expected in this type of trial. According to the Cohen cite in our previous version of the manuscript, we have taken steps to clarify in our manuscript the references used for the calculation of the pooled standard deviation that were derived from our pilot study data. We believe that these modifications significantly improve the methodological rigor and clarity of our study, and we appreciate the opportunity to improve our work based on your valuable input. (Line 436-441).

3. In response to “In the context of ‘Statistics: additional analyses’ section (lines 430 onwards), mind you that ‘Multiple linear regression models (this technique [in fact any regression technique(s) for that matter] is/are not originally developed for testing the ‘Group difference(s)’. Head-to-head comparison is expected, as this is an indirect/secondary/by-product testing, in my opinion). You said [lines 432-33] “Subgroup analyses will consider age, gender, and duration of pain” is very good but do you think that this sample size will suffice to do this? Moreover, note that though the measures/tools used are appropriate [examples: Pain intensity - Visual Analogue Scale (VAS); Plasma BDNF levels; HADS self-completion scale; EuroQoL-5D questionnaire (EQ-5D); Pain Catastrophism Scale (ECD); Chronic Pain Grading Scale (CPGS)], most of them are likely to yield data that are in ‘ordinal’ level of measurement [and not in ratio level of measurement for sure {as the score two times higher does not indicate presence of that parameter/phenomenon as double}].

We have carefully reviewed your comment and recognize that these models were not primarily intended to examine differences between groups, so we have adjusted our manuscript to accurately reflect this and avoid misunderstandings. This adjustment corresponds to one of our secondary objectives, which is to investigate the relationship between the main variable and the secondary variables of this study (baseline levels). Regarding concerns about sample size for subgroup analyzes that include age, gender, and pain duration, after reevaluating the study sample size and statistical power, we consider that, if the necessary conditions are met, this type of analysis can be carried out with the variables provided in the study. (Line 522-531)

4. In response to “Then application of suitable non-parametric (or distribution free) test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (also called ‘normal’)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s), but should be used whenever/wherever they are available. Therefore, in short use suitable non-parametric test(s)/technique(s) while dealing with data that are in ‘ordinal’ level of measurement even if [despite that] the distribution may be ‘Gaussian’. Testing ‘normality’ in sample [by using any normality test(s)} is not required/desired while dealing with data that are in ‘ordinal’ level of measurement [as most of the normality tests are not valid for ‘ordinal’ data].

Thank you so much for the appreciation regarding the use of categorical variables and ordinal level measurements in our tools, such as the Visual Analogue Scale and the others mentioned, we have considered the guidelines of relevant studies, as Rhemtulla et al. (2012), who suggest that under certain conditions, categorical variables with more than five categories can be treated as continuous. However, we are prepared to employ robust methods if the conditions for parametric testing are not met, thus ensuring the validity of our statistical analysis. We have added this explanation in the manuscript more precisely. (Line 505-513)

5. In response to “Refer to line 379 [stratified permuted block (block size of 4 and 6)], Please explain the role of ‘stratification’ in ‘permuted block’ randomization’? {i.e. how you used/executed in this study?} Moreover, please note that while using ‘permuted block randomization’, we generally do not reveal ‘block size’ [which is randomly chosen].

After careful consideration of your feedback, we have made significant revisions to that approach. In our initial submission, we incorrectly mentioned 'stratification' in the context of our 'permuted block' randomization. This was a misinterpretation on our part. Stratification was not utilized in our study; therefore, we have removed this term to prevent any misunderstanding about our randomization process.

Additionally, in line with the standard practices of 'permuted block randomization', we have revised our manuscript to exclude the explicit mention of block sizes. We acknowledge that disclosing the block sizes could potentially introduce bias into the study. The randomization will now be conducted using computer-generated random numbers with undisclosed block sizes to ensure unpredictability and methodological soundness. (Line 448-451)

Further, please refer to lines 425-27 [ANOVA test will be used to analyze the group factor in the quantitative variables and if the ANOVA reveals statistical significance, a post-hoc analysis with Bonferroni correction will be performed], according to my understanding, you may not need ANOVA and subsequent any post-hoc analysis as there are only two groups.

Furthermore, we have also realized, thanks to your observation, that our initial manuscript did not adequately explain our analytical approach regarding the interaction between time and group factors. We will indeed be employing an ANCOVA for this purpose. The manuscript has now been amended to include a thorough explanation of how we intend to explore this interaction, providing a clear rationale for the use of ANCOVA in this context. (Line 505-513 / Line 522-531)

6. In response to “In ‘Conclusion’ section of abstract [lines 24-25] you conclude that “The rigorous scientific methods used ensure that the proposed interventions will be clinically applicable across different health care systems” is not understood. What type of conclusion it is? How this study helped the authors to conclude this? In any case, remember/mind you that this is a scientific/academic document and so all details should be clearly/correctly communicated (do not take readers’ for granted).

Thank you for your comment regarding the conclusion in our abstract. We understand your concern about the clarity of our statement. The intent was to express that the methods we have employed are robust and, as such, the findings could be relevant to various health care settings. However, we acknowledge that this may have been an overstatement. To this end, we have placed greater emphasis on explaining the impact that the study may have in terms of reproducibility, providing a more comprehensive treatment approach, and objectifying the results (line 42-46).

7. In response to “In the beginning of the article (line 29) there is a list ‘Strengths and limitations of this study’ where there is hardly any limitation(s). Does that mean {according to authors} there are none?

We really appreciate you pointing out the need to address potential limitations in our study. Upon reviewing line 29, we recognize that the original manuscript did not adequately detail the main limitations. To rectify this, we have revised the section 'Strengths and limitations of this study” and included different limitations. More specifically, two principal factors that could substantially impact our findings. Firstly (line 76-71), the instability of BDNF as a biomarker is a critical concern, given its sensitivity to minor changes such as dietary variations, levels of physical activity, stress, and even ambient temperature conditions. Such fluctuations necessitate cautious interpretation of BDNF levels in clinical research settings. Secondly (line 73-77), the patient demographic for studies of this nature, for instance, those with fibromyalgia or migraine conditions, is highly specific and not broadly generalizable. This specificity is pivotal in understanding the context and applicability of our results. These primary factors, along with secondary considerations mentioned in the discussion, are crucial as they have been shown to influence outcomes in prior research significantly.

8. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No.

We acknowledge and appreciate your recommendation to have our manuscript reviewed by a language expert, considering English is not our first language. We have since engaged a professional editor, whose expertise has greatly enhanced the clarity and readability of our text. A certificate of the editing will be provided as an attachment to confirm this revision.

Once again, thanks for the possibility to review this manuscript. We deeply appreciate the time and effort you have invested in reviewing our manuscript and providing valuable feedback. We are fully prepared and willing to make any further changes if necessary, to ensure that our manuscript meets the standards of the journal.

Sincerely,

The authors.

Attachment

Submitted filename: ReviewerComments.docx

Click here for additional data file.^{(23.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0289430.r003

Decision Letter 1

Stephen D Ginsberg

27 Nov 2023

PONE-D-23-22066R1Can a specific biobehavioral-based therapeutic education program lead to changes in pain perception and brain plasticity biomarkers in chronic pain patients? A study protocol for a randomized clinical trial.

PLOS ONE

Dear Dr. Di Bonaventura,

Thank you for resubmitting your work to PLOS ONE. Please make the corrections posed by Reviewer #1 so I can render a decision on this manuscript.

Please submit your revised manuscript by Jan 11 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

Reviewer #1: No

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: COMMENTS: Although all the comments are answered and few positively attended, frankly speaking I do not agree with Rhemtulla et al. (Psychol Methods, 2012 Sep;17(3):354-73) who suggested that under certain conditions, categorical variables with more than five categories can be treated as continuous [quoted as part of answer to my comment]. Look at few of their statements like “In our initial submission, we incorrectly mentioned 'stratification' in the context of our 'permuted block' randomization. This was a misinterpretation on our part.” Which hopefully throw light on quality of work.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

PLoS One. 2024 Jan 19;19(1):e0289430. doi: 10.1371/journal.pone.0289430.r004

Author response to Decision Letter 1

27 Nov 2023

Dear reviewer, thank you again for your comments.

REVIEWER

1.- In response to “Although all the comments are answered and few positively attended, frankly speaking I do not agree with Rhemtulla et al. (Psychol Methods, 2012 Sep;17(3):354-73) who suggested that under certain conditions, categorical variables with more than five categories can be treated as continuous [quoted as part of answer to my comment].”

We understand the reviewer's discrepancy, but we would like to emphasize that the method used in our study, based on the aforementioned study by Rhemtulla et al 2012, has been widely cited and accepted by the scientific community, specifically it has been used in more than 395 articles, including 14 in Q1 journals and 88 in Q2 of the JCR, and has even been used and referenced in previous studies published in prestigious journals, including PLOS ONE, as in the article with PMID 37603578 or the one with PMID 37310969, for example. We consider that such a method is sufficiently validated and explained, and that it is relevant to our study, although we acknowledge that it could influence future results in some way, based on the concerns of reviewer 1. This point has been included in the potential limitations of our study in the manuscript.

2.- In response to:

“Look at few of their statements like “In our initial submission, we incorrectly mentioned 'stratification' in the context of our 'permuted block' randomization. This was a misinterpretation on our part.” Which hopefully throw light on quality of work.”

We also consider that the methodological quality of our work is well documented and we believe that we have correctly responded to all the considerations set out in detail in the previous review, having considerably improved the initial manuscript, and we believe that our study meets the necessary quality requirements to be considered for publication, we regret if an error we made in the drafting of the first version of the manuscript, as English is not our native language, and which we have corrected and submitted for professional editing, is put forward as an example of the quality of the manuscript, but we can do nothing other than apologize for the error made initially and corrected subsequently. Nevertheless, we sincerely thank the reviewer 1 for the time spent in improving our manuscript.

Attachment

Submitted filename: ReviewerComments.docx

Click here for additional data file.^{(17.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0289430.r005

Decision Letter 2

Stephen D Ginsberg

18 Dec 2023

Can a specific biobehavioral-based therapeutic education program lead to changes in pain perception and brain plasticity biomarkers in chronic pain patients? A study protocol for a randomized clinical trial.

PONE-D-23-22066R2

Dear Dr. Di Bonaventura,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE

PLoS One. doi: 10.1371/journal.pone.0289430.r006

Acceptance letter

Stephen D Ginsberg

9 Jan 2024

PONE-D-23-22066R2

PLOS ONE

Dear Dr. Di Bonaventura,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

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If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Stephen D. Ginsberg

Section Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. TiDier checklist.

(DOCX)

Click here for additional data file.^{(18.2KB, docx)}

S2 Checklist. CERT checklist.

(DOCX)

Click here for additional data file.^{(18.3KB, docx)}

S3 Checklist. GREET checklist.

(DOCX)

Click here for additional data file.^{(23.6KB, docx)}

S4 Checklist. SPIRIT checklist for this protocol.

(DOC)

Click here for additional data file.^{(121.5KB, doc)}

S1 File. POBTE explanation.

(DOCX)

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S2 File. Informed consent in Spanish.

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S3 File. Informed consent in English.

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Data Availability Statement

No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

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PERMALINK

Can a specific biobehavioral-based therapeutic education program lead to changes in pain perception and brain plasticity biomarkers in chronic pain patients? A study protocol for a randomized clinical trial

Silvia Di Bonaventura

Josué Fernández Carnero

Raúl Ferrer-Peña

Roles

Abstract

Background

Objective

Methods

Outcomes

Conclusion

Background

Materials and methods

Study setting

Eligibility criteria

Interventions

Intervention group (Exercise + POBTE)

Fig 1. POBTE’s strategies.

Fig 2. POBTE’s intervention.

Active control group (Exercise)

Intervention modifications

Intervention adherence

Outcomes

Primary outcome

Pain intensity

Secondary outcomes

Biochemical

Psychosocial

Others

Fig 3. Flow diagram.

Fig 5. SPIRIT figure showing the schedule of enrolment, interventions, and assessments.

Participants’ timeline

Fig 4. Trial timeline.

Sample size

Recruitment

Allocation

Blinding

Masking

Emergency unmasking

Data collection plan

Data collection plan: Retention

Data management

Statistics: Outcome

Statistics: Additional analyses

Statistics: Analyzes population and missing data

Data monitoring: Formal committee

Data monitoring: Interim analysis

Harms

Research ethics approval

Consent or assent

Consent or assent: Ancillary studies

Confidentiality

Data access

Ancillary and post-trial care

Dissemination policy: Trial results

Dissemination policy: Authorship

Dissemination policy: Reproducible research

Discussion

Supporting information

Acknowledgments

Informed consent materials

Biological specimens

Data Availability

Funding Statement

References

Decision Letter 0

Stephen D Ginsberg

Roles

Author response to Decision Letter 0

Decision Letter 1

Stephen D Ginsberg

Roles

Author response to Decision Letter 1

Decision Letter 2

Stephen D Ginsberg

Roles

Acceptance letter

Stephen D Ginsberg

Roles