This interventional prospective study was approved by the University of Missouri-Kansas City Institutional Review Board, the TriService Nursing Research Program Human Research Protection Office (HRPO), and the Wilford Hall HRPO office. All research was performed in accordance with relevant guidelines and regulations provided by these governing bodies and informed consent was obtained from all participants. Records of participant participation followed regulatory guidance including Federal Privacy Act, 5 USC 522a and its implementing regulations, the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and 45 CFR Parts 160 and 164. Additionally, all regulatory criteria met an additional ethics review at the MTHM AFB to assure proper protocol was adhered to with minimal concern for coercion. This study was registered with the grant in clinicaltrials.gov NCT04104542 (09/26/2019) and was designed to compare pain perception (intensity and interference) primarily, and secondarily depression and inflammatory cytokine biomarkers in AD women with CPP after a 6-week online MBSR or HL program.
Participants were recruited from outpatient clinics in an USAF military treatment facility (MTF) at Mountain Home (MTHM) Air Force Base, Idaho. The MTF at MTHM has family practice, mental health, and women’s health specialists who were able to assist with recruitment. The AD female population in Idaho includes Asian (N = 140 or 8.9%), Black (N = 59 or 3.7%), Hispanic (N = 146 or 9.3%), Mixed (N = 94 or 6%), White (N = 1128 or 72%).
Active-duty women with CPP, pain in the lower abdomen/back for greater than six months, were recruited through the Wilford Hall HRPO and the TriService Nursing Research Program HRPO at MTHM from June to August 2019 after assuring for participant protection. A preliminary eligibility assessment of interested participants was conducted via a telephone interview. A positive response to any of the following criteria in the initial interview led to exclusion: 1) age < 21 or age > 50; 2) menopausal, pregnant, or breastfeeding; 3) pelvic/abdominal surgery within 6 months; 4) vaginal/pelvic infection at time of enrollment (as potential confounder of cytokines drawn), underlying diseases (cancer, diabetes, autoimmune); 5) unavailable to commit three months to study; 6) no access to computer or able to get online. Initially, the list of participants came from the group practice managers (GPM) and local women’s health and family practice providers who agreed to help with recruitment of women with specific ICD 10 codes from their practice. A few women self-identified directly from flyers and a poster used for recruitment and all participants approved the primary investigator access to record review to confirm diagnosis.
Once consent was signed and diagnosis confirmed, participants were asked to complete valid and reliable questionnaires including a demographics questionnaire, a pain questionnaire (the Brief Pain Inventory-BPI), a depression questionnaire (the Patient Health Questionnaire – PHQ9), and a mindfulness questionnaire (the Five Facets of Mindfulness – FFMQ), sent through the Research Electronic Data Capture (REDCap). Through REDCap, data was managed securely with an infrastructure programming allowing for the blinded assignment of these AD women with CPP to either the MBSR or the HL interventions. Once assigned, only the PI had oversight to manage the database.
MBSR, a complementary treatment with an emphasis on cultivating a focused, contemplative self-awareness, can help patients obtain self-regulation for health improvement in positive reappraisal coping.26 The classic in-person MBSR class is the best way to learn mindfulness because of live interaction and group support, but is not always feasible. For this study, MBSR online-training consisted of classic journal and written guidance with YouTube videos found on palousemindfulness.com with weekly homework assignments, progress reports, and readings each woman could perform asynchronously for convenience. There was access to online support trainings for still and moving meditations. Each participant had access to a step-by-step guide on chapters to read from “Full Catastrophe Living” by Jon Kabat-Zin each week, the asynchronous daily mindfulness sessions, a journal, and an online guide from Dave Potter. Weekly readings and videos included a different focus. This group was required to set aside 30-minutes five-days weekly for their “homework” to remain in the study. The PI had no access of these trainings and relied on the participants acknowledgement of homework assignments. Week one focused on simple awareness, an introduction to the body scan, which is tuning in to the body and reconnecting to the physical self. Week two began sitting meditation. Week three introduced yoga and dealing with thoughts and distractions. Week four focused on one-minute breathing space, responding vs reacting. Week five focused on turning toward the difficulty instead of moving away from it. Week six focused on mountain and lake meditations and the sacred art of listening. Questionnaires were completed and lab samples collected at six-weeks.
The HL group had access to weekly voice-over slides that guided them in nutrition and exercise choices with a different focus each week. It was modeled after the Group Lifestyle Balance (GLB) course found at USAF bases used by Nutritional Medicine to work with patients with diabetes or weight concerns. This group was required to journal at least five-days weekly entering their workouts and meals with a specific target goal to meet by the end of the study. The PI was able to monitor daily journaling in the fitness tracker and send weekly reminders. Week one introduced the program, the free fitness tracker application recommendation (myfitnesspal), and basic nutrition. Week two included slides that encouraged participants to focus on their goals with nutrition tips to help them meet their targets. Week three reviewed participant goals while offering suggestions for selecting foods while shopping. Week four focused on fitness goals and training motivation. Week five discussed interactive work calculation of “typical meals” for dining out at different restaurants. Week six reviewed strength training, progress, diaries, goals pending and met. Each member documented in myfitnesspal and shared their diary with one of the authors (CDC). This free site helped the HL participant journal their diet and exercise daily and track their goals.
All AD members have access to a certified nutritionist trained in telephone coaching and these women were informed that this was still available if desired to help guide them. Many of the HL group were advised to use the fermentable oligo-, di-, mono-saccharides and polyols, or FODMAP diet due to their specific type of CPP. All slides were forwarded to the HL participants and they could elect to watch them asynchronously, when it was convenient allowing for varying schedules.
Mindfulness was measured among participants in both the MBSR and HL groups. To measure mindfulness, a multi-faceted construct characterized by a shift in attention resulting in observation of each moment experience without interpretation, elaboration, or analysis of that experience as an intentional and non-judgmental awareness, the FFMQ was used.27 The FFMQ consists of subscales that measure the five facets of mindfulness: observe, describe, act with awareness, nonreactivity, and nonjudging, with 39-statements on a 5-point Likert-type scale ranging from one to five.27 Facet scores range from 8–40, except for the nonreactivity facet, which ranges from 7–35.
Pain Perception (intensity and interference) were measured using the Brief Pain Inventory (BPI). The intensity of pain is measured by 4-items, (current as well as worst, least, and average in the past week) on 0 “no pain” to 10 “worst pain imagined” for the numerical scales. Seven activities describe the interference and include (general activity, mood, walking, work, relations with others, sleep, and enjoyment of life) where 0 refers to “no interference” and 10 “complete interference”.28 It is used in the military and can be completed in less than 5-minutes. It has established reliability (Cronbach’s alpha ranges: 0.77 to 0.91), internal consistency, good to excellent test-retest values (ICC .84-.90) and construct validity α > .70 in seven of nine studies documenting pain in cancer patients, lower back pain, range of motion, muscle tenderness.28
Depression was measured using the Patient Health Questionnaire (PHQ9), a 9-item Likert-type self-assessment nominal screening and diagnostic tool used in primary care clinics in the Department of Defense (DOD) and VA routinely for somatic symptoms in depression. The PHQ-9 scores each item from 0 to 3 providing a severity score ranging between 0 and 27. The scores 0, 1, 2, and 3 are assigned to the response categories referring to frequency of a particular symptom over the last two weeks with “not at all”, “several days”, “more than half the days”, and “nearly every day” respectively.29 The severity of depression scores is graded as none/minimal (0–4), mild (5–9), moderate (10–14), moderately severe (15–19), and severe (20–27). The PHQ9 has a sensitivity of 51% and a specificity of 94%, high validity (AUROC 0.85, 95% CI 0.82–0.88).29 The PHQ-9 has been used internationally as a criterion-based diagnosis of mental disorders translated in 25 languages with adequate reliability, and construct and criterion validity in diverse samples. The DOD used the PHQ-9 in veterans and found adequate internal consistency (Cronbach’s α = 0.92, 95% CI = 1.86–19.13) and test-retest (0.84).30
Blood draws were not standardized by time of day or menstrual cycles due to the limited time of day available for laboratory access for participants and the PI. Cytokine concentrations in plasma were measured using a multiplex electrochemiluminescence immunoassay kit developed by Meso Scale Discovery (MSD). The customized U-PLEX (Cat. #K15054D) assay consisted of the following analytes: GM-CSF, IFNg, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, TNFα, IL-1RA, MCP-1, SDF-1, and VEGFα. The assay was carried out according to the manufacturer’s instructions. Frozen plasma samples were thawed on ice then diluted fourfold, run in duplicate, and analyzed using Discovery Workbench 4.0.12 software (MSD). Calibrators supplied by MSD were used to create standard curves and extrapolate sample concentration.
The collected data stored on REDCap was transferred to R version 3.5.0 for statistical analyses. Next, data was described using standard statistical methods such as frequency distribution, graphical displays of data, and application of the appropriate descriptive statistics to determine each variable’s central tendency, distribution, and variability. Descriptive statistics were provided for subject characteristics and can be found in Table 1 provided. Categorical variables are reported with counts and percentages, while continuous variables are reported as medians and interquartile ranges. The primary outcome was considered change in scores on the BPI and secondarily, change in scores for FFMQ and PHQ-9 questionnaires. An a priori power analysis found that a sample size of N = 100 would be required to achieve a statistical power of 0.8, for an alpha level of 0.05 and an effect size of 0.5. Though underpowered with a sample size of N = 27, we maintained an alpha level of 0.05 to determine an effect size of 0.5 which is considered moderate to large.
The Mann-Whitney U (Wilcoxon signed rank) test was used to compare the distribution of values for each group determine differences between groups at baseline pre-intervention as well as within group differences for changes (pre- to post-intervention) in mindfulness facets, pain scores, depression scores, and cytokine levels. Statistical significance was defined as P < .05. Due to the exploratory nature of cytokine analyses, no adjustment was made for multiple comparisons.