Finally - Stony Brook University Hospital



A new behavioral technique for home symptom management in fibromyalgiaSpecific Aims The long-term objective of this proposal is to develop a brief, effective, and low risk non-pharmacological intervention for the high prevalence condition of fibromyalgia [58] in order to empower patients to better manage debilitating symptoms. The intervention, as developed by the applicant, is a behavioral technique termed “bilateral stimulation and desensitization” (BSD). Its core element is bilateral sensory stimulation delivered with alternating sounds or finger taps (Friedberg, 2001, 2004). The technique is derived from the psychotherapeutic protocol of Eye Movement Desensitization and Reprocessing (EMDR; Shapiro, 1995) whose main application is to treat post-traumatic stress. The proposed study is intended to establish the initial efficacy of BSD as a symptom management technique for fibromyalgia in a randomized trial. The impact of the findings on pain intervention research would be to substantively advance the development of a new, low effort and minimal risk technique for symptom management in fibromyalgia. Specific Aim 1. To test the efficacy of a new home-based behavioral technique, BSD, for the reduction of clinically significant pain and pain perception (catastrophizing) in patients with fibromyalgia. Hypothesis 1: BSD, in comparison to a symptom monitoring attention control condition, will be associated with medium effect sizes and significant reductions in pain and pain perception (catastrophizing) in fibromyalgia patients at 3- and 12- month follow-up assessments. Hypothesis 2: BSD, in comparison to a usual care/no treatment control condition, will be associated with medium effect sizes and significant reductions in pain and pain perception in fibromyalgia patients at 3-and 12-month follow-up assessments. The 2 control groups are intended to control for (i) participants’ time spent doing the active intervention (attention control) and (ii) passage of time during the study period (usual care) (Friedberg et al; 2013). Specific Aim 2: To prospectively test a biobehavioral mediation model for the effects of BSD in patients with fibromyalgia. Hypothesis 1: The effects of BSD on pain reduction will be mediated by improved parasympathetic activity and autonomic balance as measured with heart rate variability. Hypothesis 2: The effects of BSD on pain reduction will be mediated by increased relaxation, distraction, and cognitive change as assessed with online diary based self-report measures. Hypothesis 3: Changes in the adjusted direct effect of BSD is reduced when controlled for the indirect effects of heart rate variability and/or behavioral change. Specific Aim 3. To assess compliance with weekly assignments and its relation to implementation of BSD-related symptom management skills. Hypothesis 1: Online web diary compliance rates (50% average rate of daily completion per subject anticipated) will be sufficient to assess symptom ratings and their weekly patterns, and usage of specific BSD techniques over the three month intervention period. Compliance will be associated with improved outcomes, i.e., BSD dose-response relationships will be tested. Hypothesis 2: Success of specific BSD techniques will be confirmed with web diary data and in phone interviews with each participant. Phone interviews will elicit participant preferences and feedback that will further refine the delivery of the intervention to increase compliance and better target fibromyalgia symptoms. Exploratory aim: to assess effect sizes for the clinical outcome of pain in order to do a power calculation for a large follow-up randomized field trial. This home-based program will be set up on a dedicated website consisting of a BSD demonstration video (also on DVD), a downloadable BSD self-management booklet, a MP3 audio sounds BSD technique, and an online diary to record pain and stress symptoms and BSD usage. The proposed research addresses a key area in the NINR’s Strategic Plan: “To improve quality of life by… management of pervasive symptoms such as pain.[and to] improve knowledge of biological mechanisms.” This proposal also responds to PA-13-118: “Pain management should engage interdisciplinary teams…with randomized trials to reduce pain …customized to the group (i.e., targeted), and to the individual (i.e., tailored).” Finally, BSD represents a potentially new technology to deliver effective pain management to patients with debilitating pain. The use of BSD for rapid symptom reduction also challenges the current paradigm of behavioral treatment delivery that requires multiple face to face sessions with a trained interventionist. The advantage of BSD over face-to-face therapy for fibromyalgia is based on its brevity, entirely home-based protocol, and potentially greater efficacy for pain reduction. If this initial randomized trial is efficacious, a large scale follow-up field trial will be proposed to assess the potential of highly usable BSD-based symptom management to be adapted into medical care.Significance Fibromyalgia is an increasingly recognized, but medically underserved, chronic widespread pain condition (Jensen et al; 2012). It is estimated to affect 1.3–4.8% of the population, of which 80% are women [58]. In a population study of 13 chronic conditions9, FM exhibited the second highest level (after post-stroke effects) of impact with respect to: pain-related activity limitations, fair-poor self-rated health, and four or more GP visits in the last year. Newer FDA approved pharmacological treatments for FM have shown clinically relevant pain reduction for about 40%, but with frequent adverse effects (4, 16;Wiffen etal; 2013). The most studied non-pharmacological treatment, aerobic exercise (Bidonde et al; 2014; Hauser et al; 2010) can improve physical functioning if not pain, but is associated with low adherence and high attrition in -15. (Bernardy et al; 2013. . 4,16 Current treatments for FM. CBT for FM17 (Giles, 2014; bernardy et al;; 2013) is effective in slightly reducing the symptoms of fibromyalgia, but is time-consuming as it requires an average of six months of face-to-face treatment (18, 19). Also CBT is costly and not available to many patients.20 More recent internet-based CBT-based programs in FM (e.g., Williams et al; 2010) may be more accessible, but these interventions are still potentially burdensome as they involve learning multiple cognitive and behavioral skills. The potentially negative impact of high subject burden in fibromyalgia patients was suggested by the findings of a recent controlled study (Solberg et al; 2010) which found that fibromyalgia patients showed significantly less capacity to persist on consecutive tasks in comparison to healthy controls. In sum, pain and related limitations in FM continue to pose a significant unmet medical need for millions of patients.10 New intervention. As developed by the applicant (Friedberg, 2001), the proposed symptom management intervention of BSD is a rapidly acting, low cost and entirely home-based approach to pain management that offers hope and help to patients with FM. Its advantage over cognitive behavior therapy (CBT; e.g., Friedberg et al; 2012) is based on its brevity (5-10 min. at home vs. 45 min. in-person visits), its entirely self-administered protocol, and its potentially greater efficacy for pain reduction and management. The intervention is derived from EMDR (eye movement desensitization and reprocessing) which encompasses an 8 stage psychotherapeutic protocol (Shapiro, 1995). Seven literature reviews21-27(listed by number in references) concluded that EMDR showed efficacy for post-traumatic stress disorder (PTSD), its main application. In contrast to the standard EMDR protocol for PTSD which involves evocation of traumatic memories by trained therapists in face-to-face visits (Shapiro, 1995), BSD is a re-purposed, reformulated, and downsized intervention technique that focuses on management of specific symptoms (Friedberg, 2001; 2004). The field of pain treatment will be significantly enhanced if the new BSD symptom management protocol is effective because it offers a technique that is easy-to-use, minimal risk, and much more accessible for fibromyalgia patients in (and out) of medical care in comparison to standard behavioral interventions.Biobehavioral mechanisms. Scientific knowledge of biobehavioral mechanisms and mediators of BSD-based symptom management and its therapeutic effects on FM will also be advanced in this proposal. As a proposed variant of systematic desensitization (Tallis et al; 1994), BSD uses dual attention bilateral stimulation (i.e., alternating sounds or hand taps) in combination with brief pain exposures (Friedberg, 2001, 2004). In this proposal, such dual attention sensory stimulation, if focused on pain, is hypothesized to trigger pain-incompatible responses (i.e., relaxation, distraction, cognitive change; see Feasibility Studies below) and associated autonomic de-arousal that desensitizes the impact of pain-related sensations in FM (Friedberg, 2001; 2004). The consequent psychophysiological de-arousal facilitates the integration of corrective information about the meaning of pain symptoms and responses (Hekmat et al; 1994) resulting in reduced levels of sensory pain and pain perception (i.e., catastrophizing). Supportive studies using bilateral stimulation procedures in trauma patients (Elofsson et al; 2008; Wilson et al; 1996) have found post-stimulation physiological evidence for autonomic de-arousal including decreased heart rate, reduced skin conductance, and increased finger temperature. Furthermore, a non-clinical controlled study (Barrowcliff et al; 2003) found that physiological arousal caused by white noise and measured with skin conductance was significantly reduced with bilateral stimulation techniques in comparison to a control condition. These findings suggest rapid within-session autonomic de-arousal during BSD consistent with a desensitization model that is potentially applicable to pain in patients with FM.Mediation via autonomic de-arousal. To assess autonomic de-arousal, we will incorporate the measure of heart rate variability (HRV) utilizing a research-grade multifunction wristwatch monitor with data storage capability (eMotion Faros 360; three channel ECG; MegaElectronics, Kuopio, Finland). HRV has been utilized in research studies as a surrogate measure of central autonomic influences (Petzke and Clauw, 2000). Fluctuations over time in the interval between normal heartbeats are mediated by autonomic inputs to the sinus node, and thus provide a window onto the autonomic system. These fluctuations can be quantified and analyzed in either the time or frequency domain (Petzke and Clauw, 2000). High HRV?reflects the magnitude of parasympathetic nervous system (PNS) influence on heart rate associated with breathing, with PNS influence carried to the heart via the vagus nerve. Research suggests that high HRV has a protective effect and is associated with good health (Karemager & Lie, 2000) and well-being (Kemp & Quintana, 2013). In the proposed study, we hypothesize that improved parasympathetic functioning, as indicated by increased HRV, will be a mediator of pain reduction in FM. In support of this hypothesis, a pilot study of a 10-session HRV biofeedback intervention in fibromyalgia (Hassett et al., 2007) found clinically significant decreases in pain and improvement in functioning at 3 month follow-up. Also, HRV increased during biofeedback tasks. Positive HRV effects were immediate which is consistent with data on the relationships among stress, HPA axis activity (the other arm of the stress system in addition to the ANS; Marques et al; 2010) and brain function (e.g., Annerstadt et al., 2013). The immediate HRV effect is also consistent with rapid symptomatic reduction associated with the use of BSD for symptom management. Furthermore, in a recent pilot study (Berry et al., 2014) of a 4-session HRV biofeedback treatment in veterans with chronic pain, the intervention was significantly more effective than a chronic pain control condition in increasing HRV coherence (power in the upper range of the low frequency band) and in reducing perceived pain, stress, and physical activity limitation. It has been suggested that changes in HRV could serve as an objective measure of efficacy for behavioral interventions (Moustafi et al., 2011). Finally, fibromyalgia patients in comparison to arthritis patients and healthy controls have reported significantly higher scores on a validated self-report instrument (COMPASS; Methods) for assessment of autonomic symptoms that provides clinically relevant scores of autonomic symptom severity (Solano et al; 2009). This suggests that autonomic dysfunction may play an important role in the manifestation of FM and potentially in the mediation of treatment effects. Innovation The proposed clinical trial would be the first well-controlled BSD application for symptom management in FM. The study rationale seeks to shift both research and clinical practice paradigms of behavioral treatment that usually involve high costs, multi-session face to face visits with a trained professional and relatively high patient burden. The advantage of BSD over multi-session in-person cognitive-behavior therapy (CBT) [27] for chronic pain conditions such as fibromyalgia is based on its brevity, entirely home-based protocol, and potentially greater efficacy for pain reduction. Furthermore, CBT is time-consuming (6-18 visits; [88]) and not available to many patients [89]. Many communities simply do not have interventionists trained to deliver behavioral symptom management interventions; thus obtaining such care poses a significant and sometimes prohibitive travel burden. Recent internet-based CBT may offer increased accessibility, but these programs for FM remain burdensome as they require learning and scheduling of multiple techniques (e.g., cognitive restructuring, graded exercise, pacing [10]). By comparison, the rapid results and minimal time investment for the stand-alone technique of BSD shows promise to reduce pain and improve pain management without the requirement of learning and carrying out numerous lifestyle changes. Innovation is also shown in this proposal with our new highly usable delivery technology for pain management (25-min. BSD demonstration video and MP3 audio device) that replaces the more burdensome face to face sessions characteristic of behavioral interventions. Our pilot feasibility studies (below) in fibromyalgia provide supporting qualitative data (direct feedback from patients in interviews) for the advantages of home-based BSD for symptom management, including high usability, convenience and self-empowerment to better manage symptoms. Finally, this application proposes a novel and measurable theoretical mechanism of change in which the rapidly acting behavioral technique of BSD triggers pain-incompatible responses (relaxation, distraction, and cognitive change) and associated changes in autonomic cardiovascular function (HRV) that offers an explanatory biobehavioral process to account for reduced pain and improved pain management [9, 31]. ApproachPreliminary studies. The applicant has conducted 3 feasibility studies of BSD management for pain in fibromyalgia. These initial studies were intended to verify putative therapeutic effects of BSD and to adjust clinical protocols to increase compliance, lower dropout rates, and reduce subject burden. Feasibility study #1. This initial BSD study (Friedberg, 2004) in fibromyalgia (N=6) involved 2 face to face treatment sessions, wherein patients were taught by the applicant how to do BSD-based symptom management for home use. The technique was then assigned with log verification for 3 months. At 3 month follow-up, effect sizes for pain reduction were medium to large with 4/6 subjects considered treatment responders. In addition, finger temperature measured in session with a thermal sensor was significantly increased, an indication of autonomic de-arousal and relaxation (Brown, 1977). This pilot study suggested that brief BSD symptom management can be effectively utilized for pain. Feasibility study #2. Given the success of study #1 and our goal of reducing subject burden, the second pilot project eliminated all interventionist contacts and was entirely home-based. During the 3-month study period, participants (N=24) were sent a BSD instructional booklet and a MP3 player to deliver audio-based BSD. Participants also completed paper diaries of symptom ratings and BSD usage. Average compliance with the 2x/day diary was 68%, but post-enrollment dropout was 50% -- reportedly due to time constraints, unforeseen circumstances, and no response. At 3-month follow-up, significant improvements were found for pain severity (p=.02), pain interference with functioning (p=.004) (Brief Pain Inventory-Short Form) and pain magnification (Pain Catastrophizing Scale; p = .025). Representative participant comments (n=12) about the use of BSD included: “now more mindful of pain”; “helps a lot with pain management; “I can be proactive about my pain”. Transient mild side effects were reported by 21% (N=5) of subjects and included: arm pain, restless legs and jittery feelings. No subject reported dropping out due to side effects. Qual. feedbackFeasibility study #3. Based on a power analysis of study #2, 29 subjects were recruited and randomized to an active BSD condition or wait list control condition utilizing a crossover design.With the intention of reducing attrition in study #3, participant feedback from study #2 resulted in these adjustments: (1) a user-friendly BSD demonstration video was provided to all subjects and (2) 2x/day paper diaries were replaced by convenient 1x/day online web diaries. Five participants (17.2%) dropped out after enrollment. Completers vs. dropouts did not differ significantly on any baseline demographic variable. No significant differences on baseline outcome variables were found between conditions, with the exception of the pain catastrophizing scale (PCS) and the PCS magnification subscale which showed higher scores in the BSD condition (p = .04 and p = .007, respectively). The BSD condition evidenced significant reductions on the Pain Catastrophizing Scale (PCS, (t (24) = -2.24, p = .03; d = .88) and the PCS rumination subscale (t (24) = -2.71, p = .01; d = 1.07) from baseline to three-month follow-up, in comparison to the wait-list control condition. Within the BSD condition, there was a significant reduction in PCS rumination subscale (F (1, 24) = 8.43; p = .008; d = .46) and a near-significant reduction on the full PCS (F (1, 24) = 4.15; p = .053; d = .36).? Reductions in pain intensity on the BPI-SF were not significant (p=.09); however, the effect size was large (d=.94). Significant improvements were also found on numerical ratings (0-10) for self-reported pain, fatigue, and stress ratings (all p’s < .02) in the BSD condition. Conclusion: These 3 feasibility studies represent the deliberative, methodical development (Rouansville et al; 2001) of a new home-based symptom management intervention that shows potential to reduce pain and pain-related catastrophizing in patients with FM. Methods The proposed design (Figure 1) is a randomized controlled clinical trial that compares 3 conditions: (1) the feasibility-tested BSD symptom management protocol; (2) an attention control group of “symptom monitoring”; and (3) a usual care control condition. The 2 control groups are intended to control for (i) participants’ time spent doing the active intervention (attention control) and (ii) passage of time during the study period (usual care) (Friedberg et al; 2013). The study sequence begins with a recruitment effort utilizing medical records from a large primary care practice (support letters attached) that identifies patients with a diagnosis of FM, all of whom will be sent a letter signed by the PI and practice medical director inviting them to participate in the study. In addition, recruitment will involve internet advertising to FM patient organizations (e.g., FM Aware, ProHealth), contacting FM support groups, and presentations to primary care physicians at Stony Brook University Medical Center. These recruitment methods were used successfully in the PI’s completed behavioral self-management study (Friedberg et al; 2013) in chronic fatigue patients (2/3 of subjects obtained from the family medicine patient database; 1/3 from ads/referrals). Based on these recruitment patterns, roughly 50% of prospective FM patients would be screened into the study (10/20 month), and 50% of those would agree to participate (5/month; i.e., 5 subjects x 23 months recruitment = 115). To achieve an endpoint sample of 30 participants/ group based on power calculation (below), the baseline enrollment target will be 115 which assumes 20% post-enrollment attrition (56, 57). Thus, recruitment targets are expected to be easily met.For prospective subjects who express interest in the study, eligibility will be confirmed in a brief (Appendix 2) initial phone interview conducted by the nurse clinician/scientist (58) to screen subjects for (1) access to a home computer with internet (95.6% of potential subjects in the PI’s prior chronic fatigue study had a home computer); (2) screening for a confirmatory (or putative) diagnosis of FM in accordance with ACR symptom criteria (2010; Appendix); and (3) assessment for exclusion criteria (Human Subjects and Appendix) including psychosis or substance abuse in the two years prior to evaluation (58). Patients are also excluded if: (a) receiving antidepressant drugs (unless dose-stabilized for at least three months); b) at risk of suicide or in need of urgent psychiatric treatment. Appropriate medical and psychiatric referrals will be given as needed. In addition to subjects who have a diagnosis of FM on their medical record, we will request from subjects not recruited through their medical records a written diagnosis of FM from their physician. Participants that screen in with FM symptoms (e.g., clinically significant widespread pain) will have this assessment confirmed with validated self-report measures of pain (Widespread Pain Index; below). Following fully informed and documented written consent from participants, the baseline assessment will be completed, which includes mailed questionnaires, online web diaries, and HRV physiological monitoring, all fully explained in written and verbal instructions. Subjects will then be assigned by the statistician to one of the three study conditions via a computer-generated blocked randomization schedule (obtained before enrollment of the first participant). This will be followed by a 90 day period of home-based implementation of the BSD condition and the symptom monitoring attention control condition with daily web diary verification (assessments only for usual care control condition). Participants who begin a new non-study treatment (60, 61) (Treatment Questionnaire; Appendix 2) after enrollment will be included in the overall data analysis if neither baseline nor outcome assessments show significant differences. -266701-561975 Follow-Up Allocation Enrollment00 Follow-Up Allocation Enrollment2149475-63500Potential participantsassessed for eligibility 00Potential participantsassessed for eligibility 4486275514350Excluded (n = )Declined (n = )00Excluded (n = )Declined (n = )29527507715250029432251369400903605249555003486150249555002357120155575Randomized00Randomized221805543916603-Month Follow-Upassessment (n =25)003-Month Follow-Upassessment (n =25)293370031476950022180552792095Post-treatment assessment (n = )00Post-treatment assessment (n = )29337001548130002943225552450020383506350 33 allocated to Attention Control00 33 allocated to Attention Control2952756350 34 Allocated to EMDR00 34 Allocated to EMDR40633656350 33 Allocated to Usual Care control00 33 Allocated to Usual Care control488124525527000982345255270004198620207010Post-treatment assessment (n = )00Post-treatment assessment (n = )224790207010Post-treatment assessment (n = )00Post-treatment assessment (n = )4890770239395009918702393950041167051911353-Month Follow-Upassessment (n =25)003-Month Follow-Upassessment (n =25)2247901911353-Month Follow-Upassessment (n = 25003-Month Follow-Upassessment (n = 25Figure 1. BSD Self-management Study Flow ChartStudy variables Table 1. Questionnaires/diary assessments MeasuresDomainBaseline AssessmentsWidespread Pain Indexmusculoskelatal painFatigue Scalephysical and mental fatigue Short Form-36 Physical Function subscale (SF-36PF)physical functioning Beck Anxiety Index (BAI)anxietyComposite Autonomic Symptom Score 31 (COMPASS)autonomic symptoms Primary Outcome MeasureBrief Pain Inventory-Short Formpain intensity and interferenceSecondary Outcome MeasuresThe Pain Catastrophizing Scale (PCS)catastrophic thinking AnxietyAutonomic functioningBiobehavioral MediationHeart rate variability Web diaryAutonomic functioning behavioral changeComplianceWeb diary in vivo symptom ratings/BSD usageProgram Feasibility/SatisfactionTelephone feedbackprogram usabilityClient Satisfaction Questionnaire (CSQ)satisfaction with programBaseline assessmentsWidespread Pain Index (Appendix). The WPI is a brief validated self-report measure of chronic widespread pain that may be used in the diagnosis of fibromyalgia (Wolfe et al; 2010). The cutoff score for clinically significant widespread pain is a score of 7 or higher. Prospective subjects will be required to meet this threshold score for study eligibility.Fatigue Scale(Appendix). The 11-item fatigue scale contains the factorially distinct dimensions of mental and physical fatigue (Wessely & Powell, 1989; Chalder et al., 1993). The fatigue scale has been validated in chronic fatigue syndrome and medical outpatients and shows adequate internal consistency (Chalder et al., 1993). Fatigue is a common symptom in FM (Vincent et al; 2013) and therefore will be evaluated to obtain a more complete assessment of somatic symptoms in this illness. Short Form-36 Physical Function subscale (SF-36PF; appendix)). To ascertain physical functioning in relation to health status at baseline, the SF-36PF will be used. Limitations of ill health are measured on a scale of 0 (limited in all activities, including basic self-care) to 100 (no limitations, able to carry out vigorous activities). Test construction studies for the SF-36 (25, 26) have shown high internal consistency for the physical function subscale (α =.91-.94) and substantial differences in scores between patient and non-patient posite Autonomic Symptom Score 31 (COMPASS 31; Sletten et al; 2012; Appendix). This is a 31 item self-report instrument, concise and statistically robust, intended to assess autonomic symptoms and provide clinically relevant scores of autonomic symptom severity. Fibromyalgia patients in comparison to arthritis patients and healthy controls reported significantly higher scores on the COMPASS (Solano et al; 2009). Several independent groups of investigators have shown that fibromyalgia patients evidence heart rate variability changes consistent with sympathetic hyperactivity (Solano et al; 2014). The COMPASS measure is expected to confirm high levels of autonomic symptoms in our cohort consistent with identified autonomic dysfunction in fibromyalgia (Reyes del Paso et al; 2010). Primary outcome measureBrief Pain Inventory-Short Form (BPI-SF): This is a validated 9 item self-administered questionnaire used to evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The patient is asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a 10 point scale (Cleeland, 1989). The BPI-SF has been found to be sensitive to treatment change in published studies in FM (Arnold et al; 2010; Jones et al; 2012; Kroenke et al; 2009) and in our pilot BSD studies.Secondary Outcome MeasuresPain Catastrophizing Scale (PCS). The PCS (Sullivan et al; 1995) is a 13-item instrument that evaluates catastrophic thinking, a cognitive-affective process, in the dimensions of rumination, magnification, and helplessness, in relation to pain. The PCS has demonstrated high internal consistency (Cronbach’s α = 0.91), and high test-retest reliability over a 6 week period (r = 0.75; Thorn et al; 1995). Construct validity of the PCS has been demonstrated both in experimental cold pressor studies (Thorn et al; 1995) and in clinical patient samples undergoing painful procedures. The PCS has also shown sensitivity to treatment change (Thorn et al; 2007). The PCS outcome data in our pilot study in fibromyalgia showed a significant positive response to the BSD intervention. The literature on catastrophizing provides strong evidence that catastrophizing shapes emotional, functional and physiological responses to pain (Quartana et al; 2009) and that its amelioration contributes to the effectiveness of behavioral pain treatments (99,100).Beck Anxiety Inventory (BAI). The BAI is a 21-item self-report measure of anxiety and psychological distress with high internal consistency (a = .92) and established and replicated construct validity (Hewitt et al; 1993; Steer et al; 1995). Short-term behavioral intervention for FM in routine care has shown efficacy in reducing anxiety (Vazquez-Rivera et al; 2009). This assessment of psychological distress may also be associated with HRV (Moustafi et al., 2011), a measure of autonomic functioning that is proposed to play a role in mediating clinical change. Heart Rate Variability (HRV). To assess autonomic de-arousal, we will measure HRV utilizing a research-grade multifunction wristwatch monitor with data storage capability (eMotion Faros 360; three channel ECG; MegaElectronics, Kuopio, Finland). The HRV measure uses a convenient three lead ECG (one sensor on left and right collar bone, one sensor on left hip) instead of a chest strap. This model calculates respiration via either the built in accelerometer or via algorithm analyzing the ECG signal, a preferable way to control for respiration. Our expectation is that the HRV measure will show a therapeutic improvement associated with self-report outcomes of reduced pain. Improvements (i.e., increases) in HRV have been associated with pain reduction in chronic pain conditions (Hassett et al; 2007; Berry et al; 2014). Also a recent study (Reyes del Paso et al; 2010). of FM patients in comparison to healthy subjects found a link between autonomic cardiovascular regulation and pain ratings suggesting autonomic dysfunction in FM. Specifically, FM patients showed lower power in the High Frequency, Low Frequency, and very-low frequency bands of the HRV spectrum, as well as in total HRV, indicating overall decreased autonomic control of heart rate. For all study conditions, a wristwatch device will be worn by participants at home while sitting in a comfortable chair for 10 minutes ( Hassett et al; 2007; Berry et al; 2014)?in the evening preferably between 7-9pm. HRV data will be collected at these timepoints: ?the first day of resting baseline, the first day of treatment termination, and the first day of the 3- and 12-month follow-ups. These time points are intended to be representative of the intervention period while limiting participant burden. Measures for Biobehavioral Mediation Model stopOur biobehavioral mediation model will test the influences of BSD on pain reduction as mediated by an autonomic indicator (HRV) and behavioral processes (relaxation, distraction, and cognitive change). Biological measure: Heart Rate Variability (HRV). Specific Aim 2, Hypothesis 1, is intended to determine if autonomic influences, as measured with HRV, mediate the relationship between the use of BSD and pain reduction (Hassett et al; 2007; Berry et al; 2014). For the BSD condition only, the HRV wristwatch measure will be worn before (10 min.), during and after (10 min) the BSD procedures at three time points during the intervention: initiation (week 1), midpoint (week 6), and termination (week 12). (HRV measurement details above.) These time points are intended to be representative of the intervention period while limiting participant burden.Behavioral measure: Self-report ratings. Specific Aim 2, Hypothesis 2, proposes that the effects of BSD on pain reduction will be mediated by elevated ratings for distraction, relaxation, and cognitive change as assessed with self-report measures. Specifically participants in the BSD condition will rate in the online diary at the end of the day to what extent they experienced the following hypothesized changes during BSD (Friedberg, 2001) on these items: Distraction: “I couldn’t think about the problem I was focusing on” (0-10); Relaxation: “I felt more relaxed during the BSD procedure “(0-10); and cognitive change: “I felt better able to cope with the pain (or other stress) that I was focusing on” (0-10). These ratings will be made at three time points during the intervention: initiation (week 1), midpoint (week 6), and termination (week 12). These time points are intended to be representative of the intervention period while limiting participant burden.Process measure: Web diaryThe online web diary will inform the progress of the intervention through daily assessment of symptoms and BSD usage.All study conditions. For each one week assessment (baseline; treatment termination, 3- and 12-month follow-ups), a time-stamped web diary (Science Trax; Macon, Georgia) will track average symptom and stress ratings (0-10 numerical rating scale) at the end of the day. For ratings of pain, pain interference, and stress, response-activated screens will be displayed, each with a numerical rating scale (0-10). The end point anchors on the numerical scales will be None (0) and Highest (10). BSD and attention control conditions only. Daily symptom and stress ratings will be scheduled for the entire 3-month intervention period. BSD condition only. To assess BSD technique(s) used and compliance with BSD assignments, participants will record at the end of the day: (1) the type of pain used as a BSD target (e.g., neck pain), (2) the BSD technique(s) used; and (3) behavioral mediation ratings (for distraction, relaxation, and cognitive change (above)). The PI successfully designed 90-day web diaries in 2 recent CFS behavioral intervention studies (Friedberg et al; 2013; Friedberg, 2014) to record homework assignments and symptom levels. Assessment of Program Feasibility/Satisfaction Program feasibility will be examined with telephone feedback interviews to participants and the Client Satisfaction Questionnaire.Feasibility assessment Participant Feedback by Telephone. To further refine the usability of BSD from our initial feasibility studies and assess any problems with program implementation (both BSD and symptom monitoring conditions), two 15 minute phone conferences (at the end of weeks 1 and 12) will be held with each participant individually. Problems will be documented and if necessary program revisions made. The feedback sessions ask subjects questions about comprehension, interest, relevance, and credibility (62) (Appendix 3) using five point Likert scale ratings (Shegog et al., 2013). Open-ended participant responses to these items (e.g., what makes the program credible?) will then be collected as qualitative data. Client Satisfaction Questionnaire (CSQ). The CSQ, a validated 8 item instrument designed to assess client satisfaction for human service programs,63 will be administered at the 3-month post-intervention assessment. The Client Satisfaction Questionnaire (CSQ-8) assesses global client satisfaction with treatments [34]. The 8-item self-report questionnaire uses scale response options from 1 to 4, with total score ranges from 8 to 32. Previous research has reported that the CSQ-8 has high internal consistency [35] and was comparable to the Cronbach alpha in this study (Cronbach alpha=.90). The CSQ has been used to assess participants satisfaction with internet-based cognitive behavior therapy for deprssion (Donkers et al; 2013) and telephone delivery of psychiatric care (Donke et al; 2002). Based on the above described telephone feedback and the Client Satisfaction Questionnaire, the PI and the nurse scientist will jointly assess if receipt of treatment is successful.Procedure The study sequence (Figure 3) will involve an initial phone screening by the project director (nurse clinician/scientist) followed by participant completion and return of: the consent form, baseline questionnaires, and the HRV monitoring wristwatch device (part of baseline assessment). One week baseline online symptom diaries are also completed by all subjects. Then group assignments will be made, followed by sending out BSD pain self-management packages and the HRV wristwatch (for mediation assessment) to the intervention group only. Following the 3 month intervention period, subjects in all three groups complete and return the 3- and 12-month follow-up assessments including: questionnaires, one week web diaries, and HRV monitoring data/wristwatches. For both BSD and symptom monitoring conditions, two 15 minute phone conferences to assess feasibility/usability will be held with each participant at the end of weeks 1 and 12. Data analysis will then be completed. Recruitment/Enrollment Baseline/Intervention 3- and 12-Month Follow-Up 221996048260-1 week baseline (questionnaires, web diaries, HRV wristwatch)-90 day treatment/HRV/ web diary- 90 day control conditions- Web diaries/HRV monitoring 00-1 week baseline (questionnaires, web diaries, HRV wristwatch)-90 day treatment/HRV/ web diary- 90 day control conditions- Web diaries/HRV monitoring 448453638844- 1 week web diaries /HRV wristwatch-Mailed standard questionnaires __________________________Feedback phone calls: weeks 1 and 12, treatment and attention control only00- 1 week web diaries /HRV wristwatch-Mailed standard questionnaires __________________________Feedback phone calls: weeks 1 and 12, treatment and attention control only038845-Recruitment efforts-Phone screening-Referral into study-Mailed standard questionnaires/consent form/HRV wristwatches(N = 100)00-Recruitment efforts-Phone screening-Referral into study-Mailed standard questionnaires/consent form/HRV wristwatches(N = 100)427780226910200186055029337000 Figure 2. Study Timetable Human subjects: after trial, control subjects offered the BSDStatistical Plan and Data Analysis; recruited=115 at baseline. Sample size consideration: Jie; This randomized phase II study has three arms: BSD intervention group, attention control group and usual care control group. Participants will be randomized at a 1:1:1 ratio to these three arms. Block randomization with randomly chosen block sizes of 6, 9 and 12 will be used to generate the randomization sequence. All subjects that are randomized will be included in the intent-to-treat analysis. 33-34 subjects will be enrolled to each of the 3 arms at baseline (total N=100) of which it is anticipated that 75 will complete the study (25% dropout rate). This sample size has 90% power to detect a Cohen’s d of 0.7 (Cohen’s d is defined as the difference between two means divided by a standard deviation of the data) for the change in Brief Pain Inventory-Short Form within each arm using a two-sided paired-t test with Type I error at 0.05. For example, in our previous BSD trial (feasibility study #2), the standard deviation of the change in pain severity score after three months’ intervention was 6.5 and the estimated pain severity score change was 5.13 points drop (N=12). Assuming this study has the same variability, then 25 subjects will allow us to detect a 4.55 points drop with 90% power in the pain severity score after three months’ intervention. The detection power is very similar if a two-sided Wilcoxon’s signed-rank test is used instead. 25 participants in each group also has 80% power to detect a moderate Cohen’s d of 0.6 in the change in scores on the Brief Pain Inventory-Short Form (BPI-SF) between the BSD intervention group and attention control group (or between BSD intervention group and usual care control group) based on a two-sided t-test with Type I error of 0.20 (Both type I and type II error are generally relaxed in a randomized Phase II trial. This sample size allows us to detect a Cohen’s d of 0.9 with 90% power and Type I error at 0.05.). The detection power is boosted to 81% if an F-test based on one-way ANOVA comparing three groups simultaneously is used instead. Furthermore, 25 subjects in the BSD group will achieve 84% power to detect a positive Pearson’s correlation coefficient of 0.5 at a significance level of 0.05. Because of the exploratory? nature of this study, no adjustment for multiple testing problem was implemented in the power estimation and planned in the statistical analysis. Power estimation was carried out using PASS 12.Statistical analysis planStandard descriptive and summary statistics will be used to characterize the overall study population. Graphical methods will be used to examine distributions, identify potential influential points, and guide in data transformations if warranted. To examine associations among various measures, scatterplots and grouped boxplots will be produced to examine assumptions of linearity, symmetry, and homoscedascity. Specific aim 1. Efficacy of BSD pain management. The efficacy of BSD in participants with FM will be tested using two sided paired-t test or Wilcoxon’s signed rank test if the normality assumption is not met. One-way ANOVA will be used to compare the change in pain (BPI-SF) among the three groups. If the null hypothesis that three group means are equal is rejected, Dunnett’s procedure will be further used to compare the BSD group to each of other two control groups. All assumptions such as normality and linearity will be assessed, and data transformation may be needed to meet these assumptions. If the model assumption cannot be met, Kruskal-Wallis test will be used to compare three groups and Wilcoxon’s rank sum test will be used to further test the difference between the BSD group and any control group. Clinically significant reductions in pain will also be calculated. To assess clinically significant change (Ogles, 1992; Speer et al; 2001) for pain reduction, a patient will be considered clinically improved if his/her 3- and 12-month follow-up post-treatment score is more than two standard deviations below the pre-treatment sample mean on the Brief Pain Inventory-Short Form, the primary outcome measure for pain. Specific Aim 2. Mediational Analysis. To prospectively test the biobehavioral mediational model for the effects of BSD pain management in patients with FM, the analysis plan is as follows: In the initial analysis, pair-wise bivariate correlations will be calculated between pain, treatment assignment and heart rate variability (HRV). HRV mediation of BSD effects on pain and the adjusted effect of BSD change after controlling for HRV will be tested with a series of regression analyses. Due to the limited sample size the Preacher & Hayes Bootstrap method will be used to assess if there is a significant HRV mediation effect. A similar analysis will be performed to examine the mediation effect of self-reported changes in relaxation, distraction, and cognitive change as assessed in the daily web diary. Specific Aim 3. Compliance and outcomes. The correlation between the change in pain in BSD group and compliance rate will be assessed through Pearson’s correlation coefficient or Spearman’s rank correlation coefficient if normality assumption is violated. Due to the small sample size, Wilcoxon’s rank sum test will be used to compare the pain change between these participants and the rest who cannot successfully use any EMDR techniques.Specific Aim 3. To assess compliance with weekly assignments and its relation to implementation of BSD-related symptom management skills. Hypothesis 1: Online web diary compliance rates (50% average rate of daily completion per subject anticipated) will be sufficient to assess symptom ratings and their weekly patterns, and usage of specific BSD techniques over the three month intervention period. Compliance will be associated with improved outcomes, i.e., BSD dose-response relationships will be tested. Hypothesis 2: Success of specific BSD techniques will be confirmed with web diary data and in phone interviews with each participant. Phone interviews will elicit participant preferences and feedback that will further refine the delivery of the intervention to increase compliance and better target fibromyalgia symptoms. Exploratory aim. Effect sizes. Effect sizes for the clinical outcomes of pain (BPI-SF) change in the BSD group will be estimated. We will explore the relationship between the change in pain scores and clinical and demographical factors such as baseline pain, gender, age and so on. Data from all three groups will be pooled in order to get the maximal power. Multiple linear regression models will be used with the change in pain scores as the dependent variable and each factor of interest along with treatment assignment as the covariates. Due to limited sample size and the exploratory nature of the analysis, this model may not consider all of the significant factors simultaneously. All assumptions such as normality and linearity will be assessed, and data transformation may be needed to meet these assumptions. The analysis results in this exploratory aim will be valuable in guiding further design of a larger confirmatory phase III trial. All statistical analysis will be performed using SAS 9.3 (SAS Institute Inc., Cary, NC).Potential challenges and alternative strategies Placebo effects. New intervention techniques, in particular, carry the potential to produce strong placebo responses which may obscure treatment efficacy (Hrobjartsson A. Gotzsche,2010). To effectively address this type of confounding, we are incorporating two control conditions, one to control for participant attention involved in the active treatment condition (symptom monitoring attention control) and the second condition to control for passage of time, i.e., no treatment usual care condition. A previous behavioral self-management trial in unexplained chronic fatigue (Friedberg et al; 2013) conducted by the applicant using these two control conditions showed clear superiority of active treatment vs. active and inactive control conditions. Subject burden. The keeping of daily web diaries and physiological monitoring (HRV) during multiple assessment periods may engender challenges to participant compliance and retention. Our experience with daily web diaries and the wearing of actigraphs on the beltline or wrist for one week intervals in two previous self-management trials in unexplained chronic fatigue and chronic fatigue syndrome (Friedberg et al; 2013; Friedberg et al; , 2014) has shown compliance levels averaging just under 70% for 90 day web diaries and about 50% for wearing actigraphs. Given a somewhat lower burden in the proposed study, i.e., 90 day web diary and wristwatch heart rate monitor (worn for 4-5 hours in total over 90 days), we conservatively estimate 50% daily compliance for both the heart rate monitor and for daily diary data entry which is adequate for analysis of symptom patterns, BSD usage, and HRV analysis. In addition, participant retention in the entirely home-based previous trial was a high 92.7% at the 12-month follow-up (Friedberg, 2014). Heart rate variability (HRV) measurement issues. 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Deverill, The estimation of a preference-based measure of health from the SF-36, Journal of Health Economics 21 (2002), pp. 271–292. 4440803199583For each assessment period:- 1 week web diaries /HRV watch-Mailed standard questionnaires ____________________________Feedback phone calls: weeks 1, 6, 12, and 1200For each assessment period:- 1 week web diaries /HRV watch-Mailed standard questionnaires ____________________________Feedback phone calls: weeks 1, 6, 12, and 12-43815199390-Recruitment efforts-Phone screening-Referral into study-Mailed standard questionnaires/consent form(N = 100)00-Recruitment efforts-Phone screening-Referral into study-Mailed standard questionnaires/consent form(N = 100)2150828199583-1 week baseline (web diaries/HRV wristwatch)-90 day self-EMDR/HRV msmt.- 90 day control conditions-EMDR & trl: web diaries 00-1 week baseline (web diaries/HRV wristwatch)-90 day self-EMDR/HRV msmt.- 90 day control conditions-EMDR & trl: web diaries Recruitment/Enrollment Baseline/Intervention Post-Tx and 3-Month Follow-Up 179177728003500410019525654000Figure 2. Study Timetable Reyes del Paso GA, Garrido S, Pulgar A, Martin-Vasquez M, Duschek S. Aberrances in autonomic cardiovascular regulation in fibromyalgia syndrome and their relevance for clinical pain reports. Psychosom MED, 2010; 72: 462-70.99. George SZ, Zeppieri J, Cere AL, et al. A randomized trial of behavioral physical therapy interventionsfor acute and sub-acute low back pain (NCT00373867). Pain 2008;140(1):145–157. [PubMed:18786762]100??. Smeets RJ, Vlaeyen JW, Kester AD, Knottnerus JA. Reduction of pain catastrophizing mediatesthe outcome of both physical and cognitive–behavioral treatment in chronic low back pain. J Pain2006;7(4):261–271. [PubMed: 16618470]Provides evidence that reductions in pain catastrophizingmediate pain-related outcomes for cognitive–behavioral as well as physical rehabilitationinterventions. Studies of this sort have potential to shed sufficient versus necessary treatment factorsrequired to change pain catastrophizingPain catastrophizing: a critical reviewPJ Quartana, CM Campbell, RR EdwardsInforma Healthcare 9 (5), 745-758Nurse practitioners can effectively deliver pain coping skills training to osteoarthritis patients with chronic pain: A randomized, controlled trial. Broderick JE; Keefe FJ; Bruckenthal P; Junghaenel DU; Schneider S; Schwartz JE; Kaell AT; Caldwell DS; McKee D; Reed S; Gould E. Pain. 155(9):1743-54, 2014 Sep. Brief cognitive-behavioral therapy with fibromyalgia patients in routine care. Vazquez-Rivera S; Gonzalez-Blanch C; Rodriguez-Moya L; Moron D; Gonzalez-Vives S; Carrasco JL. Comprehensive Psychiatry. 50(6):517-25, 2009 Nov-Dec. Physiological correlates of eye movement desensitization and reprocessing. Elofsson UO; von Scheele B; Theorell T; Sondergaard HP. Journal of Anxiety Disorders. 22(4):622-34, 2008 May. Barrowcliff, A. L., Gray, N. S., MacCulloch, S., Freeman, T. C. A., MacCulloch, M. J. (2003). Horizontalrhythmical eye movements consistently diminish the arousal provoked by auditory stimuli. BritishJournal of Clinical Psychology. 42, 89-302.Brown BB. Stress and the art of biofeedback. New York:Harper & Row; 1977. p. 188.Beyond pain in fibromyalgia: insights into the symptom of fatigue. [Review] Vincent A; Benzo RP; Whipple MO; McAllister SJ; Erwin PJ; Saligan LN. Arthritis Research & Therapy. 15(6):221, 2013. randomized controlled trial of 8-form Tai chi improves symptoms and functional mobility in fibromyalgia patients. Jones KD; Sherman CA; Mist SD; Carson JW; Bennett RM; Li F. Clinical Rheumatology. 31(8):1205-14, 2012 Aug.Flexible dosed duloxetine in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial. Arnold LM; Clauw D; Wang F; Ahl J; Gaynor PJ; Wohlreich MM. Journal of Rheumatology. 37(12):2578-86, 2010 Dec. Internet-delivered interpersonal psychotherapy versus internet-delivered cognitive behavioral therapy for adults with depressive symptoms: randomized controlled noninferiority trial. Donker T; Bennett K; Bennett A; Mackinnon A; van Straten A; Cuijpers P; Christensen H; Griffiths KM. Journal of Medical Internet Research. 15(5):e82, 2013. [Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't] UI: 23669884 Authors Full NameDonker, Tara; Bennett, Kylie; Bennett, Anthony; Mackinnon, Andrew; van Straten, Annemieke; Cuijpers, Pim; Christensen, Helen; Griffiths, Kathleen M. HYPERLINK "" Abstract Reference HYPERLINK "" Complete Reference HYPERLINK "" Full Text?My Projects Annotate 2. Client satisfaction in a feasibility study comparing face-to-face interviews with telepsychiatry. Bishop JE; O'Reilly RL; Maddox K; Hutchinson LJ. Journal of Telemedicine & Telecare. 8(4):217-21, 2002. [Clinical Trial. Comparative Study. Journal Article. Randomized Nguyen TD, Attkisson CC, Stegner BL. Assessment of patient satisfaction: development and refinement of a service evaluation questionnaire. Eval Program Plann 1983;6(3-4):299-313. [Medline]35. Attkisson CC, Zwick R. The client satisfaction questionnaire. Psychometric properties and correlations with service utilization and psychotherapy outcome. Eval Program Plann 1982;5(3):233-237. [Medline]Evaluation of stress systems by applying noninvasive methodologies: measurements of neuroimmune biomarkers in the sweat, heart rate variability and salivary cortisol. [Review] [9 refs][Erratum appears in Neuroimmunomodulation. 2010;17(6):395] Marques AH; Silverman MN; Sternberg EM. Neuroimmunomodulation. 17(3):205-8, 2010. ................
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