Chronic Musculoskeletal Pain, Mild or Moderate Traumatic Brain Injury, Posttraumatic Stress Disorder (PTSD)
Conditions
Brief summary
The wars in Iraq and Afghanistan are creating a new generation of Veterans, including an increasing number of women Veterans, who present with comorbid PTSD and chronic pain conditions from recent deployment-related physical injuries and exposure to psychological trauma. Health behavior change has become increasingly important in treating these conditions and proactively preventing long-term negative health sequelae, in order to benefit these Veterans directly and reduce the growing challenges to the healthcare system. The proposed CDA-2 program of research will use an innovative translational research approach to study whether a chronic progressive -based exercise program will reduce chronic pain symptoms in patients with varying degrees of PTSD symptom severity and to elucidate and modify potential PTSD-related deficiencies in neurobiological and psychological responses to exercise to optimize the physical and psychological benefits of exercise for these individuals.
Detailed description
Due to the COVID-19 pandemic, and after consultation with the appropriate research oversight, all study procedures are temporarily suspended as of 3/15/20. This study will explicitly examine the effects of a 12-week progressive exercise training program on 1) the clinical symptoms of chronic pain and varying degrees of PTSD symptom severity, 2) anti-stress, anti-nociceptive neurohormones such as allopregnanolone + pregnanolone (ALLO +PA) in Veterans with trauma exposure, chronic pain and varying degrees of PTSD symptom severity. The revised study design includes a baseline cardiopulmonary exercise assessment (CPX) that will inform the exercise prescription for a 12-week progressive exercise training program, comprised of three 30-45 minute exercise sessions per week (walking or running, depending on the ability/capacity of the participant). Exercise sessions will be initially supervised by an exercise physiologist in the Clinical Studies Unit (CSU) at the VA Boston Healthcare System and then each participant will transition into the home. Intermittent telephone calls by the PI will provide additional motivational support and assistance with problem solving. Implementation of the prescribed exercise regimen will also be supported by the use of heart rate and actigraph monitors programmed for the participant to achieve their prescribed heart rate range (HRR). Finally, an endpoint maximum load exercise assessment will occur at week 13 in order to track measurable change for both psychological and neurobiological factors and to delineate their impact on pain indices and PTSD symptomatology. Both maximum load exercise tests will be performed in accordance with guidelines published by the American College of Cardiology. Measures of pain symptomatology will be implemented 30 minutes before and 30 minutes after exercise testing at baseline and endpoint. It is anticipated that differences in biological responses to aerobic and anaerobic exercise as illustrated by variability among the participants, with varying degrees of PTSD symptom severity, will predict differences in the psychological and pain-reducing benefits of aerobic and anaerobic exercise. Once identified, such factors could be augmented by modification of the exercise regimen in order to help enhance the ant-stress hormone levels for the pain/PTSD population and experience clinically significant reductions in their symptoms. In order to obtain sufficient power, the proposed recruitment is 23 participants. Data from this pilot work will be used to compute effect sizes in support of a future clinical trial incorporating individually prescribed exercise regimens and a motivationally based exercise behavior change intervention aimed at reducing pain and PTSD symptoms in our Veterans. Advanced education and training is sought by this CDA-2 award applicant in four broad areas: 1) psychophysiology of chronic pain and PTSD with a sub-focus on sex differences, 2) the neurobiology of chronic stress, PTSD, and pain, 3) exercise physiology and 4) the neuropsychology and neurobiology of traumatic brain injury (TBI). The combination of didactic and experiential training in these areas will serve the PI's long-term goal of becoming an independent scientist/practitioner in the VA focused on development of improved treatments for health conditions co-morbid with PTSD such as chronic pain and mild to moderate TBI. In the shorter-term, this CDA-2 will allow the PI to develop a more effective, motivationally based, exercise behavior change protocol that fosters long-term exercise compliance in patients with trauma-exposure, chronic pain and varying degrees of PTSD symptom severity.. This intervention will be used as an adjunct to cognitive interventions for these disorders to be further developed and studied via a larger VA, NIH, or DOD-funded grant for which the PI will apply in years 4-5 of the CDA2.
Interventions
BEHAVIORALExercise Testing and Training
The study group will perform a baseline maximum load exercise test which will inform the individualized exercise prescription for the participant. Based on a progressive methodology, the participant will engage in 12 weeks of exercise of their choice (walking, running, cycling or swimming) with the goal of working towards a maximum heart rate range of 80% between weeks 6 and 12 of the study.
Sponsors
VA Office of Research and Development
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study includes one group: Trauma-exposed participants suffering from both chronic musculoskeletal pain and varying degrees of PTSD severity. Those who meet diagnostic criteria for Chronic pain and have any symptoms of PTSD will be assigned to that group.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Only Veteran and civilian participants in whom a physical examination, medical history, EKG, and baseline laboratory studies including urine toxicology screens indicate that maximum load exercise testing will be safe will be included in this study. * Participants must be free of medications and other substances, (e.g., illicit drugs and alcohol) with effects that could hinder data interpretation for 2-6 weeks depending on the medication and frequency of use (which must be cleared by the PI's primary mentor). * If on pain medications with short half-lives, must be off of them for 5 half-lives before testing, generally about 24 hours. * Any participant with an ICD9 chronic pain diagnosis, with a musculoskeletal etiology, as confirmed by the study rehab medicine doctor, will be allowed for inclusion in the study. * Also, any participant with a confirmed psychiatric diagnosis of PTSD * or have trauma exposure without a diagnosis of PTSD but some symptoms of PTSD, including subthreshold PTSD * other psychiatric conditions * Individuals must meet for current chronic PTSD (\>3 months ) as assessed by the CAPS 1-Month Diagnostic Version.
Exclusion criteria
* Veteran and civilian participants will be excluded from participation in the study if they have: * a life threatening or acute physical illness (e.g., cancer) * current schizophreniform illnesses or bipolar disorder * or active suicidal or homicidal ideation requiring clinical intervention. * Women participants who are pregnant or are intending to become pregnant within the next six months will be excluded from participation. * Individuals with current or past alcohol and/or substance dependence (less than three months from date of screening assessment) will be excluded. * individuals without PTSD who have had greater than one major depressive episode or diagnosis of another serious psychiatric illness in their past, e.g.: * bipolar disorder or a schizophreniform disorder except for Psychosis not otherwise specified due to PTSD-related sensory hallucinations. * Individuals seeking pain treatment such as surgical interventions or who have a neuropathic origin to their pain will also be excluded. * Participants with chronic pain concerns that cannot tolerate exercising in a reclining bike and those who have had a clinical history of coronary artery disease or positive stress test * Uncontrolled cardiac arrhythmia * Moderate-to-severe aortic stenosis * Severe arterial hypertension (systolic \>200 mmHg, diastolic\>110 mm Hg) * More than first degree atrioventricular block also will be excluded from participation. * Finally, participants who screen positive by answering all four items on the TBI assessment, will be excluded from participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline: PTSD Checklist-5 (PCL-5) | Baseline and endpoint (at 13 weeks) | To be administered at: Endpoint Exercise Test Evaluation Session (week 13). The PCL is a 20-item self-report that assesses the extent to which an individual is bothered by each PTSD symptom during the past month using a 5-point Likert-type scale. The PCL-5 is undergoing validation, but the previous PCL based on DSM-IV had good sensitivity (.82) and specificity (.83). Scoring for each item is on a 0-4 scale with higher scores indicating higher symptom severity. A total symptom severity score (range - 0-80) can be obtained by summing the scores for each of the 20 items. Initial research suggests that a PCL-5 cutoff score between 31-33 is indicative of probable PTSD across samples. However, additional research is needed. Evidence for the PCL for DSM-IV suggests that a 5-10 point change represents reliable change (i.e., change not due to chance) and a 10-20 point change represents clinically significant change. |
| Change From Baseline: West Haven-Yale Multidimensional Pain Inventory- Interference Subscale (WHY-MPI) | Baseline and endpoint (at 13 weeks) | The WHY-MPI has been demonstrated to be applicable across a variety of clinical pain conditions. Its brevity, validity/ reliability, self-report nature and ease of scoring make it ideal for both clinical and research purposes. The WHY-MPI is sensitive to change following rehabilitation. Please note only the interference subscale of the WHY-MPI will be administered in this study. Scoring for each item is on a 0-6 scale; higher scores indicating greater symptom severity. Scoring for this measure includes summing up the items of the scale and dividing by the number of items for that scale to yield an average score of 0-6. |
| Change From Baseline: Pain Catastrophizing Scale | endpoint (at 13 weeks) | The PCS-R is a 13-item measure of which items were drawn from previous experimental and clinical research on catastrophic thinking in relation to pain experience Factor analyses of the PCS have shown that catastrophizing can be viewed as a multidimensional construct comprising elements of rumination (I can't stop thinking about how much it hurts), magnification (I worry that something serious may happen), and helplessness (There is nothing I can do to reduce the intensity of the pain). The factor structure of the PCS has been replicated in several investigations. Scores for each item are on a 0-4 scale with higher scores indicating greater symptom severity, the scores can range from 0-52 and a cutoff of 30 is indicative of a clinically relevant level of catastrophizing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ALLO+PA Resting (Pre-MAX-EX Testing) Post 12 Weeks of MAX-EX Testing | 13 week endpoint Cardiopulmonary Exercise Test Session (MAX-EX) | ALLO+PA are anti-stress and antinociceptive neurosteroids that were measured in plasma at rest and peak (before and after a baseline and endpoint cardiopulmonary exercise test). Higher scores reflect greater levels of the anti-stress, antinociceptive neurohormone, indicating a better outcome. |
| ALLO+PA Peak (Pre-MAX-EX Testing) Post 12 Weeks of MAX-EX Testing | 13 week endpoint Cardiopulmonary Exercise Test Session (MAX-EX) | ALLO+PA are anti-stress and antinociceptive neurosteroids that were measured in plasma at rest and peak (before and after a baseline and endpoint cardiopulmonary exercise test). Higher scores reflect greater levels of the anti-stress, antinociceptive neurohormone, indicating a better outcome. |
Countries
United States
Participant flow
Recruitment details
Recruitment took place from 8/25/2014-3/20/2020 at the VA Boston Healthcare System, Women's Health Sciences Division (WHSD), National Center for PTSD (NCPTSD). Participants were receiving care in the VA Boston Healthcare System (VABHS) or recruited from the community. Inclusion criteria for the proposed study will permit the recruitment of women as well as men from all ethnic and racial backgrounds who are at least 18 years of age, and able to speak and understand English.
Participants by arm
| Arm | Count |
|---|---|
| Chronic Pain//PTSD Group This group of trauma-exposed participants with chronic musculoskeletal pain and varying degrees of PTSD severity will receive baseline and endpoint maximum load exercise testing which will inform their individualized exercise prescription (based on a progressive methodology) of aerobic exercise. Exercise training is aimed at meeting specific heart rate ranges over time (increasing up to 80% of maximum HRR between the midpoint and endpoint (6-12 weeks).
Exercise Testing and Training: The study group will perform a baseline maximum load exercise test which will inform the individualized exercise prescription for the participant. Based on a progressive methodology, the participant will engage in 12 weeks of exercise of their choice (walking, running, cycling or swimming) with the goal of working towards a maximum heart rate range of 80% between weeks 6 and 12 of the study. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | COVID-19 institution wide halting | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | other life commitments | 6 |
| Overall Study | Participant found to not be forthcoming with screening/baseline assessments | 1 |
| Overall Study | Participants tested positive for illicit drugs on the day of the testing and/or training procedures | 2 |
Baseline characteristics
| Characteristic | Chronic Pain//PTSD Group |
|---|---|
| Age, Continuous | 44.96 years STANDARD_DEVIATION 9.17 |
| ALLO+PA at peak (30 minutes post MAX-EX testing) | 6175.29 pg/ml STANDARD_DEVIATION 16670.62 |
| ALLO +PA at rest (Pre MAX-EX testing) | 3532.53 pg/ml STANDARD_DEVIATION 5042.86 |
| Pain Catastrophizing Scale | 21.35 units on a scale STANDARD_DEVIATION 14.28 |
| Posttraumatic Stress Disorder Checklist-5 (PCL-5) | 26.21 units on a scale STANDARD_DEVIATION 14.32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 23 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 15 Participants |
| West Haven Yale Multidimensional Pain Inventory (WHYMPI) | 2.85 units on a scale STANDARD_DEVIATION 1.67 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 23 |
| other Total, other adverse events | 1 / 23 |
| serious Total, serious adverse events | 1 / 23 |
Outcome results
Primary
Change From Baseline: Pain Catastrophizing Scale
The PCS-R is a 13-item measure of which items were drawn from previous experimental and clinical research on catastrophic thinking in relation to pain experience Factor analyses of the PCS have shown that catastrophizing can be viewed as a multidimensional construct comprising elements of rumination (I can't stop thinking about how much it hurts), magnification (I worry that something serious may happen), and helplessness (There is nothing I can do to reduce the intensity of the pain). The factor structure of the PCS has been replicated in several investigations. Scores for each item are on a 0-4 scale with higher scores indicating greater symptom severity, the scores can range from 0-52 and a cutoff of 30 is indicative of a clinically relevant level of catastrophizing.
Time frame: endpoint (at 13 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain//PTSD Group | Change From Baseline: Pain Catastrophizing Scale | 13.92 units on a scale | Standard Deviation 12.06 |
Comparison: paired samples t-test to compare severity of pain catastrophizing from baseline to endpoint (week 13).p-value: 0.098t-test, 2 sided
Primary
Change From Baseline: PTSD Checklist-5 (PCL-5)
To be administered at: Endpoint Exercise Test Evaluation Session (week 13). The PCL is a 20-item self-report that assesses the extent to which an individual is bothered by each PTSD symptom during the past month using a 5-point Likert-type scale. The PCL-5 is undergoing validation, but the previous PCL based on DSM-IV had good sensitivity (.82) and specificity (.83). Scoring for each item is on a 0-4 scale with higher scores indicating higher symptom severity. A total symptom severity score (range - 0-80) can be obtained by summing the scores for each of the 20 items. Initial research suggests that a PCL-5 cutoff score between 31-33 is indicative of probable PTSD across samples. However, additional research is needed. Evidence for the PCL for DSM-IV suggests that a 5-10 point change represents reliable change (i.e., change not due to chance) and a 10-20 point change represents clinically significant change.
Time frame: Baseline and endpoint (at 13 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain//PTSD Group | Change From Baseline: PTSD Checklist-5 (PCL-5) | 15.64 units on a scale | Standard Deviation 11.34 |
Comparison: paired samples t-test to compare PTSD severity from baseline to endpoint (week 13).p-value: 0.04t-test, 2 sided
Primary
Change From Baseline: West Haven-Yale Multidimensional Pain Inventory- Interference Subscale (WHY-MPI)
The WHY-MPI has been demonstrated to be applicable across a variety of clinical pain conditions. Its brevity, validity/ reliability, self-report nature and ease of scoring make it ideal for both clinical and research purposes. The WHY-MPI is sensitive to change following rehabilitation. Please note only the interference subscale of the WHY-MPI will be administered in this study. Scoring for each item is on a 0-6 scale; higher scores indicating greater symptom severity. Scoring for this measure includes summing up the items of the scale and dividing by the number of items for that scale to yield an average score of 0-6.
Time frame: Baseline and endpoint (at 13 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain//PTSD Group | Change From Baseline: West Haven-Yale Multidimensional Pain Inventory- Interference Subscale (WHY-MPI) | 2.56 units on a scale | Standard Deviation 1.63 |
Comparison: paired samples t-test to compare degree of pain-related interference from baseline to endpoint (week 13).p-value: 0.69t-test, 2 sided
Secondary
ALLO+PA Peak (Pre-MAX-EX Testing) Post 12 Weeks of MAX-EX Testing
ALLO+PA are anti-stress and antinociceptive neurosteroids that were measured in plasma at rest and peak (before and after a baseline and endpoint cardiopulmonary exercise test). Higher scores reflect greater levels of the anti-stress, antinociceptive neurohormone, indicating a better outcome.
Time frame: 13 week endpoint Cardiopulmonary Exercise Test Session (MAX-EX)
Population: Trauma exposed participants with chronic musculoskeletal pain and varying degrees of PTSD symptom severity.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain//PTSD Group | ALLO+PA Peak (Pre-MAX-EX Testing) Post 12 Weeks of MAX-EX Testing | 4062.50 pg/ml | Standard Deviation 5971.54 |
Comparison: paired samples t-tests were conducted for comparison of peak ALLO+PA levels (30 minutes post MAXEX) from baseline to endpoint (week 13).p-value: 0.343t-test, 2 sided
Secondary
ALLO+PA Resting (Pre-MAX-EX Testing) Post 12 Weeks of MAX-EX Testing
ALLO+PA are anti-stress and antinociceptive neurosteroids that were measured in plasma at rest and peak (before and after a baseline and endpoint cardiopulmonary exercise test). Higher scores reflect greater levels of the anti-stress, antinociceptive neurohormone, indicating a better outcome.
Time frame: 13 week endpoint Cardiopulmonary Exercise Test Session (MAX-EX)
Population: Trauma exposed participants with chronic musculoskeletal pain and varying degrees of PTSD symptom severity.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain//PTSD Group | ALLO+PA Resting (Pre-MAX-EX Testing) Post 12 Weeks of MAX-EX Testing | 5855.33 pg/ml | Standard Deviation 6542.71 |
Comparison: paired samples t-tests were conducted for comparison of resting ALLO+PA levels from baseline to endpoint (week 13).p-value: 0.194t-test, 2 sided