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| ID | Type | Description | Link |
|---|---|---|---|
| RM1DA055437 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Drug Abuse (NIDA) | NIH |
| Weill Medical College of Cornell University | OTHER |
| Wake Forest University Health Sciences | OTHER |
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The proposed IMPOWR Research Center at Montefiore-Einstein (IMPOWR-ME) will create a multidisciplinary and synergistic program of research to test multimodal treatments that address both chronic pain and opioid use disorder. IMPOWR-ME will generate critical knowledge about the effectiveness, implementation, and cost effectiveness of providing Acceptance and Commitment Therapy and/or a care management smartphone app for individuals in primary care-based buprenorphine treatment. Patients with lived experience with chronic pain and/or opioid use disorder, patient and policy advocates, payors, and health system partners will be engaged in all stages of the research. IMPOWR-ME is well-positioned to become a long-lasting hub for stakeholder-engaged research with multidisciplinary senior and early stage investigators focused on reducing overdose through better treatments for OUD and CP.
Chronic pain (CP) and opioid use disorder (OUD) are leading causes of morbidity and mortality in the United States. Despite being commonly comorbid, there is a striking lack of integrated treatments accessible to people in need. This is particularly true for Black and Hispanic individuals living and seeking care in under-resourced settings like The Bronx, New York, one of the poorest and most racially diverse counties in the U.S. Submitted in response to the HEAL Initiative: Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR) (Request For Applications ID: RFA-DA-21-030), the overall goal of this proposal is to create the IMPOWR Research Center at Montefiore/Einstein ("IMPOWR-ME"), in the high-impact county of The Bronx New York. IMPOWR-ME is a synergistic multidisciplinary research center that leverages exceptional research infrastructure in CP and OUD and existing relationships with people living with CP and OUD, advocates, policymakers and payers, and health system stakeholders. The aims of IMPOWR-ME are to: 1) create a robust and sustainable research infrastructure to rigorously test and disseminate integrated and cost-effective evidence-based practices for people with CP and OUD; 2) partner with people with lived experience with CP, OUD, or both, and diverse stakeholders in all stages of the research; and 3) provide opportunities for multidisciplinary early stage investigators to become independent researchers focusing on CP and OUD. This innovative hybrid type 1 effectiveness-implementation trial is proposed to rigorously examine multi-modal evidence-based practices in diverse health care settings and populations of people with comorbid CP and OUD. Specifically, the investigators propose a 2x2 factorial trial to test Acceptance and Commitment Therapy and a care management smartphone app for individuals in primary-care based buprenorphine treatment. Participants will have both CP and OUD or opioid misuse, and specific aims will examine CP, OUD, implementation, and cost-effectiveness outcomes; additional patient-centered outcomes will be driven by people with lived experience. This project improves access to care for Black and Hispanic individuals in under-resourced settings by bringing integrated treatment of CP and OUD to them, and the interventions have high potential for dissemination and sustainability. An innovative program for pilot studies achieves a dual aim of catalyzing stakeholder-driven research and training early stage and new investigators. An exceptional team of investigators and clinical experts focused on CP and OUD, a longstanding history of collaboration with stakeholders and people with lived experience, and a high-impact population make Montefiore-Einstein an ideal site for an IMPOWR research center.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Valera smartphone application (app) alone | Active Comparator | Participants randomized to this cohort will receive the Valera app and will receive a smartphone with network connectivity if necessary. |
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| ACT + Valera app | Experimental | Participants randomized to this cohort will receive both acceptance and commitment therapy (ACT) and the Valera app (and a smartphone with network connectivity if necessary). |
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| treatment as usual (TAU) | Placebo Comparator | Participants randomized to this cohort will not receive any experimental treatments. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acceptance and commitment therapy | Behavioral | Intervention will be provided over 12 weeks with weekly 1-hour sessions using a group format with the overall goal to foster psychological flexibility. ACT will assist participants to notice their internal triggers; abandon their attempts to manage these triggers via active avoidance (suppression or other control-based strategies including opioid or other substance use) and to make commitments to engage in behaviors consistent with their chosen values or goals (rather than allowing negative thoughts, feelings, or pain symptoms to dictate behavior). |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Pain Interference | Change in Pain Interference on average over the prior 7-day period will be assessed using the Brief Pain Inventory (BPI) pain interference subscale. The BPI pain interference subscale consists of 7 items which asks patients to rate how much pain has interfered with mood, walking ability, work, relations with others, sleep, enjoyment of life, and general activity using a 0-10 numeric rating scale (NRS), where 0 represents "Does not interfere" and 10 represents "Completely interferes" such that higher scores are associate with greater pain interference. Scores from the seven items are averaged to obtain a mean score. Higher scores are indicative of more interference with daily life. Results will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, and 36 weeks |
| Illicit Opioid Use | Illicit opioid use will be a composite outcome defined by self-reported opioid use days over the past 30 days using items from a modified Addiction Severity Index questionnaire. It is defined by the maximum number of days of use of: a) heroin, b) fentanyl [unprescribed], and c) prescription opioids or analgesics [unprescribed]. The possible range of days is 0-30. Results will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, and 36 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Psychological Flexibility | Psychological flexibility is measured using the Multidimensional Psychological Flexibility Inventory - Short (MPFI-S) flexibility subscale, which consists of 12 items. Responses range from 1 ("Never true") to 6 ("Always true"). There are two subscales measuring psychological flexibility and inflexibility across key areas. A global composite score for flexibility uses the first 12 answers and divides scores by 12 to obtain a mean score. Higher scores reflect higher levels of psychological flexibility. |
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Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Hector Perez, MD | Contact | 718-920-5756 | heperez@montefiore.org | |
| Joanna Starrels, MD | Contact | joanna.starrels@einsteinmed.edu |
| Name | Affiliation | Role |
|---|---|---|
| Hector Perez, MD | Albert Einstein College of Medicine Montefiore Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Montefiore Medical Center | Recruiting | The Bronx | New York | 10461 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24912863 | Background | Nahvi S, Blackstock O, Sohler NL, Thompson D, Cunningham CO. Smoking cessation treatment among office-based buprenorphine treatment patients. J Subst Abuse Treat. 2014 Aug;47(2):175-9. doi: 10.1016/j.jsat.2014.04.001. Epub 2014 Apr 27. | |
| 23722632 | Background | Cunningham CO, Roose RJ, Starrels JL, Giovanniello A, Sohler NL. Prior buprenorphine experience is associated with office-based buprenorphine treatment outcomes. J Addict Med. 2013 Jul-Aug;7(4):287-93. doi: 10.1097/ADM.0b013e31829727b2. |
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| ID | Term |
|---|---|
| D009293 | Opioid-Related Disorders |
| D059350 | Chronic Pain |
| ID | Term |
|---|---|
| D000079524 | Narcotic-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D064869 | Acceptance and Commitment Therapy |
| D013812 | Therapeutics |
| ID | Term |
|---|---|
| D015928 | Cognitive Behavioral Therapy |
| D001521 | Behavior Therapy |
| D011613 | Psychotherapy |
| D004191 | Behavioral Disciplines and Activities |
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| University of Miami |
| OTHER |
| Valera Health | UNKNOWN |
| Tulane University | OTHER |
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| Valera Smartphone Application | Other | For those randomized to a cohort with the Valera app, the app (and cellphones if necessary) will be provided. The app is Health Insurance Portability and Accountability Act (HIPAA) compliant and Institutional Review Board (IRB) approved. It consists of 2 components: a participant-facing Smartphone Application and a corresponding online Care Manager Dashboard. Smartphones and internet access will be provided as needed for the 12-week study duration. |
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| Treatment as Usual | Other | TAU for Buprenorphine (BUP) treatment typically consists of regularly scheduled visits every 1-2 months with primary care physicians and/or nurse care managers in Montefiore primary care settings. During these 15-min follow up visits, providers typically inquire about opioid and other substance use, opioid craving, symptoms of opioid withdrawal, and risk of relapse. In addition, at each visit, urine toxicology tests are conducted and providers review results of prior urine toxicology tests with patients. If opioid or other substance use is ongoing, typically providers will intensify treatment, including increasing the frequency of visits, referring to social workers or mental health providers, recommending self-help groups, and/or recommending outpatient drug treatment programs (e.g., individual and group counseling). |
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| Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Psychological Inflexibility | Psychological inflexibility is measured using the Multidimensional Psychological Flexibility Inventory - Short (MPFI-S) inflexibility scale, which consists of 12 items. Responses range from 1 ("Never true") to 6 ("Always true"). There are two subscales measuring psychological flexibility and inflexibility across key areas. A global composite score for inflexibility uses the last 12 answers and divides scores by 12 to obtain a mean score. Higher scores reflect higher levels of psychological inflexibility. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Psychological Flexibility Related to Substance Use | Psychological inflexibility related to substance use is measured using the Acceptance and Action Questionnaire-Substance Abuse (AAQ-SA), a self-report scale. The AAQ-SA assesses the degree to which individuals avoid or struggle with substance-related thoughts, urges, and emotions, and the extent to which these experiences interfere with values-consistent behavior over recent weeks. Items are rated on a 7-point Likert scale ranging from 1 ("Never true") to 7 ("Always true"). Several items are reverse scored so that item responses can be summed to yield a total score, with lower scores indicating greater psychological flexibility (i.e., less experiential avoidance) in the context of substance use. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Committed Action | Committed action is measured using the Committed Action Questionnaire (CAQ), an 18-item self-report scale. Each item assesses the degree to which individuals persist in values-directed actions in the face of discomfort over the past several weeks and is rated on a 7-point scale ranging from 0 ("Never true") to 6 ("Always true"). Item scores are summed to produce a total score ranging from 0 to 108, with higher scores indicating greater levels of committed action. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Pain Acceptance | Pain acceptance is measured using a 20-item scale called the Chronic Pain Acceptance Questionnaire--Revised (CPAQ-R). This is designed to measure acceptance of pain. It is measured on a scale of 0 ("Never true") to 6 ("Always true"). There are two subscales: (1) activity engagement, (2) pain willingness. Total score for pain acceptance is derived from mean scores on each of the subscales. Higher scores indicate higher levels of acceptance. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Pain Catastrophizing | Pain catastrophizing is assessed via the 6-item Pain Catastrophizing Scale (PCS-6). The PCS-6 is a shortened version of the full 13-item Pain Catastrophizing Scale, designed to assess pain-related catastrophic thinking. Each items assesses maladaptive, cognitive, and emotional responses to pain experiences. Responses to items 4, 5, 6, 10, 11, and 13 from the original 13 item scale are rated on a 5-point scale ranging from 0 ("Not al all") to 4 ("All the time"). Item scores are summed to produce a total score ranging from 0-24, with higher scores indicating greater levels of pain catastrophizing. Scores will be summarized by study arm using basic descriptive statistics. | Baseline, 12 weeks, 36 weeks |
| Change in Pain Intensity | Change in pain intensity on average over the prior 7-day period will be assessed using the Brief Pain Inventory (BPI) pain intensity subscale. The BPI pain intensity subscale consists of 4 items which asks patients to rate their worst pain, least pain, average pain, and current pain using a 0-10 numeric rating scale (NRS), where 0 represents "No pain" and 10 represents "Pain as bad as you can imagine," such that higher scores are associated with greater pain intensity. Scores from the four items are averaged to obtain a mean score. Results will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, and 36 weeks |
| Heroin Use | Heroin use will be defined by self-reported heroin use days of the past 30 days using an item from a modified Addiction Severity Index questionnaire. The possible range of days is 0-30. Results will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Fentanyl Use | Fentanyl use will be defined by self-reported fentanyl use days of the past 30 days that is not prescribed, using items from a modified Addiction Severity Index questionnaire. The possible range of days is 0-30. Results will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Unprescribed Prescription Opioid Analgesic Use | Prescription opioid analgesic use will be defined by self-reported number of days of prescription opioid analgesic use that is not prescribed, over the past 30 days, using items from a modified Addiction Severity Index questionnaire. The possible range of days is 0-30. Results will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Heatlh Related Quality of Life (HRQoL) | HRQoL will be assessed using a utility score from the Patient-Reported Outcomes Measurement Information System (PROMIS)-Preference (PROPr) scoring system. PROPr summarizes several PROMIS domains into a single, preference-based score. PROPr is a health utility score which aggregates scores from 7 PROMIS domains: Cognitive Function/Abilities, Depression, Fatigue, Pain Interference, Physical Function, Sleep Disturbance, and Ability to Participate in Social Roles and Activities. PROPr scores are calculated using a multiplicative multiattribute utility function that combines the individual PROMIS domain scores into a single score. The PROPr score is expressed as a health utility index value on a scale between 0 (the utility of being dead) and 1 (utility of full health) such that higher scores are indicative of better perceived overall health utility. Scores will be summarized by study arm using basic descriptive statistics. | Baseline, 12 weeks, 24 weeks, and 36 weeks |
| Global Impression of Change | Global Impression of change from the beginning of the study will be evaluated using the Patient Global Impression of Change (PGIC) assessment. The PGIC consists of a single item which asks the participant "Since the start of the study (treatment), my overall pain is..." and asks the participant to rate their pain on a 7-point Likert scale ranging from 0 ("Very much improved") to 6 ("Very much worse"), such that lower scores are associated with an overall impression of improvement since the start of the study. Results will be summarized by study arm using basic descriptive statistics. | 12 weeks and 36 weeks |
| Depressive Symptoms | Depressive symptoms are measured using the Beck Depression Inventory (BDI), a 21-item self-report scale. Each item assesses the severity of a depressive symptom experienced over the past two weeks and is scored on a 4-point scale ranging from 0 ("Symptom not present") to 3 ("Severe symptom"). Item scores are summed to produce a total score ranging from 0 to 63, with higher scores indicating greater severity of depressive symptoms. Scores will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Anxiety Symptoms | Anxiety symptoms are measured using the Beck Anxiety Inventory (BAI), a 21-item self-report scale. Each item assesses the severity of common anxiety symptoms experienced over the past week and is scored on a 4-point scale ranging from 0 ("Not at all") to 3 ("Severely; it bothered me a lot"). Item scores are summed to produce a total score ranging from 0 to 63, with higher scores indicating greater severity of anxiety symptoms. Scores will be summarized by study arm using basic descriptive statistics. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Positive Urine for Non-prescribed Opioids | Positive urine for non-prescribed opioids will be assessed using point of care urine drug testing. Results of the test will be reported using a dichotomous variable ("Yes"/"No") where "Yes" is is indicated by positive oxycodone, fentanyl, or other opiates that were not indicated by participant as prescribed. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Anhedonia | Anhedonia will be assessed via the Snaith-Hamilton Pleasure Scale (SHAPS), a 14-item self-report scale. Each item assesses the ability to experience pleasure over the past few days and is rated on a 4-point scale consisting of "Strongly disagree," "Disagree", "Agree," or "Strongly agree". For scoring, responses will be dichotomized such that "Strongly disagree" and "Disagree" are scored as 1 point and "Strongly agree" and "Agree" are scored as 0 points. Scores are summed to yield a total score ranging from 0 to 14. Higher total scores indicate greater levels of anhedonia. | Baseline, 24 weeks, 36 weeks |
| Psychiatric Diagnoses | Psychiatric diagnoses are assessed using the Mini International Neuropsychiatric Interview (MINI), a structured diagnostic interview based on Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. The MINI is administered by trained study personnel to determine the presence or absence of current psychiatric disorders. Diagnoses are assessed at multiple time points to evaluate changes in diagnostic status over the course of the study. The total number of diagnoses at each timepoint will be reported. A higher number reflects higher burden of psychiatric disease. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Retention with Buprenorphine | Retention with buprenorphine will be measured by a dichotomous measure of whether a buprenorphine prescription occurred within 1 week of the time of a study visit. This is measured using pharmacy data obtained through I-stop, a NY State controlled substance monitoring program. Results will be summarized by study arm. | Baseline, 6 weeks, 12 weeks, 24 weeks, 36 weeks |
| Satisfaction with ACT | For participants enrolled into the ACT arm, satisfaction with ACT is measured using the Satisfaction With Therapy Scale (STS), a 14-item self-report questionnaire. The scale assesses participants' satisfaction with various aspects of their therapeutic experience. Each item is rated on a 5-point Likert scale ranging from 1 to 5, and item responses are summed to yield a total score ranging from 14-70. Higher total scores indicate greater satisfaction with ACT. | 12 weeks |
| Satisfaction with Valera | For participants enrolled into one of the Valera smartphone application arms, satisfaction with Valera is measured is measured using a novel scale measuring overall satisfaction along with satisfaction with three different components: (1) Educational articles, (2) Appointment Reminders, and (3) Messaging Care Team. Each is measured along a Likert-type scale from 1-5, with higher scores reflecting higher satisfaction or usefulness, of Valera. | 12 weeks |
| Valera Engagement with Articles | For participants enrolled into one of the Valera smartphone application arms, Valera Engagement with articles is a dichotomous measure assessing whether participants opened up each of 24 articles sent to participants twice weekly across the 12 week intervention. Each measure is measured as "Yes" or "No." Total engagement will be reflected as a percentage of total yes answers over the 24 articles. Higher percentages reflect higher engagement with articles. | 12 weeks |
| ACT Attendance | For participants enrolled into the ACT arm, ACT attendance is a measure of attendance of each of 12 ACT sessions. These will be reported as percentages. Higher percentages indicates higher attendance. | 12 weeks |
| 22989279 | Background | Fox AD, Sohler NL, Starrels JL, Ning Y, Giovanniello A, Cunningham CO. Pain is not associated with worse office-based buprenorphine treatment outcomes. Subst Abus. 2012;33(4):361-5. doi: 10.1080/08897077.2011.638734. |
| 23152245 | Background | Williams AC, Eccleston C, Morley S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev. 2012 Nov 14;11(11):CD007407. doi: 10.1002/14651858.CD007407.pub3. |
| 25365778 | Background | Davis MC, Zautra AJ, Wolf LD, Tennen H, Yeung EW. Mindfulness and cognitive-behavioral interventions for chronic pain: differential effects on daily pain reactivity and stress reactivity. J Consult Clin Psychol. 2015 Feb;83(1):24-35. doi: 10.1037/a0038200. Epub 2014 Nov 3. |
| 24491075 | Background | Garland EL, Manusov EG, Froeliger B, Kelly A, Williams JM, Howard MO. Mindfulness-oriented recovery enhancement for chronic pain and prescription opioid misuse: results from an early-stage randomized controlled trial. J Consult Clin Psychol. 2014 Jun;82(3):448-459. doi: 10.1037/a0035798. Epub 2014 Feb 3. |
| 31760109 | Background | Vowles KE, Witkiewitz K, Cusack KJ, Gilliam WP, Cardon KE, Bowen S, Edwards KA, McEntee ML, Bailey RW. Integrated Behavioral Treatment for Veterans With Co-Morbid Chronic Pain and Hazardous Opioid Use: A Randomized Controlled Pilot Trial. J Pain. 2020 Jul-Aug;21(7-8):798-807. doi: 10.1016/j.jpain.2019.11.007. Epub 2019 Nov 21. |
| 26209170 | Background | Kaiser RS, Mooreville M, Kannan K. Psychological Interventions for the Management of Chronic Pain: a Review of Current Evidence. Curr Pain Headache Rep. 2015 Sep;19(9):43. doi: 10.1007/s11916-015-0517-9. |
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| Background | Hayes, S., Strosahl, K. & Wilson, K. Acceptance and Commitment Therapy : An Experiential Approach to Behavior Change / S.C. Hayes, K.D. Strosahl, K.G. Wilson. (2011). |
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| 27278752 | Background | Kwok SS, Chan EC, Chen PP, Lo BC. The "self" in pain: the role of psychological inflexibility in chronic pain adjustment. J Behav Med. 2016 Oct;39(5):908-15. doi: 10.1007/s10865-016-9750-x. Epub 2016 Jun 8. |
| Background | Vowles, K. E. & Thompson, M. in Mindfulness and acceptance in behavioral medicine: Current theory and practice. 31-60 (New Harbinger Publications, Inc., 2011) |
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| Background | Dahl, J., Wilson, K. G. & Nilsson, A. Acceptance and commitment therapy and the treatment of persons at risk for long-term disability resulting from stress and pain symptoms: A preliminary randomized trial. Behavior Therapy 35, 785-801 (2004). https://doi.org:10.1016/s0005-7894(04)80020-0 |
| 18608312 | Background | Wicksell RK, Ahlqvist J, Bring A, Melin L, Olsson GL. Can exposure and acceptance strategies improve functioning and life satisfaction in people with chronic pain and whiplash-associated disorders (WAD)? A randomized controlled trial. Cogn Behav Ther. 2008;37(3):169-82. doi: 10.1080/16506070802078970. |
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| 28342891 | Background | Luciano JV, D'Amico F, Feliu-Soler A, McCracken LM, Aguado J, Penarrubia-Maria MT, Knapp M, Serrano-Blanco A, Garcia-Campayo J. Cost-Utility of Group Acceptance and Commitment Therapy for Fibromyalgia Versus Recommended Drugs: An Economic Analysis Alongside a 6-Month Randomized Controlled Trial Conducted in Spain (EFFIGACT Study). J Pain. 2017 Jul;18(7):868-880. doi: 10.1016/j.jpain.2017.03.001. Epub 2017 Mar 23. |
| Background | Hayes, S. C. et al. A Preliminary trial of twelve-step facilitation and acceptance and commitment therapy with polysubstance-abusing methadone-maintained opiate addicts. Behavior Therapy 35, 667-688 (2004). https://doi.org:10.1016/s0005-7894(04)80014-5 |
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| 33138925 | Background | Jakubowski A, Lu T, DiRenno F, Jadow B, Giovanniello A, Nahvi S, Cunningham C, Fox A. Same-day vs. delayed buprenorphine prescribing and patient retention in an office-based buprenorphine treatment program. J Subst Abuse Treat. 2020 Dec;119:108140. doi: 10.1016/j.jsat.2020.108140. Epub 2020 Sep 22. |
| 23795874 | Background | Cunningham CO, Giovanniello A, Kunins HV, Roose RJ, Fox AD, Sohler NL. Buprenorphine treatment outcomes among opioid-dependent cocaine users and non-users. Am J Addict. 2013 Jul-Aug;22(4):352-7. doi: 10.1111/j.1521-0391.2013.12032.x. |
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| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |