A patient-centered nurse-supported primary care-based collaborative care program to treat opioid use disorder and depression: Design and protocol for the MI-CARE randomized controlled trial.

BACKGROUND: Opioid use disorder (OUD) contributes to rising morbidity and mortality. Life-saving OUD treatments can be provided in primary care but most patients with OUD don't receive treatment. Comorbid depression and other conditions complicate OUD management, especially in primary care. The MI-CARE trial is a pragmatic randomized encouragement (Zelen) trial testing whether offering collaborative care (CC) to patients with OUD and clinically-significant depressive symptoms increases OUD medication treatment with buprenorphine and improves depression outcomes compared to usual care. METHODS: Adult primary care patients with OUD and depressive symptoms (n ≥ 800) from two statewide health systems: Kaiser Permanente Washington and Indiana University Health are identified with computer algorithms from electronic Health record (EHR) data and automatically enrolled. A random sub-sample (50%) of eligible patients is offered the MI-CARE intervention: a 12-month nurse-driven CC intervention that includes motivational interviewing and behavioral activation. The remaining 50% of the study cohort comprise the usual care comparison group and is never contacted. The primary outcome is days of buprenorphine treatment provided during the intervention period. The powered secondary outcome is change in Patient Health Questionnaire (PHQ)-9 depression scores. Both outcomes are obtained from secondary electronic healthcare sources and compared in "intent-to-treat" analyses. CONCLUSION: MI-CARE addresses the need for rigorous encouragement trials to evaluate benefits of offering CC to generalizable samples of patients with OUD and mental health conditions identified from EHRs, as they would be in practice, and comparing outcomes to usual primary care. We describe the design and implementation of the trial, currently underway. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05122676. Clinical trial registration date: November 17, 2021.

Effect of Medication Optimization vs Cognitive Behavioral Therapy Among US Veterans With Chronic Low Back Pain Receiving Long-term Opioid Therapy: A Randomized Clinical Trial.

Importance: Medication management and cognitive behavioral therapy (CBT) are commonly used treatments for chronic low back pain (CLBP). However, little evidence is available comparing the effectiveness of these approaches. Objective: To compare collaborative care medication optimization vs CBT on pain intensity, interference, and other pain-related outcomes. Design, Setting, and Participants: The Care Management for the Effective Use of Opioids (CAMEO) trial was a 12-month, comparative effectiveness randomized clinical trial with blinded outcome assessment. Recruitment of veterans with CLBP prescribed long-term opioids occurred at 7 Veterans Affairs primary care clinics from September 1, 2011, to December 31, 2014, and follow-up was completed December 31, 2015. Analyses were based on intention to treat in all randomized participants and were performed from March 22, 2015, to November 1, 2021. Interventions: Patients were randomized to receive either collaborative care with nurse care manager-delivered medication optimization (MED group) (n = 131) or psychologist-delivered CBT (CBT group) (n = 130) for 6 months, with check-in visits at 9 months and final outcome assessment at 12 months. Main Outcomes and Measures: The primary outcome was change in Brief Pain Inventory (BPI) total score, a composite of the pain intensity and interference subscales at 6 (treatment completion) and 12 (follow-up completion) months. Scores on the BPI range from 0 to 10, with higher scores representing greater pain impact and a 30% improvement considered a clinically meaningful treatment response. Secondary outcomes included pain-related disability, pain catastrophizing, self-reported substance misuse, health-related quality of life, depression, and anxiety. Results: A total of 261 patients (241 [92.3%] men; mean [SD] age, 57.9 [9.5] years) were randomized and included in the analysis. Baseline mean (SD) BPI scores in the MED and CBT groups were 6.45 (1.79) and 6.49 (1.67), respectively. Improvements in BPI scores were significantly greater in the MED group at 12 months (between-group difference, -0.54 [95% CI, -1.18 to -0.31]; P = .04) but not at 6 months (between-group difference, -0.46 [95% CI, -0.94 to 0.11]; P = .07). Secondary outcomes did not differ significantly between treatment groups. Conclusions and Relevance: In this randomized clinical trial among US veterans with CLBP who were prescribed long-term opioid therapy, collaborative care medication optimization was modestly more effective than CBT in reducing pain impact during the 12-month study. However, this difference may not be clinically meaningful or generalize to nonveteran populations. Trial Registration: ClinicalTrials.gov Identifier: NCT01236521.

Opioid Use as a Predictor of Pain Outcomes in Iraq and Afghanistan Veterans with Chronic Pain: Analysis of a Randomized Controlled Trial.

OBJECTIVE: Our objectives were to: 1) assess the relationship between self-reported opioid use and baseline demographics, clinical characteristics and pain outcomes; and 2) examine whether baseline opioid use moderated the intervention effect on outcomes at 9 months. DESIGN: We conducted a secondary analysis of data from the Evaluation of Stepped Care for Chronic Pain (ESCAPE) trial, which found stepped-care to be effective for chronic pain in military veterans. SETTING: A post-deployment clinic and five general medicine clinics at a Veteran Affairs Medical Center. SUBJECTS: In total 241 veterans with chronic musculoskeletal pain; 220 with complete data at 9 months. METHODS: Examination of baseline relationships and multivariable linear regression to examine baseline opioid use as a moderator of pain-related outcomes including Roland Morris Disability Questionnaire (RMDQ), Brief Pain Inventory (BPI) Interference scale, and Graded Chronic Pain Scale (GCPS) at 9 months. RESULTS: Veterans reporting baseline opioid use (n = 80) had significantly worse RMDQ (16.0 ± 4.9 vs. 13.4 ± 4.2, P < .0001), GCPS (68.7 ± 12.0 vs. 65.0 ± 14.4, P = .049), BPI Interference (6.2 ± 2.2 vs. 5.0 ± 2.1, P < .0001), and depression (PHQ-9 12.5 ± 6.2 vs. 10.6 ± 5.7, P = .016) compared to veterans not reporting baseline opioid use. Using multivariable modeling we found that baseline opioid use moderated the intervention effect on pain-related disability (RMDQ) at 9 months (interaction Beta = -3.88, P = .0064) but not pain intensity or interference. CONCLUSIONS: In a stepped-care trial for pain, patients reporting baseline opioid use had greater improvement in pain disability at 9 months compared to patients not reporting opioid use.

Composite measures of pain, anxiety, and depressive (PAD) symptoms: Construct and predictive validity.

OBJECTIVE: Pain, anxiety, and depression (PAD) are common, co-occurring symptoms that adversely affect one another and may respond to common treatments. PAD composite measures would be useful for tracking treatment response in patients with PAD symptoms. The goal of this study is to compare 3 different PAD composite scales in terms of construct validity, responsiveness, and utility in predicting global improvement. METHOD: The sample consisted of 294 primary care patients enrolled in a telecare trial for treating pain, anxiety, and depression. Assessments at baseline and 3 months included the Brief Pain Inventory, PHQ-9 depression scale, GAD-7 anxiety scale, PROMIS measures, Medical Outcomes Study Short-Form items, disability measures, and patient-reported global improvement. Construct validity of the PAD composite measures, their responsiveness, and their ability to predict global improvement was analyzed using Pearson correlations, standardized response means, and receiver operating characteristics analysis. RESULTS: PAD composite measures correlated strongly with one another, and moderately with measures of function, vitality, and disability. Each PAD composite measure demonstrated similar responsiveness in detecting improvement at 3 months as assessed by standardized response means (SRMs) and area under the curve (AUC analyses).The SRMs for partial and substantial global improvement corresponded to moderate (Cohen's d of 0.58 to 0.69) and large (0.81 to 0.93) effect sizes, respectively. CONCLUSIONS: Three different PAD composite measures demonstrate good construct validity as well as responsiveness in detecting global improvement of pain, anxiety and depression at 3 months.

Design and methods of the Care Management for the Effective Use of Opioids (CAMEO) trial.

Low back pain is the most common pain condition seen in primary care, with the most common treatment being analgesic medications, including opioids. A dramatic increase in opioid prescriptions for low back pain over the past few decades has led to increased non-medical use and opioid overdose deaths. Cognitive behavioral therapy (CBT) for chronic pain is an evidence-based non-pharmacological treatment for pain with demonstrated efficacy when delivered using collaborative care models. No previous studies have tested CBT compared to analgesic optimization that includes opioid management in primary care. This paper describes the study design and methods of the CAre Management for the Effective use of Opioids (CAMEO) trial, a 2-arm, randomized comparative effectiveness trial in seven primary care clinics. CAMEO enrolled 261 primary care veterans with chronic (6 months or longer) low back pain of at least moderate severity who were receiving long-term opioid therapy and randomized them to either nurse care management focused on analgesic treatment and optimization (MED) or cognitive behavioral therapy (CBT). All subjects undergo comprehensive outcome assessments at baseline, 3, 6, 9, and 12 months by interviewers blinded to treatment assignment. The primary outcome is pain severity and interference, measured by the Brief Pain Inventory (BPI) total score. Secondary outcomes include health-related quality of life, fatigue, sleep, functional improvement, pain disability, pain beliefs, alcohol and opioid problems, depression, anxiety, and stress.

Multifocal Pain as a Predictor of Pain Outcomes in Military Veterans with Chronic Musculoskeletal Pain: A Secondary Data Analysis of a Randomized Controlled Trial.

OBJECTIVE: We aimed to examine 1) the relationship between multifocal pain and clinical characteristics, including demographics, pain outcomes, somatic symptoms, health-related quality of life, depression, and anxiety, and 2) whether multifocal pain was independently associated with treatment response. METHODS: We conducted a secondary data analysis on veterans with chronic pain enrolled in the Evaluation of Stepped Care for Chronic Pain (ESCAPE) trial with complete data at 9 months (n = 222). We examined baseline relationships and used multivariable linear regression to examine whether multifocal pain was independently associated with outcomes that included Brief Pain Inventory (BPI) Interference scale and Graded Chronic Pain Scale (GCPS) scores between baseline and 9 months. RESULTS: The sample had a mean BPI Interference score of 5.3 ± 2.2 and a mean GCPS score of 65.6 ± 13.7, 55% had significant depression (Patient Health Questionnaire 9-item depression scale [PHQ-9] score of ≥10), and 42% had significant anxiety (Generalized Anxiety Disorder Scale [GAD-7] score of ≥10). Veterans reporting three or more pain sites (the "more diffuse pain" group) had significantly less improvement on GCPS (b = 4.6, standard error [SE] = 2.3, P = 0.045), BPI Interference (b = 1.0, SE = 0.2, P = 0.0011), and health-related quality of life (Short-Form 36-item scale, Physical Component Summary) (b = 4.1, SE = 1.0, P < 0.0001) than did veterans reporting fewer than three pain sites (the "less diffuse pain" group). More diffuse pain was not associated with changes in PHQ-9 or GAD-7 scores. CONCLUSIONS: Multifocal pain predicted worse pain outcomes between baseline and 9 months in veterans enrolled in a trial for treating chronic musculoskeletal pain.

Telecare management of pain and mood symptoms: Adherence, utility, and patient satisfaction.

INTRODUCTION: Pain, depression, and anxiety are prominent symptoms that frequently co-occur, causing significant debilitation and frequent primary care visits. This paper examines the acceptability of telecare and self-management modules in managing these conditions in a randomized trial. METHODS: The Comprehensive Management of Mood and Physical Symptoms (CAMMPS) trial compared an automated symptom management (ASM) plus self-management intervention with a comprehensive symptom management (CSM) intervention that added telecare facilitation of enhanced services. Data from the CAMMPS trial were analysed to compare the acceptability of these two interventions as indicated by utilization and patient satisfaction surveys. RESULTS: The mean number of automated reports completed was similar between the CSM and ASM groups (14.5 vs 14.0). Responses designated with clinically relevant "red alerts" (i.e. patient reports warranting an expedited nurse contact) were more frequent in the CSM group (10.2 vs 8.3). The CSM and ASM groups completed a similar number of the nine self-management modules (6.3 vs 5.8). The mean helpfulness score across all modules was higher in the CSM group than in the ASM group (1.8 vs 1.5; p = .003). The most common feedback suggestion from the ASM group was to have more personal interaction, while participants from both groups commonly suggested technical improvements or requests for more flexible timing of calls. DISCUSSION: Participants generally found both interventions satisfactory, with a trend in satisfaction data suggesting that patients tended to find the CSM intervention more helpful.

Assessing depression improvement with the remission evaluation and mood inventory tool (REMIT).

OBJECTIVE: The Remission Evaluation and Mood Inventory Tool (REMIT) was developed as a brief complementary measure to provide a more robust assessment of depression improvement than tracking DSM-V symptom improvement alone. This study provides further validation of the REMIT tool and examines its utility in predicting depression improvement. METHODS: The sample comprised 294 primary care patients enrolled in a telecare trial of pain plus depression and/or anxiety. Assessments collected included: REMIT, PHQ-9 and measures assessing anxiety, pain, sleep, fatigue, somatization, health-related quality of life and disability. Data was analyzed to assess the REMIT's validity, its minimally important difference (MID), and its utility in predicting 6-month depression improvement. RESULTS: Convergent and construct validity of REMIT was supported by moderate correlations with mental health measures and weaker correlation with physical health measures. MID of approximately 2 points for REMIT was estimated by two metrics: 0.5 standard deviation and 1 standard error of measurement. Both baseline and 3-month change in REMIT scores predicted depression improvement at 6 months. Indeed, REMIT was as good or better predictor than the PHQ-9. CONCLUSION: The REMIT measure is a brief 5-item tool that augments core DSM-V symptom-oriented metrics in assessing and predicting recovery from major depression.

Zfp423/OAZ mutation reveals the importance of Olf/EBF transcription activity in olfactory neuronal maturation.

Zfp423/OAZ, a multi-zinc finger protein, is proposed to participate in neuronal differentiation through interactions with the Olf/EBF (O/E) family of transcription factors and mediate extrinsic BMP signaling pathways. These activities are associated with distinct domains of the Olf/EBF-associated zinc finger (OAZ) protein. Sustained OAZ expression arrests olfactory sensory neurons (OSNs) at an immature state and alters olfactory receptor expression, but the mechanism remains elusive. We show here that constitutive expression of a C-terminal mutant OAZ (OAZΔC) in mice that selectively disrupts OAZ-O/E interaction while retaining other activities, exhibits apparently normal OSN differentiation. Additionally, interfering with potential BMP signaling pathways by inducible Follistatin expression in adult mice does not alter the neuronal lineage or differentiation status. Our results indicate that O/E-mediated processes are essential for the differentiation of OSNs and the establishment of a mature phenotype. BMP signaling pathways, if they are active in normal adult olfactory epithelium, may play a minor role in this tissue.

Inhibition of NaCl appetite when DOCA-treated rats drink saline.

Marked increases in the consumption of concentrated NaCl solution were elicited in rats by daily injection of the synthetic mineralocorticoid, deoxycorticosterone acetate (DOCA). DOCA-treated rats drank different volumes of NaCl solution depending on its concentration (between 0.15 M and 0.50 M), with less consumed (in milliliters) the more concentrated the fluid was. In consequence, total Na(+) intake (in milliequivalents) was roughly similar in all groups. Gastric emptying of Na(+) also diminished as the concentration of the ingested NaCl solution increased, and the delivery of Na(+) to the small intestine was remarkably similar in all groups. Cumulative volume of ingested fluid in the stomach and small intestine was very closely related to intake (in milliliters) of the concentrated NaCl solutions. Systemic plasma Na(+) levels did not increase until after rats stopped consuming concentrated NaCl solution, although they were elevated at the onset of water ingestion. The situation appeared to be different when 0.15 M NaCl was consumed. This isotonic solution emptied and was absorbed relatively rapidly, and DOCA-treated rats drank larger amounts of it throughout a 1-h test period than when they drank concentrated NaCl solutions. Collectively, these findings suggest that saline consumption by DOCA-treated rats may be inhibited by two presystemic factors, one related to the volume of ingested fluid (i.e., distension of the stomach and small intestine) and one related to its concentration (i.e., elevated osmolality of fluid in the small intestine and/or in adjacent visceral tissue).