Ensuring buprenorphine access in rural community pharmacies to prevent overdoses.

BACKGROUND: Opioid-related drug overdoses have been rapidly increasing in the United States, especially in rural Southern and Appalachian regions. The use of buprenorphine-containing medications to treat opioid use disorder (OUD) is an evidence-based approach proven to reduce overdose death risks. Access to such treatment is uneven, with less access in parts of the United States where overdose rates are higher. Pharmacy dispensing of buprenorphine is a key component of access, yet barriers related to perceived and actual regulatory constraints, training gaps, stigma, and challenges to prescriber-pharmacist communication limit dispensing of this life-saving medication. OBJECTIVES: The objectives of this study were to explore the experiences of rural patients with OUD filling prescriptions for buprenorphine-containing medications at community pharmacies. PRACTICE DESCRIPTION: Rural community pharmacies, both commercial chain and independent, in 2 rural South-Central Appalachian counties where the local health departments prescribe buprenorphine-containing medications. PRACTICE INNOVATION: The local county health departments each entered into dedicated dispensing arrangements with a local independent community pharmacy to ensure a stable supply of medication for their patients with OUD who were prescribed buprenorphine. EVALUATION METHODS: Qualitative interviews (n =16) with patients prescribed buprenorphine from their county health department; county health department staff, local harm reduction program staff, and harm reduction program participants prescribed buprenorphine. Transcripts were analyzed using thematic analysis. RESULTS: Participants reported problems with buprenorphine dispensing at rural community pharmacies, dispensing delays that resulted in experiencing withdrawal symptoms and hesitation to continue in treatment, high medication costs, and stigmatizing treatment by some pharmacists. Participants also reported that access improved after dedicated dispensing arrangements began. CONCLUSION: Agreements between prescribing health departments and community pharmacies could increase access to buprenorphine, especially in rural areas.

North Carolina community pharmacists' buprenorphine dispensing practices and attitudes.

BACKGROUND: Many barriers, including stocking behaviors and pharmacist attitudes, can limit access to buprenorphine in pharmacy settings. OBJECTIVES: To assess North Carolina (NC) pharmacists' (1) buprenorphine stocking behaviors, (2) awareness and interpretation of federal and state policy regarding buprenorphine, (3) perceptions about changes in buprenorphine demand, and (4) reasons for not dispensing buprenorphine, including attitudes. METHODS: A convenience sample of currently practicing community pharmacists was recruited to participate in a 10-minute online survey. The survey included demographic questions and assessed pharmacists' buprenorphine ordering, stocking, and dispensing behaviors. Descriptive statistics were calculated, and logistic regressions examined associations with whether pharmacists (1) had ever refused to fill a buprenorphine prescription and (2) perceived buprenorphine dispensing limits. RESULTS: The majority (96%) of respondents (n = 646, completion rate = 5.5%) kept buprenorphine in stock regularly or ordered it as needed, with generic formulations being stocked most often. Many pharmacists (62%) had refused to fill a buprenorphine prescription. Pharmacists with more negative buprenorphine attitudes were more likely to refuse to fill a buprenorphine prescription. Many pharmacists (31%) believed there were buprenorphine ordering limits, with wholesalers most commonly being perceived as the source. Pharmacists with more negative buprenorphine attitudes were more likely to perceive buprenorphine ordering limits, while pharmacists who worked at national chain, grocery or regional chains, and other pharmacy types were less likely to perceive ordering limits than independent pharmacies. CONCLUSION: Although most pharmacies stocked buprenorphine products, pharmacists' refusal to dispense and perceived ordering limits could limit patient access. Refusal and perceived ordering limits were associated with pharmacist attitudes and pharmacy type. Training that addresses logistical and attitudinal barriers to dispensing buprenorphine may equip pharmacists to address buprenorphine access barriers.

Project ECHO® in Primary Care: Informing Providers about COVID-19 and Its Impact on Health Care Delivery.

BACKGROUND Rural, primary care providers face particular challenges with adapting the delivery of care in the setting of the Coronavirus Disease of 2019 (COVID-19) pandemic. Project ECHO® is a virtual, case-based platform centered on collective learning. As a regional Area Health Education Center (AHEC), we developed two Project ECHO® series aimed at disseminating best practices and creating a community of shared experiences for rural providers.METHODS On March 30, 2020, we launched two Project ECHO® series pertaining to COVID-19: the Primary Care COVID-19 Collaborative series and the Practice Support for COVID-19 Preparedness series. These series each occurred twice weekly, concluding in February 2021, and were free to attend. Topics include COVID-19-specific management as well as strategies for adapting the delivery of care during the pandemic. We assessed engagement per county as well as attendee evaluations.RESULTS In the first month, we hosted 19 sessions with 283 participants from 37 counties in North Carolina. Providers felt the most impactful aspects of the sessions were the changes to their practice and the lateral learning from peers in the region.LIMITATIONS In review of our survey responses, a small percentage of our participants do not appear to have direct patient care roles, so we believe this impacted our survey results particularly in regard to relevance to clinical practice and change to clinical practice.CONCLUSIONS Project ECHO® is an effective platform for quickly disseminating information and creating a sense of community in the midst of the social distancing required during the pandemic.

Impact of elective on students' perceptions of treating patients with a substance use disorder.

OBJECTIVE: To evaluate the impact of a substance use disorder (SUD) elective curriculum on students' perceptions of treating patients with SUDs using the Drug and Drug Problems Perceptions Questionnaire (DDPPQ). METHODS: In 2017, a third-year pharmacy elective, conceptualizing SUD as a chronic, relapsing brain disease with psychosocial and societal influencers, was introduced. A linked pre- and postcourse assessment using the DDPPQ was carried out for the following categories: role adequacy, role support, job satisfaction, role-related self-esteem, and role legitimacy. RESULTS: A total of 63 students were enrolled in the elective and 54 paired questionnaires were available for analysis. There was a statistically significant improvement in attitude across all 5 categories of the DDPPQ. CONCLUSION: Students' attitudes toward working with patients with SUD improved after completing the elective. This study indicates that teaching student pharmacists about effectively recognizing and treating SUDs may result in more willingness to work with these patients in the future.

Reprint of: Impact of elective on students' perceptions of treating patients with a substance use disorder.

OBJECTIVE: To evaluate the impact of a substance use disorder (SUD) elective curriculum on students' perceptions of treating patients with SUDs using the Drug and Drug Problems Perceptions Questionnaire (DDPPQ). METHODS: In 2017, a third-year pharmacy elective, conceptualizing SUD as a chronic, relapsing brain disease with psychosocial and societal influencers, was introduced. A linked pre- and postcourse assessment using the DDPPQ was carried out for the following categories: role adequacy, role support, job satisfaction, role-related self-esteem, and role legitimacy. RESULTS: A total of 63 students were enrolled in the elective and 54 paired questionnaires were available for analysis. There was a statistically significant improvement in attitude across all 5 categories of the DDPPQ. CONCLUSION: Students' attitudes toward working with patients with SUD improved after completing the elective. This study indicates that teaching student pharmacists about effectively recognizing and treating SUDs may result in more willingness to work with these patients in the future.

Evaluation of a pharmacist-led naloxone coprescribing program in primary care.

OBJECTIVES: To determine the impact of a pharmacist-led coprescribing initiative on patient access to naloxone in a primary care setting. SETTING: Family medicine residency practice with embedded pharmacists in western North Carolina. PRACTICE INNOVATION: In June 2016, clinical pharmacists embedded in a primary care clinic initiated a naloxone coprescribing initiative with the aim of increasing access to naloxone for patients on chronic opioid therapy who were on 50 mg or greater morphine-equivalents daily (MED), on a concomitant benzodiazepine, had a history of an overdose, or had a diagnosis of a substance use disorder. Pharmacists' roles included educating providers and clinical staff regarding naloxone, creating quick links within the electronic health record to more easily prescribe naloxone, identifying patients who met criteria for naloxone, and counseling patients about naloxone. EVALUATION: This study was a single-cohort pre- and postintervention study. One year after initiation of the program, data were manually collected to assess the rates of naloxone prescribing and the reason for requiring naloxone. In addition, pharmacy students called pharmacies to determine fill rates and obtain reasons given by patients for not filling naloxone. RESULTS: A total of 234 patients remained candidates for naloxone at the end of 1 year. Naloxone coprescribing increased from 3.4% at baseline to 37.2% at follow-up (P = 0.0001). Seventy-one percent of patients required naloxone because of chronic opioid therapy doses of 50 mg or more MED, 55% were on a benzodiazepine, 6% had a diagnosis of a substance use disorder, and 1% had a history of overdose. Of the patients who received a naloxone prescription, 31.4% filled it. CONCLUSION: Embedded clinical pharmacists in primary care have the potential to increase naloxone coprescribing for high-risk patients treated with chronic opioid therapy for pain.

Physician perceptions of integrating advanced practice pharmacists into practice.

OBJECTIVES: Barriers have prevented full integration of advanced practice pharmacists (APPs) into collaborative practice in some areas despite evidence describing their value. APPs in North Carolina can be recognized as Clinical Pharmacist Practitioners (CPPs) under a collaborative practice agreement and provide comprehensive medication management under physician supervision. This study describes the perceptions of physicians regarding the barriers and benefits of integrating CPPs into interprofessional teams and compares physician and CPP perceptions. METHODS: This prospective descriptive study surveyed CPP supervising physicians in North Carolina. The questionnaire consisted of 17 multiple-choice and free-response questions. Questions included demographics, perceived benefits and challenges of incorporating CPPs into health care teams, and services provided by CPPs. Findings were compared with previously published data that assessed CPP perceptions about the same topics to gain insight into common perspectives of team members. RESULTS: Fifty-six physicians (23.1%) responded, identifying enhanced clinical outcomes (87.5%), access to drug knowledge (58.9%), and creation of a multidisciplinary model for learners (57.1%) as the top benefits of working with CPPs. Primary barriers included limited reimbursement (60.7%) and billing difficulties (51.8%). More CPPs acknowledged provider acceptance as a barrier (25.9% vs. 3.6%; P = 0.001). Twelve physicians (21.4%) and no CPPs identified space as a barrier. CONCLUSION: Physicians identified enhanced clinical outcomes, access to drug knowledge, and creation of a multidisciplinary model for learners as the top benefits of incorporating CPPs into teams, and billing difficulties and limited reimbursement were the primary barriers. These findings were similar to the perceptions of CPPs, with exceptions being that physicians were more concerned about space limitations and CPPs noted that provider acceptance may be difficult. These findings may provide guidance to providers desiring to establish collaborative practice.

Development of a targeted naloxone coprescribing program in a primary care practice.

OBJECTIVES: To develop a targeted naloxone coprescribing program in a primary care practice. SETTING: Large academic family medicine practice in western North Carolina. PRACTICE DESCRIPTION: A robust pain management program was developed at this institution in 2012 which incorporated many of the recommendations later outlined in the 2016 Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids for chronic pain. The only guideline-recommended initiative that was not addressed involves providing naloxone to patients on chronic opioid therapy at high risk for opioid overdose. PRACTICE INNOVATION: Pharmacists embedded in this practice developed a targeted naloxone coprescribing program for patients who are on chronic opioid therapy and have doses of 50 mg or more morphine equivalents daily (MED), are taking benzodiazepines, have a history of substance use disorder, or have a history of overdose. EVALUATION: A retrospective chart review was conducted to determine the number of patients on chronic opioid therapy who meet the CDC guidelines for offering naloxone. RESULTS: A total of 1297 patients were identified, and 709 met the criteria for chronic opioid use. Nearly one-half (n = 350; 49.4%) of these patients met the criteria for naloxone, although only 3.4% had naloxone on their medication list. Doses of 50 mg or more MED was the primary reason for needing naloxone (n = 216; 61%) with concomitant benzodiazepine use as the second most likely reason (n = 130; 37.1%). For patients taking 50 mg or more MED, 37.5% were also on a benzodiazepine and 4.1% also had a history of substance use disorder. CONCLUSION: Pharmacists embedded in a primary care practice are well poised to develop a targeted naloxone coprescribing program to increase patients' access to naloxone.

The Integral Role of the Clinical Pharmacist Practitioner in Primary Care.

Clinical pharmacist practitioners serve as integral team members in primary care clinics. They extend the care provided for patients with chronic illnesses, improve health and wellness, and positively impact quality metrics in patient-centered medical homes and accountable care organizations.

Interprofessional care for patients with osteoporosis in a continuing care retirement community.

OBJECTIVES: To assess the quality of care provided to patients with osteoporosis in a continuing care retirement community (CCRC) after implementation of an interprofessional osteoporosis clinic (OPC). Specifically, quality measures were evaluated, including dual-emission X-ray absorptiometry (DXA) screening, calcium and vitamin D supplementation, and prescription treatment of osteoporosis and low bone mass in an ambulatory independent living community. SETTING: Large family medicine teaching practice that provides primary care for residents in one main practice, 5 rural satellite practices, and 2 CCRCs. An interprofessional OPC was developed at the main practice in 2005. Patients at all of the organization's sites could be referred to the main practice for osteoporosis management. A needs assessment conducted at one of the CCRCs in 2011 revealed that rates of screening and treatment were suboptimal for its residents despite availability of an off-site OPC. PRACTICE INNOVATION: In 2012, a new interprofessional OPC including a physician, medical assistant, and pharmacist was replicated on-site at the CCRC so that residents had access to this service within their medical home. EVALUATION: Quality measures were evaluated after implementation of the team-based OPC on-site at a CCRC and included: 1) DXA screening; 2) calcium and vitamin D supplementation; and 3) prescription treatment of osteoporosis and low bone mass. RESULTS: Twenty-nine patients were seen in the new OPC from January 2012 to August 2013. Ninety-three percent had appropriate DXA testing after OPC implementation. Patients accepted pharmacist recommendations regarding calcium and vitamin D supplementation 90% and 86% of the time, respectively. All but 4 patients received appropriate treatment for osteoporosis or low bone mass. CONCLUSION: Providing a team-based OPC on site in a CCRC improved quality measures for screening and treatment of osteoporosis and low bone mass.

Evaluation of a Team-Based, Transition-of-Care Management Service on 30-Day Readmission Rates.

BACKGROUND: Transitions of care from the hospital to the outpatient setting often fail to meet the Triple Aim of improving quality, improving the health of populations, and decreasing the cost of care. A major push to improve the quality of transitions and reduce hospital readmissions is under way. METHODS: We implemented a team-based, transition-of-care model and assessed the impact on 30-day readmission rates. The 3 components of the intervention were contact with a nurse care manager, medication reconciliation, and follow-up with a physician. We compared 30-day readmission rates for the period before versus after implementation of this intervention. RESULTS: The 30-day readmission rate decreased from 14.2% in the usual care group to 5.3% in the intervention group (P = .011). Almost 90% of patients in the intervention group received all 3 components of the intervention. LIMITATIONS: Generalizability is limited to practices with embedded team members. Not all patients received all 3 components of the intervention. CONCLUSIONS: Development of a team-based intervention was associated with a significant reduction in hospital readmissions. This method could be implemented in other primary care offices with team-based care.

Assessing pharmacist-led annual wellness visits: Interventions made and patient and physician satisfaction.

OBJECTIVES: To quantify the nature and frequency of interventions made by pharmacists during a Medicare annual wellness visit (AWV), to determine the association between the number of medications taken and the interventions made, and to assess patient and physician satisfaction with pharmacist-led AWVs. SETTING: Large, teaching, multidisciplinary family medicine practice in North Carolina. PRACTICE DESCRIPTION: Mountain Area Health Education Center (MAHEC) is a large academic practice that serves rural, western North Carolina. There is a heavy emphasis on team-based care. PRACTICE INNOVATION: Pharmacist-led AWV. EVALUATION: Between April 2012 and January 2013, the following were evaluated for 69 patients: the nature and frequency of interventions made, the association between the number of medications taken and the interventions made, and patient and physician satisfaction scores. RESULTS: A total of 247 medication-related interventions and 342 nonmedication interventions were made during the pharmacist-led AWVs. The majority of medication interventions (69.6%) involved correcting medication list discrepancies. The number of medications taken was positively associated with the total number of medication interventions (r = 0.37, P <0.01). On a 5-point Likert scale, patients strongly agreed that the AWV is important for their overall health (mean 4.8, median 5) and that they would like to see the same provider next year (mean 4.8, median 5). Physicians strongly disagreed that they would prefer to do the visit themselves (mean 1.5, median 1) and strongly agreed that their patients benefited from a pharmacist-led AWV (mean 5, median 4.9). CONCLUSION: Pharmacists addressed both medication and nonmedication interventions during AWVs. Patients taking a greater number of medications required more medication interventions than patients taking fewer medications. Patients and physicians reported satisfaction with the pharmacist-led AWV.

Financial implications of pharmacist-led Medicare annual wellness visits.

OBJECTIVE: To determine if pharmacist-led Medicare Annual Wellness Visits (AWVs) are a feasible mechanism to financially support a pharmacist position in physicians' offices. SETTING: Large, teaching, ambulatory clinic in North Carolina. PRACTICE DESCRIPTION: The Mountain Area Health Education Family Health Center is a family medicine practice that houses a large medical residency program. The Department of Pharmacotherapy comprises five pharmacists and two pharmacy residents providing direct patient care. PRACTICE INNOVATION: In April 2012, pharmacists began conducting Medicare AWVs for patients referred by their primary care physicians within the practice. MAIN OUTCOME MEASURES: Visit reimbursement, annual revenue, number of patients who must be seen to cover the cost of a pharmacist's salary. RESULTS: A small practice requires all eligible Medicare patients to complete an AWV to generate enough revenue to support a new pharmacist position. A medium-sized practice requires a 54% utilization rate, and a large practice requires an 18% utilization rate. Two additional AWVs per half-day of clinic are needed to support an existing pharmacotherapy clinic. A total of 1,070 AWVs per year are required to support a pharmacist's salary, regardless of practice size. CONCLUSIONS: AWV reimbursement may significantly contribute to supporting the cost of a pharmacist, particularly in medium- to large-sized practices. In larger practices, enough revenue can be generated to support the cost of multiple pharmacists.

Factors in rural community buprenorphine dispensing.

Background: There are pharmacy-related barriers to the dispensing of buprenorphine for the treatment of opioid use disorders. These include pharmacists' moral objections and mistrust of treatment regimens; the perception of a limit on the amount of buprenorphine able to be ordered and dispensed; stigma and concerns about diversion; and knowledge and communication gaps. Objectives: To document pharmacy stakeholders' awareness and interpretation of regulatory policies that may impact rural community pharmacists' willingness and ability to dispense buprenorphine. To identify factors that affect rural community pharmacists' willingness and ability to dispense buprenorphine in Appalachian North Carolina. Methods: Qualitative analysis and thematic coding of phone interviews with eight pharmacists from several rural North Carolina counties where local health departments recently began prescribing MOUD and four pharmacy industry stakeholders representing knowledge of wholesale distributors and pharmacy education. Results: Three major themes were identified: stigma and misinformation, provider-prescriber communication, and perceived and actual regulatory constraints. A number of respondents indicated a desire to better understand MOUD treatment plans and displayed a misunderstanding of evidence-based treatment guidelines. Stakeholders indicated the importance of pharmacists establishing a relationship with prescribers and described pharmacist preference for dispensing buprenorphine to established patients over new or out-of-area patients. Pharmacist stakeholders and industry/education stakeholders expressed concern over a perceived DEA 'cap' for buprenorphine ordering. Conclusions: This study provides insight on possible approaches to address rural pharmacy-related barriers patients may face when filling buprenorphine prescriptions. There is a demonstrated need for further pharmacist training on evidence-based practices for treating opioid use disorders and ordering limits, as well as a need for increased communication between prescribers and pharmacists.

Billing for pharmacists' cognitive services in physicians' offices: multiple methods of reimbursement.

OBJECTIVES: To evaluate the charges and reimbursement for pharmacist services using multiple methods of billing and determine the number of patients that must be managed by a pharmacist to cover the cost of salary and fringe benefits. SETTING: Large teaching ambulatory clinic in North Carolina. MAIN OUTCOME MEASURES: Annual charges and reimbursement, patient no-show rate, clinic capacity, number of patients seen monthly and annually, and number of patients that must be seen to pay for a pharmacist's salary and benefits. RESULTS: A total of 6,930 patient encounters were documented during the study period. Four different clinics were managed by the pharmacists, including anticoagulation, pharmacotherapy, osteoporosis, and wellness clinics. "Incident to" level 1 billing was used for the anticoagulation and pharmacotherapy clinics, whereas level 4 codes were used for the osteoporosis clinic. The wellness clinic utilized a negotiated fee-for-service model. Mean annual charges were $65,022, and the mean reimbursement rate was 47%. The mean charge and collection per encounter were $41 and $19, respectively. Eleven encounters per day were necessary to generate enough charges to pay for the cost of the pharmacist. Considering actual reimbursement rates, the number of patient encounters necessary increased to 24 per day. "What if" sensitivity analysis indicated that billing at the level of service provided instead of level 1 decreased the number of patients needed to be seen daily. Billing a level 4 visit necessitated that five patients would need to be seen daily to generate adequate charges. Taking into account the 47% reimbursement rate, 10 level 4 encounters per day were necessary to generate appropriate reimbursement to pay for the pharmacist. CONCLUSION: Unique opportunities for pharmacists to provide direct patient care in the ambulatory setting continue to develop. Use of a combination of billing methods resulted in sustainable reimbursement. The ability to bill at the level of service provided instead of a level 1 visit would decrease the number of patients needed to pay for a pharmacist.

An examination of telehealth policy impacts on initial rural opioid use disorder treatment patterns during the COVID-19 pandemic.

PURPOSE: Tracking changes in care utilization of medication for opioid use disorder (MOUD) services before, during, and after COVID-19-associated changes in policy and service delivery in a mixed rural and micropolitan setting. METHODS: Using a retrospective, open-cohort design, we examined visit data of MOUD patients at a family medicine clinic across three identified periods: pre-COVID, COVID transition, and COVID. Outcome measures include the number and type of visits (in-person or telehealth), the number of new patients entering treatment, and the number of urine drug screens performed. Distance from patient residence to clinic was calculated to assess access to care in rural areas. Goodness-of-Fit Chi-Square tests and ANOVAs were used to identify differences between time periods. FINDINGS: Total MOUD visits increased during COVID (436 pre vs. 581 post, p < 0.001), while overall new patient visits remained constant (33 pre vs. 29 post, p = 0.755). The clinic's overall catchment area increased in size, with new patients coming primarily from rural areas. Length of time between urine drug screens increased (21.1 days pre vs. 43.5 days post, p < 0.001). CONCLUSIONS: The patterns of MOUD care utilization during this period demonstrate the effectiveness of telehealth in this area. Policy changes allowing for MOUD to be delivered via telehealth, waiving the need for in-person initiation of MOUD, and increased Medicaid compensation for MOUD may play a valuable role in improving access to MOUD during the COVID-19 pandemic and beyond.

A Financial Model for Team-Based Opioid Use Disorder Treatment.

INTRODUCTION: Opioid use disorder (OUD) affects 2 million Americans, yet many patients do not receive treatment. Lack of team-based care is a common barrier for office-based opioid treatment (OBOT). In 2015, we started OBOT in a family medicine practice. Based on our experiences, we developed a financial model for hiring a team member to provide nonbillable OBOT services through revenue from increased patient volume. METHODS: We completed a retrospective chart review from July 2015 to December 2016 to determine the average difference in medical visits per patient per month pre-OBOT versus post-OBOT. Secondary outcomes were the percentage of visits coded as a Level 3, Level 4, and Level 5, and the percentage of patients with Medicaid, private insurance, or self pay. With this information, we extrapolated to build a financial model to hire a team member to support OBOT. RESULTS: Twenty-three patients received OBOT during the study period. There was a net increase of 1.93 visits per patient per month (P < .001). Fourteen patients were insured by Medicaid, 7 had private insurance, and 2 were self pay. Twenty-three percent of OBOT visits were Level 3, 69% were Level 4, and 8% were Level 5. Assuming all visits were reimbursed by Medicaid and accounting for 20% cost of business, treating 1 existing patient for 1 year would generate $1,439. Treating 1 new patient would generate $1,677. CONCLUSIONS: In a fee-for-service model, the revenue generated from increased medical visits can offset the cost of hiring a team member to support nonbillable OBOT services.

Does XR injectable naltrexone prevent relapse as effectively as daily sublingual buprenorphine-naloxone?

YES. MONTHLY EXTENDED-RELEASE INJECTABLE NALTREXONE (XR-NTX) TREATS OPIOID USE DISORDER AS EFFECTIVELY AS DAILY SUBLINGUAL BUPRENORPHINE-NALOXONE (BUP-NX) WITHOUT CAUSING ANY INCREASE IN SERIOUS ADVERSE EVENTS OR FATAL OVERDOSES. (STRENGTH OF RECOMMENDATION: A, 2 GOOD-QUALITY RCTS).