Pain management in trauma: the need for trauma-informed opioid prescribing guidelines.

Background/objectives: Surgical populations and particularly injury survivors often present with complex trauma that elevates their risk for prolonged opioid use and misuse. Changes in opioid prescribing guidelines during the past several years have yielded mixed results for pain management after trauma, with a limiting factor being the heterogeneity of clinical populations and treatment needs in individuals receiving opioids. The present analysis illuminates this gap between clinical guidelines and clinical practice through qualitative feedback from hospital trauma providers and unit staff members regarding current opioid prescribing guidelines and practices in the setting of traumatic injury. Methods: The parent study aimed to implement a pilot screening tool for opioid misuse in four level I and II trauma hospitals throughout Wisconsin. As part of the parent study, focus groups were conducted at each study site to explore the facilitators and barriers of implementing a novel screening tool, as well as to examine the current opioid prescribing guidelines, trainings, and resources available for trauma and acute care providers. Focus group transcripts were independently coded and analyzed using a modified grounded theory approach to identify themes related to the facilitators and barriers of opioid prescribing guidelines in trauma and acute care. Results: Three major themes were identified as impactful to opioid-related prescribing and care provided in the setting of traumatic injury; these include (1) acute treatment strategies; (2) patient interactions surrounding pain management; and (3) the multifactorial nature of trauma on pain management approaches. Conclusion: Providers and staff at four Wisconsin trauma centers called for trauma-specific opioid prescribing guidelines in the setting of trauma and acute care. The ubiquitous prescription of opioids and challenges in long-term pain management in these settings necessitate additional community-integrated research to inform development of federal guidelines. Level of evidence: Therapeutic/care management, level V.

Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions: Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. Main Outcomes and Measures: The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. Results: A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Conclusions and Relevance: Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03866174.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Association between spine injury and opioid misuse in a prospective cohort of Level I trauma patients.

Objective: To explore patient and treatment factors explaining the association between spine injury and opioid misuse. Design: Prospective cohort study. Setting: Level I trauma center in a Midwestern city. Participants: English speaking patients aged 18 to 75 on Trauma and Orthopedic Surgical Services receiving opioids during hospitalization and prescribed at discharge. Exposure: Spine injury on the Abbreviated Injury Scale. Main outcome measures: Opioid misuse was defined by using opioids: in a larger dose, more often, or longer than prescribed; via a non-prescribed route; from someone other than a prescriber; and/or use of heroin or opium. Exploratory factor groups included demographic, psychiatric, pain, and treatment factors. Multivariable logistic regression estimated the association between spine injury and opioid misuse when adjusting for each factor group. Results: Two hundred eighty-five eligible participants consented of which 258 had baseline injury location data and 224 had follow up opioid misuse data. Most participants were male (67.8%), white (85.3%) and on average 43.1 years old. One-quarter had a spine injury (25.2%). Of those completing follow-up measures, 14 (6.3%) developed misuse. Treatment factors (injury severity, intubation, and hospital length of stay) were significantly associated with spine injury. Spine injury significantly predicted opioid misuse [odds ratio [OR] 3.20, 95% confidence interval [CI] (1.05, 9.78)]. In multivariable models, adjusting for treatment factors attenuated the association between spine injury and opioid misuse, primarily explained by length of stay. Conclusion: Spine injury exhibits a complex association with opioid misuse that predominantly operates through treatment factors. Spine injury patients may represent a subpopulation requiring early intervention to prevent opioid misuse.

Screening in Trauma for Opioid Misuse Prevention (STOMP): Results from a prospective cohort of victims of traumatic injury.

BACKGROUND: Traumatic injury frequently requires opioid analgesia to manage pain and avoid catastrophic complications. Risk screening for opioid misuse and the development of use disorder remains uninvestigated. METHODS: Participants were Trauma/Orthopedic Surgical Services patients at a Level I Trauma Center who were English speaking, aged 18-75, received an opioids prescription at discharge, and were under control of their own medications at discharge. Baseline measures included validated self-report instruments for psychosocial factors, such as anxiety, depression, pain coping, and social support. Health record data included diagnosis codes, procedures, Injury Severity Score, and pain severity (0-10 scale). Opioid use disorder (by Clinical International Diagnostic Interview-Substance Abuse Module) or opioid misuse (Current Opioid Misuse Measure (COMM) and survey items) were assessed at 24 weeks post-discharge. RESULTS: 295 patients enrolled with 237 completing the 24 week assessments. Stepwise regression modeling demonstrated pre-injury PTSD symptoms, Opioid Risk score, medication use behaviors, social support, and length of stay predicted opioid misuse. Pre-injury PTSD symptoms, pain coping, and length of stay predicted use disorder. The final regression models for opioid misuse by COMM, opioid misuse via survey items, and for opioid use disorder had highly favorable areas under the receiver operating curve (0.880, 0.790, and 0.943 respectively). CONCLUSIONS: Pre-injury presence of PTSD-related symptoms, impaired pain coping, social support, and hospitalization > 6 days predicted opioid misuse and opioid addiction at 6 months after hospital discharge. Behavioral screening and management strategies appear warranted in the population of traumatic injury victims to reduce opioid-related risks.

A Web-Based eHealth Intervention to Improve the Quality of Life of Older Adults With Multiple Chronic Conditions: Protocol for a Randomized Controlled Trial.

BACKGROUND: Multiple chronic conditions (MCCs) are common among older adults and expensive to manage. Two-thirds of Medicare beneficiaries have multiple conditions (eg, diabetes and osteoarthritis) and account for more than 90% of Medicare spending. Patients with MCCs also experience lower quality of life and worse medical and psychiatric outcomes than patients without MCCs. In primary care settings, where MCCs are generally treated, care often focuses on laboratory results and medication management, and not quality of life, due in part to time constraints. eHealth systems, which have been shown to improve multiple outcomes, may be able to fill the gap, supplementing primary care and improving these patients' lives. OBJECTIVE: This study aims to assess the effects of ElderTree (ET), an eHealth intervention for older adults with MCCs, on quality of life and related measures. METHODS: In this unblinded study, 346 adults aged 65 years and older with at least 3 of 5 targeted high-risk chronic conditions (hypertension, hyperlipidemia, diabetes, osteoarthritis, and BMI ≥30 kg/m2) were recruited from primary care clinics and randomized in a ratio of 1:1 to one of 2 conditions: usual care (UC) plus laptop computer, internet service, and ET or a control consisting of UC plus laptop and internet but no ET. Patients with ET have access for 12 months and will be followed up for an additional 6 months, for a total of 18 months. The primary outcomes of this study are the differences between the 2 groups with regard to measures of quality of life, psychological well-being, and loneliness. The secondary outcomes are between-group differences in laboratory scores, falls, symptom distress, medication adherence, and crisis and long-term health care use. We will also examine the mediators and moderators of the effects of ET. At baseline and months 6, 12, and 18, patients complete written surveys comprising validated scales selected for good psychometric properties with similar populations; laboratory data are collected from eHealth records; health care use and chronic conditions are collected from health records and patient surveys; and ET use data are collected continuously in system logs. We will use general linear models and linear mixed models to evaluate primary and secondary outcomes over time, with treatment condition as a between-subjects factor. Separate analyses will be conducted for outcomes that are noncontinuous or not correlated with other outcomes. RESULTS: Recruitment was conducted from January 2018 to December 2019, and 346 participants were recruited. The intervention period will end in June 2021. CONCLUSIONS: With self-management and motivational strategies, health tracking, educational tools, and peer community and support, ET may help improve outcomes for patients coping with ongoing, complex MCCs. In addition, it may relieve some stress on the primary care system, with potential cost implications. TRIAL REGISTRATION: ClinicalTrials.gov NCT03387735; https://www.clinicaltrials.gov/ct2/show/NCT03387735. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25175.

Psychological and endocannabinoid responses to aerobic exercise in substance use disorder patients.

BACKGROUND: Exercise has been examined as an adjunctive treatment for substance use disorders (SUDs), yet few exercise interventions have been conducted among patients undergoing intensive outpatient (IOP) treatment, who may be the most vulnerable to relapse and for whom exercise could provide the most benefits. This study examined the effects of aerobic exercise, in addition to IOP treatment, on psychological variables and endocannabinoids in individuals with SUDs. Methods: Twenty-one SUD patients (mean age 35 years) were recruited from local IOPs. Participants were randomized to either treatment-as-usual (TAU, at their outpatient clinic) or TAU plus aerobic exercise training (EX). EX participants engaged in supervised, moderate-intensity exercise for 30 min, 3 times/week for 6 weeks. TAU participants came into the laboratory once per week for assessments and a 30-min quiet rest session. Participants provided blood samples and completed questionnaires evaluating substance use, mood states, depression, anxiety, perceived stress, self-efficacy to abstain from substance use, and craving. Data were analyzed with Mann-Whitney U tests or mixed model ANOVAs to determine group differences in outcomes acutely and over 6 weeks. Results: Over 6 weeks, there were reductions in perceived stress (p < 0.01) and craving (p < 0.05) for both groups. There were no group differences in abstinence rates or changes from baseline in self-efficacy, depression, or anxiety (p > 0.05). Acutely, both exercise and quiet rest sessions led to reductions in craving, tension, depression, anger, confusion, and total mood disturbance (all ps < 0.05). In addition, the EX group experienced acute increases in vigor and circulating concentrations of the endocannabinoid, anandamide (p < 0.01). Conclusions: An adjunctive aerobic exercise program during SUD treatment was associated with similar reductions in perceived stress and drug craving as standard care. Thirty minutes of exercise or quiet rest led to acute improvements in mood, but exercise produced the additional benefit of increases in vigor and circulating anandamide.

The Balanced Opioid Initiative: protocol for a clustered, sequential, multiple-assignment randomized trial to construct an adaptive implementation strategy to improve guideline-concordant opioid prescribing in primary care.

BACKGROUND: Rates of opioid prescribing tripled in the USA between 1999 and 2015 and were associated with significant increases in opioid misuse and overdose death. Roughly half of all opioids are prescribed in primary care. Although clinical guidelines describe recommended opioid prescribing practices, implementing these guidelines in a way that balances safety and effectiveness vs. risk remains a challenge. The literature offers little help about which implementation strategies work best in different clinical settings or how strategies could be tailored to optimize their effectiveness in different contexts. Systems consultation consists of (1) educational/engagement meetings with audit and feedback reports, (2) practice facilitation, and (3) prescriber peer consulting. The study is designed to discover the most cost-effective sequence and combination of strategies for improving opioid prescribing practices in diverse primary care clinics. METHODS/DESIGN: The study is a hybrid type 3 clustered, sequential, multiple-assignment randomized trial (SMART) that randomizes clinics from two health systems at two points, months 3 and 9, of a 21-month intervention. Clinics are provided one of four sequences of implementation strategies: a condition consisting of educational/engagement meetings and audit and feedback alone (EM/AF), EM/AF plus practice facilitation (PF), EM/AF + prescriber peer consulting (PPC), and EM/AF + PF + PPC. The study's primary outcome is morphine-milligram equivalent (MME) dose by prescribing clinicians within clinics. The study's primary aim is the comparison of EM/AF + PF + PPC versus EM/AF alone on change in MME from month 3 to month 21. The secondary aim is to derive cost estimates for each of the four sequences and compare them. The exploratory aim is to examine four tailoring variables that can be used to construct an adaptive implementation strategy to meet the needs of different primary care clinics. DISCUSSION: Systems consultation is a practical blend of implementation strategies used in this case to improve opioid prescribing practices in primary care. The blend offers a range of strategies in sequences from minimally to substantially intensive. The results of this study promise to help us understand how to cost effectively improve the implementation of evidence-based practices. TRIAL REGISTRATION: NCT04044521 (ClinicalTrials.gov). Registered 05 August 2019.

Survey of Southern Wisconsin Needle Exchange Clients Regarding Opioid Overdose and Naloxone Use.

BACKGROUND: Factors surrounding opioid overdose and naloxone use must be explored from the user perspective in order to more effectively combat the current opioid crisis. METHODS: AIDS Resource Center of Wisconsin needle exchange clients were surveyed regarding overdose victim demographics, interventions, experience with naloxone, and overdose outcomes. RESULTS: Most respondents (102/108, 94.4%) reported either experiencing or witnessing an overdose. While naloxone was often used (64/102, 62.7%), other recommended interventions, such as calling 911 (44/102, 43.1%) and rescue breathing (31/102, 30.4%) often were not. Potential legal consequences were cited as a major barrier for contacting emergency medical services (42.3%). DISCUSSION/CONCLUSION: There appears to be a need for education and/or policy change to facilitate appropriate overdose prevention and use of emergency medical services in the setting of opioid overdose.

Associations between pain coping and opioid use: One-month follow-up results of a prospective study in a cohort of traumatic injury patients.

OBJECTIVE: To examine associations between Pain Catastrophizing Scale (PCS) scores and daily opioid dosage in traumatic injury patients. DESIGN: This was a prospective cohort study with patient assessments at baseline and 1-month following discharge. SETTING: Study visits were conducted at a Regional Level I Trauma Center and by phone at follow-up. PATIENTS: Forty-nine injured inpatients completed baseline PCS. A subsample of 23 patients continued to take prescribed opioid medication at 1-month postdischarge and were included in the current analyses. MAIN OUTCOME MEASURED: Associations between baseline PCS and morphine equivalent daily dose (MEDD) at 1-month follow-up. RESULTS: Controlling for baseline MEDD, baseline PCS score was positively associated with MEDD at 1-month postdischarge (ß= 0.577 [0.399, 1.535]; p = 0.002; R2 of PCS = 0.395). CONCLUSIONS: In the current sample of traumatic injury inpatients, findings indicated that a baseline measure of pain catastrophizing predicts ongoing opioid medication use and dosage at 1-month postdischarge from an inpatient trauma unit.

High dose psilocybin is associated with positive subjective effects in healthy volunteers.

AIM: The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects. METHODS: Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8-36.6 mg; 27.1-54.0 mg; 36.3-59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire. RESULTS: There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience. CONCLUSIONS: High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes.

Implementing a Mobile Health System to Integrate the Treatment of Addiction Into Primary Care: A Hybrid Implementation-Effectiveness Study.

BACKGROUND: Despite the near ubiquity of mobile phones, little research has been conducted on the implementation of mobile health (mHealth) apps to treat patients in primary care. Although primary care clinicians routinely treat chronic conditions such as asthma and diabetes, they rarely treat addiction, a common chronic condition. Instead, addiction is most often treated in the US health care system, if it is treated at all, in a separate behavioral health system. mHealth could help integrate addiction treatment in primary care. OBJECTIVE: The objective of this paper was to report the effects of implementing an mHealth system for addiction in primary care on both patients and clinicians. METHODS: In this implementation research trial, an evidence-based mHealth system named Seva was introduced sequentially over 36 months to a maximum of 100 patients with substance use disorders (SUDs) in each of three federally qualified health centers (FQHCs; primary care clinics that serve patients regardless of their ability to pay). This paper reports on patient and clinician outcomes organized according to the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. RESULTS: The outcomes according to the RE-AIM framework are as follows: Reach-Seva reached 8.31% (268/3226) of appropriate patients. Reach was limited by our ability to pay for phones and data plans for a maximum of 100 patients per clinic. Effectiveness-Patients who were given Seva had significant improvements in their risky drinking days (44% reduction, (0.7-1.25)/1.25, P=.04), illicit drug-use days (34% reduction, (2.14-3.22)/3.22, P=.01), quality of life, human immunodeficiency virus screening rates, and number of hospitalizations. Through Seva, patients also provided peer support to one another in ways that are novel in primary care settings. Adoption-Patients sustained high levels of Seva use-between 53% and 60% of the patients at the 3 sites accessed Seva during the last week of the 12-month implementation period. Among clinicians, use of the technology was less robust than use by patients, with only a handful of clinicians using Seva in each clinic and behavioral health providers making most referrals to Seva in 2 of the 3 clinics. Implementation-At 2 sites, implementation plans were realized successfully; they were delayed in the third. Maintenance-Use of Seva dropped when grant funding stopped paying for the mobile phones and data plans. Two of the 3 clinics wanted to maintain the use of Seva, but they struggled to find funding to support this. CONCLUSIONS: Implementing an mHealth system can improve care among primary care patients with SUDs, and patients using the system can support one another in their recovery. Among clinicians, however, implementation requires figuring out how information from the mHealth system will be used and making mHealth data available in the electronic health (eHealth) record. In addition, paying for an mHealth system remains a challenge.

A randomized matched-pairs study of feasibility, acceptability, and effectiveness of systems consultation: a novel implementation strategy for adopting clinical guidelines for Opioid prescribing in primary care.

BACKGROUND: This paper reports on the feasibility, acceptability, and effectiveness of an innovative implementation strategy named "systems consultation" aimed at improving adherence to clinical guidelines for opioid prescribing in primary care. While clinical guidelines for opioid prescribing have been developed, they have not been widely implemented, even as opioid abuse reaches epidemic levels. METHODS: We tested a blended implementation strategy consisting of several discrete implementation strategies, including audit and feedback, academic detailing, and external facilitation. The study compares four intervention clinics to four control clinics in a randomized matched-pairs design. Each systems consultant aided clinics on implementing the guidelines during a 6-month intervention consisting of monthly site visits and teleconferences/videoconferences. The mixed-methods evaluation employs the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Quantitative outcomes are compared using time series analysis. Qualitative methods included focus groups, structured interviews, and ethnographic field techniques. RESULTS: Seven clinics were randomly approached to recruit four intervention clinics. Each clinic designated a project team consisting of six to eight staff members, each with at least one prescriber. Attendance at intervention meetings was 83%. More than 80% of staff respondents agreed or strongly agreed with the statements: "I am more familiar with guidelines for safe opioid prescribing" and "My clinic's workflow for opioid prescribing is easier." At 6 months, statistically significant improvements were noted in intervention clinics in the percentage of patients with mental health screens, treatment agreements, urine drug tests, and opioid-benzodiazepine co-prescribing. At 12 months, morphine-equivalent daily dose was significantly reduced in intervention clinics compared to controls. The cost to deliver the strategy was $7345 per clinic. Adaptations were required to make the strategy more acceptable for primary care. Qualitatively, intervention clinics reported that chronic pain was now treated using approaches similar to those employed for other chronic conditions, such as hypertension and diabetes. CONCLUSIONS: The systems consultation implementation strategy demonstrated feasibility, acceptability, and effectiveness in a study involving eight primary care clinics. This multi-disciplinary strategy holds potential to mitigate the prevalence of opioid addiction and ultimately may help to improve implementation of clinical guidelines across healthcare. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02433496). https://clinicaltrials.gov/ct2/show/NCT02433496 Registered May 5, 2015.

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

INTRODUCTION: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. METHODS: Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. RESULTS: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. CONCLUSIONS: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. CLINICAL TRIALS IDENTIFIER: NCT02163707.

Systems consultation: protocol for a novel implementation strategy designed to promote evidence-based practice in primary care.

BACKGROUND: Adoption of evidence-based practices takes place at a glacial place in healthcare. This research will pilot test an innovative implementation strategy - systems consultation -intended to speed the adoption of evidence-based practice in primary care. The strategy is based on tenets of systems engineering and has been extensively tested in addiction treatment. Three innovations have been included in the strategy - translation of a clinical practice guideline into a checklist-based implementation guide, the use of physician peer coaches ('systems consultants') to help clinics implement the guide, and a focus on reducing variation in practices across prescribers and clinics. The implementation strategy will be applied to improving opioid prescribing practices in primary care, which may help ultimately mitigate the increasing prevalence of opioid abuse and addiction. METHODS/DESIGN: The pilot test will compare four intervention clinics to four control clinics in a matched-pairs design. A leading clinical guideline for opioid prescribing has been translated into a checklist-based implementation guide in a systematic process that involved experts who wrote the guideline in consultation with implementation experts and primary care physicians. Two physicians with expertise in family and addiction medicine are serving as the systems consultants. Each systems consultant will guide two intervention clinics, using two site visits and follow-up communication by phone and email, to implement the translated guideline. Mixed methods will be used to test the feasibility, acceptability, and preliminary effectiveness of the implementation strategy in an evaluation that meets standards for 'fully developed use' of the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance). The clinic will be the primary unit of analysis. DISCUSSION: The systems consultation implementation strategy is intended to generalize to the adoption of other clinical guidelines. This pilot test is intended to prepare for a large randomized clinical trial that will test the strategy against other implementation strategies, such as audit/feedback and academic detailing, used to close the gap between knowledge and practice. The systems consultation approach has the potential to shorten the famously long time it takes to implement evidence-based practices and clinical guidelines in healthcare.

Specialty substance use disorder services following brief alcohol intervention: a meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Brief alcohol interventions in medical settings are efficacious in improving self-reported alcohol consumption among those with low-severity alcohol problems. Screening, Brief Intervention and Referral to Treatment initiatives presume that brief interventions are efficacious in linking patients to higher levels of care, but pertinent evidence has not been evaluated. We estimated main and subgroup effects of brief alcohol interventions, regardless of their inclusion of a referral-specific component, in increasing the utilization of alcohol-related care. METHODS: A systematic review of English language papers published in electronic databases to 2013. We included randomized controlled trials (RCTs) of brief alcohol interventions in general health-care settings with adult and adolescent samples. We excluded studies that lacked alcohol services utilization data. Extractions of study characteristics and outcomes were standardized and conducted independently. The primary outcome was post-treatment alcohol services utilization assessed by self-report or administrative data, which we compared across intervention and control groups. RESULTS: Thirteen RCTs met inclusion criteria and nine were meta-analyzed (n = 993 and n = 937 intervention and control group participants, respectively). In our main analyses the pooled risk ratio (RR) was = 1.08, 95% confidence interval (CI) = 0.92-1.28. Five studies compared referral-specific interventions with a control condition without such interventions (pooled RR = 1.08, 95% CI = 0.81-1.43). Other subgroup analyses of studies with common characteristics (e.g. age, setting, severity, risk of bias) yielded non-statistically significant results. CONCLUSIONS: There is a lack of evidence that brief alcohol interventions have any efficacy for increasing the receipt of alcohol-related services.

Integrating addiction treatment into primary care using mobile health technology: protocol for an implementation research study.

BACKGROUND: Healthcare reform in the United States is encouraging Federally Qualified Health Centers and other primary-care practices to integrate treatment for addiction and other behavioral health conditions into their practices. The potential of mobile health technologies to manage addiction and comorbidities such as HIV in these settings is substantial but largely untested. This paper describes a protocol to evaluate the implementation of an E-Health integrated communication technology delivered via mobile phones, called Seva, into primary-care settings. Seva is an evidence-based system of addiction treatment and recovery support for patients and real-time caseload monitoring for clinicians. METHODS/DESIGN: Our implementation strategy uses three models of organizational change: the Program Planning Model to promote acceptance and sustainability, the NIATx quality improvement model to create a welcoming environment for change, and Rogers's diffusion of innovations research, which facilitates adaptations of innovations to maximize their adoption potential. We will implement Seva and conduct an intensive, mixed-methods assessment at three diverse Federally Qualified Healthcare Centers in the United States. Our non-concurrent multiple-baseline design includes three periods - pretest (ending in four months of implementation preparation), active Seva implementation, and maintenance - with implementation staggered at six-month intervals across sites. The first site will serve as a pilot clinic. We will track the timing of intervention elements and assess study outcomes within each dimension of the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, including effects on clinicians, patients, and practices. Our mixed-methods approach will include quantitative (e.g., interrupted time-series analysis of treatment attendance, with clinics as the unit of analysis) and qualitative (e.g., staff interviews regarding adaptations to implementation protocol) methods, and assessment of implementation costs. DISCUSSION: If implementation is successful, the field will have a proven technology that helps Federally Qualified Health Centers and affiliated organizations provide addiction treatment and recovery support, as well as a proven strategy for implementing the technology. Seva also has the potential to improve core elements of addiction treatment, such as referral and treatment processes. A mobile technology for addiction treatment and accompanying implementation model could provide a cost-effective means to improve the lives of patients with drug and alcohol problems. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01963234).

Impact of jail sanctions during drug court participation upon substance abuse treatment completion.

AIMS: This study of participants in a US drug treatment court describes the relationship between the imposition of short-term jail sanctions and substance abuse treatment dropout, and examines offender characteristics moderating or modifying the impact of jail sanctions on treatment dropout. METHODS: Data were derived from administrative information collected by the Dane County Wisconsin Drug Treatment Court from 1996-2004 on all 573 participants achieving a final disposition of treatment completion or failure during those program years. Iterative Cox proportional hazards models of time to treatment failure were created; jail sanctions during drug court participation were framed as time-dependent covariates. A theoretical framework and specific statistical criteria guided construction of a final parsimonious model of time to treatment drop-out. FINDINGS: Treatment failure was associated with unemployment [hazard ratio (HR) in unemployed versus employed = 1.41, P-value 0.0079], lower educational attainment (HR in high school non-graduate versus graduate = 1.41, P = 0.02) and application of the first jail sanction (HR 2.71, P < 0.001). The association between treatment failure and a first sanction was considerably stronger for sanctions administered earlier in participation (HR for sanction 1 at <30 days 11.34, P-value 0.0002). Conclusions An initial jail sanction for non-adherence may be more likely to foster treatment compliance in less refractory individuals (i.e. those not already acclimated or socialized to incarceration or other corrections interventions). More stringent supervisory conditions and individualized services may be required to reintegrate such offenders and promote longer-term public safety.

Systematic review of the impact of adult drug-treatment courts.

The U.S. correctional system is overburdened with individuals suffering from substance use disorders. These illnesses also exact a heavy toll on individual and public health and well-being. Effective methods for reducing the negative impact of substance use disorders comprise critical concerns for policy makers. Drug treatment court (DTC) programs are present in more than 1800 county, tribal, and territorial jurisdictions in the United States as an alternative to incarceration for offenders with substance use disorders. This review article summarizes the available descriptive information on representative DTC populations and the observational studies of drug court participants, and it specifically reviews the available experimental effectiveness literature on DTCs. The review concludes by examining the limitations of the current literature, challenges to conducting research in drug court samples, and potential future directions for research on DTC interventions. A review of nonexperimental and quasi-experimental literature regarding the impact of DTCs points toward benefit versus traditional adjudication in averting future criminal behavior and in reducing future substance use, at least in the short term. Randomized effectiveness studies of DTCs are scant (3 were identified in the literature on U.S. adult drug courts), and methodological issues develop in combining their findings. These randomized trials failed to demonstrate a consistent effect on rearrest rates for drug-involved offenders participating in DTC versus typical adjudication. The 2 studies examining reconviction and reincarceration, however, demonstrated reductions for the DTC group versus those typically adjudicated.