Addiction Medicine

Screening, Brief Intervention, and Referral to Treatment in a Retail Pharmacy Setting: The Pharmacist's Role in Identifying and Addressing Risk of Substance Use Disorder Objective: This study determined the feasibility of interviewing and screening patients presenting to a retail pharmacy using Screening, Brief Intervention, and Referral to Treatment (SBIRT) interview protocols, and to compare SBIRT results to a risk score calculated from Prescription Drug Monitoring Program (PDMP) data. Methods: Using the NIDA Quick Screen and NIDA Modified-ASSIST (NM-ASSIST) and the Alcohol Use Disorder Identification Test (AUDIT), retail pharmacy customers were screened for substance and alcohol use disorder and tobacco use. PDMP reports were collected on subjects and a PDMP-risk score was calculated based on the numbers of Schedule II-V prescriptions and prescribers over the previous 12 months. Results: A total of 24 patients were included in this study (67% response rate). SBIRT screening revealed that 20.8% were at-risk for substance use disorder (SUD), 16.7% for alcohol use disorder, and 37.5% used tobacco. Overall, 33.3% of subjects were at-risk for SUD or alcohol use disorder. Fifty percent of subjects required education and/or brief intervention based on their responses, 37.5% of all subjects were deemed at-risk based on their PDMP-risk score, and 60% of patients who were risk-positive by SBIRT screening were also PDMP-risk positive. Conclusions: This study demonstrates the feasibility of performing SBIRT-based screenings in a retail pharmacy setting and combining these with PDMP-risk analysis to screen patients for prescription and illicit drug misuse. Findings from this study will inform the design of larger multisite studies, which should validate these findings and include follow-up analysis to assess the efficacy of intervention on this patient population. Send correspondence to Richard M. Gustin, PhD, The Recovery Research Network Foundation, Atlantis, FL 33462. E-mail: Richard.Gustin@trrn.org Received 17 September, 2018 Accepted 22 February, 2019 Funding Sources: The Recovery Research Network Foundation, B.C.S. was supported by NIMH Grant K01-MH107765. The authors report no conflicts of interest. © 2019 American Society of Addiction Medicine

A Pilot Crossover Trial of Sleep Medications for Sleep-disturbed Methadone Maintenance Patients Objectives: Problems with sleep are a common and detrimental occurrence among individuals who receive methadone maintenance for opioid use disorder (OUD). Methods: We enrolled ten methadone-maintained persons with insomnia (60% female, mean age 40) in a double-blind trial using actigraphy to confirm daily sleep reports. After a no-medication week to establish baseline sleep patterns, each participant received 1 week each of mirtazapine (30 mg), zolpidem (sustained-release 12.5 mg), mirtazapine (30 mg IR) plus zolpidem (10 mg), and placebo, with a washout week between each medication week. Study medication order was randomized so that the order of each 1-week medication treatment was different for each participant, but all participants received all 4 regimens. Results: We found that mirtazapine alone improved total sleep (mean 23 minutes), sleep latency (mean 23 minutes), and sleep efficiency (mean 3%), surpassing the other regiments. Conclusions: This pilot work suggests that mirtazapine is worthy of further testing as a sleep aid for persons with OUD receiving methadone maintenance. Send correspondence to Claire E. Blevins, PhD, 345 Blackstone Blvd., Providence, RI 02906. E-mail: Claire_Blevins@Brown.edu Received 10 October, 2018 Revised 12 December, 2018 Accepted 26 December, 2018 Dr Blevins is a recipient of an Institutional Development Award (U54GM115677) from the National Institute of General Medical Sciences of the National Institutes of Health, which funds Advance Clinical and Translational Research (Advance-CTR). The other authors declare no conflicts of interest. © 2019 American Society of Addiction Medicine

Psychotropics in Your Medicine Cabinet: A Case Study of Dimenhydrinate Use Reporting of intoxication and withdrawal from aberrant use of over-the-counter medication has been sparse and inconsistent in literature. Attributed to their anticholinergic properties, medications such as dimenhydrinate (Gravol) taken in supratherapeutic doses have been associated with euphoria, anxiolysis, and hallucinations. We present a case of a woman in her forties, with a psychiatric history of bipolar disorder, and complex concurrent medical history including familial Mediterranean fever (FMF), and fibromyalgia, admitted for withdrawal management of her intravenous dimenhydrinate use. As a result of her FMF, there were numerous hospital admissions and treatment which required intravenous access. Hence, a physician-inserted intravenous access port was placed on her chest. The port was maintained monthly with the help of a community agency. In this port, she was injecting 100 to 200 mg of dimenhydrinate hourly for its euphoric and calming effects, consuming upwards of 2400 mg/d. Comprehensive laboratory work-up and urine drug screening were unremarkable. Vital signs were stable. Her mental status at time of admission was lethargic, unfocused, but calm. Her withdrawal symptoms included severe nausea, vomiting, sedation, headaches, dizziness, anxiety, and muscle stiffness. Her detoxification was managed with benztropine and lorazepam, and was well tolerated. The patient was discharged to a community inpatient rehabilitation center. Urine drug testing before discharge was negative. This case draws attention to the addictive potential of dimenhydrinate and offers a regime for its medical withdrawal management. Additionally, this case highlights that screening and management of over-the-counter medications warrants further clinical consideration and investigation. Send correspondence to Nitin Chopra, MD, Centre for Addiction and Mental Health, Toronto, ON, Canada. E-mail: nitin.chopra@camh.ca Received 25 November, 2018 Accepted 26 January, 2019 No commercial organizations had any role in the completion or publication of this article. The authors declare no competing interest during the past 36 months. © 2019 American Society of Addiction Medicine

Prescribing of Opioids and Benzodiazepines Among Patients With History of Overdose Objectives: Addiction and overdose related to prescription drugs continues to be a leading cause of morbidity and mortality in the United States. We aimed to characterize the prescribing of opioids and benzodiazepines to patients who had previously presented with an opioid or benzodiazepine overdose. Methods: This was a retrospective chart review of patients who were prescribed an opioid or benzodiazepine in a 1-month time-period in 2015 (May) and had a previous presentation for opioid or benzodiazepine overdose at a large healthcare system. Results: We identified 60,129 prescribing encounters for opioids and/or benzodiazepines, 543 of which involved a patient with a previous opioid or benzodiazepine overdose. There were 404 unique patients in this cohort, with 97 having more than 1 visit including a prescription opioid and/or benzodiazepine. A majority of prescriptions (54.1%) were to patients with an overdose within the 2 years of the documented prescribing encounter. Prescribing in the outpatient clinical setting represented half (49.9%) of encounters, whereas emergency department prescribing was responsible for nearly a third (31.5%). Conclusions: In conclusion, prescribing of opioids and benzodiazepines occurs across multiple locations in a large health care system to patients with a previous overdose. Risk factors, such as previous overdose should be highlighted through clinical decision support tools in the medical record to help prescribers identify patients at higher risk and to mobilize resources for this patient population. Prescribers need further education on factors that place their patients at risk for opioid use disorder and on alternative therapies to opioids and benzodiazepines. Send correspondence to Christopher Griggs, MD, MPH, Department of Emergency Medicine, Carolinas Trauma Network Research Center of Excellence, Atrium Health, Carolinas Medical Center, 1000 Blythe Blvd, Charlotte, NC 28203. E-mail: Christopher.Griggs@atriumhealth.org. Received 23 August, 2018 Accepted 26 January, 2019 Supported by Centers for Disease Control and Prevention grant (CE14-004 Award Number CE002520). Presented as a poster at American College of Emergency Physician in Las Vegas, NV, October 2016 and at American Public Health Association in Denver, CO, October 2016. The authors report no conflicts of interest. © 2019 American Society of Addiction Medicine

Genetic Variant in the CRH-binding Protein Gene (CRHBP) is Associated With Cessation of Cocaine Use in Methadone Maintenance Patients With Opioid Addiction Objectives: We have previously shown associations between 4 genetic variants in opioid and stress-related genes (OPRM1, NPYR1/NPYR5, NR3C1, and CRHBP) and prolonged abstinence from heroin without methadone maintenance treatment (MMT). We currently assessed the associations between these variants and MMT patients' characteristics. Methods: A non-selective group of 351 patients who stayed at least 1 year in their first admission to MMT were genotyped and their characteristics and substance in urine on admission and after 1 year were studied. Results: The proportions of patients with both cocaine and benzodiazepine abuse were reduced significantly after 1 year in MMT; however, cocaine abuse cessation was significantly associated with the non-carriers of the CRHBP (corticotrophin releasing hormone binding protein) SNP rs1500 minor C allele (GG genotype) (P = 0.0009, PBonferroni = 0.0221). More carriers of the 2 C alleles (CC genotype) than carriers of the GC and GG genotypes abused cocaine on admission (32.3% vs 19.7%, respectively, P = 0.0414, recessive model), and more of the C allele carriers (GC and CC genotypes) than non-carriers (GG genotype) abused cocaine after 1 year in MMT (25.7% vs 15.8%, respectively, P = 0.0334, dominant model). Abusers of benzodiazepine were more prevalent among carriers of the C allele compared with non-carriers on admission (60.6% vs 45.9%, respectively, P = 0.0080, dominant model), as well as after 1 year in MMT (50.9% vs 39.1%, respectively, P = 0.0362). Conclusions: Reduction in cocaine abuse among MMT patients may be mediated by a genetic effect in a stress-related gene (CRHBP SNP rs1500 minor C allele). Evaluations of larger samples, additional SNPs, and different populations are needed to support these findings. Send correspondence to Einat Peles, PhD, Adelson Clinic, Tel Aviv Medical Center, 1 Henrietta Szold St., Tel Aviv 64924, Israel. E-mail: einatp@tlvmc.gov.il Received 31 October, 2018 Accepted 14 December, 2018 The authors report no conflicts of interest. The study was funded by The Dr. Miriam and Sheldon G. Adelson Family Foundation. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.journaladdictionmedicine.com). © 2019 American Society of Addiction Medicine

Patient-centered Outcomes in Participants of a Buprenorphine Monthly Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study Objective: Opioid use disorder (OUD) is associated with physical, social, psychological, and economic burden. This analysis assessed the effects of RBP-6000, referred to as BUP-XR (extended-release buprenorphine), a subcutaneously injected, monthly buprenorphine treatment for OUD compared with placebo on patient-centered outcomes measuring meaningful life changes. Methods: Patient-centered outcomes were collected in a 24-week, phase 3, placebo-controlled study assessing the efficacy, safety, and tolerability of BUP-XR 300/300 mg (6 × 300 mg) and 300/100 mg (2 × 300 mg followed by 4 × 100 mg) injections in treatment-seeking participants with moderate-to-severe OUD. Measures included the EQ-5D-5L, SF-36v2, Medication Satisfaction Questionnaire, employment/insurance status, and healthcare resource utilization (HCRU). Changes from baseline to end of study were compared across treatment arms, using mixed models for repeated measures. Results: Participants receiving BUP-XR (n = 389) versus placebo (n = 98) had significantly greater changes from baseline on the EQ-5D-5L index (300/300 mg: difference = 0.0636, P  = 0.003), EQ-5D-5L visual analog scale (300/300 mg: difference = 5.9, P  = 0.017; 300/100 mg: difference = 7.7, P  = 0.002), and SF-36v2 physical component summary score (300/300 mg: difference = 3.8, P  < 0.001; 300/100 mg: difference = 3.2, P  = 0.002). Satisfaction was significantly higher for participants receiving BUP-XR 300/300 mg (88%, P < 0.001) and 300/100 mg (88%, P < 0.001) than placebo (46%). Employment and percentage of insured participants increased by 10.8% and 4.1% with BUP-XR 300/300 mg and 10.0% and 4.7% with 300/100 mg but decreased by 12.6% and 8.4% with placebo. Participants receiving BUP-XR compared with placebo had significantly fewer hospital days per person-year observed. Conclusions: These results show the feasibility of measuring patient-centered life changes in substance use disorder clinical studies. Participants receiving up to 6 monthly injections of BUP-XR, compared with placebo, reported better health, increased medication satisfaction, increased employment, and decreased healthcare utilization. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Send correspondence to Caitlyn T. Solem, PhD, Pharmerit International, 4350 East-West Highway, Suite 1100, Bethesda, MD 20814. E-mail: csolem@pharmerit.com Received 25 October, 2018 Accepted 4 February, 2019 Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.journaladdictionmedicine.com). This study was funded by Indivior Inc. W.L. is a consultant for Indivior Inc, Alkermes, Camurus/Braeburn, Opiant and Titan Pharmaceuticals. V.R.N., S.M.L., and C.H. are employees of Indivior Inc. N.A.R. was an employee of Indivior Inc. at the time of study conduct. C.T.S. and Y.-C.Y. are employees of Pharmerit International and are consultants for Indivior Inc. V.M. was a clinical investigator for the RBP-6000 clinical trials and consultant for Indivior Inc. The authors report no conflicts of interest © 2019 American Society of Addiction Medicine

Disparities Between US Opioid Overdose Deaths and Treatment Capacity: A Geospatial and Descriptive Analysis Introduction: With opioid-related deaths reaching epidemic levels, gaining a better understanding of access to treatment for opioid use disorder (OUD) is critical. Most studies have focused on 1 side of the equation—either provider capacity or patients' need for care, as measured by overdose deaths. This study examines the overlay between treatment program availability and opioid mortality, comparing accessibility by region. Methods: Geospatial and statistical analyses were used to model OUD treatment programs relative to population density and opioid overdose death incidence at the state and county level. We computed a ratio between program capacity and mortality called the programs-per-death (PPD) ratio. Results: There were 40 274 opioid deaths in 2016 and 12 572 treatment programs across the contiguous 48 states, yielding a ratio of 1 program for every 3.2 deaths. Texas had the lowest number of treatment programs per 100 000 persons (1.4) and Maine the highest (13.2). West Virginia ranked highest in opioid deaths (39.09 per 100 000). Ohio, the District of Columbia, and West Virginia had the greatest mismatch between providers and deaths, with an average of 1 program for every 8.5 deaths. Over 32% of US counties had no treatment programs and among those with >10 deaths, nearly 2.5% had no programs. Over 19% of all counties had a ratio ≤1 provider facility per 10 deaths. Conclusion: Assessing the overlay between treatment capacity and need demonstrated that regional imbalances exist. These data can aid in strategic planning to correct the mismatch and potentially reduce mortality in the most challenged geographic regions. Send correspondence to James R. Langabeer, PhD, University of Texas Health Science Center at Houston, Houston, TX 77030. E-mail: James.R.Langabeer@uth.tmc.edu Received 4 December, 2018 Accepted 9 February, 2019 © 2019 American Society of Addiction Medicine

Adverse Events During Treatment Induction With Injectable Diacetylmorphine and Hydromorphone for Opioid Use Disorder Objectives: The present study aims to describe a 3-day induction protocol for injectable hydromorphone (HDM) and diacetylmorphine (DAM) used in 3 Canadian studies and examine rates of opioid-related overdose and somnolence during this induction phase. Methods: The induction protocol and associated data on opioid-related overdose and somnolence are derived from 2 clinical trials and one cohort study conducted in Vancouver and Montreal (2005–2008; 2011–2014; 2014–2018). In this analysis, using the Medical Dictionary for Regulatory Activities coding system we report somnolence (ie, drowsiness, sleepiness, grogginess) and opioid overdose as adverse events. Overdoses requiring intervention with naloxone are coded as severe adverse events. Results: Data from the 3 studies provides a total of 1175 induction injections days, with 700 induction injection days for DAM, and 475 induction injection days for HDM. There were 34 related somnolence and adverse event (AE) overdoses (4.899 per 100 injection days) in DAM and 6 (1.467 per 100 days) in HDM. Four opioid overdoses requiring naloxone (0.571 per 100 injection days) were registered in DAM and 1 in HDM (0.211 per 100 injection days), all safely mitigated onsite. The first week maximum daily dose patients received were on average 433.62 mg [standard deviation (SD) = 137.92] and 223.26 mg (SD = 68.06) for DAM and HDM, respectively. Conclusions: A 3-day induction protocol allowed patients to safely reach high doses of injectable hydromorphone and diacetylmorphine in a timely manner. These findings suggest that safety is not an evidence-based barrier to the implementation of treatment with injectable hydromorphone and diacetylmorphine. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Send correspondence to Eugenia Oviedo-Joekes, PhD, St. Paul's Hospital, 575-1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6. E-mail: eugenia@cheos.ubc.ca Received 27 July, 2018 Accepted 8 January, 2019 The RUTH Study was funded by a Canadian Institutes of Health Research Project Grant. The SALOME trial was funded through an operating grant from the Canadian Institutes of Health Research in partnership with Providence Health Care with additional financial support from the InnerChange Foundation, Providence Health Care Research Institute, St. Paul's Hospital Foundation and Vancouver Coastal Health. The NAOMI study was supported by grants from the Canadian Institutes of Health Research, the Canada Foundation for Innovation, the Canada Research Chairs Program, the University of British Columbia, Providence Health Care, the University of Montreal, Centre de Recherche et Aide aux Narcomanes, the Government of Quebec, Vancouver Coastal Health, and the BC Centre for Disease Control. Further financial support was provided by the Michael Smith Foundation for Health Research Career Award and the Canada Institutes of Health Research New Investigator Award (EOJ) and the Canada Research Chairs Program (MTS). The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. The authors have no competing interests to declare. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.journaladdictionmedicine.com). © 2019 American Society of Addiction Medicine

Evaluation of the Brief Alcohol Withdrawal Scale Protocol at an Academic Medical Center Objectives: The standard of care for treatment of alcohol withdrawal is symptom-triggered dosing of benzodiazepines using a withdrawal scale. Abbreviated scales are desired for clinician efficiency. The objective of this study was to evaluate the use of the 5-item Brief Alcohol Withdrawal Scale (BAWS) protocol. Methods: This single-center, retrospective, observational, cohort study assessed patients ordered the BAWS protocol between August 1, 2016 and July 31, 2017. Data were collected on benzodiazepine exposure, duration of treatment, withdrawal severity, agitation, over-sedation, and delirium while being treated for alcohol withdrawal. Comparisons were made to analyze predetermined patient subgroups. Results: Seven hundred ninety-nine patients were initiated on the BAWS protocol. Patients received a median (IQR) of 0 (0–4) lorazepam equivalents (LEs) and were on the BAWS protocol for a median (IQR) of 44.9 (22.4–77.2) hours. Of the patients that received benzodiazepines while on the BAWS protocol, a median (IQR) of 4 (2–11) LEs were given. Seventeen (2.1%) patients had severe withdrawal. Days of agitation, over-sedation, and delirium were minimal, with the median (IQR) of 0 (0–0). Few patients received adjunctive medications for symptom management. Intensive care unit (ICU) patients had more severe withdrawal than non-ICU patients, but received the same cumulative benzodiazepine dose. Conclusions: Most patients on the BAWS protocol received little-to-no benzodiazepines; severe withdrawal, agitation, delirium, or over-sedation were uncommon. This is the first evaluation of the BAWS protocol on a diverse population of hospitalized patients. Send correspondence to Brian K. Lindner, PharmD, Department of Pharmacy, The Johns Hopkins Hospital, 600 North Wolfe Street, Carnegie 180, Baltimore, MD 21287-6180. E-mail: blindne1@jhmi.edu Received 4 September, 2018 Accepted 8 January, 2019 Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.journaladdictionmedicine.com). The authors declare no conflicts of interest. © 2019 American Society of Addiction Medicine

Initiation and Rapid Titration of Methadone in an Acute Care Setting for the Treatment of Opioid Use Disorder: A Case Report Background: Although methadone is an effective treatment for opioid use disorder, its initiation requires prescribing at a subtherapeutic dose with subsequent titration to a therapeutic dose over many weeks. Accordingly, the methadone induction period can be a challenging one for individuals and can be associated with an increased risk for ongoing illicit drug use and consequently overdose. Given its capacity for regular clinical assessments, acute care settings may offer a unique opportunity to reduce the duration of the induction period for methadone maintenance therapy. Case summary: We report a case of an individual who successfully completed initiation and rapid methadone titration for treatment of opioid use disorder in an acute care setting. Discussion: Utilizing divided dosing intervals and regular monitoring for toxicity, the patient received a cumulative methadone dose of 130 mg total within the first 48 hours of admission with continuation of a similar dose subsequently. No adverse events occurred over a 9-day follow-up period. The case report described here highlights the potential acute care settings may offer for the successful initiation and rapid titration of methadone for the treatment of opioid use disorder. Such an approach could significantly reduce the induction period associated with methadone maintenance therapy and its associated negative outcomes including ongoing illicit substance use and risk for overdose. Send correspondence to Seonaid Nolan, MD, FRCPC, Assistant Professor, University of British Columbia, Clinician Scientist, British Columbia Centre on Substance Use, 553B–1081 Burrard St. Vancouver, BC V6Z 1Y6. E-mail: seonaid.nolan@bccsu.ubc.ca Received 23 October, 2018 Accepted 12 January, 2019 The authors report no conflicts of interest. © 2019 American Society of Addiction Medicine