Evaluation of toxicity profile of kratom (Mitragyna speciosa Korth) decoction in rats.

Mitragyna speciosa Korth also known as kratom, is an herbal drug preparation for its therapeutic properties and opioid-replacement therapy. Kratom is consumed in a brewed decoction form in Malaysia and to date, no studies have characterized its chemical and toxicity profile. Thus, this study aims to evaluate kratom decoction's safety and toxicity profile after 28 days of treatment. Mitragynine content was quantified in kratom decoction and used as a marker to determine the concentration. Male and female Sprague Dawley rats were orally treated with vehicle or kratom decoction (10, 50 or 150 mg/kg) and two satellite groups were treated with vehicle and kratom decoction (150 mg/kg). Blood and organs were collected for hematology, biochemical and histopathology analysis at the end of treatment. No mortality was found after 28 days of treatment and no significant changes in body weight and hematology profile, except for low platelet count. High amounts of uric acid, AST, ALT and alkaline phosphatase were found in the biochemical analysis. Histological investigation of the heart and lungs detected no alterations except for the kidney, liver and brain tissues. In conclusion, repeated administration of kratom decoction provided some evidence of toxicity in the kidney and liver with no occurrence of mortality.

Use of Amphetamine-Type Stimulants Among Emergency Department Patients With Untreated Opioid Use Disorder.

STUDY OBJECTIVE: Concurrent use of amphetamine-type stimulants among individuals with opioid use disorder can exacerbate social and medical harms, including overdose risk. The study evaluated rates of amphetamine-type stimulant use among patients with untreated opioid use disorder presenting at emergency departments in Baltimore, MD; New York, NY; Cincinnati, OH; and Seattle, WA. METHODS: Emergency department (ED) patients with untreated opioid use disorder (N=396) and enrolled between February 2017 and January 2019 in a multisite hybrid type III implementation science study were evaluated for concurrent amphetamine-type stimulant use. Individuals with urine tests positive for methamphetamine, amphetamine, or both were compared with amphetamine-type stimulant-negative patients. RESULTS: Overall, 38% of patients (150/396) were amphetamine-type stimulant positive; none reported receiving prescribed amphetamine or methamphetamine medications. Amphetamine-type stimulant-positive versus -negative patients were younger: mean age was 36 years (SD 10 years) versus 40 years (SD 12 years), 69% (104/150) versus 46% (114/246) were white, 65% (98/150) versus 54% (132/246) were unemployed, 67% (101/150) versus 49 (121/246) had unstable housing, 47% (71/150) versus 25% (61/245) reported an incarceration during 1 year before study admission, 60% (77/128) versus 45% (87/195) were hepatitis C positive, 79% (118/150) versus 47% (115/245) reported drug injection during 1 month before the study admission, and 42% (62/149) versus 29% (70/244) presented to the ED for an injury. Lower proportions of amphetamine-type stimulant-positive patients had cocaine-positive urine test results (33% [50/150] versus 52% [129/246]) and reported seeking treatment for substance use problems as a reason for their ED visit (10% [14/148] versus 19% [46/246]). All comparisons were statistically significant at P<.05 with the false discovery rate correction. CONCLUSION: Amphetamine-type stimulant use among ED patients with untreated opioid use disorder was associated with distinct sociodemographic, social, and health factors. Improved ED-based screening, intervention, and referral protocols for patients with opioid use disorder and amphetamine-type stimulant use are needed.

Kratom and Pain Tolerance: A Randomized, Placebo-Controlled, Double-Blind Study.

Background: Kratom has a long history of traditional medicine use in Southeast Asia. Consumption of kratom products has also been reported in the US and other regions of the world. Pain relief is among many self-reported kratom effects but have not been evaluated in controlled human subject research. Methods: Kratom effects on pain tolerance were assessed in a randomized, placebo-controlled, double-blind study. During a 1-day inpatient stay, participants received a randomized sequence of kratom and placebo decoctions matched for taste and appearance. Pain tolerance was measured objectively in a cold pressor task (CPT) as time (seconds) between the pain onset and the hand withdrawal from the ice bath. Health status, vital signs, objective, and subjective indicators of withdrawal symptoms, self-reported data on lifetime kratom use patterns, and assessments of blinding procedures were also evaluated. Results: Twenty-six males with the mean (SD) age 24.3 (3.4) years were enrolled. They reported the mean (SD) 6.1 (3.2) years of daily kratom consumption. Pain tolerance increased significantly 1 hour after kratom ingestion from the mean (SD) 11.2 (6.7) seconds immediately before to 24.9 (39.4) seconds 1 hour after kratom consumption (F(2,53.7)=4.33, p=0.02). Pain tolerance was unchanged after consuming placebo drinks: 15.0 (19.0) seconds immediately before and 12.0 (8.1) seconds 1 hour after consumption of placebo (F(2,52.8)=0.93, p=0.40). No discomfort or signs of withdrawal were reported or observed during 10-20 hours of kratom discontinuation. Conclusions: Kratom decoction demonstrated a substantial and statistically significant increase in pain tolerance. Further rigorous research on kratom pain-relieving properties and a safety profile is needed.

Emergency Department-Initiated Buprenorphine for Opioid Dependence with Continuation in Primary Care: Outcomes During and After Intervention.

BACKGROUND: Emergency department (ED)-initiated buprenorphine/naloxone with continuation in primary care was found to increase engagement in addiction treatment and reduce illicit opioid use at 30 days compared to referral only or a brief intervention with referral. OBJECTIVE: To evaluate the long-term outcomes at 2, 6 and 12 months following ED interventions. DESIGN: Evaluation of treatment engagement, drug use, and HIV risk among a cohort of patients from a randomized trial who completed at least one long-term follow-up assessment. PARTICIPANTS: A total of 290/329 patients (88% of the randomized sample) were included. The followed cohort did not differ significantly from the randomized sample. INTERVENTIONS: ED-initiated buprenorphine with 10-week continuation in primary care, referral, or brief intervention were provided in the ED at study entry. MAIN MEASURES: Self-reported engagement in formal addiction treatment, days of illicit opioid use, and HIV risk (2, 6, 12 months); urine toxicology (2, 6 months). KEY RESULTS: A greater number of patients in the buprenorphine group were engaged in addiction treatment at 2 months [68/92 (74%), 95% CI 65-83] compared with referral [42/79 (53%), 95% CI 42-64] and brief intervention [39/83 (47%), 95% CI 37-58; p < 0.001]. The differences were not significant at 6 months [51/92 (55%), 95% CI 45-65; 46/70 (66%) 95% CI 54-76; 43/76 (57%) 95% CI 45-67; p = 0.37] or 12 months [42/86 (49%) 95% CI 39-59; 37/73 (51%) 95% CI 39-62; 49/78 (63%) 95% CI 52-73; p = 0.16]. At 2 months, the buprenorphine group reported fewer days of illicit opioid use [1.1 (95% CI 0.6-1.6)] versus referral [1.8 (95% CI 1.2-2.3)] and brief intervention [2.0 (95% CI 1.5-2.6), p = 0.04]. No significant differences in illicit opioid use were observed at 6 or 12 months. There were no significant differences in HIV risk or rates of opioid-negative urine results at any time. CONCLUSIONS: ED-initiated buprenorphine was associated with increased engagement in addiction treatment and reduced illicit opioid use during the 2-month interval when buprenorphine was continued in primary care. Outcomes at 6 and 12 months were comparable across all groups.

Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial.

IMPORTANCE: Opioid-dependent patients often use the emergency department (ED) for medical care. OBJECTIVE: To test the efficacy of 3 interventions for opioid dependence: (1) screening and referral to treatment (referral); (2) screening, brief intervention, and facilitated referral to community-based treatment services (brief intervention); and (3) screening, brief intervention, ED-initiated treatment with buprenorphine/naloxone, and referral to primary care for 10-week follow-up (buprenorphine). DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial involving 329 opioid-dependent patients who were treated at an urban teaching hospital ED from April 7, 2009, through June 25, 2013. INTERVENTIONS: After screening, 104 patients were randomized to the referral group, 111 to the brief intervention group, and 114 to the buprenorphine treatment group. MAIN OUTCOMES AND MEASURES: Enrollment in and receiving addiction treatment 30 days after randomization was the primary outcome. Self-reported days of illicit opioid use, urine testing for illicit opioids, human immunodeficiency virus (HIV) risk, and use of addiction treatment services were the secondary outcomes. RESULTS: Seventy-eight percent of patients in the buprenorphine group (89 of 114 [95% CI, 70%-85%]) vs 37% in the referral group (38 of 102 [95% CI, 28%-47%]) and 45% in the brief intervention group (50 of 111 [95% CI, 36%-54%]) were engaged in addiction treatment on the 30th day after randomization (P < .001). The buprenorphine group reduced the number of days of illicit opioid use per week from 5.4 days (95% CI, 5.1-5.7) to 0.9 days (95% CI, 0.5-1.3) vs a reduction from 5.4 days (95% CI, 5.1-5.7) to 2.3 days (95% CI, 1.7-3.0) in the referral group and from 5.6 days (95% CI, 5.3-5.9) to 2.4 days (95% CI, 1.8-3.0) in the brief intervention group (P < .001 for both time and intervention effects; P = .02 for the interaction effect). The rates of urine samples that tested negative for opioids did not differ statistically across groups, with 53.8% (95% CI, 42%-65%) in the referral group, 42.9% (95% CI, 31%-55%) in the brief intervention group, and 57.6% (95% CI, 47%-68%) in the buprenorphine group (P = .17). There were no statistically significant differences in HIV risk across groups (P = .66). Eleven percent of patients in the buprenorphine group (95% CI, 6%-19%) used inpatient addiction treatment services, whereas 37% in the referral group (95% CI, 27%-48%) and 35% in the brief intervention group (95% CI, 25%-37%) used inpatient addiction treatment services (P < .001). CONCLUSIONS AND RELEVANCE: Among opioid-dependent patients, ED-initiated buprenorphine treatment vs brief intervention and referral significantly increased engagement in addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services but did not significantly decrease the rates of urine samples that tested positive for opioids or of HIV risk. These findings require replication in other centers before widespread adoption. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00913770.

Research and publication gaps on kratom and kratom products: a scoping review of current literature.

PURPOSE OF REVIEW: Kratom plant, products derived from the plant, and plant phytochemicals are of great interest among researchers, clinicians, and consumers. However, there is a paucity of rigorously collected scientific data on their risk/safety profile and public health impact. This scoping review discusses original research articles published between 2022 and 2023. It focuses on identifying publication gaps on topics related to epidemiology, public health, and risk/safety profiles comparing evidence collected by researchers from Southeast Asia and the West. RECENT FINDINGS: Our review of the Scopus database identified a total of 55 publications, including clinical case reports and case series reports, surveys, studies enrolling human participants, and publications based on large-scale national surveys or large-scale national or international health system database records. SUMMARY: Overall, there is dearth of reliable data on key epidemiological factors, including the prevalence rates, and on objective and reliable indices of the risk/safety profiles. Rigorous and systematic studies including improved epidemiological surveillance, human laboratory, and controlled clinical studies are urgently needed to advance our understanding of public health consequences of consuming kratom and kratom-derived products and to improve our understanding of their risk/safety profile and additional analytical studies to better inform development of needed regulatory oversight.

Phytochemical analysis of water and ethanol liquid extracts prepared using freshly harvested leaves of Mitragyna speciosa (Korth.).

Mitragyna speciosa, also known as kratom, has been reported to have a broad range of pharmacological properties. Freshly harvested leaves and their water extracts are consumed in Southeast Asia while preparations made from dried leaf material are consumed in Western countries. Our study evaluated the phytochemical composition of freshly harvested kratom leaves using LCMS/MS analysis of water and ethanol liquid extracts. Mitragynine and its congeners, including 7-hydroxymitragynine, speciocilliatine, speciogynine, paynantheine, as well as bioactive phenolics including chlorogenic acid, o-coumaric acid, quercitrin, and rutin were identified. However, 7-hydroxymitragynine was detected solely in the water-liquid extract. Currently, unknown compounds were also present in the chromatograms and mass spectra. The study results support that 7-hydroxymitragynine is a post-harvest oxidative derivative or metabolite of mitragynine. Further rigorous and comprehensive evaluations of the phytochemical composition of freshly harvested kratom leaves utilising advanced spectrometric methods are needed to establish the full spectrum of phytochemicals within the plant.

Analgesic effects of main indole alkaloid of kratom, mitragynine in acute pain animal model.

Mitragynine exerts its analgesic effect mainly via opioid receptors activation. Additionally, the effect may be mediated via mitragynine's anti-inflammatory property and non-opioid receptor pain pathways, namely through the TRPV1 receptor. No studies identify hitherto, hence, the current study aimed to investigate the mitragynine's analgesic effect via the anti-inflammatory property, non-opioid receptor (TRPV1) and the effective dose (ED) to alleviate pain. Male and female Sprague Dawley rats were pre-treated intraperitoneally with either mitragynine (1, 5, 10, 13, 15 or 30 mg/kg), vehicle, or indomethacin (1 mg/kg) 30 min before inducing inflammatory pain using acetic acid. The writhes and pain-related withdrawal behaviour occurrence were counted within a 1-h duration. Percentage of writhes inhibition, pain-related withdrawal behaviour aggregate, ED50 and ED95 were determined. The body temperature was recorded and TRPV1 expression in the rats' brains was measured. Mitragynine (except 1 mg/kg) significantly reduced the number of writhes compared with the vehicle administered group. Mitragynine (30 mg/kg) demonstrated 99.5% inhibition of writhing behaviour and low withdrawal behaviour score compared with vehicle and indomethacin and successfully blocked the hypothermia induced by acetic acid. The overall ED50 and ED95 values of mitragynine were 3.62 and 20.84 mg/kg, respectively. The percentage of writhing inhibition and withdrawal behaviour were similar in both genders. Mitragynine (15 and 30 mg/kg) significantly reduced the TRPV1 expression in the brain of the rats. Mitragynine alleviated pain-like behaviour and showed analgesic effects via anti-inflammatory and non-opioid receptor pathways. The findings also suggest that mitragynine might regulate some physiological functions of the rat.

Missed Opportunities for HIV and Hepatitis C Screening Among Emergency Department Patients With Untreated Opioid Use Disorder.

OBJECTIVE: We assessed the frequency of emergency department (ED) HIV and hepatitis C (HCV) screening in a high-risk cohort of ED patients with untreated opioid use disorder (OUD). METHODS: This analysis used data from a prospective, observational study of English-speaking adults with untreated OUD enrolled from April 2017 to December 2018 in 4 urban, academic EDs. Two cohorts were defined for this analysis by self-reported negative/unknown status for HIV (cohort 1) and HCV (cohort 2). Sites featured structured screening programs throughout the entire enrollment period for HIV and during at least part of the enrollment period for HCV. We calculated the proportion tested for HIV and HCV during the study enrollment ED visit. RESULTS: Among 394 evaluated ED patients, 328 of 394 (83.2%) were not tested for HIV or HCV and 244 of 393 (62.1%) lacked a usual medical care provider. In cohort 1, 375 reported negative or unknown HIV status; 59/375 (15.7%) overall and 33/218 (15.1%) of those reporting recent injection drug use were tested for HIV. In cohort 2, 231 reported negative of unknown HCV status; 22/231 (9.5%) overall and 9/98 (9.2%) of those reporting recent injection drug use were tested for HCV. The proportion tested by the ED ranged from 3% to 25% for HIV and 4% to 32% for HCV across study sites. CONCLUSIONS: Emergency department HIV and HCV screening remains infrequent among patients with untreated OUD, including those who inject drugs, even in EDs committed to screening. Targeted HIV/HCV screening should be considered as an adjunct strategy until the ideal of universal screening is more fully achieved.

Implementation Facilitation to Promote Emergency Department-Initiated Buprenorphine for Opioid Use Disorder.

Importance: Emergency department (ED)-initiated buprenorphine for the treatment of opioid use disorder (OUD) is underused. Objective: To evaluate whether provision of ED-initiated buprenorphine with referral for OUD increased after implementation facilitation (IF), an educational and implementation strategy. Design, Setting, and Participants: This multisite hybrid type 3 effectiveness-implementation nonrandomized trial compared grand rounds with IF, with pre-post 12-month baseline and IF evaluation periods, at 4 academic EDs. The study was conducted from April 1, 2017, to November 30, 2020. Participants were ED and community clinicians treating patients with OUD and observational cohorts of ED patients with untreated OUD. Data were analyzed from July 16, 2021, to July 14, 2022. Exposure: A 60-minute in-person grand rounds was compared with IF, a multicomponent facilitation strategy that engaged local champions, developed protocols, and provided learning collaboratives and performance feedback. Main Outcomes and Measures: The primary outcomes were the rate of patients in the observational cohorts who received ED-initiated buprenorphine with referral for OUD treatment (primary implementation outcome) and the rate of patients engaged in OUD treatment at 30 days after enrollment (effectiveness outcome). Additional implementation outcomes included the numbers of ED clinicians with an X-waiver to prescribe buprenorphine and ED visits with buprenorphine administered or prescribed and naloxone dispensed or prescribed. Results: A total of 394 patients were enrolled during the baseline evaluation period and 362 patients were enrolled during the IF evaluation period across all sites, for a total of 756 patients (540 [71.4%] male; mean [SD] age, 39.3 [11.7] years), with 223 Black patients (29.5%) and 394 White patients (52.1%). The cohort included 420 patients (55.6%) who were unemployed, and 431 patients (57.0%) reported unstable housing. Two patients (0.5%) received ED-initiated buprenorphine during the baseline period, compared with 53 patients (14.6%) during the IF evaluation period (P < .001). Forty patients (10.2%) were engaged with OUD treatment during the baseline period, compared with 59 patients (16.3%) during the IF evaluation period (P = .01). Patients in the IF evaluation period who received ED-initiated buprenorphine were more likely to be in treatment at 30 days (19 of 53 patients [35.8%]) than those who did not 40 of 309 patients (12.9%; P < .001). Additionally, there were increases in the numbers of ED clinicians with an X-waiver (from 11 to 196 clinicians) and ED visits with provision of buprenorphine (from 259 to 1256 visits) and naloxone (from 535 to 1091 visits). Conclusions and Relevance: In this multicenter effectiveness-implementation nonrandomized trial, rates of ED-initiated buprenorphine and engagement in OUD treatment were higher in the IF period, especially among patients who received ED-initiated buprenorphine. Trial Registration: ClinicalTrials.gov Identifier: NCT03023930.

A brief intervention reduces hazardous and harmful drinking in emergency department patients.

STUDY OBJECTIVE: Brief interventions have been shown to reduce alcohol use and improve outcomes in hazardous and harmful drinkers, but evidence to support their use in emergency department (ED) patients is limited. The use of research assessments in studies of brief interventions may contribute to uncertainty about their effectiveness. Therefore we seek to determine (1) if an emergency practitioner-performed Brief Negotiation Interview or a Brief Negotiation Interview with a booster reduces alcohol consumption compared with standard care; and (2) the impact of research assessments on drinking outcomes using a standard care-no-assessment group. METHODS: We randomized 889 adult ED patients with hazardous and harmful drinking. A total of 740 received an emergency practitioner-performed Brief Negotiation Interview (n=297), a Brief Negotiation Interview with a 1-month follow-up telephone booster (Brief Negotiation Interview with booster) (n=295), or standard care (n=148). We also included a standard care with no assessments (n=149) group to examine the effect of assessments on drinking outcomes. Primary outcomes analyzed with mixed-models procedures included past 7-day alcohol consumption and 28-day binge episodes at 6 and 12 months, collected by interactive voice response. Secondary outcomes included negative health behaviors and consequences collected by telephone surveys. RESULTS: The reduction in mean number of drinks in the past 7 days from baseline to 6 and 12 months was significantly greater in the Brief Negotiation Interview with booster (from 20.4 [95% confidence interval {CI} 18.8 to 22.0] to 11.6 [95% CI 9.7 to 13.5] to 13.0 [95% CI 10.5 to 15.5]) and Brief Negotiation Interview (from 19.8 [95% CI 18.3 to 21.4] to 12.7 [95% CI 10.8 to 14.6] to 14.3 [95% CI 11.9 to 16.8]) than in standard care (from 20.9 [95% CI 18.7 to 23.2] to 14.2 [95% CI 11.2 to 17.1] to 17.6 [95% CI 14.1 to 21.2]). The reduction in 28-day binge episodes was also greater in the Brief Negotiation Interview with booster (from 7.5 [95% CI 6.8 to 8.2] to 4.4 [95% CI 3.6 to 5.2] to 4.7 [95% CI 3.9 to 5.6]) and Brief Negotiation Interview (from 7.2 [95% CI 6.5 to 7.9] to 4.8 [95% CI 4.0 to 5.6] to 5.1 [95% CI 4.2 to 5.9]) than in standard care (from 7.2 [95% CI 6.2 to 8.2] to 5.7 [95% CI 4.5 to 6.9] to 5.8 [95% CI 4.6 to 7.0]). The Brief Negotiation Interview with booster offered no significant benefit over the Brief Negotiation Interview alone. There were no differences in drinking outcomes between the standard care and standard care-no assessment groups. The reductions in rates of driving after drinking more than 3 drinks from baseline to 12 months were greater in the Brief Negotiation Interview (38% to 29%) and Brief Negotiation Interview with booster (39% to 31%) groups than in the standard care group (43% to 42%). CONCLUSION: Emergency practitioner-performed brief interventions can reduce alcohol consumption and episodes of driving after drinking in hazardous and harmful drinkers. These results support the use of brief interventions in ED settings.

Behavioral counseling and abstinence-contingent take-home buprenorphine in general practitioners' offices in Malaysia: a randomized, open-label clinical trial.

BACKGROUND AND AIM: To address the widespread severe problems with opioid use disorder, buprenorphine-naloxone treatment provided by primary care physicians has greatly expanded treatment access; however, treatment is often provided with minimal or no behavioral interventions. Whether or which behavioral interventions are feasible to implement in various settings and improve treatment outcomes has not been established. This study aimed to evaluate two behavioral interventions to improve buprenorphine-naloxone treatment. DESIGN: A 2 × 2 factorial, repeated-measures, open-label, randomized clinical trial. SETTINGS: General medical practice offices in Muar, Malaysia. PARTICIPANTS: Opioid-dependent individuals (n = 234). INTERVENTIONS: Participants were randomly assigned to one of four treatment conditions and received study interventions for 24 weeks: (1) physician management with or without behavioral counseling and (2) physician management with or without abstinence-contingent buprenorphine-naloxone (ACB) take-home doses. MEASUREMENTS: The primary outcomes were proportions of opioid-negative urine tests and HIV risk behaviors [assessed by audio computer-assisted AIDS risk inventory (ACASI-ARI)]. FINDINGS: The rates of opioid-negative urine tests over 24 weeks of treatment were significantly higher with [68.2%, 95% confidence interval (CI) = 65-71] than without behavioral counseling (59.2%, 95% CI = 56-62, P < 0.001) and with (71.0%, 95% CI = 68-74) than without ACB (56.4%, 95% CI = 53-59, P < 0.001); interaction effects between and among behavioral interventions and time were not statistically significant. Scores on ACASI-ARI decreased significantly from baseline across all treatment groups (P < 0.001) and did not differ significantly with or without behavioral counseling (P = 0.099) or with or without ACB (P = 0.339). CONCLUSIONS: Providing opioid-dependent patients in Muar, Malaysia with buprenorphine-naloxone and physician management plus behavioral counseling or abstinence-contingent buprenorphine-naloxone (ACB) resulted in greater reductions of opioid use compared with providing buprenorphine-naloxone and physician management without behavioral counseling or ACB.

COVID-19 Impact on Healthcare and Supportive Services for People Who Use Drugs (PWUDs) in Malaysia.

Background: Restrictive orders and temporary programmatic or ad hoc changes within healthcare and other supportive systems that were implemented in response to the COVID-19 epidemic in Malaysia may have created hindrances to accessing healthcare and/or receiving other supportive services for people who use drugs (PWUDs). Design: A primarily qualitative study has been conducted to evaluate how service providers and recipients were adapting and coping during the initial periods of the COVID-19 response. Settings: The study engaged several healthcare and non-governmental organizations (NGOs) in the peninsular states of Penang, Kelantan, Selangor, and Melaka. Participants: Medical personnel of methadone maintenance treatment (MMT) programs (n = 2) and HIV clinics (n = 3), staff of NGO services (n = 4), and MMT patients (n = 9) were interviewed using a semi-structured format. Results: Interviewed participants reported significant organizational, programmatic, and treatment protocols related changes implemented within the healthcare and support services in addition to nationally imposed Movement Control Orders (MCOs). Changes aimed to reduce patient flow and concentration at the on-site services locations, including less frequent in-person visits, increased use of telemedicine resources, and greater reliance on telecommunication methods to maintain contacts with patients and clients; changes in medication dispensing protocols, including increased take-home doses and relaxed rules for obtaining them, or delivery of medications to patients' homes or locations near their homes were reported by the majority of study participants. No significant rates of COVID-19 infections among PWUDs, including among those with HIV have been reported at the study sites. Conclusions: Although the reported changes presented new challenges for both services providers and recipients and resulted in some degree of initial disruption, generally, all participants reported successful implementation and high levels of compliance with the newly introduced restrictions, regulations, and protocols, resulting in relatively low rates of treatment disruption or discontinuation at the study sites.

The association between cocaine use and treatment outcomes in patients receiving office-based buprenorphine/naloxone for the treatment of opioid dependence.

Cocaine use in patients receiving methadone is associated with worse treatment outcomes. The association between cocaine use and office-based buprenorphine/naloxone treatment outcomes is not known. We evaluated the association between baseline and in-treatment cocaine use, treatment retention, and urine toxicology results in 162 patients enrolled in a 24-week trial of primary care office-based buprenorphine/naloxone maintenance. Patients with baseline cocaine metabolite-negative urine toxicology tests compared with those with cocaine metabolite-positive tests had more mean weeks of treatment retention (18.3 vs. 15.8, p = .04), a greater percentage completed 24 weeks of treatment (50% vs. 33%, p = .04) and had a greater percentage of opioid-negative urines (47% vs. 34%, p = .02). Patients with in-treatment cocaine metabolite-negative urine toxicology tests compared with cocaine metabolite-positive patients had more mean weeks of treatment retention (19.0 vs. 16.5, p = .003), a greater percentage completed 24 weeks of treatment (60% vs. 30%, p < .001), and had a greater percentage of opioid-negative urines (51% vs. 35%, p = .001). We conclude that both baseline and in-treatment cocaine use is associated with worse treatment outcomes in patients receiving office-based buprenorphine/naloxone and may benefit from targeted interventions.

Barriers and Facilitators to Clinician Readiness to Provide Emergency Department-Initiated Buprenorphine.

Importance: Treatment of opioid use disorder (OUD) with buprenorphine decreases opioid use and prevents morbidity and mortality. Emergency departments (EDs) are an important setting for buprenorphine initiation for patients with untreated OUD; however, readiness varies among ED clinicians. Objective: To characterize barriers and facilitators of readiness to initiate buprenorphine for the treatment of OUD in the ED and identify opportunities to promote readiness across multiple clinician types. Design, Setting, and Participants: Using data collected from April 1, 2018, to January 11, 2019, this mixed-methods formative evaluation grounded in the Promoting Action on Research Implementation in Health Services framework included 4 geographically diverse academic EDs. Attending physicians (n = 113), residents (n = 107), and advanced practice clinicians (APCs) (n = 48) completed surveys electronically distributed to all ED clinicians (n = 396). A subset of participants (n = 74) also participated in 1 of 11 focus group discussions. Data were analyzed from June 1, 2018, to February 22, 2020. Main Outcomes and Measures: Clinician readiness to initiate buprenorphine and provide referral for ongoing treatment for patients with OUD treated in the ED was assessed using a visual analog scale. Responders (268 of 396 [67.7%]) were dichotomized as less ready (scores 0-6) or most ready (scores 7-10). An ED-adapted Organizational Readiness to Change Assessment (ORCA) and 11 focus groups were used to assess ratings and perspectives on evidence and context-related factors to promote ED-initiated buprenorphine with referral for ongoing treatment, respectively. Results: Among the 268 survey respondents (153 of 260 were men [58.8%], with a mean [SD] of 7.1 [9.8] years since completing formal training), 56 (20.9%) indicated readiness to initiate buprenorphine for ED patients with OUD. Nine of 258 (3.5%) reported Drug Addiction Treatment Act of 2000 training completion. Compared with those who were less ready, clinicians who were most ready to initiate buprenorphine had higher mean scores across all ORCA Evidence subscales (3.50 [95% CI, 3.35-3.65] to 4.33 [95% CI, 4.13-4.53] vs 3.11 [95% CI, 3.03-3.20] to 3.60 [95% CI, 3.49-3.70]; P < .001) and on the Slack Resources of the ORCA Context subscales (3.32 [95% CI, 3.08-3.55] vs 3.0 [95% CI, 2.87-3.12]; P = .02). Barriers to ED-initiated buprenorphine included lack of training and experience in treating OUD with buprenorphine, concerns about ability to link to ongoing care, and competing needs and priorities for ED time and resources. Facilitators to ED-initiated buprenorphine included receiving education and training, development of local departmental protocols, and receiving feedback on patient experiences and gaps in quality of care. Conclusions and Relevance: Only a few ED clinicians had a high level of readiness to initiate buprenorphine; however, many expressed a willingness to learn with sufficient supports. Efforts to promote adoption of ED-initiated buprenorphine will require clinician and system-level changes.

Maintenance treatment with buprenorphine and naltrexone for heroin dependence in Malaysia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Expansion of access to effective treatments for heroin dependence is a worldwide health priority that will also reduce HIV transmission. We compared the efficacy of naltrexone, buprenorphine, and no additional treatment, in patients receiving detoxification and subsequent drug counselling, for maintenance of heroin abstinence, prevention of relapse, and reduction of HIV risk behaviours. METHODS: 126 detoxified heroin-dependent patients, from an outpatient research clinic and detoxification programme in Malaysia, were randomly assigned by a computer-generated randomisation sequence to 24 weeks of manual-guided drug counselling and maintenance with naltrexone (n=43), buprenorphine (n=44), or placebo (n=39). Medications were administered on a double-blind and double-dummy basis. Primary outcomes, assessed by urine testing three times per week, were days to first heroin use, days to heroin relapse (three consecutive opioid-positive urine tests), maximum consecutive days of heroin abstinence, and reductions in HIV risk behaviours over 6 months. The study was terminated after 22 months of enrolment because buprenorphine was shown to have greater efficacy in an interim safety analysis. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00383045. FINDINGS: We observed consistent, linear contrasts in days to first heroin use (p=0.0009), days to heroin relapse (p=0.009), and maximum consecutive days abstinent (p=0.0007), with all results best for buprenorphine and worst for placebo. Buprenorphine was associated with greater time to first heroin use than were naltrexone (hazard ratio 1.87 [95% CI 1.21-2.88]) or placebo (2.02 [1.29-3.16]). With buprenorphine, we also recorded significantly greater time to heroin relapse (2.17 [1.38-3.42]), and maximum consecutive days abstinent than with placebo (mean days 59 [95% CI 43-76] vs 24 [13-35]; p=0.003); however, for these outcomes, differences between buprenorphine and naltrexone were not significant. Differences between naltrexone and placebo were not significant for any outcomes. HIV risk behaviours were significantly reduced from baseline across all three treatments (p=0.003), but the reductions did not differ significantly between the three groups. INTERPRETATION: Our findings lend support to the widespread dissemination of maintenance treatment with buprenorphine as an effective public-health approach to reduce problems associated with heroin dependence.

Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence.

BACKGROUND: The optimal level of counseling and frequency of attendance for medication distribution has not been established for the primary care, office-based buprenorphine-naloxone treatment of opioid dependence. METHODS: We conducted a 24-week randomized, controlled clinical trial with 166 patients assigned to one of three treatments: standard medical management and either once-weekly or thrice-weekly medication dispensing or enhanced medical management and thrice-weekly medication dispensing. Standard medical management was brief, manual-guided, medically focused counseling; enhanced management was similar, but each session was extended. The primary outcomes were the self-reported frequency of illicit opioid use, the percentage of opioid-negative urine specimens, and the maximum number of consecutive weeks of abstinence from illicit opioids. RESULTS: The three treatments had similar efficacies with respect to the mean percentage of opioid-negative urine specimens (standard medical management and once-weekly medication dispensing, 44 percent; standard medical management and thrice-weekly medication dispensing, 40 percent; and enhanced medical management and thrice-weekly medication dispensing, 40 percent; P=0.82) and the maximum number of consecutive weeks during which patients were abstinent from illicit opioids. All three treatments were associated with significant reductions from baseline in the frequency of illicit opioid use, but there were no significant differences among the treatments. The proportion of patients remaining in the study at 24 weeks did not differ significantly among the patients receiving standard medical management and once-weekly medication dispensing (48 percent) or thrice-weekly medication dispensing (43 percent) or enhanced medical management and thrice-weekly medication dispensing (39 percent) (P=0.64). Adherence to buprenorphine-naloxone treatment varied; increased adherence was associated with improved treatment outcomes. CONCLUSIONS: Among patients receiving buprenorphine-naloxone in primary care for opioid dependence, the efficacy of brief weekly counseling and once-weekly medication dispensing did not differ significantly from that of extended weekly counseling and thrice-weekly dispensing. Strategies to improve buprenorphine-naloxone adherence are needed. (ClinicalTrials.gov number, NCT00023283 [ClinicalTrials.gov].).

Implementation facilitation to promote emergency department-initiated buprenorphine for opioid use disorder: protocol for a hybrid type III effectiveness-implementation study (Project ED HEALTH).

BACKGROUND: Patients with opioid use disorder (OUD) frequently present to the emergency department (ED) after overdose, or seeking treatment for general medical conditions, their addiction, withdrawal symptoms, or complications of injection drug use, such as soft tissue infections. ED-initiated buprenorphine has been shown to be effective in increasing patient engagement in treatment compared with brief intervention with a facilitated referral or referral alone. However, adoption into practice has lagged behind need. To address this implementation challenge, we are evaluating the impact of implementation facilitation (IF) on the adoption of ED-initiated buprenorphine for OUD into practice. METHODS: This protocol describes a study that is being conducted through the National Institute on Drug Abuse's Center for the Clinical Trials Network. A hybrid type III effectiveness-implementation study design is used to evaluate the effectiveness of a standard educational dissemination strategy versus IF on implementation (primary) and effectiveness (secondary) outcomes in four urban, academic EDs. Sites start with a standard 60-min "Grand Rounds" educational intervention describing the prevalence of ED patients with OUD, the evidence for opioid agonist treatment and for innovative interventions with ED-initiated buprenorphine; followed by a 1-year baseline evaluation period. Using a modified stepped wedge design, sites are randomly assigned to the IF intervention which is guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework to assess evidence, context, and facilitation-related factors impacting the adoption of ED-initiated buprenorphine. During the 6 months of IF through the 1-year IF evaluation period, external facilitators work with local stakeholders to tailor and refine a bundle of activities to meet the site's needs. The primary analyses compare the baseline evaluation period to the IF evaluation period (n = 120 patients with untreated OUD enrolled during each period) on (1) rates of provision of ED-initiated buprenorphine by ED providers with referral for ongoing medication (implementation outcome) and (2) rates of patient engagement in addiction treatment on the 30th day after the ED visit (effectiveness outcome). Finally, we will perform a cost-effectiveness analysis (CEA) to determine if the effectiveness benefits are worth the additional costs. DISCUSSION: Results will generate novel information regarding the impact of IF as a strategy to promote ED-initiated buprenorphine. TRIAL REGISTRATION: ClinicalTrials.gov NCT03023930 first posted 1/10/2017, https://clinicaltrials.gov/ct2/show/NCT03023930?term=0069&rank=1.

Brief intervention for hazardous and harmful drinkers in the emergency department.

STUDY OBJECTIVE: To determine the efficacy of emergency practitioner-performed brief intervention for hazardous/harmful drinkers in reducing alcohol consumption and negative consequences in an emergency department (ED) setting. METHODS: A randomized clinical trial (Project ED Health) was conducted in an urban ED from May 2002 to November 2003 for hazardous/harmful drinkers. Patients 18 years or older who screened above National Institute for Alcohol Abuse and Alcoholism guidelines for "low-risk" drinking or presented with an injury in the setting of alcohol ingestion were eligible. The mean number of drinks per week and binge-drinking episodes during the past 30 days were collected at 6 and 12 months; negative consequences and use of treatment services, at 12 months. A Brief Negotiation Interview performed by emergency practitioners was compared to scripted Discharge Instructions. RESULTS: A total of 494 hazardous/harmful drinkers were studied. The 2 groups were similar with respect to baseline characteristics. In the Brief Negotiation Interview group, the mean number of drinks per week at 12 months was 3.8 less than the 13.6 reported at baseline. The Discharge Instructions group decreased 2.6 from 12.4 at baseline. Likewise, binge-drinking episodes per month decreased by 2.0 from a baseline of 6.0 in the Brief Negotiation Interview group and 1.5 from 5.4 in the Discharge Instructions group. For each outcome, the time effect was significant and the treatment effect was not. CONCLUSION: Among ED patients with hazardous/harmful drinking, we did not detect a difference in efficacy between emergency practitioner-performed Brief Negotiation Interview and Discharge Instructions. Further studies to test the efficacy of brief intervention in the ED are needed.

Long-term treatment with buprenorphine/naloxone in primary care: results at 2-5 years.

To examine long-term outcomes with primary care office-based buprenorphine/naloxone treatment, we followed 53 opioid-dependent patients who had already demonstrated six months of documented clinical stability for 2-5 years. Primary outcomes were retention, illicit drug use, dose, satisfaction, serum transaminases, and adverse events. Thirty-eight percent of enrolled subjects were retained for two years. Ninety-one percent of urine samples had no evidence of opioid use, and patient satisfaction was high. Serum transaminases remained stable from baseline. No serious adverse events related to treatment occurred. We conclude that select opioid-dependent patients exhibit moderate levels of retention in primary care office-based treatment.