Marek C. Chawarski

Kratom-labeled products consumed in the United States and natural kratom consumed in Southeast Asia (SEA) are very different in their chemistry and safety profiles. Water-based decoction, frequently consumed in SEA, is prepared using freshly harvested, not dried leaves of Mitragyna speciosa tree, indigenous to the SEA region. Our research demonstrates that the decoction contains mitragynine and its congeners in organic, water-soluble salts form, not in the pure base alkaloids form. In addition, our preliminary evaluation has not detected 7-hydroxymitragynine, a highly potent oxidative derivative of mitragynine, in the decoction prepared from the freshly harvested and unprocessed leaves. The differences in the products’ chemistry may be responsible for the observed differences in safety profiles between the products consumed in the United States and in the SEA countries. Kratom-labeled products in the United States are sold under the false promises that they reflect the natural kratom products consumed in SEA. Consumers of these products and health care practitioners in the United States may not be aware that the natural kratom products traditionally consumed in SEA (ie, freshly harvested unprocessed whole leaves and a water-based decoction prepared from such leaves) have different chemistry and are consumed differently than the US products, including kratom-leaf-derived US products (ie, capsules, powders, or tea bags claiming to contain dried natural kratom leaves), as well as the highly concentrated or semisynthetic products. The traditional natural products consumed in the SEA countries may also have a different safety profile and pharmacological effects.

BACKGROUND: Risky alcohol use and alcohol dependence are common among patients with opioid dependence during remission; however, therapeutic options for co-occurring addictions remain limited. AIM: This work aimed to conduct a preliminary evaluation of the efficacy and safety of nalmefene in combination with behavioral counseling in patients with opioid dependence in remission and active alcohol dependence. METHODS: A pilot open-label clinical study (August 31, 2017–September 13, 2018; Saint Petersburg) included eight patients with opioid dependence in remission and active alcohol dependence. The intervention comprised daily use of oral nalmefene (36 mg) and weekly individual sessions of structured behavioral counseling based on motivational interviewing and cognitive behavioral therapy, aimed at maintaining remission and preventing relapse. Efficacy was assessed by opioid abstinence (according to urinalysis and self-reports), abstinence from alcohol and other psychoactive substances (self-reports), and retention in the program over 24 weeks. RESULTS: This study was terminated early due to multiple withdrawals of consent caused by adverse events or relapse in opioid dependence. Adverse effects (insomnia, fatigue, anxiety, irritability, agitation, nausea, tremor, muscle pain, increased blood pressure, and opioid craving) were observed in six participants, suggesting a possible withdrawal-like reaction triggered by nalmefene in this population, despite the fact that all participants had abstained from opioid use for at least two months prior to enrollment. CONCLUSION: The findings presented in this study reveal challenges in the use of nalmefene among patients with opioid dependence in remission and alcohol abuse, emphasizing the importance of further research to evaluate the potential of nalmefene use in individuals with combined dependence on different psychoactive substances.

Background: Misuse of prescription opioids remains a public health problem. Appropriate short-term use of these medications in opioid-naive patients is indicated in selected settings but can result in unintended prolonged opioid use (UPOU), defined as the continuation of opioid therapy beyond the period by which acute pain would have been expected to resolve. Clinical strategies aimed at preventing UPOU are lacking due to the absence of information about how this poorly understood clinical phenomenon actually develops. Objective: In this research project, 3 Clinical and Translational Science Awards (CTSA) programs (Mayo Clinic, University of Michigan, and Yale University) leveraged the conceptual framework for UPOU to investigate how patient characteristics, practice environment characteristics, and opioid prescriber characteristics facilitate or impede UPOU. All data management and analyses were conducted at a fourth CTSA program (University of Minnesota). This work was accomplished by pursuing 3 specific aims. Methods: In aim 1, opioid-naive adults receiving an initial opioid prescription were recruited for study participation. Opioid prescriptions were identified longitudinally, and patterns of use were categorized as short-term, episodic, or long-term use using established criteria. Using a prospective case-control design, patients progressing to UPOU were matched 1:1 with patients who did not develop UPOU, and differences in patient characteristics were assessed. In aim 2, clinicians who prescribed opioids to patients in aim 1 were identified and recruited for prospective assessments. Institutional and individual practice environments were assessed using a validated self-report survey. In aim 3, structural equation modeling was used to evaluate data collected in aims 1 and 2, and identified interactions were further evaluated in a large national administrative claims database. Results: Patient recruitment began on August 1, 2019. However, due to the COVID-19 pandemic, patient recruitment was slowed and intermittently interrupted over the ensuing 3-year period. As a result of regional variations in the impact of the COVID-19 pandemic on research activities, the majority of patient and clinician recruitment occurred at the Mayo Clinic site. Conclusions: Following complete data analyses, it is anticipated that electronic health record systems will be leveraged to help clinicians identify at risk patients and to develop direct-to-patient educational materials to raise awareness of the risk factors for developing UPOU. Trial Registration: ClinicalTrials.gov NCT04024397; https://clinicaltrials.gov/study/NCT04024397 International Registered Report Identifier (IRRID): DERR1-10.2196/72032

BACKGROUND Misuse of prescription opioids remains a public health problem. Appropriate short-term use of these medications in opioid-naive patients is indicated in selected settings but can result in unintended prolonged opioid use (UPOU), defined as the continuation of opioid therapy beyond the period by which acute pain would have been expected to resolve. Clinical strategies aimed at preventing UPOU are lacking due to the absence of information about how this poorly understood clinical phenomenon actually develops. OBJECTIVE In this research project, 3 Clinical and Translational Science Awards (CTSA) programs (Mayo Clinic, University of Michigan, and Yale University) leveraged the conceptual framework for UPOU to investigate how patient characteristics, practice environment characteristics, and opioid prescriber characteristics facilitate or impede UPOU. All data management and analyses were conducted at a fourth CTSA program (University of Minnesota). This work was accomplished by pursuing 3 specific aims. METHODS In aim 1, opioid-naive adults receiving an initial opioid prescription were recruited for study participation. Opioid prescriptions were identified longitudinally, and patterns of use were categorized as short-term, episodic, or long-term use using established criteria. Using a prospective case-control design, patients progressing to UPOU were matched 1:1 with patients who did not develop UPOU, and differences in patient characteristics were assessed. In aim 2, clinicians who prescribed opioids to patients in aim 1 were identified and recruited for prospective assessments. Institutional and individual practice environments were assessed using a validated self-report survey. In aim 3, structural equation modeling was used to evaluate data collected in aims 1 and 2, and identified interactions were further evaluated in a large national administrative claims database. RESULTS Patient recruitment began on August 1, 2019. However, due to the COVID-19 pandemic, patient recruitment was slowed and intermittently interrupted over the ensuing 3-year period. As a result of regional variations in the impact of the COVID-19 pandemic on research activities, the majority of patient and clinician recruitment occurred at the Mayo Clinic site. CONCLUSIONS Following complete data analyses, it is anticipated that electronic health record systems will be leveraged to help clinicians identify at risk patients and to develop direct-to-patient educational materials to raise awareness of the risk factors for developing UPOU. CLINICALTRIAL ClinicalTrials.gov NCT04024397; https://clinicaltrials.gov/study/NCT04024397 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/72032

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.

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.

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. 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. Results will generate novel information regarding the impact of IF as a strategy to promote ED-initiated buprenorphine. ClinicalTrials.gov NCT03023930 first posted 1/10/2017, https://clinicaltrials.gov/ct2/show/NCT03023930?term=0069&rank=1