Oesterle, Tyler S

AbstractBackground and ObjectivesWhen administered as prescribed, the naloxone component of buprenorphine‐naloxone combination medications is putatively considered inert due to reduced naloxone bioavailability via transmucosal. However, there is a growing body of evidence to the contrary. The aim of our study is to determine the extent of naloxone absorption in a large cohort of patients receiving sublingual buprenorphine‐naloxone.MethodsUsing the Mayo Clinic Unified Data Platform, 425 patients prescribed sublingual buprenorphine/naloxone who received a controlled substance monitoring panel (CSMP) between January 1, 2022, and January 1, 2023 were identified and included. The CSMP is an immunoassay panel that confirms positive results quantitatively with gas chromatography mass spectrometry or liquid chromatography tandem mass spectrometry. This panel provides urinary detection for buprenorphine (cutoff: 5 ng/mL), naloxone (25 ng/mL), as well as their respective metabolites norbuprenorphine (5 ng/mL), norbuprenorphine‐glucuronide (20 ng/mL), and naloxone‐glucuronide (100 ng/mL).ResultsOf our 425 patients, 76% had norbuprenorphine (n = 323), and 77% had norbuprenorphine‐glucuronide (n = 327) in their toxicology tests, respectively. Naloxone‐glucuronide was detected in 91% (n = 294) of the specimens with norbuprenorphine and 88.7% (n = 290) of the specimens with norbuprenorphine‐glucuronide.Conclusion and Scientific SignificanceTo our knowledge, this is the largest study to date demonstrating the presence of naloxone metabolites in patients taking combined buprenorphine‐naloxone medications. The results of this study refute the notion that naloxone absorption is negligible when administered in sublingual preparations. Further research on how this absorption impacts medication usage, dosing, adherence, and side effects is necessary.

Abstract Opioid use disorder (OUD) affects over 40 million people worldwide, creating significant social and economic burdens. Medication for opioid use disorder (MOUD) is often considered the primary treatment approach for OUD. MOUD, including methadone, buprenorphine, and naltrexone, is effective for some, but its benefits may be limited by poor adherence to treatment recommendations. Immunopharmacotherapy offers an innovative approach by using vaccines to generate antibodies that neutralize opioids, blocking them from crossing the blood-brain barrier and reducing their psychoactive effects. To date, only 3 clinical trials for opioid vaccines have been published. While these studies demonstrated the potential of opioid vaccines for relapse prevention, there is currently no standardized protocol for evaluating their effectiveness. We have reviewed recent preclinical studies that demonstrated the efficacy of vaccines targeting opioids, including heroin, morphine, oxycodone, hydrocodone, and fentanyl. These studies showed that vaccines against opioids reduced drug reinforcement, decreased opioid-induced antinociception, and increased survival rates against lethal opioid doses. These studies also demonstrated the importance of vaccine formulation and the use of adjuvants in enhancing antibody production and specificity. Finally, we highlighted the strengths and concerns associated with the opioid vaccine treatment, including ethical considerations.

Objective: Fatal overdoses are the third leading cause of death in the pediatric population. Substance use disorders (SUD) screening is not routinely done in primary care practices. Early screening and intervention for adolescent SUD could mitigate future harm. Methods: We conducted a 3-month pilot adapting universal screening using the CRAFFT tool in patients aged 12 to 17 presenting to an urban and a rural primary care practice during well-child and acute/sick-child visits. We collaborated with our pediatric addiction service to ensure access availability for further assessment and treatment for all positively screened patients; this was broadly communicated to primary care providers. Results: There was a higher CRAFFT completion rate in the urban site (90%, vs 52.6% in our rural site). The majority of CRAFFT questionnaires were completed during acute/sick-child visits in both study sites. Moreover, we found a higher positive screen rate in our rural practice (14.6%, vs 2.4% in our urban practice). Only 27% of positively screened patients had substance use addressed by their providers. No pediatric addiction referrals were made. Conclusions: Findings suggest provider-level barriers exist despite having adequate specialty referral sources and institutional encouragement. Future work is needed to explore these barriers.

AbstractBackground and ObjectivesCriminal‐legal (CL) referrals to addiction treatment have historically had low utilization of medications for opioid use disorder (MOUD). While state differences have been reported, an in‐depth longitudinal analysis of state‐by‐state differences is lacking.MethodsThe Substance Abuse and Mental Health Services Administration Treatment Episode Dataset‐Admissions 2000–2020 provided data for individuals entering their initial treatment with an opioid as their primary substance. Outcome was planned use of MOUD, assessing odds ratio (OR) of CL referrals relative to non‐CL referrals cumulatively over the 21‐year period and as incremental change (change in relative disparity) using effect sizes, stratified by each state.Results2,187,447 cases met the criteria. Planned MOUD occurred in 37.7% of non‐CL clients versus 6.5% of CL clients (OR = 0.11, 95% confidence interval = 0.11–0.12). For all clients, planned MOUD increased from 2000 (33.9%) to 2020 (44.8%). This increase was blunted within CL clients, increasing from 2000 (6.4%) to 2020 (13.3%). Rhode Island saw the greatest improvements in equity.Discussion and ConclusionsWhile rates of planned MOUD increased over the 21 years, a significant disparity persisted among CL clients in most states. As opioid use disorders and opioid‐related overdoses are more prevalent among those involved with the CL system, improving this has high impact.Scientific SignificanceProvides the most comprehensive analysis of state‐by‐state inequities in MOUD access for CL relative to non‐CL referrals over a 21‐year period through use of a national data set. Positive outliers are used as case examples for others to follow in pursuit of more equitable care.

AbstractThe rates of opioid use and opioid related deaths are escalating in the United States. Despite this, evidence-based treatments for Opioid Use Disorder are underutilized. There are three medications FDA approved for treatment of Opioid Use Disorder: Methadone, Buprenorphine, and Naltrexone. This article reviews the history, criteria, and mechanisms associated with Opioid Use Disorder. Pertinent pharmacology considerations, treatment strategies, efficacy, safety, and challenges of Methadone, Buprenorphine, and Naltrexone are outlined. Lastly, a practical decision making algorithm is discussed to address pertinent psychiatric and medical comorbidities when prescribing pharmacology for Opioid Use Disorder.

AbstractBackground and ObjectivesTranscranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have evidence for their potential in the treatment of substance use disorders (SUD). Medication for addiction treatment (MAT) is underutilized and not always effective. We identified randomized controlled trials (RCTs) and case studies that evaluated the effectiveness of TMS or tDCS used concurrently with MAT in SUD treatment.MethodsA systematic review of published literature following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines was conducted on 6/1/2023 by a medical librarian. Craving‐related scales were extracted for an effect size calculation. The Physiotherapy Evidence Database (PEDro) scale assessed study quality.ResultsEight studies (7 RCT, 1 case) including 253 individuals were published from 2015 to 2022, 5 of which had available data for meta‐analysis. TMS or tDCS combined with MAT significantly reduced craving‐related measures relative to sham stimulation (Hedges' g = −0.42, confidence interval: −0.73 to −0.11, p < .01). Opioid use disorder, methadone, and the dorsolateral prefrontal cortex were the most commonly studied SUD, MAT, and target region.Discussion and ConclusionsOur results show a significant effect; however, is limited by a small number of studies with heterogeneous methodology across intervention methods and SUDs. Additional trials are needed to fully assess the clinical impact and mechanisms of combined brain stimulation and pharmacotherapy. We discuss a possible mechanism for synergism from these treatment combinations.Scientific SignificanceAdds the first systematic review of combination treatment with TMS or tDCS and MAT in SUD patients to the literature and estimates its overall effect size.

AbstractBackground and ObjectivesSubstance use disorders (SUDs) are chronic relapsing diseases characterized by significant morbidity and mortality. Phenomenologically, patients with SUDs present with a repeating cycle of intoxication, withdrawal, and craving, significantly impacting their diagnosis and treatment. There is a need for better identification and monitoring of these disease states. Remote monitoring chronic illness with wearable devices offers a passive, unobtrusive, constant physiological data assessment. We evaluate the current evidence base for remote monitoring of nonalcohol, nonnicotine SUDs.MethodsWe performed a systematic, comprehensive literature review and screened 1942 papers.ResultsWe found 15 studies that focused mainly on the intoxication stage of SUD. These studies used wearable sensors measuring several physiological parameters (ECG, HR, O2, Accelerometer, EDA, temperature) and implemented study‐specific algorithms to evaluate the data.Discussion and ConclusionsStudies were extracted, organized, and analyzed based on the three SUD disease states. The sample sizes were relatively small, focused primarily on the intoxication stage, had low monitoring compliance, and required significant computational power preventing “real‐time” results. Cardiovascular data was the most consistently valuable data in the predictive algorithms. This review demonstrates that there is currently insufficient evidence to support remote monitoring of SUDs through wearable devices.Scientific SignificanceThis is the first systematic review to show the available data on wearable remote monitoring of SUD symptoms in each stage of the disease cycle. This clinically relevant approach demonstrates what we know and do not know about the remote monitoring of SUDs within disease states.

Background and Purpose Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. Experimental Approach We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. Key Results Baseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. Conclusion and Implications These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.