Time for Australia to increase take away doses in opioid agonist treatment.

Opioid Agonist Treatment is the cornerstone of minimising harms related to opioid use, however its uptake is limited by a tightly regulated and stigmatising treatment environment. The COVID-19 pandemic necessitated relaxation of some treatment restrictions, with global evidence pointing to more patient-centred care in this time. In light of local evidence to support the safety of increased access to takeaway doses and a precedent set by the Substance Abuse and Mental Health Administration, we recommend adoption of the Australian Interim Medication Assisted Treatment of Opioid Dependence guidance in Australia.

96-week retention in treatment with extended-release subcutaneous buprenorphine depot injections among people with opioid dependence: Extended follow-up after a single-arm trial.

BACKGROUND: The most recent formulation of buprenorphine treatment is extended-release depot injections (BUP-XR) that are administered subcutaneously by health care professionals. This study aimed to observe treatment outcomes of BUP-XR delivered in standard practice during a 96-week follow-up period in a community setting. METHODS: This study is an extension of the CoLAB study, a prospective single-arm, multicentre, open label trial (N=100, 7 sites in Australia) among people with opioid dependence who received monthly injections of BUP-XR to evaluate the retention in treatment. Participants were followed for 96 weeks, comprising 48 weeks of the CoLAB study followed by a 48-week extension. RESULTS: Of 100 participants at baseline, 47 were retained on BUP-XR at 96 weeks. The median time retained on monthly depot was 90 weeks. Heroin use (adjusted OR=0.19, P=0.012) in the month prior to baseline was associated with lower odds of retention on BUP-XR. Older age at first opioid use (adjusted OR= 1.08, P=0.009) and longer duration in OAT at baseline (adjusted OR= 1.12, P=0.001) were associated with increased retention. Prevalence of past four-weeks opioid use was estimated at 4% at 96 weeks of treatment (prevalence 0.04, 95%CI: 0.00-0.11) compared to 15% at baseline. Quality of life and medication treatment satisfaction improved over time for those retained in treatment. CONCLUSION: This is one of the few studies to describe long term (96 week) retention in treatment with BUP-XR in a community setting. It displayed retention rates with 47% of participants completing 96 weeks of treatment with BUP-XR. Patient reported outcomes suggest improvements in client wellbeing. FUNDING: Indivior.

Direct induction onto high-dose long-acting injectable buprenorphine: A case series.

INTRODUCTION: This case series reports on five patients with opioid use disorder (OUD) who were commenced directly onto high-dose long-acting injectable buprenorphine (LAIB). METHOD: A retrospective audit and manual review of the electronic medical record at cohealth Innerspace was conducted for patients who had been directly inducted onto high-dose LAIB. RESULTS: Five cases were identified on retrospective manual file review. All patients identified were males aged between 33 and 60 years old and were treated with either high-dose Buvidal Weekly and Monthly preparations. No immediate significant adverse effects were noticed and 4 out of 5 remain engaged with treatment. CONCLUSION: This case series shows it is possible to directly induct patients with OUD onto high-dose LAIB preparations without significant side effects or harm to the patient and could be considered a viable option in the treatment of patients with OUD.

Buprenorphine microdosing regimen using transdermal buprenorphine patches to transition from methadone to buprenorphine.

INTRODUCTION: This case series records a cohort of patients treated with transdermal buprenorphine patches as part of a buprenorphine microdose induction protocol to transition from methadone to buprenorphine in a community setting. This has historically been a difficult process to manage in community settings and this case series explored a method to gradually manage this in an outpatient setting. METHOD: A retrospective file audit was conducted of the electronic medical records of cohealth Innerspace patients who had undergone buprenorphine microdose induction using transdermal patches. A total of 32 patients were identified. RESULTS: In this case series 23 of the 32 patients successfully transitioned from methadone to sublingual or long-acting injectable depot buprenorphine preparations utilising the transdermal buprenorphine microdosing technique. All patients in this case series regardless of the success of the transition were retained in treatment. DISCUSSION AND CONCLUSIONS: A fixed-dose transdermal buprenorphine patch regimen enabled 23 of 32 patients in this case series transition from methadone to buprenorphine in an outpatient setting. Given the small sample size further research is required to demonstrate the effectiveness of this technique.

Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: A clinically silent peripheral neuropathy.

Adeno-associated virus (AAV)-based vectors are commonly used for delivering transgenes in gene therapy studies, but they are also known to cause dorsal root ganglia (DRG) and peripheral nerve toxicities in animals. However, the functional implications of these pathologic findings and their time course remain unclear. At 2, 4, 6, and 8 weeks following a single dose of an AAV9 vector carrying human frataxin transgene in rats, non-standard functional assessments, including von Frey filament, electrophysiology, and Rotarod tests, were conducted longitudinally to measure allodynia, nerve conduction velocity, and coordination, respectively. Additionally, DRGs, peripheral nerves, brain and spinal cord were evaluated histologically and circulating neurofilament light chain (NfL) was quantified at 1, 2, 4, and 8 weeks, respectively. At 2 and 4 weeks after dosing, minimal-to-moderate nerve fiber degeneration and neuronal degeneration were observed in the DRGs in some of the AAV9 vector-dosed animals. At 8 weeks, nerve fiber degeneration was observed in DRGs, with or without neuronal degeneration, and in sciatic nerves of all AAV9 vector-dosed animals. NfL values were higher in AAV9 vector-treated animals at weeks 4 and 8 compared with controls. However, there were no significant differences in the three functional endpoints evaluated between the AAV9 vector- and vehicle-dosed animals, or in a longitudinal comparison between baseline (predose), 4, and 8 week values in the AAV9 vector-dose animals. These findings demonstrate that there is no detectable functional consequence to the minimal-to-moderate neurodegeneration observed with our AAV9 vector treatment in rats, suggesting a functional tolerance or reserve for loss of DRG neurons after systemic administration of AAV9 vector.

People who use drugs in hospital settings: 'Moving towards a person-centred harm reduction model'.

People who use drugs often continue to use drugs while in hospital. However, health-care systems often expect abstinence from drugs as a condition of engagement in various services. This commentary piece proposes that this approach is inconsistent with the principles of person-centred care. A harm reduction-based approach in conjunction with collaboration of people who use drugs is proposed as a model for providing person-centred care to people who use drugs during hospital-based treatment.

Lifestyle interventions in the management of substance use disorder.

BACKGROUND: Substance use disorder (SUD) is a persistent problem within society and an issue of increasing community awareness and concern. SUD is often comorbid with significant mental health challenges, trauma and negative social determinants of health. SUDs contribute to increased burden of chronic disease and can lead to increased mortality and shorter life expectancy, not just through overdose but also through increased rates of mental and physical chronic disease. OBJECTIVE: The aim of this article is to explore the evidence regarding lifestyle interventions as either primary interventions or adjuncts to existing treatments for individuals with SUD. DISCUSSION: Lifestyle interventions can play a significant part in the management of people with SUD. These interventions play a part in SUD treatment and relapse prevention as well as improving physical and mental health and quality of life. These interventions ideally can be instituted and managed through community services and primary care.

Case series on treatment of dependence to Kamini Vidrawan Ras with opioid substitution therapy.

INTRODUCTION: A cohort of clients was recognised attending an addiction medicine clinic with similar presentations of opioid dependence from use of a rarely known Ayurvedic medication in a specific ethnic community. This retrospective case series was completed to promote wider recognition and further understanding of dependence on Kamini Vidrawan Ras (Kamini). METHODS: A retrospective file audit of the electronic medical record for clients of an addiction medicine outpatient clinic with a history of dependent use of Kamini identified 12 clients meeting inclusion criteria. RESULTS: All 12 clients were male, aged 27-41 years, all but one of north Indian origin, predominantly employed and predominantly (but not exclusively) without significant other substance use history. All 12 clients were treated with opioid substitution therapy. DISCUSSION AND CONCLUSIONS: This case series highlights an opioid dependence syndrome resulting from use of an Ayurvedic medicine by men from a specific area of India, highlighting a potential adverse effect of traditional medicines in ongoing use by migrant and ethnic populations that have emigrated to Australia.

Early Drug-Induced Liver Injury Risk Screening: "Free," as Good as It Gets.

For all the promise of and need for clinical drug-induced liver injury (DILI) risk screening systems, demonstrating the predictive value of these systems versus readily available physicochemical properties and inherent dosing information has not been thoroughly evaluated. Therefore, we utilized a systematic approach to evaluate the predictive value of in vitro safety assays including bile salt export pump transporter inhibition and cytotoxicity in HepG2 and transformed human liver epithelial along with physicochemical properties. We also evaluated the predictive value of in vitro ADME assays including hepatic partition coefficient (Kp) and its unbound counterpart because they provide insight on hepatic accumulation potential. The datasets comprised of 569 marketed drugs with FDA DILIrank annotation (most vs less/none), dose and physicochemical information, 384 drugs with Kp and plasma protein binding data, and 279 drugs with safety assay data. For each dataset and combination of input parameters, we developed random forest machine learning models and measured model performance using the receiver operator characteristic area under the curve (ROC AUC). The median ROC AUC across the various data and parameters sets ranged from 0.67 to 0.77 with little evidence of additive predictivity when including safety or ADME assay data. Subsequent machine learning models consistently demonstrated daily dose, fraction sp3 or ionization, and cLogP/D inputs produced the best, simplest model for predicting clinical DILI risk with an ROC AUC of 0.75. This systematic framework should be used for future assay predictive value assessments and highlights the need for continued improvements to clinical DILI risk annotation.

Medicare Claim-Based National Institutes of Health Stroke Scale to Predict 30-Day Mortality and Hospital Readmission.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) penalizes hospitals for higher than expected 30-day mortality rates using methods without accounting for condition severity risk adjustment. For patients with stroke, CMS claims did not quantify stroke severity until recently, when the National Institutes of Health Stroke Scale (NIHSS) reporting began. OBJECTIVE: Examine the predictive ability of claim-based NIHSS to predict 30-day mortality and 30-day hospital readmission in patients with ischemic stroke. DESIGN: Retrospective cohort study of Medicare claims data. PATIENTS: Medicare beneficiaries with ischemic stroke (N=43,241) acute hospitalization between October 2016 and November 2017. MEASUREMENTS: All-cause 30-day mortality and 30-day hospital readmission. NIHSS score was derived from ICD-10 codes and stratified into the following: minor to moderate, moderate, moderate to severe, and severe categories. RESULTS: Among 43,241 patients with ischemic stroke with NIHSS from 2,659 US hospitals, 64.6% had minor to moderate stroke, 14.3% had moderate, 12.7% had moderate to severe, and 8.5% had a severe stroke,10.1% died within 30 days, 12.1% were readmitted within 30 days. The NIHSS exhibited stronger discriminant property (C-statistic 0.83, 95% CI: 0.82-0.84) for 30-day mortality compared to Elixhauser (0.74, 95% CI: 0.73-0.75). A monotonic increase in the adjusted 30-day mortality risk occurred relative to minor to moderate stroke category: hazard ratio [HR]=2.92 (95% CI=2.59-3.29) for moderate stroke, HR=5.49 (95% CI=4.90-6.15) for moderate to severe stroke, and HR=7.82 (95% CI=6.95-8.80) for severe stroke. After accounting for competing risk of mortality, there was a significantly higher readmission risk in the moderate stroke (HR=1.11, 95% CI=1.03-1.20), but significantly lower readmission risk in the severe stroke (HR=0.84, 95% CI=0.74-0.95) categories. LIMITATION: Timing of NIHSS reporting during hospitalization is unknown. CONCLUSIONS: Medicare claim-based NIHSS is significantly associated with 30-day mortality in Medicare patients with ischemic stroke and significantly improves discriminant property relative to the Elixhauser comorbidity index.

Outcomes of a single-arm implementation trial of extended-release subcutaneous buprenorphine depot injections in people with opioid dependence.

BACKGROUND: Opioid agonist treatment (OAT) is an effective intervention for opioid dependence. Extended-release buprenorphine injections (BUP-XR) may have additional potential benefits over sublingual buprenorphine. This single-arm trial evaluated outcomes among people receiving 48 weeks of BUP-XR in diverse community healthcare settings in Australia, permitting examination of outcomes when BUP-XR is delivered in standard practice. METHODS: Participants were recruited from a network of specialist public drug treatment services, primary care and some private practices in three states. Following a minimum 7 days on 8-32 mg of sublingual buprenorphine (±naloxone), participants received monthly subcutaneous BUP-XR injections administered by a healthcare practitioner and completed monthly research interviews. The primary endpoint was retention in treatment at 48 weeks. FINDINGS: Participants (n = 100) were 28% women, mean age 44 years with a long history of OAT (median 5.8 years); heroin was the most common opioid of concern (58%). Treatment retention at 24 and 48 weeks was 86% and 75%, respectively. Participants with past-month injecting drug use (OR 0.23; 95%CI: 0.09-0.61) or heroin use (OR 0.23; 95%CI: 0.08-0.65) at baseline had lower odds of being retained in treatment to 48 weeks. Reductions in multiple forms of extra-medical drug use were observed. Improvements in quality of life, participation in employment, and treatment satisfaction measures were also observed. INTERPRETATION: This real-world implementation study of BUP-XR demonstrated high retention and treatment satisfaction. This study provides important additional data on the uptake and experience of clients, with relevance for policy makers, health service planners, administrators, and practitioners. FUNDING: Indivior. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03809143.

An orthogonal methods assessment of topical drug concentrations in skin and the impact for risk assessment in the viable epidermis.

Systemic toxicity assessments for oral or parenteral drugs often utilize the concentration of drug in plasma to enable safety margin calculations for human risk assessment. For topical drugs, there is no standard method for measuring drug concentrations in the stratum basale of the viable epidermis. This is particularly important since the superficial part of the epidermis, the stratum corneum (SC), is nonviable and where most of a topically applied drug remains, never penetrating deeper into the skin. We investigated the relative concentrations of a prototype kinase inhibitor using punch biopsy, laser capture microdissection, and imaging mass spectrometry methods in the SC, stratum basale, and dermis of minipig skin following topical application as a cream formulation. The results highlight the value of laser capture microdissection and mass spectrometry imaging in quantifying the large difference in drug concentration across the skin and even within the epidermis, and supports use of these methods for threshold-based toxicity risk assessments in specific anatomic locations of the skin, like of the stratum basale.

Seasonal Variability in Weight Gain Among American Indian, Black, White, and Hispanic Children: A 3.5-Year Study.

INTRODUCTION: Several studies have reported that children gain more weight during the summer season. Despite high obesity rates, little research has included American Indian/Alaskan Native children, and few studies have been longitudinal. This observational study examines seasonal weight variability over 3.5 years among ethnically diverse children, including 2,184 American Indian/Alaskan Native children. METHODS: Children's height and weight were measured before and after the summer from 2012-2015 and analyzed in 2019-2020, including children with ≥2 consecutive measurements (N=7,890, mean age=8.4 [SD=2.8] years). Mixed-effects models tested whether the percentage of the 95th BMI percentile and BMI differed by season (summer versus the rest of the year) and ethnicity. RESULTS: American Indian/Alaskan Native (23.7%), Hispanic (19.8%), and Black (17.8%) children had significantly higher baseline obesity rates than White children (7.1%). The percentage of the 95th BMI percentile significantly increased during the summer compared with the percentage during the rest of the year, with the strongest effects for children who were obese (b=2.69, 95% CI=1.35, 4.03, p<0.001) or overweight (b=1.47, 95% CI=0.56, 2.35, p<0.01). In BMI units, summer BMI increase was 0.50 kg/m2 higher (obese model) and 0.27 kg/m2 higher (overweight) than that of the rest of the year. Seasonal effects were significantly less pronounced for American Indian/Alaskan Native children than for White children. CONCLUSIONS: Children gained significantly more weight during the summer season, with the strongest effects for children who were obese. American Indian/Alaskan Native children had less seasonal variability than White children, but higher overall obesity rates. These data underscore summer as a critical time for obesity prevention among children who are overweight/obese but suggest that seasonal patterns may vary for American Indian/Alaskan Native children.

Experiments in the EpiDerm 3D Skin In Vitro Model and Minipigs In Vivo Indicate Comparatively Lower In Vivo Skin Sensitivity of Topically Applied Aneugenic Compounds.

Risk management of in vitro aneugens for topically applied compounds is not clearly defined because there is no validated methodology to accurately measure compound concentration in proliferating stratum basale keratinocytes of the skin. Here, we experimentally tested several known aneugens in the EpiDerm reconstructed human skin in vitro micronucleus assay and compared the results to flow cytometric mechanistic biomarkers (phospho-H3; MPM2, DNA content). We then evaluated similar biomarkers (Ki-67, nuclear area) using immunohistochemistry in skin sections of minipigs following topical exposure the potent aneugens, colchicine, and hesperadin. Data from the EpiDerm model showed positive micronucleus responses for all aneugens tested following topical or direct media dosing with similar sensitivity when adjusted for applied dose. Quantitative benchmark dose-response analysis exhibited increases in the mitotic index biomarkers phospho-H3 and MPM2 for tubulin binders and polyploidy for aurora kinase inhibitors are at least as sensitive as the micronucleus endpoint. By comparison, the aneugens tested did not induce histopathological changes, increases in Ki-67 immunolabeling or nuclear area in skin sections from the in vivo minipig study at doses in significant excess of those eliciting a response in vitro. Results indicate the EpiDerm in vitro micronucleus assay is suitable for the hazard identification of aneugens. The lack of response in the minipig studies indicates that the barrier function of the minipig skin, which is comparable to human skin, protects from the effects of aneugens in vivo. These results provide a basis for conducting additional studies in the future to further refine this understanding.

Expression of Hematopoietic Stem and Endothelial Cell Markers in Canine Hemangiosarcoma.

Several chemicals and pharmaceuticals increase the incidence of hemangiosarcomas (HSAs) in mice, but the relevance to humans is uncertain. Recently, canine HSAs were identified as a powerful tool for investigating the pathogenesis of human HSAs. To characterize the cellular phenotype of canine HSAs, we evaluated immunoreactivity and/or messenger RNA (mRNA) expression of markers for hematopoietic stem cells (HSCs), endothelial cells (ECs), a tumor suppressor protein, and a myeloid marker in canine HSAs. Neoplastic canine cells expressed EC markers and a myeloid marker, but expressed HSC markers less consistently. The canine tumor expression results were then compared to previously published immunoreactivity results for these markers in human and mouse HSAs. There are 2 noteworthy differences across species: (1) most human HSAs had HSC marker expression, indicating that they were comprised of tumor cells that were less differentiated than those in canine and mouse tumors; and (2) human and canine HSAs expressed a late-stage EC maturation marker, whereas mouse HSAs were negative, suggesting that human and canine tumors may retain greater differentiation potential than mouse tumors. These results indicate that HSA development is variable across species and that caution is necessary when discussing translation of carcinogenic risk from animal models to humans.

Circulating microRNA and automated motion analysis as novel methods of assessing chemotherapy-induced peripheral neuropathy in mice.

Chemotherapy-induced peripheral neuropathy (CiPN) is a serious adverse effect in the clinic, but nonclinical assessment methods in animal studies are limited to labor intensive behavioral tests or semi-quantitative microscopic evaluation. Hence, microRNA (miRNA) biomarkers and automated in-life behavioral tracking were assessed for their utility as non-invasive methods. To address the lack of diagnostic biomarkers, we explored miR-124, miR-183 and miR-338 in a CiPN model induced by paclitaxel, a well-known neurotoxic agent. In addition, conventional and Vium's innovative Digital Vivarium technology-based in-life behavioral tests and postmortem microscopic examination of the dorsal root ganglion (DRG) and the sciatic nerve were performed. Terminal blood was collected on days 8 or 16, after 20 mg/kg paclitaxel was administered every other day for total of 4 or 7 doses, respectively, for plasma miRNA quantification by RT-qPCR. DRG and sciatic nerve samples were collected from mice sacrificed on day 16 for miRNA quantification. Among the three miRNAs analyzed, only miR-124 was statistically significantly increased (5 fold and 10 fold on day 8 and day 16, respectively). The increase in circulating miR-124 correlated with cold allodynia and axonal degeneration in both DRG and sciatic nerve. Automated home cage motion analysis revealed for the first time that nighttime motion was significantly decreased (P < 0.05) in paclitaxel-dosed animals. Although both increase in circulating miR-124 and decrease in nighttime motion are compelling, our results provide positive evidence warranting further testing using additional peripheral nerve toxicants and diverse experimental CiPN models.

Principles of precision medicine and its application in toxicology.

Precision medicine is an approach to developing drugs that focuses on employing biomarkers to stratify patients in clinical trials with the goal of improving efficacy and/or safety outcomes, ultimately increasing the odds of clinical success and drug approval. Precision medicine is an important tool for toxicologists to utilize, because its principles can be used to decide whether to pursue a drug target, to understand interindividual differences in response to drugs in both nonclinical and clinical settings, to aid in selecting doses that optimize efficacy or reduce adverse events, and to facilitate understanding of a drug's mode-of-action. Nonclinical models such as the mouse and non-human primate can be used to understand genetic variation and its potential translation to humans, and are available for toxicologists to employ in advance of drugs moving into clinical development. Understanding interindividual differences in response to drugs and how these differences can influence the drug's risk-benefit profile and lead to the identification of biomarkers that enhance patient efficacy and safety is of critical importance for toxicologists today, and in the future, as the fields of pharmacogenomics and genetics continue to advance.