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.

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.

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.

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.

A novel endpoint for the assessment of chemotherapy-induced peripheral neuropathy in rodents: biomechanical properties of peripheral nerve.

Chemotherapy-induced peripheral neuropathy (CiPN) is a frequent adverse effect in patients and a leading safety consideration in oncology drug development. Although behavioral assessment and microscopic examination of the nerves and dorsal root ganglia can be incorporated into toxicity studies to assess CiPN risk, more sensitive and less labor-intensive endpoints are often lacking. In this study, rats and mice administered vincristine (75 µg kg-1  day-1 , i.p., for 10 days in rats and 100 µg kg-1  day-1 , i.p., for 11 days in mice, respectively) were employed as the CiPN models. Behavioral changes were assessed during the dosing phase. At necropsy, the sural or sciatic nerve was harvested from the rats and mice, respectively, and assessed for mechanical and histopathological endpoints. It was found that the maximal load and the load/extension ratio were significantly decreased in the nerves collected from the animals dosed with vincristine compared with the vehicle-treated animals (P < 0.05). Additionally, the gait analysis revealed that the paw print areas were significantly increased in mice (P < 0.01), but not in rats following vincristine administration. Light microscopic histopathology of the nerves and dorsal root ganglia were unaffected by vincristine administration. We concluded that ex vivo mechanical properties of the nerves is a sensitive endpoint, providing a new method to predict CiPN in rodent. Gait analysis may also be a useful tool in these pre-clinical animal models.

Managing attention deficit hyperactivity disorder in adults using illicit psychostimulants: A systematic review.

CONTEXT: Attention deficit hyperactivity disorder and stimulant use disorder commonly co-exist, and appropriate treatments have not been well established. OBJECTIVE: To provide guidance for treatment of co-existing attention deficit hyperactivity disorder and stimulant use disorder. DATA SOURCES: A systematic review of published English articles using MEDLINE, EMBASE, CINAHL, PsycINFO and Cochrane, utilising consistent search terms. STUDY SELECTION: Randomised controlled trials, comparing any treatment arm with a control group, for participants meeting Diagnostic and Statistical Manual of Mental Disorders or equivalent criteria for both attention deficit hyperactivity disorder and stimulant use disorder. RESULTS: Eight trials were identified for inclusion in this review. Four of eight studies showed improvement in attention deficit hyperactivity disorder outcome measures compared with placebo. Two of six studies that reported substance use outcomes showed improvement in treatment arms compared with placebo. Studies to show effect tended to be those with the highest treatment dosage. CONCLUSION: Evidence for the efficacy of treatment of patients with comorbid stimulant use disorder and attention deficit hyperactivity disorder is limited. Promising outcomes need replication in further studies utilising higher treatment dosage.

Why Do Promising Therapies Stall in Development and How Can We Move Them Forward?

There are many reasons that molecules fail to progress to market and various principles of risk-benefit decisions that can help drive the molecule through development. This symposium included discussions on global strategies involved in pushing promising molecules to market, what to do when a molecule stalls in its progress to market, and options for rescuing the molecule and pushing it forward again. Innovative partnerships that bring stalled drugs back into clinical development were also addressed. A regulatory perspective on common reasons for a molecule to fail in its forward progress was presented. In addition, situations arise when a third-party advisory committee can provide input to help overcome issues identified by a regulatory agency. Using examples from the private and public domain, presentations centered on how to repurpose a molecule and when more science is needed.

Epidemiological data on shaken baby syndrome in France using judicial sources.

BACKGROUND: The frequency of and risk factors for shaken baby syndrome remain poorly documented for several reasons: the real number of "benign" cases of shaken baby syndrome are not known; information sources used are diverse, there have been changes over time in the definition of this pathology and few population-based epidemiological studies are available. OBJECTIVE: Estimate the frequency of fatal shaken baby syndrome and determine its risk factors through research carried out on fatal cases in three regions of France while comparing them to data from international publications. MATERIALS AND METHODS: A retrospective epidemiological study of all cases of fatal shaken baby syndrome affecting infants younger than 1 year of age who were examined by the courts during a 5-year period in a defined geographical area. Shaken baby syndrome cases were compared with infanticide cases for risk factors and a comparison was made of family characteristics with those of the general population. RESULTS: Thirty-seven cases of shaken baby syndrome were recorded (a rate of 2.9 for 100,000 live births). As in other studies, we found a strong predominance of male victims (78%), young age (median age: 4 months) and a high rate of prematurity (22%). Conversely, results on family educational and socioeconomical levels differ from those reported in numerous studies. Parent perpetrators of shaken baby syndrome belong to higher social classes than those of other types of homicide and socially reflect the population they come from. CONCLUSION: Our study suggests 1) that epidemiological studies on shaken baby syndrome should include both medical and judicial information sources and 2) that primary prevention strategies (especially in maternity wards) should target all social classes.

Re-examining mandatory drug testing in Australian prisons.

Mandatory drug testing is commonly used in Australian prisons to detect and deter drug use. In this commentary, we review the limited evidence for mandatory drug testing programs, highlight potential harms associated with their implementation and provide recommendations for drug surveillance in prisons concordant with a harm minimisation framework.

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.

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.

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.

Evaluation of expression profiles of hematopoietic stem cell, endothelial cell, and myeloid cell antigens in spontaneous and chemically induced hemangiosarcomas and hemangiomas in mice.

It is unclear whether the process of spontaneous and chemically induced hemangiosarcoma and hemangioma formation in mice involves the transformation of differentiated endothelial cells (ECs) or recruitment of multipotential bone marrow-derived hematopoietic stem cells or endothelial progenitor cells (EPCs), which show some degree of endothelial differentiation. In the present study, immunohistochemical staining for hematopoietic stem cell markers (CD45 and CD34), EC markers (vascular endothelial growth factor receptor 2 [VEGFR2], CD31, and factor VIII-related antigen), and a myeloid lineage marker (CD14) was employed to better define the origin of hemangiosarcomas and hemangiomas in mice. Staining was negative for CD45, factor VIII-related antigen, and CD14 and positive for CD34, VEGFR2, and CD31, indicating that mouse hemangiosarcomas and hemangiomas are composed of cells derived from EPCs expressing CD34, VEGFR2, and CD31 but not factor VIII-related antigen. The lack of CD45 expression suggests that mouse vascular tumors may arise from EPCs that are at a stage later than hematopoietic stem cells. Since factor VIII-related antigen expression is known to occur later than CD31 expression in EPCs, our observations may indicate that these tumor cells are arrested at a stage prior to complete differentiation.  In addition, myeloid lineage cells do not appear to contribute to hemangiosarcoma and hemangioma formation in mice.

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.

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.

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.

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.

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.