Norbuprenorphine and respiratory depression: Exploratory analyses with new lyophilized buprenorphine and sublingual buprenorphine
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OBJECTIVES: To investigate plasma levels of buprenorphine and norbuprenorphine and their relationship to respiratory depression. MATERIALS AND METHODS: Opioid-dependent subjects were randomized 2 : 1 to novel lyophilized rapid-disintegrating tablet ("bup-lyo") or standard sublingual buprenorphine tablet ("bup-SL"). Measurements included oximetry scores and linked plasma buprenorphine and norbuprenorphine levels. RESULTS: Respiratory depression (cumulative duration of SpO2 < 90% over 30-minute periods) increased with corresponding exposure levels (AUC30 min) of buprenorphine and particularly with norbuprenorphine. A lower buprenorphine/norbuprenorphine ratio was predictive of respiratory depression. The mean (SD) observed ratio was significantly higher for "bup-lyo" (3.4 (2.8)) compared to "bup-SL" (1.7 (0.77)), p < 0.0001. CONCLUSION: Exploratory investigation found respiratory depression more strongly associated with norbuprenorphine than with buprenorphine. This accords with animal studies.
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Excess overdose mortality immediately following transfer of patients and their care as well as after cessation of opioid substitution therapy.

AIMS: To investigate clustering of all-cause and overdose deaths after a transfer of patients and their care to alternative treatment provider and after the end of opioid substitution therapy (OST) in opioid-dependent individuals in specialist addiction treatment. DESIGN, SETTING AND PARTICIPANTS: Mortality data were identified within a sample of 5335 patients with opioid use disorder who had received OST treatment between 1 April 2008 and 31 December 2013 from a large mental health-care provider in the United Kingdom. We investigated the circumstances and distribution of the 332 deaths identified within the observation window with a specific focus on overdose deaths (n = 103) after a planned discharge, dropout and transfer between services. MEASUREMENTS: Crude mortality rates for overdose mortality 14 days, 28 days and more than 1 month after the end of treatment/transfer for overdose mortality. FINDINGS: Of 47 individuals who died from overdose after having been transferred between services, nine died during the first 2 weeks [crude mortality rate (CMR) = 136.4, 95% confidence interval (CI) = 64.3-243.1] and a further five died during the first month post-transfer (CMR= 79.5, 95% CI = 44.2-129.7). Of the 32 individuals who died from overdose after planned OST cessation, five died during the first 2 weeks (CMR = 151.5, 95% CI = 51.1-319.0) and a further four died during the first month post-discharge (CMR = 82.6, 95% CI = 38.4-151.0). CONCLUSIONS: In the United Kingdom, opioid-dependent people who are transferred to an alternative treatment provider for continuation of their opioid substitution therapy experience high overdose mortality rates, with substantially higher rates during the first month (especially during the first 14 days) following transfer.

Randomised Comparison of a Novel Buprenorphine Oral Lyophilisate versus Existing Buprenorphine Sublingual Tablets in Opioid-Dependent Patients: A First-in-Patient Phase II Randomised Open Label Safety Study.

AIMS: To test the safety of new buprenorphine oral lyophilisate wafer ("bup-lyo") versus standard sub-lingual buprenorphine ("bup-SL"). DESIGN: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over. SETTINGS: Specialised clinical trials facility and addictions treatment facility. PARTICIPANTS: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds). MEASUREMENTS: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11). FINDINGS: Oral lyophilised buprenorphine ("bup-lyo") completely dissolved within 2 min for 58 vs. 5% for "bup-SL." Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of "hold," respiratory function. No serious adverse events (AEs), nor "severe" AEs, although more AEs and Treatment-Emergent AEs with "bup-lyo" (mostly "mild"). PK found greater bioavailability of buprenorphine with "bup-lyo" (but not norbuprenorphine). CONCLUSIONS: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with "bup-lyo" relative to "bup-SL." In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing.

Identifying mortality risks in patients with opioid use disorder using brief screening assessment: Secondary mental health clinical records analysis.

BACKGROUND: Risk assessments are widely used, but their ability to predict outcomes in opioid use disorder (OUD) treatment remains unclear. Therefore, the aim was to investigate if addiction-specific brief risk screening is effective in identifying high mortality risk groups and if subsequent clinical actions following risk assessment impacts on mortality levels. METHODS: Opioid use disorder (OUD) patients were identified in the South London and Maudsley Case Register. Deaths were identified through database linkage to the national mortality dataset. Cox and competing-risk regression were used to model associations between brief risk assessment domains and all-cause and overdose mortality in 4488 OUD patients, with up-to 6-year follow-up time where 227 deaths were registered. Data were stratified by admission to general mental health services. RESULTS: All-cause mortality was significantly associated with unsafe injecting (HR 1.53, 95% CI 1.10-2.11) and clinically appraised likelihood of accidental overdose (HR 1.48, 95% CI 1.00-2.19). Overdose-mortality was significantly associated with unsafe injecting (SHR 2.52, 95% CI 1.11-5.70) and clinically appraised suicidality (SHR 2.89, 95% CI 1.38-6.03). Suicidality was associated with a twofold increase in mortality risk among OUD patients who were not admitted to mental health services within 2 months of their risk assessment (HR 2.03, 95% CI 1.67-3.24). CONCLUSIONS: Diagnosis-specific brief risk screening can identify OUD patient subgroups at increased risk of all-cause and overdose mortality. OUD patients, where suicidality is evident, who are not admitted into services are particularly vulnerable.

Double trouble: Psychiatric comorbidity and opioid addiction-all-cause and cause-specific mortality.

BACKGROUND: Opioid misusers have recognized high mortality but the influence of psychiatric comorbidity in excess cause-specific mortality is unclear. METHODS: Opioid use disorder (OUD) patients were identified in the South London and Maudsley Case Register. Deaths were identified through database linkage to the national mortality dataset. Standard mortality ratios were calculated to compare mortality risk with the general population. Cox and competing risk regression models were used to investigate the effect of psychiatric comorbidity and psychological health on all-cause and cause-specific mortality (respectively) in OUD patients. RESULTS: Of 4837 OUD patients, 176 had died. Mortality rates were substantially higher than the general population (SMR 4.23; 95%CI 3.63-4.90). Among those with OUD, comorbid personality disorder (PD) and comorbid alcohol use disorder (AUD) was associated with increased all-cause mortality in all models, including the fully adjusted model, controlling for socio-demographic factors, severity of drug use, risk behaviours and physical health (HR2.15, 95%CI 1.17-3.95; HR2.28, 95%CI 1.54-3.36). AUD was associated with increased risk of fatal overdose (HR2.57, 95%CI 1.26-5.26) and hepatic-related deaths (HR7.26, 95%CI 2.79-18.86). Individuals with OUD and comorbid PD had almost four times greater risk of liver related deaths compared to those without PD (HR3.76, 95%CI 1.21-11.74). Comorbid severe mental illness and poor psychological health were not associated with increased mortality. CONCLUSIONS: This study highlights the importance of assessment for PD and AUD in OUD patients in order to identify individuals at substantially elevated mortality risk to enable a more personalized approach to their medical care.

[Polymorphism rs9939609 of FTO gene is related to the body mass index in children from Podlaskie voievodship]. / Polimorfizm rs9939609 genu FTO jest zwiazany ze wskaznikiem masy ciala dzieci z wojewodztwa podlaskiego.

INTRODUCTION: The presence of obesity and the features of metabolic syndrome plays a predictive role in cardiovascular diseases (CVD) in adults. It seems reasonable to seek new risk factors in the development of CVD. Defining the genetic background of obesity could help to select patients from a high risk group and help to introduce prevention and treatment, which, in consequence, lead to the lowering of morbidity and mortality. One of the genes probably related to the body weight is the Fat Mass and Obesity Associated Gene (FTO). THE AIM: of the study was an attempt to assess the relationship between the FTO polymorphism rs9939609 and body mass index in children from Podlaskie voievodship. MATERIAL AND METHODS: 405 children aged 4-18 were selected for the study. The examination included body mass index, waist circumference, blood pressure and lipid profile analysis. FTO rs9939609 polymorphism was assessed using a discrimination allele method with the application of ABI 7900HT Fast Real-Time PCR System. RESULTS: FTO rs9939609 polymorphism was related to the standarized body mass index and the AA genotype carriers had a higher risk of obesity. This polymorphism was also associated with waist circumference, systolic blood pressure and triglycerides concentration. It was not correlated with diastolic blood pressure and total HDL- and LDL-cholesterol concentrations. CONCLUSIONS: Our results demonstrate that rs9939609 FTO gene polymorphism is related to the body mass index in children. Our results should be confirmed in studies on a large cohort of healthy Polish children.