The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers

Aims Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. Design A randomized, double‐blind, placebo‐controlled, cross‐over study. Setting An in‐patient research unit at the University of Kentucky. Participants Healthy adults (n = 10) abusing, but not physically dependent on, intranasal opioids. Measurements Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject‐ and observer‐rated measures were collected before and for up to 72 hours after drug administration. Findings Both formulations produced time‐ and dose‐dependent increases on subjective and physiological mu‐opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time–course were observed. Buprenorphine bioavailability was 38–44% and T_max was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. Conclusions It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non‐dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine/naloxone administration may deter the likelihood of intranasal misuse of buprenorphine/naloxone, but not buprenorphine, in opioid‐dependent individuals.     

A prospective, randomized, multicenter acceptability and safety study of direct buprenorphine/naloxone induction in heroin-dependent individuals

Aims To provide controlled data on direct induction with buprenorphine/naloxone (BNX) versus indirect buprenorphine (BPN)‐to‐BNX induction. Design Phase 4, prospective, randomized, active‐drug controlled, parallel‐group trial consisting of a 2‐day, double‐blind, double‐dummy induction phase followed by 26 days of open‐label treatment with BNX. Setting Nineteen sites in 10 European countries from March 2008 to December 2009. Participants A total of 187 opioid‐dependent men and women ≥15 years of age. Measurements The primary objective was assessment of patient response to direct and indirect BNX induction [proportion of patients receiving the scheduled 16‐mg BNX dose on day 3 (i.e. first day post‐induction)]. Secondary assessments included illicit drug use, treatment retention and compliance, withdrawal scale scores, and safety. Findings Patient response to direct‐ versus indirect‐BNX induction was similar [direct 91.4% (85/93) versus indirect 90.4% (85/94); 95% confidence interval (CI): −7.3%, 9.2%]. Rapid dose induction (16 mg of BPN equivalent on day 2) was acceptable and 72% of patients completed treatment (day 28). There were no significant differences in secondary measures across groups. An average BNX maintenance dose of 15.3 mg across groups was associated with substantial reductions in illicit opioid use and no self‐reported intravenous misuse. Treatment compliance and retention rates were similar (98.5% and 81.3%, respectively). Treatment‐emergent adverse event rates were comparable: 75% versus 74% for direct‐ versus indirect‐induction groups, respectively. Conclusions Direct buprenorphine/naloxone induction was a safe and effective strategy for maintenance treatment of opioid dependence. Response to high‐dose direct buprenorphine/naloxone induction appears to be similar to indirect buprenorphine‐to‐buprenorphine/naloxone induction and was not associated with reports of intravenous buprenorphine/naloxone misuse.     

Sex differences in opioid use and medical issues during buprenorphine/naloxone treatment

Background: There are sex differences in buprenorphine/naloxone clinical trials for opioid use. While women have fewer opioid-positive urine samples, relative to men, a significant decrease in opioid-positive samples was found during treatment for men, but not women. In order to inform sex-based approaches to improve treatment outcomes, research is needed to determine if opioid use, and predictors of opioid use, differs between men and women during treatment. Objectives: To test for sex differences in opioid use during a buprenorphine/naloxone clinical trial and determine if sex differences exist in the associations between addiction-related problem areas and opioid use over the course of the trial. Method: This secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network (CTN) 0003 examined sex differences (men = 347, women = 169) in opioid-positive samples in a randomized clinical trial comparing 7-day vs. 28-day buprenorphine/naloxone tapering strategies. Addiction-related problem areas were defined by Addiction Severity-Lite (ASI-L) domain composite scores. Results: Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial (B = .33, p = .01) and medical issues were positively related to submitting an opioid-positive sample during treatment for women (B = 1.67, p = .01). No ASI-L domain composite score was associated with opioid-positive samples during treatment for men. Conclusion: Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial, and medical issues predicted opioid use during treatment for women but not men. Complementary treatment for medical problems during opioid replacement therapy may benefit women.     

Impact of in-patient research participation on subsequent heroin use patterns: implications for ethics and public health

Aims Research on drug dependence often involves the administration of drugs of abuse to experienced drug users under controlled laboratory conditions. The primary objective of this study was to assess whether participation in such research alters the frequency of heroin use by non‐treatment‐seeking opioid‐dependent volunteers after study completion. Design Data were examined from four in‐patient studies involving controlled opioid administration. Setting Substance Use Research Center at Columbia University, New York State Psychiatric Institute. Participants Sixty‐nine heroin‐dependent volunteers. Measurements Participants' self‐reported heroin use prior to and 1 month after study participation was compared using a Wilcoxon test. Because a number of participants reported that they had stopped using heroin, a logistic regression was used to identify correlates of heroin cessation 1 month after study completion. Findings One hundred and one participants entered laboratory studies and 69 completed them. Self‐reported heroin use significantly decreased 1 month after study participation [1.7 (±2.0) bags per day] compared to baseline [6.8 (±4.2) bags per day], P < 0.001 among the 69 completers. In addition, 42% of the completers were heroin‐abstinent 1 month after study completion. Being African American, having a history of opioid dependence treatment, reporting heavier heroin use at baseline and a longer history of heroin use were correlated with cessation of heroin use. Conclusions Participation in opioid administration studies does not increase subsequent heroin use and for some individuals leads to accessing opioid dependence treatment and cessation of heroin use in the short term.     

The Moderating Role of Purging Behaviour in the Relationship Between Sexual/Physical Abuse and Nonsuicidal Self‐Injury in Eating Disorder Patients

This study sought to examine predictors of nonsuicidal self‐injury (NSSI) in eating disorder patients and to evaluate the moderating role of purging behaviours in the relationship between a theorised predictor (i.e. sexual/physical abuse) and NSSI. Participants in this study were 177 female patients with eating disorders (age range = 14–38 years) who completed semistructured interviews assessing eating disorder symptoms and eating disorder‐related risk factors (e.g. history of sexual and physical abuse, history of NSSI and feelings of fatness). Results revealed that 65 participants (36.7%) reported lifetime engagement in NSSI, and 48 participants (27.1%) reported a history of sexual/physical abuse. Early onset of eating problems, lower BMI, feeling fat, a history of sexual/physical abuse and the presence of purging behaviours were all positively associated with the lifetime occurrence of NSSI. The relationship between sexual/physical abuse before eating disorder onset and lifetime NSSI was moderated by the presence of purging behaviours, such that the relationship was stronger in the absence of purging. These findings are consistent with the notion that purging and NSSI may serve similar functions in eating disorder patients (e.g. emotion regulation), such that the presence of purging may attenuate the strength of the association between sexual/physical abuse history (which is also associated with elevated NSSI risk) and engagement in NSSI behaviours. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.     

The Role of Non‐suicidal Self‐Injury and Binge‐Eating/Purging Behaviours in the Caregiving Experience Among Mothers and Fathers of Adolescents with Eating Disorders

This study investigated the caregiving experiences of mothers and fathers of restrictive and binge‐eating/purging eating disordered (ED) inpatients with and without non‐suicidal self‐injury (NSSI). Sixty‐five mothers and 65 fathers completed the Experience of Caregiving Inventory. All inpatients completed the Self‐Injury Questionnaire—Treatment Related to assess NSSI and the Eating Disorder Evaluation Scale to assess eating disorder symptoms. Mothers reported significant more negative and more positive caregiving experiences compared with fathers. Mothers (but not fathers) of restrictive ED patients reported more positive caregiving experiences compared with mothers of binge‐eating/purging patients. The presence of NSSI in ED patients was associated with more negative caregiving experiences of both parents. Mothers and fathers of ED inpatients differ in caregiving experiences, and both binge‐eating behaviours and NSSI negatively affect their caregiving experience. Therefore, supportive interventions for parents of ED patients are necessary, especially of those patients who engage in NSSI. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.     

Validation of a wrist‐type home nocturnal blood pressure monitor in the sitting and supine position according to the ANSI/AAMI/ISO81060‐2:2013 guidelines: Omron HEM‐9601T

This study aimed to validate the accuracy of the Omron HEM‐9601T, an automatic wrist‐type device for self‐blood pressure (BP) measurement with a timer function for automatic measurement of nocturnal BP, in the sitting position according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060‐2:2013 guidelines, and to assess its performance in the supine position by applying the same protocol as conducted in the sitting position. The mean differences between the reference BPs and HEM‐9601T readings were 1.2 ± 6.9/1.1 ± 5.5 mmHg, 2.2 ± 6.5/1.8 ± 5.7 mmHg, 0.1 ± 6.6/1.5 ± 6.2 mmHg, and ?0.8 ± 7.2/0.5 ± 6.4 mmHg for systolic BP/diastolic BP for criterion 1 in the sitting position, supine with sideways palm position, supine with upward palm position, and supine with downward palm position, respectively. In addition, the mean differences and their standard deviations for systolic BP and diastolic BP calculated according to criterion 2 in the ANSI/AAMI/ISO 81060‐2:2013 guidelines were acceptable in all four positions. In conclusion, the Omron HEM‐9601T fulfilled the validation criteria of the ANSI/AAMI/ISO81060‐2:2013 guidelines when used in the sitting position with the wrist at heart level, and its accuracy in the supine position was acceptable and roughly equivalent to that in the sitting position. The wrist‐type home BP monitor could be a more suitable tool for repeated nocturnal BP measurements at home than upper‐arm devices, and could improve the reliability of diagnosis and management of nocturnal hypertension.     

Validation of a wrist‐type home nocturnal blood pressure monitor in the sitting and supine position according to the ANSI/AAMI/ISO81060‐2:2013 guidelines: Omron HEM‐9600T

The purpose of the present study was to evaluate the performance of the Omron HEM‐9600T, an automatic wrist‐type device for self BP measurement, in the sitting position with the wrist at heart level and supine position according to the ANSI/AAMI/ISO81060‐2:2013 guidelines. In the supine position, we evaluated the device under 3 different conditions: using the supine with sideways palm position, the supine with upwards palm position, and the supine with downwards palm position. After 106 subjects were screened and 21 subjects were excluded, the same 85 subjects (38 men [44.7%] and 47 women [55.3%]) were included in the analyses for each position. The average age of the subjects was 54.5 ± 12.2 years (mean ± SD). The mean wrist circumference was 17.0 ± 2.4 cm. The wrist size distribution fulfilled the requirements of the guidelines. The mean differences between reference BPs and HEM‐9600T readings were 1.0 ± 6.7/1.4 ± 5.7 mm Hg, 6.6 ± 7.2/5.5 ± 6.0 mm Hg, 4.8 ± 7.2/4.9 ± 5.8 mm Hg, and 2.1 ± 7.2/2.8 ± 6.8 mm Hg for SBP/DBP in the sitting position, supine with sideways palm position, supine with upwards palm position, and supine with downwards palm position, respectively. In conclusion, the Omron HEM‐9600T in the sitting position fulfilled the validation criteria of the ANSI/AAMI/ISO81060‐2:2013 guidelines. On the other hand, the accuracies of HEM‐9600T in the supine position differed depending on the positioning of the palm, with only the downwards palm‐position measurement fulfilling both validation criteria of the ANSI/AAMI/ISO81060‐2:2013 guidelines.     

Rifampicin‐dependent antibodies target glycoprotein IIb/IIIa and cause clearance of human platelets in NOD/SCID mice

Dysregulation of MYC is the genetic hallmark of Burkitt lymphoma (BL) but it is encountered in other aggressive mature B‐cell lymphomas. MYC dysregulation needs other cooperating events for BL development. We aimed to characterize these events and assess the differences between adult and paediatric BLs that may explain the different outcomes in these two populations. We analysed patterns of genetic aberrations in a series of 24 BLs: 11 adults and 13 children. We looked for genomic imbalances (copy number variations), copy‐neutral loss of heterozygosity (CN‐LOH) and mutations in TP53, CDKN2A, ID3 (exon 1), TCF3 (exon17) and CCND3 (exon 6). Young patients displayed more frequent 13q31.3q32.1 amplification, 7q32q36 gain and 5q23.3 CN‐LOH, while 17p13 and 18q21.3 CN‐LOH were only detected in adult BLs. ID3 mutations were present in all adult samples, but only in 42% of childhood cases. CCND3 and ID3 double‐hit mutations, as well as 18q21 CN‐LOH, seemed to be associated with poorer outcome. For the first time, we report different genetic anomalies between adult and paediatric BLs, suggesting age‐related heterogeneity in Burkitt lymphomagenesis. This may explain the poorer prognosis of adult BLs. Additional studies are needed to confirm these results in the setting of clinical trials.