Opioids are respiratory depressants and heroin/opioid overdose is a major contributor to the excess mortality of heroin addicts. The individual and situational variability of respiratory depression caused by intravenous heroin is poorly understood. This study used advanced respiratory monitoring to follow the time course and severity of acute opioid-induced respiratory depression. 10 patients (9/10 with chronic airflow obstruction) undergoing supervised injectable opioid treatment for heroin addiction received their usual prescribed dose of injectable opioid (diamorphine or methadone) (IOT), and their usual prescribed dose of oral opioid (methadone or sustained release oral morphine) after 30 minutes. The main outcome measures were pulse oximetry (SpO2%), end-tidal CO2% (ETCO2%) and neural respiratory drive (NRD) (quantified using parasternal intercostal muscle electromyography). Significant respiratory depression was defined as absence of inspiratory airflow >10s, SpO2% < 90% for >10s and ETCO2% per breath >6.5%. Increases in ETCO2% indicated significant respiratory depression following IOT in 8/10 patients at 30 minutes. In contrast, SpO2% indicated significant respiratory depression in only 4/10 patients, with small absolute changes in SpO2% at 30 minutes. A decline in NRD from baseline to 30 minutes post IOT was also observed, but was not statistically significant. Baseline NRD and opioid-induced drop in SpO2% were inversely related. We conclude that significant acute respiratory depression is commonly induced by opioid drugs prescribed to treat opioid addiction. Hypoventilation is reliably detected by capnography, but not by SpO2% alone. Chronic suppression of NRD in the presence of underlying lung disease may be a risk factor for acute opioid-induced respiratory depression.
Functional pathology of the default mode network is posited to be central to social-cognitive impairment in autism spectrum disorders (ASD). Altered functional connectivity of the default mode network's midline core may be a potential endophenotype for social deficits in ASD. Generalizability from prior studies is limited by inclusion of medicated participants and by methods favoring restricted examination of network function. This study measured resting-state functional connectivity in 22 8–13 year-old non-medicated children with ASD and 22 typically developing controls using seed-based and network segregation functional connectivity methods. Relative to controls the ASD group showed both under- and over-functional connectivity within default mode and non-default mode regions, respectively. ASD symptoms correlated negatively with the connection strength of the default mode midline core—medial prefrontal cortex–posterior cingulate cortex. Network segregation analysis with the participation coefficient showed a higher area under the curve for the ASD group. Our findings demonstrate that the default mode network in ASD shows a pattern of poor segregation with both functional connectivity metrics. This study confirms the potential for the functional connection of the midline core as an endophenotype for social deficits. Poor segregation of the default mode network is consistent with an excitation/inhibition imbalance model of ASD.
•The DMN is a potential endophenotype for social deficits in ASD.•This study used resting state functional MRI to probe the default mode network.•MPFC–PCC connection was reduced in strength in ASD and correlated with ASD severity.•Graph theory analysis showed that DMN had greater cross-network connectivity in ASD.•Findings support DMN as an ASD endophenotype and align with a GABA theory of ASD.
Default mode network; Autism spectrum disorders; Functional connectivity; Resting state
Unstuck and On Target (UOT) is an executive function (EF) intervention for children with autism spectrum disorders (ASD) targeting insistence on sameness, flexibility, goal-setting and planning through a cognitive-behavioral program of self-regulatory scripts, guided/faded practice, and visual/verbal cueing. UOT is contextually-based because it is implemented in school and at home, the contexts in which a child uses EF skills.
To evaluate the effectiveness of UOT as compared to a social skills intervention (SS), 3rd-5th graders with ASD (mean IQ=108; UOT n=47; SS n=20) received interventions delivered by school staff in small group sessions. Students were matched for sex, age, race, intelligence, ASD symptomotolgy, medication status, and parent education. Interventions were matched for “dose” of intervention and training. Measures of pre-post change included classroom observations, parent/teacher report and direct child measures of problem-solving, EF, and social skills. Schools were randomized and evaluators, but not parents or teachers, were blind to intervention type.
Interventions were administered with high fidelity. Children in both groups improved with intervention, but mean change scores from pre- to post-intervention indicated significantly greater improvements for UOT than SS groups in: problem-solving, flexibility, and planning/organizing. Also, classroom observations revealed that participants in UOT made greater improvements than SS participants in their ability to follow rules, make transitions, and be flexible. Children in both groups made equivalent improvements in social skills.
These data support the effectiveness of the first contextually-based EF intervention for children with ASD. UOT improved classroom behavior, flexibility and problem-solving in children with ASD. Individuals with variable background/training in ASD successfully implemented UOT in mainstream educational settings.
autism; executive function; flexibility; intervention; CBT
Aims: Scotland was the first country to adopt take-home naloxone (THN) as a funded public health policy. We summarise the background and rigorous set-up for before/after monitoring to assess the impact on high-risk opiate-fatalities. Methods: Evidence-synthesis of prospectively monitored small-scale THN schemes led to a performance indicator for distribution of THN-kits relative to opiate-related deaths. Next, we explain the primary outcome and statistical power for Scotland's before/after monitoring. Results: Fatality-rate at opiate overdoses witnessed by THN-trainees was 6% (9/153, 95% CI: 2–11%). National THN-schemes should aim to issue 20 times as many THN-kits as there are opiate-related deaths per annum; and at least nine times as many. Primary outcome for evaluating Scotland's THN policy is reduction in the percentage of all opiate-related deaths with prison-release as a 4-week antecedent. Scotland's baseline period is 2006–10, giving a denominator of 1970 opiate-related deaths. A priori plausible effectiveness was 20–30% reduction, relative to baseline, in the proportion of opiate-related deaths that had prison-release as a 4-week antecedent. A secondary outcome was also defined. Conclusion: If Scotland's THN evaluation shifts the policy ground seismically, our new performance measure may prove useful on how many THN-kits nations should provide annually.
Effectiveness; overdose deaths; performance measure; prevention; public policy; Scotland; take-home naloxone
Alcohol is a major global threat to public health. Although the main burden of chronic alcohol-related disease is in adults, its foundations often lie in adolescence. Alcohol consumption and related harm increase steeply from the age of 12 until 20 years. Several trials focusing upon young people have reported significant positive effects of brief interventions on a range of alcohol consumption outcomes. A recent review of reviews also suggests that electronic brief interventions (eBIs) using internet and smartphone technologies may markedly reduce alcohol consumption compared with minimal or no intervention controls.
Interventions that target non-drinking youth are known to delay the onset of drinking behaviours. Web based alcohol interventions for adolescents also demonstrate significantly greater reductions in consumption and harm among ‘high-risk’ drinkers; however changes in risk status at follow-up for non-drinkers or low-risk drinkers have not been assessed in controlled trials of brief alcohol interventions.
Design and methods
The study design comprises two linked randomised controlled trials to evaluate the effectiveness and cost-effectiveness of two intervention strategies compared with screening alone. One trial will focus on high-risk adolescent drinkers attending Emergency Departments (Eds) and the other will focus on those identified as low-risk drinkers or abstinent from alcohol but attending the same ED.
Our primary (null) hypothesis is similar for both trials: Personalised Feedback and Brief Advice (PFBA) and Personalised Feedback plus electronic Brief Intervention (eBI) are no more effective than screening alone in alcohol consumed at 12 months after randomisation as measured by the Time-Line Follow-Back 28-day version. Our secondary (null) hypothesis relating to economics states that PFBA and eBI are no more cost-effective than screening alone.
In total 1,500 participants will be recruited into the trials, 750 high-risk drinkers and 750 low-risk drinkers or abstainers. Participants will be randomised with equal probability, stratified by centre, to either a screening only control group or one of the two interventions: single session of PFBA or eBI. All participants will be eligible to receive treatment as usual in addition to any trial intervention. Individual participants will be followed up at 6 and 12 months after randomisation.
The protocol represents an ambitious innovative programme of work addressing alcohol use in the adolescent population.
ISRCTN45300218. Registered 5th July 2014.
Adolescents; SBI; eBI; Emergency Department
The present investigation examined whether higher-functioning children with autism would demonstrate impaired response inhibition performance in an emotional Go/No-Go task, and whether severity of ADHD or autism symptoms correlated with performance.
Forty-four children (21 meeting criteria for autism; 23 typically developing controls (TDC)) completed an emotional Go/No-Go task where an emotional facial expression (angry, fearful, happy, or sad) was the Go stimulus and a neutral facial expression was the No-Go stimulus, and vice versa.
The autism group was faster than the TDC group on all emotional Go trials. Moreover, the children in the autism group who had the fastest RTs on emotional Go trials were rated as having the greatest number of symptoms (ADOS Social+Communication score); even after accounting for the association with ADHD symptoms. The autism group also made more impulsive responses (i.e., lower d′, more false alarms) than the TDC group on all No-Go trials. As d′ decreased or false alarms increased so did ADHD symptoms. Hyperactivity/Impulsivity symptoms were significantly correlated with false alarms, but Inattention symptoms were not. There was not a significant relationship between No-Go false alarms and autism symptoms, and even after partialling out associations with autism symptoms the significant correlation between ADHD symptoms and No-Go false alarms remained. Conclusions: The present findings support a comorbidity model that argues for shared and independent risk factors, because ADHD and autism symptoms related to independent aspects of emotional Go/No-Go performance.
Autism; Attention Deficit Hyperactivity Disorder; cognitive control; response inhibition; emotion
Jim McCambridge and colleagues reflect on how the concept of harm reduction may be being usurped by the alcohol industry.
Please see later in the article for the Editors' Summary
The attentional blink (AB) phenomenon was used to assess the effect of emotional information on early visual attention in typically developing (TD) children and children with autism spectrum disorders (ASD). The AB effect is the momentary perceptual unawareness that follows target identification in a rapid serial visual processing stream. It is abolished or reduced for emotional stimuli, indicating that emotional information has privileged access to early visual attention processes.
We examined the AB effect for faces with neutral and angry facial expressions in 8–14-year-old children with and without an ASD diagnosis.
Children with ASD exhibited the same magnitude AB effect as typically developing children for both neutral and angry faces.
Early visual attention to emotional facial expressions was preserved in children with ASD.
High smoking prevalence has been observed among those misusing other substances. This study aimed to establish smoking behaviours and attitudes towards nicotine dependence treatment among clients and staff in substance abuse treatment settings.
Cross-sectional questionnaire survey of staff and clients in a convenience sample of seven community and residential addiction services in, or with links to, Europe’s largest provider of mental health care, the South London and Maudsley NHS Foundation Trust. Survey items assessed smoking behaviour, motivation to quit, receipt of and attitudes towards nicotine dependence treatment.
Eighty five percent (n = 163) and 97% (n = 145) response rates of clients and staff were achieved. A high smoking prevalence was observed in clients (88%) and staff (45%); of current smokers, nearly all clients were daily smokers, while 42% of staff were occasional smokers. Despite 79% of clients who smoked expressing a desire to quit and 46% interested in receiving advice, only 15% had been offered support to stop smoking during their current treatment episode with 56% reported never having been offered support. Staff rated smoking treatment significantly less important than treatment of other substances (p < 0.001), and only 29% of staff thought it should be addressed early in a client’s primary addiction treatment, compared with 48% of clients.
A large unmet clinical need is evident with a widespread failure to deliver smoking cessation interventions to an extraordinarily high prevalence population of smokers in addiction services. This is despite the majority of smokers reporting motivation to quit. Staff smoking and attitudes may be a contributory factor in these findings.
Smoking; Substance misuse; Nicotine dependence treatment; NHS; Addictions; Staff; Alcohol; Heroin
The naloxone investigation (N-ALIVE) randomized trial commenced in the UK in May 2012, with the preliminary phase involving 5,600 prisoners on release. The trial is investigating whether heroin overdose deaths post-prison release can be prevented by prior provision of a take-home emergency supply of naloxone. Heroin contributes disproportionately to drug deaths through opiate-induced respiratory depression. Take-home emergency naloxone is a novel preventive measure for which there have been encouraging preliminary reports from community schemes. Overdoses are usually witnessed, and drug users themselves and also family members are a vast intervention workforce who are willing to intervene, but whose responses are currently often inefficient or wrong. Approximately 10% of provided emergency naloxone is thought to be used in subsequent emergency resuscitation but, as yet, there have been no definitive studies. The period following release from prison is a time of extraordinarily high mortality, with heroin overdose deaths increased more than sevenfold in the first fortnight after release. Of prisoners with a previous history of heroin injecting who are released from prison, 1 in 200 will die of a heroin overdose within the first 4 weeks. There are major scientific and logistical challenges to assessing the impact of take-home naloxone. Even in recently released prisoners, heroin overdose death is a relatively rare event: hence, large numbers of prisoners need to enter the trial to assess whether take-home naloxone significantly reduces the overdose death rate. The commencement of pilot phase of the N-ALIVE trial is a significant step forward, with prisoners being randomly assigned either to treatment-as-usual or to treatment-as-usual plus a supply of take-home emergency naloxone. The subsequent full N-ALIVE trial (contingent on a successful pilot) will involve 56,000 prisoners on release, and will give a definitive conclusion on lives saved in real-world application. Advocates call for implementation, while naysayers raise concerns. The issue does not need more public debate; it needs good science.
Recent studies have shown that rates of depression and anxiety symptoms are elevated among individuals with autism spectrum disorders (ASDs) of various ages and IQs and that depression/anxiety symptoms are associated with higher IQ and fewer ASD symptoms. In this study which examined correlates of depression and anxiety symptoms in the full school-age range of children and adolescents (age 6-18) with ASDs and IQs ≥ 70 (n=95), we also observed elevated rates of depression/anxiety symptoms, but we did not find higher IQ or fewer ASD symptoms among individuals with ASDs and depression or anxiety symptoms. These findings indicate an increased risk for depression/anxiety symptoms in children and adolescents with ASDs without intellectual disability, regardless of age, IQ, or ASD symptoms.
autism; children; adolescents; depression; anxiety; IQ
Within the UK, injecting in the femoral vein (FV), often called 'groin injecting', is a serious cause of risk and harm. This study aimed to use ultrasound scanning as a means to engage groin injectors (GIs), examine their femoral injecting sites and assess their venous health, with the intention of developing improved responses.
Between September 2006 and March 2009, GIs attending a network of community drug treatment centres in South East England were invited to attend an ultrasound 'health-check' clinic. This paper provides a narrative account of the scanning procedure and operation of the service, with descriptive statistical analysis of GIs who attended. The analysis uses a structured, specially-developed clinical data set that incorporates a categorisation for the severity of FV damage. Case studies using ultrasound images and a link to a video are provided to illustrate the range of presentations encountered and the categorisations used for severity.
A total of 160 groin scans (76 bilateral and 8 unilateral) were performed in 84 GIs. The majority were men (69.0%) and the mean age of the sample was 36.8 years. The mean duration of drug use and injecting drug use was 19.7 years and 13.8 years, respectively. FV damage at the injecting site in the right groin was graded as minimal in 20 patients (25%), moderate in 27 (33.8%), severe in 16 (20.0%) and very-severe in 17 (21.3%). Corresponding figures for left FV were 24 (30.0%), 22 (27.5%), 18 (22.5%) and 16 (20.0%). Wide variation was observed in the time to the development of these grades of FV damage.
Modern, portable ultrasound scanners make it possible to examine the venous health of GIs in community treatment settings. Ultrasound scanning identified extensive FV damage, much hitherto-unrecognised in this population. These findings should further alert clinicians, policy-makers and patients to the urgent need for effective harm reduction responses to GI behaviour. Images of damaged FV in this paper might prove to be a useful resource for discussions about GI risks.
Injecting drug use; groin injecting; femoral vein damage; ultrasonography; harm reduction
In this paper we evaluate tissue elasticity as a longstanding but qualitative biomarker for prostate cancer and sonoelastography as an emerging imaging tool for providing qualitative and quantitative measurements of prostate tissue stiffness. A Kelvin-Voigt Fractional Derivative (KVFD) viscoelastic model was used to characterize mechanical stress relaxation data measured from human prostate tissue samples. Mechanical testing results revealed that the viscosity parameter for cancerous prostate tissue is greater than that derived from normal tissue by a factor of approximately 2.4. It was also determined that a significant difference exists between normal and cancerous prostate tissue stiffness (p < 0.01) yielding an average elastic contrast that increases from 2.1 at 0.1 Hz to 2.5 at 150 Hz. Qualitative sonoelastographic results show promise for cancer detection in prostate and may prove to be an effective adjunct imaging technique for biopsy guidance. Elasticity images obtained with quantitative sonoelastography agree with mechanical testing and histological results. Overall, results indicate tissue elasticity is a promising biomarker for prostate cancer.
Cancer biomarkers; elasticity imaging; sonoelastography; ultrasound; viscoelasticity
Objective To investigate the effect of opiate substitution treatment at the beginning and end of treatment and according to duration of treatment.
Design Prospective cohort study.
Setting UK General Practice Research Database
Participants Primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990-2005. 5577 patients with 267 003 prescriptions for opiate substitution treatment followed-up (17 732 years) until one year after the expiry of their last prescription, the date of death before this time had elapsed, or the date of transfer away from the practice.
Main outcome measures Mortality rates and rate ratios comparing periods in and out of treatment adjusted for sex, age, calendar year, and comorbidity; standardised mortality ratios comparing opiate users’ mortality with general population mortality rates.
Results Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment; standardised mortality ratios were 5.3 (95% confidence interval 4.0 to 6.8) on treatment and 10.9 (9.0 to 13.1) off treatment. Men using opiates had approximately twice the risk of death of women (morality rate ratio 2.0, 1.4 to 2.9). In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years: 3.1 (1.5 to 6.6) times higher (after adjustment for sex, age group, calendar period, and comorbidity) than the rate during the rest of time on treatment. The crude mortality rate was 4.8 per 100 person years in weeks 1-2 after treatment stopped, 4.3 in weeks 3-4, and 0.95 during the rest of time off treatment: 9 (5.4 to 14.9), 8 (4.7 to 13.7), and 1.9 (1.3 to 2.8) times higher than the baseline risk of mortality during treatment. Opiate substitution treatment has a greater than 85% chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months.
Conclusions Clinicians and patients should be aware of the increased mortality risk at the start of opiate substitution treatment and immediately after stopping treatment. Further research is needed to investigate the effect of average duration of opiate substitution treatment on drug related mortality.
Objective To evaluate the impact of introduction of supervision of methadone dosing on deaths related to overdose of methadone in Scotland and England between 1993 and 2008 while controlling for increased prescribing of methadone.
Design Analysis of annual trends in deaths related to overdose of methadone in relation to defined daily doses of methadone prescribed.
Setting Scotland and England.
Population Deaths in which methadone was coded as the only drug involved or as one of the drugs implicated.
Main outcome measure Annual OD4-methadone index (number of deaths with methadone implicated per million defined daily doses of methadone prescribed in that year).
Results OD4-methadone declined substantially over the four epochs of four years between 1993 and 2008. It decreased significantly (P<0.05) in 10 of 12 epoch changes: in Scotland from 19.3 (95% confidence interval 15 to 24) to 4.1 (2.8 to 5.4) and finally to 3.0 (2.4 to 3.5) for methadone only deaths (and from 58 to 29 to 14 for deaths with any mention of methadone); in England from 27.1 (25 to 29) to 24.8 (23 to 27) and finally to 5.8 (5.3 to 6.3) for methadone only deaths (and from 46 to 42 to 12 for deaths with any mention of methadone). The decreases in OD4-methadone were closely related to the introduction of supervised dosing of methadone in both countries, first in Scotland (1995-2000) and later in England (1999-2005). These declines occurred over periods of substantial increases in prescribing of methadone (18-fold increase in defined daily doses per million population annually in Scotland and sevenfold increase in England).
Conclusions Introduction of supervised methadone dosing was followed by substantial declines in deaths related to overdose of methadone in both Scotland and England. OD4-methadone index analyses, controlled for substantial increases in methadone prescribing in both countries, identified at least a fourfold reduction in deaths due to methadone related overdose per defined daily dose (OD4-methadone) over this period.
Since the initial Swiss heroin-assisted treatment (HAT) study conducted in the mid-1990s, several other jurisdictions in Europe and North America have implemented HAT trials. All of these studies embrace the same goal—investigating the utility of medical heroin prescribing for problematic opioid users—yet are distinct in various key details. This paper briefly reviews (initiated or completed) studies and their main parameters, including primary research objectives, design, target populations, outcome measures, current status and—where available—key results. We conclude this overview with some final observations on a decade of intensive HAT research in the jurisdictions examined, including the suggestion that there is a mounting onus on the realm of politics to translate the—largely positive—data from completed HAT science into corresponding policy and programming in order to expand effective treatment options for the high-risk population of illicit opioid users.
Heroin-assisted treatment; Science; Politics; Opioid dependence; Clinical trials
Whilst unsupervised injectable methadone and diamorphine treatment has been part of the British treatment system for decades, the numbers receiving injectable opioid treatment (IOT) has been steadily diminishing in recent years. In contrast, there has been a recent expansion of supervised injectable diamorphine programs under trial conditions in a number of European and North American cities, although the evidence regarding the safety, efficacy and cost effectiveness of this treatment approach remains equivocal. Recent British clinical guidance indicates that IOT should be a second-line treatment for those patients in high-quality oral methadone treatment who continue to regularly inject heroin, and that treatment be initiated in newly-developed supervised injecting clinics.
The Randomised Injectable Opioid Treatment Trial (RIOTT) is a multisite, prospective open-label randomised controlled trial (RCT) examining the role of treatment with injected opioids (methadone and heroin) for the management of heroin dependence in patients not responding to conventional substitution treatment. Specifically, the study examines whether efforts should be made to optimise methadone treatment for such patients (e.g. regular attendance, supervised dosing, high oral doses, access to psychosocial services), or whether such patients should be treated with injected methadone or heroin.
Eligible patients (in oral substitution treatment and injecting illicit heroin on a regular basis) are randomised to one of three conditions: (1) optimized oral methadone treatment (Control group); (2) injected methadone treatment; or (3) injected heroin treatment (with access to oral methadone doses). Subjects are followed up for 6-months, with between-group comparisons on an intention-to-treat basis across a range of outcome measures. The primary outcome is the proportion of patients who discontinue regular illicit heroin use (operationalised as providing >50% urine drug screens negative for markers of illicit heroin in months 4 to 6). Secondary outcomes include measures of other drug use, injecting practices, health and psychosocial functioning, criminal activity, patient satisfaction and incremental cost effectiveness. The study aims to recruit 150 subjects, with 50 patients per group, and is to be conducted in supervised injecting clinics across England.
GPs occupy a pivotal position in relation to providing services to opiate misusers in the UK, and this is now cited to support initiatives in other countries.
To investigate GP involvement in the management of opiate misusers; and to examine the nature of this prescribing of methadone and other opioids.
GP data collected via self-completion postal questionnaire from a 10% random sample of the 30 000 GPs across England and Wales. Patient prescription data obtained on opiate misusers treated during the preceding 4 weeks.
Primary healthcare practice in England and Wales in mid-2001.
A questionnaire was mailed to a random 10% sample of GPs stratified by number of partners in the practice, with three follow-up mailshots. Data on drugs prescribed by these practitioners were also studied, including drug prescribed, form, dose and dispensing arrangements.
The response rate was 66%. Opiate misusers had been seen by 51% of GPs in the preceding 4 weeks (mean of 4.1 such patients), of whom 50% had prescribed opiate-substitution drugs. This provided a study sample of 1482 opiate misusers to whom GPs were prescribing methadone (86.7%), dihydrocodeine (8.5%) or buprenorphine (4.4%). Of 1292 methadone prescriptions, mean daily dose was 36.9 mg — 47.9% being for 30 mg or less. Daily interval dispensing was stipulated by 44.6%, while 42.9% permitted weekly take-away supply.
In 2001 nearly three times as many GPs were seeing opiate misusers than was the case in 1985. Half were prescribing substitute-opiate drugs such as methadone (to an estimated 30 000 patients). However, there are grounds for concern about the quality of this prescribing. Most doses were too low to constitute optimal methadone maintenance; widespread disregard of the availability of supervised or interval dispensing increases the risks of diversion to the blackmarket and deaths from methadone overdose. Increased quantity of care has been achieved. Increased quality is now required.
addiction; buprenorphine; methadone; narcotics; heroin; opiate-related disorders
This preliminary test of a brief intervention designed to stimulate GP incorporation of cannabis enquiry was followed up after 2-3 months. Intervention comprised face-to-face discussion based on principles of motivational interviewing, with informational adjunct. Substantially more positive attitudes and greater clinical activity were observed following receipt of intervention.