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Molecular Psychiatry Dec 2019Opioid use disorder (OUD) is associated with a high risk of premature death. Medication-assisted treatment (MAT) is the primary treatment for opioid dependence. We... (Meta-Analysis)
Meta-Analysis
Opioid use disorder (OUD) is associated with a high risk of premature death. Medication-assisted treatment (MAT) is the primary treatment for opioid dependence. We comprehensively assessed the effects of different MAT-related characteristics on mortality among those with OUD by a systematic review and meta-analysis. The all-cause and overdose crude mortality rates (CMRs) and relative risks (RRs) by treatment status, different type, period, and dose of medication, and retention time were pooled using random effects, subgroup analysis, and meta-regression. Thirty cohort studies involving 370,611 participants (1,378,815 person-years) were eligible in the meta-analysis. From 21 studies, the pooled all-cause CMRs were 0.92 per 100 person-years (95% CI: 0.79-1.04) while receiving MAT, 1.69 (1.47-1.91) after cessation, and 4.89 (3.54-6.23) for untreated period. Based on 16 studies, the pooled overdose CMRs were 0.24 (0.20-0.28) while receiving MAT, 0.68 (0.55-0.80) after cessation of MAT, and 2.43 (1.72-3.15) for untreated period. Compared with patients receiving MAT, untreated participants had higher risk of all-cause mortality (RR 2.56 [95% CI: 1.72-3.80]) and overdose mortality (8.10 [4.48-14.66]), and discharged participants had higher risk of all-cause death (2.33 [2.02-2.67]) and overdose death (3.09 [2.37-4.01]). The all-cause CMRs during and after opioid substitution treatment with methadone or buprenorphine were 0.93 (0.76-1.10) and 1.79 (1.47-2.10), and corresponding estimate for antagonist naltrexone treatment were 0.26 (0-0.59) and 1.97 (0-5.18), respectively. Retention in MAT of over 1-year was associated with a lower mortality rate than that with retention ≤1 year (1.62, 1.31-1.93 vs. 5.31, -0.09-10.71). Improved coverage and adherence to MAT and post-treatment follow-up are crucial to reduce the mortality. Long-acting naltrexone showed positive advantage on prevention of premature death among persons with OUD.
Topics: Adult; Analgesics, Opioid; Buprenorphine; Cohort Studies; Drug Overdose; Female; Humans; Male; Methadone; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders; Risk
PubMed: 29934549
DOI: 10.1038/s41380-018-0094-5 -
Fortschritte Der Neurologie-Psychiatrie Feb 2018In the last ten years, the prescriptions of the gabapentinoids gabapentin and pregabalin increased largely also in Germany. Since several national and international... (Meta-Analysis)
Meta-Analysis
In the last ten years, the prescriptions of the gabapentinoids gabapentin and pregabalin increased largely also in Germany. Since several national and international pharmacovigilance-databases have warned for abuse liabilities and overdose fatalities in association with both gabapentinoids, which moreover, became to be sold on internet and black-markets, their addictive power has been subject to an ongoing clinical debate. As pre- and post-approval clinical trials did not reveal significant signs of dependence on gabapentin or pregabalin, we systematically searched in PubMed and Scopus for clinical studies and case reports being associated with abuse of and dependence on these drugs. We found 14 clinical-epidemiologic studies and 38 case reports/series. These were evaluated for i) fulfilled dependence criteria according to ICD-10, ii) non-medical self-administration and their duration, iii) relapses, iv) social sequels, and v) cases seeking treatment for misusing gabapentin or pregabalin. Mostly, the cases of abuse of and dependence on gabapentinoids appeared to be associated with other substance dependencies, primarily opiate dependence and polyvalent drug use. Drug users preferred pregabalin citing a faster and stronger euphoria ("liking") than achievable with oral gabapentin. Both gabapentinoids were anxiolytic in therapeutic doses, stimulating in lower and sedating along with increasing doses. Fatalities have been described mainly in the population of opiate dependents and polyvalent drug users, predominantly together with excessive pregabalin overdosing. It is debated whether the gabapentinoids were indeed the main cause of death in these cases or whether gabapentin and pregabalin had been only bystanders. Tolerance and withdrawal symptoms (physical dependence) of gabapentinoids appeared to be common in medical and non-medical use of gabapentinoids. There were only 4 persons who had fulfilled behavioral dependence criteria of gabapentinoids (all had used pregabalin) and had no association with other substance use disorders (apart from nicotine). Regarding the transitions from prescription to non-medical self-administration, the frequency and duration of self-administrations as well as the number of reported relapses, pregabalin appeared also to be more addictive than gabapentin. However, all these events were reported rather infrequently compared with traditional substances of abuse. We did not find a case with social sequalea due to the use of gabapentinoids or a person who sought treatment for his gabapentin or pregabalin use. Therefore, the gabapentinoids were assumed to possess a lower "wanting" in consideration of Berridge's and Robinsons's incentive-sensitization theory of addiction. Also, anti-adverse selection of gabapentinoids is discussed to be present in the population of opioid and multi-drug users. Based upon all these results and assumptions, we have estimated the relative risk of dependence on gabapentinoids by using an algorithm which was previously developed by Griffith and Johnson for evaluation of the abuse liabilities of sedatives. Overall, the risk of harm and dependence on gabapentinoids appeared to be lower than that of other sedatives (and stimulants). In addition, pregabalin appeared to be somewhat riskier than gabapentin. We think that in patients with current or past substance use disorders, the treatment with gabapentinoids should be avoided or if indispensable, these drugs should be administered exclusively over a limited time span with caution by using a therapeutic and prescription monitoring.
Topics: Analgesics; Behavior, Addictive; Gabapentin; Germany; Humans; Pregabalin; Risk; Substance-Related Disorders
PubMed: 29179227
DOI: 10.1055/s-0043-122392 -
American Journal of Therapeutics 2019Opioids are natural, semisynthetic, or synthetic substances that act on opioid receptors in the central nervous system. Clinically, they are prescribed for pain...
BACKGROUND
Opioids are natural, semisynthetic, or synthetic substances that act on opioid receptors in the central nervous system. Clinically, they are prescribed for pain management. Opioid overdose (OOD) occurs when the central nervous system and respiratory drive are suppressed because of excessive consumption of the drug. Symptoms of OOD include drowsiness, slow breathing, pinpoint pupils, cyanosis, loss of consciousness, and death. Due to their addictive potential and easy accessibility opioid addiction is a growing problem worldwide. Emergency medical services and the emergency department often perform initial management of OOD. Thereafter, some patients require intensive care management because of respiratory failure, metabolic encephalopathy, acute kidney injury, and other organ failure.
AREAS OF UNCERTAINTY
We sought to review the literature and present the most up-to-date treatment strategies of patients with acute OOD requiring critical care management.
DATA SOURCES
A PubMed search was conducted to review all articles between 1950 and 2017 and the relevant articles were cited.
RESULTS & CONCLUSIONS
Worldwide, approximately 69,000 people die of OOD each year, and approximately 15 million people have opioid addiction. In the United States, death from OOD has increased almost 5-fold from 2001 to 2013. OOD leading to intensive care unit admission has increased by 50% from 2009 to 2015. At the same time, the mortality associated with these admissions has doubled. The management strategies include airway management, use of reversal agents, assessing and treating coingestions and associated complications, treatment of opioid withdrawal with alpha-agonists, and psychosocial support to help with opiate addiction and withdrawal. This warrants awareness among clinicians regarding the adverse effects associated with opioid use, management strategies, and calls for a multidisciplinary approach to treating these patients.
Topics: Analgesics, Opioid; Critical Care; Drug Overdose; Emergency Service, Hospital; Global Burden of Disease; Humans; Intensive Care Units; Mortality; Opioid-Related Disorders; Patient Care Team; Practice Guidelines as Topic; Resuscitation
PubMed: 28952972
DOI: 10.1097/MJT.0000000000000681 -
Presse Medicale (Paris, France : 1983) 2017Heroin use can be responsible for many respiratory complications including asthma. (Review)
Review
INTRODUCTION
Heroin use can be responsible for many respiratory complications including asthma.
OBJECTIVES
Systematic literature review of data on asthma in heroin users.
DOCUMENTARY SOURCES
Medline, on the period 1980-2017 with the following keywords: keywords: "asthma" or "bronchospasm" and "heroin" or "opiate" or "opiates", limits "title/abstract"; the selected languages were English or French. Among 97 articles, 67 abstracts have given use to a dual reading to select 23 studies.
RESULTS
The seven case reports included 21 patients (mean age: 28 years [19-46 years]; sex-ratio: 2.5 [males: 71.5%]). Heroin was inhaled (71.4%), sniffed (19%) or injected by intravenous route (9.5%). Associated addictive substances were tobacco (81%), cannabis (38%), alcohol (4.7%) and cocaine (4.7%). Outcome was fatal in 3 subjects (14.3%). Other studies included one cross-sectional study, 3 case-control studies and 12 longitudinal studies (11 retrospective studies and one prospective study). The proportion of heroin users was higher in asthmatic subjects and the prevalence of asthma and bronchial hyperreactivity was higher in heroin users. Heroin use can be responsible for asthma onset, with a temporal relationship between the onset of heroin use and asthma onset in 28 to 31% of subjects. A positive association between inhaled heroin use and acute asthma exacerbation was observed. Asthma treatment observance was lower in heroin users. In case of asthma exacerbation, heroin users were more likely to seek care in the emergency department, to be admitted in intensive care units and to require intubation and invasive ventilation. Asthma deaths related to heroin use mainly occurred following an intravenous injection (especially in the case of overdose), but also following heroin use by nasal (sniff) or pulmonary route.
CONCLUSION
Heroin use may be responsible for asthma onset, acute asthma exacerbations (which may require intubation and invasive ventilation) or deaths related to asthma. Heroin use must be sought in case of asthma exacerbation in young persons and practitioners must help heroin users to stop their consumption.
Topics: Administration, Intranasal; Asthma; Bronchial Hyperreactivity; Heroin Dependence; Humans
PubMed: 28734637
DOI: 10.1016/j.lpm.2017.06.002 -
The Cochrane Database of Systematic... Apr 2017Opioid dependence (OD) is an increasing clinical and public health problem worldwide. International guidelines recommend opioid substitution treatment (OST), such as... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Opioid dependence (OD) is an increasing clinical and public health problem worldwide. International guidelines recommend opioid substitution treatment (OST), such as methadone and buprenorphine, as first-line medication treatment for OD. A negative aspect of OST is that the medication used can be diverted both through sale on the black market, and the unsanctioned use of medications. Daily supervised administration of medications used in OST has the advantage of reducing the risk of diversion, and may promote therapeutic engagement, potentially enhancing the psychosocial aspect of OST, but costs more and is more restrictive on the client than dispensing for off-site consumption.
OBJECTIVES
The objective of this systematic review is to compare the effectiveness of OST with supervised dosing relative to dispensing of medication for off-site consumption.
SEARCH METHODS
We searched in Cochrane Drugs and Alcohol Group Specialised Register and Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, Web of Science from inception up to April 2016. Ongoing and unpublished studies were searched via ClinicalTrials.gov (www.clinicaltrials.gov) and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/).All searches included non-English language literature. We handsearched references on topic-related systematic reviews.
SELECTION CRITERIA
Randomised controlled trials (RCTs), controlled clinical trials (CCTs), and prospective controlled cohort studies, involving people who are receiving OST (methadone, buprenorphine) and comparing supervised dosing with dispensing of medication to be consumed away from the dispensing point, usually without supervision.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane.
MAIN RESULTS
Six studies (four RCTs and two prospective observational cohort studies), involving 7999 participants comparing supervised OST treatment with unsupervised treatment, met the inclusion criteria. The risk of bias was generally moderate across trials, but the results reported on outcomes that we planned to consider were limited. Overall, we judged the quality of the evidence from very low to low for all the outcomes.We found no difference in retention at any duration with supervised compared to unsupervised dosing (RR 0.99, 95% CI 0.88 to 1.12, 716 participants, four trials, low-quality evidence) or in retention in the shortest follow-up period, three months (RR 0.94; 95% CI 0.84 to 1.05; 472 participants, three trials, low-quality evidence). Additional data at 12 months from one observational study found no difference in retention between groups (RR 0.94, 95% CI 0.77 to 1.14; n = 300).There was no difference in abstinence at the end of treatment (self-reported drug use) (67% versus 60%, P = 0.33, 293 participants, one trial, very low-quality evidence); and in diversion of medication (5% versus 2%, 293 participants, one trial, very low-quality evidence).Regarding our secondary outcomes, we did not found a difference in the incidence of adverse effects in the supervised compared to unsupervised control group (RR 0.63; 96% CI 0.10 to 3.86; 363 participants, two trials, very low-quality evidence). Data on severity of dependence were very limited (244 participants, one trial) and showed no difference between the two approaches. Data on deaths were reported in two studies. One trial reported two deaths in the supervised group (low-quality evidence), while in the cohort study all-cause mortality was found lower in regular supervision group (crude mortality rate 0.60 versus 0.81 per 100 person-years), although after adjustment insufficient evidence existed to suggest that regular supervision was protective (mortality rate ratio = 1.23, 95% CI = 0.67 to 2.27).No studies reported pain symptoms, drug craving, aberrant opioid-related behaviours, days of unsanctioned opioid use and overdose.
AUTHORS' CONCLUSIONS
Take-home medication strategies are attractive to treatment services due to lower costs, and place less restrictions on clients, but it is unknown whether they may be associated with increased risk of diversion and unsanctioned use of medication. There is uncertainty about the effects of supervised dosing compared with unsupervised medication due to the low and very low quality of the evidence for the primary outcomes of interest for this review. Data on defined secondary outcomes were similarly limited. More research comparing supervised and take-home medication strategies is needed to support decisions on the relative effectiveness of these strategies. The trials should be designed and conducted with high quality and over a longer follow-up period to support comparison of strategies at different stages of treatment. In particular, there is a need for studies assessing in more detail the risk of diversion and safety outcomes of using supervised OST to manage opioid dependence.
Topics: Analgesics, Opioid; Buprenorphine, Naloxone Drug Combination; Directly Observed Therapy; Humans; Methadone; Observational Studies as Topic; Opiate Substitution Treatment; Opioid-Related Disorders; Prescription Drug Diversion; Randomized Controlled Trials as Topic
PubMed: 28447766
DOI: 10.1002/14651858.CD011983.pub2 -
BMJ (Clinical Research Ed.) Apr 2017To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and... (Meta-Analysis)
Meta-Analysis Review
To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and to characterise trends in risk of mortality after initiation and cessation of treatment. Systematic review and meta-analysis. Medline, Embase, PsycINFO, and LILACS to September 2016. Prospective or retrospective cohort studies in people with opioid dependence that reported deaths from all causes or overdose during follow-up periods in and out of opioid substitution treatment with methadone or buprenorphine. Two independent reviewers performed data extraction and assessed study quality. Mortality rates in and out of treatment were jointly combined across methadone or buprenorphine cohorts by using multivariate random effects meta-analysis. There were 19 eligible cohorts, following 122 885 people treated with methadone over 1.3-13.9 years and 15 831 people treated with buprenorphine over 1.1-4.5 years. Pooled all cause mortality rates were 11.3 and 36.1 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 3.20, 95% confidence interval 2.65 to 3.86) and reduced to 4.3 and 9.5 in and out of buprenorphine treatment (2.20, 1.34 to 3.61). In pooled trend analysis, all cause mortality dropped sharply over the first four weeks of methadone treatment and decreased gradually two weeks after leaving treatment. All cause mortality remained stable during induction and remaining time on buprenorphine treatment. Overdose mortality evolved similarly, with pooled overdose mortality rates of 2.6 and 12.7 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 4.80, 2.90 to 7.96) and 1.4 and 4.6 in and out of buprenorphine treatment. Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.
Topics: Buprenorphine; Drug Overdose; Humans; Methadone; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Risk
PubMed: 28446428
DOI: 10.1136/bmj.j1550 -
The Cochrane Database of Systematic... May 2016There are increasing concerns regarding pharmaceutical opioid harms including overdose and dependence, with an associated increase in treatment demand. People dependent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There are increasing concerns regarding pharmaceutical opioid harms including overdose and dependence, with an associated increase in treatment demand. People dependent on pharmaceutical opioids appear to differ in important ways from people who use heroin, yet most opioid agonist treatment research has been conducted in people who use heroin.
OBJECTIVES
To assess the effects of maintenance agonist pharmacotherapy for the treatment of pharmaceutical opioid dependence.
SEARCH METHODS
The search included the Cochrane Drugs and Alcohol Group's Specialised Register of Trials; the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 5); PubMed (January 1966 to May 2015); EMBASE (Ovid) (January 1974 to May 2015); CINAHL (EBSCOhost) (1982 to May 2015); ISI Web of Science (to May 2014); and PsycINFO (Ovid) (1806 to May 2014).
SELECTION CRITERIA
We included randomised controlled trials examining maintenance opioid agonist treatments that made the following two comparisons:1. full opioid agonists (methadone, morphine, oxycodone, levo-alpha-acetylmethadol (LAAM), or codeine) versus different full opioid agonists or partial opioid agonists (buprenorphine) for maintenance treatment and2. full or partial opioid agonist maintenance versus placebo, detoxification only, or psychological treatment (without opioid agonist treatment).
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodological procedures.
MAIN RESULTS
We identified six randomised controlled trials that met inclusion criteria (607 participants).We found moderate quality evidence from two studies of no difference between methadone and buprenorphine in self reported opioid use (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.08 to 1.63) or opioid positive urine drug tests (RR 0.81, 95% CI 0.56 to 1.18). There was low quality evidence from three studies of no difference in retention between buprenorphine and methadone maintenance treatment (RR 0.69, 95% CI 0.39 to 1.22). There was moderate quality evidence from two studies of no difference between methadone and buprenorphine on adverse events (RR 1.10, 95% CI 0.64 to 1.91).We found low quality evidence from three studies favouring maintenance buprenorphine treatment over detoxification or psychological treatment in terms of fewer opioid positive urine drug tests (RR 0.63, 95% CI 0.43 to 0.91) and self reported opioid use in the past 30 days (RR 0.54, 95% CI 0.31 to 0.93). There was no difference on days of unsanctioned opioid use (standardised mean difference (SMD) -0.31, 95% CI -0.66 to 0.04). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on retention in treatment (RR 0.33, 95% CI 0.23 to 0.47). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on adverse events (RR 0.19, 95% CI 0.06 to 0.57).The main weaknesses in the quality of the data was the use of open-label study designs.
AUTHORS' CONCLUSIONS
There was low to moderate quality evidence supporting the use of maintenance agonist pharmacotherapy for pharmaceutical opioid dependence. Methadone or buprenorphine appeared equally effective. Maintenance treatment with buprenorphine appeared more effective than detoxification or psychological treatments.Due to the overall low to moderate quality of the evidence and small sample sizes, there is the possibility that the further research may change these findings.
Topics: Analgesics, Opioid; Buprenorphine; Humans; Methadone; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Prescription Drug Misuse; Randomized Controlled Trials as Topic
PubMed: 27157143
DOI: 10.1002/14651858.CD011117.pub2 -
Addiction (Abingdon, England) Jul 2016Fatal outcome of opioid overdose, once detected, is preventable through timely administration of the antidote naloxone. Take-home naloxone provision directly to opioid... (Review)
Review
BACKGROUND AND AIMS
Fatal outcome of opioid overdose, once detected, is preventable through timely administration of the antidote naloxone. Take-home naloxone provision directly to opioid users for emergency use has been implemented recently in more than 15 countries worldwide, albeit mainly as pilot schemes and without formal evaluation. This systematic review assesses the effectiveness of take-home naloxone, with two specific aims: (1) to study the impact of take-home naloxone distribution on overdose-related mortality; and (2) to assess the safety of take-home naloxone in terms of adverse events.
METHODS
PubMed, MEDLINE and PsychINFO were searched for English-language peer-reviewed publications (randomized or observational trials) using the Boolean search query: (opioid OR opiate) AND overdose AND prevention. Evidence was evaluated using the nine Bradford Hill criteria for causation, devised to assess a potential causal relationship between public health interventions and clinical outcomes when only observational data are available.
RESULTS
A total of 1397 records (1164 after removal of duplicates) were retrieved, with 22 observational studies meeting eligibility criteria. Due to variability in size and quality of the included studies, meta-analysis was dismissed in favour of narrative synthesis. From eligible studies, we found take-home naloxone met all nine Bradford Hill criteria. The additional five World Health Organization criteria were all either met partially (two) or fully (three). Even with take-home naloxone administration, fatal outcome was reported in one in 123 overdose cases (0.8%; 95% confidence interval = 0.4, 1.2).
CONCLUSIONS
Take-home naloxone programmes are found to reduce overdose mortality among programme participants and in the community and have a low rate of adverse events.
Topics: Analgesics, Opioid; Drug Overdose; Humans; Naloxone; Narcotic Antagonists; Opioid-Related Disorders
PubMed: 27028542
DOI: 10.1111/add.13326 -
European Addiction Research 2016Opioid substitution treatment (OST) improves outcomes in opioid dependence. However, controlled drugs used in treatment may be misused or diverted, resulting in negative... (Review)
Review
BACKGROUND/AIMS
Opioid substitution treatment (OST) improves outcomes in opioid dependence. However, controlled drugs used in treatment may be misused or diverted, resulting in negative treatment outcomes. This review defines a framework to assess the impact of misuse and diversion.
METHODS
A systematic review of published studies of misuse and diversion of OST medicines was completed; this evidence was paired with expert real-world experience to better understand the impact of misuse and diversion on the individual and on society.
RESULTS
Direct impact to the individual includes failure to progress in recovery and negative effects on health (overdose, health risks associated with injecting behaviour). Diversion of OST has impacts on a community that is beyond the intended OST recipient. The direct impact includes risk to others (unsupervised use; unintended exposure of children to diverted medication) and drug-related criminal behavior. The indirect impact includes the economic costs of untreated opioid dependence, crime and loss of productivity.
CONCLUSION
While treatment for opioid dependence is essential and must be supported, it is vital to reduce misuse and diversion while ensuring the best possible care. Understanding the impact of OST misuse and diversion is key to defining strategies to address these issues.
Topics: Consensus; Humans; Opiate Substitution Treatment; Opioid-Related Disorders; Prescription Drug Diversion; Prescription Drug Misuse
PubMed: 26426530
DOI: 10.1159/000438988