New Australian guidelines for the treatment of alcohol problems: an overview of recommendations.

OF RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity-frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient's needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the "teach-back" technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). SUMMARY OF KEY RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).

Pharmacotherapies for Cannabis Use Disorders: Clinical Challenges and Promising Therapeutic Agents.

This chapter reviews pharmacotherapies that have been trialled for cannabis dependence, identifying those that warrant further research and those of little or uncertain value. A diverse range of medicines have been tested, representing a broad range of pharmacological strategies. These include tetrahydrocannabinol preparations, various types of antidepressant, anxiolytics, a glutamatergic modulator and the neuropeptide oxytocin. Cannabinoid agonists warrant further research. For the FAAH inhibitor PF-04457845, oxytocin, varenicline and gabapentin, although there is a signal to indicate further research is warranted, these medications do not yet have sufficient evidence to support clinical use, and larger, longer-term trials are needed in representative treatment-seeking populations. Special populations that warrant consideration are those with cannabis dependence and concurrent mental health conditions and those that develop dependence through therapeutic use.

Pharmacotherapies for cannabis dependence.

BACKGROUND: Globally, cannabis use is prevalent and widespread. There are currently no pharmacotherapies approved for treatment of cannabis use disorders.This is an update of a Cochrane Review first published in the Cochrane Library in Issue 12, 2014. OBJECTIVES: To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or no pharmacotherapy (supportive care) for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use. SEARCH METHODS: We updated our searches of the following databases to March 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and Web of Science. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs involving the use of medications to treat cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in people diagnosed as cannabis dependent or who were likely to be dependent. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 21 RCTs involving 1755 participants: 18 studies recruited adults (mean age 22 to 41 years); three studies targeted young people (mean age 20 years). Most (75%) participants were male. The studies were at low risk of performance, detection and selective outcome reporting bias. One study was at risk of selection bias, and three studies were at risk of attrition bias.All studies involved comparison of active medication and placebo. The medications were diverse, as were the outcomes reported, which limited the extent of analysis.Abstinence at end of treatment was no more likely with Δ9-tetrahydrocannabinol (THC) preparations than with placebo (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.64 to 1.52; 305 participants; 3 studies; moderate-quality evidence). For selective serotonin reuptake inhibitor (SSRI) antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine, there was no difference in the likelihood of abstinence at end of treatment compared to placebo (low- to very low-quality evidence).There was qualitative evidence of reduced intensity of withdrawal symptoms with THC preparations compared to placebo. For other pharmacotherapies, this outcome was either not examined, or no significant differences was reported.Adverse effects were no more likely with THC preparations (RR 1.02, 95% CI 0.89 to 1.17; 318 participants; 3 studies) or N-acetylcysteine (RR 0.94, 95% CI 0.71 to 1.23; 418 participants; 2 studies) compared to placebo (moderate-quality evidence). For SSRI antidepressants, mixed action antidepressants, buspirone and N-acetylcysteine, there was no difference in adverse effects compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of withdrawal from treatment due to adverse effects with THC preparations, SSRIs antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of treatment completion with THC preparations, SSRI antidepressants, mixed action antidepressants and buspirone compared to placebo (low- to very low-quality evidence) or with N-acetylcysteine compared to placebo (RR 1.06, 95% CI 0.93 to 1.21; 418 participants; 2 studies; moderate-quality evidence). Anticonvulsants and mood stabilisers appeared to reduce the likelihood of treatment completion (RR 0.66, 95% CI 0.47 to 0.92; 141 participants; 3 studies; low-quality evidence).Available evidence on gabapentin (anticonvulsant), oxytocin (neuropeptide) and atomoxetine was insufficient for estimates of effectiveness. AUTHORS' CONCLUSIONS: There is incomplete evidence for all of the pharmacotherapies investigated, and for many outcomes the quality of the evidence was low or very low. Findings indicate that SSRI antidepressants, mixed action antidepressants, bupropion, buspirone and atomoxetine are probably of little value in the treatment of cannabis dependence. Given the limited evidence of efficacy, THC preparations should be considered still experimental, with some positive effects on withdrawal symptoms and craving. The evidence base for the anticonvulsant gabapentin, oxytocin, and N-acetylcysteine is weak, but these medications are also worth further investigation.

Opioid antagonists with minimal sedation for opioid withdrawal.

BACKGROUND: Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. OBJECTIVES: To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. SEARCH METHODS: We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha2-adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient without indicating the level of care provided.The included studies were heterogeneous in terms of the type of opioid antagonist treatment regimen, the comparator, the outcome measures assessed, and the means of assessing outcomes. As a result, the validity of any estimates of overall effect is doubtful, therefore we did not calculate pooled results for any of the analyses.The quality of the evidence for treatment with an opioid antagonist-adrenergic agonist combination versus an alpha2-adrenergic agonist is very low. Two studies reported data on peak withdrawal severity, and four studies reported data on the average severity over the period of withdrawal. Peak withdrawal induced by opioid antagonists in combination with an adrenergic agonist appears to be more severe than withdrawal managed with clonidine or lofexidine alone, but the average severity over the withdrawal period is less. In some situations antagonist-induced withdrawal may be associated with significantly higher rates of treatment completion compared to withdrawal managed with adrenergic agonists. However, this result was not consistent across studies, and the extent of any benefit is highly uncertain.We could not extract any data on the occurrence of adverse events, but two studies reported delirium or confusion following the first dose of naltrexone. Delirium may be more likely with higher initial doses and with naltrexone rather than naloxone (which has a shorter half-life), but we could not confirm this from the available evidence.Insufficient data were available to make any conclusions on the best duration of treatment. AUTHORS' CONCLUSIONS: Using opioid antagonists plus alpha2-adrenergic agonists is a feasible approach for managing opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist.A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium.Using opioid antagonists to induce and accelerate opioid withdrawal is not currently an active area of research or clinical practice, and the research community should give greater priority to investigating approaches, such as those based on buprenorphine, that facilitate the transition to sustained-release preparations of naltrexone.

Supervised dosing with a long-acting opioid medication in the management of opioid dependence.

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.

Buprenorphine for managing opioid withdrawal.

BACKGROUND: Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of substitution treatment. OBJECTIVES: To assess the effects of buprenorphine versus tapered doses of methadone, alpha2-adrenergic agonists, symptomatic medications or placebo, or different buprenorphine regimens for managing opioid withdrawal, in terms of the intensity of the withdrawal syndrome experienced, duration and completion of treatment, and adverse effects. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2016), MEDLINE (1946 to December week 1, 2016), Embase (to 22 December 2016), PsycINFO (1806 to December week 3, 2016), and the Web of Science (to 22 December 2016) and handsearched the reference lists of articles. SELECTION CRITERIA: Randomised controlled trials of interventions using buprenorphine to modify the signs and symptoms of withdrawal in participants who were primarily opioid dependent. Comparison interventions involved reducing doses of methadone, alpha2-adrenergic agonists (clonidine or lofexidine), symptomatic medications or placebo, and different buprenorphine-based regimens. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 27 studies involving 3048 participants. The main comparators were clonidine or lofexidine (14 studies). Six studies compared buprenorphine versus methadone, and seven compared different rates of buprenorphine dose reduction. We assessed 12 studies as being at high risk of bias in at least one of seven domains of methodological quality. Six of these studies compared buprenorphine with clonidine or lofexidine and two with methadone; the other four studies compared different rates of buprenorphine dose reduction.For the comparison of buprenorphine and methadone in tapered doses, meta-analysis was not possible for the outcomes of intensity of withdrawal or adverse effects. However, information reported by the individual studies was suggestive of buprenorphine and methadone having similar capacity to ameliorate opioid withdrawal, without clinically significant adverse effects. The meta-analyses that were possible support a conclusion of no difference between buprenorphine and methadone in terms of average treatment duration (mean difference (MD) 1.30 days, 95% confidence interval (CI) -8.11 to 10.72; N = 82; studies = 2; low quality) or treatment completion rates (risk ratio (RR) 1.04, 95% CI 0.91 to 1.20; N = 457; studies = 5; moderate quality).Relative to clonidine or lofexidine, buprenorphine was associated with a lower average withdrawal score (indicating less severe withdrawal) during the treatment episode, with an effect size that is considered to be small to moderate (standardised mean difference (SMD) -0.43, 95% CI -0.58 to -0.28; N = 902; studies = 7; moderate quality). Patients receiving buprenorphine stayed in treatment for longer, with an effect size that is considered to be large (SMD 0.92, 95% CI 0.57 to 1.27; N = 558; studies = 5; moderate quality) and were more likely to complete withdrawal treatment (RR 1.59, 95% CI 1.23 to 2.06; N = 1264; studies = 12; moderate quality). At the same time there was no significant difference in the incidence of adverse effects, but dropout due to adverse effects may be more likely with clonidine (RR 0.20, 95% CI 0.04 to 1.15; N = 134; studies = 3; low quality). The difference in treatment completion rates translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 6), indicating that for every four people treated with buprenorphine, we can expect that one additional person will complete treatment than with clonidine or lofexidine.For studies comparing different rates of reduction of the buprenorphine dose, meta-analysis was possible only for treatment completion, with separate analyses for inpatient and outpatient settings. The results were diverse, and we assessed the quality of evidence as being very low. It remains very uncertain what effect the rate of dose taper has on treatment outcome. AUTHORS' CONCLUSIONS: Buprenorphine is more effective than clonidine or lofexidine for managing opioid withdrawal in terms of severity of withdrawal, duration of withdrawal treatment, and the likelihood of treatment completion.Buprenorphine and methadone appear to be equally effective, but data are limited. It remains possible that the pattern of withdrawal experienced may differ and that withdrawal symptoms may resolve more quickly with buprenorphine.It is not possible to draw any conclusions from the available evidence on the relative effectiveness of different rates of tapering the buprenorphine dose. The divergent findings of studies included in this review suggest that there may be multiple factors affecting the response to the rate of dose taper. One such factor could be whether or not the initial treatment plan includes a transition to subsequent relapse prevention treatment with naltrexone. Indeed, the use of buprenorphine to support transition to naltrexone treatment is an aspect worthy of further research.Most participants in the studies included in this review were male. None of the studies reported outcomes on the basis of sex, preventing any exploration of differences related to this variable. Consideration of sex as a factor influencing response to withdrawal treatment would be relevant research for selecting the most appropriate type of intervention for each individual.

Alpha2-adrenergic agonists for the management of opioid withdrawal.

BACKGROUND: Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. OBJECTIVES: To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists compared with placebo, reducing doses of methadone, symptomatic medications, or an alpha2-adrenergic agonist regimen different to the experimental intervention, for the management of the acute phase of opioid withdrawal. Outcomes included the withdrawal syndrome experienced, duration of treatment, occurrence of adverse effects, and completion of treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to November week 2, 2015), EMBASE (January 1985 to November week 2, 2015), PsycINFO (1806 to November week 2, 2015), Web of Science, and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials comparing alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 26 randomised controlled trials involving 1728 participants. Six studies compared an alpha2-adrenergic agonist with placebo, 12 with reducing doses of methadone, four with symptomatic medications, and five compared different alpha2-adrenergic agonists. We assessed 10 studies as having a high risk of bias in at least one of the methodological domains that were considered.We found moderate-quality evidence that alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.18 to 0.57; 3 studies; 148 participants). We found moderate-quality evidence that completion of treatment was significantly more likely with alpha2-adrenergic agonists compared with placebo (RR 1.95, 95% CI 1.34 to 2.84; 3 studies; 148 participants).Peak withdrawal severity may be greater with alpha2-adrenergic agonists than with reducing doses of methadone, as measured by the likelihood of severe withdrawal (RR 1.18, 95% CI 0.81 to 1.73; 5 studies; 340 participants; low quality), and peak withdrawal score (standardised mean difference (SMD) 0.22, 95% CI -0.02 to 0.46; 2 studies; 263 participants; moderate quality), but these differences were not significant and there is no significant difference in severity when considered over the entire duration of the withdrawal episode (SMD 0.13, 95% CI -0.24 to 0.49; 3 studies; 119 participants; moderate quality). The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists. The duration of treatment was significantly longer with reducing doses of methadone (SMD -1.07, 95% CI -1.31 to -0.83; 3 studies; 310 participants; low quality). Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 1.92, 95% CI 1.19 to 3.10; 6 studies; 464 participants; low quality), but there was no significant difference in rates of completion of withdrawal treatment (RR 0.85, 95% CI 0.69 to 1.05; 9 studies; 659 participants; low quality).There were insufficient data for quantitative comparison of different alpha2-adrenergic agonists. Available data suggest that lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine. AUTHORS' CONCLUSIONS: Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. We detected no significant difference in efficacy between treatment regimens based on clonidine or lofexidine and those based on reducing doses of methadone over a period of around 10 days, but methadone was associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.

Psychosocial interventions for cannabis use disorder.

BACKGROUND: Cannabis use disorder is the most commonly reported illegal substance use disorder in the general population; although demand for assistance from health services is increasing internationally, only a minority of those with the disorder seek professional assistance. Treatment studies have been published, but pressure to establish public policy requires an updated systematic review of cannabis-specific treatments for adults. OBJECTIVES: To evaluate the efficacy of psychosocial interventions for cannabis use disorder (compared with inactive control and/or alternative treatment) delivered to adults in an out-patient or community setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE, EMBASE, PsycINFO, the Cumulaive Index to Nursing and Allied Health Literature (CINAHL) and reference lists of articles. Searched literature included all articles published before July 2015. SELECTION CRITERIA: All randomised controlled studies examining a psychosocial intervention for cannabis use disorder (without pharmacological intervention) in comparison with a minimal or inactive treatment control or alternative combinations of psychosocial interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS: We included 23 randomised controlled trials involving 4045 participants. A total of 15 studies took place in the United States, two in Australia, two in Germany and one each in Switzerland, Canada, Brazil and Ireland. Investigators delivered treatments over approximately seven sessions (range, one to 14) for approximately 12 weeks (range, one to 56).Overall, risk of bias across studies was moderate, that is, no trial was at high risk of selection bias, attrition bias or reporting bias. Further, trials included a large total number of participants, and each trial ensured the fidelity of treatments provided. In contrast, because of the nature of the interventions provided, participant blinding was not possible, and reports of researcher blinding often were unclear or were not provided. Half of the reviewed studies included collateral verification or urinalysis to confirm self report data, leading to concern about performance and detection bias. Finally, concerns of other bias were based on relatively consistent lack of assessment of non-cannabis substance use or use of additional treatments before or during the trial period.A subset of studies provided sufficient detail for comparison of effects of any intervention versus inactive control on primary outcomes of interest at early follow-up (median, four months). Results showed moderate-quality evidence that approximately seven out of 10 intervention participants completed treatment as intended (effect size (ES) 0.71, 95% confidence interval (CI) 0.63 to 0.78, 11 studies, 1424 participants), and that those receiving psychosocial intervention used cannabis on fewer days compared with those given inactive control (mean difference (MD) 5.67, 95% CI 3.08 to 8.26, six studies, 1144 participants). In addition, low-quality evidence revealed that those receiving intervention were more likely to report point-prevalence abstinence (risk ratio (RR) 2.55, 95% CI 1.34 to 4.83, six studies, 1166 participants) and reported fewer symptoms of dependence (standardised mean difference (SMD) 4.15, 95% CI 1.67 to 6.63, four studies, 889 participants) and cannabis-related problems compared with those given inactive control (SMD 3.34, 95% CI 1.26 to 5.42, six studies, 2202 participants). Finally, very low-quality evidence indicated that those receiving intervention reported using fewer joints per day compared with those given inactive control (SMD 3.55, 95% CI 2.51 to 4.59, eight studies, 1600 participants). Notably, subgroup analyses found that interventions of more than four sessions delivered over longer than one month (high intensity) produced consistently improved outcomes (particularly in terms of cannabis use frequency and severity of dependence) in the short term as compared with low-intensity interventions.The most consistent evidence supports the use of cognitive-behavioural therapy (CBT), motivational enhancement therapy (MET) and particularly their combination for assisting with reduction of cannabis use frequency at early follow-up (MET: MD 4.45, 95% CI 1.90 to 7.00, four studies, 612 participants; CBT: MD 10.94, 95% CI 7.44 to 14.44, one study, 134 participants; MET + CBT: MD 7.38, 95% CI 3.18 to 11.57, three studies, 398 participants) and severity of dependence (MET: SMD 4.07, 95% CI 1.97 to 6.17, two studies, 316 participants; MET + CBT: SMD 7.89, 95% CI 0.93 to 14.85, three studies, 573 participants), although no particular intervention was consistently effective at nine-month follow-up or later. In addition, data from five out of six studies supported the utility of adding voucher-based incentives for cannabis-negative urines to enhance treatment effect on cannabis use frequency. A single study found contrasting results throughout a 12-month follow-up period, as post-treatment outcomes related to overall reduction in cannabis use frequency favoured CBT alone without the addition of abstinence-based or treatment adherence-based contingency management. In contrast, evidence of drug counselling, social support, relapse prevention and mindfulness meditation was weak because identified studies were few, information on treatment outcomes insufficient and rates of treatment adherence low. In line with treatments for other substance use, abstinence rates were relatively low overall, with approximately one-quarter of participants abstinent at final follow-up. Finally, three studies found that intervention was comparable with treatment as usual among participants in psychiatric clinics and reported no between-group differences in any of the included outcomes. AUTHORS' CONCLUSIONS: Included studies were heterogeneous in many aspects, and important questions regarding the most effective duration, intensity and type of intervention were raised and partially resolved. Generalisability of findings was unclear, most notably because of the limited number of localities and homogeneous samples of treatment seekers. The rate of abstinence was low and unstable although comparable with treatments for other substance use. Psychosocial intervention was shown, in comparison with minimal treatment controls, to reduce frequency of use and severity of dependence in a fairly durable manner, at least in the short term. Among the included intervention types, an intensive intervention provided over more than four sessions based on the combination of MET and CBT with abstinence-based incentives was most consistently supported for treatment of cannabis use disorder.

Opioid agonist treatment for pharmaceutical opioid dependent people.

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.

Pharmacotherapies for cannabis dependence.

BACKGROUND: Cannabis is the most prevalent illicit drug in the world. Demand for treatment of cannabis use disorders is increasing. There are currently no pharmacotherapies approved for treatment of cannabis use disorders. OBJECTIVES: To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or supportive care for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (to 4 March 2014), MEDLINE (to week 3 February 2014), EMBASE (to 3 March 2014) and PsycINFO (to week 4 February 2014). We also searched reference lists of articles, electronic sources of ongoing trials and conference proceedings, and contacted selected researchers active in the area. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving the use of medications to reduce the symptoms and signs of cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in participants diagnosed as cannabis dependent or who were likely to be dependent. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors assessed studies for inclusion and extracted data. All review authors confirmed the inclusion decisions and the overall process. MAIN RESULTS: We included 14 randomised controlled trials involving 958 participants. For 10 studies the average age was 33 years; two studies targeted young people; and age data were not available for two studies. Approximately 80% of study participants were male. The studies were at low risk of selection, performance, detection and selective outcome reporting bias. Three studies were at risk of attrition bias.All studies involved comparison of active medication and placebo. The medications included preparations containing tetrahydrocannabinol (THC) (two studies), selective serotonin reuptake inhibitor (SSRI) antidepressants (two studies), mixed action antidepressants (three studies), anticonvulsants and mood stabilisers (three studies), an atypical antidepressant (two studies), an anxiolytic (one study), a norepinephrine reuptake inhibitor (one study) and a glutamatergic modulator (one study). One study examined more than one medication. Diversity in the medications and the outcomes reported limited the extent that analysis was possible. Insufficient data were available to assess the utility of most of the medications to promote cannabis abstinence at the end of treatment.There was moderate quality evidence that completion of treatment was more likely with preparations containing THC compared to placebo (RR 1.29, 95% CI 1.08 to 1.55; 2 studies, 207 participants, P = 0.006). There was some evidence that treatment with preparations containing THC was associated with reduced cannabis withdrawal symptoms and craving, but this latter outcome could not be quantified. For mixed action antidepressants compared with placebo (2 studies, 179 participants) there was very low quality evidence on the likelihood of abstinence from cannabis at the end of follow-up (RR 0.82, 95% CI 0.12 to 5.41), and moderate quality evidence on the likelihood of treatment completion (RR 0.93, 95% CI 0.71 to 1.21). For this same outcome there was very low quality evidence for the effects of SSRI antidepressants (RR 0.82, 95% CI 0.44 to 1.53; 2 studies, 122 participants), anticonvulsants and mood stabilisers (RR 0.78, 95% CI 0.42 to 1.46; 2 studies, 75 participants), and the atypical antidepressant, bupropion (RR 1.06, 95% CI 0.67 to 1.67; 2 studies, 92 participants). Available evidence on gabapentin (anticonvulsant) and N-acetylcysteine (glutamatergic modulator) was insufficient for quantitative estimates of their effectiveness, but these medications may be worth further investigation. AUTHORS' CONCLUSIONS: There is incomplete evidence for all of the pharmacotherapies investigated, and for many of the outcomes the quality was downgraded due to small sample sizes, inconsistency and risk of attrition bias. The quantitative analyses that were possible, combined with general findings of the studies reviewed, indicate that SSRI antidepressants, mixed action antidepressants, atypical antidepressants (bupropion), anxiolytics (buspirone) and norepinephrine reuptake inhibitors (atomoxetine) are probably of little value in the treatment of cannabis dependence. Preparations containing THC are of potential value but, given the limited evidence, this application of THC preparations should be considered still experimental. Further studies should compare different preparations of THC, dose and duration of treatment, adjunct medications and therapies. The evidence base for the anticonvulsant gabapentin and the glutamatergic modulator N-acetylcysteine is weak, but these medications are also worth further investigation.

Alpha2-adrenergic agonists for the management of opioid withdrawal.

BACKGROUND: Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. OBJECTIVES: To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists compared with placebo, reducing doses of methadone, symptomatic medications or with comparison of different alpha2-adrenergic agonists, for the management of the acute phase of opioid withdrawal. Outcomes included the intensity of signs and symptoms and overall withdrawal syndrome experienced, duration of treatment, occurrence of adverse effects and completion of treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (Issue 7, 2013), MEDLINE (1946 to July week 4, 2013), EMBASE (January 1985 to August week 1, 2013), PsycINFO (1806 to July week 5, 2013) and reference lists of articles. We also contacted manufacturers in the field. SELECTION CRITERIA: Randomised controlled trials comparing alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent. DATA COLLECTION AND ANALYSIS: One review author assessed studies for inclusion and undertook data extraction. All review authors decided on inclusion and confirmed the overall process. MAIN RESULTS: We included 25 randomised controlled trials, involving 1668 participants. Five studies compared a treatment regimen based on an alpha2-adrenergic agonist with placebo, 12 with a regimen based on reducing doses of methadone, four with symptomatic medications and five compared different alpha2-adrenergic agonists.Alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.18 to 0.57, 3 studies, 148 participants). Completion of treatment was significantly more likely with alpha2-adrenergic agonists compared with placebo (RR 1.95, 95% CI 1.34 to 2.84, 3 studies, 148 participants).Alpha2-adrenergic agonists were somewhat less effective than reducing doses of methadone in ameliorating withdrawal symptoms, as measured by the likelihood of severe withdrawal (RR 1.18, 95% CI 0.81 to 1.73, 5 studies, 340 participants), peak withdrawal score (standardised mean difference (SMD) 0.22, 95% CI -0.02 to 0.46, 2 studies, 263 participants) and overall withdrawal severity (SMD 0.13, 95% CI -0.24 to 0.49, 3 studies, 119 participants). These differences were not statistically significant. The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists. The duration of treatment was significantly longer with reducing doses of methadone (SMD -1.07, 95% CI -1.31 to -0.83, 3 studies, 310 participants). Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 1.92, 95% CI 1.19 to 3.10, 6 studies, 464 participants) but there was no significant difference in rates of completion of withdrawal treatment (RR 0.85, 95% CI 0.69 to 1.05, 9 studies, 659 participants).There were insufficient data for quantitative comparison of different alpha2-adrenergic agonists. Available data suggest that lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine. AUTHORS' CONCLUSIONS: Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. No significant difference in efficacy was detected for treatment regimens based on clonidine or lofexidine, and those based on reducing doses of methadone over a period of around 10 days but methadone is associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.

Supplementary thiamine is still important in alcohol dependence.

AIMS: To assess the effect of mandatory thiamine enrichment of wheat flour on blood thiamine levels in an alcohol-dependent population. METHODS: Alcohol-dependent clients (n = 100) entering an inpatient service for the management of alcohol withdrawal had thiamine blood tests and diet interviews. Approximately half (n = 46) the alcohol-dependent participants reported taking vitamin supplements prior to admission. Standard treatment included thiamine supplementation in the form of an intramuscular injection and 100 mg tablets. If consent was gained, a second thiamine blood test was taken prior to discharge (n = 77). Control participants (n = 20) with no history of treatment for alcohol abuse had thiamine blood tests and diet interviews. RESULTS: Control participants consumed significantly larger amounts of thiamine in their diet compared with alcohol-dependent participants (P < 0.0001). Alcohol-dependent participants who reported no use of vitamin supplements had significantly lower (P < 0.05) blood thiamine levels compared with controls, whereas controls and those who reported using vitamin supplements had no significant difference. No significant correlation was found between thiamine blood levels and reported levels of alcohol consumption. CONCLUSION: Reduced blood levels of thiamine in people who are alcohol dependent, compared with those with no history of alcohol abuse, are likely to be because of the poor diet. Consumption of vitamin supplements appears to bring thiamine levels closer to those seen in control participants. Supplementation of dietary intake of thiamine in people who are alcohol dependent remains an important measure for the prevention of Wernicke-Korsakoff's syndrome in this population.

Oral substitution treatment of injecting opioid users for prevention of HIV infection.

BACKGROUND: Injecting drug users are vulnerable to infection with Human Immunodeficiency Virus (HIV) and other blood borne viruses as a result of collective use of injecting equipment as well as sexual behaviour OBJECTIVES: To assess the effect of oral substitution treatment for opioid dependent injecting drug users on risk behaviours and rates of HIV infections SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and PsycINFO to May 2011. We also searched reference lists of articles, reviews and conference abstracts SELECTION CRITERIA: Studies were required to consider the incidence of risk behaviours, or the incidence of HIV infection related to substitution treatment of opioid dependence. All types of original studies were considered. Two authors independently assessed each study for inclusion DATA COLLECTION AND ANALYSIS: Two authors independently extracted key information from each of the included studies. Any differences were resolved by discussion or by referral to a third author. MAIN RESULTS: Thirty-eight studies, involving some 12,400 participants, were included. The majority were descriptive studies, or randomisation processes did not relate to the data extracted, and most studies were judged to be at high risk of bias. Studies consistently show that oral substitution treatment for opioid-dependent injecting drug users with methadone or buprenorphine is associated with statistically significant reductions in illicit opioid use, injecting use and sharing of injecting equipment. It is also associated with reductions in the proportion of injecting drug users reporting multiple sex partners or exchanges of sex for drugs or money, but has little effect on condom use. It appears that the reductions in risk behaviours related to drug use do translate into reductions in cases of HIV infection. However, because of the high risk of bias and variability in several aspects of the studies, combined totals were not calculated. AUTHORS' CONCLUSIONS: Oral substitution treatment for injecting opioid users reduces drug-related behaviours with a high risk of HIV transmission, but has less effect on sex-related risk behaviours. The lack of data from randomised controlled studies limits the strength of the evidence presented in this review.

Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal.

BACKGROUND: Withdrawal (detoxification) is necessary prior to drug-free treatment or as the end point of long-term substitution treatment. OBJECTIVES: To assess the effectiveness of opioid antagonists to induce opioid withdrawal with concomitant heavy sedation or anaesthesia, in terms of withdrawal signs and symptoms, completion of treatment and adverse effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2009), Medline (January 1966 to 11 August 2009), Embase (January 1985 to 2009 Week 32), PsycINFO (1967 to July 2009), and reference lists of articles. SELECTION CRITERIA: Controlled studies of antagonist-induced withdrawal under heavy sedation or anaesthesia in opioid-dependent participants compared with other approaches, or a different regime of anaesthesia-based antagonist-induced withdrawal. DATA COLLECTION AND ANALYSIS: One reviewer assessed studies for inclusion, undertook data extraction and assessed quality. Inclusion decisions and the overall process were confirmed by consultation between all authors. MAIN RESULTS: Nine studies (eight randomised controlled trials) involving 1109 participants met the inclusion criteria for the review.Antagonist-induced withdrawal is more intense but less prolonged than withdrawal managed with reducing doses of methadone, and doses of naltrexone sufficient for blockade of opioid effects can be established significantly more quickly with antagonist-induced withdrawal than withdrawal managed with clonidine and symptomatic medications. The level of sedation does not affect the intensity and duration of withdrawal, although the duration of anaesthesia may influence withdrawal severity. There is a significantly greater risk of adverse events with heavy, compared to light, sedation (RR 3.21, 95% CI 1.13 to 9.12, P = 0.03) and probably with this approach compared to other forms of detoxification. AUTHORS' CONCLUSIONS: Heavy sedation compared to light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of commencement on naltrexone maintenance treatment. Given that the adverse events are potentially life-threatening, the value of antagonist-induced withdrawal under heavy sedation or anaesthesia is not supported. The high cost of anaesthesia-based approaches, both in monetary terms and use of scarce intensive care resources, suggest that this form of treatment should not be pursued.

Is Long-Term Benzodiazepine Use a Risk Factor for Cognitive Decline? Results of a Systematic Review.

BACKGROUND AND AIMS: Benzodiazepines have been widely used for long periods of time despite their adverse effects. The acute effects on cognition are well established. However, less is known about the long-term effects. This study critically reviewed existing evidence of the association between long-term exposure to benzodiazepines and risk of cognitive decline in adults. METHODS: A systematic review with narrative synthesis was conducted. PubMed and PsycINFO databases were searched using combinations of keywords related to "benzodiazepines" and "cognitive function" from database inception to 12 February 2018 to identify prospective longitudinal studies. The records were evaluated for relevance according to the inclusion and exclusion criteria. RESULTS: Fourteen studies involving 2145 long-term benzodiazepine users were included. Meta-analysis was not undertaken because the combined result would not be meaningful as the included studies differed in several key aspects such as frequency and duration of benzodiazepine use, follow-up periods, cognitive domains, cognitive tests, scoring systems, and statistical analysis. The definition of long-term benzodiazepine use was problematic in all the studies. The exposure was determined by measures which were assumed to represent the whole period in-between the follow-ups. Only 3 of the 14 studies provided support for an association between long-term benzodiazepine use and cognitive decline with a small to medium effect size. However, these three studies used different methods to assess the strength of this association. Global cognitive functioning, verbal memory, intelligence, psychomotor speed, and speed of processing were the cognitive domains affected which also varied across these three studies. CONCLUSIONS: Little evidence of an association between long-term benzodiazepine use and a higher risk of cognitive decline among the general adult population was found. However, discrepancies among the results and inconsistencies regarding the cognitive domains affected and methodological limitations prevent definite conclusions. Therefore, future research with prospective studies specially designed would be of great value.

Opioid antagonists with minimal sedation for opioid withdrawal.

BACKGROUND: Managed withdrawal is a necessary step prior to drug-free treatment or as the end point of long-term substitution treatment. OBJECTIVES: To assess the effectiveness of opioid antagonists in combination with minimal sedation to manage opioid withdrawal. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2008), MEDLINE (January 1966-July 2008), EMBASE (January 1985-2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. SELECTION CRITERIA: Controlled studies of interventions involving the use of opioid antagonists in combination with minimal sedation to manage withdrawal in opioid-dependent participants compared with other approaches or different opioid antagonist regimes. DATA COLLECTION AND ANALYSIS: One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors. MAIN RESULTS: Nine studies (6 randomised controlled trials), involving 837 participants, met the inclusion criteria for the review.The quality of the evidence is low, but suggests that withdrawal induced by opioid antagonists in combination with an adrenergic agonist is more intense than withdrawal managed with clonidine or lofexidine alone, while the overall severity is less. Delirium may occur following the first dose of opioid antagonist, particularly with higher doses (> 25mg naltrexone).In some situations antagonist-induced withdrawal may be associated with significantly higher rates of completion of treatment, comp[ared to withdrawal managed primarily with adrenergic agonists. However, this outcome has not been produced consistently, and the extent of any benefit is highly uncertain. AUTHORS' CONCLUSIONS: The use of opioid antagonists combined with alpha(2)-adrenergic agonists is a feasible approach to the management of opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist.A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium.Further research is required to confirm the relative effectiveness of antagonist-induced regimes, as well as variables influencing the severity of withdrawal, adverse effects, the most effective antagonist-based treatment regime, and approaches that might increase retention in subsequent naltrexone maintenance treatment.

Buprenorphine for the management of opioid withdrawal.

BACKGROUND: Managed withdrawal is a necessary step prior to drug-free treatment or as the end point of substitution treatment. OBJECTIVES: To assess the effectiveness of interventions involving the use of buprenorphine to manage opioid withdrawal, for withdrawal signs and symptoms, completion of withdrawal and adverse effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2008), MEDLINE (January 1966 to July 2008), EMBASE (January 1985 to 2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials of interventions involving the use of buprenorphine to modify the signs and symptoms of withdrawal in participants who were primarily opioid dependent. Comparison interventions involved reducing doses of methadone, alpha(2)-adrenergic agonists, symptomatic medications or placebo, or different buprenorphine-based regimes. DATA COLLECTION AND ANALYSIS: One author assessed studies for inclusion and methodological quality, and undertook data extraction. Inclusion decisions and the overall process was confirmed by consultation between all authors. MAIN RESULTS: Twenty-two studies involving 1736 participants were included. The major comparisons were with methadone (5 studies) and clonidine or lofexidine (12 studies). Five studies compared different rates of buprenorphine dose reduction.Severity of withdrawal is similar for withdrawal managed with buprenorphine and withdrawal managed with methadone, but withdrawal symptoms may resolve more quickly with buprenorphine. It appears that completion of withdrawal treatment may be more likely with buprenorphine relative to methadone (RR 1.18; 95% CI 0.93 to 1.49, P = 0.18) but more studies are required to confirm this.Relative to clonidine or lofexidine, buprenorphine is more effective in ameliorating the symptoms of withdrawal, patients treated with buprenorphine stay in treatment for longer (SMD 0.92, 95% CI 0.57 to 1.27, P < 0.001), and are more likely to complete withdrawal treatment (RR 1.64; 95% CI 1.31 to 2.06, P < 0.001). At the same time there is no significant difference in the incidence of adverse effects, but drop-out due to adverse effects may be more likely with clonidine. AUTHORS' CONCLUSIONS: Buprenorphine is more effective than clonidine or lofexidine for the management of opioid withdrawal. Buprenorphine may offer some advantages over methadone, at least in inpatient settings, in terms of quicker resolution of withdrawal symptoms and possibly slightly higher rates of completion of withdrawal.

Alpha2-adrenergic agonists for the management of opioid withdrawal.

BACKGROUND: Withdrawal is a necessary step prior to drug-free treatment or as the end point of long-term substitution treatment. OBJECTIVES: To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists to manage opioid withdrawal. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2008), MEDLINE (January 1966-July 2008), EMBASE (January 1985-2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. We also contacted manufacturers in the field. SELECTION CRITERIA: Controlled trials comparing alpha2-adrenergic agonists with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent. DATA COLLECTION AND ANALYSIS: One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors. MAIN RESULTS: Twenty-four studies, involving 1631 participants, were included. Twenty-one were randomised controlled trials.Thirteen studies compared a treatment regime based on an alpha2-adrenergic agonist with one based on reducing doses of methadone. Diversity in study design, assessment and reporting of outcomes limited the extent of quantitative analysis.Alpha2-adrenergic agonists are more effective than placebo in ameliorating withdrawal, and despite higher rates of adverse effects, are associated with significantly higher rates of completion of treatment.For the comparison of alpha2-adrenergic agonist regimes with reducing doses of methadone, there were insufficient data for statistical analysis, but withdrawal intensity appears similar to or marginally greater with alpha2-adrenergic agonists, while signs and symptoms of withdrawal occur and resolve earlier. Participants stay in treatment longer with methadone. No significant difference was detected in rates of completion of withdrawal with adrenergic agonists compared to reducing doses of methadone, or clonidine compared to lofexidine. Clonidine is associated with more adverse effects than reducing doses of methadone. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine AUTHORS' CONCLUSIONS: Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. No significant difference in efficacy was detected for treatment regimes based on clonidine or lofexidine, and those based on reducing doses of methadone over a period of around 10 days but methadone is associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.

Global statistics on alcohol, tobacco and illicit drug use: 2017 status report.

AIMS: This review provides an up-to-date curated source of information on alcohol, tobacco and illicit drug use and their associated mortality and burden of disease. Limitations in the data are also discussed, including how these can be addressed in the future. METHODS: Online data sources were identified through expert review. Data were obtained mainly from the World Health Organization, United Nations Office on Drugs and Crime and Institute for Health Metrics and Evaluation. RESULTS: In 2015, the estimated prevalence among the adult population was 18.4% for heavy episodic alcohol use (in the past 30 days); 15.2% for daily tobacco smoking; and 3.8, 0.77, 0.37 and 0.35% for past-year cannabis, amphetamine, opioid and cocaine use, respectively. European regions had the highest prevalence of heavy episodic alcohol use and daily tobacco use. The age-standardized prevalence of alcohol dependence was 843.2 per 100 000 people; for cannabis, opioids, amphetamines and cocaine dependence it was 259.3, 220.4, 86.0 and 52.5 per 100 000 people, respectively. High-income North America region had among the highest rates of cannabis, opioid and cocaine dependence. Attributable disability-adjusted life-years (DALYs) were highest for tobacco smoking (170.9 million DALYs), followed by alcohol (85.0 million) and illicit drugs (27.8 million). Substance-attributable mortality rates were highest for tobacco smoking (110.7 deaths per 100 000 people), followed by alcohol and illicit drugs (33.0 and 6.9 deaths per 100 000 people, respectively). Attributable age-standardized mortality rates and DALYs for alcohol and illicit drugs were highest in eastern Europe; attributable age-standardized tobacco mortality rates and DALYs were highest in Oceania. CONCLUSIONS: In 2015 alcohol use and tobacco smoking use between them cost the human population more than a quarter of a billion disability-adjusted life years, with illicit drugs costing further tens of millions. Europeans suffered proportionately more, but in absolute terms the mortality rate was greatest in low- and middle-income countries with large populations and where the quality of data was more limited. Better standardized and rigorous methods for data collection, collation and reporting are needed to assess more accurately the geographical and temporal trends in substance use and its disease burden.