Laura Amato

GRADE guidelines: 10. Considering resource use and rating the quality of economic evidence

OBJECTIVES In this article, we describe how to include considerations about resource utilization when making recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. STUDY DESIGN AND SETTINGS We focus on challenges with rating the confidence in effect estimates (quality of evidence) and incorporating resource use into evidence profiles and Summary of Findings (SoF) tables. RESULTS GRADE recommends that important differences in resource use between alternative management strategies should be included along with other important outcomes in the evidence profile and SoF table. Key steps in considering resources in making recommendations with GRADE are the identification of items of resource use that may differ between alternative management strategies and that are potentially important to decision makers, finding evidence for the differences in resource use, making judgments regarding confidence in effect estimates using the same criteria used for health outcomes, and valuing the resource use in terms of costs for the specific setting for which recommendations are being made. CONCLUSIONS With our framework, decision makers will have access to concise summaries of recommendations, including ratings of the quality of economic evidence, and better understand the implications for clinical decision making.

Development of dependence following treatment with opioid analgesics for pain relief: a systematic review

AIMS To assess the incidence or prevalence of opioid dependence syndrome in adults (with and without previous history of substance abuse) following treatment with opioid analgesics for pain relief. METHODS Medline, Embase, CINHAL and the Cochrane Library were searched up to January 2011. Systematic reviews and primary studies were included if they reported data about incidence or prevalence of opioid dependence syndrome (as defined by DSM-IV or ICD-10) in patients receiving strong opioids (or opioid-type analgesics) for treatment of acute or chronic pain due to any physical condition. The data were abstracted, and the methodological quality was assessed using validated checklists. RESULTS Data were extracted from 17 studies involving a total of 88 235 participants. The studies included three systematic reviews, one randomized controlled trial, eight cross-sectional studies and four uncontrolled case series. Most studies included adult patients with chronic non-malignant pain; two also included patients with cancer pain; only one included patients with a previous history of dependence. Incidence ranged from 0 to 24% (median 0.5%); prevalence ranged from 0 to 31% (median 4.5%). CONCLUSIONS The available evidence suggests that opioid analgesics for chronic pain conditions are not associated with a major risk for developing dependence.

An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results.

ISSUES Cross-sectional surveys have revealed that cannabis is the most widely used illicit substance in Western countries. Cannabis intoxication can lead to acute, transient psychotic symptoms and the short-term exacerbation of pre-existing psychotic symptoms. However, controversy exists about whether cannabis can actually cause long-term psychosis. APPROACH We summarised the findings of systematic reviews on the association between cannabis use and psychosis, searching MEDLINE, EMBASE and CINAHL up to August 2007. We assessed the methodological quality, selected the better quality reviews and analysed reasons for discordant results. KEY FINDINGS We included five systematic reviews. Four of the reviews performed a meta-analysis and showed a consistent association between cannabis use and psychosis; the fifth review considered psychological problems more broadly, did not perform a meta-analysis and reported an inconsistent association. The reasons for discordance were: different outcomes (psychosis vs. psychological problems), different inclusion criteria for primary studies and different methods for summarising the results. IMPLICATIONS This overview shows a consistent association between cannabis use and psychotic symptoms, though it is not possible to draw firm conclusions about a causal relationship. Reverse causality and residual confounding cannot be excluded. An interaction with other environmental and genetic factors is difficult to ascertain. CONCLUSION We conclude that there is insufficient knowledge to determine the level of risk associated with cannabis use in relation to psychotic symptoms and that more information is needed on both the risks of cannabis use and the benefits of preventive interventions to support evidence-based approaches in this area.

Effectiveness of Therapies for Heroin Addiction in Retaining Patients in Treatment: Results From the VEdeTTE Study

Treatment is effective in reducing heroin use and clinical and social problems among heroin addicts. The effectiveness is related to the duration of treatment. “VEdeTTE” is an Italian longitudinal study funded by the Ministry of Health to evaluate the effectiveness of treatments provided by the National Health Services. The study involved 115 drug treatment centers and 10,454 heroin users. Clinical and personal information were collected at intake through a structured interview. Treatments were recorded using a standardized form. Survival analysis and Cox Proportional Hazard model were used to evaluate treatment retention. Five thousand four hundred and fifty-seven patients who started a treatment in the 18 months of the study were included in the analysis: 43.2% received methadone maintenance therapy (MMT), 10.5% therapeutic community, and 46.3% abstinence-oriented therapy (AOT). The likelihood of remaining in treatment was 0.5 at 179 days. The median daily dose of methadone was 37 mg. Psychotherapy was provided in 7.6% of patients receiving methadone and 4.9% of those in therapeutic community. Type of therapy was the strongest predictor of retention, with AOT showing the lowest retention. In MMT patients, retention improved according to dose. Living alone, psychiatric comorbidity and cocaine use increased the risk of dropout. Psychotherapy associated halved the risk of dropout.

VEdeTTE, a longitudinal study on effectiveness of treatments for heroin addiction in Italy: study protocol and characteristics of study population.

The aim of this study was to provide a methodological overview of the study design of the national evaluation large-scale study VEdeTTE and a description of the VEdeTTE study population and to compare enrollments with refusals and the study population with the overall clients at the National Health System (NHS) treatment centers. VEdeTTE is a longitudinal study of heroin addicts recruited in 115 NHS treatment centers in Italy, 1998–2001; 11,903 people were enrolled, 3876 refused to participate; data were analysed on 10,454. Information from refusals was compared to enrollments. The characteristics of the cohort were compared to those of all patients treated in 1999 in Italy. Refusals had a lower educational level and less regular occupational status than those enrolled. Fourteen percent of enrolled patients were women; heroin users in the VEdeTTE study were older than patients attending all NHS treatment centers in Italy; incident cases were less represented. The majority of participants had more than 8 years of education, 33.5% were regularly employed, and only 2% did not have a fixed address. Injectors were 72.3%; 40.6% had a previous overdose, and 14.3% had been imprisoned for life; 15.7% shared injection equipment during the previous 6 months. The proportion of participants reporting heroin use approximately halved from the beginning of the current treatment to the time of the interview. The VEdeTTE study is the biggest cohort of heroin addicts attending treatment centers in Europe. The Italian heroin-addicted population under treatment seems to have low level of education but good social integration. Compared with men, women show a higher severity. Participants show a beneficial effect of treatment.

Cochrane systematic reviews in the field of addiction: What's there and what should be

The Cochrane Drugs and Alcohol Group aims to produce, update, and disseminate systematic reviews on the prevention, treatment, and rehabilitation of problematic drug and alcohol use. The objective of the present paper was to summarize the main characteristics of the published systematic reviews in the field of drug and alcohol dependence, in terms of the topics covered, methods used to produce the reviews, and available evidence. By January 2010, the Group had published 52 reviews with 694 primary studies included out of 2059 studies considered for inclusion. Of these publications, 44% were published in 12 journals, including Drug and Alcohol Dependence (11%) with the highest number of publications, and 68% were conducted in North America. The majority of included studies (90%) were randomized controlled trials. Evaluating their methodological quality, we found that allocation concealment methods were not properly described in the majority of studies (18% adequate, 73% unclear, 9% inadequate). The percentage of interventions shown to be beneficial varied according to the substance considered: 42% for opioids, 37% for alcohol, 14% for psychostimulants, 7% for polydrugs, and 33% for prevention. Furthermore, 75% of the reviews provided specific information on further research needs. Cochrane reviews provide information on the most effective treatments, particularly in the area of opioid and alcohol dependence, and help clarify areas for further research.

The role of Cochrane reviews in informing international guidelines: a case study of using the Grading of Recommendations, Assessment, Development and Evaluation system to develop World Health Organization guidelines for the psychosocially assisted pharmacological treatment of opioid dependence

BACKGROUND AND AIMS The World Health Organization (WHO), and a growing number of other organizations, have adopted the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system in order to both assess the quality of research evidence and develop clinical practice guidelines. In 2009 WHO published a guideline on psychosocially assisted pharmacological treatment of opioid dependence, based on the results of Cochrane Reviews summarized using the GRADE methodology. The main features of this system are an a priori definition of outcomes and their relevance, and distinction between the quality of evidence (also referred to as confidence in the estimate of intervention effect) and the strength of recommendations. We consider how successful this approach has been. ANALYSIS AND EVIDENCE We discuss the merits and limitations of using Cochrane Reviews and GRADE framework in developing guidelines in the field of drug addiction. In 2009 a panel of multi-disciplinary international experts identified 15 clinical questions and eight relevant outcomes. Cochrane reviews were available for each clinical question and four outcomes. The panel formulated 15 recommendations. Eight recommendations were classified as strong, two of which were based on high-quality evidence and three on very low-quality evidence. For example, the strong recommendation to use methadone in adequate doses in preference to buprenorphine was based on high-quality evidence, while the strong recommendation not to use the combination of opioid antagonists with heavy sedation in the management of opioid withdrawal was based on low-quality evidence. CONCLUSIONS An explicit stepwise process of moving from evaluation of the quality of evidence to the definition of the strength of recommendations is important in providing practical and clear clinical guidance for practitioners and policy-makers in addiction.

Psychopathological symptoms of patients with heroin addiction entering opioid agonist or therapeutic community treatment

BackgroundThe relationship between substance use disorders and psychiatric pathology is still an open question. The main aim of the present study was to verify whether the five psychopathological dimensions identified through the SCL-90 tool in a previous study carried out on patients with heroin addiction entering an outpatient opioid agonist treatment (OAT) were also observable in those entering a residential treatment community (TC). Further aims were to look at differences in the psychopathological profiles of patients entering a TC versus an OAT treatment and at the correlation between gender and the observed psychopathology.MethodsA confirmatory factor analysis was performed on the results of SCL-90 filled by 1,195 patients with heroin dependence entering TC treatment. It replicates the extraction method previously used on 1,055 OAT patients with heroin addiction by using a principal component factor analysis (PCA). The association between the kind of treatment received (TC or OAT), gender, and the psychopathological dimensions was assessed through logistic regression and general linear model (GLM) analysis.ResultsThe PCA carried out on the SCL-90 results of patients entering a TC yielded a five-factor solution, confirming the same dimensions observed in patients entering an OAT: `worthlessness and being trapped’, `somatization’, `sensitivity-psychoticism’, `panic anxiety’, and `violence-suicide’. The logistic regression analysis showed a statistically significant association between `somatization’ and `violence-suicide’ severity score and OAT. GLM analysis showed that psychopathological factorial scores for `worthlessness-being trapped’, `somatic symptoms’, and `panic anxiety’ dimensions were more severe in OAT vs TC male patients and in TC vs OAT female ones. `Violence suicide’ followed the same severity pattern for males, but did not differ in TC vs OAT females, while `sensitivity-psychoticism’ did not differ in OAT vs TC patients. The five dimensions did not differ in OAT males vs females.ConclusionsOur research appears to confirm the existence of a specific aggregation of psychological/psychiatric features within the category of individuals with heroin addiction. It also shows a correlation between the dominant psychopathological subgroup and the assignment to TC versus OAT. Further research is needed to clarify the differences between the five psychopathological subgroups and their determinants.

Methadone treatment in clinical practice in Italy: need for improvement

Background: Methadone at appropriate doses has been demonstrated to be the most effective means for retaining patients in treatment and suppressing heroin use. Aim: To describe the modalities of day-to-day provision of methadone maintenance treatments (MMT) in Italian public health centres and to analyze the duration of MMTs by dose and by association with psychosocial treatments. Patients and Methods: We analyzed 8,378 subjects, 18 years of age or over, enrolled between September 1998 and March 2001 in one of 115 public treatment centres for heroin dependence in Italy. Treatment data were collected for each subject from enrolment to the end of the study period (maximum of 18 months). Results: Of the total of 29,495 treatments delivered, 21.0% were methadone maintenance, and 34.4% were methadone detoxification. Fifty percent of MMTs offered had a mean dose less than or equal to 40 mg/day, and only 19% had doses higher than or equal to 60 mg/day; treatments with doses higher than 60 mg/day lasted longer than treatments with lower doses. Differences in treatment length were observed between MMTs associated with a psychosocial treatment and those offered alone, only for doses <60 mg/day. Conclusions: In Italy, MMTs are delivered at inappropriate doses in more than 80% of the cases. The increase of methadone doses to adequate levels as indicated by the literature is necessary to ensure proper and effective use of MMTs in public treatment centres for heroin users.

Comparative effectiveness and safety of erythropoiesis-stimulating agents (biosimilars vs originators) in clinical practice: a population-based cohort study in Italy

Objectives To evaluate the benefit/risk profile of epoetin α biosimilar with the erythropoiesis-stimulating agents (ESAs) originators when administered to naïve patients from clinical practice. Design Population-based observational cohort study. Setting All residents in the Lazio Region, Italy, with chronic kidney disease (CKD) or cancer retrieved from the Electronic Therapeutic Plan (ETP) Register for ESA between 2012 and 2014. Participants Overall, 13 470 incident ESA users were available for the analysis, 8161 in the CKD and 5309 in the oncology setting, respectively. Interventions ESAs identified through the ATC B03XA were divided into 3 groups: (1) biosimilars; (2) epoetin α originator and (3) other originators. Patients were exposed to ESAs from the date of activation of the ETP, until the end of a 6-month follow-up period. Outcome measures Effectiveness (all-cause mortality and blood transfusion) and safety (major cardiovascular events, blood dyscrasia). A composite outcome including all-cause mortality, blood transfusion and major cardiovascular events was predefined. HRs of any outcome were estimated through Cox regression. Results We found no differences between patients on biosimilars or all originators with regard to the risk estimates of all-cause mortality, blood transfusion, major cardiovascular events and blood dyscrasia in the CKD setting. The composite outcome confirmed these results (biosimilars vs epoetin α originators: adjusted HR=1.02, 95% CI 0.78 to 1.33; biosimilars vs other originators: adjusted HR=1.09, 95% CI 0.85 to 1.41). Comparable risk estimates were observed between biosimilars and all originators in the oncology setting. Conclusions In both settings, our findings are suggestive of no difference between biosimilars and originators on relevant effectiveness and safety outcomes. This study may contribute to settling future drug policy for the health services and provides reassurance on the approval pathway for biosimilars. The oncology setting merits further research, taking into account tumour types, tumour stage and anticancer chemotherapy administered.