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1.  Phenibut dependence 
BMJ Case Reports  2013;2013:bcr2012008381.
Phenibut is a γ-aminobutyric acid (GABA) agonist designed and used as an anxiolytic in Russia. In Western countries, phenibut is not a registered medication but is available through online stores as a supplement. We present a case of a patient who used phenibut to self-medicate anxiety, insomnia and cravings for alcohol. While phenibut was helpful initially, the patient developed dependence including tolerance, significant withdrawal symptoms within 3–4 h of last use and failure to fulfil his roles at work and at home. He finally sought medical assistance in our addictions clinic. We have gradually, over the course of 9 weeks, substituted phenibut with baclofen, which has similar pharmacological properties, and then successfully tapered the patient off baclofen. This required approximately 10 mg of baclofen for each gram of phenibut.
doi:10.1136/bcr-2012-008381
PMCID: PMC3604470  PMID: 23391959
2.  Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach 
Scientific Reports  2015;5:8126.
A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure (MOE) approach was conducted. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dose values ranged from 2 mg/kg bodyweight for heroin to 531 mg/kg bodyweight for alcohol (ethanol). For individual exposure the four substances alcohol, nicotine, cocaine and heroin fall into the “high risk” category with MOE < 10, the rest of the compounds except THC fall into the “risk” category with MOE < 100. On a population scale, only alcohol would fall into the “high risk” category, and cigarette smoking would fall into the “risk” category, while all other agents (opiates, cocaine, amphetamine-type stimulants, ecstasy, and benzodiazepines) had MOEs > 100, and cannabis had a MOE > 10,000. The toxicological MOE approach validates epidemiological and social science-based drug ranking approaches especially in regard to the positions of alcohol and tobacco (high risk) and cannabis (low risk).
doi:10.1038/srep08126
PMCID: PMC4311234  PMID: 25634572
3.  Randomized controlled trial of a minimal versus extended Internet-based intervention for problem drinkers: study protocol 
BMC Public Health  2015;15:21.
Background
Problem drinking causes great harm to the person and to society. Most problem drinkers will never seek treatment. The current trial will test the efficacy of two Internet interventions for problem drinking – one minimal and the other extended – as an alternate means of providing help to those in need.
Methods/Design
A double blinded, four-wave panel design with random assignment to two experimental conditions will be used in this study. Participants will be recruited through a comprehensive recruitment strategy consisting of online and print advertisements asking for people who are ‘interested in helping us develop and evaluate Internet-based interventions for problem drinkers.’ Potential participants will be screened to select problem drinkers who have home access to the Internet. Participants will be sent to a password-protected Internet site and, upon signing in, will be randomized to be provided access to the minimal or extended Internet-based intervention. Six-month, twelve-month, and two-year drinking outcomes will be compared between experimental conditions. The primary hypothesis is that participants in the extended Internet intervention condition will display significantly improved drinking outcomes at twelve months compared to participants in the minimal intervention.
Discussion
The findings of this trial will contribute to the growing literature on Internet interventions for problem drinkers. In addition, findings from this trial will contribute to the scarce literature available evaluating the long-term efficacy of brief interventions for alcohol problems.
Trial registration
Clinical Trials.gov #NCT01874509; First submitted June 17, 2013.
doi:10.1186/s12889-015-1347-8
PMCID: PMC4308920  PMID: 25604206
4.  The association of pattern of lifetime alcohol use and cause of death in the European Prospective Investigation into Cancer and Nutrition (EPIC) study 
Background There is limited evidence for an association between the pattern of lifetime alcohol use and cause-specific risk of death.
Methods Multivariable hazard ratios were estimated for different causes of death according to patterns of lifetime alcohol consumption using a competing risks approach: 111 953 men and 268 442 women from eight countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study were included. Self-reported alcohol consumption at ages 20, 30, 40 or 50 years and at enrolment were used for the analysis; 26 411 deaths were observed during an average of 12.6 years of follow-up.
Results The association between lifetime alcohol use and death from cardiovascular diseases was different from the association seen for alcohol-related cancers, digestive, respiratory, external and other causes. Heavy users (>5 drinks/day for men and >2.5 drinks/day for women), regardless of time of cessation, had a 2- to 5-times higher risk of dying due to alcohol-related cancers, compared with subjects with lifetime light use (≤1 and ≤0.5 drink/week for men and women, respectively). Compared with lifetime light users, men who used <5 drinks/day throughout their lifetime had a 24% lower cardiovascular disease mortality (95% confidence interval 2-41). The risk of death from coronary heart disease was also found to be 34–46% lower among women who were moderate to occasionally heavy alcohol users compared with light users. However, this relationship was only evident among men and women who had no chronic disease at enrolment.
Conclusions Limiting alcohol use throughout life is associated with a lower risk of death, largely due to cardiovascular disease but also other causes. However, the potential health benefits of alcohol use are difficult to establish due to the possibility of selection bias and competing risks related to diseases occurring later in life.
doi:10.1093/ije/dyt154
PMCID: PMC3887563  PMID: 24415611
Prospective study; lifetime alcohol use; cause-specific mortality; EPIC
5.  Harms of prescription opioid use in the United States 
Background
Consumption levels of prescription opioids (POs) have increased substantially worldwide, particularly the United States. An emerging perspective implicates increasing consumption levels of POs as the primary system level driving factor behind the observed PO-related harms. As such, the present study aimed to assess the correlations between consumption levels of POs and PO-related harms, including non-medical prescription opioid use (NMPOU), PO-related morbidity and PO-related mortality.
Findings
Pearson’s product-moment correlations were computed using published data from the United States (2001 – 2010). Consumption levels of POs were extracted from the technical reports published by the International Narcotics Control Board, while data for NMPOU was utilized from the National Survey on Drug Use and Health. Additionally, data for PO-related morbidity (substance abuse treatment admissions per 10,000 people) and PO-related mortality (PO overdose deaths per 100,000 people) were obtained from published studies. Consumption levels of POs were significantly correlated with prevalence of NMPOU in the past month (r =0.741, 95% CI =0.208–0.935), past year (r =0.638, 95% CI =0.014–0.904) and lifetime (r =0.753, 95% CI =0.235-0.938), as well as average number of days per person per year of NMPOU among the general population (r =0.900, 95% CI =0.625-0.976) and NMPOU users (r =0.720, 95% CI =0.165–0.929). Similar results were also obtained for PO-related morbidity and PO-related mortality measures.
Conclusion
These findings suggest that reducing consumption levels of POs at the population level may be an effective strategy to limit PO-related harms.
doi:10.1186/1747-597X-9-43
PMCID: PMC4223839  PMID: 25352167
Prescription opioid use; Non-medical use; Addiction treatment; Overdose mortality; Public health and pain treatment
6.  Remembering the forgotten non-communicable diseases 
BMC Medicine  2014;12(1):200.
The forthcoming post-Millennium Development Goals era will bring about new challenges in global health. Low- and middle-income countries will have to contend with a dual burden of infectious and non-communicable diseases (NCDs). Some of these NCDs, such as neoplasms, COPD, cardiovascular diseases and diabetes, cause much health loss worldwide and are already widely recognised as doing so. However, 55% of the global NCD burden arises from other NCDs, which tend to be ignored in terms of premature mortality and quality of life reduction. Here, experts in some of these ‘forgotten NCDs’ review the clinical impact of these diseases along with the consequences of their ignoring their medical importance, and discuss ways in which they can be given higher global health priority in order to decrease the growing burden of disease and disability.
doi:10.1186/s12916-014-0200-8
PMCID: PMC4207624  PMID: 25604462
Global health; Non-communicable diseases; Sickle cell disease; Chronic kidney disease; Asthma; Dementia; Gout; Substance abuse; Alcohol; Liver cirrhosis
7.  Why does society accept a higher risk for alcohol than for other voluntary or involuntary risks? 
BMC Medicine  2014;12(1):189.
Background
Societies tend to accept much higher risks for voluntary behaviours, those based on individual decisions (for example, to smoke, to consume alcohol, or to ski), than for involuntary exposure such as exposure to risks in soil, drinking water or air. In high-income societies, an acceptable risk to those voluntarily engaging in a risky behaviour seems to be about one death in 1,000 on a lifetime basis. However, drinking more than 20 g pure alcohol per day over an adult lifetime exceeds a threshold of one in 100 deaths, based on a calculation from World Health Organization data of the odds in six European countries of dying from alcohol-attributable causes at different levels of drinking.
Discussion
The voluntary mortality risk of alcohol consumption exceeds the risks of other lifestyle risk factors. In addition, evidence shows that the involuntary risks resulting from customary alcohol consumption far exceed the acceptable threshold for other involuntary risks (such as those established by the World Health Organization or national environmental agencies), and would be judged as not acceptable. Alcohol’s exceptional status reflects vagaries of history, which have so far resulted in alcohol being exempted from key food legislation (no labelling of ingredients and nutritional information) and from international conventions governing all other psychoactive substances (both legal and illegal). This is along with special treatment of alcohol in the public health field, in part reflecting overestimation of its beneficial effect on ischaemic disease when consumed in moderation.
Summary
A much higher mortality risk from alcohol than from other risk factors is currently accepted by high income countries.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0189-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0189-z
PMCID: PMC4203927  PMID: 25424648
Acceptable risk; Alcohol; Mortality; Patterns of drinking; Risk; Voluntary versus involuntary risk
8.  Alcohol consumption, drinking patterns, and ischemic heart disease: a narrative review of meta-analyses and a systematic review and meta-analysis of the impact of heavy drinking occasions on risk for moderate drinkers 
BMC Medicine  2014;12(1):182.
Background
Alcohol consumption is a major global risk factor for mortality and morbidity. Much discussion has revolved around the diverse findings on the complex relationship between alcohol consumption and the leading cause of death and disability, ischemic heart disease (IHD).
Methods
We conducted a systematic search of the literature up to August 2014 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify meta-analyses and observational studies examining the relationship between alcohol drinking, drinking patterns, and IHD risk, in comparison to lifetime abstainers. In a narrative review we have summarized the many meta-analyses published in the last 10 years, discussing the role of confounding and experimental evidence. We also conducted meta-analyses examining episodic heavy drinking among on average moderate drinkers.
Results
The narrative review showed that the use of current abstainers as the reference group leads to systematic bias. With regard to average alcohol consumption in relation to lifetime abstainers, the relationship is clearly J-shaped, supported by short-term experimental evidence and similar associations within strata of potential confounders, except among smokers. Women experience slightly stronger beneficial associations and also a quicker upturn to a detrimental effect at lower levels of average alcohol consumption compared to men. There was no evidence that chronic or episodic heavy drinking confers a beneficial effect on IHD risk. People with alcohol use disorder have an elevated risk of IHD (1.5- to 2-fold). Results from our quantitative meta-analysis showed that drinkers with average intake of <30 g/day and no episodic heavy drinking had the lowest IHD risk (relative risk = 0.64, 95% confidence interval 0.53 to 0.71). Drinkers with episodic heavy drinking occasions had a risk similar to lifetime abstainers (relative risk = 1.12, 95% confidence interval 0.91 to 1.37).
Conclusions
Epidemiological evidence for a beneficial effect of low alcohol consumption without heavy drinking episodes is strong, corroborated by experimental evidence. However, episodic and chronic heavy drinking do not provide any beneficial effect on IHD. Thus, average alcohol consumption is not sufficient to describe the risk relation between alcohol consumption and IHD. Alcohol policy should try to reduce heavy drinking patterns.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0182-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0182-6
PMCID: PMC4203905  PMID: 25567363
Alcohol; Binge drinking; Heavy drinking; Ischemic heart disease; Meta-analysis; Systematic review
9.  The Moderating Effects of Sex and Age on the Association between Traumatic Brain Injury and Harmful Psychological Correlates among Adolescents 
PLoS ONE  2014;9(9):e108167.
Background
Although it is well established that sex is a risk factor in acquiring a traumatic brain injury (TBI) among adolescents, it has not been established whether it also moderates the influence of other TBI psychological health correlates.
Methods and Findings
Data were derived from a 2011 population-based cross-sectional school survey, which included 9,288 Ontario 7th–12th graders who completed anonymous self-administered questionnaires in classrooms. Response rate was 62%. Preliminary analyses found no evidence of nonresponse bias in the reporting of TBI. TBI was defined as a hit or blow to the head that resulted in a 5 minutes loss of consciousness or at least one overnight hospitalization due to symptoms associated with it. Reports of lifetime TBI were more common among males than females (23.1%, 95% CI: 20.5, 25.8 vs. 17.1%, 95% CI: 14.7, 19.8). Thirteen correlates were examined and included cigarette smoking, elevated psychological distress, suicide ideation, bully victimization (at school, as well as cyber bullying), bullying others, cannabis use, cannabis dependence and drug use problems, physical injuries, daily smoking, drinking alcohol, binge drinking, use of cannabis, and poor academic performance. Among the outcomes examined, sex moderated the relationship between lifetime TBI and cigarette smoking. In addition, sex and age jointly moderated the relationship between lifetime TBI and daily smoking, alcohol use and physical injuries. Late adolescent males who reported lifetime TBI, relative to females, displayed elevated daily smoking and injuries, whereas their females counterparts displayed elevated past year drinking. Possible bias related to self-report procedures and the preclusion of causal inferences due to the cross-sectional nature of the data are limitations of this study.
Conclusions
TBI differences in outcomes need to be assessed for potential moderating effects of sex and age. Results have important implications for more tailored injury prevention efforts.
doi:10.1371/journal.pone.0108167
PMCID: PMC4182663  PMID: 25268238
10.  The cost-effectiveness and public health benefit of nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels: a Markov model 
BMJ Open  2014;4(9):e005376.
Objectives
To determine whether nalmefene combined with psychosocial support is cost-effective compared with psychosocial support alone for reducing alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels (DRLs) as defined by the WHO, and to evaluate the public health benefit of reducing harmful alcohol-attributable diseases, injuries and deaths.
Design
Decision modelling using Markov chains compared costs and effects over 5 years.
Setting
The analysis was from the perspective of the National Health Service (NHS) in England and Wales.
Participants
The model considered the licensed population for nalmefene, specifically adults with both alcohol dependence and high/very high DRLs, who do not require immediate detoxification and who continue to have high/very high DRLs after initial assessment.
Data sources
We modelled treatment effect using data from three clinical trials for nalmefene (ESENSE 1 (NCT00811720), ESENSE 2 (NCT00812461) and SENSE (NCT00811941)). Baseline characteristics of the model population, treatment resource utilisation and utilities were from these trials. We estimated the number of alcohol-attributable events occurring at different levels of alcohol consumption based on published epidemiological risk-relation studies. Health-related costs were from UK sources.
Main outcome measures
We measured incremental cost per quality-adjusted life year (QALY) gained and number of alcohol-attributable harmful events avoided.
Results
Nalmefene in combination with psychosocial support had an incremental cost-effectiveness ratio (ICER) of £5204 per QALY gained, and was therefore cost-effective at the £20 000 per QALY gained decision threshold. Sensitivity analyses showed that the conclusion was robust. Nalmefene plus psychosocial support led to the avoidance of 7179 alcohol-attributable diseases/injuries and 309 deaths per 100 000 patients compared to psychosocial support alone over the course of 5 years.
Conclusions
Nalmefene can be seen as a cost-effective treatment for alcohol dependence, with substantial public health benefits.
Trial registration numbers
This cost-effectiveness analysis was developed based on data from three randomised clinical trials: ESENSE 1 (NCT00811720), ESENSE 2 (NCT00812461) and SENSE (NCT00811941).
doi:10.1136/bmjopen-2014-005376
PMCID: PMC4166142  PMID: 25227627
Nalmefene; Alcohol dependence; Cost-effectiveness; Cost-utility; QALY; Economic analysis
11.  Efficacy of an alcohol-focused intervention for improving adherence to antiretroviral therapy (ART) and HIV treatment outcomes – a randomised controlled trial protocol 
BMC Infectious Diseases  2014;14(1):500.
Background
Little research has examined whether alcohol reduction interventions improve antiretroviral therapy (ART) adherence and HIV treatment outcomes. This study assesses the efficacy of an intervention for reducing alcohol use among HIV patients on ART who are hazardous/harmful drinkers. Specific aims include adapting a blended Motivational Interviewing (MI) and Problem Solving Therapy (PST) intervention for use with HIV patients; evaluating the efficacy of the intervention for reducing alcohol consumption; and assessing counsellors’ and participants’ perceptions of the intervention.
Methods/Design
A randomised controlled trial will evaluate the intervention among ART patients in public hospital-based HIV clinics in Tshwane, South Africa. We will recruit patients who are HIV-positive, on ART for at least 3 months, and classified as harmful/hazardous drinkers using the AUDIT-3. Eligible patients will be randomly assigned to one of three conditions. Patients in the experimental group will receive the MI-PST intervention to reduce harmful/hazardous alcohol use. Patients in the equal-attention wellness intervention group will receive an intervention focused on addressing health risk behaviours. Patients in the control condition will receive treatment as usual. Participants will complete an interviewer-administered questionnaire at baseline and 3, 6 and 12 months post-randomisation to assess alcohol consumption, ART adherence, physical and mental health. We will also collect biological specimens to test for recent alcohol consumption, CD4 counts and HIV RNA viral loads. The primary outcome will be reduction in the volume of alcohol consumed. Secondary outcomes include reduction in harmful/hazardous use of alcohol, reduction in biological markers of drinking, increase in adherence rates, reductions in viral loads, and increases in CD4 T-cell counts. A process evaluation will ascertain counsellors’ and participants’ perceptions of the acceptability and effectiveness of the interventions.
Discussion
We have obtained ethical approval and approval from the study sites and regional and provincial health departments. The study has implications for clinicians, researchers and policy makers as it will provide efficacy data on how to reduce harmful/hazardous alcohol consumption among HIV patients and will shed light on whether reducing alcohol consumption impacts on HIV treatment adherence and other outcomes.
Trial registration
Pan African Clinical Trials Register Number: PACTR201405000815100.
doi:10.1186/1471-2334-14-500
PMCID: PMC4174635  PMID: 25212696
HIV/AIDS; Alcohol; South Africa; Randomised controlled trial; Brief intervention
12.  A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 
Lim, Stephen S | Vos, Theo | Flaxman, Abraham D | Danaei, Goodarz | Shibuya, Kenji | Adair-Rohani, Heather | Amann, Markus | Anderson, H Ross | Andrews, Kathryn G | Aryee, Martin | Atkinson, Charles | Bacchus, Loraine J | Bahalim, Adil N | Balakrishnan, Kalpana | Balmes, John | Barker-Collo, Suzanne | Baxter, Amanda | Bell, Michelle L | Blore, Jed D | Blyth, Fiona | Bonner, Carissa | Borges, Guilherme | Bourne, Rupert | Boussinesq, Michel | Brauer, Michael | Brooks, Peter | Bruce, Nigel G | Brunekreef, Bert | Bryan-Hancock, Claire | Bucello, Chiara | Buchbinder, Rachelle | Bull, Fiona | Burnett, Richard T | Byers, Tim E | Calabria, Bianca | Carapetis, Jonathan | Carnahan, Emily | Chafe, Zoe | Charlson, Fiona | Chen, Honglei | Chen, Jian Shen | Cheng, Andrew Tai-Ann | Child, Jennifer Christine | Cohen, Aaron | Colson, K Ellicott | Cowie, Benjamin C | Darby, Sarah | Darling, Susan | Davis, Adrian | Degenhardt, Louisa | Dentener, Frank | Des Jarlais, Don C | Devries, Karen | Dherani, Mukesh | Ding, Eric L | Dorsey, E Ray | Driscoll, Tim | Edmond, Karen | Ali, Suad Eltahir | Engell, Rebecca E | Erwin, Patricia J | Fahimi, Saman | Falder, Gail | Farzadfar, Farshad | Ferrari, Alize | Finucane, Mariel M | Flaxman, Seth | Fowkes, Francis Gerry R | Freedman, Greg | Freeman, Michael K | Gakidou, Emmanuela | Ghosh, Santu | Giovannucci, Edward | Gmel, Gerhard | Graham, Kathryn | Grainger, Rebecca | Grant, Bridget | Gunnell, David | Gutierrez, Hialy R | Hall, Wayne | Hoek, Hans W | Hogan, Anthony | Hosgood, H Dean | Hoy, Damian | Hu, Howard | Hubbell, Bryan J | Hutchings, Sally J | Ibeanusi, Sydney E | Jacklyn, Gemma L | Jasrasaria, Rashmi | Jonas, Jost B | Kan, Haidong | Kanis, John A | Kassebaum, Nicholas | Kawakami, Norito | Khang, Young-Ho | Khatibzadeh, Shahab | Khoo, Jon-Paul | Kok, Cindy | Laden, Francine | Lalloo, Ratilal | Lan, Qing | Lathlean, Tim | Leasher, Janet L | Leigh, James | Li, Yang | Lin, John Kent | Lipshultz, Steven E | London, Stephanie | Lozano, Rafael | Lu, Yuan | Mak, Joelle | Malekzadeh, Reza | Mallinger, Leslie | Marcenes, Wagner | March, Lyn | Marks, Robin | Martin, Randall | McGale, Paul | McGrath, John | Mehta, Sumi | Mensah, George A | Merriman, Tony R | Micha, Renata | Michaud, Catherine | Mishra, Vinod | Hanafiah, Khayriyyah Mohd | Mokdad, Ali A | Morawska, Lidia | Mozaff arian, Dariush | Murphy, Tasha | Naghavi, Mohsen | Neal, Bruce | Nelson, Paul K | Nolla, Joan Miquel | Norman, Rosana | Olives, Casey | Omer, Saad B | Orchard, Jessica | Osborne, Richard | Ostro, Bart | Page, Andrew | Pandey, Kiran D | Parry, Charles D H | Passmore, Erin | Patra, Jayadeep | Pearce, Neil | Pelizzari, Pamela M | Petzold, Max | Phillips, Michael R | Pope, Dan | Pope III, C Arden | Powles, John | Rao, Mayuree | Razavi, Homie | Rehfuess, Eva A | Rehm, Jürgen T | Ritz, Beate | Rivara, Frederick P | Roberts, Thomas | Robinson, Carolyn | Rodriguez-Portales, Jose A | Romieu, Isabelle | Room, Robin | Rosenfeld, Lisa C | Roy, Ananya | Rushton, Lesley | Salomon, Joshua A | Sampson, Uchechukwu | Sanchez-Riera, Lidia | Sanman, Ella | Sapkota, Amir | Seedat, Soraya | Shi, Peilin | Shield, Kevin | Shivakoti, Rupak | Singh, Gitanjali M | Sleet, David A | Smith, Emma | Smith, Kirk R | Stapelberg, Nicolas J C | Steenland, Kyle | Stöckl, Heidi | Stovner, Lars Jacob | Straif, Kurt | Straney, Lahn | Thurston, George D | Tran, Jimmy H | Van Dingenen, Rita | van Donkelaar, Aaron | Veerman, J Lennert | Vijayakumar, Lakshmi | Weintraub, Robert | Weissman, Myrna M | White, Richard A | Whiteford, Harvey | Wiersma, Steven T | Wilkinson, James D | Williams, Hywel C | Williams, Warwick | Wilson, Nicholas | Woolf, Anthony D | Yip, Paul | Zielinski, Jan M | Lopez, Alan D | Murray, Christopher J L | Ezzati, Majid
Lancet  2012;380(9859):2224-2260.
Summary
Background
Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.
Methods
We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden.
Findings
In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2–7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5–7·0]), and alcohol use (5·5% [5·0–5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8–9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6–8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4–6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2–10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water we and sanitation accounting for 0·9% (0·4–1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania.
Interpretation
Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(12)61766-8
PMCID: PMC4156511  PMID: 23245609
13.  Chronic heavy drinking and ischaemic heart disease: a systematic review and meta-analysis 
Open Heart  2014;1(1):e000135.
Previous meta-analyses have reported either a protective, neutral or detrimental association from chronic heavy drinking in relation to ischaemic heart disease (IHD). We investigated the potential for systematic error because of study design. Using MOOSE guidelines, studies were identified through MEDLINE, EMBASE and Web of Science up to end of March, 2014. Epidemiological studies reporting on chronic heavy drinking and IHD risk in population studies and samples of people with alcohol use disorder (AUD) were included. Random-effects meta-analysis was used to pool eligible studies. The I2 statistic was used to assess heterogeneity across studies. In total, 34 observational studies with 110 570 chronic heavy drinkers and 3086 IHD events were identified. In population studies among men, the pooled risk for IHD incidence (fatal+non-fatal events) among chronic heavy drinkers (on average ≥60 g pure alcohol/day) in comparison to lifetime abstainers (n=11 studies) was relative risk (RR)=1.04 (95% CI 0.83 to 1.31, I2=54%). Few studies were available for women. In patients with AUD, the risk of IHD mortality in comparison to the general population was elevated with a RR=1.62 (95% CI 1.34 to 1.95, I2=81%) in men and RR=2.09 (95% CI 1.28 to 3.41, I2=67%) in women. There was a general lack of adjustment other than sex and age in studies among patients with AUD. There is no systematic evidence for a protective association from any type of chronic heavy drinking on IHD risk. Patients with AUD were at higher risk for IHD mortality, but better quality evidence is needed with regard to potential confounding.
doi:10.1136/openhrt-2014-000135
PMCID: PMC4189294  PMID: 25332827
MYOCARDIAL ISCHAEMIA AND INFARCTION (IHD)
14.  Influence of unrecorded alcohol consumption on liver cirrhosis mortality 
Unrecorded alcohol includes illegally distributed alcohol as well as homemade or surrogate alcohol which is unintended for consumption by humans (e.g., cosmetics containing alcohol). The highest unrecorded alcohol consumption occurs in Eastern Europe and some of these countries have an over proportional liver cirrhosis mortality. Compounds besides ethanol have been hypothesized as being responsible for this observation. On the other hand, chemical investigations were unable to prove that unrecorded alcohol regularly contains contaminants above toxicological thresholds. However, illegally produced spirits regularly contain higher percentages of alcohol (above 45% by volume), but for considerably less costs compared with licit beverages, potentially causing more problematic patterns of drinking. In this review, it is investigated whether patterns of drinking rather than product composition can explain the liver cirrhosis mortality rates. Statistical examination of World Health Organization country data shows that the originally detected correlation of the percentage of unrecorded alcohol consumption and liver cirrhosis mortality rates disappears when the data is adjusted for the prevalence of heavy episodic drinking. It may be concluded that there is currently a lack of data to demonstrate causality between the composition of illicit spirits (e.g., higher levels of certain contaminants in home-produced products) and liver toxicity on a population scale. Exceptions may be cases of poisoning with antiseptic liquids containing compounds such as polyhexamethyleneguanidine, which were reported to be consumed as surrogate alcohol in Russia, leading to an outbreak of acute cholestatic liver injury, histologically different from conventional alcoholic liver disease.
doi:10.3748/wjg.v20.i23.7217
PMCID: PMC4064067  PMID: 24966592
Epidemiology; Liver cirrhosis; Alcoholic beverages; Unrecorded alcohol; Risk assessment
15.  Are the 1976–1985 birth cohorts heavier drinkers? Age-period-cohort analyses of the National Alcohol Surveys 1979–2010 
Addiction (Abingdon, England)  2012;108(6):1038-1048.
Aims
To estimate age-period-cohort models predicting alcohol volume, heavy drinking and beverage-specific alcohol volume in order to evaluate whether the 1976–1985 birth cohorts drink relatively heavily.
Design
Data from seven cross-sectional surveys of the US conducted between 1979 and 2010 were utilized in negative binomial generalized linear models of age, period and cohort effects predicting alcohol measures.
Setting
General population surveys of the US.
Participants
36,432 US adults (aged 18 or older).
Measurements
Monthly number of alcohol drinks, beer, wine and spirits drinks and days drinking 5 or more drinks in the past year derived from beverage-specific graduated frequency questions.
Findings
Relative to the reference 1956–60 birth cohort, men in the 1976–1980 cohort for were found to consume more alcohol (Incidence rate ratio (IRR) =1.222: CI 1.07–1.39) and to have more 5+ days (IRR=1.365: CI 1.09–1.71) as were men in the 1980–85 cohort for volume (IRR=1.284: CI 1.10–1.50) and 5+ days (IRR=1.437: CI 1.09–1.89). For women, those in the 1980–85 cohort were found to have higher alcohol volume (IRR=1.299: CI 1.07–1.58) and more 5+ days (IRR=1.547: CI 1.01–2.36). Beverage-specific models found different age patterns of volume by beverage with a flat age pattern for both genders’ spirits and women’s wine, an increasing age pattern for men’s wine and a declining age pattern from the early 20’s for beer.
Conclusions
In the United States, men born between 1976 and 1985, and women born between 1981 and 1985 have higher alcohol consumption than in earlier or later years.
doi:10.1111/j.1360-0443.2012.04055.x
PMCID: PMC3547140  PMID: 22897662
Cohort; beer; wine; spirits; alcohol use; trends; age
16.  Tobacco Smoking, Alcohol Drinking, Diabetes, Low Body Mass Index and the Risk of Self-Reported Symptoms of Active Tuberculosis: Individual Participant Data (IPD) Meta-Analyses of 72,684 Individuals in 14 High Tuberculosis Burden Countries 
PLoS ONE  2014;9(5):e96433.
Background
The effects of multiple exposures on active tuberculosis (TB) are largely undetermined. We sought to establish a dose-response relationship for smoking, drinking, and body mass index (BMI) and to investigate the independent and joint effects of these and diabetes on the risk of self-reported symptoms of active TB disease.
Methods and Findings
We analyzed 14 national studies in 14 high TB-burden countries using self-reports of blood in cough/phlegm and cough lasting > = 3 weeks in the last year as the measures of symptoms of active TB. The random effect estimates of the relative risks (RR) between active TB and smoking, drinking, diabetes, and BMI<18.5 kg/m2 were reported for each gender. Floating absolute risks were used to examine dyads of exposure. Adjusted for age and education, the risks of active TB were significantly associated with diabetes and BMI<18.5 kg/m2 in both sexes, with ever drinking in men and with ever smoking in women. Stronger dose-response relationships were seen in women than in men for smoking amount, smoking duration and drinking amount but BMI<18.5 kg/m2 showed a stronger dose-response relationship in men. In men, the risks from joint exposures were statistically significant for diabetics with BMI<18.5 kg/m2 (RR = 6.4), diabetics who smoked (RR = 3.8), and diabetics who drank alcohol (RR = 3.2). The risks from joint risk factors were generally larger in women than in men, with statistically significant risks for diabetics with BMI<18.5 kg/m2 (RR = 10.0), diabetics who smoked (RR = 5.4) and women with BMI<18.5 kg/m2 who smoked (RR = 5.0). These risk factors account for 61% of male and 34% of female estimated TB incidents in these 14 countries.
Conclusions
Tobacco, alcohol, diabetes, and low BMI are significant individual risk factors but in combination are associated with triple or quadruple the risk of development of recent active TB. These risk factors might help to explain the wide variation in TB across countries.
doi:10.1371/journal.pone.0096433
PMCID: PMC4008623  PMID: 24789311
17.  Suicidality, Bullying and Other Conduct and Mental Health Correlates of Traumatic Brain Injury in Adolescents 
PLoS ONE  2014;9(4):e94936.
Objective
Our knowledge on the adverse correlates of traumatic brain injuries (TBI), including non-hospitalized cases, among adolescents is limited to case studies. We report lifetime TBI and adverse mental health and conduct behaviours associated with TBI among adolescents from a population-based sample in Ontario.
Method and Findings
Data were derived from 4,685 surveys administered to adolescents in grades 7 through 12 as part of the 2011 population-based cross-sectional Ontario Student Drug Use and Health Survey (OSDUHS). Lifetime TBI was defined as head injury that resulted in being unconscious for at least 5 minutes or being retained in the hospital for at least one night, and was reported by 19.5% (95%CI:17.3,21.9) of students. When holding constant sex, grade, and complex sample design, students with TBI had significantly greater odds of reporting elevated psychological distress (AOR = 1.52), attempting suicide (AOR = 3.39), seeking counselling through a crisis help-line (AOR = 2.10), and being prescribed medication for anxiety, depression, or both (AOR = 2.45). Moreover, students with TBI had higher odds of being victimized through bullying at school (AOR = 1.70), being cyber-bullied (AOR = 2.05), and being threatened with a weapon at school (AOR = 2.90), compared with students who did not report TBI. Students with TBI also had higher odds of victimizing others and engaging in numerous violent as well as nonviolent conduct behaviours.
Conclusions
Significant associations between TBI and adverse internalizing and externalizing behaviours were found in this large population-based study of adolescents. Those who reported lifetime TBI were at a high risk for experiencing mental and physical health harms in the past year than peers who never had a head injury. Primary physicians should be vigilant and screen for potential mental heath and behavioural harms in adolescent patients with TBI. Efforts to prevent TBI during adolescence and intervene at an early stage may reduce injuries and comorbid problems in this age group.
doi:10.1371/journal.pone.0094936
PMCID: PMC3988100  PMID: 24736613
18.  A comparison of the prevalence of prenatal alcohol exposure obtained via maternal self-reports versus meconium testing: a systematic literature review and meta-analysis 
Background
Maternal self-reports, used for the detection of prenatal alcohol exposure (PAE), may lack validity, necessitating the use of an objective biomarker. The detection of fatty acid ethyl esters (products of non-oxidative ethanol metabolism) in meconium has been established as a novel biomarker of PAE. The purpose of the current study was to compare the prevalence of PAE as reported via maternal self-reports with the results of meconium testing, and to quantify the disparity between these two methods.
Methods
A systematic literature search for studies reporting on the prevalence of PAE, using maternal self-reports in combination with meconium testing, was conducted using multiple electronic bibliographic databases. Pooled prevalence estimates and 95% confidence intervals (CI) were calculated based on eight studies, using the Mantel-Haenszel method, assuming a random effects model. A random effects meta-regression was performed to test for a difference.
Results
The pooled prevalence of PAE as measured by meconium testing was 4.26 (95% CI: 1.34-13.57) times the pooled prevalence of PAE as measured by maternal self-reports. Large variations across the studies in regard to the difference between estimates obtained from maternal self-reports and those obtained from meconium testing were observed.
Conclusions
If maternal self-reports are the sole information source upon which health care professionals rely, a number of infants who were prenatally exposed to alcohol are not being recognized as such. However, further research is needed in order to validate existing biomarkers, as well as discover new biomarkers, for the detection of PAE.
doi:10.1186/1471-2393-14-127
PMCID: PMC3992148  PMID: 24708684
Biomarkers; Meconium; Prenatal alcohol exposure; Prevalence; Maternal self-reports
19.  Use and nonmedical use of prescription opioid analgesics in the general population of Canada and correlations with dispensing levels in 2009 
BACKGROUND
In Canada, harm from nonmedical prescription opioid analgesic (POA) use (NMPOU) has increased in recent years; however, there are limitations to the current estimates of NMPOU. The 2009 Canadian Alcohol and Drug Use Monitoring Survey presents an opportunity to produce more accurate estimates of NMPOU.
OBJECTIVES:
To determine the prevalence of POA use, NMPOU and use of pain relievers to ‘get high’, and to assess correlations of these indicators with age, sex and provincial levels of dispensed POAs in Canada in 2009.
METHODS:
Data regarding POA use were obtained from the 2009 Canadian Alcohol and Drug Use Monitoring Survey (n=13,032). The amount of POAs dispensed in standardized daily doses was obtained from a representative sample of 2700 retail pharmacies across Canada. Associations among POA use, age, sex and the amount of POAs dispensed were evaluated using regression models. Differences in POA use across provinces were assessed using the Wald test.
RESULTS:
In Canada in 2009, the prevalence of POA use was 19.2% (95% CI 18.0% to 20.5%), NMPOU was 4.8% (95% CI 4.1% to 5.5%) and the use of pain relievers to get high was 0.4% (95% CI 0.1% to 0.8%). NMPOU was significantly associated with age. The use of pain relievers to get high varied significantly across provinces, while POA use and NMPOU did not show significant variations. The amount of POAs dispensed per province was not significantly correlated with any type of POA use.
CONCLUSIONS:
These findings confirm high POA use and NMPOU across Canada. Research is required to identify determinants of NMPOU.
PMCID: PMC3718055  PMID: 23662288
Canada; General population surveys; Pain care; Prescription opioids; Substance abuse
20.  Risk of Injury Due to Alcohol – Evaluating Potential Bias Using the Case-Crossover Usual-Frequency Method 
Epidemiology (Cambridge, Mass.)  2013;24(2):10.1097/EDE.0b013e3182801cb4.
Background
The usual-frequency case-crossover method, comparing exposure before an event with typical exposure of the same person, is widely used to estimate the risk of injury related to acute alcohol use. Prior results suggest that risk estimates might be biased upward compared with other methods.
Methods
Using data from 15 emergency-room studies in 7 countries, we compared the usual-frequency case-crossover method with case-control analysis, using non-injury patients as controls. Control-crossover analysis was performed to examine potential bias and to adjust risk estimates.
Results
The cross-study pooled odds ratio (OR) of injury related to drinking was 4.7 (2.6–8.5) in case-crossover analysis and 2.1 (1.6–2.7) in case-control analysis. A control-crossover analysis found an indication of bias (OR=2.2 [1.8–2.8]), which was larger among less frequent drinkers.
Conclusion
Findings suggest that the potential overestimation of injury risk based on the usual-frequency case-crossover method might be best explained by recall bias in usual-frequency estimates.
doi:10.1097/EDE.0b013e3182801cb4
PMCID: PMC3859247  PMID: 23348068
21.  Trends and changes in prescription opioid analgesic dispensing in Canada 2005–2012: an update with a focus on recent interventions 
Background
Prescription opioid analgesic (POA) utilization has steeply increased globally, yet is far higher in established market economies than elsewhere. Canada features the world’s second-highest POA consumption rates. Following increases in POA-related harm, several POA control interventions have been implemented since 2010.
Methods
We examined trends and patterns in POA dispensing in Canada by province for 2005–2012, including a focus on the potential effects of interventions. Data on annual dispensing of individual POA formulations – categorized into ‘weak opioids’ and ‘strong opioids’ – from a representative sub-sample of 5,700 retail pharmacies across Canada (from IMS Brogan’s Compuscript) were converted into Defined Daily Doses (DDD), and examined intra- and inter-provincially as well as for Canada (total).
Results
Total POA dispensing – driven by strong opioids – increased across Canada until 2011; four provinces indicated decreases in strong opioid dispensing; seven provinces indicated decreases specifically in oxycodone dispensing, 2011–2012. The dispensing ratio weak/strong opioids decreased substantively. Major inter-provincial differences in POA dispensing levels and qualitative patterns of POA formulations dispensed persisted. Previous increasing trends in POA dispensing were reversed in select provinces 2011–2012, coinciding with POA-related interventions.
Conclusions
Further examinations regarding the sustained nature, drivers and consequences of the recent trend changes in POA dispensing – including possible ‘substitution effects’ for oxycodone reductions – are needed.
doi:10.1186/1472-6963-14-90
PMCID: PMC3941687  PMID: 24572005
Prescription opioids; Oxycodone; Health policy; Canada; Population health
22.  The potential impact of increased treatment rates for alcohol dependence in the United Kingdom in 2004 
Background
Alcohol consumption has been linked to a considerable burden of disease in the United Kingdom (UK), with most of this burden due to heavy drinking and Alcohol Dependence (AD). However, AD is undertreated in the UK, with only 8% of those individuals with AD being treated in England and only 6% of those individuals with AD being treated in Scotland. Thus, the objective of this paper is to quantify the deaths that would have been avoided in the UK in 2004 if the treatment rate for AD had been increased.
Methods
Data on the prevalence of AD, alcohol consumption, and mortality were obtained from the Adult Psychiatric Morbidity Survey, the Global Information System on Alcohol and Health, and the 2004 Global Burden of Disease study respectively. Data on the effectiveness of pharmacological treatment and Motivational Interviewing/Cognitive Behavioural Therapy were obtained from Cochrane reviews and meta-analyses. Simulations were used to model the number of deaths under different treatment scenarios. Sensitivity analyses were performed to model the effects of Brief Interventions and to examine the effect of using AD prevalence data obtained from the National Institute for Health and Clinical Excellence.
Results
In the UK, 320 female and 1,385 male deaths would have been avoided if treatment coverage of pharmacological treatment had been increased to 20%. This decrease in the number of deaths represents 7.9% of all alcohol-attributable deaths (7.0% of all alcohol-attributable deaths for women and 8.1% of all alcohol-attributable deaths for men). If we used lower AD prevalence rates obtained from the National Institute for Health and Clinical Excellence, then treatment coverage of pharmacological treatment in hospitals for 20% of the population with AD would have resulted in the avoidance of 529 deaths in 2004 (99 deaths avoided for women and 430 deaths avoided for men).
Conclusions
Increasing AD treatment in the UK would have led to a large number of deaths being avoided in 2004. Increased AD treatment rates not only impact mortality but also impact upon the large burden of disability and morbidity attributable to AD, as well as the associated social and economic burdens.
doi:10.1186/1472-6963-14-53
PMCID: PMC3923387  PMID: 24499391
Alcohol; Mortality; Alcohol dependence; Alcohol dependence treatment; United Kingdom
23.  Measuring the Burden 
PMCID: PMC3908701  PMID: 24881319
24.  Measuring the Burden: Alcohol’s Evolving Impact 
Measuring the impact of alcohol consumption on morbidity and mortality depends on the accurate measurement of alcohol exposure, risk relationships, and outcomes. A variety of complicating factors make it difficult to measure these elements. This article reviews these factors and provides an overview of the articles that make up this special issue on current research examining alcohol’s role in the burden of disease. These topics include estimating alcohol consumption as well as alcohol-related morbidity and mortality in various demographic groups, and the burden of alcohol use disorders.
PMCID: PMC3908703  PMID: 24881320
Alcohol use consumption; alcohol use frequency; alcohol use pattern; alcohol burden; public health impact; burden of disease; morbidity; mortality; disease; measurement; outcomes; specificity of measurement; sensitivity of measurement
25.  Chronic Diseases and Conditions Related to Alcohol Use 
Alcohol consumption is a risk factor for many chronic diseases and conditions. The average volume of alcohol consumed, consumption patterns, and quality of the alcoholic beverages consumed likely have a causal impact on the mortality and morbidity related to chronic diseases and conditions. Twenty-five chronic disease and condition codes in the International Classification of Disease (ICD)-10 are entirely attributable to alcohol, and alcohol plays a component-risk role in certain cancers, other tumors, neuropsychiatric conditions, and numerous cardiovascular and digestive diseases. Furthermore, alcohol has both beneficial and detrimental impacts on diabetes, ischemic stroke, and ischemic heart disease, depending on the overall volume of alcohol consumed, and, in the case of ischemic diseases, consumption patterns. However, limitations exist to the methods used to calculate the relative risks and alcohol-attributable fractions. Furthermore, new studies and confounders may lead to additional diseases being causally linked to alcohol consumption, or may disprove the relationship between alcohol consumption and certain diseases that currently are considered to be causally linked. These limitations do not affect the conclusion that alcohol consumption significantly contributes to the burden of chronic diseases and conditions globally, and that this burden should be a target for intervention.
PMCID: PMC3908707  PMID: 24881324
Alcohol consumption; alcohol use frequency; chronic diseases; disorders; mortality; morbidity; alcohol-attributable fractions (AAF); risk factors; relative risk; AOD-induced risk; cancers; neuropsychiatric disorders; cardiovascular diseases; digestive diseases; diabetes; ischemic stroke; ischemic heart disease; burden of disease

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