Update on Alcohol, Other Drugs, and Health

Update on Alcohol, Other Drugs, and Health January–February 2012 www.aodhealth.org

Studies on Interventions & Assessments www.aodhealth.org

Lack of Efficacy of a 3-Medication Treatment Protocol for MethamphetamineDependence Ling W, et al. Addiction.2012;107(2):361–369. Summary by Kevin L. Kraemer, MD, MSc 3 www.aodhealth.org

Objectives/Methods The PROMETA™ protocol (including the benzodiazepine antagonist flumazenil, the GABA-agonist gabapentin, and the H1-histamine antagonist hydroxyzine) is unproven for the treatment of methamphetamine dependence. This double-blind trial randomized 120 patients with methamphetamine abuse or dependence to PROMETA* or placebo (hydroxyzine only). *Intravenous flumazenil 2 mg on days 1, 2, 3, 22, and 23; oral gabapentin titrated to 1200 mg per day by day 4 and continued to day 40; and oral hydroxyzine 50 mg prior to flumazenil infusion and as take-home medication through day 10. www.aodhealth.org 4

Objectives/Methods (cont’d) Each group received 14 weekly sessions of cognitive behavioral therapy. Outcomes were methamphetamine and other drug use documented by urine testing, self-reported methamphetamine craving, treatment retention, and adverse events. www.aodhealth.org 5

Results Fifty percent of the experimental group and 70% of the placebo group remained in the study through the medication phase (day 40). Only 30% of the experimental group and 43% of the placebo group remained until the end of the study (day 108). During follow-up at days 23, 40, and 108, the experimental and placebo groups did not differ significantly with regard to the following: www.aodhealth.org 6

Results (cont’d) proportion of methamphetamine-negative urine tests (0.5, 0.4, and 0.3 versus 0.5, 0.5, and 0.4, respectively); mean methamphetamine craving score (2.8, 3.1, and 2.2 versus 2.9, 2.9, and 2.4, respectively); or percentage with 3 consecutive negative urine tests (36% and 39% versus 46% and 51% at days 40 and 108, respectively). Mild, moderate, and severe adverse events were reported by 73%, 23%, and 4% of the experimental group and 59%, 40%, and 1% of the placebo group, respectively. www.aodhealth.org 7

Comments The PROMETATM protocol has been promoted and used as a treatment for methamphetamine dependence despite lack of a strong scientific rationale and proven efficacy. This randomized placebo-controlled trial found no benefit of PROMETA over placebo for treatment of methamphetamine abuse or dependence and raises serious questions about the use of PROMETA for methamphetamine dependence. www.aodhealth.org 8

Retention in Opioid Agonist Treatment after Prison Release Reduces Re-incarceration Larney S, et al. Addiction. 2012;107(2):372–380. Summary by Peter D. Friedmann, MD, MPH www.aodhealth.org 9

Objectives/Methods Opioid agonist treatment (OAT) in prison and after release might influence the risk of re-incarceration. This prospective cohort study linked data on OAT and incarceration among 375 men with heroin use originally recruited in 1996–1997 for a randomized controlled trial of OAT in prison in New South Wales, Australia. Participants were followed through 2006. www.aodhealth.org

Results During 9+ years of observation, 331 participants engaged in OAT 1081 times, with a median of 2 episodes per participant (mean length of engagement, 156 days); 58% started OAT in prison. Ninety percent of participants were re-incarcerated after the first incarceration. Engagement in OAT at the time of release had no effect on re-incarceration. Post-release retention in OAT was associated with a one-fifth reduction in the number of re-incarcerations. www.aodhealth.org 11

Comments This study affirms that retention in OAT following release is associated with reduced re-incarceration among former prisoners with opioid dependence. Although other investigations have shown that initiating OAT prior to release maximizes post-release treatment retention, the current study suggests active linkage to ongoing treatment is an essential component. www.aodhealth.org 12

Comments (cont’d) Continuing or initiating OAT during incarceration is necessary but not sufficient to optimize post-release outcomes among opioid-dependent inmates. Correctional systems and treatment providers must also provide transitional assistance to ensure that former inmates reach OAT programs after release. www.aodhealth.org 13

Adding N-Acetylcysteine to Glucocorticoids May Improve Outcomes in Patients with Severe Alcoholic Hepatitis Nguyen-Khac E, et al. N Engl J Med. 2011;365(19):1781–1789. Summary by Darius A. Rastegar, MD www.aodhealth.org 14

Objectives/Methods This randomized controlled trial conducted in 11 French university hospitals assessed whether N-acetylcysteine [NAC], an antioxidant used to treat acetaminophen-induced hepatitis, further reduced mortality in patients treated with prednisolone for severe alcoholic hepatitis. Subjects (N=174) were: age 18 or older. had consumed, on average, >50 g alcohol per day in the past 3 months. had a Maddrey’s discriminant function* of 32 or more. had histologic findings consistent with alcoholic hepatitis. *Calculated as 4.6 x [patient’s prothrombin time - control prothrombin time (in seconds)] + serum bilirubin level (mg/dL). 15

Objectives/Methods (cont’d) The long list of exclusion criteria included other possible causes of liver disease (e.g., hepatitis B or C), HIV infection, and “serious cardiac, respiratory or neurologic disease.” All patients received oral prednisolone for 28 days. Eighty-five also received intravenous NAC on days 1–5. www.aodhealth.org 16

Results Mortality rates and hazard ratios (HR) for patients in the prednisolone-only (PRED) and prednisolone plus NAC (PRED-NAC) arms were as follows: *As reported in the paper. • Adverse events were no higher in the PRED-NAC arm, and 2 major adverse events (hepatorenal syndrome and infection) were significantly lower. • Adverse events were no higher in the PRED-NAC arm, and 2 major adverse events (hepatorenal syndrome and infection) were significantly lower. www.aodhealth.org 17

Comments Although this study failed to show significantly reduced mortality at 6 months (the primary endpoint), a significant short-term benefit was seen in the PRED-NAC arm with no serious adverse events. The failure may simply have been due to lack of sufficient power. It is also possible that longer term outcomes would be better with longer courses of treatment with NAC. www.aodhealth.org 18

Corsenac P, et al. Drug Alcohol Depend. November 18, 2011 [Epub ahead of print]. Summary by Tae Woo Park, MD, & Alexander Y. Walley, MD, MSc People Receiving Buprenorphine and Methadone Are More Likely to Be Responsible for Traffic Crashes www.aodhealth.org 19

Objectives/Methods Opioid agonist treatment (OAT) does not result in substantial driving impairment in driving-simulation studies; however, the association between traffic crashes and OAT has not been studied since buprenorphine became available. This French study of 72,685 drivers involved in traffic accidents between 2005–2008 investigated the association between risk of being responsible for a crash and having a prescription for buprenorphine or methadone on the day of the crash. Responsibility was determined by police reports matched with a national crash database and linked to national pharmacy data. 20 www.aodhealth.org

Results • After adjusting for age, gender, road/vehicle conditions, and prescriptions for other medications known to impair driving ability, drivers prescribed buprenorphine or methadone had a 2-fold risk of being responsible for a road traffic crash compared with those who were not (odds ratio [OR], 2.02). • The 0.3% of drivers prescribed buprenorphine or methadone were more likely to be men, to be younger, and to have been prescribed other medications that impair driving ability (such as anxiolytics) than the 99.7% who were not. www.aodhealth.org 21

Comments Although OAT patients may not be involved in more crashes, when they are involved, this study suggests that they are more likely to be responsible. However, we do not know if the increased risk is because of OAT, because such persons tend to be riskier drivers, or if there is some other reason. Furthermore, we do not know how these risks stack up against the risk among patients with opioid addiction who are not receiving OAT. www.aodhealth.org 22

Comments (cont’d) In any case, when discussing driving risk with patients receiving OAT, it seems reasonable to reassure them that driving is not impaired under experimental conditions, while at the same time recognizing that, under real-world conditions, such patients may be more likely to be responsible for a traffic crash. www.aodhealth.org 23

Colfax GN, et al. Arch Gen Psychiatry. 2011;68(11):1168–1175.Plebani JG, et al. Drug Alcohol Depend. 2012;121(1):163–166.Stein MD, et al. Drug Alcohol Depend. 2012;120(1):65–73.Summary by Richard Saitz, MD, MPH Recent Notable Developments in Addiction Pharmacotherapies www.aodhealth.org 24

Objectives/Methods Several recent studies have potentially important implications for practice. 25

Results • In one small randomized trial (Colfax et al.), 60 methamphetamine-dependent men who have sex with men were assigned to mirtazepine or placebo, both added to counseling. Although medication adherence was modest, methamphetamine-positive urine tests were half as frequent among men in the mirtazepine group, who also reported fewer risky sexual behaviors than men in the placebo group. www.aodhealth.org

Results (cont’d) • In another small randomized trial (Plebani et al.), 37 people with cocaine dependence were assigned to varenicline or placebo. All participants received counseling. Those on varenicline were twice as likely to have negative urine tests for cocaine, and they also reported less reward from cocaine use. • In a larger (N=137) randomized placebo-controlled trial (Stein et al.), trazodone had no effect on sleep or drug use among methadone-maintained opioid-dependent patients with sleep complaints. www.aodhealth.org

Comments Despite being early reports and thus inconclusive, the 2 studies among stimulant-dependent patients are important, because pharmacological interventions targeting this group have not been particularly successful. These results hold promise if they can be replicated. Trazodone is often recommended for insomnia in patients with substance dependence because it has little addiction risk, but the study among methadone-maintained patients suggests it may not work. Thus, the search for safe and effective alternatives should continue. www.aodhealth.org 28

Studies on Health Outcomes www.aodhealth.org 29

Modest Marijuana Exposure Does Not Adversely Affect Pulmonary Function, but High Cumulative Exposure Does Pletcher MJ, et al. JAMA. 2012;307(2):173–181. Summary by Hillary Kunins, MD, MPH, MS www.aodhealth.org 30

Objectives/Methods Previous investigations have not shown a consistent impact of marijuana smoking on pulmonary function. Investigators conducted a longitudinal analysis of 5016 adults* enrolled in the CARDIA† study to assess the impact of marijuana exposure on pulmonary function (FEV1 and FVC). *Black/non-Hispanic and white/non-Hispanic men and women aged 18–30 years and healthy at enrollment in 1985. †CARDIA=Coronary Artery Risk Development in Young Adults. www.aodhealth.org

Objectives/Methods (cont’d) Marijuana exposure was assessed at 6 follow-up exams, permitting calculation of “joint-years” (where 365 joints=1 joint-year) and tobacco pack-years. Fifty-six percent of participants (n=2807) attended the 20-year follow-up examination without differential attrition by marijuana use. www.aodhealth.org

Results In adjusted analyses, the association between marijuana use and pulmonary function was nonlinear: at low lifetime exposure, marijuana use was associated with increased FEV1 and FVC. at >7 joint-years, the positive association between marijuana use and pulmonary function leveled off. at >10 joint-years, there was a nonsignificant decline in FEV1. at >20 episodes of marijuana use per month, the decline in FEV1 was significant. www.aodhealth.org 33

Comments The study design and analysis of linearity allowed investigators to elucidate the complex impact of marijuana on pulmonary function: the positive effect of marijuana smoking on FVC (hypothesized to be a “stretching and training” effect) dominated marijuana’s impact on pulmonary function at lower exposures, whereas its negative effect on FEV1 seemed to dominate at higher exposures. Estimating the impact of heavy marijuana use was imprecise because of the low number of heavy users and few non-tobacco users among the heaviest marijuana users. Nevertheless, this study may help define thresholds for riskier marijuana use similar to those defined for alcohol. www.aodhealth.org 34

Wine-specific Mortality Benefits Disappear When Studied Appropriately Holahan CJ, et al. J Stud Alcohol Drugs. 2012;73(1):80–88. Summary by Richard Saitz, MD, MPH www.aodhealth.org 35

Objectives/Methods Some have suggested that wine might be more beneficial to health than other types of alcoholic beverages because of compounds in wine besides alcohol. To test this hypothesis, investigators studied 802 past-month abstainers and drinkers of low-risk (“moderate”) amounts of alcohol (1 to <3 [14 g] drinks per day) age 55–65 years at enrollment. They assessed mortality over 20 years. www.aodhealth.org 36

Results The mortality rate was 69% for abstainers, 50% for low-wine-consumption drinkers (<one-third of alcohol from wine) (adjusted* odds ratio [AOR], 0.67), and 32% for high-wine-consumption drinkers (AOR, 0.59). Although an unadjusted analysis showed a large reduction in mortality associated with high-wine-consumption drinking compared with low-wine-consumption drinking, the difference disappeared after controlling for overall alcohol consumption, socioeconomic and health factors, and health behaviors. *Adjusted for age, gender, income and education, medical diagnoses, smoking, and physical activity. www.aodhealth.org 37

Comments If there is a mortality benefit from drinking, these results suggest beverage type doesn’t matter. But, as is very common in studies examining the potential benefits of drinking, this study tested associations between typical alcohol consumption during 1 month and mortality over 20 years without updating consumption. It also compared drinkers with those who had stopped drinking—a group well known to be less healthy (“sick quitters”). www.aodhealth.org 38

Comments (cont’d) “Moderate” drinkers are well known to be healthier than others—not because of drinking, but because health-conscious people often drink low-risk amounts. The fact that the large benefit of wine consumption disappeared with appropriate statistical adjustment should serve as yet another reminder to use caution concluding that observed associations between drinking and health benefits are causal. It would not be the first time consistent results from numerous observational studies were consistently wrong. www.aodhealth.org 39

Roerecke M, Rehm J. Addiction. January 9, 2012 [Epub ahead of print]. doi: 10.1111/j.1360-0443.2012.03780.x.Summary by Peter D. Friedmann, MD, MPH Thirty Years of Observational Studies of Alcohol’s Cardioprotective Effects: Uncertainty Remains www.aodhealth.org 40

Objectives/Methods This meta-analysis combined 44 observational studies from 1980–2010 that reported a relative risk for ischemic heart disease (IHD) in relation to average alcohol intake. www.aodhealth.org 41

Results • The well-known J-shaped curve was confirmed (i.e., compared with abstainers, IHD risk is lower in people with low-level alcohol consumption but rises with increasing consumption). • The maximum cardioprotective effects for mortality occurred between 32–63 g alcohol* per day for men and between 11–31 g per day for women. • The effects were heterogeneous, even at low levels of intake. *One standard drink averaged to 12 g pure alcohol in this study. www.aodhealth.org 42

Comments Although this study reaffirms the population-level association between low-level alcohol intake and reduced cardiovascular morbidity and mortality, the high level of heterogeneity means it is very difficult for clinicians to make inferences about individual patients. Some people benefit from low-level drinking while others are harmed, and we cannot differentiate these groups. www.aodhealth.org 43

Comments (cont’d) Furthermore, meta-analysis of even a large number of studies does not eliminate the possibility that residual confounding could explain the findings (e.g., IHD was reduced because of better risk-factor profiles among those who drink low-level amounts). Although advising patients about lower risk drinking limits is the current standard of practice, considerable uncertainty remains about what constitutes a safe level of consumption, and for whom. www.aodhealth.org 44

Lifestyle and Environmental Factors, Including Tobacco and Alcohol Use, and Risk of Cancer Parkin DM, et al. Br J Cancer. 2011;105(Suppl 2):S77–S81. Summary by R. Curtis Ellison, MD www.aodhealth.org 45

Objectives/Methods Researchers estimated the fraction of cancers occurring in the UK in 2010 that could be attributed to exposure to 14 lifestyle and environmental risk factors: tobacco; alcohol; diet (meat, fruit, vegetable, fiber, and salt consumption); overweight; lack of exercise; occupation; infection; radiation (ionizing and solar); hormone use; and breastfeeding. www.aodhealth.org 46

Results Exposure to less-than-optimum levels of the 14 risk factors was responsible for 45.3% of cancers in men and 40.1% of cancers in women (a total of about 134,000 cases). Of the lifestyle factors studied, tobacco smoking had the largest effect on the risk of cancer, responsible for 19.4% of all new cases. www.aodhealth.org 47

Results (cont’d) In men, deficient intake of fruits and vegetables (6.1%), occupational exposures (4.9%), and alcohol consumption (4.6%) had the next largest effects on risk. In women, overweight or obesity (because of the association with breast cancer) (6.9%) and infectious-agent exposure (3.7%) had the next largest effects on risk. www.aodhealth.org 48

Comments In this well-done analysis, smoking had, by far, the largest effect on cancer risk, while 4 percent of all cancer cases were attributable to alcohol intake (compared with abstaining). Although the use in this analysis of abstinence as the optimal level of alcohol consumption related to cancer risk may be reasonable, it would not be the case for cardiovascular diseases or total mortality. www.aodhealth.org 49

Comments (cont’d) Furthermore, the analysis did not examine levels of alcohol use, an important point since alcohol-related cancer risk may relate to consumption amounts. The effects related to diet may have been overestimated as well, as the values used in this analysis were much greater than those seen in most studies. Nevertheless, the results highlight the importance of targeting certain behaviors to reduce cancer risk. www.aodhealth.org 50

Update on Alcohol, Other Drugs, and Health