ABSTRACT. Modern pharmacotherapy for alcohol dependence has its roots in the failure of National Prohibition in the United States and the rise of the disease model of alcoholism (embodied in Alcoholics Anonymous). In 1948, disulfi ram was the fi rst medication approved by the U.S. Food and Drug Administration (FDA) to treat alcohol dependence, but its effi cacy has not been supported by randomized controlled trials. In the 1960s, benzodiazepines replaced older treatments for alcohol withdrawal, but sedative and dependence-producing effects limit their utility in the postwithdrawal period. In the 1980s, the focus shifted to the treatment of co-occurring psychiatric disorders and medications that modify negative mood states, which contribute to relapse to heavy drinking. In the 1990s, developments in neurobiology implicated specifi c neurotransmitter systems underlying alcohol's effects, culminating in the 1994 approval by the FDA of the opioid antagonist naltrexone to treat alcohol dependence. In 2006, the FDA approved a long-acting formulation of naltrexone. Recently, nalmefene, another opioid receptor antagonist, was approved in Europe for as-needed use to reduce heavy drinking. Acamprosate, an amino acid derivative, fi rst approved in France in 1989, received FDA approval in 2004. However, the benefi cial effects of the approved medications are only modestly greater than those of placebo, and their use is limited. Topiramate, currently under investigation for alcohol dependence, has greater effi cacy but a variety of adverse effects. In addition to the identifi cation of novel compounds, the future of alcohol dependence pharmacotherapy will depend on developments in pharmacogenetics, in which genetic variation that moderates treatment effi cacy and adverse effects is used to personalize treatment. (J. Stud.

ABSTRACT. Modern pharmacotherapy for alcohol dependence has its roots in the failure of National Prohibition in the United States and the rise of the disease model of alcoholism (embodied in Alcoholics Anonymous). In 1948, disulfi ram was the fi rst medication approved by the U.S. Food and Drug Administration (FDA) to treat alcohol dependence, but its effi cacy has not been supported by randomized controlled trials. In the 1960s, benzodiazepines replaced older treatments for alcohol withdrawal, but sedative and dependence-producing effects limit their utility in the postwithdrawal period. In the 1980s, the focus shifted to the treatment of co-occurring psychiatric disorders and medications that modify negative mood states, which contribute to relapse to heavy drinking. In the 1990s, developments in neurobiology implicated specifi c neurotransmitter systems underlying alcohol's effects, culminating in the 1994 approval by the FDA of the opioid antagonist naltrexone to treat alcohol dependence. In 2006, the FDA approved a long-acting formulation of naltrexone. Recently, nalmefene, another opioid receptor antagonist, was approved in Europe for as-needed use to reduce heavy drinking. Acamprosate, an amino acid derivative, fi rst approved in France in 1989, received FDA approval in 2004. However, the benefi cial effects of the approved medications are only modestly greater than those of placebo, and their use is limited. Topiramate, currently under investigation for alcohol dependence, has greater effi cacy but a variety of adverse effects. In addition to the identifi cation of novel compounds, the future of alcohol dependence pharmacotherapy will depend on developments in pharmacogenetics, in which genetic variation that moderates treatment effi cacy and adverse effects is used to personalize treatment. (J. Stud.

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Introduction Pregnant women exposed chronically to opioids smoked more cigarettes per day (CPD) and had a higher nicotine metabolite ratio (NMR), 3-hydroxycotinine/cotinine, a biomarker of nicotine metabolism and clearance, than those not receiving opioids. We examined CPD and NMR in a group of pregnant smokers, a quarter of whom were receiving opioid agonist therapy (OAT). Aims and Methods Pregnant smokers recruited to participate in a placebo-controlled trial of bupropion for smoking cessation provided a blood sample for measurement of NMR. Results Half (52.4%) of the 124 women with NMR data were African American. OAT-treated women (n = 34, 27.4%; 27 receiving methadone and 7 buprenorphine) were more likely to be white (79% vs. 30%, p < .001) and to have a lower mean PHQ-9 total score (2.91 [SD = 2.83] vs. 4.83 [SD = 3.82], p = .007). OAT-treated women reported smoking more CPD (9.50 [SD = 5.26] vs. 7.20 [SD = 3.65], p = .005) and had higher NMR (0.78 [SD = 0.36] vs. 0.56 [SD = 0.25], p = .001) than the non-OAT-treated group. In a linear regression analysis adjusting for race, depression severity, and CPD, NMR was greater in the OAT group (p = .025), among whom the daily methadone-equivalent dosage correlated with NMR (Spearman’s ρ = 0.49, p = .003). Conclusions Consistent with the findings of Oncken et al. (2019), we found that OAT smokers smoked more and had higher NMR than non-OAT smokers. As higher NMR is associated with a reduced likelihood of smoking cessation, the effects on NMR of both pregnancy and OAT could contribute to a lower smoking cessation rate in pregnant smokers receiving chronic opioid therapy. Implications We replicated the finding that the NMR is significantly greater among pregnant smokers receiving OAT than those not receiving this treatment for opioid use disorder. Furthermore, we found that the dosage of the OAT was significantly associated with the NMR level. These findings may contribute to a poorer response to smoking cessation treatment in pregnant women treated with OAT, particularly those receiving high-dose therapy, and raise the question of whether novel approaches are needed to treat smoking in this subgroup of pregnant smokers.

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