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Unexpectedly, the combination did not offer any advantage over either treatment alone. This study aimed to explain the lack of incremental benefit offered by the combination over either monotherapy by assessing the role of cravings as a treatment mediator and moderator.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Secondary mediation and moderation analyses of<jats:styled-content style=\"fixed-case\">COMBINE<\/jats:styled-content>study data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Eleven<jats:styled-content style=\"fixed-case\">U<\/jats:styled-content>nited<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>tates academic sites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>A total of 863 patients randomized to one of four treatment groups: naltrexone (100\u2009mg\/day;<jats:italic>n<\/jats:italic>\u2009=\u2009209), the combined behavioral intervention (<jats:styled-content style=\"fixed-case\">CBI<\/jats:styled-content>,<jats:italic>n<\/jats:italic>\u2009=\u2009236), naltrexone and<jats:styled-content style=\"fixed-case\">CBI<\/jats:styled-content>combined (<jats:italic>n<\/jats:italic>\u2009=\u2009213) and placebo naltrexone (<jats:italic>n<\/jats:italic>\u2009=\u2009205).<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>ercentage of days abstinent (<jats:styled-content style=\"fixed-case\">PDA<\/jats:styled-content>) measured between 13 and 16 weeks post\u2010baseline. Cravings, the potential mediator\/moderator, were measured at baseline, weeks 4 and 12 using the<jats:styled-content style=\"fixed-case\">O<\/jats:styled-content>bsessive\u2010<jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>ompulsive<jats:styled-content style=\"fixed-case\">D<\/jats:styled-content>rinking<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>cale.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>Compared with placebo, naltrexone,<jats:styled-content style=\"fixed-case\">CBI<\/jats:styled-content>and the combination all increased<jats:styled-content style=\"fixed-case\">PDA<\/jats:styled-content>by an additional 6\u201310 percentage points for those with high cravings (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05 for all three treatment groups). None had significant effects on<jats:styled-content style=\"fixed-case\">PDA<\/jats:styled-content>for those with low cravings. The effects of all three treatments were mediated at least partially by cravings; craving reduction explained 48\u201353% of treatment effects (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05 for all three treatment groups). Furthermore, naltrexone appeared to reduce cravings at 4 weeks, while<jats:styled-content style=\"fixed-case\">CBI<\/jats:styled-content>did not reduce cravings until 12 weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The<jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>ombining<jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>edications and<jats:styled-content style=\"fixed-case\">B<\/jats:styled-content>ehavioral<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content>nterventions for<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lcoholism (<jats:styled-content style=\"fixed-case\">COMBINE<\/jats:styled-content>) naltrexone\u2009+\u2009CBI combination may not be more beneficial than either monotherapy because craving reduction is a common mechanism of both.<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.12238","type":"journal-article","created":{"date-parts":[[2013,5,14]],"date-time":"2013-05-14T11:23:31Z","timestamp":1368530611000},"page":"1737-1744","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Cravings as a mediator and moderator of drinking outcomes in the<scp>COMBINE<\/scp>study"],"prefix":"10.1111","volume":"108","author":[{"given":"Meenakshi Sabina","family":"Subbaraman","sequence":"first","affiliation":[{"name":"Division of Epidemiology UC Berkeley School of Public Health Berkeley CA USA"},{"name":"Alcohol Research Group Emeryville CA USA"},{"name":"Department of Behavioral and Social Sciences Center for Alcohol and Addiction Studies Brown University Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Lendle","sequence":"additional","affiliation":[{"name":"Division of Biostatistics UC Berkeley School of Public Health Berkeley CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"van der Laan","sequence":"additional","affiliation":[{"name":"Division of Biostatistics UC Berkeley School of Public Health Berkeley CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee Ann","family":"Kaskutas","sequence":"additional","affiliation":[{"name":"Division of Epidemiology UC Berkeley School of Public Health Berkeley CA USA"},{"name":"Alcohol Research Group Emeryville CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Ahern","sequence":"additional","affiliation":[{"name":"Division of Epidemiology UC Berkeley School of Public Health Berkeley CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,6,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.156.11.1758"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2006.02.001"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.jcp.0000248604.58305.b3"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.295.17.2003"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1360-0443.2008.02162.x"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1360-0443.2007.02073.x"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2003.tb02873.x"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1992.01820110045007"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1992.01820110040006"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.152.4.613"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1037\/0022-006X.64.5.1044"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/105504901750532148"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1996.01830030039007"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1037\/0022-3514.51.6.1173"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.15288\/jsas.2005.s15.110"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addbeh.2004.12.011"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0022282"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1360-0443.95.8s2.10.x"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/agh073"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1996.01830030047008"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-9782-1"},{"key":"e_1_2_6_23_1","doi-asserted-by":"crossref","unstructured":"GruberS. van der LaanM.tmle: Targeted Maximum Likelihood Estimation of Point Treatment Effects. 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