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. 2011 Sep;68(9):942-52.
doi: 10.1001/archgenpsychiatry.2011.49. Epub 2011 May 2.

Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes

Rajita Sinha  1 , Helen C Fox, Kwang-Ik Adam Hong, Julie Hansen, Keri Tuit, Mary Jeanne Kreek
Affiliations

Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes

Rajita Sinha et al. Arch Gen Psychiatry. 2011 Sep.

Abstract

Context: Alcoholism is a chronic, relapsing illness in which stress and alcohol cues contribute significantly to relapse risk. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased anxiety, and high alcohol craving have been documented during early alcohol recovery, but their influence on relapse risk has not been well studied.

Objectives: To investigate these responses in treatment-engaged, 1-month-abstinent, recovering alcohol-dependent patients relative to matched controls (study 1) and to assess whether HPA axis function, anxiety, and craving responses are predictive of subsequent alcohol relapse and treatment outcome (study 2).

Design: Experimental exposure to stress, alcohol cues, and neutral, relaxing context to provoke alcohol craving, anxiety, and HPA axis responses (corticotropin and cortisol levels and cortisol to corticotropin ratio) and a prospective 90-day follow-up outcome design to assess alcohol relapse and aftercare treatment outcomes.

Setting: Inpatient treatment in a community mental health center and hospital-based research unit.

Participants: Treatment-engaged alcohol-dependent individuals and healthy controls.

Main outcome measures: Time to alcohol relapse and to heavy drinking relapse.

Results: Significant HPA axis dysregulation, marked by higher basal corticotropin level and lack of stress- and cue-induced corticotropin and cortisol responses, higher anxiety, and greater stress- and cue-induced alcohol craving, was seen in the alcohol-dependent patients vs the control group. Stress- and cue-induced anxiety and stress-induced alcohol craving were associated with fewer days in aftercare alcohol treatment. High provoked alcohol craving to both stress and to cues and greater neutral, relaxed-state cortisol to corticotropin ratio (adrenal sensitivity) were each predictive of shorter time to alcohol relapse.

Conclusions: These results identify a significant effect of high adrenal sensitivity, anxiety, and increased stress- and cue-induced alcohol craving on subsequent alcohol relapse and treatment outcomes. Findings suggest that new treatments that decrease adrenal sensitivity, stress- and cue-induced alcohol craving, and anxiety could be beneficial in improving alcohol relapse outcomes.

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Figures

Figure 1
Figure 1
Schedule of procedures is shown for the alcohol-dependent (AD) and healthy control (HC) samples in study 1 and study 2. Alcohol-dependent patients were 1-month abstinent and in inpatient treatment prior to the laboratory sessions, and controls were assessed during a 3-night research hospital stay. Alcohol-dependent patients were prospectively followed up posttreatment and participated in face-to-face interviews at 14, 30, and 90 days after discharge from inpatient treatment to assess alcohol relapse and treatment outcomes.
Figure 2
Figure 2
Study 1: mean (SEM) anxiety responses (visual analog scale: 0-10 points) to neutral, relaxing; stress; and alcohol cue exposure at baseline, immediately following imagery (0 minutes), and at 5, 15, 30, 45, 60, and 75 minutes in healthy controls (HC) and alcohol-dependent (AD) patients. Alcohol-dependent patients showed higher anxiety in the neutral, relaxing condition (P<.03) and in the alcohol cue condition (P<.001), but not the stress condition, relative to the control group. Both groups showed significant increases in anxiety levels in response to stress relative to the neutral condition (P’s<.001), validating the experimental manipulation, and the AD group showed significantly greater anxiety in the alcohol cue condition relative to the neutral condition (P<.001), but the control group showed no such increases. The AD patients had higher anxiety across conditions relative to controls (P<.03).
Figure 3
Figure 3
Study 1: mean (SEM) alcohol craving (visual analog scale: 0-10 points) responses to neutral, relaxing; stress; and alcohol cue exposure at baseline, immediately following imagery (0 minutes), and at 5, 15, 30, 45, 60, and 75 minutes in healthy controls (HC) and alcohol-dependent (AD) individuals. The AD group showed higher alcohol craving in the stress (P<.001) and the alcohol cue (P<.001) conditions than the control group. Both groups showed significant increases in alcohol craving in responses to alcohol cues (AD: P<.001; HC: P<.03), but only the AD group showed significantly greater alcohol craving in responses to stress (P<.001) relative to the neutral condition, and the control group showed no such increases.
Figure 4
Figure 4
Study 1: baseline-adjusted corticotropin and cortisol mean (SEM) responses to the stress (S), alcohol cue (C), and neutral, relaxing (N) conditions. A, Baseline-adjusted corticotropin responses show an effect of condition, with S greater than N (P<.02) and with group differences in these effects (healthy controls [HC]: S>N [P<.001] and S>C [P<.007]; alcohol-dependent [AD] patients: no differences across conditions; AD>HC in response of N [P<.01]). B, Baseline-adjusted plasma cortisol responses to S, C, and N imagery averaged across time indicated condition effects showing S greater than N (P<.003) and C greater than N (P<.001), but effects varied by group (HC: S>N [P<.001] and C>N [P<.001]; AD patients: C>N [P<.02] and no differences in S vs N). (Controls showed an increased response in S and C relative to N despite the diurnal drop in corticotropin and cortisol levels due to the circadian rhythm.)
Figure 5
Figure 5
Study 2: after holding covariates constant, estimated survival risk functions are shown for alcohol craving values for the mean (in red) and at 1, 2, and 3 SDs above the mean and at minimal craving levels (0 and 0.5) for stress-induced alcohol craving (S_CRV) (A) (χ2=4.37; P<.04; hazard ratio=1.15; 95% confidence interval, 1.01-1.31) and alcohol cue-induced craving (C_CRV) (B) (χ2=4.82; P<.03; hazard ratio=1.16, 95% confidence interval, 1.02-1.32). The proportion surviving 90-day relapse is shown on the y-axis and the time during the 90-day period when relapse occurred is shown on the x-axis. Hence, the estimated survival function at day 80 spans a 0.35 (35%) and 0.38 (38%) proportion of surviving relapse for those with an S_CRV and a C_CRV of 0, respectively, while there is only a 0.02 (0.02%) proportional chance of surviving relapse for those at 3 SDs above the mean in S_CRV and C_CRV, respectively. Note: survival functions are cut off at day 80 instead of extending to day 90 because all alcohol-dependent patients with predictor values 3 SDs above the mean had relapsed by day 80.
Figure 6
Figure 6
Study 2: after holding covariates constant, estimated survival risk functions are shown for neutral, relaxing-condition cortisol to corticotropin ratio (N_C:C ratio) (adrenal sensitivity) values for the mean (in red) and at 1, 2, and 3 SDs above the mean and at minimal ratio values (0.1 and 0.05) for N_C:C ratio predicting time to alcohol relapse (A) (χ2=7.38; P<.007; hazard ratio=2.12; 95% confidence interval, 1.23-3.63) and time to heavy drinking alcohol relapse (B) (χ2=10.4; P<.001; hazard ratio=2.55; 95% confidence interval, 1.29-4.1). The proportion surviving 90-day relapse is shown on the y-axis and the time during the 90-day period when relapse occurred is shown on the x-axis. Hence, the estimated survival function at day 80 spans a 0.40 (40%) proportion surviving relapse and 0.48 (48%) surviving heavy drinking relapse for cortisol to corticotropin ratios at 0.05, respectively, while there is only a 0.02 (0.02%) proportional chance of surviving relapse and heavy drinking relapse for those at 3 SDs above the mean in N_C:C ratio. Note: survival functions are cut off at day 80 instead of extending to day 90 because all alcohol-dependent patients with predictor values 3 SDs above the mean had relapsed by day 80.
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