1 Department of Addictive Behaviour and Addiction Medicine, Departments of
2 Clinical Psychology and
3 Biostatistics, Central Institute of Mental Health, Mannheim and
4 Department of Psychiatry of the Charité, Humboldt University, Berlin, Germany
Received 31 December 2001; in revised form 11 June 2002; accepted 28 June 2002
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ABSTRACT |
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INTRODUCTION |
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An alternative hypothesis suggests that alcohol craving is induced by the mood-enhancing, positive-reinforcing effects of alcohol and drug intake (Stewart et al., 1984; Wise, 1988
; Koob and Le Moal, 1997
). Craving for the rewarding effects of alcohol can be mediated by opioidergic and dopaminergic neurotransmission in the ventral striatum (Spanagel et al., 1992
; Di Chiara, 1995
; Volpicelli et al., 1995
). Associative learning may transform positive mood states and previously neutral environmental stimuli into alcohol-associated cues that acquire positive motivational salience and induce reward craving (Robinson and Berridge, 1993
). Among alcoholics, the appetitive character of alcohol-associated visual stimuli was indicated by an attenuation of the eyeblink startle response (Mucha et al., 2000
; Grüsser et al., 2002
). The motivational effects of positive mood states and external alcohol-associated cues on alcohol craving and consumption may be blocked by naltrexone (Monti et al., 1999
).
Anton et al. (1996) constructed the Obsessive Compulsive Drinking Scale (OCDS) which focuses on obsessivecompulsive aspects of alcohol craving. A factor analysis revealed that three factors contribute to alcohol craving as assessed with the OCDS: control impairment, obsession and interference. Obsession describes the distress or anxiety caused by a preoccupation with alcohol-associated ideas or impulses, control impairment the lack of success in the control of alcohol intake, and interference the degree of interference with social or work functioning (Roberts et al., 1999
). Naltrexone medication was associated with reduced scores for control impairment but not the other two craving factors (Roberts et al., 1999
). Recently, Verheul et al. (1999)
suggested that reward craving, withdrawal relief craving and obsessive craving are not mutually exclusive concepts, but, rather, describe different types of alcohol craving with distinguishable neurobiological correlates. The individual response to naltrexone or acamprosate medication may depend upon the relative strength of the respective alcohol craving type and its neurobiological foundation.
For the clinical identification of alcohol craving types, we measured different aspects of alcohol craving with the Obsessive Compulsive Drinking Scale (Anton et al., 1996). We tested the hypothesis of Verheul et al. (1999)
that subjects who crave for the rewarding effects of alcohol mainly consume alcohol in emotionally positive situations and show appetitive responses to alcohol cues, whereas subjects suffering from withdrawal relief craving drink mainly in negative situations and report unpleasant, withdrawal-like symptoms preceding alcohol intake. We also tested the hypothesis that negative mood states and conditioned withdrawal contribute to distressful obsessive alcohol craving (factor obsession in the OCDS) and that appetitive reactions to alcohol cues and drinking in positive situations contribute to control impairment and interference with social and work functioning.
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SUBJECTS AND METHODS |
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Psychophysiological assessment
The appetitive or aversive nature of alcohol-associated cues was measured with the affectively modulated eyeblink startle response (Lang et al., 1990). A potentiation of the startle response by the induction of negative mood states and an attenuation of the startle response by positive mood states have been widely described in studies among healthy volunteers and patients with different neuropsychiatric disorders (Vrana et al., 1988
; Bradley et al., 1990
; Cook et al., 1992
). In alcoholics, two studies reported an attenuation of the startle response during the presentation of alcohol-associated stimuli, compared with emotionally negative and neutral stimuli (Mucha et al., 2000
; Grüsser et al., 2002
).
Eight slides showing alcoholic beverages were randomly presented along with eight neutral, eight unpleasant and eight pleasant objects and 30 startle probes. The pleasant, unpleasant and neutral pictures were taken from the International Affective Picture System (IAPS; Lang, 1995) and were separately selected for male and female subjects. Pleasant, unpleasant, neutral and alcohol-associated stimuli were matched for arousal ratings; valence and arousal data were taken from the IAPS and controlled for in our patient sample. Alcohol craving was rated with the OCDS immediately before picture presentation.
The subjects were first prepared for recording from the left orbicularis oculi. To evoke the startle eyeblink response, white noise was presented via headphones with 95 dB while the subjects viewed the visual stimuli (Geier et al., 2000). Visual stimuli were presented for 7.5 s at intervals of 21 s on a high-resolution monitor (35.8 cm) of an Acer travelmate (7100TE) laptop placed 0.5 m in front of the subject. The startle probe was a 50 ms burst of white noise delivered over headphones on average 4 s after picture onset. The muscle activity was stored for off-line analysis (Geier et al., 2000
), and the startle amplitude (peak activity) was used as the outcome measure. The startle response was standardized with a z-transformation with respect to intra-subject baseline level and variability to correct for varying signal quality.
Statistical analysis
In the confirmatory part of the statistical analysis of the results of the present study, the t-statistic for paired observations was used to decide whether the data contain sufficient evidence in favour of the following (alternative) hypotheses: (1) the startle response elicited during the presentation of alcohol-associated cues is reduced, compared with the response during the presentation of affectively negative cues (Grüsser et al., 2002); (2) the startle response elicited during the presentation of alcohol-associated cues is reduced compared with the response during the presentation of affectively neutral cues (Mucha et al., 2000
; Grüsser et al., 2002
); (3) the startle response during the presentation of alcohol-associated cues is similar to the response to affectively positive stimuli among alcoholics (Grüsser et al., 2002
). In order to keep the multiple type-I error risk <5%, the sequentially rejective procedure of Holm (1979)
was applied. Accordingly, any of the significance statements made in the Results section refers to an experiment- rather than comparison-wise type-I error risk bounded by 5%. Since the first two individual hypotheses are uni- rather than bilateral, both corresponding tests were performed in a one-sided manner. Furthermore, hypothesis 3 states equivalence of alcohol-associated and affectively positive stimuli. Hence, a testing procedure appropriate for the latter is the paired t-test for equivalence as described by Wellek (2002)
. In this approach, equivalence is defined through the standardized difference
/
D of the two means under assessment. The equivalence range for
/
D was specified (-0.5, 0.5), and the P-value computed from the non-central F-distribution with 1, n - 1 degrees of freedom and non-centrality parameter 0.25n.
At the exploratory level, the following additional analyses were performed. The correlation between (1) the startle response to alcohol cues and alcohol consumption in emotionally positive situations and (2) the severity of withdrawal-like symptoms before alcohol intake and emotionally negative drinking situations was measured by means of the ordinary product-moment correlation coefficient. Finally, linear multiple regression techniques were used to assess the association of: (1) the startle response to alcohol cues; (2) alcohol consumption during positive mood states; (3) negative mood states; (4) withdrawal-like symptoms, with the craving factors obsession, control impairment and interference (Roberts et al., 1999).
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RESULTS |
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In a multiple linear regression analysis, appetitive responses to alcohol-associated cues, alcohol consumption during positive and negative mood states, and withdrawal-like symptoms explained 52% of the variance of the craving factor obsession. The severity of withdrawal-like symptoms that precede alcohol intake (CIWA score) was the only factor that substantially contributed to explaining the variance of obsessive craving (ß' = 0.59, rpart = 0.59, descriptive P < 0.005); post-hoc analysis showed that, in most patients, symptoms such as paroxysmal sweats (r = 0.58, descriptive P = 0.001) and auditory disturbances (r = 0.55, descriptive P = 0.001) contributed to this association, whereas patients hardly ever reported agitation (r = 0.12; descriptive P = 0.5) or anxiety (r = 0.20; descriptive P = 0.3).
Drinking in positive (ß' = 0.21, rpart = 0.18, descriptive P = 0.4) and negative situations (ß' = 0.02, rpart = 0.02, descriptive P = 0.9) and appetitive responses to alcohol-associated cues (ß' = -0.04, rpart = -0.04, descriptive P = 0.8) proved to be of little, if any, relevance for predicting the intensity of obsessive alcohol craving.
Interference with social and work functioning was also explained to a relevant extent by the factors of appetitive responses to alcohol-associated cues, alcohol consumption during positive and negative mood states, and withdrawal-like symptoms (r2 = 44%). Alcohol consumption in positive mood states was the only factor which showed some association with interference (ß' = 0.61, partial rpart = 0.44, descriptive P < 0.05). Neither drinking in negative situations (ß' = -0.07, rpart = -0.07, descriptive P = 0.8) nor appetitive responses to alcohol-associated cues (ß' = 0.15, rpart = 0.17, descriptive P = 0.5) or withdrawal-like symptoms preceding alcohol intake (ß' = 0.02, rpart = 0.02, descriptive P = 0.9) could be used to explain a substantial proportion of the variance of the interference of alcohol intake with social and work functioning. Finally, in a linear model relating control impairment to all four covariables taken into account, only r2 = 29% of the variance of the dependent variable could be explained by the regression function.
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DISCUSSION |
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We used the CIWA score (Sullivan et al., 1989) to assess the severity of withdrawal symptoms that precede alcohol intake. This score was developed for observer rating of acute withdrawal severity and the use of this score as a retrospective instrument for the assessment of withdrawal symptoms is purely exploratory. Moreover, some items of this scale rate symptoms which are also found in anxiety or agitation. Conditioned withdrawal may be accompanied by anxiety and anxiety may be misinterpreted by alcohol-dependent subjects as a sign of withdrawal (Cooney et al., 1997
; Verheul et al., 1999
); therefore, it may be extremely difficult to separate effects of anxiety from conditioned withdrawal. However, in this study, the items in the CIWA score which mainly contributed to the association with obsessive craving were paroxysmal sweats and auditory disturbances and not those such as agitation or anxiety, which may reflect anxiety disorders, rather than conditioned withdrawal. Given the lack of standardized assessment procedures for conditioned withdrawal, the modification of established withdrawal scores may offer a viable way to measure conditioned compensatory responses (Siegel, 1983
) in alcoholism and their association with drinking situations.
The craving factor obsession in the OCDS (Anton et al., 1996) was associated with anxiety and distressful preoccupation with alcohol-related ideas and impulses (Roberts et al., 1999
). Therefore, we hypothesized that withdrawal relief craving and drinking in negative situations contribute to this craving factor. This was confirmed for withdrawal relief craving, but not drinking in negative situations, confirming the observation that withdrawal relief craving is not exclusively associated with alcohol intake during negative mood states.
The craving factor of control impairment decreases under naltrexone medication (Roberts et al., 1999), which blocks opioid receptors and inhibits pleasant emotions evoked by alcohol intake (Volpicelli et al., 1995
). Therefore, we hypothesized that appetitive responses to alcohol-associated cues and drinking in positive situations may contribute to this craving factor, and that reward craving elicited by appetitive alcohol cues and positive mood states may also induce interference with social and work functioning. Contrary to our hypotheses, drinking in positive situations and appetitive reactions to alcohol cues contributed to the craving factor interference but not to control impairment. Both craving factors are derived from the OCDS and may not adequately reflect the concept of reward craving (Verheul et al., 1999
). In any case, alcohol consumption in positive situations was associated with problems of role functioning, reflected in the craving factor interference of the OCDS.
In summary, our study supports the notion of different pathways leading to different types of alcohol craving (Niaura et al., 1988; Verheul et al., 1999
). We observed a correlation between appetitive reactions to alcohol cues and drinking in positive situations, which contributed to the impairment of social and work functioning. Withdrawal-like symptoms that precede alcohol intake contributed to obsessive alcohol craving, a distressful preoccupation with alcohol-related ideas and impulses to consume alcohol. Contrary to our hypotheses, withdrawal-like symptoms correlated not only with drinking in negative, but also positive, situations, indicating that conditioned withdrawal may be primarily associated with hedonic dysregulation, rather than the obsessivecompulsive aspects of alcohol craving per se. We used an exploratory method to assess withdrawal relief craving, namely the self-reported occurrence of withdrawal-like symptoms, which regularly precede alcohol intake. Conditioned alcohol-opposite psychophysiological responses may be better-suited to measure the severity of conditioned withdrawal; however, this approach is limited by the fact that alcohol-like and withdrawallike psychophysiological reactions overlap clinically (Niaura et al., 1988
). The assessment of drinking situations and of appetitive and withdrawal-like reactions to alcohol in association with neuroimaging (Volkow et al., 1996
; Heinz et al., 1998
; Braus et al., 2001
) may be best suited to further explore the neurobiological pathways associated with different craving types and to select the appropriate anti-craving medication.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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