Human Laboratory Studies

Preoccupation/Anticipation Stage

For the preoccupation/anticipation stage, three major external factors and two internal factors are hypothesized to contribute to relapse. The external factors include priming doses of drug, drug-associated cues, and stressor exposure. The internal factors include the malaise of protracted abstinence and a state of stress associated with protracted abstinence that contributes to malaise. Several human laboratory procedures have been developed to reflect these aspects of the preoccupation/anticipation stage. Drug reinstatement has been developed in human laboratory models, notably in the realm of alcohol and tobacco addiction. Priming-induced drinking in alcohol-dependent subjects in a bar-like setting was greater than in social drinkers and was selectively decreased in the alcohol-dependent groups by opioid receptor antagonists. Similar results were observed in family history-positive alcohol-dependent individuals who received a priming dose of alcohol and in cigarette smokers who were primed with five cigarettes. Exposure to alcohol cues, such as the sight or smell of alcoholic beverages, using the cue reactivity paradigm reliably increases the urge to drink alcohol, salivation, and attention to cues. Cue reactivity can also predict treatment outcome and has been validated in some cases by the use of medications that successfully treat alcoholism. For example, naltrexone, but not topiramate, blocked cue reactivity in alcohol-dependent subjects, and nicotine replacement therapy decreased craving associated with smoking cues.

Stress responses, including changes in the activity of the hypothalamic–pituitary–adrenal stress axis and extrahypothalamic brain stress systems, impact all phases of the addiction cycle but may be particularly relevant to the withdrawal/negative affect and preoccupation/anticipation stages. Stress and stressors have also been associated with relapse and the vulnerability to relapse. Negative affect, stress, and withdrawal-related distress increase drug craving. Both stress and drugs of abuse activate the hypothalamic-pituitary-adrenal axis, but the glucocorticoid steroid hormone response becomes blunted with chronic high-dose drug use. High glucocorticoid tone can then drive the brain stress systems in the amygdala. As noted above, a cascade of stress hormone interactions occurs with drugs of abuse, leading to sensitization of stress-induced relapse. All of these changes may be amenable to studies in the human laboratory setting.

Stress-related responses and stress-induced craving can be elicited in addicted individuals using models of stress-induced responsivity with emotional imagery paradigms. Using such emotional imagery paradigms, individuals who administer higher amounts of cocaine and alcohol each week and recovering alcohol-dependent subjects show greater craving and physiological responses to stressors compared with social drinkers. From a validation perspective, stress-induced cocaine craving in the laboratory can predict the time to cocaine relapse. Similar results have been found in alcohol- and nicotine-dependent subjects.

Another approach to cue reactivity that has been developed for the study of craving in alcoholism during protracted abstinence is exploring the interaction between cue exposure and emotional states during protracted abstinence (for further reading, see Mason et al., 2009). A nontreatment-seeking sample of alcohol-dependent subjects was exposed to affective stimuli that had positive or negative valence and then to a beverage cue but with no opportunity to self-administer alcohol. Cue reactivity was measured using subjective measures of craving, measures of emotional reactivity, and psychophysiological measures, including heart rate, skin conductance, and facial electromyography. Alcohol exposure and both positive and negative emotional cues had the expected effects on subjective and emotional reactivity but fewer effects on psychophysiological measures. Gabapentin significantly decreased subjective craving and affectively evoked craving and improved several measures of sleep quality. These results suggest that cue reactivity, combined with an emotional overlay, may provide a powerful means of evaluating potential medications for addiction treatment. Gabapentin has been subsequently shown to significantly increase rates of abstinence and no heavy drinking in a double-blind placebo-controlled trial (for further reading, see Mason et al., 2013).

From a perspective that is different from studies that investigate how to precipitate relapse in humans, researchers can measure the resistance to relapse. A model termed “smoking lapse behavior” allows the measurement of two critical features of relapse: the ability to resist the first cigarette and subsequent smoking behavior (for further reading, see McKee, 2009). Nicotine-dependent subjects are first exposed to stimuli that can precipitate smoking relapse, such as alcohol, stress, and nicotine deprivation, and then their ability to resist smoking when presented with their preferred brand of cigarettes is measured. This model still needs to be validated with existing anti-craving medications, but it provides an intriguing extension of cue reactivity that may be useful as an intermediary step between preclinical animal models and clinical trials.

An evolving area in human laboratory relapse models is the measurement of neural correlates of cues for relapse using brain imaging studies, in which increased functional brain activation elicited by drug-associated cues may predict increased relapse risk. Cue-induced functional activation of the brain can be assessed by measuring changes in cerebral blood flow with positron emission tomography or single-photon emission computed tomography or measuring blood flow combined with functional magnetic resonance imaging. Core regions activated in most studies include the anterior cingulate, orbitofrontal cortex, basolateral amygdala, ventral striatum, and dorsal striatum. Strong cue-induced activation of similar regions, including the ventral striatum, dorsal striatum, medial prefrontal cortex, and anterior cingulate, has been observed in alcohol-dependent subjects who experience multiple relapses. Reduced functional activation of the ventral striatum in response to cues that signal nondrug rewards was observed in individuals with alcoholism, suggesting a shift in the incentive salience of drug-related cues. Thus, imaging studies may provide unique insights into subjects who exhibit the most dramatic functional activation to cues and, by extrapolation, who are more likely to relapse. Future studies can explore pharmacotherapeutic approaches to normalize such cue-induced responses and whether such measures will predict therapeutic efficacy in treatment (for further reading, see Fowler et al., 2007).

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