Helen C. Fox

Enhanced Negative Emotion and Alcohol Craving, and Altered Physiological Responses Following Stress and Cue Exposure in Alcohol Dependent Individuals

Chronic alcohol abuse is associated with changes in stress and reward pathways that could alter vulnerability to emotional stress and alcohol craving. This study examines whether chronic alcohol abuse is associated with altered stress and alcohol craving responses. Treatment-engaged, 28-day abstinent alcohol-dependent individuals (ADs; 6F/22M), and social drinkers (SDs; 10F/18M) were exposed to a brief guided imagery of a personalized stressful, alcohol-related and neutral-relaxing situation, one imagery condition per session, presented in random order across 3 days. Alcohol craving, anxiety and emotion ratings, behavioral distress responses, heart rate, blood pressure, and salivary cortisol measures were assessed. Alcohol patients showed significantly elevated basal heart rate and salivary cortisol levels. Stress and alcohol cue exposure each produced a significantly enhanced and persistent craving state in alcohol patients that was marked by increased anxiety, negative emotion, systolic blood pressure responses, and, in the case of alcohol cue, behavioral distress responses, as compared to SDs. Blunted stress-induced cortisol responses were observed in the AD compared to the SD group. These data are the first to document that stress and cue exposure induce a persistent negative emotion-related alcohol craving state in abstinent alcoholics accompanied by dysregulated HPA and physiological arousal responses. As laboratory models of stress and negative mood-induced alcohol craving are predictive of relapse outcomes, one implication of the current data is that treatments targeting decreases in stress and alcohol cue-induced craving and regulation of stress responses could be of benefit in improving alcohol relapse outcomes.

Effects of Adrenal Sensitivity, Stress- and Cue-Induced Craving, and Anxiety on Subsequent Alcohol Relapse and Treatment Outcomes

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.

Frequency of recent cocaine and alcohol use affects drug craving and associated responses to stress and drug-related cues

RATIONALE Stress is known to increase drug craving, associated physiological arousal and risk of relapse in drug dependent individuals. However, it is unclear whether these responses are altered by recent frequency of drug use. The current study examined whether frequency of cocaine and alcohol abuse alters drug craving and associated arousal with laboratory exposure to stress and to drug related cues. METHODS Fifty-four recently abstinent treatment-seeking cocaine abusers who were part of a study on stress and drug craving were categorized into high- and low-frequency users on the basis of their recent cocaine use. The high use cocaine group also consumed significantly more alcohol than the low use cocaine group. Participants were exposed to a brief 5-min guided imagery procedure that involved imagining a recent personal stressful situation, a personal drug-related situation and a neutral-relaxing situation, one imagery session on separate days presented in random order. Subjective (craving and anxiety), cardiovascular (heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP)) and biochemical (adrenocorticotropic hormone (ACTH), cortisol, prolactin) measures were assessed. RESULTS High-frequency abusers demonstrated a significantly greater drug craving, anxiety and associated cardiovascular and hypothalamic-pituitary-adrenal (HPA) response to both stress and drug-cue exposure as compared to low-frequency abusers. CONCLUSIONS Increased frequency of recent cocaine and alcohol use is associated with an enhanced stress and cue-induced drug craving and arousal response that appears to be similar to the effects of cocaine, and one that may increase the vulnerability to drug-seeking behavior and relapse in drug dependent individuals.

Enhanced Sensitivity to Stress and Drug/Alcohol Craving in Abstinent Cocaine-Dependent Individuals Compared to Social Drinkers

Chronic exposure to cocaine is associated with neuroadaptions in stress and reward circuits that may increase susceptibility to relapse. We examined whether there are alterations in stress response and craving in abstinent cocaine-dependent individuals compared with a demographically matched group of non-addicted socially drinking community controls. Forty treatment-engaged abstinent cocaine patients (17F/23M) and 40 controls (19F/21M) were exposed to a brief 5 min guided imagery of individually calibrated stressful situations, personal drug/alcohol-related situation and a neutral-relaxing situation, one imagery per session, presented in random order. Craving, anxiety, emotion rating scales, and physiological measures were assessed. Cocaine patients reported significantly higher and more persistent stress- and cue-induced drug/alcohol craving, negative emotions, and physiological responses compared with social drinkers. In cocaine patients, stress- and cue-induced drug craving was accompanied by increased anger, fear, sadness, heart rate, and SBP. Controls reported minimal stress-induced craving and only increases in anxiety and SBP during stress exposure. Cue-induced alcohol craving was accompanied only by an increase in relaxed state. Females reported increased stress-induced anxiety and sadness compared with males, while males were emotionally and physiologically more reactive in the cue condition. These findings are the first to document functional alterations in stress- and reward-related affect and physiology in recently abstinent cocaine patients that is marked by an enhanced sensitivity to stress- and drug-related cue exposure. These data suggest that recovery from chronic cocaine abuse could be hampered by a hyper-responsive stress- and drug-craving state that increases cocaine relapse susceptibility.

Sex steroid hormones, stress response, and drug craving in cocaine-dependent women: implications for relapse susceptibility.

Cocaine dependence is associated with an enhanced sensitivity to stress and drug craving. Increases in stress-induced craving and hypothalamic-pituitary-adrenal reactivity are also predictive of cocaine relapse outcomes. More important, sex differences in these responses have also been reported. To further understand the basis of the sex differences, the authors examined the influence of sex steroid hormones on subjective and physiological stress responses and drug craving in cocaine-dependent women. Women who had low progesterone levels (n=5) were compared with those with high progesterone levels (n=5) and with those with moderate levels of estradiol and progesterone (n=9) in their responses during exposure to stress, cocaine cues, and neutral imagery conditions. The high progesterone group showed significantly lower stress-induced and drug cue-induced cocaine craving ( p<.05) and reduced drug cue-induced anxiety levels ( p<.08) and lower drug cue-induced systolic and diastolic blood pressure levels compared with the low progesterone group. These data suggest that there are significant effects of sex steroid hormones on stress and drug cue-induced cocaine craving, anxiety, and cardiovascular responses. In particular, high progesterone during the midluteal phase of the cycle was associated with decreased stress-induced and drug cue-induced craving and decreased cue-induced anxiety and blood pressure responses. These findings are consistent with previous preclinical and clinical studies of progesterones effects on the behavioral responses to cocaine and warrant further research to examine the effects of progesterone on stress-induced cocaine craving, stress arousal, and cocaine relapse susceptibility in women.

Stress and Drug-Cue-Induced Craving in Opioid-Dependent Individuals in Naltrexone Treatment

BACKGROUND Naltrexone is a nonaddictive medication that blocks the euphoric effects of opioids. However, naltrexone treatment is associated with high rates of noncompliance and opioid relapse, possibly because it does not reduce stress and protracted withdrawal symptoms during early recovery. Prior clinical and preclinical research has indicated that both stress and drug-cue-related arousal response is associated with craving and vulnerability to relapse in a range of drug-using populations. AIMS To examine opioid craving and the subjective and cardiovascular response to stress and drug cues in naltrexone-treated opioid abusers. METHOD Eleven men and three women engaged in naltrexone treatment for opioid dependence. They were exposed to personalized stress, drug-cue, and neutral-relaxing imagery in a single laboratory session. Subjective (craving, emotion) and cardiovascular (heart rate, systolic blood pressure, and diastolic blood pressure) measures were assessed. RESULTS Stress and drug-cue-related imagery significantly increased opioid craving, anxiety, and negative emotions and significantly decreased positive emotions compared to neutral imagery. Selective emotional responses were greater in the stress condition than in the drug-cue condition. Only stress-related imagery was associated with an increased cardiovascular response. CONCLUSIONS Naltrexone-treated opioid abusers demonstrate vulnerability to stress and drug-cue-induced craving and arousal responses that may contribute to the high rates of noncompliance and relapse among opioid-dependent individuals undergoing naltrexone treatment. Pharmacological and behavioral interventions that specifically target the negative affectivity that co-occurs with drug-cue and stress-induced craving could be of benefit in improving naltrexone treatment outcomes in opioid dependence.

Prazosin Effects on Stress- and Cue-Induced Craving and Stress Response in Alcohol-Dependent Individuals: Preliminary Findings

BACKGROUND Stress, alcohol cues, and dysregulated stress responses increase alcohol craving and relapse susceptibility, but few pharmacologic agents are known to decrease stress- and cue-induced alcohol craving and associated stress dysregulation in humans. Here we report findings from a preliminary efficacy study of the alpha-1 receptor antagonist, prazosin, in modulating these relapse-relevant factors in alcohol-dependent individuals. METHODS Seventeen early abstinent, treatment-seeking alcohol-dependent individuals (12 men and 5 women) were randomly assigned to receive either placebo or 16 mg daily prazosin in a double-blind, placebo-controlled manner over 4 weeks. During week 4, all patients participated in a 3-day laboratory experiment involving 5-minute guided imagery exposure to stress, alcohol cue, and neutral-relaxing/control conditions, 1 exposure per day, on consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, negative emotion, cardiovascular measures, and plasma hypothalamic-pituitary-adrenal (HPA; cortisol, adenocorticotropic hormone) were assessed repeatedly in each session. RESULTS The prazosin group (n = 9) versus the placebo group (n = 8) showed significantly lower alcohol craving, anxiety, and negative emotion following stress exposure. The placebo group also showed significantly increased stress- and cue-induced alcohol craving, anxiety, negative emotion, and blood pressure (BP), as well as a blunted HPA response relative to the neutral condition, while the prazosin group showed no such increases in craving, anxiety, negative emotion, and BP, and no blunted HPA response to stress and alcohol cue exposure. CONCLUSIONS Prazosin appears efficacious in decreasing stress- and cue-induced alcohol craving and may normalize the stress dysregulation associated with early recovery from alcoholism. Further research to assess the efficacy of prazosin in reducing alcohol craving and stress-related relapse risk is warranted.

Elevated cortisol and learning and memory deficits in cocaine dependent individuals: Relationship to relapse outcomes

OBJECTIVE Cocaine dependence is characterized by stress system dysregulation, including elevated cortisol activity, emotional negativity, and behavioral disinhibition. High levels of stress and glucocorticoids are also known to affect learning, memory and executive function. Therefore, we examined the relationships between chronic cocaine use, elevated distress and learning and memory dysfunction in abstinent cocaine dependent (CD) individuals, and whether these measures were associated with cocaine relapse outcomes. METHOD Stress was assessed in 36 inpatient treatment engaged CD individuals and 36 demographically matched healthy control (HC) participants using the Perceived Stress Scale (PSS) and repeated morning salivary cortisol levels over three consecutive days. The Rey Auditory Verbal Learning Test (RAVLT) was conducted to measure verbal learning, memory, and executive function. Prospective assessment of cocaine use outcomes during 90 days following discharge from inpatient treatment was also conducted. RESULTS CD patients showed higher levels of distress compared to controls in PSS scores and cortisol levels. They also demonstrated a significantly reduced learning curve, and fewer correct responses and more errors on recognition. Elevated cortisol was significantly associated with worse RAVLT performance in CD patients. Poor memory scores, but not distress measures, were significantly associated with greater cocaine use after inpatient treatment. CONCLUSIONS These findings are the first to demonstrate that learning and memory deficits in CD individuals are associated with enhanced cortisol and with cocaine use outcomes after inpatient treatment. The findings are consistent with recent addiction models suggesting that chronic cocaine-related neuroadaptations affects learning and memory function, which in turn, influences drug use outcomes.

Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings

Cocaine dependence is associated with increased stress and drug cue-induced craving and physiological arousal but decreased prefrontal activity to emotional and cognitive challenge. As these changes are associated with relapse risk, we investigated the effects of α2 receptor agonist guanfacine on these processes. Twenty-nine early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily placebo or guanfacine (up to 3 mg) for four weeks. In a laboratory experiment, all patients were exposed to three 10-min guided imagery conditions (stress/stress, drug cue/drug cue, stress/drug cue), one per day, consecutively in a random, counterbalanced order. Subjective craving, anxiety and arousal as well as cardiovascular output were assessed repeatedly. Brain response to stress, drug cue and relaxing imagery was also assessed during a functional magnetic resonance (fMRI) imaging session. In the current study, guanfacine was found to be safe and well-tolerated. Lower basal heart rate and blood pressure was observed in the guanfacine versus placebo group. Guanfacine lowered stress and cue-induced nicotine craving and cue-induced cocaine craving, anxiety and arousal. The guanfacine group also showed increased medial and lateral prefrontal activity following stress and drug cue exposure compared with placebo. Data suggest further exploration of guanfacine is warranted in terms of its potential for reducing stress-induced and cue-induced drug craving and arousal.

Sex Differences in Drug-Related Stress-System Changes: Implications for Treatment in Substance-Abusing Women

Extensive research indicates that chronic substance abuse disrupts stress and reward systems of the brain. Gender variation within these stress-system alterations, including the impact of sex hormones on these changes, may influence sex-specific differences in both the development of, and recovery from, dependency. As such, gender variations in stress-system function may also provide a viable explanation for why women are markedly more vulnerable than men to the negative consequences of drug use. This article therefore initially reviews studies that have examined gender differences in emotional and biophysiological changes to the stress and reward system following the acute administration of drugs, including cocaine, alcohol, and nicotine. The article then reviews studies that have examined gender differences in response to various types of stress in both healthy and drug-abusing populations. Studies examining the impact of sex hormones on these gender-related responses are also reported. The implications of these sex-specific variations in stress and reward system function are discussed in terms of both comorbid psychopathology and treatment outcome.