Stress and drug-cue-induced craving in opioid-dependent individuals in naltrexone treatment.

The profile of opioid addiction has changed considerably in recent years. While heroin abuse remains a significant public health concern (Brown, 2004; Kirchmayer et al., 2002), nonmedical use and abuse of prescription opioids is increasing, and the prevalence of prescription opioid abuse has become comparable to that of heroin and cocaine abuse (Zacny et al., 2003). Children are especially at risk, given that the number of 12- to 17-year-olds abusing controlled prescription drugs increased by 212% between 1992 and 2003 (National Center on Addiction and Substance Abuse at Columbia University, 2005). These findings are alarming and indicate a need for the development of additional and more comprehensive treatments that may be better suited for this growing cohort of young opioid abusers. Naltrexone, a medication that blocks the euphoric effects of opioids, is a nonaddictive alternative to agonist maintenance treatments such as methadone and buprenorphine. The potential usefulness of naltrexone follows from operant conditioning models of behavior, which postulate that drug-seeking will extinguish if drug use is not reinforced by euphoric drug effects (Tucker & Ritter, 2000). However, its treatment efficacy has been questioned due to poor compliance and high drop-out rates (Kirchmayer et al., 2002; Rounsaville, 1995; Tucker & Ritter, 2000). Reasons given for poor compliance include its absence of euphoria-producing properties, the requirement of an opioid-free period prior to initiation, the fear of using a new drug, and a lack of genuine motivation to achieve abstinence (Tucker & Ritter, 2000). Another possible explanation for the high drop-out rates is that opioid-dependent individuals experience stress and protracted withdrawal symptoms in early recovery, which may increase craving and relapse susceptibility. Indeed, prior research has implicated stress in the perpetuation of drug use and relapse (Bradley, Phillips, Green, & Gossop, 1989; Goeders, 2003; Sinha, 2001; Wallace, 1989). Animal studies have shown that acute physical and social stress facilitates drug self-administration and reinstatement to drug-seeking behavior in drug-addicted animals that have been drug free for extended time periods (Do Couto et al., 2006; Shaham & Stewart, 1995). Although naltrexone attenuates opioid-induced drug seeking in heroin-dependent animals, it does not alter stress-induced drug seeking in the same animals (Shaham et al., 1997). This finding may be related to the possible existence of somewhat different neurochemical pathways underlying stress and drug-cue-related drug seeking and relapse (see Stewart, 2003, for review). It is important to note that this finding may also be related to the fact that both acute and chronic administration of opioid receptor antagonists, such as naltrexone and naloxone, increase stress markers and/or cardiovascular responses in healthy volunteers and ex-opioid addicts (Klein, Jamner, Alberts, Ornstein, & Leigh, 2000; Kosten et al., 1986; McCubbin et al., 1998; Uhart, Chong, Oswald, Lin, & Wand, 2006), raising the question of whether naltrexone addresses stress-induced opioid craving and associated arousal responses. Previous work has shown that imagery exposure to stressful and drug-cue experiences increase drug craving, negative affect, and physiological reactivity in cocaine-and alcohol-dependent individuals (Breese et al., 2005; Sinha, Catapano, & O’Malley, 1999, Sinha, Fuse, Aubin, & O’Malley, 2000, Sinha et al., 2003). Moreover, recent findings have indicated that stress-induced craving and hypothalamic–pituitary–adrenal responses significantly predicted relapse outcomes in both alcohol- and cocaine-dependent individuals (Brady et al., 2006; Sinha, Garcia, Paliwal, Kreek, & Rounsaville, 2006). With regard to opioid addiction, opioid-dependent individuals undergoing inpatient detoxification have been found to experience an increase in craving and physiological reactivity while imagining and describing situations involving strong urges to use opioids (Weinstein, Wilson, Bailey, Myles, & Nutt, 1997). Detoxified opioid-dependent individuals exposed to drug-related stimuli have also been shown to experience an increase in craving, dysphoria, and withdrawal-like symptoms (Powell, Bradley, & Gray, 1992). Even after detoxification and 12 weeks of intensive inpatient treatment, opioid-dependent patients continued to demonstrate increased craving and negative affect when exposed to drug-related stimuli (Franken, De Hann, Van Der Meer, Haffmans, & Hendriks, 1999). Regarding stress-induced craving responses, imagery induction of negative mood states has been found to increase opioid craving and withdrawal symptoms in detoxified opioid abusers (Childress et al., 1994). Although these studies indicated that exposure to drug cues and stress can increase opioid craving, the pattern of stress and drug-cue-induced craving in opioid-dependent individuals undergoing naltrexone treatment has not been previously investigated. The potential inability of naltrexone to attenuate stress-induced responses may be a primary reason for the high relapse rates found with naltrexone treatment. Thus, we tested the hypothesis that opioid-dependent participants would demonstrate increased opioid craving, negative emotion, and cardiovascular arousal following exposure to both stress and drug-cue-related imagery compared to neutral imagery.