A preliminary study examined whether lofexidine decreases stress-induced and cue-induced opioid craving and improves opioid abstinence in naltrexone-treated opioid-dependent individuals.
Eighteen opioid-dependent patients were stabilized for 4 weeks with naltrexone (50 mg daily) and lofexidine (2.4 mg bid) before entering a 4-week randomized, double-blind placebo-controlled discontinuation study where one group continued on lofexidine for an additional 4 weeks, while the second was tapered to placebo (Lofexidine-naltrexone vs Placebo-naltrexone). Ten patients also participated in guided imagery exposure to stress, drug cue, and neutral scenarios in a single laboratory session.
Lofexidine-naltrexone patients had higher opioid abstinence rates and improved relapse outcomes as compared to the Placebo-naltrexone group. Furthermore, Lofexidine-naltrexone patients had significantly lower heart rates and an attenuated stress and drug cue-induced opioid craving response in the laboratory as compared to the Placebo-naltrexone group.
Although preliminary, these findings are the first to document lofexidine's potential in addressing stress-related opioid craving and relapse outcomes in humans. The results also suggest that combination therapies that target both drug-related reinforcement (naltrexone) and stress- and cue-related aspects of drug seeking could be beneficial in addiction relapse prevention. Further development of lofexidine to address stress-related opioid craving and relapse is warranted.
"In another study, a high dose of guanfacine attenuated yohimbine-induced reinstatement of alcohol (but not food) seeking, whereas the α 1 -agonist prazosin blocked yohimbine-induced reinstatement of alcohol and food seeking, as well as footshock-induced reinstatement of alcohol seeking (Lê et al. 2011). Similarly, in clinical studies that all used stressful vs neutral mental imagery procedures, prazosin attenuated stressor-induced alcohol craving (Fox et al. 2012), and the α 2 -agonists clonidine and lofexidine blunted stressorinduced craving for both cocaine (Jobes et al. 2011) and opioids (Sinha et al. 2007). Therefore, noradrenergic medications with pharmacological actions that at least partially oppose those of yohimbine seem to represent one potential approach for blocking the ability of stressors to increase behavior maintained by various drug and non-drug reinforcers. "
[Show abstract][Hide abstract] ABSTRACT: RATIONALE: In laboratory animals, the biological stressor yohimbine (α(2)-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking. OBJECTIVES: This clinical study tested whether yohimbine increases opioid-seeking behavior. METHODS: Ten heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers sampled two doses of hydromorphone [12 and 24 mg IM in counterbalanced order, labeled drug A (session 1) and drug B (session 2)]. During each of six later sessions (within-subject, double-blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (drug A or B) vs money ($2) following different oral yohimbine pretreatment doses (0, 16.2, and 32.4 mg). RESULTS: Behavioral economic demand intensity and peak responding (O (max)) were significantly higher for hydromorphone 2 than 1 mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units (P (max) = 909, 3,647, and 3,225 for placebo, 16.2, and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units (P (max) = 2,656, 3,193, and 3,615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic ≈ 15 and diastolic ≈ 10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood. CONCLUSIONS: These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose.
"Morphine (Wang et al. 2001) Cocaine (Erb et al. 2000; Mantsch et al. 2010) Nicotine (Zislis et al. 2007) Cocaine users (Jobes et al. 2011) Lofexidine Cocaine (Erb et al. 2000) Alcohol (Le et al. 2005) Speedball (Highfield et al. 2001) Opiate users (Sinha et al. 2007) Guanfacine Alcohol (Lê et al. 2011) Cocaine users (Fox et al. under review) Guanabenz Cocaine (Erb et al. 2000) Psychopharmacology (Berl). Author manuscript; available in PMC 2011 November 1. "
[Show abstract][Hide abstract] ABSTRACT: RATIONALE AND BACKGROUND: High relapse rates during abstinence are a pervasive problem in drug addiction treatment. Relapse is often associated with stress exposure, which can provoke a subjective state of drug craving that can also be demonstrated under controlled laboratory conditions. Stress-induced relapse and craving in humans can be modeled in mice, rats, and monkeys using a reinstatement model in which drug-taking behaviors are extinguished and then reinstated by acute exposure to certain stressors. Studies using the reinstatement model in rats have identified the role of several neurotransmitters and brain sites in stress-induced reinstatement of drug seeking, but the degree to which these preclinical findings are relevant to the human condition is largely unknown. OBJECTIVES AND HIGHLIGHTS: Here, we address this topic by discussing recent results on the effect of alpha-2 adrenoceptors and substance P-NK1 receptor antagonists on stress-induced reinstatement in mice and rats and stress-induced craving and potentially stress-induced relapse in humans. We also discuss brain sites and circuits involved in stress-induced reinstatement of drug seeking in rats and those activated during stress-induced craving in humans. CONCLUSIONS: There is evidence that alpha-2 adrenoceptor agonists and NK1 receptor antagonists decrease stress-induced drug seeking in rats and stress-induced craving in humans. Whether these drugs would also prevent stress-induced drug relapse in humans and whether similar or different brain mechanisms are involved in stress-induced reinstatement in non-humans and stress-induced drug craving and relapse in humans are subjects for future research.
"The effect on stress-induced craving was somewhat specific; craving after a drug-cue script was blocked only by the higher dose of clonidine. These findings are consistent with rodent data that show alpha-2 adrenergic agonists can block reinstatement of cocaine seeking after a stressor and also support clinical data suggesting that in humans, the effect can generalize to drug cues (Sinha et al. 2007). Based on the preclinical literature (Highfield et al. 2001; Shaham et al. 2000), this generalization is unexpected; it may reflect a tendency for drug-associated cues to induce stress-like responses in humans, but not in rats (Sinha 2001). "
[Show abstract][Hide abstract] ABSTRACT: Reactivity to stressors and environmental cues, a putative cause of relapse in addiction, may be a useful target for relapse-prevention medication. In rodents, alpha-2 adrenergic agonists such as clonidine block stress-induced reinstatement of drug seeking, but not drug cue-induced reinstatement.
The objective of this study is to test the effect of clonidine on stress- and cue-induced craving in human cocaine users.
Healthy, non-treatment-seeking cocaine users (n = 59) were randomly assigned to three groups receiving clonidine 0, 0.1, or 0.2 mg orally under double-blind conditions. In a single test session, each participant received clonidine or placebo followed 3 h later by exposure to two pairs of standardized auditory-imagery scripts (neutral/stress and neutral/drug). Subjective measures of craving were collected.
Subjective responsivity ("crave cocaine" Visual Analog Scale) to stress scripts was significantly attenuated in the 0.1- and 0.2-mg clonidine groups; for drug-cue scripts, this attenuation occurred only in the 0.2-mg group. Other subjective measures of craving showed similar patterns of effects but Dose × Script interactions were not significant.
Clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with preclinical findings, although this was significant on only one of several measures. Our results, though modest and preliminary, converge with other evidence to suggest that alpha-2 adrenergic agonists may help prevent relapse in drug abusers experiencing stress or situations that remind them of drug use.
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