Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings.
ABSTRACT 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.
SourceAvailable from: Daisy Thompson-Lake[Show abstract] [Hide abstract]
ABSTRACT: Previous research has focused on developing theories of addiction that may explain behavior in cocaine- and methamphetamine-dependent individuals. The primary goal of this report was to compare and contrast the prevalence of self-reported measures of impulsivity, depression, lifetime stress and sensation-seeking in healthy controls versus individuals with cocaine or methamphetamine use disorders. Twenty-nine individuals with cocaine use disorders and 31 individuals with methamphetamine use disorders were matched with 31 healthy control participants on several demographic variables. All participants were administered behavioral questionnaires including the Barrett Impulsiveness Scale (assessing impulsivity), Beck Depression Inventory II (assessing depression), Life Stressor Checklist-Revised (assessing lifetime stress) and the Impulsive Sensation Seeking Scale (assessing sensation-seeking). When compared to healthy controls, individuals with cocaine and methamphetamine use disorders had significantly higher levels of impulsivity and sensation-seeking. In addition, when compared to healthy controls, individuals with cocaine use disorders had significantly higher Beck Depression Inventory II scores, while individuals with methamphetamine use disorders had significantly higher Life Stressor Checklist-Revised scores. The results revealed that there were significantly higher levels of impulsivity, depression and sensation-seeking in cocaine users and significantly higher impulsivity, lifetime stress and sensation-seeking in methamphetamine users when compared to healthy controls. © The Author(s) 2014.Journal of Psychopharmacology 11/2014; DOI:10.1177/0269881114560182 · 2.81 Impact Factor
Frontiers in Psychiatry 12/2014; 5:180. DOI:10.3389/fpsyt.2014.00180
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ABSTRACT: α2-adrenergic receptors (AR) within the bed nucleus of the stria terminalis (BNST) reduce stress-reward interactions in rodent models. In addition to their roles as autoreceptors, BNST α2A-ARs suppress glutamatergic transmission. One prominent glutamatergic input to the BNST originates from the parabrachial nucleus (PBN) and consists of asymmetric axosomatic synapses containing calcitonin gene-related peptide (CGRP) and vGluT2. Here we provide immunoelectron microscopic data showing that many asymmetric axosomatic synapses in the BNST contain α2A-ARs. Further, we examined optically evoked glutamate release ex vivo in BNST from mice with virally delivered channelrhodopsin2 (ChR2) expression in PBN. In BNST from these animals, ChR2 partially colocalized with CGRP, and activation generated EPSCs in dorsal anterolateral BNST neurons that elicited two cell-type-specific outcomes: (1) feedforward inhibition or (2) an EPSP that elicited firing. We found that the α2A-AR agonist guanfacine selectively inhibited this PBN input to the BNST, preferentially reducing the excitatory response in ex vivo mouse brain slices. To begin to assess the overall impact of α2A-AR control of this PBN input on BNST excitatory transmission, we used a Thy1-COP4 mouse line with little postsynaptic ChR2 expression nor colocalization of ChR2 with CGRP in the BNST. In slices from these mice, we found that guanfacine enhanced, rather than suppressed, optogenetically initiated excitatory drive in BNST. Thus, our study reveals distinct actions of PBN afferents within the BNST and suggests that α2A-AR agonists may filter excitatory transmission in the BNST by inhibiting a component of the PBN input while enhancing the actions of other inputs.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2014; 34(28):9319-31. DOI:10.1523/JNEUROSCI.0822-14.2014 · 6.75 Impact Factor