430745 2012
JOP0010.1177/0269881111430745Kablinger et al.Journal of Psychopharmacology
Original Paper
Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study
Journal of Psychopharmacology 0(0) 1–9 © The Author(s) 2012 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881111430745 jop.sagepub.com
Anita S Kablinger1, Marie A Lindner2, Stephanie Casso3, Franz Hefti4, George DeMuth5, Barbara S Fox4, Lindsay A McNair6, Bruce G McCarthy7 and Nicholas E Goeders4,8
Abstract Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.
Keywords Benzodiazepine, cocaine, cortisol, craving, HPA axis, metyrapone, oxazepam, stress
Introduction Cocaine dependence and abuse affect an estimated 1.6 million people in the USA (The Substance Abuse and Mental Health Services Administration (SAMHSA) 2008), exacting an enormous cost on the healthcare system, the economy, and society as a whole. There are currently no medications approved for the treatment of cocaine addiction and few medications in mid- to latestage clinical trials. There is a clear need for new approaches that may lead to the development of safe and effective pharmacotherapies for the treatment of cocaine addiction. In recent years, we and others have explored the complex relationship between stress and addiction using animal models of substance abuse. In this context, we have shown that drugs that alter physiological responses to stress also reduce cocaine self-administration in rats (Goeders, 2004, 2007). Benzodiazepines are known to decrease plasma corticosterone (Keim and Sigg, 1977), cortisol and adrenocorticotropic hormone (ACTH) (Meador-Woodruff and Greden, 1988; Torpy et al., 1993) in both rats and humans, and we have shown that they also reduce cocaine self-administration in rats (Goeders et al., 1993, 1989). Similarly, metyrapone and ketoconazole decrease plasma cortisol by directly inhibiting production of the hormone (Engelhardt et al., 1985; Haleem et al., 1988; Haynes, 1990), and we have shown that they also reduce cocaine taking in rats (Goeders and Guerin, 1996; Goeders et al., 1998). The activity of benzodiazepines and cortisol synthesis inhibitors in animal models of addiction suggest that it might be
valuable to test these compounds in cocaine-dependent human subjects. However, both classes of drugs have potential side effects that could limit their use in the treatment of cocaine addiction. For example, benzodiazepines are not usually recommended for use in cocaine-dependent subjects as these drugs have the potential for dependence and abuse (Chouinard, 2004; Lilja et al., 2001; O’Brien, 2005). Cortisol synthesis inhibitors have the potential to produce adrenal insufficiency, possibly limiting the utility of this class of drugs. The incidence of side effects produced by these two classes of drugs could be mitigated by reducing the dose. We hypothesized that combinations of drugs that affect physiological responses to
1Virginia
Tech Carilion School of Medicine, Roanoke, VA, USA Philadelphia, PA, USA 3University of Texas Health Science Center, San Antonio, TX, USA 4Embera NeuroTherapeutics, Inc., Shreveport, LA, USA 5Stat-Tech Services, Chapel Hill, NC, USA 6Equipoise Consulting LLC, Allston, MA, USA 7Afferent Pharmaceuticals, San Mateo, CA, USA 8Louisiana State University Health Sciences Center, Shreveport, LA, USA 2BioAdvance,
Corresponding author: Nicholas E Goeders, Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA Email:
[email protected]
Downloaded from jop.sagepub.com at LOUISIANA STATE UNIV SHREVEPO on January 12, 2012
2
Journal of Psychopharmacology 0(0)
stress through divergent mechanisms might reduce cocaine intake at doses that had no effect when administered alone. This hypothesis was confirmed in a rat model of cocaine dependence; the metyrapone and oxazepam combination, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats. These same combinations did not affect food-maintained responding or plasma corticosterone during the same sessions (Goeders and Guerin, 2008). In this paper, we describe our first effort at translating these preclinical findings into the clinic. Although many therapeutic agents are first tested in a human laboratory setting, we chose to move directly to an out-patient clinical treatment trial. Inhibitors of the stress response do not appear to affect the physiological processes associated with reward or reinforcement and do not block the subjective effects of either cocaine or methamphetamine in humans (Haga et al., 2003; Harris et al., 2003; Ward et al., 1998; Winhusen et al., 2005) or the discriminative effects of cocaine in rats (Mantsch and Goeders, 1999). Instead, these inhibitors are believed to block the ability of stress-related environmental cues to stimulate craving and associated drug use and relapse. Thus, we chose to test these compounds on craving and relapse in a pilot proof-of-concept clinical trial. Metyrapone and oxazepam were selected as the test agents in this exploratory study for two reasons. First, this drug combination has already been shown to be effective at reducing cocaine selfadministration in rats (Goeders and Guerin, 2008). Second, each of these drugs is expected to have a favorable safety profile in this patient population (Winhusen et al., 2005). Metyrapone is a cortisol synthesis inhibitor that is approved in the USA and internationally as a diagnostic test for HPA axis function, and in the UK for the management of Cushing’s syndrome and the sustained treatment of resistant edema due to increased aldosterone. It has fewer metabolic interactions than are seen with other cortisol inhibitors such as ketoconazole (Sonino, 1987; Thienpont et al., 1979). Moreover, although its primary use entails acute dosing, several studies have examined chronic dosing with metyrapone for the treatment of depression (Jahn et al., 2004; Murphy et al., 1998; O’Dwyer et al., 1995; Rogoz et al., 2004) and these studies suggest that long-term dosing with metyrapone is likely to be safe. Oxazepam is a benzodiazepine that is approved for the management of anxiety disorders, the relief of the symptoms of anxiety, and anxiety associated with depression. Oxazepam was selected for this study in part because it has a reduced risk of dependence when compared with other benzodiazepines. Controlled trials comparing oxazepam and diazepam showed that oxazepam induced a much lower rating of drug liking than did diazepam (Griffiths et al., 1984), and there have been only a few reports of the abuse of oxazepam over decades of clinical use (Griffiths and Johnson, 2005). The hypothesis guiding this study was that combinations of drugs that reduce physiological responses to stress would alter the ability of stress-related environmental cues to stimulate craving and the relapse to drug use at doses that should have no effect when administered alone. We report here preliminary data suggesting that the combination of metyrapone and oxazepam reduces cocaine craving and cocaine taking in cocaine-dependent individuals.
Methods This pilot study (ClinicalTrials.gov: NCT00567814) evaluated whether the combination of the cortisol synthesis inhibitor
metyrapone and the benzodiazepine oxazepam reduced cocaine craving and use in cocaine-dependent subjects in a communitybased environment. This prospective, single center, randomized, placebo-controlled, double-blind study was conducted at the Psychopharmacology Research Unit at the Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S). Subjects were randomized to a low total daily dose of 500 mg metyrapone/20 mg oxazepam, a high total daily dose of 1500 mg metyrapone/20 mg oxazepam, or placebo. The 6-week treatment period, with visits on Day 0 and Day 3 each week (Visits 1 through 12), was followed by an end-of-study visit on Week 7, Day 0 (Visit 13) and a follow-up visit 7-14 days after the end of treatment (Visit 14). Drug and placebo were supplied in two divided doses for twice daily administration. The LSUHSC-S Institutional Review Board (IRB) reviewed and approved the protocol and informed consent form.
Study population The study enrolled 45 subjects who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for cocaine dependency using the Mini-International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998). Subjects were selected from a pool referred by physicians or treatment facilities or recruited via print, radio, or television advertisements, which were also approved by the LSUHSC-S IRB. Subjects were randomized to treatment groups based on the order in which they entered the study. Subjects were men and women, 18-65 years old, who requested treatment for cocaine addiction, were able to provide written informed consent, and had a benzoylecgonine (BE)-positive urine test within the 14-day screening period. Exclusion criteria included any prominent DSM-IV axis I disorder other than cocaine dependence as determined by a psychiatrist at the initial interview. Abuse of other psychoactive substances that did not meet the criteria for dependence, and alcohol dependence that did not require medical detoxification were acceptable as long as cocaine was the primary drug of choice. Other exclusion criteria included liver enzymes >2 times normal, serum cortisol
