A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal.

CONTEXT: Lofexidine is an alpha-2-adrenergic receptor agonist that is approved in the United Kingdom for the treatment of opioid withdrawal symptoms. Lofexidine has been reported to have more significant effects on decreasing opioid withdrawal symptoms with less hypotension than clonidine. OBJECTIVE: To demonstrate that lofexidine is well tolerated and effective in the alleviation of observationally defined opioid withdrawal symptoms in opioid dependent individuals undergoing medically supervised opioid detoxification as compared to placebo. DESIGN: An inpatient, Phase 3, placebo-controlled, double-blind, randomized multi-site trial with three phases: (1) opioid agonist stabilization phase (days 1-3), (2) detoxification/medication or placebo phase (days 4-8), and (3) post detoxification/medication phase (days 9-11). SUBJECTS: Sixty-eight opioid dependent subjects were enrolled at three sites with 35 randomized to lofexidine and 33 to placebo. MAIN OUTCOME MEASURE: Modified Himmelsbach Opiate Withdrawal Scale (MHOWS) on study day 5 (second opioid detoxification treatment day). RESULTS: Due to significant findings, the study was terminated early. On the study day 5 MHOWS, subjects treated with lofexidine had significantly lower scores (equating to fewer/less severe withdrawal symptoms) than placebo subjects (least squares means 19.5+/-2.1 versus 30.9+/-2.7; p=0.0019). Lofexidine subjects had significantly better retention in treatment than placebo subjects (38.2% versus 15.2%; Log rank test p=0.01). CONCLUSIONS: Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification.

Clinical pharmacokinetics of lofexidine, the alpha 2-adrenergic receptor agonist, in opiate addicts plasma using a highly sensitive liquid chromatography tandem mass spectrometric analysis.

OBJECTIVES: The objective of this investigation was to characterize the pharmacokinetic profile of lofexidine. Lofexidine is an orally bioavailable alpha 2-adrenergic receptor agonist analogue of clonidine that acts centrally to suppress opiate withdrawal symptoms. METHODS: During the detoxification period of a phase 3 placebo-controlled, randomized, double-blind trial, six subjects were entered in this preliminary pharmacokinetic study. RESULTS: Pharmacokinetic analysis of plasma samples collected during study day 7 indicated that C(max) was 3242 +/- 917 ng/L. The mean trough levels between the study days were not significantly different (p > .05), suggesting that the subjects were at steady-state. CONCLUSIONS: Although preliminary due to the limited number of subjects, these findings are the first to document lofexidine clinical pharmacokinetics in opiate addicts using a highly sensitive liquid chromatography tandem mass spectrometric analysis.

Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine.

OBJECTIVE: Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated. METHOD: Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [(11)C]raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward. RESULTS: Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: -1.2% in cocaine-dependent participants versus -12.4% in healthy subjects; associative striatum: -2.6% versus -6.7%, respectively; sensorimotor striatum: -4.3% versus -14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money. CONCLUSIONS: Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to play a critical role in relapse.

Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior.

Striatal dopamine D2 receptors have been implicated in the neurobiology of cocaine addiction. Previous imaging studies showed reduced striatal D2 receptor availability in chronic cocaine abusers, and animal studies suggested that low D2 receptor availability promotes cocaine self-administration. Here, D2 receptor availability was assessed with positron emission tomography (PET) and [11C]raclopride in the limbic, associative, and sensori-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). Thus, this study confirms previous reports of a modest decrease in D2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-taking behavior. Additional research is warranted to unravel potential neurobiological traits that might confer vulnerability to relapse in detoxified CCD subjects.

Effects of the NMDA antagonist memantine on human methamphetamine discrimination.

RATIONALE: The discriminative stimulus effects of N-methyl- D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. OBJECTIVE: This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. METHODS: Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). RESULTS: Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. CONCLUSION: These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects.

Comparison of smoked marijuana and oral Delta(9)-tetrahydrocannabinol in humans.

RATIONALE: Although smoked marijuana contains at least 60 cannabinoids, delta(9)-tetrahydrocannabinol (delta(9)-THC) is presumed to be the cannabinoid primarily responsible for many marijuana-related effects, including increased food intake and subjective effects. Yet, there has been no systematic comparison of repeated doses of oral delta(9)-THC with repeated doses of smoked marijuana in the same individuals. OBJECTIVE: To compare the effects of oral delta(9)-THC and smoked marijuana in humans under controlled laboratory conditions. METHODS: Eleven healthy research volunteers, who reported smoking an average of six marijuana cigarettes per day, completed an 18-day residential study. Marijuana cigarettes (3.1% delta(9)-THC, q.i.d.) were smoked or delta(9)-THC (20 mg, q.i.d.) was taken orally using a staggered, double-blind, double-dummy procedure for three consecutive days. Four days of placebo administration separated each active drug condition. Psychomotor task performance, subjective effects, and food intake were measured throughout the day. RESULTS: Relative to placebo baseline, oral delta(9)-THC and smoked marijuana produced similar subjective-effect ratings (e.g., "high" and "mellow"), although some effects of smoked marijuana were more pronounced and less prone to the development of tolerance. Additionally, participants reported "negative" subjective effects (e.g., "irritable" and "miserable") during the days after smoking marijuana but not after oral delta(9)-THC. Both drugs increased food intake for 3 days of drug administration, but had little effect on psychomotor performance. CONCLUSION: These results indicate that the behavioral profile of effects of smoked marijuana (3.1% delta(9)-THC) is similar to the effects of oral delta(9)-THC (20 mg), with some subtle differences.

Depot naltrexone: long-lasting antagonism of the effects of heroin in humans.

RATIONALE: Naltrexone, an opioid antagonist, is currently approved as a treatment for heroin dependence. However, naltrexone is generally not well accepted by patients, and medication non-compliance is a difficult obstacle to treatment. A sustained-release form of naltrexone may improve compliance. OBJECTIVE: The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex). METHODS: Twelve heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, six participants received 192 mg naltrexone base and six participants received 384 mg naltrexone base. For safety, the low dose of depot naltrexone was tested before the high dose. The effects of heroin (0, 6.25, 12.5, 18.75, 25 mg, i.v.) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, and the entire dose range was tested each week. Active heroin doses were administered in ascending order during the week, while placebo could be administered on any day. Subjective, performance, and physiological effects were measured both before and after heroin administration. The hypotheses were that depot naltrexone would antagonize the effects of heroin, and that the high dose of depot naltrexone would produce a more effective and longer-lasting antagonism than the low dose. RESULTS: The low and high doses of depot naltrexone antagonized heroin-induced subjective ratings for 3 and 5 weeks, respectively. Plasma levels of naltrexone remained above 1 ng/ml for approximately 3 and 4 weeks after administration of 192 mg and 384 mg naltrexone. Other than the initial discomfort associated with the injection of depot naltrexone, there were no untoward side-effects. CONCLUSIONS: These results suggest that this depot formulation of naltrexone provides a safe, effective, long-lasting antagonism of the effects of heroin.

Effects of oral THC maintenance on smoked marijuana self-administration.

Studies have shown that the Delta(9)-tetrahydrocannabinol (Delta(9)-THC) concentration in marijuana cigarettes is an important factor for the maintenance of marijuana self-administration. Yet, the impact of oral Delta(9)-THC treatment on marijuana self-administration is unknown. Because other agonist therapies have been demonstrated to be effective for the treatment of substance use disorders, the objective of this study was to evaluate the influence of oral Delta(9)-THC maintenance on choice to self-administer smoked marijuana. During this 18-day residential study, 12 healthy research volunteers received one of three doses of oral Delta(9)-THC capsules (0, 10, 20 mg q.i.d.) for 3 consecutive days, followed by 3 consecutive days of matching placebo. The order of active Delta(9)-THC administration was counterbalanced. Each morning, except on days 6, 12, and 18, participants smoked the 'sample' marijuana cigarette (1.8% Delta(9)-THC w/w) and received a $2 voucher (redeemable for cash at study's end). Following the sample, volunteers participated in a four-trial choice procedure during which they had the opportunity to self-administer either the dose of marijuana they sampled that morning or to receive the $2 voucher. Relative to placebo Delta(9)-THC maintenance, participants' choice to self-administer marijuana was not significantly altered by either of the two active Delta(9)-THC maintenance conditions. Some 'positive' subjective drug-effect ratings following the sample marijuana cigarette were reduced: by day 3 of active oral Delta(9)-THC maintenance, participants' rating of 'Good Drug Effect' and 'High' were significantly decreased. Smoked marijuana-related total daily caloric intake was not significantly altered under any maintenance conditions. Finally, the effects of smoked marijuana on psychomotor task performance were only minimally affected by oral Delta(9)-THC maintenance. These data indicate that participants' choice to self-administer marijuana was unaltered by the oral Delta(9)-THC dosing regimen used in the present investigation.

The effects of venlafaxine on the subjective, reinforcing, and cardiovascular effects of cocaine in opioid-dependent and non-opioid-dependent humans.

The effects of maintenance on venlafaxine, which blocks both norepinephrine and serotonin reuptake, on the response to smoked cocaine (0, 12, 25, or 50 mg) in 7 opioid-free and 7 methadone-maintained cocaine abusers was examined during a 42-day study. Participants received venlafaxine (225 mg daily) and placebo as part of a double-blind crossover design. Cocaine significantly increased heart rate, blood pressure, cocaine choice, cocaine ratings, and ratings of positive subjective effects (e.g., "I feel high") in both groups. Venlafaxine significantly decreased the subjective effects of cocaine by 10-20% without affecting cocaine choice or cardiovascular response in both groups. Although the reduction in cocaine's effects was small, further studies using a longer venlafaxine maintenance period or a larger venlafaxine dose are warranted.

Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine.

The goal of this study was to determine D(1) receptor availability in human cocaine-dependent (CD) subjects and matched healthy controls (HCs). In addition, the CD subjects performed cocaine self-administration sessions in order to explore the association between D(1) receptor availability and cocaine-seeking behavior. Twenty-five CD subjects (40+/-4 years, 19M/6 F) and 23 matched HCs (38+/-4 years, 19M/4F) were scanned with PET and the radiotracer [(11)C]NNC 112. During the cocaine self-administration sessions, CD volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth $5. D(1) receptor availability was measured in the limbic, associative, and sensori-motor striatum in addition to cortical brain regions. No difference in D(1) receptor availability was seen between the two groups. A negative association was seen between D(1) receptor BP(ND) in the limbic striatum and the choice for the 6 mg dose of cocaine (r=-0.47, p=0.02, corrected for age). These results do not support the hypothesis that cocaine dependence is associated with a reduction in D(1) receptor availability in the striatum. However, within the CD subjects, low D(1) receptor availability in the ventral striatum was associated with the choice to self-administer cocaine, suggesting that low D(1) receptor availability may be associated with an increased risk of relapse in cocaine dependence.

Intravenous buprenorphine self-administration by detoxified heroin abusers.

Several sources indicate that intravenously administered buprenorphine may have significant abuse liability in humans. The present study evaluated the reinforcing effects of intravenously administered buprenorphine (0, 2, and 8 mg) in detoxified heroin-dependent participants during a 7.5-week inpatient study. Participants (n = 6) were detoxified from heroin over a 1.5-week period immediately after admission. Testing subsequently occurred in three 2-week blocks. During the first week of each 2-week block, the reinforcing effects of buprenorphine were evaluated. Participants first received a dose of buprenorphine and $20 and then were given either the opportunity to self-administer the dose or $20 during choice sessions. During the second week of each 2-week block, the direct effects of heroin were measured to evaluate potential long-lasting antagonist effects of buprenorphine. Progressive ratio break-point values were significantly higher after 2 and 8 mg of buprenorphine compared with placebo. Correspondingly, several positive subjective ratings increased after administration of active buprenorphine relative to placebo. Although there were few differences in peak effects produced by 2 versus 8 mg of buprenorphine, the higher buprenorphine dose generally produced longer-lasting effects. Heroin also produced dose-related increases in several subjective effects. Peak ratings produced by heroin were generally higher than peak ratings produced by buprenorphine. There was little evidence of residual antagonism produced by buprenorphine. These results demonstrate that buprenorphine served as a reinforcer under these conditions, and that it may have abuse liability in nonopioid-dependent individuals who abuse heroin.