A cholecystokinin B receptor antagonist and cocaine interaction, phase I study.

AIMS: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681. METHODS: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose. RESULTS: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA. CONCLUSION: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.

Bupropion for the treatment of methamphetamine dependence.

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p=0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (p<0.0001). Comorbid depression and attention-deficit/hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.

The SRPHK1 outcome measure for cocaine-dependence trials combines self-report, urine benzoylecgonine levels, and the concordance between the two to determine a cocaine-use status for each study day.

BACKGROUND: There is currently no FDA-approved medication for cocaine dependence and no standard primary outcome measure for reduction of cocaine use in cocaine-dependence trials. The ability to detect a significant medication effect will depend, in part, on the primary outcome measure utilized. The goal of the present paper is to compare self-report or either of two urine toxicology measures used alone to a relatively new measure -- the SRPHK1 -- which combines self-report, quantitative urine benzoylecgonine levels, and an estimate of the concordance between the two to determine the cocaine-use status of each study day. METHOD: Datasets from two separate randomized, placebo-controlled cocaine-dependence trials were used to compare four cocaine-use outcome measures. RESULTS: The two data sets yielded very similar findings and suggest that the combined measure is associated with significantly fewer missing data than urine toxicology and that estimated cocaine use varied significantly depending on which measure was used, with the lowest use estimate being yielded by self-report, the highest by the two urine toxicology measures evaluated, and an intermediate value obtained using the combined measure. The results also suggest that the concordance between self-report and urine toxicology is around 90% at the beginning of the clinical trial but decreases to around 75% by the end of the trial. CONCLUSION: By combining the objectivity of urine toxicology with the reduced incidence of missing data characteristic of self-report, the SRPHK1 may provide advantages over self-report or urine toxicology measures used alone. In any case, the SRPHK1 provides an interesting complement to these other outcome measures and may warrant further evaluation.

Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving.

Bupropion is an antidepressant with stimulant properties, which inhibits the reuptake of dopamine (DA) and norepinepherine, and is purported to enhance DA neurotransmission. Bupropion is considered an appealing candidate medication for the treatment of methamphetamine dependence. The current laboratory study was set forth to assess the impact of bupropion treatment on the subjective effects produced by methamphetamine in the laboratory. We also assessed the effects of bupropion treatment on craving elicited by exposure to videotaped methamphetamine cues. A total of 26 participants were enrolled and 20 completed the entire study (n=10 placebo and n=10 bupropion, parallel groups design). Bupropion treatment was associated with reduced ratings of 'any drug effect' (p<0.02), and 'high' (p<0.02) following methamphetamine administration. There was also a significant bupropion-by-cue exposure interaction on General Craving Scale total score (p<0.002), and on the Behavioral Intention subscale (p<0.001). Overall, the data reveal that bupropion reduced acute methamphetamine-induced subjective effects and reduced cue-induced craving. Importantly, these data provide a rationale for the evaluation of bupropion in the treatment of methamphetamine dependence.

Pharmacokinetics, bioavailability and opioid effects of liquid versus tablet buprenorphine.

AIMS: Two tablet formulations of buprenorphine (a buprenorphine mono-product, Subutex, and a buprenorphine/naloxone combination product, Suboxone) are available for use in the treatment of opioid addiction; however, the bulk of the clinical studies supporting its approval by the US Food and Drug Administration (FDA) were conducted with a sublingual liquid preparation. To assist the clinician in interpreting the relevant literature in establishing dosing parameters for prescription of tablet buprenorphine, this study was designed to compare the steady state: (1) pharmacokinetics and bioavailability, and (2) physiological, subjective and objective opiate effects of two 8 mg buprenorphine tablets (16 mg) to those of 1 ml (8 mg/ml) buprenorphine solution based upon early reports suggesting that the bioavailability of the tablet was approximately 50% of that of the liquid. DESIGN: Randomized, open-label, two-way crossover study. SETTING: Inpatient hospitalization for 21 days. PARTICIPANTS: Twenty-four male and females in general good health and meeting DSM-IV criteria for opiate dependence. INTERVENTION: Subjects received one of the two buprenorphine formulations in the first 10-day period, and the other for the second 10-day period with no washout. MEASUREMENTS: Pharmacokinetic analyses, opiate effects and adverse events. FINDINGS: Drug steady state was reached by Day 7 of each 10-day period, area under the curve for 16 mg (two 8 mg) tablets was higher than the solution. The only non-kinetic statistically significant difference observed between the formulations was in changes in total opioid agonist score. CONCLUSIONS: The serum concentration achieved by 16 mg of tablet buprenorphine is higher than that of the 8 mg solution, although differences between physiologic, subjective and objective opioid effects were not noted. The relative bioavailability of tablet versus solution is estimated to be 0.71; thus, with respect to dosing parameters for the tablet, clinicians should consider using less than 16 mg to achieve bioequivalence to the 8 mg solution.

Double-blind, placebo-controlled trial of selegiline transdermal system (STS) for the treatment of cocaine dependence.

BACKGROUND: Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Selegiline is an irreversible selective inhibitor of monoamine oxidase type B (MAO-B) which may affect cocaine addiction through several potential mechanisms. In this study, selegiline transdermal system (STS) was compared to placebo as a treatment for cocaine dependence. This multi-site, double-blind trial of 300 subjects with cocaine dependence assessed the efficacy of selegiline using subject self-reported cocaine use substantiated by urine benzoylecgonine (BE) as the primary outcome measure. Analysis of the data did not show a significant effect for selegiline over placebo. This study does not support a role for selegiline in treating cocaine dependence. The contrast of this result to earlier, promising preclinical and human pilot data could be due to factors associated with sample size, patient characteristics, dose, or poor predictive validity of preclinical models.

Pharmacokinetic Properties and Human Use Characteristics of an FDA-Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose.

Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose.

Placebo-controlled evaluation of a bioengineered, cocaine-metabolizing fusion protein, TV-1380 (AlbuBChE), in the treatment of cocaine dependence.

BACKGROUND: TV-1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE. METHODS: Intra-muscular injections of TV-1380 (150mg or 300mg) or placebo were administered once weekly to participants (n=66-69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of "no use" confirmed by urine testing. RESULTS: Although there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150mg and 300mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5-12 (8.1% and 14.6% for the 150mg and 300mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p=0.0056 for 300mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups. CONCLUSIONS: While the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity.

Safety of intravenous methamphetamine administration during treatment with bupropion.

RATIONALE: Methamphetamine dependence is a growing problem for which no medication treatments have proven effective. OBJECTIVES: We evaluated bupropion, an antidepressant with beneficial effects for the treatment of nicotine dependence, in patients with methamphetamine dependence, to assess the safety and tolerability of methamphetamine administration during bupropion treatment. METHODS: Twenty-six participants entered the study and 20 completed the protocol. Participants received intravenous methamphetamine (0, 15, and 30 mg) before and after randomization to twice-daily bupropion (150 mg SR) or matched placebo. Dependent measures included cardiovascular effects of methamphetamine, methamphetamine and amphetamine pharmacokinetics, and peak and trough plasma concentrations of bupropion and its metabolites. RESULTS: Bupropion treatment was well tolerated, with bupropion- and placebo-treated groups reporting similar rates of adverse events. Methamphetamine administration was associated with expected stimulant cardiovascular effects, and these were not accentuated by bupropion treatment. Instead, there was a trend for bupropion to reduce methamphetamine-associated increases in blood pressure and a statistically significant reduction in methamphetamine-associated increases in heart rate. Pharmacokinetic analysis revealed that bupropion treatment reduced the plasma clearance of methamphetamine and also reduced the appearance of amphetamine in the plasma. Methamphetamine administration did not alter the peak and trough plasma concentrations of bupropion or its metabolites. CONCLUSIONS: Methamphetamine administration was well tolerated during bupropion treatment. There was no evidence of additive cardiovascular effects when the drugs were coadministered. This study provides initial evidence for the safety of prescribing bupropion for the treatment of methamphetamine abuse and dependence. The impact of bupropion treatment in patients who abuse larger doses of methamphetamine remains undetermined.

A comprehensive assessment of the safety of intravenous methamphetamine administration during treatment with selegiline.

Selegiline (L-deprenyl) is a selective irreversible monoamine oxidase B inhibitor shown to be effective in the treatment of Parkinson's and Alzheimer's diseases. Recent evidence suggests that selegiline may also be useful in treating specific aspects of cocaine and nicotine dependence, generating interest in this compound for the treatment of methamphetamine addiction. To investigate this, we performed a randomized, single-blind, placebo-controlled study to evaluate the safety of selegiline treatment (as compared to placebo), concurrent with intravenous methamphetamine (15 or 30 mg). Secondary study objectives included determinations of plasma levels of selegiline and its metabolites, evaluating whether selegiline administration altered the pharmacokinetics of methamphetamine or its metabolites, and evaluating whether selegiline treatment alters the subjective responses to methamphetamine. Twenty-four methamphetamine-dependent participants were randomized to treatment, and 9 of these (N = 5 selegiline, N = 4 placebo) completed the entire protocol. The principal finding from this study was that intravenous administration of moderate doses of methamphetamine was safely tolerated during treatment with selegiline. No participants had electrocardiogram changes, and there were no meaningful differences in any laboratory values either between groups at screening or as a result of the study procedures. In general, adverse events were mild or moderate, and no subjects were discontinued due to adverse events or serious adverse events. Selegiline treatment did not enhance any of the cardiovascular changes (heart rate, blood pressure) produced by methamphetamine administration. Selegiline treatment slightly increased methamphetamine associated "bad effects" but did not alter any other subjective effects. The elimination half-life of methamphetamine was approximately 12 h, and selegiline did not alter clearance of methamphetamine. The available data suggest that selegiline is likely to be safe if used as a pharmacotherapy for methamphetamine dependence.

Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial.

AIM: Bupropion was tested for efficacy to achieve methamphetamine (MA) abstinence in dependent, non-daily users. METHODS: A randomized, double-blind, placebo-controlled trial, with 12-week treatment and 4-week follow-up, was conducted with 204 treatment-seeking participants having MA dependence per DSM-IV, who used MA on a less-than-daily basis. 104 were randomized to matched placebo and 100 to bupropion, sustained-release 150mg, twice daily. Participants were seen three times weekly to obtain urine for MA and bupropion assays, study assessments, and thrice weekly, 90-min, group psychotherapy. There was no biomarker for placebo adherence. The primary outcome was achievement of abstinence throughout the last two weeks of treatment; 'success' requiring at least two urine samples during each of Weeks 11 and 12, and all samples MA-negative (<300ng/mL). RESULTS: Bupropion and placebo groups did not differ significantly in the percentage achieving abstinence for the last 2 weeks of treatment (chi-square, p=0.32). Subgroup analysis of participants with lower baseline MA use (≤18 of last 30 days before consent) also revealed no difference in success between groups (p=0.73). Medication adherence per protocol (detectable bupropion, >5ng/mL, in ≥50% of urine samples from Study Weeks 1-10 and ≥66% of urine samples from Weeks 11 to 12) was achieved by 47% of participants taking bupropion. CONCLUSIONS: These data indicate that bupropion did not increase abstinence in dependent participants who were using MA less-than-daily. Medication non-adherence was a limitation in this trial. Psychosocial therapy remains the mainstay of treatment for MA dependence. Further research on subgroups who may respond to bupropion may be warranted.

Transdermal selegiline and intravenous cocaine: safety and interactions.

RATIONALE: Because the dopamine system appears to be involved in both acute and chronic effects of cocaine, medication development efforts for cocaine addiction have focused largely on agents that interact with the dopamine system. Selegiline, a selective monoamine oxidase B inhibitor, indirectly modulates dopamine levels, and research suggests selegiline may modify subjective effects of cocaine. OBJECTIVES: To evaluate further the safety and potential of transdermal selegiline as a treatment for cocaine dependence, interactions between transdermal selegiline and intravenous cocaine were studied in cocaine-dependent volunteers. METHODS: Pharmacokinetics and subjective, physiological, and endocrinological effects of intravenous cocaine (0,20 and 40 mg) were evaluated both before and during transdermal selegiline treatment (20 mg/day, 10 days) in 12 cocaine-dependent subjects. A transdermal selegiline formulation was used to avoid the risks associated with oral administration of MAO inhibitors. RESULTS: Selegiline attenuated some physiological (systolic blood pressure and heart rate) and subjective (good effects, liking, stimulated, high, desire for cocaine) effects of cocaine. Selegiline did not affect cocaine's pharmacokinetics or cocaine-induced prolactin decrease and growth hormone increase. CONCLUSIONS: The combined administration of the transdermal selegiline patch and up to 40 mg cocaine was well tolerated. Selegiline may reduce physiological and subjective effects of cocaine. A randomized trial is needed to evaluate the efficacy of selegiline for cocaine abuse.

Modafinil for the treatment of methamphetamine dependence.

AIM: Modafinil was tested for efficacy in decreasing use in methamphetamine-dependent participants, compared to placebo. METHODS: This was a randomized, double-blind, placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Eight outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, who all had a DSM-IV diagnosis of methamphetamine dependence; 68 participants to placebo, 72 to modafinil 200mg, and 70 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments, urine drug screens, and group psychotherapy. The primary outcome measure was a methamphetamine non-use week, which required all the week's qualitative urine drug screens to be negative for methamphetamine. RESULTS: Regression analysis showed no significant difference between either modafinil group (200 or 400mg) or placebo in change in weekly percentage having a methamphetamine non-use week over the 12-week treatment period (p=0.53). Similarly, a number of secondary outcomes did not show significant effects of modafinil. However, an ad-hoc analysis of medication compliance, by urinalysis for modafinil and its metabolite, did find a significant difference in maximum duration of abstinence (23 days vs. 10 days, p=0.003), between those having the top quartile of compliance (>85% of urines were positive for modafinil, N=36), and the lower three quartiles of modafinil 200 and 400mg groups (N=106). CONCLUSIONS: Although these data suggest that modafinil, plus group behavioral therapy, was not effective for decreasing methamphetamine use, the study is probably inconclusive because of inadequate compliance with taking medication.

Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial.

AIMS: Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction. DESIGN: Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. SETTING: The trial was conducted at eight medical centers in the United States. PARTICIPANTS: One hundred and forty methamphetamine-dependent adults took part in the trial. MEASUREMENTS: The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. FINDINGS: In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated. CONCLUSIONS: Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.

Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals.

BACKGROUND: Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABA(B) receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) vs placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60 mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies.

Modafinil for the treatment of cocaine dependence.

AIM: Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo. METHODS: This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days. RESULTS: The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p>0.79). However, two secondary outcomes showed significant effects by modafinil 200mg: the maximum number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p<0.02). CONCLUSIONS: These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.

Modafinil and cocaine interactions.

This Phase I trial evaluated the interaction between modafinil steady-state and cocaine. Twelve non-treatment seeking, cocaine dependent volunteers received four sets of randomized blinded infusions of saline, 20 mg IV cocaine, and 40 mg IV cocaine. Modafinil was given open label at 0 mg, 400 mg, or 800 mg. Modafinil combined with IV cocaine did not result in any significant hemodynamic interactions. Modafinil significantly dampened scores on Visual Analog Scale measures as compared to baseline cocaine conditions. No significant alterations in labs occurred. Further outpatient trials of modafinil appear to be warranted.