A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-released formulation of risperidone.

RBP-7000 is a sustained-release (once-monthly injection for subcutaneous administration) formulation of risperidone using the ATRIGEL® Delivery System, developed for treatment of schizophrenia to address compliance issues associated with oral administration. The objective of this analysis was to report the results of a population pharmacokinetic analysis and to describe the relationship between risperidone and 9-hydroxyrisperidone levels with dopamine (DA) D2-receptor occupancy, prolactin levels, and adverse events using data collected in 45 clinically stable schizophrenic patients receiving RBP-7000 in single ascending doses (risperidone) of 60, 90, and 120 mg. The population PK model accounted for an initial peak, a delayed and slow delivery, the disposition of risperidone, and the conversion of risperidone to 9-hydroxyrisperidone. BMI was a covariate affecting absorption of risperidone and ultimately formation of 9-hydroxyrisperidone. A logistic analysis indicated a correlation between the increase in Active Moiety (risperidone + 9-OH-risperidone) exposure (Cmax ) and the probability of observing GI disorders. An Emax population PK/prolactin model best described the relationship between the circulating Active Moiety and the serum prolactin levels. Gender was a significant covariate associated with Emax . These data provided a comprehensive characterization of the relationship between circulating Active Moiety and the efficacy/safety profile of RBP-7000 in clinically stable schizophrenic patients.

A randomized, double-blind, placebo-controlled study of ritanserin pharmacotherapy for cocaine dependence.

Eighty cocaine-dependent individuals enrolled in outpatient treatment took part in a randomized, double-blind, placebo-controlled trial of ritanserin, a 5-HT(2) antagonist, as an adjunct therapy. Participants attended an outpatient day hospital therapy program each day and received tablets containing placebo or 10 mg ritanserin for a 4-week period. Primary outcome measures included retention in treatment, urine drug tests, and self-reports of craving. Secondary outcome measures were depression scores on the Beck and Hamilton inventories, negative mood as measured by the Profile of Mood States, and life functioning as measured by the Addiction Severity Index. Although participants showed improvement over the 4 weeks, there were no group differences on any of the measures. These results fail to support the use of ritanserin as a complement to outpatient psychosocial therapy for cocaine dependence.

Variability in the assessment of adverse events in a multicenter clinical trial.

BACKGROUND: Consistent documentation, characterization, and evaluation of adverse events (AEs) are needed during multicenter clinical trials to ensure accuracy of data reported to the US Food and Drug Administration and in the medical literature. OBJECTIVE: The purpose of this study was to identify and characterize variations in the assessment of AEs by clinical trial personnel. METHODS: During the annual meeting of personnel from a multicenter, controlled clinical trial of an investigational new drug treatment for opioid dependence, an oral presentation of procedures for AE data collection was given to 25 principal investigators and ancillary study personnel who assessed AEs for the study. A post-test using 3 hypothetical AE cases in which AEs were categorized by type of reaction, relatedness to study drug, severity, action taken, and outcome was completed by study participants. Cases and expected responses were reviewed for content and validity by clinical research pharmacists who were not involved with the study. The level of agreement with expected responses was assessed using McNemar symmetry chi-square tests. RESULTS: Assessments of type of AE, relatedness to study drug, and severity were less frequently aligned with expected responses than were action taken and outcome (P < 0.013). Less consistency with expected responses was found in I case than in the other 2, suggesting that certain types of AEs may be more difficult to assess. CONCLUSIONS: There was considerable variability in categorization of AEs in an exercise following training for AE data collection. Type of report, relatedness, and severity were found to have more variability in reporting than did action taken or outcome. The results suggest that unless data are gathered to verify reliability of reporting, subcategorization of AE data should be undertaken cautiously. Further research is needed regarding methods for improving consistency in reporting of AEs.

The medical management of adolescent heroin dependence.

The use of heroin by American adolescents is at its highest levels since the heroin epidemic of the 1960s. This clinical perspective reviews medical issues associated with adolescent heroin dependence. Older, as well as potential newer, treatments for adolescent heroin dependence are discussed. Multiple obstacles face a heroin-dependent adolescent who seeks treatment, including a lack of evidenced-based research on pharmacotheraputic agents for this population, strict restrictions on medications with demonstrated efficacy in adults, and a general lack of clinical experience in treating this population.

Nalmefene: blockade of intravenous morphine challenge effects in opioid abusing humans.

No studies have assessed the dose-effect or duration of opioid blockade in opioid abusers produced by oral nalmefene, a micro-opioid antagonist. The present study examined the profile and time course of oral nalmefene blockade of subjective and physiological effects produced by intravenous morphine. To assess these effects, seven opioid abusers received oral nalmefene (0, 50 and 100 mg) followed by intravenous morphine (0, 10 and 20 mg) challenges every 24 h for 96 h using a Latin square randomized cross-over design. The duration of blockade varied by measure and dose. Both 50 and 100 mg nalmefene blocked morphine's effects up to 48 h.

Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine.

AIMS: Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawal symptomatology during buprenorphine dose induction, maintenance treatments (daily and alternate-day dosing) and withdrawal. DESIGN: Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate-day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52. SETTING: Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD. PARTICIPANTS: Eleven male, heroin-dependent volunteers participating in a research study. INTERVENTION: Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine). MEASUREMENTS: Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter. FINDINGS: The mean steady-state buprenorphine plasma concentration (24 hours) after daily administrations of sublingual buprenorphine for study days 21-35 was 0.80 ng/ml, and the mean alternate day steady-state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady-state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady-state (days 21-35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half-lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively. CONCLUSIONS: during daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose with alternate-day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.

Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts.

The present study, conducted as part of the development of a buprenorphine/naloxone combination product, was designed to evaluate the individual and combined effects of intravenously administered buprenorphine and naloxone. This in-patient trial used a randomized, double-blind, crossover design. Ten opioid-dependent male subjects were stabilized and maintained on morphine, 15 mg given intramuscularly four times daily. Then, at 48- to 72-h intervals, subjects received one of the following by intravenous injection: (1) placebo, (2) morphine 15 mg, (3) buprenorphine 2 mg, (4) buprenorphine 2 mg/naloxone 0.5 mg, and (5) naloxone 0.5 mg. Both naloxone and buprenorphine/naloxone produced significant (P < 0.005) opioid withdrawal effects compared to placebo as assessed with the CINA scale, an instrument which utilizes subject- and observer-reported, as well as physiological parameters. The combination of buprenorphine with naloxone in a 4:1 ratio produced opioid antagonist-like effects which should limit its potential for intravenous abuse by opioid addicts.

Double-blind comparison of carbamazepine and placebo for treatment of cocaine dependence.

This study was conducted to determine the effectiveness of carbamazepine (CBZ) for treatment of cocaine dependence. Sixty-two (CBZ = 28, placebo = 34) cocaine-dependent (DSM-III-R criteria) volunteers consented to be treated for eight weeks with standardized outpatient individual counseling twice a week plus double-blind CBZ or inactive placebo. During the 8-week trial, both groups showed increased number of urine samples negative for cocaine, significantly (P < 0.01) decreased self-reported cocaine use (money spent and grams used), and decreased Beck Depression Inventory and Symptom Check List-90-Revised (SCL-90-R) total scores. However, there were no significant differences between CBZ and placebo. This study does not support the effectiveness of CBZ for outpatient treatment of cocaine dependence.

Carbamazepine treatment for cocaine dependence.

We report on a double-blind, placebo-controlled study of carbamazepine (CBZ) treatment for cocaine dependence. A previously reported uncontrolled study found CBZ to be a beneficial pharmacotherapy for cocaine dependence. Statistical analyses were performed on data from 82 subjects who were randomized to 10 weeks' treatment with either CBZ, titrated to 4-12 micrograms/ml, (n = 37) or placebo (n = 45). The two treatment groups did not differ for primary outcome measures of retention time in treatment, urine samples positive for cocaine metabolite, subject reported desire for cocaine or for subject reported side-effects. CBZ was not an effective treatment in this study.

A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids.

We compared the short-term efficacy of a high-dose, 3 day regimen of buprenorphine to a standard 5-day course of clonidine in attenuating the signs and symptoms of the acute opioid abstinence syndrome during rapid detoxification from heroin in 25 men and women admitted to a closed inpatient research ward for this randomized, double-blind, parallel-group trial. Among the 18 completers, there were no significant differences between the buprenorphine and clonidine groups on five subjective and six physiological measures. However, clonidine lowered blood pressure and buprenorphine provided more effective early relief of withdrawal symptoms.

A national survey of drug testing policies for college athletes.

This study examined current and proposed drug testing policies from a stratified random sample of colleges and universities in the United States. Two-hundred forty-five of the 288 athletic directors surveyed responded, and 29% reported drug testing of their student athletes. Testing was most commonly conducted on a random basis, with cocaine and amphetamines the most frequently screened drugs, 85% and 83%, respectively. Only 56% tested for other specific performance-enhancing drugs such as steroids. Referral for treatment was the most common consequence of testing positive. Among schools conducting testing, the majority of students supported the program, whereas in schools without a testing program, it was anticipated that the majority of students would be opposed. It is suspected that more schools will initiate testing over the short term.

An examination of current and proposed drug-testing policies at US colleges and universities.

Administrators at 400 colleges and universities were surveyed for information regarding their schools' current or proposed policies for the urine drug testing of faculty, nonfaculty employees, and students. Three hundred seven schools (77%) responded regarding their testing policies for employees and applicants for employment, including faculty and nonfaculty; 332 (83%) responded with respect to students. Twenty-five schools reported testing one or more of these groups. None of the schools reported randomly testing applicants for either faculty or nonfaculty positions, and none tested all applicants for all positions. Fewer than 7% of the colleges and universities surveyed reported that they tested urine of employees and applicants for employment to detect drug use. In those institutions that carried out tests, the tests were most often directed toward particular types of workers. Student testing was limited to approximately 2% of the 332 responding institutions.

Preemployment drug screening at the Johns Hopkins Hospital, 1989 and 1991.

During identical 2-month periods in 1989 and 1991, all applicants for employment at a major teaching hospital participated in preemployment drug screening. In 1989, before establishment of a formal preemployment testing program, screening was conducted without identifying information. Of 593 applicants screened, 64 (10.8%) were confirmed positive for one or more drugs. Marijuana metabolites were detected with the greatest frequency (35 samples, 55% of positive screens), followed by cocaine (36%), then opiates (28%). In 1991, after a formal preemployment testing program was in place, 365 applicants were screened, and 21 (5.8%) were confirmed positive. Opiates were most often detected (48% of positive screens), followed by cocaine (38%), then marijuana metabolites (28%). During both periods, positive urine screens were associated with ethnicity (non-White) and occupational category (blue-collar). Whereas in 1989 positive screens were associated with male gender, in 1991, females were more likely to test positive. The decline in prevalence following implementation of a screening program supports the notion that preemployment testing can serve as a deterrent for drug-using persons in applying for employment.

Travel and ciguatera fish poisoning.

BACKGROUND: Ciguatera fish poisoning is a distinctive clinical syndrome associated with the consumption of contaminated marine fish. It is endemic in many popular travel destinations, including the Caribbean and Pacific Islands, where travelers are at risk. METHODS: Clinical review of 23 patients (60% were travelers) with ciguatera fish poisoning in whom consultation was provided between 1987 and 1990. RESULTS: Seven patients acquired ciguatera fish poisoning during international travel to the following destinations: Bahamas (n = 4), Dominican Republic (n = 1), British Virgin Islands (n = 1), and United States (n = 1). Suspected fish included grouper, red snapper, and amberjack. Two patients required emergency care, and four patients developed chronic symptoms. Severity was associated with chronicity, duration of peak symptoms, and worsening of symptoms with sexual activity. Chronicity was associated with severity, long latency period, and duration of peak symptoms. The three patients with complete resolution were scuba divers. Amitriptyline was the drug most often providing benefit for chronic symptoms. CONCLUSIONS: Ciguatera fish poisoning is a health risk to travelers to endemic regions, and their risk likely equals that of indigenous population groups. Barracuda should never be eaten, and travelers should exercise caution when considering other fish dishes, notably, grouper and red snapper.

Weighing up the pros and cons: help-seeking by drug misusers in Baltimore, USA.

Forty drug misusers receiving treatment in Baltimore completed questionnaires, originally administered to drug misusers in London, about their reasons for seeking help and their worries about the treatment. Seeking help was related to the experiences of addiction, loss of control over life and financial and family difficulties. The main fears were of failing treatment. These responses are similar to those obtained in the London group. There was little correlation between objective assessment and subjects' views of their problems. This study illustrates the complexities of coming for treatment and it emphasises the need for social and medical help.

A controlled trial of buprenorphine treatment for opioid dependence.

OBJECTIVE: To assess the efficacy of buprenorphine for short-term maintenance/detoxification. DESIGN: A randomized, double-blind, parallel group study comparing buprenorphine, 8 mg/d, methadone, 60 mg/d, and methadone, 20 mg/d, in a 17-week maintenance phase followed by an 8-week detoxification phase. SETTING: Outpatient facilities at the Addiction Research Center, Baltimore, Md. PATIENTS: One hundred sixty-two volunteers seeking treatment for opioid dependence. INTERVENTION: In addition to the medication, counseling using a relapse prevention model was offered but not required. PRIMARY OUTCOME MEASURES: Retention time in treatment, urine samples negative for opioids, and failure to maintain abstinence. RESULTS: Throughout the maintenance phase, retention rates were significantly greater for buprenorphine (42%) than for methadone, 20 mg/d (20%, P less than .04); the percentage of urine samples negative for opioids was significantly greater for buprenorphine (53%, P less than .001) and methadone, 60 mg/d (44%, P less than .04), than for methadone, 20 mg/d (29%). Failure to maintain abstinence during the maintenance phase was significantly greater for methadone, 20 mg/d, than for buprenorphine (P less than .03). During the detoxification phase, no differences were observed between groups with respect to urine samples negative for opioids. For the entire 25 weeks, retention rates for buprenorphine (30%, P less than .01) and methadone, 60 mg/d (20%, P less than .05), were significantly greater than for methadone, 20 mg/d (6%). All treatments were well tolerated, with similar profiles of self-reported adverse effects. The percentages of patients who received counseling did not differ between groups. CONCLUSIONS: Buprenorphine was as effective as methadone, 60 mg/d, and both were superior to methadone, 20 mg/d, in reducing illicit opioid use and maintaining patients in treatment for 25 weeks.

Background and design of a controlled clinical trial (ARC 090) for the treatment of opioid dependence.

This study represents the largest clinical trial reported to date that demonstrated the efficacy of buprenorphine for opioid dependence treatment (Johnson et al. 1992). Although the study design was adequate to demonstrate differences between treatment groups, there has not been a consensus regarding the most appropriate method for analyzing various outcome measures of this and similar studies. To present a comprehensive review of these methods, other chapters in this monograph focus on various analytical techniques for assessing one of these measures--urine toxicology screens--for illicit opioids.

Development of buprenorphine for the treatment of opioid dependence.

Data from these studies indicate that buprenorphine is efficacious in treating opioid dependence. It was possible to induct heroin addicts rapidly onto buprenorphine without precipitating an opioid withdrawal syndrome. A daily 8-mg SL dosage was sufficient to maintain individuals without producing reports of withdrawal symptoms. When buprenorphine was administered at the above dose every other day, however, mild withdrawal symptoms were reported, and responses to challenges with intravenously given hydromorphone appeared greater than when the challenges were given intramuscularly. From these results, the authors conclude that buprenorphine at this dose should be administered on a daily basis. These results are now being applied to a phase II outpatient clinical trial comparing buprenorphine with methadone.