Paul J. Fudala

Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.

CONTEXT The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful. OBJECTIVE To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth. DESIGN, SETTING, AND PATIENTS Clinical trial at 6 community programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone or a 14-day taper (detox). INTERVENTIONS Patients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling. MAIN OUTCOME MEASURE Opioid-positive urine test result at weeks 4, 8, and 12. RESULTS The number of patients younger than 18 years was too small to analyze separately, but overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12 (chi(2)(2) = 4.93, P = .09). At week 4, 59 detox patients had positive results (61%; 95% confidence interval [CI] = 47%-75%) vs 58 12-week buprenorphine-naloxone patients (26%; 95% CI = 14%-38%). At week 8, 53 detox patients had positive results (54%; 95% CI = 38%-70%) vs 52 12-week buprenorphine-naloxone patients (23%; 95% CI = 11%-35%). At week 12, 53 detox patients had positive results (51%; 95% CI = 35%-67%) vs 49 12-week buprenorphine-naloxone patients (43%; 95% CI = 29%-57%). By week 12, 16 of 78 detox patients (20.5%) remained in treatment vs 52 of 74 12-week buprenorphine-naloxone patients (70%; chi(2)(1) = 32.90, P < .001). During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less opioid use (chi(2)(1) = 18.45, P < .001), less injecting (chi(2)(1) = 6.00, P = .01), and less nonstudy addiction treatment (chi(2)(1) = 25.82, P < .001). High levels of opioid use occurred in both groups at follow-up. Four of 83 patients who tested negative for hepatitis C at baseline were positive for hepatitis C at week 12. CONCLUSIONS Continuing treatment with buprenorphine-naloxone improved outcome compared with short-term detoxification. Further research is necessary to assess the efficacy and safety of longer-term treatment with buprenorphine for young individuals with opioid dependence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00078130.

Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence

Buprenorphine is a partial μ‐opiate agonist and κ‐opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate 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.

Concurrent Validation of the Clinical Opiate Withdrawal Scale (COWS) and Single-Item Indices against the Clinical Institute Narcotic Assessment (CINA) Opioid Withdrawal Instrument

INTRODUCTION The Clinical Opiate Withdrawal Scale (COWS) is an 11-item clinician-administered scale assessing opioid withdrawal. Though commonly used in clinical practice, it has not been systematically validated. The present study validated the COWS in comparison to the validated Clinical Institute Narcotic Assessment (CINA) scale. METHOD Opioid-dependent volunteers were enrolled in a residential trial and stabilized on morphine 30 mg given subcutaneously four times daily. Subjects then underwent double-blind, randomized challenges of intramuscularly administered placebo and naloxone (0.4 mg) on separate days, during which the COWS, CINA, and visual analog scale (VAS) assessments were concurrently obtained. Subjects completing both challenges were included (N=46). Correlations between mean peak COWS and CINA scores as well as self-report VAS questions were calculated. RESULTS Mean peak COWS and CINA scores of 7.6 and 24.4, respectively, occurred on average 30 min post-injection of naloxone. Mean COWS and CINA scores 30 min after placebo injection were 1.3 and 18.9, respectively. The Pearsons correlation coefficient for peak COWS and CINA scores during the naloxone challenge session was 0.85 (p<0.001). Peak COWS scores also correlated well with peak VAS self-report scores of bad drug effect (r=0.57, p<0.001) and feeling sick (r=0.57, p<0.001), providing additional evidence of concurrent validity. Placebo was not associated with any significant elevation of COWS, CINA, or VAS scores, indicating discriminant validity. Cronbachs alpha for the COWS was 0.78, indicating good internal consistency (reliability). DISCUSSION COWS, CINA, and certain VAS items are all valid measurement tools for acute opiate withdrawal.

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.

Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence

Opiate dependence remains a fundamental challenge confronting health delivery systems and is often characterized as a social and moral issue. The impact of this disorder on healthcare policy is changing with the increased incidence of HIV, hepatitis C, and tuberculosis infections in opiate-dependent patients. These medical illnesses have substantial effect on escalating healthcare costs, and, therefore, also affect healthcare policy priorities, which are responsive to these costs. Pharmacological treatments for opiate dependence have had limited success; often the consequence of limited access to care. Hence, there is a need to develop new pharmacotherapies for opiate dependence that extend the range of clinical options, including new first-line treatment approaches. This paper will focus on the safety and health policy considerations related to the use of buprenorphine and buprenorphine/naloxone based on data derived from clinical trials and post-marketing surveillance that provide evidence for the use of the medications as first-line treatments in an office-based environment. The evaluation of this evidence formed the basis by the National Institute on Drug Abuse to support and pursue the evaluation and registration of buprenorphine/naloxone and buprenorphine in a public/private sector cooperative effort to become an office-based, first-line treatment for opiate 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.

Pharmacists' and technicians' perceptions and attitudes toward dispensing buprenorphine/ naloxone to patients with opioid dependence.

OBJECTIVE To assess the perceptions and attitudes of pharmacists and pharmacy technicians involved in an office-based opioid dependence treatment program using buprenorphine/naloxone. DESIGN Cross-sectional attitudinal assessment. SETTING Community, outpatient hospital, and clinic pharmacies. PARTICIPANTS Pharmacists and technicians participating in a clinical trial of opioid dependence treatment using buprenorphine/naloxone. INTERVENTION Written and telephone surveys followed by interviews with open-ended items. MAIN OUTCOME MEASURES Attitudes and perceptions regarding opioid-dependent patients and use of buprenorphine/naloxone for treatment of opioid dependence. RESULTS Pharmacies in seven states (New York, Virginia, Illinois, Florida, Texas, California, and Washington) participated in the clinical trial. A total of 40 pharmacists and pharmacy technicians responded to the initial written survey, representing 27 of the 32 pharmacies (84%). Follow-up interviews were obtained from one individual at 30 of those pharmacies (93.8%). Most pharmacy personnel (77.5%) involved with this study were not more concerned about theft or break-ins and would be willing to participate in opioid dependence treatment as the medication became available commercially (70%). The majority of respondents (85%) indicated that patients did not cause problems at their pharmacies. Compared with their experiences in administering other narcotic medications, most respondents did not express increased concern regarding prescription forgery (75%) or diversion (80%) of buprenorphine/naloxone. CONCLUSION The majority of respondents expressed positive attitudes and perceptions regarding patients treated for opioid dependence with buprenorphine/naloxone.

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.

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 morphines effects up to 48 h.