Measures That Identify Prescription Medication Misuse, Abuse, and Related Events in Clinical Trials: ACTTION Critique and Recommended Considerations.

Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD. PERSPECTIVE: Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation.

Phase II trial of continuous once-daily dosing of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib at 50 mg/day on the 4-weeks-on-2-weeks-off schedule is the current approved regimen for advanced/metastatic renal cell carcinoma (mRCC). Escudier et al reported that continuous, once-daily dosing with sunitinib 37.5 mg had a manageable safety profile and significant antitumor activity as second-line mRCC therapy. In this prospective, multicenter, phase II study, we evaluated the activity of continuous once-daily dosing with sunitinib 37.5 mg as first-line mRCC treatment. METHODS: One hundred nineteen treatment-naive patients with measurable mRCC received sunitinib. The primary endpoint was objective response; secondary endpoints included progression-free survival (PFS), safety, pharmacokinetic measurements, exploration of response biomarkers, and patient reported outcomes (PRO). RESULTS: Objective response rate (ORR) was 35.3%; median response duration was 10.4 months; 36% of patients had stable disease ≥12 weeks. Median PFS at 1 year was 9 months, and 1-year survival probability was 67.8%. The most common any-grade treatment-related adverse events (AEs) were diarrhea (50%) and hand-foot syndrome (43%); the most common grade 3-4 treatment-related AEs were hand-foot syndrome (13%), neutropenia (11%), and diarrhea (9%). Steady-state pharmacokinetics were reached within 3 weeks, with no disproportionate accumulation of sunitinib or its active metabolite throughout the study. No significant correlations between trough drug, active metabolite, or soluble protein levels and clinical response were observed. PRO was largely maintained, although fatigue appeared to worsen after treatment started, with improvement over time. CONCLUSIONS: Continuous once-daily dosing with sunitinib 37.5 mg was active with a manageable safety profile as first-line mRCC therapy, making this a feasible alternative dosing regimen.

Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial.

CONTEXT: Cocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy. OBJECTIVES: To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence. DESIGN: A 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24. SETTING: Cocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut. PARTICIPANTS: One hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%). INTERVENTION: Over 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein. Main Outcome Measure Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL. RESULTS: The 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 microg/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 microg/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths. CONCLUSIONS: Attaining high (>or=43 microg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. Trial Registration clinicaltrials.gov Identifier: NCT00142857.

Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction.

BACKGROUND: The prevalence, efficacy, and risk for addiction for persons receiving opioids for chronic back pain are unclear. PURPOSE: To determine the prevalence of opioid treatment, whether opioid medications are effective, and the prevalence of substance use disorders among patients receiving opioid medications for chronic back pain. DATA SOURCES: English-language studies from MEDLINE (1966-March 2005), EMBASE (1966-March 2005), Cochrane Central Register of Controlled Clinical Trials (to 4th quarter 2004), PsychInfo (1966-March 2005), and retrieved references. STUDY SELECTION: Articles that studied an adult, nonobstetric sample; used oral, topical, or transdermal opioids; and focused on treatment for chronic back pain. DATA EXTRACTION: Two investigators independently extracted data and determined study quality. DATA SYNTHESIS: Opioid prescribing varied by treatment setting (range, 3% to 66%). Meta-analysis of the 4 studies assessing the efficacy of opioids compared with placebo or a nonopioid control did not show reduced pain with opioids (g, -0.199 composite standardized mean difference [95% CI, -0.49 to 0.11]; P = 0.136). Meta-analysis of the 5 studies directly comparing the efficacy of different opioids demonstrated a nonsignificant reduction in pain from baseline (g, -0.93 composite standardized mean difference [CI, -1.89 to -0.03]; P = 0.055). The prevalence of lifetime substance use disorders ranged from 36% to 56%, and the estimates of the prevalence of current substance use disorders were as high as 43%. Aberrant medication-taking behaviors ranged from 5% to 24%. LIMITATIONS: Retrieval and publication biases and poor study quality. No trial evaluating the efficacy of opioids was longer than 16 weeks. CONCLUSIONS: Opioids are commonly prescribed for chronic back pain and may be efficacious for short-term pain relief. Long-term efficacy (> or =16 weeks) is unclear. Substance use disorders are common in patients taking opioids for back pain, and aberrant medication-taking behaviors occur in up to 24% of cases.

Effects of methadone on QT-interval dispersion.

STUDY OBJECTIVE: To evaluate the effects of methadone on QT-interval dispersion. DESIGN: Single-center, prospective, cohort study. SETTING: Methadone maintenance treatment facility. PATIENTS: One hundred eighteen patients who were newly admitted to the facility. Intervention. Twelve-lead electrocardiograms (ECGs) were performed in patients at both baseline and 6 months after the start of methadone therapy. MEASUREMENTS AND MAIN RESULTS: The ECGs were manually interpreted, and investigators were blinded to time interval and methadone dose. At least eight discernible ECG leads were required for study inclusion. Mean differences between baseline and follow-up rate-corrected QT (QTc) interval and QT dispersion were compared. Multivariate associations between clinical characteristics and magnitude of change in QT dispersion were assessed using linear regression. Mean +/- SD baseline QT dispersion was 32.9 +/- 12 msec, which increased to 42.4 +/- 15 msec (+9.5 +/- 18.6 msec, p<0.0001) after 6 months of therapy. The QTc increased by a similar magnitude (+14.1 msec, p<0.0001). No QT dispersion value exceeded 100 msec. The only variable associated with a greater increase in QT dispersion was antidepressant therapy (20 vs 8.5 msec, p=0.04). CONCLUSION: Methadone modestly increased both QTc interval and QT dispersion. Increased QT dispersion reflects heterogeneous cardiac repolarization and occurs with nonantiarrhythmic agents, such as synthetic opioids. However, the magnitude of this effect appears to be substantially less with methadone than with antiarrhythmic drugs.

Vaccine pharmacotherapy for the treatment of cocaine dependence.

BACKGROUND: Cocaine abuse has no established pharmacotherapy, but active immunotherapy with a cocaine vaccine shows promise as a therapeutic intervention. METHODS: An open label, fourteen week, dose-escalation study evaluated the safety, immunogenicity, and clinical efficacy of a novel human cocaine vaccine (TA-CD) in eighteen cocaine dependent subjects. Ten subjects (400 microg total dose group) received four-100 microg injections over the course of eight weeks. Subsequently, eight subjects (2000 microg total dose group) received five-400 microg vaccinations over twelve weeks. Intent to treat analysis of thrice weekly urine toxicologies and cocaine antibody titers were compared. RESULTS: Sixteen of 18 subjects completed the study. There were no serious adverse reactions and the vaccine was well tolerated. The 2000 microg total dose group had a significantly higher mean antibody titer response (2000 units) as compared to the 400 microg total dose group (1000 units) (p = .05). The 2000 microg group was more likely to maintain cocaine free urines than those in the 400 microg group (Z = -3.12, p = .002). Despite relapse in both groups, most reported an attenuation of cocaine's usual euphoric effects at the six month follow-up time points (63% in the 400 microg and 100% in the 2000 microg groups). CONCLUSIONS: The conjugated cocaine vaccine was well tolerated and cocaine specific antibodies persisted at least six months. The likelihood of using cocaine decreased in subjects who received the more intense vaccination schedule.

Impact of methadone treatment on cardiac repolarization and conduction in opioid users.

We prospectively assessed the effect of oral methadone on the corrected QT interval (QTc) among 160 patients free of structural heart disease and measured serum methadone concentrations and simultaneous QTc intervals in a subset of 44 participants. Mean +/- SD QTc increased by 12.4 +/- 23 ms (p <0.001) at 6 months, by 10.7 +/- 30 ms (p <0.001) at 12 months, and the QTc change from baseline to 12 months correlated with the trough (r = 0.37, p = 0.008) and peak (r = 0.32, p = 0.03) serum methadone concentrations.