ABSTRACT
Aim Development of effective medications for the treatment of cocaine dependence remains a major priority for the National Institute on Drug Abuse (NIDA) at the National Institutes of ...Health. The Cocaine Rapid Efficacy Screening Trial (CREST) paradigm was developed by the Division of Treatment Research and Development (DT R&D) at NIDA with the goal of enhancing pilot clinical trial validity when systematically assessing a range of medications and drug classes for potential utility in treatment of cocaine dependence.
Design CREST utilizes a randomized, controlled, parallel group, blinded methodology for comparing one or more marketed medications against a standard, pharmaceutical grade placebo. The trial design is comprised of a flexible 2–4‐week screening/baseline period followed by randomization to an 8‐week treatment period.
Measures Standard measures of outcomes for the CREST included urinary benzoylecgonine (primary metabolite of cocaine), retention, cocaine craving, depression, clinical global impression and HIV‐risk behaviors. In order to facilitate comparisons of data from the CREST studies across sites, drug classes and time, standardized procedures, measures and psychosocial counseling were used.
Results A total of 19 medications were evaluated in out‐patient treatment research clinics in Boston, Cincinnati, Los Angeles, New York and Philadelphia.
Conclusions Findings supported decisions to move forward three medications (cabergoline, reserpine, tiagabine) using full‐scale, adequately powered, randomized placebo‐controlled trial designs. Lessons learned from the CREST experience continue to shape cocaine pharmacotherapy trial design and execution.
Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed ...to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.
A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate ...comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.
Gabapentin (GBP, Neurontin), a new antiepileptic drug (AED) with a novel mechanism of action, exhibits low acute toxicity in mice, rats, and monkeys, and is not teratogenic. GBP pharmacokinetics are ...simple and predictable; GBP is eliminated by urinary excretion, is not protein-bound or metabolized, does not induce or inhibit hepatic enzymes, and does not interact with other AEDs. In five placebo-controlled, double-blind studies of GBP as add-on therapy, 307 patients with refractory partial seizures received placebo and 485 received GBP dosages of 600, 900, 1,200, or 1,800 mg/day for 12 weeks following a 12-week baseline. Seizure frequency, as measured by response ratio and responder rate, was improved for patients receiving GBP compared with placebo; differences were statistically significant in two of the three large, multicenter studies. Adverse events occurred in 76% of GBP-treated patients, compared with 57% of placebo-treated patients. No serious adverse events were consistently attributable to GBP therapy. Changes in clinical laboratory values were not considered clinically important. GBP represents a significant addition to the armamentarium of AEDs available for treatment of patients with epilepsy.
We evaluated the role of positron emission tomography (PET) with 18Fdeoxyglucose (FDG) (FDG-PET) for planning surgery in 53 patients who had temporal lobectomy for uncontrolled seizures at National ...Institutes of Health from 1981 to 1990. Investigators blinded to PET data used results of telemetered video-electroencephalographic ictal monitoring and other standard criteria to decide whether subdural electrodes (22 patients, i.e., the "invasive" group) should be implanted or surgery performed. PET scans were analyzed using a standard regional template. Mean lateral but not mesial temporal asymmetry was significantly higher in patients who became seizure free (p < 0.03). Patients with > or = 15% hypometabolism were significantly more likely to be seizure free in the entire study population and the invasive subgroup. Visual identification of hypometabolism was less accurate. When a clear temporal ictal surface electroencephalographic focus was present, FDG-PET provided less additional information. FDG-PET may be particularly valuable if the surface electroencephalographic scan is nonlocalizing. In addition to helping to identify the seizure focus, it may allow limitation of invasive electrode placement to those necessary for functional mapping. When PET is used to identify epileptic foci, quantitative measurements of asymmetry should be made.
We compared the relative sensitivity of two interictal PET techniques, bolus injection of 15O labeled water for estimation of cerebral blood flow (H2(15)O CBF-PET), and 18F 2-deoxyglucose (18FDG-PET) ...for cerebral glucose metabolism (CMRglc), and T2-weighted magnetic resonance imaging, in 28 patients with medically intractable complex partial seizures undergoing evaluation for surgery. There were statistically significant associations between lateralization by 18FDG-PET, and MRI, but not H2(15)O CBF-PET, and lateralization of the epileptic focus as defined by scalp-sphenoidal ictal EEG. Fifteen patients had surgery or subdural electrodes. 18FDG-PET was more closely associated with a good outcome than H2(15)O CBF-PET, which, in addition, showed hypoperfusion contralateral to the epileptic temporal lobe in several cases. H2(15)O sensitivity may have been reduced by technical factors, but 18FDG-PET appears to be more specific for localization of epileptic zones.
We used 18Fcyclofoxy (CF), a potent opiate antagonist with affinity for mu and kappa receptors, and the Scanditronix PC1024-7B PET scanner to study 14 patients with complex partial seizures (CPS), ...and 14 normal controls. Epileptic foci were localized by prolonged EEG-video monitoring. EEG was recorded continuously during each scan. Immediately before CF administration, 15Olabeled water was used to measure cerebral blood flow, and showed hypoperfusion ipsilateral to the EEG focus. Blood samples (corrected for radiolabeled metabolites) and tissue time-activity data were acquired over 90 min following bolus CF injection. Anatomic regions were outlined directly on the PET images. A kinetic model was used to derive the total volume of distribution (Vt) in each brain region. Specific binding (Vs) was determined by substracting non-specific binding (Vt) measured in a receptor-poor brain region (occipital cortex). Regions with high Vs included mesial temporal lobes, thalamus, basal ganglia, and frontal cortex. Individual patients appeared to have higher binding in temporal lobe ipsilateral to the EEG focus, but there was no asymmetry for the patients as a group in mean Vt or Vs in anterior mesial, posterior mesial, anterior lateral, posterior lateral temporal cortex, thalamus, basal ganglia, or, for Vt, in regions of low specific binding: occipital lobe, parietal lobe, cerebellum.
The efficacy of gabapentin (Neurontin
®) in generalized seizures was evaluated in this 14 week, double-blind, placebo-controlled, parallel-group, add-on, multicenter study. A total of 129 patients ...with refractory generalized seizures were randomized to receive either placebo or 1200 mg/day gabapentin as add-on therapy. Patients received their standard regimens of antiepileptic drugs (AEDs) during a 12 week baseline period, and gabapentin or placebo was added-on in the subsequent 14 week evaluation period. Results of both an intent-to-treat (ITT) and evaluable-patient analyses showed that gabapentin provided greater reduction in the frequency of generalized tonic-clonic seizures than did placebo; however, the differences between treatments were not statistically significant. Gabapentin did not affect the frequency of absence or myoclonic seizures. Adverse events were reported by 67% of gabapentin-treated patients and by 56% of placebo-treated patients. The most frequently occurring adverse events amont patients receiving gabapentin were somnolenece, fatigue, and dizziness. Gabapentin is well tolerated by patients with generalized seizures. The results of this study show a trend toward an effect of gabapentin in reducing the frequency of generalized tonic-clonic seizures and suggest that further exploration of high dose gabapentin in generalized epilepsy is warranted.
We studied the effects of valproate (VPA) on local cerebral glucose metabolism (LCMRglc) in eight patients with partial seizure disorders and two with primary generalized epilepsy. Each patient had ...two positron-emission tomography (PET) scans with 18F-2-deoxyglucose (FDG), with, and without, VPA (mean level 52 mg/dl, range 30-127 mg/dl). Patients continued carbamazepine (CBZ) for both scans: serum concentrations were not significantly changed by VPA (CBZ range 5.4-12 mg/dl). Seven patients had the "without-VPA" scan first. Mean interval between PET scans was 75 days. Global CMRglc was decreased by 22% by addition of VPA (7.2 +/- 1.8 mg/100 g/min without VPA, 5.6 +/- 1.1 g/min with VPA, p less than 0.05, corrected). Thirteen regions of interest (ROIs) were analyzed in each hemisphere in each PET scan. Metabolic rates were significantly lower in 15 of 26 ROIs with VPA (p less than 0.05, corrected). VPA depresses cerebral metabolism to a greater degree than do CBZ and phenytoin (PHT) but less than does phenobarbital (PB). The metabolic effect may be related to the mechanism of action and have neuropsychological implications.
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