Assessing methylphenidate preference in ADHD patients using a choice procedure

Rationale Methylphenidate (MPH) is widely used in the treatment of attention deficit hyperactivity disorder (ADHD) and is associated with positive clinical effects across a wide range of domains. Despite the clinical effectiveness of MPH, concern has arisen with respect to its abuse potential.Objectives To assess MPH preference in adults diagnosed with ADHD using a choice procedure and to evaluate the relationship among drug preference, therapeutic efficacy, and abuse potential in a clinical sample.Methods Participants were ten volunteers (ages 18–22 years) with ADHD who were receiving MPH treatment. Preference was assessed using a double-blind choice procedure with four sampling sessions wherein subjects received either placebo or MPH and eight choice sessions when they chose either capsule or no capsules.Results Overall, MPH was chosen significantly more often than placebo ( ²=52.5; P<0.001) and participants were equally separated into groups of those who chose MPH reliably (MPH choosers) and those who did not (MPH non-choosers). MPH decreased ADHD symptoms and resulted in lower ratings of stimulant effects among MPH choosers. MPH choosers also reported higher levels of baseline ADHD symptoms.Conclusions Despite higher preference of MPH than placebo in this clinical sample, other measures of abuse potential were not elevated, and MPH choosers were more symptomatic than non-choosers. As such, MPH preference in ADHD populations likely reflects therapeutic efficacy rather than abuse potential. Future work should examine MPH choice in diagnosed and non-diagnosed populations to further explore the role of clinical efficacy in the preference of this stimulant drug.     

Behavioral economic analysis of natural resolution of drinking problems using IVR self-monitoring

This study investigated whether a behavioral economic index of the value of rewards available over different time horizons predicted patterns of alcohol consumption shortly after natural resolution when the risk of relapse is high. Using a computerized interactive voice response (IVR) telephone system, untreated problem drinkers (n = 41) self-monitored their daily drinking, monetary expenditures, and surrounding contexts over intervals that ranged from a maximum of 42 to 128 days. Expanded Timeline Followback interviews were conducted before and after the IVR interval and 1 year after the baseline assessment. Stable resolutions generally and moderation resolutions specifically were associated with proportionally more preresolution expenditures on savings and less on alcohol compared to heavy drinking outcomes. The findings replicated and extended earlier research and suggested that the extent to which problem drinkers organized their behavior over longer intervals, even when drinking abusively, helped identify who resolved, including who transitioned to stable moderation.     

Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure

Rhesus monkeys were trained in a discretetrials choice procedure and allowed to choose between food delivery (1–16 pellets; 1 g/pellet) and intravenous injections of cocaine (0.03–0.56 mg/kg/injection;N=4) or procaine (1.0–10 mg/kg/injection;N=4) during daily 3-h sessions. Injections were available as the alternative to food. When the amount of food available as the alternative to drug was held constant and dose of drug was varied, the frequency of drug choice and total drug intake increased in a dose-related fashion for both cocaine and procaine. For both drugs, when the amount of food available as the alternative to drug was increased and the dose of the drug was held constant, the frequency of drug choice and total drug intake decreased. Thus, increases in the magnitude of an alternative non-drug reinforcer decreased cocaine and procaine self-administration. Further, the results suggest that while increasing the magnitude of the alternative reinforcer decreased the potency of cocaine as a positive reinforcer, the reinforcing efficacy of procaine was decreased. Because drug use by humans typically occurs in a context in which other reinforcers are available, the present results are consistent with the hypothesis that drug self-administration by humans can be decreased by increasing the value of alternative positive reinforcers. In addition, these results suggest that the extent to which drug self-administration is sensitive to this manipulation varies across drugs.     

Behavioral economic analysis of opioid consumption in heroin-dependent individuals: effects of unit price and pre-session drug supply

Behavioral economic analysis has been used to investigate factors underlying drug consumption in laboratory animals and, increasingly, in human drug abusers. However, there are few studies in heroin abusers, especially those who are not in treatment; such studies may be valuable for understanding the mechanisms of persistent drug use. This study investigated effects of unit price (UP) and pre-session supply of hydromorphone (HYD) on choice and consumption of HYD. Heroin-dependent research volunteers (n=13) stabilized on buprenorphine 8 mg/day completed this eight-session inpatient study. In sessions 1-2, participants sampled two total HYD doses (12 and 24 mg IM) that could be earned in later sessions. In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio schedule lasting 3h. On each trial, volunteers could earn a HYD unit dose (1 or 2 mg, for a maximum of 12 or 24 mg, respectively) or money (US dollars 2, for a maximum of US dollars 24). Fixed ratio requirements increased exponentially, generating 24 unit prices for behavioral economic analysis. Before some choice sessions, volunteers could choose (FR 1) to receive extra HYD (12 or 24 mg; at 0915), whereas on other days no supplement was available. HYD choice and peak responding (breakpoint, O(max)) measures increased with unit dose, decreased with pre-session supplements, and were greater among volunteers who used cocaine prior to the experiment. Taking pre-session supplements decreased P(max) and made group-percent HYD consumption more demand-elastic. Consumption was functionally equivalent at differing FR/unit dose combinations. Thus, opioid demand in heroin-dependent individuals not in treatment is a function of drug supply, unit price, and cocaine use.     

Assessing individual differences in ethanol preference using a cumulative dosing procedure

Preference for ethanol versus a placebo was assessed in 12 normal volunteers using a cumulative dosing preference test. The test consisted of four sampling sessions followed by three choice sessions. During the sampling sessions subjects received either five cumulating oral doses of ethanol (0.1g/kg per dose) or equal volumes of placebo, at 15-min intervals. Subjective and observer-rated drug effects, psychomotor performance, drug liking ratings, and breath ethanol levels were measured at regular intervals. During choice sessions, subjects first chose which of the two substances (drug or placebo) they wished to take and ingested one unit dose. Then, at 15-min intervals throughout the session, they could ingest up to ten additional unit doses of the same substance (i.e., up to 1.1 g/kg ethanol). On average, the subjects chose the ethanol-containing beverage on 75% of the choice sessions, and they self-administered a mean total dose of 0.8g/kg per session. Subjects varied in the amount of ethanol ingested on choice sessions, and the amount they chose was related to their subjective responses to the drug during sampling. Subjects who chose the most ethanol reported experiencing stimulant-like effects from the ethanol, whereas the subjects who chose ethanol less frequently and ingested lower doses reported primarily sedative-like effects from the drug. The results demonstrate that the cumulative dosing procedure can be used effectively to evaluate drug preferences and dose preferences in normal volunteers.     

Assessing pentobarbital preference in normal volunteers using a cumulative dosing procedure

Preference for pentobarbital was assessed in 12 normal healthy volunteers using a seven-session cumulative dosing choice procedure. On the first four sessions subjects sampled the drug and a placebo, and on the last three sessions they chose the substance they preferred. During each of the sampling sessions they ingested, at 30-min intervals, five capsules containing either pentobarbital (30 mg per dose) or placebo. During the choice sessions subjects first chose which capsules they preferred to take (drug or placebo), and then took from one to seven of these capsules, separated by 30 min between ingestions. Self-report measures of subjective effects were obtained at regular intervals during each session. Subjects chose the pentobarbital-containing capsules on average 52% of choice sessions, and ingested an average total dose of 132 mg. Although the drug produced only modest, sedative-like subjective and behavioral effects and there was little evidence of euphoric effects in the group as a whole, individual differences in drug liking and choice were observed. The results are discussed in terms of variables that affect the reinforcing effects of pentobarbital in normal volunteers, and they are contrasted to previous findings using this procedure with other sedative drugs.     

Non-Bayesian knowledge propagation using model-based analysis of data from multiple clinical studies

The ultimate goal in drug development is to establish the manner of safe and efficacious administration to patients. To achieve this in an efficient way the information contained in the clinical studies should contribute to the increasing pool of accumulated knowledge. The aim of this simulation study is to investigate different knowledge-propagation strategies when the data is analysed using a model-based approach in NONMEM. Pharmacokinetic studies were simulated according to several scenarios of the underlying model and study design, including a population-optimal design based on analysis of a previous study. Five approaches with different degrees of knowledge propagation were investigated: analysing the studies pooled into one dataset, merging the results from analysing the studies separately, fitting a pre-specified model that has been selected from a previous study on either the most recent study or on the pooled dataset, or naïvely analysing the most recent study without any regards to any previous study. The approaches were evaluated on what model was selected (qualitative knowledge, investigated by stepwise covariate selection within NONMEM) as well as parameter precision (quantitative knowledge) and predictive performance of the model. Pooling all studies into one dataset is the best approach for identifying the correct model and obtaining good predictive performance and merging the results of separate analyses may perform almost as well. Fitting a pre-specified model on new data is fast, without selection bias, and sanctioned for model-based confirmatory analyses. However, fitting the same pre-specified model to all available data is still fast and can be expected to perform better in terms of predictive performance than the unbiased alternative. Using ED-optimal design of sample times and stratification of subjects from different subgroups is a successful strategy which allows sparse sampling and handles prior parameter uncertainty.     

Effects of single or multiple choice trials per session on drug discrimination performance

Drug discrimination procedures typically provide for multiple choice opportunities per training session. This practice allows non-drug cues (presence or absence of reinforcement) to mediate choice behavior during that portion of the session following the initial choice. In this experiment, rats were trained to discriminate 1.0 mg/kg cyclazocine from saline using a novel procedure that employed a single-choice trial per training session. Drug discrimination acquisition and generalization were compared to those of rats given discrimination training with 30 choice trials per session. The one-trial procedure yielded stable and reliable acquisition but more slowly than did the multiple trials procedure. The one-trial procedure produced longer first trial choice latencies and enhanced the tendency for subjects to respond on both choice levers during the first trial. The cyclazocine generalization functions were comparable, but the one-trial subjects more often responded on both choice levers, particularly when administered intermediate test doses of cyclazocine. Control of choice behavior by the reinforcer cue was evaluated on a mid-session cue reversal test. Multiple-trial subjects persisted in responding on the saline level following a midsession injection of cyclazocine, whereas one-trial subjects shifted to the cyclazocine-appropriate lever.     

Interchangeability evaluation of multisource Ibuprofen drug products using biowaiver procedure

The WHO biowaiver procedure for BCS Class II weak acids was evaluated by running two multisource IR ibuprofen drug products (Ibuprofen, 200 mg tablets, Tatchempharmpreparaty, Russia and Ibuprofen, 200 mg tablets, Biosintez, Russia) with current Marketing Authorizations (i.e. in vivo bioequivalent) through that procedure. Risks associated with excipients interaction and therapeutic index were considered to be not critical. In vitro dissolution kinetic studies were carried out according WHO Guidance (WHO Technical Report Series, No. 937, Annexes 7 and 8) using USP Apparatus II (paddle method) at 75 rpm. Dissolution profiles of test and reference ibuprofen tablets were considered equivalent in pH 4.5 using factors f(1) (13) and f(2) (72) and not equivalent in pH 6.8 (factor f(1) was 26 and f(2) was 24). Drug release of ibuprofen at pH 1.2 was negligible due to its weak acid properties. Therefore, two in vivo bioequivalent tablets were declared bioinequivalent by this procedure, indicating that procedure seems to be over-discriminatory.     

Behavioral economic analysis of smoking: money and food as alternatives.

The relative reinforcing value of smoking versus two nonpharmacological reinforcers, money and food, was evaluated in young female smokers in two experiments. In Experiment 1 eight smokers worked for access to smoking or money on concurrent progressive variable ratio schedules of reinforcement (VR4 to VR50) across two days of Smoking Deprivation or No Deprivation. During No Deprivation money was reliably chosen over smoking. During Deprivation subjects initially (VR4) chose smoking over money, but at subsequent comparisons allocated equal time to work for smoking or money. In Experiment 2 eight smokers were provided access to smoking or food across four conditions: No Deprivation, Smoking Deprivation, Food Deprivation and Smoking + Food Deprivation, using the same progressive variable ratio schedules as in Experiment 1. Results showed an increase in the reinforcing value of food after Food Deprivation and smoking after Smoking Deprivation. On the dual deprivation day, subjects initially (VR4) chose to work for food, showed equal preferences over the next three schedule comparisons (VR8-VR20), and from VR25-VR50 shifted their choice to smoking. An increase in percent of calories as fat was observed during all deprivation conditions. The results demonstrate the use of the concurrent schedule paradigm for assessing choice among pharmacological and nonpharmacological reinforcers, and shows the relative reinforcing value of smoking depends on recent deprivation, response demands to obtain the reinforcer and availability of alternative reinforcers.     

Statistical analysis of polymorphic drug metabolism data using the Rosin Rammler Sperling Weibull distribution

Summary The Rosin Rammler Sperling Weibull distribution and its use in the analysis of complex data is explained with reference to metoprolol and acebutolol AUC values and isoniazid plasma concentrations. The technique is then applied to sparteine and debrisoquine data to resolve populations into distinct sub-groups. Goodness of fit is measured by applying the X ² test to the untransformed data. The method is simple to use and sub-groups can be identified rapidly. Each sub-group can be characterised by a simple exponential equation.     

Assessing performance of sequential analysis methods for active drug safety surveillance using observational data

The routine use of sequential methods is well established in clinical studies. Recently, there has been increasing interest in applying these methods to prospectively monitor the safety of newly approved drugs through accrual of real-world data. However, the application to marketed drugs using real-world data has been limited and work is needed to determine which sequential approaches are most suited to such data. In this study, the conditional sequential sampling procedure (CSSP), a group sequential method, was compared with a log-linear model with Poisson distribution (LLMP) through a SAS procedure (PROC GENMOD) combined with an alpha-spending function on two large longitudinal US administrative health claims databases. Relative performance in identifying known drug–outcome associations was examined using a set of 50 well-studied drug–outcome pairs. The study finds that neither method correctly identified all pairs but that LLMP often provides better ability and shorter time for identifying the known drug–outcome associations with superior computational performance when compared with CSSP, albeit with more false positives. With the features of flexible confounding control and ease of implementation, LLMP may be a good alternative or complement to CSSP.     

Behavioral economics of drug self-administration

In behavioral economics, consumption of a reinforcer is determined by its price and by the price of other available reinforcers. This study examined the effects of price manipulations on the consumption of concurrently available coffee and cigarettes. During fifteen 4-h sessions, coffee and cigarettes were concurrently available according to fixed-ratio (FR) schedules of reinforcement. After consumption stabilized under a fixed ratio 100 for both reinforcers, the response requirement for each reinforcer was varied separately (i.e., FR 100, 1000 and 2500), while the response requirement for the other reinforcer was kept at 100. Increasing the FR value decreased coffee and cigarette consumption to a similar degree. Also, as the price for cigarettes increased (and consumption decreased), coffee consumption decreased; however, as the price of coffee increased, cigarette consumption did not change. These results indicate that for this setting the reinforcing effects of cigarettes and coffee were comparable but interacted asymmetrically. These findings when analyzed and quantified via economic concepts of own-price and cross-price elasticity illustrate the viability of using behavioral economics to examine drug self-administration in a choice paradigm.This study was supported by National Institute on Drug Abuse Grants DA 06626, KO1 DA 00109, DA 04545, and T32 DA 07242.     

Behavioral economics of drug self-administration

The maintenance of a characteristic level of nicotine in a smoker's body is referred to as nicotine regulation. Considerable research has examined this question of whether smokers regulate nicotine intake. This is because nicotine regulation raises the question of whether smokers who, to decrease their intake of tar, switch to low tar/low nicotine cigarettes will increase the number and/or intensity of cigarettes smoked. Although the results of studies examining nicotine regulation are reported as generally consistent, considerable variability exists across these analyses such that the health hazards of smoking low tar/nicotine cigarettes remains uncertain. In the present analysis, these studies were analyzed to ascertain whether a behavioral-economic interpretation could better quantify the effects of changing nicotine yield on individuals' nicotine and smoke consumption. Specifically, 17 nicotine-regulation studies were reanalyzed using a unit-price analysis (i.e., cost-benefit analysis). The reanalysis showed less variability across regulation studies than previously reported; a positively-decelerating demand curve was found across most studies, consistent with previous unitprice analyses of food- and drug-maintained behavior. The benefits of this reanalysis versus the traditional regulation interpretation are that the behavioral economics approach: 1) brings unity to a variable set of data, 2) shows a nonlinear relationship, previously considered to be linear, between nicotine consumption and nicotine yield, 3) shows that nicotine yields higher, and not lower, than the smoker's usual brand decrease smoke consumption and thus decreases consumption of the harmful agents in tobacco, 4) better quantifies the data and provides a more parsimonious interpretation that generalizes to other drugs and food-maintained behavior in humans and nonhumans and, 5) integrates behavioral and pharmacological factors that control the consumption of reinforcers. These results suggest the value of behavioral economics in the study of consumptive behaviors and clinically suggest, in agreement with the studies contained herein, that decreasing the smoker's usual nicotine yield can have potential healthrisks for smokers who are unable to stop smoking.     

The discrimination of drug mixtures using a four-choice procedure in pigeons

Abstract Rationale. The purpose of these experiments was to study drug combinations as discriminative stimuli using a new four-choice procedure. Objectives. To determine whether pigeons could discriminate among a mixture of two drugs, each of the component drugs and saline, and to study other drug combinations in these birds. Methods. Pigeons were trained to discriminate among saline, 5 mg/kg morphine, 5 mg/kg pentobarbital, and a mixture of these two doses using a four-choice procedure. Results. When responding stabilized, the birds responded on the correct key more than 90% of the time. Low doses of all drugs given alone produced responding on the saline key. Higher doses of pentobarbital and chlordiazepoxide produced responding on the pentobarbital key, and higher doses of morphine produced responses on the morphine key. Methamphetamine produced responding on the saline key. None of the drugs given alone produced responding on the mixture key. When pentobarbital was combined with morphine, doses both below and above the combined training doses of these drugs usually produced responding on the mixture key. The combination of chlordiazepoxide with morphine produced similar results. Combinations of methamphetamine with pentobarbital or with morphine produced effects similar to those of pentobarbital or morphine given alone. Conclusions. A wide range of combinations of pentobarbital and morphine, or chlordiazepoxide and morphine produce responding on the mixture key, even though the pigeons were not exposed to these dose combinations during training. The four-choice procedure provides the opportunity to study drug mixtures in a detail not possible with more limited response choices. Electronic Publication     

Pharmacokinetic analysis of drug concentration data obtained during repetitive drug administration

A digital computer method that uses all drug concentration-time data collected during repetitive dosing studies was developed to simultaneously estimate pharmacokinetic parameters and fit the data. The method utilizes the nonlinear least-squares regression program NONLIN. It can accommodate changes in dose and dosing interval during the regimen and it permits curve fitting on the basis of one of a number of linear pharmacokinetic models. Theoretical data containing 10% uniformly distributed pseudorandom error and experimental data from three clinical studies were used to validate the method. Reasonably precise and accurate parameter estimates and good curve fits were obtained.Supported in part by Grant GM-20852 from the National Institute of General Medical Sciences, National Institutes of Health.