A novel electroencephalography-based tool for objective assessment of network dynamics activated by nociceptive stimuli.

BACKGROUND: Pain perception is typically assessed using subjective measures; an objective measure of the response to pain would be valuable. In this study, Brain Network Activation (BNA), a novel multivariate pattern analysis and scoring algorithm, was applied to event-related potentials (ERPs) elicited by cortical responses to brief heat stimuli. Objectives of this study were to evaluate the utility of BNA as a quantitative and qualitative measure of cortical response to pain. METHODS: Contact Heat Evoked Potentials (CHEPs) data were collected from 17 healthy, right-handed volunteers (10 M, 7F) using 5 different temperatures (35, 41, 46, 49 and 52 °C). A set of spatio-temporal activity patterns common to all the subjects in the group (Reference Brain Network Model; RBNM) was generated using the BNA algorithm, based on evoked responses at 52 °C. RESULTS: Frame by frame 'unfolding' of the brain network across time showed qualitative differences between responses to painful and non-painful stimuli. Brain network activation scores were shown to be a better indicator of the individual's sensitivity to pain when compared to subjective pain ratings. Additionally, BNA scores correlated significantly with temperature, demonstrated good test-retest reliability, as well as a high degree of sensitivity, specificity and accuracy in correctly categorizing subjects who reported stimuli as painful. CONCLUSIONS: These results may provide evidence that the multivariate analysis performed with BNA may be useful as a quantitative, temporally sensitive tool for assessment of pain perception.

Oral ketamine as a positive control in human abuse potential studies.

The selection of a relevant and appropriate positive control is of key importance in the design of a clinical abuse potential study. Ketamine is a N-methyl-d-aspartate receptor antagonist used clinically as an anaesthetic, yet also abused for its euphoric and perceptual properties. The current study sought to identify 2 doses of oral ketamine that are safe and produce subjective effects that would make them suitable for use as positive controls in abuse potential studies. A single-center, partially double-blind, placebo-controlled, ascending dose (65, 100 and 150 mg) study was carried out in 11 healthy recreational polydrug users who first passed a pharmacologic qualification session to ensure they could distinguish and like the effects of a psychoactive drug (20mg d-amphetamine) compared to placebo. Subjective data were collected through questionnaires (e.g., Addiction Research Center Inventory [ARCI] scales) and visual analog scales (VAS). Generally, oral ketamine was well tolerated and could be used safely at 65 mg and 100mg. Peak responses to ketamine were significantly different (p<0.05) from placebo on measures of positive (e.g., drug liking VAS), perceptual (e.g., VAS of floating, detached, hallucinating) and sedative (e.g., ARCI phenobarbital-chlorpromazine-alcohol group scale) effects. Effects were generally not dose-dependent, though significant differences for some subjective effects measures were observed between 65 mg and 100mg ketamine. The current study indicates that oral ketamine doses of 65 mg and 100mg are useful positive controls for future abuse potential studies of compounds with a similar mechanism of action, or with possible perception-altering and euphoric effects.

Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT2C) receptor agonist, in recreational polydrug users.

Lorcaserin is a selective and potent serotonin 2C receptor subtype (5-HT(2C)) agonist under development for the treatment of obesity. This study assessed the drug's abuse potential on the basis of its pharmacological profile. For this purpose, a double-blind, double-dummy, placebo-controlled, randomized seven-way crossover study with single oral doses of lorcaserin (20, 40, and 60 mg), zolpidem (15 and 30 mg), ketamine (100 mg), and placebo was conducted in recreational polydrug users (N = 35). Subjective and objective measures were assessed up to 24 h after the dose. We found that zolpidem and ketamine had significantly higher peak scores relative to placebo on the primary measures as well as on most of the secondary measures. The subjective effects of a 20-mg dose of lorcaserin were similar to those of placebo, whereas supratherapeutic doses of lorcaserin were associated with significant levels of dislike by users as compared with placebo, zolpidem, and ketamine. Perceptual effects were minimal after administration of lorcaserin and significantly lower than after administration of either ketamine or zolpidem. The findings suggest that, at supratherapeutic doses, lorcaserin is associated with distinct, primarily negative, subjective effects and has low abuse potential.