A dose-ranging study of the physiological and self-reported effects of repeated, rapid infusion of remifentanil in people with opioid use disorder and physical dependence on fentanyl.

RATIONALE: Understanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans. OBJECTIVES: This experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence. METHODS: An inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40-60 mg, 4x/day = 160-240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min. RESULTS: Pupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose. CONCLUSIONS: This experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.

Cocaine abstinence during the "critical period" of a contingency management trial predicts future abstinence in people with cocaine use disorder.

BACKGROUND: Contingency Management (CM) is being piloted as a treatment for stimulant use disorder in several US states, highlighting the need for treatment optimization. One important goal of optimization is decreasing drug use during the early stages of treatment, which has predicted success in other interventions. However, this "critical period" has not been reported in CM trials. The purpose of this analysis was to determine if, after accounting for baseline abstinence and incentive condition, abstinence in a CM trial for people with Cocaine Use Disorder (CUD) could be predicted by cocaine use during a first-week critical period. METHODS: Eighty-seven participants with CUD were randomized to receive contingent high or low value incentives for cocaine abstinence or were in a non-contingent control group. Generalized estimating equations (GEE) were used to analyze urine test results over 36 timepoints during the 12-week intervention. To assess for a critical period, the first three visits were included in the GEE as a covariate for remaining urine test results. RESULTS: Participants who provided more negative samples during the critical period were significantly more likely to produce a negative urine sample during the remainder of the trial, though some effects of group remained after controlling for the critical period. CONCLUSIONS: These results indicate that a critical period exists for CM trials, and it can explain a substantial amount of future performance. Early contact with an abstinence-contingent high magnitude alternative reinforcer may explain additional performance beyond the critical period, further justifying the use of high magnitude alternative reinforcers.

The endowment effect and temporal discounting of drug and non-drug commodities.

OBJECTIVES: Despite a rich history of behavioral economic research on substance use there remains a need for further exploration of behavioral mechanisms that may underlie the etiology or persistence of substance use disorder. The purpose of this study was to measure the association between delay discounting and the endowment effect in people who smoke cigarettes, use cocaine, and controls, using online crowdsourcing. METHODS: Participants were categorized to a cocaine group (n = 36), cigarette group (n = 48), or control group (n = 47) based on recent reported drug use. Based on group, participants completed up to three delay discounting tasks (i.e., money, cigarettes and cocaine), an endowment effect task for multiple commodities, and other questionnaires. RESULTS: Participants in the cocaine and cigarette group demonstrated an increased rate in discounting for money compared to controls. Participants in the cocaine group had a less pronounced endowment effect for beer, compared to controls, as suggested by willingness to accept less to sell beer. A significant negative association was found between endowment ratios for non-drug commodities and delay discounting for cigarettes, but not monetary or cocaine delay discounting, indicating an inconsistent relationship between the two measures. CONCLUSIONS: These results support prior research demonstrating a relationship between cocaine and cigarette use and delay discounting and extend that work by measuring the association between delay discounting and the endowment effect. Future research should include both loss aversion and endowment effect tasks and compare their relationship with delay discounting among people that use drugs.

Cannabis Use Disorder Treatment Preferences: A Pilot Survey in Current Users of Cannabis.

OBJECTIVES: Highly effective treatments for cannabis use disorder (CUD) are lacking, and patient preferences have not been considered during treatment development. We therefore conducted an exploratory crowdsourced survey of individuals reporting current cannabis use and a willingness to cut down or quit their cannabis use, to determine their interest in various treatment aspects. METHODS: Subjects (n = 63) were queried about their willingness to take medications as a function of type, route, and regimen and to participate in adherence monitoring. Subjects were also asked about their willingness to engage in behavioral/psychosocial interventions as a function of type, setting, and duration. Measures theorized to be associated with treatment preferences were also collected, including cannabis use variables, readiness to change, reduction or cessation goal, perceived cessation barriers, and medication use beliefs and behaviors. RESULTS: Survey responses indicated that efforts to develop CUD medications should focus on nonsynthetic compounds administered orally or by mouth spray no more than once per day to maximize patient acceptance. Remote adherence monitoring and one-on-one outpatient behavioral treatment approaches, especially contingency management, are also anticipated to enhance participation. Most subjects indicated a preference to reduce their cannabis use rather than quit. CONCLUSIONS: These data provide guidance for the development of CUD interventions based on the preferences of individuals interested in treatment for their cannabis use. Additional research is needed to confirm these results in a larger sample and determine if matching CUD patients with their preferred treatments improves success rates.

Differential impacts of economic and demographic variables on substance use patterns during the COVID-19 pandemic.

Background: The COVID-19 pandemic and subsequent economic crisis has provided a unique opportunity to investigate the effects of economic shifts on substance use. Existing literature on this relationship is limited and conflicting, warranting further exploration.Objective: This study aimed to identify relationships between socioeconomic status (SES), demographic variables, and substance use patterns before and after government-mandated business closures due to COVID-19.Methods: Participants were recruited based on self-reported substance use through Amazon's Mechanical Turk (MTurk). Qualifying participants (N = 315, 43% female, mean age = 35.35) reported their substance use and SES for two-week periods before and after pandemic-related business closures. Regression models analyzed relationships between substance use and study variables.Results: Regression models found that, during COVID-19 closures, greater financial strain predicted decreased benzodiazepine (ß = -1.12) and tobacco (ß = 1.59) use. Additionally, certain predictor variables (e.g., participants' age [ß = 1.22], race [ß = -4.43], psychiatric disorders including ADHD [ß = -2.73] and anxiety [ß = 1.53], and concomitant substance use [ß = 3.38]) predicted changes in substance use patterns; however, the directionality of these associations varied across substances.Conclusion: Specific substance use patterns were significantly and differentially impacted by economic strain, psychiatric diagnoses, and concomitant substance use. These results can help direct harm reduction efforts toward populations at greatest risk of harmful substance use following the pandemic.

An update on the clinical pharmacology of methylphenidate: therapeutic efficacy, abuse potential and future considerations.

INTRODUCTION: Methylphenidate remains a first-line medication for treating ADHD in children and adults. However, its behavioral pharmacological similarities to methamphetamine and cocaine have historically created concern for its potential as a drug of abuse. In September 2019, the FDA published a docket requesting comments for the development of abuse deterrent formulations for CNS stimulants, emphasizing the abuse of methylphenidate as a public health concern. AREAS COVERED: We conducted a narrative review of research on the clinical pharmacology, therapeutic efficacy, and abuse potential of methylphenidate. EXPERT OPINION: Several studies indicate that methylphenidate has at least some abuse potential. Methylphenidate, amphetamine, methamphetamine, and cocaine overlap in their subjective, reinforcing, and discriminative stimulus effects. Regardless, methylphenidate remains an efficacious treatment for ADHD in children and adults when properly adhered to, especially when paired with non-pharmacological treatments. The development of abuse deterrent formulations of methylphenidate is warranted.