Background: Although unapproved by the FDA for treating insomnia, trazodone is commonly prescribed in the US partly due to lack of scheduling, hence it’s perceived as safer than z-drugs and benzodiazepines. This study investigated trazodone abuse/dependence potential and safety risks. Methods: Cases involving trazodone or benzodiazepines (temazepam, triazolam, estazolam) frequently prescribed for insomnia were identified from the FDA Adverse Events Reporting System (FAERS), National Forensic Laboratory Information System (NFLIS) for confiscation data, and the American Association of Poison Control Centers’-National Poison Data System (AAPCC-NPDS). Drug-related falls risk was assessed from claims databases. Results: FAERS included 11,228 trazodone and 5120 benzodiazepine reports. Of these, drug-abuse and drug-dependence cases with trazodone were lower than benzodiazepines (drug-abuse: 6.4%/12.6%; drug-dependence: 1.1%/3.6%). Serious cases (81.8%/83.9%) and deaths (35.4%/36.0%), were similar between trazodone and benzodiazepines. NFLIS reported 612/1,575,874 (0.04%) drug-seizure cases that included trazodone. AAPCC-NPDS reported 22,225/1,446,011 (1.54%) total case mentions of trazodone/all pharmaceuticals and 8445 trazodone-related single-exposure cases. Falls risk (1year-period) in Medicare beneficiaries ≥65y and commercially-insured enrollees ≥18y was reported for trazodone and benzodiazepines: Medicare, 9.5%/11.3%; Commercially-insured: 4.6%/3.7%. Conclusions: Trazodone has abuse/dependence potential and important safety risks. Given limited data from well-controlled studies and off-label use, re-evaluation of trazodone prescribing rates in patients with insomnia is warranted.

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS Emax compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p < 0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.

REL-1017 (esmethadone, D-methadone) is the opioid-inactive d-isomer of racemic D,L-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-D-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted. We evaluated lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) Self-administration Study Rats were trained to self-administer oxycodone intravenously (IV) and then were subjected to 3-day substitution tests where saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal with functional observational batteries (FOBs). In the self-administration study, rats treated with saline, vehicle, and all REL-1017 doses showed the typical "extinction burst" pattern of response, characterized by an initial rapid increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated with oxycodone maintained stable self-injection, as expected for reinforcing stimuli. In the withdrawal study, REL-1017 did not engender either morphine or ketamine withdrawal signs over 9 days following abrupt discontinuation of drug exposure. REL-1017 showed no evidence of abuse potential and did not engender withdrawal symptomatology.

Abstract Introduction This randomized, open-label, crossover clinical study evaluated nicotine pharmacokinetics (PK) and subjective effects of the JUUL System (JS; Juul Labs, Inc.) with three nicotine concentrations compared to the usual brand (UB) cigarettes in 24 adult smokers. Methods At five study visits, subjects used either the JS in 59 mg/mL, JS 18 mg/mL (two visits), and JS 9 mg/mL (all tobacco-flavored) or smoked their UB cigarette first during a controlled puffing sequence (CPS) and then ad libitum (5 min) use sessions. Blood samples were taken at specified timepoints for 60 min in each session. The modified Product Evaluation Scale assessed subjective effects 30-min post-use in the CPS session. Results Maximum plasma nicotine concentration (Cmax-BL), total nicotine exposure (AUC0-60-BL), and rate of plasma nicotine rise were significantly lower for all JS products compared to subjects' UB cigarette in CPS and ad libitum use sessions. In both use sessions these PK parameters were significantly higher for JS 59 mg/mL compared to 18 and 9 mg/mL. Subjective measures of cigarette craving relief and “Enough Nicotine” for JS 59 mg/mL did not differ significantly from UB cigarettes, but JS 18 and 9 mg/mL were rated significantly lower than JS 59 mg/mL and UB cigarettes. Conclusions Nicotine exposure and subjective relief were directly related to JS nicotine concentration: higher nicotine concentrations gave rise to significantly greater plasma nicotine levels and relief from craving. Heavier and more dependent smokers may require the greater nicotine delivery of JS 59 mg/mL to successfully transition away from cigarettes. Implications It has been suggested that electronic nicotine delivery systems (ENDS) and other alternative nicotine delivery products that more closely mimic the nicotine pharmacokinetics (PK) of cigarettes may facilitate smokers transitioning away from cigarettes. We examined nicotine PK and subjective effects of JUUL System (JS) ENDS with three nicotine concentrations (59, 18 and 9 mg/mL) compared to combustible cigarettes. Nicotine delivery from JS ENDS was nicotine concentration dependent, with higher nicotine concentrations giving rise to higher nicotine exposure. These findings suggest that heavier and more dependent smokers may require ENDS with nicotine concentrations greater than 20 mg/mL to successfully transition away from cigarettes.

BACKGROUND:To assess the abuse liability of the JUUL System (JS) in 5.0 % (59 mg/mL) and 3.0 % (35 mg/mL) nicotine concentrations.METHODS:Adult smokers (N = 146; 45.9 % female; mean age = 41.29 years) were randomized to one of four study flavor arms and then to a within-subjects cross-over sequence for five test product categories: (1) JS 5.0 % nicotine concentration; (2) JS 3.0 % nicotine; (3) usual brand (UB) cigarette; (4) 4 mg mint nicotine gum; (5) comparator ENDS (VUSE Alto 5.0 % nicotine). Products were tested by ad libitum use (5 min for ENDS and cigarette; 30 min for gum); nicotine pharmacokinetic (PK) parameters and subjective effects were assessed following use.RESULTS:Maximum plasma nicotine concentration (Cmax-BL), rate of plasma nicotine rise and total nicotine exposure (AUC0-60-BL) of UB cigarette were significantly greater than all other test products. The comparator ENDS was significantly greater than 5.0 % and 3.0 % JS and nicotine gum on Cmax-BL, rate of plasma nicotine rise, and AUC0-60-BL; Cmax-BL of JS 5.0 % was significantly greater than JS 3.0 % and nicotine gum. Product liking and satisfying effects were significantly highest for the UB cigarette; JS products and comparator ENDS did not significantly differ and were rated higher than nicotine gum on most subjective measures.CONCLUSIONS:These results suggest that the abuse liability of both 5.0 % and 3.0 % JS is: (1) substantially lower than UB cigarette; (2) somewhat lower than comparator ENDS; and (3) higher than nicotine gum. Additionally, the abuse liability of JS 5.0 % is somewhat higher than JS 3.0 %.

BACKGROUND:The abuse liability of the JUUL System (JS) in four flavors were evaluated compared to combustible cigarettes, nicotine gum, and a comparator electronic nicotine delivery system (ENDS) with pharmacokinetics (PK) and subjective effects.METHODS:Adult smokers (N = 66; 50.0 % female; mean age = 41.1; 63.6 % white) completed a 7-arm within-subjects cross-over product-use study while confined to a clinical laboratory. Participants used JS in four flavors (Virginia Tobacco, Mango, Mint, Creme, [5.0 % nicotine; 59 mg/mL]), their usual brand (UB) cigarette, a comparator ENDS (VUSE Solo; 4.8 % nicotine, tobacco-flavor), and mint nicotine gum (4 mg) under controlled use conditions. After each product use, nicotine PK and subjective effects were assessed.RESULTS:Maximum plasma nicotine levels (Cmax-BL), rate of plasma nicotine rise, overall nicotine exposure (AUC0-60-BL), and subjective liking and satisfaction of JS were significantly lower than UB cigarettes. These parameters were generally greater for JS than nicotine gum; the comparator ENDS was somewhat lower but within the range of JS. Nicotine PK did not differ among the Mint, Mango, and Virginia Tobacco JS flavors. Mint and Mango were rated as more satisfying than Virginia Tobacco and Creme.CONCLUSIONS:Controlled use of JS among adult smokers resulted in nicotine delivery, product liking, and satisfaction that were less than that of combustible cigarettes but generally greater than nicotine gum. These results support the conclusion that JS has lower abuse liability than combustible cigarettes, higher abuse liability than nicotine gum, and may provide sufficient nicotine delivery and satisfying effects to support substitution for combustible cigarettes among adult smokers.

INTRODUCTION:Behavioral economics provides a framework for quantifying drug abuse potential that can inform public health risk, clinical treatment, and research. Hypothetical purchase task (HPT) questionnaires may provide a low-cost and sensitive method by which to measure and predict the appeal of pharmaceutical drugs that differ by formulation. However, the validity of this type of analysis must be empirically established by comparing the "essential value" (EV) of different drugs across subgroups.PROCEDURES:This pilot study used HPT assessments and the Exponential Model of Demand to quantify the EV of opioid medications-specifically, easily tampered formulations versus (vs.) abuse-deterrent formulations-in patients with a history of opioid abuse.MAIN FINDINGS:Participants had more inelastic demand for opioid pills than for cigarettes and alcohol. Participants with experience manipulating pills (M group) had more inelastic demand for standard pills vs. participants with no manipulation experience (NM group), and the M group had a more elastic demand for the abuse-deterrent opioid pill than for the standard pill. There was no effect of formulation in the NM group and there was no difference in demand elasticity for abuse-deterrent pills between the two groups. There was a positive correlation between the EVs of different drugs, and between some behavioral economic indices and treatment variables.CONCLUSIONS:Our results suggest that HPTs may provide a sensitive measure of abuse potential that can distinguish between different formulations in at-risk populations.

Background: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT((R)) instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. Objective: Use the ALERRT((R)) instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. Methods: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. Results: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0-99.0 and 77.0-99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0-14.8 and 2.3-17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators' ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5-175.8 seconds) and ER morphine sulfate (49.3-163.0 seconds) produced substantial to complete powdering in 92% of tablets. Conclusions: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.

The US Food and Drug Administration (FDA) considers the development of abuse-deterrent formulations of solid oral dosage forms a public health priority and has outlined a series of premarket studies that should be performed prior to submitting an application to the Agency. Category 1 studies are performed to characterize whether the abuse-deterrent properties of a new formulation can be easily defeated. Study protocols are designed to evaluate common abuse patterns of prescription medications as well as more advanced methods that have been reported on drug abuse websites and forums. Because FDA believes Category 1 testing should fully characterize the abuse-deterrent characteristics of an investigational formulation, Category 1 testing is time consuming and requires specialized laboratory resources as well as advanced knowledge of prescription medication abuse. Recent Advisory Committee meetings at FDA have shown that Category 1 tests play a critical role in FDA's evaluation of an investigational formulation. In this article, we will provide a general overview of the methods of manipulation and routes of administration commonly utilized by prescription drug abusers, how those methods and routes are evaluated in a laboratory setting, and discuss data intake, analysis, and reporting to satisfy FDA's Category 1 testing requirements.

Behavioral pharmacology methods and strategies are increasingly relied upon by the Food and Drug Administration (FDA) for its regulation of drug and tobacco products due to the reliability, validity, and generalizability of the findings. FDA is required to regulate products on the basis of their sci

Objective. Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design. This randomized, single-center, doubleblind, active-and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting. Inpatient clinical research site. Subjects. Forty-two randomized subjects (73.8% male, 81% white, mean age525 years). Methods. The primary objective was to evaluate single orally administered 100, 200, and 400mg NKTR-181 doses in solution compared with 40mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous systemmu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design. Results. NKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P< 0.0001). Drug Liking scores for oxycodone increased rapidly within 15minutes and peaked at approximately one hour postdose, whereas Drug Liking (and most secondary abuse potential measures) for all doses of NKTR-181 were comparable with placebo for at least the first hour. Only the 400mg Drug Liking scores were minimally differentiated vs placebo from one and a half to four hours, but remained significantly lower than oxycodone (P< 0.003). NKTR-181 treatment-related adverse effects were mild and occurred at a lower rate compared with oxycodone. Conclusions. NKTR-181 demonstrated delayed onset of CNS effects and significantly lower abuse potential scores compared with oxycodone in recreational opioid users.

Pharmaceutical risk management can be considered to be any strategies for minimizing risks and enabling the realization of the benefits of medications. Historically, risk management has been achieved through the drug label, which includes the US Controlled Substances Act (CSA) drug scheduling placement if abuse and dependence are considered sufficiently serious to warrant special restrictions. Since the late 1990s, additional strategies for addressing abuse- and dependence-related risks have been developed, including various postmarketing requirements for surveillance and reporting to the Food and Drug Administration. These strategies have been described in guidance documents and include risk assessment, risk management, and postmarketing surveillance. Preclinical abuse potential assessment provides early signals of potential risks and scheduling. Such studies are also considered in the premarket risk evaluation that guides recommendations concerning risk management strategies that go beyond drug scheduling along with the evaluation of abuse-deterrent drug products and how such evaluation might be informed by preclinical studies.