The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users.

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) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats.

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.

An Open-Label, Randomized, Controlled, Crossover Study to Assess Nicotine Pharmacokinetics and Subjective Effects of the JUUL System with Three Nicotine Concentrations Relative to Combustible Cigarettes in Adult Smokers.

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.

Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers.

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.

Abuse liability assessment of the JUUL system in two nicotine concentrations compared to combustible cigarette, nicotine gum and comparator electronic nicotine delivery system.

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 %.

Behavioral economic demand metrics for abuse deterrent and abuse potential quantification.

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.

Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared with Oxycodone.

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, double-blind, 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 age = 25 years). Methods: The primary objective was to evaluate single orally administered 100, 200, and 400 mg NKTR-181 doses in solution compared with 40 mg 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 system mu-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 15 minutes 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 400 mg 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.

The ALERRT® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets.

BACKGROUND: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT® 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® 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.

Laboratory-based testing to evaluate abuse-deterrent formulations and satisfy the Food and Drug Administration's recommendation for Category 1 Testing.

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.

Barbiturate detection in oral fluid, plasma, and urine.

BACKGROUND: Although current abuse of barbiturates is low compared with other classes of abused drugs, their narrow margin of safety, risk of dependence, and abuse liability remain a health concern. Limited information is available on the disposition of barbiturates in different biologic matrices. OBJECTIVE: The authors conducted a clinical study of the disposition of barbiturates in oral fluid, plasma, and urine after single-dose administration to healthy subjects. METHODS: Three parallel groups of 15 subjects were administered a single oral dose of one barbiturate: butalbital (50 mg), Phenobarbital (30 mg), or sodium secobarbital (100 mg). Subjects remained at the clinic for two confinement periods; the first was -1 to 36 hours postdose and again at 48 to 52 hours. Oral fluid specimens were collected by bilateral collection (Intercept; one on each side of the mouth simultaneously). Blood specimens were obtained by venipuncture and urine specimens were collected through separate collection pools of varying periods. Oral fluid specimens were analyzed for barbiturates by liquid chromatography-tandem mass spectroscopy with a limit of quantitation of 8 ng/mL. Plasma and urine specimens were analyzed by gas chromatography-mass spectroscopy with a limit of quantitation of 100 ng/mL. RESULTS: Barbiturate side effects included dizziness, drowsiness, and somnolence. All effects resolved spontaneously without medical intervention. The three barbiturates were detectable in oral fluid and plasma within 15 to 60 minutes of administration and in the first urine pooled collection at 2 hours. Butalbital and Phenobarbital remained detectable in all specimens through 48 to 52 hours, whereas secobarbital was frequently negative in the last collection. Oral fluid to plasma ratios appeared stable over the 1- to 48-hour collection period. CONCLUSION: This study demonstrated that single, oral therapeutic doses of butalbital, Phenobarbital, and secobarbital were excreted in readily detectable concentrations in oral fluid over a period of approximately 2 days. Oral fluid patterns of appearance and elimination were similar to that observed for plasma and urine.

Buprenorphine medication versus voucher contingencies in promoting abstinence from opioids and cocaine.

During a 12-week intervention, opioid dependent participants (N = 120) maintained on thrice-a-week (M, W, F) buprenorphine plus therapist and computer-based counseling were randomized to receive: (a) medication contingencies (MC = thrice weekly dosing schedule vs. daily attendance and single-day 50% dose reduction imposed upon submission of an opioid and/or cocaine positive urine sample); (b) voucher contingency (VC = escalating schedule for opioid and/or cocaine negative samples with reset for drug-positive samples); or (c) standard care (SC), with no programmed consequences for urinalysis results. VC resulted in better 12-week retention (85%) compared to MC (58%; p = 0.009), but neither differed from SC (76% retained). After adjusting for baseline differences in employment, and compared to SC, the MC group achieved 1.5 more continuous weeks of combined opioid/cocaine abstinence (p = 0.030), while the VC group had 2 more total weeks of abstinence (p = 0.048). Drug use results suggest that both the interventions were efficacious, with effects primarily in opioid rather than cocaine test results. Findings should be interpreted in light of the greater attrition associated with medication-based contingencies versus the greater monetary costs of voucher-based contingencies.

Pharmacotherapy for tobacco dependence.

Pharmacotherapy can provide effective treatment of tobacco dependence and withdrawal, and thereby facilitate efforts to achieve and sustain tobacco abstinence. Currently approved medications for smoking cessation are nicotine replacement medications (NRT), including nicotine patch, gum, lozenge, sublingual tablet, inhaler and nasal spray, the antidepressant bupropion, and the nicotinic partial agonist varenicline. This review discusses the pharmacological basis for the use of these medications, and the properties that might contribute to their efficacy, safety, and abuse liability. The review also discusses how pharmacological principles can be used to improve existing medications, as well as assist in the development of new medications.

Rapid absorption of nicotine from new nicotine gum formulations.

RATIONALE: A clinically limiting feature of currently-available nicotine gum is its slow rate of nicotine delivery and consequently slow onset of therapeutic effects. Previous research suggested that a nicotine hydrogen tartrate gum (NHTG1) that delivered nicotine more rapidly provided more effective craving relief. A subsequent gum formulation (NTHG2) was developed to further increase speed of delivery. OBJECTIVE: Compare the plasma nicotine absorption and clinical tolerability of NHTG2 to NHTG1 and Nicorette FreshMint. METHODS: A single-dose, randomized, crossover study evaluated the early kinetics of nicotine absorption and tolerability of 4 mg NHTG2 compared to NHTG1 and Nicorette. RESULTS: NHTG2 gum reached higher Cmax (p=0.059 versus Nicorette; p=0.006 versus NHTG1) and delivered significantly more nicotine than Nicorette or NHTG1 within the first 10-30 min of chewing (AUCs0-10, 0-30) and overall (AUC0-180). NHT gums and Nicorette were well tolerated, with little difference in their AE profiles. CONCLUSIONS: Study results indicate that NHTG2 gum provided more rapid uptake of nicotine in blood without notable decreases in tolerability. To the extent that rate of delivery and onset of therapeutic effects are related, these gums would be expected to provide more rapid therapeutic effects.

Computerized behavior therapy for opioid-dependent outpatients: a randomized controlled trial.

The authors evaluated the efficacy of an interactive, computer-based behavioral therapy intervention, grounded in the community reinforcement approach (CRA) plus voucher-based contingency management model of behavior therapy. Our randomized, controlled trial was conducted at a university-based research clinic. Participants comprised 135 volunteer adult outpatients who met DSM-IV criteria for opioid dependence. All participants received maintenance treatment with buprenorphine and were randomly assigned to one of three treatments: (a) therapist-delivered CRA treatment with vouchers, (b) computer-assisted CRA treatment with vouchers, or (c) standard treatment. The therapist-delivered and computer-assisted CRA plus vouchers interventions produced comparable weeks of continuous opioid and cocaine abstinence (M = 7.98 and 7.78, respectively) and significantly greater weeks of abstinence than the standard intervention (M = 4.69; p < .05), yet participants in the computer-assisted CRA condition had over 80% of their intervention delivered by an interactive computer program. The comparable efficacy obtained with computer-assisted and therapist-delivered therapy may enable more widespread dissemination of the evidence-based CRA plus vouchers intervention in a manner that is cost-effective and ensures treatment fidelity.

Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status.

Increasing the diversity and availability of medications for the treatment of tobacco dependence and/or withdrawal, to aid in the achievement of smoking cessation, is crucial to meet the diverse needs of tobacco users. Despite a general awareness that smoking is harmful and widespread interest in smoking cessation, nearly 50 million adults in the US and 1.3 billion worldwide continue to smoke. Nicotine replacement therapies are effective in the treatment of tobacco dependence and withdrawal, but do not meet the needs of all tobacco users. Improvement of tobacco dependence and/or withdrawal treatments is likely to rely on novel pharmacological approaches that include new chemical entities and new formulations of current drugs. In addition, new indications for treating tobacco dependence and withdrawal show promise for reducing tobacco use and associated disease. This article focuses on a range of novel pharmacological approaches for the treatment of tobacco dependence and/or withdrawal, including oral and pulmonary nicotine delivery and the following non-nicotinic medications: antidepressants, an alpha4beta2 nicotine partial agonist, an alpha2-noradrenergic agonist, cytochrome P450 (CYP) 2A6 inhibitors, opioid antagonists and GABAergic medications. In addition to existing medications, this article addresses novel medications in the clinical development stage and those that have been evaluated previously. Novel medications in the clinical development stage include at least three nicotine vaccines and the cannabinoid receptor acting drug rimonabant. Medications evaluated previously include lobeline, mecamylamine and an anticholinergic drug regimen comprising atropine, scopolamine and chlorpromazine. Having not been approved by major drug regulatory authorities for the treatment of tobacco dependence and/or withdrawal, these medications have been evaluated in an experimental capacity.

The relationship between temporal discounting and the prisoner's dilemma game in intranasal abusers of prescription opioids.

Previous research on college students has found that cooperation in iterated prisoner's dilemma game is correlated with preference for delayed rewards in studies of temporal discounting. The present study attempted to replicate this finding in a drug-dependent population. Thirty-one individuals who intranasally abuse prescription opioids participated in temporal discounting and iterated prisoner's dilemma game procedures during intake for a treatment study. Rate of temporal discounting was determined for each participant at two hypothetical reward magnitudes, as well as proportion of cooperation in a 60-trial iterated prisoner's dilemma game versus a tit-for-tat strategy. Cooperation in the prisoner's dilemma game and temporal discounting rates were significantly correlated in the predicted direction: individuals who preferred delayed rewards in the temporal discounting task were more likely to cooperate in the prisoner's dilemma game.

Nicotine delivery systems.

Over the past 20 years, medicinal nicotine has been used to aid smoking cessation, and has led to a significant increase in the number of smokers who successfully quit. This review describes currently available medicinal nicotine products, which include nicotine patch, gum, lozenge, nasal spray, inhaler and sublingual tablet, including their pharmacokinetics and recommended dosing. New developments in nicotine delivery that could further increase cessation rates include high-dose patches, rapid release gum, combined patch and acute forms, and several novel channels for nicotine delivery, such as nicotine drink, straw, lollipop and a pulmonary inhaler. New applications of existing and novel medicinal nicotine products may include relapse prevention, nicotine maintenance, temporary withdrawal management, reduced smoking and gradual quitting.

Pharmacotherapy for nicotine dependence.

Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on cancer, cardiovascular disease, lung disease, or other illness. This risk can be substantially reduced by smoking cessation, with greater benefits occurring the earlier in the smoking career that cessation occurs. However, cessation provides benefits at any stage, including after the onset of smoking-related disease, by improving the prognosis and quality of life. Clinicians can have a significant impact on reducing tobacco use by their patients by following the US Public Health Service Clinical Practice Guidelines. Proven strategies include structured methods of advising cigarette smokers to quit and guidance to facilitate their efforts, as well as the use of various pharmacotherapies. Pharmacotherapies for tobacco dependence include nicotine replacement medications in the form of gum, transdermal patch, lozenge, sublingual tablet, nasal spray, and vapor inhaler formulations. The only nonnicotine medication that has been approved by the US Food and Drug Administration is bupropion. Combination therapies, long-term medication therapies, and harm reduction strategies may further improve outcome with approved medications. Further, new medications such as varenicline and rimonabant are likely to reach tobacco users who are refractory to current treatments. Increasing the treatment options, increasing availability, and reducing the perceived cost of these medications may have an additional public health impact.

Tobacco abstinence symptom suppression: the role played by the smoking-related stimuli that are delivered by denicotinized cigarettes.

AIMS: Cigarette smoking causes cancer and disease, yet people find quitting difficult due to aversive symptoms that accompany tobacco abstinence. Understanding how to suppress these symptoms is critical in developing effective smoking cessation treatments. Pharmacologically, pure nicotine suppresses tobacco abstinence symptoms partially, and non-nicotine, smoking-related stimuli suppress these abstinence symptoms fully, at least for 24 hours. The current study was designed to clarify the impact of smoking-related stimuli on tobacco withdrawal, and to explore the duration of their ability to suppress withdrawal in smokers. DESIGN: Three double-blind, within-subjects, Latin square-ordered, 5-day conditions in which participants smoked nicotinized, denicotinized or no cigarettes. SETTING: Out-patient laboratory at Virginia Commonwealth University. PARTICIPANTS: Thirteen women and 19 men. MEASUREMENTS: Subjective, physiological and performance measures were collected daily and compliance with study conditions was verified objectively. FINDINGS: Smoking-related stimuli are sufficient for suppressing some symptoms of tobacco abstinence over a 5-day period [i.e. Questionnaire of Smoking Urges (QSU) factor 1, 'Desire for sweets', 'Hunger' and 'Urges to smoke'], while in this study a combination of nicotine and smoking-related stimuli suppressed other symptoms (i.e. 'Difficulty concentrating', 'Increased eating', 'Restlessness' and 'Impatient'). CONCLUSIONS: These results indicate that, while some tobacco abstinence symptoms may be suppressed with nicotine, suppressing others may also require strategies that address the absence of smoking-related stimuli.

Urine cotinine as an index of smoking status in smokers during 96-hr abstinence: comparison between gas chromatography/mass spectrometry and immunoassay test strips.

Biomarkers such as carbon monoxide (CO) and cotinine (a nicotine metabolite) are used in tobacco cessation studies to assess smoking status. CO is easy to assess, is inexpensive, and provides immediate results. However, the short half-life of CO may limit its ability to identify smokers who have abstained for several hours. Quantitative methods (e.g., gas chromatography/mass spectrometry, or GC/MS) for measuring urine cotinine, which has a longer half-life, are valid and reliable, though costly and time consuming. Recently developed semiquantitative urine cotinine measurement techniques (i.e., urine immunoassay test strips, or ITS) address these disadvantages, though the value of ITS as a means of identifying abstaining smokers has not been evaluated. The present study examined ITS as a measure of smoking status in temporarily abstaining smokers. A total of 236 breath and urine samples were collected from smokers who participated in two separate studies involving three independent, 96-hr (i.e., Monday-Friday), Latin-square-ordered, abstinence or smoking conditions; a minimum 72-hr washout separated each condition. Each urine sample was analyzed with GC/MS and ITS. Under these study conditions, CO demonstrated moderate sensitivity (83.1%) and strong specificity (100%), whereas ITS assessment showed strong sensitivity (98.5%) and weak specificity (58.5%). In this study of short-term abstinence, ITS classified as nonabstinent nearly half of the samples collected from abstaining smokers. However, it classified nearly all nonabstinent smokers as currently smoking. Validation of ITS using GC/MS results from smokers undergoing more than 96 hr of abstinence may be valuable.