Neuroinflammation drives sex-dependent effects on pain and negative affect in a murine model of repeated mild traumatic brain injury.

ABSTRACT: The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water. Repeated mild traumatic brain injury mice developed cold nociceptive hypersensitivity and negative affective states, as well as increased locomotor activity and risk-taking behavior. Minocycline reversed negative affect and pain hypersensitivities in male but not female mice. Repeated mild traumatic brain injury also produced an increase in microglial and brain-derived neurotropic factor mRNA transcripts in limbic structures known to be involved in nociception and affect, but many of these changes were sex dependent. Finally, we show that the antiepileptic drug, gabapentin, produced negative reinforcement in male rmTBI mice that was prevented by minocycline treatment, whereas rmTBI female mice showed a place aversion to gabapentin. Collectively, pain hypersensitivity, increased tonic-aversive pain components, and negative affective states were evident in both male and female rmTBI mice, but suppression of microglial reactivity was only sufficient to reverse behavioral changes in male mice. Neuroinflammation in limbic structures seems to be a contributing factor in behavioral changes resulting from rmTBI.

Menthol versus non-menthol flavouring and switching to e-cigarettes in black and Latinx adult menthol combustible cigarette smokers: secondary analyses from a randomised clinical trial.

BACKGROUND: As the US Food and Drug Administration takes regulatory action on menthol cigarettes, debate continues about how restricting menthol e-liquids might impact adult menthol smokers in switching to e-cigarettes. METHODS: Switching patterns and e-cigarette acceptability were assessed at week 6 among 64 black and Latinx menthol cigarette smokers who used JUUL menthol (n=39) or non-menthol e-cigarettes ((n=25), primarily mint or mango) as part of a randomised switching trial. RESULTS: No clear evidence of effects was found between menthol versus non-menthol e-cigarettes on use or subjective effects/acceptability, effect sizes for all comparisons were small (effect size=0.0-0.2), and Bayes factor ranged from 0.10 to 0.15. Specifically, 82.1% of participants who used menthol-flavoured e-cigarettes fully or partially switched to e-cigarettes compared with 88.0% of participants who used a non-menthol (p=0.75). Further, both groups demonstrated substantial reductions in cigarettes per day (menthol e-cigarettes: -8.5±10.4 vs non-menthol e-cigarettes: -8.8±5.8, p=0.87), comparable grams of e-liquid consumed (menthol e-cigarettes: 9.2±9.8 g vs non-menthol e-cigarettes: 11.0±11.0 g, p=0.47), and positive subjective effects, including 'just right' throat hit (menthol e-cigarettes: 70.7% vs non-menthol e-cigarettes: 66.7%, p=0.93) and flavour liking (menthol e-cigarettes: 75.6% vs non-menthol e-cigarettes: 66.7%, p=0.32). CONCLUSIONS: Both menthol and non-menthol e-cigarettes were associated with high rates of use and acceptability among menthol smokers. Findings require confirmation in a fully powered non-inferiority or equivalence study but provide preliminary evidence to inform regulatory action on menthol e-cigarettes that could slow youth initiation without impacting black and Latinx menthol cigarette smokers interested in switching to e-cigarettes. TRIAL REGISTRATION NUMBER: NCT03511001.

Denial and Diagnosis of Methamphetamine Dependence Severity.

Introduction: Denial, or lack of awareness of problems related to substance misuse, is a common feature of drug use disorders and can affect engagement in treatment and recovery. This study tested for association of denial with severity of symptoms used in the diagnosis of Methamphetamine Dependence. Methods: This secondary analysis used data from 69 participants (52.2% male) who met criteria for the diagnosis of Methamphetamine Dependence on the Structured Clinical Interview for DSM-IV (SCID). The association between diagnostic severity, determined from a SCID summary score (8 items), and denial, measured by the University of Rhode Island Change Assessment Scale (URICA) Precontemplation score, was tested by Pearson correlation. In post hoc t-tests, participants who differed on individual SCID items were compared on the Precontemplation score. The additional URICA subscales (Contemplation, Maintenance, Action) were also tested on a secondary basis. Results: SCID summary scores were negatively correlated with URICA Precontemplation scores (P = .003). Post-hoc tests revealed that participants who denied continued methamphetamine use despite persistent or recurrent problems (SCID item 6) had significantly higher Precontemplation scores than those who endorsed these problems (t = 3.066, P = .003). In contrast, positive correlations were observed between diagnostic severity and greater openness/willingness to change on the URICA (eg, Maintenance, r = .26; P = .01). Conclusions: The findings highlight the importance of a patient's insight regarding their addiction in clinical diagnosis. Because minimizing the impact of methamphetamine use may preclude or delay treatment, it is advised that self-report be supplemented to improve accuracy of diagnosis.

Effects of Marijuana Use on Smokers Switching to E-Cigarettes in a Randomized Clinical Trial.

INTRODUCTION: Co-use of tobacco and marijuana is common, and research suggests that marijuana use may be a barrier to smoking cessation. Research to date has not evaluated how marijuana use affects e-cigarette switching behaviors and related outcomes in a harm reduction trial. AIMS AND METHODS: This secondary analysis includes African American (48%) and Latinx (52%) adult smokers randomized to the e-cigarette group (N = 114) of a harm reduction clinical trial from 2018 to 2019. Participants were provided JUUL e-cigarettes and encouraged to make an exclusive switch for 6 weeks. Our primary outcome was cigarettes smoked per week. Secondary health outcomes were e-cigarette substitution (calculated by measuring e-cigarette pod use), expired carbon monoxide (CO), and respiratory symptoms. Marijuana products were recorded at three timepoints and coded for combustion. RESULTS: Marijuana use during the study (n = 52, 46%) was not associated with week 6 cigarettes smoked or e-cigarette substitution, and combustible marijuana use was not associated with week 6 respiratory symptoms (ps > .05). After controlling for cigarettes smoked at week 6, combustible marijuana use was significantly associated with a 4.4 ppm increase in CO compared with no use of marijuana (p = .001). CONCLUSIONS: Marijuana use was not a barrier to switching to e-cigarettes in this 6-week trial. Marijuana use contributed to elevated CO, reflecting greater exposure to toxic combustion products, beyond the effects of cigarette smoking. Marijuana co-use may increase risk of adverse health outcomes and may be a confounding factor when using CO as an endpoint to bioverify exclusive e-cigarette use. IMPLICATIONS: This is the first known study to examine the effects of marijuana use on smokers switching to e-cigarettes. Marijuana use was not a barrier to cigarette reduction in a 6-week randomized clinical trial. Marijuana use uniquely contributed to higher carbon monoxide among cigarette smokers, indicating greater exposure to toxic combustion products, which could increase risk of adverse health outcomes. Furthermore, combustible marijuana use may be a confounding factor when CO is used as an endpoint to bioverify exclusive e-cigarette use.

Tobacco Tracker: A New Tool to Support College Smoke and Tobacco Free Policies.

INTRODUCTION: University community members are critical to the success of their smoke and tobacco free (STF) policies. The present study evaluates changes in social enforcement-related attitudes and behaviors following introduction of a new online Tobacco Tracker tool in two university settings. METHODS: Campus wide surveys were administered to current students, faculty, and staff at two California public universities with 100% STF policies before (November 2018; N = 5078) and after (December 2019-January 2020; N = 4853) introduction of Tobacco Tracker in February 2019. Prospective surveillance reports over 12 months from Tobacco Tracker, a GIS tool for the campus community to report tobacco use and related litter that displays crowdsourced maps of hotspots, were analyzed. Outcomes included awareness and self-reported use of a tobacco reporting tool, readiness for policy social enforcement, an Intellectual Social Affective (ISA) Engagement scale, and environmental surveillance reports from Tobacco Tracker. RESULTS: In campus surveys, awareness of a tobacco reporting tool doubled (8.0%-16.9%, p < .0001), use of an online reporting tool tripled (1.1%-3.2%, p < .0001), and readiness to enforce the policy increased (p = .0008). ISA engagement did not change (p = .72). In Tobacco Tracker campus reports (N = 1163), active tobacco use was reported more frequently than tobacco-related litter. CONCLUSIONS: Tobacco Tracker is a promising tool for college communities to support STF policy. Introduction of Tobacco Tracker was associated with an increase in campus awareness and utilization of a reporting tool, readiness to enforce policy, and campus tobacco surveillance. Future research should determine how Tobacco Tracker may improve policy compliance. IMPLICATIONS: Tobacco Tracker is a promising tool for college communities to support smoke and tobacco free (STF) policy through active surveillance of smoking, vaping, and related litter on campus. Introduction of Tobacco Tracker was associated with changes in social enforcement-related attitudes and behaviors critical to realizing the preventive potential of STF policies. A crowdsourcing-based tool for monitoring tobacco use on college campuses can address a major barrier to social enforcement: discomfort confronting tobacco users. Further, it provides an alternative to punitive enforcement approaches and promises a sustainable solution to an infrastructure issue faced by many universities lacking resources to collect data on campus tobacco use and related litter.

Changes in dependence, withdrawal, and craving among adult smokers who switch to nicotine salt pod-based e-cigarettes.

BACKGROUND AND AIMS: For electronic cigarettes (e-cigarettes) to be a viable substitute for combustible cigarettes, it is likely that they must be rewarding enough for regular use, indicated by factors such as craving and dependence, important aspects of reinforcement. This study aimed to understand short-term changes in measures of nicotine dependence between groups differing by use trajectory in a switching trial, and within group changes of these measures. DESIGN: Secondary data analysis of one arm of an e-cigarette randomized clinical trial. SETTING: San Diego, California and Kansas City, Missouri, United States. PARTICIPANTS: 114 African American (n = 60) and Latinx (n = 54) smokers (58.8% male) attempting to switch to nicotine salt pod system (NSPS) e-cigarettes in a 6-week trial. MEASUREMENTS: At week 6, participants were classified by use trajectory: exclusive smokers (n = 16), exclusive e-cigarette (n = 32), or dual users (n = 66). E-cigarette, cigarette, and total nicotine dependence (cigarette + e-cigarette), use patterns, cigarette craving and nicotine withdrawal, and cotinine were assessed at baseline and week 6 using standard measures. FINDINGS: In between group comparisons, exclusive e-cigarette and dual users showed greater reductions in cigarette dependence (e-cigarette: -32.38, 95% CI = -37.7,-27.1; dual: -18.48, 95% CI = -22.2,-14.7), withdrawal (e-cigarette: -6.25, 95% CI = -8.52,-3.98; dual: -3.18, 95% CI = -5.02,-1.34), craving (e-cigarette: -11.44, 95% CI = -14.2,8.7; dual: -9.59, 95% CI = -11.6,-7.59), and cigarettes per day (CPD; e-cigarette: -11.19, 95% CI = -13.1,-9.27; dual: -9.39, 95% CI = -11.3, -7.52) compared with exclusive smokers. In within group analyses, e-cigarette and dual users showed reductions in craving and withdrawal from baseline to week 6. Exclusive e-cigarette and dual users, maintained cotinine levels (all Ps > 0.05) and showed reductions in CPD and cigarette dependence (all Ps < 0.01). Findings were inconclusive regarding changes in total nicotine dependence from baseline to week 6 among exclusive e-cigarette users (P = 0.123). Dual users showed increased total nicotine dependence (P < 0.001) and smokers showed decreased total dependence (P = 0.004). CONCLUSIONS: Smokers who switch to nicotine salt pod system e-cigarettes maintain their nicotine levels and transfer their dependence, suggesting that nicotine salt pod system e-cigarettes have a similar reinforcement potential to cigarettes and facilitate switching.

The Development of a Web-Based Tobacco Tracker Tool to Crowdsource Campus Environmental Reports for Smoke and Tobacco-Free College Policies: Mixed Methods Study.

BACKGROUND: College campuses in the United States have begun implementing smoke and tobacco-free policies to discourage the use of tobacco. Smoke and tobacco-free policies, however, are contingent upon effective policy enforcement. OBJECTIVE: This study aimed to develop an empirically derived web-based tracking tool (Tracker) for crowdsourcing campus environmental reports of tobacco use and waste to support smoke and tobacco-free college policies. METHODS: An exploratory sequential mixed methods approach was utilized to inform the development and evaluation of Tracker. In October 2018, three focus groups across 2 California universities were conducted and themes were analyzed, guiding Tracker development. After 1 year of implementation, users were asked in April 2020 to complete a survey about their experience. RESULTS: In the focus groups, two major themes emerged: barriers and facilitators to tool utilization. Further Tracker development was guided by focus group input to address these barriers (eg, information, policing, and logistical concerns) and facilitators (eg, environmental motivators and positive reinforcement). Amongst 1163 Tracker reports, those who completed the user survey (n=316) reported that the top motivations for using the tool had been having a cleaner environment (212/316, 79%) and health concerns (185/316, 69%). CONCLUSIONS: Environmental concerns, a motivator that emerged in focus groups, shaped Tracker's development and was cited by the majority of users surveyed as a top motivator for utilization.

"It is the One Thing that has Worked": facilitators and barriers to switching to nicotine salt pod system e-cigarettes among African American and Latinx people who smoke: a content analysis.

BACKGROUND: Electronic cigarettes are a harm reduction strategy for individuals who smoke cigarettes who cannot or do not want to quit using FDA-approved cessation methods. Identifying perceived facilitators and barriers to switching among people who smoke cigarettes is critical to optimizing health impact. This is particularly important for the most dominant e-cigarette device, nicotine salt pod electronic cigarettes. We investigate the experience using pod electronic cigarettes among African American and Latinx individuals who smoke, the two largest racial/ethnic minority groups who experience significant health disparities. METHODS: From July 2018 to May 2019, adults who smoked cigarettes, age 21 + (N = 114; M age = 44.6, 59.6% male, 52.6% African American from Kansas City, 47.4% Latinx from San Diego) received JUUL-brand electronic cigarettes (referred to hereafter as JUUL) for 6 weeks and answered interview questions at week six. We inquired what they liked and disliked about using JUUL, what helped with switching and made switching difficult, future intentions for continued JUUL use, and how JUUL compared to past smoking reduction methods. Responses were coded into themes by independent raters. Theme frequencies were analyzed separately by race/ethnicity and week 6 use trajectory (exclusive JUUL use, dual JUUL and cigarette use, exclusive cigarette use). RESULTS: Clean/smell was the aspect of using JUUL most commonly liked (23%), followed by convenience (19%). Coughing/harshness was a more common barrier to switching for African American (44%) than Latinx (9%), and for continuing cigarette use (56%) than for those who exclusively switched or dually used JUUL and combustible cigarettes (15-21%). Most (78% African American; 90% Latinx) reported that the benefits of using JUUL outweighed barriers, and this varied by JUUL use trajectory: 94% exclusive switch, 86% dual use, and 42% continued cigarette use. The majority said they would continue using JUUL to replace cigarettes (83% African American; 94% Latinx) and that JUUL worked better than other methods to reduce cigarettes (72%). CONCLUSION: African American and Latinx individuals who smoked experience using pod electronic cigarettes was generally positive. Understanding facilitators and impediments to switching to electronic cigarettes among racial/ethnic minority people who smoke can inform harm reduction interventions and reduce tobacco-related health disparities. Trial Registration ClinicalTrials.gov Identifier: NCT03511001 posted April 27, 2018.

Predictors of smoking reduction among African American and Latinx smokers in a randomized controlled trial of JUUL e-cigarettes.

INTRODUCTION: E-cigarette (e-cig) use is widespread and may play an important role in facilitating smoking reduction. Racial/ethnic minorities are less likely than Whites to use e-cigs and suffer disproportionate tobacco-related disease, making them a priority for harm reduction. This paper explores factors associated with smoking reduction among African American (AA) and Latinx smokers enrolled in a trial assessing toxicant exposure in those assigned to e-cigs or smoking as usual. METHODS: Participants were randomized to receive 6 weeks of JUUL e-cigs or continue smoking cigarettes as usual (N = 187). This analysis focuses on 109 participants randomized to e-cigs. We modeled cigarettes smoked in the past week at baseline and week 6 as a function of a priori selected predictors (number of JUUL pods used throughout the study, baseline cigarette dependence, and baseline cotinine) using a Poisson model fit with generalized estimating equations. RESULTS: Over the six-week study, cigarette smoking decreased from an average of 82.4 to 15.5 cigarettes per week. Greater numbers of JUUL pods used predicted a greater smoking reduction by week 6 (IRR = 0.94 [0.91, 0.96], p < 0.001). Higher baseline cigarette dependence (IRR = 1.03 [1.01, 1.05], p = 0.004), and baseline cotinine (IRR = 1.18 [1.03, 1.37], p = 0.020) predicted a lesser smoking reduction. CONCLUSIONS: AA and Latinx smokers reduced their cigarette consumption while using JUUL e-cigs. Higher e-cig use during an intervention to switch to e-cigs to reduce harm may facilitate a transition to smoking fewer cigarettes, offering an opportunity to narrow smoking-related health disparities.

Harm Reduction Associated with Dual Use of Cigarettes and e-Cigarettes in Black and Latino Smokers: Secondary Analyses from a Randomized Controlled e-Cigarette Switching Trial.

INTRODUCTION: Most adult cigarette smokers who use e-cigarettes are dual cigarette and e-cigarette (CC-EC) users, yet little is known about relative consumption of cigarettes to e-cigarettes and any associated harm reduction. METHODS: Rate of substitution from cigarettes to e-cigarettes at week 6 and change in biomarkers of exposure and potential harm were examined among dual dual cigarette and e-cigarette users [64/114 (56%); 35 Black, 29 Latino] in an e-cigarette switching randomized trial. RESULTS: Dual users averaged 79% substitution of cigarettes for e-cigarettes at week 6, resulting in a reduction from baseline of 70.0 ± 54.1 cigarettes per week (p < .001). Total nicotine consumption remained stable (baseline: 1160.5 ± 1042.1 pg/mL of cotinine, week 6: 1312.5 ± 1725.9 pg/mL of cotinine, p = .47), while significant reductions were seen in the potent lung carcinogen 4-(methylnitrosamino)-1-(3-pyridul)-1-butanol (NNAL) (-55.9 ± 88.6 ng/ml, p < .001), carbon monoxide (-6.3 ± 8.6 ppm, p < .001), and self-reported respiratory symptoms (-3.3 ± 8.0, p = .002). No significant changes were found in blood pressure or spirometry. Greater substitution from cigarettes to e-cigarettes was associated with larger reductions in NNAL (r = -.29, p = .02). CONCLUSIONS: The predominant dual-use pattern was characterized by regular e-cigarette and intermittent cigarette use. Findings demonstrate the short-term harm reduction potential of this dual-use pattern in Black and Latino smokers and suggest that the greatest benefit, aside from cessation of both products, is achieved by higher substitution of e-cigarettes for cigarettes. Findings need confirmation in a larger sample with longer follow-up in dual users with greater variability in the rate of substitution. CLINICALTRIALS.GOV IDENTIFIER: NCT03511001. IMPLICATIONS: Findings suggest short-term harm reduction potential of dual cigarette-e-cigarette use for Black and Latino smokers. Results also demonstrate the heterogeneity of dual-use, with the greatest harm reduction seen in dual users with higher rates of substitution from cigarettes to e-cigarettes. Study results should be confirmed in a full clinical trial with long-term follow-up to evaluate maintenance of dual-use patterns and associated harm reduction potential over time.

Effect of Pod e-Cigarettes vs Cigarettes on Carcinogen Exposure Among African American and Latinx Smokers: A Randomized Clinical Trial.

Importance: Fourth-generation nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) are the leading class of e-cigarettes. They contain high nicotine concentrations, which may facilitate switching among smokers, but could also lead to increased exposure to nicotine and biomarkers of potential harm. African American and Latinx smokers experience significant tobacco-related health disparities. The potential of NSPS e-cigarettes to reduce smoking-related harm among these groups is unknown. Objective: To compare the harm reduction potential of NSPS e-cigarette vs combustible cigarettes. Design, Setting, and Participants: This unblinded randomized clinical trial compared 6 weeks of e-cigarette use vs cigarettes as usual from to 2018 to 2019 among smokers in the San Diego, California, and Kansas City, Missouri, areas. Participants included African American and Latinx adult combustible cigarette smokers who smoked at least 5 cigarettes/d on at least 25 of the past 30 days for at least 6 months and were interested in switching to e-cigarettes. Data were analyzed from September 18, 2019, to September 4, 2020. Interventions: 6 weeks of e-cigarette use in a choice of pod flavors (5% nicotine) along with brief education, training, and action planning to completely switch to e-cigarettes from combustible cigarettes. The control group smoked combustible cigarettes as usual. Main Outcomes and Measures: The primary outcome was reduction in urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentration at week 6. Secondary outcomes were change in urinary cotinine, expired carbon monoxide (CO), respiratory symptoms, lung function, blood pressure, past 7-day consumption of combustible cigarettes, and switching rates (e-cigarette group only) at weeks 2 and 6. Results: This study included 186 participants, including 92 African American participants and 94 Latinx participants. The mean (SD) age was 43.3 (12.5) years, and 75 (40.3%) were women. Participants smoked a mean (SD) of 12.1 (7.2) cigarettes/d on 6.8 (0.6) d/wk at baseline. A total of 125 participants were randomized to the e-cigarette group and 61 were randomized to the control group. At baseline, median (interquartile range) NNAL was 124 (45-197) pg/mL in the e-cigarette group and 88 (58-197) pg/mL in the control group. At week 6, the e-cigarette group had significantly greater reductions in NNAL (relative risk [RR], 0.36 [95% CI, 0.23-0.54]; P < .001), CO (RR, 0.53 [95% CI, 0.42-0.68]; P < .001), respiratory symptoms (RR, 0.63 [95% CI, 0.47-0.85]; P = .002), and number of cigarettes smoked in the past 7 days among those still smoking (RR, 0.30 [95% CI, 0.20-0.43]; P < .001) than the control group and maintained their cotinine levels (RR, 0.80 [95% CI, 0.58-1.10]; P = .17). Lung function and diastolic and systolic blood pressure remained unchanged and did not differ between groups. For participants randomized to receive e-cigarettes, 32 participants (28.1%) were exclusively using e-cigarettes at week 6, while 66 participants (57.9%) were dual using and 16 participants (14%) resumed exclusively using cigarettes. Conclusions and Relevance: These findings suggest that e-cigarettes may be an inclusive harm reduction strategy for African American and Latinx smokers. Trial Registration: ClinicalTrials.gov Identifier: NCT03511001.

The highly selective dopamine D3R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents.

Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of R-VK4-40, a highly selective dopamine (DA) D3 receptor (D3R) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of R-VK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with R-VK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D3 antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with R-VK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, R-VK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with R-VK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and R-VK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest R-VK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of R-VK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.