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Neuroinflammation is implicated in the development and maintenance of alcohol use disorder (AUD) and neuroimmune therapeutics show promise in treating AUD. Proinflammatory signaling contributes to progressive elevations in the dysfunction of mood and alcohol craving. The current study sought to examine potential biobehavioral mechanisms of neuroimmune modulation in AUD under experimental conditions. In a community sample of individuals with AUD who completed a placebo-controlled crossover trial of ibudilast, we tested the effect of ibudilast on the relationship between mood states and alcohol craving. Multilevel modeling analyses tested the hypothesis that ibudilast would moderate the effect of positive and negative mood states on alcohol craving during stress and cue exposures. Results revealed that after stress-induction, participants' feelings of depression and happiness were more strongly predictive of their craving for alcohol while taking ibudilast as compared with placebo (

ObjectivePharmacological treatments that can concomitantly address cigarette smoking and heavy drinking stand to improve health care delivery for these highly prevalent co-occurring conditions. This superiority trial compared the combination of varenicline and naltrexone against varenicline alone for smoking cessation and drinking reduction among heavy-drinking smokers.MethodsThis was a phase 2 randomized double-blind clinical trial. Participants (N=165) who were daily smokers and drank heavily received either 2 mg/day of varenicline plus 50 mg/day of naltrexone or 2 mg/day of varenicline plus matched placebo pills for 12 weeks. Primary outcomes were 7-day point prevalence of nicotine abstinence (bioverified by a breath CO reading ≤5 ppm) at the 26-week follow-up and number of drinks per drinking day during the 12-week treatment phase.ResultsSmoking abstinence at week 26 was significantly higher in the varenicline plus placebo condition than in the varenicline plus naltrexone condition (N=37 [45.1%] compared with N=22 [26.5%]). For drinks per drinking day, there was a medication effect favoring the combination of varenicline and naltrexone over varenicline alone across the 12-week treatment phase, although it did not meet the significance threshold.ConclusionsThese findings suggest that smoking cessation and drinking reduction can be concomitantly targeted with pharmacotherapy and that while varenicline alone may be sufficient as a smoking cessation aid in heavy-drinking smokers, the combination of varenicline and naltrexone may confer benefits with regard to drinking outcomes, particularly during the 12-week period of active medication treatment.

BACKGROUND: There is a strong bidirectional relationship between the use of alcohol and cigarettes which results in various challenges for treating those who co-use both substances. While varenicline and naltrexone each have FDA-approval for nicotine and alcohol use disorder, respectively, there is evidence that their clinical benefit may extend across the two disorders. Critically, the effect of combined varenicline and naltrexone on neural reactivity to alcohol cues among heavy drinking smokers has not yet been studied. Probing the effect of the combination therapy on alcohol cue-reactivity may give insight to the mechanisms underlying its efficacy. METHODS: Forty-seven heavy drinking smokers enrolled in two medication studies were randomized to receive varenicline alone (n = 11), varenicline plus naltrexone (n = 11), or placebo (n = 25). Participants completed an fMRI alcohol cue-reactivity task and rated their in-scanner alcohol craving. Whole-brain analyses examined the effect of medication on alcohol cue-elicited neural response. RESULTS: Varenicline plus naltrexone attenuated alcohol cue-elicited activation in mesolimbic regions relative to varenicline alone and to placebo (Z > 2.3, p < 0.05). The combination varenicline and naltrexone group also endorsed lower in-scanner alcohol craving relative to varenicline alone group (p = 0.04). CONCLUSIONS: These findings provide evidence for the benefit of combined therapy of varenicline and naltrexone over varenicline alone for the attenuation of alcohol cue-elicited neural activation. This study provides a preliminary proof-of-mechanism for this combination pharmacotherapy and suggests that naltrexone may be driving the reductions in cue-elicited alcohol craving in the brain. Further clinical studies using the combined therapy to treat heavy drinking smokers are warranted.

Ibudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast’s effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD. Fifty-two nontreatment-seeking individuals with AUD were randomized to receive ibudilast (n = 24) or placebo (n = 28). Participants completed a 2-week daily diary study during which they filled out daily reports of their past day drinking, mood, and craving. Participants completed an functional magnetic resonance imaging (fMRI) alcohol cue-reactivity paradigm half-way through the study. Ibudilast did not have a significant effect on negative mood (β = −0.34, p = 0.62). However, ibudilast, relative to placebo, reduced the odds of heavy drinking across time by 45% (OR = 0.55, (95% CI: 0.30, 0.98)). Ibudilast also attenuated alcohol cue-elicited activation in the ventral striatum (VS) compared to placebo (F(1,44) = 7.36, p = 0.01). Alcohol cue-elicited activation in the VS predicted subsequent drinking in the ibudilast group (F(1,44) = 6.39, p = 0.02), such that individuals who had attenuated ventral striatal activation and took ibudilast had the fewest number of drinks per drinking day in the week following the scan. These findings extend preclinical and human laboratory studies of the utility of ibudilast to treat AUD and suggest a biobehavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking.

Ensuring the mental health and well-being of the healthcare workforce globally, especially women healthcare workers (HCWs), is an ongoing challenge that has been accentuated by the novel coronavirus (COVID-19) pandemic. Already at high risk of experiencing symptoms of stress, burnout, and depression, women HCWs are now also facing the psychosocial impacts of the COVID-19 pandemic. Although different types of mental health interventions have been introduced to support HCW well-being, the current needs of women HCWs have not been emphasized and replicable processes for developing and implementing specific emotional support services for women HCWs have not yet been well-described in the literature. Therefore, in this perspective, we discuss the approach our institution (University of California, Los Angeles) took for developing emotional support services for women HCWs that incorporate aspects of disaster behavioral health models and address various barriers to support and treatment. In addition, we describe and illustrate the process that we utilized to develop individual-level and institutional-level emotional support services. Finally, based on our institution's experience, we share recommendations for developing emotional support services for women HCWs during the COVID-19 pandemic and other future crises.

Institutions across the world are working to develop initiatives aimed at supporting the well-being of healthcare workers (HCWs) facing the psychological impacts of the novel coronavirus (COVID-19) pandemic. This Commentary identifies risks that HCWs are experiencing, reviews sources of fear and stress, and describes the implementation of a three-tiered model for the provision of emotional support and mental health services for clinical and nonclinical HCWs. The model recognizes the fluid, ever-evolving nature of the COVID-19 pandemic and includes proactive, visible, and easy-to-access supportive psychological services that expand the safety net and help address immediate and future mental health challenges of HCWs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The prevalence rate of addiction among physicians is similar to the general population, with approximately 10% to 12% of U.S.-based physicians developing substance use disorders (SUDs) during their lifetimes. To address this public health concern, physician health programs (PHPs) have been created to facilitate the early identification, evaluation, treatment, and monitoring of physicians. Although a number of published studies provide outcome information from PHPs, there has been no comprehensive review of the related literature. The objective of this narrative review is to summarize the treatment outcomes, including treatment types, rates of relapse, rates of contract completion or extension, as well as licensure and work status rates of a nationally representative physician cohort and related subpopulations from a single dataset. Based on the studies included in this review, our findings reveal that physicians who completed their PHP contracts have more favorable treatment outcomes than members of the general population who receive mainstream treatment. In addition, our review describes unique features of physician rehabilitation facilitated by PHPs. However, further prospective research is needed to ensure a standardized and comparable dataset and facilitate performance improvement.

The Allostatic Model proposes that Alcohol Use Disorder (AUD) is associated with a transition in the motivational structure of alcohol drinking: from positive reinforcement in early-stage drinking to negative reinforcement in late-stage dependence. However, direct empirical support for this preclinical model from human experiments is limited. This study tests predictions derived from the Allostatic Model in humans. Specifically, this study tested whether alcohol use severity (1) independently predicts subjective responses to alcohol (SR; comprised of stimulation/hedonia, negative affect, sedation and craving domains), and alcohol self-administration and 2) moderates associations between domains of SR and alcohol self-administration. Heavy drinking participants ranging in severity of alcohol use and problems (N = 67) completed an intravenous alcohol administration paradigm combining an alcohol challenge (target BrAC = 60 mg%), with progressive ratio self-administration. Alcohol use severity was associated with greater baseline negative affect, sedation, and craving but did not predict changes in any SR domain during the alcohol challenge. Alcohol use severity also predicted greater self-administration. Craving during the alcohol challenge strongly predicted self-administration and sedation predicted lower self-administration. Neither stimulation, nor negative affect predicted self-administration. This study represents a novel approach to translating preclinical neuroscientific theories to the human laboratory. As expected, craving predicted self-administration and sedation was protective. Contrary to the predictions of the Allostatic Model, however, these results were inconsistent with a transition from positively to negatively reinforced alcohol consumption in severe AUD. Future studies that assess negative reinforcement in the context of an acute stressor are warranted.

Author(s): Ray, Lara A; Green, ReJoyce; Roche, Daniel J O; Bujarski, Spencer; Hartwell, Emily E; Lim, Aaron C; Rohrbaugh, Taylor; Ghahremani, Dara; Hutchison, Kent; Miotto, Karen | Abstract: Genetic variation in the endogenous opioid system has been identified as 1 potential source of individual variability in naltrexone treatment outcomes. The majority of naltrexone pharmacogenetic studies have focused on a particular single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1; rs1799971; commonly known as the Asn40Asp SNP) in Caucasian samples with decidedly mixed results. The goal of this study was to test the pharmacogenetic effects of naltrexone on subjective response to alcohol and self-administration of alcohol in individuals of East Asian descent. We hypothesized that naltrexone, compared with placebo, would potentiate the aversive and sedative effects of alcohol and reduce alcohol self-administration to a greater extent in Asp40 carriers.Participants (Nn=n77; Asn40Asn, nn=n29; Asn40Asp, nn=n34, and Asp40Asp, nn=n14) completed 2 double-blinded and counterbalanced experimental sessions: one after taking naltrexone (50nmg/d) for 5ndays and one after taking matched placebo for 5ndays. In each experimental session, participants received a priming dose of intravenous alcohol up to the breath alcohol concentration target of 0.06ng/dl which was immediately followed by an alcohol self-administration period (1nhour).There were no pharmacogenetic effects observed for alcohol-induced stimulation, sedation, craving for alcohol, or alcohol self-administration in the laboratory. During the self-administration period, Asp40 carriers consumed fewer drinks and had a longer latency to first drink as compared to Asn40 homozygotes.These findings in East Asians add to the mixed literature on naltrexone pharmacogenetics from predominantly Caucasian samples and highlight the complexity of these effects and their overall limited replicability. It is plausible that a consistent pharmacogenetic effect in tightly controlled preclinical and experimental medicine models "fades" in more complex and heterogeneous settings and samples.

Purpose To examine the prevalence of comorbid chronic pain among patients with opioid use disorder (OUD) and to compare other comorbidities (substance use disorder (SUD), mental health disorders, health/disease conditions) among patients in four categories: no chronic pain (No Pain), OUD prior to pain (OUD First), OUD and pain at the same time (Same Time), or pain condition prior to OUD (Pain First). Methods Using an electronic health record (EHR) database from 2006–2015, the study assessed 5307 adult patients with OUD in a large healthcare system; 35.6% were No Pain, 9.7% were OUD First, 14.9% were Same Time, and 39.8% were Pain First. Results Most OUD patients (64.4%) had chronic pain conditions, and among them 61.8% had chronic pain before their first OUD diagnosis. Other SUDs occurred more frequently among OUD First patients than among other groups in terms of alcohol (33.4% vs. 25.4% for No Pain, 20.7% for Same Time, and 20.3% for Pain First), cocaine (19.0%, vs. 13.8%, 9.4%, 7.1%), and alcohol or drug-induced disorders. OUD First patients also had the highest rates of HIV (4.7%) and hepatitis C virus (HCV; 28.2%) among the four groups. Pain First patients had the highest rates of mental disorder (81.7%), heart disease (72.0%), respiratory disease (68.4%), sleep disorder (41.8%), cancer (23.4%), and diabetes (19.3%). Conclusions The alarming high rates of chronic pain conditions occurring before OUD and the associated severe mental health and physical health conditions require better models of assessment and coordinated care plans to address these complex medical conditions.

Deaths due to heroin overdoses are increasing and are the leading cause of death among intravenous heroin users. Although medication-assisted treatment (MAT) improves morbidity and mortality in patients with opioid use disorders, it is underutilized. Most efforts to expand access to MAT have focused on outpatient settings. Although the inpatient medical setting presents a critical opportunity to initiate treatment, general hospitals are often unfamiliar with MAT, creating a number of barriers to its use. In this report, we describe the case of a woman with heroin use disorder who was initiated on buprenorphine maintenance treatment while hospitalized for cardiac disease related to her intravenous heroin use. Barriers to initiating buprenorphine in this case included patient, practitioner, and organizational factors, and, ultimately, shared misperceptions about the feasibility of administering buprenorphine in a general medical hospital. These barriers were addressed, buprenorphine was initiated, and the patient demonstrated reduced craving, improved postoperative pain control, improved overall well-being, increased engagement in discharge planning, and acceptance of referral for addiction specialty aftercare. Our experience with this patient suggests that it is feasible to initiate buprenorphine in acute medical settings and that such treatment can improve patient outcomes. Our review of the literature reveals emerging evidence supporting the value of this practice.

Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by ∼50%. To advance medication development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in nontreatment-seeking individuals with current (ie, past month) mild-to-severe AUD. This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50 mg b.i.d.) on primary measures of subjective response to alcohol as well as secondary measures of cue- and stress-induced changes in craving and mood. Participants (N=24) completed two separate 7-day intensive outpatient protocols that included daily visits for medication administration and testing. Upon reaching a stable target dose of IBUD (or matched placebo), participants completed a stress-exposure session (day 5; PM), an alcohol cue-exposure session (day 6; AM), and an i.v. alcohol administration session (day 6; PM). Participants stayed overnight after the alcohol administration, and discharge occurred on day 7 of the protocol. Medication conditions were separated by a washout period that was ⩾7 days. IBUD was well tolerated; however, there were no medication effects on primary measures of subjective response to alcohol. IBUD was associated with mood improvements on the secondary measures of stress exposure and alcohol cue exposure, as well as reductions in tonic levels of craving. Exploratory analyses revealed that among individuals with higher depressive symptomatology, IBUD attenuated the stimulant and mood-altering effects of alcohol as compared with placebo. Together, these findings extend preclinical demonstrations of the potential utility of IBUD for the treatment of AUD and suggest that depressive symptomatology should be considered as a potential moderator of efficacy for pharmacotherapies with neuroimmune effects, such as IBUD.

Background and Objectives Opioids increase the risk for sleep disordered breathing (SDB), but there are few studies examining the prevalence and risk factors for SDB, specifically central sleep apnea (CSA), and obstructive sleep apnea (OSA) in chronic pain patients on opioids as well as methadone maintained patients (MMPs). Methods A literature review was conducted in which SDB was confirmed by polysomnography (PSG) in chronic pain patients on opioids as well as patients with a diagnosis of an opioid use disorder or opioid dependence on methadone maintenance treatment (MMT). Results About 22 reports were included. Six were with MMPs, and 16 were with chronic pain patients on opioids. Among MMPs, the prevalence of SDB ranged from 42.3% to 70%; 0–60% had CSA and 10–35.2% had OSA. In chronic pain patients on opioids, the prevalence of SDB ranged from 71% to 100%; 17–80% had CSA and 20–39% had OSA. In MMPs, studies found a positive association between BMI, weight gain, duration of MMT, non-Caucasian race and the number of obstructive apneas, as well as blood methadone concentrations and the number of central apneas. In chronic pain patients on opioids, older age, higher BMI, male gender, and higher opioid doses predicted more obstructive apneas; older age, lower BMI, male gender, higher pain levels, higher benzodiazepine doses, and higher opioid doses predicted more central apneas. Conclusion and Scientific Significance CSA and OSA are common in MMPs and chronic pain patients on opioids. Among chronic pain patients, higher opioid doses appear to be a risk factor for CSA, and to a lesser extent OSA. Therefore, it is important for providers to screen these patient populations for SDB. (Am J Addict 2016;25:452–465)

BACKGROUND: Alcohol use disorder (AUD) and its associated consequences remain significant public health concerns. Given that AUD represents a spectrum of severity, treatment options represent a continuum of care, ranging from single-session brief interventions to more intensive, prolonged, and specialized treatment modalities. OBJECTIVE: This qualitative literature review seeks to describe the best practices for AUD by placing a particular emphasis on identifying those practices which have received the most empirical support. METHOD: This review summarizes psychological and pharmacological intervention options for AUD treatment, with a focus on the relapse prevention phase of recovery. Psychological and pharmacological treatments are summarized in terms of the empirical evidence favoring each approach and the level of AUD severity for which they are most indicated. SCIENTIFIC SIGNIFICANCE: One of the broad assertions from this review is that while AUD is highly prevalent, seeking treatment for AUD is not. There are a myriad of behavioral and pharmacological treatments that have shown compelling evidence of efficacy for the treatment of AUD. In the behavioral treatment literature, Cognitive Behavioral Therapy (CBT) has received the most consistent support. Opioid antagonism (via naltrexone) has been the most widely studied pharmacotherapy and has produced moderate effect sizes. While none of the treatments reviewed herein represents a so called “silver bullet” for AUD, they each have the potential to significantly improve the odds of recovery. Precision medicine, or the identification of best treatment matches for individual patients, looms as an important overarching goal for the field; although specific matches are not yet sufficiently reliable in their empirical evidence to warrant clinical dissemination.

OBJECTIVE Prescription Drug Monitoring Programs (PDMPs) are intended to help reduce prescription drug misuse and opioid overdose, yet little is known about the longitudinal patterns of opioid prescribing that may be associated with mortality. This study investigated longitudinal opioid prescribing patterns among patients with opioid use disorder (OUD) and without OUD in relation to mortality using PDMP data. METHODS Growth modeling was used to examine opioid prescription data from the California PDMP for a 4-year period before death or a comparable period ending in 2014 for those remaining from a sample of 7728 patients (2576 with OUD, and 5152 matched non-OUD controls) treated in a large healthcare system. RESULTS Compared to controls, individuals with OUD (alive and deceased) had received significantly more opioid prescriptions, greater number of days' supply, and steeper increases of opioid dosages over time. For morphine equivalents (ME, in grams), the interaction of OUD and mortality was significant at both intercept (β = 10.4, SE = 4.4, P

Background Despite known genetic variation across races, studies examining pharmacogenetics of a single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1) on clinical response to naltrexone have been conducted in predominantly Caucasian samples. Evidence is mixed for pharmacogenetic OPRM1 and naltrexone effects on neural responses to alcohol cues. The current study tests the pharmacogenetic effects of naltrexone and OPRM1 on neural responses to alcohol taste cues in heavy drinkers of East Asian descent. Methods Participants (N = 41) completed two double-blinded and counterbalanced functional magnetic resonance imaging (fMRI) sessions: one after taking naltrexone (50 mg/day) for four days and one after taking placebo for four days. Following titration, participants completed an fMRI alcohol taste-cues task. Analyses tested effects of naltrexone, OPRM1, and their interaction in whole-brain and region of interest (ROI) analyses of functional activation and functional connectivity in response to alcohol versus water taste cues. Results We found no effects of naltrexone orOPRM1 on neural activation in whole-brain and ROI analyses, which included left and right ventral striatum (VS), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Naltrexone increased functional connectivity between left VS and clusters in medial prefrontal cortex, posterior cingulate gyrus, as well as right VS and occipital cortex, compared to placebo. Conclusions Naltrexone treatment enhanced functional connectivity in a key reinforcement-related pathway during alcohol versus water taste cues, corroborating neuroimaging work with other substances. Null medication and pharmacogenetics effects on functional activation add to a mixed naltrexone literature and may underscore the modest size of these effects in East Asians.

Background: An evidence-based trauma-informed resilience skills training program developed for deployed military personnel was adapted and pilot-tested with pediatric residents. We anticipated high satisfaction ratings and changes in knowledge, beliefs, and self-efficacy related to coping with stress and trauma. Methods: The intervention included 6 skill-based modules covering emotion regulation, communication with angry patients and parents, reflective narrative, inspirational goal setting, problem-solving, and developing a self-care toolbox. An optional survey was administered before and after the training. Results: After training, 76% rated resilience skills as important, 60% were satisfied, and 82% indicated the training changed how they will respond to patient-related grief and trauma. They became more likely to believe attendings are affected by patient deaths and to know what helps them cope when they disagree with the medical decision making of others, more skilled in recognizing signs of stress and trauma, and more knowledgeable about evidence-based interventions.

ObjectivesElevated mortality has been observed among individuals with opioid use disorder (OUD) treated in addiction specialty clinics or programs. Information about OUD patients in general healthcare settings is needed in light of the current effort to integrate addiction services into primary healthcare systems. This study examined mortality rates, causes of death, and associated risk factors among patients with OUD in a large general healthcare system.MethodsMortality data were linked with electronic health records of 2576 OUD patients cared for in a large university health system from 2006 to 2014.ResultsThere were 465 deaths confirmed (18.1% of the study participants), corresponding to a crude mortality rate of 48.6 per 1000 person-years and standardized mortality ratio of 10.3 (95% confidence interval [CI] 9.4-11.3). Drug overdose and disorder (19.8%), cardiovascular diseases (17.4%), cancer (16.8%), and infectious diseases (13.5%, including 12% hepatitis C virus [HCV]) were the leading causes of death. HCV (hazard ratio [HR] 1.99, 95% CI 1.62-2.46) and alcohol use disorder (HR 1.27, 95% CI 1.05-1.55) were 2 clinically important indicators of overall mortality risk. Tobacco use disorder (adjusted HR [AHR] 2.58, 95% CI 1.60-4.17) was associated with increased risk of cardiovascular death, HCV infection (AHR 2.55, 95% CI 1.52-4.26) with cancer mortality risk, and HCV (AHR 1.92, 95% CI 1.03-3.60) and alcohol use disorder (AHR 5.44, 95% CI 2.95-10.05) with liver-related mortality risk.ConclusionsPatients with OUD in a general healthcare system demonstrated alarmingly high morbidity and mortality, which challenges healthcare systems to find innovative ways to identify and treat patients with substance use disorder.

RationaleHeavy-drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.ObjectivesThe present study used a double-blind, randomized, 2 × 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), low dose naltrexone alone (L-NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n = 130) of heavy-drinking daily smokers (≥10 cigarettes/day).MethodsAll participants were tested after a 9-day titration period designed to reach a steady state on the target medication. Testing was completed at 12 h of nicotine abstinence, after consuming a standard dose of alcohol (target breath alcohol concentration = 0.06 g/dl) and after smoking the first cigarette of the day.ResultsThe combination of VAR + L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol "high," and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period.ConclusionsThese preliminary findings indicate that clinical studies of the combination of VAR + L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers.

Serious mental illness (SMI) has been defined as a persistent psychiatric disorder that has resulted in a substantial impairment in functioning. Approximately 1 in 25 (14 million) adults in the USA are living with SMI (NAMI 2015). Schizophrenia, bipolar disorder, and recurrent major depression are common disorders that often meet this definition. About 1 % (two million) and 3 % (six million) of the population have been diagnosed with schizophrenia and bipolar disorder, respectively (NAMI 2015). Of these, only 64 % with schizophrenia and 56 % with bipolar disorder are receiving treatment, often from locations such as community mental health centers, hospitals, or jails and prisons (Substance Abuse and Mental Health Services, 2014). Recurrent major depression is a leading cause of disability and affects 7 % of the population (15 million). Despite high treatment success rates for depressive disorders, nearly two out of three people with these disorders do not seek or receive treatment (Young, Klap, Sherbourne, & Wells, 2001; Young, Klap, Shoai, & Wells, 2008). The disease burden of SMI is amongst the largest of the medical disorders. Short-term adverse effects include impaired ability to carry out daily activities in productive roles (job, school, housework) and social roles (family, friends). Serious psychiatric disorders have an earlier age of onset than most chronic physical disorders, which contributes to the magnitude of their long-term adverse effects (Kessler et al., 2007). Early-onset mental disorders predict a persistent disabling course and development of a wide range of physical disorders including obesity, diabetes, cancer, and cardiovascular diseases (Kessler et al., 2009).

Pharmacotherapies for opioid addiction under active development in the US include lofexidine (primarily for managing withdrawal symptoms) and Probuphine®, a distinctive mode of delivering buprenorphine for six months, thus relieving patients, clinicians, and regulatory personnel from most concerns about diversion, misuse, and unintended exposure in children. In addition, two recently approved formulations of previously proven medications are in early phases of implementation. The sublingual film form of buprenorphine + naloxone (Suboxone®) provides a less divertible, more quickly administered, more child-proof version than the buprenorphine + naloxone sublingual tablet. The injectable depot form of naltrexone (Vivitrol®) ensures consistent opioid receptor blockade for one month between administrations, removing concerns about medication compliance. The clinical implications of these developments have attracted increasing attention from clinicians and policymakers in the US and around the world, especially given that human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases are recognized as companions to opioid addiction, commanding more efforts to reduce opioid addiction. While research and practice improvement efforts continue, reluctance to adopt new medications and procedures can be expected, especially considerations in the regulatory process and in the course of implementation. Best practices and improved outcomes will ultimately emerge from continued development efforts that reflect input from many quarters.

Tramadol is commonly prescribed for pain control because it presents a lower risk for addiction and respiratory depression compared to other opioids. However, tramadol's serotonin and norepinephrine reuptake inhibitory effects result in a unique adverse effect profile. Two such adverse events are serotonin syndrome and seizures. The prevalence of tramadol-induced serotonin syndrome and seizures is modest in the general population, but if left untreated, the morbidity and mortality can be high; therefore, prompt recognition and management is essential. Various risk factors such as medical comorbidities, use or abuse of supratherapeutic doses of tramadol, and concomitant administration of proconvulsant serotonergic cytochrome P-450 inhibitors will help clinicians identify individuals at an elevated risk for serotonin toxicity and seizures. Serotonin syndrome and seizures can be effectively treated by administering benzodiazepines, providing supportive care, and discontinuing tramadol and other contributing agents. Cyproheptadine should be administered in moderate to severe cases of serotonin syndrome. Our objective is to summarize the literature on the pharmacology, epidemiology, risk factors, clinical presentations, and evidence-based management of tramadol-related seizures and serotonin syndrome.

There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies.

Naltrexone is an opioid receptor antagonist with established efficacy, albeit moderate, for the treatment of alcohol dependence. This manuscript provides a critical review of the literature on naltrexone as a pharmacotherapy for alcoholism by covering the following areas: (a) clinical findings from treatment studies; (b) pharmacokinetics and safety data; (c) medication compliance and persistence; and (d) neurobiological and biobehavioral mechanisms of action of naltrexone for the indication of alcohol dependence. This review will then focus on the emerging literature on naltrexone pharmacogenetics, which has the potential to identify responders on the basis of genetic variation and to use genetic tools to individualize the use of this medication. Limitations and future directions in the research and practice of naltrexone for alcoholism are also outlined.

Objectives The objective of this study was to investigate lofexidine urine and plasma pharmacokinetics using three different dosing regimens in opioid dependent subjects. To date, there have been no published studies on lofexidine appearance and excretion in urine of opioid dependent subjects. Methods Subjects were stabilized with 100 mg morphine sulphate on days 3-8 of the study. The dosing regimens of lofexidine hydrochloride were .8 mg twice a day (BID), 1.2 mg BID, or .8 mg three times a day (TID) on days 9 through 16 of the study. Plasma and urine samples were collected at appropriate time points. Area under the concentration-time curve (AUC), maximum concentration in plasma (C(max)), time when maximum concentration was reached (T(max)) and fraction excreted unchanged in urine (Fe) were calculated. Results The average half-life obtained from all profiles was 12.1 +/- 6.3 hr. Steady-state (SS) was reached by study day 15. The plasma pharmacokinetic parameters for 1.2 mg BID and .8 mg TID dosing regimens did not seem to be different at steady state (day 15). T(max) was not statistically significantly different across dosing regimens. Fe values ranged between .01% and 34% with high variability within the same dosing regimen. For the total dose of 2.4 mg/day the two dosing regimens that were evaluated, namely 1.2 mg BID and .8 mg TID, did not show a significant statistical difference in plasma and urine pharmacokinetic parameters. Conclusion Although preliminary due to the limited number of subjects, these findings are the first to document lofexidine urine pharmacokinetics in opiate addicts using a highly sensitive liquid chromatography tandem mass spectrometric analysis.

Objectives: The objective of this investigation was to characterize the pharmacokinetic profile of lofexidine. Lofexidine is an orally bioavailable α 2-adrenergic receptor agonist analogue of clonidine that acts centrally to suppress opiate withdrawal symptoms. Methods: During the detoxification period of a phase 3 placebo-controlled, randomized, double-blind trial, six subjects were entered in this preliminary pharmacokinetic study. Results: Pharmacokinetic analysis of plasma samples collected during study day 7 indicated that Cmax was 3242 ± 917 ng/L. The mean trough levels between the study days were not significantly different (p >. 05), suggesting that the subjects were at steady-state. Conclusions: Although preliminary due to the limited number of subjects, these findings are the first to document lofexidine clinical pharmacokinetics in opiate addicts using a highly sensitive liquid chromatography tandem mass spectrometric analysis.

Background Ivermectin (IVM) is an antiparasitic agent that has been shown to reduce alcohol intake in mice, suggesting IVM as a potential treatment for alcohol use disorder (AUD). However, the safety profile of IVM administered in combination with an intoxicating dose of alcohol has not been characterized in humans. Methods This pilot project sought to provide the first clinical evidence that IVM could be repositioned as an AUD pharmacotherapy by examining (i) the safety of combining IVM (30 mg oral , once a day [QD]) with an intoxicating dose of intravenous alcohol (0.08 g/dl) and (ii) the effects of IVM on alcohol cue-induced craving and subjective response to alcohol. Eleven individuals with AUD participated in a randomized, placebo-controlled, crossover study in which they received the study medication, participated in a cue exposure paradigm followed by intravenous alcohol administration, and remained in an inpatient unit overnight for observation. Results IVM treatment, versus placebo, did not increase the number or severity of adverse effects during alcohol administration or throughout the visit. However, IVM did not reduce cue-induced craving nor did it significantly affect subjective response to alcohol. Conclusions These results suggest that IVM (30 mg oral, QD) is safe in combination with an intoxicating dose of alcohol, but do not provide evidence that this dose of IVM is effective in reducing alcohol craving or its reinforcing effects. Given the preclinical data suggesting IVM is effective in reducing alcohol consumption in mice, additional studies testing larger samples and alternate dosing regimens are warranted to further characterize the potential efficacy of IVM as an AUD treatment.

There is a great deal of interest in understanding addiction neurobiology and in translating findings from pre-clinical studies to clinical samples. Functional magnetic resonance imaging (fMRI) represents an important tool in translating pre-clinical insights to brain function in humans affected by addictive disorders. While there has been a focus on developing fMRI-based biomarkers for psychiatric disorders in general (Fu & Costafreda, 2013), the field of addictions has yet to identify reliable biomarkers, fMRI based or otherwise. Importantly, diagnostic and prognostic biomarkers are only as useful as their ability to add value to existing clinical and behavioral systems. Perhaps most promising is the notion that understanding addiction neurobiology at the level of the individual’s brain function will allow for the development of more efficacious treatments, including the prediction of relapse and the test of promising behavioral and pharmacological interventions. In particular, it has been argued that therapies for addiction must target brain structures that are altered by the disorder through neuropsychological and pharmacological interventions (Konova et al., 2013b). Further, studies suggest that functional neuroimaging provides an objective and quantifiable measure for evaluating changes associated with treatment beyond what can be gathered from self-report or behavior alone (Menossi et al., 2013).

Assessing for the presence of addiction in the chronic pain patient receiving chronic opioid analgesia is a challenging clinical task. This paper presents a recently developed screening tool for addictive disease in chronic pain patients, and pilot efficacy data describing its ability to do so. In a small sample of patients (n = 52) referred from a multidisciplinary pain center for "problematic" medication use, responses to the screening questionnaire were compared between patients who met combined diagnostic criteria for a substance use disorder and those who did not, as assessed by a trained addiction medicine specialist. Responses of addicted patients significantly differed from those of nonaddicted patients on multiple screening items, with the two groups easily differentiated by total questionnaire score. Further, three key screening indicators were identified as excellent predictors for the presence of addictive disease in this sample of chronic pain patients.

The authors examined characteristics of successful completers of an outpatient clonidine/oxazepam detoxification procedure for opioid dependence. Of 215 initial applicants, 167 received medication, and 65 successfully completed by taking a dose of naltrexone. Those who completed were more likely to have last used an opioid other than heroin, to be heroin smokers, rather than intravenous users, to have used benzodiazepines in the 30 days before treatment, and to have abstained from opioids for a longer time before presenting for treatment. New users (for less than 2 years) did no better than those using longer than 2 years. These findings may help in the continued refinement of patient placement criteria.

The authors examined characteristics of successful completers of an outpatient clonidine/oxazepam detoxification procedure for opioid dependence. Of 215 initial applicants, 167 received medication, and 65 successfully completed by taking a dose of naltrexone. Those who completed were more likely to have last used an opioid other than heroin, to be heroin smokers, rather than intravenous users, to have used benzodiazepines in the 30 days before treatment, and to have abstained from opioids for a longer time before presenting for treatment. New users (for less than 2 years) did no better than those using longer than 2 years. These findings may help in the continued refinement of patient placement criteria.

OBJECTIVE: As part of a synthesis of evidence regarding the efficacy and safety of ephedra, the authors describe data on psychiatric adverse events from reports submitted to the Food and Drug Administration (FDA). METHOD: The authors reviewed all 1,820 adverse event reports related to dietary supplements containing herbal ephedra from FDA MedWatch files as of Sept. 30, 2001. Fifty-seven serious psychiatric events were reported. RESULTS: The most commonly reported events were psychosis, severe depression, mania or agitation, hallucinations, sleep disturbance, and suicidal ideation. Ten events involved physical harm to self or others; five events resulted in legal action due to criminal behavior. Twenty-six events resulted in hospitalization, at least six of which were involuntary. Of importance, two-thirds of all cases involved patients with preexisting psychiatric conditions and /or use of other medications or illicit substances. CONCLUSIONS: Clinicians should be aware that serious psychiatric symptoms co...

Bath salts are designer drugs with stimulant properties that are a growing medical and psychiatric concern due to their widespread availability and use. Although the chemical compounds in the mixtures referred to as "bath salts" vary, many are derivatives of cathinone, a monoamine alkaloid. Cathinones have an affinity for dopamine, serotonin, and norepinephrine synapses in the brain. Because of the strong selection for these neurotransmitters, these drugs induce stimulating effects similar to those of methamphetamines, cocaine, and 3,4-methylenedioxy-N-methylamphetamine (MDMA). Much of the emerging information about bath salts is from emergency department evaluation and treatment of severe medical and neuropsychiatric adverse outcomes. This review consists of a compilation of case reports and describes the emergent literature that illustrates the chemical composition of bath salts, patterns of use, administration methods, medical and neuropsychiatric effects, and treatments of patients with bath salt toxicity.

As opiate therapy is increasingly accepted for the management of chronic pain, the consultation-liaison psychiatrist is often challenged to diagnose and provide treatment recommendations for addictive disease in chronic pain patients. Reviewed are the defining characteristics of addiction within the context of chronic pain, and the interesting commonalities between addictive disease and chronic pain. Guidelines for assessment of addiction in patients with chronic pain are presented, as are suggestions for the management of these concurrent disorders. Underlying this review is a belief that opiates should not be withheld from persons with chronic pain, even in the presence of addictive disease.

The safest pain treatment strategy for an individual at risk or recovering from addiction is a nonopioid and benzodiazepine-free approach. If an opioid treatment is necessary, the extent of the risk can be stratified by the use of a biopsychosocial assessment and opioid screening tools. Individuals at high risk should have the greatest amount of structure and monitoring. A written informed consent and treatment agreement can provide a framework for the patient and the patient’s family, as well as the clinician. The structure of treatment should specify only that one prescribing physician will write a limited supply of opioids, without refills, until the analgesic efficacy, adverse events, and goals for functional restoration can be assessed. An additional recommendation is that prescriptions should be filled at the same pharmacy with no refill by phone or opportunity for replacement because of loss, damage, or stolen medications. Additionally, random urine drug screens and PDMP reports obtained will help determine if the patient is taking other substances, as well as monitor the patient’s medication use patterns. It is important to assess for risk factors in treating chronic pain with opioids; clinicians need to have a realistic appreciation of the resources available to them and the types of patients that can be managed in their practice. Chronic pain treatment with opioids should not be undertaken in patients who are currently addicted to illicit substances or alcohol. With the support of family and friends, ideally the patient can be motivated to participate in an intensive substance abuse treatment. In patients without an immediate risk, precautionary steps should be taken when prescribing opioids. Clinicians and patients need to review the risk factors for opioid-related problems including younger age, benzodiazepine use, and comorbid conditions such as depression, anxiety, and heavy smoking. Both the provider and the patient need a personal investment in the treatment plan and protocol to increase the safety of opioid treatment. New medications and treatment monitoring are being developed to provide maximal relief for the patient while protecting the public health. The optimal ingredients for safe opioid treatment include a strong provider-patient relationship and clinician training in the assessment and treatment of addiction and pain.

Opioids are the most effective pain medication available, yet concerns about their safety may limit their administration to those in need. In efforts to identify analgesics with lower potential for abuse and dependence, recent evidence suggests that combinations of opioids with ultra-low doses of the opioid antagonist naloxone may enhance the analgesic effect with increased safety. This study investigated the use of buprenorphine (0.3 mg) plus ultra-low-dose naloxone (0.02 mg) (BUP + ULDN) as compared with buprenorphine alone (0.3 mg) (BUP) for the treatment of pain.In a double-blind, placebo-controlled, randomized cross-over design, 12 study participants with lingering, noncancer pain received each medication intravenously for 5 days of dosing, separated by an intertrial interval of at least 7 days to avoid possible carryover effects.We found no order effects and no differences between medications in pre- to postdose pain ratings, side effects, or adverse events.These findings suggest that BUP + ULDN is not more effective in reducing pain than BUP.

Recent clinical and laboratory studies have shown that the effects of naltrexone for alcoholism may be moderated by the Asn40Asp single-nucleotide polymorphism (SNP) of the μ-opioid receptor gene (OPRM1). Allele frequencies for this polymorphism, however, have been shown to vary substantially as a function of ethnic background, such that individuals of Asian descent are more likely to carry the minor (Asp40) allele. The objective of this study is to test the naltrexone pharmacogenetic effects of the Asn40Asp SNP in a sample of Asian Americans. This study consists of a double-blinded, randomized, placebo-controlled laboratory trial of naltrexone. Participants (n=35, 10 females; 13 Asn40Asn and 22 Asp40 carriers) were non-treatment-seeking heavy drinkers recruited from the community. After taking naltrexone or placebo, participants completed an intravenous alcohol administration session. The primary outcome measures were subjective intoxication and alcohol craving. Results suggested that Asp40 carriers experienced greater alcohol-induced sedation, subjective intoxication, and lower alcohol craving on naltrexone, as compared to placebo, and to Asn40 homozygotes. There results were maintained when controlling for ALDH2 (rs671) and ADH1B (rs1229984) markers and when examining the three levels of OPRM1 genotype, thereby supporting an OPRM1 gene dose response. These findings provide a much-needed extension of previous studies of naltrexone pharmacogenetics to individuals of Asian descent, an ethnic group more likely to express the minor allele putatively associated with improved biobehavioral and clinical response to this medication. These findings help further delineate the biobehavioral mechanisms of naltrexone and its pharmacogenetics.

Todd Zorick1, Rajkumar J Sevak1, Karen Miotto1, Steven Shoptaw2,4, Aimee-Noelle Swanson2, Clayton Clement1, Richard De La Garza II1*, Thomas F Newton1*, Edythe D London1,3,41Departments of Psychiatry and Biobehavioral Sciences, 2Family Medicine, 3Molecular and Medical Pharmacology, 4The Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA; *Present address: Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USAAbstract: Despite the worldwide extent of methamphetamine dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Animal research suggests that enhancement of central cholinergic activity, possibly at nicotinic acetylcholine receptors (nAChRs), can reduce methamphetamine-related behaviors. Further, preliminary findings indicate that rivastigmine, a cholinesterase inhibitor, may reduce craving for methamphetamine after administration of the drug in human subjects. We therefore performed a double-blind, placebo-controlled, crossover pilot study of the safety and tolerability of varenicline in eight methamphetamine-dependent research subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4b2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over one week to reach 1 mg twice daily, and then was co-administered with 30 mg methamphetamine, delivered in 10 intravenous (iv) infusions of 3 mg each. Varenicline was found to be safe in combination with iv methamphetamine, producing no cardiac rhythm disturbances or alterations in vital sign parameters. No adverse neuropsychiatric sequelae were detected either during varenicline titration or following administration of methamphetamine. The results suggest that varenicline warrants further investigation as a potential treatment for methamphetamine dependence.Keywords: varenicline, methamphetamine, treatment, safety, nicotinic, acetylcholine

Knowledge of substance use disorders is essential for health care providers treating pregnant women. Early intervention is vital to improve the health and welfare of both the mother and child. This chapter provides an overview of the consequences and treatments of maternal substance use disorders during pregnancy and breast-feeding. Effective techniques for assessment and intervention are reviewed, as well as psychosocial problems that often accompany maternal substance abuse. Information about various illicit drugs is presented along with strategies for managing withdrawal symptoms. This chapter also outlines potential short- and long-term effects on the child from drug exposure during pregnancy and breast-feeding. Reporting and legal issues are addressed for cases of drug- and/or alcohol-dependent women who present late in pregnancy or who do not respond to available treatments before delivery.

The objective of this review is to describe psychiatric adverse events occurring after ingestion of dietary supplements containing herbal ephedra and to assess the possible relationship between supplement use and the events. The authors reviewed all adverse event reports related to dietary supplements containing herbal ephedra from US FDA MedWatch files as of 30 September, 2001. Psychosis, mania or severe agitation, severe depression, hallucinations, delusions, suicide attempts, paranoia and violent behaviour were classified as serious psychiatric events. Events were categorised based on the amount of information supporting a causal relationship. Out of almost 1800 total adverse events, 57 were classified as both psychiatric in nature and serious. Two-thirds of these psychiatric cases involved patients with pre-existing psychological/psychiatric conditions and/or use of other mood-altering medications or illicit substances. The majority of case reports were insufficiently documented to make an informed judgment about a relationship between the use of ephedra and the adverse event in question. The case reports evaluated do not prove a definitive causal link between ephedra and psychiatric complications. However, they do raise concern that such a relationship may exist.

The phenomenon of acute opioid physical dependence (APD) is an established and well-characterized experimental model for studying the clinical phenomenon of physical dependence to opioids in humans. In this paradigm, an opioid withdrawal syndrome is elicited in non-opioid-dependent humans by the parenteral administration of naloxone (NX) following a single large dose of opioid agonist. Although induced by various opioids and NX administration schedules, lacking is a direct comparison of different induction protocols with respect to withdrawal severity. Using a crossover design, we compared withdrawal severity in four healthy male subjects pretreated with morphine (MS; 18 mg/70 kg im), MS (10 mg/70 kg iv) and hydromorphone (HM; 2 mg/70 kg) followed 2 or 6 h later with NX (10 mg/70 kg iv). Dependent measures included both physiological and subjective indicators of withdrawal. All opioid pretreatments reliably induced APD and repeated-measures analysis of variance (ANOVA) showed that both pattern and severity of precipitated withdrawal were similar across conditions. Thus, despite altering the pretreatment opioid and route of administration, all three APD protocols produced similar and reliable withdrawal symptoms in humans.

Naltrexone is an opiate antagonist used as a pharmacologic adjuvant for the treatment of opiate and alcohol addiction. It has been hypothesized that naltrexone blocks the stress-response and well-being effects associated with opioid peptides. This raises the clinical concern that naltrexone may cause dysphoria. The authors reviewed pharmacological and clinical data in alcohol, opioid, and nicotine studies to determine if an association between naltrexone and dysphoria exists. These studies did not reveal dysphoria to be a serious side effect produced by naltrexone treatment. Additional studies to evaluate long-term endocrine effects and antidepressant combination therapy are warranted.

In a study evaluating naltrexone with either an intensive psychosocial protocol or standard community treatment for opioid dependence, 13 of 81 subjects overdosed within a 12-month period of study participation. There were four fatalities, one of which was a suicide. Among the nine nonfatal overdoses, there were four suicide attempts. Characteristics of subjects and naltrexone-taking are described.