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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.

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.

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: 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.

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).

Background Subjective response to alcohol has been examined as a marker of alcoholism risk. The A118G single-nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1) gene has been previously associated with subjective response to alcohol in heavy drinkers. This study seeks to extend the literature by examining the effect of OPRM1 genotype on responses to alcohol in a sample of alcohol-dependent individuals. A secondary aim of this study is to examine alcoholism severity as a predictor of subjective responses to alcohol. Methods Nontreatment seeking problem drinkers (n = 295) were assessed in the laboratory for clinical dimensions of alcohol dependence. Following prospective genotyping, 43 alcohol-dependent individuals across the 2 genotype conditions (AA, n = 23 and AG/GG, n = 20) were randomized to 2 intravenous infusion sessions: 1 of alcohol (target breath alcohol concentration = 0.06 g/dl) and 1 of saline. Measures of subjective responses to alcohol were administered in both infusion sessions. Results Alcohol-dependent G-allele carriers reported greater alcohol-induced stimulation, vigor, and positive mood, as compared to A-allele homozygotes. There was no genotype effect on alcohol-induced sedation or craving. There was a statistical trend-level severity × alcohol interaction such that individuals at higher levels of severity reported greater alcohol-induced tension reduction. Conclusions These results support the hypothesis that OPRM1 genotype moderates the hedonic effects of alcohol, but not the sedative and unpleasant effects of alcohol, in a sample of alcohol-dependent patients. Results are discussed in light of a clinical neuroscience framework to alcoholism.

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.

Aims Withdrawal symptoms have been linked to a propensity for relapse to drug abuse. Inasmuch as this association applies to methamphetamine (MA) abuse, an understanding of the course of MA withdrawal symptoms may help to direct treatment for MA dependence. Previous studies of symptoms manifested during abstinence from MA have been limited in size and scope. We asked (i) whether debilitating psychological and/or physical symptoms appear during the first several weeks of MA abstinence, (ii) how craving for MA evolves and (iii) whether psychiatric symptoms (e.g. depression, psychosis) persist beyond a month of abstinence. Design A study of MA‐dependent participants, who initiated and maintained abstinence from the drug for up to 5 weeks, compared to a matched healthy comparison group. Setting In‐patient research hospital ward (MA‐dependent subjects) and out‐patient (comparison subjects). Participants Fifty‐six MA‐dependent and eighty‐nine comparison subjects. Measurements Rater‐assessed MA withdrawal questionnaire and self‐report assessment of craving (MA‐dependent subjects) and self‐report assessment of psychiatric symptoms (both groups). Findings At study entry, MA‐dependent subjects exhibited a wide range in severity of depressive symptoms, with the average score at a mild–moderate level of severity. Symptoms of psychosis were also prevalent. While depressive and psychotic symptoms largely resolved within a week of abstinence, craving did not decrease significantly from the time of initiating abstinence until the second week, and then continued at a reduced level to the fifth week. Conclusions Depressive and psychotic symptoms accompany acute withdrawal from methamphetamine but resolve within 1 week. Craving is also present and lasts at least 5 weeks.

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.

© 2015 American College of Neuropsychopharmacology Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of ‘crave drug,’ ‘stimulated,’ and ‘would like drug access,’ decreased the the post-MA administration timecourse of ‘anxious’ and increased ratings of ‘bad drug effects,’ as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.Neuropsychopharmacology advance online publication, 15 April 2015; doi:10.1038/npp.2015.83.

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.

RationaleHeavy drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.ObjectiveThe present study used a double-blind, randomized, 2 × 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), naltrexone alone (NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on neural activation to cigarette cues in a sample (n = 40) of heavy drinking daily smokers (≥10 cigarettes/day).MethodsAll participants were tested after a 10-12-day titration period designed to reach steady state on the target medication. Participants underwent functional neuroimaging (fMRI) for examination of brain responses to visual smoking-related (vs. neutral) cues.ResultsRegion of interest (ROI) analyses of brain responses to Cigarette vs. Neutral Cues indicated that the combination of VAR + NTX was associated with reduced activation of the bilateral anterior cingulate cortex as compared to placebo and to NTX alone. Exploratory whole-brain analyses also indicated significant differences in brain activation during cigarette cues in the active medications versus placebo condition. All medications suppressed left nucleus accumbens activation relative to placebo, suggesting the possibility that both medications, either alone or in combination, reduce neural signals associated with appetitive behavior.ConclusionsAlthough preliminary, these neuroimaging findings indicate that clinical studies of the combination of VAR + NTX for heavy drinkers trying to quit smoking may be warranted.

Ecstasy (MDMA), gamma-hydroxybutyrate (GHB), ketamine, and methamphetamine are 4 examples of club drugs that are increasing in popularity. Although the pharmacological classifications of these drugs vary, MDMA has structural similarities to both amphetamine and the hallucinogen mescaline. Ketamine and GHB are anesthetic agents and methamphetamine is a long-acting psychostimulant. Medical visits for club drug-related toxicity have sharply increased across the country. This article provides a brief review of the literature on club drugs.

The clinical application of the narcotic antagonist, naltrexone for the treatment of opioid dependence has been minimal. This study evaluated the impact of a multi-component, manualized, psychosocial protocol designed to enhance the clinical value of naltrexone for opioid dependence treatment. Eighty-one detoxified individuals meeting DSM-IV criteria for opioid dependence were inducted onto naltrexone and randomly assigned to either a standard (ST) group, with monthly medical monitoring visits, or an enhanced (EN) group in which participants received counseling and educational interventions three times per week. EN group participants took more study medication, were retained in treatment longer, used less opioids while in treatment and showed greater improvement on a number of psychological/affective dimensions. The improved performance of the EN group was relatively short-lived as there were no significant group differences at 6- or 12-month post-admission follow-up points. \[Rawson RA, McCann MJ, Shopta...

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.

A six-session cognitive behavioral protocol has been developed for substance abusers who meet the description "hazardous users." This category includes individuals evidencing mild to moderate use of alcohol or other drugs, whose lifestyles are minimally disrupted, or who are displaying signs of problem use or abuse, but are unwilling to enter intensive treatment. The treatment model is nonconfrontational and is designed to motivate the individual to recognize the problems associated with his or her substance use and initiate treatment-seeking behavior. The intervention may be particularly useful in situations where employees have tested positive for substances but deny having a problem, where friends or family members report help is needed but the individual denies any problem, or where an alcohol or other drug problem is clearly evidenced but the individual doesn't acknowledge a problem. A positive outcome is indicated by the client taking action which is consistent with an increased awareness of the problem as conceptualized by Prochaska and DiClemente (1982). This model is an alternative to the traditional confrontational models of "breaking through denial." The philosophies employed by William Miller and associates and by the Matrix treatment models form the basis of the intervention.

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.

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.

The available treatments for alcoholism are only modestly effective, and patients vary widely in their treatment response. Quetiapine, an atypical antipsychotic medication with antagonist activity at D1 and D2, 5-HT(1A) and 5-HT(2A), H(1), and α1 and α2 receptors was shown to promote abstinence, reduce drinking days, and reduce heavy drinking days in a 12-week double-blind placebo-controlled trial.Although quetiapine represents one of the promising pharmacotherapies for the treatment of alcoholism, its mechanisms of action are poorly understood. The objective of this study is to elucidate the biobehavioral mechanisms of action of quetiapine for alcoholism, by examining its effects on subjective intoxication and craving.A total of 20 non-treatment-seeking alcohol-dependent individuals were randomized to one of the following conditions in a double-blind, placebo-controlled design: (1) quetiapine (400 mg/day); or (2) matched placebo. Participants were on the target medication dose (or matched placebo) for 4 weeks during which they completed weekly assessments of drinking, sleep, mood, and anxiety. Participants completed two counterbalanced intravenous placebo-alcohol administration sessions as well as cue-reactivity assessments.Analyses revealed a significant effect of quetiapine in reducing craving during the alcohol administration, the alcohol cue-exposure, and the weekly reports of alcohol craving. Quetiapine was also found to reduce subjective intoxication and alcohol-induced sedation during the alcohol administration paradigm.This study contributes critical new information about mechanisms of response to quetiapine for alcoholism, which, in turn, can inform larger-scale studies and ultimately, clinical practice.

Methamphetamine (MA) use disorders are pervasive global social problems that produce large medical and public health burdens. Abnormalities in pituitary hormonal regulation have been observed in preclinical models of substance abuse and in human substance abusers. They have, however, not been studied before in MA-dependent human subjects.To determine if MA-dependent research volunteers differ from healthy control subjects in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, or prolactin, or in pituitary dopamine D(2) receptor availability during early abstinence from MA.MA-dependent subjects (N = 31), who were not seeking treatment, resided on an inpatient ward for up to 5 weeks. Abstinence was confirmed by daily urine drug screening. Venous blood was sampled for plasma hormone levels, and positron emission tomography with [(18)F]fallypride was performed to determine dopamine D(2) receptor availability during the first week of abstinence. Venous blood was sampled again for hormone levels during the fourth week of abstinence. Matched healthy volunteers (N = 23) participated as a comparison group.MA-dependent and healthy comparison subjects did not differ in plasma ACTH or cortisol levels, but had an elevated plasma prolactin at both the first week and fourth week of abstinence. There was no group difference in pituitary dopamine D(2) receptor availability.MA-dependent individuals have abnormalities in prolactin regulation, which is not likely due to alterations in pituitary dopamine D(2) receptor availability.MA dependence is associated with elevated prolactin levels, which may contribute to medical comorbidity in afflicted individuals.

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.

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.

Background Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. Objective To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. Design Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. Setting Participants were recruited from the general community to a research center. Participants Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). Main Outcome Measures Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. Results Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. Conclusions Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.