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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.

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).

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.

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.

© 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.

Aims Previous research has reported that both contingency management (CM) and cognitive-behavioral therapy (CBT) are efficacious interventions for the treatment of stimulant abusers. The present study sought to directly compare the effectiveness of (CM) and (CBT) alone and in combination in reducing stimulant use. Design Randomized clinical trial. Participants Stimulant-dependent individuals (n = 171). Intervention CM, CBT or combined CM and CBT, 16-week treatment conditions. CM condition participants received vouchers for stimulant-free urine samples. CBT condition participants attended three 90-minute group sessions each week. Measurements Participants were interviewed at baseline and weeks 17, 26 and 52. Measures included psychiatric disorders and alcohol and drug use and concomitant social problems. Findings CM procedures produced better retention and lower rates of stimulant use during the study period. Self-reported stimulant use was reduced from baseline levels at all follow-up points for all groups and urinalysis data did not differ between groups at follow-up. While CM produced robust evidence of efficacy during treatment application, CBT produced comparable longer-term outcomes. There was no evidence of an additive effect when the two treatments were combined. Conclusions This study suggests that CM is an efficacious treatment for reducing stimulant use and is superior during treatment to a CBT approach. CM is useful in engaging substance abusers, retaining them in treatment and helping them achieve abstinence from stimulant use. CBT also reduces drug use from baseline levels and produces comparable outcomes on all measures at follow-up.

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).

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...

Gamma-hydroxybutyric acid (GHB) is gaining popularity as a drug of abuse. Reports of toxicity and lethality associated with GHB use have increased. This survey study was designed to identify patterns of GHB use, its effects, and withdrawal syndrome. A survey inquiring about the effects of GHB was administered to 42 users. The results showed that GHB was used to increased feelings of euphoria, relaxation, and sexuality. Adverse effects occurred more frequently in daily users and polydrug users than in occasional GHB users. Loss of consciousness was reported by 66%, overdose by 28%, and amnesia by 13% of participants during GHB use and by 45% after GHB use. Three daily users developed a withdrawal syndrome that presented with anxiety, agitation, tremor, and delirium. Participants described GHB intoxication as having similarities to sedative-hypnotic or alcohol intoxication. Regular use has been shown to produce tolerance and dependence. Participants dependent on GHB reported using multiple daily doses around the clock. High frequency users appeared at the greatest risk for developing withdrawal delirium and psychosis after abrupt discontinuation of GHB use.

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.

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.

Varenicline is a partial agonist of the α4β2 nicotinic acetylcholine receptor approved by the FDA for the treatment of nicotine dependence. While the clinical efficacy of varenicline for smoking cessation is well-supported, its biobehavioral mechanisms of action remain poorly understood. This randomized, crossover, placebo-controlled, human laboratory study combines guided imagery stress exposure with in vivo presentation of cigarette cues to test the effects of varenicline on stress-induced and cue-induced craving for cigarettes.A total of 40 (13 females) daily smokers (≥10 cigarettes per day) completed a guided imagery exposure (stress and neutral) followed by the presentation of cigarette cues at the target dose of varenicline (1mg twice per day) and on matched placebo.Multilevel regression models revealed a significant main effect of varenicline (p.01) such that it reduced cigarette craving across the experimental paradigm, compared to placebo. There was also a significant medication×stress×trial interaction indicating that varenicline attenuated cue induced craving following neutral imagery but not when cues were preceded by stress induction (i.e., stress+cues).These results elucidate the biobehavioral effects of varenicline for nicotine dependence and suggest that varenicline-induced amelioration of cigarette craving is unique to tonic craving and cue-induced craving following neutral imagery but does not extend to the combination of stress plus cues.

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.

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.

Fourteen strains of Shigella dysenteriae type 1 (Shiga bacillus) isolated from people in diverse locations from 1940 to 1987 were studied. Southern hybridization with three cloned Escherichia coli genes, Shiga-like toxin I (SLTI), frd, and ompF, was used to determine restriction fragment length polymorphism (RFLP) of the genomic DNA of these strains. Digestion with each of four restriction endonucleases generated fragments of identical size to which the frd and ompF hybridized for each of the 14 strains, indicating the conservation of these genes and their flanking sequences. In contrast, after digestion with HindIII, EcoRV, and ClaI and probing with SLTI, there were RFLP among the strains. The results showed three clones of the Shiga bacillus, and suggested that dissemination of a single clone may continue for decades within a wide geographical area.