Chemotherapy-induced peripheral neuropathy in the detroit research on cancer survivors (ROCS) cohort.

PURPOSE: Improved life expectancy has increased the likelihood for long-term complications from chemotherapy among cancer survivors. One burdensome complication is chemotherapy-induced peripheral neuropathy (CIPN). We evaluated rates of CIPN outcomes in the Detroit Research on Cancer Survivorship (ROCS) cohort. METHODS: The population included 1,034 African American (AA) survivors who received chemotherapy for breast, colorectal, lung or prostate cancer. CIPN prevalence was based on initial occurrence of worsening of self-reported pain, numbness or tingling after chemotherapy. Current CIPN included symptoms still present at the time of the survey, and persistent CIPN symptoms were present 12 or more months post-chemotherapy. CIPN severity was ranked as mild, moderate or severe. Logistic regression was utilized to evaluate sociodemographic and clinical factors associated with the various categories of CIPN. RESULTS: CIPN prevalence was 68%, with 53% current and 52% persistent. The symptom severity distribution based on prevalent CIPN included 32.2% mild, 30.8% moderate, and 36.9% severe. Factors associated with prevalent CIPN (odds ratio, 95% confidence interval) included primary cancer site (breast: 3.88, 2.02-7.46); and (colorectal: 5.37, 2.69-10.73), lower risk for older age at diagnosis (0.66, 0.53-0.83) and divorced/separated marital status (2.13, 1.42-3.21). Current CIPN was in addition, associated with more advanced stage disease trend (1.34, 1.08-1.66) and greater number of co-morbid medical conditions trend (1.23, 1.09-1.40), as was persistent CIPN. Severity of prevalent CIPN was associated with history of arthritis (1.55, 1.06-2.26) and severity of persistent CIPN with higher BMI (1.58, 1.07-2.35). CONCLUSIONS: CIPN is a common and persistent complication in AA cancer survivors. Further research is needed to improve our understanding of CIPN predictors in all groups of cancer survivors.

Cannabis and complementary/alternative self-treatment approaches for symptom management among African American persons living with HIV.

Persons living with HIV (PLWH) experience symptoms from disease progression and side effects of antiretroviral treatment. This study examines in African American PLWH (N = 259) commonly-endorsed symptoms, types and self-rated efficacy of therapies for symptom alleviation. Analyses were stratified by gender (n = 178 males, n = 81 females) and cannabis use typology: non-users (n = 90), mostly recreational use (n = 46), mixed recreational/therapeutic use (n = 51), or mostly therapeutic use (n = 72). Females reported greater severity for pain, fatigue, depression, weight change and tingling in extremities, but there were no gender differences for ratings of poor sleep, anxiety, poor appetite, or headache. Both marijuana (used therapeutically by females more than males) and medication(s) were among the 3 top methods for managing pain, poor sleep, anxiety, and headache. Marijuana was most often used for poor appetite, and medications for depression. Perceived efficacy of self-treatment approaches was moderately good. Among African American PLWH, symptom severity was higher for females and for therapeutic users of cannabis. Marijuana and medicine were often used to self-treat symptoms, but many participants did nothing. These results highlight the need for careful evaluation and management of symptoms in this underserved population.

Optimizing buprenorphine training during undergraduate medical education: Medical student feedback and attitudes.

BACKGROUND AND OBJECTIVES: Strong evidence supports efficacy of medications for opioid use disorder (MOUD), but stringent prescribing policies impair access. Many physicians report discomfort prescribing MOUD due to inadequate knowledge. Most medical students believe MOUD training should occur during undergraduate medical education (UME). As legislation surrounding buprenorphine prescribing shifts, it is timely to consider how best to incorporate MOUD training into UME. METHODS: At the start of 3rd year, all students (n = 290) received a survey regarding experiences working with people with OUDs, and beliefs and knowledge regarding harm reduction and treatment. During orientation, students completed an 8-h online MOUD training. Afterwards, students completed another survey, including questions about training perceptions. RESULTS: One-third of students (32.8%) completed MOUD training and both surveys. Before training, 60.0% had not heard of the waiver, but 82.1% endorsed interest in prescribing buprenorphine. Despite mixed feelings about training content and delivery, 79.1% believed future classes should receive it. Most thought it should be integrated longitudinally throughout the curriculum rather than as separate online training. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Medical students want more MOUD education throughout their training; however, the 8-h online training may be less-than-optimal. As this training is no longer required to prescribe buprenorphine, there is an opportunity to modify the content presented. There is an urgent need for physicians with the knowledge and willingness to treat patients with OUD. Introducing integrated training about MOUD should help future physicians feel confident in their knowledge to treat patients and comfortable applying for the waiver.

Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder.

BACKGROUND: BUP-XR (SUBLOCADE®) is the first buprenorphine extended-release subcutaneous injection approved in the USA for monthly treatment of moderate-to-severe opioid use disorder (OUD). Among patients with OUD, those who inject or use high doses of opioids likely require higher doses of buprenorphine to maximize treatment efficacy. The objective of this analysis was to compare the efficacy and safety of 100-mg versus 300-mg maintenance doses of BUP-XR in OUD patients who inject opioids. METHODS: This was a secondary analysis of a randomized, double-blind, placebo-controlled study in which adults with moderate or severe OUD received monthly injections of BUP-XR (2 × 300-mg doses, then 4 × 100-mg or 300-mg maintenance doses) or placebo for 24 weeks. Abstinence was defined as opioid-negative urine drug screens combined with negative self-reports collected weekly. Each participant's percentage abstinence was calculated after the first, second, and third maintenance doses in opioid-injecting and non-injecting participants. The proportion of participants achieving opioid abstinence in each group was also calculated weekly. Treatment retention rate following the first maintenance dose was estimated for opioid-injecting participants with Kaplan-Meier method. Risk-adjusted comparisons were made via inverse propensity weighting using propensity scores. Buprenorphine plasma concentration-time profiles were compared between injecting and non-injecting participants. The percentages of participants reporting treatment-emergent adverse events were compared between maintenance dose groups within injecting and non-injecting participants separately. RESULTS: BUP-XR 100-mg and 300-mg maintenance doses were equally effective in non-injecting participants. However, in opioid-injecting participants, the 300-mg maintenance dose delivered clinically meaningful improvements over the 100-mg maintenance dose for treatment retention and opioid abstinence. Exposure-response analyses confirmed that injecting participants would require higher buprenorphine plasma concentrations compared to non-injecting opioid participants to achieve similar efficacy in terms of opioid abstinence. Importantly, both 100- and 300-mg maintenance doses had comparable safety profiles, including hepatic safety events. CONCLUSIONS: These analyses show clear benefits of the 300-mg maintenance dose in injecting participants, while no additional benefit was observed in non-injecting participants relative to the 100-mg maintenance dose. This is an important finding as opioid-injecting participants represent a high-risk and difficult-to-treat population. Optimal buprenorphine dosing in this population might facilitate harm reduction by improving abstinence and treatment retention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02357901.

A Neuropharmacological Model to Explain Buprenorphine Induction Challenges.

Buprenorphine induction for treating opioid use disorder is being implemented in emergency care. During this era of high-potency synthetic opioid use, novel and divergent algorithms for buprenorphine induction are emerging to optimize induction experience, facilitating continued treatment. Specifically, in patients with chronic fentanyl or other drug exposures, some clinicians are using alternative buprenorphine induction strategies, such as quickly maximizing buprenorphine agonist effects (eg, macrodosing) or, conversely, giving smaller initial doses and slowing the rate of buprenorphine dosing to avoid antagonist/withdrawal effects (eg, microdosing). However, there is a lack of foundational theory and empirical data to guide clinicians in evaluating such novel induction strategies. We present data from clinical studies of buprenorphine induction and propose a neuropharmacologic working model, which posits that acute clinical success of buprenorphine induction (achieving a positive agonist-to-withdrawal balance) is a nonlinear outcome of the opioid balance at the time of initial buprenorphine dose and mu-opioid-receptor affinity, lipophilicity, and mu-opioid-receptor intrinsic efficacy (the "ALE value") of the prior opioid. We discuss the rationale for administering smaller or larger doses of buprenorphine to optimize the patient induction experience during common clinical situations.

Developing and validating an opioid overdose prevention and response curriculum for undergraduate medical education.

Introduction: As rates of overdose and substance use disorders (SUDs) increase, medical schools are starting to incorporate more content on SUDs and harm reduction in undergraduate medical education (UME). Initial data suggest these additions may improve medical student knowledge and attitudes toward patients with SUDs; however, there is no standard curriculum. Methods: This project uses a six-step approach to UME curricular development to identify needs and goals regarding SUDs and opioid overdose at a large single-campus medical school in the United States. We first developed and delivered a pilot curriculum to a small group of medical students. Pilot results and a larger survey led to implementing a one-hour Opioid Overdose Prevention and Response (OOPR) Training for first-year students. Effects of training were tracked using baseline and post-training surveys examining knowledge and attitudes toward opioid overdose and patients with SUDs. Results: Needs assessment indicated desire and need for training. The pilot study (N = 66) resulted in significantly improved knowledge regarding opioid overdose; 100% of students enjoyed training and believed others should receive it. The larger replication study surveyed all incoming students (N = 266) to gauge initial knowledge and experiences with these topics. Results prompted enhancement of the OOPR Training curriculum, which was delivered to half of the first-year class. Post-training survey results replicated the pilot study findings. The majority (95.2%) of students enjoyed training and 98.4% believed all students should receive it. Conclusion: Delivering a thorough curriculum on SUDs and harm reduction in UME is critical. Although many schools are implementing training, there is no standard curriculum. We outline a low-resource training intervention for OOPR. Our findings identified key features to include in these UME curricula. This approach provides a replicable template for schools seeking to develop brief educational interventions and identify essential content for curricula in SUDs and harm reduction.

A Virtual Reality Meditative Intervention Modulates Pain and the Pain Neuromatrix in Patients with Opioid Use Disorder.

OBJECTIVE: Standard of care for opioid use disorder (OUD) includes medication and counseling. However, there is an unmet need for complementary approaches to treat OUD patients coping with pain; furthermore, few studies have probed neurobiological features of pain or its management during OUD treatment. This preliminary study examines neurobiological and behavioral effects of a virtual reality-based meditative intervention in patients undergoing methadone maintenance treatment (MMT). DESIGN: Prospective, non-blinded, single-arm, 12-week intervention with standardized assessments. SETTING: Academic research laboratory affiliated with an on-site MMT clinic. METHODS: Fifteen (11 female) MMT patients completed a virtual reality, therapist-guided meditative intervention that included breathing and relaxation exercisessessions were scheduled twice weekly. Assessments included functional magnetic resonance imaging (fMRI) of pain neuromatrix activation and connectivity (pre- and post-intervention), saliva cortisol and C-reactive protein (CRP) at baseline and weeks 4, 8 and 12; and self-reported pain and affective symptoms before and after each intervention session. RESULTS: After each intervention session (relative to pre-session), ratings of pain, opioid craving, anxiety and depression (but not anger) decreased. Saliva cortisol (but not CRP) levels decreased from pre- to post-session. From pre- to post-intervention fMRI assessments, pain task-related left postcentral gyrus (PCG) activation decreased. At baseline, PCG showed positive connectivity with other regions of the pain neuromatrix, but this pattern changed post-intervention. CONCLUSIONS: These preliminary findings demonstrate feasibility, therapeutic promise, and brain basis of a meditative intervention for OUD patients undergoing MMT.

N-acetylcysteine reduces cocaine-seeking behavior and anterior cingulate glutamate/glutamine levels among cocaine-dependent individuals.

N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm3 ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.

ß-Arrestin 2 (ARRB2) Polymorphism is Associated With Adverse Consequences of Chronic Heroin Use.

BACKGROUND AND OBJECTIVES: ß-arrestin 2 is an intracellular protein recruited during the activation of G-protein-coupled receptors. In preclinical studies, ß-arrestin 2 has been implicated in µ-opioid receptor desensitization and internalization and the development of opioid tolerance and dependence. The present study investigated relationships between variants in the gene encoding ß-arrestin 2 (ARRB2) and clinically relevant phenotypes among individuals with opioid use disorder (OUD). We hypothesized that ARRB2 variants would be associated with the negative effects of long-term heroin use. METHODS: Chronic heroin users (N = 201; n = 103 African American; n = 98 Caucasian) were genotyped for ARRB2 r1045280 (synonymous, also affecting binding motif of transcription factor GTF2IRD1), rs2036657 (3'UTR) and rs3786047 (intron) and assessed for the past-month frequency of use, injection use, and lifetime duration of heroin use, number of heroin quit-attempts, and heroin use-related consequences. RESULTS: Lifetime heroin-use consequences (especially occupational and health-related) were significantly lower for African American ARRB2 r1045280 C-allele carriers compared with the TT genotype. There was no significant genotype difference in the Caucasian group. ARRB2 rs2036657 was in strong linkage disequilibrium with rs1045280. DISCUSSION AND CONCLUSIONS: These results, consistent with extant data, illustrate a role for ancestry-dependent allelic variation in ARRB2 r1045280 on heroin-use consequences. The ARRB2 r1045280 C-allele played a protective role in African-descent participants. SCIENTIFIC SIGNIFICANCE: These first-in-human findings, which should be replicated, provide support for mechanistic investigations of ARRB2 and related intracellular signaling molecules in OUD etiology, treatment, and relapse prevention. (Am J Addict 2021;00:00-00).

Incoming medical students' knowledge of and attitudes toward people with substance use disorders: Implications for curricular training.

Background: Medical students may be in an ideal position to identify patients with substance use disorders (SUDs) and provide them with information about harm reduction and treatment options. Specific education regarding opioid use disorder (OUD) and naloxone during undergraduate medical training may help students identify these patients and decrease their own negative attitudes toward patients with OUD. To plan for curriculum development, this study aimed to understand baseline knowledge and attitudes among students entering medical school. Methods: During orientation, all first-year medical students (Class of 2023) were asked to complete a survey that explored their previous experiences in healthcare and with SUDs as well as their attitudes toward opioid overdose and patients with SUDs. We administered the Opioid Overdose Knowledge Scale (OOKS), Opioid Overdose Attitudes Scale (OOAS), Medical Conditions Regard Scale (MCRS), and Naloxone Related Risk Compensation Beliefs (NaRRC-B). Results: 266 students (89.6% of the class) completed the survey. Generally, these students were relatively proficient in opioid overdose knowledge, but did not feel they were competent enough to respond to an overdose. Attitudes toward patients with SUDs were mixed. Approximately half of the students thought naloxone distribution should be unrestricted, but many were uncertain whether naloxone receipt would deter individuals from seeking treatment or increase opioid use. Students' previous experiences in healthcare (e.g., employment) results in significantly different knowledge and attitudes toward opioid overdose response. Conclusions: These incoming medical students have greater healthcare experience and level of opioid overdose knowledge than the general population, but still harbor significant misinformation and stigma toward patients with SUDs. These findings provide a foundation upon which to tailor didactic efforts, starting early in medical school, so that graduating physicians can be adequately prepared for clinical care.

Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 treatment centres in the USA. Treatment-seeking adults aged 18-65 years who had moderate or severe opioid use disorder (as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders) entered an open-label run-in phase of up to 2 weeks' treatment with buprenorphine-naloxone sublingual film. Eligible participants were then randomly assigned (4:4:1:1) with an interactive voice/web-response system to receive BUP-XR 300 mg/300 mg (six injections of 300 mg), BUP-XR 300 mg/100 mg (two injections of 300 mg plus four injections of 100 mg), or volume-matched placebo every 28 days, and received weekly individual drug counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use from week 5 to week 24, analysed in the full analysis set. Safety was assessed in all participants who received at least one dose of BUP-XR or placebo. This study is registered with ClinicalTrials.gov, number NCT02357901. FINDINGS: From Jan 28, 2015, to Nov 12, 2015, 1187 potential participants were screened, 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg (n=201), BUP-XR 300 mg/100 mg (n=203), or placebo (n=100). Mean participants' percentage abstinence was 41·3% (SD 39·7) for BUP-XR 300 mg/300 mg and 42·7% (38·5) for 300 mg/100 mg, compared with 5·0% (17·0) for placebo (p<0·0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting. INTERPRETATION: Participants' percentage abstinence was significantly higher in both BUP-XR groups than in the placebo group. Treatment with BUP-XR was also well tolerated. The availability of this monthly formulation, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products. FUNDING: Indivior.

Heroin delay discounting and impulsivity: Modulation by DRD1 genetic variation.

BACKGROUND: Dopamine D1 receptors (encoded by DRD1) are implicated in drug addiction and high-risk behaviors. Delay discounting (DD) procedures measure decisional balance between choosing smaller/sooner rewards vs larger/later rewards. Individuals with higher DD (rapid discounting) are prone to maladaptive behaviors that provide immediate reinforcement (eg, substance use). DRD1 variants have been linked with increased DD (in healthy volunteers) and opioid abuse. This study determined whether four dopaminergic functional variants modulated heroin DD and impulsivity. METHODS: Substance use, DD, and genotype data (DRD1 rs686 and rs5326, DRD3 rs6280, COMT rs4680) were obtained from 106 current heroin users. Subjects completed an array of DD choices during two imagined conditions: heroin satiation and withdrawal. Rewards were expressed as $10 heroin bag units, with maximum delayed amount of 30 bags. Delays progressively increased from 3 to 96 hours. RESULTS: DRD1 rs686 (A/A, n = 25; G/A, n = 56; G/G, n = 25) was linearly related to the difference in heroin DD (area under the curve; AUC) between the heroin satiation and withdrawal conditions; specifically, G/G homozygotes had a significantly smaller (satiation minus withdrawal) AUC difference score had higher drug-use impulsivity questionnaire scores, relative to A/A homozygotes, with G/A intermediate. DRD3 and COMT variants were not associated with these DD and impulsivity outcomes. CONCLUSION: DRD1 rs686 modulated the difference in heroin DD score between pharmacological states and was associated with drug-use impulsivity. These data support a role of DRD1 in opioid DD and impulsive behaviors.

A neurobiological correlate of stress-induced nicotine-seeking behavior among cigarette smokers.

Stress is known to influence smoking relapse. Experimental studies indicate that acute stress increases nicotine-seeking behavior, yet neurobiological mechanisms remain poorly understood. Herein, we investigated disrupted excitatory neural activity in the dorsolateral prefrontal cortex (dlPFC) as a mechanism of stress-induced nicotine-seeking behavior. Non-treatment-seeking cigarette smokers were screened for psychiatric, medical, and neuroimaging contraindications. Using a double-blind, placebo-controlled, randomized crossover design, participants (N = 21) completed two oral-dosing sessions: stress (yohimbine 54 mg + hydrocortisone 10 mg) vs placebo (lactose 54 mg + lactose 10 mg). During each experimental session, working memory proficiency, dlPFC excitatory neural activity, nicotine-seeking behavior, and subjective effects were measured. dlPFC excitatory neural activity was quantified via glutamate modulation during working memory performance using functional proton magnetic resonance spectroscopy. Nicotine-seeking behavior was assayed using a cigarette puffs vs money choice progressive ratio task. Results indicated that yohimbine + hydrocortisone evoked a sustained physiological stress response (elevated heart rate, blood pressure, saliva cortisol, and saliva α-amylase levels; ps < .05). Relative to placebo levels, acute stress increased nicotine-seeking behavior (ps < .05), disrupted dlPFC glutamate modulation (p = .025), and impaired dlPFC function (working memory proficiency; ps < .05). The stress-induced increase in nicotine-seeking behavior was linearly related to the stress-induced disruption of dlPFC glutamate modulation (R2  = 0.24-0.37; ps < .05). These findings suggest that disrupted dlPFC excitatory neural activity is a neurobiological correlate of acute stress-induced nicotine-seeking behavior. These findings further emphasize the central role of the dlPFC in regulating drug-seeking behavior. Future studies are needed to evaluate interventions to improve dlPFC resilience to acute stress effects, including neurostimulation, working memory training, and "anti-stress" medications.

A Comparison of Substance Use Patterns Among Lifetime Heroin-Injecting Individuals By Racial Groups.

BACKGROUND: Studies have identified differential substance use patterns by racial groups. One of the most commonly reported differences is a higher rate of injection drug use (IDU) among Non-Hispanic Whites compared to African Americans, but this is complicated by factors related to IDU (e.g., earlier drug-use initiation) that overlap with being White. OBJECTIVE: We explored differential substance use-patterns by racial groups within a sample of injection heroin users. METHODS: Substance-use data were collected from 373 not-in-treatment heroin users who endorsed any lifetime injection use (69.4% male). We examined differences in substance-use patterns (e.g., age of initiation, gateway adherence) by racial groups. Multiple t-tests with Bonferroni correction were conducted to understand which demographic and substance-use characteristics varied by racial groups. RESULTS: Relative to Non-Hispanic Whites, African Americans (45.8% of sample) were more likely to start using heroin earlier in their life, but also more likely to experience a longer delay between starting and regularly using heroin. We also identified differences in the degree of (injection) heroin-use consequences by racial groups. After correcting for multiple comparisons and controlling for age and gender, we observed differences for six substance-use and demographic characteristics by racial group. White participants were younger, started cocaine use earlier, and experienced more heroin-use consequences across two separate domains. CONCLUSIONS: After controlling for injection use, we observed differential substance-use characteristics by racial groups. The findings could be used to develop targeted prevention and harm-reduction strategies.

Pharmacological stress impairs working memory performance and attenuates dorsolateral prefrontal cortex glutamate modulation.

Working memory processes are associated with the dorsolateral prefrontal cortex (dlPFC). Prior research using proton functional magnetic resonance spectroscopy (1H fMRS) observed significant dlPFC glutamate modulation during letter 2-back performance, indicative of working memory-driven increase in excitatory neural activity. Acute stress has been shown to impair working memory performance. Herein, we quantified dlPFC glutamate modulation during working memory under placebo (oral lactose) and acute stress conditions (oral yohimbine 54 mg + hydrocortisone 10 mg). Using a double-blind, randomized crossover design, participants (N = 19) completed a letter 2-back task during left dlPFC 1H fMRS acquisition (Brodmann areas 45/46; 4.5 cm3). An automated fitting procedure integrated with LCModel was used to quantify glutamate levels. Working memory-induced glutamate modulation was calculated as percentage change in glutamate levels from passive visual fixation to 2-back levels. Results indicated acute stress significantly attenuated working memory-induced glutamate modulation and impaired 2-back response accuracy, relative to placebo levels. Follow-up analyses indicated 2-back performance significantly modulated glutamate levels relative to passive visual fixation during placebo but not acute stress. Biomarkers, including blood pressure and saliva cortisol, confirmed that yohimbine + hydrocortisone dosing elicited a significant physiological stress response. These findings support a priori hypotheses and demonstrate that acute stress impairs dlPFC function and excitatory activity. This study highlights a neurobiological mechanism through which acute stress may contribute to psychiatric dysfunction and derail treatment progress. Future research is needed to isolate noradrenaline vs. cortisol effects and evaluate anti-stress medications and/or behavioral interventions.

Risk of incident claims for chemotherapy-induced peripheral neuropathy among women with breast cancer in a Medicare population.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling consequence of neurotoxic therapies, yet factors that modulate the development and clinical impact of CIPN are poorly understood. This epidemiological analysis identifies risk factors for the incidence of CIPN. METHODS: This retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data examined predictors of incident CIPN claims among 11,149 women aged 66 years or older with American Joint Commission on Cancer (AJCC) stage II to IV breast cancer (and no secondary cancer diagnosis or preexisting neuropathy) who received chemotherapy. RESULTS: Overall, new CIPN claims occurred for 8.3% of patients within 1 year of starting chemotherapy. Risk emerged approximately 3 months after the start of chemotherapy and increased throughout 1 year. Paclitaxel as part of first-line therapy increased CIPN risk 2.7-fold in comparison with nonneurotoxic agents (15.9% vs 5.0%), with lower incidence rates for carboplatin and paclitaxel (11.9%), carboplatin and docetaxel (9.3%), carboplatin alone (7.7%), and docetaxel alone (6.6%). The CIPN incidence rate was higher for women who at the time of their breast cancer diagnosis were relatively young (within this Medicare sample), were at AJCC stage II or III, were married or had an equivalent status, and had fewer comorbidities, but it did not differ by race/ethnicity or poverty level. CONCLUSIONS: These Medicare claims database findings indicate that women aged 66 years or older with breast cancer are susceptible to CIPN from taxane and/or platinum compounds, with risk emerging approximately 3 months into treatment. Prospective studies of symptom emergence and clinical response (eg, stopping chemotherapy and adjunctive treatments) are indicated to determine how best to inform patients of this risk and to manage CIPN in this population.

Gender-specific predictors of methadone treatment outcomes among African Americans at an urban clinic.

Background: African American patients with opioid use disorder (OUD) have demonstrated poorer methadone maintenance treatment (MMT) outcomes compared with white patients. This issue is further complicated in urban settings, where African Americans experience high rates of poverty and publicly funded treatment. Despite interrelated factors that disadvantage African Americans, the literature focusing on this population is scant. To address this shortcoming, we conducted the first investigation of gender differences and gender-specific MMT outcome predictors among African Americans (or any racial minority population). This study provides gender-specific findings to improve African American MMT outcomes. Methods: We studied 211 African American patients (male: n = 137, 64.9%) at an urban, university-affiliated MMT clinic. We used existing intake data to assess baseline demographic, substance use, mental health, and interpersonal factors. Primary outcomes were 3-month drug+ (positive) urine drug screen (UDS) results and treatment retention. Results: Women were more likely (than men) to endorse histories of interpersonal violence, substance abuse in their social network, and mental health problems. Men reported a greater likelihood (than women) for early opioid-use onset and a lack of prior MMT. There were no gender differences in 3-month drug+ UDS or treatment retention. In multivariable analyses among women, no baseline factors predicted 3-month opioid+ UDS and physical abuse history predicted a higher proportion of 3-month cocaine+ UDS. Among men, primary injection opioid use and older age best predicted a higher proportion of 3-month cocaine+ UDS and parent substance abuse predicted shorter retention. In both gender-stratified analyses, higher proportions of 3-month opioid+ UDS and cocaine+ UDS predicted shorter retention. Conclusions: This study offers an analysis of gender differences in risk factors, MMT outcomes, and gender-specific predictors among African American patients. MMT clinics should tailor assessment and treatment protocols to address gender-specific needs.

Mediational Pathways Among Trait Impulsivity, Heroin-use Consequences, and Current Mood State.

BACKGROUND: This study examined whether lifetime heroin-use consequences mediate the relationship between trait impulsivity and three current mood outcomes: depression symptoms, stress levels, and perception of life events. METHOD: Regular heroin users (N = 163) were assessed using the Barratt Impulsiveness Scale (BIS-11) to measure trait impulsivity; a standardized Drug History and Use Questionnaire to measure lifetime adverse consequences of heroin use; Beck Depression Inventory II to measure current depression symptoms; Stress subscale of the Depression Anxiety Stress scale; and Hassles and Uplifts scale to measure perception of life events. RESULTS: BIS-11 Attentional and Motor impulsivity were positively related to number of adverse heroin-use consequences, depression symptoms, and stress level, and negatively associated with positive perception of events. A greater number of heroin-use consequences was related to more depression symptoms, higher stress, more negative perception of events, injection heroin use, and earlier ages of first and regular heroin use. In six mediation models, lifetime heroin-use consequences partially mediated relationships between two trait impulsivity domains (Attentional, Motor) and current mood measures (depression symptoms, stress, perception of events). CONCLUSIONS: The present findings suggest that current negative mood can be a response to the accumulated burden of heroin-use consequences, particularly in the presence of high trait impulsivity.

Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder.

A major goal for the treatment of opioid use disorder is to reduce or eliminate the use of illicit opioids. Buprenorphine, a µ-opioid receptor partial agonist and kappa opioid receptor antagonist, is now being developed as a monthly, sustained-release formulation (RBP-6000). The objective of this study was to demonstrate that RBP-6000 blocks the subjective effects and reinforcing efficacy of the µ-opioid receptor agonist hydromorphone (intramuscularly administered) in subjects with moderate or severe opioid use disorder. Subjects were first inducted and dose stabilized on sublingual buprenorphine/naloxone (8-24 mg daily; dose expressed as the buprenorphine component), then received two subcutaneous injections of RBP-6000 (300 mg) on Day 1 and Day 29. Hydromorphone challenges (6 mg, 18 mg or placebo administered in randomized order) occurred on 3 consecutive days of each study week before and after receiving RBP-6000. Subjects reported their responses to each challenge on various 100-mm Visual Analogue Scales (VAS). Subjects also completed a choice task to assess the reinforcing efficacy of each hydromorphone dose relative to money. At baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg versus placebo were 61 mm (95% confidence interval, 52.3-68.9) and 45 mm (95% confidence interval, 37.2-53.6), respectively. After 300 mg RBP-6000 was administered, mean VAS score differences from placebo were less than 10 mm through week 12. The reinforcing efficacy of hydromorphone decreased in a parallel manner. This study demonstrated that RBP-6000 at a 300 mg dose provides durable and potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe opioid use disorder.

Functional mu opioid receptor polymorphism (OPRM1 A(118) G) associated with heroin use outcomes in Caucasian males: A pilot study.

BACKGROUND: Heroin's analgesic, euphoric and dependence-producing effects are primarily mediated by the mu opioid receptor (MOR). A single gene, OPRM1, encodes the MOR. The functional polymorphism A(118)G, located in exon 1 of the OPRM1 gene, results in anatomically-specific reductions in MOR expression, which may alter an individual's response to heroin. In prior studies 118G (rare allele) carriers demonstrated significantly greater opioid tolerance, overdose vulnerability, and pain sensitivity than 118AA homozygotes. Those findings suggest OPRM1 genotype may impact characteristics of heroin use. METHODS: The present pilot study characterized the impact of OPRM1 genotype (rs1799971, 118G allele carriers vs. 118AA homozygotes) on heroin-use phenotypes associated with heroin dependence severity in a sample of male, Caucasian chronic heroin users (n = 86). RESULTS: Results indicate that 118G allele carriers reported significantly more heroin use-related consequences and heroin-quit attempts, and were more likely to have sought treatment for their heroin use than 118AA homozygotes. CONCLUSIONS: These preliminary findings, consistent with extant data, illustrate a role for OPRM1 allelic variation on heroin use characteristics, and provide support for considering genotype in heroin treatment and relapse prevention.