Relationship between opioid cross-tolerance during buprenorphine stabilization and return to opioid use during buprenorphine dose tapering.

RATIONALE: Opioid injection drug use (IDU) has been linked to a more severe pattern of use (e.g. tolerance, overdose risk) and shorter retention in treatment, which may undermine abstinence attempts. OBJECTIVES: This secondary data analysis of four human laboratory studies investigated whether current opioid IDU modulates subjective abuse liability responses to high-dose hydromorphone during intermediate-dose buprenorphine stabilization (designed to suppress withdrawal but allow surmountable agonist effects), and whether hydromorphone response magnitude predicts latency of return to opioid use during buprenorphine dose-tapering. METHODS: Regular heroin users not currently seeking treatment (n = 54; 29 current injectors, 25 non-injectors) were stabilized on 8-mg/day sublingual buprenorphine and assessed for subjective responses (e.g. 'liking', craving) to hydromorphone 24-mg intramuscular challenge (administered 16-hr post-buprenorphine) under randomized, double-blinded, controlled conditions. A subgroup (n = 35) subsequently completed a standardized 3-week outpatient buprenorphine dose-taper, paired with opioid-abstinent contingent reinforcement, and were assessed for return to opioid use based on thrice-weekly urinalysis and self-report. RESULTS: During buprenorphine stabilization, IDU reported lower 'liking' of buprenorphine and post-hydromorphone peak 'liking', 'good effect' and 'high' compared to non-IDU. Less hydromorphone peak increase-from-baseline in 'liking' (which correlated with less hydromorphone-induced craving suppression) predicted significantly faster return to opioid use during buprenorphine dose-tapering. CONCLUSIONS: In these buprenorphine-stabilized regular heroin users, IDU is associated with attenuated 'liking' response (more cross-tolerance) to buprenorphine and to high-dose hydromorphone challenge and, in turn, this cross-tolerance (but not IDU) predicts faster return to opioid use. Further research should examine mechanisms that link cross-tolerance to treatment response.

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.

Effects of cocaine and/or heroin use on resting cardiovascular function.

BACKGROUND: Regular cocaine and/or heroin use is associated with major health risks, especially cardiovascular disease, but confounded by other factors. We examined effects of chronic (years regular use) and recent (past-month) cocaine and heroin use, controlling for other factors, on resting cardiovascular function. METHODS: In a sample of 292 cocaine and/or heroin users, we assessed demographics, body mass index (BMI), substance use history, electrocardiogram, heart rate (HR) and blood pressure (BP). Three-block (1: demographics, BMI; 2: tobacco, alcohol, cannabis; 3: cocaine, heroin) regression analyses were conducted to predict cardiovascular measures. RESULTS: Higher BMI predicted increased systolic and diastolic BP (as did older age), increased supine HR, and longer QRS duration, QTc interval, PR interval, and P-wave duration. Past-month cannabis-use days predicted higher systolic BP, lower supine HR, and greater likelihood of early repolarization and ST elevation; average daily cannabis use predicted shorter QTc interval. Average daily alcohol use predicted higher diastolic BP, higher supine HR and lower likelihood of sinus bradycardia (HR < 60 bpm). Past-month tobacco-use days predicted shorter QTc interval and lower lower likelihood of profound bradycardia (HR < 50 bpm). Past-month heroin-use days predicted lower seated HR, greater likelihood of sinus bradycardia and lower likelihood of left ventricular hypertrophy. More years of regular cocaine use and past-month cocaine-use days predicted longer QTc interval. CONCLUSIONS: Cocaine and heroin use incrementally predicted modest variance in resting bradycardia and QTc interval. Clinicians should first consider demographics and recent use of tobacco, alcohol and cannabis before assuming cocaine and heroin affect these measures.

Chemotherapy-Induced Peripheral Neuropathy: Mechanisms and Therapeutic Avenues.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious and often persistent adverse consequence of certain chemotherapeutic agents. It is a major dose-limiting factor of many first-line chemotherapies, affecting 20-50% of patients at standard doses and nearly all patients at high doses. As cancer survivorship continues to increase with improvements in early diagnosis and treatment, more patients will experience CIPN despite completing cancer treatment, which interferes with recovery, leading to chronic pain and worsening quality of life. The National Cancer Institute has identified CIPN as a priority in translational research. To date, there are no FDA-approved drugs for preventing or treating CIPN, with emerging debate on mechanisms and promising new targets. This review highlights current literature and suggests novel approaches to CIPN based on proposed mechanisms of action that aim either to confer neuroprotection against chemotherapy-induced neurotoxicity or reverse the downstream effects of painful neuropathy.

Chemotherapy-induced peripheral neuropathy in African American cancer survivors: Risk factors and quality of life outcomes.

BACKGROUND: Epidemiological studies of chemotherapy-induced peripheral neuropathy (CIPN) have predominantly focused on non-Hispanic White patients, despite the observation that African Americans are more likely to experience CIPN. To address this health disparities gap, we sought to identify non-genetic risk factors and comorbidities associated with CIPN in African American cancer survivors using the Detroit Research on Cancer Survivors study. METHODS: Logistic regression was used to evaluate relationships between presence of self-reported CIPN and relevant clinical characteristics in 1045 chemotherapy-treated African American cancer survivors. Linear regression was used to evaluate risk factors for CIPN and quality of life outcomes that reflect physical, social, emotional, and functional domains of health. RESULTS: Patients with CIPN were more likely to report hypertension (OR = 1.28, 95% CI: 0.98-1.67, p = 0.07), hypercholesterolemia (OR = 1.32, 95% CI: 1.001-1.73, p = 0.05), history of depression (OR = 1.62, 95% CI: 1.18-2.25, p = 0.003), and diabetes (OR = 1.33, 95% CI: 0.98-1.82, p = 0.06) after adjustment for age at diagnosis, sex, and cancer site. BMI (OR = 1.02 kg/m2 , 95% CI: 1.006-1.04 kg/m2 , p = 0.008) was also positively associated with CIPN. In addition, CIPN status was significantly associated with quality of life (FACT-G total: ß = -8.60, 95% CI: -10.88, -6.32) p < 0.0001) and mood (PROMIS® Anxiety: ß = 4.18, 95% CI: 2.92-5.45, p < 0.0001; PROMIS® Depression: ß = 2.69, 95% CI: 1.53-3.84, p < 0.0001) after adjustment for age at diagnosis, sex, cancer site, and comorbidities. Neither alcohol consumption (OR = 0.88, 95% CI: 0.68-1.14, p = 0.32) nor tobacco use (ever smoked: OR = 1.04, 95% CI: 0.80-1.35, p = 0.76; currently smoke: OR = 1.28, 95% CI: 0.90-1.82, p = 0.18) was associated with increased CIPN risk. CONCLUSION: Risk factor profiles in African Americans are not entirely consistent with those previously reported for non-Hispanic White patients. Neglecting to understand the correlates of common chemotherapy-induced toxicities for this patient population may further contribute to the health disparities these individuals face in receiving adequate healthcare.

Prevalence and predictors of peripheral neuropathy after breast cancer treatment.

BACKGROUND: Many of the 3.8 million breast cancer survivors in the United States experience long-term side effects of cancer therapy including peripheral neuropathy (PN). We assessed the prevalence and predictors of PN among women with breast cancer followed in the Women's Health Initiative's Life and Longevity After Cancer survivorship cohort. METHODS: The study population included 2420 women with local (79%) or regional (21%) stage disease. Presence of PN was based on the reports of "nerve problems and/or tingling sensations" after treatment and PN severity was assessed using the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group/Neurotoxicity instrument. Logistic regression analysis was used to evaluate the socio-demographic and clinical factors associated with PN prevalence and severity. RESULTS: Initial breast cancer treatment included surgery-only (21%), surgery and radiation (53%), or surgery and chemotherapy (±radiation) (26%). Overall, 17% of women reported PN occurring within days (30%), months (46%), or years (24%) after treatment and 74% reported ongoing symptoms at a median of 6.5 years since diagnosis. PN was reported by a larger proportion of chemotherapy recipients (33%) compared to those who had surgery alone (12%) or surgery+radiation (11%) (p < 0.0001). PN was reported more commonly by women treated with paclitaxel (52%) and docetaxel (39%), versus other chemotherapy (17%) (p < 0.0001). In multivariable analyses, treatment type (chemotherapy vs. none; OR, 95% CI: 3.31, 2.4-4.6), chemotherapy type (taxane vs. no-taxane; 4.74, 3.1-7.3), and taxane type (paclitaxel vs. docetaxel; 1.59, 1.0-2.5) were associated with higher odds of PN. CONCLUSION: PN is an important long-term consequence of taxane-based chemotherapy in breast cancer survivors.

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.

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).

Demand curve analysis of marijuana use among persons living with HIV.

BACKGROUND: Despite medicalization and legalization of marijuana use, factors influencing demand for marijuana among persons living with HIV (PLWH) are incompletely understood. This knowledge gap undermines effective clinical management and policies. This study used demand curve simulation methods to address these issues. METHODS: Marijuana-using PLWH (N = 119) completed experimental tasks to simulate amount of marijuana purchasing/use across different costs (money or time), and likelihood of reselling marijuana or marijuana therapeutic-use registration card in relation to profits. Additional simulations assessed purchasing of marijuana relative to other drug and non-drug goods. RESULTS: Simulated marijuana use decreased as money and time costs increased. Consumption was greater for participants with more severe Cannabis Use Disorder (CUD) and anxiety, intermediate pain levels, and past 90-day opioid use. Whereas few participants chose to sell their registration card, marijuana resale (diversion) steeply increased with profit. Likelihood of seeking marijuana therapeutic-use certification decreased in relation to registration card money cost, having to visit more physicians to get a signature, and delay to receiving the card, and increased with duration of certification. Participants who reported recent opioid use were more likely to seek certification. Consumption of several commodities assessed was independent of marijuana. CONCLUSIONS: Simulated marijuana use was related to participants' clinical profile (CUD, anxiety and pain symptoms, recent opioid use), and unrelated to purchasing other goods. Likelihood of seeking marijuana therapeutic-use registration was affected by several types of costs and recent opioid use. Participants were unlikely to divert registration cards. We discuss clinical and policy implications of these findings.

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.

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.

History of regular nonmedical sedative and/or alcohol use differentiates substance-use patterns and consequences among chronic heroin users.

BACKGROUND: Concurrent use of sedating substances (e.g. alcohol or benzodiazepines) with opioids is associated with increased negative consequences of opioid use; however, few studies have attempted to differentiate effects of using sedating substances on heroin-use outcomes. This study examines differences between heroin users who use alcohol or misuse sedatives regularly and those who do not. METHODS: Substance-use data were collected from 367 non-treatment seeking, chronic heroin-using, 18-to-55 year-old participants. We created 4 groups based on self-reported lifetime history of regular (at least weekly) substance use: heroin only (n = 95), heroin and sedatives (n = 21), heroin and alcohol (n = 151), and heroin, sedative, and alcohol (n = 100). Chi-square analyses and ANOVAs with Bonferroni post hoc tests were used to explore differences between these groups. RESULTS: Heroin users who denied lifetime alcohol or nonmedical sedative use regularly endorsed fewer consequences associated with any substance they had used. Total adverse consequences of heroin use (e.g. health problems) were significantly higher among those who misused sedatives regularly, irrespective of alcohol use history (F(3,361) = 10.21; p < .001). Regular alcohol use did not independently impact heroin consequences but was associated with increased use of other substances. CONCLUSIONS: Although polysubstance use is normative among heroin users, the risks depend on the substances used. Regular sedative use is associated with increased heroin consequences whereas regular alcohol use is not. This study refines the investigation of polysubstance use and highlights subgroup differences depending on types of substances used regularly. This knowledge is critical for understanding substance-use motivations and creating avenues for harm reduction.

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.

Factors associated with sedative use and misuse among heroin users.

BACKGROUND: Rates of both opioid and sedative use and misuse are rising. Comorbid opioid and sedative use is associated with especially severe consequences (e.g., overdose and poor health outcomes). Heroin users report multiple motivations for sedative use, including self-medication. We aimed to understand differences in lifetime substance use characteristics between heroin users with different sedative use histories. METHODS: Substance use data were collected from 385 non-treatment seeking heroin users. Subjects were divided into four lifetime sedative-use groups: no use, medical use only, non-medical use only, and mixed medical and non-medical use. We examined patterns of use of various substances of abuse (tobacco, alcohol, marijuana, cocaine, heroin, and sedatives) and individual characteristics associated with each. RESULTS: Non-medical sedative use (alone or in addition to medical use) was associated with more negative consequences from using all substances. Medical sedative use alone was not related to increased overdose or emergency room visits associated with heroin use. Non-medical sedative use was associated with increases in 15 of the 21 measured heroin consequences and only one of those - health problems - was also associated with medical sedative use. CONCLUSIONS: Concomitant non-medical sedative use and heroin use is associated with significantly greater negative outcomes than those experienced by heroin users who report use of sedatives only as prescribed. Understanding these differences offers insight into risks related to using both substances and may help treatment providers create targeted harm reduction interventions for this population.

Developing a scale of domains of negative consequences of chronic heroin use.

BACKGROUND: Chronic use of heroin typically leads to numerous negative life consequences and serious clinical impairment. Increased negative consequences can result in poor treatment outcomes as well as adverse health effects and impaired social functioning. Certain risk factors, including early substance use initiation, concurrent use of other illicit substances, and injection drug use are associated with an increase in negative consequences. This study examined whether there are unique domains of heroin consequences and, if so, whether these domains are related to specific substance use characteristics. METHODS: Data regarding substance use characteristics were collected from 370 non-treatment seeking, heroin-using, 18 to 55year-old participants from the Detroit metropolitan area. Principal component analysis (PCA) was used to analyze the factor structure of 21 negative heroin consequence items. RESULTS: PCA demonstrated that heroin consequences could be divided into 5 unique domains. These unique domains were related to specific substance use characteristics and heroin consequence domains. Injection heroin use was significantly associated with increased Factor 1 consequences (primarily acute medical problems) but not with consequences in other domains. Certain substance use characteristics, such as injection status and earlier onset of marijuana use, were associated with increased consequences in specific domains. CONCLUSIONS: These findings support the existence of unique domains of negative consequences, and indicate that some risk factors (e.g. injection use) may be specific to these domains. Potential tailored-treatment strategies aimed at improving treatment engagement and reducing harm for heroin use based on person-specific risks and negative consequences are discussed.

Characterizing fentanyl use in methadone-maintained clients.

AIMS: Deaths attributed to fentanyl have increased in the United States. However, little is known about fentanyl use among substance abuse treatment clients. To fill this gap, we assessed prevalence of fentanyl exposure, characteristics of clients testing positive for fentanyl, other substances detected concurrently or simultaneously with fentanyl, and clients' perception of how many people are actively seeking to use fentanyl. METHODS: A retrospective chart review was conducted of all clients at one methadone maintenance treatment clinic between January 2015 and May 2016 in Wayne County, Michigan. Urine drug screens (UDS) including fentanyl (and its metabolite norfentanyl) were conducted clinically. To obtain additional data, 113 clients in this clinic subsequently completed an anonymous survey. RESULTS: Of 368 unique clients with UDS, 38.0% had at least one and 26.1% had ≥2 fentanyl-positive UDS results. None had a fentanyl prescription. Clients ever testing positive for fentanyl were significantly (p<0.05) more likely to use cocaine, have multiple treatment admissions to the clinic, and leave treatment sooner. Fentanyl-positive UDS results coincided most commonly with metabolites of cocaine- and heroin-positive UDS results. Of the anonymously surveyed clients, most (67.3%) reported they did not know anyone seeking fentanyl, a proportion significantly higher than for heroin, cocaine, alprazolam, hydrocodone and morphine. CONCLUSIONS: Fentanyl was commonly detected during this period with some clients having multiple fentanyl-positive UDS. Most clients did not know anyone seeking to obtain fentanyl. Regardless, the high exposure underscores that naloxone training and distribution is needed.

Magnitude and duration of cue-induced craving for marijuana in volunteers with cannabis use disorder.

AIMS: Evaluate magnitude and duration of subjective and physiologic responses to neutral and marijuana (MJ)-related cues in cannabis dependent volunteers. METHODS: 33 volunteers (17 male) who met DSM-IV criteria for Cannabis Abuse or Dependence were exposed to neutral (first) then MJ-related visual, auditory, olfactory and tactile cues. Mood, drug craving and physiology were assessed at baseline, post-neutral, post-MJ and 15-min post MJ cue exposure to determine magnitude of cue- responses. For a subset of participants (n=15; 9 male), measures of craving and physiology were collected also at 30-, 90-, and 150-min post-MJ cue to examine duration of cue-effects. RESULTS: In cue-response magnitude analyses, visual analog scale (VAS) items craving for, urge to use, and desire to smoke MJ, Total and Compulsivity subscale scores of the Marijuana Craving Questionnaire, anxiety ratings, and diastolic blood pressure (BP) were significantly elevated following MJ vs. neutral cue exposure. In cue-response duration analyses, desire and urge to use MJ remained significantly elevated at 30-, 90- and 150-min post MJ-cue exposure, relative to baseline and neutral cues. CONCLUSIONS: Presentation of polysensory MJ cues increased MJ craving, anxiety and diastolic BP relative to baseline and neutral cues. MJ craving remained elevated up to 150-min after MJ cue presentation. This finding confirms that carry-over effects from drug cue presentation must be considered in cue reactivity studies.

Heroin delay discounting: Modulation by pharmacological state, drug-use impulsivity, and intelligence.

Delay discounting (DD) refers to how rapidly an individual devalues goods based on delays to receipt. DD usually is considered a trait variable but can be state dependent, yet few studies have assessed commodity valuation at short, naturalistically relevant time intervals that might enable state-dependent analysis. This study aimed to determine whether drug-use impulsivity and intelligence influence heroin DD at short (ecologically relevant) delays during two pharmacological states (heroin satiation and withdrawal). Out-of-treatment, intensive heroin users (n = 170; 53.5% African American; 66.7% male) provided complete DD data during imagined heroin satiation and withdrawal. Delays were 3, 6, 12, 24, 48, 72, and 96 hours; maximum delayed heroin amount was thirty $10 bags. Indifference points were used to calculate area under the curve (AUC). We also assessed drug-use impulsivity (subscales from the Impulsive Relapse Questionnaire [IRQ]) and estimated intelligence (Shipley IQ) as predictors of DD. Heroin discounting was greater (smaller AUC) during withdrawal than satiation. In regression analyses, lower intelligence and IRQ Capacity for Delay as well as higher IRQ Speed (to return to drug use) predicted greater heroin discounting in the satiation condition. Lower intelligence and higher IRQ Speed predicted greater discounting in the withdrawal condition. Sex, race, substance use variables, and other IRQ subscales were not significantly related to the withdrawal or satiation DD behavior. In summary, heroin discounting was temporally rapid, pharmacologically state dependent, and predicted by drug-use impulsivity and estimated intelligence. These findings highlight a novel and sensitive measure of acute DD that is easy to administer.

Methadone maintenance dose modulates anterior cingulate glutamate levels in heroin-dependent individuals: A preliminary in vivo (1)H MRS study.

Mu-opioid receptor agonists alter brain glutamate (GLU) levels in laboratory animals. This clinical study used proton magnetic resonance spectroscopy ((1)H MRS) to examine regional brain GLU levels during experimental manipulation of methadone (MTD) maintenance dose under double-blind, within-subject conditions in seven heroin-dependent volunteers. Subjects were scanned first at a high MTD dose (100 mg/day), underwent a 3-week outpatient MTD dose taper, and then were scanned again at a low MTD dose (10-25 mg/day; modified for participant comfort). Five age- and cigarette smoking-matched controls were scanned once. In vivo short echo time (TE = 22 ms), single voxel (1)H MRS data from midline pregenual anterior cingulate cortex (ACC) and thalamus (4.5 cm(3) each) were collected using PRESS on a 4-Tesla MRI system. Absolute metabolite levels were quantified. GLU levels in the ACC, but not the thalamus, were higher at the low relative to the high MTD dose in heroin-dependent subjects. No other metabolites differed by MTD dose, or between control vs. heroin-dependent subjects (at either MTD dose). GLU levels in the ACC were inversely related to the duration of cigarette smoking (controls) and heroin use (experimental group). Future studies are warranted to investigate the relationship between GLU levels during treatment (and detoxification), and withdrawal symptoms or relapse.