Detailed Mechanisms Underlying Neutrophil Bactericidal Activity against Streptococcus pneumoniae.

Neutrophils are an essential cellular component of innate immunity and control bacterial infections through a combination of intracellular and extracellular killing methods. Although the importance of neutrophils has been established, the exact methods used to handle particular bacterial challenges and the efficiency of bacterial killing remain not well understood. In this study, we addressed how neutrophils eliminate Streptococcus pneumoniae (Spn), a leading cause of community acquired and post-influenza bacterial pneumonia. We analyzed killing methods with variable bacterial:neutrophil concentrations and following priming with PAM3CSK4 (P3CSK), an agonist for Toll-like-receptor 2 (TLR2). Our results show that murine neutrophils display surprisingly weak bactericidal activity against Spn, employing a predominantly extracellular mode of killing at lower concentrations of bacteria, whereas challenges with higher bacterial numbers induce both extracellular and intracellular elimination modes but require TLR2 activation. TLR2 activation increased reactive oxygen species (ROS) and neutrophil extracellular trap (NET) formation in response to Spn. Despite this, supernatants from P3CSK-stimulated neutrophils failed to independently alter bacterial replication. Our study reveals that unstimulated neutrophils are capable of eliminating bacteria only at lower concentrations via extracellular killing methods, whereas TLR2 activation primes neutrophil-mediated killing using both intracellular and extracellular methods under higher bacterial burdens.

The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis.

INTRODUCTION: Ketamine intravenous therapy (KIT) appears effective for treating depression in controlled trials testing a short series of infusions. A rapidly proliferating number of clinics offer KIT for depression and anxiety, using protocols without a strong evidence basis. Controlled comparison of mood and anxiety from real-world KIT clinics, and the stability of outcomes, is lacking. METHODS: We performed a retrospective controlled analysis on patients treated with KIT in ten community clinics across the US, between 08/2017-03/2020. Depression and anxiety symptoms were evaluated using the Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS) and the Generalized Anxiety Disorder 7-item (GAD-7) scales, respectively. Comparison data sets from patients who did not undergo KIT were obtained from previously published real-world studies. RESULTS: Of 2758 patients treated, 714 and 836 met criteria for analysis of KIT induction and maintenance outcomes, respectively. Patients exhibited significant and concordant reduction in both anxiety and depression symptoms after induction (Cohen's d = -1.17 and d = -1.56, respectively). Compared to two external datasets of KIT-naive depressed patients or patients starting standard antidepressant therapy, KIT patients experienced a significantly greater reduction in depression symptoms at eight weeks (Cohen's d = -1.03 and d = -0.62 respectively). Furthermore, we identified a subpopulation of late-responders. During maintenance, up to a year post-induction, increases in symptoms were minimal. LIMITATIONS: Due to the retrospective nature of the analyses, interpreting this dataset is limited by incomplete patient information and sample attrition. CONCLUSIONS: KIT treatment elicited robust symptomatic relief that remained stable up to one year of follow-up.

Examining attendance patterns across integrated therapies for posttraumatic stress disorder and alcohol use disorder.

A substantial body of evidence supports the use of integrated treatments for posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). Integrated trauma-focused exposure therapies reduce PTSD symptoms more than comparison treatments, including integrated coping skills therapies, but demonstrate lower attendance, raising questions regarding the relationships between attendance, outcomes, and treatment type. We aimed to examine these relationships in a RCT comparing integrated prolonged exposure (Concurrent Treatment for PTSD and Substance Use Disorders Using Prolonged Exposure, COPE; n = 58), to integrated coping skills therapy (Seeking Safety, SS; n = 52) offered in 12 sessions, with an option to extend up to four additional sessions. Participants were categorized based on number of sessions attended (0-4; 5-8; 9-12; 13-16). Multilevel modeling revealed that only when examining therapy attendance segments individually, clinical outcomes were comparable across treatments except in the 9-12 group, with COPE resulting in greater reductions in PTSD symptoms (p < 0.001), but not in alcohol use. Extending past 12 sessions was not associated with additional clinically meaningful symptom improvement for either treatment. These results suggest that attending a complete or near complete course of exposure therapy may enhance PTSD outcomes relative to non-trauma-focused therapies.

Neutrophils drive pulmonary vascular leakage in MHV-1 infection of susceptible A/J mice.

Background: Lung inflammation, neutrophil infiltration, and pulmonary vascular leakage are pathological hallmarks of acute respiratory distress syndrome (ARDS) which can lethally complicate respiratory viral infections. Despite similar comorbidities, however, infections in some patients may be asymptomatic while others develop ARDS as seen with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections for example. Methods: In this study, we infected resistant C57BL/6 and susceptible A/J strains of mice with pulmonary administration of murine hepatitis virus strain 1 (MHV-1) to determine mechanisms underlying susceptibility to pulmonary vascular leakage in a respiratory coronavirus infection model. Results: A/J animals displayed increased lung injury parameters, pulmonary neutrophil influx, and deficient recruitment of other leukocytes early in the infection. Moreover, under basal conditions, A/J neutrophils overexpressed primary granule protein genes for myeloperoxidase and multiple serine proteases. During infection, myeloperoxidase and elastase protein were released in the bronchoalveolar spaces at higher concentrations compared to C57BL/6 mice. In contrast, genes from other granule types were not differentially expressed between these 2 strains. We found that depletion of neutrophils led to mitigation of lung injury in infected A/J mice while having no effect in the C57BL/6 mice, demonstrating that an altered neutrophil phenotype and recruitment profile is a major driver of lung immunopathology in susceptible mice. Conclusions: These results suggest that host susceptibility to pulmonary coronaviral infections may be governed in part by underlying differences in neutrophil phenotypes, which can vary between mice strains, through mechanisms involving primary granule proteins as mediators of neutrophil-driven lung injury.

Bidirectional relationship of posttraumatic stress disorder (PTSD) symptom severity and alcohol use over the course of integrated treatment.

Posttraumatic stress disorder (PTSD) and alcohol use disorder commonly co-occur. Little is known about how symptoms of one affect subsequent week symptoms of the other during the course of integrated treatment for both disorders. The sample included 107 veterans who were randomized to receive either Concurrent Treatment of PTSD and Substance Use Disorder Using Prolonged Exposure (COPE; an exposure-based trauma focused treatment) or Seeking Safety (SS; a present-focused coping skills-based treatment) and completed measures of PTSD and alcohol use at every other session. Multilevel models estimated the prospective associations between PTSD and alcohol use during treatment. Results indicated that greater PTSD symptom severity was associated with greater future alcohol use (b = 0.20, p = .024), and greater alcohol use was associated with greater future PTSD symptom severity (b = 0.13, p = .003). The effect size for PTSD symptoms to future alcohol use was larger than the reciprocal relationship. When using lagged PTSD severity to predict future drinking, results revealed that clinically significant differences in PTSD severity levels were associated with comparably large differences in drinking. Treatment condition did not moderate the effect of PTSD symptom severity on alcohol use (or the reciprocal relationship). Findings lend support to the mutual maintenance model of addiction. Integrated treatments that treat both PTSD and alcohol use may be preferential to sequential model of care where individuals are expected to achieve abstinence or reduced use prior to receiving trauma-focused treatment. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Effects of craving on opioid use are attenuated after pain coping counseling in adults with chronic pain and prescription opioid addiction.

OBJECTIVE: Risk for prescription opioid addiction is an endemic public health concern, especially for adults with chronic pain. This study examined craving as a mediator from pain to opioid use outcomes during prescription opioid addiction treatment and tested whether counseling in pain coping skills moderated the effects of craving on treatment outcomes. METHOD: Secondary analysis on a sample (N = 148) randomized to standard or enhanced counseling for 12 weeks with adjunct opioid maintenance medication. Multilevel analyses examined mediated effects between weekly pain, craving, and opioid use, and tested the interaction between craving and a counseling module on pain coping skills. RESULTS: Greater pain predicted greater craving (ß = 0.25, p < .001), which predicted next-week opioid use (ß = 0.17, p < .001). A statistically significant indirect effect of craving (ß = 0.04, 95% CI [0.02, 0.06]) mediated 95% of the total effect from pain to opioid use. A significant interaction (b = -0.22, p < .01) revealed that after receiving the pain coping module, the association between craving and next-week opioid use was reduced, with greater exposure to the module associated with stronger effects (b = -0.12, p < .01). CONCLUSION: More severe pain predicts greater opioid use due to the association between pain and cravings. Pain coping skills counseling suppressed the association between cravings and opioid use. For adults with chronic pain receiving treatment for prescription opioid addiction, interventions that address cravings through behavioral pain coping skills may be crucial for achieving optimal treatment outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Short Communication: Effect of Seminal Plasma on Functions of Monocytes and Granulocytes.

Most HIV-1 transmissions occur at mucosae and involve exposure to semen. Semen contains immunomodulatory factors, which inhibit anti-HIV-1 natural killer cell and T cell responses. We demonstrate high concentrations (1:2 dilution) of seminal plasma (SP) inhibit monocyte phagocytosis and anti-HIV-1 Fc-dependent functions of both neutrophils and monocytes. In addition, slightly lower SP concentrations (1:2-1:10 dilutions) inhibit granulocyte phagocytosis and oxidative burst of both monocytes and granulocytes. These observations may have implications for HIV-1 infectivity after mucosal exposure.

Predictors of reduced smoking quantity among recovering alcohol dependent men in a smoking cessation trial.

INTRODUCTION: Adults with alcohol dependence (AD) have exceptionally high smoking rates and poor smoking cessation outcomes. Discovery of factors that predict reduced smoking among AD smokers may help improve treatment. This study examined baseline predictors of smoking quantity among AD smokers in a pharmacotherapy trial for smoking cessation. METHODS: The sample includes male, AD smokers (N = 129) with 1-32 months of alcohol abstinence who participated in a 12-week trial of medication (topiramate vs. placebo) and adjunct counseling with 6 months of follow-up. Baseline measures of nicotine dependence, AD severity, psychopathology, motivation to quit smoking, and smoking-related cognitions were used to predict smoking quantity (cigarettes per day) at post-treatment and follow-up. RESULTS: Overall, the sample had statistically significant reductions in smoking quantity. Greater nicotine dependence (Incidence rate ratios (IRRs) = 0.82-0.90), motivation to quit (IRRs = 0.65-0.85), and intrinsic reasons for quitting (IRRs = 0.96-0.98) predicted fewer cigarettes/day. Conversely, greater lifetime AD severity (IRR = 1.02), depression severity (IRRs = 1.05-1.07), impulsivity (IRRs = 1.01-1.03), weight-control expectancies (IRRs = 1.10-1.15), and childhood sexual abuse (IRRs = 1.03-1.07) predicted more cigarettes/day. CONCLUSIONS: Smokers with AD can achieve large reductions in smoking quantity during treatment, and factors that predict smoking outcomes in the general population also predict greater smoking reductions in AD smokers. Treatment providers can use severity of nicotine dependence and AD, motivation to quit, smoking-related cognitions, and severity of depression to guide treatment and improve outcomes among AD smokers.

Neutrophils mediate HIV-specific antibody-dependent phagocytosis and ADCC.

There is growing evidence to support the role of Fc-mediated effector functions, such as Antibody-Dependent Cellular cytotoxicity (ADCC) and Antibody-Dependent Phagocytosis (ADP) in the protection and control of HIV. The RV144 trial and other recent HIV vaccine studies have highlighted the importance of ADCC responses in protection against HIV. The role of neutrophils, the most abundant leukocyte in the blood, has not been thoroughly evaluated for Fc-mediated effector functions to HIV. We optimized HIV-specific neutrophil ADCC and Antibody-Dependent Neutrophil Phagocytosis (ADNP) assays using freshly isolated primary human neutrophils from blood. We also developed methods to study ADP using the neutrophil-like HL-60 cell line. We found that neutrophils mediate both HIV-specific ADP and ADCC responses. In vitro, neutrophil-mediated ADCC responses peaked at 4 h, much faster than primary NK cell or monocyte-mediated responses. We detected a wide range of responses in the ADNP, HL-60 mediated ADP and ADCC across a cohort of 41 viremic antiretroviral therapy naïve HIV positive subjects. HL-60 and Neutrophil-mediated ADP and ADCC responses correlated well with each other, suggesting that they measure overlapping functions. The ADNP and HL-60 ADP inversely correlated with HIV viral load, suggesting that these antibody-mediated neutrophil-based assays should prove useful in dissecting HIV-specific immunity.

Effects of sleep on substance use in adolescents: a longitudinal perspective.

Substance use (SU) and sleep problems appear interrelated, but few studies have examined the influence of adolescent sleep patterns on development of SU disorders. This study prospectively examined the influence of sleep habits on subsequent SU in youth who later transitioned into heavy drinking. At time 1 (T1), participants (n = 95) were substance-naive 12- to 14-year-olds. Path-analytic models examined whether the effects of T1 risk factors (familial SU disorder, inhibition control, and externalizing and internalizing traits) on time 3 (M = 19.8 years old) tobacco, alcohol, and cannabis were mediated by time 2 (M = 15.1 years old) sleep chronotype, daytime sleepiness, and erratic sleep/wake behaviors. Significant direct path effects of T1 risk factors and time 2 sleep behaviors on time 3 SU were found, Ps < 0.05. In models that examined the effect of each individual sleep behavior separately on SU, more erratic sleep/wake and greater daytime sleepiness predicted higher lifetime use events for all substances (Ps < 0.01). Higher evening chronotype tendencies predicted lower tobacco and higher alcohol and cannabis lifetime use events (Ps < 0.01). Erratic sleep/wake behaviors mediated the effect of inhibitory control on subsequent SU; less erratic sleep/wake behaviors predicted better inhibition control ( ß̂= -0.20, P < 0.05). Early-mid adolescent psychiatric health and sleep behaviors prior to drinking onset predicted greater SU 5 years later. Participants were substance-naïve at baseline, allowing for the examination of temporal order in the relationship between sleep problems and alcohol use. Early adolescent sleep problems may be an important risk factor for SU in later life.

Type A/Type B Alcoholism Predicts Differential Response to Topiramate in a Smoking Cessation Trial in Dually Diagnosed Men.

OBJECTIVE: Babor's A/B typology characterizes alcohol-dependence subtypes, which differ across multiple defining variables; however, differences in cigarette smoking and cessation between these subtypes have not been previously investigated. Topiramate reduces heavy drinking and has separately been found to help non-alcohol-dependent individuals quit smoking. This study tested the hypothesis that topiramate's effects on smoking would be moderated by alcohol-dependence subtype, and explored craving as a mediator of this response. METHOD: One hundred twenty-nine abstinent alcohol-dependent outpatient male smokers participated in this 12-week, randomized controlled trial comparing topiramate (maximum dosage 200 mg/day) with placebo, both with brief counseling, for smoking cessation. Participants were followed for 24 weeks following end of treatment. RESULTS: Of the 125 participants with sufficient subtyping data, k-means cluster analysis categorized 52 (42%) as Type A alcoholics and 73 (58%) as Type B. Types A and B did not differ on baseline smoking characteristics, urges to smoke, or smoking consequence scores. Longitudinal mixed-effects regression indicated that the effect of treatment on smoking was moderated by the Type × Time interaction. Specifically, during the nontreatment follow-up phase, Type B's treated with topiramate had relative suppressed levels of smoking compared with placebo-treated Type B's. This moderating effect of the Type × Time interaction was mediated by intention to smoke and craving related to relief of negative affect. CONCLUSIONS: Type B alcoholics demonstrated suppressed levels of smoking in response to topiramate treatment as compared with placebo, but only during the nontreatment follow-up phase. This effect was mediated, in part, through intention to smoke and craving to smoke to relieve negative affect. Our findings extend other studies demonstrating a differential medication response by alcoholism subtype.

Naltrexone moderates the relationship between cue-induced craving and subjective response to methamphetamine in individuals with methamphetamine use disorder.

RATIONALE: Reductions in cue-induced craving and subjective response to drugs of abuse are commonly used as initial outcome measures when testing novel medications for the treatment of addiction. Yet neither the relationship between these two measures at the individual level nor the moderating effects of pharmacotherapies on this relationship has been examined. OBJECTIVE: This secondary data analysis sought to examine (1) the predictive relationship between cue-induced craving and subsequent acute subjective response to methamphetamine (MA) and (2) whether the opioid-receptor antagonist naltrexone moderated this association in a sample of non-treatment-seeking individuals who met DSM-IV criteria for MA use disorder (abuse or dependence). METHODS: Participants (n = 30) completed two 4-day medication regimens (oral naltrexone 50 mg or placebo, in a randomized, counterbalanced, and double-blind fashion). On day 4 of each medication regimen, participants completed a cue-reactivity paradigm followed by intravenous MA administration. Methamphetamine craving was assessed after the cue-reactivity paradigm, and subjective response to MA was assessed during MA infusion. RESULTS: Cue-induced craving for MA was positively associated with post-infusion subjective MA effects, including positive (i.e., stimulation, good effects, feel drug, high), negative (i.e., anxious and depressed), and craving-related (i.e., want more, would like access to drug, crave) responses. Naltrexone, vs. placebo, significantly reduced the association between cue-induced craving and positive subjective response to MA. CONCLUSIONS: The findings indicate that naltrexone moderates the predictive relationship between cue-induced craving and positive subjective effects of MA, thereby suggesting a behavioral mechanism by which naltrexone may be efficacious in treating MA use disorder.

Volatility and change in chronic pain severity predict outcomes of treatment for prescription opioid addiction.

BACKGROUND AND AIMS: Buprenorphine-naloxone (BUP-NLX) can be used to manage prescription opioid addiction among persons with chronic pain, but post-treatment relapse is common and difficult to predict. This study estimated whether changes in pain over time and pain volatility during BUP-NLX maintenance would predict opioid use during the taper BUP-NLX taper. DESIGN: Secondary analysis of a multi-site clinical trial for prescription opioid addiction, using data obtained during a 12-week BUP-NLX stabilization and 4-week BUP-NLX taper. SETTING: Community clinics affiliated with a national clinical trials network in 10 US cities. PARTICIPANTS: Subjects with chronic pain who entered the BUP-NLX taper phase (n = 125) with enrollment occurring from June 2006 to July 2009 (52% male, 88% Caucasian, 31% married). MEASUREMENTS: Outcomes were weekly biologically verified and self-reported opioid use from the 4-week taper phase. Predictors were estimates of baseline severity, rate of change and volatility in pain from weekly self-reports during the 12-week maintenance phase. FINDINGS: Controlling for baseline pain and treatment condition, increased pain [odds ratio (OR) = 2.38, P = 0.02] and greater pain volatility (OR = 2.43, P = 0.04) predicted greater odds of positive opioid urine screen during BUP-NLX taper. Increased pain (IRR = 1.40, P = 0.04) and greater pain volatility [incidence-rate ratio (IRR) = 1.66, P = 0.009] also predicted greater frequency of self-reported opioid use. CONCLUSIONS: Adults with chronic pain receiving out-patient treatment with buprenorphine-naloxone (BUP-NLX) for prescription opioid addiction have an elevated risk for opioid use when tapering off maintenance treatment. Those with relative persistence in pain over time and greater volatility in pain during treatment are less likely to sustain abstinence during BUP-NLX taper.

A Randomized Trial Evaluating Whether Topiramate Aids Smoking Cessation and Prevents Alcohol Relapse in Recovering Alcohol-Dependent Men.

BACKGROUND: Alcohol and nicotine dependence frequently co-occur, and quitting smoking might enhance long-term alcohol abstinence. Topiramate appears to help non-alcohol-dependent individuals quit smoking, and our pilot work suggested efficacy only in men. It also prevents relapse to alcohol in recently detoxified alcoholics. We evaluated topiramate in abstinent alcohol-dependent men to assess whether this medication (i) promotes smoking cessation and (ii) prevents alcohol and other drug relapse in the context of smoking cessation treatment. METHODS: One hundred and twenty-nine alcohol-abstinent (mean ~6 months) alcohol-dependent male smokers (80% with other substance use disorders) participated in this 12-week randomized, double blind, parallel group comparison of topiramate (up to 200 mg/d) and placebo with a 24-week nontreatment follow-up period. The study was carried out sequentially at 2 academic centers in the Midwest and Southern California between March 23, 2009 and November 20, 2014. All participants received manual-guided smoking cessation counseling combined with medication-focused compliance enhancement therapy. Randomization was block designed by the research pharmacist in a 1:1 ratio. Participants, investigators, and research personnel were masked to treatment assignment. The primary smoking end point was biochemically confirmed 4-week continuous abstinence from smoking during weeks 9 to 12, while the secondary end point was relapse to any drinking or drug use during the entire 36-week evaluation period. Logistic regression was used to determine the effects of topiramate on quitting smoking and alcohol relapse, controlling for relevant covariates. The trial is registered at ClinicalTrials.gov (number NCT00802412) and is now closed. RESULTS: Only a small proportion (7.9%) of topiramate-treated participants were able to quit smoking, and this cessation rate was similar to placebo (10.6%; odds ratio = 1.60; 95% confidence interval 0.4, 6.5; p = 0.51). Roughly 30% of the sample had a documented relapse to drinking or drug use during the study, and these rates were similar in the topiramate (20/63; 31.8%) and placebo groups (18/66; 27.3%; p = 0.58). Results of a longitudinal logistic regression model examining time to any alcohol relapse revealed no medication effect. CONCLUSIONS: Topiramate at a daily dosage of up to 200 mg per day, combined with smoking cessation and medication adherence counseling, had no effects on smoking cessation or the prevention of alcohol or drug relapse in male smokers who were in early or sustained full remission from alcohol and motivated to make a quit attempt. Alternative approaches for treating this high-risk, dually dependent population are needed.

Risky driving and sexual behaviors as developmental outcomes of co-occurring substance use and antisocial behavior.

PURPOSE: To examine the associations between substance use and antisocial behavior trajectories and seven risky behaviors over time. METHOD: Data were collected from a high-risk sample of adolescents followed into young adulthood. Five trajectory classes, identified based on dual development of substance use and antisocial behavior symptoms, were used to predict three risky driving and four risky sexual behaviors. RESULTS: In this high-risk sample (n=530), participants reported notably high overall rates of reckless driving (55.5%) and unprotected sex under the influence (44.8%) in the past year. Risky behaviors that are typically of low base rates in population-based studies were also elevated, with 8.8% reporting past-year driving under the influence (DUI) charge, 17.6% reporting lifetime sexually transmitted infection (STI), and 10.4% reporting lifetime injection drug use. The Dual Chronic class had the highest levels of all seven risky behaviors, and were 3-4 times more likely to report risky driving, lifetime STI, and injection drug use than the Relatively Resolved class. Rates of past-year reckless driving and DUI were elevated among classes with persistent antisocial behavior, whereas rates of DUI, DUI charge, and unprotected sex under the influence were elevated among classes with persistent substance use. CONCLUSIONS: Young adults with persistent co-occurring substance use and antisocial behavior engage in multiple very costly risky behaviors. Differential associations between risky behaviors and trajectory classes highlight the need for targeted interventions.

Effect of adolescent substance use and antisocial behavior on the development of early adulthood depression.

Major depressive disorder (MDD) is a prevalent and frequently comorbid psychiatric disorder. This study evaluates the development of depressive symptoms, MDD diagnosis, and suicidal ideation in a high-risk sample (N=524) diagnosed with conduct disorder (CD) and substance use disorder (SUD) symptoms as youth and re-assessed approximately 6.5 years later. Dual trajectory classes of both alcohol and other drug use (AOD) and antisocial behavior (ASB), previously identified using latent class growth analyses (LCGA), were used to predict depression outcomes. The Dual Chronic, Increasing AOD/Persistent ASB, and Decreasing Drugs/Persistent ASB classes had higher past-week depression scores, more past-year MDD symptoms, and were more likely to have past-year MDD than the Resolved class. The Dual Chronic and Decreasing Drugs/Persistent ASB classes also had more past-year MDD symptoms than the Persistent AOD/Adolescent ASB class. Youth at highest risk for developing or maintaining depression in adulthood had the common characteristic of persistent antisocial behavior. This suggests young adulthood depression is associated more with persistent antisocial behavior than with persistent substance use in comorbid youth. As such, interventions targeting high-risk youth, particularly those with persistent antisocial behavior, are needed to help reduce the risk of severe psychosocial consequences (including risk for suicide) in adulthood.

Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study.

BACKGROUND: Despite numerous clinical trials no efficacious medications for methamphetamine (MA) have been identified. Neuroinflammation, which has a role in MA-related reward and neurodegeneration, is a novel MA pharmacotherapy target. Ibudilast inhibits activation of microglia and pro-inflammatory cytokines and has reduced MA self-administration in preclinical research. This study examined whether ibudilast would reduce subjective effects of MA in humans. METHODS: Adult, non-treatment seeking, MA-dependent volunteers (N=11) received oral placebo, moderate ibudilast (40 mg), and high-dose ibudilast (100mg) via twice-daily dosing for 7 days each in an inpatient setting. Following infusions of saline, MA 15 mg, and MA 30 mg participants rated 12 subjective drug effects on a visual analog scale (VAS). RESULTS: As demonstrated by statistically-significant ibudilast × MA condition interactions (p<.05), ibudilast reduced several MA-related subjective effects including High, Effect (i.e., any drug effect), Good, Stimulated and Like. The ibudilast-related reductions were most pronounced in the MA 30 mg infusions, with ibudilast 100mg significantly reducing Effect (97.5% CI [-12.54, -2.27]), High (97.5% CI [-12.01, -1.65]), and Good (97.5% CI [-11.20, -0.21]), compared to placebo. CONCLUSIONS: Ibudilast appeared to reduce reward-related subjective effects of MA in this early-stage study, possibly due to altering the processes of neuroinflammation involved in MA reward. Given this novel mechanism of action and the absence of an efficacious medication for MA dependence, ibudilast warrants further study to evaluate its clinical efficacy.

Pain volatility and prescription opioid addiction treatment outcomes in patients with chronic pain.

The combination of prescription opioid dependence and chronic pain is increasingly prevalent and hazardous to public health. Variability in pain may explain poor prescription opioid addiction treatment outcomes in persons with chronic pain. This study examined pain trajectories and pain volatility in patients with chronic pain receiving treatment for prescription opioid addiction. We conducted secondary analyses of adults with chronic pain (n = 149) who received buprenorphine/naloxone (BUP/NLX) and counseling for 12 weeks in an outpatient, multisite clinical trial. Good treatment outcome was defined as urine-verified abstinence from opioids at treatment endpoint (Week 12) and during at least 2 of the previous 3 weeks. Pain severity significantly declined over time during treatment (b = -0.36, p < .001). Patients with greater pain volatility were less likely to have a good treatment outcome (odds ratio = 0.55, p < .05), controlling for baseline pain severity and rate of change in pain over time. A 1 standard deviation increase in pain volatility was associated with a 44% reduction in the probability of endpoint abstinence. The significant reduction in subjective pain during treatment provides observational support for the analgesic effects of BUP/NLX in patients with chronic pain and opioid dependence. Patients with greater volatility in subjective pain during treatment have increased risk of returning to opioid use by the conclusion of an intensive treatment with BUP/NLX and counseling. Future research should examine underlying mechanisms of pain volatility and identify related therapeutic targets to optimize interventions for prescription opioid addiction and co-occurring chronic pain.

Using behavioral economics to predict opioid use during prescription opioid dependence treatment.

BACKGROUND: Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. METHODS: Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N=353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. RESULTS: Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR=1.30, p<.001) and a greater proportion of their income on drugs (OR=1.31, p<.001) were more likely to use opioids during treatment. CONCLUSIONS: Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population.