William J. Kowalczyk

Preexposure Prophylaxis and Predicted Condom Use Among High-Risk Men Who Have Sex With Men

Objectives:Preexposure prophylaxis (PREP) is an emerging HIV prevention strategy; however, many fear it may lead to neglect of traditional risk reduction practices through behavioral disinhibition or risk compensation. Methods:Participants were 180 HIV-negative high-risk men who have sex with men recruited in New York City, who completed an Audio Computer Assisted Self Interview-administered survey between September 2007 and July 2009. Bivariate and multivariate logistic regression models were used to predict intention to use PREP and perceptions that PREP would decrease condom use. Results:Almost 70% (n = 124) of participants reported that they would be likely to use PREP if it were at least 80% effective in preventing HIV. Of those who would use PREP, over 35% reported that they would be likely to decrease condom use while on PREP. In multivariate analyses, arousal/pleasure barriers to condom use significantly predicted likelihood of PREP use (odds ratio = 1.71, P < 0.05) and risk perception motivations for condom use significantly predicted decreased condom use on PREP (odds ratio = 2.48, P < 0.05). Discussion:These data provide support for both behavioral disinhibition and risk compensation models and underscore the importance of developing behavioral interventions to accompany any wide-scale provision of PREP to high-risk populations.

Morphine-6β-glucuronide Rapidly Increases Pain Sensitivity Independently of Opioid Receptor Activity in Mice and Humans

Background:Previous data indicate that morphine-6&bgr;-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-d-aspartate receptor activity in mice. Methods:Nociception after acute injection (10 mg/kg) and chronic infusion (1.6 mg/kg per 24 h) of M6G or saline was assayed using the tail-withdrawal test in CD-1 mice implanted with pellets containing the opioid antagonist naltrexone or placebo and in knockout mice lacking &mgr;-, &kgr;-, and &dgr;-opioid receptors and their B6129F1 controls. In volunteers, responses to heat pain were tested after a M6G (0.4 mg/kg) injection in the presence of a continuous high naloxone (0.04-mg/kg bolus followed by 0.04 mg/kg per hour) or saline background infusion. Results:Acute M6G injection evoked analgesia in CD-1 mice implanted with placebo pellets and B6129F1 control mice, whereas it caused hyperalgesia in CD-1 mice treated concurrently with naltrexone and in knockout mice. Continuous M6G infusion produced hyperalgesia within 24 h, lasting for a minimum of 6 days, in both placebo- and naltrexone-pelleted mice. The N-methyl-d-aspartate receptor antagonist MK-801 (0.05 mg/kg) blocked and reversed hyperalgesia after the acute injection and continuous infusion of M6G, respectively. In humans, M6G increased heat pain sensitivity for at least 6 h independently of simultaneous naloxone infusion. Conclusions:These data indicate that M6G causes hyperalgesia independent of previous or concurrent opioid receptor activity or analgesia. In mice, a causal role for the N-methyl-d-aspartate receptor is also indicated.

Profiles of Executive Functioning: Associations with Substance Dependence and Risky Sexual Behavior

The present investigations applied a theoretical perspective regarding the impact of executive functioning (EF) on sexual risk among substance users, using a methodological approach designed to examine whether EF subtypes differentially predict behavior patterns. Participants included 104 substance-using HIV-negative gay and bisexual men. Participants completed 5 neuropsychological assessment tasks selected to tap discrete EF components, and these data were linked to data on substance dependence and behavioral reports of substance use and sexual risk in the past 30 days. Cluster analysis identified 3 EF subtypes: (a) high performing (good performance across all measures); (b) low performing (poor performance across all measures); and (c) poor IGT performance (impairment on the Iowa Gambling Task [IGT] and its variant, but good performance on all other tasks). The 3 subtypes did not differ in amount of substance use, but the low-performing subtype was associated with greater rates of substance dependence. The low-performing subtype reported the highest rates of sexual behavior and risk, while the poor-IGT-performance subtype reported the lowest rates of sexual risk taking. Global associations between substance use and sexual risk were strongest among the low-performing subtype, but event-level associations appeared strongest among individuals in the high-performing subtype. These data suggest complex associations between EF and sexual risk among substance users, and suggest that the relationship between substance use and sexual risk may vary by EF subtypes.

Progesterone rapidly recruits female-typical opioid-induced hyperalgesic mechanisms

Continuous morphine treatment can paradoxically increase nociception (i.e. hyperalgesia) in male and female mice, but sex differences have been reported. Here, we studied progesterone modulation of these differences by assessing nociception on the tail-withdrawal test in male and female mice rendered hyperalgesic during continuous infusion of two different morphine doses (1.6 and 40.0mg/kg/24h). Although the lower morphine infusion dose increased nociception in both sexes by infusion Day 4, this hyperalgesia dissipated by Day 6 in males and ovariectomized females, but not gonadally intact females. A single subcutaneous progesterone (0.0016mg/kg) injection to males and ovariectomized females on Day 6 caused hyperalgesia to recur within 30min and to persist for a minimum of 120min. The larger morphine infusion dose also increased nociception in both sexes on Days 4 and 6. However, the NMDA receptor antagonist MK-801 (0.05mg/kg) reversed hyperalgesia in males and ovariectomized females but not gonadally intact females on infusion Day 6. Subcutaneous progesterone (0.0016mg/kg) injection inhibited this reversal in male and ovariectomized female mice but had no effect on nociception in saline-infused mice of either sex. These data confirm our previous findings that male and female mice utilize distinct hyperalgesic mechanisms, and show for the first time that a single progesterone bolus dose can recruit female-typical hyperalgesia in ovariectomized females and males.

Exacerbated Craving in the Presence of Stress and Drug Cues in Drug-Dependent Patients

In addiction, risk factors for craving and use include stress and drug-related cues. Stress and cues have additive or more-than-additive effects on drug seeking in laboratory animals, but, surprisingly, seem to compete with one another (ie, exert less-than-additive effects) in human laboratory studies of craving. We sought heretofore elusive evidence that human drug users could show additive (or more-than-additive) effects of stress and cues on craving, using ecological momentary assessment (EMA). Outpatients (N=182) maintained on daily buprenorphine or methadone provided self-reports of stress, craving, mood, and behavior on electronic diaries for up to 16 weeks. In three randomly prompted entries (RPs) per day, participants reported the severity of stress and craving and whether they had seen or been offered opioids, cocaine, cannabis, methamphetamine, alcohol, or tobacco. In random-effects models controlling for between-person differences, we tested effects of momentary drug-cue exposure and stress (and their interaction) on momentary ratings of cocaine and heroin craving. For cocaine craving, the Stress × Cue interaction term had a positive mean effect across participants (M=0.019; CL95 0.001–0.036), denoting a more-than-additive effect. For heroin, the mean was not significantly greater than 0, but the confidence interval was predominantly positive (M=0.019; CL95 −0.007–0.044), suggesting at least an additive effect. Heterogeneity was substantial; qualitatively, the Stress × Cue effect appeared additive for most participants, more than additive for a sizeable minority, and competitive in very few. In the field, unlike in human laboratory studies to date, craving for cocaine and heroin is greater with the combination of drug cues and stress than with either alone. For a substantial minority of users, the combined effect may be more than additive.

Affective differences in Iowa Gambling Task performance associated with sexual risk taking and substance use among HIV-positive and HIV-negative men who have sex with men

ABSTRACT We investigated the relationship between emotional distress and decision making in sexual risk and substance use behavior among 174 (ages 25 to 50 years, 53% black) men who have sex with men (MSM), a population at increased risk for HIV. The sample was stratified by HIV status. Measures of affective decision making, depression, anxiety, sex acts, and substance use during the past 60 days were collected at our research center. Negative binomial regression models were used to examine the relationship between age, HIV status, anxiety, depression, and IGT performance in the prediction of number of risky sex acts and substance use days. Among those without anxiety or depression, both number of risky sex acts and drug use days decreased with better performance during risky trials (i.e., last two blocks) of the IGT. For those with higher rates of anxiety, but not depression, IGT risk trial performance and risky sex acts increased concomitantly. Anxiety also interacted with IGT performance across all trials to predict substance use, such that anxiety was associated with greater substance use among those with better IGT performance. The opposite was true for those with depression, but only during risk trials. HIV-positive participants reported fewer substance use days than HIV-negative participants, but there was no difference in association between behavior and IGT performance by HIV status. Our findings suggest that anxiety may exacerbate risk-taking behavior when affective decision-making ability is intact. The relationship between affective decision making and risk taking may be sensitive to different profiles of emotional distress, as well as behavioral context. Investigations of affective decision making in sexual risk taking and substance use should examine different distress profiles separately, with implications for HIV prevention efforts.

Aripiprazole for cocaine abstinence: a randomized-controlled trial with ecological momentary assessment.

Aripiprazole blocks psychostimulant seeking in a rat model of relapse. However, in humans, it may increase ongoing use. We tested aripiprazole specifically for relapse prevention. Methadone-maintained outpatients who were abstinent from cocaine in weeks 11–12 were randomized to double-blind aripiprazole (15 mg daily) or placebo in weeks 13–27 after 12 weeks of contingency management. Participants reported craving through ecological momentary assessment. We stopped the trial because very few (18/41) participants fulfilled the abstinence criterion. The results suggested that aripiprazole delayed lapse [hazard ratio (HR)=0.45, 95% confidence interval (CI)=0.14–1.42, P=0.17] and relapse (HR=0.31, 95% CI=0.07–1.27, P=0.10), but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group (Fisher’s exact P=0.026), although the frequency of craving was similar in the aripiprazole and placebo groups (1.89 vs. 1.16%, reffect=0.43, 95% CI=−0.08−0.76). The results suggest that in recently abstinent cocaine users, aripiprazole might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle.

The effects of age and physical health on processing speed in HIV

The impact of age and physical health on processing speed was investigated in 42 non-demented HIV+ individuals ranging in age from 30 to 75. We used the Medical Outcomes Study-HIV Healthy Survey (MOS-HIV) to measure self-reported physical health, neuropsychological tests to measure psychomotor and cognitive processing speed (Delis–Kaplan Executive Function System Trail Making Test, Grooved Pegboard Test, letter and category fluency), and a test of the foreperiod effect to measure reaction time under increasing attentional load. Results indicated that aging and worse physical health each independently contributed to slowing on different processing speed measures, while the interaction between aging and physical health did not contribute to processing speed. These findings highlight the importance of considering physical health separately from age when measuring cognitive function in HIV+ adults.

Testing the PPAR hypothesis of tobacco use disorder in humans: A randomized trial of the impact of gemfibrozil (a partial PPARα agonist) in smokers

Previous pre-clinical studies demonstrated a promising role of alpha-type peroxisome proliferator-activated receptors (PPARα) agonists in decreasing nicotine self-administration and nicotine-seeking behavior in animals. Our goal was to investigate the potential of gemfibrozil, a PPARα agonist, on reducing tobacco smoking in humans. Methods: This was a double-blind, placebo-controlled, crossover study evaluating the effects of gemfibrozil (1200 mg/day) on smoking in 27 treatment-seeking smokers. The study had two 2-week phases separated by a washout period of at least 1 week. In each phase and after 1 week on medication, participants underwent a lab session where cue reactivity and forced choice paradigms were conducted. Physiological responses and self-reported craving were monitored during the presentation of smoking and neutral cues. In addition, two types of cigarettes were used in the forced choice paradigms: the Nicotinized cigarettes (Nic) and the Denicotinized cigarettes (Denic). The goal of the forced choice was to calculate the percentage of choice of Nic cigarettes while taking gemfibrozil or placebo. The number of quit days was calculated during the two quit attempts weeks (one while taking gemfibrozil and one while taking placebo) of the study. Results: There were no significant differences between gemfibrozil and placebo groups in the percentage of choice of Nic cigarettes, the cue-reactivity (both physiological and subjective measures), or in the number of days of abstinence. Conclusions: Although preclinical studies with PPAR α agonists showed promising results, this preliminary study did not demonstrate positive effect of gemfibrozil on tobacco use and cessation indices.

Compulsive Seekers: Our take. Two Clinicians’ Perspective on a New Animal Model of Addiction

Compulsive Seekers: Our take. Two Clinicians’ Perspective on a New Animal Model of Addiction