Verena E. Metz

Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users

In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine‐maintained population. Heroin‐using volunteers (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self‐administered above the level of placebo. The addition of naloxone dose dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self‐administered significantly more than placebo. These data suggest that within a buprenorphine‐dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse.

Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.

This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3 : 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures – that is, a drug versus money and a drug versus drug procedure – were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3 : 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest.

No evidence of compensatory drug use risk behavior among heroin users after receiving take-home naloxone

INTRODUCTION Some fear that distribution of naloxone to persons at risk of experiencing an opioid overdose may reduce the perceived negative consequences of drug use, leading to riskier patterns of use. This study assessed whether participation in naloxone/overdose training altered drug use frequency, quantity or severity among heroin users in and out of treatment. METHODS Clinical interviews were performed assessing patterns of heroin and other drug use prior to, and at multiple timepoints after overdose education and naloxone training. This study compared baseline drug use to that at 1 and 3months post training. RESULTS Both current heroin users (n=61) and former users in agonist maintenance (n=69) typically showed decreases in heroin and polydrug use at both 1 and 3months after training. The Addiction Severity Index drug composite score also decreased at follow up. CONCLUSIONS This analysis found no evidence of compensatory drug use following naloxone/overdose training among two groups of heroin users. These findings support the acceptance and expansion of naloxone distribution to at-risk populations and may assist in allaying concerns about the potential for unintended negative consequences on drug use.

Effects of Ibudilast on the Subjective, Reinforcing and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence.

Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate–severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers (n=11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active ibudilast condition. Our data suggest that ibudilast may be useful for treating opioid use disorders and it may enhance the analgesic effects of oxycodone.

Need and utility of a polyethylene glycol marker to ensure against urine falsification among heroin users

BACKGROUND Deceptive methods of falsifying urine samples are of concern for anyone who relies on accurate urine toxicology results. A novel method to combat these efforts utilizes polyethylene glycol (PEG) markers administered orally prior to providing a urine sample. By using various PEG combinations to create a tracer capsule of unique composition, each urine sample can be matched to that individual. The goal of this study was to determine the effectiveness of using the PEG marker system among active heroin users screening for research studies. METHODS Upon each screening visit, participants (N=55) were randomized to provide an unobserved urine sample, or the PEG tracer procedure was used. LCMS analysis was used to distinguish the PEG combinations, and allowed us to provide a unique qualitative analysis of patterns of drug use (N=168, total urine specimens). RESULTS The unique composition of the tracer capsules was accurately detected in 83.5% of the urine specimens. Analyses of inconsistencies implicated a number of possible attempts at fraudulence (11.4%) and investigator/lab error (5.1%). Among this sample, the concurrent use of multiple classes of psychoactive drugs was more common than not, though concomitant drug use was often underreported. CONCLUSION Urine drug testing should be the minimum standard for obtaining information about drug use as self-report was unreliable even in a situation where there were no perceived adverse consequences for full disclosure. In cases where there are significant pressures for individuals to falsify these data, more protective collection methods such as the PEG marker system should be considered.

Characteristics and quality of life of opioid-dependent pregnant women in Austria

This study investigated pregnant opioid-dependent women undergoing maintenance therapy, applying a multidisciplinary, case-management approach at the Addiction Clinic of the Medical University of Vienna, Austria. It aimed at characterizing the patients’ basic demographic and clinical parameters and evaluating their overall quality of life (QoL) prepartum and postpartum. Three hundred ninety women were treated between 1994 and 2009 with buprenorphine (n = 77), methadone (n = 184), or slow-release oral morphine (SROM) (n = 129) on an outpatient basis throughout their pregnancy and postpartum period. All patients were subject to standardized prepartum and postpartum medical and psychiatric assessments, including QoL assessments using a German adaptation of the Lancashire QoL Profile (Berliner Lebensqualitaetsprofil), and regular supervised urine toxicologies. No medication group differences were revealed regarding basic demographic or clinical data. Mean maintenance doses (SD) at time of delivery were as follows: 64 mg (36 mg) methadone, 10 mg (6 mg) buprenorphine, 455 mg (207 mg) SROM. However, buprenorphine-medicated women showed significantly less concomitant benzodiazepine consumption than methadone- or SROM-maintained women (p = 0.005), and significantly less concomitant opioid consumption than methadone-maintained women (p = 0.033) during the last trimester. Overall QoL was good prepartum and postpartum in all measured domains except “finances” and “prospect of staying in the same housing situation,” and no differences were observed in QoL among the three medication groups (p = 0.177). QoL improved significantly after delivery in most of the domains (p < 0.001). Although opioid-dependent pregnant women face high-risk pregnancies and show variability in addiction severity, they report good QoL independent of the medication administered. These results show that individually tailored treatment interventions are effective for this patient population and suggest a QoL improvement after delivery.

Characteristics of drug use among pregnant women in the United States: Opioid and non-opioid illegal drug use

BACKGROUND The opioid epidemic in the US is affecting pregnant women and their offspring, with rising numbers of maternal and neonatal treatment episodes. The aim of this study was to characterize pregnant drug users in order to inform intervention strategies based on sociodemographic, mental health, and substance use characteristics. METHODS Data on pregnant women aged 18-44 reporting past-year, nonmedical opioid use or use of non-opioid illegal drugs (other than marijuana) were analyzed from the National Survey on Drug Use and Health (2005-2014). Women (N = 818) were categorized into 3 groups: 1) use of opioids only (n = 281), 2) opioid-polydrug users (n = 241), and 3) other (non-opioid) illegal drug users (n = 296). Characteristics between the 3 groups of women were compared using bivariable analyses. RESULTS Most women were non-Hispanic White (67.6%), had a high school diploma or less education (61.0%), a household income <

Pioglitazone, a PPARγ agonist, reduces nicotine craving in humans, with marginal effects on abuse potential

20,000/year (72.2%), and health insurance coverage (84.3%). No significant differences between the three groups were found regarding sociodemographic characteristics. Past-30-day marijuana use was less prevalent among opioid-only users (10.9%) compared to opioid-polydrug users (43.6%) and other pregnant illegal drug users (27.6%) (P < 0.001) and past-year drug/alcohol treatment was less prevalent among opioid-only users (6.3%) compared to opioid-polydrug users (20.3%) and other illegal drug users (8.3%) (P = 0.002). Opioid-only users also reported lower prevalence of past-year depression (P < 0.001) and anxiety (P = 0.039). CONCLUSIONS Pregnant drug-using women were often of low socioeconomic status, with mental health and substance use patterns suggesting the need for targeted mental health/substance use screening and interventions before and during pregnancy, particularly for opioid-polydrug users.

The PPARγ Agonist Pioglitazone Fails to Alter the Abuse Potential of Heroin, But Does Reduce Heroin Craving and Anxiety

Abstract Possibly through their actions upon glia, peroxisome proliferator‐activated receptor agonists (PPAR) have been shown to alter the abuse potential of addictive drugs in several preclinical models. The current study extends this research into the human laboratory as the first clinical study into the effects of the PPAR gamma agonist, pioglitazone, on the abuse potential of nicotine. Heavy smokers were recruited for this 3‐week study. Upon admission, participants were randomized to either active (45 mg, n = 14) or placebo (0 mg, n = 13) PIO maintenance conditions for the duration of the study. After 5–7 days of stabilization on a 7 mg nicotine patch, participants began laboratory testing. On the 1st–4th test days, participants could self‐administer cigarettes or receive money by making verbal choices for either option. On the 5th day, participants were administered 10 puffs of their usual brand of cigarette in the morning and later chose between smoking and money by making finger presses on a computer mouse in a progressive ratio self‐administration task. Later on the 5th day participants also underwent a smoking cue exposure session. The 8th–11th test days were identical to the 1st–4th test days with the exception that during one of the test weeks de‐nicotinized cigarettes were available, and during the other nicotinized cigarettes were available. Nicotinized cigarettes were always administered on the 5th and 12th days. On some measures PIO increased indicators of abuse potential, though this effect was typically not statistically significant. However, PIO did significantly reduce measures of craving. HighlightsThe ability of pioglitazone to alter the effects of nicotine in humans is tested.The PPAR&ggr; agonist, pioglitazone, significantly reduced measures of nicotine craving.Pioglitazone moderately increased nicotine self‐administration.Pioglitazone moderately increased the positive subjective effects of nicotine.

The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users

ABSTRACT Possibly through its effects on glia, the peroxisome proliferator-activated gamma receptor (PPARγ) agonist pioglitazone (PIO) has been shown to alter the effects of heroin in preclinical models. Until now, these results have not been assessed in humans. Heroin-dependent participants were randomized to either active (45 mg, n = 14) or placebo (0 mg, n = 16) PIO maintenance for the duration of the three-week study. After stabilization on buprenorphine (8 mg), participants began a two-week testing period. On the first to fourth test days, participants could self-administer drug or money by making verbal choices for either option. On the fifth day, active heroin and money were administered and participants could work to receive heroin or money using a progressive ratio choice procedure. Test days 6–10 were identical to test days 1–5 with the exception that, during one of the test weeks, placebo was available on the first four days, and during the other week heroin was available. PIO failed to alter the reinforcing or positive subjective effects of heroin, but it did reduce heroin craving and overall anxiety. Although we were unable to replicate the robust effects found in preclinical models, these data provide an indication of drug effects that deserves further exploration.