P.6.c.009 Comparison of a benzodiazepine and alcohol challenge in opioid dependent human participants

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P.6.c. Addiction − Drugs (clinical)

to unipolar depression: a transcranial color-coded real-time sonography study. Biol Psychiatry. 1995 Aug 1; 38(3): 180−4. [2] Budisic M, Karlovic D, Trkanjec Z, Lovrencic-Huzjan A, Vukovic V, Bosnjak J, Demarin V.Brainstem raphe lesion in patients with major depressive disorder and in patients with suicidal ideation recorded on transcranial sonography. Eur Arch Psychiatry Clin Neurosci. 2010 Apr; 260(3): 203−8. [3] Cowan RL, Roberts DM, Joers JM.Neuroimaging in human MDMA (Ecstasy) users. Ann N Y Acad Sci. 2008 Oct;1139:291−8.

P.6.c.008 Treatment approach effects on maternal and neonatal outcome in pregnant opioiddependent women maintained on methadone vs. buprenorphine

both groups. Superior results were achieved in neonates prenatally exposed to buprenorphine regarding NAS treatment duration (mean duration of methadone-exposed infants 21.25 days in SP vs. 9.29 days in CT; 6.62 days in buprenorphine-exposed neonates in SP vs. 6.90 days in CT; p = 0.005) and related morphine dose administered (p = 0.005) compared to methadone (see table). Conclusions: Comparably favorable outcomes for mothers and infants as well as efficacy and safety of buprenorphine and methadone were shown in both treatment approaches. Neonatal care could benefit from transferring successful procedures applied in the CT, including blinded NAS assessment and post-partal supportive care and rooming-in with the mothers, into clinical practice. References

V. Metz1 ° , K. Graf-Rohrmeister2 , R. Jagsch3 , N. Ebner4 , J. W¨urzl1 , A. Pribasnig1 , C. Aschauer1 , G. Fischer1 . 1 Medical University of Vienna, Psychiatry and Psychotherapy, Vienna, Austria; 2 Medical University of Vienna, Pediatrics and Adolescent Medicine, Vienna, Austria; 3 University of Vienna, Faculty of Psychology, Vienna, Austria; 4 Medical University of Vienna, Child and Adolescent Psychiatry, Vienna, Austria Aims: To compare maternal and neonatal outcome of opioiddependent women maintained on buprenorphine or methadone throughout pregnancy in a clinical trial (CT) involving very rigid treatment procedures [1] with a prospectively followed comparison group − representative for the pregnant opioid-dependent field population − undergoing a structured standard protocol (SP). The evaluation of two different treatment approaches at the same center in the same time frame should yield new insight and knowledge about crucial factors leading to the most beneficial results for mothers and children. Methods: One-hundred and eighteen subjects in opioid maintenance therapy between June 2005 and December 2009 at the Addiction Clinic of the Medical University of Vienna, Austria, were included in the analysis, with 77 in SP (n = 51 methadone, n = 26 buprenorphine), and 41 in CT (n = 21 methadone, n = 20 buprenorphine). Main outcome measures included maternal concomitant consumption of benzodiazepines, cocaine, opioids and cigarettes during third trimester of pregnancy, demographic birth data, duration of treatment for neonatal abstinence syndrome (NAS), required morphine dose for NAS treatment, and length of neonatal hospital stay (LOS). Results: Both study groups yielded healthy neonates with no significant differences in demographic birth data or the proportion of infants needing pharmacological NAS treatment (62.7% in SP vs. 75.6% in CT, p = 0.156). Mothers were maintained on comparable doses of opioids at time of delivery (mean methadone dose in SP 74.16 mg vs. 65.71 mg in CT, p = 0.399; mean buprenorphine dose in SP 9.85 mg vs. 13.30 mg in CT, p = 0.067) and had equivalently low rates of concomitant consumption during the last trimester despite applied contingency management in the CT group. However, the course of NAS showed significantly better results in the CT regarding total medication dose administered to neonates (mean morphine dose for methadone-exposed neonates in SP 21.61 mg vs. 4.80 mg in CT; mean morphine dose for buprenorphine-exposed neonates in SP 4.30 mg vs. 1.89 mg in CT; p = 0.008) and LOS (mean duration = 29.36 days for methadoneexposed infants in SP vs. 16.52 days in CT; 13.92 days for buprenorphine-exposed neonates in SP vs. 13.40 days in CT; p = 0.008). Correlations between NAS parameters and maternal opioid dose were low and non-significant for both medications in

[1] Jones, H.E., Kaltenbach, K., Heil, S.H., Stine, S.M., Coyle, M.G., Arria, A.M., O’Grady, K.E., Selby, P., Martin, P.R., Fischer, G. 2010. Neonatal Abstinence Syndrome Following Methadone or Buprenorphine Exposure. NEJM 363 (24), 2320–2331.

P.6.c.009 Comparison of a benzodiazepine and alcohol challenge in opioid dependent human participants R. Lees1 ° , T. Williams1 , D. Nutt2 , G. Henderson3 , 1 University of M. Hickman4 , M. Lingford-Hughes2 . Bristol, Psychopharmacology Unit, Bristol, United Kingdom; 2 Imperial College London, Neuropsychopharmacology Unit, London, United Kingdom; 3 University of Bristol, Physiology and Pharmacology, Bristol, United Kingdom; 4 University of Bristol, Department of Social Medicine, Bristol, United Kingdom Introduction: Concomitant use of central nervous system depressants has been identified as a risk factor for heroin overdose. Benzodiazepines have been identified in 50−80% of heroin related deaths, whilst alcohol has been identified in 50% of deaths. Alcohol inversely correlates with post-mortem morphine levels in heroin overdose, strongly indicating an adverse interaction [1,2]. Emerging evidence suggests opioids may modulate the receptor function of other neurotransmitter systems, including the GABAergic system, which is a key target for both benzodiazepines and alcohol. We used both an alcohol and a benzodiazepine challenge to investigate the sensitivities to both drugs in opioiddependent participants. Methods: 23 opioid-dependent participants receiving opioidsubstitution therapy were recruited to receive either the alcohol or benzodiazepine challenge. Of these 7 were eligible to receive both an alcohol and benzodiazepine challenge allowing within subject comparisons (5 taking oral methadone (12−85 mg daily), 2 taking buprenorphine (16 mg daily)). Subjects received an alcohol challenge (400ml drink containing 0.8 g/kg alcohol) and/or a benzodiazepine challenge (midazolam 50 mg/kg) on separate days. Following drug administration (alcohol/benzodiazepine) participants objective responses were recorded using both saccadic eye movements (SEM) and respiratory parameters (heart rate, respiration rate, oxygen saturation, nasal etCO2 ). Results were analysed using repeated measures two-way ANOVA. Results: Breath alcohol concentration and blood midazolam concentration significantly increased following administration of 0.8 g/kg alcohol or 50 mg/kg midazolam respectively (p < 0.0001). End tidal C02 significantly increased over time, with alcohol eliciting a 7.9±4.3% increase, and midazolam eliciting a 9.12±2.2%

P.6.c. Addiction − Drugs (clinical) increase at 105 minutes. For midazolam, but not alcohol, significant differences were observed between methadone and buprenorphine patients for etCO2 at both 30 and 75 minutes post infusion (p = 0.025 and p = 0.029 respectively), for methadone participants this increase was positively correlated with methadone dose at 30 minutes (r 0.781, p = 0.013). Respiratory rate did not significantly change over time following either alcohol or midazolam administration, nor were there significant differences between groups (alcohol/midazolam). Heart rate was significantly higher following the alcohol challenge, but this was not observed for the benzodiazepine challenge (p = 0.042). Saccadic eye movements (peak velocity, acceleration, saccade error, reaction time), were significantly impaired following drug (alcohol/midazolam) administration (p < 0.05). Peak velocity was maximally impaired at 90 minutes for alcohol (32.1±13.8% reduction) and 45 minutes for midazolam (21.0±5.9% reduction), with no significant differences between groups (alcohol/midazolam). Conclusions: Both alcohol and benzodiazepines impair measures of receptor sensitivity in opioid dependent participants. In general, participants responded similarly to both an alcohol and a benzodiazepine challenge, with no significant differences observed between groups. One exception is heart rate, likely due to the excessive sleepiness and inactivity observed in participants following a dose of midazolam (in contrast to alcohol which induced alertness, activity and excitement). The significant increase in C02 observed following both alcohol and benzodiazepine administration suggests alcohol/benzodiazepines may impair respiration in opioid dependent participants. Of particular interest is the difference observed in etCO2 response between methadone and buprenorphine. Understanding such interactions may have significant implications for clinical prescribing, and our understanding of opioid-drug interactions and overdose. References [1] Ruttenber AJ, Luke JL. 1984. Heroin-related deaths: new epidemiologic insights. Science 226(4670): 14−20. [2] Zador D, Sunjic S, Darke S. 1996. Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances. The Medical Journal of Australia 164(4): 204–207. Disclosure statement: Financial Support: MRC Programme grant (GO40075) and studentship.

P.6.c.010 Drug-induced changes in performance on the Divided Attention Task in subjects with a history of recreational drug use

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Participants were provided with a joystick to maintain the image of an airplane over a randomly curving road, while simultaneously responding to a randomly presented visual target. Changes in mean scores for target hits (accuracy and attention), hit latency (reaction time), and root mean square (RMS) distance, furthest diagonal distance from the road and percentage over road (motor control) were recorded at various time points pre- and post-dose. Peak effects (Emax /Emin ) were compared between drug class and placebo. Summary of Results: Subjects were impaired compared to placebo on all DAT variables (percentage over road, greatest distance from road, RMS distance, hit latency, and target hits) after receiving 1.5 and 3 mg alprazolam doses (p < 0.05 on all parameters, e.g. Emax /Emin ). Likewise, subjects receiving ethanol 1.0 g/kg showed impairment on all DAT measures compared to placebo (p < 0.05 for all relevant parameters). Administration of 16 mg hydromorphone resulted in significant impairment in motor control compared to placebo (mean percentage over the road, p < 0.05); however, no significant treatment differences were observed at lower doses. Administration of d-amphetamine (15 and 30 mg), significantly decreased mean hit latency (Emax ) relative to placebo (p < 0.05 for both doses), and no differences were observed for percentage over the road, RMS distance, and mean target hits (p > 0.05). Although a trend toward differences in DAT measures was observed, no significant overall treatment effects on Emax values for any DAT measures were found when subjects received 20 mg and 40 mg of dronabinol compared to placebo (p > 0.05). Conclusions: These findings suggest that drugs of abuse from various different classes are associated with changes in psychomotor performance in RDU; however, the patterns and duration vary. Depressants (alprazolam and ethanol) were associated with a generalized impairment in elements of accuracy, attention, motor control, and reaction time; whereas the opioid and stimulant drugs had more selective negative effects. High dose opioid administration resulted in impaired motor control and stimulant administration was associated with improved performance on reaction time. No statistically significant effects were observed on any DAT variable following administration of a cannabinoid. Taken together, these results provide a profile of cognitive effects, specific for various drug classes in individuals with recreational drug experience. Despite all subjects having experience with the drug class of interest, only cannabinoid users showed evidence of possible tolerance to disruptive cognitive drug effects.

S. Harrison1 ° , N. Levy-Cooperman1 , B. Danilov1 , K. Schoedel1 . 1 Kendle Early Stage − Toronto, Research Consulting, Toronto Ontario, Canada

P.6.c.011 Analysis of impact of different forms of naltrexone on the syndrome of anhedonia and depression among heroin addicts

Purpose of the Study: Drug effects on psychomotor performance in recreational drug users (RDU) have not been well-characterized and performance can be influenced by drug-use history, dose, and drug class. This analysis investigated psychomotor performance in RDU, following administration of a depressant, (alprazolam, 1.5 and 3 mg); ethanol (1.0 g/kg); a cannabinoid (dronabinol, 20 and 40 mg); an opioid (hydromorphone, 4, 8 and 16 mg); and a stimulant (d-amphetamine 15 and 30 mg) in RDU experienced with the drug class of interest. Methods Used: Data from 5 single-dose, randomized, doubleblind, placebo-controlled, crossover studies, (N = 182 subjects in total) were summarized for the Divided Attention Task (DAT), a computerized manual tracking and visual target detection task.

A. Tiurina1 ° , E. Krupitsky2 , E. Zvartau3 , G. Woody4 . 1 Pavlov State Medical University, Laboratory of clinical psychopharmacology of addictive states Valdman Institute of Pharmacology, St. Petersburg, Russia; 2 St.-Petersburg Bekhterev Psychoneurological Research Institute, Departemnt of Addictions, St. Petersburg, Russia; 3 Pavlov Medical University, Laboratory of clinical psychopharmacology of addictions Valdman Institute of Pharmacology, St. Petersburg, Russia; 4 University of Pennsylvania, Department of Psychiatry, Philadelphia, USA Background: After withdrawal arrest in many heroin addicts, they displayed the syndrome of anhedonia including affective disorder (depression). Anhedonia is often the cause for recurrence