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CORK Bibliography: Benzodiazepines

33 citations. July 2009 to present

Prepared: June 2010

Acikkol M; Mercan S; Karadayi S. Simultaneous determination of benzodiazepines and ketamine from alcoholic and nonalcoholic beverages by gc-ms in drug facilitated crimes. Chromatographia 70(7-8): 1295-1298, 2009. (23 refs.)

A GC-MS method with HP-5MS capillary column was developed for the simultaneous determination of underivatized flunitrazepam, clonazepam, alprazolam, diazepam and ketamine from drinks by extraction with chloroform: isopropanol 1:1 (v/v). All linearity ranges were between 50 and 1,000 mu g mL(-1) for all compounds both in beer and in peach juice. Limit of detection was between 1.3 and 34.2 mu g mL(-1), limit of quantification was between 3.9 and 103.8 mu g mL(-1), the range of recoveries was 73.0 and 112.6% for all drugs in both beverages. The reported method was sensitive, rapid, and suitable for the analysis of the spiked drinks as evidence of sexual assault and robbery phenomena.

Assar S; Hatami S; Lak E; Pipelzadeh M; Joorabian M. Acute poisoning in children. Pakistan Journal of Medical Sciences 25(1): 51-54, 2009. (19 refs.)

Objectives: To find out the common causes of poisoning in infants and children. Methodology: In a retrospective cross-sectional study we evaluated all infants and children who were hospitalized due to acute poisoning between 2001 to 2004 in two Ahwaz university hospitals. Results: One hundred forty three cases were evaluated, 71% of poisonings occurred in the age range of 1-5 years. Causes were accidental ingestion (77.8%), given by others (16%) and suicide attempts (6.2%). The most common ingested substances were petroleum products (16%). Alkaline cleaners(12.6%), Opiates (11.9%), Tricyclic Antidepressants (8.4%) and Benzodiazepines (7.7%). About 2.8% of cases were multi-drug poisoning. Opiates were the most common agents which accounted for poisoning in below 6 months old. Decreased level of consciousness (67.6%) and vomiting (50%) were the most common signs and symptoms. There was no mortality in this study. Conclusion: Petroleum products are still common source of poisoning but their frequency is decreasing. Parents should be educated about the harms of some herbal agents containing opiates and on safe storage of medicines and household products.

Barrons R; Roberts N. The role of carbamazepine and oxcarbazepine in alcohol withdrawal syndrome. Journal of Clinical Pharmacy and Therapeutics 35(2): 153-167, 2010. (27 refs.)

Objective: The goal of this review is to evaluate the efficacy and safety of carbamazepine and oxcarbazepine in treatment of alcohol withdrawal syndrome (AWS) and determine the role in therapy of both agents. Methods: Relevant literature was identified through a search of MEDLINE (1966-June 2008), PubMed (1966-June 2008); Cochrane database was performed to identify English-language publications. Search terms included carbamazepine, oxcarbazepine, AWS, alcoholism, substance syndrome withdrawal. Results: In seven studies, including 612 patients, carbamazepine demonstrated significant reduction in alcohol withdrawal scores. However, in comparative trials with a benzodiazepine agent, carbamazepine's ability to prevent alcohol withdrawal seizures (OR = 0 center dot 93; 95% CI = 0 center dot 06-14 center dot 97, P = NS) and delirium tremens (DTs; OR = 1 center dot 25; 95% CI = 0 center dot 28-5 center dot 64, P = NS) was uncertain as a result of insufficient patient enrolment. In three trials, carbamazepine failed to reduce alcohol withdrawal symptoms possibly as a result of delayed administration, inadequate dosage or inadequate sample size. At daily doses of 800 mg either fixed or tapered over 5-9 days, carbamazepine was well tolerated, and safely administered when blood alcohol concentration dropped below 0 center dot 15%. The role of oxcarbazepine in AWS is undefined because of inconsistent findings in two trials. Conclusion: Carbamazepine has demonstrated safety, tolerability and efficacy in treatment of moderate to severe symptoms of alcohol withdrawal in the inpatient setting. However, trials of carbamazepine provide inconclusive evidence for prevention of alcohol withdrawal seizures and DTs in comparison with benzodiazepines. Benzodiazepines remain the primary treatment of moderate to severe AWS.

Darke S; Duflou J; Torok M. A reduction in blood morphine concentrations amongst heroin overdose fatalities associated with a sustained reduction in street heroin purity. Forensic Science International 198(1-3): 118-120, 2010. (16 refs.)

To determine the effects of a sudden and sustained reduction in heroin purity on the toxicology of heroin overdose, 959 consecutive heroin overdose cases autopsied at the NSW Department of Forensic Medicine (1/1/1998-31/12/2006) were analysed. There was a significant reduction in blood morphine concentration across the study period (beta = -0.07), declining from a median of 0.50 mg/L in the years 1998-2000 prior to 0.40 mg/L in the period 2001-2006. There was no significant change in the proportion of alcohol positive cases, but the proportion of benzodiazepine positive cases increased across time (OR 1.11), as did methadone positive cases (OR 1.12). The decline in blood morphine concentrations remained significant after controlling for these factors (beta = -0.07). In determining toxic and lethal morphine concentrations, the fact that the toxicology of overdose is responsive to changes in the opioid street market needs to be borne in mind.

Darke S; Duflou J; Torok M. The comparative toxicology and major organ pathology of fatal methadone and heroin toxicity cases. Drug and Alcohol Dependence 106(1): 1-6, 2010. (23 refs.)

In order to determine the comparative toxicology and systemic disease of cases of death due to methadone and heroin toxicity, 1193 coronial cases of opioid overdose that occurred in New South Wales, Australia between I January 1998 and 31 December 2007 were inspected. These comprised 193 cases in which cause of death involved methadone toxicity (METH) and 1000 cases in which cause of death involved heroin toxicity in the absence of methadone (HER). METH cases were significantly more likely to have benzodiazepines (63.7% vs. 32.2%), and less likely to have alcohol (23.6% vs. 42.7%) detected. METH cases were significantly more likely to be diagnosed with pre-existing systemic pathology (94.3% vs. 79.9%), and Multiple organ system pathology (68.8% vs. 41.4%). Specifically, METH cases were more likely to have cardiac (58.9% vs. 34.5%), pulmonary (53.6% vs. 30.9%), hepatic (80.7% vs. 62.8%) and renal (25.0% vs. 9.5%) disease. Given the notable differences in toxicology and disease patterns, great caution appears warranted in prescribing benzodiazepines to methadone users, and regular physical examinations of methadone treatment patients would appear clinically warranted.

Denham BE. Association between narcotic use and anabolic-androgenic steroid use among American adolescents. Substance Use & Misuse 44(14): 2043-2061, 2009. (52 refs.)

Drawing on the data gathered in the 2006 Monitoring the Future study of American youth, the present research examines associations between use of narcotics and use of anabolic-androgenic steroids (AASs) among high-school seniors (n = 2,489). With independent measures and controls including sex, race, media exposure, socializing with friends, participation in recreational and school-sponsored sports, perceptions of drug use among professional athletes, and perceptions of steroid use among close friends, binary logistic regression analyses revealed significant associations between AAS use and the use of alcohol, crack cocaine, Vicodin, gamma-hydroxybutyrate (GHB), Ketamine, and Rohypnol. While use of both AASs and the narcotic drugs generally did not eclipse 5% of the sample, the numbers extend to many thousands in larger populations. Implications for health practitioners and recommendations for future research are offered. The study's limitations are noted.

Eisenbach-Stangl I; David A; Dressel M. 'Viennese Blend': Municipal drug services, their development and their governance. Drugs: Education, Prevention and Policy 16(6): 537-549, 2009. (18 refs.)

After the fall of the Iron Curtain drug consumption in Vienna approached that of other Western European cities. Psycho pharmaceuticals (benzodiazepines) and substitution drugs ('morphines') are frequently used as replacement and as complement to the illegal 'classics' heroin, cocaine and cannabis, especially by members of the marginalized drug scene. The municipal drug services have expanded and diversified since the 1990s and have targeted marginalized poly drug users. During the last 20 years the aim of harm reduction has been successfully established, the thresholds of the services have been lowered and new user groups - also socially integrated ones - reached. Before 1990 the development of the drug services was governed by drug professionals, after that time a rapidly expanding municipal drug administration took over. The 'Addiction and Drug Coordination Vienna', which is closely linked to the major and the city council and thus to political decisions, furthered the socio-political integration of drug users, of drug consumption and of the drug services, but it also heralded the socio-economic rationalization of the services and promoted their collaboration with the repressive forces, operating along different rationales decided on different political layers.

Fang SY; Chen CY; Chang IS; Wu ECH; Chang CM; Lin KM. Predictors of the incidence and discontinuation of long-term use of benzodiazepines: A population-based study. Drug and Alcohol Dependence 104(1-2): 140-146, 2009. (43 refs.)

Long-term use of benzodiazepines (BZDs) has been linked with an array of negative health consequences and increased medical costs and social burden. In this study, we sought to investigate the factors accounting for differential risks in the process from incident BZD use to long-term use and discontinuation in the general population. On the basis of a random sample of 187,413 people enrolled in Taiwan's National Health Insurance program on January 1, 2000, data of 2000-2002 healthcare and pharmacological services utilization were retrieved. Long-term use (LTU) was defined by having received BZD prescriptions for 180 or more days within any given calendar year. Multivariate logistic regression analyses were carried out to assess the strength of associations while adjusting for the effects of individual sociodemographics, service providers, and pharmacological agents simultaneously. Results indicated that males, elderly, and those with physical or mental disorders were more likely to become long-term users of BZDs. Having received BZD prescriptions in multiple pharmacological agents, short-acting or mixed-type agents, and hypnotic indication were associated with a roughly 2- to 5-fold increased risk of BZD LTU soon after prescription initiation. With respect to discontinuation, the effects of pharmacological characteristics seem more salient as compared to those of individual and service-provider factors. Future strategies targeting individual factors and modifying service-provider prescription behaviors may be considered to reduce possible negative consequences of BZD LTU.

Hallinan R; Crettol S; Agho K; Attia J; Besson J; Croquette-Krokar M et al. Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: A transnational study. European Journal of Clinical Pharmacology 65(11): 1113-1120, 2009. (45 refs.)

To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. Cannabis use and higher methadone doses in MMT could in part be a response to --or a cause of- more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Hartz I; Lundesgaard E; Tverdal A; Skurtveit S. Disability pension is associated with the use of benzodiazepines 20 years later: A prospective study. Scandinavian Journal of Public Health 37(3): 320-326, 2009. (25 refs.)

Aim: The Norwegian government states that actions are needed to stimulate working capacity in disability pension (DP) recipients with such a potential. Identification of factors that may impair rehabilitation efforts, such as information on the start of benzodiazepines in DP recipients, may be useful in this context. Thus, the aim of the study was to describe the association between receipt of DP and later prescriptions of benzodiazepines among non-users at baseline. Methods: We followed a cohort reporting non-use of benzodiazepines, 6645 men and 6455 women aged 40-42 years who underwent health surveys in 1985-89 in two Norwegian counties, with respect to subsequent use of benzodiazepines by linkage to the Norwegian Prescription Database for 2004-2006. At baseline, 83 men and 163 women reported receiving DP. Results: In both genders, the proportion started on at least one prescription of a benzodiazepine was approximately doubled among those reporting being on a DP 20 years in the past, 21% of all men and 29% of all women, respectively. Univariate odds ratios for a benzodiazepine prescription for men and women on a DP were 2.6 (95% confidence interval (CI) = 1.5-4.4) and 2.1 (95% CI = 1.5-2.9), respectively, as compared with those not receiving a DP. After adjustment for alcohol use, smoking habits, physical activity, socioeconomic and health variables, the odds ratios were lowered for both genders, being 2.1 (95% CI = 1.2-3.7) (men) and 1.6 (95% CI = 1.1-2.3) (women). Conclusions: For both men and women, the chance of being prescribed benzodiazepines was higher among those reporting being DP recipients 20 years in the past.

Hutton J; Dent A; Buykx P; Burgess S; Flander L; Dietze P. The characteristics of acute non-fatal medication-related events attended by ambulance services in the Melbourne Metropolitan Area 1998-2002. Drug and Alcohol Review 29(1): 53-58, 2010. (32 refs.)

Introduction and Aims. To describe the characteristics of non-fatal medication-related ambulance attendances in Melbourne. Design and Methods. A retrospective analysis of 16 705 patient care records completed by ambulance paramedics in Melbourne where medications had a causal role in the attendance. Results. A single medication only was implicated in 11 765 cases (70% of the total). Of these, 85% involved one of six types of medication: benzodiazepines (52%), paracetamol (15%), selective serotonin re-uptake inhibitors (6.5%), combination paracetamol and opioids (4%), phenothiazines (3.4%) and tricyclic antidepressants (TCA) (3.7%). Cases involving benzodiazepines were significantly (P < 0.001) older (Average = 37 years) than those involving paracetamol (Average = 30 years). Thirty-four per cent of cases involved concurrent alcohol use, and this varied according to drug type (paracetamol 26%, benzodiazepines 40%, selective serotonin re-uptake inhibitors 35%, paracetamol and opioids 35%). An abnormal Glasgow Coma Scale score was found in 19% of cases, again varying according to drug type (paracetamol 10%, TCA 39%, benzodiazepines 21%, paracetamol and opioids 17%, phenothiazines 15%). Ten per cent of cases were not transported to hospital ranging from 3% for TCA to 13% for benzodiazepines. Discussion and Conclusions. The majority of non-fatal medication events attended by ambulance paramedics involve one of six substances. Benzodiazepines were most commonly implicated and, as management may require only simple supportive treatment, significant numbers are not transported to hospital. The unique clinical population is identified in this study and the ongoing medical and psychiatric treatment of these patients not transported to hospital in the study period needs to be considered.

Jones AW; Holmgren A. Concentration distributions of the drugs most frequently identified in post-mortem femoral blood representing all causes of death. Medicine, Science and the Law 49(4): 257-273, 2009. (69 refs.)

Interpreting the concentrations of drugs determined in post-mortem blood is not an easy task owing to poly-drug use, adverse drug-drug interactions, as well as a host of pre-analytical factors and various artefacts in post-mortem toxicology. Highly sensitive and specific methods (GC-FID, GC-NPD. GC-MS and LC-MS) were used to determine the concentrations of drugs in femoral blood from 24,876 autopsies representing all causes of death. Ethanol topped the list of psychoactive substances (N=8,108 or 33%) at mean, median and highest concentrations of 1.43 g/L, 1.20 g/L and 8.0 g/L, respectively. In second place was paracetamol (N=2,741 or 11%). Amphetamine and cannabis were the major illicit drugs at 13th and 15th positions, respectively. Newer antidepressants, citalopram (no 3), sertraline (no 14), venlafaxine (no 16) were prominent as were sedative-hypnotics, such as diazepam (no 4), zopiclone (no 5) and zolpidem (no 18). This compilation of drugs and their concentration distributions will be useful to identify and flag for a likely overdose or drug-related poisoning death. The drug concentration together with the findings at autopsy and the police report can then be used to reach a conclusion about the cause and manner of death.

Karjalainen KK; Lintonen TP; Impinen AO; Lillsunde PM; Ostamo AI. Poly-drug findings in drugged driving cases during 1977-2007. Journal of Substance Use 15(2): 143-156, 2010. (52 refs.)

Background: Driving under the influence of drugs (DUID) is an increasing public health and traffic safety related problem. We examined the poly-drug findings and their trends among all apprehended DUID offenders in Finland. Methods: A register data from 1977 to 2007 was analysed. The data included a total of 31,963 suspected DUID cases with a positive finding for an illicit/licit drug impairing driving performance. Blood and/or urine specimens were analysed in one central laboratory. Results: Poly-drug findings were common among suspected DUID cases during the entire study period. Seventy-seven per cent of the specimens had a finding from two or more substance groups. Benzodiazepines with alcohol (20% of poly-drug cases) and amphetamines with benzodiazepines (18%) were the most frequently found combinations. Benzodiazepines were present in the five most frequent combinations. The proportion of cases including drugs only increased more rapidly than the proportion of cases including a combination of drugs and alcohol during the last three decades. The level of aggravated drink-driving limit in Finland (BAC>1.2 parts per thousand) was exceeded in 44% of the cases including alcohol. Conclusion: In addition to amphetamines, benzodiazepines formed a major concern among suspected DUID cases. The large proportion of poly-drug findings may indicate extensive substance abuse among DUID offenders.

Lintzeris N; Nielsen S. Benzodiazepines, methadone and buprenorphine: Interactions and clinical management. (review). American Journal on Addictions 19(1): 59-72, 2010. (122 refs.)

Benzodiazepines (BZDs) are widely used by heroin users not in treatment, and by patients in methadone and buprenorphine (BPN) treatment. This review examines the epidemiology of BZD use by opioid users, and the range of harms that are associated with BZD use in this group, including the association of BZD use with opioid-related mortality. Preclinical and clinical data regarding pharmacokinetic and pharmacodynamic interactions between methadone, buprenorphine, and BZDs are reviewed. An overview of treatment approaches for managing BZD use in this population is presented, including strategies for minimizing abuse and addressing BZD dependence.

Madea B; Musshoff F. Knock-out drugs: Their prevalence, modes of action, and means of detection. (review). Deutsches Arzteblatt International 106(20): 341-U12, 2009. (25 refs.)

Background: Knock-out drugs are used to facilitate the commission of a crime, generally either robbery or sexual assault. Although media reports on the use of knock-out drugs have become more frequent, there are no robust epidemiological data on the incidence of drug-facilitated robbery or sexual assault, presumably because many crimes of these types do not enter into official statistics. Methods: The authors describe the modes of action and toxicological means of detection of the substances most frequently used as knock-out drugs on the basis of a selective literature research on the terms "drug-facilitated sexual assaults" (DFSA) and "drug-facilitated crimes" (DFC). Results: The most frequently used drug in cases of sexual assault is still alcohol (ca. 40% to 60%), followed by illegal drugs (cannabis, cocaine). The presence of involuntarily consumed medications and drugs of abuse is demonstrated by routine toxicological analysis only in relatively few cases (ca. 2%). The substances most commonly found are benzodiazepines, followed by other hypnotics. In Europe, the illegal substance gamma-hydroxybutyric acid (GHB, "Liquid Ecstasy"), often mentioned as a "date-rape drug," is only rarely detected with sufficient medicolegal certainty. This may be due to its rapid elimination (it is detectable in blood for up to 8 hours, in urine for up to 12 hours) as well as its physiological occurrence in the body. If the toxicological analysis of blood and urine is negative in a case of suspected DFSA, then the analysis of a hair sample about four weeks after the assault can detect the presence of drugs consumed at that time. If the victim has long hair, it may be possible to detect knock-out drugs taken more than four weeks earlier. In Europe, convictions for drug-facilitated crimes are comparatively rare, mainly because of the difficulty of demonstrating conclusive evidence. Conclusions: A careful medical history and physical examination and the careful taking of biological samples for toxicological analysis form the basis for the detection of drug-facilitated crimes.

Martinotti G; di Nicola M; Frustaci A; Romanelli R; Tedeschi D; Guglielmo R et al. Pregabalin, tiapride and lorazepam in alcohol withdrawal syndrome: A multi-centre, randomized, single-blind comparison trial. Addiction 105(2): 288-299, 2010. (85 refs.)

Introduction: The aim of this trial was to compare lorazepam with non-benzodiazepine medications such as pregabalin and tiapride in the treatment of alcohol withdrawal syndrome (AWS). These drugs were chosen for their inhibitorial effects on the hypersecretion of neurotransmitters usually observed in AWS. Craving reduction and improvement of psychiatric symptoms were the secondary end-points. Methods: One hundred and ninety subjects affected by current alcohol dependence were considered consecutively: 111 were enrolled and divided into three groups of 37 subjects each. Within a treatment duration of 14 days, medication was given up to the following maximum doses (pregabalin 450 mg/day; tiapride 800 mg/day; lorazepam 10 mg/day). Withdrawal (CIWA-Ar), craving [visual analogue scale (VAS); Obsessive and Compulsive Drinking Scale (OCDS)], psychiatric symptoms [Symptom Check List 90 Revised (SCL-90-R)] and quality of life (QL-index) rating scales were applied. Results: On the CIWA-Ar score, all the groups showed a significant reduction between times (P < 0.001) with a higher reduction for the pregabalin group (P < 0.01) on items regarding headache and orientation. Retention in treatment was lower in the tiapride group (P < 0.05), while the number of subjects remaining alcohol free was higher in the pregabalin group (P < 0.05). Significant reduction between baseline and the end of the treatment was found in all the groups at the OCDS and the VAS for craving, at the SCL-90-R and QL-index (P < 0.001). Discussion: All the medications in the trial showed evidence of safety and efficacy in the treatment of uncomplicated forms of AWS, with some particular differences. The efficacy of pregabalin was superior to that of tiapride, used largely in research trials and, for some measures, to that of the 'gold standard', lorazepam. Accordingly, pregabalin may be considered as a potentially useful new drug for treatment of AWS, deserving further investigation.

Moberg CA; Curtin JJ. Alcohol selectively reduces anxiety but not fear: Startle response during unpredictable versus predictable threat. Journal of Abnormal Psychology 118(2): 335-347, 2009

Recent theory and empirical research have suggested that fear and anxiety are distinct processes with separable neurobiological substrates. Furthermore, a laboratory procedure has been developed to manipulate fear versus anxiety independently via administration of predictable or unpredictable electric shock, respectively. Benzodiazepines appear to selectively reduce anxiety but not fear in this procedure. The primary aim of this experiment was to determine if alcohol produced a similar selective reduction in anxiety. Intoxicated (target blood alcohol concentration of .08%) and nonintoxicated participants viewed a series of colored squares separated by variable intertrial intervals (ITIs) in 3 conditions. In the predictable shock condition, shocks were administered contingently during every square. In the unpredictable shock condition, shocks were administered noncontingently during both squares and ITIs. In the no-shock condition, no shocks were administered at any time. Alcohol significantly reduced startle potentiation during cues signaling unpredictable but not predictable shock, consistent with the thesis that alcohol selectively reduces anxiety but not fear. In addition, alcohol's effect on startle potentiation during unpredictable shock was mediated by vigilance. This anxiolytic effect may clarify the nature of alcohol's reinforcing effects in social and problem drinkers.

Myrick H; Malcolm R; Randall PK; Boyle E; Anton RF; Becker HC et al. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcoholism: Clinical and Experimental Research 33(9): 1582-1588, 2009. (40 refs.)

Introduction: Some anticonvulsants ameliorate signs and symptoms of alcohol withdrawal, but have an unacceptable side effect burden. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol that could increase psychomotor deficits, increase cognitive impairment, or increase intoxication. The aim of this study was to evaluate alcohol use and symptom reduction of gabapentin when compared with lorazepam in the treatment of alcohol withdrawal in a double-blinded randomized clinical trial. Methods: One hundred individuals seeking outpatient treatment of alcohol withdrawal with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) ratings >= 10 were randomized to double-blind treatment with 2 doses of gabapentin (900 mg tapering to 600 mg or 1200 tapering to 800 mg) or lorazepam (6 mg tapering to 4 mg) for 4 days. Severity of alcohol withdrawal was measured by the CIWA-Ar on days 1 to 4 of treatment and on days 5, 7, and 12 post-treatment and alcohol use monitored by verbal report and breath alcohol levels. Results: CIWA-Ar scores decreased over time in all groups; high-dose gabapentin was statistically superior but clinically similar to lorazepam (p = 0.009). During treatment, lorazepam-treated participants had higher probabilities of drinking on the first day of dose decrease (day 2) and the second day off medication (day 6) compared to gabapentin-treated participants (p = 0.0002). Post-treatment, gabapentin-treated participants had less probability of drinking during the follow-up post-treatment period (p = 0.2 for 900 mg and p = 0.3 for 1200 mg) compared to the lorazepam-treated participants (p = 0.55). The gabapentin groups also had less craving, anxiety, and sedation compared to lorazepam. Conclusions: Gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal in our population especially at the higher target dose (1200 mg) used in this study. Gabapentin reduced the probability of drinking during alcohol withdrawal and in the immediate postwithdrawal week compared to lorazepam.

Officer J. Trends in drug use of Scottish drivers arrested under Section 4 of the Road Traffic Act: A 10 year review. Science & Justice 49(4): 237-241, 2009. (12 refs.)

A Study of Section 4 RTOA cases Submitted to the SPSA forensic science laboratory in Edinburgh over a 12 year period was carried out. The main aims of the study were to identify the most frequently encountered drugs and to determine if there were any major drugs trends from the data collected. Three groups of cases from 1996 to 2000 (102 cases), 2003 (26 cases) and 2008 (295 cases) were examined. The large increase in Submissions was mainly due to the introduction of SPSA, whereby the laboratory began to carry out the analysis for all criminal and RTOA cases in Scotland. The preliminary results for the 8 drug groups (amphetamine and related compounds, benzodiazepines, cannabinoids, cocaine, methadone, methylamphetamine and related compounds, morphine and opiates) identified a number of major trends: cannabinoids were consistently present in 40-50% of cases: benzodiazepines more than doubled in frequency to over 80%; there has been a significant increase in cases positive for morphine and methadone - up from less than 2% each to 31% and 23% respectively; there has been an increase in the number of cases screening positive for opiates (19% to 29%); and the frequency of positive cases for cocaine, amphetamine and methylamphetamine remained unchanged (approximately 22%, 6% and 5% respectively), A significant finding was the huge increase in polydrug use. The number of cases positive for 4 or more drug groups has increased from 4% in 1996-2000 to 25% in 2008. In comparison, in the 1996-2000 group 72% of cases were only positive for one drug group compared to 17% in 2008. For those cases which were negative for all 8 drug groups, a screen for potentially impairing prescription and over the counter medicines was carried Out. The most frequently encountered medicines were sedatives, sedative antidepressants, sedative antihistamines and antiemetics. These were often found in conjunction with alcohol below the legal limit for driving.

Oulis P; Konstantakopoulos G. Pregabalin in the treatment of alcohol and benzodiazepines dependence. (review). CNS Neuroscience & Therapeutics 16(1): 45-50, 2010. (39 refs.)

We review all available studies on the use of the newer anticonvulsant drug pregabalin (PGB) in the treatment of both alcohol dependence (AD) and benzodiazepine dependence (BD). In AD, the available evidence includes one open-label and one double-blind randomized studies, whereas in BD, only a few case reports and one open-label study are as yet available. In both conditions, PGB was found efficacious with significant improvement in withdrawal symptoms at the dosage ranges of 150-450 mg/day (AD) and 225-900 mg/day (BD). Moreover, its side effects were mild and transient. Despite the limited quality of the studies design, their findings suggest that PGB might constitute a novel efficacious and safe option in the treatment of both AD and BD.

Parr JM; Kavanagh DJ; Young RM; Connor JP. Development of self-efficacy and expectancy measures for benzodiazepines. Addictive Behaviors 34(9): 751-756, 2009. (43 refs.)

This study aimed to develop and assess the reliability and validity of a pair of self-report questionnaires to measure self-efficacy and expectancy associated with benzodiazepine use, the Benzodiazepine Refusal Self-Efficacy Questionnaire (BRSEQ) and the Benzodiazepine Expectancy Questionnaire (BEQ). Internal structure of the questionnaires was established by principal component analysis (PCA) in a sample of 155 respondents, and verified by confirmatory factor analyses (CFA) in a second independent sample (n = 139) using structural equation modeling. The PCA of the BRSEQ resulted in a 16-item, 4-factor scale, and the BEQ formed an 18-item, 2-factor scale. Both scales were internally reliable. CFA confirmed these internal structures and reduced the questionnaires to a 14-item self-efficacy scale and a 12-item expectancy scale. Lower self-efficacy and higher expectancy were moderately associated with higher scores on the SDS-B. The scales provide reliable measures for assessing benzodiazepine self-efficacy and expectancies. Future research will examine the utility of the scales in prospective prediction of benzodiazepine cessation.

Ramirez OA; Perez MF. The plastic phenomenon underlying the associative processes in the addictive properties of diazepam and other psychoactive drugs. (review). Mini-Reviews in Medicinal Chemistry 9(7): 869-877, 2009. (123 refs.)

Benzodiazepines are commonly prescribed for the therapy of disorders such as anxiety and sleep disturbance, but develop dependence in many patients. In this review we discuss the impact of different brain areas that modulate the reward system in the development of tolerance and dependence to benzodiazepine and the associative processes underlying those phenomena.

Rapeli P; Fabritius C; Kalska H; Alho H. Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: Longitudinal change in comparison to healthy individuals. Substance Abuse Treatment, Prevention and Policy 4: e-article 6, 2009. (65 refs.)

Background: Opioid-substitution treatment (OST) for opioid dependence (OD) has proven effective in retaining patients in treatment and reducing illegal opiate abuse and crime. Consequently, the World Health Organization (WHO) has listed the opioid agonists methadone and buprenorphine as essential drugs for OD that should be available worldwide. In many areas of the world, OD is often associated with concomitant benzodiazepine (BZD) dependence and abuse, which complicates treatment. However, possible changes in the cognitive functioning of these patients are not well-known. The present study is the first to examine longitudinal stability of memory function in OST patients with BZD use, thus providing a new tool for health policy authorities in evaluating the usefulness of OST. Methods: Within the first two months (T1) and between 6-9 months (T2) after OST admission, we followed the working memory, immediate verbal memory, and memory consolidation of 13 methadone-and 15 buprenorphine- or buprenorphine/naloxone-treated patients with BZD dependence or abuse disorder. The results were compared to those of fifteen normal comparison participants. All participants also completed a self-reported memory complaint questionnaire on both occasions. Results: Both patient groups performed statistically significantly worse than normal comparison participants in working memory at time points T1 and T2. In immediate verbal memory, as measured by list learning at T1, patients scored lower than normal comparison participants. Both patient groups reported significantly more subjective memory problems than normal comparison participants. Patients with more memory complaints recalled fewer items at T2 from the verbal list they had learned at T1 than those patients with fewer memory complaints. The significance of the main analyses remained nearly the same when the statistical tests were performed without buprenorphine- only patients leaving 12 patients to buprenorphine/naloxone group. Conclusion: Working memory may be persistently affected in OST patients with BZD use. A high number of memory complaints among OST patients with BZD use may indicate memory consolidation impairment. These findings show that recovery of memory function in OD patients treated along with BZDs takes time, and their memory complaints may have practical relevance.

Rapoport MJ; Lanctot KL; Streiner DL; Bedard M; Vingilis E; Murray B et al. Benzodiazepine use and driving: A meta-analysis. Journal of Clinical Psychiatry 70(5): 663-673, 2009. (56 refs.)

Objective: The purpose of the present study was to examine the experimental and epidemiologic evidence linking benzodiazepine use to driving impairment. Data Sources: We searched MEDLINE, PsycINFO, the Cochrane Collaboration, and EMBASE using the key terms ("benzodiazepines". OR "exp benzodiazepines") AND ("automobile driving" OR "accidents, traffic" OR "driving" OR "driver$") and limited the results to English citations from 196,6 to August 5, 2005, with auto-updates for MEDLINE and PsycINFO to November 30, 2007. Study Selection and Data Extraction: Experimental studies using driving simulators and on-road tests were sought, as were epidemiologic studies of a case-control or cohort design. Data were extracted by blinded raters and pooled using random-effects models. We excluded studies without control groups or without measures of driving or collisions. Studies with driving measures that could not be combined were also excluded. Data Synthesis: Of 405 potential articles, 11 epidemiologic and 16 experimental studies were included in the meta-analysis. Associations between motor vehicle collisions (MVCs) and benzodiazepine use were found among 6 case-control studies (OR = 1.61, 95% CI = 1.21 to 2.13, p < .001), and 3 cohort Studies (OR = 1.60, 95% CI = 1.29 to 1.97, p < .0001). Only 10 of 97 experimental driving variables could be pooled for analysis. While no consistent findings were observed in studies using driving simulators, increased deviation of lateral position was found on on-road driving tests (standardized mean difference = 0.80, 95% CI = 0.35 to 1.25, p = .0004). Conclusions: Benzodiazepine users were found to be at a significantly increased risk of MVCs compared to nonusers, and these differences may be accounted for by a difficulty in maintaining road position.

Senna MC; Augsburger M; Aebi B; Briellmann TA; Donze N; Dubugnon JL et al. First nationwide study on driving under the influence of drugs in Switzerland. Forensic Science International 198(1-3): 11-16, 2010. (41 refs.)

In Switzerland, a two-tier system based on impairment by any psychoactive substances which affect the capacity to drive safely and zero tolerance for certain illicit drugs came into force on 1 January 2005. According to the new legislation, the offender is sanctioned if Delta(9)-tetrahydrocannabinol THC is >= 1.5 ng/ml or amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), cocaine, free morphine are >= 15 ng/ml in whole blood (confidence interval +/- 30%). For all other psychoactive substances, impairment must be proven in applying the so-called "three pillars expertise". At the same time the legal blood alcohol concentration (BAC) limit for driving was lowered from 0.80 to 0.50 g/kg. The purpose of this study was to analyze the prevalence of drugs in the first year after the introduction of the revision of the Swiss Traffic Law in the population of drivers suspected of driving under the influence of drugs (DUID). A database was developed to collect the data from all DUID cases submitted by the police or the Justice to the eight Swiss authorized laboratories between January and December 2005. Data collected were anonymous and included the age, gender, date and time of the event, the type of vehicle, the circumstances, the sampling time and the results of all the performed toxicological analyses. The focus was explicitly on DUID; cases of drivers who were suspected to be under the influence of ethanol only were not considered. The final study population included 4794 DUID offenders (4243 males, 543 females). The mean age of all drivers was 31 +/- 12 years (range 14-92 years). One or more psychoactive drugs were detected in 89% of all analyzed blood samples. In 11% (N = 530) of the samples, neither alcohol nor drugs were present. The most frequently encountered drugs in whole blood were cannabinoids (48% of total number of cases), ethanol (35%), cocaine (25%), opiates (10%), amphetamines (7%), benzodiazepines (6%) and methadone (5%). Other medicinal drugs such as antidepressants and benzodiazepine-like were detected less frequently. Poly-drug use was prevalent but it may be underestimated because the laboratories do not always analyze all drugs in a blood sample. This first Swiss study points out that DUID is a serious problem on the roads in Switzerland. Further investigations will show if this situation has changed in the following years.

Stapleton RD; Comiskey CM. Alcohol usage and associated treatment outcomes for opiate users entering treatment in Ireland. Drug and Alcohol Dependence 107(1): 56-61, 2010. (20 refs.)

Evidence has shown that frequency and quantity of drug usage are reduced after treatment but the effect of opioid addiction treatment on alcohol consumption remains unclear. As part of the national Research Outcome Study in Ireland Evaluating drug treatment effectiveness (ROSIE, see www.nuim.ie/rosie) comprehensive drug and alcohol data on 404 opiate users were collected. This study recruited and followed up at 1 and 3 years a prospective cohort of 404 users entering a new treatment episode. Descriptive and inferential statistics were computed and logistic modelling was used to identify key factors effecting outcomes. The cohort represented 8.2% of all new treatments. Follow-up interview rate at 3 years was 88%. Analysis revealed that those who abstained from alcohol use at 3 years were less likely to be using heroin at 3 years than non-abstainers. In addition, those who abstained from alcohol use at 3 years were also less likely to be using methadone, benzodiazepines and cocaine at 3 years than alcohol users. Outcomes for medium and heavy drinkers were found not to be as good as alcohol abstainers. Finally males tended to reduce the frequency and level of alcohol usage after entering treatment more than females. Results: demonstrate to clinicians that an alcohol strategy is a key component of opiate treatment planning and a comprehensive and regular assessment of the client's alcohol and drug use profile is essential if treatment interventions are to have maximum impact on outcomes.

Starer J; Chang G. Hyperammoneic encephalopathy, valproic acid, and benzodiazepine withdrawal: A case series. American Journal of Drug and Alcohol Abuse 36(2): 98-101, 2010. (13 refs.)

Background: Benzodiazepine withdrawal is accompanied by a risk of seizures, delirium, and death. While a gradual outpatient taper off of benzodiazepines is the most commonly recommended method for discontinuation, acute inpatient detoxification and seizure prophylaxis may be necessary for some. Complications related to the use of valproic acid for seizure prophylaxis are presented. Objectives: The study's objectives are to highlight an uncommon and possibly unrecognized complication of valproic acid when used for seizure prophylaxis during acute inpatient detoxification from benzodiazepines in the context of current practice. Methods: Case series. Results: Three patients with hyperammoneic encephalopathy are described. Conclusions: Hyperammoneic encephalopathy can occur as a distinct entity separate from hepatotoxicity with the use of valproic acid and may be an unrecognized complication among patients receiving this drug during benzodiazepine detoxification. Scientific Significance: A previously unreported complication among the addiction patient population is reported. This underscores the need for a better evidence base regarding the prevention of seizures during acute benzodiazepine detoxification, particularly in terms of indications, safety, and efficacy.

Toblin RL; Paulozzi LJ; Logan JE; Hall AJ; Kaplan JA. Mental illness and psychotropic drug use among prescription drug overdose deaths: A medical examiner chart review. Journal of Clinical Psychiatry 71(4): 491-496, 2010. (25 refs.)

Objective: Between 1999 and 2006, there was a 120% increase in the rate of unintentional drug overdose deaths in the United States. This study identifies the prevalence of mental illness, a risk factor for substance abuse, and chronic pain among prescription drug overdose deaths in West Virginia and ascertains whether psychotropic drugs contributing to the deaths were used to treat mental illness or for nonmedical purposes. Method: In 2007, we abstracted data on mental illness, pain, and drugs contributing to death from all unintentional prescription drug overdose deaths in 2006 recorded by the West Virginia Office of the Chief Medical Examiner. Decedent prescription records were obtained from the state prescription drug monitoring program. Results: Histories of mental illness and pain were documented in 42.7% and 56.6% of 295 decedents, respectively. Psychotropic drugs contributed to 48.8% of the deaths, with benzodiazepines involved in 36.6%. Benzodiazepines contributing to death were not associated with mental illness (adjusted odds ratio [AOR] =1.1; 95% CI, 0.6-1.8), while all other psychotropic drugs were (AOR = 3.9; 95% CI, 2.0-7.6). Of decedents with contributory benzodiazepines, 46.3% had no prescription for the drug. Conclusions: Mental illness may have contributed to substance abuse associated with deaths. Clinicians should screen for mental illness when prescribing opioids and recommend psychotherapy as an adjunct or an alternate to pharmacotherapy. Benzodiazepines may have been used nonmedically rather than as a psychotropic drug, reflecting drug diversion. Restricting benzodiazepine prescriptions to a 30-day supply with no refills might be considered.

Toprak S; Sam B; Akgul E; Silan C; Baysal E. Psychoactive drug related traumatic deaths in Istanbul between 1990-2000. Romanian Journal of Legal Medicine 18(1): 69-74, 2010. (43 refs.)

The objective of this study was to identify characteristics of drug related traumatic deaths in Istanbul between 1990 and 2000. This retrospective descriptive study was set in the Council of Forensic Medicine, Ministry of Justice. During the period studied 143 people (86 % males, 14 % females) who took a drug died after traumatic events. The mean age was 37.7 +/- 13.6 years. The most common causes of deaths were asphyxia and blunt force injury. Benzodiazepines, cannabis and heroin were the most commonly used drugs. While benzodiazepines are common in self-directed violence cases such as suicide by asphyxia, cannabis was frequent among interpersonal violence cases as homicide by shooting. Heroin was approximately equally seen in all traumatic deaths. Benzodiazepine and heroin use are especially frequent among non-violence deaths (road traffic accidents).

Vallersnes OM; Lund C; Duns AK; Netland H; Rasmussen IA. Epidemic of poisoning caused by scopolamine disguised as Rohypnol (TM) tablets. Clinical Toxicology 47(9): 889-893, 2009. (13 refs.)

Objective. An epidemic of scopolamine poisonings occurred in Oslo in 2008 among users of illicit drugs, caused by fake Rohypnol (TM) pills. The clinical features, diagnostic process, and handling of the epidemic are presented. Methods. Suspected cases of scopolamine poisoning were extracted by reviewing registration forms from an ongoing prospective clinical study of acute poisonings in Oslo. Medical records of extracted contacts were examined and cases included according to specified clinical criteria. Results. Forty-four cases of probable scopolamine poisoning were registered. Main clinical features were mydriasis, visual hallucinations, plucking behavior, agitation, and coma. No clinical diagnosis of anticholinergic syndrome was made prior to forensic analysis of the tablets, the most frequent diagnosis up to this point being unspecified drug-induced psychosis. Later in the epidemic, scopolamine poisoning became the dominating diagnosis. Ten patients were admitted to psychiatric hospitals, the rest recovered in medical units, or left health care against medical advice. Discussion. Scopolamine poisonings are rare, but the resulting anticholinergic syndrome is well described. The syndrome was not recognized until the forensic analysis result strikingly changed how the patients were diagnosed and handled. A unique aspect of this epidemic was the intoxicating agent being scopolamine-containing tablets looking like Rohypnol (TM), sold and used under the impression of being the latter. Conclusion. Recognizing the anticholinergic syndrome is important to provide proper treatment. Forensic analysis was the key to correct diagnosis in this outbreak, demonstrating its importance in verifying an epidemic of poisoning by fake drugs.

Voyer P; Roussel ME; Berbiche D; Preville M. Effectively detect dependence on benzodiazepines among community-dwelling seniors by asking only two questions. Journal of Psychiatric and Mental Health Nursing 17(4): 328-334, 2010. (41 refs.)

Consumption of benzodiazepines (BZDs) is common among seniors. When used over a long period of time, BZDs can induce dependence. The present study aimed to equip nurses with valid screening questions for detecting BZD dependence among seniors, applicable to clinical practice and based on the DSM-IV-TR version. A random sample of 707 BZD users aged 65 years and over was screened for BZD dependence using the DSM-IV-TR criteria for substance dependence. To predict a diagnosis of BZDs dependence, sensitivity and specificity were computed for each pair of items. Results showed that an affirmative answer to 'Have you tried to stop taking this medication?' and 'Over the past 12 months, have you noticed any decrease in the effect of this medication?' led to a sensitivity of 97.1% and a specificity of 94.9% to detect BZD dependence. Asking these two simple questions can be easily integrated into clinical practice and have considerable potential for identifying cases of BZD dependence.

Wu LT; Parrott AC; Ringwalt CL; Patkar AA; Mannelli P; Blazer DG. The high prevalence of substance use disorders among recent MDMA users compared with other drug users: Implications for intervention. Addictive Behaviors 34(8): 654-661, 2009. (55 refs.)

Aim: In light of the resurgence in MDMA use and its association with polysubstance use, we investigated the 12-month prevalence of substance use disorders (SUDs) among adult MDMA users to determine whether they are at risk of other drug-related problems that would call for targeted interventions. Methods: Data were drawn from the 2006 National Survey on Drug Use and Health. Past-year adult drug users were grouped into three mutually exclusive categories: 1) recent MDMA users, who had used the drug within the past year; 2) former MDMA users, who had a history of using this drug but had not done so within the past year; and 3) other drug users, who had never used MDMA. Logistic regression procedures were used to estimate the association between respondents' SUDs and MDMA use while adjusting for their socioeconomic status, mental health, age of first use, and history of polydrug use. Results: Approximately 14% of adults reported drug use in the past year, and 24% of those past-year drug users reported a history of MDMA use. Recent MDMA users exhibited the highest prevalence of disorders related to alcohol (41%), marijuana (30%). cocaine (10%), pain reliever/opioid (8%), and tranquilizer (3%) use. Adjusted logistic regression analyses revealed that, relative to other drug users, those who had recently used MDMA were twice as likely to meet criteria for marijuana and pain reliever/opioid use disorders. They were also about twice as likely as former MDMA users to meet criteria for marijuana, cocaine, and tranquilizer use disorders. Conclusions: Seven out of ten recent MDMA users report experiencing an SUD in the past year. Adults who have recently used MDMA should be screened for possible SUDs to ensure early detection and treatment.

Wu LT; Parrott AC; Ringwalt CL; Yang CM; Blazer DG. The variety of ecstasy/MDMA users: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. American Journal on Addictions 18(6): 452-461, 2009. (55 refs.)

This study investigates the potential heterogeneity of ecstasy or MDMA (3,4-methylenedioxy-N-methylamphetamine) users. Data came from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Latent class analysis (LCA) and multinomial logistic regression procedures were used to identify subtypes of ecstasy users. Approximately 1.6% (n = 562) of adult participants (N = 43,093) reported lifetime ecstasy use. LCA identified three subtypes of ecstasy users. Class 1 exhibited pervasive use of most drug classes (ecstasy-polydrug users, 37%). Class 2 reported a high rate of use of marijuana and cocaine and a moderate use of amphetamines (ecstasy-marijuana-stimulant users, 29%). Class 3 was characterized by a high rate of use of marijuana and a low use of primarily prescription-type drugs (ecstasy-marijuana users, 34%). Subtypes were distinguished by family income, history of substance abuse treatment, and familial substance abuse. Class 1 exhibited the highest prevalence of disorders related to the use of marijuana (77%), tobacco (66%), amphetamines (36%), opioids (35%), sedatives (31%), and tranquilizers (30%). The recent resurgence in ecstasy use among adults underscores the need to monitor trends in its use.