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Abstracts from the Medical Literature

Looking for the best resource on Benzodiazepines & Withdrawal? See: Benzodiazepines: How they Work & How to Withdraw (The Ashton Manual) by Professor C Heather Ashton, August 2002.

Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? In: Eur Neuropsychopharmacol 1999, Dec;9 Suppl 6:S399-405. Professor Malcolm H Lader, Institute of Psychiatry, University of London, UK. The benzodiazepines are still extensively used in psychiatry, neurology and medicine in general. Anxiety disorder and severe insomnia are important syndromal indications, but these drugs are widely prescribed at the symptomatic level, resulting in potential overuse. The official data sheets recommend short durations of usage and conservative dosage. Although short-term efficacy is established, long-term efficacy remains controversial, as relevant data are scanty and relapse, rebound and dependence on withdrawal not clearly distinguished. The risks of the benzodiazepines are well-documented and comprise psychological and physical effects. Among the former are subjective sedation, paradoxical release of anxiety and/or hostility, psychomotor impairment, memory disruption, and risks of accidents. Physical effects include vertigo, dysarthria, ataxia with falls, especially in the elderly. Dependence can supervene on long-term use, occasionally with dose escalation. The benzodiazepines are now recognised as major drugs of abuse and addiction. Other drug and non-drug therapies are available and have a superior risk benefit ratio in long-term use. It is concluded that benzodiazepines should be reserved for short-term use - up to 4 weeks - and in conservative dosage

Anxiolytic drugs: dependence, addiction and abuse. Eur Neuropsychopharmacol 1994 Jun;4(2):85-91. Professor Malcolm H Lader, Department of Clinical Psychopharmacology, Institute of Psychiatry, London, UK. The concepts of dependence, addiction and abuse comprise overlapping clinical phenomena. The earlier anxiolytic drugs, in particular the barbiturates, were prone to abuse, i.e., non-medical use, and to high-dose misuse. Their modern counterparts, the benzodiazepines, are abused in a patchy way and are sometimes taken in regularly high doses. However, the main problem is physical dependence as manifested by a withdrawal syndrome on discontinuation of the drug. The withdrawal syndrome has been carefully described and comprises physical and psychological features. In particular, perceptual symptoms such as photophobia, hyperacusis and feelings of unsteadiness may predominate. The syndrome may come on during dosage reduction but generally starts 2-10 days after cessation of the benzodiazepine, depending on its elimination half-life. About a third of long-term users suffer a recognisable syndrome even after a tapered withdrawal, its duration usually being only a few weeks. A few patients go on to a prolonged withdrawal syndrome, often characterised by muscular spasm. The treatment of the withdrawal syndrome is supportive and non-specific. A few patients started on benzodiazepine therapy escalate the dose. They tend to show the characteristic 'passive-dependent' personality features and may previously have misused other CNS depressants such as the barbiturates and alcohol. Abuse of benzodiazepines occurs in a rather varied way from country to country. Worldwide, flunitrazepam has caused concern but, in the UK, the main problem has been the intravenous use of temazepam. The molecular pharmacology of the benzodiazepine receptor has been extensively studied and is undoubtedly complex.

The treatment of benzodiazepine dependence. Addiction 1994 Nov;89(11):1535-41, Ashton C H, Department of Pharmacological Sciences, University of Newcastle upon Tyne, UK, Withdrawal of benzodiazepines is currently advised for long-term benzodiazepine users because of doubts about continued efficacy, risks of adverse effects, including dependence and neuropsychological impairment and socio-economic costs. About half a million people in the UK may need advice on withdrawal. Successful withdrawal strategies should combine gradual dosage reduction and psychological support. The benzodiazepine dosage should be tapered at an individually titrated rate which should usually be under the patient's control. The whole process may take weeks or months. Withdrawal from diazepam is convenient because of available dosage strengths, but can be carried out directly from other benzodiazepine. Adjuvant medication may occasionally be required (antidepressants, propranolol) but no drugs have been proved to be of general utility in alleviating withdrawal-related symptoms. Psychological support should be available both during dosage reduction and for some months after cessation of drug use. Such support should include the provision of information about benzodiazepines, general encouragement, and measures to reduce anxiety and promote the learning of non-pharmacological ways of coping with stress. For many patients the degree of support required is minimal; a minority may need counselling or formal psychological therapy. Unwilling patients should not be forced to withdraw. With these methods, success rates of withdrawal are high and are unaffected by duration of usage, dosage or type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history or personality disorder. Longer-term outcome is less clear; a considerable proportion of patients may temporarily take benzodiazepines again and some need other psychotropic medication. However, the outcome may be improved by careful pharmacological and psychological handling of withdrawal and post-withdrawal phases.

Benzodiazepines in primary health care: a survey of general practitioners prescribing patterns. Boixet M, Batlle E, Bolibar I, Unitat Assistencial de Drogodependencias, Servei de Psiquiatria, Barcelona, Spain. This paper presents the results of a survey carried out to investigate the benzodiazepine (BZD) prescribing patterns of the general practitioners (GP) in the catchment area of a Drug Dependence Unit located in a general hospital in Mataro (Barcelona, Spain). The aims of the survey were: (i) to obtain descriptive information on the knowledge of the GPs about BZD and its potential for dependence; (ii) to study the frequency of their prescribing; and (iii) to examine different factors linked to their prescribing. The study was carried out using a combination of a personal interview and a self-administered questionnaire. A total of 68 doctors (88.3%) completed the questionnaire. The results show that the GPs have, in general, correct knowledge about the therapeutic indications for BZD prescribing, but are far less aware of their potential to induce dependence and how to manage withdrawal. The rate of prescribing seems to be high. Furthermore, the results of the external check of validity point out that doctors tend to underestimate the number of prescriptions. The majority of GPs express the need for alternative resources to BZD prescribing. No significant associations have been found between doctor's characteristics, such as postgraduate training and type of practice, and their knowledge about BZD and frequency of their prescribing. In our view, a more accurate knowledge about BZD and alternatives to its use, both factors closely linked to training, together with the availability of non-pharmacological resources, are likely to improve the quality of doctors prescribing habits, thus preventing risks such as dependence of BZD.

Benzodiazepines and addiction. Psychiatr Clin North Am 1993 Mar;16(1):75-86. Juergens SM, Virginia Mason Outpatient Chemical Dependency Program, Virginia Mason Clinic. Benzodiazepines are medications that are addicting--both in combination with other drugs and alone. The scope of the problem is thought to be wide, but it has not been well documented for unclear reasons. Pharmacologic dependence has been documented in virtually all long-term users. Adverse effects occur secondary to their use and these effects are often subtle, but significant. Various benzodiazepines present differences in reinforcement, withdrawal, and adverse effects. Diagnostic issues, withdrawal, and treatment issues are discussed.

Addolorato G; Balducci G; Capristo E; Attilia ML; Taggi F; Gasbarrini G. Gamma-hydrobutyric acid (GHB) in the treatment of alcohol withdrawal syndrome: A randomized comparative study versus benzodiazepine. Alcoholism: Clinical and Experimental Research 23(10): 1596-1604, 1999. (64 refs.) Background: Benzodiazepine has been shown to be one of the most effective class of drugs in the management of alcohol withdrawal syndrome (AWS). Gamma-hydroxybutyric acid (GHB) has recently been introduced in the treatment of alcohol problems, including AWS. At present there are no comparative studies between benzodiazepines and GHB in AWS treatment. The aim of the present randomized, controlled, single-blind study was to evaluate the efficacy and safety of GHB compared with diazepam in the treatment of AWS. Methods: Sixty alcoholics affected by AWS were enrolled in the study. Diazepam (0.5-0.75 mg/kg body weight for 6 days, tapering the dose 25% daily until day 10) was administered orally to 30 patients (25 males, 5 females; mean age 44.3 10.9 years); GHB (50 mg/kg body weight for 10 days) was administered orally to 30 patients (26 males, 4 females; mean age 41.7 10.4 years). The Clinical Institute Withdrawal Assessment for Alcohol-revised scale (CIWA-Ar) was used to evaluate the AWS physical symptoms. The State Anxiety Inventory test for current anxiety assessment and the Zung self-rating Depression Scale for current depression assessment were performed. Results: Eight patients (26.6%) in the diazepam group and 4 patients (13.3%) in the GHB group dropped out. Both treatments were effective in reducing AWS. No significant difference was found between the groups in CIWA-Ar total score at baseline and at the different times of observation. Considering the CIWA-Ar subscore and Zung scale, a significant reduction of anxiety on day 4 (p < 0.02), agitation on day 5 (p < 0.02) and time of recovery of depression on day 5 (p < 0.02) was observed in the GHB group with respect to the diazepam group. Drowsiness and vertigo developed after initial drug administration in the GHB (19.2%) and diazepam (36.4%) groups and quickly resolved in both groups. Conclusions: GHB is as effective in the management of AWS as benzodiazepine and it seems to be quicker in reducing anxiety, agitation, and depression. Both drugs are safe and well-tolerated in AWS management.

Anderson JF; McEwan KL. Utilization of common analgesic and anxiolytic medications by registered first nations residents of western Canada. Substance Use & Misuse 35(4): 601-616, 2000. (15 refs.) The study examined utilization of acetaminophen with codeine and benzodiazepine drugs among Non-Insured Health Benefits (NIHB) program registered First Nations residents in the four western provinces of Canada and sought preliminary indicators of factors influencing utilization. A small percentage of NIHB clients in the four western provinces were excessive users of acetaminophen with codeine and/or benzodiazepines, but overall utilization of these central nervous system drugs was moderate and within the bounds of non-First Nations population use examined in this study. The study also demonstrated that utilization of acetaminophen with codeine among NIHB claimants was inversely related to the stringency of provincial regulation.

Argyropoulos SV; Nutt DJ. The use of benzodiazepines in anxiety and other disorders. European Neuropsychopharmacology 9(Supplement): 407-412, 1999. (37 refs.) Benzodiazepines have come under scrutiny and attack over recent years because of their abuse liability, withdrawal reactions and development of tolerance. Consequently, practitioners worldwide are discouraged from prescribing them. While some of these risks may have been exaggerated, benzodiazepines remain a useful therapeutic tool, alone or in combination, in a number of psychiatric and medical conditions. Withholding such treatment may be unjustified and detrimental to the patients' health. Further, benzodiazepines have helped researchers in their attempts to elucidate the neurobiological mechanisms underlying anxiety. This, in return, leads to the development of new effective anxiolytic treatments, with fewer problems compared to the traditional benzodiazepine compounds. Such new agents are already available or at the closing stages of clinical trials.

Barrett AM; Walshe K; Kavanagh PV; McNamara SM; Moran C; Burdett J; Shattock AG. A comparison of five commercial immunoassays for the detection of flunitrazepam and other benzodiazepines in urine. Addiction Biology 4(1): 81-87, 1999. (14 refs.) Five commercially available immunoassay test kits (SYVA EMIT(R) d.a.u(TM), SYVA EMIT(R) II assay, Abbott FPLA, Cozart Auto-Lyte(R) and Roche Abuscreen(R) Online(TM), all used for the benzodiazepine group of drugs) were evaluated for their ability to detect flunitrazepam, its major urinary metabolite, 7-aminoflunitrazepam, and several other benzodiazepines at serial dilutions (final concentration 25-1000 ng/ml) in drug-free urine and in urines following oral administration of flunitrazepam (1-3 mg). For comparison, gas chromatography/mass spectrometry was used to measure urinary levels of 7-aminoflunitrazepam. Levels of drug detected in the study were compared with the cross-reactivities presented by the manufacturers for each individual kit. One to three mg doses of flunitrazepam were taken by volunteers and levels excreted in urine analysed over several hours. A positive response was obtained in several samples from volunteers who had taken 2 mg or 3 mg doses, but not a 1 mg dose. Thirty-five clinical samples from the individuals suspected of benzodiazepine abuse were also examined. The results were not consistent among the kits evaluated. We conclude that the test kits evaluated in this study do not detect flunitrazepam reliably due primarily to their poor sensitivities.

Bendtsen P; Hensing G; McKenzie L; Stridsman AK. Prescribing benzodiazepines: A critical incident study of a physician dilemma. Social Science and Medicine 49(4): 459-467, 1999. (34 refs.) Use of benzodiazepines has been discussed extensively both among the public and within the medical society. The aim of this study was to explore the quality of dilemmas experienced by physicians when prescribing benzodiazepines. A questionnaire was sent to 213 Swedish General Practitioners. The critical incident technique was chosen as an appropriate method for surveying professional experiences. Concern for the patient and threats to the integrity of the physician were common dilemmas. The physicians did not believe that the patients were telling the truth or did not trust the patients' ability to handle the medicine. The most frequent consequences of the dilemmas were worry about a disturbed relationship with patients indicating an uncertainty as to how to create a good relationship with them. The participants in the study were aware of the national guidelines for prescribing benzodiazepines, but due to insufficient time a prescription was often chosen as a way to handle the dilemmas. Improvement in the rational use of benzodiazepines is not achieved by the medical board making new rules but rather by offering physicians education in communication and negotiating skills as well as more time with the individual patient who is requesting benzodiazepines.

Bleich A; Gelkopf M; Schmidt V; Hayward R; Bodner G; Adelson M. Correlates of benzodiazepine abuse in methadone maintenance treatment. A 1 year prospective study in an Israeli clinic. Addiction 94(10): 1533-1540, 1999. (26 refs.) Aims. This study addressed the following questions for patients after 1 year of methadone maintenance treatment (MMT); (I) What are the demographic features and past history of drug use of benzodiazepine (BZD) abusers? (2) Do BZD abusers abuse more heroin, cocaine and/or cannabis and do they receive a higher methadone dosage level? (3) Do BZD abusers suffer more from hepatitis C (HCV) and do they have more HIV/HCV risk-taking behaviors than non-abusers? (4) Do BZD abusers have more psychopathology and more emotional distress than non- abusers? Design. All 148 patients who completed I year of MMT underwent random and twice-weekly observed urine analysis for various drugs of abuse, responded to self-report questionnaires (SCL-90-R; POMS; HIV/HCV risk-taking behaviors), interviews (ASI) and underwent testing for hepatitis C. Abuse in this study is defined as any use during the 12th month of treatment. Findings. After I year of MMT, more BZD abusers (n = 63) were single, had spent time in prison, were unemployed and had at least one parent with an addiction problem or mental illness in comparison to non-abusers (n = 85). They had started using heroin and cocaine earlier and currently abused more cocaine, heroin and cannabis. They had significantly more psychopathology and negative mood. They had significantly more HCV and reported more HIV/HCV risk-taking behavior. Implications. We suggest that this group of patients is in need of more intensive pharmacological and psychological treatment.

Briesacher BA; Stuart B; Peluso R. Drug use and prescribing problems in the community-dwelling elderly: A study of three state Medicaid programs. Clinical Therapeutics 21(12): 2156-2172, 1999. (18 refs.) This paper describes a study of drug use and drug-related problems in community-dwelling elderly (greater than or equal to 65 years) Medicaid recipients in Maryland, Iowa, and Washington from 1989 through 1996. A claim-by-claim review of Medicaid prescriptions was conducted to detect 5 types of prescribing problems (dose, duration of therapy, duplicative therapy, drug-drug interactions, and contraindications or initial therapy). The study examined 8 drug categories: angiotensin-converting enzyme (ACE) inhibitors, antidepressant agents, antipsychotic agents, benzodiazepines, calcium channel blockers, digoxin, histamine(2)-receptor antagonists, and nonsteroidal anti-inflammatory drugs. The total number of persons with prescriptions in any of the 8 drug classes increased over the 8- year period, with the greatest growth in ACE inhibitors. Mean annual drug use per person declined in Maryland but increased in Washington and Iowa. Despite increasing use, the overall incidence of prescribing problems fell dramatically in all 3 states, particularly for dose- and duration-related criteria. Except in the area of drug-drug interactions, this elderly population was less likely to have received a prescription falling outside commonly accepted drug utilization review criteria for 8 major drug classes in 1996 than in 1989.

Bursztajn HJ. Melatonin therapy: From benzodiazepine-dependent insomnia to authenticity and autonomy. (editorial). Archives of Internal Medicine 159(20): 2393-2395, 1999. (21 refs.)

Busto UE; Bremner KE; Knight K; terBrugge K; Sellers EM. Long-term benzodiazepine therapy does not result in brain abnormalities. Journal of Clinical Psychopharmacology 20(1): 2-6, 2000. (25 refs.) Studies on the association between long-term benzodiazepine use and brain abnormalities have yielded conflicting results. The computed tomographic (CT) scans of 20 long-term users of benzodiazepine (65% men; mean age a SD [range], 42 12.1 years [23-59]; mean daily benzodiazepine dose [diazepam equivalents], 19.5 16.2 mg [2.5-70]; mean cumulative benzodiazepine exposure, 55.2 g [1.8-198]) were compared with 36 age-(3 years) and sex-matched controls. Controls were prospectively recruited from 96 patients attending a neurology clinic and were interviewed to screen for alcohol and substance use disorders and other conditions possibly leading to brain atrophy. Three neuroradiologists blindly assessed each CT scan for atrophy and measured ventricles (V1, V2, V3), sulci, fissures, cisterns, and folia, Reliability among observers ranged from 0.92 to <0.1, in which case deleting one observer increased all reliabilities to >0.45. No difference in atrophy was found between benzodiazepine users and controls. V1 measures were significantly higher for benzodiazepine users than for controls (mean a SD, 12.1 1.3 vs. 11.1 2.0; p = 0.02), but measures of third and fourth largest sulci were significantly higher in controls than in benzodiazepine users, Right third and fourth largest sulci (mean SD), respectively, were the following: controls, 0.72 0.4 and 0.74 0.7; benzodiazepine users, 0.51 0.3 and 0.46 0.3 (p < 0.02), Left third and fourth largest sulci, respectively, were the following: controls, 0.77 0.6 and 0.65 0.3; benzodiazepine users, 0.53 0.3 and 0.5 0.3 (p < 0.02), Long-term benzodiazepine therapy does not result in brain abnormalities that can be demonstrated on CT scans.

Campbell AJ; Robertson MC; Gardner MM; Norton RN; Buchner DM. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: A randomized, controlled trial. Journal of the American Geriatrics Society 47(7): 850-853, 1999. (23 refs.) Objective: To assess the effectiveness of psychotropic medication withdrawal and a home-based exercise program in reducing falls in older people. DESIGN: A randomized controlled trial with a two by two factorial design. Setting: Seventeen general practices in Dunedin, New Zealand. Participants: Women and men aged 65 years registered with a general practitioner and currently taking psychotropic medication (n = 93). Interventions: Two interventions: (1) gradual withdrawal of psychotropic medication versus continuing to take psychotropic medication (double blind) and (2) a home-based exercise program versus no exercise program (single blind). Measurements: Number of falls and falls risk during 44 weeks of follow-up. Analysis was on an intent to treat basis. Results: After 44 weeks, the relative hazard for falls in the medication withdrawal group compared with the group taking their original medication was .34 (95% CI, .16-.74). The risk of falling for the exercise program group compared with those not receiving the exercise program was not significantly reduced. Conclusions: Withdrawal of psychotropic medication significantly reduced the risk of falling, but permanent withdrawal is very difficult to achieve.

Carrigan TD; Field H; Illingworth RN; Gaffney P; Hamer DW. Toxicological screening in trauma. Journal of Accident & Emergency Medicine 17(1): 33-37, 2000. (20 refs.) Objectives-To determine the prevalence and patterns of alcohol and drug use in patients with major trauma. Methods-Consecutive trauma patient enrollment, 24 hours a day, was envisaged with anonymised patient data on gender, age band, and mechanism of injury collected. The study group had surplus plasma quantitatively analysed for ethanol concentration, and urine samples were initially screened, via immunoassay, for opiates, cannabinoids, amphetamines, benzodiazepines, cocaine, and methadone. Confirmation and specification of individual positive results was then performed using thin layer or gas-liquid chromatography. Drugs of treatment given in the resuscitation room, if subsequently detected in the urine samples, were excluded from the final results. Results-There were 116 eligible trauma patients assessed and treated in the resuscitation room over a six month period, of which 93 (80%) were enrolled. Altogether 27% of this trauma population had plasma ethanol concentrations greater than 80 mg/dl. There was a significantly higher prevalence of alcohol intoxication in the group not involved in a road traffic accident (RTA) compared with the group who were involved in a RTA. Initial screening of urine for drugs revealed a prevalence of 51%. After 12 exclusions due to iatrogenic administration of opiates, the final confirmed prevalence was 35% in this trauma population. The individual drug prevalence was 13% for cannabinoids, 11% for codeine, 8% for morphine, 6% for amphetamine, 6% for benzodiazepines, 3% for cocaine, 1% for dihydrocodeine, and 1% for methadone. Conclusions-There is a notable prevalence of drug and alcohol use in this British accident and emergency trauma population. A significantly higher prevalence for alcohol intoxication was found in the non-RTA group compared with the RTA group. The patterns of drug usage detected reflect local influences and less cocaine use is seen compared with American studies. The association between alcohol, drugs, and trauma, together with ethically acceptable methods of screening, are discussed.

Christophersen AS; Ceder G; Kristinsson J; Lillsunde P; Steentoft A. Drugged driving in the Nordic countries: A comparative study between five countries. Forensic Science International 106(3): 173-190, 1999. (39 refs.) The purpose of this study was to compare whether the high incidence of drugged driving in Norway was different to that in the other Nordic countries. All blood samples received by Nordic forensic institutes during one week in 1996, from drivers suspected by the police of driving under the influence (Denmark: n=255, Finland: n=270, Iceland: n=40, Sweden: n=86, Norway: n=149), were analysed for alcohol and drugs (benzodiazepines, cannabinoids, amphetamines, cocaine, opiates and a number of antidepressant drugs) independent of the primary suspicion, and using the same analytical cut-off levels at the different institutes. The primary suspicion was directed towards drugs in more than 40% of the Norwegian cases, drugs were detected in more than 70% of these samples. In only 0-3% of the cases from Denmark, Finland and Iceland, were drugs suspected, while the corresponding frequency for Sweden was 17%. However, evidential breath analyses were used for about three-quarters of the Swedish drivers suspected to be influenced by alcohol. Blood alcohol concentrations (BAC's) below the legal limits were found in 32, 18 and 2% of the Norwegian, Icelandic and Finnish cases, respectively (BAC<0.05%), in 10% of the Danish cases (BAC<0.08%) and in 20% of the Swedish cases (BAC<0.02%). Drugs were most frequently found in the Norwegian and Swedish cases with no alcohol (80-83%). Similar frequencies of drugs in samples with BAC's above the legal limits (19- 22%), were obtained for all countries. Benzodiazepines, tetrahydrocannabinol and amphetamine represented the most commonly detected drugs. Our results show that differences between Norway and other Nordic countries with regard to drugs and driving, are connected to the selection criteria made by the police and with more focus on drugged driving in Norway.

Chutuape MA; Silverman K; Stitzer M. Contingent reinforcement sustains post-detoxification abstinence from multiple drugs: A preliminary study with methadone patients. Drug and Alcohol Dependence 54(1): 69-81, 1999. (52 refs.) This study examined the efficacy of a urinalysis-based contingency management program for preventing relapse to abused drugs following a brief residential detoxification. Fourteen methadone maintenance patients who were chronic benzodiazepine users were enrolled in a 7- day inpatient benzodiazepine detoxification and randomly assigned to receive Contingency Management (N = 7) or Standard Care (N = 7) therapy upon return to outpatient methadone treatment. In the Contingency Management condition, a methadone take-home dose or a US $25 voucher (patient's choice) could be earned for each urine sample submitted on a Monday, Wednesday or Friday that was free of opiates, cocaine and benzodiazepines. Data analysis and interpretation focused on within-group post-hoc differences due to group differences on employment and legal status, potentially confounding baseline variables. Repeated measures analysis of variance showed that Contingency Management patients submitted significantly more drug- free urine samples during the intervention compared to pre- detoxification (p < 0.01), whereas no significance changes were observed from pre- to post-detoxification in the Standard Care patients. Employment and legal status of patients may have facilitated response to contingency management procedures, but did not prevent relapse when contingency management procedures were withdrawn. Overall, these preliminary results suggest that abstinence-based contingency management is a promising strategy for preventing relapse to multiple drugs of abuse in a subset of methadone maintenance patients when abstinence has been initiated through brief inpatient treatment.

Collins RL; Gollnisch G; Morsheimer ET. Substance use among a regional sample of female nurses. Drug and Alcohol Dependence 55(1/2): 145-155, 1999. (31 refs.) We assessed the prevalence of licit (e.g. alcohol) and illicit (e.g. cocaine) drug use, as well as prescription (e.g. tranquillizers) and over-the-counter medications (e.g. analgesics), in a regional sample of female nurses. Surveys were mailed to a random sample of 4000 nurses in Western New York. The survey focused on lifetime and current use of substances, negative consequences of alcohol consumption and dependence. Three mailings resulted in a return of 2400 (60%) surveys, of which 1951 (49%) were usable. We examined lifetime and current use in each of the four classes of substances in the context of nursing related-factors (e.g. type of nurse, nursing specialty, work setting) and demographic characteristics (e.g. age, marital status). There were significant differences within each of the different groupings. Lifetime experience of negative consequences were relatively rare and few nurses reported dependence on substances other than tobacco and caffeine.

Darke S; Ross J. Heroin-related deaths in South Western Sydney, Australia, 1992-96. Drug and Alcohol Review 18(1): 39-45, 1999. (27 refs.) The coronial files of all 176 heroin-related fatalities that occurred in the South Western Sydney region over the period 1992-96 were inspected. Heroin-related fatalities rose from 20 in 1992 to 54 in 1996. The mean age of cases was 29.9 years, 89% were male and 92% were classified as dependent on heroin at the time of death. There was a significant increase over the study period in the proportion of fatalities that occurred in public settings. No intervention occurred in 71% of cases. Morphine concentrations rose over the study period from 0.16 mg/l in 1992 to 0.37 mg/l in 1996.The majority of cases involved heroin in combination with other drugs: alcohol (40%), benzodiazepines (30%) and antidepressants (9%). In only a third of cases was morphine the sole drug detected.

Darke S; Ross J. Heroin-related deaths in regional New South Wales, 1992-96. Drug and Alcohol Review 19(1): 35-40, 2000. (9 refs.) The coronial files of all 188 heroin-related fatalities that occurred in regional New South Wales between 1992 and 1996 were inspected. There was a significant increase in fatalities, rising from 23 deaths in 1992 to 53 during 1996. The regions in which the most deaths occurred were Wollongong/Illawarra (43 deaths), Newcastle/Hunter (35) and the far north coast (25). The mean age of cases was 31.5 years and 83% were male, and there were no significant trends in demographic characteristics of cases over the study period. The median blood morphine concentration of cases was 0.39 mg/l (range 0.05-4.5 mg/l). Alcohol was detected in 50% of cases and benzodiazepines in 29%. There were large regional variations in toxicology results, with median blood morphine concentrations ranging from 0.25 mg/l among south coast cases to 0.56 mg/l in mid-western New South Wales. Compared to Sydney metropolitan cases, regional cases had a higher median blood morphine concentration, were less likely to have cocaine detected, were more likely to have died in a home environment and to have been born in Australia.

de Las Cuevas C; Sanz E; de la Fuente JA; Cabrera C; Mateos A. Prescribed daily doses and 'risk factors' associated with the use of benzodiazepines in primary care. Pharmacoepidemiology and Drug Safety 8(3): 207-216, 1999. (44 refs.) Objective - To assess the extent, characteristics and determinants of benzodiazepine prescription in outpatient Primary Health Care. Methods - A clinical audit of a stratified random sample of Primary Health Care Centres in the seven islands and 1.6 million inhabitants region of 'Canarias' in Spain was carried out. From those centres, a random sample of 1045 clinical records was reviewed and information on diagnosis, prescription and prescribed dosages was collected in a structured questionnaire. A multivariate logistic regression analysis was performed in order to determine the 'risk: factors' for the use of benzodiazepines. Results - Benzodiazepine prescription was recorded in 23.4% of all clinical records; 87.7% of these were for benzodiazepines classified as anxiolytics (N05B) and 12.3% for hypnotics (N05C2). Benzodiazepine prescription was more common for women, elderly, widowed, divorced, low educational background, housewives and retired people. Using multivariate logistic regression, the probability of benzodiazepine prescription was found to be closely related to age, gender and employment status, but not with educational level. Prescribed Daily Doses were lower than Defined Daily Doses (DDD) in 77.1% of all anxiolytic prescriptions, but were in agreement with DDD in 90% of hypnotic prescriptions. The duration of treatment recorded in the clinical records was 25 21 months, with a range of 1 and 144 months. General Practitioners were responsible for 67% of all benzodiazepine prescription. Anxiolytics were prescribed as a single daily dose in 57% of the cases, and only 'at supper' in 48.6%. Conclusion - In the general population attending Primary Health Care Centres of the Canary Islands Health System the prescription of benzodiazepines is higher for women and the elderly, and the most common use is chronic, with a duration of over 2 years in most cases. Anxiolytics are prescribed in doses which are much lower than those used as DDD and were used only 'at night' in almost half of the cases. This could represent an overlapping of the indications with hypnotics, and explain part of the huge difference in the use of anxiolytics in Spain compared with other figures in Europe. This fact must also be taken into account when making inferences of benzodiazepine use from sales statistics, which are very imprecise measures of drug use.

De las Cuevas C; Sanz EJ; De la Fuente JA; Padilla J; Berenguer JC. The Severity of Dependence Scale (SDS) as screening test for benzodiazepine dependence: SDS validation study. Addiction 95(2): 245-250, 2000. (19 refs.) Aims. To assess the validity of the Severity of Dependence Scale (SDS) as a screening test to detect benzodiazepine dependence in regular benzodiazepine users. Method. One hundred regular benzodiazepine users, recruited from neurotic benzodiazepine users attending the Mental Health Outpatient Services of the Canary Islands Health Service, were administered the SDS and responses were compared with the Composite International Diagnostic Interview (CIDI) diagnosis of benzodiazepine dependence. Receiver Operating Characteristic (ROC) analysis was used to determine which cut-off score on SDS allowed the best trade-off between sensitivity and specificity. Results. SDS was shown to have high diagnostic utility, and a score higher than six on the scale appears to be an appropriate threshold for problematic benzodiazepine use. The SDS had a specificity of 94.2% and a sensitivity of 97.9%, and the area under the curve was of 0.991. Conclusion. The SDS was found to be a valid brief self-report questionnaire for the assessment of benzodiazepine dependence in patients using benzodiazepines.

Deighan CJ; Wong KM; McLaughlin KJ; Harden P. Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse. QJM. Quarterly Journal of Medicine 93(1): 29-33, 2000. (134 refs.) Rhabdomyolysis is a common cause of acute renal failure (ARF) associated with drug misuse. Abuse of the gel formulation of temazepam has been a particular problem in the West of Scotland. We performed a retrospective review of dialysis-dependent ARF from rhabdomyolysis and drug misuse in the West of Scotland, 1986-1997. We identified 76 patients, of whom 87% were male. Seventeen cases occurred in the first 6 years, compared with 59 in the subsequent 6 years. Median age was 32. Thirty cases followed intravenous drug misuse, 46 followed oral drug misuse. The substances most frequently misused were alcohol (54%), heroin (24%) and parenteral temazepam (17%). The temazepam cases all followed the introduction of the gel formulation. Three out of 4 patients requiring limb amputation had injected temazepam. Of intravenous drug misusers tested, 72% were hepatitis-C-positive. Some 43% of patients had deprivation scores in the worst category. ARF due to rhabdomyolysis from substance misuse is increasing in our area. Alcohol is frequently responsible. The introduction of the gel formulation of temazepam has contributed to the increase. Those at risk in this study were young, male, had a high incidence of hepatitis C and lived in the most deprived areas.

Elian AA. Detection of low levels of flunitrazepam and its metabolites in blood and bloodstains. Forensic Science International 101(2): 107-111, 1999. Detection of low levels of flunitrazepam and its metabolites was developed using solid-phase extraction to isolate the drugs from whole liquid blood and dried bloodstains, with subsequent derivatization with pentafluoropropionic anhydride (PFPA) followed by N-(tert-butyldimethylsilyl)-N-methyl-trifluoroacetamide (MTBSTFA) with 1% TBDMSCI. Analysis was confirmed by gas chromatography/mass spectroscopy using select ion monitoring (sim) in electron impact mode. The limit of detection of this procedure using 1 ml of blood was determined to be 0.1 mu g/dl.

ElSohly MA; Salamone SJ. Prevalence of drugs used in cases of alleged sexual assault. Journal of Analytical Toxicology 23(3): 141-146, 1999. (24 refs.) In recent years, there has been an increase in the number of reports in the U.S. of the use of drugs, often in conjunction with alcohol, to commit sexual assault. A study was undertaken to assess the prevalence of drug use in sexual assault cases in which substances are suspected of being involved. Law enforcement agencies, emergency rooms, and rape crisis centers across the U.S. were offered the opportunity to submit urine samples collected from victims of alleged sexual assault, where drug use was suspected, for analysis of alcohol and drugs which may be associated with sexual assault. Each sample was tested by immunoassay for amphetamines, barbiturates, benzodiazepines, cocaine metabolite (benzoylecgonine), cannabinoids, methaqualone, opiates, phencyclidine and propoxyphene. The positive screen results were confirmed by gas chromatography-mass spectroscopy (GC-MS). In addition, each sample was tested for flunitrazepam metabolites and gamma-hydroxybutyrate (GHB) by GC-MS and for ethanol by gas chromatography-flame ionization detection (GC-FID). Over a 26-month period, 1179 samples were collected and analyzed from 49 states, Puerto Rico, and the District of Columbia. The states sending the most samples were California (183), Texas (119), Florida (61), Pennsylvania (61), New York (61), Minnesota (50), Illinois (47), Indiana (44), Michigan (40), Maryland (37), Virginia (32), and Massachusetts (31). Four-hundred sixty eight of the samples were found negative for all the substances tested; 451 were positive for ethanol, 218 for cannabinoids, 97 for benzoylecgonine, 97 for benzodiazepines, 51 for amphetamines, 48 for GHB, 25 for opiates, 17 for propoxyphene, and 12 for barbiturates. There were no samples identified as positive for phencyclidine or methaqualone. In addition, 35% of the drug-positive samples contained multiple drugs. This study indicates that, with respect to alleged sexual assault cases, the prevalence of ethanol is very high, followed by cannabinoids, cocaine, benzodiazepines, amphetamines, and GHB. Although only a couple of substances have been implicated with sexual assault, this study has shown that almost 20 different substances have been associated with this crime. This study also raises the concern of illicit and licit drug use in sexual assault cases and suggests the need to test for a range of drugs in these cases. It also highlights the need to test for GHB, which is not generally tested for in a normal toxicology screen.

Fountain J; Griffiths P; Farrell M; Gossop M; Strang J. Benzodiazepines in polydrug-using repertoires: The impact of the decreased availability of temazepam gel-filled capsules. Drugs: Education, Prevention and Policy 6(1): 61-69, 1999. (16 refs.) Reporting on a research project which used a qualitative methodology, this paper examines the role benzodiazepines played in the polydrug-using repertoires of a sample of long-term, polydrug-using, opiate addicts. The impact of a decrease in the availability of temazepam gel-filled capsules is monitored, showing the effect on both the illicit market for diverted prescription drugs and on the drug-using patterns of those who bought benzodiazepines there. The paper illustrates the complex factors which affect the substances polydrug users include in, or exclude from, their drug-using repertoires, and is an example of how measures aimed at harm reduction can have both positive and negative implications. It is argued that such measures must be evaluated in the context of their impact on a series of dynamic, interrelated changes.

Frank B; Galea J. Current drug use trends in New York City. Community Epidemiology Work Group, eds. Epidemiologic Trends in Drug Abuse. Volume II: Proceedings. December 1998. Bethesda MD: National Institute on Drug Abuse, 1999. pp. 184-198. (0 refs.) Cocaine and heroin continue to dominate the drug scene in New York City, albeit at relatively stable levels; marijuana trends continue to show dramatic increases. There may be renewed interest in powder cocaine, but crack continues to account for more than 80 percent of cocaine arrests and smoking is reported as the primary mode of use by more than 70 percent of treatment admissions with cocaine as the primary drug of abuse. Snorting heroin continues to increase, with about 59 percent of primary heroin admissions to treatment reporting this mode of use. The DEA identifies three international source areas for the heroin coming into New York City; the purity of retail-level heroin remains higher than 60 percent. "Speedballing" -- the use of heroin and cocaine together -- may be increasing, according to field workers. Cannabis arrests continue to mount: they may surpass cocaine arrests and heroin arrests by the end of 1998. The selling of various psychoactive prescription drugs on the streets continues, with alprazolam (Xanax) becoming more available and diazepam less available. While methamphetamine activity remains at low levels, PCP and LSD are at moderate levels of availability. Injecting drug use continues to be the major risk factor for AIDS in New York City.

Gambi F; Conti CMV; Grimaldi MR; Giampietro L; De Berardis D; Ferro FM. Flunitrazepam: A benzodiazepine most used among drug abusers. (review). International Journal of Immunopathology and Pharmacology 12(3): 157-159, 1999. (16 refs.) Flunitrazepam (FZ) is a sedative/hypnotic nitro-benzodiazepine. This drug has been accepted by both patients and physicians and in the last 20 years flunitrazepam has been included and studied in many clinical trials so, in many countries, flunitrazepam is one of the most prescribed hypnotic. Since 1980 it has been found that FZ began to be a popular drug among drug abusers all over the word, However, little is known about the difference between Fz and other benzodiazepines in capacity to produce physiologic dependence or in ability to produce drug taking or drug seeking behaviour. Flunitrazepam has little risk of abuse by the vast majority of patients; however when the drug is taken i.v. or intranasally, its effect is much faster and risk of abuse is much greater. In this report we examine the reasons why some populations of drug abusers prefer flunitrazepam over the other benzodiazepines.

Garne E; Bergman U. Benzodiazepine use in pregnancy and major malformations or oral clefts: Induced abortions should be included. (letter). British Medical Journal 319(7214): 918-918, 1999. (2 refs.)

Gatzonis SD; Angelopoulos EK; Daskalopoulou EG; Mantouvalos V; Chioni A; Zournas C; Siafakas A. Convulsive status epilepticus following abrupt high-dose benzodiazepine discontinuation. Drug and Alcohol Dependence 59(1): 95-97, 2000. (11 refs.) The misuse of benzodiazepines (BNZ)s may result in serious side effects. Three cases of convulsive status epilepticus (CSE) following abrupt discontinuation of long-term use of 25 mg of lorazepam in one patient and more than 20 mg of flunitrazepam in two patients are presented; they were non-epileptics and free of other high-risk factors for seizures. A favorable outcome for all three cases was noted. They remain free of seizures without antiepileptic treatment. Nevertheless, because of the extensive use of benzodiazepines, such rare high-risk side effects must be emphasized.

Gelkopf M; Bleich A; Hayward R; Bodner G; Adelson M. Characteristics of benzodiazepine abuse in methadone maintenance treatment patients: A 1 year prospective study in an Israeli clinic. Drug and Alcohol Dependence 55(1/2): 63-68, 1999. (36 refs.) We aimed to study the prevalence patterns and course of benzodiazepine (BZD) abuse in an Israeli methadone maintenance (MMT) clinic using repeated random observed urine analysis as well as self- report data. Lifetime and current prevalence of BZD abuse were found in 66.3 and 50.8% patients, respectively. It was found that 44.6% of patients who abused BZDs during their first month of treatment ceased to do so after 1 year, while 27.4% who had not abused BZDs at the beginning of MMT did so after I year in treatment. Flunitrazepam was the most commonly abused BZD (92.9%), followed by diazepam (54.3%) and oxazepam (38.6%). Most of the patients swallowed BZDs (92.8%), 42.9% also smoked or snorted them while 8.6% injected BZDs intravenously. BZDs were used as self-medication for alleviating emotional problems rather than for recreational or other reasons. We conclude that BZD abuse is a significant clinical problem in heroin addicts both before entering and during MMT. MMT may have a positive as well as a negative influence on BZD abuse with the former being more prevalent.

Grad R; Tamblyn R; Holbrook AM; Hurley J; Feightner J; Gayton D. Risk of a new benzodiazepine prescription in relation to recent hospitalization. Journal of the American Geriatrics Society 47(2): 184-188, 1999. (37 refs.) Objective: To determine if recent hospital admission was associated with new outpatient prescribing of benzodiazepines among community-dwelling older people. Design: Nested case-control study using administrative data sets of the provincial health insurance board. Setting: Province of Quebec. Participantss: Cases were 4127 community-dwelling older people who were newly dispensed a benzodiazepine during an g-month period in 1990. Controls were 16,486 community-dwelling older people who were dispensed any drug (except a benzodiazepine) on the same day as the case-defining index prescription. Exposure and Outcome Measures: Admission to an acute care hospital within a 30-day period before a new dispensing of a benzodiazepine. Other variables measured were patient age, gender, number of ambulatory physician visits, healthcare region, Chronic Disease Score (CDS), and use of drugs for depression and psychosis. Results: Cases were more than three times as likely as controls to have been hospitalized in the 30-day period before the index date (adjusted odds ratio (OR) 3.09; 95% CI, 2.78-3.45). The use of prescription drugs for physical health problems modified this association in that cases who used more medication were also more likely to receive a new benzodiazepine prescription following a recent hospital admission (adjusted OR 4.09; 95% CI, 3.59-4.65 when the CDS was equal to 5 vs adjusted OR 1.96; 95% CI, 1.66-2.31 when the CDS was equal to 0). Conclusions: Recent hospitalization confers an increased risk of a new outpatient benzodiazepine prescription among community-dwelling older people in Quebec. Those who use more medication, and who may be more vulnerable to drug-related adverse events, are more likely to be newly dispensed a benzodiazepine following a recent, acute-care hospital admission.

Graham K; Wilsnack SC. The relationship between alcohol problems and use of tranquilizing drugs: Longitudinal patterns among American. Addictive Behaviors 25(1): 13-28, 2000. (30 refs.) A previous community study of older adults (Graham et al., 1996) indicated a relationship between alcohol problems and use of tranquilizing drugs despite no relationship between alcohol consumption and tranquilizer use. The present paper explores this issue further using longitudinal data from a representative sample of American women. The results replicated previous findings of a significant relationship between alcohol problems and tranquilizer use that was unrelated to alcohol consumption. Analyses of longitudinal patterns indicated that alcohol problems in 1981 predicted subsequent use of tranquilizing drugs and that this relationship may be moderated by anxiety, with the relationship being strongest for respondents who reported few or no problems with anxiety. The results indicated no support for the relationship being due to: a pharmacological interaction of alcohol with tranquilizing drugs; use of tranquilizing drugs precipitating alcohol problems: or depression, anxiety, poor health or childhood sexual abuse being common causes of both alcohol problems and tranquilizer use. The link between alcohol problems and use of tranquilizing drugs needs to be investigated further to increase understanding of addictive behaviors.

Gravel NR; Searle NR; Sahab PG; Carrier M. Sedation in critically ill patients: Practical recommendations. CNS Drugs 11(1): 9-22, 1999. (61 refs.) Provision of anxiolysis and analgesia in critically ill patients is mandatory to improve patient comfort without undue autonomic or haemodynamic adverse effects, The assessment of the level of sedation in the intensive care unit (ICU) by means of scoring systems is important because both undersedation and oversedation can be counterproductive, Scoring systems, such as the Ramsay Sedation Score or the Modified Observer's Assessment of Alertness/Sedation Scale, offer an accurate means of communicating clinical information and monitoring clinical progress, Understanding how the pharmacokinetic and pharmacodynamic profiles of sedative and analgesic agents are altered in critically ill patients is essential for administering effective care, Midazolam and lorazepam are commonly used to provide anxiolysis and amnesia, Although there are variations in morphine metabolism and/or excretion in certain disease states, it remains the opioid of choice for critically ill patients, Because of its unique pharmacokinetic properties, remifentanil may eventually prove to be an interesting alternative. Propofol possesses many characteristics of the ideal sedative agent: rapid onset of effect, easy titration, unaltered pharmacokinetics in hepatic and renal dysfunction, and rapid recovery after prolonged infusion. Conditions most likely encountered in the ICU are reviewed and practical recommendations are provided. Sedation in patients with multiple organ failure raises several interesting problems regarding distribution volumes, plasma protein binding, metabolic rate, tissue perfusion, drug excretion and requirement for prolonged sedation. Weaning from prolonged sedation can be difficult and may reveal drug dependency. The use of propofol can case the transition from long term benzodiazepine use. Patients with respiratory failure are a special group in whom propofol seems to have a favourable profile. Unless absolutely necessary, neuromuscular blocking agents should be avoided. If these agents must be used, it is incumbent to provide appropriate sedation and monitor the neuromuscular junction with a peripheral nerve stimulator. Opioid drugs should be used sparingly. Compared with other medical conditions, sedation post-cardiac surgery has received a lot of attention. Propofol or midazolam in association with morphine are effective and well tolerated. Both can be use for short term sedation without jeopardising early tracheal extubation.

Groenewegen PP; Leufkens HG; Spreeuwenberg P; Worm W. Neighbourhood characteristics and use of benzodiazepines in The Netherlands. Social Science and Medicine 48(12): 1701-1711, 1999. (43 refs.) This paper analyses the relationship between individual and neighbourhood characteristics and the use of benzodiazepines within a Dutch city. It is hypothesized that the proportion of users is lower in more socially integrated and less deprived neighbourhoods. Hypotheses have been tested by using multi-level analysis to distinguish between composition and context effects. Age and gender have a clear relation to the use of benzodiazepines and neighbourhood differences in the proportion of users are partly the effect of population composition by age and gender. The proportion of users is higher in neighbourhoods with a higher percentage of one-parent families, with a lower percentage of social rented housing and with a larger number of rooms per person. The strength of the relation between age and use is influenced by neighbourhood characteristics. Neighbourhood variation in the amount used only depends on population composition.

Hajak G. A comparative assessment of the risks and benefits of zopiclone: A review of 15 years' clinical experience. (review). Drug Safety 21(6): 457-469, 1999. (91 refs.) Zopiclone is a cyclopyrrolone hypnosedative that is chemically unrelated to the benzodiazepines but nevertheless potentiates gamma-aminobutyric acid-mediated neuronal inhibition, and has demonstrated proven efficacy and good tolerability in the treatment of insomnia over 15 years of use. Zopiclone is indicated for short term use, and should not be prescribed for more than 4 weeks. This review compares the efficacy of zopiclone with that of a number of commonly used short-, medium- and long-acting benzodiazepines. Zopiclone at dosages of 7.5 mg/day has demonstrated efficacy equivalent and in some cases greater to that of flurazepam 30 mg/day, nitrazepam 5 mg/day, flunitrazepam 1 to 2 mg/day, temazepam 20 mg/day, triazolam 0.125 to 0.5 mg/day and midazolam 15 mg/day. Zopiclone-treated patients reported themselves to be less impaired by daytime sedation than patients treated with the medium- and long- acting hypnosedatives flurazepam, nitrazepam and flunitrazepam. Zopiclone and temazepam showed similar effects on daytime behaviour while zopiclone appeared to have somewhat better effects on daytime well-being than the short-acting triazolam and midazolam, There has been no clinical comparison with the frequently used medium-acting benzodiazepines lormetazepam and brotizolam and the imidazopyridine hypnosedative zolpidem. Data from clinical trials, pooled analyses and postmarketing surveillance including over 30 000 patients showed that with the exception of bitter taste (reported by <10% of zopiclone recipients), the tolerability profile of zopiclone is similar to that of placebo. Clinical trials found no evidence for significant rebound insomnia and indicated that the risk of withdrawal reactions with therapeutic doses of zopiclone is very low. In addition, to date, dependency appears very low, although abuse potential should be considered following a history of addiction or psychiatric illness. Evaluation of the accumulated evidence from over 2.5 billion units dispensed in more than 30 countries indicates that zopiclone is effective, well tolerated and an excellent alternative to benzodiazepines in the short term treatment of insomnia.

Hatzitaskos P; Soldatos CR; Kokkevi A; Stefanis CN. Substance abuse patterns and their association with psychopathology and type of hostility in male patients with borderline and antisocial personality disorder. Comprehensive Psychiatry 40(4): 278-282, 1999. (31 refs.) The aim of this study was to investigate the prevalence of substance use disorder in young adult patients with borderline personality disorder (BPD) and antisocial personality disorder (APD) and to ascertain the specific substances each of these groups choose to abuse. An additional aim was to assess whether alcohol and drug abuse in the patients related to their psychopathology and hostility. The study subjects were 41 hospitalized patients with BPD and 44 hospitalized patients with APD. The diagnoses of personality disorders and substance use disorders were made using DSM-III criteria. Psychopathology patterns were assessed using the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, and State- Trait Anxiety inventory Hostility was assessed using the Hostility and Direction of Hostility Questionnaire. Abuse of one or more substances was reported by 76% of BPD patients and 95% of APD patients. There was no difference between the two groups in terms of alcohol abuse, but certain substances (such as benzodiazepines, anticholinergics, cannabis, and opioids) were abused more than twice as often by APD patients versus BPD patients. APD patients were more likely than BPD patients to be multiusers. In BPD patients, the number of substances abused showed a negative association with depression, while in APD patients it was positively related to state anxiety. In both patient groups, there was no correlation of the number of abused substances with the degree of extroverted or introverted hostility.

Hindmarch I; Brinkmann R. Trends in the use of alcohol and other drugs in cases of sexual assault. Human Psychopharmacology 14(4): 225-231, 1999. (37 refs.) Recent media coverage has raised awareness of the involvement of drugs, both licit and illicit, in the crime of 'date' or 'acquaintance' rape. The term 'date rape drug' has been coined and has been used to label a few specific drugs because of their alleged properties. These include flunitrazepam (Rohypnol), gamma hydroxybutyrate (GHB) and ketamine. Concerns over reports of flunitrazepam in connection with 'date rape' led to action by the manufacturer of Rohypnol (flunitrazepam) F. Hoffman-La Roche Ltd. who undertook an educational campaign warning of the dangers of drug- assisted sexual assault, and changed their drug's formulation internationally to prevent its clandestine use. Despite the media interest, there has been little evidence and no systematic investigation to date of the incidence of drug use in the crime of sexual assault. The present study, from the USA, was therefore instigated to assess the extent to which different drugs were present in the urinalysis of samples supplied by victims of rape where drugs were allegedly involved. The study was so designed as to examine any changes over time in the patterns of drug use in sexual assault. Between June 1996 and May 1998, 1033 samples were tested. Nearly 20 different substances were detected among the 611 specimens that tested positive. Of these, 382 (37 per cent of all specimens) were positive for alcohol and 191 (18.5 per cent) were positive for cannabinoids. GHB was detected in 4.4 per cent of samples. Only six (< 0.6 per cent) specimens showed evidence of flunitrazepam, and four of those contained other substances including cocaine, alcohol and/or morphine. Thus, only 0.2 per cent of all samples were positive for flunitrazepam alone. These data clearly indicate that there is no evidence of widespread misuse of flunitrazepam in sexual assault. Alcohol remains the substance most frequently associated with this type of crime.

Holbrook AM; Crowther R; Lotter A; Cheng CC; King D. Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. Canadian Medical Association Journal 160(5): 649-655, 1999. Objective: To analyse the evidence for the efficacy and potential harmful effects of benzodiazepines compared with other therapies in the treatment of acute alcohol withdrawal. Data sources: MEDLINE and the Cochrane Controlled Trials Registry were searched for English-language articles published from 1966 to December 1997 that described randomized controlled trials (RCTs) of benzodiazepines in the treatment of acute alcohol withdrawal. Key words included "benzodiazepines" (exploded) and "randomized controlled trial." Bibliographies of relevant articles were reviewed for additional RCTs, and manufacturers of benzodiazepines were asked to submit additional RCT reports not in the literature. Study selection: Articles were considered for the meta-analysis if they were RCTs involving patients experiencing acute alcohol withdrawal and comparing a benzodiazepine available in Canada with placebo or an active control drug. Of the original 23 trials identified, 11 met these criteria, representing a total of 1286 patients. Data extraction: Data were extracted regarding the participants, the setting, details of the intervention, the outcomes (including adverse effects) and the methodologic quality of the studies. Data synthesis: The meta-analysis of benefit (therapeutic success within 2 days) showed that benzodiazepines were superior to placebo(common odds ratio [OR] 3.28, 95% confidence interval [CI] 1.30-8.28). Data on comparisons between benzodiazepines and other drugs, including P-blockers, carbamazepine and clonidine, could not be pooled, but none of the alternative drugs was found to be clearly more beneficial than the benzodiazepines. The meta-analysis of harm revealed no significant difference between benzodiazepines and alternative drugs in terms of adverse events (common OR 0.67, 95% CI 0.34-1.32) or dropout rates (common OR 0.68, 95% CI 0.47-0.97). Interpretation: Benzodiazepines should remain the drugs of choice for the treatment of acute alcohol withdrawal.

Hughes PH; Storr CL; Brandenburg NA; Baldwin DC Jr; Anthony JC; Sheehan DV. Physician substance use by medical specialty. Journal of Addictive Diseases 18(2): 23-37, 1999. (34 refs.) Self-reported past year use of alcohol, tobacco, marijuana, cocaine, and two controlled prescription substances (opiates, benzodiazepines); and self-reported lifetime substance abuse or dependence was estimated and compared for 12 specialties among 5,426 physicians participating in an anonymous mailed survey. Logistic regression models controlled for demographic and other characteristics that might explain observed specialty differences. Emergency medicine physicians used more illicit drugs. Psychiatrists used more benzodiazepines. Comparatively, pediatricians had overall low rates of use, as did surgeons, except for tobacco smoking. Anesthesiologists had higher use only for major opiates. Self-reported substance abuse and dependence were at highest levels among psychiatrists and emergency physicians, and lowest among surgeons. With evidence from studies such as this one, a specialty can organize prevention programs to address patterns of substance use specific to that specialty, the specialty characteristics of its members, and their unique practice environments that may contribute risk of substance abuse and dependence.

Iwata N; Cowley DS; Radel M; Roy-Byrne PP; Goldman D. Relationship between a GABA(A)alpha 6 Pro385Ser substitution and benzodiazepine sensitivity. American Journal of Psychiatry 156(9): 1447-1449, 1999. (14 refs.) Objective: In humans, interindividual variation in sensitivity to benzodiazepine drugs may correlate with behavioral variation, including vulnerability to disease states such as alcoholism. In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABA(A)alpha 6 receptor. The authors detected a Pro385Ser [1236C>T] amino acid substitution in the human GABA(A)alpha 6 that may influence alcohol sensitivity. In this pilot study, they evaluated the contribution of this polymorphism to benzodiazepine sensitivity. Method: Sensitivity to diazepam was assessed in 51 children of alcoholics by using two eye movement measures: peak saccadic velocity and average smooth pursuit gain. Association analysis was performed with saccadic velocity and smooth pursuit gain as dependent variables and comparing Pro385/Ser385 heterozygotes and Pro385/Pro385 homozygotes. Results: The Pro385Ser genotype was associated with less diazepam-induced impairment of saccadic velocity but not with smooth pursuit gain. Conclusions: The Pro385Ser genotype may play a role in benzodiazepine sensitivity and conditions, such as alcoholism, that may be correlated with this trait.

Jain R. Utility of thin layer chromatography for detection of opioids and benzodiazepines in a clinical setting. Addictive Behaviors 25(3): 451-454, 2000. (11 refs.) This study examined the utility of thin layer chromatography (TLC) for detection of recent use of opioids and benzodiazepines among drug addicts seeking treatment at the Drug Dependence Treatment Centre of All India Institute of Medical Sciences, New Delhi, India. Over a period of 5 years (1991-1995), 6,055 urine samples were analyzed for opioids (morphine, codeine, buprenorphine, dextropropoxyphene, pentazocine) and benzodiazepines (diazepam, nitrazepam) by TLC. Out of all the drug tests (n = 9,922) carried out, 24% of the drugs had been used during the past 72 hr. Averaged across all drugs, the detection rates corresponding to 24, 48, and 72 hr by TLC were 37%, 36%, and 31%, respectively. A high percentage of negative TLC results was observed in these samples. Moderate sensitivity of the TLC assay procedure, low consumption of drug, short time between drug use and urine collection, over-reporting by the subjects, and drug use history of the subject obtained from multiple sources led to high negative results. These findings suggest that all the TLC negative results also need further confirmation by an alternative, more sensitive technique in a clinical setting. This will make the drug abuse testing program more meaningful.

Jonasson B; Jonasson U; Holmgren P; Saldeen T. Fatal poisonings where ethylmorphine from antitussive medications contributed to death. International Journal of Legal Medicine 112(5): 299-302, 1999. (11 refs.) The hypothesis that antitussives containing ethylmorphine are abused by alcoholics and drug addicts and that this may lead to fatal poisonings where ethylmorphine causes or contributes to death was investigated. For this purpose 14 cases were analysed where a blood ethylmorphine concentration above the therapeutic level of greater than or equal to 0.3 mu g/g was found in autopsy blood samples. Alcohol was found in 8 of the 14 cases and alcoholism or drug addiction was noted on 8 of the 14 death certificates. Other drugs, mostly benzodiazepines, were found in all 14 cases. The cause of death was fatal poisoning in 8 of the 14 cases and although there were no mono-intoxications, the cause of death was specified as fatal ethylmorphine poisoning in 2 cases. Among the unspecified medicinal drug poisonings there were five cases with very high blood levels of ethylmorphine, indicating that this drug played an important contribution to the cause of death. The results indicate that deaths due to ethylmorphine in antitussive medicines may occur among drug addicts and alcoholics taking it in overdose. Physicians should therefore be restrictive in prescribing cough mixtures containing ethylmorphine to these categories of patients. Prescription of large amounts of the drug should be avoided.

Jorm AF; Grayson D; Creasey H; Waite L; Broe GA. Long-term benzodiazepine use by elderly people living in the community. Australian and New Zealand Journal of Public Health 24(1): 7-10, 2000. (24 refs.) Objective: To investigate the prevalence of long-term benzodiazepine use in an elderly community sample, and factors associated with such use. Method: Data came from the Sydney Older Persons Study, a longitudinal study of people aged 75 or over. There were 337 subjects who were interviewed in 1991-93, and subsequently followed up after three and 4.5 years. At the first interview, subjects were assessed for sociodemographic characteristics, physical and mental health, and use of health services. At the first and subsequent interviews, subjects were asked about use of medications, including benzodiazepines. Results: There were 16.6% who were using benzodiazepines at the time of all three interviews, while a further 19.6% were using them at one or two interviews. In a multivariate ordered legit regression model, long-term benzodiazepine use was associated with treatment for nervous conditions, restless sleep, being female, being divorced and greater contact with medical services. Conclusions: The prevalence of benzodiazepine use in the elderly is high and much of this use is long term. The high prevalence of benzodiazepine use stands in contrast to the findings from national surveys that the elderly living in the community tend to have better mental health than younger age groups. Implications: Efforts are needed to reduce the number of elderly people becoming long-term users. The use of benzodiazepines in this age group is of particular concern, because they may be a risk factor for falls and for cognitive impairment in the elderly.

Kan CC; Breteler MHM; Timmermans EAY; van der Ven AHGS; Zitman FG. Scalability, reliability, and validity of the Benzodiazepine Dependence Self-report Questionnaire in outpatient benzodiazepine users. Comprehensive Psychiatry 40(4): 283-291, 1999. (32 refs.) As there is no multidimensional instrument available that reflects the severity of benzodiazepine (BZD) dependence comprehensively. the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ) was developed and investigated. The Bendep-SRQ. Symptom Checklist-90 (SCL- 90), Schedules for Clinical Assessments in Neuropsychiatry (SCAN), and Addiction Severity Index-Revised (ASI-R) were administered to 115 general practice (GP) patients, 124 Psychiatric outpatients, and 33 self-help patients who were using BZDs. Factor and Rasch analyses were applied to construct scales. Reliability assessments were made in terms of subject discriminability, item discriminability, and test- retest stability. To support the construct validity of the scales, theoretical rationales were required to explain the specific item order provided by the Rasch scale values. To assess the concurrent and discriminant validity, a matrix consisting of the above-mentioned measures was factor-analyzed. Four Rasch-homogeneous scales were delineated: problematic use, preoccupation, lack of compliance, and withdrawal. Nearly all subject discriminability, item discriminability, and test-retest results indicated good reliability. A BZD dependence factor was extracted with high loadings for the Rendep-SRQ scales and the concurrent measures. The discriminant measures had high loadings on other factors. The scalability, reliability, and validity of the Bendep-SRQ scales appeared to be good. The Bendep-SRQ shows great promise as a useful and easily manageable instrument for assessment of the severity of BZD dependence in clinical practice and scientific research.

Kanemoto K; Miyamoto T; Abe R. Ictal catatonia as a manifestation of de novo absence status epilepticus following benzodiazepine withdrawal. Seizure: European Journal of Epilespy 8(6): 364-366, 1999. (10 refs.) To describe ictal catatonia as a manifestation of de novo absence status epilepticus following benzodiazepine withdrawal. Ictal catatonia was documented by concurrent EEG recordings. A catatonic syndrome, first diagnosed as a psychogenic reaction, was found to be an ictal event by EEG recording. De novo absence status and benzodiazepine withdrawal should be considered when a catatonic syndrome suddenly occurs in elderly patients.

Kirby M; Denihan A; Bruce I; Radic A; Coakley D; Lawlor BA. Benzodiazepine use among the elderly in the community. International Journal of Geriatric Psychiatry 14(4): 280-284, 1999. (18 refs.) Benzodiazepines are the most commonly prescribed psychotropic drug in the elderly. Benzodiazepines with a long duration of action can produce marked sedation and psychomotor impairment in older people, and are associated with an increased risk of hip fracture and of motor vehicle crash. One thousand seven hundred and one individuals of 65 years and over, identified from General Practitioner lists, were interviewed using the Geriatric Mental State-AGECAT package and current psychotropic drug use was recorded. Benzodiazepines were classified as having a short or long elimination half-life. Two hundred and ninety-five (17.3%) individuals were taking a benzodiazepine, with use in females being twice that in males. Of the 295, 152 (51.5%) were taking a long acting benzodiazepine and the use of long acting anxiolytic type benzodiazepines was particularly common. Fifty-two (17.6%) benzodiazepine users were taking one or more other psychotropic drugs. A benzodiazepine was used by eight of 18 (44.4%) subjects with an anxiety disorder, 62 of 180 (34.4%) individuals with depression, and seven of 71 (9.9%) people with dementia. Four-fifths of older people on a psychotropic drug were taking a benzodiazepine, highlighting the importance of this class of drug in the elderly population. The choice of a benzodiazepine with a long duration of action, which have been shown to be associated with serious adverse events in the elderly in over one half of benzodiazepine users, is of concern. The potential for adverse effects was further accentuated by polypharmacy practices. The choice of benzodiazepine for an older person has important consequences and should be addressed in greater detail with primary care.

Koski-Jannes A; Turner N. Factors influencing recovery from different addictions. Addiction Research 7(6): 469-492, 1999. (38 refs.) This study deals with environmental and behavioural factors that play a role in the recovery from addictive behaviours. Two primary questions are asked: To what extent the factors influential in resolving addictive behaviours and the means of maintaining the change differ by addictions, and to what extent the former factors predict the latter? Subjects (n=76, 38 women) who had managed to resolve their addiction and maintain the change for more than three years were recruited by newspaper ads. The sample included addictions to alcohol (26), multiple substances (16), nicotine (15), binge eating(11), and other (8), which included sex, gambling and benzodiazepine, The mean time of recovery was 9.3 years. Two types of factor analyses were used to define factors that played a role in resolving the problem and in maintaining the change. Seven change factors and four maintenance factors were supported by both methods. The change factors were: Tiring Out, Love, 12 Steps, Revival, Family, Social Consequences, and Peer Group change. The maintenance factors were: Self-Control, Professional Treatment, 12 Steps and Spirituality, as well as Social and Cognitive Coping. Significant (p<.05) addiction-related differences appeared in four change factors and three maintenance factors, thus displaying the differing routes to recovery in different addictions.

Longo LP; Johnson B. Addiction: Part I. Benzodiazepines: Side effects, abuse risk and alternatives. American Family Physician 61(7): 2121-2128, 2000. (34 refs.) Benzodiazepines are widely prescribed for a variety of conditions, particularly anxiety and insomnia. They are relatively safe and, with overdose, rarely result in death. However, used chronically, benzodiazepines can be addicting. These agents are often taken in combination with other drugs of abuse by patients with addiction disorders. In such patients, alternatives to benzodiazepines may be preferable and may include antidepressants, anticonvulsants, buspirone, antihypertensive agents and the newer neuroleptic medications. Caution must be used when prescribing benzodiazepines to patients with a current or remote history of substance abuse.

Macdonald S; Wells S; Giesbrecht N; Cherpitel CJ. Demographic and substance use factors related to violent and accidental injuries: Results from an emergency room study. Drug and Alcohol Dependence 55(1/2): 53-61, 1999. (45 refs.) Objective The primary goal of this study was to identify demographic and substance use factors associated with violent injuries, accidental injuries, and medical conditions or illnesses (non- injured). Method Data were examined from a sample of 1701 admissions to emergency rooms at two Canadian hospitals. These patients were interviewed and provided urine samples to detect the presence of drug metabolites for alcohol, THC, benzodiazepines, barbiturates, morphine, and codeine. Results Those with violent injuries were significantly (P < 0.0001) more likely to be male and have lower incomes compared with both the accidental injury and non-injury groups. About 37% of violent injuries occurred at a bar or restaurant, which was significantly more than 3% for accidental injuries and 2% for non-injuries (P < 0.00001). The violent injury group was significantly more likely than the other two groups to report feeling the effects off alcohol at the time of the injury and to report negative consequences of alcohol use (P < 0.00001). Furthermore, about 42% of those with violent injuries had a blood alcohol level (BAL) over 80 mg% compared to only 4% with accidental injuries (P < 0.00001) and 2% of non-injuries (P < 0.00001). In terms of drug tests for other substances, the violent injury group was significantly more likely to test positive for benzodiazepines than the accidental injury group (P < 0.01) while all between group comparisons for other drugs were not significant.

Martinez-Cano H; De Gauna MDI; Vela-Bueno A; Wittchen HU. DSM-III-R co-morbidity in benzodiazepine dependence. Addiction 94(1): 97-107, 1999. (44 refs.) Aim, sample and measures. Co-morbidity has been shown to influence the clinical course of mental disorders. This paper describes DSM-III- R 1-month co-morbidity across axes I, II and III in a sample of 153 benzodiazepine dependants. All patients were evaluated through several in-depth clinical interviews across all five DSM-III-R axes. Results. Extensive co-morbidity existed across three DSM-III-R axes. All patients had at least one diagnosis in axis I; 81 (52.9%) in axis II and 50 (32.7%) ill axis Ill. The most Prevalent diagnoses were: insomnia, anxiety disorders and affective disorders in axis I; obsessive-compulsive, histrionic and dependent personality disorders in axis II and rheumatological, neurological and cardiovascular disorders ill axis III. Conclusions. There were no cases of benzodiazepine dependence appearing alone. There were associations within and between axes, suggesting potential predisposing factors and a sequential model for benzodiazepine dependence is proposed. The findings reinforce the need for exhaustive diagnostic evaluation of patients prior to prescribing benzodiazepine.

Matos ME; Burns MM; Shannon MW. False-positive tricyclic antidepressant drug screen results leading to the diagnosis of carbamazepine intoxication. Pediatrics 105(5): E661-E663, 2000 Ingestion of toxic substances is a common problem in pediatrics. When presented with the limited history of an unknown ingestion in a patient with altered mental status, a clinician depends on the physical examination and a toxic screen to determine the ingested substance(s). Some toxic screens yield false-positive or false negative results that confound identification of ingested toxins. Three cases are presented in which carbamazepine ingestions were identified because of the false-positive tricyclic antidepressant serum toxic screen result in each case. Carbamazepine ingestion is one of the most common pediatric overdoses. Side effects include altered mental status, tachycardia, mydriasis, seizures, coma, and death. Several other substances also cause false-positive tricyclic antidepressant toxic screen results, including certain antipsychotic medications, antihistamines, and the muscle relaxant cyclobenzaprine. Specific tests and drugs causing false-positive results are presented in table form. More modern methods, specifically gas chromatographic-mass spectrometric, are more reliable in distinguishing these drugs. Knowledge of which substances commonly cause false-positive results on a given toxic screen can still lead the clinician to the correct diagnosis.

Mattila MJ; Vanakoski J. Stimulated drving in light and dark conditions: Effects of alcohol and diazepam. British Journal of Clinical Pharmacology 45: 206, 1999. (3 refs.) Night-time driving can increase accident risk due to fatigue and compromised visual conditions. This report considers the additional factors of alcohol and benzodiazepine use. It is concluded that under stimulated driving conditions, the effect of night driving did not further compromise the effects of alcohol or benzodiazepine use that are found in day driving.

Mattila MJ; Vanakoski J. Simulated driving in light and dark conditions: Elderly subjects, alcohol and diazepam. British Journal of Clinical Pharmacology 47(5): 600, 1999. (4 refs.) Night-time driving can increase accident risk due to fatigue and compromised visual conditions. This report considers the additional factors of alcohol and benzodiazepine use. It is concluded that while elderly subjects had poor baseline performance, under stimulated driving conditions, the effect of night driving did not further compromise the effects of alcohol or benzodiazepine use that are found in day driving.

Möller HJ. Effectiveness and safety of benzodiazepines. Journal of Clinical Psychopharmacology 19(6 Supplement): 2S-11S, 1999. (82 refs.) Benzodiazepines have been used to treat a wide variety of disorders, including generalized anxiety disorder, panic disorder, sleep disorders, somatopsychic disorders, and depression. Concerns regarding physiologic dependence, withdrawal, and abuse potential with benzodiazepines prompted the development of strict guidelines for the use of these agents. Studies have shown that the risk of physiologic dependence increases with factors such as the dose of the benzodiazepine used and the duration of treatment. Restrictions involving benzodiazepines have led to the substitution of alternative medicines that may have decreased efficacy and greater safety concerns. There is a need for a more balanced assessment of the benefits and risks associated with benzodiazepine use to ensure that patients who would truly benefit from these agents are not denied appropriate treatment.

Mullins ME. Laboratory confirmation of flunitrazepam in alleged cases of date rape. Academic Emergency Medicine 6(9): 966-968, 1999. (10 refs.) This brief report summarizes the outcome of more than 1,000 consecutive tests performed through May 1998, in cases suspected of involving flunitrazepam (Rohypnol). [Flunitrazepam has never been marketed in the US., but has been marketed in Europe and Latin America for treatment of insomnia and as a pre-operative sedative.] This is being used illicitly in the US and has become identified as the "date rape" drug. Hoffman-La Roche has assisted "date rape" victims by providing free, comprehensive testing for flunitrazepam to EDs, law enforcement agencies, and sexual assault crisis clinics. The testing is conducted on urine samples. Of the 1,077 tests conducted, funitrazepam was present in only six assays. A total of 41% of all assays were negative for all drugs tested. The remaining 59% had one or more detectable drugs including alcohol. A total of 400 assays (36%) detected alcohol, and 200 (18%) detected marijuana. All other benzodiazepines, excluding Flunitrazepam, were found in 131 positive test (12%). Gamma-hydroxy-butyrate was identified in 46 samples (4%), (the limit of detection was 2 ng/mL). Thus while widely reported, the actual documented occurrence of flunitrazepam in "date rape" appears to be relatively rare.

O'Connor K; Belanger L; Marchand A; Dupuis G; Elie R; Boyer R. Psychological distress and adaptational problems associated with discontinuation of benzodiazepines. Addictive Behaviors 24(4): 537-541, 1999. (16 refs.) This study compared subjects who had received standard tapered withdrawal of benzodiazepine (BZD) (group 1) with a group with comparable diagnosis still receiving BZD (group 2) and a control group of comparable diagnosis not yet receiving treatment (group 3). Sixty subjects aged 21-65 years with a diagnosis of nonpsychotic anxiety or insomnia were included. The assessment of psychological distress and quality of life was timed to coincide with the maximum immediate effect of BZD discontinuation, as calculated according to drug half-life. Subjects diagnosed with insomnia reported lower distress in all three groups. The pattern of distress experienced by group 1 was closer to group 3 than to group 2, indicating the potential importance of re-emergence of anxiety. High neuroticism, lower education level, and lower quality of life were associated with higher levels of distress during withdrawal.

Oswald LM; Roache JD; Rhoades HM. Predictors of individual differences in alprazolam self-medication. Experimental and Clinical Psychopharmacology 7(4): 379-390, 1999. (65 refs.) Twenty-seven patients with generalized anxiety or panic disorder participated in a 6-week outpatient study. Participants received capsules containing either alprazolam or placebo and were free to choose between them for anxiety treatment. Measures of drug use included alprazolam preference, amount, and frequency of use. Alprazolam clearly was preferred over placebo; however, there were large between-subjects differences in the amount of medication used. A variety of demographic, drug history, personality, mood, and expectational variables were examined for correlation with medication use. Findings indicated that a substantial amount of variance in medication use could be explained by patients' intake characteristics. Findings also suggested that the tendency to consume capsules frequently may signal a greater risk factor for dependence than does drug preference in and of itself.

Petrovic M; Pevernagie D; van den Noortgate N; Mariman A; Michielsen W; Afschrift M. A programme for short-term withdrawal from benzodiazepines in geriatric hospital inpatients: Success rate and effect on subjective sleep quality. International Journal of Geriatric Psychiatry 14(9): 754-760, 1999. (24 refs.) Objective. We tested the hypothesis that a short-term programme for withdrawal of benzodiazepines (BZD) is feasible in hospitalized geriatric patients, Methods. Fifty-six geriatric subjects who had been taking BZD for at least 3 months were asked to discontinue these drugs upon admission to the inpatient ward. A withdrawal programme including initial substitution therapy combined with psychological consulting was offered. The usual BZD medication was replaced by either lormetazepam 1 mg or trazodone 50 mg, administered at bedtime. After 1 week of replacement therapy all sedative medication was stopped. The subjective estimations of sleep quality were evaluated four times during a period of 6 weeks. Results. Forty-nine patients agreed to participate. In this group four subjects (8.2%) resumed BZD use while in the hospital and another seven subjects (14.3%) relapsed after discharge. Therefore, the overall success rate was 77.6% in the group of volunteers and 67.9% in the total group of eligible patients. The data of the present study further demonstrate that no major withdrawal symptoms occurred and that the subjective quality of sleep remained virtually unchanged in the course of the programme. The sleep quality was not significantly different in patients on trazodone versus patients on lormetazepam, The success rate was similar in both drug substitution groups. Conclusions. Short-term withdrawal of BZD may be achieved in two-thirds of elderly hospital inpatients without deterioration of sleep quality or other deleterious side-effects.

Poulin C; Van Til L; Wilbur B; Clarke B; MacDonald CA; Barcelo A. Alcohol and other drug use among adolescent students in the Atlantic provinces. Canadian Journal of Public Health 90(1): 27-29, 1999. (16 refs.) The objective of the study reported was to estimate the prevalence of alcohol and other drug use among students in junior and senior high school in the Atlantic region, and the specific prevalence in Nova Scotia, Newfoundland and Labrador, and Prince Edward Island. Characteristics of the sample are outlined and use within the past 12 months ascertained for the following substances: alcohol, cigarettes, marijuana, LSD, stimulants, other hallucinogens, tranquilizers, cocaine, steroids, inhalants, PCP, heroin and barbiturates. The results are summarized in three tables, that highlight the differences between provinces, the role of gender.

Raymon LP; Steele BW; Walls HC. Benzodiazepines in Miami-Dade County, Florida driving under the influence (DUI) cases (1995-1998) with emphasis on Rohypnol (R): GC- MS confirmation, patterns of use, psychomotor impairment, and results of Florida legislation. Journal of Analytical Toxicology 23(6): 490-499, 1999. (52 refs.) Benzodiazepines are central nervous system depressant drugs often detected in biological samples from driving under the influence (DUI) offenders. They are associated with marked psychomotor impairment and represent up to 20% of all Miami-Dade County, Florida DUI urine samples analyzed in our laboratory annually. Flunitrazepam emerged in the mid-1990s as an illegal drug in the U.S. that was predominantly abused recreationally and associated with sexual assaults. Immunoassays for benzodiazepines do not discriminate between different benzodiazepines, and certain metabolites, such as 7-aminoflunitrazepam, react poorly with immunoassay reagents. A simple and sensitive method for the detection and quantitation of major benzodiazepines and metabolites by gas chromatography with mass selective detection is presented. This method was used to confirm benzodiazepines in general and flunitrazepam in particular. Data collected over a three-and-a-half-year period are summarized. Whereas flunitrazepam was present in up to 10% of DUI cases in 1995 and 1996 and had fast become the most frequently encountered benzodiazepine in Miami-Dade County DUI-related urine samples, a dramatic drop in case numbers followed the legal reclassification of the drug as a Schedule I substance in Florida in February 1997. Flunitrazepam was often used alone or in combination with cannabis and cocaine. A recent rise in clonazepam cases coincides with the decrease in flunitrazepam confirmation and may indicate a new trend in the abuse of benzodiazepines in South Florida.

Rickels K; DeMartinis N; Rynn M; Mandos L. Pharmacologic strategies for discontinuing benzodiazepine treatment. Journal of Clinical Psychopharmacology 19(6 Supplement): 12S-16S, 1999. Benzodiazepines have been shown to have broad-spectrum activity, rapid onset of action, and a wide therapeutic window compared with other anxiolytic medications. Yet the use of benzodiazepines has been limited by concern regarding dependence, withdrawal, and abuse. Agents such as antidepressants, serotonergic anxiolytics, anticonvulsants, and B-blockers have been used with varying degrees of success to help facilitate the tapering of benzodiazepines. Carbamazepine, imipramine, valproate, and trazodone have been beneficial in the management of benzodiazepine discontinuation, but not in decreasing the severity of benzodiazepine withdrawal, a stepwise approach to discontinuing benzodiazepines is offered.

Rickels K; Lucki I; Schweizer E; Garcia-Espana F; Case WG. Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation. Journal of Clinical Psychopharmacology 19(2): 107-113, 1999. (26 refs.) Long-term (mean, 8 years) users of benzodiazepines (BZs) were administered a small battery of cognitive tests on three occasions (before BZ taper, and 5 and 12 weeks post taper) as part of their BZ discontinuation program. Ninety-six patients had 8-week and 77 patients had 12-week data. For taper successes, BZ-free status was confirmed by weekly BZ plasma level determinations. Age and education, as well as baseline test scores, were used as covariates for all data analyses. Patients who successfully tapered off BZ were able to complete symbol copying (SC) and digit symbol substitution (DSST) tasks faster than patients still taking BZ (p < 0.05). In addition, using an adjective check list, patients with taper success, i.e., BZ-free patients, reported lower levels of mental and physical sedation and higher levels of tranquilization (p < 0.05) than did patients still taking BZ. These results were confirmed in two multiple regression analyses with SC and DSST as the dependent variables. Higher baseline, younger age, and successful taper status (off BZ) were selected as significant independent predictors of SC and DSST scores. In summary, cognitive functions improved for many long-term BZ users after discontinuing their BZ intake.

Rickert VI; Wiemann CM; Berenson AB. Prevalence, patterns, and correlates of voluntary flunitrazepam use. Pediatrics 103(1): E61-E65, 1999. Objective. To determine prevalence, patterns, and correlates of voluntary flunitrazepam use in a sample of sexually active adolescent and young adult women 14 to 26 years of age. Design. Cross-sectional survey. Setting. University-based ambulatory reproductive health clinics. Patients or Other Participants. There were 904 women self-identified as white, African-American, or Mexican-American. Interventions. None. Main Outcome Measure. Lifetime, frequency, patterns, and physical effects of flunitrazepam use. Results. Lifetime use was reported by 5.9% (n = 53) of subjects, with frequency of use ranging from I to 40 times. Flunitrazepam was taken most often with alcohol (74%), and 49% took this substance with other illicit drugs. Logistic regression analyses controlling for age and race/ethnicity found that users were significantly more likely than were nonusers to report lifetime use of marijuana (odds ratio [OR] = 3.6) or LSD (OR = 5.2), having a peer or partner who used flunitrazepam (OR = 21.7), pressure to use flunitrazepam when out with friends (OR = 2.7), and a mother who had at least a high school education (OR = 2.6). Finally, 10% of voluntary users reported experiencing subsequent physical or sexual victimization. Conclusions. Voluntary use of flunitrazepam is becoming a health concern to sexually active young women who reside in the southwestern United States. Young women who have used LSD or marijuana in the past or who have a peer or partner who used this drug appear to be at the greatest risk.

Rooney S; Kelly G; Bamford L; Sloan D; O'Connor JJ. Co-abuse of opiates and benzodiazepines. Irish Journal of Medical Science 168(1): 36-41, 1999. (19 refs.) The objective of the study was to assess what differences exist between individuals who are dependent on opiates and benzodiazepines and compare to those who are dependent on opiates. A questionnaire was compiled and administered to patients who had been consecutively admitted to an inpatient drug treatment unit. The prevalence of benzodiazepine dependency was 54 per cent [n=34]. Patients dependent on benzodiazepines and opiates were significantly older, had been admitted for methadone stabilisation and were more likely to have been prescribed a methadone maintenance programme prior to admission. They had used heroin longer, benzodiazepines more frequently, at larger doses for a longer duration of time and tended to use more drugs in general. They were found to be more psychologically vulnerable than those not dependent on benzodiazepines as they were significantly more likely to have described a past experience of depression and a past episode of deliberate self harm.

Rush CR; Baker RW; Wright K. Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans. Psychopharmacology 144(3): 220-233, 1999. (60 refs.) The present study examined the acute behavioral effects and abuse potential of three drugs commonly used to treat sleep disorders, trazodone, zolpidem and triazolam, and placebo in ten male volunteers with histories of alcohol and drug abuse. Trazodone (100, 200 and 300 mg), a triazolopyridine antidepressant, was included because antidepressants are being used more frequently to treat sleep disorders, but it is unclear whether they have a distinct behavioral pharmacologic profile relative to benzodiazepine hypnotics. Zolpidem (15, 30 and 45 mg), an imidazopyridine hypnotic, was tested because it is the most commonly prescribed hypnotic and purportedly has a unique benzodiazepine-receptor binding profile. Triazolam (0.25, 0.5 and 0.75 mg), a triazolobenzodiazepine hypnotic, was included as the standard component because previous laboratory studies have demonstrated that it has at least some abuse potential. Trazodone, zolpidem and triazolam generally produced comparable dose-related increases in scores on the PCAG scale of the ARCI, which suggests the doses tested were equivalent on some behavioral dimension. The effects of trazodone on subject-rated items thought to measure abuse potential (e.g., subject ratings of Willing to Take Again) were less than those observed with triazolam. Zolpidem and triazolam produced comparable effects on these measures. The highest dose of zolpidem, but not triazolam, increased ratings of "Like Drug," "Happy," "Good Effects", "Friendly," "Elated," "Carefree and "Bad Effects". Triazolam and zolpidem produced dose-dependent impairment on all of the performance tasks. Trazodone impaired performance on some, but not all, of these tasks. Consistent with the pharmacokinetics of these compounds, the time-action functions of trazodone, zolpidem and triazolam were similar on these measures. These data suggest that trazodone has less abuse potential than triazolam, and may be a viable alternative to benzodiazepine hypnotics in individuals with histories of alcohol or drug abuse. By contrast, despite its unique neuropharmacological profile, the acute behavioral effects and abuse potential of zolpidem are comparable to those of triazolam.

Sarid-Segal O; Knapp CM; Ciraulo AM; Greenblatt DJ; Shader RI; Ciraulo DA. Decreased EEG sensitivity to alprazolam in subjects with a parental history of alcoholism. Journal of Clinical Pharmacology 40(1): 84-90, 2000. Altered benzodiazepine sensitivity in subjects with a history of parental alcoholism (PHP) compared to control subjects (NC) has been reported for regional brain blood volume, eye movement tasks, and subjective effects. This study tests the hypothesis that PHP subjects are less sensitive to benzodiazepine effects on EEG activity than are NC subjects. Total EEG activity was recorded in PHP and NC subjects after administration of the benzodiazepine, alprazolam (1 mg), or placebo. PHP subjects had decreased sensitivity to the EEG effects of alprazolam compared to NC subjects. Significant differences were detected for change in percent relative beta activity and alpha and theta band power. Pharmacokinetic parameters did not differ significantly between groups. These results suggest that PHP subjects are less sensitive to the effects of alprazolam on central electrophysiological activity than are NC subjects.

Seymour A; Oliver JS. Role of drugs and alcohol in impaired drivers and fatally injured drivers in the Strathclyde police region of Scotland, 1995-1998. Forensic Science International 103(2): 89-100, 1999. (22 refs.) During the 4-year study period, 1995-1998, the Department of Forensic Medicine and Science, University of Glasgow received a total of 752 biological samples from drivers suspected of driving under the influence of drink and/or drugs in the Strathclyde region of Scotland. The majority of samples were blood and had been primarily obtained from males. Drugs were detected in 68 and 90% of blood and urine samples, respectively. Toxicological analyses revealed that cannabis was the most frequently encountered illegal drug which was detected in 39% of all drug positive blood samples. Benzodiazepines were detected in the majority of drug positive samples with 82% containing at least one member of this group. Polydrug use was prevalent, with the average number of drugs detected per sample increasing from 2.0 in 1995 to 3.1 in 1998. For comparison, the results of toxicological analyses from 151 fatally injured drivers are described. Although the majority of samples tested negative for the presence of drugs and alcohol, drugs were found to be present in 19% and alcohol was detected in 33%. As the majority of drugs had been prescribed or administered post-accident, this study shows that alcohol was the main causative factor conducive to fatal road traffic accidents.

Sgadari A; Lapane KL; Mor V; Landi F; Bernabei R; Gambassi G. Oxidative and nonoxidative benzodiazepines and the risk of femur fracture. Journal of Clinical Psychopharmacology 20(2): 234-239, 2000. (34 refs.) Benzodiazepine use is a well-identified risk factor for falls and the resulting femur fractures in elderly adults. Benzodiazepines not requiring hepatic biotransformation may be safer than agents undergoing oxidation because oxidative activity has been shown to decline with age. The association between the use of either oxidative or nonoxidative benzodiazepines and the risk of femur fracture among elderly adults Living in nursing homes was studied. A nested case-control study was conducted using the Systematic Assessment of Geriatric drug use via Epidemiology (SAGE) database; the records of 9,752 patients hospitalized for incident femur fracture during the period 1992 to 1996 mere extracted, matching by age, gender, state, and index date to the records of 38,564 control patients. Conditional logistic regression models were conducted to estimate the odds ratios (ORs) for femur fracture with adjustment for potential confounders. The adjusted OR for the overall use of benzodiazepines was 1.10 (95% confidence interval [CI], 0.98-1.20); the risk seemed of only slightly greater magnitude for exposure to nonoxidative agents (1.18; 95% CI, 1.03-1.36) than to oxidative benzodiazepines (1.08; 95%, CI, 0.95-1.23). Among the latter, the effect has mainly accounted for by the use of agents with a long elimination half-life. A dose relationship was observed exclusively among users of long half-life oxidative benzodiazepines. The risk associated with the use of nonoxidative benzodiazepines showed no relationship to the age of the patients. In contrast, patients aged 85 years or older receiving oxidative benzodiazepines at high dosages or as needed had a two- to three-fold increased risk of femur fracture than did patients in the younger age group. Among older individuals, the use of benzodiazepines slightly increased the risk of femur fracture, mainly irrespective of the metabolic fate of the drug. Our results suggest that the use of nonoxidative benzodiazepines does not carry a lower risk for femur fracture than does the use of oxidative benzodiazepines. However, the latter agents may be associated with a somewhat higher risk of side effects among the oldest old, especially at higher dosages.

Simmer ED. A fugue-like state associated with diazepam use. Military Medicine 164(6): 442-443, 1999. (9 refs.) Diazepam is a long-acting benzodiazepine, Although diazepam is commonly associated with a variety of side effects, it is generally not believed to cause fugue-like states or retrograde amnesia. This report presents the case of an active duty patient who developed a brief fugue-like state with retrograde amnesia. This was associated with the short-term oral use of diazepam. There was no other apparent cause for his symptoms, which resolved within 24 hours after the diazepam was discontinued. This case suggests that short-term use of diazepam can lead to a brief fugue-like state with retrograde amnesia that has not been reported previously.

Smith DE; Wesson DR. Benzodiazepines and other sedative-hypnotics. IN: Galanter M; Kleber HD, eds. Textbook of Substance Abuse Treatment, Second Edition. Washington DC: American Psychiatric Press, 1999. pp. 239-250. (52 refs.) This is one of 11 chapters, discussing treatment for specific drugs of abuse, in the third section, of a reference text on substance abuse.

Spiegel DA. Psychological strategies for discontinuing benzodiazepine treatment. Journal of Clinical Psychopharmacology 19(6 Supplement): 17S-22S, 1999. (38 refs.) Successful discontinuation of therapeutic drugs requires patients to negotiate two potentially difficult phases. First, they must complete the drug discontinuation procedure itself, which may entail coping with rebound and withdrawal symptoms as well as anxiety due to stopping a treatment on which they depend psychologically. Second, they must maintain drug abstinence over time, despite possible exacerbations or recurrences of the disorder that the drug was treating. For optimal success, interventions aimed at assisting patients to discontinue drug use must address both of those tasks. Patients' ability to discontinue benzodiazepines seems to be strongly influenced by cognitive appraisals of the threat represented by symptoms and of their own competence to cope with it without medication. For problems of that kind, cognitive and behavioral techniques such as those developed for the treatment of panic disorder may be especially well-suited. Currently, the most successful approaches to benzodiazepine discontinuation include the following components: (1) assisting with initial drug discontinuation, educating patients about benzodiazepine dependence and withdrawal, and about the kinds of symptoms that can emerge as the drug dose is decreased, combined with a flexible drug taper conducted in supportive collaboration with the patient; and (2) dealing with exacerbations of the illness, and providing disorder- specific cognitive-behavioral treatment as an alternative to the resumption of pharmacotherapy. It seems to be crucial that the drug taper be completed before psychological treatment concludes.

Stewart SH; Westra HA; Thompson CE; Conrad BE. Effects of naturalistic benzodiazepine use on selective attention to threat cues among anxiety disorder patients. Cognitive Therapy and Research 24(1): 67-85, 2000. (55 refs.) The present study examined the effects of naturalistic benzodiazepine (BZ) use on selective attention to threat cues in 50 patients diagnosed with anxiety disorders, according to DSM-IV (APA, 1994) criteria. Patients provided information on their BZ use histories, demographics, and severity of anxiety symptomatology, and completed a computerized Stroop task involving color naming of social threat, physical threat, and matched no-threat control words. Patients were selected to fill two age-, gender-, and diagnosis-matched groups based on self-reported BZ use histories: 25 current BZ users versus 25 medication nonusing controls. Planned comparisons were conducted to determine whether BZ use groups differed in degree of selective attention to either the physical and/or social threat stimuli, or overall. Even with BZ use group differences in anxiety severity covaried out, the BZ risers demonstrated significantly greater selective attention to threat than the medication nonusers, particularly in the case of physical threat stimuli. These findings are consistent with Westra and Stewart's (1998) suggestion that use may increase preferential attention to physical threat cues, since BZs are often taken on an "as needed" (prn) basis. This "prn enhancement" interpretation was further supported through the finding of a significant positive correlation between frequency of prn use of BZs and degree of physical threat-related interference on the Stroop among the BZ users group. Theoretical explanations and clinical implications of these findings are discussed.

Straand J; Rokstad KS. Elderly patients in general practice: Diagnoses, drugs and inappropriate prescriptions. A report from the More & Romsdal Prescription Study. Family Practice 16(4): 380-388, 1999. (44 refs.) Background. Elderly patients are particularly vulnerable and most at risk of suffering adverse drug reactions, which are often caused by inappropriate prescribing practice. Gaining insight into physicians' drug prescribing patterns in order to identify prescribing problems is the fundamental first step in trying to improve the quality of prescribing. Objectives. We aimed to describe drug prescribing in general practice for elderly patients, using patients' age and sex, encounters, indications for prescribing and the occurrence of some predefined inappropriate drug prescriptions. Methods. A cross-sectional, descriptive study was conducted in the Norwegian county of More & Romsdal. All patient contacts (n = 16 874) and prescriptions (n = 16 774) issued during two months in general practice were recorded. In defining inappropriate prescriptions, explicit criteria were used. Results. Prescriptions (of which 72% were repeat) were issued during two-thirds of all contacts, and 63% were for females. Seventy per cent of all prescriptions were made up by the ten most commonly prescribed therapeutic groups, for which the three most frequent diagnostic indications for prescribing comprised between 47 and 89% of all diagnoses for prescribing each of them. About one in six patients who received a benzodiazepine tranquillizer was concurrently prescribed another benzodiazepine for sleeping problems. In total, 13.5% of all prescriptions met at least one of the criteria listed for pharmacological inappropriateness. Conclusion. Inappropriate drug prescriptions for elderly patients are common in general practice. Since the majority of the prescribing practice is made up by rather few diagnoses and drugs, improved practice for only a few may nevertheless have a large impact on the total profile.

Tiplady B; Harding C; McLean D; Ortner C; Porter K; Wright P. Effects of ethanol and temazepam on episodic and semantic memory: A dose-response comparison. Human Psychopharmacology 14(4): 263-269, 1999. (27 refs.) Drug-induced memory impairment is most apparent for long-term memory, but it is unclear whether this effect is restricted to episodic memory with no effect on semantic memory. Here we compare how the formation of new. semantic and episodic memories are affected by ethanol and temazepam. Eighteen subjects (12 male, 6 female; age 19- 43 years; weight 52-104 kg) took part in five sessions in which they received by mouth, in random order: (E2) ethanol, 0.8 g/kg, maximum 60 g males, 50 g females; (E1) ethanol, 75 per cent of the dose for E1; (T2) temazepam 20 mg: (T1) temazepam 15 mg; (P) placebo. They carried out a series of tests including learning of invented 'facts, a measure of the acquisition of new semantic memory; the Buschke lest, a measure of short- and long-term learning of words; Digit- Symbol substitution, a measure of psychomotor speed; and Visual Analogue Scales. Both acquisition of new semantic memory and the long- term measure from the Buschke were impaired by both drugs. The effects of ethanol were more marked than those of temazepam for the memory tests at the doses used here, particularly for the Buschke. Psychomotor impairment as assessed by Digit-Symbol substitution speed was equally affected by both drugs. Subjects rated themselves more drunk on ethanol than on temazepam, but drowsiness was similar for the two drugs. These results show that both drugs impair the acquisition of new semantic memory as well as new episodic memory, and suggest that it is new long-term memory formation that is impaired by these drugs and not the formation of a specific type of memory, such as episodic memory.

Uhlenhuth EH; Balter MB; Ban TA; Yang K. International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders. Journal of Clinical Psychopharmacology 19(6 Supplement): 23S-29S, 1999. Despite decades of relevant basic and clinical research, active debate continues about the appropriate extent and duration of benzodiazepine use in the treatment of anxiety and related disorders. The primary basis of the controversy seems to be concern among clinicians, regulators, and the public about the dependence potential and the abuse liability of benzodiazepines. This article reports systematically elicited judgments on these issues by a representative panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depressive disorders, a panel which was constituted by a multistage process of peer nomination. The criterion for inclusion at each stage was the nomination by at least two peers as one of the "professionally most respected physicians of the world with extensive experience and knowledge in the pharmacotherapy of anxiety and depressive disorders." Sixty-six respondents (90%) completed a comprehensive questionnaire covering a wide range of topics relevant to the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. Overall, the expert panel judged that benzodiazepines pose a higher risk of dependence and abuse than most potential substitutes but a lower risk than older sedatives and recognized drugs of abuse. There was little consensus about the relative risk of dependence and abuse among the benzodiazepines. Differences between benzodiazepines with shorter and longer half- lives in inducing withdrawal symptoms are much less clear during tapered than during abrupt discontinuation. There was little agreement about the most important factors contributing to withdrawal symptoms and failure to discontinue benzodiazepines. The pharmacologic properties of the medication may be the most important contributors to withdrawal symptoms. In contrast, the clinical characteristics of the patient may be the most important contributors to failure to discontinue medication. The experts' judgment seems to support the widespread use of benzodiazepines for the treatment of bona fide anxiety disorders, even over long periods. The experts generally viewed dependence and abuse liability as clinical issues amenable to appropriate management, as for other adverse events related to therapy. However, more definitive clinical research on the remaining controversial issues is urgently needed to promote optimal patient care.

Van Valkenburg C; Akiskal HS. Which patients presenting with clinical anxiety will abuse benzodiazepines? Human Psychopharmacology 14(Supplement): S45-S51, 1999. (50 refs.) Although benzodiazepines represent much safer alternatives to the old generation of sedative-hypnotics, in contemporary practice a minority of patients still abuse them. Many physicians are leery of prescribing benzodiazepines for fear of inadvertently contributing to such abuse. In the present investigation of a stratified sample of 134 adult patients from anxiety and chemical dependency clinics in two university medical centers were systematically evaluated in semi- structured interviews based on a modification of Washington University criteria. Sedative (mostly benzodiazepines) abuse was significantly associated with such indicators of long-term maladjustment as antisocial personality and somatization hysteria, labile moods, temper outbursts, unstable interpersonal relationships, alcoholism, and a history of suicide attempts. Family history of alcoholism was not significant when controlled for familial antisocial personality. Neither depression, nor its chronicity or family history for depression, had any bearing on abuse of benzodiazepines. Logistic regression identified unstable tempestuous relationships and family history of antisocial behavior as the most powerful predictors, in particular, absence of such history correctly classified 80 per cent of those who did not abuse these drugs. Our data can help physicians decide which clinically anxious patients can be prescribed benzodiazepines with relative peace of mind. Apart from the foregoing patient characteristics, physicians must consider pharmacokinetic factors which suggest that benzodiazepines with longer half-lives are least likely to result in dependence. Finally, non-benzodiazepine anxiolytic agents-such as hydroxyzine and SSRIs- should receive serious consideration as less problematic agents in the clinical management of anxiety disorders. Whenever available, brief psychotherapeutic approaches should also be provided.

Vescovi PP; Coiro V. Effect of diazepam on growth hormone secretion in abstinent alcoholic men. Addiction Biology 4(1): 67-71, 1999. (13 refs.) The present study was performed in order to establish, with a simple and safe neuroendocrinological test, whether alcoholism is associated with alterations in sensitivity to benzodiazepines. For this purpose, we tested the stimulatory effects of diazepam on GH secretion. An intravenous bolus of 10 mg diazepam was injected in 51 (33-51-year- old) alcoholic men after at least 5 weeks of abstinence and in 20 age- and weight-matched normal controls. On a different occasion, a control test with placebo (physiological saline) was performed in the same subjects. Diazepam but not placebo administration induced a striking increase of GH secretion in the normal controls. In contrast, neither diazepam nor placebo treatment significantly changed the basal serum GH levels in alcoholic men. These data show that alcoholism is associated with disrupted benzodiazepine activity on the hypothalamic-pituitary control of GH secretion. The simplicity of the diazepam GH-releasing test makes the drug suitable for clinical research in alcoholism.

Waltzman ML. Flunitrazepam: A review of "roofies". (review). Pediatric Emergency Care 15(1): 59-60, 1999. (6 refs.) This provides a brief review of a benzodiazepine Rohypnol, not licensed for use in the US, but licit in Europe and Asia as a short-term treatment of insomnia and as a sedative-hypnotic as well as a pre-anesthetic medication. Its potency is 10 times that of diazepam. It is available in the US on the black market. In the US it is most widely used in conjunction with alcohol, with which it has a synergistic effects and is known as the "date rape drug." It is reported to be used to potentiate and extend the sedative effects of heroin and methadone. This article discusses the clinical pharmacology, the acute effects, signs of overdose, laboratory analysis, and management of overdose.

White JM. Behavioral effects of caffeine co-administered with nicotine, benzodiazepines, and alcohol. IN: Gupta BS; Gupta U, eds. Caffeine and Behavior. Boca Raton: CRC Press Inc, 1999. pp. 75-86. (59 refs.) This chapter discusses the interactions of caffeine with nicotine, with benzodiazepines, and with alcohol. With nicotine, on the basis of animal studies, there appears to be additive effects, but there is little human research. With the benzodiazepines there appears to be a mutually antagonistic relationship. Caffeine in the presence of benzodiazepines has been seen to block the impairment of cognitive skills, block the increase in muscle relaxation, as well as the subjective sense of calming. This occurs at doses of caffeine that have little effect when administered alone. The interaction between caffeine and alcohol is complex. There has been seen a potentiation of some effects at low doses of caffeine and antagonism at higher does, a biphasic effect, with the same level of alcohol. Conversely the stimulant effects of alcohol are enhanced by low doses of caffeine and blocked by higher levels.

Whitman M. Case Study: The role of CEWG in identifying, tracking, and responding to Flunitrazepam (Rohypnol) abuse. Community Epidemiology Work Group, eds. Epidemiologic Trends in Drug Abuse. Volume II: Proceedings. December 1998. Bethesda MD: National Institute on Drug Abuse, 1999. pp. 437-439. (0 refs.) One of the roles of the Community Epidemiology Work Group (CEWG) is providing community-level surveillance of drug abuse by collecting and analyzing epidemiologic research and describing emerging drug abuse trends. Specifically, this paper discusses CEWG's role in identifying, tracking and responding to the flunitrazepam (Rohypnol) abuse epidemic in the United States from 1992 to 1997.

Yegles M; Marson Y; Wennig R. Influence of bleaching on stability of benzodiazepines in hair. Forensic Science International 107(1-3): 87-92, 2000. (8 refs.) In order to study the influence of hair bleaching on benzodiazepines concentrations, hair was treated with a bleaching product (Poly Blonde, Schwarzkopf & Henkel) for 20 min. The treated hair specimen was obtained from a person who died after an overdose of several illicit drugs associated with benzodiazepines. Bleached and non bleached hair were washed (acetone and water), pulverised and then incubated for 2 h in a thioglycolic solution. In the extracts obtained by solid-phase extraction on C-18 columns, the different drugs with the corresponding deuterated standards were derivatized and determined by GC-MS in a SLM mode. These results show that the concentrations of all the drug detected decreased in bleached hair in comparison with non treated hair. Whereas the diminution was less important for cocaine and benzoylecgonine (decrease of 24.6 and 36.4%, respectively), concentrations for codeine, 6- monoacetylmorphine and morphine decreased more significantly (decrease of 57.5, 88.6 and 67.4%, respectively) as well as those of diazepam, nordazepam and 7-aminoflunitrazepam (decrease of 39.7, 67.7 and 61.8%, respectively). The results in this study agree with those of other authors that bleaching affects the stability of cocaine and opiates incorporated in hair. These findings also point out that bleaching influences the stability of entrapped benzodiazepines in hair. Finally, these results reconfirm that it is very important to consider the cosmetic history of a hair sample in the interpretation of hair analysis results.

Yoshida K; Smith B; Kumar R. Psychotropic drugs in mothers' milk: A comprehensive review of assay methods, pharmacokinetics and of safety of breast-feeding. (review). Journal of Psychopharmacology 13(1): 64-80, 1999. (117 refs.) Many mentally ill women want to breast-feed their babies but, if they are taking psychotropic drugs, there is very little systematic data upon which to base decisions about whether or not it is safe to do so. We therefore attempt to provide a comprehensive and critical summary of existing case reports and of studies of breast-feeding in relation to commonly used psychotropic drugs. The literature review focuses on the following drugs: antidepressants: tricyclics and serotonin selective reuptake inhibitors (SSRIs); antipsychotic drugs: chlorpromazine, perphenazine, haloperidol and clozapine; mood stabilizers: lithium and carbamazepine; and benzodiazepines. The research literature consists mainly of single case reports and there have been very few attempts at controlled, longitudinal investigations. Findings are often difficult to compare because of differences in methods or because of lack of key information. Most data are available about the tricyclic antidepressants but even here we have found that the reports cover only a grand total of 66 mother- infant pairs. Dilemmas about whether or not to contraindicate breast-feeding arise most commonly in relation to postnatal depression. The findings to date suggest that provided that infants are healthy at the outset it is likely that the benefits of breast-feeding will outweigh potential hazards if their mothers are taking established tricyclic drugs at recommended dose levels. Much less is known about risks associated with SSRI antidepressants or about antipsychotic drugs such as phenothiazines and butyrophenones or mood stabilizers such as carbamazepine, all of which enter breast-milk. Safeguards are suggested for future single case studies, which, as they accumulate, will provide a platform for mounting controlled prospective studies properly to test for any acute toxic effects and for possible long- term adverse effects of such drugs on infants' development. Appendix I is a review of assay methods. Appendix 2 examines pharmacokinetic factors in newborn preterm and sick infants with special reference to contraindications to breast-feeding. Appendix 3 is a review of methods for assessing infant health and development.

Zack M; Toneatto T; MacLeod CM. Clinical use of benzodiazepines and decreased memory activation in anxious problem drinkers. Alcoholism: Clinical and Experimental Research 23(1): 174-182, 1999. (60 refs.) Clinical use of benzodiazepines (BZDs) may improve treatment outcome in anxious problem drinkers. Decreased activation of alcohol-related memories by negative affective cues may partly explain the beneficial effects of BZDs. To explore this possibility, the present study assessed semantic priming of alcohol words by negative affective words in anxious problem drinkers who received their standard dose of BZD and in unmedicated controls. Two groups of nine subjects each were matched on levels of anxiety, alcohol use, and alcohol dependence before performing a lexical decision task. Medicated subjects displayed significantly less activation than did unmedicated subjects on trials containing negative affective primes and alcohol- related targets, but displayed equivalent activation on control trials with neutral, categorized words. Degree of activation also correlated with a drug's affinity for the BZD receptor. These preliminary results suggest that BZD-induced amnesia may contribute to the therapeutic effects of these drugs in anxious problem drinkers.


Benzodiazepines have been widely prescribed as sedatives, hypnotics, anticonvulsants, anxiolytics and relaxants for more than 30 years. They are the most commonly prescribed group of drugs in the western world (1).

The benzodiazepines are considered safe and effective for use over a short period of time. However, this group of drugs has been widely over-prescribed, used as something of a 'cure-all' for all symptoms related to stress and their use has not been confined to patients whose anxiety is clearly handicapping. In the USA, as many as 13% of the population have used anxiolytic or sedative medication, mainly benzodiazepines (2). A MORI poll in 1985 on the use of tranquillizers in the UK, showed that around 23% of the adult population (10 million people) had been prescribed benzodiazepines at some time in their life (3); at this time, there were around 3 million chronic users in the UK (3,4).

It was originally thought that addiction to the benzodiazepines was rare (5) although the possibility of physical dependence was first described in 1963 (6). However, it is now clear that dependence can readily occur and, in some patients, very quickly. The vast majority (90%) of patients using benzodiazepines take the drug for less than 8 weeks and are able to stop without any problems (2). Long-term use, however, can produce dose-related extensions of the initial therapeutic action of the drug and withdrawal symptoms due to the development of tolerance and dependency.

There is an increasing number of people who have become addicted to the newer benzodiazepines which tend to have a shorter half-life than the older varieties such as diazepam. This situation has arisen as the awareness of the dependency properties of benzodiazepines has increased and because of a mistaken impression that newer varieties are less addictive. However, the possibilities for dependence seem to be essentially the same for all drugs in this group (7).

About one-third of patients taking benzodiazepines for longer than six months become addicted and for some, the period is much shorter (8,9,10); in the UK, it is estimated that about 500,000 are now dependent. In the USA, 1-3% of the population taking this group of drugs take them for longer than 12 months (2,11). All this despite claims that benzodiazepines are no longer effective as anxiolytics after 14 months treatment (12,13) and chronic usage is no more effective than brief counselling for the relatively minor affective disorders for which the drug is widely prescribed (l4). Severe withdrawal symptoms are not common if the drug is stopped within 2 weeks of the first dose and it has been recommended that regular administration should be limited to periods of 7 to 14 days (15).

Withdrawal symptoms occur in between 2-45% of benzodiazepine users (16). The acute and protracted withdrawal syndromes have been formally characterized (17,18,19). Withdrawal should be regarded as a severe illness with patients suffering considerable mental and physical distress. The onset of symptoms is related to the half-life of the specific drug being withdrawn, appearing soonest in those with the shortest half-life.

Initial symptoms are characterized by acute anxiety and psychotic symptoms 1-2 weeks after cessation (9) followed by a protracted period, often over many months, of gradual lessening of mental and somatic symptoms. The syndrome involves mixed psychological, neurological, cardiovascular and gastrointestinal symptoms and most patients experience many of them. Symptoms include insomnia, phobias - especially agoraphobia, panic attacks, rage, irritability, perceptual distortions, paraesthesia, numbness, ataxia, double or blurred vision, micturition problems, palpitations, hyperventilation, loss of libido, 'flu'-like symptoms, nausea, constipation, diarrhoea, dysphagia. It is thought that these symptoms do not represent a recurrence of the original anxiety or stressed state for which the drugs were first prescribed.

As well as inducing dependence, long-term use of benzodiazepines can also produce other problems (see 15,19). During pregnancy, the drugs cross the placenta, and if taken during late pregnancy, can cause depression and withdrawal symptoms in the neonate, as well as appearing in breast milk. Chronic use can produce depression and dulling of emotions and can aggravate presenting symptoms such as depression, insomnia, hyperactivity, exacerbation of seizures as well as causing uncharacteristic behaviour such as violence or petty theft. Endocrine symptoms include pre-menstrual irregularities, breast swelling in males and females. There is a possibility that chronic use is associated with structural changes in the brain.

As well as being used under prescription, benzodiazepines are used also by multiple-drug abusers 'on the street' but in a secondary role for self medication, often by addicts on methadone to alleviate anxiety. There has been the development of 'look-alike' drugs in the sedative/hypnotic/opiate area. These resemble a controlled drug but contain substances which are not controlled.


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  2. Baiter, M.B., Manheimer, D.I., Mellinger, G.D. et al. (1983). A cross-national comparison of antianxiety/sedative use. Curr Med Res Opinions 8 (Suppl 4), 5-20.

  3. Lacey, R. & Woodward, S. (1985). Survey on Tranquillisers. London, BBC Publications.

  4. National Tranquillizer Advisory Council. Annual Report 1985.

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  5. Murphy, S.M., Owen, R.T. & Tyrer, P.J. (1984). Withdrawal symptoms after six weeks' treatment with diazepam. Lancet ii, 1389.

  6. Kales, A., Scharf, M.B. & Kales, J.D. (1978). Rebound insomnia: a new clinical syndrome. Science (Wash) 201, 1039-1041.

  7. Boethius, G. (1983). Prescription pattern in 234 individuals with first prescription of hypnotic/sedatives in 1976 a 6 year follow-up. Proceedings of the Second World Conference on Clinical Pharmacology and Therapeutics, Abstract No. 418.

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  9. Burrows, G.D. & Davies, B. (1984). Recognition and management of anxiety. In: Antianxiety Agents. Eds. Burrows, G.D., Norman, T.R. & Davies, B., Amsterdam, Elsevier Science Publishers BV, pp. 1-11.

  10. Catalan, J. Br Gath, D.H. (1985). Benzodiazepines in 1976.

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  13. Hallström, C. & Lader, M.H. (1981). Benzodiazepine withdrawal phenomena. Int Psychopharmacol 16, 235-2A4.

  14. Petursson, H. & Lader, M.H. (1981). Withdrawal from long-term benzodiazepine treatment. Brit Med J 283, 643645.

  15. Ashton, H. (1984). Benzodiazepine withdrawal: an unfinished story.

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