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CORK Bibliography: Benzodiazepines

88 citations. 2008 to present

Prepared: June 2009

Alvarenga JM; de Loyola AI; Firmo JOA; Lima-Costa MF; Uchoa E. Prevalence and sociodemographic characteristics associated with benzodiazepines use among community dwelling older adults: Bambui Health and Aging Study (BHAS). Revista Brasileira de Psiquiatria 30(1): 7-11, 2008. (30 refs.)

Objectives: To assess the prevalence and sociodemographic characteristics associated with benzodiazepine use among community-dwelling older adults. Method. 1606 subjects, aged >= 60 years, corresponding to 92% of the residents of Bambui city, participated in this study. The information about medication use was obtained by means of a standard interview and the review of medication packaging. Substances were classified using the Anatomical Therapeutic Chemical Index. Results: The prevalence of benzodiazepine current use was 21.7% (26.7% among females and 14.0% among males). From these, 68.7% had been taking the medication for over one year 31.3% for over five years and 53.2% were using long half-life benzodiazepines. The medication most frequently used was bromazepam (35.6%), followed by diazepam (22.5%), clonazepam (12.6%) and lorazepam (7.8%). After adjustment for confounders, female gender (RP = 1.93; C195% = 1.51-2.46) was the only sociodemographic characteristic found to be independently associated with substance consumption. Conclusions: The prevalence of benzodiazepine use in the study population was high, but within the variation observed in developed countries. Chronic use of benzodiazepines and long half-life medications predominated.

Ambrozic J; Bunc M; Osredkar J; Brvar M. S100B protein in benzodiazepine overdose. Emergency Medicine Journal 25(2): 90-92, 2008. (22 refs.)

Background: Severe benzodiazepine overdose can result in coma and respiratory depression that might cause brain hypoxia, necrosis and delayed post-anoxic leucoencephalopathy with permanent neurological sequelae. The aim of this study was to assess the possible role of S100B, a structural protein of astroglial cells, as a biochemical marker of brain injury in acute benzodiazepine overdose. Methods: Serum S100B determination was performed in 38 consecutive patients admitted to the emergency department (ED) in Ljubljana with benzodiazepine overdose. The level of consciousness and respiratory insufficiency on the scene were assessed by responsiveness to a verbal stimulus and pulse oximetry. Blood samples were taken immediately after arrival at the ED and S100B concentrations were measured with a commercial immunoluminometric assay. 20 healthy sex- and age-matched volunteers formed a control group. Results: There were significant differences in S100B levels between the control group and the patients with benzodiazepine overdose according to their responsiveness to a verbal stimulus. Post hoc test results showed that S100B levels in patients with benzodiazepine overdose who were unresponsive to a verbal stimulus were significantly higher than those in patients responsive to a verbal stimulus (median 0.31 vs 0.11 mu g/l; p = 0.001). Both groups of patients with benzodiazepine overdose had significantly higher S100B levels than the control group (median 0.07 mu g/; both p = 0.001). Arterial oxygen saturation of patients with benzodiazepine overdose unresponsive to a verbal stimulus was significantly lower than in patients responsive to a verbal stimulus (median 83% vs 94%; p = 0.001). There was no significant difference in the systolic blood pressure of patients with benzodiazepine overdose responsive or unresponsive to a verbal stimulus. Conclusion: Raised levels of S100B protein are associated with depressed levels of consciousness and respiratory insufficiency in patients with benzodiazepine overdose.

Arbanas G; Arbanas D; Dujam K. Adverse effects if benzodiazepines in psychiatric outpatients. Psychiatria Danubina 21(1): 103-107, 2009. (18 refs.)

Background. Benzodiazepines are among the most frequently prescribed drugs. Of all their side. effects, hip fractures and possibility of developing dependence are usually studied. Objective: The aim of this study was to determine how often do psychiatric outpatients suffer from adverse effects of benzodiazepines, and which adverse effects do they notice. Subjects and method. 109 patients on two consecutive days were asked to fill in the questionnaire. Among them were 29 women and 80 men, Ten women (113) and 20 men (114) refused to participate in the study. Results: 68% of women and 93% of men used benzodiazepines at least once ill a lifetime; 40% of women used benzodiazepines in the last seven days, and 93% of men (32% of women and 44% of men used benzodiazepines every day for the last seven days). Unfortunately, 8%. of men used more then one benzodiazepine daily. All of the women who used benzodiazepines had at least one adverse effect; and 91% of men had adverse effects. One third of women and one quarter of met? stopped taking benzodiazepines due to adverse effects. The mean number of adverse effects was 4.8 both in men and women. Those who stopped taking benzodiazepines didn't have more adverse effects in comparison to those who continued to use them. More than half of the participants suffered from sleepiness, slowness and fatigue. One third of the participants said they noticed the change in sexual drive. More then 30% of women noticed dizziness and only 6% of men. None of the participants said to have jaundice after using benzodiazepines, The same adverse effects were present in those who stopped taking the drugs and in those who continued to use them. Conclusion: The prevalence of benzodiazepine use is very high in psychiatric patients. Many of them notice adverse effects, but mainly continue to use the drug.

Babalonis S; Emurian CS; Martin CA; Lile JA; Kelly TH. Modulation of the discriminative stimulus effects of triazolam across the menstrual cycle phase in healthy pre-menopausal women. Drug and Alcohol Dependence 94(1/3): 276-280, 2008. (31 refs.)

Pre-clinical studies indicate that changes in progesterone levels across menstrual cycle phases modulate the behavioral effects of sedative drugs acting at GABA(A) receptor sites. In this study, seven healthy women learned to discriminate triazolam (0.25 mg/70 kg) from placebo. After acquiring the discrimination. a ran-e of triazolam doses (0.00, 0.06, 0.12 and 0.25 mg/70 kg) was tested during the early follicular and mid-luteal menstrual cycle phases. During the mid-luteal phase, when progesterone levels were elevated, 0.12 mg/70 kg triazolam was identified as the active triazolam training dose (0.25 mg/70 kg), whereas 0.12 mg/70 kg triazolam was identified as placebo during the early follicular phase, when progesterone levels were low. Triazolam engendered prototypical sedative effects on subjective effect, performance and cardiovascular measures that were generally independent of cycle phase. These results suggest that the discriminative stimulus effects of the positive GABAA modulator, triazolam, are sensitive to menstrual cycle phase in healthy adult women.

Barry H; Appel J. Early preclinical studies of discriminable sedative and hallucinogenic drug effects. (review). Psychopharmacology 203(2): 193-201, 2009. (80 refs.)

One important technique in behavioral pharmacology is to train laboratory animals to discriminate between a psychoactive drug effect and a nondrug condition. Tests with different drugs have identified several categories of drugs that have different discriminable effects. The two authors describe and discuss the early research on discriminable effects of sedative and hallucinogenic drugs and their acquaintance with each other at Yale University prior to their early and frequent Publications on discriminable drug effects. Herb Barry studied sedative drugs primarily and Jim Appel studied hallucinogenic drugs. Sedative drugs include ethyl alcohol, barbiturates, and benzodiazepines. Their discriminable effects are largely attributable to the activation of an inhibitory neurotransmitter, gamma-amino butyric acid. Alcohol has the most pervasive effect in accordance with the high dose required to alter behavior. Hallucinogenic drugs include lysergic acid diethylamide and mescaline. They increase the activity of the neurotransmitter 5-hydroxytryptamine and, perhaps, dopamine in the central nervous system (CNS). In spite of their relatively low concentrations in the brain, both of these neurotransmitters have many important behavioral effects. Various sedative drugs cause a discriminable decrease in the function of the CNS. Different types of sedatives can be discriminated from each other. Indole and phenylethylamine hallucinogens have potent discriminative stimulus properties, which are related to the actions of biogenic amine neurotransmitters in the CNS.

Benitez CIP; Smith K; Vasile RG; Rende R; Edelen MO; Keller MB. Use of benzodiazepines and selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: A longitudinal and prospective study. American Journal of Geriatric Psychiatry 16(1): 5-13, 2008. (39 refs.)

Objective: The purpose of this study was to examine the use of benzodiazepines (BZs) and selective serotonin reuptake inbibitors/selective norepinepbrine reuptake inhibitors (SSRIs/SNRIs) over nine years of follow-up in middle-aged and older adults with diagnoses of panic disorder with or without agoraphobia, social phobia, or generalized anxiety disorder. Setting and Participants: Participants in this study were enrolled in the Harvard/Brown Anxiety Research Project (HARP). HARP is a naturalistic, longitudinal, multisite study of adults with anxiety disorders who are recruited from psychiatric settings. The analytic sample consisted of 51 participants with anxiety disorders who were 55 to 70 years old at baseline and a younger cobort of 211 participants added for comparative analysis. Design: The authors examined patterns of medication use (BZs and SSRIs/SNRIs) in participants with anxiety disorders as the aged, by assessing the proportion of participants taking they medications using generalized estimating equation modeling. Measurements: The present data were derived from the structured diagnostic interview administered at enrollment using a combination of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Third Edition-R Non-Affective Disorder, Patient Version, Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime, and subsequent follow-up interviews over a nine-year period using the Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis. Results: Findings showed that rates of BZ use were high among both the older (53% at baseline) and the younger (57.4%) age groups and did not significantly decrease over time, after controlling for time in episode of their anxiety disorders. There was a statistically significant increase in SSRI/SNRI use over time in both groups. At the beginning of the study, 18% of the older group and 21% of the younger group were using SSRIs/SNRls; however, at the end of the study, the rates increased to 35% and 43%, respectively, Conclusions: Although there was an increase in SSRI/SNRI use in older participants with anxiety disorders over the course of study, at nine years of follow-up, only 35% of participants were utilizing SSRI/SNRI medication, while more than one-half of the same participants were continuing to use BZs. To the authors' knowledge, there are no randomized clinical trials that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population. However, there is documented evidence of adverse effects of chronic BZ use and the risk of developing dependency in older populations.

Blythe CE; Aspey S; Pereira L; Milton D; Lewis R. Analysis of benzodiazepines in serum. LC GC Europe 2008(Supplement): 28-28, 2008. (0 refs.)

This application note details a method for the extraction and isolation of benzodiazepines from a biological matrix (serum) and their subsequent HPLC analysis.

Brands B; Blake J; Marsh DC; Sproule B; Jeyapalan R; Li S. The impact of benzodiazepine use on methadone maintenance treatment outcomes. Journal of Addictive Diseases 27(3): 37-48, 2008. (31 refs.)

The purposes of this study were to examine predictors of benzodiazepine use among methadone maintenance treatment patients, to determine whether baseline benzodiazepine use influenced ongoing use during methadone maintenance treatment, and to assess the effect of ongoing benzodiazepine use on treatment outcomes (i.e., opioid and cocaine use and treatment retention). A retrospective chart review of 172 methadone maintenance treatment patients (mean age = 34.6 years; standard deviation = 8.5 years; 64% male) from January 1997 to December 1999 was conducted. At baseline, 29% were "non-users" (past year) of benzodiazepine, 36% were "occasional users," and 35% were "regular/problem users." Regular/problem users were more likely to have started opioid use with prescription opioids, experienced more overdoses, and reported psychiatric comorbidity. Being female, more years of opioid use, and a history of psychiatric treatment were significant predictors of baseline benzodiazepine use. Ongoing benzodiazepine users were more likely to have opioid-positive and cocaine-positive urine screens during methadone maintenance treatment. Only ongoing cocaine use was negatively related to retention. Benzodiazepine use by methadone maintenance treatment patients is associated with a more complex clinical picture and may negatively influence treatment outcomes.

Brekke M; Rognstad S; Straand J; Furu K; Gjelstad S; Bjorner T et al. Pharmacologically inappropriate prescriptions for elderly patients in general practice: How common? Scandinavian Journal of Primary Health Care 26(2): 80-85, 2008. (33 refs.)

Objective. To assess Norwegian general practitioners' (GPs') level of potentially harmful drug prescribing for elderly patients. Design. Prescription data for 12 months were retrospectively retrieved from the Norwegian Prescription Database (NorPD). Data were assessed in relation to 13 prescription quality indicators. Setting. General practice. Subjects. A total of 454 GPs attending continuous medical education (CME) groups in Southern Norway, 85 836 patients >= 70 years who received any prescription from the GPs during the study period. Main outcome measures. Number of prescriptions assessed in relation to pharmacological inappropriateness based on a list of 13 explicit prescription quality indicators. Results. Some 18.4% of the patients (66% females with mean age 79.8 years, 34% males with mean age 78.7 years) received one or more inappropriate prescriptions from their GP. An NSAID in a potentially harmful combination with another drug (7%) and a long-acting benzodiazepine (4.6%) were the most frequent inappropriate prescriptions made. Doctor characteristics associated with more inappropriate prescribing practice were old age and working single-handed with many elderly patients. Conclusion. The study reveals areas where GPs' prescribing practice for elderly patients can be improved and which can be targeted in educational interventions.

Bulat T; Castle SC; Rutledge M; Quigley P. Clinical practice algorithms: Medication management to reduce fall risk in the elderly. Part 3, benzodiazepines, cardiovascular agents, and antidepressants. Journal of the American Academy of Nurse Practitioners 20(2): 55-62, 2008. (55 refs.)

There are associations between falls and the use of sedatives, psychotropics, cardiovascular agents, antidepressants, and polypharmacy. Our third article in the series will review the development of specific subalgorithms for benzodiazepines (BZDs), cardiovascular agents, and antidepressants (algorithms 3-5). We presented the process of development in our first article and the summary algorithm (algorithms 1 and 2) in our second article in this series. There are a number of ways in which drugs might increase the risk of an elderly person falling, most common being sedation, impaired balance and reaction time, orthostatic hypotension, and drug-induced parkinsonism. Medications are a potentially modifiable factor which can reduce fall risk The Guideline for the prevention of falls in older persons (American Geriatrics Society, British Geriatrics Society and American Academy of Orthopaedic Surgeons Panel of Falls Prevention, 2001) states that patients who have fallen should have their medications reviewed and altered or stopped as appropriate in light of their risk of future falls.

Caldentey CV; Gelabert FF; Garrido EG; Ojeda EM; Sabater CM; Canaves JL. Long-term effectiveness of an intervention to discontinue chronic benzodiazepine use. Actas Espanolas de Psiquiatria 36(5): 295-298, 2008. (13 refs.)

Introduction. We establish the long-term effectiveness of a brief intervention to withdraw from chronic benzodiazepine use. Methods. Follow-up after a randomized clinical trial. Setting: Three health care centers covering 82,000 inhabitants. Subjects: 135 patients who completed the previous clinical trial (66 from the intervention group, 63 from the control group, 6 had died). Intervention-measurements: The previous clinical trial compared an intervention consisting of standardized advice and a dose tapering schedule against a control group followed by usual care. Results were evaluated at 12 months. Main outcome: benzodiazepine use three years after the end of the clinical trial, type of drug and the reason for prescription. Results. After 3 years of follow up, 25/66 (37.9%) subjects from the intervention group and 14/63 (22.2%) from the control group were benzodiazepine free. The probability of withdrawal from benzodiazepine between patients in the intervention group was 41 % higher than in the control group. Relative risk: 1.41 (95% confidence interval: 0.98-1.66). In the intervention group, 16 from 31 (51.6%) patients who had withdrawn at 12 months were benzodiazepine free after 3 years. The most prescribed benzodiazepine is lorazepam (27.9%), followed by alprazolam (12.4%) and the main reason for prescription is anxiety (16.3%) followed by anxious-depressive disorder (10.9%). Conclusions. Even though there is a substantial relapse rate, the intervention to reduce chronic benzodiazepine use remains effective in the long-term.

Chang CM; Wu ECH; Chang IS; Lin KM. Benzodiazepine and risk of hip fractures in older people: A nested case-control study in Taiwan. American Journal of Geriatric Psychiatry 16(8): 686-692, 2008. (39 refs.)

Objective: To examine the characteristics of benzodiazepines usage and their associations with hip fractures. Method: All subjects were aged 65 and older and enrolled in the National Health Insurance program in Taiwan, 2001-2004. Cases (N = 217) were elderly patients who were identified with hip fractures for the first time in their outpatient claims. They were individually matched to 1,214 comparison patients based on age, gender, and index year. Benzodiazepine usage (doses, duration, half-life) and the other covariates including comorbidities, health care utilization, and psychotropic medications used in the 180 days before index events were constructed. Results: Using nonusers as reference group, use of benzodiazepines was significantly associated with hip fractures (adjusted odds ratio [AOR] = 1.7, 95% confidence interval [CI] = 1.2-2.5). Such risks appear to be particularly high during the first month (AOR = 5.6, 95% CI = 2.7-11.8) of exposure, doses higher than 3.0 mg/day in diazepam equivalents (AOR = 1.8, 95% CI = 1.1-3.1), and using short-acting benzodiazepines (AOR = 1.8, 95% CI = 1.3-2.7). Conclusions: Benzodiazepine exposure in the elderly increases the risk of hip fractures. This is true even with modest dosage, short-acting agents and short-term exposures. Clinicians should prescribe benzodiazepines judiciously with the elderly to minimize drug-related hip fractures.

Charlson F; Degenhardt L; McLaren J; Hall W; Lynskey M. A systematic review of research examining benzodiazepine-related mortality. (review). Pharmacoepidemiology and Drug Safety 18(2): 93-103, 2009. (66 refs.)

Purpose: This paper will review literature examining the association of benzodiazepine use and mortality. Methods: An extensive literature review was undertaken to locate all English-language published articles that examine mortality risk associated with use of benzodiazepines from 1990 onwards. Results Six cohort Studies meeting the criteria above were identified. The results were mixed. Three of the studies assessed elderly populations and did not find an increased risk of death associated with benzodiazepine use, whereas another study of the general population did find an increased risk, particularly for older age groups. A study of a middle aged population found that regular benzodiazepine use was associated with an increased mortality risk, and a Study of 'drug misusers' found a significant relationship between regular use of non-prescribed benzodiazepines and fatal overdose. Three retrospective population-based registry studies were also identified. The first unveiled a high relative risk (RR) of death due to benzodiazepine poisoning versus other outcomes in patients 60 or older when compared to those under 60. A positive but non-significant association between benzodiazepine use and driver-responsible fatalities in on-road motor vehicle accidents was reported. Drug poisoning deaths in England showed benzodiazepines caused 3.8% of all deaths caused by poisoning from a single drug. Conclusion: On the basis of existing research there is limited data examining independent effects of illicit benzodiazepine use upon mortality. Future research is needed to carefully examine risks of use in accordance with doctors' prescriptions and extra-medical use.

Christophersen AS; Morland J. Frequent detection of benzodiazepines in drugged drivers in Norway. Traffic Injury Prevention 9(2): 98-104, 2008. (25 refs.)

Objective. To describe the Norwegian system for handling suspected drugged driving cases according to an impairment-based law, with primary focus on benzodiazepines (BZDs), blood concentrations and combination with other psychoactive compounds. Methods. Routines for handling suspected driving under the influence of drugs other than alcohol are described. These include primary police investigation, blood sampling, and clinical tests of impairment performed by a police physician, a standard analytical program covering the most relevant illegal drugs and medicines relevant to traffic safety (approximately 25 compounds), and expert witness statements prepared for the court. The drug use patterns, blood drug concentrations, and frequency of multi-drug use have been recorded, with primary focus on benzodiazepines ( BZDs). Use of BZDs among apprehended drivers has been compared with patient prescriptions recorded for the same BZDs. Results. One or more drugs have been detected in approximately 80% of the cases received for analysis every year. BZDs have been the most prevalent drugs and have been detected in 38-57% of the cases, which is more frequent than other common illegal drugs; e. g., tetrahydrocannabinol (THC; 30-43%) and amphetamine (33-39%). The majority of the BZDs have been detected at supratherapeutic blood concentrations and frequently in combination with illegal drugs, other psychoactive medicines, or alcohol. Less than 5% of the BZDs ( except for nitrazepam - 7.6%) have been found to be the only drug present at therapeutic blood levels. The majority of the drivers were 20-39 years old (median age 29-33), while the majority of BZDs prescribed were to users over 50 years of age. Conclusions. Drivers with BZD detected are probably not representative of ordinary patients with BZD prescriptions, as shown by the age disparity of drivers and patients. The frequent detection of BZDs suggests that these compounds should be included in the analytical program used for blood samples from apprehended drivers and for studies on drug involvement in road traffic accidents and risk calculations.

Clements RM. Reducing psychotropic medications in elderly rehabilitation inpatients with a fall-related admission: How often is it happening? Geriatrics & Gerontology International 8(3): 139-142, 2008. (13 refs.)

Aim: To assess the frequency of psychotropic medication withdrawal in an inpatient geriatric rehabilitation population with a fall-related admission diagnosis. Methods: A retrospective medical record audit. The medical records department randomly selected 100 patients admitted between October 2006 and April 2007 to the geriatric rehabilitation ward of Casey Hospital with a fall-related admission diagnosis. Results: The population was predominantly female (71%) and elderly (average age, 80 years) with the vast majority of patients living at home (88%) prior to admission. Twenty-six of 49 (53%) of patients admitted on psychotropic medication were on a reduced regime by discharge (reduced dose or number of psychotropic medications). Just 7 of 100 patients had an increased psychotropic medication regime by discharge. Benzodiazepines were far more likely to be reduced (20/24, 83%) than other psychotropic medications. Conclusion: This audit does suggest an acceptable awareness in this geriatric rehabilitation setting of the fall risk posed by psychotropic medication. It needs to be further explored why benzodiazepines are so much more likely to be reduced in this population than other psychotropic medications, despite those other types also posing a significant fall risk.

Crouch DJ; Walsh JM; Cangianelli L; Quintela O. Laboratory evaluation and field application of roadside oral fluid collectors and drug testing devices. Therapeutic Drug Monitoring 30(2): 188-195, 2008. (16 refs.)

This study was a part of a collaborative U.S./E.U. international research effort (Roadside Testing Assessment, ROSITA 111) to assess illegal drug use among motor vehicle operators suspected of driving while under the influence of drugs and to evaluate the effectiveness of point-of-collection oral fluid drug detection technologies. A goal of the study was to assess commercial oral fluid drug testing devices for potential use in law enforcement. Ten devices were evaluated in the laboratory for their ability to meet manufacturers' claimed (and proposed) cutoff concentrations for the detection of amphetamine(s), cocaine/metabolite, opiates, cannabinoids, and benzodiazepines (2 devices). The field study portion of the research was conducted in major cities in the United States and Western Europe by teams of scientists working in collaboration with the local police. In Salt Lake City, Utah, the Drugwipe, Securetec, Ottobrunn, Germany (Securetec) oral fluids drug testing device was also evaluated in the field by testing suspected drug-impaired drivers. During the initial phase of the field study, 40 subjects were recruited. Drugwipe results were compared with laboratory-based immunoassay and mass spectrometry results and demonstrated that calculated sensitivities were between 75% and 100% depending on drug class. Specificities varied from 36% for cannabinoids to over 95% for opiates. During the second phase of the field study, 267 subjects were recruited. The Drugwipe sensitivities were 36.4%, 35.9%, 42.9%, and 7.7%, respectively, for amphetamine(s), cocaine, opiates, and cannabinoids. The Drugwipe specificifies were 99.2%, 97.4%, 99.6%, and 99.6%, respectively, for amphetamine(s), cocaine, opiates, and cannabinoids. Drugwipe failed to meet the study criteria for acceptable device performance, required performance sensitivities, and specificifies 90% or greater.

Culberson JW Ziska M. Prescription drug misuse/abuse in the elderly. Geriatrics 63(9): 22+, 2008. (25 refs.)

One quarter of the prescription drugs sold in the United States are used by the elderly, often for problems such as chronic pain, insomnia, and anxiety. The prevalence of abuse may be as high as 11% with female gender, social Isolation, depression, and history of substance abuse Increasing risk. Screening instruments for prescription drug abuse have not been validated in the geriatric population. Benzodiazepines, opiate analgesics, and some skeletal muscle relaxants may result in physical dependence; however, tolerance, withdrawal syndrome, and dose escalation may be less common in the older patient. Lower doses may decrease the risk of abuse and dependence; however, fear of abuse often results in a failure to adequately treat symptoms such as anxiety, pain, and insomnia.

Da Silveira DX; Rosa-Oliveira L; Di Pietro M; Niel M; Doering-Silveira E; Jorge MR. Evolutional pattern of drug use by medical students. Addictive Behaviors 33(3): 490-495, 2008. (10 refs.)

Recent use of psychoactive substances among 456 medical students throughout the six grades was surveyed by way of a self-report questionnaire using World Health Organisation criteria. Among male medical students, the most frequently used substances were alcohol (80.5%), cannabis (25.3%), solvents (25.2%), and tobacco (25.2%), whereas among female students the most frequently used drugs were alcohol (72.6%), tobacco (14.6%), solvents (10.5%), and tranquillizers (7.5%). Switch from illegal to legal drugs were observed only among female medical students. Male students tend to alternate cannabis and solvents throughout college years. Interventions aiming to influence patterns of drug consumption among medical students must consider both gender differences and evolutional patterns of substance use throughout medical course.

de Lusignan S; Buxton N; Kent A. 10-minute consultation: New patient asking for a benzodiazepine prescription. (editorial). British Medical Journal 337(e-article 658), 2008. (0 refs.)

Demyttenaere K; Bonnewyn A; Bruffaerts R; De Girolamo G; Gasquet I; Kovess V; Haro JM; Alonso J. Clinical factors influencing the prescription of antidepressants and benzodiazepines: Results from the European Study of the Epidemiology of Mental Disorders (ESEMeD). Journal of Affective Disorders 110(1/2): 84-93, 2008. (25 refs.)

Objective: To examine factors associated with the use of antidepressants (AD) and benzodiazepines (BZD) in 6 European countries. Methods: A cross-sectional, population-based study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. 21,425 non-institutionalized individuals aged 18 years and over were interviewed using the third version of the Composite International Interview (C[D]-3.0). Respondents were asked about AD and BZD use, and whether they consulted formal health services for emotional problems in the previous year. Sociodemographic variables, presence of mood/anxiety disorders and of painful physical symptoms were collected. Results: 34.38% and 9.17% of the sample reported the use of AD and BZD respectively in the previous 12 months. Only 29.95% of subjects with a 12-month prevalence of major depressive episode (MDE) had been taking antidepressants. After controlling for several clinical and non-clinical factors, help seeking for emotional problems was the most important independent predictor for the use of AD or BZD (OR: 13.58 and 5.17, respectively). Higher age was the second important predictor (OR: 6.52 and 4.86, respectively). A 12-month or lifetime prevalence of MDE or an anxiety disorder were also predictors for AD or BZD use (OR for MDE: 5.00 and 2.82, OR for anxiety disorders: 2.13 and 1.85). Finally, the presence of painful physical symptoms also predicted the use of AD and BZD, while female gender, lower education and higher age predicted only the use of BZD. Conclusion: Less than one third of subjects with a 12-month prevalence of MDE had been taking antidepressants. But seeking help for emotional problems was a more important predictor of the use of ADs or BZDs than a formal (DSM-IV) psychiatric diagnosis, suggesting that usage of ADs is not always according to the licensed DSM-IV indication.

Dubois S; Bedard M; Weaver B. The impact of benzodiazepines on safe driving. Traffic Injury Prevention 9(5): 404-413, 2008. (48 refs.)

Objective. Benzodiazepines are prescribed to relieve anxiety and aid sleep. Studies demonstrate that benzodiazepines increase odds of crash involvement, but little evidence exists regarding their impact on crash responsibility. We examined the impact of benzodiazepines on crash responsibility by drug half-life and driver age, using a case-control design with drivers aged 20 and over involved in fatal crashes in the United States from 1993-2006. Methods. Drivers (all with BAC = 0) were classified as having no benzodiazepines detected versus short, intermediate, or long half-life benzodiazepines. Cases were drivers with at least one potentially unsafe driving action (UDA) in relation to the crash (e.g., speeding), a proxy measure for crash responsibility; controls had no UDAs recorded. Odds ratios (ORs) of any UDA by benzodiazepines half-life exposure were calculated, with adjustment for age, sex, other medication usage, and prior driving record. Results. Compared with drivers not using benzodiazepines, drivers taking intermediate or long half-life benzodiazepines demonstrated increased odds of an UDA from ages 25 (intermediate OR: 1.59; 95% CI = 1.08, 2.33; long OR: 1.68; 95% CI = 1.34, 2.12) to 55 (intermediate OR: 1.50; 95% CI = 1.09, 2.06; long OR: 1.33; 95% CI = 1.12, 1.57). Drivers taking short half-life benzodiazepines did not demonstrate increased odds compared to drivers not using benzodiazepines. Conclusions. Given the potential impact of benzodiazepines on driver safety, further experimental research is needed to better understand the effect of benzodiazepines on crash responsibility.

Elger BS. Prisoners' insomnia: To treat or not to treat? Medical decision-making in places of detention. Medicine, Science and the Law 48(4): 307-316, 2008. (43 refs.)

Insomnia is a frequent reason for medical and psychiatric consultation in prisons. Medical decision-making in correctional health care should be based on the same principles as outside correctional institutions. In places of detention, principles should be balanced according to the same criteria as outside correctional institutions, while taking into account the unique harm-benefit ratios related to the specific context. The aim of this paper was to examine the existing attitudes and ethical issues related to decision-making about insomnia evaluation and treatment in places of detention. An analysis of the ethical issues and an evidence-based review of the consequences of different attitudes and treatments with regard to prison medicine were carried out. Insomnia is a public health problem and requires adequate evaluation and treatment to avoid more serious health consequences both within and outside correctional institutions. Insomnia treatment in places of detention is an ethical dilemma, but there is no evidence-based reason to avoid benzodiazepines in prison completely and to use only neuroleptics and antidepressants, which might represent more dangerous and less efficient treatment. In prison medicine, should we even treat insomnia? Widely accepted ethical strategies of decision-making indicate that we should. Institutional guidelines on insomnia should be based on ethically sound decision-making that takes into account the available evidence.

Farrell M; Marsden J. Acute risk of drug-related death among newly released prisoners in England and Wales. Addiction 103(2): 251-255, 2008. (18 refs.)

Aims: To investigate drug-related deaths among newly released prisoners in England and Wales. Design Database linkage study. Participants National sample of 48 771 male and female sentenced prisoners released during 1998-2000 with all recorded deaths included to November 2003. Findings There were 442 recorded deaths, of which 261 (59%) were drug-related. In the year following index release, the drug-related mortality rate was 5.2 per 1000 among men and 5.9 per 1000 among women. All-cause mortality in the first and second weeks following release for men was 37 and 26 deaths per 1000 per annum, respectively (95% of which were drug-related). There were 47 and 38 deaths per 1000 per annum, respectively, among women, all of which were drug-related. In the first year after prison release, there were 342 male deaths (45.8 were expected in the general population) and there were 100 female deaths (8.3 expected in the general population). Drug-related deaths were attributed mainly to substance use disorders and drug overdose. Coronial records cited the involvement of opioids in 95% of deaths, benzodiazepines in 20%, cocaine in 14% and tricyclic antidepressants in 10%. Drug-related deaths among men were more likely to involve heroin and deaths among women were more likely to involve benzodiazepines, cocaine and tricyclic antidepressants. Conclusions: Newly released male and female prisoners are at acute risk of drug-related death. Appropriate prevention measures include overdose awareness education, opioid maintenance pharmacotherapy, planned referral to community-based treatment services and a community overdose-response using opioid antagonists.

Focazio MJ; Kolpin DW; Barnes KK; Furlong ET; Meyer MT; Zaugg SD et al. A national reconnaissance for pharmaceuticals and other organic wastewater contaminants in the United States - II) Untreated drinking water sources. Science of the Total Environment 402(2-3): 201-216, 2008. (57 refs.)

Numerous studies have shown that a variety of manufactured and natural organic compounds such as pharmaceuticals, steroids, surfactants, flame retardants, fragrances, plasticizers and other chemicals often associated with wastewaters have been detected in the vicinity of municipal wastewater discharges and livestock agricultural facilities. To provide new data and insights about the environmental presence of some of these chemicals in untreated sources of drinking water in the United States targeted sites were sampled and analyzed for 100 analytes with sub-parts per billion detection capabilities. The sites included 25 ground- and 49 surface-water sources of drinking water serving populations ranging from one family to over 8 million people. Sixty-three of the 100 targeted chemicals were detected in at least one water sample. Interestingly, in spite of the low detection levels 60% of the 36 pharmaceuticals (including prescription drugs and antibiotics) analyzed were not detected in any water sample. The five most frequently detected chemicals targeted in surface water were: cholesterol (59%, natural sterol), metolachlor (53%, herbicide), cotinine (51%, nicotine metabolite), beta-sitosterol (37%, natural plant sterol), and 1,7-dimethylxanthine (27%, caffeine metabolite); and in groundwater: tetrachloroethylene (24%, solvent), carbamazepine (20%, pharmaceutical), bisphenol-A (20%, plasticizer), 1,7-dimethylxanthine (16%, caffeine metabolite), and tri (2-chloroethyl) phosphate (12%, fire retardant). A median of 4 compounds were detected per site indicating that the targeted chemicals generally occur in mixtures (commonly near detection levels) in the environment and likely originate from a variety of animal and human uses and waste sources. These data will help prioritize and determine the need, if any, for future occurrence, fate and transport, and health-effects research for subsets of these chemicals and their degradates most likely to be found in water resources used for drinking water in the United States.

Fonad E; Emami A; Wahlin TBR; Winblad B; Sandmark H. Falls in somatic and dementia wards at Community Care Units. Scandinavian Journal of Caring Sciences 23(1): 2-10, 2009. (57 refs.)

Falls and fall injuries are common problems for patients at nursing homes in Sweden. Impaired cognitive function, a poor sense of orientation and a high intake of medicine, can lead to an increase in falls among older people. The objective of this study was to investigate the associations between falls and: fall risks, fractures, the use of physical restraints and the use of certain medications in somatic and dementia wards, respectively. The study design is ecological, and aggregated data regarding falls, fall risk assessments, fractures, the use of physical restraints and medication were collected between 2000 and 2003. The Pearson correlation analysis and regression analyses were used to investigate associations between fall risks, medication, fractures, wheelchair-bound situations, bed rails and falls. The total number of reported fall incidents was 2651; of these, 737 incidents were registered in dementia wards and 1914 in somatic wards. Dementia wards and somatic wards differed regarding falls and fractures, as it was only in dementia wards that falls were associated with fractures. There was also a significant correlation between falls and assessed risk of falling, the use of certain medication, and physical restraints such as wheelchairs and bed rails in dementia wards. Falls at somatic wards were associated with the use of sleeping pills with benzodiazepines. For dementia wards there were associations between falls and fractures, physical restraints and the use of certain medications. Fractures were associated with the use of neuroleptics, sleeping pills and sleeping pills with benzodiazepines. At somatic wards, falls correlated with the use of sleeping pills with benzodiazepines, and with the use of wheelchairs and bed rails.

Ghitza UE; Epstein DH; Preston KL. Self-report of illicit benzodiazepine use on the Addiction Severity Index predicts treatment outcome. Drug and Alcohol Dependence 97(1-2): 150-157, 2008. (56 refs.)

The relationship between pre-treatment illicit benzodiazepine use (days of use in the last 30) assessed on the Addiction Severity Index (ASI) and treatment outcome was investigated by retrospective analysis of data from two controlled clinical trials in 361 methadone maintained cocaine/opiate users randomly assigned to 12-week voucher- or prize-based contingency management (CM) or control interventions. Based on screening ASI, participants were identified as non-users (BZD-N; 0 days of use) or users (BZD-U; >0 days of use). Outcome measures were: urine drug screens (thrice weekly): quality of life and self-reported HIV-risk behaviors (every 2 weeks): and current DSM-IV diagnosis of cocaine and heroin dependence (study exit). In the CM group, BZD-U had significantly worse outcomes on in-treatment cocaine use, quality-of-life scores, needle-sharing behaviors, and current heroin dependence diagnoses at study exit compared to BZD-N. In the control group. BZD-U had significantly higher in-treatment cocaine use but did not differ from BZD-N on psychosocial measures. Thus, in a sample of non-dependent BZD users, self-reported illicit BZD use on the ASI, even at low levels, predicted worse outcome on cocaine use and blunted response to CM.

Gibson JE; Hubbard RB; Smith CJP; Tata LJ; Britton JR; Fogarty AW. Use of self-controlled analytical techniques to assess the association between use of prescription medications and the risk of motor vehicle crashes. American Journal of Epidemiology 169(6): 761-768, 2009. (22 refs.)

Case-crossover and case-series analyses are 2 epidemiologic approaches that can be used to evaluate the association of exposures with acute events. Using a primary care database from the United Kingdom and these 2 statistical approaches, the authors investigated the impact of using benzodiazepines, nonbenzodiazepine hypnotics, beta-blockers, selective serotonin reuptake inhibitors, tricyclic antidepressants, opioids, and antihistamines on the risk of motor vehicle crashes in 1986-2004. For 49,821 individuals aged 18-74 years, involvement in a motor vehicle crash was documented. The outcome of the case-crossover analyses varied according to the choice of control period, so the case-series approach was preferred. The first 4 weeks of treatment with a combined acetaminophen and opioid preparation was associated with an increased risk of motor vehicle crash (incidence rate ratio = 2.06, 99% confidence interval: 1.84, 2.32), as was use of an opioid alone (incidence rate ratio = 1.70, 99% confidence interval: 1.39, 2.08) and benzodiazepines (incidence rate ratio = 1.94, 99% confidence interval: 1.62, 2.32). Use of selective serotonin reuptake inhibitors, nonbenzodiazepine hypnotics, and antihistamines for more than 4 weeks was associated with motor vehicle crash, but shorter term use was not. The results obtained are broadly consistent with those from well-designed case-control studies and demonstrate how case-only techniques optimize the use of routinely collected data for epidemiologic studies.

Gidai J; Acs N; Banhidy F; Czeizel AE. A study of the teratogenic and fetotoxic effects of large doses of chlordiazepoxide used for self-poisoning by 35 pregnant women. Toxicology and Industrial Health 24(1-2): 41-51, 2008. (34 refs.)

The human teratogenic potential of chlordiazepoxide is debated. To study the effects on the fetal development of very large doses of chlordiazepoxide that were used for a suicide attempt during pregnancy, self-poisoned pregnant women were identified from patients in a toxicological inpatient clinic in Budapest, Hungary. Comparisons were made between congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status of the exposed children born to mothers who attempted suicide with chlordiazepoxide alone or in combination with other drugs during pregnancy and their sib controls. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 88 (8.4%) used chlordiazepoxide with or without other drugs for suicide attempt;. 35 of these women delivered five-born infants. Doses of chlordiazepoxide taken ranged between 20 and 300 mg, with a mean of 117 +/- 86 mg. Of 35 exposed children, six (17.1%) were affected with congenital abnormalities compared with three (13.6%) of their 22 sibs (OR with 95% CI: 1.3 (0.3-4.4). Of 18 pregnant women who attempted suicide between the 4th and 12th postconceptional week, the period most sensitive to congenital malformation, four delivered live-born children affected with a congenital abnormality (atrial septal defect type II, complex defect of respiratory system, mild pyelectasis because of the stenosis of ureteropelvic junction, congenital inguinal hernia). Two other children had fetal alcohol syndrome and unrecognized multiple congenital abnormality including talipes equinovarus, deformation type, and four minor anomalies. The pregnancy age-specific mean birth weight indicated intrauterine fetal growth retardation, which was confirmed by a dose-response relationship and by the higher rate of : low birth-weight newborns. Cognitive status and behavioral scale of exposed children did not indicate neurotoxic effects. Very large doses of chlordiazepoxide used for suicide attempts during pregnancy did hot induce a higher rate of congenital abnormalities but were associated with dose-dependent intrauterine growth retardation.

Gidai J; Acs N; Banhidy F; Czeizel AE. An evaluation of data for 10 children born to mothers who attempted suicide by taking large doses of alprazolam during pregnancy. Toxicology and Industrial Health 24(1-2): 53-60, 2008. (27 refs.)

FDA has identified alprazolam, a new type of benzodiazepine, as pregnancy category D. The objective of this study was to evaluate the effects on fetal development of very large doses of alprazolam that were used for suicide attempts during pregnancy. Pregnant women were identified among the patients of the Department of Toxicology Internal Medicine, Koranyi Hospital, Budapest, who were admitted as self-poisoned subjects from a total population of the three million people of Budapest and its surrounding region. Rates of congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status were compared between children born to mothers who attempted suicide during pregnancy using alprazolam alone or in combination with other drugs and in their sib controls. Between 1984 and 1993, 559 pregnant women attempted suicide during pregnancy with drugs: 30 of these women self-poisoned with alprazolam, 10 delivered live-born infants who were examined. Doses of alprazolam used were between 7.5 and 100 mg, with a mean of 30 mg. Six of the 10 exposed children were born to mothers who attempted suicide between the 6th and 12th postconceptional weeks. Of the 10 exposed children, two had congenital abnormalities. One-had a multiple congenital abnormality that included atypical gastroschisis and minor anomalies; an association of this defect and the 30 mg alprazolam used for self-poisoning in the 14th postconceptional week cannot be excluded. Another exposed child had mild pectus excavatum, but the times of the suicide attempt and the critical period for producing this defect did not overlap. Of 12 sibs, one had a multiple congenital abnormality. Thus, the rate of congenital abnormalities did not significantly differ between exposed children and their sibs. Mean birth weight was higher for babies born to mothers who attempted suicide by alprazolam during pregnancy than in their sib controls. Cognitive status and behavioral scale of the exposed children did not indicate fetotoxic effects, including neurotoxic effects, of large doses of alprazolam. The large doses of alprazolam used for self-poisoning during pregnancy did not result in a significantly higher rate of congenital abnormalities: however, there were only 10 self-poisoned pregnant women, and an association of one multiple congenital abnormality with a large dose of alprazolam cannot be excluded. The findings in this study did not identify fetotoxicity, including neurotoxicity, of very large doses of alprazolam. Our study shows that the self-poisoning model is feasible and provides beneficial information for use in estimating human teratogenic and fetotoxic risks of drugs.

Gidai J; Acs N; Banhidy F; Czeizell AE. No association found between use of very large doses of diazepam by 112 pregnant women for a suicide attempt and congenital abnormalities in their offspring. Toxicology and Industrial Health 24(1-2): 29-39, 2008. (40 refs.)

The teratogenic potential of diazepam is debated. The objective of this study was to examine the effects of extremely high doses of diazepam used for attempted suicide during pregnancy on embryo-fetal development. Pregnant women were identified from the female patients of the Department of Toxicology Internal Medicine, Koranyi Hospital, Budapest, who had been admitted as, self-poisoned subjects from the three million people of Budapest and the surrounding region. This evaluation compares the incidences and types of congenital abnormalities observed in exposed children born to mothers who attempted suicide with diazepam alone or in combination with other drugs during pregnancy with their sib controls. The database consists of a total of 1044 women with self-poisoning during pregnancy between 1960 and 1993. Of these 1044 self-poisoned pregnant women, 229 (21.9%) used diazepam with or without other drugs for a suicide attempt; 112 of these women delivered live-born infants. Doses of diazepam taken ranged between 25 and 800 mg. Of 112 exposed children, 15 (13.4%) had congenital abnormalities, whereas of their 112 matched sibs, eight (7.1%) had congenital abnormalities (odds ratios with 95% confidence intervals: 2.0, 0.8-5.0). Of 37 pregnant women who attempted suicide between the 4th and 12th postconceptional weeks, five (13.5%) delivered live-born babies with a congenital abnormality (undescended testis in two exposed children; congenital dysplasia of the hip, talipes equinovarus deformation type, congenital inguinal hernia-each in one exposed child). The suicide attempts of the mothers of these children did not occur during the critical periods for induction of these defects, indicating that the observations were unrelated to diazepam. The very large doses of diazepam used for self-poisoning during pregnancy did not increase the rate of congenital abnormalities in the offspring.

Glintborg B; Olsen L; Poulsen H; Linnet K; Dalhoff K. Reliability of self-reported use of amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates among acutely hospitalized elderly medical patients. Clinical Toxicology 46(3): 239-242, 2008. (21 refs.)

Background. Undisclosed use of illicit drugs and prescription controlled substances is frequent in some settings. The aim of the present study was to estimate the reliability of self-reported use of amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates among acutely hospitalized medical patients. Methods. Patients admitted to an acute medical department were interviewed about their drug use. Patients provided blood and urine samples for drug analysis. Results of a toxicology screen were compared to self-reported drug use. Toxicology screens positive for drugs not reported during the interview were only considered truly positive after verification by a substance specific analysis. Results. Five hundred patients were included. The median age was 72 years and 298 (60%) were female. In total, 103 patients (21%) reported use of opiates and 65 patients (13%) used benzodiazepines. Only 8 patients reported use of illicit drugs (cannabinoids, 2%). Toxicology analyses were performed in a randomly selected sub-sample of 100 patients. Among 27 patients (27%), the analyses indicated use of one or more drugs, mainly benzodiazepines (15 patients), morphine (12 patients) or cannabinoids (5 patients). Another 6 patients had screenings unexpectedly positive for opiates, but the verification analysis indicated use of codeine-containing drugs. The overall sensitivity of self-reports in detecting drug use was 66%. The negative predictive value of a patient not reporting use of a drug was over 90% for all 7 drug-types screened. Conclusion. Among 100 randomly selected mainly elderly medical patients, undeclared use of illicit drugs was rare. However, some patients underreported use of benzodiazepines and cannabinoids.

Godfrey C; Heather N; Bowie A; Brodie J; Parrott S; Ashton H et al. Randomised controlled trial of two brief interventions against long-term benzodiazepine use: Cost-effectiveness. Addiction Research & Theory 16(4): 309-317, 2008. (9 refs.)

Previous findings have indicated that a letter from a patient's General Practitioner (GP) and a short GP consultation leads to reduced intake among long-term benzodiazepine (BZD) users. To compare the cost-effectiveness and potential cost savings of these two brief interventions. Economic evaluation conducted alongside a prospective randomised controlled trial from the perspective of the NHS. A total of 273 long-term BZD users (double right arrow 6 mos) at seven general practices and regarded by their GPs as suitable to take part in the study within the Newcastle and North Tyneside District Health Authority were identified from repeat prescription computer records. Patients were randomised to usual GP care + assessment only or the offer of a short consultation (12 mins approx) with the patient's GP (or practice pharmacist/practice nurse) or a letter signed by the GP advising gradual reduction in BZD intake. Economic measures taken were: costs of intervention; savings (costs) of changes in health service use from before to after intervention; savings to the NHS from reductions in drug use and dispensing costs; total costs of brief intervention; simulations of savings (costs) extrapolated to the District Health Authority. The letter was the more cost-effective intervention when taking into account changes in health service use and savings to the drugs bill. If all GPs in Newcastle and North Tyneside screened long-term BZD users on their lists and sent the letter studied here to those considered suitable to receive it, it is estimated that savings to the District Health Authority would be a minimum of 4.9 pound million per annum. Routine implementation of the letter intervention in general practice throughout the UK would result in large financial gains to the NHS. These savings represent a conservative estimate of savings to the public sector, as wider savings to the social care system may also be expected as a result of the policy.

Gompel CHPAV; Wensing M; De Smet PAGM. Implementation of a discontinuation letter to reduce long-term benzodiazepine use: A cluster randomized trial. Drug and Alcohol Dependence 99(1-3): 105-114, 2009. (42 refs.)

Rationale: Although it is recommended to restrict long-term use of benzodiazepines, and considerable attention has been paid to this, long-term use continues to be a problem. An informative discontinuation letter for patients has been shown to reduce long-term benzodiazepine use in general practice. However, little is known about its wide scale implementation in primary care. Objective: To determine the effectiveness of an intensive Support programme for community pharmacies to send discontinuation letters to patients in cooperation with GPs. Methods: In a Cluster randomized trial, 43 control pharmacies received a written manual and 47 experimental pharmacies received an intensive Support programme. Primary outcome measures were the percentage of GPs who reviewed and returned lists of eligible patients and the percentage of long-term users who were sent it discontinuation letter within 4 months. Results: The outcomes did not differ for the experimental versus control groups: 38% and 31% of the GPs, respectively, returned the patient lists; 14% and 10% of all long-term users in the two groups, respectively, received the discontinuation letter within 4 months. Substantially more pharmacies in the experimental group than in the control group finally managed to send discontinuation letters (70% vs. 40%). Conclusion: About one third of the pharmacies in the control group and two thirds of the pharmacies in the intervention group finally implemented the discontinuation letter. However, this difference was not apparent in the primary outcome measures. It seems crucial to involve GPs more effectively ill implementation of the discontinuation letter.

Gorgels W; Voshaar RO; Mol A; Van de Lisdonk E; Mulder J; Van den Hoogen H et al. A benzodiazepine discontinuation programme does not increase the frequency of contacts with the family practice. Scandinavian Journal of Primary Health Care 26(2): 74-79, 2008. (15 refs.)

Objective. The efficacy of programmes to reduce long-term benzodiazepine use could be compromised by subsequent increases in contacts with the family practice. In this study the hypothesis was tested as to whether participation in a benzodiazepine discontinuation programme affects the frequency of contacts with the family practice. Design. A controlled stepped-care intervention programme to decrease long-term benzodiazepine use. Setting. Family practices in the Netherlands. Subjects. The experimental group consisted of 996 long-term benzodiazepine users and a control group of 883 long-term benzodiazepine users. Main outcome measures. Practice contacts before and up to 12 months after the start of the programme. Results. There was a general tendency visible for contacts to decrease during the follow-up time. The course of the number of contacts during the follow-up was not different for the experimental and control groups (p = 0.45). The level of non-benzodiazepine prescriptions was generally not altered. The number of non-benzodiazepine prescriptions decreased in benzodiazepine quitters during the follow-up of the programme. Conclusion. No clinically important differences in practice contacts were observed when the course of the number of contacts and non-benzodiazepine prescriptions were compared between the experimental and control groups. Family practitioners do not have to anticipate an increased workload associated with participation in such a benzodiazepine discontinuation programme.

Gustavsen I; Brarnness JG; Skurtveit S; Engeland A; Neutel I; Morland J. Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam. Sleep Medicine 9(8): 818-822, 2008. (31 refs.)

Background: Despite the high prescription rate of benzodiazepine-like hypnotics (z-hypnotics), there is limited information on the road traffic accident risk associated with the use of these drugs. We wanted to investigate whether filling a prescription for zopiclone or zolpidem was associated with increased risk of road traffic accidents at a national population level. Nitrazepam and flunitrazepam were used as comparator drugs. Method: All Norwegians 18-69 years (3.1 million) were followed-up from January 2004 until the end of September 2006. Information on prescriptions, road traffic accidents and emigration/death was obtained from three Norwegian population-based registries. The first week after the hypnotics had been dispensed was considered to be the exposure period. Standardized incidence ratios (SIRs) were calculated by comparing the incidence of accidents in the exposed person-time to the incidence of accidents in the unexposed person-time. Results: During exposure, 129 accidents were registered for zopiclone, 21 for zolpidem, 27 for nitrazepam and 18 for flunitrazepam. The SIRs were (SIR for all ages and both sexes combined; 95% CI): z-hypnotics (zopiclone + zolpidem) 2.3; 2.0-2.7, nitrazepam 2.7; 1.8-3.9 and flunitrazepam 4.0; 2.4-6.4. The highest SIRs were found among the youngest users for all hypnotics. Conclusions: This study found that users of hypnotics had a clearly increased risk of road traffic accidents. The SIR for flunitrazepam was particularly high.

Hausken A; Furu K; Skurtveit S; Engeland A; Bramness J. Starting insomnia treatment: The use of benzodiazepines versus z-hypnotics. A prescription database study of predictors. European Journal of Clinical Pharmacology 65(3): 295-301, 2009. (29 refs.)

Drugs prescribed for the treatment of insomnia can be either benzodiazepine hypnotics or the newer z-hypnotics, zopiclone and zolpidem. This paper explores possible explanations for the choice made. Data from the Norwegian Prescription Database covering the entire population was studied for incident users of hypnotics. Possible predictors were age, gender, previous psychotropic or analgesic drug use and prescriber speciality. Of the 73,163 incident users of hypnotics, 3876 were prescribed benzodiazepine hypnotics in 2006. The strongest predictors for being prescribed benzodiazepines were previous use of anxiolytics [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.7-2.0] and male gender (OR 1.5, 95% CI 1.4-1.6). Other significant predictors were antipsychotic or opioid drug use and the prescriber being a psychiatrist. Z-hypnotics were commonly prescribed. Norwegian drug therapy recommendations also suggest a preference for z-hypnotics. The clear predominance of the shorter acting z-hypnotics may be due to the fact that only longer acting benzodiazepines are available in Norway. Reasons for prescribing benzodiazepines may be co-morbid psychiatric illness, such as anxiety, or a belief that benzodiazepine hypnotics are more effective than z-hypnotics.

Henthorn TK; Krejcie TC; Avram MJ. Early drug distribution: A generally neglected aspect of pharmacokinetics of particular relevance to intravenously administered anesthetic agents. (editorial). Clinical Pharmacology and Therapeutics 84(1): 18-22, 2008. (24 refs.)

There is considerable variability in response to intravenously administered anesthetic drugs (e.g., hypnotics, benzodiazepines, and narcotics) that have a rapid onset of effect (such as hypnosis, anxiolysis, and analgesia) and a low margin of safety (because of cardiovascular or respiratory depression, etc.). although the onset of effect for these drugs occurs seconds to minutes after injection, traditional pharmacokinetic models are based on blood samples that are first obtained after drug effects have peaked. As a result, many studies have failed to provide a pharmacokinetic rationale for dosage adjustments of these drugs.

Horowitz A; Galanter M; Dermatis H; Franklin J. Use of and attitudes toward club drugs by medical students. Journal of Addictive Diseases 27(4): 35-42, 2008. (12 refs.)

This study assesses medical students' use of and attitudes towards club drugs, classified as "Generation I" (i.e., cocaine and lysergic acid diethylamide), and "Generation II" (ie, methylenedioxymethamphetamine [MDMA], ketamine, gamma hydroxybutyrate, methamphetamine, rohypnol, dextromethorphan) club drugs based on their initial widespread use in club settings. An anonymous questionnaire was administered to 340 medical students. The prevalence of any club drug use was 16.8%, with MDMA (11.8%) and cocaine (5.9%) the most commonly used. Results discussed also include the relationship of age and gender to having ever used club drugs and to their attitudes regarding use. Additionally, the study identifies differences in patterns of use and attitudes toward Generation I versus Generation II club drugs based on age, gender, and participants' prior club drug use. Findings are compared to those of earlier studies about medical students and those in a similar age group in the general population.

Hovda KE; Bjornaas MA; Skog K; Opdahl A; Drottning P; Ekeberg O et al. Acute poisonings treated in hospitals in Oslo: A one-year prospective study (I): Pattern of poisoning. Clinical Toxicology 46(1): 35-41, 2008. (25 refs.)

Objectives. Prospective design is mandatory to study pattern of poisoning and suicidal intention of patients. Material and Methods. Prospective cross-sectional multi-center study of all patients contacting health care services because of acute poisoning during one year in Oslo, irrespective of intention. Data on the adult hospitalized patients ( :16 years) are presented here. Results. Of a total of 3,775 such adult contacts (3,025 episodes), there were 947 (31%) hospitalizations; annual incidence 1.9 (per 1,000) in males and 2.1 in females. Median age was 36 years (range 16 - 89); 54% females. Benzodiazepines (18%), ethanol (17%), paracetamol (12%), opioids (7%), and gamma hydroxybutyric acid (GHB) (7%) were most frequently taken. Patients stated suicidal intention in 29% of the admissions; physicians in 10%. Conclusion. Benzodiazepines and ethanol were the most common agents, but newer illicit drugs were frequent, especially GHB. Males often took ethanol and drugs of abuse; females often used prescription drugs with suicidal intention.

Iyer S; Naganathan V; McLachlan AJ; Le Couteur DG. Medication withdrawal trials in people aged 65 years and older: A systematic review. (review). Drugs & Aging 25(12): 1021-1031, 2008. (72 refs.)

The objective of this review was to assess the benefits and risks of medication withdrawal in older people as documented in published trials of medication withdrawal. This was done by systematic review of the evidence from clinical trials of withdrawal of specific classes of medications in patient populations with a mean age of >= 65 years. We identified all relevant articles published between 1966 and 2007 initially through electronic searches on PubMed and manual searches of review articles. Numerous search terms related to the withdrawal of medication in older people were utilized. Clinical trials identified were reviewed according to predetermined inclusion/exclusion criteria. Only trials that focused on the withdrawal of specific classes of medication were included. Thirty-one published studies (n = 8972 subjects) met the inclusion criteria, including four randomized and placebo-controlled studies (n = 448 subjects) of diuretic withdrawal, nine open-label and prospective observational studies (n = 7188 subjects) of withdrawal of antihypertensives (including diuretics), 16 studies (n = 1184 patients) of withdrawal of sedative, antidepressant, cholinesterase inhibitor and antipsychotic medications, and I study each of withdrawal of nitrates and digoxin. These studies were of heterogeneous study design, patient selection criteria and follow-up. Withdrawal of diuretics was maintained in 51-100% of subjects and was unsuccessful primarily when heart failure was present. Adverse effects from medication withdrawal were infrequently encountered. After withdrawal of anti hypertensive therapy, many subjects (20-85%) remained normotensive or did not require reinstatement of therapy for between 6 months and 5 years, and there was no increase in mortality. Withdrawal of psychotropic medications was associated with a reduction in falls and improved cognition. In conclusion, there is some clinical trial evidence for the short-term effectiveness and/or lack of significant harm when medication withdrawal is undertaken for anti hypertensive, benzodiazepine and psychotropic agents in older people.

Jofre-Bonet M; Petry NM. Trading apples for oranges? Results of an experiment on the effects of heroin and cocaine price changes on addicts' polydrug use. Journal of Economic Behavior & Organization 66(2): 281-311, 2008. (56 refs.)

This paper studies polydrug use patterns in Heroin and Cocaine addicts from experiments measuring drug elasticities during changes in Heroin and Cocaine prices. Heroin addicts' demand for Heroin is inelastic; Cocaine, Marijuana, and Alcohol are complements, and Valium and Cigarettes are substitutes for Heroin. Heroin addicts' demand for Cocaine is inelastic; Marijuana and Valium are substitutes, and Alcohol is a complement. Cocaine addicts' demand for Cocaine is elastic; complements are Heroin and Alcohol, and substitutes are Marijuana and Valium. Cocaine addicts' demand for Heroin is inelastic; Alcohol is a complement while Cocaine, Marijuana and Valium are substitutes.

Karbakhsh M; Zandi NS. Pattern of poisoning in the elderly: An experience from Tehran. Clinical Toxicology 46(3): 211-217, 2008. (30 refs.)

Introduction. Poisoning is considered a significant health problem in the elderly. This study aimed to portray the pattern of poisoning in the elderly population of Tehran. Methods. This cross-sectional study included all patients aged 60 years and older with acute poisoning who attended the emergency department of the Loghman-Hakim hospital over a six-month period (n=299). Results. Episodes of poisoning were more common in men (70.9%) and the majority of incidents took place in the patient's own home (84.3%). Most episodes were accidental (53.2%) followed by attempted suicide (32.4%). Opioids and opiate products accounted for 54.02% of the non-pharmaceutical substances that were involved in episodes of poisoning. Overdose with opioids and opiate products, was higher in male patients than in female patients. The most frequently involved drug groups were benzodiazepines, antidepressants, and analgesics. The most common cause of accidental poisoning was overdose by drug abusers. The Poisoning Severity Score was minor in 25.4%, moderate in 52.2%, and severe in 17.1% of patients. Asymptomatic patients accounted for 5.4% of the total. Unfortunately, 11.7% of patients died. The main agents involved in the fatal cases were opioids and opiate products. Conclusion. The commonest method of accidental poisoning was overdose in opioid and opiate abusers. Attempted suicide was also very common comprising about one third of all cases. The high mortality observed in this study warrants attention to the risk factors and prognostic factors of poisoning in elderly.

Lader M. Coming off tranquillizers: A Sisyphean toil. (commentary). Addiction 104(1): 25-26, 2009. (10 refs.)

Lader M; Tylee A; Donoghue J. Withdrawing benzodiazepines in primary care. (review). CNS Drugs 23(1): 19-34, 2009. (103 refs.)

The use of benzodiazepine anxiolytics and hypnotics continues to excite controversy. Views differ from expert to expert and from country to country as to the extent of the problem, or even whether long-term benzodiazepine use actually constitutes a problem. The adverse effects of these drugs have been extensively documented and their effectiveness is being increasingly questioned. Discontinuation is usually beneficial as it is followed by improved psychomotor and cognitive functioning, particularly in the elderly. The potential for dependence and addiction have also become more apparent. The licensing of SSRIs for anxiety disorders has widened the prescribers' therapeutic choices (although this group of medications also have their own adverse effects). Melatonin agonists show promise in some forms of insomnia. Accordingly, it is now even more imperative that long-term benzodiazepine users be reviewed with respect to possible discontinuation. Strategies for discontinuation start with primary-care practitioners, who are still the main prescribers. This review sets out the stratagems that have been evaluated, concentrating on those of a pharmacological nature. Simple interventions include basic monitoring of repeat prescriptions and assessment by the doctor. Even a letter from the primary-care practitioner pointing out the continuing usage of benzodiazepines and questioning their need can result in reduction or cessation of use. Pharmacists also have a role to play in monitoring the use of benzodiazepines, although mobilizing their assistance is not yet routine. Such stratagems can avoid the use of specialist back-up services such as psychiatrists, home care, and addiction and alcohol misuse treatment facilities. Pharmacological interventions for benzodiazepine dependence have been reviewed in detail in a recent Cochrane review, but only eight studies proved adequate for analysis. Carbamazepine was the only drug that appeared to have any useful adjunctive properties for assisting in the discontinuation of benzodiazepines but the available data are insufficient for recommendations to be made regarding its use. Antidepressants can help if the patient is depressed before withdrawal or develops a depressive syndrome during withdrawal. The clearest strategy was to taper the medication; abrupt cessation can only be justified if a very serious adverse effect supervenes during treatment. No clear evidence suggests the optimum rate of tapering, and schedules vary from 4 weeks to several years. Our recommendation is to aim for withdrawal in < 6 months, otherwise the withdrawal process can become the morbid focus of the patient's existence. Substitution of diazepam for another benzodiazepine can be helpful, at least logistically, as diazepam is available in a liquid formulation. Psychological interventions range from simple support through counselling to expert cognitive-behavioural therapy (CBT). Group therapy may be helpful as it at least provides support from other patients. The value of counselling is not established and it can be quite time consuming. CBT needs to be administered by fully trained and experienced personnel but seems effective, particularly in obviating relapse. The outcome of successful withdrawal is gratifying, both in terms of improved functioning and abstinence from the benzodiazepine usage. Economic benefits also ensue. Some of the principles of withdrawing benzodiazepines are listed. Antidepressants may be helpful, as may some symptomatic remedies. Care must be taken not to substitute one drug dependence problem for the original one.

Lavie E; Fatseas M; Denis C; Auriacombe M. Benzodiazepine use among opiate-dependent subjects in buprenorphine maintenance treatment: Correlates of use, abuse and dependence. Drug and Alcohol Dependence 99(1-3): 338-344, 2009. (34 refs.)

Background: Previous studies from North America, Europe and Australia have reported high levels of benzodiazepine use among opiate-dependent patients in opiate maintenance treatment. However, to date, there are no available data on patterns of abuse and dependence on benzodiazepines according to DSM criteria among these patients. Aims: To describe the independent correlates of use, abuse and dependence on benzodiazepines among buprenorphine patients selected from standard treatment settings. Methods: Cross-sectional study in France between June 2001 and June 2004. Buprenorphine patients treated for over 3 months were recruited via physicians prescribing buprenorphine. Patients answered a self-administered questionnaire, the DSM-IV criteria for benzodiazepine abuse and dependence, the Beck Anxiety and Depression Inventories (BAI, BDI) and the Nottingham Health Profile (NHP). Main outcome was modalities of benzodiazepine use: no use vs. simple use vs. problematic use (abuse or dependence according to DSM-IV). Results: 170 patients were recruited. 54% did not use benzodiazepines during the previous month, 15% were simple users and 31% were problematic users. Benzodiazepine use (all modalities) was associated with poly-use of psychotropics. Simple users of benzodiazepines were not statistically different from non-users for the other factors explored. Problematic users of benzodiazepines had higher depression and anxiety levels, correlated with quality of life impairment and precariousness. They used higher dosages of benzodiazepines than simple users. Conclusions: Characteristics of simple benzodiazepine users were distinct from problematic users but not from non-users in this sample of buprenorphine patients. This should be taken into account in the clinical management of benzodiazepine use among buprenorphine patients.

Lidder S; Ovaska H; Archer JRH; Greene SL; Jones AL; Dargan PI; Wood DM. Doctors' knowledge of the appropriate use and route of administration of antidotes in the management of recreational drug toxicity. Emergency Medicine Journal 25(12): 820-823, 2008. (22 refs.)

Background: Specific antidotes (eg, naloxone, flumazenil, cyproheptadine and benzodiazepines) are available for the management of certain recreational drug-induced toxicities. Some controversies surround the use of some of these antidotes, especially flumazenil in benzodiazepine toxicity. There are no previously published data on doctors' knowledge of the use of these specific antidotes. Methods: A questionnaire survey was designed to determine internal/emergency medicine doctors' knowledge of the appropriate use of antidotes in the management of clinical scenarios of acutely poisoned patients. For nine simulated clinical scenarios of acute toxicity from recreational drugs (benzodiazepines, cocaine, N-methyl-L-(3, 4-methylene-dioxyphenyl)-2-aminopropane (MDMA)-induced serotonin toxicity and opioids), they were asked to indicate whether the suggested antidote and route of administration were correct. Results: 42 physicians of all grades completed the questionnaire. The mean correct score was 5.4 (SD 1.1) (median 6, interquartile range 5-7). The percentages correct for the various clinical scenarios were 68.3% for opioid toxicity, 81% for benzodiazepine toxicity, 28.6% for MDMA-induced serotonin toxicity and 70.2% for cocaine toxicity. Doctors were more likely to record an answer of "unsure'' for the use of cyproheptadine in ST serotonin toxicity (28.6%) compared with the use of the other antidotes (1.4%; p < 0.001). Conclusion: Knowledge of the appropriate use of antidotes in recreational drug toxicity is not consistent, with poorer knowledge on the use of newer antidotes such as cyproheptadine in serotonin toxicity. Education is required both to increase overall knowledge on the use of specific antidotes in the management of recreational drug-induced toxicity, as well as focusing on newer antidotes such as cyproheptadine.

Luijendijk HJ; Tiemeier H; Hofman A; Heeringa J; Stricker BHC. Determinants of chronic benzodiazepine use in the elderly: A longitudinal study. British Journal of Clinical Pharmacology 65(4): 593-599, 2008. (21 refs.)

AIMS: The risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related factors that predict new-onset chronic benzodiazepine use in community-dwelling elderly. METHODS: This study was embedded in an ongoing cohort study among 5364 persons aged >= 57 years. Drug-dispensing medication records were available for the period between 1991 and 2003. We defined chronic benzodiazepine use as use during at least 180 days in a period of 365 consecutive days. The association of various social, psychiatric and somatic variables with new-onset chronic benzodiazepine use was studied with a Cox proportional hazards analysis. RESULTS: Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new-onset chronic use. In the subsample of participants who had filled at least one prescription in the follow-up period, of these variables only pain related joint complaints increased the risk of new-onset chronic use. Living alone protected against chronic benzodiazepine use. CONCLUSIONS: The elderly with poor mental and physical health are at an increased risk of chronic benzodiazepine use. Living alone was found to decrease the risk of chronic use, which suggests that social factors may determine drug usage patterns. Very few characteristics predicted chronic benzodiazepine use once patients had received their first prescription. For clinicians, identification of patients at high risk is therefore not straightforward.

Majumder MMA; Basher A; Faiz MA; Kuch U; Pogoda W; Kauert GF et al. Criminal poisoning of commuters in Bangladesh: Prospective and retrospective study. Forensic Science International 180(1): 10-16, 2008. (36 refs.)

Travel-related poisoning is an emerging social and public health emergency in Bangladesh but its cause and significance have not been determined. To investigate this syndrome we performed a prospective clinical study and retrospective analysis of hospital records in a general medicine unit of a public tertiary care teaching hospital in Dhaka, Bangladesh, using toxicological analysis by fluorescence polarization immunoassay (FPIA) and liquid chromatography coupled to time-of-flight mass spectrometry (LC-TOF MS). The participants of the prospective study were 130 consecutive patients aged 16-80 years who were admitted with central nervous system depression (Glasgow Coma Score 3-14) after using public transportation, in the absence of other abnormalities, from January through June 2004, and a convenience sample of 15 such patients admitted during 3 days in May 2006. In 2004-2006, travel-related poisoning increased from 6.1 to 9.5% of all admissions (210-309 of 3266-3843 per year), representing 46.6-55.7% of all admitted poisoning cases. Incidents were associated with bus (76%), taxi, train, and air travel, or local markets: 98% of patients remembered buying or accepting food or drinks before losing consciousness. Direct financial damage (missing property) was diverse and frequently existential. Among 94 Urine samples analyzed by FPIA, 74% tested positive for benzodiazepines. Among 15 urine samples analyzed by LC-TOF MS, lorazepam was detected in all: five also contained diazepam or metabolites: nitrazepam was present in three. FPIA results obtained for these 15 samples were below the recommended cut-off in eight (53%; lorazepam only). Our findings show that the massive medicosocial emergency of travel-related poisoning in Bangladesh is the result of drug-facilitated organized crime and that benzodiazepine drugs are used to commit these crimes, suggesting modifications to the local emergency management of the victims of this type of poisoning. They also highlight the need for more research in the neglected field of acute poisoning in Bangladesh, and for Criminal investigations of the use of benzodiazepine drugs in this country.

Malanciuc C; Arama C; Saramet I; Monciu CM; Nedelcu A; Constantinescu C. Analytical characterization of flunitrazepam. Farmacia 57(2): 167-183, 2009. (25 refs.)

Supported by personal research and literature data, a comprehensive physical, chemical and analytical characterization of flunitrazepam is presented. It includes physical constants, mass, IR and UV spectra, thermal analysis data, acid-base properties in solution and most representative methods for the assay of flunitrazepam.

Manchikanti L; Manchikanti KN; Pampati V; Cash KA. Prevalence of side effects of prolonged low or moderate dose opioid therapy with concomitant benzodiazepine and/or antidepressant therapy in chronic non-cancer pain. Pain Physician 12(1): 259-267, 2009. (41 refs.)

Background: Opioid use in the management of chronic pain is widespread in chronic pain settings. Opioid prescriptions for non-cancer pain and overall opioid sales have been soaring with the increasing nonmedical use of opioids in the United States. Prolonged use of high dose opioids has been associated with adverse consequences including tolerance, abuse, addiction, hyperalgesia, hormonal effects, and immunosuppression. Studies of high dose therapy have shown pain relief with a 30% decrease in the intensity of pain and that only 44% of the patients continue the treatment between 7 and 24 months. However, there is no data available on the prevalence of side effects associated with low or moderate dose opioid use in chronic non-cancer pain when administered in conjunction with interventional techniques. Objective: To evaluate the prevalence of side effects, of low or moderate dose opioid therapy with or without benzodiazepines, antidepressants, and their combinations. Methods: The evaluation was conducted by interviewing 1,000 patients on stable doses of opioids, with or without benzodiazepines, antidepressants, and their combinations. Patients were categorized into 4 groups with Group 1 receiving opioids only (n = 143), Group 2 receiving opioids and benzodiazepines (n = 159), Group 3 receiving opioids and antidepressants (n = 113), and Group 4 received opioids, benzodiazepines, and antidepressants (n = 118). Results: Inclusion criteria was met in 533 patients receiving opioid therapy for longer than 6 months. The incidence of side effects in Group 1 was 18%, in Group 2 was 8%, in Group 3 was 17%, and in Group 4 was 14%. The most frequent complications were in patients receiving methadone (52%) followed by oxycodone (41 %) and morphine (36%). Patients receiving hydrocodone had the least incidences of side effects with 7.5%. There were no significant differences noted based on the duration of therapy, age of the patient, and gender. Severe side effects accounted for only 14 of 137 instances. Limitations: Limitations of this study include the inability to incorporate multiple other drugs due to complicated nature with multiple groups and data collection and analysis. The other limitation is that the proportion of patients receiving methadone, oxycodone, morphine, and propoxyphene was low compared to hydrocodone with 77% of the patients. Conclusion: Moderate or low dose opioid therapy in conjunction with or without benzodiazepines, antidepressants, or in combinations are associated with minor side effects.

Mandrioli R; Mercolini L; Raggi MA. Benzodiazepine metabolism: An analytical perspective. (review). Current Drug Metabolism 9(8): 827-844, 2008. (186 refs.)

Benzodiazepines are currently among the most frequently prescribed drugs all over the world. They act as anxiolytics, sedatives, hypnotics, amnesics, antiepileptics and muscle relaxants. Despite their common chemical scaffold, these drugs differ in their pharmacokinetic and metabolic properties. In particular, they are biotransformed by different cytochrome P450 isoforms and also by different UDP-glucuronosyltransferase subtypes. The most important studies on the metabolic characteristics of several 1,4-benzodiazepines, carried out from 1998 onwards, are reported and briefly discussed in this review. Moreover, the analytical methods related to these studies are also described and commented upon and their most important characteristics are highlighted. Most methods are based on liquid chromatography, which provides wide applicability and good analytical performance granting high precision, accuracy and feasibility. Mass spectrometry is gaining widespread acceptance, particularly if the matrix is very complex and variable, such as human or animal blood. However, spectrophotometric detection is still used for this purpose and can grant sufficient selectivity and sensitivity when coupled to suitable sample pre-treatment procedures. A monograph is included for each of the following benzodiazepines: alprazolam, bromazepam, brotizolam, clotiazepam, diazepam, etizolam, flunitrazepam, lorazepam, midazolam, oxazepam and triazolam.

Maxwell JC. Are we becoming more alike? Comparison of substance use in Australia and the United States as seen in the 1995, 1998, 2001 and 2004 national household surveys. Drug and Alcohol Review 27(5): 473-481, 2008. (33 refs.)

Introduction. This paper reports the results of the 1995, 1998, 2001 and 2004 Australian and US household surveys, with emphasis on changes since 2001. Design and Methods. The US survey data were recalculated to match age groups in the Australian data. Statistically significant changes are reported. Differences in prevalence of use by gender within age group were tested for significance. Results. The past-year use of 'any illicit drug', cannabis, cocaine, tranquillisers and injecting drugs decreased between 2001 and 2004 in Australia, but remained stable for all these drugs except ecstasy between 2002 and 2004 in the United States. The use of hallucinogens decreased in both countries. Alcohol and use of many illicit drugs by teenage girls in both countries increased to rates similar to or higher than boys, and teens in both countries reported binge and heavy drinking in the past month. Australians in their 20s had the highest rates of use, but in the United States, past-year use of many drugs was highest among teenagers. Discussion. More treatment services are needed, particularly for people dependent upon non-opiate drugs. The changes in acceptability of use of different drugs and their perceived availability are related to changes in prevalence rates. Even with the similarities in levels of use, there are differences in patterns of use and preferences for certain drugs in each country, and geographic proximity to drug sources is a factor.

McCabe SE; Cranford JA; West BT. Trends in prescription drug abuse and dependence, co-occurrence with other substance use disorders, and treatment utilization: Results from two national surveys. Addictive Behaviors 33(10): 1297-1305, 2008. (33 refs.)

Objectives: This study examined trends in prescription drug abuse and dependence (sedatives, tranquilizers, opioids, and stimulants), co-occurrence with other substance use disorders and substance abuse treatment utilization among those with diagnoses of prescription drug abuse and dependence in two large, nationally representative, independent samples of adults in the United States in 1991-1992 and 2001-2002. Methods: Two nationally representative cross-sectional samples of civilian non-institutionalized adults 18 years or older in the United States, of which 52% were women. Data were collected from structured diagnostic interviews using the NIAAA Alcohol Use Disorder and Associated Disabilities interview Schedule: Diagnostic and Statistical Manual version IV (DSM-IV). National prevalence estimates were derived from the 1991-1992 National Longitudinal Alcohol Epidemiologic Survey (n = 42,862) and the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n = 43.093). Results: The past-year prevalence of prescription sedative abuse, sedative dependence, opioid abuse, and opioid dependence increased from 1991-1992 to 2001-2002. The majority of individuals with past-year sedative (56.8%), tranquilizer (89.0%), stimulant (67.9%) and opioid (74.2%) use disorders also met DSM-IV criteria for an additional past-year substance use disorder. The co-occurrence of several forms of prescription drug use disorders and other substance use disorders increased from 1991-1992 to 2001-2002. A minority of individuals with past-year prescription drug abuse and approximately one-half of those with past-year prescription drug dependence utilized substance abuse treatment Conclusions: The findings reinforce the importance of continued national monitoring based on the increases in prescription drug abuse and dependence, high co-occurrence with other substance use disorders, and underutilization of substance abuse treatment services.

Molina AS; Miasso AI. Benzodiazepine use among employees of a private company. Revista Latino-Americana de Enfermagem 16(Special Issue): 517-522, 2008. (13 refs.)

This study aimed to identify variables associated to the consumption of benzodiazepine among workers of a private company in the VIII Region, Chile. This is a cross-sectional and correlative study. Study population: 40 employees of a private company. The instruments included a questionnaire on socio-demographic variables and a benzodiazepine questionnaire. There was no record of benzodiazepine consumption at the moment of the study. Twenty percent (20%) of the interviewees had already used benzodiazepine in the past, whereas, half of them (10%) in the last year. The bivariate analysis of the last year consumption of benzodiazepine with work hours variables showed no significant relation (p=0.073). No association was found between benzodiazepine consumption and socio-demographic variables among the study participants.

Nakamae T; Shinozuka T; Sasaki C; Ogamo A; Murakami-Hashimoto C; Irie W et al. Case report: Etizolam and its major metabolites in two unnatural death cases. Forensic Science International 182(1-3): E1-E6, 2008. (18 refs.)

A simultaneous analytical method for etizolam and its main metabolites (alpha-hydroxyetizolam and 8-hydroxyetizolam) in whole blood was developed using solid-phase extraction, TMS derivatization and ion trap gas chromatography tandem mass spectrometry (GC-MS/MS). Separation of etizolam, TMS derivatives of alpha-hydroxyetizolam and 8-hydroxyetizolam and fludiazepam as internal standard was performed within about 17 min. The inter-day precision evaluated at the concentration of 50 ng/mL etizolam, alpha-hydroxyetizolam and 8-hydroxyetizolam was evaluated 8.6, 6.4 and 8.0% respectively. Linearity occurred over the range in 5-50 ng/mL. This method is satisfactory for clinical and forensic purposes. This method was applied to two unnatural death cases suspected to involve etizolam. Etizolam and its two metabolites were detected in these cases.

Niveau G; Ritter C. Route of administration of illicit drugs among remand prison entrants. European Addiction Research 14(2): 92-98, 2008. (30 refs.)

Aims: To describe the self-reported routes of administration of illicit drugs among subjects entering a remand prison and the different drugs used by this population. Methods: A cross-sectional study, with a sample of 770 subjects, was conducted in Geneva ( Switzerland). Participants were assessed with the semi-structured interview from the Council of Europe Pompidou Group multi-city study. Results: 428 (55.6%) subjects admitted to having used illicit drugs during the 3 months prior to entry. Amongst these illicit drug users, 54.7% took several drugs. Injectable drugs ( heroin, cocaine or illicit benzodiazepines) were taken by 75.7% of drug users but the majority (84.1%) declared that they had not injected drugs during the 3 months prior to entering prison. 68 subjects (8.8% of the total sample) declared that they had injected drugs during the 3 months prior to entering prison, either alone or in association with other methods. Conclusion: By extrapolation it is possible to suggest that about 200 intravenous drug users entered the remand prison in Geneva in 1 year. This confirms the need for prison health services to implement a policy of treatment, prevention and education adapted to patterns of drug use in the local context.

Ojaniemi KK; Lintonen TR; Impinen AO; Lillsunde PM; Ostamo AI. Trends in driving under the influence of drugs: A register-based study of DUID suspects during 1977-2007. Accident Analysis and Prevention 41(1): 191-196, 2009. (52 refs.)

Our aim was to describe the incidence and trends of driving under the influence of drugs (DUID) and to examine the main drug findings and their trends in suspected DUID cases in Finland. A register-based study was conducted of all suspected DUID cases during 1977-2007. The data included 31,963 DUID offenders apprehended by the police with a positive finding for illicit/licit drug impairing driving performance. Toxicological results were analyzed in blood and/or urine specimens in one central laboratory. The incidence Of Suspected DUID cases increased 18-fold during 1977-2007. Most of the suspects were men (89.7%). However, the male-female ratio decreased from 13.9 to 7.3. The mean age decreased from 36.2 years in 1977 to 29.9 years in 2001 but has since reincreased. Most often found substances were benzodiazepines (75.7%), amphetamines (46.0%), cannabinoids (27.7%) and opioids (13.8%). Most common illicit drugs, amphetamines and cannabinoids, started to appear at the end of the 1980s. Poly-drug findings were common (77.1%). Suspected DUID cases have increased sharply after the introduction of a zero tolerance law, especially in regard to amphetamines. DUID is an increasing problem in Finland, and needs serious attention.

Oulis P; Konstantakopoulos G; Kouzoupis AV; Masdrakis VG; Karakatsanis NA; Karapoulios E et al. Pregabalin in the discontinuation of long-term benzodiazepines' use. Human Psychopharmacology: Clinical and Experimental 23(4): 337-340, 2008. (20 refs.)

Objective: Tolerance, dependence, and adverse effects on cognitive functions are well-known consequences of long-term use of benzodiazepines (BDZ), especially at high doses, raising thorny therapeutic problems in their discontinuation. One promising pharmacological agent in BDZ discontinuation might be the newer anti-epileptic pregabalin, already successfully tested in the treatment of anxiety disorders. Methods: We report on a sample of 15 patients with long-term, mostly high-dose dependence from BDZ, treated with pregabalin in an open-label study at doses 225-900 mg. Results All patients discontinued successfully BDZ in 3-14 weeks, moreover with a significant reduction of their previous anxiety levels under BDZ. In addition, patients showed also a significant amelioration in their cognitive functioning. Pregabalin's side-effects were mild and transient, lasting only during the first 2 weeks of treatment. Conclusion: Although preliminary, our findings suggest that pregabalin may be one new promising agent in the treatment of BDZ dependence.

Oulis P; Masdrakis VG; Karakatsanis NA; Karapoulios E; Kouzoupis AV; Konstantakopoulos G et al. Pregabalin in the discontinuation of long-term benzodiazepine use: A case-series. International Clinical Psychopharmacology 23(2): 110-112, 2008. (21 refs.)

Tolerance, dependence, and adverse effects on cognitive functions are well known consequences of long-term use of benzodiazepines (BDZ), especially at high doses; this raises thorny therapeutic problems in their discontinuation. One promising pharmacological agent in BDZ discontinuation might be the newer antiepileptic, pregabalin (PGB), which has already successfully been tested in the treatment of anxiety disorders. We report on a series of four women with long-term, high-dose dependence on BDZ, who were treated with PGB at doses of 225-600 mg. All four patients discontinued BDZ successfully in 3-7 weeks. Moreover, they had an impressive reduction of their previous anxiety levels under BDZ. In addition, the patients showed a clinically significant amelioration in their cognitive functioning. The side effects of PGB were mild and transient, persisting only during the first 2 weeks of treatment. Although our findings are preliminary, they suggest that PGB might be one of the most promising of the newer agents in the treatment of BDZ dependence.

Pandharipande P; Cotton BA; Shintani A; Thompson J; Pun BT; Morris JA et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. Journal of Trauma, Injury, Infection and Critical Care 65(1): 34-41, 2008. (37 refs.)

Background: Although known to be an independent predictor of poor outcomes in medical intensive care unit (ICU) patients, limited data exist regarding the prevalence of and risk factors for delirium among surgical (SICU) and trauma ICU (TICU) patients. The purpose of this study was to analyze the prevalence of and risk factors for delirium in surgical and trauma ICU patients. Methods: SICU and TICU patients requiring mechanical ventilation (MV) >24 hours were prospectively evaluated for delirium using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method for the ICU (CAM-ICU). Those with baseline dementia, intracranial injury, or ischemic/hemorrhagic strokes that would confound the evaluation of delirium were excluded. Markov models were used to analyze predictors for daily transition to delirium. Results: One hundred patients (46 SICU and 54 TICU) were enrolled. Prevalence of delirium was 73% in the SICU and 67% in the TICU. Multivariable analyses identified midazolam [OR 2.75 (CI 1.43-5.26, p = 0.002)] exposure as the strongest independent risk factor for transitioning to delirium. Opiate exposure showed an inconsistent message such that fentanyl was a risk factor for delirium in the SICU (p = 0.007) but not in the TICU (p = 0.936), whereas morphine exposure was associated with a lower risk of delirium (SICU, p = 0.069; TICU p = 0.024). Conclusion: Approximately 7 of 10 SICU and TICU patients experience delirium. In keeping with other recent data on benzodiazepines, exposure to midazolam is an independent and potentially modifiable risk factor for the transitioning to delirium.

Papadodima SA; Athanaselis SA; Stefanidou ME; Dona AA; Papoutsis I; Maravelias CP et al. Driving under the influence in Greece: A 7-year survey (1998-2004). Forensic Science International 174(2-3): 157-160, 2008. (28 refs.)

Alcohol is one of the main causes of traffic accidents worldwide. Its use decreases significantly the driving ability of an individual increasing in this way the possibilities of their involvement in motor-vehicle accidents. The above possibilities are increased when a psychoactive substance has been taken in combination with alcohol due to their synergistic effect. The Laboratory of Forensic Medicine and Toxicology of the University of Athens is authorized to perform the toxicological investigation of traffic accidents that happen in the southern part of Greece. The objective of the present study was to identify the prevalence of alcohol and other psychoactive substances among drivers involved in road traffic accidents in Greece during the period 1998-2004. Alcohol was detected in the blood of about 37% of the drivers involved in traffic accident during the years 1998-2000. The detection of alcohol was lower (29%) in the years 2001-2004. Cannabis, benzodiazepines, opiates, and cocaine were found in 4%, 4%, 4% and 1% of the total number of cases, respectively. The above values were compared with those of a previous study concerning the period 1995--1997 and the reasons for the reduction of the number of alcohol-related traffic accidents during the last years are discussed.

Paredes NP; Miasso AI; Tirapelli CR. Consumption of benzodiazepines without prescription among first-year nursing students at the University of Guayaquil, school of nursing, Ecuador. Revista Latino-Americana de Enfermagem 16(Special Issue): 634-639, 2008. (18 refs.)

This study aimed to determine the consumption of benzodiazepines without prescription among first-year students from a nursing school of a public University in Ecuador. This is a descriptive, transversal and explanatory study with a quantitative approach. A questionnaire was used for data collection. The population studied was of 181 students. The results showed that 10.5% of the students had consumed benzodiazepine without prescription once in their lives. Of these, 6.1% consumed benzodiazepine in the last year, and 3.9% are currently consuming it. The diazepam was the most consumed BZD without prescription and pharmacies, were the place of higher access. The main reasons for the benzodiazepine consumption were: insomnia, anxiety, stress, depression, family and economical problems. The use of benzodiazepines with non-medicinal purposes is related to problems such as memory loss, retirement syndrome and sedation. When benzodiazepines are consumed jointly with alcohol or other drugs they can lead to coma or death. This study shows the serious consequences benzodiazepines cause when used by nursing students in Ecuador.

Pariente A; Dartigues JF; Benichou J; Letenneur L; Moore N; Fourrier-Reglat A. Benzodiazepines and injurious falls in community dwelling elders. Drugs & Aging 25(1): 61-70, 2008. (62 refs.)

Background: Benzodiazepines are frequently used medications in the elderly, in whom they are associated with an increased risk of falling, with sometimes dire consequences. Objective: To estimate the impact of benzodiazepine-associated injurious falls in a population of elderly persons. Method: A nested case-control study was conducted using data collected during 10 years of follow-up of the French PAQUID (Personnel Agees QUID) community-based cohort. The main outcome measure was the occurrence of an injurious fall, which was defined as a fall resulting in hospitalization, fracture, head trauma or death. Controls (3 : 1) were frequency-matched to cases. Benzodiazepine exposure was the use of benzodiazepines over the previous 2 weeks reported at the follow-up visit preceding the fall. Results: Benzodiazepine use was significantly associated with the occurrence of injurious falls, with a significant interaction with age. The adjusted odds ratio for injurious falls in subjects exposed to benzodiazepines was 2.2 (95% CI 1.4, 3.4) in subjects aged >= 80 years and 1.3 (95% CI 0.9, 1.9) in subjects aged <80 years. The population attributable risk for injurious falls in subjects exposed to benzodiazepines was 28.1% (95% CI 16.7, 43.2) for subjects aged >= 80 years. The incidence of injurious falls in subjects aged >= 80 years exposed to benzodiazepines in the PAQUID cohort was 2.8/100 person-years. Over 9% of these falls were fatal. According to these results and to recent population estimates, benzodiazepine use could be held responsible for almost 20 000 injurious falls in subjects aged >= 80 years every year in France, and for nearly 1800 deaths. Conclusion: Given the considerable morbidity and mortality associated with benzodiazepine use and the fact that existing good practice guidelines on benzodiazepines have not been effective in preventing their misuse (possibly because they have not been applied), new methods for limiting use of benzodiazepines in the elderly need to be found.

Parr JM; Kavanagh DJ; Cahill L; Mitchell G; Young RM. Effectiveness of current treatment approaches for benzodiazepine discontinuation: A meta-analysis. Addiction 104(1): 13-24, 2009. (61 refs.)

Aims: To assess the effectiveness of current treatment approaches to assist benzodiazepine discontinuation. Methods: A systematic review of approaches to benzodiazepine discontinuation in general practice and out-patient settings was undertaken. Routine care was compared with three treatment approaches: brief interventions, gradual dose reduction (GDR) and psychological interventions. GDR was compared with GDR plus psychological interventions or substitutive pharmacotherapies. Results: Inclusion criteria were met by 24 studies, and a further eight were identified by future search. GDR [odds ratio (OR) = 5.96, confidence interval (CI) = 2.08-17.11] and brief interventions (OR = 4.37, CI = 2.28-8.40) provided superior cessation rates at post-treatment to routine care. Psychological treatment plus GDR were superior to both routine care (OR = 3.38, CI = 1.86-6.12) and GDR alone (OR = 1.82, CI = 1.25-2.67). However, substitutive pharmacotherapies did not add to the impact of GDR (OR = 1.30, CI = 0.97-1.73), and abrupt substitution of benzodiazepines by other pharmacotherapy was less effective than GDR alone (OR = 0.30, CI = 0.14-0.64). Few studies on any technique had significantly greater benzodiazepine discontinuation than controls at follow-up. Conclusions: Providing an intervention is more effective than routine care. Psychological interventions may improve discontinuation above GDR alone. While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.

Patra J; Fischer B; Maksimowska S; Rehm J. Profiling poly-substance use typologies in a multi-site cohort of illicit opioid and other drug users in Canada-a latent class analysis. Addiction Research & Theory 17(2): 168-185, 2009. (85 refs.)

'Poly-substance use' is increasingly prevalent among street drug user populations. The objective was to employ latent class analysis (LCA) to empirically categorize and extract potential typologies of poly-substance users within a multi-site cohort of illicit opioid and other drug users (OPICAN) in Canada, and examine potential associations with social and health indicators. Drug use patterns of 582 participants from the most recent follow-up (2005) of the cohort study-focusing on drug use prevalence indicators in the past 30 days-were empirically analyzed via LCA. These classes were further examined for associations with social and health variables using chi-square, ANOVA. Binomial logistic regression models were used to predict class membership. LCA analysis resulted in eight distinct user typologies, characterized both by the distinct relative prevalence of different substances (e.g., including: heroin, prescription opioids, benzodiazepines, cocaine, crack, alcohol, cannabis, and others) used and administration routes (e.g., injection or noninjection), the majority of which were described by the predominant use of two or more distinct substance groups (e.g., opioids and stimulants). At least two of the active poly-substance user classes were described by predominant noninjection as the primary route of administration. 'Poor or fair' health status was reported at the highest prevalence level by the class of intensive poly-substance injectors, while HCV-positive status was disproportionately low in the classes of current noninjectors. Analytical examination of poly-substance use patterns is a distinct challenge for meaningful drug use monitoring, also providing important evidence for targeted prevention and treatment interventions.

Pehrsson A; Gunnar T; Engblom C; Seppa H; Jama A; Lillsunde P. Roadside oral fluid testing: Comparison of the results of Drugwipe 5 and Drugwipe Benzodiazepines on-site tests with laboratory confirmation results of oral fluid and whole blood. Forensic Science International 175(2-3): 140-148, 2008. (31 refs.)

Drugged drivers pose a serious threat to other people in traffic as well as to themselves. Reliable oral fluid screening devices for on-site screening of drugged drivers would be both a useful and convenient means for traffic control. In this study we evaluated the appropriateness of Drugwipe 5 and Drugwipe Benzodiazepines oral fluid on-site tests for roadside drug screening. Drivers suspected of driving under the influence of drugs were screened with the Drugwipe tests. Oral fluid and whole blood samples were collected from the drivers and tested for amphetamine-type stimulant drugs, cannabis, opiates, cocaine and benzodiazepines by immunological methods, GC and GC-MS. The performance evaluations of the tests were made by comparing the results of the Drugwipe tests with laboratory GC-MS confirmation results of oral fluid or whole blood. In addition to the performance evaluations of the Drugwipe tests based on laboratory results, a questionnaire on the practical aspects of the tests was written for the police officers who performed the tests. The aim of the questionnaire was to obtain user comments on the practicality of the tests as well as the advantages and weak points of the tests. The results of the performance evaluations were: for oral fluid (sensitivity; specificity; accuracy) amphetamines (95.5%; 92.9%; 95.3%), cannabis (52.2%; 91.2%: 85.1%), cocaine (50.0%; 99.3%; 98.6%), opiates (100%; 95.8%; 95.9%), benzodiazepines (74.4%; 84.2%; 79.2%) and for whole blood accordingly, amphetamines (97.7%; 86.7%; 95.9%), cannabis (68.3%; 87.9%; 84.9%), cocaine (50.0%; 98.5%; 97.7%), opiates (87.5%; 96.9%; 96.6%) and benzodiazepines (66.7%; 87.0%; 74.4%). Although the Drugwipe 5 successfully detected amphetamine-type stimulant drugs and the police officers were quite pleased with the current features of the Drugwipe tests, improvements must still be made regarding the detection of cannabis and benzodiazepines.

Preville M; Boyer R; Grenier S; Dube M; Voyer P; Punti R et al. The epidemiology of psychiatric disorders in Quebec's older adult population. Canadian Journal of Psychiatry 53(12): 822-838, 2008. (24 refs.)

Objective: To document the prevalence of psychiatric disorders in Quebec's older adult population. Method: Data came from the Enquete sur la sante des aines study conducted in 2005-2006 using a representative sample (n = 2798) of community-dwelling older adults. Results: Our results indicate that 12.7% of the respondents met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for depression, mania, anxiety disorders, or benzodiazepine dependency. The 12-month prevalence rate of major depression was 1.1% and the prevalence of minor depression 5.7%. A total of 5.6% of the respondents reported an anxiety disorder. The most prevalent anxiety disorders were specific phobia (2.0%), obsessive-compulsive disorder (OCD) (1.5%), and generalized anxiety disorder (GAD) (1.2%). Agoraphobia without panic disorder and panic disorder were reported by 0.3% and 0.6% of the respondents, respectively. The prevalence rate of benzodiazepine dependency was 2.3%. The 12-month comorbidity prevalence rate between any psychiatric disorders was 2.2%. Among those with depressive disorder, the most frequent comorbidity was observed between minor depression and specific phobia (4.3%), GAD (4.3%), OCD (3.7%), and mania (1.3%). Further, only 39% of those having at least one active DSM-IV diagnosis reported having used health services for their psychological distress symptoms during the previous 12 months. Among those who consulted health services, 85% visited a general practitioner. Conclusions: Our results indicate that a large proportion of the elderly population in Quebec presents mental health needs. Longitudinal research focusing on the individual and social consequences of mental health problems reported by older adults is needed to avoid misinterpretation of this finding.

Rickels K; Garcia-Espana F; Mandos LA; Case GW. Physician Withdrawal Checklist (PWC-20). Journal of Clinical Psychopharmacology 28(4): 447-451, 2008. (26 refs.)

Anxiety disorders are the most common mental illnesses in the United States. Despite having a number of medication options readily available, benzodiazepines (BZs) and antidepressants have achieved remission rates of only 35% after 8 weeks of acute treatment. In the development of new anxiolytics, particularly those that affect the gamma-aminobutyric acid system, it is essential to assess the new compound's potential to cause discontinuation symptoms after stopping the medication as part of both short- and long-term treatment. This report describes the development of the 20-item Pennsylvania Physician Withdrawal Checklist (PWC), a smaller version of the original 35-item PWC, and examines its validity, internal consistency, test-retest and interrater reliability, and factor structure. The PWC scores, assessed at the peak of withdrawal severity, were selected from 143 of our patients for an orthogonal factor analysis. Our results suggest that the Pennsylvania Physician Withdrawal Checklist is a simple and accurate method to assess anxiolytic discontinuation symptoms.

Rossi R; De Giorgio F; Benucci G; Oliva A; Fucci N. Acute intoxication by triazolam and promazine: a case report. Medicine, Science and the Law 49(1): 65-68, 2009. (13 refs.)

A fatality due to ingestion of triazolam and promazine is reported. Triazolam is a benzodiazepine widely prescribed as a hypnotic drug for the treatment of sleep disorders. Promazine is a neuroleptic drug. There is no previous evidence in the literature of death due to an overdose related to the contemporaneous intake of these two drugs. In this report the authors present the case of a 76-year-old woman who was found deceased at home with no evidence of trauma or asphyxia; near the body several empty pharmaceutical boxes containing triazolam and promazine were noticed. Toxicological analyses were performed and drug levels measured by means of gas chromatography coupled with mass spectrometry. The triazolam concentration in each specimen,was as follows: blood 1100 ng/ml; gastric content 1300 ng/ml; the promazine concentration in blood and in gastric content was 3450 ng/ml and 5800 ng/ml respectively, Based on the autopsy findings, patient history find toxicological results, the cause of death was determined to be acute intoxication due to the effect of triazolam and promazine and the manner of suicide.

Schreiber S; Peles E; Adelson M. Association between improvement in depression, reduced benzodiazepine abuse, and increased psychotropic medication use in methadone maintenance treatment patients. Drug and Alcohol Dependence 92(1/3): 79-85, 2008. (29 refs.)

We had evaluated the depressive symptoms severity of 75 former heroin addicts in methadone maintenance treatment using the 21-item Hamilton rating scale for depression and re-assessed 63 of them 1.6 +/- 0.3 years later. The second mean Hamilton score was lower than the first (11.8 +/- 8.4 versus 17.4 +/- 6.2, p < 0.0005). Benzodiazepine abuse was lower although not significantly (p = 0.06) during the month preceding the second analysis (32/63, 50.8%) than the month preceding the first one (40/63, 63.5%). Psychotropic medication usage was higher at the second assessment than at the first one (50/63, 79.4% versus 27/63, 42.9%, p < 0.0005). 21-HAM-D score reduced significantly over time among 13 "no psychotropic medication" patients (13.5 +/- 6.3 versus 6.8 +/- 6.8, p = 0.005) and in 27 who started medication following the first assessment (19.3 +/- 3.8 versus 11.0 +/- 18.4, p < 0.0005), but not in those who were already taking any medication before the first assessment (17.7 +/- 7.0 versus 15.0 +/- 8.0, p = n.s). The Hamilton score reduced in all Benzodiazepine groups but scores were still highest in the 32 patients who continued benzodiazepine abuse (19.4 +/- 5.6 versus 15.2 +/- 7.7) followed by 14 who stopped it (16.8 +/- 6.4 versus 9.6 +/- 9.1) and were lowest in 17 patients who never abused BDZ (14.2 +/- 5.2 versus 7.2 +/- 6.4) (repeated measured, time and group effect, each p < 0.0005). Predictors for being depressed at follow-up were pre-existing depression only. Stopping benzodiazepine abuse and starting psychotropic treatment was associated with a reduction of depressive symptoms among methadone maintenance patients.

Shannon LM; Havens JR; Mateyoke-Scrivner A; Walker R. Contextual differences in substance use for rural Appalachian treatment-seeking women. American Journal of Drug and Alcohol Abuse 35(2): 59-62, 2009. (20 refs.)

Objective: To examine differences in substance use among a sample of women entering treatment from rural Appalachian and non-Appalachian areas. Participants: A total of 2,786 women participating in state-funded substance abuse treatment programs statewide. Measures: Substance use measures were based on the SAMHSA CSAT Government Performance and Results Act (GPRA) gathering information on lifetime and past 12-month use of alcohol, marijuana, opiates, sedatives/tranquilizers, cocaine, and stimulants. Results: Women entering treatment in rural Appalachia had disproportionately high rates of opiate and sedative/tranquilizer use while methamphetamine, cocaine, marijuana, and alcohol were more prevalent for women in non-Appalachian areas. Conclusions: Women entering treatment in rural Appalachia were significantly more likely to report opiate and sedative/tranquilizer use compared to non-Appalachian women. In order to begin to understand the elevated rates of prescription drug abuse in rural Appalachian Kentucky, substance use must be considered within the context of demographic, geographic, social, and economic conditions of the region.

Siavash M; Janghorbani M; Gheshlaghi F; Adeli SH; Saljoughi M; Moradi F et al. A case series of abuse of a new opioid combination, Norjizak. Journal of Addictive Diseases 28(2): 180-185, 2009. (19 refs.)

Cushing's syndrome results from lengthy and inappropriate exposure to excessive concentrations of either endogenous or exogenous glucocorticoids. This study described 30 patients with a novel type of severe exogenous Cushing's syndrome in a group of intravenous drug users due to illicit use and dependence on a new opioid combination, Norjizak. Thirty consecutive patients (2 women and 28 men) who presented with a novel type of severe exogenous Cushing's syndrome and other complications were admitted to the emergency departments of Qom and Isfahan University of Medical Sciences, Isfahan, Iran, between September 2005 and September 2007 were enrolled. All participating patients were intravenous drug users who used a narcotic drug called Norjizak, a combination of different opioids with dexamethason or benzodiazepines. Patients were first evaluated and managed based on the current illness, and then entered into a detoxification program by a medical team. Clinical data were collected by an open interview and the patient's files using a standard form. High-performance liquid chromatography was used to determined glucocorticoid existence in the brand. The major complaints and clinical findings were withdrawal symptoms, severe edema, osteoporotic fracture, impairment in glucose tolerance, decreased libido, and sepsis (including necrotizing pneumonia, cutaneous infection, multivalvular endocarditis, osteomyelitis, and urogenital infection). Most patients had started with 2 or 3 vials per day and then increased the dose compulsively to maximum of approximately 15 to 20 vials per day. The concentration of Dexamethhasone disodium phosphate in each 2 mL vial was 0.4 to 1 mg/mL. Heroin was also found in them. We are witnessing a special exogenous Cushing syndrome due to the mixing of opiates and dexamethasone. Norjizak syndrome is the clinical condition of poisoning with a second material when it is combined with opiates due to compulsive dose increment and long duration.

Smith AJ; Sketris I; Cooke C; Gardner D; Kisely S; Tett SE. A comparison of benzodiazepine and related drug use in Nova Scotia and Australia. Canadian Journal of Psychiatry 53(8): 545-552, 2008. (47 refs.)

Objective: Benzodiazepines can be a problem if used for long periods, or in at-risk populations, such as the elderly. We compared the use of benzodiazepine and related prescription medicines in Nova Scotia and Australia. Methods: The Nova Scotia Pharmacare Program and the Pharmaceutical Benefits Scheme in Australia were used to obtain dispensing data in comparable populations for all publicly subsidized benzodiazepines and related compounds. Usage was compared from 2000 to 2003, using the World Health Organization anatomical therapeutic chemical and defined daily dosage (DDD) system. We also determined differences in the types of benzodiazepines prescribed. Results: The use of benzodiazepines increased at a steady but comparable rate in both areas. However, the use of benzodiazepines in Nova Scotia was more than double that of Australia in 2000 (123 and 48 DDD/1000 beneficiaries per day, respectively) through 2003 (138 and 57 DDD/1000 beneficiaries per day, respectively). Eight different benzodiazepines made up 90% of the drug use in Nova Scotia by contrast to only 4 different benzodiazepines in Australia. Conclusions: Large differences exist between the type and rate of benzodiazepine prescribing in Nova Scotia and Australia, with Nova Scotia reporting more than twice as much use. Benzodiazepine use in both jurisdictions is increasing. The Canadian findings are especially concerning as benzodiazepine use in the Atlantic provinces has been reported to be less than other provinces. The variations between the 2 jurisdictions may be due to factors such as fewer benzodiazepines available in Australia, differences in prescriber, patient attitudes and behaviours, or different initiatives to influence benzodiazepine use.

Smith AJ; Tett SE. How do different age groups use benzodiazepines and antidepressants? Analysis of an Australian administrative database, 2003-6. Drugs & Aging 26(2): 113-122, 2009. (40 refs.)

Background: The use of antidepressants and benzodiazepines is increasing in Australia and worldwide, and it is thought that some of the prescribing of these classes of drugs may be inappropriate. However, the demographic characteristics of the subgroups of the population responsible for this increase remain unexplored. Objective: The aim of this study was to examine changes in the utilization of antidepressants and benzodiazepines between different age groups within Australia from 2003 to 2006. Methods: The Australian Pharmaceutical Benefits Scheme administrative database was used to obtain dispensing data for all antidepressants and Publicly subsidized benzodiazepines. Changes in utilization (amounts and patterns of use of different compounds) were compared between different age groups from 2003 to 2006. The WHO Anatomic Therapeutic Chemical/Defined Daily Dose system was used. Results: Use of antidepressants increased from 2003 to 2006, and in each year increased with age, with those >= 65 years having the greatest use. Differences were seen in the antidepressant most utilized, with the elderly using more tricyclic antidepressants than those who are younger. The utilization of benzodiazepines decreased from 2003 to 2006 in elderly individuals and those receiving social welfare benefits. Individuals aged >= 85 years had the highest use of benzodiazepines and used more long-acting benzodiazepines compared with those aged 35-44 years. Conclusion: The elderly still account for most use per capita of benzodiazepines. Some of this use may be inappropriate (e.g. use of long-acting benzodiazepines) and, hence, may represent a useful target for future educational intervention. The elderly also still account for the largest per capita use of antidepressants.

Stein K; Ramil M; Fink G; Sander M; Ternes TA. Analysis and sorption of psychoactive drugs onto sediment. Environmental Science & Technology 42(17): 6415-6423, 2008. (44 refs.)

An analytical method was developed to analyze eight psychoactive pharmaceuticals -- including the antiepileptic carbamazepine, the opiates morphine, codeine, dihydrocodeine, the opiode tramadol, and the tranquilizers diazepam, oxazepam, temazepam -- and the antibiotic sulfa methoxazole as well as three metabolites (10,11-dihydrocarbamazepine (DHC), 10,11-dihydroxy-10, 11-dihydrocarbamazepine, and N-4-acetylsulfamethoxazole) in river sediments. Relative recoveries of all analytes exceeded 97% using either deuterated or (CN)-C-13-N-15-labeled surrogate standards. Sorption isotherms of all analytes were constructed at pH 6.5-6.6 on two natural river sediments (Burgen and Dausenau) that differed in organic carbon contents and particle size distributions. Affinities of all analytes were up to an order of magnitude higher for the Dausenau sediment in comparison to the Burgen sediment. Isotherms were well described by the Freundlich model. Sorption of all analytes was linear on the Burgen sediment except for structurally similar carbamazepine (n = 0.90) and DHC (n = 0.88). Conversely, most analytes showed pronounced nonlinear sorption to the Dausenau sediment (n = 0.77-0.92) except for positively charged codeine, dihydrocodeine, and tramadol. Linear sorption of the latter was taken to arise from concentration-independent electrostatic interactions of the organocations with negatively charged surfaces on clay minerals or in the sediment organic matter. Desorption gave rise to hysteresis in 13 out of 16 investigated analyte-sorbent systems. Hysteresis was likely due to slow desorption kinetics beyond 24 h used in the experiment.

Stowell KR; Chang CCH; Bilt J; Stoehr GP; Ganguli M. Sustained benzodiazepine use in a community sample of older adults. Journal of the American Geriatrics Association 56(12): 2285-2291, 2008. (29 refs.)

To identify factors associated with sustained benzodiazepine use in older adults. Twelve-year cohort study. Community-based epidemiological survey. One thousand three hundred forty-two individuals aged 65 and older. Demographics, medication use, depressive symptoms, sleep complaints, alcohol use, and smoking assessed at 2-year intervals; descriptive analysis to characterize benzodiazepine users and identify factors associated with sustained benzodiazepine use (use at two consecutive waves); and longitudinal lag-time analysis to determine characteristics that predicted sustained use. Initially, 5.5% of men and 9.8% of women were using benzodiazepines. Users were significantly more likely than nonusers to be female and less educated, report more depressive and anxiety symptoms, use more prescription medications, have lower self-rated health, have difficulty maintaining sleep, and be less likely to consume alcohol. Approximately 50%, 44%, and 25% of these users aged 65 to 74, 75 to 84, and 85 and older, respectively, were sustained users at follow-up. Being female, using two or more nonbenzodiazepine prescription medications, and smoking were independently associated with subsequent sustained benzodiazepine use. At the population level, women, smokers, and users of at least two prescription drugs have higher probabilities of sustaining benzodiazepine use once started. This information can facilitate risk assessment and counseling of older adults before prescribing benzodiazepines.

Strac DS; Vlainic J; Jembrek MJ; Pericic D. Differential effects of diazepam treatment and withdrawal on recombinant GABA(A) receptor expression and functional coupling. Brain Research 1246: 29-40, 2008. (67 refs.)

Prolonged exposure to benzodiazepines, drugs known to produce tolerance and dependence and also to be abused, leads to adaptive changes in GABA(A) receptors. To further explore the mechanisms responsible for these phenomena, we studied the effects of prolonged diazepam treatment on the recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors, stably expressed in human embryonic kidney (HEK) 293 cells. The results demonstrating that long-term (48 and 72 h) exposure of cells to a high concentration of diazepam (50 mu M) enhanced the maximum number (B-max) of [H-3]flunitrazepam, [H-3]muscimol and [H-3]t-butylbicycloorthobenzoate ([H-3] TBOB) binding sites, without changing their affinity (K-d), suggested the up-regulation of GABA(A) receptors. As demonstrated by cell counting and WST-1 proliferation assay, the observed increase in receptor expression was not a consequence of stimulated growth of cells exposed to diazepam. Semi-quantitative RT-PCR and Western blot analysis, showing elevated levels of alpha(1) subunit mRNA as well as beta(2) and gamma(2) subunit proteins, respectively, suggested that prolonged high dose diazepam treatment induced de novo receptor synthesis by acting at both transcriptional and translational levels. The finding that the number of GABA(A) receptor binding sites returned to control value 24 h following diazepam withdrawal, makes this process less likely to account for the development of benzodiazepine tolerance and dependence. On the other hand, the results demonstrating that observed functional uncoupling between GABA and benzodiazepine binding sites persisted after the termination of diazepam treatment supported the hypothesis of its possible role in these phenomena.

Ten Wolde GB; Dijkstra A; Van Empelen P; Neven AK; Zitman FG. Social-cognitive predictors of intended and actual benzodiazepine cessation among chronic benzodiazepine users. Addictive Behaviors 33(9): 1091-1103, 2008. (50 refs.)

Long-term benzodiazepine use is associated with a variety of negative health consequences. Cessation of long-term use is therefore an important health goal. In a prospective study among chronic benzodiazepinc users (N=356) social-cognitive factors of benzodiazepine cessation were examined with a nine-month follow-up. Results showed that outcome expectations, self-efficacy and disengagement beliefs predicted intention, and that intention in turn predicted benzodiazepine cessation. More specifically, benzodiazepine users reported a more positive intention to quit when they perceived more positive consequences and fewer negative consequences of cessation. In addition, a higher self-efficacy to quit and lower disengagement beliefs related to lower higher intention. Intention, in turn was the only significant psychosocial predictor of actual quitting at 9 months. The implications of these results will be discussed in terms of possible intervention strategies.

Ten Wolde GB; Dijkstra A; Van Empelen P; van den Hout W; Neven AK; Zitman F. Long-term effectiveness of computer-generated tailored patient education on benzodiazepines: A randomized controlled trial. Addiction 103(4): 662-670, 2008. (38 refs.)

Aims: Chronic benzodiazepine use is highly prevalent and is associated with a variety of negative health consequences. The present study examined the long-term effectiveness of a tailored patient education intervention on benzodiazepine use. Participants A randomized controlled trial was conducted comprising three arms, comparing (i) a single tailored intervention; (ii) a multiple tailored intervention and (iii) a general practitioner letter. The post-test took place after 12 months. Participants Five hundred and eight patients using benzodiazepines were recruited by their general practitioners and assigned randomly to one of the three groups. Intervention Two tailored interventions, the single tailored intervention (patients received one tailored letter) and the multiple tailored intervention (patients received three sequential tailored letters at intervals of 1 month), were compared to a short general practitioner letter that modelled usual care. The tailored interventions not only provided different and more information than the general practitioner letter; they were also personalized and adapted to individual baseline characteristics. The information in both tailored interventions was the same, but in the multiple tailored intervention the information was provided to the participants spread over three occasions. In the multiple tailored intervention, the second and the third tailored letters were based on short and standardized telephone interviews. Measurements Benzodiazepine cessation at post-test was the outcome measure. Findings: The results showed that participants receiving the tailored interventions were twice as likely to have quit benzodiazepine use compared to the general practitioner letter. Particularly among participants with the intention to discontinue usage at baseline, both tailored interventions led to high percentages of those who actually discontinued usage (single tailored intervention 51.7%; multiple tailored intervention 35.6%; general practitioner letter 14.5%). Conclusions: It was concluded that tailored patient education can be an effective tool for reducing benzodiazepine use, and can be implemented easily.

Tsakiris P; Oelke M; Michel MC. Drug-induced urinary incontinence. Drugs & Aging 25(7): 541-549, 2008. (50 refs.)

Physiological urinary continence depends on many factors that are potentially vulnerable to adverse drug effects, which may lead to incontinence. In principle, drugs could cause incontinence by lowering bladder outlet resistance and/or by increasing intravesical pressure, which disrupts the normal pressure relationship between the bladder and urethra and leads to urinary leakage; other possibilities include disturbances of central nervous control of voiding or an overproduction of urine. While many drug groups could theoretically induce urinary incontinence based upon pathophysiological considerations, evidence demonstrating a cause-effect relationship between drug usage and incontinence is sparse. Drug classes in which induction of incontinence has been proposed include (xi-adrenoceptor antagonists, antipsychotics, benzodiazepines, antidepressants and hormone replacement therapy in postmenopausal women. However, other drug classes are not innocent in terms of causing urinary incontinence and physicians are well advised to closely monitor patients for the occurrence of incontinence after new prescriptions and/or major dosage changes.

Uchida H; Suzuki T; Mamo DC; Mulsant BH; Kikuchi T; Takeuchi H et al. Benzodiazepine and antidepressant use in elderly patients with anxiety disorders: A survey of 796 outpatients in Japan. Journal of Anxiety Disorders 23(4): 477-481, 2009. (37 refs.)

Since the literature on benzodiazepine use in elderly patients with anxiety disorders is limited, a large cross-sectional review of psychotropic prescriptions in 796 patients with neurotic disorders (ICID-10) (age range = 11-91 years) was conducted across 30 sites in Japan. Use of benzodiazepine-derivative anxiolytics was approximately 70% in all decades without a group difference. The proportion of subjects who received prescriptions for benzodiazepine-derivative anxiolytics in the absence of antidepressants was higher in older age groups (e.g., 27.7% and 43.2% in the third and sixth decades, respectively). On the other hand, antidepressants were less frequently prescribed in older age groups (e.g., 59.8% and 41.5% in the third and sixth decades, respectively). The very high use of anxiolytics in the elderly, especially in the absence of concomitant antidepressant use, is a cause for concern since they are not a preferred long-term treatment strategy given their adverse effects in the elderly.

Uhlmann C; Froscher W. Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: Results from a Questionnaire Study. CNS Neuroscience & Therapeutics 15(1): 24-31, 2009. (29 refs.)

There is no systematical research about the topic of dependence on antiepileptic drugs (AED) for patients with epilepsy, despite the fact that barbiturates and benzodiazepines comprise a potential risk of dependence. We hypothesize that there is no psychological substance dependence for patients with epilepsy, possibly because of their outcome expectations. The aim of the study was to examine these patients in terms of substance dependence. One hundred inpatients at the Lake Constance Epilepsy Center were asked about their experiences with AED in terms of dependence in a structured interview. We registered general statements about dependence of AED, markers for substance dependence, and outcome expectations. About 50% of the patients reported withdrawal symptoms and the development of tolerance, but less than 10% noticed loss of control and craving. Withdrawal symptoms and development of tolerance were significantly lower in a group of patients without barbiturates or clobazam versus patients with barbiturates or/and clobazam. There was no significant difference between these two groups in psychological criteria of dependence, that is, loss of control and craving. Outcome expectations of AED were clearly related to the efficacy against seizures, and only to a small amount to psychotropic effects. The study demonstrates that physiological variables of dependence are present more in patients with epilepsy with a permanent intake of barbiturates or clobazam, but psychological variables of dependence are rarely present in epileptic patients, with or without an intake of barbiturates and clobazam. These results confirm our hypothesis that substance dependence is not a major problem in benzodiazepines and barbiturates in patients with epilepsy. Outcome expectations seem to be related mainly to the anticonvulsant and not the psychotropic effect. This might be the reason for the absence of dependence.

van der Hooft CS; Schoofs MWCJ; Ziere G; Hofman A; Pols HAP; Sturkenboom MCJM et al. Inappropriate benzodiazepine use in older adults and the risk of fracture. British Journal of Clinical Pharmacology 66(2): 276-282, 2008. (15 refs.)

AIMS: The Beers criteria for prescribing in elderly are well known and used for many drug utilization studies. We investigated the clinical value of the Beers criteria for benzodiazepine use, notably the association between inappropriate use and risk of fracture. METHODS We performed a nested case-control study within the Rotterdam Study, a population-based cohort study in 7983 elderly. The proportion of 'inappropriate' benzodiazepine use according to the Beers criteria was compared between fracture patients and controls. 'Inappropriate' use for elderly implies use of some long-acting benzodiazepines and some intermediate/short-acting ones exceeding a suggested maximum daily dose. Also, alternative criteria were applied to compare the risk of fracture. Cases were defined as persons with incident fracture between 1991 and 2002 who were current benzodiazepine users on the fracture date. Controls were matched on fracture date and were also current benzodiazepine users. RESULTS: The risk of fracture in 'inappropriate' benzodiazepine users according to the Beers criteria was not significantly different from 'appropriate' users [odds ratio (OR) 1.07, 95% confidence interval (CI) 0.72, 1.60]. However, a significantly higher risk of fracture was found in 'high dose' users and a longer duration of use (14-90 days), irrespective of the type of benzodiazepine (OR 3.45, 95% CI 1.38, 8.59). CONCLUSIONS: These findings suggest that inappropriate benzodiazepine use according to the Beers criteria is not associated with increased risk of fracture. Daily dose and longer duration of use (> 14 days) is associated with higher risk of fracture, irrespective of the type of benzodiazepine prescribed.

Voaklander DC; Rowe BH; Dryden DM; Pahal J; Saar P; Kelly KD. Medical illness, medication use and suicide in seniors: A population-based case control study. Journal of Epidemiology and Community Health 62(2): 138-146, 2008. (49 refs.)

Background: Suicide among seniors is a significant health problem in north America, particularly for men in whom the rates rise steadily after 50 years of age. The goal of this study was to examine elder suicides identified from a large population-based database using case control methods to determine disease and medication factors related to suicide. Methods: A population-based 1 : 5 case-control study was conducted comparing seniors aged 66 years and older who had died by suicide with age and sex-matched controls. Case data were obtained through British Columbia (BC) Vital Statistics, whereas controls were randomly selected from the BC Health Insurance Registry. Cases and controls were linked to the provincial PharmaCare database to determine medication use and the provincial Physician Claims and Inpatient Hospitalization databases to determine co-morbidity. Results: Between 1993 and 2002 a total of 602 seniors died by suicide in BC giving an annual rate of 13.2 per 100 000. Firearms were the most common mechanism (28%), followed by hanging/suffocation (25%), self-poisoning (21%), and jumping from height (7%). In the adjusted logistic model, variables related to suicide included: lower socioeconomic status, depression/psychosis, neurosis, stroke, cancer, liver disease, parasuicide, benzodiazepine use, narcotic pain killer use and diuretic use. There was an elevated risk for those prescribed inappropriate benzodiazepines and for those using strong narcotic pain killers. Conclusion: This study is consistent with previous studies that have identified a relationship between medical or psychiatric co-morbidity and suicide in seniors. In addition, new and potentially useful information confirms that certain types and dosages of benzodiazepines are harmful to seniors and their use should be avoided.

Vrublevska K; Rukmane J; Burmistrs R; Sipols J; Muceniece R. Dispensing of psychotropic drugs to adults in community pharmacies in Latvia. Pharmacy World & Science 30(6): 934-939, 2008. (26 refs.)

Objective: To estimate outpatient utilization of psychotropic drugs before and after pharmaceutical reform in Latvia. Setting Data concerning prescribing and dispensing of psychotropic drugs were collected in six community pharmacies in the region of Latgale of Latvia. Method: An exploratory analysis of prescription data provided by six community pharmacies from 2004 to 2007. Drugs included in the study were classified according to an Anatomical-Therapeutic-Chemical (ATC) drug classification system, and ATC data were used to calculate defined daily doses (DDD) per 1,000 inhabitants. The National SSK-10 classification was used for analysis of codes of disease diagnosis. Main outcome measures Identification of the most often prescribed psychotropic drug and prescribing physician, patient characterization by age and gender, and analysis of codes of diseases. Results Benzodiazepines and benzodiazepine-related drugs were mainly prescribed in outpatient practice. Diazepam was the most frequently prescribed benzodiazepine-12 DDD/1,000/day. The drugs were prescribed mainly by family physicians (in 66% of cases). Female residents bought more psychotropic drugs than males. In addition, residents of cities bought little more drugs than those living outside urban areas. Accordingly to the recorded disease codes, the codes for neurotic and behavioral disorders dominated. Conclusion: The introduction of new norms neither increased nor decreased the number of psychotropic drug prescriptions filled. The most often prescribed psychotropic drugs over 4-year period were benzodiazepines and their derivates. Disease codes on the prescriptions fully justified a reason for psychotropic drug use.

Wallner C; Stollberger C; Hlavin A; Finsterer J; Hager I; Hermann P et al. Electrocardiographic abnormalities in opiate addicts. Addiction 103(12): 1987-1993, 2008. (29 refs.)

To determine in a cross-sectional study the prevalence of electrocardiographic (ECG) abnormalities in opiate addicts who were therapy-seeking and its association with demographic, clinical and drug-specific parameters. In consecutive therapy-seeking opiate addicts, a 12-lead ECG was registered within 24 hours after admission and evaluated according to a pre-set protocol between October 2004 and August 2006. Additionally, demographic, clinical and drug-specific parameters were recorded. Included were 511 opiate-addicts, 25% female, with a mean age of 29 years (range 17-59 years). One or more ECG abnormalities were found in 314 patients (61%). In the 511 patients we found most commonly ST abnormalities (19%), QTc prolongation (13%), tall R- and/or S-waves (11%) and missing R progression (10%). ECG abnormalities were more common in males than in females (64 versus 54%, P < 0.05), and in patients with positive than negative urine findings for cannabis (68 versus 57%, P < 0.05). Patients with ST abnormalities were more often males than females (21 versus 11%, P < 0.05), had a history of seizures less often (16 versus 27%, P < 0.05), had positive than negative urine findings for cannabis more often (26 versus 15%, P < 0.01) and had negative than positive urine findings for methadone more often (21 versus 11%, P < 0.05). QTc prolongation was more frequent in patients with high dosages of maintenance drugs than in patients with medium or low dosages (27 versus 12 versus 10%, P < 0.05) and in patients whose urine findings were positive than negative for methadone (23 versus 11%, P < 0.001) as well as for benzodiazepines (17 versus 9%, P < 0.05). Limitations of the data are that in most cases other risk factors for the cardiac abnormalities were not known. ECG abnormalities are frequent in opiate addicts. The most frequent ECG abnormalities are ST abnormalities, QTc prolongation and tall R- and/or S-waves. ST abnormalities are associated with cannabis, and QTc prolongation with methadone and benzodiazepines.

Weinberg JA; Magnotti LJ; Fischer PE; Edwards NM; Schroeppel T; Fabian TC et al. Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: Results of a randomized trial. Journal of Trauma, Injury, Infection and Critical Care 64(1): 99-104, 2008. (21 refs.)

Background: Although benzodiazepines are the recommended first-line therapy for the prevention of alcohol withdrawal syndrome (AWS), the administration of intravenous ethanol as an alternative prophylactic agent persists in many surgical ICUs. Advocates of this therapy argue that ethanol provides effective prophylaxis against AWS without the excessive sedation observed with benzodiazepine therapy. No study to date, however, has compared the two therapies with regard to their sedative effects. The purpose of this study was to prospectively evaluate the efficacy of intravenous ethanol compared with benzodiazepines for the prevention of AWS with particular emphasis on the sedative effects of each therapy. Methods: During a 15-month period, trauma patients admitted to the ICU with a history of chronic daily alcohol consumption greater than or equal to five beverage equivalents per day were prospectively randomized to one of two 4-day prophylactic regimens: intravenous ethanol infusion (EtOH) versus scheduled-dose diazepam (BENZO). Patients were evaluated with the Riker sedation-agitation scale, a 7-point instrument for the subjective assessment of both sedation (1 = unarousable) and agitation (7 = dangerous agitation). According to protocol, regimens were titrated to achieve and maintain a Riker score of 4 (calm and cooperative). Deviation from a score of 4 during the course of treatment was compared between groups. Results: Fifty patients met study criteria and were randomized after obtainment of informed consent (EtOH, n = 26; BENZO, n = 24). Overall, the EtOH group had a significantly greater proportion of patients who deviated from a score of 4 during the course of treatment (p = 0.020). In both groups, the majority of deviation from a score of 4 reflected periods of under-sedation rather than over-sedation. One patient in the EtOH group failed treatment, requiring diazepam and haloperidol for control of AWS symptoms as per protocol, whereas no patient in the BENZO group failed treatment (p = NS). Conclusion; Concerning the prophylaxis of AWS, intravenous ethanol offers no advantage over diazepam with respect to efficacy or adverse sedative effects. The purported benefit of intravenous ethanol as a prophylactic agent against AWS was not evident.

Wong SC; Curtis JA; Wingert WE. Concurrent detection of heroin, fentanyl, and xylazine in seven drug-related deaths reported from the Philadelphia Medical Examiner's Office. Journal of Forensic Sciences 53(2): 495-498, 2008. (17 refs.)

Recreational drugs, such as cocaine and heroin, are often adulterated with other pharmacological agents to either enhance or diminish the drug effects. Between April 21, 2006 and August 8, 2006, the Philadelphia Medical Examiner's Office detected xylazine (a veterinary sedative) and fentanyl (a synthetic opioid) in specimens taken from seven cases. Initial immunoassay screening was performed on urine and blood for fentanyl, opiate, cocaine, phencyclidine (PCP), and benzodiazepines. All tests reported positive were confirmed by gas chromatography-mass spectrometry. All seven xylazine positive cases tested positive for fentanyl and six cases tested positive for 6-acetylmorphine (a metabolite and definitive marker for heroin). The seventh case was positive for morphine and had a history of heroin abuse. Xylazine was present in urine in all seven cases and blood levels were detected in three cases. The blood concentrations ranged from trace to 130 ng/mL. Fentanyl was present in the blood and urine in each case and blood concentrations ranged from 4.7 to 47 ng/mL. Adulteration of illicit drugs has become an epidemic health concern for drug users. Healthcare professionals need to be aware of this issue, so the patients can be treated in an effective, timely manner.