Long-term Benzodiazepine Treatment Research Articles

Benzodiazepine Discontinuation and Mortality Among Patients Receiving Long-Term Benzodiazepine Therapy

There is interest in reducing long-term benzodiazepine prescribing given harms associated with use, but the cumulative risks or benefits of discontinuation are unknown. To identify the association of benzodiazepine discontinuation with mortality and other adverse events among patients prescribed stable long-term benzodiazepine therapy, stratified by baseline opioid exposure. This comparative effectiveness study with a trial emulation approach included data from a US commercial insurance database between January 1, 2013, and December 31, 2017. Eligible participants were adults with stable long-term benzodiazepine prescription treatment. Data were analyzed between December 2022 and November 2023. Benzodiazepine discontinuation, defined as no benzodiazepine prescription coverage for 31 consecutive days identified during a 6-month grace period after baseline. Mortality during 12 months of follow-up; secondary outcomes included nonfatal overdose, suicide attempt or self-inflicted injury, suicidal ideation, and emergency department use, identified in medical claims. Inverse probability weighting was used to adjust for baseline confounders that potentially affected treatment assignment and censoring due to death or disenrollment. Primary analysis used an intention-to-treat approach; a secondary per-protocol analysis estimated associations after accounting for nonadherence. Analyses were stratified by opioid use. The study included 213 011 (136 609 female [64.1%]; mean [SD] age, 62.2 [14.9] years; 2953 Asian [1.4%], 18 926 Black [8.9%], 22 734 Hispanic [10.7%], and 168 398 White [60.2%]) and 140 565 (91 811 female [65.3%]; mean [SD] age, 61.1 [13.2] years; 1319 Asian [0.9%], 15 945 Black [11.3%], 11 989 Hispanic [8.5%], and 111 312 White [79.2%]) patients with stable long-term benzodiazepine use without and with opioid exposure, respectively. Among the nonopioid exposed, the adjusted cumulative incidence of death after 1 year was 5.5% (95% CI, 5.4%-5.8%) for discontinuers, an absolute risk difference of 2.1 percentage points (95% CI, 1.9-2.3 percentage points) higher than for nondiscontinuers. The mortality risk was 1.6 (95% CI, 1.6-1.7) times that of nondiscontinuers. Among those with opioid exposure, the adjusted cumulative incidence of death was 6.3% (95% CI, 6.0%-6.6%) for discontinuers, an absolute risk difference of 2.4 percentage points (95% CI, 2.2-2.7 percentage points) higher than for nondiscontinuers and a mortality risk 1.6 (95% CI, 1.5-1.7) times that of nondiscontinuers. Cumulative incidence of secondary outcomes was also higher among discontinuers. This study identifies small absolute increases in risk of harms among patients with stable long-term prescription benzodiazepine treatment who appear to discontinue relative to continuing treatment, including those with and without recent prescription opioid exposure. Policy broadly promoting benzodiazepine discontinuation may have unintended risks.

Resolving the Paradox of Long-Term Benzodiazepine Treatment: Toward Evidence-Based Practice Guidelines.

Resolving the Paradox of Long-Term Benzodiazepine Treatment: Toward Evidence-Based Practice Guidelines.

Prescription Benzodiazepine Use in Privately Insured U.S. Children and Adolescents

Benzodiazepines are commonly prescribed in the U.S. but entail safety concerns, including dependency. In pediatrics, many indications lack trial data. Authors aimed to describe youth initiating prescription benzodiazepine treatment, identify potential indications and prescribing concerns, estimate the duration of treatment by potential indication, and identify factors that predict long-term use. The study cohort included children (aged 3-12 years) and adolescents (aged 13-17 years) initiating prescription benzodiazepine treatment (≥3 days' supply) from January 2010 to September 2015 in a U.S. commercial claims database. Potential indications included selected ICD-9-CM diagnoses (≤30 days prior). Long-term (≥6 months) benzodiazepine treatment was estimated with Kaplan-Meier estimation and modified Poisson regression identified independent predictors of long-term benzodiazepine treatment (analysis completed in 2018). Of 24,504 children and 61,046 adolescents initiating benzodiazepines, 62% of the children and 68% of the adolescents had a potential indication. Anxiety disorders were the most common indication, with mental health indications more common among adolescents (45%) than children (23%) and epilepsy and movement disorders higher in children. Recent opioid prescriptions were common before benzodiazepine initiation (children, 22%; adolescents, 21%). Six percent of the initiators became long-term benzodiazepine users. Potential indication, provider contact, psychotropic medication, and chronic conditions independently predicted long-term benzodiazepine treatment in adolescents and children. U.S. children and adolescents are prescribed benzodiazepines for various mental health and other medical conditions, many lacking evidence of pediatric efficacy. Long-term benzodiazepine treatment, concurrent opioid prescriptions, psychotropic use, and prior substance use disorder diagnoses suggest safety risks among some youth prescribed benzodiazepines.

Trends in the long-term use of benzodiazepine anxiolytics and hypnotics: A national register study for 2006 to 2014.

Long-term benzodiazepine (BZD) treatment continues to be a debated topic. Because individual BZDs have different clinical profiles, we assessed the nationwide trends of long-term BZD use at active substance level during years 2006 to 2014. This study covered all reimbursed BZD purchases (n=408572-521823 annually) for adults recorded in the Finnish Prescription Register. We assessed long-term use (annual cumulative purchase of ≥180 defined daily doses) in general, and at active substance level with the most commonly used BZD anxiolytics (oxazepam, diazepam, alprazolam, and clonazepam for nonepilepsy indications) and hypnotics (zopiclone, zolpidem, and temazepam) included. The persistence rates for each substance were assessed separately. The prevalence of long-term BZD use among Finnish adults declined significantly from 5.3% to 3.6%, during years 2006 to 2014. Despite this decline, there was a significant increase in the long-term use of clonazepam for nonepilepsy indications and zolpidem (28.0% and 17.5%, respectively). Long-term use was common in the aged population, as well as among the users of hypnotics or clonazepam. Persistent use of 9 consecutive calendar years varied between 7.5% for incident alprazolam users and 21.0% for incident clonazepam users. We found a declining trend in long-term BZD use, but the decline was not uniform between the substances-the long-term use of clonazepam and zolpidem even increased. Follow-up research is needed to assess whether the decline in BZD use is accompanied by an increased use of other types of anxiolytic or hypnotic drugs or other forms of treatment.

Initiation and long‐term use of benzodiazepines and Z‐drugs in bipolar disorder

Increasing evidence points to the harmful effects of long-term benzodiazepine treatment. Our objective was to study the incidence of, and predictors for, long-term use of benzodiazepines and Z-drugs in bipolar disorder. We conducted a population-based cohort study, using data from Swedish national registers. Swedish residents aged 18-75 years with a recorded diagnosis of bipolar disorder or mania between July 2006 and December 2012, and no history of benzodiazepine/Z-drug use in the past year, were included. Patients were followed for 1year with regard to prescription fills of benzodiazepines/Z-drugs. Initiators were followed for another year during which continuous use for >6months was defined as "long-term". Patient and prescription characteristics were investigated as potential predictors for long-term use in multivariate logistic regression models. Out of the 21883 patients included, 29% started benzodiazepine/Z-drug treatment, of whom one in five became long-term users. Patients who were prescribed clonazepam or alprazolam had high odds for subsequent long-term use (adjusted odds ratios [aORs] 3.78 [95% confidence interval (CI) 2.24-6.38] and 2.03 [95% CI 1.30-3.18], respectively), compared to those prescribed diazepam. Polytherapy with benzodiazepines/Z-drugs also predicted long-term use (aOR 2.46, 95% CI 1.79-3.38), as did age ≥60years (aOR 1.93, 95% CI 1.46-2.53, compared to age <30years), and concomitant treatment with psychostimulants (aOR 1.78, 95% CI 1.33-2.39). The incidence of subsequent long-term use among bipolar benzodiazepine initiators is high. Patients on clonazepam, alprazolam or benzodiazepine/Z-drug polytherapy have the highest risk of becoming long-term users, suggesting that these treatments should be used restrictively.

Long-term Benzodiazepine Treatment in Patients with Psychotic Disorders Attending a Mental Health Service in Rural Greece.

Introduction:Long-term benzodiazepine (BZD) treatment in patients with mental disorders is widespread in clinical practice, and this is also the case of patients with schizophrenia, although the evidence is weak and BZD prescription is discouraged by guidelines and medical authorities. Data on BZD prescription are usually derived from national or regional databases whereas information on the use of BZD by patients with schizophrenia and related psychoses in general population-based samples is limited.Materials and Methods:Information for 77 patients with psychotic disorders who were regularly attending follow-up appointments with the multidisciplinary Mobile Mental Health Unit of the prefectures of Ioannina and Thesprotia, Northwest Greece, during 1-year period (2015) was obtained from our database.Results:From the total of 77 engaged patients, 30 (39%) were regularly prescribed BZDs in the long term, as part of their treatment regimen. Prescribed BZDs were mostly diazepam and lorazepam, in 43.3% of cases each. The mean daily dose of these compounds was 13 mg and 3.77 mg, respectively. Statistical analysis showed a correlation of long-term BZD use with the history of alcohol/substance abuse. Most patients were receiving BZD continuously for several years, and the mean dose was steady within this interval.Conclusions:A large proportion of patients with psychotic disorders were regularly prescribed BZD in long term. It appears that when BZDs are prescribed for some period in the course of a psychotic disorder, their use commonly exceeds the recommended interval and then becomes a regular part of the chronic treatment regimen. Future research should address the factors that may be related to the long-term BZD use by patients with psychotic disorders. Interventions for the reduction of regular BZD prescription should target the primary care setting and all those who treat first episode patients.

Benzodiazepine Maintenance Treatment in Schizophrenia.

To the Editor: Data are conflicting concerning the utility of benzodiazepines in management of schizophrenia with comorbid substance use. We present 2 cases that offer different rationale for benzodiazepine maintenance therapy. Case reports. Ms A is a 54-year-old woman with schizophrenia (DSM-51) and a 17-year history of benzodiazepine and opioid use. Prior to her initial hospitalization, Ms A was on a prescribed 4-year regimen of 30 mg of diazepam. During this time, she experienced chronic delusions and hallucinations but was stable enough that she did not require antipsychotic treatment or hospitalization. After taper of diazepam, the patient underwent several psychiatric hospitalizations for psychotic decompensation. During her most recent hospitalization, Ms A was started on haloperidol decanoate; however, she did not improve sufficiently for discharge on haloperidol alone. Low-dose benzodiazepines were resumed (clonazepam), and Ms A’s psychosis improved sufficiently to facilitate discharge, but did not remit fully. Mr B is a 29-year-old man with schizophrenia (DSM-51) complicated by tardive dyskinesia, plus remote history of LSD (lysergic acid diethylamide) and cocaine use disorders (DSM-51). He was admitted to the psychiatric unit within the hospital for clozapine initiation and lorazepam taper. He had been started on lorazepam 1.5 mg/d for catatonia 4 years prior to admission. During these years, while concurrently taking risperidone 3 mg twice daily, Mr B’s lorazepam dose was increased to 10 mg/d. He remained consistent in his belief that only lorazepam alleviated his paranoia and somatic delusions. On a therapeutic clozapine dose, Mr B’s psychotic symptoms improved, but he remained unwilling to taper lorazepam. The use of benzodiazepines as monotherapy or as an adjunct to antipsychotics in schizophrenia has been assessed with conflicting results.2–4 Dold et al2 reviewed 34 randomized controlled trials evaluating benzodiazepine treatment in schizophrenia. The reviewers reported no conclusive evidence supporting use of benzodiazepines alone or in combination with other medications.2 In contrast, other studies3,4 reported that short-term monotherapy treatment with benzodiazepines decreased positive and negative symptoms in one-third to one-half of patients; these studies demonstrated efficacy of benzodiazepines as antipsychotic treatment adjuncts. Literature reporting γ-aminobutyric acid (GABA) dysfunction in schizophrenia suggests a role for benzodiazepine pharmacotherapy.5 In schizophrenia, cortical GABAergic neurotransmission appears to be down-regulated, leading to changes associated with impaired somatosensory information processing.5 Likely as a compensatory mechanism for excitatory desynchronization, up-regulation of high-affinity postsynaptic GABAA receptors occurs, independent of antipsychotic treatment duration.5 By targeting GABAA receptors, benzodiazepines might normalize GABAergic transmission, allowing for a novel mechanism of treatment for psychosis.5 This hypothesis is supported by the case of Ms A, who did not require antipsychotic medication until her 50s. Although not definitive treatment for schizophrenia, benzodiazepines may have facilitated sufficient health for Ms A to remain in the community with relatively high quality of life for a long period of time. Once hospitalized, Ms A did not recover sufficiently for discharge without benzodiazepines, which may have been due to direct treatment effect, although it cannot be definitively proven. The evidence supporting benzodiazepine use in schizophrenia is challenged by the risks of prescribing a highly abused substance to a vulnerable population.6 In a prospective analysis6 of benzodiazepine use in patients with bipolar disorder or schizophrenia and comorbid substance abuse, patients prescribed benzodiazepines were more likely to have abused benzodiazepines during the study compared to those not prescribed benzodiazepines. While exposure does appear to play a role in this abuse profile, patients taking prescribed benzodiazepines displayed increased illness severity at presentation.6 It remains unclear whether benzodiazepine access alone increases risk of misuse.7 Current treatment for benzodiazepine use disorder focuses on controlled withdrawal, followed by abstinence.8 However, in patients who develop a use disorder secondary to long-term benzodiazepine treatment for psychiatric indications, abstinence may not be a feasible goal. In Mr B’s case, although the benzodiazepines were initially indicated for catatonia, he developed an overvalued belief in their role in his treatment. Abstinence became unachievable, although dose reduction occurred. Therefore, in the cases described here, long-term use of benzodiazepines either was useful in clinical improvement (Ms A) or became intricately tied to delusions and belief in one’s own improvement (Mr B), making abstinence impractical. With the infeasibility of abstinence for patients such as Mr B, agonist substitution might be an alternative.8 Using this model, maintenance treatment with a long-acting, slow-onset benzodiazepine would be analogous to methadone maintenance for opiate use.8 By using a benzodiazepine and maintaining stable blood benzodiazepine levels, patients would be less likely to experience sedation, withdrawal complications, and craving.8 Agonist substitution could facilitate treatment retention in an unstable patient population, rather than “doctor shopping” for benzodiazepine prescriptions during withdrawal.8 Given evidence supporting a GABAergic mechanism for schizophrenia, treatment with benzodiazepines may target a novel therapeutic mechanism beyond the scope of traditional antipsychotics. In patients using benzodiazepines for relief of psychotic symptoms, we present a role for maintenance therapy using agonist substitution.

Major depression treatment in Germany–descriptive analysis of health insurance fund routine data and assessment of guideline-adherence

BackgroundGuideline oriented treatment strategies of Major depressive disorder (MDD) improve treatment outcomes and reduce risks of chronicity and recurrence. AimsDescription of routine treatment reality and analysis of guideline fidelity in first episode MDD in Germany. Indicators: patients with severe or psychotic depression or severe psychiatric comorbidities’ treatment by specialists, adequate antidepressant pharmacotherapy, permanent treatment with more than one antidepressant, long-term benzodiazepine treatment and provision of psychotherapy. MethodDescriptive analysis of routine data of the German statutory health insurance fund Barmer GEK in the index year 2011 that covers a population of 7,501,110. Results236,843 patients were diagnosed a depressive episode. 53.0% of the patients with severe depression, 34.4% with psychotic depression and 50.9% with severe psychiatric comorbidities were treated by specialists; of the patients treated by a general practitioner 48.1% with severe and 47.3% with psychotic depression received an antidepressant; 9.7% of all patients with MDD got two antidepressants simultaneously; 8.3% received longterm benzodiazepine prescriptions; 26.1% got psychotherapy. Limitationsthe analyses depends on the indicators definitions that cannot cope with the variety of individual treatment path; comparison with guidelines was complicated by a large fraction of patients with recurrent MDD that was wrongly diagnosed with first episode depression; due to the data structure, not all guideline recommendations could be examined ConclusionsRoutine practice was oriented upon the guidelines recommendations. However some aspects could be identified that bear potential for improvements.

Prescriptions médicamenteuses potentiellement inadaptées chez les personnes âgées : une étude en Provence-Alpes-Côte d’Azur à partir des données de remboursements de l’Assurance maladie

BackgroundThis study conducted in the region of Provence-Alpes-Côte d’Azur (PACA) sought to assess the feasibility of constructing and using indicators of potentially inappropriate prescriptions for the elderly from health insurance reimbursement data. We present and discuss different indicators of inappropriate prescriptions for people aged 70 years or older (at-risk prescriptions, dangerous or at-risk coprescriptions, absence of necessary coprescriptions) and reports their prevalence in PACA. MethodsThe indicators were constructed from the French list of inappropriate prescriptions, national agency guidelines, and the advice of experts in the field. The indicators selected were applied to the databases of the PACA Salaried Workers’ Health Insurance Fund for 2008 for all recipients aged 70 years or older and compared according to age, sex, chronic disease status, and, after standardization for age and sex, according to district of residence. ResultsIn January 2009, 500,904 recipients aged 70 years or older were identified in the data base of the Salaried Workers’ Health Insurance Fund, 60.8% of whom were women and 52.1% of whom had approved coverage for a chronic disease. The potentially inappropriate prescriptions most frequently observed here, in decreasing order, were: prescription of an NSAID without the coprescription of gastric protection (28.1%); long-term benzodiazepine treatment (21.5%); prescription of long half-life benzodiazepine (14.9%), and long-term treatment with NSAIDs (11.6%). Overall, the prevalence of each increased significantly with age and was higher among women and people with chronic diseases. Significant variations were also observed between the different districts of PACA. ConclusionOur results confirm that a substantial proportion of elderly people receive potentially inappropriate prescriptions. They also suggest that health insurance reimbursement data could be used in some prescription domains for monitoring trends in the potentially inappropriate prescriptions in the populations of various territories, provided that specific limitations are considered.

Current use of benzodiazepines in anxiety disorders

The aim of this study is to provide a review of articles published between July 2007 and August 2008 on the current use and rationale of benzodiazepines in anxiety disorders. Recent review articles confirm selective serotonin reuptake inhibitors as first-choice drugs for treating anxiety disorders, alongside newer agents such as pregabalin or serotonin-norepinephrine reuptake inhibitors, and combined with cognitive-behavioural therapy. Benzodiazepines are still widely used by clinicians for these disorders, as shown by recent surveys, even though their anxiolytic effectiveness is questioned. Newer agents are in development and may in the future resolve the therapeutic dilemma. Despite current guidelines, benzodiazepines are still considered by many clinicians to remain good treatment options, in both the acute and the chronic phase of the treatment of anxiety disorders, partially because of their rapid onset of action and their efficacy with a favourable side effect profile, and also because of the sometimes only incomplete therapeutic response and the emergence of side effects of alternative medications. Having experienced good initial symptom relief with benzodiazepine treatment, patients may also be reluctant to taper it down. Clinicians should, however, bear in mind the frequent physiological dependence associated with these substances, and suggest both pharmacological and psychological treatment alternatives before opting for a long-term benzodiazepine treatment, which may remain necessary in certain clinical conditions.

Tolerance development to Morris water maze test impairments induced by acute allopregnanolone

The progesterone metabolite allopregnanolone, like benzodiazepines, reduces learning and impairs memory in rats. Both substances act as GABA agonists at the GABA-A receptor and impair the performance in the Morris water maze test. Women are during the menstrual cycle, pregnancy, and during hormone replacement therapy exposed to allopregnanolone or allopregnanolone-like substances for extended periods. Long-term benzodiazepine treatment can cause tolerance against benzodiazepine-induced learning impairments. In this study we evaluated whether a corresponding allopregnanolone tolerance develops in rats. Adult male Wistar rats were pretreated for 3 days with i.v. allopregnanolone injections (2mg/kg) one or two times a day, or for 7 days with allopregnanolone injections 20mg/kg intraperitoneally, twice a day. Thereafter the rats were tested in the Morris water maze for 5 days and compared with relevant controls. Rats pretreated with allopregnanolone twice a day had decreased escape latency, path length and thigmotaxis compared with the acute allopregnanolone group that was pretreated with vehicle. Pretreatment for 7 days resulted in learning of the platform position. However, the memory of the platform position was in these tolerant rats not as strong as in controls only given vehicle. Allopregnanolone treatment was therefore seen to induce a partial tolerance against acute allopregnanolone effects in the Morris water maze.

Effects of long-term benzodiazepine medication. A prospective cohort study: Methodological and clinical aspects

Benzodiazepine (BDZ) drug impact on mental functions was explored in a cohort study of 30 psychiatric outpatients on long-term BDZ medication. A new questionnaire, the Drug Impact on Mental Processes (DIMP) was used and evaluated. The patients were rated three times: on inclusion in the study, after about 18 months and, finally, only a few days later. Test–retest reliability was evaluated for the two last ratings and was found acceptable for 19/23 items. The DIMP scores indicated negative effects on crisis reaction, intensified defence mechanisms and reduced cognitive, emotional and conative functions. Long-term BDZ treatment intensified passive coping. The drug impact on mental functions ranged between a mild and a moderate degree. The clinical outcomes of the patients’ psychiatric disorders were evaluated at a 1-year follow-up after continued or discontinued BDZ treatment. In the subgroup that had discontinued the BDZ treatment at follow-up, significantly more patients reported reduced severity of their psychiatric disorders and significantly more patients had paid jobs. The overall clinical improvement after discontinued BDZ treatment may be explained by recovery from an addiction syndrome. It may also be related to a shift from passive to active coping.

Empiric Use of Flumazenil in Comatose Patients: Limited Applicability of Criteria to Define Low Risk

Study objective: To develop clinical rules for the safe and effective use of flumazenil in suspected benzodiazepine overdose. Methods: We assembled a retrospective series of 35 consecutive comatose patients admitted between October 1992 and July 1993 to a toxicologic ICU with the presumptive diagnosis of drug overdose. These patients were divided into two groups. Group A (low-risk) patients had a clinical picture compatible with uncomplicated benzodiazepine intoxication (calm, without abnormalities in pulse or blood pressure, lateralizing signs, hypertonia, hyperreflexia, or myoclonus) in the absence of predefined electrocardiographic or clinical signs of tricyclic antidepressant or other proconvulsant overdose, and absence of an available history of long-term benzodiazepine treatment or an underlying seizure disorder. Group B ("non-low risk") comprised all other patients. Efficacy of flumazenil was categorized as complete awakening (with normal level of alertness), partial awakening, or no change in alertness level. The safety of flumazenil was defined on the basis of the absence of seizures or death. Results: In group A (n=4), flumazenil was associated with complete awakening in three patients and partial awakening in one. No seizures were observed. In group B (n=31), flumazenil was associated with complete awakening in 4 patients, partial awakening in 5, and no response in 22. In group B, five seizures occurred. Conclusion: Comatose patients with clinical or ECG criteria thought to contraindicate the use of flumazenil have a reasonably high risk of seizures after administration of this drug. Low-risk patients may be able to receive flumazenil safely, but they may be only a small portion of comatose patients with suspected overdose. [Gueye PN, Hoffman JR, Taboulet P, Vicaut E, Baud FJ: Empiric use of flumazenil in comatose patients: Limited applicability of criteria to define low risk. Ann Emerg Med June 1996;27:730-735.]

The Use of Benzodiazepines in the Workplace

Benzodiazepines differ from many of the other abused substances in that there are legitimate medical indications for their use. Any prescription for benzodiazepines must be preceded by a careful risk-benefit analysis that considers the specifics of an individual's particular life situation, personality style, and psychiatric diagnosis. The risk of benzodiazepine abuse by chemically dependent individuals and the problems of cognitive and/or psychomotor impairment and dependence for all individuals have to be balanced against the therapeutic benefits of these drugs for patients who experience disabling anxiety disorders or anxiety that accompanies chronic medical illness. Problems of dependence can be minimized by utilizing a variety of pharmacologic and psychotherapeutic strategies to ameliorate withdrawal symptoms that might accompany the discontinuation of long-term benzodiazepine treatment.

The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria?

In an attempt to establish whether prolonged withdrawal symptoms after stopping intake of benzodiazepines is caused by return of anxiety, hysteria, abnormal illness behaviour or the dependence process itself producing perhaps a prolonged neurotransmitter imbalance, a group of such patients suffering prolonged withdrawal symptoms (PWS) was compared on a range of psychophysiological measures with matched groups of anxious and conversion hysteria patients and normal controls. It was found that the psychophysiological markers of anxiety were not marked in the PWS group; nor were the averaged evoked response abnormalities found to be associated with cases of hysterical conversion in evidence. The PWS group were hard to distinguish from normal controls on the basis of psychophysiological measures and thus it was felt to be unlikely to be an affective disturbance. It was concluded that PWS is likely to be a genuine iatrogenic condition, a complication of long-term benzodiazepine treatment.

Carbamazepine treatment for benzodiazepine withdrawal.

Nine patients were given carbamazepine before rapid discontinuation of benzodiazepines. Most patients had had long-term benzodiazepine treatment and had abused benzodiazepines; five had taken high doses. All patients tolerated rapid discontinuation well and none developed significant withdrawal symptoms.

Resumption of benzodiazepine use after withdrawal in hospital--a follow-up study.

Despite the ongoing controversy about the benefit-risk-ratio of benzodiazepines in psychiatrie treatment (3, 5), they are still widely used (4, 6). In our hospital we follow the general policy that there is hardly any indication for long-term benzodiazepine treatment. Thus, patients who take benzodiazepines and get admitted to our hospital are regularly withdrawn. This study was intended to investigate how many patients would start to take benzodiazepines again after discharge and how far characteristics of the patients could prediet that resumption of benzodiazepine use.

Long-term benzodiazepine treatment reduces neuronal responsiveness to cholecystokinin: an electrophysiological study in the rat

Acute benzodiazepine administration has been reported to antagonize the effect of cholecystokinin both in the periphery and in the central nervous system. A two-week treatment with either diazepam (5 mg/kg per day) or flurazepam (15 mg/kg per day) markedly reduced the excitatory effect of microiontophoretically applied sulphated cholecystokinin octapeptide-(26–33) on rat CA 3 hippocampal pyramidal neurons but not that of acetylcholine. In view of the sustained anxiolytic activity of benzodiazepines that contrasts with their transient sedative effect, the present results suggest that the reduction of neuronal responsiveness to cholecystokinin by these drugs might be related to their anxiolytic property.

The effects of long-term benzodiazepine treatment and graded withdrawal on psychometric performance.

Twelve patients were assessed prior to and during 4 weeks' graded withdrawal from long-term benzodiazepine treatment. A control group of ten healthy drug-free individuals were assessed over the same period. Psychometric measures included Four Choice Reaction Time--Decision (FCRT-D), Four Choice Reaction Time--Movement (FCRT-M), Sensory Threshold Detection (STD) and Key Tapping Rate (KTR). Patients anxiety level was monitored using the Hamilton Rating Scale (HAM) and a Visual Analogue Self-Report Measure (VASR). There was no evidence of psychometric practice effects and no significant changes in patients anxiety ratings. Prior to withdrawal the patient group showed significantly impaired performance compared to the control group on FCRT-D and STD, tasks primarily involving visual sensory information processing, but there were no differences between the two groups on FCRT-M and KTR, tasks primarily involving motor speed. During withdrawal the patient group showed significant improvements compared to the control group on FCRT-D and STD.

Benzodiazepine sensitivity testing in the management of intractable seizure disorders in childhood

The use of benzodiazepine sensitivity testing in the management of 40 children with intractable seizure disorders was studied. The aetiology and clinical syndromes varied widely with myoclonic, atonic and complex absence seizures predominating. Twenty-five cases had mixed seizure disorders. There was, likewise, a wide range of EEG abnormalities. Seven cases were in non-convulsive status at the time of testing. Diazepam (0.2 mg/kg) was given slowly intravenously and its effect on the EEG was observed. In 21 cases epileptiform activity was abolished. No change was seen in 13 cases and an unusual result was seen in 3. There was a paradoxical response in 3 cases, two of these associated with clinical seizures. Only 1 child in non-convulsive status had a positive result. Following testing, 32 patients went on to long-term oral benzodiazepine treatment. Twenty-one of these patients showed subsequent clinical improvement and 16 21 (76%) had had a positive sensitivity test previously. Eleven of these patients did not improve on long-term treatment. Seven out of the 11 (64%) had had a negative sensitivity test. These results suggest that the benzodiazepine sensitivity test is of value in the long-term management of intractable seizure disorders in childhood, but also emphasise the variability and unpredictability of response to benzodiazepine treatment.