JUNIO 2001





1: Rev Neurol 2001 Feb 1-15;32(3):247-50
[Article in Spanish]
Mauri-Llerda JA, Tejero-Juste C, Iniguez C, Morales-Asin F.
Servicio de Neurologia, Hospital Clinico Universitario Lozano Blesa, San Juan Bosco, 15. E-Zaragoza 50009.
OBJECTIVE: To review the current treatment and usefulness of lamotrigine in absence seizures. DEVELOPMENT: Absence seizures are classified amongst the generalized epilepsies. They are defined as a transient loss of consciousness of sudden onset and recovery characteristically associated with generalized spike-and-wave discharges on the EEG. In recent years, the epileptic syndromes associated with this type of seizure have been better defined, basically by means of video-EEG studies. The International League Against Epilepsy has recognized four epileptic syndromes with typical absences: absence-epilepsy of childhood, juvenile absence-epilepsy, juvenile myoclonic epilepsy and epilepsy with myoclonic absences. The classical treatment for this type of seizure was based on ethosuximide, or more often, sodium valproate. Sometimes both drugs together were necessary. Other useful drugs are the benzodiazepines such as clobazam. CONCLUSIONS: We review studies of the efficacy and tolerance of lamotrigine in the treatment of absence seizures, one of the groups of seizures in which this drug has been shown to be most effective. Although studies comparing lamotrigine, valproate and ethosuximide are necessary, we emphasize the possibility that lamotrigine may be a drug of choice in absence seizures.

2: Rev Neurol 2001 Jan 1-15;32(1):77-82
[Article in Spanish]
Mauri-Llerda JA, Pascual-Millan LF, Tejero-Juste C, Iniguez C, Escalza-Cortina I, Morales-Asin F.
Servicio de Neurologia, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Espana.
OBJECTIVE: The neuropsychological assessment of the epileptic patient is a very important aspect of diagnosis and treatment. It may be used to contribute to localization of the hemisphere involved in the seizures, differentiate situations of anxiety or depression or when planning treatment for rehabilitation. We review the different aspects of neuropsychological changes in patients with epilepsy. DEVELOPMENT: Firstly we review the different tests used in the neuropsychological assessment of epilepsy. Dodrill's neuropsychological battery of tests, in which the patients score less than the controls, is the most commonly used. We then evaluate and study the so-called 'transient cognitive disorder'. We also study memory problems in epilepsy. There may be episodes of seizures with amnesic features ('amnesic epileptic seizures'). Finally, the possibility of neuropsychological dysfunction secondary to antiepileptic drugs should always be considered. CONCLUSIONS: Epileptic patients have lower scores than persons taken as controls for the results of various neuropsychological tests, although there is less difference between the two groups when the patient group is made up of persons with a normal intelligence quotient. Transient cognitive involvement is common in epileptics and may cause underachievement at school or psychological problems. Memory disorders, particularly subjective, are common in epileptics, although neuropsychological tests other than those generally used may be necessary to evaluate this. It is possible that such memory disorders, if occurring as seizures, may be due to amnesic partial crises, which should always be differentiated from the diagnosis of transient global amnesia. Almost all antiepileptic drugs can cause negative neuropsychological effects, especially the benzodiazepines and barbiturates.

3: Sleep 2000 Feb 1;23 Suppl 1:S39-47
Nonselective and selective benzodiazepine receptor agonists--where are we today?
Mitler MM.
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Insomnia is problematic for many individuals, causing them to seek treatment. There is a long history of therapies aimed at restoring normal sleep patterns, each having its advantages and disadvantages. This review traces the history of insomnia drug therapies from chloral hydrate and the barbiturates through the benzodiazepines and explores the newest selective benzodiazepine receptor agonists, including zolpidem and zaleplon. The mechanisms of action of the benzodiazepine receptor agonists are compared and contrasted. A pharmacokinetic comparison is presented showing the importance that parameters such as dose, onset of action, lipophilicity, metabolites, half-life, and receptor-binding affinity have on clinical effects. The possible adverse effects of sleep aids are discussed, including residual sedation and psychomotor impairment, daytime anxiety, anterograde amnesia and cognitive impairment, rebound insomnia, and drug tolerance and dependence. Effects on sleep efficiency and staging are also discussed. Recommendations for the primary care physician on the selection of hypnotics are also provided. Benzodiazepine receptor agonists are often appropriate agents in the treatment of insomnia; however, individual drug and patient considerations are important in matching the most appropriate agent to the individual patient. Zolpidem and zaleplon, newer selective benzodiazepine receptor agonists, offer additional treatment options.

4: Am Fam Physician 2000 Apr 1;61(7):2121-8 [Texto completo]
Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives.
Longo LP, Johnson B.
University of Wisconsin Medical School, Milwaukee, USA.
Benzodiazepines are widely prescribed for a variety of conditions, particularly anxiety and insomnia. They are relatively safe and, with overdose, rarely result in death. However, used chronically, benzodiazepines can be addicting. These agents are often taken in combination with other drugs of abuse by patients with addiction disorders. In such patients, alternatives to benzodiazepines may be preferable and may include antidepressants, anticonvulsants, buspirone, antihypertensive agents and the newer neuroleptic medications. Caution must be used when prescribing benzodiazepines to patients with a current or remote history of substance abuse.
Publication Types:
Review, tutorial

5: CMAJ 2000 Jan 25;162(2):225-33 [Texto completo]
Meta-analysis of benzodiazepine use in the treatment of insomnia.
Holbrook AM, Crowther R, Lotter A, Cheng C, King D.
Centre for Evaluation of Medicines, St. Joseph's Hospital, Hamilton, Ont.
OBJECTIVE: To systematically review the benefits and risks associated with the use of benzodiazepines to treat insomnia in adults. DATA SOURCES: MEDLINE and the Cochrane Controlled Trials Registry were searched for English-language articles published from 1966 to December 1998 that described randomized controlled trials of benzodiazepines for the treatment of insomnia. Key words included "benzodiazepines" (exploded), "randomized controlled trial" and "insomnia." Bibliographies of relevant articles were reviewed for additional studies and manufacturers of benzodiazepines were asked to submit additional randomized controlled trial reports not in the literature. STUDY SELECTION: Articles were considered for the meta-analysis if they were randomized controlled trials involving patients with insomnia and compared a benzodiazepine with placebo or another active agent. Of the 89 trials originally identified, 45 met our criteria, representing a total of 2672 patients. DATA EXTRACTION: Data were extracted regarding the participants, the setting, details of the intervention, the outcomes (including adverse effects) and the methodologic quality of the studies. DATA SYNTHESIS: The meta-analyses of sleep records indicated that, when compared with placebo, benzodiazepines decreased sleep latency by 4.2 minutes (non-significant; 95% confidence interval (CI -0.7 to 9.2) and significantly increased total sleep duration by 61.8 minutes (95% CI 37.4 to 86.2). Patient-reported outcomes were more optimistic for sleep latency; those randomized to benzodiazepine treatment estimated a sleep latency decrease of 14.3 minutes (95% CI 10.6 to 18.0). Although more patients receiving benzodiazepine treatment reported adverse effects, especially daytime drowsiness and dizziness or light-headedness (common odds ratio 1.8, 95% CI 1.4 to 2.4), dropout rates for the benzodiazepine and placebo groups were similar. Cognitive function decline including memory impairment was reported in several of the studies. Zopiclone was not found to be superior to benzodiazepines on any of the outcome measures examined. INTERPRETATION: The use of benzodiazepines in the treatment of insomnia is associated with an increase in sleep duration, but this is countered by a number of adverse effects. Additional studies evaluating the efficacy of nonpharmacological interventions would be valuable.
Publication Types:

6: Eur Neuropsychopharmacol 1999 Dec;9 Suppl 6:S407-12
Comment in:
 Eur Neuropsychopharmacol. 1999 Dec;9 Suppl 6:S391-2
The use of benzodiazepines in anxiety and other disorders.
Argyropoulos SV, Nutt DJ.
Psychopharmacology Unit, School of Medical Sciences, University of Bristol, UK.
Benzodiazepines have come under scrutiny and attack over recent years because of their abuse liability, withdrawal reactions and development of tolerance. Consequently, practitioners worldwide are discouraged from prescribing them. While some of these risks may have been exaggerated, benzodiazepines remain a useful therapeutic tool, alone or in combination, in a number of psychiatric and medical conditions. Withholding such treatment may be unjustified and detrimental to the patients' health. Further, benzodiazepines have helped researchers in their attempts to elucidate the neurobiological mechanisms underlying anxiety. This, in return, leads to the development of new effective anxiolytic treatments, with fewer problems compared to the traditional benzodiazepine compounds. Such new agents are already available or at the closing stages of clinical trials.
Publication Types:
Review literature

7: Can J Clin Pharmacol 1999 Winter;6(4):185-6
Benzodiazepines: the science and the myths.
Busto UE.
Centre for Addiction and Mental Health, Toronto, Canada.
Publication Types:
Review, tutorial

8: J Clin Psychopharmacol 1999 Dec;19(6 Suppl 2):23S-29S
International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders.
Uhlenhuth EH, Balter MB, Ban TA, Yang K.
Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Despite decades of relevant basic and clinical research, active debate continues about the appropriate extent and duration of benzodiazepine use in the treatment of anxiety and related disorders. The primary basis of the controversy seems to be concern among clinicians, regulators, and the public about the dependence potential and the abuse liability of benzodiazepines. This article reports systematically elicited judgments on these issues by a representative panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depressive disorders, a panel which was constituted by a multistage process of peer nomination. The criterion for inclusion at each stage was the nomination by at least two peers as one of the "professionally most respected physicians of the world with extensive experience and knowledge in the pharmacotherapy of anxiety and depressive disorders." Sixty-six respondents (90%) completed a comprehensive questionnaire covering a wide range of topics relevant to the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. Overall, the expert panel judged that benzodiazepines pose a higher risk of dependence and abuse than most potential substitutes but a lower risk than older sedatives and recognized drugs of abuse. There was little consensus about the relative risk of dependence and abuse among the benzodiazepines. Differences between benzodiazepines with shorter and longer half-lives in inducing withdrawal symptoms are much less clear during tapered than during abrupt discontinuation. There was little agreement about the most important factors contributing to withdrawal symptoms and failure to discontinue benzodiazepines. The pharmacologic properties of the medication may be the most important contributors to withdrawal symptoms. In contrast, the clinical characteristics of the patient may be the most important contributors to failure to discontinue medication. The experts' judgment seems to support the widespread use of benzodiazepines for the treatment of bona fide anxiety disorders, even over long periods. The experts generally viewed dependence and abuse liability as clinical issues amenable to appropriate management, as for other adverse events related to therapy. However, more definitive clinical research on the remaining controversial issues is urgently needed to promote optimal patient care.
Publication Types:
Consensus development conference

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

10: J Clin Psychopharmacol 1999 Dec;19(6 Suppl 2):2S-11S
Effectiveness and safety of benzodiazepines.
Moller HJ.
Psychiatric Hospital, Ludwig-Maximilians University, Munich, Germany.
Benzodiazepines have been used to treat a wide variety of disorders, including generalized anxiety disorder, panic disorder, sleep disorders, somatopsychic disorders, and depression. Concerns regarding physiologic dependence, withdrawal, and abuse potential with benzodiazepines prompted the development of strict guidelines for the use of these agents. Studies have shown that the risk of physiologic dependence increases with factors such as the dose of the benzodiazepine used and the duration of treatment. Restrictions involving benzodiazepines have led to the substitution of alternative medicines that may have decreased efficacy and greater safety concerns. There is a need for a more balanced assessment of the benefits and risks associated with benzodiazepine use to ensure that patients who would truly benefit from these agents are not denied appropriate treatment.
Publication Types:
Review literature

11: J Clin Pharm Ther 1999 Oct;24(5):347-55
Clinically significant pharmacokinetic drug interactions with benzodiazepines.
Tanaka E.
Institute of Community Medicine, University of Tsukuba, Japan.
The reports of interactions between benzodiazepines (BZPs) and other drugs (e.g., antidepressants, selective serotonin reuptake inhibitors, antiulcer drugs, antiepileptic drugs, macrolide antibiotics) during their combined use are reviewed. In general, metabolism of BZPs is delayed when combined with a number of other drugs but some reports have suggested otherwise. In recent years, the cytochrome P450 (P450 or CYP) isoenzyme that catalyses the metabolism of BZPs has also been identified. BZPs are mainly catalysed by CYP3A4. When published reports are studied, it appears necessary to be exceptionally careful about interactions mainly between BZPs and selective serotonin reuptake inhibitors, cimetidine, antiepileptic drugs, macrolide antibiotics and antimycotics. More information is necessary to identify individuals at greatest risk of drug interactions and adverse events.
Publication Types:
Review, tutorial

12: Support Care Cancer 1999 Nov;7(6):379-85
Comment in:
 Support Care Cancer. 1999 Nov;7(6):371-2
Psychopharmacology in supportive care in cancer: a review for the clinician. I. Benzodiazepines.
Stiefel F, Berney A, Mazzocato C.
Service de Psychiatrie de Liaison, CHUV, CH-1011 Lausanne, Switzerland.
Benzodiazepines are widely utilized in the cancer setting. Most aspects relevant to their use in supportive care are reviewed to assist the clinical oncologist in prescribing such drugs. This review covers pharmacokinetics, indications, adverse effects and drug interactions, and compares the profiles of different benzodiazepines. Finally, controversial issues with regard to benzodiazepines are discussed.
Publication Types:
Review, tutorial

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