Attitudes toward benzodiazepines over the years

Benzodiazepines have been used extensively for the treatment of anxiety and related disorders since the 1960s. Although they have been proven to be effective as first-line treatment for anxiety disorders, during the 1980s public perception and concern for abuse liability and physical dependence with long-term use gave rise to a great deal of controversy. Negative perceptions toward the use of benzodiazepines for treating anxiety not only caused severely ill patients to go untreated or under-treated but also called into question whether the illness itself was worthy of treatment. Although new pharmacologic and psychological treatments for anxiety are available, psychopharmacologists continue to endorse benzodiazepines as primary or adjunct treatment for anxiety disorders. The intent of this article is to provide a historic overview of these issues and to offer some general clinical principles to help minimize the risk of abuse and dependence with benzodiazepine use.     

Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need

Cognitive-behavioral therapy (CBT) is effective in the treatment of anxiety disorders when used in conjunction with benzodiazepine pharmacotherapy and when used as a monotherapy. Patients using CBT alone have dropout rates similar to or lower than those patients undergoing other forms of therapy, including benzodiazepines. CBT also works well with patients who do not respond adequately to pharmacotherapy. Combined CBT and benzodiazepine treatment has additive effects when compared with benzodiazepine monotherapy; however, patients receiving combined therapy who subsequently discontinue benzodiazepine treatment experience a loss of efficacy compared with CBT and placebo, perhaps due to fear extinction being context dependent. To avoid this loss of efficacy, CBT may be administered alone or as a bridge between benzodiazepine use and discontinuation during a medication taper. The case report upon which this supplement is based questions the value of CBT for patients experiencing cognitive impairment due to an anxiety disorder, benzodiazepine medication, substance abuse, or a combination of these factors. This article addresses this concern and asserts that CBT is a valuable treatment option in these cases.     

Clobazam in the Treatment of Epilepsy: A Review of the Literature

Summary: The literature was reviewed to define the role of clobazam (CLB) in the treatment of epilepsy. CLB is an effective antiepileptic drug (AED) in most varieties of seizures and epilepsies for both short-term and long-term treatment. Tolerability of CLB is satisfactory, better than for conventional benzodiazepines. CLB has no significant interaction with other drugs. Tolerance may develop, but this aspect may have been overemphasized: a long-term benefit figure of 28% can be expected without tolerance. When CLB maintains efficacy, patients continue to benefit for years without drug dependence or unwanted side effects. CLB appears to be a useful treatment for epilepsy as intermittent or short-term add-on therapy; but it should also be tried as long-term therapy in some situations, especially as add-on therapy for patients with refractory epilepsy, as add-on or monotherapy for patients with anxiety, or in some women in association with oral contraceptives.     

Hooked on benzodiazepines: GABAA receptor subtypes and addiction

Benzodiazepines are widely used clinically to treat anxiety and insomnia. They also induce muscle relaxation, control epileptic seizures, and can produce amnesia. Moreover, benzodiazepines are often abused after chronic clinical treatment and also for recreational purposes. Within weeks, tolerance to the pharmacological effects can develop as a sign of dependence. In vulnerable individuals with compulsive drug use, addiction will be diagnosed. Here we review recent observations from animal models regarding the cellular and molecular basis that might underlie the addictive properties of benzodiazepines. These data reveal how benzodiazepines, acting through specific GABA(A) receptor subtypes, activate midbrain dopamine neurons, and how this could hijack the mesolimbic reward system. Such findings have important implications for the future design of benzodiazepines with reduced or even absent addiction liability.     

Relative abuse liability of triazolam: experimental assessment in animals and humans

The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic benzodiazepine, triazolam, has been controversial. This paper reviews animal and human studies bearing on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discriminative stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol, anterograde amnesia, impaired awareness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other benzodiazepines.     

Interest of propranolol in the treatment of school refusal anxiety: about three clinical observations

School refusal anxiety is a pathopsychological disorder which touches the young child, between 8 and 13 years. Even if the school refusal is studied for a long time, there is not still consensus as for the specific definition of this disorder or on the best way of treating it. Nevertheless, accountable of long-lasting difficulties in school integration, its short and medium term consequences are serious and well known: school desertion, mood disorder and behavioral problems. Speed and quality of the medico-psychological and educational interventions represent a important factor for evolution and prognosis. Although, psychological interventions remain essential, sometimes the interest of an associated psychotropic medication should be discussed. This one can indeed either improve their results or supporting their installations. Despite more than twenty controlled trials in the pediatric population, no definitive psychopharmacological treatment data exist for anxiety disorder in childhood and especially for school refusal disorder. The majority of the studies stress as well the interest of benzodiazepines as tricyclic antidepressants but without being able to specify the possible superiority of a chemical on the other. On the other hand, the side effects of each one are well-documented, in particular for the benzodiazepines (potential abuse, sedation, potential desinhibition, mnemonic disorder), limiting thus their uses in child. In this work, we would like to emphasize the interest of propranolol in the treatment of somatic symptoms usually met in school refusal anxiety. Although beta-blockers have been used in the treatment of neurovegetative symptoms associated with situational anxiety disorders, there is no controlled data and only some open data to guide pediatric use for anxiety disorders in children. Nevertheless, prescribed with low posology and in substitution of benzodiazepine, this medication enabled us in three severe clinical cases to shorter notably the time of school rehabilitation. Well tolerated on the clinical level, with a greater efficiency on the somatic signs related to anxiety than benzodiazepines and with not having their side effects, this therapeutic can constitute a significant support in the psychological treatment of these children. However, these present results require to be confirm by other observations, which will be lead perhaps to a controlled study.     

Prégabaline et risque d’addiction : une nouvelle demande de soin ?

PurposePregabalin (PRG) is a gamma-aminobutyric acid (GABA) analogue used for treatment of epilepsy, neuropathic pain, generalised anxiety disorder and currently being studied for other indications. Supported by the results of case studies and a limited number of studies, there is an ongoing debate about the addictive potential of PRG. However, evidence is scarce and no definitive assessment on the potential for abuse and dependence to PRG is available. The objective of our study was to identify the number of cases of abuse or dependence to PRG published and to study potential risk factors of addiction to PRG.MethodsWe have identified on PubMed and ScienceDirect published case studies of PRG abuse or dependence and analysed these cases on the basis of several clinical parameters.ResultsA total of 118 cases of PRG abuse or dependence were identified, including 21 isolated cases (mean age 33 years, 67 % men). The mean daily dose of PRG was 2,9 g. Current or past polydrug abuse was present in the majority of cases. Psychiatric diagnoses, other than substance-related disorders, were reported in as many patients, and almost all patients experienced withdrawal symptoms when PRG was discontinued.ConclusionCurrent literature suggests an important and growing concern for the abuse of PRG. Male sex, psychiatric and/or addiction history, including opioid addiction, may be potential risk factors for the development of addictive behaviours associated with PRG.     

Medication dependence and anxiety

Anxiety disorders are common and costly psychiatric illnesses. Pharmacological treatment was enhanced with the introduction of benzodiazepines, which proved safer and more effective than older drugs. The risk of dependence, however, has made clinicians reluctant to use these medications. In fact, few patients appear to develop significant difficulties with these drugs, given how widely they are used. Careful planning for discontinuation of therapy is important. In addition, for some individuals, there appears to be a complex and as yet unelucidaied relationship between dependence on drugs or alcohol and anxiety. The newer antidepressants offer efficacy without abuse or dependence liability, but are expensive and have side effects that are intolerable for some patients. Pharmacological therapy for anxiety should be prescribed and managed so as to minimize any existing risk, while aiming to restore the patient to wellness in terms of symptoms and function.     

The acute treatment of anxiety and depression

Anxiety and depression are commonly occurring symptoms. Anxiety disorders and mood disorders usually share common symptoms and they frequently co-exist. There is a considerable body of research that has demonstrated that anxiety and depression can be distinguished from each other at the syndrome level. There is also evidence that such a distinction is arbitrary and not well substantiated. Clinically, the practitioner is often faced with the problem of treating a patient who presents with anxiety and depressive symptoms at the same time. It is well-established that the first line of treatment in major mood disorder is the used of tricyclic antidepressant in adequate dosage. The first line of treatment for the anxiety disorders is usually the administration of benzodiazepine anxiolytics. The anti-depressants have to be given for some months to the majority of patients whereas the anxiolytics are given for short periods. The tricyclics have a relatively slow onset of action compared to the benzodiazepines. Recent evidence is available about the effectiveness of the triazolo-benzodiazepines in panic disorder with or without secondary major mood disorder. There are also reports of the effects of the triazolo-benzodiazepines in primary mood disorder. In these mood disorders, the benzodiazepines caused rapid relief of both anxious and depressive symptomatology. The effects of the benzodiazepines occur even in the presence of melancholic depression. Where anxiety and depression coexist, the clinician may wish to consider beginning anti-depressant therapy with combined tricyclic antidepressant and benzodiazepine to produce rapid symptom relief. After four weeks the benzodiazepine should be faded out and therapy continued with the tricyclic medication alone.     

Reinforcement of irritability during therapy with benzodiazepines

BACKGROUND: Often, long-term treatment with benzodiazepines is a subject of discussion due to potential side effects, with dependence on benzodiazepines as the most serous one. After longer period of benzodiazepines tolerance on their anxiolytic effects develops. Discontinuation is usually beneficial as it is followed by improved psychomotor and cognitive functioning, particularly in the elderly. Previous studies confirmed occurrence of physical dependence in high percentage of patients in long term treatment with benzodiazepines at therapeutic dosages. Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. The aim of this article is to report a case of a patient who was taking 15 tablets of oxazepam daily for a period of time, during which reinforcement of irritability occurred. CONCLUSION: It is necessary to warn patients who take benzodiazepines in therapy that reinforcement of irritability may occur in case of higher dosage of benzodiazepines, which may be misinterpreted as worsening in mental condition.     

The treatment of sedative-hypnotic dependence: evaluating clinical predictors of outcome

BACKGROUND: The objectives of this 6-month prospective study were to evaluate the efficacy of detoxification treatment for sedative-hypnotic dependence, examine the demographic and clinical predictors of outcome, and determine whether anxiety or other psychiatric comorbidity has a negative impact on outcome. METHOD: Eighty-two patients with alcohol or benzodiazepine dependence (DSM-IV diagnostic criteria) were consecutively recruited upon entering treatment and were assessed by clinical and semistructured interviews, the Global Assessment Scale, the Hamilton Rating Scale for Depression, the Beck Depression Inventory, the revised 90-item Symptom Checklist, and urine drug screening. RESULTS: Both alcohol- and benzodiazepine-dependent patients succeeded in reducing their reported use of sedative-hypnotic substances during the follow-up period. However, at 3 months, benzodiazepine-dependent patients fared less well than alcohol-dependent patients in terms of several outcome measures: they reported a lower rate of achieving abstinence, shorter periods of continuous abstinence, and more frequent drug use. At 6 months, the differences in outcome among the drug groups were not maintained. Variables such as sex, drug group, and indicators of psychiatric status had little impact on outcome measures. Benzodiazepine-dependent patients reported significant decreases in their level of anxiety over the follow-up period despite substantial reductions in benzodiazepine use. CONCLUSION: Clinicians may be encouraged regarding the detoxification of patients who have used benzodiazepines at high doses or for long periods of time, or who have comorbid anxiety or other psychiatric disorders.     

Panic disorder and alcoholism]

Relationships between alcoholism and anxiety disorder are well known by clinicians. Studies have recently shown that the prevalence of alcohol abuse or dependence is very high in patients with panic disorder with or without agoraphobia (Thyer et al., 1986; Bibb and Chambless, 1986). The aims of this study were to determine the prevalence and comorbidity of alcohol abuse and dependence in a population of panic outpatients who were consecutive referrals for treatment of panic disorder (PD) in an anxiety clinic. Patients were interviewed with the Schedule for Affective Disorders and Schizophrenia-Lifetime Version Modified for the study of anxiety disorders (SADS-LA) which is a standardized and semi-structured interview allowing to make diagnoses according to RDC, DSM III and DSM III-R criteria. One hundred and three panic patients (39 males and 64 females) were included in the study. Their mean age was 38.5 years (SD: 11.6). In this sample, 24.3% met the DSM III-R criteria for alcohol abuse and 8.7% those for alcohol dependence. Among these patients, 26.2%, abused of benzodiazepines and 16.5% of them of other substances. We found a high comorbidity rate. In fact, 6.8% of the patients met diagnostic criteria for PD alone, 31.0% for one more diagnosis, 29.1% for two more and 33.0% for three or more besides PD. In this study, we found an association between alcohol abuse and the presence of a lifetime diagnosis of major depressive episode and/or other addictive behaviors. Otherwise, alcohol abuse did not occur more often in patients suffering from panic disorder associated with agoraphobia and/or social phobia.     

Biological basis of drug-induced tolerance, rebound, and dependence. Contribution of recent research on benzodiazepines

It is proposed that the general biological basis of acquired drug tolerance, of rebound phenomena induced by drugs, and of physiological dependence is a drug-induced adaptive syndrome. Several examples of the compensatory molecular, cellular and system responses are presented that may be induced by the primary drug-induced perturbation in the base-line of various neuronal and non-neuronal activities. Some form of adaptive syndrome is the inevitable consequence of the reciprocal interaction between most or all major classes of drugs and the organism. Knowledge of the molecular and cellular targets of drugs provides an understanding of the various phenomena of the drug-induced adaptive syndrome as well as of the means to avoid or attenuate their potential danger for subjects chronically exposed to drugs. Psychological dependence is discussed as a further factor which, in combination with drug-induced adaptive changes, facilitates drug abuse and, in particular, addiction or drug-seeking behavior. The phenomena of the adaptive syndrome induced by benzodiazepines are discussed against the background of medical science's present advanced knowledge of the molecular and synaptic mechanisms of action of this class of drugs.     

Long-term benzodiazepine users 3 years after participation in a discontinuation program

OBJECTIVE: Clinical status and use of benzodiazepines and other psychotropic drugs at follow-up were assessed in patients who had been chronically dependent on benzodiazepines and had been referred for participation in a discontinuation study. METHOD: Of 123 benzodiazepine-dependent patients screened for entry into a tapered discontinuation program, 48 had completed the program, 38 had not, and 37 had not undergone drug tapering. Follow-up information was obtained through a structured telephone interview and a mail questionnaire that included a global severity scale assessing anxiety and depression and the Hopkins Symptom Checklist. The time to follow-up was 2.7-5.0 years, and the mean +/- SD interval between screening and follow-up was 2.9 +/- 0.9 years. RESULTS: Outcome at follow-up significantly favored the patients who had completed the discontinuation program; 73% were not using benzodiazepines, compared to 39% in the unsuccessful taper group and 14% in the no-taper group. Moderate or marked anxiety was still reported by 35% of the patients who were taking benzodiazepines and 25% of those who were not. At follow-up, 22% of the patients were being treated with nonbenzodiazepine psychotropic agents, primarily antidepressants. CONCLUSIONS: The high percentage of patients who were benzodiazepine-free at follow-up and the continued anxiety and depression present in many patients suggest that some patients may have been taking benzodiazepines because of chronic or recurrent anxiety or depression, not physical dependence.     

Glutamate and anxiety disorders

Anxiety disorders are among the most prevalent psychiatric disorders, but they represent a particular challenge for treatment. The standard first-line treatments, including antidepressants, benzodiazepines, and buspirone, result in significant response rates for a majority of patients; however, unfavorable side effect profiles or risk for dependency for particular agents might limit their use by anxious patients, who often have low thresholds for medication discontinuation. Novel pharmacologic agents that modulate particular receptors, ion channels, or transporters relevant to glutamatergic neurotransmission may represent a new approach to the treatment of anxiety disorders, with generally more favorable side effect profiles. Although the role of glutamate in the pathophysiology of anxiety disorders is still being elucidated, the use of these agents in treatment of anxiety disorders and commonly comorbid conditions such as substance abuse and mood disorders will continue to increase.     

Abuse of and dependence on zolpidem: a report of seven cases

Zolpidem is an hypnotic drug that belongs to the imidazopyridine family. Its chemical structure is different from that of benzodiazepines though both type of drugs bind specifically to the same site of the GABA-A macromolecular complex: the omega 1 benzodiazepine receptor. This mechanism of action could be responsible for the predominantly hypnotic properties of zolpidem and its reduced liability to induce dependence in comparison with benzodiazepines. Yet, several cases of zolpidem abuse and dependence have been published recently. We report seven cases, from which three are detailed, of zolpidem abuse and/or dependence. These patients did not suffer from sedative effects of this drug despite important doses. We even noticed stimulating and euphorising effects in two of these patients, an effect that may explain at least in part the dependence to zolpidem. We will discuss the clinical similarities existing between zolpidem and benzodiazepines' effects. Furthermore we will discuss a molecular genetic hypothesis that may explain the differential effect of a specific benzodiazepine ligand on its receptors.