No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Protracted Withdrawal From Benzodiazepines: The Post-Withdrawal Syndrome
Abstract
Discusses the protracted withdrawal (PW) experienced by possibly 10–25% of chronic benzodiazepine (BZ) users, which may last for many months. PW is seen as a combination of pharmacological withdrawal, psychological symptoms, and possibly ill-understood neurological effects of BZs. Some common acute BZ withdrawal symptoms are listed and compared with symptoms common to all anxiety states. PW symptoms (e.g., anxiety, insomnia, depression, perceptual and motor symptoms, tinnitus, paresthesia, and gastrointestinal symptoms) are discussed, together with a description of the usual course of these symptoms. Withdrawal from slow-acting BZs is usually easier than withdrawal from rapid-action BZs. The recommended management of BZ withdrawal includes gradual dosage reduction and long-term therapeutic contact with appropriate psychological support. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
... The condition known as Postacute Withdrawal Syndrome (PAWS) can occur when symptoms persist for several weeks or even months after the discontinuation of benzodiazepines, and the severity of the symptoms can vary [30]. Most benzodiazepine withdrawal symptoms are due to increased brain excitability [14,15,17]. All symptoms can be divided into three main groups -psychological, physical, and sensory symptoms. ...
... All symptoms can be divided into three main groups -psychological, physical, and sensory symptoms. The most common psychological symptoms are anxiety, depression, sleep disturbances, decreased concentration, and confusion [14][15][16][17][18]. Physical and sensory symptoms include muscle spasms, pain, sweating, tremors, paresthesia, hypersensitivity or hyposensitivity to environmental changes, arrhythmias, and palpitations [14][15][16][17][18]. Seizures are possible in rare cases [15]. ...
... All symptoms can be divided into three main groups -psychological, physical, and sensory symptoms. The most common psychological symptoms are anxiety, depression, sleep disturbances, decreased concentration, and confusion [14][15][16][17][18]. Physical and sensory symptoms include muscle spasms, pain, sweating, tremors, paresthesia, hypersensitivity or hyposensitivity to environmental changes, arrhythmias, and palpitations [14][15][16][17][18]. Seizures are possible in rare cases [15]. ...
Introduction
Benzodiazepines are commonly prescribed but often misused, leading to dependence and withdrawal symptoms. Increased worldwide prescriptions raise adverse effects and overdose concerns, especially for the elderly. Caution is needed in prescribing and considering alternative treatments to minimize risks.
Aim
Narrative literature review of potential atrial fibrillation mechanism of action induced by discontinuation of benzodiazepines.
Materials and methods
Database PubMed was searched using the combinations of keywords – “Benzodiazepine AND atrial fibrillation OR peripheral benzodiazepine receptors”, “history of benzodiazepines”, “benzodiazepines mechanism of action”, “benzodiazepines indications”, “benzodiazepines adverse effects” and “benzodiazepines withdrawal effects”. Non-full-text and non-English scientific publications were removed. A total of 31 publication was included.
Discussion
Benzodiazepines (BZDs) were synthesized in 1955 and initially considered less toxic than barbiturates. They interact with GABA-A receptors, causing hyperpolarization and inhibitory effects in the central nervous system. BZDs are used to treat various clinical disorders, but long-term use can lead to adverse effects and withdrawal symptoms. There is evidence that genetic diversity can influence the response to BZDs through GABA receptors. The interaction between benzodiazepines and peripheral benzodiazepine receptors may influence calcium ion channels, affecting cardiac action potential and contractility, and discontinuation of these medications can potentially contribute to atrial fibrillation. Additionally, benzodiazepines may directly affect calcium channels, causing antiarrhythmic effects and vasodilation.
Conclusion
In summary, benzodiazepines, once considered safer sedatives, now raise concerns about misuse, dependence, and withdrawal symptoms. While there is a potential link between discontinuing benzodiazepines and atrial fibrillation through mechanisms involving peripheral benzodiazepine receptors and cardiac calcium channels, causality remains uncertain and multifaceted. Further research is needed to clarify these mechanisms, and healthcare providers should exercise caution in long-term benzodiazepine prescriptions while exploring alternative treatment strategies to mitigate risks.
... 3,87 Prescribers should request immediate report of any odd symptoms, keeping in mind the mnemonics FINISH ["flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal (anxiety/agitation)" 3,82 ] or similar do not capture the universe of withdrawal symptoms or PWS. 16,27,32,35 Carefully monitored gradual tapering not only minimizes withdrawal symptoms while tapering and acute withdrawal upon drug cessation, 72,73 it reduces the risk of an even more serious consequence -PWS, persistent nervous system destabilization when off the drug. 32,36,54 Harm reduction tapering For decades, in both psychiatry and addiction medicine, there have been calls for research into tapering protocols for psychotropics so as to avoid withdrawal symptoms, [88][89][90][91][92] with little result. ...
... 16,27,32,35 Carefully monitored gradual tapering not only minimizes withdrawal symptoms while tapering and acute withdrawal upon drug cessation, 72,73 it reduces the risk of an even more serious consequence -PWS, persistent nervous system destabilization when off the drug. 32,36,54 Harm reduction tapering For decades, in both psychiatry and addiction medicine, there have been calls for research into tapering protocols for psychotropics so as to avoid withdrawal symptoms, [88][89][90][91][92] with little result. We have found that very gradual dosage reduction at an individualized pace minimizes the emergence of withdrawal symptoms. ...
... 106,138,139 Unlike ADRs or relapse, withdrawal symptoms generally occur in sharp, sporadic waves unrelated to the drug schedule. 13,28,32,140 To prevent paradoxical reactions, which peak after drug ingestion, or interdose withdrawal, particularly with short-acting benzodiazepines, arranging the dosing schedule or dividing doses to maintain drug plasma level more evenly over 24 h may establish a more stable symptom pattern. It is essential to do this before initiating a taper, to avoid mistaking drug adverse effects for withdrawal symptoms. ...
Although psychiatric drug withdrawal syndromes have been recognized since the 1950s – recent studies confirm antidepressant withdrawal syndrome incidence upwards of 40% – medical information about how to safely go off the drugs has been lacking. To fill this gap, over the last 25 years, patients have developed a robust Internet-based subculture of peer support for tapering off psychiatric drugs and recovering from withdrawal syndrome. This account from the founder of such an online community covers lessons learned from thousands of patients regarding common experiences with medical providers, identification of adverse drug reactions, risk factors for withdrawal, tapering techniques, withdrawal symptoms, protracted withdrawal syndrome, and strategies to cope with symptoms, in the context of the existing scientific literature.
Keywords: antidepressant, deprescribing, discontinuation syndrome, iatrogenic, kindling, post-acute withdrawal, polypharmacy, psychotropic, tapering, withdrawal syndrome
... Benzodiazepine withdrawal syndrome can be mild or severe [6]. Potent benzodiazepine, chronic or high dose intake, anxiety, or neuroticism results in severity of the syndrome [6,27]. ...
... Benzodiazepine withdrawal syndrome can be mild or severe [6]. Potent benzodiazepine, chronic or high dose intake, anxiety, or neuroticism results in severity of the syndrome [6,27]. Benzodiazepine tolerance is produced by neuroadpative routes including sensitization of glutamatergic receptors and desensitization of g-aminobutyric acid (GABA) receptors. ...
... Receptors modifications during tolerance might be slow and reverse at different rates. This possibly explains the difference of development and duration of symptoms along with prolongs nature of benzodiazepine withdrawal [6]. Agmatine selectively antagonize the glutamate receptor channels of NMDA [37,39] and inhibits NOS. ...
Background
Drug withdrawal syndrome occurs due to abrupt cessation of an addictive substance. Dependence to diazepam can be manifested by withdrawal syndrome which may include symptoms such as irritability, psychosis, sleep disturbance, seizures, mood disturbance, and anxiety. Studies have described the therapeutic role of agmatine in various neurological disorders such as depressive mood, learning deficits, anxiety, memory impairment, and psychosis. Various studies have also validated agmatine as a putant neuromodulator and revealed its mechanism of action with other neurotransmitters. The study was designed to reveal the potentials of agmatine in benzodiazepine withdrawal syndrome by maintaining GABA/glutamate balance. The study aimed to determine the underlying mechanism of action of agmatine at synaptic level using behavioral and biochemical evaluations.
Results
Agmatine significantly enhanced locomotion in open filed test and decreased anxiety as observed in elevated plus maze test ( p < 0.01). Agmatine also reduced withdrawal symptoms scores along with compulsive behaviors in marble burying test and improved muscular strength by decreasing latency to fall in inverted screen test ( p < 0.01). Moreover, agmatine established GABA/glutamate balance by increasing GABA levels and decreased glutamate concentration significantly ( p < 0.01).
Conclusion
The present study reveals the possible mechanism of action of agmatine on NMDA receptor at GABA interneurons and glutamate post synaptic neuron that may lead to GABA/glutamate balance during withdrawal syndrome.
... 3,87 Prescribers should request immediate report of any odd symptoms, keeping in mind the mnemonics FINISH ["flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal (anxiety/agitation)" 3,82 ] or similar do not capture the universe of withdrawal symptoms or PWS. 16,27,32,35 Carefully monitored gradual tapering not only minimizes withdrawal symptoms while tapering and acute withdrawal upon drug cessation, 72,73 it reduces the risk of an even more serious consequence -PWS, persistent nervous system destabilization when off the drug. 32,36,54 Harm reduction tapering For decades, in both psychiatry and addiction medicine, there have been calls for research into tapering protocols for psychotropics so as to avoid withdrawal symptoms, [88][89][90][91][92] with little result. ...
... 16,27,32,35 Carefully monitored gradual tapering not only minimizes withdrawal symptoms while tapering and acute withdrawal upon drug cessation, 72,73 it reduces the risk of an even more serious consequence -PWS, persistent nervous system destabilization when off the drug. 32,36,54 Harm reduction tapering For decades, in both psychiatry and addiction medicine, there have been calls for research into tapering protocols for psychotropics so as to avoid withdrawal symptoms, [88][89][90][91][92] with little result. We have found that very gradual dosage reduction at an individualized pace minimizes the emergence of withdrawal symptoms. ...
... 106,138,139 Unlike ADRs or relapse, withdrawal symptoms generally occur in sharp, sporadic waves unrelated to the drug schedule. 13,28,32,140 To prevent paradoxical reactions, which peak after drug ingestion, or interdose withdrawal, particularly with short-acting benzodiazepines, arranging the dosing schedule or dividing doses to maintain drug plasma level more evenly over 24 h may establish a more stable symptom pattern. It is essential to do this before initiating a taper, to avoid mistaking drug adverse effects for withdrawal symptoms. ...
Although psychiatric drug withdrawal syndromes have been recognized since the 1950s – recent studies confirm antidepressant withdrawal syndrome incidence upwards of 40% – medical information about how to safely go off the drugs has been lacking. To fill this gap, over the last 25 years, patients have developed a robust Internet-based subculture of peer support for tapering off psychiatric drugs and recovering from withdrawal syndrome. This account from the founder of such an online community covers lessons learned from thousands of patients regarding common experiences with medical providers, identification of adverse drug reactions, risk factors for withdrawal, tapering techniques, withdrawal symptoms, protracted withdrawal syndrome, and strategies to cope with symptoms, in the context of the existing scientific literature.
... A number of authors have described both an acute and a protracted withdrawal phase [25][26][27] with acute withdrawal lasting 5-28 days and protracted withdrawal lasting for up to 12 months or longer [27]. It has been estimated that between 10-25% of chronic benzodiazepine users suffer protracted withdrawal symptoms upon cessation [26]. ...
... A number of authors have described both an acute and a protracted withdrawal phase [25][26][27] with acute withdrawal lasting 5-28 days and protracted withdrawal lasting for up to 12 months or longer [27]. It has been estimated that between 10-25% of chronic benzodiazepine users suffer protracted withdrawal symptoms upon cessation [26]. Both psychological and physical withdrawal symptoms are common in both acute and protracted withdrawal and have been well described in the literature [5,26,28]. ...
... It has been estimated that between 10-25% of chronic benzodiazepine users suffer protracted withdrawal symptoms upon cessation [26]. Both psychological and physical withdrawal symptoms are common in both acute and protracted withdrawal and have been well described in the literature [5,26,28]. Severity of acute withdrawal has been shown to be associated with higher dosage of benzodi-azepines, the use of multiple benzodiazepines, oral rather than injected use [29], duration of use, shorter half-life benzodiazepines and more rapid tapering [30]. Patient variables have also been indicated such as higher pretreatment anxiety and depression, personality pathology, panic disorder diagnosis, and history of alcohol/drug abuse [27]. ...
Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management - benzodiazepine tapering - is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABA(A) -benzodiazepine receptor antagonist/partial agonist flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for four days significantly reduced acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.
... Ashton [2] observed hundreds of patients withdrawing from benzodiazepines. She described a protracted withdrawal syndrome characterized by a multitude of mental and physical symptoms, lasting months or years, and affecting 10-15% of long-term users who had withdrawn from benzodiazepines [2]. ...
... Ashton [2] observed hundreds of patients withdrawing from benzodiazepines. She described a protracted withdrawal syndrome characterized by a multitude of mental and physical symptoms, lasting months or years, and affecting 10-15% of long-term users who had withdrawn from benzodiazepines [2]. Some individuals may be permanently affected [3]. ...
... I sintomi di astinenza da BDZ tipicamente durano 4-6 settimane, tuttavia per alcuni consumatori a lungo termine (con assunzione per 20 anni o più e con esperienze astinenziali negative) la sindrome astinenziale perdura più a lungo; in una minoranza di circa il 10-15% si sviluppa una sindrome post-astinenza, che può permanere per mesi o perfino 2-3 anni prima di scomparire. I sintomi astinenziali protratti comprendono: ansia, insonnia, depressione, vari sintomi sensoriali (tinnito, formicolii, torpore, dolore profondo o bruciante, …) e motori (dolore muscolare, debolezza, crampi dolorosi, tremori, clonie, …), disturbi gastrointestinali e riduzione della memoria e della cognitività (Ashton, 1984(Ashton, , 1995(Ashton, , 1997(Ashton, , 2002. È importante informare i pazienti del range dei possibili sintomi astinenziali e della loro durata; nel caso di consumatori cronici di BDZ (10-15%) l'astinenza tardiva può perdurare anche 1 anno (Redman & Cannard, 2010). ...
... È importante informare i pazienti del range dei possibili sintomi astinenziali e della loro durata; nel caso di consumatori cronici di BDZ (10-15%) l'astinenza tardiva può perdurare anche 1 anno (Redman & Cannard, 2010). I fattori farmacologici della sintomatologia astinenziale sono rappresentati da: durata d'uso, dosi, emivita, potenza e velocità di cessazione; una riduzione graduale delle BDZ riduce la severità degli altri fattori farmacologici (dose giornaliera, emivita e potenza) (Schweizer e coll., 1990;Lader, 1991;Ashton, 1995;Rickels & Freeman, 2000). I fattori del paziente che possono influenzare la presentazione clinica della sintomatologia astinenziale (inizio, decorso e severità) sono la comorbilità psichiatrica, le caratteristiche e i disturbi di personalità, il danno organico cerebrale, il poliabuso e l'età avanzata (Schweizer e coll., 1990(Schweizer e coll., , 1998Lader, 1991). ...
Benzodiazepines are commonly prescribed as a treatment for DSM-IV mental disorders, especially for anxiety and
... Approximately 40% of people on benzodiazepines for more than six months will have a moderate to severe withdrawal if the drug is stopped suddenly [48]. Withdrawal symptoms include anxiety-related symptoms, perceptual distortion, and seizures [49][50][51]. Acute withdrawal lasts approximately 5-28 days, whilst protracted withdrawal can last for up to 12 months or longer [49]. Severity of withdrawal is associated with benzodiazepines use history, more rapid taper [52], and patient variables such as pre-existing anxiety and depression, panic disorder, and a history of alcohol/drug abuse [49]. ...
... Whilst the precise cause of withdrawal is unknown there is some evidence for down-regulation of benzodiazepine binding sites in the GABA A complex, and for increased calcium flux and serotonin (5-HT) activity during withdrawal. The calcium channel antagonist verapamil [49][50][51], the GABA B agonist baclofen [52], and the 5-HT3 receptor antagonist zacopride [53], have all prevented withdrawal responses in rats. ...
This review paper discusses the central role of gamma-aminobutyric acid (GABA) in diverse physiological systems and functions and the therapeutic potential of the benzodiazepine antagonist flumazenil (Ro 15-1788) for a wide range of disorders of the central nervous system (CNS). Our group and others have studied the potential of flumazenil as a treatment for benzodiazepine dependence. A small but growing body of research has indicated that flumazenil may also have clinical application in CNS disorders such as Parkinson's disease, idiopathic hypersomnia and amyotrophic lateral sclerosis. Despite this body of research the therapeutic potential of flumazenil remains poorly understood and largely unrealized. The purpose of this paper is not to provide an exhaustive review of all possible therapeutic applications for flumazenil but rather to stimulate research interest, and discussion of the exciting therapeutic potential of this drug for a range of chronic debilitating conditions.
... The most common adverse reactions associated with use of BZD hypnotics are residual daytime e¤ects such as daytime sedation and daytime performance decrements (Vogel 1992), anterograde amnesia (Wood et al. 1988), and rebound insomnia, characterized as a transient period of recurrence of insomnia to levels worse than the pretreatment baseline (Gillin et al. 1989). BZDs were also found to disrupt normal sleep patterns and to alter sleep architecture by suppressing both slow wave sleep and rapid eye movement sleep (Ashton 1995b). ...
... It is possible that these rebound symptoms may cause su¦cient clinical distress so as to perpetuate continued drug use (Greenblatt et al. 1987;Scharf 1993). Therefore, there is a general agreement that withdrawal from long-term administration of BZD should be tapered gradually (Perry and Alexander 1986;Schweizer and Rickels 1991;Mendelson 1992), followed by appropriate psychological support (Kirmil-Gray et al. 1985;Otto et al. 1993;Ashton 1995b). Studies of hypnotic withdrawal typically report success rates around 50 % (Golombok et al. 1987), with follow-up duration often less than 1 month after the withdrawal (Shapiro et al. 1995). ...
Twenty-four volunteers (19 women and five men) with insomnia and a history of chronic use of benzodiazepine hypnotics participated in a randomized, double blind, controlled clinical trial. The study was designed to assess the effects of substituting zopiclone (ZOP)- as an hypnotic- among chronic users of flunitrazepam (FLU), and to compare the subsequent withdrawal of ZOP with placebo controlled withdrawal of FLU. During the 5 weeks of a withdrawal protocol, sleep and physiological parameters were assessed by polysomnographic measures for 11 nights and by nightly actigraphic recordings for weeks 1, 3, and 5. Subjective effects of the withdrawal process were evaluated with daily sleep diaries, and with various weekly self-report symptom checklists. Paired t-tests performed on differences in objective sleep parameters between baseline and the last weeks of the withdrawal program showed a significant decrease in sleep quality within the FLU group, but not in the ZOP group. Subjective sleep diaries consistently reflected the objectively measured changes in sleep throughout the withdrawal program, indicating significant changes in sleep parameters only in the FLU group. The results obtained from the self report inventories aimed at assessing withdrawal symptoms, however, revealed no differences between the baseline week and the termination week of the program in any of the groups. After completing the pharmacological withdrawal, all subjects received a short-term cognitive behavioral intervention focused on improving their coping strategies with symptoms of insomnia; they were evaluated immediately after concluding the intervention, and at 3 and 12 month follow- ups.
... 30,31 Moderate-tosevere withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology. 2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities. 34 ...
These agents are not first-line treatments for many of the conditions for which they are used. When they are used, there should be a plan in place for deprescribing.
... Acute benzodiazepine (BZD) withdrawal can cause anxiety, tremors, tachycardia, hypertension, hallucinations and seizures, which is indicative of a dysregulated central nervous system (Holbrook et al., 1999). The protracted post-withdrawal syndrome is characterised by long-lasting anxiety and insomnia, depression, sensory and motor disturbances, and gastrointestinal disturbances (Ashton, 1995). For patients initially using BZDs for insomnia, the subsequent rebound insomnia after cessation is often worse than before pharmacological treatment (Whittlesea and Hodson, 2018). ...
Background: The estimated annual prevalence of drug use disorders is as high as 3%, underpinning the need to continually develop more effective treatments. Central nervous system dysregulation, contributing to acute and post-withdrawal syndromes, has traditionally been managed with benzodiazepines; however, a small but growing body of data indicate that the GABAA receptor antagonist, flumazenil, may offer some advantages over traditional management. Aim: To review the literature on the safety and efficacy of flumazenil in benzodiazepine use disorders and identify gaps in the literature. Method:
A systematic method was used to identify randomised control trials. Where randomised control trials existed, non-randomised control trials were included to supplement findings. Results: Eleven flumazenil trials were included with varying doses, frequencies and routes of administration. The evidence for flumazenil alone showed generally a reduction in withdrawal symptoms with the exception of one study where withdrawal symptoms initially increased. Flumazenil plus benzodiazepine tapering was assessed in one randomised control trial and a series of non-randomised control trials. Randomised control trial results showed that flumazenil plus benzodiazepine tapering was superior at reducing withdrawal symptoms compared to benzodiazepine tapering alone and placebo. Flumazenil was associated with no serious adverse events; however there remains a risk of seizures. Conclusion: Although flumazenil shows promising efficacy in the management of benzodiazepine use disorders and withdrawal, more randomized control trials are required before a definitive recommendation can be made around its use.
... (Murphy & Tyrer, 1991). Cette approche progressive contribue aussi à minimiser les symptômes de sevrage lors de l'arrêt (Ashton, 1995). ...
... [10][11][12] Abrupt cessation of chronic treatment with BZDs causes the appearance of withdrawal effects comprising re-bound anxiety, restlessness, epilepsy, and motor agitation. [13,14] In the light of adverse effects associated with the synthetic drugs, researchers have been exploring natural resources to find out safer and effective drugs. Investigating plants, based on their use in traditional systems of medicine, is a sound, viable and cost effective strategy to develop new drugs. ...
... It is possible that these rebound symptoms may cause sufficient clinical distress so as to perpetuate continued drug use (Greenblatt, Harmatz, Zinny, & Shader, 1987; Scarf, 1993). Therefore, there is a general agreement that withdrawal from long term administration of hypnotics should be tapered gradually (Schweizer, Rickels, Case, & Greenblatt, 1991; Mendelson, 1992; Perry & Alexander, 1986), followed by appropriate psychological support (Ashton, 1995a; Otto et al., 1993; Kirmil-Gray et al., 1985). The present study was designed to investigate the effects of a short-term cognitive intervention, as part of a comprehensive medical project of withdrawal from hypnotics, on attitudes toward insomnia. ...
This study was designed to investigate the effects of a short-term
cognitive-behavioural intervention, as part of a comprehensive medical
project of withdrawal from hypnotics, on attitudes toward
insomnia. Twenty-four subjects volunteered to participate in a withdrawal
project conducted in a sleep clinic for five weeks. All subjects were
chronic users of a long-acting hypnotic, and free from other psychotropic
drugs. Along with the gradual decrease in hypnotics’ dosage, the
programme consisted of sleep evaluations by polysomnography, actigraphic
monitoring, daily sleep diaries, and periodical medical examinations. Upon
termination of the withdrawal stage, all subjects received a short-term
cognitive-behavioural treatment consisting of six sessions and directed at
attitude change and correction of misconceptions about sleep and insomnia,
and on promoting psychological strategies for coping with the sleep
disturbances. Attitudes toward insomnia were measured by the DBAS –
Dysfunctional Beliefs and Attitudes about Sleep Scale, administered
at three points of time: on the first day of the programme (Time 1), at the
termination of the medical withdrawal stage (Time 2), and a week after
completion of the short-term cognitive behavioural treatment (Time 3). A
multivariate analysis showed a significant effect of the time of measurement
on all five subscales of the DBAS. Subsequent analyses indicated that the
major change in attitudes was specific to the direct cognitive-behavioural
intervention and occurred between Time 2 and Time 3. In follow-ups conducted
at 3 and 12 months after completion of the withdrawal project, the majority
of the participants (72%) reported refrain from hypnotic use, and regarded
the psychological intervention as the major cause of their successful
withdrawal from sleeping pills.
... Whereas the prevalence of dependence and undesirable effects appears to be lower than that with BZDs (Israel & Kramer, 2002), long-term use still is not recommended (Roth, 1999). Supervised gradual withdrawal scheduled over an 8-to 10-week period has been shown to be effective in helping 50%-67% of chronic users to completely discontinue their hypnotic drug and in minimizing withdrawal symptoms during discontinuation (Ashton, 1995;Murphy & Tyrer, 1991). A few studies have assessed the benefits of adding a cognitive-behavioral treatment (CBT) for insomnia (e.g., stimulus control, relaxation, multicomponent) to facilitate hypnotic taper and to help maintain abstinence. ...
This study aimed to assess the efficacy of a minimal intervention focusing on hypnotic discontinuation and cognitive-behavioral treatment (CBT) for insomnia. Fifty-three adult chronic users of hypnotics were randomly assigned to an 8-week hypnotic taper program, used alone or combined with a self-help CBT. Weekly hypnotic use decreased in both conditions, from a nearly nightly use at baseline to less than once a week at posttreatment. Nightly dosage (in lorazepam equivalent) decreased from 1.67 mg to 0.12 mg. Participants who received CBT improved their sleep efficiency by 8%, whereas those who did not remained stable. Total wake time decreased by 52 min among CBT participants and increased by 13 min among those receiving the taper schedule alone. Total sleep time remained stable throughout withdrawal in both CBT and taper conditions. The present findings suggest that a systematic withdrawal schedule might be sufficient in helping chronic users stop their hypnotic medication. The addition of a self-help treatment focusing on insomnia, a readily available and cost-effective alternative to individual psychotherapy, produced greater sleep improvement.
... The use of benzodiazepines has only been proven effective when used short term12345. Long-term use is not only non-effective, it can even be problematic because it is related to several negative health effects such as addiction, falls, hip fractures, phases of depression and impaired cognition67891011121314151617. Because of this, guidelines for general practitioners have been established, for example, by the Dutch College of General Practitioners (NHG) regarding how and when to prescribe benzodiazepines to patients. ...
General practitioners and pharmacists do not properly educate their patients about the disadvantages of benzodiazepines. In order to increase and improve education, this study will investigate which psychological factors (i.e., beliefs, outcome expectation, social norm and self-efficacy) predict the intention to educate.
A cross-sectional survey study was conducted in which 339 general practitioners and 149 pharmacists in the Netherlands completed a questionnaire.
The Results show that the above-mentioned factors play an important role in forming intentions to educate. However, differences exist between general practitioners and pharmacists.
General practitioners and pharmacists intend to educate in cases where they think that benzodiazepines have well-defined disadvantages, when the education they undertake leads to success, when they feel pressure to educate from their surroundings and when they are capable of educating. Implications for practice These findings contribute to a better understanding of patient education and are of great value in developing new interventions to improve education.
To the Editor The recent Viewpoint about the risks and benefits of benzodiazepines¹ dismissed the alarming statistics that 12.6% of people in the US are using benzodiazepines (4 times the rate in other high-income nations), 17% of them are misusing these drugs, and benzodiazepine-related deaths have risen 10-fold in the US over the past 20 years.
Benzodiazepines and related compounds (benzodiazepine receptor agonists [BzRAs]) cause a wide range of adverse reactions, including withdrawal symptoms, even when normal or low dosages are used. Deprescribing is recommended when there is loss of efficacy, major side effects, or use longer than four weeks. The withdrawal syndrome is due to physiologic dependence based on various receptor adaptations. Psychological, neurophysiologic, and somatic complaints can be misdiagnosed as psychiatric, psychosomatic, or substance use disorder. These symptoms may be severe and prolonged. The discontinuation process should include careful planning, support, and the use of cognitive behavioral therapy. Tapering, perhaps after substituting with a long-acting BzRA, should be patient-led and proceed slowly, anticipating completion over 12 to 18 months or even longer. In a proportion of patients, symptoms may continue months or years after complete BzRA cessation, requiring ongoing medical care.
In Deutschland weisen 3,4 % der Bevölkerung eine Abhängigkeit von Schmerz-, Schlaf- bzw. Beruhigungsmitteln oder Stimulanzien auf. Die Abhängigkeit erscheint häufig iatrogen verursacht. Zu den Symptomen gehören: längerer als beabsichtigter Gebrauch der Substanz, fortgesetzter Gebrauch trotz schädlicher Folgen, verminderte Kontrolle über Gebrauch sowie Toleranz- und Entzugssymptome. Medikamente mit Abhängigkeitspotenzial interagieren mit Neurotransmittern. Ein Rückgang der Produktion endogener Substanzen, Veränderungen der Rezeptormechanismen sowie soziokulturelle Faktoren und Lernerfahrungen erscheinen für die Abhängigkeitsentwicklung relevant. Bei der psychologischen Behandlung des Benzodiazepinentzugs hat sich das Symptommanagementtraining als wirksam erwiesen. Die Patienten lernen Techniken, um Kontrolle über ihre Entzugssymptome zu erlangen. Für Patienten mit Abhängigkeit von anderen Medikamenten liegen bislang keine spezifischen Programme vor.
After reviewing this chapter, dental practitioners will be able to: Define key terminology important to the disease of substance use disorder. Discuss the signs, symptoms, and behaviors of a person under the influence of a specific substance of abuse and the subsequent withdrawal patterns. Describe treatment interventions, both psychopharmacologic and psychosocial, that are available to manage the disease of substance use disorder
Benzodiazepine tranquillisers were the most commonly prescribed drugs in the world in the 1970s and many patients took them regularly for years. Benzodiazepines include anxiolytics, such as diazepam, chlordiazepoxide, lorazepam, oxazepam and clonazepam; hypnotics, such as nitrazepam, temazepam, lormetazepam and loprazolam; and anticonvulsants such as clobazam. However, in the early 1980s long-term prescribed benzodiazepine users themselves realized that the drugs were associated with adverse effects. In particular, patients found it difficult to stop taking benzodiazepines because of withdrawal effects. Controlled trials of such patients (Petursson & Lader, 1981; Tyrer et al., 1981) demonstrated beyond doubt that withdrawal symptoms in chronic users of ‘therapeutic’ doses of benzodiazepines were real and that such reactions indicated dependence on the drugs. However, definitions of drug dependence have shifted in the last decade. A withdrawal syndrome is no longer considered sufficient evidence of dependence. The present criteria for a diagnosis of substance dependence include tolerance, escalation of dosage, continued use despite efforts to stop and knowledge of adverse effects and a withdrawal reaction (Table 1). Benzodiazepine dependence meets all these criteria and many long-term users develop a classic drug-dependence syndrome. Tolerance and dosage escalation Benzodiazepines exert five therapeutic actions: hypnotic, anxiolytic, anticonvulsant, muscle relaxant and amnesic effects (Table 2). Tolerance develops at different rates and to different degrees for these various actions. Tolerance to the hypnotic effects develops rapidly, within days or weeks of regular use, during which sleep profiles tend to return to pre-treatment levels.
Benzodiazepines have been for years widely used for a number of medical indications. In recent times, discoveries related to the adverse effects of their longterm and uncontrollable use have appeared. The present concepts on the indications for their use, dependence and withdrawal problems, alternative approach, and future perspectives of this group of drugs were evaluated on the basis of available literature in the field.
Differentiates benzodiazepine (BZ) addiction behavior from physiological dependence. Tolerance and dependence are normal adaptations to the continued use of BZs, while addiction is characterized by preoccupation with acquiring drugs, compulsive use, and use despite adverse consequences. The action of BZs in the brain and BZ withdrawal symptoms are described, and the hazards of combining BZs with alcohol are noted. The difference between tolerance and dependence and BZ addiction are illustrated by 3 case studies. In chronic BZ users, drug use can be discontinued successfully in spite of withdrawal symptoms, which can be managed by a gradual tapering off of medication. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Presents an overview of studies of long-term benzodiazepine (BZ) use, and discusses the confusion between pharmacological dependence (PD) and addictive use of BZs. Illustrations are provided by 3 case histories. Results of controlled studies of abrupt discontinuation, tapered reduction, short-term and long-term outcomes after taper, and comparison of alprazolam and imipramine in the management of panic disorder are discussed. Findings indicate that long-term use of BZs results in decreased efficacy, induction of PD, and risk for the development of addiction. Since the symptoms of PD are indistinguishable from the symptoms of anxiety disorders, it is recommended that diagnosis of insomnia or anxiety disorder be made after the patient is free of BZs. Signs and symptoms of BZ withdrawal are presented. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This study compared subjects who had received standard tapered withdrawal of benzodiazepine (BZD) (group 1) with a group with comparable diagnosis still receiving BZD (group 2) and a control group of comparable diagnosis not yet receiving treatment (group 3). Sixty subjects aged 21–65 years with a diagnosis of nonpsychotic anxiety or insomnia were included. The assessment of psychological distress and quality of life was timed to coincide with the maximum immediate effect of BZD discontinuation, as calculated according to drug half-life. Subjects diagnosed with insomnia reported lower distress in all three groups. The pattern of distress experienced by group 1 was closer to group 3 than to group 2, indicating the potential importance of re-emergence of anxiety. High neuroticism, lower education level, and lower quality of life were associated with higher levels of distress during withdrawal.
Met nadruk op methodologische problemen wordt de effectiviteit besproken van a antipsychotica bij schizofrene psychosen, b antidepressiva bij unipolaire depressies en c anxiolytica, antidepressiva en antipsychotica bij angststoornissen. Achtereenvolgens komen aan de orde: de korte-termijneffectiviteit van acute behandelingen in vergelijking met die van een placebo; de effectiviteit op langere termijn, wanneer de behandeling voortgezet of gestaakt wordt; vergelijkingen met de effectiviteit van cognitieve gedragstherapieën (CGT). De strekking luidt als volgt: ad a Het nut bij acute behandelingen kan nauwelijks betwijfeld worden. De waarde van jarenlang gebruik is moeilijker te taxeren. De effectiviteit is afhankelijk van psychosociale karakteristieken van de omgeving van de patiënt. Over de algemene en blijvende effectiviteit van CGT valt nog niets te zeggen. Ad b en c Het gemiddelde verschil in effectiviteit tussen medicijnen en placebo bij acute behandelingen is klein; uitgedrukt in effectgroottes kleiner dan 0,5 bij depressies, gegeneraliseerde angststoornissen en paniekstoornissen, en misschien iets groter bij dwangstoornissen en sociale fobieën; met enkele amenderingen lijken, waar onderzocht, benzodiazepinen, antidepressiva en antipsychotica even effectief bij angststoornissen. Gezien de nadelen van de alternatieven, is een SSRI altijd een goede eerste keuze, ongeacht de diagnose. De waarde van zeer langdurige medicamenteuze behandelingen is onduidelijk. De gemiddelde effectiviteit van CGT is minstens zo groot als van medicatie en de verbeteringen beklijven minstens zo goed. Bij een ‘modale’ patiënt met een depressie of angststoornis valt er vooralsnog veel voor te zeggen medicatie als een optie van tweede keuze te beschouwen, mede gezien de bijwerkingen die een enkele keer zeer ernstig kunnen zijn. Meer onderzoek naar de mogelijke meerwaarde van een combinatie van psychologische en medicamenteuze behandelingen is geboden.
Medikamentenabhängigkeit ist unter den stoffgebundenen Abhängigkeiten die unauffälligste Sucht, die vom Umfeld der Betroffenen
und auch den Patienten selbst häufig nicht oder erst sehr spät wahrgenommen wird. Die Abgrenzung zwischen sachgerechtem Gebrauch
und schädlichem oder abhängigem Gebrauch ist oft schwierig, insbesondere dann, wenn das Medikament zu Beginn zur Linderung
von körperlichen oder psychischen Beschwerden verordnet wurde und — wie in den meisten Fällen — keine auffälligen Dosissteigerungen
vorgenommen werden. Hat sich im Medikationsverlauf eine Abhängigkeit entwickelt, erfolgt die Einnahme jedoch nicht mehr zur
Linderung der initialen Krankheitssymptome. Im Mittelpunkt steht nun die Aufrechterhaltung der Sucht und die Beseitigung von
Entzugssymptomen, die die Patienten nicht selten als eine Verschlimmerung ihrer ursprünglichen Symptomatik fehlinterpretieren.
Darüber hinaus bleiben die Betroffenen nach außen meist weitgehend unauffällig. Dies mögen Gründe dafür sein, dass dem Thema
Medikamentenabhängigkeit auch in Fachkreisen nur vergleichsweise eingeschränkte Aufmerksamkeit gewidmet wird, obgleich die
Zahl der Betroffenen seit Jahren konstant hoch beziffert wird.
In the United States, roughly 2/3 of all hypnotic prescriptions go to chronic users, who have taken hypnotics for an average of 5 years or more. Two large prospective epidemiological studies have shown that reported hypnotic use, especially use 30 times per month, is associated with an excess hazard of death. Indeed, use of hypnotics 30 times per month is associated with a similar mortality hazard to smoking 1-2 packs of cigarettes per day. Moreover, the hypnotic user's wish to improve daytime function is usually unfulfilled. The preponderance of evidence is that hypnotics impair performance, cognition and memory, increase the risk of automobile accidents and falls and promote unfavourable changes in personality. Due to tolerance, the sleep-promoting effects of hypnotics appear to be lost with chronic use. With long-term use, there is little controlled evidence that hypnotics produce benefits of any sort. More study of long-term hypnotic effects by public agencies is needed, but available evidence weighs strongly against long-term prescribing.
Despite repeated recommendations to limit benzodiazepines to short-term use (2-4 weeks), doctors worldwide are still prescribing them for months or years. This over-prescribing has resulted in large populations of long-term users who have become dependent on benzodiazepines and has also led to leakage of benzodiazepines into the illicit drug market. This review outlines the risks of long-term benzodiazepine use, gives guidelines on the management of benzodiazepine withdrawal and suggests ways in which dependence can be prevented.
Recent literature shows that benzodiazepines have all the characteristics of drugs of dependence and that they are inappropriately prescribed for many patients, including those with physical and psychiatric problems, elderly residents of care homes and those with comorbid alcohol and substance abuse. Many trials have investigated methods of benzodiazepine withdrawal, of which the keystones are gradual dosage tapering and psychological support when necessary. Several studies have shown that mental and physical health and cognitive performance improve after withdrawal, especially in elderly patients taking benzodiazepine hypnotics, who comprise a large proportion of the dependent population.
Benzodiazepine dependence could be prevented by adherence to recommendations for short-term prescribing (2-4 weeks only when possible). Withdrawal of benzodiazepines from dependent patients is feasible and need not be traumatic if judiciously, and often individually, managed.
A double-blind placebo-controlled trial of 23 chronic benzodiazepine users showed that overall, buspirone did not appear to be helpful in alleviating benzodiazepine withdrawal symptoms. Buspirone (5 mg t.d.s.) or placebo was administered for four weeks before, during and after diazepam withdrawal. Patients taking buspirone had a markedly higher dropout rate (seven out of 11) than those taking placebo (one out of 12). Mean daily diazepam dosage at entry was significantly higher in the buspirone group, but overall initial diazepam dosage was not related to outcome. Higher subjectively rated anxiety at the start of withdrawal was significantly related to higher dropout rate, irrespective of treatment, and was greater (although not significantly so) in the buspirone group.
Benzodiazepine dependence is a frequent complication of regular prescriptions for 4 weeks or longer, occurring in almost one-third of patients. Although it is also manifested by tolerance to drug effects and occasional drug seeking behaviour, particularly in those prone to drug abuse, most dependence is characterised by a withdrawal syndrome on stopping treatment. The withdrawal syndrome includes symptoms of anxiety and those of perceptual disturbance such as depersonalisation, hypersensitivity of all major senses, dysphoria and (rarely) epileptic seizures and psychotic episodes. Risk factors for dependence include high dosage, use of more potent and short acting benzodiazepines, long duration of therapy and dependent premorbid personality characteristics. If none of these apply, benzodiazepines can be prescribed with safety.
need to understand the brain systems that control the kind of behaviour involved [in the] disturbance . . . which gives rise to psychiatric disorder
three . . . neuropsychological systems that are important in the control of emotional behaviour / brief description of each in both behavioural and neurological terms as they have emerged from experiments with animals
neurotransmitters involved
speculations about possible interactions between the three systems and about their relations to dimensions of normal personality
approach system / mediates behaviour elicited by rewards
fight/flight system / mediates the behavioural effects only of unconditioned punishing events
behavioral inhibition system / organizes responses to conditioned aversive stimuli (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Discusses the adverse effects (AEs) of benzodiazepines (BZs), and presents the main pharmacological actions and clinical uses of BZs. Elimination half-life and approximate dosage equivalents for various BZs are also given. There are few short-term AEs of BZs, mainly oversedation and addictive effects with other CNS depressants. Long-term use is associated with more serious AEs, including memory impairment, depression, tolerance, and dependence. BZs cross the placenta, and regular use by the mother late in pregnancy can cause neonatal complications, since the fetus metabolizes BZs slowly. Older individuals and those with chronic respiratory disease, liver disease, depression, or personality disorder are more vulnerable to increased AEs from BZs. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
40 patients seen in general practice and psychiatric outpatient clinics who had taken lorazepam or diazepam alone in regular dosage for a mean period of 3.6 years had their benzodiazepine replaced by propranolol (60-120 mg/day) or placebo for two weeks under double-blind conditions. Depending on the criteria for the definition of an abstinence syndrome, 27-45% of the patients had withdrawal symptoms during the study. Propranolol did not affect the drop-out rate or the incidence of withdrawal symptoms but significantly reduced their severity in patients completing the study. The percentage fall in serum levels of desmethyldiazepam in patients who experienced withdrawal symptoms after stopping diazepam was significantly greater than in patients with no withdrawal symptoms.
The potential of the benzodiazepine antagonist flumazenil (Ro 15-1788) to lessen persisting benzodiazepine withdrawal symptoms was demonstrated in 11 patients who had been drug free for between 1 month and 5 years. Doses ranging from 0.2 to 2.0 mg divided into three intravenous injections over a few hours relieved long-standing symptoms to varying extents. These included clouded thinking, tiredness, muscular symptoms such as neck tension, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles, burning skin, pain and subjective sensations of bodily distortion. Mood disorder, when present, also improved but the reduction in anxiety and depression may have reflected relief of physical symptoms. The onset of maximum response was sometimes delayed by as much as a day but was usually prompt. Side effects were reported to be either absent or typically described as lightheadedness or dizziness, lasted only a few minutes and were usually well tolerated. The benefits last between a few hours and several days despite flumazenil's otherwise short duration of action. However, symptoms did return to varying degrees in most cases, suggesting the need for repeated doses.
Rebound insomnia followed the withdrawal of three benzodiazepine hypnotic drugs, each of which had been administered in a single nightly dose for only short-term periods. The intense worsening of sleep is attributed to the short duration of the action of these drugs. A hypothesis involving benzodiazepine receptors in the brain is proposed in which there is a delay or lag in replacement of endogenous benzodiazepine-like molecules after the abrupt withdrawal of exogenous drugs.
The benzodiazepine withdrawal syndrome is a complex phenomenon which presents serious difficulties in definition and measurement. It is particularly difficult to set out precise limits on its duration. Many withdrawal symptoms are a result of pharmacodynamic tolerance to benzodiazepines, some mechanisms for which are discussed. Such tolerance develops unevenly in different brain systems and may be slow to reverse. Withdrawal symptoms occurring in the first week after cessation of drug use tend to merge with more persistent symptoms that may last for many months. These prolonged symptoms do not necessarily constitute "true" pharmacological withdrawal symptoms, but are nevertheless related to long-term benzodiazepine use. Such symptoms can include anxiety, which may partly result from a learning deficit imposed by the drugs, and a variety of sensory and motor neurological symptoms. The protracted nature of some of these symptoms raises the possibility that benzodiazepines can give rise not only to slowly reversible functional changes in the central nervous system, but may also occasionally cause structural neuronal damage.
A self-report questionnaire is described which records the main symptoms experienced during withdrawal from benzodiazepines in pharmacologically dependent patients. The questionnaire consists of 20 items; evidence is given that these are reasonably independent and are sensitive in detecting withdrawal symptoms from a study of 68 patients undergoing slow withdrawal from benzodiazepines.
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.
Clinical outcome was assessed in SO consecutive patients who completed a course of supervized benzodiazepine withdrawal following referral to a Clinical Pharmacology Unit. The patients had been taking prescribed benzodiazepines regularly for 1–22 years and all wished to stop. On presentation, all had many symptoms which they attributed to benzodiazepines. The outcome 10 months to 3.S years later was judged as excellent (fully recovered) in 48%, good (much better) in 22%, moderate (better) in 16% and poor (no better) in 6%. One patient failed to withdraw and three relapsed onto benzodiazepine use after withdrawal. Younger age was significantly associated with a favourable outcome, but outcome was not related to duration or dosage of benzodiazepines, type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history, marital status, or sex.
Synopsis
In 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients ( N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients ( N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.
The presence of protracted tinnitus after discontinuation of long-term therapeutic doses of diazepam (less than or equal to 30 mg/day) is described in three patients. In one of these patients, the association of the tinnitus appearance with the drug discontinuation was documented in a double-blind, randomized, crossover single case study. Objective confirmation of drug use or of abstinence was performed by obtaining plasma benzodiazepine concentrations. The findings provide further documentation that sensory disturbances of short- and long-term duration are among the most distinctive clinical features of the benzodiazepine withdrawal syndrome.
We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.
Long-term, normal-dose benzodiazepine treatment was discontinued in 16 patients who were suspected of being dependent on their medication. The withdrawal was gradual, placebo-controlled, and double-blind. All the patients experienced some form of withdrawal reaction, which ranged from anxiety and dysphoria to moderate affective and perceptual changes. Symptom ratings rose as the drugs were discontinued, but usually subsided to prewithdrawal levels over the next two to four weeks. Other features of the withdrawal included disturbance of sleep and appetite and noticeable weight loss. Electroencephalography showed appreciable reduction in fast-wave activity as the drugs were withdrawn, and an improvement in psychological performance was recorded by the Digit Symbol Substitution Test. Because of the risk of dependence on benzodiazepines these agents should probably not be given as regular daily treatment for chronic anxiety.
A withdrawal syndrome is described in 10 patients who claimed to be unable to discontinue benzodiazepines. A high dose group took the equivalent of a mean of 135 mg diazepam/day, and the normal dose group of 20 mg/day. Associated with the gradual reduction of medication was the emergence of severe symptoms of anxiety as well as sensory intolerance, perceptual disturbances and weight loss. The withdrawal syndrome subsided after 2 weeks and was similar in both groups of patients. EEG changes were detected on withdrawal opposite to those known to be associated with initiation of diazepam treatment. The measures tended to revert to the baseline after a drug-free period. One reason why chronic users of diazepam experience difficulty in stopping medication may be the development of a withdrawal syndrome even after moderate dosage.
41 outpatients who were long-term consumers of diazepam in therapeutic dosage were gradually withdrawn from the drug over 3 months by stepwise reduction. In a double-blind procedure half the patients began withdrawal immediately and half after 8 weeks. Of 36 patients who completed treatment, 16 (44.4%) experienced true withdrawal phenomena on reducing their drugs, but 8 other patients had pseudo-withdrawal reactions at a time when their drug treatment was unchanged. The pseudo-withdrawal reactions consisted of an increase in anxiety symptoms only, whereas true withdrawal symptoms also included perceptual changes and psychotic symptoms. Examination of pharmacological and clinical predictors of withdrawal phenomena and later relapse showed that personality factors were the most important, patients with passive-dependent traits having a significantly greater prevalence of withdrawal reactions.
Classical pharmacological dependence accompanied by euphoria, clinical evidence of tolerance and escalation of dosage are very rare with the benzodiazepines. However, there is now abundant evidence that prolonged administration of doses within the therapeutic range leads to true dependence in a significant minority of patients. This dependence is characterised by withdrawal symptoms on stopping treatment; these include perceptual disturbances, epileptic seizures, weight loss, insomnia and autonomic symptoms. As some of the symptoms are qualitatively different from those of anxiety neurosis, and as the withdrawal syndrome commonly lasts between 5 and 15 days, the possibility that the symptoms represent a return of pre-existing anxiety can be discounted.
The withdrawal syndrome is more likely if: (a) the benzodiazepine has been taken in regular dosage for more than 4 months; (b) higher dosages have been used; (c) the drug is stopped suddenly; and (d) a short acting benzodiazepine has been taken. The withdrawal syndrome is most likely to occur when there is a rapid fall in blood benzodiazepine concentrations; this may be associated with altered sensitivity of benzodiazepine receptors. The syndrome can best be avoided by gradual reduction of dosage. The temporary prescription of other drugs, particularly β-adrenoceptor blocking drugs, may attenuate withdrawal symptoms, but antipsychotic drugs in low dosage are of no benefit.
Synopsis
Depression following withdrawal from long- or short-term use of benzodiazepines is not uncommon, yet it is under-reported in the benzodiazepine withdrawal literature. Four cases of depressive illness supervening during benzodiazepine withdrawal are reported. Depression may, it is suggested, be an integral part of the benzodiazepine withdrawal syndrome.
Benzodiazepines, the most widely used of all drugs, are powerful anxiolytics, anticonvulsants and muscle relaxants. Dependence is difficult to induce in animals but has been induced by high doses in man. Case reports of benzodiazepine dependence are rare compared with the usage of these drugs, but do not provide a proper epidemiological framework for the estimation of risk. Patients taking these drugs for four months or more may develop a physical withdrawal syndrome, characterized by anxiety, dysphoria, malaise, depersonalization, and by perceptual changes such as hyperacusis and unsteadiness. In our experience drawn from over 20 patients, withdrawal from therapeutic doses of a benzodiazepine may be attended by a fully-developed physical withdrawal syndrome.
Benzodiazepine dependence is a frequent complication of regular prescriptions for 4 weeks or longer, occurring in almost one-third of patients. Although it is also manifested by tolerance to drug effects and occasional drug seeking behaviour, particularly in those prone to drug abuse, most dependence is characterised by a withdrawal syndrome on stopping treatment. The withdrawal syndrome includes symptoms of anxiety and those of perceptual disturbance such as depersonalisation, hypersensitivity of all major senses, dysphoria and (rarely) epileptic seizures and psychotic episodes. Risk factors for dependence include high dosage, use of more potent and short acting benzodiazepines, long duration of therapy and dependent premorbid personality characteristics. If none of these apply, benzodiazepines can be prescribed with safety.
Petursson H5 Lader MH. Benzodiazepine dependence
Smith DE Wesson DR. Benzodiazepine dependency