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nnales Pharmaceutiques Françaises (2009) 67, 408—413

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enzodiazepine dependence: Focus on withdrawalyndrome

épendance aux benzodiazépines : le syndrome de sevrage

N. Authiera,b,d,∗, D. Balayssaca,b, M. Sautereauc,A. Zangarelli a, P. Courtyc, A.A. Somogyid, B. Vennate,P.-M. Llorcac, A. Eschalierb

a Laboratoire de toxicologie, faculté de pharmacie, , 63000 Clermont-Ferrand, Franceb Inserm 766, faculté de médecine, 63000 Clermont-Ferrand, Francec Pôle de psychiatrie, CHU de Clermont-Ferrand, 63000 Clermont-Ferrand, Franced Discipline of Pharmacology, Medical School, University of Adelaide, North Wind, FromeRoad, Adelaide, SA 5005, Australiae Laboratoire de pharmacie galénique, faculté de pharmacie, 63000 Clermont-Ferrand, France

Received 21 April 2009; accepted 22 July 2009Available online 18 September 2009

KEYWORDSAddiction;Benzodiazepine;Dependence;Elderly;Pregnancy;Drug abuse

Summary Benzodiazepines are potentially addictive drugs: psychological and physical depen-dence can develop within a few weeks or years of regular or repeated use. The socioeconomiccosts of the present high level of long-term benzodiazepine use are considerable. These conse-quences could be minimised if prescriptions for long-term benzodiazepines were decreased.However, many physicians continue to prescribe benzodiazepines and patients wishing towithdraw receive little advice or support. Particular care should be taken in prescribing benzo-diazepines for vulnerable patients such as elderly persons, pregnant women, children, alcohol-or drug-dependent patients and patients with comorbid psychiatric disorders. The followingupdate gives recent research results on the withdrawal pathophysiology and practical informa-tion in order to treat or prevent benzodiazepine withdrawal syndrome.© 2009 Elsevier Masson SAS. All rights reserved.

MOTS CLÉSAddiction ;Benzodiazépine ;Dépendance ;

Résumé Les benzodiazépines anxiolytiques et hypnotiques sont des médicaments dont lepotentiel addictif est maintenant bien connu. L’utilisation de ces molécules sur de longues péri-odes allant de plusieurs semaines à plusieurs années provoque des manifestations psychiqueset physiques de dépendance dont le coût socioéconomique, bien que difficile à estimer, sembleêtre très important compte tenu de leur large prescription. Le respect des recommandations

∗ Corresponding author.E-mail address: authier@hotmail.com (N. Authier).

003-4509/$ — see front matter © 2009 Elsevier Masson SAS. All rights reserved.oi:10.1016/j.pharma.2009.07.001

The benzodiazepine withdrawal syndrome 409

Sujet âgé ;Grossesse ;Toxicomanie

pour leur prescription, la sensibilisation des médecins et pharmaciens à cette dépendancetrop souvent sous-estimée et la multiplication des actions d’information envers les patientsdevraient participer à minimiser le mésusage des benzodiazépines. Certaines populations depatients telles que les sujets âgés, les femmes enceintes, les enfants, les patients présentantune autre addiction ou une pathologie psychiatrique doivent faire l’objet d’une attention par-ticulière vis-à-vis de ce risque de dépendance aux benzodiazépines. Cet article met à journotamment les connaissances concernant la physiopathologie et la prise en charge de ce syn-drome de sevrage.© 2009 Elsevier Masson SAS. Tous droits réservés.

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Introduction

Although recommendations for benzodiazepine use withprescription suggest that duration be limited to a few weeks,patients are known to take these drugs for months, years, oreven decades. In the 1996 Australian National Health Survey,58% of the 359,300 benzodiazepine users had been takingthis medication for at least 6 months and in another study,84% of 3234 benzodiazepine users identified in a study of 15general practices were still using them 8 months later [1,2].According to different National and European epidemiologi-cal surveys, France had the highest annual rate of anxiolyticuse, within a range of 12% to 19%. Duration of benzodi-azepine use was more than 6 months in 70 to 75% of usersand increased with age [3,4]. Such long-term use occurs inspite of evidence that the benefits of benzodiazepine maydecrease with time, while the potential for adverse effectsremains. Potential adverse effects include cognitive decline,unwanted sedation, reduced coordination, increases in riskof accidents, as well as psychological and physical depen-dence (Table 1). Benzodiazepines have long been known tocause amnesia, an effect that is utilised when the drugs areused as premedication before major surgery or for minorsurgical procedures. Oral doses of benzodiazepines in thedosage range used for insomnia or anxiety can also causeepisodic memory impairment. Acquisition of new informa-

tion is deficient, partly because of lack of concentration andattention [5]. According to Neutel [6], the overriding factorassociated with likelihood of benzodiazepine use was that ofprevious use. Other factors associated with benzodiazepineuse, whether related to the person or the reason for benzodi-

Table 1 Benzodiazepine main adverse effects and con-sequences.Principaux effets secondaires des benzodiazépines et leursconséquences.

Adverse effect Life consequences

Oversedation Increased risk of accidentMemory impairment Increased risk of

attempted suicideParadoxical stimulant

effectsIncreased risk of antisocialacts

Overdose (respiratoryfailure)

Increased risk ofunemployment/job loss

Tolerance anddependence

Increased risk of maritalbreakdown

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zepine use, were considerably less important for long-termsers. It may be concluded that once benzodiazepine useas started, specific reasons such as poor health pain orhronic diseases become much less important in long-termse than they are in the earlier phases of benzodiazepinese.

In clinical practice, benzodiazepines should be used forcute anxiety management rather than long-term treat-ent. However, benzodiazepines continue to be frequentlyrescribed for the initial treatment of panic disorders, asell as other anxiety disorders and chronic insomnia. Theseedications are undoubtedly drugs associated with prob-

ems on attempted reduction in dosage or withdrawal. Theiscontinuation syndrome can be severe and can preventhe long-term user from ever stopping the medication. Inhis update on benzodiazepine withdrawal syndrome, wettempted to explain who is vulnerable, why this syndromexists and how to withdraw from these drugs.

ulnerable patients to withdrawalymptoms

articular care should be taken in prescribing benzodi-zepines for vulnerable patients such as elderly, pregnantomen and the foetus, children, alcohol and drug abuseependent patients and patients with comorbid psychiatricisorders.

lder people

here are particularly compelling reasons why older peo-le should withdraw from benzodiazepines since, as agedvances, they become more proned to falls and frac-ures, confusion, memory loss and psychiatric problems. Theigh incidence of insomnia with aging is paralleled by anncreased use of hypnotic drugs among older adults. Pro-onged users are mostly older adults who report greaterleep dissatisfaction, higher psychological distress and morehronic medical illnesses. Elderly residents of care homesre particularly concerned by these chronic prescriptions ofenzodiazepines. Several physiological (withdrawal symp-oms) and psychological factors (anticipatory anxiety, fear of

ebound insomnia) can perpetuate the vicious cycle and leado hypnotic-dependent insomnia in this vulnerable popula-ion [5,7]. Discontinuation is usually beneficial, particularlyn the elderly as it is followed by improved psychomotor andognitive functioning.

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Table 2 Benzodiazepine main withdrawal symptoms.Principaux symptômes de sevrage des benzodiazépines.

Psychological symptoms Physical symptoms

Sleep disturbance Muscles symptomsMemory impairment PainSensor hypersensitivity Bodily sensationsAnxiety, panics and phobias Weakness and fatigue

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regnant women and the foetus

bout pregnant women, the foetus and neonate metaboliseenzodiazepines very slowly and appreciable concentrationsay persist in the infant up to 2 weeks after birth, resulting

n the ‘‘floppy infant syndrome’’ of lax muscles, overse-ation and failure to suckle. Withdrawal symptoms mayevelop after about 2 weeks with hyperexcitability, high-itched crying and feeding difficulties. Benzodiazepines inherapeutic doses doest not appear to have a strong terato-enic potential. However, chronic maternal use may inducereterm birth and impair foetal intrauterine growth, lowirth weight. There is increasing concern that such chil-ren in later life may be prone to attention deficit disorder,yperactivity, learning difficulties and a spectrum of autisticisorders [8,9].

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oncerning children, withdrawal syndromes related toenzodiazepine (midazolam) administration in pediatricntensive care may affect 20% of exposed children and areelated to infusion duration and total dose. Common symp-oms include tremors, agitation, inconsolable crying andleeplessness [10]. However, recognition of withdrawal inediatric intensive care unit may be difficult because theymptoms may strongly overlap clinical signs of inadequateedation, such as agitation, anxiety and movement disorders11].

lcohol, drugs, drugs abuse

hile benzodiazepine withdrawal can be challenging, ces-ation of use can be even more difficult if there are othero-addiction such as alcohol/drugs use disorders. Comorbidlcohol use disorder patients are vulnerable to long-termenzodiazepine prescriptions, managing themselves theirhort-time withdrawal period but also in order to improvehronic mood and anxiety disorders induced by chronic alco-ol consumption. The use of benzodiazepine as recreationalrugs concern at least half of opiates, amphetamines,ocaine and alcohol abusers. Many illicit benzodiazepinesers become dependent and present typical withdrawalymptoms which can be severe. For high-dose benzodi-zepine abusers in whom benzodiazepine use often forms aart of polydrug abuse pattern, they need in- or outpatientetoxification for the primary drug [5,12].

sychiatric disorders

ther long-term prescribed users who are likely to be depen-ent are patient with psychiatric problems and for whom wean avoid prescribing anxiolytics. Indeed, considering theicense extension of antidepressants and some anticonvul-ant drugs, but also the development of agonist melatoninor insomnia, newer drugs being generally better toleratedithout risk of dependence or abuse, this has open-up the

rescriber’s therapeutic choices [13]. An italian epidemio-ogical study on benzodiazepine use in psychiatric practiceevealed that use was particularly frequent in individualsith affective illness and in those with a long psychiatricistory [14]. According to a recent meta-analysis, there is no

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vidence to recommend benzodiazepines neither as a soleor as an adjunctive agent in schizophrenia or schizophrenia-ike psychoses. The only significant effects were seen inerms of short-term sedation [15].

linical aspects

he development of tolerance is one of the reasons peo-le become dependent on benzodiazepines and also setshe scene for the withdrawal syndrome. This syndrome is aey sign of benzodiazepine dependence. Withdrawal symp-oms occur when there is a decline in the blood or tissueoncentration of any dependence-forming substance thatn individual has been continuously taking. These symptomsre generally the opposite of the acute effects of the drug,r they may mimic the symptoms for which the drug wasriginally taken. They are time-limited, usually occuring fornly 1 or 2 weeks after the discontinuation of the drug, buthe duration varies according to the drug and the individ-al person. Withdrawal symptoms are usually relieved bydministration of the substance from which the patient isithdrawing. Three factors seem to influence the intensitynd/or the duration of the withdrawal:the amount of time spent in treatment (the most signifi-cant);the dose of medication (in combination with duration)and;the half-life of the benzodiazepine (short half-life) [16].

Benzodiazepine withdrawal symptoms can be dividednto two categories (Table 2). First of all, psycholog-cal symptoms such as increased anxiety, excitability,nsomnia and nightmares, panic attacks and agoraphobia,ocial phobia, perceptual distortions, depersonalisation,erealisation, hallucinations, misperceptions, depression,bsessions, paranoid thoughts, irritability, poor memorynd concentration. About these last symptoms, it is well-nown that poor memory and concentration, but alsompairment of intellectual abilities and intrusive memo-ies are also features of benzodiazepine withdrawal andre probably due to continued effects of the drug. Mosttudies on this question indicate that improvement maye very slow. Secondly, physical symptoms are observedike headache and pain/stiffness (limbs, back, neck, teeth,

aw), seizure, tingling, numbness, altered sensation (limbs,ace, trunk), weakness, fatigue, influenza-like symptoms,uscle twitches, jerks, tics, ‘‘electric shocks’’, tremor,izziness, light-headedness, tinnitus, hypersensitivity (light,ound, touch, taste, smell), gastrointestinal symptoms (nau-

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sea, vomiting, diarrhoea, constipation, pain, distension,difficulty swallowing), appetite/weight change, dry mouth,metallic taste, unusual smell [5].

It is important to differentiate between benzodiazepinewithdrawal and relapse of anxiety. First, they differ bythe length of time between discontinuation of drug andappearance of symptoms and tendency of the symptoms toimprove or worsen. Indeed, withdrawal symptoms usuallystart within few days of stopping benzodiazepine and con-tinue to improve until they eventually disappear. Secondly,there is a difference between relapse and withdrawal in thesymptoms themselves. Certain symptom clusters are par-ticularly characteristic of benzodiazepine withdrawal suchas hypersensitivity to light and sound, tinnitus, feelings of‘‘electric shocks’’, tremors, myoclonic jerks, perceptualchanges.

Finally, a minority of people who have withdrawn frombenzodiazepines seem to suffer long-term effects (pro-tracted symptoms) that just don’t go away after months oreven years. It has been estimated that perhaps 10% to 15% oflong-term benzodiazepine users develop a ‘‘postwithdrawalsyndrome’’. Many of these people have taken benzo-diazepines for 20 years or more and/or have had badexperiences in withdrawal. The symptoms most likely to belong-lasting include anxiety, insomnia, depression, varioussensory and motor symptoms, gastrointestinal disturbancesand poor memory and cognition. The reasons why thesesymptoms persist in some people are not clear [17].

Biological aspects

The pharmacological mechanisms underlying benzodi-azepine withdrawal are complex and still not clear. Theresult of a rapid or abrupt withdrawal of the benzodiazepineis underactivity of inhibitory GABA (�-aminobutyric acid)functions and a surge in excitatory nervous activity, givingrise to many of the benzodiazepine symptoms.

First, it is well-established that following chronic expo-sure to benzodiazepines, there are alterations in GABAergicneurotransmission (up/down regulation GABA-a receptorsubunits), contributing to the symptoms of tolerance,dependence and withdrawal. Changes in nucleus accum-bens, Papez circuit and basolateral amygdala were observedon withdrawal, implicating a common circuitry in thewithdrawal process. In addition, increases in AMPA (�-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and N-MethylD-Aspartic acid (NMDA) receptor expression also occur upondiazepam withdrawal, resulting in an increased expressionof the NR1 and NR2B NMDA receptors subunits in the hip-pocampus. These are downstream adaptations in response tooverstimulation of GABA-a receptors [18]. Recent preclinicalresults in rats displayed that a blockade of AMPA-kainate andNMDA receptors in the dorsal periaqueductal gray reducesthe effect of diazepam withdrawal, confirming that this neu-ronal hyperexcitability is mediated by glutamate [19]. Daset al. [20] suggest that the enhanced glutamatergic strength

at hippocampal CA1 pyramidal neurons synapses duringbenzodiazepine withdrawal is mediated by increased incor-poration of GluR1-containing AMPA receptors. Accordingto Xiang et al. [21], withdrawal enhances high voltage-activated calcium channel function in transitory manner

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receding the potentiation of AMPA function and may beentral to CA1 neuron AMPA receptor synaptic plasticity andenzodiazepine physical dependence.

Besides, clear evidence exists that benzodiazepinesnterfere with the activity of the hypothalamic-pituitarydrenocortical (HAP) axis, also acting on a suprahy-othalamic level by modulating neurotransmitters likeeuropeptide Y and cholecystokinin (CCK). During benzo-iazepine withdrawal an increase in HPA axis activity waseported, with significant increased adreno cortico trophinormone (ACTH) and corticosterone plasma levels [22]. Areexisting dysregulation of the HPA axis could be correlatedo the severity of withdrawal symptoms [23]. Therefore,CK levels seem to be up-regulated, associated to an

ncrease in the number of CCK-8 receptors in the frontalortex and the hippocampus. Accordingly, CCK antagonistsave been reported to attenuate withdrawal reactions [24].inally, a recent preclinical study in rats showed thathe corticotropin-releasing factor (CRF) 1 receptor subtypelays a major role in mediating the effect of CRF 1 oneuroendocrine and behavioural responses during benzodi-zepine withdrawal [25].

linical management

hy stopping benzodiazepine? Because long-term use ofenzodiazepines can give rise to many unwanted effects,ncluding poor memory and cognition, emotional blunt-ng, depression, increasing anxiety, physical symptoms andependence, with important social and economic conse-uences. All benzodiazepines can produce these effectshether taken as anti-anxiety drugs or sleeping pills. Sev-ral clinical options exist for discontinuing benzodiazepinereatment, including gradual tapering of the current benzo-iazepine, substitution with a long-acting benzodiazepine,reating the symptoms of withdrawal and psychologicalnterventions.

First, we have to define a realistic goal regarding thexpectations of both patient and doctor and to explain theikely course of withdrawal (length, intensity, symptoms,ithout forgetting the potential relapse) which may reduceatient experiencing withdrawal severity [26]. The physicianlso has to look into the history of the patient, the exis-ence of a psychiatric disorder (anxiety or mood disorders)hose symptoms could be mistaken for benzodiazepineithdrawal symptoms. Secondly, the rate of reduction wille scheduled with the patient (benzodiazepine withdrawals never an emergency). During the withdrawal phase,octor must maintain close contact with patient, monitor-ng anxiety/mood level but also being aware of potentialncreased alcohol, nicotine or illicit drugs consumption. Inact, the rate of withdrawal should be individually adjustedo the patient’s need, taking into account factors such asosage, type of benzodiazepine, reason for prescription,ifestyle, personality and environmental stresses. A person-lised approach, with a patient in control of his own personal

eduction rate and proceed, is likely to result in feweratients dropping out [5].

Denis et al. [27], in a Cochrane review meta-analysis,oncluded that progressive withdrawal (over 10 weeks)ppeared preferable if compared to abrupt withdrawal,

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ince the number of dropouts was lower and the proce-ure judged more favourable by the patients. Switchingrom short half-life benzodiazepine to long half-life benzo-iazepine before gradual taper withdrawal did not receiveuch support from this meta-analysis. In the literature,

he taper schedules vary from abrupt discontinuation to5% weekly reduction of dosage, discontinuation in stepsf about one-eight to one-tenth of the daily dose everyortnight to, finally, symptom-guided withdrawal with theime needed for withdrawal varying from about 4 weeks to aear or more. Another meta-analysis by Oude Voshaar et al.28] reported that providing a brief targeted interventionas more effective than routine care, that psychological

ntervention provided an additive effect to gradual doseeduction alone and that substitutive pharmacotherapy waslso slightly more effective than the gradual reduction dose.

Carbamazepine was the only drug that appeared to haveny useful adjunctive properties for assisting in the dis-ontinuation of benzodiazepines, but the available datare insufficient for recommendations to be made regardingts use. When managing the withdrawal period, the treat-ent of a preexisting anxiety or mood disorder is of major

mportance and antidepressant agents or mood stabilizershould be used and associated with the benzodiazepine grad-al dose reduction. A recent clinical trial studied, withositive preliminary results, a new way in benzodiazepineiscontinuation using low-dose flumazenil continuous infu-ions, a medication commonly used in the treatment ofenzodiazepine overdose. However, further developmentsre needed, particularly about refinement of novel deliveryystems [29]. At present, the most conservative conclusionor practitioners is that current evidence is not sufficiento support the prescription of adjunctive pharmacotherapy30].

Otherwise, according to the most recent meta-analysisn data available from the literature search, psychologicalnterventions may provide a small but significant additionalenefit over gradual dose reduction alone at postcessa-ion and at follow-up. Psychological interventions rangerom simple support through counselling to expert cognitive-ehavioural therapy (CBT). However, further studies areeeded to determine which kind of psychological interven-ion is more effective and whether the intervention haso be delivered face-to-face in order to make a signifi-ant added contribution to cessation [30]. Group therapyay be helpful as it, at least, provides support from otheratients. CBT needs to be administered by fully trainednd experienced personnel but seems effective, particularlyn obviating relapse [13]. Psychological support should bevailable both during and after withdrawal since patientsay remain vulnerable to stress for a few months, from a

ingle brief consultation to a more formal therapy such asBT, relaxation techniques and stress-coping strategies.

Relapses rates, 1 to 5 years after withdrawal varyetween to 57% in different studies but are probably mini-ized by using individualized withdrawal programmes [5].

onclusions

he socioeconomic costs of the present high level ofong-term benzodiazepine use are considerable, although

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ifficult to quantify. These consequences could be min-mised if prescriptions for long-term benzodiazepines wereecreased. Yet, many doctors continue to prescribe benzo-iazepines and patients wishing to withdraw receive littledvice or support on how to go about it.

Due to the variability in medications and researchesigns, it is not possible to assess conditions under whichubstitutive pharmacotherapy provided a better outcomehan gradual dose reduction alone. So larger controlled clin-cal trials are needed to confirm first that switching shortalf-life benzodiazepine to long half-life benzodiazepineefore gradual taper withdrawal did not have any impactegarding intensity of withdrawal symptoms, secondly toonfirm that failure rate was higher for short half-life thanong half-life benzodiazepine gradual taper. Thirdly, moreontrolled clinical studies will be carried out to assessotential benefits of several drugs such as carbamazepine,regabaline, flumazenil or antidepressants. Finally, differ-nt taper schedules have never been directly compared in aandomised controlled study.

onflicts of interest

one.

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