Psychiatry Research xxx (2012) xxx–xxx

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Psychiatry Research

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High dose benzodiazepine dependence: Description of 29 patients treated withflumazenil infusion and stabilised with clonazepam

Gianluca Quaglio a,⁎, Cristian Pattaro b, Gilberto Gerra c, Sophie Mathewson a, Paul Verbanck d,Don C. Des Jarlais e, Fabio Lugoboni a

a Medical Service for Addictive Disorders, University of Verona, Italyb Institute of Genetic Medicine, European Academy of Bolzano/Bozen (EURAC), Bolzano/Bozen, Italyc Health and Human Development Section, Division for Operations, United Nations Office on Drugs and Crime, Vienna, Austriad Department of Psychiatry, Université Libre de Bruxelles, Belgiume Edmond de Rothschild Foundation Chemical Dependency Institute, Beth Israel Medical Center, New York City, United States

⁎ Corresponding author at:Medical Service for AddictivePoliclinico GB Rossi, 37134 Verona, Italy. Tel.: +39 045812

E-mail address: gianluca.quaglio@ospedaleuniveron

0165-1781/$ – see front matter © 2012 Elsevier Irelanddoi:10.1016/j.psychres.2012.02.008

Please cite this article as: Quaglio, G., et al.,sion and stabilised with clonazepam, Psych

a b s t r a c t

a r t i c l e i n f o

Article history:Received 24 May 2011Received in revised form 3 February 2012Accepted 6 February 2012Available online xxxx

Keywords:Benzodiazepine withdrawalFlumazenilDependenceDetoxificationClonazepam

Thewithdrawal syndrome from benzodiazepine (BZD) can be severe and in some casesmay impede cessation ofthe use of the drug.We present here a case series of benzodiazepine detoxification by flumazenil infusion, stabi-lised with clonazepam. Patients were treated with flumazenil 1.35 mg/day for a median of 7 days. Self-reportedphysical withdrawal symptoms were recorded daily. In addition to flumazenil, antidepressants were given be-fore treatment commenced and clonazepam was administered nightly with both being continued after dis-charge. Twenty-nine patients were treated. No patients dropped out from the treatment programme. Ninepatients (31%) required a temporary reduction/cessation of the infusion. The linear trend in the reduction ofthe daily withdrawal scores in the overall study population was significant. The linear trends were also signifi-cant in the group of patients for whom a temporary reduction/suspension of the flumazenil was required. Sixmonths after treatment, 15 patients (53%) were abstinent from clonazepam and other BZDs. For five (21%) theBZD dependence were reinstated. More than two-thirds of the subjects tolerated the procedure well andabout half had a good long term response. Slow flumazenil infusion appears to merit consideration as a possiblefuture treatment. Suggestions for future research are examined.

© 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Benzodiazepines (BZDs), typically used to treat anxiety and sleepdisorders, are among the most commonly prescribed psychotropicmedications worldwide (De Las Cuevas et al., 2000; Kaufman et al.,2002). Overall, the prevalence of long-term use in the general popu-lation is approximately 2–7%, with estimates for long-term useamong BZD users ranging from 25% to 76% (Lagnaoui et al., 2004;Gorgels et al., 2005; Neutel, 2005; Petitjean et al., 2007; Fang et al.,2009). The problem of use of BZDs is also related to the use of highdoses. In a population based cross-sectional study with 520,000 pat-ents, Petitjean et al. (2007) estimated that approximately 6.6% ofthe Swiss adult population uses BZDs in doses exceeding the maximalrecommended daily dose (at least) twice, and 1.6% used BZDs in veryhigh doses, exceeding the maximal recommended daily dose morethan twice. Notably, surveys from France, Germany, Italy, and UnitedKingdom carried out during the 1990s showed that 3.9% and 3.2% ofcurrent hypnotic and anxiolytic users had been taking a higher dose

Disorders, University of Verona,8296; fax: +39 0458128290.a.it (G. Quaglio).

Ltd. All rights reserved.

High dose benzodiazepine diatry Res. (2012), doi:10.101

than the recommended therapeutic range (Ohayon and Lader,2002). Misuse of BZD can cause deficits in learning, attention, memory,depression and injurious falls, traffic and other accidents (Barker et al.,2004; Pariente et al., 2008). The risk of dependence after long-termuse has been described, as reflected in the appearance of a series ofsymptoms when the drug is abruptly withdrawn (De Las Cuevas et al.,2000; Ashton, 2005). In addition to subjects that begin using BZDs totreat anxiety and insomnia disorders and end up using them inappro-priately, there are subjects that deliberately misuse BZDs. In this caseBZDs taken in an attempt to fight anxiety or increase the effect ofother drugs such as alcohol or opioids form part of a polydrug use pat-tern (Darke, 1994; Crane and Lemanski, 2004; O'Brien, 2005).

Withdrawal syndrome can occur even from regular therapeuticdoses of BZDs. It can be severe and in some cases may preclude thepatient from ceasing the use of the drug (Ashton, 2005; Lader et al.,2009). The reported incidence varies between 30 and 100% in differentstudies (Ashton, 2005). Many symptoms are common to anxiety statesin general: insomnia, anxiety, panic attacks, poor memory and concen-tration, restlessness, palpitations, tremor, etc. Others are more specificto BZD withdrawal such as perceptual distortions, depersonalization,hallucinations, excitability, distortion of body image, hypersensitivity,psychotic symptoms, and convulsions.

ependence: Description of 29 patients treated with flumazenil infu-6/j.psychres.2012.02.008

2 G. Quaglio et al. / Psychiatry Research xxx (2012) xxx–xxx

The severe discomfort experienced by patients stopping long-term BZD use led to the development of treatment strategies for dis-continuing these medications (Denis et al., 2006; Voshaar et al.,2006). The common management of BZD withdrawal syndrome in-cludes, either individually or in combination: i) a gradual taperingof the drug; ii) switching to an equivalent dose of a long half-lifeBZD before tapering withdrawal (Denis et al., 2006; Lader et al.,2009) and iii) adding medications prior to detoxification and continu-ing those medications after discontinuation (Rickels et al., 1990;Denis et al., 2006). A potential approach of particular pharmacologicalinterest is the abrupt discontinuation of the medication and a rapidBZD detoxification using flumazenil. Flumazenil is commonly usedin the treatment of BZD overdose; it is usually considered a BZD an-tagonist (Thomson et al., 2006). When compared with placebobolus infusion of flumazenil (1 mg in 5 min) produced effects consis-tent with BZD withdrawal in BZD users (Mintzer et al., 1999 ; Mintzerand Griffiths, 2005). Nonetheless, results of studies in chronic BZDusers who have discontinued BZD use suggest that multiple slowbolus infusions of flumazenil reduce the symptoms of withdrawal(Saxon et al., 1997; Gerra et al., 2002; Quaglio et al., 2005; Hood et al.,2009; Lugoboni et al., 2011).

It is not completely understood how flumazenil acts in reducingthe withdrawal effects. γ-aminobutyric acid (GABA) is the main in-hibitory neurotransmitter in humans. GABA exerts the majority ofits effects through ionotropic GABAA receptors. BZD binds to amodula-tory site on the GABAA receptor complex, enhancing (agonist action)GABAA activity. Chronic high dose use of BZD causes allosteric alter-ations of the sites for BZD reducing the affinity between the site forBZD and site for GABA in the GABAA complex (Klein et al., 1994; Aliand Olsen, 2001). Flumazenil appears to be able to up-regulate GABAA

receptors. Different potential mechanisms have been suggested thatmight up-regulate expression of receptors of the cell surface: i) exocy-tosis of intracellular receptors; ii) decreasing receptor endocytosis anddegradation; and iii) de novo synthesis of receptor subunits(Jazvinscak et al., 2008).

BZDs have differences in pharmacodynamic and pharmacokineticprofiles that explain their different therapeutic properties. There areBZDs with fast-acting anxiolytic properties and BZDs which can actas long-acting anticonvulsants. Their different behaviours can beused as an indicator of their potential of abuse (Poisnel et al., 2009;Liebrenz et al., 2010). For example, BZDs requiring metabolism (inthe form of a prodrug active metabolite mechanism) appear less like-ly to be abused. Differing distribution half-lives and lipid solubilitieswhich allow BZDs to pass the blood–brain barrier more or less easilyseem to be of critical importance. BZDs with a slower onset tend to beabused less often (O'Brien, 2005; Liebrenz et al., 2010). The profile ofclonazepam suggested that this drug would be effective as an anti-convulsant and a type of substitutive treatment after detoxificationfrom high doses of BZDs.

Co-morbidity with depression is a common problem in patientswith anxiety and insomnia. On the basis of their ability to down-regulate mono-aminergic receptors and to reduce both depressionand anxiety levels antidepressants might have benefits as adjunctivetherapy in BZD detoxification treatment (Denis et al., 2006; Lader etal., 2009).

Clinical trials for registration of new drugs and treatments are fre-quently criticised for relying on highly selected sample populations(Sacristan et al., 1998; Hood et al., 2009). The previous experiencewith flumazenil infusion in a controlled clinical setting of one of theauthors (Gerra et al., 2002), suggested the rationale for applying themethod in a more “real clinical context”. We present here an observa-tional case-series of flumazenil infusion procedure and stabilisationusing clonazepam and antidepressants in 29 BZD dependent patientsin an in-patient setting. The treatment population had high levels ofBZD use, including polydrug habits and were under other pharmaco-logical treatments. The outcome of this naturalistic-type intervention

Please cite this article as: Quaglio, G., et al., High dose benzodiazepine dsion and stabilised with clonazepam, Psychiatry Res. (2012), doi:10.101

was: i) the evaluation of the degree of compliance during the treat-ment (number of subjects which drop out); ii) the acceptability ofthe procedure in terms of tolerance; iii) the long term responsethrough a follow up to 6 months.

2. Methods

2.1. Subjects

The study describes our early (first 30 months) experience with flumazenil infu-sion. All patients described had a history of BZD dependence according to Diagnosticand Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria(American Psychiatric Association, 2000). Before hospitalisation, all patients wereinterviewed by a physician to evaluate the degree of BZD dependence and generalhealth conditions. Subjects were informed that the treatment might help them with-draw and abstain from BZD. However, they were warned that they might experiencebrief, unpleasant symptoms during treatment. All patients had voluntarily contactedthe Addiction Unit of Verona University Hospital and were aware of their BZD depen-dence. Patients were included for the treatment if: i) they had been taking BZDs in nontherapeutic doses (>30 mg per day of diazepam or equivalent); ii) they had been takingBZDs continuously for a period ofmore than6 months; iii) the patient had previously triedto taper the BZD dosage, under medical supervision and had failed due to the develop-ment of withdrawal symptoms. Individuals were excluded if: i) they currently abused il-licit drugs, defined as a history of illicit drug dependence or abuse within the previous6 months (however patients with history of heroin dependence who had been stabilisedwith substitutive treatment were considered eligible for the treatment); ii) they had ac-tive medical illnesses or psychosis, or if iii) they had a previous history of seizures, butnot due to BZD withdrawal.

In our first 30 months of experience with flumazenil, 62 subjects contacted the Ad-diction Unit of Verona University Hospital with problems of BZD dependence. Twelvepatients were ineligible due to a poorly stabilised concomitant dependence on a sub-stance other than BZD, six patients consumed a dose of BDZb30 mg per day of diaze-pam or equivalent and four patients were subjects with psychosis that was notadequately stabilised. In addition, a group of patients were treated with flumazenilbut excluded from the present analysis because they were taking either carbamazepine(four subjects) or valproate (three patients) which can be a confounding factor in theevaluation of the withdrawal score; one patient was excluded because he had receivedtreatment twice; and three were not included because they received detoxificationtreatment simultaneously for BDZ and opiates. The treatment of the remaining 29 pa-tients is presented here. The patients gave written informed consent before beginningthe treatment. The treatment was approved by the Institutional Review Board.

2.2. General procedures

Physical examination, blood sample (aspartate aminotransferase (AST), alanineaminotransferase (ALT), liver function tests, creatinine, hemocrom), Electrocardiogram(ECG) and personal medical history were collected for all patients at the beginning ofthe treatment. Physiological measures, including blood pressure, heart rate and respi-ratory rate, were monitored daily during the detoxification procedure. A forearm veinwas kept open, utilising a stable catheter to avoid daily punctures.

To assess possible flumazenil-induced withdrawal effects, a total withdrawal scorewas derived from 33 subject-rated symptoms that have been shown to be indicative ofBZD withdrawal in previous studies (Griffiths et al., 1993; Gerra et al., 2002; Mintzerand Griffiths, 2005). The subject rated each item on a five-point scale from 0 (not atall) to 4 (extremely). The symptoms presented in the subject-rated withdrawal scalewere: confused or disorientated, dizzy or lightheaded, weaker than usual, difficultyconcentrating, blurred vision, tired, tense, hungry, aches or pains, heart pounding orbeating faster than usual as in influenza, hands feeling trembly, nervous or anxious, afeeling of unreality, muscle or stomach cramps, headachy, pins and needles, musclestwitching involuntarily, irritable or grumpy, nauseated, fearful or apprehensive, noisesand sounds seeming louder than usual, sweaty, as if the subject was moving or thingswere moving around him, shaky or jittery, detached or withdrawn, sore eyes, de-pressed, unable to control movements, lights seeming brighter than usual, smellsseeming stronger than usual, peculiar taste in the mouth, more sensitive to touchthan usual. In order to assess the magnitude of possible withdrawal symptoms, anoverall withdrawal score was calculated by combining the ratings of the 33 symptoms.

2.3. Treatment

The BZD used chronically was stopped on day 1 of admission. Subjects were trea-ted with flumazenil 1 mg in 500 ml saline, infused with 50–60 ml/h from 8 h to 22 hfrom day 1 to the last day of treatment, with a mobile infusion pump (with a potentialmaximum daily dose of 1.6 mg/day). The therapeutic approach is referred to previousexperience with flumazenil infusion in BZD medically supervised withdrawal (Gerra etal., 2002; Quaglio et al., 2005). The decision to not use flumazenil during the night wasmade in order to improve the quality of sleep. The patients were told that they couldask to slow down or stop the infusion at any point during administration if they felt un-comfortable. In addition to flumazenil, the treatment involved the administration ofclonazepam, at dose of 2–6 mg/day before sleeping. Anti-depressant medications

ependence: Description of 29 patients treated with flumazenil infu-6/j.psychres.2012.02.008

3G. Quaglio et al. / Psychiatry Research xxx (2012) xxx–xxx

were also prescribed: 3 weeks before hospitalisation or the first day of admission for 14patients, potentiated or modified for three subjects during the first day of admissionand continued for the 12 patients who arrived to our observation already in antidepres-sant therapy. In themajority of cases selective serotonin re-uptake inhibitors (citalopram,paroxetine and sertraline), were used. The therapy with clonazepam and antidepressantwas continued after discharge. After discharge, patients were followed-up as outpatientsfor the management of the gradual tapering of clonazepam. Relapse rate of BZD depen-dence was evaluated 6 months after detoxification. The recurrence of dependence wasassessed through face-to-face interviews.

2.4. Statistical analysis

Given the small sample size, differences in the distribution of categorical factorswere assessed by Fisher's exact test and differences in the distribution of continuousvariables were assessed by means of the Wilcoxon's rank sum test. The trend of thewithdrawal symptom scores over the 8 days of treatment was assessed with a linearregression model on the daily median scores. Daily median and their 95% confidenceintervals (95% CI) were obtained and the difference of score distributions betweenthe group of patients for whom a temporary reduction/suspension of the flumazenil in-fusion was required and in the group of patients for whom flumazenil infusion wasgiven without cessation was assessed separately for each day with a Wilcoxon ranksum test. Alpha was set a 0.05. All statistical analyses were performed using the R sta-tistical package version 2.12.2 (The R foundation for Statistical Computing, 2011).

3. Results

Twenty-nine patients were treated with flumazenil of whom 20(69%) were female, with a median age of 38 years (range 25–61).Nineteen patients (65%) had been diagnosed with generalized anxi-ety disorder and eight (28%) with insomnia; 27 (93%) showed de-pressive trait symptoms. Their general characteristics are show inTable 1. Lormetazepam and lorazepam were the BZDs most frequently

Table 1General characteristics of the 29 patients treated with flumazenil.

Variable No. %

GenderMale 9 31Female 20 69

EmploymentEmployed 9 31Unemployed 20 69

Education≤8 years 18 62>8 years 11 38

Contact with the hospital viaPCDUa 12 41General practitioner 3 10Internet 2 7Others 12 41

Source of the BZDb

Pharmacist without prescription 21 72General practitioner 10 34Other doctor 5 17Doctor in the PCDU 3 10Falsification of prescription 4 14

Psychiatric diagnosisInsomnia 8 28Anxiety 16 55Anxiety with panic disorder 3 10Dysthymia or depression NOSc 27 93Dependenced 15 52Somatoform disorders 1 3Psychotic disorders 3 10Personality disorders 7 24

Dependenced,e

None 14 48Heroin 12 41Cocaine 1 3Alcohol 2 7

a Public centre for drug use.b More than one answer was allowed.c Not otherwise specified.d Dependence in addition to that of BZD.e The substance reported here is the primary substance of use in addition to BZD.

Please cite this article as: Quaglio, G., et al., High dose benzodiazepine dsion and stabilised with clonazepam, Psychiatry Res. (2012), doi:10.101

used (Table 2). The BZD daily dose (converted to diazepam equivalent)in the 3 months prior to treatment ranged from 38 to 1800 mg per day(median 333 mg/day). The daily dose was higher in the group of pa-tients with anxiety compared to subjects with insomnia (340 vs.246 mg/day, p value=0.668). The duration of chronic BZD use rangedfrom 6 to 396 months (median 84). The length of BZD in months washigher in the group of patients with anxiety compared to subjectswith insomnia (156 vs. 66 months, p value=0.023). Patientswere trea-tedwithflumazenil for amedian of 7 days,with 1.35 mg/day andwith amedian time of 13.4 h/day. In nine patients (31%) withdrawal symp-toms required the temporary reduction/cessation of the infusion. Thetemporary reduction/cessation of the flumazenil infusion was morecommon during the first 3 days of treatment.

Fig. 1 shows the reduction of the withdrawal symptom scoresmeasured from the first to the last day of the treatment. The medianwithdrawal score was 27.5 (95% CI: 18.5–31.0) at day 1 and8 (6.0–13.0) at the end of the treatment. The linear trend in the reduc-tion of the daily withdrawal scores in the overall study population (29patients) was significant (p valueb0.0001), with an average decreaseof 2.90 points per day. Similarly, significant decreasing trends werealso observed in the group of patients for whom a temporary reduc-tion/suspension of the flumazenil infusion was required (nine patients)(p valueb0.0001) and in the group of patients for whom flumazenil in-fusionwas given without cessation (20 patients) (p valueb0.0001). Forevery single day, higher withdrawal symptom scores were observed inthe group of patients for whom flumazenil infusion was given withoutcessation compared with patients for whom a temporary reduction/suspension was required (p values ranged between 0.0002 and0.0373) (Fig. 1).

Six months after treatment, 15 patients (52.9%) were abstinentfrom clonazepam and other BZDs, nine patients (26.5%) were usingclonazepam at a therapeutic dosage under the care of a physicianand five (20.6%) were using BZDs different than clonazepam and athigher than therapeutic dosages (dependence reinstatement).

Table 2Type and modality of assumption of BZD among the 29 study patients treated withflumazenil.

Parameter Number %

Type of BZDLormetazepam 12 41Lorazepam 11 38Zolpidema 5 17Alprazolam 3 10Bromazepam 1 3Triazolam 1 3Diazepam 2 7Etizolam 1 3Ketazolam 1 3

Number of BZD used1 23 792 or more 6 21

Assumption of BZDOral 24 83Injecting 4 14Sniffing 1 3

Median Range

Diazepam-equivalent dose mg/dayAll patients 333 38–1800Patients with anxiety 340 38–1800Patients with insomnia 246 53–1200

Length of BZD use, monthsAll patients 84 6–396Patients with anxiety 156 6–396Patients with insomnia 66 12–144

a Zolpidem is technically not a BZD.

ependence: Description of 29 patients treated with flumazenil infu-6/j.psychres.2012.02.008

0

5

10

15

20

25

30

35

40

45

50

day 1p=0.0002

day 2p=0.0002

day 3p=0.0002

day 4p=0.0008

day 5p=0.0011

day 6p=0.0014

day 7p=0.0373

day 8p=0.0215

With

draw

al s

ympt

om s

core

s

Fig. 1. Scores of withdrawal symptoms measured during treatment in the overall studypopulation (solid black line, all 29 patients); in the group of patients in which a tempo-rary reduction/cessation of the flumazenil was required (dashed line, nine patients)and in the group of patients in which flumazenil infusion was administered without re-duction/cessation (dotted line, 20 patients). Values are expressed as the median scoreper day with 95% confidence intervals (95% CIs). On the x-axis, the p-value of the Wil-coxon rank sum test for the difference in the score distributions between the twogroups is reported for each day of treatment.

4 G. Quaglio et al. / Psychiatry Research xxx (2012) xxx–xxx

4. Discussion

These clinical data indicate that approximately two-thirds of thesubjects tolerated the procedure well and approximately half had agood long term response. Flumazenil infusion appears effective inpeople who are stabilised as in-patients on clonazepam and antide-pressants. The withdrawal syndrome was problematic in nine pa-tients, requiring a temporary reduction/cessation of the infusion.Other studies that used the same approach with slow infusion didnot report these complications (Gerra et al., 2002; Hood et al.,2009). In these previous studies tapered doses of oxazepam wereused: it is likely that oxazepam is a medication that treats anxietysymptoms better than clonazepam in withdrawal syndromes.

Because of the possibility of withdrawal reactions, based on our ex-perience treatment with flumazenil is recommended in a residentialsetting. As already mentioned, the role of flumazenil remains unclear.Its action may facilitate coupling of the GABAA and BZD receptor com-plexes, potentially reversing the down-regulation/uncoupling that oc-curs with long-term BZD misuse (Ali and Olsen, 2001). This couldexplain its ability to attenuate withdrawal symptoms after chronic ex-posure to the drug, since it exercises weak agonistic action on thenow normalised BZD receptor (Gerra et al., 2002). Drug use in dosesof 100 μg/h for an average of 14 h/day is an infusion level that is likelyto reach only a small number of receptors at any one time. This is con-sistent with the gradual improvement that occurs the longer the infu-sion is administered.

Although the withdrawal syndrome required the reduction of theinfusion and in some cases the temporary cessation, no patients with-drew from the treatment. Retention in treatment is a problem fre-quently observed in tapering medication, because of increasedsymptoms which preclude further reduction at the planned time(Denis et al., 2006). Retention in treatment with flumazenil is appar-ently more favourable compared to other methods of abrupt with-drawal using other medications such as propanolol, buspirone andhydroxizine (Lader and Olajide, 1987; Cantopher et al., 1990;Lemoine et al., 1997).

The severity of BZD withdrawal may be a consequence of: i) doseof BZD pre-treatment (Rickels et al., 1983; Roy-Byrne and Hommer,1988); ii) pre-treatment duration of BZD (Griffiths et al., 1993); iii)the half-life of BZD (the withdrawal symptoms tend to be more se-vere with shorter half-life BZDs) (O'Brien, 2005; Rosenbaum, 2005);iv) dose and rate of flumazenil infusion (Gerra et al., 2002); and v)

Please cite this article as: Quaglio, G., et al., High dose benzodiazepine dsion and stabilised with clonazepam, Psychiatry Res. (2012), doi:10.101

psychiatric comorbidity and the context in which BZD is used(Bernik et al., 1998; Brady et al., 2003; O'Connor et al., 2004;Ashton, 2005). Given that the small sample size gave limited powerto detect differences, no statistical analysis was performed to analysethe factors which may have exacerbated withdrawal symptoms insubjects whose infusion was stopped, compared with those whose in-fusion continued.

The view that flumazenil resets the receptor's set-point appearsinconsistent with findings that repeated flumazenil administrationdoes not restore sensitivity to the sedative effects of BZDs after toler-ance to these effects has developed with chronic use (Mintzer andGriffiths, 2005). This has also been our clinical observation. Therefore,while the efficacy of flumazenil in patients attempting to discontinuechronic BZD use is interesting, further research is needed to under-stand the mechanisms and the consistency of the tolerance effects.

Many of the patients treated are polydrug users in opiate substitu-tion treatment. In contrast to another recent report (Hood et al.,2009) we did not find any effect of the flumazenil treatment in signif-icantly reducing the use or craving for other substances. Additionalstudies are needed on this issue.

4.1. The use of clonazepam and antidepressants

The use of BZDs, albeit at therapeutic dosage, raises concernsabout the capacity of some patients to maintain control of theirdrug use in the long term (Kurihara, 2007). Clonazepam, because ofits pharmacological profile – a slow onset of action, half life of18–50 h, lacking active metabolites (Estivill et al., 2003; Chouinard,2004) – was beneficial in these patients during and after treatmentas an anxiolytic and anticonvulsant. The idea of a maintenance ap-proach in patients with BZD dependence is not new. Albeck (1987)describes a potential role of clonazepam in detoxification from BZDdependence. O'Brien suggests that the continuation of BZD treatmentmight be the most viable option if discontinuation is especially dis-tressing for patients due to extremely high dependence or the recur-rence of rebound anxiety after several attempts to discontinue BZDs(O'Brien, 2005). Liebrenz et al. (2010) argue that the high number ofpatients receiving prescriptions for BZDs in higher than recommendeddoses suggests that, although not named as a substitution treatment, amaintenance treatment approach is, in clinical reality, already carriedout. Nevertheless, the potential misuse and abuse of clonazepam isrecognised (Frauger et al., 2009; Steentoft and Linnet, 2009). Therefore,we evaluated the opportunity to replace BZDs with different adjunctivetherapies: anticonvulsants are increasingly being tested as medicationsfor a more rapid and safer BZD tapering (Rickels et al., 1999; Ashton,2005; Croissant et al., 2008; Lader et al., 2009).

In the case of antidepressants, they are generally well toleratedwithout a risk of dependence or abuse. A more precise psychiatric di-agnosis, particularly at primary care level, with a more accurate use ofantidepressants, could be useful for reducing the number of patientschronically using BZDs. For example, when insomnia is secondary todocumented depression, priority should be given to antidepressanttherapy (Thase, 2000; Estivill et al., 2003). In subjects with severemental disorders, the absence of concomitant antipsychotics andmood stabilisers is a risk factor for long-term BZD use (Veronese etal., 2007). Furthermore, panic attacks which can be effectively treatedwith serotoninergic antidepressants are still improperly treated withBZDs.

4.2. Research implications

In spite of its potential benefits, a number of aspects of this thera-peutic approach need to be clarified. With respect to the inclusion cri-teria, questions that could be posed are: what is the minimumdiazepam-like BZD dosage threshold for recommending flumazeniltreatment, and what is the minimum time of continuous use of BZD

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beyond which the flumazenil treatment can be recommended?Should patients with a history of seizures be excluded from the treat-ment? Should the treatment be used only after tapering detoxifica-tion has failed? As regards the treatment: could increasing the timeof infusion per day or decreasing the dosage of flumazenil be suitablestrategies for reducing the discontinuation syndrome? It will be nec-essary to better elucidate the end point of the treatment: after howmany days could the treatment be considered concluded? Is a slowsubcutaneous infusion of the medication a potential modality oftreatment? Although a promising strategy the opportunity to use ad-junctive medications (anticonvulsants, antidepressants, etc.), needsto be explored further and more clearly defined.

4.3. Limitations of this case series

This study has several limitations: i) it was conducted in a clinicalsetting, without double blinding, randomisation or reference to a con-trol group. To the best of our knowledge, there is only one study thatcompares flumazenil infusion with a control (Gerra et al., 2002). Inthat study flumazenil infusion was compared with a control groupof oxazepam tapering and placebo. In comparison with oxazepamand placebo, flumazenil reduced withdrawal symptoms on both self-reported and observer-rated withdrawal scales. Flumazenil also re-duced craving scores during the detoxification procedure. In addition,during oxazepam tapering patients experienced paradoxical symptomsthat were not apparent in flumazenil patients. However, it should bementioned that the study was single blinded which may limit the con-clusions that can be drawn from it. Others potential limitations of thiscase series that need to be taken into account are: ii) the limited samplesize; iii) the multiple parallel treatments; iv) and the possibility that inthe follow-up period, subjects who returned to substance use did notreport it. In addition, as this report is naturalistic, we are aware of thedanger of over-interpreting analysis of observational datasets. Nonethe-less, these are limitations commonly cited in studies carried out in thistype of setting and with these patients, many of them with polydrughabits.

5. Conclusion

This report presents data on the use of flumazenil in BZD depen-dent subjects, representing a step forward in the elucidation of thepotential and limitations of this treatment in a “real life” context.This is a naturalistic-type intervention, usual in studies of this patienttype to enhance clinical applicability. Slow-withdrawal appears apromising approach in peoplewhohave stabilised as in-patients on clo-nazepam and received early treatment with antidepressants. Flumaze-nil infusion needs further refinement before becoming a possibletreatment. Nonetheless, it may be an alternative to tapering detoxifica-tion treatment. The use of flumazenil may be particularly useful forhigh-dose BZD users, in situations where BZDs are part of a polydruguse pattern, in subjects with psychiatric disturbances and in patientsfor whom compliance with gradual scale-down methods is difficult. Anumber of issues remain to be clarified through the course of further re-search such as carrying out double blind studieswith flumazenil vs. pla-cebo, flumazenil plus clonazepam vs. flumazenil plus anticonvulsants,flumazenil and clonazepam vs. anticonvulsants alone, etc.

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