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Off-Label Use of Medications for Treatment of Benzodiazepine Use Disorder Pamela Sabioni1, Jonathan Bertram2 and Bernard Le Foll1-7* 1
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada; Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, ON, Canada; 3Campbell Family Mental Health Research Institute, CAMH, Toronto, ON, Canada; 4Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; 5Department of Pharmacology, University of Toronto, Toronto, ON, Canada; 6 Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada; 7 Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada 2
Abstract: There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multiple indications (anxiety, seizures, alcohol withdrawal, muscular relaxation and anesthesia). Benzodiazepines are also adPamela Sabioni dictive substances and a non-negligible fraction of regular users will develop dependence. There is currently no approved pharmacotherapy for benzodiazepine use disorder treatment and optimal strategies for treatment are unclear. In this review, we aimed to summarize the findings on off-label pharmacologic therapy that have been used for BZD dependence. One classical approach is to provide a slow taper associated with counseling. Anti-epileptic drugs appear also to alleviate symptoms of withdrawal. The long-term strategies of maintenance therapy (with benzodiazepine) or of blocking therapy (with a GABA antagonist such as flumazenil) could provide some clinical benefit but have not yet been tested appropriately. Pregabalin appears promising and deserves further investigation. There is a clear need for more clinical trials in this area to improve care.
Keywords: Off-label, medication, benzodiazepine, dependence, treatment, pregabalin, replacement, agonist. INTRODUCTION Benzodiazepines (BZD) are substances approved for the treatment of anxiety and insomnia; for the control of seizures, as adjunctive agents in anesthesia and as muscle relaxants [1]. In the USA, according to the NIDA (National Institute on Drug Abuse), 4.3% of the population had used benzodiazepines in the last year, and the National Survey on Drug Use and Health (2012) pointed that there were 252, 000 new users of benzodiazepines between 2009 and 2010. Additionally, according to the Substance Abuse and Mental Health Services Administration in 2012, 7.6% of the drug treatment admissions in the adult population involved benzodiazepines and the prevalence of use, abuse and dependence of benzodiazepines among the general population is around 4.5%. In Canada, the 2011 Canadian Alcohol and Drug Use Monitoring Survey indicated that over 9% of respondents had used sedatives or tranquilizers in the past year. Benzodiazepine effects are produced via the allosteric modulation of GABAA receptors, with the final result of increasing the effectiveness of gamma-aminobutyric acid (GABA) transmission. GABA is the most widespread inhibitory neurotransmitter of the central nervous system [2]. The onset of action of benzodiazepines depends on the pharmacokinetic characteristics of specific compounds [1, 3]. For example, diazepam is one of the most lipophilic benzodiazepines reaching the brain very quickly following oral administration, resulting in a higher abuse liability risk compared to other agents [4]. Among the prescriptions drugs, the two most frequent reported for their addictive potential are benzodiazepines and opioid drugs (data from Drug Abuse Warning Network; http: //www.nida.nih.gov). It is estimated that around 20% of the benzodiazepine’s regular users become dependents [5]. According to the DSM-V, the benzodiazepine use disorder is characterized by its use *Address correspondence to this author at the Centre for Addiction and Mental Health, 33 Russell Street, Toronto, Canada M5S 2S1; Tel: 416-5358501; Ext: 34772; Fax: 416-595-6922; E-mail:
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in larger amounts or longer than was intended; a persistent desire or unsuccessful efforts to cut down or control use; a great deal of time spent in activities necessary to obtain the drug; giving up or reducing important social, occupational, or recreational activities because of its use; continued use despite causing problems in relationships and knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by benzodiazepines, needing larger amounts to get the desired effect (tolerance) and the development of withdrawal symptoms [6]. It appears that BZD are able to stimulate the dopaminergic pathway and that this could be a contributor to its addictive potential (see the review of Tan et al. for discussion on the neurobiological mechanisms underlying benzodiazepine addiction [7]). The chronic use of benzodiazepines may decrease the efficacy of GABAA receptors, which contributes to the development of tolerance, and abrupt discontinuation may cause a withdrawal syndrome characterized by intense anxiety, agitation and insomnia, memory and concentration impairments, among other symptoms [5]. This withdrawal is frequent with an incidence reported between 30 and 100% in different studies [8] and with potential high severity. The non-prescribed use of benzodiazepines can be associated with the use of illicit drugs and alcohol. In such circumstances, the symptoms of dependence may develop faster [1]. It has been debated that there are two basic forms of benzodiazepine dependence(a) inappropriate use arising from BZD treatment of sleep and anxiety disorders, as well as (b) those who use BZD for recreational purposes [9]. The resulting high dose dependence that often requires treatment is due to the resulting declining motor performance, cognitive impairment, and personality changes that can ensue. Some reviews on discontinuation of long-term BDZ use were performed and demonstrated that gradual BZD dose reduction (GDR) is a good strategy, and that the addition of pharmacological and/or psychological treatments to GDR have shown some effectiveness [10-12]. There is also evidence that some medications might be helpful for BZD discontinuation when used “off-label”, meaning that the drug is being used in a manner not specified by the Food and Drug Ad© 2015 Bentham Science Publishers
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ministration (FDA). In this review, we aimed to compile and summarize the findings on off-label use of pharmacotherapies that have been used to discontinue the long-term use of BZD, and are also helpful in alleviating or decreasing the occurrence of withdrawal symptoms. ADJUNCTIVE TREATMENTS TO ALLEVIATE WITHDRAWAL The principal approach used so far for treatment based on assisting users to go through the BZD withdrawal in a comfortable way and subsequently to help them maintaining abstinence (using mostly behavioral approaches). The intensity of withdrawal is usually reduced if subjects taper gradually their BZD [9] and this is usually done over several months as BZD withdrawal can be very severe and long lasting. Another possibility is to decrease the intensity of withdrawal symptoms by using adjunctive treatment. The adjunctive treatments for benzodiazepine withdrawal fall into two main groups. The administration of drugs that are cross-tolerant with the BZD from which withdrawal is being attempted has shown some benefits. This includes other BZDs and barbiturates [13]. The second category consists of agents that alleviate some of the withdrawal symptoms by alternate mechanisms. We will summarize here the findings into this area by class of drugs, with a focus on pregabalin, which has shown some promising effects recently. PREGABALIN Recent evidence supports the use of pregabalin for the treatment of benzodiazepine withdrawal. Pregabalin has a mechanism of action distinct of benzodiazepines, binding to the alpha-2-delta subunit of the presynaptic neuron's voltage-gated calcium channels. It modulates the activity of over-excited neurons, resulting in a decrease in the release of neuroexcitatory neurotransmitters including glutamate, substance P, calcitonin gene-related peptide, and monoaminergic neurotransmitters and possibly returns to a “normal” physiologic state [14-16]. Pregabalin has no clinically significant effects at GABA receptors, and it is not converted metabolically into GABA or a GABA agonist, even with its structural analogy to GABA [17, 18]. The interest in the clinical effects of pregabalin reducing benzodiazepine withdrawal is recent, initiated with some case reports in 2007. Preliminary findings demonstrated discontinuation of BZD use and decrease of anxiety levels in long-term BZD users within few weeks of treatment with pregabalin [19, 20]. From those results, Oulis and colleagues developed a small open-label study with the objective of testing the pregabalin effects on the BZD discontinuation and cognitive functions. Fifteen patients with chronic BZD dependence (DSM-IV), with a mean duration of BZD use of 13 years were enrolled in this study. Participants fully transitioned from BZD to pregabalin in an average of 5.5 weeks, whereas the pregabalin dosage ranged from 225 to 900 mg/day, at a mean of 465 mg/day. Furthermore, patient’s scores on the Hamilton Anxiety Scale (HARS) and on the Depression Scale (HDRS) [21, 22], both decreased by over 50%, whereas their Mini Mental State Examination [23] increased by 9.4% [20]. Although these preliminary findings are promising, this study had several limitations. First, the sample size was small and second, this was an open study with no control group or randomization. Furthermore, some confound factors might have been involved in the interpretation of the results, for example, the concomitant use of other medications, mainly antidepressants, that could interfere with the pregabalin therapeutic and side effects. A secondary analysis of an uncontrolled observational study [24] on the effects of pregabalin on the discontinuation of the longterm use of BZDs provided the findings demonstrated by Rubio and colleagues in 2011 [25]. Patients who met the DSM-IV-TR BZD dependence criteria were selected to the study. The aims of this secondary analysis were to analyse the effect of pregabalin on the
Sabioni et al.
subjective sleep quality and disturbance symptoms from the benzodiazepine withdrawal, and the correlation between the sleep changes with changes in withdrawal symptoms, anxiety and severity of disease. The BZD tapering followed the gradual titration of pregabalin to completely withdrawn of BZD after 4 weeks. The final sample size consisted of 211 participants with a dose of 315 mg/day of pregabalin at the end of the study. The success rate, evaluated by the Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ), between the participants that completed the 12week follow-up was 70%. Patients demonstrated significant improvement of anxiety symptoms throughout the study (69% decrease from the baseline score in the HARS). In addition, there was a clinically significant improvement of 55% on the Medical Outcomes Study Sleep Scale (MOS sleep scale) summary index and in all 6 dimensions of the MOS sleep scale. There was a low correlation between the improvement in subjective sleep measures and the improvement of withdrawal symptoms, and a moderate correlation with the improvement of anxiety symptoms and severity of disease. Regardless of the findings suggesting that pregabalin may be a promising treatment for BZD withdrawal associated with anxiety symptoms and subjective sleep quality, the study presents major limitations. First, due to the observational and uncontrolled design of the study, selection bias of patients cannot be disregarded. In addition, a good amount of patients had current psychiatric disorder (34%) and substance-related disorders (47%) other than BZD dependence. Other confound factors are that almost 40% of the patients received pregabalin in combination with other benzodiazepine, instead of as monotherapy; and over 30% received psychotherapy. Also, some studies have shown that the BZD discontinuation by itself may improve subjective sleep quality [26, 27]. The lack of a controlled design for this study jeopardizes the interpretation of the results and may lead to an overestimation of the treatment effects. To our knowledge, the first double-blind, placebo controlled trial evaluating the effects of pregabalin on the discontinuation of long-term BZD use was published in 2012 by Hadley and colleagues [28]. 106 patients that were taking benzodiazepines for 852 weeks were enrolled in the study and submitted to a stabilization phase with alprazolam treatment for 2 weeks. After this phase, the patients were randomized to either pregabalin (n=56) or placebo (n=50) for 12 weeks in a double-blinded design. Pregabalin treatment started with a dose of 75 mg B.I.D and was titrated throughout the following weeks up to the range dose of 150 – 600 mg/day, while tapering off alprazolam for a maximum of 6 weeks to complete the taper. At the end, 49 patients had completed the study; 30 in the pregabalin group and 19 in the placebo group. The findings showed that the patients treated with pregabalin presented significantly less withdrawal symptoms compared to the placebo group, both during the taper phase and for the following 6 weeks that the patients were free of BZD. Anxiety symptoms were also significantly reduced at study endpoint in the pregabalin treatment as measured by the HAM-A. In addition, the relapse rate was lower between the patients treated with pregabalin, as compared to placebo. Although, the authors suggest the low success rate has high correlation with patients dropping out prematurely, which is the main limitation of this study. However, the attrition rate due to the low efficacy in treating anxiety and withdrawal symptoms was higher in the placebo group (32%) compared to the pregabalin group (12%). Changes in cognitive functions after successful treatment of long-term BZD with pregabalin were further investigated by Oulis group [29]. Patients underwent neuropsychological assessment before the initiation of pregabalin treatment and a second time at the completion of the substitution process, at 2 months follow-up. The mini-mental state examination (MMSE) and its component subtests [23] were used to assess gross cognitive functioning followed by specific neuropsychological assessments (Cambridge
Off-Label Use of Medications for Treatment of Benzodiazepine Use Disorder
Neuropsychological Test Automated Battery). Patients also underwent the motor screening task (MOT) and paired association learning (PAL), spatial recognition memory (SRM), and intra extradimensional set shift (IED). Most cognitive measures were substantially improved, for example, MMSE scores, MOT, attention, concentration and in tests of visuospatial memory and learning involving fronto-parietal and frontal lobes (PAL and SRM, respectively). The major limitations of this study are its small sample-size, the open-label design and, above all, the lack of a control group. Although, the findings suggest that the treatment with pregabalin for the discontinuation of long-term BZD dependence facilitates the recovery of neuropsychological functioning compromised by the BZD use. ANTI-EPILEPTIC MEDICATIONS Benzodiazepine medications are known to act as anti-epileptic medications. There are a variety of drugs that have been used as anti-epileptic mediations that can also produce similar effects and has been shown to allow substituting BZD to another drug class with less abuse potential. The oldest strategy consists at using barbiturates. Nonetheless, barbiturates may cause over sedation, confusion, cognitive impairments and are also addictive. Gabapentin is an anticonvulsant drug structurally analogous to GABA, promoting GABA release. It has been demonstrated to be effective in the management of anxiety, alcohol withdrawal and pain syndromes. Gabapentin was reported effective for BZD discontinuation, in which 600 mg/daily was helpful to replace alprazolam after unsuccessful treatment with clonazepam, alleviating specially anxiety symptoms [30]. Nonetheless, this study is a case report and more structured studies on the effectiveness of gabapentin for BZD dependence are clearly needed to address its effects. Carbamazepine, another anticonvulsant drug, has also shown some evidence supporting its use as an adjunctive therapy for BZD withdrawal. Carbamazepine 200 to 800 mg/daily demonstrated to be effective in discontinuing long-term BZD use, and five weeks after taper, significantly more patients who had received carbamazepine than placebo remained benzodiazepine free, and also reported larger decrease in withdrawal symptoms [31]. ANXIOLYTIC/ANTIPSYCHOTIC MEDICATIONS Antipsychotic can have some utility to reduce anxiety, which is a classical symptom of benzodiazepine withdrawal. However, antipsychotic can also lower the seizure threshold, which could be a problem in case of benzodiazepine withdrawal. The antipsychotic cyamemazine, which has 5-HT blocking effects as well as dopamine-blocking actions, was superior to bromazepam (90% versus 75% of the patients remaining BZD abstinent) after 6 months of BZD discontinuation, demonstrating to be a good alternative to bromazepam replacement therapy [32, 33]. In contrast, the nonBZD anxiolytic, buspirone, was largely ineffective. Patients on buspirone 15 mg/day treatment for 4 weeks had markedly higher dropout rate than the placebo group and also didn’t have any improvements on BZD withdrawal symptoms [34]. LONG-TERM AGONIST THERAPY (BZD REPLACEMENT TREATMENT) By analogy with the use of methadone as a long-term agonist treatment for opioid use disorder, it could be proposed that long term BZD treatment may be required to provide some long-term stability. Indeed, treatment that is provided for short-term stability does not appear to demonstrate the achievement of long-term abstinence through discontinuation treatment in patients suffering from high dose and otherwise problematic BZD use [35, 36]. There is a paucity of alternatives to abstinence-targeted strategies for benzodiazepine dependence in the literature [10, 12]. Petrovic and colleagues developed a randomized double blind, placebo-controlled trial in a geriatric inpatient population with re-
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porting on subjective estimates of sleep quality and withdrawal symptoms while on low dose replacement BZD. Forty patients who had been using BZDs for at least 3 months fully transitioned from their average daily BZD dose to either a placebo replacement dose or low dose lormetazepam (less than half their daily average dose) over the course of 1 week. The daily dose of lormetazepam was 1 mg, equivalent to 5 mg diazepam. Patient’s sleep quality and withdrawal symptoms were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) with worse scores present in the placebo replacement group than in the low dose BZD group [37]. With the exception of 1 participant in the lormetazepam group, none of the participants discontinued treatment for the duration of the replacement therapy. The main limitations of this study were a small sample size, insufficient time spent on low dose replacement (participants were all discontinued after initial withdrawal management). Additionally, confounding factors arise from the unequal dropout rate in both treatment groups due to incidence of ongoing psychological dependence, worsening insomnia, and delirious withdrawal symptoms. While low dose replacement presents some intriguing possibilities in the context of withdrawal treatment, the question still remains as to whether low dose maintenance can provide sustainable treatment. The idea of a maintenance approach in patients with BZD dependence extends back for some time [38]. Additionally, it has been suggested that the continuation of BZD treatment might be the most viable option in attempts to prevent rebound anxiety after several attempts to discontinue BZDs [9]. Various parties have thus put forward the principle of low dose BZD substitution as a maintenance strategy [39]. As substitution therapy is an effective therapeutic approach for opiate and nicotine dependence [40, 41], there has been support for further research into this area [42]. While the number of studies exploring this avenue are not of the same number as abstinence oriented strategies, there has been interest initiated, looking at low dose maintenance especially in combination with common BZD detoxification treatment [12, 43]. BLOCKING THERAPY (GABA ANTAGONIST) Flumazenil acts as a specific benzodiazepine antagonist (neutral modulator) [44]. Primary indications for the use of flumazenil have been the management of suspected benzodiazepine overdose and sedative effects associated with general anesthesia [45]. In the context of flumazenil studies [46, 47], Quaglio and colleagues uniquely explored the response of BZD dependent individuals to flumazenil treatment in conjunction with low dose BZD [48]. Twenty-nine patients with a history of Benzodiazepine Dependence (DSM-IV) stopped the chronic use of BZD on day 1 of admission and a flumazenil infusion was administered. In addition to flumazenil, the treatment involved the administration of clonazepam, at the dose of 2–6 mg/day before sleeping. After discharge, patients were followed-up as outpatients for management of their clonazepam use. The findings showed that, after 6 months, 79.4% of patients from this group did not have dependence reinstatement (using BZDs differently from clonazepam and at higher than therapeutic dosages). Of those patients avoiding dependence reinstatement, 37.5% (9 patients) remained on a therapeutic dosage of clonazepam. Withdrawal scores were also lower in this group of patients, though this undoubtedly had its limitations because it was an evaluative condition for flumazenil infusion. However, clonazepam was beneficial in these patients after treatment as an anxiolytic and an anticonvulsant because of its pharmacological profile. In addition to the sample size, limitations must also include that this was conducted in a clinical setting without double blinding, randomization, or a control group. The use of antidepressants in some of the treatment stems and self-reporting of clonazepam use were also seen as confounding factors. It appears unclear also what produced the therapeutic response: the flumazenil administration or the long-term clonazepam treatment.
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CONCLUSION Despite a high prevalence of benzodiazepine use and benzodiazepine use disorder, there is limited number of studies performed in this area. It seems that the long-term outcomes obtained by using a slow taper followed by an abstinence phase are poor and that alternative strategies could provide some benefits. However, there is limited evidence based studies to guide clinicians in this area. It seems that treatment that mimic BZD such as various anti-epileptic have clear utility to allow attenuating withdrawal and obtaining abstinence faster than a gradual taper. Based on our current understanding of the substance use disorder processes, it is reasonable to think that long-term treatment such as maintenance therapy or blocking therapy could ‘theoretically’ provide some benefits, but there is no clear demonstration that those approaches provide clinical benefit in clinical practice. Clinicians should inform their patients at those approaches are still experimental. Based on our review, the off-label use of pregabalin for BZD discontinuation appears very promising and warrants further consideration, especially when other therapies have been ineffective. Nonetheless, the very limited number of studies prevent us to ensure that pregabalin is in fact effective for BZD use disorder, implying that more structured, double-blind, randomized, placebo controlled studies should be performed. Although the number of studies is limited, serious adverse events regarding the use of pregabalin were not reported and it demonstrated to be so far well tolerated. Even though the findings on pregabalin seem encouraging, two important factors should not be disregarded: its use as a treatment for BZD discontinuation is off-label and its safety for this condition is not yet ensured. Therefore, there is a clear need for more clinical trials in this area to improve care and alleviate the symptoms of the BDZ withdrawal.
Sabioni et al. [12] [13] [14]
[15]
[16] [17]
[18] [19] [20] [21] [22] [23] [24]
CONFLICT OF INTEREST We declare that we have no conflicts of interest. Pamela Sabioni received financial support from CNPq - Brazil (process # 245670/2012-2).
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ACKNOWLEDGEMENTS Declared none.
[27]
[25]
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Lalive AL, Rudolph U, Luscher C, Tan KR. Is there a way to curb benzodiazepine addiction? Swiss Med Wkly 2011; 141: w13277. Griffin CE, 3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J 2013; 13: 214-23. Longo LP, Johnson B. Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives. Am Fam Physician 2000; 61: 2121-8. Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry 2005; 66 (Suppl 9): 31-41. Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol 2014; 77: 295-301. Association AP. Diagnostic and statistical manual of mental disorders. Washington, D.C. 2013. Tan KR, Rudolph U, Luscher C. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci 2011; 34: 188-97. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry 2005; 18: 249-55. O'Brien CP. Benzodiazepine use, abuse, and dependence. J Clin Psychiatry 2005; 66 (Suppl 2): 28-33. Parr JM, Kavanagh DJ, Cahill L, Mitchell G, Mc DYR. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction 2009; 104: 13-24. Voshaar RC, Couvee JE, van Balkom AJ, Mulder PG, Zitman FG. Strategies for discontinuing long-term benzodiazepine use: metaanalysis. Br J Psychiatry 2006; 189: 213-20.
[28]
[29] [30] [31]
[32]
[33]
[34] [35]
Denis C, Fatseas M, Lavie E, Auriacombe M. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev 2006: CD005194. Lader M. Benzodiazepines revisited--will we ever learn? Addiction 2011; 106: 2086-109. Dooley DJ, Donovan CM, Pugsley TA. Stimulus-dependent modulation of [(3)H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther 2000; 295: 108693. Fehrenbacher JC, Taylor CP, Vasko MR. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 2003; 105: 133-41. Martinotti G. Pregabalin in clinical psychiatry and addiction: pros and cons. Expert Opin Investig Drugs 2012; 21: 1243-5. Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003; 23: 240-9. Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry 2003; 160: 533-40. Biermann T, Bleich S, Kornhuber J, Hillemacher T. Pregabalin in benzodiazepine withdrawal. Pharmacopsychiatry 2007; 40: 292-3. Oulis P, Konstantakopoulos G, Kouzoupis AV, et al. Pregabalin in the discontinuation of long-term benzodiazepines' use. Hum Psychopharmacol 2008; 23: 337-40. Hamilton M. The assessment of anxiety states by rating Br J Med Psychol 1959; 32: 50-55. Hamilton M. A rating scale for depression J Neurol Neurosurg Psychiatry 1960; 23: 56-62. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189-98. Bobes J, Rubio G, Teran A, et al. Pregabalin for the discontinuation of long-term benzodiazepines use: an assessment of its effectiveness in daily clinical practice. Eur Psychiatry 2012; 27: 301-7. Rubio G, Bobes J, Cervera G, et al. Effects of pregabalin on subjective sleep disturbance symptoms during withdrawal from longterm benzodiazepine use. Eur Addict Res 2011; 17: 262-70. Poyares D, Guilleminault C, Ohayon MM, Tufik S. Chronic benzodiazepine usage and withdrawal in insomnia patients. J Psychiatr Res 2004; 38: 327-34. Petrovic M, Pevernagie D, Van Den Noortgate N, Mariman A, Michielsen W, Afschrift M. A programme for short-term withdrawal from benzodiazepines in geriatric hospital inpatients: success rate and effect on subjective sleep quality. Int J Geriatr Psychiatry 1999; 14: 754-60. Hadley SJ, Mandel FS, Schweizer E. Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial. J Psychopharmacol 2012; 26: 461-70. Oulis P, Kalogerakou S, Anyfandi E, et al. Cognitive effects of pregabalin in the treatment of long-term benzodiazepine-use and dependence. Hum Psychopharmacol 2014; 29: 224-9. Crockford D, White WD, Campbell B. Gabapentin use in benzodiazepine dependence and detoxification. Can J Psychiatry 2001; 46: 287. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry 1991; 48: 448-52. Bourin M, Dailly E, Hascoet M. Preclinical and clinical pharmacology of cyamemazine: anxiolytic effects and prevention of alcohol and benzodiazepine withdrawal syndrome. CNS Drug Rev 2004; 10: 219-29. Lemoine P, Kermadi I, Garcia-Acosta S, Garay RP, Dib M. Double-blind, comparative study of cyamemazine vs. bromazepam in the benzodiazepine withdrawal syndrome. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 131-7. Ashton CH, Rawlins MD, Tyrer SP. A double-blind placebocontrolled study of buspirone in diazepam withdrawal in chronic benzodiazepine users. Br J Psychiatry 1990; 157: 232-8. Vorma H, Naukkarinen H, Sarna S, Kuoppasalmi K. Long-term outcome after benzodiazepine withdrawal treatment in subjects
Off-Label Use of Medications for Treatment of Benzodiazepine Use Disorder
[36]
[37]
[38] [39] [40] [41]
with complicated dependence. Drug Alcohol Depend 2003; 70: 309-14. Voshaar RC, Gorgels WJ, Mol AJ, et al. Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program. Can J Psychiatry 2006; 51: 445-52. Petrovic M, Vandierendonck A, Mariman A, van Maele G, Afschrift M, Pevernagie D. Personality traits and socioepidemiological status of hospitalised elderly benzodiazepine users. Int J Geriatr Psychiatry 2002; 17: 733-8. Albeck JH. Withdrawal and detoxification from benzodiazepine dependence: a potential role for clonazepam. J Clin Psychiatry 1987; 48 (Suppl): 43-9. Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010; 105: 1870-4. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009: CD002209. Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008: CD000146.
Received: April 9, 2015
Accepted: June 11, 2015
Current Pharmaceutical Design, 2015, Vol. 21, No. 22 [42] [43] [44] [45] [46]
[47] [48]
5
Le Strat Y. Agonist treatment in substance use disorders. Addiction 2010; 105: 2031. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23: 19-34. Hoffman EJ, Warren EW. Flumazenil: a benzodiazepine antagonist. Clin Pharm 1993; 12: 641-56; quiz 699-701. Weinbroum A, Rudick V, Sorkine P, Fleishon R, Geller E. Longterm intravenous and oral flumazenil treatment of acute diazepam overdose in an older patient. J Am Geriatr Soc 1996; 44: 737-8. Gerra G, Zaimovic A, Giusti F, Moi G, Brewer C. Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study. Addict Biol 2002; 7: 385-95. Hood S, O'Neil G, Hulse G. The role of flumazenil in the treatment of benzodiazepine dependence: physiological and psychological profiles. J Psychopharmacol 2009; 23: 401-9. Quaglio G, Pattaro C, Gerra G, et al. High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam. Psychiatry Res 2012; 198: 457-62.
