***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: PURPOSE To evaluate the effectiveness and tolerability of pregabalin in the management of the discontinuation of benzodiazepines in long-term users . SUBJECTS AND METHODS We performed a 12-week , prospect i ve , uncontrolled , non-interventional , and observational study in patients aged 18 years old or above , who met DSM-IV-TR criteria for benzodiazepine dependence without other major psychiatry disorder . Evaluations included the Benzodiazepine Withdrawal Symptom Question naire , the Hamilton Anxiety Rating Scale , the Clinical Global Impression Scale , and the Sheehan Disability Scale . A urine drug screen for benzodiazepines was performed at baseline and every 4 weeks thereafter . The primary effectiveness variable was success rate , defined as achievement of benzodiazepine-free status at week 12 according to the urine drug screen . RESULTS AND DISCUSSION The mean dose at week 12 was 315 ( ±166 ) mg/day . The success rate of the benzodiazepine taper in the primary efficacy population ( n=282 ) was 52 % ( 95 % confidence interval [ CI ] , 46 - 58 ) . Success rates for women and men were 58 % ( 95 % CI , 49 - 67 ) and 46 % ( 95 % CI , 38 - 55 ) , respectively . The success rates did not differ according to either the benzodiazepine of abuse or the presence of other substance use disorders . Significant and clinical ly relevant improvements were observed in withdrawal and anxiety symptoms , as well as in patients ' functioning . At week 12 , tolerability was rated as good or excellent by 90 % and 83 % of the clinicians and patients , respectively . CONCLUSION Our results suggest that pregabalin  is an efficacious and well-tolerated adjunctive treatment for benzodiazepine withdrawal Chronic normal-dose benzodiazepine users requesting drug withdrawal were allocated to substitution with either the new anxiolytic alpidem  ( n = 13 ) or placebo  ( n = 12 ) . During the first 2 weeks of the tapering programme , the dose of benzodiazepine was kept constant ; for the next 2 weeks it was halved and half-dose alpidem ( 25 mg twice daily ) or placebo substituted ; for weeks 5 and 6 , the benzodiazepine was discontinued and full-dose alpidem or placebo given ; next alpidem or placebo were tapered to half-dose and then finally discontinued . Regular anxiety and tranquillizer withdrawal ratings were made . Nine of 12 patients given placebo  withdrew successfully compared with four of 13 alpidem-treated patients .  Anxiety and other symptom levels increased in the alpidem but not the placebo patients . It was concluded that alpidem is not helpful in helping patients withdrawing from a benzodiazepine withdrawal perhaps because of partial agonist properties . These actions may imply a lesser propensity to induce dependence on long-term use Abstract Twenty-four volunteers ( 19 women and five men ) with insomnia and a history of chronic use of benzodiazepine hypnotics  participated in a r and omized , double blind , controlled clinical trial . The study was design ed 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 objective ly 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 aim ed 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 Objective To evaluate the association between use of benzodiazepines and incident dementia . Design Prospect i ve , population based study . Setting PAQUID study , France . Participants 1063 men and women ( mean age 78.2 years ) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up . Main outcome measures Incident dementia , confirmed by a neurologist . Results During a 15 year follow-up , 253 incident cases of dementia were confirmed . New use of benzodiazepines was associated with an increased risk of dementia ( multivariable adjusted hazard ratio 1.60 , 95 % confidence interval 1.08 to 2.38 ) . Sensitivity analysis considering the existence of depressive symptoms showed a similar association ( hazard ratio 1.62 , 1.08 to 2.43 ) . A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia . The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 ( 1.10 to 1.94 ) . Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50 % increase in the risk of dementia ( adjusted odds ratio 1.55 , 1.24 to 1.95 ) compared with never users . The results were similar in past users ( odds ratio 1.56 , 1.23 to 1.98 ) and recent users ( 1.48 , 0.83 to 2.63 ) but reached significance only for past users . Conclusions In this prospect i ve population based study , new use of benzodiazepines was associated with increased risk of dementia . The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study . Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population , indiscriminate widespread use should be caution ed against Withdrawal from hypnotics can produce a variety of problems , especially sleep difficulties , some of which may arise from the multiple actions of most hypnotics , thus producing a range of rebound effects . This study examined whether switching patients to a hypnotic with a narrower range of action and of a different class would reduce these problems . One hundred and thirty-four patients participated ; they were r and omly allocated to one of three methods of switching from " previous hypnotic " to zopiclone ( a cyclopyrrolone ) . The methods were gap ( an interval between taking the two drugs ) ; abuttal ( taking zopiclone immediately on stopping previous drug ) ; and overlap ( gradually reducing previous drug after starting zopiclone ) . The main findings were that zopiclone was associated with better sleep and increased alertness ; the abuttal method was the best method of switching ; and no serious side effects from zopiclone were reported . It was concluded that zopiclone has a useful role in benzodiazepine withdrawal , and that immediate substitution is the best method ABSTRACT Background : Benzodiazepine use disorders are a common clinical problem among methadone maintenance treatment patients and have adverse effects on clinical outcomes . Objectives : To evaluate gabapentin for the outpatient treatment of benzodiazepine abuse or dependence in methadone maintenance patients . Methods : Participants ( n = 19 ) using benzodiazepines at least 4 days per week were enrolled into an 8-week r and omized double-blind placebo-controlled outpatient pilot trial . All participants received a manual-guided supportive psychotherapy aim ed to promote abstinence . Study medication was titrated over a 2-week period to a maximum dose of gabapentin 1200 mg or placebo three times a day . Benzodiazepine use was assessed using urine toxicology confirmed self-report .  Benzodiazepines were not provided as part of study participation ; participants were provided guidance to gradually reduce benzodiazepine intake . Results : Sixteen participants had post-r and omization data for analysis . Retention at week eight was 50 % . The mean dose of gabapentin achieved by titration was 2666 mg/day ( SD = ± 1446 ) . There were no significant between group differences on benzodiazepine use outcomes ( amount benzodiazepine per day [ Mann-Whitney U = 27 , p = 0.745 ] , abstinent days per week [ U = 28 , p = 0.811 ] ) and Clinical Instrument Withdrawal Assessment (CIWA)-benzodiazepines scale ( U = 29.0 , p = 0.913 ) . One participant in the gabapentin group discontinued study medication because of peripheral edema . Two participants in the placebo group requested admission for inpatient detoxification treatment . Conclusion : In outpatient methadone-maintained patients with benzodiazepine use disorder  , gabapentin did significantly decrease benzodiazepine use relative to placebo . The small sample recruited for this trial may have limited the ability to detect a group difference Ten long-term users of benzodiazepines ( average daily dose , 20 mg of diazepam or equivalent ) who had experienced problems in withdrawing from the drugs were given an i.v . challenge with either the benzodiazepine antagonist flumazenil ( 1 mg injected over 30 s ) or placebo ( vehicle solution ) in a r and omized double-blind design . There were no ' pseudo withdrawal ' responses to either single-blind or double-blind placebo injections , whereas flumazenil produced dramatic panic reactions in all four subjects tested , followed by characteristic benzodiazepine withdrawal symptoms . There were also small but significant rises in pulse rate and blood pressure , but no change in serum cortisol .  Flumazenil-induced panic could not be entirely accounted for by a past or present diagnosis of panic disorder , and did not seem to be related to previous withdrawal problems , present benzodiazepine dosage , or to the severity of withdrawal symptoms precipitated by flumazenil in the same challenge test . Attempts to reduce  benzodiazepine intake over the next 3 weeks tended to be more successful in the flumazenil group . The results are discussed with reference to possible changes in the GABA-benzodiazepine system in long-term benzodiazepine users Objectives . We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder . Methods . R and omised , placebo-controlled , blinded , parallel superiority trial of 24 weeks duration . Participants were r and omised to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage . The primary outcome was mean benzodiazepine daily dosage at 24 weeks . Secondary outcomes included pattern of benzodiazepine dosage over time , benzodiazepine cessation proportion , and benzodiazepine withdrawal symptoms . Results . In total , 86 patients ( 21–74 years ) were enrolled : 42 were r and omised to melatonin versus 44 to placebo .  We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks ( melatonin group 8.01 mg versus placebo group 5.72 mg diazepam equivalents ; difference between means –2.29 ; 95 % CI –5.78 to 1.21 ; P = 0.20 ) . Benzodiazepine cessation proportion was 38.1 % ( 16/42 ) in the melatonin group versus 47.7 % ( 21/44 ) in the placebo group ( OR 0.64 ; 95 % CI 0.26 to 1.56 ; P = 0.32 ) . Prolonged-release melatonin had no effect on benzodiazepine withdrawal symptoms . Conclusions . Benzodiazepine dosage was comparably low between the groups after 24 weeks of guided gradual dose reduction . In this context , prolonged-release melatonin did not seem to further facilitate benzodiazepine discontinuation Since recent research has suggested that the major metabolites of progesterone are barbiturate-like modulators of GABAergic function , we undertook a pilot study of the efficacy of micronized progesterone in attenuating withdrawal and facilitating discontinuation in benzodiazepine-dependent patients with a minimum of 1 year of continuous daily use . Forty-three patients taking a mean daily dose of 16.2 mg of diazepam ( or its equivalent ) were assigned , double-blind , to treatment with either placebo  ( n=13 ) or progesterone  ( n=30 ) . Progesterone was titrated to a mean daily dose of 1983 mg , and was co-administered for 3 weeks , after which the benzodiazepine was tapered by 25 % per week . Progesterone ( or placebo ) was then continued for 4 weeks before being discontinued . There was no progesterone versus placebo difference 
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Likewise , magnesium aspartate decreased the proportion of participants discontinuing benzodiazepines ( 1 study , 144 participants ; RR 0.80 , 95 % CI 0.66 to 0.96 ; NNTH 5.8 ; very low- quality evidence ) .Generally , adverse events were insufficiently reported .
AUTHORS ' CONCLUSIONS Given the low or very low quality of the evidence for the reported outcomes , and the small number of trials identified with a limited number of participants for each comparison , it is not possible to draw firm conclusions regarding pharmacological interventions to facilitate benzodiazepine discontinuation in chronic benzodiazepine users .