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TITLE: High Dose and Watchful Dosing of Benzodiazepines: A Review of the Safety and Guidelines

DATE: 21 November 2012

CONTEXT AND POLICY ISSUES

Benzodiazepines are compounds that enhance the activity of gamma-aminobutyric acid (GABA)-A receptors by increasing the affinity of the receptors for GABA.2 Therefore, benzodiazepines are prescribed as . In Canada, the labeled indications include, the treatment of disorders, disorder, , disorders, skeletal muscle spasticity, and withdrawal (Table 1).3

The relative safety and effectiveness of the benzodiazepines led to their widespread use.5 Two benzodiazepines, and , are classified by the World Health Organization as "essential " that should be available in all countries for medical purposes.6 However, the use of benzodiazepines have also been associated with several adverse effects, including , dizziness, over-sedation, anterograde , and dependence.7

The current review will evaluate the evidence regarding benzodiazepine dosing and the evidence supporting benzodiazepine watchful doses. Watchful doses are doses above which additional assessment and patient monitoring are required.

Table 1. Summary of the Available Benzodiazepines in Canada Diazepam Maximum Indicated Equivalent Oral Health Canada Indication Dose (mg)* Dose (mg)** Long-acting 40 20-50 Anxiety disorders Anxiety, panic, seizure disorders, and alcohol 60 15 withdrawal Anxiety disorders, perioperative , Diazepam 40 10 seizure, skeletal muscle spasticity, and alcohol withdrawal 30 30 Insomnia Intermediate-acting 10 1 Anxiety and 60 6-12 Anxiety disorders

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH.

Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

Table 1. Summary of the Available Benzodiazepines in Canada Diazepam Maximum Indicated Drug Equivalent Oral Health Canada Indication Dose (mg)* Dose (mg)** 80 20 Seizure disorders Clonazepam 20 0.5-2 Seizure disorders Perioperative medication, anxiety and seizure 4 1-2 disorders 10 10-20 Insomnia, seizure disorders 120 30 Anxiety disorders, alcohol withdrawal 30 20-30 Insomnia Short-acting † 0.1 mg/kg Not applicable Perioperative medication 0.5 0.5 Insomnia * Information was obtained from Health Canada approved product monograph for each drug3 ** Equivalent doses are approximate and were retrieved from the Canadian National Use Guideline.10 † Parenteral use only

RESEARCH QUESTIONS

1. What is the clinical evidence for safety of high-dose (>10 mg diazepam equivalent) benzodiazepine use?

2. What is the clinical evidence regarding the safety of different watchful doses of benzodiazepines?

3. What are the evidence-based guidelines regarding watchful dosing or high-dose of benzodiazepine?

KEY FINDINGS

The available evidence suggests that benzodiazepines can be used, under specific circumstances, in higher doses than 10 mg diazepam equivalent without major safety concerns. However, the available information does not support specific values for benzodiazepine watchful doses.

METHODS

Literature Search Strategy

A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2012, Issue 10), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2007 and October 24, 2012.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed for relevance. Full texts of any relevant titles/abstracts were retrieved

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and assessed. The final article selection was based on the inclusion criteria presented in Table 2.

Table 2: Selection Criteria Population Adults or adolescents receiving benzodiazepines

Intervention Benzodiazepine (> 10mg diazepam equivalent)

Comparator Other benzodiazepine doses or usual care

Outcomes Safety, reduction in high dose prescribing, addiction, misuse/abuse, and clinical practice guidelines Study Designs Health technology assessment, systematic review, meta-analysis, randomized controlled trials, and non-randomized studies

Exclusion Criteria Studies were excluded if they did not meet the selection criteria. Duplicate reports of the same outcomes from the same trials were also excluded. Studies evaluating benzodiazepines analogues were also excluded.

Critical Appraisal of Individual Studies

Critical appraisal of the included studies was based on study design. The methodological quality of the included randomized controlled trials was evaluated using the SIGN50 checklist for the controlled studies.12 The observational studies included in this review were evaluated using the SIGN50 checklist for the cohort studies.13

For the included studies a numeric score was not calculated. Instead, the strengths and limitations of each study were described.

SUMMARY OF EVIDENCE

Quantity of Research Available

A total of 348 potential citations were identified by the search in bibliographic database, with 328 citations being excluded during the title and abstract screening based on irrelevance to the questions of interest. The full text documents of the remaining 20 articles were retrieved. Of these 20 articles, 15 did not meet the inclusion criteria and were excluded, leaving five articles that reported from five unique studies to be included in this review.1,4,8,9,11 The literature search did not identify any relevant health technology assessments, systematic reviews, meta-analyses or evidence-based clinical guidelines. A PRISMA diagram demonstrating the study selection process is presented in APPENDIX 1.

Summary of Study Characteristics

Five studies that addressed at least one of the two review questions about the safety of high and watchful doses of benzodiazepine were included in this review, including two RCTs evaluating efficacy and safety of the perioperative use of different doses of midazolam,1,8 one RCT that assessed the bioavailability and safety of different doses of diazepam in healthy volunteers,4 and two observational studies evaluating the safety of a high-dose midazolam

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sedation protocol9 and the safety of long-term use of benzodiazepines in high doses.11 Details regarding primary study characteristics are tabulated in APPENDIX 2.

Eren et al.1 and Talebi et al.8 conducted two RCTs in perioperative settings. The first trial evaluated the efficacy of in preoperative sedation. The trial treatment was compared against placebo and three doses of midazolam (0.02, 0.04, and 0.06 mg/kg) in an open-label design. The study evaluated the above interventions in patients undergoing minor to moderate surgical procedures under general . The second trial evaluated the effects of intrathecal on post-operative pain among male patients undergoing elective ipsilateral open inguinal herniorrhaphy under spinal anesthesia. The trial compared the combination of lidocaine with midazolam (fixed doses; 0.5 mg and 1 mg) to lidaocaine alone. The included patients in both trials were classified group I-II according to the American Society of Anesthesiologists (ASA). Group I-II ASA is defined as normal healthy patients or patients with mild systemic disease with no functional limitation.1,8

The bioavailability and safety of intramuscular (IM) auto-injected diazepam was evaluated in healthy volunteers in an open-label, single-dose and crossover RCT.4 Three doses of diazepam (5, 10 and 15 mg) were compared to each other; the 10 mg diazepam administered by IM auto- injection was compared to 10 mg diazepam administered by rectal gel. This trial provided safety information about dose-related adverse effects of diazepam.

Spain et al.9 conducted a prospective observational study to evaluate the safety and effectiveness of a high-dose midazolam sedation protocol. Midazolam was administered in 10 mg increments at 10 minutes intervals, starting with 10 mg and titrated up to 40 mg. The study evaluated this protocol among adult patients with severe behavioural disturbance suspected to be from psycho- use. Patients’ data were obtained from a single emergency department.

Hermos et al.11 studied 6-year retrospective cohort data to evaluate the association of high, long-term benzodiazepine doses among post-traumatic syndrome (PTSD) patients. Authors retrieved data on patients diagnosed with PTSD and one of the following disorders:

and abuse, -related medical and psychiatric diagnoses, dependence, drug abuse and withdrawal syndromes

Prescription patterns of alprazolam, clonazepam, diazepam and lorazepam were analyzed. The average treatment period was approximately 21 months, and the analysis focused on the high dose treatment as defined by an average daily dose in the top 10% for each agent.

Summary of Critical Appraisal

The strength and limitations of included studies are summarized in APPENDIX 3.

The review included three randomized controlled trials; randomization method was not specified in the three trials.1,4,8 Two trials had an open-label design which could bias the evaluation of outcomes favoring one trial treatment over others.1,4 The trials by Eren et al.1 and Talbi et al.8 included patients classified group I-II according to the American Society of Anesthesiologists. These patients are usually healthy patients or patients with mild systemic disease with no

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functional limitations. These patients’ characteristics may limit the generalizability of safety results to more compromised patients who may develop respiratory depression and altered hemodynamics. Lamson et al.4 included healthy volunteers, but authors did not report on the experience history of the included patients with benzodiazepines. Long-term users of benzodiazepines may develop tolerance against some of its adverse events.

Spain et al.9 used a prospective observational study design. The advantage of this design is that the intervention and outcomes are predefined; however, such design does not provide conclusive evidence to support clinical decisions because the treatment was not compared other interventions. Furthermore, the trial used fixed doses of midazolam; midazolam dosing is estimated by body weight. In order to generalize the results obtained from fixed dose interventions with midazolam, information about the weight of the included patients is required; however, authors did not report on this information.

Hermos et al.11 used data from three large databases, and used patient-level data; both criteria provide reliability to the study and its results. However, the study was limited by the fact that benzodiazepine doses were estimated through the number of prescriptions and refills and not on the actual doses used by each patient. Another potential limitation is that the analysis did not take into account the concurrent use of different benzodiazepines; 291 patients of the 2,183 enrolled in the study used more than one benzodiazepine concurrently. And finally, this study focused on the long-term use of benzodiazepines, and patients who use benzodiazepine for extended periods of time may develop tolerance to some of the adverse effects of benzodiazepines. Therefore, safety results obtained from this analysis should not be generalized to the acute or occasional prescription of benzodiazepines.

Summary of Findings

Eren et al.1 included 125 patients in the trial, and reported on adverse events including bradycardia, nausea and hypoxemia. No bradycardia or nausea events were recorded in any of the midazolam groups (0.02, 0.04, or 0.06 mg/kg). Six patients had hypoxemia; four (26.7%) in the 0.06 mg/kg group and two (13.3%) in the 0.04 mg/kg group. Only the 0.06 mg/kg was associated with statistically significantly higher prevalence of hypoxemia. Although the three doses of midazolam are below the maximum dose allowed by Health Canada approved product monograph (0.1 mg/kg), this study showed that adverse events increased with higher doses of midazolam.

In their trial report, Lamson et al.4 reported the adverse events associated with three doses of diazepam (5 mg, 10mg and 15 mg). The reported results showed that both the 10 mg and 15 mg groups had relatively higher total treatment-emergent events than the 5 mg group; total number (%) of events were 7 (30%), 7 (32%) and 4 (17%) respectively. One event of tachycardia was reported in each of the 5 mg and 15 mg groups, no events were reported in the 10 mg group.

Talbi et al.8 reported higher incidence of nausea in the 1 mg midazolam group when combined with lidocaine compared to lidocaine alone or lidocaine combined with 0.5 mg midazolam; the number of events (%) were 13 (93%), 8 (80%), and 10 (77%). Only one case of bradycardia was reported in the trial, and it was reported in the 0.5 mg midazolam + lidocaine group.

The study by Spain et al.9 showed that adverse events were reported with the first dose of midazolam (10 mg) and reached a plateau by the third dose (total of 30 mg); the fourth dose

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was not associated with new adverse events. However, the number of patients requiring the third and fourth dose was relatively small (n=7 and 5 respectively), and this fact changes any conclusion about the safety of higher doses of midazolam. Interpretation of the results is further complicated by the fact that the study used fixed dose-increments of midazolam rather than per- weight titration, and it did not report weight information of the included patients.

Hermos et al.11 included 2,183 patients who had 2,474 benzodiazepine treatment episodes. The analysis showed that benzodiazepine was used in higher doses than the maximum doses approved by Health Canada. In the trial, diazepam was used in high doses reaching 60 mg/day, the average daily dose (in the highest 10% of all dose ranges) was 37.5 mg. The average daily doses, in the highest 10% of all dose ranges, of alprazolam, clonazepam and lorazepam was 4 mg. The report did not indicate any safety concerns associated with the use of benzodiazepines in high doses. Of the included population, 234 patients used the high doses of benzodiazepine for extended periods. Almost 60% of these patients were diagnosed with PTSD alone, 21% had PTSD associated with alcoholism and drug abuse, 14% had PTSD and alcoholism, and 6% had both PTSD and drug abuse. These results do not show causality relationship between high- doses of benzodiazepine and . However, authors suggested that considerable caution be applied in prescribing benzodiazepines to PTSD patients, particularly those with prior diagnoses of drug abuse or dependence.

Limitations

Benzodiazepines are relatively old drugs, with diazepam first introduced in the market in 1960s. Therefore, most of the clinical trials evaluating these drugs may have been conducted many years before our literature search limits, and consequently could not be reviewed. No systematic reviews or meta-analyses of the older literature were identified. However, a supplemental literature search suggested that expanding the inclusion limit to 10 years wouldn’t likely have added useful information. Further extension of the literature search limits beyond 10 years may identify additional relevant trials; however, this would also multiply the volume of literature to be screened and reviewed, and this is not feasible due to the scope and relatively short timelines of Rapid Response reviews.

Fourteen members of the benzodiazepine family are available in Canada; of these, evidence on five drugs was discussed in this review. Furthermore, three out of five studies evaluated midazolam. The safety and efficacy results obtained for midazolam cannot be generalized to other benzodiazepine drugs because midazolam does not have an established diazepam oral equivalent dose. The available data for the other four drugs included in this review are not sufficient to support a watchful dose to be generalized for all benzodiazepine drugs.

The literature search did not identify any health technology assessments, systematic reviews, meta-analyses or evidence-based clinical guidelines evaluating the review questions. Furthermore, the included studies were not designed specifically to answer our review questions directly; therefore, results from these trials may not be useful to support definitive conclusions about the watchful doses of benzodiazepines.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

This report evaluated the clinical evidence for the safety of high doses of benzodiazepines and if a watchful dose of benzodiazepines can be determined. Evidence-based guidelines were also

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searched for but none were identified for inclusion. A total of three RCTs and two observational studies were retrieved.

With respect to the safety of high-doses of benzodiazepines equivalent to 10 mg diazepam, data was limited to those obtained mainly from a non-randomized trial. It was reported that benzodiazepines could be used in doses higher than the 10mg diazepam-equivalent doses. For example, diazepam was used in daily average dose of 37.5mg, and 4 mg/day for alprazolam clonazepam and lorazepam. These findings must be considered in light of the fact that the study was not designed specifically to evaluate the safety of high doses of benzodiazepines.

With regards to the clinical evidence regarding the safety of different watchful doses of benzodiazepines, the available evidence does not suggest any watchful doses for benzodiazepines.

PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

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REFERENCES

1. Eren G, Cukurova Z, Demir G, Hergunsel O, Kozanhan B, Emir NS. Comparison of dexmedetomidine and three different doses of midazolam in preoperative sedation. J Anaesthesiol Clin Pharmacol [Internet]. 2011 Jul [cited 2012 Nov 20];27(3):367-72. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161464/?report=printable

2. Möhler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8.

3. Drug product database [Internet]. Ottawa: Health Canada; 2009 -. Drug Product Database online query; 2012 [cited 2012 Oct 31]. Available from: http://webprod3.hc-sc.gc.ca/dpd- bdpp/index-eng.jsp

4. Lamson MJ, Sitki-Green D, Wannarka GL, Mesa M, Andrews P, Pellock J. Pharmacokinetics of diazepam administered intramuscularly by autoinjector versus rectal gel in healthy subjects: a phase I, randomized, open-label, single-dose, crossover, single- centre study. Clin Drug Investig. 2011;31(8):585-97.

5. DuPont RL, Greene W, Lydiard RB. and abuse and dependence: pharmacology and epidemiology. 2010 Mar 22 [cited 2012 Nov 14]. In: UpToDate [Internet]. Version 14.3. Waltham (MA): UpToDate; c2005 - . Available from: www.uptodate.com Subscription required.

6. World Health Organization. The use of essential drugs: ninth report of the WHO Expert Committee [Internet]. Geneva: WHO; 2000. [cited 2012 Nov 14]. Available from: http://apps.who.int/medicinedocs/en/d/Js2281e/#Js2281e

7. e-CPS [Internet]. Ottawa: Canadian Pharmacists Association. Benzodiazepines; 2009 [cited 2010 Sep 15]. Available from: https://www.e-therapeutics.ca Subscription required.

8. Talebi H, Yazdi B, Alizadeh S, Moshiry E, Nourozi A, Eghtesadi-Araghi P. Effects of combination of intrathecal lidocaine and two doses of intrathecal midazolam on post- operative pain in patients undergoing herniorrhaphy: a randomized controlled trial. Pak J Biol Sci. 2010 Dec 1;13(23):1156-60.

9. Spain D, Crilly J, Whyte I, Jenner L, Carr V, Baker A. Safety and effectiveness of high- dose midazolam for severe behavioural disturbance in an emergency department with suspected psychostimulant-affected patients. Emerg Med Australas. 2008 Apr;20(2):112- 20.

10. National Opioid Use Guideline Group (NOUGG). Canadian guideline for safe and effective use of for chronic non- pain [Internet]. Hamilton (ON): McMaster University; 2010. [cited 2012 Oct 31]. Available from: http://nationalpaincentre.mcmaster.ca/opioid/

11. Hermos JA, Young MM, Lawler EV, Rosenbloom D, Fiore LD. Long-term, high-dose benzodiazepine prescriptions in veteran patients with PTSD: influence of preexisting alcoholism and drug-abuse diagnoses. J Trauma Stress. 2007 Oct;20(5):909-14.

12. Scottish Intercollegiate Guidelines Network. Methodology checklist 2: randomized controlled trials [Internet]. In: SIGN 50: a guideline developer's handbook. Edinburgh:

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SIGN; 2008 [cited 2012 Nov 20]. Available from: http://www.sign.ac.uk/guidelines/fulltext/50/checklist2.html.

13. Scottish Intercollegiate Guidelines Network. Methodology checklist 3: cohort studies [Internet]. In: Sign 50: a guideline developer's handbook. Edinburgh: SIGN; 2008 [cited 2012 Nov 20]. Available from: http://www.sign.ac.uk/guidelines/fulltext/50/checklist3.html.

14. Detke HC, Zhao F, Garhyan P, Carlson J, McDonnell D. Dose correspondence between long-acting injection and oral olanzapine: recommendations for switching. Int Clin Psychopharmacol. 2011 Jan;26(1):35-42.

15. Hill AL, Sun B, Karagianis JL, Watson SB, McDonnell DP. Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with . BMC Psychiatry [Internet]. 2011 [cited 2012 Oct 29];11:28. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048520/pdf/1471-244X-11-28.pdf

16. Lipkovich I, Adams DH, Mallinckrodt C, Faries D, Baron D, Houston JP. Evaluating dose response from flexible dose clinical trials. BMC Psychiatry [Internet]. 2008 [cited 2012 Oct 29];8:3. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254403/pdf/1471- 244X-8-3.pdf

17. Majumder S, Mandal SK, Guha G, Bandyopadhyay D, Chowdhury SR. A single fatal dose of olanzapine. Neurol India. 2009 Jul;57(4):497.

18. Mattes JA. High-dose olanzapine versus . J Clin Psychiatry [Internet]. 2008 Oct [cited 2012 Oct 29];69(10):1660-1. Available from: http://www.psychiatrist.com/privatepdf/2008/v69n10/v69n1017.pdf

19. Meltzer HY, Bobo WV, Roy A, Jayathilake K, Chen Y, Ertugrul A, et al. A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry [Internet]. 2008 Feb [cited 2012 Oct 29];69(2):274-85. Available from: http://www.psychiatrist.com/privatepdf/2008/v69n02/v69n0214.PDF

20. Long-acting injectable olanzaoine. Inadequate assessment and a risk of overdose. Prescrire Int. 2010 Jun;19(107):114.

21. Severus WE, Lipkovich IA, Licht RW, Young AH, Greil W, Ketter T, et al. In search of optimal levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005. Eur Psychiatry. 2010 Dec;25(8):443-9.

22. Zanarini MC, Schulz SC, Detke HC, Tanaka Y, Zhao F, Lin D, et al. A dose comparison of olanzapine for the treatment of borderline : a 12-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry [Internet]. 2011 Oct [cited 2012 Oct 29];72(10):1353-62. Available from: http://www.psychiatrist.com/privatepdf/2011/v72n10/v72n1009.pdf

23. Kinon BJ, Volavka J, Stauffer V, Edwards SE, Liu-Seifert H, Chen L, et al. Standard and higher dose of olanzapine in patients with schizophrenia or : a

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randomized, double-blind, fixed-dose study. J Clin Psychopharmacol. 2008 Aug;28(4):392- 400.

24. Kumra S, Kranzler H, Gerbino-Rosen G, Kester HM, De Thomas C, Kafantaris V, et al. Clozapine and "high-dose" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry. 2008 Mar 1;63(5):524-9.

25. Citrome L, Kantrowitz JT. Olanzapine dosing above the licensed range is more efficacious than lower doses: fact or fiction? Expert Rev Neurother. 2009 Jul;9(7):1045-58.

26. Reeves R. Guideline, education, and peer comparison to reduce prescriptions of benzodiazepines and low-dose in prison. J Correct Health Care. 2012 Jan;18(1):45-52.

27. Donaldson M, Goodchild JH. Maximum cumulative doses of sedation medications for in- office use. Gen Dent. 2007 Mar;55(2):143-8.

28. Gold JA, Rimal B, Nolan A, Nelson LS. A strategy of escalating doses of benzodiazepines and administration reduces the need for in tremens. Crit Care Med [Internet]. 2007 Mar [cited 2012 Oct 29];35(3):724-30. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417045/pdf/nihms179527.pdf

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APPENDIX 1: Selection of Included Studies

348 citations identified from electronic literature search and screened

328 citations excluded

20 potentially relevant articles retrieved for scrutiny (full text, if available)

0 potentially relevant reports retrieved from other sources (grey literature, hand search)

20 potentially relevant reports

15 reports excluded: -irrelevant intervention (14)14-27 -irrelevant outcomes (1)28

5 reports included in the review (Eren et al. 2011,1 Lamson et al. 2011,4 Talebi et al. 2010,8 Spain et al. 2008,9 Hermos 200711)

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APPENDIX 2. Characteristics of the Included Studies

Objectives and Design Population Intervention Comparator Notes Eren et al. 2011,1 Turkey To compare the efficacy of Patient undergoing minor or moderate in-hospital Dexmedetomide Placebo The maximum dose for dexmedetomidine and surgical procedures under general anesthesia. Midazolam (0.02 midazolam, as midazolam in preoperative Patients were classified group I-II according to the mg/kg) recommended by sedation. American Society of Anesthesiologists. Midazolam (0.04 Health Canada mg/kg) approved product Randomized, open-label, Midazolam (0.06 monograph, is single-dose study mg/kg) 0.1mg/kg. This trial provides dose-related safety information. Lamson et al. 20114 - To evaluate and compare Healthy adult volunteers. Part I: Part I: This trial was included the bioavailability and safety Diazepam 5, 10, and the different to provide information of diazepam administered by 15mg (each subject was doses were about the dose-related IM auto-injection or rectal crossed-over the three compared to safety of diazepam gel. doses) administered by each other IM auto-injection Randomized, open-label, Part II: Part II: single-dose, crossover study Diazepam 10mg Diazepam 10mg administered by IM auto- administered by injection rectal gel Talebi et al. 20108 – Iran To evaluate the effects of Male patients undergoing elective ipsilateral open Intrathecal lidocaine Intrathecal The maximum intrathecal lidocaine on post- inguinal herniorrhaphy under spinal anesthesia. 5% (75mg) plus lidocaine 5% midazolam operative pain. Patients were classified group I-II according to the 0.5mg midazolam (75mg) recommended dose by American Society of Anesthesiologists. Health Canada is 0.1 Randomized double-blind Intrathecal lidocaine mg/kg. This trial controlled trial 5% (75mg) plus 1mg provides dose-related midazolam safety information. Spain et al. 20089 – Australia To evaluate the safety and Adult patients with severe behavioural disturbance midazolam in 10 mg Not applicable Midazolam was used in effectiveness of high-dose suspected to be from psychostimulant. Patients increments, i.m. or high doses; 10 mg up midazolam sedation recruited in a single emergency department i.v., at 10 min to 40 mg. The protocol. intervals, up to four maximum dose doses recommended by Prospective observational Health Canada is 0.1 study mg/kg. Hermos et al. 200711 - USA To evaluate the association Patients treated with benzodiazepine in the New Alprazolam, clonazepam, Lower doses of The trial was not

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Objectives and Design Population Intervention Comparator Notes of high, long-term anxiolytic England Veteran Affaire Medical Centers and diazepam, or lorazepam. benzodiazepine designed to determine benzodiazepne doses affiliated clinics Treatment used in either the therapeutic among PTSD patients with high dose (average daily benefits or risks of and without substance The following clinical diagnoses were retrieved dose for their longest long-term abuse diagnoses. retrospectively: treatment episode was in benzodiazepine PTSD, the top 10% for each prescriptions for PTSD Retrospective observational Alcohol dependence and abuse, alcoholism- agent), and patients with comorbid 6-year cohort study related medical and psychiatric diagnoses, for long-term treatment Psychoactive drug dependence, (average 21.3 months), diagnoses. Drug abuse and withdrawal syndromes Results from this trial Inclusion required that each substance abuse can give insight on the diagnosis was recorded prior to or concurrent with high doses of the initial benzodiazepine prescription. benzodiazepine when used for extended duration PTSD= post-traumatic stress syndrome

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APPENDIX 3. Critical Appraisal of the Included Studies

Strengths Weaknesses Eren et al. 2011,1 Turkey Treatment allocation was randomized; The study included ASA I-II patients, these patients are usually not much compromised; furthermore, the however, the randomization method was not average age was 37 years. These patients’ characteristics may limit the generalizability of safety results to specified. geriatric and more compromised patients who may develop respiratory depression and altered hemodynamics. The trial had an open-label design; therefore, outcomes assessment might be biased favoring dexmedetomide or the highest dose of midazolam in the efficacy outcomes or exaggerating safety outcomes for these two treatments. Lamson et al.4 2011 Treatment allocation was randomized; The study recruited healthy volunteers, and this is ideal for pharmacokinetic studies. However, it was not however, the randomization method was not reported if these subjects were benzodiazepine naïve or had prior experience with diazepam. Therefore specified. safety outcomes could not be conclusive, because long-term use of benzodiazepine may develop tolerance against some of the adverse events. The trial has an open-label design, and outcome evaluation might be biased. Talebi et al.8 2010 – Iran The sample size was estimated based on the The study included ASA I-II patients; these patients are usually not much compromised. These patients’ expected duration of anesthesia after characteristics may limit the generalizability of safety results to more compromised patients who may develop operation. However, the trial’s main outcome respiratory depression and altered hemodynamics. was the severity of post-operative pain and The trial patients were pre-medicated with 5mg oral diazepam 60 minutes before the intervention, the effect not the duration of anesthesia. of combining midazolam with diazepam was not taken into consideration. Treatment allocation and outcome evaluation was double-blinded Spain et al. 20089 – Australia This was an observational study designed The average weight of the included patients was not reported. Midazolam dose is determined by patients’ prospectively. weight; it would be challenging to generalize the results of this trial without information about patients’ weight. Hermos et al. 200711 - USA The study retrieved and analyzed patient’ Benzodiazepine doses were estimated through the number of prescriptions and refills and not on the actual level data from three databases. The large doses used by each patient. Although this might be the best way to estimate the doses retrospectively, this size of the analyzed data provides reliability to kind of estimation tends to exaggerate the amount and doses of drugs truly used. the study results. 291 patients had received concurrent benzodiazepines; the effect of this concurrent use was not taken into consideration in the dose estimation. The study reported the rates of patients in each benzodiazepine dose category, but it did not provide the association/ risk measurements. The study used data about patients who used benzodiazepines for long-term. This type of patients might have developed a sort of tolerance for the high doses of benzodiazepines; patients who use these drugs occasionally may not have the same tolerance. Therefore, the reported doses may not be generalizable to the acute use of benzodiazepines or drug naïve patients. ASA= American Society of Anesthesiologists; PTSD= post-traumatic stress syndrome

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APPENDIX 4. Main Study Findings and Authors’ Conclusions

Authors’ Conclusions – Reviewer’s Study Findings Comments Eren et al. 2011,1 – Turkey Authors concluded that dexmedetomidine is an 125 patients were included effective agent for preoperative sedation, and it Weight and adverse events reported for the study patients resulted in equal or even longer sedation

Midazolam 0.02mg/kg Midazolam 0.04mg/kg Midazolam 0.06mg/kg compared to high dose (0.06mg/kg) of Placebo (n=15) (n=15) (n=15) midazolam. (n=40) Reviewer’s comments: Weight (kg), 66.8 (11.8) 65.9 (11.0) 73.5 (14.2) 67.3 (7.6) The study used lower doses of midazolam mean (SD) than the maximum dose provided Health Adverse Effects, n (%) Canada product monograph for midazolam Bradycardia 0 0 0 0 (0.1mg/kg). Only the highest dose (0.06mg/kg) Nausea 0 0 0 0 was associated with statistically significantly Hypoxemia 0 0 2 (13.3) 4 (26.7) higher prevalence of hypoxemia. Lamson et al.4 2011

Adverse events reported in subjects taking diazepam Diazepam IM administration via the 5mg IM 10mg IM 15mg IM Type of Adverse Event autoinjector may offer a reliable method for (N=23), n(%) (N=23),n(%) (N=22), n(%) caregivers to administer medication for the Treatment-emergent 4 (17.4) 7 (30.4) 7 (31.8) treatment of Acute repetitive . Serious 0 0 0 Most common treatment-emergent adverse events There was no evidence of respiratory injection site pain 1 (4.3) 5 (21.7) 6 (27.3) depression following IM diazepam headache 1 (4.3) 2 (8.7) 1 (4.6) administration with the autoinjector. tachycardia 1 (4.3) 0 1 (4.6) Talebi et al.8 2010 – Iran

45 patients were included in this trial Authors concluded that the intrathecal Lidocaine Lidocaine + 0.5 mg midazolam Lidocaine + 1 mg midazolam midazolam, combined with lidocaine, was

alone (n=10) (n=13) (n=14) effective in reducing post-operative pain and Weight, mean kg (SD) 63.6 (6.1) 65.6 (8.2) 63.1 (5.8) was not associated with severe adverse Adverse Effects, n (%) events. Nausea 8 (80) 10 (77) 13 (93) Reviewer’s comments: The approximate average doses of midazolam Emesis 0 5 (38) 0 per body weight were 0.01 mg/kg and 0.02 Headache 8 (80) 8 (62) 7 (50) mg/kg. The maximum recommended dose by 0 0 0 Health Canada (0.1 mg/kg). Bradycardia 0 1 (8) 0

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Authors’ Conclusions – Reviewer’s Study Findings Comments Spain et al. 20089 – Australia 62 patients were included in the trial Authors concluded that there were significant Midazolam was used in increments of 10mg up to four times safety concerns with potential therapeutic overdose occurring with the high-dose Number and percentage of patients who failed safety criteria regimen. 1 dose 2 doses 3 doses 4 doses Safety Criteria (n=62), n% (n=20), n% (n=7), n% (n=5), n% Reviewer’s comments: GCS <8 4 (7) 3 (15) 1 (14) 0 The maximum dose recommended by Health Airway adjunct 2 (3) 2 (10) 0 0 Canada is 0.1 mg/kg. Adverse events were reported for the lowest midazolam dose (10 BP <90 mmHg 3 (5) 3 (15) 1 (14) 0 mg) and reached a plateau after the third dose Cumulative total 9 (14) 17 (27) 19 (31) 19 (31) (30 mg total). However, the trial did not report patients’ weight, and without this information it is difficult to conclude based on these results Hermos et al. 200711 – USA 2,183 PTSD patients were identified who had 2,474 benzodiazepine treatment episodes.

Distribution by Percentiles of Benzodiazepine Doses Authors concluded that the study findings Alprazolam Clonazepam Diazepam Lorazepam Average daily dose suggest that considerable caution be applied in mg/day mg/day mg/day mg-day percentile prescribing benzodiazepines to PTSD patients, (n=277) (n=285) (n=505) (n=823) particularly those with prior diagnoses of drug Top 10%, 95% 4 3.8 37.5 4 abuse or dependence. (90%,100%) (3.3, 6) (3, 7.9) (30, 60) (3, 8.1) Middle-quartiles, 50% 1 1.3 11.7 1.5 Reviewer’s comments: (25%, 75%) (0.5, 2) (1, 2) (7.7, 19.3) (1, 2) The study reported that 234 patients used high doses of benzodiazepines for extended Distribution of Benzodiazepine Doses in Patients With and Without Alcoholism and Drug Abuse durations. Relative to the “equivalent oral Diagnoses doses” in Table 1, diazepam was used up to PTSD + PTSD + drug PTSD + 60 mg/day (1.5 times more than the maximum Average daily doses, % PTSD only alcoholism abuse alcoholism + drug dose approved by health Canada), while of population n (%) n (%) n (%) abuse, n (%) alprazolam, clonazepam and lorazepam were Total, N=2,183 391 (17.9) 61 (2.8) 342 (15.7) 1,389 (63.9) used in doses 2 to 4 times higher than their Top 10%, N=234 34 (14.5) 13 (5.6) 50 (21.4) 137 (58.6) 10mg-diazepam equivalent doses Middle quartile (25%, 208 (18.7) 27 (2.4) 165 (14.8) 713 (64.1) 75%) N=1,113 BP= blood pressure; GCS= Glasgow Score; IM= intramuscular; PTSD= post-traumatic stress syndrome

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