Research In Nursing

Our academic writers are ready and waiting to assist with any assignment you may have. From simple essays to full dissertations, you're guaranteed we've got a writing expert to perfectly match your needs.

Order a Similar Paper Order a Different Paper

Discuss barriers to Evidence Based Practice.

Post a brief statement of your Evidence Based Practice (EBP) findings. How do you overcome barriers to implementing change in practice? Describe the anticipated barriers to the change process in your institution (or where the change will be implemented). Include the organization’s culture, its reaction to change, and your leadership role for a change. 

Articles you can use are attached. 

*For correspondence: [email protected]

Competing interests: The

authors declare that no

competing interests exist.

Received: 03 May 2018

Accepted: 20 August 2018

Published: 20 February 2019

This article is Open Access:

CC BY license (https://


Author Keywords:

benzodiazepines , elderly,

healthcare professional,

qualitative research, Z drugs,

general practice

Copyright s 2019, The Authors;



Long-term use of benzodiazepines and Z
drugs: a qualitative study of patients’ and
healthcare professionals’ perceptions and
possible levers for change
Aliaksandra Mokhar, MSc1*, Silke Kuhn, PhD2, Janine Topp, MSc3,
Jörg Dirmaier, PhD, Dipl Psych4, Martin Härter, MD, PhD, Dipl Psych5,
Uwe Verthein, PhD6

1Scientific Associate, Department of Medical Psychology, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany; 2Researcher, Department of Psychiatry
and Psychotherapy, Center for Interdisciplinary Addiction Research, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Scientific Associate,
Institute for Health Services Research in Dermatology and Nursing, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Research Group Leader,
Department of Medical Psychology, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany; 5Institute Director, Department of Medical Psychology,
University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 6Head of
Center for Interdisciplinary Addiction Research, Department of Psychiatry and
Psychotherapy, Center for Interdisciplinary Addiction Research, University Medical
Center Hamburg-Eppendorf, Hamburg, Germany

Background: Although long-term use of benzodiazepines (BZDs) and Z drugs is associated with

various side effects, they remain popular among the older population. Possible reasons for this

phenomenon could be ineffective ways of transmitting information on the health risks associated

with long-term use, and communication gaps between patients and healthcare professionals.

Aim: The aim was to investigate the views of patients, physicians, nurses, and pharmacists

regarding long-term BZD and Z drug use.

Design & setting: The qualitative study design used focus group interviews with physicians,

pharmacists, and nurses in Hamburg. Patient interviews were conducted in Lippstadt, Germany.

Method: The interviews were audiotaped with each participant’s permission, transcribed, and

thematically analysed using a software program for qualitative research (MAXQDA).

Results: The data from the four focus groups consisting of 28 participants were analysed. Patients

indicated lack of knowledge about risks and side effects, difficult access to alternatives, and fears

of ceasing drug use without professional support. Although the physicians were reported to be

cautious about prescribing BZDs and Z drugs, the psychosocial problems of older patients are

often considered to be complex and treatment knowledge, experience, and resources are

frequently unsatisfactory. Nurses described that when BZDs were prescribed, they did not feel it

was their responsibility to evaluate their effects. Pharmacists were reported to be strongly

ambivalent in informing patients about the risks, which may contradict the prescription advice

provided by the physician.

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 1 of 10


Conclusion: Patients, physicians, nurses, and pharmacists reported differences in the perception of

long-term BZD and Z drug use. Nevertheless, all of the participants described lack of information

and expressed the need for greater communication exchange.

How this fits in
Several reasons have been identified for the associations between the long-term use of BZDs and Z

drugs in the older population, and the importance of the role of communication and collaboration

between patients and healthcare professionals. The results of the focus group interviews suggest

that more informational exchange is needed between patients and their healthcare professionals, as

well as more collaboration between different healthcare professionals.

The inappropriate prescribing of psychotropic drugs and polypharmacy are present in institutional-

ised and non-institutionalised older adults, which can cause serious side effects and might reduce

patients’ quality of life.1 Some of the most common potentially inappropriate prescribed medica-

tions in older people are BZDs.1 BZDs are effective drugs for treating anxiety symptoms, as well as

inducing and maintaining sleep, and muscle relaxation.2,3 The incidence of BZD prescription rates is

high worldwide, and treatment duration is often inappropriately longer than the recommended max-

imum 8-week period.3,4 Despite the fact that these drugs are effective in the short term, long-term

BZD therapy is associated with many side effects, the development of tolerance and, finally, addic-

tion.5 Long-term BZD and Z drug use occurs mainly in the older population.6 This patient group are

at particular risk of side effects because of their age-related physiological changes.7 Serious side

effects include cognitive disturbance, an increased risk of falls and therefore hip fractures,8–11 hospi-

talisation, and increased morbidity and mortality.12 Continual medication use after the primary indi-

cation usually results in physical and psychological dependency,13 manifesting in withdrawal


Recent research has identified several reasons for this occurrence; on the patient side, reasons for

prolonged use include chronic personal stress and sleep problems, fear of recurring symptoms, lack

of knowledge about risks and side effects, difficult access to alternatives, and poor motivation to

cease drug use.13–15 Research has shown that although physicians were cautious regarding initiating

BZD treatment, the psychosocial problems of patients are often considered to be complex, and

Table 1. Description of sample size


size, n


n Participant characteristics


8 3 5 P1: late 40s, male patient, 22 years BZD-dependent
P2: 24 year old male patient, 3 years of BZD use
P3: 75 year old female patient, 29 years of BZD use, 2.5 years without BZD
P4: 85 year old female patient, 40 years of BZD use, 3 years without BZD
P5: 58 year old male patient, 20 years of BZD and opiate use with massive dose increase, 6.5 years without
BZD and opiates
P6: mid-50s female patient, 30 years of use of opiates and occasional BZD, detoxified for the last 3 days
P7: late 30s, female pain patient, BZD (if needed)
P8: late 40s, female pain patient, BZD (if needed)


7 2 5 Working area:
3 � own practice
1 � practice and hospital
2 � psychiatric hospital, institute outpatient clinic
1 � psychiatrist (parental leave)


6 0 6 All of them reported years of experience in pharmacies throughout Hamburg


7 0 7 Working area:
2 � inpatient care
5 � outpatient care, including one nursing service and one task line

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 2 of 10


knowledge is often lacking regarding managing the psychological changes associated with ageing,

altered pharmacokinetics and pharmacodynamics, or using alternative strategies.15–18 Assessing the

issues and investigating the causes of the patient’s symptoms are often neglected because of a lack

of resources for the management of long-term medication use by older adults.19–21 Pharmacists play

an important role within the interprofessional healthcare team during the medical treatment of older

patients. They evaluate the appropriateness, effectiveness, safety, and compliance of medications

for a given patient.22,23 Other roles of the pharmacist include informing patients about the risks of

using the prescribed medications, which may contradict the prescription information provided by

the physician.21,22 Last but not least, nurses are involved in the healthcare management of older

patients, especially in nursing homes. Evidently, older people in nursing homes often have complex

illness profiles and require care and support concerning various symptoms. Nurses fulfil their duties,

but they often lack responsibility regarding the medication process in relation to BZD and Z drugs.24

An increased emphasis on patient-centred care could address the described reasons for long-

term use of BZD. International guidelines and reviews on improved medication use in general

address patient-centred care dimensions and stress the importance of clinician–patient communica-

tion and/or cooperation, shared decisionmaking, and information provision.25,26 The explanation of

the reasons for the long-term use of BZDs shows that there is missing information and a need for

cooperation between healthcare professionals and patients. The aim of this study is to investigate

the perspectives of physicians, nurses, pharmacists, and patients in focus groups to assess their per-

ceptions of the reasons for long-term BZD and Z drug use and find possible solutions to the identi-

fied difficulties.

The following research questions were addressed: first, different professional groups (physicians,

nurses, and pharmacists) were asked to describe long-term drug use and what they think about man-

aging this situation from the patient’s perspective. Second, all of the participants were asked about

the conditions that motivated them to seek a long-term prescription, and why it is problematical to

discontinue use. Third, the participants were asked for ideas, information they need, and ways to

communicate and solve the problem of long-term BZD and Z drug use.


Study design
The qualitative study design is indicated to better understand the individual experience of the indi-

vidual role of the participants, and to discuss possible solution strategies for this topic.27 The qualita-

tive study design was used based on the requirements of the standard guidelines for qualitative


Participant recruitment and setting
A qualitative study in focus group design was conducted with patients, physicians, pharmacists, and

nurses. The participants were eligible if they had been using BZDs or Z drugs for >4 weeks (patients)

or if they were involved in the medical care process as doctor, pharmacist, or nurse; if they were Ger-

man-speaking; and if they were physically and mentally able to take part in the focus group.

The study was performed as part of the project ’Benzodiazepines and Z drugs: concepts for risk

reduction among older patients’, sponsored by the Federal Ministry of Health. Physicians and phar-

macists were contacted directly by the medical and pharmacist association in Hamburg. Nurses were

recruited from an outpatient nursing service in Hamburg. Patients were recruited at the LWL-Klinik in

Lippstadt, Germany, because of the existing cooperation in the context of the research project, in

which patients with long-term BZD use are treated. All of the participants were volunteers and

received financial compensation.

Four focus groups were conducted from June–August 2015. All of the applications the research

team received could be included in the focus groups. There were no withdrawals. Each group com-

prised 6–8 participants. Focus groups with physicians and pharmacists were conducted at the Uni-

versity Medical Center Hamburg-Eppendorf. The focus group with nurses was held at the

Martha Foundation, and the group with patients was conducted at the project associated partner

LWL-Klinik. Each focus group lasted 120 minutes. Focus groups were moderated by three members

of the research team.

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 3 of 10


The participants in the focus groups were informed about the research project and signed a letter

of agreement.

Data acquisition and analysis
The interview guide for the focus groups was developed based on the research questions.

. Assess views on using BZDs and Z drugs for a long time:
. What could you say about the long-term use of BZDs and Z drugs (for example, reasons,

symptoms, and knowledge about side effects)?
. Do you think you know enough about this medication?

. Explore barriers and changing points to reduce the long-term use of BZDs and Z drugs:
. Have you ever tried to reduce the use (as patients) or initiate the reduction (as healthcare

physicians) of BZDs and Z drugs?
. Did it work? If not, how would you explain that?
. What do you think about the possible changing points in reducing the long-term use of

BZDs and Z drugs?

The complete interviews were audio-recorded with the participants’ consent. The data were ano-

nymised and thematically transcribed by student assistants at the University Medical Center Ham-

burg-Eppendorf. The content analysis was performed using MAXQDA software (version 10), which is

a qualitative research software program. The MAXQDA software prepares the data for further analy-

sis steps, in which it evaluates the transcripts to develop thematically categories. Two team members

independently coded the transcripts from each focus groups. Most of the categories showed high

consistency. Next, the final codes were cross-checked by a third team member. Any lack of clarity

was discussed with the research team. All the information from the transcripts was used for the anal-

ysis. When more than one quotation was available for a category, only one example was selected

and cited.

There were four focus groups consisting of physicians (n = 7), pharmacists (n = 6), nurses (n = 7), and

patients (n = 8), as shown in Table 1 .

Views on long-term use of BZDs and Z drugs
Prescribers apply caution in prescribing BZDs and Z drugs. Participants have reported that the long-

term use of BZDs and Z drugs often starts in hospitals and its prescription is continued by GPs. The

reasons for the use of these medications were sleep problems and anxiety-related symptoms pro-

ducing especially an acute crisis:

’If a patient is in an acute crisis, I often have two options: either giving him BZD, or sending him

to the clinic.’ (Physician 3)

’In the clinic, there is an even stronger tendency towards BZD, even less in line with the

guideline.’ (Physician 4)

’BZD (e.g. lorazepam) are often prescribed for anxiety, not to help patients fall asleep. I’d say

patients only take it when they need it.’ (Pharmacist 6)

’Long-term use occurs, especially in cases of mourning and when social support is lacking.

Patients receive the medication during their hospital stay, notice that they slept fine and see the

physician to continue the prescription.’ (Pharmacist 2)

’Sleep disorders, anxiety, and depression are the most common causes of long-term BZD use.’

(Nurse 4)

The continued long-term prescription of BZDs and Z drugs often occurs because of problematical

factors in the clinical routine, such as overcrowded waiting rooms or lack of time to speak with

patients about their individual needs:

’I have 5 minutes per patient. When one patient sits there and cries, it makes me nervous and

aggressive, as I know that there are 20 other patients waiting for their doctor’s appointment

outside. These are not good conditions for making a differentiated decision.’ (Physician 4)

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 4 of 10


’If we refer the patient back to the physician, this is often perceived as an encroachment. We’re

not supposed to interfere in things that don’t concern us.’ (Pharmacist 1)

’We know it from our patients that they have seen the physician, waited 2 hours and were inside

for 5 minutes.’ (Nurse 3)

Another reason for long-term use is that many patients are already familiar with these medica-

tions, and they directly demand prescriptions for BZDs or Z drugs without knowing about the nega-

tive aspects of the medications. In particular, pharmacists observe that patients have a careless

attitude. Nurses emphasise that most patients do not demand these medications:

’In my situation when I could not sleep anymore, I could not have taken up information about

side effects anyway. I wanted a pill so I could sleep.’ (Patient 3)

’I also realise that many patients know BZD, perhaps not the exact name but they have some

knowledge, saying: “My husband has the same pill and I occasionally take some of it”.’

(Physician 2)

’Maybe they do not even know what they are taking. They get it prescribed and they take it. I

think it has less to do with memory than with the fact that they have no idea about the

medication.’ (Nurse 3)

All of the professional groups agree that patients lack understanding about the likelihood of

addiction regarding long-term use of BZDs and Z drugs. The drugs are fully integrated into the

patients’ daily routine, awareness of potential problems is missing, and side effects such as dizziness,

unsteadiness while walking, or depression are not associated with the medications. The patients

themselves claimed that they did not feel addicted, although they were aware that consistent intake

was present, and the physicians claimed to clearly emphasise the side effects:

’I remember being fixed on a single pill of lexotanil for years: no more, no less. In the evening

exactly 6 mg bromazepam [. . .] and I did not think about dependency until I stopped taking the

drug and noticed these withdrawal symptoms. So, I was literally trapped.’ (Patient 5)

’Again and again, I experience that patients do not have a feeling for what they are taking.’

(Physician 6)

’Patients do not have the impetus to say: “I want to get away from it”. The medication is

integrated in their everyday lives. Patients have no problem awareness, and nobody addresses

the problem, especially when they live alone.’ (Pharmacist 3)

Nevertheless, the pharmacist tends to take a critical view of the physician informing the patient

about all types of side effects (including the dangers of addiction):

’As pharmacists, we have an awe of medicines and we do not experience this awe in the

everyday life of the patients and the physicians . . . For them, it is self-evident. When I am

hungry, I eat a piece of bread. When I have a headache, I take a pill. When I cannot sleep, I take

a pill. That’s it.’ (Pharmacist 1)

Nurses commented that many patients could not say why they had received their medication after

their appointment with the physician, and said that patients had not been informed because of the

brief consultation time:

’ [. . .] especially the older ladies and gentlemen, they are happy if they had seen the physician

and left with a prescription of a new medication. And once they are asked what the physician

explained to them, they say it was too fast and they had no time to ask questions.’ (Nurse 4)

Barriers and changing points to reduce the long-term use of BZDs and Z
Nearly all of the interviewed patients had the experience of receiving BZDs over a long to very long

period (ranging from a number of weeks to many years) without any difficulties and then, suddenly

and inexplicably, they were denied the prescription or they were urged to discontinue the medica-

tion. There were no preparatory discussions or jointly made decisions, according to them:

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 5 of 10


’I have taken the medication for years and subsequently increased the dosage [because of

husband’s care and death]. One day, the physician, who had been prescribing the medications,

said, “I think the medication needs to be withdrawn”.’ (Patient 4)

While physicians and some nurses tend not to initiate medication discontinuation among the old-

est patients nor discuss the dangers of addiction, pharmacists believe discontinuing the drugs is

beneficial at any stage of life. Pharmacists also report that GPs often abruptly stop prescribing, with-

out suggesting a more gradual discontinuation process. Based on this experience, they recommend

and motivate their customers to contact a psychiatrist, who can initiate and support a qualified step-

wise reduction:

’If patients are aware of the problem, we encourage them to find another physician [psychiatrist]

who can competently advise discontinuation of drug use.’ (Pharmacist 2)

’I have a patient [female, aged 85 years], I have been prescribing drugs to for years and I will

continue prescribing BZD to her for the rest of her life. I do not see the point in

discontinuing.’(Physician 6)

’Discontinuation rarely happens and is very difficult particularly in older people. Patients start

asking: “Where is half my pill for the night?” or they tell me: “I cannot sleep without it.” There is

no possibility of discontinuing the medication because they insist on this pill, whether they really

need it or not.’ (Nurse 1)

Alternative treatments were not discussed, and in one case, they were denied. Pharmacists

believe that if prescribers with further experience and knowledge of, for instance, homeopathy or

palliative medicine manage their patients more thoroughly, they would be more likely to oversee

attempts at discontinuation of drug use:

’Being a physician includes addressing alternative treatment options. I think that this is a

problem for many physicians.’ (Pharmacist 2)


In the four focus groups with patients, physicians, pharmacists, and nurses, the primary reasons for

prescribing BZDs and Z drugs were identified. These reasons were often sleep problems, anxiety

symptoms, and individual crises, and the initial drug use is often in an acute hospital setting. The rea-

sons for transitioning to long-term drug use are varied. Patients are often not informed of the poten-

tial risks and side effects when they initially receive the drug. Often patients do not know who to

contact when the drug use exceeds the expiration date, nor do they know with whom to discuss

medical issues when symptoms occur. The majority of the patients do not feel that using this medica-

tion is a problem. Physicians see the responsibility for the use of BZDs as in the patient’s hands, and

vice versa. Furthermore, there is often a lack of resources, time, or specific knowledge regarding

how to address sleep- or anxiety-related symptoms in older patients. Noticing reckless drug pre-

scriptions and intake behaviours, pharmacists often inform patients and motivate them to discon-

tinue the medication. Nonetheless, pharmacists are hesitant to contact the physician. Nurses

noticing the problematic BZD and Z drug use often feel unsure, and lack competency and knowl-

edge to inform patients or initiate discontinuation of the medication.

To the authors’ knowledge, this qualitative study is the first of its kind that looks at the percep-

tions of patients, as well as different healthcare professionals, on long-term use or prescription of

BZDs and Z drugs. As has been found in previous studies exploring BZD use from single perspec-

tives, the authors of the present study conclude that long-term use is an ongoing problem particu-

larly in older patients.1,6 Although physicians seem to be more cautious in prescribing medications,

further strategies need to be developed to tackle inappropriate long-term use. Therefore, the fol-

lowing issues need to be addressed: physicians do not know of appropriate treatment alternatives;

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 6 of 10


patients have insufficient knowledge on health risks associated with long-term intake of BZDs; and

different professions collaborate insufficiently.

Recommendations for the improvement of the care process can be derived from the reported

reasons for long-term use and barriers to the guideline-compliant prescription. Recommendations

are based on the principles of patient-centred care, which is an approach in health care that focuses

on the individual needs and values of the patient, and aims to improve the general quality of the

care process.29 The integrated model of patient-centredness, as described by Scholl et al30 includes

15 dimensions of patient-centred care, many of which could be referred to in order to improve BZD

use and prescription in the older population.

The results from the focus groups support the view that present difficulties in health care may be

solved by changing the perceptions of one’s role in the care process. For example, for physicians,

there is an evident need for improved clinician–patient communication, which is essential for patient-

centred care. It is necessary to actively involve patients in the treatment process.31,32

Patients often ask for comprehensive information and discussions with their physician; therefore,

a more active role in treatment and support for receiving self-management is needed.33 Self-man-

agement education is particularly important for older patients, to enable them to manage their

symptoms.34 None of the patients interviewed were able to recall such a discussion, while all believ-

ing that comprehensive clinician–patient communication would have prevented inappropriate use of

BZDs. Many studies have linked patient information with improved heath and increased health-

related quality of life.35–37 Joint consideration about the best course of treatment should form the

primary focus, and several evidence-based communication methods could facilitate that process.35

Furthermore, communication between different healthcare professionals is needed to ensure

coordination and continuity of care, which is another facilitator for patient-centred care. Active inter-

action between all stakeholders, open communication, and a consensual clear line of treatment is

recommended in order to best meet the need of the individual patient.26,27 This includes the transi-

tion between inpatient and outpatient care, as well as the coordination of care in the outpatient


The results from the focus groups indicate that pharmacists and nurses are engaged closely with

patients. The close relationship between pharmacist and patient is, so far, underutilised for the opti-

misation of the prescription. Pharmaceutical expertise rarely shapes and impacts a physician’s deci-

sionmaking. Pharmacists express uneasiness about contacting physicians and discussing problematic

prescriptions. They also worry that informing the patients about prescription problems might inter-

fere with the physician’s advice and might cause the patient–physician relationship to become dis-

tant or strained, thus creating potential conflict. Active exchange between both groups should allow

the pharmacist to call the physician in cases of problematic or complex prescriptions. Arranging a

time to discuss specific questions may be an option, in which the patient’s health will be the primary

focus. This change of action and thinking could result in shared responsibility, improved coordina-

tion, and continuity of care.

The results from the focus groups also suggest room for improvement in nursing. Nurses are willing

to assume more responsibility and play a more active part in medicinal treatment, serving as a link

between physicians and patients. While case conferences may be created by recapping the documen-

tation of a complex course, professional exchange may occur between the person in charge of the

nursing team and a physician colleague. The subsequent responsibility of passing on conference

results lies with the respective disciplines. These steps create benefits for all parties concerned. Physi-

cians can transfer parts of their expertise to nursing, thereby sharing some of the responsibility while

retaining a close watch. Nurses, meanwhile, gain knowledge and skills allowing them to handle specific

medicinal problems, and they assume increased responsibility for the patient. They may reflect about

the benefits and limitations of medicinal treatment, and they can support the patient in overcoming

the difficulties at hand. Improved communication and cooperation across all parties would help to

ensure successful treatment of older patients; indeed, the importance of communication and coopera-

tion form part of the international guidelines for improving the quality of healthcare systems.1

Strengths and limitations
The present study has several strengths. First, four different and very important perspectives on the

problem of long-term use of BZDs and Z drugs were presented. Second, the problems were identi-

fied and various practical options were considered with the agreement and support for all

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 7 of 10


interviewed parties. Third, the sample size of each focus group was appropriate according to the


There are several limitations to the study. First, the recruitment of the participants proved to be

difficult. It is, therefore, assumed that the participants took part in the study because of the financial

incentive. The research team could not completely control the number of or characteristics of the

invited participants, and there is a likelihood of selection bias. The sample was a convenience sample

recruited through several pathways. The authors only captured the sample size and sex of the

healthcare professionals. Second, there is a limitation regarding the sex of the sample size because

it consisted of more female participants than male. Third, in the focus group, the issues of reducing

the long-term use of BZD and Z drugs were not discussed in detail due to time constraints. Future

research is warranted to produce an additional perspective on this matter. Fourth, the focus was on

BZD and Z drug use in older age and important issues, such as polypharmacy, physical illness, or

social situation, were not discussed. Fifth, the bias of the personality of the moderator was mini-

mised by providing a structured steps protocol of questions and also by discussing any abnormalities

regarding the interviews. Nevertheless, moderator bias still existed.

Comparison with existing literature
Training to improve communication and collaboration with other specialists in the field of depres-

cribing BZDs and Z drugs in the older population is needed.23 Furthermore, previous studies have

produced sophisticated and multifaceted concepts that address cooperation among the various par-

ties, improve educational activities, and communication exchange with patients.24,40 Collaborative

team-based models can improve safe medication use and treat the symptoms.41 Dollman and col-

leagues’ multistrategic approach highlights the benefits of providing medication reduction care to

older people, showing a significant reduction in BZD use while successfully promoting new non-med-

ical alternatives.42 Those concepts could be transferred and integrated into ambulatory care in


Assisting and supporting patients in drug withdrawal is possible in several ways. For example,

while some patients may seem to require a lot of effort, several studies have shown that patient-cen-

tred care, combined with a specific method for drug discontinuation, can reduce and stop BZD


Implications for research and practice
Those involved in the healthcare system, namely, nurses, physicians, pharmacists, and patients, play

increasingly interdependent roles. Problems arise every day that do not have easy or singular solu-

tions. Leaders who merely give directions and expect them to be followed will not succeed in this

environment. What is needed is a style of leadership that involves working with others as full part-

ners in a context of mutual respect and collaboration. For this, new evidence-based approaches to

better communication and collaboration between the different healthcare professionals are needed.

A systematic review is needed to synthesise knowledge about all existing interventions that focus on

the long-term use of BZDs in older people and combined approaches for the stakeholders. Physi-

cians, pharmacists, and nurses must work together to break down the walls of hierarchical silos and

hold each other accountable for improving quality, and decreasing preventable adverse events and

medication errors. Future research should pay more attention to the sample characteristics; a more

comprehensive description is needed of the individual characteristics of the healthcare professionals

(such as age and years working). All of these players must display the ability to adapt to the continu-

ally evolving dynamics of the healthcare system. There is a need for more scientific research to bet-

ter understand which strategies are most effective and could be implemented in the daily clinical



This study was funded by the Federal Ministry of Health (reference number: IIA5-2513DSM235)

Ethical approval

Ethical approval was obtained from the medical ethics committees of Hamburg and Muenster for

the LWL-Klinik in Lippstadt (Hamburg PV4688, 27 May 2014 and Muenster 2014-330-b-S, 10 June


Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 8 of 10



Freely submitted; externally peer reviewed.


The authors are grateful to all of the participants who took part in the focus group interviews.

1. Ćurković M, Dodig-Ćurković K, Erić AP, et al. Psychotropic medications in older adults: a review. Psychiatr

Danub 2016; 28(1): 13–24.
2. Mehdi T. Benzodiazepines revisited. British Journal of Medical Practitioners. 2012; 5(1): 501.
3. Gallagher H. Addressing the issue of chronic, inappropriate benzodiazepine use: how can pharmacists play a

role? Pharmacy 2013; 1(2): 65–93. doi: 10.3390/pharmacy1020065
4. Holzbach R. [Benzodiazepine long-term use and dependence] Benzodiazepin-Langzeitgebrauch und –

abhängigkeit (in German). Fortschritte der Neurologie-Psychiatrie 2010; 78(07): 425–434.
5. Smink BE, Egberts AC, Lusthof KJ, et al. The relationship between benzodiazepine use and traffic accidents:

A systematic literature review. CNS drugs 2010; 24(8): 639–653. doi: 10.2165/11533170-000000000-00000
6. Olfson M, King M, Schoenbaum M. Benzodiazepine use in the United States. JAMA Psychiatry 2015; 72(2):

136–142. doi: 10.1001/jamapsychiatry.2014.1763
7. Wolter DK. [Main topic: sleep aids and sedatives in old age] Themenschwerpunkt: Schlaf- und

Beruhigungsmittel im Alter (in German). Zeitschrift fu€r klinische Psychologie, Psychopathologie und
Psychotherapie 2008; 56(1): 19–25.

8. Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip
fracture. JAMA 1989; 262(23): 3303–3307. doi: 10.1001/jama.1989.03430230088031

9. Rummans TA, Davis LJ, Morse RM, et al. Learning and memory impairment in older, detoxified,
benzodiazepine-dependent patients. Mayo Clin Proc 1993; 68(8): 731–737. doi: 10.1016/S0025-6196(12)

10. Pat McAndrews M, Weiss RT, Sandor P, et al. Cognitive effects of long-term benzodiazepine use in older
adults. Hum Psychopharmacol 2003; 18(1): 51–57. doi: 10.1002/hup.453

11. Cumming RG, Le Couteur DG. Benzodiazepines and risk of hip fractures in older people. A review of the
evidence. CNS Drugs 2003; 17(11): 825–837. doi: 10.2165/00023210-200317110-00004

12. Clyne B, Bradley MC, Hughes CM, et al. Addressing potentially inappropriate prescribing in older patients:
development and pilot study of an intervention in primary care (the OPTI-SCRIPT study). BMC Health Serv
Res 2013; 13(1): 307. doi: 10.1186/1472-6963-13-307

13. Cook JM, Biyanova T, Masci C, et al. Older patient perspectives on long-term anxiolytic benzodiazepine use
and discontinuation: a qualitative study. J Gen Intern Med 2007; 22(8): 1094–1100. doi: 10.1007/s11606-

14. Anthierens S, Habraken H, Petrovic M, et al. First benzodiazepine prescriptions: qualitative study of patients’
perspectives. Can Fam Physician 2007; 53(7): 1200–1201.

15. Anthierens S, Habraken H, Petrovic M, et al. The lesser evil? Initiating a benzodiazepine prescription in
general practice. Scand J Prim Health Care 2007; 25(4): 214–219. doi: 10.1080/02813430701726335

16. Parr JM, Kavanagh DJ, Young RM, et al. Views of general practitioners and benzodiazepine users on
benzodiazepines: a qualitative analysis. Soc Sci Med 2006; 62(5): 1237–1249. doi: 10.1016/j.socscimed.2005.

17. Perodeau G, Grenon É, Grenier S, et al. Systemic model of chronic benzodiazepine use among mature
adults. Aging Ment Health 2016; 20(4): 380–390. doi: 10.1080/13607863.2015.1015961

18. Turnheim K. Drug therapy in the elderly. Exp Gerontol 2004; 39(11-12): 1731–1738. doi: 10.1016/j.exger.

19. Brett J, Murnion B. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015; 38(5): 152–
155. doi: 10.18773/austprescr.2015.055

20. Tjagvad C, Clausen T, Handal M, et al. Benzodiazepine prescription for patients in treatment for drug use
disorders: a nationwide cohort study in Denmark, 2000–2010. BMC Psychiatry 2016; 16: 168. doi: 10.1186/

21. Martin P, Tamblyn R, Ahmed S, et al. An educational intervention to reduce the use of potentially
inappropriate medications among older adults (EMPOWER study): protocol for a cluster randomized trial.
TRIALS 2013; 14: 80. doi: 10.1186/1745-6215-14-80

22. Farrell B, Shamji S, Dalton D. Managing chronic diseases in the frail elderly: More than just adhering to
clinical guidelines. Can Pharm J (Ott) 2014; 147(2): 89–96. doi: 10.1177/1715163513514021

23. Schuling J, Gebben H, Veehof LJ, et al. Deprescribing medication in very elderly patients with
multimorbidity: the view of Dutch GPs. A qualitative study. BMC Fam Pract 2012; 13: 56. doi: 10.1186/1471-

24. Forsetlund L, Eike MC, Gjerberg E, et al. Effect of interventions to reduce potentially inappropriate use of
drugs in nursing homes: a systematic review of randomised controlled trials. BMC Geriatr 2011; 11: 16. doi:

25. Légaré F, Stacey D, Turcotte S, et al. Interventions for improving the adoption of shared decision making by
healthcare professionals. Cochrane Database Syst Rev 2014; 9(9): CD006732. doi: 10.1002/14651858.

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 9 of 10


26. Royal Australian College of General Practitioners, Newman R. Prescribing drugs of dependence in general
practice. Part B Benzodiazepines.2015;
Part-B-Benzodiazepines.pdf. (accessed 14 Feb 2019).

27. Wilkinson S. Focus group methodology: a review. Int J Soc Res Methodol 1998; 1(3): 181–203. doi: 10.1080/

28. Tong A, Sainsbury P, Craig J. Consolidated criteria for reporting qualitative research (COREQ): a 32-item
checklist for interviews and focus groups. Int J Qual Health Care 2007; 19(6): 349–357. doi: 10.1093/intqhc/

29. Institute of Medicine (US) Committee on Quality of Health Care in America. Crossing the quality chasm: a
new health system for the 21st century. Washington, DC: National Academies Press (US), 2001.

30. Scholl I, Zill JM, Härter M, et al. An integrative model of patient-centeredness — a systematic review and
concept analysis. PLoS One 2014; 9(9):e107828. doi: 10.1371/journal.pone.0107828

31. Loh A, Simon D, Kriston L, et al. [Patient involvement in medical decisions] Patientenbeteiligung bei
medizinischen Entscheidungen (in German). Deutsches A€rzteblatt 2007; 104(21): A1483–1488.

32. Joosten EA, DeFuentes-Merillas L, de Weert GH, et al. Systematic review of the effects of shared decision-
making on patient satisfaction, treatment adherence and health status. Psychother Psychosom 2008; 77(4):
219–226. doi: 10.1159/000126073

33. de Silva D. Evidence: helping people help themselves. A review of the evidence considering whether it is
worthwhile to support self-management. 2011;
HelpingPeopleHelpThemselves.pdf (accessed 14 Feb 2019).

34. Bodenheimer T, Lorig K, Holman H, et al. Patient self-management of chronic disease in primary care. JAMA
2002; 288(19): 2469–2475. doi: 10.1001/jama.288.19.2469

35. Mugunthan K, McGuire T, Glasziou P. Minimal interventions to decrease long-term use of benzodiazepines
in primary care: a systematic review and meta-analysis. Br J Gen Pract 2011; 61(590): e573–e578. doi: 10.

36. Rao JK, Anderson LA, Inui TS, et al. Communication interventions make a difference in conversations
between physicians and patients: a systematic review of the evidence. Med Care 2007; 45(4): 340–349. doi:

37. Farmer AP, Légaré F, Turcot L, et al. Printed educational materials: effects on professional practice and
health care outcomes. Cochrane Database Syst Rev 2008; 3(3): CD004398. doi: 10.1002/14651858.

38. Marshall B, Cardon P, Poddar A, et al. Does Sample Size Matter in Qualitative Research?: A Review of
Qualitative Interviews in is Research. Journal of Computer Information Systems 2013; 54(1): 11–22. doi: 10.

39. Sandelowski M. Sample size in qualitative research. Res Nurs Health 1995; 18(2): 179–183. doi: 10.1002/nur.

40. Grimshaw JM, Shirran L, Thomas R, et al. Changing provider behavior: an overview of systematic reviews of
interventions. Med care 2001; 39(8 Suppl 2): II2–45.

41. Furbish SML, Kroehl ME, Loeb DF, et al. A pharmacist-physician collaboration to optimize benzodiazepine
use for anxiety and sleep symptom control in primary care.. J Pharm Pract 2017; 30(4): 425–433. doi: 10.

42. Dollman WB, Leblanc VT, Stevens L, et al. Achieving a sustained reduction in benzodiazepine use through
implementation of an area-wide multi-strategic approach. J Clin Pharm Ther 2005; 30(5): 425–432. doi: 10.

43. Tannenbaum C, Martin P, Tamblyn R, et al. Reduction of inappropriate benzodiazepine prescriptions among
older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med
2014; 174(6): 890–898. doi: 10.1001/jamainternmed.2014.949

Mokhar A et al. BJGP Open 2019; DOI: 10.3399/bjgpopen18X101626 10 of 10


50 AANA Journal February 2022 Vol. 90, No. 1

With a brief summary of selected literature identi-
fied by a multidisciplinary panel of subject matter
experts, the authors share their experience with the
development of an institutional perioperative pain
management guideline for patients on maintenance
medication for addiction treatment (MAT), stressing
the importance of perioperative continuation of opioid
agonists such as methadone and partial agonists such

as buprenorphine; and the discontinuation of opioid
antagonists, such as naltrexone. The authors’ protocol
is appended as an example of a standardized approach
to perioperative management of patients on MAT.

Keywords: Anesthesiology, medication for addiction
treatment, pain management, perioperative manage-
ment, substance use disorder.

Perioperative Management of Patients on

Maintenance Medication for Addiction Treatment:

The Development of an Institutional Guideline

Gillian A. Beauchamp, MD

Jill L. Hanisak, DNP, CRNA

Alexandra M. Amaducci, DO

Andrew L. Koons, DO

Jason Laskosky, PharmD, BCPS

Bernadette M. Maron, RN, BHCM

Thomas M. McLoughlin, Jr, MD

ublic health in the United States is challenged
by the intertwined relationship of the morbid-
ity associated with chronic pain syndromes and
the mortality associated with a crisis of opioid
overdoses.1-4 Factors contributing to this crisis

are multifactorial and extensively described in the existing
literature, but include the influence of the pharmaceutical
industry, pressure from medical governing bodies to link
pain relief with patient satisfaction, and a historical lack of
adequate screening and monitoring for at-risk patients.5
Given that the majority of opioids prescribed in the post-
operative setting go unused, and are neither stored nor
disposed of properly, over-prescribing has undoubtedly
contributed to the risk of harmful opioid use, the develop-
ment of iatrogenic opioid use disorder, and the alarming
rate of opioid overdoses which surpassed 50,000 deaths
in 2019.6,7

Managing pain in the context of the ongoing crisis of
overdose deaths remains a challenge that involves weigh-
ing the risks and benefits of pain management modalities
while assessing risk related to medical issues, psychiatric
comorbidities, and substance use disorder (SUD).2 The
medical community continues to explore how to safely
and effectively manage perioperative pain while minimiz-
ing the risk of iatrogenic opioid use disorder or exacerba-
tion of existing SUD.3

Efforts to reduce risk have included opioid-sparing
modalities for pain management, reduction in post-
operative prescribed opioids, and screening patients for

SUD risk factors.4 Standardized approaches to risk as-
sessment for harmful substance use and recurrence of
use are lacking in many settings where opioids are used
to manage pain.8,9

The use of medications such as methadone, buprenor-
phine, and naltrexone to support recovery from SUD,
also known as medication for addiction treatment (MAT)
is supported by the existing literature and considered the
standard of care for management of SUD.10 The periop-
erative management of patients on maintenance warrants
effective pain control without substantially increasing
risk of recurrence of substance use.11 Specifically, non-
opioid or opioid-sparing multimodal approaches to
perioperative pain management are an important consid-
eration and may include agents such as nonsteroidal anti-
inflammatory medications (NSAIDs), gabapentinoids,
ketamine, and neuraxial and regional anesthesia.12,13

Institutional guidelines directing SUD-focused periop-
erative considerations should include: assessing psycho-
logical support needs, multimodal approaches, dosing
strategies that account for potential opioid tolerance,
withdrawal management, avoiding hyperalgesia, assess-
ing risk of recurrence of use, deciding whether to con-
tinue MAT, and cautious monitoring.11,14-17

Description of Project
With a brief summary of selected literature identified
by a multidisciplinary group of institutional subject
matter experts, the authors share their experience with AANA Journal February 2022 Vol. 90, No. 1 51

the development of an institutional perioperative pain
management guideline for patients on MAT, stressing
their recommendations around the importance of peri-
operative continuation of opioid agonist MAT and the
discontinuation of opioid antagonist MAT.16,18-20 The
protocol is appended (See Figures 1-3) as an example of
a standardized approach to perioperative management of
patients on MAT. A perioperative plan that includes ef-
fective multimodal pain management and opioid sparing
strategies, while managing withdrawal and decreasing
risk factors for recurrence of substance use, is essential
for effective care for patients on maintenance MAT.21

MAT: Methadone
Methadone is a full mu opioid receptor agonist with
additional N-methyl-d-aspartate (NMDA) receptor an-
tagonism and reuptake inhibition of serotonin and
norepinephrine, utilized for patients with opioid use
disorder and/or moderate to severe chronic pain.18,22,23
Methadone and other medications to support recovery
are intended to reduce harm from chronic opioid use,
prevent withdrawal, and reduce patient preoccupation

with opioids and cravings.24 Methadone’s elimination is
biphasic, with a short analgesic phase (8-12 hours) and
a long sub-analgesic and withdrawal suppression phase
(30-60 hours).18,25 The equianalgesic conversion ratio
for methadone to and from other opioids is variable and

Perioperative Considerations: Methadone
Prior studies have reported that patients on maintenance
methadone may have an increased opioid tolerance con-
comitant with a decreased tolerance for pain, and thus
may need higher perioperative and post-operative ad-
junctive opioid doses compared to patients who are not
tolerant to opioids.23,26 In addition to its use as a medica-
tion to support recovery from opioid use disorder, meth-
adone has gained popularity for perioperative pain relief
in patients undergoing painful surgical procedures.27

As a full mu receptor agonist, continuing baseline
methadone dosing throughout the perioperative period
assists with perioperative analgesia and is easily supple-
mented with additional opioids as needed, providing a
basal level of opioid support for patients accustomed to
daily methadone dosing. Continuation of methadone in

Figure 1. Guidelines for Methadone

52 AANA Journal February 2022 Vol. 90, No. 1

the perioperative period is generally recommended.28
Maintaining doses of chronic full mu agonist medications
like methadone likely reduces the risk of perioperative
opioid withdrawal, labile intraoperative hemodynamics,
and severe pain.29 Given a lack of definitive evidence to
suggest superiority of one approach over another, the
authors feel there are two feasible approaches to continu-
ing a patient’s baseline methadone dose: the dose may be
provided as a single morning (QAM) dose, as is typically
the practice at methadone treatment programs; or the pa-
tient’s total daily methadone dose could be divided three
times a day (TID) or four times a day (QID) during the
day of the surgery or procedure. The reason to continue
QAM dosing is to avoid the occurrence of methadone
withdrawal or anxiety related to a fear of withdrawal, as
the patient enters the perioperative setting on the day
of the procedure or operation. On the other hand, if the
patient is amenable, dividing the total baseline daily dose
TID or QID has potential to provide better pain control
throughout the day of the surgery or procedure.

There is risk for additive effects of other sedative and
analgesic medications in patients receiving methadone.
Strategies for opioid sparing perioperative pain manage-

ment include a multimodal approach with regional an-
algesia techniques when possible, while continuing the
daily methadone maintenance dose. The NMDA receptor
effects of methadone reduce hyperalgesia while also pro-
viding anti-allodynic properties, and thus may help to
avoid tolerance, reduce adjunctive opioid requirement,
and reduce the duration of postoperative pain.27

MAT: Buprenorphine
Buprenorphine is a semisynthetic opioid with complex
pharmacology.30-32 Buprenorphine acts as a partial
agonist at the mu receptor and an antagonist at the
kappa receptor, lending to its description as a mixed
opioid receptor agonist-antagonist.33,34 Clinical trial data
have shown a dose-response effect with analgesia, but
a ceiling effect for respiratory depression (eg, doubling
the dose from 0.2 mg to 0.4 mg IV resulted in a 3.5 fold
increase in analgesic effect, but no change in the mag-
nitude of respiratory depression).35 Respiratory ceiling
effects have been shown with the sublingual formulation
whereby doses of 32 mg resulted in no more respiratory
depression than 16 mg among patients without physical

Figure 2. Guidelines for Buprenorphine AANA Journal February 2022 Vol. 90, No. 1 53

Buprenorphine displays a bell-shaped analgesic effect
in rodents, but a reduced analgesic effect at the upper
range of normally prescribed doses has not been observed
in humans.30,32 Buprenorphine possesses a high mu re-
ceptor affinity resulting in a relative, but not absolute,
inability of agents with lower mu receptor affinity (eg,
morphine) to displace buprenorphine from receptor sites.
Full mu opioid agonists with higher affinity, or at higher
doses, can provide additional analgesia when administered
to patients already receiving buprenorphine. Conversely,
high receptor affinity explains why buprenorphine, when
newly initiated in patients receiving full mu opioid ago-
nists of lower affinity, can precipitate withdrawal due to
net displacement of full mu agonists by buprenorphine.31
When given sublingually (SL), buprenorphine has a
mean elimination half-life ranging from 24 to 42 hours
permitting daily or twice daily maintenance dosing for
withdrawal suppression.33 The reported duration of an-
algesia (SL formulation) is considerably shorter at only
4-8 hours, so more frequent divided doses may be con-
sidered for perioperative patients receiving maintenance
buprenorphine for withdrawal suppression, eg, instead of
standard BID dosing, half-dose QID may be considered.34

Other commercially available formulations of bu-
prenorphine in the United States include: a long acting
subdermal implant; a subcutaneous injection depot for-
mulation intended for maintenance treatment of opioid
use disorder; and a transdermal patch intended for man-
agement of severe pain—all possess longer durations of
action resulting from drug formulation rather than any
change in in vivo metabolism.31

When administered SL, buprenorphine undergoes
first pass metabolism to the active metabolite norbu-
prenorphine by CYP isoenzymes.31 Routes of administra-
tion that avoid the first pass effect (intravenous or intra-
nasal) result in less norbuprenorphine formation, which
may be of clinical relevance.31 Given hepatic metabolism
via CYP3A4, consideration should be given to patients
receiving concurrent CYP3A4 inhibitors and inducers
given potential CYP mediated drug-drug interactions.33

In efforts to reduce potential for harmful use of SL
and buccal buprenorphine, buprenorphine is most often
prescribed as co-formulated with naloxone (ratio 4:1).33
Interestingly, SL naloxone has been shown to precipi-
tate withdrawal in doses of more than 2 mg, but not at
lower doses.36

Figure 3. Guidelines for Naltrexone Inj. (Vivitrol)

54 AANA Journal February 2022 Vol. 90, No. 1

Perioperative Considerations: Buprenorphine
There are several published approaches for perioperative
management and acute pain management of patients re-
ceiving buprenorphine, but clear evidence to support any
one approach is limited.37,38 Common practice at many
institutions includes cessation of maintenance buprenor-
phine 48-72 hours prior to surgery, yet this practice is
based on scant data.39

Silva et al39 describe the properties of buprenorphine
that have been extrapolated to develop poorly supported
theories around perioperative management of MAT
patients. First, because buprenorphine is a partial mu
agonist, it is inferred that it is not a potent analgesic.
Second, because buprenorphine has a ceiling effect on
respiratory depression, some assume that it also has a
ceiling effect on analgesia. Third, it has been assumed
that buprenorphine acts as a “blockade” to the analgesic
effects of other co-administered opioids due to its strong
binding affinity. Although studies have demonstrated a
ceiling effect for buprenorphine-induced euphoria and
respiratory depression, a ceiling effect for analgesia has
never been demonstrated.39

As recently as 2014, it was common for practitioners
to believe that since buprenorphine is a partial opioid
agonist with a high affinity for mu-opioid receptors,
patients on buprenorphine were expected to require a
higher dose of opioid during the perioperative period. It
was also assumed that a standard opioid-based anesthesia
plan may be insufficient for patients on buprenorphine,
thus a patient’s buprenorphine would need to be discon-
tinued and replaced with full agonist opioids to ensure
proper pain management.40 However, more recent guide-
lines recommend continuing a patient’s buprenorphine
in the perioperative period. Acampora et al37 propose
that continuing buprenorphine and adding a full agonist
opioid (FAO) is safe and may provide increased analge-
sia, thus reducing the perioperative FAO requirement
and limiting risk of recurrence of harmful post-operative
substance use in this population.

The lack of clear guidelines for the perioperative man-
agement of patients on MAT may cause apprehension
for both the patient and the medical team.37 Maintaining
buprenorphine preoperatively has not been associated
with worse clinical outcomes. In fact, discontinuation
of opioid maintenance therapy can lead to recurrence of
harmful opioid use, with estimates of up to 90% recur-
rence of use when MAT is discontinued prematurely.15
In a multicenter trial of primary heroin or prescription
opioid users seeking treatment for opioid dependence,
82% of the 516 participants enrolled had recurrence of
harmful opioid use within one month following an inci-
dence of perioperative buprenorphine cessation.41

Maintaining patients on buprenorphine at a dose that
allows for a sufficient proportion of unoccupied mu re-
ceptors will allow for binding of any full mu agonists that

are administered perioperatively.38 High-dose buprenor-
phine therapy (described as 24 mg per day sublingually)
may occupy too large a percentage of mu opioid receptors,
and therefore render commonly used FAOs ineffective;
however standard buprenorphine dosing is 8 mg BID.
Consideration may be given for careful tapering to a
lower, moderate daily dose of buprenorphine dose before
painful, elective surgery in patients on daily doses of bu-
prenorphine 24 mg/day.38 Receptor availability studies
show that for high buprenorphine maintenance doses
(24-32 mg daily), the availability of mu-opioid receptors
is minimal whereas at lower doses (8-12 mg daily), there
is still up to 20% mu-opioid receptor availability.15

Acampora et al37 suggest a structured dosing strategy
throughout the perioperative period to avoid withdrawal
and risk of recurrence of harmful substance use while
maximizing pain management. They recommend 8 mg of
buprenorphine/naloxone twice daily for a total of 16 mg
of buprenorphine the day before surgery to prevent crav-
ings, followed by 4 mg twice a day on the day of surgery
and postoperatively to open some mu receptors for avail-
ability to FAOs as needed. Because buprenorphine has a
high affinity and long duration of effect at the mu recep-
tor, it provides significant analgesia at relatively low sub-
lingual doses. Analgesic doses of buprenorphine (ideally
4 mg BID) in combination with FAOs produce synergis-
tic analgesia. Buprenorphine effects at the mu receptor
are reversible, and within 24 hours after reducing the
daily buprenorphine dose among patients on high-dose
buprenorphine, 40% of opioid receptors become unoc-
cupied again.37 It is the opinion of the authors that where
stable buprenorphine dosing is maintained, or reduced
from high dose regimens to increase the available mu re-
ceptors for concomitant full mu-agonist administration,
the continuation of buprenorphine in the perioperative
period is effective in avoiding withdrawal, cravings, and
risk of recurrence of harmful opioid use.

Goel et al20 report that the current level of evi-
dence as described by the Grading of Recommendations,
Assessment, Development and Evaluations (GRADE)
tool regarding perioperative management of patients
on buprenorphine is weak. The number of studies to
address this perioperative dilemma is limited, and few
directly evaluate the question of continuing versus dis-
continuing buprenorphine. They suggest with Level 5
evidence that it is almost always appropriate to continue
buprenorphine at the preoperative maintenance dose
and that it is rarely appropriate to reduce the buprenor-
phine dose. Postoperatively, they suggest with Level 4
evidence that after analgesic adjuncts have been initiated,
it is appropriate to consider a full mu agonist to manage
pain. If inadequate analgesia persists in the perioperative
setting, one can consider buprenorphine dose reduction
in the context of full mu-agonist use. They also recom-
mend always prescribing non-opioid adjunct analgesia, AANA Journal February 2022 Vol. 90, No. 1 55

such as NSAIDs, acetaminophen, gabapentin/pregabalin,
ketamine, dexmedetomidine, lidocaine, and regional an-
esthesia when appropriate. In the post-operative setting,
it is almost always appropriate to discharge patients
with a plan to continue their pre-operative maintenance
dose of buprenorphine, with close monitoring and com-
munication with the patient’s outpatient buprenorphine
prescriber.20 Quaye et al,42 reported a significant re-
duction in the need for post-operative opioids, as well
as improved early recovery pain scores, in patients for
whom buprenorphine was continued versus held in the
perioperative setting.

Elective procedures provide the luxury of time to
adequately plan, counsel patients, and discuss avail-
able strategies with an interdisciplinary team. However,
emergent procedures allow much less flexibility and may
require more urgent strategizing.38

MAT: Naltrexone
Unlike the mixed receptor pharmacology of methadone
and buprenorphine, naltrexone (like naloxone) is a pure
opioid antagonist with high affinity for the mu recep-
tor.34,43-45 While the mechanism of action of naltrexone
in the management of opioid use disorder centers around
mu receptor blockade, its efficacy in the management of
alcohol use disorders hinges on its ability to blunt the en-
dogenous opioid reward pathway resulting in decreased
euphoria from ethanol.46

When administered in its oral formulation (tablet), na-
ltrexone is typically prescribed daily and, after administra-
tion for 7 days, the half-life is approximately 10 hours.43
Given extensive metabolism to an active metabolite (6
beta naltrexol) and dependence on renal elimination of
both the parent compound and metabolite, hepatic and
or renal insufficiency may prolong duration of action.
In addition to an immediate release tablet, naltrexone
has been more recently available as an extended release
(monthly IM injection) formulation.47 Following IM in-
jection, plasma concentrations peak within 1-2 hours, fall
transiently and then demonstrate a second peak at higher
concentrations by day 2-3. Beginning approximately 14
days after dosing, concentrations slowly decline, with
measurable concentrations for greater than 1 month.46

Perioperative Considerations: Naltrexone
Both oral and IM naltrexone yield full mu opioid antago-
nism, but due to their differing pharmacokinetics, need
to be treated differently in the perioperative setting. No
consensus recommendations exist, and perioperative
planning should be done on a case-by-case basis. In our
opinion, specific risk-benefit decisions must be made
between the surgical and anesthesiology teams as well
as the naltrexone prescriber in regard to the timing for
surgery, ability to use opioid-sparing techniques and, if
needed, the timing for discontinuation and reinstitution

of naltrexone therapy. It may be prudent to continue nal-
trexone for procedures that are expected to cause mild or
no pain, or that can be managed with non-opioid modali-
ties, especially in those patients deemed to be high-risk
for recurrence of harmful use.

For surgical procedures that are expected to result
in moderate to severe pain, it may be necessary to stop
naltrexone pre-operatively to improve analgesia. To
account for 5 half-lives, and allow for effective opioid
agonist action, oral naltrexone should be discontinued 72
hours before surgery (or potentially longer in the setting
of renal or hepatic insufficiency). The timeline for IM
naltrexone is not as clear, but successful pain manage-
ment with opioids is reported starting at least 21 days
post-injection, with increased success as time progresses
towards the end of the 28-day injection cycle.48 For those
surgeries that are unplanned and emergent, and for which
naltrexone discontinuation is not an option, the surgical
and anesthesiology team must rely heavily on non-opioid
analgesics and modalities such as regional anesthesia,
since opioids are not likely to have their intended effect.

It is important to note that this subset of patients is
particularly prone to variability in their opioid response
both peri- and postoperatively. Patients who are recently
or remotely dependent on opioids can demonstrate a
tolerance to their effects. However, when a patient starts
naltrexone therapy, they become susceptible to both
attenuation and enhancement of the opioid effect.18
Therefore, the authors recommend that opioids provided
in this context be used at low doses and titrated to effect.
Naltrexone has a higher affinity for mu-opioid receptors
than full-mu agonists. It will displace and block the re-
ceptor from opioid agonism and precipitate withdrawal if
given when opioid agonists are still circulating in the pa-
tient’s system.49 Thus, postoperatively, the patient should
not be restarted on their naltrexone until 7-10 days after
their last dose of opioid.50

At the authors’ institution, as the number of patients
treated for substance use disorder continues to rise,
provisions for the perioperative management of surgi-
cal patients with substance use disorder are a priority. A
multidisciplinary workgroup including representatives
from anesthesiology, surgery, pharmacy, pain medicine,
quality and safety, medical toxicology, and addiction
medicine, collaborated in the development of a clinical
guideline and treatment algorithm. The consensus of our
multidisciplinary team is that discontinuing medications,
such as buprenorphine and methadone, in the periopera-
tive setting increases risk for withdrawal, recurrence of
substance use, delays to re-initiation of post-operative
MAT, and increased pain. Challenges and opportunities
involved in the consensus process included ensuring that
all stakeholders were familiarized with the literature as

56 AANA Journal February 2022 Vol. 90, No. 1

selected by our institutional subject matter experts, and
implementing practice change, particularly around the
notion of continuing perioperative buprenorphine. The
authors’ pathway includes discontinuation of the mu
antagonist naltrexone prior to surgery when possible, but
continuation of partial or full mu agonist medications,
such as buprenorphine and methadone, throughout the
perioperative period. A multimodal approach for periop-
erative pain management that included guidance around
whether to continue MAT was developed to provide
maximal pain relief with minimal risk of recurrence of
harmful substance use. A limitation of guideline devel-
opment was the leveraging of subject matter expertise
in lieu of a systematic review and grading of the litera-
ture. Clinician education and development of electronic
medical record decision support related to this guideline
is ongoing to further enhance the delivery of quality peri-
operative care for patients on MAT. Future areas of study
include assessing both effectiveness of, and barriers to,
guideline implementation. The guidelines are shared with
the hope that they may assist others in developing similar
protocols (See Figures 1-3).

REFERENCES AANA Journal February 2022 Vol. 90, No. 1 57

Gillian A. Beauchamp, MD, is an emergency physician, medical toxi-
cologist, and addiction specialist, Department of Emergency and Hospital
Medicine, Lehigh Valley Health Network/University of South Florida
(USF) Morsani College of Medicine, Allentown, Pennsylvania. Email: Gil-
[email protected]

Jill L. Hanisak, DNP, CRNA, is the education coordinator of the
Department of Anesthesiology for Lehigh Valley Health Network.

Alexandra M. Amaducci, DO, is a medical toxicology fellow and
emergency medicine physician, Department of Emergency and Hospital
Medicine, Division of Medical Toxicology, Lehigh Valley Health Network/
University of South Florida (USF) Morsani College of Medicine.

Andrew L. Koons, DO, is an emergency physician and medical toxi-
cologist, Department of Emergency and Hospital Medicine, Division of
Medical Toxicology, Lehigh Valley Health Network/University of South
Florida (USF) Morsani College of Medicine.

Jason Laskosky, Pharm D, BCPS, is a clinical pharmacy specialist in
Critical Care, Department of Pharmacy, Lehigh Valley Health Network.

Bernadette M. Maron, RN, BHCM, is a quality nurse specialist and
certified professional in Health Care Quality, Department of Anesthesia
and Perioperative division at Lehigh Valley Health Network.

Thomas M. McLoughlin, Jr, MD, is chair of the Department of Anes-
thesiology for Lehigh Valley Health Network/University of South Florida
(USF) Morsani College of Medicine.

Name: Gillian A. Beauchamp, MD
Contribution: This author made significant contributions to the concep-
tion, synthesis, writing and final editing and approval of the manuscript
to justify inclusion as an author.
Disclosures: None
Name: Jill L. Hanisak, DNP, CRNA
Contribution: This author made significant contributions to the concep-
tion, synthesis, writing and final editing and approval of the manuscript
to justify inclusion as an author.
Disclosures: None
Name: Alexandra M. Amaducci, DO
Contribution: This author made significant contributions to the concep-
tion, synthesis, writing and final editing and approval of the manuscript
to justify inclusion as an author.
Disclosures: None
Name: Andrew L. Koons, DO
Contribution: This author made significant contributions to the concep-
tion, synthesis, writing and final editing and approval of the manuscript
to justify inclusion as an author.
Disclosures: None
Name: Jason Laskosky, Pharm D, BCPS
Contribution: This author made significant contributions to the concep-
tion, synthesis, writing and final editing and approval of the manuscript
to justify inclusion as an author.
Disclosures: None
Name: Bernadette M. Maron, RN, BHCM
Contribution: This author made significant contributions to the concep-
tion, synthesis, writing and final editing and approval of the manuscript
to justify inclusion as an author.
Disclosures: None
Name: Thomas M. McLoughlin, Jr, MD
Contribution: This author made significant contributions to the concep-
tion, synthesis, writing and final editing and approval of the manuscript
to justify inclusion as an author.
Disclosures: None
The authors did discuss off-label use within the article. Disclosure state-
ments are available for viewing upon request.

Copyright of AANA Journal is the property of American Association of Nurse Anesthetists
and its content may not be copied or emailed to multiple sites or posted to a listserv without
the copyright holder’s express written permission. However, users may print, download, or
email articles for individual use.

Frontiers in Psychiatry | www.frontiersin.or

Edited by:
Yanhui Liao,

Sir Run Run Shaw Hospital, China

Reviewed by:
Yu-Tao Xiang,

University of Macau, China
Xiao Jun Xiang,

Central South University, China
Yanbo Zhang,

University of Alberta, Canada

Yanqing Tang

[email protected]

Specialty section:
This article was submitted to

Addictive Disorders,
a section of the journal
Frontiers in Psychiatry

Received: 21 May 2020
Accepted: 16 July 2020

Published: 17 September 2020

Liu L, Jia L, Jian P, Zhou Y, Zhou J,

Wu F and Tang Y (2020) The Effects of
Benzodiazepine Use and Abuse on

Cognition in the Elders: A Systematic
Review and Meta-Analysis
of Comparative Studies.

Front. Psychiatry 11:00755.
doi: 10.3389/fpsyt.2020.00755

published: 17 September 2020
doi: 10.3389/fpsyt.2020.00755

The Effects of Benzodiazepine Use
and Abuse on Cognition in the
Elders: A Systematic Review and
Meta-Analysis of Comparative
Linzi Liu1, Linna Jia1, Peiying Jian2, Yifang Zhou3, Jian Zhou1, Feng Wu1

and Yanqing Tang1,3*

1 Department of Psychiatry, The First Affiliated Hospital, China Medical University, Shenyang, China, 2 Department of
Psychology, Queen’s University, Kingston, ON, Canada, 3 Department of Geriatrics, The First Affiliated Hospital, China
Medical University, Shenyang, China

Objective: Benzodiazepines (BZD) are one of the most frequently prescribed drugs
worldwide. However, the cognitive effects of benzodiazepines in the elderly are highly
debated. This systematic review and meta-analysis aims to explore the following two
questions in the elderly population: (i) Do BZD lead to any impairments in cognitive
functions in elderly users? and (ii) Which specific cognitive domains are most affected by
BZD use and abuse?

Methods: First, we performed a literature search following the PRISMA guidelines.
Electronic databases, including PubMed, PsycINFO, EMBASE, Cochrane Library, and
Web of Science were searched until May 14th, 2020. After selecting the relevant articles,
we integrated the results of the selected studies with a standardized cognitive
classification method. Next, we performed meta-analyses with the random-effects
model on the cognitive results. Finally, we specifically examined the cognitive
impairments of BZD in the abuse subgroup.

Results: Of the included studies, eight of the thirteen had meta-analyzable data.
Compared to the controls, elderly BZD users had significantly lower digital symbol test
scores (n=253; SMD: -0.61, 95% CI: -0.91 to 0.31, I² = 0%, p < 0.0001). There was no
significant difference in Mini-Mental State Examination, Auditory Verbal Learning Test, and
Stroop Color and Word Test scores between BZD users and controls. According to the
subgroup analyses, BZD abusers performed significantly worse than controls in Mini-
Mental State Examination (n=7726; SMD: -0.23, 95% CI: -0.44 to -0.03, I² = 86%, p =
0.02), while there was no significant difference between the regular BZD users and the
controls (n=1536; SMD: -0.05, 95% CI: -0.59 to 0.48, I² = 92%, p =0.85).

Conclusion: In the elderly population, the processing speed (digital symbol test scores)
was significantly impaired in BZD users; global cognition (Mini-Mental State Examination
scores) was significantly impaired in BZD abusers but not in BZD regular users. This study

g September 2020 | Volume 11 | Article 007551

Liu et al. Cognitive Effect of BZD

Frontiers in Psychiatry | www.frontiersin.or

provides insight into the factors that interact with BZD cognitive effects, such as aging,
testing tools, and abuse. Clinicians should be cautious when prescribing BZD for the

Systematic Review Registration: PROSPERO, identifier CRD42019124711.

Keywords: benzodiazepines, cognitive function, substance addiction, aged, meta-analysis, cognitive dysfuction


Benzodiazepines (BZD) are two-ring heterocyclic compounds
consisting of a benzene ring fused with a diazepine ring. Since its
discovery in the 1950s, BZD’s sedative, hypnotic, anti-anxiety,
and anti-convulsive effects have been increasingly accepted,
making BZD use highly prevalent among adults (1) and
especially in the elders (2). The prevalence of BZD use in
elders varies between 10% and 42% worldwide (3). For
example, BZD and related drugs are the third most abused
prescription drug in America, with roughly 1-3% of the world
population being subject to abuse (4). However, inappropriate
BZD prescriptions can promote BZD misuse, facilitate the
development of BZD addiction, and significantly affect the
users’ overall quality of life (5, 6). Therefore, it is critical for
pharmacists, clinicians, and patients to be informed on the latest
research regarding the adverse effects of BZD use and abuse.

Since the 1970s, research has found negative effects of BZD on
recipients’ cognitive functions (7). A meta-analysis in 2017
investigated the long-term cognitive impacts of BZD among
adults. This analysis reported impairments in working memory,
language, and processing speed, but not in executive function
(reasoning and planning) (8). The participants in the meta-
analysis, however, included adults of all ages. Compared to young
adults, elderly populations require more cautiousness when
undertaking BZD therapy. The elderly are more susceptible to
cognitive impairment than young adults (9). During the progress
of aging, cognitive function continues to decline with structural and
functional neurological changes (10, 11). The pharmacokinetics of
BZD in the elderly are different than in young adults, so the effects of
BZD in older adults may have unique characteristics than in any
other age group (12).

In recent years, several systematic reviews have found that
BZD use was significantly associated with a higher risk of
dementia and mild cognitive impairments (MCI). Dementia
and MCI introduced a significant growth in mortality and
financial burdens worldwide (13, 14). The most prominent
symptom of these neurological disorders is a decline in
cognitive function, measured by tests such as the Mini-Mental
State Examination (MMSE). Sufficient evidence has shown that
the risk of dementia correlates with cumulative dose, treatment
duration, and long-acting effects of BZD molecules (15–18).
However, previous literature failed to provide a causal account
for the link between BZD use and the risk of dementia (18). To
understand the mechanism behind the adverse effects of BZD, it
is crucial to investigate the specific areas of cognitive functions
that are impacted by BZD use and abuse.

g 2

Literature in the past 50 years presents contradicting evidence
on whether BZD impairs cognitive functioning in the elderly
(19–24). Among the studies that suggest an association between
BZD use and cognitive impairment in elders, the type and degree
of cognitive impairment reported are inconsistent across studies
(19, 20, 22). Moreover, the neurological alterations due to the
long-term effects of BZD use remains unclear (9). In 2018, Picton
and colleagues summarized the cognitive effects of BZD in the
elderly from published evidence. They found mixed findings of
the association between BZD therapy and cognitive decline in
elderly users (25). Given the lack of consensus in the current
literature, a meta-analysis study may help reveal the critical effects
of BZD use in the elderly and identify areas that require further
research. To our knowledge, there are no systematic reviews with a
meta-analysis that summarizes the current status of the cognitive
effect of BZD use and abuse in the elderly population.

This systematic review and meta-analysis aims to explore the
following two questions in the elderly: (i) Is BZD use associated
with impairment in cognitive functions in the elderly? and (ii)
Which cognitive domains have declined functionality associated
with BZD use and abuse? The answers could help characterize
the specific cognition impairments associated with BZD use, and
identify individuals vulnerable to the negative effects of BZD.
This meta-analysis may also help identify and monitor the
cognitive effects associated with BZD use and abuse to prevent
BZD addiction. With the high prevalence of BZD being
prescribed to older populations worldwide, it is essential to
inform clinicians and patients about the possible cognitive
impairments associated with BZD use and abuse. Given the
refractory rate and adverse effects of dementia and MCI (26), the
results may also help reduce inappropriate BZD prescriptions to
attenuate dementia risk in the elderly population.


Systematic Review Protocol
The process of this systematic review follows the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines, 2009 (27).

Databases and Search Strategy
We searched relevant articles in electronic databases, PubMed,
PsycINFO, EMBASE, Cochrane Library, and Web of Science,
from their inception to May 14, 2020. Specific search keywords
included “benzodiazepines”, “cognition”, and “aged”. The query
used for PubMed is ((Benzodiazepines[mh]) OR (Benzodiazepines

September 2020 | Volume 11 | Article 00755

Liu et al. Cognitive Effect of BZD

Compounds[Title/Abstract]) OR (Benzodiazep*[Title/Abstract]))
AND (cognit *’ OR memory OR attention OR visual-spatial OR
visuospatial OR recall OR recognition OR problem solving OR
reaction time OR vigilance OR executive function*’ OR reasoning
OR psychomotor OR motor OR processing OR planning OR
verbal fluency OR inhibit *’) AND ((Aged[mh]) OR (Elder*[Title/
Abstract]) OR (older adults[Title/Abstract])).

Additionally, we searched in Google Scholar and searched the
reference list for relevant articles to ensure that no studies
were missed.

Inclusion Criteria and the Process to
Identify Studies
We developed the inclusion criteria according to the PICOS
guideline. Appropriate papers met the following criteria: 1)
Participants were human adults, older than 60 years, mean
sample age over 65 years; 2) the treatment groups were BZD
users; 3) the studies had placebo or non-users of BZD as controls;
4) the outcomes included performances of cognitive functions
measured using any standardized neuropsychological instruments;
and 5) any type of published clinical studies except for case reports
or conference abstracts were used. We only included articles
reported in English.

Endnote was used to delete the duplicated articles. Two
reviewers (LL and JL) independently scanned the references by
title/abstract to exclude irrelevant articles, then read the full text
to identify the appropriate studies based on the above inclusion
criteria. Finally, the debated studies were determined through
discussions with a third reviewer (YT).

Risk of Bias and Quality Assessment
Two reviewers assessed the quality of each included study
independently with the modified Newcastle-Ottawa Scale
(mNOS) (28). The mNOS examines the quality of non-
randomized studies by four bias reduction items: (1) selection
bias, (2) performance bias, (3) detection bias, and (4) reporting
bias. Each item is graded from 0 (low quality) to 3 (high quality)
according to the example given for each risk level. Disagreements
were resolved by discussions with a third reviewer (Y.T.).
Publication bias was tested by using the funnel plot and Begg’s
tests on the outcome which synthesizes more than five studies.

Data Extraction
After generating a list of the included articles, two reviewers
made the data extraction form collectively. The two reviewers
then extracted the data independently. The data extraction form
contained the following information: (1) author and publication
year, (2) study design, (3) setting (country), (4) study design, (5)
mean age, (6) gender distribution, (7) education, (8) participants
sources, (9) details of BZD use (BZD types, using time, dosage,
and the definition of BZD use), and (10) outcomes (cognitive
task, cognitive domain, and main findings). The authors were
contacted in order to obtain any missing data.

Data Synthesis and Statistical Analyses
The included studies utilized a variety of psychometric
measurements, rendering it challenging to produce generalizable

Frontiers in Psychiatry | 3

and informative conclusions. In this paper, we organize cognitive
domains based on a commonly used framework (29, 30). According
to this framework, we summarized the outcomes of the cognitive
task from each included study to include a balanced and
comprehensive view. Due to the discrepancy in psychometric
screening tools between studies, the meta-analysis would only
synthesis the data from the same neuropsychological instruments,
such as the MMSE and the Auditory Verbal Learning Test (AVLT).

The RevMan software (31) was used to perform the meta-
analysis. We adopted the random-effects model in our meta-
analysis because it is more conservative than the fixed-effects
model. Standardized mean difference (SMD) with 95% confidence
intervals (CIs) was used for continuous outcomes. The study’s
heterogeneity was measured using I2. I2>50% indicated significant
heterogeneity (32). The meta-analytic outcomes were two-tailed,
with a significance level of 0.05. Based on BZD use information
reported in each study, we divided all the BZD users into two
categories: regular BZD users and BZD abusers. BZD regular use is
an appropriate pattern of BZD use that follows the prescription
instruction. BZD abuse behaviors include meeting sedative,
hypnotic, and anxiolytic use disorder criteria according to the
Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, and using a higher frequency or dose, or longer use time
than prescribed, or without a prescription (1, 4, 33). We then
conducted a subgroup analysis to explore the cognitive changes in
BZD abusers and regular BZD users.


Search Results and Studies Included
The study selection process of this systematic review is
summarized in Figure 1. A total of 5072 references were
returned by the initial search and scan, with 44 from relevant
reviews and Google Scholar. After removing duplicated and
irrelevant articles by title and abstract, the full texts of the
remaining 79 were screened and 15 articles finally met the
inclusion criteria. Two articles (34, 35) were from the same
cohort study named The Canadian Study of Health and Aging
(36). Another two articles had repeated participants (22, 37).
Overall, 13 studies were included in the literature review. In the
13 studies, eight had meta-analyzable data.

Risk of Bias and Quality Assessment
The risk bias of the included studies was assessed by the mNOS
and detailed in Table S1 in the Supplementary Materials. The
scores ranged from 13-19 out of 21. Nine studies (34, 38–45) had
a sample size of more than one thousand participants. Nine
studies (34, 38, 40–42, 44–47) used instruments that measured
multi cognition domains. Eleven studies matched or adjusted
education level as covariates and 12 studies matched or adjusted
age as covariates. Therefore, the overall risk bias of the included
studies is reasonably low. We tested the publication bias of the
meta-analysis results of MMSE scores; the funnel plot (Figure S1
in Supplementary Materials) and Begg’s tests (p=0.673) did not
find publication bias.

September 2020 | Volume 11 | Article 00755

Liu et al. Cognitive Effect of BZD

Studies Characteristics
There were 26033 participants (6374 BZD users) included in this
systematic review and 10666 (2318 BZD users) included in the
meta-analysis. As shown in Table 1, all studies were carried out
in America or Europe. Six out of thirteen were published in the
last five years. Eight were cohort studies; the remaining five were
cross-sectional studies. The mean age of the participants is 72.5
in the cohort studies at baseline, and 83.8 in the cross-sectional
studies. Therefore, both users and controls included in this
review were elderly participants. In the 13 studies, a total of 36
tasks were used to measure cognitive functions; each study
utilized one to nine cognitive tasks.

Synthesized Findings
Benzodiazepine Use and Cognitive Decline
in the Elders
Table 2 provides an overview of the effects on cognitive function
from BZD use consolidated from all the included studies. The
classification cognitive function division was adapted from a
commonly used method of understanding and measuring
cognitive domains (29). Eight of the thirteen studies with
cognitive performance data had meta-analyzable data. They
used the same cognitive measurements and reported the
quantitative results required for meta-analysis (Table 1). Our
meta-analysis synthesized data obtained with the same cognitive

Frontiers in Psychiatry | 4

tasks across the included studies. Overall, the meta-analysis
included the following cognitive functions: global cognition
measured with the MMSE, processing speed measured with the
digital symbol test, memory (recognition) measured with the
AVLT, and executive functions (inhibitory control) measured
with the Stroop Color and Word Test (SCWT) (Figures 2A–D).

Eleven out of 14 experiments on global cognition in the 13
studies showed no relationship between BZD use and decreased
performance in global cognition. However, two experimental results
(42, 47) showed that BZD users with higher socioeconomic status
and BZD abusers performed worse in the MMSE than non-using
controls. The remaining study by Bierman et al. (38) provided a
third alternative result. The population-based 9-year cohort study
concluded that, although there is a significant negative correlation
between the MMSE scores and the accumulated BZD, the decrease
in the MMSE scores with BZD use was relatively small. Moreover,
the authors reported no correlation between dosage of BZD and
MMSE scores. Taken together, the conclusions drawn from the
literature are consistent with our meta-analysis results (Figure 2A);
BZD users did not show significantly worse performance in the
MMSE compared to the controls (n=9262; SMD: -0.18, 95% CI:
-0.36 to 0.00, I² = 87%, p=0.05).

Seven studies tested the processing speed of BZD users. Four
studies concluded that BZD use in the elderly population may
result in significant impairment (41, 42, 47). They tested this

FIGURE 1 | Flow diagram of the search and study identification process.

September 2020 | Volume 11 | Article 00755

TABLE 1 | Summary of included articles.

itive task Cognitive domain

General Cognition
General Cognition

RAVLT; FTT General Cognition; Processing speed;
Immediate recall: verbal/visual; Gross motor

g Task; RAVLT; General Cognition; Processing speed;
Immediate recall: verbal/visual; Reasoning/

; TMT-A; BVRT; General Cognition; Processing speed;
Immediate recall: verbal/visual; Verbal fluency

SB General Cognition

T FAS; IGT; Tower
t; N-Back; SCWT

General Cognition; Vigilance/focus; Processing
speed; Immediate recall: verbal/visual; Delayed
recall: verbal/visual; Recognition: verbal/visual;
Verbal fluency; Reasoning/planning; Working
memory; Inhibitory control

T; semantic verbal
ls in one minute);

General Cognition; Immediate recall: verbal/
visual; Delayed recall: verbal/visual; Verbal
fluency; Reasoning/planning; Processing speed

SCWT; DVT General Cognition; Vigilance/focus; Immediate
recall: verbal/visual; Delayed recall: verbal/visual;
Recognition: verbal/visual; Inhibitory control

esign; Buschke
VLT Trial 6; Verbal
n Test; WAIS
AIS Similarities;

Processing speed; Immediate recall: verbal/
visual; Recognition: verbal/visual; Fine motor
speed; Verbal Fluency; Semantic processing;

LT-I; PLT-d;
rd Chart

General Cognition; Processing speed;
Immediate recall: verbal/visual; Delayed recall:
verbal/visual; Inhibitory control
General Cognition

General Cognition

Mental State Examination; TMT-B, The Trail Making Test, part B; DSS, The
rail Making Test, part A; BVRT, The Benton Visual Retention Test; IST, Isaacs
T, Rey Complex Figure Test; CVLT, California Verbal Learning Test; COWAT
e and Cued Selective Reminding Test; CDT, clock drawing test; DST, digit
ure Learning Test-delay.














Study Study design Country Samples (BZD

Mean Age
(BZD users)

Male per-

(BZD users)

Participants sources Cogn

Gray et al. (39) cohort study U.S. 3434(1018) 74.4(74.5) 40.4(33.1) population based CASI
Hanlon et al. (40) cohort study U.S. 2765(400) range(65-105) 33.5 community SPMSQ; OM
Paterniti et al. (42)a cohort study France 1176(159) 65(65.3) 41.6(23.7) population based TMT-B; DSS;

Bierman et al. (38)b cohort study Netherlands 2105(1189) 69.2 47.5 population based MMSE; Codin

Mura et al. (41)a,b cohort study France 5195(969) 73.5(74.6) 40.1(23.1) community MMSE; TMT-

Zhang et al. (43)b cohort study U.S. 5423(405) 73.0(73.6) 34.1(30.6) Alzheimer’s disease


Ros-Cucurull et al.

cohort study Spain 64(33) 73.2(73.5) 28.13(21.9) BZD users from
hospital; controls are

of London Te

Del Ser et al. (44) cohort study Spain 1087(810) 74.7 36.1 community MMSE; FCSR
fluency (anim

Hoiseth et al. (46)a cross-sectional

Norway 241(168) 78.6(78.1) 27.8(25.0) hospital MMSE; HVLT

Helmes and Ostbye


Canada 1754(408) 79.7(79.6) 38.7 community WAIS Block D
Free Recall; A
Fluency; Toke
Information; W
WAIS Compr

van Vliet et al. (45)a,


Netherlands 2275(702) range(85-90) 28.0(20.0) community MMSE; LDT;
SCWT the Th

Puustinen et al.


Finland 119(64) 81.6(82.1) 23.53(15.6) hospital MMSE

Hessmann et al.


Germany 395(49) 78.8(84.0) 31.9(28.6) hospital MMSE

CASI, Cognitive Abilities Screening Instrument; SPMSQ, Short Portable Mental Status Questionnaire; OMC, Orientation-Memory-Concentration Test; MMSE, Min
Digit Symbol Substitution Test; RAVLT, Rey Auditory Verbal Learning Test; FTT, Finger Tapping Test; RCPM, Raven’s Coloured Progressive Matrices; TMT-A, The T
Set Test; CDR-SB, Clinical Dementia Rating Sum of Boxes; CPT-II, Conners Continuous Performance Test II-Omissions; SDMT, Symbol Digits Modalities Test; RC
FAS, Controlled Oral Word Association Test; IGT, Iowa Gambling Task; SCWT, Stroop Color and Word Test; FCSRT, total immediate and delayed recall in the Fr
symbol test; HVLT, Hopkins Verbal Learning Test; DVT, Digit Vigilance Test; LDT, Letter Digit Coding Test; PLT-I, Picture Learning Test-immediately; PLT-d, Pic
Participants’ characteristics were collected according to baseline information.
aThe authors report meta-analyzable data.
bThe BZD abuse studies.










Liu et al. Cognitive Effect of BZD

TABLE 2 | Overview of tasks used to assess cognitive functioning in benzodiazepine users across different cognitive domains.

Cognitive domain Task Studies Sensitivitya

Attention and processing speed
Vigilance/focus Conners Continuous Performance Test II-Omissions (CPT-II) Ros-Cucurull et al. (47)* 1/1

Digit Vigilance Test (DVT) Hoiseth et al. (46) 0/1
Processing speed TMT-B Paterniti et al. (42); Mura et al. (41)* 2/2

TMT-A Mura et al. (41)* 1/1
The Digit Symbol Substitution (DSS) test Paterniti et al. (42) 1/1
Coding task Bierman et al. (38)* 0/1
Symbol Digits Modalities Test (SDMT) Ros-Cucurull et al. (47)* 1/1
WAIS Block Design Helmes and Ostbye (34) 0/1
Letter Digit Coding Test (LDT) van Vliet et al. (45)* 0/1
Digit Symbol Test (DST) Del Ser et al. (44) 1/1

Memory and learning
Immediate recall: verbal/

Rey Auditory Verbal Learning Test (RAVLT) Paterniti et al. (42); Bierman et al. (38) 0/2

The Benton Visual Retention Test (BVRT) Mura et al. (41)* 1/1
Rey Complex Figure Test (RCFT) Immediate recall Ros-Cucurull et al. (47)* 1/1
California Verbal Learning Test (CVLT) Ros-Cucurull et al. (47)* 1/1
Hopkins verbal learning test (HVLT) Hoiseth et al. (46) 0/1
Buschke free recall Helmes and Ostbye (34) 1/1
Picture Learning Test (PLT-i) van Vliet et al. (45)* 0/1
Free and Cued Selective Reminding Test (FCSRT)-immediate

Del Ser et al. (44) 1/1

Delayed recall: verbal/

Rey Auditory Verbal Learning Test (RAVLT) Paterniti et al. (42); Bierman et al. (38)* 1/2

Rey Complex Figure Test (RCFT) Delayed recall Ros-Cucurull et al. (47)* 1/1
California Verbal Learning Test (CVLT) Ros-Cucurull et al. (47)* 0/1
Hopkins verbal learning test (HVLT) Hoiseth et al. (46) 0/1
Picture Learning Test (PLT-d) van Vliet et al. (45)* 0/1
the Orientation- Memory-Concentration Test (OMC) hanlon1998* (40) 1/1
Buschke free recall Helmes and Ostbye (34) 1/1
Free and Cued Selective Reminding Test (FCSRT)-delayed

Del Ser et al. (44) 0/1

Recognition: verbal/visual Rey Auditory Verbal Learning Test (RAVLT) Paterniti et al. (42); Bierman et al. (38)*; Helmes and

Ostbye (34)

Rey Complex Figure Test (RCFT) recognition Ros-Cucurull et al. (47)* 0/1
California Verbal Learning Test (CVLT) Ros-Cucurull et al. (47)* 0/1
Hopkins Verbal Learning test (HVLT) Hoiseth et al. (46) 0/1


Gross motor speed the Finger Tapping Test (FTT) Paterniti et al. (42) 1/1
Fine motor speed WAIS Block Design Helmes and Ostbye (34) 0/1

Verbal fluency The Isaacs Set Test (IST) Mura et al. (41)* 1/1

Controlled Oral Word Association Test (COWAT FAS) Ros-Cucurull et al. (47)* 1/1
verbal fluency Helmes and Ostbye (34); Del Ser et al. (44) 0/2

Semantic processing Token Test Helmes and Ostbye (34) 1/1
WAIS Information Helmes and Ostbye (34) 0/1

Executive functions
Reasoning/planning Raven’s Colored Progressive Matrices (RCPM) Bierman et al. (38)* 1/1

Iowa Gambling Task(IGT) Ros-Cucurull et al. (47)* 0/1
Tower of London Test Ros-Cucurull et al. (47)* 1/1
WAIS Similarities Helmes and Ostbye (34) 0/1
WAIS Comprehension Helmes and Ostbye (34) 1/1
clock drawing test Del Ser et al. (44) 0/1

Working memory N-Back Ros-Cucurull et al. (47)* 1/1
Inhibitory control SCWT Ros-Cucurull et al. (47)*; Hoiseth et al. (46) 1/2

the third chart of the 40-item SCWT van Vliet et al. (45)* 0/1

Frontiers in Psychiatry | www.fro 6

September 2020 | Volume 11 | A

* for BZD abuse studies.

rticle 00755

Liu et al. Cognitive Effect of BZD

domain mainly with the Trail Making Test (TMT) or the digit
symbol test. The results showed that BZD users performed
significantly worse across all the abovementioned tests than the
controls. A meta-analysis (Figure 2B) was performed using
the two studies that utilized the TMT. The results showed that
in the elderly, the BZD users performed significantly worse than
controls in digit symbol tests (n=253; SMD: -0.61, 95% CI: -0.91 to
0.31, I² = 0%, p < 0.0001). However, three other studies (34, 38, 45)
suggested that the BZD users’ processing speed was not
significantly impaired during a coding task and block design task.

An overview of the eight studies that tested memory and
learning ability is presented in Table 2. Five out of nine tasks
showed impairment in verbal/visual immediate recall among
BZD users. More specifically, three out of five verbal immediate
recall tasks and two out of four visual immediate recall tasks
showed worse performances in BZD users than controls. When
measuring with verbal/visual delayed recall tasks, four out of
nine studies showed less accurate responses among BZD users.
In these tasks, three out of seven verbal delayed recall tasks and
one out of two visual delayed recall tasks showed BZD users
performed worse than controls. The meta-analysis of the AVLT
results (Figure 2C) is high in heterogeneity and non-significant
(n=2580; SMD: -0.04, 95% CI: -0.15 to 0.06, I² = 84%, p=0.41).

Results of the tasks for motor, language ability, and executive
functions are controversial (Table 2). In the domains of language

Frontiers in Psychiatry | 7

ability and reasoning/planning function, three (34, 38, 47) out of
four studies (44) that tested the respective domain showed a
significantly worse performance in BZD users. Only one paper
tested working memory (47) and showed that BZD users had a
significantly worse performance than controls. In the domain of
inhibitory control, the SCWT data sourced from two studies can
be used for meta-analysis (Figure 2D). The results were non-
significant and had high heterogeneity (n=1802; SMD: -0.07,
95% CI: -0.43 to 0.30, I² = 84%, p =0.72).

Benzodiazepine Abuse and Cognitive Decline in the
We conducted subgroup analyses of BZD abusers (Figure 3).
Seven studies included participants with BZD abuse (38, 40, 41,
43, 45, 47, 48) (Table 1). In the BZD abuse subgroup, the abusers
received significantly lower MMSE scores compared to the
controls (n=7726; SMD: -0.23, 95% CI: -0.44 to -0.03, I² =
86%, p =0.02). Meanwhile, in the BZD regular use subgroup,
the MMSE scores of BZD users versus controls were not
significantly different (n=1536; SMD: -0.05, 95% CI: -0.59 to
0.48, I² = 92%, p =0.85). Considering I² >50%, the heterogeneity
between the studies cannot be ignored.

Due to the discrepancy in the type of cognitive tasks used in
the included studies, we could not obtain meta-analyzable data to
examine the effects of BZD abuse on specific cognitive functions.





FIGURE 2 | (A) Effect of BZD use on Mini Mental State Examination in the elderly: forest plot. (B) Effect of BZD use on Digital Symbol test in the elderly: forest plot.
(C) Effect of BZD use on Auditory Verbal Learning Test in the elderly: forest plot. (D) Effect of BZD use on Stroop Color and Word Test in the elderly: forest plot.

September 2020 | Volume 11 | Article 00755

Liu et al. Cognitive Effect of BZD

Nevertheless, the results of the experiments in these studies were
summarized in Table 2. Notably, for language ability, Mura et al.
used the Isaacs Set Test to explore the effect of BZD abuse (41),
and Ros-Cucurull used the Controlled Oral Word Association
Test (47). Both results showed that BZD abusers performed
worse than the control groups. In the domain of recognition,
BZD abusers performed worse than controls in three different
tasks in two studies (38, 47). Experiments testing performance on
other cognitive divisions showed mixed results.


Main Findings of BZD Use
This meta-analysis and systematic review included 6374 BZD
users and 19,659 controls to comprehensively investigate the
affected cognition domains by BZD use and abuse in elders. A
total of 13 papers met the inclusion criteria and were included in
the literature review. Eight out of the 13 papers had appropriate
tests and sufficient information for the meta-analysis.

Consistent with previous systematic reviews, our meta-analysis
suggests no impairment in global cognition among elderly BZD
users (49, 50). Interestingly, studies with young adults showed
opposing results (51, 52), suggesting BZD use significantly
impairs participants’ global cognitive functioning. One reason for
these results may be the fact that the negative effect of various risk
factors on global cognitive decline decreases with age (53).

The results consistently showed impairment in elderly BZD
users’ processing speed, but not inhibitory control. Processing
speed, defined by the time it takes for a person to complete a
mental task, has been found to be associated with caudate activity
in neuroimaging studies (54). Meanwhile, a higher BZD dose is
associated with volume reductions in the caudate nucleus (55).
This imaging evidence supports our results of decreased
processing speed among BZD users. Our result in memory
functions, however, is inconsistent with previous studies. While

Frontiers in Psychiatry | 8

the meta-analysis (8) with adults of all ages found that BZD users
had a significantly impaired working memory and immediate
memory ability, our systematic review and meta-analysis did not
find sufficient support for the effect. However, the interaction
between age and BZD’s effect on memory requires more
robust validation.

Main Findings of BZD Abuse
The BZD abuse subgroup in this review included 1673 BZD abusers
and 6053 controls. The subgroup analysis showed that BZD abusers
received significantly lower MMSE scores than the controls, while
the BZD regular users’ scores were not significantly different from
controls. These results demonstrated that impairment in global
cognition occurs after the BZD user develops into abuse. However,
the high heterogeneity in the results cannot be ignored. According
to the results of the subgroup analysis, the confidence intervals of
the two subgroups overlapped, and the difference between the two
groups was not statistically significant (56). However, the subgroup
analyses results, especially when not pre-specified at the beginning
of the trial, cannot reflect the differences between the effect of
interventions in subgroups (57). Future studies that directly contrast
the cognition of BZD users and abusers are necessary. Only two
studies tested language ability in BZD abusers; both found
significantly worse language performance in BZD abusers
compared to controls. Meanwhile, only two studies tested
recognition ability; neither found a significant difference in the
performance between BZD abusers and controls. These findings,
however, are not conclusive because of the heterogeneity in the
statistical results, and the small number of studies in the analyses.
Therefore, more experiments are needed to reach more
reliable conclusions.

After searching the databases, we did not find a meta-analysis
investigating the cognitive effects of BZD abuse. The most relevant
studies are two systematic reviews and meta-analyses papers on
dementia risk in the elderly with long-duration and high dosage
BZD users (58, 59). In 2015, Zhong and colleagues summarized six
nested case-control or prospective cohort studies and concluded

FIGURE 3 | Subgroup analysis of the effect of BZD abuse and regular use on mini mental state examination in the elderly.

September 2020 | Volume 11 | Article 00755

Liu et al. Cognitive Effect of BZD

that higher dosage BZD users had an increased risk of dementia
(59). In 2019, He et al. found that the risk of dementia was higher in
patients taking BZD for a longer duration (>3 years) among six
case-control and four cohort studies (58). Although long-term or
high dosage use is not equivalent to dependence, BZD addiction is
more likely to occur in long-term and high-dose users (60). These
studies support the results of our subgroup analysis to some extent,
but the mechanism and effects behind BZD addiction and abuse
needs further investigation.

Strengths and Limitations of This Review
This study is, to our knowledge, the first systematic review and
meta-analysis of the cognitive effects of BZD use and abuse in
elders. We attempted to consolidate results from studies testing
different cognitive functions and data from a variety of cognitive
tasks by utilizing a mature cognitive domain classification
catalogue. The subgroup analysis of BZD abusers allowed us to
preliminarily compare the effects of BZD use and abuse. This
analysis encourages further studies to examine the qualitative
difference of BZD use and abuse. These results can help identify
and monitor the cognitive effects of BZD use and abuse, shedding
light on awareness and prevention of BZD addiction at early
stages, providing evidence for clinical decision-making, and
improving the life quality of the elderly.

There are some limitations to this meta-analysis and systematic
review. First, the number of studies and cognitive domains
examined in this meta-analysis was limited. Five of the thirteen
studies did not report cognitive tests data, and the domains of
motor and language did not have meta-analysis results. Second,
although the n is quite large, the meta-analysis results of the digital
symbol test, AVLT, and SCWT were drawn from two small
sample size studies, which is difficult to justify or interpret,
considering the biased nature of the original studies. In the
subgroup analysis of MMSE, the sample size of studies in the
BZD regular users’ subgroup varied from hundreds to 2500, which
are much smaller than the sample size of the abusers’ subgroup
(>7000). Although the random effects model was used to reduce
the impact caused by the difference between the sample size of the
two subgroups, there was no analyzable data for further analysis.
Third, due to the limitation of meta-analysis methodology, we
could not directly compare the cognitive differences between
BZD users and abusers. Fourth, other variabilities existed in the
13 studies in terms of the participants’ source (hospital or
community), sample size, sex ratio, and cognitive measurements.
These factors could also bias the findings to an uncertain extent.
Fifth, users and controls were not well matched in the analysis.
Participants in the experimental groups of the studies had different
preexisting conditions such as anxiety, depression, insomnia, and
APOE e4 status. One study did not age match the intervention
group with the control group or as a covariable, which means the
study could not completely distinguish the cognition impaired by
BZD and by natural aging. Other factors related to cognition, such
as the use of other psychotropic medications, certain physical
diseases, and educational level, were not examined in most
studies. Finally, due to the limited number of studies, sources of
heterogeneity were not examined.

Frontiers in Psychiatry | 9

Implications and Future Directions
Our meta-analysis confirmed the negative effects of BZD on
elderly users’ processing speed. Therefore, doctors should be
cautious when prescribing BZD drugs to elderly patients,
especially those with family histories of dementia, Alzheimer’s
disease, and other aging-related cognitive deficits. Additionally,
although global cognition was not impaired in BZD regular
users, BZD abusers had significantly worse performance in
global cognition. This research can inform more individualized
prescription decisions. For example, elderly patients whose
daily activities require higher cognitive processing should be
informed of BZD’s potential side effects on their cognitive
processing speed. Patients with a history of addiction should
prioritize alternative treatments to BZD therapy to prevent BZD
dependence and abuse.

Another important finding in this study is that the results of
cognitive performance are highly dependent on the type of cognitive
measurements in the study. For example, as previously reported,
BZD users had significantly lower processing speeds when tested
with the TMT. However, studies measuring processing speed with
the coding task or block design task did not reveal any significant
findings. Therefore, clinical practitioners should be mindful when
selecting cognitive tests. It might be reasonable to use tests with
higher sensitivity to reduce missed diagnoses.

In addition, through our exploration in the literature on the
cognitive effects of BZD use, few studies paid attention to BZD
abuse and addiction in participants (47, 61, 62). BZD use and
abuse can be qualitatively different from BZD use. A survey
conducted in 2015-2016 showed that BZD abusers accounted
for about 17% of BZD users (6). Moreover, approximately half
of the patients who used BZD for longer than 1 month are
subject to BZD abuse or addiction (60). The neglect of the BZD
abuse subgroup may be accountable for the mixed conclusions
from studies on the cognitive effects of BZD use. Therefore, we
encourage future researchers to separate BZD regular users and
BZD abusers to achieve more precise and rigid conclusions.


In conclusion, this meta-analysis indicated no significant global
cognition deficit (MMSE scores) in BZD users, but did reveal
deficits in elders with BZD abuse behaviors. BZD users performed
significantly worse in the cognition domain of processing speed
(digit symbol test scores) than the controls, but not in memory and
learning (AVLT scores) or inhibitory control (SCWT scores).
Studies that tested the other cognitive domains, however, showed
conflicting results. Unfortunately, these cognitive domains’
measurements varied across studies, rendering it unavailable to be
merged into meta-analysis. Clinicians should be cautious when
prescribing BZD for the elderly, especially to patients with a family
history of age-related cognitive deficits. Moreover, the majority of
the included studies did not clearly distinguish between the use and
abuse of BZD, making it challenging to evaluate the effects of BZD
abuse. Future well-designed studies are needed in order to verify the
cognitive effects of BZD use and abuse.

September 2020 | Volume 11 | Article 00755

Liu et al. Cognitive Effect of BZD


The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation, to any
qualified researcher.


LL and YT: conceptualization. LL and LJ: data curation and
analysis. FW and YT: project administration. LL, YZ, JZ, and PJ:
supervision, writing—review, and editing. LL and PJ: writing—
original draft.


National Key Research and Development Program of China
(2018YFC1311604 and 2016YFC1306900 to YT), National
Science Fund for Distinguished Young Scholars (81725005 to
Fei Wang), Liaoning Education Foundation (Pandeng Scholar to

Frontiers in Psychiatry | 10

Fei Wang), Innovation Team Support Plan of Higher Education
of Liaoning Province (LT2017007 to Fei Wang), Major Special
Construction Plan of China Medical University (3110117059 and
3110118055 to Fei Wang), Joint fund of National Natural Science
Foundation of China (U1808204 to FW), Natural Science
Foundation of Liaoning Province (2019-MS-05 to FW).


The authors thank Xiang YT and Guo WB for providing
theoretic guidance.


The Supplementary Material for this article can be found online at:


1. Blanco C, Han B, Jones CM, Johnson K, Compton WM. Prevalence and
Correlates of Benzodiazepine Use, Misuse, and Use Disorders Among Adults in
the United States. J Clin Psychiatry (2018) 79(6). doi: 10.4088/JCP.18m12174

2. Marra EM, Mazer-Amirshahi M, Brooks G, van den Anker J, May L, Pines JM.
Benzodiazepine Prescribing in Older Adults in U.S. Ambulatory Clinics and
Emergency Departments (2001-10). J Am Geriatr Soc (2015) 63(10):2074–81.
doi: 10.1111/jgs.13666

3. Voshaar RC, Couvée JE, van Balkom AJ, Mulder PG, Zitman FG. Strategies
for discontinuing long-term benzodiazepine use: meta-analysis. Br J
Psychiatry J Ment Sci (2006) 189:213–20. doi: 10.1192/bjp.189.3.213

4. Votaw VR, Geyer R, Rieselbach MM, McHugh RK. The epidemiology of
benzodiazepine misuse: A systematic review. Drug Alcohol Depend (2019)
200:95–114. doi: 10.1016/j.drugalcdep.2019.02.033

5. Airagnes G, Pelissolo A, Lavallee M, Flament M, Limosin F. Benzodiazepine
Misuse in the Elderly: Risk Factors, Consequences, and Management. Curr
Psychiatry Rep (2016) 18(10):89. doi: 10.1007/s11920-016-0727-9

6. Maust DT, Lin LA, Blow FC. Benzodiazepine Use and Misuse Among Adults
in the United States. Psychiatr Serv (2019) 70(2):97–106. doi: 10.1176/

7. Salzman C, Shader RI, Harmatz J, Robertson L. Psychopharmacologic
investigations in elderly volunteers: Effect of diazepam in males. J Am
Geriatr Soc (1975) 23(10):451–7. doi: 10.1111/j.1532-5415.1975.tb00929.x

8. Crowe SF, Stranks EK. The Residual Medium and Long-term Cognitive Effects of
BenzodiazepineUse: AnUpdatedMeta-analysis.Arch Clin Neuropsychol Off J Natl
Acad Neuropsychol (2018) 33(7):901–11. doi: 10.1093/arclin/acx120

9. Lipnicki DM, Crawford JD, Dutta R, Thalamuthu A, Kochan NA, Andrews G,
et al. Age-related cognitive decline and associations with sex, education and
apolipoprotein E genotype across ethnocultural groups and geographic
regions: a collaborative cohort study. PloS Med (2017) 14(3):e1002261.
doi: 10.1371/journal.pmed.1002261

10. Goyal MS, Vlassenko AG, Blazey TM, Su Y, Couture LE, Durbin TJ, et al. Loss
of Brain Aerobic Glycolysis in Normal Human Aging. Cell Metab (2017) 26
(2):353–60.e3. doi: 10.1016/j.cmet.2017.07.010

11. Kovacs GG, Milenkovic I, Wöhrer A, Höftberger R, Gelpi E, Haberler C, et al.
Non-Alzheimer neurodegenerative pathologies and their combinations are more
frequent than commonly believed in the elderly brain: a community-based autopsy
series. Acta Neuropathol (2013) 126(3):365–84. doi: 10.1007/s00401-013-1157-y

12. Dingemanse J, Häussler J, Hering W, Ihmsen H, Albrecht S, Zell M, et al.
Pharmacokinetic-pharmacodynamic modelling of the EEG effects of Ro 48-6791,

a new short-acting benzodiazepine, in young and elderly subjects. Br J anaesth
(1997) 79(5):567–74. doi: 10.1093/bja/79.5.567

13. Wimo A, Guerchet M, Ali GC, Wu YT, Prina AM, Winblad B, et al. The
worldwide costs of dementia 2015 and comparisons with 2010. Alzheimer’s
Dementia J Alzheimer’s Assoc (2017) 13(1):1–7. doi: 10.1016/j.jalz.2016.07.150

14. Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimer’s
Dementia J Alzheimer’s Assoc (2016) 12(4):459–509. doi: 10.1016/j.jalz.2016.03.001

15. Penninkilampi R, EslickGD.A Systematic Review andMeta-Analysis of the Risk of
Dementia Associated with Benzodiazepine Use, After Controlling for Protopathic
Bias. CNS Drugs (2018) 32(6):485–97. doi: 10.1007/s40263-018-0535-3

16. Islam MM, Iqbal U, Walther B, Atique S, Dubey NK, Nguyen PA, et al.
Benzodiazepine Use and Risk of Dementia in the Elderly Population: A
Systematic Review and Meta-Analysis. Neuroepidemiology (2016) 47(3-
4):181–91. doi: 10.1159/000454881

17. Gomm W, von Holt K, Thome F, Broich K, Maier W, Weckbecker K, et al.
Regular Benzodiazepine and Z-Substance Use and Risk of Dementia: An
Analysis of German Claims Data. J Alzheimer’s Dis JAD (2016) 54(2):801–8.
doi: 10.3233/jad-151006

18. de Gage SB, Pariente A, Begaud B. Is there really a link between
benzodiazepine use and the risk of dementia? Expert Opin Drug Saf (2015)
14(5):733–47. doi: 10.1517/14740338.2015.1014796

19. Panel BtAGSBCUE. American Geriatrics Society 2019 Updated AGS Beers
Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am
Geriatr Soc (2019) 67(4):674–94. doi: 10.1111/jgs.15767

20. Coyle-Gilchrist IT, Peck LF, Rowe JB. Research paper does not show causal
link between benzodiazepine use and diagnosis of dementia. BMJ (Clin Res ed)
(2012) 345:e7984; author reply e93. doi: 10.1136/bmj.e7984

21. Basu R, Dodge H, Stoehr GP, Ganguli M. Sedative-hypnotic use of
diphenhydramine in a rural, older adult, community-based cohort: effects
on cognition. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry
(2003) 11(2):205–13. doi: 10.1097/00019442-200303000-00011

22. Vaapio S, Puustinen J, Salminen MJ, Vahlberg T, Salonoja M, Lyles A, et al.
Symptoms associated with long-term benzodiazepine use in elderly
individuals aged 65 years and older: a longitudinal descriptive study. Int J
Gerontol (2015) 9(1):34–9. doi: 10.1016/j.ijge.2014.03.009

23. Murphy P, Hindmarch I, Hyland CM. Aspects of short-term use of two
benzodiazepine hypnotics in the elderly. Age Ageing (1982) 11(4):222–8.
doi: 10.1093/ageing/11.4.222

24. Nikaido AM, Ellinwood EHJr., Heatherly DG, Gupta SK. Age-related increase
in CNS sensitivity to benzodiazepines as assessed by task difficulty.
Psychopharmacology (1990) 100(1):90–7. doi: 10.1007/bf02245796

September 2020 | Volume 11 | Article 00755

Liu et al. Cognitive Effect of BZD

25. Picton JD, Marino AB, Nealy KL. Benzodiazepine use and cognitive decline in the
elderly. Am J Health-Syst Pharm (2018) 75(1):E6–E12. doi: 10.2146/ajhp160381

26. Grasset L, Matthews FE, Pérès K, Foubert-Samier A, Helmer C, Dartigues JF, et al.
Evolution of dementia diagnosis over time (1988-2013): Evidence from French and
English cohorts. Implication for secular trends analyses. Alzheimer’s Dementia
(Amsterdam Netherlands) (2018) 10:490–7. doi: 10.1016/j.dadm.2018.07.005

27. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. PloS Med
(2009) 6(7):e1000097. doi: 10.1371/journal.pmed.1000097

28. Bawor M, Dennis BB, Anglin R, Steiner M, Thabane L, Samaan Z. Sex differences
in outcomes of methadone maintenance treatment for opioid addiction: a
systematic review protocol. System Rev (2014) 3:45. doi: 10.1186/2046-4053-3-45

29. Galioto R, Spitznagel MB. The Effects of Breakfast and Breakfast Composition on
Cognition in Adults. Adv Nutr (Bethesda Md) (2016) 7(3):576s–89s. doi: 10.3945/

30. Lezak MD HD, Bigler ED, Tranel D. Neuropsychological assessment. 4th ed ed.
Oxford University Press: New York (2012).

31. Review Manager (RevMan). The Cochrane Collaboration. 2019. Copenhagen:
The Nordic Cochrane Centre TCC (2014). Available at:

32. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
meta-analyses. BMJ (Clin Res ed) (2003) 327(7414):557–60. doi: 10.1136/

33. Yen CF, Ko CH, Chang YP, Yu CY, Huang MF, Yeh YC, et al. Dependence,
misuse, and beliefs regarding use of hypnotics by elderly psychiatric patients
taking zolpidem, estazolam, or flunitrazepam. Asia-Pacific Psychiatry Off J
Pacific Rim Coll Psychiatrists (2015) 7(3):298–305. doi: 10.1111/appy.12147

34. Helmes E, Ostbye T. Associations between Benzodiazepine Use and
Neuropsychological Test Scores in Older Adults. Can J Aging = La Rev Can
du vieillissement (2015) 34(2):207–14. doi: 10.1017/s0714980815000082

35. Ebly EM, Hogan DB, Fung TS. Potential adverse outcomes of psychotropic
and narcotic drug use in Canadian seniors. J Clin Epidemiol (1997) 50(7):857–
63. doi: 10.1016/S0895-4356(97)00118-2

36. Canadian Study of Health and Aging working Group. Canadian study of health
and aging: study methods and prevalence of dementia. CMAJ CanMed Assoc J = J
l’Association Med Can (1994) 150(6):899–913. doi: 10.1001/jama.271.11.872

37. Puustinen J, Nurminen J, Kukola M, Vahlberg T, Laine K, Kivela SL. Associations
between use of benzodiazepines or related drugs and health, physical abilities and
cognitive function – A non-randomised clinical study in the elderly. Drugs Aging
(2007) 24(12):1045–59. doi: 10.2165/00002512-200724120-00007

38. Bierman EJM, Comijs HC, Gundy CM, Sonnenberg C, Jonker C, Beekman
ATF. The effect of chronic benzodiazepine use on cognitive functioning in
older persons: Good, bad or indifferent? Int J Geriatr Psychiatry (2007) 22
(12):1194–200. doi: 10.1002/gps.1811

39. Gray SL, Dublin S, Yu O, Walker R, Anderson M, Hubbard RA, et al.
Benzodiazepine use and risk of incident dementia or cognitive decline:
Prospective population based study. BMJ: Br Med J (2016) 352:i90. doi:

40. Hanlon JT, Horner RD, Schmader KE, Fillenbaum GG, Lewis IK, Wall WE Jr.,
et al. Benzodiazepine use and cognitive function among community-dwelling
elderly. Clin Pharmacol Ther (1998) 64(6):684–92. doi: 10.1016/S0009-9236

41. Mura T, Proust-Lima C, Akbaraly T, Amieva H, Tzourio C, Chevassus H, et al.
Chronic use of benzodiazepines and latent cognitive decline in the elderly:
Results from the Three-city study. Eur Neuropsychopharmacol (2013) 23
(3):212–23. doi: 10.1016/j.euroneuro.2012.05.004

42. Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive
decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin
Psychopharmacol (2002) 22(3):285–93. doi: 10.1097/00004714-200206000-00009

43. Zhang Y, Zhou XH, Meranus DH, Wang L, Kukull WA. Benzodiazepine Use
and Cognitive Decline in Elderly with Normal Cognition. Alzheimer Dis Assoc
Disord (2016) 30(2):113–7. doi: 10.1097/WAD.0000000000000099

44. Del Ser T, Zea MA, Valenti M, Olazaran J, Lopez-Alvarez J, Rebollo-Vazquez
A, et al. Effects of commonly prescribed drugs on cognition and mild cognitive
impairment in healthy elderly people. J Psychopharmacol (2019) 33(8):965–
74. doi: 10.1177/0269881119857206

45. van Vliet P, van der Mast RC, van den Broek M, Westendorp RGJ, de Craen
AJM. Use of benzodiazepines, depressive symptoms and cognitive function in
old age. Int J Geriatr Psychiatry (2009) 24(5):500–8. doi: 10.1002/gps.2143

Frontiers in Psychiatry | 11

46. Hoiseth G, Tanum L, Tveito M, Kristiansen KM, Kvande K, Lorentzen B, et al. A
Clinical Study of the Cognitive Effects of Benzodiazepines in Psychogeriatric
Patients. Pharmacopsychiatry (2013) 46(6):209–13. doi: 10.1055/s-0033-1349131

47. Ros-Cucurull E, Palma-Álvarez RF, Garcıá-Raboso E, Cardona-Rubira C,
Jacas C, Grau-López L, et al. Benzodiazepine Use Disorder and Cognitive
Impairment in Older Patients: A Six-Month-Follow-Up Study in an
Outpatient Unit in Barcelona. J Stud Alcohol Drugs (2018) 79(6):844–52.
doi: 10.15288/jsad.2018.79.844

48. Hessmann P, Dodel R, Baum E, Muller MJ, Paschke G, Kis B, et al.
Prescription of Benzodiazepines and Related Drugs in Patients with Mild
Cognitive Deficits and Alzheimer’s Disease. Pharmacopsychiatry (2019) 52
(2):84–91. doi: 10.1055/s-0044-100523

49. Nader D, Gowing L. Is Long-TermBenzodiazepine Use a Risk Factor for Cognitive
Decline? Results of a Systematic Review. J Addict (2020) 2020:1569456.
doi: 10.1155/2020/1569456

50. Lapeyre-Mestre M. [Benzodiazepines, cognitive decline and dementia: A
review of causality criteria from published observational studies]. Therapie
(2019) 74(3):407–19. doi: 10.1016/j.therap.2018.09.071

51. Barker MJ, Greenwood KM, Jackson M, Crowe SF. An evaluation of persisting
cognitive effects after withdrawal from long-term benzodiazepine use. J Int
Neuropsychol Soc (2005) 11(3):281–9. doi: 10.1017/s1355617705050332

52. Federico A, Tamburin S, Maier A, Faccini M, Casari R, Morbioli L, et al.
Multifocal cognitive dysfunction in high-dose benzodiazepine users: a cross-
sectional study. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol
(2017) 38(1):137–42. doi: 10.1007/s10072-016-2732-5

53. Legdeur N, Heymans MW, Comijs HC, Huisman M, Maier AB, Visser PJ. Age
dependency of risk factors for cognitive decline. BMC Geriatr (2018) 18
(1):187. doi: 10.1186/s12877-018-0876-2

54. De Simoni S, Jenkins PO, Bourke NJ, Fleminger JJ, Hellyer PJ, Jolly AE, et al.
Altered caudate connectivity is associated with executive dysfunction after
traumatic brain injury. Brain J Neurol (2018) 141(1):148–64. doi: 10.1093/

55. Huhtaniska S, Jaaskelainen E, Heikka T, Moilanen JS, Lehtiniemi H, Tohka J, et al.
Long-term antipsychotic and benzodiazepine use. and brain volume changes in
schizophrenia: The Northern Finland Birth Cohort 1966 study. Psychiatry Resh-
Neuroimaging (2017) 266:73–82. doi: 10.1016/j.pscychresns.2017.05.009

56. Higgins JPT TJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. Cochrane
Handbook for Systematic Reviews of Interventions. 2nd Edition ed. Chichester
(UK): John Wiley & Sons (2019).

57. Wang SS, Ou YC, Cheng CL, Dahm P. Evidence-based urology in practice: when
to believe a subgroup analysis? BJU Int (2010) 105(2):162–4. doi: 10.1111/j.1464-

58. He Q, Chen X,Wu T, Li L, Fei X. Risk of Dementia in Long-Term Benzodiazepine
Users: Evidence from a Meta-Analysis of Observational Studies. J Clin Neurol
(Seoul Korea) (2019) 15(1):9–19. doi: 10.3988/jcn.2019.15.1.9

59. Zhong G, Wang Y, Zhang Y, Zhao Y. Association between Benzodiazepine Use
and Dementia: A Meta-Analysis. PloS One (2015) 10(5):e0127836. doi: 10.1371/

60. Soyka M. Treatment of Benzodiazepine Dependence. New Engl J Med (2017)
376(12):1147–57. doi: 10.1056/NEJMra1611832

61. Bergman H, Borg S, Engelbrektson K, Vikander B. Dependence on sedative-
hypnotics: neuropsychological impairment, field dependence and clinical course in
a 5-year follow-up study. Br J Addict (1989) 84(5):547–53. doi: 10.1111/j.1360-

62. Chu C, Sivakumar K, Melinosky C. A Case of Reversible Bilateral
Hippocampal Injury Secondary to Benzodiazepine Abuse (P3.1-017).
Neurology (2019) 92(15 Supplement):P3.1–017.

Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.

Copyright © 2020 Liu, Jia, Jian, Zhou, Zhou, Wu and Tang. This is an open-access
article distributed under the terms of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice. No
use, distribution or reproduction is permitted which does not comply with these terms.

September 2020 | Volume 11 | Article 00755

  • The Effects of Benzodiazepine Use and Abuse on Cognition in the Elders: A Systematic Review and Meta-Analysis of Comparative Studies
    • Introduction
    • Methods
      • Systematic Review Protocol
      • Databases and Search Strategy
      • Inclusion Criteria and the Process to Identify Studies
      • Risk of Bias and Quality Assessment
      • Data Extraction
      • Data Synthesis and Statistical Analyses
    • Results
      • Search Results and Studies Included
      • Risk of Bias and Quality Assessment
      • Studies Characteristics
      • Synthesized Findings
        • Benzodiazepine Use and Cognitive Decline in the Elders
        • Benzodiazepine Abuse and Cognitive Decline in the Elders
    • Discussion
      • Main Findings of BZD Use
      • Main Findings of BZD Abuse
      • Strengths and Limitations of This Review
      • Implications and Future Directions
    • Conclusions
    • Data Availability Statement
    • Author Contributions
    • Funding
    • Acknowledgments
    • Supplementary Material
    • References

/ASCII85EncodePages false
/AllowTransparency false
/AutoPositionEPSFiles true
/AutoRotatePages /PageByPage
/Binding /Left
/CalGrayProfile (Dot Gain 20%)
/CalRGBProfile (sRGB IEC61966-2.1)
/CalCMYKProfile (U.S. Web Coated 50SWOP51 v2)
/sRGBProfile (sRGB IEC61966-2.1)
/CannotEmbedFontPolicy /Warning
/CompatibilityLevel 1.4
/CompressObjects /Tags
/CompressPages false
/ConvertImagesToIndexed true
/PassThroughJPEGImages true
/CreateJDFFile false
/CreateJobTicket false
/DefaultRenderingIntent /Default
/DetectBlends true
/DetectCurves 0.0000
/ColorConversionStrategy /LeaveColorUnchanged
/DoThumbnails false
/EmbedAllFonts true
/EmbedOpenType false
/ParseICCProfilesInComments true
/EmbedJobOptions true
/DSCReportingLevel 0
/EmitDSCWarnings false
/EndPage -1
/ImageMemory 1048576
/LockDistillerParams false
/MaxSubsetPct 1
/Optimize true
/OPM 1
/ParseDSCComments true
/ParseDSCCommentsForDocInfo true
/PreserveCopyPage true
/PreserveDICMYKValues true
/PreserveEPSInfo true
/PreserveFlatness false
/PreserveHalftoneInfo false
/PreserveOPIComments true
/PreserveOverprintSettings true
/StartPage 1
/SubsetFonts true
/TransferFunctionInfo /Apply
/UCRandBGInfo /Preserve
/UsePrologue false
/ColorSettingsFile ()
/AlwaysEmbed [ true
/NeverEmbed [ true
/AntiAliasColorImages false
/CropColorImages false
/ColorImageMinResolution 300
/ColorImageMinResolutionPolicy /OK
/DownsampleColorImages true
/ColorImageDownsampleType /Bicubic
/ColorImageResolution 300
/ColorImageDepth -1
/ColorImageMinDownsampleDepth 1
/ColorImageDownsampleThreshold 1.50000
/EncodeColorImages true
/ColorImageFilter /DCTEncode
/AutoFilterColorImages true
/ColorImageAutoFilterStrategy /JPEG
/ColorACSImageDict <<
/QFactor 0.40
/HSamples [1 1 1 1] /VSamples [1 1 1 1]
/ColorImageDict <<
/QFactor 0.15
/HSamples [1 1 1 1] /VSamples [1 1 1 1]
/JPEG2000ColorACSImageDict <<
/TileWidth 256
/TileHeight 256
/Quality 30
/JPEG2000ColorImageDict <<
/TileWidth 256
/TileHeight 256
/Quality 30
/AntiAliasGrayImages false
/CropGrayImages false
/GrayImageMinResolution 300
/GrayImageMinResolutionPolicy /OK
/DownsampleGrayImages true
/GrayImageDownsampleType /Bicubic
/GrayImageResolution 300
/GrayImageDepth -1
/GrayImageMinDownsampleDepth 2
/GrayImageDownsampleThreshold 1.50000
/EncodeGrayImages true
/GrayImageFilter /DCTEncode
/AutoFilterGrayImages true
/GrayImageAutoFilterStrategy /JPEG
/GrayACSImageDict <<
/QFactor 0.40
/HSamples [1 1 1 1] /VSamples [1 1 1 1]
/GrayImageDict <<
/QFactor 0.15
/HSamples [1 1 1 1] /VSamples [1 1 1 1]
/JPEG2000GrayACSImageDict <<
/TileWidth 256
/TileHeight 256
/Quality 30
/JPEG2000GrayImageDict <<
/TileWidth 256
/TileHeight 256
/Quality 30
/AntiAliasMonoImages false
/CropMonoImages false
/MonoImageMinResolution 1200
/MonoImageMinResolutionPolicy /OK
/DownsampleMonoImages true
/MonoImageDownsampleType /Bicubic
/MonoImageResolution 1200
/MonoImageDepth -1
/MonoImageDownsampleThreshold 1.50000
/EncodeMonoImages true
/MonoImageFilter /CCITTFaxEncode
/MonoImageDict <<
/K -1
/AllowPSXObjects false
/CheckCompliance [
/PDFX1aCheck false
/PDFX3Check false
/PDFXCompliantPDFOnly false
/PDFXNoTrimBoxError true
/PDFXTrimBoxToMediaBoxOffset [
/PDFXSetBleedBoxToMediaBox true
/PDFXBleedBoxToTrimBoxOffset [
/PDFXOutputIntentProfile ()
/PDFXOutputConditionIdentifier ()
/PDFXOutputCondition ()
/PDFXRegistryName ()
/PDFXTrapped /False

/Description <<
/ENU (T&F settings for black and white printer PDFs 20081208)
/ExportLayers /ExportVisibleLayers
/Namespace [
/OtherNamespaces [
/AsReaderSpreads false
/CropImagesToFrames true
/ErrorControl /WarnAndContinue
/FlattenerIgnoreSpreadOverrides false
/IncludeGuidesGrids false
/IncludeNonPrinting false
/IncludeSlug false
/Namespace [
/OmitPlacedBitmaps false
/OmitPlacedEPS false
/OmitPlacedPDF false
/SimulateOverprint /Legacy
/AddBleedMarks false
/AddColorBars false
/AddCropMarks false
/AddPageInfo false
/AddRegMarks false
/BleedOffset [
/ConvertColors /NoConversion
/DestinationProfileName ()
/DestinationProfileSelector /DocumentCMYK
/Downsample16BitImages true
/FlattenerPreset <<
/ClipComplexRegions true
/ConvertStrokesToOutlines false
/ConvertTextToOutlines false
/GradientResolution 300
/LineArtTextResolution 1200
/PresetName ([High Resolution])
/PresetSelector /HighResolution
/RasterVectorBalance 1
/FormElements false
/GenerateStructure true
/IncludeBookmarks true
/IncludeHyperlinks true
/IncludeInteractive false
/IncludeLayers false
/IncludeProfiles false
/MarksOffset 6
/MarksWeight 0.250000
/MultimediaHandling /UseObjectSettings
/Namespace [
/PDFXOutputIntentProfileSelector /DocumentCMYK
/PageMarksFile /RomanDefault
/PreserveEditing true
/UntaggedCMYKHandling /LeaveUntagged
/UntaggedRGBHandling /UseDocumentProfile
/UseDocumentBleed false
/AllowImageBreaks true
/AllowTableBreaks true
/ExpandPage false
/HonorBaseURL true
/HonorRolloverEffect false
/IgnoreHTMLPageBreaks false
/IncludeHeaderFooter false
/MarginOffset [
/MetadataAuthor ()
/MetadataKeywords ()
/MetadataSubject ()
/MetadataTitle ()
/MetricPageSize [
/MetricUnit /inch
/MobileCompatible 0
/Namespace [
/OpenZoomToHTMLFontSize false
/PageOrientation /Portrait
/RemoveBackground false
/ShrinkContent true
/TreatColorsAs /MainMonitorColors
/UseEmbeddedProfiles false
/UseHTMLTitleAsMetadata true
>> setdistillerparams
/HWResolution [2400 2400]
/PageSize [612.000 792.000]
>> setpagedevice

Do you need help with this or a different assignment? In a world where academic success does not come without efforts, we do our best to provide the most proficient and capable essay writing service. After all, impressing professors shouldn’t be hard, we make that possible. If you decide to make your order on our website, you will get 15 % off your first order. You only need to indicate the discount code GET15.

Order a Similar Paper Order a Different Paper