⁶Republican Vilnius University Hospital, Vilnius, Lithuania

Abstract

Background. Chronic use of benzodiazepines frequently leads to physical dependence. In Lithuania, detoxification services are provided to individuals suffering from benzodiazepine addiction.

Aim. The purpose of our study was to find out the existing links and differences between patient gender, age, characteristics of benzodiazepine consumption, and the course of treatment.

Materials and methods. This retrospective study was conducted at Toxicology Centre of Republican Vilnius University Hospital. 48 patients who had been treated from 2011 January to 2018 March with the principal diagnosis of sedative, hypnotic or anxiolytic-related dependence (ICD-10 F13.2) were included in the final analysis. MS Excel and IBM SPSS 23.0 were used for data analysis, statistical significance was assumed when p<0.05.

Results. An indirect intermediate correlation between benzodiazepine dose-at-arrival for treatment and age was found (rPhi=-0.16, p=0.029), as well as a direct weak link between dose-at-arrival and dose-at-discharge from the hospital (rPhi=0.420, p=0.005). Male patients used higher doses of benzodiazepines (p=0.012). Alcohol-consuming patients spent less time hospitalized (p=0.02). Women were hospitalized longer than men (p=0,02). Link between durations of inpatient treatment and benzodiazepine consumption was intermediate and direct (Spearman‘s r=0.310, p=0.032). An intermediate direct relationship between the duration of benzodiazepine consumption and number of additionally administered medicines was found (Spearman’s r=0.420, p=0.005).

Conclusions. Men and younger patients had used higher doses of benzodiazepines. Patients, who had used higher doses, were prescribed a higher dose of benzodiazepines and a higher number of additional medicines at discharge. Inpatient treatment time was longer for women and for the patients, who had used benzodiazepines longer. Detoxification from benzodiazepines was shorter for alcohol-consuming patients.

Keywords: benzodiazepines; withdrawal; addiction; detoxification.

Full article

https://doi.org/10.53453/ms.2023.2.14

Fighting benzodiazepine misuse in Lithuania: detoxification

treatment results in the single-centre toxicology department

Gabija Valauskaitė

1

, Gabrielė Repšytė

2

, Deimantė Andriuškevičiūtė

3

, Deima Eitmontaitė

4

, Robertas

Badaras

5,6

1

Lithuanian University of Health Science, Department of Intensive Care, Kaunas, Lithuania

2

Lithuanian University of Health Science, Department of Psychiatry, Kaunas, Lithuania

3

Lithuanian University of Health Sciences, Faculty of Medicine, Kaunas, Lithuania

4

Vilnius University, Faculty of Medicine, Clinic of Emergency Medicine, Vilnius, Lithuania

5

Vilnius University, Faculty of Medicine, Clinic of Anaesthesiology and Intensive Care, Centre of Toxicology,

Vilnius, Lithuania

6

Republican Vilnius University Hospital, Vilnius, Lithuania

Abstract

Background. Chronic use of benzodiazepines frequently leads to physical dependence. In Lithuania,

detoxification services are provided to individuals suffering from benzodiazepine addiction.

Aim. The purpose of our study was to find out the existing links and differences between patient gender, age,

characteristics of benzodiazepine consumption, and the course of treatment.

Materials and methods. This retrospective study was conducted at Toxicology Centre of Republican Vilnius

University Hospital. 48 patients who had been treated from 2011 January to 2018 March with the principal

diagnosis of sedative, hypnotic or anxiolytic-related dependence (ICD-10 F13.2) were included in the final

analysis. MS Excel and IBM SPSS 23.0 were used for data analysis, statistical significance was assumed when

p<0.05.

Results. An indirect intermediate correlation between benzodiazepine dose-at-arrival for treatment and age was

found (r

Phi

=-0.16, p=0.029), as well as a direct weak link between dose-at-arrival and dose-at-discharge from the

hospital (r

Phi

=0.420, p=0.005). Male patients used higher doses of benzodiazepines (p=0.012). Alcohol-

consuming patients spent less time hospitalized (p=0.02). Women were hospitalized longer than men (p=0,02).

Link between durations of inpatient treatment and benzodiazepine consumption was intermediate and direct

(Spearman‘s r=0.310, p=0.032). An intermediate direct relationship between the duration of benzodiazepine

consumption and number of additionally administered medicines was found (Spearman’s r=0.420, p=0.005).

Conclusions. Men and younger patients had used higher doses of benzodiazepines. Patients, who had used

higher doses, were prescribed a higher dose of benzodiazepines and a higher number of additional medicines at

discharge. Inpatient treatment time was longer for women and for the patients, who had used benzodiazepines

longer. Detoxification from benzodiazepines was shorter for alcohol-consuming patients.

Keywords: benzodiazepines; withdrawal; addiction; detoxification.

Journal of Medical Sciences. 22 Feb, 2023 - Volume 11 | Issue 2. Electronic - ISSN: 2345-0592

Medical Sciences 2023 Vol. 11 (2), p. 114-125, https://doi.org/10.53453/ms.2023.2.14

114

Piknaudžiavimas benzodiazepinų grupės vaistais Lietuvoje:

detoksikacinio gydymo rezultatai

Gabija Valauskaitė

1

, Gabrielė Repšytė

2

, Deimantė Andriuškevičiūtė

3

, Deima Eitmontaitė

4

, Robertas

Badaras

5,6

1

Lietuvos sveikatos mokslų universitetas, Intensyvios terapijos klinika, Kaunas, Lietuva

2

Lietuvos sveikatos mokslų universitetas, Psichiatrijos klinika, Kaunas, Lietuva

3

Lietuvos sveikatos mokslų universitetas, Medicinos fakultetas, Kaunas, Lietuva

4

Vilniaus universitetas, Medicinos fakultetas, Skubios medicinos klinika, Vilnius, Lietuva

5

Vilniaus universitetas, Medicinos fakultetas, Anesteziologijos ir reanimatologijos klinika, Toksikologijos

centras, Vilnius, Lietuva

6

Respublikinė Vilniaus universitetinė ligoninė, Vilnius, Lietuva

Santrauka

Įvadas. Ilgai trunkantis benzodiazepinų vartojimas dažnai sukelia priklausomybę. Lietuvoje detoksikacijos

paslaugos teikiamos asmenims, kenčiantiems nuo priklausomybės benzodiazepinams.

Tikslas. Šio tyrimo tikslas buvo išsiaiškinti egzistuojančius ryšius ir skirtumus tarp pacientų su TLK- 10 F13.2

diagnoze lyties, amžiaus, žalingų įpročių, vartojimo bei gydymo ypatumų.

Metodika. Šiame retrospektyviame tyrime dalyvavo 48 pacientai, kurie gydėsi 2011 m. sausio – 2018 m. kovo

mėn. Respublikinės Vilniaus universitetinės ligoninės toksikologijos centre, turėję psichikos ir elgesio

sutrikimai dėl raminamųjų ir migdomųjų medžiagų vartojimo, priklausomybės sindromo (F13.2) diagnozę, kaip

pagrindinę. Statistinei analizei naudoti MS Excel ir IBM SPSS 23.0 programiniai paketai, duomenys laikyti

statistiškai reikšmingais, kai p<0,05.

Rezultatai. Atvirkštinė vidutinio stiprumo priklausomybė tarp benzodiazepinų dozės atvykus ir amžiaus,

r

Spearmano

=-0,316, p=0,029, tiesioginė silpna priklausomybė tarp dozės atvykus ir išrašant, r

Spearmano

=0,304,

p=0,036. Vyrai vartojo didesnes benzodiazepinų dozes, p=0,012. Vartojantys alkoholį pacientai stacionare

išbuvo trumpiau p=0,02. Ilgiau stacionare išbuvo moterys, p=0,02. Nustatytas tiesioginis vidutinio stiprumo

ryšys tarp hospitalizacijos ir vartojimo trukmės, r

Spearmano

=0,310, p=0,032, tiesioginė vidutinio stiprumo

priklausomybė tarp vartojimo trukmės ir papildomai skirtų medikamentų skaičiaus, r

Spearmano

=0,420, p=0,005.

Išvados. Vyrai ir jaunesni pacientai buvo linkę vartoti didesnes benzodiazepinų dozes. Pacientams, vartojusiems

didesnes benzodiazepinų dozes, buvo išrašytos didesnės dozės detoksikacinio gydymo tęsimui ambulatoriškai ir

didesnis papildomų medikamentų skaičius. Moterims bei ilgiau benzodiazepinus vartojusiems pacientams,

stacionarinis gydymas truko ilgiau. Vartojantiems alkoholį, priklausomybės gydymas nuo benzodiazepinų buvo

trumpesnis.

Raktažodžiai: benzodiazepinai; abstinencija; priklausomybe; detoksikacija.

Journal of Medical Sciences. 22 Feb, 2023 - Volume 11 | Issue 2. Electronic - ISSN: 2345-0592

115

1. Introduction

Benzodiazepines (BZDs) are one of the most

frequently prescribed drugs worldwide,

primarily used for their anxiolytic properties.

However, it should be noted that

benzodiazepine prescriptions are suitable only

in one-third of all cases [1]. BZDs are used to

treat anxiety, seizures, withdrawal states,

insomnia, agitation, and are commonly used for

procedural sedation [2,3]. However, there is

significant concern regarding overprescribing

of benzodiazepines and the resultant harms, as

evidence suggests that long-term use of

benzodiazepines causes dependency, cognitive

decline and falls [4].

In 2017, benzodiazepines and other

tranquillizers were the third most commonly

misused illicit or prescription drug in the United

States [5]. In Lithuania, the use of anxiolytics

was more than twice compared to Estonia and

Latvia during the period 2010-2015 [6]. Even

though in Lithuania the consumption of

benzodiazepines showed a progressive decline

from 40.781 defined daily doses (DDDs) per

1000 inhabitants in 2016 down to 29.610 DDDs

per 1000 inhabitants in 2020, they are still

widely prescribed despite guidelines [8].

Chronic use of benzodiazepines usually causes

physical dependence. Importantly, upon

discontinuation, withdrawal syndrome is

observed in many long-term BZD users [9]. In

Lithuania, detoxification and rehabilitation

services are provided to individuals suffering

from benzodiazepine addiction [10]. Therefore,

the aim of our study was to find out the existing

links and differences between patient gender,

age, characteristics of benzodiazepine

consumption, and the course of treatment.

2. Materials and Methods

2.1. Study population

The patient inclusion criteria were the

following: diagnosed benzodiazepine addiction

(ICD-10 code F13.2 Mental and behavioural

disorders due to use of sedatives or hypnotics

Dependence syndrome), being hospitalized at

the Toxicology centre of Republican Vilnius

University hospital for planned BZD

detoxification and benzodiazepine use for at

least six months. Acute BZD intoxication,

addiction to other than benzodiazepine

anxiolytics or hypnotics and addiction to more

than one psychoactive substance (except for

alcohol) were the reasons to exclude a patient

from the study. There were 48 patients from the

period of 2011 to March 2018 included in the

final analysis.

2.2. Ethics

The research was carried out with the

permission of the institutional Bioethics

Committee of Republican Vilnius University

Hospital, Vilnius, Lithuania, on 28

th

of

February, 2018 (permission number 158200-

18/3-1013-513).

2.3. Data collection

The data were collected retrospectively from

medical documentation. Demographics,

information about patient smoking status,

alcohol use, earlier detoxification treatment,

specialist referring for detoxification, used BZD

types, their doses before and after the treatment,

total duration of BZD use, withdrawal

symptoms after one day of treatment,

psychiatric comorbidities and other than BZD

medicines prescribed for outpatient treatment

after detoxification were gathered. Furthermore,

Journal of Medical Sciences. 22 Feb, 2023 - Volume 11 | Issue 2. Electronic - ISSN: 2345-0592

116

doses of various types of BZDs were converted

into diazepam equivalents (DE) [5] (Table 1).

Table 1. Diazepam equivalents.

Benz

odiazepine

Dose equal to 5

mg of Diazepam (mg)

Alpra

zolam

0.5

Brom

azepam

3

Clona

zepam

0.5

Loraz

epam

1

2.4. Data analysis

MS Excel and IBM SPSS 23.0 were used for

data analysis. Quantitative variables were tested

for normality using the Shapiro-Wilk test.

Mann-Whitney U test was used to compare not

normally distributed variables in two

independent samples. Spearman’s correlation

coefficient was applied to assess the correlation

between non-normally distributed data. To

analyse the correlation between categorical

variables χ

2

and Phi coefficient were used.

Statistical significance was assumed when

p<0.05.

3. Results

48 patients were included in the study. The age

median was 46 years (range 40-63 years) and

there was no significant age difference between

male and female subjects, p=0.191 (table 2).

There was a weak positive correlation between

gender and smoking suggesting that males had

been more likely to smoke than females, χ

2

=

4.286, r

Phi

=0.299, p=0.038. Also, a positive

intermediate relationship between gender and

alcohol use was found indicating that males of

this sample were more likely to use alcohol

than females, χ

2

=5.943, r

Phi

=0.352, p=0.015.

Smoking and alcohol use frequencies are shown

in table 2.

Table 2. Distribution of patient characteristics according to gender.

Mal

es

Fe

males

Total p

Number (%) 20

(41.7)

28

(58.3)

48

(100)

Age median, years 45 46 46 0.19

1

Smoking, n* (%) 7

(35)

2

(7.1)

9

(18.75)

0.03

8

Alcohol use, n* (%) 10

(50)

6

(21.4)

16

(33.33)

0.01

5

BZD use duration

median, years

12 12,5 14

0.36

9

Duration quartiles, years 8-

18.5

9.5-

21

9-20

Psychiatric comorbidity,

n* (%)

12

(60)

16

(57.1)

28

(58.3)

0.84

3

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117

Depression spectrum, n*

(%)

5

(25)

11

(55)

16

(33.3)

0.30

1

Alcohol dependence

(F10.2) frequency (%)

6

(30)

5

(17.9)

11

(22.9)

0.32

4

Hospitalization median,

days

7 10 9 0.02

* n – number of patients

** mg – milligram

The study revealed that patients were referred

for the detoxification treatment mostly by

family practitioners (37.5%, n=18) and

psychiatrists (35.42%, n=17), while others were

referred following the consultation by clinical

toxicologist (27.02%, n=13). For 22.9% of

patients (n=11), the detoxification treatment,

included in this study, was not the first one,

however, there was no data on how many

hospitalisations a patient has previously had.

BZD use duration median was equal to 14 years

(range 9-20 years) and it did not differ

significantly between males and females.

Diazepam equivalent dose median before the

treatment was 58 mg (range 30-90 mg). In this

sample, males have been consuming

significantly higher doses than females

(p=0.012). Moreover, younger patients have

been using higher DE doses, as a negative

intermediate correlation between age and DE

dose at arrival was observed, r

Spearman‘s

=-0.316,

p=0.029.

It was found that before arriving for the

detoxification patients have been using five

different types of BZDs: lorazepam was the

most common one (n=21), meanwhile

bromazepam was used only in combinations

with other benzodiazepines. It should be noted

that 14 patients (29.17%) have been combining

two different benzodiazepines. The evidencing

results are given in Fig. 1.

Figure 1. Use of different BZDs.

Alprazolam Bromazepam Diazepam Clonazepam Lorazepam

0

5

10

15

20

25

13 (27.08%)

4 (8.33%)

8 (16.67%)

16 (33.33%)

21 (43.75%)

Benzodiazepine

Number of patients

Table 3. Withdrawal symptoms and lorazepam use.

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118

Lorazepam

users

Non-

users

Total

Withdrawal symptoms,

median

2 1 1

Quartiles 1 - 2 1 - 2 2 - 2

p 0.018

After the first hospitalization day, patients

experienced the following withdrawal

symptoms: anxiety, insomnia, headache, tremor

and increased sweating. However, the number

of symptoms differed between the patients.

Importantly, lorazepam users, n=21 (43.75%),

had slightly more withdrawal symptoms than

others, p=0.018 (Table 3).

The study revealed that 58.3% (n=28) of the

patients had been diagnosed with psychiatric

comorbidities, and 9 subjects were diagnosed

with two different comorbidities. It should be

noted that comorbidity prevalence did not differ

significantly between females and males,

p=0.301. 22.9% (n=11) of the patients had

F10.2 diagnosis – mental and behavioural

disorders due to alcohol use, alcohol

dependence. The results demonstrated that

prevalence of alcohol dependence (F10.2) did

not differ significantly between males (30%,

n=6) and females (17.9%, n=5), p=0.324 (table

2) in this study. Other comorbidities included

depression spectrum disorders (F32, F33) and

their frequency did not differ significantly by

gender (Table 2).

The median of hospitalization days was equal to

9 days (range 6.5-11 days). Hospitalization of

female patients was significantly longer than

males, p=0.02 (Table 2). In addition, alcohol

users have been hospitalized for a longer period

than non-users, p=0.02 (Table 4). What is more,

it was found that longer BZD use is

significantly correlated with longer

hospitalization, r

Spearman‘s

=0.310, p=0.032 (Table

4).

After the detoxification, 62.5% (n=30) of the

patients were able to discontinue BZD use. The

remaining 37.5% of the subjects had been

discharged with DE doses ranging from 5 to 30

mg. These patients were suggested to continue

outpatient detoxification treatment. There was a

weak positive correlation between DE dose

before and DE dose after the treatment,

r

Spearman‘s

=0.304, p=0.036 (Figure 3).

Table 4. Hospitalization days and alcohol use.

Alcohol

users

Non-

users

Total

Hospitalization days, median 6.5 9 9

Quartiles 5 – 8.5 7 – 11 6.5 –

11

p 0.012

Figure 2. The relationship of diazepam equivalent dose before and after the detoxification treatment.

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119

It was found that 91.67% (n=44) of the patients

have been prescribed additional non-

benzodiazepine medicine for outpatient

treatment after hospitalization. These

prescriptions included escitalopram,

mirtazapine, quetiapine, carbamazepine,

gabapentin and propanolol. 14 patients out of

44 have been prescribed two different drugs.

According to the data, longer BZD use was

significantly positively correlated with the

number of additional non-BZD drugs

prescribed after the detoxification,

r

Spearman‘s

=0.420, p=0.005 (moderate correlation

strength). Figure 3 shows additional medicines,

their combinations and distribution in the

sample.

Figure 3. Medicines for outpatient treatment after the BZD detoxification.

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120

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Number of patients

Percentage

4. Discussion

According to the earlier study, conducted in

Lithuania, it might be argued that the largest

amount of BZDs is prescribed by family

practitioners [11]. Our study revealed that most

of the patients have been referred for the

detoxification treatment by a family

practitioner. This shows the importance of

primary health care in solving the BZD-related

problem. It is important to note that certain

actions in Lithuanian health care system have

been taken to improve regulations and decrease

misuse of BZDs. Since 1

st

of July, 2021,

benzodiazepines can only be prescribed by an

electronic prescription or a special controlled

drugs form [12]. This has replaced earlier paper

prescriptions and should prevent fake

prescriptions. Furthermore, as electronic

prescriptions are easier to track, this should

decrease “doctor shopping” and limit the BZD

total that can be bought by one patient. Also,

following new regulations, benzodiazepines can

only be prescribed for 30 days of use and the

patient must buy them within 10 days of

prescription. The aforementioned restriction

should encourage BZD-using-patients to visit

their family practitioners or psychiatrists more

often, thus, acquiring more medical attention,

while using benzodiazepines. Overall, primary

medical care remains one of the main targets

for BZD addiction and misuse prevention in

Lithuania.

It is suggested that long-term BZD use should

be defined as the use for six months or more. In

our study, the shortest duration of BZD use was

9 years, therefore, all the subjects can be

considered as long-term users. Quite a few

studies state that in general population females

are more likely to use BZDs [11–15]. Our study

is in compliance with the findings of earlier

studies, concluding that general determinant of

BZD use cannot be applied to long-term BZD

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121

users [15], since no significant differences in

BZD use duration were found between male

and female patients.

Although the duration of use did not differ

between genders, DE doses before the

detoxification treatment were slightly higher in

males than in females. This result might

coincide with findings that women have higher

GABAA-BZ receptor availability than men,

which means that they are more sensitive to

BZD effects [13]. Age-determined (younger

patients use higher DE doses before

detoxification) DE dose differences might be

seen due to age-related pharmacokinetic and

neuronal changes, therefore, younger people are

able to consume higher doses with less

undesirable effects [16–18]. In addition, it has

been noted, that recreational BZD use is very

common among young adults [19,20]. These

results bring out the significance of

benzodiazepine representation in popular

media: glorification of benzodiazepines among

the youth might be highly affected by social

media, as there is a bulk of popular songs,

movies or series, showing benzodiazepines as

easily accessible pleasure-inducing drugs.

The result, stating that lorazepam is the most

common BZD, is specific to the Lithuanian

population, since similar studies in other

countries show other benzodiazepines being the

most popular [21]. Before 1

st

of July 1, 2021,

lorazepam used to be included in the B list of

reimbursable medicines in Lithuania, meaning

that particular diagnoses allow reimbursement

of the drug. This situation could possibly

encourage irrational use of the pharmaceutical.

Following the example of the Netherlands,

exclusion of lorazepam from the list, would

help to reduce its misuse [22].

Longer BZD use was related to the need for

longer hospitalization and more non-BZD

medicines prescribed for outpatient treatment

after detoxification. This might indicate that

longer BZD use might aggravate the process of

detoxification for the patient causing worse

withdrawal symptoms that last for a longer

time, therefore, discontinuation of BZD is more

difficult to achieve. Hospitalization and

detoxification treatment was also longer in

females than in males which is a common result

in many studies: men are more likely to leave

the hospital against medical advice [23–25].

Earlier studies have found that mental

disorders, especially anxiety and mood

disorders, increase the risk of any BZD use in

the general population [11,14]. Also, heavy

alcohol consumption in BZD users is thought to

be lower than in the general population

allegedly due to physicians and pharmacists’

warnings [26]. More than half (58.3%) of the

patients in this study had been diagnosed with

some psychiatric disorder (other than F13.2)

and the most common ones were alcohol

dependence, as well as depression spectrum

disorders. This might be due to the fact that

alcohol withdrawals are typically treated using

BZDs and some of the patients, suffering from

substance abuse disorder, are prone to replace

one substance with other. In addition, alcohol

users had been hospitalized for longer period

than non-users. The importance of mental

disorders in BZD misuse is undeniable,

however, alcohol misuse appears to have a

more complex role in the pathogenesis of BZD

addiction. Therefore, more detailed studies are

needed to analyse the relationship between

mental disorders, alcohol abuse, and BZD

addiction.

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122

Certain limitations of this study should be

noted. First, quite a small sample does not

reflect the population and the results concerning

BZD use disorder in Lithuania can be

inadequate. Second, the retrospective study

offers scarce details about BZD use and earlier

detoxification treatments, therefore, prospective

studies with additional questioning of the

patients and larger samples should be

conducted.

5. Conclusions

Among long-term BZD users, males have been

using higher BZD doses than females, also,

higher doses have been the characteristic of

younger patients. The patients, who had used

higher BZD doses before the detoxification

treatment, have been discharged with higher

BZD doses and more non-BZD medicines

prescribed for outpatient treatment. It is

important to note that lorazepam remains the

most common BZD among people with BZD

addiction in Lithuania. Longer BZD use was

related to a longer period of detoxification.

Females have been hospitalized longer than

males, and alcohol users have been hospitalized

for a shorter time than non-users. Nevertheless,

prospective studies with larger samples are

needed to verify the strength of these results.

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