Risks of dependence on benzodiazepine drugs: a major problem of

Risks

of

dependence

on

benzodiazepine

drugs:

a

major

problem

of

long

term

treatment

Heather

Ashton

Phlegmatic

people

dislike

taking

benzodiazepine

drugs.

In

those

with

low'anxiety

traits

benzodiazepines

are

dysphoric

and

may

paradoxically

increase

anxiety.'

In

normal

subjects

benzodiazepines

improve

perform-

ance

under

experimental

stress

but

worsen

it

under

conditions

of

low

stress.2

Benzodiazepines

relieve

pre-

operative

anxiety

in

patients

with

high

anticipatory

anxiety

but

not

in

those

with

low

anticipatory

anxiety.3

Thus

like

0i

receptor

blocking

agents

benzodiazepines

require

some

underlying

tone

upon

which

to

exert

their

anxiolytic

effects.

In

general,

the

greater

the

anxiety

the

greater

the

anxiolytic

efficacy.

It

follows

that

most

people

who

take

benzodiazepines

are

anxious.

In

students

a

history

of

prescribed

benzodiazepines

correlates

with

a

high

anxiety

trait.4

Long

term

users

likewise

have

high

scores

for

neuroti-

cism.

6

These

findings

apply

when

benzodiazepines

are

used

both

as

anxiolytic

and

as

hypnotic

agents.

Thus

people

who

take

and

keep

on

taking

benzodiazepines

are

a

self

selected

population

with

high

anxiety

traits

or

states.

Reasons

for

dependence

on

benzodiazepines

Dependence

on

benzodiazepines

in

the

sense

that

users

require

the

drugs

for

psychological

comfort

and

suffer

withdrawal

symptoms

when

they

stop

taking

them

develops

rapidly.7

The

same

patients

who

find

benzodiazepines

efficacious

are

also

prone

to

dependence

and

to

withdrawal

effects,

which

are

themselves

largely

manifestations

of

anxiety.

This

vulnerability

occurs

for

several

reasons.

Firstly,

anxious

people

are

more

likely

to

complain

of

symp-

toms.8

Secondly,

long

term

users

of

benzodiazepines

tend

to

have

poor

abilities

in

coping

with

stress.

The

pharmacological

basis

for

both

anxiety

and

a

poor

ability

to

cope

with

stress

may

be

low

activity

in

limbic

system

pathways

utilising

y-aminobutyric

acid9

or

high

activity

in

those

utilising

serotonin,'0

or

both.

Such

activity

is

counteracted

by

benzodiazepines."

Benzodiazepines,

however,

impair

learning

of

strategies

to

cope

with

stress,

such

as

behavioural

treatment

for

agoraphobia.)

2

Other

characteristics

(passive-dependent

personality,

resourcelessness7

13)

also

increase

the

vulnerability

to

withdrawal

symptoms

and

the

motivation

for

continued

use.

Benzodiazepine

deprivation

in

such

users

leaves

them

unprotected

from

stress

and

re-exposes

their

limitations

of

coping.

Finally,

anxious

people

may

be

innately

sensitive

to

punishing

stimuli.'4

Benzodiazepines

are

"depunish-

ing"

drugs.

Even

in

animals

they

protect

against

punishing

stimuli'5

and

are

taken

therapeutically

by

many

people

as

protective

drugs.6

In

contrast,

those

who

take

benzodiazepines

at

high

doses

for

kicks'6

form

a

different

population,

innately

less

sensitive

to

punishment'4

that

also

tends

to

abuse

other

drugs4

17

(see

box).

Clinical

Psychopharmacology

Unit,

Medical

School,

Newcastle

upon

Tyne

NE2

4HH

Heather

Ashton,

FRCP,

reader

in

clinical

psychopharmacology

BrMedJf

1989;298:103-4

Withdrawal

syndrome

with

benzodiazepines

The

overall

incidence

of

a

withdrawal

syndrome

after

long

term

therapeutic

doses

of

benzodiazepines

is

unknown.

Estimates

vary

with

the

population

studied,

the

duration

of

drug

use,

the

rate

of

withdrawal,

the

length

of

follow

up,

and

the

definition.

Lader

and

colleagues

reported

a

100%

incidence:

all

patients

experienced

withdrawal

symptoms

(increased

anxiety,

Profiles

of

dependence

on

drugs

People

who

become

dependent

on

drugs

are

suggested

to

be

two

different

populations

at

the

extremes

of

a

normal

distribution.

Those

who

take

drugs

for

pro-

tection

are

anxious,

have

high

scores

for

neuroticism

(N),46

17

are

highly

susceptible

to

punishment,'4

tender

minded,

and

socially

compliant.4

Their

preferred

drugs

are

benzodiazepine

tranquillosedatives,

which

they

tend

to

take

long

term

in

low,

prescribed

doses.

They

are

sensitive

to

withdrawal

largely

because

of

their

anxiety

and

poor

abilities

in

coping

with

stress.

In

contrast,

those

who

take

drugs

for

kicks

have

high

scores

for

psychoticism

(P),'7

are

highly

sensitive

to

reward,'4

impulsive,

tough

minded,

antisocial,

and

seek

sensation.4

'7

They

tend

to

abuse

hard

and

soft

drugs,

often

illicitly,4

'7

which

they

take

intermittently

or

long

term

in

high

doses.

They

experience

an

abstinence

syndrome

largely

because

of

the

high

doses

used.

The

general

population,

which

is

less

dependent

on

drugs,

occupies

the

middle

of

the

curve.

Nicotine

and

alcohol

(which

have

both

tranquillising

and

directly

rewarding

properties

over

a

moderate

range

of

doses30)

cover

the

whole

spectrum-a

fact

which

probably

explains

their

widespread

use.

Drugs

for

protection

Benzodiazepines

High

N

score,

ar4XiOLiS,

highly

susceptible

to

punishment,

tender

minded,

socially

compliant

Prescribed,

low

doses,

long

term

Drugs

for

kicks

Soft

drugs,for

example

Cannabis

Hart]

drugs

Personality

High

P

score,

irnmulsive,

highly

susceptibale

to

reward,

tough

wilindec],

antisocial

Use

of

druqs

Recreational

anid

illicit,

lon(g

term

or

intermitten

other

psychological

and

somatic

symptoms,

and

perceptual

disturbances),'6

1

'although

slow

with-

drawal

minimises

symptoms.20

Tyrer

et

al

estimated

that

only

30-45%

experienced

true

withdrawal

symp-

toms,

defined

as

a

temporary

increase

in

anxiety

to

half

or

more

above

prewithdrawal

values

or

the

develop-

ment

of

two

or

more

new

symptoms

("pseudowith-

drawal"

occurred

in

some

patients

who

thought

that

they

were

withdrawing.

)13

21

Others

report

similar

results.

16

22

23

Withdrawal

criteria

based

on

differences

from

pre-

withdrawal

measures,

however,

underestimate

the

true

incidence.

I

have

observed

that

long

term

users

of

benzodiazepines

develop

further

symptoms

while

taking

the

drugs."

'

These

include

increasing

anxiety

and

also

paraesthesiae

and

perceptual

disturbances,

new

symptoms

generally

associated

with

withdrawal.

'

These

symptoms

may

result

from

tolerance

to

some

effects

of

benzodiazepines

so

that

a

withdrawal

syn-

drome

emerges

despite

continued

drug

use.

Support-

ing

this

observation

is

the

fact

that

increasing

the

dose

of

benzodiazepines

temporarily

alleviates

symptoms.

A

large

escalation

in

dose

is

reputedly

rare7

no

doubt

BMJ

VOLUME

298

14

JANUARY

1989

103

Controversies

in

Therapeutics

because

benzodiazepines

are

medically

prescribed

to

patients

who

are

generally

compliant.

Nevertheless,

7 5-10-0

mg

lorazepam

daily"

is

not

uncommon

(equivalent

to

75-100

mg

diazepam24).

Withdrawal

symptoms

occurring

during

long

term

use

are

more

noticeable

with

potent

benzodiazepines

that

are

rapidly

eliminated.

Patients

taking

lorazepam'

or

alprazolam25

commonly

experience

craving

or

dysphoria

between

doses,

and

daytime

withdrawal

effects

from

the

use

of

triazolam

as a

hypnotic

are

well

recognised."

Thus

the

motivation

to

use

ben-

zodiazepines

for

anxiolysis

or

hypnosis

gradually

merges

with

the

need

to

avoid

withdrawal

effects.

For

this

reason

it

may

be

impossible

to

measure

withdrawal

effects

precisely.

Recently

Murphy

et

al

broadened

their

withdrawal

criteria

to

include

a

temporary

increase

in

anxiety

to

less

than

initial

values.'6

In

this

study

ratings

before

benzodiazepine

were

available

and

the

incidence

of

withdrawal

symptoms

was

again

30%.

Diazepam

was,

however,

given

for

only

six

weeks

and

the

results

may

not

apply

to

those

who

use

it

for

longer.

Furthermore,

many

long

term

users

(46

out

of

86

in

one

study27)

decline

to

undertake

withdrawal

and

many

drop

out

(18

of

the

remaining

4027

)

because

of

fear

or

experience

of

withdrawal.

Taking

account

of

these

subjects

would

substantially

raise

the

apparent

incidence.

Pharmacological

mechanisms

The

pharmacodynamic

mechanism

of

benzo-

diazepine

tolerance

and

dependence

is

probably

homoeostatic

down

regulation

of

y-aminobutyric

acid

and

benzodiazepine

receptors

in

the

limbic

system.28

Once

this

has

occurred,

withdrawal

of

the

drug

results

in

a

state

of

underactivity

of

pathways

utilising

y-aminobutyric

acid

with

a

pattern

of

unapposed

neuronal

excitation

characteristic

of

benzodiazepine

withdrawal29

and

anxiety

states."'

Similar

brain

mechanisms

mediate

the

psychological

and

somatic

symptoms

of

both

conditions,

which

are

in

many

respects

inseparable.

Lader

notes

that

even

non-anxious

people

may

develop

benzodiazepine

withdrawal

symptoms,20

although

they

may

be

less

prone

to

do

so.7

There

may

be

a

population

of

stable

people

who

discard

benzo-

diazepines

without

difficulty

when

a

temporary

stress

has

passed.

I

suggest,

however,

that

most

people

who

continue

to

use

benzodiazepines

are

dependent

on

the

drugs

for

enhancement

of

the

effects

of

y-aminobutyric

acid.

All

will

suffer

withdrawal

symptoms

unless

they

withdraw

slowly

and

simultaneously

learn

alternative

strategies

of

coping.

Long

term

control

of

anxiety

probably

requires

learned

changes

in

endogenous

y-aminobutyric

acid

transmission

rather

than

the

imposition

of

an

exogenous

cover

up

with

benzodiaze-

pines.

1

Parrott

AC,

Kentridge

R.

Personal

constructs

of

anxiety

under

the

1,5

benzodiazepine

clobazam

related

to

trait-anxiety

levels

of

the

personality.

Psychopharmacology

1982;75:353-7.

2

Parrott

AC,

Davies

S.

Effects

of

a

1,5

benzodiazepine

upon

performance

in

an

experimental

stress

situation.

Psychopharmacology

1983;79:367-9.

3

O'Boyle

CA,

Harris

D,

Barry

H,

Cullen

JH.

Differential

effects

of

benzodiaze-

pine

sedation

in

high

and

low

anxious

patients

in

'real

life'

stress

setting.

Psychopharmacology

1986;88:266-9.

4

Golding

JF,

Cornish

AM.

Personality

and

life-style

in

medical

students:

psychopharmacological

aspects.

Psychology

and

Health

1987;1:287-301.

5

Ashton

H.

Benzodiazepine

withdrawal:

an

unfinished

story.

Br

Med

J

1984;288:

1135-40.

6

Ashton

H,

Golding

JF.

Tranquillisers:

prevalence

and

possible

consequences:

data

from

a

large

United

Kingdom

survey.

BrJ3

Addict

(in

press).

7

Murphy

SB,

Tyrer

P.

The

essence

of

benzodiazepine

dependence.

In:

Lader

M,

ed.

The

psychopharmacology

of

addiction.

Oxford:

Oxford

University

Press,

1988:157-67.

8

Bond

MR.

Personality

and

pain.

In:

Lipton

S,

ed.

Persistent

pain:

modern

methods

of

treatment.

Vol

2.

London:

Academic

Press,

1980:1-26.

9

Leonard

BE.

New

antidepressants

and

the

biology

of

depression.

Stress

Medicine

1985;1:9-16.

10

Gray

JA.

The

neuropsychology

of

anxiety.

Oxford:

Clarendon

Press,

1982.

11

Ashton

H.

Benzodiazepine

withdrawal:

outcome

in

50

patients.

Br

J

Addict

1987;82:665-7

1.

12

Gray

JA.

Interactions

between

drugs

and

behaviour

therapy.

In:

Eysenk

HJ,

Martin

I,

eds.

Theoretical

foundations

of

behaviour

therapy.

New

York:

Plenum

Press,

1987:433-47.

13

Tyrer

P,

Owen

R,

Dawling

S.

Gradual

withdrawal

of

diazepam

after

long-term

therapy.

Lancet

1983;i:

1402-6.

14

Gray

JA.

The

neuropsychology

of

emotion

and

personality.

In:

Stahl

SM,

Iverson

SD,

Goodman

EC,

eds.

Cognitive

neurochemistry.

Oxford:

Oxford

University

Press,

1987:171-90.

15

Iverson

SD,

Iverson

LL.

Behavioural

pharmacology.

New

York:

Oxford

University

Press,

1981.

16

Woods

JH,

Katz

jL,

Winger

G.

Abuse

liability

of

benzodiazepines.

Pharmacol

Rev

1987;39:251-419.

17

Eysenck

HJ,

Eysenck

SBG.

Manual

of

the

Eysenck

personality

questionnaire

Essex:

Hodder

and

Stoughtoni,

1975.

18

Petursson

H,

Lader

MH.

Withdrawal

from

long-term

benzodiazepine

treat-

ment.

BrMedJ3

1981;283:643-5.

19

Lader

MH,

Olajide

D.

A

comparison

of

buspirone

and

placebo

in

relieving

benzodiazepine

withdrawal

symptoms.

J

Clin

Psychopharmacol

1987;7:

11-5.

20

Lader

M,

ed.

The

psychopharmacology

of

addiction.

Oxford:

Oxford

University

Press,

1988:1-14.

21

Tyrer

P,

Rutherford

D,

Huggett

T.

Benzodiazepine

withdrawal

symptoms

and

propranolol.

Lancet

1981

;i:520-2.

22

Rickels

K,

Case

WG,

Downing

RW,

Winokur

A.

Long-term

diazepam

therapy

and

clinical

outcome.

JAMA

1983;250:767-71.

23

Busto

U,

Sellers

EM,

Naranjo

CA,

Cappell

HP,

Sanchez

CM,

Sykora

K.

Withdrawal

reaction

after

long-term

therapeutic

use

of

benzodiazepines.

N

EnglJ7

Med

1986;315:654-9.

24

Northern

Regional

Health

Authority.

Benzodiazepine

dependence

and

withdrawal-an

update.

Drug

Newsletter

1985;31:125-8.

25

Hermann

JB,

Brotman

AW,

Rosenbaum

JF.

Rebound

anxiety

in

panic

disorder

patients

treated

with

shorter-acting

benzodiazepines.

I

Clin

Psychiatry

1987;48(suppl

10):22-8.

26

Murphy

SM,

Owen

R,

Tyrer

P.

Comparative

assessment

of

efficacy

and

withdrawal

symptoms

after

six

and

twelve

weeks

treatment

with

diazepam

or

buspirone.

BrJ3

Psychiatry

(in

press).

27

Tyrer

P.

Round

table

discussion.

In:

Costa

E,

ed.

The

benzodiazepines:

from

molecular

biology

to

clinical

practice.

New

York:

Raven

Press,

1983:400-6.

28

Nutt

D.

Benzodiazepine

dependence

in

the

clinic:

reason

for

anxiety?

Trends

in

Neurosciences

1986;9:547-60.

29

Cowen

PJ.

Psychotropic

drugs

and

human

5-HT

neuroendocrinology.

Trends

in

Pharmacological

Sciences

1987;8:105-8.

30

Ashton

H.

Brain

systems,

disorders,

and

psychotropic

drugs.

Oxford:

Oxford

University

Press,

1987.

Peter

Tyrer

continuedfrom

page

102

is

excluded

the

features

associated

with

dependence

-

high

dosage,

long

duration

of

treatment,

and

previous

dependence

on

psychotropic

drugs-are

avoided

and

the

prescription

becomes

short

term,

low

dosage,

and

comparatively

free

of

risk

(table).

Doctors

need

to

realise

that

benzodiazepines

now

have

no

value

in

long

Influence

ofpremorbidpersonalityonfactorspredisposingto

dependence

on

benzodiazepines

Type

of

premorbid

personality

Risk

factor

Normal

Dependent

Dose

Low

Variable

Frequency

Intermittent

Regular

Duration

of

treatment

Short

Long

Previous

dependence

on

prescribed

psvchotropic

drugs

Rare

Common

Nature

of

benzodiazepine

Determined

by

Determined

prescriber

by

prescriber

term

prescribing.

These

drugs

should

not

be

given

for

longer

than

four

weeks;

if

given

for

longer

they

are

less

effective

than

antidepressants

and

psychological

procedures

such

as

cognitive

therapy

and

self

help

packages.'3

They

should

be

confined

to

short

term

intervention

when

rapid

relief

of

anxiety

and

insomnia

is

considered

to

be

essential.

In

making

the

decision

to

prescribe

benzodiazepines

doctors

need

to

diagnose

symptoms,

circumstances,

and

person.

If

they

do

this

successfully

they

have

no

reason

to

fear

dependence.

1

Murphy

SM,

Tyrer

P.

The

essence

of

benzodiazepine

dependence.

In:

Lader

M,

ed.

The

psychopharmacoloZy

of

addiction.

Oxford:

Oxford

University

Press,

1988;157-67.

2

Petursson

H,

Lader

MH.

Withdrawal

from

long-term

benzodiazepine

treat-

ment.

BrMedJ7

1981;283:643-5.

3

Ashton

H.

Benzodiazepine

withdrawal:

an

unfinished

story.

Br

Med

J

1984;288:

1135-40.

4 Busto

U,

Sellers

EM,

Naranjo

CA,

Cappell

H,

Sanchez-Craig

M,

Sykora

K.

Withdrawal

reaction

after

long-term

therapeutic

use

of

benzodiazepines.

N

Englj

Med

1986;315:854-9.

104

BMJ

VOLUME

298

14

JANUARY

1989