Pnq. NeurirPsycbpW

a Bcoi-Psychtot PrInted tn Great Brttatn. Au tights mseivcd

1992. Vol. 16. pp. 9-16

0278- 5845/O2$15.00 0 I OS2Pergamon Pressplc

INTERNATIONAL REGULATION OF BENZODIAZEPINES INAYAT KHAN

Psychotropic and Narcotic Drugs Unit. World Hcaltb Ogantzatlon. Geneva. Switzerland

(Final

form,

June 1991 f

Contents 9 10 10 10 12 13 15 15 16

Abstract Introduction Methodology The Conventions The Role of WHO Discussion Conclusions Acknowledgements Reference8

1. 2. 2.1. 2.2. 3. 4.

Abstract

International Regulation of Benzodiszepines Khan, Inayat: Psychopharmacol. 6 Biol. Psychol. 1992, -16(1):9-16.

Prog.

Neuro-

1.

The UN Convention 1971 on Psychotic substances requires the World Health Organization to recommend psychotropic substancea for international control,

2.

This convention is based particular on the public

on evaluating the benefit and risk ratio, in health and social problems associated with its

uss.

3.

The UN Commission on Narcotic Drugs takes a final decision recommendations and is then binding in countries which sre convention.

4.

Presently 34 commercially available benzodiazepines are under international schedule IV of the 1971 convention, to be control at minimum level, prescription and not over the counter. available on the physicians’

Keywords : 34 benzodiazepines, of 1971 Convention.

dependence

liability

on these party to the

and abuse potential,

Schedule

IV

Commission on Narcotic Drugs (CND), International Narcotics Control Abbreviations: Board (INCB), UN Convention on PsychotropicSubstances of 1971 (1971 Convention), World Health Organization (WHO). ____________________--‘Dr

I.

Khan, Formerly

Chief

Medical

Officer

10

I. Khan

1. This

paper

“1971

outlines

Convention”

work

in

authorities.

commercially

available

WHO has

selected

committee 2.1

by WHO in with

This

paper

and

response

concerned details

2.

Methodology

for

review

informal

of

the

its

responsibilities

Nations

to

steps

control

submitted

for

under

organs

various

taken

and

review

to

United

and decisions

substances

dependence

the

gives

Henzodiazepines

these

on drug

undertaken

collaboration

and national

Introduction the

and agencies

taken

34 of

to

reviev

these.

discussion

by a”

expert

groups:

The Conventions

The various al.

conventions

on::

“Psychotropic

and Narcotic

Drugs”

are

discussed

(Rexed

et

1984): Psychoactive

and

substances

alcohol

continue

substances

have

pharmacopiss health sre

to

in in

from

placing

with

we have

1961

problems

crested United

and

The

the

the most

international

dangerous

subjected

to

of

a number which

control

to

situation

in

sre

grave

control drugs

and

of

defined

production,

wss of

in

agreement

eliminated

“The

from

drug

the

problems.

as

cots

in

response

deals

leaf

world

and to

December

the

1988)

by drug

on Illicit

control Drugs which

and

precursors

has

Traffic

or

can

also

provide

been

witnessed. Substances.

a framework substances.

beneficial

and distribution

be

Regional

and Psychotropic

psychotropic

The potentially trade

are

substances.

abuse

drugs

manufacture,

in

population

primarily

(in

Convention

which

instruments

use.

social

protocol

decided

treaties.

their

and

to

finalized.

chemicals

narcotic

protect

as well

crested 1986

society

liability.

control

was created

finally

on Narcotic are

to

the

community

dependence

health

resin

and psychotropic

friends

treaties

vas

and

in

public

The 1909

drug

amending

Substances” It

the

control

1972

and cannabis

Substances

American

of

the

with

placed

created

international

and use public

substances. the

of

Tobacco other

and are

have

individual

international

ratify

the

internationally.

part

produce

and

cannabis

narcotic

neighbours

drug

to

Drugs”,

and Psychotropic

South

to

A new instrument

of

regulation

liable

the

substances day

terms

which

of

and the

immemorial.

Some of

in modern

health

on

present

are

respond

covers

the

the

on Psychotropic

manufacture

is

the

countries

cover

Convention”

One example

to

time

substances,

nationally

for

trafficking.

between

The

also

safety

other

on psychoactive

by psychotropic

cooperation

and the

sttemtpt

of

Convention

to

efficacy

control

on Narcotic

Nations

in many societies.

danger

first

which

but

1971

Drugs

“1988 in

rigid the

since

accepted

Many of

3 conventions

illicit

Narcotic

used

of

restrictions

drugs

“The

the

most

Convention

narcotic

abuse

tests

by human beings

used

and pose

was

substances

cocaine.

by

been

socially

was a forerunner

selected

“The

the

Shanghai

Conference

Today,

the

problems

subject

cooperate

in

passed

social

Conference

This

be

in many countries.

and

“ov

have

to

so

ones that

for The are

their

use

Intcmational regufatlon ofbcnzodlazepfnes

can be limited Conventions

exclusively

embody a policy

drug regulatory substances

work,

of

balance

between

therapeutic

public

of

some of

health

of

advertising

for

specisl

substance

and after

United

process

for

control

liability of

While

that

use

on medical the prescriptions of

the retail

be prohibited.

the prevention abusers.

in the control

the public

The

of

and eocial

on Narcotic

collaboration

of

of each problems

Drugs (CND) for

to the Secretary-General

industry

and

levels

usefulness

health

the

assign

substances

and at adequate

to the Commission

and

of abuse and for

The convention

and therapeutic

on an extensive

on the

and degree

the general

the labelling

purposes

by a notification

reats

production

use and warning 8s necessary

of

of changes

to

depending

are available

as a rule

members and the pharmaceutical

drugs

has four

It includes

I.

risk

to public

between

in collecting

of

the

the

all

the

is

firm

very

for

manufacturers,

distribution,

and

export

specific

without

reports

for

prescription

medical

labelling Schedule

sre

also

II.

These have very as phencyclidine,

nature

to limit

statistical

their

any,

and include

and

of a dangerous

therapeutic

special

close!

Narcotics

Control

use sra permitted

special

Board (INCB).

and for

7 licenses

to prohibit

necessary

to

a

on

under article

to require

is

posing

Controls

supervision It

suthorization.

nature

use.

provisions

to research,

and to require

to the International limited

if

use chiefly

etc.

agreement

for

which are drugs

and of doubtful,

of the strictest control

schedules:

LSD, DMT, etc.

health

for

medicine.

their

reintegration

for

are subjected

to ensure

that

and

information.

Schedule

these

for

the seriousness

Initiated

measures

should

dependence

the

the rest

measures

schedules

by WHOor s party and its

The “1971 Convention”

serious

for

to WHOin respect

evaluating

This

Nations

necessary

public

abuse makes a recommendation

control.

Organization

for

“The stimulants

System

and use,

with drug abuse.

practice,

directions

and social

them in appropriate

to its

provides

substsnces

of dependence

is prohibited,

provision

WHOhas to assess

related

associated

sound medical

includes

responsibilities

placing

controls.

its

with

and rehabilitation

specific

and the risk

traffic.

Nervous

distribution

and

the controlled

and benzodiazepinesl

The controlled

to the general

contains

treatment

problems

The convention

barbiturates

manufacture,

usefulness

the substance

convention

(e.g.

of

illicit

such as Central

the

in legislation

utilization

abuse and to counteract

substances

in accordance

that

in trade,

Furthermore, needed

controls

the rational

substances

hypnotic

and social

only.

issued

also

control

the controlled

prescription

their

LSD and mescaline).

degrees

of

of

purposes.

the type of

to promote

psychoactive

various

packages

helping

sedative

(e.g.

and medical

and indicate

thus

covers

amphetamine),

hallucinogens

are

scientific

and the prevention

1971 Convention” (e.g.

for

11

import

furnish

full

Requirements

statistical

reports

and

mandatory.

These contain limited which

These are all

stimulants

therapeutic

or sympathomimetic

usefulness,

is of no human therapeutic drugs

known to be highly

but also

usefulness addictive

type of drugs e.g.

contain

narcotic

amphetamine.

snalgesics

such

but is used in veterinary and the controls

over

them

12

1. Khan

are

generally

presented

in

the

same as

article

7.

for

drugs

in

The control

Schedule

I but

requirements

are

short

and medium

acting

are

therapeutically

without

the

different

special

in

control

degree

measures

rather

than

in

type. Schedule

to

This

III.

seriously

abused,

those

for

drugs

authorization

are

the

that

is

IV.

have

for

marked

of

licensing

of

on

of

level

its

control

of

production

is

no

that

have

been

The requirements requirement

and use, labelling

of

of

etc. and

for for

are

import

submission

licensing

of

similar

and export to

trade,

INCB. etc.

are

so much used.

drugs,

although

it

from

is

of

must

evidence

similarity

in

the

the

risk

therapeutically

not

It

for

is

drugs

although

strict

degree

insignificant.

practice,

a supply

in

of

a

control

The requirements labelling

possible

for

difficulty

and

for

a party

might

abuse

must

into

force

the

that

to

vary

otherwise

either or

the

the

arise.

of

the

is

likely

if

ill

above

is

being social

problem,

to

Finally,

a basic

premise

be weighed

against

the

is

criterion

be abused

warranting

the under

possibility

the of

dependence

such

criteria

must

also

an extent of

“1971

it

characteristics

There to

an

specified

placing

be

addition

makes

pharmacological

alternatives.

and

in

produce

also

should

as drugs

there

alternative

for

a drug effects

substances

of

control

Convention”

Convention”

evaluation

Secretary-

responsibility

convention,

“1971

distinct

the

the

international

substances,

that This

have

on to

added

similar

controlled

The “1971

under

single

Under

effects.

based

recommend

further

and produces

demonstrating

drugs

to

drug

has

Under

prototypic

controlled.

control.

of

is

a narcotic

abuse

system

to

It

Convention.

to

of

a responsibility

drugs.

Convention”

involves

addition

health

Nations

to WHO.

nervous

substance

international

medical

and analgesic

A less

where

placing

Single

presently

a public

to

“1971

similar

new types

drugs

that

the

central

be met

causing

to

This

control

to

as

The

of

narcotic

substances

criterion.

to

still

used

remains.

drugs

League of

liable

criterion

possible

the

Nations

to

unrelated

widely

medical

still

these

risk

control.

under

certain

is

sound

trade

for

and

United

it

and have

with

and

scheduled

this

tranquilizers

but

psychotropic

alternative

hypnotics,

WHO

of

if

of

not

already

the

that

it

substance

Convention”

limiting

be

is

legitimate

use. the

critical (CND).

wrote

coming

examination Experts

and explicit and

there

prescription,

properties

manufacture

the

controlled

With

but

a variety

accordance

benefit

and

that

II

them are

these in

inherited

the

General

under

medical

barbiturates

useful.

some of

requirements

WHO has

is

statistics

to

addictive

for

The Role

which

I and

includes

countries,

prescription

data

full

This

prescription

2.2

Schedules

relating

suggested

for

they

same.

Schedule

number

in

and

The conditions

includes

although

of

of

procedures

who participated The process

process. a rnnort

that

the

specified

“1971

Convention”

and methods in

the began

in

have

when WHO Expert

laboratory

WHO set

by WHO, Commission

used,

evaluations

1976,

procedures

recommended Committee that

were

in motion

a

on Narcotic

a more on Drug

acceptable

Drugs

formalized Dependence for

met

International

assessing stated

dependence that

and CNS alterations

because

the

property

common

in

repeated

use

drugs

of

administration

Assessing

physical

1980

of

use,

the

principle.

the

of

light

19811,

types

ofdata.

the

Single

WHO REview

gained

plenipotentiary

control

benzodiazepines, These

recommendations Dependence

of

WHO to

the

urgently

commercially the

third

the

the i)

type

1981);

Review

chemical convulsant

Report of

of

Group

1986)

on No.

the

437,

and anxiolytic

the

the

and

in

those

all

“1971

as

health possible

estimating

drugs

extent

for The document

Psychoactive the

its

Substance

approved

changes

eighty-fifth

and

session

as

were

Guidelines,

of

available

of

1970).

held

proposed

to

in them

1990).

19821

Drugs.

The

bindiny! of

place

the

Committee

recommendations in in

on

List

not

listed

market

Drugs the

two

1). review

for in

characteristics, nervous

for

“1971

accepted

that

by the

report.

accepted.

which

4

requested

international to

place

33

Convention”

based

This

was

review

groups earlier

recommendations

sedative, effects.

not

P resolution

1983,

decided

(Table

earlier

to

February

the

IV of

were

response

to

new

on Drug

justification

central

under

These

1983,

criteria

time,

Expert

17th

Drugs

were

that

on

took

and nitrasepam.

The

the

Convention

the

Schedule

made by

1971

a discussion

oxasepam

on Narcotic

MNH.83.20,

the

at

was convened

on Narcotic

under

on seven

of

Convention”.

1971,

benzodiasepines

profile

for

review

guidelines

creation

report

drugs

MNH.82.44,

receptor

in

Board

widely

the

recommendations

on Narcotic

methods

summarizes

to

UN Commission

WHO Docu.

public

as well

Discussion

were

Commission

was based

structure,

withdrawal

met and

determining

Dependence-Producing

for

psychoactive

(WHO Docu.

used

in January/February

benzodiazepines

and

self-

dependence.

whether

control

covered

chlordiazepoxide,

and assess

UN Commissions

8th

diazepam,

1984,

available

this

MNH.81.37. of

review

recommendations of

as

which

Nations

In February

control.

on

review

United

early

WHOwere based

(WHO Technical

The WHO’s eighth (xxx)

were

from

physical

committee

for for

by WHO (WHO Revised

conference as

useful

Convetion

of

some modifications

experiences

Substances,

four

were

The WHO Executive

Psychotropic

convention.

drug

a the

problems.

3. During

data

expert

considered

The report

social

the

another

of

being

(WHO Guidelinen,

approved

the

656,

the

under the

underlying have

is

important

produce

determine

group

perpetuate using

Another

to

This

behaviaur

and/or

properties

ability to

1978).

taking

produce

dependence. its

618,

and drug

that

important

WHO new procedures

for Control”

1990

is

No.

reinforcing

predicting abuse

by a drug

and

recommendations

International

their

of

particularly

No.

types

health

“Guidelines

January in

these

1984,

seeking

substances

evaluation

of

Report

threatening.

produced

related in

scheduling entitled

is

defining

drug

on drug

for

a drug

specifically

obtaining

the

essential of

Report

Beginning

for

is

life

problems,

for

effect

13

of benzodiazepines

(WHO Technical

psychotropic

in humans,

(WHO Technical

social

means

of

dependence

are

deliberated and

types

property

manifestations In

reinforcing

all

methods

pharmacological

regulation

These hypnotic

the

(WHO Docu. sessions made by were: anti-

I. Khan

14

animal

ii)

iii)

data

on psycholoNica1

human experimental clinical

iv) V) Vi)

data

data

extent

or

of

abuse result

utilization

the

to

on data substances

number

recommend

on

to

thesc

seven

However,

to

hove

of

abuse

to

cnnatitutc

placing

of

the

as

substance

other

the

above.

than

unanimous

under

but

they

capacity a public

(2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) In April

1989,

787,1989),

under i) ii) iii) iv) v)

met and These

earlier.

the

the

and social

Convention”

vns

status

that

point

vii)

if

on a number in

the

of

case

the

a substance

a state

of

nnd sncial

list

of R

was

fulfills

dependence

problem

of

and

warranting,

the

1

of

etizolam,

on Drug

Haloxarolam Ketaxolam Loprazolam Lorazepam Lormetarepam Medaaepam Nimetazepam Nitrazepam Nordazepam Oxaxepam Oxazolam Pinasepam Prarepam Temezepam Tetrnzepam Triazolam Hedazolam Dependence

4 benzodiazepines, midazolam

under

and

(WHO Technical which

quazepam.

were The

not data

Report

No.

reviewed was

reviewed

headings: identification to

dependence

potential

liability

therapeutic

the

health

was available

that

health

“1971

found

and

produce

(18) 19) ( 20) 21) 22) 23) 24) 25) 26) 27) (ZA) ( 29) (30) (31) (32) (33) (34)

Committee

brotizolam,

similarity

abuse

(i)

34 Cenrodiazepines Controlled 1971 Convention

Expert

reviewed

were

folloving

substance

26th

public

control.

Alprazolam Bromazepam Cmaxepam Chlordirrepoxtde Clohazam Clonazepam Clorarepste Clotinzepam Cloxazolam Delorazepam Diazepam Estarolrm Ethyl loflazepate Pludiazepam Flunitrazepam Flurazepam Hnlazepam

(1)

Nroup

decided

to

international

of

of

under

Data

the

point

Table List

problems.

scheduling

points.

was adjuged so

for

listed

it

ltkelihood

social

and seriousness

7 points

(i),

was not

potential.

problems.

therapy.

the

The group

and

abuse

potential.

and ahuse

ahuse.

in

no dnta

dependence

health

health

33 substances

the

substances,

public

of

of

available. point

on public likelihood

1nH f corn such

relevant

physical dependence

and

and usefulness

The decisions based

and

on hoth

on dependence

epidemiological

problems Vii)

data

already

known

(likelihood usefulness

substances

of

abuse)

and effects

on the

central

nervous

system

regulation of benmdiazpinea

IntemaUonal

The group control

recommended

was,

dependence as

“On the potential

moderate

social

and

problems

benzodiazepine that

midasolam observed

is the

placing

the

Committee

of

In case

cut

the

The 27th

currently

the

under

under

recommend

high.

such

from

liability

of

dependence

in

midasolam

health

As with the

a

profile,

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inferred

a public

of

the

and

all

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human subjects

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to

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concerning the

27th

met

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problem

light

“1971

with

the Expert

as

to

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of

the

assessment, Convention”.

liability high.

the

In view with

midarolam

warranting

this

of

the abuse

associated

problems

by

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an injectable

that

as moderate

quasepam

reviewed

social

IV of

rated

in

considered

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problems

decision

substance

and

usefulness

and social

a firm

3 drugs

drug

Committee

and with

the

health

therapeutic

and social to

of

therefore

control.

the

the

and

few

availability

The Committee

international

placing

health

Committee No.

on Drug 808,

Dependence

1991).

They

Benzodiazepines.

34 substances,

flunitrasepam

placed

of

abuse

midasolam.

of

for

pharmacological

the

to

use

be

the

use

the

of

lack

of

substances,

scheduling

of

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clear

the

these

drugs.

on Drug

1990.

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constitute

come

September

controlled of

the can

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to

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that

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were

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Expert

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recommendations

rated

as moderate

a state

of

the

public

was unable

in

Their concerning

Committee

with

date,

3 substances,

and etisolsm

(WHO Technical

not

substance

produce

and of

to

noted

as

3 substances

recommended

status

so

other

Dependence

and

abused

the

Committee It

Committee

the

abuse

the

producing

likelihood

of

brotirolam

abuse,

data

usefulness

of

recommended

to

midasolam.

associated

for

capability

for

available

diazepam.

the

be

the

studied

capable

the

to

moderate

therapeutic currently

is

enhances

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with

In addition,

only

of

and actual

agonists

that

form

control

basis

15

under

critical

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The Committee recommended

surveillance reviewed

scheduling

in

data

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reviewed

anyhow

order

related

to to

Geneva,

September

information did that

determine

brotizolam,

not

24 to

28 1990

to

34

related

recommend

WHO continue whether

to or

etizolam

any

the

changes

keep

not

they

in

the

diasepam merit

and quazepam

being

but

did

substances.

Conclusion It

is

included

concluded in

flunitrarepam merit

being

that

Schedule

are placed

of

the

IV of

to

be kept

under

currently

the

“1971

under

critical

commercially Convention”.

surveillance review

to

available Two others,

by WHO to consider

benzodiasepines, i.e.,

determine

appropriate

34 are

diszepam whether

and or

not

scheduling.

Acknowledgement The author

is

grateful

to

MS Nancy

Lacsamans

for

helping

in

typing

this

material.

they

16

1. Khan

References REXED, B; EDHONSON, K.; KHAN, I and SAMSON, R.J. (1984) Guidelines for the Control of Narcotic and Psychotropic Substances, ISBN924 1541725, WHO, Geneva. WHO (1981) Review of Psychoactive Substances Document MNH81.37, WHO, Geneva. WHO (1982) Review of Psychoactive Substances Document MNH82.44, WHO, Geneva. WHO (19831 Review of Psychoactive Substances Document MNH83.20, WHO, Geneva. WHO (1986) Guidelines for the WHO Review of Dependence Producing Psychotropic Substances for the International Control. Docu. MNH/PAD, 86.5, WHO, Geneva. WHO (1990) Revised Guidelines for WHO Review of Dependence Producing Psychoactive Substances for International Control in Executive Board Docu EB85/1990/Rec 1, WHO, Geneva. WHO

(1978) Expert Committee on Drug Dependence 21 report Techni. Rep. Series No. 618, WHO, Geneva.

WHO (1981) Expert Committee on Drug Assessment of public health and social problems associated with the use of psychotropic drugs, Techni. Rep. Series No. 656, WHO, Geneva. WHO (19701 Expert Committee on Drug Deper.dence, Techni. Rep. Series No. 437, pp 16 to 18. WHO, WHO

Geneva.

(1989)

Expert

Committee

on

Drug Dependence, Techni. Rep. Series No. 787, pp 8 to 14,

WHO, Geneva. WHO (1991) Expert Committee on Drug Dependence Techni. Rep. Series No. 808, pp 2 to 8, WHO, Geneva.

Inquiries and reprint requests should be addressed to: Dr I. Khan 10 chemin des Bugnons 1217 Meyrin, Geneva, Switzerland