Studies

BY

of EN-1639A

RICHARD

B.

(Naltrexone):

RESNICK,

M.D.,

JAN

A New

VOLAVKA,

M.D.,

ALFRED

Narcotic
M.

FREEDMAN,

DURING
INDUCTION
to maintenance
levels of cyclazocine,
which is the narcotic
antagonist
most widely
used for the
treatment
of heroin
addiction,
patients
may experience
dysphoric
effects.
Although
tolerance
to this agonistic
activity
develops,
the presence
of these
effects
has been a
limiting
factor
in cyclazocines
acceptance
as a treatment
modality.
The
narcotic
antagonist
naloxone,
although
virtually
devoid
of agonistic
activity,
has a duration
of
action
too short
for general
clinical
usefulness.
On the assumption
that the longer
duration
of activity
of cyclazocine
might
be related
to the n-methylcyclopropyl side chain
on the benzomorphan
molecule,
a similar
n-methylcyclopropyl
substitution
of naloxone
was synthesized
by Endo
Laboratories.
This compound,
naltrexone, was found
in preliminary
studies
to be free of major
agonistic
activity,
with a dose of 50 mg. per day producing a degree
of blockade
to the effects
of morphine
comparable
to 4 mg. per day of cyclazocine
(1).
This
report
summarizes
the results
of a study
undertaken
to assess the clinical
effects
of naltrexone,
the duration of its narcotic
blocking
activity,
its acceptability
to
patients,
and its usefulness
as a treatment
for heroin
addiction.
The
subjects
were
37 patients
from
a special
study
ward
of Kirby
Hospital
in New
York
City
who
were detoxified
from
opiates
and induced
to naltrexone
between
January
and April
1973.

Assistant
is Professor
This

Professor,
and

Dr. Volavka

Chairman,

and

N.Y.

is Associate
Ms.

Thomas

10029.

New York
where

Professor,

Medical

Dr. Resnick

is

Dr. Freedman

is an Instructor.

work

was supported
in part by contract
HSM
42-72-207
with the
National Institute
of Mental
Health
and the Health
Services
and Mental Health
Administration
and by a contract
with the New York State
Drug Addiction
Control
Commission.
The authors
acknowledge
the collaboration
of Thelma
Jones,
and Rhea
Dornbush,
Ph.D.,
and the assistance
and cooperation
rael
Kesselbrenner,
M.D..
Director
of Kirby
Hospital.
and
Crown,
Ph.D.

646

AmJ

Psychiatry

131.6.June

1974

AND

MURIEL

THOMAS,

R.N.

The patients
were volunteers
and were addicted
to either heroin
or methadone
at the time of admission
to the
program.
Some
patients
volunteered
for treatment
following
a period
in a methadone
maintenance
program.
One patient
had previously
been maintained
on 10 mg.
per day of cyclazocine.
The
patients
ranged
in age
from
2 1 to 40 years
(mean
28.3 years).
They
were predominantly
black
or
Puerto
Rican,
of low income
and low education
levels,
and had a high incidence
of unemployment
and use of
public
assistance.
Their
opiate
addiction
had lasted
from
2 to 20 years.
Before
starting
on naltrexone,
the 37 patients
were detoxified
from
opiates
with
decreasing
doses
of methadone.
They
were then
kept drug
free for at least
one
week
before
the administration
of naltrexone.
During
this time each patient
received
a complete
physical
examination
and the following
laboratory
tests:
chest
x-ray,
SMA-6,
SMA-12,
complete
blood
count,
reticulocyte
count,
platelet
count,
erythrocyte
sedimentation
rate, and
urinalysis.
These
examinations
were
repeated
before
each patients
discharge
from the hospital
and at monthly
intervals
thereafter.
Patients
were
followed
in the outpatient
clinic,
where
they were maintained
on naltrexone
at daily doses of 120 mg. to 200 mg.
All patients
received
placebo
naltrexone
before
starting on active
medication.
A symptom
checklist
was completed
at least every other day beginning
with the first day
on placebo.
During
the latter
half of this study
we incorporated
the procedure
of administering
intravenous
naloxone
(0.4 mg.) at least one day before
the patient
began
active
naltrexone.
This was done to test for precipitated
abstinence
symptoms
that might
be mistaken
for naltrexone side effects.
The patients
blood
pressure,
temperature,
and pulse
were measured
before
they received
medication
and every
hour
for six hours
after
medication
while
they were receiving
placebo
naltrexone,
on their
first day of active
naltrexone,
and on days when their naltrexone
dose was
increased
(except
for the initial
six patients,
for whom
these measurements
were taken
every day).
The naltrexone
was administered
as a single
oral daily
dose. Initial
subjects
were given a starting
dose of 20 mg.
per day. Subsequent
patients
were started
on 30, 40, or 50
mg. per day. The daily dose increments
were 10 or 20 mg.
per day.
Patients
were stabilized
for three
to five days at vary=

of Psychiatry,

M.D.,

METHOD

The narcotic
antagonist
EN-1639A
(naltrexone)
was
studied
in 37 heroin
addicts
andfound
to be clinically
useful.
with a low incidence
ofside
effects,
lack of toxicily. high degree
ofacceptabiity
to the patient.
and capacily
to antagonize
the euphoric
effects
ofheroinfor
up
to 72 hours after a single oral dose. Thesefindings
provide a basis for expanding
studies
ofthe
clinical
efficacy
of naltrexone
in the treatment
ofopiate
dependence.

The authors
are with the Department
College,
5 East 102nd St., New York,

Antagonist

M.D.,
of IsPeter

RESNICK,

ing dosages
during
this induction
period
before
being
tested
for narcotic
blockade
by the intravenous
administration
of heroin.
Twenty-seven
patients
received
heroin
challenges;
these
were done before
induction
to naltrexone and at 6 hours,
24 hours,
48 hours,
and 72 hours after
the patient
received
various
doses
of naltrexone
(not all
27 patients
received
all the challenges).
The patients
received
placebo
on the days
before
the 48-hour
and 72hour challenges.
Following
the challenges
they were given
the next scheduled
dose of naltrexone.
Just before
the patients
received
the heroin,
their
pupils were photographed
after three minutes
accommodation to the dark.
We used a specially
designed
Polaroid
camera
with electronic
flash. An aqueous
solution
of 10
mg./cc.
of heroin
was then
freshly
prepared.
The test
dose of 2.5 cc. (25 mg.) of heroin
was administered
intravenously
over a period
of 1 5 to 20 seconds.
Another
photograph
of the pupils
was taken
in five minutes-again,
after accommodation
to the dark.
We then determined
the subjective
effects
of the injection
through
the use of a heroin
effects
questionnaire.
Depending
on the results
of the initial
post-naltrexone
challenge
the patient
was either
maintained
on the same
dose of naltrexone
and challenged
again after a longer
interval
or inducted
to a larger
dose
before
being
challenged
again.
Some
patients
also received
placebo
challenges
by intravenous
administration
of saline.
Ten of the patients
were abruptly
withdrawn
from 200
mg. per day of naltrexone,
after receiving
the medication
for three
to eight
weeks,
by substitution
of naltrexone
placebo
for five days.
Following
this withdrawal
period
they were reinducted
on active
medication
with a starting
dose of 50 mg.

RES

ULTS

Untoward
Effects
During
Initial
Two Days on Naltrexone
Approximately
30 percent
of the patients
(13 out of 37)
experienced
some
untoward
effects
during
the two days
following
the first dose of naltrexone.
Only those
effects
that failed
to occur
while
patients
had been on placebo
were taken
into account.
Six patients
felt tired or sluggish, seven
felt nervous
or irritable,
and nine had difficulty
falling
asleep
at night.
These
effects
were rated
as
mild or moderate
in intensity
and in most instances
subsided
within
a few days, even with further
increments
in
dose.
Gastrointestinal
symptoms
were reported
by five
patients:

Two

complained

of

abdominal

pains,

two

had

nausea,
and one vomited
after meals.
The other
24 patients
reported
no effects
after starting
active
naltrexone.
No patient
reported
the persistence
of
effects
following
stabilization
on a fixed daily dose.
Our clinical
impression
is that these
untoward
effects
may, in part,
have been the result
of precipitated
abstinence
from the opiate.
This is supported
by the following
observations:
1. After
the initial
dose of naltrexone
the frequency
of
gastrointestinal
upset decreased
with increasing
doses.

VOLAVKA,

FREEDMAN,

AND

THOMAS

2. The untoward
effects
noted
were similar
to those
occur
during
protracted
drug abstinence.
3. The
incidence
of untoward
effects
was lower
in
patients
who entered
the study
after
we introduced
testing with naloxone,
even though
these
patients
received
larger
initial
doses,
and fewer untoward
effects
were evidencei
at a starting
dose of 50 mg. (4 out of I 7, or 24
percent)
than at 25 mg. (9 out of2O, or45
percent).
4. Of seven patients
who received
their starting
dose of
naltrexone
four
weeks
or more
after
their
last opiate
dose, none experienced
any untoward
effects.
5. Of four patients
who initially
experienced
some
untoward
effects
at a 20-mg.
starting
dose,
none
experienced any untoward
effects
when reinducted
on 50 mg. of
naltrexone
after
five days
on placebo
to test for naltrexone
withdrawal
reactions.
One
patient
reported
that
he was tripping,
like on
LSD,
following
an initial
dose of4O
mg. This effect totally subsided
within
60 seconds
after
he was given
0.4
mg. intravenous
naloxone.
This patient
had taken
LSD
five
times
in the past two years
(the last time being
six
months
earlier);
this
LSD-like
effect
began
after
he
smoked
marijuana
before
receiving
naltrexone
and became
intensified
about
one-half
hour after the naltrexone
was administered.

that

Untoward

Effects

During

Period

ofDaily

Increments

Twenty-two
of34 patients
experienced
no untoward
effects while the dose was being increased
to a daily dose of
120 to 200 mg.
We found
no consistent
difference
between
the incidence
or intensity
of untoward
effects
appearing
with
lO-mg.-per-day
increments
as compared
to 20-mg.-perday increments.
There
appeared
to be wide individual
variation
in dose response.
Effects
reported
during
the
increment
periods
were transient
and were the same
as
those which occurred
following
the initial dose-i.e.,
feelings of being
tired or sluggish,
feeling
irritable,
and having difficulty
sleeping.
These
effects
subsided
spontaneously
or were relieved
by the addition
of 10-20
mg. per
day of diazepam.
One patient
who had no complaints
when receiving
increments
of 10 mg. per day as he was inducted
to 120
mg. per day developed
symptoms
of feeling
not
right,
like
I wasnt
here,
floating,
inability
to concentrate,
and slight
dizziness
when the increments
were increased
to 20 mg. during
his succeeding
induction
to 200 mg. per
day.
Five patients
complained
of abdominal
cramps,
sometimes
accompanied
by mild nausea,
but had no vomiting
or changes
in bowel
habits.
These
complaints
were variable and appeared
to be unrelated
to dosage.
One patient
with a history
of duodenal
ulcer experienced the severe
epigastric
pain typical
of his previous
ulcer attacks;
this was relieved
by antacids.
He had a negative upper-gastrointestinal
and gall bladder
x-ray series.
Headache
was a fairly common
transient
symptom.
Toxicity
Blood

pressure

appeared

AmJ

unchanged

Psychiatry

l3l.6.June

at all doses,

with

1974

647

NEW

NARCOTIC

ANTAGONIST

TABLE

Blockade

of Subjective

Efficts

of 25 ng.

Heroin

at Varying

Times

and with

Varying

Time
Dose

6 Hours

24 Hours

20 mg.

2 blocked
2 not blocked

2 not
3
4
3
I
4

40mg.
50 mg.
60 mg.
80 mg.
120 mg.
160 mg.
200

*This
**One

blocked
not blocked
blocked
blocked
blocked

I blocked

mg.

of Challenge

Withdrawal

Effects

No withdrawal
effects
were noted
before
the 48-hour
and 72-hour
challenges
at naltrexone
doses
ranging
from
60 mg. to 200 mg.
Of the 10 patients
abruptly
withdrawn
from
200 mg.
per day of naltrexone
by substitution
of placebo
for five
days,
8 experienced
no effects
during
the withdrawal
penod. One patient
accurately
differentiated
placebo
from
active
medication.
During
the placebo
days
he complained
he felt bad,
tired, sluggish,
and had headaches.
One patient
had abdominal
pains and chills for one day,
beginning
one-half
hour after his first dose of placebo.
Blockade

to Heroin

When
heroin
challenges
were done
prior
to patients
receiving
the antagonist
(N = 12), all patients
reported
feeling
high.
The amount
of money
they stated
they
would
be willing
to pay for the heroin
shot
ranged
from 5 to 20 dollars,
with a mean
of 12 dollars.
After
11
placebo
challenges
by intravenous
administration
of saline, no patient
reported
he felt high,
and all patients
placed
a zero dollar
value on the shot.
Table
1, which
excludes
one patient
reported
separately,
summarizes
the results
of 72 heroin
challenges
done at varying
time periods
after specified
doses of nal-

AmJ

Psychiatry

131:6,June

1974

72 Hours

48 Hours

I
I
2
6
5

not blocked
blocked
not blocked
blocked
blocked

5
I
2
4
5

3 blocked
2 not blocked

includes
the results of 72 challenges performed on 26 subjects
and excludes
results for one subject,
subject was originally
not blocked
at this dose and time; on rechallenging
he was blocked.

the suggestion
ofa trend toward
narrowed
pulse pressure.
Heart
rates
fluctuated
without
apparent
relation
to dosage. There
appeared
to be no fluctuations
in body
temperature
related
to dosage.
Two patients
with mild hypertension
showed
no significant blood
pressure
changes
related
to naltrexone.
Control of their
hypertension
was maintained
with diuretics
(Hydrodiuril,
Aldactone)
and, for one ofthem,
reserpine
in addition.
No adverse
drug interactions
were noted
with
naltrexone.
Changes
in laboratory
tests were not statistically
significant
or indicative
of toxicity.

648

of Na/i rexone*

blocked

9 blocked
3 blocked

I blocked

Doses

whose

results

are given

not blocked
blocked
not blocked
blocked
not blocked

in table

2.

trexone
in 26 subjects,
using the patients
subjective
reports
as the criterion
for blockade.
Patients
who did not
report
experiencing
a high
from
the heroin
and who
valued
the shot
at zero dollars
were rated
as blocked.
Patients
who reported
feeling
high,
appeared
sleepy
or
high,
or placed
a dollar
value on the shot
were rated
as not blocked.
All patients
in this group
reported
experiencing
complete blockade
24 hours
after
a 50 mg. or larger
dose of
naltrexone.
All but two patients
reported
blockade
48
hours
after
a 120 mg. or larger
dose.
One of these
two
patients
was subsequently
rechallenged
48 hours
after receiving
200 mg. of naltrexone
and evidenced
blockade.
In
four out of nine trials blockade
was reported
72 hours
after a dose of 200 mg.
One patient
required
200 mg. per day of naltrexone
to
achieve
blockade
at 24 hours.
Six additional
challenges
done
on this patient
at various
time
periods
and with
varying
doses
of naltrexone
indicated
that he was receiving no or only
partial
protection
from
heroin
effects
(table
2). The subjective
effects
he reported,
however,
decreased
with increased
doses of naltrexone.
This last finding is consistent
with results
obtained
from other subjects
who received
multiple
challenges.
We found pupillary
constriction
to be a highly
sensitive
index
of heroin
effect.
No patient
reported
effects
from
heroin
without
having
associated
pupillary
constriction.
Some
had slight
pupillary
constriction
with
absent
or
minimal
subjective
effects.
The average
pupillary
constriction
in the challenges
reported
by patients
as blocked
was 0.87 mm. In the nonblocked
challenges,
the average
constriction
was 2.22 mm. The average
pupillary
constriction
after 25 mg. of heroin
in patients
unprotected
by
naltrexone
was 4.10 mm. There
was a positive
relationship between
degree
of pupillary
miosis
and subjective
effects as measured
by the amount
of money
the subject
stated
he would
be willing
to pay for the shot
(see figure 1).

RESNICK,

TABLE

VOLAVKA,

FREEDMAN,

AND

THOMAS

Subjective

Effects

of 25 mg.

Heroin

on One Subject

at

Varying

Times

and with

Varting

Doses

of Naltrexone*

Dose
Effects

20mg.

6-hour
challenge
Blockage
Value
of shot
Heroin
effect score
24-hour
challenge
Blockage
Value
of shot
Heroin
effect score
48-hour
challenge
Blockage
Value of shot
Heroin
effect score
*fore

receiving

naltrexone

Not

40 mg.

160 mg.

120 mg.

80mg.

200 mg.

blocked
$10
9
Partial
$5
3
Partial

was willing

to pay $15 to $20 for a heroin

Blocked
$0
0

Partial

$5
4
the subject

Partial
$2
Not available

Partial
$3
2

Not

shot and

scored

14 (out

$5
available
of a maximum

score

of 15) on the heroin

effects

question-

naire.

FIGURE

Means

and Total
Ranges
for Decrease
in Pupillarv
Diameter
After
Intravenous
Heroin
Versus
Amount
of Monet
Subject
Would
Be
Willing To Par for a Single Shot

4.0

E
E
z

3.0

0
0

0)

0
0
>-

-J

1.0
a-

C
$0-2

$2-4
PRICE

#{182}4-6
WILLING

TO

$6-8

$8-b

PAY

DISCUSSION

Narcotic
antagonists
have been shown
to be effective
therapeutic
agents
in the treatment
of opiate
dependence (2-3).
Their
use is based
upon a conditioning
theory of narcotic
addiction
(4). For the period
in which the
narcotic
antagonist
is taken
the detoxified
addict
is protected
against
readdiction
and can be engaged
in a rehabilitation
program
during
which
his conditioned
drugseeking
behavior
may be altered.
Following
this period
of

treatment
the narcotic
antagonist
can be discontinued
without
the patients
experiencing
withdrawal
effects.
The relative
absence
of dysphoric
effects
of naltrexone
and its ability
to provide
effective
narcotic
antagonism
for 24 hours
following
a single
initial
dose (50 mg.) for
most
patients,
without
the need
for a slow
induction
schedule,
as is the case with cyclazocine,
makes
it a potentially
more useful therapeutic
agent.
Furthermore,
the relative
ease with which patients
can
be inducted
to doses
providing
effective
narcotic
antagonism for 72 hours
is advantageous
when compared
with
cyclazocine
(5). The
untoward
effects
reported
in this
study
may
in part
be due to precipitated
abstinence
symptoms,
to which they are similar
(6).
In this report
no attempt
has been made to analyze
the
degree
of blockade
experienced
by patients
who were not
completely
blocked.
Even a mild or transient
heroin
effect was rated as not blocked.
It is likely that under
clinical conditions
there
would
be a greater
incidence
of narcotic
blockade
(after
an equal
time
period
and equal
naltrexone
dose) because
the amount
of pure heroin
used
by addicts
in the streets
is most
frequently
less than
25
mg. per injection.
We are currently
studying
the effects
of parenterally
administered
naltrexone,
including
the relationship
between plasma
levels ofthe
medication
and its narcotic
antagonist
effect.
These
studies
may help elucidate
the extent to which
individual
variations
in narcotic
blocking
activity
are due to gastrointestinal
absorption
or metabolic factors
and also may provide
a basis for judging
the
feasibility
of incorporating
naltrexone
into a slow-release
implant.
To be clinically
useful
in treating
opiate
dependence
a
narcotic
antagonist
should
be orally
effective,
nonaddicting,
and should
provide
blockade
to heroin
for
more
than 24 hours
following
a single
dose.
Naltrexone
appears
to fulfill these criteria.

AmfPsychiatrv

131:6,June

1974

649

NEW

NARCOTIC

ANTAGONIST

3. Resnick
R, Fink M, Freedman
dependence
a progress
report.

REFERENCES

4.

I. Martin
for

the

WR,

iasinski

treatment

of

28:784-791,
1973
2. Resnick
R, Fink
opiate dependence.

650

AmJ

DR.

Mansky

heroin

PA: Naltrexone,

dependence.

Arch

M, Freedman
AM: A cyclazocine
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131:6,June

1974

an antagonist
Gen

5.

Psychiatry

typology
1970

in

6.

AM:

Cyclazocine

therapy

of opiate

Compr
Psychiatry
12:49 1-502,
1971
drug dependence.
Arch Gen Psychiatry

Wikler
A: Dynamics
of
28:611-616,
1973
Resnick
R, Fink M, Freedman
AM: High-dose
cyclazocine
of opiate
dependence.
Am J Psychiatry
13 1:595-597,
1974
Martin
WR, Jasinski
DR, Haertzen
CA, et al: Methadone-a
evaluation.
Arch Gen Psychiatry
28:286-295,
1973

therapy
re-