The Clinical Pharmacology of MeperidineComparison of Routes of Administration JOHN

M

E. STAMBAUGH

narcotic absorbed

tration.

Ph.D..

by

The

commonly

all

routes

of

intramuscular

employed

ported

until

adminis-

ment

of

for

meperi-

of pharmacokinetic humans using

sidered

and oral adminishas been reported to be less efficaat comparable doses.1 Pain relief meperidine appears to be variable

tration cious with

and chronic administration

dosing is con-

hazardous

due to marked individual differences after both acute and chronic dosing.2 Although meperidine has been in clinical use since 1939, by

a comparison different

the

correlation

meperidine effects

with

serum the

drug

and the identified

by

metabolites in 1956

These

initial

doses

of

tions

of

not

Burns of by

of or

been of

studies assay

and

therapeutic

have

meperidine the

attained

concentration

pharmacokinetics described

levels

of administration

of

of the

The were

of drug

routes

toxic

reported.

al.3

in

meperidine Plotnikoff

were

limited

owing

to

procedures.

et

the

Department

of

of Clinical Pharmacology, Thomas versity, Philadelphia, Penn. 19107.

1976

a study

further

to

Section

Uni-

of side

such

Materials Six were They

was correlate effects

meperidine a comparison,

certain

aspects

healthy chosen ranged

sug-

the study pharmacoindividual

to

might

intraaddition, recorded the onset serum

con-

or metabolites. it was hoped

regarding

meperidine

and

and sub-

in normal of

in each

of

of

of ad-

same

after intravenous, oral dosing. In

symptomatology to perhaps

duration

usage fined.

ex-

study

undertaken

objective meperidine

metabolism

centrations

From

phar-

have

routes

pilot

in

dosed with meperidine of administration gave levels between 1 and 2

was

subjective in order

No

initial

The compare

were al.4

Mn. SANSTEAD was supported in part by the Thomas Jefferson University’s Summer Oncology Training Program, N.I.H. Clinical Cancer Training Grant #CA 08111-09. Ms. HEMPHILL was supported in part by Oncology and Hematology Associates, Haddonfield, New Jersey 08033. May-June,

an

1955,

and

of various

patients routes serum

and

limita-

Jefferson

Since

a group and

to high

clinical we

pharmacokineties of meperidine in the

volunteers.

was

of the

on the

gested that by various comparable hours,

for studies

and metabolic data clinical doses.5’6

effect

metabolism

jects.

assays

meperidine,

and as muscular,

the

Pharmacology,

the

re-

develop-

comparison

a study

of

been the

sensitive

usual

of

ministration

that From

part

macology amined

Penn.

have

permitted

kinetics

meperidine

et

As

and

Philadelphia.

when

more

meperidine

for both intravenous

K. SANSTEAD.

studies recently

is most

dine since

more

W. WAINER.. Ph.D.. JOHN DOROTHEA M. HEMPHILL

pharmacokinetic

route

clinically

acute

IRVING

effective substan-

is a widely used, analgesic that is

EPERIDINE

tially

M.D.

the be

clinical

better

de-

Methods medical student volunteers for the comparison study. in age from 21 to 30 years 245

STAMBA

and their height 10 per cent of

in

1.96

Metropolitan Tables.7 The

Life

m2,

examination. corded, and

history inquiry

to any previous meperidine sensitivities, allergic disorders, especially

disease.

Laboratory

complete count,

chemistry urinalysis,

cardiogram. physical cluded jects

screen, and a

Any

had

hepatic

or

complete 12-lead

abnormality

been

taking

any

subjects groups

were randomized using a Latin-square

The

study

was

then

venous just

and prior

received

parenterally

mg/m2

for study. and the

the

subjects

were

urine collections comparison of

meperidine more than

content 0.5 per

prepara-

triplicate

and did cent from

not the

All

from

the

samples

no subjects study. After 246

received had

to

intravenous

all three be

excluded dosing,

study, were

method

with with

ether,

at

the Two

g/m1

serum

before

by for

performed blinded and the

urine samples

for

The

by

following milliliters of the

Journal

for

water. basic with 6

seconds

in

centrifuge tube. by centrifuga-

5 minutes. of

30

in were

standard in

for

screw-top were separated

and

alterations serum

was made extracted

vortexed

the

Mather

internal

solution 1111 NaOH,

4000Xg

serum

followed

benzphetamine

and

a Teflon-lined, The phases tion

all

described

10 d

resulting 200 l

the

was personnel

procedure

recently

The with

venous

for

24-hour

determined clearances

concentration

vary by expected

from

frozen

assay

and

analytical

25

and

cx-

collected at and 24-48

and

assayed

meperidine

and

doses

ad-

identified.

The

ml

subjects

for of

Adequate

were creatinine

subject. The the laboratory

for

concentration.

was 8-24,

date.

each with

mixed

various in

modes urinary

coded,

at a later

The

N.,J.

intra-

frozen

three

cumulative

removed,

Cherry

assayed

the

analyses

were

after

blood samples the serum was

stored

all

ade-

The volumes and pH of the urine were recorded, and 20-mi aliquots

Tucker8 extraction.

Hill,

and

hours. samples

50 mg manuNew intra-

are

time-concentra-

All the clot, and

For

were

previously

samples

serum

three beas

samples

had

meperidine

coded,

were ESI meperidine by Elkins-Sinn, Inc.,

were

of

ministration,

samples

periods

we

these the

muscular dosing.5 were allowed to

venous preparations HC1 manufactured tions

sampling

that

analysis.

21/2,

dosing.

venous

because

removed,

45,

as 2,

after venous

and

latter

established

30,

1, 11/2, 2, 2#{189},3, 48 hours. After

1/2,

ei’etion of each subject 0-1, 1-2, 2-4, 4-6, 6-8,

meperidine

received

The

was the

1, 2, 4, 6, 8, 12, 24, and

1/2,

frequent

later

hours

three

to an approxi-

meperidine as Demerol HC1 tablets factured by Winthrop Laboratories, York, N.Y. Intramuscular and

at

hours.

ill-

physio-

25,

as well

48

dosing,

taken

less

by

20,

administration,

curve

mate average clinical dose of 50 mg meperidine in a 1.92 m2 subject. For oral testing,

31/2,

48

exsub-

urine samples were colto dosing. Each subject 26

oral

15,

minutes and

collected at 1/4, 4, 6, 8, 12, 24,

tion

on

corresponding

90

either

separate days, with at least two weeks tween each experimental day to serve a washout period. On each experimental day, lected

and

6, 8, 24,

were

all

patent

1, 3, 5, 10,

to define

into design.

conducted

at

75,

through

kept

Each 10-15 ml sample repeated flushing of

quate

medication the

catheter 60,

collected

saline. after

were a

da’a No

four weeks prior to consent was obtained,

catheter

blood electroof

or laboratory from the study.

were

intramuscular

renal

included

samples

After

drug under-

HEMPHILL

dwelling

3, 4,

was rewas made

evaluation

findings a subject

at least Informed

m2 to 1.92±

usage, or

AND

logic taken

subjects

entering the study, each pass a complete physical

A health particular

illness,

SANSTEAD,

Insur-

six

body surface from 1.88 with an average size of

0.08 m2. Before subject had to

lying

WAINER,

and weight fell within the range of normal as

defined by the ance Statistical varied

UGH,

Clinical

The

ether

Pharmacology

MEPERIDINE

was

decanted

into

a second

ing 400 JL1 of 1)11 1101, were again vortexed and fore. carded, to

tube

contain-

and the separated

coded,

phases as be-

The organic phase was then disand the aqueous phase was heated

remove

phase

the

was

residual

made

ether.

basic

NaOH, vortexed

extracted with and centrifuged.

covery obtained

of

greater in this

A tograph

Perkin-Elmer equipped

sampler tector

and a was used

The

with 40

than manner.

245#{176}C, and

97

per

respectively,

cent

ionization the serum

temperature

flows of nitrogen,

35,

Q. Under

retention

time

of

to he 5.4 minutes, of benzphetamine fication

was

60,

and

these meperidine

by the

tion

was

in the

urine

have

adjuvant

which

the

ten

above

“How

been

described

study subjects

was

time.

were

criteria.

Subjects

selected

to

the severity.

feel?”

was

In

to

small

however, varied with with a range in size

respect to body size from 1.48 m2 to 2.03

m2,

1.80±0.16

and

at

to

severe,

and

yielded adequate

group

severe

was

testing after relaboratory

results

consistent

ranging

analysis

with

tested.

Results Intravenous mean

Administration

serum

of

administration

I.

Following

the

study,

pres-

24 hours. A scale of 1 to 5 rep. mild, mild to moderate, mod-

for

The

in

quesat each

4 hours,

stimulus

else-

onset,

blood

pain

of

an

were recorded 1 hour, at each

moderate

peak at-

of

asked

addition,

up

cent

studies,

The

for the study. Analgesic not be performed since preliminary trials no

tile

de-

per

time

and

interval

enough

to

subjective

used could peated

using

in this

of the

recorded

and respiration intervals to

30-minute

90

erate,

the found

designed

do you

sure, pulse, at 15-minute

compari-

sensitivity

all

as

of onset,

for

of

where.#{176} An

symptomatology

purpose

was

6, 8, and resenting

and

0.001 g/ml. The analytical for the determination and normeperidine concentra-

with observer

while the retention time was 7.1 minutes. Quanti-

accomplished

needed

Simultaneous

The

study

of of

through-

conditions, was

assay.

the

of variability of indiorder to determine the

a study limits.

sampling

600

hydrogen,

maintained

son of the meperidine/benzphetamine height ratio. The limit of tainable procedures meperidine

power of confidence

duration

deand

for of

the degree subjects in

was

out the study. Analyses were carried out on a 2-mm-i.d.X6-ft coiled glass column packed with 3% OV-17 on 100-200 mesh Gas-Chrom

termine vidual

independent

temperature temperature

stored

portion

and re-

gas chromaAS-41 auto-

detector

were

and

this

tion

dual-flame for both

gas for

of

2-TI

400

3920 with an

a

235#{176}Cwith mi/minute

aqueous

tl CHC13, An average

urine analyses. A column 175#{176}Cand injection port

air,

PHARMACOKINETICS

levels are

intravenous

maximum

are

data appear of a study

was

observed 1 minute The pharmaeokinetic the disposition of intravenous in Table

to correlate with recently reported

adminThese

the results by Mather (29

subject was dosed three times vith 50 mg meperidine by the intramuscular route, with no compensation of dosage for body

dosed corinitial

volume bution

distri-

size

the

in

method blood May-June,

order

to

of

correspond

of dosing in clinical samples were collected 1976

m2.

to

the

Each

usual

practice. The as described,

and serum

which

II.

subjects

a mean

in

Table

concentration

following presented

co-workers

route

in

patients and 4 volunteers) were with 50 mg meperidine 1101 without rection for mean body size.#{176}The

with

and

each

administration,

serum

0.523±0.115 g/ml after administration. constants describing meperidine istration

for

presented

33

of distribution, at steady state

(V,,,

and

slow

rapid

(T/2a)

mean

(Vt,)

total are

body shown

volume

of

), half-life (T/2) clearance for the

of phase,

six

from sub247

STAMBA

UGH,

WAINER,

SANSTEAD,

TABLB Mean

Concentration

Serum

(X)

Intramuscular,

and

AND

I

of Meperidine Following Oral Administration*

I.V. Time 1 3 5 10 15

jects. 0.33 and

The

r

I

S.D.

±

S.D.

11.4 10.1

3.7 2.9

9.9

3.1

8.4 7.1

4.4 2.1

hr

8.1 6.6

2.6 1.9

8.0 6.2

3.0 2.3

4.8 4.6

0.5 3.6

mill miii mill

mill mill nun

mm mm mill

hr hr

hr concentration

biologic

g/rnl

in

half-life

was

x 100;

3.93±

and serum clearances for slow phases appear to follow first-

order kinetics. The major

±

hr hr

mm

Serum

hours, rapid

S.D.

16.6 12.9 16.8 10.3

mill

75

*

±

P.O.

11.5 7.6 6.2 3.6 21.3 16.7 11.3 5.3 13.5 11.0 7.0 2.2 6.2 2.6

25 30 45 60

8

Intravenous,

I.M.

52.3 42.5 24.5 25.0 23.0 22.5 20.0 14.0 13.5 17.7

mm

20

90 2 2.5 3 4 6

HEMPHILL

recorded

shown

in

serum

concentration

Fig.

1

side

along

effects

with curve

venous administration. the study, every subject

the after

In this reported

are mean intra-

portion of lethargy

or sedation, euphoria or lightheadedness, and dry mouth. Other isolated reported

Constants

and

Oral

8.5

3.2

3.0

17.4

4.4

3.4

3.2

19.7

7.0

9.0

7.0

14.4

5.2

13.2 14.3 12.7

6.3 8.0 4.3

administered

Following

Administration

dose,

symptoms

26 mg/rn2.

included

nausea

vertigo (2 subjects), the nose (1 subject). The average serum

(2

and

subjects),

itching

clearance

about

of meperi-

dine for all subjects after intravenous administration was 0.70±0.11/mm (Table II), and significant amounts of meperidine were after renal The

TABLE Pharmacokinetic

16.4

detected

in

dosing clearance mean

the

urine

(Fig. 2), between

cumulative

within with hours

1 hour maximum 1 and

48-hour

excretion

II Intravenous,

Intramuscular,

of Meperidine* I.M.

I.V.

P.O.

T/2a

(mill)

4.20±1.34

-

-

T/2p

(hr)

3.93±0.33

3.25±0.71

3.49±0.37

V

(liters)

242

±57

Vd

(liters)

198

±94

‘‘.1 *

248

(serum)

Administered

(liters/mm)

dose,

0.71±0.11

26

357

356

±29 -

±42 -

1.18±0.26

1.27±0.39

mg/rn2.

The

Journal

of

Clinical

Pharmacology

2. of

MEPERIDINE

PHARMACOKINETICS

SUBJECTIVE

SYMPTOMATOLOGY

LETHARGY DRY MOUTH v EUPHORIA

&

LIGHTHEADEDNESS 114

0

1+3

C’) U.

0 I.. P2

w >

w C’)

lie

1/2 TIMF

Fig. 1. Serum tration of 26 2=mild

to

time-concentration mg/rn2 dose of

moderate,

curve meperidine

3=moderate,

CUMULATIVE

IN

of

HOURS

meperidine vs.

4=moderate

EXCRETION

OF

following

subjective to

the

symptornatology. severe,

MEPERIDINE

and

(50

intravenous Scale:

adminismild,

1 =

5=severe.

MG)

P0 IM IV

HOURS Fig.

2.

oral

administration

May-June,

Cumulative

1976

excretion of

26

of mg/rn2

meperidine doses

following of

the

intravenous,

intramuscular,

and

meperidine. 249

STAMBA

UGH,

CUMULATIVE

WAINER,

SANSTEAD,

EXCRETION

OF

AND

HEMPHILL

NORMEPERIDINE

P0

#{149} IV

#{149}1 1 4

Fig. and

3. Cumulative oral administration

meperidine

was

excretion

1.93±1.08,

cent of the administered levels of normeperidine the

urine

until

of

normeperidine

of 26 mg/rn2

or

3.9

2 hours

after

the

in

administra-

3. The rate of exreached a maxi-

nornieperidiiie

0.070

and

The

TABLE The

Elimination Following

and

I.V. I.M. P.O. *

250

Admmnistered

dosing

are

shown

Administration

time-concentration reached

g/ml)

pharex-

curve

its maximum

1 hour

after

(0.197±

intramuscular

III

Rate Constants Intramuscular,

tion rate

constant k, (hr-I)

constant K5 (hr-i) 0.198 0.192 0.169

dose,

serum

essen-

and

and

Renal

of Meperidine

Clearance

Oral

Administration*

Excre-

Elimination rate Route

Excretion Intravenous,

were

8 hours. The for meperidine

intravenous

Jut ranuscular

ministered

ineperidine

concentrations

cretion after in Table III.

nieperidinc

Both

intramuscular,

tially negligible after maeokinetic parameters

mum of 134± 55 jLg/hr at hour 4, with a mean 48-hour cumulative excretion of 2.10±1.83 mg, or 4.2 per cent of the addose.

intravenous,

of ineperidine.

per

dose. Significant did not appear

tion, as shown in Fig. cretion of normeperidine

following

doses

0.006 0.009 0.005 26

0-1

10.71 27.90 9.12

hr

Renal

clearance

hr

2-4

1-2 36.40 37.49 21.20

(ml/min) hr

28.76 31.08 33.32

4-6

hr

30.42 26.79 50.48

6-8

hr

9.12 18.03 36.41

mg/rn2. The

Journal

of Clinical

Pharmacology

of

MEPERIDINE

PHARMA

COKINETICS

SUBJECTIVE SYMPTOMATOLOGY LETHARGY DRY MOUTH iS EUPHORIA & LIGHTHEADEDNESS

0

I..

a

a, U.

0

0

3

1/4

TIME

Fig.

4.

Serum

ministration i=mild,

time-concentration of

was

no

the

curves

with

significant

serum

following

muscular comparison

an

aver-

difference

be-

time-concentration intravenous

and

intra-

observed

using

an

side

analysis

effects

were

of

vari-

less

in-

tense than those reported following intravenous administration (Fig. 4). It was observed that vertigo was only noted with the within

intravenous 5

minutes

cretion kinetics administration May-June,

1976

dosing after following are shown

and dosing.

occurred The

intramuscular in Table

meperidine

III.

following

vs. 4=moderate

the

intramuscular

renal

clearance

The mean meperidine per

between

cent

of

the

observed tive 1.07 tered

urine rate

at 4 hours.

excretion mg, or dose

served after tween

level

1 and

(Fig.

2.

excretion mg, or dose

of 4.5 (Fig.

of normeperidine

ap-

at hour 2, and a maxiof 106±34 pg/hr was The

48-hour

cumula-

was 2.75± the adminis-

3). Administration

oral

administration,

of 0.143±0.080

at 2 hours. It should 2 hours, no significant the

hours

of normeperidine 5.5 per cent of

Oral

Following

the urine maximum

administered levels

in the excretion

Scale:

in with

cumulative 48-hour was 2.36±1.20

Significant

peared mum

ad-

subjective symptomatology. to severe, and 5=severe.

Meperidine was detected within 1 hour after dosing,

serum ex-

a

1

HOURS

2).

dosing as determined by the of individual and mean seruni

concentrations ance program. The

hours,

clearance of 1.27±0.39 liters/ 30 minutes, there appeared to

statistically

tween

of meperidine

appears to follow firstThe biologic half-life,

3.25 ±0.71

age serum mm. After be

and

curve dose of 3=moderate,

26 mg/rn2 to moderate,

2=mild

administration order kinetics. T/2p,

a

S

4

IN

three

serum

a peak tg/ml

was

be noted difference

obthat be-

time-concentra251

STAMBA

UGH,

tion curves was detected vidual and mean serum were compared using an

WAINER,

when the indiconcentrations analysis of vari-

ance program. Side effects following administration were reported by subjects 45 minutes after dosing-two porting

dry

mouth

lightheadedness. was

of the

estimated

under

and

The

availability

by

the

one

relative

oral

dose

oral three re-

body

area

time-concentration

distribution.

Significant detected and curred 48-hour

amounts in the

the

urine

maximum

of meperidine 1 hour renal

between hours 4 and cumulative excretion

were

after

dosing,

clearance

lug,

or 3.3 per The excretion a maximum

hours

after

was

2.96±1.06

oc-

6. The mean was 1.67±

From free

the

ing,

of the administered

of iiormnepcridinc of 232±9 g/Iir by 8 The of or

mean 48-hour normepcridine

6.2

per

previous meperidine

urine,

despite the

their

appear degree

and normeperidine metabolic pathway products

meperidinic

acids

to the

to of

5).

in low

directly cormetabolism the amount Meperidine

mcperidinic remain

levels

(Fig.

levels

relatively

are central of meperidine

hydrolytic

excreted

of the

observations, the and normeperidinc

meperidine and not drug administered.3’4’6

tional

cent

dose.

concentration, relate to of of

cent

dosing. excretion

cumulative

of

curves following the oral and intravenous administration. Based on the comparison, 61 per cent of the oral dose is available for whole

i31

HEMPHILL

dose. reached

physiologic of meperidine the

AND

administered

reporting

comparing

serum

SANSTEAD,

and

directly

of the Therefore,

free

to and

the the nor-

proporprecursors a compari-

CH3

COOC2H5

Meperidine

Meperidinic

Normeperidine

Normeperidinic

Fig. 252

5.

Major

pathways

of

meperidine

acid

acid

biotransformation. The

Journal

of

Clinical

Pharmacology

MEPERIDINE

PHARMA

COKINE

TABLE Power

of the

IV

Study

Analysis Peak

of

the

all

three

both

dine

are

delayed

reflecting

the

dition,

the

after slightly

Excretion administration

thaii

with

tration,

12.5

13.5

9.7

12.2 14.0 10.7

13.6 149 16.7

13.2 14.6 14.9

S.D.

±

Serum

1.80

± 0.16

at

concentrations

11.8 13.2 13.4 12.6 11.5 12.7

± 1.9

the

administration

cumulative

excretion

normeperidine of administration maximum

rates

meperidine

and

after

delay

oral

in

of

following demonof

exci’e-

normepcri-

administration

absorption.

of

In

ad-

normcpcridine

other

two

of

routes

the

is dosfollowing

of

at least

decrease

the

delayed phase.

in

May-June,

and

the

are

1976

analysis peak

mean presented

minimum

serum the serum

to a power

Cohen.1#{176} The

calculated

the

of nieperidine,

of the

1 through to

body

as described

serum

concentra-

sizes of the ten in Table IV. The

effect

size

index

(d)

was

required

than

less

serum

for

the

ten

subjects

the

difference

it

in index

On

that

would

of

were size,

the

of

which subjects 90 per cent

than

12

the basis

for

minimum 1.36,

to

less

the

meperidine adjusted

of

these

data,

body size is the greatest subject variability. By to body size doses, it appears,

trapolation

of power

population

as

the mepcridine.

hour

population1#{176}

to achieve

level.

dosing according to standardized

define

cal-

at

which

increases to

in order

appears

The

1.46,

levels body

corresponds

confidence

sub-

12.

the

needed

of from

and

index

subject

When

size

effect

pooled size

to

pre-

data

analysis. effect

subgroup the

the The

independent

above

order

and

study,

6 were

minimum this

the

of subjects

considered.

to

were

number

was

a requirement

confidence.1#{176} In

was

effect

data

to achieve

of

power

culated

subjects

subjects

the

jected

the to

size

ab-

pharmaco-

all

serve

reduce

Stud,j

4 for

body

determinant

by

of a 50-mg

corresponds 44

level

cent

difference

hour

desired

4 for

greater of adminis-

that the the metabolic

at

also

tions subjects

(for

w-hich

subjects

administration with intravenous is significantly

found 0.68,

In order to determine the number of subiects required to provide a 90 per cent level of confidence that the experimental procedure would detect at least a 15 per

subjected

all doses)

13.4

following

1 hr

13.0 17.6 12.6 16.8 17.7 11.3

of meperidine.

Pou’er

kinetics

C

F F F

indicating increases

sorption

Dose

M

of normeperidine the

100)

B

1.65 1.48 1.67

excretion

ing.

x

Dose

1.77

intramuscular greater than

oral

A

7

the

of

I)ose

8 9 10

routes

tion

Sex

14.8 13.5 11.8 13.5 11.6 12.9

mean

that

(m2)

M M M M M M

and

strated

Size

1.92 1.88 1.96 1.90 1.80 2.03

dose

meperidine

concentration

1 2 3 4 5 6

Mean

son

serum

(zg/ml

Subject no.

*

TICS

small

pharmacokinetic

tables, as

six

as

that can

oppOSe(1 from exa subject

be

parameters

used

to of

253

STAMBA

UGH,

WAINER,

SANS

Discussion Meperidine intramuscular utes,

is rapidly injection,

serum

observed

with

(Fig. dine tion,

6). are and

are

comparable

intravenous

Significant

of

in

the

relief

of

acute

plained if the assumption is free drug levels of meperidine to analgesic

efficacy.

tramuscular route onset of analgesia

In of was

the

case

a

oral is ex-

ished

made that correlate

at 19.4

administration mg doses with

240

minutes.12

serum

miii-

of 50 a dura-

Correlation

tion,

the

onset is

dose

meperidine

serum

of

observable

delayed.

In

observed the

levels

are

CNS

previous

a 10-minute

intravenous and

MEPERIDINE

50MG

the

onset

side

delay

injection of

of

be50 mg

respiratory

C ONCENTRATIONS

P0

0 I-

I-

r

4

I

Fig.

6.

muscular, 254

Serum

and

time-concentration

orol

administration

curves

IN

HOUIS

of

of 26 mg/rn2

meperidine

following

doses

of meperidine. The

Journal

the

of

intravenous,

Clinical

in-

studies,

Iv

TINt

at

lower,

unsustained (120 concentrations of oral administration the reported dimin-

significant

Rodman

SERUM

of the

immediately following both and intramuscular administra-

effects

et al. reported

Thus,

efficacy.

achieved travenous

in-

concentration g/ml.

and relatively peak serum following the basis for

Although

administration, the observed at 15 min-

Bachrach

to

critical

tween

since

of analgesia the 100

0.099-0.101

utes after 100-mg doses of meperidine and lasted up to 240 minutes.11 The onset and duration of analgesia do not appear to be related

onset

up

delayed, minutes) meperidine may be

at

of the

of

least

levels

pain

following 75 rug, and

of

at

less-than-equivaobserved after

average

of these times and the observed serum concentration in the study suggest that the relief of pain is related to the attainment

meperi-

which approximate serum for parentcral administration

HEMPHILL

utes tion

to those

AND

the fig,

min-

administration amounts

time. The reported analgesic potency

dosing

after 30

absorbed after oral administrapeak serum levels are reached

2 hours observed that lent

levels

absorbed and by

rEAD,

intra-

Pharmacology

MEPERIDJNE

depression.’3

Following

muscular

observed ance of

a

Schiffrin

dose,

a 15-minute the same

study,

the

observed

began

15

minutes

100-mg and

intraous

co-workers

delay in the side effcct. CNS

PHARMACOKINETICS

only

appearIn this

dosing

1

By

suggesting serum drug

extrapolation

a direct level and of

the

interest, hours

however, before the

toxicity

and

In addition, prolonged CNS

toxicity

factors

other

parallels the This metabolite twice

as

and

appears free

that toxicity concentration g/ml. Of

and

of

2

to be related

but been

half

is partly more

to

ing

critical

serum

dosing

appears

dosing

in

levels.

comparable

the

management

tration doses chronic

using

ment of ministration nificantly dine

and

cumulative May-June,

higher

would appear or repeated

doses

toxicity. 1976

peridine

after

muscular,

and

potentially

greater

acute

and

curves of

meintraof

determined

and

lowing intravenous administration intramuscular administration; and hours,

all

curves

three

were

of

serum

26

com-

the

the

dine

and

as

of administration, lowing lay in

same.

rates with

other

trials levels

to

route

meperi-

routes

of administration

data pain,

side

of

ad-

delayed phase.

ab-

and

the

curves were examined.

time-eoncentra-

previous

of

fol-

oral adminadequate ab-

that metabolic

analgesic

was made, for induction

production

route

delay

reflecting a dethe excretion

two

serum

cussed. From the the case of acute

three

the

symptomatology

of the

curves

both

a marked

time-concentration and their relationship

Comparison

and

of

following despite

the

Subjecti-e

tion

all

reflect

oral administration absorption. Further,

serum compared

of the

demonstrated

normeperidinc

than

2

of mcperidine

following

of normeperidinc istration is greater

toxicity serum

Comparison

excretion

maximum

and after

time-concentration

administration

that

parenteral

both

administration

were

niiiiistration, indicating sorption increases the

than

of

pared. After 30 minutes, there was no statistically significant difference between the serum time-concentration curve fol-

be

to be of value with dosing for the manage-

analgesics

intravenous,

oral

doses

normeperidine

pain,

other

the

and

no better with sigadminis-

but

parameters

sorption

acute

data

time-concentration

routes

chronic pain. However, oral adleads to the excretion of siggreater amounts of normeperitherefore

serum

Intramuscular of

of such usage

of

to intravenous

with the latter possibly offering efficacy after 10 minutes and nificantlv greater toxicity. Oral

are

proper

pharmacokinetic

related closely

that oral for relievill attain-

trials

the

control

cumulative

mcperidine.14

comparison

the

it

pharniaco-

analgesic

define

mean

efficacious

From this study, it appears dosing would be a poor choice ing acute pain due to the delay

that

levels.

of normeperidine. reported to as

The and

reached,

pain.

mg/m2

toxicity

meperidinc

lethargy levels

formation has

toxic

the

clinical

in

data to previof meperidinc

conclusion

meperidine

well

Summary

to

effect of lethargy is extent than other

than

It appears that to meperidine

as

serum levels of either a delay in receptor activity.

the CNS to a greater

only

data

persistence

significant suggesting or delayed

not

chronic

is the delay of 1 to attainment of maximal

the

much beyond meperidine, CNS uptake

better

relationship CNS effects.

oral

onset of toxicity, it appears is observed when the serum is in the range of 0.0340-0.0900

and

would

our trials

siniultaneous

and

needed

of

the

that

kinetic

(Figs.

and 4) and lasted up to 8 hours. The CNS side effects parallel the serum time-concentration curves in their intensity and duration, between

supports

appears

symptomatology

after

Since comparison clinical analgesia

and of effects

and

minimum analgesia arc

dis-

it appears that the intramuscular

in

is as beneficial

as 255

STA

the

intravenous

less

efficacious

concentrations, less of the

route, due

rather

route

be

WAINER,

oral

lower

as

SANSTEAD,

dosing

peak

a predetermined

but

the

to normeperidinc

possibility

Pharmacol.

5th

6.

bionvailabihity Pharn,acol. Stambaugh,

as 7.

of cumula8.

should

nibaugli,

Mather,

Sci. 9.

Acknowledgments would

for

like

assistance

analysis

of

the

Brenner

for

technical

to in

thank the

experimental

Dr.

II.

statistical

data

and

Ira 10.

assistance.

References 1.

Lasagna, morphine

P1,arm.

11. L.: and

Rev.

The its 16:47

chemical substitutes (1964).

evaluation as analgesics.

of

12.

2.

Eddy, N. 0. J.: phine-like 17:717

3.

Burns, J. J., Berger, B. L., Lief, P. A., Wallack, A., Pnpper, E. M., and Brodie, B. B.: The physiological disposition and fate of ineperidine (Denierol) in man and a method for its estimation in plasma. J. Pharinacol. Ezp. Therap. 114:289 (1955). Plotnikoff, N. P., Way, E. L., and Elliot,

4.

H. W.: meperidine

256

B., Halbach, H., and Braenden, Synthetic substances with moreffect. Ball. World Health Org. (1957).

Biotransformation excreted in

products the

urine

of

Theraj.

117:414

of man.

E.,

a ml

Wainer,

I.

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nieperidme. 14:552 (1974). J. E., and Wainer,

W. : ‘rue Clin.

.1. I.

W.:

The

of meperidiiie using urine meperidine and normeperidine. J. Clin. Pharmacoi. 15:269 (1975). Metropolitan Life insurance Co., Statistical Bulletin 50, Table of Desirable Weights of Adults, Nov.-Dec. 1959. and the

Time authors

Exp.

bioavailahility assays for

may

of

.1.

5.

considered.

Menduke

HEMPHILL

(1956).

basis dose

due

pain,

toxicity

J.

regardshould

on a mg/rn2

AND

is

serum

used. Oral administration some benefit in the treatment

chronic

tive

that to

clinically

than

have

UGH,

and that all doses, of administration,

be administered currently

MBA

13.

14.

L.

E.,

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Tucker,

other basic drugs: determination in 63:306 (1974).

G. T.: general plasma.

Meperidine method for J. Pharm.

E., Tucker, 0. T., Pflerg, A. E., M. J., and Wilkerson, C.: kinetics in man: intravenous injection in surgical patients and volunteers. Can. Pharm. Therap. 17:21 (1975). Cohen, J.: Power Analysis for Behavioral Scieiices. New York, Academic Press, 1969, p. 34. Schiffrin, M. J., Balagot, R. C., and Sadove, M. S.: Some effects of levallorphan on responses to meperidine. Can. Anesth. Soc. J. Mather, L. Lindrop, Meperidine

4:372 (1975). Bachrach, E. H., Godhalm, A. N., and Botcher, A. M.: Clinical observations on the use of alphaprodine (Nisentil) for postoperative analgesia. Surgery 37:440 (1955). Rodman, B. I.: Depression of respiration by the opiates and its antagonism by nalorphine. Proc. Royal Soc. Med. 46:923 (1953). Millem-, .1. W., and Anderson, H. H.: The effect of N-demethylation on certain punymnacologieal actions of morphine, codine and meperidine in the mouse. J. Pharnmacol. E.rp. Therap. 112:191 (1954).

Time Journal

of

Clinical

Pharmacology