Frank

L Greenway

ABSTRACI’ studies wk

a

The

combined

analysis

anorectic

drugs

ofprescription

more

1985,

weight

loss than

the combined

PPA

with

cebo,

but

in the

caffeine since

1985,

this

(P

scription bination,

ceased

kg/wk

with

end

more

weight

The

with

PPA

anorectic drugs, were compared

kg/

studies.

In

and

is not subject

loss than

pla-

subject of repeated Weintraub (3),

kg/wk

of adverse

were

19% and

14%

were mild, howThe two nonpreand their Benzocaine

corngave

controlled

C/in Nutr KEY

loss

Am J

l992;55:203S-5S.

WORDS

Obesity,

ylpropanolamine,

anorectic

benzocaine,

drugs,

weight

loss, phen-

caffeine

Only disorder

Old attitudes,

has obesity begun to be viewed as a regulatory fat mass rather than a result ofpoor self control.

however,

are slow to change

and much

still surrounds the use of drugs for the treatment In 1973, the controversy over the effectiveness

controversy of obesity. of anorectic

agents prompted the US Food and Drug Administration view the 105 double-blind, placebo-controlled studies rectic

agents

Scoville

(1) reported on this review, which on drug and 4543 patients on placebo.

tients

submitted

to it in support

ofnew

drug

applications.

contained These

3182 palasted

studies

3, 4, 8, or more weeks. The following conclusions were 1) At 4 wk of treatment, patients on drug treatment

kg/wk these

more studies

than

patients

patients

more than placebo in their side effects

On the basis were latory it would

parison

based

this is the largest seem

drug

to be the

with drugs

ofthis

(Fig

treatment

analysis, and

had

lost

upon

prescription were

their

placed safety

ofPPA

ofdata

on anorectic

most

logical

standard

on PPA

plus

by Conte

for use as an anorectic Am J C/in Nuir

agent

l992;55:203S-5S.

is sold and

thus

Printed

not

in USA.

equivalent

were patients

was 0.23

loss more

of weight appear

directly

PPA

and reanalyzed. The and PPA plus caffeine

difference

of these

placebo

at the end of

and

prescription

anorectics

loss. can be seen

between

and studies

PPA

loss. Weight on mazindol,

on dextroamphetamine,

0.84

ofO.64

kg/wk

kg/wk

in 123

in 12 1 patients.

in 54 patients

and

There

a

medi-

loss in these studies was 1.0 kg/wk in 41 patients

kg/wk

patients

demonstrate

the prescription

propion, and 0.64 kg/wk in 121 patients In these four studies, prescription drugs of 0.86

in the study

diethylpropion

could

and

cations in terms of weight 0.68 kg/wk in 28 patients

loss

(Fig there

than

dextroamphetamine, None

studies drugs,

(1973, on file at Thompson Medical), on file at Thompson Medical) who

(

PPA.

New

loss. Therefore,

at the end ofthe of prescription

in causing weight for this conclusion

(4), Bohensky Noble 1977,

with

significant

that

Medical,

weight

combined on PPA

placebo.

in one study

on file at Thompson

to cause

mazindol,

compared

on

on PPA. combined PPA

for a weight

gave

are too

diethyl-

a weight

few studies

loss

to apply

a statistic but there seems to be a small consistently greater weight loss in the groups on prescription anorectics than in the PPA group.

PPA is no longer combined with caffeine in the United States and there have been seven double-blind placebo-controlled studies (5) (A Conte; 1983, 1985; on file at Thompson Medical)

agents

different

reguprofiles.

medications,

(6-8) patients

comparing

(3). These

PPA

studies

on placebo.

There

with

include was

placebo

since

341 patients a combined

the Weintraub

on PPA weight

loss

and 302 of 0.21

anal-

a prescription included

directly

review

for com-

in the Scoville

was

were directly

placebo analysis

compared

kg/wk

varied

to use

without

than placebo. than

groups of studies group of 1098

ofAltschuler Conte (4),

caffeine, and at the end of

more

lost 0.22

(1977,

it would

included

more

and were found

kg/wk

placebo-

analysis

on PPA lost 0.28 kg/wk

lost 0.27 kg/wk more than I). Because, in the Scoville

I

(PPA)

This

the

caffeine

PPA and PPA plus caffeine York)

been

double-blind

1982.

Patients

studies.

Patients

because

also

kg/wk

ysis (1). Phenylpropanolamine

largely has

the

before

profile

0.23

side-effect

body

done

to the

safety

agents

anorectic into

and

class not included

reached: lost 0.25

1). 2) At the end of

1). 3) The various anorectic not in their effectiveness.

effective

categories

Because

on (Fig but

of this

considered

on placebo

to reof ano-

probably

to amphetamines,

controversy. in 1985, reviewed

are equally effective Further evidence

recently ofbody

(2). PPA,

related

a better

these

the studies,

Introduction

chemically has

on PPA, 587 patients on PPA plus on placebo. Weight loss was analyzed

the two combined

weight

agents,

5 1 1 patients 784 patients

scription was not

4 wk, and benzocaine.

although

similarity

trials

performed

in studies exceeding by combination with

PPA,

anorectic

to abuse

of its chemical

less weight loss than PPA (P < 0.05 ANOVA). Thus, PPA is safe and effective for weight loss, appears less effective than preanorectics enhanced

(1).

and

to 0.14

PPA and benzocaine, in a 40-patient study.

analysis

amphetamine-like

(PPA)

incidence

These adverse reactions drug discontinuation.

Scoville

0.23

of the

has dropped

PPA.

studies

0.02). with




studies placebo

conducted whereas

pos-

loss

in the

was 35% overweight in the newer studies

d in this placebo.

vOlved

a wide

another

range

was the lack

do the new studies mates the heavier used

a 2-wk

The use explanation

patients

the

2 wk

week

2-wk

in the

older

studies

run-in

run-in

4 on diets

without

parable to the weight with a 2-wk placebo

diet,

one

a 2-wk losses run-in

for analysis

flaws inand only

could

argue

placebo

run-in

that

period

on week 2 of medication period. If one analyzes

at 4 wk

with

loss

at

are comon diets the 19 1 pa-

on these

in the

new

since

the

weight before

studies patients spent an to pursue this line of rea1982

compared

40 patients

and

the

in the

two

to apply

10 wk in

>

with

four

new l0-wk

weight studies

statistics

and do not support explain the reduced

than lost

but

the

the hypotheses weight loss

in

same

The

study more

not

1985. Even extend ofthe

for

loss that

the than

during were

this

at the

kg/wk

seen

difference

study

performed

by

1 3 1 patients on the 0.23 kg/wk

the past conducted

5 y. with

2-wk

medication in general

is less effective

than

4 wk, this may have in which PPA is used.

im-

loss ofO.2

1

to the 0.25

seen in the analysis of weight loss of 0. 14 kg/

end

of the studies

in the

could

participants to the

of time spent on of anorectic drugs if PPA

placebo (1). The

placebo

0.23

to be due

>

was

data of 1973 (1). In view ofthe large number study, it appears unlikely that prescription

than the

or lighter

to way

study

kg/wk more than is actually greater

weight loss than drugs by Scoville more

appear

length trials

8-wk

designs suggest that at 4 wk the weight than placebo with PPA is comparable

reasons

of PPA

An

loss seen in the give less weight

comparing fluoxetine against placebo The 131 patients on 60 mg fluoxetine/

are giving less weight these new studies

to be less than

four studies with a 2-wk kg/wk more weight loss to 0.2 1 kg/wk, which is

medication

anorectics Therefore,

wk on PPA

during

weight

The

loss

especially

than the 4-wk in the studies

before

were

period.

in 1989 manner.

study lost 0.43 This difference

kg/wk more prescription

possible studies.

ofweight

weight

before 1982 lost 0.24 kg/wk more the 152 patients in the four new

seen in the Scoville of patients in this

proved kg/wk

which elimnew studies

is another in the new

amount

tients on week 2 of medication in the placebo run-in period, one finds 0.22 than placebo, which is almost identical the value studies.

range, seven

Not

for

period.

lose a disproportionate of any

period.

a narrower weight but four out ofthe

of a 2-wk placebo run-in period for reduced weight loss seen

Because first

used placebo

of weights ofa

contain subjects,

placebo

several criticism

conducted

medication,

1985-1990

studies weight

out One

studies,

differences appear dramatic that the study length could

Levine et al (9) in a double-blind

(3) pointed he analyzed.

in the new In an effort

only 0.07 kg/wk more than placebo. The number of studies is too small

either, there is a suggestion that the older studies utilized patients since the mean entry criteria weight in the older

In his 1985 review, Weintraub in study design in these studies

the studies,

newer studies. One other explanation of the reduced weight newer studies could be that all weight loss studies

studies

criteria

for of the

10 wk in length.

sibility heavier

whereas the mean entry was only 30% overweight.

length

the

directly

this

explanation

be the

at 4 wk and at

weight loss was more affected average length of time on PPA

the

length

of studies)

new PPA studies

possible could

soning,

1983, on file at Thompson Medical) and there significant difference between them, but the did show

and

(end

1982 was 141 d whereas average of 66 d on PPA.

new studies were of sustained-released two different sustained-release forms

preparation

Another

studies

used PPA preparation

of studies)

studies,

end-of-study loss. The

the newer

kg/wk more than placebo). No studies are available comparing immediate and sustained-release PPA. Another possibility might be that patients in the older

old PPA

studies

of patients

with

(end

of the greater

reasons for this difference be differences in the prepa-

studies

studies

of studies)

Scoville

involve in the

run-in

the new

period,

appears

analysis release studies the

(1). form but

do

increased

in the new study, or that show less weight loss since prescription

drugs

as studies

little impact clinically because In 1983, a study by Compton

Downloaded from https://academic.oup.com/ajcn/article-abstract/55/1/203S/4715270 by Cornell University Library user on 13 January 2019

drugs (4 weeks)

WAY

CLINICAL Advertising weight

surveyed

over

400

patients

loss in 15 geographically

at Thompson Medical). who use over-the-counter

who

dispersed

This study anorectics

STUDIES had

used

markets

OF PPA

(1983;

revealed that do so for

205S

PHENYLPROPANOLAMINE kg/wk

for

on file

80% of patients 4 wk. (I)

Safety

issues

with

PPA

have

also

been

controversial,

primarily

because of case reports with questionable validity. None individual studies on file at Thompson Medical comparing with placebo found a significant difference in side effects on file at Thompson

Medical).

When

one

combines

transient,

Medical).

resolving

with

of concerns about not been realized In addition States effects. sensory

benzocaine

is available

because

at the interaction to address

and 45% overweight after a 2-wk placebo PPA,

in chewing

gum

tients

this

instructed

taste, signal

40 women

or PPA

in a 1000-cal as evidenced

(

of side

and/or the No study

in producing between

15%

over 8 wk ofactive treatment The patients were randomized one time/d;

times/d;

smell, hunger.

benzocaine,

plus

diet.

All patients

by history,

and laboratory evaluation. The results the placebo group lost 0. 1 1 kg/wk (n

12 mg

benzocaine.

physical

All pa-

were

healthy

examination,

ofthis study showed 5), the PPA group

that lost

=

(n (n

kg/wk (n = 6), the benzocaine group lost 0 kg/wk the PPA plus benzocaine group lost 0. 12 kg/wk

=

7),

=

9)

(Fig 2). The

numbers

between

OVA).

of patients

PPA

and

Nonetheless, PPA

had

zocaine

was less effective

benzocaine

casting

some

anorectic

agent.

There

is only

placebo

the

reported

upon

on benzocaine

loss

paper (1 1) in

28 patients

the

whereas

combination

back

to the

benof PPA

placebo

of benzocaine

combining

who

level, as an

benzocaine trial.

198 1, contained

on placebo

difference

(P < 0.05 by ANare still surprising

placebo-controlled

by Collipp and

The

effectiveness

published

in a double-blind

only

to placebo

placebo.

weight

on

one

relation

than

brought

and

significant

of this study

the expected

doubt

small

was

the results

because and

are

benzocaine

That

with study,

24 patients were

studied

for

6 wk. Patients on benzocaine lost 0.32 kg/wk more than placebo, which is actually better than the data reported by Scoville (1) on prescription

medication.

In conclusion, it appears weight loss. 2) Based upon effective than prescription exceeds

4 wk but

80%

3) Because

of its excellent

ferred

line

first

anorectic

that 1) PPA is safe and effective for the newer studies, PPA may be less anorectic as the length of treatment

of those safety when

that

use

records, a medication

PPA

PPA

do so for

4 wk.

may be the preof this

class

PPA

PPA

+

benzocaine

FIG 2. Interaction

of benzocaine

and PPA on weight loss.

has I 0).

United

lack

Benzocaine

and

fear

in the

two agents

question,

75 mg capsules eight

not pregnant

0.23 and

mild

In spite

of its virtual

ofthese

were evaluated run-in period.

to placebo; were

were

and a 1989,

ofmedication.

It is thought to act by numbing afferents from the stomach that

In an effort

effects

discontinuation

a prescription

has yet looked weight loss.

and

side

abuse and addiction potential, this in either animal studies or in humans

to PPA,

without

These

.a)

the

trials, one finds a 19% incidence of side effects on PPA 14% incidence ofside effects on placebo (P < 0.02) (Lee, on file at Thompson

0 C C)

is felt

to be indicated.

4) Benzocaine

weight loss seen with PPA. indicated to further evaluate an anorectic

agent.

does

not

appear

to increase

5) Additional studies appear the effectiveness of benzocaine

the to be as

U

References 1. Scoville BA. Review ofamphetamine like dregs by the Federal Dreg Administration: clinicaldata and valuejudgments, In: George Bray, ed., Obesity in perspective. Washington, DC: US Government Printing Office, 1973. [DHEW publication (NIH) 75-708.] 2. Morgan IP. Pheny/propano/amine: a critica/ ana/ysis of reported adverse reactions and over-dosage. Fort Lee, NJ: Jack K Burgess, 1986. 3. Weintraub M. Phenylpropanolamine as an anorexiant agent weight control: a review ofpublished and unpublished studies. In: Morgan ID, Kagan DV, Brody IS, eds. Phenylpropanolamine: risks, benefits and controversies. New York: Praeger Publishers, 1985:53-79. 4. Altschuler 5, Conte A, Sebok M, Marlin RL, Winick C. Three controlled trials of weight loss with phenylpropanolamine. Int I Obes 1982;6:549-56. 5. Bradley M, Raines I. Effects ofphenylpropanolamine, hydrochloride in overweight patients with controlled stable hypertension. Curr Ther Res l989;46:74-84. 6. Greenway FL. A double-blind clinical evaluation of the anorectic activity ofphenylpropanolamine versus placebo. Gin Ther l989;l I: 584-9. 7. Weintraub M, Ginsberg G, Stein EC, et al. Phenylpropanolamine OROS (Acutrim) versus placebo in combination with caloric restnction and physician managed behavior modification. Clin Pharmacol Ther 1986;39:501-9. 8. Schteingart DE. Effectiveness ofphenylpropanolamine (PPA) as an adjunct in the dietary management of obesity. Int I Obes 1989;l3: 405(abstr). 9. Levine LR, Enas GG, Thompson WL, et al. The use of fluoxetine, a selective serotonin uptake inhibitor in the treatment of obesity, a dose response study. tnt I Obes l989;l3:635-45. 10. Lasagna L. Phenylpropanolamine, a review. New York: John Wiley andSons, 1988. 1 1. Collipp P1. The treatment ofexogenous obesity by medicated benzocaine candy: a double blind placebo study. Obes Bariatric Med 198 1; 10: 123-5.

Downloaded from https://academic.oup.com/ajcn/article-abstract/55/1/203S/4715270 by Cornell University Library user on 13 January 2019

1989,

C,)

of the PPA (I Lee,