American Journal of Gastroenterology ISSN 0002-9270C© 2005 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2005.40925.xPublished by Blackwell Publishing
Efficacy and Safety of Traditional Medical Therapies forChronic Constipation: Systematic ReviewDavendra Ramkumar, M.D., and Satish S.C. Rao, M.D., Ph.D.Division of Gastroenterology, University of Iowa Carver College of Medicine, Iowa City, Iowa
OBJECTIVES: Constipation is common, and its treatment is unsatisfactory. Although many agents have beentried, there are limited data to support their use. Our aim was to undertake a systematic review ofthe efficacy and safety of traditional medical therapies for chronic constipation and to makeevidence-based recommendations.
METHODS: We searched the English literature for drug trials evaluating treatment of constipation by usingMEDLINE and PUBMED databases from 1966 to 2003. Only studies that were randomized,conducted on adult subjects, and published as full manuscripts were included. Studies wereassigned a quality score based on published methodology. Standard forms were used to abstractdata regarding study design, duration, outcome measures, and adverse events. By using thecumulative evidence of published data for each agent, recommendations were made regardingtheir use following the United States Preventive Services Task Force guidelines.
RESULTS: Good evidence (Grade A) was found to support the use of polyethylene glycol (PEG) and tegaserod.Moderate evidence (Grade B) was found to support the use of psyllium, and lactulose. There was apaucity of quality data regarding many commonly used agents including milk of magnesia, senna,bisacodyl, and stool softeners.
CONCLUSIONS: There is good evidence to support the use of PEG, tegaserod, lactulose, and psyllium. Surprisingly,there is a paucity of trials for many commonly used agents. These aspects should be consideredwhen designing trials comparing new agents with traditional therapies because their use may notbe well validated.
(Am J Gastroenterol 2005;100:936–971)
INTRODUCTION
Constipation is a common problem, with an estimated preva-lence of 2–20% (1–4). It is one of the more common present-ing complaints to both general practitioners and gastroen-terologists, and carries a significant economic impact (4, 5).Constipation appears to be more prevalent in the elderly,women, nonwhites, and persons in lower socio-economic andeducation classes (4).
Although a common problem, the treatment of constipa-tion has been far from satisfactory. A recent metaanalysissuggested that there was little credible evidence to supportmany of the drugs that are commonly used in the treatmentof this disorder (6). However, this analysis lumped all agentsinto a single “laxative group,” which may have obscured anybenefits of individual medications.
It is generally recommended that lifestyle measures such asadequate hydration, nonstrenuous exercise, increased naturalfiber intake, and dedicated time to have a bowel movementbe attempted first before medical therapy is tried. It shouldbe noted that none of these measures has been validated in aproper controlled trial.
With regard to medical therapy, the following categoriesof drugs have been used to treat constipation:
a. Bulk or hydrophilic laxatives—psyllium (isphagula),methylcellulose, bran, celandine, plantain derivatives, andaloe vera
b. Surfactant or softening or wetting agents—docusate,poloxalkol
c. Osmotic laxatives—lactulose, sorbitol, milk of magne-sia (MOM) (magnesium hydroxide), polyethylene glycol(PEG) solutions
d. Peristaltic stimulants or sometimes referred to as irri-tant laxatives—senna, bisacodyl, danthron, cascara, ery-thromycin, misoprostol
e. Others (prokinetic, prosecretors)—colchicine, tegaserod.
The purpose of this systematic review is to assess the avail-able evidence in the English literature, particularly random-ized, controlled trials addressing the efficacy and safety ofvarious medical therapies in adult patients with chronic con-stipation.
936
Efficacy and Safety of Traditional Medical Therapies 937
Literature SearchMEDLINE and PUBMED databases for the period from1966 to 2004 were used to search the literature. Consti-pation was combined with the following terms: osmoticlaxatives, irritant laxatives, stimulant laxatives, bulk lax-atives, fecal softeners, lactulose, sorbitol, MOM, magne-sium sulfate, PEG, senna, bisacodyl, danthron, cascara,psyllium, methylcellulose, calcium polycarbophil, isphagula,bran, celandin, plantain, alovera, aloe vera, docusate, polox-alkol, mineral oil, glycerine, misoprostol, erythromycin, lox-iglumide, tegaserod, herbal remedies, traditional medicine,Chinese herbal, plantain, and colchicine. Exploded termswere reviewed, and where appropriate, the search was ex-panded to include them.
Abstracts of the English language articles were allscreened. Potentially relevant studies were then reviewed, andselection criteria applied. The bibliographies of the studiesfound by this method and in reviews were manually searched.
Selection CriteriaStudies were included if they were (i) randomized (open-labeled or placebo-controlled, parallel design or crossoverdesign) comparing the agent in question with placebo, orcomparing two separate agents for efficacy and safety in pa-tients with chronic constipation; (ii) conducted using adultsubjects; and (iii) published in full manuscript form.
Data Extraction and AnalysisThe articles were reviewed and the relevant data were ab-stracted to standard forms. Data extracted included (i) thetherapy studied; (ii) the control agent; (iii) study design; (iv)number of patients; (v) mean age or age range; (vi) analysisby sex if available; (vii) duration of the study or crossoverperiods and, where necessary, wash-out intervals; (viii) out-come measures including stool frequency and consistency,straining, use of rescue medications; (ix) results in the formof percentage improvement or other suitable variable measur-ing the degree of change in the outcome measure in individ-ual patients as well as between patients treated with differentmeasures; and (x) an assessment of adverse reactions andother aspects of the safety of the treatment measure. Meta-analysis was not performed.
Qualitative Assessment of Study MethodologyThe identified studies were carefully assessed using criteriapreviously established (7, 8), for methodology that minimizesbias and enhances validity of trials about therapy. The follow-ing were evaluated (i) how randomization was performed anddescribed; (ii) use of concealed allocation; (iii) blinding; and(iv) completeness of follow-up. A scoring system was thenused to rate the strength of the studies. A score of 1 or 2was given for randomization (2 for appropriate randomiza-tion technique and concealed allocation explicitly stated ordescribed, 1 for study simply described as “randomized”).Scores of 0–2 were given for blinding (2 when both subjectsand investigators were explicitly said to be blinded to the
treatment by use of identical placebo or other technique, 1when the study is described as “double-blind,”, and 0 whenthe study was not double-blind). A score of 0 or 1 was givenfor frequency of withdrawals (1 when the number of with-drawals and reason for withdrawals were stated and 0 whenno statement was made pertaining to withdrawals). Thus, thequality score ranged from 1 to 5 with 5 being the highest pos-sible score. The studies were all reviewed by both authors,and scored independently. When there were discrepancies,the papers were reviewed again, and the final scores weredecided by consensus.
Levels of Evidence and Grading of RecommendationsThe strength of evidence and grading of recommendationswas as utilized by the U.S. Preventive Services Task Force(9).
LEVELS OF EVIDENCE.
(i) Good evidence (Level I)—consistent results from well-designed, well-conducted studies.
(ii) Fair evidence (Level II)—results show benefit, butstrength is limited by the number, quality, or consistencyof the individual studies.
(iii) Poor evidence (Level III)—insufficient because of lim-ited number or power of studies, flaws in their design orconduct.
CLASSIFICATION OF RECOMMENDATIONS.
(i) Grade A—good evidence in support of the use of amodality in the treatment of constipation.
(ii) Grade B—moderate evidence in support of the use of amodality in the treatment of constipation.
(iii) Grade C—poor evidence to support a recommendationfor or against the use of the modality.
(iv) Grade D—moderate evidence against the use of themodality.
(v) Grade E—good evidence to support a recommendationagainst the use of a modality.
RESULTS
Effectiveness and Safety of PEG Solution in the Treatmentof ConstipationPEG is a nonabsorbable, nonmetabolized osmotic agent thatis most often used in lavage solutions for gut cleansing forcolonoscopy and surgery. Its use as a laxative has garneredmuch interest recently.
Eight studies were found that satisfied the selection criteria(10–17). These are summarized in Table 1. Five of these stud-ies evaluated the efficacy of PEG solutions versus placebo,while one compared PEG solution to lactulose in patients withchronic constipation. Another evaluated the efficacy and tol-erance of PEG solutions, lactulose, and placebo in relieving
938 Ramkumar and RaoTa
ble
1.S
umm
ary
ofth
eT
rial
sE
valu
atin
gth
eE
ffica
cyan
dS
afet
yof
PE
Gin
the
Tre
atm
ento
fC
onst
ipat
ion
Pati
ent
Out
com
esS
tudy
Mea
nA
geR
efer
ence
sS
core
Inte
rven
tion
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
105
PE
G(8
–16
ozs)
orpl
aceb
oD
oubl
e-bl
ind,
plac
ebo-
cont
roll
ed,
cros
sove
r
3262
28/9
Two
5-da
ype
riod
sw
ith
2-da
yw
asho
ut
SF,
SC
,SE
,and
UO
LS
F(P
EG
7.75
±4.
55v
spl
aceb
o4.
88±
2.62
,p
<0.
01)
SC
(PE
G2.
56±
1.17
vs
plac
ebo
1.91
±0.
94,
p<
0.05
)
Sid
eef
fect
sof
PE
G(c
ram
ping
,gas
,na
usea
,unp
leas
ant
tast
e,an
dlo
ose
stoo
ls)
wer
em
inim
alan
dto
lera
ble∗
115
PE
G(2
6g/
day)
orla
ctul
ose
(20
g/da
y)
Mul
tice
nter
,ra
ndom
ized
,co
mpa
rativ
e
99of
115
com
plet
ed30
to≤6
5>
43to
6594
/21
4+
8w
kop
enS
Fan
dst
rain
ing,
use
ofad
diti
onal
laxa
tives
,liq
uid
stoo
ls,fl
atus
,bl
oati
ngru
mbl
ing,
abdo
min
alpa
in
PE
Ggr
oup
had
mor
eda
ilyst
ools
(1.3
vs
0.9,
p=
0.00
5)an
dle
ssst
rain
ing
(p=
0.00
01)
Low
dose
PE
Gw
asm
ore
effe
ctiv
eth
anla
ctul
ose
and
bett
erto
lera
ted
(on
visu
alan
alog
scal
ep
=0.
001)
No
sign
ifica
ntad
vers
eev
ents
inei
ther
grou
p.S
igni
fica
ntly
mor
efl
atul
ence
,wit
ha
tend
ency
tom
ore
bloa
ting
,ab
dom
inal
pain
,an
dru
mbl
ing
wit
hla
ctul
ose
Ope
n-la
bele
dph
ase
wit
hP
EG
foll
owin
gth
est
udy—
nolo
ssof
effi
cacy
Les
sus
eof
addi
tion
alla
xativ
esin
the
PE
Ggr
oup
(p=
0.04
)12
3P
EG
(17
g/da
y)or
plac
ebo
Ran
dom
ized
doub
lecr
osso
ver
tria
lof
plac
ebo
vs17
gof
PE
Gda
ily
2347
.722
/17-
day
plac
ebo
cont
rolp
erio
dth
en14
days
SF,
SC
,EO
D,
cram
ping
,rec
tal
irri
tati
on,a
ndfl
atus
.Adv
erse
even
ts
PE
Gin
crea
sed
mea
nda
ilyS
Fto
1pe
rda
yby
the
last
7da
ysof
the
14-d
aytr
eatm
ent
peri
odvs
plac
ebo,
whi
chpr
ovid
edab
out
1bo
wel
mov
emen
tev
ery
2da
ysdu
ring
the
last
wee
kof
ther
apy
(p=
0.00
01)
No
sign
ifica
ntad
vers
eev
ents
.No
clin
ical
lysi
gnifi
cant
chan
ges
inbl
ood
chem
istr
y,co
mpl
ete
bloo
dco
unt(
CB
C),
orur
inal
ysis
The
rew
asst
atis
tica
llysi
gnifi
cant
impr
ovem
enti
nsu
bjec
tive
scor
esfo
rS
C,E
OD
,cra
mpi
ng,
and
rect
alir
rita
tion
,bu
tnot
for
pass
age
offl
atus
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 939Ta
ble
1.C
onti
nued
Pati
ent
Out
com
esS
tudy
Mea
nA
geR
efer
ence
sS
core
Inte
rven
tion
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
135
PE
G(1
7g/
day)
orpl
aceb
oM
ulti
cent
er,
doub
le-b
lind
,pl
aceb
o-co
ntro
lled
para
llel
grou
ptr
ial
48of
55co
mpl
eted
25P
EG
,23
plac
ebo
48±
1537
/11
4w
kpl
aceb
oru
nin
,the
n8
wk
(tw
o4-
wk
peri
ods)
SF,
SC
,str
aini
ng,u
seof
laxa
tives
,and
tran
sitt
imes
PE
Gin
crea
sed
SF
at4
wk
and
atth
e8
wk
(PE
G:4
.8±
2.3
vs
plac
ebo:
2.8
±1.
6;p
<0.
002)
PE
Gde
crea
sed
stra
inin
gat
defe
cati
on(p
<0.
01)
The
rew
asno
diff
eren
cebe
twee
nco
ntro
lsan
dP
EG
-tre
ated
pati
ents
inab
dom
inal
sym
ptom
san
dsi
deef
fect
s
PE
Gim
prov
edS
C(p
<0.
02)
Oro
anal
,lef
tcol
on,
and
rect
altr
ansi
tti
mes
wer
esi
gnifi
cant
lysh
orte
ned
byP
EG
trea
tmen
tP
EG
decr
ease
dus
eof
laxa
tives
(p<
0.03
)14
5P
EG
(17
g/da
y)or
plac
ebo
Dou
ble-
blin
d,pl
aceb
o-co
ntro
lled
,pa
rall
elgr
oup
stud
y
70of
78M
ean
43(1
8–73
)58
/12
4w
kru
nin
wit
hP
EG
foll
owed
by rand
omiz
atio
nto
PE
Gor
plac
ebo
for
20w
kin
resp
onde
rs
SF
and
mod
alit
yof
evac
uati
on,U
OL
,an
dre
leva
ntsy
mpt
oms
PE
Ggr
oup
had
sign
ifica
ntly
high
erS
F(w
eek
12:7
.4vs
4.3
BM
/wk,
and
wee
k24
:7.4
vs5.
4B
M/w
k)
No
sign
ifica
ntdi
ffer
ence
sin
adve
rse
even
tsbe
twee
nth
etw
ogr
oups
for
sym
ptom
s(i
nclu
ding
naus
ea,
vom
itin
g,an
ddi
scom
fort
),la
bora
tory
valu
es,h
eart
rate
,and
bloo
dpr
essu
re
Ate
nd,7
7%of
the
PE
Ggr
oup
and
20%
ofth
epl
aceb
ogr
oup
wer
eno
tcon
stip
ated
(p<
0.01
)P
EG
repo
rted
less
hard
/pel
lety
stoo
lsat
defe
cati
onL
ess
UO
Lin
PE
Ggr
oup
and
redu
ced
mea
nnu
mbe
rof
PE
Gsa
chet
sus
edP
EG
grou
pha
dle
ssdr
opou
tsfo
rth
erap
yfa
ilur
e(1
6vs
3;p
<0.
005)
.
940 Ramkumar and Rao
154
PE
G(1
7g/
day)
orpl
aceb
oR
ando
miz
ed,
plac
ebo-
cont
roll
ed,
blin
ded,
mul
tice
nter
para
llel
tria
l
151
45.2
131
F20
M2
wk
SF,
SC
,EO
D,c
ram
ps,
and
flat
us.
Inve
stig
ator
and
pati
ents
ubje
ctiv
eas
sess
men
tof
perc
epti
onof
trea
tmen
tef
fect
iven
ess
SF
impr
oved
wit
hP
EG
wee
k2
4.5
BM
/wk
com
pare
dto
plac
ebo
2.7
BM
/wk
(p<
0.00
1)
No
sign
ifica
ntch
ange
sin
adve
rse
sym
ptom
s,C
BC
,bl
ood
chem
istr
ies,
and
urin
alys
isw
ere
note
dbe
twee
nth
etw
ogr
oups
Pati
ente
valu
atio
nsof
SC
show
edsi
gnifi
cant
impr
ovem
enti
nth
eac
tive
trea
tmen
tgr
oup
(p<
0.00
1)Pa
tien
teva
luat
ions
ofE
OD
show
edsi
gnifi
cant
impr
ovem
enti
nth
eac
tive
trea
tmen
tgr
oup
(p<
0.00
1)In
vest
igat
or(p
<0.
005)
and
pati
ent
(p<
0.00
1)su
bjec
tive
asse
ssm
ento
fpe
rcep
tion
oftr
eatm
ent
effe
ctiv
enes
sw
ere
bett
erw
ith
PE
G16
3P
EG
(8oz
s/da
y),
plac
ebo,
lact
ulos
e(3
0m
l/da
y)
Ran
dom
ized
,tr
iple
cros
sove
raf
ter
cont
rol
run-
in
57—
allo
nop
iate
s18
–50
Not st
ated
One
wee
kru
nin
cont
rol(
notr
eatm
ent)
foll
owed
by3
trea
tmen
tph
ases
of2
wk
each
SF,
SC
,UO
L,E
OD
,an
dS
EP
EG
solu
tion
and
lact
ulos
epr
oduc
edm
ore
“non
hard
”st
ools
than
the
plac
ebo
(p<
0.01
)an
dco
ntro
l(p
<0.
003)
.PE
Gpr
oduc
edth
elo
oses
tst
ool(
p<
0.00
01)
com
pare
dw
ith
the
cont
rol
No
chan
gein
elec
trol
ytes
note
dbe
twee
nth
egr
oups
.L
actu
lose
had
mor
ead
vers
eef
fect
s∗(p
resu
mab
lyab
dom
inal
pain
,bl
oati
ng,a
ndna
usea
,bas
edon
the
desc
ript
ion
ofth
em
etho
d)T
here
wer
eno
sign
ifica
ntdi
ffer
ence
sin
stoo
lco
nsis
tenc
yin
eith
erex
peri
men
talg
roup
,bu
tbot
hw
ere
bett
erth
anha
ving
noth
ing
orju
stth
epl
aceb
oU
OL
incr
ease
don
lyin
grou
ptr
eate
din
the
run-
inco
ntro
lper
iod
Efficacy and Safety of Traditional Medical Therapies 941
Tabl
e1.
Con
tinu
ed
Pati
ent
Out
com
esS
tudy
Mea
nA
geR
efer
ence
sS
core
Inte
rven
tion
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
174
Hyp
o-os
mot
icP
EG
4000
(For
lax)
10or
20g
and
iso-
osm
otic
PE
G33
50(T
rans
ipeg
)5.
9or
11.8
g
Pro
spec
tive,
rand
omiz
ed,
doub
le-b
lind
,pa
rall
el-
grou
p
263
of26
652
±18
.585
% wer
eF
Ran
dom
ized
to1
of4
trea
tmen
tgr
oups
:Hig
hor
low
dose
PE
G40
00,o
rhi
ghor
low
dose
PE
G33
50fo
r4
wk
SF
seco
ndar
yef
fica
cypa
ram
eter
sin
clud
edS
C,d
ate
ofoc
curr
ence
offi
rstm
otio
n,S
t,re
ctal
evac
uati
on,
abdo
min
alpa
in,
and
dist
ensi
on
SF
was
sign
ifica
ntly
incr
ease
dco
mpa
red
wit
hba
seli
nein
all
trea
tmen
tgro
ups
(p=
0.00
01)
wit
hno
diff
eren
cebe
twee
ngr
oups
All
med
icat
ions
wer
ew
ell
tole
rate
d.T
hehi
gher
dose
grou
psha
dm
ore
repo
rts
ofdi
arrh
ea.
Dis
tens
ion,
flat
ulen
ce,a
ndab
dom
inal
pain
occu
rred
even
lyin
allf
our
grou
ps∗ .
SC
sign
ifica
ntly
impr
oved
com
pare
dw
ith
base
line
inal
ltr
eatm
entg
roup
s(p
=0.
0001
).T
hepe
rcen
tage
ofpa
tien
tsw
ith
norm
alS
Cw
assi
gnifi
cant
lyhi
gher
for
stan
dard
-dos
eP
EG
3350
vsbo
thm
axim
um-d
ose
trea
tmen
ts(p
<0.
01).
≥67.
3%ha
dth
eir
firs
tst
oolw
ithi
n1
day
ofst
arti
ngtr
eatm
ent
Rec
tale
vacu
atio
n,st
rain
ing,
bloa
ting
,an
dpa
inw
ere
also
sign
ifica
ntly
impr
oved
com
pare
dw
ith
base
line
inal
ltr
eatm
entg
roup
s(p
=0.
0001
)
SF,
stoo
lfre
quen
cy;S
C,s
tool
cons
iste
ncy;
St,
stra
inin
g;U
OL
,use
ofad
diti
onal
laxa
tives
;EO
D,e
ase
ofde
feca
tion
;SE
,sid
eef
fect
s;,n
otot
herw
ise
spec
ified
.
942 Ramkumar and Rao
Table 2. Methodologic Quality of Trials with PEG
Statement onReference Randomization Blinding Withdrawals Total Score
10 2 2 1 511 2 2 1 512 1 2 0 314 2 2 1 513 2 2 1 515 1 2 1 416 1 2 0 317 1 2 1 4
A score of 1 or 2 was given for randomization (2 for appropriate randomizationtechnique and concealed allocation explicitly stated or described, 1 for study simplydescribed as “randomized”). Scores of 0–2 were given for blinding (2 when bothsubjects and investigators were blinded to the treatment by use of identical placeboor other technique, 1 when the study is described as “double-blind,” and 0 when thestudy was not double-blind). Score of 0 or 1 was given for frequency of withdrawals (1when the number of withdrawals and reason for withdrawals were stated and 0 whenno statement was made pertaining to withdrawals).
opiate-induced constipation (16). The last study comparedtwo doses of two commercially available PEG formulations,an iso-osmotic preparation, and a hypo-osmotic solution (17).Constipation was variously defined, with only two studiesutilizing the Rome criteria to identify suitable patients (13,14). Six of the studies evaluated the short-term efficacy andsafety of PEG solution. The longest duration in this categorywas 8 wk. One trial looked at the same parameters over a 6-month period (14) and therefore provides longer-term data.The qualitative assessment of these studies and the extracteddata are presented in Table 2.
PEG is an effective form of treatment with few side effectsand it is modestly more effective than lactulose. Decisionanalysis modeling suggests that PEG, despite its higher cost,is ultimately more cost-effective than lactulose, at least fromthe perspective of the National Health Service of the UnitedKingdom. (18).
PEG: Level I Evidence, Grade A Recommendation.
Efficacy and Safety of Lactulose in the Treatmentof ConstipationLactulose is a nonabsorbable synthetic disaccharide whichfunctions as an osmotic laxative and which appears to havebeen accorded the role of the standard against which neweragents are compared for efficacy and safety. Three studiescompared lactulose with placebo (19–21). The others wereall comparisons with other agents in which the efficacy oflactulose was determined by the improvement from baselinein the parameters that assess constipation (11, 16, 22–27).The characteristics and results are summarized in Table 3.The qualitative assessments of these studies are summarizedin Table 4.
Lactulose appears to be an effective and safe agent foruse in idiopathic constipation, with the most common sideeffects (bloating, flatulence, and loose stools) being an ex-tension of its mechanism of action. Compared to PEG solu-tions, lactulose was less efficacious and had more side effects
(11, 16). An open-labeled, randomized, parallel study whichcompared lactulose, psyllium, and placebo suggested that thetwo treatment agents were equally effective in the treatmentof constipation (26). A single trial that compared the efficacyand safety of lactulose and sorbitol suggested that the twoagents were similarly effective, but lactulose had a greaterpropensity to cause nausea (23).
Lactulose: Level II Evidence, Grade BRecommendation.
Sorbitol: Level III Evidence, Grade CRecommendation.
Efficacy and Safety of MOM in the Treatment ofConstipationThere is one trial in the English literature evaluating the ef-ficacy of MOM in the treatment of constipation (28). MOMwas compared to a bulk laxative and was found to causemore frequent bowel movements than bulk laxative, and addi-tional laxative was not needed as often as with bulk laxative.Stool consistency was more normal during the magnesiumhydroxide treatment. In two patients, serum magnesium wasover 1.25 mmol/L after the magnesium hydroxide treatmentbut there were no clinical signs of hypermagnesemia. Thisis more likely to be a problem in patients with renal insuf-ficiency. Hypermagnesemia, paradoxically, causes paralyticileus that in turn leads to obstipation. This study suggeststhat MOM is effective, but there is a risk of hypermagne-semia with frequent use.
There are no trials that have evaluated the utility of mag-nesium sulfate (Epsom salts) in the treatment of constipationafter 1966.
MOM: Grade III Evidence, Grade CRecommendation.
Efficacy and Safety of Stimulant Laxatives in theTreatment of ConstipationFor the period reviewed, no placebo-controlled trials werefound. The studies reviewed all compared a laxative contain-ing only an irritant/stimulant agent, or agents containing anirritant/stimulant as one of its active ingredients with otheragents (22, 24, 25, 27, 29–34). Tables 5 and 6 summarizethe study characteristics and methodologic assessment. Threestudies that compared a preparation containing psyllium andsenna with lactulose suggested that the fiber/stimulant com-bination was more efficacious and may even be more cost-effective (22, 24, 25). Another study compared lactulose withirritant laxatives containing senna, anthraquinone derivatives,or bisacodyl (31). Lactulose was found to be more effectivethan each of these three irritant laxatives. A comparison be-tween bisacodyl and bisoxatin acetate, both irritant laxatives,showed similar efficacy (32). The latter agent is no longermarketed. Preparations with and without senna were evalu-ated (30); laxation appears to be similar, with the combina-tion appearing to cause more side effects compared with just
Efficacy and Safety of Traditional Medical Therapies 943
Tabl
e3.
Sum
mar
yof
the
Tri
als
Eva
luat
ing
the
Effi
cacy
and
Saf
ety
ofL
actu
lose
inth
eT
reat
men
tof
Con
stip
atio
n
Pati
ent
Out
com
esS
tudy
Mea
nA
geR
efer
ence
sS
core
Inte
rven
tion
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
193
Lac
tulo
se(6
0m
l/da
y)or
plac
ebo
Con
stip
ated
subj
ects
doub
le-b
lind
para
llel
2410
took
lact
ulos
e14
took
plac
ebo
28.2
22/2
1w
kba
seli
ne—
allt
ook
plac
ebo
(sin
gle-
blin
d),
the
seco
ndw
eek
was
ado
uble
-bli
ndtr
eatm
ent
peri
od
SF,
stoo
lwei
ght,
volu
me,
SC
,and
wat
erco
nten
t
SF
—la
ctul
ose
syru
ppr
oduc
edcl
inic
ally
and
stat
isti
cally
sign
ifica
ntin
crea
ses
(4.5
vs1.
6st
ools
per
wee
k,p
<0.
05)
Adv
erse
effe
cts
wer
eal
lex
tens
ions
(flat
ulen
ce)
ofth
eph
arm
acol
ogic
effe
cts
ofth
edr
ugan
dw
ere
inge
nera
lwel
lto
lera
ted
SC
—la
ctul
ose
prod
uced
stoo
lsof
soft
erco
nsis
tenc
yco
mpa
red
toba
seli
neva
lues
,as
wel
las
toa
sucr
ose-
trea
ted
cont
rolg
roup
inbo
thno
rmal
and
cons
tipa
ted
subj
ects
Lac
tulo
sepr
oduc
edst
ools
ofgr
eate
rw
eigh
t,vo
lum
e,an
dw
ater
cont
ent
214
Lac
tulo
se(1
5–30
ml/
day)
orpl
aceb
odo
sees
cala
tion
allo
wed
Mul
tice
nter
,ra
ndom
ized
,do
uble
-bli
nd,
plac
ebo-
cont
roll
ed,
para
llel
stud
y
103
>60
Not st
at-e
d2-
wk
run-
in.
3-w
ktr
eatm
ent,
then
2-w
kle
adou
t
SF,
UO
L,p
ossi
ble
SE
The
succ
ess
rate
for
lact
ulos
ew
as86
vs60
%pl
aceb
o(p
<0.
02).
Tru
lyco
nsti
pate
dpa
tien
tsw
ere
dete
rmin
edba
sed
onth
eir
laxa
tive
requ
irem
ent
post
trea
tmen
t.T
hesu
cces
sra
teof
lact
ulos
ew
asin
crea
sed
to80
%in
thes
epa
tien
tsan
dpl
aceb
o33
%(p
<0.
01)
Non
em
enti
oned
944 Ramkumar and Rao
204
Lac
tulo
se(3
0m
lof
50%
solu
tion
)or
plac
ebo
(glu
cose
)
Ran
dom
ized
,do
uble
-bli
nd,
plac
ebo-
cont
roll
ed
47of 55
—nu
rsin
gho
me
pati
ents
19la
ctul
ose,
23gl
ucos
e
84.7
39F
6M
2-w
kru
n-in
,12
-wk
trea
tmen
t,th
en1-
wk
obse
rvat
ion
SF,
sym
ptom
sof
cons
tipa
tion
,ep
isod
esof
stoo
lim
pact
ion,
UO
L
SF
—la
culo
sew
assu
peri
orto
gluc
ose
wit
hm
ean
BM
per
day
of0.
7vs
0.5
(p<
0.02
)an
din
the
perc
enta
geof
days
inw
hich
atle
asto
nebo
wel
mov
emen
tocc
urre
d(p
<0.
05)
No
adve
rse
clin
ical
ofla
bora
tory
effe
cts
Red
ucti
onin
the
seve
rity
ofea
chof
cram
ping
,gri
ping
,fl
atul
ence
,te
nesm
us,b
loat
ing
was
grea
ter
wit
hla
ctul
ose.
For
reli
efof
allfi
vesy
mpt
oms,
lact
ulos
ew
asm
ore
effe
ctiv
eth
angl
ucos
e(p
<0.
04)
The
redu
ctio
nin
the
num
ber
offe
cal
impa
ctio
ns(6
inth
ela
ctul
ose
pati
ents
vs66
inth
eco
ntro
ls)
was
high
lysi
gnifi
cant
(p<
0.01
5)T
hela
ctul
ose
pati
ents
need
edfe
wer
enem
asth
andi
dth
eco
ntro
ls11
5P
EG
(26
g/da
y)or
lact
ulos
e(2
0g/
day)
Mul
tice
nter
,ra
ndom
ized
,co
mpa
rativ
e
115–
91co
mpl
eted
30to
≤65
>43
to65
94/2
1Tw
o5-
day
peri
ods
wit
h2-
day
was
hout
SF
and
St
PE
Ggr
oup
had
mor
eda
ilyst
ools
and
less
stra
inin
g
No
sign
ifica
ntad
vers
eev
ents
inei
ther
grou
p.M
ore
flat
ulen
cew
ith
lact
ulos
eL
owdo
seP
EG
was
mor
eef
fect
ive
than
lact
ulos
ean
dbe
tter
tole
rate
dO
pen-
labe
led
phas
ew
ith
PE
Gfo
llow
ing
the
stud
y—no
loss
ofef
fica
cy
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 945Ta
ble
3.C
onti
nued
Pati
ent
Out
com
esS
tudy
Mea
nA
geR
efer
ence
sS
core
Inte
rven
tion
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
163
PE
G(8
ozs/
day)
,pl
aceb
o,la
ctul
ose
(30
ml/
day)
Ran
dom
ized
,tr
iple
cros
sove
raf
ter
cont
rol
run-
in
57—
allo
nop
iate
s18
–50
Not st
ated
1-w
kru
nin
cont
rol(
notr
eatm
ent)
foll
owed
byth
ree
trea
tmen
tph
ases
of2
wk
each
SF,
SC
,and
EO
DP
EG
solu
tion
and
lact
ulos
epr
oduc
edm
ore
“non
hard
”st
ools
than
the
plac
ebo
(p<
0.01
)an
dco
ntro
l(p
<0.
003)
.PE
Gpr
oduc
edth
elo
oses
tst
ool(
p<
0.00
01)
com
pare
dw
ith
the
cont
rol
Lac
tulo
seha
dm
ore
adve
rse
effe
cts
The
rew
ere
nosi
gnifi
cant
diff
eren
ces
inS
Cin
eith
erex
peri
men
tal
grou
p,bu
tbot
hw
ere
bett
erth
anha
ving
noth
ing
orju
stth
epl
aceb
o22
2L
actu
lose
30cc
ora
prep
arat
ion
cont
aini
ngis
pagh
ula
(psy
lliu
m)
and
senn
a(A
giol
ax)
Ope
n,ra
ndom
ized
,an
dco
ntro
lled
cros
sove
r
30lo
ng-s
tay
geri
atri
cpa
tien
ts
81.8
25/5
1-w
kru
nin
foll
owed
two
5-w
ktr
eatm
ent
peri
ods
sepa
rate
dby
1w
k
SF,
SC
,UO
L(b
isac
odyl
),an
dS
E
The
Agi
olax
prod
uced
4.5
BM
/wk
(in
both
peri
ods)
com
pare
dw
ith
2.2
and
1.9
per
wk
inpe
riod
son
ean
dtw
o,re
spec
tivel
y,fo
rla
ctul
ose
No
sign
ifica
ntad
vers
eef
fect
sno
ted
The
freq
uenc
yof
loos
est
ools
was
grea
ter
wit
hA
giol
axth
anw
ith
lact
ulos
e(p
<0.
05)
245
Lac
tulo
se(3
0–60
ml/
day)
and
com
bina
tion
ofps
ylli
uman
dse
nna
pod
(Agi
olax
10–2
0m
l/da
y)
Mul
tice
nter
,do
uble
-bli
ndcr
osso
ver
77of
85lo
ng-s
tay
geri
atri
cpa
tien
ts
82.9
57/2
8S
enna
-fibr
eco
mbi
nati
onor
lact
ulos
ew
ith
mat
chin
gpl
aceb
ofo
rtw
o14
-day
peri
ods,
wit
h3–
5da
ysbe
fore
and
betw
een
trea
tmen
ts
SF,
SC
,EO
D;
devi
atio
nfr
omre
com
men
ded
dose
;dai
lydo
sean
dco
stpe
rst
ool;
adve
rse
effe
cts
SF
was
grea
ter
wit
hth
ese
nna-
fibr
eco
mbi
nati
on(0
.8pe
rda
yth
anla
ctul
ose
(0.6
per
day,
p≤
0.00
1)
No
diff
eren
cein
adve
rse
effe
cts
Sco
res
for
SC
and
EO
Dw
ere
sign
ifica
ntly
high
erfo
rth
ese
nna-
fibr
eco
mbi
nati
onth
anfo
rla
ctul
ose
946 Ramkumar and Rao
The
reco
mm
ende
ddo
sew
asex
ceed
edm
ore
freq
uent
lyw
ith
lact
ulos
eth
anth
ese
nna-
fibr
eco
mbi
nati
on(χ
2=
8.38
,p
≤0.
01)
The
cost
per
stoo
lwas
appr
oxim
atel
yfo
urti
mes
high
erfo
rla
ctul
ose
than
for
the
senn
a-fi
ber
com
bina
tion
262
Lac
tulo
se(3
0m
l/da
y)or
isph
agul
a(p
syll
ium
)7
g/da
y
Ope
n,ra
ndom
ized
,pa
rall
elgr
oup
stud
y
112
50.6
Not st
ated
4w
kS
F,S
C,S
t,gl
obal
impr
ovem
ent,
med
icat
ion
acce
ptab
ilit
y
Bot
htr
eatm
ents
resu
lted
inst
atis
tica
llysi
gnifi
cant
(p<
0.00
01)
incr
ease
sin
stoo
lfre
quen
cyov
erba
seli
nebu
tnot
betw
een
the
trea
tmen
tgro
ups
(bas
elin
e2
per
wee
kvs
6.5
per
wee
kfo
rla
ctul
ose
and
7.5
per
wk
for
ispa
ghul
a)
No
seri
ous
adve
rse
effe
cts
Bot
htr
eatm
ents
caus
edim
prov
edS
C(p
=0.
027)
,but
ther
ew
ere
nodi
ffer
ence
sbe
twee
nth
egr
oups
The
rew
asno
sign
ifica
ntdi
ffer
ence
inS
tT
here
was
nosi
gnifi
cant
clin
ical
diff
eren
cein
glob
alim
prov
emen
tM
ore
pati
ents
foun
dis
pagh
ula
unpa
lata
ble
at28
days
(15.
7vs
4.2%
)p
=0.
063
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 947
Tabl
e3.
Con
tinu
ed
Pati
ent
Out
com
esS
tudy
Mea
nA
geR
efer
ence
sS
core
Inte
rven
tion
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
253
Lac
tulo
se15
ml
orA
giol
ax10
ml(
mix
ture
ofis
pagh
ula
and
senn
a)
Ran
dom
ized
,do
uble
-bli
nd,
cros
sove
r
77lo
ng-s
tay
geri
atri
cpa
tien
ts
82.9
57/2
0Tw
o14
-day
trea
tmen
tpe
riod
sw
ith
3–5
dla
xativ
efr
eepe
riod
befo
rean
dbe
twee
ntr
eatm
ents
SF,
SC
,EO
D,
adve
rse
effe
cts
Agi
olax
resu
lted
inst
atis
tica
llysi
gnifi
cant
incr
ease
sin
SF
(0.8
per
day
vs
0.6
per
day
p<
0.00
1)
No
diff
eren
ces
inad
vers
eef
fect
sbe
twee
nth
etr
eatm
entg
roup
s
Agi
olax
resu
lted
inst
atis
tica
llysi
gnifi
cant
impr
ovem
enti
nS
C(p
<0.
005)
Agi
olax
resu
lted
inst
atis
tica
llysi
gnifi
cant
impr
ovem
enti
nE
OD
(p=
0.02
)23
5S
orbi
tola
ndla
ctul
ose—
upto
60m
l/da
yof
eith
er
Ran
dom
ized
,do
uble
-bli
nd,
cros
sove
rtr
ial
3065
–86
All
men
Lac
tulo
sean
d70
%so
rbit
olw
ere
each
give
nfo
r4
wk
prec
eded
bya
2-w
kw
asho
utpe
riod
SF,
pref
eren
ceof
laxa
tive,
adve
rse
effe
cts
The
aver
age
num
ber
ofbo
wel
mov
emen
tspe
rw
eek
was
6.71
wit
hso
rbit
olan
d7.
02w
ith
lact
ulos
e,an
dth
eav
erag
enu
mbe
rof
days
per
wee
kw
ith
bow
elm
ovem
ents
was
5.23
wit
hso
rbit
olan
d5.
31w
ith
lact
ulos
e
The
rew
ere
nosi
gnifi
cant
diff
eren
ces
betw
een
sorb
itol
and
lact
ulos
ein
any
outc
ome
mea
sure
dex
cept
naus
ea,w
hich
was
incr
ease
dw
ith
lact
ulos
e(p
≤0.
05).
11pa
tien
tsst
ated
apr
efer
ence
for
sorb
itol
,12
for
lact
ulos
e,an
d7
had
nopr
efer
ence
948 Ramkumar and Rao
On
avi
sual
anal
ogsc
ale
mea
suri
ngse
veri
tyof
cons
tipa
tion
(0–1
00m
m),
the
aver
age
scor
efo
rso
rbit
olw
as35
.6vs
37.1
mm
for
lact
ulos
eT
heso
rbit
olan
dla
ctul
ose
trea
tmen
tpe
riod
sw
ere
also
sim
ilar
inpe
rcen
tof
bow
elm
ovem
ents
reco
rded
as“n
orm
al”
271
Lac
tulo
se(2
0m
l/da
y)or
Dor
bane
x10
ml/
day—
mix
ture
ofpo
loxa
lkol
and
anan
thra
quin
one—
orco
ntro
l(e
nem
asif
noB
Min
5da
ys)
Ran
dom
ized
,op
entr
ial
wit
hco
ntro
lgr
oup
37lo
ng-s
tay
geri
atri
cpa
tien
ts
82N
ot stat
edR
ando
mly
assi
gned
toon
eof
the
trea
tmen
tgr
oups
for
27da
ys
80%
tran
sitt
ime
(TT
—ti
me
for
80%
ofin
gest
edm
arke
rsto
bede
feca
ted)
All
pati
ents
had
80%
TT
prio
rto
trea
tmen
t.10
/14,
12/1
5,an
d6/
6ha
s80
%T
Taf
ter
6d
ays
foll
owin
g27
days
oftr
eatm
ent
wit
hla
ctul
ose,
Dor
bane
x,an
dco
ntro
l,re
spec
tivel
y
No
seri
ous
adve
rse
effe
cts.
19la
ctul
ose,
23gl
ucos
e
Efficacy and Safety of Traditional Medical Therapies 949
Table 4. Methodologic Scores for the Studies Evaluating Lactulose
Statement onReference Randomization Blinding Withdrawals Total Score
11 2 2 1 519 1 2 0 322 1 0 1 223 2 2 1 524 2 2 1 520 1 2 1 421 2 2 0 426 1 0 1 225 1 2 0 327 1 0 0 116 1 2 0 3
A score of 1 or 2 was given for randomization (2 for appropriate randomizationtechnique and concealed allocation explicitly stated or described, 1 for studysimply described as “randomized”). Scores of 0–2 were given for blinding (2when both subjects and investigators were blinded to the treatment by use ofidentical placebo or other technique, 1 when the study is described as “double-blind,” and 0 when the study was not double-blind). Score o f 0 or 1 was givenfor frequency of withdrawals (1 when the number of withdrawals and reason forwithdrawals were stated, and 0 when no statement was made pertaining to withdrawals).
psyllium. Sodium picosulfate, a stimulant laxative similar tobisacodyl, has been compared to senna. The agents appearto be similar in their beneficial effects on stool frequency,although sodium picosulfate seems to cause more side ef-fects. An agent comprised of the combination of a surfactant(poloxalkol) and an anthraquinone performed well comparedwith placebo in postpartum constipation (33), and similar tolactulose in another study (27). This combined agent wassimilar in efficacy to the stimulant sodium picosulfate (34).
While few studies suggest that combining stimulant lax-atives with fiber or surfactant agents may provide some re-lief of symptoms in patients with constipation, there are noplacebo-controlled trials.
Stimulant Laxatives: Level III Evidence,Grade C Recommendation.
Efficacy and Safety of Bulk Laxatives in the Treatmentof ConstipationA study which compared increased dietary fiber with regu-lar diet in posthysterectomy patients suggested that increaseddietary fiber is beneficial in improving stool frequency, stoolconsistency, time to defecate, and other symptoms of difficultdefecation (35). The individual agents that can be used to sup-plement the diet with fiber are discussed below. The charac-teristics of the trials evaluating bulking agents and qualitativeassessment of the methodology are summarized in Tables 7and 8.
Efficacy and Safety of Methylcellulose in the Treatmentof ConstipationThere are no placebo-controlled trials. One study (36) com-paring three doses of methylcellulose against psyllium satis-fied the screening criteria and is summarized in Table 5. Thelack of an appropriate control group and its low methodologicscore argues against accepting the results.
Methylcellulose: Level III Evidence, Grade CRecommendation.
Efficacy and Safety of Bran in the Treatmentof ConstipationThe studies evaluating the efficacy of bran and increased di-etary fiber on constipation all suggest benefits (37–41). Ina trial of the addition of wheat bran and corn bran supple-ments compared with no fiber supplementation, there wasimprovement in stool frequency and consistency, with noappreciable side effects (37). When bran was compared tojust a regular diet in elderly patients, there was a decreasein laxative requirements, but, paradoxically, these patientsseemed to require more assistance with actual defecationas evidenced by increased use of enemas and suppositories(41). A smaller study compared wheat bran with regular dietin elderly patients (42). There was significant improvementin stool frequency and consistency (42). No significant dif-ference was found in laxative or suppository requirements.Another study also showed the beneficial effects on stoolfrequency, and also suggested that oroanal transit times im-proved, but only in patients with slow colonic transit and notin those with slow rectal transit times (38). Comparison ofcorn bran and wheat bran showed that both products werebeneficial from the standpoint of improvement in stool fre-quency and intestinal transit times, but corn bran was rated bypatients as being better at relieving the symptoms of consti-pation (39). A comparison of bran with senna suggested thatthere was no significant difference on frequency and consis-tency of stools, but bran decreased the incidence of “large”stools (40).
Level III Evidence, Grade C Recommendation.
Efficacy and Safety of Psyllium in the Treatmentof ConstipationPsyllium (ispagula), a derivative of the husk of Plantagoovata, has been evaluated in several trials (30, 36, 43–47).Compared with placebo, psyllium seems to clearly improvestool frequency (43, 44). One study suggested that total guttransit time improved (44), while another suggested that therewas no change in colon transit (43). Similarly, the effect onstool consistency in these placebo-controlled trials was con-troversial with one study suggesting no change (44) and an-other suggesting significant improvement (43). A third largertrial with a single-blind design comparing psyllium withplacebo showed statistically significant improvement in bothstool frequency and consistency with both the investigator,and patient noting significant improvement in the constipa-tion (48). In an open trial, psyllium was noted to be superiorto three different stimulant/irritant laxatives, lactulose, andmagnesium sulfate in the treatment of constipation as well asbeing more palatable and acceptable to patients (46). A com-parison of a preparation of psyllium with senna, and psylliumalone showed the combination to be more effective than
950 Ramkumar and Rao
Tabl
e5.
Sum
mar
yof
the
Tri
als
Eva
luat
ing
the
Effi
cacy
and
Saf
ety
ofIr
rita
ntan
dS
tim
ulan
tLax
ativ
esin
the
Tre
atm
ento
fC
onst
ipat
ion
Pati
ent
Out
com
es
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
NM
ean
Age
Wom
enD
urat
ion
Out
com
eM
easu
reR
esul
tsS
afet
yA
naly
sis
312
Lac
tulo
se15
ml
b.i.d
.or
“irr
itan
t”la
xativ
es(o
fpa
tien
tsch
oice
)co
ntai
ning
senn
a,an
thra
quin
one
deri
vativ
esor
bisa
cody
l
Ope
n,ra
ndom
ized
,cr
osso
ver
194
of22
7N
otst
ated
Not
stat
edTw
otr
eatm
ent
peri
ods
of1
wk
sepa
rate
dby
1-w
kw
asho
ut
Sto
olco
nsis
tenc
y,si
deef
fect
sB
yda
y7,
58%
ofth
ela
ctul
ose-
trea
ted
grou
pw
ere
pass
ing
ano
rmal
stoo
lw
here
ason
ly42
%(p
<0.
001)
ofth
epa
tien
tsre
ceiv
ing
an“r
rita
nt”
laxa
tive
Lac
tulo
sepr
epar
atio
nha
da
pers
iste
ntca
rry-
over
effe
ctth
anth
eir
rita
ntla
xativ
es
No
diff
eren
cew
asno
ted
inth
ere
cord
ing
ofsi
deef
fect
sdu
ring
trea
tmen
tand
nont
reat
men
tpe
riod
s
322
Bis
acod
yl10
mg/
day
orbi
soxa
tin
acet
ate
60m
g/da
y
Ran
dom
ized
,do
uble
-bli
nd,
com
para
tive
51of
6121
–69
All
mal
epr
ison
ers
Two
cons
ecut
ive
4-w
kpe
riod
sO
nset
offi
rstB
M,
stoo
lfre
quen
cy,
cons
iste
ncy,
pati
ent
sati
sfac
tion
,ad
vers
ere
acti
ons
The
rew
ere
nodi
ffer
ence
sbe
twee
nbi
soxa
ntin
and
bisa
cody
lin
the
mea
nti
me
tofi
rst
BM
(7vs
5h)
Bis
acod
ylap
pear
edto
caus
em
ore
abdo
min
alpa
in
No
diff
eren
cein
stoo
lfr
eque
ncy
(1.7
per
day
vs2.
1pe
rda
y)N
odi
ffer
ence
inst
ool
cons
iste
ncy
The
rew
ere
less
sati
sfac
tion
wit
hbi
saco
dyl(
73%
vs82
%)
222
Lac
tulo
se30
ccor
apr
epar
atio
nco
ntai
ning
ispa
ghul
a(b
ulki
ngag
ent)
and
senn
a(A
giol
ax)
Ope
n,ra
ndom
ized
,an
dco
ntro
lled
cros
sove
r
30lo
ng-s
tay
geri
atri
cpa
tien
ts
81.8
25F
5M
1-w
kru
nin
foll
owed
two
5-w
ktr
eatm
ent
peri
ods
sepa
rate
dby
1w
k
Sto
olfr
eque
ncy,
cons
iste
ncy,
use
ofad
diti
onal
laxa
tive
(bis
acod
yl)
and
side
effe
cts
The
Agi
olax
prod
uced
4.5
stoo
lsa
wee
k(i
nbo
thpe
riod
s)co
mpa
red
wit
h2.
2an
d1.
9pe
rw
eek
inpe
riod
son
ean
dtw
o,re
spec
tivel
y,fo
rla
ctul
ose
The
freq
uenc
yof
loos
est
ools
was
grea
ter
wit
hA
giol
axth
anw
ith
lact
ulos
e(p
<0.
05)
No
sign
ifica
ntad
vers
eef
fect
sno
ted
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 951Ta
ble
5.C
onti
nued
Pati
ent
Out
com
es
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
NM
ean
Age
Wom
enD
urat
ion
Out
com
eM
easu
reR
esul
tsS
afet
yA
naly
sis
302
Psy
lliu
m(P
)an
dps
ylli
umw
ith
senn
a(P
S)
Ope
n,ra
ndom
ized
,si
ngle
-bli
ndco
ntro
lled
40of
4226
.135
F5
M1
wk
plac
ebo
and
1w
ktr
eatm
ent
SF,
SC
sym
ptom
sw
ith
BM
sB
oth
laxa
tives
incr
ease
dS
F[P
3.6
BM
/wk
vsP
S6.
8B
M/w
k(p
<0.
001)
]B
oth
Pan
dP
Sin
crea
sed
wet
and
dry
stoo
lwei
ghts
wit
hth
ead
ded
effe
ctof
the
senn
acl
earl
yev
iden
t.O
nly
the
psyl
lium
wit
hse
nna
incr
ease
dst
ool
moi
stur
e
Pgr
oup
3/22
cram
ping
and
gas
PS
grou
p7/2
2ha
dcr
amps
,un
com
fort
able
diar
rhea
,bl
oati
ngga
s,an
dna
usea
Bot
hla
xativ
esim
prov
edS
C(s
imil
ar)
Bot
hla
xativ
espr
ovid
eda
high
degr
eeof
subj
ectiv
ere
lief
245
Lac
tulo
se(L
)30
ml/
day
and
com
bina
tion
offi
bre—
ispa
ghul
a(p
syll
ium
)an
dse
nna
pod
(PS
)—M
anev
ac10
–20
ml/
day
Mul
tice
nter
,do
uble
-bli
nd,
cros
sove
r
77of
85lo
ng-s
tay
geri
atri
cpa
tien
ts
82.9
57F
Sen
na-fi
bre
com
bina
tion
orla
ctul
ose
wit
hm
atch
ing
plac
ebo
for
two
14-d
aype
riod
s,w
ith
3–5
days
befo
rean
dbe
twee
ntr
eatm
ents
SF,
SC
,EO
D;
devi
atio
nfr
omre
com
men
ded
dose
;dai
lydo
se,
and
cost
per
stoo
l;ad
vers
eef
fect
s
SF
was
grea
ter
wit
hth
ese
nna-
fibr
eco
mbi
nati
on(0
.8pe
rda
yth
anla
ctul
ose
(0.6
per
day,
p≤
0.00
1)S
core
sfo
rS
Can
dE
OD
wer
esi
gnifi
cant
lyhi
gher
for
the
senn
a-fi
bre
com
bina
tion
than
for
lact
ulos
eT
here
com
men
ded
dose
was
exce
eded
mor
efr
eque
ntly
wit
hla
ctul
ose
than
the
senn
a-fi
bre
com
bina
tion
(χ2=
8.38
,p
≤0.
01)
The
cost
per
stoo
lwas
appr
oxim
atel
yfo
urti
mes
high
erfo
rla
ctul
ose
than
for
the
senn
a-fi
ber
com
bina
tion
No
diff
eren
cein
adve
rse
effe
cts
952 Ramkumar and Rao
253
Lac
tulo
se15
ml
orA
giol
ax10
ml(
mix
ture
ofIs
pagh
ula
(psy
lliu
m)
and
senn
a)
Ran
dom
ized
,do
uble
-bli
nd,
cros
sove
r
77lo
ng-s
tay
geri
atri
cpa
tien
ts
82.9
57F
20M
Two
14-d
aytr
eatm
ent
peri
ods
wit
h3–
5da
ysla
xativ
efr
eepe
riod
befo
rean
din
betw
een
trea
tmen
ts
SF,
SC
,EO
D,
adve
rse
effe
cts
Agi
olax
resu
lted
inst
atis
tica
llysi
gnifi
cant
incr
ease
inS
F(0
.8pe
rda
yvs
0.6
per
day,
p<
0.00
1)A
giol
axre
sult
edin
stat
isti
cally
sign
ifica
ntim
prov
emen
tin
SC
(p<
0.00
5)A
giol
axre
sult
edin
stat
isti
cally
sign
ifica
ntin
crea
ses
in(p
=0.
02)
EO
D
No
diff
eren
ces
inad
vers
eef
fect
sbe
twee
nth
etr
eatm
entg
roup
s
292
Sod
ium
pico
sulf
ate
SP
10m
g/da
yor
stan
dard
ized
senn
a(S
)2
tabs
/day
Ope
n,ra
ndom
ized
para
llel
50lo
ng-s
tay
geri
atri
cpa
tien
ts
78.5
36F
14M
2w
kS
tool
freq
uenc
y,ti
min
g,co
nsis
tenc
y,an
dsi
deef
fect
s
The
num
ber
ofB
Ms
per
wee
kw
ere
sim
ilar
for
S(4
.41)
and
SP
(4.9
7)S
Pca
used
mor
elo
ose
orun
form
edst
ools
than
senn
a
The
rew
ere
few
min
orsi
deef
fect
sal
lrel
ated
toth
eac
tion
ofth
edr
ugs
onth
ebo
wel
333
Dor
bane
x(m
ixtu
reof
polo
xalk
olan
ddi
hydr
o-an
thro
quin
olon
e)(P
D)
orpl
aceb
o
Ran
dom
ized
,do
uble
-bli
nd,
plac
ebo-
cont
roll
ed
200
post
par-
tum
pati
ents
wit
hco
n-st
ipat
ion
Chi
ld-
bear
ing
age
rang
e(c
anno
tin
fer
from
data
)
All
wom
en6
days
Sto
olou
tput
,re
quir
emen
tfor
enem
asan
dsu
ppos
itor
ies,
By
the
seco
ndda
yof
trea
tmen
t50%
inth
etr
eatm
entg
roup
had
aB
Mco
mpa
red
wit
hle
ssth
anon
e-ei
ghth
inth
epl
aceb
ogr
oup
(p<
0.00
1).
Dec
reas
edre
quir
emen
tfo
ren
emas
and
supp
osit
orie
s(s
tati
stic
ally
sign
ifica
nt)
No
adve
rse
effe
cts
obse
rved
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 953
Tabl
e5.
Con
tinu
ed
Pati
ent
Out
com
es
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
NM
ean
Age
Wom
enD
urat
ion
Out
com
eM
easu
reR
esul
tsS
afet
yA
naly
sis
272
Lac
tulo
se20
ml
b.i.d
.or
Dor
bane
x(m
ixtu
reof
polo
xalk
olan
ddi
hydr
o-an
thro
quin
olon
e)(P
D)—
10m
l/da
y,or
enem
aif
noB
Min
5da
ys(c
ontr
olgr
oup)
Ope
n,ra
ndom
ized
,co
ntro
lled
35of
37lo
ng-s
tay
elde
rly
pati
ents
8130
F7
M27
days
Impr
ovem
enti
ntr
ansi
ttim
esby
Hin
ton
met
hod
The
rew
ere
stat
isti
cally
sign
ifica
ntim
prov
emen
tsin
the
tran
sitt
imes
inth
ela
ctul
ose
and
PD
grou
psbo
thw
ithi
nth
egr
oup
com
pare
dw
ith
base
line
,and
whe
nco
mpa
red
wit
hth
eco
ntro
lgro
up
No
sign
ifica
ntad
vers
eef
fect
sno
ted
342
Sod
ium
pico
sulf
ate
(SP
—10
mg/
day)
orD
orba
nex
(mix
ture
ofpo
loxa
lkol
and
dihy
dro-
anth
roqu
inol
one
(PD
—10
ml/
day)
Ope
n,ra
ndom
ized
,cr
osso
ver
38of
40lo
ng-s
tay
pati
ents
75.6
31F
7M
2-w
kru
nin
foll
owed
bytw
o2-
wk
trea
tmen
tpe
riod
sw
ith
a3-
day
was
hout
inbe
twee
n
Sto
olfr
eque
ncy,
size
,sid
eef
fect
sT
heav
erag
enu
mbe
rof
BM
per
day
incr
ease
dfr
om0.
56in
the
pret
rial
peri
od,
to0.
96fo
rS
Pan
d0.
86fo
rP
DB
oth
SP
and
PD
resu
lted
inno
rmal
izat
ion
inst
ools
ize
inth
em
ajor
ity
ofpa
tien
ts
Hig
hin
cide
nce
ofin
cont
inen
cein
the
grou
pth
atre
ceiv
edS
Pas
thei
rfi
rst
trea
tmen
t.O
ther
effe
cts
wer
em
inim
al
954 Ramkumar and Rao
Table 6. Methodologic Scores of the Studies Evaluating the Stimu-lant and Irritative Laxatives
Statement onReference Randomization Blinding Withdrawals Total Score
22 1 0 1 224 2 2 1 525 1 2 0 330 1 0 1 231 1 0 1 232 1 2 1 429 1 0 1 227 1 0 1 233 1 2 0 334 1 0 1 2
A score of 1 or 2 were given for randomization (2 for appropriate randomizationtechnique and concealed allocation explicitly stated or described, 1 for studysimply described as “randomized”). Scores of 0–2 were given for blinding (2when both subjects and investigators were blinded to the treatment by use ofidentical placebo or other technique, 1 when the study is described as “double-blind,” and 0 when the study was not double-blind). Score o f 0 or 1 was givenfor frequency of withdrawals (1 when the number of withdrawals and reason forwithdrawals were stated, and 0 when no statement was made pertaining to withdrawals).
psyllium alone. However, the combination appeared to causemore side effects. A study evaluating the efficacy of psylliumcompared with docusate revealed that psyllium was superiorin its effect on stool frequency, stool water content, total stooloutput, and the combination of several objective measuresof constipation (45). The combination of psyllium, celandin,and aloe vera was superior to placebo in the treatment of con-stipation (47). Three studies that compared a combination ofpsyllium and senna with lactulose are discussed in the sec-tion on lactulose and stimulant/irritant laxatives (22, 24, 25).The comparison of two preparations of psyllium and senna,one with a higher dose of senna, revealed that the preparationwith the higher senna dose increased stool frequency morethan the other (49). In elderly, bed-ridden, nursing home pa-tients, psyllium and calcium polycarbophil have been notedto be similar in their effect in improvement in stool frequency,stool consistency, and ease of defecation (50). Psyllium andmethylcellulose were similarly effective in constipated sub-jects in another study (36).
Level II Evidence, Grade B Recommendation.
The Efficacy and Safety of Calcium Polycarbophil in theTreatment of ConstipationApart from the study mentioned in the discussion of psyllium,no other trials were found in the English literature evaluatingthis drug. Additional clinical trials are required to furtherevaluate the utility of this agent.
Level III Evidence, Grade C Recommendation.
Efficacy and Safety of Cisapride in the Treatmentof ConstipationThree randomized studies are presented (51–53). These aresummarized in Tables 9 and 10. Two of these studies includedplacebo (51, 53); in the third (52) study, comparative results
of efficacy were inferred from periods when study patientswere not receiving any therapy. The results demonstratingthe efficacy of cisapride in the treatment of idiopathic con-stipation were seen in a pilot study as well (54). Open trialshave evaluated the efficacy of cisapride in the constipationof Parkinson’s disease (55, 56); over the long-term, the effi-cacy may wane (56). The drug may also be useful for treatingconstipation patients with spinal cord injury (57) and sys-temic sclerosis (58), although this remains to be validated ina controlled manner.
Though it appears that cisapride may be a useful agentin the treatment of idiopathic constipation, it is no longermarketed in the United States.
Cisapride: No Recommendation.
Efficacy and Safety of Colchicine in the Treatmentof ConstipationNo randomized studies in otherwise healthy patients with id-iopathic constipation have been reported, apart from a singlestudy that is in abstract only. One randomized trial performedon developmentally disabled patients is presented (59). Thisis summarized in Tables 11 and 12. In an open-labeled trialin seven patients with chronic constipation, the mean num-ber of spontaneous bowel movements significantly increased(p < 0.05) from 1.7 ± 0.5 noted during routine therapy ofconstipation with laxatives and enemas to 6.4 ± 0.7 per week;mean colonic transit time significantly (p < 0.05) decreasedfrom 58.1 ± 2.5 to 47.1 ± 5.0 h; and symptoms of abdominalpain, nausea, and bloating significantly (p < 0.05) improvedduring therapy with colchicine (60). This pilot study wasfollowed by a double-blind, placebo-controlled, randomized,crossover study in 16 chronically constipated subjects. Asalluded to above, this has been published in abstract formonly to date (61). Colchicine 0.6 mg t.i.d. was the dose andschedule utilized in a 4-wk treatment interval. Colchicine re-sulted in reduced transit time and increased number of bowelmovements per week (9.9 vs 3.8) compared with placebo.A significant placebo effect was noted. No significant sideeffects were observed. Observations in patients with Parkin-son’s disease (62) and persistent constipation after total ab-dominal colectomy with ileorectostomy for colonic inertia(63) suggest that colchicine may be useful in these settings aswell.
The utility of colchicine in the treatment of chronic idio-pathic constipation remains to be confirmed.
Colchicine: Level III Evidence, Grade CRecommendation.
Effectiveness and Safety of Misoprostol in the Treatmentof ConstipationOnly one suitable randomized trial was found (64). The num-ber of patients was small (n = 8). The qualitative assessmentof this study and the extracted data are presented in Tables 13and 14.
Efficacy and Safety of Traditional Medical Therapies 955
Tabl
e7.
Sum
mar
yof
the
Tri
als
Eva
luat
ing
the
Effi
cacy
and
Saf
ety
ofth
eB
ulk
Lax
ativ
es
Pati
ent
Out
com
esM
ean
Age
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
371
10g
fibe
rfr
omco
rn-b
ased
bisc
uits
(gp
A),
whe
atbr
an(g
pB
),or
noin
terv
enti
on(g
pC
)
Ran
dom
ized
open
inpa
tien
tsin
the
thir
dtr
imes
ter
ofpr
egna
ncy
4028
2-w
kba
seli
nefo
llow
edby
2-w
ktr
eatm
ent
SF,
SC
,pre
senc
eof
pain
,str
aini
ng,
and
bloo
d
Mea
nda
ilydi
etar
yfi
bre
inta
kein
allg
roup
s,in
the
firs
t2w
k20
.4g
was
sim
ilar
toth
atin
the
gene
ral
popu
lati
on.
The
rew
asa
tend
ency
for
the
fibe
rsu
pple
men
ted
grou
psto
expe
rien
cele
sspa
inan
dst
rain
ing,
but
this
did
nota
chie
vest
atis
tica
lsi
gnifi
canc
e
Inth
efi
nal2
-wk
chan
ges
infi
ber
inta
kes
wer
eG
pA
,m
ean
incr
ease
7.2
g/da
y(p
<0.
001)
;Gp
B,m
ean
incr
ease
9.1
g/da
y(p
<0.
001)
;Gp
Cm
ean
decr
ease
3.50
g/da
y(p
<0.
005)
.S
tool
freq
uenc
yim
prov
edin
Gps
Aan
dB
wit
hno
chan
ges
inG
pC
.S
tool
freq
uenc
yan
dco
nsis
tenc
yim
prov
edin
Gps
Aan
dB
,wit
hno
chan
ges
inG
pC
.38
4B
ran
6.6
gt.i
.d.
orpl
aceb
oR
ando
miz
ed,
doub
le-b
lind
,pl
aceb
o-co
ntro
lled
,cr
osso
ver
24of
2937
(20–
65)
26/3
3w
eek
base
line
,th
entw
oco
nsec
utiv
e4-
wk
trea
tmen
tpe
riod
s
Seg
men
talt
rans
itti
mes
,SF,
stoo
lw
eigh
t,an
dot
her
sym
ptom
s
SF
for
plac
ebo
was
1.2
±1.
3pe
rw
kvs
3.5
±1.
8fo
rbr
an(p
<0.
01)
No
sign
ifica
ntad
vers
eef
fect
s
The
rew
asno
diff
eren
cein
stoo
lwei
ght
Dur
ing
bran
trea
tmen
tor
oana
ltra
nsit
tim
eno
rmal
ized
only
inpa
tien
tsw
ith
slow
colo
nic
tran
sita
ndno
tin
thos
ew
ith
slow
rect
altr
ansi
t
956 Ramkumar and Rao
The
occu
rren
cean
dse
veri
tyof
the
mos
tfr
eque
ntac
com
pany
ing
sym
ptom
sof
chro
nic
cons
tipa
tion
did
not
diff
erw
ith
plac
ebo
and
bran
trea
tmen
ts39
110
gb.
i.d.o
fco
rnbr
anor
whe
atbr
an
Ope
n,ra
ndom
ized
,co
ntro
lled
1026
.310
/01-
wk
adju
stm
ent,
2-w
kco
ntro
l,an
d2-
wk
trea
tmen
tpe
riod
Feca
lwei
ght,
feca
lm
oist
ure
cont
ent,
SF,
inte
stin
altr
ansi
ttim
e,an
dsy
mpt
oms
The
adm
inis
trat
ion
ofbo
thbr
anpr
oduc
tsw
asas
soci
ated
wit
han
incr
ease
infe
cal
wei
ght(
157%
,p
<0.
05),
and
whe
reas
Non
ere
port
ed
Bra
nin
crea
sed
SF
(2.3
±0.
3to
3.5
±0.
5B
M/w
k;55
%,
p<
0.05
)B
ran
decr
ease
din
test
inal
tran
sitt
ime
(50%
)Pe
rcen
tage
feca
lm
oist
ure
incr
ease
don
lyw
ith
whe
atbr
an(6
7.4–
72.1
%)
Cor
nbr
anw
assi
gnifi
cant
lybe
tter
than
whe
atbr
anin
reli
evin
gsy
mpt
oms
ofco
nsti
pati
on(p
<0.
05)
492
Agi
olax
and
Lun
elax
Ope
n,ra
ndom
ized
,co
ntro
lled
,cr
osso
ver
19of
2083
16/4
1-w
kru
n-in
foll
owed
bytw
oco
nsec
utiv
etr
eatm
ent
peri
ods
SF,
SE
,tas
teof
the
prep
arat
ion,
use
ofen
emas
The
SF
tend
edto
behi
gher
wit
hL
unel
ax(w
hich
cont
ains
ahi
gher
dose
ofse
nna)
than
wit
hA
giol
ax
No
side
effe
cts
seen
The
rew
ere
nodi
ffer
ence
inth
e“e
ase
ofsw
allo
win
g”T
here
wer
eno
diff
eren
cein
“eas
eof
adm
inis
trat
ion”
and
The
rew
ere
nodi
ffer
ence
sin
“tas
te”
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 957
Tabl
e7.
Con
tinu
ed
Pati
ent
Out
com
esM
ean
Age
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
401
10g
unre
fine
dbr
an,1
0g
ofbr
anas
bran
bisc
uits
or10
mlo
fse
noko
t
Ope
n,ra
ndom
ized
23ps
ycho
-ge
riat
ric
pati
ents
50.3
15/8
Eac
hre
ceiv
edth
eth
ree
agen
tsin
thre
eco
nsec
utiv
epe
riod
sof
3w
k,th
ese
quen
cera
ndom
lyde
term
ined
SF,
SC
,siz
eof
bow
elm
ovem
ents
,use
ofen
emas
The
rew
asno
sign
ifica
ntdi
ffer
ence
SF.
The
rew
asno
sign
ifica
ntdi
ffer
ence
inus
eof
enem
as.
The
rew
asno
sign
ifica
ntdi
ffer
ence
inth
eco
nsis
tenc
yof
the
mot
ions
.T
here
was
litt
ledi
ffer
ence
inth
epr
opor
tion
of“l
arge
”st
ools
inth
eth
ree
trea
tmen
tper
iods
,but
asi
gnifi
cant
lyhi
gher
prop
orti
onof
smal
ler
stoo
lsw
ere
repo
rted
wit
hbr
an.
Non
em
enti
oned
483
Ispa
ghul
a(p
syll
ium
)3.
6g
t.i.d
.or
plac
ebo
Mul
tice
nter
,ra
ndom
ized
,pl
aceb
o-co
ntro
lled
,si
ngle
-bli
nd,
para
llel
201
4915
1/50
14da
ysS
F,S
C,a
bdom
inal
disc
omfo
rt,#
ofsa
chet
sta
ken
SF
—sh
owed
stat
isti
cally
sign
ifica
ntin
crea
ses
from
2.3
per
wee
kba
seli
ne,t
o7
per
wee
kw
ith
ispa
ghul
aan
d4.
5pe
rw
eek
for
plac
ebo.
No
sign
ifica
ntad
vers
eef
fect
s
SC
—th
enu
mbe
rof
hard
-or
pell
et-l
ike
stoo
lsw
ere
also
sign
ifica
ntly
low
er,
and
loos
eor
wat
ery
stoo
lsin
crea
sed
inth
eis
pagh
ula
grou
pS
tati
stic
ally
sign
ifica
ntde
crea
ses
inab
dom
inal
disc
omfo
rt,
and
stra
inin
gin
the
isph
agul
agr
oup
Bot
hin
vest
igat
ors
and
pati
ents
note
dst
atis
tica
llysi
gnifi
cant
impr
ovem
enti
nth
eco
nsti
pati
on
958 Ramkumar and Rao
422
Whe
atbr
an1.
5–4.
5g
qdor
regu
lar
diet
Ope
n,ra
ndom
ized
,pa
rall
el
12of
14lo
ng-s
tay
geri
atri
cpa
tien
ts
8014
/06
wk,
then
plac
ebo
grou
pw
ere
trea
ted
wit
hbr
anas
wel
l
SF,
stoo
lsiz
e,S
C,
EO
D,U
OL
SF
—th
enu
mbe
rof
spon
tane
ousl
ypa
ssed
BM
sin
the
bran
grou
pw
asst
atis
tica
llysi
gnifi
cant
com
pare
dto
the
plac
ebo
grou
p
One
pati
ent
repo
rted
diffi
cult
ysw
allo
win
gbr
an
All
pati
ents
inth
ebr
angr
oup,
and
the
pati
ents
inth
epl
aceb
ogr
oup
foll
owin
gco
mm
ence
men
tof
bran
supp
lem
enta
tion
show
edim
prov
emen
tin
the
quan
tity
and
cons
iste
ncy
ofst
ools
pass
ed41
1B
ran
(0.5
–1.5
g)or
regu
lar
diet
Ope
n,ra
ndom
ized
,co
ntro
lled
37of
50>
60yr
—ex
tend
edca
reho
spit
al
—13
wk
Req
uire
men
tfor
laxa
tive
use
The
rew
asan
over
all
decr
ease
inla
xativ
eus
ein
the
bran
grou
p.H
owev
er,t
here
was
also
anin
crea
sein
the
use
ofen
emas
and
supp
osit
orie
s
No
sign
ifica
ntad
vers
eef
fect
s
353
Hig
hfi
ber
(22.
9g
daily
)di
etor
regu
lar
diet
Ope
n,ra
ndom
ized
,co
ntro
lled
35of
49pa
tien
tsun
derg
oing
radi
calh
ys-
tere
ctom
y17
cont
rol
(C)
18tr
eatm
ent
(T)
3549
/07
mon
ths
SF,
SC
,EO
Dga
s,cr
ampi
ngS
F—
Tgr
oup
had
asi
gnifi
cant
incr
ease
inth
efr
eque
ncy
ofB
M(p
=0.
0096
);th
isw
asno
tsee
nin
the
Cgr
oup.
The
Tgr
oup
took
less
tim
eto
defe
cate
(p<
0.00
1)bu
thad
mor
eB
Ms
acco
mpa
nied
byga
s(p
<0.
001)
.T
heC
grou
pha
dsi
gnifi
cant
lym
ore
BM
wit
hcr
amps
(p<
0.00
1),s
trai
ning
(p<
0.00
1),a
ndre
tent
ion
(p<
0.00
1)
No
sign
ifica
ntad
vers
eef
fect
s
SC
—th
eC
grou
pha
dsi
gnifi
cant
lym
ore
BM
s,w
hich
wer
eha
rd(p
<0.
001)
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 959Ta
ble
7.C
onti
nued
Pati
ent
Out
com
esM
ean
Age
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
462
Ispa
ghul
a(I
S)
(psy
lliu
m)
3.5
g,or
anot
her
laxa
tive
(lac
tulo
se,
bisa
cody
l,do
cusa
te,
senn
a,an
dm
agne
sium
sulf
ate)
Ope
n,m
ulti
cent
er,
rand
omiz
ed,
cont
roll
ed
381
of39
422
4(5
6.9%
)is
pagh
ula
170
(43.
1%)
othe
rla
xativ
e
30–5
925
0/13
94
wk
SF
/SC
ofso
ilin
g,ac
cept
abil
ity,
pala
tabi
lity
,tr
eatm
ent-
rela
ted
upse
ts
ISw
asas
sess
edby
the
GP
sto
besu
peri
orto
the
othe
rtr
eatm
ents
inim
prov
ing
bow
elfu
ncti
onan
din
over
all
effe
ctiv
enes
s.IS
was
mor
epa
lata
ble
and
acce
ptab
leto
pati
ents
.IS
prod
uced
ahi
gher
perc
enta
geof
norm
al,
wel
l-fo
rmed
stoo
lsan
dfe
wer
hard
stoo
lsth
anot
her
laxa
tives
.In
cide
nces
ofso
ilin
g,di
arrh
ea,a
ndab
dom
inal
pain
wer
elo
wer
inth
eIS
grou
p.
No
sign
ifica
ntad
vers
eef
fect
s
433
Psy
lliu
m24
g/da
yor
plac
ebo
Sin
gle-
blin
d,ra
ndom
ized
,pl
aceb
o-co
ntro
lled
fibe
rin
terv
enti
onw
ith
cros
sove
r
10>
605/
54
wk
inea
char
mS
F,S
C,a
ndw
eigh
tsda
ilyFi
ber
decr
ease
dto
talg
uttr
ansi
ttim
efr
om53
.9h
(pla
cebo
cond
itio
n)to
30.0
h(p
<.0
5).
Sto
olw
eigh
tsan
dco
nsis
tenc
yw
ere
not
sign
ifica
ntly
impr
oved
byfi
ber.
No
sign
ifica
ntad
vers
eef
fect
s
The
rew
asa
tren
dto
war
dan
incr
ease
inS
F(1
.3vs
0.8B
M/d
ay)
inth
efi
ber
grou
p44
4P
syll
ium
(10
g/da
y)an
dpl
aceb
o
Dou
ble-
blin
d,pl
aceb
o-co
ntro
lled
2251
14/8
8w
kw
ith
4-w
kru
n-in
onpl
aceb
oan
d4
wk
was
hout
SF,
SC
,EO
Dan
dw
eekl
yst
ool
wei
ght.
Col
ontr
ansi
tand
AR
M
SF
incr
ease
dsi
gnifi
cant
lyaf
ter
8w
kof
psyl
lium
trea
tmen
t(3.
8vs
2.9
BM
/wk,
p<
0.05
)
No
sign
ifica
ntad
vers
eef
fect
s
Sub
ject
sre
port
edim
prov
emen
tin
SC
(sto
olco
nsis
tenc
ysc
ore:
3.2
±0.
2vs
3.8
±0.
2,p
<0.
05)
onps
ylli
umE
OD
impr
oved
onps
ylli
um(p
ain
scor
e:2.
0±
0.4
vs2.
6±
0.5,
p<
0.05
)C
olon
tran
sita
ndA
RM
unch
ange
d
960 Ramkumar and Rao
302
Psy
lliu
m(P
)7.
2g/
day
and
psyl
lium
wit
hse
nna
(PS
)(6
.5+
1.5
g/da
y)
Ope
n,ra
ndom
ized
,si
ngle
-bli
ndco
ntro
lled
40of
4226
.135
F5
M1-
wk
plac
ebo
and
1-w
ktr
eatm
ent
SF,
SC
,sym
ptom
sw
ith
BM
sB
oth
laxa
tives
incr
ease
dS
F[P
3.6
vsP
S6.
8B
M/w
k(p
<0.
001)
]
Pgr
oup
3/22
cram
ping
and
gas
PS
grou
p7/
22ha
dcr
amps
,un-
com
fort
able
diar
rhea
,bl
oati
ngga
s,an
dna
usea
Bot
hla
xativ
esim
prov
edS
C(s
imil
ar)
Bot
hP
and
PS
incr
ease
dw
etan
ddr
yst
ool
wei
ghts
wit
hth
ead
ded
effe
ctof
the
senn
acl
earl
yev
iden
t.O
nly
the
psyl
lium
wit
hse
nna
incr
ease
dst
oolm
oist
ure
Bot
hla
xativ
espr
ovid
eda
high
degr
eeof
subj
ectiv
ere
lief
455
Psy
lliu
m5.
1g
b.i.d
.and
docu
sate
100
mg
b.i.d
.
Mul
tice
nter
,ra
ndom
ized
,do
uble
-bli
nd,
para
llel
desi
gn
170
of18
737
.215
6/14
1-w
kw
asho
utfo
llow
edby
1-w
kba
seli
ne(p
lace
bo)
foll
owed
by2-
wk
trea
tmen
t
Sto
olw
ater
cont
ent
(SW
C),
stoo
lw
ater
wei
ght
(SW
W),
tota
lst
oolo
utpu
t,S
F
Com
pare
dto
base
line
,ps
ylli
umin
crea
sed
SW
Cvs
docu
sate
(psy
lliu
m2.
33%
vsdo
cusa
te0.
01%
,p
=0.
007
and)
Non
est
ated
Psy
lliu
mal
soin
crea
sed
SW
W(8
4.0
g/B
M)
vsdo
cusa
te(7
1.4
g/B
M);
p=
0.04
Tota
lsto
olou
tput
high
erw
ith
psyl
lium
(359
.9g/
wk)
vsdo
cusa
te(2
71.9
g/w
k);p
=0.
005
Psy
lliu
mha
da
high
erO
’Bri
enra
nk-t
ype
scor
eco
mbi
ning
obje
ctiv
em
easu
res
ofco
nsti
pati
on(p
syll
ium
475.
1;do
cusa
te40
3.9;
p=
0.00
2)S
Fw
assi
gnifi
cant
lygr
eate
rfo
rps
ylli
um(3
.5B
M/w
k)vs
docu
sate
(2.9
BM
/wk)
intr
eatm
entw
eek
2(p
=0.
02)
(con
tinu
ed)
Efficacy and Safety of Traditional Medical Therapies 961Ta
ble
7.C
onti
nued
Pati
ent
Out
com
esM
ean
Age
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
N(y
ear)
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
473
Psy
lliu
m,
cela
ndin
,and
aloe
vera
com
bina
tion
(CA
P)
1–3
caps
ules
per
day
orpl
aceb
o
Dou
ble-
blin
dra
ndom
ized
,pl
aceb
o-co
ntro
lled
32of
3551
.522
/10
28da
ysto
-2w
kpr
etri
alba
seli
ne
SF,
SC
,and
othe
rsy
mpt
oms
Inth
e(C
AP
)gr
oup,
bow
elm
ovem
ents
beca
me
mor
efr
eque
nt(4
.6vs
7.9
BM
/wk)
.(p
<0.
002)
No
side
effe
cts
dete
cted
∗
SC
—st
ools
soft
erin
CA
Pgr
oup
com
pare
dw
ith
plac
ebo.
(p<
0.00
2)L
ess
laxa
tive
depe
nden
cein
CA
Pgr
oup
(p<
0.01
)A
bdom
inal
pain
was
not
redu
ced
inei
ther
grou
p50
1C
alci
umpo
lyca
rbop
hil
(C)
2ta
bs/d
ayor
psyl
lium
(P)
two
teas
poon
s/da
y
Ope
n,ra
ndom
ized
cont
roll
ed,
cros
sove
r
32be
d-ri
dden
nurs
ing
hom
ere
side
nts
77±
10.4
26/6
Two
cons
ecut
ive
3-w
ktr
eatm
ent
peri
ods
SF,
SC
,EO
DT
here
wer
eno
stat
isti
cally
sign
ifica
ntch
ange
sin
SF
(for
C7.
2±
2.4
vsfo
rP
7.22
±2.
2)
Non
em
enti
oned
No
diff
eren
cein
EO
DN
odi
ffer
ence
inS
CM
ore
pati
ents
seem
edto
favo
rC
362
1,2,
or4
gof
met
hylc
ellu
-lo
se(M
)or
3.4
gmof
psyl
lium
(P)
Two
phas
e50
heal
thy
subj
ects
,59
chro
nica
llyco
nsti
pate
d
27(1
8–70
)28
(18–
70)
56/3
1-w
kru
n-in
(tak
ing
plac
ebo)
,the
n10
-day
trea
tmen
tpe
riod
wit
hon
eof
the
regi
men
sde
scri
bed
SF,
stoo
lwei
ght,
stoo
lwat
eran
dso
lids
.Adv
erse
even
ts
Hea
lthy
subj
ects
:m
ethy
lcel
lulo
sein
daily
dose
sof
4g
dem
onst
rate
da
stat
isti
cally
sign
ifica
ntin
crea
sein
feca
lfr
eque
ncy,
feca
lwat
er,
and
feca
lsol
ids
No
diff
eren
cein
the
inci
denc
eof
abdo
min
alcr
amps
,fl
atul
ence
,or
abdo
min
alpa
inbe
twee
nth
etr
eatm
ent
and
plac
ebo
peri
ods
Chr
onic
ally
cons
tipa
ted
indi
vidu
als—
alld
oses
ofM
and
Pst
atis
tica
llysi
gnifi
cant
incr
ease
sin
SF
Chr
onic
ally
cons
tipa
ted
indi
vidu
als—
alld
oses
ofM
and
Pst
atis
tica
llysi
gnifi
cant
incr
ease
dw
ater
cont
ent,
and
feca
lso
lids
The
rew
asno
incr
ease
inin
divi
dual
stoo
lwei
ght
from
any
ofth
ela
xativ
edo
ses
∗Bec
ause
this
stud
yis
doub
le-b
lind
and
plac
ebo-
cont
roll
ed,t
heto
tals
core
here
ishi
ghly
base
don
the
crit
eria
seto
ut;t
hest
udy
desc
ript
ion
reve
als
very
litt
lein
form
atio
n,an
das
such
the
over
allq
uali
tyis
nota
sgo
odas
the
scor
esu
gges
ts.
962 Ramkumar and Rao
Table 8. Methodologic Scores of the Studies Evaluating the BulkLaxatives
Statement onReference Randomization Blinding Withdrawals Total Score
38 1 2 1 437 1 0 0 139 1 0 0 149 1 0 1 240 1 0 0 148 1 1 1 342 1 0 1 241 1 0 0 135 2 0 1 346 1 0 1 230 1 0 1 244 1 2 1 445 2 2 1 543 1 1 1 347 1 2 1 450 1 0 0 136 1 1 0 2
A score of 1 or 2 was given for randomization (2 for appropriate randomizationtechnique and concealed allocation explicitly stated or described, 1 for studysimply described as “randomized”). Scores of 0–2 were given for blinding (2when both subjects and investigators were blinded to the treatment by use ofidentical placebo or other technique, 1 when the study is described as “double-blind,” and 0 when the study was not double-blind). Score o f 0 or 1 was givenfor frequency of withdrawals (1 when the number of withdrawals and reasonfor withdrawals were stated, and 0 when no statement was made pertaining towithdrawals).
Misoprostol: Level III Evidence, Grade C Recommen-dation.
Efficacy and Safety of Stool Softeners in the Treatment ofConstipationDocusate sodium and docusate calcium are the major drugs inthis category. Poloxalkol is another stool softener; no studieswere found in which this agent was used by itself in a treat-ment arm. The studies reviewed are summarized in Tables15 and 16. Three studies where it is combined with a stim-ulant/irritant laxative are summarized in the section dealingwith this latter class of drugs. Four studies are presented thatevaluate the utility of docusate in the treatment of consti-pation (45, 65–67). One of these compares it with psyllium(45). Psyllium appears to be superior to docusate sodium inthe doses utilized. The other studies either compare docusatesodium and docusate calcium or these drugs versus placebo.One study suggests that docusate calcium may be more effec-tive than docusate sodium (65). The efficacy of docusate inthe treatment of constipation is modest at best, with one study,albeit small, suggesting no significant benefit compared withplacebo (66). There are studies that have evaluated docusateprior to 1966, and these have been included in previous re-views (68).
Docusate: Level III Evidence, Grade CRecommendation.
Efficacy and Safety of Other Agents on the Treatmentof ConstipationA recent randomized, double-blind placebo-controlled trialevaluated the efficacy of tegaserod in the management ofchronic constipation (69). This drug is a selective agonist ofthe serotonin subtype 4 (5-HT4). It has been shown to enhancegastrointestinal motility in animals and healthy volunteers,and it has also been shown to be effective for symptom re-lief in patients with constipation predominant irritable bowelsyndrome. This was a large well-designed trial with a qual-ity score of 5. The doses used were tegaserod 2 mg b.i.d.,tegaserod 6 mg b.i.d., or placebo. A total of 1,116 patientscompleted the treatment phase of the trial. The mean age was47 yr and 90% of the subjects were women. Treatment du-ration was 12 wk. Responders were patients treated for ≥7days with an increase of ≥1 complete spontaneous BM perweek versus baseline during weeks 1–4 (primary variable)and weeks 1–12 (secondary variable). Other secondary vari-ables included SF, stool form, abdominal bloating/distention,straining, and abdominal pain/discomfort, and global assess-ment of constipation and bowel habits. Responder rates forcomplete spontaneous bowel movement during weeks 1–4were significantly greater (p < 0.0001) in the tegaserod 2mg twice daily (41.4%) and 6 mg twice daily groups (43.2%)versus placebo (25.1%). This effect was maintained over 12wk. Statistically significant improvements over placebo wereobserved across the majority of secondary variables for bothtegaserod doses. No rebound effect was observed after treat-ment withdrawal. As such, there appears to be clear, statisti-cally significant benefit of the two doses used versus placebo,with no clear benefit of the higher dose compared with thelower dose. Overall, tegaserod was well tolerated; headacheand nasopharyngitis, the most frequent adverse events, weremore common in the placebo group than in either tegaserodgroup.
Tegaserod: Level I Evidence, Grade A Recommen-dation.
A pilot study was undertaken to evaluate the efficacy oforal erythromycin in the treatment of idiopathic constipation(70). Eleven male patients were treated for 1 month with ery-thromycin (1 g/day for 2 wk then 500 mg/day for 2 wk) in anopen, nonrandomized trial. Colon transit time improved asdid stool frequency (2.3–6.7 per week). Two of the patientscomplained of borborygmi, otherwise there were no signif-icant side effects. These results suggest that erythromycinwarrants trial in a controlled manner to see if this dramaticimprovement could be reproduced.
Loxiglumide, a cholecystokinin antagonist, was evaluatedfor its efficacy in a prospective, randomized, double-blindcontrolled trial (71) in 21 nursing home patients with a meanage of 83 yr. There were 13 male and 8 female patients.They were randomized to receive loxiglumide 800 mg t.i.d.or identical placebo.
Efficacy and Safety of Traditional Medical Therapies 963Ta
ble
9.S
umm
ary
ofth
eS
tudi
esE
valu
atin
gth
eE
ffica
cyan
dS
afet
yof
Cis
apri
dein
the
Tre
atm
ento
fC
onst
ipat
ion
Pati
ent
Out
com
es
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
NM
ean
Age
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
515
Cis
apri
de20
mg
b.i.d
.or
plac
ebo
Ran
dom
ized
,do
uble
-bli
nd,
plac
ebo-
cont
roll
ed
126
(64
cisa
prid
e,62 pl
aceb
o)
50.5
75/5
14-
wk
base
line
phas
e,8-
wk
trea
tmen
tph
ase
and
4-w
kru
nou
t(p
lace
bo)
phas
e
SF,
SC
,EO
D,U
OL
,an
dov
eral
lsta
tew
ith
resp
ectt
oco
nsti
pati
on(v
isua
lana
log
scal
e)
Cis
apri
dean
dpl
aceb
oin
crea
sed
spon
tane
ous
SF
from
1.1
to3.
0B
M/w
k(p
≤0.
001)
and
from
1.2
to1.
5B
M/w
k(p
>0.
05),
resp
ectiv
ely
No
data
Lax
ativ
eco
nsum
ptio
nw
asde
crea
sed
from
3.6
to1.
8do
ses
per
wee
kby
cisa
prid
e(p
≤0.
001)
and
from
3.3
to2.
8by
plac
ebo
(p<
0.05
).B
oth
drug
sim
prov
edco
nsti
pati
onas
asse
ssed
byth
epa
tien
tby
mea
nsof
avi
sual
anal
ogsc
ale,
but
cisa
prid
edi
dso
toa
larg
erex
tent
than
plac
ebo
525
Dif
fere
ntdo
ses
ofci
sapr
ide
orno
trea
tmen
t
Ran
dom
ized
,do
uble
-bli
nd.
Two
grou
ps:
Aan
dB
119
Gp
A—
12w
kof
cisa
prid
e20
mg/
day,
then
12w
kof
free
dom
tota
keup
to20
mg/
day
in5
mg
incr
emen
ts.
Gp
B—
20m
g/da
yfo
r6
wk,
then
10m
g/da
yfo
r6
wk,
then
notr
eatm
entf
or12
wk
SF
and
UO
LS
Fw
asin
crea
sed
inbo
thgr
oups
duri
ngac
tive
trea
tmen
tand
was
not
redu
ced
whe
nth
edo
sew
asde
crea
sed
from
20to
10m
gtw
ice
daily
ingr
oup
Bbu
twas
mai
ntai
ned
ingr
oup
AL
axat
ive
inta
kefe
llby
50%
inbo
thgr
oups
,bu
tthi
sef
fect
was
mai
ntai
ned
duri
ngfo
llow
-up
ingr
oup
Aon
lyG
roup
Apa
tien
tsto
okne
arly
the
max
imum
dosa
geof
cisa
prid
eta
blet
sal
low
eddu
ring
foll
ow-u
p(3
.3ta
blet
spe
rda
y±
0.2
SE
M)
No
data
964 Ramkumar and Rao
534
One
oftw
oci
sapr
ide
dose
s(5
or10
mg)
orpl
aceb
o
Ran
dom
ized
,do
uble
-bli
nd,
para
llel
grou
pde
sign
46of
48M
edia
nof
50yr
34F
12M
Thr
ee phas
es—
3-w
kba
seli
ne,
foll
owed
by12
-wk
doub
le-b
lind
peri
od,a
nd4-
wk
foll
ow-u
p
SF,
SC
,EO
D,U
OL
,S
EB
oth
cisa
prid
e5
and
10m
gin
crea
sed
stoo
lfr
eque
ncy
byab
out
70%
from
base
line
afte
r8–
12w
k(p
<0.
002)
,but
plac
ebo
also
incr
ease
dS
Fby
43%
(p<
0.07
).T
hedi
ffer
ence
betw
een
the
trea
tmen
tgro
ups
did
notm
eets
tati
stic
alsi
gnifi
canc
e
Pati
ents
inth
eci
sapr
ide
repo
rted
abdo
min
alcr
amps
(4),
dysp
epsi
a,ga
stri
cpr
oble
ms,
epig
astr
icpa
in,
flat
ulen
cedi
arrh
ea,a
nddi
zzin
ess
(1ea
ch)
Cis
apri
dede
crea
sed
SC
and
resu
lted
ingr
eate
rE
OD
com
pare
dw
ith
plac
ebo,
both
ina
stat
isti
cally
sign
ifica
ntm
anne
r(p
<0.
002
and
p<
0.00
2,re
spec
tivel
y)C
isap
ride
ther
apy
decr
ease
dla
xativ
eco
nsum
ptio
n,w
hile
the
plac
ebo
grou
pdi
dno
tR
elap
seaf
ter
wit
hdra
wal
ofth
erap
yoc
curr
edsl
owly
.No
sign
ifica
ntdi
ffer
ence
was
foun
dbe
twee
nth
etw
odi
ffer
entd
oses
ofci
sapr
ide
Efficacy and Safety of Traditional Medical Therapies 965
Table 10. Methodologic Scores of the Trials Evaluating Cisapride
Statement onReference Randomization Blinding Withdrawals Total Score
51 2 2 1 552 2 2 1 553 1 2 1 4
A score of 1 or 2 was given for randomization (2 for appropriate randomizationtechnique and concealed allocation explicitly stated or described, 1 for studysimply described as “randomized”). Scores of 0–2 were given for blinding (2when both subjects and investigators were blinded to the treatment by use ofidentical placebo or other technique, 1 when the study is described as “double-blind,” and 0 when the study was not double-blind). Score o f 0 or 1 was givenfor frequency of withdrawals (1 when the number of withdrawals and reasonfor withdrawals were stated, and 0 when no statement was made pertaining towithdrawals).
It was noted that stool frequency improved from 3.9 perweek in the placebo group to 4.8 per week in the treatmentgroup (p < 0.006). Colon transit time was also significantlyimproved. No serious side effects or exocrine pancreatic in-sufficiency was encountered. These results suggest a largertrial involving more patients is indicated to further define therole of this agent in the treatment of constipation, and such atrial is ongoing.
No studies were found in the English literature that sup-ported the use of herbal remedies in the treatment of con-stipation, although there may be studies in the Chinese andJapanese literature.
DISCUSSION
The tables summarize individual studies where subjects wererandomized to receive either the active drug or placebo. A sur-prising observation was that apart from PEG and Tegaserod,there was paucity of placebo-controlled studies of high qual-ity. Without placebo-controlled trials, it is impossible to judgean agent’s efficacy. Also, in general, sample sizes were small.Consequently, two drugs, PEG and tegaserod, were accordeda Grade A recommendation and two drugs, lactulose and psyl-lium were given a Grade B recommendation. One of our keyobservations was that the definition of constipation was quitevaried among the various studies. While many of the studiesdefined constipation as the presence of less than 2 or 3 stoolsper week, and a few confirmed this in an observation periodprior to randomization, very few utilized criteria developedin consensus meetings, such as the Rome criteria. This pre-vented effective comparisons of trials that were otherwisesimilar. Similar difficulties were encountered when assessingoutcome measures for different trials. Stool frequency andmeasures of stool consistency were the most common param-eters that were assessed. Other measures that were reportedincluded ease of defecation use of additional laxatives, stoolweight, stool water content, and transit times. These problemsnotwithstanding, based on the results, the following recom-mendations can be made regarding the currently availableagents for the treatment of chronic constipation. Ta
ble
11.
Sum
mar
yof
the
Stu
dyE
valu
atin
gth
eE
ffica
cyan
dS
afet
yof
Col
chic
ine
inth
eT
reat
men
tof
Con
stip
atio
n
Pati
ent
Out
com
es
Stu
dyM
ean
Age
Out
com
eS
afet
yR
efer
ence
sS
core
Inte
rven
tion
Des
ign
N(y
ear)
F/M
Dur
atio
nM
easu
reR
esul
tsA
naly
sis
595
Col
chic
ine
(1.2
or1.
8m
g/da
y)or
plac
ebo
inde
velo
pmen
tally
disa
bled
pati
ents
Dou
ble-
blin
d,cr
osso
ver
11of
12co
mpl
eted
24–6
07/
54-
wk
base
line
,fo
llow
edby
two
8-w
ktr
eatm
ent
peri
ods
wit
ha
3-w
kw
ash-
outi
nbe
twee
n
SF,
and
need
for
addi
tion
alla
xativ
es
8of
11pa
tien
tsex
peri
ence
dan
impr
oved
bow
elpa
tter
nw
hile
onco
lchi
cine
com
pare
dw
ith
plac
ebo,
asde
fine
dby
anin
crea
sein
SF
ora
decr
ease
into
taln
umbe
rof
rect
alla
xativ
esus
ed.
7of
8pa
tien
tsw
hoha
dan
incr
ease
inS
Fre
quir
eda
decr
ease
inre
ctal
laxa
tive
use.
No
sign
ifica
ntcl
inic
alor
lab
com
plic
atio
nsw
ere
reco
gniz
ed
966 Ramkumar and Rao
Table 12. Methodologic Score of the Study Evaluating Colchicinein the Treatment of Constipation
Statement on TotalReference Randomization Blinding on Withdrawals Score
59 2 2 1 5
A score of 1 or 2 was given for randomization (2 for appropriate randomizationtechnique and concealed allocation explicitly stated or described, 1 for studysimply described as “randomized”). Scores of 0–2 were given for blinding (2when both subjects and investigators were blinded to the treatment by use ofidentical placebo or other technique, 1 when the study is described as “double-blind,” and 0 when the study was not double-blind). Score o f 0 or 1 was givenfor frequency of withdrawals (1 when the number of withdrawals and reason forwithdrawals were stated, and 0 when no statement was made pertaining to withdrawals).
Osmotic Laxatives(i) Lactulose (Kristalose)—three placebo-controlled trials
(19–21) with quality scores of 3, 4, 4. Evidence fair,Grade B recommendation.
(ii) PEG (Miralax)—five placebo-controlled trials (10, 12–15) (9, 11, 12, 13, 14) with quality scores of 5, 3, 5,5, 4; two lactulose-controlled trials (10, 15) with qualityscores of 5, 3. Evidence good, Grade A recommendation.PEG superior to lactulose.
Bulking Agents(i) Psyllium (Metamucil)—three placebo-controlled trials
(43, 44, 48) with quality scores of 3, ˙, 3; two lactulose-controlled trial (26, 46) with quality scores of 2, 2. Evi-dence fair, Grade B recommendation.
Table 13. Summary of the Study Evaluating the Efficacy and Safety of Misoprostol in the Treatment of Constipation
Patient Outcomes
Study Mean Age Outcome SafetyReferences Score Intervention Design N (year) F/M Duration Measure Results Analysis
64 4 Misoprostol(1,200µg/day) orplacebo
Randomized,double-blind,crossover
8 of 9 18 and older.Nototherwisequalified
9/0 Two 1-wktreatmentperiods(placebo ormisoprostol)separated by1-wkwashout
Colon transittime, SF,and stoolweight
Colonic transit timewas significantlyand consistentlydecreased bymisoprostolcompared toplacebo [66 ± 10.2vs 109.4 ± 8.1 h(p = 0.0005)]
No differencesin theincidences ofabdominalpain
Misoprostolsignificantlyincreased the totalstool weight perweek [976.5 ±288.8 vs 434.6 ±190.5 g(p = 0.001)]
Misoprostolsignificantlyincreased thenumber of stoolsper week comparedto placebo[6.5 ± 1.3 vs2.5 ± 0.11(p = 0.01)]
Table 14. Methodologic Score of the Study Evaluating Misoprostolin the Treatment of Constipation
Statement onReference Randomization Blinding Withdrawals Total Score
64 1 2 1 4
A score of 1 or 2 was given for randomization (2 for appropriate randomizationtechnique and concealed allocation explicitly stated or described, 1 for studysimply described as “randomized”). Scores of 0–2 were given for blinding (2when both subjects and investigators were blinded to the treatment by use ofidentical placebo or other technique, 1 when the study is described as “double-blind,” and 0 when the study was not double-blind). Score o f 0 or 1 was givenfor frequency of withdrawals (1 when the number of withdrawals and reason forwithdrawals were stated, and 0 when no statement was made pertaining to withdrawals).
(ii) Calcium polycarbophil (Perdiem fiber therapy)—onetrial against psyllium (50) with quality score of 1. Evi-dence poor, Grade C recommendation.
(iii) Bran—one placebo-controlled trial (38) with qualityscore of 4; one trial against “no treatment” (37) witha quality score of 1; one trial of wheat bran versus cornbran versus baseline (39) with a quality score of 1. Evi-dence poor, Grade C recommendation.
(iv) Methylcellulose—one nonplacebo-controlled trial witha quality score of 2 (36). Evidence poor, Grade C rec-ommendation.
Wetting AgentsA. Dioctyl sulfosuccinate—one trial of dioctyl calcium (not
available in the United States) and dioctyl sodium (DSS,Colace) versus placebo (65) with a quality score of 3; two
Efficacy and Safety of Traditional Medical Therapies 967
Tabl
e15
.S
umm
ary
ofth
eS
tudi
esE
valu
atin
gth
eE
ffica
cyan
dS
afet
yof
Sto
olS
ofte
ners
inth
eT
reat
men
tof
Con
stip
atio
n
Pati
ent
Out
com
es
Ref
eren
ces
Sco
reIn
terv
enti
onS
tudy
Des
ign
NM
ean
Age
F/M
Dur
atio
nO
utco
me
Mea
sure
Res
ults
Saf
ety
Ana
lysi
s
653
Dio
ctyl
sodi
umsu
l-fo
succ
inat
e(C
olas
e)(D
SS
)10
0m
gqd
or10
0m
gb.
i.d.o
rdi
octy
lca
lciu
msu
l-fo
succ
inat
e(S
urfa
k)D
CS
,240
mg
qd
Ran
dom
ized
,si
ngle
-bli
nd,
cont
roll
ed
46of
4782
.140
/62-
wk
run-
in(p
lace
bo)
foll
owed
by3-
wk
trea
tmen
tph
ase
SF,
SC
,di
sim
pact
ion,
adve
rse
effe
cts
SF
—81
%of
the
pati
ents
rece
ivin
gD
CS
impr
oved
1.75
–2.8
3B
M/w
k,(p
<0.
02).
DS
Sca
used
nosi
gnifi
cant
impr
ovem
ent
over
plac
ebo
inei
ther
the
qdor
b.i.d
.dos
ing
(1.5
–1.9
5B
M/w
kan
d1.
76–2
.29
BM
/wk,
resp
ectiv
ely)
No
sign
ifica
ntad
vers
eef
fect
sor
chan
ges
inla
bora
tory
mea
sure
men
tsw
ere
repo
rted
inan
yof
the
grou
ps
The
mea
nnu
mbe
rof
natu
ralb
owel
mov
emen
ts(w
itho
utot
her
laxa
tives
ordi
sim
pact
ion)
amon
gth
eD
CS
grou
pin
crea
sed
appr
oxim
atel
y62
%ov
erth
epl
aceb
ope
riod
,mor
eth
antw
ice
the
30%
incr
ease
seen
wit
hD
SS
adm
inis
tere
dei
ther
bid
orqd
455
Psy
lliu
m5.
1g
b.i.d
.and
docu
sate
100
mg
b.i.d
.
Mul
tice
nter
,ra
ndom
ized
,do
uble
-bli
nd,
para
llel
desi
gn
170
of18
737
.215
6/14
1-w
kw
asho
utfo
llow
edby
1-w
kba
seli
ne(p
lace
bo)
foll
owed
by2-
wk
trea
tmen
t
Sto
olw
ater
cont
ent,
stoo
lwei
ght,
tota
lsto
olou
tput
,S
F
Com
pare
dto
base
line
,ps
ylli
umin
crea
sed
SW
Cvs
docu
sate
(psy
lliu
m2.
33%
vsdo
cusa
te0.
01%
,p=
0.00
7and
)
Non
est
ated
Psy
lliu
mal
soin
crea
sed
SW
W(8
4.0
g/B
M)
vsdo
cusa
te(7
1.4
g/B
M);
p=
0.04
968 Ramkumar and Rao
Tota
lsto
olou
tput
high
erw
ith
psyl
lium
(359
.9g/
wk)
vsdo
cusa
te(2
71.9
g/w
k);p
=0.
005)
Psy
lliu
mha
da
high
erO
’Bri
enra
nk-t
ype
scor
eco
mbi
ning
obje
ctiv
em
easu
res
ofco
nsti
pati
on(p
syll
ium
475.
1;do
cusa
te40
3.9;
p=
0.00
2)67
4D
ioct
ylso
dium
sul-
fosu
ccin
ate
(DS
S)
100
mg
t.i.d
.or
plac
ebo
Ran
dom
ized
,do
uble
-bli
nd,
plac
ebo-
cont
roll
ed,
cros
sove
r
34of
40el
derl
yG
eria
tric
—no
tot
herw
ise
spec
ified
Not
spec
-ifi
edTw
oco
nsec
utiv
e4-
wk
trea
tmen
tpe
riod
s
SF,
over
all
impr
ovem
enti
nco
nsti
pati
on
DS
Sin
crea
sed
SF
bya
mea
nof
1B
M/w
kco
mpa
red
wit
hpl
aceb
o(p
<0.
01)
Non
est
ated
The
diff
eren
cein
the
over
alli
mpr
ovem
enti
nco
nsti
pati
onw
asst
atis
tica
llysi
gnifi
cant
(p<
0.05
)66
4D
ioct
ylca
lciu
msu
l-fo
succ
inat
e(D
CS
)24
0m
gb.
i.d.o
rpl
aceb
o
Ran
dom
ized
,do
uble
-bli
nd,
plac
ebo-
cont
roll
ed,
cros
sove
r
15of
2278
yr4/
112-
wk
run-
in,t
wo
3-w
ktr
eatm
ent
sepa
rate
dby
a2-
wk
was
hout
SF,
SC
,UO
LN
osi
gnifi
cant
diff
eren
ces
inth
est
oolf
requ
ency
,vo
lum
e,an
dne
edfo
rad
diti
onal
laxa
tives
betw
een
the
docu
sate
and
plac
ebo
grou
ps
Non
est
ated
Pati
entp
erce
ptio
nof
cons
tipa
tion
and
disc
omfo
rtw
ith
defe
cati
onw
asal
sono
tsi
gnifi
cant
lydi
ffer
ent
betw
een
the
grou
ps
Efficacy and Safety of Traditional Medical Therapies 969
Table 16. Methodologic Scores of the Studies Evaluating Stool Soft-eners
Statement onReference Randomization Blinding Withdrawals Total Score
65 1 1 1 345 2 2 1 567∗ 1 2 1 466 1 2 1 4
∗Because this study is double-blind and placebo controlled, the total score here is highbased of the criteria set out; the study description reveals very little information, and assuch the overall quality is not as good as the score suggests.A score of 1 or 2 was givenfor randomization (2 for appropriate randomization technique and concealed allocationexplicitly stated or described, 1 for study simply described as “randomized”). Scores of0–2 were given for blinding (2 when both subjects and investigators were blinded to thetreatment by use of identical placebo or other technique, 1 when the study is describedas “double-blind,” and 0 when the study was not double-blind). Score o f 0 or 1 wasgiven for frequency of withdrawals (1 when the number of withdrawals and reason forwithdrawals were stated, and 0 when no statement was made pertaining to withdrawals).
trials of DSS versus placebo (66, 67) with quality scoresof 4, 4; one trial of DSS versus psyllium (45) with a qual-ity score of 5. Evidence poor, Grade C recommendation.Psyllium superior.
Stimulant Laxatives(i) Senna (Sennokot, Perdiem overnight therapy)—one trial
versus sodium picosulfate (not available in the UnitedStates) (29) with a quality score of 2; one trial versus bran(40) with a quality score of 2. Evidence poor, Grade Crecommendation.
(ii) Bisacodyl (Gentlax)—one trial versus bisoxatin (notAvailable in the United States) (32) with a quality scoreof 2. Evidence poor, Grade C recommendation.
(iii) “Irritant”—one trial versus lactulose (31) with a qualityscore of 2. Lactulose better.
OthersTegaserod (Zelnorm) one very large trial with a quality scoreof 5. Evidence good. Category A recommendation.
WHAT IS KNOWN AND WHAT THIS PAPER ADDS
(i) Constipation is a common problem for which a widerange of medicines are used.
(ii) Many of the current recommendations for clinical prac-tice are based on evidence from trials.
(iii) Although metaanalysis of drug treatment of constipationhas been reported, there has been no systematic reviewof the quality or number of clinical trials or an in-depthevaluation of the safety and efficacy of these agents.
(iv) This review could serve to enlighten practitioners aboutthe evidence pertaining to various agents that are tradi-tionally used to treat constipation, and thus serve as aguide for selecting appropriate agents.
(v) In addition, this review highlights the fact that there isminimal or weak evidence to support the use of manycommonly used drugs for the treatment of constipation.
ACKNOWLEDGMENT
The authors would like to thank Dr. Philip Schoenfeld for hisadvice and the invaluable critique and thoughtful appraisalof Dr. W. Peterson in the preparation of this manuscript. Theauthors also wish to thank Novartis Pharmaceuticals for anunrestricted educational grant.
Reprint requests and correspondence: Satish S.C. Rao, M.D.,Ph.D., Neurogastroenterology, University of Iowa Carver Collegeof Medicine, Iowa City, IA 52242.
Received June 8, 2004; accepted November 15, 2004.
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