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September 1996 Volume 28 No.3

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.) National International
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~ - Advisory Board Advisory Board
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iLi ,~i\\ Abdul Hamid AI-\hihana Abdulla Borhan Eg\pi
Abdul-Reda Lari A. R. ~:Joossa [,SA

The Journal of Abdul Razak AI-Nefesi A.S. Daar 011/(/11

Ade! AI-AwaJi Bertel Bcrg Sii "cdeli

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Origina[ .9Lrticfe

A Prostaglandin Synthesis Inhibitor:

Indomethacin and Imipramine in the
Treatment of Primary Nocturnal Enuresis
The Journal (}(The Kiiimi! Medical Associariim1996. 2H 13): 279-2H2

In this stud)!,we tried to determine efficacy of indomethacin, a prostaglandin synthesis inhibitor, with
a tricyclic antidepressant imipramine together in the treatment of primary nocturnal ennresis. This
study included 78 patients with primary nocturnal enuresis (PNE) living in the same environmental
and social condition. Imipramine (50 mg per night) and indomethacin (25 mg per night) was
adminisifred during 8 weeks. At the end of this time, medical therapy W3Sgradually finished and
dryness was followed-up. We concInde that indomethacin is a good alternatiye agent for nocturnal
enuresis particularly as a supplementary treatment combined with imipramine, with 78.6% complete
response and 74.7% dryness rate.

KEY WORDS: imipramine HCl, indomethacin, primary nocturnal ennresis,

>!-Nureddin Vurgun, **Bilali H Gumus, Introduction

Nocturoal enuresis has been
*Akin Iscan, **Mustafa Yeter, described as an involuntary urination
***Sedar Tarhan, ****Sedat Gonenc in the bed during sIeep. it is not an
important problem in medicine. but
'Dept. of Pediatrics it is an extremely distressing
'.Dept. of Urology condition for the familyand their
"'Dept of Radiology child. Most children have controlaf
Celal Bayar University Hospital
bladder at the age of 3 or 4 years.
Manisa - Turkey
Some studies suggest that the
incidence of noctumal enuresis is
""Society for Protection of Children
and Social Services i alk in 6 year aids and 5q} in i 4 year
Manisa - Turkey aids Although noctumal enuresis
ii-'i.
is see n two or three times morc
frequently among hoys until i i years
of age. af ter that age the ratio
increases a little more among girls
141. When the night control of
urinatioii has never heen completely
Addrcss rorrespondi'ni!t' to : successful. it is ealled primary
!\:ur...ddinVurgun. MD nocturnal eiiuresis (PNE). and if the
(\'lal Bayar llni\cr,ii...,i child stays dry 6 mollths or a year
Tip Fahili...,i -t5020 and then starts lo siiff'er frol1l
Mani,a ~
noclurnal enuresis. ihis is lermed
Turkc'y.
secondary noeiumal enliresis. In

The Journal ofThe KlIwail Medkal Ass()i:iaiinn '279 Scptcmt>..., 199(, Volumc 2X No..'
 Nur~dJin Vurgun. Bilali H Gumus. .-\kin Is~an. :\hisiaf;i Y~I~r. S~rJar Tarhan. S~(bi Gon~nc

most studies. it has been reponed that

XO'k of nocturna! enuresis cases are
Treatment groups primaryl'..,i. Different treatment
modalities and phariiiacological
Group i (19) Imipramine HCl 50 mg/day (lMP) agents have been studied in the
Group II (14) Indomethacin 25 mg/day ONO) management of noctumal enLIresis.
Group III (28) Indomethacin 25 mg/day Medical treatment has been the most
+ Imipramine HCl 50 mg/day (lNDIIMP) acceptable therapy among the
Group LV (17) Placebo families. children and physicians.
Tricyclic anti dep res san ts.
anticholinergics. and desmopressin
(DDAVP) are the most commonly
4~ used pharmacological agents 10-"1.It
is known that prostaglandins cause
dilatation of renal blood vessels.
c'"
.. increase renal blood flow. and
J.5
.§. Sodilim excretion and also increase
-'"
.... . -IND+IMJ'ln~2iS) !
!. -"'-IMI'(o=l'l) i..--.._...._._..--.. the ton e of bladder muscle and
~
.E reduce the urethral presslife and
' -l'loccoo(0=17)
'cQ" _..
", resistance. In addition. it has been
1
i
,_IND(n=14) ;t.-'X... .;t-'-:r c
o/) .'~ '%--i--:t '%'
c demonstrated that renal
.~ 2 - - . I~ u_-
~ prostaglandins inhibit antidioreric
lio
... 15 '._.n
.[ hormone: they also increase renal
- --~i-:':-.'~- -_. sodilim excretion and urine volumeP-
o
Z
~I-Suppression of renal prostaglandin
synthesis limits excretion of free
05 ,... . .._-
Redüciionpenoo' öftreatrnent water and redules sodilim excretion
and renal blood flOWIXI.Therefore
LI
il 2 to 'i Lu II 12 IJ 14 15 diclofenac sodilim. a prostaglandin
Treaiment duraiion (wc~ks) synthesis inhibitor. has been used in
the treatment of noctumal enuresIs
Fig. I: Ai ihe beginning of the Irealmeni of all paiieni groups. ihere \\ as no differen,'ein the number of the
as an alternating treatment methodlY'
average bedweiiings Ip > 0.051. In the 5th week of the treatment. there was a deerea", in the number of the
average bedweiiings in all groups. exeept plaeebo group. In the i(jth week during the period of diminishing the 101.In this studyo we also investigated
medidne. the bedweiiing scores showed an inerease in the group who [ook onl~ imipramine and only the effectiveness of indomethacin,
indomethaein. but we did not observe any importani inerease in the group given indomethaein and imipramine one of the antisteroidal anti-
iogether tp < 0.0011. This differenee eontinued at the end of the treatment. 100 tp < 0.001 i. inflamatory drugs and a
prostaglandin synthesis inhibitor. and
imipramine.tügether in the treatment
of noctumal enuresis.

JIl
Patients and Methods
! D Before treatment We applied this study to children
'"
.!:!
251 Q .p<lJ
001 !L !§1After"...,, treatment ..- i
staying in the boys' dormItories of the
o; Society for Protection of Children
5 lO and Social Services and the children
ii
.... 15 who had noctumal enuresis and came
o
...
... to Celal Bayar University Hospita!
J:> 10
E between the dates November 1994
Z 5 and February !996. The age s of the
78 children were between 9 to 15
(i (Mean :t SO: 12.3:t 1.8) and they
Imipramine+ Indomethacin Imipramine Placebo were not previously treated at ali. We
Indome:thacin HCl separated the children who had
primary noctumal enuresis at random
into four groups ( Table i) and
Fig. 2: The eases in the group of imipramine plus indonietha,'in eontinued to stay dry more ihan the others about collected all the detai!ed information
three monihslat<rafter w<had linishedthetreatm<niIp> o.onil. The ,nh<rgroups.whoprovidedeure afier the about the urination and medical
treatment did not have any superioriiy to each "ther froni the point of the ,ase number Ip> 0.05 i.
history of all children. We made

The: Journal ni' The Kuwaii Me:Jical Assnciaiion 280 September 19% Yolume 2X No-,
 A Pn"la~landin Synihöi, InhihilOr: Indol11cihai'in and 1l11ipral11inein ih~ Tr~all11enl of Pril11ar~ ""ctum:i! Enur~sis

routine physical examination of the groups ip > 0.05 i. We saw a pliarmacoJogieaJ agents Iias heen
ineluding abdominal. pehic. exierna] considerable decrease in ihe el1lployed from sed aii ve s to
genitalia and neurological bedwetting scores al the end of ihe siimulani or sympathomimetic
examination. The first morning urine 4 weeks of the trealment with drugs agents Ihl:. Different methods have
was taken for complete analysis of vs. placebo. Bed wening scores be en tried besides ihese
urine from these children. We decreased in all drug groups that is pharmaeo]ogical treatments. The
analyzed the density of urine. in IMP and IND groups in ihal order. behavior change treatment methods
searched for glucose and protein. and but'more obviously in the IMP + IND i behavioral therap)'. bladder
looked for cells and the casts groups (p < 0.001). This deerease exercises) psychotherapy. diel
microscopically. We a]so analyzed was provided by IMP at the same therapy. electro-acupuncture and
the serum e]ectro]yte. BUN. the rale as for the IND group (p < 0.05 I. hypnosis are the main methods
fasting b]ood sugar of the cases. \Ve bui there was a significant decrease among them 11.'-1"1. According to the
examined the patients by the direct in IMP+IND group compared with p]acebo results. only imipramine
urinary radiogram and tested the X- all other groups (p < 0.005). Ai the which is a tncydic antidepressant.
ray film for uro]ithiasis. bone end of the 10ih week. while the became part]y superior among the
deformities and we noted whether bedwetting frequency was medical treatment methorls. Apart
there were urinary system anomalies decreasing in all groups. we saw a from these medical agents an
or not. by performing urinary statistically significant increase in anticho]inergic agent (oxybutynin)
ultrasonographic and intravenous the group taking only IMP (p = and antidiuretic hormone
urogram evaluations. Patients who 0.005). The use of IMP+IND vs. only desmopressin (DDAYP) have also
had abnormal physical and IND showed no significant been emp]oyed 111.171.In the treatment
neurological findings and also difference by the end of the i Oth of enuresis. many drugs were used
abnormal urination functions were week (p > 0.05). Bui when we cam e a]one but a]so combined v,'ith other
excluded from the studyo We gave to the end of the treatment. the agents or with other methods iiI.I~I.
imipramine (50mg/day) and increase in the bedwetting score of The mechanisms of the effect of the
indomethacin (25mg/day) to patients the IMP group was less than placebo tricyc]ic antidepressants in the
for two months, and gave only starch (p = 0.026). but not different from treatment are not known exact]y.
capsules as placebo to the control only IND (p > 0.05). The score of However it is suggested that
group 30 minutes before going to bed staying dry. when using IMP+IND imipramine exerts its effect by
every evening. We asked our patients was more than for children using making some changes in the
to inform us conceming their 'dry' only IMP (p < 0.007). The great mechanism of s]eepiness and
and 'wet" nights. When the study and bedwetting score that was seen at the wakefulness. and by having an
control groups started to take the beginning in the group given anticholinergic effect. The treatment
medical agents, we scored their daily IMP+IND diminished considerably with imipramine shows its effect in
dryness according to their dry (74.7%) by the end of the treatment. approximately 50% of the enuretic
situations (dry=ü. a little wet = I, very Af ter the treatment was finished, the children especially in the first week
wet =2) iili.At the end of 8 weeks we cases given only IMP and only IND and is successful at the 30-50% rate
reduced imipramine and could not maintain the rate of staying i 1.151. In the enuretic cases it can be

indomethacin medication to one day dry. obtaining in the first 4th and said that urinating in the bed happens
in a week and then we completely 8th week. So treatment with IMP or during REM sieep; the
stopped them in the i 5th week of the IND alone produced higher relapse antidepressant agents decrease the
treatment. The children in the control rates than that of IMP+IND ( Fig. I). amount of deep sieep. However.
and study group were generally in the The exact treatment rates obtained at recent studies do not show any
same social environment and they the evaluations of 3 months later af ter connection between the depth of
were fed with similar foods. For the finishing the treatment were: placebo s]eep and noeturna] enuresis 117.1"1.
statistical analysis. the unpaired 1/17 i5.9lk). IMP4/19 (21.llk), IND Although it is suggested that
studentfs t-test and chi-square test 5/1 4 (35. 7lk). IMP+IND 22/28 imipramine pmvides an increase in
were used. A 'p' value of less than t78.6lk) (Fig. 2). We did not the b]adder capacity with its
0.05 was considered siatistically encounter any side effects when anticholinergic and antispasmodie
significant. using the two drugs together. Wl' did effects 115_~"1. In our studyo treatment
not have any medical problem to with imipmmine aleme is not seen as
Results indieate stopping the treatment and completely effective in the
The number ofhedweiiing events the patients were ple~ised wiih their management of noctuma] enuresis.
was approximaiely 4 days i range: treatment. Prostaglandin E2 (PGE2) which
2-0 days) in a week in the study and is primarily formed in ihe renal distal
conlrol gwlIps. Ai ihe heginning Discussion tubules and in ihe colleclor cana]
ihere were no differenees hL'1ween In ihe treatment of PNE. a very epiilielia. is etrective in ihe ibnsporl
the averagcs of the hcdweiiing. scores exicnsi,'e spei.trum of the of waler and salt. PGE2 inhihits

The Journal ofThc Kuwaii Ml'ui,al Asso,i;iii,ni 2~1 Sl'PIL'ni"'-'r i 'NI> V..luin.. ~~ 1\]" ~
 :'IIiir,'ddili Vurguii, Bilali H GUlliu" .-\~iii I',':in, \hi,iara Yei"", Serdar Tarhan. Seda! GIIlleli,

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iherapy or enure,i, alarni anu de'ITIoprc"in
fnrmation of less urine. According il1nintil1t.'I1t.'t.'in 7 ~t.'ar "lu Swt.'ui,h "choo!
in the (reatmt.'ni of not.'lurnal t.'nure,i,. Eur J
to this hypothesis. PGE2 is t.'ntranh. Eur J Pt.'diatr IlJ':i(): I.N:.G4-,G7.
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sodium and water. The deereLIse in enureiic frt.'queney and sleep stages.
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prostaglandin formation by using Urol 1995: 75: 427-434.
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indomethacin increases vasopressin 5. Rushion HG. Not.'ium:il t.'nuresis: Epidemi-
20. Forsythe W i and Redmond A. Enurt.',i, and
activity and consequently inereases 'ponianeous curt.' rale. Study or 1129
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subjects, indomethaein as a 21. Rubinger D. W:ild H. Seherzer P. Popo\'!zer
l+i(suppl): 691-69b.
prostaglandin synthesis inhibitor. 6. J:inknegi RA, Smans AJ. Tremmeni wiih
MM. Renal sodium handling and stimulanion
increases reabsorption of Sodium of meduHary Na-K-ATPase during blockade
desmopres,in in severe nocium:il enuresis in
and decreases its excretionl~"~"I. In of prostaglandin synihesis. Prosiaglandins
childhood. Br J Urol 1990: 66: 535-537.
this study, we thought that sodium 7. Anderson RJ. BenT. ;\olcDonald KD. Evidence
1990: 39: 179-194.
excretion may be higher in enuretic for an in vivo anlagonism beiween vaso-
22. Prescon LE Maiiison P. Menzies DG,
cases and indomethacin may increase Manson LM. The comp:irati\'e effects of pa-
pressin and prosiaglandin in iht.' m:immalian
Sodium reabsorption with the racet:imol :ind indomeihacIn on renal func-
kidney. J Clin In\'esl 1975: 56: 420-426.
inhibitory effect prostaglandin 8, W:ilker RM. Brown RS. Sloff JS. Role of re.
tion in helthy fem:ile volunteers. Br J Clin
synthesis and consequently that will Pharniacol 1990: 29: -i03-4 i 2.
nal prosiaglandin's during antidiuresis and
be effeeiiye in the night urinating of w:iier diuresis in m:in. Kidney ini 1982:
23. Monn E. Prosiaglandin syntheiase inhibiiors
enuretic casesl~.ii.The cases of our in the treatment of nephrogenie diabetes in-
21 :365-370.
study responded to the therapy of sipidus. Acta Paediatr Scand 1981: 70: 39-
9. \Ieiin A. Akyol N. Diclofen:ie sodium sup-
prostaglandin synthesis inhibitors in 42.
posiiory in iht.' tre:itmeni of primary noetur-
a short time. At the end of 15 weeks 24. Vurgun N. Gumu. B. Ari- Z: lsean A. Yeter
n:il enuresis. ini Erol :-':t.'phrol 1992: 24: 113-
of treatment, 78.6Cff of the cases 117.
M. Rt.'nal Functions of Enurt.'iic and
managed to stay dry without 10. Baiislam E. :-.ruhoglu B. Peskireioglu lo Emir
~onenurt.'tic Children: Hypt.'matriuria :ind
relapsing (Fig, 2). In some of the Kaliuresis :is Causes of Noeiurnal Enuresis.
lo UygurC. Germiy:inoglu C. Erol D. Apros-
cases given indomethacin. we also European Urology (in print).
t:iglandin syntht.',is inhibitor. diclofen:it.' so-
observed an increase in sweating to dilim in ille treatment of primary noclurnal
according to the pretreatment period. t.'nuresis, Acla Urol Belg 1995: 63: 35-38.
As a consequence of our observation. ii. Wille S. PrimaT)' not.'iurnal enuresis in t.'hil-
we thought that indomethacin effects
drt.'n. Background and treatment. ScanJ Uro!
sweat glands and increases sweating,
Nephrol Suppl 1994: 156:1-49.
so it decreases renal water and salt
12. Khosroshahi HE. Bozkurt V. Sadikglu N.
excretion. In conclusion, we
Alakan C. Treatment of noctumal enure,is:
suggested that the treatment of
a plaeebo-conrolled trial ""iih piract.'tam.
nocturnal enuresis with imipramine
dipht.'nylhyuantoin and psychother:ipy. Turk
and indomethacin is together more J Pt.'diatr 1':189: 31: 215-220.
effective than monotherapy due to 13. Howe Ac. Walker CE. Bt.'h:ivior;11
having different mechanisms. After
nianagmt.'ni of ioilet iraining. enuresi,. anD
we stopped the treatment with ~neopresi,. Pediair Clin :-.rorth Am 1992:
IMP+IND the relapsing rate 39: 413-432.
decI'eLlsedconsiderably over those of 14. \IotTan \IE. :-':ot.'lUmalt.'nure,is: p,ychologi-
the other agents. In this study we
cal implications of trt'alment and non Ireal-
suggest that imipramine and mt.'nt. J Pt.'dialr 1989n 114esuppl): 697- 704.
indomethacin are effeetive and eheap 15. Selimin BD. :-':oeturnal t.'nure,i,. An upd:ite
treatment modalities instead of an
on treatment. Pediair Ci in :'I:orth Am 1982:
alarming method. which is effective 29:21-36.
but has an application dirrichIlyo and 16. Tuzuner E Kedk Y. üzdemir S. Canakei-:-':.
~xpensive DDAYP treatments.
Ekt.'iro-acupunt.'turt.' in the treatment of t.'nu-

rht.' Journal of The Kuwait \1edical A,siici:iii"n ""