CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009:7:944-952
ORIGINAL ARTICLES-ALIMENTARY TRACT
Effect of Zolpidem on the Sleep Arousal Response to Nocturnal
Esophageal Acid Exposure
GREGG S. GAGLIARDI,' ASHISH P. SHAI,- N,4ARA GOLDSTEIN,- SUSIE DENUA_RIVERA,- KARL DOGHRAN,4JI,+
SIDNEY COHEN,- and ANTHONY J. Dll\,4AFlNO, JF-
'Divisian af Gastraenterolary and Hepatalagy, Thanas Jetferson University Haspital, Philadelphia, Pennsylvantat +Jefferson Sleep Disarders Center, Thamas
Jetferson Univercitv, Philadelphla, Pennsvlvania
See Editorial on page 919.
BACKGROUND & AIMS: Nocturnal acid reflux is associ-
ared t'ich complicated gastroesophageal refltu (GER) disease.
Nocturnal GER iniriates a protective arousal reflex, which in-
duces a swallow to clear esophageal acid. The purpose of chis
study was to determine che effecc of zolpidem on the sleep
arousal mechanism and acid clearance in paciencs with docu-
mented GER, compared with control subjects with normal acid
exposure. METHODS: Eighr controls and 16 GER patiencs
were enrolled in a randomized, double-blind, placebo-con-
rrollrd ,rudy. Zolprdcm or placebo u:, grvcn on sepJrarr
nights. Refltx events and refltrx-associated arousals or awaken
ings were recorded using simultaneous esophageal pH record-
ing and standard polyson-rnography. RESULTS: Nocturnal
acid exposure resulted in a sleep arousal 89o/o of the time in
participants (with and wichour GER) given placebo buc only 40%
in those given zolpidem (P < .01). In controls given placebo, acid
reflux events lasred 1.15 a 0.28 seconds; in conrrols given
zolpidem, they lasted 15.67 ! 12.12 seconds (P < .01). In GER
patients given placebo, the acid reflux events lasted 37.8 a 17.2
seconds compared wirh 363.3 ! 139.3 seconds witl-r zolpiderr
(P < .01). \flith zolpidem reflux evencs lasted 630.6 :! 236.5
seconds when no arousal occurred and 49.2 :! 19.11 seconds
u'hen an arousal was recorded (P < .001). CONCLUSIONS:
Zolpidem reduced the arousal response to nocturnal acid
exposure and increased the duration of each esophageal
acid reflux event in healthy individuals and patients with
GER Because noctutrral acid exposure was prolonged, h1p-
notic use by patients with GER could lead to increased risk
fot comolicated disease.
fl,,L r.,e.ophageal reflur disease iCfRDl rs a chronrc drs-
\J ord". *iih aln c.rinr.rred 20% olrhe US rdulr poprrhnon
experiencing CERD-relaced symptoms at least once a week.
Recent epidemiological srudies have srggesced that disturbed
sleep occurs in as many as 75% oF patients with frequent
daycime hearrburn. Nocturnal acid reflux may be especially
damaging because acid exposure is of longer duracion and has
been associated witl-r complications of esophagitis, including
Barrect's esophagus and adenocarcinoma.l 9
It has been shown that nocrurnal acid refltx results in a sleep
arousal or awakening, which leads co a swallow reflex- The
swallowing rnechanism iniriates perisralsis which results in neu-
tralization of esophageal concenrs wich saliva rich in bicarbon-
ate. Studies have shown that arousals and awakenings fron
sleep facilicate esophageal acid clearance bu! fragment and
disrupt sleep.ro13 Nocturnal refltx and its sleep arousal re-
sponse have been implicated in sleep disrupcion causing poor
daytirne performance and productivity.'zas
lnsomnia, the complaint oF init;aring or maincaining sleep,
is common, affecting 307o of che US population. Sleep aids are
commonly utilized by insonnia sufferers rvith an estimated
159o of the US populacion reported using eicher a prescription
sleep medication (87.) ar-rd/or an over tire counter (OTC) sleep
aid (107o) co help them sleep.ra.rs
While hypnocic use is increasing, there is iittle informacion
regarding the effect of these medications on arousals, which is
an esophageal prorecrive mechanism to help clear acid in re-
sponse to noccurnal gastroesophageal reflrl (GER). Suppress-
ing nocturnal arousals with hypnotic medications may lead ro
prolonged acid exposure and co n-rucosal injury over time.
The purpose of the present dotble-blind placebo-controlled
trial was to detetmine che simultaneous effect of a rvldely
prescribed hypnotic on nocturnal acid exposure and sleep
arousal in subjects with and withouc known GER. The sftrdy
demonstraces thac a hypnoric prolongs esophageal acid expo-
sure wich each ref'lu-r event by the proposed mechanism of
suppression of the sleep arousal/acid clearance mechanism.
Methods
Stttd! PoPttl4ttion
Twenty-four subjects were recruited on the basis of a
chart review ofesophageal pH and notility test results from the
Thomas Jefferson Universiry Hospiral Division of Morility. The
review identified 2 groups of subjects. The 6rst group had
normal 24-hour esophageal pH tesr resulrs (normal DeMeester
criteria; nornal score <14.7) and normal esophageal m:Lnom
Abbrcviations used in this paper: ACf, acid clearance time; CNS,
central nervous system; GER, gastroesophageal reflux; GERD, gastrcr
esophageal reflux disease.
o 2009 by the AGA Institute
15/t2-3565,/09/$36.00
doi r10.1o16lj.cgh.2009.04.026
 September 2009
ZOLPIDEM AND NOCTURNAL ESOPHAGEAL ACID 949

etry. The second group had abnortral 2ul hour supine esopha ome. A standard polysomnograph montage \ras utilized ro
geal pH and norll1al esophageal manometry. Lighr normal and tecord nocrurnal physiological,:iata, including electroencepha
16 GER parients w€re stu.lied in a 2:l randomizarion. All Iogram. eleccro oculogram, eleccromyogr:rrn of chin :rnd anre_
patients had sropped acid suppression, proron inhibicor drugs rior tibralis muscles, electrocarciiogram, respirarorv florv ancl
7 days prior to pH tescing. Fourteen subjects from rhe GER excursion, and transcucaneous oximetty. Follorving rhe over_
group \r,ere using proron pump inhibicor medication ar the nighr sleep study, rhc pH probe rvas rernoved_ A physical exam
time oF recrlrirment_ Fifteen srrbjects from rhe GER group lnaoon !r'as perlormed to evaluare subjects' levei of aiertness
feporred regular synpronls oF heartburn. No subjecr in the ancl salerl lor discharge to home. StLbjecrs rerurncd rvithin a
nornlal group reported hearcburn. 2-rr'eek period co undergo a second sleep saudy using che above
protocol.
Protocol
On che basis of dre chart review, eligible subjcccs $,ere Measarements
contacted and con-rpleted questionnaires pertaining to inclrr
The total number of reflux events *,as recorded, as lr,ell
sion and exclusion criter.ia_ Ifsubjecrs tere inreresred in parric_
as the number oF reflux-associaced arousals or arvakenings. An
iparing in rhe srudv and met inirial criceria lor stu<ly enriy, tl-re
acid reflux evenr uas defined as a pH heasurement <4.0 in rhe
strrdy u,as Furrher explained and rhey \yere provided a srudy
consenc forrll. A compLere hiscory and physical examination u,as
r-lisral esophagus. All polysomnographically de6ned arousaLs
ancl awakenings rhar had no ocher identifiable sollrce rhat
then complered_ (The clinic:rl trial is regisrered in rhe r.egiscry
occurred during the acid reflux event and up to 5 minlrtes afret
ClinicalTrials.gov wirh identifier nLimber NCTO0462137.t Th;
che pH retLLrn co ).1.0, were considered to be reflux,associatecl.
control and parient compensarion schedule was approved in Arousals or atr'akenings chat occurred in conjuncrion tirh an
the clinical rrials tevieu'.
apnea or hypopnea event, an isolared hypoxernic episode (SaOz
Subjecrs rvere eiigible if they rvcre 18 year.s oF age and older,
decremenc of nore rhan 296 From baseline), or a periodic limb
and had docrmenred 2,t-hour pH testing and norrral esopha_
movement rvere scored separately and u,ere not considered to be
geat manometry prior ro enrollrrent in rhe srudy. Exclusion
reflux-associared, and. thus, eliminated from the analysis. Jn
cnteria inclrrded a hisrory of symproltls suggesti,,,e of sleep
addirion, acid ciearance time (ACT) for each refltx evenr u,as
apnea syndrone, resrless legs syndrome and periodic limt
measured and recorded as the number oF seconds rhe pH $,as
r11ovenenr disorder, narcolepsy, or anv defined sleep disorder.
below 4.0 All records rvere read and recorded in a blindecl
Parients lvirh any prior histow of an esophagcal morility dis,
tashion. Blinding was noa broken uncil all stuclies \t,ere com_
orqer. esophagogasrnc surgery, prior use oF prescribed hypnor
p1etecl.
rcs and prior complainrs insomnia u,ere also excluded. Sub_
oF
Je.!s lneering diagnosric crirlrria fof sleep apnea syndrome and Data Analysi.s
periodic lilnb mov€menr disorder follorving subseqrrently con_
Dara were reviewed and v;lidated by a cerrified poly_
dlLcted polysorrrnography (see below) were also excluded. Sub-
somnographer. Polysomnograpic recororngs were scorect trran-
Jecrs \r'irh a body trass index above J5 or who were pregnant
ually by a rrained technician in 30-second epochs according ro
uere nor cligible for thc study.
srandard criceria (Rechrschaffen and Kales).r, Arousals were
Each subjecr under-rvenr 2 separare nocturnal sleep studies
scored according ro rhe American Sleep I)isorders Associa.ion
t'irh simulrancous polysomnography and esophage:rl pH resr_
criteria.rT Dara from rhe esophage:rl pH recording u,ere inte_
ing in the Jeffer.son Sleep Disorders Cenrer. Subjects 6rst ar-
r;ved to rhe Thonas Jefferson Hospiral Mocilir,v Laboratory.
grated into rhe polysomnographic recordings on a real time
basis utilizing rlte sanle software (Asrromed-Grass_TeleFactor,
rvhere an csophageal pH cathecer was placed transnasally in
West Warwick, fu). A comparison of rhe mean acicl clearance
scandard fashion (Medrronic, Minneapolis, MN). The pH carh_
cin-te between placebo and zolpidem adminisrrarion was exam
erer had a buift in reference eleccrode. The cacheter $,as cali_
ined fo r' ,s tacis rical significance by Studenr t cesr for p:1ired and
brated at pH 7 and l, rrich a buffer solurion. The pH catherer
unpaired sanples. The data are presenred as nean I srandard
lvas posirioned 5 cm abovc rhe krrver. esophageal sphincrer.
error of rhe mean.
Sul:jects thcn proceederl to rl-re Jefferson Sleep Laboritory_
In a double blind, cross-over fashion, borh normal subjecrs
and GER pacienrs rvere administer.ecl zolpidem tarrrace (Am- Results
blen@. Sanofi Avenris. Bridgewater, NewJersey) 10 mg or pla_ A roral of
2,1 sutrjecrs were enrolled in rhe srudy. Eighr
cebo approxin-ratelv 30 m;nutes prior to bedtime. Drug and control subjecrc had normal 24ltollr pH resring and lr,ere
placebo resembled ea.h other in color and size. Drugs were classi6ed as nornal subjects. Sixteen subjects hacl Jocurnenred
adrninisrered by a coinvesrigator in a Fully blinded ranclom abaormal supine esophageal acid exposure pr-ior to study en_
fashion. The pH probe posirion u,as confirnred prior ro beci_ rollment and nere classified as GER pacienrs. One CER pacient

Table 1. Baserine 24'Hour pH Resurtsa for Normar subjects and Gastroesophagear Refrux patients
PH results Normal subjects Gastroesophageal ref ux patients
Total (mean percent time pH <4.0) 1.96 I 0.36 9.23 1 1.81 <.01
Supine (mean percent tirne pH <4.0) 0.59 :t 0.24 10.95 12.07 <.01
Upright (mean percent time pH <4.0) 3.06 i O.45 8.33 :t 2.O7 <.01
aData are given as mean
: standard error of the mean.
950 GAGLIARDI ET AL
lvas eliminated frorn the stucly after he was diagnosed u'irh
obsrmcrive sleep apnea on the 6rsr sleep sftldv nighr. A total oF
23 subjecrs completed the study. The mean age for rhe conrrol
subjects was 41.3 years compared lr'irh 51.1 years in the CER
patienrs (P : not sr:rtisticallv significant). Among normal
control sllbjects. mean supine acid exposure was 0.5996 a
0.24% conrpared wirh 10.95% ! 2.07a/o tn CER parients (P <
.01j Table 1).
ln rl-re normal subjects there tere a total of22 acid reflux
events. or 2.8 acid reflux events per sleep study (95% confidence
inten'al, 1.7 4.2). l.-ifteen occurred during placebo adninisrra
tion. Scvcn acid reflux evenrs occurred du|ing zolpidem admin-
istrarion. ln rhe GER patienrs there lvere a cotal of 125 reflux
events or 8.3 acid reflux events per sleep study (95"/" confidence
interval. 6.8 9.8). Seventy'one occurred with placebo adminis
tration rl4rile 54 occurred g,ith zolpidem. C-hanges in number of
acid reflrx events in ea.h group \r,as not significanr (P > .05)
rvidr zolpidem.
ReJIoox-As sociate d Aroasals
Arnong all 23 suLrjecrs (controls and GER), a nocturnal
acid reflux evenr led to an arousal or atakening 8996 ofthe rime
when pla.ebo was adminiscered. ln comparison. as shown in
Ijigure l, reflux ever-rts \r,ere associated \r'ith an arousal or alr'ak
ening only 40Yo of the time on nights when zolpidem was
administered (P < .01). Absence of rhe arousal response was
noted in the first part of the evening (6rst 3 hours post zolpi
dem) with an intact arousal response prior to morning arvak-
ening. Thus, che arousal response was presenc in borh groups
regardless of rhe dtration of acid exposure suppressed by zol,
pidem.
Esophageal Acid. Clearance Times
Mean esopl-rageal acid cl€arance cine for an acid GER
event was measured in the GER patiencs and norlral slLbjecrs
!r'hen given placebo versus zolpiden-r. ln rhe 8 norrnal subjeccs,
rhe mean ACT for each nocrurnal acid reflux event rvas 1.15 l:
0.28 seconds. On the nights when zolpiderTr was adninisrered
as sho$n in Figure 2, the mean ACT For an acid CER event rvas
15.67 1 13.42 seconds t'frich u,as significanrly higher when
conpared wich placebo (P < .01).
BO
70
89o/"
60
30
20
10
Placebo Zolpidem
Figure 1. Percent of GER events assocated with an arousa or awak
ening as a functon of placebo vs zopder| use. n the presence ol
zolpidem, there was a rnarked reduction in reflux associated seep
arousas n the normal subjects and GEF patents (P < .0T).
cLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.7. No.9
30
25
2A
15
10
Placebo
Placebo Zolpidem
Figure 2. Mean ACT (in seconds) for a nocturna GER event in the
contro sublects with normal nocturna acd exposure when laking pla
cebo vszo pidem. ACTwas sgnificanUy proionged wth zo pidem com-
pared wth pacebo (P < .05). These physio ogica Teflux events in nor
ma sublects, athough proonged with zolpdem, st lreman relatvely
brief when compared wth those of the GER pat ents.
As shorvn in Figure 3A. in the GER patients rhe lrrean ACT
lor.r grverr r'flrLX r\, r'r rvlr,.n .iren placcbo u.r. \-.-9 -: l- 25
seconds compared wirh 363.3 | 139.29 seconds when zolpidern
was given (P { .01). Thlls, noccurnalacid exposure tas dramat-
ically increasecl per each event over rhe enrire sleep period.
To Further exanine the inportance oF the arousal response
in acid clearance, we examined the dac:r for acid clearance rimes
in GER pacienrs in che presence or abscnce of an arousal rvich
zolpiden as seen in Figure 38.
In the GER patienrs rhe nean ACT in response to an acid
CER event lr.hen an arousal occurred \r'as ,19.18 I 19.11 sec-
onds compared with 630.58 :! 236.52 se.onds $,hen no arousal
occurred (P < .001). The more malked acid exposure times \r'ith
zolpidem were seen in rhe first 3 hours of sleep t'hen rhe
arousal response rvith acid exposure was infrequenr.
Discussion
The presenc scudy indicares that a nedication com-
rnonly used to induce sleep prolongs nocrurnal esophageal acid
exposure in conjuncrion *'irh inhibicion of rhe centrally medi
ated, sleep arorLsal acid clearance nechanism. It has been pre-
viously demonscrated that nocturnal esophageal acid reflux is
cieared by an esophageal iniriared central nervous sysrern (CNS)
reflex. Hydrogen ions initiare the CNS response which rhen
causes a sleep arousal and a su,allorving response. This sleep
arousal mechanism was inicially demonstrated in normal sub-
jects using 15 mL acicl perfusions of different pH.r1 The sleep
arousal mechanism in our srudv was not conrrolled becalrse
volume oF acid refluxare and pH were clinical events and nor
experimentally regul:rred. However, prior studies have collected
reflux volunres oF 2 7 mL per horr in che fasrillg state.l3
Despire these srudy differences, pathologic: reflrrr evenrs of
varying volumes acid clearan.e through rhe CNS-medi-
'nitiate
ated alousal rcsponse simiiar ro the earlier reports-rlThis srudv
also indicated thar rhe vely brief "p hysiological" reflux event in
normal subjects may also iniriace an arousal response.
The duration oF esophageal acid exposure during sleep has
significant implicarions on rhc developnenr of complicated
September 2009
Figure 3. F) N,/ean ACT (n seconds) for a nocturna
reflux event in the GER patents when tak ng pacebo vs
zo p dem. Zo p dem was associated wth proongation
of ACT n patents with abnorma screening pH studies
(P < .01). (B) Mean ACT (in seconds) for a nocturnal
refux event n the GER patents n the presence or ab-
cor e o .r clro, d rtr opden. lh- doc6^ e or d
^
sleep arousal with zolpidern ed to a marked proonga
Placebo
tion of ACT with each reflux event (P < .001).
GIJRD including elosive esophagiris. srricture Formarion, Bar-
rett's €sophagus and esophageai adenocarcinorna.l 6.1e.20 lr is
uell escablisl-red that esophageal acid exposure during sleep is
prolonged in both normal subjects and in parients wich CERD.
and that arorLsals and ar.vakenings in response to acid reflux are
critical ro enable acid clearance during sleep-7!)12.21 Orr er al
have previously clemonscrared thar slcep inpairs esophageal
acid clearance cime and rhar acicl clearance occurs ln assoctanolt
rvith arousals From sleep.T Thus. facrors that suppress arousals
an,-l arvakenings rnal fllrther prolong esophageal acid conra.r
time. Insonrnia, or self-described r-lisrurbed sleep, is a common
conplaint in rhe US aclult popularion.
In rhis stlrdy, rve Found rhar zolpiden. a conrnonly pre-
sclibed sleep-inducing hypnotic, suppressed nocmrnal arousals
and arvakenings in lcsponse co acid reflru events which resufted
in plolonged esophageal acicl clearance rime. Thus. zolpidem
haci che effecr of enabling suLrjecrs to "sleep chrough" reflur
evenrs. thereby increasing nocturnal acid exposure.
Zolp;dem is an imidazopyridine agent rhar is an agonisr ar
the beozodiazepine recepror component of rhe 7 arninobutyric
acid d-receptor colrrple-\. Zolp;dem enhances the inhibirorv
eTccr olt y .rurr,.'buLr rlc .r.,ci rrr
"', n, ral excrr.rr orr rrr, di;LirS
ics hypnotic cfFects. Ir h:ls been shown ro redlLce rime to onser
and co prolong the duration of sleep withouc affecring orhL'r
aspects of sleep archirecrure. The drug is rapicllv absorbed,
reaching n&\il11unl concentration in the serum at 1,6 hours
afrer administration. Ir is cxrensivclv nerabolized by rhe cyco-
chrome P450 isoenzyrnes, resulting in a short elimination half-
Iile of 2.5 hours. Therefore, psvchomotor and nemory impair-
n1enr is limited ro rhe first few hours afcer adminisrracion and
these effecrs are generallv noc obsen'ed ar 6 hours afrer adnin
iscration.lz This shorc durarion of act;on of zolpidem may
ac.ounc For rhe no|e marked suppfession oF che arousal re-
sponses eariy in the evening, rvhen CI-R evenrs are most com-
trton, wich rerurn ro nomral in che period beFore morning
arvakening.zl This efFect of zolpitlem rvas also seen in normal
subjects u4rere prolongation in acrd exposure was recorded,
albeir stiLl brief in duration compared wirh the reflux parients
rvho were selected on rhe b:rsis of prior abnorrn:rl pH studies.
Singh ec al have previously shown thar noccurnal adrninis
cration of rhe benzodiazepine, alp|azolam, prolongs esophageal
acid .learance ti111e versus placebo.2r Hou'ever, polysomnogr:r
pfry *as nor utilized and therefore it is unclear from dris study
rvlrat eFFecc alprazolun had on arousals and arvakenings and
overall sleep:uchitecrure. Fass er ai, in a longirudinal srudy oF
over 15,000 sllbjects in rhe Narional Instirrrtes of Health Sleep
Heart Hcalch srudy, found benzodiazepine use, along with
inson-rnia, bocly mass index, sofr drink consunption,:rnd hy-
perrension to be scrong preclictors oF heartburn drLring sleep.l5
ZOLPIDEITI AND NOCTURNAL ESOPHAGEAL ACID 951
600
500
300
200
100
0
Zolpidem
C)ur scudv objectively' denonstraced. rrsing polyson-rnographv.
that zolpidem impairs arousals. This is likely a resulr ol :r
blunting of the CNS response co acid in rhe distal esophagus.
Failure to induce an arousal prevents a prorecdve swalLo\r'ing
reflex. As a resLllt. rhere is increased esophageal acid exposure.
uhich may lead ro addirional cornplications of CERD. Sini
larly. other CNS depressants or ps1'chotropic nredicarions may
also have rhis effect.
This mechaniscic srudy may have clinical relevance. The
rr crd. rcc of esoplrrg, :l adcnoc.,r'crn,,rna c^n r il| , s r, \ 'nr r..lsc
in mosr of the developed world.r, The cause of rhis rise is srill
noc cLear. Ho$,ever, CERD. and especiallv Barrett's esopha!!s.
is a fecognized precursor lesion. Increasingly. Americans are
using sleep aids on a Frequenr or rcgular basis.lrThis srudy
demonstrates the CNS bltrnring eFfecas of such rnedicarions on
the arousal response to acid in rhc distal esophagts drar pro
longs acid exposure. This increased acid exposLlre afrer hvpnot,
ics occurs boch in normal subjects trrt cven nrore so in reflux
patienrs, !r'hich would be expected to increase mucosal damag-
ing efFects. The inc|eased acid exposure in pacienrs with GERD
may contribute. along v,ith other faccors, ro complicaced gas
rroesophageal refltrx disease.
To prove a long term delererious cffecc of hypnoric use on
gas.roesophageal reflux clisease will require an epiderniological
cohort study in a large popuLation base over time. However, as
many as 15o/o 3096 ofpadenrs rvith disturbed sleep may h:rfbor
uncliagnosed GERD.2r.16 27 If rhis effect of blrrnred arousals or
awakenings by frypnorics noted in chis sturly is subsranriared.
d-ris t,ordd suggesr caution in the use ofsleep aids uithout firsr
considering GERD as an eriologic fxctor in patienrs rvirh com
plainrs of disturbed sleep.']s.'?s.l'l
One possible limirarion of rhis study is a function of che
relatively small san,ple size. Howevet. ue ninimized stLch el.-
fects by analyzing dara by evenrs and not by subjecr. In addition
chere are linitations inrrinsic in any study using polysornnog-
rapl-rv. Slecp pacrerns lrrav vary from nighr to night in a given
sLLbject. In addition, previous sruclies which rrtilizecl polysom
nography. have demonsrrated thac an adaprarion effecr is noted
after the initial sleep srudy. characterized by improvemenr in
sleep conrinuity measures in srLbsequenr sleep studies.rrr rr Bv
randonizing che patients ro placebo or zolpidem on differenr
nigbcs we arrenpted co limir rhis effect.
In conclusion, rhis srtLdy. uriltzing objeccive paralneters ao
measure acid leflux and sleep nechanics demonstrared drat
hypnoric medication use in pacienrs s,ith and l,ithour estab-
lished noccurnal GER prolongs esophageal acid conract time by
impairing reflui associated arousals and alakenings. H1'pnotic
medicarions should be used wich caution in parienrs with
knouer supine cERD. GERD should be suspecred and invesri,
t-
952 GAGLIARDI FT AL
gated as a cause in patients wirh insomnia or disrurbed sleep.
Furthermore, use of hypnoric medicarions shorld be restricted
during 2,1 hour pH testing to avoid false posirive results.
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Repfint requests
Address requests for reprints to: Anthony J. Dilvlarino, Jr, lvlD, Divi-
sion of Gastroenterology and Hepatology, Thomas Jefferson University
Hospital, 132 South 10th Street, Suite 480 Main, Philadelphia, Penn-
sylvania 19107. e-mail: anthony.dimarino@jefferson.edu; fax: (215)
955-O472.
Conflicb of intercst
Karl Doghramji, MD, serues as a consultant for Sandolfi-Aventis. The
remaining authors disclose no conflicts.
Funding
This research was supported mainly through a grant from the Com-
monwealth of Pennsylvania with approximately 2070 support from the
lnvestigatols Sponsored Study Program of Astrazeneca.