Therapeutic Options FOCUS ON GASTROESOPHAGEAL REFLUX DISEASE

Therapeutic
TherapeuticOptions
Options
FOCUS
FOCUS
ONON
GASTROESOPHAGEAL
GASTROESOPHAGEAL
REFLUX
REFLUX
DISEASE
DISEASE
Gastroesophageal
Gastroesophageal
refluxreflux
disease
disease
(GERD)
(GERD)
is oneisof
one
theofmost
the most
common
common
gastrointestinal
gastrointestinal
disorders,
disorders,
with an
with an
estimated
estimated
prevalence
prevalence
of 10–20%
of 10–20%
1,2
1,2
in developed
in developed
Western
Western
countries.
countries.
WhileWhile
somesome
refluxreflux
of gastric
of gastric
contents
contents
into the
intoesophagus
the esophagus
occurs
occurs
normally,
normally,
GERDGERD
can be
can
defined
be defined
as as
refluxreflux
that causes
that causes
troublesome
troublesome
symptoms
symptoms
and/or
and/or
esophageal
esophageal
1
1
mucosal
mucosal
injury.*
injury.*
Despite
Despite
beingbeing
associated
associated
with low
withdiseaselow diseaserelated
related
mortality,
mortality,
GERDGERD
imposes
imposes
an important
an important
burden
burden
of illness,
of illness,
with evidence
with evidence
to suggest
to suggest
that that
health-related
health-related
quality
quality
of lifeofislife is
worseworse
in patients
in patients
with GERD
with GERD
than in
than in
thosethose
with diabetes,
with diabetes,
hypertension,
hypertension,
3
3
mild heart
mild heart
failure,
failure,
and arthritis.
and arthritis.
or cause
or cause
pathologic
pathologic
refluxreflux
include
include
reduced
reduced
LES tone,
LES tone,
hiatalhiatal
hernia,
hernia,
esophageal
esophageal
peristaltic
peristaltic
dysfunction,
dysfunction,
esophageal
esophageal
hypersensitivity,
hypersensitivity,
increased
increased
intragastric
intragastric
pressure,
pressure,
and and
1,4,5
1,4,5
delayed
delayed
gastric
gastric
emptying.
emptying.
Several
Several
medications
medications
may reduce
may reduce
LES LES
tone (e.g.,
tone anticholinergic
(e.g., anticholinergic
agents,
agents,
benzodiazepines,
benzodiazepines,
beta-agonists,
beta-agonists,
dihydropyridine
dihydropyridine
calcium
calcium
channel
channel
blockers,
blockers,
estrogens,
estrogens,
nitrates,
nitrates,
opioids,
opioids,
progesterone,
progesterone,
theophylline)
theophylline)
or cause
or cause
mucosal
mucosal
damage
damage
(e.g., (e.g.,
bisphosphonates,
bisphosphonates,
iron preparations,
iron preparations,
nonsteroidal
nonsteroidal
anti-inflammatory
anti-inflammatory
6
6
drugs,drugs,
potassium
potassium
chloride).
chloride).
A definite
A definite
relationship
relationship
between
between
GERDGERD
and obesity
and obesity
has been
has been
2
2
established.
established.
Evidence
Evidence
shows
shows
that obesity
increases
increases
the risk
the risk
This article
This article
provides
provides
a briefa overview
brief overview that obesity
of GERD
of GERD
in adults,
in adults,
with awith
focus
a focus
on on
of reflux
of reflux
symptoms,
symptoms,
prolonged
prolonged
the pharmacological
the pharmacological
management
management esophageal
esophageal
acid exposure,
acid exposure,
and and
1
1
of core
ofsymptoms
core symptoms
and complications
and complications GERDGERD
complications.
complications.
Increased
Increased
with prescription
with prescription
medications.
medications.
abdominal
abdominal
pressure
pressure
is theispivotal
the pivotal
mechanistic
mechanistic
factorfactor
in obesityin obesity1
1
PATHOGENESIS
PATHOGENESIS
& RISK
& RISK
FACTORS
FACTORS related
related
GERD.GERD.
Pregnancy
Pregnancy
is also
is also
a well-established
a well-established
GERDGERD
risk risk
Transient
Transient
lowerlower
esophageal
esophageal
sphincter
sphincter factor.
factor.
As with
As obesity,
with obesity,
pregnancy
pregnancy
(LES)(LES)
relaxations
relaxations
represent
represent
the the
is associated
is associated
with increased
with increased
primary
primary
mechanism
mechanism
responsible
responsible
intragastric
intragastric
pressure;
pressure;
pregnancypregnancy1
1
for gastroesophageal
for gastroesophageal
reflux.reflux.
related
related
hormonal
hormonal
changes
changes
also also
resultresult
in reduced
in reduced
LES tone.
LES 1,4
tone.1,4
TheseThese
relaxation
relaxation
events
events
are are
triggered
triggered
by gastric
by gastric
distension
distension
and serve
and serve
to enable
to enable
gas venting
gas venting
SYMPTOMS
SYMPTOMS
& COMPLICATIONS
& COMPLICATIONS
1
1
from from
the stomach
the stomach
(belching).
(belching).
OtherOther
factors
factors
that predispose
that predispose
to to
Heartburn
Heartburn
and regurgitation
and regurgitation
are are
*
the two
themost
two most
typical
typical
symptoms
symptoms
of of
1,2
1,2
GERD.GERD.
Classic
Classic
heartburn
heartburn
manifests
manifests
as a painful
as a painful
retrosternal
retrosternal
burning
burning
sensation
sensation
that isthat
fairly
is fairly
brief in
brief in
duration
duration
(several
(several
minutes);
minutes);
however,
however,
somesome
patients
patients
describe
describe
anginaangina1
like chest
like chest
pain.1 pain.
Regurgitation
Regurgitation
is
is
characterized
characterized
by the
bybackflow
the backflow
of of
gastric
gastric
content
content
into the
intomouth,
the mouth,
not innot
association
in association
with nausea
with nausea
or
or
1
1
retching.
retching.
Reflux
Reflux
and heartburn
and heartburn
are most
are most
common
common
during
during
the day,
the day,
especially
especially
postprandially,
postprandially,
but but
1
1
both both
can also
can occur
also occur
nocturnally.
nocturnally.
Less typical
Less typical
symptoms
symptoms
of GERD
of GERD
include
include
dysphagia,
dysphagia,
dyspepsia,
dyspepsia,
epigastric
epigastric
pain, pain,
nausea,
nausea,
bloating,
bloating,
2
2
and belching.
and belching.
While
While
all ofall
these
of these
symptoms
symptoms
may be
may
indicative
be indicative
of of
GERD,GERD,
they also
they overlap
also overlap
with with
2
2
otherother
conditions.
conditions.
Extraesophageal
Extraesophageal
manifestations
manifestations
may include
may include
chronic
chronic
cough,
cough,
asthma,
asthma,
and laryngitis
and laryngitis
accompanied
accompanied
by hoarseness,
by hoarseness,
although
although
establishing
establishing
that such
that such
problems
problems
are caused
are caused
by GERD
by GERD
may may
1,2
not be
not
possible.
be possible.
It is1,2currently
It is currently
unclear
unclear
whether
whether
a trueaassociation
true association
existsexists
between
between
GERDGERD
and pharyngitis,
and pharyngitis,
sinusitis,
sinusitis,
pulmonary
pulmonary
fibrosis,
fibrosis,
recurrent
recurrent
1
1
otitis otitis
media,
media,
or sleep
or sleep
apnea.
apnea.
Esophageal
Esophageal
complications
complications
associated
associated
with pathologic
with pathologic
refluxreflux
include
include
erosive
erosive
esophagitis,
esophagitis,
esophageal
esophageal
stricture,
stricture,
and Barrett’s
and Barrett’s
A broader
* A broader
definition
definition
proposed
proposed
in the 2013
in the
guidelines
2013 guidelines
for the for
diagnosis
the diagnosis
and management
and management
of GERD
offrom
GERD
the
from
American
the American
CollegeCollege
of Gastroenterology
of Gastroenterology
is as follows:
is as follows:
“GERD “GERD
2
should be
should
defined
be defined
as symptoms
as symptoms
or complications
or complications
resulting
resulting
from the
from
reflux
theofreflux
gastric
of contents
gastric contents
into theinto
esophagus
the esophagus
or beyond,
or beyond,
into theinto
oralthe
cavity
oral(including
cavity (including
larynx) or
larynx)
lung.”or
lung.”2
THERAPEUTIC
THERAPEUTIC
OPTIONS
OPTIONS
JANUARY/FEBRUARY/MARCH
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2014 2014
I
I
esophagus (the replacement
of normal squamous mucosa
by potentially precancerous
metaplastic columnar cells).1,4,5
In addition, patients with
GERD are at increased risk of
esophageal adenocarcinoma.4
CLASSIFICATION & DIAGNOSIS
Gastroesophageal reflux disease
can be classified according to
the presence or absence of
esophageal injury on endoscopic
examination. When no esophageal
abnormalities or erosions are
present, as is the case in most
instances, patients are said to have
non-erosive reflux disease (NERD;
also referred to as endoscopynegative reflux disease).1-3 If
endoscopy shows mucosal damage,
erosive reflux disease, or erosive
esophagitis, is said to exist.1,2
A diagnosis of GERD is
generally established using
some combination of symptom
presentation, endoscopy,
ambulatory reflux monitoring,
and response to antisecretory
drug therapy.2 In many instances,
a presumptive diagnosis of GERD
is based on the presence of
typical symptoms of heartburn
and regurgitation.2 Further details
and recommendations regarding
diagnosis are available in the
2013 guidelines for the diagnosis
and management of GERD
from the American College of
Gastroenterology (ACG)2 (see
References, below, for URL).
MANAGEMENT
Nonpharmacological Interventions
Lifestyle and dietary modifications
often recommended for patients
with GERD are summarized in Box 1.
It is notable that, with the exception
of elevation of the head of the
bed, evidence for the efficacy of
these interventions does not come
from randomized controlled trials.2
It is also worth mentioning that
smoking cessation, while sensible
to recommend for overall health
benefits, has not been shown
to improve GERD symptoms or
esophageal pH in clinical studies.2
Pharmacotherapy
Medications that suppress gastric
acid are the mainstay of treatment
for GERD.4 The primary therapeutic
alternatives include antacids and
alginates, histamine2-receptor
II
Box 1 – Lifestyle and dietary interventions for GERD1,2,5
Weight loss
• Recommended for patients who are overweight (BMI of 25.0–29.9)
or obese (BMI ≥30), or for patients whose symptom onset was
concurrent with weight gain within the normal BMI range (18.5–24.9)
Head of bed elevation
• Recommended for patients with nocturnal symptoms
Avoidance of late evening meals (i.e., 2–3 hours before bedtime)
• Recommended for patients with nocturnal symptoms
Elimination of specific foods/beverages
• Routine global elimination of foods and beverages that have
been reported to cause symptoms (e.g., chocolate, mint, coffee/
tea/caffeinated beverages, carbonated beverages, alcohol,
acidic or spicy foods, fried/fatty foods) is not recommended;
however, it is reasonable to suggest avoiding specific foods and
beverages that, in the patient’s experience, trigger symptoms
Consumption of smaller/more frequent meals
• Suggested by some experts for postprandial symptoms
Avoidance of lying down after meals
• Reasonable to suggest if postprandial recumbency brings about symptoms
BMI = body mass index; GERD = gastroesophageal reflux disease
antagonists (H2RAs), and proton
pump inhibitors (PPIs). The choice
of drug depends on the severity
and frequency of symptoms, as
well as the presence or absence
of esophageal mucosal injury.4
esophagitis, and for maintenance
of symptom control and healing.1,3-5
Still, H2RAs may be reasonable
for selected patients with nonerosive disease,4 especially if
cost is a significant concern.
Dosing recommendations and
other pertinent information about
antisecretory medications used to
treat GERD are presented in Table 1.
According to the ACG guidelines,2
a PPI is recommended to treat
extraesophageal symptoms in
patients who also have typical
symptoms of GERD. In the absence
of typical GERD symptoms,
though, the guidelines suggest
considering reflux monitoring
prior to a trial of PPI therapy.2
Initial Treatment
For patients with mild and
infrequent symptoms, as-needed
treatment with over-the-counter
antacids, alginates, and low-dose
H2RAs is often sufficient.1,3 When
choosing between antacids and
H2RAs, it should be kept in mind
that antacids have a quicker onset
of action, whereas H2RAs have a
longer duration of action.4 Regular
treatment with standard-dose
H2RAs is an option for patients
with frequent mild symptoms
and non-erosive disease.4
In patients with moderate to
severe symptoms, and those with
erosive esophagitis, PPI treatment
is generally considered first-line
therapy.1-4 PPIs are superior to
H2RAs with respect to reduction
of heartburn and healing of
Assessment of symptomatic
response to antisecretory
therapy should generally take
place after four to eight weeks.3
However, it should be kept in
mind that the proportion of
patients whose symptoms
respond to therapy may continue
to increase up to 16 weeks.3
When there is partial, but
inadequate, response to therapy
with a course of standard-dose PPI
given once daily, good adherence
and proper administration (see
Table 1) should be verified. After
these variables are ruled out
as causes for lack of response,
THERAPEUTIC OPTIONS JANUARY/FEBRUARY/MARCH 2014
Table 1. Antisecretory medications for GERD1-7
Drug
Standard Oral Adult Dosea
Commentsb
Histamine2-receptor antagonists
Cimetidine
600 mg twice daily
Famotidine
20 mg twice daily
Nizatidine
150 mg twice daily
Ranitidine
150 mg twice daily
• All H2RAs are similarly effective in GERD, and are less effective
than PPIsc
• Generally reserved for treatment of mild and infrequent (e.g., <3
times/week) symptoms in patients with NERD
Proton pump inhibitors
Dexlansoprazole
30 mg once daily
Esomeprazole
20 mg once daily
Lansoprazole
30 mg once daily
Omeprazole
20 mg once daily
Pantoprazole
40 mg once daily
Rabeprazole
20 mg once daily
• All standard-dose PPIs are similarly effective in GERD, and are more
effective than H2RAsc
• Complete symptom relief with PPIs can be expected in ~70–80%
of patients with erosive reflux disease and ~60% of patients with
NERD; others may obtain partial relief
• An 8-week course of therapy is recommended in the ACG guidelines
for both symptom relief and healing of erosive esophagitisd
• PPIs should generally be administered 30–60 minutes before the
first meal of the day to ensure maximal pH control and efficacy;e
the product monograph for dexlansoprazole indicates it may be
administered without regard to food
• Maintenance therapy should be titrated to the lowest dose that
provides effective symptom control; dosing may be “continuous”,f
“intermittent”,f or “on-demand”;f periodic reassessment of the need
for continued therapy is recommended
ACG = American College of Gastroenterology; GERD = gastroesophageal reflux disease; H2RA = histamine2-receptor antagonist;
NERD = non-erosive reflux disease; PPI = proton pump inhibitor
a. For proton pump inhibitors, quoted standard doses are from the RxFiles Drug Comparison Charts6 and are based on a report from the Canadian
Agency for Drugs and Technologies in Health.8 Other references3,5 cite a higher standard dose for esomeprazole (40 mg). For dexlansoprazole
and esomeprazole, monograph-approved daily doses for healing of reflux esophagitis are twice those listed (i.e., dexlansoprazole 60 mg,
esomeprazole 40 mg).7
b. It is notable that comments do not focus on safety aspects of the treatment options, including use during pregnancy; however, online guidelines 2
and other sources5 provide a more detailed discussion of this subject matter (see References, below, for URLs).
c. Several references2,3,5 cite a large meta-analysis that demonstrated superior erosive esophagitis healing rates for PPIs compared with H2RAs
(84% vs. 52%). Some data indicate esomeprazole 40 mg/day results in small improvements (~4%) in healing rates compared with other PPIs;
however, the clinical relevance of such differences is debatable and results have not been consistently replicated. 2,3 The RxFiles Drug Comparison
Charts6 report that there are no clinically important differences among standard doses of PPIs for treatment of esophagitis or NERD, noting that
patient variation in response may be seen.
d. When dosing is increased to twice daily administration due to inadequate response, 8-week courses of therapy are recommended by some
experts prior to repeat symptom assessment.1
e. Once daily therapy administered prior to the evening meal may be more effective for nocturnal acid control.4 Twice daily therapy should be
administered 30–60 minutes before breakfast and dinner.5
f. According to a Canadian consensus conference document on GERD, “continuous” therapy is taken daily for an indefinite period of time;
“intermittent” therapy is taken daily for a finite period of time (usually 2–8 weeks); and “on-demand” therapy is taken daily for a period sufficient
to resolve symptoms, at which point it is discontinued until symptoms recur.3 Continuous therapy is recommended following peptic stricture
dilation to improve dysphagia and reduce the need for repeated dilations.2
a trial of twice daily PPI (i.e.,
twice the standard dose) may
be considered.2,3 Alternatively,
switching to a different PPI at
the standard dose may improve
symptoms, but it should be
noted that this approach is
based on limited data.2
Adding a bedtime dose of an H2RA
to ongoing PPI therapy has been
shown to further reduce nocturnal
acid secretion; however, data
indicate that this effect lasts only a
few weeks.1 In addition, concomitant
therapy with PPIs and H2RAs has
not been supported by studies using
THERAPEUTIC OPTIONS JANUARY/FEBRUARY/MARCH 2014
clinical endpoints.3,5 Nonetheless,
the ACG guidelines state that
bedtime H2RA therapy can be
added to daytime PPI therapy in
selected patients with objective
evidence of night-time reflux,
noting that tachyphylaxis of pH
control may develop after a month
III
of therapy.2 As-needed, as opposed
to continuous, H2RA dosing may
help mitigate tachyphylaxis.2
Prokinetic or promotility agents,
either alone or in conjunction
with standard therapies, are not
recommended for routine initial
treatment of GERD.2,3 Neither
domperidone nor metoclopramide
appear to be very effective for
GERD.3 In fact, some evidence
suggests they are ineffective.1
Although data for cisapride
indicate some benefit in patients
with GERD,1,3 the drug is no longer
commercially marketed.†
Treatment of Refractory Disease
No consensus exists as to what
constitutes refractory GERD.2 Some
experts define refractory GERD
as reflux-related symptoms or
mucosal lesions not responding
to a high dose of PPI1 (e.g., twice
daily therapy). In any case, good
compliance and proper PPI
administration (see Table 1) should
be confirmed and optimized as
appropriate.2 For patients who
have only received standarddose PPI treatment, a trial of
twice daily therapy should be
considered, especially if there
References
1. Bredenoord AJ, Pandolfino JE,
Smout AJ. Gastro-oesophageal
reflux disease. Lancet. 2013
Jun 1;381(9881):1933-42.
2. Katz PO, Gerson LB, Vela
MF. Guidelines for the
diagnosis and management
of gastroesophageal reflux
disease. Am J Gastroenterol. 2013
Mar;108(3):308-28. Available
from: http://gi.org/guideline/
diagnosis-and-managemenof-gastroesophagealreflux-disease/
3. Armstrong D, Marshall JK, Chiba
N, Enns R, Fallone CA, Fass R,
Hollingworth R, Hunt RH, Kahrilas
PJ, Mayrand S, Moayyedi P,
Paterson WG, Sadowski D, van
Zanten SJ; Canadian Association
of Gastroenterology GERD
was partial response to once daily
dosing.1,2 A trial of a different PPI
is also an option for patients with
refractory symptoms.2 Further
evaluation and/or diagnostic
testing should be considered
for PPI non-responders.1,2
Patients with refractory symptoms
(despite PPI optimization) who
have objective evidence of
ongoing reflux as the cause of
symptoms should be considered for
additional anti-reflux therapies.1,2
Examples of such therapies include
surgery and baclofen, which
inhibits transient LES relaxations
and has been shown to reduce
postprandial and nocturnal reflux
activity.2,4 The suggested dose of
baclofen is 5–20 mg three times
daily.2 Clinicians and patients
should be aware that central side
effects (e.g., drowsiness, dizziness,
lightheadedness) are common with
baclofen, and that long-term data
in patients with GERD are lacking.2,4
Patients in whom all objective
testing (e.g., endoscopy, ambulatory
reflux monitoring) is negative
are unlikely to have GERD and
PPI therapy in such individuals
should be discontinued.2
Consensus Group. Canadian
Consensus Conference
on the management of
gastroesophageal reflux
disease in adults – update 2004.
Can J Gastroenterol. 2005
Jan;19(1):15-35. Available from:
http://farncombe.mcmaster.
ca/documents/Armstrongetal.
CanJGastroenterol200519115-35.pdf
4. Drugs for peptic ulcer disease
and GERD. Treat Guidel Med
Lett. 2011 Sep;9(109):55-60.
5. Kahrilas PJ. Clinical practice.
Gastroesophageal reflux
disease. N Engl J Med. 2008
Oct 16;359(16):1700-7. Author
manuscript available from:
http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3058591/
pdf/nihms209815.pdf
Maintenance Treatment
The majority of patients with
GERD will require some form of
maintenance therapy to control
symptoms and/or maintain
esophageal healing.3 Indeed, data
suggest that 70–100% of patients
with esophagitis and approximately
75% of patients with NERD will
relapse within six months of
treatment discontinuation.3
The ACG guidelines recommend
maintenance PPI therapy for
patients who have symptoms
after a PPI is discontinued, as
well as for patients who initially
presented with complications,
including erosive esophagitis
and Barrett’s esophagus.2 Stepdown maintenance therapy with
H2RAs is an option for patients
with NERD if these agents provide
adequate symptom relief.2
The lowest medication dosage
and frequency that provide
effective control of symptoms
should be employed in longterm maintenance therapy.2,3
Dosing strategies may include
intermittent or on-demand
treatment2,3 (see Table 1).
6. RxFiles Drug Comparison Charts
– 9th Edition. Editors: Jensen
B, Regier L. Saskatoon, SK:
Saskatoon Health Region; 2012.
Available from: www.RxFiles.ca
7. Canadian Pharmacists
Association. e-CPS [database
on the Internet; cited 2013
Oct 16]. Ottawa: Canadian
Pharmacists Association; 2013.
8. Canadian Agency for Drugs
and Technologies in Health.
Evidence for PPI use in
gastroesophageal reflux
disease, dyspepsia and peptic
ulcer disease: scientific report.
COMPUS Optimal Therapy
Report. 2007 Mar;1(2). Available
from: http://www.cadth.ca/
media/compus/reports/compus_
Scientific_Report_final.pdf
† Cisapride is available via Health Canada’s Special Access Programme.
Disclaimer: The Drug Information and Research Centre (DIRC) of the Ontario Pharmacists Association provides this material to health professionals for informational
purposes only. It is provided without warranty of any kind by DIRC and DIRC assumes no responsibility for any errors, omissions or inaccuracies therein. It is the
responsibility of the health professional to use professional judgment in evaluating this material in light of any relevant clinical or situational data.
IV
THERAPEUTIC OPTIONS JANUARY/FEBRUARY/MARCH 2014
`