An Evidence-Based Approach to
                                                          Cost-Effective Management
                                                            Mary Knudtson, MSN, FNP, PNP and Rick H. Davis, Jr, PA-C

                                                   LEARNING OBJECTIVES FOR THIS CONTINUING
                                                   EDUCATION ARTICLE*
This Independent Study Activity is                 Upon completion of this program, participants will be able to:
approved for 1.0 contact hours by the
Washington State Nurses Association, an            1. Differentiate symptoms of frequent heartburn (FHB) from episodic
accredited approver by the American Nurses            heartburn.
Credentialing Center’s Commission on
Accreditation (ANCC). The accreditation for        2. Counsel patients appropriately on lifestyle changes and determine
this program expires 1 year from the date of          pharmacotherapeutic interventions for FHB.
publication (that is, on January 31, 2006).
                                                   3. Evaluate the cost-effectiveness of intermittent therapy for FHB.
This activity is provided to you at no charge
through FnP Associates. To obtain continu-
                                                   4. Identify patients who need further evaluation of heartburn symptoms.
ing education credit for this activity:
1. Log on to
2. Go to the menu.                                             Heartburn is a sensation of burning discomfort that generally
2. Select the “test only” option.                              starts in the retrosternal area and moves upward toward the throat.1
                                                               It may be accompanied by a sour taste in the mouth (“acid indiges-
3. Register, take the Post-test, and fill out
the Evaluation Form and Registration                           tion”), and is caused by reflux of gastric contents into the esophagus.
Form.                                                          Heartburn may be self-limited, or it may be a symptom of gastroe-
If you score 80% or higher on the post-test,                   sophageal reflux disease (GERD), a condition characterized by fre-
you will be able to print a Certificate of                     quent gastroesophageal (GE) symptoms and/or mucosal damage of
Completion. If you do not score 80% or                         the upper gastrointestinal (GI) tract.2 It may occur on an episodic
higher, you will have a second opportunity                     basis (eg, after eating a hot spicy meal), an intermittent basis (once
to take the test.                                              monthly to once weekly), or a frequent basis (≥2 times per week).
If you do not have Internet access and need                    This article focuses on the diagnosis and treatment of frequent heart-
a hard copy of the post-test, evaluation                       burn (FHB), which may overlap with the approach to GERD.
form, and registration form, please contact
FnP Associates, LLP at fiona@fnpassociates
                   ,                                           Although many patients self-treat their heartburn symptoms with
or call (360) 297-1274.                                        over-the-counter (OTC) medications, they should consult their
                                                               healthcare professional for guidance in this regard. Primary care
Full references for this article are also avail-               nurse practitioners (NPs) need to be able to distinguish between
able at
                                                               episodic and frequent heartburn—each has different treatments and
This program was supported by an unre-                         health implications—and then guide patients in choosing the best
stricted educational grant from Procter &                      agent for them, one that is not only effective but is also cost-effective
Gamble.                                                        in “extinguishing” the problem.

                                                                                Vol. 9 No. 1 January 2005 The American Journal for Nurse Practitioners   I   137
                            SPECIAL SUPPLEMENT
PREVALENCE AND                                                         emotional role limitations, and men-      for reflux in monozygotic pairs, as com-
DEMOGRAPHICS                                                           tal health.10                             pared with dizygotic pairs, suggesting
Heartburn afflicts nearly two thirds of US                             This same group of patients had           genetic, rather than environmental,
adults at some point in their lives.3                                  lower scores on a test of emotional       effects.13 The investigators stated that her-
According to a large survey conducted                                  well-being than did patients with         itability accounted for 31% (23%-39%)
16 years ago by the Gallup Organization,                               diabetes or hypertension.10               of the tendency to develop reflux disease
44% of adults suffer from heartburn at                                 The 2000 Gallup survey showed             in this population. Finally, estrogens
least once a month, 20% experience it at                               that, among 1000 respondents with         may exacerbate the risk: A population-
least once a week, and 7% have it every                                heartburn, the following proportions      based, cross-sectional, case-control
day.4 In 1997, a population-based study                                reported moderate to severe impair-       study revealed that the association
of 2200 residents of Olmstead County,                                  ment in their:                            between obesity and reflux symptoms
Minnesota, came up with the same find-                                 – ability to eat/drink what they want:    was significantly stronger among pre-
ings in terms of the proportion of US                                    46%                                     menopausal women than among post-
adults who experience heartburn and/or                                 – ability to get a good night's sleep:    menopausal women, and that the use of
acid regurgitation on at least a weekly                                  40%                                     hormone replacement therapy (HRT) in
basis: 19.8%.5 In 2004, a cross-sectional                              – ability to sleep when they want to:     the postmenopausal group significantly
survey of 496 employees at a Veterans                                    36%                                     increased the strength of the association.14
Administration medical center revealed                                 – ability to eat/drink when they
that heartburn occurring at least weekly                                 want: 36%                               PHYSIOLOGY AND
was reported by 27% of blacks, 23% of                                  – mood and general well-being: 35%        PATHOPHYSIOLOGY
whites, and 24% of members of other                                    – day-to-day functioning: 25%             In normal, healthy individuals, billions
racial groups; thus the rate of heartburn                              – social activities: 23%                  of tiny pumps in the stomach manufac-
was similar across racial lines.6                                      – functioning at work: 23%                ture hydrochloric acid, which breaks
Heartburn does show a “preference” for                                 – spouse’s sleep: 18%.9                   down food. The lower esophageal
gender, though: Among persons with                                                                               sphincter (LES) in these individuals
                                                                    If FHB is a manifestation of full-blown      keeps the acidic gastric contents from
FHB—that is heartburn occurring at                                  GERD, then patients are at risk for the
least twice a week, 58% are female and                                                                           rising back into the esophagus. In some
                                                                    sequelae of prolonged esophageal injury.11   individuals, however, the LES temporar-
42% are male.7,8 The average FHB suf-
ferer is between the ages of 45 and 50.7                                                                         ily relaxes, allowing reflux of the acidic
                                                                    RISK FACTORS                                 gastric contents into the esophagus,
   In 2000, the American Gastroenter-                               The aforementioned study of people in
ological Association (AGA) commissioned                                                                          which causes the sensation of heartburn.
                                                                    Olmstead County, Minnesota, revealed             Transient LES relaxation may be
the Gallup Organization to conduct a poll                           that obesity and a positive family history
of individuals with heartburn occurring                                                                          caused by eating certain foods or bever-
                                                                    were the main risk factors for frequent      ages or by pressure on the stomach.
on at least a weekly basis to find out more                         reflux symptoms.12 Other risk factors
about the pattern of their symptoms.9                                                                            Increased abdominal pressure may be
                                                                    cited in this study included a past his-     caused by frequent bending and lifting,
Among 1000 respondents, 79% reported                                tory of smoking, consuming seven or          vigorous exercise, or pregnancy.15-17
having nocturnal heartburn—with 60%                                 more drinks per week, and a higher psy-      Conditions such as hiatal hernia, gastro-
experiencing symptoms that were severe                              chosomatic symptom checklist score.          paresis, defective esophageal acid clear-
enough to disturb their sleep and com-                              The following diet/lifestyle choices and     ance, impaired mucosal defense, and
promise their work and quality of life                              behaviors are also associated with an        delayed gastric emptying can also pre-
(QoL) the next day.                                                 increased risk of heartburn:                 dispose individuals to heartburn and
                                                                       exercising after eating;                  GERD. In addition, certain medica-
ADVERSE CONSEQUENCES OF                                                                                          tions, including calcium antagonists (eg,
UNTREATED HEARTBURN                                                    lying down shortly after meals;
                                                                       bending over or straining soon after      amlodipine [Norvasc ®], diltiazem
At the very least, FHB can restrict nor-                                                                         [Cardizem®], nifedipine [Adalat®, Pro-
mal activities and have an adverse                                     meals;
                                                                                                                 cardia®], verapamil [Calan, Isoptin]),
impact on QoL:                                                         drinking several alcoholic, carbon-
                                                                                                                 theophylline, HRT, and muscle relax-
   One study showed that patients who                                  ated, and/or caffeinated beverages
                                                                                                                 ants, can reduce LES pressure.17
   had a history of heartburn for at least                             daily;
                                                                                                                     Not all reflux is pathologic: Normal
   6 months, when compared with a                                      eating fried, fatty, acidic, or spicy     persons may experience up to 50 episodes
   random sample of healthy US adults,                                 foods; and                                of reflux per day, with acid present in the
   fared significantly worse on all eight                              eating chocolate or spearmint/            esophagus for up to 4% of a given 24-hour
   scales of the Medical Outcomes                                      peppermint candy.                         period.18 In healthy persons, gravity and
   Study short-form 36 Health Survey:                                  Genes may play a major role in deter-     peristalsis clear the refluxed material, and
   physical function, bodily pain, physi-                           mining heartburn risk. A study of more       bicarbonate ions in the saliva and secre-
   cal role limitations, vitality, general                          than 8000 twin pairs aged 55 years or        tions from submucosal glands in the
   health perceptions, social function,                             older showed an increased concordance        esophagus neutralize the acid that remains

138   I   The American Journal for Nurse Practitioners January 2005 Vol. 9 No. 1
                           SPECIAL SUPPLEMENT
in the esophagus. Heartburn and, in           to distinguish between episodic or inter-                 “alarm” symptoms (anemia, bleed-
many cases, GERD develop when these           mittent heartburn (1 episode/week) and                    ing, chest pain, dysphagia [difficulty
protective mechanisms and/or mucosal          FHB (≥2 episodes per week), because                       swallowing], hematemesis, involun-
defenses are impaired. That is, peristalsis   the treatment approaches differ. In the                   tary weight loss, melena, odynopha-
may be ineffective, or salivary or            subset of patients with FHB, they may                     gia [severe pain on swallowing],
esophageal secretions may be reduced,         need to determine whether other patho-                    persistent vomiting) are present.25
leading to inadequate clearance or neu-       physiologic processes are going on, and               Endoscopy—Routine endoscopy is not
tralization of refluxate.                     whether damage to esophageal tissue                   recommended for patients with heart-
    It is important to note that not all      has occurred.                                         burn and regurgitation only;25 most
patients with heartburn or even GERD                                                                patients who have heartburn more than
                                              Differential Diagnosis—In taking the
have esophageal damage: 53% to 71%                                                                  twice per week have no endoscopic
                                              history, NPs need to distinguish heart-
of heartburn sufferers have endoscopi-                                                              esophageal mucosal damage.26 However,
                                              burn/GERD from entities such as gastri-
cally normal esophageal mucosa.19 This                                                              patients who have symptoms for 7 to 10
condition is sometimes called nonero-         tis, infectious esophagitis (typically
                                              caused by Candida species), peptic ulcer              years should undergo screening endos-
sive reflux disease, or NERD.20 Some                                                                copy for Barrett's esophagus. Endoscopy
patients with NERD experience heart-          disease (typically caused by Helicobacter
                                              pylori infection), non-ulcer dyspepsia,               is also recommended in patients who
burn symptoms despite having normal                                                                 are experiencing alarm symptoms
levels of esophageal acid exposure as         biliary tract disease, coronary artery dis-
                                              ease, and esophageal motor disorders.23               and/or extra-esophageal manifestations
assessed by 24-hour pH study (see sec-                                                              of GERD (eg, asthma; chronic bronchi-
tion on “Ambulatory Esophageal pH             Another common cause of heartburn-
                                              like pain is pill esophagitis, which occurs           tis, cough, or sinusitis; noncardiac
Monitoring”); these patients, may, in                                                               chest pain; excessive throat clearing;
fact, have esophageal hypersensitivity to     when a pill is swallowed into the esoph-
                                              agus but gets “stuck” on the esophagus                hoarseness; otalgia; pharyngitis; stri-
physiologic degrees of acid reflux. Other                                                           dor).27 This test is particularly useful for
patients with NERD have abnormal acid         wall and burns the lining of the esopha-
                                              gus, causing chest pain and esophageal                diagnosing GERD complications,
exposure but have not developed overt                                                               although it is neither highly sensitive
mucosal injury.                               ulcers. Medications associated with pill
                                              esophagitis include non-steroidal anti-               nor highly specific for GERD itself.11,23

DIAGNOSIS                                     inflammatory drugs (NSAIDs) such as                   Ambulatory Esophageal pH Moni-
HISTORY                                       ibuprofen (Motrin®), naproxen sodium                  toring—According to guidelines from the
When patients present with typical symp-      (Aleve®), aspirin, and celecoxib (Cele-               American College of Gastroenterology
toms of heartburn and no complications,       brex®), and bisphosphonates such as                   (ACG), ambulatory esophageal pH moni-
the diagnosis is usually straightforward      alendronate (Fosamax®) and risedronate                toring helps to confirm GE reflux in
and can be made from the medical his-         (Actonel®). Pill esophagitis can be avoid-            patients with persistent symptoms with-
tory.11 Most patients with heartburn          ed if patients swallow pills according to             out evidence of mucosal damage.24 A pH
describe the following symptoms:              the package directions.                               monitor is placed in the esophagus above
                                                                                                    the LES for 24 hours. While the monitor is
    a retrosternal burning sensation          DIAGNOSTIC TESTING                                    in place, patients keep a diary of symptom
    that radiates toward the throat;          It is not necessary to perform a diagnos-             occurrence. This test is highly sensitive
    a sensation that food is “coming          tic evaluation in all patients who com-               and specific, but it is not widely available
    back up”;                                 plain of heartburn, particularly in those             and it is invasive, time-consuming, and
    a sour or bitter taste in the throat      with infrequent symptoms.22 Even with                 expensive. The AGA recommends pH
    and/or mouth; and/or                      GERD, symptom analysis offers reason-                 recording for patients with equivocal or
    pain that increases when bending          able sensitivity and specificity, and most            abnormal endoscopy results and persis-
    over, lying down, exercising, or          typical cases can be diagnosed on the                 tent reflux symptoms that are refractory to
    lifting heavy objects.21                  basis of symptoms alone. Diagnostic                   proton pump inhibitor (PPI) therapy.28 It is
Symptom Duration and Severity—                testing is recommended in the following               also beneficial in patients with atypical or
Symptoms may last a few minutes to a          cases:                                                extra-esophageal symptoms.
few hours. Their severity depends on              the history is atypical and the diag-             Barium X-rays—An upper GI series is
the reason for LES relaxation, the                nosis is unclear;                                 taken after patients drink a barium solu-
amount of acid entering the esophagus,            symptoms are long-term, frequent,                 tion. Only one third of patients with
and the degree to which the patient's             and/or refractory to treatment;                   GERD, and an even smaller minority of
saliva is able to neutralize the acid.21 Of       continuous long-term therapy is                   patients with documented abnormal
note, patients without macroscopic                likely needed;                                    pH, have radiologic signs of esophagi-
mucosal lesions do not necessarily have
                                                  complications arise (eg, adenocarci-              tis.11 Therefore, this test is considered to
milder symptoms than those with more
                                                  noma of the esophagus, Barrett’s                  be of little practical value in patients
severe esophagitis.22
                                                  esophagus, esophageal bleeding and                with FHB or GERD, although it may be
Symptom Frequency: Episodic Versus                ulcers, esophagitis, strictures, ulcera-          helpful in the detection of esophageal
Frequent Heartburn—NPs will need                  tions);11,23,24 and/or                            strictures or hiatal hernias in patients

                                                                                  Vol. 9 No. 1 January 2005 The American Journal for Nurse Practitioners   I   139
                           SPECIAL SUPPLEMENT
with dysphagia. It may also be helpful in
identifying pathologies unrelated to                                 TABLE 1. MANAGING HEARTBURN IN “THE REAL WORLD”:
GERD, including diverticula, swallowing                                       EASY-TO-DIGEST PRACTICE TIPS
dysfunction, and motility dysfunction.                               I    Encourage patients who present with episodic, intermittent, or frequent heartburn to
                                                                          institute lifestyle modifications to reduce or eliminate heartburn triggers.
MANAGEMENT                                                           I    Recommend use of an antacid or OTC H2RA in patients whose episodic or intermittent
Goals of heartburn management are to                                      heartburn persists despite lifestyle changes.
reduce inappropriate LES relaxation, to
                                                                     I    Recommend a PPI (either OTC or prescription) in patients with FHB.
reduce production of gastric acid, to neu-
tralize gastric acid, and, in some cases, to                         I    Make sure that PPI users are using the product correctly.
promote gastric emptying. A broader goal                             I    Counsel patients about the basic mechanics of reflux, the importance of lifestyle adjust-
is to prevent complications such as                                       ments, the reason for taking the PPI, and the dosing recommendations for the PPI.
esophageal stricture and Barrett's esopha-                           I    Instruct patients with FHB who are using the OTC PPI to take omeprazole magnesium
gus. These goals may be accomplished to                                   once daily, 30-60 minutes before the first meal of the day, for 14 days.
some extent by lifestyle modifications,                              I    Ask patients whose symptoms persist beyond 2 weeks to contact you for further
although hard evidence is lacking that                                    instructions.
these interventions work.25,29 If patients
                                                                     OTC = over-the-counter; H2RA = histamine H2-receptor antagonist;
have difficulty instituting these changes,                           PPI = proton pump inhibitor; FHB = frequent heartburn.
then they may try one or more of three
classes of OTC medications. The efficacy
of these agents has been supported by sci-                           TABLE 2. LIFESTYLE MODIFICATIONS TO EASE HEARTBURN11,24,30
entific research. Of note, one of these
                                                                     Dietary Recommendations
classes has been shown to be particularly
                                                                     Avoid or limit ingestion of caffeinated products, alcohol, carbonated soft drinks, chocolate,
cost effective for patients with FHB. Patient                        tomato-based products, spearmint, peppermint, spicy foods, fatty or greasy foods, onions,
education, counseling, and encourage-                                garlic, and citrus fruits and juices.
ment should be ongoing throughout the
                                                                     Avoid eating before bedtime or 3 to 4 hours before lying down.
course of therapy. Patients whose symp-
toms or treatment refractoriness suggests                            Avoid eating large-volume meals.
that their condition is more serious than                            Lose weight if necessary.
FHB may need to undergo a full round of
                                                                     Physical Recommendations
diagnostic tests and be referred to a gas-
                                                                     Elevate the head of the bed by 4 to 8 inches (in patients with nocturnal symptoms).
troenterologist or other specialist. Table 1
offers NPs practical tips for the general                            Avoid wearing clothing that is tight around the waist.
management of heartburn.                                             Avoid excessive bending over (eg, gardening) or lifting, especially after meals.

                                                                     Miscellaneous Recommendations
                                                                     Review medications that may potentiate heartburn symptoms, including calcium antagonists,
A variety of lifestyle alterations can, at
                                                                     bisphosphonates, and theophylline.
least in theory, mitigate, alleviate, or
even prevent heartburn (Table 2).                                    Stop smoking.
Despite the lack of extensive evidence                               Chew gum or suck on hard candy or lozenges to stimulate saliva production.
supporting the effectiveness of these                                Eat several small meals instead of three large meals throughout the day.
changes as the sole approach, they will
likely enhance the effectiveness of phar-
                                                                    own from one of the many medications                    47% self-medicated for more than 2
macotherapy. In fact, the ACG recom-
                                                                    available OTC (Table 3). According to                   days in a row;
mends that lifestyle modification be
                                                                    one data set, more than 86% of FHB                      34% had used a prescription med-
initiated and continued throughout the
course of therapy.24 The college also                               sufferers report using OTC medica-                      ication to manage heartburn; and
asserts that, despite the lack of data, it is                       tions.33 Before the US Food and Drug                    4% used OTC histamine H2-recep-
reasonable to educate patients about fac-                           Administration (FDA) approved an                        tor antagonists (H2RAs).34
tors that may precipitate reflux. Because                           OTC PPI (Prilosec OTC™) specifically
                                                                                                                         Of interest, approximately 25% of
many patients will not be able to insti-                            for the treatment of FHB symptoms,
                                                                                                                         patients with FHB use 70% of the OTC
tute or maintain these lifestyle changes,                                80% of patients with FHB used                   heartburn products.
periodic drug therapy for symptom                                        antacids;                                           OTC medications are divided into
relief is in order.                                                      58% had spoken to their healthcare              two main groups: antacids, which neu-
OTC MEDICATIONS                                                          provider about heartburn;                       tralize gastric acid,31,32 and acid suppres-
Patients with mild and/or intermittent                                   55% took medications for heartburn              sants, which reduce gastric acid
heartburn typically seek relief on their                                 prevention;                                     secretion and include H2RAs and PPIs.

140   I   The American Journal for Nurse Practitioners January 2005 Vol. 9 No. 1
                               SPECIAL SUPPLEMENT
Medication Trade Name(s)                Indicated           Duration of           Mechanism of Action                Potential Adverse Effects11
Class                                   Specifically        Action
                                        for FHB             (one dose)
Antacids        Tums®                   No                  1-2 hours             Rapidly elevate                    Aluminum salts: constipation,
                Rolaids®                                                          esophageal pH                      accumulation in patients with
                Maalox®                                                           and neutralize                     renal failure, hypophosphatemia,
                Mylanta®                                                          esophageal acid                    osteomalacia (rare); calcium salts:
                Gaviscon®                                                         for up to 90 minutes               constipation, milk-alkali syndrome
                and others                                                        after dosing31,32                  with high doses, rebound hyperacidity
                                                                                                                     (dose-dependent); magnesium salts: diar-
                                                                                                                     rhea, accumulation in patients with renal
                                                                                                                     failure; sodium bicarbonate: milk-alkali
                                                                                                                     syndrome with high doses (these agents
                                                                                                                     should be avoided in sodium-restricted
                                                                                                                     patients); magnesium/aluminum combina-
                                                                                                                     tions: minor changes in bowel function
H2RAs           Tagamet HB 200®         No                  Up to 12 hours        Inhibit gastric acid               Diarrhea, headache, constipation;
                Zantac 75®                                                        secretion                          gynecomastia and low sperm
                Pepcid® AC                                                                                           count (in male users of high-dose
                Axid AR®                                                                                             cimetidine)
PPI             Prilosec OTC™           Yes                 Up to 24 hours*       Shuts down the active              Diarrhea, headache, nausea,
                                                                                  pumps that make                    abdominal pain
                                                                                  gastric acid
*As part of a 14-day course of therapy.
OTC = over-the-counter; FHB = frequent heartburn; H2RA = histamine H2-receptor antagonist; PPI = proton pump inhibitor.

 Antacids—Many patients with heart-                    following medications:35                                  Antacids are less appropriate for patients
 burn self-treat with OTC antacids such as                 allopurinol (Zyloprim)                                with FHB: Their short duration of action
 Mylanta®, Maalox®, Rolaids®, Tums®, or                    aspirin, salicylates                                  means that FHB sufferers would need to
 Gaviscon®, the lattermost of which also                                                                         take multiple doses per day, which
                                                           benzodiazepines (Valium®, Xanax®)
 contains alginic acid. Alginic acid reacts                                                                      would likely lead to side effects even if
                                                           anticoagulants (Coumadin®)
 with saliva to produce a foam barrier on                                                                        patients did adhere to the regimen.11
 top of the stomach that buffers the                       chloroquine (Aralen®)
                                                                                                                 Another drawback is their inadequacy as
 refluxed material. Antacids are composed                  corticosteroids (prednisone,                          heartburn prophylaxis.
 of different combinations of three salts                  Deltasone®, Medrol)
 (magnesium, calcium, and aluminum)                        diabetes medicines (Diabinese®,                       Histamine H2-Receptor Antagonists—
 with hydroxide or bicarbonate ions. They                  Micronase®, Glucotrol®)                               Three types of receptors trigger produc-
 are effective for quick relief of episodic                digoxin (Lanoxin®)                                    tion of hydrochloric acid in the stom-
 heartburn. For maximum relief, antacids                   iron (Feosol®, ferrous sulfate,                       ach. H2RAs block one of these
 should be used as needed, and should be                   Nu-Iron®)                                             receptors—the histamine H2 receptor—
 taken immediately after meals if symp-                    isoniazid (INH)                                       on the gastric parietal cell, thereby
 toms occur.13 Many clinical studies con-                                                                        impeding the formation of hydrochloric
                                                           nitrofurantoin (Macrodantin®)
 ducted in the 1970s, 1980s, and 1990s                                                                           acid. H2RAs that are available OTC
                                                           penicillamine (Depen®, Cuprimine®)
 have shown that antacids are more effec-                                                                        include cimetidine (Tagamet HB 200®),
                                                           phenothiazines (Thorazine® ,                          ranitidine (Zantac 75®), famotidine
 tive than placebo in relieving heartburn.                 Stelazine®, Compazine®)
 However, in addition to having side                                                                             (Pepcid® AC), and nizatidine (Axid
                                                           phenytoin type drugs (Dilantin®,                      AR®). Dosages of these OTC versions are
 effects in some patients (eg, diarrhea,
                                                           Mesantoin®, Peganone®, Cerebyx®)                      one half of the standard lowest prescrip-
 abdominal discomfort, constipation),
 antacids can interact adversely with a                    quinidine (Quinidex®, Quinaglute®)                    tion dosage. (OTC famotidine was
 host of other drugs by preventing or lim-                 tetracycline                                          recently approved at the original pre-
 iting their absorption. For example, a                    thyroid hormone (Synthroid®,                          scription dosage.) Although these four
 combination OTC antacid containing                        levothyroxine)                                        agents differ somewhat in potency, they
 aluminum hydroxide, magnesium                             ticlopidine (Ticlid®)                                 can be used interchangeably according
 hydroxide, calcium carbonate, and sime-                   ulcer medications (Tagamet®,                          to the ACG.24 They are particularly use-
 thicone may interact adversely with the                   Zantac®, Pepcid®, Axid®)                              ful in patients with episodic heartburn

                                                                                               Vol. 9 No. 1 January 2005 The American Journal for Nurse Practitioners   I   141
                            SPECIAL SUPPLEMENT
who take the medication before an activ-                            in 355 patients with symptomatic GERD           (Prilosec®), this drug class includes lan-
ity that is likely to produce reflux symp-                          without esophagitis.46 On days 7 and 27,        soprazole (Prevacid®), pantoprazole (Pro-
toms (eg, eating a heavy or spicy meal).                            respectively, daily proportions of              tonix®), esomeprazole (Nexium®), and
    Comparisons between antacids and                                patients who were heartburn-free were           rabeprazole (Aciphex®). PPIs are highly
the H2RAs are limited, but it has been                              higher in the 20-mg omeprazole group            effective in controlling symptoms and
suggested that the former provide a more                            (62% and 74%) than in the 10-mg                 healing esophagitis, and are used as
rapid response (onset of action, 30 min-                            omeprazole group (41% and 49%) or               maintenance therapy to prevent GERD
utes vs up to 90 minutes),36 whereas the                            the placebo group (14% and 23%).                flare-ups.30 In general, standard-dose
latter are generally more effective and                                 Clinical trials and post-marketing          PPIs will relieve symptoms and heal
have a much longer duration of action.24,36                         surveillance of the prescription formula-       esophagitis in 85% to 90% of patients.50
Efficacy trials have shown that the H2RAs                           tion of omeprazole have demonstrated            Patients with GERD are advised to take
are superior to placebo for the relief of                           the excellent safety profile of this agent.47   the PPI immediately before breakfast.50
episodic heartburn.37-40 Placebo-con-                               No new safety issues have emerged with          Prokinetic Agents—Instead of neutral-
trolled studies have also demonstrated                              the OTC formulation. PPI-related side           izing stomach acid, prokinetic agents
the efficacy of these agents in preventing                          effects include diarrhea, headache, nau-        increase LES pressure, enhance gastric
heartburn.41,42                                                     sea, and abdominal pain, and occur in           emptying, and improve peristalsis.
    Side effects of H2RAs include diarrhea,                         fewer than 10% of users.44 As an                Older prokinetics such as bethanechol
headache, and constipation.11 In males,                             inhibitor of CYP-2C19, omeprazole may           (Urecholine®) and metoclopramide
high-dose cimetidine may cause gyneco-                              increase serum levels of other drugs            (Reglan®) are rarely used because of their
mastia and/or a decreased sperm count.43                            metabolized by 2C19, including war-             side-effect profiles.23 Although cisapride
Drug interactions occur more frequently                             farin (Coumadin®), phenytoin (Dilan-            (Propulsid®) has been found to be equiv-
with cimetidine than with the other                                 tin®), and diazepam (Valium®), and it           alent to standard-dose H2RAs in reliev-
H2RAs because cimetidine impedes                                    may alter absorption of medications such        ing reflux symptoms and healing
hepatic metabolism of these other drugs.11                          as itraconazole (Sporanox®) and digoxin         esophagitis, this medication has been
This list of drugs includes warfarin,                               (Lanoxin®). However, many patients can          associated with cardiac arrhythmias and
theophylline, phenytoin, diazepam, pro-                             use PPIs safely with oral contraceptives        is available on a limited basis. The manu-
pranolol, calcium channel blockers,                                 and with medications for hypertension,          facturer recommends that a baseline
metronidazole, lidocaine, certain tricyclic                         arthritis, and angina.43,48,49                  electrocardiogram be performed before
antidepressants (TCAs), and other drugs                                                                             cisapride therapy is started.51 Concurrent
                                                                    PRESCRIPTION MEDICATIONS
metabolized by the hepatic cytochrome P                                                                             use of cisapride with agents that increase
                                                                    Most patients with typical symptoms of
(CYP)-450 isoenzyme system.11 In addi-                                                                              cisapride blood levels (eg, macrolides,
                                                                    GERD do not have esophagitis;23 as
tion, any H2RA may decrease the                                                                                     nefazodone, antifungals, certain AIDS
                                                                    mentioned earlier, many clinicians rec-
bioavailability of drugs whose effects                                                                              medications) or that predispose patients
                                                                    ognize this as a separate entity called
depend on an acidic gastric pH.44                                                                                   to fatal arrhythmias (eg, class IA or class
                                                                    nonerosive reflux disease or NERD. NPs
                                                                                                                    III antiarrhythmics; certain TCAs, tetra-
Proton Pump Inhibitor—Like H2RAs,                                   must ascertain whether FHB is self-lim-
                                                                                                                    cyclic antidepressants, or antipsychotics)
PPIs suppress gastric acid production.                              ited or a presenting symptom of GERD
                                                                                                                    is contraindicated.51
However, they do so at the source, by                               so that treatment can focus not only on
blocking parietal cell hydrogen/potas-                              relieving heartburn, but also on healing        Comparative Trials—Many studies
sium ion adenosine triphosphatase,                                  the mucosal damage to the esophagus             and two meta-analyses involving pre-
known as the proton pump. This is the                               and preventing further damage. Along            scription-strength medications have
final common pathway in the process of                              with long-standing FHB, other signs and         demonstrated that PPIs are more effec-
gastric acid secretion. Only one PPI,                               symptoms of GERD include regurgita-             tive than other drug classes or placebo in
omeprazole, is available over the                                   tion of sour-tasting material into the          relieving heartburn in patients with
counter: Prilosec OTC™. This medica-                                throat or mouth and frequent belching.          GERD or NERD.
tion contains the equivalent of prescrip-                           Various prescription medications are                A randomized, double-blind trial
tion-strength omeprazole, although it is                            FDA approved for GERD treatment.                    conducted on 310 patients who
formulated as a magnesium salt tablet.                                                                                  received omeprazole 20 mg daily or
                                                                    H2RAs—When given in standard
Bioavailability of omeprazole is similar                                                                                cimetidine 400 mg 4 times daily
                                                                    dosages used for peptic ulcer disease,
in both formulations.45 Omeprazole                                                                                      revealed that after 4 weeks of treat-
                                                                    H2RAs can alleviate mild to moderate
magnesium is the only OTC medication                                                                                    ment, a significantly larger propor-
                                                                    symptoms of GERD.24 In fact, before the
specifically indicated for FHB.                                                                                         tion of omeprazole recipients than
                                                                    introduction of PPIs, these agents were
According to the package labeling, this                                                                                 cimetidine recipients were asympto-
                                                                    the treatment of choice for reflux and
medication is to be taken once daily for                                                                                matic (46% vs 22%; P <0.001).52 In
                                                                    erosive esophagitis.24 However, they are
14 days.                                                                                                                addition, diary cards completed dur-
                                                                    not as effective in either domain as the
   The efficacy of omeprazole 20 mg                                                                                     ing the first 2 weeks showed that
                                                                    prescription-strength PPIs.24,50
was demonstrated in a study comparing                                                                                   omeprazole users experienced fewer
it with omeprazole 10 mg and placebo                                PPIs—In addition to omeprazole                      daytime and night-time symptoms.

142   I   The American Journal for Nurse Practitioners January 2005 Vol. 9 No. 1
                           SPECIAL SUPPLEMENT
   A meta-analysis of 43 studies that         of published economic studies of                      which entails a 7-day course of
   enrolled 7635 patients with GERD           GERD treatments showed that PPIs                      high-dose omeprazole followed by a
   showed that PPIs, relative to H2RAs,       were more cost-effective than H2RAs                   step-down approach (sequential
   provided faster and more complete          because of their fast healing of                      therapeutic trials with less intensive
   relief of heartburn.53 A much larger       esophagitis, early relief of symptoms,                therapy), with sequential invasive
   proportion of PPI recipients than          and prevention of recurrent esophagitis               diagnostic testing in nonresponders.
   H2RA recipients were rendered              and development of complications.57                   Over 1 year, the PPI test strategy, as
   heartburn free during the treatment        In 2000, researchers at Stanford                      compared with the traditional strate-
   period (77.4% vs 47.6%).                   University sought to determine the                    gy, resulted in greater symptom relief
   A randomized, double-blind, multi-         cost-effectiveness of various first-line              and improved QoL, as well as more
   center trial was conducted on 677          empiric therapies for patients with                   appropriate utilization of invasive
   patients with GERD (heartburn and          typical symptoms of GERD.58 The six                   diagnostic testing.
   normal endoscopy findings or mild          treatment arms included (1) lifestyle                 Because many patients with mild
   erosive changes) who received              therapy, including antacids; (2)                      GERD and infrequent symptom
   omeprazole 10 to 20 mg daily or ran-       H2RA therapy, with endoscopy per-                     relapses use a PPI only when symp-
   itidine 150 mg twice daily for 2           formed in nonresponders; (3) step-                    toms demand, one researcher looked
   weeks.54 Participants were followed        up therapy with H2RAs followed by                     at the results of four randomized,
   for 12 months, during which time           PPIs in nonresponders; (4) step-                      controlled studies, and found that
   they could reinstitute therapy for         down therapy with a PPI followed by                   the use of on-demand or intermittent
   heartburn recurrences. Omeprazole          an H2RA as needed; (5) PPI on-                        PPIs reduced symptoms, improved
   20 mg daily, as compared with the          demand therapy (8 weeks of treat-                     QoL, and was cost-effective.61
   H2RA, provided faster relief of heart-     ment for symptomatic recurrence,                      A summary of findings to date states
   burn in patients with erosive or           with no more than 3 treatments/                       that, “in terms of economics, the
   nonerosive disease. Intermittent           year); and (6) PPI continuous thera-                  management strategies that appear to
   treatment was effective in managing        py. Results showed that the PPI on-                   result in the most cost-efficient gains
   symptoms in half of the patients with      demand therapy was the most                           in health appear to be PPI-based
   uncomplicated GERD.                        cost-effective approach.                              step-down or ‘on-demand’ strategies”
   The Dutch Reflux Study Group eval-         Another 2000 study entailed a cost-                   [versus H2RAs and prokinetics].62
   uated acute and long-term treatment        utility analysis of four alternatives to
   of 446 patients with mild GERD with                                                              Table 4 lists the cost of a 2-week
                                              treat uncomplicated heartburn:
   standard-dose omeprazole or high-                                                            course of various OTC H2RAs and the
                                              empiric PPI with dose escalation for
   dose ranitidine, and found that the                                                          OTC PPI. These prices are approxima-
                                              nonresponders, empiric H2RA with
   proportions of patients who were                                                             tions, and may not reflect the cost of
                                              PPI for nonresponders, esophagogas-
   asymptomatic after 4 and 8 weeks of                                                          each medication in every part of the
                                              troduodenoscopy (EGD) followed by
   treatment were 61% and 74% for                                                               country. The concept of cost-effective-
                                              treatment, and upper GI series fol-
   omeprazole recipients, respectively,                                                         ness represents not only the actual cost
                                              lowed by treatment.59 Empiric treat-
   and 31% and 50% for ranitidine                                                               of the medication, but also the amount
                                              ment appeared to be the optimal
   recipients, respectively.55                                                                  of time that patients are rendered symp-
                                              initial management strategy for
   Another Dutch team performed a                                                               tom free after the course of therapy such
                                              patients with heartburn, with a PPI
   meta-analysis of 23 trials in which                                                          that further medication is not needed, at
                                              projected to provide the greatest qual-
   nearly 9000 patients underwent                                                               least in the short run.
                                              ity-adjusted survival and an H2RA
   empiric treatment for heartburn
                                              projected to be less costly. In other             REFERRAL
   associated with GERD or treatment
                                              words, the choice of a PPI versus an              NPs can diagnose and manage most
   for NERD (these patients had under-
                                              H2RA should depend on the impact                  cases of FHB, and even GERD, especially
   gone endoscopy).56 PPIs were superi-
                                              of heartburn on a patient’s QoL.                  when no other symptoms are present
   or to both H2RAs and prokinetic
   agents in achieving heartburn remis-       In 2002, investigators at the Cedars-             and the problem can be controlled with
   sion. H2RAs were also effective in         Sinai Health System in Los Angeles                medication. NPs should refer patients
   promoting symptom remission, but           used decision analysis to assess the              with alarm symptoms, GERD complica-
   the prokinetics were less helpful.         clinical and economic impact of two               tions, a prolonged history of GERD
                                              competing management strategies for               symptoms, an uncertain diagnosis, or
COST-EFFECTIVENESS DATA                       GERD.60 They studied the “tradition-              treatment-refractory symptoms to a gas-
Several studies have focused on the cost-     al” strategy, which incorporates a                troenterologist.63 Patients with extra-
effectiveness of various strategies for       step-up approach (sequential thera-               esophageal symptoms should be advised
treating heartburn, which is usually in       peutic trials with more intensive                 to see an otorhinolaryngologist, pulmo-
the setting of GERD:                          therapy), followed by sequential                  nologist, or other specialist. Finally, a
   In 1996, when H2RAs and PPIs were          invasive diagnostic testing in nonre-             surgical consult may be indicated in
   available by prescription only, a review   sponders; and the “PPI test” strategy,            patients with:

                                                                              Vol. 9 No. 1 January 2005 The American Journal for Nurse Practitioners   I   143
                            SPECIAL SUPPLEMENT
   TABLE 4. OTC H2RAs AND PPI: DOSAGE AND COST                                                                      bureau for Procter & Gamble Pharmaceu-
                                                                                                                    ticals and Abbott Laboratories, Inc. Rick H.
   Medication                                           Dosage                                    Cost ($)*         Davis, Jr., serves on the speaker bureau for
   H2RAs                                                                                                            Procter & Gamble Pharmaceuticals and Astra
   Cimetidine (generic)                                 200 mg 1 or 2 times daily PRN             4.29              Zeneca Pharmaceuticals.
   Tagamet HB 200®                                      200 mg 1 or 2 times daily PRN             8.59
   Ranitidine (generic)                                 75 mg 1 or 2 times daily PRN              4.25              MAJOR REFERENCES*
   Zantac 75®                                           75 mg 1 or 2 times daily PRN              8.49              American Gastroenterological Association
   Famotidine (generic)                                 10 mg 1 or 2 times daily PRN              6.99              medical position statement: guidelines on
   Pepcid® AC                                           10 mg 1 or 2 times daily PRN              7.97              the use of esophageal pH recording. Gastro-
   Axid AR®                                             75 mg 1 or 2 times daily PRN              8.39              enterology. 1996;110:1981.
   OTC PPI                                                                                                          Bardhan KD, Muller-Lissner S, Bigard MA, et
                                                                                                                    al. Symptomatic gastro-oesophageal reflux
   Prilosec OTC™
                                                                                                                    disease: double blind controlled study of
   (omeprazole magnesium)                               20.6 mg once daily                        9.99
                                                                                                                    intermittent treatment with omeprazole or
   Prescription PPIs                                                                                                ranitidine. The European Study Group. BMJ.
   Omeprazole (Prilosec®)                               20 mg daily                               59.26             1999;318(7182):502-507.
   Lansoprazole (Prevacid®)                             30 mg daily                               71.96             Bardhan KD. Intermittent and on-demand
   Rabeprazole (Aciphex®)                               20 mg daily                               69.48             use of proton pump inhibitors in the man-
   Pantoprazole (Protonix®)                             40 mg daily                               57.02             agement of symptomatic gastroesophageal
   Esomeprazole (Nexium®)                               40 mg daily                               72.05             reflux disease. Am J Gastroenterol. 2003;98(3
   *Cost for 2 weeks' treatment with the highest dosage (discount pharmacy in New Jersey).
                                                                                                                    Berardi RR. Heartburn self-treatment: focus
   The prescription PPIs are generally given for 4 to 8 weeks, depending on the indication.
                                                                                                                    on nonprescription omeprazole. Rx Con-
   OTC = over-the-counter; H2RA = Histamine H2-receptor antagonist; PRN = pro re nata (as
                                                                                                                    sultant. 2004;13:1-8.
   needed); PPI = proton pump inhibitor.
                                                                                                                    DeVault KR, Castell DO, and the Practice
                                                                                                                    Parameters Committee of the American
   documented GERD symptoms that                                    duced OTC PPI does not act as quickly as        College of Gastroenterology. Updated guide-
                                                                                                                    lines for the diagnosis and treatment of gas-
   are responsive to medical therapy but                            antacids and H2RAs, but it is more effec-       troesophageal reflux disease. Practice
   who do not wish to continue long-                                tive and longer-lasting than the other two      Guidelines. 1999;94(6):1434-1442.
   term medical therapy;                                            medication classes, and it will likely prove    The Gallup Organization. A Gallup Survey on
   documented GERD symptoms that                                    cost-effective in the long run because it       Heartburn Across America. Princeton, NJ;
   are unresponsive to medical therapy                              prevents heartburn from occurring.              1988.
   because of patient noncompliance,                                    Although all of these medications are       The Gallup Organization. A Gallup Survey on
   inability to afford medications, or                              available OTC, it is optimal for NPs to         Heartburn Across America. Princeton, NJ;
                                                                                                                    May 1, 2000.
   relapse;                                                         guide patients in their use, and to make
                                                                                                                    Heidelbaugh JJ, Nostrant TT, Kim C, Van
   complications of GERD such as                                    sure that patients do not have a more seri-
                                                                                                                    Harrison R. Management of gastroe-
   Barrett's esophagus or grade III or IV                           ous underlying condition or complica-           sophageal reflux disease. Am Fam Physician.
   esophagitis;                                                     tions that warrant further attention.           2003;68(7):1311-1318.
   peptic stricture;                                                Finally, NPs should counsel patients in         Heudebert GR, Centor RM, Klapow JC, et al.
   recurrent symptomatic aspiration;                                terms of lifestyle modifications that will      What is heartburn worth? A cost-utility
   medical complications attributable to                            mitigate, if not eliminate, FHB symptoms.       analysis of management strategies. J Gen
                                                                                                                    Intern Med. 2000;15(3):175-182.
   a large hiatal hernia such as bleeding                           Mary Knudtson is a professor in the             Kahrilas P. Clinical manifestations and diag-
   or dysphagia;                                                    Department of Family Medicine at the            nosis of esophageal reflux. UptoDate.
   atypical symptoms such as asthma or                              University of California, Irvine. She is        Over-the-counter omeprazole (Prilosec
   chest pain with abnormal 24-hour                                 nationally certified as a family and a pedi-    OTC). Med Lett Drugs Ther. 2003; 45(1162):
   pH monitoring study results; or                                  atric nurse practitioner. She is a practicing   61-62.
   severe symptoms that they would                                  clinician in primary care at UCI and is the     Locke GR 3rd, Talley NJ, Fett SL, et al.
   prefer to have treated surgically                                                                                Prevalence and clinical spectrum of gastroe-
                                                                    director of their family nurse practitioner     sophageal reflux: a population-based study
   rather than medically.11,25                                      program. Rick H. Davis, Jr, is a senior         in Olmsted County, Minnesota. Gastro-
CONCLUSION                                                          physician assistant at the University of        enterology. 1997;112(5):1448-1456.
Patients suffering from heartburn have a                            Florida, Department of Medicine, Division       Scott M, Gelhot AR. Gastroesophageal reflux
number of OTC treatments from which                                 of Gastroenterology, Hepatology, and            disease: diagnosis and management. Am Fam
                                                                    Nutrition, in Gainesville, Florida.             Physician. 1999;59(5):1161-1169.
to choose. For those with episodic heart-
                                                                                                                    Wolfe MM. Overview and comparison of the
burn, antacids and H2RAs provide fast                                                                               proton pump inhibitors for the treatment of
and reliable relief. For those with frequent                        DISCLOSURE STATEMENTS
                                                                    Mary Knudtson has current consulting agree-     acid-related disorders. UpToDate.
episodes of heartburn, however, omepra-                             ments with Procter & Gamble Pharma-             *Full references corresponding to the
zole magnesium, taken once daily for 14                             ceuticals, Eli Lilly and Company, and           numbers in the text are available at
days, is preferred. The recently intro-                             GlaxoSmithKline, and serves on the speaker

144   I   The American Journal for Nurse Practitioners January 2005 Vol. 9 No. 1

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