HHS Public Access

Author manuscript
Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
Author Manuscript

Published in final edited form as:

Ann N Y Acad Sci. 2022 April ; 1510(1): 5–17. doi:10.1111/nyas.14728.

An Update on Current Treatment Strategies for

Laryngopharyngeal Reflux Symptoms
Amanda J. Krause1, Erin H. Walsh2, Philip A. Weissbrod2, Tiffany H. Taft3, Rena Yadlapati1
1.Department of Medicine, Division of Gastroenterology & Hepatology, University of California San
Diego, La Jolla, CA, USA
2.Department of Otolaryngology, University of California San Diego, La Jolla, CA, USA
Author Manuscript

3.Department of Medicine, Division of Gastroenterology & Hepatology, Feinberg School of

Medicine, Northwestern University, Chicago, IL, USA

Abstract
Laryngopharyngeal reflux (LPR) is a syndrome caused by reflux of gastric contents into the
pharynx or larynx which leads to symptoms of throat clearing, hoarseness, pain, globus sensation,
cough, excess mucus production in the throat, and dysphonia. LPR is a challenging condition
as there is currently no gold standard for diagnosis or treatment and thus presents a burden to
the healthcare system. Strategies for treatment of LPR are numerous. Medical therapies include
proton pump inhibitors, which are first line, H2 receptor antagonists, alginates, and baclofen.
Other non-invasive treatment options include lifestyle therapy and the external upper esophageal
Author Manuscript

sphincter compression device. Endoscopic and surgical options include anti-reflux surgery,
magnetic sphincter augmentation, and transoral incisionless fundoplication. Functional laryngeal
disorders and laryngeal hypersensitivity can present as LPR symptoms with or without GERD.
Though there are minimal studies in this area, neuromodulators and behavioral interventions
are potential treatment options. Given the complexity of these patients and numerous available
treatment options, we propose a treatment algorithm to help clinicians diagnose and triage patients
into an appropriate therapy.

Keywords
Laryngopharyngeal reflux; Extraesophageal reflux; Gastroesophageal reflux; Treatment
Author Manuscript

Introduction
Laryngopharyngeal reflux (LPR) is a syndrome where reflux of gastric contents causes
laryngeal symptoms including throat clearing, hoarseness, pain, globus sensation, cough,
excess mucus in the throat, and dysphonia.1–3 The incidence and prevalence of LPR are
challenging to ascertain due to the lack of a gold standard diagnostic test; however, in
a study of patients presenting with laryngeal and voice disorders, 50% were diagnosed

Corresponding Author: Rena Yadlapati, MD, MSHS, University of California, San Diego, Division of Gastroenterology, ACTRI
Building 1W517, 9500 Gilman Drive MC 0956, La Jolla, CA 92093, [email protected].
 Krause et al. Page 2

with LPR based on 24-hour double-probe pH monitoring.4 Further, gastroesophageal

Author Manuscript

reflux disease (GERD) is the most common gastrointestinal disease in North America
with the last consensus from 2004-2011 indicating that symptoms of GERD affected
between 18.1%-27.8% of individuals in the US and between 2.5%-33.1% of individuals
worldwide.5 LPR presents both a diagnostic and treatment dilemma, as current diagnostic
testing typically lacks in either sensitivity or specificity and our knowledge about the best
treatment option remains unclear. Ambiguity exists in symptoms as well; extra-esophageal
manifestation can occur independently from common GERD symptoms.6 Consequently,
patients end up seeing on average 10 specialists and undergoing 6 tests in the initial year of
evaluation, often without diagnostic clarity or improvement. 7–10 Current clinical approaches
are estimated to cost $5,438/patient, equating to over $50 billion in annual health care costs.
7

There are several theories as to the pathophysiology behind LPR and why some
Author Manuscript

individuals may be responsive to PPIs. The reflux theory explains that LPR develops from
microaspiration of acid, bile acids, and pepsin that can directly injure the larynx and cause
symptoms.6,11,12 This has been supported by the finding of elevated salivary pepsin and bile
acid levels in patients with LPR, diagnosed via high-resolution manometry and combined
multichannel intraluminal impedance and 24h pH monitoring.13 It has been postulated that
even minor pepsin reflux reaching the larynx can be damaging, as the microenvironment
at the level of the larynx is less protective against insults14 and this may explain why
some patients do not respond to PPIs alone.15 Alternatively the reflex theory postulates that
reflux of acidic gastric contents in the distal esophagus stimulates vagally induced laryngeal
symptoms.16

Heterogeneous clinical presentations and pathophysiologic mechanisms driving laryngeal

Author Manuscript

symptoms leads to differences observed in both incidence of and treatment outcomes for
LPR. In this review we aim to outline current LPR treatment in an algorithmic approach
and attempt to identify how clinicians can identify patients that may be more responsive to
certain therapies.

Diagnosis of LPR
Unfortunately there is no diagnostic gold standard when assessing LPR.11 Therefore,
optimal evaluation likely involves consultation with both an otolaryngologist and
gastroenterologist in addition to certain targeted tests. Flexible laryngoscopy is an important
initial test to exclude other laryngeal pathology.11 In addition, careful examination for
rhinorrhea, nasal purulence or prominent lymphoid tissue at the posterior pharyngeal
wall should be done to exclude other diagnoses such as allergic rhinitis or sinusitis.
Author Manuscript

Ambulatory reflux monitoring plays an important diagnostic role to measure esophageal

reflux burden.17 Recent guidelines recommend ambulatory reflux monitoring off acid
suppression in the evaluation of LPR symptoms and recommend testing patients prior
to starting empiric pharmacotherapy in patients with LPR symptoms in the absence of
heartburn or regurgitation.17 This is guided by the fact that up to 50-60% of patients
with isolated laryngeal symptoms will not have gastroesophageal reflux pathology and
will not respond to anti-reflux therapies.11,17 On the other hand, a small proportion

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 3

of patients with isolated laryngeal symptoms may have true LPR, commonly referred
to as “silent reflux”.11,17 At present, data supports that the best outcomes are seen in
Author Manuscript

patients with elevated esophageal acid burden, disrupted anti-reflux barrier, and concomitant
presence of esophageal reflux symptoms.17,18 However, even in patients with pathologic
reflux, laryngeal symptoms may not resolve with typical anti-reflux therapies.17 Ultimately,
diagnosis of LPR remains a challenge and is an area that requires further investigation.

Dietary and Lifestyle Therapy

A plant based diet is hypothesized as enhancing laryngopharyngeal mucosal recovery due
to altered microbiota of the hypopharyngeal-esophageal reflux events as measured on the
hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring.19 In a
retrospective chart review of 85 patients with LPR treated with PPI and standard reflux
precautions (avoidance of coffee, tea, chocolate, soda, greasy, fried, fatty, and spicy foods,
Author Manuscript

and alcohol) and 99 patients with LPR treated with alkaline water and a 90% plant based
Mediterranean diet and standard reflux precautions, researchers found that there was no
difference in the proportion reaching a 6-point reduction in their RSI; however, when
comparing the mean percent reduction in the RSI, the data significantly favored the plant-
based diet approach.20

In another retrospective chart review of 65 patients with LPR, all patients were treated
with pantoprazole 20mg twice daily and all were counseled on lifestyle changes as well
as an alkaline, protein, low fat, low-acid diet.21 Patients were divided into 2 groups
based on adherence to dietary and lifestyle recommendations and the researchers found
that RSI and RFS significantly improved in both groups; however, the improvement in
RSI was significantly higher in the patients who adhered to the dietary and lifestyle
Author Manuscript

recommendations when compared to those who did not.21 With regards to the recommended
lifestyle habits, these included stress control, tobacco cessation, small meals, hot lunch
instead of a hot dinner, eating slowly, avoiding talking while eating, avoiding tight
clothing, and avoiding certain drugs (non-steroidal anti-inflammatory drugs, corticosteroids,
aspirin, theophylline, progesterone, iron supplementation, calcium channel blockers,
nitroderivatives, and anticholinergic medications).21 The dietary changes were focused
on avoiding fatty animal products (including meats/chicken/fish and dairy), fried foods,
refined carbohydrates, nuts, spicy foods, shallots, onion, garlic, tomato, aspartame, rhubarb,
blueberries, refined sugar, alcohol, coffee, tea, and citrus juices.21 Further supporting this
diet is the knowledge that patients who consume high-fat, low-protein, high-sugar, and
high-acid foods tend to have higher numbers of proximal reflux episodes with multichannel
intraluminal impedance-pH monitoring.22
Author Manuscript

In a small study of 12 male and 8 female patients with PPI resistant LPR, it was found that
on a strict, low-acid diet (all foods pH≥5), there was a statistically significant improvement
in both the mean pre-diet versus post-diet RSI and RFS scores.23 Along this same line,
another group of researchers conducted a retrospective study of patients completing an LPR
induction program versus patients prescribed only anti-reflux medications and behavioral
modifications.24 The LPR induction program included a 2-week induction diet (low fat
foods, all with a pH≥5) followed by a similar but less strict diet, high dose anti-reflux

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 4

medication, at least 16 oz alkaline water, and behavioral modifications (weight loss,

Author Manuscript

smoking cessation, alcohol avoidance, minimizing tight clothing, avoiding eating 3 hours
before lying down, taking PPI 30-60 minutes before meals).24 The control group had a
high dose PPI (with or without H2 blocker) and behavioral modifications.24 Researchers
found that patients undergoing the induction program (average of 32-day first follow-up) had
significant improvements in their RSI scores whereas those in the control group (average of
62-day first follow-up) did not.24

With regards to obesity, in a retrospective review of 285 patients with clinical LPR
(determined by history, RFS, and RSI) who underwent pH-probe studies and found that
abnormal esophageal reflux events correlated significantly with increasing BMI, whereas
abnormal pharyngeal reflux events did not correlate with increasing BMI.25

Overall, certain reflux-centric lifestyle adjustments (Table 1) as well as favoring lower fat,
Author Manuscript

lower acid, plant-based foods seems reasonable to propose to patients hoping to reduce their
symptomatic burden from LPR. In general it seems worthwhile to combine both medical
treatment and lifestyle/dietary changes to maximize symptomatic improvement.

Pharmacotherapy
Proton Pump Inhibitors
Historically, management of patients with suspected LPR typically began with an empiric 8
to 12 week double-dose proton pump inhibitor (PPI) trial.6 Current guidelines recommend
high dose PPI therapy given its high probability (91 to 99%) of restricting physiologic
esophageal acid exposure.11,26 In a recent double-blind, placebo controlled trial in patients
with persistent throat symptoms, researchers investigated the effectiveness of Lansoprazole
Author Manuscript

30mg BID for 16 weeks versus placebo and found that in 220 individuals who completed
the study, mean RSI scores were not significantly different between groups, and these results
held after 12 months of treatment.27 Similarly in the TOPPITS randomized controlled
clinical trial, patients with persistent throat symptoms were also randomized to the
aforementioned groups and researchers found that in 267 patients completing the primary
outcomes, there was no significant difference between RSI scores at 16 weeks or 12 months
of follow-up.28 Notably neither of these studies evaluated patients for objective findings of
GERD. Several reviews and meta-analyses assessing the efficacy of PPIs in patients with
suspected LPR have reported mixed results.29–33 In fact, in a recent systematic review,
researchers evaluated published systematic reviews and meta-analyses that evaluated PPIs
in patients with persistent throat symptoms and found 10 systematic reviews that were
all at high risk of bias, except for one.34 The inconsistency in symptomatic response in
Author Manuscript

these studies likely reflects the variability in study design with respect to dosing, frequency,
and PPI choices, as well as the mixed response patients have to PPIs depending on their
underlying disease pathology, which further complicates the ability to apply these results to
patients.

There are two overarching explanations for the suboptimal response to PPI therapy in
patients with suspected LPR. First, extra-esophageal symptoms are nonspecific for LPR and
most studies examining LPR likely include a diluted and heterogeneous patient population,

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 5

some of whom may not actually have LPR and instead have a range of other diagnoses
Author Manuscript

including laryngeal hypersensitivity or functional laryngeal disorders. Consequently, recent

studies have attempted to delineate which patients are more likely to respond to PPIs.
A recent multicenter study of 302 adults with chronic laryngeal symptoms identified
distinct phenotypes of patients, which included LPR/GERD with a hiatal hernia, LPR
with mild GERD, no LPR or GERD, reflex cough, and mixed/possible obstructive EGJ.35
Individuals with LPR/GERD with hiatal hernia would likely be most responsive to PPI
followed by LPR and LPR with mild GERD and reflux cough, thus separating patients into
distinct phenotypic categories may help to inform which treatments are effective for which
patients.35 Second, it is possible that esophago-pharyngeal refluxate is not entirely acidic,
and prior studies demonstrate that acid reducing agents are likely ineffective in patients
with nonacid reflux events.15,36,37 For these reasons, current societal guidelines recommend
ambulatory reflux monitoring in patients with isolated extra-esophageal symptoms as
Author Manuscript

opposed to empiric trials of PPI therapy in order to facilitate early identification of LPR
and improve efficacy of PPI therapy (Table 1).

H2 Receptor Antagonists
H2 Receptor Antagonists are another class of drug that has been studied in LPR, but as
is the case with GERD, is considered more of a second line therapy due to their short
duration of action and lower potency of acid suppression compared to PPI.1 In one study of
patients presenting with symptoms of chronic laryngitis, researchers treated patients with an
escalating regimen of lifestyle changes, Famotidine 20mg nightly, followed by Omeprazole
20mg nightly.38 They found that symptoms resolved in 51% (93/182) on standard antireflux
precautions, 54% (48/89) of those who failed standard reflux precautions responded to
Famotidine 20mg nightly, and in the remaining 41 participants 34 (83%) had improvement
in their symptoms with Omeprazole 20mg nightly.38 H2 Receptor Antagonists may be an
Author Manuscript

option in patients for breakthrough symptoms on a PPI, but are unlikely to be effective in
individuals with frequent symptoms given the aforementioned shortcomings.

Alginates
Alginates are an oral pharmacologic therapy that creates a barrier at the esophago-gastric
junction and a mechanical raft above the gastric contents to prevent gastro-esophageal
reflux events, whether acidic or nonacidic. In addition, Alginates inhibit pepsin and bile
salts. Alginates are often used as an adjunct to PPI therapy in patients with GERD
that have not symptomatically improved with acid suppresion.11 Placebo controlled trials
demonstrate significant symptom improvement with alginates in patients with typical GERD
symptoms.39,40
Author Manuscript

Alginates also improve symptoms in LPR patients. In one randomized controlled trial of
patients with Reflex Symptom Index (RSI) scores of >10 and Reflux Finding Scores (RFS)
scores of >5, the group that received Gaviscon Advanced had greater symptom improvement
at 2, 4, and 6 months post-treatment as well as laryngoscopic improvement per the RFS
at 6 months compared to the group that received no treatment.41 Limitations of this study
include lack of a placebo and lack of PPI trial prior to treatment. On the other hand, a
double-blind placebo-controlled study in patients with RSI>10 and RFS >5 comparing 8

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 6

weeks of Alginos Oral Suspension with a placebo, identified significant reduction of the
Author Manuscript

total RSI, RFS, and total number of reflux events on multichannel intraluminal impedance
pH monitoring in both arms, suggesting that liquid alginate is not superior to placebo.42 One
of the notable components of this study was that all patients were counseled on lifestyle
modification, which could have contributed to the similar findings in both groups. In a
prospective study of patients with LPR and RSI >10, researchers found that Gaviscon
Advance alone is effective in treating LPR and co-prescription with a high dose PPI did not
offer an additional symptom improvement.43 Of note is that patients were not randomized
and if patients were on a PPI prior to the trial initiation, this was optimized to high-dose
twice daily dosing. Despite the mixed data, alginates are well tolerated and postulated to
have a role in LPR, particularly in patients with nonacid or mixed reflux whose symptoms
do not improve with an initial PPI trial.1 When used for LPR, the typical dose is Gaviscon
Advanced with recommended doses ranging from 10 to 20mL after meals and/or at bedtime
(Table 1). 41,43 42
Author Manuscript

Baclofen
Baclofen is a gamma-aminobutyric acid receptor type-B agonist that inhibits transient lower
esophageal sphincter relaxations and potentially prevents reflux events, both acidic and
non-acidic.44 Most extensively studied in GERD, a meta-analysis of 9 RCTs identified a
significant reduction in the incidence of gastroesophageal reflux, the length of the reflux
episodes, and the occurrence of transient lower esophageal sphincter relaxation when
comparing patients on baclofen versus placebo.45

While baclofen studies are primarily targeting cough, there are potential LPR applications.
In a study of 16 patients with refractory GERD induced chronic cough whom had failed
omeprazole 20mg twice daily plus domperidone, baclofen improved cough in 56.3% and
Author Manuscript

responders had a significantly lower number of acid reflux events when compared to non-
responders.46 Notably 1 participant withdrew due to side effects (persistent nausea and
diarrhea) and 3 participants withdrew because of deterioration or no improvement in their
cough.46 In another study of 32 subjects with LPR symptoms despite PPI therapy, 53% met
symptom response (>50% improvement in RSI from baseline) with lansoprazole 15mg twice
daily and baclofen 10mg three times daily for 3 months and lifestyle counseling.44 The
efficacy of baclofen in LPR is unclear given limited and low quality data. Also, given its
challenging side effect profile, it is not routinely recommended as a first-line or adjunctive
therapy in LPR (Table 1).

External Upper Esophageal Sphincter Compression Device

Author Manuscript

One of the newer and novel therapies being tested for LPR is the External Upper Esophageal
Sphincter (UES) Compression Device (Figure 1). The idea behind this device came after
researchers found that in individuals with typical reflux symptoms plus supra-esophageal
symptoms (chronic cough, burning throat, or hoarseness) had impaired esophageal and UES
response to simulated reflux events and thus these individuals could be at a greater risk of
esophagopharyngeal reflux.47

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 7

Based on this initial research, the utility of an External UES Compression Device was
Author Manuscript

proposed and it was found that using 20-30 mmHg of cricoid pressure lead to a significant
increase in the UES intraluminal pressure and thus prevented pharyngeal reflux events.48
The initial study conducted with this device enrolled 95 patients with esophagopharyngeal
reflux with extra-esophageal symptoms and RSI > 13 whom were instructed to wear
the External UES Compression Device at night.49 They found that RSI scores at 2 and
4-week follow-ups were significantly improved.49 Based on this research, the Reflux Band
(Somna Therapeutics, Germantown, WI) was approved by the FDA.49 Another group
tested the External UES Compression Device in 15 participants with an RSI ≥13 whom
were trialed on 14 consecutive nights of therapy.50 They found that 29% were complete
responders (>50% reduction in RSI and post-intervention RSI<13), 58% were partial
responders (reduction from baseline RSI but not meeting complete responder criteria), and
14% were non-responders.50 Compared to baseline, mean RSI was significantly improved
Author Manuscript

post-intervention and there was a statistically significant reduction in salivary pepsin in the
group of complete responders.50 In a two-phase prospective clinical trial in adults with
at least 8 weeks of laryngeal symptoms, participants were given double dose PPI for 4
weeks followed by the addition of the external UES compression device for 4 weeks, and
researchers found that 55% of the 31 participants achieved either an RSI score ≤ 13 and/or
a > 50% reduction in RSI.51 When comparing non-responders to responders, it was found
that responders tended to have lower BMI (24.2 kg/m2 vs. 28.6, p=0.02), significantly higher
salivary pepsin at baseline (145.0 ng/mL vs. 34.6 ng/mL, p=0,01) and tended to have a lower
separation between the LES and crural diaphragm on manometry.51 Therefore, the authors
suggest that individuals with a hiatal hernia, central obesity, and cough with mechanical
reflux, may be less likely to respond to the external UES compression device with PPI
therapy.51 Adverse events from this device were minimal.51 When contacted for the 3-month
follow-up, 14 (67%) were still using the external UES compression device and seven had
Author Manuscript

discontinued for intolerance (4, 57%), poor symptom control (2, 29%), and rash (1, 14%).51
Given this data it seems reasonable to consider the External UES Compression Device to
be used at nighttime for patients with established GERD whom are also suffering from LPR
whose symptoms are not fully controlled on a PPI (Table 1).51 Given the limited data and
lack of randomized controlled trials, more information is needed to determine the duration
of therapy and whether concomitant therapy, namely with a PPI, is warranted.

Endoscopic and Surgical Interventions

While the role of anti-reflux surgery is well established for PPI refractory GERD, its
role is less clear in LPR and experts warn that a cautious approach is warranted when
recommending surgical therapy for LPR.11 The most recent American Gastrointestinal
Author Manuscript

Association (AGA) guidelines outline that surgical therapy can be considered in patients
with extraesophageal symptoms whom are refractory to medical therapy and have objective
findings of GERD.11 In addition it is noted that patients with mechanical defects (hiatal
hernia) may also benefit.11

In a study of 27 patients with PPI refractory extra-esophageal symptoms (twice daily

PPI for at least 12 weeks with a <50% improvement in symptoms) whom had objective
findings of GERD and underwent a standard Nissen laparoscopic fundoplication for

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 8

treatment, researchers found that 59% had at least partial improvement in their main
symptom following fundoplication.52 Characteristics that helped predict which patients
Author Manuscript

would symptomatically improve included individuals who also had heartburn with or
without regurgitation and a distal esophageal acid exposure time (pH less than 4.0) of
greater than 12%.52 Symptom improvement was assessed by asking patients to indicate
their percentage improvement of their primary symptom and responders were defined has a
greater than 50% improvement from baseline.52

In a review of 27 observational studies, researchers found that the effectiveness of antireflux

surgery for LPR was anywhere from 10 to 93%.53 In another, more recent, review, 34 studies
of patients with LPR who had fundoplication (29 studies laparoscopic, 1 study endoluminal/
transoral, 3 studies with other approaches) were examined and researchers found that due
to the extreme variability with regards to their diagnostic method, exclusion criteria, and
outcomes used to determine efficacy of surgery, that the review was inconclusive with
Author Manuscript

regards to whether fundoplication is effective for LPR.54

Magnetic sphincter augmentation (MSA) has shown success in patients with typical GERD,
thus researchers retrospectively investigated the effects of MSA on patients with objective
evidence of GERD on ambulatory pH monitoring and LPR symptoms and found that mean
RSI scores significantly improved from 20.9 to 8.1 (p<0.01) after MSA.55

Another potential option for patients is endoscopic therapy with transoral incisionless
fundoplication (TIF). In a study of 34 patients with GERD and/or LPR who underwent
TIF, researchers found that TIF resulted in symptomatic improvement with mean RSI scores
reduced from 19.2 pre-TIF on PPI to 6.1 post-TIF (p<0.001).56

Overall, endoscopic and surgical interventions (Table 1) should be considered as a last line
Author Manuscript

treatment for patients with LPR as the outcomes are quite variable. In addition, only select
patients, as outlined above, should be considered for surgery or endoscopic intervention.
Further investigation regarding endoscopic and surgical therapies for LPR are warranted.

Treatment Approach for Functional Laryngeal Disorder and Laryngeal

Hypersensitivity
Functional laryngeal disorders can present with a variety of symptoms, many of which can
be challenging to distinguish from LPR. Diagnosis in this subset of patients is made when
an individual demonstrates no reflux on pH testing and in whom other causes of laryngeal
dysfunction have been excluded.57 To qualify, patients should have the following criteria for
at least 3 months with symptom onset at least 6 months prior to diagnosis: 1) Laryngeal
Author Manuscript

symptoms (cough, throat clearing, sore/burning throat) at least several times per week, 2)
No evidence that GERD is the etiology, and 3) They should be free of sinus, endocrine,
pulmonary, or laryngeal disorders other than just irritation.57 Functional laryngeal disorders
are thought to be due in part to laryngeal hypersensitivity, which is hypothesized to occur
after an insult, such as an upper respiratory tract infection or aspiration, or in association
with another comorbidity, such as asthma or chronic rhinosinusitis, which then causes
sensitization of the larynx and an exaggerated response to triggers.58 This hypersensitivity

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 9

may explain why some individuals who are presumed to have LPR, do not respond to PPI
treatment.59 This patient population can be hard to distinguish from LPR patients clinically,
Author Manuscript

and likely represents a major confounder in accurate diagnosis and effective treatment
of LPR. Further, laryngeal hypersensitivity can coexist with LPR, just as esophageal
hypersensitivity can coexist with esophageal motility disorders and GERD, which can
ultimately influence how these patients are managed. It is plausible that in patients who do
not respond to PPIs, there are likely other factors, such as hypervigilance, elevated anxiety
levels, allodynia, and hyperalgesia that are contributing to their symptoms.60 Given this
information, clinicians should have a high index of suspicion of laryngeal hypersensitivity
when treating patients with laryngeal symptoms whom are non-responders to typical
treatments. In addition, validated laryngeal hypersensitivity scoring systems, such as the
EHAS score for esophageal hypersensitivity, are needed.

Pharmacologic Neuromodulation
Author Manuscript

Neuromodulators are one of the main treatments used in patients with functional and
laryngeal disorders due to hypersensitivity, and have been most studied with chronic cough.6
While these are typically regarded as different diagnoses, some treatment strategies may
be extrapolated from experience with chronic cough and applied to treatment of laryngeal
hypersensitivity and LPR patients more broadly.

Gabapentin (in doses of up to 1800 mg/d) has been shown in a randomized, double-
blind, placebo-controlled trial in 62 patients to significantly improve patient’s scores
on the Leicester Cough Questionnaire (LCQ) when compared to placebo.61 Current
CHEST guidelines recommend considering a trial of Gabapentin in individuals with
chronic unexplained cough.62 In another randomized placebo controlled trial of 40
patients with refractory chronic cough that compared speech therapy with and without
Author Manuscript

the addition of Pregabalin, researchers found that patient’s scores on the LCQ improved
with both interventions; however, in the speech therapy with Pregabalin group, there was
a significantly greater improvement.62 In another study focused on patients presenting
with chronic cough, globus sensation, odynophonia, and or odynophagia, researchers
retrospectively reviewed 12 consecutive patients prescribed Pregabalin and found that out
of the 10 who tolerated the medication, symptom severity rating improved from 3.9 pre-
treatment to 1.2 post-treatment.63 Amitriptyline has also demonstrated effectiveness with
a decrease in the cough severity and frequency in a randomized controlled study of 28
participants with cough due to post-viral vagal neuropathy when compared to codeine/
guaifenesin.64 Neuromodulators, such as tricyclic antidepressants, serotonin reuptake
inhibitors, and serotonin-norepinephrine reuptake inhibitors are also commonly used in
patients with reflux hypersensitivity or functional heartburn.65
Author Manuscript

Other therapies have aimed to target neuronal hyperresponsiveness of the cough reflex,
such as P2X3 receptors located in airway vagal afferent nerves, which are suspected
to add to sensory neuron hypersensitization.66 In a double-blind, placebo-controlled, two-
period, crossover study of 34 individuals, researchers found that cough frequency was
significantly reduced in the treatment group (AF-219, an oral P2X3 antagonist) when
compared to placebo.66 More recently, a P2X3 receptor antagonist (Gefapixant) was studied

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 10

in a 12-week, phase 2b, randomized, double-blind placebo controlled study in patients

with refractory cough.67 253 patients were randomly assigned to placebo or differing doses
Author Manuscript

of Gefapixant, and researchers found that with a dose of 50mg twice daily there was a
significant decrease in objective cough frequency, as measured through a 24-hour sound
recording, when compared to placebo.67

Speech Therapy
In addition to medications for chronic cough, speech therapy has also been shown to be
effective and is recommended by the current CHEST guidelines.62 In a study of 20 patients
with cough and paradoxical vocal fold movement disorder who underwent treatment with
a PPI for 6 months and 3-5 sessions of respiratory retaining therapy, a form of speech and
breathing therapy that targets the abdominal and oropharyngeal musculature, researchers
found that 100% had improvement in their cough and 85% had improvement in RSI.68 In
Author Manuscript

a single blind, randomized, placebo controlled trial in 87 patients with chronic cough who
underwent a speech pathology intervention or placebo intervention (education of healthy
lifestyle such as relaxation, stress management, exercise, and diet), researchers found that
the treatment group had significant improvements in their symptoms (cough, breathing,
voice, upper airway, and limitations in performing everyday activity).69 The placebo group
also had statistically significant improvements in breathing, cough, and limitations in
performing everyday activities; however, the amount of improvement was significantly less
than seen in the intervention cohort.69 Neuromodulators and speech therapy have both
shown promise in patients with chronic cough and may potentially improve other laryngeal
hypersensitivity symptoms; however, additional research into this area is warranted.

Behavioral Therapy
Author Manuscript

Hypnotherapy is another targeted treatment strategy in patients suffering from bothersome

laryngeal symptoms. In a small case series of 10 patients presenting with globus sensation,
researchers found that after a standardized, semi-structure, 7-session relaxation protocol
(included modifying breathing and relaxing muscles) and 5-sessions of esophagus-directed
hypnotically assisted relaxation, there was a statistically significant decrease in overall
symptom severity.70 In another study examining 9 patients with functional heartburn who
underwent 7 weekly sessions of a protocol targeting esophageal-directed hypnotherapy,
researchers found statistically significant improvements in patient’s heartburn symptoms,
visceral anxiety, and quality of life.71 In a recent review, the authors concluded that
hypnotherapy for patients presenting with dysphagia, globus, functional chest pain/non-
cardiac chest pain, dyspepsia, and functional heartburn was warranted based on current
evidence.72
Author Manuscript

Cognitive Behavioral Therapy (CBT) has been well studied in patients with functional bowel
disorders; however, the data for patients with esophageal complaints is less robust.65 In
CBT, a health psychologist will work with the patient on skills such as stress management,
cognitive restructuring, coping strategies, problem solving, and controlling anxiety.65

Though data for esophageal disorders is less robust than for other functional gastrointestinal
disorders, behavioral therapies are safe and effective options to trial for patients suffering

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 11

from functional esophageal symptoms,65,72–74 and this data can likely be extrapolated
Author Manuscript

for use in patients with laryngeal hypersensitivity and functional laryngeal disorders.
However, additional research in the area of behavioral therapies in the treatment of laryngeal
hypersensitivity and functional laryngeal disorders is warranted.

Conclusion
LPR presents as a challenge both to the treating clinician and patients (Figure 2). In addition,
the exact mechanism of disease pathology leading to LPR is unknown and likely due to a
multitude of factors, which further complicates the picture. A variety of therapeutic options
from lifestyle/dietary modifications, to medications, to the External UES Compression
Device, and potentially even surgery exist for patients with LPR (Table 1). Though an
empiric PPI trial is a simple first line therapeutic approach in individuals presenting with
symptoms of LPR, this is no longer recommended as many patients fail PPIs and thus
Author Manuscript

additional research is warranted to help define patient characteristics and diagnostic testing
strategies that could potentially help to personalize the treatment algorithm. Based on LPR
research, we propose the following treatment algorithm (Figure 3) that helps clinicians to
systematically diagnose and triage patients to variable treatment options. Ultimately with
improvement in our understanding of LPR, as well as our ability to diagnose and categorize
patients into variable groups based on diagnostic testing, we can hopefully develop a more
streamlined approach to manage these complex patients.

Funding Support:
RY is supported by NIH K23 DK125266 (PI: Yadlapati).

Disclosures
Author Manuscript

RY: Consultant: Medtronic (Institutional), Ironwood Pharmaceuticals (Institutional), Phathom Pharmaceuticals;

Research support: Ironwood Pharmaceuticals; Advisory Board with Stock Options: RJS Mediagnostix

AJK, EHW, PAW, THT: No relevant disclosures

References
1. Lechien JR, Akst LM, Hamdan AL, et al. Evaluation and Management of Laryngopharyngeal
Reflux Disease: State of the Art Review. Otolaryngol Head Neck Surg. 2019;160(5):762–782.
[PubMed: 30744489]
2. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus G. The Montreal definition
and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J
Gastroenterol. 2006;101(8):1900–1920; quiz 1943. [PubMed: 16928254]
3. Olson NR. Laryngopharyngeal manifestations of gastroesophageal reflux disease. Otolaryngol Clin
Author Manuscript

North Am. 1991;24(5):1201–1213. [PubMed: 1754220]

4. Koufman JA, Amin MR, Panetti M. Prevalence of reflux in 113 consecutive patients with laryngeal
and voice disorders. Otolaryngol Head Neck Surg. 2000;123(4):385–388. [PubMed: 11020172]
5. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal
reflux disease: a systematic review. Gut. 2014;63(6):871–880. [PubMed: 23853213]
6. Barrett CM, Patel D, Vaezi MF. Laryngopharyngeal Reflux and Atypical Gastroesophageal Reflux
Disease. Gastrointest Endosc Clin N Am. 2020;30(2):361–376. [PubMed: 32146951]
7. Francis DO, Rymer JA, Slaughter JC, et al. High economic burden of caring for patients with
suspected extraesophageal reflux. Am J Gastroenterol. 2013;108(6):905–911. [PubMed: 23545710]

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 12

8. Lenderking WR, Hillson E, Crawley JA, Moore D, Berzon R, Pashos CL. The clinical
characteristics and impact of laryngopharyngeal reflux disease on health-related quality of life.
Author Manuscript

Value Health. 2003;6(5):560–565. [PubMed: 14627062]

9. Carrau RL, Khidr A, Crawley JA, Hillson EM, Davis JK, Pashos CL. The impact of
laryngopharyngeal reflux on patient-reported quality of life. Laryngoscope. 2004;114(4):670–674.
[PubMed: 15064622]
10. Carrau RL, Khidr A, Gold KF, et al. Validation of a quality-of-life instrument for
laryngopharyngeal reflux. Arch Otolaryngol Head Neck Surg. 2005;131(4):315–320. [PubMed:
15837899]
11. Vaezi MF, Katzka D, Zerbib F. Extraesophageal Symptoms and Diseases Attributed to GERD:
Where is the Pendulum Swinging Now? Clin Gastroenterol Hepatol. 2018;16(7):1018–1029.
[PubMed: 29427733]
12. Cherry J, Margulies SI. Contact ulcer of the larynx. Laryngoscope. 1968;78(11):1937–1940.
[PubMed: 5722896]
13. Sereg-Bahar M, Jerin A, Jansa R, Stabuc B, Hocevar-Boltezar I. Pepsin and bile acids in saliva
in patients with laryngopharyngeal reflux - a prospective comparative study. Clin Otolaryngol.
Author Manuscript

2015;40(3):234–239. [PubMed: 25516364]

14. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a
clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental
investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope.
1991;101(4 Pt 2 Suppl 53):1–78.
15. Sharma N, Agrawal A, Freeman J, Vela MF, Castell D. An analysis of persistent symptoms
in acid-suppressed patients undergoing impedance-pH monitoring. Clin Gastroenterol Hepatol.
2008;6(5):521–524. [PubMed: 18356117]
16. Wright RA, Miller SA, Corsello BF. Acid-induced esophagobronchial-cardiac reflexes in humans.
Gastroenterology. 1990;99(1):71–73. [PubMed: 2344943]
17. Gyawali CP, Carlson DA, Chen JW, Patel A, Wong RJ, Yadlapati RH. ACG Clinical Guidelines:
Clinical Use of Esophageal Physiologic Testing. Am J Gastroenterol. 2020;115(9):1412–1428.
[PubMed: 32769426]
18. Zerbib F, Bredenoord AJ, Fass R, et al. ESNM/ANMS consensus paper: Diagnosis
and management of refractory gastro-esophageal reflux disease. Neurogastroenterol Motil.
Author Manuscript

2021;33(4):e14075. [PubMed: 33368919]

19. Lechien JR, De Vos N, Everard A, Saussez S. Laryngopharyngeal reflux: The microbiota theory.
Med Hypotheses. 2021;146:110460. [PubMed: 33359943]
20. Zalvan CH, Hu S, Greenberg B, Geliebter J. A Comparison of Alkaline Water and Mediterranean
Diet vs Proton Pump Inhibition for Treatment of Laryngopharyngeal Reflux. JAMA Otolaryngol
Head Neck Surg. 2017;143(10):1023–1029. [PubMed: 28880991]
21. Lechien JR, Huet K, Khalife M, et al. Alkaline, protein, low-fat and low-acid diet
in laryngopharyngeal reflux disease: Our experience on 65 patients. Clin Otolaryngol.
2019;44(3):379–384. [PubMed: 30548197]
22. Lechien JR, Bobin F, Muls V, et al. Patients with acid, high-fat and low-protein diet have higher
laryngopharyngeal reflux episodes at the impedance-pH monitoring. Eur Arch Otorhinolaryngol.
2020;277(2):511–520. [PubMed: 31679054]
23. Koufman JA. Low-acid diet for recalcitrant laryngopharyngeal reflux: therapeutic benefits and their
implications. Ann Otol Rhinol Laryngol. 2011;120(5):281–287. [PubMed: 21675582]
Author Manuscript

24. Yang J, Dehom S, Sanders S, Murry T, Krishna P, Crawley BK. Treating laryngopharyngeal
reflux: Evaluation of an anti-reflux program with comparison to medications. Am J Otolaryngol.
2018;39(1):50–55. [PubMed: 29100672]
25. Halum SL, Postma GN, Johnston C, Belafsky PC, Koufman JA. Patients with isolated
laryngopharyngeal reflux are not obese. Laryngoscope. 2005;115(6):1042–1045. [PubMed:
15933517]
26. Charbel S, Khandwala F, Vaezi MF. The role of esophageal pH monitoring in symptomatic patients
on PPI therapy. Am J Gastroenterol. 2005;100(2):283–289. [PubMed: 15667483]

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 13

27. O’Hara J, Stocken DD, Watson GC, et al. Use of proton pump inhibitors to treat persistent
throat symptoms: multicentre, double blind, randomised, placebo controlled trial. BMJ.
Author Manuscript

2021;372:m4903. [PubMed: 33414239]

28. Wilson JA, Stocken DD, Watson GC, et al. Lansoprazole for persistent throat symptoms in
secondary care: the TOPPITS RCT. Health Technol Assess. 2021;25(3):1–118.
29. Karkos PD, Wilson JA. Empiric treatment of laryngopharyngeal reflux with proton pump
inhibitors: a systematic review. Laryngoscope. 2006;116(1):144–148. [PubMed: 16481828]
30. Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor therapy for suspected GERD-
related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol.
2006;101(11):2646–2654. [PubMed: 17037995]
31. Guo H, Ma H, Wang J. Proton Pump Inhibitor Therapy for the Treatment of Laryngopharyngeal
Reflux: A Meta-Analysis of Randomized Controlled Trials. J Clin Gastroenterol. 2016;50(4):295–
300. [PubMed: 25906028]
32. Spantideas N, Drosou E, Bougea A, AlAbdulwahed R. Proton Pump Inhibitors for the Treatment
of Laryngopharyngeal Reflux. A Systematic Review. J Voice. 2020;34(6):918–929. [PubMed:
31160182]
Author Manuscript

33. Lechien JR, Saussez S, Schindler A, et al. Clinical outcomes of laryngopharyngeal reflux
treatment: A systematic review and meta-analysis. Laryngoscope. 2019;129(5):1174–1187.
[PubMed: 30597577]
34. Cosway B, Wilson JA, O’Hara J. The acid test: Proton pump inhibitors in persistent throat
symptoms: A systematic review of systematic reviews. Clin Otolaryngol. 2021.
35. Yadlapati R, Kaizer AM, Sikavi DR, et al. Distinct Clinical Physiologic Phenotypes of Patients
With Laryngeal Symptoms Referred for Reflux Evaluation. Clin Gastroenterol Hepatol. 2021.
36. Tutuian R, Vela MF, Hill EG, Mainie I, Agrawal A, Castell DO. Characteristics of symptomatic
reflux episodes on Acid suppressive therapy. Am J Gastroenterol. 2008;103(5):1090–1096.
[PubMed: 18445095]
37. Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms
despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH
monitoring. Gut. 2006;55(10):1398–1402. [PubMed: 16556669]
38. Hanson DG, Kamel PL, Kahrilas PJ. Outcomes of antireflux therapy for the treatment of chronic
Author Manuscript

laryngitis. Ann Otol Rhinol Laryngol. 1995;104(7):550–555. [PubMed: 7598368]

39. Reimer C, Lodrup AB, Smith G, Wilkinson J, Bytzer P. Randomised clinical trial: alginate
(Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response
to a once daily proton pump inhibitor. Aliment Pharmacol Ther. 2016;43(8):899–909. [PubMed:
26909885]
40. Wilkinson J, Wade A, Thomas SJ, Jenner B, Hodgkinson V, Coyle C. Randomized clinical trial: a
double-blind, placebo-controlled study to assess the clinical efficacy and safety of alginate-antacid
(Gaviscon Double Action) chewable tablets in patients with gastro-oesophageal reflux disease. Eur
J Gastroenterol Hepatol. 2019;31(1):86–93. [PubMed: 30272584]
41. McGlashan JA, Johnstone LM, Sykes J, Strugala V, Dettmar PW. The value of a liquid alginate
suspension (Gaviscon Advance) in the management of laryngopharyngeal reflux. Eur Arch
Otorhinolaryngol. 2009;266(2):243–251. [PubMed: 18506466]
42. Tseng WH, Tseng PH, Wu JF, et al. Double-blind, placebo-controlled study with alginate
suspension for laryngopharyngeal reflux disease. Laryngoscope. 2018;128(10):2252–2260.
[PubMed: 29399800]
Author Manuscript

43. Wilkie MD, Fraser HM, Raja H. Gaviscon(R) Advance alone versus co-prescription of
Gaviscon(R) Advance and proton pump inhibitors in the treatment of laryngopharyngeal reflux.
Eur Arch Otorhinolaryngol. 2018;275(10):2515–2521. [PubMed: 30062580]
44. Lee YC, Jung AR, Kwon OE, Kang JW, Huh JH, Eun YG. The effect of baclofen combined with
a proton pump inhibitor in patients with refractory laryngopharyngeal reflux: A prospective, open-
label study in thirty-two patients. Clin Otolaryngol. 2019;44(3):431–434. [PubMed: 30703288]
45. Li S, Shi S, Chen F, Lin J. The effects of baclofen for the treatment of gastroesophageal
reflux disease: a meta-analysis of randomized controlled trials. Gastroenterol Res Pract.
2014;2014:307805. [PubMed: 25389436]

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 14

46. Xu XH, Yang ZM, Chen Q, et al. Therapeutic efficacy of baclofen in refractory gastroesophageal
reflux-induced chronic cough. World J Gastroenterol. 2013;19(27):4386–4392. [PubMed:
Author Manuscript

23885151]
47. Babaei A, Venu M, Naini SR, et al. Impaired upper esophageal sphincter reflexes in patients with
supraesophageal reflux disease. Gastroenterology. 2015;149(6):1381–1391. [PubMed: 26188682]
48. Shaker R, Babaei A, Naini SR. Prevention of esophagopharyngeal reflux by augmenting the
upper esophageal sphincter pressure barrier. Laryngoscope. 2014;124(10):2268–2274. [PubMed:
24782387]
49. Slivers SL VM, Nimish B, et al. Prospective study of upper esophageal sphincter assist device for
treating extraesophageal reflux. Otolaryngol Open J. 2016;2(1):8.
50. Yadlapati R, Craft J, Adkins CJ, Pandolfino JE. The Upper Esophageal Sphincter Assist
Device Is Associated With Symptom Response in Reflux-Associated Laryngeal Symptoms. Clin
Gastroenterol Hepatol. 2018;16(10):1670–1672. [PubMed: 29408585]
51. Yadlapati R, Pandolfino JE, Greytak M, et al. Upper Esophageal Sphincter Compression Device as
an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux. Dig Dis Sci. 2021.
52. Francis DO, Goutte M, Slaughter JC, et al. Traditional reflux parameters and not impedance
Author Manuscript

monitoring predict outcome after fundoplication in extraesophageal reflux. Laryngoscope.

2011;121(9):1902–1909. [PubMed: 22024842]
53. Sidwa F, Moore AL, Alligood E, Fisichella PM. Surgical Treatment of Extraesophageal
Manifestations of Gastroesophageal Reflux Disease. World J Surg. 2017;41(10):2566–2571.
[PubMed: 28508234]
54. Lechien JR, Dapri G, Dequanter D, et al. Surgical Treatment for Laryngopharyngeal Reflux
Disease: A Systematic Review. JAMA Otolaryngol Head Neck Surg. 2019;145(7):655–666.
[PubMed: 31046069]
55. Ward MA, Ebrahim A, Kopita J, et al. Magnetic sphincter augmentation is an effective
treatment for atypical symptoms caused by gastroesophageal reflux disease. Surg Endosc.
2020;34(11):4909–4915. [PubMed: 31792691]
56. Trad KS, Turgeon DG, Deljkich E. Long-term outcomes after transoral incisionless fundoplication
in patients with GERD and LPR symptoms. Surg Endosc. 2012;26(3):650–660. [PubMed:
21959689]
Author Manuscript

57. Patel DA, Blanco M, Vaezi MF. Laryngopharyngeal Reflux and Functional Laryngeal Disorder:
Perspective and Common Practice of the General Gastroenterologist. Gastroenterol Hepatol (N Y).
2018;14(9):512–520. [PubMed: 30364386]
58. Hull JH, Backer V, Gibson PG, Fowler SJ. Laryngeal Dysfunction: Assessment and Management
for the Clinician. Am J Respir Crit Care Med. 2016;194(9):1062–1072. [PubMed: 27575803]
59. Roman S, Keefer L, Imam H, et al. Majority of symptoms in esophageal reflux PPI non-responders
are not related to reflux. Neurogastroenterol Motil. 2015;27(11):1667–1674. [PubMed: 26337396]
60. Kahrilas PJ, Keefer L, Pandolfino JE. Patients with refractory reflux symptoms: What do they have
and how should they be managed? Neurogastroenterol Motil. 2015;27(9):1195–1201. [PubMed:
26303047]
61. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised,
double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583–1589. [PubMed: 22951084]
62. Gibson P, Wang G, McGarvey L, et al. Treatment of Unexplained Chronic Cough: CHEST
Guideline and Expert Panel Report. Chest. 2016;149(1):27–44. [PubMed: 26426314]
63. Halum SL, Sycamore DL, McRae BR. A new treatment option for laryngeal sensory neuropathy.
Author Manuscript

Laryngoscope. 2009;119(9):1844–1847. [PubMed: 19554633]

64. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants
in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope.
2006;116(12):2108–2112. [PubMed: 17146380]
65. Riehl ME, Chen JW. The Proton Pump Inhibitor Nonresponder: a Behavioral Approach to
Improvement and Wellness. Curr Gastroenterol Rep. 2018;20(7):34. [PubMed: 29886565]
66. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory
chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet.
2015;385(9974):1198–1205. [PubMed: 25467586]

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 15

67. Smith JA, Kitt MM, Morice AH, et al. Gefapixant, a P2X3 receptor antagonist, for the treatment
of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group,
Author Manuscript

phase 2b trial. Lancet Respir Med. 2020;8(8):775–785. [PubMed: 32109425]

68. Murry T, Tabaee A, Owczarzak V, Aviv JE. Respiratory retraining therapy and management
of laryngopharyngeal reflux in the treatment of patients with cough and paradoxical vocal fold
movement disorder. Ann Otol Rhinol Laryngol. 2006;115(10):754–758. [PubMed: 17076097]
69. Vertigan AE, Theodoros DG, Gibson PG, Winkworth AL. Efficacy of speech pathology
management for chronic cough: a randomised placebo controlled trial of treatment efficacy.
Thorax. 2006;61(12):1065–1069. [PubMed: 16844725]
70. Kiebles JL, Kwiatek MA, Pandolfino JE, Kahrilas PJ, Keefer L. Do patients with globus
sensation respond to hypnotically assisted relaxation therapy? A case series report. Dis Esophagus.
2010;23(7):545–553. [PubMed: 20459447]
71. Riehl ME, Pandolfino JE, Palsson OS, Keefer L. Feasibility and acceptability of esophageal-
directed hypnotherapy for functional heartburn. Dis Esophagus. 2016;29(5):490–496. [PubMed:
25824436]
72. Riehl ME, Keefer L. Hypnotherapy for Esophageal Disorders. Am J Clin Hypn. 2015;58(1):22–33.
Author Manuscript

[PubMed: 26046715]
73. Vasant DH, Whorwell PJ. Gut-focused hypnotherapy for Functional Gastrointestinal Disorders:
Evidence-base, practical aspects, and the Manchester Protocol. Neurogastroenterol Motil.
2019;31(8):e13573. [PubMed: 30815936]
74. Riehl ME, Kinsinger S, Kahrilas PJ, Pandolfino JE, Keefer L. Role of a health psychologist in the
management of functional esophageal complaints. Dis Esophagus. 2015;28(5):428–436. [PubMed:
26174953]
Author Manuscript
Author Manuscript

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 16
Author Manuscript
Author Manuscript

Figure 1:
Image of the External Upper Esophageal Sphincter Compression Device
Author Manuscript
Author Manuscript

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 17
Author Manuscript
Author Manuscript

Figure 2:
Conceptual diagram outlining both the diagnostic and therapeutic challenges of LPR.
Author Manuscript
Author Manuscript

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Krause et al. Page 18
Author Manuscript
Author Manuscript

Figure 3:
Proposed diagnostic algorithm for patients presenting with suspected LPR. Given the
lack of a gold standard for diagnosis of LPR, we recommend flexible laryngoscopy and
ambulatory reflux monitoring to assess the reflux burden. Pending the results, providers
Author Manuscript

can treat patients with a sequential strategy for patients with LPR and GERD or Laryngeal
hypersensitivity. For the LPR/GERD category, providers should initially start with a PPI
trial with GERD lifestyle modifications, and if symptoms persist, move down the treatment
algorithm trialing different therapies as outlined in the diagram.
Author Manuscript

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Table 1:

Therapeutic options for patients presenting with LPR symptoms

Therapy Dose/Frequency Mechanism Special Considerations

Krause et al.

PPI High-dose PPI for 8 weeks Block secretion of gastric acid by binding irreversibly to Patients with predominately nonacid reflux events may be
the hydrogen-potassium ATPase pump on gastric parietal non-responders
cells.

H2 Receptor Antagonists Variable dosing regimens Block secretion of gastric acid by reversibly binding to May be an option in patients for breakthrough symptoms on
histamine H2 receptors on gastric parietal cells. a PPI, but are unlikely to be effective in individuals with
frequent symptoms

Alginates GA, 10mL to 20mL after meals and/or at Mucosal barrier near the gastroesophageal junction, May be helpful in patients with nonacid or mixed acid reflux
bedtime prevention of gastric reflux by forming a mechanical raft who are PPI non-responders and those prone to post-prandial
above gastric content, and inhibition of pepsin and bile acid pocket
salts.

Baclofen Variable dosing regimens used in studies Gamma-aminobutyric acid receptor type-B agonist that Modest efficacy in LPR and does carry important side effect
inhibits lower esophageal sphincter relaxation profile

Dietary and Lifestyle Plant-based, low fat, low acid diet with Acid suppression Relatively effective and should be included when discussing
Therapy standard reflux precautions symptom management

External UES 20-30 mmHg of cricoid pressure, nightly Increases the upper esophageal sphincter intraluminal Newer therapy with potential efficacy in LPR
Compression Device while sleeping pressure to prevent pharyngeal reflux events

Endoscopic and Surgical Laparoscopic fundoplication, Magnetic Re-creation of a gastro-esophageal flap valve to restore the Should only be considered if symptoms are refractory to
Interventions sphincter augmentation, Transoral anti-reflux barrier medical therapy and the patient has objective findings of
incisionless fundoplication GERD

Pharmacologic Variable dosing/frequency. Gabapentin, Focused on laryngeal hypersensitivity and functional Mainly studied in chronic cough, reflux hypersensitivity, and
Neuromodulators* Pregabalin, Tricyclic Antidepressants, laryngeal disorders functional heartburn.
Serotonin Reuptake Inhibitors, Serotonin-
Norepinephrine Reuptake Inhibitors, and
P2X3 antagonists.

Speech Therapy* Variable interventions Focused on laryngeal hypersensitivity and functional Mainly studied in chronic cough, requires experienced/trained
laryngeal disorders practitioners

Hypnotherapy and Cognitive Behavioral Focused on laryngeal hypersensitivity and functional Less robust evidence in laryngeal/esophageal disorders and

Ann N Y Acad Sci. Author manuscript; available in PMC 2023 April 01.
Behavioral Therapy*
Therapy laryngeal disorders requires experienced/trained practitioners

*
Consider for patients who have laryngeal hypersensitivity or whom are not responding to therapy, as laryngeal hypersensitivity may be present in patients with LPR/GERD.
Page 19