Sage Journals: Discover world-class research

Abstract

Importance

Proton pump inhibitors (PPIs) do not demonstrate superiority over placebo in laryngopharyngeal reflux disease (LPRD). While poorly used, many alternative medical treatments exist for controlling the gastroduodenal and gastro-pharyngeal reflux processes.

Objective

To investigate the clinical findings of controlled studies comparing therapeutic regimens for treating LPRD.

Design

PubMED, Scopus, and Cochrane Library systematic review without meta-analysis using the PRISMA statements.

Setting

Review of prospective or retrospective cohort studies comparing 2 medical regimens in patients with suspected or confirmed LPRD.

Participants

Patients with suspected or confirmed LPRD.

Intervention

Comparison of PPI therapy to other therapeutic regimens for LPRD.

Outcomes

Symptom, sign changes, and therapeutic responses were considered from pre- to posttreatment. Bias analysis was conducted with Methodological Index for Non-Randomized Studies (MINORS). Implications for practice were summarized with a focus on the pharmacological and biological findings of all drug classes in the LPRD pathophysiology.

Results

Fourteen studies met the inclusion criteria, including 1269 patients. There were 675 females (59.6%) and 458 males (40.4%). The mean age of patients was 49.1 years. Substantial variability was observed among studies regarding both pharmacological interventions and participant selection criteria. Two of the four comparative studies demonstrated superior therapeutic efficacy with prokinetic-PPI combination therapy compared with PPI monotherapy. The alginate-PPI combination yielded enhanced symptom amelioration compared with PPI alone.

The mean MINORS score of 9.1 ± 1.2 indicated an important heterogeneity between randomized and non-randomized controlled studies for inclusion and exclusion criteria, LPRD diagnosis, therapeutic regimens, and outcomes. Recommendations are provided for future randomized controlled studies.

Conclusion

To date, only a few studies investigated the effectiveness of alternative medications to PPIs in the treatment for LPRD, which represents an important gap with the gastroesophageal reflux disease literature. Although the limited number of studies and their heterogeneity preclude definitive conclusions, the preliminary findings from this review support the need for future randomized controlled trials examining the therapeutic potential of alginates and prokinetics in patients with primary or refractory LPRD.

Graphical Abstract

Keywords

laryngeal larynx otolaryngology head neck surgery controlled studies alginates antacids treatment

Key Messages

The number of studies comparing proton pump inhibitors (PPIs) with other medication is still limited.

Prokinetic-PPI combination therapy should be superior to PPI monotherapy, while the alginate-PPI combination yielded enhanced symptom amelioration compared with PPI alone.

Future randomized controlled trials examining the therapeutic potential of alginates and prokinetics in patients with primary or refractory laryngopharyngeal reflux disease are needed.

Introduction

Laryngopharyngeal reflux disease (LPRD) is defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract.¹ The diagnosis of LPRD consists of the identification of more than one pharyngeal acidic, weakly-acidic, or alkaline reflux events at the 24 hour hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing (HEMII-pH), while gastroesophageal reflux disease (GERD) diagnosis is based on Lyon criteria and acidic exposure in low esophagitis or related complications.¹ Nowadays, the primary treatment for LPRD includes diet and lifestyle recommendations, and the prescription of once-daily– or twice-daily–proton pump inhibitors (PPIs).^2,3 However, the treatment for LPRD remains challenging with moderate effectiveness of PPIs,⁴ ensuring symptom relief in approximately 50% of cases.⁴ Moreover, the last meta-analyses reported that PPIs do not still demonstrate superiority over placebo.³ The limited efficacy of PPIs in LPRD can be attributed to fundamental pathophysiological distinctions between GERD and LPRD. While GERD is characterized primarily by acidic liquid reflux, typically defined by greater than 6% acid exposure time in the distal esophagus—leading to complications such as esophagitis, stricture formation, and potential Barrett’s metaplasia—the pathophysiology of LPRD is more complex. In GERD, PPI therapy makes sense as it effectively raises gastric pH, thereby reducing both acid-mediated injury and pepsin activity.^1,2 However, this therapeutic approach may be insufficient for LPRD, where even mildly-acidic or nonacidic refluxate containing activated pepsin can cause significant laryngopharyngeal injury. The pathophysiology of LPRD involves the gaseous weakly-acidic and alkaline back-flowed droplets of gastroduodenal content into the upper aerodigestive tract mucosa through the transient relaxations of both lower and upper esophageal sphincters.^5,6 As for GERD, many alternative medical treatments exist for controlling the gastroduodenal reflux processes and the related esophageal dysmotility, including sodium alginates, antacids, prokinetics, H2 blockers, transient lower esophageal sphincter relaxation inhibitors, or potassium- competitive acid blockers.⁷

This systematic review aimed to review the controlled studies investigating the effectiveness of alternative medical treatments to PPIs in the management of LPRD.

Materials and Methods

The criteria for study inclusion were based on the population, intervention, comparison, outcome, timing, and setting (PICOTS) framework.⁸ The study data were reviewed and collected regarding the PRISMA checklist for systematic reviews.⁹

Types of Studies

A systematic review of the content of controlled prospective or retrospective studies published between 1990 and 2024 was conducted if the studies investigated the effectiveness of alternative treatments to PPI therapy for LPRD. The studies were published in English, Spanish, or French peer-reviewed journals. The authors only considered studies reporting data of 10 or more adult patients.

Populations, Inclusion, and Exclusion Criteria

To be included, the authors had to report the inclusion and exclusion criteria, diagnosis criteria of LPRD, treatment regimens, and therapeutic outcomes. The studies including the pediatric population were excluded. In study’s populations, the diagnosis of LPRD was confirmed if patients had more than one pharyngeal reflux event at the 24 hour HEMII-pH, which is consistent with the Dubai consensus.¹ The use of oropharyngeal pH monitoring, dual-probe or triple-probe pH monitoring with pharyngeal pH sensor can support but not confirm the diagnosis.¹ The LPRD diagnosis was suspected but not confirmed for patients included through the use of patient-reported outcomes questionnaires [eg, reflux symptom index (RSI),¹⁰ reflux symptom score (RSS)¹¹] and validated sign instruments [eg, reflux finding score (RFS),¹² reflux sign assessment (RSA)¹³]. Patients with LPRD symptoms completing GERD diagnosis criteria (eg, Montreal, Lyon consensus)¹ were suspected of LPRD diagnosis. In this review, patients with confirmed or suspected LPRD were included, as well as those with GERD and LPRD symptoms.

Outcomes

The following outcomes were reviewed: study design; number of patients; gender ratio; age; diagnosis criteria; therapeutic regimens; diet and lifestyle recommendations, therapeutic outcomes, and duration of treatments. The following medications were considered as an alternative therapy to PPIs: alginates, antacids, prokinetics, H2 blockers, potassium-competitive acid blockers, transient lower esophageal sphincter relaxation inhibitors (ie, GABA receptor agonists, metabotropic glutamate receptors, CB1 receptor agonists/antagonists, neuromodulators).

Intervention and Comparison

The following therapeutic comparisons were considered: PPIs versus alginate, antacids, prokinetics, or transient lower esophageal sphincter relaxation inhibitors; PPIs + an alternative medication versus transient lower esophageal sphincter relaxation inhibitors. The nonmedical therapeutic approaches were not included in the present review. Heterogeneity among included articles in LPRD diagnosis, inclusion/exclusion criteria, therapeutic regimens, diet and lifestyle recommendations, therapeutic duration, and outcomes precluded statistically pooling the data into a formal meta-analysis, thereby limiting the analysis to a qualitative rather than quantitative summary of the available information.

Timing and Setting

There were no criteria for specific timing in the “disease process” of the study population.

Search Strategy

Two investigators (J.R.L. and a librarian) conducted the PubMed, Scopus, and Cochrane Library database research for relevant peer-reviewed controlled studies related to medical therapies of LPRD. The following keywords were used “Laryngopharyngeal,” “Reflux,” “Laryngitis,” “Extra-esophageal,” “Alginate,” “Antacids,” “Proton pump inhibitors,” “Prokinetics,” “H2-blockers,” “potassium- competitive acid blockers,” “transient lower esophageal sphincter relaxation inhibitors” to identify clinical controlled prospective, and retrospective studies, reviews, and meta-analyses. The 2 investigators considered only studies with database abstracts, available full-texts, or titles containing the search terms. The findings of the research strategy were reviewed for relevance and the reference lists of these articles were examined for additional pertinent studies. Implications for practice were summarized with a focus on the pharmacological and biological effects of alternative medication in the LPRD pathophysiology. Ethics committee approval was not required.

Bias Analysis

The bias analysis was carried out with the Methodological Index for Non-Randomized Studies (MINORS) tool,¹⁰ and the Tool to Assess Risk of Bias in Cohort Studies¹¹ developed by the Clarity Group and Evidence Partners. The MINORS tool includes items related to the analysis of methodological points of comparative studies. Each item was rated as 0 if absent; 1 when reported but inadequate; and 2 when reported and adequate. The aim of the study was rated as clearly stated (2), unclear (1), or absent (0). The patients were included consecutively (2), or not (1), with prospective data collection as perfectly prospective (2), retrospective analysis of prospective recruited patients (1), or absent (0). The quality of endpoints (therapeutic outcomes) was judged as high (2) when authors carefully evaluated the pretreatment to posttreatment outcomes with validated, standardized, and structured outcomes (including patient-reported outcome questionnaires or validated clinical instruments). The use of unvalidated structured outcomes was judged as incomplete (1), while the use of subjective unvalidated and nonstructured outcomes was judged as low (0). A 2 to 3 month treatment was considered as an adequate therapeutic duration (2) according to the Dubai consensus.¹ A duration of less than 2 months was less reliable (1), while a shorter duration was considered inadequate. The consideration of a <5% rate of patients who were lost to follow-up was rated as adequate (2). The last MINORS outcome evaluates the report of a study size prospective calculation (2). The ideal MINORS score was 24 for comparative studies.¹⁰

Some items that are not evaluated in MINORS were assessed with the Tool to Assess Risk of Bias in Cohort Studies,¹¹ which provides an analysis of selection; detection; performance; attrition; and reporting biases.¹¹ The following items were evaluated: diagnosis method of LPRD (optimal with 24 hour HEMII-pH, moderate with 24 hour dual-probe or triple-probe pH monitoring, low with validated thresholds or patient-reported outcome questionnaire and clinical finding instruments, and very low with evaluation of symptoms and findings without validated and standardized instruments), and exclusion criteria of confounding factors. The evaluations of symptoms and findings met the same criteria as the evaluation of the diagnosis method. Note that the fiberscope findings need to be evaluated blindly regarding symptoms and patient features (groups). The quality of the randomized process of randomized controlled trials was evaluated in the bias analysis.¹¹

Results

Of the 230 identified studies, 14 studies met our inclusion criteria and data were extracted (Figure 1 and Table 1).^12-25 There were 5 monocentric controlled prospective studies [evidence level (EL): IIB],^{12,14,15,17,18} and 9 randomized-controlled studies (IB),^{13,16,19,20-25} accounting for 1269 patients with suspected LPRD. There were 675 females (59.6%) and 458 males (40.4%). The mean age of patients was 49.1 years (n = 1123). The diagnosis approach and the therapeutic regimen features are reported in Table 2.

Figure 1.

PRISMA flow chart.

Table 1.

Controlled Studies Evaluating Alternative Therapies to Proton Pump Inhibitors.

References	Design	EL	N	F/M	Age (y)	Diagnosis	Groups	Diet	Outcomes	Clinical changes	Timing
Park et al (2005)¹²	MPC	IIB	30	56/29	49	Symptoms and signs	Gr1: PPI 2/d	+	Symptom CS	Gr1 = Gr2	4 mo
			30			Single probe	Gr2: PPI 2/d + ranitidine 1/d	+		Gr1 > Gr3
			25			pH monitoring	Gr3: PPI 1/d	+		Gr2 > Gr3
Ezzat et al (2011)¹³	RCT	IB	42	34/53	33.5	Symptoms and signs	Gr1: Pantoprazole 40 mg 1/d + itopride 50 mg 3/d	+	Symptom CS	Gr1 > Gr2	2 mo
Ezzat et al (2011)¹³			45				Gr2: Pantoprazole 40 mg 1/d + placebo	+	RFS	Gr1 > Gr2
Pedersen and Eeg (2012)¹⁴	MPC	IIB	78	56/22	42	Symptoms and signs	Gr1: Diet	+	Symptom CS	Gr1 = Gr2 = Gr3	2 wk
			70	53/17	42		Gr2: Omeprazole 40 mg 1/d	+	Sign CS	Gr1 = Gr2 = Gr3
			89	63/26	41		Gr3: Omeprazole 40 mg 1/d + alginate (after dinner)	+
Hunchaisri (2012)¹⁵	MPC	IIB	32	25/7	45.8	RSI > 13	Gr1: Omeprazole 20 mg 1/d + Domperidone 10 mg 3/d	+	RSI	Gr1 = Gr2	3 mo
Hunchaisri (2012)¹⁵			33	26/7	47.0		Gr2: Omeprazole 20 mg 1/d	+
Chun and Lee (2013)¹⁶	RCT	IB	32	16/16	52.2	RSI > 13 and RFS > 7	Gr1: Lansoprazole 30 mg 1/d	NP	RSI	Gr2 > Gr1	3 mo
Chun and Lee (2013)¹⁶			29	15/14	51.2		Gr2: Lansoprazole + itopride 50 mg 3/d	NP	RFS	Gr1 = Gr2
Dabirmoghaddam et al (2013)²³	RCT	IB	30	45/45	40.0	Symptoms (RSI) and RFS > 7	Gr1: Omeprazole 20 mg 2/d + N-acetylcysteine 1/d	NP	RSI	Gr1 > Gr2 > Gr3	3 mo
			30				Gr2: Omeprazole 20 mg 2/d + placebo 1/d		RFS	Gr1 > Gr2 > Gr3
			30				Gr3: N-acetylecysteine 1/d + placebo 2/d
Wilkie et al (2018)¹⁷	MPC	IIB	39	22/17	66	RSI > 10	Gr1: Gaviscon Advance 3/d	+	RSI	Gr1 = Gr2	3 mo
Wilkie et al (2018)¹⁷			33	17/16	63		Gr2: PPI 2/d + Gaviscon Advance 3/d	+
Yoon et al (2018)²⁵	RCT	IB	29	10/19	59.2	Symptoms (RSI) and signs (RFS)	Gr1: Ilaprazole 10 mg 1/d	+	RSI and RFS	Gr1 = Gr2 = Gr3	3 mo
			27	14/13	60.1		Gr2: Ilaprazole 10 mg 2/d	+
			44	23/21	57.8		Gr3: Ilaprazole 10 mg 2/d + mosapride 5 mg 3/d	+
Jo et al (2019)²²	RCT	IB	15	8/22	53.0	RSI > 13 and RFS > 7	Gr1: Rabeprazole 20 mg 1/d	NP	RSI	Gr1 = Gr2	2 mo
Jo et al (2019)²²			15				Gr1: Rabeprazole 20 mg 1/d + N-acetylcysteine 2/d	NP	RFS	Gr1 = Gr2
Suzuki et al (2019)²⁴	RCT	IB	20	20/20	50.0	Symptoms (RSI) and signs (RFS)	Gr1: Omeprazole 20 mg 1/d	NP	RSI	Gr1 > Gr2	2 mo
Suzuki et al (2019)²⁴			20		47.1		Gr2: Famotidine 20 mg 1/d		RFS	Gr1 = Gr2
Chae et al (2020)²¹	RCT	IB	59	42/17	60.2	RSI > 12 and RFS > 6	Gr1: Rabeprazole 10 mg 2/d	+	RSI	Gr1 = Gr2	3 mo
Chae et al (2020)²¹			57	37/20	55.5		Gr2: Rabeprazole 10 mg 2/d + acebrophylline 2/d	+	RFS	Gr1 = Gr2
Mathew and Shilpa (2022)¹⁸	MPC	IIB	50	58/42	46	RSI > 13 and RFS > 7	Gr1: Pantoprazole 40 mg 2/d	+	RSI	Gr2 > Gr1	2 mo
Mathew and Shilpa (2022)¹⁸			50				Gr2: Pantoprazole 40 mg 2/d + Sodium Alginate 2/d	+	RFS	Gr2 > Gr1
Pizzorni et al (2022)¹⁹	RCT	IB	25	19/6	68.5	RSI > 12 and RFS > 6	Gr1: Magnesium Alginate 3/d	+	RSI	Gr1 = Gr2	2 mo
Pizzorni et al (2022)¹⁹			25	16/9	70		Gr2: Omeprazole 20 mg 1/d	+	RFS	Gr1 = Gr2
Kim et al (2024)²⁰	RCT	IB	68	NP	NP	RSI > 12 and RFS > 6	Gr1: Esomeprazole 40 mg 1/d	+	RSI, RSS-12	Gr1 = Gr2	1, 2 mo
			68	NP	NP		Gr2: Fexuprazan 40 mg 1/d	+	RFS	Gr1 = Gr2

Abbreviations: MPC, monocentric prospective controlled; PPI, proton pump inhibitor; RCT, randomized controlled trial; RFS, reflux finding score; RSI, reflux symptom index; RSS-12, reflux symptom score-12; CS, Clinical score; NP, Not provided.

Table 2.

Diagnosis and Therapeutic Outcomes of Controlled Studies.

Outcomes	N	%	References
Diagnosis approaches (total)	14	100
Symptoms and findings (no PROM and VCI)	3	21.4	[12-14]
RSI > 13 and RFS > 7	3	21.4	[16,18,22]
RSI > 12 and RFS > 6	3	21.4	[19-21]
RSI > 13	1	7.1	[15]
RSI > 10	1	7.1	[17]
RFS > 7 and symptoms	1	7.1	[23]
RSI and RFS without cutoffs	2	14.3	[24,25]
Therapeutic regimens (total)	32	100
Proton pump inhibitors
Proton pump inhibitors 1/d	9	28.1	[12,14-16,19,20,22,24,25]
Proton pump inhibitors 2/d	4	12.5	[12,18,21,25]
Proton pump inhibitors 2/d and H2 blockers 1/d	1	3.1	[12]
Proton pump inhibitors 2/d and prokinetics 3/d	4	12.5	[13,15,16,25]
Proton pump inhibitors 2/d and alginates 2/d	1	3.1	[18]
Proton pump inhibitors 2/d and alginates 3/d	1	3.1	[17]
Proton pump inhibitors 1/d and mucolytics	1	3.1	[22]
Proton pump inhibitors 2/d and mucolytics	2	6.3	[21,23]
Proton pump inhibitors and placebo	2	6.3	[13,23]
Alginates 3/d	2	6.3	[17,19]
Alginates 1/d	1	3.1	[14]
Diet and behavioral changes	1	3.1	[14]
H2 blockers	1	3.1	[24]
Mucolytics and placebo	1	3.1	[23]
Potassium-competitive acid blockers	1	3.1	[20]
Therapeutic outcomes (total)	26	100
Symptom composite score (unvalidated)	3	11.5	[12-14]
Sign composite score (unvalidated)	1	3.8	[14]
RSI	11	42.3	[15-25]
RSS-12	1	3.8	[20]
RFS	10	38.5	[13,16,18-25]
Treatment duration (total)	11	100
2 wk	1	9.1	[14]
2 mo	3	27.3	[13,18-20,22,24]
3 mo	7	63.6	[15-17,21,23,25]
4 mo	1	9.1	[12]

Abbreviations: H2 blockers, histamine receptor-2 blockers; PROM, patient-reported outcome questionnaire; RFS, reflux finding score; RSI, reflux symptom index; VCI, validated clinical instruments (signs).

Thirteen diagnosis methods have been used in the studies, all using symptom and/or sign evaluation. Among them, validated patient-reported outcome questionnaires (RSI and RFS) were used in 76.8% of cases. However, the initial thresholds defined by Belafsky et al for suggesting the LPRD diagnosis (RSI > 13 and RFS > 7)^26,27 were used in only 2 studies.^16,18,22 In twelve studies, the authors conducted a controlled study with once-daily or twice-daily PPI as the treatment for the control group (Table 2).^{12-16,18-22,24,25} The pretreatment to posttreatment outcomes were primarily the composite or validated patient-reported outcome questionnaires or clinical instruments used for the diagnosis (Table 2). The duration of treatment ranged from 2 weeks to 4 months (Table 2). Four studies did not detail the diet and lifestyle recommendations for patients.^16,22-24

Benefits of Prokinetics

Prokinetics enhance gastric motility and accelerate gastric emptying through multiple mechanisms, including antagonism of dopamine D2 receptors (metoclopramide, domperidone) or activation of 5-HT4 receptors (prucalopride), while simultaneously increasing lower esophageal sphincter pressure and improving esophageal clearance.¹³ Then, prokinetics reduce reflux episodes by minimizing the retrograde flow of gastroduodenal contents and decreasing the volume of material available for reflux. The therapeutic benefits of prokinetics were investigated in 4 studies.^13,15,16,25 Ezzat et al observed that the combination of PPI with prokinetics (3/day) was associated with a significantly-higher reduction in a composite laryngeal symptom score (eg, hoarseness, irritative cough, throat pain, and throat clearing) and a composite laryngeal sign score (eg, laryngeal mucosa erythema, edema, granulation, and ulceration) after 2 months of treatment compared to the intake of PPI with a placebo.¹³ These findings were corroborated in the study of Chun and Lee, who observed a superiority of the association between lansoprazole and itopride over the lansoprazole treatment in terms of RSI reduction.¹⁶ In the study of Hunchaisri and Yoon et al, there were no significant differences between PPI and PPI + prokinetic groups.^15,25 However, both teams used lower doses of PPIs than those by Ezzat et al¹³ and Chun and Lee¹⁶ (Table 1).

Benefits of Alginates

Alginates form a rapid-acting, floating mechanical barrier on the top of the gastric contents within minutes of contact with gastric acid, physically blocking reflux events.¹⁴ The raft formation occurs through a chemical reaction where sodium alginate reacts with gastric acid to form alginic acid, while sodium bicarbonate releases CO₂ that gets trapped within the gel matrix, creating a low-density foam barrier that can persist for up to 4 hours. Moreover, the potassium bicarbonate or calcium carbonate components provide local buffering effects. Alginate is the second drug class that was investigated in controlled studies.^14,17-19 Wilkie et al reported that the prescription of twice-daily PPIs and thrice-daily alginates reported similar symptom relief to the use of thrice-daily alginate.¹⁷ In the study of Matheuw and Shilpa, the patients treated with a combination of twice-daily PPIs and sodium alginates had higher symptom and sign reliefs than those treated with twice-daily PPIs only.¹⁸ The daily doses of PPIs in these 2 studies were significantly higher than the doses used by Pizzorni et al who did not report a superiority of once-daily omeprazole (20 mg) over thrice-daily magnesium alginate.¹⁹ The non-inferiority of alginates over the PPIs was however not supported by Pedersen and Eeg, who did not observe significant differences between PPI and PPI + alginate groups.¹⁴ It is however important to note that alginate was prescribed after dinner (once-daily) in the study of Pedersen.¹⁴

Benefits of Mucolytics

Three studies evaluated the effectiveness of oral^21,23 or inhaled²² mucolytics in addition to PPIs. Jo et al and Chae et al did not find the superiority of PPI + mucolytics over PPI at the 2nd and 3rd month posttreatment,^21,22 while Dabirmoghaddam et al reported that the association between twice-daily omeprazole (20 mg) and mucolytics led to a higher reduction in RSI and RFS scores at the 3rd month posttreatment than by twice-daily omeprazole (20 mg) and placebo, and mucolytics and placebo.²³

Benefits of H2 Blockers and Potassium-Competitive Acid Blockers

H2-receptor antagonists competitively block histamine type 2 receptors on gastric parietal cells, thereby inhibiting one of the major pathways of acid secretion and reducing both basal and food-stimulated acid production by approximately 70%.²⁴ The 3 last studies compared PPI with potassium-competitive acid blockers,²⁰ H2 blockers,²⁴ or PPI + H2 blockers.¹² No study demonstrated the superiority of H2 blockers or PPI and H2 blockers over the twice-daily PPI therapy.^20,24 In these 2 last studies, only the twice-daily PPI regimen was suggested as superior to the use of once-daily PPI.¹² Note that Park et al used several PPIs with high doses (lansoprazole 30 mg 2/day, omeprazole 20 mg 2/day, or esomeprazole 40 mg 4/day).¹²

Epidemiological Analysis

The mean MINORS of studies was 9.1 ± 1.2, which indicates a low score for controlled studies (Table 3). There was no study reaching the cutoff of 24. A few teams included consecutive patients,^12,16,17,19 and none reported an adequate rate of patients who were lost to follow-up (Table 3). The study size population was calculated in 2 studies,^14,20 while the randomized process was detailed and adequate in most studies (Table 3). Their diagnosis was not based on 24 hour HEMII-pH, MII-pH, or oropharyngeal pH monitoring in studies. Considering a clinical LPRD diagnosis, the exclusion criteria of confounding conditions were judged as adequate in 2 studies (Appendix 1).^17,25 Others included patients with systemic or ear, nose, and throat conditions with nonspecific symptoms and findings that can mimic LPRD. For example, Chae et al and Wilkie et al included smokers, drinkers (chronic laryngopharyngitis), and patients with psychiatric illnesses.^17,21 Respiratory diseases (chronic obstructive pulmonary disease, asthma) and their related treatments (inhaled corticoids), which can be both associated with respiratory symptoms or drug-induced laryngitis¹ were excluded in only 3 studies.^18,19,22 Similar observations can be made for chronic rhinosinusitis or allergy (Appendix 1). There was an important heterogeneity between studies for the therapeutic regimens of the control group (PPIs) in terms of molecules, doses, and intake. Pedersen and Eeg recommended Omeprazole 40 mg at bedtime,¹⁴ which does not match with the pharmacological recommendations for taking PPIs (30 minutes to 1 hour before meals).¹ Some teams recommended twice-daily PPIs,^12,18,21,25 while others prescribed once-daily low doses.^15,19,21 At the exception of one study,¹⁴ the therapeutic duration was adequate according to consensus paper.¹ The outcomes used for analyzing the therapeutic response were judged as incomplete. The validated RSI and RFS were used in most studies.^15-25 However, RSI is an incomplete patient-reported outcome questionnaire that does not document all LPRD symptoms. Only Kim et al used both RSI and reflux symptom score-12 (RSS-12),²⁰ which report higher sensitivity and specificity than RSI.²⁸ RFS was not evaluated blindly regarding the patient history and symptoms, which can bias the analysis.²⁹

Table 3.

Bias Analysis.

References	MINORS									Oxford tool
References	Clearly-stated aim	Consecutive patients	Prospective data collection	Endpoints appropriate to study	Unbiased endpoint assessment	Follow-up adequate period	<5% lost of follow-up	Study size population calculation	Total MINORS score	LPRD diagnosis	Adequate randomized process	Exclusion criteria	Adequate symptom assessment	Adequate finding assessment
Park et al¹²	2	2	2	1	1	2	—	0	10	Probably no	Probably yes	Probably no	Probably no	Probably no
Ezzat et al¹³	2	—	2	1	1	2	0	0	8	Probably no	Yes	Probably no	Probably no	No
Pedersen and Eeg¹⁴	2	—	2	1	1	0	0	2	8	No	Yes	No	Probably no	No
Hunchaisri¹⁵	2	—	2	1	1	2	—	0	8	Probably no	Probably yes	—	Yes	No
Chun and Lee¹⁶	2	2	2	1	1	2	0	0	10	Probably no	Probably yes	Probably no	Yes	Probably no
Dabirmoghaddam et al²³	2	—	2	1	1	2	—	0	8	No	Yes	Probably no	Yes	Probably no
Wilkie et al¹⁷	2	2	2	1	1	2	0	0	10	Probably no	No	No	Yes	No
Yoon et al²⁵	2	—	2	1	1	2	0	0	8	No	Probably yes	Yes	Yes	Probably no
Jo et al²²	2	—	2	1	1	2	0	0	8	Probably no	Yes	Yes	Yes	Probably no
Suzuki et al²⁴	2	—	2	1	1	2	2	0	10	Probably no	Yes	Probably yes	Yes	Probably no
Chae et al²¹	2	—	2	1	1	2	2	0	10	Probably no	Yes	Probably no	Yes	Probably no
Mathew and Shilpa¹⁸	2	—	2	1	1	2	—	0	8	Probably no	Probably yes	Probably yes	Yes	Probably no
Pizzorni et al¹⁹	2	2	2	1	2	2	—	0	11	Probably no	Yes	Probably yes	Yes	Yes
Kim et al²⁰	2	—	2	2	1	2	—	2	11	Probably no	Yes	Probably yes	Yes	Probably no

Two complementary bias tools were used: the MINORS tool,¹⁰ and the Tool to Assess Risk of Bias in Cohort Studies¹¹ developed by the Clarity Group and Evidence Partners.

Abbreviations: LPRD, laryngopharyngeal reflux disease; MINORS, Methodological Index for Non-Randomized Studies.

Discussion

The treatment for LPRD has long time been based on the GERD recommendations. Indeed, a recent review of the literature suggests that of the 53 prospective clinical studies of LPRD treatment conducted in the past 25 years, PPIs were used as primary medication in 94.0% of therapeutic regimens (33% in association with other drugs).³⁰ This observation corroborates the data of a recent international survey, highlighting that more than 50% of otolaryngologists exclusively treat LPRD with PPIs.³¹ However, LPRD differs from GERD for many pathophysiological and biological mechanisms,^1,32 with the most blatant being the weakly-acidic and alkaline nature of most gastroesophagopharyngeal reflux events,^5,6 which supports the lower effectiveness of PPI therapy in LPRD than in GERD.³³

The low number of clinical controlled studies comparing PPIs to alternative medical therapies is the primary finding of the present review. However, some interesting preliminary reports suggested a potential effectiveness in associating prokinetics with PPIs for treating LPRD symptoms.^13,16 The prokinetics’ effectiveness can be attributed to the increase in the lower and upper sphincter tonicities, which reduces the number and duration of transient relaxation episodes of both sphincters and, consequently, the gaseous droplets with gastroduodenal enzymes reaching the upper aerodigestive tract. This hypothesis is supported by recent studies showing that patients with LPRD have a longer duration of upper esophageal sphincter (UES) transient relaxation episodes than controls,³⁴ or a high prevalence of proximal esophageal dysmotility disorders.³⁵ The weakly-acidic or alkaline nature of most pharyngeal reflux events at the 24th hour HEMII-pH supports the use of alginates or antacids in the treatment for LPRD.^5,6 Of the 4 studies investigating the benefits of alginates, 3 supported the non-inferiority of alginates over PPIs in the treatment for LPRD.^17-19 The epidemiological quality of the study reporting no benefits of alginate was low, with a bias analysis supporting the occurrence of many inclusion and therapeutic biases that can limit the conclusion of the study¹⁴ (Table 3). The potential interest in using alginates or antacids in the treatment for LPRD was strengthened by recent uncontrolled large-cohort studies of patients with a confirmed LPRD diagnosis. Thus, it has been found that patients with LPRD treated with alginate and antacids had higher therapeutic response rates³⁶ than the mean therapeutic response rates found in the literature.⁴ Magaldrate is the primary antacids used in Western countries. Magaldrate is a complex aluminum-magnesium hydroxide compound, acting as a rapid antacid by neutralizing gastric acid through chemical buffering, resulting in the formation of aluminum and magnesium chlorides plus water, thereby increasing gastric pH within minutes of administration. In addition, magaldrate exhibits cytoprotective effects by forming a protective barrier on the mucosa and binding to pepsin and bile salts, while its crystalline structure provides a longer duration of action compared to traditional aluminum/magnesium hydroxide combinations. The compound adsorbs lysolecithin and bile acids, potentially reducing their damaging effects on the esophageal mucosa.¹

In this review, only one study investigated the benefits of H2 blockers, while another compared PPIs to potassium-competitive acid blockers, which is insufficient to conclude for these 2 drugs.

Regardless of the alternative medication to PPIs, the findings of this review support the need to conduct future randomized controlled studies investigating the effectiveness of alternative medications in the treatment for patients with LPRD. The epidemiological analysis supports the need to consider some further methodological points. First, because LPRD is associated with nonspecific symptoms and findings,^37,38 the use of 24-h HEMII-pH is required for including patients with a confirmed diagnosis. Indeed, the inclusion of patients with some prevalent confounding conditions, such as allergy, chronic rhinitis, or tobacco-induced laryngopharyngitis, can undoubtedly bias the pretreatment to posttreatment assessments.^39,40 Second, despite a confirmed diagnosis, the control of the additional ear, nose, and throat disorders has to be optimal to differentiate the symptoms related to LPRD from those due to other disorders. Third, critical attention must be paid to the diet and lifestyle recommendations as an influencing factor on the therapeutic effectiveness. In this way, some controlled and uncontrolled studies have demonstrated that an alkaline, low-fat, low-high-released sugars, high-protein diet can lead to LPRD symptom relief in a few months.^41-43 The adherence to an antireflux diet and the reduction in triggers of autonomic nerve dysfunction (stress, anxiety, depression) can be considered as a treatment and, consequently, can influence the posttreatment outcomes. They should be controlled and matched between groups in future studies. Fourth, adherence to the medication is an additional confounding factor in the assessment of the effectiveness of medications. Pisegna et al reported that 62.7% of patients treated with PPIs described an incorrect routine in taking their medication, taking it with other pills, with food/drink, and uncertainty about which pill is for reflux.⁴⁴ The adherence to diet, lifestyle changes, and good practice in taking the medications have been not investigated in the controlled studies. Moreover, from a pharmacological standpoint, the several drug regimens used in LPRD treatments were based on GERD regimens, and they require future investigations. Thus, some authors used once-daily PPI,²⁰ while others recommended twice daily.¹² There was an important heterogeneity in the doses of PPIs, ranging from 20 mg/day to 80 mg/day. According to some pharmacological investigations, the steady-state inhibition on once-a-day dosing is about 66% of maximal acid output for a PPI taken at least 30 minutes beforehand, while the intake of a morning dose, and an evening dose before meals (twice-daily-PPI regimen), results in about 80% inhibition of maximal acid output.⁴⁵ Physiologically, studies suggested that an increase in the PPI dose (80 mg/day) has virtually no effect once the optimal dosage has been reached.⁴⁵ For alginates and antacids, the GERD recommendations consist of an intake 1 hour post-meals (3/day) or at bedtime to neutralize the acidity of the gastric pocket during daytime and/or nighttime.^1,46 Given the occurrence of most pharyngeal reflux events during daytime, upright, and after meals, as well as the weakly-acidic or alkaline nature of events, this regimen can be put into question. The bedtime intake of alginates or antacids does not make sense regarding the lack of pharyngeal reflux events at nighttime. Moreover, practitioners could favor the immediate post-meal intake of alginate and antacids to reduce the number of gaseous pharyngeal reflux events that occur in the immediate post-meal time.⁴⁷

The heterogeneity between studies in inclusion criteria, diagnosis approaches, therapeutic regimens, and outcomes is the primary limitation of this review, making difficult the comparison across studies. The low number of patients included in the study groups, the lack of full information on the diet and lifestyle recommendations, the use of incomplete patient-reported outcomes measures, and the adherence to the medication regimens are additional limitations. Concerning patient-reported outcomes measures, RSI²⁶ does not consider some prevalent LPRD symptoms, such as throat pain, halitosis, odynophagia, or ear pain, which has been found to reduce its accuracy for the clinical diagnosis and the follow-up of symptoms through treatment.^28,32 Table 4 reports some potential recommendations for further studies comparing several drug classes in the treatment for LPRD.

Table 4.

Recommendations for Future Controlled Studies.

Recommendations
Design
1. Consider the international recommendations for conducting high-quality randomized controlled trials.
2. Consider the inclusion of consecutive patients, and a rate of lost-to-follow-up less than 5%.
3. Consider a study size calculation of randomized groups.
4. Consider using a bias evaluation before starting the study to improve the data collection and analyses.
5. Detail in the study description of the randomized process.
Diagnosis
1. Consider the use of 24 h HEMII-pH to confirm the diagnosis (>1 pharyngeal reflux events).
2. Consider the exclusion of the following confounding conditions associated with nonspecific ear, nose, and throat symptoms and findings: active allergy, chronic rhinosinusitis, alcohol-induced or tobacco-induced laryngopharyngitis, respiratory chronic or acute infection, histamine sensitivity, gluten/lactose intolerance, upper GI disorders (eg, Zenker diverticulum, systemic disease affecting upper aerodigestive tract, cancer, benign lesions of upper aerodigestive tract, neck history of radiation or laryngopharyngeal surgery, psychiatric illness).
3. GERD is not an exclusion criterion, but it can be considered in the analysis of treatments (eg, PPIs).
4. Esophageal dysmotility is not an exclusion criterion because it can be involved in the development of LPRD treatment.
Treatments
1. Consider the use of twice-daily PPIs in case of PPI therapy. PPIs have to be taken 1 hour before meals, except rabeprazole that can be taken during meals.
2. Alginates and antacids have to be taken after meals. Prokinetics have to be taken before meals.
3. Consider 2 months as the minimal duration of treatment to observe symptom changes.
4. Consider the use of placebo.
Therapeutic outcomes
1. Consider otolaryngological, digestive, and respiratory symptoms described in LPRD and not only laryngeal ones.
2. Consider laryngeal and extra-laryngeal signs associated with LPRD, including pharyngeal, oral signs.
3. Use validated patient-reported outcome questionnaires and clinical instruments. For symptoms, the questionnaire has to be validated in the language of the user, assessing frequency, severity, and impact of QoL.
4. Consider rating finding score blindly regarding the patient features (eg, symptoms, groups) to avoid the subjective part of sign assessment.
5. Assess the treatment adherence, changes in lifestyle (stress, anxiety, depression), and the diet recommendation adherence.

The recommendations were elaborated with the last consensus statements of laryngopharyngeal reflux disease management.^1,4

Abbreviations: GERD, gastroesophageal reflux disease; GI, gastrointestinal; HEMII-pH, hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring; LPRD, laryngopharyngeal reflux disease; PPIs, proton pump inhibitors; QoL, quality of life.

Conclusion

To date, only a few studies investigated the effectiveness of alternative medications to PPIs in the treatment for LPRD, which represents an important gap with the GERD literature. Some preliminary results suggest a non-inferiority of some drugs to PPIs (alginates, potassium-competitive acid blockers), but the low number and the quality of studies limit the drawing of reliable conclusions. These data can encourage the conduction of future randomized controlled studies investigating the benefits of alternative drugs in the treatment for patients with a primary or recalcitrant LPRD.

Footnotes

Appendix 1

Exclusion Criteria of Studies.

References	Exclusion criteria
References	Respiratory conditions	GI conditions	Drugs and others
Park et al (2005)¹²	—	GERD surgery	GERD medical treatment, cancer
Ezzat et al (2011)¹³	Endotracheal intubation (3 mo), vocal fold lesions	GERD surgery	Pregnancy, obesity, continuous medication for systemic disease, NSAIDs, antidiabetics, anti-HT Psychiatric illness, chronic disease
Pedersen and Eeg (2012)¹⁴	Cancer		Pregnancy
Hunchaisri (2012)¹⁵	NP
Chun and Lee (2013)¹⁶	Vocal cord paralysis, laryngeal cancer	GERD diagnosis or complications, GI surgery	PPI (1 mo)Allergy to PPIs and prokineticsPregnancy, brest feeding
Dabirmoghaddam et al (2013)²³	Laryngeal cancerLaryngitis	—	Medication reactionPrevious reflux treatment
Wilkie et al (2018)¹⁷	NP
Yoon et al (2018)²⁵	Airway infection, allergiesAlcohol or drug dependenceHistory of surgery	Gastroenterological diseaseGI surgery	Pregnant or lactating NSAIDs, glucocorticoids, H2 blockers, PPIs
Jo et al (2019)²²	Acute/chronic rhinosinusitis infection, asthma, COPD, pneumonia, lung cancer, pharynx, larynx, oral lesions		PregnantPPI intakePsychiatric medicationsDepression, insomnia
Suzuki et al (2019)²⁴	Smokers, cancer history	Surgery history	Pregnant
	Surgery history, infection	Infection
	Radiation history
Chae et al (2020)²¹	Laryngeal/neck surgery	GERD, gastritis (3 mo)Upper GI surgery	PPI intake, polypharmacyContraindication to PPI
Mathew and Shilpa (2022)¹⁸	Previous surgery, premalignant or malignancy, COPD, rhinosinusitis, laryngitis	Upper GI cancer	Allergy to PPIs and alginates
			Psychiatric disorders
			Pregnancy, breastfeeding
Pizzorni et al (2022)¹⁹	Laryngopharyngeal surgery, cancer, dysphonia not due to LPRD, respiratory diseases	GERD surgery, gastroenterological diseases	Immunosuppression/deficiency, diabetes, cystic fibrosis, cardiac disease, alcohol/drug abuse, pregnancy, breastfeeding
Kim et al (2024)²⁰	Cancer, radiotherapy history	Cancer, GERD, GERD complications	Antireflux medication (2 wk)Abnormal biological testing

Abbreviations: COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; GI, gastrointestinal; HT, hypertension; NP, not provided; NSAID, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitor(s).

Acknowledgements

The author would like to thank the librarian for the review.

Author Contributions

Jérôme R. Lechien: design, acquisition of data, data analysis and interpretation, drafting, final approval, and accountability for the work; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

ORCID iD

Jérôme R. Lechien

References

Lechien

Vaezi

Chan

, et al. The Dubai definition and diagnostic criteria of laryngopharyngeal reflux: the IFOS consensus. Laryngoscope. 2024;134(4):1614-1624. doi:10.1002/lary.31134

Ford

CN.

Evaluation and management of laryngopharyngeal reflux. JAMA. 2005;294(12):1534-1540. doi:10.1001/jama.294.12.1534

Lechien

Saussez

Schindler

, et al. Clinical outcomes of laryngopharyngeal reflux treatment: a systematic review and meta-analysis. Laryngoscope. 2019;129(5):1174-1187. doi:10.1002/lary.27591

Lechien

Muls

Dapri

, et al. The management of suspected or confirmed laryngopharyngeal refluxpatients with recalcitrant symptoms: a contemporary review. Clin Otolaryngol. 2019;44(5):784-800. doi:10.1111/coa.13395

Lechien

Bobin

Dapri

, et al. Hypopharyngeal-esophageal impedance-pH monitoring profiles of laryngopharyngeal reflux patients. Laryngoscope. 2021;131(2):268-276. doi:10.1002/lary.28736

Sikavi

Cai

Leung

, et al. Impaired proximal esophageal contractility predicts pharyngeal reflux in patients with laryngopharyngeal reflux symptoms. Clin Transl Gastroenterol. 2021;12(10):e00408. doi:10.14309/ctg.0000000000000408

Kung

Hsu

, et al. Recent advances in the pharmacological management of gastroesophageal reflux disease. Dig Dis Sci. 2017;62(12):3298-3316. doi:10.1007/s10620-017-4830-5

Thompson

Tiwari

Moe

Buckley

DI.

A Framework to Facilitate the Use of Systematic Reviews and Meta-Analyses in the Design of Primary Research Studies. Agency for Healthcare Research and Quality; 2012.

McInnes

MDF

Moher

Thombs

, et al. Preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: the PRISMA-DTA statement. JAMA. 2018;319(4):388-396.

10.

Slim

Nini

Forestier

Kwiatkowski

Panis

Chipponi

Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003;73(9):712-716. doi:10.1046/j.1445-2197.2003.02748.x

11.

Systematic and literature review resources 2011. Accessed July 2015. http://distillercer.com/resources

12.

Park

Hicks

Khandwala

, et al. Laryngopharyngeal reflux: prospective cohort study evaluating optimal dose of proton-pump inhibitor therapy and pretherapy predictors of response. Laryngoscope. 2005;115(7):1230-1238.

13.

Ezzat

Fawaz

Fathey

El Demerdash

Virtue of adding prokinetics to proton pump inhibitors in the treatment of laryngopharyngeal reflux disease: prospective study. J Otolaryngol Head Neck Surg. 2011;40(4):350-356.

14.

Pedersen

Eeg

Laryngopharyngeal reflux–a randomized clinical controlled trial. Otolaryngology. 2012;1:004.

15.

Hunchaisri

Treatment of laryngopharyngeal reflux: a comparison between domperidone plus omeprazole and omeprazole alone. J Med Assoc Thai. 2012;95(1):73-80.

16.

Chun

Lee

DS.

The effect of itopride combined with lansoprazole in patients with laryngopharyngeal reflux disease. Eur Arch Otorhinolaryngol. 2013;270(4):1385-1390.

17.

Wilkie

Fraser

Raja

Gaviscon® Advance alone versus co-prescription of Gaviscon® Advance and proton pump inhibitors in the treatment of laryngopharyngeal reflux. Eur Arch Otorhinolaryngol. 2018;275(10):2515-2521. doi:10.1007/s00405-018-5079-0

18.

Mathew

Shilpa

Is adjunctive alginate therapy beneficial in the treatment of laryngopharyngeal reflux disease in a rural Indian population? A prospective randomized study. Indian J Otolaryngol Head Neck Surg. 2022;74(Suppl 2):2104-2110. doi:10.1007/s12070-020-02005-6

19.

Pizzorni

Ambrogi

Eplite

, et al. Magnesium alginate versus proton pump inhibitors for the treatment of laryngopharyngeal reflux: a non-inferiority randomized controlled trial. Eur Arch Otorhinolaryngol. 2022;279(5):2533-2542. doi:10.1007/s00405-021-07219-0

20.

Kim

Lee

Cha

, et al. Efficacy and safety of fexuprazan in patients with symptoms and signs of laryngopharyngeal reflux disease: a randomized clinical trial. Eur Arch Otorhinolaryngol. 2024;281:5873-5883. doi:10.1007/s00405-024-08877-6

21.

Chae

Jang

Kim

Kwon

A prospective randomized clinical trial of combination therapy with proton pump inhibitors and mucolytics in patients with laryngopharyngeal reflux. Ann Otol Rhinol Laryngol. 2020;129(8):781-787. doi:10.1177/0003489420913592

22.

Choi

YK.

The use of inhaled N-acetylcysteine for laryngopharyngeal reflux disease: a randomized controlled trial. J Voice. 2021;35(4):618-624. doi:10.1016/j.jvoice.2019.11.017

23.

Dabirmoghaddam

Amali

Motiee Langroudi

Samavati Fard

Hejazi

Sharifian Razavi

The effect of N-acetyl cysteine on laryngopharyngeal reflux. Acta Med Iran. 2013;51(11):757-764.

24.

Suzuki

Yokota

Matsumoto

, et al. Proton pump inhibitor ameliorates taste disturbance among patients with laryngopharyngeal reflux: a randomized controlled study. Tohoku J Exp Med. 2019;247(1):19-25. doi:10.1620/tjem.247.19

25.

Yoon

Park

Lee

Park

Chang

Koo

BS.

Efficacy of three proton-pump inhibitor therapeutic strategies on laryngopharyngeal reflux disease; a prospective randomized double-blind study. Clin Otolaryngol. 2019;44(4):612-618. doi:10.1111/coa.13345

26.

Belafsky

Postma

Koufman

JA.

Validity and reliability of the reflux symptom index (RSI). J Voice. 2002;16(2):274-277. doi:10.1016/s0892-1997(02)00097

27.

Belafsky

Postma

Koufman

JA.

The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111(8):1313-1317. doi:10.1097/00005537-200108000-00001

28.

Lechien

Bobin

Rodriguez

, et al. Development and validation of the short version of the reflux symptom score: reflux symptom score-12. Otolaryngol Head Neck Surg. 2021;164(1):166-174. doi:10.1177/0194599820941003

29.

Lechien

Schindler

De Marrez

, et al. Instruments evaluating the clinical findings of laryngopharyngeal reflux: a systematic review. Laryngoscope. 2019;129(3):720-736. doi:10.1002/lary.27537

30.

Lechien

JR.

Pharmacological and clinical relevance in the medical treatment of laryngopharyngeal reflux: a state-of-the-art review. J Voice. 2024;S0892-1997(24)00398-9. doi:10.1016/j.jvoice.2024.11.014

31.

Lechien

Allen

Barillari

, et al. Management of laryngopharyngeal reflux around the world: an international study. Laryngoscope. 2021;131(5):E1589-E1597. doi:10.1002/lary.29270

32.

Lechien

Akst

Hamdan

, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review. Otolaryngol Head Neck Surg. 2019;160(5):762-782. doi:10.1177/0194599819827488

33.

Fossmark

Ness-Jensen

Sørdal

Ø.

Is empiric proton pump inhibition in patients with symptoms of extraesophageal gastroesophageal reflux justified?

BMC Gastroenterol. 2023;23(1):303. doi:10.1186/s12876-023-02945-7

34.

Watson

Simmons

Adebowale

, et al. Manometric abnormalities in patients with and without chronic cough. Am J Otolaryngol. 2024;45(6):104445. doi:10.1016/j.amjoto.2024.104445

35.

Sikavi

Cai

Carroll

Chan

WW.

Prevalence and clinical significance of esophageal motility disorders in patients with laryngopharyngeal reflux symptoms. J Gastroenterol Hepatol. 2021;36(8):2076-2082. doi:10.1111/jgh.15391

36.

Lechien

Bobin

Muls

, et al. The efficacy of a personalised treatment depending on the characteristics of reflux at multichannel intraluminal impedance-pH monitoring in patients with acid, non-acid and mixed laryngopharyngeal reflux. Clin Otolaryngol. 2021;46(3):602-613. doi:10.1111/coa.13722

37.

Lechien

Bobin

Variability and accuracy of multiple saliva pepsin measurements in laryngopharyngeal reflux patients. J Otolaryngol Head Neck Surg. 2023;52(1):66. doi:10.1186/s40463-023-00670-5

38.

Randhawa

Mansuri

Rubin

JS.

Is dysphonia due to allergic laryngitis being misdiagnosed as laryngopharyngeal reflux?

Logoped Phoniatr Vocol. 2010;35(1):1-5.

39.

Eren

Arslanoğlu

Aktaş

, et al. Factors confusing the diagnosis of laryngopharyngeal reflux: the role of allergic rhinitis and inter-rater variability of laryngeal findings. Eur Arch Otorhinolaryngol. 2014;271(4):743-747.

40.

Kayalı Dinc

Cayonu

Sengezer

Sahin

MM.

Smoking cessation improves the symptoms and the findings of laryngeal irritation. Ear Nose Throat J. 2020;99(2):124-127. doi:10.1177/0145561319881559

41.

Zalvan

Greenberg

Geliebter

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. doi:10.1001/jamaoto.2017.1454

42.

Koufman

JA.

Low-acid diet for recalcitrant laryngopharyngeal reflux: therapeutic benefits and their implications. Ann Otol Rhinol Laryngol. 2011;120(5):281-287. doi:10.1177/000348941112000501

43.

Lechien

Crevier-Buchman

Distinguin

, et al. Is diet sufficient as laryngopharyngeal reflux treatment? A cross-over observational study. Laryngoscope. 2022;132(10):1916-1923. doi:10.1002/lary.29890

44.

Pisegna

Yang

Purcell

Rubio

A mixed-methods study of patient views on reflux symptoms and medication routines. J Voice. 2017;31(3):381.e15-381.e25.

45.

Shin

Sachs

Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep. 2008;10(6):528-34. doi:10.1007/s11894-008-0098-4

46.

Kamal

Dhar

Bock

, et al. Best practices in treatment of laryngopharyngeal reflux disease: a multidisciplinary modified Delphi study. Dig Dis Sci. 2023;68(4):1125-1138. doi:10.1007/s10620-022-07672-9

47.

Lechien

JR.

Clinical update findings about pH-impedance monitoring features in laryngopharyngeal reflux patients. J Clin Med. 2022;11(11):3158. doi:10.3390/jcm11113158

Treatment for Laryngopharyngeal Reflux Disease: A Systematic Review of Controlled Studies

Abstract

Importance

Objective

Design

Setting

Participants

Intervention

Outcomes

Results

Conclusion

Keywords

Key Messages

Introduction

Materials and Methods

Types of Studies

Populations, Inclusion, and Exclusion Criteria

Outcomes

Intervention and Comparison

Timing and Setting

Search Strategy

Bias Analysis

Results

Benefits of Prokinetics

Benefits of Alginates

Benefits of Mucolytics

Benefits of H2 Blockers and Potassium-Competitive Acid Blockers

Epidemiological Analysis

Discussion

Conclusion

Footnotes

Appendix 1

Acknowledgements

Author Contributions

Declaration of Conflicting Interests

Funding

Ethical approval

ORCID iD

References