European Journal of Cardiovascular Medicine

Laryngopharyngeal reflux (LPR) refers to the retrograde movement of gastric contents, including acid and pepsin, into the laryngopharynx, resulting in symptoms such as hoarseness, chronic throat clearing, globus sensation, chronic cough and dysphagia [1]. Unlike classical gastro-oesophageal reflux disease (GERD), LPR is frequently associated with minimal or absent heartburn, making it a diagnostic challenge that is often missed or misattributed to other causes of chronic laryngitis [2]. LPR is now recognised as one of the most common conditions encountered in ENT outpatient practice, with reported prevalence estimates ranging from 10% to nearly 40% among patients presenting with voice and throat complaints [3].

Indian otolaryngology literature has also drawn attention to the burden of this condition in the local population. A study from a tertiary care centre in northern India reported that a considerable proportion of patients attending the ENT outpatient department with chronic throat symptoms had abnormal Reflux Symptom Index and Reflux Finding Score values, underscoring the need for greater clinical awareness of LPR among Indian practitioners [4]. Similarly, an earlier Indian study evaluating the correlation between symptom scores and laryngoscopic findings in suspected reflux laryngitis highlighted that clinical diagnosis based on RSI and RFS alone, without pH-metry, remained a practical and widely used approach in resource-limited settings [5].

The pathophysiology of LPR is multifactorial and involves both direct mucosal injury from acid and pepsin exposure and vagally mediated reflex mechanisms triggered by oesophageal acidification [6]. The laryngopharyngeal mucosa is considerably more sensitive to acid and pepsin injury than the oesophageal mucosa, which explains why even limited reflux episodes can produce disproportionately severe symptoms [1,6]. Upper and lower oesophageal sphincter dysfunction, delayed gastric emptying, and impaired oesophageal motility are all implicated in the pathogenesis of LPR [7].

Proton pump inhibitors remain the first-line pharmacological therapy for LPR, based on the rationale of reducing gastric acidity and thereby limiting pepsin activation and mucosal injury [2]. However, response rates to PPI monotherapy are inconsistent, with several studies reporting inadequate symptomatic relief in 30–40% of patients even after prolonged treatment courses of 8–12 weeks [8]. An Indian study evaluating outcomes of proton pump inhibitor therapy in patients with reflux laryngitis similarly observed that a meaningful subset of patients had persistent or recurrent symptoms despite adequate compliance, prompting interest in adjunctive or alternative therapeutic strategies [9].

Magnesium is an essential intracellular cation that plays a central role in neuromuscular transmission, smooth muscle relaxation and enzymatic function throughout the gastrointestinal tract [10]. It has been proposed to influence lower oesophageal sphincter tone, modulate gastric motility, and support mucosal healing processes, all of which are relevant to reflux pathophysiology [11]. Furthermore, chronic PPI use itself has been linked to hypomagnesemia through reduced intestinal magnesium absorption, a phenomenon documented in an Indian case series of long-term PPI users presenting with unexplained neuromuscular symptoms [12]. This bidirectional relationship — magnesium influencing reflux physiology, and PPIs potentially depleting magnesium stores — provides a plausible rationale for evaluating magnesium supplementation as an adjunct in LPR management.

Despite this theoretical basis, there is a paucity of clinical studies, particularly from India, examining the role of magnesium supplementation specifically in LPR. Most available evidence is extrapolated from general GERD literature or from small case series [13]. The present study was therefore designed to prospectively evaluate whether the addition of oral magnesium supplementation to standard PPI therapy provides measurable symptomatic and clinical benefit over PPI therapy alone in patients diagnosed with LPR, using validated scoring instruments.

The gold standard for objective diagnosis of LPR is multichannel intraluminal impedance–pH (MII-pH) monitoring, which can detect both acid and non-acid or weakly acidic reflux episodes reaching the proximal oesophagus and hypopharynx [7].

However, this investigation is invasive, costly, and not widely accessible, particularly in high-volume outpatient settings typical of Indian tertiary care hospitals. Consequently, most clinicians continue to rely on the combination of the Reflux Symptom Index (RSI), a validated patient-reported questionnaire, and the Reflux Finding Score (RFS), a videolaryngoscopy-based clinician-assessed grading tool, for both diagnosis and monitoring of treatment response [2]. These two instruments, though imperfect surrogates for pH-impedance monitoring, have been extensively validated and remain the most practical tools for busy clinical practice, including in the Indian setting where they have been applied and cross-validated in several outpatient-based studies [4,5].

Beyond pharmacological acid suppression, dietary and lifestyle modification continues to form an important cornerstone of LPR management, including avoidance of late-night meals, caffeine, carbonated beverages, and tobacco, together with weight reduction where relevant and elevation of the head end of the bed [3]. Nevertheless, lifestyle measures alone are rarely sufficient to control symptoms in patients with moderate to severe disease, and pharmacological therapy — most commonly PPIs — remains central to management, reinforcing the need to identify effective adjuncts for the subset of patients who respond incompletely [8,9].

Aims and Objectives:

1. To compare the change in Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) between patients receiving PPI plus oral magnesium supplementation and those receiving PPI alone, over an 8-week period.
2. To assess changes in serum magnesium levels in both treatment groups.
3. To evaluate the safety and tolerability of adjunctive oral magnesium supplementation in patients with LPR.

Study Design and Setting:

This was a prospective, randomized, open-label, parallel-group comparative interventional study conducted jointly in the Departments of Otorhinolaryngology–Head & Neck Surgery and Gastroenterology of a tertiary care teaching hospital, over a period of 12 months, after obtaining Institutional Ethics Committee approval and written informed consent from all participants.

Sample Size:

Assuming a mean difference in RSI reduction of 3 points between groups with a standard deviation of 5, at 95% confidence level and 80% power, a minimum sample size of 52 patients per group was calculated. To account for an anticipated 10–15% attrition, 60 patients were enrolled in each group, giving a total sample size of 120.

Inclusion Criteria:

• Age 18–65 years of either sex; • Clinical diagnosis of LPR based on RSI score greater than 13 and/or RFS score greater than 7; • Symptom duration of at least 8 weeks; • Willingness to comply with the study protocol and follow-up schedule.

Exclusion Criteria:

• History of laryngeal or oesophageal malignancy; • Prior laryngeal or upper airway surgery; • Known renal impairment (estimated GFR < 60 mL/min) or pre-existing magnesium metabolism disorder; • Current use of magnesium-containing antacids or supplements; • Pregnancy or lactation; • Use of medications with known significant interaction with magnesium (e.g., certain antibiotics, bisphosphonates); • Uncontrolled diabetes mellitus or cardiac arrhythmia.

Randomization and Grouping:

Eligible patients were allocated using a computer-generated random number sequence into two groups of 60 patients each:

Group A: Tablet Pantoprazole 40 mg once daily before breakfast + Oral Magnesium Glycinate 300 mg/day (elemental magnesium), for 8 weeks.

Group B: Tablet Pantoprazole 40 mg once daily before breakfast alone, for 8 weeks.

All patients received standardized lifestyle and dietary counselling regarding reflux precautions (avoidance of late meals, caffeine, carbonated beverages, and elevation of the head end of the bed).

Outcome Measures and Assessment Tools:

• Reflux Symptom Index (RSI) — a validated 9-item, patient-reported questionnaire scored 0–45, recorded at baseline, 4 weeks and 8 weeks.
• Reflux Finding Score (RFS) — an 8-item, clinician-assessed videolaryngoscopic grading scale scored 0–26, recorded at baseline, 4 weeks and 8 weeks by an examiner blinded to group allocation.
• Serum magnesium levels — measured at baseline and at 8 weeks by colorimetric assay.
• Adverse events — recorded at each visit through direct questioning and a structured checklist covering gastrointestinal and neuromuscular symptoms.

Ethical Considerations:

The study protocol was approved by the Institutional Ethics Committee prior to initiation. Written informed consent was obtained from every participant after explaining the study objectives, procedures, potential risks and benefits, and the voluntary nature of participation, in accordance with the principles of the Declaration of Helsinki. Participants were free to withdraw from the study at any point without any effect on their ongoing clinical care. Confidentiality of patient data was maintained throughout the study and during subsequent analysis and reporting.

Statistical Analysis:

Data were entered in Microsoft Excel and analysed using SPSS software (version 26.0). Continuous variables were expressed as mean ± standard deviation and compared using paired t-test (within-group) and independent samples t-test (between-group). Categorical variables were expressed as frequencies and percentages and compared using the Chi-square test. Repeated-measures analysis was used to assess the trend of RSI and RFS scores across the three time points within each group. A p-value of less than 0.05 was considered statistically significant throughout the analysis.

A total of 120 patients were enrolled and randomized, with 6 patients lost to follow-up (3 in each group), leaving 57 patients in Group A and 57 in Group B who completed the 8-week study protocol and were included in the final analysis.

Table 1: Baseline Demographic and Clinical Characteristics

SD: standard deviation; RSI: Reflux Symptom Index; RFS: Reflux Finding Score. Between-group differences at baseline were not statistically significant, confirming comparability of the two groups.

Table 2: Reflux Symptom Index (RSI) at Baseline, 4 Weeks and 8 Weeks

Table 3: Reflux Finding Score (RFS) at Baseline, 4 Weeks and 8 Weeks

Table 4: Serum Magnesium Levels (mg/dL)

Group A showed a statistically significant rise in serum magnesium levels, while Group B showed a mild non-significant decline, consistent with the known effect of prolonged PPI use on magnesium absorption.

Figure 1: Trend of Mean RSI and RFS Scores Across Study Visits

Figure 1 The progressively greater downward trend in both RSI and RFS scores in Group A (PPI + magnesium) relative to Group B (PPI alone) across the three assessment points.

Table 5: Symptom-wise Improvement at 8 Weeks (Proportion of Patients Reporting Improvement)

Table 6: Adverse Events Reported During the Study Period

No serious adverse events, electrolyte disturbances, or study discontinuations attributable to magnesium supplementation were recorded.

Overall, both groups demonstrated statistically significant improvement in RSI and RFS from baseline to 8 weeks (within-group p < 0.001). However, the magnitude of improvement was significantly greater in Group A (PPI + magnesium) compared with Group B (PPI alone) at both the 4-week and 8-week assessments (between-group p < 0.05 at all time points beyond baseline). Serum magnesium levels increased significantly in Group A and showed a mild, non-significant decline in Group B. Adverse events were generally mild, self-limiting and predominantly gastrointestinal, with no statistically significant difference in overall tolerability between the two groups.

The present study demonstrates that the addition of oral magnesium supplementation to standard proton pump inhibitor therapy produces a significantly greater reduction in both symptom-based (RSI) and clinician-assessed (RFS) scores in patients with laryngopharyngeal reflux, compared with PPI monotherapy. These findings are consistent with the proposed physiological role of magnesium in modulating lower oesophageal sphincter tone and supporting gastrointestinal smooth muscle function [10,11].

The observed PPI-monotherapy response in our Group B, while significant, mirrors the incomplete symptomatic resolution reported in earlier literature, where a considerable minority of patients with reflux laryngitis remained symptomatic despite adequate PPI compliance [8]. An Indian study evaluating outcomes of acid-suppressive therapy in suspected reflux laryngitis similarly noted that nearly a third of patients had persistent RSI elevation at 8 weeks, a finding closely comparable to our Group B outcomes, and had called for exploration of adjunctive strategies to improve response rates [9].

Our finding of a significant rise in serum magnesium levels in the supplementation arm, contrasted with a mild decline in the PPI-alone arm, corroborates earlier Indian observations that prolonged PPI therapy can reduce intestinal magnesium absorption and precipitate subclinical or overt hypomagnesemia, particularly with therapy extending beyond several weeks [12]. This raises the possibility that part of the benefit observed in the magnesium-supplemented group may relate not only to a direct pro-motility or sphincter-tone effect, but also to correction of PPI-associated magnesium depletion that might otherwise blunt therapeutic response.

The greater improvement in individual symptoms such as hoarseness, throat clearing and globus sensation in the magnesium-supplemented group is in keeping with the broader understanding that laryngopharyngeal mucosa is particularly sensitive to even minor residual reflux events, such that small additional reductions in reflux burden may translate into disproportionately noticeable symptomatic benefit [1,6]. This is consistent with observations from an earlier Indian correlative study of RSI and RFS in suspected LPR, which emphasised that even modest objective improvement in laryngoscopic findings was often accompanied by substantial patient-reported symptomatic relief [5].

The safety profile of oral magnesium supplementation observed in this study was reassuring, with only mild, self-limiting gastrointestinal adverse effects and no electrolyte disturbances, consistent with the generally favourable tolerability profile reported for oral magnesium salts in gastrointestinal literature [13]. This supports the feasibility of magnesium supplementation as a low-risk adjunct in everyday clinical practice, particularly relevant in Indian outpatient settings where cost-effective adjunctive therapies are of practical value [4].

The dose of elemental magnesium used in this study (300 mg/day as magnesium glycinate) was selected based on commonly recommended daily supplementation ranges reported in the general magnesium therapeutics literature, balancing adequate physiological effect against the risk of osmotic gastrointestinal side effects such as loose stools, which are more prevalent with less bioavailable salts such as magnesium oxide or magnesium sulphate [13]. The relatively low incidence of diarrhoea observed in our Group A (12.3%) supports the tolerability of the glycinate formulation at this dose, though comparative studies with other magnesium salts and dose-ranging studies would help refine optimal regimens for LPR specifically.

Comparing our findings with the broader international literature, meta-analyses of PPI therapy in suspected reflux laryngitis have generally shown only modest superiority of PPIs over placebo, with symptom response rates rarely exceeding 60–70% [8,16]. More recent reviews have emphasised the multifactorial nature of LPR, including non-acid and weakly acidic reflux components not addressed by acid suppression alone, which may partly explain why adjuncts that act through complementary mechanisms — such as alginate barriers, prokinetic agents, or agents influencing sphincter tone like magnesium — could offer incremental benefit beyond PPI therapy alone [15,19]. Our results, showing a significantly greater proportional improvement in the magnesium-supplemented arm, are broadly in line with this emerging paradigm of multimodal management for LPR.

Strengths of the Study:

This study benefits from a prospective randomized design, adequately powered sample size based on a priori calculation, use of validated and widely accepted outcome measures (RSI and RFS), blinded laryngoscopic scoring, and objective biochemical confirmation of the physiological rationale through serial serum magnesium measurement. The inclusion of a structured adverse event assessment also allows a balanced appraisal of both efficacy and safety, which is important for any adjunctive therapy proposed for routine use.

Limitations:

This study has several limitations. First, the open-label design introduces potential observer and reporting bias, despite blinding of the laryngoscopic assessor. Second, diagnosis of LPR was based on RSI and RFS criteria without confirmatory 24-hour pH-impedance monitoring, which remains the gold standard but was not feasible in this resource setting. Third, the follow-up duration of 8 weeks does not allow assessment of long-term symptom recurrence after discontinuation of magnesium supplementation. Finally, the single-centre design and the specific magnesium formulation and dose studied limit the generalisability of these findings to other populations, formulations, or dosing regimens. Future double-blind, placebo-controlled, multicentric trials with larger sample sizes, objective reflux monitoring, and longer follow-up are warranted to confirm these findings and to establish optimal dosing and duration of magnesium supplementation in the management of laryngopharyngeal reflux disease.

Adjunctive oral magnesium supplementation, when combined with standard proton pump inhibitor therapy, was associated with significantly greater improvement in both symptom-based (RSI) and clinical (RFS) outcomes in patients with laryngopharyngeal reflux disease compared with PPI therapy alone, over an 8-week period, with a favourable safety profile. These preliminary findings suggest a potential role for magnesium as a simple, low-cost adjunct in the multimodal management of LPR, particularly in patients with incomplete response to PPI monotherapy, though confirmation through larger blinded randomized controlled trials is necessary before it can be recommended as routine clinical practice.

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