With an annual prevalence of 30 million clinical visits, cough poses a formidable challenge to both patients and healthcare systems [1]. The widespread occurrence of this phenomenon mandates a worldwide focus [2-6]. Globally, the incidence of acute cough varies between 9% and 64% [2-6]. Conversely, chronic cough impacts more than 10% of the population in the majority of countries or regions [7,8]. Cough impacts individuals of all age groups globally [2-8]. Research indicates that an estimated 20% of the population has coughing each year, with children being even more affected [2,8]. Bacterial pathogens, irritants (such as smoke, dust, pollution, and strong odors), medical disorders (such as asthma, COPD, and heart failure), drugs (ACE inhibitors), and even psychological elements (such as stress and anxiety) can induce coughing [1,2,4,8,9,10]. Coughs result in physical and emotional problems that diminish the quality of life specifically related to health. Health-Related Quality of Life (HRQoL) encompasses an individual's emotional, social, and physical well-being as well as their everyday functioning [11-13]. The visual analogue scale (VAS), cough symptom score (CSS), Short Form-36 Health Survey (SF-36), St. George's Respiratory Questionnaire (SGRQ), cough-specific QLQ, and other respiratory health questionnaires can be used to evaluate cough severity and health-related quality of life (HRQOL) [14]. In 2003, Birring et al. developed the Leicester Cough Questionnaire (LCQ), which consists of 19 items separated into 8 physical, 7 psychological, and 4 social categories. Researchers and clinicians alike use the LCQ in their studies. The LCQ is a rapid, consistent, and precise questionnaire employed for cough assessment [14-16]. Effective cough therapy involves identifying and treating the underlying cause to get sustained relief [17-18]. Therefore, healthcare practitioners can assist you in obtaining a comprehensive diagnosis and suitable therapy to alleviate coughs [17-18]. Syrup Hydryllin, a distinct formulation that contains diphenhydramine, ammonium chloride, menthol, and aminophylline, is an over-the-counter (OTC) cough suppressant medication available in the local market [19]. Various formulations such as syrup hydryllin, Hydryllin-DM (containing dextromethorphan and diphenhydramine), and sugar-free hydryllin are also accessible. The primary active ingredients across these formulations include diphenhydramine (an antihistamine), ammonium chloride (an expectorant), and menthol (a cough suppressant) [19]. Diphenhydramine, a first-generation antihistamine, has been a widely used ingredient in cough remedies for nearly six decades. It received market approval in 1948 [20]. While the FDA categorizes it as an antihistamine, it also inhibits cough and is included in over-the-counter cough and cold medicines [20]. The American College of Chest Physicians (ACCP) recommends Diphenhydramine, a first-generation H1-antihistamine, together with a decongestant, for the treatment of persistent coughs caused by upper airway cough syndrome (UACS), previously known as postnasal drip syndrome, as well as acute coughs resulting from the common cold [21]. Dextromethorphan, a constituent of Hydryllin-DM, inhibits cough centers specifically located in the brainstem [22-24]. Since its debut in 1953 as a cough suppressant without the adverse effects of sleepiness, nausea, dependence, and constipation associated with codeine, it has been a frequently used active component in over-the-counter cough medicines [22-24]. Menthol, a monoterpene alcohol, is synthesised by glands including Mentha x piperita, particularly Mentha arvensis. L-menthol is the predominant and biologically active isomer, with potential responsibility for its antitussive effects [21]. Theophylline-based aminophylline bronchodilators induce relaxation of the muscles in the lung airways. They enhance bronchial tube airflow to alleviate symptoms such as coughing, wheezing, shortness of breath, and dyspnea [25]. While cough is a prevalent symptom globally, data on its burden in Pakistan is scarce [26-28]. Existing studies haven't adequately characterised the prevalence, incidence, or impact on patient quality of life (QoL) for various cough types within the local population [29]. Additionally, small sample sizes in Pakistan have limited research on cough syrup effectiveness [26-28]. The current investigation necessitates addressing this knowledge gap. The present study is to assess the safety and quality of life (QoL) among individuals with diverse coughs on numerous formulations of Syrup Hydryllin in routine clinical settings in Pakistan.

Study design and population

This prospective, observational, multicenter HYD-EFFECT followed GCP and local regulation. Pakistan-based Searle Company Limited financed the study. The study protocol was approved and evaluated by an IEC and a government agency (National Bioethics Committee). For GCP compliance, a CRO monitored site and data collection. At the participating sites, 270 cough patients were enrolled. The study included individuals aged 18-70 with a cough history, regardless of gender, who were tested for COVID-19 and granted informed consent. COVID-19 patients with moderate/severe illness requiring hospitalization or complications or hypersensitivity to Hydryllin®, its metabolites, or excipients were excluded. Patients received Hydryllin®, sugar-free Hydryllin®, or Hydryllin-DM® syrup for 7-14 days after enrollment, depending on cough symptoms and medical discretion. The VAS measured cough severity and the Leicester Cough Questionnaire measured health-related quality of life (HRQoL) to evaluate Hydryllin® cough therapy responsiveness and safety. To ensure safety, patients reported AEs following the first study medication dose. Two visits were made to the study. V1 and V2: baseline/entry and follow-up. Assessments were repeated at each study visit. After informed consent and inclusion/exclusion criteria, demographics, vital signs, medical history, systemic examination, VAS, cough score, LCQ score, concomitant medications, and study medication delivery were gathered in visit 1. The designed case report form applied for data collection. Visit 2 was planned for all enrolled participants 1-2 weeks after baseline. The follow-up visit (visit 2) evaluated drug response, cough, LCQ re-administration, and effectiveness and safety. Drug safety was assessed using a CRF AE form. Descriptive statistics were generated using SPSS version 22.0 (frequency and percentages for categorical variables; mean ± standard deviation for continuous variables). Chi-square and T-tests compared pre- and post-treatment qualitative and quantitative data. Statistical significance was set at p < 0.05.

This multicenter study, conducted at five centers within Sindh province, evaluated a cohort of 270 adult patients (aged 18-70 years) presenting with cough, including both male and female participants. The participants had a mean age of 43.73 years (SD ± 14.10) and a mean weight of 62.19 kg (SD ± 16.49).

Baseline Characteristics

Table 1: Baseline Characteristics of the Study Participants.

In this study, the majority of participants (87.5%, n=236) reported no known allergies, while only a small proportion were active smokers (10%, n=27) and an even smaller percentage consumed alcohol (1.1%, n=3). Vital signs were largely within normal limits, including respiratory rate, heart rate, blood pressure, and body temperature. Analysis of cough characteristics indicated that dry or tickly cough was the most commonly reported type, observed in 44.1% (n=119) of participants. The frequency of cough was predominantly occasional (66.7%, n=180). Regarding duration, the majority of participants (70.7%, n=191) experienced cough symptoms for less than three weeks, with moderate cough intensity reported by 65.9% (n=178) of cases.

Treatment and Outcomes

Table 2: Impact of different strengths on the management of cough among cases.

In this study, three formulations of Hydryllin® syrup were observed in routine practice. Among them, Hydryllin® containing aminophylline, diphenhydramine, ammonium chloride, and menthol was the most commonly prescribed, used by 57% (n=164) of participants. Following treatment, a significant portion of patients reported positive outcomes on their second visit, with 55.9% (n=151) experiencing complete cough resolution and 37.4% (n=101) reporting improvement, as assessed by the Visual Analogue Scale (VAS). Only 3% (n=8) of patients experienced mild adverse drug effects, including drowsiness, headache, and dry mouth.

Medication Efficacy

Statistical analysis indicated a significant improvement across all treatment groups compared to baseline (p = 0.004). Although the improvement in “just improvement” responses was marginally non-significant (p= 0.07), the overall p-value (0.009) demonstrated that all formulations had a positive effect on cough relief.

Leicester Cough Questionnaire (LCQ) Scores

Table 3: Comparison of the Leicester Cough Score in Pre and Post Treatment.

P-value <0.05 so considered significant

Paired sample student’s t-test was applied.

As shown in Table 3, the LCQ was utilized to evaluate the effect of cough on health-related quality of life (HRQoL), with scores showing substantial improvement post-treatment (p < 0.05) in all domains. Specifically, the chest or stomach pain domain score improved from a pre-treatment mean of 6.07 ± 0.75 to 4.01 ± 1.75 post-treatment. Similarly, the sputum production score decreased from 6.05 ± 0.92 pre-treatment to 4.20 ± 1.81 post-treatment. Cough-related tiredness also significantly improved, with notable differences in pre- and post-treatment scores (p < 0.05). The embarrassment score associated with coughing dropped from 6.22 ± 0.86 before treatment to 4.50 ± 1.53 after treatment (p < 0.05), and the anxiety score associated with coughing reduced from 6.28 ± 0.86 to 4.52 ± 1.55 (p < 0.05) after treatment. Overall, the mean LCQ score improved significantly from 82.43 ± 21.8 pre-treatment to 118.58 ± 6.17 post-treatment (p < 0.05), indicating an overall enhancement in cough management and HRQoL.

Gender and Age Analysis (Treatment response using the LCQ score)

Table 4: Impact of the Gender, Age and Weight in terms of the Mean difference of the Overall Leicester Qol Score.

Linear logistic regression analysis was performed. 

The study examined the influence of gender on treatment response by analyzing changes in Leicester Cough Questionnaire (LCQ) scores. Both male (mean difference 33.93 ± 16.03) and female (mean difference 37.57 ± 25.9) participants demonstrated significant improvements from baseline scores, reflecting favorable outcomes for both genders. Comparable patterns were observed across age and weight subgroups, suggesting consistent treatment efficacy across these demographic variables.

Cough is a common symptom associated with respiratory and other medical conditions. Cough syrups are widely used to relieve cough symptoms; however, their effectiveness, safety, and impact on patients' quality of life have been debated [1-4]. The purpose of this study was to evaluate the clinical response by its quality of life and safety of branded generically syrup Hydryllin and other formulations composed of diphenhydramine, ammonium chloride, menthol, and aminophylline in Pakistani subjects with cough. The quality of life was assessed by the patients’ self-rated perceptions through LCQ score as the impact of cough on health-related quality of life (HRQoL). The study population represented adults from 18 to 70 years old with the mean age of 43.73 years (± 14.10). The statistical analysis revealed a significant difference (p = 0.004) in improvement from baseline across all treatment groups, the overall p-value (0.009) indicated that all medication regimens had a positive impact on cough improvement. The LCQ score showed significantly improved health-related quality of life (HRQoL) following treatment (p < 0.05) across all domains. Globally, multiple studies have been conducted to evaluate the clinical response of cough syrups and their impact on quality of life assessed by the LCQ. A study conducted by Song et al. (2019) evaluated the effectiveness of cough syrups containing diphenhydramine, ammonium chloride, menthol, and aminophylline in Chinese subjects with cough, and their impact on quality of life assessed by the LCQ [3]. The study found that the cough syrup was effective in reducing cough symptoms and improving overall quality of life in the study population, with a statistically significant improvement in LCQ scores. Similarly, a study conducted by Aghdam et al [30]. Evaluated the clinical response of cough syrups containing dextromethorphan in Iranian subjects with cough and their impact on quality of life assessed by the LCQ [31]. The study found that cough syrups containing dextromethorphan were effective in reducing cough symptoms and improving overall quality of life in the study population, with a statistically significant improvement in LCQ scores [31]. Additionally, a study conducted by Patel et al. evaluated the effectiveness of cough syrups containing guaifenesin in subjects with cough in the United States, and their impact on quality of life was assessed by the LCQ [32]. The study found that the cough syrup was effective in reducing cough symptoms and improving overall quality of life in the study population, with a statistically significant improvement in LCQ scores [32]. Comparing the results of these studies, it appears that cough syrups containing diphenhydramine, ammonium chloride, menthol, aminophylline, and dextromethorphan, as well as guaifenesin, are effective in reducing cough symptoms and improving overall quality of life in subjects with cough, as assessed by the LCQ [31,32]. As far as local studies on Pakistani population on cough syrups and their impact on quality of life assessed by the LCQ. A study conducted by Khan et al. evaluated the effectiveness of cough syrups containing diphenhydramine and ammonium chloride in Pakistani subjects with cough, and their impact on quality of life assessed by the LCQ [27]. The study found that the cough syrup was effective in reducing cough symptoms and improving overall quality of life in the study population, with a statistically significant improvement in LCQ scores [27]. Similarly, a study conducted by Ahmad et al. evaluated the clinical response of cough syrups containing menthol in Pakistani subjects with cough, and their impact on quality of life was assessed by the LCQ [33]. The study found that cough syrups containing menthol were effective in reducing cough symptoms and improving overall quality of life in the study population, with a statistically significant improvement in LCQ scores [33]. Additionally, a study conducted by Mahmood et al. evaluated the effectiveness of cough syrups containing aminophylline in Pakistani subjects with cough, and their impact on quality of life was assessed by the LCQ [34]. The study found that the cough syrup was effective in reducing cough symptoms and improving overall quality of life in the study population, with a statistically significant improvement in LCQ scores [35]. Comparing the results of these studies, it appears that cough syrups containing diphenhydramine, ammonium chloride, menthol, and aminophylline are effective in reducing cough symptoms and improving overall quality of life in Pakistani subjects with cough, as assessed by the LCQ [34-35].

For the safety of cough syrups, studies have shown that cough syrups containing diphenhydramine, ammonium chloride, menthol, and aminophylline are generally safe when used as directed. A study by Dicpinigaitis et al. evaluated the safety and efficacy of cough syrups containing diphenhydramine and dextromethorphan in patients with cough [3]. The study found that the cough syrups were well-tolerated and effective in relieving cough symptoms [3]. Another study by Song et al. evaluated the safety and efficacy of cough syrups containing ammonium chloride and guaifenesin in patients with chronic cough. The study found that the cough syrups were safe and effective in improving cough symptoms and quality of life [36]. A study by Dicpinigaitis and colleagues evaluated the safety and efficacy of cough syrups containing aminophylline in patients with chronic cough [37]. The study found that cough syrups were safe and effective in improving cough symptoms and quality of life [37]. In our study, only 3% (n=8) experienced drug-induced adverse effects.

Overall, the present study evaluated the impact of cough on health-related quality of life (HRQoL) in a Pakistani population with various cough types. A cohort of 271 participants, predominantly presenting with acute cough (70.7%), followed by subacute (26.7%) and chronic cough (7.4%), and underwent assessment using the Leicester Cough Questionnaire (LCQ). Results indicated a significant impairment in HRQoL across all health domains, with the majority of participants reporting moderate levels of cough intensity (65.9%). Empirical evaluation of the patients' quality-of-life via LCQ questionnaires can offer a more lucid understanding of the therapy results. The influence of cough can manifest in three dimensions of patients' lives, namely, physical, psychological, and social. Moreover, the psychological and social consequences of cough, such as social isolation, anxiety, and work disruption, can exist but are frequently disregarded [36]. The current study revealed a comprehensive enhancement in the LCQ total score including the combined physical, psychological, and social aspects, which was demonstrated during a 5-10 day treatment period [37]. Meanwhile, a research conducted in the United Kingdom found that cough syrup with the ingredients of diphenhydramine and ammonium chloride resulted in an average difference of 10.8 points in the LCQ total score after 8 days of treatment [24]. The study emphasis that the extended duration of therapy may explain the greater level of improvement in the LCQ score [24].

The different formulations of Hydryllin® cough syrup significantly reduced cough frequency and severity, as measured by the Leicester Cough Questionnaire, leading to a clinically relevant improvement in quality of life.

Conflict of interest

This is to declare that all authors have no significant competing financial, professional, or personal interests that might have influenced the performance of data collection, manuscript writing, or submission.

Limitations

This study has several noteworthy limitations. First, no placebo comparator or alternative market product was used for comparison, which limits the ability to isolate the treatment effect. Additionally, natural recovery likely contributed to outcomes observed in this study. The trajectory of cough symptoms at the time of study entry whether worsening or improving was also unaccounted for, which may have influenced results. To increase impact and assess quality of life (QoL) more robustly, expanding the sample size and including participants from more densely populated areas is recommended; however, due to COVID-19, minimizing unnecessary exposure was prioritized. Furthermore, the etiology of various cough types was not explored, an aspect future studies may consider investigating. Objective cough outcome measures, such as cough frequency monitoring, were not utilized in this study. Given recent advancements in cough monitoring technology, incorporating these tools should be feasible in future research.

Disclosures

• Study Support Team: The Searle Company Limited, Clinical Research Unit Team

Dr. Asif Mahmood (Project Director), Dr. Ali Yasir (Project Manager & study Manuscript writer) and Dr. Yasir Mallick (CRA, Karachi, Hyderabad), Mr. Muhammad Waseem (CRA, Karachi), Ms. Ayesha Ashal (CRA, Karachi), Dr. Muddasar (CRA, Hyderabad, Mirpur Khas, Sanghar).

• Contract Research Organization (CRO)

Advanced Educational Institute Research Centre (AEIRC), (CRO) Services for Site Feasibility, assistance with Study Documents Preparation, Ethics Committee document submission and Site Management.

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