A Hospital Based Prospective Interventional Study to Measure Medication Efficacy in Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a global disease, and evidence suggests that its prevalence is increasing.[1] Clinical presentation of GERD ranges from typical, atypical symptoms to alarming symptoms, and if left untreated, these symptoms might progress to further complications.[2] Gender, age group, BMI, education level, self-reported use of NSAIDs and aspirin, smoking habits, income level, and diet are among the most common risk factors for GERD.[3] The basic symptoms and the outcome of an empiric treatment with acid suppression are the conventional criteria for diagnosing GERD.[4] The diagnostic tools available include upper GI endoscopy, high-resolution manometry, esophageal pH- metry, impedance-pH monitoring, and Bravo system.[5] PPIs are the preferred first-line treatment, and second-line treatments include prokinetic drugs, H2RAs, alginate, and sucralfate antacids.[4] Non-pharmacological therapies can also help to alleviate GERD symptoms.[6]

The most practical therapeutic approach targets the individual elements of GERD pathophysiology according to each clinical situation, focusing on inhibiting acid secretion due to the key role of acid contact with esophageal mucosa in generating symptoms and inducing inflammatory lesions. PPIs are the most powerful antisecretory drugs available and have rapidly replaced the less potent H2RAs as first-choice drugs in controlling this relevant element in the pathogenesis of GERD. In cases with partial response to PPIs, combining with mucosal protective drugs or bile acid sequestrants can achieve a consistent therapeutic gain.[5]

Effective lifestyle changes can prevent or manage complications in GERD by altering daily habits, including medication, diet, sleep, and exercise.[7] Patients require education to self- manage their condition effectively, fostering self-reliance and confidence to perform self- care responsibilities.[8] Recommendations for lifestyle changes are based on the recognition that certain factors, including diet, sleep patterns, smoking, and obesity, disrupt the body's defense against reflux.[9] Weight management is crucial, and dietary adjustments, including reducing high-fat intake and limiting carbonated drinks, are recommended to mitigate GERD risks. Meal timing is also important, with suggestions to avoid large meals late at night and opt for smaller, more frequent meals. Elevating the head of the bed is recommended to reduce nighttime symptoms and provide relief from heartburn. These comprehensive strategies aim to improve patient outcomes by effectively managing GERD symptoms.[10,11]

Adherence to pharmacotherapeutic treatment, involving taking medications, following diets, changing lifestyle, and attending scheduled visits, is crucial for the effective management of GERD. Non-adherence continues to be a problem of epidemic proportions, mainly among patients with chronic diseases, with only approximately 40% of patients fully adhering to prescribed treatments. This non-adherence is a potential cause of therapeutic failure in several diseases, including GERD. The medical management of GERD commonly involves PPIs, but lack of adherence to prescribed treatment is a significant issue. This study was conducted to assess treatment adherence in GERD patients, review the impact of low adherence on clinical outcomes, and identify its potential predictors.[12]

Irrational drug use can lead to increased death, illness rates, development of side effects, and higher costs.[13] The misuse of medications remains common in healthcare settings, contributing to treatment failures [14]. This study evaluates the appropriateness and effectiveness of pharmacological treatments for GERD within hospital settings against established guidelines from the ACG, WGO and, the BNF.

Overall, this study aims to comprehensively evaluate the multifaceted aspects of GERD management in a hospital setting, focusing on lifestyle factors, medication efficacy, adherence, and rational pharmacological therapy to improve patient outcomes.

NEED FOR STUDY

Globally, the prevalence of GERD symptoms in the general population ranges from approximately 10% to 30%.[15] In Asia, particularly in Central and West Asia, has risen over the last decade due to environmental, genetic, and socioeconomic factors [16] and, it has been rising by approximately 4% annually.[17] A meta-analysis reported a pooled prevalence of 15.6% in India, with significant heterogeneity among studies.[16] GERD is widespread, leading to over 5.6 million annual physician visits. The direct economic impact of GERD and its complications exceeded $18 billion, with PPIs contributing $12.4 billion.[17] PPIs are widely prescribed for GERD and have proved to be efficacious in its management. But long-term use of PPI can lead to various ADRs and requires withdrawal. Since PPIs are easily available without prescription, self-medication with PPIs is increasing and there is irrational use of PPI.[18] This may interfere with diagnosis and worsen disease condition.

The prevalence of GERD varies across development levels and geographical locations, with limited and heterogeneous data hindering accurate analysis. Recognizing the need for more localized insights, studies at the district level are emphasized.[3] Hence, the current study is designed to focus at the district level to establish a connection between risk factors and to understand their correlation with the progression of GERD. Additionally, the study aims to investigate the management of the condition, identify determinants influencing its course, and assess the rationality in drug usage.

OBJECTIVES OF THE STUDY

Primary Objective:

• To measure medication efficacy in GERD.

Secondary objectives:

• To analyse the effect of intervention on lifestyle modifications and to correlate it with the prognosis.
• To analyse medication efficacy via symptom improvement (FSSG), healing and safety
• To investigate effect of intervention on medication adherence and its determinants.
• To evaluate rationality of pharmacological therapy giving special emphasis to PPI.

REVIEW OF LITERATURE

1. Ahmed S et al.,[2] investigated the association between lifestyle factors and GERD symptoms in a Pakistani population. The study involved a total of 2000 respondents who completed a validated GERD questionnaire. The authors found that lifestyle factors such as less physical activity, late evening meals, inadequate sleep, smoking, and post- dinner lying were associated with GERD symptoms. Conversely, raising the head of the bed during sleep and post-dinner walks were found to be effective in relieving symptoms. The study concluded that lifestyle factors play a significant role in the development of GERD symptoms and that lifestyle modifications can be an effective way to management.

2. Guadagnoli et al.,[19] assessed patient adherence to lifestyle changes for managing GERD. They focused on medication use, dietary recommendations, and sleep modifications, examining factors influencing adherence and its impact on symptom severity and quality of life. Findings revealed moderate-high medication adherence associated with symptom improvement, although the direction of the relationship was unclear. Dietary adherence was higher, but its impact on symptoms was uncertain. Sleep modification correlated with symptom reduction and improved quality of life. Patient and physician perceptions, knowledge, and communication were identified as crucial factors affecting adherence, emphasizing the importance of enhancing education, provider training, and shared decision-making.

3. Matsuura M et al.,[20] compared the FSSG and GerdQ questionnaires for diagnosing GERD and correlated them with clinical findings. They enrolled 103 consecutive patients who had gastrointestinal symptoms and underwent upper gastrointestinal endoscopy. They evaluated the sensitivity, specificity, and OR of the FSSG and GerdQ for GERD diagnosis, using either the patient’s medical history or endoscopic findings as the gold standard and concluded that FSSG is inferior to GerdQ in specificity, but superior in sensitivity for GERD diagnosis. The study suggests, inclusion of questions directed at both acid reflux-associated symptoms and dyspeptic (dysmotility) symptoms allows the FSSG to identify GERD symptoms and monitor the therapeutic response of GERD more effectively.

4. Danjo A et al.,[21] compared the sensitivity, specificity and accuracy of the FSSG and QUEST in relation to the endoscopic findings of GERD. The authors enrolled 475 patients with symptoms of upper abdominal pain or discomfort, and asked them to complete both FSSG and QUEST questionnaires before undergoing esophagogastroduodenoscopy. The patients were then classified into four groups based on their endoscopic diagnosis. They found that the FSSG score increased with the endoscopic severity of GERD, while the QUEST score did not. So, they conclude that the FSSG and QUEST questionnaires have similar diagnostic performance for GERD, but the FSSG score reflects the endoscopic severity of GERD better than the QUEST score.

5. Dal-Paz K et al.,[12] assessed adherence to proton pump inhibitor (PPI) treatment and associated variables in patients with GERD. The study included 240 adult patients with GERD who were prescribed continuous PPI treatment. The authors used a Morisky questionnaire to assess the adherence and a modified Velanovich symptom scale to assess the clinical outcome and the impact of low adherence. It was found that 47.5% of patients exhibited low adherence and the factors associated with low adherence included younger age, being married, and experiencing GERD symptoms. The study shows high prevalence of low adherence to prescribed PPI therapy, which may contribute to therapy failure. The study recommends tailored interventions to improve adherence and cooperation with pharmacists to address the issue.

6. Yuswar MA et al.,[22] examined the rationality of drug use and drug distribution patterns among GERD patients at RSUD Dr. Soedarso Pontianak outpatient installation. The study, based on medical records and prescriptions, employed purposive sampling with a sample size of 98 patients. The findings revealed that Lansoprazole was the most frequently used monotherapy for GERD patients, with or without comorbidities. The most common combination involved PPI paired with sucralfate. Notably, the study indicated a higher rationality of drug use among GERD patients without comorbidities, particularly in terms of correct drug selection.

7. Bhatia S et al.,[23] recommend empiric treatment for patients with typical symptoms of GERD in the community with PPI or H2RA for 4-8 weeks, without the need for invasive investigations. Patients who do not respond adequately to PPI therapy (PPI-refractory GERD) should be evaluated for the presence of alarm symptoms, alternative diagnoses, compliance issues, and ongoing acidic or non-acidic reflux. Further investigations such as upper gastrointestinal endoscopy and ambulatory pH monitoring is recommended to confirm or exclude GERD and its complications. Patients experiencing recurrent symptoms after initial treatment are advised to take the lowest effective dose of PPI or H2RA on demand or intermittently. Long-term PPI therapy is suggested for patients with severe erosive esophagitis, Barrett’s esophagus, or peptic stricture. For patients requiring ongoing medical management with proven GERD, authors recommend an evaluation for surgery or endoscopic anti-reflux procedures as alternative options.

8. Cho JH et al.,[24] compared the effects of high-dose and standard-dose rabeprazole on both typical and atypical symptoms of GERD. Patients with GERD were randomly assigned to receive either 20 mg of rabeprazole once daily or 20 mg twice daily for 8 weeks. Symptom assessment was done through a questionnaire before and after treatment. The primary endpoint was achieving sufficient improvement in reflux symptoms after 8 weeks, defined as a ≥50% reduction from the initial score. The secondary endpoint aimed to compare score differences after treatment between the two dosing groups for each symptom. Results indicated that the high-dose group exhibited significantly higher rates of sufficient improvement for total and typical GERD symptoms compared to the standard-dose group. In conclusion, the study suggests that high-dose rabeprazole is more effective than standard-dose rabeprazole in relieving typical GERD symptoms and some atypical symptoms.

METHODOLOGY

MATERIALS AND METHODS

Study design: A Prospective Interventional study was conducted over a period of 6 months in the SIMS & RC, Mukka-574146.

Sample size: 182 ^[25]

Study criteria:

Inclusion criteria

• Patients ≥18 years of age diagnosed with GERD.
• Patients who consented to participate in the study.

Exclusion Criteria:

• Patients who refused to participate in the study.
• Patients below age of 18.

Source of data collection: Relevant data were collected using a data collection form, patients' medical records and through interview.

Study period: The study period was divided into 4 phases –

PHASE 1: Preparation for the study

• Data Collection Form: Included patient's demographic details, medical history, medication, dietary habits, lifestyle.
• Assessment Tools: FSSG contain 12 questions comprised of 5 acid reflux related symptoms and 7 dyspepsia or dysmotility-related symptoms with maximum score of 48 and a score ≥ 8 was considered to indicate probable GERD. The lifestyle questionnaire, consisting of 22 Yes/No questions, evaluated dietary habits, sleep habits, and other GERD-related factors, with a total possible score of 22. MMAs-8 is eight-item scale consisting of 7 items answered with a yes or no and 1 item with a 5-point Likert scale, used to assess medication adherence.
• Ethics Approval: Ethical clearance was obtained from the IEC of SIMS & RC, Mangalore.

PHASE 2: Patient Selection and Consent 

• Patient selection: Based on inclusion and exclusion criteria.
• Obtaining informed consent: Explained the study to participants during their hospital visit and obtained consent. Data were collected through personal discussions with participants.

PHASE 3:

Subject categorization:

• All participants meeting the inclusion and exclusion criteria were included in the investigation of rationality and adherence.
• For investigating medication efficacy, participants required a score of >8 on the FSSG.
• For the analysis of lifestyle factors, participants needed both a score of >8 on the FSSG and a score of ≥11 on the lifestyle questionnaire. Based on these scores, participants were randomized into intervention and control groups for the lifestyle analysis.

Intervention:

• All patients included in the medication adherence evaluation were given counseling about improving medication adherence.
• The intervention group received lifestyle intervention in the form of patient information leaflets.

Post analysis/Follow-up assessment:

• Participants were followed up after 4-8 weeks to collect the same set of data (FSSG, lifestyle questionnaire, and MMAS-8) to assess the impact of interventions on prognosis, medication efficacy, and medication adherence.

PHASE 4: Data review

This involved verifying the collected information for completeness, checking for discrepancies, and evaluating the fulfillment of study objectives.

Statistical analysis:

Statistical analysis involved collecting and scrutinizing every data sample, with suitable statistical tests applied to analyze the data.

Operational modality:

Fig. 1 Operational Modality

RESULT

Socio-demographics

Table 1 presents the socio-demographic characteristics of the 182 participants enrolled in the study. The majority of the participants are within the 36-45 age range, accounting for 46.60% of the total. The gender distribution shows a higher number of males (66.02%) compared to females. A majority, 56.59%, live in rural areas, while 43.41% are from urban areas. Most participants, 65.93%, have comorbidities, whereas 34.07% do not. Regarding education, 34.07% are illiterate, 27.47% can read/write, 26.92% have intermediate education, and 11.54% have a university degree.

Effect of lifestyle modifications and its correlation with the prognosis

Selection criteria

Table 2 outlines the selection criteria used in the study, which involved screening 182 participants. To be included in the study, participants needed to meet both criteria: having an FSSG score greater than 8 and a lifestyle questionnaire score of 11 or higher. Out of the total participants, 104 met these criteria and were included, while 78 did not meet both criteria and were excluded from the study.

Dietary Habits

Table 3 provides a comparison of dietary habits between the intervention and control groups, both before and after the dietary interventions aimed at mitigating symptoms of GERD. In the intervention group, the study documented substantial dietary improvements, with the proportion of participants consuming large and infrequent meals decreasing from 61.54% to 46.15%, and those eating spicy foods dropping from 63.46% to 42.31%. Similarly, midnight snack consumption was reduced from 46.15% to 38.46%, and the habit of eating quickly was curtailed from 65.38% to 57.69%. Notably, the intervention also influenced the timing of the last meal, with participants eating less than 3 hours before bedtime reducing from 61.54% to 48.08%. Additionally, there was a decline in the consumption of fatty foods (61.54% to 51.92%), caffeinated (57.69% to 51.92%), and carbonated drinks (53.85% to 48.08%). In contrast, the control group showed little to no change in these eating behaviors, highlighting the effectiveness of the intervention in modifying dietary patterns linked to exacerbating GERD symptoms.

Table 5 tracks changes in physical activity, clothing tightness, and weight changes. In the intervention group, habitual physical activity showed a positive trend, increasing from 53.85% to 57.69% post-intervention and the proportion of participants wearing tight clothing significantly decreased from 55.77% to 40.38%, indicating the effectiveness of targeted interventions in promoting physical activity for GERD management. Additionally, over half of the participants in both groups reported a significant weight gain in adulthood.

Table 6 displays the comparison of lifestyle questionnaire scores before and after intervention for both the intervention and control groups, with a total of 104 participants. In the intervention group, the mean score for dietary habits decreased from 9.194 pre- intervention to 4.3714 post-intervention, sleep-related habits improved, with the mean score dropping from 4.596 to 2.19, and other lifestyle factors also showed positive changes, with the mean score decreasing from 2.30 to 1.094. Conversely, in the control group, there was little change in all respects.

Figure 2. Frequency of responses to other lifestyle related factor

Figure 3. Comparison of lifestyle questionnaire scores

Table 7 quantifies the changes in FSSG scores for both groups. Intervention Group had a significant reduction in FSSG scores from 26.25 ± 6.6 pre-intervention to 12.47 ± 4.1 post- intervention, with a mean change of 13.78 ± 2.5 whereas, control group showed a minor change in FSSG scores, with a mean change of 0.5 ± 0.96, suggesting that without the intervention, GERD symptoms slightly improved, likely due to natural variability or other non-controlled factors.

Figure 4. Comparison of FSSG scores

The correlation analysis between changes in the FSSG scores and Lifestyle questionnaire scores was conducted (Table 8) to assess the strength and direction of the relationship due to the interventions. In the intervention group, there was a strong positive correlation (r = 0.9657, p < 0.00001) which indicates that as lifestyle scores decreased (indicating better management of lifestyle factors), FSSG scores also decreased (indicating a reduction in GERD symptoms). In the control group, the correlation was weaker. These results demonstrate that targeted lifestyle interventions can significantly enhance the prognosis of GERD by influencing lifestyle behaviors, which in turn positively affect the severity of GERD symptoms.

Medication efficacy in terms of symptom improvement (FSSG), healing and safety

Out of the total 182 participants, 104 of them had an FSSG score greater than 8 and out of 104, 42 underwent an endoscopic examination.

Classification of GERD Patients based on Endoscopic findings

Table 9 presents the classification of patients diagnosed with GERD, categorized based on the severity of esophagitis. This classification system enables a detailed characterization of the extent of esophageal mucosal injury among GERD patients, providing valuable insights into the distribution and severity of the disease within our study cohort. In this study, 9 out of 42 patients (21.43%) fall into Non-erosive esophagitis category which refers to cases where there is inflammation in the esophagus due to reflux of stomach contents, but no visible erosion or damage to the tissue,18 patients (40.47%) fall into grade A and 11 patients (26.19%) fall into grade B which represents the mildest form of erosive esophagitis, 4 patients (9.52%) fall into grade C indicating a moderate level of erosive damage, no patients were classified under Grade D which is the most severe form of erosive esophagitis.

Figure 5. Classification based on endoscopy

More Frequently Prescribed Drugs in GERD patients

Table 10 provides information on the drugs that are more frequently prescribed for patients with GERD, categorized by the focus of therapy. Therapy focused on Antacids: 4 patients (1.87%), Sucralfate: 34 patients (15.89%), PPIs: 87 patients (40.65%), Domperidone: 14 patients (2.14%), Ondansetron: 19 patients (8.9%), Acetaminophen: 21 patients (9.81%), Tramadol: 23 patients (10.75%), Hyoscine: 2 patients (0.93%) and Multivitamin: 10 patients (4.67%). Highlighting the prevalence of PPIs as the most frequently prescribed acid suppression therapy.

Esophageal Healing

Table 11 outlines the efficacy of different medication regimens in achieving esophageal healing among patients with erosive esophagitis. In case of 2 drug regimen, administered to 11 out of 32 patients, initial assessments revealed that 7 patients had Grade A esophagitis and 4 had Grade B before treatment. Following treatment, 5 patients progressed to Grade A, while 1 patient advanced to Grade B. In 3 drug Regimen, which was administered to 12 patients, 7 exhibited Grade A esophagitis and 5 had Grade B prior to treatment. Post- treatment, 6 patients saw an improvement to Grade A, with 1 patient improving to Grade B. In 4 drug Regimen, involving 9 patients, initial evaluations indicated that 3 had Grade A esophagitis, 2 had Grade B, and 4 had Grade C. After treatment, 2 patients advanced to Grade A, 3 improved to Grade B, and 1 progressed to Grade C. These findings suggest that certain medication regimens, particularly 3 drug regimens (75%) and 4 drug regimen (88.88%) demonstrate a higher efficacy in achieving esophageal healing compared to 2 drug regimen (72.72%).

Table 12 quantifies the changes in FSSG scores before and after treatment. The results showed a significant reduction in FSSG scores from a pre-treatment mean of 27.465 ± 6.95 to a post-treatment mean of 16.985 ± 6.54, with a mean change of 22.24 ± 7.49 (p=0.0001), indicating substantial symptom improvement following treatment.

Efficacy of Different Drug Regimens in GERD Symptom Improvement

Table 13 illustrates the efficacy of different drug regimens in improving symptoms of GERD, categorized by the extent of symptom improvement based on the FSSG score. Among those treated with one drug, 37.93% experienced less than a 50% reduction in symptoms, while 62.1% experienced a 50% or more reduction. For two-drug regimens 56.75% had a 50% or more reduction, three-drug regimens resulted in 66.67% with a 50% or more reduction, four-drug regimens had 75% with a 50% or more reduction, Five-drug regimens had only two participants, both of whom experienced a 100% reduction in symptoms. Overall, across all drug regimens, 62.5% of participants experienced a ≥50% reduction in symptoms, while 37.5% experienced less than a 50% reduction.

Safety

Table 14 presents findings regarding AEs experienced by patients, along with the medications implicated in causing these AEs. Five AEs were experienced by eleven (11.44%) patients at week 4. These events were stomach upset, stomach pain, constipation, flatulence and epigastric pain; none of these events were serious or severe in nature and all were resolved. No other AEs or SAEs were reported during the study period.

Distribution of patients according to the level of adherence

Table 15 presents the distribution of patients according to their adherence to medication, as assessed by the Morisky questionnaire. The table displays responses to various questions related to medication adherence, both before and after the intervention. Before the intervention, a significant proportion of patients reported instances of forgetting to take their medications (28.57%), skipping medication on certain days (74.17%), and even stopping medication without informing their doctor due to worsening symptoms (37.36%). Additionally, a considerable number of patients admitted to forgetting their medication when traveling or leaving home (60.43%) and experiencing difficulty in remembering to take all their medications (22.52% reported "all the time" or "usually"). Post-intervention, there was an improvement in adherence across several parameters. For instance, the percentage of patients reporting forgetting to take medications decreased from 28.57% to 22.52%, and those who skipped medication in the past two weeks decreased from 74.17% to 65.38%. Similarly, the proportion of patients who stopped medication without informing their doctor reduced from 37.36% to 35.71%.

1 for No, 0 for Yes, <6 low adherence, 6 - 8 medium adherence, 8 high adherence.

*chi-square

Association between adherence and demographic characteristics

Table 17 shows that while there were no statistically significant differences in adherence between males (21.66%) and females (45.16%), significant variations were observed based on education level, with illiterate individuals showing the lowest adherence (3.22%) and university-educated individuals showing the highest (95%). Age and residency did not exhibit significant associations with adherence. However, the presence of comorbidities significantly impacted adherence, with comorbid patients demonstrating higher non- adherence rates (71.66%) compared to those without comorbidities (28.33%). These findings underscore the importance of considering educational background and comorbidities when addressing medication adherence in GERD management.

Table 18 presents several factors that may influence adherence to treatment. Travel was not significantly associated with low adherence to treatment (p = 0.2980, OR = 1.28). No significant association was found between experiencing side effects and low adherence (p = 0.7897, OR = 0.355). While there was a weak association between having symptoms under control and low adherence (p = 0.0576, OR = 0.699), it did not reach conventional levels of significance. Forgetfulness emerged as the most significant determinant of low adherence to treatment. It showed a strong association (p < 0.0001, OR = 2.721). Being fed up with treatment was not significantly associated with low adherence (p = 0.5452, OR = 1.247). No significant association was found between comorbidities and low adherence to treatment (p = 0.8034, OR = 1.258). These findings suggest that forgetfulness significantly increases the likelihood of low adherence to treatment for GERD, while other factors such as travel, side effects, symptoms control, being fed up with treatment, and comorbidities do not show significant associations. Further research with a larger sample size may provide more conclusive results.

Rationality of pharmacological therapy

Rationality in Dose and Frequency

Table 19 outlines the recommended dosages and rationality of administration for various medications commonly used in the treatment of GERD. Pantoprazole, a proton pump inhibitor (PPI), was prescribed at a dose of 40 mg once or twice daily, aligning with the recommended dosage of 40 mg. A high proportion (86.49% for once daily and 99.07%) for twice daily of patients received the prescribed dose, demonstrating rationality in dosage. Similarly, other medications like Sucralfate, Domperidone, Ondansetron, Tramadol + Acetaminophen, and Hyoscine were also prescribed according to recommended dosages, with a high adherence rate. Rationality in the time interval of administration was also observed across all medications, indicating that the timing of medication administration was consistent with guidelines. These findings suggest that healthcare providers followed appropriate prescribing practices, ensuring effective management of GERD symptoms.

Table 20 outlines the recommended time of administration for various medications commonly used in the treatment of GERD. Pantoprazole, a proton pump inhibitor (PPI), was administered to all 182 participants, with 100% compliance, 30 minutes before food or 1 hour after food intake. Magaldrate with Simethicone, an antacid, was given to all 13 participants 1 hour after food. Domperidone, a prokinetic agent, was taken by all 36 participants 30 minutes to 1 hour before eating. Ondansetron, an antiemetic, and tramadol with acetaminophen, an analgesic, were taken by all 29 and 46 participants, respectively, as needed. Lastly, hyoscine, an anticholinergic, was administered to all 8 participants either before or after meals. These percentages indicate full adherence to the recommended timing for medication administration across the study population, ensuring optimal therapeutic effects.