Clinical effectiveness of a new antacid chewing gum on heartburn and oesophageal ph control

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1 Aliment Pharmacol Ther 2002; 16: doi: /j x Clinical effectiveness of a new antacid chewing gum on heartburn and oesophageal ph control K. L. COLLINGS*, S. RODRIGUEZ-STANLEY*, H. M. PROSKIN, M. ROBINSON* & P. B. MINER JR* *Oklahoma Foundation for Digestive Research, Oklahoma City, OK, USA; Howard M. Proskin and Associates, Rochester, NY, USA Accepted for publication 19 August 2002 SUMMARY Background: Oesophageal acid neutralization with antacids depends on the duration of oesophageal antacid exposure and acid neutralizing capacity. A gum that releases antacid as it is chewed could take advantage of both mechanisms to enhance heartburn relief. Methods: Twenty-four subjects were crossed over to four regimens: placebo, chewable antacid tablets (1000 mg CaCO 3 ), lower dose gum (600 mg CaCO 3 ) and higher dose gum (900 mg CaCO 3 ). A dual ph probe was placed, subjects ate a standardized provocative meal and self-dosed once as needed. Symptoms were recorded every 15 min using visual analogue and Likert scales. Results: Symptoms: Both gums decreased heartburn compared to placebo for 120 min. Higher dose gum decreased heartburn more than chewable antacids up to 120 min post-dose. ph: Active chewable antacid and gums immediately increased oesophageal ph, with significant improvement min post-dose. Summary: (i) both gums promptly decreased heartburn and elevated oesophageal ph; (ii) both gums provided sustained relief for 120 min; (iii) antacid gums provided faster and more prolonged symptom relief and ph control than chewable antacids. Conclusions: Calcium carbonate gum effectively neutralizes oesophageal acidity and relieves symptoms following a meal, and is superior to chewable antacids in terms of the duration of heartburn relief. INTRODUCTION Heartburn is a common symptom of substernal discomfort and burning that is treated by most of the population with either folk remedies or over-the-counter medications. The pathophysiology of gastro-oesophageal reflux involves the movement of gastric contents into the oesophagus, often due to abnormal oesophageal function. These gastric contents include ingested food, mucus, fluid secreted by the stomach and gastric acid. A common misperception amongst heartburn sufferers is that their discomfort is due to acid in the stomach, when it is, in fact, the refluxed gastric contents which Correspondence to: Dr P. B. Miner Jr, Oklahoma Foundation for Digestive Research, 711 Stanton L. Young Blvd Suite 619, Oklahoma City, OK 73104, USA. sheila-stanley@ouhsc.edu may contain acid and may cause a burning sensation when they come into contact with the oesophageal mucosa. For this reason, antacids are often selected as the most popular over-the-counter treatment for occasional episodes of heartburn. Careful and properly controlled scientific studies also attest to the effectiveness of antacids for the management of heartburn and to the ability of antacids to reduce the exposure of the oesophagus to acid, but, interestingly, this improvement is not reflected in dramatic changes in the gastric ph. 1, 2 In fact, gastric acid neutralization may not be needed; it may only be necessary to neutralize the small volume of gastric contents that actually enters the oesophagus during a reflux episode. This hypothesis is given credence by the observation that chewable antacids seem to have a therapeutic advantage over liquid antacids in providing symptom relief. 3 The reason Ó 2002 Blackwell Science Ltd 2029

2 2030 K. L. COLLINGS et al. why chewable antacids are superior to liquid antacids is unclear. One theory suggests that chewable antacids stay in the mouth longer and take longer to swallow than a liquid bolus, exposing the oesophagus to smaller amounts of antacid over a relatively longer period. The present study was designed to delineate the details of chewable antacid pharmacology in subjects with heartburn using a traditional chewable antacid and an antacid gum that would enable a slow, sustained release of calcium carbonate. AIMS The primary objectives of this study were: (i) to demonstrate symptomatic relief of meal-induced heartburn by an antacid-containing chewing gum; and (ii) to concurrently monitor the neutralization of oesophageal acid. MATERIALS AND METHODS The Western Institutional Review Board approved all aspects of this single-site, single-blind, placebocontrolled study, and informed consent was obtained from each study subject prior to enrolment. Physical examination and medical history Subjects were seen for a screening visit in order to perform a physical examination and collect a medical history confirming good health and a 6-month history of mealrelated heartburn. Once subjects were deemed qualified to continue, they returned for four meal sessions. Experimental design and study treatments This study followed a single-blind, four-treatment crossover design. At the subjects first testing session, they were randomly assigned to a treatment order sequence that indicated which of the four study treatments would be administered during each study session. The four study treatments were: (i) two pellets of an antacid chewing gum formulation, each containing 300 mg of calcium carbonate (lower dose gum; 600 mg calcium carbonate in total; Surpass antacid chewing gum regular strength, Wrigley Healthcare); (ii) two pellets of an antacid chewing gum formulation, each containing 450 mg of calcium carbonate (higher dose gum; 900 mg calcium carbonate in total; Surpass antacid chewing gum extra strength, Wrigley Healthcare); (iii) two tablets of an over-the-counter chewable antacid formulation, each containing 500 mg of calcium carbonate (chewable antacid; 1000 mg calcium carbonate in total; Tums Regular Strength, SmithKline Beecham); (iv) a swallowed placebo capsule, taken with 60 ml of water (placebo; 0 mg calcium carbonate). Oesophageal ph monitoring At the beginning of each test session, subjects were intubated transnasally with a dual electrode ph catheter (15 cm spacing) with an internal reference electrode (Medtronics Synectics). The catheter was positioned with the proximal electrode 5 cm above the upper margin of the manometrically identified lower oesophageal sphincter (oesophagus) and the distal electrode 10 cm below the lower oesophageal sphincter (stomach). Continuous electronic recording of the oesophageal ph profile was accomplished with a Mk III Digitrapper. Provocative meal At each session, following a 1-h baseline period, subjects consumed a provocative meal consisting of: (i) a sausage, egg and cheese biscuit fortified with 30 g of raw onion; (ii) 240 ml of chocolate milk; and (iii) a large peppermint patty. 4 Subjects were given 30 min to consume up to two portions of each of the meal components. Subjects were required to consume the same amount at each subsequent meal session as they did at the initial session. Symptom assessment Symptoms were assessed at 15-min intervals starting with the end of the 30-min meal session. At each assessment time point, subjects were given the option of self-dosing with their respective study treatment as designated by randomization. During the 15-min period immediately following self-dosing, subjects provided additional assessments of heartburn symptoms at 5-min intervals. Symptom assessments were scored using two methods: (i) by a 100-mm visual analogue scale, according to which subjects placed a mark on a line representing the continuum of heartburn severities, ranging from no symptoms to severe symptoms ; and (ii) by selecting a score on a five-point Likert scale which provided five discrete scoring categories ranging from none to severe.

3 ANTACID CHEWING GUM FOR HEARTBURN 2031 Data management The ph measurements recorded using the Digitrappers were downloaded into ASCII files, from which SAS databases were developed. Written logs of meal and symptom assessment times were also produced. From this information, as well as the symptom assessment score sheets, a master database was constructed which provided scores for the following parameters for each 15-min interval of time (and for the three 5-min intervals immediately following dosing): visual analogue scale scores for heartburn symptoms, recorded on a continuous scale ranging from 0 (representing no symptoms) to 100 (representing severe symptoms); Likert scale scores for heartburn symptoms, recorded on a five-point numerical scale ranging from 0 (representing no symptoms) to 4 (representing severe symptoms); oesophageal acid contact time (percentage of time that the ph was below 4); mean oesophageal ph; and mean gastric ph. The 15-min intervals were denoted by the time point at which they ended. The dosing time interval consisted of the 15-min interval which immediately preceded the point at which the subject opted to self-dose with his or her respective treatment. Statistical evaluation Separate statistical analyses were performed for each parameter for each scoring interval, as previously described, commencing with the dosing interval. Additionally, analyses were performed for mean ph for each of the first 20 min after dosing. To account for skewness and heteroscedasticity (non-uniform variability) in the data, scores for the parameter percentage of time that the oesophageal ph was less than 4 were transformed via logarithms (base 10) prior to analyses. All parameters were summarized through the calculation of means and standard deviations. Comparisons between the treatment groups were made using analysis of variance (anova), suitable for the analysis of data from a cross-over experimental design. Included amongst the factors in this anova were sequence (treatment sequence order), period (experimental period) and treatment. The test for significance of the treatment sequence order, which employs the factor subjects within sequence as its error term, provided a means for investigating the presence of possible carryover effect. Analyses of the subjective heartburn severity scores were adjusted for the level of symptom indicated immediately prior to dosing. Post-anova pairwise treatment comparisons were performed using two-tailed t-tests. All statistical tests of hypotheses employed a level of significance of P ¼ RESULTS Patient population Twenty-six subjects (17 females and nine males; mean age, 43.5 years; range, years) with at least a 2-month history of heartburn were recruited for this study. As dosing was dependent on each subject s selfassessment of heartburn symptoms, it was possible that some subjects would not dose after each meal. Two subjects did not have heartburn at one of the meal sessions, and therefore did not receive their study treatment and did not provide a complete set of data for all four treatment periods. To maintain balance in the cross-over analyses, the remaining data from these subjects were excluded from all statistical analyses. No significant carryover effect was noted for any of the parameters measured over the course of this study. Subjective measurements of heartburn severity visual analogue scale The mean scores for subjective heartburn severity using the visual analogue scale are illustrated in Figure 1. All three of the active study treatments provided significantly lower levels of heartburn severity than did placebo at all post-dosing assessment time points up to 120 min post-dose. The higher dose gum yielded significantly lower scores than did the chewable antacid at both the 5-min and 105-min assessment time points. No other statistically significant difference was indicated between the active treatment groups. Subjective measurements of heartburn severity Likert scale The mean scores for subjective heartburn severity using the Likert scale are illustrated in Figure 2. Both the higher dose and lower dose gum provided significantly lower heartburn severity scores than did placebo at all post-dosing assessment time points up to 120 min postdose. Chewable antacid tablets provided significantly lower scores at all post-dosing assessment time points than did placebo up to 45 min post-dose, and again at

4 2032 K. L. COLLINGS et al. 60 Mean VAS heartburn severity HigherDose Gum Marking time point (min post-dosing) Figure 1. Self-assessment of heartburn severity VAS (100-point visual analogue scale). Mean visual analogue scale (VAS) heartburn assessments (range 0 100) were taken at 5-min intervals for the first 15 min post-dosing and at 15-min intervals thereafter. Both gums were better than placebo after dosing up to 120 min (P < 0.05). 4 Mean Likert heartburn severity Marking time point (min post-dosing) Figure 2. Self-assessment heartburn severity Likert (5-point scale). Mean Likert assessments (0 5) were taken at 5-min intervals for the first 15 min post-dosing and at 15-min intervals thereafter. Both gums provided significantly lower heartburn severity scores than placebo after dosing up to 120 min (P < 0.05). the 75-min post-dose assessment time point. Higher dose gum provided significantly lower scores than did chewable antacid at the 5-, 10-, 15-, 75-, 105- and 120-min post-dose assessment time points. Lower dose gum provided significantly lower scores than did the chewable antacid at the 10-, 60-, 75- and 90-min postdose assessment time points. Lower dose gum provided a significantly lower score than did the higher dose gum at the 5-min post-dose assessment time point. Oesophageal acid contact time (percentage of time that the oesophageal ph < 4.0) The mean scores for the percentage of time that the oesophageal ph was below 4.0 are illustrated in Figure 3. The scores for all three active treatment groups were significantly lower than those for the placebo group over the span of time between dosing and 60 min post-dosing. Additionally, the scores for both the higher dose and lower dose gum were significantly lower than the placebo scores between 60 min and 75 min post-dosing. Both the higher dose and lower dose gum provided significantly lower scores than did the chewable antacid over the span of time between 10 and 30 min post-dosing. Mean oesophageal ph The mean scores for the mean oesophageal ph over each 1-min time interval between dosing and 20 min postdosing are illustrated in Figure 4(a) (In this figure, values illustrated for each dosing time point represent mean values for the 15 min immediately preceding the administration of the study treatment.) The mean oesophageal ph was significantly higher for all three active treatment groups for every 1-min time interval between 1 min and 20 min post-dose (and for all but the higher dose gum over the 1-min time interval between dosing and 1-min post-dose) vs. placebo. Furthermore, both the higher dose and lower dose gum provided significantly

5 ANTACID CHEWING GUM FOR HEARTBURN Figure 3. Percentage of time oesophageal ph is less than 4.0. The mean percentage of time that the oesophageal ph was less than 4.0 was assessed over time periods corresponding to the post-dose diary markings (5-min periods for the first 15 min, 15-min periods for the remainder of the session). Both gums were better than placebo after dosing up to 75 min (P < 0.05). Mean percentage of time oesophageal ph < (a) 7.0 Mean oesophageal ph Figure 4. (a) Mean oesophageal ph (by minute). The mean oesophageal ph scores for all subjects were calculated over each minute post-dosing from 1 to 20 min. Both gums did better than placebo over each of the 1-min periods between 1 min and 20 min post-dose (P < 0.05). (b) Mean oesophageal ph. The mean oesophageal ph scores for all subjects were calculated over time periods corresponding to the post-dose diary markings (5-min periods for the first 15 min, 15-min periods for the remainder of the session). Both chewing gums provided significantly higher oesophageal ph than placebo after dosing up to 75 min (P < 0.05). (b) Mean oesophageal ph higher mean ph scores for every 1-min interval between 3 min post-dose and 20 min post-dose when compared to the effects of the chewable antacid tablets. The mean oesophageal ph over the usual time spans is illustrated in Figure 4(b). The scores for all three active treatment groups were significantly higher than for placebo between dosing and 45 min post-dosing. Additionally, scores for both the higher dose and lower dose gum were significantly higher than for placebo for the interval between 45 and 75 min post-dosing. The score for chewable antacid tablets was significantly lower than for placebo between 90 min and 105 min

6 2034 K. L. COLLINGS et al. post-dosing. Both the higher dose and lower dose gum provided significantly higher scores than the chewable antacid tablets between 5 min and 90 min post-dosing. Additionally, the score for the higher dose gum was significantly higher than that for the chewable antacid tablets between 90 min and 105 min post-dosing. Mean gastric ph The mean scores for the mean gastric ph are illustrated in Figure 5. Scores for the higher dose gum were significantly higher than for placebo between 5 min and 120 min post-dosing. The gastric ph was higher with the lower dose gum than with placebo between 5 min and 90 min post-dosing. The scores for chewable antacid were significantly higher than for placebo between 10 min and 45 min post-dosing, and between 75 and 120 min post-dosing. Additionally, the score for the higher dose gum was significantly higher than for chewable antacid tablets between 30 min and 45 min post-dosing, and higher than for lower dose gum between 105 min and 120 min post-dosing. The mean gastric ph did not exceed 3.0 for all treatments. by the Likert scale. Post-dose symptom assessment for chewable antacids and gum preparations revealed both a faster onset of action and more prolonged symptom relief with both the lower and higher dose gums. Oesophageal ph findings The abrupt increase in oesophageal ph with dosing confirms the efficacy of chewable antacid and demonstrates the efficacy of antacid gum in neutralizing oesophageal acid. This can be seen within the minute by minute mean oesophageal ph measurements for the first 20 min after dosing. The beneficial impact of these products is corroborated by the traditional method of assessing the effect of acidity in subjects with gastrooesophageal reflux: the percentage of time that the oesophageal ph is below 4.0. Each active treatment was effective in changing this important parameter of oesophageal pathophysiology. One of the most interesting observations made during this study was the apparent prolonged decrement in oesophageal acid exposure that persisted long after discontinuation of gum chewing and swallowing of the chewable antacid. DISCUSSION Effect on symptoms Both the visual analogue scale and categorical Likert assessments demonstrated that all three active treatments promptly relieved heartburn symptoms compared to placebo. However, heartburn severity was significantly lower with higher and lower dose gum vs. chewable antacid at significant time frames directly after the meal and in the extended time periods, as measured Gastric ph findings In the past, it has been widely accepted that antacids control heartburn symptoms by increasing the gastric ph through the neutralization of gastric contents that might subsequently reflux into the oesophagus. The gastric ph data presented in the current study clearly refute this hypothesis, as the mean gastric ph remained below 3.0 following dosing with either chewable antacid or lower and higher dose gum preparations, despite the profound effects on oesophageal ph by all Mean gastric ph Figure 5. Mean gastric ph. The mean gastric ph scores for all subjects were calculated over time periods corresponding to the post-dose diary markings (5-min periods for the first 15 min, 15-min periods for the remainder of the session). The mean gastric ph did not exceed 3.0 for all treatments.

7 ANTACID CHEWING GUM FOR HEARTBURN 2035 active antacid agents. The neutralizing effect of the antacids is profound in the oesophagus, but only arrests the continued fall in gastric ph and does not abruptly neutralize gastric contents, nor even raise the gastric ph to levels greater than ph 4.0. Comparison of the two strengths of gum There were no significant differences between the two gum preparations, suggesting that oesophageal acid neutralization is saturated at the lower dose. This may explain why the lower strength gum occasionally outperformed the gum with more calcium carbonate. Although the data do not provide definitive evidence for the precise mechanism of action for such striking effects on oesophageal ph, they are certainly consistent with predominant intra-oesophageal acid neutralization. Mode of action of the gum product Swallowing is a complex physiological process which influences heartburn in a number of ways that may either benefit or complicate the problem of gastrooesophageal reflux. Each swallow induces relaxation of the lower oesophageal sphincter, the muscular barrier which protects the oesophagus from the reflux of gastric contents. This relaxation prepares the lower oesophagus to receive the swallowed bolus for transfer into the stomach. Early physiological experiments demonstrated that carefully timed, repetitive swallowing can significantly lower the lower oesophageal sphincter barrier. 5 7 Chewing gum is associated with repetitive swallowing which might theoretically increase the risk of gastrooesophageal reflux. However, there is no evidence that any such effect occurred in this study. Enhanced salivary secretion by gum chewing may be beneficial in gastro-oesophageal reflux by inducing the secretion of alkaline saliva to assist in the process of neutralization, as well as providing a volume bolus to clear the oesophagus of any noxious irritants. It is obvious and easily demonstrated statistically that, within the first minute of treatment usage, the chewable antacid and lower and higher dose chewing gums neutralized oesophageal acid. From these data, it is hypothesized that the amount of antacid released by chewing these preparations promptly neutralizes the relatively small amount of acid present in the oesophageal lumen. The hypothesis of acid neutralization depends only on the chemical properties of the antacid and saliva within the oesophagus and is independent of changes in oesophageal physiology. In conclusion, chewable antacid gum relieves the symptoms of meal-induced heartburn rapidly, with neutralization of the oesophageal ph immediately and long after chewing has been completed. Unlike other approaches to the management of acid reflux, this product does not change the gastric ph with treatment. ACKNOWLEDGEMENTS This study was funded by an unrestricted grant from Wrigley Healthcare. REFERENCES 1 Decktor DL, Robinson M, Maton PN, Lanza FL, Gottlieb S. Effects of aluminum magnesium hydroxide and calcium carbonate on esophageal and gastric ph in subjects with heartburn. Am J Ther 1995; 2: Decktor DL, Robinson M, Gottlieb S. Comparative effects of liquid antacids on esophageal and gastric ph in patients with heartburn. Am J Ther 1995; 2: Robinson M, Rodriguez-Stanley S, Miner PB, McGuire AJ, Fung K, Ciociola AA. Effects of antacid formulation on postprandial oesophageal acidity in patients with a history of episodic heartburn. Aliment Pharmacol Ther 2002; 16: Rodriguez S, Miner P, Robinson M, Greenwood B, Maton P, Pappa K. Meal type affects heartburn severity. Dig Dis Sci 1998; 43(3): Nebel TO, Castell D. Lower esophageal sphincter pressure changes after food ingestion. Gastroenterology 1972; 63: Dent J, Odds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980; 65: Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in subjects with reflux esophagitis. N Engl J Med 1982; 307:

Effects of antacid formulation on postprandial oesophageal acidity in patients with a history of episodic heartburn

Aliment Pharmacol Ther 2002; 16: 435±443. Effects of antacid formulation on postprandial oesophageal acidity in patients with a history of episodic heartburn M. ROBINSON*, S. RODRIGUEZ-STANLEY*, P. B.