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Night-time GERD: Understanding the Role of Esomeprazole
Gastro-oesophageal reflux disease (GERD) is a common chronic diseased state, with studies highlighting a global pooled prevalence rate of 13.98%, varying between geographical locations and races (1). It is characterized by involuntary reflux of gastric contents into the oesophagus (2) . The primary symptoms associated with GERD are acid reflux and heartburn (3,4), which if left untreated, can take a drastic toll on the quality of life of the patient.
The association of chronic GERD with reflux esophagitis, sleep inadequacy, reduced work productivity due to increased daytime sleepiness, and poor health-related quality of life has long been established (5,6,7). To complicate matters, growing evidence highlights that 79% of patients reporting GERD suffer from nocturnal symptoms (8, 9,10). According to a review article by Orr et al, nighttime heartburn and sleep-related gastro-oesophageal reflux (GOR) represent a distinct clinical entity that deserves specific attention in the diagnosis and optimal treatment of GERD(11). Life-threatening medical complications such as oesophagitis, Barrett's oesophagus, laryngeal disorders such as laryngopharyngitis, and pulmonary aspiration can be aggravated in cases of moderate to severe chronic GERD(12).
Night-time GERD occurs as a result of prolonged acid contact with the gastroesophageal mucosa, being further aggravated by a decreased ability to neutralize reflux events owing to lower saliva production, reduced swallowing frequency, and gastric emptying at night (13).
Acid suppression by proton pump inhibitors (PPIs) forms the cornerstone of managing GERD. Over the years, the efficacy of various PPIs like lansoprazole, omeprazole, and pantoprazole has been extensively studied. Among these, of particular importance is Esomeprazole, which has been shown to have more potent acid suppression compared to other PPIs, due to an improved pharmacokinetic profile (14,15,16).
Esomeprazole: Molecular background
Esomeprazole is the latest PPI, made up of a single active optical isomer, specifically the S-isomer of omeprazole (17). Currently approved by FDA for use in the treatment of symptomatic GERD, including healing and maintenance of healing of erosive esophagitis (18), this drug has an edge over other PPIs with enhanced pharmacokinetic and pharmacodynamic features, owing to its molecular composition.
A trial by Andersson T et al demonstrated that Esomeprazole magnesium daily was more effective than omeprazole, with inhibition of peak acid output rates at28%, 62%, and 90% for the 5, 10, and 20-mg/day dosages respectively, in healthy volunteers at the end of 5 days(19). With a plasma half-life of 1–1.5 hours, and 97% plasma protein-bound (18), Esomeprazole has a lower intrinsic clearance rate due to its minimal first-pass metabolism, less hydroxylation via CYP2C19,(18) thus maintaining the peak levels in the body for a longer period. This pharmacodynamic uniqueness, taken together, accounts for the better clinical efficacy of this drug when compared with its predecessors.
Clinical uses of esomeprazole in GERD
Reduction of gastric acidity- Cumulative evidence from studies has concluded that Esomeprazole maintains intragastric pH at a higher level and above 4 for a longer period than other PPIs (20) . This forms the basis of its exceptional capability to reduce acidity as has been resonated in studies by Lind et al, Ross et al, Miner et al and Johnson et al (20).
Reduction of esophageal acidity-Low nocturnal intragastric pH correlates with high nocturnal intraesophageal acid reflux. A study by RW Yeh and associates revealed that Esomeprazole, when administered at high doses, was associated with the significant breakthrough of intraesophageal acid control, particularly at night in a patient suffering from chronic GERD (21). Yet another study (22) by Schmitt C et al, noted that healing rates with Esomeprazole were significantly higher than those with omeprazole at weeks 4 (60.8% vs 47.9%; P = 0.02) and 8(88.4% vs 77.5%; P = 0.007) in patients with moderate to severe erosive esophagitis.
Healing of erosive GERD- A notable study by Kahrilas et al. (12) among 1960 patients with erosive GERD, has shown that Esomeprazole magnesium 20 and 40 mg were superior to omeprazole 20 mg for healing at eight weeks. The researchers further noted that safety and tolerability with Esomeprazole were equivalent to omeprazole. Addressing the issue of resolution of GERD-associated symptoms, accumulating evidence suggests that Esomeprazole 40 mg od is more effective than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg (23,24,25).
Maintenance therapy of healed erosive GERD-With a high relapse rate of 26–48% following discontinuation of PPIs(26), most GERD patients need to follow lifelong drug therapy. A study by Johnson et al (27) demonstrated that in patients with healed esophagitis, healing was maintained in 93.6% of patients treated with Esomeprazole 40 mg, 93.2% treated with Esomeprazole 20 mg, and 57.1% treated with Esomeprazole 10 mg, against only 29.1% treated with placebo, even after 6 months.
Improves health-related quality of life-GERD along with its associated symptoms can be very detrimental to the physical as well as the mental well-being of a patient. Studies assessing the health-related QoL have concluded that within 2 weeks, after treatment with Esomeprazole in GERD patients, both symptoms and QoL improved in all subscales. (28) Similar findings were reported by Pace et al, who opined that esomeprazole 40 mg OD, when given in non-erosive and mild erosive GERD, for 4 weeks, led to profound improvements in QoL indices (20).
Indications and formulary recommendations
Esomeprazole magnesium is currently indicated in FDA-approved labelling for use in the treatment of symptomatic GERD (20 mg once daily for 4 weeks; maximum, 8 weeks), including use for healing (20 or 40 mg once daily for 4–8 weeks; maximum, 16 weeks) and maintenance of healing (20 mg once daily; studies of maintenance therapy for six months exist) in erosive esophagitis. (29)
Available as an enteric-coated delayed-release capsule, esomeprazole is advocated to be taken at least one hour before a meal (29). Studies have affirmed that esomeprazole dosage adjustments are not recommended for elderly patients (30) or patients with mild to moderate renal insufficiency, while at the same time highlighting that patients with severe hepatic insufficiency should not receive esomeprazole dosages greater than 20 mg once daily.
The advent of esomeprazole has brought a revolution in the current treatment protocols of GERD. As evidence grows supporting the unmatched efficacy of this drug, not only in acid suppression but also in ameliorating the associated symptoms of GERD, the novel advantages provided by esomeprazole continue to unravel. The medical fraternity looks forward to more future studies to establish the unanimous superiority of this drug among all other concurrent PPIs used today to manage GERD.
- Nirwan, J.S., Hasan, S.S., Babar, ZUD. et al. Global Prevalence and Risk Factors of Gastro-oesophageal Reflux Disease (GORD): Systematic Review with Meta-analysis. Sci Rep 10, 5814 (2020). https://doi.org/10.1038/s41598-020-62795-1
- Vakil N, Fennerty MB. 2003. Direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther,18:559–68.
- Kulig M, Leodolter A, Vieth M et al. Quality of life in relation to symptoms in patients with gastro-oesophageal reflux disease – an analysis based on the ProGERD initiative. Aliment Pharmacol Ther 2003; 18: 767–76.
- Wiklund I, Carlsson J, Vakil N. Gastro-esophageal reflux symptoms and well-being in a random sample of the general population of a Swedish community. Am J Gastroenterol 2006; 101:18–28.
- Liker H., Hungin P, Wiklund I. Managing gastroesophageal reflux disease in primary care: the patient perspective. J Am Board Fam Pract 2005;18:393-400
- Dubois RW, Aguilar D, Fass R, et al. Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life and work productivity.Aliment Pharmacol Ther 2007;25:487-500
- Calleja JL, Bixquert M, Maldonado J. Impact of nocturnal heartburn on quality of life, sleep, and productivity: the SINERGE study. Dig Dis Sci 2007;52:2858-65
- Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487-93
- Gerson LB, Fass R. A systematic review of the definitions, prevalence, and response to treatment of nocturnal gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2009;7:372-8
- Dean BB, Aguilar D, Johnson LF, et al. Night-time and daytime atypical manifestations of gastro-oesophageal reflux disease: frequency, severity and impact on health-related quality of life.Aliment Pharmacol Ther 2008;27:327-37
- Orr WC. Review article: sleep-related gastro-oesophageal reflux as a distinct clinical entity. Aliment Pharmacol Ther. 2010 Jan;31(1):47-56. doi: 10.1111/j.1365-2036.2009.04124.x. PMID: 19691671.
- Kahrilas PJ, Falk GW, Johnson DA, et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther2000;14(10):1249-58
- Orr WC, Heading R, Johnson LF, et al.Review article: sleep and its relationship to gastro-oesophageal reflux. Aliment Pharmacol Ther 2004; 20(Suppl 9): 39–46.
- Hatlebakk JG. 2003. Review article: gastric acidity – comparison of esomeprazole with other proton pump inhibitors. Aliment Pharmacol Ther,(Suppl 1):10–15; discussion 16–17.
- Hellstrom PM, Vitols S. 2004. The choice of proton pump inhibitor: does it matter? Basic Clin Pharmacol Toxicol, 94:106–11.
- Kendall MJ. 2003. Review article: Esomeprazole – the fi rst proton pump inhibitor to be developed as an isomer. Aliment Pharmacol Ther,17(Suppl 1):1–4.
- Andersson T, Hassan-Alin M, Hasselgren G, Röhss K, Weidolf L. Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet. 2001;40(6):411-26
- Johnson TJ, Hedge DD. Esomeprazole: a clinical review. Am J Health Syst Pharm. 2002 Jul 15;59(14):1333-9. doi: 10.1093/ajhp/59.14.1333. PMID: 12132559.
- Andersson T, Rohss K, Hassan-Alin M, Bredberg E. Pharmacokinetics (PK) and dose-response relationship of esomeprazole (E). Gastroenterology. 2000;4(118):A1210
- Kalaitzakis, E., & Björnsson, E. (2007). A review of esomeprazole in the treatment of gastroesophageal reflux disease (GERD). Therapeutics and clinical risk management, 3(4), 653–663.
- Yeh RW, Gerson LB, Triadafilopoulos G. Efficacy of esomeprazole in controlling reflux symptoms, intraesophageal, and intragastric pH in patients with Barrett's esophagus. Dis Esophagus. 2003;16(3):193-8. doi: 10.1046/j.1442-2050.2003.00327.x. PMID: 14641308.
- Schmitt C, Lightdale CJ, Hwang C, et al. 2006. A multicenter, randomized,double-blind, 8-week comparative trial of standard doses of esomeprazole 40 mg. and omeprazole 20 mg. for the treatment of erosive esophagitis. Dig Dis Sci, 51:844–50.
- Richter JE, Kahrilas PJ, Johanson J, et al. 2001. Effi cacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol,96:656–65.
- Castell DO, Kahrilas PJ, Richter JE, et al. 2002. Esomeprazole 40 mg. compared with lansoprazole 30 mg. in the treatment of erosive esophagitis. Am J Gastroenterol, 97:575–83.
- Vcev A, Begić I, Ostojić R, Jurcić D, Bozić D, Soldo I, Gmajnić R, Kondza G, Khaznadar E, Mićunović N. Esomeprazole versus pantoprazole for healing erosive oesophagitis. Coll Antropol. 2006 Sep;30(3):519-22
- Lei, W. Y., Chang, W. C., Wen, S. H., Yi, C. H., Liu, T. T., Hung, J. S., Wong, M. W., & Chen, C. L. (2019). Predicting factors of recurrence in patients with gastroesophageal reflux disease: a prospective follow-up analysis. Therapeutic advances in gastroenterology, 12, 1756284819864549. https://doi.org/10.1177/1756284819864549
- Johnson DA, Benjamin SB, Vakil NB, et al. 2001. Esomeprazole once daily for 6 months is effective therapy for maintaining healed erosive esophagitis and for controlling gastroesophageal refl ux disease symptoms: a randomized, double-blind, placebo-controlled study of effi cacy and safety. Am J Gastroenterol, 96:27–34.
- Kulig M, Leodolter A, Vieth M, et al. 2003. Quality of life in relation to symptoms in patients with gastro-oesophageal refl ux disease – an analysis based on the ProGERD initiative. Aliment Pharmacol Ther,18:767–76
- Nexium (esomeprazole magnesium) delayed-release capsules package insert. Wilmington, DE: AstraZeneca; 2001.
- Hasselgren G, Hassan-Alin M, Andersson T et al. Pharmacokinetic study of esomeprazole in the elderly. Clin Pharmacokinet. 2001; 40:145-50.
Dr. Vatsya has completed three professional Degrees, a graduation degree MBBS from University College Of Medical Sciences, New Delhi, a post-graduation MD in Internal Medicine from Maulana Azad Medical College, New Delhi, and a super specialty degree DM in Gastroenterology and has been rewarded by renowned personalities for excelling vastly in this domain. He was granted the Smt. Ram Pyari Gold Medal and Shri L.N. Chugh Memorial Gold Medal for getting the first position in Medicine in MBBS. The second one was the K. Sridharan Gold Medal for his first position in Pharmacology. He also won the Young Scholar Award Gastroenterology 2017.