Chronobiology of Digestive Diseases*
Many common digestive diseases such as gastro-esophageal-reflex disease (GERD) heartburn and ulcer display strong rhythms in their symptoms and response to medications.
Acid reflux and heartburn occurs after daytime meals and nighttime sleep. The positioning of a tiny acid sensor in the esophagus makes it possible to study the 24-hour pattern of acid reflux. In one typical study, the time of day of acid reflux was assessed in 120 persons with normal esophageal function and 84 heartburn sufferers (1). The 24-hour pattern in the acid level differed markedly between the two groups. The heartburn group experienced numerous reflux episodes after every meal, especially after supper when their incidence was 3-fold greater in number then after breakfast. Moreover, in this group the length of time the acid level was high enough to cause injury to the esophagus was 2.5 times longer after supper than breakfast. Furthermore, sleep-time episodes of intense reflux were extensive. Things were different in the non-heartburn group, meal and nighttime bouts of reflux were inconsequential.
There are several reasons why heartburn is worse after meals and at night. First, stomach acid production is highly circadian rhythmic. Research studies on fasted volunteers show stomach acid secretion is 2-3 times greater between 22:00 and 02:00 than in the day (2). Second, eating and drinking immediately stimulates stomach acid production (3). Daytime heartburn symptoms arise from meal-triggered acid secretion, while nighttime ones result from the circadian rhythm of stomach acid production that peaks at night.
Chronic heartburn problems require medications such as cimetidine, famotidine, nizatidine, ranitidine, lansoprazole and omperazole that suppress stomach acid secretion. The time of dosing of these medications determines in part their effectiveness.
One study examined the therapeutic efficiency of omeprazole and lansoprazole, taken in equal doses in the morning and evening (4). The objective of this trial was to determine the degree to which this widely used treatment schedule prevented severe bouts of acid reflux in heartburn sufferers. The findings of around-the-clock studies on 61 people indicated that even though the medicines were taken faithfully as directed, 70% of the heartburn sufferers experienced severe nocturnal episodes of acid reflux.
Using the same investigative methods, the investigators compared the effect of omeprazole when taken at different times of day and by different schedules. 18 healthy non-heartburn people volunteered (5). In one trial, they took the entire 40 milligrams of the medication in the morning before breakfast. In a second, they took half that amount, 20 milligrams, before breakfast and the other half before dinner. Finally, in a third, they took the entire 40 milligrams before dinner. On the last day of each 7-day treatment schedule, stomach acid secretion was assessed continuously around the clock. The 3 schedules were equally effective in controlling stomach acid production in the daytime. However, they were not equally effective in controlling it at night. The morning treatment schedule was worst. The twice-a-day and evening only medication schedules were equally effective and both were significantly better than the morning one.
Other studies compared the effect of the acid-blocker, ranitidine when split into equal morning and evening doses versus when taken as a single ingestion in the evening (6). The aim of this study was to learn the best time to take the medicine to inhibit acid secretion at night. Stomach acid levels were measured continuously for 24 hours using ambulatory monitors. The evening once-a-day schedule was only somewhat better in effect than the twice-a-day one; however, it was preferred by the patients because it was easier to remember to take the medicine one rather than 2 times a day.
The results of these studies show that the evening once-a-day and the twice-a-day treatment schedules are comparable in controlling the secretion of stomach acid during the critical overnight period when heartburn is worst. However, because it is easier to take medicines only one time a day rather than 2, the evening once-a-day schedule is regarded as the best.
Ulcer disease is another medical condition of the digestive system that exhibits prominent 24-hour as well as weekly and annual cycles. Gastric and duodenal ulcers are commonly caused by infection, stress and over-indulgent alcohol and tobacco consumption. They also result from prolonged and frequent use of aspirin and arthritis medications.
In 1910, the prominent Irish surgeon Moynihan remarked ulcer pain "comes usually two hours or little more after food has been taken... The pain, as a rule, is noticed, at first, only or chiefly after the heaviest meal of the day; if a large meal is taken between 13:00 and 14:00, the pain will come with unvarying regularity at, or near, 16:00. For a long period this may be the only time of day when discomfort is felt... With progression of the disease, the pain becomes more frequent, occurring usually about two hours following each meal... It is a characteristic feature of pain that it wakes the patient in the night and usually the time of awakening is said to be around 02:00" (7,8).
Later research confirms the writings of Moynihan; ulcer disease is worse at night. A 1946 British study interviewed 84 ulcer sufferers to determine the time of day they experienced stomach pain. Nearly 75 percent said it occurred after meals and at night (9). Another British investigation found 88 percent of duodenal ulcer sufferers had nighttime pain from time to time, and 45 percent had it at least 3 or 4 times a week during ulcer flare-ups (10). Stomach ulcer sufferers also experienced bouts of nighttime pain but not as often as in those who had duodenal ulcer (9,10).
Ulcer disease is often caused by Helicobacter pylori bacterial infection (11). However, the question still remains, why is ulcer disease worse at night? Stomach acid aggravates ulcer disease. Day-night patterns of ulcer pain and flare up result from the same 2 processes that induce heartburn: 1) food-triggered, and 2) the circadian rhythm of stomach acid secretion. Food consumption stimulates the secretion of copious amounts of digestive substances, including acid. After the stomach empties its contents, usually within 1 to 2 hours of eating, residual acid and digestive enzymes are thought to initiate the ulcer causing the discomfort and pain. Apart from the secretion after food uptake the peak of the circadian rhythm of acid secretion being at night helps explain why ulcer pain is worse then. Indeed, the amount of acid secreted between 22:00 and 02:00 is 2 to 3 times higher than in the morning and afternoon (2).
Under normal conditions, the peak of acid secretion occurs at a time when other rhythms of the stomach, such as in the secretion of acid buffering substances, thickness of the protective lining and blood flow, naturally protect it against injury. Some investigators hypothesize that alteration of the time relationships of the peak and trough of the stomach’s circadian rhythms may under some circumstances play a role in the development of ulcer disease. In animals with stomach ulcers, for example, the circadian rhythm of acid production is no longer balanced by rhythms that are protective of the stomach lining (3). Perhaps, this is why rotating shift workers have higher rates of ulcer disease. With every change in the work shift that requires an alteration of the sleep-wake cycle, the individual rhythms of the stomach are disturbed resulting in a transient span of imbalance between the factors that evoke ulcer disease and ones which resist it.
Ulcer disease can also arise as a side effect from the prolonged use of non-steroid anti-inflammatory medications (NSAIDs), like aspirin and flurbiprofen, taken e.g. to combat arthritic symptoms. These medications attack the lining of the stomach creating many small ulcer-like lesions, even after a single ingestion. If large amounts of these medicines are taken for a long period of time, the risk of ulcer disease is high.
The time the NSAID is routinely taken determines the amount of damage it causes. In one study, volunteers ingested a large amount of aspirin at 10:00 on one occasion and at 22:00 on another (12). The morning ingestion resulted in twice as many lesions than the evening one. The findings of this study show the safest time to take aspirin and other NSAIDs is in the evening.
If the cause of ulcer disease is Helicobacter pylori infection, antibiotics and bismuth therapy are used for its cure (13). However, additional acid-fighting medications like the ones used to treat heartburn are required as well. Several studies show ulcer healing is directly related to how well acid secretion is inhibited during the nighttime (14). Antacids give temporary and at best only partial relief by neutralizing stomach acid. Acid-suppressing medicines are much more effective since they directly inhibit stomach acid secretion and their effect is long lasting. The schedule and time of day that acid-blocking medicines are taken make a marked difference in their efficiency in relieving pain and healing ulcers. Twice-a-day morning-evening treatment schedules fail to effectively avert flare-ups or heal ulcers rapidly because they do not sufficiently suppress acid secretion at night (3).
Several studies have explored the chronotherapy of ulcer medicines as a means to improve their effect. A variety of treatment schedules and times have been evaluated such as twice-a-day and morning and evening once-a-day ones. It was found that acid secretion is best suppressed when ulcer medicines are taken at a single time in the evening (3). However, even the exact time they are taken in the evening matters. A suppertime as opposed to bedtime treatment schedule best inhibits acid secretion not only in the evening, but during overnight and in the day; moreover, it effectively heals ulcers (14,15).
Complications of Ulcer Disease - Perforated Ulcer
If ulcer disease is not properly treated or is unresponsive to treatment, medical complications are probable. One serious complication is rupture, or perforation, of the lining of the stomach or intestine at the site of the ulcer. This event is marked by sudden and severe pain in the abdominal region. Some 60 years ago a French physician reported ulcer perforations were more frequent during the day than during the night (16). Follow-up studies in Australia, Canada, Scotland and elsewhere confirm this observation (17-24). The findings of a Scottish study are illustrative. The occurrence of 951 perforated ulcer crises exhibited prominent circadian rhythmicity with the number of crises at 18:00 being quadruple that at 03:00 (17,18).
A recent Norwegian investigation comprehensively studied the temporal pattern of perforated ulcer (24). The clock time, day of week and month of year of 1480 perforated ulcers was ascertained by searching the medical records of five hospitals in Bergen, Norway. In both men and women ulcer perforations were about 4 times more frequent in the afternoon and evening than between 04:00 and 08:00 when they are rare in occurrence. The pattern was identical in young, middle-aged and elderly people. Slight differences in the peak time of stomach and intestinal ulcer perforations were identified. Stomach ulcer perforations peaked between 11:00 and 13:00 and were uncommon between 02:00 and 08:00. Intestinal perforations were greatest between 14:00 and midnight and were least frequent between 05:00 and 10:00. The number of perforations also varied with the day of the week and month of the year. Most studies report attacks are higher by up to 50 percent on Fridays than on Sundays or Mondays (17,19,21). Two studies found they occurred up to twice as often in December or January than August or September (18,19). Presumably, 24-hour, 7-day and seasonal patterns in perforation of stomach and intestinal ulcers result from circadian, weekly and annual rhythms in the biology of these organs. However, other factors undoubtedly are involved, such as cyclic variations in environmental and emotional stresses and patterns of tobacco and alcohol consumption, things that aggravate ulcer conditions. Moreover, seasonal differences in the virulence of Helicobacter pylori, a bacterial infection that is a common cause of ulcer disease, also probably play a role (25). The time of day ulcer-fighting medications are taken may also be involved. Failure to curb high stomach acid secretion at nighttime results in a worsening of the ulcer condition, making perforation more likely. Taking acid-inhibiting medications in equal amounts in the morning and night is not as effective in curbing acid secretion as a dinnertime treatment schedule.
Timewise Tips For Digestive Diseases
1. Acid reflux with heartburn most frequently occurs after meals and at night.. If symptoms occur chiefly or only at night, a suppertime medication schedule is best. If they are worse after meals and snacks during the daytime, then twice-a-day schedule is likely to be best.
2. While antacid medicines are useful for the short-term relief of ulcer flare- ups, they do not avert the worsening of the disease or promote healing of ulcer lesions. Taking acid-suppressing medications once-a-day with dinner is best since it halts ulcer growth and promotes rapid healing. Newer acid suppressing medications, called proton-pump inhibitors, seem to work effectively throughout the 24 hours when taken in the morning.
3. For antiarthritic or antiimflammatory agents like aspirin or other NSAIDs such as indomethacine, flurbiprofen and ketoprofen morning ingestion schedules are more harmful to the stomach than evening ones. Prolonged use of these medicines, especially when routinely taken in the morning, can lead to serious ulcer conditions. Once-day medication schedules are safer and best relieve the prominent morning symptoms of rheumatoid arthritis.
*Summary of background information for chapter 15 in:
SMOLENSKY M.H. and LAMBERG L: Body Clock Guide to Better Health; H.Holt, NY., 2001.
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(2) Moore JG, Halberg F. Circadian rhythm of gastric acid secretion in active duodenal ulcer: chronobiological statistical characteristics and comparison of acid secretory and plasma gastrin patterns with healthy subjects and post-vagotomy and pyloroplasty patients. Chronobiology International. 1987;4:101-110.
(3) Moore JG, Merki H. Gastrointestinal tract. In: Physiology and Physiology of Biological Rhythms. Peter H. Redfern and Bjorn Lemmer, Editors. Berlin, Springer, 1997, pp.351-373.
(4) Katz PO, Anderson C, Khoury R et al. Gastro-esophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Alimentary Pharmacology Therapeutics. 1998;12:1231-1234.
(5) Hatlebakk JG, Katz PO, Kuo B et al. Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily. Alimentary Pharmacology and Therapeutics. 1998;12:1235-40.
(6) Ireland A, Colin-James DG, Gear P. et al. Ranitidine 150 mg twice daily vs. 300 mg nightly in treatment of duodenal ulcers. Lancet. 1984;ii:274-276.
(7) Moynihan BGA. Duodenal Ulcer. Saunders. Philadelphia, 1910, pp. 101-121.
(8) Monyihan BGA. Some remarks on dyspepsia. Dublin Journal of Medical Science. 1910;130 (No. 463, 3rd series):1-15.
(9) Gainsborough H, Slater E. A study of peptic ulcer. British Medical Journal. 1946;ii:253-258.
(10) Earlam R. A computerized questionnaire analysis of duodenal ulcer symptoms. Gastroenterology. 1976;71:314-317.
(11) Bianchi Porro GB, Lazzaroni M. Colloidal Bismuth Subcitrate. In: Ulcer Disease. Investigation and Basis for Treatment. Edward A. Swabb and Sandor Szabo, Editors. New York, Marcel Dekker, Inc. 1991,pp.287-319.
(12) Moore JG, Goo RH. Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man. Chronobiology International. 1987;4:111-116.
(13) Nebiki H, Higuchi K, Arakawa T et al. Effect of rebamipide on Helicobacter pylori infection in patients with peptic ulcer. Digestive Diseases and Sciences. 1998;43(9 Suppl.):203S-206S.
(14) Howden CW, Hunt RH. The histamine H2-receptor antagonists. In: Ulcer Disease. Investigation and Basis for Therapy. Edward A. Swabb and Sandor Szabo, Editors. New York, Marcel Dekker, Inc. 1991, pp. 189-215.
(15) Merki H, Witzel L, Hare K et al. Single dose treatment with H2-receptor antagonists: is bedtime administration too late? Gut. 1987;28:451-454.
(16) Yudine S. Etude sur les ulceres gastriques et duodenaux perfores. Journal International Chir. 1939;4:219-338.
(17) Illingworth CFW, Scott LDW. Acute perforated peptic ulcer. Frequency and incidence in the west of Scotland. British Medical Journal. 1944;ii:617-620.
(18) Illingworth CFD, Scott LDW. Acute perforated peptic ulcer. Frequency and incidence in the West of Scotland. British Medical Journal. 1944;ii:655-659.
(19) Jamieson RA. Acute peptic ulcer. Frequency and incidence in the West of Scotland. British Medical Journal. 1955;ii:222-227.
(20) McKay C. Perforated peptic ulcer in the West of Scotland: a survey of 5343 cases during 1954-1963. British Medical Journal. 1966;ii:701-705.
(21) Devitt JE, Taylor GA. Perforated peptic ulcer. Canadian Medical Association Journal. 1967;96:519-523.
(22) Hennessy E. Perforated peptic ulcer: Mortality and morbidity in 603 cases. Australian and New Zealand Journal of Surgery. 1969;38:243-251.
(23) Cohen MM. Perforated peptic ulcer in the Vancouver area: a survey of 852 cases. Canadian Medical Association Journal. 1971;104:201-205.
(24) Svanes C, Sothern RB, Sorbye H. Rhythmic patterns in incidence of peptic ulcer perforation over 5.5 decades in Norway. Chronobiology International. 1998;15:241-264.
(25) Raschka C, Schorr W. Is there seasonal periodicity in the prevalence of Helicobacter pylori? Chronobiology International. 1999, in press.
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