Canadian Medical Association Journal 1996; 154: 49-53
Paper reprints of the full text may be obtained from: Dr. Richard H. Hunt, Division of Gastroenterology, McMaster University Medical Centre, 1200 Main St. W, Hamilton ON L8N 3Z5
Abstract
Introduction
Prevalence of dyspepsia
Implications of OTC availability for H2-receptor antagonists
A strategy for management
Conclusion
References
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Introduction
In this era of increasing cost containment in health care, formulary committees and governments in many countries, including Canada,(1) are giving increasing attention to the benefits of converting a variety of prescription medications to over-the-counter (OTC) status. One such class of widely prescribed drugs, the H2-receptor antagonists, are available over the counter in Denmark, the United Kingdom, New Zealand and the United States and are now being considered for OTC status in Canada. In Western countries, fiscal and governmental arguments for switching drugs to OTC status are reinforced by the increasingly popular philosophy that consumers are well educated and are capable of taking more responsibility for their own health care.(2) However, there appears to be some resistance among health care providers to giving OTC status to H2-receptor antagonists. General and specialist physicians as well as pharmacists have expressed the view that these drugs should remain prescription drugs or be available only from "behind the counter." A sample of general practitioners surveyed in the United Kingdom for their opinion on the OTC status of a spectrum of drugs gave least support to the idea of patients initiating self-treatment of dyspepsia with H2-receptor antagonists.(3) Jones(4) commented that this finding may have reflected habits, prejudice and power issues more than clinical practice, although concern about the possibility of masking serious disease with self-medication was an important reservation.
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Prevalence of dyspepsia
Dyspepsia is sufficiently common and distressing to make it an important concern for many patients, physicians and pharmacists. Symptoms of dyspepsia may suggest a spectrum of disease ranging from nonulcer dyspepsia to duodenal or gastric ulcer, gastroesophageal reflux or, more rarely, gastric cancer.(5,6) Nonulcer dyspepsia is roughly 10 times more common than peptic ulcer and has been classified by some authors into reflux-like, ulcer-like, dysmotility-like and mixed types.(7) In the general population roughly 7% suffer from heartburn daily, 13% once a week and 24% at least once a month, although the reported prevalence of esophagitis varies considerably from study to study because of bias in patient selection.(8) Heartburn is usually predictive of reflux with a specificity of about 89% and a sensitivity of about 38%.(9)
Dyspepsia is common in most countries. In a large community-based study in the United Kingdom 38% of 2066 subjects complained of dyspeptic symptoms.(10) A follow-up survey 2 years later found that the overall 6-month prevalence rate remained 38%; 26% of the subjects had experienced dyspepsia in the past, and 36% had never complained of the symptoms described in the questionnaire.(11) The second survey also showed that 74% of the respondents who had been experiencing dyspeptic symptoms 2 years earlier still had symptoms; this was true of both men and women. However, in a study in Denmark one quarter of a sample of patients with dyspepsia had no further symptoms at the end of the study period and two thirds of those who had had frequent symptoms at baseline were experiencing them less frequently.(12) In a Canadian study 38% of 1024 subjects (42% of the women and 34% of the men) complained of mild to moderate acid-related symptoms: a prevalance rate identical to that found in the UK study.(13)
Stress has been considered an important factor in nonulcer dyspepsia, but most data on this subject are vague and difficult to interpret. However, in one study 62 patients with nonulcer dyspepsia were found to be more neurotic, to be less mature in their coping skills and to have less high-quality emotional support than controls.(14)
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Implications of OTC availability
for H2-receptor antagonists
What impact has the conversion of H2-receptor antagonists to OTC status in other countries had with respect to effectiveness and safety? How would switching these drugs to OTC status affect patients and prescribers in Canada?
In Denmark the H2-receptor antagonists cimetidine and ranitidine were transferred to OTC use at full prescription dose more than 5 years ago. This decision was made on the basis of the known low toxicity of these drugs, the relatively low incidence of adverse reactions and the wide experience that had been gained in the use of these drugs in research and clinical settings.(2) In approving OTC status the licensing body requested that the impact on safety be monitored closely. Several research studies were set up to monitor, in particular, the potential for drug or alcohol interactions, the mistreatment of disorders mistaken for dyspepsia and delayed diagnosis of gastric cancer. The packaging for these drugs clearly states that patients should report to their physician if pain persists after 4 weeks of self-treatment. Nothing has arisen from the Danish experience to challenge the view that H2-receptor antagonists are safe and effective in nonprescription use.(2,15,16) However, the switch to OTC status has had no economic impact with respect to either the prescription of other drugs or hospital admissions resulting from ulcer complications.
In Canada it is proposed that the recommended dose for OTC H2-antagonists will be half the recommended prescription dose (to be taken as required to a maximum of two doses per day) and that the packaging will instruct patients to report to their physician if pain persists after 2 weeks of self-treatment. It is reasonable to assume that this will ensure an even wider margin of safety than that achieved in Denmark. The apparent lack of change in drug utilization in Denmark is perhaps disappointing with respect to the hope of shifting more responsibility for primary health care to the consumer in Canada. The lack of effect on hospital admissions for ulcer complications is less surprising, given that little, if any, change was seen in the frequency of ulcer complications after the introduction of H2-receptor antagonists as prescription drugs. This may be a consequence of the increasing use of nonsteroidal anti-inflammatory drugs (NSAIDs) and their more commonly experienced silent complications.(2) But it may also be related to the lack of a medical strategy that gives OTC H2-receptor antagonists an effective place in the overall management of acid-related disorders. Such a strategy should be developed in order to optimize the potential benefits for patients and provincial health ministries of making H2-receptor antagonists available over the counter. But before the use of OTC H2-receptor antagonists can be made more strategic a number of questions must be addressed.
Famotidine, which is the most potent H2-receptor antagonist on a molar basis, was shown in one study(18) to be effective in self-directed treatment in the 10-mg OTC dose for intermittent heartburn and to prevent food- induced symptoms. Antacids, which were used as a control, were also found to be effective. Both treatments were equally well tolerated.
Of most concern, apparently, is the question of whether OTC H2-receptor antagonists might mask symptoms of a more serious disease. This has been a concern since the H2-receptor antagonists first became more widely used by family physicians in the early 1980s. In 1985 the American College of Physicians published guidelines for the initial management of dyspepsia;(32) these recommended that patients under the age of 45 with no alarm symptoms be treated with antacids or an H2-receptor antagonist at the prescription dose for 2 weeks and be referred to a specialist only if they failed to respond. Some gastroenterologists are concerned that this approach might mask symptoms of gastric cancer: these symptoms can respond to antisecretory drugs, and malignant gastric ulcers may partially or completely heal. However, follow-up and case-history studies have not shown an increase in rates of gastric cancer among patients treated with cimetidine.(27,28,33) A case-control study in the United States revealed that the crude odds ratio of gastric cancer among users of cimetidine versus that among nonusers was 2.1 (95% confidence interval [CI] 0.7 to 6.3); the odds ratio among users of antacids versus that among nonusers was similar, at 1.9 (95% CI 1.0 to 3.7). This finding suggests that explanations other than a direct association of cimetidine with carcinoma are likely.(34)
Although gastric cancer is relatively less common in Canada than in Japan and Southeast Asia, there is increasing awareness and some concern about the changing pattern of this disease: a decline in gastric antral neoplasms but an increase in neoplasms involving the cardiac region of the stomach, which may be related to alcohol and tobacco consumption.(35,36) The relation of this increasingly frequent finding to short-segment Barrett's syndrome and gastroesophageal reflux must be clarified in view of the propensity of those who experience heartburn to self-medicate and the likelihood that such patients will be the principal users of OTC H2- receptor antagonists.(37) Gastric cancer is relatively rare among people under age 45 in Western society. Alarm symptoms of weight loss, anemia, anorexia or dysphagia in association with persistent dyspepsia or heartburn should always mandate endoscopy, especially for patients over age 45.
These observations notwithstanding, data from clinical studies suggest that the conversion of H2-receptor antagonists to OTC status is safe. For those concerned about the possibility of a serious disease being missed when patients diagnose themselves and initiate treatment with H2-receptor antagonists, the results of a large endoscopic survey of dyspeptic patients should be reassuring. Endoscopic examination provides an opportunity for accurate assessment of the mucosa of the esophagus, stomach and duodenum in patients who complain of persistent upper gastrointestinal symptoms; it has a high sensitivity and specificity for esophagitis or esophageal cancer, duodenal or gastric ulcer and gastric cancer. In a Norwegian study endoscopy was performed in almost the whole population of one small town.(38) Gastric erosive changes were found in 35% of subjects with dyspepsia, as compared with 38% of controls, and were associated positively with duodenitis and smoking; however, no gastric cancer was found.
What about symptoms of other lesions that might be masked? A study involving 562 people with dyspepsia who medicated themselves with OTC famotidine included endoscopic and esophageal motility studies. At baseline, 40% had grade II to IV esophagitis, 4% had duodenal ulcers, and 2% had gastric ulcers. No cases of gastric cancer were found.(39) Most of the lesions healed during self-directed treatment with famotidine (10 mg), antacid or placebo, and no complications were encountered. These data are very reassuring and are supported by the extensive experience gained from numerous duodenal ulcer trials in which patients assigned treatment with a placebo had no serious complications and fared no worse than those on active treatment.(40)
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A strategy for management
Who will benefit from the switch of H2-receptor antagonists to OTC use? What place will these drugs take in the management of acid-related disorders? Will prescribing patterns change? Consumers who purchase OTC H2-receptor antagonists may include people with dyspepsia who never consult their primary care physician. They may change from OTC antacids and achieve as good or greater relief with longer effect and perhaps at less cost. For those who do consult their physicians OTC H2-receptor antagonists will offer greater convenience and the opportunity to take more control of the treatment of their symptoms. This applies particularly to patients with reflux-like dyspepsia. However, to maximize the benefit to consumers and providers, OTC H2-receptor antagonists must be seen as a first-line treatment for mild and infrequent heartburn and dyspepsia within an overall strategy for the treatment of acid-
related disorders.
Because the incidence of gastric cancer remains relatively low in Canada, the guidelines for the initial management of dyspepsia published by the American College of Physicians(32) should still be considered appro- priate in primary care. Gastroenterologists should continue to feel comfortable with this approach, albeit with the lower OTC dose of H2-receptor antagonists. However, it is not clear whether family physicians will, rather than initiating a full-dose prescription, take the logical step of suggesting that patients purchase an OTC H2- receptor antagonist for intermittent mild dyspepsia or heartburn.
Pharmacists can advise patients with mild intermittent symptoms to take an OTC H2-receptor antagonist for up to 2 weeks before reporting to their primary care physician, taking care to emphasize the importance of seeking a consultation if symptoms persist. For patients who do not respond to the OTC dose, family physicians will have the choice, after giving advice on lifestyle changes that may be of benefit, of prescribing a full dose of the H2-receptor antagonist or a proton-pump inhibitor. It will be important to assess the impact on the outcomes of these decisions and their economic implications in the postmarketing period.
It is also important to consider the possible involvement of Helicobacter pylori; patients with duodenal ulcer or gastric ulcer unrelated to NSAID use can be cured by successful treatment of this infection. In patients with established symptoms of gastroesophageal reflux the decision to choose acid-suppression treatment alone is appropriate and straightforward and may require high and frequent doses of an H2-receptor antagonist or, more conveniently, a single dose of a proton-pump inhibitor. If symptoms suggest peptic ulcer, endoscopy should be undertaken to confirm the presence of H. pylori infection. Endoscopy may also be valuable at this stage in patients with more frequent or severe symptoms of reflux to determine the severity of esophagitis and whether Barrett's syndrome is present. For the remaining patients (who are probably the majority) careful studies of the role of H. pylori in dyspepsia are urgently needed.
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Conclusion
The switch of H2-receptor antagonists to OTC status is part of a rapidly evolving approach to acid-related disorders. On the basis of experience in several other countries and our knowledge of the H2-receptor antagonists in general, I believe that an OTC status for these drugs is appropriate. However, if a switch to OTC status is made, physicians will need to consider carefully the management and education of patients with heartburn and dyspepsia. Making H2-receptor antagonists available over the counter offers patients the opportunity to assume more responsibility for their own symptoms, pharmacists a greater role in advising and educating consumers, and governments an opportunity for significant savings.