Nocturnal reflux and sleep disturbances: an overlooked link in the past.

Commentary Gastro-oesophageal reflux disease (GORD) is highly prevalent in western countries. The main clinical manifestations are represented by heartburn and regurgitation and they are commonly used for the diagnosis of GORD, although their accuracy is far from optimal (1). The above symptoms can occur during the daytime and also throughout the nocturnal period. In the past, the progressively widespread use of 24-hour oesophageal pH-metry showed that the majority of reflux events belong to the post-prandial periods, while they are much less frequent during the nighttime (2). This temporal distribution of abnormal reflux episodes provided the rationale to explain, at least in part, the benefit of proton pump inhibitors (PPIs) in patients with GORD. In fact, these drugs are more effective during the daytime, when proton pumps are activated by fractioned meals, than through the nighttime, when their main pharmacological target does not work because of sleep (3). Despite the above findings, in the last decade we have witnessed a mounting evidence of the role of nighttime GORD in provoking a decreased quality of life, a variety of sleep disorders and diminished work performances (4). Several epidemiological surveys have confirmed that nocturnal reflux symptoms, in particular heartburn and regurgitation, can be reported by 2 out of 3 patients with GORD (5) and the relationship between GORD and sleep disorders has been recently established by many studies which have clearly demonstrated that 47%-57% of the GORD patients and approximately 25% of the US adult general population report having heartburn that awakens them from sleep during the night (6,7). Of the GORD patients, 63% report that they are unable to sleep well, 42% are unable to sleep during a full night, 39% have to take naps during the day and 34% have to sleep in a seated position because of nighttime heartburn (7). It has also been shown that sleep deprivation per se can adversely influence GORD, in that the inability to have a complete rest during the night is a potential mechanism for increasing the perception of symptoms in patients with GORD (8). Another important issue is the still poorly understood role of nocturnal reflux in determining extra-oesophageal and particularly respiratory symptoms because of the well-known longer-lasting duration and the slower clearing of supine refluxes compared with the daytime ones (9). Finally, the use of impedance-pH monitoring has shown that nocturnal weakly acidic reflux is as common as acid reflux in GORD patients (10) and a recent study has also proposed that this kind of nighttime reflux can sensitize oesophageal mucosa to the point to favor the occurrence of diurnal symptoms, such as sour or bitter taste in the mouth (11). The observational study performed in this field by French researchers (12) represents a further confirmation of the relevance of nocturnal reflux symptoms in the genesis of sleep disturbances leading to a reduced quality of life and work productivity on the day after. The strengths of the study consist in the high number of involved primary care physicians and the great sample of patients with nighttime GORD recruited by them. Nocturnal reflux symptoms were reported by 63,9% of the patients they analyzed and regular sleep disorders by 61,7% of them. These rates are quite similar to those already registered in previous epidemiological studies on this matter in western countries (4-7). In the study from Cadiot et al, multivariate statistical analysis demonstrated that nocturnal GORD symptoms, the age over 50 years and the use of hypnotic drugs were independent predictors of sleep disturbances. The last factor is of particular interest, because many doctors and patients ignore that drugs such as benzodiazepines, which are frequently taken by elderly people chronically and life-long, are associated with a slowing of gastric emptying and a reduction of lower oesophageal sphincter basal pressure, two of the main mechanisms favoring reflux events (8). The French Authors also showed that the control of GORD by administration of PPI therapy provoked a substantial decrease of nocturnal symptoms from 98,8% to 39,3% in patients reporting at least one nocturnal GORD symptom during the previous week and this was associated with the considerable improvement of other features pertaining to sleep disturbances. This is an important outcome of medical therapy of nighttime GORD, although the persistence of symptoms in about 40% of patients treated for 1 month with PPI therapy is a confirmation of the difficulty in blocking completely nocturnal reflux by the most powerful anti-secretory drugs at present used to cure GORD. In fact, they are more effective during the daytime than the nighttime as result of the activation of proton pumps by meals, unless we give them as double fractioned daily doses (3) or before dinner instead of before breakfast (13). Unfortunately, however, there is no mention of the dosing of PPIs, which were taken by almost all patients evaluated by Cadiot et al in their study. It must be acknowledged that the French investigation has other important limitations. Firstly, it has not been described whether the questionnaire the Authors used to collect symptom data was previously validated or was one of those already adopted for similar studies in the same field. It is well known that many of the questionnaires aimed at collecting subjective variables, such as symptoms, are questionable (14) and this is particularly true when changes of symptoms over time are monitored, as it was done before and one month after drug intake in patients with nocturnal symptoms who were recruited by the physicians coordinated by Cadiot et al. Secondly, PPI therapy was not only poorly defined in terms of dosage and timing of intake, but it is also evident that it was administered in uncontrolled manner. This represents a relevant bias in the interpretation of the results they obtained, even though the Authors themselves recognize that it would have been very difficult to organize a randomized, controlled trial in relation of the complex setting of the study. Thirdly, nocturnal cough cannot be considered with certainty as a reflux symptom, because it can be due to many causes and therefore needs to be substantiated by the use of more objective measurements. On the other hand, also typical reflux symptoms were defined in the study as GORD–related exclusively on the basis of patients’ perception and a more sound way to establish this relationship was lacking. Once again, this limitation is clearly due to large scale observational studies, which do not allow us to use more rigorous methods to show a firm link between symptoms and reflux events. In conclusion, this French research adds new fuel to the clinical relevance of an overlooked feature of reflux disease in the past, that is the important role of nocturnal reflux in inducing sleep disturbances and reduced work productivity on the day after. It is likely that we have to address more attention to nighttime GORD and to find additional drugs which are able to control it better than PPIs, which represent the first choice anti-reflux therapy today available. However, if the relationship between nocturnal reflux and sleep disturbances is established with great accuracy on the basis of instrumental methods, it is likely that patients with poor response to medical treatment can benefit from surgical fundoplication as further therapeutic option, even though data on the impact of this intervention on the improvement of sleep parameters related to nighttime reflux are very limited.