Antidepressants for Functional Esophageal Disorders: Evidence- or Eminence-Based Medicine?
2014; Elsevier BV; Volume: 13; Issue: 2 Linguagem: Inglês
10.1016/j.cgh.2014.09.044
ISSN1542-7714
AutoresCarla Maradey–Romero, Ronnie Fass,
Tópico(s)Gastrointestinal motility and disorders
ResumoSince establishing the first Rome criteria, antidepressants have been the mainstay of treatment for functional esophageal disorders, presumably through their pain-modulatory effect. However, the list of different types of antidepressants that have been proposed to improve symptoms in patients with these disorders has expanded over the years and currently includes tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), trazodone, and serotonin-norepinephrine reuptake inhibitors.1Dickman R. Maradey-Romero C. Fass R. The role of pain modulators in esophageal disorders–no pain no gain.Neurogastroenterol Motil. 2014; 26: 603-610Google Scholar Similarly, the list of esophageal disorders that have been suggested to include a functional component and thus may benefit from antidepressants, also have increased and now include nonerosive reflux disease, refractory gastroesophageal reflux disease, and a hypersensitive esophagus, in addition to the traditional functional esophageal disorders (functional heartburn, functional chest pain of presumed esophageal origin, globus and functional dysphagia).2Hershcovici T. Fass R. Nonerosive reflux disease (NERD) - an update.J Neurogastroenterol Motil. 2010; 16: 8-21Google Scholar, 3Fass R. Functional heartburn: what it is and how to treat it.Gastrointest Endosc Clin N Am. 2009; 19 (v): 23-33Google Scholar The popularity of antidepressants as the first-line treatment for functional esophageal disorders remains high, primarily owing to a lack of specific esophageal pain modulators. Attempts to develop these types of compounds, such as the transient receptor potential vanilloid 1 antagonist, have failed thus far because of a lack of efficacy and significant adverse events.4Krarup A.L. Ny L. Gunnarsson J. et al.Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain.Scand J Gastroenterol. 2013; 48: 274-284Google Scholar, 5Krarup A.L. Ny L. Astrand M. et al.Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain.Aliment Pharmacol Ther. 2011; 33: 1113-1122Google Scholar Other classes of drugs also have been studied and shown to confer an analgesic effect on the esophagus. These drugs include adenosine antagonists, serotonin agonists (5-hydroxytryptamine-4) and antagonists (5-hydroxytryptamine-3), antiepileptics, a somatostatin analog, and pregabalin.6Maradey-Romero C. Fass R. New therapies for non-cardiac chest pain.Curr Gastroenterol Rep. 2014; 16: 390Google Scholar The common thread of all esophageal disorders with a functional component is the presumed presence of esophageal hypersensitivity as an important underlying mechanism for symptoms. Esophageal hypersensitivity is defined as the perception of nonpainful esophageal stimuli as being painful, and painful esophageal stimuli as being more painful.7Knowles C.H. Aziz Q. Visceral hypersensitivity in non-erosive reflux disease.Gut. 2008; 57: 674-683Google Scholar Approximately 80% of patients with unexplained chest pain show lower esophageal sensory thresholds for painful stimuli compared with controls during esophageal sensory testing (ie, esophageal barostat, impedance planimetry).8Rao S.S. Hayek B. Summers R.W. Functional chest pain of esophageal origin: hyperalgesia or motor dysfunction.Am J Gastroenterol. 2001; 96: 2584-2589Google Scholar In addition, esophageal hypersensitivity has been shown in 75% of patients with functional heartburn and in 86% of patients with nonerosive reflux disease.2Hershcovici T. Fass R. Nonerosive reflux disease (NERD) - an update.J Neurogastroenterol Motil. 2010; 16: 8-21Google Scholar, 9Shapiro M. Green C. Bautista J.M. et al.Functional heartburn patients demonstrate traits of functional bowel disorder but lack a uniform increase of chemoreceptor sensitivity to acid.Am J Gastroenterol. 2006; 101: 1084-1091Google Scholar Antidepressants appear to diminish esophageal hypersensitivity through their modulatory effect on central hyperalgesia and to some degree on peripheral hyperalgesia, although other mechanisms of action also have been described.1Dickman R. Maradey-Romero C. Fass R. The role of pain modulators in esophageal disorders–no pain no gain.Neurogastroenterol Motil. 2014; 26: 603-610Google Scholar, 10Sperber A.D. Drossman D.A. Review article: the functional abdominal pain syndrome.Aliment Pharmacol Ther. 2011; 33: 514-524Google Scholar In this issue of Clinical Gastroenterology and Hepatology, Weijenborg et al11Weijenborg P.W. de Schepper H.S. Smout A.J.P.M. et al.Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review.Clin Gastroenterol Hepatol. 2015; 13: 251-259Abstract Full Text Full Text PDF Scopus (63) Google Scholar reported their findings from a systematic review of the literature on the role of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease. As they reported, there are very few well-designed, randomized, controlled trials that have evaluated in rigorous fashion the value of any class of antidepressants in controlling symptoms of patients with functional disorders of the esophagus. Consequently, Weijenborg et al11Weijenborg P.W. de Schepper H.S. Smout A.J.P.M. et al.Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review.Clin Gastroenterol Hepatol. 2015; 13: 251-259Abstract Full Text Full Text PDF Scopus (63) Google Scholar ended up with 15 randomized controlled trials, 1 abstract, and 2 case reports. They concluded that antidepressants (primarily TCAs and SSRIs) essentially can modulate esophageal sensation and improve symptoms in patients with functional chest pain of presumed esophageal origin. There also was limited information to support a beneficial effect of the antidepressants in a subgroup of patients with heartburn. More importantly, Weijenborg et al11Weijenborg P.W. de Schepper H.S. Smout A.J.P.M. et al.Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review.Clin Gastroenterol Hepatol. 2015; 13: 251-259Abstract Full Text Full Text PDF Scopus (63) Google Scholar pointed out that despite the wide use of antidepressants in clinical practice, there is no evidence for their value in most esophageal disorders, including traditional functional esophageal disorders. Thus, it appears that their use is driven primarily by expert opinion as well as a lack of other effective and well-tolerated therapeutic strategies. Table 1 summarizes the potential therapeutic modalities for functional esophageal disorders and esophageal disorders with a functional component.Table 1Antidepressants With the Best Evidence to Support Their Use in a Specific Esophageal Disorder With a Functional ComponentEsophageal disorderMedicationClassDoseFunctional chest painImipramineTCA25–50 mgaEscalating dose.SertralineSSRI50–200 mgaEscalating dose.VenlafaxineSNRI75 mgHypersensitive esophagusCitalopramSSRI20 mgRefractory GERDFluoxetineSSRI20 mgGlobusAmitriptylineTCA25 mgGERD, gastroesophageal reflux disease; SNRI, serotonin-norepinephrin reuptake inhibitors.a Escalating dose. Open table in a new tab GERD, gastroesophageal reflux disease; SNRI, serotonin-norepinephrin reuptake inhibitors. In general, few studies have evaluated the effect of antidepressants or other medications with different pharmacologic mechanisms on esophageal hypersensitivity by determining perception thresholds for pain during esophageal stimulation. Importantly, it is unclear which esophageal stimulation should be used (chemical, mechanical, electric, or thermal) and what stimulus protocol to use while testing the effect of a potential pain modulator.12Fass R. Sensory testing of the esophagus.J Clin Gastroenterol. 2004; 38: 628-641Google Scholar This is compounded by the fact that the rate, duration, or location of esophageal stimulation may alter perception thresholds for pain and, as a result, esophageal sensitivity assessment.12Fass R. Sensory testing of the esophagus.J Clin Gastroenterol. 2004; 38: 628-641Google Scholar Consequently, it is difficult to interpret many of the esophageal stimulation studies and also place them in the proper physiological context. Furthermore, studies evaluating the effect of antidepressants in patients with esophageal disorders are highly heterogeneous, which likely explains the different results reported from these studies. Overall, it is difficult to recruit patients to these trials, especially if the focus is one of the functional esophageal disorders. For example, to recruit patients to a functional heartburn study, it usually is required to show a negative upper endoscopy and pH testing as well as a lack of association between symptoms and acid reflux events.13Galmiche J.P. Clouse R.E. Bálint A. et al.Functional esophageal disorders.Gastroenterology. 2006; 130: 1459-1465Google Scholar In addition, based on the Rome 3 criteria, they have to show a lack of symptomatic response to 2 months of treatment with an antireflux medication.13Galmiche J.P. Clouse R.E. Bálint A. et al.Functional esophageal disorders.Gastroenterology. 2006; 130: 1459-1465Google Scholar These extensive inclusion and exclusion criteria make such a study labor intensive for the investigator and difficult for patients because of the need for multiple invasive tests. Weijenborg et al11Weijenborg P.W. de Schepper H.S. Smout A.J.P.M. et al.Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review.Clin Gastroenterol Hepatol. 2015; 13: 251-259Abstract Full Text Full Text PDF Scopus (63) Google Scholar did not evaluate the studies based on the type of Rome criteria that were used to make the diagnosis of a functional esophageal disorder. Some studies used Rome I criteria, and other studies used Rome II or III criteria for patient selection. The use of different types of Rome criteria in these therapeutic trials also may explain the diverse symptomatic response of patients who receive antidepressant treatment. For example, patients with a hypersensitive esophagus were included in the functional heartburn group based on Rome II criteria for functional esophageal disorders.14Clouse R.E. Richter J.E. Heading R.C. et al.Functional esophageal disorders.Gut. 1999; 45: II31-II36Google Scholar However, based on Rome III criteria these patients were removed from the functional heartburn group and incorporated into the nonerosive reflux disease group.13Galmiche J.P. Clouse R.E. Bálint A. et al.Functional esophageal disorders.Gastroenterology. 2006; 130: 1459-1465Google Scholar Thus, the character of the functional heartburn group has changed profoundly from Rome II to Rome III. Many of the antidepressant therapeutic trials have used escalating doses to a goal that was determined by patient maximal response or the development of serious adverse events.15Hershcovici T. Achem S.R. Jha L.K. et al.Systematic review: the treatment of noncardiac chest pain.Aliment Pharmacol Ther. 2012; 35: 5-14Google Scholar Unfortunately, the escalating-dose protocol was different from one study to another. In addition, in most cases, the escalating-dose protocol was chosen arbitrarily. The main rule in many of the studies that evaluated TCAs and SSRIs was the initial use of a low, non–mood-altering dose of the antidepressant. In clinical practice, adverse events, which are common with antidepressants, especially in the elderly population, are an important limiting factor in further escalating the dose of an antidepressant. If side effects develop, the dose of the antidepressant commonly is reduced or the drug is replaced with a different antidepressant. Another important contributing factor to the diverse clinical responses achieved by TCAs that was not addressed fully by Weijenborg et al11Weijenborg P.W. de Schepper H.S. Smout A.J.P.M. et al.Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review.Clin Gastroenterol Hepatol. 2015; 13: 251-259Abstract Full Text Full Text PDF Scopus (63) Google Scholar was their main receptor affinity.10Sperber A.D. Drossman D.A. Review article: the functional abdominal pain syndrome.Aliment Pharmacol Ther. 2011; 33: 514-524Google Scholar TCAs are a heterogeneous group of medications with different affinity to 4 receptors: histamine 1, norepinephrine, acetylcholine, and serotonin. The different affinity may determine their effectiveness in an individual patient and at the same time the side-effect profile that the patient may experience. Consequently, if one type of TCA does not improve a patient’s symptoms, it is possible that another type with a different receptor affinity profile will be found to be efficacious in the same patient. For example, amitriptyline and imipramine have a high affinity to histamine I receptor, whereas desipramine and nortriptyline have a higher affinity to the norepinephrine receptor. In summary, antidepressants are likely to remain the mainstay of treatment of functional esophageal disorders and esophageal disorders with a functional component despite limited evidence from well-designed clinical trials for their efficacy. Lack of evidence owing to a paucity of clinical trials may not be interpreted as a lack of efficacy of these drugs. In addition, it should provide a modicum of caution and careful consideration of harm versus benefit when using these medications. Patients with functional esophageal disorders or esophageal disorders with a functional component are very common in gastrointestinal practice and represent an area of unmet need. Thus, the study by Weijenborg et al11Weijenborg P.W. de Schepper H.S. Smout A.J.P.M. et al.Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review.Clin Gastroenterol Hepatol. 2015; 13: 251-259Abstract Full Text Full Text PDF Scopus (63) Google Scholar should serve as the impetus for future research into the currently available antidepressants, nonantidepressant pain modulators, such as pregabalin and Gabapentin, and the new esophageal pain modulators for patients with the earlier-mentioned esophageal disorders. Effects of Antidepressants in Patients With Functional Esophageal Disorders or Gastroesophageal Reflux Disease: A Systematic ReviewClinical Gastroenterology and HepatologyVol. 13Issue 2PreviewPatients with functional esophageal disorders present with symptoms of chest pain, heartburn, dysphagia, or globus in the absence of any structural abnormality. Visceral hypersensitivity is a feature of these functional disorders, and might be modulated by antidepressant therapy. We evaluated evidence for the efficacy of antidepressant therapy for symptoms associated with esophageal visceral hypersensitivity in patients with functional esophageal disorders or gastroesophageal reflux disease (GERD). Full-Text PDF
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