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Esophageal motility disorders and their response to calcium channel antagonists
EDITORIALS
July 1987
4. Kvietys PR, Miller T, Granger DN. Intrinsic control of colonic blood flow and oxygenation. Am J Physiol1980;238:G476-64. 5. Holm-Rutili L, Perry MA, Granger DN. Autoregulation of gastric blood flow and oxygen uptake. Am J Physiol 1981; 241:G143-9.
6. Kvietys PR, McLendon JM, Bulkley GB, Perry MA, Granger DN. Pancreatic circulation: intrinsic regulation. Am J Physiol 1982;242:G596-602.
7. Lautt WW. Hepatic presinusoidal sphincters affected by altered arterial pressure and flow, venous pressure, and nerve stimulation. Microvasc Res 1976;15:309-17. a. Richardson PDI, Withrington RG. Pressure-flow relationships and effects of noradrenaline and isoprenaline on the hepatic arterial and portal venous vascular beds of the dog. J Physiol (Lond) 1978;282:451-70. 9. Kiel JW, Riedel GL, Shepherd AP. Autoregulation of canine gastric mucosal blood flow. Gastroenterology 1987;93:12-20. 10. Lundgren 0, Svanvik J. Mucosal hemodynamics in the small
201
intestine of the cat during reduced perfusion pressure. Acta Physiol Stand 1973;88:551-63. 11. Granger DN, Kvietys PR, Mailman D, Richardson PDI. Intrinsic regulation of functional blood flow and water absorption in canine colon. J Physiol 1980;307:443-51. 12. Perry MA, Murphree D, Granger DN. Oxygen uptake as a determinant of gastric blood flow autoregulation. Dig Dis Sci 1982;27:675-9. 13. Davis MJ, Gore RW. Capillary
pressures in rat intestinal muscle and mucosal villi during venous pressure elevation. Am J Physiol 1985;249:H174-67. 14. Kiel JW, Riedel GL, DiResta GR, Shepherd AP. Gastric mucosal blood flow measured by laser-Doppler velocimetry. Am J Physiol 1985;249:G539-45. Address requests for reprints: Dr. Karen D. Crissinger, Department of Physiology and Biophysics, Louisiana State University Medical Center, P.O. Box 33932, Shreveport, Louisiana 71130. 0 1987 by the American Gastroenterological Association
Esophageal Motility Disorders and Their Response to Calcium Channel Antagonists The Sphinx
Revisited
The goals of clinical research in the esophageal motility disorders are direct and simple-identify a motility event that correlates with clinical symptoms and then define a treatment that alters these motor events thus abolishing the patient’s symptoms. Despite these clearly defined goals, the progress in identifying esophageal motility disorders and their therapy has been slow. In this editorial, I would like to examine the general guidelines used to define esophageal motility disorders and to review the current status of one type of drug, the calcium channel antagonists used to treat these conditions. In 1971,the late Franz Ingelfinger wrote an editorial in which he likened the lower esophageal sphincter (LES) to the enigmatic sphinx (1). It is ironic that now almost two decades later, there remain so many sphinxlike qualities to the clinical derangements in esophageal function. Despite extensive study of the basic physiology of esophageal muscle, neural mechanisms, receptor properties, and membrane characteristics, the simple question of the relationship between esophageal symptoms and measured esophageal motor events remains unresolved. The reason why studies on the esophagus continue to elude these simple answers may be explicable. Esophageal clinical motility research has evolved into a pattern that has limited its progression. Methodology has varied greatly over the years, each new method giving different results and each method being accepted as the “gold standard.” Single manometric events obtained by a new method have been
given the title and recognition of a bona fide clinical disorder. Many of these proposed disorders have received popular names, further promoting their acceptance. The fallacy of this type of investigative approach is obvious. First, not all new methods are valid nor should they replace other methods of clinical evaluation. Second, not all events measured by a new method represent legitimate new disease entities. It is understandable that the clinical investigator is anxious to resolve the apparently simple functional disorders of the esophagus, thus allowing a more rapid acceptance of new methodology and results. The results of a given method of measuring motility, however, vary greatly with minimal alterations such as rate of fluid perfusion, compliance of the catheter, rapidity of the pull-through technique, location of the recording orifice, and length or geometry of the orifice. To obviate these problems in recording techniques, we must provide more meaningful criteria for the diagnosis of esophageal motility disorders. Otherwise, the future will provide an endless proliferation of confusing new “diseases” such as the “hypertensive LES,” the “hypercontracting LES,” the “hypotensive LES,” “dyschalasia,” “nutcracker LES relaxation.” esophagus,” and “inappropriate Are these diseases, manometric events, or artifacts of a new recording technique? One clinical approach to resolving the issue of whether a single manometric event is the cause of symptoms is to alter this esophageal abnormality in an appropriate direction. In the current issue of
202
EDITORIALS
GASTROENTEROLOGY, Dr. Richter and colleagues have tested this approach (2). The report describes a double-blind, controlled trial using the calcium channel antagonist nifedipine to alter noncardiac chest pain in patients with the nutcracker esophagus. The trial conditions are ideal to test the hypothesis of whether high-amplitude peristaltic waves (i.e., the nutcracker effect) are an esophageal manometric event that cause noncardiac chest pain in humans. The drug to be tested is a potent calcium channel antagonist approved for usage in humans for the control of angina pectoris, hypertension, and other cardiovascular diseases. The antagonists are safe in humans and may be useful in treating gastrointestinal disease if efficacy is proven. They act by limiting the passage of calcium into the muscle cell by inhibiting voltage-dependent calcium channel pathways. The antagonists reduce muscle contraction in response to a wide variety of neurohumoral stimuli that act through these voltage-dependent calcium channels (3). In humans and animals, the antagonists reduce the amplitude of esophageal contractions as well as the tonic pressure within the physiologic LES (3,4). The antagonists reduce the force of contraction only. The drugs do not restore normal peristaltic function in esophageal disorders nor do they enhance the magnitude of lower esophageal relaxation. The manometric derangement in the nutcracker esophagus thus seems ideal to test an agent that reduces contractile force, the only change in the proposed disorder. The trial result is of interest. Nifedipine, as predicted from earlier studies, does indeed reduce the amplitude of the peristaltic event but does not alter the frequency or magnitude of the chest pain (2,4). These findings suggest two important conclusions. First, the hypothesis that high-amplitude esophageal peristaltic waves cause chest pain is not valid. Second, the wide usage of calcium channel antagonists for the treatment of esophageal motor disorders may not be justified. The promising role of calcium channel antagonist therapy for gastrointestinal motor disorders should not be abandoned based on a single study in a select patient population. The drugs alter force of gut muscle contraction in a convincing fashion. Studies should be continued with other patient groups, using different antagonists and even different dose regimens. The trial by Dr. Richter et al. enrolled patients with only high-amplitude contractions. Would the drug be more effective in patients with more classic diffuse esophageal spasm with repetitive nonperistaltic waves? The usage of calcium channel antagonist therapy in achalasia may be more promising (5). The antagonists effectively reduce LES pressure and enhance esophageal emptying.
GASTROENTEROLOGY
Vol. 93, No. 1
Symptoms are improved, although studies remain limited. Effective oral or sublingual therapy of an antagonist may be used in patients with achalasia where more definitive dilation or surgical therapy may be difficult. The more definitive therapies are preferable in the long-term care of the patient. The overall clinical value of calcium channel antagonist therapy in esophageal disease is unclear at present. The expected benefit in patients with esophageal motor disorders with chest pain is highly questionable at this time. The usage in achalasia is more promising but will most likely be beneficial only for short-term management. Now, I would like to consider the question of whether the nutcracker esophagus is a true clinical disorder or simply a manometric finding. I would like to propose certain general criteria that might be used to test the validity of attributing symptoms of disease to alterations in manometric events. First, the motility event must be a major alteration in esophageal physiology, not a minor variation in function. Second, the motility change must be associated clinically with a symptom of esophageal disease and must be in appropriate temporal relationship with it. Third, the abnormality in esophageal function must be demonstrated or confirmed with some other independent measurement. Fourth, the symptoms or signs of esophageal abnormality must be improved if the disordered esophageal event is corrected. In essence, the esophageal motility changes must be of consequence, the methodology valid, and the symptoms responsive to changes in the motor event. Using these criteria, let us evaluate the nutcracker esophagus. The presence of high-amplitude contractions, per se, has not been shown to cause a major disruption in esophageal function nor has an abnormality in esophageal function been confirmed by some other methodology. The measurement of esophageal pressure using the low-compliance infusion system is valid in that it gives a frequency response that allows true recording of rapid transients in intraluminal pressure. The pressure value is valid but its meaning is unclear. High-amplitude esophageal contractions may be found more frequently in patients with noncardiac chest pain (6,7). However, the high-amplitude waves have not been related temporally to pain. They have not been shown to impair esophageal function, nor have they been an accurate predictor of chest pain elicited by pharmacologic provocative tests (8). Lastly, chest pain, now the hallmark of the disease, did not correlate with reduction in the amplitude of the esophageal contractions. Pain did decrease with time and patient reassurance (2). Therefore, at best, we have only a weak epidemiologic relationship
EDITORIALS
July 1987
between the presence of noncardiac chest pain and high-amplitude esophageal peristaltic waves. These findings indicate that the relationship of chest pain and high-amplitude esophageal peristaltic waves is not a causal one. The authors, themselves, have come to a similar conclusion, thus suggesting the end to yet another colorful esophageal disease. But before closing the chapter, we must consider the suggestion made by the authors that highamplitude esophageal contractions may be an unassociated marker of this pain syndrome. This indeed may be the case, but interestingly, it may not be a marker of esophageal disease or esophageal-related pain. Patients with hyperresponsive coronary arteries (i.e., coronary artery spasm or Prinzmetal’s angina) may also have high-amplitude esophageal peristalsis (Epstein S, Chief of Cardiology, NIH, personal communication). The pain may be due to cardiac ischemia but may be within the small vessels and thus not seen during coronary arteriography, or by use of provocative coronary studies. This possible relationship between small vessel coronary artery disease and esophageal findings must be further studied. The sphinxlike qualities of the clinical derangements of the esophagus and its sphincter persist. It is now apparent that the further definition of esophageal motor disorders and their relationship to clinical symptoms will remain a difficult problem. Simple alterations in a manometric pattern do not constitute a disease entity. Improved methods of assessing gastrointestinal smooth muscle function and the relationship to symptoms must be developed. Most importantly, the exclusion of functional derangements in other organ systems must be enhanced before accepting the relationship between a symptom and gastrointestinal dysfunction.
203
Finally, the ultimate proof of the relationship between an esophageal motor disorder and a patient’s symptoms may depend on clinical trials using potent drugs, such as the calcium channel antagonists, to determine if the alteration in the motor event produces the desired clinical response. SIDNEY COHEN, M.D.
Temple University School of Medicine Philadelphia, Pennsylvania References 1. Ingelfinger
2.
3.
4.
5.
6. 7.
8.
FJ. The sphincter that is a sphinx. N Engl J Med 1971;284:1095-6. Richter J, Dalton C, Bradley L, Caste11 D. Oral nifedipine in the treatment of noncardiac chest pain in patients with the nutcracker esophagus. Gastroenterology 1987;93:21-8. Goyal R, Rattan S. Effects of sodium nitroprusside and verapamil on lower esophageal sphincter. Am J Physiol 1980;238:40-4. Richter J, Dalton C, Buice R, Caste11 D. Nifedipine: a potent inhibitor of contractions in the body of the human esophagus. Gastroenterology 1985;89:549-54. Bartolloti M, Labo G. Clinical and manometric effects of nifedipine in patients with esophageal achalasia. Gastroenterology 1981;80:39%44. Brand D, Martin D, Pope C. Esophageal manometrics in patients with angina-like chest pain. Dig Dis Sci 1977;22:300-4. Benjamin S, Gerhardt D, Caste11 D. High amplitude peristaltic contractions associated with chest pain and/or dysphagia. Gastroenterology 1979;77:478-83. Lee CA, Reynolds JC, Ouyang A, Baker L, Cohen S. Esophageal chest pain: the value of high-dose provocative testing with edrophonium chloride in patients with normal esophageal manometrics. Dig Dis Sci (in press)
Address requests for reprints to: Sidney Cohen, M.D., Chairman, Department of Internal Medicine, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, Pennsylvania 19140 % 1987 by the American Gastroenterological Association
July 1987
4. Kvietys PR, Miller T, Granger DN. Intrinsic control of colonic blood flow and oxygenation. Am J Physiol1980;238:G476-64. 5. Holm-Rutili L, Perry MA, Granger DN. Autoregulation of gastric blood flow and oxygen uptake. Am J Physiol 1981; 241:G143-9.
6. Kvietys PR, McLendon JM, Bulkley GB, Perry MA, Granger DN. Pancreatic circulation: intrinsic regulation. Am J Physiol 1982;242:G596-602.
7. Lautt WW. Hepatic presinusoidal sphincters affected by altered arterial pressure and flow, venous pressure, and nerve stimulation. Microvasc Res 1976;15:309-17. a. Richardson PDI, Withrington RG. Pressure-flow relationships and effects of noradrenaline and isoprenaline on the hepatic arterial and portal venous vascular beds of the dog. J Physiol (Lond) 1978;282:451-70. 9. Kiel JW, Riedel GL, Shepherd AP. Autoregulation of canine gastric mucosal blood flow. Gastroenterology 1987;93:12-20. 10. Lundgren 0, Svanvik J. Mucosal hemodynamics in the small
201
intestine of the cat during reduced perfusion pressure. Acta Physiol Stand 1973;88:551-63. 11. Granger DN, Kvietys PR, Mailman D, Richardson PDI. Intrinsic regulation of functional blood flow and water absorption in canine colon. J Physiol 1980;307:443-51. 12. Perry MA, Murphree D, Granger DN. Oxygen uptake as a determinant of gastric blood flow autoregulation. Dig Dis Sci 1982;27:675-9. 13. Davis MJ, Gore RW. Capillary
pressures in rat intestinal muscle and mucosal villi during venous pressure elevation. Am J Physiol 1985;249:H174-67. 14. Kiel JW, Riedel GL, DiResta GR, Shepherd AP. Gastric mucosal blood flow measured by laser-Doppler velocimetry. Am J Physiol 1985;249:G539-45. Address requests for reprints: Dr. Karen D. Crissinger, Department of Physiology and Biophysics, Louisiana State University Medical Center, P.O. Box 33932, Shreveport, Louisiana 71130. 0 1987 by the American Gastroenterological Association
Esophageal Motility Disorders and Their Response to Calcium Channel Antagonists The Sphinx
Revisited
The goals of clinical research in the esophageal motility disorders are direct and simple-identify a motility event that correlates with clinical symptoms and then define a treatment that alters these motor events thus abolishing the patient’s symptoms. Despite these clearly defined goals, the progress in identifying esophageal motility disorders and their therapy has been slow. In this editorial, I would like to examine the general guidelines used to define esophageal motility disorders and to review the current status of one type of drug, the calcium channel antagonists used to treat these conditions. In 1971,the late Franz Ingelfinger wrote an editorial in which he likened the lower esophageal sphincter (LES) to the enigmatic sphinx (1). It is ironic that now almost two decades later, there remain so many sphinxlike qualities to the clinical derangements in esophageal function. Despite extensive study of the basic physiology of esophageal muscle, neural mechanisms, receptor properties, and membrane characteristics, the simple question of the relationship between esophageal symptoms and measured esophageal motor events remains unresolved. The reason why studies on the esophagus continue to elude these simple answers may be explicable. Esophageal clinical motility research has evolved into a pattern that has limited its progression. Methodology has varied greatly over the years, each new method giving different results and each method being accepted as the “gold standard.” Single manometric events obtained by a new method have been
given the title and recognition of a bona fide clinical disorder. Many of these proposed disorders have received popular names, further promoting their acceptance. The fallacy of this type of investigative approach is obvious. First, not all new methods are valid nor should they replace other methods of clinical evaluation. Second, not all events measured by a new method represent legitimate new disease entities. It is understandable that the clinical investigator is anxious to resolve the apparently simple functional disorders of the esophagus, thus allowing a more rapid acceptance of new methodology and results. The results of a given method of measuring motility, however, vary greatly with minimal alterations such as rate of fluid perfusion, compliance of the catheter, rapidity of the pull-through technique, location of the recording orifice, and length or geometry of the orifice. To obviate these problems in recording techniques, we must provide more meaningful criteria for the diagnosis of esophageal motility disorders. Otherwise, the future will provide an endless proliferation of confusing new “diseases” such as the “hypertensive LES,” the “hypercontracting LES,” the “hypotensive LES,” “dyschalasia,” “nutcracker LES relaxation.” esophagus,” and “inappropriate Are these diseases, manometric events, or artifacts of a new recording technique? One clinical approach to resolving the issue of whether a single manometric event is the cause of symptoms is to alter this esophageal abnormality in an appropriate direction. In the current issue of
202
EDITORIALS
GASTROENTEROLOGY, Dr. Richter and colleagues have tested this approach (2). The report describes a double-blind, controlled trial using the calcium channel antagonist nifedipine to alter noncardiac chest pain in patients with the nutcracker esophagus. The trial conditions are ideal to test the hypothesis of whether high-amplitude peristaltic waves (i.e., the nutcracker effect) are an esophageal manometric event that cause noncardiac chest pain in humans. The drug to be tested is a potent calcium channel antagonist approved for usage in humans for the control of angina pectoris, hypertension, and other cardiovascular diseases. The antagonists are safe in humans and may be useful in treating gastrointestinal disease if efficacy is proven. They act by limiting the passage of calcium into the muscle cell by inhibiting voltage-dependent calcium channel pathways. The antagonists reduce muscle contraction in response to a wide variety of neurohumoral stimuli that act through these voltage-dependent calcium channels (3). In humans and animals, the antagonists reduce the amplitude of esophageal contractions as well as the tonic pressure within the physiologic LES (3,4). The antagonists reduce the force of contraction only. The drugs do not restore normal peristaltic function in esophageal disorders nor do they enhance the magnitude of lower esophageal relaxation. The manometric derangement in the nutcracker esophagus thus seems ideal to test an agent that reduces contractile force, the only change in the proposed disorder. The trial result is of interest. Nifedipine, as predicted from earlier studies, does indeed reduce the amplitude of the peristaltic event but does not alter the frequency or magnitude of the chest pain (2,4). These findings suggest two important conclusions. First, the hypothesis that high-amplitude esophageal peristaltic waves cause chest pain is not valid. Second, the wide usage of calcium channel antagonists for the treatment of esophageal motor disorders may not be justified. The promising role of calcium channel antagonist therapy for gastrointestinal motor disorders should not be abandoned based on a single study in a select patient population. The drugs alter force of gut muscle contraction in a convincing fashion. Studies should be continued with other patient groups, using different antagonists and even different dose regimens. The trial by Dr. Richter et al. enrolled patients with only high-amplitude contractions. Would the drug be more effective in patients with more classic diffuse esophageal spasm with repetitive nonperistaltic waves? The usage of calcium channel antagonist therapy in achalasia may be more promising (5). The antagonists effectively reduce LES pressure and enhance esophageal emptying.
GASTROENTEROLOGY
Vol. 93, No. 1
Symptoms are improved, although studies remain limited. Effective oral or sublingual therapy of an antagonist may be used in patients with achalasia where more definitive dilation or surgical therapy may be difficult. The more definitive therapies are preferable in the long-term care of the patient. The overall clinical value of calcium channel antagonist therapy in esophageal disease is unclear at present. The expected benefit in patients with esophageal motor disorders with chest pain is highly questionable at this time. The usage in achalasia is more promising but will most likely be beneficial only for short-term management. Now, I would like to consider the question of whether the nutcracker esophagus is a true clinical disorder or simply a manometric finding. I would like to propose certain general criteria that might be used to test the validity of attributing symptoms of disease to alterations in manometric events. First, the motility event must be a major alteration in esophageal physiology, not a minor variation in function. Second, the motility change must be associated clinically with a symptom of esophageal disease and must be in appropriate temporal relationship with it. Third, the abnormality in esophageal function must be demonstrated or confirmed with some other independent measurement. Fourth, the symptoms or signs of esophageal abnormality must be improved if the disordered esophageal event is corrected. In essence, the esophageal motility changes must be of consequence, the methodology valid, and the symptoms responsive to changes in the motor event. Using these criteria, let us evaluate the nutcracker esophagus. The presence of high-amplitude contractions, per se, has not been shown to cause a major disruption in esophageal function nor has an abnormality in esophageal function been confirmed by some other methodology. The measurement of esophageal pressure using the low-compliance infusion system is valid in that it gives a frequency response that allows true recording of rapid transients in intraluminal pressure. The pressure value is valid but its meaning is unclear. High-amplitude esophageal contractions may be found more frequently in patients with noncardiac chest pain (6,7). However, the high-amplitude waves have not been related temporally to pain. They have not been shown to impair esophageal function, nor have they been an accurate predictor of chest pain elicited by pharmacologic provocative tests (8). Lastly, chest pain, now the hallmark of the disease, did not correlate with reduction in the amplitude of the esophageal contractions. Pain did decrease with time and patient reassurance (2). Therefore, at best, we have only a weak epidemiologic relationship
EDITORIALS
July 1987
between the presence of noncardiac chest pain and high-amplitude esophageal peristaltic waves. These findings indicate that the relationship of chest pain and high-amplitude esophageal peristaltic waves is not a causal one. The authors, themselves, have come to a similar conclusion, thus suggesting the end to yet another colorful esophageal disease. But before closing the chapter, we must consider the suggestion made by the authors that highamplitude esophageal contractions may be an unassociated marker of this pain syndrome. This indeed may be the case, but interestingly, it may not be a marker of esophageal disease or esophageal-related pain. Patients with hyperresponsive coronary arteries (i.e., coronary artery spasm or Prinzmetal’s angina) may also have high-amplitude esophageal peristalsis (Epstein S, Chief of Cardiology, NIH, personal communication). The pain may be due to cardiac ischemia but may be within the small vessels and thus not seen during coronary arteriography, or by use of provocative coronary studies. This possible relationship between small vessel coronary artery disease and esophageal findings must be further studied. The sphinxlike qualities of the clinical derangements of the esophagus and its sphincter persist. It is now apparent that the further definition of esophageal motor disorders and their relationship to clinical symptoms will remain a difficult problem. Simple alterations in a manometric pattern do not constitute a disease entity. Improved methods of assessing gastrointestinal smooth muscle function and the relationship to symptoms must be developed. Most importantly, the exclusion of functional derangements in other organ systems must be enhanced before accepting the relationship between a symptom and gastrointestinal dysfunction.
203
Finally, the ultimate proof of the relationship between an esophageal motor disorder and a patient’s symptoms may depend on clinical trials using potent drugs, such as the calcium channel antagonists, to determine if the alteration in the motor event produces the desired clinical response. SIDNEY COHEN, M.D.
Temple University School of Medicine Philadelphia, Pennsylvania References 1. Ingelfinger
2.
3.
4.
5.
6. 7.
8.
FJ. The sphincter that is a sphinx. N Engl J Med 1971;284:1095-6. Richter J, Dalton C, Bradley L, Caste11 D. Oral nifedipine in the treatment of noncardiac chest pain in patients with the nutcracker esophagus. Gastroenterology 1987;93:21-8. Goyal R, Rattan S. Effects of sodium nitroprusside and verapamil on lower esophageal sphincter. Am J Physiol 1980;238:40-4. Richter J, Dalton C, Buice R, Caste11 D. Nifedipine: a potent inhibitor of contractions in the body of the human esophagus. Gastroenterology 1985;89:549-54. Bartolloti M, Labo G. Clinical and manometric effects of nifedipine in patients with esophageal achalasia. Gastroenterology 1981;80:39%44. Brand D, Martin D, Pope C. Esophageal manometrics in patients with angina-like chest pain. Dig Dis Sci 1977;22:300-4. Benjamin S, Gerhardt D, Caste11 D. High amplitude peristaltic contractions associated with chest pain and/or dysphagia. Gastroenterology 1979;77:478-83. Lee CA, Reynolds JC, Ouyang A, Baker L, Cohen S. Esophageal chest pain: the value of high-dose provocative testing with edrophonium chloride in patients with normal esophageal manometrics. Dig Dis Sci (in press)
Address requests for reprints to: Sidney Cohen, M.D., Chairman, Department of Internal Medicine, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, Pennsylvania 19140 % 1987 by the American Gastroenterological Association