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8 Therapeutic advances in oesophageal motility disorders
8
Therapeutic advances in oesophageal motility disorders MARTIN WILHELM THOMAS
WIENBECK BERGES FRIELING
Oesophageal motility disorder is the common term for a heterogeneous group of neuromuscular disturbances which may cause a variety of clinical symptoms. Their incidence is unknown. Epidemiological studies suggest that achalasia occurs in about 1 in 200 000 persons per annum (Mayberry and Atkinson, 1985). The incidence of other oesophageal motility disorders may be higher than that of achalasia (Benjamin and Castell, 1983). Thus, these disorders are not rare. Since their symptoms are frequently misinterpreted and since in many cases therapy is delayed or inefficient, they pose quite significant diagnostic and therapeutic problems. It is, therefore, worthwhile to review current therapy of primary motor disorders of the oesophagus.
PRIMARY
OESOPHAGEAL
MOTILITY
DISORDERS
Achalasia Achalasia is characterized by incomplete or missing relaxations of the lower oesophageal sphincter after swallowing, and aperistalsis in the body of the oesophagus. Major symptoms are dysphagia, regurgitation, pain and bronchopulmonary aspiration. Pain may become the prominent symptom in vigorous achalasia. Treatment is aimed at reducing the tension of the lower oesophageal sphincter in order to facilitate transit into the stomach. But a complete loss of the sphincter action should be avoided, otherwise reflux oesophagitis may become a problem, and even Barrett’s oesophagus may develop. Diffuse oesophageal spasm In classical oesophageal spasm the oesophagus exhibits aperistaltic contractions of high amplitude and prolonged duration, but relaxation of the lower Baillihre’s
Clinical
Gastroenterology
- Vol.
1, No.
4, October
1987
857
858
M. WIENBECK,
W.
BERGES
AND
T. FRIELING
oesophageal sphincter is normal. Pain is the most prominent clinical symptom, dysphagia being second. Therapeutic attempts should be made to reduce the amplitude and duration of oesophageal contractions since this may improve symptoms. The force of contractions does not, however, correlate strictly with the symptoms. Hypercontractile
oesophagus (nutcracker oesophagus)
This motility disorder has not been described as a separate entity until recently (Benjamin et al, 1979). In contrast to diffuse oesophageal spasm the contractions of the oesophagus are peristaltic in nature, yet also high in amplitude and/or prolonged in duration. Pain is usually the first symptom and dysphagia the second. The therapeutic strategy corresponds to that in diffuse oesophageal spasm. Other oesophageal motility disorders This heterogeneous group of motor abnormalities comprises intermediate types of the disorders mentioned above and non-specific oesophageal motor disorders, such as hypertensive lower oesophageal sphincter, decreased or absent amplitude of oesophageal contractions with a normal sphincter, and abnormal wave forms of oesophageal contractions (Benjamin and Castell, 1983). If symptoms occur, treatment should be aimed at reducing oesophageal contractions, if these are too strong or too long, or at decreasing lower oesophageal sphincter pressure. For most types of contraction abnormalities there is no known specific therapy.
DRUG
TREATMENT
Smooth muscle relaxing agents These drugs are indicated if symptoms are due to too strong oesophageal contractions or to incomplete relaxation of the lower oesophageal sphincter. Since there are no selective antagonists of smooth muscle contractions for different parts of the oesophagus, the agents usually act on both the lower oesophageal sphincter and the body of the oesophagus, and they may also affect other parts of the gastrointestinal tract and the cardiovascular system. Originally most of these agents were designed to exert selective actions within the cardiovascular system. Calcium antagonists Calcium ions play an essential role in the excitation-contraction coupling process of smooth muscle cells. Calcium channel blockers may inhibit the entry of calcium ions into the cell and thus impair smooth muscle contraction. These drugs include a variety of agents with different actions which may or may not affect oesophageal motility within their therapeutic range. If effects
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
MOTILITY
859
DISORDERS
mm Hg 40-I
Nifedipine
30
T
T
-r
I 10
I 20
I 30
20
10 1 0-l
[ 0
I 40
I 50
I
60 min
Figure 1. Effect of two different doses of sublingual nifedipine pressure in 12 patients with achalasia of the oesophagus.
on the lower
oesophageal
sphincter
occur they consist of a decrease in lower oesophageal sphincter pressure and a reduction in contraction frequency within the body of the oesophagus (Weiser et al, 1977). Most studies have been done with nifedipine, less with verapamil and diltiazem, and they all have been shown to alter oesophageal motility under specific conditions. Nifedipine lowers basal pressure of the lower oesophageal sphincter in normal subjects and in patients with achalasia without affecting sphincter relaxation (Hong0 et al, 1984b); the effect is dose dependent (Figure 1). Nifedipine is well-absorbed perlingually. This route of administration is preferable to swallowing tablets since it circumvents the impaired oesophageal transit. In achalasia 20 mg of nifedipine given perlingually lowers the sphincter pressure by more than 50%. The effect lasts for more than 60 min. Pressure reduction is usually sufficient to make the hydrostatic pressure exerted by oesophageal contents overcome the remaining pressure barrier of the sphincter and, thus, improve dysphagia and regurgitation. Nifedipine also lowers the amplitude of oesophageal contractions (Richter et al, 1985), but this effect appears to be weaker than that on the sphincter (Hong0 et al, 1984a). Nifedipine has been shown to be a useful drug in the long-term treatment of achalasia (Bortolotti and Lab& 1981) although its effectiveness may be less than that of nitrates (Gelfond et al, 1982). In long-term administration of nifedipine its effect and the compliance of the patient often wear off, and so it is not the therapy of first choice in achalasia. Its main use is for patients with very early or intermediate type of achalasia or as a remedy if other types of treatment have failed (Wienbeck and Berges, 1983). Nifedipine may also be given for diffuse oesophageal spasm and hypercontractile oesophagus, both on a regular schedule before meals or on demand. The reduction of the amplitude of oesophageal contractions is dose dependent (Richter et al, 1985).
860
M. WIENBECK,
W.
BERGES
AND
T. FRIELING
Verapamil given as an intravenous infusion lowers the amplitude and also the duration of oesophageal contractions in baboons (Richter et al, 1982). But given as an oral medication the drug does not appear to be useful in patients with oesophageal motility disorders. In contrast, the calcium antagonist diltiazem in a dose of 90 mg four times daily has been shown to reduce the amplitude and duration of oesophageal contractions in patients with hypercontractile oesophagus, and at the same time to improve pain and dysphagia (Richter et al, 1984). Controlled studies, however, have not yet been carried out. Nitrates Nitrates act directly on the smooth muscle of the oesophagus and other organs in that they reduce smooth muscle contractile activity. Glyceryl trinitrate and similarly amyl nitrite are rapidly absorbed from the tongue. This form of application is therefore used to obtain rapid relief from painful oesophageal contractions in diffuse oesophageal spasm (Swamy, 1977). Long-acting nitrates are generally used in preference. Isosorbide dinitrate has been shown to improve symptoms of achalasia and oesophageal transit in a higher percentage of patients than nifedipine (Gelfond et al, 1982). But sideeffects such as headache, hypertension and tachycardia were also more prominent with this nitrate. Its place in therapy, therefore, is mainly that of a ‘spare’ drug in treatment failures (Wienbeck and Berges, 1983). The effect of isosorbide dinitrate in diffuse oesophageal spasm and hypercontractile oesophagus is less well documented. In some studies it was without effect (Mellow, 1982). In a similar way to the use of nitrates in cardiovascular diseases, nitrate treatment should be discontinued for at least 8 h at night in order to prevent increasing nitrate tolerance. Hydralazine hydrochloride Hydralazine is another cardiovascular drug which not only reduces blood pressure but also may inhibit spastic contraction of the oesophagus and accompanying chest pain (Mellow, 1982). Since it may be effective even if nitrates fail, it may be considered as the drug of last choice. The dose should be increased slowly in order to find an effective dose with as few cardiovascular side-effects as possible. Nevertheless, hypotension frequently becomes so severe that treatment has to be discontinued. Anticholinergic
agents
Anticholinergics reduce the amplitude and duration of oesophageal contractions (Erckenbrecht et al, 1982) but since cholinergic input contributes only to some degree to the pressure of the lower oesophageal sphincter, a reduction in lower oesophageal sphincter pressure similar to that seen after treatment with nifedipine and nitrates does not occur after the application of anticholinergics (Hong0 et al, 1984). Because they mainly reduce only the strength of oesophageal contractions, their use is contraindicated in achalasia. The
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
before
MOTILITY after
Figure 2. Effect of 10 mg intravenous pirenzepine on oesophageal diffuse oesophageal spasm. The numbers 24, 29 and 34 indicate recording orifices from the teeth.
861
DISORDERS 10 mg
Pirenzepine
manometry the distance
in a patient with (cm) of the three
achalasic oesophagus may become increasingly dilated during anticholinergic therapy. Anticholinergic agents may be of some help to patients in hypercontractile states. The amplitude and duration of oesophageal contractions in diffuse oesophageal spasm are decreased (Figure 2). Anticholinergics of the atropine type may be used in severe oesophageal spasm. Their effect, however, is disappointing in most cases. Adrenergic agonists and antagonists Since oesophageal motility is also affected by the adrenergic system a few studies with adrenergic agonists and antagonists have been done in man. Betaadrenergic agonists reduce the force of oesophageal contractions and the velocity of propagation of oesophageal contractions in healthy persons (Lyre& and Abrahamsson, 1986) but studies in motility disorders have not been made. In a first attempt, a-adrenergic blockade has been used successfully in the treatment of achalasia (Schmidt and Bruch, 1978). Controlled studies are necessary to determine the exact role of these drugs in oesophageal motility disorders. Smooth muscle stimulating agents Substituted benzamides The substituted benzamides metoclopramide, bromopride, domperidone and, more recently, cisapride transiently raise the pressure in the lower oesophageal sphincter (Figure 3). They may also increase the force and effectiveness of oesophageal contractions. This principle has been successfully used in patients with gastro-oesophageal reflux disease. In achalasia, however, their use is contraindicated because the rise in sphincter pressure may worsen the clinical symptoms. In diffuse oesophageal spasm and hypercontractile oesophagus a reinforcement of oesophageal contractions makes no sense, and the drugs have not been tested in other non-reflux types of motor disorders.
862
M. WIENBECK,
W.
BERGES
AND
T. FRIELING
LESP ImmW
Figure 3. Effect of cisapride, lower oesophageal sphincter
metoclopramide and placebo solution pressure of 10 normal volunteers.
after
before
given
edrophonium
intravenously
on the
80 ug / kg b.w.
mtn Hg
22 -4
km
22
32
Respiration
Swallows ,, .
.
.
.
.
v.,
-WA-
Figure 4. The cholinesterase inhibitor edrophonium chloride improves the amplitude of oesophageal contractions in the striated muscle area (17 and 22 cm from the teeth) and smooth muscle area (32 cm from the teeth) in a patient with myasthenia gravis. b.w. = body weight.
Cholinergic and anticholinergic agents Bethanechol has been studied and successfully used in gastro-oesophageal reflux disease, but not in the motility disorders discussed here. Unexpectedly, strong oesophageal contractions were induced by the anticholinergic agent trospium chloride in the striated muscle part of the oesophagus (Frieling et al, 1986). Trospium chloride is a quaternary
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
MOTILITY
DISORDERS
863
60
.
. .
. . ” ::
.
Figure 5. Immediate and late effect of pneumatic dilatation on the lower oesophageal sphincter pressure in 38 patients with achalasia of the oesophagus. 0 before dilatation; v after dilatation; m 5 years later.
ammonium base which acts partly on smooth muscle Mz-receptors and partly at ganglionic sites. Whether its effects can be used therapeutically in patients with neuromuscular diseases has not yet been demonstrated. In myasthenia gravis the amplitude of contractions is diminished in the whole oesophagus, and the basal pressure may be reduced both in the upper and lower oesophageal sphincter (Weihrauch, 1981). Muscle weakness and accompanying clinical symptoms such as dysphagia and bronchopulmonary aspiration may be transiently improved by inhibitors of acetylcholine esterase (Figure 4). However, treatment should be primarily aimed at improving the underlying muscle disease.
FORCEFUL
DILATATION
In many studies all over the world, forceful dilatation of the lower oesophageal sphincter has been shown to be highly effective therapy with little risk in patients with achalasia of the oesophagus (Vantrappen and Hellemans, 1982). The procedure reduces the pressure in the lower oesophageal sphincter and thus improves transit and clinical symptoms of the disease (Wienbeck et
864
M. WIENBECK,
6. Schematic illustration of guided introduction mega-oesophagus and an eccentrically located exit.
Figure
W.
BERGES
of a pneumatic
AND
dilator
T. FRIELING
in achalasia
with
al, 1985). The effect is of long duration in most cases (Figure 5). Even in patients with a recurrence after Heller’s myotomy, pneumatic dilatation can be performed with excellent results (Wienbeck and Berges, 1983). Problems with the introduction of the dilator may arise when the oesophagus is grossly dilated and tortuous and when its exit to the stomach is eccentrically located. In these cases different procedures of guidance have been proposed to facilitate the introduction of the dilating balloon (Figure 6). Either a thread which was previously swallowed or pulled by an endoscope may act as a guide, or the dilator may be mounted directly on an endoscope (Vantrappen and Hellemans, 1980; Witzel, 1981). Thus there are now few patients with achalasia who need surgery as their primary therapy. Pneumatic dilatation has also been used in patients with diffuse oesophageal spasm and severe symptoms failing to res’pond to medical therapy (Vantrappen and Hellemans, 1980). In the spastic oesophagus this treatment is clearly less successful than in achalasia, and it appears that only patients with an accompanying sphincter dysfunction have a chance of improvement with this method (Ebert et al, 1983).
SURGERY Although in achalasia a modified Heller’s type of myotomy may be comparable or even better in its results than pneumatic dilatation (Csendes et al, 1981), surgery is usually not the first type of therapy in this motility disorder. This is mainly due to the rather frequent occurrence of postoperative gastro-oesophageal reflux oesophagitis, which may be as high as 52% (Vantrappen and Hellemans, 1982). A combination of myotomy and an antireflux procedure has been proposed, but this may interfere with the therapeutic goal of the myotomy. The fundoplication wrapping the lower oesophagus may become a new and severe obstacle to the passage of food from the oesophagus into the stomach. Therefore, in most places, surgical treatment of achalasia is only carried out if a carcinoma of the cardia cannot
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
MOTILITY
DISORDERS
865
completely be excluded, if the patient does not cooperate in the procedure of dilatation, or if dilatation fails. The diagnosis of treatment failure should only be made if severe symptoms recurred after at least three attempts of dilatation and if the remaining symptoms are not amenable to medical therapy. In severe cases of diffuse oesophageal spasm unresponsive to medical therapy a long oesophagomyotomy extending to above the level of involvement of the oesophageal muscle has been advocated and successfully performed (Ellis et al, 1964; Leonardi et al, 1977). The procedure is, however, difficult to perform well; inadvertent perforation and postoperative leakage occur, and the results in general are not as good as in achalasia. In rare cases extended oesophagomyotomy may even be indicated in the hypercontractile oesophagus (Horton and Goff, 1986).
CURRENT
THERAPEUTIC
APPROACH
Achalasia A smooth muscle relaxant, preferably nifedipine lo-20 mg sublingually immediately before meals or whenever symptoms occur may be used to treat early cases of achalasia without significant oesophageal dilatation, patients exhibiting some but not all characteristics of achalasia and vigorous achalasia. In classical achalasia, however, pneumatic dilatation is the treatment of choice. If symptoms of impaired transit such as dysphagia and regurgitation recur, dilatation may be repeated at least three times. If pain becomes the prominent symptom after treatment the patient may benefit from nifedipine. Longitudinal oesophagomyotomy is advocated only in treatment failures, uncooperative patients and patients with suspected carcinoma. Recurrences after surgery frequently respond to pneumatic dilatation. Much more difficult to handle is postoperative reflux oesophagitis. It may necessitate a surgical reintervention.
Diffuse oesophageal spasm and hypercontractile
oesophagus
Patients with diffuse oesophageal spasm and hypercontractile oesophagus are recommended to avoid, if possible, all types of food and drink which have repeatedly aggravated their symptoms in the past. In addition they are told to take nifedipine lo-20 mg before meals or as needed. If this does not work or is badly tolerated, isosorbide dinitrate, 5-10 (-20) mg three times daily, may be given and thereafter hydralazine or dihydralazine 12.5 mg three times daily which may be slowly increased to 50 mg or even 75 mg three times daily. Sedatives and anticholinergics usually offer little additional help. If drugs fail, an attempt may be made with pneumatic dilatation, and, in the very rare event of intractable and incapacitating clinical symptoms, even a long oesophagomyotomy may be considered.
866
M. WIENBECK,
W.
BERGES
AND
T. FRIELING
Other oesophageal motility disorders Intermediate types of primary oesophageal motility disorders are treated according to the predominant clinical symptom: dysphagia is attacked by pneumatic dilatation, pain by a muscle relaxant. In scleroderma and other immunological diseases affecting oesophageal motility and causing dysphagia an attempt may be made with metoclopramide and other substituted benzamides. But it is more important to treat the underlying disease and if complicated by reflux oesophagitis to start a proper treatment of that. In myasthenia gravis, symptomatic improvement of dysphagia may be brought about by the prescription of cholinesterase inhibitors.
REFERENCES SB & Caste11 DO (1983) Oesophageal causes ofchest pain. In Caste11 DO&Johnson LF (eds) Oesophageal Function in Health and Disease, pp 85598, Oxford: Elsevier Biomedical. Benjamin SB, Gerhardt D & Caste11 DO (1979) High amplitude, peristaltic contractions associated with chest pain and/or dysphagia. Gastroenterology 77: 478-483. Bortolotti M & Labo G (1981) Clinical and manometric effects of nifedipine in patients with oesophageal achalasia. Gastroenterology 80: 39-44. Csendes A, Velasco N, Braghetto I & Henriquez A (1981) A prospective randomised study comparing forceful dilatation and oesophagomyotomy in patients with achalasia of the oesophagus. Gastroenterology 80: 189-795. Ebert EC, Ouyang A, Wright SH et al (1983) Pneumatic dilatation in patients with symptomatic diffuse oesophageal spasm and lower oesophageal sphincter dysfunction. Digestive Diseases and Sciences 28: 481-485. Ellis PH Jr, Olsen AM, Schlegel JF & Code CF (1964) Surgical treatment of oesophageal hypermotility disturbances. Journal of the American Medical Association 188: X62-866. Erckenbrecht E, Berges W, Sonnenberg A, Erckenbrecht J & Wienbeck M (1982) The effect of pirenzepine on oesophageal motility. Scandinavian Journal of Gastroenterology 17 (supplement 72): 185-190. Frieling T, Wienbeck M, Liibke H, Enck P & Erkenbrecht JF (1986) The effect of a parasympatholytic agent on oesophageal myoelectric and contractile activity. Gastroenterology 90: 1421. Gelfond M, Rozen P & Gilat T (1982) Isosorbide dinitrate and nifedipine treatment of achalasia: a clinical, manometric and radionucleide evaluation. Gastroenterology 83: 963-969. Hongo M, Traube M & McCallum RW (1984a) Comparison of effects of nifedipine, propantheline bromide and the combination on oesophageal motor function in normal volunteers. Digestive Diseases and Sciences 29: 300-304. Hongo M, Traube M, McAllister RG & McCallum RW (1984b) Effects of nifedipine on oesophageal motor function in humans: correlation with plasma nifedipine concentration. Gastroenterology 86: 8-12. Horton ML & Goff JS (1986) Surgical treatment of nutcracker oesophagus. Digestive Diseases and Sciences 31: 878-883. Leonardi HK, Shea JA, Crosier RE & Ellis FE Jr (1977) Diffuse spasm of the oesophagus. Clinical, manometric and surgical considerations. Journal of Thoracic and Cardiovascular Surgery 74: 736-743. Lyrenls W & Abrahamsson H (1986) Beta-adrenergic influence on oesophageal peristalsis in man. Gut 27: 260-266. Mayberry JF & Atkinson M (1985) Studies of incidence and prevalence of achalasia in the Nottingham area. Quarterly Journal of Medicine 56: 451-456. Mellow M (1982) Effect of isosorbide and hydralazine in painful primary oesophageal motility disorders. Gastroenterology 83: 364-370.
Benjamin
THERAPEUTIC
ADVANCES
IN
OESOPHAGEAL
MOTILITY
DISORDERS
867
Richter JE, Sinar DR, Cordova CM & Caste11 DO (1982) Verapamil a potent inhibitor of oesophageal contractions in the baboon. Gastroenterology 82: 882-886. Richter JE, Spurling TJ, Cordova CM & Caste11 DO (1984) Effects of oral calcium blocker, diltiazem on oesophageal contractions: studies in volunteers and patients with nutcracker oesophagus. Digestive Diseases and Sciences 29: 649-656. Richter JE, Dalton CB, Buice RG & Caste11 DO (1985) Nifedipine: a potent inhibitor of contractions in the body of the human oesophagus. Studies in healthy volunteers and patients with the nutcracker oesophagus. Gastroenterology 89: 549-554. Schmidt E & Bruch HP (1978) Erste Erfahrungen mit dem alpha-Rezeptorenblocker Phentolamin bei Achalasie. Chirurg 49: 22-24. Swamy N (1977) Oesophageal spasm: clinical and manometric response to nitroglyceride and long acting nitrates. Gastroenterology 72: 23-27. Vantrappen G & Hellemans J (1980) Treatment of achalasia and related motor disorders. Gastroenterology 79: 1444154. Vantrappen G & Hellemans J (1982) Oesophageal spasm and other muscular dysfunction, Clinics in Gastroenterology 11: 453-477. Weihrauch TR (198 1) Oesophagealmanometry. Methods and clinicalpractice. Miinchen: Urban & Schwarzernberg. Weiser HF, Lepsien G, Golenhofen K, Schattenmann G & Siewert JR (1977) Klinische und experimentelle untersuchungen zur Wirkung von Nifedipine auf die glatte Muskulatur des &ophagus. Zeitschriffiir Gastroenterologie 15: 691-698. Wienbeck M & Berges W (1983) In Demling L, Lux G & Domschke W (eds) Therapie postoperativer StBrungen des Gastrointestinaltraktes, pp 71-79. Stuttgart, New York: Thieme. Wienbeck M, Groeneveldt U & Berges W (1985) Achalasie des ijsophagus. Therapiewoche 35: 368378. Witzel L (1981) Treatment of achalasia with a pneumatic dilator attached to a gastroscope. Endoscopy 13: 176-177.
Therapeutic advances in oesophageal motility disorders MARTIN WILHELM THOMAS
WIENBECK BERGES FRIELING
Oesophageal motility disorder is the common term for a heterogeneous group of neuromuscular disturbances which may cause a variety of clinical symptoms. Their incidence is unknown. Epidemiological studies suggest that achalasia occurs in about 1 in 200 000 persons per annum (Mayberry and Atkinson, 1985). The incidence of other oesophageal motility disorders may be higher than that of achalasia (Benjamin and Castell, 1983). Thus, these disorders are not rare. Since their symptoms are frequently misinterpreted and since in many cases therapy is delayed or inefficient, they pose quite significant diagnostic and therapeutic problems. It is, therefore, worthwhile to review current therapy of primary motor disorders of the oesophagus.
PRIMARY
OESOPHAGEAL
MOTILITY
DISORDERS
Achalasia Achalasia is characterized by incomplete or missing relaxations of the lower oesophageal sphincter after swallowing, and aperistalsis in the body of the oesophagus. Major symptoms are dysphagia, regurgitation, pain and bronchopulmonary aspiration. Pain may become the prominent symptom in vigorous achalasia. Treatment is aimed at reducing the tension of the lower oesophageal sphincter in order to facilitate transit into the stomach. But a complete loss of the sphincter action should be avoided, otherwise reflux oesophagitis may become a problem, and even Barrett’s oesophagus may develop. Diffuse oesophageal spasm In classical oesophageal spasm the oesophagus exhibits aperistaltic contractions of high amplitude and prolonged duration, but relaxation of the lower Baillihre’s
Clinical
Gastroenterology
- Vol.
1, No.
4, October
1987
857
858
M. WIENBECK,
W.
BERGES
AND
T. FRIELING
oesophageal sphincter is normal. Pain is the most prominent clinical symptom, dysphagia being second. Therapeutic attempts should be made to reduce the amplitude and duration of oesophageal contractions since this may improve symptoms. The force of contractions does not, however, correlate strictly with the symptoms. Hypercontractile
oesophagus (nutcracker oesophagus)
This motility disorder has not been described as a separate entity until recently (Benjamin et al, 1979). In contrast to diffuse oesophageal spasm the contractions of the oesophagus are peristaltic in nature, yet also high in amplitude and/or prolonged in duration. Pain is usually the first symptom and dysphagia the second. The therapeutic strategy corresponds to that in diffuse oesophageal spasm. Other oesophageal motility disorders This heterogeneous group of motor abnormalities comprises intermediate types of the disorders mentioned above and non-specific oesophageal motor disorders, such as hypertensive lower oesophageal sphincter, decreased or absent amplitude of oesophageal contractions with a normal sphincter, and abnormal wave forms of oesophageal contractions (Benjamin and Castell, 1983). If symptoms occur, treatment should be aimed at reducing oesophageal contractions, if these are too strong or too long, or at decreasing lower oesophageal sphincter pressure. For most types of contraction abnormalities there is no known specific therapy.
DRUG
TREATMENT
Smooth muscle relaxing agents These drugs are indicated if symptoms are due to too strong oesophageal contractions or to incomplete relaxation of the lower oesophageal sphincter. Since there are no selective antagonists of smooth muscle contractions for different parts of the oesophagus, the agents usually act on both the lower oesophageal sphincter and the body of the oesophagus, and they may also affect other parts of the gastrointestinal tract and the cardiovascular system. Originally most of these agents were designed to exert selective actions within the cardiovascular system. Calcium antagonists Calcium ions play an essential role in the excitation-contraction coupling process of smooth muscle cells. Calcium channel blockers may inhibit the entry of calcium ions into the cell and thus impair smooth muscle contraction. These drugs include a variety of agents with different actions which may or may not affect oesophageal motility within their therapeutic range. If effects
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
MOTILITY
859
DISORDERS
mm Hg 40-I
Nifedipine
30
T
T
-r
I 10
I 20
I 30
20
10 1 0-l
[ 0
I 40
I 50
I
60 min
Figure 1. Effect of two different doses of sublingual nifedipine pressure in 12 patients with achalasia of the oesophagus.
on the lower
oesophageal
sphincter
occur they consist of a decrease in lower oesophageal sphincter pressure and a reduction in contraction frequency within the body of the oesophagus (Weiser et al, 1977). Most studies have been done with nifedipine, less with verapamil and diltiazem, and they all have been shown to alter oesophageal motility under specific conditions. Nifedipine lowers basal pressure of the lower oesophageal sphincter in normal subjects and in patients with achalasia without affecting sphincter relaxation (Hong0 et al, 1984b); the effect is dose dependent (Figure 1). Nifedipine is well-absorbed perlingually. This route of administration is preferable to swallowing tablets since it circumvents the impaired oesophageal transit. In achalasia 20 mg of nifedipine given perlingually lowers the sphincter pressure by more than 50%. The effect lasts for more than 60 min. Pressure reduction is usually sufficient to make the hydrostatic pressure exerted by oesophageal contents overcome the remaining pressure barrier of the sphincter and, thus, improve dysphagia and regurgitation. Nifedipine also lowers the amplitude of oesophageal contractions (Richter et al, 1985), but this effect appears to be weaker than that on the sphincter (Hong0 et al, 1984a). Nifedipine has been shown to be a useful drug in the long-term treatment of achalasia (Bortolotti and Lab& 1981) although its effectiveness may be less than that of nitrates (Gelfond et al, 1982). In long-term administration of nifedipine its effect and the compliance of the patient often wear off, and so it is not the therapy of first choice in achalasia. Its main use is for patients with very early or intermediate type of achalasia or as a remedy if other types of treatment have failed (Wienbeck and Berges, 1983). Nifedipine may also be given for diffuse oesophageal spasm and hypercontractile oesophagus, both on a regular schedule before meals or on demand. The reduction of the amplitude of oesophageal contractions is dose dependent (Richter et al, 1985).
860
M. WIENBECK,
W.
BERGES
AND
T. FRIELING
Verapamil given as an intravenous infusion lowers the amplitude and also the duration of oesophageal contractions in baboons (Richter et al, 1982). But given as an oral medication the drug does not appear to be useful in patients with oesophageal motility disorders. In contrast, the calcium antagonist diltiazem in a dose of 90 mg four times daily has been shown to reduce the amplitude and duration of oesophageal contractions in patients with hypercontractile oesophagus, and at the same time to improve pain and dysphagia (Richter et al, 1984). Controlled studies, however, have not yet been carried out. Nitrates Nitrates act directly on the smooth muscle of the oesophagus and other organs in that they reduce smooth muscle contractile activity. Glyceryl trinitrate and similarly amyl nitrite are rapidly absorbed from the tongue. This form of application is therefore used to obtain rapid relief from painful oesophageal contractions in diffuse oesophageal spasm (Swamy, 1977). Long-acting nitrates are generally used in preference. Isosorbide dinitrate has been shown to improve symptoms of achalasia and oesophageal transit in a higher percentage of patients than nifedipine (Gelfond et al, 1982). But sideeffects such as headache, hypertension and tachycardia were also more prominent with this nitrate. Its place in therapy, therefore, is mainly that of a ‘spare’ drug in treatment failures (Wienbeck and Berges, 1983). The effect of isosorbide dinitrate in diffuse oesophageal spasm and hypercontractile oesophagus is less well documented. In some studies it was without effect (Mellow, 1982). In a similar way to the use of nitrates in cardiovascular diseases, nitrate treatment should be discontinued for at least 8 h at night in order to prevent increasing nitrate tolerance. Hydralazine hydrochloride Hydralazine is another cardiovascular drug which not only reduces blood pressure but also may inhibit spastic contraction of the oesophagus and accompanying chest pain (Mellow, 1982). Since it may be effective even if nitrates fail, it may be considered as the drug of last choice. The dose should be increased slowly in order to find an effective dose with as few cardiovascular side-effects as possible. Nevertheless, hypotension frequently becomes so severe that treatment has to be discontinued. Anticholinergic
agents
Anticholinergics reduce the amplitude and duration of oesophageal contractions (Erckenbrecht et al, 1982) but since cholinergic input contributes only to some degree to the pressure of the lower oesophageal sphincter, a reduction in lower oesophageal sphincter pressure similar to that seen after treatment with nifedipine and nitrates does not occur after the application of anticholinergics (Hong0 et al, 1984). Because they mainly reduce only the strength of oesophageal contractions, their use is contraindicated in achalasia. The
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
before
MOTILITY after
Figure 2. Effect of 10 mg intravenous pirenzepine on oesophageal diffuse oesophageal spasm. The numbers 24, 29 and 34 indicate recording orifices from the teeth.
861
DISORDERS 10 mg
Pirenzepine
manometry the distance
in a patient with (cm) of the three
achalasic oesophagus may become increasingly dilated during anticholinergic therapy. Anticholinergic agents may be of some help to patients in hypercontractile states. The amplitude and duration of oesophageal contractions in diffuse oesophageal spasm are decreased (Figure 2). Anticholinergics of the atropine type may be used in severe oesophageal spasm. Their effect, however, is disappointing in most cases. Adrenergic agonists and antagonists Since oesophageal motility is also affected by the adrenergic system a few studies with adrenergic agonists and antagonists have been done in man. Betaadrenergic agonists reduce the force of oesophageal contractions and the velocity of propagation of oesophageal contractions in healthy persons (Lyre& and Abrahamsson, 1986) but studies in motility disorders have not been made. In a first attempt, a-adrenergic blockade has been used successfully in the treatment of achalasia (Schmidt and Bruch, 1978). Controlled studies are necessary to determine the exact role of these drugs in oesophageal motility disorders. Smooth muscle stimulating agents Substituted benzamides The substituted benzamides metoclopramide, bromopride, domperidone and, more recently, cisapride transiently raise the pressure in the lower oesophageal sphincter (Figure 3). They may also increase the force and effectiveness of oesophageal contractions. This principle has been successfully used in patients with gastro-oesophageal reflux disease. In achalasia, however, their use is contraindicated because the rise in sphincter pressure may worsen the clinical symptoms. In diffuse oesophageal spasm and hypercontractile oesophagus a reinforcement of oesophageal contractions makes no sense, and the drugs have not been tested in other non-reflux types of motor disorders.
862
M. WIENBECK,
W.
BERGES
AND
T. FRIELING
LESP ImmW
Figure 3. Effect of cisapride, lower oesophageal sphincter
metoclopramide and placebo solution pressure of 10 normal volunteers.
after
before
given
edrophonium
intravenously
on the
80 ug / kg b.w.
mtn Hg
22 -4
km
22
32
Respiration
Swallows ,, .
.
.
.
.
v.,
-WA-
Figure 4. The cholinesterase inhibitor edrophonium chloride improves the amplitude of oesophageal contractions in the striated muscle area (17 and 22 cm from the teeth) and smooth muscle area (32 cm from the teeth) in a patient with myasthenia gravis. b.w. = body weight.
Cholinergic and anticholinergic agents Bethanechol has been studied and successfully used in gastro-oesophageal reflux disease, but not in the motility disorders discussed here. Unexpectedly, strong oesophageal contractions were induced by the anticholinergic agent trospium chloride in the striated muscle part of the oesophagus (Frieling et al, 1986). Trospium chloride is a quaternary
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
MOTILITY
DISORDERS
863
60
.
. .
. . ” ::
.
Figure 5. Immediate and late effect of pneumatic dilatation on the lower oesophageal sphincter pressure in 38 patients with achalasia of the oesophagus. 0 before dilatation; v after dilatation; m 5 years later.
ammonium base which acts partly on smooth muscle Mz-receptors and partly at ganglionic sites. Whether its effects can be used therapeutically in patients with neuromuscular diseases has not yet been demonstrated. In myasthenia gravis the amplitude of contractions is diminished in the whole oesophagus, and the basal pressure may be reduced both in the upper and lower oesophageal sphincter (Weihrauch, 1981). Muscle weakness and accompanying clinical symptoms such as dysphagia and bronchopulmonary aspiration may be transiently improved by inhibitors of acetylcholine esterase (Figure 4). However, treatment should be primarily aimed at improving the underlying muscle disease.
FORCEFUL
DILATATION
In many studies all over the world, forceful dilatation of the lower oesophageal sphincter has been shown to be highly effective therapy with little risk in patients with achalasia of the oesophagus (Vantrappen and Hellemans, 1982). The procedure reduces the pressure in the lower oesophageal sphincter and thus improves transit and clinical symptoms of the disease (Wienbeck et
864
M. WIENBECK,
6. Schematic illustration of guided introduction mega-oesophagus and an eccentrically located exit.
Figure
W.
BERGES
of a pneumatic
AND
dilator
T. FRIELING
in achalasia
with
al, 1985). The effect is of long duration in most cases (Figure 5). Even in patients with a recurrence after Heller’s myotomy, pneumatic dilatation can be performed with excellent results (Wienbeck and Berges, 1983). Problems with the introduction of the dilator may arise when the oesophagus is grossly dilated and tortuous and when its exit to the stomach is eccentrically located. In these cases different procedures of guidance have been proposed to facilitate the introduction of the dilating balloon (Figure 6). Either a thread which was previously swallowed or pulled by an endoscope may act as a guide, or the dilator may be mounted directly on an endoscope (Vantrappen and Hellemans, 1980; Witzel, 1981). Thus there are now few patients with achalasia who need surgery as their primary therapy. Pneumatic dilatation has also been used in patients with diffuse oesophageal spasm and severe symptoms failing to res’pond to medical therapy (Vantrappen and Hellemans, 1980). In the spastic oesophagus this treatment is clearly less successful than in achalasia, and it appears that only patients with an accompanying sphincter dysfunction have a chance of improvement with this method (Ebert et al, 1983).
SURGERY Although in achalasia a modified Heller’s type of myotomy may be comparable or even better in its results than pneumatic dilatation (Csendes et al, 1981), surgery is usually not the first type of therapy in this motility disorder. This is mainly due to the rather frequent occurrence of postoperative gastro-oesophageal reflux oesophagitis, which may be as high as 52% (Vantrappen and Hellemans, 1982). A combination of myotomy and an antireflux procedure has been proposed, but this may interfere with the therapeutic goal of the myotomy. The fundoplication wrapping the lower oesophagus may become a new and severe obstacle to the passage of food from the oesophagus into the stomach. Therefore, in most places, surgical treatment of achalasia is only carried out if a carcinoma of the cardia cannot
THERAPEUTIC
ADVANCES
IN OESOPHAGEAL
MOTILITY
DISORDERS
865
completely be excluded, if the patient does not cooperate in the procedure of dilatation, or if dilatation fails. The diagnosis of treatment failure should only be made if severe symptoms recurred after at least three attempts of dilatation and if the remaining symptoms are not amenable to medical therapy. In severe cases of diffuse oesophageal spasm unresponsive to medical therapy a long oesophagomyotomy extending to above the level of involvement of the oesophageal muscle has been advocated and successfully performed (Ellis et al, 1964; Leonardi et al, 1977). The procedure is, however, difficult to perform well; inadvertent perforation and postoperative leakage occur, and the results in general are not as good as in achalasia. In rare cases extended oesophagomyotomy may even be indicated in the hypercontractile oesophagus (Horton and Goff, 1986).
CURRENT
THERAPEUTIC
APPROACH
Achalasia A smooth muscle relaxant, preferably nifedipine lo-20 mg sublingually immediately before meals or whenever symptoms occur may be used to treat early cases of achalasia without significant oesophageal dilatation, patients exhibiting some but not all characteristics of achalasia and vigorous achalasia. In classical achalasia, however, pneumatic dilatation is the treatment of choice. If symptoms of impaired transit such as dysphagia and regurgitation recur, dilatation may be repeated at least three times. If pain becomes the prominent symptom after treatment the patient may benefit from nifedipine. Longitudinal oesophagomyotomy is advocated only in treatment failures, uncooperative patients and patients with suspected carcinoma. Recurrences after surgery frequently respond to pneumatic dilatation. Much more difficult to handle is postoperative reflux oesophagitis. It may necessitate a surgical reintervention.
Diffuse oesophageal spasm and hypercontractile
oesophagus
Patients with diffuse oesophageal spasm and hypercontractile oesophagus are recommended to avoid, if possible, all types of food and drink which have repeatedly aggravated their symptoms in the past. In addition they are told to take nifedipine lo-20 mg before meals or as needed. If this does not work or is badly tolerated, isosorbide dinitrate, 5-10 (-20) mg three times daily, may be given and thereafter hydralazine or dihydralazine 12.5 mg three times daily which may be slowly increased to 50 mg or even 75 mg three times daily. Sedatives and anticholinergics usually offer little additional help. If drugs fail, an attempt may be made with pneumatic dilatation, and, in the very rare event of intractable and incapacitating clinical symptoms, even a long oesophagomyotomy may be considered.
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T. FRIELING
Other oesophageal motility disorders Intermediate types of primary oesophageal motility disorders are treated according to the predominant clinical symptom: dysphagia is attacked by pneumatic dilatation, pain by a muscle relaxant. In scleroderma and other immunological diseases affecting oesophageal motility and causing dysphagia an attempt may be made with metoclopramide and other substituted benzamides. But it is more important to treat the underlying disease and if complicated by reflux oesophagitis to start a proper treatment of that. In myasthenia gravis, symptomatic improvement of dysphagia may be brought about by the prescription of cholinesterase inhibitors.
REFERENCES SB & Caste11 DO (1983) Oesophageal causes ofchest pain. In Caste11 DO&Johnson LF (eds) Oesophageal Function in Health and Disease, pp 85598, Oxford: Elsevier Biomedical. Benjamin SB, Gerhardt D & Caste11 DO (1979) High amplitude, peristaltic contractions associated with chest pain and/or dysphagia. Gastroenterology 77: 478-483. Bortolotti M & Labo G (1981) Clinical and manometric effects of nifedipine in patients with oesophageal achalasia. Gastroenterology 80: 39-44. Csendes A, Velasco N, Braghetto I & Henriquez A (1981) A prospective randomised study comparing forceful dilatation and oesophagomyotomy in patients with achalasia of the oesophagus. Gastroenterology 80: 189-795. Ebert EC, Ouyang A, Wright SH et al (1983) Pneumatic dilatation in patients with symptomatic diffuse oesophageal spasm and lower oesophageal sphincter dysfunction. Digestive Diseases and Sciences 28: 481-485. Ellis PH Jr, Olsen AM, Schlegel JF & Code CF (1964) Surgical treatment of oesophageal hypermotility disturbances. Journal of the American Medical Association 188: X62-866. Erckenbrecht E, Berges W, Sonnenberg A, Erckenbrecht J & Wienbeck M (1982) The effect of pirenzepine on oesophageal motility. Scandinavian Journal of Gastroenterology 17 (supplement 72): 185-190. Frieling T, Wienbeck M, Liibke H, Enck P & Erkenbrecht JF (1986) The effect of a parasympatholytic agent on oesophageal myoelectric and contractile activity. Gastroenterology 90: 1421. Gelfond M, Rozen P & Gilat T (1982) Isosorbide dinitrate and nifedipine treatment of achalasia: a clinical, manometric and radionucleide evaluation. Gastroenterology 83: 963-969. Hongo M, Traube M & McCallum RW (1984a) Comparison of effects of nifedipine, propantheline bromide and the combination on oesophageal motor function in normal volunteers. Digestive Diseases and Sciences 29: 300-304. Hongo M, Traube M, McAllister RG & McCallum RW (1984b) Effects of nifedipine on oesophageal motor function in humans: correlation with plasma nifedipine concentration. Gastroenterology 86: 8-12. Horton ML & Goff JS (1986) Surgical treatment of nutcracker oesophagus. Digestive Diseases and Sciences 31: 878-883. Leonardi HK, Shea JA, Crosier RE & Ellis FE Jr (1977) Diffuse spasm of the oesophagus. Clinical, manometric and surgical considerations. Journal of Thoracic and Cardiovascular Surgery 74: 736-743. Lyrenls W & Abrahamsson H (1986) Beta-adrenergic influence on oesophageal peristalsis in man. Gut 27: 260-266. Mayberry JF & Atkinson M (1985) Studies of incidence and prevalence of achalasia in the Nottingham area. Quarterly Journal of Medicine 56: 451-456. Mellow M (1982) Effect of isosorbide and hydralazine in painful primary oesophageal motility disorders. Gastroenterology 83: 364-370.
Benjamin
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Richter JE, Sinar DR, Cordova CM & Caste11 DO (1982) Verapamil a potent inhibitor of oesophageal contractions in the baboon. Gastroenterology 82: 882-886. Richter JE, Spurling TJ, Cordova CM & Caste11 DO (1984) Effects of oral calcium blocker, diltiazem on oesophageal contractions: studies in volunteers and patients with nutcracker oesophagus. Digestive Diseases and Sciences 29: 649-656. Richter JE, Dalton CB, Buice RG & Caste11 DO (1985) Nifedipine: a potent inhibitor of contractions in the body of the human oesophagus. Studies in healthy volunteers and patients with the nutcracker oesophagus. Gastroenterology 89: 549-554. Schmidt E & Bruch HP (1978) Erste Erfahrungen mit dem alpha-Rezeptorenblocker Phentolamin bei Achalasie. Chirurg 49: 22-24. Swamy N (1977) Oesophageal spasm: clinical and manometric response to nitroglyceride and long acting nitrates. Gastroenterology 72: 23-27. Vantrappen G & Hellemans J (1980) Treatment of achalasia and related motor disorders. Gastroenterology 79: 1444154. Vantrappen G & Hellemans J (1982) Oesophageal spasm and other muscular dysfunction, Clinics in Gastroenterology 11: 453-477. Weihrauch TR (198 1) Oesophagealmanometry. Methods and clinicalpractice. Miinchen: Urban & Schwarzernberg. Weiser HF, Lepsien G, Golenhofen K, Schattenmann G & Siewert JR (1977) Klinische und experimentelle untersuchungen zur Wirkung von Nifedipine auf die glatte Muskulatur des &ophagus. Zeitschriffiir Gastroenterologie 15: 691-698. Wienbeck M & Berges W (1983) In Demling L, Lux G & Domschke W (eds) Therapie postoperativer StBrungen des Gastrointestinaltraktes, pp 71-79. Stuttgart, New York: Thieme. Wienbeck M, Groeneveldt U & Berges W (1985) Achalasie des ijsophagus. Therapiewoche 35: 368378. Witzel L (1981) Treatment of achalasia with a pneumatic dilator attached to a gastroscope. Endoscopy 13: 176-177.