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OESO©2011
 
Volume: Primary Motility Disorders of the Esophagus
Chapter: Treatments of diffuse esophageal spasms
 

What is the role of smooth muscle relaxants in the treatment of diffuse esophageal spasm ?

C. Scarpignato, A. Franze (Parma)

Diffuse esophageal spasm (DES) is a motility disorder of the esophagus which usually presents with chest pain, and sometimes dysphagia. Unfortunately, the criteria for diagnosis are not firmly established and the precise definition of the condition has not been generally agreed [1]. Ten years ago, spasm was said to be evidenced by esophageal contractions which were of high amplitude and prolonged duration and repetitive in nature [2], but it is now argued that none of these features is essential for the diagnosis, and the swallow-induced non propulsive contractions with preservation of some peristalsis should be the core criteria [3].

Despite the uncertainty about the definition of esophageal spasm, its clinical features are not in dispute : patients of any age may be affected, and the pain they suffer varies from recurrent retrosternal discomfort to episodes of severe crushing chest pain radiating to the back, neck and arms, accompanied by sweating and a sensation of chocking. Intermittent mild and poorly localized dysphagia may be apparent with both solids and liquids; more prolonged episodes of esophageal obstruction occur in a few patients.

The therapeutic approach to diffuse esophageal spasm should be directed towards its most disturbing symptoms, i.e. chest pain and dysphagia, and should attempt to reduce the abnormal esophageal motility. If pathologic gastroesophageal reflux (GER) has been diagnosed as the underlying problem, a trial of an antireflux regimen is justified. To abolish GER is therefore an additional aim of the medical management.

A synopsis of the available options for the treatment of DES is shown in table 1. Explanation and reassurance are the most important elements in the management of such patients. With the report that their symptoms are not due to cardiac disease, many patients will improve. A further step in the medical approach is obviously drug treatment. Few and sparce published reports have described drug therapy in the management of DES. The discouraging therapeutic response for this disorder has recently been replaced by some hope and promise.

Smooth muscle relaxants are useful because they reduce abnormal esophageal

motility. These drugs include anticholinergics and myolitics, short- and long-acting nitrates, hydralazine and calcium channel blockers (table 1). These last compounds will be discussed below by R.W. McCallum.

Table 1. Synopsis of the therapeutic options in the treatment of DES.

Medical management

Reassurance

Smooth muscle relaxants :

Anticholinergics and myolitics

Short- and long-acting nitrates

Hydralazine

Calcium channel blockers

Psychotropic Drugs :

Diazepam and other benzodiazepines

Trazodone

Pneumatic dilatation

Surgery

Anticholinergics and myolitics

Anticholinergics strongly affect esophageal motility (for review, see [4]). Since a cholinergic mechanism seems to be involved in the control of lower esophageal sphincter (LES) pressure, the resting sphincter closure tension in man is reduced by atropine or propantheline. A well conducted study by Fournet and co-workers [5] showed that an optimally effective dose (determined according to Sun and Shay) of propantheline, besides decreasing the resting LESP, dramatically lowers the peristaltic wave amplitude in the smooth muscle part of the esophagus. Hongo et al. [6] actually reported oral propantheline (15 mg) more effective than nifedipine (20 mg sublingually) in reducing contraction amplitude in the body of the esophagus, an effect which was enhanced by concomitant nifedipine administration.

Anticholinergics could be therefore useful in the treatment of DES. Unfortunately, controlled trials are lacking and their use is restricted to the control of severe acute spasms after parenteral administration. The oral bioavailability of these compounds is indeed very poor.

Myolitics also relax esophageal smooth muscle (figure 1) both, in vitro and in vivo [7]. Although theoretically useful, these compounds have not been studied in patients with primary esophageal motor disorders.

0235F1.JPG

Figure 1. Effect of some smooth muscle relaxants on substance P (10g/ml) induced contractions in isolated rat LES. x = washing and recording stopped for 15 min. P = papaverine ; M = mebeverine ; V = verapamil; N = nifedipine. Doses are in g/ml, time is min. On the ordinate, tension of the transducer in g.

Nitrates

Nitrates relax smooth muscle through activation of guanylate cyclase and increase of intracellular cyclic GMP content [8]. They are generally considered in the context of vasodilatation and their usefulness for the treatment of angina pectoris is unquestionable. However, the pharmacologic action of nitrates on smooth muscle is a non specific one, and these drugs affect all smooth muscle, including that of the gastrointestinal tract. It is important to recognize and understand the basic pharmacologic actions of drugs and avoid exclusive attention to selected uses implied by conventional therapeutic classifications. Thus, although nitrates may be classified as antianginal drugs, relief of chest or back pain by nitroglycerin (TNG) does not always mean that the pain is of cardiac origin, as it might have relieved muscular spasm of the esophagus or biliary tract.

In patients with DES, administration of TNG sublingually is followed by elimination of repetitive contractions after swallows, an effect which is unfortunately short-lasting [9]. Reduction in amplitude of esophageal contractions is usually followed by relief of pain [10]. Long-acting nitrates (i.e. erythrityl tetranitrate or isosorbide dinitrate) are preferable to prevent major esophageal spasms. After one week treatment on Cardilate®, abnormal esophageal activity is usually controlled

and pain is absent [10]. A recent study [11], performed in achalasic patients, suggests that transdermal nitroglycerin could be an effective alternative to orally administered long-acting nitrates.

When nitrates are used for long-term therapy, the presence of GER may strongly influence the response : Swamy [10] reported that in the patients who had significant reflux associated with spasm, the response to nitroglycerin was unpredictable.

On the contrary, in the patients with DES but without reflux, the response -both clinical and manometric was uniformly good (figure 2).

0235F2.JPG

Figure 2. Clinical and manometric response to TNG and long-acting nitrates in DES patients with and without associated GER (drawn from data in Ref. 10).

Hydralazine

Hydralazine causes direct relaxation of arteriolar vascular smooth muscle. The mechanism of this effect seems to be similar to that of organic nitrates, in that it appears to involve activation of guanylate cyclase and accumulation of cyclic GMP[12]. The drug was tested in patients with painful primary esophageal disorders (EMD), most of whom had DES [13]. Compared with isosorbide (20 mg orally), hydralazine (10mg intramuscularly) was significantly more effective in reducing distal esophageal contractions in response to cholinergic stimulation (figure 3). Consequently, the bethanechol-induced pain was relieved in a greater proportion of patients after premedication with hydralazine (60% versus 20%, respectively) [13].

Taking into account the favourable results of acute pharmacological studies, long-term therapy with hydralazine (75-200 mg/day orally) was tested in patients with primary EMD [13]: all patients placed on oral hydralazine experienced symptom improvement and, in all of them, a significant decrease of amplitude and duration of esophageal contraction could be demonstrated (figure 4).

0235F3.JPG

Figure 3. Distal esophageal contractions in response to subcutaneous bethanechol (55g/kg) in patients with primary EMD : effect of premedication with isosorbide or hydralazine (drawn from data in Ref. 13).

0235F4.JPG

Figure 4. Effect of hydralazine therapy on esophageal motility in patients with primary EMD. * p < 0.05 ; ** p < 0.005 (drawn from data in Ref. 13).

Conclusions

To summarize, sublingual nitroglycerin can be used to abort the acute attacks of chest pain in patients with DES. Long-acting nitrates are however preferable to prevent major motor spasms. Although several patients have short-term

improvement, within 3 months these drugs usually loose their efficacy because of development of tolerance.

Compared with long-acting nitrates (i.e. isosorbide), hydralazine is more effective in reducing esophageal motor response to bethanechol and to prevent chest pain in response to cholinergic stimulation. Accordingly, long-term hydralazine therapy gives rise to improvement in chest pain and dysphagia, with concomitant decrease of amplitude and duration of esophageal contractions.

It must be emphasized however that, because of their untoward effects, these drugs are not a first choice in the medical treatment of DES.

References

1. Cohen S (1983) Classification of the esophageal motility disorders. Gastroenterology 84: 1050-1051.

2. Castell DO (1976) Achalasia and diffuse esophageal spasm. Arch Intern Med 136 : 571-579.

3. Richter JE, Castell DO (1984) Diffuse esophageal spasm a reappraisal. Ann Intern Med 100: 242-245.

4. Scarpignato C (1988) Pharmacological bases of the medical treatment of gastroesophageal reflux disease. Dig Dis Sci 6 : 117-148.

5. Fournet J, Bost R, Hostein J et al (1983) Effets de la propantheline sur l'activite motrice de 1'oesophage chez l'homme normal. Gastroenterol Clin Biol 7: 457-464.

6. Hongo M, Traube M, McCallum RW (1984) Comparison of effects of nifedipine, propantheline bromide, and the combination on esophageal motor function in normal volunteers. Dig Dis Sci 29: 300-304.

7. Bertaccini G, Coruzzi G, Scarpignato C (1981) Exogenous and endogenous compounds which affect the contractility of the lower esophageal sphincter. In : Medical and Surgical Problems of the Esophagus, Stipa S, Belsey RHR and Moraldi A, Eds, London: Academic Press, pp 22-29.

8. Ahlner J, Axelsson KL (1987) Nitrates. Mode of action at a cellular level. Drugs 33 (Suppl4): 32-38.

9. Orlando RC, Bozymski EM (1973) Clinical and manometric effects of nitroglycerin in diffuse esophageal spasm. N Engl J Med 289: 23-25.

10. Swamy N (1977) Esophageal spasm: clinical and manometric response to nitroglycerin and long acting nitrates. Gastroenterology 72 : 23-27.

11. Bassotti G, Gaburri M, Bucaneve G, Farroni F, Pelli MA, Morelli A (1988) Effects of transdermal nitroglycerin on manometric and clinical parameters in patients with achalasia of the esophagus. A Pilot study. Curr Ther Res 44 : 391-396.

12. Rudd P, Blaschke TF (1985) Antihypertensive agents and the drug therapy of hypertension. In : The Pharmacological Basis of Therapeutics Gilman A, Goodman LS, Rall TD and Murad F, Eds, New York : MacMillan Publ. Co., pp 784-805.

13. Mellow MK (1982) Effect of isosorbide and hydralazine in painful primary esophageal motility disorders. Gastroenterology 83 : 364-370.


Publication date: May 1991 OESO©2011