What are the indications for treatment of achalasia with pharmacologic agents?
M. Bortolotti (Bologna)
Achalasia is a disease characterized by an impairment in the non adrenergic-non cholinergic (NANC) inhibitory system, which is responsible for both the relaxation of the lower esophageal sphincter (LES) and the propagation of peristaltic waves. Histochemical studies demonstrated a more or less pronounced decrease in the esophageal wall content of the inhibitory neurotransmitters vasoactive intestinal peptide (VIP) and nitric oxide (argyrophile cells), while the cholinergic nerves are relatively spared (argyrophobe cells) [1-3]. This disequilibrium between the inhibitory and stimulatory nervous fibers of the esophagus in favor of the latter, is responsible of the increase of LES tone and esophageal body contractile activity . The pharmacologic treatment by means of inhibitory drugs acting on intramural nerves or on muscle cells is aimed to rebalance the equilibrium between stimulatory and inhibitory fibers and, by relieving the spasm of LES, decrease the resistance of the cardia to a level that allows the esophageal content to pass into the stomach. However, the activity of the inhibitory system is not completely impaired in all patients with achalasia and in some cases the ability of LES sphincter to relax and of the esophageal body to perform peristaltic contractions occasionally reappear. This is confirmed by the finding of sporadic more or less complete LES relaxations with a prolonged stationary recording and of sporadic peristaltic waves at 24-hour ambulatory manometry . The appearance of peristaltic waves is more frequent in achalasic patients with slightly dilated esophagus, than in patients in whom the esophageal stasis has led to a marked distention of the esophageal body, with consequent further impairment of intrinsic nervous system. In these latter patients, histology reveals most severe nervous lesions . In addition, there are many examples showing that some capacity of recovery of the function of the inhibitory system exists and this is observed, not only after LES myotomy and pneumatic dilation, which in some patients lead to the reappearance of peristalsis [7, 8], but also after nifedipine treatment, which was followed by the reappearance of some peristaltic sequences and some LES relaxations . The return of peristalsis and improvement of LES relaxations is clearly due to an improvement of the performance of intrinsic neurons, which may be ascribed in part to the reduction of esophageal wall distention after abolition of the resistance to flow at the cardia. In fact, the removal of a stenosing neoplasia of the cardia restored a normal peristalsis [10, 11] and the artificial stenosis of the LES with application of a goretex band in cats induced dilation of the esophageal body and aperistalsis similar to that observed in achalasia, while the removal of the band resulted in a prompt return of normal peristalsis . Another reason of the reappearance of peristalsis after medical therapy with spasmolytic drugs might be connected to their hemodynamic effect. In fact patients with primary motor disorders of the esophagus have a decrease in esophageal blood flow  and the intramural inhibitory neurons are particularly sensitive to ischemia . Nifedipine and nitroderivatives, able to improve the tissue perfusion could relieve this ischemia, improving in this way the function of these neurons. In conclusion, the finding and reappearance of a normal motor activity in some patients with achalasia could be explained by the persistence of a number of inhibitory neurons spared by the pathologic process and by a restoration of their activity after the relieve of the esophageal stasis and ischemia of the esophageal wall.
From these considerations emerges the most interesting indication for the medical therapy of achalasia: patients in whom the pathologic process has not completely destroyed the inhibitory neurons, with some possibility of recovery of those functionally impaired. Patients who fall in this category are in general those with a short history of the disease, and without a marked dilation of the esophagus at X-rays (transverse diameter less than 5 cm), but this is not always the rule. Consequently, these patients are better defined by the results of esophageal manometry which demonstrates sporadic LES relaxations with pressure waves of normal amplitude, while 24-hour esophageal ambulatory manometry reveals some peristaltic waves. In our centre, during the last 19 years, we considered for pharmacologic therapy 54 patients with achalasia selected on the basis of these criteria. However, the definitive choice for the medical treatment with spasmolytic drugs was based in each case on the results of a manometric test on the effectiveness of nifedipine 20 mg in decreasing the LES pressure (30% during the following hour).
There are many substances able to relax LES (Table I), but those used in clinical practice are less numerous (Table II). Among them, nifedipine and isosorbide dinitrate are the most indicated for the treatment of achalasia. While isosorbide dinitrate is more effective and faster in relaxing LES, nifedipine has the advantage of reducing less the amplitude of esophageal pressure waves . The efficacy of these drugs in the treatment of achalasia has been demonstrated with manometric and clinical studies [15-18]. The side effects of the drugs which may limit their use are headache, flushing, arterial hypotension with dizziness and tachycardia, development of tolerance (nitroderivatives) and swelling of the ankles (nifedipine). The dose of nifedipine was 10-20 mg before each meal and was administered 30-45 min before the meals by sublingual way, followed after few minutes by a sip of water, while the dose of isosorbide dinitrate was 5 mg by sublingual way 15-30 min before meals. In addition, after two weeks of treatment the patient was asked about the efficacy and side effects of the treatment and a decision was taken about continuing the medical treatment with the same or higher dosage or stopping it and perform pneumatic dilation or Heller myotomy. Of 54 achalasic patients, who fit the above mentioned criteria of selection, 11 did not respond sufficiently to nifedipine administration and 6 presented severe side effects during the first two weeks of treatment and therapy was stopped. Consequently, in the treatment were included only 37 patients who were good responders to nifedipine. Of these patients 12 are still under treatment, 8 with nifedipine and 4 with an association of nifedipine and isosorbide (follow-up 4.3 years range 3 months-7 years), while the remaining 25 stopped the therapy after an average of 2.8 years (range 2 months-5 years):
5 because symptoms disappeared persistently after treatment and 3 for unknown reasons, while 17 underwent dilation or surgery. Besides the impredictable course of the disease, there are some other reasons for the success or failure of the therapy (Table III).
As an effective pharmacologic therapy rarely exceeds 5 years in duration and is unavoidably replaced by surgical therapy or dilatations, one can ask why undertake this therapy which results only in a postponement of a more definitive therapy. The main reason for doing it is the possibility of regression of the disease in some patients in whom the disease is at the beginning and the pharmacologic treatment could stop the vicious circle (stasis-dilation-neural impairment-stasis, etc.). The possible occurrence of these cases testified by the reappearance of a consistent quote of peristaltic activity and LES relaxations during pharmacologic therapy, may justify a trial of treatment of 6-12 months in all patients selected with the above mentioned criteria. If the disease shows a clear manometric improvement (reappearance of a consistent quote of peristaltic activity and LES relaxations) the therapy may be continued. If this does not happens, other kinds of therapy can be carried out. As the cost of the pharmacologic therapy is not high (about 200 US$ a year) I believe that it is worth trying this possibility, even it is rare. These occasions would be less rare if the diagnosis of achalasia could be done at the beginning of the disease and not after years of dysphagia.
However, besides these cases, there are other indications for a pharmacologic therapy (Table IV) which came from the fact that myotomy and dilation do not represent the "panacea" for achalasia and do not guarantee a persistence of good results for life. In fact, as time goes along, some problems inevitably arise. One of the reasons to choose myotomy is to avoid a long lasting pharmachologic therapy with spamolytics, but this goal is sometimes frustrated by the need of a prolonged antireflux therapy for the remaining life, because of the failure of the antireflux procedure and appearance of a gastroesophageal symptomatic reflux after operation [19-22] sometimes of a degree which needs a reoperation . In other cases, however, the gastroesophageal reflux (GER) is not symptomatic and this may lead to a development of Barrett's esophagus  or peptic stenosis [20, 23]. The same problem of GER, although less frequently, may arise also after dilation  and may lead to peptic stenosis . Pneumatic dilation may benefit of a pharmacologic therapy both before and after dilation. In fact in some patients, especially young and with vigorous achalasia [27-30] the treatment with pneumatic dilation is usually scarcely effective. A period of pharmacologic treatment before dilation could render the esophagus "mature" for dilation. In addition, if the first dilation obtains poor results or there is a rapid recurrence of symptoms, a treatment with spasmolytics is also indicated, because the effect of a subsequent dilation is usually scarce . However, even after successful dilation LES pressure tends to increase again with time  and consequently a pharmacologic treatment may be indicated in the case of recurrence. Other patients, who may benefit from the pharmacologic treatment, are those with an incomplete myotomy or recurrence of the muscular stenosis. In children and young patients, who respond well to drug treatment, the operation may be postponed to the end of the growth . Some patients refuse invasive treatments (dilation and myotomy) or refuse to undergo subsequent dilatations because the first treatment induced a very high pain : in these cases a treatment with spasmolytic drugs may be an acceptable solution. Finally, a pharmacotherapy of achalasia has a primary role in the treatment of elderly patients  and of those with operatory risks for myotomy and pneumatic dilation.
In conclusion, a treatment with drugs able to reduce the LES pressure, thus reducing the cardia resistance, is indicated in a series of patients who did not benefit fully of surgical or dilating therapy as well as in particular cases (young, old and severely ill patients), provided that their LES is sensitive to spasmolytics. However, besides these indications, we believe that this treatment should be the first choice in patients with initial achalasia, in whom a possibility of regression of alterations exists. Before cutting or ripping the circular fibers of the LES, a tentative of retrieve the inhibitory neurons with pharmacologic therapy could be done following the above mentioned criteria. I would conclude with a consideration: if the problem of achalasia would have had the same social impact as peptic ulcer, a pharmacologic therapy as effective as that of peptic ulcer would have been developed.
17. Coccia G, Bortolotti M, Michetti M, et al. Prospective clinical and manometric study comparing pneumatic dilation and sublingual nifedipine in the treatment of oesophageal achalasia. Gut 1991;32:604-606.