AJG - January 1998

COMMENT

Anal fissures often present as a chronic, nagging problem that may be difficult to manage. The usual symptoms in- clude pain with defecation and often outlet rectal bleeding. Suggested medical management is generally not complex and includes wti sitz baths, stool softeners, and fiber supplements (1). Hot perineal baths have no effect on anal sphincter ‘pressures (2). If medical management has been considered a failure, a partial lateral internal sphincterotomy may be advised. It requires a properly trained and experi- enced surgeon, and incontinence rates of up to 20% have been reported after surgery.

It is a pleasure to see the present attempts aimed at translating into daily clinical practice a volume of new physiological information about the regulation of gastroin- testinal sphincters. In treatment studies, the use of boruli- num toxin for injection therapy in achalasia has been quite exciting, even though the mechanism of action remains uncertain (3). In related preliminary work, intrasphincteric injections of borulinum toxin has been examined in patients with anismus or anal fissures.

Related work has focused on the ability. of inhibitory neurochemicals to reverse disorders of gastrointestinal sphincters. Initial clinical research examined the ability of the inhibitory neuropeptide, vasoactive intestinal peptide, to relax the lower esophageal sphincter in patients with acha- lasia (4). This remains a difficult area because of the short half-life of this neuropeptide in viva.

Many workers have now examined the role of production of nitric oxide in the relaxation of gastrointestinal sphincters (5, 6). Nitric oxide as an inhibitory neurochemical activates guanylate cyclase to induce production of cyclic guanosine monophosphate. There is evidence that nitric oxide can be produced in the gut by a membrane-bound nitric oxide synthase in smooth muscle cells linked to activation of a VIP receptor. This work formed the basis for the present study. The proposed treatment is simple, relatively cheap, and produces mild to minimal side effects.

This study has several important limitations. It is not yet clear whether effective treatment of acute anal fissure will prevent development of chronic anal fissure. Recurrence of acute anal fissure would require retreatment. It is unlikely that nitric oxide production would be helpful in treatment of chronic anal fissure since it is known that this condition is associated with significant fibrosis (7).

Timothy R. Koch, M.D. Section of Gastroenterology

West Virginia University, Morgantown, WV

REFERENCES

1. Smith LE. Anorectal disorders. In: Bayless TM, ed. Current therapy in gastroenterology and liver disease. St. Louis: Mosby, 1994:426-30.

2. Pinho M, Correa JCO, Futtado A, et al. Do hot baths promote anal sphincter relaxation? Dis Colon Rectum 1993;36:273-4.

3. Pasricha PJ, Ravich WJ, Hendrix TR, et al. Treatment of achalasia with

WORLD LITERATURE REVIEW 129

intrasphincteric injection of botulinum toxin: A pilot trial. Ann Intern Med 1994:121:590-l. Guehud M, Rossiter A, Souney PF, et al. The effect of vasoactive intestinal polypeptide on the lower esophageal sphincter in achalasia. Gastroenterology 1992;103:377-82. Rattan S, Chakder S. Role of nitric oxide as a mediator of internal anal sphincter relaxation. Am J Physiol (Gastrointest Liver Physiol). 1992; 262:G107-G112. Preiksaitis HG, Tremblay L, Diamant ml Nitric oxide mediates inhib- itory nerve effects in human esophagus and lower esophageal sphincter. Dig Dis Sci 1994;39:770-5. Sumfest JM, Brown AC, Rozwadowski JV. Histopathology of the internal anal sphincter in chronic anal fissure. Dis Colon Rectum 1989; 32:680-3.

THE AMBULATORY pH STUDY IS NORMAL, BUT THE PATIENT IS NOT-THE IMPORTANCE OF

THE SYMPTOMS INDEX

Watson RGP, Tham TCK, Johnston BT, et al.

Double Blind Crossover Placebo Controlled Study of Omeprazole in the Treatment of Patients With Reflux

Symptoms and Physiologic Levels of Acid Reflux-The “Sensitive Oesophagus”

Gut 1997:40:587&J

ABSTRACT

The authors conducted a double blind, crossover, pla- cebo controlled trial of Omeprazole 20 mg twice daily versus placebo in patients with heartburn and regurgi- tation with normal esophagoscopy and esophageal acid exposure during ambulatory pH monitoring of less than 5% of the total monitoring time who had at least one symptom episode during the pH monitoring period. The authors .calculated a symptom index using previously described cutoff of 50% as indicating positive or nega- tive (1).

Each crossover period was 4 wk and the trial was done in a randomized, double blind fashion. Patients com- pleted the SF-36 Quality of Life questionnaire (a well- validated instrument that gives a score for each of eight quality of life parameters) at the start of the trial and at 4 and 8 wk. Heartburn and regurgitation were graded on a scale of O-3 from absent to severe. Patients were also evaluated for other upper gastrointestinal symp- toms, including epigastric discomfort, postprandial full- ness, early satiety, anorexia, nausea, belching, vomiting, pain on swallowing, nocturnal cough, and nocturnal wheeze. Subjects were asked at 4 and 8 wk whether they were the same, better, or worse compared to the previ- ous 4 wk and given a score of 0, + 1, and -1, respec- tively. Alginate tablets were allowed, and the number used was recorded on a diary card. Patients also re- corded symptom frequency on a daily diary card. Sta- tistical comparisons were by paired sign tests, except for the Quality of Life tests which were done by paired t-tests.

130 WORLD LITERATURE REVIEW AJG - Vol. 93, No. I, 1998

lation of symptoms with reflux events and using the symp-

tom index in patients with typical reflux symptoms as well.

The finding of an 18% prevalence of the acid-sensitive

esophagus in patients with heartburn and regurgitation un-

derscores its importance. Clinicians are cautioned not to

dismiss a study as normal without looking carefully for

symptom correlation. This is especially important in situa-

tions where patients are referred to laboratories for “testing”

only; an adequate history must accompany the patient. In

our laboratory, the technicians are careful to instruct the

patient to record all symptoms on a diary as well as on the

data logger and are scrupulous in noting these on the tracing

when analyzed. Without this, many symptom-related epi-

sodes will be overlooked.

The authors considered a positive symptom association, if

the reflux episode occurred coincidentally with or within 2

min of a reflux episode. I believe this is a useful and

practical definition though we are not certain of how much

and how often reflux must occur to produce chest pain. A

recent abstract has suggested that additional reflux events in

the previous 30 min before a chest pain event were more

likely to correlate with positive symptom association (2).

Others have demonstrated that esophageal acid infusion will

increase sensitivity to subsequent infusions in normal sub-

jects and those with gastroesophageal reflux disease

(GERD) (3, 4).

The authors chose a high dose of Omeprazole as their

“therapeutic trial.” This is consistent with the “standard” of

practice in extraesophageal GERD and is a reasonable rec-

ommendation. Though this dose was apparently sufficient to

demonstrate improvement over placebo and the likelihood

that acid was responsible for symptoms, this high dose did

not eliminate symptoms or the need for additional alginate.

Perhaps these patients, like those with unexplained chest

pain, ears, nose, throat, or pulmonary disease related to

GERD need longer treatment trials, perhaps 12 wk or more

to achieve optimal improvement. Two of 12 (17%) patients

with a positive symptom index failed to respond to this dose

of Omeprazole and one patient who had a negative symp-

toms index did report improvement. The failure of improve-

ment in the two with positive symptom index could be

caused by inadequate acid suppression. Failure to respond to

BID proton pump inhibitors should prompt an ambulatory

pH monitoring study done on therapy with an intragastric

and intraesophageal probe to ascertain adequacy of acid

suppression and symptom correlation, before assuming the

dosage was a failure. In summary, the acid-sensitive esophagus is a real

clinical entity, appears to be present in a fair proportion

of patients with typical as well as atypical symptoms, and

may require higher doses of acid suppression for longer

periods of time to achieve optimal outcomes. “Normal”

ambulatory pH studies may be seen in patients with reflux

disease.

Over a 1-yr period, 44 of 244 patients (18%) were found to have an acid-sensitive esophagus. Nineteen were recruited for the study. Fifteen were excluded be- cause of .distance from the study sight, and the remaining 10 were excluded for reasons not revealed. Thirteen had positive symptom index and six negative. Six were men, 13’women, mean age was 41.7 yr. Two patients dropped out because of severe symptoms or unacceptable side effects. These two were regarded as treatment failures and included in the final analysis.

Twelve of the 18 patients had a better overall im- provement of .symptoms with Omeprazole 20 mg bid compared to placebo (p < .Ol). Only one patient was worse on Omeprazole compared to placebo with five reporting no difference. Quality of Life scores showed improvement in parameters of bodily pain and vitality on Omeprazole compared to placebo with no differ- ence in the other six scores (physical function, general health, emotional role, physical role, social function, mental health). Ten of 12 (83%) with a positive symp- tom index reported a better overall level of improve- ment with Omeprazole compared to placebo @ < .02). In the patients with a negative symptom index, there was no significant difference compared to the two groups. Heartburn and regurgitation decreased in the positive symptom index group @ < .Ol) on Omepra- zole as did the average number of days per week when alginate tablets were needed. The average number of days per week with symptoms was 4.75 on Omepra- zole and 5.8 on placebo @ < .Ol). Alginate tablets were used an average of 3 days per week in Omeprazole and 5.21 in the placebo group @ c .Ol). The other upper gastrointestinal symptoms showed no significant dif- ference between the two treatment groups. It is of interest that Quality of Life scores improved signifi- cantly from baseline in vitality, social function, phys- ical role, emotional role, and bodily pain on Omepra- zole, but not on placebo. (Am J Gastroenterol1998;93: 129-131. 0 1998 by Am. Coil. of Gastroenterology)

COMMENT

This is a well-designed study that shows that patients with heartburn and regurgitation can have acid-related symp- toms, despite normal endoscopy and physiological esopha- geal acid exposure on ambulatory pH monitoring. This paper reminds us that “normal” laboratory studies do not always rule out disease.

We are aware that patients with so-called atypical or extraesophageal reflux may have physiological esophageal acid exposure, yet reflux into the hypopharynx or have strong association with cough, asthma episodes, or unex- plained chest pain. Symptom correlation and calculation of a symptom index has become an important part of evaluat- ing ambulatory pH monitoring studies in this group. The present article underscores the importance of careful corre-

AJG - January 1998 WORLD LITERATURE REVIEW 131

Philip Katz, M.D., F.A.C.G. Allegheny University Hospital, Graduate,

Philadelphia, PA

REFERENCES

2. Beedassey A, Katz P, Gruber A, et al. Prior sensitization of esophageal mucosa by acid reflux predisposes to reflux-induced chest pain. Gas- troenterology 1997; I 12:A69.

3. Smith JL, Opekun AR, Larkai E, et al. Sensitivity of the esophageal mucosa to pH in gastroesophageal reflux disease. Gastroenterology 1989:96:638 -9.

I. Singh S. Richter JE, Bradley LA, et al. The symptom index: Differential usefulness in suspected acid-related complaints of heartburn and chest pain. Dig Dis Sci 1993:38:1402-8.

4. Siddiqui MA, Johnston BT, Leite LP, et al. Sensitization of esophageal mucosa by prior acid infusion: Effect of decreasing intervals between infusions. Am J Gastroenterol 1996;91: 1745-8.