Fw: [cfs_research] Irritable Bowel Syndrome

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[cfs_research] Irritable Bowel Syndrome

Via: CO_CURE@...

Jan van Roijen

Help ME Circle, 5 maart 2001

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IBS Article:

New Insights Into Irritable Bowel Syndrome;

Abstract: Peppermint Oil Capsules for the Treatment of Irritable

Bowel Syndrome in Children

[Moderator's Note: Irritable Bowel Syndrome is one of the

conditions whose signs and symptoms overlap with those of

CFS/ME and/or FM. The following abstract and the

article New Insights Into Irritable Bowel Syndrome

(appended) may be helpful to this CFS/ME/FM subset.]

The Journal of Pediatrics January 2001

(Volume 138, Number 1)

Enteric_Coated, pH_Dependent Peppermint Oil Capsules for the

Treatment of Irritable Bowel Syndrome in Children

Kline RM, Kline JJ, Di Palma J, et al J Pediatr.

2001;138:125_128

Peppermint oil has been reported to have medicinal value for

almost 400 years. Clinically, the oil has been shown to

relax the lower esophageal sphincter and relieve symptoms of

dyspepsia by acting as a calcium channel blocker in

gastrointestinal smooth muscle. Studies of its efficacy in

adults have shown variable effects. This may be due to an

increase in esophageal reflux secondary to the relaxation

effect. Enteric_coated products that release the oil in the

small bowel have been shown to be more effective. This study

attempted to determine the efficacy of these products in

children.

The study included 42 children between 8 and 17 years of age

(mean age = 12 years) who had been diagnosed with irritable

bowel syndrome (IBS). Reflecting disease incidence, a small

majority were girls (60%); 82% were white. None of the

children were receiving medication or had chronic illnesses

such as Crohn's disease. Using a randomized, double_blinded,

controlled methodology, children were given an

enteric_coated, pH_dependent, hard gelatin capsule

containing either peppermint oil or placebo for a period of

2 weeks.

There was a dramatic reduction in reports of pain in

children receiving the peppermint oil as measured by symptom

scales and daily diaries. Three quarters (76%) of the

children reported a clear improvement in pain as opposed to

improvement in only 19% of children receiving placebo. Of

note, these children did not report any significant

improvement, however, in other symptoms of IBS, such as

abdominal distension, gas, belching, and heartburn. No

adverse effects to the oil were found in this short_term

study, though symptoms such as diarrhea and constipation

were not studied. The authors concluded that peppermint oil

should be considered as treatment for children experiencing

mild to moderate pain associated with IBS.

Abstract

Related articles:

__ New Insights Into Irritable Bowel Syndrome

__ Defining and Diagnosing IBS

American College of Gastroenterology 65th Annual Scientific

Meeting

Day 1 _ October 16, 2000

New Insights Into Irritable Bowel Syndrome

W. Olden, MD

Introduction

Irritable bowel syndrome (IBS) is a well_known disorder for

both gastroenterologists and primary care physicians. It has

been described traditionally as affecting 15% of the North

American population. However, the diagnosis of IBS has

suffered in the past from a lack of precise diagnostic

criteria and difficulties in defining adequate treatment and

measuring the impact of that treatment in an effective

manner. A number of research and clinical symposia were

presented at the Annual Meeting of the American College of

Gastroenterology that shed new light on the epidemiology,

treatment, and economics of the disease burden of IBS.

The Challenge of Diagnosis

The Rome Criteria

In an attempt to develop standardized diagnostic criteria

for clinical practice and research in IBS, international

working teams developed the ROME I diagnostic criteria in

1990. In 1999, those criteria were revised and simplified,

resulting in the ROME II criteria. Investigators have now

begun to evaluate the sensitivity, specificity, and

congruence of the ROME II criteria with the ROME I criteria.

In one study, Grant , MD, and colleagues[1] from the

University of Ottawa and McMaster University in Ontario,

Canada, compared the congruence of both the ROME I and II

criteria prospectively in a large population of Canadians.

Using standard random telephone polling, the investigators

recruited 1149 people, adjusting for demographic variables

including age and gender. The prevalence of IBS by ROME II

criteria was 12% compared with 13% using the ROME I

criteria. When gender was evaluated, the prevalence of IBS

was found to be 15% in females and close to 9% in males

using ROME II, compared with 18.1% and 18.5% in females and

males, respectively, using the ROME I criteria.

Investigators concluded that the new ROME II criteria

produced similar results when compared with the older ROME I

criteria. These findings suggest that the ROME II criteria

may indeed provide equal efficacy in identifying patients

with IBS while being much simpler to use.

A very different study was presented by M. Zuckerman, MD,

from Texas Tech University in El Paso, and G. Nguyen, MD,

from Cho Ray Hospital in Ho Chi Minh City, Vietnam.[2] These

investigators surveyed 516 predominately healthy Vietnamese

healthcare workers and relatives of patients treated at the

Cho Ray Hospital. The individuals were surveyed using an

instrument that included the ROME I criteria. A total of 233

individuals (42%) responded. A 6% prevalence of IBS was

reported in this sample. Five percent of males and 7% of

females met the ROME I diagnostic criteria for IBS. Of

interest, the gender difference was not significant, putting

this study at odds with research done in North America and

Europe where the female_to_male ratio in IBS is skewed

toward a higher prevalence in women. The investigators

concluded that IBS in a Vietnamese population may present

different epidemiologic factors, including lower overall

presence and less gender variation. This study is important

in that it demonstrates that further epidemiologic studies

in populations outside of North America and Europe are

needed to better understand the nature of IBS around the

world.

Disease Burden

The issue of the disease burden of IBS has been investigated

only recently. Previous studies have demonstrated the cost

of morbidity due to IBS in the United States to be over $8

billion. To further evaluate the economic burden of IBS,

Eisen and colleagues[3] sampled 2354 individuals from large

health maintenance organizations in New Mexico. Of the total

contacted, 1032 (44%) agreed to participate in a telephone

survey. Data collected included demographic characteristics,

the presence of a diagnosis of IBS by ROME I criteria, and

quality of life measured by the SF_36 questionnaire, a

validated general quality_of_life measure and the IBS_QOL,

an instrument that is specific for IBS. Patients were

screened psychologically with a checklist that measured

psychiatric comorbidity and levels of psychosocial distress.

The investigators found that 9% of their sample (94

individuals) met the diagnosis of IBS by the ROME I

criteria. There were no demographic differences, including

age, gender, race, marital status, education, or income

between IBS patients and nonpatient responders. The

respondents with IBS were found, on review of their medical

records, to have had greater number of outpatient visits in

the year preceding the survey compared with non_IBS

respondents. However, IBS responders did not differ from

non_IBS responders in number of hospitalizations. The

patients with IBS tended to use more medications and

incurred increased charges for both outpatient visits and

prescription drugs. There was also a trend towards higher

total costs for all healthcare services for IBS patients

during the year that healthcare utilization was measured

compared with non_IBS responders. The patients who met the

ROME I criteria for IBS had significantly lower scores on

the SF_36 compared with non_IBS responders (P < .0001).

The investigators concluded that using a cohort of patients

in a managed care organization where healthcare utilization

and costs could be tracked easily demonstrated that IBS

sufferers had significantly more outpatient visits and use

of prescription medications than patients without IBS.

Further, IBS patients experienced decreased levels of

health_related quality of life as opposed to non_IBS

respondents. The investigators believed that these findings

demonstrated a significant disease burden for IBS.

Levy and colleagues[4] presented a similar study that was

performed at a large health maintenance organization (HMO)

in the Puget Sound area of Washington State. These

investigators performed a retrospective study of patients

who had been diagnosed with IBS. The medical records of 3153

patients who were diagnosed with IBS were examined and

compared with 3153 age_ and gender_matched controls from the

same HMO who were not diagnosed with IBS and an additional

3153 individuals who were also age_ and gender_matched who

presented for routine checkups and new medical complaints.

Cost of overall care and GI_related costs of care were

measured for a 3_year period. The investigators found that

for the index year of diagnosis, the total cost of care for

IBS patients was $4044, or $1415 higher than for controls.

In addition, the IBS patients continued to have healthcare

utilization costs approximately $1000 more per person than

in the 2 subsequent years of tracking after the initial

diagnosis was made.

When GI_related care was specifically measured, the IBS

group consumed $582 in the index year; that was reduced to

some degree in the 2 subsequent years after diagnosis. The

largest components of GI_related costs in the first year of

the IBS diagnosis were primary care visits ($178),

medications ($108), outpatient procedures ($98),

radiographic procedures ($77), and specialists' visits

($64). Of interest, there were no significant differences in

the number of emergency department visits, inpatient care,

or laboratory tests between IBS and non_IBS patients. When

all medical problems in both the IBS patients and controls

were examined, it was found that less than half of the

difference in costs was explained by the cost of IBS_related

care. The investigators concluded that IBS indeed had a

greater cost_of_care burden, particularly in the first year

of diagnosis.

Innovations in Treatment

Significant advances in the treatment of IBS have been

evolving over the last few years. The increase in our

understanding of the enteric nervous system and the

importance of neurotransmitters present in the gut have been

described by various investigators. These findings, in turn,

have led to an explosion in research to develop specific

agents that can positively affect neurotransmitter function

in the treatment of IBS patients. Consequently, the American

College of Gastroenterology sponsored a symposium on the

treatment of IBS, which was moderated by Drs. Olden

and Arnold Wald.[5] The symposium addressed the difficulties

of designing valid clinical trials for IBS and identified

the psychosocial and gender factors associated with

treatment response as well as the psychiatric and

psychological comorbidity that can influence a patient's

behavior and treatment response. The use of antidepressant

medications and active agents now being developed and

entering clinical practice were all discussed in detail.

The Difficulties in Designing Clinical Trials

Dr. Talley[5] from the University of Sydney,

Australia, began the symposium by outlining the difficulties

associated with performing high_quality clinical trials for

any therapeutic approaches to IBS and the methodologic

deficiencies of trials published over the last 30 years

(including issues of patient recruitment, lack of

standardized diagnostic criteria, lack of controls,

inadequate consideration to the high placebo response rate

seen in IBS, and inadequate outcome measures). Dr. Talley

concluded that over these last 3 decades, we have yet to

produce a clinical trial that meets the " gold standard. " Nor

was there any one trial that we could point to and declare

unequivocally the efficacy of any particular treatment

approach. The absolute importance of maximizing methodologic

quality in testing any proposed treatment for IBS was

emphasized, lest erroneous or inaccurate conclusions be

drawn. Important to further emphasize is that this

literature, although advancing quite rapidly, is still

immature and thus there are additional lessons to be learned

in planning the " ideal " IBS clinical trial.

The Role of Psychosocial and Hereditary Factors

Dr. Rona Levy[5] from the University of Washington focused

on recent research on family dynamics and heredity as they

influence IBS expression in patients. In her research, Dr.

Levy found that patients with IBS were slightly more likely

to have children who would also develop IBS. However, Dr.

Levy was quick to emphasize that the reasons for this

association remain unclear. Whether this finding represents

a genetic phenomenon, as proposed by some investigators, or

socialization, family dynamics, or learned healthcare

behavior needs to be further determined. Identifying these

issues has important treatment implications because there

may be a strong level of concern and anxiety within a family

about the significance of IBS and its effect on that family

that in turn, can influence patient behavior. Data were also

presented demonstrating that women have a tendency to

respond differently from men to visceral pain, which in turn

may influence response to drug treatment. The importance of

designing trials adequately balanced between men and women

and paying attention to gender_based response differences is

clearly important for generating high_quality data on drug

and other interventions for IBS.

Psychologic Comorbidity

Dr. Arnold Wald from the University of Pittsburgh Medical

Center reviewed the prevalence of psychiatric comorbidity in

patients with IBS.[5] Dr. Wald discussed well_established

data showing the high prevalence of anxiety disorders,

particularly panic disorder, mood disorders, and

somatization disorder in patients with IBS. It should be

emphasized that IBS is not a psychological disorder and does

not represent " a form fruste " of a psychiatric disorder.

Rather, it is important to understand psychiatric disorders

as comorbid conditions that can influence presentation,

healthcare seeking, drug response, and prognosis. Using case

studies, Dr. Wald presented psychiatric_disorder patients

from his practice who, at first view, would seem to have

IBS. Likewise, he presented patients with IBS who, although

distressed, did not have a diagnosable psychiatric disorder

on further investigation but who could have easily been

misperceived as having one.

Dr. Wald presented illustrative cases to demonstrate the

importance of taking an adequate history and the utility of

office_based psychological screening instruments for

identification of psychological issues. Dr. Wald stressed

the ease of using these screening instruments in this

setting, their applicability to office_based practice, and

how to present them to the patient in a positive and helpful

manner.

The Role of Antidepressants*

The use of antidepressants in IBS was discussed by

Olden, MD, of the Mayo Clinic in sdale, Arizona.[5] Dr.

Olden reviewed the history of antidepressants in

gastroenterology. Specifically, the anticholinergic

properties of the older tricyclic antidepressants and their

presumed effect on GI motility and the usefulness of

tricyclic antidepressants in the treatment of neuropathic

nongastrointestinal pain syndrome, such as peripheral

neuropathy, were addressed. Dr. Olden also described the

effect of neurotransmitter systems found in the gut. He

reviewed clinical trials, particularly those by Greenbaum,

Cannon, and Clouse, that investigated the use of

desipramine,* imipramine,* and trazodone,* respectively, for

treating functional gastrointestinal disorders.

Dr. Olden emphasized the commonality of the findings of

these separate trials using 3 different antidepressants. In

all of them, the subjects had no significant demonstrable

changes in gastrointestinal motility nor any significant

changes in their psychiatric status as a result of the

antidepressant intervention. However, the patients did have

significant improvement in their GI symptom ratings as well

as __ most important __ significant improvement in their

overall sense of well being. Dr. Olden emphasized that these

findings suggest a site of action of antidepressants both in

the gut as well as in the central nervous system where the

sensations produced in the gut by IBS are processed and

modulated to produce the patient's " report " of his or her

symptoms. Patients can begin on low doses of these

antidepressants and are less likely to experience

troublesome side effects. Dr. Olden stressed the importance

of understanding that these drugs, when used in the setting

of IBS, are an " off_label " indication, and, therefore,

physicians should proceed with caution and ensure their

patients' understanding of the reasons for their use.

Finally, Dr. Olden reviewed the opportunities that are

emerging for the use of antidepressants in gastroenterologic

practice. The development of an ever increasing number of

new antidepressive agents, including the selective serotonin

reuptake inhibitors (SSRIs) and agents that tend to have

lower side effect profiles, all deserve further study in GI

practice to help define their role in treating IBS and other

functional gastrointestinal disorders (such as functional

dyspepsia, esophageal dysmotility, and functional abdominal

pain).

The Role of Serotonin

The session was concluded by Dr. Lin Chang from the UCLA

School of Medicine, who addressed the use of newer

serotonergically active agents for IBS. Dr. Chang reviewed

the significance of serotonin as a target neurotransmitter

in the therapeutic intervention of the functional

gastrointestinal disorders. She emphasized that 95% of

serotonin contained in the body is located in the

gastrointestinal tract, with the extraneous 5% being

primarily located within the brain.

Dr. Chang presented the latest data on alosetron (Lotronex),

a 5HT3 antagonist and a significant inhibitor of

gastrointestinal motility. This inhibitive property makes

alosetron an ideal agent for the treatment of

diarrhea_predominant IBS. Dr. Chang also discussed the

clinical data supporting the efficacy of alosetron in

reducing stool frequency in patients with

diarrhea_predominant IBS and its ability to decrease

abdominal pain and rectal urgency. Other properties of the

drug include a lack of adverse interactions, the need for

dose adjustment with age, and the absence of metabolic

changes in patients with renal or liver dysfunction. Because

of its significant antiprokinetic effect, alosetron can

commonly produce constipation, which occasionally can be

severe. It is important for the physician to be proactive in

treating constipation early if seen in these patients.

Dr. Chang also presented data on agents still in

development, including tegaserod and prucalopride, both of

which act on 5HT4 receptor sites. These drugs are being

developed specifically for the treatment of

constipation_predominant IBS because of their prokinetic

effect. Preliminary data published to date studying the

effect of tegaserod on gastrointestinal transit and its

ability to decrease bloating and abdominal pain in patients

with constipation_predominant IBS appear promising.

Additional Studies and Strategies for IBS

Drotaverine

In addition to this symposium on the treatment of IBS, a

number of clinically relevant research abstracts were

presented. Misra and colleagues[6] from the University of

New Delhi Medical School in India presented the results of a

randomized double_blind, placebo_controlled trial of

drotaverine for the treatment of IBS. Drotaverine is a

selective inhibitor of phosphodiesterase isoenzyme IV, which

has been found useful in smooth muscle motility disorders.

Seventy consecutive patients between the ages of 18 and 60

diagnosed with IBS using their own criteria were studied in

this prospective trial. Patients were treated with

drotaverine 80 mg 3 times a day and compared with placebo

during a 4_week trial and an additional 4_week follow_up

period. These investigators found that drotaverine

significantly reduced pain compared with placebo (P < .001).

Pain severity scores also increased significantly in the

drotaverine group compared with placebo (P < .001). Patients

treated with drotaverine also experienced significant

improvement in global relief of abdominal pain, again

compared with placebo (P < .001), and significant

improvement in stool frequency (P < .001). No adverse

effects were observed in any of the patients either in the

placebo or treatment groups. The study authors concluded

that drotaverine produced significant global improvement in

abdominal pain in patients with IBS.

Alosetron**

Recently, the 5_HT3 antagonist alosetron was approved by the

FDA for the treatment of diarrhea_predominant IBS in women.

And, in the wake of this, a number of new studies were

presented. Jhingran and colleagues[7] studied patient

satisfaction in individuals with nonconstipated IBS treated

with alosetron. A total of 801 women were studied using a

12_week randomized, double_blind, placebo_controlled

multicenter trial of alosetron 1 mg twice daily. These

investigators found that overall satisfaction in those

patients treated with alosetron was significantly higher

than in the placebo group (P < .001). On entry into the

trial, less than 10% of all subjects reported that they were

either satisfied or extremely satisfied with their previous

IBS treatment regimens. In contrast, at the conclusion of

the alosetron trial, 12 (69%) of the subjects treated with

alosetron reported that they were either satisfied or

extremely satisfied with treatment compared with only 42% of

the controls (P < .001). They also found a high correlation

between overall patient satisfaction as well as satisfactory

control of rectal urgency and global improvement of all IBS

symptoms. Constipation was the only adverse event reported

significantly more frequently in the treatment group (39% vs

14% of controls). The study authors concluded that above and

beyond standard outcome measures such as decreased pain and

change in bowel movements, patients treated with alosetron

also experienced high levels of satisfaction with their

care.

In a related study, Markowits and colleagues[8] studied the

efficacy of alosetron in patients with rectal urgency. Over

800 patients were studied in a 12_week randomized,

double_blind, placebo_controlled multicenter trial of the

efficacy and tolerability of alosetron 1 mg twice a day.

(During the screening period, subjects had reported a lack

of satisfaction with control of their symptoms of bowel and

rectal urgency at least 50% of the time.) This factor was

followed throughout the course of the clinical trial over 12

weeks. The study authors found that patients treated with

alosetron were significantly more likely to report

improvement in rectal or bowel urgency (P < .001). There was

a high correlation seen between improvement in global

well_being and satisfactory control of rectal urgency at

week 12 (r = 0.54). The investigators concluded that

alosetron selectively improved control of rectal urgency in

the context of global improvement of IBS symptoms compared

with placebo.

** [Ed. Note: At the request of the US Food and Drug

Administration (FDA), Glaxo Wellcome announced on November

28, 2000, that it will voluntarily withdraw alosetron

(Lotronex) from the US Market. For more information, please

see the Medscape Newsbeat.]

Acupuncture?

Lu and colleagues[9] discussed the use of acupuncture,

investigated in a randomized, controlled trial of 27

patients with IBS diagnosed by their own criteria and

assigned to receive acupuncture treatment or relaxation

sessions. Using a crossover design method, the subjects

received both modalities. In addition to demographic

information and specific IBS symptoms reported, patients

also rated their overall quality of life on entry to and

exit from the study. The study authors treated the patients

with acupuncture or relaxation sessions 3 times a week for a

period of 2 weeks. A follow_up observation run was then

performed for 4 weeks.

These investigators found that patients' quality_of_life and

gastrointestinal symptom scores were improved equally in the

23 who completed both the acupuncture trial and the

relaxation sessions. A statistically significant reduction

in abdominal pain was observed in both groups at the end of

the trial. However, when the patients were followed for the

4_week period posttrial, only in the acupuncture group did

pain reduction persist (P < .05). Furthermore, a significant

reduction in stress perception was also observed in the

acupuncture group, but not in the relaxation group (P <

..05). It was concluded that acupuncture appears to be an

effective modality in the treatment of IBS, particularly for

pain and disease_related stress, and exceeds standard

relaxation treatment. This intriguing finding is of

particular interest because of the increasing attention paid

to so_called alternative treatments for IBS by patients and

the medical community itself. Additional studies will be

needed to confirm these results. The work of Lu and

colleagues, however, is an important step in this direction.

Clearly, acupuncture as well as other alternative modalities

deserve additional study in this disease setting.

Conclusion

Irritable bowel syndrome continues to pose a significant

challenge to the physician in terms of both diagnosis and

management. The material presented during these meeting

proceedings serves to underscore not only the progress that

has been made in recognizing this disease entity (eg,

establishment of the Rome Criteria), but also the promise of

new therapeutic interventions (eg, tegaserod) that are

waiting in the wings.

* The United States Food and Drug Administration has not

approved this medication for this use.

References

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