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Simethicone in the Treatment of Infant Colic: A Randomized, Placebo-Controlled, Multicenter Trial

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Simethicone

in the

Treatment

of Infant

Colic:

A Randomized,

Placebo-Controlled,

Multicenter

Trial

Thomas

J.

Metcalf, M1Y; Thomas G. Irons, MDX; Lawrence D. Sher, MD; and Paul C. Young, MDIJ

ABSTRACT. Objective. To determine the efficacy of simethicone in the treatment of infant colic.

Design. Randomized, double blind,

placebo-con-trolled.

Setting. Three general pediatric practices in distinct

geographic regions.

Patients. Eighty-three infants between 2 and 8 weeks

of age with infant colic.

Interventions. Treatment with simethicone and

pla-cebo in double blind crossover fashion.

Results. A total of 166 treatment periods, ranging from 3 to 10 days, were evaluated in the 83 infants.

Compared to baseline, improvement in symptoms was reported for 54% of the treatment periods, worsening was

reported for 22%, and, for 24%, there was no change. The

likelihood of the treatment period being rated as

show-ing improvement, worsening, or no change was the same whether the infant was receiving placebo or simethicone. Twenty-eight percent of he infants responded only to simethicone, 37% only to placebo, and 20% responded to both. No statistically significant differences were noted among these three groups of responders. No difference

could be shown even when infants with “gas-related

symptoms” (by parental report) were separated out as a group.

Conclusion. Although both produced perceived

im-provements in symptoms, simethicone is no more

effec-five than placebo in the treatment of infantile colic. Pediatrics 19949429-34; colic, simethicone, infant.

Infant colic continues to be a problem for babies,

parents, and physicians. Recognized since at least the sixth century, yet still defying precise understanding,

colic produces variable amounts of distress for 10%

to 20% of infants and their parents during the first 3

months of life.’5 According to Carey research to

improve the understanding and management of colic has been confounded by: 1) lack of a uniform

defi-nition of the problem; 2) poorly supported

conclu-sions regarding its basic etiology; 3) few

well-de-signed studies of therapy; and 4) inaccurate

measurement of the amount of crying as an outcome. From a clinical perspective, a colicky infant is

typ-From the *jfl Creek Pediatrics, Salt Lake City, UT; Department of

Pediatrics, East Carolina University School of Medicine, Greenville, NC;

§Peninsula Allergy Associates, Rolling Hills Estates, CA; and lDepartment

ofPediatrics, The University of Vermont College of Medicine, Burlington, VT.

Dr Young’s current address is theDepartment ofPediatrics, The University

of Utah School of Medicine, Salt Lake City, UT.

Received for publication Sep 7, 1993; accepted Dec 3,1993.

Reprint requests to (P. C. Y.) Department of Pediatrics, The University of Utah School ofMedicine, 50 North Medical Drive, Salt LakeCity, UT, 84132.

PEDIATRXS (ISSN 0031 4005). Copyright C 1994 by the American Aced. emy of Pediatrics.

ically described as an otherwise normal infant, 2

weeks to 3 months old, who fusses or screams for an extended period of time, usually in the afternoon and evening, draws his or her legs up, is largely incon-solable, and sometimes seems temporarily but incon-sistently relieved by passing gas. For research pur-poses, Wessel’s’ more specific definition of an infant with colic as, “one who, otherwise healthy and well-fed, has paroxysms of irritability, fussing or crying lasting for more than three hours a day and

occur-ring on more than three days in any one week,” has

been widely accepted in the literature and was used

by our group for this study.

A wide range of explanations for the cause of colic

can be found in the medical literature. Allergy or

intolerance to cow milk, either in the infant’s or the nursing mother’s diet, has its proponents and opponents.7#{176}

Although “maternal tension”1 has been largely dis-carded as a cause, problems in the interaction between the infant and the “environment” (parents)’2 or, more specifically, inappropriate response(s) to the infant’s crying by the parents’3 are believed by some to cause or

contribute to the problem. Implicit in the strategies

recommended by many is the belief that colic is not a

pathologic entity at all but simply an extreme variant of

“normal” crying which can be caused by hunger,

dis-comfort from a soiled or wet diaper, boredom, or from unidentifiable causes.14’6 Similarly, many interven-tions to prevenV7 or manage colic have been reported.

These range from increased carrying,18 or

simu-lated automobile rides,’9 dietary changes for the infant or mother,7’#{176} counseling parents to respond “appro-priately” to the crying,’3’2#{176}and medications.

Dicyclo-mine hydrochloride has been reported as being

effective but is now contraindicated in infants

under 6 months because of reports of apnea in

infants who were receiving t.fl24

Another agent, simethicone (methylpolysioxane),

has been promoted as being of value because of the

impression that increased intestinal gas is causally associated with colic. It is advertised in professional

journals as being beneficial and is often

recom-mended by physicians who care for children. Sime-thicone is a defoaming agent, known to change the surface tension of gas bubbles, causing them to coa-lesce, and accelerates the passage of gas through the

intestine although the actual volume of gas is not

changed. Simethicone is not toxic, and is not

ab-sorbed from the intestine. Its safety has been well-documented.26’7

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Studies of simethicone in the treatment of colic

have shown varying results. Dugger and

Inchaust-eguP in both a double blind study of 20 infants and

a nonblinded study of 14 infants with colic were

unable to show benefit, save in two of the latter 14,

where colic was “possibly improved.” Danielson and

Hwang studied 27 infants ranging from 2 to 8 weeks of age in a double blind, crossover fashion. The infants were given 0.3 cc of simethicone solution

before each meal, and their responses were

mea-sured by interviews, 3-4-hour behavioral observa-tions, and 24-hour records by parents of the infants’ crying, fussing, eating, and stools. Placebo and sime-thicone treatments were equivalent by all measures, regardless of order of treatment, but, interestingly,

the authors noted a decrease in crying during both

treatment phases. This was interpreted as possible evidence for colic being self-limited and the study demonstrating the natural course of the complaint, or that a placebo effect had taken place. The authors felt that either simethicone does not in fact reduce intestinal gas, or that abdominal cramping caused by

intestinal gas is not a pathogenic mechanism in

in-fantile colic. A recent open-label study of 51 infants

showed nine with symptoms resolved in 7 days, 35

improved, and seven with no improvement.#{176} How-ever, neither parents nor investigators were blinded. A recent study by Sethi and Sethi31 claimed efficacy

of simethicone in a randomized, double blind

cross-over study of 26 infants. However, colic was not

defined, criteria for study entrance were not speci-fled, the dosage used was variable, and the effective dose was not clearly described. In an earlier

open-label pilot study, our group found 50% to 80% of 41

infants to have a positive response to administration of 0.3 ml of simethicone with feedings (unpublished data).

To determine the efficacy of simetkicone for treat-ing infant colic, we designed a study to overcome the deficiencies of earlier work. We used the generally accepted rigorous definition of colic by Wessel,1 em-ployed a double blind, placebo-controlled, crossover format, and recruited a broad cross-section of colicky infants from several areas of the country. Addition-ally, we planned our study so that we could ascertain

whether a subset of infants with colic, those who

were felt by their parents to have symptoms sugges-five of increased intestinal gas, might have a

differ-ent response to simethicone from those without such

symptoms.

Patients

MATERIALS AND METHODS

Patients were recruited from three centers: University

Pediat-tics, the general pediatric practice of the department of pediatrics of the University of Vermont College of Medicine in Burlington,

Vermont; The Pediatric Clinic of the East Carolina University

School of Medicine, Greenville, North Carolina; and Wifiow Creek

Pediatrics, a private office practice in Salt Lake City, Utah. Infants

with crying sufficient to meet the criteria of Wessel’s definition

(see above), who were full term infants, appropriate for

gesta-tional age, between 2 and 8 weeks of age, with a weight gain of 5

ounces or more per week, and with a normal history and physical

exam were eligible for entrance into the study. Infants with

con-genital or acquired abnormalities which might predispose them to

irritability were excluded, as were infants with a prior or currently

diagnosed illness or a history of treatment for hyperbilirubinemia.

Possible subjects for the trial were identified during well child or

sick visits; caregivers were then questioned specifically to

estab-lish whether their infants fit the above criteria for inclusion in the study. A physical exam was performed; if normal, the study concept and design were described to the caretakers, as well as an

explanation of simethicone, its hypothesized effect, and lack of

side effects. Informed written consent was obtained. The Parent

Questionnaire (Fig. 1) and Initial Colic Assessment Form (Fig. 2) were completed. The Daily Diary (Fig. 3) for the first trial period

was explained and given to the caregiver along with the randomly

selected medication for the first period. Caregivers received

mod-est incentives (dependent on the individual study center) upon completion of both study periods. For example, Utah subjects

received $25 cash upon completion of both study periods, and

were not charged for initial or follow-up visits. The study was approved by the Institutional Review Boards of each institution.

Study Design

The study followed a randomized, double blind, crossover

protocol, using outcome measures which could be utilized in a

practice setting and permit statistical evaluation. Each patient trial

consisted of two study periods of approximately I week each

(minimum, 3 days; maximum, 10 days.) Infants first received

either simethicone or placebo, based on a schedule determined by

random number tables, followed by the alternate substance for the

second study period. Caregivers were given a bottle of coded

medication and instructed to give 0.3 ml with each feeding. They

were asked to record in the Daily Diary each administration of medication and to provide written comments on any events

deemed noteworthy, including any modifications in dietary habits or feeding schedule. At the end of each day they were to rate their child’s colic compared to when they had first sought treatment for

the infant. A five-point scale was used to identify the child’s

symptoms as: definitely better or symptom-free (+2), possibly

better (+1), the same (0), possibly worse (-I), or definitely worse (-2).

After the first study period, caregivers returned the diary and

any unused medication to the physician’s office, or gave it to a

nurse study coordinator during a home visit. At this time, parents provided an overall response, ie, to the entire treatment period for the first medication on the same 5-point scale, ranging from +2 to -2. They were then provided with the alternative medication and

a new diary. At the end of the second treatment period the diary and any unused medication were again collected, and the overall score for that period was assigned by the caregiver. If the

present-ing symptoms were unresolved, the child was then treated at the discretion of the physician. Patients could be withdrawn from the study by their caregivers at any time for any reason, and patients were dropped from the trial if an intercurrent medical condition

developed.

Study medications were provided by Stuart Pharmaceuticals, then a Division of ICI Pharmaceuticals Group, and consisted of either simethicone (Mylicon Drops) or a placebo, indistinguish-able in taste, smell, and appearance from Mylicon. Patient consent

forms were designed at each center to conform with requirements of the respective Institutional Review Boards who approved the

study at each site.

Statistical Evaluation

Analysis of the data was performed by statisticians from Stuart

Pharmaceuticals and by an independent statistidan from the

Urn-versity of Utah. Based on the 5-point rating scale described above analysis of variance techniques appropriate for a crossover design were used. Results of the two statistical analyses were identical.

Daily Diaries of each patient were reviewed, scores for individual

days were averaged, and these were compared to the whole

number scores assigned by caregivers for each overall treatment

period. Since the two sets of scores were not significantly different,

the overall treatment period scores were used in the statistical

evaluation of the results.

Simethicone “Responders” were those infants judged by their caregivers to have had a positive response (+2 or +1) only to

simethicone, and no change or a negative response (0, -1 or -2) to placebo. Responders to placebo were similarly defined. For

purposes of analysis the first day of the second treatment period

was considered a washout period to allow the original condition

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- Both breast milk and formula

Fig 1. Parent Questionnaire.

_Yes

14. Does passing gas from his or her rectum seem to relieve the symptoms even

temporarily? _No ..Yes

15. How many stools does your baby have in a 24 hour period?

16. Does your baby have trouble passing astool?

17. Are your baby’s stools too hard?

_No _Yes

_No Yes

18. What have you tried to do to decrease your baby’s symptoms before coming in

today?

19. Are you doing any of these things now? ...Yes-please list below

PARENT QUESTIONNAIRE

1. At what age was your baby when the problem began?...

2. What is your baby drinking?

...Breast milk ...jormula

3. If your baby is breast feeding, are you taking any medication?

No _Yes-Please list below

4. If your baby isbeing fed formula, what formula are you currently using?

Also, list any other formula you have previously used

5. Is your baby eating any solid foods?

..No .Yes-Please list below:

6. Does your baby spit up after feedings?

...No ....Yes-Is 1t ...Rarely ...Often ...Always

7. Does your baby seem to have a lot of gas? _No

8. Does your baby’s stomach seem swollen, bloated, or distended?_No _Yes

9. Does your baby pass a lot of gas from his or her rectum? ...No _Yes

10. Does your baby’s stomach growl gurgle or chum? Yes

1 1. Is your baby easy to burp after feedings? Yes

12. Are you able to burp your baby after every feeding? _Yes

13. Does burping seem to relieve his or her symptoms even temporarily? .No

to reassert itseff. Ratings for that day were not induded in the

analysis of data. Simethicone responders were compared to pla-cebo responders using either clii square of Student’s ttest depend-ing on the variable. Patients who failed to complete the stipulated

duration of both study periods were excluded from the study.

RESULTS

The study was carried out between March and

August of 1988. Ninety-two patients were enrolled

from the three centers. Eight were excluded for fail-ure to keep follow-up visits. One child developed an upper respiratory tract infection and was excluded. Eighty-three patients provided data adequate for

analysis. The demographic makeup of these 83

pa-tients is shown in Table 1. Racial composition and

feeding methods reflected the populations served by the three centers.

A total of 166 treatment periods were evaluated,

two for each infant. Treatment periods averaged 7

days with a range of 3 to 10 days. The length of the

treatment periods were influenced chiefly by

logisti-cal considerations including the parents’ or the re-search nurses’ schedules. Length of treatment period

did not vary with whether the infant was receiving

placebo or simethicone. As shown in Table 2, 89

(54%) of the treatment periods resulted in either

definite (28%) or probable (26%) improvement of

symptoms compared to baseline. Twenty-two

per-cent resulted in definite (11%) or probable (11%)

worsening of symptoms, and in 24% there was no

change. Forty-one of the 83 treatment periods (25%)

associated with simethicone administration and 48

(29%) of 83 associated with placebo resulted in def-mite or probable improvement. No significant

differ-ences were seen between simethicone and placebo

treatment periods in improvement or worsening. In Table 3, infants are divided into “Responders” (definite or probable improvement) to simethicone alone (no change or worsening with placebo,)

pla-cebo alone, or those who improved with both.

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#2-definitely hrr.r iw cvmnrnm fr ii nncelhlv h.rr#{248}r. (

- mo/da/yr

--2

1

1

1

couc ASSESSMENT FORM

STUDY NO.

SUBJECT NO

SUBJECr IDENT: ISEX IBIRTHDATE IASST DATE

INAL SEVERITY OF COLIC

BIRTHWEIGHT PRESENT WEIGHT mild U moderate Ii

severefi

ORIGIN:

0WHiTE

DIAGNOSES 0Th

a

BLACK 0 HISPANIC 0 ASIAN U OTHER (specify)

ER THAN COLIC ONONE

STUDY DRUG ADMiNISTRATION

TREATMENT FROM

PERIOD mo/da/vr

TO RESPONSE

(-2 to +21

Fig 2. Colic Assessment Form.

CONCOMITANT THERAPY (Include all therapy initiated during study) UNONE

COMPANY ThERAPY DOSE/FREQIJENCij FROM ‘1’ IND1CA’flON

IIvrThnv

ADDITIONAL DEMOGRAPHIC DATA

Is PRIMARY CARE GIVER OTHER THAN PARENT(S)

caregiver (e.g. grandmother)

MOTHER FATHER CAREGIVER

AGE

EDUCA11ONAL LEVEl. A1TAINED

MARITAL STAThS

NUMBER OF CHILDREN

COMMENTS

INVESTIGATOR’S NAME

to simethicone, 31 (37%) infants were termed Placebo

Responders, and 17 (20%) showed improvement

with both agents. Twenty-one infants (15%) showed

no improvement with either agent. Analysis of the characteristics (sex, race, formula versus breast, or

whether the colic was rated as mild, moderate, or

severe) of those considered to be simethicone

re-sponders compared to the placebo responders

showed no statistically significant differences. Eval-uations of responses were done comparing infants

who received simethicone in the first treatment

pe-riod to those who received placebo first; no

statisti-cally significant differences were found. Finally, to

test the hypothesis that simethicone would have had

its greatest effect in infants whose colic was felt to be

secondary to intestinal gas, the group of infants

termed simethicone responders was compared to

placebo responders on the basis of the caregivers answering “yes” to the questions on the Parent Ques-tionnaire which defined a sub-group of “gassy’

in-fants (questions 7-14, Fig. 1). The number and

per-INVESTIGATOR’S SIGNATURE DATE (mo/da/yr)

centages of gassy infants in simethicone and placebo groups were not statistically different.

DISCUSSION

Our study is in agreement with that of Danielsson

and Hwang in 27 infants in 1985. Both their study

and ours showed that treatment with either

simethi-cone or placebo produced improvement in

symp-toms more than twice as often as either resulted in no

change or worsening of symptoms. They suggested

that the improvement might be due to a tendency for

colic symptoms to lessen as infants aged. Since

im-provement in our infants was as likely to occur dur-ing the first as during the second treatment period,

and since we studied a population between 2 and 8

weeks of age, the time of increasing intensity of

colic.2’ the improvement we found is unlikely to be

due to a natural decrease in symptoms with

increas-ing age. A more plausible explanation is that the

perceived improvement from the treatments was

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Fig 3. Daily Diary.

COMPARED TO ThE PERIODBEFORE THE STUDY BEGAN, YOUR GIILD’S

CONDITION TODAY WAS:

UDEFINITELY BETI’ERORSYMPTOM FREE 0 POSSIBLY BE1TER U SAME

0 POSSIBLY WORSE U DEFINITELY WORSE

WAS ANY GIANGE MADE IN ThE CHILD’S DIET OR FEEDING SCHEDULE?

UNO DYES (Explain)

WERE ANY MEDICATIONS OilIER ThAN STUDY MEDICATIONS GIVEN TODAY?

0NO U YES (Indicate medication, dosage and time given)

DID THE S11JDY MEDICATION HAVE ANY UNEXPECTED EFFECF?

U NO U YES (explain)

EPISODES OF COLIC

DURATION

TIME (main)

INDICATE (X)

AM PM

INDICATE SEVERflY (X)

MILD MOD SEVERE

DAILY DIARY

STUDY MEDICATION ADMINISTRATION

TIME

DATE (mo/da/yr)

INDICATE (X)

AM PM

TABLE 1. Demographics

NC UT VT Total

Males 10 23 8 41

Females 13 20 9 42

White 13 40 17 70

Black 10 0 0 10

Hispanic 0 2 0 2

Asian 0 1 0 1

Breast-fed 2 14 6 22

Formula-fed 16 16 10 42

Breast/formula 5 13 1 19

Mildcolic 3 8 0 11

Moderate colic 11 27 11 49

Severe colic 9 6 5 20

positive effects of simethicone noted in our earlier pilot study and in other open label

studies.#{176}Differ-ent results were reported by Sethi and Sethi,31 who

showed significant decreases in both the frequency and amplitude of daily crying spells in infants given

simethicone compared to those receiving placebo.

Deficiencies in their study include the lack of a clear definition of colic for study entry and a relatively small number of

subjects?-Simethicone would be an appealing agent to

re-lieve the symptoms of colicky infants if it were effec-five. It has a very narrow range of purported

thera-peutic activity, ie, it reduces intestinal gas by

decreasing its transit time within the gut.

More-over, being inert and not absorbed from the gastro-intestinal tract, it has no dangerous side effects, an important consideration in treating a self-limited dis-order. The fact that it is no more effective than pla-cebo suggests that intestinal gas is not playing any

substantial role in the symptoms of colic. Indeed,

even in the infants in our study whose parents noted

many symptoms of “gas,” placebo was as effective as

simethicone in reducing the amount of crying. The

presence of “gas” may be simply a marker of colic

and air swallowing rather than a cause; thus reduc-ing gas would not be expected to provide relief.

There is little data to support the notion that colic is a pathological process, or that the colicky infant is

in any way abnormal,1’ but the explanation for the

excessive crying remains elusive. Fussy, crying in-fants may be seeking more doseness to their caregivers.

Hunziker and Barr demonstrated that increasing the

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TABLE 2. Effect of Treatment Number (%) of Treatment Periods Showing Change

Agent Definite

Improvement

Probable

Improvement

No

Change

Probable

Worsening

Definite

Worsening

Total

Simethicone 20 (12) 21 (13) 23 (14) 9 (5) 10 (6) 83

Placebo 26 (16) 22(13) 16 (10) 10 (6) 9 (5) 83

Total 46 (28) 43 (26) 39 (24) 19 (11) 19 (11) 166

TABLE 3. Number (%) of Infants Showing Improvement to

Simethicone, Placebo, or Both

Definite or Partial

Improvement

Simethicone alone 23(28)

Placebo alone 31(37)

Both 17(20)

Total 71 (85)

and fussiness and increased contentment in normal

infants.32 When employed as a treatment for colicky infants, increased carrying was ineffective.’8

Recom-mendations made during prenatal and health

mainte-nance visits that parents hold and carry their infants, explaining normal and excessive crying,17 and ways to respond to the crying13 may prevent the need for med-ications, formula changes, or other methods to treat well-entrenched colic later on. Being supportive and empathic as well as offering step-by-step instructions for what to do when the infant is crying along the lines suggested by Taubman’3 are likely to be the most help-flil things that physicians can do. Physicians who ad-vise the use of simethicone, or acquiesce to its use by

parents, should realize they are advocating the use of

an expensive ($7.00 to $10.00 for 30 ml in Salt Lake City) placebo, albeit an apparently harmless one.

ACKNOWLEDGMENT

Supported by a grant from Stuart Pharmaceuticals; formerly a

division of ICI Pharmaceutical Group.

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1994;94;29

Pediatrics

Thomas J. Metcalf, Thomas G. Irons, Lawrence D. Sher and Paul C. Young

Multicenter Trial

Simethicone in the Treatment of Infant Colic: A Randomized, Placebo-Controlled,

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1994;94;29

Pediatrics

Thomas J. Metcalf, Thomas G. Irons, Lawrence D. Sher and Paul C. Young

Multicenter Trial

Simethicone in the Treatment of Infant Colic: A Randomized, Placebo-Controlled,

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