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A Randomized Placebo-Controlled Trial of Mebendazole for Halitosis
Bahri Ermis, MD;
Turan Aslan, MD;
Levent Beder, MD;
Murat Unalacak, MD
Arch Pediatr Adolesc Med. 2002;156:995-998.
ABSTRACT
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Objective To test whether mebendazole, an antiparasitic drug, would affect recovery
from halitosis.
Design We conducted a randomized, double-blind, placebo-controlled trial between
April 1999 and September 2001.
Setting A referral medical center.
Patients One hundred sixty-two children aged 5 to 16 years whose parents complained
about their chronic bad breath.
Interventions Children were randomly assigned to receive mebendazole (n = 82) or placebo
(n = 80).
Main Outcome Measure Parents whose children had halitosis were evaluated for halitosis at
2 months of treatment by questionnaire. The microbiologist investigated the
stool samples of children for parasitosis at the beginning of the trial and
also at the end of the trial in children who were treated with mebendazole.
Results Among those children who had evidence of parasites in stool samples
at the beginning of the trial, 18 of 28 who were treated with mebendazole
recovered from halitosis, compared with 2 of 24 who received placebo (relative
risk [RR] for recovery, 7.7; 95% confidence interval [CI], 2.0-29.9). Among
those who did not have stool parasites, 14 of 52 improved with mebendazole,
compared with 10 of 48 taking placebo (RR, 1.3; 95% CI, 0.6-2.6). Mebendazole
intake made a significant difference whether or not the children had parasites
(P = .002).
Conclusions Parasitosis should be considered as a possible cause of halitosis in
the pediatric patient population. Mebendazole therapy seems to offer benefit
to those children with parasites as a potential cause of their halitosis.
INTRODUCTION
HALITOSIS (bad breath) is defined as a foul odor arising from a person's
oral cavity or nasal passages.1 It is a common
ailment in children and adults, and 50% to 60% of the general population has
chronic halitosis.2-4
Most cases of halitosis may have oral causes.2, 5-7
Besides the oral cavity problems, it is associated with chronic sinusitis,
upper and lower respiratory tract diseases, various systemic diseases, and
usage of certain drugs.1, 6-9
Bad breath originating from gastrointestinal disorders is considered to be
extremely rare.10 It was reported in 1941 that
19% of the children visiting an outpatient clinic at Children's Hospital of
Boston (Boston, Mass) were infected with pinworms.11
Prevalence levels as high as 100% have been recorded for some parasites, especially Enterobius vermicularis in the United States and northwestern
Europe.12 Using standard methods, the prevalence
levels have been shown to be around 35% to 87% in Turkey.13-14
Although most of the children infested with parasites may be asymptomatic,
others suffer from deficits in their physical, intellectual, and cognitive
growth.15
We have no knowledge of medical literature reporting the relationship
between halitosis and parasitosis. When a mother stated that the bad breath
of her child, who was infested with E vermicularis,
disappeared after antiparasitic treatment with mebendazole, we became suspicious
that halitosis might be a consequence of parasitic infection and decided to
see if a randomized trial with mebendazole could influence recovery from halitosis.
PATIENTS AND METHODS
We conducted a randomized, double-blind, placebo-controlled trial. The
Ethical Committee of Karaelmas University (Zonguldak, Turkey) approved the
trial. Parents were informed, and their consent was obtained before enrollment.
PATIENTS AND SETTING
Children aged 5 to 16 years whose parents complained about their chronic
bad breath were included in the trial. Participants were enrolled between
April 1999 and September 2001 from the outpatient clinics of the Department
of Pediatrics at the Research Hospital of Karaelmas University.
INCLUSION CRITERIA
When parents spontaneously reported bad breath in their children who
were taken to outpatient clinics for various nonpathologic reasons (well-child
care, growth follow-up, lack of appetite, etc), these children were included.
The parents reported no recent acute infection.
EXCLUSION CRITERIA
A pediatrician, an otorhinolaryngologist, and a dentist examined all
of the children. If needed, their pulmonary and/or Water view radiographs
were taken. According to any suspicion of adenoiditis or sinusitis during
the ear-nose-throat examination, endoscopic and tomographic investigations
were done. Also, liver function tests (alanine aminotransferase and aspartate
aminotransferase levels), serum urea nitrogen levels, creatinine levels, fasting
blood glucose levels, uric acid levels, and hemograms were studied for all
children.
RANDOMIZATION
A random-number table was used to generate random sequences of allocation,
which were generated by a research coordinator. Numbered containers were used
for allocation concealment. The investigators, who were blinded to the trial,
were assigned participants to their treatment groups. The parents, investigators,
and the research coordinator were unaware of the assigned treatment. Follow-up
data collection and effectiveness of blinding were evaluated by questionnaire
at the end of the trial.
We assumed a 30% difference in children who had parasites, and a 40%
clinical success rate in the mebendazole group. To achieve 80% power with 
= .05, we needed to enroll 29 children with parasites in each study group.
The 58 children who had parasites were recruited from those 190 children with
halitosis.
LABORATORY INVESTIGATIONS
Fresh stool specimens were submitted to the laboratory in sterile containers
with tight-fitting lids, and these containers were then placed into plastic
bags before transport. All fresh and liquid specimens were examined within
1 hour or 30 minutes of passage, respectively. Examination of 3 specimens
collected every other day was considered the minimum necessary to perform
an adequate ova and parasite evaluation (National Committee for Clinical Laboratory
Standards, Wayne, Pa, unpublished data, 1993).
Direct wet mounts and iodine (1:5 dilution of Lugol iodine) staining
of fresh stool specimens were examined microscopically for motile trophozoites
or helminth larvae. We performed either a Faust zinc sulfate centrifugal flotation
technique or the Richie technique of formalin-ether sedimentation to increase
yield, in addition to direct wet mount examinations according to the standard
procedures. For false-negative test results, attention must be paid to the
recommended speed and time of centrifugation, as well as excessive amounts
of fat content in feces.16
The eggs, or occasionally, the adult worms of the pinworm, E vermicularis, may be detected on examination of a clear adhesive
cellophane tape pressed against the perianal region. Specimens were collected
late at night, when the worms are most active, or first thing in the early
morning before bathing or defecation, then evaluated by microscopic examination
in the standard manner.
In children who had parasites, 37 were found in the first, 14 were found
in the second, and 7 were found in the third stool samples to be positive
for parasites. The parents were not informed about parasitosis during follow-up.
The stool samples that had parasites were investigated once at the end of
the trial in the mebendazole group.
TREATMENT
Children were randomly assigned to receive mebendazole (100 mg twice
daily for 3 consecutive days) or placebo. Pills were administered by the parents
and were taken on an empty stomach 30 minutes before meals.
EVALUATION OF TREATMENT RESPONSE
A clinical improvement was acknowledged if parents declared the disappearance
or notable decrease of their children's bad breath. Clinical failure was defined
as parents sustaining reports of bad breath in their children.
STATISTICAL ANALYSIS
The differences between groups were analyzed by using the Pearson  2 test. A Mantel-Haenszel test was used for point estimates (risk ratios)
and 95% confidence intervals (CIs).
RESULTS
Of the 190 children, 28 (6 also had parasites) were excluded from the
trial: 8 had tonsillitis and/or adenoiditis, 6 had chronic sinusitis, 7 had
dental problems, 1 had chronic persisting hepatitis, and 6 refused to participate
in the trial. Of the 58 children who had parasites, 6 were not meeting eligibility
criteria (refused to participate and/or had other etiological reasons for
halitosis) and were excluded from the trial. One hundred sixty-two children
met the eligibility criteria and were randomized as shown in Figure 1. Ten children were excluded from the trial during follow-up:
5 were lost to follow-up, 2 were excluded for unknown reasons, 2 had varicella,
and 1 child was excluded for noncompliance (Figure 1). Follow-up interviews were successfully completed in 93%
of children. The characteristics of the study group and the parasites detected
in stool samples are presented in Table
1. Stool examinations revealed that 28 children (35%) in the mebendazole
group had parasites vs 24 (33%) in the placebo group. Of the 28 children with
parasites who were treated with mebendazole, 18 (64%) recovered from halitosis
vs only 2 (8%) of the 24 children with parasites who received placebo (relative
risk [RR] for recovery, 7.7; 95% CI, 2.0-29.9). Among those who did not have
stool parasites, 14 of 52 improved with mebendazole, compared with 10 of 48
taking placebo (RR, 1.3; 95% CI, 0.6-2.6). Mebendazole intake made a significant
difference whether or not the children had parasites (P = .002) (Table 2).
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Participant flow diagram.
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Table 1. Characteristics of Children and Parasites Detected on Stool
Examination*
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Table 2. Recovery From Halitosis in Children With or Without Parasites*
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Those 18 children who had parasites and improved for halitosis with
mebendazole therapy were also cleared of parasites following mebendazole intake
at the end of the trial. Of the 10 children who had parasites but did not
improve for halitosis with mebendazole therapy, 4 had E
vermicularis, and 2 had Giardia lamblia in
their stool samples at the end of the trial. Of the rest of those, 2 were
cleared from Ascaris lumbricoides, and 2 were cleared
from Taenia saginata.
COMMENT
Stool examinations revealed that 28 children (35%) in the mebendazole
group had parasites vs 24 (33%) in the placebo group. Of the 28 children with
parasites who were treated with mebendazole, 18 (64%) recovered from halitosis
vs only 2 (8%) of the 24 children with parasites who received placebo (RR
for recovery, 7.7; 95% CI, 2.0-29.9). In our preliminary trial, mebendazole
treatment seemed to encourage recovery from bad breath. It seemed to work
in children with evidence of parasitic infection. By a search of MEDLINE,
we do not find any literature to date regarding a relationship between halitosis
and parasitosis. There might be several possible explanations for parasitosis
as the cause of halitosis. First, excess saliva secretion stimulated by parasites
leads to stasis, which may be a more convenient environment for bacterial
overgrowth, especially during sleeping.17 Second,
pulmonary migrations of some parasites and their larvae (eg, A lumbricoides and Trichuris trichiura). Third,
it is suggested that halitosis should be considered in the presence of an
increased formation of intestinal gases.18
At usual recommended dosages (100-200 mg daily), mebendazole seems to
cause minimal adverse effects. Adverse effects seem to occur more frequently
when higher dosages are used, and they may be related to effects resulting
from drug-induced killing of the parasites in some cases.19
Transient diarrhea, abdominal pain, nausea, vomiting, headache, tinnitus,
and dizziness also have been occasionally reported during mebendazole therapy.
Myelosuppression manifesting as neutropenia and/or thrombocytopenia has also
been reported in patients receiving high-dose (30-50 mg/kg daily) mebendazole
therapy for extraintestinal infections.19 However,
international trials have shown that mebendazole is safe and effective in
eradicating many parasites.15, 20-21
Biddulph22 has reported that widespread use
of mebendazole in less-developed countries indicates that it is probably safe
for infants and children, except for children with blood dyscrasias, leukopenia,
or liver diseases.
Limitations to our study design included the fact that some parents
reported that a child's bad breath showed a notable decrease, but did not
disappear, and we accepted this to be a positive response to treatment. It
may have been better to develop some grading for the improvement, or to use
more objective tests for the assessment of halitosis.
In this trial, we found an association between mebendazole therapy and
the resolution of halitosis through the resolution of parasitosis. We think
that mebendazole improved bad-smelling breath among children who were infected
with parasites.
| What This Study Adds
Halitosis is defined as a foul odor arising from a person's oral cavity
or nasal passages. It is a common ailment in children and adults, and 50%
to 60% of the general population suffers from chronic halitosis. In this trial,
we have presented an association between mebendazole therapy and resolution
of halitosis through the resolution of parasitosis.
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AUTHOR INFORMATION
Accepted for publication May 10, 2002.
Corresponding author: Bahri Ermis, MD, Department of Pediatrics,
Yakutiye Research Hospital, Ataturk University, 25240, Erzurum, Turkey (e-mail: bahriermis{at}yahoo.com).
From the Departments of Pediatrics (Dr Ermis), Infectious Diseases
(Dr Aslan), Otorhinolaryngology (Dr Beder), and Family Medicine (Dr Unalacak),
School of Medicine, Karaelmas University, Zonguldak, Turkey.
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