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Journal of LSTR Therapy (International WEB version) VOL 7: 1-5, 2008

Non-surgical treatment of pulpitis, including those with history of spontaneous pain,using a combination of antibacterial drugs
1, 3Toyohiko Takushige , D.D.S., Ph.D., Edward Venzon Cruz
1, 2
Etsuro Hoshino , D.D.S., Ph.D.
1

1, 2, D.D.S., Ph.D., Md. Ali Asgor Moral

1, 2, D.D.S., Ph.D.,

2

Oral Ecology in Health and Infection and Cariology Research Unit ,3
Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan, and Takushige Dental Clinic ,Sendai, Japan
Abstract
This is a retrospective clinical study of 360 teeth diagnosed with pulpitis and treated locally with a combination of three antibacterial
drugs (ciprofloxacin, metronidazole and minocycline, “3Mix-MP”) without a pulpectomy procedure. Consecutive patients with aclinical diagnosis of pulpitis had pre-operative factors collected (spontaneous pain, pulp exposure, depth of carious lesion) and weretreated by placement of 3Mix-MP onto the pulpal floor of the carious lesion where softened dentin was intentionally left, if any waspresent. The treated lesions were then sealed by glass-ionomer cement and restored by resin inlays. A good clinical outcome wasdefined as the lack of any spontaneous pain, no mechanical allodynia to biting and the presence of pulpal responsiveness to cold orelectrical stimuli. Using these criteria, a good clinical outcome was found in 342 (95%) of the 360 cases. Six cases progressed topulpal necrosis and the remaining 12 cases required re-treatment using the same 3Mix-MP, resulting in a subsequent good outcome.
Recalcification of softened dentin was evident on postoperative radiographs. These data suggest that 3Mix-MP may be worth
evaluating in prospective randomized clinical trials for treatment of pulpitis including cases of so-called “irreversible” pulpitis.
Key words:
3Mix-MP, LSTR 3Mix-MP, SavePulp Therapy, pulpitis with spontaneous pain

Introduction
Most cases of pulpitis are associated with bacteria. Bacteriapresent in carious lesions, together with reactive inflammatory
and immunological host responses, lead to the clinicaldevelopment of pulpitis. Using this conceptual framework,
bacterial constituents of carious dentin (1), pulpitis lesions (2),infected root dentin and necrotic pulps (3, 4), periapical lesions
and infected cementum (5) have been analyzed under strict
anaerobic conditions to understand which bacteria are present
in these lesions. In addition, bacteria at other oral sites,
including dental plaque (6), tongue plaque (7), denture plaque(8), saliva (9), periodontal pockets (10) and osteomyelitis sites(11) have been also analyzed with strict anaerobic procedures
because these were possible sources of bacteria invading
pulpal lesions. These studies included a large number of the“difficult to culture” species of bacteria (12). Importantly, all ofthese bacteria were found to be sensitive against a
combination of three antibacterial drugs, namely ciprofloxacin,
metronidazole and minocycline (5, 13-21), together with othercombinations (17).
These findings led to a new hypothesis for treating these
infections. The ‘Lesion Sterilization and Tissue Repair’ (LSTR)
hypothesis proposes that removal or disinfection of bacteriapresent in these lesions by local application of an antibacterial
drug combination may lead to resolution of dentinal, pulpal andperiapical lesions (21). The repair of damaged lesions can be
expected when lesions are fully disinfected. Further, affected
dentin that is clinically softened upon probing could be recalcified after disinfection (14), and, so, affected dentin could
be intentionally left in a carious lesion. In addition, when 3Mix(i.e., ciprofloxacin, metronidazole and minocycline) was mixed
with macrogol (M) and propylene glycol (P), the combination
has been demonstrated to penetrate efficiently dentinal lesions
via dentinal tubules (22), suggesting that bacteria in pulpal
lesions could be killed by placement of 3Mix-MP at the bottom
Accepted: Aug. 1 2008
Published: Sep. 1 2008of a carious lesion. Thus, one important prediction of the
LSTR hypothesis is that local delivery of effective antibiotics inan appropriate vehicle to a carious lesion may lead to healingof cases of irreversible pulpitis without a need for conventional
pulpectomy procedures. The aim of this retrospective clinicalstudy was to evaluate the clinical outcomes of this hypothesis
by following up cases of irreversible pulpitis treated by local
application of 3Mix-MP, which is called as “LSTR 3Mix-MP
SavePulp therapy”.

Materials and Methods
Patients and teeth involved in this study
Each of the patients visited the Takushige Dental Clinic fordental treatment. Prior to their inclusion to this study, they
were informed of the aim, expected clinical results, as well as
the risks and alternatives of the treatment, and they
subsequently completed an IRB approved informed consent.
The patients were treated by one of the four dentists in theclinic.
The diagnosis of pulpitis required the presence of a carious
lesion extending to the pulp chamber upon radiographic or
clinical examination, or the combination of a deep carious
lesion with spontaneous pain.
Although this diagnosis
conforms to the classic definition of “irreversible pulpitis”, wehave classified this as “pulpitis” in this study in accordancewith the LSTR hypothesis. The distribution of these clinicalfindings in the 360 cases is presented in Fig. 1. A total of 268
teeth had pulp exposure and this included 264 cases ofradiographically evident carious dentin extending to the pulp
chamber as well as a subset of 74 teeth with clinically evident
pulp exposure; 4 additional teeth had pulp exposures thatwere clinically but not radiographically evident. A total of 233
teeth had carious lesions with spontaneous pain. Some cases
were comprised of a combination of these criteria (Fig. 1).
１

Takushige & Hoshino

Fig. Pulpitis cases treated by LSTR 3Mix-MP SavePulp
therapy.

Clinical and radiographic observations
Clinical symptoms, such as swelling, abscess, sinus tract,
induced pain on cold and hot conditions, pain on bite,
spontaneous pain, were recorded before and after thetreatment.
Preoperative radiographs were taken prior totreatment to observe development of caries lesions to pulp
chambers and periodontium conditions.
Postoperative
radiographs were also taken to observe re-calcification ofsoftened dentin, closure of exposed pulps, and radiographic
changes in periradicular lesions.
Preparation of 3Mix-MP
Commercially prepared chemotherapeutic agents, namely,
ciprofloxacin (Ciproxan, Bayer, Osaka, Japan), metronidazole(Trichocide, Green Cross, Osaka, Japan) and minocycline(Minomycine, Ledeale-Japan, Tokyo, Japan) were used.
Preparation procedures of 3Mix-MP were described elsewhere(21, 23, 24). In short, after removal of the capsules or coating
materials that enclose the drug products, each of the drugs
was pulverized to fine powders using porcelain mortars andpestles, and then stored separately in a tightly capped
porcelain container to prevent exposure to light and humidity.
A small amount of silica gel in a bag was placed inside thecontainer to maintain low humidity. The powdered drugs wereused within a month of preparation. On the day of treatment,
powdered ciprofloxacin, metronidazole and minocycline weremixed in a ratio of 1:3:3 (by volume). The vehicle, of an
ointment consistency, was prepared separately by mixing
macrogol (M; Solbase, Meiji, Tokyo, Japan) and propylene
glycol (P) in a ratio of 1:1 (by volume). The 3Mix antibiotics
and MP vehicle were thoroughly mixed to form 3Mix-MP in aratio of 7:1 for standard consistency and, then, ball-likeparticles (1 mm diameter) of 3Mix-MP were prepared. 3MixMP preparation should be prepared and used on the day of
preparation.
Clinical procedure of LSTR therapy for pulpitis
The clinical procedures are described elsewhere (23). In brief,
previous restoration, if any, was removed. Softened dentin
was not removed intentionally unless the access cavity was<1.5 mm in depth in dentin. Care was taken not to damage thepulp during the preparation.
The dentinal walls of the
preparation were treated with 12% EDTA for 1 min to remove
the smear layer. In pulpitis cases without visible pulp exposure,the 3Mix-MP placed on the bottom of caries cavities for local
disinfection. In pulpitis cases with visible pulp exposure or
accidental pulp exposure, the additional removal of carious

2

LSTR 3Mix-MP SavePulp treatment

dentin was stopped to prevent expansion of the size of the pulp
exposure. The exposed pulps were chemically cleaned with
NaClO gel (AG Gel, GC, Tokyo, Japan) and further disinfectedby 3Mix-MP placed on the dentine floor of the cavities. 3MixMP was not placed directly onto exposed pulp. Patients were
not anesthetized with local anesthesia, because the above
procedures do not give pain to patients. Under anesthetizedconditions, dentists may not recognize damaging the pulps andgiving pain to patients.
MP placed on the bottom of caries cavities for local disinfection.
In pulpitis cases with visible pulp exposure or accidental pulp
exposure, the additional removal of carious dentin was stopped
to prevent expansion of the size of the pulp exposure. The
exposed pulps were chemically cleaned with NaClO gel (AGGel, GC, Tokyo, Japan) and further disinfected by 3Mix-MP
placed on the dentine floor of the cavities. 3Mix-MP was notplaced directly onto exposed pulp.
Patients were notanesthetized with local anesthesia, because the above
procedures do not give pain to patients. Under anesthetizedconditions, dentists may not recognize damaging the pulps andgiving pain to patients.
Once the access preparation was completed, a 1 mm
diameter ball-like particle of 3Mix-MP preparation was placed
onto the bottom of the restoration cavity, and, using a cottonball, pressed to a thin layer on the cavity floor. Then, a firstlayer of glass-ionomer cement (Fuji IX, GC, Tokyo) was applied
to seal 3Mix-MP with care not to express 3Mix-MP out of thecavity. The cavity was then entirely sealed with the second
layer of glass-ionomer cement. Then, a widely open-angled
restoration cavity for a composite resin-inlay restoration wasmade as small in size as possible. The wider margin areas on
enamel were provided to reinforce the seal and to ensuresufficient adherence and retention of the composite resin-inlay
restoration following etching with 35% phosphoric acid solution.
The resin-inlay, made using the Clearfil composite resin(Kuraray, Tokyo, Japan) on the tooth, was cemented using the
Panavia F 2.0 Estenia Cementing Kit (Kuraray, Tokyo, Japan)
according to the manufacture’s manual. In certain cases with
undermined cusps, an onlay form of the composite resin
restoration was provided.
In cases with extensive coronal
destruction, metal inlays fixed by resin cement were used. In
most cases, the treatment was completed in one visit.
Post-treatment observations, including those using postoperative radiographs, were made to assess the changes of
the clinical symptoms. Vitality of pulp was checked byelectronic method using a Pulp Detector (Dentotest, Medinale,
Zürlich, Switzerland). Pulp sensations evoked by cold and hot
stimuli were also confirmed. In addition, any pain or discomfort
on biting or chewing on the treated tooth was noted.
The three clinical outcomes were defined as follows. A “good”
clinical outcome was defined as the lack of any spontaneouspain, no mechanical allodynia to biting and the presence of
pulpal responsiveness to cold or electrical stimuli. An outcomeof pulpal necrosis was defined by the lack of pulpal
responsiveness to cold or electrical stimuli, although no clinicalsymptoms and no mechanical allodynia to biting were observed.
Thus, these cases were clinically good and no further treatment
was needed. The outcome of “root canal re-treatment” wasdefined as the presence of symptoms at the follow-up visit;these cases were treated with a second application of 3Mix-MP.

Results
A total 360 cases is included in the present study, and all
were diagnosed as pulpitis, because they had either
radiographically evident carious dentin extending to the pulp
chamber (264 cases; 73 %), clinically evident pulp exposureTakushige & Hoshino

LSTR 3Mix-MP SavePulp treatment

Table 1. Clinical outcomes of 3Mix-MP pulpitis treatment
Clinical Outcome

Cases with spontaneous pain
222 (95%)
2 ( 1%)
9 ( 4%)

Cases without spontaneouspain
120 (94%)
4 ( 3%)
3 ( 2%)Good
Necrotic
Root Canalre-treatment
Total

Total
342 (95%)
6 ( 1%)
12 ( 3%)

233

127

360

Table 2. Clinical outcomes of pulpitis cases with spontaneous pain
Clinical Outcome
Good
Necrotic
Root Canalre-treatment
Total

Occasional
Pain (%)
179 (96%)
2 ( 1%)
6 ( 3%)

Pain atNight
12 (86%)0 ( 0%)
2 (14%)

Continuous pain

Total

31 (97%)0 ( 0%)
1 ( 3%)

222 (95%)
2 ( 1%)
9 ( 4%)

187

14

32

233

Table 3Clinical outcomes of cases with spontaneous pain with or without pulp exposure
Clinical Outcome
Good
Necrotic
Root Canalre-treatment
Total

Cases with Pulp Exposure(%)
35 (92%)1 ( 2%)
2 ( 4%)

Cases without Pulp Exposure

Total

187 (96%)1 (0.5%)
7 ( 4%)

222 (95%)
2 ( 1%)
9 ( 4%)

38

195

233

(78 cases; 22%) or spontaneous pain (233 cases; 65%). Somecases were comprised of a combination of these criteria (Fig.
1). Nearly all cases (357 of 360) were vital as defined by apositive pain sensation to a cold stimulus. About 30% of thecases (130 of 360) had mechanical allodynia as defined as
pain to percussion with such a mirror handle.
Of the 264 cases with carious lesions extending to pulps, 262(99%) were hypersensitive to cold water, 74 (28%) had
exposed pulps, 95 (36%) had mechanical allodynia, 139 (53%)
complained of spontaneous pain, and 28 (11%) had
periradicular radiolucent areas.
Out of 233 cases withspontaneous pain, 231 (99%) were hypersensitive to cold
water, 38 (16%) had exposed pulps, 139 (60%) had carious
lesions extending to pulps, 110 (57%) had mechanicalallodynia, and 23 (10%) had periradicular radiolucent areas.
Among these 233 patients, 187 (80%) complained ofoccasional spontaneous pain, 14 (6%) reported spontaneous
pain at night, and 32 (14%) had experienced continuous
spontaneous pain including pulsing pain.
Out of 78 cases with clinically exposed pulps, all were
hypersensitive to cold water, 23 (29%) had mechanicalallodynia, 38 (49%) complained spontaneous pain, and 6 (8%)
had periradicular radiolucent areas.
Patients were periodically examined for post-operative
findings several times when the patients visited the clinic andthe final follow-up examination was done 123–2065 days after
the treatment. As shown in Table 1, 342 (95%) cases out of
360 cases, treated with LSTR 3Mix-MP therapy, were classified
as having a good outcome, because the pulps were vital andthe patients could bite on the teeth without discomfort whenevaluated more than one month after the treatment. An
additional 12 (3%) cases required a second application of
3Mix-MP due to an initial failure to resolve symptoms; thesecases were associated with poor margins on the composite
restorations, and all subsequently met the criteria for a goodoutcome. An additional 6 cases were justified as pulpal
necrosis (dead pulps), and no clinical symptoms anddiscomfort were reported, meaning that the cases, as thedental treatment, were successful. Thus, the dead pulps after
disinfected did not show any clinical symptoms and no further
treatment was given.
We next evaluated various subsets of the 360 cases todetermine if prognostic factors were evident that could predictthe clinical outcome. Treatment with LSTR 3Mix-MP wasclassified as good regardless of the presence of spontaneous
pain (Table 1) or the temporal nature of the pain report (Table2). In addition, the clinical outcome of cases with spontaneous
pain and either the presence of absence of a clinically evident
visual pulp exposure was similar (Table 3). Finally, thepresence of radiographic carious lesions extending to the pulp
(Table 4) or clinically evident carious exposure of the pulp
(Table 5) did not alter the outcome of the 3Mix-MP treatment.
It should be noted that these excellent clinical outcomes wereobtained even though carious dentin including softened dentin
was intentionally left in all cases. Visibly exposed holes topulps were not extended any more intentionally, and, instead,pulp tissue was disinfected with 3Mix-MP placed on overlying
dentin with closure of the exposing hole with glass-ionomer
cement, and, as the result, the pulp was kept vital without any
clinical symptoms in 91% cases (Table 5).
No other adverse effects were observed in this case series
including allergic reactions, a “flare-up” of pain or swelling, or
bleeding from the exposed pulps.
The decalcified areas on pre-operative X-ray photographs
increased radio-opaque density on post-operative ones
apparently, indicating the areas were re-calcified. Although

Journal of LSTR Therapy (International WEB version) VOL 7: 1-5, 20083

Takushige & Hoshino

LSTR 3Mix-MP SavePulp treatment

quantitative differentiation or determination of radio-opaquedensity was not easy, in most cases (85 %) re-calcification
were apparently observed when checked after one year.

Table 4.
Clinical outcomes of cases with carious dentin
extending to the pulp
ClinicalOutcomeGood
Necrotic
Root Canalre-treatment
Total

Cases with
ExposedPulp
67 (91%)4 ( 5%)
3 ( 4%)

Cases
without Pulp
Exposure181 (95%)
2 ( 1%)
7 ( 4%)

Total
248 (94%)
6 ( 2%)
10 ( 4%)

74

190

264

Table 5. Clinical outcomes of cases with exposed Pulp
ClinicalOutcomeGood
Necrotic
Root Canalre-treatment
Total

Cases with
SpontaneousPain
35 (92%)
1 ( 3%)
2 ( 5%)

Cases without
SpontaneousPain
36 (90%)3 ( 8%)
1 ( 2%)Total
71 (91%)4 ( 5%)
3 ( 4%)

38

40

78

significant pulpal blood flow remains even in cases diagnosed
as having irreversible pulpitis. Taken together, these findings
suggest that the definition of so-called irreversible pulpitis
should be reconsidered.
We definitely call this pulpitis
treatment as LSTR 3Mix-MP SavePulp therapy, because mostinflamed pulps were saved to be alive instead of the removal of
pulp tissue in the conventional endodontic therapy.
The LSTR hypothesis predicts a successful clinical outcome
by local bacterial eradication. In addition to the treatment of
pulpitis cases that are reported in the present study, permanent
teeth (21) and primary teeth (24) with periradicular lesions havebeen also successfully treated by 3Mix-MP endodontic therapy.
These might indicate that 3Mix-MP therapy may have broad
applications for endodontic treatment by creating conditions forpulpal healing, revascularization or control of infection. For
example, it is also possible to provide revisionary endodontic
treatment (i.e. ”re-treatment”) of cases with 3Mix-MP without
removal of previous root canal obturating materials (Takushige& Hoshino, unpublished data).
The results of this retrospective clinical study indicate that
LSTR therapy using 3Mix-MP, a mixture of metronidazole,
ciprofloxacin and minocycline (3Mix), and macrogol andpropylene glycol (MP), provided excellent clinical outcomes intreatment of cases with caries dentin extended to pulps, caseswith exposed pulps and cases of pulpitis with spontaneous pain.
These data provide a strong rationale for conducting
prospective randomized clinical trials and offer the potential fora new model for treating infections of the pulpodentin complex.
References

Discussion
It has been reported that bacteria can invade pulp tissue evenunder conditions of shallow carious lesions or when clinicallyintact dentin still remains (2). This indicates that bacteria can
invade not only through a visible exposed holes opened to pulp
chamber but also through certain dentinal tubules beneathcaries cavities, and inflammation and/or infection of pulp may
occur even in early stage of dentin caries. One implication ofthis finding is that complete elimination of bacteria may require
resection of a rather large area of dentin. However, this may
weaken tooth structure or expose the pulp tissue. Even so,bacteria may be present beneath any subsequent restoration
with eventual induction of pulpitis (25).
In the present study, we selected cases of pulpitis with
carious dentin extending to the pulp, as evidenced byradiographic examination. Cases with exposed pulps andcases with spontaneous pain also included in this study. It is
likely that bacteria or their byproducts, may have alreadyinvaded the pulp tissue with subsequent inflammatory or
immune host responses (2). The conventional treatment ofcases classified as having “irreversible pulpitis” is to surgicalremove the pulp by a pulpectomy procedure. However, theLSTR hypothesis proposes that the local application of
antimicrobial agents, such as the 3Mix-MP combination
evaluated in the present retrospective study, would disinfectthese lesions by eradicating bacteria in dentinal or pulpal
lesions. The results in the present clinical study support thisconcept since >90% of cases fulfilling the criteria of“irreversible” pulpitis were classified as having a good longterm outcome after local application of 3Mix-MP. In addition,
we note prior short-term studies where cases of irreversible
pulpitis were symptomatically controlled and remained vital
after systemic steroid injection (26). Interestingly, this systemic
steroid treatment led to significantly reduced pulpal levels of
inflammatory mediators (27), suggesting that clinically4

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Correspondent:
Professor HOSHINO Etsuro
Oral Ecology in Health and Infection,
Niigata University Graduate School of Medical and Dental Sciences
Gakkocho-dori 2, Niigata 951-8514 Japan
Fax: +81 (0)25-227-0806; Tel: +81 (0)25-227-2838; e-mail: hoshino@dent.niigata-u.ac.jp------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Supported by the Grants-in-aid for Scientific Research (14406028, and 17390500) from the Ministry of Education, Culture, Sports, Science andTechnology, and by the grants for the Joint Research Program from the Japan Society for the Promotion of Science.

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Journal of LSTR Therapy (International WEB version) VOL 7: 1-5, 20085