DENTOALVEOLAR SURGERY

Oral Bromelain for the Control of

Facial Swelling, Trismus, and Pain
After Mandibular Third Molar Surgery:
A Systematic Review and Meta-Analysis
Shaopeng Liu, MDS,* Haoming Zhao, MDS,y Ye Wang, MDS,z
Huaqiang Zhao, MD, PhD,x and Chuan Ma, MD, PhDk
Purpose: The purpose of this study was to evaluate whether bromelain can decrease trismus, pain, and
facial swelling in patients undergoing impacted third molar surgery.
Materials and Methods: Three databases were searched to identify relevant studies through November
1, 2017. Randomized controlled trials (RCTs) that compared the effect of bromelain versus placebo after
mandibular third molar surgery were included. The main outcome measures, pain, facial swelling, and
trismus, were assessed in the early stage (2 to 3 days) and the late stage (7 days) after surgery. Standardized
mean differences (SMDs) and weighted mean differences (WMDs) were calculated using fixed-effect
models. All statistical analyses were implemented using Review Manager 5.3.
Result: Six RCTs were included in this meta-analysis. The pooled results suggested that bromelain
appears to be effective for decreasing facial swelling in the early and late stages after surgery (early-stage
SMD, 0.24; 95% confidence interval [CI], 0.46 to 0.02; P = .03; late-stage SMD, 0.54; 95% CI, 0.84
to 0.24; P = .0004). Bromelain alleviated postoperative pain 7 days after surgery (SMD, 0.54; 95%
CI, 0.87 to 0.20; P = .002), but there was no significant difference in pain levels at the early stage.
For trismus, analyses showed that bromelain had no apparent effect on early or late trismus.
Conclusion: Bromelain conferred moderate relief of postoperative discomfort after third molar surgery.
Ó 2019 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg -:1-9, 2019

According to a previous meta-analysis that involved 49
studies, the worldwide third molar impaction preva-
lence was 24.40% (95% confidence interval [CI],
18.97-30.80).1 Because of the high morbidity rates of
impaction, third molar surgery is the most common
oral and maxillofacial surgical procedure.2 Impacted
third molar surgery commonly involves elevating the
mucoperiosteal layer, guttering the bone adequately,
and performing an odontectomy. These procedures
cause severe soft tissue and bone damage and inevi-
tably lead to the release of various inflammation medi-
ators, including bradykinin, histamine, and serotonin,
which precede pain, swelling, and trismus after third
molar surgery.3,4
In recent years, there has been increased interest
in systemic proteolytic enzyme therapy using com-
pounds, such as chymotrypsin, serratiopeptidase,
aprotinin, and bromelain, that have been reported to
work through a common mechanism.5-9 Systemic
proteolytic enzyme therapy has dramatic effects and

Received from College of Stomatology, Shandong University, Jinan, Address correspondence and reprint requests to Dr Ma: Depart-
Shandong Province, China. ment of Oral and Maxillofacial Surgery, College of Stomatology, Shan-
*Resident. dong University, Number 44, Wen Hua Xi Lu, Jinan City, Shandong
yResident. Province 250012, People’s Republic of China; e-mail:
zResident. machuan0817@163.com
xProfessor. Received November 29 2018
kLecturer. Accepted February 28 2019
Shaopeng Liu, Haoming Zhao and Ye Wang contributed equally to Ó 2019 American Association of Oral and Maxillofacial Surgeons
this work. 0278-2391/19/30256-3
Conflict of Interest Disclosures: None of the authors have any https://doi.org/10.1016/j.joms.2019.02.044
relevant financial relationship(s) with a commercial interest.

1
2 BROMELAIN AFTER MANDIBULAR THIRD MOLAR SURGERY
a widespread clinical application, especially for
wound healing and anti-inflammation. However, the
anti-inflammatory effects of proteolytic enzymes are
not confirmed, and the only approved clinical applica-
tion for bromelain was issued in 2012 by the European
Medicines Agency for a topical medication called Nex-
oBrid (MediWound Ltd, Yavne, Israel) used to remove
dead tissue in severe skin burns.10
In addition, several researchers have evaluated the
anti-inflammatory efficacy of bromelain after third
molar surgery, but the results have not been consis-
tent.11-15 In 2014, de la Barrera-N

un~ ez et al15 showed
that oral administration of bromelain after surgery
decreased inflammation and improved mouth opening
motion, but the results were not statistically relevant.
In contrast, Majid and Al-Mashhadani14 reported that
bromelain could substantially decrease postoperative
pain and swelling after third molar surgery.
The present study aimed to provide evidence-based
results for the evaluation of bromelain in decreasing
postoperative symptoms and signs after third molar sur-
gery. The authors hypothesized that bromelain could
markedly decrease postoperative discomforts. The spe-
cific aim of the study was to compare trismus, pain, and
facial swelling in bromelain and control groups of
patients undergoing mandibular third molar surgery.
Materials and Methods
STUDY DESIGN AND SAMPLE
To address the research purpose, the authors de-
signed and implemented a systematic review and
PubMed/Medline
,GHQWLILFDWLRQ
Records identified Cochrane Records
through database identified through
searching database searching
(n =10 ) (n=11)
6FUHHQLQJ
10 enrolled after duplicates removed
(OLJLELOLW\
9 full-test articles assessed for eligibility
,QFOXGHG
6 studier fulfilling inclusion criterria
5 with swelling data
4 with pain data
3 with trismus data
FIGURE 1. Flow diagram of selection process of included studies.
Liu et al. Bromelain After Mandibular Third Molar Surgery. J Oral Maxillofac Surg 2019.
meta-analysis. The PubMed, Web of Science, and
Cochrane Library databases were searched to identify
relevant studies through November 1, 2017. The key
search words were: (Bromelains OR Bromelins OR
Bromelin OR Bromelain) AND (Third Molar OR Third
Molars OR Tooth, Wisdom OR Wisdom Tooth). The
detailed search strategies are listed in the Appendix.
To ensure that the included studies were relevant, a
reference list of included studies and reviews was
compiled and searched. The study selection proced-
ure was based on the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)
guidelines.16 The PRISMA format is shown
in Figure 1.
The included studies met the following criteria: 1)
trials were randomized controlled trials (RCTs); 2)
there was no language restriction; 3) trials compared
the effect of bromelain with placebo after third molar
surgery in humans; 4) trials reported the data of any
outcomes (swelling, trismus, pain, wound healing,
side effects); and 5) trials had sufficient data to calcu-
late the weighted mean difference (WMD) or standard-
ized mean difference (SMD) with the corresponding
95% CI. The inclusion criteria included animal studies,
case reports, in vitro studies, and reviews.
VARIABLES
The main outcome measures, pain, facial swelling,
and trismus, were assessed in the early stage (2 to
3 days) and late stage (7 days) after surgery.
Web of Science Records
identified through database
searching
(n = 11)
Records excluded(Non
controlled clinical trials,pilot
studies,historical
reviews,cohort,observation al
and descriptive studies,In vitro
studies,review,case
reports,editorial letters)
3 excluded by deails
1 patients with hematologic tumor
2 no commention on Placedo group
LIU ET AL
DATA EXTRACTION
Two authors (Shaopeng Liu and Ye Wang) read the
full text of eligible studies and independently ex-
tracted data using a data extraction form. The
following data were extracted: first author, publication
year, study country, patients’ characteristics, study
design, operation time, third molar impaction type,
and bromelain dosage.
DATA ANALYSIS
The Cochrane Collaboration tool was used to eval-
uate the quality of included studies and included
sequence generation, allocation concealment, blind-
ing, incomplete outcome data, selective outcome re-
porting, and other sources of bias.17
To assess whether bromelain therapy could mark-
edly decrease trismus, pain, and facial swelling
compared with control groups, the pooled WMD or
SMD with the corresponding 95% CI was calculated.
Because different measurements with different mea-
surement units were used in the studies, the SMD
was used.18 The level of statistical heterogeneity
among studies was qualitatively and quantitatively as-
sessed using the Cochran Q test and I2 statistic, respec-
tively. When the I2 was less than 50%, a fix-effect
model was used in this meta-analysis. Otherwise, a
random-effect model was used. To compare the char-
acteristics of patients, interventions, and clinical out-
comes of the included studies, clinical heterogeneity
was assessed. Methodologic heterogeneity was judged
by the Cochrane risk of bias tool.19 By omitting the
study data sequentially, a sensitivity analysis was imple-
mented to explore potential intergroup heterogeneity.
Funnel plot graphs were used to evaluate publica-
tion bias.20
All statistical analyses were implemented using Re-
view Manager 5.3 (The Nordic Cochrane Center, Co-
penhagen, Denmark). A 2-sided P value less than .05
was regarded as statistically significant.
Results
CHARACTERISTICS OF SELECTED STUDIES
From the PubMed, Web of Science, and Cochrane Li-
brary databases, 31 studies were retrieved from the
initial database search. After screening the titles and
abstracts, 21 were duplicates and 1 was excluded.
The remaining 9 articles were reviewed in depth,
and 3 articles were excluded for different reasons
(Fig 1). No additional articles from the reference lists
of included studies were included in this meta-
analysis. Overall, 6 articles were included in this sys-
tematic review and meta-analysis.11-15
All the included articles evaluated the curative ef-
fects of bromelain or placebo for preventing edema,
3
trismus, and pain after third molar surgery. A total of
352 patients were included in the present meta-
analysis, with 208 in the bromelain group and 212 in
the control group. Of the 6 articles, 1 was a crossover
study12 and 5 were parallel studies.11,13-15 The main
characteristics of the included studies are presented
in Table 1. Patients received a course of postoperative
antibiotics13-15 or a single prophylactic dose.11 Anal-
gesic medication was administered as needed.11-15
The rescue drug given in all studies was paracetamol
(acetaminophen). Because the intervention measures
were applied to all patients in the study, differences
between the bromelain and control groups can be
attributed to the effects of the bromelain. The
quality assessment of the included studies is
illustrated in Figure 2. Three main outcomes (pain,
facial swelling, and trismus) were reported in the 5
included trials and pooled in this meta-analysis.
QUALITY ANALYSIS AND RISK OF BIAS
The quality assessment of the included studies is
illustrated in Figure 2. All included studies were cate-
gorized as having a low risk of bias for reporting bias
and other bias. Two studies presented a low risk of
bias for most criteria.12,15 Two studies failed to
provide all data (mean and standard deviation [SD])
for each group and were classified as having a high
risk of attrition bias.11,22
FACIAL SWELLING
The following methods were used to evaluate facial
swelling: 1) lines between pre-established points on
landmarks of the face were added and measured11,14;
2) a visual analog scale (VAS) 10 cm in length was
used15; 3) a semiquantitative score that ranged from
0 to 4 was used13; and 4) a 3-dimensional face scan-
ning system was used.12 The difference between pre-
operative baselines and postoperative measurements
was calculated and pooled to evaluate facial swelling.
Five studies comprising 320 extractions (158 with
bromelain and 162 with placebo) in 252 patients
included facial swelling outcomes during the early
stage after surgery.11-15 On the second or third day
after surgery, bromelain decreased postoperative
swelling (bromelain vs control group: SMD, 0.24;
95% CI, 0.46 to 0.02) significantly (P = .03; Fig
3A). Four studies assessed late facial swelling; 90 pa-
tients received bromelain and 92 received pla-
cebo.11,13-15 The bromelain group showed
significantly decreased facial swelling (bromelain vs
control group: SMD, 0.54; 95% CI, 0.84 to 0.24;
P = .0004), with low heterogeneity (P = .35; I2 = 9%;
Fig 3B).
 4
Table 1. MAIN CHARACTERISTICS OF INCLUDED STUDIES

Patients, n
Double Impaction Control
Study (Year) Location Blind Type Bromelain Control Men, % Age (yr), Mean Bromelain Dosage Type Effect of Bromelain

de la Barrera- Spain Yes Koerner 17 17 50 24.67B, 22.88P 50 mg tid  1-3 days, Placebo There were no
N
un~ ez et al15 index 50 mg bid  statistically relevant
(2014) (5-6) 4-7 days differences between
treatment groups
Bormann et al12 Germany Yes Partial bony 68 68 NR 15-40 1,000 FIP, 3,000 FIP, Placebo Results showed a clear
(2016) 4,500 FIP trend in favor of
bromelain for all
assessments but no
statistically relevant
differences
Ghensi et al11 Italy No Class II, 19 41 54 26.9B, 27.3P 40 mg every Placebo Bromelain used singly
(2017) position B 6 hr  6 days showed moderate anti-
inflammatory efficacy,
decreasing
postoperative swelling

BROMELAIN AFTER MANDIBULAR THIRD MOLAR SURGERY

Hotz (1989)21 Germany Yes Partial bony 50 50 36 24.06  0.80B, 80 mg tid  6 days Placebo Results suggested that
23.56  0.97P bromelain might be
effective for
decreasing facial
swelling in early stage
Majid and Al- Iraq Yes Partial bony 15 15 37 23.7B, 23.8P 250 mg every Placebo Oral bromelain is
Mashhadani14 6 hr  4 days effective therapy to
(2014) improve QOL after
surgical removal of
impacted lower third
molars
Ordesi et al13 Italy No Partial bony 40 40 44 28,7B, 30P 50 mg bid  5 days Placebo Postoperative pain,
(2014) edema, and erythema
were markedly lower
in bromelain group
than in control group
Note: In the included studies, bromelain was administered orally.
Abbreviations: B, bromelain group; bid, 2 times a day; NP, no report; P, placebo group; QOL, quality of life; tid, 3 times a day.
Liu et al. Bromelain After Mandibular Third Molar Surgery. J Oral Maxillofac Surg 2019.
LIU ET AL 5

FIGURE 2. Quality assessment of included studies.

Liu et al. Bromelain After Mandibular Third Molar Surgery. J Oral Maxillofac Surg 2019.

PAIN CI, 0.87 to 0.20; P = .002; Fig 4B), with low

Two methods were used to evaluate postoperative
pain in this meta-analysis: VASs ranging from 0 to
1012,14,15 and a semiquantitative scoring scale
ranging from 0 to 4.13 Three trials that included
139 patients who received bromelain and 141 who
received placebo reported early pain.13-15 The
pooled results showed that bromelain had no
apparent effect on early pain (SMD, 0.13; 95% CI,
0.37 to 0.10; P = .27; Fig 4A), with moderate het-
erogeneity (P = .10; I2 = 52%). Three trials that
included 71 patients who received bromelain and
73 who received placebo reported late pain.13-15
On the seventh day after surgery, the pooled
results showed that bromelain significantly
decreased postoperative pain (SMD, 0.54; 95%
heterogeneity (P = .79; I2 = 0).
Moreover, 3 articles reported on analgesic usage
during the first 7 days after surgery.11,12,14 The
pooled results suggested that the bromelain groups
had less analgesic usage than the control groups
(MD, 1.14; 95% CI, 2.29 to 0.02; P = .05; Fig 4C),
with low heterogeneity (P = .85; I2 = 0).
TRISMUS
The difference in interincisal distance between
the preoperative and postoperative values was re-
corded and evaluated for trismus. Three trials that
included 50 patients who received bromelain and
52 who received placebo reported trismus.11,14,15
The pooled results showed that bromelain had no

FIGURE 3. Forest plots comparing bromelain and control groups for facial swelling. A, Early swelling. B, Late swelling. CI, confidence interval;
SD, standard deviation.
Liu et al. Bromelain After Mandibular Third Molar Surgery. J Oral Maxillofac Surg 2019.
6 BROMELAIN AFTER MANDIBULAR THIRD MOLAR SURGERY

FIGURE 4. Forest plots comparing bromelain and control groups for pain. A, Early pain. B, Late pain. C, Rescue analgesic consumption at
7 days. CI, confidence interval; SD, standard deviation.
Liu et al. Bromelain After Mandibular Third Molar Surgery. J Oral Maxillofac Surg 2019.

apparent effect on early trismus (MD, 2.56 mm; PUBLICATION BIAS

95% CI, 5.59 to 0.46; P = .10; Fig 5A) or late A small sample was included in this meta-analysis;
trismus (MD, 1.56 mm; 95% CI, 3.80 to 0.69; however, publication bias could not be assessed.
P = .17; Fig 5B).

COMPLICATIONS Discussion
No serious complications or side effects were re- The purpose of this systematic review and meta-
ported for the bromelain or control group. analysis was to evaluate the effectiveness of oral

FIGURE 5. Forest plots comparing bromelain and control groups for the difference between baseline maximal interincisal opening and each
postoperative measurement. A, Early trismus. B, Late trismus. CI, confidence interval; SD, standard deviation.
Liu et al. Bromelain After Mandibular Third Molar Surgery. J Oral Maxillofac Surg 2019.
LIU ET AL
bromelain to control postoperative complications af-
ter mandibular third molar surgery. The authors hy-
pothesized that oral bromelain could relieve
uncomfortable symptoms. Facial swelling, trismus,
and pain between the bromelain and control groups
were assessed and compared to illustrate the specific
aim of this meta-analysis.
The pooled results of this study confirm the hypoth-
esis that bromelain appears to be effective for
decreasing facial swelling in the early and late stages
after surgery (early-stage SMD, 0.24; 95% CI, 0.46
to 0.02; P = .03; late-stage SMD, 0.54; 95% CI,
0.84 to 0.24; P = .0004). For pain, this meta-
analysis showed a statistically significant difference
between the bromelain and control groups during
the late stage (SMD, 0.54; 95% CI, 0.87 to 0.20;
P = .002), but there was no significant difference dur-
ing the early stage (SMD, 0.13; 95% CI, 0.37 to
0.10; P = .27). For trismus, analyses showed that
bromelain had no apparent effect on early trismus
(MD, 2.56 mm; 95% CI, 5.59 to 0.46; P = .10;
Fig 5A) or late trismus (MD, 1.56 mm; 95%
CI, 3.80 to 0.69; P = .17).
In addition, a survey on postoperative discomfort in
conjunction with quality-of-life measures showed that
the bromelain group had lower scores on all subscales
compared with the placebo group.14
Bromelain is a mixture of proteolytic enzymes found
in pineapple (Ananas comosus) plants.22 Several
studies reported that bromelain prevented the forma-
tion of edema and decreased existing edemas in a se-
ries of animal experiments.23 In addition, several
studies have suggested multiple anti-inflammatory
mechanisms of bromelain.10 The main mecha-
nisms include:
 Returning the interstitial fluid and inflammatory
component cells into the bloodstream, thus
decreasing swelling of the area.
 Decreasing pain mediators such as proinflamma-
tory prostaglandin E2 and substance P.
Safe and effective medicines with anti-inflammatory
properties and free of side effects would be an excel-
lent option for controlling postoperative complica-
tions, mainly facial swelling, trismus, and pain.
Several studies have compared the efficacy and safety
of bromelain and other anti-inflammatory drugs.
Corticosteroids, which are commonly used to
decrease postoperative inflammation after third molar
surgery, have been indicated to be effective.24-26
Ghensi et al11 compared the curative effects of brome-
lain and dexamethasone after third molar surgery and
concluded that dexamethasone was more effective in
alleviating early swelling but had the same effect on
7
late swelling and trismus compared with bromelain.
However, the use of corticosteroids can be linked to
some complications, including hirsutism, infection,
and hyperglycemia.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
used worldwide and can decrease postoperative symp-
toms after third molar surgery.27,28 Majid and Al-
Mashhadani14 compared the curative effects between
diclofenac and bromelain and concluded there was no
relevant difference between the 2 groups. Inchingolo
et al29 compared the curative effects of ketoprofen
(100 mg every 12 hours for 6 days) with bromelain
(40 mg every 6 hours for 6 days) after third molar sur-
gery and found no relevant difference between the 2
groups. Therefore, they concluded that bromelain
could be as effective as NSAIDs in treating postopera-
tive inflammation after third molar surgery. However,
NSAIDs have many adverse effects, the most common
of which are mucosal hemorrhage, gastritis, and hypo-
tension. In this meta-analysis, no serious complica-
tions and side effects were recorded for the
bromelain or control group.
In addition, recent research has shown that brome-
lain has important clinical effects in patients with he-
matologic tumors after third molar surgery during
chemotherapy.30 Interestingly, bromelain has been
proved to enhance the effects of antibiotics by
increasing tissue permeability.31 Overall, bromelain
conferred similar clinical effects on postoperative dis-
comforts and could be as effective as NSAIDs and cor-
ticosteroids; bromelain could be a viable alternative
for its clinical prospects.
In this meta-analysis and systematic review, 6 studies
evaluated 3 outcomes (pain, swelling, and trismus).
Apart from 1 study, all included studies were double-
blinded RCTs. All 3 outcomes were incorporated
into the meta-analysis and systematic review. More-
over, sensitivity analysis indicated consistent results.
Therefore, in general, the conclusions in the meta-
analysis were credible. Unavoidably, several limita-
tions are present in this meta-analysis. First, there
was no consensus on the dosage of bromelain used.
In addition, only 2 studies included in this meta-
analysis described the impaction type in detail,11,15
which were Koerner index (5 to 6) and Class II
position B; the rest were described as partial bony
impaction.12-14 Hence, more rigorously designed and
high-quality RCTs should be conducted. Second,
when the SD of the difference was not directly avail-
able, a conservative method was applied during the
process of data extraction. Inevitably, conservative
estimates of the SD can lead to a wider CI for the over-
all pooled results. Third, the sample in each trial was
relatively small.
8 BROMELAIN AFTER MANDIBULAR THIRD MOLAR SURGERY
Bromelain conferred moderate benefits to postoper-
ative discomfort in patients who underwent mandib-
ular third molar surgery. Additional high-quality and
rigorously designed RCTs should be designed to verify
these conclusions.
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Appendix
SEARCH STRATEGIES
PubMed
#1: ‘‘Bromelains’’[Mesh] 1312
#2: (Bromelins) OR Bromelin) OR Bromelain) OR
Dayto Anase) OR Debrase) OR Dontisanin) OR
Ananase) OR Mucozym) OR Proteozym) OR
Traumanase) OR Bromelain-POS) OR Bromelain
POS) OR BromelainPOS) OR Extranase) OR
pineapple enzyme 1476
#3: #1 OR #2 1976
#4: ‘‘Molar, Third’’[Mesh] 5939
#5: (Molars, Third) OR Third Molar) OR Third Mo-
lars) OR Tooth, Wisdom) OR Wisdom Tooth)
OR Teeth, Wisdom) OR Wisdom Teeth) 11546
#6: #4 OR #5 12861
#7: #3 AND #6 10
Cochrane Library
#1: Bromelins:ti,ab,kw or Bromelin:ti,ab,kw or
Bromelain:ti,ab,kw or Dayto Anase:ti,ab,kw or
Debrase:ti,ab,kw or Dontisanin:ti,ab,kw or
9
Ananase:ti,ab,kw or Mucozym:ti,ab,kw or Pro-
teozym:ti,ab,kw or Traumanase:ti,ab,kw or
Bromelain-POS:ti,ab,kw or Bromelain POS:-
ti,ab,kw or BromelainPOS:ti,ab,kw or Extrana-
se:ti,ab,kw or pineapple enzyme 112
#2: Molars, Third:ti,ab,kw or Third Molar:ti,ab,kw
or Third Molars:ti,ab,kw or Tooth, Wisdom:-
ti,ab,kw or Wisdom Tooth:ti,ab,kw or Teeth,
Wisdom:ti,ab,kw or Wisdom Teeth:ti,ab,kw or
Molar, Third 2399
#3: #1 AND #2 11
Web of Science
#1: TS=(Bromelins OR Bromelin OR Bromelain
OR Dayto Anase OR Debrase OR Dontisanin
OR Ananase OR Mucozym OR Proteozym
OR Traumanase OR Bromelain-POS OR
Bromelain POS OR BromelainPOS OR Extra-
nase) 2870
#2: TS=(Molars, Third OR Third Molar OR Third
Molars OR Tooth, Wisdom OR Wisdom Tooth
OR Teeth, Wisdom OR Wisdom Teeth OR Molar,
Third ) 17078
#3: TS=#1 AND #2 11