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Effect of Eucalyptus Oil Inhalation on Pain and Inflammatory Responses after Total Knee Replacement: A Randomized Clinical Trial

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Eucalyptus oil has been reported effective in reducing pain, swelling, and inflammation. This study aimed to investigate the effects of eucalyptus oil inhalation on pain and inflammatory responses after total knee replacement (TKR) surgery. Participants were randomized 1 : 1 to intervention group (eucalyptus inhalation group) or control group (almond oil inhalation group). Patients inhaled eucalyptus or almond oil for 30 min of continuous passive motion (CPM) on 3 consecutive days. Pain on a visual analog scale (VAS), blood pressure, heart rate, C-reactive protein (CRP) concentration, and white blood cell (WBC) count were measured before and after inhalation. Pain VAS on all three days (P < .001) and systolic (P < .05) and diastolic (P = .03) blood pressure on the second day were significantly lower in the group inhaling eucalyptus than that inhaling almond oil. Heart rate, CRP, and WBC, however, did not differ significantly in the two groups. In conclusion, inhalation of eucalyptus oil was effective in decreasing patient's pain and blood pressure following TKR, suggesting that eucalyptus oil inhalation may be a nursing intervention for the relief of pain after TKR.
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Evidence-Based Complementary and Alternative Medicine
Volume , Article ID , pages
http://dx.doi.org/.//
Research Article
Effect of Eucalyptus Oil Inhalation on Pain and
Inflammatory Responses after Total Knee Replacement:
A Randomized Clinical Trial
Yang Suk Jun,1Purum Kang,1Sun Seek Min,2Jeong-Min Lee,3
Hyo-Keun Kim,3and Geun Hee Seol1
1Department of Basic Nursing Science, School of Nursing, Korea University, Anam-dong, Seongbuk-gu, Seoul 136-713, Republic of Korea
2Department of Physiology and Biophysics, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
3KT&G Research Institute, Daejeon 305-805, Republic of Korea
Correspondence should be addressed to Geun Hee Seol; ghseol@korea.ac.kr
Received  April ; Revised  June ; Accepted  June 
Academic Editor: Vincenzo De Feo
Copyright ©  Yang Suk Jun et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Eucalyptus oil has been reported eective in reducing pain, swelling, and inammation. is study aimed to investigate the eects
of eucalyptus oil inhalation on pain and inammatory responses aer total knee replacement (TKR) surgery. Participants were
randomized  :  to intervention group (eucalyptus inhalation group) or control group (almond oil inhalation group). Patients
inhaled eucalyptus or almond oil for  min of continuous passive motion (CPM) on  consecutive days. Pain on a visual analog
scale (VAS), blood pressure, heart rate, C-reactive protein (CRP) concentration, and white blood cell (WBC) count were measured
before and aer inhalation. Pain VAS on all three days (𝑃 < .001) and systolic (𝑃 < .05)anddiastolic(𝑃 = .03) blood pressure
on the second day were signicantly lower in the group inhaling eucalyptus than that inhaling almond oil. Heart rate, CRP, and
WBC, however, did not dier signicantly in the two groups. In conclusion, inhalation of eucalyptus oil was eective in decreasing
patient’s pain and blood pressure following TKR, suggesting that eucalyptus oil inhalation may be a nursing intervention for the
relief of pain aer TKR.
1. Introduction
Osteoarthritis, the most prevalent musculoskeletal disorder
throughout the world, is a common chronic disease that
causes pain, restricts activity, and reduces quality of life
[]. Osteoarthritis may occur in all joints, but the knee
is the most frequent site []. e most common clinical
features of osteoarthritis include pain, stiness, swelling, and
inammation. Surgery may be considered in patients who do
not show symptom improvements on nonsurgical treatments,
especially when severe pain interferes with daily life []. Total
knee replacement (TKR) is a surgical procedure in which
deformed knee cartilage is resected and replaced by a metal
structure lled with polyethylene, resulting in a new joint
structure. TKR has been shown to improve the quality of life
of patients with severe arthritis by relieving knee pain and
increasing knee function []. Inammation by infection aer
TKR has a negative impact on patient prognosis, with deep
infection requiring a second operation []. us, inamma-
tion control as well as pain management are required for rapid
recovery and functionality. Eucalyptus (Eucalyptus globulus)
oil has been widely used as a folk medicine to treat upper
respiratory infections, gastritis, and diabetes [].
Eucalyptus oil contains 𝛼-pinene and ,-cineole and acts
as an antioxidant, with strong radical scavenging activity [].
In a mouse model of pain-causing edema in the feet, oral
administration of ,-cineole, which accounts for –%
(w/w) of the contents of eucalyptus oil, suppressed edema
formation and reduced inammation and pain []. is eect
of ,-cineole is due to its inhibition of cytokine secretion
by T-lymphocytes []. Electromyography has shown that
application of eucalyptus oil to a healthy subject had a
myorelaxant eect, as well as promoting emotional stability
[]. Moreover, in a rat model of susceptibility to pain from
a hot plate, eucalyptus oil was not only analgesic but reduced
edema formation and had an anti-inammatory eect [].
Evidence-Based Complementary and Alternative Medicine
Although eucalyptus oil has been found to reduce pain
and suppress edema and inammation in animal models, its
eects on pain in patients who have undergone TKR have not
been determined. We therefore assessed whether eucalyptus
oil inhalation could eectively reduce pain and inammatory
responses in patients who have undergone TKR.
2. Materials and Methods
2.1. Study Design and Sample Size. Patients were randomly
assigned using table of random numbers to inhalation of
eucalyptus oil or almond oil (used as solvent, control) during
continuous passive motion (CPM) aer TKR, with both
investigators and subjects blinded to treatment assignment.
Basedonaneectsizeof.,astatisticalpowerof.,and
a signicance level of ., the minimum number of patients
required to compare dierences between the experimental
and control group was estimated to be  patients per group.
Twenty-eight subjects were originally assigned to each group,
with  completing the study,  in the experimental and 
in the control group.
2.2. Participants. Patients diagnosed with osteoarthritis by
the same physician and who underwent TKR were invited
to participate. All subjects () had been prescribed pain
medications, including oxycodone hydrochloride, fentanyl,
nonsteroidal anti-inammatory drugs (NASID), and antibi-
otic pills, () had no complications or other inammatory
diseases aer surgery, () were not being treated with any
antidepressant, hormone, or aroma therapy, () did not
smoke, () were conscious and oriented, and () had a
pain score on a visual analog scale (VAS) >beforearoma
inhalation. e study design and protocol were approved by
the Ethical Review Committee of the Korea University Med-
ical Center (Code: ED), and all participants provided
written informed consent.
2.3. Gas Chromatography-Mass Spectrometry Analysis. Gas
chromatography-mass spectrometry (GC-MS) was per-
formed to analyze compositions of eucalyptus oil. GC-
MS analysis was performed using an Agilent  gas
chromatograph with a  inert mass spectrometer (USA),
and analytical capillary column was performed on HP-
Innowax ( m ×. mm i.d., . 𝜇mlmthickness,
Agilent, USA). Carrier gas was helium and owrate was
. mL/min. e injector temperature was increased to
C. And samples (. 𝜇L) were injected at a split ratio of
 : . e column temperature was initially maintained at
C(holdformin),rampto
Cat
C/min, and nally
held for  min. e ion source and transfer line temperature
were set at Cand
C. e mass spectrometer was
operated in the electron impact ionization mode ( eV).
2.4. Intervention. Eucalyptus oil and almond oil were sup-
plied by Aromarant Co. Ltd. (Rottingen, Germany). Euca-
lyptus oil was dissolved at a concentration of % (v/v) in
almond oil. In experimental group, eucalyptus oil (dissolved
in almond oil) was placed onto a 4×2inch gauze pad,
which was positioned between the nose and philtrum for
 minutes of CPM on  consecutive days, beginning on
thethirddayaersurgery.econtrolgroupreceivedthe
same treatment of experimental group except for eucalyptus.
Eucalyptus oil and almond oil have a similar color and were
packed same-shaped bottles. All experiments were carried
out separately. e compounder was the only one who knows
which participant aliated to which group according to the
assigned number on bottle. Patients and investigator were not
informed about the types and eects of aroma oil.
2.5. Outcome Measurement. Pain was measured using the
VAS pain score. It is also used in most studies of anxiety,
consists of a horizontal scale, ranging from  (no pain) on
the le side and  (extreme pain) on the right side [].
Patients were asked to indicate VAS pain score by number
at each determination. Blood pressure and heart rate were
measured on each day of oil inhalation, before and aer CPM,
as indicators of the reaction of the autonomic nervous system
to pain. Blood pressure was measured in the brachial artery
using a Deluxe Aneroid Sphygmomanometer (Mac-check,
Japan) aer a -minute rest in a lying position. Pulse was
measured at the radial artery for  minute.
In this study, CRP was measured by a Latex Immunoassay
with LX- (Eiken Inc., Japan) and WBC was measured
by semiconductor ow cytometry with an XE- (Sysmex,
Inc., Japan).
2.6. Data Collection. Blood samples were collected before
breakfast on the rst day of aroma inhalation and on days
 and  for measurements of C-reactive protein (CRP)
concentrations and white blood cell (WBC) count. Pain VAS,
blood pressure, and heart rate were measured before and aer
each  min inhalation session.
2.7. Statistical Analysis. All statistical analyses were per-
formed using the Statistical Package for the Social Sciences,
SPSS .. e demographic and clinical characteristics of the
two groups were compared using t-tests, Fisher’s exact tests,
and Chi-square tests, as appropriate. All data are presented
as frequency, percentages, and standard error of the mean
(SEM) or standard deviation (SD). Dierences in the VAS
pain scores before and aer aroma inhalation within each
groupwerecomparedusingtheWilcoxonsrank-sumtestand
paired t-test, and dierences between groups were analyzed
using Mann-Whitney U-tests and unpaired t-tests.
3. Results
3.1. Compositions of Eucalyptus Oil. A total of  compounds
were identied (Tab l e  ). e major volatile avor com-
pounds of eucalyptus oil were ,-cienol (.%), limonene
(.%), 𝜌-cymene (.%), 𝛾-terpinene (.%), and 𝛼-
pinene (.%).
3.2. Characteristics of the Participants and Test of Homo-
geneity. Fiy-two individuals were randomized,  to the
eucalyptus oil and  to the almond oil (control) group.
Evidence-Based Complementary and Alternative Medicine
T : Chemical compositions of the eucalyptus oil determined by
GC-MS.
RTa(min) KIbCompound Area %c
.  𝛼-pinene .
.  𝛼-fenchene .
.  Camphene .
.  𝛽-pinene .
.  o-cymene .
.  b-myrcene .
.  𝛼-phellandrene .
.  𝛼-terpinene .
.  Limonene .
.  ,-cineole .
.  trans-𝛽-ocimene .
.  𝛾-terpinene .
.  𝜌-cymene .
.  𝛼-terpinolen .
.  Isoamyl isovalerate .
.  o-menthone .
.  𝛼-pinene epoxide .
.  Dehydro-𝜌-cymene .
.  cis-Limonene oxide .
.  Linalool .
.  Fenchyl alcohol .
.  -Terpineol .
.  trans-pinocarveol .
.  cis-Citral .
.  Crypton .
.  𝛼-terpineol .
.  𝛼-terpinyl acetate .
.  Borneol .
.  Carvone .
.  cis-Carveol .
.  trans-Geraniol .
aRT: retention time. bKI: Kovatsindices. cCalculated with peak area obtained
from GC/MS.
Demographic and disease-associated characteristics were
similar in the two groups, including type of surgery, duration
of osteoarthritis, and treatments with oral antihypertensive
and antidiabetic agents (Ta b l e  ). e mean age of the 
participants was . years (range, – years), and most
were female. eir average body mass index (BMI) was
26.4 ± 3.1kg/m2, and all  were overweight/obese (BMI
 kg/m2). irty-seven patients (.%) underwent a unilat-
eral TKR and  (.%) underwent a simultaneous, bilateral
TKR. e mean durations of osteoarthritis in the eucalyptus
and almond oil groups were 8.5 ±5.7 years and 6.0 ±5.2 years,
respectively. Before aroma inhalation, VAS pain score, sys-
tolic blood pressure, diastolic blood pressure, heart rate, CRP,
and WBC count were similar in the two groups (Table  ).
3.3. Eects of Eucalyptus Oil on VAS Pain Score. VA S p a i n
scores aer aromatherapy on days – decreased 1.1 ± 0.2,
1.2 ± 0.2,and.2 ± 0.2 points, respectively, from the scores
before inhalation (Figure (a)). In the control group, however,
VASpainscoresondaysincreased0.4 ± 0.2,0.3 ± 0.2,
and 0.1 ± 0.1 points, respectively, from the scores before
inhalation. Overall, VAS pain scores were signicantly lower
in the eucalyptus oil group than in the control group (𝑃<
.001,Figure (a)).
3.4. Eects of Eucalyptus Oil on Heart Rate and Blood
Pressure. Relative to pretreatment heart rate, heart rate in the
eucalyptus oil group increased 0.3±1.6beats/min on day  of
CPM and decreased 1.7±1.7beats/min and 0.6±1.0beats/min
on days  and , respectively (Figure (b)). e heart rate in
the control group, however, showed increases aer CPM of
2.1±0.7,1.5±0.9,and0.8±0.7 beats/min on days – of CPM,
respectively. Between-group dierences in heart rate did not
dier signicantly.
Systolic blood pressure on days – decreased 0.8 ±
1.9mmHg, 4.8±2.2 mmHg, and 2.0±2.0 mmHg, respectively,
in the eucalyptus oil group, while increasing 0.4 ±1.7 mmHg,
3.3 ± 2.2 mmHg, and 1.9 ± 1.6mmHg, respectively, in the
control group (Figure (c) ). On day , SPB was signicantly
lowerintheeucalyptusoilthaninthecontrolgroup(𝑃<
.05,Figure (c)). Similarly, diastolic blood pressure in the
eucalyptus oil group decreased 0.4 ± 1.5mmHg, 0.8 ±
1.5mmHg, and 0.0 ± 1.2mmHg, respectively, on days –
, while increasing 1.1 ± 1.5mmHg, 3.7 ± 1.4mmHg, and
2.6±1.1 mmHg, respectively, in the control group on the same
days. Diastolic blood pressure on day  was signicantly lower
intheeucalyptusoilgroupthaninthecontrolgroup(𝑃 = .03,
Figure (d)).
3.5. Eects of Eucalyptus Oil on Inammatory Responses.
Serum CRP concentrations before inhalation and on days
andwere7.2 ± 3.9,53.5 ± 6.8,and48.8 ± 11.0 mg/L,
respectively, in the eucalyptus oil group, and 4.89±2.0,68.2±
8.2,and46.8 ± 7.7 mg/L, respectively, in the control group
(Figure (a)). Although CRP concentrations in both groups
tended to increase gradually aer surgery and then decrease,
no between-group signicant dierences were observed.
WBC counts before inhalation and on days  and  were
,513.2 ± 417.0 × 103/𝜇L, 7,062.0 ± 377.9 × 103/𝜇L, and
7,450.0 ± 383.5 × 103/𝜇L, respectively, in the eucalyptus oil
group, and 6,793.3±268.8×103/𝜇L, ,112.6±336.9×103/𝜇L,
and 7,970±502.4×103/𝜇L, respectively, in the control group
(Figure (b)). None of these dierences reached statistical
signicance.
4. Discussion
Since eucalyptus oil has been reported eective in reducing
pain and suppressing inammation in the various animal
models, we tested whether inhalation of eucalyptus oil
aected pain, blood pressure, heart rate, CRP concentration,
and WBC count following TKR in patients with osteoarthri-
tis.
Pain is an emotion which is quintessentially subjective
and personal [,]. To assess patient’s subjective pain, we
Evidence-Based Complementary and Alternative Medicine
T : General characteristics of the eucalyptus oil and control groups (𝑁=52).
Characteristics Tota l
(𝑛=52)
Control
(𝑛=27)
Eucalyptus oil
(𝑛=25)𝑡or 𝜒2P-value
Age (years) . (.) . (.) . (.) . .a
Gender
Female  (.)  (.)  () . .b
Male  (.)  (.)  (.)
Surgical classication
Unilateral  (.)  (.)  (.) . .c
Bilateral  (.)  (.)  (.)
BMI (kg/m). (.) . (.) . (.) . .a
Education
Elementary  (.)  (.)  (.) . .b
Middle  (.)  (.)  ()
High  (.)  (.)  (.)
Marital status
Married  ()  ()  ()
Employed
Ye s  (.)  (.)  (.) . .c
No  (.)  (.)  (.)
Duration of osteoarthritis (years) . (.) . (.) . (.) . .a
Hypertension medication
Ye s  (.)  (.)  () . .c
No  (.)  (.)  ()
Diabetes medication
Ye s  (.)  (.)  () . .c
No  (.)  (.)  ()
Data reported as mean (SD) or 𝑛(%).
Abbreviations: SD: standard deviation, BMI: body mass index.
at-test.
bFisher’s exact test.
cChi-square test.
T : Outcomes in the eucalyptus oil and control groups (𝑁=
52).
Variabl e s Control
(𝑛=27)
Eucalyptus oil
(𝑛=25)P-value
VA S ( s c o r e ) 5.0 ± 1.0 5.0 ± 0.0 .
sBP (mm Hg) 120.0 ± 20.0 120.0 ± 20.0 .
dBP (mm Hg) 80.0 ± 10.0 80.0 ± 10.0 .
HR (beats/min) 78.0 ± 8.0 78.0 ± 10.0 .
CRP (mg/L) 4.9 ± 10.5 7.2 ± 19.3 .a
WBC (×/𝜇L) 6793.3 ± 1396.6 6513.2 ± 2084.9 .a
Abbreviations: VAS: visual analog scale; sBP: systolic blood pressure; dBP:
diastolic blood pressure; HR: heart rate; CRP: C-reactive protein; WBC:
white blood cell.
Wilcoxon’s rank sum test. Data presented as median ±interquartile range.
at-test. Data presented as mean ±standard deviation.
used a VAS measurement tools. We found that inhalation
of eucalyptus oil signicantly decreased VAS pain scores
compared with our control group. e major component of
eucalyptus oil is ,-cineole, which had a morphine-like eect
relieving pain in mice []. Another study also found that ,-
cineole exhibited antinociceptive properties in rats and mice
[]. ese ndings, taken together with our results, suggest
that subjective pain-reducing eects of eucalyptus oil are due,
at least in part, to ,-cineole.
Serotonin has been considered to have an important
role in the control of pain []. Activation of serotonin
receptor presents on C-bers has been shown mediating
serotonin-induced pronociceptive eects []. Recent studies
have shown that essential oils act via modulating of the
central neurotransmitter system. Hypericum perforatum is
considered to inhibit the synaptosomal uptake of serotonin
[]. Also, lemon oil reported to have an antixiolytic eects
via the suppression of monoamines dopamine and enhancing
serotonergic neurons []. erefore pain-relieving eects of
eucalyptus oil in the present results should be considered
an involvement of serotonergic system. Pain and stress aer
TKR and during CPM are thought to act on the central and
Evidence-Based Complementary and Alternative Medicine
Dierence in VAS (score)
−2
−1
0
1
2
1st 2nd 3rd
Cont.
Exp.
∗∗∗ ∗∗∗ ∗∗∗
Inhalation day
(a)
Dierence in HR (beats/min)
−4
−2
0
2
4
1st 2nd 3rd
Cont.
Exp.
Inhalation day
(b)
Dierence in sBP (mmHg)
−8
−4
0
4
8
1st 2nd 3rd
Cont.
Exp.
Inhalation day
(c)
Dierence in dBP (mmHg)
−4
0
4
8
1st 2nd 3rd
Cont.
Exp.
Inhalation day
(d)
F : Eects of inhalation on (a) VAS, (b) HR, (c) sBP, and (d) dBP in the eucalyptus oil (𝑛=25) and control (almond oil; 𝑛=27)groups.
Results are expressed as mean ±SEM. 𝑃 < .05,∗∗∗𝑃 < .001 compared with the control group. Abbreviations: VAS, visual analog scale; HR,
heart rate; sBP, systolic blood pressure; dBP, diastolic blood pressure.
sympathetic nervous systems, increasing blood pressure and
pulse. In the present study, group treated with eucalyptus
oil inhalations showed statistically signicant reduction in
blood pressure, suggesting that eucalyptus oil could promote
relaxation by reducing sympathetic activity while augment-
ing parasympathetic during CPM aer TKR. A possible
pathway for this explanation may include the olfactory
system. Autonomic nervous system is aected by odorants,
thus inhalation of essential oil is direct actions on the auto-
nomic nervous system via olfactory system [,]. Recent
study has shown that olfactory stimulation with lavender
essential oil and its active component, linalool reduced the
sympathetic nerve activity in rats []. erefore, eucalyptus
oil also may modulate autonomic responses such as blood
pressure via central nervous system and autonomic nervous
system. e cardiovascular eects of ,-cineole were also
investigated in several research. ,-cineole decrease blood
pressure in normotensive rate and elicited a endothelium-
dependent vasorelaxation in rate aorta [,]. Other reports
have shown that the administration of ,-cineole reduces
contractile activity in rat []. us, there is a possibility that
,-cineole contributes to hypotensive eects of eucalyptus
essential oil.
Eucalyptus oil has been used to treat inuenza infection,
owing to its anti-inammatory and antibacterial eects [].
Moreover, ,-cineole was found to reduce cytokines that
Evidence-Based Complementary and Alternative Medicine
Cont.
Exp.
0
100
200
CRP (mg/L)
Day aer inhalation
Pre 4th 7th
(a)
0
5,000
10,000
WBC (×1000/𝜇L)
Pre 4th 7th
Day aer inhalation
Cont.
Exp.
(b)
F : Eects of inhalation on (a) CRP and (b) WBC in the eucalyptus oil (𝑛=25) and control (almond oil; 𝑛=27) groups. Values are
expressed as mean ±SEM. Abbreviations: CRP, C-reactive protein; WBC, white blood cell.
cause inammation in guinea pigs [], and to signicantly
reduce edema and CRP at sites of inammation throughout
the entire body []. ese studies prompted us to hypoth-
esizethateucalyptusoilwouldreducepainfollowingTKR
by lessening inammatory reactions. However, markers of
inammatory responses, such as CRP concentration and
WBC count, did not dier signicantly between the our
eucalyptus oil and control groups although comparisons
before and aer inhalation showed that the WBC count
tended to be lower in the eucalyptus than in the control
group, which may have been due to the time of inspection, the
concentration of eucalyptus oil inhaled, and/or its frequency
of application.
In summary, this study, which investigated the eects
of eucalyptus oil inhalation on patients who underwent
TKR, showed that eucalyptus oil inhalation was eective
inreducingpatientssubjectivepainandbloodpressure
aer surgery. ese ndings suggest that the inhalation of
eucalyptus oil might be a valuable nursing intervention for
pain relief aer TKR.
Conflict of Interests
e authors declare they have no conict of interests.
Acknowledgments
e rst two authors (Yang Suk Jun and Purum Kang)
contributed equally to this work. is work was supported
by the National Research Foundation of Korea (NRF) Grants
funded by the Korea government (MEST) (nos. 
and ).
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... Eucalyptus globulus which belongs to the Myrtaceae family is one of the medicinal plant products (Hayat et al., 2015). It has been widely benefited to treat upper respiratory conditions (Her et al., 2022) and other diseases such as diabetes, gastritis, and knee pain (Jun et al., 2013). The existing studies also reported that E. globulus has analgesic and anti-inflammatory properties (Nakamura et al., 2020). ...
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