Keywords curcumin patch - orofacial pain - cleft lip surgery - acute pain - postoperative pain
- activity - cry - consolability - cleft palate surgery
Introduction
The latest meta-analysis study performed by Salari et al about the prevalence of cleft
lip, cleft palate, as well as cleft lip and palate, revealed that the prevalence of
cleft palate based on the 59 studies included in the meta-analysis was 0.33 in every
1,000 live birth (95% confidence interval [CI]: 0.28–0.38); the prevalence of cleft
lip based on the 57 studies included was 0.3 in every 1,000 live birth (95% CI: 0.26–0.34);
and the prevalence of cleft lip and palate based on 55 studies included was 0.45 in
every 1,000 live birth (95% CI: 0.38–0.52), indicating the high prevalence of these
birth defects[1 ] and their common occurrence in human beings.[2 ] Aside from its high prevalence, patients and/or family member of patients with cleft
lip and/or cleft palate also reported impacted quality of life.[3 ]
[4 ]
Considering the high prevalence as well as the impact on patients' quality of life,
the treatment of cleft lip and/or cleft palate is performed early in life. The course
of treatment for cleft lip and/or cleft palate patients consists of several stages,
with surgery being the first corrective procedure to go through.[5 ]
[6 ] It is important to conduct surgery as early as possible as it is crucial to make
the patient has a (close to) normal anatomical structure that can function as (near
to) normal as possible.[7 ] Unfortunately, similar to any other invasive approach, surgery has postoperative
consequences, one of which is postoperative pain, regardless of the existing postoperative
pain management.[8 ]
[9 ]
[10 ] In a study conducted by Augsornwan et al, it was reported that 48% of patients who
underwent palatoplasty have moderate-to-severe postoperative pain at the 4th hour,[8 ] indicating the importance of adequate pain management, considering that patients
of labioplasty (corrective surgery of cleft lip) and palatoplasty (corrective surgery
of cleft palate) are mainly very young children that cannot properly communicate their
pain level (yet).
Unlike postoperative pain control in adult patients that can involve the usage of
opioid analgesics, the usage of opioid analgesics in infants who underwent surgery
has been reported for its disadvantages, namely postoperative sedation, respiratory
depression, as well as consequent airway compromise.[9 ]
[11 ] Therefore, various combinations of methods have been applied to reduce this postoperative
pain experienced by postlabioplasty and postpalatoplasty patients, namely the addition
of local anesthesia procedure to the standardized anesthesia procedure, the usage
of opioids and the usage of nonsteroid anti-inflammation drugs.[9 ]
[11 ]
[12 ]
[13 ] Yet, regardless of these various attempts, no single postoperative pain control
procedure for postlabioplasty and postpalatoplasty has been strongly recommended,
which might be due to the various results.
Considering that most of the current postoperative pain control methods consist of
invasive procedure(s) with possible additional side effects, ongoing research that
evaluates the efficacy of postoperative pain control methods for postlabioplasty and
postpalatoplasty patients is currently taking place, including the ones that involve
the utilization of natural ingredients. One of the natural ingredients that have been
widely evaluated and acknowledged for its analgesic effect is curcumin.[14 ]
[15 ]
[16 ]
[17 ] Based on these previous findings, a study that aimed at evaluating the analgesic
effect of curcumin was designed. Therefore, the current study aimed to evaluate the
effectiveness of a curcumin patch as an adjuvant analgesic agent in managing acute
postoperative pain in postlabioplasty and/or postpalatoplasty patients. Considering
that the patient will have a postoperative wound in the oral and facial area, the
curcumin patch will be placed on the patient's chest.
Materials and Methods
Fifty-five (33 male: 22 female) participants aged 36 months old or younger that went
through corrective surgery for a cleft lip or cleft palate at Unpad Dental Hospital
in Bandung, Indonesia, were recruited for the current study. Prior to the start of
the study, ethical clearance was gained from the Universitas Padjadjaran Research
Ethics Committee (No. 715/UN6.KEP/EC/2020). To confirm, every procedure and ethical
aspect of the current research has been conducted in full accordance with the World
Medical Association Declaration of Helsinki. All participants signed informed consent
to consent to their participation and any future scientific publication as the result
of their participation in the current study.
Inclusion and Exclusion Criteria
Participants that fulfilled the following inclusion criteria (1) who had completed
the cleft lip and/or cleft palate surgery procedure; (2) aged 36 months or less; (3)
had no allergic history to curcumin; (4) had an initial pain score of 3 or greater
than 3 on a scale of 0–10; (5) did not have any injuries at other parts of the body
that have the potential to cause pain, aside from the postoperative wounds, were recruited.
Those who (1) consumed additional pain or anti-inflammatory medication in addition
to the curcumin patch or the standard analgesic medication prescribed by the doctor
in charge and (2) removed the curcumin patch position from the initial location given
by the investigator during the study period were excluded from the study.
Sample Size Calculation
The sampling in this study was performed by using a nonprobability sampling technique
with a purposive sampling type. The sample size calculation is performed using the
following formula:
Information
n1 = n2 = sample size
Zα = type I error = 5% (Zα value based on Z table is 1.64)
Zβ = 20%, type II error, (the Zβ value based on the Z table is 0.84)
X1- X2 = minimum difference which is considered significant.
S = Because there is no data regarding the standard deviation of the mean difference
between patients receiving curcumin and those receiving standard drugs, the researchers
suspect that the standard deviation is twice the minimum of the mean difference that
is considered significant = 2×10 = 20.
Based on the above calculations, the number of participants for each group is 25 participants.
Curcumin Patch
The curcumin patch was formulated from a mixture of curcumin extract (obtained from
an Indonesian national brand Sidomuncul), hydroxypropyl methylcellulose, ethyl cellulose,
polyvinylpyrrolidone, Nipagin, Nipasol, Tween 80, and 95% ethanol. The curcumin patch
was in a form of a 6cm×10cm patch ([Fig. 1 ]). Every patch contained 100 mg of curcumin and was prepared based on the procedure
described in the previous study.[18 ] Once the anesthesia effect wore off, our field investigator applied the curcumin
patch to the chest area of the participant ([Fig. 2 ]). The patch was applied for 8hours before it was removed.
Fig. 1 A 100 mg curcumin patch sized 6×10cm used as an adjuvant analgesic agent to manage
acute post-surgery orofacial pain.
Fig. 2 Curcumin patch placement procedure (A-B-C-D subsequently).
Study Design
All participants in this study followed the postsurgery standardized operational procedures
(SOP) for cleft lip or cleft lip surgery patients. According to the SOP, once the
surgical procedure was completed, participants who weighed more than 10kg received
100 mg suppository ketoprofen, while participants who weighed less than 10kg received
50 mg. The next dose of ketoprofen was registered 12hours after the first dose.
Randomization and Blinding
Once the participants completed the operation and received the standard postsurgery
analgesic agent, initial pain evaluation by the #1 and #2 field researchers was performed.
Participants were then randomly assigned to the control group, where the participants
did not receive a curcumin patch; or the treatment group, in which the participants
received a 100 mg curcumin patch. The #3 field researcher that was assigned for curcumin
placement took a sealed envelope that contained the name of the group the participant
was assigned to. Once revealed, this #3 field researcher made a note about which group
the patient was assigned to and performed the patch placement procedure. Therefore,
the field researchers who were assigned to perform the pain evaluation did not have
the knowledge of which group the participant was assigned to.
Pain Evaluation
The pain evaluation was performed by two field researchers simultaneously by using
the face, leg, activity, cry, and consolability (FLACC) pain scale. The FLACC is a
scale that consists of five subsections that are used to assess pain in children aged
from 2-month-old to 7-year-old who are unable to communicate their pain. It has been
validated and tested for reliability and validity in several previous studies. For
each subsection, the pain level is scored as 0, 1, or 2. Therefore, the lowest total
scoring would be 0 (zero), while the highest is 10 (ten). Further explanation of the
FLACC and the scoring system can be viewed in previous studies.[19 ]
[20 ]
Data Analysis
Prior to the main analysis, all data were analyzed by the Kolmogorov–Smirnov normality
test. The data were then analyzed by the Mann–Whitney U test to compare the mean differences
between the two groups.
Results
This current study recruited 55 participants aged between 0 and 36 months old, where
most of the participants are males aged between 0 and 18 months ([Table 1 ]). Most of the participants went through a labioplasty procedure. Three participants
went through a labiopalatoplasty procedure, which means the participants underwent
two procedures (labioplasty combined with palatoplasty) at once. Out of these three
participants, two participants were in the experimental group, and one participant
was in the control group.
Table 1
Demographical and clinical characteristics of the participants
Variable
Number of participants (n )
Sex
Male
Female
33 participants
22 participants
Age
0–18 months
19–36 months
36 participants
19 participants
Type of operation
Labioplasty
Palatoplasty
Labiopalatoplasty
33 participants
19 participants
3 participants
Group
Control
Treatment
28 participants
27 participants
Pain evaluation by using FLACC revealed that the mean pain score immediately after
the general anesthesia wore off (T0) for both groups from a scale of 0 to 10 was 8.02
(standard deviation [SD] = 1.99), while the pain score in the control group for this
evaluation point was 7.54 (SD = 2.12) and the experimental group was 8.52 (SD =
1.76) ([Table 2 ]). The application of the curcumin patch in the experimental group resulted in significant
pain score reduction, which resulted in a mean pain score of 2.48 for the 8th hour
postoperative pain evaluation (T2). Although the control group also showed pain reduction,
the T2 pain score for the control group was still higher than those of the experimental
group.
Table 2
Comparison of the pain score between the control group and the treatment group by
using FLACC pain scale
Group
Minimum
Maximum
Mean
SD
Both
T0 (immediately after anesthesia wore off)
3
10
8.02
1.995
T1 (4hours after the first evaluation)
0
8
3.96
2.045
T2 (8hours after the first evaluation)
0
9
3.05
1.890
Control
T0
3
10
7.54
2.117
T1
1
8
4.04
1.953
T2
1
8
3.61
1.685
Treatment
T0
4
10
8.52
1.762
T1
0
8
3.89
2.172
T2
0
9
2.48
1.949
Abbreviations: FLACC, face, leg, activity, cry, and consolability; SD, standard deviation.
For the main analysis, a Mann–Whitney U test that was used to evaluate the pain score
difference between the control group and the experimental group showed no significant
differences between the first evaluation point (T0) and the second evaluation point
(T1 = four hours after the first evaluation point). While for the third evaluation
point (T2 = eight hours after the first evaluation point), there was a significant
difference (p = 0.005) for the mean pain score ([Table 3 ]).
Table 3
Results of the Mann–Whitney U test for significant mean pain score between the control
group and the treatment group
Time point
Group
Mean rank
p -Value (significant if p < 0.05)
T0
Control
24.16
0.63
Treatment
31.98
T1
Control
28.79
0.70
Treatment
27.19
T2
Control
33.82
0.005
Treatment
21.96
As for side effects, no side effects of the curcumin patch in the current study were
reported nor detected.
Discussion
The current study revealed that most of the participants were male participants. This
finding is consistent with previous findings,[21 ]
[22 ]
[23 ]
[24 ]
[25 ] of which the male predominance in these types of birth defects was mainly reported.
In a literature review by Mairaj et al, it was revealed that male predominance was
reported for the prevalence of cleft lip and palate with a male/female sex ratio of
1.81 (CI 95%: 1.75–1.86).[23 ] In another study conducted by Martelli et al, it was reported that there was a strong
association found between the male gender and the presence of clefts (odds ratio = 3.51;
CI 95%: 2.83–4.37), and that the majority of infants included in their study were
male (61%).[24 ] The current study also found that most operated cases were those of cleft lips ([Table 1 ]), indicating a higher prevalence of this type of cleft. This specific finding is
different from those of the previous findings, where the prevalence of cleft lip and
palates was higher than those of cleft lips or cleft palates alone.[22 ]
[24 ]
In the current study, the difference in pain scores reduction between the control
group and the experimental group was detected. This might be due to the effect of
the curcumin patch applied in the experimental group. A study conducted by Anil et
al on postsurgical patients that underwent a periodontal surgery procedure that evaluated
the efficacy of curcumin as an inflammation and analgesic agent through the transmucosal
route revealed that postoperative pain scores were significantly reduced in the experimental
group. The transmucosal route of drug delivery ensures that the potential therapeutic
agent has a maximum contact period of the desired concentration while also ensuring
better drug absorption.[26 ] Another study conducted by Kriplani et al about the efficacy of curcumin-containing
patches for the treatment of osteoarthritis also indicated the efficacy of curcumin
in providing anti-inflammatory as well as analgesic effects for inflammation of the
bone.[27 ]
Additionally, previous evaluations of the effective curcumin dose in humans have been
reported.[14 ]
[28 ]
[29 ] In these human studies, curcumin was reported to be taken as much as 600 mg per
day,[14 ] 500 to 8,000 mg per day for short-term usage and 440 to 2,200 mg per day for long-term
usage,[29 ] and 180 mg per day for consumption period of 6 months.[28 ] In our study, the dose of the curcumin patch was only 100 mg and was found to be
significantly effective in reducing pain scores at 8hours postsurgery. The low yet
effective dose of curcumin might be due to the delivery method. Curcumin has been
identified for its poor bioavailability due to poor absorption, rapid metabolism,
and rapid systemic elimination.[26 ] Delivery of curcumin through a transdermal route, a similar route to the one used
in our study, has been known as a better delivery route to increase curcumin's penetration
efficacy.[30 ]
[31 ] It was found that the release of curcumin through this delivery method will increase
with time,[30 ] which might be the underlying explanation for the significant difference in pain
scores found on the eighth hour postsurgery.
The significant reduction in pain scores in the experimental group compared with the
control group might be due to curcumin's pathway as an analgesic agent. A preclinical
study of curcumin showed its efficacy of curcumin in managing acute pain. Curcumin
was proven to show antihyperalgesic activity by reversing mechanical hyperalgesia
through a dose-dependent manner. Furthermore, when given in a repeated manner, curcumin
was also proven to be effective in managing postoperative pain.[16 ]
[32 ] Additionally, postoperative pain has been associated with an increased level of
prostaglandin-E2 (PGE2) that is associated with postoperative inflammation.[33 ]
[34 ] Inflammation, which is a natural process following surgery, will induce the release
of several inflammation mediators that will then be followed by the infiltration of
the inflammatory cells to the damaged site and the activation of nociceptive nerve
fibers to produce pain signal. One of the mediators that are increased during the
inflammation period of the postoperative healing period is PGE2,[34 ]
[35 ] a mediator that was also found to be increased in patients with postoperative pain.[36 ]
[37 ]
This increased level of PGE2 in postoperative patients is of advantage for curcumin's
mechanism of action as curcumin is known for its effect in downregulating PGE2.[38 ]
[39 ] The result of previous studies revealed that curcumin affects the arachidonic acid
metabolism through the blocking of cytosolic phospholipase phosphorylation, which
will then reduce the expression of cyclooxygenase-2 as well as PGE2.[40 ]
[41 ] Furthermore, a study conducted by Sahbaie et al about the efficacy of curcumin in
attenuating pain after incision revealed that perioperative curcumin treatment was
proven to be effective in attenuating hyperalgesia due to incision when mice were
challenged with subsequent application of hind paw PGE2,[42 ] indicating the direct effect of curcumin on PGE2. Conclusively, this direct mechanism
of curcumin on PGE2 is one of the potential underlying mechanisms of the significant
difference in pain scores reduction found between the control group and the experimental
group in the current study.
Study Limitation
Even though this study was conducted in a pragmatic method that increases its external
validity, several factors have been identified as the limitation of our study. In
the current study, considering our hypothesis of the direct effect of curcumin on
PGE2, it will be more evident if the PGE2 level was also measured. Therefore, we are
currently conducting other studies that involve the measurement of PGE2 in different
types of surgery. Hopefully, these ongoing studies will provide better evidence in
supporting our current hypothesis of the analgesic potential of curcumin. Additionally,
a qualitative study that investigates the effect of curcumin through the caregiver's
(medical staff) perspective, as well as the parent's perspective would have added
additional value to the study.
Conclusion
In summary, the current study showed a very promising future for curcumin to be used
as an adjuvant analgesic agent for the management of acute orofacial pain due to operative
procedures. And considering that our study applied a pragmatic design by following
the standardized treatment protocol for acute pain management in postsurgery cleft
lip and cleft palate patients, it can be concluded that the external validity of this
study is high and therefore, the result is very much applicable in daily practice.
Last but not least, considering the direct effect of curcumin on PGE2 found in preclinical
studies, it is important to provide further evidence in future clinical studies.
