Chen 2021

Download as pdf or txt
Download as pdf or txt
You are on page 1of 8

Phytomedicine 80 (2021) 153380

Contents lists available at ScienceDirect

Phytomedicine
journal homepage: www.elsevier.com/locate/phymed

Efficacy of cinnamon patch treatment for alleviating symptoms of


overactive bladder: A double-blind, randomized, placebo-controlled trial
Lih-Lian Chen a, b, Yuh-Chiang Shen a, c, d, Chih-Chun Ke e, Zuha Imtiyaz a, Hui-I Chen a,
Chin-Hsien Chang b, f, Mei-Hsien Lee a, g, h, *
a
PhD Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
b
Department of Traditional Chinese Medicine, En Chu Kong Hospital, 399 Fuxing Road, New Taipei City 23702, Taiwan
c
National Taipei University of Nursing and Health Sciences, 365 Mingde Road, Taipei 11219, Taiwan
d
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, 155-1 Linong Street, Sec. 2, Taipei 11221, Taiwan
e
Department of Urology, En Chu Kong Hospital, 399 Fuxing Road, New Taipei City 23702, Taiwan
f
Department of Cosmetic Science, Chang Gung University of Science and Technology, 261 Wenhua 1st road, Taoyuan City 33303, Taiwan
g
Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
h
Center for Reproductive Medicine & Sciences, Taipei Medical University Hospital, 252 Wuxing Street, Taipei 11031, Taiwan

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Current treatments for overactive bladder (OAB) have limited efficacy, low persistence and a high
overactive bladder rate of adverse events commonly leading to treatment cessation in clinical practice. Clinicians in Asia commonly
cinnamon use traditional Chinese medicine as an alternative for OAB treatment despite it having uncertain efficacy and
herbal patch
safety. To evaluate the efficacy and safety of cinnamon patch (CP) treatment for alleviating symptoms of OAB, a
acupoint
overactive bladder symptom score
double-blind randomized, placebo-controlled trial was conducted in the present study.
Materials and Methods: In this 6-week randomized clinical trial conducted in an outpatient setting, 66 subjects
diagnosed as having OAB were enrolled and treated with a placebo (n=33) or CP (n=33). The OAB symptom
score (OABSS) was selected as the primary end point, and a patient perception of bladder condition (PPBC), an
urgency severity scale (USS), and post-voiding residual urine (PVR) volume were selected as secondary end
points. Statistical analyses were performed with IBM SPSS Statistics 20. Groups were compared using an inde­
pendent sample t-test, Fisher exact test, and Chi-squared test.
Results: In total, 66 participants (40 women and 26 men), 60.35 ± 12.77 years of age, were included in the
intention-to-treat analyses. Baseline characteristics were comparable between the CP (n ==33) and placebo (n
==33) groups. Treatment with a CP showed statistically significant differences in reductions in OABSS scores
(9.70 ± 2.20 to 6.33 ± 2.42), PPBC scores (3.36 ± 0.60 to 2.15 ± 0.83), and USS scores (2.67 ± 0.54 to 1.64 ±
0.60).
Conclusions: Compared to a placebo, treatment with CP might be considered an effective and safe complementary
therapy for OAB. Further studies employing a positive control, different dosage forms, larger sample sizes, and
longer treatment periods are warranted.

Introduction nocturia (D’Ancona et al., 2019; Haylen et al., 2010). OAB affects pa­
tients’ physical function, social life, and sleep quality, and causes situ­
Overactive bladder (OAB) is a clinical syndrome characterized by ations like loss of productivity, a lower self-image, and increased
frequent urination, with or without urge incontinence, urgency, and morbidity, such as falls and fractures, and mortality (Szabo et al., 2018).

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CP, cinnamon patch; Cr, serum creatinine; MID,
minimally important difference; OAB, overactive bladder; OABSS, overactive bladder symptom score; PPBC, patient perception of bladder condition; PVR, post-
voiding residual; SAE, severe adverse event; TCM, traditional Chinese medicine; US, ultrasound; USS, urgency severity scale.
* Corresponding author: Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan, Tel.:
+886-2-27371661 ext. 6151; fax: +886-2-27357983
E-mail address: lmh@tmu.edu.tw (M.-H. Lee).

https://doi.org/10.1016/j.phymed.2020.153380
Received 24 April 2020; Received in revised form 20 September 2020; Accepted 11 October 2020
Available online 12 October 2020
0944-7113/© 2020 Elsevier GmbH. All rights reserved.
L.-L. Chen et al. Phytomedicine 80 (2021) 153380

One of the largest population-based surveys that studied the prevalence investigator who handed it to the patient. Neither the patient nor
of lower urinary tract symptoms and OAB conducted in five European investigator was aware of which treatment was being administered. The
countries in 2016 discovered that the prevalence of OAB was 11.8% study was approved by the Institutional Review Board of En Chu Kong
(Eapen and Radomski, 2016). In Taiwan, 19.8% of people suffer from Hospital (no. ECKIRB1051203, Supplement 1), and registered at Clin­
OAB symptoms, and its prevalence increases with age, with similar icalTrials.gov (NCT03532789 https://clinicaltrials.gov/ct2/show/NC
proportions in both sexes (18.7% of women and 19.9% of men) (Chiu T03532789).
et al., 2012). Several conditions may contribute to signs and symptoms
of OAB, including neurological disorders, such as stroke and multiple Interventions
sclerosis, diabetes, acute urinary tract infections (UTIs), abnormalities of
the bladder, such as tumors or bladder stones, and declining cognitive Patients visited our clinic four times over a time span of 7 weeks:
function due to aging (Patra and Patra, 2014). Current treatments of screening (visit 1), 1 week later for randomization and start of patch
OAB, including behavioral therapy, medication with antimuscarinic treatment (visit 2, baseline), 2 weeks after beginning treatment (visit 3,
drugs, and sacral neuromodulation or intradetrusor onabotulinumtoxin end of treatment), and 4 weeks after the end of treatment (follow-up)
A injections are not completely effective (Michel, 2020). In addition, (Fig. 2). At visit 2, the experimental group was treated with a CP 4 h
these treatments can cause various side effects, like dry mouth, con­ every 2 days. Each CP contained 1.5 g of crude cinnamon powder (batch
stipation, migraines, infections, and gross hematuria (Corcos et al., no.: BA101012A, containing 2.58% cinnamaldehyde; Ministry of Health
2017). and Welfare Manufacturing no. 053990) manufactured by Shen Chang
The main manifestations of OAB such as “frequent urination”, GMP-certified Pharmaceutical (Taoyuan, Taiwan), 1 g of corn starch,
“nocturia”, and “urinary incontinence” are clearly recorded in a Chinese and 4 ml of reverse-osmosis water in a 11.6 × 7.8-cm-sized patch. The
medical classic Zhu bing yuan hou lun (諸病源候論) from the Sui Dynasty placebo patch for the control group contained 2.5 g of corn starch and 4
(581~618 CE) (Chao, 1966). Several traditional Chinese medicine ml of reverse-osmosis water in the same-sized patch. Crude cinnamon
(TCM) prescriptions, such as cinnamon twig decoction plus cinnamon powder was qualitatively tested by ultra-performance liquid
(桂枝加桂湯), which contains an incremental dose of cinnamon, are chromatography-diode array detector-tandem mass spectrometry
used to promote the elimination of coldness and water in the urinary (UPLC-DAD-MS/MS) (Supplement 2) in accordance with specifications
bladder (Pan et al., 2006). TCM physicians usually prescribe a decoction using appropriate reference standards. All analytical methods were
of cinnamon bark with other herbs to reduce abdominal pain and in­ validated for selectivity, accuracy, and precision. All study products
crease the blood circulation, especially in the urogenital system and were kept in a secure, locked place and were only accessible to autho­
lower extremities (Zhang et al., 2019). Several studies confirmed the rized personnel. The application sites for all patches was between the
role of cinnamaldehyde and cinnamic acid in reducing cardiovascular umbilicus and pubic symphysis and in front of the urinary bladder, and
diseases (Rao and Gan, 2014). Cell culture studies provided evidence for acupoints CV3, CV4, CV5, and CV6 were covered (Fig. 1). In total, seven
the efficacy of cinnamaldehyde in inhibiting angiogenesis and patches were distributed to each patient for 2 weeks, then the patient
enhancing tumor cell apoptosis (Abbasi et al., 2020). Other pharmaco­ returned 4 weeks after finishing treatment for the final follow-up.
logical activities of cinnamon were reported, including Duration of patch treatment was according to the result of our pre­
anti-inflammatory, antioxidant, neuroprotective, antidiabetic, and liminary study (Supplement 3). After dispensing, all patches were stored
antimicrobial activities (Rao and Gan, 2014). OAB is closely related to at a temperature of 4~8 ◦ C in each patient’s refrigerator before use.
neurological dysfunction. Therefore, the neuroprotectivity of the
essential oil of cinnamon could be beneficial to OAB. Participants
In TCM, qi energy flows throughout the body along pathways known
as meridians. Located along these meridians are acupuncture points Adults over the age of 20 years with symptoms of OAB which were
(acupoints) where the qi rises to the surface of the body. Manipulation of simultaneously diagnosed by the urologist, Dr. Ke, and the traditional
acupoints is used to effectively reduce postoperative analgesic re­ Chinese physician, Dr. Chen, were recruited via a variety of advertising
quirements in patients undergoing lower abdominal surgery (Lin et al., media. The inclusion criteria for participants at the baseline visit were: aged
2002) and improve urine leakage in women with stress urinary incon­ ≥ 20 years, an OABSS total score of ≥ 3 points, and a question 3 (urgency)
tinence (Liu et al., 2017). Accordingly, in this study, with approaches of the OABSS of ≥ 2 points (Yamaguchi et al., 2009). Since OAB is defined by
Western medicine and TCM tools, we carried out a randomized subjective rather than objective symptoms, the patient’s perspective is
double-blind, placebo-controlled clinical trial (RCT) of a cinnamon important in managing this disease. Thus, the OABSS was used as an in­
patch (CP) treatment on acupoints in OAB patients using OABSS, pa­ clusion criterion and diagnostic tool in our study (Chuang et al., 2018).
tient’s perception of their bladder condition (PPBC), and urgency Exclusion criteria were patients with an acute urinary tract infection ; a
severity scale (USS) to investigate the efficacy of CP treatment, as well as recurrent urinary tract infection of more than five times in the past year;
using abdominal ultrasound (US) scanning to measure changes in the hematuria; bladder stones; ongoing estrogen treatment for > 2 months
post-voiding residual (PVR) volume. before the trial; permanent or intermittent catheterization; pregnancy or
breastfeeding; a spinal cord injury; mental illness or substance abuse; and
Materials and Methods any intake of bladder-affecting drugs such as anticholinergics,
alpha-adrenergic blockers, diuretics, and phytotherapeutics in the previous
Trial design month.

An RCT (double-blind randomized and placebo-controlled) was Measurements


conducted at the Department of Traditional Chinese Medicine and
Urology of En Chu Kong Hospital, Taiwan from May 2018 to September The primary outcome of this RCT was the effect of the CP on the OABSS.
2019. Permuted block randomization was used to allocate participants This scoring system, OABSS, is rational, involves all OAB symptoms, and
to two treatment groups with a block size of four (https://www.sealed places more weight on the scores for urgency and urgency incontinence
envelope.com/randomisation/internet/). All patients were well- (with a maximum score of 5), which are the most bothersome symptoms,
informed and signed a consent form, the trial was conducted in accor­ than on micturition frequency (with a maximum score of 2 or 3). The
dance with Good Clinical Practice guidelines, and we abided by all OABSS is widely used to identify patients with OAB and to evaluate the
applicable local regulatory requirements and laws. The medication severity of OAB, as well as treatment outcomes (Chuang et al., 2018).
patch was dispensed in a blinded manner at visit 2 (baseline) by the Secondary outcomes were effects of the CP on PPBC, USS, and PVR.

2
L.-L. Chen et al. Phytomedicine 80 (2021) 153380

Figure 1. Application site including acupoints (CV3, CV4, CV5, and CV6) for the placebo and cinnamon patch.

Bladder symptoms rating scale blood urea nitrogen (BUN)), adverse events, adverse drug reactions, and
severe adverse events (SAEs) as evaluated or reported by patients.
The OABSS, PPBC, and USS are three questionnaires validated in the
Chinese language for people with bladder symptoms (Chou et al., 2014). Statistical analysis
The OABSS consists of four items that correspond to daytime frequency,
urinary urgency, incontinence, and nocturia. The relative weighting of The sample size of this study (n ==66) was calculated from the effect
the maximal score was respectively designated 2:3:5:5 for daytime fre­ size (n ==52, G*power 3.1) (Faul et al., 2007) according to results of our
quency, nocturia, urgency, and urge incontinence. The overall score is preliminary study (Supplement 3) and loss to follow-up rate (20%) was
the sum of the four scores, and the diagnostic criteria for OAB are a total also considered. All data analyses were performed with IBM SPSS Sta­
OABSS of ≥ 3 and an urgency score for question 3 of ≥ 2. In the event tistics 20 (SPSS, Chicago, IL). The groups were compared at visit 2 using
that the OABSS is used as the standard for assessing the severity of OAB an independent-sample t-test, Fisher exact test and Chi-squared test.
(Homma et al., 2006), it is recommended that a total score of ≤ 5 be Baseline characteristics were evaluated for the 66 patients that finished
defined as mild, a score of 6~11 as moderate, and a score of ≥ 12 as the study (33 in the placebo patch group and 33 in the CP group).
severe symptoms. The PPBC (score range of 0~5) is a single item that Comparisons of primary outcomes between the two groups are
assesses a patient’s subjective impression of their current urinary expressed as the mean ± standard deviation (SD).
problems (Coyne et al., 2006). The USS (score range of 0~4) is a vali­
dated patient-reported measure of urgency (Nixon et al., 2005). The Results
higher the score, the greater the severity associated with increased
symptom bother and a worse health-related quality of life. All three of General characteristics
these scales were completed at visits 2, and 3, and at the final follow-up.
The primary outcome was the change in the OABSS total score from visit Among 91 patients screened, 66 patients who were enrolled at the
2 to visit 3, while secondary outcomes included changes in voiding baseline in this study, were equally and randomly assigned to a placebo
symptoms if any. group (including four patients who withdrew) and CP group. Reporting
of this randomized trial followed the Consort 2010 checklist (Fig. 2).
PVR volume by US There were no statistically significant differences between the placebo
group and the CP group in terms of age, sex, parturition, number of
Evaluating the PVR volume is typically performed using US with a comorbidities, or consumption of alcohol, tea, tobacco, and betel nuts at
bladder scanner. The PVR volume is the amount of urine retained in the the start of the study (p > 0.05). At visit 2 (baseline), there were no
bladder after voluntary voiding and functions as a diagnostic tool. For statistically significant differences between the CP group and placebo
the transabdominal bladder volume evaluation, the probe was placed group in the OABSS (9.70 ± 2.20 vs. 10.52 ± 2.12), including frequency
over the suprapubic area with the patient in a prone position. Bladder (1.06 ± 0.35 vs. 1.18 ± 0.46), nocturia (2.46 ± 0.79 vs. 2.36 ± 0.65),
images were recorded in both the sagittal and transverse planes. The urgency (4.42 ± 0.50 vs. 4.48 ± 0.57), or incontinence (1.76 ± 1.73 vs.
greatest transverse (width), anteroposterior (depth), and superior- 2.48 ± 1.79) (all p > 0.05) (Table 2), or subjective feelings of the bladder
inferior (height) distances were recorded: volume = length × width × condition, PPBC, and USS (p > 0.05). Basic demographics and study data
height × 0.52. The PVR volume was determined at visits 2 and 3. were collected at the baseline (Table 1).

Safety assessments Effects of the CP on the OABSS

A safety analysis was conducted at every visit and consisted of blood CP treatment had statistical significance in decreasing the OABSS by
routine, liver function (aspartate aminotransferase (AST) and alanine 34.7% (9.70 to 6.33), the score of nocturia by 36.7% (2.45 to 1.55), the
aminotransferase (ALT)), renal function (serum creatinine (Cr) and score of urgency by 36.2% (4.42 to 2.82), and the score of incontinence

3
L.-L. Chen et al. Phytomedicine 80 (2021) 153380

Figure 2. Consolidated Standards of Reporting Trials (CONSORT) flow chart of enrollment and follow-up showing progression of patients throughout the trial.

by 43.2% (1.76 to 1.00) (Table 2). For the primary endpoint, the severity Effects of the CP on the PPBC and USS
of the OABSS was categorized as moderate at visit 2 (baseline) (placebo
group 10.52 ± 2.12, CP group 9.70 ± 2.20, p > 0.05). At visit 3 (after Subjective feelings of the bladder condition were evaluated by the
treatment), the OABSS exhibited a statistically significant reduction in PPBC and USS (Figs. 3, S3 and Table 3). After CP treatment, PPBC and
the CP group versus the placebo group (6.33 ± 2.42 vs. 9.73 ± 2.52, p < USS scores were statistically significantly lower at visit 3 (PPBC 2.15 ±
0.001). Especially in terms of nocturia, urgency, and incontinence, CP 0.83, p < 0.001 and USS 1.64 ± 0.60, p < 0.001). After 4 weeks of
treatment was better than the placebo at visit 3 (1.55 ± 0.90 vs. 2.18 ± follow-up, the PPBC and USS were still statistically significantly lower in
0.77, p < 0.001, 2.82 ± 1.24 vs. 4.18 ± 0.73, p < 0.001, and 1.00 ± 1.37 the CP group (PPBC 2.24 ± 0.83, p < 0.001 and USS 1.64 ± 0.65, p <
vs. 2.12 ± 1.88, p < 0.01, respectively). At 4 weeks following visit 3, the 0.001). There were no statistically significant differences between the
decrease in the OABSS in the CP group had still further statistical sig­ placebo and CP groups in either the PPBC (placebo group 3.36 ± 0.86,
nificance (6.33 ± 2.57 vs. 9.76 ± 2.55, p < 0.001 compared to the CP group 3.36 ± 0.60, p > 0.05) or USS (placebo group 2.52 ± 0.67, CP
placebo group). This result revealed the efficacy of CP treatment for the group 2.67 ± 0.54, p > 0.05) at visit 2. We used the minimally important
three OAB symptoms of nocturia, urgency, and incontinence, and the difference (MID) (1 point for PPBC) to evaluate clinically relevant im­
effect appeared to maintain rather than having been further change at provements of subjects (Coyne et al., 2006). The results show that the
least 4 weeks (Table 2). number of patients that had achieved recognizable response by visit 3
were 93.9% (31/33) in CP group and 15.2% (5/33) in placebo group.

4
L.-L. Chen et al. Phytomedicine 80 (2021) 153380

Table 1 Effects of the CP on the PVR volume


Comparison of demographic characteristics between the placebo group and the
cinnamon patch group Transabdominal US was used to examine changes in the PVR volume
Placebo (n = Cinnamon (n = p between the placebo and CP groups. For practical purposes, a volume of
33) 33) Value < 50 ml was considered clinically insignificant (Patel and Rickards,
Agea 61.97 ± 58.73 ± 11.57 0.31 2010). Here, only 18.2% (12/66) of patients had an abnormal PVR
13.87 volume (≥ 50 ml) at visit 2. After treatment, changes in abnormal PVR
Gender (No. [%])f Male 14 (42.4) 12 (36.4) 0.80 volumes showed no statistical significance between the two groups
Female 19 (57.6) 21 (63.6)
a (Table 4).
Parturition 1.12 ± 1.45 1.24 ± 1.37 0.73
No. of co- 1.48 ± 1.00 1.58 ± 1.25 0.75
morbiditiesa
Tea (No. [%])f Never 8 (24.2) 5 (15.2) 0.61
Occasionally 18 (54.5) 22 (66.7)
Usually 6 (18.2) 6 (18.2)
Quit 1 (3.0) 0 (0)
Coffee (No. [%])b Never 8 (24.2) 10 (30.3) 0.42
Occasionally 12 (36.4) 15 (45.5)
Usually 13 (39.4) 8 (24.2)
Quit 0 (0) 0 (0)
Alcohol (No. [%])f Never 15 (45.5) 14 (42.4) 1.00
Occasionally 17 (51.2) 18 (54.5)
Usually 0 (0) 0 (0)
Quit 1 (3.0) 1 (3.0)
Tobacco (No. Never 24 (72.7) 21 (63.6) 0.41
[%])f Occasionally 0 (0) 3 (9.1)
Usually 1 (3.0) 1 (3.0)
Quit 8 (24.2) 8 (24.2)
Betel nut (No. Never 32 (97.0) 30 (90.9) 0.61
[%])f Occasionally 0 (0) 0 (0)
Figure 3. Urgency severity scale (USS) scores at visit 2, visit 3, and the 4-week
Usually 0 (0) 0 (0)
follow-up for 66 patients intended to receive treatment. Independent sample t-
Quit 1 (3.0) 3 (9.1)
OABSSa 10.52 ± 2.12 9.70 ± 2.20 0.13
test. *** p < 0.001.
PPBCa 3.36 ± 0.86 3.36 ± 0.60 1.00
USSa 2.52 ± 0.67 2.67 ± 0.54 0.31
PVRa 24.02 ± 26.15 ± 41.98 0.80 Table 3
24.13 Comparison of the differences between patient perception of bladder condition
(PPBC) at visit 2 and visit 3 and visit 3 and the 4-week follow-up between the
Continuous data are presented as the mean ± standard deviation (SD). Cate­
placebo group and the cinnamon patch group
gorical data are presented as the number of patients (percentage). p < 0.05
indicate statistical significance. Placebo Cinnamon p Value
a difference (n=33) (n=33)
Based on independent-sample t-test. Data are the mean ± SD.
b
Based on Chi-squared test: data are the number of patients (%). PPBC (V3-V2)† > -1‡ 28 (84.8) 2 (6.1) 4.6 ×
f
Based on Fisher exact test: data are the number of patients (%). (No. [%]) 10− 11***
<= -1 5 (15.2) 31 (93.9)
PPBC (V4 -V2)† > -1 29 (87.9) 3 (9.1) 6.5 ×
After 4 weeks of follow-up, 90.9% (30/33) of patients in the CP group
(No. [%]) 10− 11***
and 12.1% (4/29) of patients in the placebo patch group had achieved <= -1 4 (12.1) 30 (90.9)
recognizable response as displayed in Table 3. Adjusted mean differ­ †
V2: visit 2 (baseline), V3: visit 3 (after treatment), V4: follow-up, V3-V2:
ences in PPBC for the CP versus placebo patch were -1.21 ± 0.65 at visit
difference between PPBC at baseline and after treatment, V4-V2: difference
3 and -1.12 ± 0.60 at follow-up which were statistically significant and
between PPBC at baseline and follow-up.
more than the MID of PPBC (Fig. S3). Therefore, indicating that the ‡
Minimally important difference (MID): 1 point for PPBC.
efficacy of CP treatment in terms of subjective sensation lasted for at ***
p < 0.001 indicate statistical significance by Fisher exact test: data are the
least 4 weeks (Figs. 3 and S3 and Table 3). number of patients (%).

Table 2
Comparison of overactive bladder symptom score (OABSS) at visit 2, visit 3 and the 4-week follow-up between the placebo group and the cinnamon patch group
Visit 2 (baseline) Visit 3 (end of treatment) Four-week follow-up
Placebo Cinnamon p Value Placebo Cinnamon p Value Placebo Cinnamon p Value
(n=33) (n=33) (n=33) (n=33) (n=33) (n=33)

OABSS (total score 10.52 ± 2.12 9.70 ± 2.20 1.3 × 9.73 ± 2.52 6.33 ± 2.42 5.1 × 9.76 ± 2.55 6.33 ± 2.57 9.2 ×
1
0~15) 10− 10− 7*** 10− 7***
1
Frequency (score 0~2) 1.18 ± 0.46 1.06 ± 0.35 2.3 × 1.00 ± 0.56 0.97 ± 0.30 7.9 × 10− 0.97 ± 0.53 0.97 ± 0.30 1.0
1
10−
Nocturia (score 0~3) 2.36 ± 0.65 2.45 ± 0.79 6.1 × 2.18 ± 0.77 1.55 ± 0.90 3.1 × 2.21 ± 0.82 1.48 ± 0.91 1.1 ×
1 3
10− 10− ** 10− 3**
Urgency (score 0~5) 4.48 ± 0.57 4.42 ± 0.50 6.5 × 4.18 ± 0.73 2.82 ± 1.24 1.4 × 4.27 ± 0.72 2.85 ± 1.30 1.3 ×
1 6
10− 10− *** 10− 6***
Incontinence (score 2.48 ± 1.79 1.76 ± 1.73 9.8 × 2.12 ± 1.88 1.00 ± 1.37 7.4 × 2.06 ± 1.90 1.03 ± 1.45 1.6 × 10− 2*
1 3
0~5) 10− 10− **

OABSS Score 0~15 (0 = no bother, 15 = maximum restraint). Data are the mean ± standard deviation.
*
p < 0.05
**
p < 0.01
***
p < 0.001, by an independent-sample t-test.

5
L.-L. Chen et al. Phytomedicine 80 (2021) 153380

Safety assessments Table 5


Comparison of serum concentrations of liver and renal function parameters
To monitor the safety of cinnamon treatment during this study, pa­ between the placebo and cinnamon patch groups
tients’ blood routine was evaluated at visits 2 and 3. Serum concentra­ Visit 2 (baseline) Visit 3 (end of treatment)
tions of AST, ALT, Cr, and BUN displayed no statistically significant Placebo Cinnamon p Placebo Cinnamon p
differences between the two groups before and after treatment (p > (n=33) (n=33) Value (n=33) (n=33) Value

0.05) (Table 5). In our study, each CP used contained only 0.6% cin­ AST 26.55 ± 25.82 ± 0.73 24.54 ± 26.41 ± 0.36
namaldehyde, and contact dermatitis was found in 1 patient (3.4%) in 10.93 4.58 8.09 7.56
ALT 25.09 ± 28.06 ± 0.28 23.43 ± 29.66 ± 0.10
the placebo group and in three patients (9.1%) in the CP group.
11.70 10.56 10.90 17.54
Cr 0.87 ± 0.88 ± 0.23 0.91 0.91 ± 0.91 ± 0.33 0.85
Discussion 0.19 0.19
BUN 15.97 ± 15.88 ± 0.94 16.93 ± 16.09 ± 0.51
To the best of our knowledge, this is the first double-blind, ran­ 4.59 4.88 4.40 5.16

domized, placebo-controlled trial to evaluate the efficacy and applica­ AST, aspartate aminotransferase; ALT, alanine aminotransferase; Cr. creatinine;
bility of treatment of OAB with a CP through improving changes in BUN, blood urea nitrogen.
urinary behavior, bladder US, and safety. According to TCM principles, Based on an independent-sample t-test. Data are the mean ± standard deviation.
an unbalanced constitution can represent an individual’s susceptibility
to and recurrence of specific diseases, especially chronic diseases and antimuscarinic treatment of OAB patients resulted in a considerable
their complications (Huang et al., 2019). Coyne’s team reported that as 58.24% (3.64 to 1.52) reduction in USS (Liu et al., 2009). Adjusted mean
people get older, they are at an increased risk of developing OAB (Coyne differences in PPBC (-1.21 at visit 3 and -1.12 at follow-up) were sta­
et al., 2011). They are also at higher risk of getting diseases and disor­ tistically significantly greater than the MID in PPBC, which produced
ders which lead to polypharmacy, such as depression, visual or auditory clinically significant effects in response to OAB treatment (Fig. S3). In
hallucinations, and anxiety (Dagli and Sharma, 2014). To prevent addition, our study showed no significant change in the PVR volume,
problems of polypharmacy from the oral intake of multiple medications, which is the same result as previous research (Chughtai et al., 2013; Liu
there are some third-line treatments of choice, such as peripheral tibial et al., 2009). Overall, 18.2% of patients were found to have a PVR
nerve stimulation and sacral neuromodulation (Corcos et al., 2017). volume which was not normal (normal PVR < 50 ml) in our trial. The
Previous studies showed that increased dosages of cinnamon in pre­ population of OAB patients enrolled in our study displayed relatively
scribed decoctions can increase bladder circulation and urine elimina­ smaller impacts on the PVR volume, and the changes in the PVR volume
tion (Wiseman et al., 2009). The formula containing Cinnamomi in patients between the placebo and CP treatment groups were statisti­
Ramulus, Aconiti Lateralis Radix, and Asari Radix decoction was pre­ cally insignificant.
scribed to treat symptoms of nocturia in patients diagnosed with a yang Cinnamon contains about 1%~2% essential oils which are mainly
deficiency pattern (Pan et al., 2006). Therefore, we use CP treatment, comprised of 65%~80% cinnamaldehyde, with a lesser amount of
based on TCM principles, by topical application instead of oral admin­ eugenol (Bansode, 2012). In this study, crude cinnamon powder con­
istration to reduce the complexity of polypharmacy. tains 2.16 ± 0.03 mg/g cinnamaldehyde (supplement 2). Aromatic
The study showed significant improvements in urgency, nocturia, aldehyde and phenol volatile oils exhibited potential neuroprotective
and urinary incontinence compared to the placebo group after 2 weeks effects via inhibition of neuroinflammation through attenuating induc­
of treatment, which reduced the overall OABSS. In this study, CP ible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expres­
treatment revealed a 34.69% (9.70 to 6.33) decline in OABSSs. After sions and the nuclear factor (NF)-κB signaling pathway after ischemic
ceasing CP treatment, the beneficial effects apparently lasted 4 weeks. stroke in a previous study (Chen et al., 2016). Cinnamaldehyde, the most
Because of improvements in OAB symptoms, patients’ overall sensations specific transient receptor potential ankyrin 1 (TRPA1) agonist, excites a
of the bladder and urgency also statistically significantly decreased. The subset of sensory neurons highly enriched in cold-sensitive neurons and
results are in accord with the results of previous studies (Chughtai et al., elicits nociceptive signals. The transient receptor potential (TRP) su­
2013; Garely et al., 2007; Xiao et al., 2016). Results of a study by perfamily contains relatively non-selective cation channels, and some of
Chughtai et al. indicated that administration of Gosha-jinki-gan, them are expressed in the bladder, especially in primary afferent neu­
composed of cinnamomi cortex and nine other herbs, in OAB patients rons and the urothelium, and their modulators were found to have
decreased OABSSs by 34.67% (7.5 to 4.9) (Chughtai et al., 2013). Xiao therapeutic potential for OAB in animal studies (Fry et al., 2019).
et al. reported that treatment with Weng-li-tong plus tolterodine caused a Around 9.1% (3/33) of patients in the CP group and 3.4% (1/29) of
statistically significant decrease in OABSSs by 40.62% (9.6 to 5.7) (Xiao patients in the placebo group reported a mild skin allergy, such as
et al., 2016). In this study, the CP treatment group revealed a 36.01% redness, swelling, burning, bumps, and a rash at the application site. In
(3.36 to 2.15) decline in PPBC and a 38.58% (2.67 to 1.64) decline in our study, each CP contained only 0.6% cinnamaldehyde, which was
USS. Garely et al. demonstrated that solifenacin treatment for OAB with less than a 3% concentration of cinnamaldehyde which produced irri­
incontinence resulted a statistically significant 36.96% (4.6 to 2.9) tation on volunteers’ skin in a previous study (Bickers et al., 2005).
reduction in PPBC (Garely et al., 2007). The findings of the current study Besides contact dermatitis, there was no liver or renal toxicity or other
are in agreement with those of Liu et al. who demonstrated that SAE was found in this study. However, the lack of directly measured

Table 4
Comparison of the post-voiding residual (PVR) volume at visits 2 and 3 between the placebo group and the cinnamon patch group.
Visit 2 (baseline) Visit 3 (end of treatment)
Placebo(n=33) Cinnamon(n=33) p Value Placebo(n=33) Cinnamon(n=33) p Value

PVR Volume (ml)a 24.02 ± 24.13 26.15 ± 41.98 0.80 21.72 ± 28.16 20.74 ± 24.61 0.88
normal (No. [%])b 27 (81.8) 27 (81.8) 1.00 26 (78.8) 30 (90.9) 0.17
abnormal 6 (18.2) 6 (18.2) 7 (21.2) 3 (9.1)

Abnormal: PVR volume of ≥ 50 ml, normal: PVR volume of < 50 ml.


a
Based on independent-sample t-test. Data are the mean ± standard deviation.
b
Based on Chi-squared test. Data are the number of patients (%).

6
L.-L. Chen et al. Phytomedicine 80 (2021) 153380

disease-related variables is a major limitation of the study. The OAB References


severity in patients enrolled in our study was moderate (mean OABSS
score of 10.03), therefore, results of this trial might not be applicable to Abbasi, A., Hajialyani, M., Hosseinzadeh, L., Jalilian, F., Yaghmaei, P., Jamshidi
Navid, S., Motamed, H., 2020. Evaluation of the cytotoxic and apoptogenic effects of
patients with milder or more-severe OAB. In this study, relatively cinnamaldehyde on U87MG cells alone and in combination with doxorubicin. Res
smaller impacts on the PVR volume of enrolled OAB patients were dis­ Pharm Sci 15, 26–35.
played, and changes in the PVR volume in patients between the placebo Bansode, V.J., 2012. A review on pharmacological activities of Cinnamomum cassia
Blume. International Journal of Green Pharmacy (IJGP) 6.
and CP groups could not be effectively evaluated. Bickers, D., Calow, P., Greim, H., Hanifin, J.M., Rogers, A.E., Saurat, J.H., Sipes, I.G.,
Smith, R.L., Tagami, H., panel, R.e., 2005. A toxicologic and dermatologic
Conclusions assessment of cinnamyl alcohol, cinnamaldehyde and cinnamic acid when used as
fragrance ingredients. Food Chem Toxicol 43, 799–836.
Chao, Y., 1966. General treatise on causes and manifestations of all diseases. China
This is the first double-blind randomized, placebo-controlled trial to literature publications, Beijing.
evaluate the efficacy and applicability of the TCM prescription, CP, in Chen, Y.F., Wang, Y.W., Huang, W.S., Lee, M.M., Wood, W.G., Leung, Y.M., Tsai, H.Y.,
2016. Trans-cinnamaldehyde, an essential oil in cinnamon powder, ameliorates
treating OAB. Our results showed that CP treatment was effective in
cerebral ischemia-induced brain injury via inhibition of neuroinflammation through
decreasing the score of urgency, nocturia, and incontinence using attenuation of iNOS, COX-2 expression and NF-κB signaling pathway. Neuromol Med
OBBSSs as compared to the placebo group. In the study group, we 18, 322–333.
observed an ameliorated patient’s perception of their bladder condition Chiu, A.F., Huang, M.H., Wang, C.C., Kuo, H.C., 2012. Prevalence and factors associated
with overactive bladder and urinary incontinence in community-dwelling
using PPBC, and a decreased score of urinary urgency associated with Taiwanese. Tzu Chi Med J 24, 56–60.
each urination using USS, however, the effect did not replicate on PVR Chou, E.C., Hung, M.J., Yen, T.W., Chuang, Y.C., Meng, E., Huang, S.T., Kuo, H.C., 2014.
volume by the abdominal US. With significant efficacy for urgency, The translation and validation of Chinese overactive bladder symptom score for
assessing overactive bladder syndrome and response to solifenacin treatment.
nocturia, and incontinence, and no apparent side effects, the CP could be J Formos Med Assoc 113, 506–512.
considered as a new complementary therapy for OAB. Chuang, F.C., Hsiao, S.M., Kuo, H.C., 2018. The overactive bladder symptom score,
international prostate symptom score-storage subscore, and urgency severity score in
patients with overactive bladder and hypersensitive bladder: which scoring system is
Author contributions best? Int Neurourol J 22, 99–106.
Chughtai, B., Kavaler, E., Lee, R., Te, A., Kaplan, S.A., Lowe, F., 2013. Use of herbal
All data were generated in-house, and no paper mill was used. All supplements for overactive bladder. Rev Urol 15, 93–96.
Corcos, J., Przydacz, M., Campeau, L., Gray, G., Hickling, D., Honeine, C., Radomski, S.
authors agree to be accountable for all aspects of work ensuring integrity B., Stothers, L., Wagg, A., Lond, F., 2017. CUA guideline on adult overactive bladder.
and accuracy. Can Urol Assoc J 11, E142–E173.
Coyne, K.S., Matza, L.S., Kopp, Z., Abrams, P., 2006. The validation of the patient
perception of bladder condition (PPBC): a single-item global measure for patients
Funding
with overactive bladder. Eur Urol 49, 1079–1086.
Coyne, K.S., Sexton, C.C., Vats, V., Thompson, C., Kopp, Z.S., Milsom, I., 2011. National
This research was funded by the Ministry of Higher Education community prevalence of overactive bladder in the United States stratified by sex
(MOHE) and the National Research Institute of Chinese Medicine and age. Urology 77, 1081–1087.
D’Ancona, C., Haylen, B., Oelke, M., Abranches-Monteiro, L., Arnold, E., Goldman, H.,
(NRICM) in Taiwan (MOHE108-NRICM-325-113-401) and (MOHE109- Hamid, R., Homma, Y., Marcelissen, T., Rademakers, K., Schizas, A., Singla, A.,
NRICM-325-123-401). Soto, I., Tse, V., de Wachter, S., Herschorn, S., Standardisation Steering Committee,
I.C.S., the, I.C.S.W.G.o.T.f.M.L.U.T., Pelvic Floor, S., Dysfunction, 2019. The
International Continence Society (ICS) report on the terminology for adult male
CRediT authorship contribution statement lower urinary tract and pelvic floor symptoms and dysfunction. Neurourol Urodyn
38, 433–477.
Lih-Lian Chen: Conceptualization, Methodology, Investigation, Dagli, R.J., Sharma, A., 2014. Polypharmacy: a global risk factor for elderly people. J Int
Oral Health 6 i-ii.
Writing - original draft, Visualization, Project administration. Yuh- Eapen, R.S., Radomski, S.B., 2016. Review of the epidemiology of overactive bladder.
Chiang Shen: Formal analysis, Supervision, Writing - review & editing. Res Rep Urol 8, 71–76.
Chih-Chun Ke: Resources, Data curation. Zuha Imtiyaz: Writing - re­ Faul, F., Erdfelder, E., Lang, A.G., Buchner, A., 2007. G*Power 3: a flexible statistical
power analysis program for the social, behavioral, and biomedical sciences. Behav
view & editing. Hui-I Chen: Formal analysis. Chin-Hsien Chang: Su­ Res Methods 39, 175–191.
pervision. Mei-Hsien Lee: Writing - review & editing, Supervision, Fry, C.H., Chakrabarty, B., Hashitani, H., Andersson, K.E., McCloskey, K., Jabr, R.I.,
Funding acquisition. Drake, M.J., 2019. New targets for overactive bladder-ICI-RS 2109. Neurourol
Urodyn.
Garely, A.D., Lucente, V., Vapnek, J., Smith, N., 2007. Solifenacin for overactive bladder
Declaration of Competing Interest with incontinence: symptom bother and health-related quality of life outcomes. Ann
Pharmacother 41, 391–398.
The authors declare no conflict of interest. Haylen, B.T., de Ridder, D., Freeman, R.M., Swift, S.E., Berghmans, B., Lee, J., Monga, A.,
Petri, E., Rizk, D.E., Sand, P.K., Schaer, G.N., 2010. An International
Urogynecological Association (IUGA)/International Continence Society (ICS) joint
Acknowledgements report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 21,
5–26.
Homma, Y., Yoshida, M., Seki, N., Yokoyama, O., Kakizaki, H., Gotoh, M., Yamanishi, T.,
The present study was performed at the Department of Traditional Yamaguchi, O., Takeda, M., Nishizawa, O., 2006. Symptom assessment tool for
Chinese Medicine and Department of Urology, En Chu Kong Hospital, overactive bladder syndrome–overactive bladder symptom score. Urology 68,
New Taipei City, Taiwan. We sincerely thank management by Dr. 318–323.
Huang, Y.C., Lin, C.J., Cheng, S.M., Lin, C.K., Lin, S.J., Su, Y.C., 2019. Using Chinese
Chung-Cheng Wang and Dr. Sunny Jui-Shan Lin for their valuable sup­ Body Constitution Concepts and Measurable Variables for Assessing Risk of Coronary
port and consultation by Dr. Yi-Ting Hwang and the Biostatistics Center, Artery Disease. Evid Based Complement Alternat Med 2019. https://doi.org/
Office of Data Science, Taipei Medical University. The authors would 10.1155/2019/8218013.
Lin, J.G., Lo, M.W., Wen, Y.R., Hsieh, C.L., Tsai, S.K., Sun, W.Z., 2002. The effect of high
also like to thank all patients who took part in this study. and low frequency electroacupuncture in pain after lower abdominal surgery. Pain
99, 509–514.
Supplementary materials Liu, H.T., Chancellor, M.B., Kuo, H.C., 2009. Decrease of urinary nerve growth factor
levels after antimuscarinic therapy in patients with overactive bladder. BJU
International 103, 1668–1672.
Supplementary material associated with this article can be found, in Liu, Z., Liu, Y., Xu, H., He, L., Chen, Y., Fu, L., Li, N., Lu, Y., Su, T., Sun, J., Wang, J.,
the online version, at doi:10.1016/j.phymed.2020.153380. Yue, Z., Zhang, W., Zhao, J., Zhou, Z., Wu, J., Zhou, K., Ai, Y., Zhou, J., Pang, R.,
Wang, Y., Qin, Z., Yan, S., Li, H., Luo, L., Liu, B., 2017. Effect of electroacupuncture
on urinary leakage among women with stress urinary incontinence: a randomized
clinical trial. JAMA 317, 2493–2501.

7
L.-L. Chen et al. Phytomedicine 80 (2021) 153380

Michel, M.C., 2020. Where will the next generation of medical treatments for overactive Wiseman, N., Willms, S., Ye, F., 2009. Jin Gui Yao Lue-Essential prescriptions of the
bladder syndrome come from? Int J Urol 27, 289–294. Golden Coffer. Summer: Paradigm Publications.
Nixon, A., Colman, S., Sabounjian, L., Sandage, B., Schwiderski, U.E., Staskin, D.R., Xiao, D.D., Lv, J.W., Xie, X., Jin, X.W., Lu, M.J., Shao, Y., 2016. The combination of
Zinner, N., 2005. A validated patient reported measure of urinary urgency severity in herbal medicine weng-li-tong with tolterodine may be better than tolterodine alone
overactive bladder for use in clinical trials. J Urol 174, 604–607. in the treatment of overactive bladder in women: a randomized placebo-controlled
Pan, L., Wang, M., Wang, J.G., Wu, B., Hui, K.M., 2006. Clinical and molecular prospective trial. BMC Urol 16, 49. https://doi.org/10.1186/s12894-016-0167-1.
evaluation of warming and tonic herb treatment for sibling patients of a typical Yamaguchi, O., Nishizawa, O., Takeda, M., Yokoyama, O., Homma, Y., Kakizaki, H.,
kidney-yang deficiency family. Am J Chinese Med 34, 387–400. Obara, K., Gotoh, M., Igawa, Y., Seki, N., Yoshida, M., Neurogenic Bladder, S., 2009.
Patel, U., Rickards, D., 2010. Imaging and urodynamics of the lower urinary tract. Clinical guidelines for overactive bladder. Int J Urol 16, 126–142.
Springer, London. Zhang, C., Fan, L., Fan, S., Wang, J., Luo, T., Tang, Y., Chen, Z., Yu, L., 2019.
Patra, P.B., Patra, S., 2014. Research findings on overactive bladder. Curr Urol 8, 1–21. Cinnamomum cassia Presl: a review of its traditional uses, phytochemistry,
Rao, P.V., Gan, S.H., 2014. Cinnamon: a multifaceted medicinal plant. Evid Based pharmacology and toxicology. Molecules 24, 3473. https://doi.org/10.3390/
Complement Alternat Med. https://doi.org/10.1155/2014/642942. molecules24193473.
Szabo, S.M., Gooch, K.L., Walker, D.R., Johnston, K.M., Wagg, A.S., 2018. The
association between overactive bladder and falls and fractures: a systematic review.
Adv Ther 35, 1831–1841.

You might also like