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KEYWORDS: channa striatus, knee osteoarthritis, pain, symptom, quality of life, analgesic consumption
Abstract
Channa striatus is a fresh water fish known as natural remedy for traditional medicine in Southeast Asian
region. This is a randomized, double-blind, placebo-controlled trial comparing the effects of oral Channa
striatus extract 500 mg/day with placebo given for 3-month intervention period among primary knee osteoarthritis patients. Eighty eight
patients were randomly assigned to C.striatus and placebo group. The objectives were to compare pain, symptoms, activity of daily
living, sports and quality of life between intervention and control group using Knee Injury and Osteoarthritis Outcome Score (KOOS).
Analgesic consumption was also compared using analgesic score.
There were significant improvement of pain, symptoms and quality of life (QOL) domain score (p<0.05) in C. striatus group compared to
patients who received placebo. There were no changes in safety profile parameters among the patients before and after treatment. In
conclusion, the oral administration of Channa striatus extract would be a new alternative for knee osteoarthritis treatment.
The therapeutic effect of oral
Channa striatus extract on primary
knee osteoarthritis patients
44
INTRODUCTION
Channa striatus (CS) is a freshwater snakehead sh that
belongs to the Channidae family (1). Recognized as a
valuable source of protein throughout the Asia Paci c region,
the sh is a well known natural remedy in traditional medicine
and has been long been used by people in the region for
healing wounds, particularly post-partum and post-operative
wounds (1). Studies done on the biochemical composition
of the sh have revealed that it contains both fatty acids
and amino acids that are important for wound healing (2-6)
and anti-nociceptive processes (7, 8). The major amino acids
in its extract are glycine, alanine, lysine, aspartic acid, and
praline (2, 3). In addition, the major fatty acids are oleic acid,
stearic acid, linoleic acid, and arachidonic acid (2, 3). These
essential amino acids and fatty acids have been shown to
facilitate wound healing while simultaneously enhancing anti-
nociceptive activity (2-8).
Osteoarthritis (OA), a degenerative joint disease, involves the
structural and functional failure of synovial joints. The disease
is the leading cause of chronic disability in the elderly, and
is particularly tied to knee and hip issues (9). While the exact
biochemical cause of OA remains unclear, there is evidence
that the disease may be tied to up-regulations of various
pro-in ammatory mediators during in ammatory processes.
The in ammation, which is due to progressive articular
destruction, appears to be localized within the particular
joint affected (10). Simple analgesia, mainly non-steroidal
anti-in ammatories (NSAIDS) and COX-2 speci c NSAIDS,
are currently being used for OA pain relief (10). However,
these pharmacologic therapies are suboptimal and have
side-effects (12). As a result, complementary and alternative
medicines are gaining popularity (11).
In animal models,
CS extract has been reported to be
bene cial in treating OA (11). In a study done by Michelle et
al. in 2004, in ammation of the arthritic joints in animals was
reduced when treated by CS as evidenced by radiographic
overall innervations of the synovial membrane and changes
in pro-in ammatory mediators (prostaglandin) (13). The
bene cial effects of CS are supported by studies in animal
models, but these have yet to be clinically validated. As
a result of this initial evidence, it is here postulated that CS
may have bene cial effects in treating patients suffering
from osteoarthritis.The present study seeks to determine the
effectiveness and safety of CS extract in the treatment of
knee osteoarthritis patients.
MATERIALS AND METHODS
Study design and setting
This randomised, double-blinded, placebo-controlled
study sought to compare the effects of CS extract and
a placebo among primary knee osteoarthritis patients at
the Hospital Universiti Sains Malaysia (HUSM) from June to
December of 2011.
JOINT HEALTH
AZIDAH ABDUL KADIR
1
*, SITI ZUBAIDAH AB WAHAB
2
, MARYAM MOHD ZULKIFLI
1
, NORHAYATI MOHD NOOR
1
,
SARINGAT BIN BAI @ BAIE
3
, JUHARA HARON
4
*Corresponding Author:
1. University Sains Malaysia, School of Medical Sciences, Department of Family Medicine,
Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
2. University Sains Malaysia, School of Medical Sciences, Women Health Development Unit,
Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
3. University Sains Malaysia, School of Pharmaceutical Sciences, 11800, Pulau Pinang, Malaysia
4. University Sains Malaysia, School of Medical Sciences, Department of Radiology,
Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
Agro FOOD Industry Hi Tech - vol 25(3) - May/June 2014
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Agro FOOD Industry Hi Tech - vol 25(3) - May/June 2014
long-term osteoarthritis and knee injuries (16). This instrument
holds 42 items in the following 5 separately scored subscales:
pain, other symptoms, function in daily living (ADL), function
in sport and recreation (Sport), and knee-related quality of
life (QOL) (15). Standardized answer options were given on
the KOOS questionnaires (5 Likert boxes), with each question
receiving a score from 0 to 4. A normalized score (with 100
indicating no symptoms and 0 indicating extreme symptoms)
was calculated for each subscale. The Malay version of the
KOOS was validated with a Cronbach’s alpha ranging from
0.94 to 0.96 and a factor loading of 0.25 to 0.89.
CS extract preparation
Whole CS were cleaned, weighed, and placed into an
autoclave bin. The water mixture for autoclaving was
prepared relative to a sh’s weight with respect to the
volume of water used. Preservatives were then added.
The preservatives used in this study were a combination
of two esters of p-hydroxy benzoic acids: methyl paraben
0.1 percent and propyl paraben 0.02 percent. Sterilization
was carried out with a temperature setting of 110°C for 15
minutes. Upon completion of sterilization, the sh were mixed
thoroughly and then dried using an industrial oven at 60°C
for 48 hours continuously. Upon completion, sheets of crispy
akes were ground into a rened powder.
Statistical analysis
The study’s sample size calculations were based on
power and sample size calculation software (17) for
the comparison of two means (α =0.05, Power= 0.9). A
sample size of 37 in each group was needed to detect the
decrease of 2.4 in the analgesic score at month 3 of the
study with standard deviation of 3.1. Forty-four patients in
each group were enrolled to allow for 10 percent dropout.
Analysis was done using SPSS version 20.0. Randomized
groups were compared in order to recognize possible
differences at baseline using independent-T, Pearson
chi-square, and simple logistic regression. To determine
the differences in the outcome parameters, repeated
co-variance (ANCOVA) was used while controlling for the
baseline values. Changes were reported as estimated
marginal means with the condence interval (CI) adjusted
at 95 percent. All reported p-values were 2-tailed with
values less than 0.05 considered signicant. There was no
co-variate used for the analgesic score, and the Kruskal-
Wallis test was used to detect differences in score between
the two groups.
Approval by the research and ethics committee
The protocol of the study was approved by the Research
Ethics Committee (Human) at the School of Medical
Sciences, Universiti Sains Malaysia [Ref: USMKK/PPP/JEPeM
[236.3.(12)].
RESULTS
Eighty-eight patients completed the study. There were no
statistical differences between the baseline characteristics
of the CS group and the placebo group in terms of
demographics, clinical characteristics, radiographic
features, or the KOOS baseline scores of all domains (i.e.,
pain, other symptoms, activity in daily living, function in
sport and recreation, and quality of life) (Table 1).
Participants and instruments
The study’s participants included those aged 40 years
and older who were diagnosed with primary monolateral
or bilateral knee osteoarthritis according to the clinical
and radiological criteria of the American College of
Rheumatology (ACR) (14). The study’s participants had body
mass indexes (BMI) ranging from 18 to 30 kg/m
2
, and showed
radiologic evidence of knee osteoarthritis (grades I to III)
using the Kellgren-Lawrence method.
The study excluded those with secondary knee OA, as
well as those with severe co-morbid conditions, such as
severe-hematologic disorders, renal disease, liver disease,
neoplasms, and other rheumatic diseases. In addition,
patients with severe knee pain and were waiting for surgical
intervention, patients who had joint lavage, arthroscopy
performed, treatment with hyaluronic acid, or has been
taking glucosamine during the previous six months,
and patients who had been treated with intra-articular
corticosteroids during the past three months were also
excluded from the study.
The study’s participants were acquired from the Outpatient
and Orthopaedic Clinic at the Hospital Universiti Sains
Malaysia. Informed consent was obtained once they agreed
to participate in the study. Having satised the inclusion
and exclusion criteria, the patients were then randomly
placed into two groups using a computer-generated table
of random numbers. One group received 500 mg of freeze-
dried CS extract daily, while the other group received a 500
mg placebo of maltodextrin daily. This was done for each
group for three months. The investigators were not aware
of the randomization scheme. Compliance was measured
using the numbers of capsules taken. Any subject taking less
than 80 percent of the trial medications provided would be
considered non-compliant.
The participants’ past medical and orthopaedic histories
were assessed. Physical examinations of blood pressure,
weight, and height were performed at the beginning of the
study, and each patient was assessed in following at month
1, 2, and 3 after randomization, respectively. Upon each visit,
the patients were given self-administered Knee Injury and
Osteoartritis Outcome Score (KOOS) questionnaires to assess
their knee osteoarthritis pain, symptoms, activity in daily
living (ADL), function in sport and recreation, and quality
of life (QOL) (15). For patients with bilateral OA, the most
compromised knee was used as a reference. The patients
also needed to report to the investigators any possible side
effects that ensued after taking the medication. Blood
samples were taken in order to assess renal function, liver
function, and full blood count in study-safety proles created
at both the beginning and end of the study.
Patients were allowed to consume tablets of
acetaminophen (1 g) or ibuprofen (400 mg) as needed for
rescue analgesia. Patients were not allowed to change to
other forms of analgesia without having previously informed
the investigators. The patients were asked to document
the types, dosage, and number of analgesia tablets they
took in a diary to be brought to every visit. To calculate the
analgesic score, acetaminophen (1000 mg) was scored as
1, and ibuprofen (400 mg) was scored as 2.5. The score was
assessed at month 1, 2, and 3, respectively.
The KOOS, which was developed as an extension of
the WOMAC Osteoarthritis Index, was used in this study
(15)
because it is a valid, reliable, and responsive self-
administered instrument in the follow-up of short-term and
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Agro FOOD Industry Hi Tech - vol 25(3) - May/June 2014
There were also improvements seen in the
domain of ADL and function in sport and
recreation, but they were not significant.
There were 10 (11.4 percent) subjects in the
intervention group and 13 (14.8 percent) subjects
in the control group who took analgesics
during the study period. There was a decrease
in analgesia usage in the CS group. However,
this did not represent a statistically signicant
difference (Table 3).
Overall compliance with the study’s medication
was 98.8 percent. There were also no changes
adapted in the safety prole parameters (full
blood count, renal prole, and liver function test)
before or after treatment. A total of six adverse
events were reported: three in the placebo
group (acute pharyngitis, hypertension, and
hypotension) and three in the CS group (vaginal
candidiasis, leg edema, and toothache). These
adverse effects were considered to be unrelated
to the investigational drugs.
DISCUSSION
Studying the impact of treatments on knee OA
in trials has been challenging due to the fact
that no specic biomarkers have been identied
to monitor or prognosticate the illness, or to use
in clinical trials to assess the effectiveness of
treatment (18). Clinical trials dealing with knee OA have
typically included two main features: a composite scoring
system for pain, and function and joint space measurement
(10). A pain radiograph is insufcient for determining the
progression and outcome of intervention or treatment
over a short period of time. Therefore, in this study we used
composite scoring system.
The results of this study suggest
that CS extract is associated
with signicant improvements
in knee OA symptoms, such
as pain and quality of life.
Improvements were observed
in terms of ADL and function
in sport and recreation.
However, these improvements
did not represent statistically
signicant results. This is likely
due to the fact that most
patients in the study had
good ADL function prior to
the trial, as well as minimal
involvement in sports. Thus, it
does not show much change
in the ADL component
compare to the baseline.
OA primarily occurs in weight-
bearing joints accompanied
with subchondral responses
and synovitis, which
contribute to its pathogenesis
through the formation of
Table 2 shows a comparison of mean pain, symptoms, ADL,
function in sport and recreation, and QOL among the CS
and placebo groups over the course of the study (time-
treatment interaction). There were signicant improvements
seen in terms of pain, symptoms, and QOL score between
the CS and placebo groups over time (p< 0.001 ANCOVA).
Table 1. Baseline characteristic of CS and placebo groups
Table 2: Comparison of mean pain, symptoms, ADL, sport and QOL scores among CS and placebo group
based on time (time-treatment interaction)
* p-value is signicant
Repeated measures ANCOVA between group analysis with regard to time was applied
Numerical covariates (baseline scores) was controlled by using repeated measures ANCOVA
Assumptions of normality, homogeneity of variances, compound symmetry and homogeneity of
regression were checked and were fullled
*Determined by Independent t-test,
∞Determined by Pearson chi-square test
**Determined by Simple logistic regression
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Agro FOOD Industry Hi Tech - vol 25(3) - May/June 2014
terms of analgesic score, there was no
significant difference between the CS
group and the placebo group. This was
probably a result of the small number
of patients (only 23) taking analgesic
rescue in this study. Therefore, the effect
of analgesic consumption is not seen in
this study.
The CS extract was well tolerated in
this study. There was no drop-out in this
study for both groups of patients. The
type and frequency of AEs were similar
between the CS and placebo groups.
Routine laboratory parameters remained
within normal limits during CS treatment,
supporting the tolerability of this agent.
This study has a few limitations. The duration of this
study was short and the sample size was small. A larger
study with multiple doses of CS extract and a longer
treatment period is recommended. Comparison of the CS
extract with other modalities of treatment, for example
glucosamine, would be beneficial.
CONCLUSION
In conclusion, the oral administration of CS extract could
be a new alternative for knee osteoarthritis treatment,
as it is safe and associated with a statistically significant
reduction in pain, improvement of symptoms, and quality
of life in patients with primary knee osteoarthritis.
ACKNOWLEDGEMENT
This study was supported by Universiti Sains Malaysia Short
Term grant (304/PPSP/61312003). The authors also would
like to thank the Research Ethics Committee (Human),
School of Medical Sciences, Universiti Sains Malaysia [Ref:
USMKK/PPP/JEPeM [236.3.(12)] for approving this study.
Conflict of interest statement
We declare there is no financial and personal
relationship with other people or organizations that could
inappropriately influence the research.
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