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Effects of Hyaluronate Sodium on Pain and Physical Functioning in Osteoarthritis of the Knee
A Randomized, Double-blind, Placebo-Controlled Clinical Trial
Robert John Petrella, MD, PhD;
Mathew Dennis DiSilvestro, MSc;
Catherine Hildebrand, PhD
Arch Intern Med. 2002;162:292-298.
ABSTRACT
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Background Intra-articular hyaluronate sodium is a relatively new therapy for the
treatment of osteoarthritis of the knee. This randomized, double-blind clinical
trial was conducted at a large primary care medical center to determine the
impact of hyaluronate sodium vs conventional therapy on measures of pain,
stiffness, and disability at rest and following functionally relevant walking
and stepping activities.
Methods A total of 120 patients (mean age, 67 years) with unilateral grades
1 to 3 medial compartment knee osteoarthritis were randomized to 1 of 4 treatment
groups: group 1, 2 mL of hyaluronate sodium at a concentration of 10 mg/mL
and placebo (100 mg of lactose); group 2, nonsteroidal anti-inflammatory drugs
(NSAIDs) (75 mg of diclofenac and 200 µg of misoprostol) and hyaluronate
sodium; group 3, NSAIDs and placebo (2 mL of isotonic sodium chloride solution
[saline]); and group 4, placebo (lactose and saline). Intra-articular hyaluronate
sodium or saline (2 mL) was administered once weekly over 3 weeks while NSAIDs
or lactose were administered twice daily over 12 weeks.
Main Outcome Measures (1) Western Ontario McMaster Universities Index (WOMAC) global measure
of pain, stiffness, and disability; (2) visual analog scale (VAS) scores for
pain at rest and following functional walking and stepping activities (self-paced
walking and stepping); and (3) functional performance (exercise time, heart
rate, and predicted maximum oxygen uptake) at baseline and weeks 4 and 12.
Results At week 4, significant improvement in WOMAC scores for pain and disability
and VAS score for resting pain was observed in groups 1 to 3 compared with
baseline measures. Groups 1 and 2 showed significantly lower self-paced stepping
pain, while no change was observed in group 4. At week 12, groups 1 to 3 showed
significantly greater improvement in WOMAC pain subscale score and VAS score
for resting pain; however, these differences did not vary from week 4. Following
self-paced walking and stepping, groups 1 and 2 reported significantly less
activity pain, while group 1 showed significantly faster self-paced walking
and stepping test results. Groups 1 to 3 improved self-paced walking and stepping
time at week 12 compared with baseline measures, while predicted maximum oxygen
uptake was significantly higher in the hyaluronate sodium groups 1 and 2 at
weeks 4 and 12 compared with baseline measures.
Conclusions For resting pain relief, hyaluronate sodium seems to be as effective
as NSAIDs. Further, for pain with physical activity and functional performance,
hyaluronate sodium may be superior to placebo alone or NSAIDs alone.
INTRODUCTION
DESPITE the increasing morbidity and economic costs of osteoarthritis
(OA),1 standard therapies have not progressed
significantly over the past several years. Current therapies are directed
at controlling pain and maintaining articular function rather than altering
physical functioning and the disease process.2
Osteoarthritis is the result of mechanical and biological events that destabilize
the normal degradation synthesis of articular cartilage.3-4
Hyaluronic acid (HA) is a major component of the articular matrix, assuming
an important role in its viscoelastic structural and functional balance.4
Osteoarthritis is characterized by a decrease in the concentration and
molecular weight of HA,5 which may lead to
the hallmark signs of pain and loss of function in weight-bearing joints such
as the knee.6 Intra-articular viscosupplementation
may restore the concentration and molecular weight of HA in the articular
matrix, resulting in improved pain control and function.5
Hence, HA may provide clinicians with a novel approach to address the clinical
course of OA. Further, the possible mechanical improvement of the intra-articular
matrix may provide added benefit for pain control during functional activity
of the knee. This study was undertaken to determine the effect of treatment
with hyaluronate sodium compared with standard therapy and placebo for pain
relief and physical functioning in patients with OA of the knee over 12 weeks.
SUBJECTS AND METHODS
SUBJECTS
Patients were recruited from a large primary care referral center (Centre
for Activity and Ageing, London, Ontario) for assessment of knee OA. The study
was approved by the University of Western Ontario ethics review board. Those
with radiographic evidence of grades 1 to 3 medial compartment unilateral
knee OA,7 but who did not exhibit non-OA arthritides,
previous nonsteroidal anti-inflammatory drug (NSAID) intolerance, gastrointestinal
hemorrhage, peptic ulcer disease, avian allergy, regular consumption of "herbal"
OA products (ie, glucosamine sulfate), or an intra-articular injection of
HA or corticosteroid in the previous 6 months were given a screening examination
with their consent. Patients were also asked to discontinue all current OA
medications and were scheduled to return 2 weeks later for baseline outcome
assessments (see the following section) in addition to demographic data collection
(age, sex, body mass index [BMI]), and comorbidities). Those who displayed
grades 1 to 3 OA on radiographs and who described at least 3-cm current rest
pain using a visual analog scale (VAS) (see "Outcome Measures" section below)
at baseline were included.
OUTCOME MEASURES
We included measures of pain at rest and following a functional task.
Measures of physical functioning and global assessment of pain and physical
functioning as recommended in the literature were also included.8
Pain
The primary outcome measure of pain was determined in 2 ways: (1) self-report
of current pain (CP) using a VAS9 and (2) the
pain subscale of the Western Ontario McMaster Universities Index (WOMAC)8 using the VAS format. In brief, the CP-VAS consisted
of a 10-cm horizontal line anchored with descriptors of pain including "no
pain" on one end (left) and "extreme pain" on the other (right). After sitting
for 10 minutes, subjects struck a vertical line through the 10-cm VAS representing
their CP, and the distance from left end (no pain) to the vertical line was
recorded in centimeters. The WOMAC consists of 24 questions: 5 determine subject
global assessment of pain, 2 assess joint stiffness, and 17 assess physical
functioning. A 10-cm horizontal VAS line with anchored descriptors such as
"no pain" or "no stiffness" at one end and "extreme pain" or "extreme stiffness"
at the other end was used to score responses. The WOMAC was completed following
a 10-minute rest. Individual scores for pain, stiffness, and physical functioning
were generated by summing the appropriate terms.
Activity-related pain measures were determined by completion of the
CP-VAS immediately following 2 physical activity tests (see the "Physical
Functioning" section below). These tests were separated by 15 minutes or until
the time the CP-VAS score returned to the baseline value.
Physical Functioning
Physical functioning was determined in 2 ways: (1) the stiffness and
physical disability subscales of the WOMAC and (2) functional performance
of a self-paced walking (SPW) test10 and a
self-paced stepping (SPS) test.11 The WOMAC
global assessments have been described above in the "Pain" section. In brief,
the SPW consisted of a 40-m walk at a pace chosen by the subject to reflect
a "normal" or comfortable pace, and the SPS consisted of stepping up and down
small (9.5 in [24.13 cm]) steps 20 times at a similar normal or comfortable
pace. Data collected following these activities included time in seconds and
heart rate. These data, along with age, sex, and BMI, were used to predict
the metabolic cost of the activity or oxygen uptake ( O2max).11 The psychometric properties of these predictive tests
have been previously reported.10-11
The SPW and SPS tests were administered in random order and separated by at
least 15 minutes.
DEMOGRAPHIC AND CLINICAL VARIABLES
Information on age, sex, comorbidities, and medications were obtained
by self-report, medical history, and physical examination. Osteoarthritis
in joints other than the index knee was defined as a physician having told
the subject he or she had OA in the hands, spine, hips, or feet. Other chronic
diseases including hypertension, coronary artery disease, and diabetes mellitus
were defined as self-report and clinical confirmation with or without current
use of medications for that condition.
Height and weight were measured by a standard protocol and BMI was calculated
as weight in kilograms divided by the square of height in meters. Standing
anterior-posterior knee radiographs were obtained at baseline and week 12
to confirm grades 1 to 3 OA and to determine the treatment effects on radiographic
disease. Films were read by a single radiologist masked to treatment group
assignment and timing of the radiograph. The classification scheme7 included grading of both medial and lateral compartments
for osteophytes, subchondral sclerosis, subchondral cysts, and loss of joint
space. Passive range of motion was determined as the total degrees of flexion
from full extension using a standard handheld goniometer.
TREATMENTS
Two milliliters of intra-articular sodium hyaluronate solution at a
concentration of 10 mg/mL (Suplasyn; Bioniche Life Sciences Inc, Belleville,
Ontario) or placebo (2 mL of isotonic sodium chloride solution [saline]) was
injected under sterile field using a medial approach at baseline and weeks
2 and 3 by a blinded physician. From baseline to week 12, NSAIDs (75 mg of
oral diclofenac and 200 µg of misoprostol [Arthrotec; Pharmacia Inc,
Peapack, NJ]) or placebo (100 mg of lactose) were ingested twice daily. Subjects
were also given 325 mg of acetaminophen as rescue medication to be taken as
needed up to 650 mg 4 times daily.
STUDY DESIGN
Following baseline assessments, subjects were randomized by computer
program to 1 of the following 4 groups: group 1, hyaluronate sodium and placebo
tablet; group 2, NSAIDs and hyaluronate sodium; group 3, NSAIDs and placebo
injection; and group 4, placebo tablet and placebo injection. Injections were
administered following all outcome assessments at baseline and weeks 1 and
2. At baseline, all subjects were also given instructions regarding a 10-minute
home-based resistance exercise program12-13
by a blinded kinesiologist. An accompanying videotape was made available to
assist with the exercises that were to be performed at least 3 (but preferably
on most) days of the week and recorded in a patient log. At week 3, subjects
returned to the clinic for outcome measures only and were scheduled for a
12-week follow-up visit. Oral study medications as well as regular-strength
(325 mg) acetaminophen for rescue analgesic purposes were also dispensed at
this time. All data were collected by staff masked to treatment assignments.
STATISTICAL ANALYSIS
Pain reduction using the WOMAC global assessment was the primary outcome
measure. The trial was designed to randomize 30 subjects to each intervention
group to achieve at least 25 subjects in each group at the end of 12 weeks.
A study sample of 100 was projected to provide a power of 0.8 to detect a
20% difference in pain reduction among groups.
Primary analyses were conducted by intent to treat with participants
analyzed according to the initial randomized assignments. All tests of hypotheses
and reported P values are 2-sided. Post hoc secondary
analyses were performed to examine outcomes by subgroup (age, sex, BMI, and
more than 1 comorbidity).
Analysis of variance and the  2 test were used to test
for differences in baseline characteristics by treatment group. The effects
of treatments on pain and physical functioning measured at weeks 4 and 12
were determined by repeated-measures analysis of covariance. Analyses were
conducted using Sigma Stat (SPSS Inc, Chicago, Ill) and Microsoft Excel (Microsoft
Corp, Redmond, Wash).
Analyses of group differences were adjusted for the prerandomization
level of baseline factors used in the blocked randomization to provide the
correct variance estimates for the randomization design. The analyses were
also adjusted for prerandomization values of other factors (ie, SPW and SPS
time, predicted O2max, BMI, and WOMAC physical disability
score). All values were significantly associated with the outcome variables
after adjusting for the other terms in the model. The baseline value of the
outcome of interest was also included in the analyses. The frequency of adverse
events in each group was evaluated with the 2 statistic to
establish a safety profile for the various treatments.
RESULTS
Recruitment of participants was conducted over 6 months. The study sample
comprised 120 individuals (71 women and 49 men), who provided informed consent
and were screened and randomized into 1 of 4 study groups. Of the subjects,
58% presented with right knee OA. Twelve subjects failed to complete the study:
1 was lost to follow-up; 2 had moderate gastrointestinal irritation; 1 failed
to comply with study tablet protocol; and 8 dropped out without reason prior
to treatment (after randomization). In the study sample, severity of OA was
grade 1 for 23%, grade 2 for 45%, and grade 3 for 32%. The characteristics
of all the participants are shown in Table
1. There were neither statistically significant differences among
the 4 groups nor differences in the dropouts among groups for demographic
characteristics, baseline physical functioning, or grade of OA.
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Table 1. Subject Demographic Characteristics*
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Overall compliance with the exercise program (at week 12) was 76% in
group 1, 70% in group 2, 77% in group 3, and 71% in group 4. Compliance with
the exercise interventions overall declined during the trial: 85% at week
4 to 75% at week 12. There was no statistically significant difference in
the decline in compliance with the exercise program among the 4 groups.
No serious adverse events occurred during the study. It is interesting
that most adverse events were reported in group 3, although this was not statistically
significant.
MAIN OUTCOMES
Pain
The primary outcome in the trial was self-reported pain using the WOMAC
global assessment. Baseline measures of pain were similar in all 4 groups
(Table 2). At week 4, groups 1
to 3 showed significant decrease in the pain subscale as reported on the WOMAC
global assessment (Table 2). At
week 12, the difference in pain scores among groups compared with those at
baseline were unchanged from week 4 in groups 1 and 3 but was significantly
greater in group 2 (P = .005).
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Table 2. WOMAC Subscale Indices of Pain, Disability, and Stiffness
at Baseline and Week 4*
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Pain at rest using the VAS was significantly reduced in all groups at
week 4 (Table 3). There was no
further pain reduction from weeks 4 to 12.
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Table 3. Physical Functioning and Pain at Baseline and Week 4*
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Physical Functioning, Stiffness, and Pain With Activity
Groups 1 to 3 showed significant (P<.05)
improvement in the WOMAC global assessment of physical disability at week
4, while groups 1 and 2 showed further significant (P<.05)
improvement from weeks 4 to 12 (Table 2). The WOMAC global assessment of stiffness significantly (P<.05) improved from baseline in all groups at week
4; however, no further improvement was observed at week 12 (Table 2). Group 2 showed a greater reduction in stiffness at week
4 but not at week 12 compared with the other groups, but this did reach statistical
significance.
Pain (CP-VAS) at rest and following activity was evaluated with the
SPW and SPS tests (Table 3). There
were no differences in pain (CP-VAS) following either test nor differences
in exercise time, exercise heart rate, or predicted O2max
among groups at baseline. All 4 groups reported significantly (P<.05) less activity pain 4 weeks after the SPW test, while only
groups 1 to 3 reported less pain 4 weeks after the SPS test (Table 4). There were no differences among groups 1 to 3. At week
4, we observed significantly faster SPW exercise times and higher O2max in groups 1 and 2 and significantly faster SPS exercise times in
group 1 (Table 4). At week 12,
activity pain after the SS test was significantly (P<.05)
lower in group 1, unchanged in group 2, and significantly (P<.05) higher in groups 3 and 4 compared with week 4 measures (Table 3). There were no significant differences
among the 4 groups in SPW pain, exercise times, or O2max
(Table 4) between weeks 4 and
12.
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Table 4. Physical Functioning at Baseline and Week 4*
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DEMOGRAPHIC AND CLINICAL OUTCOMES
There were no differences at baseline among demographic characteristics
(Table 1). There were no differences
in radiography scores among the groups at baseline and week 12 nor differences
in O2max among the groups at baseline.
Range of motion (measured as the degrees of passive flexion of the study
knee) was similar among all 4 groups at baseline. There was significant improvement
in flexion in all 4 groups at week 4 and no differences among groups at weeks
4 and 12.
SUBGROUP ANALYSES
We performed post hoc analyses to examine whether differences among
groups on the WOMAC subscale scores and the SPW and SPS test results were
influenced by demographic or clinical characteristics (age, sex, BMI, radiography
grade, and number of comorbidities). Similar significant (P<.05) effects on outcomes were seen among subgroups from groups
1 to 3. To determine if there was a dose response between compliance with
the exercise program and effects on outcomes, we also examined the influence
of percentage compliance on the WOMAC subscale scores. These analyses showed
that there were no significant differences among the WOMAC subscale scores
for pain, functional performance, and stiffness with differing compliance.
All groups showed high rates of compliance with this simple program.
COMMENT
This double-blind, placebo-controlled, randomized study provides support
for the use of viscosupplementation with HA in the treatment of OA of the
knee. With standard of care treatment (NSAIDs alone or with additives), pain
at rest and following physical activity was reduced and physical functioning
was improved compared with baseline measures. Moreover, the effect of hyaluronate
sodium on activity-related pain and functional performance seems to improve
with time from intervention compared with the effect of NSAIDs, which does
not show continued improvement after 4 weeks of treatment.
Despite the increasing morbidity of pain and functional impairment,
as well as the economic costs that ensue, standard therapies for OA have not
progressed over the past few years even with the introduction of more selective
anti-inflammatory medications.2, 14-15
Standard therapies currently include the use of NSAIDs despite evidence of
increased frequency and severity of adverse effects and associated morbidity,
particularly in elderly patients.16-17
Exercise is also suggested as standard treatment; however, adoption rates
are disappointingly low.18-19
Further, no consistent long-term improvement of physical function with the
use of NSAIDs has been reported.20-21
LaMontagna et al22 found that improvement in
daily living activities with 2 different NSAIDs was limited to the first few
weeks of treatment, then falling to baseline levels. Critics even suggest
that the removal of objective pain sensation may lead to increased rates of
cartilage deterioration with long-term NSAID use21
and lead to further pain and functional decline. Certainly, new therapies
are desirable, including intra-articular hyaluronate sodium therapy23-25 and the better promotion
of exercise therapy,19 both of which address
underlying pathophysiologic conditions, improve symptoms, and are relatively
free of adverse events.
The literature lacks substantial investigation comparing HA with placebo
and other standard OA therapies.26 A few studies24, 27-28 have systematically
investigated the effect of HA and found variable effects on pain control,
and none to our knowledge have investigated the effect on physical functioning.
In contrast, dose-finding studies have shown impressive improvement in pain
control after 3 injections of HA in up to 82% of patients at 26 weeks29-31 with a low adverse
event profile.32
The mechanism of action of intra-articular HA injection has not been
determined. Removal of water-soluble mediators of inflammation and articular
breakdown products could explain the therapeutic effect in part.3
However, Dawes et al33 found that tidal irrigation
of the knee conferred no long-term benefit over saline injection. Instead,
there is support for HA restoration of the rheological (including the complex
interaction of flow and deformation of the articular matrix during the loading
and unloading of the joint) properties of the osteoarthritic joint. Hyaluronic
acid is a large molecular component of the articular matrix that acts as a
"lubricant" when movements are slow (viscous properties) and as a "shock absorber"
when movements are fast (elastic).34 There
also seems to be free radical scavenger activity of HA.35
If the OA knee joint is characterized by lower HA concentration and molecular
weight, reduced elastoviscosity has been hypothesized to lead to reduced joint
stability during loading, resulting in pain and reduced function.35 Hence, it has been hypothesized that supplementation
of the OA articular matrix with exogenous HA may restore the joint environment
to a level of greater function and less pain.
Although the therapeutic effect on pain relief may be lost after several
months because of finite residence time (between 8 and 16 months35),
HA can be readministered with no apparent adverse effects. However, the efficacy
for pain and functional improvement at an optimal dosing regimen has not been
described.31 Therefore, further investigation
of the impact of HA differing in molecular weight, concentration, dosing intervals,
and number of injections on functional outcomes are needed.
The significant improvement in pain and physical functioning from baseline
among all groups, including control group 4, could be attributed to the concomitant
introduction of a simple resistive exercise program.13
The low rate of adverse events and high rate of exercise compliance in group
4 suggests and supports the recommendations18, 20
that a combination of exercise and other medical therapy should be considered
for most patients with OA. Presently, low levels of activity among this population
suggest that there is room for low-intensity exercise therapy. However, modest
effects of exercise on pain, disability, and physical functioning support
our observation.36 We chose functional tasks
within the clinical range of patients with knee OA as key outcomes.13 Certainly, self-selection of functional tasks (ie,
walking and stair climbing or stepping) help define the level of functional
independence and is useful in determining the effectiveness of therapeutic
interventions in this population. Marks37 observed
that reporting of joint pain in patients with knee OA was correlated most
with stair climbing rather than other observations, including BMI or disease
severity. Thus, we believe these functional measures are important determinants
of therapeutic intervention in this study and should be used in future efficacy
studies in OA.
In summary, intra-articular hyaluronate sodium therapy was similar to
NSAID therapy in improving pain at rest, while the introduction of a simple
exercise program improved functional performance in all 4 groups compared
with baseline measures. It seems that hyaluronate sodium therapy may show
greater efficacy for activity-related pain and improve functional performance
more than NSAID or exercise therapy alone. Future studies regarding optimal
dosing, concentration, and the long-term impact of hyaluronate sodium on OA
in the knee and other weight-bearing joints are needed.
AUTHOR INFORMATION
Accepted for publication July 31, 2001.
This study was supported by an unrestricted educational grant from Bioniche
Life Sciences Inc. Dr Petrella is a Canadian Institutes of Health Research
(CIHR) investigator. Special thanks to Charlene Bartha, RN, and Stan Alkemade,
DVM, for their assistance with the study and manuscript.
Corresponding author and reprints: Robert J. Petrella, MD, PhD, Centre
for Activity and Ageing, University of Western Ontario, 1490 Richmond St N,
London, Ontario, Canada N6G 2M3.
From the Centre for Activity and Ageing, Lawson Research Institute
and Faculties of Medicine and Health Sciences, University of Western Ontario,
London (Dr Petrella); the Faculty of Medicine, University of Calgary, Calgary,
Alberta (Mr DiSilvestro); and Bioniche Life Sciences Inc, Belleville, Ontario
(Dr Hildebrand).
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