Efficacy of Sodium Hyaluronate

The ef®cacy of intra-articular sodium hyaluronate

in patients with reducing displaced disc

of the temporomandibular joint

S. HEPGULER*, Y. S. AKKOC*, M. PEHLIVAN², C. OZTURK*, G. CELEBI²,A. SARACOGLU³ & B. OZPINAR³

*Department of Physical Medicine and Rehabilitation, ²Department of Biophysics,

and ³Department of Prosthetic Dentistry, School of Medicine, School of Dentistry, Ege University, Izmir, Turkey

SUMMARYSUMMARY In this clinical trial, we examined the

ef®cacy of intra-articular hyaluronic acid (HA) treat-

ment in 38 patients with reducing displaced disc of

the temporomandibular joint (TMJ). Subjects

received two unilateral upper space injections of

HA or physiological saline solution with 1 week

apart. Ef®cacy was based on the following measure-

ments: pain and sound intensity of the joint meas-

ured by visual analogue scale (VAS), modi®ed

Helkimo's clinical dysfunction index and the inten-

sity of joint vibration during opening and closing the

mouth measured by accelerometers. These meas-

urements were performed before the ®rst injection

and 1 and 6 months after the last injection. In the

treatment group (n � 19), all measurements

improved signi®cantly at month 1 and at month 6

compared with the baseline (P < 0á01). The same

measurements, in the placebo group (n � 19), did

not show any change, except for the pain intensity

which improved at month 1 and month 6 (P < 0á05).

The change in baseline measurements of all of the

ef®cacy criteria at month 1 and at month 6 in the

treatment group was signi®cantly better compared

with the change obtained with placebo at the same

time intervals. This study demonstrates that intra-

articular sodium hyaluronate (OrthoviscÒ) injection

into the TMJ is an effective treatment for a reducing

displaced disc.

KEYWORDSKEYWORDS: intra-articular therapy, sodium hyalur-

onate (hyaluronan), temporomandibular joint

Introduction

Temporomandibular joint (TMJ) disorders may have

intracapsular, extracapsular or combined intracapsular

and extracapsular origins. Extracapsular disorders gen-

erally result from the muscles surrounding the TMJ.

Thus, conservative therapies such as heat application,

soft diet and exercise can often be effective in the

treatment of these disorders (Clark & Merrill, 1992). In

contrast, intracapsular disorders are the result of the

pathology of the articular surfaces or abnormalities in

the mechanical relationship of articular structures

(Guralnick et al., 1978). The conservative treatment

of the symptomatic intracapsular disorders are not

always successful, surgical and non-surgical approa-

ches including administration of intra-articular corti-

costeroids are often necessary (Agus et al., 1983).

Because of the signi®cant morbidity risk of these

therapies for intracapsular articular disease, new

improved approaches carrying low risk have been

investigated. Reducing displaced disc (RDD) is one of

the most prevalent intracapsular TMJ disorders and

one for which no satisfactory treatment is currently

available. There is limited data suggesting that intra-

articular hyaluronic acid (HA) injections may offer a

new prospect of approach in the treatment of TMJ

disorders, including RDD (Kopp et al., 1985, 1987;

Bertolami et al., 1993).

Hyaluronic acid is a linear polysaccharide consisting

of repeating disaccharide units of glucuronic acid and

N-acetyl glucosamine linked by B1-3 and B1-4 glycos-

idic bonds. It is available in the extracellular matrix of

various mammalian tissues including skin, cartilage,

umbilical cord, rooster comb and synovial ¯uid

ã 2002 Blackwell Science Ltd 80

Journal of Oral Rehabilitation 2002 29; 80±86

(Abantagelo & O'Regan, 1995). Intra-articular HA

injections have been reported to have a bene®cial

effect in the treatment of knee, hip and shoulder

disorders (Leardini et al., 1988; Bragantini & Molinaroli,

1994; Huskisson & Donnelly, 1999). OrthoviscÒ* which

has a molecular weight > 1000 kDa is a natural, non-

crosslinked, extensively puri®ed, high viscosity hyal-

uronan extracted from rooster combs. In this study, we

have compared intra-articular injections of OrthoviscÒ

and placebo in order to detect whether this compound

is effective in the treatment of RDD of TMJ.

Materials and methods

This was a randomized, double-blind, placebo-con-

trolled study with a 6-month follow-up period, com-

paring the ef®cacy of intra-articular injections of HA

with intra-articular injections of placebo in patients

with RDD of TMJ joint. Reducing displaced disc was

diagnosed according to the standard clinical diagnostic

criteria based on symptoms, clinical signs and radio-

graphic ®ndings (Bertolami et al., 1993). These criteria

are summarized in Table 1. Patients over 21 years of

age who were resistant to conservative treatment for at

least 2 months and who ful®lled the standard clinical

diagnostic criteria were included in this study. Those

who were pregnant or lactating, exhibited poor oral

health, received previous joint injections or surgery

were excluded from the study. Written informed

consent was obtained from all subjects.

The patients were randomly divided into two groups

and subjected to intra-articular injection with HA (HA

group, n � 19) or saline (placebo group, n � 19).

Although the HA and control solutions, were coded

and randomized by the manufacturer, were both clear

colourless ¯uids that were not visibly distinguishable, it

was still necessary to use a blind observer because of

the differences in viscosity between the drug and

placebo. Thus, different physicians carried out the

administration of the intra-articular injections and the

ef®cacy assessments. Neither was aware of the treat-

ment given. A volume of 0á5 mL of HA (15 mg mL±1,

OrthoviscÒ) or physiological saline solution was

administered into the superior joint compartment of

the TMJ with the mouth opened maximally and was

repeated 1 week later.

Clinical evaluation was carried out before the ®rst

injection and at 1 and 6 months after the ®nal injec-

tion. The level of TMJ pain was measured by VAS

(0 � no pain, 10 � constant and severe pain), as well as

the severity of joint sound (click) (0 � no sound, 10 � a

joint sound that is easily perceptible from outside by

another person). The patients were also evaluated by a

modi®ed Helkimo's clinical dysfunction index (Kurita

et al., 1997). According to the modi®ed Helkimo's

clinical dysfunction index, pain on movement of the

mandible, TMJ pain, maximal mouth opening, signs of

TMJ sound and disc derangement, and muscle pain in

masticatory muscles are scored between 0 and 5.

Treatment response in this index is as follows: 1 ± total

remission, if the index components all went down to

the 0 or 1 level; 2 ± partial remission, if one index

component was at a level >1; 3±unchanged, if none of

the components went up or down; 4 ± exacerbated, if

one or more of the index components went up (Kurita

et al., 1997).

The severity of TMJ vibrations and pain measured by

VAS, and the TMJ vibration amplitudes recorded at

different periods were compared using Friedman test to

determine the within group differences and Mann±

Whitney U-test to determine between-group differences.

The improvement frequencies of both groups according

to the Helkimo's clinical dysfunction index were com-

pared with the v2 test.

Temporomandibular joint vibrations were captured

by two small accelerometers (Dytran, 3115AS²) ®xed

over each joint with a double-sided tape. Each accel-

erometer was placed about 1±1á5 cm front of tragus

over the skin on the articular eminence. This site

was reported to be the best site for detecting TMJ

vibrations with accelerometers (Yoshida et al., 1994).

Vibration recording instrumentation consisted of an

Table 1. Diagnostic criteria for reducing displaced disc of the TMJ

Symptoms Temporomandibular joint pain (variable)

Clicking

Physical signs Joint tenderness (variable)

Reciprocal clicking

Jaw deviates toward side of click until click

occurs then returns to midline

Radiographic

®ndings

Magnetic resonance imaging shows displaced

disc that reduces on opening

*Anika Therapeutics Inc., Woburn, MA, USA. ²Dytran Instruments Inc., Chatsworth, CA, USA.

E F F I C A C Y O F H Y A L U R O N A N I N T M J D I S C D I S P L A C E M E N T 81

ã 2002 Blackwell Science Ltd, Journal of Oral Rehabilitation 29; 80±86

electronic goniometer, two accelerometers, an ampli-

®er deck, a custom designed table to keep the head

upright for mandibular angle detection, an IBM

compatible computer with a 12 bit data acquisition

card (Advantech PCL-812PG³) to digitize the signals

and a software to record and analyse vibrations and

angle (Fig. 1). Ampli®cation gain was set between 200

and 500 and vibrations were sampled at 2 kHz for each

channel within 5±1000 Hz ®lter range. The sampling

rate and ®lter settings were in the suggested range for

vibration recording with accelerometers (Yoshida et al.,

1994). The accelerometers were factory calibrated to

10 mV g±1, and had almost a ¯at response up to

10 kHz. The experimental set-up was calibrated as 1 V

RMS (root mean square) amplitude corresponding to

100 m s±2 acceleration.

Each patient was seated upright on a comfortable

chair which was closely placed to the experiment table.

Patients were instructed to open and close their

mandible at every 1-s period for 20 s. Two channel

TMJ vibration signals and one channel TMJ angle data

were stored on a computer hard disc during this 20-s

period, and was repeated for about 5±8 times. Jaw

opening and closing angular velocity of each record was

almost equal to each other. Very slow or incomplete

cycles of jaw opening or closing were rejected and

extracted from calculations.

A computer program was developed in our laborat-

ory by using a data acquisition program (DASYLab§) to

segment the vibrations according to jaw opening and

closing cycles and to calculate the RMS vibration

amplitudes. Every peak was detected independently

and its RMS value was calculated by using the

following formula then the results were added to each

other to calculate the vibration amplitude for each

segment.

Vrms �

��1

t

Z t

0

V 2�t� dt

vuuutOther measures, such as jaw angle of vibration onset or

correlation of jaw opening and closing speed and

vibration amplitude, and the number of detected peaks

in a segment can also be recognized and calculated by

the developed program.

Results

Baseline characteristics of the active treatment and

control groups were comparable (Table 2). All patients

in both groups completed the treatment course and

6-month follow-up.

Pain and sound intensity of the TMJ measured by

VAS, modi®ed Helkimo's clinical dysfunction index and

Table 2. Patient characteristics at baseline (n � 19)

Hyaluronan group Placebo group

Age (year) (mean � s.d.) 31á94 � 12á67 31á10 � 11á25*

Sex (F/M) 13/6 13/6*

Duration of symptoms

(months) (mean � s.d.)

18á52 � 20á11 21á26 � 18á31*

Pain intensity (VAS)

(mean � s.d.)

6á68 � 1á56 5á73 � 1á82*

Sound intensity (VAS)

(mean � s.d.)

8á0 � 1á63 7á15 � 1á60*

Helkimo's index (score)

(mean � s.d.)

6á47 � 0á96 6á15 � 0á83*

*P > 0á05.

Fig. 1. Schematic diagram

of TMJ vibration recording system.

³Advantech Co, Ltd, Cincinnati, OH, USA.§DATALOG GmbH & Co. KG, Moenchengladbach, Germany.

S . H E P G U L E R et al.82


vibration intensity during opening and closing the

mouth measured by accelerometers showed greater

reductions at month 1 and month 6 in the HA group

compared with the placebo group, with statistically

signi®cant within group differences in the HA group

being observed for all these individual parameters at the

same time intervals compared with the baseline meas-

urements (P < 0á05) (Figs. 2±4). Within group analysis

of the placebo group showed no signi®cant difference

except for the joint intensity measured at month 1 and

month 6 compared with the baseline value.

Evaluation of patients by modi®ed Helkimo's clinical

dysfunction index in the HA group showed improve-

ment (total or partial remission) in 17 patients (89á5%)

at 1 month and 12 patients (63%) at 6 months. In the

placebo group, only four (21%) and ®ve (26%) patients

at month 1 and month 6, respectively, showed

improvement (total or partial remission) (Fig. 3). The

difference between the two groups was signi®cant at

both time intervals (P < 0á001 and P < 0á05, respect-

ively).

Discussion

Temporomandibular joint disorders contain a group of

conditions affecting the TMJ, masticatory muscles or

both. These conditions are characterized by pain in the

pre-auricular region aggravated by chewing and other

jaw functions. Physical examination ®ndings may

include limitation of jaw movement, joint sounds,

palpable muscle tenderness or joint pain (Mohl, 1993).

Although patients with TMJ disorder may often respond

to conservative treatments such as heat application, soft

diet and exercise, some have prolonged intra-articular

pain and tenderness in spite of the treatment. Surgical

treatment is an alternative, but with a signi®cant risk of

morbidity. As a non-surgical treatment alternative,

intra-articular corticosteroid injections may be tried.

However, this kind of treatment is known to exert

deleterious effects on joints (Sevastik & Lemperg, 1969).

Thus, there is a requirement to search for alternative

therapeutic agents in these disorders.

Since the ®rst therapeutic studies of HA in knee

osteoarthritis in the early 1970s, intra-articular injec-

tions of HA have been tried in various joint disorders

including TMJ (Rydell & Balazs, 1971; Peyron & Balazs,

1974; Kopp et al., 1985; Kopp et al., 1987; Leardini

et al., 1988; Bragantini & Molinaroli, 1994; Huskisson &

Donnelly, 1999). In those few studies carried out in

various TMJ disorders, improvement in subjective

symptoms and clinical ®ndings was obtained (Kopp

et al., 1985; Kopp et al., 1987; Bertolami et al., 1993;

Sato et al., 1997). In the study performed by Bertolami

et al. (1993), the primary bene®cial effect was seen for

the RDD category of TMJ disorders. In their study, a

clear and consistent bene®cial effect lasting for

6 months was reported in patients with RDD with a

single intra-articular injection of HA. Our study con®rm

their ®ndings. With two intra-articular injections of HA,

1 week apart, we detected improvement at month 1

and month 6 compared with the baseline evaluation for

all of the outcome measures including pain and sound

Fig. 3. Clinical evaluation of patient groups after treatment

according to modi®ed Helkimo's clinical dysfunction index.

Fig. 2. Pain and sound intensities measured by VAS before and

after treatment in each group.



intensity measured by VAS, the modi®ed Helkimo's

clinical dysfunction index and the intensity of joint

vibration measured by accelerometer. In the placebo

group, only pain intensity measured by VAS showed a

signi®cant improvement compared with the baseline

measures. However, VAS scores of pain intensity at

month 1 and month 6 were signi®cantly lower in the

HA group compared with the control group.

The decrease seen in the intensity of joint vibration

measured by the accelerometer in the HA group

provide further objective evidence indicating the

effectiveness of such treatment. Recording and analy-

sing the TMJ vibrations is a non-invasive and easily

applicable method which can provide objective data to

evaluate the effectiveness of treatment for TMJ disor-

ders. The TMJ vibrations before and after intra-articular

application of HA were recorded by arthrophonometry

in one study (Bertolami et al., 1993). However, in this

study joint vibrations were characterized in terms of

location relative to mandibular displacement for the

RDD category.

In our study, TMJ vibration during opening and

closing the mouth was measured by an accelerometer

which has been accepted as a reliable method for

measuring amplitudes of TMJ vibrations (Yoshida et al.,

1994). Although accelerometers are considered as low

frequency sensors because of skin thickness and its

resonance, the frequency range can be considered

suf®cient to measure vibration amplitudes. Miniature

condenser microphones or electronic stethoscopes

placed over the TMJ are frequently used techniques

to record sounds. To capture TMJ sounds using accel-

erometers may be more convenient than the micro-

phones, as microphones can easily be affected by

environmental sounds. Thus, patients could be instruc-

ted during recording as no interference from the

instructor's voice was expected.

If there was no sense of clinically palpated vibration

during recording, instrumentation did not show any

signal of vibration except for very low amplitude

background noise which was caused by electronic

ampli®er circuits. Duration of every peak was measured

Fig. 4. Temporomandibular joint vibration amplitudes in placebo group (A and B) and hyaluronan group (C and D) according to jaw

opening (A and C) and closing (B and D) cycles before and after treatment.



by the computer with 0á5 ms resolution and its RMS

value was calculated by integrating as described in the

materials and methods. Then, every peak RMS value

was added to ®nd the total vibration RMS amplitude of

the segment. By this way, only the signals produced

from the TMJ was evaluated.

The precise mechanism by which HA alleviates

symptoms of RDD is unknown. It provides lubrication

for the articular surfaces and is largely responsible for

synovial ¯uid viscosity. As it has a short half life,

restoration of viscosity is improbable to explain the

prolonged symptomatic relief. A purely mechanical

effect, through interruption of the obstruction and/or

trauma cycle of the disc by short-term lubricating action

of sodium hyaluronate has been suggested to be

responsible for the long lasting symptomatic improve-

ment (Bertolami et al., 1993).

Hansson (19921 ) has indicated that, in patients with

RDD, constant trauma by the condyle to the posterior

loose tissue of the disc or to the junction between the

disc and capsule leads to in¯ammation which may lead

to intra-articular swelling and to displacement of the

disc. Hyaluronic acid has been reported to reveal anti-

in¯ammatory effects (Brandt et al., 1976; Sato et al.,

1988; Punzi et al., 1989). The interruption of this

vicious circle by the anti-in¯ammatory effects of HA

may be another mechanism contributing to the pro-

longed symptomatic relief obtained in RDD patients

with intra-articular HA injections.

In conclusion, intra-articular HA is a safe and

effective therapeutic approach with a long lasting effect

for at least 6 months in patients with RDD.

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Fiziksel Tip ve Rehabilitasyon Anabilim Dali, 35100 Bornova, Izmir,

Turkey.

E-mail: [email protected], [email protected]



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Efficacy of Sodium Hyaluronate