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Original article Effect of Glucosamine Sulfate, Chondrotin Sulfate, Methylsulfonylmethane Phonophoresis on Knee Osteoarthritis Soheir SR Samaan 1, Joseph W Saweris 2 1 Assisstant professor of physical therapy, Department of Basic Sciences, Faculty of Physical therapy, Cairo University, Egypt 2 Physical therapist, Institute of Oncology, Cairo University Corresponding author: Soheir Shehata RezkAllah, Department of Basic Sciences, Faculty of Physical therapy, Cairo University, 7 Ahmed ElZayyaet st., Dokki, Giza, Egypt. Email: [email protected] Running heads Soheir and Joseph Journal of clinical rehabilitation 0(0) 1 Abstract Glucosamine sulfate and chondroitin sulfate are believed to relieve pain, decrease joint narrowing, stimulate the production of new cartilage components, and help the body to repair damaged cartilage. Methylsulfonylmethane is an analgesic and anti-inflammatory drug is usually used with the previous drugs. Phonophoresis was believed to influence drug delivery by increasing cell permeability, causing particle oscillations within the tissue and drug milieu. Methods: Thirty patients of both sexes randomly assigned in three groups. Group A received pulsed ultrasound (50% duty cycle), 1 MHZ, 1.5 w/cm2, 5 min using Glucosamine sulfate, Chondroitin sulfate and Methylsulfonylmethane gel as a coupling medium in addition to a traditional physical therapy program included stretch of the hamstring and calf muscles, and isometric strengthening of the quadriceps, group B received topical application of Glucosamine sulfate, Chondroitin sulfate and MSM gel with sham ultrasound in addition to the same traditional physical therapy program, group C received the traditional exercise program only. Treatment was provided 3 times per week for 4 successive weeks. Patients were assessed before and treatment using visual VAS for pain level, electronic goniometer for ROM, and The WOMAC Index of Osteoarthritis for functional level of the knee joint. Patients in all groups showed a significant improvement of pain level, ROM; and functional level of the knee joint, improvement in group A 2 was higher than in group B and both were better than group C. Conclusion: Glucosamine sulfate, Chondroitin sulfate and Methylsulfonylmethane gel phonophoresis is effective in the treatment of knee osteoarthritis. Key words: Knee osteoarthritis, glucosamine methylsulfonylmethane, phonophoresis. 3 sulfate, chondroitin sulfate, Introduction Osteoarthritis (OA) is a disorder that affects the synovial joints; it is characterized by damaging of focal areas to articular cartilage, changing of the underlying bone and the formation of osteophytes at joint margins and mild synovitis [1]. Knees are of the most commonly affected joints by osteoarthritis [2]. The most common symptom of Knee osteoarthritis is pain, it aggravates with joint movement and relieved by rest. Inflammation leads some patients to experience pain at rest. Pain is caused by stretch on the periosteum by osteophytes, bony changes at the ligamentous attachments, and muscle spasm which aim at immobilizing the painful joint [3]. Pharmacological treatment of knee osteoarthritis includes analgesics, non-steroidal antiinflammatory drugs (NSAIDs), corticosteroids and opiods, and gluco-samine sulfate. NSAID are widely prescribed and purchased over-the-counter for osteoarthritic complaints but have significant side effects and are associated with >16,000 deaths annually in the United States [4]. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of cartilage, research has focused on the potential for supplemental glucosamine to beneficially influence cartilage structure and alleviate arthritis [5]. 4 Clinical trials have suggested that glucosamine sulfate (GS) is an effective drug for the management of symptoms of OA when it used as a medium and long term treatment [6]. This symptom modification is sustained for years, and there is an intriguing suggestion of possible disease (structure) modification [7,8]. These long-term effects are particularly relevant [9], given the chronic and progressive nature of this degenerative joint disease. Glucosamine sulfate may potentially delay joint structure changes in OA [7,8]. Chondroitin sulfate (CS) is a major component of the extracellular matrix (ECM) of many connective tissues, including cartilage, bone, skin, ligaments and tendons [10]. Chondroitin sulfate, as a natural component of the ECM, is a sulfated glycosaminoglycan (GAG) composed of a long unbranched polysaccharide chain with a repeating disaccharide structure of N-acetylga-lactosamine and glucuronic acid. Chondroitin sulfate is responsible for many of the important biomechanical properties of cartilage, such as resistance and elasticity. Its high content in the aggrecan plays a major role in allowing cartilage to resist pressure stresses during various loading conditions [11]. Chondroitin sulfate is recommended as a therapeutic intervention in the treatment of OA. CS has the capacity to accumulate in joint tissue including synovial fluid and cartilage after oral administration in humans [12]. GS and CS were administered orally, or by intravenous injection. Topical application of glucosamine and chondroitin sulfate is effective in relieving the pain from OA of the 5 knee and improvement is evident within 8 weeks [13]. Few studies reported modest effects of oral glucosamine intake on increasing fasting glucose, increasing the glucose threshold for insulin secretion, and decreasing insulin sensitivity [14]. Oral or intravenous administration of GS was reported to have minimal adverse effects; such as nausea, GIT troubles but it was proved that it does not causes insulin resistance despite it enters the hexosamine biosynthetic pathway directly [15,16]. Methylsulfonylmethane (MSM) is a popular dietary supplement used as a single agent and in combination with other nutrients, and reported to be beneficial for arthritis. SM (3g twice a day) improved symptoms of pain and physical function during the short intervention without major adverse events. [17]. MSM is an organosulfur molecule that can be synthesized commercially from dimethylsulfoxide (DMSO). It is even naturally present in the human body as it is metabolized from ingested DMSO. It can be found in cerebrospinal fluid and plasma at 0-25 μmol/l concentrations [18]. Minimal knowledge is known about how these effects may benefit patients with OA of the knee, long-term trials on MSM may yield additional and greater improvements in knee OA symptoms [19]. Glucoseamine was used in combination with MSM for treating OA. They produced an analgesic and anti-inflammatory effect. Combination therapy showed better efficacy in reducing pain and swelling and in improving the functional ability of joints than the individual agents [20]. 6 Phonophoresis was known to enhance penetration of any medication through the normal skin by ultrasound irradiation. It can be obtained with the medication gel or cream either used as a coupling medium for the ultrasound head or with any regular coupling gel, the actual medication gel or cream being applied on the irradiated area immediately thereafter [21]. Phonophoresis was believed to influence drug delivery by increasing cell permeability, causing particle oscillations within the tissue and drug milieu, and perhaps inducing drug molecule motion through radiation pressure forces. The most likely mechanical explanation is thought to be intercellular diffusion from high-speed vibration of drug molecules along with vibration of the cell membrane and its component [22]. Many trials were attempted to investigate the effect of phonophoresis with different drugs in the treatment of OA. Drugs used with phonophoresis were ibuprofen [23], ketoprofin [24], dexamethasone sodium phosphate [25], and piroxicam [26]. Phonophoresis was proved to be effective in pain relief and improving patient symptoms and function. Similarly this study was conducted to investigate the efficacy of GS, CS and SMS phonophoresis versus topical application on symptoms and function of knee OA. Material and methods Subjects 7 Thirty patients with knee OA (male and female) participated in the study. Their ages ranged between 45 to 65 years. They were randomly assigned into 3 groups of equal number, 2 experimental groups and a control group. The study is a randomized controlled trial. Group (A): Consisted of 10 patients, they received GS, CS and MSM gel phonophoresis with pulsed ultrasound therapy (50% duty cycle),1 MHZ, 1.5 w/cm2, 5 min according to Cagnie, et al 2003; plus a traditional exercise program that included stretching exercises of the hamstrings and calf muscles, straight leg raising (SLR) of the knee, and isometric strengthening of the quadrecipes. Group (B): Consisted of 10 patients, they received topical application of GS, CS and MSM gel plus the traditional exercise program. Group (C): Consisted of 10 patients, they received only the traditional exercise program. The treatment was given three sessions per week for four weeks. All patients gave written informed consent prior to entering the study. The protocol was approved by the Institutional board of the faculty of physical therapy, Cairo University. The study was conducted at the out clinic of faculty of physical therapy, Cairo University from September 2013 to February 2014. Eligibility was defined as symptomatic knee OA for at least 6 months according to the clinical criteria of the American College of Rheumatology (ACR) [27] and radiographic confirmed knee OA according to the Kellgren & Lawrence scale [28]. Exclusion criteria included acute septic arthritis; inflammatory arthritis; any other type of arthritis; history of knee 8 buckling or recent knee injury; lack of physical or mental ability to perform or comply with the treatment procedure; diabetes mellitus; fibromyalgia or other chronic pain syndromes; concurrent anti-coagulant/anti-platelet drugs; arthroscopy or intra-articular injections in the previous 3 months. Patients using other arthritis therapies (CAM, etc.) and patients using NSAIDs were required to undergo a 10-day washout period before enrollment. Enrollment Thirty patients with knee OA whose age ranged from 45 to 65 years participated in this randomized controlled trial. The participants were selected randomly from the out clinic of faculty of physical therapy and from the orthopedics outpatient’s clinic, faculty of medicine, Cairo University. Over several months at those clinics hundreds of patients came in to be examined for regular medical problems. 42 patients who were examined by orthopedists for knee OA problems consented to enter the study. These patients were assessed by the orthopedists on staff for eligibility to the study according to the inclusion and exclusion criteria. 30 patients were determined to meet the study criteria and were enrolled into the study. The 30 selected patients were assigned to phonophoresis sessions or topical application with sham ultrasound or a traditional exercise program. For phonophoresis, pulsed ultrasound was used with frequency 1 MHz, intensity 1.5 W/cm², and (50% duty cycle) for 5 minutes /session. Glucosamine sulfate 30mg/g, Chondroitin sulfate 50mg/g and MSM 10mg/g gel were put on 9 ultrasound head before application. Topical application was done by applying of GS, CS and MSM gel on the head of US and moving it on the knee for 5 minutes with sham ultrasound where the device is off and all controls on zero. Randomization The study was a 4-week randomized controlled trial by using random numbers. Random numbers were assigned as follows: Once the orthopedist on staff determined a patient's eligibility to the study, the patient was given a unique number for the duration of the study. Assignment in a group was done by asking each patient to select a number from 1-30 from a opaque envelope, then it was put in one of the three groups as follows: numbers from 1-10 in group A, numbers from 11 to 20 in group B and numbers from 21-30 in group C. After being assigned a number and after being scored in all the study measurements for baseline data. The serial numbers were examined at the end of the 4 weeks. The traditional exercise program in the form of: 1) Stretching of the hamstring muscles from supine lying position for 3 successive times, 30 seconds each with rest for 1 minute in between stretches, 2) Stretching of the calf muscles from supine lying position for 3 successive times, 30 seconds each with rest for 1 minute in between stretches [29], 3) Straight leg raising exercise in which the patients were positioned in the crook lying position with the unexercised limb is the flexed one then the patients was asked to contract the quadriceps muscle and elevate the limb to 45º and hold for 6 10 seconds, slowly lower the limb and then relax for 6 seconds, three sets of 10 repetitions were be done [30], 4) Isometric strengthening of the quadriceps muscle in the form of 3 sub maximal isometric contractions of increasing intensity followed by 6 maximal 5 seconds isometric contractions, the isometric contractions were repeated at multiple knee angles (30º–60º–90º) degrees respectively, each contraction was followed by 30 seconds rest period and each set of contractions at each knee angle was followed by 1 minute rest [31]. Patient evaluation The patients were scored at baseline and 4 weeks. The primary outcomes of the study were the VAS for pain, the modified electro-goniometer for knee flexion ROM, and the WOMAC questionnaire. The VAS is a subjective measurement that the patient reports on a 10 cm horizontal line, where 0 indicates no pain and 10 the worst pain. The VAS is particularly useful in assessing changes in pain for individuals receiving therapy [32]. Penny and Giles electrogoniometer (Penny and Giles Biometrics Ltd, Gwent, UK) was attached by double-sided tape to the lateral aspect of the thigh and lower leg. To allow the goniometer to be positioned accurately during assessment, the subjects were marked with ink at the center of the lateral femoral condyle and then 7 (cm) above and below that point on the line connecting the greater trochanter of the hip to the head of the fibula. The mechanical signals from the measuring element in the end-blocks were converted into a digital signal by a datalog acquisition unit which connected the 11 electrogoniometer to a display unit [33]. The WOMAC includes 24 points that includes pain, stiffness, and physical function. Scoring and interpretation from 0 to 5. 0=none response, 1=slight, 2=moderate, 3=severe, 4=extreme [34, 35]. Data analyses Data were analyzed for this randomized controlled trial using descriptive statistics and with a 3×2 mixed model analysis of variance (ANOVA) with the treatment groups (2 experimental vs. control) used as the between subjects factor and time of assessment (pretreatment, post treatment) used as the within subjects factor. The software used for statistical analysis was the SPSS version 20. The P-value was set at 0.05. The dependent variables were pain level, Knee flexion ROM and functional disability of the knee joint. Before data analysis, Shapiro–Wilk test was used to test the normality of the data and Levene’s test was used to test the equality of variances. The differences in demographic characteristics for both groups were assessed using one way ANOVA test. A preliminary power analysis with a power 80% determined a sample size of 30 subjects in each group. Results Demographic data of the participant is presented in Table (1). No statistical differences were found between groups in demographic data. All data of the dependent variables are normally distributed as revealed by Shapiro– Wilk test and all data showed no violations of the assumptions of equality of variance as revealed by Levene’s test. All 12 pretreatment dependent variables showed no significant difference between groups (P>0.05). Table (1): Demographic data of participates Group A Group B Group C F-value P value 57±6.39 0.28 0.75 Age (Years) 55.4± 6.34 55.2 ± 4.77 Weight (Kg) 81 ± 4.83 80.8 ± 7.37 83.6±6.55 0.6 0.55 Height (cm) 167.4 ± 6.43 166.9 ± 5.7 167.7±5.07 0.04 0.95 BMI (mmHg) 28.98± 2.23 29.1 ± 2.42 29.75±2.12 0.37 0.69 *SD: standard deviation, P: probability, S: significance, NS: non-significant. Descriptive statistics of pain level, knee flexion ROM and functional disability are demonstrated in Table (2) and figures (1), (2), (3). The 3×2 mixed-model ANOVA analysis demonstrated significant reduction in pain level in the three groups as the main effect of time was statistically significant (p=0.0001). But the experimental groups A and B showed significant improvement than the control group post treatment as the main effect of group was statistically significant where (p=0.01) and interaction 13 between time and group was also significant (p=0.0001) as presented in table (3). Post hoc tests revealed no significant difference between group A and B and between group B and C (p=0.42,0.25) respectively, while there was a significant difference between group A and C (p=0.008) as presented in table 4. Table 2. Pain level, knee flexion ROM and functional disability of the knee joint of the 3 groups pre and 4 weeks post treatment Variables Pain level (VAS) Groups Pre treatment Experimental group A 8.47±0.81 4.13±0.95 Experimental group B 8.1±0.87 6.4±1.4 7.98±1.16 7.67±1.2 Control group C Knee flexion ROM Functional disability of the knee (WOMAC) Post treatment Experimental group A 104.04±14.75 121.63±12.96 Experimental group B 104.63±8.48 112.2±7.38 Control group C 100.27±7.98 102.39±7.56 Experimental group A 71.6±13.51 26.7±9.93 Experimental group B 65.1±13.69 49±11.05 Control group C 65.2±8.06 59±8.04 Knee flexion ROM was significantly increased post treatment in all groups as the main effect of time was statistically significant (p=0.0001). All groups showed significant 14 improvement in knee flexion ROM 4 weeks post treatment as the main effect of group was statistically insignificant (p=0.51) and interaction between time and group was significant (p=0.0001) as shown in table (3). Post hoc tests revealed no significant difference between group A and B and between group B and C (p=0.59,0.27) respectively, while there was a significant difference between group A and C (p=0.042) as shown in table (4). The functional disability of the knee joint (WOMAC) showed significant decrease in all groups post treatment as the main effect of time was statistically significant (p=0.0001). The experimental groups A and B showed significant improvement than the control group post treatment as the main effect of group was statistically significant where (p=0.27) and interaction between time and group was significant (p=0.0001) as shown in table (3). Post hoc tests revealed no significant difference between group A and B and between group B and C (p=0.2,0.51) respectively, while there was a significant difference between group A and C (p=0.02) as shown in table (4). Table 3. Results of 3x2 mixed model ANOVA 15 Source of variance Pain level (VAS) Between groups F-value P-value 5.365 0.01٭ (Main effect of group) Within subjects 367.811 0.0001٭ (Main effect of time) Interaction between time and group 100.08 Knee flexion ROM Between groups 3.331 0.0001٭ 0.51 (Main effect of group) Within subjects 140.178 0.0001٭ (Main effect of time) Functional level Interaction between time and group 34.793 0.0001٭ Between groups 0.27 4.138 (Main effect of group) Within subjects 218.579 0.0001٭ (Main effect of time) Interaction between time and group 58.692 Table 4. Multiple comparisons between groups (Post hoc tests) 16 0.0001٭ Source of variance Pain level (VAS) Knee flexion ROM Functional disability (WOMAC) Mean P-value Mean difference P-value difference Mean P-value difference Group A vs. group B 0.77 0.42 4.42 0.59 7.9 0.2 Group A vs. group C 1.5 0.008٭ 11.50 0.042٭ 12.9 0.02٭ Group B vs. group C 0.75 0.25 7.08 0.27 5.05 0.51 Discussion The present work is the first study to compare the efficacy of GS, CS and MSM phonophoresis versus topical application on pain level, ROM, functional disability of the knee joint in patients with knee OA. The current study primary end point was the functional impact of treatment based on a validated instrument such as VAS, modified electrogoniometer, and WOMAC scale. Significant improvements in pain level, knee ROM were attained with phonophoresis, topical application, and traditional exercise. The degree of improvement was different in the three groups; phonophoresis was superior to topical application and traditional exercise that may be due to the deeper penetration of the GS, CS and MSM by the action of the ultrasound in addition to the primary ultrasound effect (double action). 17 Therapeutic ultrasound is frequently used in physiotherapy clinics to treat various musculoskeletal disorders [36]. Phonophoresis is the use of US with specific medication to encourage transdermal penetration of the compound. Significant amounts of drug are picked up by the subcutaneous circulation with phonophoresis. Both the thermal and non-thermal characteristics of high frequency sound waves can enhance the diffusion of topically applied drugs. Heating from US increases the kinetic energy of the molecules in the drug and in the cell membrane, dilates points of entry such as the hair follicles and the sweat glands, and increases the circulation to the area treated with US. These physiological changes enhance the opportunity for drug molecules to diffuse through the stratum corneum and be collected by the capillary network in the dermis. Both the thermal and non-thermal effects of US increase cell permeability. The mechanical characteristics of the sound wave also enhance drug diffusion by oscillating the cells at high speed, changing the resting potential of the cell membrane and potentially disrupting the cell membrane of some of the cells in the area [37]. Topically applied drugs can induce local and systemic effects that can be distinguished by examining local tissue drug concentrations (under the site of application) and blood or urine level. Topically applied drugs with particularly systemic effects diffuse through the epidermis to the dermis to reach the capillary network. Drugs with local targets diffuse into the area immediately below the administration site, such as subcutaneous tissue, muscle, synovium, ligaments, tendons, and joints [38]. 18 The current study results come in line with the work of Cagnie et al. who examined the influence of ultrasound on the transdermal delivery of ketoprofen in humans and to compare the concentrations found after continuous and pulsed application. The results indicate that, in contrast to sham phonopheresis, ultrasound can increase the transdermal delivery of ketoprofen [24]. The findings of this study come also in agreement with the work of Koeke et al who compared the treatment efficacy of topical application of hydrocortisone and phonophoresis with hydrocortisone on the rat's Achilles tendon repair process after tenotomy. Their results showed that the treated group with the topical application of hydrocortisone has not been delivered transdermally and that the molecule of collagen responds to the ultrasonic stimulation. The treatment with phonophoresis was the more efficient method. They concluded that the US stimulates the acceleration of tissue repair processes and induces the transdermal delivery of hydrocortisone in a therapeutic concentration on the tendon [39]. Also they are consistent with case report study in which the effect of Gluucosaminoglycan phonophoresis was investigated in the treatment of temporomandibular joint pain; it was reported to reduce pain significantly [40]. They also agree with Zjuzin et al who analysed 130 persons with osteoarthritis of knee and compared efficiency of Deep Relief gel with phonophoresis and ultrasound with standard gel. Deep Relief has significant better effect for less pain and better 19 improvement of functional capacity in comparison with ultrasound. There were significant difference between the phonophoresis and ultrasound group [41]. In this study the pain level was detected using VAS. The validity and the reliability of this scale in the assessment of the pain level have been demonstrated by Boonstra [42]. The range of motion was measured by the modified electrogoniometer, the validity and the reliability of this instrument in the assessment of the range of motion have been demonstrated by Elerian [43].The functional level was measured by the WOMAC Functional assessment scale. The Reliability, validity and repeatability of this scale in the assessment of the functional scale have been demonstrated by Salaffi et al. [44]. Within the limitations of this randomized controlled study, statistically significant difference with varying degrees were detected in the therapeutic phonophoresis group, topical application group and control group in the pain level (P = 0.0001) , range of motion (P = 0.001) and functional level (P = 0.0001), the highest percent of improvement was in the phonophoresis group. There was improvement in pain level in the three groups. Group A showed a higher improvement more than group B and group B more than group C. The highest improvement in group A may be attributed to the triple effect of higher penetration of drugs included analgesic (MSM) and cartilage rebuilding enhancer (Gluucosamine sulfate and chondrotin sulfate) enhanced by phonophoresis , the effect of US itself on pain and the effect of exercise program. The higher improvement found in group B 20 more than in group C may be attributed to the double effect of drug that include analgesic (MSM) and cartilage rebuilding enhancer (Gluucosamine sulfate and chondrotin sulfate) and the effect of exercise program. The improvement found in group C is attributed only to the effect of stretching and strengthing exercise program. Pain improvement in Groups A and B may be attributed to the effects of MSM which is a basic gradient of the gel used for the treatment that evoked a number of pharmacological effects deep within the knee soft tissues, including analgesia, reducing inflammation, and inhibition of prostaglandins production [45]. Pain improvement may be also attributed to the Glucosamine sulfate and Chondroitin sulfate. They are the building blocks for proteoglycans and stimulate chondrocytes to make new collagen and proteoglycans. Because these supplements stimulate the production of new cartilage components that may be able to help the body repair damaged cartilage [46]. On the other hand Glucosamine sulfate serves as a precursor for, and inhibits the degradation of, proteoglycans (the ground substance of articular cartilage); it rebuilds experimentally induced cartilaginous damage; and it has chondroprotective and antiarthritic effects (Vidal, 2008), it has very mild antiinflammatory and antireactive effects on edema-provoking agents including carrageenan, dextran, acetic acid and formalin. Also pain improvement in Group A by phonophoresis may be the attributed to ultrasound that relieves pain, decreases muscle spasm and increase tissue extensibility 21 [47], it is mostly used in combination with stretching exercises to achieve optimal tissue length. The non-thermal mechanical characteristics of ultrasound also can enhance drug diffusion by oscillating the cells at high speed, changing the resting potential of the cell membrane and potentially disrupting the cell membrane of some of the cells in the area sonicated. There may be some pushing and pulling of the cells with the propagation of the sound wave through the tissues, the effect of ultrasound on a biological system also may be associated with cavitation that is the formation of small gaseous bubbles. Cavitation may cause mechanical stress, temperature elevation, or enhanced chemical reactivity, thus affecting drug transport. The US helps more and efficient absorption of the gel which infiltrates the tissue to a higher depth than topical application [48]. Range of motion improvement in Group A, B might be due to the effects of the introduced drugs that regenerate the cartilage and inhibit pain, this allowed easier application of stretching and strengthening techniques. The increased ROM enables the patients to maintain more active knees and reduce its immobilization. The accumulated effect of stretching exercises through 12 sessions that tend to increase knee capsule extensibility and increase joint range of motion in addition to its sedative effect [49]. For Group C (the traditional exercise group) the significant difference after treatment might be due to the influence of stretching exercise which leads to increase muscle flexibility so minimize shortening of muscle and capsule and decrease pain and increase range of motion which maintained by strengthening exercise leading to more practice 22 and activities that patient can do through daily living activities so improve functional performance. Range of motion improvement might be due to the effects of the introduced materials that inhibit pain; this allowed the application of stretching techniques and the therapeutic exercises program. In addition to that the increased ability of the patients to maintain their daily living activities and to maintain their home care program, enable them to maintain more active knees and avoid its immobilization. The accumulated effect of stretching exercises through 12 sessions that tend to increase knee capsule extensibility and increase joint range of motion in addition to its sedative effect. Pain level improvement was due to the effects of MSM gel that evoked a number of pharmacological effects deep within the knee soft tissues, including analgesia, reducing inflammation [17]. The effect of therapeutic ultrasound on ROM would be caused by a combination of the changes in SP threshold and tissue extensibility. One of these changes in the SP threshold and tissue extensibility is due to the thermal effect of ultrasound [50]. This come in line with a double-blind, placebo controlled study; used indomethacin phonophoresis in the treatment of temporomandibular joint pain in 20 patients, and significant pain relief was reported [51]. Similarly, the efficacy of trolamine salicylate phonophoresis and ultrasound therapy was evaluated on delayed onset muscle soreness. 23 The investigators found that ultrasound enhanced the development of delayed onset muscle soreness but this effect was prevented by the application of salicylate phonophoresis [52]. Conclusions Within the limitation of this study; the use of ultrasound phonophoresis or topical application of Glucosamine sulfate, Chondroitin sulfate and Methylsulfonylmethane gel are effective and safe modalities for the treatment of OA but ultrasound phonophoresis may be better for drug transportation than topical application. Acknowledgments Authors of this paper are very thankful to our patients who have helped us in making the present study possible. 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