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Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial
Journal of Bodywork & Movement Therapies xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Bodywork & Movement Therapies journal homepage: www.elsevier.com/jbmt
Original Research
Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial Decha Pinkaew a, *, Kanokwan Kiattisin b, Khanittha Wonglangka a, Pisittawoot Awoot c a b c
Department of Physical Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand Department of Pharmaceutical Sciences. Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 January 2019 Received in revised form 22 April 2019 Accepted 26 April 2019
Objective: This study examined the effects of treatment with Phyllanthus amarus nanoparticle gel applied by phonophoresis (PP) and ultrasound therapy (UT) in patients with symptomatic knee osteoarthritis (OA) using a randomized, double-blind, controlled trial. Methods: Patients with knee OA (n ¼ 40; mean age ± SD, 64.30 ± 9.71 years), who had visual analogue scale (VAS) scores for knee pain intensity of 68.00 ± 9.58 (UT group) and 71.00 ± 8.74 (PP group, respectively) before treatment, were randomly allocated into two groups. Both groups were treated with an ultrasound program in continuous mode, 1.0 W/cm2, 10 min per session, for 10 sessions. Nanoparticles of P. amarus were used in the PP group, whereas a nondrug coupling gel was used in the UT group. The 6min walk test (6-MWT) was performed to evaluate functional capacity. The VAS and the 6-MWT were evaluated before and after 10 treatment sessions in both groups using a double-blind procedure. Results: VAS and 6-MWT showed significant improvement after treatment in both groups (p < 0.05). The PP group showed more significant effects than the UT group, in terms of both reducing the VAS pain score (p < 0.05) and improving 6-MWT (p < 0.05). Conclusions: PP is suggested as an effective method for the treatment of symptomatic knee OA for reducing pain and improving functional capacity. © 2019 Elsevier Ltd. All rights reserved.
Keywords: Knee osteoarthritis Phyllanthus amarus Phonophoresis Ultrasound therapy 6-minute walk test
1. Introduction Osteoarthritis (OA) of the knee is a common, degenerative joint cartilage condition that causes chronic joint pain, synovial inflammation, and functional limitations in older adults (Masiero et al., 2017; Li et al., 2016; Sutbeyaz et al., 2007). It is most common in persons aged more than 50 years. The symptoms of knee OA are knee pain; limited joint movement; and weight-bearing activities including standing, walking, climbing stairs, and changes in posture such as from sitting to standing. In addition to age, obesity is one of the contributing factors, as additional weight increases forces at the knee joint, which can aggravate both pain and pathology. International guidelines for treating knee OA include pharmacological agents such as nonsteroidal anti-inflammatory drugs
* Corresponding author. E-mail address: [email protected] (D. Pinkaew).
(NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors and thermal modalities including ultrasound (Lambova et al., 2017; Petrella and Wakeford, 2015; Theiler et al., 2002). However, prolonged drug treatments carry the risk of gastrointestinal side effects such as vomiting, dyspepsia, nausea, and other serious gastric problems (Nagi et al., 2015), whereas thermal modalities present fewer side effects and are safer for long-term treatment. In ultrasound, deep heat is produced when electrical energy is transformed into acoustic waves. This technique can be used to relieve pain in several musculoskeletal pathologies by increasing the pain threshold, increasing nerve conduction velocity (Robertson and Baker, 2001; van der Windt and et al., 1999), increasing the extent of soft tissue repair (Watson, 2008), nchez et al., 2010), and increasing blood circulation (Loyola-Sa increasing tissue extensibility (Wong et al., 2007). Phonophoresis is the use of ultrasound to deliver drug therapeutics by absorption and permeation through the skin (Souza et al., 2013). Several studies showed that phonophoresis of NSAIDs relieved
https://doi.org/10.1016/j.jbmt.2019.04.013 1360-8592/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013
2
D. Pinkaew et al. / Journal of Bodywork & Movement Therapies xxx (xxxx) xxx
inflammation and symptoms of pain in many pathological conditions including shoulder pain, myofascial pain, and knee OA (Boyaci et al., 2013). Phonophoresis offers a noninvasive alternative treatment for knee OA, as it carries minimal risk compared to oral drugs. Kozanoglu et al. (2003) reported that phonophoresis of ibuprofen significantly reduced pain in knee OA. The ultrasound parameters were set at 1 MHz frequency and 1 W/cm2 power for 5e10 min per session and 10 times per day. Many Thai herbs including Phyllanthus amarus have antiinflammatory and antioxidant properties, which have been shown to reduce pain (Kaur et al., 2017). As such, this study investigated the potential effectiveness of using P. amarus nanoparticle gel by phonophoresis when compared with conventional ultrasound gel for treating knee OA by measuring changes in perceived pain and the 6-min walk test (6-MWT). 2. Material and methods 2.1. Study design The study design was a randomized controlled trial. Participants were randomized by the physician to two groups (PP group and UT group) using blocks of 2 randomization schedules, which were computer-generated and sealed in opaque envelopes. The doubleblind method involved an independent investigator for outcome measures. Both gels (PP group and UT group) did not have any odor and had the same appearance. Therefore, the participants did not know the group to which they were assigned. The study was approved by the Ethics Committee of the University, under reference no. AMSEC-60EX-019.
2.4. Outcome measures The clinical efficacy outcomes were monitored at baseline and after two weeks of treatment. 2.4.1. Visual Analogue Scale (VAS) VAS was evaluated before and after 10 sessions of ultrasound treatment. VAS is measured on a numeric rating scale of 0e100 (0, no pain/limitation; 100, very severe pain/limitation), anchored with the extremes of subjective pain (Carlsson, 1983). 2.4.2. Six-minute walk test (6-MWT) The 6-MWT is one of the most widely used distance tests used in clinical practice; it is an exercise test that measures the distance covered when walking for 6 min to assess the submaximal level of functional capacity. The distance that the patient was able to walk in 6 min was determined in a measured corridor. The 6-MWT was performed following the guidelines of the American Thoracic Society (American Thoracic Society, 2002). The patients were given standardized instructions to walk as fast as possible for 6 min without running. The test was performed twice, and the results of the better distance walked were reported. 2.5. Statistical analyses The values were expressed as mean ± SD. The baseline and the post-training data were compared within the groups using nonparametric (Wilcoxon) tests. Statistical analysis was carried out by repeated measures ANOVA, followed by Tukey's post hoc test. The level of significance was taken as p ¼ 0.05. 3. Results
2.2. Participants The study protocol was approved by the Institutional Review Board of the Faculty of Associated Medical Sciences, Chiang Mai University. All enrolled participants provided written informed consent. Forty patients who were diagnosed with primary knee OA according to the American College of Rheumatology (ACR) Classification Criteria were recruited (Altman et al., 1986). The sample size required for each group was 15 [including 15% for drop out] (power ¼ 0.9 and significance level ¼ 0.05), which was calculated in et al., 2017). The inclusion criteria from a previous study (Yeg were subjects who had knee pain of 5 score on the Visual Analogue Scale (VAS) and who met at least one of the following features: age 50 years, morning stiffness < 30 min, and crepitus on motion. The exclusion criteria were history of peptic ulcer, intraarticular injection of steroid/hyaluronic acid within three months, inability to walk, hypersensitivity to NSAIDs, or concomitant use of anti-inflammatory or analgesic drugs. Baseline data were collected for each patient, including age, sex, height, weight, duration of pain, presence of pain in one or both knees, presence of generalized OA, previous knee surgery, and current pain medications. 2.3. Treatment procedures 2.3.1. Phonophoresis of Phyllanthus amarus The gel was prepared by mixing the P. amarus gel with a standard coupling agent at a ratio of 4:11 by volume. Patients received ultrasound therapy set to continuous mode (1.0 W/cm2 power and 1 MHz frequency) once daily for 10 sessions. The participants were randomly assigned to a group by using a computer program and examined by a physician double-blinded to the group to which they were assigned.
There were no significant differences between the two groups in terms of age and BMI at the start of the study. The general characteristics are shown in Table 1. 3.1. Demographics and baseline clinical characteristics Forty patients (70% female, n ¼ 28) were diagnosed with knee OA. The mean age of patients in the US and PP groups was 64.30 ± 9.71 and 65.20 ± 8.34 years, respectively, and the mean duration of OA pain in the US and PP groups were 2.00 ± 1.30 and 2.20 ± 1.48 years. The patients in both groups did not differ in sex, BMI, or duration of knee pain, as shown in Table 1. 3.2. VAS results The average VAS score was reduced significantly in both the US and PP groups compared to that before treatment (p < 0.05) (see Table 2). Moreover, the PP group showed significant increase in the average VAS score between the groups. These data suggested that
Table 1 Baseline characteristic of enrolled participants in both groups. Characteristics
US (n ¼ 20)
PP (n ¼ 20)
Mean ± SD
Mean ± SD
Age (years) Sex Male (n) Female (n) BMI (kg/m2) Duration of symptoms (years)
64.30 ± 9.71
65.20 ± 8.34
6 14 22.63 ± 8.61 2.00 ± 1.30
6 14 23.62 ± 5.21 2.20 ± 1.48
BMI, body mass index; OA, osteoarthritis; SD, standard deviation.
Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013
D. Pinkaew et al. / Journal of Bodywork & Movement Therapies xxx (xxxx) xxx
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Table 2 VAS values in pre-to post treatment of US and PP group. Measure
VAS of pain Pretreatment Posttreatment
US (n ¼ 20)
PP (n ¼ 20)
Mean ± SD
Mean ± SD
68.00 ± 9.58 38.10 ± 5.74a,b
71.00 ± 8.74 15.50 ± 7.53a
p < 0.05. a Showed significant compare pretreatment in each group. b Showed significant compared post treatment of US group.
pain decreased significantly in the PP group considering both the intra-item group and between groups.
Fig. 1. The values of 6 MWT(m) in pre-to post treatment of US and PP group. a showed significant compare pretreatment in each group, b showed significant compared post treatment of US group,p < 0.05.
3.3. Assessment of functional exercise capacity (6-MWT) There was a significant difference between the two groups after 10 sessions of intervention as compared to the observations before the study. Moreover, after treatment, the mean walking distance in 6 min increased significantly in both the PP and US groups. There were significant differences between the groups in 6-MWT in within-group analysis, which showed a significant improvement between the pre- and post-treatment values in both groups. The increase in the PP group was significantly greater than that in the US group (p < 0.05), as shown in Table 3 and Fig. 1. In addition, the application of P. amarus nanoparticle gel had no side effects. 4. Discussion In this study, patients with knee OA showed higher levels of pain in both the US and PP groups at the pretreatment stage. The baseline clinical characteristics were not significant in either of the groups. After intervention, both groups showed a significant reduction in pain and an increased 6-MWT compared with preintervention values. A reduction in VAS of 30.0 mm in pain severity represents a minimum clinically improved difference (MCID) (Lee and et al., 2003). This study demonstrated the clinical 6-MWT significance. The poste6-MWT result increased significantly in both groups compared to the pree6-MWT result. This corroborates the results of other studies such as that by Mascarin et al. (2012), in which ultrasound groups (n ¼ 10) demonstrated significantly longer 6-MWT distances. A further study conducted by RodríguezGrande et al. (2017) compared pain and function before and after the intervention and stated that patients who underwent ultrasound had reduced pain and improved function. This study suggested that pulsed therapeutic ultrasound treatment of knee OA using a frequency of 1 MHz for 4 min showed significant differences in et al. (2017) reported that treating after the fifth session. Yeg patients with knee OA (n ¼ 30) with 1 W/cm2, 1 MHz continuous ultrasound, applied for 8 min, for 10 sessions over 2 weeks significantly improved VAS and function. However, this study showed that phonophoresis of P. amarus gel significantly improved VAS and
Table 3 The values of 6 MWT (m) in pre-to post treatment of US and PP group. Measure
6 MWT (m) Pretreatment Posttreatment
US (n ¼ 20)
PP (n ¼ 20)
Mean ± SD
Mean ± SD
163.90 ± 14.81 243.10 ± 19.17a
168.50 ± 19.27 305.10 ± 24.99a,b
p < 0.05. a Showed significant compare pretreatment in each group. b Showed significant compared post treatment of US group.
function to a greater extent than US. Phonophoresis is an ultrasound technique performed to increase percutaneous drug absorption through the stratum corneum of the skin (William et al., 2004). Many studies have reported that phonophoresis with a variety of drugs significantly decreased pain (VAS) and improved function in knees, such as lidocaine (Ebrahimi et al., 2012) and piroxicam (Luksurapan and Boonhong, 2013). The piroxicam research was a randomized, double-blind study with two groups: ultrasound therapy (n ¼ 23) and phonophoresis of piroxicam (n ¼ 23) treated with ultrasound at continuous mode, 1.0 W/cm2, 10 min per session, 5 times per week for 2 weeks. VAS score significantly decreased after treatment in both groups (P < 0.001). It decreased more significantly in the phonophoresis of piroxicam group. Ultrasound with mineral water or aqua gel reduced pain and improved the effectiveness for treating OA of knee joints (Abdalbary, 2016). The PP group in our study showed a significantly increased 6MWT compared with the US group. These findings suggested that these changes were associated with the phonophoresis treatment of P. amarus nanoparticle gel, which could improve functional capacity in patients with OA knees. Phonophoresis of the P. amarus nanoparticle gel also significantly reduced pain compared with the UT gel, and in addition, it did not exert any side effects. Other treatments have also shown some efficacy, such as electrical stimulation techniques (including transcutaneous electrical stimulation), whole-body vibration (Newberry et al., 2017), and Baduanjin exercise (An et al., 2013), which significantly improved 6-MWT (565.7 ± 94.6 vs. 610.5 ± 66.7) among 22 patients (29 knees) and reduced pain, stiffness, emotional health status, and body mass index. Furthermore, another study reported that it was a safe exercise option for knee OA; and kinesiotherapy (n ¼ 16) that significantly increased 6-MWT distances and reduced VAS values (Mascarin et al., 2012). Thus, phonophoresis of P. amarus nanoparticle gel is one of the treatments for relieving symptomatic knee OA and improving functional capacity. One of the limitations in this study was that only the short-term effect of treatments was investigated. Hence, the long-term effect of phonophoresis of P. amarus should also be studied in future research. In addition, further research should compare various treatments such as baduanjin exercise that promote both emotional health and physical health to determine the most effective treatment for relieving pain and increasing function. 5. Conclusion Phonophoresis of P. amarus was effective for reducing pain and improving 6-MWT results in patients with OA knees, suggesting that the P. amarus nanoparticle gel may be a potential treatment
Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013
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D. Pinkaew et al. / Journal of Bodywork & Movement Therapies xxx (xxxx) xxx
approach for knee OA. Funding This work was supported by the grants funded by the Faculty of Associated Medical Sciences and CMU Junior Research Fellowship Program of Chiang Mai University, Thailand. Conflicts of interest None. Acknowledgments This work was supported by grants funded by the Faculty of Associated Medical Sciences and CMU Junior Research Fellowship Program of Chiang Mai University, Thailand. We would like to acknowledge all patients who participated in this study. The authors also express gratitude Mr. Komsan Tejah, Miss Chanyaphak Munyuen, and Miss Chanunya Wongkiti for collecting part of the data. References Abdalbary, S.A., 2016. Ultrasound with mineral water or aqua gel to reduce pain and improve the WOMAC of knee osteoarthritis. Future Sci. OA 2 (1), FSO110. Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., et al., 1986. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis Rheum. 29 (8), 1039e1049. American Thoracic Society, 2002. ATS statement: guidelines for the six-minute walk test. J. Respir. Crit. Care Med. 166, 111e117. An, B.C., Wang, Y., Jiang, X., Lu, H.S., Fang, Z.Y., Wang, Y., et al., 2013. Effects of Baduanjin exercise on knee osteoarthritis: a one-year study. Chin. J. Integr. Med. 19 (2), 143e148. Boyaci, A., Tutoglu, A., Boyaci, N., Aridici, R.,, Koca, I., 2013. Comparison of the efficacy of ketoprofen phonophoresis, ultrasound, and short-wave diathermy in knee osteoarthritis. Rheumatol. Int. 33 (11), 2811-2318. Carlsson, A.M., 1983. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain 16 (1), 87e101. Ebrahimi, S., Abbasnia, K., Motealleh, A., Kooroshfard, N., Kamali, F., Ghaffarinezhad, F., 2012. Effect of lidocaine phonophoresis on sensory blockade: pulsed or continuous mode of therapeutic ultrasound? Physiotherapy 98 (1), 57e63. Kaur, N., Kaur, B., Sirhindi, G., 2017. Phytochemistry and pharmacology of Phyllanthus niruri L.: a review. Phytother Res. 31 (7), 980e1004. Kozanoglu, E., Basaran, S., Guzel, R., Guler-Uysal, F., 2003. Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis. Swiss Med. Wkly. 133 (23e24), 333e338. Lambova, S., Hermann, W., Müller-Ladner, U., 2017. Current treatment options for osteoarthritis. Curr. Rheumatol. Rev. https://doi.org/10.2174/15733971136661
70829155149. Lee, J.S., Hobden, E., Stiell, I.G., Wells, G.A., 2003. Clinically important change in the visual analog scale after adequate pain control. Acad. Emerg. Med. 10 (10), 1128e1130. Li, Z.C., Jiang, L., Zhang, S., Qin, X.Y., White, Pt DK., Hou, Y.F., et al., 2016. Evaluation of physical function for the end-stage osteoarthritis patient waiting for the total knee replacement. Beijing Da Xue Xue Bao Yi Xue Ban 48 (2), 257e262. nchez, A., Richardson, J., MacIntyre, N.J., 2010. Efficacy of ultrasound Loyola-Sa therapy for the management of knee osteoarthritis: a systematic review with meta-analysis. Osteoarthritis Cartilage 18 (9), 1117e1126. Luksurapan, W., Boonhong, J., 2013. Effects of phonophoresis of piroxicam and ultrasound on symptomatic knee osteoarthritis. Arch. Phys. Med. Rehabil. 94 (2), 250e255. Mascarin, N.C., Vancini, R.L., Andrade, M.L., Magalh~ aes Ede, P., de Lira, C.A., Coimbra, I.B., 2012. Effects of kinesiotherapy, ultrasound and electrotherapy in management of bilateral knee osteoarthritis: prospective clinical trial. BMC Muscoskelet. Disord. 13, 182. Masiero, S., Vittadini, F., Ferroni, C., Bosco, A., Serra, R., Frigo, A.C., et al., 2017. The role of thermal balneotherapy in the treatment of obese patient with knee osteoarthritis. Int. J. Biometeorol. https://doi.org/10.1007/s00484-017-1445-7. Nagi, R., Yashoda, Devi B.K., Rakesh, N., Reddy, S.S., Patil, D.J., 2015. Clinical implications of prescribing nonsteroidal anti-inflammatory drugs in oral health care–a review. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 119 (3), 264e271. Newberry, S.J., FitzGerald, J., SooHoo, N.F., Booth, M., Marks, J., Motala, A., et al., 2017. Treatment of Osteoarthritis of the Knee: an Update Review. Agency for Healthcare Research and Quality (US), Rockville (MD). 17-EHC011-EF. Petrella, R.J., Wakeford, C., 2015. Pain relief and improved physical function in knee osteoarthritis patients receiving ongoing hylan G-F 20, a high-molecular-weight hyaluronan, versus other treatment options: data from a large real-world longitudinal cohort in Canada. Drug Des. Dev. Ther. 9, 5633e5640. Rodríguez-Grande, E.I., Osma-Rueda, J.L., Serrano-Villar, Y., Ramírez, C., 2017. Effects of pulsed therapeutic ultrasound on the treatment of people with knee osteoarthritis. J. Phys. Ther. Sci. 29 (9), 1637e1643. Robertson, V.J., Baker, K.G., 2001. A review of therapeutic ultrasound: effectiveness studies. Phys. Ther. 81 (7), 1339e1350. Souza, J., Meira, A., Volpato, N.M., Mayorga, P., Gottfried, C., 2013. Effect of phonophoresis on skin permeation of commercial anti-inflammatory gels: sodium diclofenac and ketoprofen. Ultrasound Med. Biol. 39 (9), 1623e1630. Sutbeyaz, S.T., Sezer, N., Koseoglu, B.F., Ibrahimoglu, F., Tekin, D., 2007. Influence of knee osteoarthritis on exercise capacity and quality of life in obese adults. Obesity (Silver Spring) 15 (8), 2071e2076. Theiler, R., Bischoff, H.A., Good, M., Uebelhart, D., 2002. Rofecoxib improves quality of life in patients with hip or knee osteoarthritis. Swiss Med. Wkly. 132 (39e40), 566e573. van der Windt, D.A., van der Heijden, G.J., van den Berg, S.G., et al., 1999. Ultrasound therapy for musculoskeletal disorders: a systematic review. Pain 81, 257e271. Watson, T., 2008. Ultrasound in contemporary physiotherapy practice. Ultrasonics 48, 321e329. William, W.T., Cortney, D.V., Richard, D.S., 2004. Review of traditional and novel modalities that enhance the permeability of local therapeutics across the stratum corneum. Int. J. Dermatol. 43, 538e547. Wong, R.A., Schumann, B., Townsend, R., Phelps, C.A., 2007. A survey of therapeutic ultrasound use by physical therapists who are orthopaedic certified specialists. Phys. Ther. 87 (8), 986e994. in, T., Altan, L., Kasapog lu, A.M., 2017. The effect of therapeutic ultrasound on Yeg pain and physical function in patients with knee osteoarthritis. Ultrasound Med. Biol. 43 (1), 187e194.
Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013
Contents lists available at ScienceDirect
Journal of Bodywork & Movement Therapies journal homepage: www.elsevier.com/jbmt
Original Research
Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial Decha Pinkaew a, *, Kanokwan Kiattisin b, Khanittha Wonglangka a, Pisittawoot Awoot c a b c
Department of Physical Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand Department of Pharmaceutical Sciences. Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 January 2019 Received in revised form 22 April 2019 Accepted 26 April 2019
Objective: This study examined the effects of treatment with Phyllanthus amarus nanoparticle gel applied by phonophoresis (PP) and ultrasound therapy (UT) in patients with symptomatic knee osteoarthritis (OA) using a randomized, double-blind, controlled trial. Methods: Patients with knee OA (n ¼ 40; mean age ± SD, 64.30 ± 9.71 years), who had visual analogue scale (VAS) scores for knee pain intensity of 68.00 ± 9.58 (UT group) and 71.00 ± 8.74 (PP group, respectively) before treatment, were randomly allocated into two groups. Both groups were treated with an ultrasound program in continuous mode, 1.0 W/cm2, 10 min per session, for 10 sessions. Nanoparticles of P. amarus were used in the PP group, whereas a nondrug coupling gel was used in the UT group. The 6min walk test (6-MWT) was performed to evaluate functional capacity. The VAS and the 6-MWT were evaluated before and after 10 treatment sessions in both groups using a double-blind procedure. Results: VAS and 6-MWT showed significant improvement after treatment in both groups (p < 0.05). The PP group showed more significant effects than the UT group, in terms of both reducing the VAS pain score (p < 0.05) and improving 6-MWT (p < 0.05). Conclusions: PP is suggested as an effective method for the treatment of symptomatic knee OA for reducing pain and improving functional capacity. © 2019 Elsevier Ltd. All rights reserved.
Keywords: Knee osteoarthritis Phyllanthus amarus Phonophoresis Ultrasound therapy 6-minute walk test
1. Introduction Osteoarthritis (OA) of the knee is a common, degenerative joint cartilage condition that causes chronic joint pain, synovial inflammation, and functional limitations in older adults (Masiero et al., 2017; Li et al., 2016; Sutbeyaz et al., 2007). It is most common in persons aged more than 50 years. The symptoms of knee OA are knee pain; limited joint movement; and weight-bearing activities including standing, walking, climbing stairs, and changes in posture such as from sitting to standing. In addition to age, obesity is one of the contributing factors, as additional weight increases forces at the knee joint, which can aggravate both pain and pathology. International guidelines for treating knee OA include pharmacological agents such as nonsteroidal anti-inflammatory drugs
* Corresponding author. E-mail address: [email protected] (D. Pinkaew).
(NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors and thermal modalities including ultrasound (Lambova et al., 2017; Petrella and Wakeford, 2015; Theiler et al., 2002). However, prolonged drug treatments carry the risk of gastrointestinal side effects such as vomiting, dyspepsia, nausea, and other serious gastric problems (Nagi et al., 2015), whereas thermal modalities present fewer side effects and are safer for long-term treatment. In ultrasound, deep heat is produced when electrical energy is transformed into acoustic waves. This technique can be used to relieve pain in several musculoskeletal pathologies by increasing the pain threshold, increasing nerve conduction velocity (Robertson and Baker, 2001; van der Windt and et al., 1999), increasing the extent of soft tissue repair (Watson, 2008), nchez et al., 2010), and increasing blood circulation (Loyola-Sa increasing tissue extensibility (Wong et al., 2007). Phonophoresis is the use of ultrasound to deliver drug therapeutics by absorption and permeation through the skin (Souza et al., 2013). Several studies showed that phonophoresis of NSAIDs relieved
https://doi.org/10.1016/j.jbmt.2019.04.013 1360-8592/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013
2
D. Pinkaew et al. / Journal of Bodywork & Movement Therapies xxx (xxxx) xxx
inflammation and symptoms of pain in many pathological conditions including shoulder pain, myofascial pain, and knee OA (Boyaci et al., 2013). Phonophoresis offers a noninvasive alternative treatment for knee OA, as it carries minimal risk compared to oral drugs. Kozanoglu et al. (2003) reported that phonophoresis of ibuprofen significantly reduced pain in knee OA. The ultrasound parameters were set at 1 MHz frequency and 1 W/cm2 power for 5e10 min per session and 10 times per day. Many Thai herbs including Phyllanthus amarus have antiinflammatory and antioxidant properties, which have been shown to reduce pain (Kaur et al., 2017). As such, this study investigated the potential effectiveness of using P. amarus nanoparticle gel by phonophoresis when compared with conventional ultrasound gel for treating knee OA by measuring changes in perceived pain and the 6-min walk test (6-MWT). 2. Material and methods 2.1. Study design The study design was a randomized controlled trial. Participants were randomized by the physician to two groups (PP group and UT group) using blocks of 2 randomization schedules, which were computer-generated and sealed in opaque envelopes. The doubleblind method involved an independent investigator for outcome measures. Both gels (PP group and UT group) did not have any odor and had the same appearance. Therefore, the participants did not know the group to which they were assigned. The study was approved by the Ethics Committee of the University, under reference no. AMSEC-60EX-019.
2.4. Outcome measures The clinical efficacy outcomes were monitored at baseline and after two weeks of treatment. 2.4.1. Visual Analogue Scale (VAS) VAS was evaluated before and after 10 sessions of ultrasound treatment. VAS is measured on a numeric rating scale of 0e100 (0, no pain/limitation; 100, very severe pain/limitation), anchored with the extremes of subjective pain (Carlsson, 1983). 2.4.2. Six-minute walk test (6-MWT) The 6-MWT is one of the most widely used distance tests used in clinical practice; it is an exercise test that measures the distance covered when walking for 6 min to assess the submaximal level of functional capacity. The distance that the patient was able to walk in 6 min was determined in a measured corridor. The 6-MWT was performed following the guidelines of the American Thoracic Society (American Thoracic Society, 2002). The patients were given standardized instructions to walk as fast as possible for 6 min without running. The test was performed twice, and the results of the better distance walked were reported. 2.5. Statistical analyses The values were expressed as mean ± SD. The baseline and the post-training data were compared within the groups using nonparametric (Wilcoxon) tests. Statistical analysis was carried out by repeated measures ANOVA, followed by Tukey's post hoc test. The level of significance was taken as p ¼ 0.05. 3. Results
2.2. Participants The study protocol was approved by the Institutional Review Board of the Faculty of Associated Medical Sciences, Chiang Mai University. All enrolled participants provided written informed consent. Forty patients who were diagnosed with primary knee OA according to the American College of Rheumatology (ACR) Classification Criteria were recruited (Altman et al., 1986). The sample size required for each group was 15 [including 15% for drop out] (power ¼ 0.9 and significance level ¼ 0.05), which was calculated in et al., 2017). The inclusion criteria from a previous study (Yeg were subjects who had knee pain of 5 score on the Visual Analogue Scale (VAS) and who met at least one of the following features: age 50 years, morning stiffness < 30 min, and crepitus on motion. The exclusion criteria were history of peptic ulcer, intraarticular injection of steroid/hyaluronic acid within three months, inability to walk, hypersensitivity to NSAIDs, or concomitant use of anti-inflammatory or analgesic drugs. Baseline data were collected for each patient, including age, sex, height, weight, duration of pain, presence of pain in one or both knees, presence of generalized OA, previous knee surgery, and current pain medications. 2.3. Treatment procedures 2.3.1. Phonophoresis of Phyllanthus amarus The gel was prepared by mixing the P. amarus gel with a standard coupling agent at a ratio of 4:11 by volume. Patients received ultrasound therapy set to continuous mode (1.0 W/cm2 power and 1 MHz frequency) once daily for 10 sessions. The participants were randomly assigned to a group by using a computer program and examined by a physician double-blinded to the group to which they were assigned.
There were no significant differences between the two groups in terms of age and BMI at the start of the study. The general characteristics are shown in Table 1. 3.1. Demographics and baseline clinical characteristics Forty patients (70% female, n ¼ 28) were diagnosed with knee OA. The mean age of patients in the US and PP groups was 64.30 ± 9.71 and 65.20 ± 8.34 years, respectively, and the mean duration of OA pain in the US and PP groups were 2.00 ± 1.30 and 2.20 ± 1.48 years. The patients in both groups did not differ in sex, BMI, or duration of knee pain, as shown in Table 1. 3.2. VAS results The average VAS score was reduced significantly in both the US and PP groups compared to that before treatment (p < 0.05) (see Table 2). Moreover, the PP group showed significant increase in the average VAS score between the groups. These data suggested that
Table 1 Baseline characteristic of enrolled participants in both groups. Characteristics
US (n ¼ 20)
PP (n ¼ 20)
Mean ± SD
Mean ± SD
Age (years) Sex Male (n) Female (n) BMI (kg/m2) Duration of symptoms (years)
64.30 ± 9.71
65.20 ± 8.34
6 14 22.63 ± 8.61 2.00 ± 1.30
6 14 23.62 ± 5.21 2.20 ± 1.48
BMI, body mass index; OA, osteoarthritis; SD, standard deviation.
Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013
D. Pinkaew et al. / Journal of Bodywork & Movement Therapies xxx (xxxx) xxx
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Table 2 VAS values in pre-to post treatment of US and PP group. Measure
VAS of pain Pretreatment Posttreatment
US (n ¼ 20)
PP (n ¼ 20)
Mean ± SD
Mean ± SD
68.00 ± 9.58 38.10 ± 5.74a,b
71.00 ± 8.74 15.50 ± 7.53a
p < 0.05. a Showed significant compare pretreatment in each group. b Showed significant compared post treatment of US group.
pain decreased significantly in the PP group considering both the intra-item group and between groups.
Fig. 1. The values of 6 MWT(m) in pre-to post treatment of US and PP group. a showed significant compare pretreatment in each group, b showed significant compared post treatment of US group,p < 0.05.
3.3. Assessment of functional exercise capacity (6-MWT) There was a significant difference between the two groups after 10 sessions of intervention as compared to the observations before the study. Moreover, after treatment, the mean walking distance in 6 min increased significantly in both the PP and US groups. There were significant differences between the groups in 6-MWT in within-group analysis, which showed a significant improvement between the pre- and post-treatment values in both groups. The increase in the PP group was significantly greater than that in the US group (p < 0.05), as shown in Table 3 and Fig. 1. In addition, the application of P. amarus nanoparticle gel had no side effects. 4. Discussion In this study, patients with knee OA showed higher levels of pain in both the US and PP groups at the pretreatment stage. The baseline clinical characteristics were not significant in either of the groups. After intervention, both groups showed a significant reduction in pain and an increased 6-MWT compared with preintervention values. A reduction in VAS of 30.0 mm in pain severity represents a minimum clinically improved difference (MCID) (Lee and et al., 2003). This study demonstrated the clinical 6-MWT significance. The poste6-MWT result increased significantly in both groups compared to the pree6-MWT result. This corroborates the results of other studies such as that by Mascarin et al. (2012), in which ultrasound groups (n ¼ 10) demonstrated significantly longer 6-MWT distances. A further study conducted by RodríguezGrande et al. (2017) compared pain and function before and after the intervention and stated that patients who underwent ultrasound had reduced pain and improved function. This study suggested that pulsed therapeutic ultrasound treatment of knee OA using a frequency of 1 MHz for 4 min showed significant differences in et al. (2017) reported that treating after the fifth session. Yeg patients with knee OA (n ¼ 30) with 1 W/cm2, 1 MHz continuous ultrasound, applied for 8 min, for 10 sessions over 2 weeks significantly improved VAS and function. However, this study showed that phonophoresis of P. amarus gel significantly improved VAS and
Table 3 The values of 6 MWT (m) in pre-to post treatment of US and PP group. Measure
6 MWT (m) Pretreatment Posttreatment
US (n ¼ 20)
PP (n ¼ 20)
Mean ± SD
Mean ± SD
163.90 ± 14.81 243.10 ± 19.17a
168.50 ± 19.27 305.10 ± 24.99a,b
p < 0.05. a Showed significant compare pretreatment in each group. b Showed significant compared post treatment of US group.
function to a greater extent than US. Phonophoresis is an ultrasound technique performed to increase percutaneous drug absorption through the stratum corneum of the skin (William et al., 2004). Many studies have reported that phonophoresis with a variety of drugs significantly decreased pain (VAS) and improved function in knees, such as lidocaine (Ebrahimi et al., 2012) and piroxicam (Luksurapan and Boonhong, 2013). The piroxicam research was a randomized, double-blind study with two groups: ultrasound therapy (n ¼ 23) and phonophoresis of piroxicam (n ¼ 23) treated with ultrasound at continuous mode, 1.0 W/cm2, 10 min per session, 5 times per week for 2 weeks. VAS score significantly decreased after treatment in both groups (P < 0.001). It decreased more significantly in the phonophoresis of piroxicam group. Ultrasound with mineral water or aqua gel reduced pain and improved the effectiveness for treating OA of knee joints (Abdalbary, 2016). The PP group in our study showed a significantly increased 6MWT compared with the US group. These findings suggested that these changes were associated with the phonophoresis treatment of P. amarus nanoparticle gel, which could improve functional capacity in patients with OA knees. Phonophoresis of the P. amarus nanoparticle gel also significantly reduced pain compared with the UT gel, and in addition, it did not exert any side effects. Other treatments have also shown some efficacy, such as electrical stimulation techniques (including transcutaneous electrical stimulation), whole-body vibration (Newberry et al., 2017), and Baduanjin exercise (An et al., 2013), which significantly improved 6-MWT (565.7 ± 94.6 vs. 610.5 ± 66.7) among 22 patients (29 knees) and reduced pain, stiffness, emotional health status, and body mass index. Furthermore, another study reported that it was a safe exercise option for knee OA; and kinesiotherapy (n ¼ 16) that significantly increased 6-MWT distances and reduced VAS values (Mascarin et al., 2012). Thus, phonophoresis of P. amarus nanoparticle gel is one of the treatments for relieving symptomatic knee OA and improving functional capacity. One of the limitations in this study was that only the short-term effect of treatments was investigated. Hence, the long-term effect of phonophoresis of P. amarus should also be studied in future research. In addition, further research should compare various treatments such as baduanjin exercise that promote both emotional health and physical health to determine the most effective treatment for relieving pain and increasing function. 5. Conclusion Phonophoresis of P. amarus was effective for reducing pain and improving 6-MWT results in patients with OA knees, suggesting that the P. amarus nanoparticle gel may be a potential treatment
Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013
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approach for knee OA. Funding This work was supported by the grants funded by the Faculty of Associated Medical Sciences and CMU Junior Research Fellowship Program of Chiang Mai University, Thailand. Conflicts of interest None. Acknowledgments This work was supported by grants funded by the Faculty of Associated Medical Sciences and CMU Junior Research Fellowship Program of Chiang Mai University, Thailand. We would like to acknowledge all patients who participated in this study. The authors also express gratitude Mr. Komsan Tejah, Miss Chanyaphak Munyuen, and Miss Chanunya Wongkiti for collecting part of the data. References Abdalbary, S.A., 2016. Ultrasound with mineral water or aqua gel to reduce pain and improve the WOMAC of knee osteoarthritis. Future Sci. OA 2 (1), FSO110. Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., et al., 1986. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis Rheum. 29 (8), 1039e1049. American Thoracic Society, 2002. ATS statement: guidelines for the six-minute walk test. J. Respir. Crit. Care Med. 166, 111e117. An, B.C., Wang, Y., Jiang, X., Lu, H.S., Fang, Z.Y., Wang, Y., et al., 2013. Effects of Baduanjin exercise on knee osteoarthritis: a one-year study. Chin. J. Integr. Med. 19 (2), 143e148. Boyaci, A., Tutoglu, A., Boyaci, N., Aridici, R.,, Koca, I., 2013. Comparison of the efficacy of ketoprofen phonophoresis, ultrasound, and short-wave diathermy in knee osteoarthritis. Rheumatol. Int. 33 (11), 2811-2318. Carlsson, A.M., 1983. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain 16 (1), 87e101. Ebrahimi, S., Abbasnia, K., Motealleh, A., Kooroshfard, N., Kamali, F., Ghaffarinezhad, F., 2012. Effect of lidocaine phonophoresis on sensory blockade: pulsed or continuous mode of therapeutic ultrasound? Physiotherapy 98 (1), 57e63. Kaur, N., Kaur, B., Sirhindi, G., 2017. Phytochemistry and pharmacology of Phyllanthus niruri L.: a review. Phytother Res. 31 (7), 980e1004. Kozanoglu, E., Basaran, S., Guzel, R., Guler-Uysal, F., 2003. Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis. Swiss Med. Wkly. 133 (23e24), 333e338. Lambova, S., Hermann, W., Müller-Ladner, U., 2017. Current treatment options for osteoarthritis. Curr. Rheumatol. Rev. https://doi.org/10.2174/15733971136661
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Please cite this article as: Pinkaew, D et al., Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial, Journal of Bodywork & Movement Therapies, https://doi.org/10.1016/j.jbmt.2019.04.013