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Clinical effectiveness of bee venom acupuncture and physiotherapy in the treatment of adhesive capsulitis: a randomized controlled trial
J Shoulder Elbow Surg (2013) -, 1-10
www.elsevier.com/locate/ymse
Clinical effectiveness of bee venom acupuncture and physiotherapy in the treatment of adhesive capsulitis: a randomized controlled trial Pil Seong Koh, OMDa, Byung Kwan Seo, OMD, PhDa, Nam Su Cho, MD, PhDb, Hyung Soon Park, PTc, Dong Suk Park, OMD, PhDa, Yong Hyeon Baek, OMD, PhDa,* a
Department of Acupuncture & Moxibustion, Center for Arthritis & Rheumatism, Kyung Hee University Hospital at Gangdong, Seoul, South Korea b Department of Orthopaedic Surgery, Kyung Hee University Hospital at Gandong, Seoul, South Korea c Department of Physical Therapy, Center for Arthritis & Rheumatism, Kyung Hee University Hospital at Gangdong, Seoul, South Korea Background: Bee venom acupuncture (BVA) has been used in the treatment of adhesive capsulitis (AC) in the clinical field. This study aimed to investigate whether the addition of BVA to physiotherapy (PT) would be more effective in the management of AC, and whether BVA would have a dose-dependent effect. Materials and methods: Sixty-eight patients diagnosed with AC were recruited into 3 groups; BV 1 (1:10,000 BVA plus PT), BV 2 (1:30,000 BVA plus PT), and group 3 (normal saline (NS) injection, as a control, plus PT). PT was composed of 15 minutes of transcutaneus electrical nerve stimulation (TENS), transcutaneus infrared thermotherapy (TDP), and manual PT. Treatments were given in 16 sessions within 2 months. Shoulder pain and disability index (SPADI), pain visual analogue scale (VAS), and 3) active/passive range of motion (ROM) were measured before treatment and at 2, 4, 8, and 12 weeks after the treatment. Results: All 3 groups showed statistically significant improvements in SPADI, pain VAS scores, and active/passive ROM. The BV 1 group showed significantly better outcomes in SPADI at 8 and 12 weeks, in pain VAS (at rest) at 8 weeks, and in pain VAS (during exercise) at 12 weeks than the NS group. No significant differences were found in active/passive ROM among all the groups. Conclusion: BVA in combination with PT can be more effective in improving pain and function than PT alone in AC. However, the effectiveness of BVA was not shown in a dose-dependent manner. Level of evidence: Level I, Randomized Controlled Trial, Treatment Study. Ó 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Keywords: Adhesive capsulitis; bee venom acupuncture; physiotherapy
Funding: This study was supported by a grant from the Kyung Hee University in 2010. (KHU-20100713). IRB: This protocol was approved by the institutional review board (IRB) as Kyung Hee University Hospital (Seoul, South Korea): ClinicalTrialsl.gov Identifier: NCT01526031.
*Reprint requests: Yong Hyeon Baek, OMD, PhD, Department of Acupuncture & Moxibustion, Center for Arthritis & Rheumatism, Kyung Hee University Hospital at Gangdong, #149 Sangil-dong, Gangdong-gu, Seoul, 134-727, South Korea. E-mail address: [email protected] (Y.H. Baek).
1058-2746/$ - see front matter Ó 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. http://dx.doi.org/10.1016/j.jse.2012.10.045
2 Adhesive capsulitis (AC) is recognized as a disorder confined to the articular capsule including the synovial cyst and underlying tissues, affecting 2-5% of the population in the age of 40-60 years.36 AC generally lasts from 12 to 42 months, and some degree of motion limitation remains in a portion of patients (39-76%).35 The mechanism of the disease is still being debated; however, the currently accepted hypothesis states that synovial inflammation is the major pathologic process in the onset of the disease and subsequently induces reactive articular capsule fibrosis which appears in the later stages.24 In the conventional treatment of AC, physiotherapy (PT) has been recognized as one of the main treatments. The characteristics of AC are predominant adhesive capsule associated with soft tissue tightness, thus mobilization techniques have been a part of essential clinical treatment approaches and research studies.38 When several types of PT are applied in combination with other interventions, they could be more valuable conventional treatments in the management of AC. For example, a combination of intraarticular corticosteroid and PT has been recognized as a more effective treatment method, and bee venom acupuncture (BVA) has been used in combination with physiotherapy in the case of patients for whom intra-articular corticosteroids are not suitable. BVA, as an alternative method for acupuncture, has been recently used for a long time in oriental medicine as a traditional medical approach to relieve pain and inflammation.2 Bee venom (BV) contains many kinds of components which show pharmacologic actions such as anti-inflammatory, anti-nociceptive, and anti-arthritic effects. Among those components, adolapin has an anti-inflammatory effect by inhibiting the prostaglandin synthesis through COX inhibition13,27 and melittin also regulates inflammatory response by inhibiting the DNAbinding activity of NF-kB.21,22 Other bioamines (apamine, histamine, serotonin, norepinephrine) of BV have an antinociceptive and mobility restoring effects.1,28 However, there have been no randomized-controlled trials addressing the effectiveness of BVA alone or BVA in combination with physiotherapy in the treatment of AC. In the clinical field, 1:10,000 and 1:30,000 concentrations of BVA have been widely used in the treatment of AC patients, so we wanted to identify the optimal concentration of BVA for AC. In this background, the aim of the present study was to examine whether the addition of BVA to PT would be more effective than PT alone in the management of AC, and whether BVA would display a dose-dependent effect.
Materials and methods Between January 2010 and December 2010, we performed a randomized, placebo-controlled, patient and assessor blinded trial in participants with AC who were diagnosed by a specialist from the department of orthopaedic surgery (ClinicalTrials.gov Identifier: NCT01526031).
P.S. Koh et al. Inclusion criteria were: age 18 years; symptoms of pain (>VAS 5) lasting over 1 month and under 12 months; marked limitation of active and/or passive motion range in predominantly 1 shoulder (minimum 25% limitation in 2 planes of movement); and patients who could receive 16 separate sessions of BVA. Exclusion criteria were: history of major shoulder injury or surgery; patients with other disorders which could account for the presenting shoulder symptoms, diagnosed either by clinical signs or radiologic testing; patients with cervical neuropathy, paralysis, or neurological changes of the affected upper limb; patients with hypersensitive reactions after bee venom skin testing, renal or hepatic disorders, diabetes with complications, hematopoietic diseases, cerebrovascular disorders, allergies, fractures, open wounds at the bee venom administration site, malignant cancer, mental disorders which may affect the diagnosis or progression of the disorder, or degenerative, inflammatory, or infectious arthritis; patients with past intra-articular injection treatment regarding the presenting shoulder pain within the past 4 weeks before the first visit; pregnant or breastfeeding patients; patients deemed by the researcher as unable to normally adhere to the research protocol; and lack of written informed consent. Of the 192 patients enrolled in this study, 124 were excluded because they did not meet inclusion criteria. Therefore, 68 patients who agreed to participate were finally recruited to this study. Although these patients were requested not to receive any other intervention during the follow-up period, they were allowed to receive other interventions if there was intractable pain. They were also allowed to leave the study at any time. After obtaining informed consent, the patients were randomly allocated to one of the 3 groups by the 6 block randomization method (Fig. 1). The 3 groups are BV 1 group (n ¼ 22, 1:10,000 concentration BVA plus PT), BV 2 group (n ¼ 23, 1:30,000 concentration BVA plus PT), and NS group (n ¼ 23, NS injection plus PT). The demographic data for the patients in the 3 groups are summarized in Table I. Chi-square test was performed on sex ratio, age, and disease duration to assess homogeneity of variance among the groups, and the result showed that there were no differences among the groups in demographic factors (P > .05).
Treatment procedure All patients were assessed at baseline, 2, 4, 8, and 12 weeks after initial treatment. Patients were removed from the study in cases of nonattendance to assessment visits, refusal to take further bee venom acupuncture, breaks in treatment for over 2 weeks, occurrence of difficulties in assessing treatment effect such as severe side effects after treatment, and expression of desire to withdrawal. All patients in three groups were given PT reported to be effective for frozen shoulder. PT was performed at each visit by one physical therapist with over 7 years of clinical experience. Fifteen minutes of transcutaneous electrical nerve stimulation (TENS 21; Homer Ion Laboratory Co., Ltd., Shibuya-Ku, Tokyo, Japan)19,20 and 15 minutes of transcutaneous infrared thermotherapy (TDP 100; ITC Co., Ltd., Daedeok-Gu, Daejeon, South Korea) were given 2 times a week, and manual physical therapy was given for 15 minutes once a week. During the first visit, a simple home exercise program leaflet was given out and patients were educated with the material. They were told to perform the home exercises 2 times daily until the
Synergistic effect of acupuncture on physiotherapy
3
Assessed for eligibility (n = 192)
Excluded (n = 124)
Enrollment Not meeting inclusion criteria (n = 119)
Randomized (n = 68)
Refused to participate (n = 5)
Allocation
Allocated to intervention (n = 22)
Allocated to intervention (n = 23)
Allocated to intervention (n = 23)
Received allocated intervention (n = 22)
Received allocated intervention (n = 23)
Received allocated intervention (n = 23)
Not receive allocated intervention (n = 0)
Not receive allocated intervention (n = 0)
Not receive allocated intervention (n = 0)
Follow-Up
Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Discontinued Intervention (n = 1) Allergy reponse
Discontinued intervention (n = 1) No effect
Discontinued Intervention (n = 3) No effect
Analyzed (n = 22)
Analyzed (n = 23)
Analyzed (n = 23)
Excluded from analysis (n = 0)
Excluded from analysis (n = 0)
Excluded from analysis (n = 0)
Analysis
Figure 1 Total enrolled patients were 192, and 124 patients were excluded according to the exclusion criteria. Allocated 68 patients were divided by 3 groups. completion of all 16 sessions, and a researcher checked their progress at each visit. The simple home exercise program was based on former studies.7,31,32 It comprised of 5 activities, which the patients were instructed to perform 1-2 hours daily. To check compliance, a record booklet was given out to patients. Patients in the BV 1 group and BV 2 group were intramuscularly injected with bee venom using a 1 cc syringe (Hwajin medical 30 gauge; Hwajin Medical Co.,Ltd., Seoul, Korea) at a depth of 0.5-1.0 cm. The bee venom used for this study was prepared in the Traditional Korean medical pharmacy in Kyung Hee University Hospital. Dried bee venom powder (Yoomil Garden, Hwasun, Korea) was diluted and prepared as follows: add 300 cc (1:30000) or 100 cc (1:10000) of saline (Joongwe Pharmaceuticals, Seoul, Korea) to 10 mg of dried bee venom powder, and dissolve thoroughly; filter using 0.22 mm filters and fill sterilized vials with 20 mL of preparation; seal with rubber lid, and cap with aluminum capping; store at 4 C. The preparation process took place in the injection preparation room, and empty vials were first sterilized and then filled due to protein denaturation concerns. Patients in the NS group were intramuscularly injected with saline (Choongwae Pharmaceuticals, Seoul, Korea) instead of bee venom. The target acupuncture points were sterilized with 70% alcohol before injection. Before the first BVA treatment, a skin reaction test was performed to all patients to check for any
possible hypersensitivity to bee venom. 0.05 ml of 1:30,000 concentration BVA was injected subcutaneously at LI 11 with a 1 cc syringe (Hwajin medical 30 gauge; Hwajin Medical Co.,Ltd.). Local redness and swelling were measured at the peak of response between 15 and 20 minutes after administration. Local swelling over 10 mm in diameter, or local redness over 20 mm in diameter, was considered a positive reaction. Patients who did not show positive reactions were included in this study. Following this, 0.1 ml of BVA or NS was injected at each acupuncture point. A total of 0.4 ml was injected at 4 points on the first visit, 0.6 ml at 6 points on the second, 0.8 ml at 8 points on the third, and 1.0 ml at 10 points throughout visits 4-16. The gradual increase of dose is for close observation of hypersensitivity, because, even though patients are safe after the skin reaction test, sudden high dose of bee venom treatment can cause an unexpected hypersensitivity. All patients were given treatments by the same acupuncture specialist with over 15 years of clinical experience. The injection volumes were based on the previous study.6 The acupuncture points were selected as: LI15 (located between the anterior end of lateral border of the acromion and the greater tubercle of the humerus); LI16 (located between the acromial end of the calvicle and the spine of the scapula); TE14 (located between the acromial angle and the greater tubercle of the humerus); GB21 (located at the midpoint of the line connecting the spinous process of the
4
P.S. Koh et al. Table I
Clinical characteristics of the BV 1, BV 2 and NS groups at baseline
Characteristics Age (years) Sex Male Female Lesion Right Left Duration (months) ROM Active abduction Active forward flexion Active extension Active external rotation Passive abduction Passive forward flexion Passive extension Passive external rotation Pain VAS usual Pain VAS nocturnal Pain VAS during exercises SPADI
BV 1 (n ¼ 22)
BV 2 (n ¼ 23)
54.95 6.79
56.18 6.70
NS (n ¼ 23) 55.13 7.01
Sum 54.35 7.21
6 (27.27) 16 (72.73)
8 (34.78) 15 (65.22)
6 (26.09) 17 (73.91)
20 (29.41) 48 (70.59)
9 (40.91) 13 (59.09) 6
8 (34.78) 15 (65.22) 5.24
9 (39.13) 14 (60.87) 6.65
26 (38.24) 42 (61.76) 5.96
96.18 122.91 35.91 34.95 114.59 135.91 46.82 41.59 6.59 6.66 7.39 62.55
32.17 27.11 9.73 12.12 33.27 24.23 11.52 11.57 1.76 2.04 1.38 11.50
91.74 114.43 39.09 37.00 112.17 130.26 49.26 44.22 6.78 6.80 7.28 58.81
26.07 22.33 11.12 12.23 23.44 19.82 10.37 11.20 1.76 1.76 1.40 13.97
84.35.33.44 110.26 27.01 35.30 9.49 38.04 15.60 108.04 30.80 129.00 24.16 45.61 9.75 41.91 12.95 6.94 1.55 6.91 1.87 7.33 1.24 66.10 12.71
BV 1, 1:10,000 concentration BVA + PT group; BV 2, 1:30,000 concentration BVA + PT group; NS, normal saline injection + PT group; ROM, range of motion; VAS, visual analogue scale; SPADI, Shoulder and Pain Disability Index. Values are the mean SD.
seventh cervical vertebra (C7) with the lateral end of the acromion); SI11 (located between the upper one third and lower two thirds of the line connecting the midpoint of the spine of the scapula with the inferior angle of the scapula); and additionally 5 points around the shoulder.37
Sample size and blinding There was no randomized clinical comparison study on the effectiveness of BVA compared to PT in the treatment of AC. However, a similar previous study showed that the control group had a 37.9 improvement of shoulder pain and disability index (SPADI) after 3 months with a standard deviation of 15.1 Under the assumption that 1) the a value of the 2-tailed test is 0.05 with 80% power, 2) the test group will show 35% more improvement compared to the control, and 3) the standard deviations of the test group and the control group are the same, the number of patients needed for each group would be 19. An additional assumption of a 15 % drop-out rate raised the required number of patients to 22 for each group. The researcher delivering treatment can distinguish between treatment groups and control group based on local reactions of BVA, so this study was designed as a patient-outcome assessor blinded study. The researcher delivering treatment minimized all unnecessary conversation with patients. The assessor determined patient inclusion, obtained informed consent, assigned serial numbers to patients, organized schedules, and took care of medical consultations. The assessor was blinded to treatment, and questions were restricted to those filling out case record sheets. Data assessment was performed by an independent statistician.
Patients were informed that they had the same chance of random distribution (33%) into either of the 2 test groups or the control group. The patients were prohibited from speaking with other patients, and were all given treatment in an ordinary oriental medical clinic or hospital by the same physician using identical syringes. Blinding validity was assessed by credibility testing after treatment completion.
Outcome assessments The primary outcome measure was the Shoulder Pain and Disability Index (SPADI), a tool used for QOL assessment consisting of 13 items divided into 2 subscales, 5 items about pain and 8 items about disability.23 Items are checked on a 10-point Likert scale (0 means ‘no pain’ or ‘no difficulty’, 9 means ‘worst imaginable pain’ or ‘so difficult it required help’). A SPADI score is calculated out of 100 (higher score means more pain/disability). A pain visual analogue scale (VAS) was used as a secondary outcome measure and marked in 3 conditions, namely ‘VAS at rest,’ ‘VAS at night,’ and ‘VAS during motion.’ ‘‘A painless state’’ was recorded as 0, and ‘‘the most excruciating pain imaginable’’ was recorded as 10. The other secondary outcome measures were active and passive range of motions (ROMs) in 4 motions. The 4 motions were abduction (range, 0 -180 ), forward flexion (range, 0 -180 ), extension (range, 0 -75 ), and external rotation (range, 0 -90 , arm by side). The 4 motions were measured using the BTE primus (BTE technology, USA, 2006). The BTE primus is able to assess joint motion range accurately and has been shown to have high test-retest reliability (R ¼ .97) and validity (R ¼ .96).26
Synergistic effect of acupuncture on physiotherapy Table II
5
Mean changes in scores of SPADI and VAS among groups at baseline, 2, 4, 8 and 12 weeks 2 weeks
4 weeks
8 weeks
12 weeks
P)
11.50 13.97 12.71
48.46 12.21 48.98 14.53 57.46 14.19 0.052
40.98 13.05 42.26 15.08 47.81 16.42 0.269
23.15 12.82a 28.08 18.59ab 37.44 19.84b 0.025z
15.42 12.63a 20.30 16.78ab 30.21 20.94b 0.017z
<.01 <.01 <.01
1.76 1.76 1.55
5.25 1.76 5.74 1.94 6.24 1.35 0.156
4.48 1.72 4.65 21.92 5.33 1.63 0.238
2.66 1.69a 3.28 2.14ab 4.15 2.12b 0.048z
2.07 1.83 2.37 1.90 3.28 2.22 0.110
<.01 <.01 <.01
2.04 1.76 1.87
5.59 2.17 5.57 1.59 6.15 1.77 0.485
4.66 2.17 4.61 1.64 5.33 1.82 0.363
2.82 2.15 2.85 1.77 3.89 2.40 0.159
2.07 2.12 2.02 1.65 3.06 2.33 0.160
<.01 <.01 <.01
1.38 1.40 1.24
5.80 1.68 6.26 1.42 6.76 1.20 0.089
4.98 1.85 5.09 1.50 5.80 1.64 0.201
3.09 1.80 3.33 1.79 4.33 2.24 0.086
2.21 21.88a 2.41 1.67ab 3.65 2.20b 0.029z
<.01 <.01 <.01
Baseline SPADI BV 1 62.55 BV 2 58.81 NS 66.10 Py VAS (at rest) BV 1 6.59 BV 2 6.78 NS 6.94 Py VAS (at night) BV 1 6.66 BV 2 6.80 NS 6.91 Py VAS (motion) BV 1 7.39 BV 2 7.28 NS 7.33 Py
BV 1, 1:10,000 concentration BVA + physiotherapy (PT) group; BV 2, 1:30,000 concentration BVA + PT group; NS, normal saline injection + PT group; VAS, visual analogue scale; SPADI ¼ Shoulder and Pain Disability Index. Values are the mean SD. ) Differences within groups by using Repeated Measures analysis of variance (ANOVA) (there were no interactions between treatment and time). y Differences among groups by using one way ANOVA. Tukey’s HSD test was performed if the results showed statistically significant differences, and showed as zP < .05.
To improve assessment quality, a single medical doctor with 4 years of clinical experience assessed all patients and underwent 10 education sessions (1-hour per each session) on clinical trials. All measurements were repeated and the means were presented.
calculated and the lack of statistically significant differences (ANOVA, P > .05) showed homogeneity of variance among the 3 groups (Table I).
Statistical analysis
Effectiveness in SPADI and VAS
Statistical analysis was performed using SPSS 12.0 for windows (SPSS, Chicago, IL, USA), and homogeneity of variance was tested by 1-way ANOVA and Chi square (c2) test. Repeated measures ANOVA were performed to compare the SPADI, VAS, active/passive ROM at 2, 4, 8, and 12 weeks after initial treatment. One-way ANOVA was used to compare the differences among the groups and Tukey’s HSD testing was used for post hoc comparison. Credibility testing was performed to check blinding validity and Chi square test was used for result assessment. P < .05 was regarded as statistically significant. The statistical analyses were performed on an intention-to-treat basis. Data from drop-out patients were processed with the last observation carried forward (LOCF) method, and the last known values were used under the assumption that no further improvement will occur.
In the SPADI scores as a primary outcome assessment, all 3 groups showed significant improvements as treatment sessions progressed from 2 to 12 weeks after treatment initiation. The 1:10,000 concentration BVA plus PT group (BV 1 group) showed significantly better improvements compared to the normal saline plus PT group (NS group) at 8th and 12th weeks after treatment initiation (Tukey’s HSD, P ¼ .025, P ¼ .014, respectively). However, there were no significant differences between the BV 1 and BV 2 groups. Thus the results of the SPADI index suggest that BVA treatment did not proceed in a dose-dependent manner (Table II, Fig. 2). In the VAS scores as a secondary outcome assessment, all 3 groups also showed significant improvements over time in the VAS at rest, VAS at night, and VAS during motion scores. Compared to the NS group, the BV 1 group showed statistically better effectiveness in the VAS at rest score at 8th week and in the VAS during motion score at 12th week, but not in the VAS at night score. There were no differences between the BV 1 and BV 2 groups in the VAS scores. Furthermore, BVA treatment was not effective in a dose-dependent manner shown by the VAS scores (Table II, Fig. 2).
Results Before treatment initiation, the SPADI, VAS (during rest, at night, and during motion) and active/passive ROM (abduction, forward flexion, extension, and external rotation) were measured. The mean SD of these data were
6
P.S. Koh et al. BV 1 (n=22) BV 2 (n=23) NS (n=23)
100 80
8
VAS (at rest)
60
SPADI
BV 1 (n=22) BV 2 (n=23) NS (n=23)
10
40 20
*
0
baseline
2
4
8
6 4 2
*
*
12
baseline
2
weeks BV 1 (n=22) BV 2 (n=23) NS (n=23)
6 4 2
4
12
8
12
BV 1 (n=22) BV 2 (n=23) NS (n=23)
10
VAS (during motion)
VAS (at night)
8
2
8
weeks
10
baseline
4
8 6 4 2
* baseline
2
4
8
12
weeks
weeks
Figure 2
Mean changes in SPADI and VAS for the bee venom acupuncture (BVA) and placebo groups at baseline, 2, 4, 8, and 12 weeks. , 1:10,000 concentration BVA þ PT (physiotherapy) group; , 1:30,000 concentration BVA þ PT group; , normal saline(control) þ PT group; *, significant effectiveness of BV1 group compare to control group.
Effectiveness in active and passive ROM In the secondary outcome assessments of active and passive ROM (abduction, forward flexion, extension, and external rotation), all 3 groups showed significant effectiveness as treatment sessions progressed 2-12 weeks after treatment initiation (P < .01). After the end of the 8-week treatment, all the groups significantly improved the ROM of all planes for at least more 4 weeks up to the 12th week from treatment initiation; however, there were no significant differences among the groups in all ROMs. Even though the BVA plus PT groups had a tendency to show more improvements than the PT only group, statistically significant differences were not found. Furthermore, the BV 1 group (1:10,000 concentration BVA plus PT group) did not show significantly better improvements than the BV 2 group (1:30,000 concentration BVA plus PT group). However, the degree of ROM improvements in the BV 1 group was higher than those of the BV 2 group (Table III, Fig. 3).
Credibility assessment and side effect After trial completion, 68 patients who finished the study were tested for blinding validity. Among the 45 patients in group BV 1 and BV 2 who received BVA, 25 thought they received bee venom injections, 5 thought they received normal saline injections, and 15 were unclear. Among the patients in group NS, 6 thought they received bee venom injections, 6 thought they received normal saline injections, and 8 were unclear. Chi square independence testing showed
there was no statistical difference between the bee venom groups and the normal saline control group (P ¼ .073), and thus the present blinding could be regarded as acceptable. In the present study, among the 45 patients who received bee venom treatment, 30 experienced slight pruritus, local swelling, and/or redness (under 20 mm in diameter), which were Mueller Grade 0. One subject from group BV 1 displayed mild, generalized swelling and aching which were classified as Mueller Grade 1 reactions, and 3 among 23 patients from group NS showed slight redness and pruritus. No subject showed severe reactions over Mueller Grade 2.16
Discussion Adhesive capsulitis (AC) is a disease of uncertain etiology characterized by shoulder joint pain and progressive limitation of both active and passive motion in the affected shoulder.17,18,34 The causes are very diverse, and the exact cause, main pathology and mechanisms are still unclear.15 However, rotator cuff tendinitis, bicipital tenosynovitis, muscular imbalance, and reflexive sympathetic dystrophy etc. are reported as possible causes of secondary AC disorder.33 It is reported that up to 40% of patients with AC suffer from remaining symptoms and stiffness for over 3 years,29 and 15% of patients have long-term disabilities such as muscle weakness from disuse, limitation of ROM and low quality of life (QOL).11 In this background, the aim of our study was to reveal the effectiveness of combination of BVA and several types of physiotherapy on reducing the
Synergistic effect of acupuncture on physiotherapy Table III
7
Mean changes in active/passive range of motion among groups at baseline, 2, 4, 8 and 12 weeks 2 weeks
4 weeks
8 weeks
12 weeks
P)
32.17 26.07 33.44
120.09 36.14 111.17 24.82 101.17 34.67 >0.05
134.73 39.65 122.52 25.56 119.48 40.34 >0.05
155.73 18.71 139.83 28.68 137.00 38.24 >0.05
162.55 16.47 146.83 28.76 146.78 29.12 >0.05
<.01 <.01 <.01
27.11 22.33 27.01
141.73 24.28 134.57 19.72 126.17 31.35 >0.05
146.86 25.89 140.87 14.70 135.00 31.12 >0.05
159.50 17.57 153.78 18.69 148.17 28.53 >0.05
164.86 15.01 155.13 20.34 154.30 24.21 >0.05
<.01 <.01 <.01
9.73 11.12 9.49
45.55 12.24 46.04 12.83 42.35 10.62 >0.05
48.36 10.27 43.61 9.61 46.91 12.55 >0.05
54.05 13.62 50.43 12.52 48.65 12.68 >0.05
58.50 9.97 53.39 14.97 54.91 14.09 >0.05
<.01 <.01 <.01
12.12 12.23 15.60
42.55 13.90 41.17 10.29 42.22 20.03 >0.05
41.27 11.21 42.48 11.64 41.87 13.91 >0.05
47.00 11.86 49.13 12.32 45.78 13.92 >0.05
50.14 11.67 47.22 13.17 45.91 14.22 >0.05
<.01 <.01 <.01
33.28 23.44 30.80
142.23 30.09 143.35 22.46 125.78 35.32 >0.05
150.59 23.27 146.43 19.84 137.26 33.89 >0.05
165.05 14.02 160.78 18.90 149.87 28.12 >0.05
169.23 10.21 163.57 16.21 158.17 20.07 >0.05
<.01 <.01 <.01
33.28 19.82 24.13
153.95 20.09 152.13 17.98 145.22 23.16 >0.05
156.82 21.27 155.09 16.64 149.39 26.41 >0.05
166.00 13.78 161.57 17.35 157.70 24.01 >0.05
170.73 9.00 163.39 15.49 163.65 15.15 >0.05
<.01 <.01 <.01
11.52 10.37 9.75
58.68 12.89 57.87 11.26 53.22 11.93 >0.05
61.41 10.49 56.30 9.87 59.00 13.46 >0.05
66.50 11.68 64.65 10.66 59.91 13.18 >0.05
72.14 7.09 64.57 13.55 63.74 14.48 >0.05
<.05 <.05 <.05
11.57 11.21 12.95
49.41 13.64 53.26 12.37 43.78 13.69 >0.05
49.73 12.97 53.91 10.75 50.65 14.15 >0.05
57.23 11.91 58.09 12.21 55.57 15.26 >0.05
61.77 11.74 57.70 13.97 54.00 15.57 >0.05
<.05 <.05 <.05
Baseline Active Abduction BV 1 96.18 BV 2 91.74 NS 84.35 Py Forward flexion BV 1 122.91 BV 2 114.43 NS 110.26 Py Extension BV 1 35.91 BV 2 39.09 NS 35.30 Py External rotation BV 1 34.95 BV 2 37.00 NS 38.04 Py Passive Abduction BV 1 114.59 BV 2 112.17 NS 108.04 Py Forward flexion BV 1 135.91 BV 2 130.26 NS 129.00 Py Extension BV 1 46.82 BV 2 49.26 NS 45.61 Py External rotation BV 1 41.59 BV 2 44.22 NS 41.91 Py
BV 1, 1:10,000 concentration BVA + physiotherapy (PT) group; BV 2, 1:30,000 concentration BVA + PT group; NS, normal saline injection + PT group. Values are the mean SD. ) Differences within groups by using Repeated Measures ANOVA. y Differences among groups by using one way ANOVA.
long-term disabilities, with a special focus in the limitation of range of motion (LOM), QOL and pain. In relation to AC treatment, it has shown that a combination of supervised physiotherapy and intra-articular corticosteroids were more effective than supervised physiotherapy alone for improving pain, function, and ROM in patients with AC.3 Among several types of PT, it was reported that end-range mobilization (ERM) and Mobilization with movement (MWM) were more effective than mid-range
mobilization (MRM) in increasing mobility and functional ability.5,14,25,38 In accordance with this finding, PT of our study was composed of ERM and MWM manual techniques, TENS, TDP and a simple home exercise program. In our study, BVA was treated as a combination treatment of PT to induce synergistic effectiveness in the treatment of AC. BVA, as one of the several acupuncture types, has been used in the oriental medical field to relieve pain and to treat chronic inflammatory diseases like rheumatoid arthritis,8,30
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along with studies on the safety and efficacy of BV.4,6 Clinically, combination treatment of BVA and PT has been explosively used in our arthritis center, but there has been a lack of evidence from randomized controlled trials (RCT). In this aspect, we designed a RCT to examine whether the addition of BVA to PT would be more effective than PT alone in the management of AC, and to determine an appropriate concentration of BVA. Another reason for this
study would be to make an observation for a future largescale randomized controlled trial. All three groups showed statistically significant improvements in SPADI scores, pain VAS, and active/passive ROM. This indicates that combinations of BVA and physiotherapy, and normal saline and physiotherapy were all effective in AC patients. The primary outcome measurement, SPADI, showed significantly better improvements in group
Synergistic effect of acupuncture on physiotherapy BV 1 compared to group NS at the 8th and 12th weeks after treatment initiation. SPADI improvements of over 10 % are clinically meaningful3 and the results of this study showed a 15 % difference between the 2 groups. Group BV 1 also showed significant improvements compared to group NS in VAS (at rest) at 8th week after treatment initiation and in VAS (during motion) at 12th week. In active and passive ROM, significant differences were not found among the groups. These results are in line with the previous study in which acupuncture did not induce statistically meaningful ROM improvements but did improve pain and quality of life, and reached a conclusion that acupuncture and physiotherapy should be used in conjunction in AC treatment. Another reason for the improvements would be that in our study, 4 types of PT were applied (manual techniques, TENS, TDP, and simple home exercise program); the effectiveness of PT alone would therefore be very powerful especially in terms of ROM improvement. In this study, the effectiveness of the 2-month treatments in 3 groups were significantly elevated for 3 months. One study revealed that no long-term differences were found in patients treated with both physiotherapy and corticosteroids, either physiotherapy or corticosteroids, or normal saline after 12 months; but at 3 months, statistically different recovery was induced.3 Another study reported that electro acupuncture produced significantly greater reduction in pain intensity than did placebo acupuncture even at the 6-month followup.10 In order to clarify the long-term effects, we are scheduled to follow our patients up to 1 year. Our results showed no statistically significant differences between the 1:10,000 and 1:30,000 BV concentration groups. Of course, group BV 1 generally showed better improvements compared to those of group BV 2; however, these results were not statistically significant, and it cannot be concluded that these effects are dose-dependent. This may partly be due to the small difference in concentration, as there is only a 3-fold difference between the 2 groups. This study does not have any relevant previous researches, and results cannot be accepted as a generalized fact. Randomized controlled trials with BV should be performed on the basis of the present study, in order to make conclusions on dosedependent effects and/or optimum concentration. The present study applied physiotherapy to all 3 groups. Physiotherapy was used with research evidence, and was employed to address the ethical issue arising from the disparity in treatment effects that may arise when the control group is only given normal saline injections for 2 months and no treatment for an additional month. Furthermore, this study followed strict inclusion criteria, and an orthopedist was involved in the inclusion process for objectivity. Recent conventional medical research has shown that the precision of corticosteroid injections is related to clinical outcome, and thus a specialist clinician with over 15 years of experience was chosen to inject the bee venom preparation or normal saline.9,12 This researcher in charge of treatment performed all injections (16 sessions
9 per patient, 16 68 times in 68 patients throughout the 11-month period). Moreover, 1 physical therapist handled all physiotherapy, as having multiple physical therapists could result in treatment differences. These were done in an attempt to improve research reliability. The limitations of the present study include the small number of patients. It is difficult to find enough patients who fit all the criteria during the 11-month study period, as Carette et al have also noted.3 The small sample size could result in flawed results. Furthermore, the lack of former similarly designed researches on AC make it difficult to accept the present results as a generalized fact. The present practice of BVA relies mainly on the clinician’s experience to adjust the concentration of the acupuncture preparation; a standardized guideline is therefore needed. Moreover, further study is needed to compare the effectiveness between BV and intraarticular corticosteroids.
Conclusion BVA combined with physiotherapy may have better clinical effectiveness in functional improvement and pain reduction than physiotherapy alone on adhesive capsulitis patients. Even though the 1:10,000 concentration bee venom acupuncture showed generally better effects compared to the 1:30,000 concentration, there was no statistical difference. Further trials are needed to confirm this.
Acknowledgment The authors thank Jung Woo Lee for his assistance with data collection.
Disclaimer The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.
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by suppression of NF-kappaB through interaction with the p50 subunit. Arthritis Rheum 2004;50:3504-15. http://dx.doi.org/10.1016/ j.intimp.2007.04.005 Park HJ, Son DJ, Lee CW, Choi MS, Lee US, Song HS. Mellitin inhibits inflammatory target gene expression and mediator generation via interaction with IkappaB kinase. Biochem Pharmacol 2007;73: 237-47. http://dx.doi.org/10.1016/j.bcp.2006.09.023 Roach KE, Budiman-Mak E, Songsiridej N, Lertratanakul Y. Development of a shoulder pain and disability index. Arthritis Care Res 1991;4:143-9. Rodeo S, Hannafin J, Tom J, Warren R, Wickiewicz T. Immunolocalization of cytokines and their receptor in frozen shoulder of the shoulder. J Orthop Res 1997;15:427-36. Ryans I, Montgomery A, Galway R, Dernohan W, Mckane R. A randomized controlled trial of intra-articular triamcinolone and/or physiotherapy in shoulder capsulitis. Rheumatology (Oxford) 2005; 44:529-35. http://dx.doi.org/10.1093/rheumatology/keh535 Shechtman O, Davenport R, Malcolm M, Nabavi D. Reliability and validity of the BTE-Primus grip tool. J Hand Ther 2003;16:36-42. http://dx.doi.org/10.1016/S0894-1130(03)80022-4 Shkenderov S, Koburova K. Adolapin-a newly isolated analgesic and anti-inflammatory polypeptide from bee venom. Toxicon 1982;20: 317-21. Shuba MF, Vladimirova IA. Effect of apamin on the electrical responses of smooth muscle to adenosine 5’-triphosphate and to nonadrenergic, non-cholinergic nerve stimulation. Neuroscience 1980;5: 853-9. Simmonds FA. Shoulder pain with particular reference to the frozen shoulder. J Bone Joint Surg Br 1949;318:426-32. Somerfield SD, Brandwein S. Bee venom and adjuvant arthritis. J Rheumatol 1988;15:1878. Stam H. Frozen shoulder: a review of current concepts. Physiotherapy 1994;80:588-98. Sun K, Chan K, Lo S, Fong D. Acupuncture for frozen shoulder. Hong Kong Med J 2001;7:381-91. Turek S. Orthopedics. Principle and their application. 4th ed. Toronto: Lippincott Company; 1984. Vermeulen HM, Obermann WR, Berger BJ. End-range mobilization techniques in adhesive capsulitis of the shoulder joint: a multiplesubject case report. Phys Ther 2000;80:1204-13. Wiley A. Arthroscopic appearance of frozen shoulder. Arthroscopy 1991;7:138-43. Wolf JM, Green A. Influence of comorbidity of self-assessment instrument scores of patients with idiopathic adhesive capsulitis. J Bone Joint Surg Am 2002;82:1167-72. World Health Organization (Western Pacific Region). WHO standard acupuncture point locations in the western pacific region. Switzerland: World Health Organization; 2008. Yang J, Chang C, Chen S, Wang S, Lin J. Mobilization techniques in subjects with frozen shoulder syndrome: randomized multiple-treatment trial. Physical Therapy 2007;87:1307-15. http://dx.doi.org/10.2522/ptj. 20060295
www.elsevier.com/locate/ymse
Clinical effectiveness of bee venom acupuncture and physiotherapy in the treatment of adhesive capsulitis: a randomized controlled trial Pil Seong Koh, OMDa, Byung Kwan Seo, OMD, PhDa, Nam Su Cho, MD, PhDb, Hyung Soon Park, PTc, Dong Suk Park, OMD, PhDa, Yong Hyeon Baek, OMD, PhDa,* a
Department of Acupuncture & Moxibustion, Center for Arthritis & Rheumatism, Kyung Hee University Hospital at Gangdong, Seoul, South Korea b Department of Orthopaedic Surgery, Kyung Hee University Hospital at Gandong, Seoul, South Korea c Department of Physical Therapy, Center for Arthritis & Rheumatism, Kyung Hee University Hospital at Gangdong, Seoul, South Korea Background: Bee venom acupuncture (BVA) has been used in the treatment of adhesive capsulitis (AC) in the clinical field. This study aimed to investigate whether the addition of BVA to physiotherapy (PT) would be more effective in the management of AC, and whether BVA would have a dose-dependent effect. Materials and methods: Sixty-eight patients diagnosed with AC were recruited into 3 groups; BV 1 (1:10,000 BVA plus PT), BV 2 (1:30,000 BVA plus PT), and group 3 (normal saline (NS) injection, as a control, plus PT). PT was composed of 15 minutes of transcutaneus electrical nerve stimulation (TENS), transcutaneus infrared thermotherapy (TDP), and manual PT. Treatments were given in 16 sessions within 2 months. Shoulder pain and disability index (SPADI), pain visual analogue scale (VAS), and 3) active/passive range of motion (ROM) were measured before treatment and at 2, 4, 8, and 12 weeks after the treatment. Results: All 3 groups showed statistically significant improvements in SPADI, pain VAS scores, and active/passive ROM. The BV 1 group showed significantly better outcomes in SPADI at 8 and 12 weeks, in pain VAS (at rest) at 8 weeks, and in pain VAS (during exercise) at 12 weeks than the NS group. No significant differences were found in active/passive ROM among all the groups. Conclusion: BVA in combination with PT can be more effective in improving pain and function than PT alone in AC. However, the effectiveness of BVA was not shown in a dose-dependent manner. Level of evidence: Level I, Randomized Controlled Trial, Treatment Study. Ó 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Keywords: Adhesive capsulitis; bee venom acupuncture; physiotherapy
Funding: This study was supported by a grant from the Kyung Hee University in 2010. (KHU-20100713). IRB: This protocol was approved by the institutional review board (IRB) as Kyung Hee University Hospital (Seoul, South Korea): ClinicalTrialsl.gov Identifier: NCT01526031.
*Reprint requests: Yong Hyeon Baek, OMD, PhD, Department of Acupuncture & Moxibustion, Center for Arthritis & Rheumatism, Kyung Hee University Hospital at Gangdong, #149 Sangil-dong, Gangdong-gu, Seoul, 134-727, South Korea. E-mail address: [email protected] (Y.H. Baek).
1058-2746/$ - see front matter Ó 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. http://dx.doi.org/10.1016/j.jse.2012.10.045
2 Adhesive capsulitis (AC) is recognized as a disorder confined to the articular capsule including the synovial cyst and underlying tissues, affecting 2-5% of the population in the age of 40-60 years.36 AC generally lasts from 12 to 42 months, and some degree of motion limitation remains in a portion of patients (39-76%).35 The mechanism of the disease is still being debated; however, the currently accepted hypothesis states that synovial inflammation is the major pathologic process in the onset of the disease and subsequently induces reactive articular capsule fibrosis which appears in the later stages.24 In the conventional treatment of AC, physiotherapy (PT) has been recognized as one of the main treatments. The characteristics of AC are predominant adhesive capsule associated with soft tissue tightness, thus mobilization techniques have been a part of essential clinical treatment approaches and research studies.38 When several types of PT are applied in combination with other interventions, they could be more valuable conventional treatments in the management of AC. For example, a combination of intraarticular corticosteroid and PT has been recognized as a more effective treatment method, and bee venom acupuncture (BVA) has been used in combination with physiotherapy in the case of patients for whom intra-articular corticosteroids are not suitable. BVA, as an alternative method for acupuncture, has been recently used for a long time in oriental medicine as a traditional medical approach to relieve pain and inflammation.2 Bee venom (BV) contains many kinds of components which show pharmacologic actions such as anti-inflammatory, anti-nociceptive, and anti-arthritic effects. Among those components, adolapin has an anti-inflammatory effect by inhibiting the prostaglandin synthesis through COX inhibition13,27 and melittin also regulates inflammatory response by inhibiting the DNAbinding activity of NF-kB.21,22 Other bioamines (apamine, histamine, serotonin, norepinephrine) of BV have an antinociceptive and mobility restoring effects.1,28 However, there have been no randomized-controlled trials addressing the effectiveness of BVA alone or BVA in combination with physiotherapy in the treatment of AC. In the clinical field, 1:10,000 and 1:30,000 concentrations of BVA have been widely used in the treatment of AC patients, so we wanted to identify the optimal concentration of BVA for AC. In this background, the aim of the present study was to examine whether the addition of BVA to PT would be more effective than PT alone in the management of AC, and whether BVA would display a dose-dependent effect.
Materials and methods Between January 2010 and December 2010, we performed a randomized, placebo-controlled, patient and assessor blinded trial in participants with AC who were diagnosed by a specialist from the department of orthopaedic surgery (ClinicalTrials.gov Identifier: NCT01526031).
P.S. Koh et al. Inclusion criteria were: age 18 years; symptoms of pain (>VAS 5) lasting over 1 month and under 12 months; marked limitation of active and/or passive motion range in predominantly 1 shoulder (minimum 25% limitation in 2 planes of movement); and patients who could receive 16 separate sessions of BVA. Exclusion criteria were: history of major shoulder injury or surgery; patients with other disorders which could account for the presenting shoulder symptoms, diagnosed either by clinical signs or radiologic testing; patients with cervical neuropathy, paralysis, or neurological changes of the affected upper limb; patients with hypersensitive reactions after bee venom skin testing, renal or hepatic disorders, diabetes with complications, hematopoietic diseases, cerebrovascular disorders, allergies, fractures, open wounds at the bee venom administration site, malignant cancer, mental disorders which may affect the diagnosis or progression of the disorder, or degenerative, inflammatory, or infectious arthritis; patients with past intra-articular injection treatment regarding the presenting shoulder pain within the past 4 weeks before the first visit; pregnant or breastfeeding patients; patients deemed by the researcher as unable to normally adhere to the research protocol; and lack of written informed consent. Of the 192 patients enrolled in this study, 124 were excluded because they did not meet inclusion criteria. Therefore, 68 patients who agreed to participate were finally recruited to this study. Although these patients were requested not to receive any other intervention during the follow-up period, they were allowed to receive other interventions if there was intractable pain. They were also allowed to leave the study at any time. After obtaining informed consent, the patients were randomly allocated to one of the 3 groups by the 6 block randomization method (Fig. 1). The 3 groups are BV 1 group (n ¼ 22, 1:10,000 concentration BVA plus PT), BV 2 group (n ¼ 23, 1:30,000 concentration BVA plus PT), and NS group (n ¼ 23, NS injection plus PT). The demographic data for the patients in the 3 groups are summarized in Table I. Chi-square test was performed on sex ratio, age, and disease duration to assess homogeneity of variance among the groups, and the result showed that there were no differences among the groups in demographic factors (P > .05).
Treatment procedure All patients were assessed at baseline, 2, 4, 8, and 12 weeks after initial treatment. Patients were removed from the study in cases of nonattendance to assessment visits, refusal to take further bee venom acupuncture, breaks in treatment for over 2 weeks, occurrence of difficulties in assessing treatment effect such as severe side effects after treatment, and expression of desire to withdrawal. All patients in three groups were given PT reported to be effective for frozen shoulder. PT was performed at each visit by one physical therapist with over 7 years of clinical experience. Fifteen minutes of transcutaneous electrical nerve stimulation (TENS 21; Homer Ion Laboratory Co., Ltd., Shibuya-Ku, Tokyo, Japan)19,20 and 15 minutes of transcutaneous infrared thermotherapy (TDP 100; ITC Co., Ltd., Daedeok-Gu, Daejeon, South Korea) were given 2 times a week, and manual physical therapy was given for 15 minutes once a week. During the first visit, a simple home exercise program leaflet was given out and patients were educated with the material. They were told to perform the home exercises 2 times daily until the
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Figure 1 Total enrolled patients were 192, and 124 patients were excluded according to the exclusion criteria. Allocated 68 patients were divided by 3 groups. completion of all 16 sessions, and a researcher checked their progress at each visit. The simple home exercise program was based on former studies.7,31,32 It comprised of 5 activities, which the patients were instructed to perform 1-2 hours daily. To check compliance, a record booklet was given out to patients. Patients in the BV 1 group and BV 2 group were intramuscularly injected with bee venom using a 1 cc syringe (Hwajin medical 30 gauge; Hwajin Medical Co.,Ltd., Seoul, Korea) at a depth of 0.5-1.0 cm. The bee venom used for this study was prepared in the Traditional Korean medical pharmacy in Kyung Hee University Hospital. Dried bee venom powder (Yoomil Garden, Hwasun, Korea) was diluted and prepared as follows: add 300 cc (1:30000) or 100 cc (1:10000) of saline (Joongwe Pharmaceuticals, Seoul, Korea) to 10 mg of dried bee venom powder, and dissolve thoroughly; filter using 0.22 mm filters and fill sterilized vials with 20 mL of preparation; seal with rubber lid, and cap with aluminum capping; store at 4 C. The preparation process took place in the injection preparation room, and empty vials were first sterilized and then filled due to protein denaturation concerns. Patients in the NS group were intramuscularly injected with saline (Choongwae Pharmaceuticals, Seoul, Korea) instead of bee venom. The target acupuncture points were sterilized with 70% alcohol before injection. Before the first BVA treatment, a skin reaction test was performed to all patients to check for any
possible hypersensitivity to bee venom. 0.05 ml of 1:30,000 concentration BVA was injected subcutaneously at LI 11 with a 1 cc syringe (Hwajin medical 30 gauge; Hwajin Medical Co.,Ltd.). Local redness and swelling were measured at the peak of response between 15 and 20 minutes after administration. Local swelling over 10 mm in diameter, or local redness over 20 mm in diameter, was considered a positive reaction. Patients who did not show positive reactions were included in this study. Following this, 0.1 ml of BVA or NS was injected at each acupuncture point. A total of 0.4 ml was injected at 4 points on the first visit, 0.6 ml at 6 points on the second, 0.8 ml at 8 points on the third, and 1.0 ml at 10 points throughout visits 4-16. The gradual increase of dose is for close observation of hypersensitivity, because, even though patients are safe after the skin reaction test, sudden high dose of bee venom treatment can cause an unexpected hypersensitivity. All patients were given treatments by the same acupuncture specialist with over 15 years of clinical experience. The injection volumes were based on the previous study.6 The acupuncture points were selected as: LI15 (located between the anterior end of lateral border of the acromion and the greater tubercle of the humerus); LI16 (located between the acromial end of the calvicle and the spine of the scapula); TE14 (located between the acromial angle and the greater tubercle of the humerus); GB21 (located at the midpoint of the line connecting the spinous process of the
4
P.S. Koh et al. Table I
Clinical characteristics of the BV 1, BV 2 and NS groups at baseline
Characteristics Age (years) Sex Male Female Lesion Right Left Duration (months) ROM Active abduction Active forward flexion Active extension Active external rotation Passive abduction Passive forward flexion Passive extension Passive external rotation Pain VAS usual Pain VAS nocturnal Pain VAS during exercises SPADI
BV 1 (n ¼ 22)
BV 2 (n ¼ 23)
54.95 6.79
56.18 6.70
NS (n ¼ 23) 55.13 7.01
Sum 54.35 7.21
6 (27.27) 16 (72.73)
8 (34.78) 15 (65.22)
6 (26.09) 17 (73.91)
20 (29.41) 48 (70.59)
9 (40.91) 13 (59.09) 6
8 (34.78) 15 (65.22) 5.24
9 (39.13) 14 (60.87) 6.65
26 (38.24) 42 (61.76) 5.96
96.18 122.91 35.91 34.95 114.59 135.91 46.82 41.59 6.59 6.66 7.39 62.55
32.17 27.11 9.73 12.12 33.27 24.23 11.52 11.57 1.76 2.04 1.38 11.50
91.74 114.43 39.09 37.00 112.17 130.26 49.26 44.22 6.78 6.80 7.28 58.81
26.07 22.33 11.12 12.23 23.44 19.82 10.37 11.20 1.76 1.76 1.40 13.97
84.35.33.44 110.26 27.01 35.30 9.49 38.04 15.60 108.04 30.80 129.00 24.16 45.61 9.75 41.91 12.95 6.94 1.55 6.91 1.87 7.33 1.24 66.10 12.71
BV 1, 1:10,000 concentration BVA + PT group; BV 2, 1:30,000 concentration BVA + PT group; NS, normal saline injection + PT group; ROM, range of motion; VAS, visual analogue scale; SPADI, Shoulder and Pain Disability Index. Values are the mean SD.
seventh cervical vertebra (C7) with the lateral end of the acromion); SI11 (located between the upper one third and lower two thirds of the line connecting the midpoint of the spine of the scapula with the inferior angle of the scapula); and additionally 5 points around the shoulder.37
Sample size and blinding There was no randomized clinical comparison study on the effectiveness of BVA compared to PT in the treatment of AC. However, a similar previous study showed that the control group had a 37.9 improvement of shoulder pain and disability index (SPADI) after 3 months with a standard deviation of 15.1 Under the assumption that 1) the a value of the 2-tailed test is 0.05 with 80% power, 2) the test group will show 35% more improvement compared to the control, and 3) the standard deviations of the test group and the control group are the same, the number of patients needed for each group would be 19. An additional assumption of a 15 % drop-out rate raised the required number of patients to 22 for each group. The researcher delivering treatment can distinguish between treatment groups and control group based on local reactions of BVA, so this study was designed as a patient-outcome assessor blinded study. The researcher delivering treatment minimized all unnecessary conversation with patients. The assessor determined patient inclusion, obtained informed consent, assigned serial numbers to patients, organized schedules, and took care of medical consultations. The assessor was blinded to treatment, and questions were restricted to those filling out case record sheets. Data assessment was performed by an independent statistician.
Patients were informed that they had the same chance of random distribution (33%) into either of the 2 test groups or the control group. The patients were prohibited from speaking with other patients, and were all given treatment in an ordinary oriental medical clinic or hospital by the same physician using identical syringes. Blinding validity was assessed by credibility testing after treatment completion.
Outcome assessments The primary outcome measure was the Shoulder Pain and Disability Index (SPADI), a tool used for QOL assessment consisting of 13 items divided into 2 subscales, 5 items about pain and 8 items about disability.23 Items are checked on a 10-point Likert scale (0 means ‘no pain’ or ‘no difficulty’, 9 means ‘worst imaginable pain’ or ‘so difficult it required help’). A SPADI score is calculated out of 100 (higher score means more pain/disability). A pain visual analogue scale (VAS) was used as a secondary outcome measure and marked in 3 conditions, namely ‘VAS at rest,’ ‘VAS at night,’ and ‘VAS during motion.’ ‘‘A painless state’’ was recorded as 0, and ‘‘the most excruciating pain imaginable’’ was recorded as 10. The other secondary outcome measures were active and passive range of motions (ROMs) in 4 motions. The 4 motions were abduction (range, 0 -180 ), forward flexion (range, 0 -180 ), extension (range, 0 -75 ), and external rotation (range, 0 -90 , arm by side). The 4 motions were measured using the BTE primus (BTE technology, USA, 2006). The BTE primus is able to assess joint motion range accurately and has been shown to have high test-retest reliability (R ¼ .97) and validity (R ¼ .96).26
Synergistic effect of acupuncture on physiotherapy Table II
5
Mean changes in scores of SPADI and VAS among groups at baseline, 2, 4, 8 and 12 weeks 2 weeks
4 weeks
8 weeks
12 weeks
P)
11.50 13.97 12.71
48.46 12.21 48.98 14.53 57.46 14.19 0.052
40.98 13.05 42.26 15.08 47.81 16.42 0.269
23.15 12.82a 28.08 18.59ab 37.44 19.84b 0.025z
15.42 12.63a 20.30 16.78ab 30.21 20.94b 0.017z
<.01 <.01 <.01
1.76 1.76 1.55
5.25 1.76 5.74 1.94 6.24 1.35 0.156
4.48 1.72 4.65 21.92 5.33 1.63 0.238
2.66 1.69a 3.28 2.14ab 4.15 2.12b 0.048z
2.07 1.83 2.37 1.90 3.28 2.22 0.110
<.01 <.01 <.01
2.04 1.76 1.87
5.59 2.17 5.57 1.59 6.15 1.77 0.485
4.66 2.17 4.61 1.64 5.33 1.82 0.363
2.82 2.15 2.85 1.77 3.89 2.40 0.159
2.07 2.12 2.02 1.65 3.06 2.33 0.160
<.01 <.01 <.01
1.38 1.40 1.24
5.80 1.68 6.26 1.42 6.76 1.20 0.089
4.98 1.85 5.09 1.50 5.80 1.64 0.201
3.09 1.80 3.33 1.79 4.33 2.24 0.086
2.21 21.88a 2.41 1.67ab 3.65 2.20b 0.029z
<.01 <.01 <.01
Baseline SPADI BV 1 62.55 BV 2 58.81 NS 66.10 Py VAS (at rest) BV 1 6.59 BV 2 6.78 NS 6.94 Py VAS (at night) BV 1 6.66 BV 2 6.80 NS 6.91 Py VAS (motion) BV 1 7.39 BV 2 7.28 NS 7.33 Py
BV 1, 1:10,000 concentration BVA + physiotherapy (PT) group; BV 2, 1:30,000 concentration BVA + PT group; NS, normal saline injection + PT group; VAS, visual analogue scale; SPADI ¼ Shoulder and Pain Disability Index. Values are the mean SD. ) Differences within groups by using Repeated Measures analysis of variance (ANOVA) (there were no interactions between treatment and time). y Differences among groups by using one way ANOVA. Tukey’s HSD test was performed if the results showed statistically significant differences, and showed as zP < .05.
To improve assessment quality, a single medical doctor with 4 years of clinical experience assessed all patients and underwent 10 education sessions (1-hour per each session) on clinical trials. All measurements were repeated and the means were presented.
calculated and the lack of statistically significant differences (ANOVA, P > .05) showed homogeneity of variance among the 3 groups (Table I).
Statistical analysis
Effectiveness in SPADI and VAS
Statistical analysis was performed using SPSS 12.0 for windows (SPSS, Chicago, IL, USA), and homogeneity of variance was tested by 1-way ANOVA and Chi square (c2) test. Repeated measures ANOVA were performed to compare the SPADI, VAS, active/passive ROM at 2, 4, 8, and 12 weeks after initial treatment. One-way ANOVA was used to compare the differences among the groups and Tukey’s HSD testing was used for post hoc comparison. Credibility testing was performed to check blinding validity and Chi square test was used for result assessment. P < .05 was regarded as statistically significant. The statistical analyses were performed on an intention-to-treat basis. Data from drop-out patients were processed with the last observation carried forward (LOCF) method, and the last known values were used under the assumption that no further improvement will occur.
In the SPADI scores as a primary outcome assessment, all 3 groups showed significant improvements as treatment sessions progressed from 2 to 12 weeks after treatment initiation. The 1:10,000 concentration BVA plus PT group (BV 1 group) showed significantly better improvements compared to the normal saline plus PT group (NS group) at 8th and 12th weeks after treatment initiation (Tukey’s HSD, P ¼ .025, P ¼ .014, respectively). However, there were no significant differences between the BV 1 and BV 2 groups. Thus the results of the SPADI index suggest that BVA treatment did not proceed in a dose-dependent manner (Table II, Fig. 2). In the VAS scores as a secondary outcome assessment, all 3 groups also showed significant improvements over time in the VAS at rest, VAS at night, and VAS during motion scores. Compared to the NS group, the BV 1 group showed statistically better effectiveness in the VAS at rest score at 8th week and in the VAS during motion score at 12th week, but not in the VAS at night score. There were no differences between the BV 1 and BV 2 groups in the VAS scores. Furthermore, BVA treatment was not effective in a dose-dependent manner shown by the VAS scores (Table II, Fig. 2).
Results Before treatment initiation, the SPADI, VAS (during rest, at night, and during motion) and active/passive ROM (abduction, forward flexion, extension, and external rotation) were measured. The mean SD of these data were
6
P.S. Koh et al. BV 1 (n=22) BV 2 (n=23) NS (n=23)
100 80
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VAS (at night)
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8 6 4 2
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Figure 2
Mean changes in SPADI and VAS for the bee venom acupuncture (BVA) and placebo groups at baseline, 2, 4, 8, and 12 weeks. , 1:10,000 concentration BVA þ PT (physiotherapy) group; , 1:30,000 concentration BVA þ PT group; , normal saline(control) þ PT group; *, significant effectiveness of BV1 group compare to control group.
Effectiveness in active and passive ROM In the secondary outcome assessments of active and passive ROM (abduction, forward flexion, extension, and external rotation), all 3 groups showed significant effectiveness as treatment sessions progressed 2-12 weeks after treatment initiation (P < .01). After the end of the 8-week treatment, all the groups significantly improved the ROM of all planes for at least more 4 weeks up to the 12th week from treatment initiation; however, there were no significant differences among the groups in all ROMs. Even though the BVA plus PT groups had a tendency to show more improvements than the PT only group, statistically significant differences were not found. Furthermore, the BV 1 group (1:10,000 concentration BVA plus PT group) did not show significantly better improvements than the BV 2 group (1:30,000 concentration BVA plus PT group). However, the degree of ROM improvements in the BV 1 group was higher than those of the BV 2 group (Table III, Fig. 3).
Credibility assessment and side effect After trial completion, 68 patients who finished the study were tested for blinding validity. Among the 45 patients in group BV 1 and BV 2 who received BVA, 25 thought they received bee venom injections, 5 thought they received normal saline injections, and 15 were unclear. Among the patients in group NS, 6 thought they received bee venom injections, 6 thought they received normal saline injections, and 8 were unclear. Chi square independence testing showed
there was no statistical difference between the bee venom groups and the normal saline control group (P ¼ .073), and thus the present blinding could be regarded as acceptable. In the present study, among the 45 patients who received bee venom treatment, 30 experienced slight pruritus, local swelling, and/or redness (under 20 mm in diameter), which were Mueller Grade 0. One subject from group BV 1 displayed mild, generalized swelling and aching which were classified as Mueller Grade 1 reactions, and 3 among 23 patients from group NS showed slight redness and pruritus. No subject showed severe reactions over Mueller Grade 2.16
Discussion Adhesive capsulitis (AC) is a disease of uncertain etiology characterized by shoulder joint pain and progressive limitation of both active and passive motion in the affected shoulder.17,18,34 The causes are very diverse, and the exact cause, main pathology and mechanisms are still unclear.15 However, rotator cuff tendinitis, bicipital tenosynovitis, muscular imbalance, and reflexive sympathetic dystrophy etc. are reported as possible causes of secondary AC disorder.33 It is reported that up to 40% of patients with AC suffer from remaining symptoms and stiffness for over 3 years,29 and 15% of patients have long-term disabilities such as muscle weakness from disuse, limitation of ROM and low quality of life (QOL).11 In this background, the aim of our study was to reveal the effectiveness of combination of BVA and several types of physiotherapy on reducing the
Synergistic effect of acupuncture on physiotherapy Table III
7
Mean changes in active/passive range of motion among groups at baseline, 2, 4, 8 and 12 weeks 2 weeks
4 weeks
8 weeks
12 weeks
P)
32.17 26.07 33.44
120.09 36.14 111.17 24.82 101.17 34.67 >0.05
134.73 39.65 122.52 25.56 119.48 40.34 >0.05
155.73 18.71 139.83 28.68 137.00 38.24 >0.05
162.55 16.47 146.83 28.76 146.78 29.12 >0.05
<.01 <.01 <.01
27.11 22.33 27.01
141.73 24.28 134.57 19.72 126.17 31.35 >0.05
146.86 25.89 140.87 14.70 135.00 31.12 >0.05
159.50 17.57 153.78 18.69 148.17 28.53 >0.05
164.86 15.01 155.13 20.34 154.30 24.21 >0.05
<.01 <.01 <.01
9.73 11.12 9.49
45.55 12.24 46.04 12.83 42.35 10.62 >0.05
48.36 10.27 43.61 9.61 46.91 12.55 >0.05
54.05 13.62 50.43 12.52 48.65 12.68 >0.05
58.50 9.97 53.39 14.97 54.91 14.09 >0.05
<.01 <.01 <.01
12.12 12.23 15.60
42.55 13.90 41.17 10.29 42.22 20.03 >0.05
41.27 11.21 42.48 11.64 41.87 13.91 >0.05
47.00 11.86 49.13 12.32 45.78 13.92 >0.05
50.14 11.67 47.22 13.17 45.91 14.22 >0.05
<.01 <.01 <.01
33.28 23.44 30.80
142.23 30.09 143.35 22.46 125.78 35.32 >0.05
150.59 23.27 146.43 19.84 137.26 33.89 >0.05
165.05 14.02 160.78 18.90 149.87 28.12 >0.05
169.23 10.21 163.57 16.21 158.17 20.07 >0.05
<.01 <.01 <.01
33.28 19.82 24.13
153.95 20.09 152.13 17.98 145.22 23.16 >0.05
156.82 21.27 155.09 16.64 149.39 26.41 >0.05
166.00 13.78 161.57 17.35 157.70 24.01 >0.05
170.73 9.00 163.39 15.49 163.65 15.15 >0.05
<.01 <.01 <.01
11.52 10.37 9.75
58.68 12.89 57.87 11.26 53.22 11.93 >0.05
61.41 10.49 56.30 9.87 59.00 13.46 >0.05
66.50 11.68 64.65 10.66 59.91 13.18 >0.05
72.14 7.09 64.57 13.55 63.74 14.48 >0.05
<.05 <.05 <.05
11.57 11.21 12.95
49.41 13.64 53.26 12.37 43.78 13.69 >0.05
49.73 12.97 53.91 10.75 50.65 14.15 >0.05
57.23 11.91 58.09 12.21 55.57 15.26 >0.05
61.77 11.74 57.70 13.97 54.00 15.57 >0.05
<.05 <.05 <.05
Baseline Active Abduction BV 1 96.18 BV 2 91.74 NS 84.35 Py Forward flexion BV 1 122.91 BV 2 114.43 NS 110.26 Py Extension BV 1 35.91 BV 2 39.09 NS 35.30 Py External rotation BV 1 34.95 BV 2 37.00 NS 38.04 Py Passive Abduction BV 1 114.59 BV 2 112.17 NS 108.04 Py Forward flexion BV 1 135.91 BV 2 130.26 NS 129.00 Py Extension BV 1 46.82 BV 2 49.26 NS 45.61 Py External rotation BV 1 41.59 BV 2 44.22 NS 41.91 Py
BV 1, 1:10,000 concentration BVA + physiotherapy (PT) group; BV 2, 1:30,000 concentration BVA + PT group; NS, normal saline injection + PT group. Values are the mean SD. ) Differences within groups by using Repeated Measures ANOVA. y Differences among groups by using one way ANOVA.
long-term disabilities, with a special focus in the limitation of range of motion (LOM), QOL and pain. In relation to AC treatment, it has shown that a combination of supervised physiotherapy and intra-articular corticosteroids were more effective than supervised physiotherapy alone for improving pain, function, and ROM in patients with AC.3 Among several types of PT, it was reported that end-range mobilization (ERM) and Mobilization with movement (MWM) were more effective than mid-range
mobilization (MRM) in increasing mobility and functional ability.5,14,25,38 In accordance with this finding, PT of our study was composed of ERM and MWM manual techniques, TENS, TDP and a simple home exercise program. In our study, BVA was treated as a combination treatment of PT to induce synergistic effectiveness in the treatment of AC. BVA, as one of the several acupuncture types, has been used in the oriental medical field to relieve pain and to treat chronic inflammatory diseases like rheumatoid arthritis,8,30
P.S. Koh et al. 180
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70
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Figure 3 weeks.
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Mean changes in active and passive ROM for the bee venom acupuncture (BVA) and placebo groups at baseline, 2, 4, 8 and 12 , 1:10,000 concentration BVA þ PT (physiotherapy) group; , 1:30,000 concentration BVA þ PT group; , normal saline(control) þ PT group.
along with studies on the safety and efficacy of BV.4,6 Clinically, combination treatment of BVA and PT has been explosively used in our arthritis center, but there has been a lack of evidence from randomized controlled trials (RCT). In this aspect, we designed a RCT to examine whether the addition of BVA to PT would be more effective than PT alone in the management of AC, and to determine an appropriate concentration of BVA. Another reason for this
study would be to make an observation for a future largescale randomized controlled trial. All three groups showed statistically significant improvements in SPADI scores, pain VAS, and active/passive ROM. This indicates that combinations of BVA and physiotherapy, and normal saline and physiotherapy were all effective in AC patients. The primary outcome measurement, SPADI, showed significantly better improvements in group
Synergistic effect of acupuncture on physiotherapy BV 1 compared to group NS at the 8th and 12th weeks after treatment initiation. SPADI improvements of over 10 % are clinically meaningful3 and the results of this study showed a 15 % difference between the 2 groups. Group BV 1 also showed significant improvements compared to group NS in VAS (at rest) at 8th week after treatment initiation and in VAS (during motion) at 12th week. In active and passive ROM, significant differences were not found among the groups. These results are in line with the previous study in which acupuncture did not induce statistically meaningful ROM improvements but did improve pain and quality of life, and reached a conclusion that acupuncture and physiotherapy should be used in conjunction in AC treatment. Another reason for the improvements would be that in our study, 4 types of PT were applied (manual techniques, TENS, TDP, and simple home exercise program); the effectiveness of PT alone would therefore be very powerful especially in terms of ROM improvement. In this study, the effectiveness of the 2-month treatments in 3 groups were significantly elevated for 3 months. One study revealed that no long-term differences were found in patients treated with both physiotherapy and corticosteroids, either physiotherapy or corticosteroids, or normal saline after 12 months; but at 3 months, statistically different recovery was induced.3 Another study reported that electro acupuncture produced significantly greater reduction in pain intensity than did placebo acupuncture even at the 6-month followup.10 In order to clarify the long-term effects, we are scheduled to follow our patients up to 1 year. Our results showed no statistically significant differences between the 1:10,000 and 1:30,000 BV concentration groups. Of course, group BV 1 generally showed better improvements compared to those of group BV 2; however, these results were not statistically significant, and it cannot be concluded that these effects are dose-dependent. This may partly be due to the small difference in concentration, as there is only a 3-fold difference between the 2 groups. This study does not have any relevant previous researches, and results cannot be accepted as a generalized fact. Randomized controlled trials with BV should be performed on the basis of the present study, in order to make conclusions on dosedependent effects and/or optimum concentration. The present study applied physiotherapy to all 3 groups. Physiotherapy was used with research evidence, and was employed to address the ethical issue arising from the disparity in treatment effects that may arise when the control group is only given normal saline injections for 2 months and no treatment for an additional month. Furthermore, this study followed strict inclusion criteria, and an orthopedist was involved in the inclusion process for objectivity. Recent conventional medical research has shown that the precision of corticosteroid injections is related to clinical outcome, and thus a specialist clinician with over 15 years of experience was chosen to inject the bee venom preparation or normal saline.9,12 This researcher in charge of treatment performed all injections (16 sessions
9 per patient, 16 68 times in 68 patients throughout the 11-month period). Moreover, 1 physical therapist handled all physiotherapy, as having multiple physical therapists could result in treatment differences. These were done in an attempt to improve research reliability. The limitations of the present study include the small number of patients. It is difficult to find enough patients who fit all the criteria during the 11-month study period, as Carette et al have also noted.3 The small sample size could result in flawed results. Furthermore, the lack of former similarly designed researches on AC make it difficult to accept the present results as a generalized fact. The present practice of BVA relies mainly on the clinician’s experience to adjust the concentration of the acupuncture preparation; a standardized guideline is therefore needed. Moreover, further study is needed to compare the effectiveness between BV and intraarticular corticosteroids.
Conclusion BVA combined with physiotherapy may have better clinical effectiveness in functional improvement and pain reduction than physiotherapy alone on adhesive capsulitis patients. Even though the 1:10,000 concentration bee venom acupuncture showed generally better effects compared to the 1:30,000 concentration, there was no statistical difference. Further trials are needed to confirm this.
Acknowledgment The authors thank Jung Woo Lee for his assistance with data collection.
Disclaimer The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.
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