Chinese medicine packet plus wax therapy for periarthritis of the shoulder: study protocol for a multi-center, randomized controlled trial

Ye Wang＊

Rehabilitation Center, the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province,China

Background

Periarthritis of the shoulder is a chronic degenerative disease involving a variety of soft tissues around the shoulder joint,and is characterized by diffuse shoulder pain and movement disorder (China Association of Chinese Medicine, 2013).Its incidence rate is 3–5% (Manske and Prohaska, 2008).Periarthritis of the shoulder is an aseptic in flammation (Ji et al., 2015), and presents with congestion, edema, in flammatory exudate, tissue thickening, muscle spasms in the early stages, and then bone tissue atrophy, adhesions and spasms of the joint capsule and synovial bursa as well as limited motion because of long-term joint disuse and reduced local metabolism (Neviaser, 1980; Lee et al., 2003; Neviaser and Neviaser, 2011; Yoon et al., 2015). Degenerative changes in the shoulder joint and surrounding muscles often cause shoulder pain. Consequently, patients are unwilling to perform activities, and over time they suffer from muscle stiffness (Buchbinder et al., 2004; Neviaser and Neviaser,2011). Although there is a tendency for self-healing, it is often unsatisfactory in patients with periarthritis of the shoulder (Reeves, 1975; Rizk and Pinals, 1982; Shaffer et al., 1992). Therefore, it is necessary to develop a therapeutic method to promote the full recovery of shoulder function and reduce sequelae in patients with periarthritis of the shoulder.

The theory of Traditional Chinese Medicine (TCM)states that periarthritis of the shoulder is caused by chronic strain and wind-cold-dampness, and has three types: windcold-dampness, stasis and de ficiency of qi and blood (Li et al., 2014). Damage to the meridians of the shoulder cause stagnancy of qi and blood stasis, which is a morbid condition manifested as severe localized pain and formation of mass or slough. Therefore, an appropriate therapy is to promote blood circulation by removing blood stasis and activating collaterals at relieve pain. Unfortunately,simple closure, massageor acupuncture cannot effectively relieve adhesions and contractures of the joint capsule and synovial bursa (Huang, 2004; Ma et al., 2005; Xiong and Wei, 2009; Xia, 2012). The Chinese medicine packet is a hop-pocket containing Chinese herbs that activate meridians to stop pain, promote blood circulation by removing blood stasis, warm meridians to promote blood circulation,dispel cold and relieve arthralgia, which can be heated and placed directly on the affected area to improve local blood circulation, accelerate absorption of in flammatory exudates, increase local nutrition, and relieve muscle atrophy(Gu and Guo, 2012; Huang et al., 2013). Wax therapy is a therapeutic method using paraf fin wax as the raw material.Because of its high thermal capacity, low thermal conductivity and long cooling time, paraf fin wax is a good medium for hyperthermia conduction when in close contact with the body. Clinically, wax therapy is commonly used in the treatment of wind-cold-dampness-induced pain (Dong et al.,2009; Meng et al., 2010; Zhou et al., 2012). When paraf fin wax is heated and externally applied to an affected area, it heats local tissues, dilates blood vessels, promotes blood circulation and increases cell permeability. Because of the long duration of heat therapy, it has deep edema dissipation,anti-in flammation and analgesia effects (Dong et al., 2009;Meng et al., 2010; Zhou et al., 2012).

We will develop a new Chinese medicine therapy for periarthritis of the shoulder by combining Chinese medicine packets and wax therapy. This combined therapy will be tested to determine whether it can reduce pain-inducing factors, eliminate in flammation and delay joint aging.The study will be a multi-center randomized double-blind placebo-controlled trial to evaluate quantitatively the safety and effectiveness of Chinese medicine wax therapy for periarthritis of the shoulder.

Methods/design

Study design

This is a prospective, multi-center, randomized, doubleblind, placebo-controlled trial (Figure 1).

Study setting

This study will be conducted at the Second Af filiated Hospital of Heilongjiang University of Chinese Medicine,China; Chinese Medicine Hospital of Fuxin City, China;Orthopedics Hospital of Haicheng City, China; and Af filiated Hospital of Liaoning University of TCM, China.

Ethical review and informed consent

The study protocol follows the Declaration of Helsinki and has been approved by the Ethics Committee of the Af filiated Hospital of Liaoning University of TCM, China (approval No. 2014ZX(KT)-010-02). Any study modi fication will be approved by the Ethics Committee of the Af filiated Hospital of Liaoning University of TCM, China. Investigators or investigator-authorized of ficers will be responsible for explaining the objective, content, study procedures, bene fits and risks of participating in the clinical trial to each patient or the patient's legal representative. Written informed consent will be obtained from all patients before the trial.

Study participants

Recruitment of patients with periarthritis of the shoulder is ongoing according to the principle of voluntary participation, through television, radio, newspapers, community and hospital outlets.

Inclusion criteria

● In accordance with the Western diagnostic criteria for periarthritis of the shoulder (Hanchard et al., 2011,2012; Lewis, 2015)

●Wind-cold-dampness type (State Administration of TCM of China, 1994)

● Aged 40–70 years

● Either gender

● Written informed consent to undergo the therapeutic regimen

● Approval by the Ethics Committee of the Af filiated Hospital of Liaoning University of TCM

Exclusion criteria

● Ages ＜ 40 years or ＞ 70 years

Figure 1: Flowchart of the trial protocol.

● Acute soft tissue injuries, fractures, or dislocation of shoulder

● Cervical spondylosis, rheumatoid arthritis or gout

● Patients with complications including severe heart failure; severe primary diseases of the lung, liver, kidney,hematopoietic system and endocrine system; cancer;gastrointestinal bleeding; stomach ulcers; bleeding tendencies

● Patients with neuropathy, mental illness, illiteracy or poor compliance who cannot complete the questionnaire in the screening process

● Lactating and pregnant women or women who are preparing to conceive

● Patients who cannot take medicine as directed, and have poor compliance

● Allergic constitution

● Patients who are participating or have participated in other clinical trials within 1 month before the present trial

● Pain caused by cancer or infections

● Dislocation, fractures, osteomyelitis, tuberculosis,cancer and severe osteoporosis reveled by X-ray examination

Withdrawal criteria

The patients in this study may be discontinued if one of the following occurs:

● Dissatisfaction with the therapy

● Intolerance to adverse reactions

● Allergic reactions or serious adverse events

● Symptoms aggravated (the subjects need to take other drugs or other therapeutic options)

● Presence of complications or special physiological changes that will disturb the judgement of therapeutic ef ficacy and safety

● Non-compliance

● On the request of a regulatory agency

Randomization

Random allocation sequences for each patient will be generated by SAS 9.0 software that will be input into the central stochastic system of the Clinical Assessment Center, China Academy of Chinese Medicine Sciences,China. A study secretary who cannot directly participate in the clinical trial is responsible for screening patients who have provided written informed consent and applies for random numbers online or by telephone. Patients will be equally randomized into test and control groups. The patients will be treated strictly in accordance with the randomized numbers.

Treatment

Treatmeat group: Ramulus Mori (30 g), frankincense (15 g), myrrh (15 g), Ramulus cinnamomi (30 g), Natrii Sulfas(10 g), Radix Achyranthis Bidentatae (20 g), Flos Carthami(30 g), Herba Lycopodii (30 g), Caulis Impatientis (30 g),Cortex Erythrinae (20 g), Rhizoma Corydalis (30 g), Radix Angelicae Dahuricae (30 g), Radix Saposhnikoviae (20 g) and Radix Clematdis (30 g), provided by the Af filiated Hospital of Liaoning University of TCM, China, will be ground, soaked in water for 30 minutes, and boiled for 15 minutes to separate the decoction. The above-mentioned procedures will be repeated three times. Decoctions are separated, merged, concentrated and heated to 45–55°C. A gauze packet is then immersed in the prepared decoction for 10–20 minutes. These procedures will be completed at the Drug Manufacturing Room of the Af filiated Hospital of Liaoning University of TCM, China. The prepared Chinese medicine packet will be placed onto the shoulder joint followed by a warm paraf fin cake (2–4 cm × 20 cm × 30 cm, 45–55°C) as a hot compress, fixed with a cotton pad,once a day for 20 minutes, totally for 4 weeks.

Control group: Chinese medicine packets will be replaced by Chinese medicine placebo containing food coloring and essence (provided by the Drug Manufacturing Room of the Af filiated Hospital of Liaoning University of TCM). All other procedures will be identical to the test group.

Blinding and unblinding

Both researchers and subjects will be unaware of the grouping. Subjects will be issued with the drugs in accordance with the order number by a drug manager, who is blinded to the randomization information. Data collection and data analysis will be conducted blindly.

The drugs are packaged as required by a drug provider.Drug numbering will be completed by an independent statistical institute, and then sent to different test centers.The remaining drugs will be recovered uniformly at the end of the test. Drug number and emergency unblinding rules will be printed on the group assignment envelope,which will be opaque. If the envelope is opened in an emergency, the opening person, date and reasons for the emergency break will be recorded in the medical record.The envelope contains the subject’s medication information, setting and address. The group assignment envelope will be sent to different centers and recovered at the end of the test. All drug encoding processes including the blind record will be written into a file and saved as a clinical trial document. All blinding codes, initial random numbers,and block length will be sealed and saved in duplicate at the Scienti fic Research Of fice, the Af filiated Hospital of Liaoning University of TCM and the statistical institution.During the trial, the blinding codes cannot be exposed. If the blinding codes are revealed to impact the test objectivity,the trial will be regarded as invalid. The drug manager will administer the treatment strictly according to the visiting sequence and drug numbering, and the drug number will remain unchanged throughout the testing process.

Random allocation sequences will be stored in the central stochastic system of the Clinical Assessment Center, China Academy of Chinese Medicine Sciences, and revealed at the end of the trial. If severe adverse events occur, which are con firmed to be related to the therapeutic measures by experts in the research institute, the emergency break will be carried out.

Outcome measures

Outcome measures will be assessed at baseline and 1, 2,and 4 weeks after treatment.

Primary outcomes

● McGill pain questionnaire score (Melzack and Torgerson, 1971)

Secondary outcomes

● Shoulder disability questionnaire (van der Heijden et al., 2000)

● Oxford shoulder score (Dawson et al., 1996)

● American Shoulder and Elbow Surgeons (ASES) score(Richards et al., 1994)

● University of California, Los Angeles (UCLA) shoulder score (Amstutz et al., 1981)

● TCM syndromes (including clinical symptoms, signs,tongue, pulse) evaluated using the nimodipine scoring formula with reference to the Clinical Guidelines for New Chinese Herbs, formulated by the Stat Administration of TCM, China (Zheng, 2002) and patient conditions

● Visual analog scale score (Huskisson, 1982)

● Constant-Murley shoulder score (Harvie et al., 2005)

The outcome assessment is shown in Table 1.

Table 1: Outcome assessment schedule

Data management

The clinical observation schedule will be completed by the clinical researchers to ensure that the data are accurate,complete, timely, and the original records will be preserved.To ensure real and effective data, the subjects will be asked to specify the date of completion and the time spent to complete a table. A basic questionnaire will be surveyed within 14 days prior to treatment and enrollment information will be completed within the speci fied date ± 2 days.A data administrator from the statistical institute will be responsible for data entry and management. To ensure the accuracy of the data, two independent data administrators will be in charge of data inputting and proofreading. If there is doubt about the case report form, the data administrators will provide a question table for the researchers. The researchers should answer as soon as possible and return the table. The data administrators can modify, af firm and input the data according to the answers from the researchers. If necessary, the question table will be issued again. At the end of the trial, the established database will be reviewed by the clinical researchers, data administrators and statisticians. After the database is con firmed successfully by blind review, the database will be locked by the major researchers and statisticians, and cannot be modi fied further.

Sample size calculation

This study is a trial to explore optimal superiority. A onesided test will be performed, and the number of patients in the two groups will be the same. The effective rates of Chinese medicine packet + wax therapy (t) and Chinese medicine placebo + wax therapy (r) are 0.75 and 0.5,respectively. Therefore, the following parameters will be set: Uα = 1.645 (α = 0.05), Uβ = 0.84 (β = 0.2), P = (0.75+ 0.5) ÷ 2 = 0.75, Δ = 0.1, N = 2 × (Uα + Uβ) 2 × P (1–P)÷ (Pt – Pr–Δ) 2, N = 128.6505 ≈ 130. U is clinical point value; α is the probability of type I error; β is the probability of type II error; P is the combined ef ficiency; Δ is the minimum difference with clinical signi ficance; N is sample size. There will be 130 cases in the test group and 130 in the control group; therefore, Nr = Nt = 130 (260 in total).Considering loss during the trial (a failure rate of ＜ 15% is allowed), 160 eligible cases of periarthritis of the shoulder in each group will be enrolled. The number of collected cases in different centers is listed in Table 2.

Table 2: Case collection in different centers

Statistical analysis

All data will be statistically analyzed using SAS 9.0 statistical software by the study statistician. The ef ficacy to treat TCM syndromes will be presented by the case number and percentage, and other data will be expresed by the mean ±SD. Differences at different time points will be analyzed by Radit analysis. Proportionality of baseline data will be analyzed by Fisher’s test. Intergroup measurement data will be compared using the homogeneity test of variance. If the data in the two groups are of normal distribution and show homogeneity of variance, a t-test will be performed. If the data are not normally distributed, a rank sum test will be performed. A value of P ＜ 0.05 is considered statistically signi ficant.

Safety

Any adverse events reported by patients or detected by physical examination and laboratory tests will be recorded on the case report forms and followed up appropriately. If there are abnormalities by laboratory inspection, the abnormal parameters will be measured at least once a week until they return to normal. To ensure the safety of subjects,necessary measures will be taken immediately when any severe adverse events are reported. In addition, the severe adverse events will be reported to the Ethics Committee,the Af filiated Hospital of Liaoning University of TCM within 24 hours.

DISCUSSION

Although periarthritis of the shoulder can sometimes heal itself between 6 months and 2 years, pain and inconvenience seriously affect patients’ quality of life (Reeves, 1975; Neviaser, 1980; Rizk and Pinals, 1982; Shaffer et al., 1992; Lee et al., 2003; Neviaser and Neviaser, 2011; Yoon et al., 2015). To date, numerous therapies have been reported for the treatment of periarthritis of the shoulder, but there is still no effective therapy with obvious advantages. It is important to develop a safe, highly ef ficient, and cost-effective therapeutic method with few side effects, to alleviate the suffering of patients and shorten the course of disability (Huang, 2004; Ma et al.,2005; Xiong and Wei, 2009; Xia, 2012). For periarthritis of the shoulder, nonsurgical treatment is preferred with a treatment principle of local analgesia, functional training,and functional recovery of the shoulder joint. In this multicenter, randomized, double-blind controlled trial, Chinese medicine placebo consisting of food coloring and essence will be used as a control. If the Chinese medicine packet plus wax therapy relieves the symptoms of periarthritis of the shoulder, this trial will provide experimental evidence to establish therapeutic guidelines and technical standards for Chinese medicine packet plus wax therapy for the treatment of periarthritis of the shoulder.

Trial status

Recruiting is ongoing at submission.

Conflicts of interest

None declared.

Author contributions

YW conceived and designed the trial procedure, wrote the paper, read and approved the final version of the paper for publication.

Plagiarism check

This paper was screened twice using CrossCheck to verify originality before publication.

Peer review

This paper was double-blinded and stringently reviewed by international expert reviewers.

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