Bee venom acupuncture, NSAIDs or combined treatment for chronic neck pain: study protocol for a randomized, assessor-blind trial

This is a randomized, assessor-blind clinical trial with three parallel arms (1:1:1 ratio) conducted at the spine center at Kyung Hee University Hospital at Gangdong (KHUHGD). We will compare the effects of BVA, NSAIDs and the combined treatment of BVA and NSAIDs in patients with CNP. The trial has been registered with the United States (US) National Institutes of Health Clinical Trials registry (NCT01922466) and has been approved by the Institutional Review Board (IRB) of KHUHGD (KHNMC-OH-IRB 2012–019). Outcome assessment and statistical analyses will be performed by independent researchers who are blinded to the patient assignment (Figure 1).

Sixty participants with non-specific neck pain will be recruited to the study from KHUHGD through advertisements in local newspapers, on hospital websites and on bulletin boards. All participants will be interviewed by telephone and scheduled for a screening visit by the clinical research coordinator (CRC). After completing the screening questions, participants will be guided through the informed consent process. Participants will be informed that they may be randomly allocated into any of the three treatment groups (BVA, NSAIDs and combined treatment), and that they may withdraw their voluntary participation at any stage. Patients will be provided enough time to deliberate their participation in the independent waiting room with the written information and the informed consent form. As a screening process for eligibility, a skin hypersensitivity test will be performed on each patient at LI11 acupoints, using a subcutaneous injection of 0.05 ml of a 1:20,000 bee venom preparation. Local swelling greater than 10 mm in diameter or redness greater than 20 mm in diameter will be considered a positive reaction, and these patients will be excluded from the study. Eligible participants will be randomly allocated into one of three parallel groups at a ratio of 1:1:1, (BVA:NSAIDs:combined treatment). After random allocation, the interviewer (CRC) will schedule treatment sessions. All recruitment procedures will be recorded in a log file.

Patients between 18 and 65 years of age who can read and write in Korean, who agree to participate after providing written informed consent, and who have been experiencing non-specific, uncomplicated neck pain for at least three months preceding the time of the screening visit will be selected as study volunteers.

Patients will be excluded from the study if they have: 1) exhibited abnormalities on neurological examination (such as cervical nerve function, deep tendon reflexes, voluntary muscle activation and sensory function); 2) radicular pain; 3) serious spinal disorders including malignancy, vertebral fracture, spinal infection or inflammatory spondylitis; 4) other chronic diseases that could affect or interfere with the therapeutic outcomes including cardiovascular disease, diabetic neuropathy, active hepatitis, fibromyalgia, rheumatoid arthritis, dementia or epilepsy; 5) previous spinal surgery or scheduled procedures during the study; 6) a painful condition induced by a traffic accident; 7) a substantial musculoskeletal problem generating pain from an area other than the neck; 8) conditions for which administration of BVA might not be safe including clotting disorders, administration of an anticoagulant agent, pregnancy and seizure disorders; 9) a documented hypersensitive reaction to previous BVA treatments, bee stings or insect bites; 10) a positive reaction observed during a skin hypersensitivity test; 11) a severe psychiatric or psychological disorder; 12) current use of corticosteroids, narcotics, muscle relaxants or herbal medicines to treat neck pain or any medication considered inappropriate by the investigator; and 13) pending lawsuits or receipt of compensation due to neck pain.

The BVA group will be treated with a bee venom (BV) increment protocol of six sessions over three weeks. The NSAIDs group will be prescribed loxoprofen (loxonin, 60 mg/Tab, Dong Wha Pharm Co., Ltd, Seoul, Korea), at a dose of one tablet administered orally three times per day over three weeks. The combined treatment group will be treated according to the BV increment protocol and will be prescribed loxoprofen over three weeks.

BVA will be prepared as dried bee venom powder (Yoomil Garden, Hwasun, Korea), diluted (1:20,000) and filtered in normal saline (0.9% NaCl) at the Korean medical pharmacy at KHUHGD. BVA treatment will be conducted using 26-gauge sterile disposable syringes (Green Cross Co., Yongin, Korea) containing bee venom diluted with normal saline (0.9% NaCl).

After sterile skin preparation, participants will be administered a perpendicular, subcutaneous injection at a depth of 0.5 to 1.0 cm with the patient lying in the prone position. The acupuncturist will treat participants under the predefined BVA protocol at predefined acupoints. BVA intervention will consist of six sessions twice a week for three weeks, under the following weekly BVA incremental protocol: 0.2 ml for the first week, 0.4 ml for the second week and 0.8 ml for the third week. The predefined points (SI12, SI14, BL11, BL12, TE15 and GB21) have been carefully selected from textbooks and research articles by a process of consensus among participating Korean medical doctors (KMD), all of whom are experienced in the treatment of chronic neck pain.

During the study period, all other interventions, drugs and treatments for neck pain will be prohibited including surgical procedures, injections, acupuncture, physical therapy or the use of muscle relaxants, narcotics and analgesics. Regular medications not intended to affect neck-pain related dysfunction will be allowed. Any change in concurrent treatment will be recorded at every visit.

Assessment of neck pain-related dysfunction, pain and quality of life will be collected five times over eight weeks: at screening, visit two (baseline), four, six, eight (4th week assessment) and nine (8th week assessment) follow-up sessions. Medical history and sociodemographic characteristics, including age, gender, marital status, residence, occupation and education level will be taken from the screening visit. Any unpredicted, adverse events will be recorded at each visit (Table 1).

bothersomeness of chronic neck pain will be evaluated using the 10 cm visual analog scale (VAS) for CNP. Participants will be asked to report the degree of clinical severity and impact on activities of daily life experienced within the past week on a continuous discomfort scale of 0 to 10 (0, absence of discomfort; 10, the worst discomfort imaginable) [24] at screening, visit two (baseline), four, six, eight (4th week assessment) and nine (8th week assessment) follow-up sessions. The primary end point will be the VAS score at the four-week follow-up, one week after the completion of the three-week treatment session.

All adverse events and vital signs will be observed and reported according to the standard operating protocol (SOP) of the KHUHGD IRB. Liver and renal functions of each participant will be assessed before the treatment and one week after the end of treatment. A pregnancy test will be performed for female participants of childbearing age at any time required.

Although there are previous researches on the effect of BVA and NSAIDs on chronic neck pain, there are insufficient data to estimate the clinical meaningful minimal change of the combined treatment of BVA and NSAIDs. This study is designed to provide the clinical evidence to estimate the sample size required for a full-scale RCT. As a pilot trial, we will recruit 60 patients into three parallel groups (BVA, NSAIDs or combined treatment). We will assess the impact of the interventions and the safety of combined treatment of different interventions on a limited number of patients.

A total of 60 participants will be randomly assigned following simple randomization procedures, with a 1:1:1 allocation ratio. The randomization sequence will be generated by an independent researcher using a computerized, random-number generator through a Microsoft Office Excel 2007 software package. Opaque envelopes labeled by study patient number will be conveyed to the interviewer (CRC). The CRC will open the sealed envelopes and allocate participants into the predefined treatment arms. Allocation concealment will not be broken until the completion of the study. The random allocation assignment will be performed only after a participant is confirmed to be eligible and written informed consent has been obtained. Detailed information, including the treatment arm and randomization number from an individual participant will be recorded in the case report form (CRF) and randomization table.

As assessor-blind RCT, the researcher performing the outcome measure assessment will be blinded to each patients’ treatment allocation and will be prohibited from taking part in any conversation about the treatment procedures. It is not possible to conceal BVA practitioners to patient allocations. BVA practitioners will be prohibited from any conversations other than those regarding BVA treatment. NSAIDs will be prescribed by another researcher who will be blinded to the patient allocations and will not be allowed to take part in any conversation regarding the patients' condition. Participants will receive their medication at the KHUHGD pharmacy. Pharmacists will be blinded to the patient allocations and will only be allowed to provide general information regarding medication administration. Statistical analysis will be performed by an independent statistician who will be blinded to patient allocation. All researchers will undergo training prior to participation in this study.

Two licensed KMDs who specialize in acupuncture and moxibustion will be designated as the BVA treatment practitioners and will take educational courses to ensure their strict adherence to the study protocol and to become familiar with administering study treatments. In order to ensure consistency in the BVA treatment, the two acupuncturists will undergo intensive and customized training for a full understanding of the BVA increment protocol, including details such as acupuncture points and weekly bee venom dose increments.

Participation in the study will end at any stage if the patient refuses to continue, withdraws consent, violates inclusion or exclusion criteria or the trial protocol, or completes less than four treatment sessions as determined by the attending KMD researchers. The trial will be stopped if the principle investigator believes that there are unacceptable risks of serious adverse events. No interim analysis will be conducted.

This study has been approved by the KHUHGD IRB (KHNMC-OH-IRB 2012–019; April 2013). Study procedures and documents will be monitored by a qualified clinical research associate (CRA) from the Korea Institute of Oriental Medicine (KIOM).

Data obtained during the study will be confidentially treated according to the standard operation protocol (SOP) of the KHUHGD IRB, and will be stored in lockable cabinets. All data will be processed using the participants’ numbers which will be unrelated to participants’ personal information. Data will be compiled into CRFs and data integration will be thoroughly verified by independent researchers. Non-obvious errors or omissions will be put into data query forms, which will be used for the researchers’ workshop. Data will be gathered and summarized with respect to demographic baseline characteristics, effectiveness and safety observations.

This study began in July 2013 after IRB approval. Trial completion is expected by July 2014.