The main purpose of this trial is to gather evidence for the designed treatment in group A (FC) and investigate the effect of designed treatment on relieve the acute pain phase in AHZ. Another objective would also analyse the correlation between the concentration of substance P and β-endorphin (â-Ep) in peripheral plasma and changes in pain intensity by FC intervention.
As shown in Figure 1, this study is a three-arm open randomized controlled trial consisting of three groups. The interventions are fire needle plus cupping (FC) in group A, famciclovir plus gabapentin (FG) in group B and fire needle plus cupping plus famciclovir (FCF) in Group C. After a randomization selection process, Group A and Group C received a total of 7 treatment sessions of fire needles cupping therapy within 1 week trial time. The administration of gabapentin depends on the needs of the patient of Group B. In addition, if the acute pain cannot be endured, patients will give the temporary analgesics medicine.
The visual analogue scale (VAS) scores, symptoms, and physical scores are due to obtain for pre- and post-treatment periods. The concentrations of SP and β-Ep in peripheral plasma also will be detected, and demand for temporary analgesics and side effects of the patients are recorded daily. As the final stage, after 6 months, the participants are due to be followed up for postherpetic neuralgia, 6 months after treatment (Figure 2).
Participants and recruitment
This study aims to recruit 105 patients by postering public posters in both local dermatology and acupuncture clinics and the website of the Sixth Affiliated Hospital of Kunming Medical University. When potential participants have read the poster they can contact the dermatologists Zuohui Liang and Xiuhong Liu through the contact phone number indicated on the poster. Potential patients then got enrolled and signed the consent form if they meet the inclusion criteria by the assessment of dermatologists. Meanwhile, a randomized grouping technique has been conducted. While preparing and unpacking all relevant information, Shihua Li is responsible for such matter. The first formal trial recruitment began in November 2018. The assistant researcher will assess and record the baseline status of the participants (Table 3).
In order to achieve an adequate enrolment rate, we have developed two attractive offerings to gather patients’ attention as well as publicize recruitment notices. They are: First, all treatment and cost under this trial are free of charge for selected patients r. Second, if participants with postherpetic neuralgia six months later, they are entitled for another 10 sessions free comprehensive acupuncture treatments t.
Randomisation and allocation concealment
(1) Block setting: 105 participants are numbered 1-105 according to the time of participation, the block length is 6, and 16 blocks are set.
(2) Obtaining random numbers: Start with any two-digit number in the random number table, and take 105 numbers to the right.
(3) Grouping: 6 random numbers of each block are sorted from small to large, sorts 1 and 2 are group A, sorts 3 and 4 are group B, and sorts 5 and 6 are group C.
(4) Random group concealment: The grouping conditions of participants are packed into 105 envelopes, and all the envelopes are numbered in order and sealed. To ensure the randomization process, the serial number will be printed on the outside of the opaque envelope and the assignment of the group will be sealed on the inside of the envelope.
Shihua Li, an otolaryngologist at the Sixth Affiliated Hospital of Kunming Medical University, is responsible for the above matters and she doesn’t get involved in the process of treatment and the data collection of this study.
The envelope will be opened according to the patient’s serial number, and the dermatologists will be responsible to inform patients by phone on their random number and assignment.
In order to eliminate operational shortcoming of blinding issues since treatment for FC and FCF group could not be performed blind, we will, instead, first conceal information related to randomized grouping and the results association with the grouping of subjects, and then we seek to provide sensory tests (outcome evaluators), data inspectors and statistical analysts who are not aware of the detail grouping and treatment of subjects as a blind.
Participating physicians in the trial are doctors selected from the departments of dermatology and acupuncture and moxibustion at the Sixth Affiliated Hospital of Kunming Medical University. As acupuncturists are responsible for the treatment of FC and FCF, the all highly qualified and have received a master’s degree in acupuncture and moxibustion as well as have undergone training in unified Standardized operation plan.
Patient and public involvement
Patients and/or public were not involved in the design of this study.
- 18 to 60 years old, with no gender difference;
- Skin rash and clustered blister in asymmetrical skin area;
- Precursor symptoms such as general discomfort and fatigue before rash;
- Nervous pain in the affected area, skin hypersensitivity,
- The rash is distributed along the innervated area;
- Unilateral, not exceeding the midline of the body;
- Pain intensity as assessed by VAS (0-100 mm) of 50 mm ≤ pain intensity ≤80 mm；
- Insulin-dependent diabetes mellitus or other diseases that affect peripheral sensitivity (e.g., polyneuropathy, chronic pain syndrome);
- Bleeding tendency (e.g., taking anticoagulants, coagulation dysfunction, thrombocytopenia, etc.);
- Pregnancy or lactation;
- Surgery within the past 3 months;
- Diseases affecting quality of life (e.g., cancer, paralysis);
- Mental illness (e.g., depression, schizophrenia, dementia) or severe heart/lung/kidney disease;
- Exposure to fire needle, cupping, painkillers, or other complementary and alternative treatments for this disease prior to treatment;
- Contraindications for famciclovir, gabapentin, mecobalamin, paracetamol, tramadol, dextrozine, fire needles, and cupping.
(1) Subjects experienced other comorbidities, complications, or special physiological changes during the trial. They are classified as not suitable to continue the trial.
(2) During the trial, serious adverse events and important adverse events occur in the subjects, so that they are not suitable to continue the trial, and investigators decide to withdraw.
(3) Subjects have poor compliance. Medication compliance is calculated using the tablet counting method. Medication compliance = dose taken / prescription dose × 100%, medication compliance <80% or missed fire needle plus cupping treatment ≥ 1 time is defined as poor compliance.
(4) Violation of the test plan. Subjects change or add drugs other than the study protocol, and received other treatments other than the study protocol during the trial period.
(5) The subject withdrew out by himself.
(6) Lost follow-up at the final stage.
Management of dropout cases
For dropout cases, researchers should actively take measures to complete the last laboratory test as far as possible in order to analyse its efficacy and safety. For all dropout cases, the test conclusion form and reason for dropout shall be filled in the case report form.
This group will be treated with only FC.
- Acupoints: The main points are Ashi points (lesion area), corresponding nerve segment Jiaji points, and branch ditch points (SJ6); matching points are selected according to syndrome differentiation, pattern of dampness-heat in the liver meridian with Yang Ling Quan (GB34), pattern of dampness-heat in the spleen meridian with Yin Ling Quan (SP9), and pattern of obstruction of collaterals by blood stasis with blood sea (SP10).
- Appliances: Medium-sized fire needle (diameter 0.4mm), large-sized fire needle (diameter 0.65mm), glass fire cup No.1-5, medical cotton ball, alcohol lamp, lighter, iodophor, etc.
- Operational methods: Routine disinfection of skin with iodophor with the order of the head, middle, and tail of herpes will be carrying out firstly. Holding 95% alcohol lamp by the left hand close to the needle, and to burn the needle in the right hand to whitening by the external flame of the fire, acupuncturist will prick the head of the herpes cluster. Then the needles will be pricked into the blisters or rashes quickly from the surface of the skin to the base of the herpes. Pricking early-onset herpes at first, for larger pustules or blood blisters (diameter ≥5cm) with a large-scale fire, acupuncturist will extrude blister fluid with disinfection cotton ball after puncture, and then cup with a suitable size of glass fire cup for 5-10 minutes. If the area of the herpes cluster is too large, more than one cup can be used. The remaining acupuncture points are treated with fire needle pricking, and each acupuncture point should be pricked three times. Finally, the skin should be sterilized with iodophor more than one times. The treatment should be performed once a day for a total of 7 days.
- Skin care: After treatment, the iodophor is used to clean and disinfect the skin, and to keep the patient’s skin dry and clean during the treatment.
- Courseof treatment: The course of treatment is one week and from one to seven times. If there is no pain any more after one time of FC treatment, the course is just one time. Meanwhile, if the patient is still suffering pain, the FC will continue once a day unless the pain disappears. All the treatments will not be more than seven times no matter the pain or not.
Mechanism of fire needle cupping
Based on the theory of traditional Chinese medicine, the main causes of herpes zoster are dampness and heat, which could block the meridians and collaterals, and then led to the stagnation of blood and Qi, and finally the pain is generated. FC has a strong effect to eliminate the dampness and heat, and make the Qi and blood smooth running, and then the pain will be alleviated. Previous studies hint that FC can accelerate crusting and shedding of herpes, and also adjust the concentration of substance P in serum [11-12].
Patients in Group B are intervened with famciclovir plus gabapentin (FG). The famciclovir hydrochloride dosage is 0.25g/time, 3 times a day according to the manufacturer’s (Livzon Pharmaceutical Factory) recommendation. The individual dose of gabapentin is 900-3600 mg per day. According to the manufacturer’s (Jiangsu Hengrui Pharmaceutical Co., Ltd.) recommendation (Table 1), the initial dose of 300 mg per day is gradually increased to 900 mg per day and then increased according to the patient’s needs, and the maximum dose is 3600 mg per day.
Table 1 demonstrates the gabapentin intake scheme used to reach the wanted therapeutic dosage.
In group C, patients will receive the treatment of FC plus famciclovir (FCF). The FC is performed as same as group A, and the usage and dosage of famciclovir hydrochloride are in line with group B.
If the patients in the three groups who still cannot endure the pain during the treatment or after one week treatment, For all patients who have difficulties to endure pain during the trial, as an intra-trial arrangement, temporarily analgesics medicine will be given to those in need with careful observation. According to the recommendations of the World Health Organisation, all three groups are likely to receive standardized analgesic treatment as step 1: non-opioid analgesics (paracetamol 4 × 1.0g), 60mm≤ VAS≤ 50mm; step 2: moderate-strength opioids (tramadol tablets, maximum dose 600mg/d), 80mm≤ VAS≤ 70mm; step 3: moderate-strength opioids (tramadol injection, 0.1g, once a day), VAS=90mm; step 4: recommend the use of stronger opioids (dezocine injection, 5mg, once a day), VAS=100mm. Patients are forbad to use other analgesic drugs or therapies. Temporary analgesics demand will be recorded (table 2).
Adverse events like symptoms or diseases occurring during the trial will be recorded (table 2) and assessed at each session of intervention. There may be adverse events of abnormal gastrointestinal reactions, allergic reactions, dizziness, burns and other medical conditions. The relevance and severity of the adverse events will be assessed. Whether the participant could continue the treatment or not will be decided according to the assessments. To those who suffer harm as a result of the treatment will be compensated in accordance with relevant regulations.
To evaluate the incidence of postherpetic neuralgia symptom, a follow-up call is designed and recorded 6 months later posted after the end of the one week treatment. (table 2).
The primary outcome has been the changes in pain intensity pre- and post-treatment (VAS 0-100 mm, where 0 = painless and 100 = maximum imaginable pain).
First of all, pre- and post-treatment periods, the plasma of the participants are carefully collected and centrifuged and stored in a - 80℃ refrigerator. It is then the substance P and â-Epin in serum can be detected by an enzyme-linked immunosorbent assay. Quantitative scoring methods have been further applied to evaluate the symptoms and physical signs before and after treatment, including pain intensity local itching burning sensation rash colour, numbers of blisters clusters ulcers fever local lymphadenopathy rash area (Table 2).
Data management and monitoring
The study will be conducted according to common guidelines for clinical trials (Helsinki Statement, 2008 Chinese Edition, http://www.chictr.org.cn/index.aspx) and will be jointly audited by the Audit Office, Science and Technology Department and Finance Department of Kunming Medical University. Trial auditing will be twice a year since that is the frequency of meeting with the Trial Steering Group of principal investigators. Data will be uploaded to the ResMan Public Management Platform of the China Clinical Trial Registry for adequate quality and safety control. The registration number is ChiCTR1800015372. Therefore, no Data Safety Monitoring Committee is needed. The principal investigator is responsible for project oversight, will make the final decision to terminate the trial, and will have access to the final trial dataset.
Confidentiality and dissemination
The personal information of all the participants stored on computers is kept on a secure server and will always be kept confidential. All the documentations of this study will be kept in a locked and secure environment (locked office and cabinets) at the Six Affiliated Hospital of Kunming Medical University. The review will be submitted to a peer-reviewed journal prospectively to spread our findings.
Sample size estimation
We will compare the difference in efficacy of the three groups. Sample size estimation is based on the method of the book of health statistics , with type I error alpha = 0.05 and type II error beta = 0.1, using the bilateral test. According to the literature, the cure rates of famciclovir and for fire needle plus cupping for HZ were 37.8% and 76.4%, respectively. It was speculated that the cure rate of famciclovir plus fire needle plus cupping was 80.0%, which was substituted into the formula:
Where Pmax =0.80 and Pmin =0.378. The calculated result was a sample size of 32 subjects per group. Therefore, the number of samples required for the three groups was 96. This study required a total of 105 samples adding a 9%-10% dropout rate.
The purpose of this study is to confirm whether the therapeutic effect of experimental therapy (fire needle cupping) is different from that of reference therapy (famciclovir plus gabapentin and fire needle cupping plus famciclovir). Spss20.0 statistical software will be used for data analysis. When the main efficacy indicators of individual subjects are missing, the last observation carried forward will be conducted, and the non-main efficacy indicators will not be carried forward. The mean ± standard deviation is used for statistical description of measurement data, and the frequency (constituent ratio) is used for statistical description of counting data. The baseline characteristics will be recorded as in Table 3. The group t-test (Bonferroni method) will be used to compare the measurement data between groups. All reported P values will be two-tailed with 95% confidence intervals. The value of P ≤0.05 will be considered statistically significant. PPS analysis and Fas analysis will be performed at the same time. SS analysis is used for safety evaluation.